TW201021798A - Amide acetate derivative having inhibitory activity on endothelial lipase - Google Patents
Amide acetate derivative having inhibitory activity on endothelial lipase Download PDFInfo
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- TW201021798A TW201021798A TW098135057A TW98135057A TW201021798A TW 201021798 A TW201021798 A TW 201021798A TW 098135057 A TW098135057 A TW 098135057A TW 98135057 A TW98135057 A TW 98135057A TW 201021798 A TW201021798 A TW 201021798A
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- -1 Amide acetate derivative Chemical class 0.000 title claims description 187
- 102100031375 Endothelial lipase Human genes 0.000 title claims description 45
- 101710087274 Endothelial lipase Proteins 0.000 title claims description 45
- 230000002401 inhibitory effect Effects 0.000 title claims description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 489
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 140
- 150000003839 salts Chemical class 0.000 claims abstract description 112
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 98
- 239000001257 hydrogen Substances 0.000 claims abstract description 97
- 239000012453 solvate Substances 0.000 claims abstract description 96
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 60
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 59
- 150000002367 halogens Chemical class 0.000 claims abstract description 58
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- 238000006467 substitution reaction Methods 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 117
- 125000001072 heteroaryl group Chemical group 0.000 claims description 98
- 125000003118 aryl group Chemical group 0.000 claims description 96
- 239000002904 solvent Substances 0.000 claims description 78
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 76
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000004104 aryloxy group Chemical group 0.000 claims description 45
- 125000003545 alkoxy group Chemical group 0.000 claims description 42
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 40
- 150000001412 amines Chemical class 0.000 claims description 37
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
- 125000003277 amino group Chemical group 0.000 claims description 33
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims description 33
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 32
- 230000002792 vascular Effects 0.000 claims description 31
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 30
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 29
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 25
- 125000005110 aryl thio group Chemical group 0.000 claims description 25
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 25
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 18
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 18
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 11
- 125000004149 thio group Chemical group *S* 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
- 150000001924 cycloalkanes Chemical class 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000006612 decyloxy group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000005549 heteroarylene group Chemical group 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 229940124770 endothelial lipase inhibitor Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 286
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 254
- 238000000034 method Methods 0.000 description 183
- 238000005160 1H NMR spectroscopy Methods 0.000 description 178
- 238000005481 NMR spectroscopy Methods 0.000 description 142
- 230000014759 maintenance of location Effects 0.000 description 130
- 235000019439 ethyl acetate Nutrition 0.000 description 110
- 239000000243 solution Substances 0.000 description 110
- 238000006243 chemical reaction Methods 0.000 description 90
- 239000012044 organic layer Substances 0.000 description 69
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
- 239000012267 brine Substances 0.000 description 39
- 239000002585 base Substances 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 238000012360 testing method Methods 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
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- 239000007864 aqueous solution Substances 0.000 description 20
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- 238000003756 stirring Methods 0.000 description 18
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 102000019267 Hepatic lipases Human genes 0.000 description 13
- 108050006747 Hepatic lipases Proteins 0.000 description 13
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- 108010010234 HDL Lipoproteins Proteins 0.000 description 11
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
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- 229940049920 malate Drugs 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
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- 229910052987 metal hydride Inorganic materials 0.000 description 1
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- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- CZFNISFYDPIDNM-UHFFFAOYSA-N n,n-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 1
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CPQCSJYYDADLCZ-UHFFFAOYSA-N n-methylhydroxylamine Chemical compound CNO CPQCSJYYDADLCZ-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CDZOGLJOFWFVOZ-UHFFFAOYSA-N n-propylaniline Chemical compound CCCNC1=CC=CC=C1 CDZOGLJOFWFVOZ-UHFFFAOYSA-N 0.000 description 1
- PLXPTFQGYWXIEA-UHFFFAOYSA-N nitroformonitrile Chemical compound [O-][N+](=O)C#N PLXPTFQGYWXIEA-UHFFFAOYSA-N 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- SIWVEOZUMHYXCS-UHFFFAOYSA-N oxo(oxoyttriooxy)yttrium Chemical compound O=[Y]O[Y]=O SIWVEOZUMHYXCS-UHFFFAOYSA-N 0.000 description 1
- LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
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- 229940116369 pancreatic lipase Drugs 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- PMJHHCWVYXUKFD-UHFFFAOYSA-N piperylene Natural products CC=CC=C PMJHHCWVYXUKFD-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- VXUYSKXBQCGVSG-UHFFFAOYSA-N pyridine;pyrrolidin-2-one Chemical compound C1=CC=NC=C1.O=C1CCCN1 VXUYSKXBQCGVSG-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 150000003254 radicals Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 150000001420 substituted heterocyclic compounds Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- HALKLPHYNWBHPB-UHFFFAOYSA-N tert-butyl 3-(aminomethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC(CN)=C1 HALKLPHYNWBHPB-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 150000008634 thiazolopyrimidines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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- A61K31/425—Thiazoles
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- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Description
201021798 六、發明說明: 【發明所屬之技術領域】 本發明爲有關具有血管內皮脂肪酶(Endothelial Lipase ’以下稱EL)抑制活性,作爲醫藥有用之化合物。 【先前技術】
血管內皮脂肪酶(EL)爲與脂蛋白脂肪酶(LPL)、肝脂肪 酶(HL)並列爲三酸甘油酯脂肪酶家族,由於其強力磷醯脂 肪酶活性而參與HDLc之代謝乃依其基因剔除小鼠或導入 外來基因小鼠之解析而明白,作爲規定血中HDLc量之因 子備受注目(非專利文獻1)。 自古已知於冠動脈疾病(CAD)與血中HDLc量成立負之 相關關係。HDLc乃仲介抗氧化作用·抗炎症作用.膽固醇 逆轉送作用等而呈示抗動脈硬化作用,已知低HDLc血症 是CAD之危險因子之一。 故EL抑制劑乃仲介HDLc之上昇而成爲CAD治療藥, 實際上於將EL予以基因剔除之病態小鼠呈示HDLc上昇 和動脈硬化病變部位之減少之報告(非專利文獻2)。 這些知見暗示EL之選擇性抑制劑作爲脂質代謝異常症 或動脈硬化症之治療藥之有用性。 於專利文獻1、2和3雖掲示具有肝脂肪酶和/或血管內 皮脂肪酶抑制活性之種種化合物,但如本發明化合物等具 有乙醯胺基之衍生物皆無掲示。 於專利文獻4雖掲示具有三酸甘油酯脂肪酶、脂蛋白脂 肪酶、肝脂肪酶、胰脂肪酶、血管內皮脂肪酶抑制活性之 201021798 化合物,但如本發明化合物等具有乙醯胺基之衍生物並無 掲示。 於專利文獻5〜13雖掲示具有EL抑制活性之種種化合 物,但如本發明化合物等具有乙醯胺基之衍生物皆無掲示 〇 專利文獻 14雖掲示具有 MIF(Macrophage Migration Inhibitory Factor)抑制作用,但對於EL抑制作用或HDLc 上昇作用並無掲示。 專利文獻15作爲睡眠障害治療藥有用之化合物’雖掲示 苯并噻唑或苯并噚唑之2位以乙醯胺基取代之衍生物’但 無EL抑制作用之記載。 (先行技術文獻) 【專利文獻】 【專利文獻1】國際公開第2004/093872號小冊 【專利文獻2】國際公開第20 04/094 3 93號小冊 【專利文獻3】國際公開第2004/094394號小冊 【專利文獻4】國際公開第2006/053250號小冊 【專利文獻5】國際公開第2007/042178號小冊 【專利文獻6】國際公開第2007/045392號小冊 【專利文獻7】國際公開第2007/045393號小冊 【專利文獻8】國際公開第2〇〇7/11〇216號小冊 【專利文獻9】國際公開第2〇〇7/11〇2丨5號小冊 【專利文獻10】國際公開第2007/13 123 1號小冊 【專利文獻11】國際公開第2007/1 3 1232號小冊 201021798 【專利文獻12】國際公開第2007/13 1233號小冊 【專利文獻13】國際公開第2006/1 1 1 321號小冊 【專利文獻14】特開2001 -097979號公報 【專利文獻15】FR2904973 (非專利文獻) 【非專利文獻1】TCM、第14卷、第5號、2004年 、p.202-206
【非專利文獻 2】The Journal of Biological Chemistry Vol.279, No.43, 22, 45085-45092, 2004 【發明內容】 (發明欲解決之課題) 本發明之目的爲提供優異之EL抑制劑。 (解決課題之手段) 本發明者等致力硏究之結果,成功合成具有EL抑制作用 優異之化合物。 也即本發明爲 (1) 一種具有血管內皮脂肪酶抑制活性之醫藥組成物,其係 含有如下式(I)化合物,
(式中, 環A爲含氮雜環, 該環爲可有呈式:-C^R^Rq-CpCO-NW之基及式:-1^之 201021798 基以外取代, 虛線表示鍵之存在或不存在, Z 爲-NR6-、=N-、-0 -或-S- ’ R6爲氫、取代或非取代之烷基、取代或非取代之烯基、φ 代或非取代之炔基、取代或非取代之芳基、取代或非取# 之雜芳基、取代或非取代之環烷基、取代或非取代之環燦 基或取代或非取代之雜環基, R1及R2各自獨立爲氫、鹵素、氰基、硝基、羧基或取代 或非取代之烷基, R3爲氫或取代或非取代之烷基, R4爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 之雜芳基、取代或非取代之環烷基、取代或非取代之環嫌 基、取代或非取代之雜環基或取代或非取代之胺基, R3和R4也可與鄰接之氮原子一起形成取代或非取代之環 R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非取代 之烷基、取代或非取代之烯基、取代或非取代之炔基、取 代或非取代之芳基、取代或非取代之雜芳基、取代或非取 代之環烷基、取代或非取代之環烯基、取代或非取代之雜 環基、取代或非取代之烷氧基、取代或非取代之芳氧基、 取代或非取代之雜芳氧基、取代或非取代之環烷氧基、取 代或非取代之環烯氧基、取代或非取代之雜環氧基、取代 或非取代之烷硫基、取代或非取代之芳硫基、取代或非取 201021798 代之雜芳硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之雜環硫基、取代或非取代之 烷磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜 芳磺醯基、取代或非取代之環烷磺醯基、取代或非取代之 環烯磺醯基、取代或非取代之雜環磺醯基、取代或非取代 之醯基、取代或非取代之胺甲醯基或取代或非取代之胺基 但環A爲噻唑并嘧啶,且R3和R4與鄰接之氮原子一起形 成取代或非取代之環之化合物除外), 及其製藥容許鹽或其等之溶劑合物, (2)含有Z爲-S-之前述(1)記載之化合物、其製藥容許鹽或 其等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫藥組 成物,
(3) 含有環A爲單環之含氮芳香族雜環之前述(1)或(2)記載 之化合物、其製藥容許鹽或其等之溶劑合物之具有血管內 皮脂肪酶抑制活性之醫藥組成物, (4) 含有環A爲二環之含氮芳香族雜環之前述(1)或(2)記載 之化合物、其製藥容許鹽或其等之溶劑合物之具有血管內 皮脂肪酶抑制活性之醫藥組成物, (5) 含有R5爲取代或非取代之芳基、取代或非取代之雜芳 基、取代或非取代之環烷基、取代或非取代之環烯基、取 代或非取代之雜環基、取代或非取代之芳氧基、取代或非 取代之雜芳氧基、取代或非取代之環烷氧基、取代或非取 代之環烯氧基、取代或非取代之雜環氧基、取代或非取代 201021798 之芳硫基、取代或非取代之雜芳硫基、取代或非取代之環 烷硫基、取代或非取代之環烯硫基、取代或非取代之雜環 硫基、取代或非取代之芳磺醯基、取代或非取代之雜芳礎 醯基、取代或非取代之環烷磺酿基、取代或非取代之環稀 磺醯基、取代或非取代之雜環磺醯基或取代或非取代之胺 基之前述(1)〜(4)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫藥 組成物, (6) 含有R5爲取代或非取代之芳基、取代或非取代之雜芳 基、取代或非取代之芳氧基、取代或非取代之雜芳氧基、 取代或非取代之芳硫基、取代或非取代之雜芳硫基、取代 或非取代之芳磺醯基、取代或非取代之雜芳磺醯基或取代 或非取代之胺基之前述(1)〜(5)中任一項記載之化合物、 - 其製藥容許鹽或其等之溶劑合物之具有血管內皮脂肪酶抑 _ 制活性之醫藥組成物, (7) 含有R*爲取代或非取代之烷基' 該取代或非取代之烷 基爲取代或非取代之芳烷基或取代或非取代之雜芳烷基之 BIJ述(1)〜(6)中任一項記載之化合物、其製藥容許鹽或其 等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫藥組成 物, (8) —種如下式(II)化合物,
10- 201021798 (式中, z1 爲-〇-或-s-, 環B爲芳香族碳環、芳香族雜環、非芳香族碳環或非芳香 族雜環, R1及R2各自獨立爲氫、鹵素、氰基、硝基、羧基或取代 或非取代之烷基, R3爲氫或取代或非取代之烷基, R4a爲取代或非取代之芳烷基、取代或非取代之雜芳烷基 €p 、取代或非取代之環烷烷基、取代或非取代之環烯烷基、 取代或非取代之雜環烷基, 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、鹵 素、羥基、羧基、取代或非取代之烷基、取代或非取代之 烷氧基、取代或非取代之芳基、取代或非取代之雜芳基、 取代或非取代之環烷基、取代或非取代之環烯基或取代或 非取代之雜環基,η爲1〜10之整數),
R9 爲-OR10 或-NW2, R1。爲氫、取代或非取代之烷基、取代或非取代之芳基、 取代或非取代之雜芳基、取代或非取代之環烷基、取代或 非取代之環烯基或取代或非取代之雜環基, R11及R12各自獨立爲氫、取代或非取代之烷基、取代或非 取代之烷氧基、取代或非取代之芳氧基、取代或非取代之 雜芳氧基、取代或非取代之烷磺醯基、取代或非取代之芳 基、取代或非取代之雜芳基、取代或非取代之環烷基、取 代或非取代之環烯基或取代或非取代之雜環基)之基或 -11 - 201021798 式:-C(R7R8)n-〇-R13 (其中R7、R8和n與上述同意義,Rl3 爲氫或取代或非取代之烷基)之基, R3和R4a也可與鄰接之氮原子一起形成取代或非取代之環 > R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非取代 之烷基、取代或非取代之烯基、取代或非取代之炔基、取 代或非取代之芳基、取代或非取代之雜芳基、取代或非取 代之環烷基、取代或非取代之環烯基、取代或非取代之雜 環基、取代或非取代之烷氧基、取代或非取代之芳氧基、 取代或非取代之雜芳氧基、取代或非取代之環烷氧基、取 代或非取代之環烯氧基、取代或非取代之雜環氧基、取代 或非取代之烷硫基、取代或非取代之芳硫基、取代或非取 代之雜芳硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之雜環硫基、取代或非取代之 烷磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜 芳磺醯基、取代或非取代之環垸擴醯基、取代或非取代之 環烯磺醯基、取代或非取代之雜環磺醯基、取代或非取代 之醯基、取代或非取代之胺甲醯基或取代或非取代之胺基
Rx爲鹵素、羥基、氰基、硝基、羧基、取代或非取代之院 基、取代或非取代之烯基、取代或非取代之炔基、取代或 非取代之芳基、取代或非取代之雜芳基、取代或非取代之 環烷基、取代或非取代之環烯基、取代或非取代之雜環基 、取代或非取代之烷氧基、取代或非取代之芳氧基、取代 -12- 201021798
或非取代之雜芳氧基、取代或非取代之環烷氧基、取代或 非取代之環烯氧基、取代或非取代之雜環氧基、取代或非 取代之烷硫基、取代或非取代之芳硫基、取代或非取代之 雜芳硫基、取代或非取代之環烷硫基、取代或非取代之環 烯硫基、取代或非取代之雜環硫基、取代或非取代之烷磺 醯基、取代或非取代之芳磺醯基、取代或非取代之雜芳磺 醯基、取代或非取代之環烷磺醯基、取代或非取代之環烯 磺醯基、取代或非取代之雜環磺醯基、取代或非取代之醯 基、取代或非取代之胺甲醯基或取代或非取代之胺基、m 爲0〜3之整數。 但Z1爲- S-、環B爲嘧啶環,且R3和尺“與鄰接之氮原子 一起形成取代或非取代之環之化合物, Z1爲- 〇·、環b爲苯環,R5爲甲基,m爲0,且R3和R4s 與鄰接之氮原子一起形成取代或非取代之環之化合物, Z1爲-〇-,環b爲苯環,r5爲氫,„!爲i,Rx爲甲基,且 R3和I R4a與鄰接之氮原子一起形成取代或非取代之環之化 合物’和如下示化合物: -13- 201021798
除外), 及其製藥容許鹽或其等之溶劑合物’ (9)前述(8)記載之化合物、其製藥容許鹽或其等之溶劑合 -14- 201021798 物’其中Z1爲-s-, (10) 則述(8)或(9)記載之化合物、其製藥容許鹽或其等之溶 劑合物’其中環B爲芳香族碳環, (11) 即述(8)〜(ίο)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中環B爲苯環, (12) 目ij述(8)或(9)記載之化合物、其製藥容許鹽或其等之溶 劑合物,其中環B爲單環之芳香族雜環,
(13) 則述(9)〜'(12)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中式(Π)化合物爲如下式(ΙΠ)化合 物,
γ 〇 〇 R4a (III) (式中,X及Υ各自獨立爲-CRX=、-CH =或-Ν=,RY爲氫或 Rx,R1、R2、R3、、RS及RX與前述⑴同意義), (14) 前述(9)〜(12)中任—項記載之化合物、其製藥容許鹽 或其等之溶劑合物’其中式(II)化合物爲如下式(IV)化合物
(IV) (式中,X及Y各自獨立爲_CRX=、-.CH =或-N=,RY爲氫或 Rx,R1、R2、R3 ' ;R“、RS 及 RX 與前述(8)同意義), (15) X及Y各自獨立爲- Crx =或_CH =之前述(13)或(14)記載 之化合物、其製藥容許鹽或其等之溶劑合物, (16) R4a爲取代或非取代之芳烷基或取代或非取代之雜芳烷 -15- 201021798 基之前述(8)〜(15)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物, (17) R4a爲取代或非取代之芳烷基之前述(8)〜(16)中任〜項 記載之化合物、其製藥容許鹽或其等之溶劑合物, (18) 前述(8)〜(16)中任一項記載之化合物,其製藥容許鹽 或其等之溶劑合物,其中Ria爲如下式基
代或非取代之烷基、取代或非取代之烯基、取代或非取代 之炔基、取代或非取代之芳基、取代或非取代之環烷基、 取代或非取代之環烯基、取代或非取代之雜芳基、取代或 非取代之雜環基、取代或非取代之烷氧基、取代或非取代 之芳氧基、取代或非取代之矽烷氧基、取代或非取代之胺 基、取代或非取代之胺甲醯基、取代或非取代之胺甲醯氧 基、取代或非取代之醯基、取代或非取代之烷磺醯基、取 代或非取代之芳磺醯基、取代或非取代之胺磺醯基或取代 或非取代之烷氧羰基, R14及Ri5各自獨立爲氫、鹵素、羥基、氰基、硝基、羧基 、取代或非取代之烷基、取代或非取代之烯基或取代或非 取代之炔基, b爲0〜3之整數), (19)前述(18)項記載之化合物、其製藥容許鹽或其等之溶 劑合物,其中R4a爲如下式基 201021798 广5(Ra)c R14 R15 或 (其中Ra、R14及R1S與前述(18)同意義,c爲〇〜2之整數)
(20)前述(8)〜(15)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中R4a爲式:_(CR7R8)n-C( = 0)-R9( 其中R7、R8、R9及η與前述(8)同意義)之基, (2 1)前述(20)記載之化合物、其製藥容許鹽或其等之溶劑 合物,其中R9爲-〇Rie, (22)前述(20)記載之化合物、其製藥容許鹽或其等之溶劑 合物,其中R9爲-NR^R12,
(23) 前述(22)記載之化合物、其製藥容許鹽或其等之溶劑 合物,其中R12爲取代或非取代之烷基, (24) 前述(22)或(23)記載之化合物、其製藥容許鹽或其等之 溶劑合物,其中R11爲氫, (25) 前述(20)〜(24)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中η爲1, (26) 前述(20)〜(25)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中R7及R8爲氫, (27) 前述(8)〜(26)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中R1及R2爲氫, -17- 201021798 (28)前述(8)〜(27)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,其中R3爲氫, 之化合物、其製藥容許鹽 取代或非取代之芳基、取 取代之環烷基、取代或非 雜環基、取代或非取代之 基、取代或非取代之環烷 、取代或非取代之雜環氧 代或非取代之雜芳硫基、 或非取代之環烯硫基、取 非取代之芳磺醯基、取代 非取代之環烷磺醯基、取 或非取代之雜環磺醯基或 之化合物、其製藥容許鹽 取代或非取代之芳基、取 取代之芳氧基、取代或非 之芳硫基、取代或非取代 磺醯基、取代或非取代之 基, 之化合物、其製藥容許鹽 氫、取代或非取代之烷基 非取代之炔基、取代或非 芳基、取代或非取代之環 (2 9)前述(8)〜(2 8)中任一項記載 或其等之溶劑合物,其中R5爲 代或非取代之雜芳基、取代或非 取代之環烯基、取代或非取代之 芳氧基、取代或非取代之雜芳氧 氧基、取代或非取代之環烯氧基 基、取代或非取代之芳硫基、取 取代或非取代之環烷硫基、取代 代或非取代之雜環硫基、取代或 或非取代之雜芳磺醯基、取代或 代或非取代之環烯磺醯基、取代 取代或非取代之胺基, (3 0)前述(8)〜(29)中任一項記載 或其等之溶劑合物,其中R5爲 代或非取代之雜芳基、取代或非 取代之雜芳氧基、取代或非取代 之雜芳硫基、取代或非取代之芳 雜芳磺醯基或取代或非取代之胺 (3 1)前述(8)〜(28)中任一項記載 或其等之溶劑合物,其中R5爲 、取代或非取代之烯基、取代或 取代之芳基、取代或非取代之雜 -18- 201021798 院基、取代或非取代之雜環基、取代或非取代之烷氧基、 取代或非取代之芳氧基、取代或非取代之芳磺醯基或取代 或非取代之醯基, (32)—種如下式(V)化合物,
(式中,
環C爲單環或雙環之雜環, R4b爲取代芳烷基(該取代芳烷基之環上之取代基爲羧基、 取代或非取代之胺甲醯基、取代或非取代之烷磺醯基或取 代或非取代之胺磺醯基)、取代雜芳烷基(該取代雜芳烷基 之環上之取代基爲羧基、取代或非取代之胺甲醯基、取代 或非取代之烷磺醯基或取代或非取代之胺磺醯基)、取代 環烷烷基(該取代環烷烷基之環上之取代基爲羧基、取代 或非取代之胺甲醯基、取代或非取代之烷磺醯基或取代或 非取代之胺磺醯基)、取代環烯烷基(該取代環烯烷基之環 上之取代基爲羧基、取代或非取代之胺甲醯基、取代或非 取代之烷磺醯基或取代或非取代之胺磺醯基)、取代雜環 院基(該取代雜環院基之環上之取代基爲殘基、取代或非 取代之胺甲醯基、取代或非取代之烷磺醯基或取代或非取 代之胺磺醯基),或 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、齒 素、羥基、羧基、取代或非取代之烷基、取代或非取代之 烷氧基、取代或非取代之芳基、取代或非取代之雜芳基、 -19- 201021798 取代或非取代之環烷基、取代或非取代之環烯基或取代或 非取代之雜環基、η爲1〜10之整數, R9 爲-OR1。或-NRllR12, R1()爲氫、取代或非取代之烷基、取代或非取代之芳基、 取代或非取代之雜芳基、取代或非取代之環烷基、取代或 非取代之環烯基或取代或非取代之雜環基, R11及R12各自獨立爲氫、取代或非取代之烷基、取代或非 取代之烷氧基、取代或非取代之芳氧基、取代或非取代之 雜芳氧基、取代或非取代之烷磺醯基、取代或非取代之芳 基、取代或非取代之雜芳基、取代或非取代之環烷基、取 代或非取代之環烯基或取代或非取代之雜環基)之基、 R5爲氫、鹵素、經基、氰基、硝基、竣基、取代或非取代 之烷基、取代或非取代之烯基、取代或非取代之炔基、取 代或非取代之芳基、取代或非取代之雜芳基、取代或非取 代之環烷基、取代或非取代之環烯基、取代或非取代之雜 環基、取代或非取代之烷氧基、取代或非取代之芳氧基、 取代或非取代之雜芳氧基、取代或非取代之環烷氧基、取 代或非取代之環烯氧基、取代或非取代之雜環氧基、取代 或非取代之烷硫基、取代或非取代之芳硫基、取代或非取 代之雜芳硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之雜環硫基、取代或非取代之 院磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜 芳磺醯基、取代或非取代之環烷磺醯基、取代或非取代之 環稀磺醯基、取代或非取代之雜環磺醯基、取代或非取代 -20- 201021798 之醯基、取代或非取代之胺甲醯基或取代或非取代之胺基
Rx爲鹵素、羥基、氰基、硝基、羧基、取代或非取代之烷 基、取代或非取代之烯基、取代或非取代之炔基、取代或 非取代之芳基、取代或非取代之雜芳基、取代或非取代之 環烷基、取代或非取代之環烯基、取代或非取代之雜環基 、取代或非取代之烷氧基、取代或非取代之芳氧基、取代 或非取代之雜芳氧基、取代或非取代之環烷氧基、取代或 W 非取代之環烯氧基、取代或非取代之雜環氧基、取代或非 取代之烷硫基、取代或非取代之芳硫基、取代或非取代之 雜芳硫基、取代或非取代之環烷硫基、取代或非取代之環 烯硫基、取代或非取代之雜環硫基、取代或非取代之烷磺 ' 醯基、取代或非取代之芳磺醯基、取代或非取代之雜芳磺 - 醯基、取代或非取代之環烷磺醯基、取代或非取代之環烯 磺醯基、取代或非取代之雜環磺醯基、取代或非取代之醯 ’ 基、取代或非取代之胺甲醯基或取代或非取代之胺基、m y 爲〇〜3之整數, 但如下示化合物:
iTC00Me
除外), 及其製藥容許鹽或其等之溶劑合物, (3 3)前述(3 2)記載之化合物、其製藥容許鹽或其等之溶劑 合物,其中環C爲雙環。 -21 - 201021798 (34)—種醫藥組成物,其係含有前述(8)〜(33)中任一項記 載之化合物、其製藥容許鹽或其等之溶劑合物, (3 5)—種具有血管內皮脂肪酶抑制活性之醫藥組成物,其 係含有前述(8)〜(33)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物, (3 6)前述(1)〜(7)或(3 4)中任一項記載之醫藥組成物,用以 治療和/或預防脂質代謝異常症, (37) 前述(1)〜(7)或(34)記載之醫藥組成物,用以治療和/ 或預防高脂血症, (38) 前述(1)〜(7)或(34)記載之醫藥組成物,用以治療和/ 或預防動脈硬化症, (3 9)—種脂質代謝異常症之預防或治療方法,其特徴爲投 與前述(1)〜(33)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物, (40) —種高脂血症之預防或治療方法,其特徴爲投與前述 (1)〜(3 3)中任一項記載之化合物、其製藥容許鹽或其等之 溶劑合物, (41) 一種動脈硬化症之預防或治療方法,其特徴爲投與前 述(1)〜(33)中任一項記載之化合物、其製藥容許鹽或其等 之溶劑合物, (42) —種前述(1)〜(33)中任一項記載之化合物、其製藥容 許鹽或其等之溶劑合物之使用,用以製造脂質代謝異常症 治療藥和/或預防藥, (4 3)—種前述(1)〜(3 3)中任一項記載之化合物、其製藥容 -22- 201021798 許鹽或其等之溶劑合物之使用,用以製造高脂血症治療藥 和/或預防藥, (44) 一種前述(1)〜(33)中任一項記載之化合物、其製藥容 許鹽或其等之溶劑合物之使用,用以製造動脈硬化症治療 藥和/或預防藥,
(45)前述(1)〜(33)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,用以治療和/或預防脂質代謝異常症。 (4 6)前述(1)〜(3 3)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,用以治療和/或預防高脂血症, (47)前述(1)〜(33)中任一項記載之化合物、其製藥容許鹽 或其等之溶劑合物,用以治療和/或預防動脈硬化症, 又本發明包含: (A1) 一種具有血管內皮脂肪酶抑制活性之醫藥組成物,其係含 有如下式(I)化合物,
(式中, 環A爲含氮雜環, 該環爲可有式·· -CiRiRq-cpCO-NRSR4之基及式:-R5之基 以外取代, 虛線表示鍵之存在或不存在, Z 爲-NR6.、=n-、-0-或- S-, -23- 201021798 R6爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 之雜芳基、取代或非取代之環烷基、取代或非取代之環烯 基或取代或非取代之雜環基, R1及R2各自獨立爲氫、鹵素、羥基、氰基、硝基、羧基 或取代或非取代之烷基, R3爲氫或取代或非取代之烷基, R4爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 之雜芳基、取代或非取代之環烷基、取代或非取代之環稀 基、取代或非取代之雜環基或取代或非取代之胺基, R3和R4也可與鄰接之氮原子一起形成取代或非取代之環 > _ R5爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 之雜芳基、取代或非取代之環烷基、取代或非取代之環稀 基、取代或非取代之雜環基、取代或非取代之烷氧基、取 代或非取代之環烷氧基、取代或非取代之芳氧基、取代或 非取代之雜芳氧基、取代或非取代之雜環氧基、取代或非 取代之烷硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之芳硫基、取代或非取代之雜 芳硫基、取代或非取代之雜環硫基、取代或非取代之烷擴 醯基、取代或非取代之環烷磺醯基、取代或非取代之環嫌 磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜芳 -24- 201021798 磺醯基、取代或非取代之雜環磺醯基、取代或非取代之醯 基或取代或非取代之胺基), 及其製藥容許鹽或其等之溶劑合物, (A2) 含有Z爲-S-之前述(A1)記載之化合物、其製藥容許鹽或其 等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫藥組成 物, (A3) 含有環A爲單環之含氮芳香族雜環之前述(A1)或(A2)記載 之化合物、其製藥容許鹽或其等之溶劑合物之具有血管內 皮脂肪酶抑制活性之醫藥組成物, (A4) ' 含有環A爲二環之含氮芳香族雜環之前述(A1)或(A2)記載 - 之化合物、其製藥容許鹽或其等之溶劑合物之具有血管內 皮脂肪酶抑制活性之醫藥組成物,
(A5) 含有R4爲取代或非取代之烷基、該取代或非取代之烷基 爲取代或非取代之芳烷基或取代或非取代之雜芳烷基之前 述(A1)〜(A4)中任一項記載之化合物、其製藥容許鹽或其 等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫藥組成 物, (A6) 式(Π): -25- 201021798
(式中, Z1 爲- Ο-或- S- .’ 環Β爲芳香族烴環、芳香族雜環、非芳香族烴環或非芳香 族雜環, R1及R2各自獨立爲氫、鹵素、羥基、氰基、硝基、羧基 或取代或非取代之烷基, R3爲氫或取代或非取代之烷基, R4a爲取代或非取代之芳烷基、取代或非取代之雜芳烷基 、取代或非取代之環烷烷基、取代或非取代之環烯烷基、 取代或非取代之雜環烷基, 式:-C(R7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、羧 基、取代或非取代之烷基、取代或非取代之芳基、取代或 非取代之雜芳基、取代或非取代之環烷基、取代或非取代 之環烯基或取代或非取代之雜環基,η爲1〜10之整數, R9 爲-OR10 或-NR11!?·12 , R10 ' R11 Μ R12各自獨立爲氫或取代或非取代之烷基)之基 或 式:-C(R7R8)n-0-R13(其中R7、R8和η與上述同意義,R" 爲氫或取代或非取代之烷基)之基, R3和R4a也可與鄰接之氮原子一起形成取代或非取代, R5爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 -26- 201021798 之雜芳基、取代或非取代之環烷基、取代或非取代之環缔 基、取代或非取代之雜環基、取代或非取代之烷氧基、取 代或非取代之環烷氧基、取代或非取代之芳氧基、取代或 非取代之雜芳氧基、取代或非取代之雜環氧基、取代或非 取代之烷硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之芳硫基、取代或非取代之雜 芳硫基、取代或非取代之雜環硫基、取代或非取代之烷磺 醯基、取代或非取代之環烷磺醯基、取代或非取代之環嫌 cP 磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜芳 磺醯基、取代或非取代之雜環磺醯基、取代或非取代之醯 基或取代或非取代之胺基,
Rx爲鹵素、羥基、氰基、硝基、羧基、取代或非取代之烷 基、取代或非取代之烯基、取代或非取代之芳基、取代或 . 非取代之雜芳基、取代或非取代之環烷基、取代或非取代 之環烯基、取代或非取代之雜環基、取代或非取代之烷氧 基、取代或非取代之胺基或取代或非取代之胺甲醯基,m Θ爲〇〜3之整數, 但Z1爲- 0-,環B爲苯環,R5爲甲基,m爲0,且R3和 R4a與鄰接之氮原子一起形成取代或非取代之環之化合物 ,和 如下示化合物: -27- 201021798
除外), 及其製藥容許鹽或其等之溶劑合物, (A7) -28- 201021798 Z1爲-S-之前述(A6)記載之化合物、其製藥容許鹽或其等之 溶劑合物, (A8) 環B爲芳香族烴環之前述(A6)或(A7)記載之化合物、其製 藥容許鹽或其等之溶劑合物, (A9) 環B爲苯環之前述(A6)〜(A8)中任—項記載之化合物、其
製藥容許鹽或其等之溶劑合物, (A10) 環B爲單環之芳香族雜環之前述(A6)或(A7)記載之化合物 、其製藥容許鹽或其等之溶劑合物, (All) R4a爲取代或非取代之芳烷基或取代或非取代之雜芳烷基 之前述(A6)〜(A10)中任—項記載之化合物、其製藥容許鹽 或其等之溶劑合物, R a爲取代或非取代之芳烷基之前述(A6)〜(A1 〇中任—項 記載之化合物、其製藥容許鹽或其等之溶劑合物, (A13) 前述(A6)〜(A11)中任—項記載之化合物,其中爲如下 式基,
-29- 201021798 代或非取代之烷基、取代或非取代之烯基、取代或非取代 之炔基、取代或非取代之芳基、取代或非取代之環烷基、 取代或非取代之環烯基、取代或非取代之雜芳基、取代或 非取代之雜環基、取代或非取代之烷氧基、取代或非取代 之芳氧基、取代或非取代之矽烷氧基、取代或非取代之胺 基、取代或非取代之胺甲醯基、取代或非取代之胺甲醯氧 基、取代或非取代之醯基、取代或非取代之烷磺醢基、取 代或非取代之芳磺醯基、取代或非取代之胺磺醯基或取代 或非取代之烷氧羰基, R14及R15各自獨立爲氫、鹵素、羥基、氰基、硝基、羧基 、取代或非取代之烷基、取代或非取代之烯基或取代或非 取代之炔基, b爲0〜3之整數), 及其製藥容許鹽或其等之溶劑合物, (A14) R4a爲
R'*· R_。 执 FT* R'° %
Ra (其中Ra、R14及R15與前述(A 13)同意義,c爲0〜2之整 數)之前述(A1 3)記載之化合物、其製藥容許鹽或其等之溶 劑合物, (A15) R1及R2各自獨立爲氫、羥基或取代或非取代之烷基之前 -30- 201021798 述(A6)〜(A1 4)中任一項記載之化合物、其製藥容許鹽或其 等之溶劑合物, (A16) R爲氫之前述(A6)〜(A 1 5)中任一項記載之化合物、其製 藥容許鹽或其等之溶劑合物, (A17)
R爲氫、取代或非取代之烷基、取代或非取代之烯基、取 代或非取代之炔基、取代或非取代之芳基、取代或非取代 之雜芳基、取代或非取代之環烷基、取代或非取代之雜環 基、取代或非取代之烷氧基、取代或非取代之芳氧基、取 代或非取代之芳磺醯基或取代或非取代之醯基之前述(A6) 〜(A 16)中任一項記載之化合物、其製藥容許鹽或其等之 溶劑合物, (A18) 含有前述(A6)〜(A17)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物之醫藥組成物, (A19) 含有前述(A6)〜(A 17)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物之具有血管內皮脂肪酶抑制活性之醫 藥組成物, (A20) 治療和/或預防脂質代謝異常症之前述(A1 8)記載之醫藥組 成物, (A21) -31- 201021798 治療和/或預防高脂血症之前述(A 18)記載之醫藥組成物, (A22) 治療和/或預防動脈硬化症之前述(A 18)記載之醫藥組成物 (A23) 投與前述(A6)〜(A1 7)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物爲特徴之脂質代謝異常症之預防或治 療方法, (A24) 投與前述(A6)〜(A17)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物爲特徴之高脂血症之預防或治療方法 (A25) 投與前述(A6)〜(A 17)中任一項記載之化合物、其製藥容許 鹽或其等之溶劑合物爲特徴之動脈硬化症之預防或治療方 法, (A26) 前述(A6)〜(A17)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物之使用,用以製造脂質代謝異常症治療藥 和/或預防藥, (A27) 前述(A6)〜(A 17)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物之使用,用以製造高脂血症治療藥和/或預 防藥, -32- 201021798 (A28) 前述(A6)〜(A 17)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物之使用,用以製造動脈硬化症治療藥和/或 預防藥, (A29) 前述(A6)〜(A1 7)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物’用以治療和/或預防脂質代謝異常症,
(A30) 前述(A6)〜(A 17)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物,用以治療和/或預防高脂血症, (A31) 前述(A6)〜(A1 7)中任一項記載之化合物、其製藥容許鹽或 其等之溶劑合物,用以治療和/或預防動脈硬化症。 (發明之效果) 因本發明化合物具有血管內皮脂肪酶抑制作用,故含有 本發明化合物之醫藥組成物作爲醫藥品,尤其脂質代謝異 常症、·高脂血症、動脈硬化、粥樣性動脈硬化、高膽固醇 血症、高三酸甘油酯血症、糖尿病、肥胖和/或症候群X 之治療和/或預防醫藥非常有用。又本發明化合物選擇性抑 制血管內皮脂肪酶,對肝脂肪酶(HL)和脂蛋白脂肪酶 (LPL)具有高選擇性,其他具備醫藥之有用性。包括作爲 醫藥之有用性,於代謝安定性佳,藥物代謝酵素之衍生也 少,代謝其他藥劑之藥物代謝酵素之抑制也小,經口吸收性 高之化合物,清除率小,或呈現藥效之半衰期充分長等。 -33- 201021798 【實施方式】 (實施發明之最佳形態) 以下說明本說明書中使用之各用語°又本說明書1中’各 用語爲於單獨使用之場合’或與其他用語一起形成使用之 場合皆具有同一意義。 「鹵素」爲氟、氯、溴和碘。 「院基」爲碳數1〜10個之直鏈狀或分枝狀之烷基,例 如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二 丁基、第三丁基、正戊基、異戊基、新戊基、正己基、異 己基、正庚基、正辛基、正壬基、正癸基等。宜爲碳數1 〜6或1〜4個之烷基,例如甲基、乙基、正丙基、異丙基 、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊 基、新戊基、正己基、異己基。 「烯基」爲於上述「烷基」有1個或其以上之雙鍵之碳 數2〜8個之直鏈狀或分枝狀之烯基,例如乙烯基、1·丙 烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1,3-丁 二烯基、3·甲基-2-丁烯基等。 「炔基」爲於上述「烷基」具有1個或其以上三鍵之碳 數2〜8個之直鏈狀或分枝狀之炔基,例如乙炔基、丙炔 基、丁炔基等。更也可有雙鍵。 「環烷基」爲碳數3〜15之環狀飽和烴基,例如環丙基 '環丁基、環戊基、環己基、環庚基、環辛基、交聯環式 烴基、螺烴基等。宜爲環丙基、環丁基、環戊基、環己基 、交聯環式烴基》 -34- 201021798 「交聯環式烴基」爲包括由2以上之環共有2個或其以 上原子之碳數5〜8之脂肪族環去除一個氫而成之基。具 體而言爲雙環[2·1.0]戊基、雙環[2.2.1]庚基、雙環[2.2.2] 辛基和雙環[3.2.1]辛基、三環[2.2.1.0]庚基等。 「螺烴基」爲包括由2個烴環共有1個碳原子所構成之 環去除一個氫而成之基。具體而言爲螺[3.4]辛基等。
「環烯基」爲碳數3〜10之環狀不飽和脂肪族烴基’例 如環丙烯基(例如1-環丙烯基)、環丁烯基(例如1-環丁烯 基)、環戊烯基(例如1-環戊烯-1-基、2-環戊烯-1-基、3-環 戊烯-1-基)、環己烯基(例如1-環己烯-1-基、2-環己烯-1-基、3-環己烯-1-基)、環庚烯基(例如1-環庚烯基)、環辛 烯基(例如1-環辛烯基)等。宜爲環丙烯基、環丁烯基、環 戊烯基、環己烯基。環烯基也包括環中具有不飽和鍵之交 聯環式烴基和螺烴基。 「芳基」爲單環芳香族烴基(例:苯基)及多環芳香族烴 基(例:1-萘基、2-萘基、1-蒽基、2-蒽基、9-蒽基、1-菲 基、2-菲基、3-菲基、4-菲基、9-菲基等)》宜爲苯基或萘 基(1-萘基、2-萘基)。 「雜芳基」乃指單環芳香族雜環式基及稠合芳香族雜環 式基。 「單環芳香族雜環式基」爲由環內也可含有1〜4個氧原 子、硫原子、和/或氮原子之5〜8員芳香環衍生之於取代 可能之任意位置可有鍵結之基。 「稠合芳香族雜環式基」爲環內也可含有1〜4個氧原子 -35- 201021798 、硫原子、和/或氮原子之5〜8員芳香環,與1〜4個5〜 8員芳香族碳環或其他5〜8員芳香族雜環稠合之於取代可 能之任意位置也可有鍵結之基。 「雜芳基」可爲例如呋喃基(例:2-呋喃基、3·呋喃基)、 噻吩基(例:2-噻吩基、3-噻吩基)、吡咯基(例:1-吡咯基 、2-吡咯基、3-吡咯基)、咪唑基(例:1-咪唑基、2-咪唑基 、4-咪唑基)、吡唑基(例:1-吡唑基、3-吡唑基、4-吡唑基 )、三唑基(例:1,2,4-三唑-1-基、1,2,4·三唑-3-基、1,2,4-三唑-4-基)、四唑基(例:1-四唑基、2-四唑基、5-四唑基) 、噚唑基(例:2-噚唑基、4-噚唑基、5-噚唑基)' 異噚唑基( 例:3-異噚唑基、4-異噚唑基、5-異噚唑基)、噻唑基(例: 2-噻唑基、4-噻唑基、5-噻唑基)、噻二唑基、異噻唑基( 例:3-異噻唑基、4-異噻唑基、5-異噻唑基)、吡啶基(例 :2-吡啶基、3-吡啶基、4-吡啶基)、嗒畊基(例:3-嗒阱基 、4-嗒阱基)、嘧啶基(例:2-嘧啶基、4-嘧啶基、5-嘧啶基 )、呋吖基(例:3-呋吖基)、吡阱基(例:2-吡畊基)、噚二 唑基(例:1,3,4·噚二唑-2-基)、苯并呋喃基(例:2-苯并[b] 呋喃基、3-苯并[b]呋喃基、4-苯并[b]呋喃基、5-苯并[b] 呋喃基、6-苯并[b]呋喃基、7-苯并[b]呋喃基)、苯并噻吩 基(例:2-苯并[b]噻吩基、3-苯并[b]噻吩基、4-苯并[b]噻 吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基、7-苯并[b]噻 吩基)、苯并咪唑基(例:1-苯并咪唑基、2-苯并咪唑基、 4-苯并咪唑基、5-苯并咪唑基)、二苯并呋喃基、苯并噚唑 基、苯并噻唑基、喹喏啉基(例:2-喹喏啉基、5-喹喏啉基 -36- 201021798 、6-喹喏啉基)、啐喏啉基(例:3-啐喏啉基、4-啐喏咐基 、5-啐喏啉基、6-晬喏啉基、7-晬喏啉基、8-啐喏啉基)、 喹唑啉基(例:2-喹唑啉基、4-喹唑啉基、5-喹唑啉基、6_ 喹唑啉基、7 -唾唑啉基、8 -喹唑啉基)、喹啉基(例:2_喹 啉基、3-喹啉基、4-唾啉基、5-唾啉基、6-喹啉基、7-喹 啉基、8-喹啉基)、呔阱基(例:1-呔畊基、5-呔哄基、6-口太 畊基)、異喹啉基(例:1-異喹啉基、3-異喹啉基、4-異嗤 啉基、5-異唾啉基、6-異喹啉基、7-異喹啉基、8-異喹_ 基)、嘌呤基、喋啶基(例:2-喋啶基、4-喋啶基、6-喋陡 基、7-喋啶基)、咔唑基、啡啶基、吖啶基(例:1-吖啶基 、2-吖啶基、3-吖啶基、4-吖啶基、9-吖啶基)、吲哚基(例 :1-吲哚基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基 、6-吲哚基、7-吲哚基)、異吲哚基、啡畊基(例:1-啡哄 基、2-啡阱基)或啡噻畊基(例:1-啡噻阱基、2-啡噻阱基 、3-啡噻哄基、4-啡噻畊基)等。
「雜環基」爲環內至少有1以上氮原子、氧原子、或硫 原子之於取代可能之任意位置也可有鍵結之非芳香族雜環 式基。又如此非芳香族雜環式基也可更以碳數1〜4之伸 烷基鏈交聯,也可有環烷(以5〜6員較佳)或苯環稠合。又 「非芳香族雜環式基」爲只要爲非芳香族、則可飽和也可 不飽和。宜5〜8員環。例如1-吡咯啉基、2 -吡咯啉基、 3-吡咯啉基、1-吡咯啶基、2-吡咯啶基、3-吡咯啶基、1-咪唑啉基、2-咪唑啉基、4-咪唑啉基、1-咪唑啶基、2-咪 唑啶基、4-咪唑啶基、1-吡唑啉基、3-吡唑啉基、4-吡唑 -37- 201021798 啉基、1·吡唑啶基、3 -吡唑啶基、4 -吡唑啶基、N哌啶基 、2-哌啶基、3-哌啶基、4-哌啶基、1-哌畊基、2-哌阱基 、2-嗎啉基、3-嗎啉基、N嗎啉基、四氫吡喃基等。 「醯基」爲甲醯基、取代或非取代之烷羰基、取代或非 取代之烯羰基、取代或非取代之環烷羰基、取代或非取代 之環烯羰基、取代或非取代之芳羰基、取代或非取代之雜 芳羰基、取代或非取代之雜環羰基。 「取代或非取代之烷氧基」、「取代或非取代之烷硫基 」、「取代或非取代之烷磺醯基」、「取代或非取代之芳 烷基」、「取代或非取代之雜芳烷基」、「取代或非取代 之環烷烷基」、「取代或非取代之環烯烷基」、「取代或 非取代之雜環烷基」和「取代或非取代之烷氧羰基」之院 基部分爲上述「烷基」。 「取代或非取代之環烷氧基」、「取代或非取代之環院 硫基」、「取代或非取代之環烷磺醯基」和「取代或非取 代之環烷烷基」之環烷基部分爲上述「環烷基」。 「取代或非取代之環烯硫基」、「取代或非取代之環嫌 磺醯基」、「取代或非取代之環烯氧基」和「取代或非取 代之環烯烷基」之環烯基部分爲上述「環烯基」。 取代或非取代之芳氧基」、「取代或非取代之芳硫基 」、「取代或非取代之芳磺醯基」和「取代或非取代之芳 院基」之芳基部分爲上述「芳基」。 硫基 「取代或非取代之雜芳氧基」、「取代或非取代之雜芳 取代或非取代之雜芳磺酿基」和「取代或非取 201021798 代之雜芳烷基」之雜芳基部分爲上述「雜芳基」。 「取代或非取代之雜環氧基」、「取代或非取代之雜環 硫基」、「取代或非取代之雜環磺醯基」和「取代或非取 代之雜環烷基」之雜環基部分爲上述「雜環基」。 「雜環」爲環內至少有1以上由]^、〇及s任意選擇之雜 原子之環。該環包括單環或稠合環(宜爲二環)、可爲芳香 族雜環或非芳香族雜環。「雜環」爲例如以下者。
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又若上述雜環有取代基時,可於取代可能之任意位置取 代,也可-NH-之氫被取代。 「含氮雜環」爲環內至少1個有N,也可更有0、S、 -42- 201021798 N(R6)之環。該環包括單環或稠合環、可芳香族雜環或非 芳香族雜環。例如以下者。
43 201021798 又若上述含氮雜環有取代基時,可於取代 置取代,也可-NH-之氫被取代。 「取代或非取代之烷基」、「取代或非取 「取代或非取代之炔基」、「取代或非取代 取代或非取代之雜芳基」、「取代或非取代 「取代或非取代之環烯基」、「取代或非取 、「取代或非取代之烷氧基」、「取代或非 基」、「取代或非取代之芳氧基」、「取代 芳氧基」、「取代或非取代之雜環氧基」、 代之烷硫基」、「取代或非取代之環烷硫基 非取代之環烯硫基」、「取代或非取代之芳 代或非取代之雜芳硫基」、「取代或非取代 、「取代或非取代之烷磺醯基」、「取代或 磺醯基」、「取代或非取代之環烯磺醯基」 取代之芳磺醯基」、「取代或非取代之雜芳 取代或非取代之雜環磺醯基」、「取代或非 、「取代或非取代之芳烷基」、「取代或非 基」、「取代或非取代之環烷烷基」、「取 環烯烷基」、「取代或非取代之雜環烷基」 取代之胺甲醯基」、「取代或非取代之矽院 代或非取代之胺甲醯氧基」、「取代或非取 」、「取代或非取代之烷氧羰基」、「R3和 氮原子一起形成之環」或「R3和R4a與鄰接 形成之環」中取代基可爲例如: 可能之任意位 代之烯基」、 之方基」、「 之環烷基」、 代之雜環基」 取代之環烷氧 或非取代之雜 「取代或非取 」、「取代或 硫基」、「取 之雜環硫基」 非取代之環烷 、「取代或非 磺醯基」、「 取代之醯基」 取代之雜芳烷 代或非取代之 、「取代或非 氧基」、「取 代之胺磺醯基 丨R4與鄰接之 之氮原子一起 ~ 44 - 201021798 鹵素、羥基、竣基、硝基、氰基, 取代或非取代之烷基(取代基可爲鹵素、羥基、殘基、 氰基、胺基、烷基、芳基、環烷基、雜芳基、雜環基、烷 氧羰基、院氧羰胺基、胺甲醯基。例:甲基、乙基、異丙 基、第三 丁基、CF3、CH2〇H、CH2COOCH3、CH2NH2、苄 基、環戊基甲基、第三丁氧羰胺基甲基、甲氧羰基甲基)
取代或非取代之烯基(取代基可爲鹵素、殘基、烷基、 芳基、環院基、雜芳基、雜環基。例:乙烯基), 取代或非取代之炔基(取代基可爲鹵素、烷基、芳基、 環烷基、雜芳基、雜環基。例··乙炔基), 取代或非取代之芳基(取代基可爲鹵素、烷基、芳基、 環烷基、雜芳基、雜環基。例:苯基、萘基), 取代或非取代之環烷基(取代基可爲鹵素、烷基、芳基 、環烷基、雜芳基、雜環基。例:環丙基), 取代或非取代之環烯基(取代基可爲鹵素、烷基、芳基 、環烷基、雜芳基、雜環基。例:環丙烯基), 取代或非取代之雜芳基(取代基可爲鹵素、烷基、芳基 、環烷基、雜芳基、雜環基。例:四唑基、吲哚基、吡唑 基), 取代或非取代之雜環基(取代基可爲鹵素、烷基、芳基 、環烷基、雜芳基、雜環基。例:吡咯啶基、嗎啉基、哌 畊基、哌啶基), 取代或非取代之烷氧基(取代基可爲鹵素、羧基、氰基 -45- 201021798 、烷基、芳基、環烷基、雜芳基、雜環基。例: 乙氧基、丙氧基、丁氧基、〇cf3), 取代或非取代之芳氧基(取代基可爲鹵素、烷 、環烷基、雜芳基、雜環基。例:苯氧基), 取代或非取代之矽烷氧基, 取代或非取代之胺基(例··烷胺基(例:甲胺基 、二甲胺基)、醯胺基(例:乙醯基胺基、苄醯胺3 胺基(例··苄基胺基、三苯甲基胺基)、羥胺基、 基(例:二乙胺基甲基)、烷氧羰胺基、烷磺醯胺 醯基胺基、雜環羰胺基、芳磺醯胺基、雜芳磺醯f 取代或非取代之胺甲醯基(取代基可爲羥基、氟 或非取代之烷基、烷氧基、烷磺醯基。例:烷基 (例:甲基胺甲醯基、乙基胺甲醯基、二甲基胺 苯基乙基胺甲醯基、二甲胺基乙基胺甲醯基、異 基、經基乙基胺甲醯基)、烷磺醯基胺甲醯基 基胺甲醯基、取代或非取代之烷氧基胺甲醯基), 取代或非取代之胺甲醯氧基(取代基可爲鹵素 芳基、環烷基、雜芳基' 雜環基), 取代或非取代之醯基(取代基可爲鹵素、烷基 環院基、雜芳基、雜環基。例:烷羰基、芳羰基 基'雜環羰基、甲醯基、乙醯基), 取代或非取代之烷磺醯基(取代基可爲鹵素、 基、環烷基、雜芳基、雜環基。例:甲磺醯基、 甲氧基、 基、芳基 、乙胺基 S)、芳烷 烷基胺烷 基、胺甲 丨安基), 基、取代 胺甲醯基 甲醯基、 丙基胺甲 、雜芳烷 、烷基、 、芳基、 、雜芳羰 烷基、芳 乙磺醯基 -46- 201021798 取代或非取代之芳磺醯基, 取代或非取代之雜芳磺醯基(取代基可爲鹵素、烷基' 芳基、環烷基、雜芳基、雜環基), 取代或非取代之胺磺醯基, 取代或非取代之烷氧羰基(取代基可爲鹵素、烷基、芳 基、環烷基、雜芳基、雜環基。例:甲氧羰基、乙氧基羰 基、第三丁氧羰基)、芳氧羰基、雜芳氧羰基、雜環氧羰 基,
環烷磺醯基、雜芳磺醯基、雜環磺醯基, 烷亞磺醯基、環烷亞磺醯基、芳亞磺醯基、雜芳亞磺醯 基、雜環亞磺醯基, 亞硝基, 烯氧基(例:乙烯氧基、烯丙氧基), 芳基烷氧基(例:苄氧基), 疊氮基, 異氰基、異氰氧基、硫氰氧基、異硫氰氧基、氫硫基、 烷硫基(例:甲硫基), 甲醯氧基、鹵甲醯基、酸草醯基、硫甲醯基、硫羧基、 —硫竣基、硫胺甲醯基、亞碌酸基、擴酸基、擴酸基胺基 、肼基、脲基、脒基、胍基'酞醯亞胺基、側氧基等而成 之組選擇。可有1〜4個該取代基取代。 「取代或非取代之胺基」、「取代或非取代之胺甲醯基 」、「取代或非取代之胺甲醯氧基」、「取代或非取代之 胺磺醯基」之取代基可舉出宜爲烷基、烯基、取代或非取 -47- 201021798 代之芳基(取代基可爲羧基、烷氧基、胺磺醯基)、雜芳基 '烷羰基、芳羰基、雜芳羰基、雜環羰基、烷氧羰基、芳 氧擬基、雜芳氧羰基、雜環氧羰基、胺磺醯基、烷磺醯基 '胺甲醯基、環烷磺醯基、芳磺醯基、雜芳磺醯基、雜環 磺醯基、醯基、羥基、烷亞磺醯基、環烷亞磺醯基、芳亞 擴醯基、雜芳亞磺醯基、雜環亞磺醯基、胺基等。 「院氧幾基」、「院氧簾胺基」、「院胺基」、「芳院 胺基」、「烷基胺烷基」、「烷氧羰胺基」、「烷磺醯胺 基」、「烷基胺甲醯基」、「烷磺醯基胺甲醯基」、「取 代或非取代之烷氧基胺甲醯基」、「烷羰基」、「烷亞磺 酿基」、「芳基烷氧基」、「烷硫基」及「烷磺醯基」之 烷基部分爲上述「烷基」。 「烯氧基」之烯基部分爲上述「烯基」。 「芳烷胺基」、「芳磺醯胺基」、「芳羰基」、「芳氧 幾基」、「芳亞磺醯基」及「芳基烷氧基」、「芳磺醯基 」之芳基部分爲上述「芳基」。 「雜芳羰基」、「雜芳氧羰基」、「雜芳磺醯基」及「 雜芳亞磺醯基」之雜芳基部分爲上述「雜芳基」。 「雜環羰基」、「雜環羰胺基」、「雜環氧羰基」、Γ 雜環磺醯基」及「雜環亞磺醯基」之雜環基部分爲上述「 雜環基」。 「環焼磺醯基」及「環烷亞磺醯基」之環烷基部分爲上 述「環烷基」。 本發明化合物中以如下態樣之化合物較佳。 -48- 201021798 式⑴中環A爲於式·· -(^RiRq-CpOhNW之基鍵之碳原 子鄰接之一方之原子爲氮原子、他方之原子爲雜原子之含 氮雜環。式(I)中,虛線表示鍵之存在或不存在。 於環A不僅單環也含有稠合環(2〜3個之稠合環),尤以單 環或二環較佳。環A除上述式(I)所示氮原子以外也可雜原 子、環A之構成原子可爲碳原子、氧原子、氮原子、硫原 子。構成環A之鍵可爲單鍵、雙鍵。
又環A也可以式:_c(riR2)_c( = 〇)_nr3r4之基及式:r5 之基以外取代。 例如式:
之基可爲如下環:
-49- 201021798
-50- 201021798 R5-
N
N. N) NRe
<NXS,
μ丨1心'R5d φ
Cp
%
代之任意位置取代。於R5、R6取代之位置以外之環A之 構成原子也可經R5、R6之基以外取代) 宜爲如下環: -51- 201021798
特宜爲如下環: -52- 201021798
外之取代基取代。 其中「式:-C^WhCpCO-NieR4之基及式:-R5之基」 以外之取代基可爲鹵素、羥基、氰基、硝基、羧基、取代 或非取代之烷基、取代或非取代之烯基、取代或非取代之 炔基、取代或非取代之芳基、取代或非取代之雜芳基、取 代或非取代之環烷基、取代或非取代之環烯基、取代或非 • 取代之雜環基、取代或非取代之烷氧基、取代或非取代之 , 芳氧基、取代或非取代之雜芳氧基 '取代或非取代之環烷
氧基 '取代或非取代之環烯氧基、取代或非取代之雜環氧 基、取代或非取代之烷硫基、取代或非取代之芳硫基、取 代或非取代之雜芳硫基、取代或非取代之環烷硫基、取代 或非取代之環烯硫基、取代或非取代之雜環硫基、取代或 非取代之烷磺醯基、取代或非取代之芳磺醯基、取代或非 取代之雜芳磺醯基、取代或非取代之環烷磺醯基、取代或 非取代之環烯磺醯基、取代或非取代之雜環磺醯基、取代 或非取代之醯基、取代或非取代之胺甲醯基或取代或非取 代之胺基等。也可以1〜3個該取代基取代。 Z 爲-NR6-、=N·、-0-或-S-,宜爲-〇-或-S-,更宜爲-S-。 -53- 201021798 Z中-NR6-之R6爲氫、取代或非取代之烷基、取代或非 取代之烯基、取代或非取代之炔基、取代或非取代之芳基 、取代或非取代之雜芳基、取代或非取代之環烷基、取代 或非取代之環烯基或取代或非取代之雜環基。宜爲氫或取 代或非取代之烷基。 R1及R2各自獨立爲氫、鹵素、氰基、硝基、羧基或取 代或非取代之烷基。宜爲氫或取代或非取代之烷基。更宜 爲氫。 R3爲氫或取代或非取代之烷基。宜爲氫。 R4爲氫、取代或非取代之烷基、取代或非取代之烯基、 取代或非取代之炔基、取代或非取代之芳基、取代或非取 代之雜芳基、取代或非取代之環烷基、取代或非取代之環. 烯基、取代或非取代之雜環基或取代或非取代之胺基。宜 取代或非取代之烷基、取代或非取代之芳基、取代或非取 _ 代之雜芳基、取代或非取代之環烷基、取代或非取代之雜 環基或取代或非取代之胺基。更宜取代或非取代之烷基。 R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非取〇 代之烷基、取代或非取代之烯基、取代或非取代之炔基、 取代或非取代之芳基、取代或非取代之雜芳基、取代或非 取代之環烷基、取代或非取代之環烯基、取代或非取代之 雜環基、取代或非取代之烷氧基、取代或非取代之芳氧基 、取代或非取代之雜芳氧基、取代或非取代之環烷氧基、 取代或非取代之環烯氧基、取代或非取代之雜環氧基、取 代或非取代之烷硫基、取代或非取代之芳硫基、取代或非 -54- 201021798 取代之雜芳硫基、取代或非取代之環烷硫基、取代或非取 代之環烯硫基、取代或非取代之雜環硫基、取代或非取代 之院磺醯基、取代或非取代之芳磺醯基、取代或非取代之 雜芳磺醯基、取代或非取代之環烷磺醯基、取代或非取代 之環烯磺醯基、取代或非取代之雜環磺醯基、取代或非取 代之醯基、取代或非取代之胺甲醯基或取代或非取代之胺 基。
宜爲取代或非取代之芳基、取代或非取代之雜芳基、取 代或非取代之環烷基、取代或非取代之環烯基、取代或非 取代之雜環基、取代或非取代之芳氧基、取代或非取代之 雜芳氧基、取代或非取代之環烷氧基、取代或非取代之環 嫌氧基、取代或非取代之雜環氧基、取代或非取代之芳硫 基、取代或非取代之雜芳硫基、取代或非取代之環烷硫基 、取代或非取代之環烯硫基、取代或非取代之雜環硫基、 取代或非取代之芳磺醯基、取代或非取代之雜芳磺醯基、 取代或非取代之環烷磺醯基、取代或非取代之環烯磺醯基 、取代或非取代之雜環磺醯基或取代或非取代之胺基。 更宜爲取代或非取代之芳基、取代或非取代之雜芳基、 取代或非取代之芳氧基、取代或非取代之雜芳氧基、取代 或非取代之芳硫基、取代或非取代之雜芳硫基、取代或非 取代之芳磺醯基、取代或非取代之雜芳磺醯基或取代或非 取代之胺基。 Z1 爲 _0·或- S-0 宜爲- S-。 式(II)中環B可爲於鄰接之5員環稠合之芳香族碳環、 -55- 201021798 芳香族雜環、非芳香族碳環或非芳香族雜環。環B爲可取 代之任意位置以R5(包括氫)取代、其以外之可取代之任意 位置也可有〇〜3個Rx取代。 「芳香族碳環」包括單環芳香族碳環(例:苯環)和稠合 芳香族碳環。其中「稠合芳香族碳環」可爲例如碳數10〜 14之稠合芳香族碳環等、具體而言爲萘、菲、蒽等。
「芳香族雜環」爲環內有1以上除如碳原子以外由氮原 子、硫原子和氧原子任意選擇之雜原子之芳香族環。該環 包括單環或稠合環。 「非芳香族碳環」可爲飽和或部分有不飽和鍵之芳基或 可與芳香族雜環稠合之5〜10員非芳香族之碳環。 「非芳香族雜環」爲環內有1以上除如碳原子以外由氮 原子、硫原子和氧原子任意選擇之雜原子之非芳香族之環 。該環爲飽和或部分有不飽和鍵之芳基或可與芳香族雜環 稠合之5〜10員環。
環B可爲例如以下之環。又於以下之環,也可於R5 (包 括氫)取代之位置以外之任意位置〇〜3處被Rx取代。
-56- 201021798 (其中R5與前述同意義)
宜爲以下之環。
〇 R4a爲取代或非取代之芳烷基、取代或非取代之雜芳烷 基、取代或非取代之環烷烷基、取代或非取代之環烯烷基 、取代或非取代之雜環烷基、 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、 鹵素、羥基、羧基、取代或非取代之烷基、取代或非取代 之烷氧基、取代或非取代之芳基、取代或非取代之雜芳基 、取代或非取代之環烷基、取代或非取代之環烯基或取代 或非取代之雜環基,η爲1〜10之整數, -57- 201021798 R9 爲-OR10 或-NRHR12, R]°爲氫、取代或非取代之烷基、取代或非取代之芳基 、取代或非取代之雜芳基、取代或非取代之環烷基、取代 或非取代之環烯基或取代或非取代之雜環基, R11及R12各自獨立爲氫、取代或非取代之烷基、取代或 非取代之烷氧基、取代或非取代之芳氧基、取代或非取代 之雜芳氧基、取代或非取代之烷磺醯基、取代或非取代之 芳基、取代或非取代之雜芳基、取代或非取代之環烷基、 取代或非取代之環烯基或取代或非取代之雜環基)之基或 式:-C(R7Rs)n-〇-R"(其中r7、尺8和^與上述同意義,R" 爲氫或取代或非取代之烷基)之基。 宜爲取代或非取代之芳烷基、取代或非取代之雜芳烷基 或式:-(CR7R8)n-C( = 〇)-R9 之基。 . 尤其R4a中取代或非取代之芳烷基和取代或非取代之雜 芳烷基以如下基較佳。
其中Ra、Rl4及R15與前述(18)同意義,b爲0〜3之整數 b以1或2之整數較佳。 R4a中取代或非取代之芳烷基和取代或非取代之雜芳烷
-58-
201021798 其中Ra、R14及R15與前述(18)同意義,c爲0〜
Ra可爲鹵素、羥基、羧基、硝基、氰基、疊氮 或非取代之烷基、取代或非取代之烯基、取代或 炔基、取代或非取代之芳基、取代或非取代之環 代或非取代之環烯基、取代或非取代之雜芳基、 取代之雜環基、取代或非取代之烷氧基、取代或 芳氧基、取代或非取代之矽烷氧基、取代或非取 、取代或非取代之胺甲醯基、取代或非取代之胺 、取代或非取代之醯基、取代或非取代之烷磺醯 或非取代之芳磺醯基、取代或非取代之雜環磺醯 或非取代之胺磺醢基或取代或非取代之烷氧羰基 宜爲羧基、氰基、取代或非取代之雜芳基、取 代之胺基、取代或非取代之胺甲醯基、取代或非 甲醯氧基、取代或非取代之烷磺醯基或取代或非 磺醯基。 更宜爲羧基、取代或非取代之雜芳基、取代或 胺甲醯基、取代或非取代之胺甲醯氧基、取代或 烷磺醯基或取代或非取代之胺磺醯基。 R7和R8各自獨立爲氫、鹵素、羥基、羧基、 取代之烷基、取代或非取代之烷氧基、取代或對 基、取代或非取代之雜芳基、取代或非取代之琿 代或非取代之環烯基或取代或非取代之雜環基。 宜爲氫。 2之整數 基、取代 非取代之 烷基、取 取代或非 非取代之 代之胺基 甲醯氧基 基、取代 基、取代 〇 代或非取 取代之胺 取代之胺 非取代之 非取代之 取代或非 取代之芳 烷基、取 -59- 201021798 η爲1〜10之整數。宜爲1〜3之整數。更宜爲1。 R1()爲氫、取代或非取代之烷基、取代或非取代之芳基、 取代或非取代之雜芳基、取代或非取代之環烷基、取代或 非取代之環烯基或取代或非取代之雜環基。 宜爲氫或取代或非取代之烷基。
Rl1及R12各自獨立爲氫、取代或非取代之烷基、取代或 非取代之烷氧基、取代或非取代之芳氧基、取代或非取代 之雜芳氧基、取代或非取代之烷磺醯基、取代或非取代之 芳基、取代或非取代之雜芳基、取代或非取代之環烷基、 取代或非取代之環烯基或取代或非取代之雜環基。 R11以氫較佳。 R12宜爲取代或非取代之烷基、取代或非取代之烷氧基、 取代或非取代之芳氧基、取代或非取代之雜芳氧基、取代 或非取代之烷磺醯基、取代或非取代之芳基、取代或非取 代之雜芳基、取代或非取代之環烷基、取代或非取代之環 烯基或取代或非取代之雜環基。 R3和R4與鄰接之氮原子—起形成之環、R3和與鄰 接之氮原子一起形成之環可爲環內除該氮原子以外可有1 〜4個氧原子、硫原子、及/或氮原子之3〜15員非芳香族 雜環。又如此非芳香族雜環更可以碳數1〜4之伸烷基鏈 交聯’也可與環烷(以5〜6員環較佳)或苯環稠合。只要爲 非芳香族、則可飽和也可有部分不飽和鍵。宜爲5〜8員 環。 例如可例示以下之基。 -60- 201021798
宜爲以下之基。
Rx可爲鹵素、羥基、氰基、硝基、羧基、取代或非取代 之烷基、取代或非取代之烯基、取代或非取代之炔基、取 代或非取代之芳基、取代或非取代之雜芳基、取代或非取 代之環烷基、取代或非取代之環烯基、取代或非取代之雜 -61 - 201021798 環基、取代或非取代之烷氧基、取代或非取代之芳氧基、 取代或非取代之雜芳氧基、取代或非取代之環烷氧基、φ 代或非取代之環烯氧基、取代或非取代之雜環氧基、取代 或非取代之烷硫基、取代或非取代之芳硫基、取代或非取 代之雜芳硫基、取代或非取代之環烷硫基、取代或非取代 之環烯硫基、取代或非取代之雜環硫基、取代或非取代之 院磺醯基、取代或非取代之芳磺醯基、取代或非取代之雜 芳擴酿基、取代或非取代之環烷磺醯基、取代或非取代之 環稀磺醯基、取代或非取代之雜環磺醯基、取代或非取代 之醯基、取代或非取代之胺甲醯基或取代或非取代之胺基 〇 m可爲0〜3之整數。宜爲〇或丨之整數。 式(III)和式(IV)中X可爲-CRX=、-CH=或-N=。宜爲· CH=。 式(III)和式(IV)中Y可爲-CRX=、-CH=或·Ν=。宜爲-CH=。 式(V)中環C爲單環或雙環之雜環,該環可爲芳香族雜 環或非芳香族雜環。環C於取代可能之任意位置有R5 (包 括氫)取代’其以外之取代可能之任意位置也可有〇〜3個 Rx取代。 環C之構成原子可爲碳原子、氧原子、氮原子硫原子 。構成環C之鍵可爲單鍵、雙鍵。 例如以下之環。 -62- 201021798 Η ί!,
-63- 201021798
-64- 201021798
Ή Η 〇^〇 ζΧ^。〇cn>=。0^Ν^° Η ΙΝ Η Η Η Η >° Η
Ο Η
Ν, Ο
〇
上述環 C於可取代之任意位置可有式:-ch2-c(=o)-NHR4b之基、式:-R5之基及式:-Rx之基取代。 又上述環上之-NH-之氫可代以式:-CH2-C( = 0)-NHR4b2 -65- 201021798 基、式:-Rs之基或式:-Rx之基來取代。 式(V)中R4b爲取代芳烷基(該取代芳烷基之環上之取代 基爲羧基、取代或非取代之胺甲醯基、取代或非取代之烷 磺醯基或取代或非取代之胺磺醯基)、取代雜芳烷基(該取 代雜芳院基之環上之取代基爲竣基、取代或非取代之胺甲 醯基、取代或非取代之烷磺醯基或取代或非取代之胺磺醯 基)、取代環烷烷基(該取代環烷烷基之環上之取代基爲羧 基、取代或非取代之胺甲醯基、取代或非取代之烷磺醯基 或取代或非取代之胺磺醯基)、取代環烯烷基(該取代環烯
IJ 烷基之環上之取代基爲羧基、取代或非取代之胺甲醯基、 取代或非取代之烷磺醯基或取代或非取代之胺磺醯基)、 取代雜環烷基(該取代雜環烷基之環上之取代基爲羧基、 取代或非取代之胺甲醯基、取代或非取代之烷磺醯基或取 代或非取代之胺磺醯基)或 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、 鹵素、羥基、羧基、取代或非取代之烷基、取代或非取代 之烷氧基、取代或非取代之芳基、取代或非取代之雜芳基 、取代或非取代之環烷基、取代或非取代之環烯基或取代 或非取代之雜環基,η爲1〜10之整數, R9 爲 _〇R10 或-NR1112, R1()爲氫、取代或非取代之烷基、取代或非取代之芳基 、取代或非取代之雜芳基、取代或非取代之環烷基、取代 或非取代之環烯基或取代或非取代之雜環基, R11及Ri2各自獨立爲氫、取代或非取代之烷基、取代或 -66- 201021798 非取代之烷氧基、取代或非取代之芳氧基、取代或非取代 之雜芳氧基、取代或非取代之烷磺醯基、取代或非取代之 芳基、取代或非取代之雜芳基、取代或非取代之環烷基、 取代或非取代之環烯基或取代或非取代之雜環基)之基。
宜爲取代芳烷基(該取代芳烷基之環上之取代基爲羧基 '取代或非取代之胺甲醯基、取代或非取代之烷磺醯基或 取代或非取代之胺磺醯基)、取代雜芳烷基(該取代雜芳烷 基之環上之取代基爲羧基、取代或非取代之胺甲醯基、取 代或非取代之烷磺醯基或取代或非取代之胺磺醯基)或 式:-(CR7R8)n-C( = 0)-R9 之基。 本發明化合物之製藥容許鹽可爲以下之鹽。 鹼性鹽可例如鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼 土類金屬鹽;銨鹽;三甲胺鹽、三乙胺鹽、二環己胺鹽、 乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、普羅卡因鹽、葡甲 胺鹽、二乙醇胺鹽或乙二胺鹽等脂肪族胺鹽:N,N-二苄基 乙二胺、苯明鹽等芳烷基胺鹽;吡啶鹽、甲基吡啶鹽、喹 啉鹽、異喹啉鹽等雜環芳香族胺鹽;四甲銨鹽、四乙銨鹽 、苄基三甲銨鹽、苄基三乙銨鹽、苄基三丁銨鹽、甲基三 辛銨鹽、四丁銨鹽等第四級銨鹽;精胺酸鹽、離胺酸鹽等 鹼性胺基酸鹽等。 酸性鹽可爲例如鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、碳 酸鹽、碳酸氫鹽、過氯酸鹽等無機酸鹽;乙酸鹽、丙酸鹽 、乳酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、蘋果酸鹽、 檸檬酸鹽、抗壞血酸鹽等有機酸鹽;甲磺酸鹽、羥乙磺酸 -67- 201021798 鹽、苯磺酸鹽、對甲苯磺酸鹽等磺酸鹽;天冬胺酸鹽、麩 胺酸鹽等酸性胺基酸等》 溶劑合物乃指本發明化合物或其製藥容許鹽之溶劑合物 ’例如醇(例:乙醇)合物或水合物等。水合物可爲1水合 物、2水合物等。 用語「抑制j乃指本發明化合物抑制EL之作用。 用語「製藥容許」意指預防上或治療上無害。 本發明化合物之一般製法例示如下。又萃取,精製等可 依通常有機化學之實驗處理施行。 式(1-1)化合物可如下合成。
Hal Μ 第1工程 CHR1R2-COO-ak 鹼
第2工程 r4-nr3h 鹼
Hal
第3工裎 r5-b(oh): 鹼
Pd喁合 (式中,各記號與前述同意義,式(Γ-1)化合物可用公知之 化合物,也可用由公知化合物依常法衍生之化合物。「ak 爲碳數1〜3之垸基’ 「Hal」爲_素) 第1工程 將式(Ι’-l)化合物與式:CHW-COO-ak之化合物反應’ 來製造式(I,-2)化合物之工程。 反應溶劑可爲N,N-二甲基甲醯胺、二甲亞碾、芳香族烴 -68- 201021798 類(例如甲苯、苯、二甲苯等)、飽和烴類(例如環己烷、己 烷等)、鹵化烴類(例如二氯甲烷、氯仿、1,2-二氯乙烷等) 、醚類(例如四氫呋喃、乙醚、二噚烷、1,2-二甲氧基乙烷 等)、酯類(例如乙酸甲酯、乙酸乙酯等)、酮類(例如丙酮 、丁酬等)' 腈類(例如乙腈等)、醇類(例如甲醇、乙醇、 第三丁醇等)、水和其等之混合溶劑等。
鹼可爲例如金屬氫化物(例如氫化鈉等)、金屬氫氧化物( 例如氫氧化鈉、氫氧化鉀、氫氧化鋰、氫氧化鋇等)、金 屬碳酸鹽(例如碳酸鈉、碳酸鈣、碳酸鉋等)、金屬烷氧化 物(例如甲醇鈉、乙醇鈉、第三丁醇鉀等)、碳酸氫鈉、金 屬鈉、金屬胺、有機胺(例如三乙胺、二異丙基乙胺、DBU 、2,6-二甲吡啶等)、吡啶、烷基鋰(正丁基鋰、第二丁基 鋰、第三丁基鋰)等。 適宜反應溶劑可用芳香族烴類(例如甲苯、苯、二甲苯等 )或醚類(例如四氫呋喃、乙醚、二曙烷、1,2-二甲氧基乙烷 等)、鹼可用金屬鈉或金屬胺。 可於-78〜30 °C反應〇.5〜12小時。 式:CHR^f-COO-ak所示化合物可爲例如乙酸丁酯或乙 酸乙酯。 第2工程 將式(Γ-2)化合物與式:R4_NR3H所示化合物反應,來製 造式(Γ-3)化合物之工程。 反應溶劑可用工程1記載之溶劑。宜爲N,N-二甲基甲醯 胺、二甲亞碾、N-甲基-2-吡咯啶酮。使用微波爐來反應時 -69- 201021798 ,可於不用溶劑之條件下反應。 鹼可用工程1記載之鹼。宜爲有機胺(例如三乙胺、二異 丙基乙胺、DBU、吡啶、2,6-二甲吡啶等)。 可於使用溶劑回流之溫度反應0.5〜.12小時。 使用微波爐來反應時,可於80〜2 00 °C反應5分鐘〜1小 時。溶劑可用上述溶劑,但也可不用。 式:R4-NR3H所示化合物可爲例如苯甲酸第三丁基3_胺 基甲酯鹽酸鹽等。 第3工程 將式(Γ-3)化合物,與式:R5-B(OH)2所示化合物於把觸 媒下反應,來製造式(1-1)化合物之工程。 溶劑可用工程1記載之溶劑。宜爲芳香族烴類(例如甲苯 、苯、二甲苯等)、醚類(例如四氫呋喃、乙醚、二噚院、 1,2-二甲氧基乙烷等)。使用微波爐來反應時,可於不用溶 劑之條件下反應。 鹼可用工程1記載之鹼。宜爲金屬碳酸鹽(例如碳酸鈉、 碳酸鈣、碳酸絶等)、有機胺(例如三乙胺、二異丙基乙胺 、DBU、2,6 -二甲吡啶等)。 反應可於鈀觸媒(例:Pd(PPh3)4、PdCl2、Pd(OAc)2、 Pd(dba)2等)和膦配體(例:PPh3、BINAP等)之存在下,使 用溶劑回流之溫度反應0.5〜12小時。使用微波爐來反應 時,可於80〜200 °C反應5分鐘〜1小時。溶劑可用上述溶 劑,但也可不用。 式:R5-B(OH)2所示化合物可爲例如苯基硼酸等。 -70- 201021798 式(π-1)化合物也可與上述流程同樣合成。
第1工程 CHR1R2-COO-ak 鹽基
R4a-NR3H 鹽基 第2工程
r5-b(oh)2 鹽基 Pd〆禹合 第3工程
(式中,各記號與前述同意義,式(II’-1)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基,「Hal」爲鹵素)
式(III-1)化合物也可與上述流程同樣合成 Ry、^x、___n 第 1 工程J X >_Hal ——. 第2工程
Hal, Υ' CHR1R2-COO-ak Hal 鹸 R4a-NR3H 鹼
IIM
R5-B(OH)2 鹸 Pd-偶合 第3工程 lll,-2
(式中,各記號與前述同意義,式(ΠΓ-1)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak 」爲碳數1〜3之烷基,「Hal」爲鹵素) 式(IV-1)化合物也可與上述流程同樣合成。 -71 - 201021798
Hak :XrvHa. 第1工程 CHR1R2-COO-ak 鹽基
Hak 第2工程 IV'-2 Ι^-Νί^Η 鹽基 IV-1
IV-3 第3工程 r5-b(oh)2 鹽基 合 R1 R2 R3 IV-1 (式中’各記號與前述同意義’式(IV,-1)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak
」爲碳數1〜3之烷基,「Hal」爲鹵素)
第3工程 r5-b(oh)2 鹼 Pd-偶合
式(V-1)化合物也可與上述流程同樣合成。 第1工程 第2工程 Har CH3-COO-aK R4b-NH2 V-1 鹼 V-2 鹼 (式中,各記號與前述同意義,式(ν’-1)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 舄碳數1〜3之烷基,「Hal」爲鹵素) 作爲本發明化合物之一般合成法之別法,可於式:- CO^RO-CO-NieR4之基之導入前,導入式:-R5之基。 例如以第4〜6工程說明如下。 -72- 201021798
Hal r-4 N A Hal
第5工程 R5-B(OH)2 Pd-偶合
r-5 第6工程 r4-nr3h
驗 Μ
(式中,各記號與前述同意義,式(Γ-4)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基,「Hal」爲鹵素) 第4工程 將式(Γ-4)化合物,與式:CHWRLCOO-ak所示化合物反 應,來製造式(Γ-2)化合物之工程。 反應可於工程1記載之條件下施行。 第5工程
將式(Γ-2)化合物,與式:R5-B(OH)2所示化合物於鈀觸 媒下反應,來製造式(Γ-5)化合物之工程。 反應可於第3工程記載之條件下施行。 第6工程 將式(1’-5)化合物,與式:R4-NR3H所示化合物反應,來 製造式(1-1)化合物之工程。 反應可於第2工程記載之條件下施行。 式(II-1)化合物也可與上述流程同樣合成。 -73- 201021798
Hal 第4工程 CHR1R2-COO-ak 鹽基
R5-B(OH)2 Pd碉合 第5工程
(式中,各記號與前述同意義,式(ΙΓ-4)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基,「Hal」爲鹵素) 式(III-1)化合物也可與上述流程同樣合成。
CHR1R2-COO-ak 鹼 第4工程 第5工程 R5-B(OH). 鹼’ P<MS 合
ΙΙΙ··5 第6工程 R4a-NR3H 鹼 Ι·Ι·-2
111-1 (式中,各記號與前述同意義,式(ΙΙΓ-4)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak 」爲碳數1〜3之烷基,「Hal」爲鹵素) 式(IV-1)化合物也可與上述流程同樣合成。 -74- 201021798
第4工程 CHR1R2-COO-ak 鹽某
第5工程 R5-B(OH)2 鹽基 Pd·^ 合 第6工程
R4a-NR3H 鹽基 (式中,各記號與前述同意義,式(IV,_4)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak
CP
IV-1 」爲碳數1〜3之烷基,「Hal」爲鹵素) 式(V-1)化合物也可與上述流程同樣合成
R5-B(OH) 鹼 Pd·® 合 〇 第5工程
(式中,各記號與前述同意義,式(V,-4)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之院基,「Hal」爲鹵素) 式(1-1)化合物也可依如下方法合成。
•'-5 _··$ 稠合劑 μ (式中’各記號與前述同意義,式(I,-5)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基) -75- 201021798 第7工程 將式(Γ-5)化合物予以加水分解,來製造式(Γ-6)化合物 之工程。 溶劑可用工程1記載之溶劑。宜爲醇類(例如甲醇、乙醇 、第三丁醇等)。 鹼可用工程1記載之鹼。宜爲金屬氫氧化物(例如氫氧化 鈉、氫氧化鉀、氫氧化鋰、氫氧化鋇等)。 可於-20〜90°C反應0.5〜24小時 第8工程 將式(Γ-6)化合物,與式:R4-NR3H所示化合物反應,來 製造式(1-1)化合物之工程。 反應可於第2工程記載之條件下施行。 宜爲稠合劑可用(例如Ν,Ν-二環己基碳化二亞胺等水溶性碳 化二亞胺),觸媒可用羥基苯并三唑,羥基丁二醯亞胺等。 式(II-1)化合物也可與上述流程同樣合成。
ΙΓ-5
R4a-NR3H ΙΓ-6 第8工程 稠合劑
il-1 (式中,各記號與前述同意義,式(ir-5)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基) 式(III-1)化合物也可與上述流程同樣合成。 -76- 201021798
lll'-5 第7工程 水解 XX)^Na ΙΙΓ-6 第8工程 R4a-NR3H 稠合劑
(式中,各記號與前述同意義,式(III’-5)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak
爲碳數1〜3之烷基) 式(IV-1)化合物也可與上述流程同樣合成。
IV-5 第7工程 水解
IV'-6 第8工程 R4a-NR3H 稠合劑
IV-1
(式中,各記號與前述同意義’式(IV’-5)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak 爲碳數1〜3之院基) 式(V-1)化合物也可與上述流程同樣合成
第8工程 R4b-NH2 稠合劑
-77- 201021798 (式中,各記號與前述同意義’式(V,- 5)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基) 式(Γ-2)化合物也可依如下方法合成。
(式中,各記號與前述同意義,式(Γ-7)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基,「Hal」爲鹵素) 第9工程 將式(Γ-7)化合物,與式:(ak-0)2C0所示化合物反應, 來製造式(Γ-2)化合物之工程。 反應溶劑可用工程1記載之溶劑。宜爲醚類(例如四氫呋 喃、乙醚、二噚烷等)。 鹼可用工程1記載之鹼。宜有機胺(例如三乙胺、二異丙 基乙胺、DBU、2,6-二甲吡啶等)'吡啶、烷基鋰(正丁基 鋰、第二丁基鋰、第三丁基鋰)。 可於-78〜30°C反應0.5〜24小時。 式:(ak-0)2C0所示化合物可爲例如碳酸二乙酯等。 式(ΙΓ-2)化合物也可與上述流程同樣合成。
-78- 201021798 (式中,各記號與前述同意義,式(ΙΓ-7)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「akj 爲碳數1〜3之烷基,「Hal」爲鹵素) 式(ΙΙΓ-2)化合物也可與上述流程同樣合成。
第9工程 (ak-o)2CO ΙΙΓ·7 鹼
Oak 111.-2 (式中,各記號與前述同意義,式(ΠΓ-7)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak 」爲碳數1〜3之烷基,「Hal」爲鹵素) 式(IV’-2)化合物也可與上述流程同樣合成。
第9工程 (ak-o)2CO 鹸 IV-2 (式中,各記號與前述同意義,式(IV’-7)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「ak 」爲碳數1〜3之烷基’ 「Hal」爲鹵素) 式(V,-2)化合物也可與上述流程同樣合成(RX)m/7Y.u 第 9工程 (RX)m/T\ i ° 〜― ' Γ Oak
V-7 CH3 (ak-o)2CO 鹼
V-2 (式中,各記號與前述同意義,式(V’-7)化合物可用公知化 合物,也可用由公知化合物依常法衍生之化合物。「ak」 爲碳數1〜3之烷基,「Hal」爲鹵素) 式(ΙΙΓ-10)化合物可如下合成。 -79- 201021798
第1 0工程 nr>8 NC -氧化劑
lll'>9
III.-10 第1 1工程 鹵化 (式中,各記號與前述同意義,式(III,-8)化合物可用公知 化合物’也可用由公知化合物依常法衍生之化合物。「 Hal j Μ, mm) 第10工程 將式(ΙΙΓ-8)化合物,與硫氰酸鉀反應,來製造式(ΙΙΓ-9) 化合物之工程。 溶劑可用工程1記載之溶劑。宜爲鹵化烴類、乙酸或水 。氧化劑可用溴、碘。 可於-20〜50°C反應0.5〜48小時。
第1 1工程 將式(ΙΙΓ-9)化合物鹵化,來製造式(ΙΙΓ-10)化合物之工 程。 溶劑可用工程1記載之溶劑。宜爲腈類。 鹵化劑可用氯化銅(Π)、溴化銅(II)。 可於-20〜90°C反應0.5〜48小時。 式(IV,-10)化合物也可與上述流程同樣合成。 -80- 201021798
第1 0工程 NC-^K 氧化剤
IV'-9 第1 1工程 鹵化
(式中,各記號與前述同意義,式(IV’-8)化合物可用公知 化合物,也可用由公知化合物依常法衍生之化合物。「 Hal」爲鹵素)
本發明化合物之各種之取代基可参考(l)Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry (2) Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry II (3)RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS 等來導入。
Hal 本發明化合物具有優異之血管內皮脂肪酶抑制活性。故 可用於血管內皮脂肪酶參與之疾病,尤其用於脂質代謝異 常症、高脂血症、糖尿病、肥胖、動脈硬化症、粥樣性動 脈硬化症和/或症候群X等疾病之治療或預防。尤其高脂 血症、動脈硬化症和脂質代謝異常症之治療或預防有用。 本發明使用之化合物可經口或非經口投與。經口投與時 ,本發明使用之化合物可作成通常之製劑,例如錠劑、散 劑、顆粒劑、膠囊劑等固形劑;水劑;油性懸浮劑;或糖 漿劑或酏劑等液劑之任何劑形使用。依非經口投與時,本 發明使用之化合物可作成水性或油性懸浮.注射劑、點鼻液 -81- 201021798 使用。其調製時,可任意使用慣用之賦形劑、結合劑、滑 澤劑、水性溶劑'油性溶劑、乳化劑、懸浮化劑、保存劑 、安定劑等。尤其以作成經口劑使用較佳。 本發明使用之化合物之製劑也可將治療有效量本發明使 用之化合物與製藥容許載體或稀釋劑組合(例:混合)來製 造。本發明使用之化合物之製劑可用周知之容易購入之成 分依既知之方法製造。 本發明使用之化合物之投與量雖依投與方法、患者之年 齡、體重、狀態及疾病之種類而異,通常經口投與之場合 ,成人每日投與約 0.05mg〜3000mg,宜約 O.lmg〜 lOOOmg、必要時可分割投與。又非經口投與之場合,成人 每日投與約 O.Olmg〜lOOOmg,宜約 0_05mg〜500mg。又 投與時也可與其他治療劑倂用。 茲舉實施例來更詳細說明本發明,但這些非限定本發明 以下列示本發明化合物和其中間體之NMR光譜或LC/MS 數據。 LC/MS乃依以下3條件之任一來測定。 方法 A : 測定使用 Luna 5 μ C18(2)100A, 50x4.6mm(Phenomenex 公 司製),按流速3ml/分予以乙腈/水(甲酸0.1%) 10 ·· 90〜 100 : 0/3分之直線梯度後,將乙腈流通1分來測定。 方法 C : 測定使用Shim-pack XR-ODS 50Lx3.0(島津公司製),按 -82- 201021798 流速 1.6ml/分予以乙腈/水(甲酸 0·1%)10 : 90〜100 : 0/3 分之直線梯度後,將乙腈流通30秒來測定。 方法 D : 測定使用Shim-pack XR-ODS 50Lx3.0(島津公司製),按 流速1.6ml/分予以乙腈/水(甲酸0.1 %)10 : 90〜1〇〇 : 〇/8 分之直線梯度來測定。 又實施例中之各用語之意義如下。
NaHMDS:雙三甲基矽院基醯胺鈉
NMP : N-甲基-2-耻咯啶酮 TFA :三氟乙酸 THF :四氫呋喃 DMF :二甲基甲醯胺 WSCD: 1-乙基-3-(3-二甲胺基丙基)碳化二亞胺 BOC :第三丁氧羰基 Bn :苄基 LHMDS:六甲基二矽氮烷鋰 HATU : 0-(7-吖苯并三唑-1-基)-Ν,Ν,Ν’,Ν’-四甲基脲六氟 磷酸鹽
Pd2(dba)3:貳(二苯亞甲基丙酮)鈀 mCPBA:間-氯過氧苯甲酸 X-Phos : 2-二環己基膦_2’,4’,6'-三-I-丙基-1,1'-聯苯基 NCS : N-氯琥珀醯亞胺 Fe(acac)3 :乙醯基乙醯酸鐡 H-Gly-OtBu:甘胺酸第三丁酯 -83- 201021798 (實施例1)
AcOEt
BPH OH
Pd(PPh3)4 Na2〇〇3
於2M之NaHMDS四氫呋喃溶液(111 mL,211 mmol)之 無水甲苯375mL溶液將乙酸乙酯(11.30 mL,116 mmol)於 氮氣流下-60 °C以10分滴下。其後於-601攪拌1小時後’ 滴下6-溴-2-氯苯并噻唑 1(25 g, 101 mmol)之無水甲苯 125 mL溶液。滴下終了後,於〇°C攪拌2小時。 於反應液加1M鹽酸及乙酸乙酯來萃取後,有機層以飽 和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶劑,殘渣以己 烷和二異丙醚之混合溶劑洗淨,得化合物2(27.lg,9〇 %)黄 色固體。 化合物 2 ; 1H-NMR(CDC13)5 : 1.31(t,J = 7.2,3.0Hz,3H), -84- 201021798 4.15(s, 2H), 4.26(q, J = 7.2 Hz, 2H), 7.57(dd, J = 8.7, 1.8Hz, 1H), 7.86(d, J = 9.0Hz, 1H), 8.01(d, J = 1.8Hz, 1H) 將化合物2(5g,16.7mm〇l)溶解於NMP50ml。添加3-(胺 甲基)苯甲酸第三丁酯鹽酸鹽(4_9g,20mmol)和三乙胺 (3.5ml,25mm〇l),於微波爐170T:照射15分鐘。於反應液 加1M鹽酸及乙酸乙酯來萃取後,有機層以飽和食鹽水洗 淨,以硫酸鎂乾燥。減壓蒸除溶劑後,殘渣以柱層析精製 ,得化合物 3(4.9g,64%)。
化合物 3 ; 1 H-NMR(DMSO-d6)3 : 1.5 1 (s,9H),4.14(s,2H), 4.40(d, J = 5.7 Hz, 2H), 7.45(t, J = 7.2Hz, 1H), 7.54(d, J =7.8Hz, 1H), 7.64(d, J = 10.8Hz, 1H), 7.76-7.82(m, 3H), 7.89(d, J = 8.4Hz, 1H), 8.36(s, 1H), 8.95(t, J = 6.0Hz, 1H) 於化合物3(60mg,0.13 mmol)之無水1,4-二噚烷 4mL 溶液,添加苯基硼酸(24mg,0.20mmol)、肆(三苯膦)鈀 8mg、2N碳酸鈉水溶液200 /z 1,於微波爐1401照射15 分鐘。於反應液添加1M鹽酸及乙酸乙酯來萃取後,有機 層以飽和碳酸氫鈉溶液及飽和食鹽水洗淨,以硫酸鈉乾燥 。減壓蒸除溶劑,殘渣以柱層析精製,得化合物4(37mg, 62%)。 化合物 4 ; lH-NMR(DMS0_d6)S : 1.52(s,9H),4.15(s,2H), 4.41(d, J = 6.1 Hz, 2H), 7.37-7.57(m, 5H), 7.74-7.86(m, 4H), 7.92(s, 1H), 8.02(d, J = 8.6 Hz, 1H), 8.38(d, J = 1.5 Hz, 1H), 8.95(t, J = 6.1 Hz, 1H) 於化合物4(37mg,0.08mmol)之二氯甲烷 1ml溶液添加 -85- 201021798 三氟乙酸1 ml,於室溫攪拌2小時。減壓蒸除溶劑,以乙 醚結晶化後,濾取而得化合物(II-l-l)29mg(88%)。 化合物(II-1-1) ; lH-NMR(DMSO-d6)5 : 4.1 5(s, 2H), 4.41(d, J = 6.1 Hz, 2H), 7.3 7-7.57(m, 5H), 7.74-7.86(m> 4H), 7.92(s, 1H), 8.02(d, J = 8.6 Hz, 1H), 8.38(d, J = 1.5 Hz, 1H), 8.95(t, J = 6.1 Hz, 1H), 12.96(br s, 1H). (實施例2)
於化合物3(200mg, 0.43 mmol)之乙酸乙醋 3mL溶液’ 添加三氟乙酸銅.苯錯合物(22mg, 0.043mmol)、萘甲酸
(1 49mg, Ο _ 8 7mmol)、苯酣(82mg, Ο · 8 7mmο 1)、碳酸絶 (282mg, 0.87mmol),於微波爐140t照射3小時。於反應f 液添加1M鹽酸及乙酸乙酯來萃取後,有機層以飽和食鹽 水洗淨,以硫酸鈉乾燥。減壓蒸除溶劑,殘渣以柱層析精 製,得化合物5(26mg,13%)。 化合物 5 ; lH-NMR(DMSO-d6)8 : 1.52(s, 9H),4.10(s,2H), 4.40(d, J = 6.1 Hz, 2H), 7.04(d, J = 8.1 Hz, 2H), 7.13-7.20(m, 2H), 7.3 8-7.4 8 (m, 3H), 7.54(d, J = 7.6 Hz, 1H), 7.72(d, J = 2.5 Hz, 1H), 7.83(d, J = 7.6 Hz, 1H), 7.90(s, 1H), 7.95(d, J = 8.6 Hz, 1H), 8.92(t, J = 5.8 Hz, 1H). -86- 201021798 仿實施例1得化合物(II-1-2)(23mg,100%)。 化合物(II-1-2) ; lH-NMR(DMSO-d6)6 : 4.10(s, 2H), 4.40(d, J = 6.1 Hz, 2H), 7.04(d, J = 8.1 Hz, 2H), 7.13-7.20(m, 2H), 7.3 8 - 7.4 8 (m, 3H), 7.54(d, J = 7.6 Hz, 1H), 7.72(d, J = 2.5 Hz, 1H), 7.83(d, J = 7.6 Hz, 1H), 7.90(s, 1H)S 7.95(d, J = 8.6 Hz, 1H), 8.92(t, J = 5.8 Hz, 1H), 12.96(br s, 1 H). (實施例3)
於5-溴-2-甲基苯并噻唑 6(6.5 g,28.5 mmol)之無水四 氫呋喃260mL溶液,氮氣流下-60°C滴下 1M之LHMDS 四氫呋喃溶液(59.8 mL,59.8 mmol)»其後於-60〜-781攪 拌80分鐘後,添加碳酸二乙酯(3.80 mL,31.3 mmol),於 0°C攪拌1小時。 於反應液添加1M鹽酸及乙酸乙酯來萃取後,有機層以 飽和碳酸氫鈉溶液及飽和食鹽水洗淨,以硫酸鈉乾燥。減 -87- 201021798 壓蒸除溶劑,殘渣以己烷洗淨,得化合物7(7.19g,84%)茶 色固體。 化合物 7 ; iH-NMR^CDClOS : 1.31(t,J = 7.1 Hz, 3H), 4.17(s, 2H), 4.26(q, J = 7.1 Hz, 2H), 7.50(dd, J = 8.6, 2.0 Hz, 1H), 7.74(d, J = 8.6 Hz, 1H), 8.16(d, J = 2.0 Hz, 1H). 仿實施例1得化合物8(984mg,43%)。 化合物 8 ; 'H-NMR^CDCIOS : 1.58(s,9H),4.1 l(s,2H), 4.55(d, J = 6.1 Hz, 2H), 7.37(t, J = 7.6 Hz, 1H), 7.45(d, J =7.6 Hz, 1H), 7.50-7.53 (m, 2H), 7.73(d, J = 8.1 Hz, 1H), 7.89-7.90(m, 2H), 8.14(s, 1H). 仿實施例1得化合物9(45mg,66%)。 化合物 9 ; W-NMRCCDCIJS : 1.56(s,9H),4.15(s,2H), 4_57(d,J = 6.1 Hz,2H),7.34-7.39(m,3H),7.45-7.61(m, 3H), 7.69(s, 1H), 7.78(d, J = 7.6 Hz, 1H), 7.8 7-7.91 (m, 3H), 7.95(s, 1H). 仿實施例1得化合物(n-l-3)(29mg,88%)。 化合物(II-1-3) ; W-NMI^DMSO-cUH : 4.17(s,2H),4.41(d, J = 5.6 Hz, 2H), 7.36(d, J = 8.1 Hz, 1H), 7.44-7.50(m, 2H), 7.55(d, J = 7.6 Hz, 1H), 7.65(t, J = 7.6 Hz, 1H), 7.76(t, J = 7.6 Hz, 1H), 7.82-7.91(m, 4H), 8.12(d, J = 8.1 Hz, 1H), 8.94(t, J = 5.8 Hz, 1H), 12.95(br s, 1H). (實施例4) -88- 201021798
i) TFA/CH2CI2
OuOl2
DMF
THF
MeCN NaHMDS
ii) BnBr, Et3N, DMF
ξΡ
於氯化銅(II)(1.90g,14.10mmol)之無水二甲基甲醯胺溶 液5ml,將亞硝酸異丁酯(2.37ml,17.62mmol)、化合物 10(3g,11.75mniol)之無水二甲基甲醯胺l〇ml懸浮液於冰 冷下順次滴下。昇溫爲5Ot而攪拌2小時後,於反應液添 加飽和氯化銨水溶液50ml及乙酸乙酯50ml來萃取。有機 層以飽和食鹽水40ml洗淨3回,以硫酸鎂乾燥後,減壓 蒸除溶劑,殘渣以矽膠柱層析(正己烷:乙酸乙酯=5 : 1)精 製,得化合物11(1.62g,50%)白色囿體。 化合物 11 ; 1H-NMR(CDC13) : 8(ppm)1.49(s,9H),2.82(t,J =5.6 Hz, 2H), 3.73(t, J = 5.6 Hz, 2H), 4.55(s, 2H). 於-60°C將 1.9M NaHMDS/四氫呋喃溶液 1.47ml (2.73mmol)以無水四氫呋喃1 · 5 m 1稀釋後,滴下乙腈 (95μ1, 1.82mmol)而攪拌。30分鐘後,滴下化合物 ll(250mg, 0.91mmol)之無水四氫呋喃2ml溶液,於室溫攪 拌1小時後,以2M鹽酸3ml稀釋,以乙酸乙酯5ml萃取 。油層以飽和氯化鈉水溶液5ml洗淨後,減壓蒸除溶劑, -89- 201021798 殘渣以矽膠柱層析(正己烷:乙酸乙酯=3 : 1)精製,得化合 物 12(1 50mg, 59%)紅色油。 化合物 12 ; lH-NMR(DMSO-d6) : 5(ppm)1.42(s, 9H), 2.75(t, J = 5.6 Hz, 2H), 3.63(t, J = 5.6 Hz, 2H), 4.50(s, 2H), 4.58(s, 2H) 將化合物 12(120mg, 0.430mmol)溶解於二氯甲烷1.2ml ,於〇尤添加TFA(0.50ml, 6.44mmol),攪拌2小時。減壓 蒸除二氯甲烷、三氟乙酸,殘渣溶解於無水DMF1.5ml, 添加三乙胺(0.12ml,0.86mmol)、苄基溴(51 μ 1,0.43mmol) ,於室溫攪拌2.5小時。將反應液以飽和碳酸氫鈉水(5ml) 稀釋,以乙酸乙酯l〇ml萃取。有機層以飽和碳酸氫鈉水 (5ml)洗淨後,減壓蒸除溶劑,殘渣以矽膠柱層析(氯仿: 甲醇=99 : 1)精製,得化合物13(77.5mg, 67%)黄色油。 化合物 13 ; lH-NMR(DMSO-d6) : 5(ppm)2.73(m,2H), 2.89(m, 2H), 3.64(s, 2H), 3.70(s, 2H), 4.47(s, 2H), 7.29-7.37(m, 5H). 將化合物13(67mg,0.249mmol)溶解於乙醇後,添加5M 氫氧化鈉水溶液(〇.15ml,0.746mmol)而加熱回流一小時。 減壓蒸除溶劑,得化合物14(70mg,95%)褐色油。 化合物 14 ; LC/MS Rt = 0.60min,MS : 288.90,方法:A 於化合物 14(77 mg, 0.248 mmol)之 DMF1.5ml 溶液,添 加三乙胺(0.206 ml,1.489 mmol)、HOBt(67.1 mg,0.496 mmol)、WSCD 鹽酸鹽(95 mg, 0.496 mmol)、3-(胺甲基)苯 甲酸第三丁酯鹽酸鹽(121 mg, 0.496 mmol),於室溫攪拌一 -90- 201021798 晚。反應液以水5ml稀釋,以乙酸乙酯l〇ml萃取。油層 以水5ml和飽和食鹽水 5ml洗淨,以硫酸鎂乾燥後,減 壓蒸除溶劑》殘渣以矽膠柱層析(氯仿:甲醇=50 : 1)精製 ,得化合物15(2 0 mg,17%)褐色油。 化合物 15 ; LC/MS Rt = 2.38min,MS : 478.20,方法:A 於化合物15(20 mg,0.042 mmol)之二氯甲烷1.0ml溶液 ,添加TFA(5 00 μ 1,6.49 mmol),於室溫攪拌。一小時後 ,減壓蒸除溶劑,於水-乙腈系(5〜95%(乙腈)/15min)以逆 相HPLC分取’得化合物(11-1-4)(8.7 mg,49%)白色固體。 化合物(II-1-4); lH-NMR(DMS〇-d6)S: 2.68-2.82(m,4H), 3.61(s, 3H), 3.70(s, 2H), 3.88(s, 2H), 4.36(d, J = 5.6 Hz, 2H), 7.21-7.55(m, 7H), 7.75-7.90(m, 2H), 8.80(t, J = 5.6 Hz, 1 H). • (實施例5)
-91 201021798 於氯化銅(II)9.15g(68.1mmol)之無水乙腈l〇〇ml懸浮液 ,將亞硝酸異丁酯(11.46ml,85mmol)、化合物 16(10g, 56.7mmol)之無水乙腈l〇〇ml懸浮液於冰冷下順次滴下後 ,昇溫爲50°C而攪拌3小時。濾除不溶物而減壓蒸除溶劑 後,於殘渣添加乙酸乙酯200ml及1M鹽酸 100ml來萃 取。有機層以飽和食鹽水1 〇〇ml洗淨,以硫酸鎂乾燥後, 減壓蒸除溶劑,殘渣以矽膠柱層析(正己烷:乙酸乙酯=99 :1)精製,得化合物17(2·5g,23%)白色固體。 化合物 17; lH-NMR(DMS0-d6): 5(ppm)7.34-7.44(m,1H), 7.44-7.50(m, 2H), 7.86-7.94(m, 2H), 8.12(s, 1H). 於-60t:將 1.9M NaHMDS/四氫呋喃溶液(8.07ml, 1 5.3 3 mmol)以無水四氫呋喃 1 0 ml稀釋後,滴下乙腈 (531μ1,l〇.22mmol)來攪拌。30分鐘後,滴下化合物 17(lg, 5.11mmol)之無水四氫呋喃l〇ml溶液,於0七攪拌 1小時後,以2M鹽酸 10ml稀釋,以乙酸乙酯50ml萃 取。油層以飽和氯化鈉水溶液50ml洗淨後,減壓蒸除溶 劑,殘渣以矽膠柱層析(正己烷:乙酸乙酯=4 : 1)精製,得 化合物1 8(740mg,72%)緑色固體。 化合物18;lH-NMR(DMSO-d6):δ(ppm)4.63(s,2H),7.33-7.40(m, 1H), 7.42-7.51(m, 2H), 7.90-8.00(m, 2H), 8.13(s, 1H). 於化合物18(130mg,_ 0.649mmol)之乙醇 1.5ml溶液添加 5M氫氧化鈉水溶液(〇.3 89ml,1.947mmol),加熱回流1小 時後,以1M鹽酸水溶液5ml稀釋,以氯仿10ml萃取5 -92- 201021798 回。有機層以硫酸鎂乾燥後,減壓蒸除溶劑,殘渣以矽膠 柱層析(氯仿:甲醇:乙酸 =10 : 1 : 0·1)精製’得化合物 19(77.2 mg,54%)褐色油。 化合物19;lH-NMR(DMSO-d6):δ(ppm)4·13(s,2H),7.30-7.37(m, 1H), 7.39-7.47(m, 2H), 7.90-7.97(m, 2H), 8.04(s, 1H), 12.81(brs, 1H)
於化合物19(60mg,0.274 mmol)之DMF lml溶液,添加 三乙胺(0.19ml, l_368mmol)、WSCD ·鹽酸鹽(79mg, 0.410mmol)、HOBt(56mg,0.410mmol)、3-(胺甲基)苯甲酸 第三丁酯鹽酸鹽(133 mg,0.547 mmol),於室溫攪拌。12 小時後,以1M鹽酸水溶液2.0ml稀釋,以乙酸乙酯10ml 萃取。油層以水 5ml和飽和食鹽水 5ml洗淨,以硫酸鎂 乾燥後,減壓蒸除溶劑。殘渣以矽膠柱層析(正己烷:乙 酸乙酯=1 : 1)精製,得化合物20(61.4mg,55%)黄色非晶質 〇 ^ 化合物 20 ; lH-NMR(DMSO-d6)S : 1.53(s,9H),4,05(s, 2H),4.40(d,J = 5.6Hz,2H),7.30-7.37(m,lH),7.39-7.49(m, 3H), 7.55(d, J = 7.6 Hz, 1H), 7.76-7.85(m, 2H), 7.93(d, J = 7.6 Hz, 2H), 8.00(s, 1H), 8.87(t, J = 5.6 Hz, 1 H). 於化合物20(58mg, 〇.142mmol)之二氯甲烷1.0ml溶液添 加TFA(0·328 ml, 4.2 6 mmol),於室溫攪拌。二小時後, 減壓蒸除溶劑,所得黄色固體懸浮於乙酸乙酯5ml而攪拌 1小時。將此濾取,得化合物(1-1-1)(33.3mg,67%)白色固 -93- 201021798 η«*>» 體。 化合物(1-1-1); lH-NMR(DMSO-d6)S: 4.05(s,2Η),4.40(d, J = 6.1 Hz, 2H), 7.33(dd J = 7.1, 8.1 Hz, 1H), 7.40-7.49(m, 3H), 7.55(d, J = 7.6 Hz, 1H), 7.83(d, J = 7.6 Hz, 1H), 7.88-7.96(m, 3H), 8.00(s, 1H), 8.87(t, J = 6.1 Hz, 1 H). (實施例6)
11-2-1 於化合物2(20g,67 mmol)之無水1,4-二噚烷200mL溶 液,於室溫添加肆(三苯膦)鈀(0)(5.39 g,4.66 mmol)、苯 基硼酸(9.75 g,80 mmol)、隣酸鉀(35.4 g, 167 mmol)而加 熱回流6小時。將反應回復室溫,添加1M鹽酸及乙酸乙 酯來萃取後’有機層以飽和食鹽水洗淨,以硫酸鈉乾燥。 減壓蒸除溶劑,所得殘渣以柱層析精製,得化合物 21(16.1g,81%)黄色固體。 化合物 21; iH-NMRCCDCnH: 1.31(t,J = 6.9 Hz,3H), 4.19(s, 2H), 4.27(q, J =7.2 Hz, 2H), 7.38(t, J = 7.5Hz, 1H), 7.48(t, J = 7.2Hz, 2H), 7.63-7.73(m, 3H), 8.06(m, -94- 201021798 2H) 於化合物21(5g,16.8 mmol)之無水四氫呋喃35mL溶液 ,添加2N氫氧化鈉水溶液(11 mL,20 mmol),於室溫攪拌 40分。反應終了後,於反應液添加正己烷,將析出之不溶 物濾取後,以乙酸乙酯洗淨。將所得粗生成物減壓乾燥’ 得化合物22(4.9g,定量)黄色固體。
於氮氣流下,室溫於化合物22(2g,6.87mmol)之無水二 甲基甲醯胺溶液20ml順次加2-胺基乙酸第三丁酯鹽酸鹽 (1.38g, 8.24mmol)、吡啶(2.78ml, 34.3mmol) ' HATU(3.13g,8.24mmol)而攪拌4小時。於反應液添加1M 鹽酸及乙酸乙酯來萃取後,有機層以飽和食鹽水洗淨’以 硫酸鈉乾燥。減壓蒸除溶劑,所得殘渣以柱層析精製’得 化合物 23(1.63g,62%)。 化合物 23; e-NMRCCDCUH: 1.46(s,9H),4.01(d,J = 5.1Hz, 2H), 4.13(s, 2H), 7.38(d, J = 6.6 Hz, 1H), 7.48(t, J =7.2 Hz, 2H), 7.64(d, J = 6.9Hz, 2H), 7.72(m, 1H), 8.06-8.10(m, 2H) 於化合物23(1.6g,4.18 mmol)之無水二氯甲烷5mL溶液 添加三氟乙酸 5m,於室溫攪拌2小時。減壓蒸除溶劑, 於所得殘渣添加乙醚而結晶化後,濾取而得化合物 24(1.12g, 8 2%)° 化合物 24; iH-NMR^DMSO-dJS: 3.85(d,J = 5·7Ηζ,2H), 4.15(s, 2H), 7.39(d, J = 6.9 Hz, 1H), 7.50(t, J = 7.8Hz, 2H), 7.74-7.81(m, 3H), 8.02(d, J = 8.7Hz, 1H), 8.38(s, -95- 201021798 2H),8.71(m,lH) 於氮氣流下化合物24(1.0g, 3.06mmol)之二甲基甲酿胺 10ml溶液順次加2-胺基乙腈鹽酸鹽(340 mg,3.68 mmol)、 HATU(1.4 g,3.68 mmol)、三乙胺(1.27mL,9.2 mmol),於 室溫攪拌3小時。反應終了後,於反應液添加1M鹽酸及 乙酸乙酯來萃取,有機層以10%碳酸氫鈉水、飽和食鹽水 洗淨,以硫酸鈉乾燥。減壓蒸除溶劑,所得殘渣以柱層析 精製,得化合物(11-2-1)(5 4〇mg,4 8%)白色固體。 化合物(II-2-1); W-NMI^DMSO-dJS: 3.84(d,J = 5·7Ηζ, 2H), 4.17(d, J = 5.4Hz, 4H), 7 · 3 9 (t,J = 7 · 5 Hz,1H), 7.50(t, J = 7.2Hz, 2H), 8.02(d, J = 8.4Hz, 1H), 8.38(s, 1H), 8.69-8.75(m, 2H) (實施例7)
於室溫氮氣氛圍下,5-溴-2-甲基苯并噻唑 6(1.3 g,5.70 mmol)之1,4-二噚烷(13 mL)溶液添加苯硫酚之鈉鹽(0.828 g, 6.27 mmol) 、 xantpho s(0.3 30 g, 0.570 mmol)、 Pd2(dba)3(0.261 g,0.285 mmol),於微波照射下,140t:攪 拌30分鐘。將反應液注入水,以乙酸乙酯萃取,所得有 機層以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨。有機層以 硫酸鎂乾燥後,減壓蒸除溶劑,所得殘渣以矽膠柱層析( 己烷:乙酸乙酯)精製,得化合物25(2.34 g, 9.09 mmol,87 %)黄色液體。 -96- 201021798 化合物 25; iH-NMRCCDClsH: 2.82(s, 3H),7.25-7.3 9(m, 6H), 7.74(d, J = 8.6 Hz, 1H), 7.89(d, J = 1.5 Hz, 1H).
於冰冷下化合物25 (2.34 g,9.09 mmol)之二氯甲烷(50 mL)溶液中徐徐添加mCPBA(5.07 g,19.09 mmol),其後於 冰冷下攪拌2小時。反應終了後,將反應液注入飽和碳酸 氫鈉水溶液,以乙酸乙酯萃取,有機層以1 〇%硫代硫酸 鈉水溶液及飽和食鹽水洗淨。有機層以硫酸鈉乾燥後,減 壓蒸除溶劑,所得固體以乙酸乙酯和異丙醚之混合液洗淨 ,得化合物26(2.28 g,7.88 mmol, 87 %)白色固體。 化合物 26; iH-NMR^CDCDS: 2.86(s,3H),7.48-7.58(m, 3H), 7.89-7.99(m, 4H), 8.52(d, J = 1.0 Hz, 1H).
(實施例8)
於化合物27(10.3 g, 62.7 mmol)之2-丙醇(3 00 mL)溶液 ,於室溫氮氣氛圍下添加N氯丁二醯亞胺(8.79 g,65.9 mmol)後,於室溫攪拌2小時。反應終了後,冷却至室溫 ,將反應液注入飽和碳酸氫鈉水溶液,以二氯甲烷萃取2 回後,有機層以飽和食鹽水洗淨。.以硫酸鈉乾燥後,減壓 蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製 ,得化合物28(4.95 g,24.92 mmol,40 %)薄橙色固體。 -97- 201021798 化合物 28 ; iH-NMR^CDClJS : 2.77(s,3H),4· 1 l(s,2H) 6.88(d, J = 8.6 Hz, 1H), 7.63(d, J = 8.6 Hz, 1H). 將化合物28(0.9 g, 4.53 mmol)之濃鹽酸5 mL以5 水稀釋後,冰冷下滴下亞硝酸鈉(344 mg,4_98 mmol)水溶 液5 mL而攪拌30分鐘。將碘化鉀(2707 mg,16.31 mmol) 水溶液25 mL徐徐滴下後,昇溫爲室溫而攪拌1小時。將 反應液冰冷下以飽和碳酸氫鈉水溶液中和後,以氯仿萃取 。有機層以1 〇%硫代硫酸鈉水溶液、飽和食鹽水洗淨,以 硫酸鎂乾燥。減壓蒸除溶劑,所得殘渣以矽膠柱層析(己 烷:乙酸乙酯)精製,得化合物29(740 mg, 2.391 mmol,53 %)白色固體。
化合物 29 ; LC/MS Rt = 2.54min,MS : 3 09.80(M+1),方法:c 於室溫氮氣氛圍下,於化合物29(740mg,2.391 mmol)之 1,4-二嗶烷(10 mL)及水(2.0 mL)混合溶液添加苯基硼酸 (364 mg,2.99 mmol)、肆三苯膦鈀(276 mg,0.239 mmol)及 碳酸氫鈉(502 mg,5.98 mmol)。 其後將混合溶液於微波 照射下1 00°C攪拌1 5分鐘。反應終了後,於反應液添加乙 酸乙酯、有機層以矽膠柱層析(己烷··乙酸乙酯)精製,得 化合物 30(5 88 mg,2.264 mmol,95 %)。 化合物 30: LC/MS Rt = 2.56min,MS : 260.0(M+1),
方法:C (實施例9) -98- 201021798
\ NH Fe(acac)3
CuO CS2OO3 於室溫氮氣氛圍下,5·胺基-2-甲基苯并噻唑 31(10 g, 60.9 mmol)之2-丙醇(200 mL)溶液添加N溴丁二醯亞胺 (23.84 g,134 mmol)後,於65T:攪拌20分鐘。更添加N 溴丁二醯亞胺(10.84 g,60.9 mmol),於65t:攪拌30分鐘 。將反應液注入飽和碳酸氫鈉水溶液,以二氯甲烷萃取, 有機層以飽和食鹽水洗淨。有機層以硫酸鈉乾燥後,減壓 蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製 ,得化合物 32(12.15 g,37.7 mmol 62 %)固體。 化合物 32 ; 1H-NMR(CDC13)5 : 2.84(s,3H),4.71(br s, 2H), 7.84(s, 1H). 於室溫氮氣氛圍下,於化合物32(12.15 g,37.7 mmol)之 1,4-二噚烷(120 mL)及水(30 mL)混合溶液,添加苯基硼酸 (5.75 g,47.2 mmol)、肆三苯膦钯(4.36 g,3.77 mmol)及碳 酸鈉(8.00 g,75 mmol)。其後將混合溶液加熱回流7小時 。反應終了後,將反應液注入水’以乙酸乙酯和四氫呋喃 -99- 201021798 之混合溶劑萃取,有機層以飽和食鹽水洗淨後’以硫酸鎂 乾燥。減壓蒸除溶劑,所得殘渣以乙酸乙酯:己烷再結晶 ,得化合物 33(9.6 g,30.1 mmol, 80 %)固體。 化合物 33; W-NMIUDMSO-deM: 2.78(s,3H),4.84(br s, 2H), 7.41-7.53(m,5H),7.65(s,1H)_
於室溫氮氣氛圍下,於化合物33(8 g,25.06 mmol)之四 氫呋喃(40mL)和甲醇(40mL)混合溶液,添加 Pd/C(10%, 含水)(13.34 g,6.27 mmol),次加甲酸銨(15.80 g,251 mmol)。將此混合溶液於50°C加熱攪拌2小時後,添加 Pd/C(10%,含水)(13.34 g,6·27 mmol)’ 於 50^〇加熱攪拌 4小時。將反應液冷却至室溫,添加乙酸乙酯後,以矽藻 土過濾,將濾液減壓濃縮,所得殘渣以水稀釋。以乙酸乙 酯萃取,有機層以硫酸鎂乾燥後,減壓蒸除溶劑。所得固 體以乙酸乙酯:己烷洗淨,得化合物34(3.16 g,13.15 mmol, 53 %)茶色固體。
化合物 34; iH-NMR^DMSO-dda: 2.72(s,3H),4.86(br s, 2H), 7.26(s, 1H), 7.3 5-7.40(m, 1H), 7.45-7.49(m, 4H), 7_57(s,1H). 於冰冷氮氣流下,於亞硝酸異丁酯(1.707 mL,12.17 mmol)之乙腈(40 mL)溶液,添加溴化銅(1.397 g,9·74 mmol)後,將化合物34(1.95 g,8_11 mmol)徐徐添加》冰冷 下攪拌20分鐘後,於501更攪拌2小時。將反應液注入 0.1Μ鹽酸水溶液,以乙酸乙酯萃取,有機層以飽和碳酸 氫鈉水溶液及飽和食鹽水洗淨。有機層以硫酸鎂乾燥後, -100- 201021798 減壓蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯) 精製,得化合物 3 5( 1.005 g,3.30 mmol, 41 %)固體。 化合物 35; W-NMI^CDCIOS: 2.86(s,3H),7.40-7.46(m, 5H),7.76(s,1H),8.25(s,1H). 於室溫氮氣氛圍下,於化合物3 5(400 mg, 1.315 mmol) 之 NMP(1 mL)溶液,添加吡唑(134 mg,1.972 mmol)、 Fe(acac)3(139 mg, 0.394 mmol)、氧化銅(11)(20.92 mg,
0.263 mmol)、碳酸铯(8 57 mg,2· 63 mmol),於微波照射下 180°C攪拌30分鐘後,更微波照射下190t:攪拌1小時。 將反應液注入水,以乙酸乙酯萃取,所得有機層以飽和食 鹽水洗淨。有機層以硫酸鈉乾燥後,減壓蒸除溶劑,所得 殘渣以矽膠柱層析(己烷:乙酸乙酯)精製,得化合物 36(1 50 mg, 0.515 mmol, 39 %) °
化合物 36 ; LC/MS Rt = 2.21min,MS : 29 2.0 5 0(M+1), 方法:C
於氮氣氛圍下化合物37(300 mg,1.248 mmol)和三乙胺 (0.260 mL,1.872 mmol)之二氯甲院(6 mL)溶液、邊冰冷邊 添加甲擴醯氯(0.107 mL,1.373 mmol),於室溫攪拌5小時 。追加三乙胺(0.346 mL,2.497 mmol)和甲磺醯氯(〇· 1 46 mL,1.872 mmol),於室溫更攪拌12小時。反應終了後, -101 - 201021798 將反應液注入0.1M鹽酸,以乙酸乙酯萃取,有機層以飽 和碳酸氫鈉水溶液及飽和食鹽水洗淨。有機層以硫酸鎂乾 燥後,減壓蒸除溶劑,得化合物38(452 mg,1.140 mmol, 91%)。 化合物 38 ; W-NMRiCDCMS : 2.88(s,3H),3.01(s,6H), 7.42-7.50(m, 3H), 7.60-7.61(m, 2H), 7.87(s, 1H), 7.95(s, 1H). 於化合物 3 8(452 mg, 1.140 mmol)之四氫呋喃(4 mL)和 甲醇(2 mL)混合溶液,於室溫添加2M氫氧化鈉水溶液,0 就此攪拌2小時。其後將反應液減壓下濃縮,所得殘渣以 水稀釋後,以1 〇%檸檬酸水溶液作成酸性,以乙酸乙酯萃 取。有機層以飽和食鹽水洗淨後,以硫酸鎂乾燥,減壓蒸 除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製, 得化合物 39(290mg,0.911mmol,80%)。 化合物 39 ; iH-NMRCCDCUM : 2,86(s,3H),2.93(s,3H), 6.50(br s, 1 Η), 7.36-7.3 8(m,2H), 7.46-7.54(m, 3H),
7.70(s, 1H), 8.23(s, 1H). (實施例11)
-102- 201021798 於化合物31(2.36 g,14.37 mmol)之2-丙醇(35mL)溶液 ,於室溫氮氣氛圍下添加N氯丁二醯亞胺(2.111 g,15.81 mmol)後,於65°C攪拌20分鐘。反應終了後,冷却至室溫 ,將反應液注入飽和碳酸氫鈉水溶液,以二氯甲烷萃取2 回後,有機層以飽和食鹽水洗淨。以硫酸鈉乾燥後,減壓 蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製 ,得化合物40( 1.73 g,8,71 mmol, 61%)薄橙色固體。
化合物 40 ; iH-NMI^CDChN : 2.84(s,3H),4.18(d,J = 1.0 Hz, 2H), 6.85(d, J = 8.6 Hz, 1H), 7.47(d, J = 8.1 Hz, 1H). 於化合物40(1.72 g,8.66 mmol)之2-丙醇(35mL)溶液, 於室溫氮氣氛圍下添加N溴丁二醯亞胺(1.695 g,9.52 mmol)後,於65°C攪拌15分鐘。反應終了後,冷却至室溫 ,將反應液注入飽和碳酸氫鈉水溶液,以氯仿萃取2回後 ,有機層以飽和食鹽水洗淨。以硫酸鎂乾燥後,減壓蒸除 溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製,得 化合物 41(1.93 g,6.95 mmol,80 °/〇)薄黄色固體。 化合物 41 ; e-NMRCCDClJS : 2.77(s,3H),4.55(br s,2H), 7.94(s, 1H). 於室溫氮氣氛圍下,於化合物41(0.96 g,3.46 mmol)之 1,4-二噚烷(10 mL)及水(2.0 mL)混合溶液添加苯基硼酸 (0.633 g,5.19 mmol)、肆三苯膦鈀(0)(0.400 g,0.346 mmol)及碳酸鈉(0.916 g, 8.65 mmol)。其後將混合溶液於 微波照射下14〇°C攪拌20分鐘。反應終了後,於反應液添 加乙酸乙酯,將有機層濃縮後,以矽膠柱層析(己烷:乙 -103- 201021798 酸乙酯)精製,得化合物42(1.44 g,5.24 mmol,76 %)黄色 固體。 化合物 42; e-NMIUDMSO-deN: 2.78(s,3H),4.88(br s, 2H), 7.42-7.5 3 (m, 5H), 7.63(s, 1H). 於冰冷,氮氣流下,於亞硝酸異丁酯(0.515 mL,3.82 mmol)之乙腈(14 mL)溶液添加氯化銅(428 mg, 3,18 mmol) 後,徐徐添加化合物42(700 mg,2.55 mmol)。冰冷下攪拌 20分鐘後,更於5〇°C攪拌2小時。將反應液注入〇.1M 鹽酸水溶液,以乙酸乙酯萃取,有機層以飽和碳酸氫鈉水 溶液及飽和食鹽水洗淨。有機層以硫酸鎂乾燥後,減壓蒸 除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製, 得化合物43(636 mg,2.162 mmol,85 %)白色固體。 化合物 43; iH-NMRCCDClOSiaJSU,3H),7.43-7.51(m, 5H), 7.71 (s, 1 Η).
於化合物42(683 mg, 2.486 mmol)之甲酸(14 mL)溶液於 室溫加35%甲醛(1.956 mL,24.86 mmol)後,加熱回流1小 時。反應液冷却至室溫、徐徐加飽和碳酸氫鈉水溶液來作 成鹼性後,以乙酸乙酯萃取,有機層以水及飽和食鹽水洗 淨。有機層以硫酸鎂乾燥,減壓蒸除溶劑,所得殘渣以矽 膠柱層析(己烷:乙酸乙酯)精製,得化合物44(213 mg, -104- 201021798 0.703 mmol, 28·3 %)固體。 化合物 44; 1H-NMR(CDC13)5: 2.68(s, 6Η),2.88(s,3Η), 7.35 -7.44(m,5H),7.56(s,1H)_ (實施例13)
mmol)之乙腈(11 mL)溶液添加溴化銅(340 mg,2.371 mmol) 後,徐徐添加化合物42(543 mg, 1.976 mmol)。冰冷下攪 拌20分鐘後,更於50尤攪拌2小時。將反應液注入0.1 Μ 鹽酸水溶液,以乙酸乙酯萃取,有機層以飽和碳酸氫鈉水 溶液及飽和食鹽水洗淨。有機層以硫酸鎂乾燥後,減壓蒸 除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製, 得化合物 45(325 mg, 0.960 mmol, 49 %)固體。 化合物 45 ; e-NMR^DMSO-dje : 2.87(s,3H),TjI- T.SUm, 5H), 8.07(s, 1H). 於室溫、氮氣氛圍下,於化合物 45(120 mg,0.354 mmol)之1,4-二噚烷(1.4 mL)和水(0.35 mL)混合溶液,添 加肆三苯隣鈀(0)(20.47 mg,0.018 mmol)、苯基硼酸(51.8 mg, 0.425 mmol)及碳酸氫鈉(74.4 mg,0.886 mmol),於微 波照射下,13〇°C攪拌40分鐘。將反應液注入水,以乙酸 乙酯萃取,有機層以飽和食鹽水洗淨。有機層以硫酸鈉乾 燥後,減壓蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙 酸乙酯)精製,得化合物46(107 mg,0.319 mmol,90 %)。 -105- 201021798 化合物 46; 'H-NMRiCDCIsM: 2.93(s,3H),7.06-7.28(m, 10H), 7.77(s, 1H). (實施例14)
dNXXs^
H 47 t-BuONa X-phos
於室溫、氮氣氛圍下’ 2-甲基苯并[d]噻唑-6-胺27(lg, 6.09 mmol)之甲苯(1〇 niL)和第三丁醇(2 mL)混合溶液’添 加溴苯(1.004 g,6.39 mmol)、乙酸細(0.068 g,0.304 mmol)、X-Phos(0.290 g, 0.609 mmol)' 第三丁醇鈉(0.819 g,8.52 mmol),於微波照射下15 0°C攪拌30分鐘。將反應 液注入水,以乙酸乙酯萃取’有機層以飽和碳酸氫鈉水溶 液及飽和食鹽水洗淨。有機層以硫酸鈉乾燥’減壓蒸除溶
劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製’得化 合物 47(1.29 g,5.37 mmol, 88 %)固體。 化合物 47 ; W-NMRCCDC^H : 2.81(s,3H),5.83(br s,1H), 6.97-7.01(m, 1H), 7.10-7.17(m, 3H), 7.29-7.34(m, 2H), 7.53(d, J = 2.4 Hz, 1H), 7.83(d, J = 8.6 Hz, 1H). 於- 60^、氮氣氛圍下,化合物47(450 mg,1,872 mmol) 之四氫呋喃(45 mL)溶液滴下 LHMDS(6.18 mL,6.18 mmol) ,於-601攪拌30分鐘。於-60°C加碳酸二乙酯(0.347 mL, 4.12 mmol),其後昇溫至而攪拌1小時。將反應液注 -106- 201021798 入0.1M鹽酸,以乙酸乙酯萃取,有機層以飽和碳酸氫鈉 水溶液及飽和食鹽水洗淨。有機層以硫酸鈉乾燥後,減壓 蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯)精製 ,得化合物 48(503 mg, 1.411 mmol, 75 %)褐色液體》 化合物 48; 1H-NMR(CDC13)5: 3.77(s,3H),3.78(s,3H), 4.16(s,2H),7.22-7.27(m,3H),7.33-7.37(m,3H),7.79(d,J =2.0 Hz, 1H), 7.94(d, J = 8.6 Hz, 1H). (實施例15)
於室溫、氮氣氛圍下,於5-溴-2-甲基苯并噻唑 6(300 mg,1.315 mmol)之甲苯(3.0 mL)和第二丁醇(0.6 mL)混合 溶液’添加哌啶(224 mg,2.63 mmol)、乙酸鈀(14.76 mg, 0.066 mmol)、X-Phos(62.7 mg, 0.132 mmol)、第三丁醇鈉 (177 mg, 1.841 mmol),於微波照射下150T:攪拌20分鐘 cp 。將反應液注入水,以乙酸乙酯萃取’有機層以飽和食鹽 水洗淨。有機層以硫酸鎂乾燥,減壓蒸除溶劑’所得殘渣 以矽膠柱層析(己烷:乙酸乙酯)精製’得化合物49(211 mg, 0.908 mmol, 69 %) 〇 化合物 49 ; 1H-NMR(CDC13)6 : 1.60-1.65 (m, 2H), 1.74- 1.80(m, 4H), 3.22(t, J = 5.6 Hz, 4H), 7.09(dd, J - 8.9, 2.3 Hz, 1H), 7.48(d, J = 2.5 Hz, 1H), 7.65(t, J = 4.6 Hz, 1H). (實施例16) -107- 201021798
t-BuONa X-phos
於室溫、氮氣氛圍下,於5-溴·2-甲基苯并噻唑 6(1.2 g,5.26 mmol)之甲苯(10 mL)和第三丁醇(2 mL)混合溶液, 添加N·甲基苯胺(620 mg,5.79 mmol)、乙酸鈀(59.1 mg, 0.263 mmol)、X-Phos(251 mg,0.526 mmol)、第三丁醇鈉 (7 0 8 mg,7.3 6 mmol),於微波照射下150°C攪拌20分鐘。 將反應液注入水,以乙酸乙酯萃取,有機層以飽和食鹽水 洗淨。有機層以硫酸鎂乾燥,減壓蒸除溶劑,所得殘渣以 矽膠柱層析(己烷:乙酸乙酯)精製,得化合物5 0(820 mg, 3.22 mmol, 61 %)。 化合物 50 ; iH-NMR^CDCldS : 2.81(s,3H), 3.37(s,3H), 6.97(t, J = 7.4 Hz, 1H), 7.04-7.07(m, 3H), 7.27-7.30(m, 2H), 7.59(d, J = 2.0 Hz, 1H), 7.63(d, J = 8.6 Hz, 1H). (實施例17)
52
6 51 H X-phos, Pd(OAc)2 t-BuONa_
toluene/t-BuOH 將5-溴-2-甲基苯并噻唑 6(1.2 g,5.26 mmol)和N-丙 基苯胺 5 1 (0.782 g,5.79 mmol)、Pd(OAc)2(0.059 g,0.263 mmol)、X-phos(0.251 g, 0 · 5 2 6 mmo 1)、第三 丁醇鈉(〇 · 70 8 g,7.3 6 mmol),於氮氣氛圍下懸浮於甲苯(10 mL)和第三丁 -108- 201021798 醇(2 mL)之混合溶液,所得混合液於微波爐150X:、照射 30 分鐘。於反應液添加 Pd(OAc)2(0.059 g,0.263 mmol)和 X-phos(0.251 g,0.526 mmol),更於微波爐 I50t:照射 30 分鐘。反應液以矽藻土過濾,添加水和乙酸乙酯來萃取後 ,有機層以飽和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶 劑,殘渣以柱層析精製,得化合物52(1.29 g,4.57 mmol)
化合物 52 ; W-NMI^CDClaW : 〇.96(t,J = 7·6 Hz,3H), 1.69-1.77(m, 2H), 2.82(s, 3H), 3.72(t, J = 7.6 Hz, 2H), 6.96(t, J = 7.4 Hz, 1H), 7.02(d, J = 8.6 Hz, 3H), 7.25-7.29(m, 2H), 7.58(d, J = 2.0 Hz, 1H), 7.62(d, J = 8.6 Hz, 1H)_ (實施例18)
toluene/t-BuOH N-甲*苯胺,.Pd(OAc)2 X-phos, t-BuONa
54
將 6-溴-2-甲基苯并噻唑 53 (900 mg,3.95 mmol)和 Pd(OAc)2(44.3 mg,0.197 mmol)、X-phos(188 mg,0.395 mmol)、第三丁醇鈉(531 mg,5.52 mmol),於氮氣氛圍下 懸浮於甲苯(9.2 mL)和第三丁醇(2.2 mL)之混合溶液。於 所得混合液添加N-甲基苯胺(0.470 ml,4.34 mmol)後,於 微波爐1501照射20分鐘。於反應液添加水和乙酸乙酯來 萃取後,有機層以飽和食鹽水洗淨,以硫酸鎂乾燥。減壓 蒸除溶劑,殘渣以柱層析精製,得化合物54(868 mg, 3.41 mmol) 〇 -109- 201021798 化合物 54; W-NMI^CDClsW: 2.82(s,3H),3.38(s,3H), 6.97-7.08(m, 3H), 7.15(dd, J = 8.9, 2.4 Hz, 1H), 7.27- 7.35(m, 2H), 7.44(d, J = 2.4 Hz, 1H), 7.83(d, J = 8.9 Hz, 1H). (實施例19)
PhSNa, Pd2(dba)3 xantphos
Dioxane, 130 °C, 15 min
55 53
將 6-溴-2-甲基苯并噻唑 53 (70< Pd2(dba)3(l 4 1 mg, 0.153 mmol)、Xantphos (1 7 8 mg, 0.307
mmol)於氮氣氛圍下懸浮於二噚烷(l〇 mL)。於所得混合液 添加苯硫酚鈉鹽(487 mg,3.68 mmol)後’於微波爐130°C 照射15分鐘。於反應液添加0.1 N鹽酸水和乙酸乙酯來 萃取後,有機層以飽和碳酸氫鈉水和飽和食鹽水洗淨,以 硫酸鎂乾燥。減壓蒸除溶劑,殘渣以柱層析精製,得化合 物 5 5 (5 87 mg,2,28 mmol)。
化合物 55; 'H-NMRCCDCIJS: 2.85(s, 3H),7.24-7.3 9(m, 5H), 7.46(dd, J = 8.6, 1.8 Hz, 1H), 7.83(dd, J = 1.8, 0.5 Hz, 1H), 7.89(d, J = 8.6 Hz, 1H). 於化合物5 5(5 86.6 mg,2.279 mmol)之二氯甲烷溶液(12 mL),於 Ot:加 mCPBA(1452 mg,5.47 mmol),就此溫度攪 拌1小時。於反應液添加飽和碳酸氫鈉水溶液和乙酸乙酯 來萃取後,有機層以10%硫代硫酸鈉水溶液和飽和食鹽 水洗淨,以硫酸鎂乾燥。減壓蒸除溶劑,將殘渣予以結晶 化精製,得化合物56(259 mg, 0.894 mmol)。 -110- 201021798 化合物 56 ; 1H-NMR(CDC13)5 : 2.90(s,3H),7.49-7.62(m, 3H),7.96-8.07(m,4H),8.52(dd,J = 1.8,0.6 Hz,1H). (實施例20)
58
於5-胺基-2-甲基苯并噻唑 31(3 g,18.27 mmol)之2-丙 醇(30 mL)溶液添加NCS(2.56 g,19.18 mmol),於室溫攪 拌1.5小時。於反應液添加水和乙酸乙酯來萃取後,有機 層以飽和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶劑,殘 渣以柱層析精製,得化合物57(1.90 g,9.56 mmol)。 化合物 57 ; 'H-NMI^CDCMS : 2.86(s,3H),4.20(br s,2H), 6.86(d, J = 8.6 Hz, 1H), 7.49(d, J = 8.6 Hz, 1H). 將亞硝酸鈉(726 mg,10.52 mmol)溶解於水(10 ml),於0 C滴下化合物57(1.90 g,9.56 mmol)之濃鹽酸(10 mL)懸浮 液,就此溫度攪拌30分鐘。於反應液將碘化鉀(23.8 g, 143 mmol)水溶液(50 ml)於0七滴下,更就此溫度攪拌1 小時。反應液以飽和碳酸氫鈉水溶液中和後,以氯仿萃取 ,有機層以1 〇%硫代硫酸鈉水溶液和飽和食鹽水洗淨, 以硫酸鎂乾燥。減壓蒸除溶劑,將殘渣予以結晶化精製, 得化合物 58(1.48 g,4.79 mmol)» 化合物 58 ; 'H-NMR^CDCUM : 2.91(s,3H),7.48(d,J = 8.4 -111- 201021798
Hz, 1H), 7.81(d, J = 8.4 Hz, 1H). 將化合物58(799 mg, 2_58 mmol)和 4 -氟苯硼酸(542 mg, 3.87 mmol),肆(三苯膦)钯(298 mg,0.25 8 mmol)、碳酸氫 鈉(542 mg,6.45 mmol),於氮氣氛圍下懸浮於二噚烷(8 mL)和水(2 mL)之混合溶液。所得混合液於微波爐1201照 射1小時。於反應液添加水和乙酸乙酯來萃取後,有機 層以飽和碳酸氫鈉水溶液和飽和食鹽水洗淨,以硫酸鎂乾 燥。減壓蒸除溶劑,殘渣以柱層析精製’得化合物59(464 mg,1.67 mmol)。 化合物 59; l-NMR^CDCUM: 2.93(s,3H),7.14-7.21(m, 2H), 7.34(d, J = 8.2 Hz, 1H), 7.45-7.52(m, 2H), 7.77(d, J =8.2 Hz, 1H). (實施例21)
THF
MeMgBe, Fe(acac)3 NMP 將 6-溴-2-氯苯并噻唑 1(15 g,60.4 mmol)和 Fe(acac)3 (1·〇7 g,3·02 mmol)溶解於四氫呋喃(200 mL)和 NMP(20 mL)之混合液。所得混合物於0 °C加3M甲基溴化鎂乙醚 溶液(24.14 ml, 7 2.4 mmol),於室溫攪拌1.5小時。於反應 液添加3M甲基溴化鎂乙醚溶液(10.1 ml,30.2 mmol),更 於室溫攪拌1小時》於反應液添加IN鹽酸水和乙酸乙酯 來萃取後,有機層以飽和食鹽水洗淨,以硫酸鎂乾燥。減 壓蒸除溶劑,殘渣以柱層析精製,得化合物53(10.6 g, 46.5 mmol)。 -112- 201021798 化合物 53; W-NMIUCDChH: 2.82(s,3H),7.54(dd,J = 8.7, 2.0 Hz, 1H), 7.80(d, J = 8.7 Hz, 1H), 7.95(d, J = 2.0 Hz, 1H). (實施例22)
4-溴-2-氯苯胺 60(2.50g, 12.11 mmol)之乙酸 25 ml 溶
〇 液於室溫加硫氰酸鉀(4.71 g,48.4 mmol)後,於室溫下以 15分滴下溴(1.25 ml, 24·22 mmol)之乙酸5ml溶液。滴下 終了後,於室溫攪拌15分鐘,更於3 OC攪拌1小時。反 應終了後,冰冷下以氫氧化鈉水溶液中和,以乙酸乙酯萃 取。有機層以飽和碳酸氫鈉水和飽和食鹽水洗淨,以硫酸 鈉乾燥。減壓蒸除溶劑,所得殘渣以乙酸乙酯:二異丙醚 濾取而得化合物61(2.02 g,產率43.3%)黄色固體》 化合物 61 ; W-NMI^DMSO-cUW : 7.48(dd,J = 2.1,0.9 Hz, 1H), 7.89(dd, J = 2.7,1.8 Hz, 1H), 7.97(brs, 2H). 於氮氣流下將氯化銅(11)(1.78 g,13.20 mmol)懸浮於乙 腈29 1111,於冰冷下添加硝酸異戊酯(2.221111,16.51111111〇1) ,以1〇分加2-胺基-6-溴-4-氯苯并[d]噻唑 61(2.90 g, 11.00 mmol),於室溫攪拌10分鐘後,加熱60°C2小時。 反應終了後,添加2N鹽酸,以乙酸乙酯萃取。有機層以 水和飽和食鹽水洗淨,以硫酸鈉乾燥。減壓蒸除溶劑,所 得殘渣以層析(己烷:乙酸乙酯=4: 1)精製,得化合物 62(1.60g,產率 5 1.4%)。 -113- 201021798 化合物 62 ; iH-NMi^DMSO-deW : 7.93(d,J = 1.8 Hz,1H), 8.40(d, J = 1 .8 Hz, 1H). (實施例23)
63 64 65 4-溴-2·氟苯胺 63(5.0 g, 26.30 mmol)之乙酸50 ml溶液 於室溫加硫氰酸鉀(10.23 g, 105.00 mmol)後,於室溫以15 分鐘滴下溴(2.71 ml,52.60 mmol)之乙酸12ml溶液。滴 下終了後,於室溫攪拌2小時。反應終了後,冰冷下以氫 氧化鈉水溶液中和,以乙酸乙酯萃取。有機層以飽和碳酸 氫鈉水和飽和食鹽水洗淨,以硫酸鈉乾燥。減壓蒸除溶劑 ,所得殘渣以層析(氯仿:甲醇=20 : 1)精製,得化合物 -64(3.67g,產率56.1%)黄色固體。 化合物 64; 'H-NMRCDMSO-deJS : 7.35(dd, J = 10.5,1.8
Hz, 1H), 7.77(d, J = 2.1 Hz, 1H), 7.84(brs, 2H). 於氮氣流下將氯化銅(11)(645 mg,4.80 mmol)懸浮於乙腈 10 ml和N -甲基-2-B比嗜Π定酮2 ml,於冰冷下添加硝酸異 戊酯(0.81 ml,6.00 mmol)’以1〇分加2-胺基-6-溴-4-氟苯 并[d]噻哩 64(988 mg,4.00 mmol)’於室溫攪拌1〇分鐘後 ,於60°C加熱1小時。反應終了後,添加2N鹽酸,以乙 酸乙酯萃取。有機層以水和飽和食鹽水洗淨,以硫酸鈉乾 燥。減壓蒸除溶劑,所得殘渣以層析(氯仿)精製,得化合 物65 (3.67g,產率56.1%)黄色固體。 -114- 201021798 化合物 65; iH-NMR^DMSO-dja: 7.78(dd,J = 10.2,1.8 Hz, 1H), 8.27(dd, J = 1.5, 0.6 Hz, 1H). (實施例24)
於2-胺基-3,5-二溴吡啶 66(5.0 g,19.85 mmol)之丙酮 50 ml溶液冰冷下滴下異氰酸苄醯酯(3.83 ml,28.5 mmol) ,於室溫下攪拌18小時。濾取沈澱之固體,以己烷洗淨 。將所得粗生成物減壓乾燥,得化合物67(7.30g,產率 83.0%)白色固體。 化合物 67 ; iH-NMR^DMSO-dJS : 7.56(t, J = 7.8 Hz, 2H), 7.68(t, J = 5.7 Hz, 1H), 8.00(d, J = 7.5 Hz, 2H), 8.59(d, J =1.5 Hz, 1H), 8.67(d, J = 2.1 Hz, 1H), 11.89(s, 1H), 12.38(s, 1H). 將N-(3,5-二溴吡啶-2-基胺甲硫醯基)苄醯胺 67(7.3 0g, 17.59 mmol)於懸浮於甲醇8 ml,添加2N氫氧化鈉水溶液 (70_3 ml,175 mmol)而加熱回流1小時。反應終了後,於 -115- 201021798 室溫放冷,濾取沈澱而水洗。將所得粗生成物減壓乾燥’ 得化合物68(5.10 g,產率 93%)白色固體。 化合物 68 ; W-NMR^DMSO-cUe : 8.43(d,J = 2.4 Hz,1H), 8.52(d, J = 2.1Hz, 1H), 8.61(brs, 1 H), 9 · 3 2 (b r s,1 H), 9.69(brs, 1H). 於60%氫化鈉(2.03 g,50.80 mmol)之二甲基甲醯胺75 ml溶液冰冷下以15分鐘加l-(3,5-二溴吡啶-2-基)硫脲 6 8(5.10 g,16.40 mmol),於室溫下攪拌 15分鐘後,於 8〇°C攪拌3小時。反應終了後,冷却而添加飽和氯化銨和 水來攪拌30分鐘,濾取沈澱而水洗。將所得粗生成物減 壓乾燥,得黄色固體之化合物69(3.0g,產率80%)。 化合物 69 ; iH-NMR^DMSO-dJS : 8.1 1 (brs,2H),8.28(dd, J = 2.4, 0.9 Hz, 1H), 8.32(dd, J = 2.4, 0.9 Hz, 1H). 於氮氣流下將氯化銅(11)(2.10g,15.65 mmol)懸浮於N-甲基-2-吡咯啶酮 30 ml,冰冷下添加硝酸異戊酯(2.63 ml, 19.56 mmol),以 10分加 6-溴噻唑并[4,5-b]吡啶-2-胺 69(3.00 g,13.04 mmol),於室溫攪拌10分鐘後,於60C 加熱1小時。反應終了後,添加2N鹽酸,以乙酸乙酯萃 取。有機層以水和飽和食鹽水洗淨,以硫酸鈉乾燥。減壓 蒸除溶劑,所得殘渣以層析(氯仿:甲醇=30 : 1)精製,得 化合物70(1.50g,產率46.1%)黄色固體。 化合物 70 ; iH-NMIUDMSO-ddS : 8.81(d,J = 2.4 Hz,1H), 8.9〇(d, J = 2.4 Hz, 1H). 於氮氣流下,2M NaHMDS 四氫呋喃溶液(0.464 ml, -116- 201021798 0.882 mmol)之無水甲苯2.5 mL溶液於_6〇°C以i〇分鐘滴 下乙酸乙酯(0.043 ml, 0.88 mmol)。其後於-6〇°c攪拌1小 時後,滴下6·溴-2-氯噻唑并[4,5-b]吡啶 70(100 mg, 0.401 mmol)之無水四氫肤喃 8 ml和甲苯2.5 ml溶液。 滴下終了後,於〇°C 攪拌2小時。 於反應液添加飽和氯化銨及乙酸乙酯來萃取後,有機層 以飽和食鹽水洗淨’以硫酸鎂乾燥。減壓蒸除溶劑,殘渣 以層析(氯仿:甲醇=20 : 1)精製,得化合物71 :
71’(mix)(107mg,產率 89.0%)黄色固體。 化合物 71 : 71’(mix) ; e-NMR^DMSO-deM : l.l9(t,J = 6.3 Hz, 2H), 1.24(t, J = 6.3 Hz, 3H), 4.07(q, J = 6.8 Hz, 2H), 4.18(q, J = 6.8 Hz, 2H), 4.42(s, 2H), 5.41(s, 1H), 8.21(d, J = 2.1 Hz, 1H), 8.25(d, J = 2.1 Hz, 1H), 8.77(d, J =2.1 Hz, 1H), 8.93(d5 J = 2.1 Hz, 1 H) 1 2.4 2 (b rs, 1H).
(實施例25)
CuOl2 xxs>-c,
Br, 、N, 、s 75 r\
50ml溶液,添加異氰酸乙酯(2.31 ml, 19_6 mmol) ’於 100C加熱回流10分,添加甲醇8ml後’於80t:攪拌30 0 201021798 分鐘。冷却而濾取沈澱之固體,以水:甲醇(2: 1)洗淨》 將所得粗生成物減壓乾燥,得化合物73(48 7mg,產率 82.0%)茶色固體。 化合物 73 ; iH-NMRiDMSO-deH : 1.30(t,.J = 7.2 Hz,3H), 4.30(q, J = 1.2 Hz, 2H), 8.72(d, J = 1.2 Hz, 1H), 12.75(brs, 1H). 將6-溴噻唑并[4,5-b]吡畊-2-基胺甲酸乙酯 73(480 mg, 1.5 8 mmol)懸浮於甲醇8 ml,添加2N氫氧化鈉水溶液 (7.91 ml,15.83 mmol)而加熱回流5小時。反應終了後, 以2N鹽酸作成酸性,次以飽和碳酸氫化鈉中和後,以乙 酸乙酯萃取。有機層以飽和碳酸氫鈉水和飽和食鹽水洗淨 ,以硫酸鈉乾燥。減壓蒸除溶劑,濾取析出之不溶物,得 化合物7 4(334mg,產率91.0%)白黄色固體。 化合物 74 ; 1H-NMR(DMSO-d6)5 : 8.37(s, 1H), 8.59(brs, 2H). 於氮氣流下,將氯化銅(II)(2.17g, 16.20 mmol)懸浮於 N-甲基-2-吡咯啶酮30 ml,於冰冷下添加硝酸異戊酯(2.73 ml, 20.25 mmol),以10分鐘加2-胺基-6-溴噻唑并[4,5-b] 吡阱 74(3.12 g, 13.50 mmol),於室溫下攪拌1〇分鐘後, 於6 Ot:加熱1小時。反應終了後,添加2N鹽酸,以乙酸 乙酯萃取。有機層以水和飽和食鹽水洗淨,以硫酸鈉乾燥 。減壓蒸除溶劑,所得殘渣以層析(氯仿)精製,得化合物 75(3.67g,產率56.1%)黄色固體。 化合物 75 ; iH-NMI^DMSO-ddS : 8.99(d,J = 0·9 Hz,1H). -118- 201021798 於氮氣流下’ 2M之NaHMDS四氫呋喃溶液(3.700 ml, 7.03 mmol)之無水甲苯8.0 mL溶液於-60°C以10分鐘滴 下乙酸乙醋(0.34 ml, 3.51 mmol)。其後於-60 °C 攪拌1小 時後,滴下6-溴-2-氯噻唑并[4,5-b]吡畊 75(800 mg, 3.19 mmol)之無水四氫呋喃8 ml和甲苯8.0 ml溶液。滴下終 了後,於-60°C攪拌1小時。 於反應液添加飽和氯化銨及乙酸乙酯來萃取後’有機層 以飽和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶劑’殘渣 以層析(氯仿:甲醇=20 : 1)精製,得黄色固體 76 : 76’ (mix)(650mg,產率 67.4%)。 化合物 76、76’(mix); iH-NMR^DMSO-dja: 1.21(t,J = 6.4 Hz, 3H), 1.24(t, J = 6.4 Hz, 3H), 4.11(q, J = 6.4 Hz, 2H), 4.20(q, J = 6.4 Hz, 2H), 4.48(s, 2H), 5.25(s, 1H), 8.25(s, 1H), 8.94(s, 1H), 12.75(brs, 1H). (實施例26)
將化合物77(300 mg, 1.45 mmol)乙酸20 mL溶液於室溫 加硫氰酸鉀(565 mg, 5.81 mmol)後’於冰冷下徐徐滴下溴 (0.112 mL, 2.18 mmol)之乙酸4 mL溶液。滴下終了後,昇 溫至室溫而攪拌3小時。反應終了後’冰冷下以氫氧化鈉 水溶液中和,以乙酸乙酯萃取。有機層以飽和碳酸氫鈉水 和飽和食鹽水洗淨,以硫酸鈉乾燥。減壓蒸除溶劑,所得 殘渣以層析(己烷:乙酸乙酯=1 : 1)精製,得化合物78及 -119- 201021798 化合物79之1: 1混合物白色固體(190mg)。 化合物 78 ; W-NMR^DMSO-dJS : 7.22(d,J = 8.11 Hz, 1H), 7.52(s, 1H), 7.55(d, J = 8.11 Hz, 1H), 7.81(s, 2H), 7.86(s, 2H), 8.09(s, 1H). (實施例27)
83 於化合物80(5 g, 24.8 mmol)之丙酮150mL溶液添加異 氰酸苄醯酯(3.83 mL,28.5 mmol) ’於冰冷下攪拌60分鐘 。濾取生成之固體後,以乙醚洗淨。將所得粗生成物減壓 乾燥,得化合物81(8.1 g,90%)白色固體。 化合物 81 ; 1H-NMR(DMSO-d6)5 : 3.8 6 ( s,3 Η), 7.2 7 (m, 1H), 7.52-7.70(m, 5H), 7.98(d, J = 8.11 Hz, 2H), 11.64(s, 1H), 12.64(s, 1H). 將化合物 81(8 g, 21.9 mmol)懸浮於甲醇80 ml,添加 2N氫氧化鈉水溶液(88 mL,175 mmol)而加熱回流2小時 。反應終了後,放冷至室溫,減壓蒸除甲醇’濾取生成之 不溶物而水洗。將所得粗生成物減壓乾燥’得化合物 82(5.3 g,93%)白色固體。 化合物 82; iH-NMR^DMSO-deM: 3.82(s,3H),6.90(dd,J =8.62, 2.03 Hz, 1H), 7.36(d, J = 2.03 Hz, 1H), 7.47(d, J = -120- 201021798 8.62 Hz, 1H), 9.77(s, 1H).
於化合物82(5 g, 19.15 mmol)之乙酸75 mL懸浮液’冰 冷下,徐徐滴下溴(0.987 mL, 19.15 mmol)之乙酸15 mL溶 液。滴下終了後,於室溫攪拌1小時,昇溫至5〇°C ’更攪 拌1小時。反應終了後,冰冷下以氫氧化鈉水溶液中和’ 以乙酸乙酯萃取。有機層以飽和碳酸氫鈉水和飽和食鹽水 洗淨,以硫酸鈉乾燥。減壓蒸除溶劑,所得殘渣懸浮於乙 酸乙酯50 mL而攪拌1小時後,濾取而得化合物83(4.73 g, 95%)白色固體。 化合物 83 ; e-NMIUDMSO-deW : 3.83(s,3H),7.06(s, 1H), 7.56(brs, 2H), 7.83(s, 1H).
(實施例28) h2n
34 84 85 將化合物34(3 50 mg,1.46 mmol)之濃鹽酸2 mL水溶液 以2 mL水稀釋後,於冰冷下滴下亞硝酸鈉(111 mg,1.60 mmol)水溶液2 mL而攪拌30分鐘。徐徐滴下碘化鉀(3.6 3 g,21.85 mmol)水溶液10 mL後,昇溫爲室溫而攪拌1小 時。將反應液於冰冷下以氫氧化鈉水溶液中和後,以氯仿 萃取。有機層以1 0%硫代硫酸鈉水溶液、飽和食鹽水洗淨 ,以硫酸鎂乾燥。減壓蒸除溶劑,所得殘渣以矽膠柱層析 (己烷:乙酸乙酯=4 : 1)精製,得化合物84(360 mg,70%) 白色固體。 化合物 84 ; iH-NMR^DMSO-dJS : 2.82(s,3H), 7.34- -121- 201021798 7.50(m, 5H), 8.03(s, 1H), 8.49(s, 1H).
於碘化銅(1)(191 mg,1.00 mmol)之DMF 1.5 mL懸浮液添 加2,2-二氟-2-(氟磺醯基)乙酸甲酯(0.403 mL,3,19 mmol) 、滴下化合物84(320 mg,0.911 mmol)之DMF3 mL溶液後 ,於1 20t加熱攪拌1小時。反應液以飽和氯化銨水溶液 驟冷後,以乙酸乙酯萃取,有機層以水、飽和食鹽水洗淨 。減壓蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙 酯=4 : 1)精製,得化合物85( 1 80 mg, 67%)白色固體。 化合物 7.40(m, 2H), 7.43-7.48(m, 3H), 8.13(s, 1H), 8.32(s, 1H). (實施例29)
於化合物86(8.2 g, 40.6 mmol)之丙酮250 mL溶液,添 加異硫氰酸苄醯酯(6.27 mL,46.7 mmol),於冰冷下攪拌 60分鐘。濾取生成之固體後’以乙醚洗淨。將所得粗生成 物減壓乾燥,得化合物87(12.7 g,86%)白色固體。 化合物 87; W-NMR^DMSO-dsN: 3.88(s,3H),7.16(d,J = 8.62 Hz, 1H), 7.52-7.58(m, 3H), 7.67(m, 1H), 7.96-8.00(m, 3H), 11.58(s, 1H), 12.43(s, 1H). 將化合物87(12.7 g,34.8 mmol)懸浮於甲醇120 ml’添 -122- 201021798 加2N氫氧化鈉水溶液(139 mL,278 mmol),加熱回流2小 時。反應終了後,放冷至室溫,減壓蒸除溶劑甲醇,據取 生成之不溶物而水洗。將所得粗生成物減壓乾燥,得化合 物88(8.72 g,96%)白色固體。 化合物 88 ; e-NMR^DMSO-dja : 3.82(s,3H),7.07(d,J = 9.12 Hz, 1H),7.27(dd, J = 9.12, 2.03 Hz, 1H), 7.64(d, J = 2.03 Hz, 1H), 9.54(s, 1H).
於化合物88(3 g,11.49 mmol)之乙酸60 mL懸浮液,冰 冷下徐徐滴下溴(0.651 mL,12.64 mmol)之乙酸12 mL溶液 。滴下終了後,昇溫至50尤而攪拌4小時。反應終了後, 冰冷下以氫氧化鈉水溶液中和,以乙酸乙酯萃取。有機層 以飽和碳酸氫鈉水和飽和食鹽水洗淨,以硫酸鈉乾燥。減 壓蒸除溶劑,所得殘渣懸浮於乙酸乙酯30 mL而攪拌1小 時後,濾取而得化合物89(2.18 g,73%)白色固體。 化合物 89; 1H-NMR(DMSO-d6)a : 3.81(s,3H),7,41(brs, 2H), 7.50(s, 1H), 7.51(s, 1H). (實施例30)
-NH^ 於 1M LHMDS/四氫呋喃溶液(18.5 mL, 18.5 mmol),將 -123- 201021798 化合物90( 1 · 5 g,8.42 mmol)之四氫呋喃 15 mL溶液於-60°C徐徐滴下而攪拌30分鐘。於此反應液添加碳酸二乙酯 (1.23 mL,10.11 mmol),昇溫爲〇°C而攪拌4小時。反應終 了後,以飽和氯化銨水溶液驟冷而以乙酸乙酯萃取。有機 層以飽和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶劑,所 得殘渣以矽膠柱層析(己烷:乙酸乙酯=4 : 1)精製,得化合 物9 1 (900 mg, 43%)黄色油狀物質。 化合物 91 ; LC/MS Rt=1.86 min,MS : 25 1.8 5(M+1),方法:
於化合物91(900 mg,3.60 mmol)之四氫呋喃 9.0 ml和 乙醇 4.5 mL溶液添加2N氫氧化鈉水溶液(2.0mL,3.96 mmol),於室溫攪拌2小時》反應終了後,減壓蒸除溶劑 ,所得殘渣溶解於DMF 9.0 mL,順次加H-Gly-OtBu鹽酸 鹽(905 mg,5.40 mmol)、HATU(2.1 g,5.40 mmol)、Π比陡 (0.871 mL,10.80 mmol),於室溫攪拌3小時。反應終了後 ,以1 〇%檸檬酸水溶液驟冷,以乙酸乙酯萃取。有機層以 飽和碳酸氫鈉水、飽和食鹽水洗淨,以硫酸鎂乾燥。減壓 蒸除溶劑,所得殘渣以矽膠柱層析(己烷:乙酸乙酯=1 : 1) 精製,得化合物92(264 mg,22%)黄色油狀物質。 化合物 92 ; LC/MS Rt=1.81 min,MS : 336.95(M+1),方法:
C 於化合物92(230 mg,0.686 mmol)之二噚烷3mL溶液, 添加(E)-苯乙烯基硼酸(152 mg,1.029 mmol)、肆(三苯膦) 餓(55.5 mg,0.048 mmol)和 3M 碳酸鉀水溶液(0.686 mL、 -124- 201021798 1 2.0 5 8 mmol),於微波照射下12〇°C攪拌25分鐘。反應終 了後’不溶物以矽藻土過濾,將濾液以乙酸乙酯萃取。有 機層以水、飽和食鹽水洗淨,以硫酸鎂乾燥。減壓蒸除溶 劑’所得殘渣以矽膠柱層析(己烷:乙酸乙酯=1 : 1)精製, 得化合物93(70 mg,29%)黄色油狀物質。 化合物 93; iH-NMRCCDClsM: 1.47(s,9H),3.96-3.99(m, 4H), 6.86(d, J = 16.22 Hz, 1H), 7.16(d, J = 16.22 Hz, 1H), 7.28-7.40(m, 3H), 7.44-7.50(m, 3H), 7.68(s, 1H).
以下列示之化合物也同樣合成。就各化合物列示NMR或 LC/MS之測定結果。 (註:以下【表2】至【表128】的第1列標題與【表1】所示 相同,其中『化合物番号』意指『化合物編號』;『retention time』意指『留存時間』;『Mass』意指『質量』;『method 』意指『方法』) -125- 201021798 【表1】 化合物 編號 構造式 NMR(i5) 留存 時間 質量 方法 11-1-5 ° co2h 1H-NMR (DMSO-d6) δ : 4.16 (s. 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.38-7.56 (m, 5H), 7.72-7.78 (m, 3H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 1.0 Hz, 1H), 8.94 (t, J = 5.8 Hz, 1H). 12.95 (brs, 1H). 11-1-6 1H-NMR (DMS0-d6) δ : 4.14 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.88-7.90 (m, 2H), 8.36 (d, J = 2.0 Hz, 1H), 8.94 (t. J = 5.8 Hz, 1H), 12.93 (brs, 1H). ft 11-1-7 F3Cja^:">^0H 1H-NMR (DMSO-d6) δ : 4.17 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.82-7.88 (m, 4H), 7.91 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 8.07 (d, J = 8.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.96 (brs, 1H). 11-1-8 1H-NMR (DMS0-d6) δ : 3.99 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.34-7.41 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.68-7.73 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H). 8.91 (t. J = 5.8 Hz, 1H), 12.97 (br s. 1H). f 11-1-9 1H-NMR (DMS0-d6) <5 1.84 (s, 3H). 4.35 (d, J = 6.6 Hz, 2H). 7.19 (brs, 1H). 7.39 - 7.42 (m, 2H). 7.46 -7.53 (m, 3H)_ 7.75 - 7.87 (m, 5H). 8.05 (d, J = 8.7Hz,1H). 8.38 (d, J = 1.5 Hz, 1H). 8.82 (t, J = 5.7 Hz 1H). 12.89 (brs, 1H). -126- 201021798 【表2】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-10 1H-NMR (DMS〇-d6) δ : 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H). 7.46 (t J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.71-7.77 (m, 2H), 7.82-7.91 (m, 3H), 8.04-8.10 (m, 3H), 8.51 (s, 1H), 8.95 (t J = 5.8 Hz, 1H), 12.97 (br s, 1H). IM-11 〇 so2nh2 1H-NMR (DMS0-d6) δ : 4.16 (s, 2H), 4.43 (d, J = 5.5 Hz, 2H), 7.39 (t, J = 7.6 Hz. 3H), 7.51 (m, 4H), 7.76 (m, 5H). 8.03 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.99 (s. 1H). 11-1-12 〇γ^^ν^〇η 1H-NMR (DMS0-d6) 5;1.72(s, 6H), 4.34 (d, J = 5.1Hz, 2H), 7.40-7.53(m,5H).7.73-7.87(m,5H),8.05(d,J=8.4Hz, 1H),8.38- 8.42(m,2H),12.89(brs,1H). II-M3 0、 OH O J—NH 1H-NMR (DMS0-d6) δ : 4.16 (s. 2H). 4.39 (d, J = 5.9 Hz, 2H), 7.52-7.37 (m, 5H), 7.62 (d, J = 7.4 Hz, 1H), 7.81-7.72 (m, 4H), 8.02 (d, J = 8.6 Hz, 1H). 8.38 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 5.9 Hz. 1H). 9.04 (s. 1H), 11.21 (s, 1H). 11-1-14 0. 0 V-OH 1H-NMR (DMS0-d6) δ 4.21 (s, 2H), 4.51 (d. J = 5.7 Hz, 2H), 7.39-7.50 (m 3H). 7.65 (d, J = 5.4 Hz 1H), 7.76-7.80 (m, 3H) 8.04-8.07 (m, 2H), 8.39 (s 1H), 8.69 (d, J = 5.5 Hz 1H), 9.12 (s, 1H). -127- 201021798 【表3】 化番合号物 構造式 retention time
Mass method IM-15
1H-NMR (DMSO-d6) δ : 1.59-1.65 (m, 2H), 1.72-1.78 (m, 2H). 2.18-2.24 (m, 2H), 2.41-2.45 (m, 2H), 4.10 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.26 (br s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.53-7.57 (m, 2H), 7.81- 7.90 (m, 3H), 8.05 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 12.95 (br s, 1H) 11-1-16
MeO'
1H-NMR (DMS0-d6) δ 3.81 (s, 3H). 4.14 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.46 (t, J = 7.6 Hz. 1H). 7.55 (d, J = 7.6 Hz, 1H), 7.68-7.75 (m, 3H), 7.83 (d =7.6 Hz, 1H), 7.91 (s. 1H), 7.98 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.93 (t, J = 5.8 Hz, 1H). 12.97 (br s, 1H).
NMe2 1H-NMR (DMSO-d6) δ : 2.85 (br s, 3H). 2.95 (br s, 3H), 4.15 (s, 2H), 4.39 (d, J 6.1 Hz. 2H), 7.26-7.41 (m, 5H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H). 8.38 (s, 1H), 8.91 (t, J = 5.8 Hz, 1H). 11-1-18
NHMe 1H-NMR (DMSO-d6) <5 2.78 (d, J = 4.6 Hz, 3H), 4.15 (s, 2H), 4.39 (d. J 5.6 Hz, 2H), 7.37-7.52 (m, 5H), 7.69-7.81 (m, 5H), 8.02 (d, J = 8.1 Hz, 1H) 8.38-8.42 (m, 2H). 8.91 (t J = 5.8 Hz, 1H). 11-1-19
1H-NMR (DMSO-d6) δ : 4.16 (s, 2H), 4.40 (br s, 2H), 7.36-7.52 (m, 6H), 7.75-7.83 (m, 5H), 7.96 (br s, 1H), 8.03 (dd, J = 8.1, 3.5 Hz, 1H), 8.38 (s, 1H), 8.90 (br s, 1H). -128- 201021798【表4】
化合物 番号 構造式 NMR(«5) retention time Mass method 11-1-20 1H-NMR (DMS0-d6) δ : 3.55 (s, 2H), 4.31 (s, 2H), 6.98 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.38-7.55 (m. 5H), 7.72-7.81 (m, 3H), 8.04 (d, J = 8.6Hz, 1H), 8.40 (s, 1H), 10.46 (s, 1H), 12.35 (br s, 1H). 11-1-21 1H-NMR (DMS0-d6) <5 : 3.22 (s, 3H), 3.49 (s, 3H), 4.15 (s, 2H), 4.40 (d. J = 5.4 Hz, 2H), 7.42-7.50 (m, 7H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.92-8.95 (br m, 1H). 11-1-22 0、 0- 〇 Vnh 1H-NMR (DMSO-d6) δ : 3.70 (s, 3H), 4.16 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 7.40-7.49 (m, 5H), 7.61 (d, J = 7.1 Hz. 1H), 7.73-7.79 (m. 4H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H). 8.90-8.93 (br m, 1H), 11.74 (s, 1H). 11-1-23 1H-NMR (DMS0-d6) <5 ;4.29(s,2H),4.44(d.J=6.0H z,2H),7.47(t,J=7.5Hz,1H),7.5 6(d.J=7.8Hz,1H).7.83(d,J=7. 8Hz,1H), 7.90(s,1H),8.06(d,J=8.4Hz,1 H),8.62(d,J=8.4Hz,1H),9.01( t,J=5.7Hz,1H),12.97(brs,1H) 11-1-24 0 %-NH N 1H-NMR (DMS0-d6) δ 2.38 (d, J = 5.0 Hz, 3H) 4.16 (s, 2H). 4.44 (d, J = 6.2 Hz, 2H), 7.39-7.81 (m 10H), 8.02 (d, J = 8.7 Hz 1H), 8.37 (s, 1H), 8.97-9.01 (br m, 1H). -129- 201021798【表5】 化合物 番号 構造式 NMR(d) retention time
Mass method
1H-NMR (DMSO-d6) δ : 2.54 (s. 6H), 4.16 (s. 2H), 4.46 (d. J = 5.9 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.63-7.67 (m, 4H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.98-9.00 (br m, 1H). 11-1-26
1H-NMR (CDCI3) δ: 1.55 (s. 9H), 3.97 (s. 2H), 4.48 (d, J = 5.6 Hz, 2H), 4.76 (br s, 2H), 7.18 (dd, J = 8.6, 2.0 Hz, 1H), 7.28-7.55 (m, 4H), 8.03-7.81 (m, 3H). 1.84 400.30 (ES+) 〇
OH 1H-NMR (DMS0-d6) δ : 3.19 (s, 3H), 4.17 (s, 2H). 4.47 (d. J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H). 7.61-7.68 (m, 2H), 7.74-7.83 (m, 4H), 7.88 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.00 (t, J = 5.8 Hz. 1H). 1H-NMR (DMS0-d6) δ : 4.17 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.41-7.49 (m. 3H), 7.56 (d. J = 7.6 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.82-7.88 (m, 2H), 7.92 (s, 1H), 8.00-8.02 (m, 2H), 8.95 (t. J = 5.6 Hz, 1H). 12.97 (br s, 1H). 11-1-29
1H-NMR (DMS0-d6) δ : 4.14 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 7.06 (d, J = 3.9 Hz, 1H), 7.39-7.81 (m, 7H), 8.00-8.03 (m, 1H), 8.39 (s. 1H), 9.06-9.09 (br m. 1H). -130- 201021798【表6】
化合物 番号 構造式 NMR(5) retention time Mass method 11-1-30 1H-NMR (DMS0-d6) δ : 1.24-1.82 (m, 10Η), 2.6〇-2.67 (m, 1Η), 4.09 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.35 (dd, J = 8.4, 1.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.81-7.90 (m, 4H), 8.90 (t, J = 5.8 Hz. 1H). IM-31 0 /-NH HN—\ 1H-NMR (DMSO-d6) 5 : 3.80 (dd, J = 19.3, 5.6 Hz, 4H), 4.15 (s, 2H), 7.34-7.53 (m, 3H), 7.69-7.82 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H). 8.28 (s, 1H), 8.38 (d, J = 10.0 Hz, 1H), 8.67 (s, 1H). 1.64 384.00 (ES+) C IM-32 1H-NMR (CDCI3) δ : 3.74 (s, 3H), 4.08 (dd, J = 7.4, 5.8 Hz, 4H), 4.15 (s, 2H), 6.79 (s, 1H), 7.26 (s. 2H), 7.34-7.52 (m. 3H). 7.60-7.76 (m. 3H), 7.87 (s, 1H), 8.09-8.00 (m, 2H). IM-33 1H-NMR (DMS0-d6) δ ; 4.20(s,2H), 4.42(d,J = 6.0Hz, 2H), 7.45-7.57(m, 4H), 7.92(s ,1H), 8.15-8.18(m, 3H), 8.41 (d,J = 8.4Hz, 1H) 8.97(t,J = 5.7Hz, 1H), 12.99(brs, 1H), 11-1-34 1H-NMR (CDCI3) (5: 4.13 (s, 2H), 4.53 (s, J = 5.7Hz, 2H), 7.25-7.49 (m. 9H) 7.61-7.65 (m, 2H), 7.71 (d J = 1.8, 8.7 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H), 8.06(s 1H) -131- 201021798 【表7】 化合物 番号 構造式 NMR(S) retention time Mass method IM-35 1H-NMR (CDCI3) <5: 2.91 (t, J = 7.1 Hz, 2H), 3.66-3.72 (m, 2H), 4.13 (s, 2H), 4.54 (d, J = 6.1 Hz, 2H), 6.15 (s, 1H), 7.21-7.49 (m, 10H), 7.56-7.72 (m, 6H), 8.01 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H). 11-1-36 1.93 421,42 (ES+) A 11-1-37 Ί1 1.61 446.45 (ES+) A 11-1-38 丨 σ 2.07 429.45 (ES+) A c 11-1-39 1H-NMR (DMSO-d6) <5 4.22(s,2H),4.42(d.J=5.7Hz,2 H),7.34(dd,J=8.4Hz,1 H),7.83 (d,J=7.8Hz,1H),7.92(s,1H),8. 21(d, J=8.4Hz, 1 H),8.46(d, J=8.4Hz ,1H),8.69-8.76(m,1H),8.69-8.76(m1H),8.98-9.01(m,2H),12.81(brs,1H). -132- 201021798【表8】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-40 1H-NMR (DMSO-d6) δ ; 4.189(s,2H),4.43(d,J=6.9Hz, 2H),7.36(t,J=7.2H2,2H),7.56 (d,J=7.8Hz,1 H),7.83(d.J=7.8 Hz,1H),7.92(s,1H). 8.13(d,J=8.4Hz,1H).8.22(d,J 6.6Hz,1H),6.23(d,J=,6.6Hz,1 H),8.40(d,J=8.4Hz.1H),8.99( tJ=6.0Hz,1H),12.99(brs,1H) .(s, 2H), 8.37 (d, J = 7.2Hz, 1H), 12.53 (s, 1H) 11-1-41 0 1H-NMR (DMSO-d6) δ : 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.47 (dd, J = 7.6. 8.1 Hz, 1H), 7.56 (d, J =7.6 Hz, 1H), 7.80-7.93 (m. 5H). 8.00-8.08 (m, 3H). 8.48 (d. J = 1.5 Hz, 1H), 8.95 (t, J = 5.6 Hz, 1H), 12.99 (brs, 2H). 11-1-42 χ° 1H-NMR (DMS0-d6) δ : 3.32(s, 3H), 4.18 (s, 2H), 4.42 (d. J = 5.7 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 6.6Hz. 1H), 7.75-7.96 (m, 5H). 8.10 (dd, J = 7.5, 15Hz, 3H), 8.27 (s, 1H), 8.53 (s, 1H), 8.97(m, 1H). 11-1-43 0 0 V〇H 1H-NMR (DMS0-d6) δ : 4.15 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 6.80 (dd, J = 2.0· 7.6 Hz. 1H). 7.08-7.18 (m, 2H), 7.28 (dd, J = 7.6, 8.1Hz, 1H), 7.47 (dd. J = 7.6, 8.1 Hz, 1H). 7.56 (d. J =7.6 Hz, 1H), 7.71 (dd, J = 2.0, 8.1 Hz, 1H), 7.84 (d, J =8.1 Hz, 1H), 7.91 (s. 1H), 8.00 (d, J = 8.6 Hz. 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.94 (t, J = 5.6 Hz, 1H), 9.57 (brs, 1H), 13.00 (brs, 1H). 11-1-44 〇Γ^>^°Η 1H-NMR (DMSO-d6) 6 4.18 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H). 7.46 (t, J = 7.6 Hz, 1H), 7.55 (d. J = 7.6 Hz, 1H), 7.79-7.84 (m, 3H), 7.90-7.94 (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 8.57 (d, J =1.5 Hz, 1H), 8.67 (d, J = 6.1 Hz, 2H), 8.96 (t, J = 5.8 Hz, 1H), 12.97 (brs, 1H). -133- 201021798 【表9】 化合物 番号 構造式 NMR(5) retention time Mass method 11-1-45 〇、 V〇H HO人0 1H-NMR (DMSO-d6) δ : 4.16 (s, 2Η), 4.42 (d, J = 6.1 Hz, 2H), 7.47 (dd, J = 7.6. 8.1 Hz, 1H), 7.56 (d, J =7.6 Hz, 1H). 7.64 (dd, J = 7.6, 8.1 Hz, 1H), 7.79-7.86 (m, 2H). 7.91(s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.99-8.07 (m, 2H). 8.27 (m, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 6.1 Hz, 1H), )3.03 (brs, 2H). 11-1-46 1H-NMR (DMS0-d6) <5 : 1.88 (d, J = 5.6 Hz, 3H), 4.10 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.40 (dt, J = 16.9, 5.4 Hz, 1H), 6.53 (d, J =16.2 Hz, 1H), 7.41-7.55 (m. 3H), 7.82-7.90 (m, 3H), 8.02 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 12.95 (br s, 1H). r 11-1-47 0 0 V〇H 1H-NMR (DMS0-d6) δ : 4.17 (s, 2H), 4.41 (d, J = 6.1Hz, 2H), 7.41-7.50 (m, 3H), 7.53-7.58 (m, 1H), 7.77-7.88 (m, 4H). 7.91 (s, 1H), 8.04 (d. J = 1.5 Hz, 1H), 8.99 (t, J = 6.1 Hz. 1H). 11-1-48 ^^ν>^ν^0Λ〇η 1H-NMR (DMS0-d6) δ 4.11 (s. 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.60-7.38 (m. 3H), 7.94-7.67 (m, 4H) 9.00 (t, J = 5.8 Hz, 1H). < 11-1-49 α°:ί>^〇Η 1H-NMR (DMS0-d6) δ 2.72(m,2H),7.35(m,2H),3.77( m,2H),4.14(s,2H),4.40(d, J=6 .0Hz,2H)6.31((s,1H),7.48(t,7 •5Hz. 2H),7.55(d,J=7.5Hz,1H), 7.82(d,J=7.5Hz,2H),7.92(-7.95(m,3H),8.18d,J=1.84Hz, 1H)8.99(t,J=6.oHz,1H),9.29( brs,1H). -134- 201021798【表10】
化合物 番号 構造式 NMR(5) retention time Mass method 11-1-50 2.66 377.05 WESI C 11-1-51 0、 〇 y~〇H Η 1H-NMR (DMS0-d6) δ : 2.07 (s, 3H), 4.14 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.46 (dd, J = 7.6, 8.1 Hz. 1H), 7.52-7.58 (m. 1H), 7.70 (m, 4H), 7.76 (dd, J = 1.5, 8.6 Hz, 1H), 7.80-7.86 (m, 1H), 7.91 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H). 8.33 (d, J = 1.5 Hz, 1H), 8.94 (t. J = 5.6 Hz. 1H). 10.05 (s, 1H), 12.94 (brs, 1H). 11-1-52 ^r-NH2 1H-NMR (DMS0-d6) <5 : 4.04 (s, 2H), 7.26 (s, 1H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H). 8.38 (d, J 二 1.8 Hz, 1H). Π-1-53 ^^s>>n^^oh 1H-NMR (DMS0-d6) δ : 0.90 (t, J = 7.1 Hz, 3H), 1.59-1.69 (m, 2H), 2.68 (t, J = 7.6 Hz, 2H), 4.09 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.81-7.90 (m, 4H), 8.91 (t, J = 6.1 Hz, 1H). 11-1-54 〇、 0 V〇H 1H-NMR (DMS0-d6) δ : 3.14 (s, 6H). 4.17 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.42-7.60 (m, 5H), 7.80-7.88 (m, 2H), 7.91 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 1.5 Hz), 8.99 (t. J = 5.6 Hz, 1H). -135- 201021798 【表11】 化合物 番号 構造式 NMR(d) retention time Mass method 11-1-55 0 0 V〇H 1H-NMR (DMSO-d6) δ : 4.18 (s. 2H), 4.42 (d, J = 6.1 Hz, 2H), 7.36-7.42 (m, 1H), 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.52-7.65 (m, 2H), 7.67-7.86 (m, 4H), 7.91 (brs, 1H), 8.07 (d, J = 8.1Hz, 1H), 8.38 (d. J = 1.5 Hz, 1H), 9.01 (t. J = 6.1 Hz, 1H). 11-1-56 0. 0 V-OH 1H-NMR (DMS0-d6) δ : 2.08 (s, 3H), 4.16 (s, 2H). 4.41 (d, J = 5.6 Hz. 2H), 7.34-7.50 (m, 3H), 7.52-7.61 (m, 2H). 7.71 (dd, J = 8.1, 2.0 Hz, 2H), 7.81-7.86 (m, 1H), 7.91 (s, 1H). 7.97 (s, 1H), 8.03 (d, J = 8.6 Hz. 1H), 8.30 (d, J 二 1.5 Hz, 1H), 8.95 (t J = 5.6 Hz, 1H), 10.05 (s, 1H), 12.96 (brs, 1H). f % 11.1-57 ο^:对 1H-NMR (DMS0-d6) δ : 4.17 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H). 7.47 (dd, J = 7.6, 8.1 Hz, 1H), 7.51-7.60 (m, 3H). 7.80-7.87 (m, 1H), 7.89-7.99 (m, 4H), 8.00-8.10 (m. 3H), 8.33 (s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 8.96 (t, J = 5.6 Hz, 1H), 12.97 (brs, 1H). 11-1-58 0 0 V〇H of广d r° 1H-NMR (DMSO-d6) 6 : 0.89 (t, J = 7.1 Hz, 3H), 4.02 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H). 4.42 (d, J = 5.6 Hz, 2H), 7.37 (dd, J = 1.8, 8.4 Hz. 1H), 7.44-7.56 (m, 4H), 7.61-7.68 (m, 1H), 7.76-7.86 (m, 2H), 7.92 (s. 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.6 Hz, 1H). 12.96 (brs, 1H). < IM-59 ^O^s^-NV〇 1H-NMR (DMSO-d6) δ 1.40 (d, J : 6.9 Hz, 3H) 4.12 (s, 2H). 4.97 (t, J = 7.3 Hz. 1H), 7.24-7.25 (m, 1H) 7.33-7.39 (m, 5H). 7.50 (t J = 7.5 Hz, 2H), 7.75-7.7S (m, 3H), 8.01 (d, J = 8.6 Hz 1H), 8.37 (s, 1H), 8.84 (d, J = 7.4 Hz, 1H). -136- 201021798 【表12】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-60 nrCXsvyN^N 0 C02Bn 1H-NMR (DMSO-d6) δ : 4.19 (s, 2H). 4.47 (d,' J = 6.0 Hz. 2H), 5.37 (s, 2H). 7.34-7.58 (m, 9H), 7.75-7.80 (m, 3H), 8.02-8.04 (m, 2H). 8.37 (s, 1H). 8.66 (d, J =5.2 Hz, 1H), 9.03-9.06 (br m, 1H). 11-1-61 ^nhnh2 1H-NMR (DMS0-d6) δ : 4.00 (s, 2H), 4.37 (d, J = 4.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t J = 7.6 Hz, 2H). 7.74-7.80 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.38 (d. J = 1.5 Hz, 1H), 9.47 (s. 1H). 11-1-62 0.98 432.47 (ES+) A 11-1-63 Qj 〇,〜。H 1.41 526.48 (ES+) A 11-1-64 ^jCKs^NiT^ HCI ° nh2 1H-NMR (DMS0-d6) <5 4.16 (s, 2H), 4.36 (d, J = 5.2 Hz, 2H), 7.14-7.22 (m. 3H), 7.39-7.50 (m, 4H), 7.76-7.80 (m, 3H). 8.02 (d J = 8.4 Hz, 1H), 8.39 (s 1H), 8.99 (br s, 1H). -137- 201021798 【表13】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-1-65 1H-NMR (DMS0-d6) <5 : 4.12 (s, 3H), 4.38 (d, J = 6.6 Hz, 2H). 7.44 (t. J = 7.8 Hz, 1H), 7.51-7.59 (m, 3H), 7.78 (dd, J = 8.1, 12Hz, 2H). 7.88(s. 1H), 7.94(d, J 二 8.4Hz, 1H). 8.36 (s, 1H). 8.92(m, 1H). 11-1-66 r^XX)^_N/rQ U 0 0〜NH 1H-NMR (DMS0-d6) δ : 2.01 (s, 3H)t 4.13 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H), 6.97 (d, J = 7.2 Hz, 1H), 7.24 (t. J = 8.3 Hz, 1H), 7.44 (dd, J = 25.3, 6.6 Hz, 5H). 7.76-7.79 (m. 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.85-8.88 (br m, 1H), 9.92 (s, 1H). 11-1-67 1H-NMR (CDCI3) (5: 1.57 (s, 9H), 4.11 (s, 2H), 4.54 (d, J = 5.7Hz, 2H), 6.99 (t, J = 9.0Hz, 1H), 7.18 (br-s, 1H), 7.35-7.41 (m, 2H), 7.47 (m. 1H), 7.87-7.91 (m, 2H). IM-68 NMe2 1H-NMR (CDCI3) δ : 2.26 (s, 6H), 2.51 (t. J = 5.8 Hz. 2H). 3.51-3.52 (m, 2H), 4.14 (s, 2H). 4.57 (d. J = 5.6 Hz, 2H). 6.85 (s, 1H), 7.37-7.49 (m, 5H), 7.62-7.76 (m, 6H), 8.02 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H). c 11-1-69 1H-NMR (DMSO-d6) δ 1.16 (d, J = 6.6 Hz, 6H) 4.02-4.15 (m, 3H), 4.39 (d J = 5.6 Hz, 2H), 7.37-7.52 (m, 5H), 7.70-7.81 (m, 5H) 8.02 (d, J = 8.6 Hz, 1H) 8.19 (d. J = 8.1 Hz, 1H) 8.38 (d, J = 1.5 Hz, 1H) 8.90 (t, J = 5.8 Hz, 1H). , t -138- 201021798 1【表14】
化合物 番号 構造式 NMR(5) retention time Mass method 11-1-70 NMe2 1H-NMR (DMS0-d6) δ : 2.19 (s, 6H), 2.36 (t, J = 6.6 Hz, 2H), 3.22-3.23 (m, 2H), 4.07 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.33 (br s, 1H). 8.38 (d, J = 1.5 Hz, 1H). 11-1-71 OH 1H-NMR (CDCI3) δ : 2.66 (br s, 1H). 3.59-3.63 (m. 2H), 3.82-3.83 (m, 2H), 4.14 (s. 2H), 4.55 (d, J = 6.1 Hz, 2H). 6.69 (br s, 1H), 7.36-7.49 (m, 5H), 7.62-7.75 (m, 6H), 8.01 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H). 11-1-72 1H-NMR (DMS〇-d6) δ : 4.15 (s, 2H), 4.34 (d. J=5.7Hz.2H), 7.22 (d, J = 5.1 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H). 7.49 (d.J=7.8Hz,2H), 7.74-7.83 (m, 5H), 8.02 (d, J = 8.4 Hz. 1H),8.38(d,J = 1.5Hz,1H). 8.93 (d.J = 6.3Hz,1H). 1卜1-73 F s 0 0 1H-NMR (DMSO-d6) δ : 4.18 (s, 2H), 4.41 (d, J=5.4Hz,2H), 7.40-7.57 (m, 3H), 7.82-7.89 (m, 3H), 8.96 (m, 1H), 12.9(br-s, 1H) 11-1-74 1.76 445.47 (ES+) A -139- 201021798 【表15】
化合物 番号 構造式 NMR(5) retention time Mass method 1M-75 2.19 459.44 (ES+) A IM-76 F 1.96 421.48 (ES+) A IM-77 Α°η 2.08 417.5 (ES+) A 11-1-78 令 Η 1.86 409.39 (ES+) A c 11-1-79 sv^>YnXVh D 2.15 459.44 (ES+) A -140- 201021798【表16】
化合物 番号 構造式 NMR(5) retention time Mass method 11-1-80 2.22 487.47 (ES+) A 11-1-81 ό 2.25 495.51 (ES+) A 11-1-82 1.56 496.45 (ES+) A 11-1-83 s 0 〇 1.72 393.41 (ES+) A 11-1-84 Ό 1.26 454.43 (ES+) A -141- 201021798 【表17】
化合物 番号 構造式 NMR(d) retention time Mass method 11-1-85 2.07 449.46 (ES+) A 11-1-86 2.66 473.53 (ES+) A c 11-1-87 ^XXrV^Y0H 〇 0 HN^ 1.22 393.45 (ES+) A 11-1-88 2.04 393.44 (ES+) A € 11-1-89 1.26 405.42 (ES+) A -142- 201021798【表18】
化合物 番号 構造式 NMR(^) retention time Mass method 11-1-90 ° co2h 1.29 404.2 (ES+) A 11-1-91 u co2h 2 417.41 (ES+) A 11-1-92 (X。以 2.02 525.38 (ES+) A IM-93 Η〇χτ°^^°ΤΗ 1.48 433.44 (ES+) A 11-1-94 〈c^yx^i^V 1.88 447.41 (ES+) A -143- 201021798 【表19】
化合物 番号 構造式 NMR(6) retention time Mass method H-1-95 (Λ 2.03 462.45 (ES+) A 11-1-96 δ 2.08 449.41 (ES+) A 11-1-97 /0 1.77 493.49 (ES+) A 11-1-98 J^y^J〇Y〇H 2.35 479.41 (ES+) A r 11-1-99 今 Η 2.14 435.49 (ES+) A -144- 201021798【表20】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-100 1.76 463.44 (ES+) A 11-1-101 F:cro^V^0rH 2.15 435.41 (ES+) A IM-102 F 2.07 439.4 (ES+) A U-1-103 V 2.25 431.45 (ES+) A 11-1-104 Jpja>YxVH F 1.91 451.48 (ES+) A -145- 201021798 【表21】
化合物 番号 構造式 NMR((S) retention time Mass method 11-1-105 2.1 447.46 (ES+) A 11-1-106 F 2.06 439.38 (ES+) A Γ IM-107 2.22 431.45 (ES+) A IM-108 2.15 455.4 (ES+) A c IM-109 nh2 0.95 432.53 (ES+) A -146- 201021798【表22】 0
化合物 番号 構造式 NMR(5) retention time Mass method IM-110 2.3 527.5 (ES+) A 11-1-111 2.35 479.43 (ES+) A II-M12 1.64 436.41 (ES+) A 11-1-113 U , Κ>Λ 1.87 403.32 (ES+) A 11-1-114 ~V-NH ^ 〇 1.99 389.34 (ES+) A -147- 201021798 【表23】 化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-115 1.63 341.29 (ES+) A 11-1-116 OH (DMS0-d6) δ : 2.89 (1H, s), 3.16 (2H, s). 4.07 (1H, s), 4.26 (1H, s). 4.32 (1H, s), 4.42(1 H.s) 7.40 (1H, d, J = 7.1 Hz), 7.50 (2H, t, J = 7.2 Hz), 7.78 (3H, t, J= 11.2 Hz), 8.01 (1H, t, J = 7.2 Hz), 8.39 (1H, s). c 11-1-117 0=( OH OH (DMS0-d6) δ : 1.97 (2H, s), 3.71 (2H, d, J = 22.7 Hz). 4.20 (1H, s), 4.34 (1H, s), 7.39 (1H, s). 7.50 (2H, s). 7.77 (2H. t. J = 11.5 Hz), 8.01 (1H, d. J = 7.8 Hz), 8.38 (1H, s), 8.66 (1H, s). 11-1*118 〇XX》 OH 2.13 267.25 (ES+) A i II-M19 OH (DMS0-d6) δ : 0.92 (6H, t J = 5.1 Hz), 2.10 (1H, dd, J =13.3, 7.2 Hz), 4.20 (2H, d J = 9.3 Hz), 4.24 OH, d, J =8.8 Hz), 7.39 (1H, t, J = 7.3 Hz), 7.50 (2H, t. J = 7.6 Hz), 7.75 (2H, d, J = 7.6 Hz), 7.79 (1H, d, J = 8.6 Hz), 8.01 (1H, d, J = 8i Hz), 8.38 (1H, s), 8.59 (1H d, J = 7.8 Hz). -148- 201021798【表24】 Ο Ο 化番合号物 構造式 NMR(i5) retention time
Mass method 11-1-120 11-1-122 ΙΜ-124
Ο—
s> Ν λ—Ν Ο Ν~^ 於 ΟΗ Ο
S. ^'\ ,Η Ν ^—Ν Ο
ΟΗ Ο (DMS0-d6) δ : 1.95 (2H, dd. J = 12.5, 5.9 Hz), 2.19 (1H, t, J = 8.7 Hz), 3.46 (2H, s), 3.69 (2H, dd, J = 12.5, 6.7 Hz), 4.31 (1H, d, J 7.1 Hz), 4.35 (1H, d, J = 6.3 Hz), 7.39 (1H, t J = 7.1 Hz), 7.50 (2H. t, J = 7.3 Hz), 7.77 (3H, t, J = 11.1 Hz), 8.01 (1H, t, J = 7.2 Hz), 8.38 (1H, s). (DMS0-d6) δ : 1.87 (1H, s), 2.05 (1H, s). 2.42 (2H, s), 3.59 (3H. s), 4.14 (2H s). 4.30 (1H. s), 7.40 (1H, d J = 7.3 Hz), 7.49 (2H, d, J 6.8 Hz), 7.77 (3H, dd, J = 15.7, 7.6 Hz), 8.01 (1H, d, J 9.1 Hz), 8.38 (1H, s), 8.72 (1H. d, J = 7.1 Hz).
Η Η Η Η Η 4 7 13 1 /V /V /ι\ /V /IV 7 9 9 5 8 5 5 3 7 3 2·3·7·7·8· .\Λ \Λ \λ \Λ d s s s S )Η· Η' Η· Η* 6 3 2 2 1 to /ν /ι\ /V /V 5-9 7 ο 2 C 1 3 5 ο Ms3·4·7·8· \Α VIA \Λ \Α s s s s S
Η- Η Η Η Η 4 7 13 1 /ι\ /ι\ /1, #ί\ /IV 7 9 9 5 8 5·5·3·7·3 2·3·7·7·8· • · \Λ \Λ \Λ \Λ Λο s s s S 6)3Η·2Η·2Η·1Η· /ι\ #ιχ /ι\ -ί\ 5-9 7 ο 2 C 1— 3 5 ο Ms3·4·7·8· D \Λ \Λ \Λ \Λ \Λ s s s s S
S //~\ /~\ ΟΗ ν y-N 0 \~/ ' (DMSO-d6) δ : 1.48 (2Η, dt, J = 47.4, 10.2 Hz), 1.85 (2H, d, J = 11.4 Hz). 2.01 (1H, s), 2.82 (1H, t, J = 12.9 Hz), 3.19 (1H. t. J = 13.8 Hz), 3.97 (1H, d, J = 16.7 Hz), 4.25 (1H. d, J = 13.1 Hz), 4.36 (2H, s). 7.39 (1H, s), 7.49 (2H, d, J = 7.8 Hz), 7.77 (3H, t, J = 11.2 Hz), 8.01 (1H, d. J = 8.6 Hz), 8.38 (1H. s). -149- 201021798 【表25】 化合物 番号 構造式 NMR(5) retention time Mass method IM-125 0 sbjo (DMSO-d6) δ : 1.48 (2Η, dt, J = 47.4, 10.2 Hz), 1.85 (2H, d, J = 11.4 Hz), 2.01 (1H, s). 2.82 (1H, t, J = 12.9 Hz), 3.19 (1H. t, J = 13.8 Hz), 3.97 (1H, d, J 二 16.7 Hz), 4.25 (1H, d, J = 13.1 Hz). 4.36 (2H, s). 7.39 (1H. s), 7.49 (2H, d, J = 7.8 Hz), 7.77 (3H, t, J = 11.2 Hz), 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s). II-M26 s^a〇, (DMSO-d6) δ : 4.37 (2H, s), 7.09 (1H, s), 7.39 (2H. s), 7.46 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 7.3 Hz), 7.68 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 7.6 Hz), 7.81 (1H, d, J = 9.3 Hz). 8.05 (1H, d. J = 8.6 Hz), 8.42 (1H, s), 11.78 (1H, s). k IM-127 ρ_ α0^ (DMS0-d6) δ : 0.86 (1H, s), 1.99 (1H, s), 2.04 (2H, d, J = 8.3 Hz), 3.81 (2H, t, J = 6.6 Hz), 4.13 (2H, s), 4.32 (2H, d, J = 5.6 Hz), 7.29 (2H, d. J = 7.1 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.49 (2H, d, J = 6.1 Hz), 7.60 (2H, d. J = 8.1 Hz), 7.73-7.81 (4H, m), 8.01 (1H. d, J =8.3 Hz), 8.39 (1H, s), 8.85 (1H, s). IM-128 2.19 389.29 (ES+) Af 11-1-129 ΗΝ^ο 0^¾ (DMS0-d6) δ : 1.38 (9H, s), 4.12 (2H, s), 4.14 (2H s), 4.33 (2Ht d, J = 5.3 Hz) 5.75 (1H, s), 7.15 (3H, d, J =11.6 Hz), 7.28 (1H, s) 7.39 (2H, s), 7.49 (2H, d, J =7.3 Hz), 7.77 (3H, dd, J = 15.8, 8.0 Hz), 8.02 (1H, d, J =7.8 Hz), 8.38 (1H, s), 8.88 (1H, s). -150- 201021798【表26】
化合物 番号 構造式 NMR(5) retention time Mass method II-M30 HO /=\ (DMS0-d6) δ : 4.12 (2H. s), 4.25 (2H, d, J = 5.8 Hz). 5.75 (1H, s), 5.98 (2H, s). 6.78 (1H, d, J = 8.8 Hz). 6.86 (2H, d, J = 10.9 Hz), 7.40 (1H. s), 7.49 (2H, d. J =7.6 Hz), 7.78 (3H, t, J = 12.4 Hz), 8.01 (1H, d. J = 7.8 Hz). 8.38 (1H, s), 8.80 (1H, s). 11-1-131 2.16 403.31 (ES+) A 11-1-132 γΛ (DMS0-d6) δ : 4.22 (2Ht s), 4.54 (2H. d, J = 5.3 Hz), 7.41 (1H, d, J = 6.8 Hz), 7.49 (3H, d, J = 6.8 Hz). 7.63 (1H, d, J = 7.1 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.73 (3H. dd, J = 18.3, 8.7 Hz). 7.80 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 8.3 Hz), 8.39 (1H. s). 8.97 (1H. s). 11-1-133 (DMS0-d6) <5 : 4.18 (2H. s), 4.45 (2H, d, J = 5.8 Hz), 7.41 (1H, d, J = 6.6 Hz), 7.52 (4H, dd, J = 17.4, 8.1 Hz), 7.71 (2H, d, J = 8.1 Hz), 7.76 (2H, d, J = 7.8 Hz), 7.80 (1H. d, J = 8.3 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 8.99 (1H, s). 11-1-134 (DMS0-d6) δ : 4.18 (2H, s), 4.46 (2H, d. J = 5.8 Hz), 7.40 (1H, t, J = 7.2 Hz), 7.50 (2H, t, J = 7.5 Hz), 7.61 (3H, d, J = 8.3 Hz), 7.67 (1H, s), 7.76 (2H, d, J =7.8 Hz), 7.81 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.39 (1H, s). 8.99 (1H, k -151- 201021798 【表27】 化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-135 、N— (DMS0-d6) 6 : 2.84 (3H, s), 3.61 (3H, s). 4.18 (2H, s), 4.43 (2H, d, J = 29.8 Hz), 7.38 (2H, dd, J = 14.5, 5.7 Hz), 7.50 (2H, t, J = 7.7 Hz), 7.58 (1H, d. J = 8.8 Hz), 7.71 (2H, d, J = 9.3 Hz). 7.75 (2H, d, J = 7.6 Hz). 7.80 (1H, d, J = 10.6 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.38 (1H, s), 9.00 (1H, s). 11-1-136 〇〇 Cr^^H (DMS0-d6) δ : 2.84 (4H, s), 3.61 (4H, s), 4.18 (2H. s), 4.47 (2H, s), 7.39 (1H, s), 7.49 (2H, d, J = 7.1 Hz), 7.59 (2H, d, J = 8.1 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.3 Hz), 7.80 (1H, d, J = 8.6 Hz), 8.03 (1H, d, J = 9.1 Hz), 8.39 (1H, s), 9.00 (1H, s). r 11-1-137 OH (DMS0-d6) δ : 4.22 (2H, s). 5.40 (1H, d. J = 6.8 Hz), 7.41 (7H, t J = 8.6 Hz), 7.49 (2H. d, J = 6.8 Hz), 7.75 (2H. d, J = 7.1 Hz), 7.99 (1H, s), 8.37 (1H. s). 9.18 (1H, s). 11-1-138 OH (DMS0-d6) (5: 3.10 (1H, d, J = 7.8 Hz), 3.22 (1H, d. J =9.1 Hz), 4.12 (2H, d. J = 3.8 Hz), 4.56 (1H, d, J = 5.8 Hz), 6.96 (1H, t, J = 7.6 Hz), 7.05 (1H. t, J = 7.3 Hz), 7.18 (1H, s), 7.33 (1H. d, J = 7.8 Hz), 7.39 (1H, t, J = 7.5 Hz), 7.51 (3H, dd, J =18.8, 7.7 Hz), 7.77 (3H, t, J = 9.9 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.35 (1H, s), 8.73 (1H, d, J = 8.1 Hz), 10.87 (1H. s). c 11-1-139 j^TVa h u °〇^K-<0 OH NH2 (DMS0-d6) δ : 1.80 (1H s), 1.99 (2H, s), 2.17 (2H s), 4.14 (2H, s), 4.23 (1H s), 6.78 (1H, s), 7.31 (1H s), 7.39 (1H, s), 7.49 (2H, d J = 6.8 Hz), 7.75 (3H. d, J =7.8 Hz), 8.01 (1H, d, J : 7.8 Hz), 8.38 (1H, s), 8.72 (1H, s). -152- 201021798【表28】
化合物 番号 構造式 NMR(5) retention time Mass method IM-140 jQcV\ η OH U V〇° h2n (DMS0-d6) δ : 2.59 (1H, s), 4.14 (2H, s), 4.56 (1H, s), 6.93 (1H, s). 7.39 (2H, s), 7.49 (2H, d, J = 7.1 Hz), 7.77 (3H, t, J = 11.5 Hz), 8.01 (1H, d, J = 8.3 Hz). 8.37 (1H, s), 8.67 (1H, s). IM-141 OH (DMS0-d6) 5: 0.86 (3H, d, J = 6.1 Hz), 0.91 (3H, d, J =6.6 Hz), 1.56 (2H, s), 1.68 (1H, s), 4.14 (2H, s), 4.28 (1H, s). 7.40 (1H, d, J = 6.8 Hz), 7.50 (2H, t, J = 7.8 Hz), 7.77 (3H, t, J = 11.4 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.38 (1H, s), 8.68 (1H, d, J = 8.6 Hz). 11-1-142 OH ^NHg 1.08 398.3 (ES+) A II-M43 c^N>>4^-s OH \ (DMSO-d6) (5 : 1.90 (2H, s). 2.04 (3H, s), 4.15 (2H, s), 4.39 (2H, s), 7.39 (1H, s). 7.49 (2H, d, J = 7.6 Hz), 7.74 (2H, s), 8.01 (1H, d, J =7.1 Hz), 8.38 (1H, s), 8.73 (1H, s). IM-144 OH (DMSO-d6) δ : 2.92 (1H, t, J = 11.6 Hz), 3.11 (1H. t, J =7.2 Hz), 4.09 (2H, s), 4.50 (1H, d, J = 4.8 Hz), 7.19 (1H, s), 7.23 (4H, s), 7.40 (1H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.5 Hz). 7.77 (3H, t, J = 10.4 Hz), 8.00 (1H, d, J = 8.3 Hz), 8.36 (1H. s). 8.75 (1H, d, J = 8.3 Hz). -153- 201021798 【表29】
化合物 番号 構造式 NMR(5) retention time Mass method J IM-145 η 0 V-N V〇H u d OH (DMSO-d6) δ : 2.70 (2H, dd, J = 17.7, 6.1 Hz), 4.15 (2H, s), 4.60 (1H. d, J = 6.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.77 (3H, t, J = 11.7 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.38 (1H, s), 8.79 (1H, d, J = 7.8 Hz). 11-1-146 OH (DMS0-d6) <5 : 1.40 (6H, s), 4.09 (2H, s), 7.40 (1H, d, J = 7.6 Hz) 7.50 (2H, t, J = 7.3 Hz), 7.77 (3H, t. J= 10.9 Hz) 8.01 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 8.63 (1H, s). f 11-1-147 2.12 475.39 (ES+) A 11-1-148 〇γ^Κ.〇η:η 1.84 409.33 (ES+) A 11-1-149 。Q co2h 2.29 403.25 (ES+) A -154- 201021798【表30】
化合物 番号 構造式 NMR(i5) retention time Mass method IM-150 。Cl OOgMe 1.54 417.31 (ES+) A IM-151 1.75 353.28 (ES+) A 11-1-152 2.38 423.51 (ES+) A 11-1-153 c^:>r 1.27 461.39 (ES+) A 11-1-154 2.05 401.29 (ES+) A -155- 201021798 【表31】 化合物 番号 構造式 NMR(fi) retention time Mass method IM-155 0— 1.39 486.39 (ES+) A 11-1-156 >0^ 2.53 503.43 (ES+) A r IM-157 O^KcH— 2,19 423.39 (ES+) A IM-158 2.53 453.38 (ES+) A 1 IM-159 (DMS0-d6) δ : 3.52 (2H s), 4.31 (2H. s). 7.22 (2H, d J = 8.8 Hz), 7.40 (1H, s) 7.50 (2H. s). 7.56 (2H, d. J =8.1 Hz), 7.75 (3H, s), 8.03 (1H, s), 8.40 (1H, s), 10.45 (1H, s). -156- 201021798【表32】
化合物 番号 構造式 NMR(6) retention time Mass method IM-160 。Q ^X^C02Me 2.23 417.45 (ES+) A II-M61 1.65 355.32 (ES+) A 11-1-162 1.89 369.42 (ES+) A 11-1-163 rrN R〇\ (DMS0-d6) δ : 2.82 (3H, s), 5.75 (1H,s), 7.40 (1H, d, J = 7.3 Hz), 7.49 (2H, t, J = 7.5 Hz), 7.76 (3H, t, J = 10.1 Hz), 7.97 (1H, d, J = 8.6 Hz), 8.35 (1H, s). IM-164 (DMSO-d6) δ : 4.17 (2H, s), 4.42 (2H, d, J = 6.1 Hz), 7.32 (2H, s), 7.40 (1H, d, J =7.1 Hz), 7.50 (4H, t. J = 8.1 Hz), 7.78 (5H, dd, J = 16.5, 8.7 Hz), 8.03 (1H, d, J =8.3 Hz), 8.39 (1H, s), 8.97 (1H, s). -157- 201021798 【表33】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-165 (DMSO-d6) δ : 2.54 (2H, s), 2.98 (6H. s), 4.28 (2H, d, J = 5.3 Hz), 5.75 (1H, s), 7.04 (1H, s). 7.25 (2H, s), 7.40 (1H, d, J = 6.3 Hz), 7.50 (2H, t, J = 6.9 Hz), 7.75-7.82 (4H. m), 8.01 (1H, d, J = 8.3 Hz), 8.38 (1H, s), 8.80 (1H, s). 11-1-166 (DMSO-d6) δ : 4.18 (2H, s), 4.42 (2H, d, J = 5.3 Hz), 7.40 (1H, t, J = 7.1 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.66 (1H, d, J = 7.1 Hz), 7.73-7.81 (5H, m). 8.04 (1H, d, J = 8.6 Hz). 8.39 (1H, s), 8.95 (1H, s). i 11-1-167 \N- 2.53 353.27 (ES+) A II-M68 〇r^sVK^ 2.47 409.49 (ES+) A 11-1-169 〇— 2,23 389.45 (ES+) A -158- 201021798【表34】
化合物 番号 構造式 NMR(5) retention time Mass method 11-1-170 2.47 360.25 (ES+) A 11-1-171 1.26 442.39 (ES+) A 11-1-172 2.3 365.38 (ES+) A 11-1-173 〇r^>N;^〇 2.07 348.38 (ES+) A 11-1-174 〇rj^CsV>NC〇 2.31 371.28 (ES+) A -159- 201021798 【表35】
化合物 番号 構造式 NMR(5) retention time Mass method II-M75 1.52 410.42 (ES+) A 11-1-176 2.26 444.48 (ES+) A r & 11-1-177 2.3 425.36 (ES+) A IM-178 〇τ^Η_〇^ 2.19 403.28 (ES+) A c IM-179 〇γ^ 〇Η 2.23 389.38 (ES+) A 160- 201021798【表36】
化合物 番号 構造式 NMR(5) retention time Mass method II-M80 Ο- HO 1.51 371.38 (ES+) A IM-181 ρ H 1.78 383.25 (ES+) A 11-1-182 A H〇 1.63 355.29 (ES+) A IM-183 〇、 H 1.19 396.38 (ES+) A 11-1-184 O 2.41 467.59 (ES+) A -161 - 201021798 【表37】
化合物 番号 構造式 NMR(<5) retention time Mass method 3 11-1-185 0 2.65 474.39 (ES+) A 11-1-186 Oh'。 1.22 472.51 (ES+) A c H-1-187 0.23 354.47 (ES+) A 11-1-188 OH 0.24 340.44 (ES+) A c IM-189 厂]r-NH、OH U 。 1.5 342.41 (ES+) A -162- 201021798【表38】
化合物 番号 構造式 NMR(^) retention time Mass method 11-1-190 °\ 1.67 356.43 (ES+) A 11-1-191 〇^Η_οη 1.5 342.41 (ES+) A 11-1-192 [IJ 〇 co2h 1H-NMR (DMSO-d6) δ : 4.19 (s, 2H), 4.44 (d. J = 5.2 Hz. 2H), 7.36-7.52 (m, 4H), 7.76-7.79 (m, 3H), 7.96 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.55 (d, J = 4.7 Hz, 1H), 9.05 (br s, 1H). 11-1-193 1H-NMR (CDCI3) δ: 1.57 (s, 9H), 4.15 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 7.21-7.42 (m, 2H), 7.47-7.54 (m. 1H). 7.64-7.69 (m, 1H), 7.75-7.94 (m. 4H). 11-1-194 1H-NMR (CDCI3) 5: 1.56 (s. 9H), 4.13 (s. 2H), 4.51 (s, 2H), 7.26-7.55 (m. 6H) 7.62-7.64 (m, 2H), 7.74 (d J = 7.6 Hz, 1H), 7.85-7.89 (m, 3H), 8.27 (s. 1H). 2.79 459.15 (ES+) C -163- 201021798 【表39】 化合物 番号 構造式 NMR(5) retention time Mass method tl-1-195 4.09 417.25 (ES+) D II-M96 Br 1H-NMR (DMS0-d6) <5 : 4.19 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 7.34 (t, J 二 7.9 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.55-7.57 (m, 1H), 7.73-7.74 (m, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.03-8.12 (m, 1H), 8.96 (t, J = 5.6 Hz, 1H), 12.94 (s. 1H). 1,76 407.00 (ES+) C K 11-1-197 1H-NMR (DMS0-d6) δ : 4.14 (s. 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.40-7.58 (m, 7H). 7.84 (dd, J = 21.0. 14.4 Hz, 4H), 8.07 (d, J = 8.1 Hz, 1H), 8.90 (t, J = 5.8 Hz, 1H), 12.93 (s, 1H). 2.1 403.05 (ES+) C 11-1-198 S 〇 〇 1H-NMR (DMS0-d6) δ : 3.94 (s, 3H), 4.10 (s, 2H), 7.02(d, J = 8.1Hz, 1H). 7.35(t, J = 8.1Hz, 1H), 7.46(t, J = 7.5Hz, 1H), 7.57 (dd, J = 7.5Hz, 2H), 7.83 (d, J = 7.2Hz, 1H). 7.89 (s, 1H), 8.92 (m, 1H), 12.94 (br-s, 1H). IM-199 00^气sX 0 1H-NMR (DMS0-d6) δ 1.20 (s, 9H), 4.15 (s, 2H) 4.40 (d, J = 5.9 Hz, 2H) 7.39-7.52 (m, 5H), 7.69-7.76 (m. 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 1.7 Hz, 1H), 8.90-8.94 (br m 1H), 10.93 (s, 1H). -164- 201021798 【表40】
化合物 番号 構造式 NMR( δ) retention time Mass method 11-1-200 ||^ 〇 ^NH C02H 1H-NMR (DMSO-d6) <5 : 4.15 (s, 2H), 4.39 (d, J = 5.5 Hz, 2H), 4.50 (s, 2H), 7.42-7.50 (m, 5H), 7.64 (d, J = 7.4 Hz, 1H), 7.76-7.79 (m, 4H), 8.02 (d. J = 8.4 Hz, 1H). 8.38 (s, 1H), 8.91 (br s. 1H). 11-1-201 1H-NMR (DMSO-d6) <5 : 2.20 (s, 3H), 4.08 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 1H), 7.10-7.13 (m, 2H), 7.23 (t, J = 7.1 Hz, 1H), 7.34 (d, J =7.1 Hz. 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.54-7.54 (m, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.90-7.92 (m, 2H), 8.89 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H). 11-1-202 CF3 V〇H 1H-NMR (DMS0-d6) δ : 4.18 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.47 (t, J = 7.6 Hz. 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.74-7.84 (m, 4H), 7.91 (s, 1H), 8.07-8.11 (m, 2H). 8.18 (d, J = 8.1 Hz, 1H). 8.32 (d, J = 1.5 Hz, 1H), 8.95 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H). H-1-203 1H-NMR (CDCI3) 5: 1.46 (s, 9H), 4.00 (d, J = 5.1 Hz, 2H), 4.12 (s, 2H), 7.33-7.42 (m, 1H), 7.43-7.50 (m, 2H), 7.54-7.66 (m, 3H), 7.71 (dd, J = 8.4, 1.8 Hz, 1H), 8.11-8.02 (m, 2H). 11-1-204 t-Bu02C 1H-NMR (DMSO-d6) δ : 1.54 (s, 9H), 4.18 (s, 2H), 4.62 (d, J = 5.5 Hz, 2H), 7.42-7.49 (m, 6H), 7.76-7.80 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s. 1H), 8.75 (br s, 1H). -165- 201021798 【表41】 化合物 番号 構造式 NMR((5) retention time Mass method IM-205 1H-NMR (DMSO-d6) δ: 3.60 (s. 3H), 4.17 (s, 2H), 6.27-6.38(m, 3H), 7.03(t,J=7.8Hz, 1H), 7.50(t,J=7.2Hz, 1H), 7.75-7.90(m,4H), 8.39 (d.J=1.8Hz,1H).,10.11(s,1H). 11-1-206 气 0 1H-NMR (DMS0-d6) δ : 4.19 (s, 2H), 6.99(d,J=6.3, 2.4Hz,1H), 737-7.41 (m, 2H), 7.50(t,J=7.8Hz, 2H), 7.52-7.82 (m,3H), 8.06 (d,J=8.7 Hz,1H).,8.16(d,J=2.4Hz,1H), 8.39(d,J=2.4Hz,1H),10.23(d, J=2.4H2,1H).12.78(brs,1H). Φ 11-1-207 1H-NMR (DMS0-d6) <S : 4.18 (s, 2H). 6.68-6.80(m. 3H), 7.14(t,J=7.2Hz, 2H), 7.41(t,J=7.2Hz, 1H), 7.53(t,J=7.2Hz,2H), 7.81(dd,J=8.4, 1.5Hz.1H).,7.89(d,J=2.4HZ,1 H),8.03(d,J=1.8Hz,1H),10.12 (d,J=2.7Hz,1H) 11-1-208 U 0 為叫 1H-NMR (DMSO-d6) δ : 4.20(s, 2H). 694(dd,J=8.1,2.4Hz, 1H). 7.17(d,J=7.8Hz, 1H), 7.24-7.42(m, 3H), 7.75(d,J=7.5Hz,2H),7.81 (dd,J=7.2, 1.5Hz,1H).,8.05(d,J=8.4Hz,1 H).8.35(d,J=1.8Hz,1H),8.39( d,J=1.8Hz,1H),10.17(d,J=2. 1Hz,1H) c IM.209 hnN''n 1H-NMR (DMSO-d6) δ 4.18 (s, 2H), 4.46 (d, J = 5.7 Hz, 2H). 7.39-7.42 (m 1H), 7.48-7.61 (m, 4H) 7.74-7.81 (m, 3H), 7.93 (d J = 7.2 Hz, 1H), 8.02 (d, v. =8.4 Hz, 2H), 8.38 (d, J = 1.5 Hz, 1H), 9.00 (br s. 1H) -166 - 201021798【表42】
化合物 番号 構造式 mn(6) retention time Mass method 11-1-210 H U 1H-NMR (DMSO-d6) δ : 3.85 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 7.93-7.28 (m, 12H), 8.83 (t, J = 6.1 Hz, 1H). 11-1-211 ho2c 1H-NMR (DMSO-d6) δ : 4.19 (s, 2H), 4.69 (d, J = 5.7 Hz, 2H), 7.39-7.41 (m, 2H), 7.47-7.55 (m, 4H). 7.74-7.82 (m, 3H), 7.89 (dd, J = 7.7, 1.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.77 (br s, 1H). 11-1-212 ccxhsXVf 1H-NMR (CDCI3) <5: 1.57 (s, 9H), 4.04 (s, 2H), 4.54 (d, J = 5.7Hz, 2H), 6.06 (s, 2H), 7.21 (s, 1H), 7.33-7.41 (m, 2H), 7.44-7.47 (m, 1H), 7.59 (br-s. 1H), 7.87-7.90 (m, 2H) 11-1-213 cct>V^t°h 1H-NMR (DMSO-d6) δ : 4.04 (s, 2H), 4.39(d, J = 6.0Hz, 2H), 6.11(s, 2H), 7.46(t, J = 8.4Hz, 2H), 7.55 (t, J = 7.5Hz, 2H). 7.83 (d, J = 7.5Hz, 1H), 7.89 (s, 1H), 8.89 (m, 1H), 12.96 (br-s, 1H). 11-1-214 1H-NMR (DMSO-d6) <5 4.19 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H). 7.26-7.52 (m, 5H). 7.76-7.79 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.52 (d, J = 4.4 Hz. 1H), 8.97 (br s, 1H). -167- 201021798【表43】 化合物 番号 構造式 NMR(d) retention time
Mass method
1H-NMR (DMS0-d6) δ : 4.19 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H). 7.34-7.48 (m, 5H), 7.76-7.80 (m, 3H), 8.03 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H). 8.51 (d, J = 5.5 Hz, 2H), 8.96 (br s, 1H). 11-1-216
co2h 1H-NMR (DMS0-d6) δ : 1.43-1.68 (m, 6H), 1.78-1.92 (m, 2H), 2.34-2.43 (m, 1H). 3.71-3.82 (m, 1H), 4.06 (s, 2H), 7.34-7.53 (m 3H), 7.70-7.81 (m, 3H), 8.00 (d. J = 8.1 Hz, 1H), 8.40-8.26 (m, 2H). 3.69 394.95 (ES+) IM-217
O 1H-NMR (DMS〇-d6) <5 4.18 (s, 2H), 4.41 (d, J 6.1 Hz, 2H), 7.46 (t. J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.78-7.86 (m, 4H), 7.91 (s, 1H), 8.01 (d. J 8.1 Hz. 2H), 8.20 (d,J = 8.1 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H), 8.94 (t. J = 5.8 Hz, 1H), 12.94 (br s, 1H). 1H-NMR (DMS0-d6) δ 11-1-218
2.29 (s, 4.40 (d, 6.84 (t, 6.97 (d, 7.17 (d, 7.27 (t, 7.46 (t, 7.55 (d, 7.71
3H), J J J J J J J 4.11 (s, 2H). 5.6 Hz, 2H). Hz, 2H). Hz, 1H). Hz, 1H). Hz, 1H), Hz, 1H), Hz, 1H), 7.3 7.1 9.1 7.6 7.18.1 1H), 7.83 (d, J 7.1 Hz. 1H), 7.90-7.96 (m, 2H), 8.93 (br s, 1H), 12.79 (br s, 1H). _
Q 11-1-219 1H-NMR (DMS〇-d6) <5 4.16 (s, 2H), 4.40 (d, J N 0、 5.6 Hz, 2H), 7.46 (t, J = 7.6 n V~OH H2, 1H)f 7.54 (d, J = 8.1 Hzt 1H), 7.58 (dd, J = 8.6t 2.0 Hz, 1H), 7.83 (d, J = 7.6 〇 Hz, 1H), 7.89 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.93 (t, J = 5.8 Hz, 1H), 12.94 (br s, 1H). -168- 201021798 【表44】
化合物 番号 構造式 NMR(fi) retention time Mass method 11-1-220 1H-NMR (DMS0-d6) (5 : 1.12-1.45 (m, 4H), 1.81-1.98 (m, 4H), 2.10-2.24 (m, 1H), 3.45-3.66 (m, 1H), 4.03 (s, 2H), 7.39 (dd, J = 7.4, 3.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.83-7.70 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H). 3.62 394.75 (ES+) C 11-1-221 ^co2h 1H-NMR (DMSO-d6) δ : 0.83-2.19 (m, 10H). 2.98 (t, J = 6.1 Hz, 2H), 4.05 (s, 2H). 7.54-7.34 (m, 3H), 7.82-7.71 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.32-8.37 (m, 2H). 3.74 408.75 (ES+) C 11-1-222 1H-NMR (DMSO-d6) δ : 1.01-1.44 (m, 4H). 1.68-2.10 (m. 5H), 2.24-2.36 (m, 1H), 4.03 (s, 2H), 7.34-7.53 (m, 3H), 7.71-7.82 (m, 3H), 8.00 (d, J = 8.1 Hz, 1H), 8.30-8.40 (m, 2H). 3.72 394.75 (ES+) C 11-1-223 ^Is^>n^^oh 1H-NMR (DMS0-d6) δ : 4.26 (s, 2H), 4.43 (d, J = 6.1 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H). 7.56-7.64 (m, 2H), 7.70 (t, J = 6.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.91-7.93 (m, 2H), 8.07 (d. J = 8.1 Hz, 1H), 8.12 (d, J =8.6 Hz. 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.97 (t, J = 5.8 Hz, 1H), 12.95 (br s, 1H). 11-1-224 0 0 I 1H-NMR (DMS0-d6) δ 1.54 (s, 9H), 3.82 (s, 2H) 4.38 (d, J = 5.6 Hz, 2H) 7.06-7.20 (m, 2H), 7.58-7.40 (m, 4H), 7.78 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H) 8.81 (t, J = 5.8 Hz, 1H) 12.26 (s, 1H). -169- 201021798 【表45】 化合物 番号 構造式 NMR(^) retention time Mass method 11-1-225 y~NH N·^ 1H-NMR (DMS0-d6) δ : 4.17 (s, 2H), 4.64 (d, J = 6.0 Hz, 2H), 7.39 (t. J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.73-7.81 (m. 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 9.25 (br s, 1H). 11-1-226 qt^sXVy 1H-NMR (DMS0-d6) δ : 1.54 (s, 9H), 3.76 (s, 3H), 3.95 (s, 2H), 4.37 (d, J = 5.6 Hz, 2H), 7.26-7.12 (m, 2H), 7.58-7.41 (m, 4H), 7.78 (d, J 二 7.6 Hz, 1H), 7.83 (s. 1H), 8.85 (t,J = 5.8 Hz, 1H). t 11-1-227 qXXs^Vn^n^n 1H-NMR (DMSO-d6) δ : 4.17 (s, 2H), 4.64 (d, J = 5.5 Hz, 2H), 7.39-7.52 (m. 3H), 7.76-7.79 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H). 8.39 (s, 1H), 9.10 (br s, 1H). 11-1-228 ° 0 X F3C OH 1H-NMR (DMSO-d6) δ : 4.23 (s, 2H). 4.43 (d, J = 6.1 Hz. 2H), 7.54-7.44 (m, 3H), 7.58 (d, J = 7.6 Hz, 1H), 7.82-7.75 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H). 7.92 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H). 0.97 309.65 (ES+) C < 11-1-229 (X'^V^VH。 \^N\ Ο o g f3c*^oh 1H-NMR (DMS0-d6) δ 3.92 (s, 3H), 4.28 (s, 2H) 4.42 (d, J = 6.1 Hz, 2H) 7.42-7.61 (m, 4H), 7.94-7.73 (m, 4H), 9.05 (t, J = 5.6 Hz, 1H). 1.08 323.90 (ES+) c -170- 201021798【表46】 〇 化合物 番号 構造式 NMR(5) retention time Mass method IM-230 1H-NMR (DMSO-d6) δ : 1.88 (d, J = 6.1 Hz, 3H), 4.11 (s, 2H), 4.40 (d, J = 4.5 Hz, 2H), 6.39-6.46 (m, 1H), 6.56 (d, J = 16.2 Hz, 1H), 7.46-7.55 (m, 3H). 7.82-8.02 (m. 4H), 8.93 (br s, 1H). 11-1-231 HJ 0 conh2 1H-NMR (DMSO-d6) δ : 4.20 (s, 2H). 4.47 (d, J = 5.7 Hz, 2H), 7.43-7.57 (m, 5H), 7.76-7.79 (m, 3H), 8.03-8.08 (m, 3H), 8.38 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 9.04 (br s. 1H). 11-1-232 qXXs^-n^n 1H-NMR (DMS0-d6) 6 : 4.11 (s, 2H), 4.57 (d, J = 5.7 Hz, 2H), 7.39-7.42 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H). 7.74-7.81 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.98-9.02 (m, 2H). Π-1-233 1H-NMR (DMS0-d6) δ : 4.02 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H). 7.48 (td, J = 7.6, 2.2 Hz, 3H), 7.57 (d, J = 7.6 Hz, 1H). 7.66-7.85 (m, 5H), 7.95 (d, J = 14.7 Hz, 2H), 8.92 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H). 11-1-234 1H-NMR (CDCI3) d: 1.54 (s, 6H), 3.71 (s. 3H), 4.00 (d, J = 5.1 Hz, 2H), 4.14 (s 2H), 6.76 (s, 1H), 7.34-7.51 (m, 3H), 7.59-7.86 (m, 4H) 8.08-8.02 (m, 2H). -171- 201021798 【表47】 化合物 番号 構造式 NMR(5) retention time Mass method 11-1.235 義讨Η 1H-NMR (DMSO-d6) <5 : 4.12 (s, 2H), 4.39 (d. J = 6.1 Hz, 2H), 7.05 (d, J = 7.6 Hz. 2H), 7.14-7.18 (m, 2H), 7.38-7.55 (m, 5H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H). 8.06 (d. J = 8.6 Hz, 1H), 8.91 (t, J = 5.8 Hz, 1H). 12.95 (br s, 1H). 11-1-236 1H-NMR (DMS0-d6) δ : 4.05 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 6.91 (dd, J = 8.6, 2.0 Hz, 1H), 7.28 (d. J =2.0 Hz, 1H), 7.46 (t. J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.89 (s, tH), 8.88 (t, J = 5.8 Hz, 1H), 9.61 (s, 1H), 12.90 (br s, 1H). c 11-1-237 ηο^3^Νη_^〇Η 1H-NMR (DMS0-d6) δ :4.02(s, 2H), 4.38(d,J=6.0 Hz, 2H), 6.29(dd,J=8.3, 2.4 Hz), 7.32(d, J-2.4Hz,1H),7.47(t,J=7.5 Hz, 1H),7.54(d. J=7.8 Hz, 1H),7.73(d, J=8.7 Hz ,1H) ,7.81-7.84(m. 1H), 7.89(s, 1H), 8.88(t, J=5.7 Hz ,1H),9.71(s ,1H),12.95(brs, 1H). 11-1-238 丫 χχί 1H-NMR (DMSO-d6) δ : 1.30 (dd, J = 6.1, 1.5 Hz, 6H), 4.08 (s, 2H), 4.39 (d, J =6.1 Hz, 2H), 4.67-4.73 (m, 1H), 7.02 (dd, J = 8.6, 2.0 Hz, 1H), 7.44-7.55 (m, 3H), 7.82-7.90 (m, 3H) 8.89 (t, J = 5.3 Hz, 1H), 12.94 (br s, 1H). < 11-1-239 /~CO2H 1H-NMR (DMS0-d6) <5 3.54 (s, 2H), 4.14 (s, 2H) 4.33 (d, J = 5.7 Hz, 2H) 7.15-7.18 (m, 3H), 7.28 (t J = 7.8 Hz, 1H), 7.39 (t.J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.74-7.81 (m, 3H) 8.02 (d, J = 8.7 Hz, 1H) 8.38 (s, 1H), 8.86 (br s 1H). -172- 201021798【表48】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-1-240 1H-NMR (DMS0-d6) <5 : 2.59 (s, 3H), 4.21 (s, 2H), 4.38 (d, J = 5.7 Hz, 2H), 7.26 (d, J = 5.0 Hz, 1H), 7.39-7.42 (m, 1H), 7.50 (t J = 7.6 Hz, 2H), 7.76-7.80 (m, 3H). 8.03 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.64 (d, J =5.4 Hz, 1H), 9.02 (br s, 1H). 11-1-241 ocf3 ^〇Cs^N(T^ 1H-NMR (DMS0-d6) δ : 4.16 (s, 2H), 4.41 (d. J = 6.0 Hz, 2H), 7.26-7.52 (m, 7H), 7.74-7.82 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz. 1H), 8.94 (br s, 1H). 11-1-242 1H-NMR (CDCI3) δ : 1.22-2.43 (m, 5H)t 3.18-3.42 (m. 4H), 3.91-4.02 (m, 2H), 4.08 (s, 2H), 7.33-7.77 (m, 7H), 7.99-8.11 (m, 2H). 3.7 367.05 (ES+) C 11-1-243 1H-NMR (CDCI3) <5 : 2.06-1.47 (m, 5H), 2.84-4.08 (m, 6H), 7.28-7.52 (m, 4H), 7.57-7.77 (m, 3H). 7.98-8.13 (m, 2H). 3.77 353.00 (ES+) C 11-1-244 1H-NMR (CDCI3) <5: 4.10 (s, 2H), 4.51 (d, J = 5.6 Hz, 2H), 6.24 (d, J = 3.0 Hz, 1H), 6.32 (t. J = 2.5 Hz, 1H), 7.32-7.67 (m, 7H), 7.72 (dd, J = 8.4, 1.8 Hz 1H), 8.08-8.00 (m, 2H). 4.18 349.15 (ES+) C -173- 201021798 【表49】 化合物 番号 構造式 NMR( δ) retention time Mass method 11-1-245 1H-NMR (DMS0-d6) δ : 4.16 (s, 2H), 4.40 (d, J = 6.1 Hz, 2H), 7.30-7.54 (m, 8H), 7.59-7.68 (m, 4H), 7.72-7.82 (m. 3H). 8.03 (d, J = 8.6 Hz, 1H), 8.36-8.40 (m, 1H), 8.89 (t, J = 5.6 Hz, 1H). 5.46 435.05 (ES+) 〇 11-1-246 co2h 1.83 410.00 (ES+) C 1 -174- 201021798 【表50】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-2 (DMS0-d6) 5: 4.13 (s. 2H), 4.40 (d, J = 5.58 Hz. 2H), 7.25-7.35 (m, 3H). 7.44-7.56 (m, 2H), 7.62 (m, 1H), 7.82-7.90 (m. 3H), 8.00 (d.J = 9.12 Hz, 1H). 8.93 (t, J = 5.58 Hz, 1H), 12.96 (brs, 1H). 11-2-3 (DMS0-d6) <5: 1.14(t, J =7.1 Hz, 3H), 4.10-4.15 (m, 4H), 4.39 (d, J = 6.1 Hz, 2H), 7.23 (t, J = 7.1 Hz, 1H), 7.29-7.39 (m, 5H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz. 1H), 7.82 (d, J = 7.6 Hz. 1H), 7.91 (t, J = 7.1 Hz. 2H), 8.03 (d, J = 2.0 Hz, 1H), 8.91 (t, J = 6.1 Hz, 1H), 12.98 (br s. 1H). 11-2-4 a.xx^^o 〇V〇H (DMS0-d6) <5: 2.20 (s, 3H), 4.09 (s, 2H), 4.39 (d, J =6.08 Hz, 2H), 6.93 (d. J = 8.11 Hz, 1H), 7.09-7.15 (m, 2H), 7.23 (m, 1H), 7.35 (d, J = 7.10 Hz, 1H), 7.46 (m, 1H), 7.53-7.56 (m, 2H). 7.83 (d, J = 7.60 Hz, 1H). 7.91 (m, 2H), 8.91 (t, J = 5.58 Hz. 1H). 12.96 (brs, 1H). 11-2-5 ΡΧΧ0ΧΧΙ^Ν^ y〇H 0 (DMS〇-d6) <5: 4.10 (s, 2H), 4.40 (d, J = 5.58 Hz, 2H), 7.09-7.13 (m, 2H), 7.17 (dd, J = 8.62, 2.53 Hz, 1H), 7.20-7.28 (m, 2H), 7.43-7.57 (m, 2H), 7.69 (d, J = 2.53 Hz, 1H), 7.83 (d,J = 8.11 Hz, 1H), 7.88-7.97 (m, 2H), 8.92 (t. J = 5.83 Hz, 1H), 12.96 (brs, 1H). 11-2-6 χι0χχ:^ΝίΌ 〇V〇H (DMS〇-d6) δ: 2.30 (s, 3H), 4.09 (s, 2H), 4.39 (d, J =5.58 Hz, 2H), 6.95 (d. J = 8.11 Hz, 2H), 7.15 (dd, J = 8.62, 2.53 Hz, 1H), 7.21 (d, J = 8.11 Hz, 2H), 7.46 (m, 1H), 7.54 (d. J = 7.60 Hz, 1H), 7.65 (d, J = 2.53 Hz, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.95-7.88 (m, 2H), 8.91 (t, J = 5.83 Hz, 1H), 12.95 (brs, 1H). -175- 201021798 【表51】 化合物 番号 榷造式 NMR(d) retention time Mass method 11-2-7 λ〇Η (DMSO-de) d: 4.14 (s, 2H), 4.41 (d. J = 5.58 Hz, 2H). 6.98-6.94 (m, 2H), 7.31 (dd, J = 8.87. 2.28 Hz, 1H), 7.46 (m, 1H), 7.55 (d, J = 7.60 Hz, 1H), 7.83 (d, J =7.60 Hz, tH), 7.91 (s, 1H), 7.96 (d, J = 2.03 Hz, 1H). 8.03 (d, J = 9.12 Hz, 1H), 8.47 (d, J = 5.07 Hz, 2H). 8.94 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H). 11-2-8 V-〇H 0 (DMSO-d6) 5: 2.88 (s, 6H), 4.07 (s, 2H). 4.39 (d, J =5.58 Hz. 2H), 6.78 (d, J = 8.62 Hz, 2H). 6.96 (d, J = 9.12 Hz, 2H), 7.09 (dd, J = 8.62, 2.53 Hz, 1H). 7.42-7.56 (m, 3H), 7.81-7.90 (m, 3H), 8.90 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H). 11-2-9 α^:ν>^0Η (DMS0-d6) δ: 4.03 (s, 2H), 4.39 (d, J = 5.6 Hz. 2H), 6.86 (t J = 7.4 Hz, 1H), 7.11-7.19 (m, 3H), 7.26 (t, J = 7.9 Hz, 2H), 7.45 (t, J = 7.6 Hz. 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.77-7.83 (m, 2H), 7.90 (s, 1H). 8.36 (s, 1H), 8.88 (t, J = 5.8 Hz, 1H), 12.97 (br s, 1H). 11-2-10 νΊ〇〇2η 1H-NMR(DMS0-d6) <5: 4.16 (s, 2H), 4.64 (d. J = 6.1 Hz, 2H). 5.66 (s. 2H), 7.40 (d,J = 7.6 Hz, 1H), 7.50 (t J = 7.6 Hz, 2H), 7.74-7.80 (m, 4H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J =1.5 Hz, 1H), 9.12 (s, 1H). 11-2-11 0 (DMS〇-d6) 5: 4.11 (s, 2H), 4.40 (d. J = 6.08 Hz, 2H), 7.02 (d, J = 7.10 Hz, 1H), 7.25 (dd, J = 8.62, 2.53 Hz, 1H). 7.43-7.63 (m, 5H), 7.73-7.85 (m, 3H), 7.89-8.03 (m, 3H), 8.12 (d, J = 8.11 Hz, 1H), 8.91 (t, J =5.83 Hz. 1H), 12.95 (brs, 1H). -176- 201021798 【表52】
化合物 番号 構造式 mmd) retention time Mass method 11-2-12 1H-NMR(DMSO-d6) 6-. 4.15 (s, 2H), 4.42 (d, J = 5.1 Hz, 2H), 7.44 (m, 3H), 7.77 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.28-8.35 (m, tH), 8.91 (s, 1H), 13.88 (s. 1H). 11-2-13 o^s>>W (DMS0-d6) δ: 4.21 (s, 2H), 4.42 (d, J = 5.6 Hz, 2H), 7.44-7.57 (m, 8H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.01 (d, J 二 8.6 Hz, 1H), 8.98 (t, J = 5.3 Hz, 1H), 12.96 (br s, 1H). 11-2-14 〇v〇h (DMSO-d6) 5: 4.12 (s, 2H), 4.40 (d, J = 6.08 Hz, 2H), 7.25-7.57 (m, 7H), 7.80-7.85 (m, 3H), 7.90-7.94 (m, 2H), 7.99 (d, J = 9.12 Hz, 2H). 8.93 (t, J = 5.58 Hz, 1H), 12.96 (brs, 1H). 11-2-15 a〇XX:^NiLq λ0Η (DMS〇-d6) <5: 1.41-1.78 (brm, 10H), 1.94-2.03 (m, 2H), 4.05 (s, 2H), 4.39 (d, J =6.08 Hz, 2H), 4.54-4.60 (m, 1H), 7.03 (dd, J = 8.62, 2.53 Hz. 1H), 7.46 (t, J = 7.60 Hz. 1H), 7.52-7.59 (m, 2H), 7.78-7.85 (m, 2H), 7.90 (s, 1H), 8.88 (t, J = 5.58 Hz, 1H). 12.95 (s. 1H). 11-2-16 Ο0ΧΧ:^Ν^ 〇V〇H (DMS〇-d6) 5: 1.49-1.93 (brm, 14H), 4.05 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 4.55 (brs, 1H), 7.02 (d, J = 7.10 Hz. 1H), 7.43-7.59 (m. 3H), 7.78-7.91 (m, 3H), 8.88 (t, J = 5.58 Hz, 1H), 12.95 (brs, 1H). -177- 201021798 【表53】 化合物 番号 構造式 NMRC5) retention time Mass method 11-2-17 ό (DMSO-d6) (5 : 4.07 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H). 7.01-7.06 (m, 6H), 7.13 (dd, J = 8.9, 2.3 Hz, 1H), 7.31 (t, J = 7.6 Hz, 4H), 7.45 (t J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.81-7.89 (m, 3H), 8.90 (t, J = 5.8 Hz, 1H). 11-2-18 nh2 (DMS0-d6) δ : 3.72 (d, J =5.6 Hz, 2H), 4.15 (s, 2H), 7.11 (s, 1H), 7.39 (t,J = 7.6 Hz, 1H), 7.46-7.52 (m, 3H), 7.74-7.81 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.58 (t,J = 5.3 Hz, 1H). 11-2-19 (DMS0-d6) 5:4.16(sf 2H). 4.41 (d, J = 5.7 Hz, 2H), 7.78 (d, J = 0.9 Hz, 1H). 7.82-7.85 (m. 1H), 7.92 (s. 1H), 8.01-8.04 (m, 2H), 8.22-8.25 (m, 2H), 8.82 (d, J = 1.2Hz, 1H), 8.95 (t, J = 5.4 Hz, 1H), 12.93 (brs, 1H). II-2-20 lX〇^N^ (DMS〇-de) δ: 4.07 (s, 2H), 4.39 (d. J = 6.08 Hz, 2H). 5.17(s. 2H), 7.15 (dd, J = 9.12, 2.53 Hz, 1H), 7.31-7.56 (m, 7H), 7.72 (d, J = 2.53 Hz, 1H), 7.81-7.86 (m, 2H), 7.90 (s, 1H), 8.90 (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H). 11-2-21 V-NH 1H-NMR(DMS0-d6) δ : 3.08 (t, J = 6.6 Hz, 2H), 3.51-3.53 (m, 2H), 4.05 (s, 2H), 7.39-7.50 (m, 3H), 7.75-7.79 (m. 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.56 (s, 1H), 16.04 (s, 1H). -178- 201021798【表54】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-22 (CDCI3) δ : 1.29 (t,J = 7.1 Hz, 3H), 4.09 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.63 (d. J = 5.6 Hz, 2H), 5.12 (s, 2H). 7.38 (t, J = 7.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62-7.64 (m, 2H), 7.70-7.73 (m, 2H), 7.83 (br s. 1H), 8.03-8.06 (m. 2H). 11-2-23 (DMS0-d6) δ: 2.41 (s, 3H), 4.15 (s, 2H), 4.41 (d, J =5.7 Hz. 2H), 7.32-7.56 (m, 8H), 7.84 (d J = 7.5 Hz, 1H), 7.91 (s, 1H),8..02(d, J =6.3 Hz, 1H), 8.04 (s, 1H), 8.82 (d, J = 0.9 Hz, 1H), 8.94 (t. J = 5.7Hz, 1H),12.96 (brs. 1H). 11-2-24 (DMS0-d6) 5: 4.16 (s. 2H), 4.41 (d, J 二 5.7 Hz, 2H), 7.38-7.62 (m, 5H), 7.82 (d J = 7.8 Hz, 1H). 7.91 (d, J = 6.9 Hz, 1H), 8..03 (dd, J = 5.7, 2.8 Hz, 2H), 857 (d, J = 2.8 Hz, 1H), 8.75 (d, J = 4.5 Hz, 1H), 8.86 (s. 1H), 8.95 (t, J = 5.7Hz, 1H), 9.40 (s, 1H), 12.96 (brs, 1H). 11-2-25 ^sXX:>^〇H (DMS0-d6) δ: 2.33 (s, 3H), 4.12 (s, 2H). 4.39 (d. J =6.1 Hz, 2H), 7.19-7.35 (m, 5H). 7.46 (t. J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz. 1H), 7.83 (d, J = 7.6 Hz. 1H). 7.89-7.94 (m, 2H), 7.99 (d, J= 1.5 Hz, 1H), 8.93 (t. J = 6.1 Hz, 1H), 12.96 (br s, 1H). 11-2-26 (DMS0-d6) <5: 4.12 (s, 2H), 4.40 (d. J = 5.6 Hz, 2H), 5.24 (s, 2H), 7.39 (t, J =7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m. 3H), 7.96-8.02 (m, 2H), 8.37 (d, J = 2.0 Hz. 1H), 8.91 (t, J = 5.6 Hz. 1H). 179 201021798 【表55】 化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-27 (DMS0-d6) δ : 2.40 (s, 3Η). 4.16 (s, 2H), 4.41 (d, J =5.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.55-7.57 (m, 3H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.13 (d,J = 8.1 Hz, 1H), 8.19 (d,J = 1.5 Hz. 1H), 8.95 (t. J = 5.8 Hz, 1H), 12.95(brs, 1H). H-2-28 nh2 Γ Τ V-\ ΗΝ^; HCI 0^0-^ νη 1H-NMR(DMS0-d6) 6: 4.17 (s, 2H), 4.38 (d, J = 6.1 Hz. 2H), 7.11-7.24 (m, 3H). 7.43-7.48 (m, 8H). 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.96-8.99 (m, 1H), 9.95 (s, 1H). 11-2-29 0-Ν (DMSO-d6) 5: 4.17 (s, 2H), 4.56 (d, J = 5.58 Hz, 2H), 6.76 (s. 1H), 7.39 (m, 1H), 7.47-7.53 (m, 2H), 7.73-7.82 (m, 3H), 8.03 (d, J = 8.11 Hz, 1H), 8.39 (d, J =1.01 Hz. 1H), 9.08 (t, J = 5.83 Hz. 1H). 11-2-30 〇ca:^q (DMSO-de) δ: 2.20 (s, 3H), 4.09 (s, 2H), 4.39 (d, J =6.08 Hz. 2H). 6.93 (d, J = 8.11 Hz, 1H), 7.08-7.15 (m. 2H), 7.23 (m. 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.46 (m, 1H), 7.52-7.56 (m, 2H), 7.83 (d, J = 7.60 Hz, 1H), 7.88-7.94 (m, 2H), 8.91 (t, J = 5.83 Hz, 1H), 12.96 (s. 1H). 11-2-31 ^-C02Me 1H-NMR(DMS0-d6) δ : 3.62-3.67 (m, 5H), 4.17 (s, 2H), 4.36 (d, J = 6.0 Hz, 2H), 7.18-7.22 (m, 3H), 7.29-7.32 (m, 1H), 7.42-7.44 (m, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.78-7.82 (m, 3H), 8.04 (d, J = 8.6 Hz. 1H), 8.41 (s, 1H), 8.89-8.92 (m, 1H). 201021798【表56】
化合物 番号 構造式 NMR(i) retention time Mass method 11-2-32 ^0Χτ:^ν^_〇η (DMS〇-d6) d: 1.19(d, J = 6.59 Hz, 6H), 3.22 (m, 1H), 4.09 (s, 2H), 4.39 (d, J = 5.58 Hz, 2H), 6.90 (m, 1H), 7.10 (dd, J = 9.12, 2.53 Hz, tH), 7.16-7.25 (m, 2H), 7.407.48- (m, 2H), 7.52- 7.58 (m, 2H), 7.83 (d, J = 7.60 Hz, 1H), 7.88-7.94 (m, 2H), 8.9t (t, J = 5.83 Hz, 1H), 12.96 (brs, 1H). 11-2-33 Cl 〇As>>n^oh (DMS0-d6) δ: 4.22 (s, 2H), 4.43 (d, J = 5.7 Hz, 2H), 7.39-7.58 (m, 6H), 7.77-7.89 (m, 5H), 7.91 (s, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.98 (t J = 5.7Hz, 1H),12.96 (brs, 1H). 11-2-34 jQcV^nh NV- 1H-NMR(DMSO-d6) δ: 4.51 (s, 2H), 7.45-7.53 (m, 3H), 7.68-7.86 (m, 3H), 8.04-8.07 (m. 1H), 8.46 (s, 1H), 12.55 (s. 1H). 11-2-35 〇Γ^δ>>Ν^^〇Η (DMSO-d6) <5: 4.16 (s, 2H), 4.40 (d, J = 5.7 Hz, 2H), 7.38-7.55 (m. 9H), 7.82-7.85 (m, 4H). 7.89-7.91 (m, 3H), 8..38 (d, J = 1.5 Hz, 1H), 8.93 (tJ = 5.4Hz, 1H), 12.86 (brs, 1H). 11-2-36 \NH N^/C〇2Me U 0 (CDCI3) δ: 3.92 (s, 3H), 4.16 (s, 2H), 4.71 (d, J = 5.6 Hz. 2H), 7.39 (t. J = 7.6 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.64 (d, J = 7.6 Hz. 2H), 7.74 (d, J = 8.6 Hz, 1H), 8.06-8.08 (m, 2H), 8.16 (br s. 1H), 8.19 (s, 1H)‘ -181- 201021798 【表57】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-37 o^s^n^c〇2H (DMS0-d6) 5: 4.23 (s, 2H), 4.43 (d. J = 5.6 Hz, 2H), 7.09-7.59 (m, 13H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.09 (s, 1H), 8.99 (t, J = 5.6 Hz, 1H). 11-2-38 1H-NMR(DMS0-d6) δ: 3.90 (s, 3H). 4.17 (s. 2H), 4.31 (d, J = 5.7 Hz, 2H), 6.99 (d, J = 8.6 Hz, 1H), 7.45-7.52 (m, 4H), 7.73-7.96 (m, 4H). 8.04 (d, J = 8.4 Hz, 1H), 8.41-8.41 (m, 1H), 8.89-8.91 (m, 1H), 10.45 (s, 1H). 11-2-39 1H-NMR(DMS0-d6) 6: 3.82 (s. 3H), 4.15 (s, 2H), 4.32 (d, J = 5.7 Hz. 2H), 7.11 (d. J = 8.7 Hz. 1H), 7.42-7.63 (m, 5H), 7.78- 7.82 (m. 3H), 8.04 (d, J = 8.4 Hz, 1H), 8.40 (s. 1H), 8.88 (t, J = 5.8 Hz, 1H), 12.63 (s, 1H). 11-2-40 F3CrVr. 1H-NMR(DMS0-d6) 6: 3.57 (s, 2H), 4.19 (s, 2H), 4.37 (d, J = 5.5 Hz, 2H), 7.19-7.31 (m, 5H). 7.83-7.88 (m, 3H), 8.04 (d, J = 8.1 Hz, 2H), 8.23 (d, J = 8.2 Hz, 2H), 8.34 (s, 1H), 8.92 (s. 1H), 12.39 (s, 1H). 11-2-41 —V-NH /—'\ COot-Bu u 1H-NMR(CDCI3) δ: 1.38-1.45 (m, 11H), 1.67-1.69 (m, 3H), 2.17-2.19 (m, 2H), 2.94-2.97 (m, 2H), 3.11 (s, 2H), 3.23 (t. J = 6.3 Hz. 2H). 4.08 (s, 2H), 7.38-7.40 (m, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.73 (dd, J = 8.6, I. 5 Hz, 1H). 8.05 (dd. J = II. 7, 5.1 Hz. 2H). -182- 201021798【表58】
化合物 番号 構造式 NMRCd) retention time Mass method 11-2-42 V—NH N^^C02H U 0 (DMS0-d6) 5: 4.17 (s, 2H). 4.50 (d. J = 5.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38(d, J= 1.0 Hz, 1H), 8.64 (s, 1H), 9.11 (brs, 1H). 11-2-43 (DMS0-d6) <5: 4.17 (s, 2H), 4.38 (d, J = 5.7 Hz, 2H), 6.53 (d, J = 15.3 Hz.1H), 7.35-7.42 (m, 3H), 7.52 (t J = 7.5 Hz, 2H), 7.63 (d. J = 9.6 Hz. 2H). 7.74-7.81. (m,, 3H), 8.04 (d, J = 5.4 Hz, 1H), 8.37 (t, J = 1.2Hz, 1H),8.89(t, J = 5.7Hz, 1H),12.41 (brs, 1H). 11-2-44 (CDCI3) δ : 1.35 (t,J = 7.1 Hz, 3H), 4.17 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.83 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz. 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.64 (d, J = 7.1 Hz, 2H), 7.74 (dd, J = 8.6, 1.5 Hz, 1H), 8.04-8.08 (m, 2H), 8.29 (s, 1H), 8.32 (br s, 1H). 11-2-45 ^XXhHA)。、 (DMS0-d6) <5:3.01-3.06 (m, 3H), 3.74-3.78 (m, 3H), 4.11-4.22 (m, 6H). 7.38 (t, J = 7.2Hz, 1H), 7.47 (t J = 7.8Hz, 2H). 7.63 (d, J = 7.5Hz, 2H). 7.71 (dd, J = 9.0, 2.1Hz, 2H), 8.02-8.10 (m, 2H) 11-2-46 0 V〇H 〇^5>^° (DMS0-d6) d:4.15(s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 4.63 (s, 2H). 6.77-6.80 (m, 1H), 6.88-6.91 (m, 2H), 7.23 (t, J = 7.8 Hz. 1H), 7.39 (t, J = 7.5 Hz, 1H). 7.50 (t, J = 7.2 Hz, 2H), 7.74-7.81 (m, 3H), 8.03 (d, J = 5.7 Hz, 1H), 8.37 (d, J =1.5 Hz,1H), 8.85 (t, J = 5.7Hz, 1H), 12.96 (brs, 1H). -183- 201021798 【表59】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-47 (DMSO-d6) δ : 4.15 (s, 2Η), 4.32 (d, J = 5.7 Hz, 2H), 4.64 (s, 2H), 6.77-6.81 (m, 1H), 6.88-6.91 (m, 2H), 7.24 (t, J = 7.5 Hz, 1H), 7.74-7.81 (m, 3H) ,8..03 (d, J = 5.4 Hz. 1H), 8.38 (d, J =1.5 Hz,1H), 8.67 (t. J = 5.4Hzt 1H),12.96 (brs, 1H). 11-2-48 广Ν 4。 (CDCI3) δ: 1.19-1.28 (m, 3H), 4.08-4.26 (m, 4H), 4.41 (d, J = 17Hz, 2H), 4.83 (d, J = 23Hz, 2H), 7.18-7.23 (m, 2H), 737-7.49 (m. 4H), 7.63-7.71 (m, 4H), 7.96-8.06 (m, 2H), 8.49-8.58 (m, 1H) 11-2-49 (DMS〇-d6) δ : 1.32 (t,J = 7.10 Hz, 3H). 4.40 (q, J = 7.10 Hz, 2H), 4.21 (s, 2H), 4.74 (d, J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.50 (t, J = 7.60 Hz, 2H), 7.73-7.82 (m, 3H), 8.02 (d, J = 8.11 Hz, 1H), 8.39 (d, J = 1.01 Hz, 1H), 9.28 (t, J = 5.58 Hz, 1H). 11-2-50 (CDCI3) <5: 1.40 (s, 9H), 3.30 (m, 2H), 4.07 (s, 2H). 4.96 (br-s, 1H), 7.38-7.50 (m, 4H), 7.62-7.73 (m, 3H), 8.05-8.08 (m, 2H) 11-2-51 (CDCI3) (5: 2.91 (s, 3H), 3.04 (m, 2H), 3.24 (q. J = 6.0Hz, 2H), 4.08 (s, 2H), 7.10 (br-s, 1H), 7.39 (t, J = 7.5Hz, 1H), 7.50 (t,J = 8.1Hz· 2H),7.73-7.81 (m, 3H), 8.02 (d. J = 8.7Hz, 1H), 8.38 (s, 1H), 8.47 (br-s, 1H) -184- 201021798【表60】
化合物 番号 構造式 NMR(<$) retention time Mass method 11-2-52 (DMS0-d6) 5: 1.80 (s, 3H), 3.11-3.18 (m. 4H), 4.06 (s, 2H), 7.39 (t, J = 6.6Hz, 1H), 7.49 (t, J = 8.1Hz, 2H), 7.73-7.80 (m, 3H), 7.91 (m, 1H), 8.06 (d, J = 8.4Hz, 1H), 8.38 (s, 1H), 8.42 (m, 1H) 11-2-53 (DMSO-d6) <5:3.57 (d, J = 5.07 Hz, 2H), 4.13(s, 2H), 7.38 (m, 1H), 7.46-7.52 (m, 2H), 7.73-7.80 (m. 3H), 8.00 (d, J = 8.62 Hz, 1H), 8.18 (t,J = 5.07 Hz. 1H), 8.36 (d. J= 1.52 Hz, 1H). 11-2-54 人 (DMS0-d6) δ: 3.85 (d, J = 5.7Hz, 2H), 4.18 (s, 2H), 7.78-7.86 (m. 4H), 7.98-8.02 (m, 3H), 8.20 (d, J = 8.4Hz, 1H). 8.31 (s, 1H), 8.72 (m, 1H) 11-2-55 (7^S^N^\nh 1H-NMR(DMS0-d6) <5: 2.57-2.97 (m, 2H). 3.46-3.50 (m, 2H), 4.16 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 6.67-6.88 (m, 1H), 7.41-7.49 (m, 6H), 7.71-7.80 (m, 5H), 8.02 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H), 8.58-8.59 (m, 1H), 8.95-8.97 (m, 1H), 11.82-12.00 (m, 1H). 11-2-56 rrCO>Nir^F |1 J o co2h 1H-NMR (DMSO-d6) δ : 4.17 (s, 2H), 4.39 (d, J = 5.7 Hz, 2H), 7.42-7.55 (m, 6H), 7.78-7.84 (m, 5H), 8.05 (d, J = 8.7 Hz, 1H), 8.40 (s, 1H), 8.96 (s, 1H), 13.30 (s, 1H). -185- 201021798 【表61】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-57 2.12 432.95 C 11-2-58 (DMSO-d6) 6: 3.83 (s, 3H), 4.09 (s, 2H), 4.41 (d, J =5.7 Hz. 2H), 7.33-7.38 (m, 1H), 7.41-7.56 (m, 6H), 7.79 (d, J = 5.7 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 8.91 (t, J = 5.7 Hz, 1H), 12.96 (brs, 1H). 11-2-59 CX〇jCI)V’k〜 (DMSO-d6) (5:2.20(s, 3H), 3.81 (d, J = 6.0Hz. 2H), 4.09 (s. 2H), 4.16 (d, J =5.7Hz, 2H), 6.93 (d, J = 7.8Hz, 1H), 7.08-7.15 (m, 2H), 7.23 (t, J = 8.1Hz, 1H), 7.34 (d. J 二 7.2Hz. 1H), 7.54 (st1H), 7.92 (d, J = 9.0Hz. 1H), 8.66-8.69 (m, 2H) 11-2-60 (J 0 (DMSO-d6) δ : 2.89 (q, J = 6.0Hz, 2H), 3.18 (q, J 二 6.0Hz, 2H), 4.03 (s, 2H), 7.39-7.81 (m, 6H), 7.99-8.02 (m, 2H), 8.19 (m, 1H), 8.37 (s, 1H), 8.43 (m, 1H), 8.82 (d, J = 6.0Hz, 1H), 8.95 (s, 1H) 11-2-61 £ V〇. cAs>>4°h (DMS0-d6) δ: 4.20 (s, 2H), 4.41 (d, J = 5.7 Hz, 2H), 7.38-7.48 (m, 2H), 7.53 (t J = 6.6 Hz, 3H), 7.8-7.92 (m, 5H), 8..04 (s, 1H). 8.32 (s, tH), 871-8.89 (m, 2H), 8.95 (t, J = 5.7Hz, 1H),9.34 (s, 1H). -186- 201021798 【表62】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-62 X Η 、入AN1NVC0NH2 Η 〇 (DMS〇-d6) δ: 3.66 (d. J = 6.08 Hz, 2H), 3.82 (d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.09 (s, 1H), 7.25 (s. 1H), 7.39 (m, 1H). 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H). 8.01 (d, J = 8.62 Hz. 1H), 8.23 (t, J = 5.83 Hz, 1H), 8.38 (d, J = t.01 Hz, 1H). 8.69 (t, J = 5.58 Hz. 1H). 11-2-63 •VN 1H-NMR(DMS0-d6) δ: 3.10 (t, J = 7.1 Hz, 2H), 3.60-3.61 (m, 2H), 4.16 (s, 2H), 4.39 (d, J = 6.1 Hz, 2H), 7.37-7.51 (m, 5H), 7.75 (tt, J = 19.3, 6.5 Hz, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (s, 1H), 8.64-8.65 (m, 1H), 8.92 (t, J = 5.6 Hz, 1H). 11-2-64 (DMS〇-de) <5: 2.65 (t, J = 6.34 Hz, 2H), 3.33 (dt, J = 6.34, 5.58 Hz, 2H), 3.79 (d, J = 6.08 Hz. 2H). 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.34 (t,J = 5.58 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.67 (t, J = 5.58 Hz, 1H). 11-2-65 (DMS〇-d6) <5: 1.31 (t. J = 7.10 Hz, 3H). 2.20 (s, 3H), 4.14 (s. 2H), 4.40 (q, J = 7.27 Hz, 2H), 4.72 (d, J = 5.58 Hz, 2H), 6.93 (d, J = 8.11 Hz, 1H), 7.09 -7.15 (m. 2H), 7.23 (m. 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.54 (d, J = 2.53 Hz, 1H), 7.92 (d. J = 9.12 Hz, 1H), 9.25 (t, J = 5.58 Hz, 1H). 11-2-66 CCO^H (DMS〇-de) δ: 2.20 (s. 3H), 3.55 (d, J = 5.07 Hz, 2H), 4.06 (s, 2H), 6.92 (d, J = 8.11 Hz, 1H), 7.06-7.14 (m, 2H), 7.22 (m, 1H), 7.34 (d, J = 7.60 Hz, 1H), 7.53 (d, J = 2.53 Hz, 1H), 7.90 (d, J = 8.62 Hz, 1H), 8.15 (t, J = 5.07 Hz, 1H). -187- 201021798 【表63】 化合物 番号 構造式 NMR(d) retention time Mass method 11-2-67 1 Η s^n-YnXCN (DMS0-de) <5: 1.13 (dd,J =8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz. 2H), 4.16 (s. 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.74-7.81 (m, 3H), 8.01 (d. J = 8.62 Hz, 1H). 8.38 (d, J = 1.01 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H). 11-2-68 0 /-NH 〇、M PhXX〆、义 _2 (DMS〇-de) δ: 4.21 (s, 2H), 4.71 (d, J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.82 (m, 3H), 8.02 (d, J = 8.62 Hz, 1H), 8.10 (brs, 1H), 8.31 (brs, 1H), 8.39 (d. J = 1.52 Hz, 1H), 9.26 (t, J = 5.58 Hz, 1H). 11-2-69 1 H (DMS0-de) 5:4.10(d, J = 6.08 Hz, 2H), 4.19 (s. 2H), 7.23 (d. J = 3.55 Hz, 1H), 7.39 (m, 1H), 7.46-7.53 (m, 3H), 7.73-7.82 (m, 3H). 8.04 (d, J = 8.62 Hz, 1H), 8.39 (s, 1H), 8.81 (t, J = 5.58 Hz, 1H), 12.21 (s, 1H). 11-2-70 Λ Q (DMS〇-de) ¢: 4.02 (d, J = 5.58 Hz, 2H), 4.20 (s, 2H), 7.34-7.41 (m, 2H). 7.47-7.52 (m. 2H), 10.27 (s, 1H), 7.73-7.81 (m, 3H), 8.00-8.04 (m, 2H), 8.28 (m, 1H), 8.39 (d, J = 1.52 Hz, 1H), 8.74 (d, J = 2.53 Hz, 1H). 8.79 (t, J = 5.83 Hz. IH). 11-2-71 0 f—L N~CN VNH '~/ 1H-NMR(DMS0-d6) δ: 1.19-1.24 (m, 2H), 1.57-1.68 (m, 3H), 2.99-3.03 (m, 4H). 3.36-3.39 (m, 2H), 4.05 (s, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t. J = 7.6 Hz, 2H), 7.76-7.78 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.37-8.43 (m, 2H). 201021798【表64】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-72 (DMS0-d6) 5: 3.75 (s, 3H), 4.12 (s, 2H). 4.25 (d, J =5.7Hz, 2H), 6.84-6.95 (m, 3H), 7.37-7.41 (m, 3H), 7.74-7.53 (m, 3H), 8.02 (d, J = 5.7 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.79 (t,J = 5.7 Hz, 1H), 12.97 (brs, 1H). 11-2-73 i η Η 0 (DMS〇-de) δ : 1.70 (tt, J =6.25, 7.35 Hz, 2H), 2.48 (t, J = 7.35 Hz, 2H), 3.17 (dt, J = 6.25, 5.58 Hz, 2H), 3.75 (d, J = 5.58 Hz, 2H). 4.15 (s, 2.0H), 7.39 (m. 1.0H), 7.47-7.52 (m, 2.0H), 7.73-7.81 (m, 3.0H), 8.01 (d, J = 8.11 Hz, 1.0H), 8.04 (t, J = 5.58 Hz, 1.0H), 8.38 (d, J = 1.01 Hz, 1.OH), 8.64 (t, J = 5.58 Hz, 1.0H). 11-2-74 (DMS〇-d6) δ : 1.75 (tt,J =7.10, 6.59 Hz, 2H), 2.54 (t, J = 6.59 Hz, 2H), 3.21 (dt, J = 7.10, 5.58 Hz, 2H), 4.06 (s, 2H), 7.38 (m, 1H), 7.50 (m, 1H), 7.73-7.81 (m. 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d,J = 1.01 Hz, 1H), 8.46 (t, J = 5.58 Hz, 1H). 11-2-75 h S 丫qcn (DMS〇-d6) (5: 1.21-1.70 (br m, 8H), 2.14-2.21 (m, 2H), 3.85 (d. J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.11 Hz. 1H), 8.39 (d, J =3.04 Hz, 2.0H), 8.65 (t, J =5.58 Hz, 1.OH). 11-2-76 〇v ^Ν-ίο VNH ^1 、 a01〆 1H-NMR(DMS0-d6) δ: 1.21-1.23 (m, 2H), 1.55- I. 59 (m, 1H), 1.76 (d, J = 12.2 Hz, 2H), 2.67 (tJ = II. 7 Hz, 2H), 2.83-2.84 (m, 3H), 3.06-3.07 (m, 2H), 3.55 (d, J= 11.2 Hz, 2H)t 4.08 (s, 2H), 7.38-7.40 (m, 1H), 7.49-7.51 (m, 2H). 7.74-7.80 (m, 3H), 8.00- 8.02 (m, 1H), 8.39-8.43 (m, 2H). 189- 201021798 【表65】 化合物 番号 構造式 NMR(d) retention time Mass method 11-2-77 1 1 Η 0 (DMS〇-de) <5: 2.90-3.09 (m, 3H), 4.11 (d. J = 5.58 Hz. 2H), 4.19 (s, 2H), 4.40-4.67 (m, 2H), 7.39 (m. 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz. 1H). 8.38 (d, J = 1.01 Hz, 1H), 8.62 (t, J = 5.58 Hz, 1H) 11-2-78 0 /~(—、N-d=0 t!cl 1H-NMR(DMS0-d6) δ : 1.22-1.25 (m, 2H), 1.43-1.55 (m, 1H), 1.74-1.76 (m, 2H), 2.39-2.42 (m. 2H), 3.03 (t J = 6.1 Hz, 2H), 3.61 (d, J = 11.7 Hz, 2H), 4.06 (s, 2H), 7.36-7.40 (m, 2H). 7.48-7.54 (m. 3H), 7.76-7.78 (m, 3H). 8.00 (d, J = 8.6 Hz, 1H). 8.37-8.38 (m, 2H). 11-2-79 0 /—\ N —v ^y0-yJ^NH ^ VNHz 1H-NMR(DMS0-d6) 6 : 1.22-1.25 (m, 2H), 1.38- I. 42 (m, 1H), 1.63 (d, J = II. 2 Hz, 2H), 1.97-2.01 (m, 2H), 2.78-2.81 (m, 4H), 3.02 (t, J = 6.1 Hz, 2H). 4.07 (s, 2H), 7.09-7.11 (m, 2H). 7.39 (t J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.36-8.37 (m, 2H). 11-2-80 yNi7^N 飞 N 1H-NMR(DMS0-d6) δ : 1.16-1.20 (m, 2H), 1.37-1.46 (m, 1H), 1.67-1.69 (m, 2H), 2.07-2.13 (m, 2H), 2.70-2.76 (m, 2H), 3.03 (t, J = 6.3 Hz. 2H), 3.68 (s, 2H). 4.04 (s, 2H), 7.39 (t. J =7.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.74-7.80 (m, 3H), 8.00 (d, J = 8.6 Hz, 1H), 8.36-8.38 11-2-81 〇^Λ-〇5 1H-NMR(DMS0-d6) 5: 4.13-4.15 (m, 2H), 4.39-4.40 (m, 2H), 7.23-7.26 (m, 2H), 7.43-7.50 (m. 4H), 7.75-7.80 (m, 3H), 8.02-8.04 (m, 1H), 8.38 (s, 1H), 8.86-8.87 (m, 1H). 10.54-10.56 (m, 1H), 11.29-11.34 (m, 1H). -190- 201021798【表66】
化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-82 (CDCI3) 6 : 3.02-3.21 (m, 3H), 4.09-4.32 (m. 4H), 1.44-1.46 (m. 9H), 7.37 (m, 1H), 7.47 (t, J = 7.5Hz, 2H), 7.63-7.71 (m, 3H). 8.02-8.07 (m, 2H) 11-2-83 (DMS0-d6) δ: 3.22 (s, 1H), 4.05 (s, 2H), 4.17-4.26 (m, 2H), 4.42 (s, 2H), 7.39 (m, 1H), 7.50 (t, J = 7.2Hz, 2H), 7.74-7.81 (m, 3H). 8.01 (m, 1H), 8.38 (s, 1H), 8.66 (m, 1H) 11-2-84 1H-NMR(DMS0-d6) <5: 1.27 (d, J = 3.5 Hz, 3H), 4.15-4.16 (m. 4H), 4.33-4.34 (m, 1H)t 7.39-7.41 (m, 1H), 7.49-7.50 (m, 2H), 7.76-7.78 (m, 3H), 7.99-8.02 (m, 1H), 8.38 (s. 1H), 8.72-8.74 (m, 2H). 11-2-85 1H-NMR (DMS0-d6) 5: 1.27 (d, J = 7.1 Hz, 3H), 4.14-4.16 (m, 4H), 4.33-4.35 (m, 1H), 7.38-7.40 (m, 1H), 7.50 (t. J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J= 1.5 Hz, 1H), 8.72-8.74 (m, 2H). 1 卜 2-86 jQcVa V-NH Ό 0 M / 〇 \ (CDCI3) 5: 1.46 (s, 9H), 4.00-4.14 (d, J = 5.1Hz, 2H), 4.09 (s, 2H). 7.42 (br-s, 1H), 7.59 (m, J = 9.3Hz, 1H), 7.88 (d, J = 8.7Hz, 1H), 8.01 (s. 1H) -191- 201021798 【表67】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-87 C rxw^ 、八0 (DMSO-d6) δ : 4.10-4.14 (m. 4H), 7.39-7.51 (m, 3H), 7.63-7.66 (m, 2H), 7.74 (m, 1H), 8.05-8.09 (m, 2H) 11-2-88 3cV\ s y-m p 6 Μ: HN飞 CN (DMSO-d6) <5: 3.82 (2H, J = 6.0 Hz, dd), 4.15-4.17 (4H, m), 7.63 (1H, J = 9.3Hz, d), 7.88 (d, J = 9.0Hz. 1H), 8.36 (s, 1H), 8.68-8.74 (m, 2H) 11-2-89 會 (DMSO-d6) <5: 1.43 (d, J = 7.60 Hz, 3H), 3.77-3.88 (m, 2H), 4.16 (s, 2H), 4.79 (dq, J = 7.60, 7.10 Hz. 1H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.70 (t,J = 5.83 Hz, 1H), 8.75 (d, J = 7.10 Hz, 1H). 11-2-90 (DMSO-d6) δ: 1.43 (d,J = 7.60 Hz, 3H), 3.77-3.88 (m, 2H), 4.16 (s. 2H), 4.79 (dq, J = 7.60, 7.10 Hz, 1H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.38 (d, J =1.52 Hz. 1H), 8.70 (t, J = 5.83 Hz,1H), 8.75 (d, J = 7.10 Hz. 1H). 11-2-91 1H-NMR(DMS0-d6) δ: 4.02 (d, J = 5.6 Hz, 2H), 4.20 (s, 2H), 7.39 (t, J = 7.4 Hz. 1H), 7.49-7.55 (m, 4H). 7.76-7.79 (m. 3H). 8.02 (d, J = 8.6 Hz, 1H), 8.39-8.44 (m. 3H), 8.80 (t, J = 5.6 Hz, 1H), 10.45 (s, 1H). -192- 201021798【表68】
化合物 番号 構造式 NMR(d) retention time Mass method 11-2-92 CI (DMS0-d6) δ: 4.24 (s, 2H), 4.41 (d, J = 6.1 Hz. 2H), 7.41-7.53 (m, 7H), 7.82 (d, J = 7.6 Hz, 1H), 7.89 (s, IH), 8.13 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H). 11-2-93 CI —V-NH Ο U 0 Μ V m—χ CN (DMS0-d6) <5: 3.84 (d, J = 5.6 Hz, 2H), 4.16 (d,J = 5.6 Hz. 2H), 4.25 (s, 2H), 7.45-7.52 (m, 5H), 8.14 (s, 1H). 8.70 (t, J = 5.3 Hz, 1H), 8.79 (t, J = 5.6 Hz, 1H). 11-2-94 rxv^^rcN MeO^^ 1.8 394.95 (ES+) C 11-2-95 F3C^XXVT^!1^CN 2.08 432.90 (ES+) C 11-2-96 (yCxhKA〜 (DMS0-d6) (5: 2.25 (3H, s), 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.26-7.32 (m, 4H), 7.44 (d, J = 8.1Hz, 1H), 8.03 (t, J = 8.4Hz, 2H), 8.69-8.74 (m, 2H) -193- 201021798 【表69】 化合物 番号 構造式 NMR(<S) retention time Mass method 11-2-97 ^^cf3 (DMSO-d6) δ:3.83(2Η, J =6.0 Hz, d), 4.16-4.18 (4Η. m), 7.42 (1H, J = 9.3Hz, d), 7.48 (1H, J = 7.5Hz, d), 7.65-7.75 (m, 2H), 8.87 (d, J = 8.7Hz,1H),1H),7.98-8.04 (m, 2H). 8.69-8.74 (m, 2H) 11-2-98 1H-NMR(DMSO-d6) δ : 1.37 (s, 9H), 2.98-3.00 (m, 2H), 3.09-3.11 (m, 2H), 3.75 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 6.80-6.83 (m, 1H), 7.39-7.41 (m, 1H), 7.48-7.51 (m, 2H), 7.74-7.80 (m, 3H), 8.01-8.02 (m, 2H), 8.38 (d, J = 2.0 Hz, »H), 8.60-8.63 (m, 1H). ( 11-2-99 1H-NMR(DMS0-d6) δ : 2.12 (s, 6H), 2.27 (t, J = 6.8 Hz, 2H), 3.17 (q,J = 6.3 Hz, 2H), 3.75 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m. 3H), 7.84-7.87 (m, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.62-8.64 (m, 1H). 11-2-100 °\ CN ΝΗ ΗΝ —^ ^Cis〆 π、 (DMSO-de) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd,J = 8.11,5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 7.78-7.87 (m, 3H). 8.01 (d, J = 8.62 Hz, 2H), 8.20 (d, J = 8.62 Hz, 1H), 8.31 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H). 11-2-101 〇^χ>ν->Γον ^ Η 1H-NMR(DMS0-d6) <5: 2.38 (t, J = 7.1 Hz, 2H), 4.05 (s, 2H), 4.14 (d, J = 5.6 Hz, 2H), 7.40-7.41 (m. 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.79 (m. 3H), 8.00 (d. J = 8.6 Hz. 1H), 8.37 (d, J = 1.5 Hz. 1H), 8.46-8.49 (m, 1H), 8.63-8.65 (m, 1H). 201021798 【表70】
化合物 番号 構造式 NMR((5) retention time Mass method 11-2-102 (DMS0-d6) δ: 2.61 (s, 6Η), 4.17(s, 2Η), 4.41 (d, J =5.6 Hz, 2H), 7.38-7.49 (m, 6H), 7.55 (d, J = 7.6 Hz, 1H), 7.82-7.90 (m, 3H), 8.96 (t, J = 5.8 Hz, 1H). 11-2-103 (DMS0-d6) d: 4.16 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 4.41 (d, J = 6.1 Hz, 2H), 7.39 (t J = 7.4 Hz. 1H), 7.45-7.53 (m, 4H), 7.74-7.83 (m, 5H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.94 (t,J = 5.8 Hz, 1H), 9.22 (t, J = 5.1 Hz, 1H). 11-2-104 H g Η (DMSO-de) (5:3.65(d, J = 5.58 Hz, 2H), 3.82 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz. 1H), 8.26 (t, J = 5.58 Hz, 1H), 8.38 (d, J= 1.52 Hz, 1H), 8.63 (t, J = 5.32 Hz. 1H), 8.83 (s, 1H), 10.48 (s, 1H). 11*2-105 Q^S^>T/ HN^ CN (DMS0-d6) δ: 2.61 (s, 6H), 3.83 (d, J = 5.6 Hz, 2H), 4.15-4.18 (m. 4H), 7.37-7.49 (m, 5H), 7.86 (s, 1H), 8.69 (t J = 5.6 Hz, 1H). 8.75 (t, J = 5.6 Hz, 1H). 11-2-106 Η Π Η (DMS〇-d6) δ : 2.73 (s, 3H), 3.52 (d, J = 5.07 Hz, 2H), 3.80 (d, J = 6.08 Hz, 2H), 4.15 (s, 2H). 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.69-7.81 (m, 4H), 8.02 (d. J = 8.62 Hz, 1H), 8.38 (s. 1H), 8.67 (t, J = 5.58 Hz, 1H). -195- 201021798 【表71】 化合物 番号 構造式 NMR(<5) retention time Mas$ method 11-2-107 1H-NMR(DMS0-d6) δ: 3.86 (d. J = 5.6 Hz, 2H), 3.92-3.95 (m, 2H), 4.16 (s. 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz. 2H), 7.74-7.81 (m, 3H), 8.01 (d. J = 8.6 Hz, 1H), 8.38 (d, J =1.5 Hz, 1H), 8.62-8.64 (m, 1H), 8.69-8.72 (m, 1H). 11-2-108 1H-NMR(DMS0-d6) 5: 3.15 (q, J = 5.9 Hz, 2H), 3.40-3.41 (m, 2H), 3.77 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.67-4.69 (m, 1H), 7.39-7.41 (m. 1H), 7.50 (t J = 7.6 Hz. 2H), 7.75-7.80 (m. 3H), 7.98-8.01 (m, 2H), 8.38 (d, J= 1.5 Hz, 1H), 8.59-8.62 (m, 1H). 11-2-109 Vcn 1H-NMR(DMS0-d6) (5: 3.18-3.20 (m. 4H), 3.61 (s, 2H), 4.06 (s, 2H), 7.39-7.41 (m, 1H)t 7.50 (t. J = 7.6 Hz, 2H), 7.76-7.78 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.34-8.41 (m, 3H). 11-2-110 H J Η (DMS0-de) <5: 3.58 (s. 3H), 3.64 (d. J = 5.58 Hz, 2H), 3.83 (d, J = 5.58 Hz, 2H). 4.16 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.62 Hz, 1H), 8.29 (t, J =5.58 Hz. 1H). 8.38 (s, 1H), 8.66 (t J = 5.32 Hz, 1H), 11.07 (brs, 1H). 11-2-111 (DMS0-d6) δ: 3.83 (2H, J = 6.0 Hz, d), 4.16-4.18 (4H, m), 7.83-7.88 (m, 3H), 8.50 (s, 1H). 8.69-8.75 (m, 2H) -196- 201021798【表72】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-112 (DMS0-d6) 5:3.83 (2H, J =6.0 Hz, d), 4.16-4.18 (4H, m), 7.31-7.38 (m, 2H), 7.44 (m, 1H), 7.58-7.68 (m, 2H), 8.03 (d,J = 8.1Hz, 1H), 8.26 (s, 1H), 8.69-8.74 (m, 2H) 11-2-113 (DMS0-d6) 5: 3.83 (2H. J = 6.0 Hz, d). 4.16-4.18 (4H, m), 7.23 (t, J = 9.3Hz, 1H), 750-7.64 (m, 4H). 7.83 (d, J = 9.3Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 8.45 (s, 1H), 8.68-8.76 (m, 2H) 11-2-114 (DMS0-d6) δ : 3.83 (2H, J =6.0 Hz, d), 4.16-4.18 (4H, rn). 7.33 (t, J = 8.7Hz, 1H), 7.76-7.80 (m, 3H), 8.01 (d, J = 8.4Hz, 1H), 8.37 (s, 1H), 8.69-8.74 (m, 2H) 11-2-115 “s,c〇2H 1H-NMR (DMS0-d6) (5: 2.39 (t, J = 7.1 Hz, 2H)t 3.26-3.30 (m, 2H), 3.74 (d, J = 5.6 Hz, 2H). 4.15 (s, 2H), 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01-8.03 (m, 2H), 8.38 (d. J = 1.5 Hz, 1H), 8.60-8.63 (m, 1H), 12.22-12.24 (m, 1H). 11-2-116 〇^X>N-Y^s〇2Me 1 H-NMR (DMS0-d6) ¢: 3.00 (s. 3H), 3.25 (t J = 6.8 Hz, 2H), 3.49-3.51 (m, 2H), 3.76 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H). 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz. 2H), 7.77 (td, J = 9.6, 3.5 Hz, 3H), 8.01 (d, J = 8.1 Hz, 1H). 8.24 (t, J = 5.6 Hz, 1H), 8.38 (d,J = 1.5 Hz, 1H), 8.67 (t, J = 5.8 Hz, 1H). -197- 201021798 【表73】 化合物 番号 檐造式 NMR(6) retention time Mass method 11-2-117 1H-NMR(DMSO-d6) δ: 3.96 (d, J = 5.6 Hz, 2H), 4.J7(s, 2H), 7.39 (tJ = 7.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H). 8.01 (d, J = 8.6 Hz. 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H). K-2-118 v“〇 >-NH OH (DMSO-de) <5: 3.85 (d, J = 6.08 Hz, 2H), 4.t5 (s, 2H), 7.39 (m, 1H), 7.47 -7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d, J = 8.11 Hz, 1H), 8.38 (d. J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (brs, 1H). 11-2-119 HN-^ CN (DMS0-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.16-4.19 (m, 2H), 7.78 (t, J = 7.8Hz, 1H), 7.88-7.96 (m, 2H), 8.08 (d, J = 8.7 Hz, 1H), 8.13 (d.J = 7.8 Hz, 1H), 8.26 (s, 1H), 8.54 (s, 1H), 8.67-8.77 (m, 2H) 11-2-120 (Το ΗΝΛν (DMS0-d6) δ: 3.27 (s, 3H), 3.84 (d, J = 5.7 Hz, 2H), 4.16-4.19 (m, 4H), 7.86-8.09 (m, 6H), 8.52 (d, J = 5.1Hz, 1H), 8.63-8.81 (m, 2H) 11-2-121 1H-NMR(DMS0-d6) 5: 3.15 (s, 3H), 3.85-3.88 (m, 2H), 4.16 (s, 2H), 7.37-7.51 (m, 4H), 7.74-7.80 (m, 4H), 8.00-8.02 (m, 1H), 8.37-8.38 (m, 1H), 8.62-8.63 (m, 1H). -198- 201021798【表74】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-122 ~~\^ΝΗ 〇 (DMS0-d6) δ : 1.47 (s, 9H), 4.01 (d, J = 5.4 Hz, 2H), 4.08-4.16 (m, 2H). 7.48 (br-s, 1H), 7.58 (t, J = 7.5Hz, 1H), 7.65-7.69 (m, 2H), 7.87 (d, J = 9.0 Hz, 1H), 7.91 (s, 1H), 8.05 (s, 1H), 8.12(d, J = 8.4Hz, 1H) 11-2-123 1H-NMR (DMS0-d6) 6 : 3.24-3.25 (m, 5H), 3.34-3.36 (m, 1H), 3.77 (d, J = 6.1 Hz, 2H). 4.15 (s. 2H), 7.37-7.41 (m, 1H), 7.48-7.51 (m, 2H), 7.76-7.79 (m, 3H), 8.01-8.04 (m. 2H), 8.38 (d, J = 1.5 Hz, 1H), 8.62 (t, J = 5.8 Hz, 1H). 11-2-124 丫- Η 〇 Ms (CDCI3) <5 : 2.95 (s, 3H), 3.55 (dd, J = 6.08, 5.58 Hz. 2H), 4.07 (d, J = 5.58 Hz. 2H), 4.15 (s, 2H). 4.97 (dt, J = 6.08, 6.59 Hz, 1H), 6.27 (t, J = 6.59 Hz, 1H), 7.31-7.44 (m, 3H), 7.55 (d, J = 7.60 Hz, 2H), 7.63 (dd, J = 8.11,1.52 Hz, 1H), 7.91-7.99 (m, 3H), 8.10 (t, J = 5.58 Hz, 1H). 11-2-125 NC 丫、~~\^NH 0 U 。”〇H (DMSO-d6) (5: 3.85 (d, J = 5.7 Hz, 2H). 4.17 (s, 2H), 7.70 (t, J = 7.5Hz, 1H), 7.86 (t, J = 9.0Hz, 2H), 8.04 (d, J = 8.7Hz, 1H), 8.12 (d,J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.73 (m, 1H), 12.61 (br-s, 1H) 11-2-126 (DMS0-d6) δ: 1.47 (s, 9H), 4.01 (d, J = 5.4 Hz, 2H), 4.16 (s, 2H), 7.48 (br-s, 1H), 7.65-7.82 (m, 5H), 8.05-8.12 (m, 2H) -199- 201021798 【表75】 化合物 番号 構造式 NMR(6) retention time Mass method 11-2-127 NC 八’ 〇H (DMS0-d6) δ: 3.85 (d, J = 6.0 Hz, 2H), 4.17 (s, 2H), 7.88 (d,J = 9.0Hz, IH), 7.89-7.97 (m, 4H), 8.06 (d, J = 8.4Hz, 1H), 8.52 (s, IH), 8.73 (s, IH), 12.64 (br-s, 1H) 11-2-128 上 h 1H-NMR(DMS0-d6) δ : 1.04 (s, 6H), 3.05 (d, J = 6.1 Hz, 2H), 3.82 (d, J = 6.1 Hz, 2H), 4.15 (s, 2H), 4.44 (s, 1H). 7.39-7.41 (m, 1H), 7.50 (t, J = 7.6 Hz. 2H), 7.74-7.80 (m, 4H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J =1.5 Hz, 1H), 8.60-8.62 (m, 1H). 11-2-129 〇Q?J^Voh 1H-NMR(DMS0-d6) δ: 1.18 (s, 7H), 3.39 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 5.6 Hz. 2H), 4.15 (s, 2H). 4.79 (t. J = 5.8 Hz, 1H), 7.37-7.40 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.49-8.52 (m, 1H). 11-2-130 1H-NMR(DMS0-d6) <5: 1.52-1.59 (m, 2H), 3.13-3.14 (m, 2H), 3.40-3.42 (m, 2H), 3.74 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.43 (t J = 5.3 Hz, 1H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.74-7.80 (m, 3H). 7.93 (t. J = 5.3 Hz, 1H), 8.01 (d, J =8.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.62 (tJ = 5.6 Hz, 1H). 11-2-131 丄Η 1H-NMR(DMS0-d6) δ: 1.00-1.05 (m. 3H). 3.02-3.04 (m, 2H), 3.64-3.65 (m, 1H), 3.78 (d. J = 5.6 Hz, 2H), 4.15 (s, 2H). 4.67 (d. J =4.6 Hz. 1H). 7.38-7.40 (m, 1H), 7.48-7.51 (m. 2H), 7.74-7.80 (m, 3H), 7.91 (t. J = 5.8 Hz, 1H), 8.01 (d, J =8.1 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.61 (t, J = 5.8 Hz. 1H). -200- 201021798 【表76】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-132 1H-NMR(DMS0-d6) δ : 1.03 (d, J = 6.6 Hz, 3H), 3.22-3.25 (m, 1H), 3.36-3.37 (m, OH). 3.76-3.79 (m, 3H), 4.15 (s, 2H), 4.69 (t, J =5.6 Hz, 1H), 7.37-7.41 (m, 1H), 7.48-7.51 (m, 2H), 7.73-7.77 (m, 5H), 8.01 (d, J = 8.1 Hz, 1H), 8.38 (d,J =1.5 Hz, 1H), 8.57 (t,J = 5.6 Hz, 1H). 11-2-133 ~p 6 Μ: ΗΝ^ CN (DMSO-d6) 5: 1.52-1.68 (m, 6H), 3.18 (t, J = 5.3 Hz, 4H), 3.81 (d, J = 5.6 Hz, 2H), 4.06 (s, 2H), 4.16 (d, J =5.6 Hz, 2H), 7.14 (dd, J = 8.9, 2.3 Hz, 1H), 7.37 (d, J =2.5 Hz, 1H). 7.80 (d, J = 8.6 Hz, 1H), 8.68 (t,J = 5.3 Hz, 2H). 11-2-134 ~y_NH 0 U 0 Μ: ΗΝ-^ CN (DMSO-d6) δ: 3.83 (d, J = 6.0 Hz, 2H). 4.16-4.18 (m. 4H), 7.70(t, J = 8.1Hz, 1H), 7.87 (t, J = 8.4Hz. 2H), 8.05 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.26 (s, 1H), 8.50 (s, 1H), 8.69-8.75 (m, 2H) 11-2-135 ΗΝ-^ CN (DMS0-d6) (5: 3.83 (d, J = 6.0 Hz, 2H), 4.18 (s, 2H), 7.88 (d, J = 8.7Hz, 1H), 7.90-8.04 (m, 4H), 8.06 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.69-8.75 (m, 2H) 11-2-136 1H-NMR (DMS0-d6) δ : 1.02 (t, J = 7.1 Hz, 3H), 3.10-3.12 (m, 2H), 3.73 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 7.40-7.41 (m, 1H), 7.48-7.51(m.2H),7.74-7.81 (m, 3H), 7.96-8.00 (m, 2H), 8.38 (d. J = 1.5 Hz, 1H), 8.61 (s, 1H). -201 - 201021798 【表77】 化合物 番号 構造式 NMR((5) retention time Mass method 11-2-137 1H-NMR(DMS0-d6) 6: 3.36-3.37 (m, tH), 3.42-3.44 (m, 1H), 3.79 (d, J = 5.6 Hz, 2H), 4.15 (s, 2H), 4.37 (t, J = 5.1 Hz, 1H). 4.49 (t, J = 5.1 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H). 7.76-7.79 (m, 4H), 8.01 (d, J = 8.1 Hz, 1H). 8.23 (t, J = 5.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.65 (t. J = 5.8 Hz, 1H). 11-2-138 Cl Cl H 1H-NMR(DMS0-d6) 6 : 3.29-3.36 (m, 4H), 7.43 (t. J = 7.4 Hz, 1H), 7.52 (t. J = 7.6 Hz, 2H), 7.78-7.79 (m, 2H), 7.93 (dd, J = 8.6, 2.0 Hz, 1H), 8.15(d, J = 8.6 Hz, 1H), 8.53 (d, J = 1.5 Hz, 1H), 9.00 (t, J = 5.6 Hz, 1H), 9.57 (s, 1H). 11-2-139 σκχχ;>>ΝΗ 0 〇Γ μ: ΗΝ-^ CN (DMSO-d6) δ: 3.81 (d, J =6.1 Hz, 2H), 4.08 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H). 6.85 (t, J = 7.4 Hz, 1H). 7.11-7.17 (m, 3H). 7.26 (t, J = 7.6 Hz, 2H), 7.59 (d, J =2.0 Hz, 1H), 7.86 (d. J = 8.6 Hz, 1H), 8.33 (s, 1H), 8.66-8.69 (m, 2H). 11-2-140 I 0Γ^δ^>Ν^:0 ΗΝ-^ CN (DMS0-d6) δ: 3.82 (d, J = 5.6 Hz, 2H),4.11 (s, 2H), 4.17 (d, J = 5.6 Hz, 2H), 7.34 (t. J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.57-7.60 (m, 3H), 7.81 (s. 1H), 8.69 (t. J = 5.6 Hz, 2H). II-2-H1 C^O^S^NH 0 0 Μ / 0十 (CDCI3) <5: 1.46 (s, 9H), 3.99 (d, J = 5.1 Hz, 2H), 4.07 (s, 2H), 7.04 (d, J = 7.8Hz, 1H), 7.13-7.41 (m, 6H), 7.51 (m, 1H), 7.97 (d, J = 9.0Hz, 1H) -202- 201021798【表78】
化合物 番号 構造式 NMR(6) retention time Mass method 11-2-142 α0χχ:^_0 〇r Μ: OH (DMS0-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.10 (s, 2H). 7.04 (d, J = 8.1Hz, 2H), 7.13-7.21 (m. 2H), 7.41 (t, J = 7.5Hz, 2H), 7.73 (s, 1H), 7.95 (d, J = 9.0Hz, 1H), 8.69 (m, 1H) 11-2-143 Ci〇XX)->Nh 〇 6 Μ: HN—^ CN (DMS0-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.11 (s, 2H). 4.16(d,J = 5.1Hz, 2H), 7.04 (d, J = 8.7Hz, 2H), 7.15-7.20 (m, 2H), 7.40 (t J = 7·8Ηζ, 2H). 7.73 (s, 1H), 7.95 (d, J = 8.7 Hz. 1H), 8.68-8.71 (m, 2H) 11-2-144 〇r^s/-N^° HN—\ CN (DMSO-d6) <5: 3.81 (s, 2H), 3.84 (s, 2H), 4.13 (s, 2H), 4.18 (d,J = 5.7 Hz, 2H), 7.34-7.38 (m, 1H). 7.40-7.45 (m, 2H), 7.50-7.53 (m, 2H), 7.63 (s, 1H), 7.94 (s, 1H9, 8.68 (t, J = 6.0 Hz,1H9, 8.71 (t, J = 6.0 Hz, 1H). 11-2-145 HN) CN (DMS0-d6) 5: 3.87 (d, J = 5.7 Hz, 2H), 4.19 (d.J = 5.5 Hz, 2H), 4.25 (s, 2H), 7.44-7.56 (m, 3H), 7.81 (d, J = 7.1 Hz, 2H). 7.92 (d, J =1.7 Hz, 1H), 8.42 (d, J = 1.0 Hz, 1H), 8.71 (t, J = 5.5 Hz, 1H), 8.80 (t, J = 6.0 Hz, 1H). 11-2-146 ΗΝ-Λ ^-OH (DMSO-d6) δ: 3.17 (q, J = 5.7 Hz, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 5.4 Hz, 2H). 4.12 (s. 2H), 4.69 (d, t= 5.4 Hz, 1H), 7.43 (t. J =6.9 Hz, 2H), 7.50-7.53 (m, 2H). 7.98 (t J = 5.7 Hz, 1H), 8.58 (t, J = 5.7 Hz, 1H). -203 - 201021798 【表79】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-147 丫 (DMS〇-d6) <S:3.85(d, J = 5.58 Hz, 2H), 4.16 (s. 2H). 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.83 (m, 1H), 8.02 (d, J = 8.11 Hz, 1H), 8.45 (d, J =1.01 Hz, 1H), 8.72 (t, J = 5.58 Hz, 1H), 12.64 (brs, 1H). ίΙ-2-148 1 Η OH H 0 (DMS〇-d6) 5:3.15(dt, J =6.08, 5.32 Hz, 2H), 3.41 (dt, J = 6.08, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 4.68 (t, J = 5.32 Hz, 1H), 7.23 (m, 1H), 7.50-7.64 (m. 3H), 7.83 (m, 1H). 7.96 (t, J = 5.32 Hz, 1H), 8.02 (d, J = 8.62 Hz, 1H). 8.45 (s, 1H), 8.61 (t J = 5.58 Hz, 1H). ί 11-2-149 〇r^s ΗΝ-λ^ CN (DMS0-d6) δ : 3.83 (d, J = 6.1 Hz, 2H), 4.16-4.19 (m, 4H), 7.43-7.50 (m. 5H), 8.15 (d,J = 5.1 Hz, 2H), 8.69 (t J = 5.3 Hz, 1H), 8.75 (t, J = 5.6 Hz, 1H). 11-2-150 H l (DMS〇-de) (5: 3.81 (s, 3H). 3.84 (d, J = 5.58 Hz, 2H), 4.14 (s, 2H), 7.05 (d, J =8.62 Hz. 2H), 7.69 (d, J = 8.62 Hz, 2H), 7.74 (dd, J = 8.62, 1.52 Hz, 1H), 7.97 (d, J = 8.62 Hz, 1H), 8.31 (d, J =1.52 Hz, 1H). 8.70 (t, J = 5.58 Hz, 1H), 12.63 (brs, 1H). it 11-2-151 .、〇H 〇b (DMS0-d6) (5: 3.28 (s, 3H). 3.86 (d, J = 6.0 Hz. 2H), 4.18 (s, 2H), 7.88 (dd, J = 8.7, 2.1Hz, 1H). 8.03-8.08 (m, 5H), 8.52 (d, J = 1.8Hz, 1H), 8.73 (m, 1H) -204- 201021798 【表80】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-152 從 ΗΝΛν (DMS0-d6) δ: 3.27 (s, 3H), 3.84 (d, J = 4.2 Hz, 2H). 4.19 (s, 4H), 7.87 (d, J =5.1Hz, 1H), 7.90-8.08 (m, 5H), 8.52 (s, 1H), 8.70-8.75 (m, 2H) 11-2-153 F V OH (DMS0-d6) 5:3.85(d, J = 5.7 Hz, 2H), 4.15 (s. 2H), 7.33 (t, J = 8.7Hz, 2H), 7.75-7.79 (m. 3H), 8.01 (d, J = 8.4Hz, 1H), 8.37 (s, 1H), 8.72 (m, 1H) 11-2-154 H 0 (DMS0-d6) δ: 3.60 (s, 3H), 3.69 (d, J = 5.07 Hz, 2H), 4.15 (s, 2H), 7.39 (m, 1H), 7.47-7.52 (m, 2H), 7.73-7.81 (m. 3H). 8.01 (d. J = 8.62 Hz, 1H), 8.38 (d, J = 1.52 Hz, 1H), 8.68 (tJ = 5.07 Hz, 1H), 11.20 (br s. 1H). 11-2-155 i h H 0 C02Me (DMS〇-de) δ: 3.59-3.73 (m. 5H), 3.82-3.93 (m. 2H), 4.15 (s, 2H), 4.38 (dt, J = 7.60, 5.07 Hz, 1H), 5.08 (t, J = 5.83 Hz, 1H), 7.39 (m, 1.0H), 7.47-7.52 (m, 2H), 7.73-7.81 (m, 3H), 8.01 (d. J = 8.62 Hz, 1H), 8.31 (d, J =7.60 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.62 (t, J = 5.58 Hz, 1H). 11-2-156 〇^?Λ 彳 C 1H-NMR (DMS0-d6) 5: 3.76 (s, 3H), 3.93-3.95 (m, 2H), 4.16 (s, 2H), 5.45-5.47 (m, 1H), 7.37-7.41 (m, 1H), 7.48-7.51 (m, 2H). 7.76-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d. J = 1.5 Hz, 1H), 8.70 (t. J = 5.8 Hz, 1H), 9.24 (d,J = 9.1 Hz. 1H). -205- 201021798 【表81】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-157 丄 1H-NMR(DMS0-d6) δ: 3.50-3.54 (m. 2H), 3.83 (d, J = 5.6 Hz, 2H), 4.16 (s, 2H), 5.87-6.15 (m, 1H), 7.37-7.41 (m, 1H). 7.48-7.51 (m, 2H), 7.75-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.35-8.38 (m, 2H), 8.68 (t, J = 5.6 Hz, 1H). 11-2-158 1H-NMR(DMS0-d6) d: 2.85 (s, 1.5H), 3.00 (s, 1.5H), 3.35-3.36 (m, 2H), 3.46- 3.48 (m, 1H), 3.54-3.55 (m, 1H), 4.02 (d, J = 5.1 Hz, 1H), 4.10 (d,J = 5.1 Hz. 1H), 4.18 (d, J = 4.1 Hz, 2H), 4.66 (t, J = 5.6 Hz, 0.5H), 4.88 (t, J = 5.3 Hz, 0.5H), 7.39 (t, J = 7.4 Hz, 1H). 7.50 (t, J = 7.9 Hz. 2H). 7.74-7.80 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.46- 8.47 (m, 1H). 11-2-159 1H-NMR(DMS0-d6) d : 1.24 (d,J = 7.1 Hz, 3H). 3.80-3.89 (m, 2H), 4.16 (s, 2H), 4.58-4.62 (m, 1H), 7.38-7.40 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.74-7.80 (m. 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 8.6 Hz, 1H),8.66(t, J = 5.8Hz. 1H). 11-2-160 〇^Q;x>n^Hn^〇cf3 1H-NMR(DMSO-d6) δ: 3.40-3.41 (m, 2H), 3.79 (d, J = 6.1 Hz, 2H), 4.08 (t, J = 5.3 Hz, 2H), 4.15 (s, 2H), 7.39 (t,J = 7.4 Hz, 1H), 7.50 (t. J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01 (d, J = 8.1 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.66 (t, J = 5.6 Hz, 1H). -206- 201021798【表82】
化合物 番号 構造式 nmr(5) retention time Mass method 11-2-161 Η 0 (DMSO-d6) <5: 3.15 (dt. J =6.08, 6.08 Hz, 2H), 3.41 (dt, J = 5.58, 6.08 Hz, 2H), 3.76 (d, J = 5.58 Hz, 2H), 3.81 (s, 3H). 4.14 (s, 2H), 4.68 (t, J = 5.83 Hz, 1H), 7.05 (d, J = 8.62 Hz, 2H), 7.70 (d, J 二 8.62 Hz, 2H), 7.74 (dd. J = 8.36, 1.77 Hz, 1H), 7.94-7.99 (m, 2H), 8.32 (d, J = 1.77 Hz, 1H), 8.60 (t, J = 5.58 Hz, 1H). 11-2-162 F3C V^N-γ^ΟΗ Η 〇 (DMS〇-d6) 5:3.16(dt J =6.08, 6.08 Hz, 2H), 3.41 (dt, J = 5.58. 6.08 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 4.69 (t,J = 6.08 Hz. 1H), 7.78-7.87 (m, 3H). 7.95-8.03 (m, 3H). 8.20 (d,J = 8.62 Hz. 1H), 8.32 (s, 1H), 8.62 (t. J = 5.58 Hz, 1H). 11-2-163 —\-m p 〇r M: HN-^ CN (DMS0-d6) δ: 1.97-2.00 (m, 4H), 3.26-3.30 (m, 4H), 3.81 (d, J = 6.1 Hz, 2H), 4.04 (s, 2H), 4.17 (d, J = 5.6 Hz, 2H), 6.75 (dd, J = 8.6, 2.0 Hz. 1H). 6.99 (d, J =2.0 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 8.65-8.69 (m, 2H). 11-2-164 食 1H-NMR (DMS0-d6) δ : 3.60-3.66 (m, 2H), 3.86-3.94 (m, 2H), 4.16 (s, 2H), 4.53-4.56 (m,1H), 5.18 (t, J = 5.8 Hz. 1H), 7.38-7.40 (m, 1H). 7.50 (t,J = 7.6 Hz, 2H), 7.74-7.80 (m, 3H), 8.01 (d, J 二 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz. 1H), 8.50 (d, J = 9.1 Hz. 1H), 8.65 (t,J = 5.6 Hz. 1H). 11-2-165 (DMS0-d6) 5: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d,J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.47-7.56 (m, 3H), 8.12-8.18 (m. 3H), 8.41 (d, J = 8.4 Hz, 1H), 8.69 (t, J = 5.7 Hz, 1H), 8.77 (t, J = 5.7 Hz, 1H).. -207 - 201021798 【表83】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-166 (DMS0-d6) δ: 3.15 (q, J = 5.7 Hz, 2H), 3.42 (q, J = 5.7 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 419(s,2H), 4.68 (t, t= 5.7 Hz, 1H), 7.43-7.59 (m, 2H), 7.50-7.53 (m, 3H). 7.97 (t, J = 5.7 Hz, 1H), 8.11-8.19 (m, 3H), 8.40 (d, J =5.7 Hz, 1H), 8.64 (t, J = 5.7 Hz, 1H). 11-2-167 (〇MS〇-d6) d: 2.91 (s, 3H), 3.00 (q, J = 6.3 Hz, 2H), 3.20 (q, J = 6.3 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 419 (s, 2H), 7.06 (t, J = 6.0 Hz, 1H), 8.13-8.19 (m. 3H), 8.41 (d, J = 8.4 Hz, 1H), 8.67 (t, J = 5.7 Hz, 1H). I Ιί-2-168 / (DMS0-d6) δ: 2.90 (s, 3H), 3.00 (q, J = 5.7 Hz, 2H), 3.76 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 3.84 (s, 2H), 4.12 (s, 1H), 7.05 (t, J = Hz. 1H), 7.32-7.37 (m, 3H), 7.40-7.45 (m, 2H), 7.62 (s, 1H). 7.94 (s, 1H), 8.05 (t, J =5.7 Hz, 1H), 8.60 (t, J = 5.7Hz,1H). 11-2-169 ^ ηνγν>、 1H-NMR(DMS0-d6) (5: 3.86 (d, J 二 5.6 Hz, 2H), 4.16(s, 2H). 4.60(d, J = 5.6 Hz, 2H), 7.39 (t, = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.77 (td, J = 9.1, 3.5 Hz, 3H), 8.01 (d, J = 8.6 Hz,出),8.38 (d, J = 1.5 Hz, 1H), 8.66 (t, J = 5.6 Hz, 1H), 8.74 (t, J = 5.6 Hz, 1H). < 11-2-170 (DMS0-d6) δ : 3.84 (d, J = 5.4 Hz, 2H), 4.11 (s, 2H), 7.26 (s, 1H), 7.39-7.51 (m, 3H), 7.77 (d, J - 7.2Hz, 2H), 7.90 (s, 1H), 8.69 (m, 1H), 12.67 (br-s, 1H) -208 - 201021798【表84】
化合物 番号 檐造式 NMR(d) retention time Mass method 11-2-171 Η Π (DMS〇-de) δ: 3.85 (d, J = 5.58 Hz, 2H), 4.16(s, 2H), 7.39 (m. 1H), 7.47-7.53 (m, 2H), 7.71-7.79 (m, 3H), 8.14 (d, J = 8.11 Hz, 1H), 8.21 (br s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 12.64 (brs, 1H). 11-2-172 H Q (DMS〇-d6) 6: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4.0H), 7.40 (m, 1H), 7.47-7.53 (m, 2H), 7.72-7.79 (m, 3H), 8.14 (d,J = 8.11 Hz, 1H), 8.21 (d,J = 1.01 Hz, 1H), 8.69 (t, J = 5.32 Hz, 1H), 8.74 (t. J = 5.83 Hz, 1H). 11-2-173 〇 M: HN-\ CN (DMSO-d6) 6: 3.83 (d, J =6.1 Hz. 2H), 4.02 (s, 2H), 4.19 (d,J = 5.6 Hz, 2H), 7.38 (t. J = 6.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.66-7.73 (m, 3H), 7.78 (d, J = 8.1 Hz, 1H), 7.98 (s, 1H), 8.71 (q, J = 5.2 Hz, 2H). 11-2-174 (DMS0-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d,J = 5.7 Hz, 2H), 4.23 (s, 2H), 8.71-8.61 (m, 2H), 8.79 (t, J = 5.7 Hz,, 1H), 8.90 (d, J = 2.1 Hz, 1H). 11-2-175 (DMS0-d6) δ: 3.86 (d, J = 5.7 Hz, 2H). 4.19 (d, J = 5.7 Hz, 2H), 4.24 (s, 2H). 7.42-7.18 (m, 1H), 7.54-7.57 (m,2H), 7.80-7.63 (m. 2H), 8.75-8.82 (m, 2H), 8.86 (d, J = 2.4 Hz, 1H), 8.86 (d, J = 2.4 Hz,, 1H). 8.98 (d, J = 2.4 Hz. 1H). -209- 201021798 【表85】 化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-176 1H-NMR(DMS0-d6) δ : 4.17 (s, 2Η), 4.62-4.63 (m, 4Η), 7.38-7.40 (m, 1H), 7.49-7.51 (m, 2H), 7.75-7.80 (m, 3H), 8.02 (d, J = 8.1 Hz, 1H), 8.38(d, J = 1.5 Hz, 1H), 9.17 (t, J = 5.8 Hz, 1H). 11-2-177 厂)γ-νη /〇 υ Γ Μ ΗΝ 飞 ^ΟΗ (DMS0-d6) <5: 0.85 (t, J =6.8 Hz, 6H), 2.87 (q, J = 7.1 Hz, 4H), 3.16 (q,J = 5.9 Hz, 2H), 3.41 (q, J = 5.7 Hz, 2H), 3.76 (d, J = 6.1 Hz. 2H), 4.10 (s, 2H), 4.68 (t, J = 5.6 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.82 (s, 1H), 7.96 (t, J = 5.1 Hz, 1H),8.57(t, J = 5.3Hz, 1H). 11-2-178 (T^s ΗΝ-^ CN (DMSO-d6) δ: 0.85 (t, J =6.3 Hz, 6H). 2.87 (q, J = 6.8 Hz, 4H), 3.82 (d, J = 5.1 Hz, 2H), 4.11 (s, 2H), 4.17 (d. J = 4.6 Hz, 2H), 7.30-7.44 (m, 3H), 7.55-7.64 (m, 6H), 7.84 (s, 1H), 8.67-8.71 (m. 2H). 11-2-179 1H-NMR(DMS0-d6) δ : 3.23-3.28 (m, 4H), 4.08 (s, 2H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.76-7.79 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.52-8.53 (m, 1H), 9.52 (s, 1H). 11-2-180 1H-NMR(DMS0-d6) (5: 3.73 (s, 3H), 3.94 (d. J = 6.1 Hz, 2H), 4.17 (s, 2H), 6.43 (d. J = 2.0 Hz. 1H), 7.37-7.41 (m, 1H), 7.49-7.53 (m, 3H), 7.76-7.79 (m, 3H), 8.05 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.69 (t, J = 5.6 Hz, 1H), 10.42 (s, 1H). -210- 201021798 【表86】
化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-181 (DMS0-d6) δ: 4.24 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H), 7.44-7.54 (m, 5H), 8.61 (d, J = 2.1 Hz, 1H), 8.99(t, J = 5.7 Hz,, 1H), 1296 (brs, 1H). II-2-182 會 1H-NMR(DMS0-d6) 5: 2.45 (s, 2H), 4.03-4.05 (m, 2H), 4.18 (s, 2H), 7.39 (t, J =7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.75-7.81 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.80 (t, J = 5.6 Hz, 1H), 11.63-11.66 (m, 1H). 11-2-183 Η 〇 (DMS〇-d6) 6: 3.60 (s, 3H), 3.70 (d, J = 5.07 Hz, 2H), 4.16 (s, 2H), 7.23 (m, 1H), 7.50-7.64 (m. 3H), 7.84 (dd, J = 8.62, 1.01 Hz, 1H), 8.01 (d, J = 8.62 Hz, 1H), 8.45 (d, J= 1.01 Hz, 1H), 8.69 (t, J = 5.07 Hz, 1H), 11.25 (s, 1H). 11-2-184 b Η N-N 1H-NMR (DMS0-d6) (5: 1.32 (t, J = 7.1 Hz, 3H), 4.19 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H ), 4.69 (d, J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.48-7.51 (m, 2H), 7.74-7.81 (m, 3H), 8.01 (d, J = 8.6 Hz, 1H), 8.39 (d, J =2.0 Hz, 1H), 9.24 (t, «J = 5.6 Hz, 1H). 11-2-185 〇 0 N~\ HN—\ CM (DMS0-d6) δ : 3.82 (d, J =5.6 Hz, 2H), 4.10 (s, 2H), 4.16 (d, J = 5.6 Hz, 2H), 6.60 (td, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J=11.7 Hz, 1H), 6.91 (dd, J = 8.1, 1.0 Hz. 1H), 7.18-7.28 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.58 (s, 1H), 8.66-8.71 (m, 2H). -211 - 201021798 【表87】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-186 〇^^xAn^xVC0NH2 s η Ν-Ν 1H-NMR (DMS0-d6) <5: 4.19 (s, 2H), 4.66 (d,J = 6.1 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.76-7.79 (m, 3H)t 8.02 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.61 (s, 1H), 9.20 (t, J = 5.6 Hz, 1H). 11-2-187 1H-NMR(DMSO-d6) δ : 4.18-4.21 (m, 2H), 4.73-4.74 (m, 2H), 7.41-7.50 (m, 3H), 7.74-7.81 (m, 3H), 8.01-8.02 (m, 1H), 8.39 (s, 1H), 9.24-9.25 (m, 1H). 11-2-188 〇 ΗΝ飞 CN (CDCI3) δ: 3.40 (s, 3H), 4.07 (m, 4H), 4.14 (d, J = 6.1 Hz, 2H), 7.07-7.14 (m, 4H), 7.32-7.37 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.56 (s. 1H), 7.65 (d, 〇 = 8.6 Hz, 1H), 7.82 (s, 1H). 11-2-189 、&Q I Ο^Λβ^μη^ο HN—\ CN (CDCI3) δ : 2.99 (s, 3H), 4.12-4.14 (m, 4H), 4.26 (d, J = 5.6 Hz, 2H), 6.57 (s, 1H), 7.37 (d,J = 7.6 Hz. 2H), 7.49-7.64 (m, 5H), 7.76 (s, 1H), 8.28 (s. 1H). 11-2-190 ^V_ M 0 R"CN Ογ^Κ^Ί (DMS〇-d6) 6: 3.83 (d, J = 5.58 Hz, 2H), 4.03 (s, 2H). 4.18 (d,J = 5.58 Hz, 2H), 7.39 (m, 1H), 7.46-7.52 (m, 2H), 7.66-7.80 (m, 4H), 8.01 (s, 1H), 8.68-8.73 (m, 2H). -212- 201021798【表88】
化合物 番号 構造式 NMR(6) retention time Mass method 11-2-191 b Η Ν-Ν 1H-NMR(DMS0-d6) δ: 4.16 (s, 2Η), 4.46 (d, J = 5.1 Hz, 2H), 7.38-7.40 (m, 1H), 7.50 (t,J = 7.6 Hz, 2H), 7.69-7.81 (m, 4H), 8.00-8.03 (m, 2H), 8.39 (s, 1H), 8.97 (s, 1H). 11-2-192 〇 ην-^Ν Χ^Ν yNiri (DMS0-d6) δ: 3.83 (d, J =5.7 Hz, 2H), 4.15 (d, J 二 5.7 Hz, 2H), 4.17 (s, 2H), 7.38-7.52 (m, 6H), 7.62-7.82 (m,5H), 8.39 (d, J = 1.5 Hz, 1H), 8.68 (t,J = 5.7 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H). 11-2-193 〇^9 Q ην-^νΓ (DMS0-d6) δ: 2.89 (s, 3H), 2.98 (q, J = 5.7 Hz, 2H), 3.21 (q, J = 5.7 Hz, 2H), 3.76 (d. J = 5.7 Hz, 2H), 4.16 (s, 2H), 7.05 (t, J = 5.7 Hz, 6H), 7.81-7.92 (m, 5H), 2H), 8.04 (t, J = 5.7 Hz, , 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.60 (t, J = 5.7 Hz. 1H). 11-2-194 〇^Λ々:Γ3 1H-NMR (DMS0-d6) δ: 4.21-4.22 (m, 4H), 7.38-7.40 (m, 1H), 7.48-7.51 (m, 2H), 7.76-7.80 (m, 3H), 8.03 (d, J = 8.6 Hz, 1H), 8.39 (d, J= 1.5 Hz, 1H), 8.93 (t, J = 5.6 Hz, 1H), 13.42 (s, 1H). 11-2-195 σχχ〜。η ° π (DMS0-d6) <5: 3.83 (d. J =5.6 Hz, 2H), 4.13 (s, 2H), 7.30-7.40 (m, 6H). 7.86 (d, J = 1.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.70 (t, J = 5.6 Hz, 1H). -213- 201021798 【表89】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-196 Xls^NH 〇 〇Γ Μ: ΗΝ—\ CN (DMS0-d6) δ : 3.81 (d, J =6.1 Hz, 2H), 4.14-4.16 (m, 4H), 7.32-7.41 (m, 6H), 7.87 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H)t 8.67 (t, J = 5.3 Hz, 1H), 8.72 (t, J = 5.8 Hz, 1H). 11-2-197 1H-NMR(DMS0-d6) 5: 4.18 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H). 7.39-7.52 (m, 3H), 7.76-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.39 (d,J= 1.5 Hz, 1H), 9.11 (t, J = 5.6 Hz, 1H), 15.16 (s, 1H). 11-2-198 1H-NMR(DMSO-d6) δ : 3.71 (d, J = 5.6 Hz, 2H), 4.13 (s, 2H), 7.37-7.40 (m, 1H), 7.49 (t,J = 7.6 Hz, 2H), 7.75-7.79 (m, 3H), 8.01 (d, 0 = 8.6 Hz, 1H), 8.37-8.37 (m. 2H). 11-2-199 F (DMS〇-de) δ: 2.38 (t, J = 7.10 Hz, 2H), 3.34 (dt, J = 7.10, 5.32 Hz, 2H).8.64 (t, J =5.58 Hz, 1.OH), 4.05 (s, 2H), 4.14 (d,J = 5.58 Hz, 2H), 7.22 (m, 1.0H), 7.50-7.64 (m, 3H), 7.83 (dd, J = 8.36, 1.77 Hz, 1H), 8.01 (d, J = 8.11 Hz, 1H), 8.43 (d, J =1.01 Hz, 1H), 8.48 (t, J = 5.32 Hz, 1H). 11-2-200 VNyv\ 0 、\ ΗΝ-λ^ CN (DMS0-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.16-4.18 (m, 4H), 6.59 (s, 1H), 7.79 (d. J =2.1 Hz, 1H), 7.97 (dd, J = 8.4, 2.1 Hz, 1H), 8.18 (d, J = 8.7Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.63 (d, J = 2.7 Hz, 1H). 8.67-8.78 (m, 2H) -214- 201021798【表90】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-201 F3CV^\ (DMS〇-de) δ: 1.21-1.70 (m, 8H), Z.13-2.21 (m, 2H), 3.85 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H). 7.78-7.87 (m, 3H), 8.01 (d, J = 8.11 Hz, 2H), 8.20 (dd, J = 8.62, 1.52 Hz. 1H), 8.31 (d, J = 1.52 Hz, 1H), 8.40 (s, 1H), 8.66 (t, J = 5.58 Hz, 1H). I 卜 2-202 (DMSO-de) δ: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.40 (m, 1H), 7.48-7.53 (m, 2H), 7.71- 7.79 (m. 3H), 8.14 (d,J = 8.11 Hz, 1H), 8.21 (d, J = 1.01 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H). I 卜 2-203 ΗΝ—\ CN (DMS〇-d6) δ: 3.30 (s, 3H), 3.81 (d, J = 5.6 Hz, 2H), 4.08 (s, 2H), 4.16 (d, J =5.6 Hz, 2H), 7.00 (dd, J = 8.6, 2.0 Hz, 1H), 7.09-7.18 (m, 4H), 7.43 (d, J = 2.0 He, 1H), 7.86 (d, J = 8.6 Hz. 1H), 8.65-8.70 (m, 2H). II-2-204 F (DMS〇-d6) 5: 4.18 (s, 2H), 4.24 (d, J = 5.07 Hz, 2H), 7.22 (m, 1H). 7.51-7.64 (m, 3H), 7.85 (dd, J = 8.36, 1.52 Hz, 1H), 8.03 (d, J = 8.36 Hz, 1H), 8.47 (d, J =1.52 Hz, 1H). 9.09 (t, J = 5.07 Hz, 1H). I 卜 2-205 fX7 Ocv>Nh〇 〇Γ Μ: ΗΝ飞 OH (DMS0-d6) δ : 3.14 (q, J =5.7 Hz, 2H), 3.29 (s, 3H), 3.40 (q, J = 5.4 Hz, 2H), 3.75 (d, J = 5.6 Hz, 2H), 4.07 (s, 2H), 4.67 (t, J = 5.3 Hz, 1H), 6.99 (dd, J 二 8.9, 2.3 Hz, 1H), 7.09-7.18 (m, 4H), 7.44 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.95 (t,J = 5.1 Hz, 1H), 8.56 (t, J = 5.8 Hz, 1H). -215- 201021798 【表91】 化合物 番号 構造式 NMR(fi) retention time Mass method 1(-2-206 〇 o〜/CN (DMSO-de) <5: 4.06 (d. J = 5.58 Hz. 2H), 4.17 (s, 2.0H), 5.03 (s, 2.0H), 7.37-7.52 (m, 3H), 7.74-7.81 (m, 3H), 8.02 (d, J = 8.62 Hz, 1H), 8.38 (d, J = 1.01 Hz, 1H), 8.92 (t, J = 5.83 Hz, 1H). 11-2-207 叫Η貪 (DMSO-de) 6 : 1.12 (dd,J =8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 6.08 Hz, 2H), 4.16 (s. 2H), 7.22 (mt 1H), 7.50-7.64 (m, 3H), 7.84 (dd, J = 8.62. 1.52 Hz, 1H), 8.02 (d. J = 8.11 Hz. 1H), 8.45 (d, J = 1.52 Hz. 1H), 8.68 (t, J = 6.08 Hz, 1H), 8.91 (s. 1H). 11-2 208 h h °o (DMS〇-d6) δ: 1.21-1.70 (m, 8H), 2.14-2.21 (m, 2H), 3.85 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.84 (dd, J = 8.62, 2.03 Hz. 1H), 8.02 (d, J = 8.62 Hz, 1H), 8.40 (s, 1H), 8.45(d, J 二 2.03 Hz, 1H), 8.65 (t, J = 5.58 Hz, 1H). 11-2-209 S巧丫、〇〜F 0 (DMS〇-d6) (5: 3.71 (d, J = 5.07 Hz, 2H), 3.99 (t, J = 2.54 Hz, 1H), 4.06 (t, J = 2.54 Hz, 1H), 4.15 (s, 2H), 4.54 (t, J = 2.54 Hz, 1H), 4.66 (t, J = 2.54 Hz, 1H), 7.22 (m. 1H). 7.50-7.65 (m, 3H), 7.83 (dd, J = 8.62, 1.52 Hz. 1H), 8.02 (d,J = 8.62 Hz, 1H), 8.45 (d, J = 1.52 Hz, 1H), 8.69 (t,J = 5.07 Hz, 1H), 11.36 (s, 1.0H). 11-2-210 0 (DMSO-d6) δ: 3.90 (d, J = 5.07 Hz, 2H), 4.18 (s, 2H), 7.00-7.07 (m, 3H), 7.19-7.35 (m, 3H), 7.50-7.64 (m, 3H). 7.83 (dd, J = 8.62, 2.Q3 Hz, 1H), 8.00 (d, J = 8.62 Hz, 1H), 8.46 (d, J = 2.03 Hz, 1H), 8.84 (t, J = 5.07 Hz, 1H), 12.01 (s, 1H). -216- 201021798【表92】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-211 Η 〇 (DMS〇-d6) 5: 3.13 (s, 1 Η), 3.79 (d, J = 5.6 Hz, 2H), 3.90 (m, 2H), 4.16 (s, 2H), 7.36-7.42 (m, 1H), 7.46-7.52 (m. 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.40-8.48 (m, 1H), 8.65-8.70 (m, 1H). 11-2-212 η ι (DMS〇-de) δ : 3.91 (d, J = 5.2 Hz, 2H), 4.19 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 7.36-7.44 (m, 1H), 7.47-7.53 (m, 2H), 7.72-7.80 (m, 3H), 7.90 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.78-8.89 (m, 4H). 11-2-213 Η 0 (DMS〇-d6) δ : 3.72-3.80 (m, 5H), 4.10-4.18 (m, 4H), 7.31 (s, 1H), 7.37-7.43 (m, 1H), 7.46-7.57 (m, 3H). 7.72-7.82(m, 3H), 7.97-8.02 (m, 1H), 8.23-8.28 (m, 1H), 8.38 (s, 1H), 8.61-8.67 (m, 1H). Π-2-214 η δ 2.16 415.95 (ES+) C 11-2-215 Η ι (DMSO-de) δ: 1.05-1.18 (m, 2H), 1,48-1.68 (m, 3H), 2.96-3.02 (m, 2H), 3.21 (t. J = 11.2 Hz, 2H), 3.74-3.85 (m, 4H), 4.16 (s, 1H), 7.36-7.42 (m, 1H). 7.47-7.54 (m, 2H), 7.72-7.82 (m, 3H), 7.91-7.97 (m, 1H), 7.98-8.04 (m, 1H). -217- 201021798 【表93】 化合物 番号 構造式 NMR(d) retention time Mass method 11-2-216 H 0 1.29 439.05 (ES+) C 11-2-217 α-Qxx 9 Η 0 (DMS〇-de) δ: 4.00 (d, J = 5.2 Hz, 2H), 4.21 (s, 2H), 7.02-7.08 (m, 1H), 7.28-7.35 (m, 2H), 7.35-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.72-7.82 (m, 3H). 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.73-8.79 (m, 1H), 10.05 (s, 1H). 11-2-218 Η 0 (DMSO-de) δ: 4.06 (dr J = 4.4 Hz, 2H), 4.21 (s, 2H), 7.37-7.43 (m, 1H), 7.47-7.53 (m, 2H). 7.73-7.82 (m, 3H), 8.02 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H). 8.81-8.87 (m, 1H), 8.91 (s, 1H), 9.00 (s, 2H), 10.51 (s, 1H). 11-2-219 (DMS0-d6) δ: 3.43 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.38-7.53 (m, 3H), 7.69 (d J = 13.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 2H), 8.26 (d, J = 0.9 Hz, 1H), 8.63 (t, J = 5.4Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H). II-2-220 F 〇^Λακ,°Η (DMS0-d6) <5:3.16(q, J = 5.7 Hz, 2H). 3.10 (q, J = 5.7 Hz, 2H), 3.78 (d. J = 5.7 Hz, 2H), 4.20 (s, 2H), 4.67 (t, J = 5.7 Hz, 1H). 741 (t, J = 5.7 Hz, 1H), 7.51 (t, J = 5.7 Hz, 2H), 7.67 (d. J = 12.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H),7.95(t, J = 1.8 Hz, 1H). 8.26 (d, J 二 0.9 Hz, 1H), 8.63 (t, J = 5.7Hz, 1H). -218- 201021798【表94】
化合物 番号 構造式 NMR( δ) retention time Mass method 11-2-221 K1 〇 (DMS〇-de) δ : 3.83 (s, 2H), 4.05 (s, 2H), 4.17 (s. 2H), 7.50-7.58 (m, 2H), 7.84 (dd, J = 8.62, 1.52 Hz, 1H), 7.91-8.00 (m, 3H), 8.17 (brs, 1H), 8.24 (s, 1H). 8.72 (brs, 2H). II-2-222 ^Λ-γ0Η H 0 (DMS〇-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.53 (m, 1H), 7.61-7.66 (m, 2H), 7.77 (dd, J = 8.62, 1.52 Hz, 1H), 8.16 (d, J = 8.62 Hz, 1H), 8.27 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (s, 1H). II-2-223 s ϋ M: HN^ CN (DMS0-d6) 5: 0.93 (t, J = 7.4 Hz, 3H), 1.62-1.64 (m, 2H), 3.74 (t, J = 7.6 Hz, 2H), 3.84 (d, J = 5.9 Hz, 2H), 4.11 (s, 2H), 4.18 (d,J =5.7 Hz, 2H), 6.90-7.04 (m, 3H), 7.09 (dd, J = 8.6, 2.3 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 7.53 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 8.63-8.74 (m, 2H). II-2-224 /N 丫、—^NH p XX ° ^ CN (CDCI3) δ: 3.03 (s, 6H), 3.76 (s, 2H). 4.08-4.15 (m, 4H), 6.80 (dd, J = 9.0, 2.4Hz, 1H), 6.97-7.01 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.74 (d, J = 15Hz, 1H), 7.81 (br-s, 1H), 8.03-8.06 (m, 2H). I 卜 2-225 F_0_ H 6 (DMS〇-d6) δ : 3.83 (d, J = 5.58 Hz, 2H), 4.16-4.19 (m, 4H), 7.23 (m, 1H), 7.50-7.66 (m, 3H), 7.77 (dd, J = 8.62, 1.52 Hz, 1H), 8.16 (d, J = 8.62 Hz, 1H), 8.27 (d, J =1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H). -219- 201021798 【表95】 化合物 番号 構造式 NMR((5) retention time Mass method 11-2-226 (DMS〇-de) δ: 1.12 (dd, J = 8.11,5.83 Hz, 2H). 1.49 (dd,J = 8.11,5.58 Hz, 2H). 3.78 (d, J = 5.83 Hz. 2H), 4.17 (s, 2H), 7.23 (m, 1H), 7.51-7.66 (m, 3H), 7.77 (dd, J 二 8.36, 1.52 Hz, ΪΗ). 8.16 (d, J = 8.36 Hz, 1H), 8.27 (d, J = 1.52 Hz, 1H), 8.69 (t, y) = 5.83 Hz, 1H), 8.92 (s, 1H). 11-2-227 丫 (DMSO-d6) d: 3.85 (d, J = 5.58 Hz, 2H), 4.16 (s, 2.0H), 7.32 (t, J = 8.61 Hz, 2H), 7.71 (dd, J = 8.11, 1.52 Hz, 1H). 7.79-7.84 (m, 2H), 8.14 (d,J = 8.11 Hz, 1H), 8.20 (d,J = 1.52 Hz. 1H), 8.71 (t, J = 5.83 Hz, 1H), 12.64 (s, 1H). 11-2-228 Η Π (DMSO-d6) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4H), 7.33 (t, J = 8.87 Hz. 2H), 7.71 (dd, J = 8.62, 1.52 Hz, 1H), 7.79-7.84 (m, 2H), 8.14 (d,J = 8.62 Hz, 1H), 8.20 (d, J= 1.52 Hz. 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.73 (t, J = 5.83 Hz, 1H). 11-2-229 (DMSO'd6) 6 : 1.12 (dd,J = 8.36. 5.32 Hz, 2H), 1.49 (dd. J = 8.36, 5.32 Hz. 2H), 3.77 (d, J = 5,58 Hzf 2H), 4.16 (s, 2H), 7.29-7.35 (m, 2H), 7.71 (dd.J = 8.62, 1.52 Hz, 1H)( 7.79-7.84 (m, 2H), 8.14 (d, J = 8.62 Hz, 1H), 8.20 (d, J= 1.52 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H). 8.91 (s, 1H). 11-2-230 f3〇-^C) ^?Λ 丫 (DMSO-d6) 5: 3.85(d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.71-7.83 (m, 3H), 8.07-8.12 (m, 2H), 8.19 (d, J = 8.11 Hz, 1H), 8.32 (d, J = 1.52 Hz, 1H), 8.72 (t,J = 5.83 Hz, 1H). -220- 201021798【表96】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-231 p3CH0 Η 0 (DMS0-d6) δ : 3.84 (d, J = 6.08 Hz, 2H), 4.16-4.20 (m, 4H), 7.71-7.84 (m, 3H), 8.07-8.12 (m, 2H), 8.19 (d, J = 8.62 Hz, 1H), 8.32 (d, J =1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1H). 11-2-232 Ρ3〇_^0 (DMS〇-d6) δ : 1.13 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd, J = 8.11, 5.58 Hz, 2 H), 3.78 (d, J = 6.08 Hz, 2H), 4.18 (s, 2H), 7.71-7.84 (m, 3H), 8.06-8.12 (m, 2H), 8.19 (d,J = 8.62 Hz, 1H), 8.32 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H). 11-2-233 H s (DMS0-d6) 5: 3.13 (t, J = 2.53 Hz, 1H), 3.78 (d, J = 6.08 Hz, 2H), 3.90 (dd, J = 5.58, 2.53 Hz, 2H), 4.16 (s, 2H), 7.40 (t J = 7.35 Hz. 1H), 7.47-7.53 (m, 2H), 7.73 (dd, J = 8.62, 1.52 Hz, 1H), 7.77 (d, J = 7.10 Hz, 2H), 8.14 (d, J = 8.62 Hz, 1H), 8.22 (d, J = 1.52 Hz, 1H), 8.44 (t, J = 5.32 Hz, 1H), 8.67 (t, J = 5.83 Hz, 1H). 11-2-234 F^:JUN^^ H 〇 (DMS〇-d6) 5: 3.12 (t, J = 2.53 Hz, 1H), 3.78 (d, J = 5.58 Hz, 2H>. 3.90 (dd, J = 5.58, 2.53 Hz, 2H), 4.16 (s, 2H), 7.22 (m, 1H), 7.50-7.64 (m, 3H), 7.84 (dd. J = 8.62, 1.77 Hz, 1H), 8.02 (d, J = 8.62 Hz, 1H), 8.40-8.46 (m, 2H), 8.67 (t, J = 5.83 Hz, 1H). 11-2-235 (DMS0-d6) 5:3.83-3.87 (m, 5H), 4.15 (s, 2H), 6.96 (m, 1H), 7.26-7.35 (m, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.6, 1.8 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.71 (t, J = 6.1 Hz, 1H). -221- 201021798 【表97】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-236 HN—\ CN (DMS0-d6) δ: 3.81-3.86 (m, 5H). 4.15-4.19 (m, 4H), 6.96 (dd, J = 8.1,2.5 Hz, 1H), 7.27-7.34 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.80 (dd, J = 8.5, 1.9 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.40(d, J = 1.8 Hz, 1H), 8.65-8.77 (m, 2H). 11-2-237 C 丨丫 0 ^-COOH (DMSO-d6) «5: 3.85 (d, J = 5.7 Hz, 2H), 4.16(s, 2H), 7.46 7.53 (t, J = 7.8 Hz, 1H), 7.72-7.76 (m, 1H), 7.81-7.85 (m, 2H), 8.02 (d, J = 8.4 Hz. 1H), 8.45 (d, v)= 1.5 Hz. 1H), 8.72 (t,J = 5.8 Hz. 1H). 11-2-238 H 0 (DMSO-d6) δ: 2.88 (s, 1H), 3,01 (s, 2H), 4.02-4.23 (m, 6H), 7.36-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.82 (m, 3H). 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.53-8.59 (m, 1H). 11-2-239 °^un^XH2 Η Π (DMSO-de) δ: 3.93 (d, J = 5.2 Hz, 2H), 4.30 (s, 2H). 7.11-7.18 (m, 1H), 7.35-7.43 (m. 1H), 7.46-7.56 (m, 3H), 7.72-7.87 (m, 5H), 8.03 (d, J = 8.4 Hz, 1H), 8.31-8.35 (m, 1H), 8.38 (m, 1H). 8,56 (d. J = 8.4 Hz, 1H), 9.09-9.13 (巾,1H), 12.21 (s, 1H). 11-2-240 nh2 H 0 (DMSO-de) <5: 4.01 (d, J = 4.8 Hz, 2H), 4.21 (s, 2H), 7.32-7.43 (m, 3H), 7.45-7.59 (m, 3H), 7.72-7.83 (m, 5H), 7.93-7.97 (m, 1H), 7.99-8.07 (m, 2H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.17 (s, 1H). - 222- 201021798【表98】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-241 〇γΝΗ2 H 0 (DMS0-d6) 5:4.01 (d, J = 5.2 Hz, 2H), 4.20 (s. 2H). 7.22-7.28 (m, 1H), 7.37-7.43 (m, 1H), 7.45-7.54 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.72-7.88 (m, 6H), 8.02 (d, 8.4 Hz, 1H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.27 (s, 1H). II-2-242 H 0 (DMS〇-d6) δ: 4.03 (d, J = 4.8 Hz, 2H), 4.22 (s, 2H), 7.32-7.54 (m, 8H), 7.56-7.63 (m, 3H), 7.72-7.82 (m, 3H), 7.92 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H). 8.75-8.81 (m, 1H), 10.15 (s, 1H). 11-2-243 Η 0 (DMS0-de) 5:4.17 (d,J = 3.2 Hz, 2H), 4.24 (s, 2H), 7.35-7.43 (m, 1H), 7.45-7.56 (m, 4H), 7.64-7.69 (m, 1H). 7.72-7.82 (m, 3H), 7.94 (d, J = 7.2 Hz, 2H), 8.05-8.11 (m, 2H), 8.39 (s, 1H). 8.84-8.90 (m, 1H), 10.05 (s, 1H). 11-2-244 0 o=s-nh2 Η 0 (DMS〇-d6) δ: 4.03 (d, J = 4.8 Hz, 2H), 4.21 (s, 2H), 7.27 (s, 2H), 7.35-7.43 (m, 1H), 7.45-7.54 (m, 2H), 7.71-7.83 (m, 7H). 8.02 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.75-8.82 (m, 1H), 10.40 (s, 1H). 11-2-245 Η 0 (DMS〇-d6) 5: 3.73 (s, 3H), 4.00 (d, J 二 5.2 Hz, 2H), 4.21 (s, 2H), 6.64 (d, J = 7.6 Hz, 1H), 7.13 (d,J = 7.6 Hz, 1H), 7.18-7.26 (m, 1H), 7.31 (s, 1H), 7.35-7.42 (m, 1H), 7.45-7.53 (m, 2H), 7.72-7.82 (m, 3H). 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.73-8.79 (m, 1H), 10.04 (s, 1H). -223 - 201021798 【表99】 化合物 番号 檐造式 NMR(5) retention time Mass method 11-2-246 Η 〇 (DMSO-d6) δ : 3.39 (s, 3H), 3.97 (d. J = 4.4 Hz, 2H), 4.20 (s, 2H), 6.89 (d, J =8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.45-7.53 (m, 4H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.77 (m, 1H), 9.90 (s, 1H). 11-2-247 o=s— h S (DMSO-d6) <5: 3.17 (s, 3H), 4.05 (d, J = 4.0 Hz. 2H), 4.21 (s, 2H), 7.37-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.90 (m, 7H), 8.02 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H). 8.77-8.83 (m, 1H), 10.51 (s, 1H). I 11-2-248 F F——F H l (DMSO-d6) <5: 4.03 (d, J = 5.2 Hz, 2H), 4.20 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H). 7.66-7.83 (m, 7H), 8.02 (d, J = 8.8 Hz, 1H), 8.39 (s. 1H), 8.76-8.82 (m, 1H), 10.43 (s, 1H). 11-2-249 HN—\ CN (DMS0-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.16-4.18 (m, 4H), 6.58 (s, 1H), 7.79 (s, 1H), 8.00-8.06 (m, 2H), 8.54-8.57 (m, 2H), 8.68-8.74 (m, 2H) < 11-2-250 i j^tVa /Ντχ^8 rN^° HN—\ (DMS0-d6) δ: 2.98 (s, 6H), 3.65 (s, 4H), 3.94 (d, J =5.4Hz, 2H), 4.15 (s, 2H), 6.75 (d, J = 9.6Hz, 1H), 6.98-7.01 (m, 2H), 7.29 (t, J = 7.5Hz, 1H), 7.77 (d, J = 8.4Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 8.36 (s. 1H), 8.82 (br-s, 1H) -224- 201021798【表100】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-251 f3c Η 0 (DMS〇-de) δ: 3.83 (d, J = 6.08 Hz, 2H), 4.18-4.15 (m, 4H), 7.36 (d, J = 7.60 Hz, 1H), 7.49 (d, J = 7.60 Hz. 1H), 7.65 (dd, J = 7.35, 7.60 Hz, 1H), 7.76 (dd, J = 7.35, 7.60 Hz, 1H), 7.85-7.89 (m, 2H), 8.13 (d, J = 8.11 Hz, 1H). 8.68 (t, J = 5.58 Hz, 1H), 8.74 (t. J = 5.58 Hz. 1H). "-2-252 CN ΗΝ-7 μ °\\ Γ~\ (DMSO-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.18 (d,J = 5.4 Hz, 2H), 4.25 (s,2H), 7.26-7.30 (m, 1H), 7.54-7.64 (m, 1H), 7.67-7.73 (m, 1H), 8.75-8.81 (m, 1H), 8.93 (d, J = 2.4 Hz. 2H). 9.02 (d, J =2.41 Hz, 1H). H-2-253 CN ΗΝ」 fxj^s (DMSO-d6) 6:3.86(d, J = 5.7 Hz, 2H), 4.19 (d, J = 5.4 Hz, 4H), 4.25 (s, 2H), 7.34-7.41 (m, 2H), 7.85-7.89 (m, 2H), 8.75-8.82 (m, 2H), 8.86 (d, J = 2.4 Hz. 1H), 8.962 (d,J = 2.4 Hz, 1H). II-2-254 (DMS0-d6) <5: 2.26-2.33 (m, 2H), 2.84 (s, 1H), 3.18-3.25 (m, 2H), 3.77 (d, J = 5.2 Hz, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.82 (m, 3H). 8.02 (d, J 二 8.8 Hz, 1H), 8.12-8.18 (m, 1H), 8.38 (s, 1H), 8.62-8.68 (m, 1H). II-2-255 (DMSO-d6) <5: 0.13-0.19(m, 2H), 0.37-0.43 (m, 2H), 0.86-0.93 (m, 1H), 2.94-3.02 (m, 2H), 3.77 (d, J = 5.2 Hz, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H), 8.60-8.66 (m, 1H). -225 - 201021798 【表101】 化合物 番号 構造式 NMR((5) retention time Mass method 11-2-256 CII7 〇 6 Μ; ΗΝ-\ CN (DMSO-d6) δ: 3.82 (d, J = 6.1 Hz, 2H), 4.11 (s, 2H), 4.16(d, J = 5.6Hz, 2H), 6.94-6.97 (m, 2H), 7.16 (dd. J = 8.6. 2.5 Hz, 1H), 7.27-7.28 (m, 2H), 7.62 (d, J = 2.5 Hz. 1H), 7.96 (d, J = 8.6 Hz, 1H), 8.66-8.71 (m, 2H). 2.1 428.00 (ES+) C 11-2-257 0 〇Γ Μ: ΗΝ飞 ^-ΟΗ (DMSO-d6) δ: 3.14 (q, J = 5.9 Hz, 2H), 3.40 (q, J = 5.9 Hz. 2H), 3.75 (d, J = 5.6 Hz, 2H), 4.08 (s, 2H), 4.67 (t, J = 5.6 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 7.03 (d, J =7.6 Hz. 2H), 7.09 (dd, J = 8.9, 2.3 Hz, 1H), 7.29 (t, J = 8.1 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H). 7.95 (t, J = 5.3 Hz, 1H), 8.56 (t, J = 5.6 Hz, 1H). 1.75 398.95 (ES+) C 11-2-258 CI 丫~Vnh ο ν ΗΝ-λ^ CN (DMSO-d6) 5: 3.84 (d, J =5.9 Hz, 2H), 4.15-4.20 (m. 4H), 7.44-7.47 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.74 (dt, J = 7.6, 1.5 Hz, 1H), 7.81-7.85 (m, 2H), 8.03 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.65-8.78 (m. 2H) 11-2-259 F>T^rVvi:i^s —^νη ο IT ^ Μ: τ ΗΝ飞 F CN (DMSO-d6) 5: 3.84 (d, J = 5.9 Hz. 2H), 4.15-4.20 (m, 4H), 7.26 (tt, J = 9.3, 2.3 Hz, 1H), 7.51-7.59 (m, 2H), 7.88 (dd. J = 8.6. 1.9 Hz, 1H), 8.03 (d, J = 8.6Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.65-8.78 (m, 2H). 11-2-260 Ργ^χχ>·>ΝΗ pXJ 0 ^COOH (DMS0-d6) d:3.85(d, J = 5.7 Hz, 2H). 4.16 (s, 2H), 7.49-7.67 (m, 2H), 7.78-7.92 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 8.43 (d, J = 1.7 Hz. 1H), 8.72 (t,J = 5.8 Hz, 1H). - 226- 201021798 【表102】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-261 I TFA 0 ^-COOH (DMS0-d6) δ: 3.32 (s, 3Η). 3.83 (d. J = 5.7 Hz, 2H), 4.06 (s, 2H), 6.92-7.06 (m, 2H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H). 7.27-7.32 (m, 3H), 7.66 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 8.66 (t, J = 5.5 Hz, 1H). M-2-262 α'χΧΗ,ο 0 Ν~\ ΗΝ~^ CN (DMS0-d6) δ: 3.45 (s, 3H), 3.82 (d. J = 6.1 Hz, 2H), 4.14-4.18 (m, 4H), 6.55 (d, J = 8.6 Hz, 1H), 6.69 (dd, J = 7.1, 5.1 Hz, 1H), 7.35 (dd,J = 8.6, 2.0 Hz, 1H), 7.43 (td. J = 7.9, 1.9 Hz, 1H). 7.85 (d, J = 2.0 Hz, 1H). 8.08 (d. J = 8.6 Hz, 1H), 8.17 (dd,J = 4.8, 1.3 Hz, 1H), 8.66-8.73 (m, 2H). H-2-263 ΗΝ-^ Vn^O (DMSO-d6) 6: 3.80 (d, J = 6.0 Hz, 2H). 3.90 (d, J = 5.4 Hz, 2H), 4.20 (s, 2H), 7.47-7/56 (m,3H), 8.12-8.18 (m, 3H), 8.39-8.42 (m, 2H), 8.69 (t, J = 5.4 Hz, 1H). II-2-264 Ο s^n-YKXCN (DMSO-d6) (5: 1.12 (dd, J =8.36. 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.17 (s, 2H), 7.36 (d, J = 8.11 Hz. 1H), 7.49 (d, J = 7.60 Hz. 1H), 7.65 (dd, J = 8.11, 7.60 Hz, 1H), 7.76 (dd, J = 7.60, 8.11 Hz. 1H), 7.85-7.89 (m, 2H), 8.13 (d, J = 8.11 Hz, 1H), 8.69 (t, J =5.58 Hz, 1H), 8.91 (s, 1H). H-2-265 σΝχχΗ_ 〇 ι七 CN (CDCI3) δ: 0.97 (t, J = 7.4 Hz, 3H), 1.16-1.20 (m, 2H), 1.42-1.46 (m, 2H), 1.69-1.78 (m, 2H), 3.73 (t, J = 7.6 Hz, 2H), 4.00 (d, J = 6.1 Hz, 2H), 4.06 (s, 2H), 7.03-7.11 (m, 4H), 7.33 (t, J = 8.1 Hz, 2H), 7.53 (s, 1H), 7.62-7.69 (m, 3H). -227- 201021798 【表103】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-266 HN~\ CN (DMS0-d6) δ: 3.82 (d, J = 5.9 Hz, ZH), 4.08 (s, 2H), 4.17 (d, J = 5.7 Hz, 2H), 6.93-7.06 (m, 3H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.66 (d, J =2.4 Hz, 1H), 7.80 (d. J = 9.1 Hz, 1H), 8.68 (m, 2H). 1.9 394.00 (ES+) C 11-2-267 1 H 叫ΎΧΧ k (DMS0-d6) <5: 1.27-1.34 (m, 3H), 3.93-4.00 (m, 4H), 4.20 (s, 2H), 6.87 (d, J 二 8.0 Hz, 2H), 7.36-7.43 (m, 1H). 7.46-7.53 (m, 4H), 7.72-7.82 (m. 3H), 8.02 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.78 (m, 1H), 9.89 (s, 1H). ( 11-2.268 X H (DMS0-d6) δ: 3.94 (d, J = 4.8 Hz, 2H), 4.19 (s, 2H), 6.71 (d, J = 8.4 Hz, 2H), 7.33-7.43 (m, 3H), 7.45-7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.70-8.76 (m, 1H), 9.22 (s, 1H), 9.78 (s, 1H). 11-2-269 叫丫 χχ 十 (DMS0-d6) 6:4.01 (d, J = 3.2 Hz, 2H), 4.20 (s, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.36-7.43 {m, 1H), 7.46-7.53 (m, 2H), 7.66-7.82 (m, 5H). 8.02 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.76-8.82 (m, 1H), 10.27 (s, 1H). 11-2-270 (DMS0-d6) δ: 1.23 (d, J = 5.6 Hz, 6H), 3.96 (d, J = 4.0 Hz, 2H), 4.20 (s. 2H), 4.48-4.55 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 4H), 7.72-7.82 (m, 3H), 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s. 1H), 8.71-8.78 (m, 1H), 9.89 (s, 1H). -228- 201021798【表104】
化合物 番号 構造式 NMR(6) retention time Mass method 11-2-271 Η ί ό (DMSO-d6) δ: 1.51-1.92 (m, 8H), 3.96 (d, J = 5.2 Hz, 2H), 4.19 (s, 2H), 4.71-4.78 (m, 1H),6.85(d, J = 8.4Hz, 2H), 7.36-7.53 (m, 5H), 7.72-7.82 (巾,3H), 8.01 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.70-8.77 (m, 1H), 9.87 (s, 1H). 11-2-272 血 ό (DMS0-d6) <5: 1.50-1.59 (m, 2H), 1.90-1.98 (m, 2H), 3.41-3.50 (m, 2H), 3.78-3.88 (m. 2H), 3.96 (d, J = 4.8 Hz, 2H), 4.20 (s, 2H), 4.44-4.53 (m. 1H). 6.93 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.45-7.52(m, 4H), 7.72-7.82 (m, 3H). 8.01 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.71-8.78 (m, 1H), 9.90 (s, 1H). 11-2-273 叫m。 (DMSO-d6) δ: 3.98 (d, J = 4.8 Hz. 2H), 4.20 (s, 2H), 5.13 (s, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.36-7.43 (m, 1H), 7.46-7.52 (m, 2H), 7.52-7.60 (m, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.0 Hz, 1H), 8.39 (s, 1H). 8.72-8.79 (m, 1H), 10.02 (s, 1H). 11-2-274 (DMSO-d6) δ: 4.04 (d, J = 5.2 Hz, 2H), 4.22 (s, 2H), 7.36-7.52(m, 4H), 7.70-7.82 (m, 4H), 8.02 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.38 (s, 1H), 8.66 (s, 1H), 8.74-8.83 (m. 1H), 10.36 (s, 1H). 11-2-275 (DMS0-d6) δ: 4.05 (d, J = 4.8 Hz, 2H), 4.23 (s, 2H), 6.77 (d, J = 6.8 Hz, 1H), 7.19-7.29 (m, 2H), 7.35-7.43 (m, 1H), 7.45-7.56 (m, 3H), 7.71-7.82 (m, 3H), 7.99-8.11 (m, 2H), 8.18 (s, 1H), 8.39(s, 1H), 8.77-8.83 (m, 1H). 10.07 (s, 1H), 10.20 (s, 1H). -229 - 201021798 【表105】 化合物 番号 構造式 NMR((5) retention time Mass method 11-2-276 1 Η Η (DMS0-d6) δ: 2.02 (s. 3H). 3.97 (d, J = 4.8 Nz, 2H), 4.20 (s, 2H), 7.35-7.45 (m, 1H), 7.47-7.53 (m, 6H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.72-8.78 (m, 1H), 9.88 (s, 1H), 9.97 (s. 1H). 11-2-277 η 〇 (DMSOde) <5:3.81 (d,J = 6.08 Hz, 2H), 3.98 (s, 2H), 4.16 (d,J = 5.58 Hz, 2H), 6.94 (d,J = 16.22 Hz, 1H), 7.28 (m, 1H), 7.34-7.40 (m, 2.0H), 7.45 (d,J = 16.22 Hz, 1H), 7.56-7.59 (m, 2H), 7.76 (s, 1H), 8.64 (t. J = 5.83 Hz, 1H), 8.68 (t, J = 5.58 Hz, 1H). <I 11-2-278 OMe V~NH P U 〇r M: OH (DMS0-d6) δ: 3.83 (d, J = 6.0 Hz, 2H), 4.04 (s, 3H), 4.13 (s,2H〉,4.17 (d,J = 5.7 Hz, 2H), 7.27 (s, 1H), 7.39-7.52 (m, 3H), 7.77 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H), 8.67-8.73 (m, 2H) 11-2-279 戶N HN-/ Vnh o (DMS0-d6) δ: 1.12 (dd, J = 8.1,5.1 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.39-7.44 (m, 1H), 7.48-7.54 (m, 2H), 7.77-7.97 (m, 2H), 7.88 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H),. ( 11-2-280 n jPTV~\ ΗΝ-λ, CN (DMS0-d6) 5: 1.15 (t, J = 7.3 Hz, 3H). 3.41 (q, J = 7.3 Hz, 2H), 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.21 (m, 4H), 7.79 (t.J = 7.7 Hz, 1H), 7.86-7.93 (m, 2H), 8.07 (d, J = 8.4 Hz, 1H), 8.15 (m, 1H), 8.21 (m, 1H). 8.54 (d, J = 1.7 Hz, 1H), 8.65-8.79 (m, 2H). -230- 201021798【表106】 化番合号物 構造式 NMR(<5) retention time
Mass method 11-2-281 11-2*282 11-2-283 11-2-284
(DMS0-d6) 5: 1.12 (dd, J :8.1, 5.1 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.07 (s, 2H), 6.92-7.15 (m, 4H), 7.30 (t, J = 7.6 Hz, 2H), 7.66 (d. J = 2.4 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 8.63 (t, J = 5.5 Hz, 1H), 8.90 (s. 1H).
O
(DMS0-d6) δ: 2.83 (d, J = 4.5 Hz, 3H). 3.84 (d, J = 5.9 Hz, 2H), 4.15-4.21 (m, 4H), 7.58 (t, J = 7.7 Hz, 1H), 7.81-7.94 (m, 3H), 8.05 (d, = 8.6 Hz, 1H), 8.21 (brs, 1H), 8.46 (d, J= 1.8 Hz, 1H). 8.58 (q, J = 4.7 Hz. 1H), 8.67-8.77 (m. 2H).
S ^r-NH 0 ^—COOH (DMS0-d6) 5: 1.15 (t, J = 7.3 Hz, 3H). 3.41 (q, J = 7.3 Hz, 2H), 3.86 (d, J = 5.9 Hz, 2H), 4.18 (s, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.88-7.91 (m, 2H), 8.07 (d. J = 8.6 Hz, 1H), 8.15 (d,J = 7.9 Hz, 1H), 8.21 (s, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.73 (t, J = 5.7 Hz, 1H). OMe
N \V / s 〇W HN (DMSO-d6) δ: 3.83 (d, J : 6.0 Hz, 2H), 4.04 (s, 3H), 4.13 (s. 2H), 4.17(d, J = 5.7 Hz, 2H), 7.27 (s. 1H), 7.39-7.52 (m, 3H), 7.77 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H), 8.67-8.73 (m, 2H)
CN 11-2-285
Η O (DMSO-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.81 (dd, J = 8.11, 1.52 Hz, 1H), 7.93-8.03 (m, 4H), 8.20 (d,J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz, 1H), 8.72 (t, J = 5.58 Hz, 1H). -231- 201021798 【表107】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-286 NCx Η 0 (DMS〇-de) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.16-4.19 (m, 4H), 7.81 (dd. J = 8.11, 1.52 Hz, 1H), 7.94-8.02 (m, 4H), 8.20 (d, J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz. 1H), 8.69 (t, J = 5.32 Hz, 1H). 8.74 (t, J = 5.83 Hz, 1.0H). 11-2-287 Ncx (DMS〇-d6) <5: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd,J = 8.11, 5.58 Hz, 2H), 3.78 (d, J = 5.58 Hz, 2H), 4.18 (s, 2H), 7.81 (dd, J = 8.t1, 1.52 Hz, 1H), 7.94-8.03 (m, 4H), 8.20 (d, J = 8.11 Hz, 1H), 8.33 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H). 11-2-288 t-Bu 丫 (DMS〇-d6) 5: 1.33 (s, 9H). 3.85 (d, J = 5.58 Hz, 2H), 4.15 (s, 2H), 7.51 (d, J =8.11 Hz, 2H), 7.67-7.73 (m, 3H), 8.12 (d,J = 8.11 Hz, 1H), 8.19 (d,J= 1.52 Hz, 1H), 8.71 (t, J = 5.83 Hz, 1H). 11-2-289 F3C,〇 t) 丫 (DMS〇-d6) δ: 3.85 (d, J = 6.08 Hz, 2H), 4.17(s, 2H), 7.48 (d, J = 8.62 Hz. 2H), 7.74 (dd, J = 8.62, 1.52 Hz, 1H), 7.90 (d,J = 8.62 Hz, 2.0H), 8.17 (d, J = 8.62 Hz, 1H), 8.25 (d,J 二 1.52 Hz, IH), 8.72 (t, J = 5.83 Hz, 1H), 12.64 (brs, 1H). H-2-290 t-Bu V (DMS〇-d6) (S: 1.12 (dd, J =8.36, 5.32 Hz, 2H), 1.33 (s, 9H), 1.49 (dd. J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 6.08 Hz, 2H), 4.16 (s, 2H), 7.51 (d, J = 8.62 Hz, 2H), 7.73-7.67 (m, 3H), 8.12 (d, J = 8.11 Hz, 1H), 8.19 (d,J = 1.52 Hz, 1H), 8.67 (t,J = 5.58 Hz, 1H), 8.91 (s, 1H). - 232- 201021798 【表108】
化合物 番号 構造式 NMR((5) retention time Mass method 11-2-291 f3c-0 % H 0 (DMS〇-de) δ: 3.83 (d, J = 5.58 Hz, 2H), 4.15-4.19 (m, 4H), 7.49 (d, J = 8.62 Hz. 2H). 7.75 (dd,J = 8.11, 1.52 Hz, 1H), 7.90 (d, J = 9.12 Hz, 2H), 8.17 (d,J = 8.11 Hz. 1H), 8.25 (d, J = 1.52 Hz, 1H), 8.69 (t, J = 5.83 Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H). II-2-292 F3C-0 % s 以 (DMS〇-d6) δ: 1.12 (dd,J =8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.49 (d, J = 8.62 Hz, 2H), 7.75 (dd, J = 8.11, 1.52 Hz, 1H), 7.90 (d, J = 8.62 Hz, 2H), 8.17 (d, J = 8.11 Hz, 1H), 8.25 (d, J = 1.52 Hz, 1H), 8.68 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H). II-2-293 Ac*^NH \ 丫 (DMSO-de) 5: 2.08 (s, 3H), 3.85 (d. J = 6.08 Hz, 2H), 4.15 (s, 2H), 7.68-7.74 (m, 5H), 8_11 (d, J = 8.62 Hz, 1H), 8.18 (d, J = 1.52 Hz, 1H), 8.71 (t, J = 5.58 Hz, 1H), 10.05 (s, 1H). II-2-294 F r~K -Ν ^~ΝΗ 0 (DMS0-d6) (5: 0.86-1.12 (m, 3H)t 3.82 (dd, J = 5.7, 3.3 Hz, 2H). 4.22 (s, 2H), 4.56 and 4.81 (m, 1H), 7.39-7.44 (m, 1H), 7.48-7.53 (m, 2H), 7.88 (d, J = 1.8 Hz, 1HX 8.17 (d,J = 8.9 Hz, 1H), 8.63 (t, J = 1.8 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H). II-2-295 Ac-NH % sX^An^yLcn Η 0 (DMS〇-d6) δ: 2.07 (s, 3H), 3.83 (d, J = 6.08 Hz, 2H), 4.14-4.19 (m, 4H), 7.69-7.73 (m, 5H). 8.11 (d, J = 8.62 Hz, 1H), 8.18 (d. J =1.52 Hz, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.73 (t, J = 5.58 Hz, 1H), 10.05 (s, 1H). -233- 201021798 【表109】 化合物 番号 構造式 NMR(5) retention time Mass method 11-2-296 Ac-NH (DMSO-d6) δ : 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd,J = 8.11,5.58 Hz, 2H), 2.07 (s, 3H), 3.77 (d, J = 5.58 Hz, 2H), 4.15 (s. 2H), 7.67-7.74 (m, 5H), 8.11 (d, J = 8.62 Hz, 1H), 8.18 (d,J =1.01 Hz, 1H), 8.67 (t,J = 5.83 Hz, 1H), 8.92 (s, 1H), 10.05 (s, 1H). 11-2-297 \ H 0 (DMSO-de) <5:3.83(d, J = 5.58 Hz, 2H), 4.14-4.19 (m, 4H), 7.29 (m, 1H), 7.38-7.42 (m, 4H), 7.64 (d, J = 7.60 Hz, 2H), 7.73 (dd, J = 8.62, 1.15 Hz, 1H), 8.05 (d, J = 8.62 Hz. 1H), 8.15 (d,J = 1.15 Hz, 1H), 8.69(1, J = 5.58 Hz, 1H), 8.73 (t, J = 5.83 Hz, 1H). 省! 11-2-298 (DMS〇-d6) (5:3.84(d, J = 5.58 Hz, 2H), 4.17 (d.J = 5.58 Hz, 2.0H), 4.20 (s, 2H), 7.65-7.47 (m. 5H), 7.83 (d. J = 8.62 Hz, 1H), 7.98-8.05 (m, 3H), 8.21 (d, J = 8.11 Hz, 1H), 8.69 (t, J = 5.32 Hz, 1H), 8.75 (t, J = 5.83 Hz, 1H). 11-2-299 (DMS〇-de) d: 1.13 (dd, J =8.36, 5.32 Hz, 2H), 1.49 (dd, J : 8.36, 5.32 Hz, 2H), 3.79 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.47-7.65 (m, 5H), 7.83 (d, J = 8.11 Hz, 1H), 7.98-8.05 (m, 3H), 8.21 (d, J = 8.11 Hz, 1H), 8.70 (t, J = 5.83 Hz, 1H), 8.92 (s, 1H). 11-2-300 Ms-NH 3.04 (s, 3H), 3.83 (d, J = 5.58 Hz, 2.0H), 4.15-4.19 (m, 4.0H), 7.33 (d, J = 8.62 Hz, 2H), 7.71 (dd, J = 8.11, 1.52 Hz, 1H). 7.76 (d. J = 8.62 Hz, 2H). 8.12 (d, J = 8.11 Hz, 1H), 8.19 (d,J = 1.52 Hz, 1H), 8.68 (t,J = 5.58 Hz, 1H), 8.73 (t, J = 5.83 Hz. 1H), 9.87 (s, 1H). - 234- 201021798【表110】
化合物 番号 構造式 NMR((5) retention time Mass method Π-2-301 (DMS〇-d6) δ: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.14 (s, 2H), 7.29 (m, 1H), 7.35-7.45 (m, 4H), 7.64 (d. J = 7.60 Hz, 2H), 7.73 (dd, J = 8.62, 1.52 Hz, 1H). 8.05 (d, J = 8.62 Hz, 1H), 8.14 (d, J = 1.52 Hz, 1H), 8.67 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H). 11-2-302 Ό-s^Vnh 0 6 Μ: ΗΝ— CN (DMS0-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.13 (s, 2H). 4.16 (d,J = 5.7 Hz, 2H), 7.05 (d, J = 9.7 Hz, 2H), 7.13-7.20 (m, 2H), 7.37-7.44 (m, 2H). 7.52 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.64-8.74 (m, 2H). 11-2-303 ΗΝΛ Ν (DMS0-d6) 5: 3.84 (d, J = 5.6 Hz, 2H), 4.17 (d,J = 5.6 Hz, 2H), 4.22 (s, 2H), 6.32 (t, J = 2.0 Hz, 1H), 7.07-7.11 (m, 2H). 7.28-7.31 (m, 3H), 7.55 (d, J = 2.0 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 8.05 (s, 1H), 8.24 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.75 (t, J = 5.8 Hz, 1H). 11-2-304 〇Γ XX^y_ 0 1七 CN (DMS0-d6) δ: 1.11 (dd, J =8.2, 5.5 Hz, 2H), 1.48 (dd, J = 8.2, 5.4 Hz, ZH), 3.76 (d. J = 5.7 Hz, 2H), 4.13 (s, 2H), 7.06 (d, J = 5.4 Hz, 2H), 7.13-7.20 (m, 2H), 7.37-7.45 (in, 2H), 7.51 (d, J = 2.4 Hz, 1H), 8.08 (d, J 二 8.7 Hz. 1H), 8.66 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H). 11-2-305 F>r^rsi^'s —\^nh p CN (DMSO-d6) δ: 3.83 (d, J = 5.7 Hz, 2H), 4.14-4.20 (m, 4H), 7.50-7.67 (m, 2H), 7.79-7.93 (m, 2H), 8.02 (d, J = 8.6 Hz, 1H), 8.43 (d, J 二 1.7 Hz, 1H). 8.65-8.77 (m. 2H). -235- 201021798 【表111】 化合物 番号 構造式 NMR(iS) retention time Mass method 11-2-306 —V-nh 0 V · 。七 F CN (DMS0-d6) δ: 1.12 (dd, J =8.4, 5.5 Hz, 2H), 1.50 (dd, J = 8.4, 5.4 Hz, 2H), 3.78 (d, J = 5.9 Hz, 2H), 4.17 (s, 2H), 7.26 (tt, J = 9.2, 2.2 Hz, 1H), 7.51-7.60 (m. 2H), 7.88 (dd, J = 8.6, 1.8 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 8.51 (d, J= 1.8 Hz, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.92 (s, 1H). Π-2-307 0 (DMSO-d6) δ: 3.84 (d, J = 6.08 Hz, 2H), 3.86 (s, 3H), 4.12 (s, 2H), 7.19 (m, 1H), 7.33-7.39 (m, 2H), 7.46 (m, 1H), 7.65 (s, 1H), 8.00 (s, 1H), 8.68 (t. J = 5.58 Hz, 1H), 12.63 (s, 1H). 11-2-308 0 (DMS〇-d6) δ: 3.84 (d, J = 5.05 Hz, 2H), 3.87 (s, 3H). 4.14 (s, 2H), 4.18 (d,J = 5.56 Hz, 2H), 7.20 (m, 1H), 7.337-51 (m, 2H), 7.65 (s, 1H), 8.01 (s, 1H), 8.66-8.73 (m, 2H). 11-2-309 0 (0MS0-de) δ: 3.85 (d, J = 5.88 Hz, 2H), 3.88 (s. 3H), 4.13 (s, 2H), 7.19-7.32 (m, 3H), 7.66 (s, 1H). 8.06 (s, 1H), 8.69 (t, J = 5.79 Hz, 1H), 12.64 (s, 1H) 11-2-310 0 (DMSO-d6) <5: 3.82-3.88 (m, 5H), 4.13 (s, 2H), 7.40-7.59 (m, 4H), 7.65 (s, 1H), 8.00 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H). - 236- 201021798【表112】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-311 0 (DMS〇-d6) δ: 3.83 (d, J = 5.71 Hz, 2H). 3.86 (s, 3H), 4.14 (s, 2H), 4.18 (d,J = 5.54 Hz, 2H), 7.40-7.52 (m, 3H), 7.57 (m, 1.0H), 7.65 (s, 1H), 8.00 (s, 1H), 8.65-8.75 (m, 2H). 11-2-312 0 (DMSO-de) δ: 3.83 (d, J = 5.37 Hz, 2H), 3.88 (s. 3H), 4.15 (s, 2H), 4.17 (d, J .= 5.37 Hz, 2H), 7.19-7.31 (m, 3H), 7.66 (s, 1H), 8.06 (s, 1H), 8.64-8.76 (m, 2H). 11-2-313 0 (DMS0-d6) δ: 3.84 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 8.71-8.61 (m, 3H), 8.89 (d, J = 2.1 Hz, 1H). 11-2-314 0 ^ (DMS0-d6) d: 1.13 (dd, J = 8.7, 5.7 Hz, 2H), 1.49 (dd, J = 8.7, 5.7 Hz, 2H), 3.77 (d. J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.33-7.39 (m, 1H), 7.81-7.92 (m, 2H), 8.25 (d, J = 8.1 Hz, 1H), 8.45 (d, J =8.1 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.92 (s, 1H). 11-2-315 | H 0 (DMS0-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 5.7 Hz, 2H), 4.23 (s, 2H), 7.30 - 7.36 (m, 2H), 7.88 (d. J = 1.8 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.68 (t,J = 5.7 Hz. 1H), 8.76 (t, J = 5.7 Hz, 1H). -237- 201021798 【表113】 化合物 番号 構造式 NMR(0) retention time Mass method 11-2*316 \^ΝΗ-γΝχϋΝ 0 ^ (DMS0-d6) <5: 1.13 (dd, J =8.7, 5.7 Hz, 2H), 1.50 (dd, J = 8.7, 5.7 Hz, 2H), 3.79 (d, J = 5.7 Hz, 2H). 4.21 (s, 2H), 7.30-7.36 (m, 2H), 7.81-7.56 (m, 2H), 7.88 (d, J = 1.4 Hz, 1H), 8.37 (d, J =1.4 Hz, 1H), 8.71 (t, J = 5.7 Hz, 1H), 8.91 (s, 1H). 11.2-317 °^UAhYH ο (DMS0-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.20 (s, 2H), 7.38-7.48 (m, 1H), 7.47-7.52 (m, 2H), 7.66 (d, J = 1.8 Hz. 1H), 7.77-7.79 (m, 2H), 8.26 (d, J = 5.4 Hz, 1H), 8.74 (t, J = 5.7 Hz, 1H), 12.66 (brs, 1H).. I 11-2-318 〇-<^X 9 ο (DMS0-d6) 5: 3.87 (d, J = 5.7 Hz, 2H). 4.22 (s,2H), 7.39-7.53 (m, 1H), 7.77 (d, J = 5.4Hz, 2H), 7.89 (d, J = 1.8 Hz, 1H), 8.39 (d,J = 1.4Hz, 1HX 8.75 (t, J = 5.7 Hz, 1H). 12.66 (brs, 1H). 11-2-319 0 (DMS0-d6) δ: 3.86 (d, J = 5.7 Hz, 2H), 4.2t (s, 2H); 7.30-7.69 (m, 1H), 7.81-7.83 (m, 2H), 7.89 (d, J = 1.8 Hz, 1H), 8.37(d,J = 1.8Hz, 1H), 8.75 (t, J 二 5.7 Hz, 1H), 12.63 (brs, 1H). ( II-2-320 XXjCC^Vnh 〇 i cf Μ: ΗΝ-λ, CN (DMS0-d6) δ: 3.29 (s, 3H), 3.81 (d, J = 6.0 Hz, 2H), 4.06 (s, 2H), 4.16 (d,J =5.5 Hz, 2H), 7.00 (dd, J = 8.7, 2.4 Hz, 1H). 7.07-7.22 (m. 4H), 7.56 (d, J = 2.4 Hz 1H), 7.76 (d, J = 8.9 Hz, 1H), 8.63-8.71 (m, 2H). - 238- 201021798【表114】
化合物 番号 構造式 NMR(5) retention time Mass method JI-2-321 (DMS〇-de) δ: 2.80 (t, J = 5.83 Hz, 2H), 3.65 (t, J = 5.83 Hz. 2H), 3.78 (d, J = 5.58 Hz, 2H), 3.91 (s, 2H), 4.15 (d,J = 5.58 Hz, 2H), 4.46 (s, 2H), 6.76 (t, J = 7.35 Hz, 1H), 7.02 (d, J = 8.11 Hz, 2H), 7.21 (dd, J = 8.11, 7.35 Hz, 2H), 8.58 (t, J = 5.83 Hz, 1H), 8.64 (t, J =5.58 Hz, 1H). II-2-322 0 ^ (DMSO-d6) 5: 1.13 (dd, J =8.36, 5.32 Hz, 2H), 1.50 (dd, J = 8.36, 5.32 Hz, 2H). 3.77 (d, J = 6.08 Hz, 2H), 3.84 (s, 3H), 4.12 (s, 2H), 7.35 (m, 1H), 7.40-7.46 (m, 2H), 7.52 (d, J = 7.10Hz, 2H), 7.63 (s, 1H), 7.94 (s, 1H), 8.64 (t, J = 5.83 Hz, 1H), 8.91 (s, 1H). II-2-323 0 (DMS〇-d6) 5:3.13(t, J = 2.53 Hz, 1H), 3.78 (d, J = 5.58 Hz, 2H), 3.85 (s, 3H), 3.91 (dd, J = 5.58, 2.53 Hz, 2H), 4.12 (s, 2H), 7.35 (m. 1H). 7.40-7.45 (m, 2H), 7.48-7.54 (m, 2H), 7.63 (s, 1H), 7.94 (s, 1H), 8.43 (t, J =5.58 Hz, 1H), 8.64 (t, J = 5.58 Hz, 1H). II-2-324 〇 (DMS0-d6) (S:3.86(d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.22-7.28 (m, 1H), 7.63-7.69 (m, 2H), 7.95 (d, J = 1.4 Hz, 1H), 8.45 (d,J = 1.4Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H), 12.66 (brs, 1H). II-2-325 Ο (DMS0-d6) <5: 3.87 (d, J = 5.7 Hz, 2H). 4.23 (s, 2H), 7.22-7.32 (m, 1H), 7.58-7.26(m, 2H),8.02(d, J = 1.2 Hz, 1H), 8.50 (d.J = 0.9Hz, 1H), 8.76 (t, J = 5.4 Hz, 1H). 12.66 (brs, 1H).. -239 - 201021798 【表115】 化合物 番号 構造式 NMR(d) retention time Mass method 11-2-326 1 Η 0 (DMSO-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.17 (d, J = 5.4 Hz, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64-7.69 (m, 2H), 7.95 (s, 1H), 8.45 (s, 1H), 8.69 (t, J = 5.4 Hz, 1H), 8.78 (t, J = 5.4 Hz, 1H). 11-2-327 0 (DMS0-d6) δ: 3.85 (d, J = 5.7 Hz, 2H), 4.17 (d,J = 5.4 Hz, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.50-7.58 (m, 1H), 7.64-7.69 (tn, 2H), 7.95 (s, 1H), 8.45 (s, 1H), 8.69 (t. J = 5.4 Hz, 1H),8.78(t,J = 5.4Hz, 1H). 11-2-328 Η 0 (DMSO-d6) 5 : 1.77 (s, 3H), 3.78 (d, J = 5.2 Hz, 2H), 3.83-3.89 (m, 2H), 4.16 (s, 2H), 7.36-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.72-7.82 (m, 3H), 8.02 (d, J = 8.4 Hz. 1H), 8.33-8.40 (m, 2H), 8.62-8.68 (m, 1H). 11-2-329 C02Me 0 C02h (DMS0-d6) δ : 3.65 (s, 3H), 3.82 (d. J = 5.6 Hz, 2H), 4.12 (s, 2H), 7.24 (t, J =7.1 Hz, 1H), 7.31-7.41 (m, 5H), 7.91 (d, J = 8.6 Hz, 1H).8.06(d, J = 2.0Hz, 1H), 8.67 (t. J = 5.6 Hz, 1H), 12.63 (br s, 1H). 11-2-330 CXn-O-s^Vnh 0 ?人。 0 丨 CN (DMS0-d6) δ: 3.65 (s, 3H), 3.81 (d, J = 5.6 Hz, 2H), 4.13(s, 2H), 4.16 (d.J =5.6 Hz, 2H), 7.24 (t, J = 7.1 Hz, 1H), 7.31-7.41 (m, 5H), 7.92 (d. J = 8.6 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.65-8.71 (m, 2H). -240- 201021798【表116】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-331 Η ^s^nh-YnXcn 〇 ^ (DMSO-d6) δ: 1.12 (dd, J =7.8 H2, 2H), 1.48 (dd, J = 7.8 Hz, 2H), 3.78 (d, J = 5.4 Hz, 2H), 4.22 (s, 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64-7.69 (m. 2H), 7.95 (d, J = 1.8 Hz, 1H), 8.45 (d, J 二 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H). 11-2-332 Η ^s-^nh-ynxcn 0 ^ (DMS0-d6) <5: 1.12(dd, J =7.8 Hz, 2H), 1.48 (dd, J = 7.8 Hz, 2H), 3.78 (d, J = 5.4 Hz. 2H), 4.22 (s. 2H), 4.24 (s, 2H), 7.22-7.28 (m, 1H), 7.64-7.69 (m, 2H), 7.95 (d, J= 1.8 Hz, 1H), 8.71 (t, J = 5.4 Hz, 1H), 8.91 (s, 1H). 11-2-333 \ 0 ^ (DMS〇-de) ά: 1.12 (dd, J = 8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 6.08 Hz, 2H), 4.17 (s, 2H), 7.42-7.47 (m, 3H), 7.56-7.63 (m, 3H), 8.11-8.15 (m, 2H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s. 1H). 11-2-334 \ V^nh-YnH-cn 0 (DMS〇-de) 5: 3.83 (d, J = 5.58 Hz. 2H), 4.15-4.19 (m, 4H), 7.42-7.48 (m, 3H), 7.56-7.63 (m, 3H), 8.10-8.15 (m, 2H), 8.68 (t, J = 5.32 Hz, 1H), 8.74 (t, J = 5.83 Hz, 1H). 11-2-335 l H 0 (DMSO-d6) <5: 3.61 (s, 3H), 3.69 (d, J = 5.07 Hz, 2H), 3.84 (s, 3H), 4.11 (s, 2H), 7.35 (m, 1H), 7.40-7.46 (m, 2H), 7.49-7.53 (m, 2H). 7.62 (s, 1H), 7.94 (s, 1H), 8.66 (t, J = 5.07 Hz, 1H), 11.26 (brs, 1H). -241- 201021798 【表117】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-336 η 从η 丫 15 (DMSO-d6) 6: 3.84 (s, 3H), 3.98 (d. J = 5.58 Hz, 2H), 4.16 (s, 2H), 7.05 (m, 1H), 7.28-7.63 (m, 10H), 7.94 (s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 10.01 (s. 1H). 11-2-337 (DMSO-de) δ: 1.30 (t,J = 6.84 Hz, 3H), 3.83 (s, 3H), 3.92-4.01 (m, 4H), 4.16 (s, 2H), 6.87 (d, J = 8.62 Hz, 2H). 7.32-7.53 (m, 7H), 7.61 (s, 1H), 7.94 (s, 1H), 8.70 (t, J = 5.32 Hz, 1H), 9.86 (s, 1H). 11-2-338 CXnXXs^>Nh〇 ?人。 0 ^ 丨 CN (DMSO-d6) 5 : 1.11 (dd, J =8.4, 5.3 Hz, 2H), 1.48 (dd, J = 8.4, 5.3 Hz, 2H), 3.65 (s, 3H), 3.75 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 7.24 (t, J =7.1 Hz, 1H), 7.31-7.41 (m, 5H)t 7.91 (d, J = 8.6 Hz, 1H). 8.06 (d, J = 2.0 Hz, 1H), 8.64 (t, J = 5.8 Hz. 1H), 8.89 (s, 1H). 11-2-339 \\\\~\ CN (DMS0-d6) 5: 3.19 (s, 3H), 3.82 (d, J = 6.1 Hz, 2H), 4.08 (s, 2H), 4.16 (dt J =5.6 Hz, 2H), 7.25 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (d, J =7.6 Hz, 1H), 7.40 (dd, J = 7.9, 1.8 Hz, 1H), 7.48-7.54 (m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 8.65-8.70 (m, 2H), 8.82 (s, 1H). 11-2-340 cr^s>>N^0 HN 飞 CN (DMS0-d6) (5: 3.06 (s, 3H), 3.80 (d, J = 5.9 Hz, 2H), 4.00 (s. 2H), 4.16 (d,J =5.7 Hz, 2H), 4.65 (s. 2H), 6.96 (dd. J = 9.1,2.4 Hz, 1H), 7.17-7.35 (m, 6H), 7.69 (d, J = 9.1 Hz, 1H), 8.60-8.69 (m, 2H). - 242- 201021798【表118】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-341 ^ΝΗ-γΟΗ 0 (DMS〇-de) 5: 3.82-3.86 (m, 5H). 4.12 (s, 2H), 7.35 (m, 1H), 7.40-7.53 (m, 4H), 7.63 (s, 1H), 7.94 (s, 1H), 8.67 (t, J = 5.58 Hz, 1H), 12.62 (s. 1H). II-2-342 V 0 (DMS〇-d6) ¢5: 3.06-2.92 (m, 4H), 3.81 (d, J = 5.58 Hz, 2H), 4.11 (s, 2H), 4.16 (d, J = 5.58 Hz, 2H), 7.14-7.31 (m. 6.0H), 7.77 (s, 1H), 7.93 (d, J = 8.11 Hz, 1H), 8.64-8.72 (m, 2H). II-2-343 0 ^ (DMS〇-d6) (5: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd,J = 8.11, 5.58 Hz, 2H), 2.92-3.07 (m, 4H), 3.76 (d, J = 5.58 Hz. 2H), 4.10 (s, 2H), 7.14-7.31 (m, 6H). 7.77 (s, 1H), 7.93 (d, J = 8.11 Hz, 1H). 8.64 (t,J = 5.58 Hz, 1H), 8.90 (s, 1H). II-2-344 (DMS0-d6) δ: 3.87 (d, J = 5.7 Hz, 2H), 4.16 (d,J = 5.4Hz, 2H). 4.31 (s, 2H), 7.54-7.62 (m, 3H), 8.22 (d, J = 8.1 Hz. 1H), 8.73 (t, J = 5.7 Hz, 1H), 8.83 (t, J = 5.7Hz, 1H), 9.366 (s, 1H). 11-2-345 rrCCv>NH L^J 0 ^COOH (DMS0-d6) 6: 1.20-1.55 (m, 5H), 1.66-1.91 (m, 5H), 2.64 (m. 1H). 3.83 (d, J = 5.9 Hz, 2H), 4.09 (s, 2H), 7.36 (dd, J = 8.4, 1.7 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 8.66 (t,J = 5.8 Hz, 1H). -243- 201021798 【表119】 化合物 番号 構造式 NMR(S) retention time Mass method 11-2-346 〇r^s>>N^0 H'N 飞 CN (DMS0-d6) δ : 1.22-1.56 (m, 5H), 1.66-1.91 (m, 5H), 2.64 (m, 1H), 3.81 (d, J = 5.9 Hz, 2H), 4.10 (s, 2H), 4.16 (d,J = 5.5 Hz, 2H), 7.36 (dd, J = 8.6, 1.7 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 8.62-8.72 (m, 2H). 11-2-347 N HN飞 cf3 (DMS0-d6) δ: 3.86 (d, J = 6.1 Hz, 2H), 3.89-3.98 (m, 2H), 4.18 (s, 2H), 7.57 (dd, J = 8.1, 5.1 Hz, 1H), 7.87 (dd, J 二 8.6, 2ΌΗζ, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.23 (dt J = 8.1, 2.0 Hz, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.61-8.65 (m, 2H), 8.71 (t, J = 5.8Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H). 11-2-348 —V-NH 0 (J cT M N HN-^ CN (DMSO-d6) (5:3.83(d, J = 5.6 Hz, 2H), 4.16-4.18 (m, 4H), 7.52 (dd. J = 8.1, 4.6 Hz, 1H), 7.86 (dd. J = 8.4, 1.8 Hz, 1H), 8.06 (d, J 二 8.6 Hz, 1H), 8.17 (dt, J = 7.9, 1.9 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 4.6, 1.5 Hz, 1H), 8.68 (t,J = 5.6 Hz, 1H), 8.73 (t,J = 5.8 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H). 11-2-349 —V-NH 0 。1七 ο 0 CN (DMS0-d6) 5: 1.12 (dd, J -8.1, 5.6 Hz, 2H), 1.49 (dd, J = 8.1, 5.6 Hz, 2H), 3.27 (s. 3H), 3.78 (d, J = 6.1 Hz, 2H), 4.18 (s, 2H), 7.88 (dd, J = 8.4, 1.8 Hz, 1H). 8.03-8.07 (m, 5H), 8.52 (d, J = 2.0 Hz, 1H), 8.69 (t,J = 5.8 Hz, 1H), 8.91 (s, 1H). 11-2,350 〇 ^M-fV-OMe (DMSO-d6) δ : 3.81 (s, 3H), 3.98 (d, J = 5.4Hz, 2H), 4.20 (s, 2H), 6.81 (d, J =9.0Hz, 1H). 7.39 (t, J = 6.9Hz, 1H), 7.50 (t, J = 7.2Hz, 2H), 7.74-7.90 (m, 5H), 8.01 (d, J = 8.4Hz, 1H), 8.34-8.39 (2H, m). 8.76 (1H, m), 10.07 (s, 1H) -244- 201021798【表120】
化合物 番号 構造式 NMR((5) retention time Mass method 11-2-351 6 Μ: OH (DMSO-d6) 5: 3.82 (d, J =6.0Hz, 2H), 4.08 (s, 2H), 5.20 (s, 2H), 7.13 (d, J = 9.0Hz, 1H), 7.32-7.50 (m, 5H), 7.56 (s, 1H). 7.92 (d, J =9.0Hz, 1H), 8.66 (m, 1H) II-2-352 NH 0 ό Μ: HN—\ CN (DMS0-d6) δ : 3.81 (d, J = 5.7Hz, 2H), 4.09 (s, 2H), 4.16 (d, J = 5.4Hz, 2H), 5.20 (s, 2H), 7.13 (d, J = 9.0Hz, 1H), 7.33-7.50 (m, 5H), 7.56 (s, 1H), 7.92 (d, J =9.0Hz, 1H), 8.67-8.69 (m, 2H) II-2-353 λ—NH 0 〇 "I七 CN (DMS0-d6) 6 : 1.09-1.14 (m, 2H), 1.46-1.51 (m, 2H), 3.75 (d, J = 6.3Hz, 2H), 4.09 (s, 2H), 5.20 (s, 2H), 7.13 (d,J = 9.0Hz, 1H). 7.33-7.57 (m, 6H), 7.93 (d, J 二 9.0Hz, 1H), 8.62 (m, 1H), 8.67-8.69 (m, 2H) II-2-354 M-s^V-nh 0 ο Μ: 〇 HN—^ CN (DMS0-d6) δ : 1.97-2.03 (m. 2H). 2.25-2.32 (m, 2H), 2.55-2.59 (m, 2H), 3.81 (d, J = 5.7Hz, 2H), 4.09 (s, 2H), 5.20 (s, 2H), 7.12 (d.J =9.0Hz, 1H), 7.33-7.56 (m, 6H), 7.92 (d, J = 9.0Hz, 1H), 8.62 (m, 1H), 8.92 (s, 1H) II-2-355 〇xx>r //〇 HN-^ CN (DMS0-d6) <5: 1.62 (m, 2H), 1.75 (m, 2H), 2.22 (m, 2H), 2.43 (m, 2H), 3.82 (d, J = 5.9 Hz. 2H), 4.11 (s, 2H), 4.16 (d,J = 5.4 Hz, 2H), 6.26 (m, 1H), 7.56 (dd, J = 8.6, 1.8 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.64-8.73 (m, 2H). -245 - 201021798 【表121】 化合物 番号 構造式 NMR(d) retention time Mass method Π-2-356 fvy_ V-NH Ο U cf M: _r> ▽ HN-火^ CN (DMS0-d6) d: 1.12 (dd, J = 8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.1, 5.4 Hz. 2H), 1.62 (m, 2H), 1.76 (m, 2H), 2.21 (m, 2H), 2.44 (m, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.11 (s, 2H), 6.26 (s, 1H), 7.56 (dd, J = 8.6, 1_8 Hz, 1H), 7.86 (d, J = 8.6 Hz. 1H), 8.06 (d, J = 1.5 Hz, 1H), 8.65 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H). 11-2-357 CIsXXs^Vnh 0 ^-COOH (DMS0-d6) (5: 3.83 (d, J = 5.7 Hz, 2H), 4.14 (s, 2H), 7.26-7.40 (m, 5H), 7.45 (dd. J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.15 (d, J= 1.8 Hz, 1H), 8.70 (t,J = 5.7 Hz, 1H). 11-2-358 CXs-O^S^NH 〇 0 N~\ HN~ CN (DMS0-d6) δ: 3.82 (d, J = 5.9 Hz, 2H), 4.13-4.19 (m, 4H), 7.26-7.40 (m. 5H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 8.64-8.76 (m, 2H). 11-2-359 dsXXVy 0 CN (DMS0-d6) δ : 1.12 (dd, J =8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.1, 5.5 Hz, 2H), 3.76 (d, J = 5.7 Hz, 2H), 4.14 (s, 2H), 7.26-7.41 (m, 5H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 8.15 (d,J= 1.8 Hz, 1H), 8.67 (t, J = 5.4 Hz, 1H), 8.90 (s, 1H). 11-2-360 F (DMS〇-d6) <5: 3.85 (d, J 二 5.58 Hz, 2H), 4.19 (s, 2H). 7.38-7.22 (m, 3H), 8.19 (s, 1H), 8.22 (s, 1H), 8.73 (t,J =5.58 Hz, 1H), 12.64 (brs, 1H). - 246- 201021798【表122】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-361 F (DMS〇-de) <5: 3.85 (d, J = 6.08 Hz, 2H), 4.18 (s, 2H), 7.26-7.37 (m, 3.0H), 7.54 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 8.73 (t, J = 5.58 Hz, 1H). 12.65 (brs, 1H). II-2-362 ρ Cl o ti ,cn F (DMS〇-d6) δ: 3.83 (d, J = 6.08 Hz, 2H) 4.16 (d.J = 5.58 Hz, 2H), 4.20 (s, 2H), 7.23-7.38 (m, 3H), 8.19 (s, 1H), 8.22 (s, 1H), 8.68 (t.J =5.32 Hz, 1H), 8.75 (t, J = 5.83 Hz, 1H). 11-2-363 F (DMSO-d6) 5: 1.12 (dd, J =8.36, 5.32 Hz, 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz. 2H), 4.20 (s, 2H). 7.23-7.38 (m, 3H), 8.19 (s, 1H), 8.22 (s, 1H), 8.70 (t, J = 5.58 Hz, 1H), 8.91 (s. 1H). 11-2-364 F (DMS〇-de) δ: 3.83 (d, J = 6.08 Hz. 2H), 4.16 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.25-7.37 (m, 3H), 7.54 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H),8.68(t,J = 5.58Hz, 1H), 8.74 (t, J = 5.58 Hz, 1H). 11-2-365 p^j^CN F (DMS〇-d6) δ: 1.12 (dd, J =8.36, 5.32 Hz. 2H), 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.77 (d, J = 5.58 Hz, 2H), 4.19 (s, 2H), 7.25-7.37 (m, 3H), 7.53 (m, 1H), 8.17 (s, 1H), 8.19 (s, 1H), 8.69 (t,J =5.58 Hz, 1H), 8.91 (s, 1H) -247- 201021798 【表123】 化合物 番号 構造式 NMR(<5) retention time Mass method M-2-366 O^CC〜η O^b 0 ^COOH (DMS0-d6) «5: 3.84 (d, J = 5.7 Hz, 2H), 4.21 (s, 2H), 7.59-7.73 (m, 3H), 7.95-8.03 (m, 3H), 8.12 (d, J = 8.7 Hz, 1H), 8.72 (t, J = 5.6 Hz, 1H), 8.86 (d, J= 1.8 Hz. 1H), 12.65 (brs, 1H). 11-2-367 1.9 403 C 11-2-368 〇^^;-〇〇^ (DMS0-d6) δ : 1.30 (t, J = 6.9Hz, 3H), 3.94-3.98 (m, 4H)t 4.23 (s, 2H), 6.87 (d, J =9.0Hz, 2H), 7.46-7.54 (m, 5H), 8.15(t, J = 8.7Hz, 3H), 8.40 (t, J = 8.4Hz, 1H), 8.76 (1H, m), 9.88 (s, 1H) 11-2-369 ▽ HN-^ CN (DMS0-d6) δ: 3.85 (d, J 二 6.1 Hz, 2H), 4.17(d, J = 5.6 Hz, 2H), 4.22 (s, 2H), 7.44-7.56 (m, 6H), 8.01 (d, J = 8.6 Hz, 1H). 8.69 (t, J = 5.3 Hz, 1H). 8.77 (t, J = 5.6 Hz, 1H). 11-2-370 ζλ8ΧΪ>^_ 〇/Λ〇 〇 Μ ΗΝ-^ CN (DMS0-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.15 (d,J = 5.5 Hz. 2H), 4.22 (s, 2H), 7.57-7.73 (m, 3H), 7.95-8.03 (m, 3H), 8.13 (d,J = 8.4 Hz, 1H), 8.62-8.78 (m, 2H), 8.86 (m, 1H). -248- 201021798【表124】
〇
化合物 番号 構造式 NMR((5) retention time Mass method 11-2-371 θ' ο 〇 CN (DMS0-d6) δ: 1.13 (dd, J =8.4, 5.3 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.79 (d, J = 5.6 Hz, 2H), 4.21 (s, 2H), 7.44-7.56 (m, 6H), 8.00 (d,J = 8.1 Hz. 1H), 8.71 (t, J = 5.8 Hz, 1H), 8.92 (s, 1H). ΙΙ-2-372 卜V~NH 0 〇 1七 CN (DMS0-d6) ¢: 1.12 (dd,J = 8.4, 5.3 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.76 (d. J = 5.6 Hz, 2H), 4.12 (s, 2H), 5.33 (d, J = 10.6 Hz, 1H). 5.93 (d,J= 17.7 Hz, 1H). 6.85 (dd, J = 17.5, 10.9 Hz, 1H), 7.63 (dd, J = 8.6, 1.5 Hz, 1H). 7.90 (d, J =8.6 Hz, 1H), 8.15 (s, 1H), 8.66 (t, J = 5.8 Hz, 1H), 8.90 (s, 1H). ΙΙ-2-373 Η (DMS0-d6) (5: 4.21 (s, 2H). 4.57 (d, J = 5.6 Hz, 2H), 7.12-7.18 (m, 2H), 7.37-7.57 (m, 5H), 7.74-7.80 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 9.05 (t, J = 5.6 Hz, 1H), 12.30 (s, 1H). ΙΙ-2-374 HN-Vnh (DMSO-d6) δ: 4.21 (s, 2H), 4.53 (d. J = 9.0Hz, 2H), 5.72 (s. 2H), 5.96 (d, J =9.0Hz, 1H), 7.39(m, 1H), 7.50(t, J = 7.5Hz, 2H), 7.74-7.81 (m, 3H), 8.0-8.04 (2H, m), 8.38(s, 1H), 8.80 (m, 1H) ΙΙ-2-375 HNArNH N 1.95 406 C -249- 201021798 【表125】 化合物 番号 構造式 NMR(fi) retention time Mass method 11-2-376 (DMS〇-de) 5: 1.12 (dd, J = 8.11, 5.58 Hz, 2H), 1.49 (dd,vl = 8.11,5.58 Hz. 2H), 3.77 (d. J = 5.58 Hz, 2H), 4.18 (s. 2H), 7.40-7.52 (m, 5H), 8.146 (s, 1H), 8.154 (s. 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.91 (s, 1H). 11-2-377 (DMS〇-d6) 6 : 1.30 (t, J = 6.84 Hz, 3H), 3.93-4.01 (m, 4H), 4.22 (s, 2H), 6.84-6.89 (m, 2H), 7.42-7.52 (m, 7H), 8.15 (s, 2H). 8.74 (t, J = 5.58 Hz, 1H), 9.87 (s, 1H). H-2-378 S’ Η 0 (DMS〇-d6) (5 : 1.12 (dd, J = 8.11, 5.58 Hz, 2H). 1.49 (dd,J = 8.11,5.58 Hz, 2H). 3.76 (d, J = 5.58 Hz, 2H), 3.83 (s. 3H), 4.09 (s, 2H), 7.23-7.29 (m, 2H), 7.53-7.59 (m, 2H), 7.79 (s, 1H), 7.80 (s, 1H), 8.64 (t,J = 5.58 Hz, 1H), 8.90 (s, 1H). 11-2-379 FxxrY, c1A^s^^-nh ο 0 4七 - \ (DMS0-d6) δ: 1.12 (dd, J = 8.1,5.6 Hz, 2H), 1.49 (dd, J = 8.4, 5.3 Hz, 2H), 3.77 (d, J = 5.6 Hz, 2H), 4.17(s, 2H). 7.30-7.34 (m, 2H), 7.51-7.56 (m, 2H), 7.93 (s, 1H), 8.36 (s, 1H), 8.68 (t,J =5.8 Hz, 1H), 8.91 (s, 1H). 11-2-380 FOyrN CI^^S^^r-NH 0 0 N~\ HN飞 CN (DMS0-d6) (5: 3.83 (d, J = 6.1 Hz. 2H). 4.15-4.18 (m, 4H), 7.32 (t, J = 8.9 Hz, 2H), 7.52-7.55 (m, 2H), 7.94 (s, 1H), 8.36 (s, 1H), 8.68 (t, J = 5.3 Hz, 1H), 8.74 (t,J = 5.8 Hz, 1H). -250- 201021798【表126】
化合物 番号 構造式 NMR(5) retention time Mass method 11-2-381 ρό〇γΝ ΗΝ-^ CN (DMS0-d6) δ: 3.84 (d, J = 5.9 Hz, 2H), 4.16 (d,J = 5.7 Hz, 2H), 4.23 (s, 2H). 7.34 (m, 2H), 7.45 (d, J = 8.2 Hz, 1H). 7.51-7.57 (m. 2H), 8.11 (d. J = 8.2 Hz, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.77 (t, J = 5.7 Hz, 1H). II-2-382 ΡΌαΓ^ ο 。 CN (DMS0-d6) <5: 1.12 (dd, J =8.2, 5.5 Hz, 2H), 1.49 (dd, J = 8.2, 5.4 Hz, 2H), 3.78 (d, J = 5.7 Hz, 2H), 4.22 (s, 2H), 7.34 (t, J = 9.0 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1H), 7.51-7.59 (m, 2H), 8.11 (d, J = 8.2 Hz, 1H), 8.72 (t, J = 5.5 Hz, 1H). 8.91 (s, 1H). II-2-383 άΝϋΟ^>Ν" Η V-^ ΗΝ^ CN (DMSO-d6) δ: 3.82 (d, J = 5.7 Hz, 2H), 4.07 (s, 2H), 4.17 (d,J= 5.7 Hz, 2H), 6.61 (td, J = 8.7, 2.4 Hz. 1H), 6.81-6.94 (m, 2H), 7.18-7.30 (m, 2H), 7.77 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 8.60 (s, 1H), 8.63-8.72 (m, 2H). II-2-384 0^^~NHu^y 2.07 447.3 C II-2-385 (DMS0-d6) 5:1.52-1.58 (m, 2H), 1.92-1.99 (m, 2H), 3.46 (t, J = 10.8 Hz. 2H), 3.80-3.86 (m, 2H), 3.96 (d, J = 5.4 Hz, 2H), 4,23 (s, 2H), 4.48 (m, 1H), 6.93 (d. J = 9.3 Hz, 2H), 7.46-7.56 (m, 5H), 8.15 (t, J = 7.2 Hz, 3H). 8.39 (d, J = 8.4 Hz, 1H), 8.74 (m, 1H), 9.88 (s, 1H). -251 - 201021798 【表127】 化合物 番号 構造式 NMR(<5) retention time Mass method ΙΪ-2-386 丫' 〇 色』 (DMS〇-de) «5:4.15(d, J = 5.58 Hz, 2H), 4.22 (s, 2H), 7.40-7.52 On, 5H), 8.15 (s. 1H), 8.18 (s, 1H), 8.87 (t,J = 5.58 Hz, 1H), 9.18 (s, 1H), 12.68 (s, 1H). 11-2-387 〇CNi^Vy Η 6Γ Μ: ΗΝ~、 CM (DMS0-d6) <5: 3.81 (d, 0 = 6.1 Hz, 2H), 4.04 (s, 2H), 4.16 (d,J = 6.1 Hz, 2HX 6.96 (dd, J= 12.9, 6.3 Hz, 1H), 7.11 (t, J = 8.1 Hz, 1H). 7.16 (dd,J = 8.6, 2.5 Hz, 1H)( 7.23 (dd, J = 11.7, 8.1 Hz, 1H), 7.33(1:, J = 8.1 Hz,1H), 7.53 (d, J = 2,0 Hz, 1H). 7.78 (d. J = 8.6 Hz, 1H), 8.14 (s, 1H), 8.62-8.69 (m, 2H). 11-2-388 \-ΝΗ Ο 〇 (DMS0-d6) 6 : 1.12 (dd,J = 8.4, 5.3 Hz, 2H), 1.49 (dd, J= 8.4, 5.3 Hz, 2H), 1.88 (d, J = 6.1 Hz, 3H), 3.76 (d, J = 5.6 Hz, 2H), 4.10 (s, 2H), 6.35-6.43 (m, 1H). 6.53 (d, J = 16.7 Hz, 1H), 7.53 (dd, J = 8.6, 1.5 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H). 8.64 (t, J = 5.6 Hz, 1H), 8.89 (s, 1H). 11-2-389 (DMS0-d6) (S :4.00 (d,J = 5.7 Hz, 2H). 4.20 (s, 2H), 7.39-7.52 (m, 3H), 7.74-7.81 (m, 3H), 8.03 (d, J = 8.4 Hz, 1H), 8.37-8.42 (m, 3H), 8.78 (br-s, 1H), 9.31 (s, 1H), 10.88 (s, 1H) 11-2*390 一V-NH p IJ 6 M: N^, (DMS0-d6) δ :2.34 (s, 3H), 4.07 (d, J = 5.7 Hz, 2H), 4.19 (s, 2H). 7.15(s, 1H), 7.38-7.52 (m. 3H), 7.74-7.81 (m, 3H), 8.04 (d, J = 8.7 Hz, 1H). 8.38 (s, 1H), 8.79 (m, 1H), 12.00 (s, 1H) - 252- 201021798【表128】
化合物 番号 構造式 NMR(<5) retention time Mass method 11-2-391 CisrCC 汐 〇 〇 r> HN—^ CN (DMS0-d6) δ: 1.11 (dd, J =8.4, 5.3 Hz, 2H). 1.48 (dd, J = 8.4, 5.3 Hz, 2H), 3.76 (d, J = 5.6 Hz, 2H), 4.21 (s, 2H), 7.59-7.72 (m, 3H), 7.96-8.01 (m, 3H), 8.12 (d, J = 8.6 Hz, 1H), 8.68 (t, J = 5.6 Hz, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.89 (s, 1H). II-2-392 "0 H cf Μ; HN—\ CN (DMS0-d6) 5: 3.11 (s, 3H), 3.82 (d, J = 5.6 Hz, 2H), 4.09 (s, 2H), 4.16 (d,J = 5.6 Hz, 2H), 7.18 (d.J = 9.1 Hz. 2H). 7.29 (dd, J 二 8.9. 2.3 Hz, 1H), 7.71 (d, J =9.1 Hz, 2H), 7.87-7.92 (m, 2H), 8.69 (q, J = 6.1 Hz, 2H). 9.05 (s, 1H). II-2-393 nCM5s^>Nh 0 H 〇 >~~^ HN飞 CN (DMS0-d6) δ: 3.81 (d, J =6.1 Hz, 2H), 4.06 (s, 2H), 4.16 (d, J =5.6 Hz, 2H), 7.20 (dd, J = 8.9, 2.3 Hz, 1H), 7.26 (dd,J = 8.1, 4.6 Hz, 1H), 7.52-7.54 (m, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 8.06 (d, J =4.6 Hz, 1H), 8.39 (d, J = 3.0 Hz, 1H), 8.56 (s, 1H), 8.67 (t, J = 4.6 Hz, 2H). II-2-394 f3c 1H-NMR(DMS0-d6) (5: 1.12 (dd,J = 8.36, 5.32 Hz, 2H). 1.49 (dd, J = 8.36, 5.32 Hz, 2H), 3.78 (d, J = 5.58 Hz. 2H), 4.23 (s, 2H), 7.35-7.39 (m, 2H), 7.45-7.48 (m, 3H), 8.16 (s, 1H), 8.36 (s, 1H), 8.71 (t, J = 5.58 Hz, 1H), 8.92 (s, 1H). II-2-395 f3c 1H-NMR(DMS0-d6) <5: 3.84 (d, J = 6.08 Hz, 2H), 4.16 (d,J = 5.58 Hz, 2H). 4.24 (s, 2H), 7.37-7.38 (m, 2H), 7.43-7.50 (m, 3H), 8.16 (s, 1H), 8.36 (s, 1H), 8.69 (t, J = 5.58 Hz, 1H), 8.77 (t, J = 5.83 Hz, 1H). -253 - 201021798 (試驗例1) 使用人血管內皮脂肪酶(EL)抑制作用之人高密度脂蛋白 (HDL)之評價法 於由 20mM Tris鹽酸緩衝液(pH7.4)、牛血清蛋白素 (0.5%)、氯化鈣(4mM)、氯化鈉(150mM)、人 HDL(2mg/ml) 構成之反應溶液添加以DMSO溶解調製之本發明化合物使 呈0.5% DMSO後,添加EL酶(全量20μ1 )。 於37°C反應4小時後,將依EL由HDL生成之游離脂肪 酸(NEFA)以市售之分析套組測定,以其NEFA量爲酵素活0 性指標。以不含抑制劑時之酵素活性爲對照値,算出對本 發明化合物各濃度之對照値之抑制率,由其抑制曲線求出 本發明化合物之50%抑制濃度(IC50値)。 試驗例1之結果如下。 化合物(II-l-l):IC5〇 = 〇.23gM ' 化合物(I1-1-11): 1C 5 0 = 0.5 6 μΜ 化合物(ΙΙ-1-17): Ι€50=1·3μΜ 化合物(ΙΙ-1-190): ΙΟ5 0 = 2·1μΜ 〇
化合物(ΙΙ-1 -202): IC50 = 0.29pM 化合物(II-1 -246) : Ι050 = 0.28μΜ 化合物(ΙΙ-2-1): Ι050 = 0·11μΜ
化合物(ΙΙ-2-291): IC50 = 0.056pM
化合物(II-2-211): IC50 = 0.032pM
化合物(11-2-67): IC50 = 0.029pM
化合物(II-2-131): IC50 = 0.092pM -254- 201021798 化合物(Π-2-144) : ΙΟ50 = 0.029μΜ 又本發明化合物乃如試驗例1所示,將血管內皮脂肪酶 選擇性抑制,對肝脂肪酶(HL)和脂蛋白脂肪酶(LPL)具用 高選擇性。就選擇性依如下試驗調査。 (試驗例2) 使用人肝脂肪酶(HL)抑制作用之人超低密度脂蛋白(VLDL) 之評價法 於由 2〇mM Tris鹽酸緩衝液(ρΗ7·4)、牛血清蛋白素 ^ (0.5%)、氯化鈣(4mM)、氯化鈉(150mM)、人 VLDL(0.5mg /ml)構成之反應溶液添加以DMSO溶解調製之抑制劑使呈 0.5% DMSO後,添加HL酵素(全量20μ1 )。 於37°C反應4小時後,將依HL由VLDL生成之游離脂 肪酸(NEFA)以市售之分析套組測定,以其NEFA量爲酵素 ' 活性指標。以不含抑制劑時之酵素活性爲對照値,算出對 抑制劑各濃度之對照値之抑制率,由其抑制曲線求出抑制 劑之50%抑制濃度(IC50値)。 & (試驗例3) 使用人脂蛋白脂肪酶(LPL)抑制作用之人超低密度脂蛋白 (VLDL)之評價法 , 於由 20mM Tris鹽酸緩衝液(ρΗ7·4)、牛血清蛋白素 (0.5%)、氯化鈣(4mM)、氯化鈉(15〇mM)、人 VLDL(0.5mg /ml)構成之反應溶液添加以DMSO溶解調製之抑制劑使呈 〇.5%DMS〇後,添加LPL酵素(全量20μ1 )。 於3 7°C反應4小時後,將依LPL由HDL生成之游離脂肪 -255 - 201021798 酸(NEFA)以市售之分析套組測定,以其NEFA量爲酵素活 性指標。以不含抑制劑時之酵素活性爲對照値,算出對抑 制劑各濃度之對照値之抑制率,由其抑制曲線求出抑制劑 之50%抑制濃度(IC50値)。 由試驗例2及3之結果,確認本發明化合物將血管內皮 脂肪酶選擇性抑制,對肝脂肪酶(HL)和脂蛋白脂肪酶 (LPL)具有高選擇性。 就血清HDL膽固醇上昇作用,可調査如下。 HDL上昇作用之藥理試驗 將8〜25週齡之C57BL/6J小鼠分爲一組5〜9隻,將試 驗化合物(20-200mg/kg/day)經口投與。於對照組經口投與 媒體之0.5%甲基纖維素水溶液(10mL/kg)。投與前和投與 之24小時後,由尾靜脈採血,使用膽固醇試劑N HDL(第 一化學藥品公司)測定血清HDL膽固醇濃度。分組時,將 動物分組成體重和血清HDL膽固醇値之平均値於各試驗 組間略相等。試驗化合物之效果以對投與前之投與後之變 化率(HDL膽固醇上昇率;%起始)表示,以與對照組之顯 著性差異檢定。 作爲醫藥之有用性,乃以如下試驗等調査。 CYP3A4螢光MBI試驗 CYP3A4蛋光MBI試驗爲調査依代謝反應之化合物增強 抑制CYP3A4之試驗,使用大腸菌表現CYP3A4之酵素, 7-苄氧基三氟甲基香豆素(7-BFC)由CYP3A4酵素而脫苄基 化,以生成發螢光之代謝物7-羥基三氟甲基香豆素(HFC) -256- 201021798 之反應爲指標來施行。 反應條件乃如下:基質:5.6μιηοΐα 7-BFC ;預反應時間 :0或30分鐘;反應時間:15分鐘;反應溫度:25°C (室 溫);CYP3A4含量(大腸菌表現酵素),預反應時 62.5pmol/mL,反應時6.2 5pmol/mL( 1 0倍稀釋時);被檢藥 物濃度:0.625、1·25、2.5、5、10、20pmol/L(6 點)。 於96穴盤作爲預反應液於K-Pi緩衝液(PH7.4)中將酵素 ,被檢藥物溶液以上述預反應之組成添加,於別的96穴 ^ 盤以基質和K-Pi緩衝液稀釋成1/10而使其一部分移行’ 添加輔酶之NADPH來開始作爲指標之反應(無預反應)、 所定之時間反應後,添加乙腈/〇.5mol/L Tris(參羥胺基甲 烷)= 4/1來停止反應。又於殘留之預反應液也添加NADPH 而開始預反應(有預反應),所定小時預反應後,於別盤以 '基質和K-Pi緩衝液稀釋成1/10使一部分移行爲指標來開 始反應。所定時間反應後,添加乙腈/〇.5m〇l/L Tris(參羥 胺基甲烷)= 4/1來停止反應。將施行各自指標反應之盤以 Θ 螢光盤讀機測定代謝物7-HFC之螢光値。(EX = 420nm、 Em = 5 3 5 nm) 以於反應系只添加溶解藥物之溶劑 DMSO之爲對照 (100%),算出添加被檢藥物溶液之於各自濃度之殘存活性 (%),使用濃度和抑制率,依邏輯模式之逆推定算出ICsc 。以IC5。値之差爲5μΜ以上之場合爲(+ ),以3μΜ以下之 場合爲(-)。 CYP抑制試驗 -257- 201021798 使用市售之凍結肝細胞人肝微粒體,作爲人主要CYP5 分子種(CYP1A2、2C9、2C19、2D6、3A4)之典模基質代謝 反應以 7-乙氧基試菌靈(Resorufin)之 0-脫乙基化 (CYP1A2)、甲苯磺丁醯胺之甲基-氫氧化(CYP2C9)、美芬 妥因(mephenytoin)之 4’-氫氧化(CYP2C19)、 右美沙芬 (dextromethorphan)之 0 脫甲基化(CYP2D6)、特非那定 (Terfenadinum)之氫氧化(CYP3A4)爲指標,評價各自之代 謝物生成量受被檢化合物抑制之程度。 反應條件如下:基質:〇·5 Km〇i/L 乙氧基試菌靈 (CYP1A2)、100 μηιοΙ/L 甲苯擴 丁醯胺(CYP2C9)、50 μπιοΙ/L S-美芬妥因(〇丫?2(:19)、50111〇1/[右美沙芬 (CYP2D6) ' 1 μιηοΙ/L 特非那定(CYP3 A4);反應時間:15 分鐘;反應溫度:37°C ;酵素:凍結肝細胞人肝微粒體 0.2mg 蛋白質/mL ;被檢藥物濃度:1、5、10、20 gmol/L(4 點)。 於96穴盤作爲反應溶液,於50mMHepeS緩衝液中按上 述組成添加各5種基質、人肝微粒體、被檢藥物,添加輔 酶NADPH,開始作爲指標之代謝反應,於37°C反應15分 鐘後,添加甲醇/乙腈=1/1 (v/v)溶液來停止反應。操作 3000rpm、15分鐘之離心後,將離心上清中之試菌靈 (CYP1A2代謝物)以螢光多標識計數機,將甲苯磺丁醯胺 氫氧化體(CYP2C9代謝物)、美芬妥因 4’氫氧化體 (CYP2C19 代謝物)、右醇芬(dextrolphan )(CYP2D6 代謝物 )、特非那定(Terfenadinum)醇體(CYP3A4代謝物)以 -258- 201021798 LC/MS/MS 定量。 以於反應系只添加溶解藥物之溶劑DMSO者爲對照 (100%) ’算出添加被檢藥物溶液之各自濃度之殘存活性 (%),使用濃度和抑制率,依邏輯模式逆推定來算出IC5。 〇 溶解性試驗 化合物之溶解度乃於 1%DMS0添加條件下決定。以 DMSO調製1 OmM化合物溶液,將化合物溶液6μί添加於 ^ pH 6·8人工腸液594μί(於0.2 mol/L磷酸二氫鉀試液 250 mL加0·2 mol/L氫氧化鈉試液1 1 8 mL、水作成 1000 mL)。於25 °C靜置16小時後,將混液吸引過漉。濾液以甲 醇/水=1/1稀釋2倍,依絶對檢量線法使用HPLC或 LC/MS/MS測定濾液中濃度。 ' 代謝安定性試驗
使用市售之凍結肝細胞人肝微粒體,將對象化合物反應 一定時間,比較反應樣品與未反應樣品來算出殘存率,評 價由肝代謝之程度。 於含有人肝微粒體〇.5mg蛋白質/mL之〇.2mL之緩衝液 (5〇mmol/L tris•鹽酸 pH7.4、 15 Ommol/L 氯化鉀、 1〇 mmol/L 氯化鎂)中,有lmmol/L N ADPH存在下於37°C反 應〇分或30分鐘(氧化反應)。反應後,於甲醇/乙腈 = l/l(v/v)溶液之100μί添加反應液50 j_iL來混合,以 3 OOOrpm離心15分鐘。將其離心上清中之試驗化合物以 LC/MS/MS定量,將反應後試驗化合物之殘存量以0分反 -259- 201021798 應時之化合物量爲100%計算。 BA試驗 經口吸收性之檢討實驗材料和方法 (1) 使用動物:使用SD大鼠。 (2) 飼育條件··大鼠自由攝取固形飼料和滅菌自來水。 (3) 投與量、分組之設定:將經口投與、靜脈內投與依所定 投與量投與。設定組如下(可依化合物而投與量有變更)。 經口投與 1〜30mg/kg(n = 2〜3)
靜脈內投與 0.5〜10mg/kg(n = 2〜3) (4)投與液之調製:經口投與乃以溶液或懸浮液投與。靜脈 內投與可溶化來投與。 (5) 投與方法:經口投與乃以經口消息子強制於胃內投與。 靜脈內投與乃以附注射針之注射筒由尾靜脈投與》
(6) 評價項目:經時採血,將血漿中藥物濃度以LC/MS/MS 測定。 (7)統計解析:就血漿中濃度推移,使用非線形最小二乗法 程式WinNonlin(註冊商標)算出血漿中濃度-時間曲線下面 〇 積(AUC),由經口投與組和靜脈內投與組之AUC算出生物 利用性(BA)。 (製劑例1) 硬質明膠膠嚢乃用如下成分製造: 用量 活性成分 (mg/膠囊) 250 -260- 201021798 澱粉(乾燥) 200 硬脂酸鎂 10 合計 460η (製劑例2) 錠劑乃用如下成分製造: 用量 Cme/餘劑) 活性成分 250
纖維素(微結晶) 400 二氧化矽(濕) 10 硬脂酸 5 合計 665mg 混合成分,壓縮而作成各重量665mg之錠劑。 (製劑例3) 製造含有以下成分之氣溶膠溶液: _重量 活性成分 0.25 乙醇 25.75 推進劑22(氯二氟甲烷) 74.00 合計 100.00 混合活性成分和乙醇,將此混合物加入推進劑22之一部 分,冷却爲-30°C,移入充塡裝置。次將必要量供給不鏽鋼 容器,以剩餘之推進劑稀釋。於容器裝閥單元。 (製劑例4) •261- 201021798 製造含有活性成分6 0mg之錠劑如下: 活性成分 6 Omg 澱粉 45mg 微結晶性纖維素 3 5mg 聚乙烯基吡咯啶酮(水中10%溶液) 4mg 羧甲基鈉澱粉 4.5η ng 硬脂酸鎂 0.5r ng 滑石 1 m e 合計 1 5 0m j g 將活性成分、澱粉、和纖維素篩過No.45篩孔U.S.之篩 子,充分混合。將含有聚乙烯基吡咯啶酮之水溶液與所得 粉末混合,次將混合物篩過No .14篩孔 u. s.之篩子 。將所 得顆粒於50°C乾燥,篩過No.18篩孔U. s.之篩子。 將預先 篩過No.60篩孔U.S.之篩子之羧甲基鈉澱粉、硬脂酸鎂、 和滑石加入此顆粒,混合後,以打錠機壓縮,得各重量 1 5 0 m g之錬劑。 (製劑例5) 製造含有活性成分8 0mg之膠囊劑如下 ; 活性成分 8 Omg 澱粉 5 9mg 微結晶性纖維素 5 9mg 硬脂酸鎂 2me 合計 200mg 混合活性成分、澱粉、纖維素、和 硬脂酸鎂 ,締過 -262- 201021798
No.45篩孔U.S.之篩子,於硬質明膠膠囊各充塡200mg。 (製劑例6) 製造含有活性成分22 5mg之坐劑如下: 活性成分 225mg 飽和脂肪酸甘油酯 2Q00mg 合計 2225mg 將活性成分篩過No.60篩孔U.S.之篩子,懸浮於預先加 熱必要最小限來融解之飽和脂肪酸甘油酯。次將此混合物 ^ 注入視2 g之模而冷却。 (製劑例7) 製造含有活性成分50mg之懸浮劑如下: 活性成分 5 0 m g 羧甲基鈉纖維素 50mg 糖漿 1.25ml 苯甲酸溶液 0.10ml 香料 q. v. & 色素 q.v. 加精製水爲合計 5ml 將活性成分篩過No.45篩孔U.S.之篩子,與羧甲基鈉纖 維素和糖漿混合成滑順之膏狀。將苯甲酸溶液和香料以水 之一部分稀釋來添加而攪拌。次加充分量水作成必要之體 積。 (製劑例8) 製造靜脈用製劑如下: -263 - 201021798 活性成分 1 OOmg 飽和脂肪酸甘油酯 1 000ml 上述成分之溶液通常以1分lml之速度於患者靜脈內投 與。 (産業上之利用可能性)
由以上之試驗例明白,本發明之化合物呈示血管內皮脂 肪酶抑制作用。故本發明之化合物作爲脂質代謝異常症治 療藥、高脂血症治療藥和動脈硬化症治療藥非常有用。 i圖式簡單說明 無。 【主要元件符號說明】 無。
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Claims (1)
- 201021798 十、申請專利範圍: 1. 一種具有血管內皮脂肪酶抑制活性之醫藥組成物,其係 含有如下式⑴化合物,(式中, 環A爲含氮雜環,該環爲可呈式:-C^RUCbCO-NI^R4之基及式:-R5之 基以外取代, 虛線表示鍵之存在或不存在, Z 爲-NR6-、=N-、-0·或- S-, R6爲氫、取代或非取代之烷基、取代或非取代之烯基、 取代或非取代之炔基、取代或非取代之芳基、取代或非 取代之雜芳基、取代或非取代之環烷基、取代或非取代 之環烯基或取代或非取代之雜環基, R1及R2各自獨立爲氫、鹵素、氰基、硝基、羧基或取 代或非取代之烷基, R3爲氫或取代或非取代之烷基, R4爲氫、取代或非取代之烷基、取代或非取代之烯基、 取代或非取代之炔基、取代或非取代之芳基、取代或非 取代之雜芳基、取代或非取代之環烷基、取代或非取Θ 之環烯基、取代或非取代之雜環基或取代或非取代之@ 基, -265 - 201021798 R3和R4也可與鄰接之氮原子一起形成取代或非取代之 環, R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非取 代之烷基、取代或非取代之烯基、取代或非取代之炔基 、取代或非取代之芳基、取代或非取代之雜芳基、取代 或非取代之環烷基、取代或非取代之環烯基、取代或非 取代之雜環基、取代或非取代之烷氧基、取代或非取代 之芳氧基、取代或非取代之雜芳氧基、取代或非取代之 環烷氧基、取代或非取代之環烯氧基、取代或非取代之 雜環氧基、取代或非取代之烷硫基、取代或非取代之芳 硫基、取代或非取代之雜芳硫基、取代或非取代之環院 硫基、取代或非取代之環嫌硫基、取代或非取代之雜環 硫基、取代或非取代之烷磺醯基、取代或非取代之芳擴 醯基、取代或非取代之雜芳磺醯基、取代或非取代之環 烷磺醯基、取代或非取代之環烯磺醯基、取代或非取代 之雜環磺醯基、取代或非取代之醯基、取代或非取代之 胺甲醯基或取代或非取代之胺基, 但環A爲噻唑并嘧啶,且R3和R4與鄰接之氮原子一起 形成取代或非取代之環之化合物除外), 及其製藥容許鹽或其等之溶劑合物。 2. 如申請專利範圍第1項之具有血管內皮脂肪酶抑制活性 之醫藥組成物,其中含有Z爲-S-之化合物、其製藥容許 鹽或其等之溶劑合物。 3. 如申請專利範圍第1或2項之具有血管內皮脂肪酶抑制 -266- 201021798 活性之醫藥組成物’其中含有環A爲單環之含氮芳香族 雜環之化合物、其製藥容許鹽或其等之溶劑合物。 4. 如申請專利範圍第1或2項之具有血管內皮脂肪酶抑制 活性之醫藥組成物,其中含有環A爲二環之含氮芳香族 雜環。5. 如申請專利範圍第1〜4項中任一項之具有血管內皮脂肪 酶抑制活性之醫藥組成物’其中含有R5爲取代或非取代 之芳基、取代或非取代之雜芳基、取代或非取代之環院 基、取代或非取代之環烯基、取代或非取代之雜環基、 取代或非取代之芳氧基、取代或非取代之雜芳氧基、取 代或非取代之環烷氧基、取代或非取代之環烯氧基、取 代或非取代之雜環氧基、取代或非取代之芳硫基、取代 或非取代之雜芳硫基、取代或非取代之環院硫基、取代 或非取代之環稀硫基、取代或非取代之雜環硫基、取代 或非取代之芳磺醯基、取代或非取代之雜芳磺醯基、取 代或非取代之環烷磺醯基、取代或非取代之環烯磺醯基 、取代或非取代之雜環磺醯基或取代或非取代之胺基化 合物、其製藥容許鹽或其等之溶劑合物。 6. 如申請專利範圍第1〜5項中任一項之具有血管內皮脂肪 酶抑制活性之醫藥組成物,其中含有R5爲取代或非取代 之芳基、取代或非取代之雜芳基、取代或非取代之芳氧 基、取代或非取代之雜芳氧基、取代或非取代之芳硫基 、取代或非取代之雜芳硫基、取代或非取代之芳磺醯基 、取代或非取代之雜芳磺醯基或取代或非取代之胺基之 -267 - 201021798 化合物、其製藥容許鹽或其等之溶劑合物。 7. 如申請專利範圍第1〜6項中任一項之具有血管內皮脂肪 酶抑制活性之醫藥組成物,其中含有R4爲取代或非取代 之烷基、該取代或非取代之烷基爲取代或非取代之芳院 基或取代或非取代之雜芳烷基之化合物、其製藥容許鹽 或其等之溶劑合物。 8. —種如下式(II)之化合物、其製藥容許鹽或其等之溶劑# 物,Z1 爲-0-或-S-, 環B爲芳香族碳環、芳香族雜環、非芳香族碳環或非芳 香族雜環, R1及R2各自獨立爲氫、鹵素、氰基、硝基、羧基或取 代或非取代之烷基, R3爲氫或取代或非取代之烷基, R4>爲取代或非取代之芳烷基、取代或非取代之雜芳院基 、取代或非取代之環烷烷基、取代或非取代之環烯烷基 、取代或非取代之雜環烷基, 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、鹵 素、羥基、羧基、取代或非取代之烷基、取代或非取代 之烷氧基、取代或非取代之芳基、取代或非取代之雜芳 基、取代或非取代之環烷基、取代或非取代之環烯基或 取代或非取代之雜環基,η爲1〜10之整數, -268 - 201021798 R9 爲-OR1。或-NRUR12, Rl。爲氫、取代或非取代之烷基、取代或非取代之芳基 、取代或非取代之雜芳基、取代或非取代之環烷基、取 代或非取代之環烯基或取代或非取代之雜環基,R11及R12各自獨立爲氫、取代或非取代之烷基、取代或 非取代之烷氧基、取代或非取代之芳氧基、取代或非取 代之雜芳氧基、取代或非取代之烷磺醯基、取代或非取 代之芳基、取代或非取代之雜芳基、取代或非取代之環 烷基、取代或非取代之環烯基或取代或非取代之雜環基) 之基或 式:-C(R7R8)n-0-R13(其中R7、R8和n與上述同意義, 爲氫或取代或非取代之烷基)之基, R3和R4a也可與鄰接之氮原子一起形成取代或非取代之 -pm 環, R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非取 代之烷基、取代或非取代之烯基、取代或非取代之炔基 、取代或非取代之芳基、取代或非取代之雜芳基、取代 或非取代之環烷基、取代或非取代之環烯基、取代或非 取代之雜環基、取代或非取代之烷氧基、取代或非取代 之芳氧基、取代或非取代之雜芳氧基、取代或非取代之 環烷氧基、取代或非取代之環烯氧基、取代或非取代之 雜環氧基、取代或非取代之烷硫基、取代或非取代之芳 硫基、取代或非取代之雜芳硫基、取代或非取代之環院 硫基、取代或非取代之環烯硫基、取代或非取代之雜環 -269- 201021798 硫基、取代或非取代之烷磺醯基、取代或非取代之芳擴 醯基、取代或非取代之雜芳磺醯基、取代或非取代之環 烷磺醯基、取代或非取代之環烯磺醯基、取代或非取代 之雜環磺醯基、取代或非取代之醯基、取代或非取代之 胺甲醯基或取代或非取代之胺基, Rx爲鹵素、羥基、氰基、硝基、羧基、取代或非取代之 院基、取代或非取代之嫌基、取代或非取代之炔基、取 代或非取代之芳基、取代或非取代之雜芳基、取代或非 取代之環烷基、取代或非取代之環烯基、取代或非取代 之雜環基、取代或非取代之烷氧基、取代或非取代之芳 氧基、取代或非取代之雜芳氧基、取代或非取代之環烷 氧基、取代或非取代之環烯氧基、取代或非取代之雜環 氧基、取代或非取代之烷硫基、取代或非取代之芳硫基 、取代或非取代之雜芳硫基、取代或非取代之環烷硫基 、取代或非取代之環烯硫基、取代或非取代之雜環硫基 、取代或非取代之烷磺醯基、取代或非取代之芳磺醯基 、取代或非取代之雜芳磺醯基、取代或非取代之環烷磺 醯基、取代或非取代之環烯磺醯基、取代或非取代之雜 環磺醯基、取代或非取代之醯基、取代或非取代之胺甲 醯基或取代或非取代之胺基,m爲〇〜3之整數, 但Z1爲-S-,環B爲嘧啶環,且V和R“與鄰接之氮原 子一起形成取代或非取代之環之化合物, Z1爲-0-,環B爲苯環,115爲甲基,111爲0,且113和114 與鄰接之氮原子一起形成取代或非取代之環之化合物, -270- 201021798 Z1爲-0-,環B爲苯環,R5爲氫,m爲1,Rx爲甲基,且 R3和R“與鄰接之氮原子一起形成取代或非取代之環之 化合物,和如下示化合物:-271 - 201021798 除外)。 9. 如申請專利範圍第8項之化合物、其製藥容許鹽或其等 之溶劑合物,其中Z1爲-S-。 10. 如申請專利範圍第8或9項之化合物、其製藥容許鹽或 其等之溶劑合物,其中環B爲芳香族碳環。 11. 如申請專利範圍第8〜10項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中環B爲苯環。 12. 如申請專利範圍第8或9項之化合物、其製藥容許鹽或 其等之溶劑合物’其中環B爲單環之芳香族雜環。 13. 如申請專利範圍第9〜12項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中式(II)化合物爲如下式 (III)化合物,(式中,X及Y各自獨立爲-CRX=、-(:心或-N=,RY爲氫 或Rx,R1、R2、R3、R4a、R5及rx與申請專利範圍第8 項同意義)。 14.如申請專利範圍第9〜12項中任~項之化合物' 其製藥 容許鹽或其等之溶劑合物,其中式(11)化合物爲如下式 (IV)化合物,Rl Υ ^ Ο (式中,X及Y各自獨立爲-CRX= ' -CH =或-N=,RY爲氮 或Rx,R1、R2、R3、R4a、R5及Rx與申請專利範圍第 -272- 201021798 項同意義)。 15_如申請專利範圍第13或14項中任一項之化合物、其製 藥容許鹽或其等之溶劑合物,其中X及γ各自獨立爲_ CRX =或-CH=。 16·如申請專利範圍第8〜15項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物’其中R4a爲取代或非取代之 芳烷基或取代或非取代之雜芳烷基。 17.如申請專利範圍第8〜16項中任一項之化合物、其製藥 ^ 容許鹽或其等之溶劑合物,其中R4a爲取代或非取代之 芳烷基。 18_如申請專利範圍第8〜16項中任一項之化合物、其製藥 ^ 容許鹽或其等之溶劑合物,其中R4a爲如下式基0 取代或非取代之烷基、取代或非取代之烯基、取·代或非 取代之炔基、取代或非取代之芳基、取代或非取代之環 烷基、取代或非取代之環烯基、取代或非取代之雜芳基 、取代或非取代之雜環基、取代或非取代之烷氧基、取 代或非取代之芳氧基、取代或非取代之矽烷氧基、取代 或非取代之胺基、取代或非取代之胺甲醯基、取代或非 取代之胺甲醯氧基、取代或非取代之醯基、取代或非取 代之烷磺醯基、取代或非取代之芳磺醯基、取代或非取 代之胺磺醯基或取代或非取代之烷氧羰基, -273- 201021798 R14及R15各自獨立爲氫、鹵素、羥基、氰基、硝基、羧 基、取代或非取代之烷基、取代或非取代之烯基或取代 或非取代之炔基, b爲〇〜3之整數)。 i 9.如申請專利範圍第18項之化合物、其製藥容許鹽或其 等之溶劑合物,其中R4a爲如下式基爲0〜2之整數)。 20.如申請專利範圍第8〜15項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中r “爲式:-(CR7R*)n_ C( = 0)-R9(其中R7、R8、R9及η與申請專利範圍第8項 同意義)之基。 21·如申請專利範圍第20項之化合物、其製藥容許鹽或其 等之溶劑合物’其中;^9爲_〇以。。 22. 如申請專利範圍第20項之化合物、其製藥容許鹽或其 等之溶劑合物,其中R9爲_NRURI2。 23. 如申請專利範圍第22項之化合物、其製藥容許鹽或其 等之溶劑合物’其中R12爲取代或非取代之烷基。 24. 如申請專利範圍第22或23項之化合物、其製藥容許鹽 或其等之溶劑合物,其中Rn爲氫。 25. 如申請專利範圍第20〜24項中任一項之化合物、其製 -274- 201021798 藥容許鹽或其等之溶劑合物,其中n爲1。 26. 如申請專利範圍第20〜25項中任一項之化合物、其製 藥容許鹽或其等之溶劑合物,其中…及R8爲氮。 27. 如申請專利範圍第8〜26項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中以及V爲氫。 28·如申請專利範圍第8〜27項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中R3爲氫。29.如申請專利範圍第8〜28項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物’其中R5爲取代或非取代之 芳基、取代或非取代之雜芳基、取代或非取代之環烷基 、取代或非取代之環烯基、取代或非取代之雜環基、取 代或非取代之芳氧基、取代或非取代之雜芳氧基、取代 或非取代之環烷氧基、取代或非取代之環烯氧基、取代 或非取代之雜環氧基、取代或非取代之芳硫基、取代或 非取代之雜芳硫基、取代或非取代之環烷硫基、取代或 非取代之環烯硫基、取代或非取代之雜環硫基、取代或 非取代之芳磺醯基、取代或非取代之雜芳磺醯基、取代 或非取代之環烷磺醯基、取代或非取代之環烯磺醯基、 取代或非取代之雜環磺醯基或取代或非取代之胺基。 3〇·如申請專利範圍第8〜29項中任一項之化合物、其製藥 容許鹽或其等之溶劑合物,其中R5爲取代或非取代之 芳基、取代或非取代之雜芳基、取代或非取代之芳氧基 、取代或非取代之雜芳氧基、取代或非取代之芳硫基、 取代或非取代之雜芳硫基、取代或非取代之芳磺醯基、 -275- 201021798 取代或非取代之雜芳磺醯基或取代或非取代之胺基。 31. 如申請專利範圍第8〜28項中任一項之化合物、其製藥 合許鹽或其等之溶劑合物,其中R5爲氨、取代或非取 代之烷基、取代或非取代之烯基、取代或非取代之炔基 、取代或非取代之芳基、取代或非取代之雜芳基、取代 或非取代之環烷基、取代或非取代之雜環基、取代或非 取代之烷氧基、取代或非取代之芳氧基、取代或非取代 之芳磺醯基或取代或非取代之醯基。 32. —種如下之式(V)化合物、其製藥容許鹽或其等之溶劑 合物,(式中 環C爲單環或雙環之雜環, R4b爲取代芳烷基(該取代芳烷基之環上之取代基爲羧基 、取代或非取代之胺甲醯基、取代或非取代之烷磺醯基 或取代或非取代之胺磺醯基)、取代雜芳烷基(該取代雜 芳烷基之環上之取代基爲羧基、取代或非取代之胺甲醯 基、取代或非取代之烷磺醯基或取代或非取代之胺磺醯 基)、取代環烷烷基(該取代環烷烷基之環上之取代基爲 羧基、取代或非取代之胺甲醯基、取代或非取代之烷磺 醯基或取代或非取代之胺磺醯基)、取代環烯烷基(該取 代環烯烷基之環上之取代基爲羧基、取代或非取代之胺 甲醯基、取代或非取代之烷磺醯基或取代或非取代之胺 -276- 201021798 磺醯基)、取代雜環烷基(該取代雜環烷基之環上之取代 基爲羧基、取代或非取代之胺甲醯基、取代或非取代之 烷磺醯基或取代或非取代之胺磺醯基),或 式:-(CR7R8)n-C( = 0)-R9(其中R7和R8各自獨立爲氫、 鹵素、羥基、羧基、取代或非取代之烷基、取代或非取 代之烷氧基、取代或非取代之芳基、取代或非取代之雜 芳基、取代或非取代之環烷基、取代或非取代之環烯基 或取代或非取代之雜環基,η爲1〜10之整數, R9 爲-OR1。或-NRnR12, R111爲氫、取代或非取代之烷基、取代或非取代之芳基 、取代或非取代之雜芳基、取代或非取代之環烷基、取 代或非取代之環烯基或取代或非取代之雜環基、R11及R12各自獨立爲氫、取代或非取代之烷基、取代或 非取代之烷氧基、取代或非取代之芳氧基、取代或非取 代之雜芳氧基、取代或非取代之烷磺醯基、取代或非取 代之芳基、取代或非取代之雜芳基、取代或非取代之環 院基、取代或非取代之環烯基或取代或非取代之雜環基 )之基, R5爲氫、鹵素、羥基、氰基、硝基、羧基、取代或非 取代之烷基、取代或非取代之烯基、取代或非取代之炔 基、取代或非取代之芳基、取代或非取代之雜芳基、取 代或非取代之環烷基、取代或非取代之環烯基、取代或 非取代之雜環基、取代或非取代之烷氧基、取代或非取 代之芳氧基、取代或非取代之雜芳氧基、取代或非取代 -277- 之環烷氧基、取代或非取代之環烯氧基、取代或非取代 之雜環氧基、取代或非取代之烷硫基、取代或非取代之 芳硫基、取代或非取代之雜芳硫基、取代或非取代之環 烷硫基、取代或非取代之環烯硫基、取代或非取代之雜 環硫基、取代或非取代之烷磺醯基、取代或非取代之芳: 磺醯基、取代或非取代之雜芳磺醯基、取代或非取代之 環烷磺醯基、取代或非取代之環烯磺醯基、取代或非& 代之雜環磺醯基、取代或非取代之醯基、取代或非取代 之胺甲醯基或取代或非取代之胺基, Rx爲鹵素、羥基、氰基、硝基、殘基、取代或非取代 之烷基、取代或非取代之烯基、取代或非取代之炔基、 取代或非取代之芳基、取代或非取代之雜芳基、取代或 非取代之環烷基、取代或非取代之環烯基、取代或非取 代之雜環基、取代或非取代之烷氧基、取代或非取代之 芳氧基、取代或非取代之雜芳氧基、取代或非取代之環 烷氧基、取代或非取代之環烯氧基、取代或非取代之雜 環氧基、取代或非取代之烷硫基、取代或非取代之芳硫 基、取代或非取代之雜芳硫基、取代或非取代之環烷硫 基 '取代或非取代之環烯硫基、取代或非取代之雜環硫 基、取代或非取代之烷磺醯基、取代或非取代之芳磺醯 基、取代或非取代之雜芳磺醯基、取代或非取代之環烷 磺醯基、取代或非取代之環烯磺醯基、取代或非取代之 雜環磺醯基、取代或非取代之醯基、取代或非取代之胺 甲醯基或取代或非取代之胺基,m爲0〜3之整數, -278 - 201021798 但如下示化合物:除外)◊ 3 3.如申請專利範圍第32項之化合物、其製藥容許鹽或其 等之溶劑合物,其中環C爲雙環。 34. —種醫藥組成物,其係含有如申請專利範圍第8〜33項 中任一項之化合物、其製藥容許鹽或其等之溶劑合物。 35. —種具有血管內皮脂肪酶抑制活性之醫藥組成物,其係 含有如申請專利範圍第8〜33項中任一項之化合物、其 製藥容許鹽或其等之溶劑合物。-279- 201021798 四、指定代表圖: (一) 本案指定代表圖為:無。 (二) 本代表圖之元件符號簡單說明: 無。 五、本案若有化學式時,請揭示最能顯示發明特徵的化學式:
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- 2009-10-15 JP JP2010533922A patent/JP5605844B2/ja active Active
- 2009-10-15 EP EP09820619.6A patent/EP2351744B1/en not_active Not-in-force
- 2009-10-15 WO PCT/JP2009/067845 patent/WO2010044441A1/ja active Application Filing
- 2009-10-16 TW TW098135057A patent/TW201021798A/zh unknown
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2014
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US8957219B2 (en) | 2015-02-17 |
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EP2351744A4 (en) | 2012-08-22 |
US20140288302A1 (en) | 2014-09-25 |
JP5605844B2 (ja) | 2014-10-15 |
US20110251386A1 (en) | 2011-10-13 |
WO2010044441A1 (ja) | 2010-04-22 |
JPWO2010044441A1 (ja) | 2012-03-15 |
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