TWI831011B - Egfr抑制劑、其製備方法及用途 - Google Patents
Egfr抑制劑、其製備方法及用途 Download PDFInfo
- Publication number
- TWI831011B TWI831011B TW110118592A TW110118592A TWI831011B TW I831011 B TWI831011 B TW I831011B TW 110118592 A TW110118592 A TW 110118592A TW 110118592 A TW110118592 A TW 110118592A TW I831011 B TWI831011 B TW I831011B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- piridinyl
- pyridinyl
- sulfonyl
- formyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940121647 egfr inhibitor Drugs 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 20
- 239000012453 solvate Substances 0.000 abstract description 18
- 230000002265 prevention Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 abstract 1
- -1 small molecule compounds Chemical class 0.000 description 2054
- 229910052757 nitrogen Inorganic materials 0.000 description 639
- 239000001257 hydrogen Substances 0.000 description 383
- 229910052739 hydrogen Inorganic materials 0.000 description 383
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 220
- 238000000132 electrospray ionisation Methods 0.000 description 214
- 125000004076 pyridyl group Chemical group 0.000 description 203
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 182
- 238000005481 NMR spectroscopy Methods 0.000 description 171
- 150000002431 hydrogen Chemical class 0.000 description 162
- 239000011737 fluorine Substances 0.000 description 158
- 229910052731 fluorine Inorganic materials 0.000 description 158
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 156
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 120
- 125000000217 alkyl group Chemical group 0.000 description 108
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 94
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 77
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 66
- 125000003373 pyrazinyl group Chemical group 0.000 description 56
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 51
- 239000000460 chlorine Substances 0.000 description 51
- 229910052801 chlorine Inorganic materials 0.000 description 51
- 229910052760 oxygen Inorganic materials 0.000 description 50
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 47
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 45
- 229910052794 bromium Inorganic materials 0.000 description 45
- 125000001424 substituent group Chemical group 0.000 description 45
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 44
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 42
- 239000001301 oxygen Substances 0.000 description 42
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 41
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 39
- 125000004093 cyano group Chemical group *C#N 0.000 description 38
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 37
- 238000000034 method Methods 0.000 description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 36
- 125000003545 alkoxy group Chemical group 0.000 description 34
- 125000005842 heteroatom Chemical group 0.000 description 34
- 125000002098 pyridazinyl group Chemical group 0.000 description 34
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 33
- WKJOQYHMXRVQDK-UHFFFAOYSA-N 2-(dimethylamino)acetamide Chemical compound CN(C)CC(N)=O WKJOQYHMXRVQDK-UHFFFAOYSA-N 0.000 description 31
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 28
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 27
- 102000001301 EGF receptor Human genes 0.000 description 25
- 108060006698 EGF receptor Proteins 0.000 description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 24
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 24
- 230000035772 mutation Effects 0.000 description 24
- ZIAFMQXEAJYWKJ-UHFFFAOYSA-N n-(methylamino)formamide Chemical compound CNNC=O ZIAFMQXEAJYWKJ-UHFFFAOYSA-N 0.000 description 24
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 24
- PAFZNILMFXTMIY-UHFFFAOYSA-N Cyclohexylamine Natural products NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 22
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 22
- OIZBTNMSPCPUJT-UHFFFAOYSA-N n-(ethylamino)formamide Chemical compound CCNNC=O OIZBTNMSPCPUJT-UHFFFAOYSA-N 0.000 description 22
- YRGVVYIPLJBQIR-UHFFFAOYSA-N n-(propylamino)formamide Chemical compound CCCNNC=O YRGVVYIPLJBQIR-UHFFFAOYSA-N 0.000 description 22
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 125000000753 cycloalkyl group Chemical group 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- SJMCLWCCNYAWRQ-UHFFFAOYSA-N propane-2-sulfonamide Chemical compound CC(C)S(N)(=O)=O SJMCLWCCNYAWRQ-UHFFFAOYSA-N 0.000 description 20
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 20
- 125000002883 imidazolyl group Chemical group 0.000 description 19
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 19
- TZGPACAKMCUCKX-UHFFFAOYSA-N 2-hydroxyacetamide Chemical compound NC(=O)CO TZGPACAKMCUCKX-UHFFFAOYSA-N 0.000 description 18
- MTEZLAATISORQK-UHFFFAOYSA-N 2-methoxyacetamide Chemical compound COCC(N)=O MTEZLAATISORQK-UHFFFAOYSA-N 0.000 description 18
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 125000006262 isopropyl amino sulfonyl group Chemical group 0.000 description 18
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 description 18
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 18
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 13
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 125000002757 morpholinyl group Chemical group 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 12
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 11
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 11
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-M ethanimidate Chemical compound CC([O-])=N DLFVBJFMPXGRIB-UHFFFAOYSA-M 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 201000005202 lung cancer Diseases 0.000 description 10
- 208000020816 lung neoplasm Diseases 0.000 description 10
- ODEHTVSJNVTBES-UHFFFAOYSA-N n-(propan-2-ylamino)formamide Chemical compound CC(C)NNC=O ODEHTVSJNVTBES-UHFFFAOYSA-N 0.000 description 10
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 8
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 7
- 125000006308 propyl amino group Chemical group 0.000 description 7
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 6
- DMEKUKDWAIXWSL-UHFFFAOYSA-N n,n-dimethyl-7-nitro-9h-fluoren-2-amine Chemical compound [O-][N+](=O)C1=CC=C2C3=CC=C(N(C)C)C=C3CC2=C1 DMEKUKDWAIXWSL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 5
- JCBJVAJGLKENNC-UHFFFAOYSA-N potassium;ethoxymethanedithioic acid Chemical compound [K+].CCOC(S)=S JCBJVAJGLKENNC-UHFFFAOYSA-N 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 4
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 4
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000008052 alkyl sulfonates Chemical class 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229960005395 cetuximab Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- PFWWSGFPICCWGU-UHFFFAOYSA-N cyclopropanesulfonyl chloride Chemical compound ClS(=O)(=O)C1CC1 PFWWSGFPICCWGU-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 4
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 230000003449 preventive effect Effects 0.000 description 4
- OVPLZYJGTGDFNB-UHFFFAOYSA-N propan-2-yl carbamate Chemical compound CC(C)OC(N)=O OVPLZYJGTGDFNB-UHFFFAOYSA-N 0.000 description 4
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Abstract
本發明涉及EGFR抑制劑、其製備方法及用途,具體地,涉及具有EGFR抑制活性化合物及其藥學上可接受的鹽或藥學上可接受的溶劑合物,其製備方法、包含該化合物的藥物組合物,以及這些化合物在製備用於EGFR激酶介導的癌症及其他疾病的預防及/或治療的藥物的用途。
Description
本發明涉及藥物化學領域,具體地,涉及EGFR抑制劑、其製備方法及用途。
癌症是目前威脅人類生命健康的最主要疾病之一。近年來全球每年新增癌症約1800萬例,因癌致死約950萬人。幸運的是,隨著靶向藥物的發展,癌症的治療領域取得了一定的進展。比如,針對非小細胞肺癌,靶向表皮生長因數受體(EGFR)的小分子抑制劑可選擇性地阻礙EGFR與ATP的結合,從而抑制EGFR的活化及下游信號通路,導致細胞生長、增殖與轉移停滯,進而發生凋亡,實現EGFR介導的腫瘤的有效控制。
遺憾的是,臨床上使用EGFR抑制劑後很容易出現獲得性耐藥,其中主要的方式為EGFR發生點突變,導致小分子不能有效地與之結合,出現抑制作用下降甚至消失的情況,如最為常見的T790M突變。針對這種情況,研究者們逐步開發出了新一代抑制劑,可以有效克服上一代的耐藥問題。目前,第三代EGFR抑制劑奧希替尼與阿美替尼已在國內上市,可有效克服T790M突變,並且對野生型EGFR的活性較弱,降低了二代藥物的毒副作用。然而,針對奧希替尼的耐藥已經出現(Nature Medicine
, 2015,21
, 560-562),其主要機制是EGFR的797位半胱氨酸殘基突變為絲氨酸殘基(C797S),導致Cys與抑制劑之間的共價鍵作用消失而出現耐藥,約占40%的比例。
因此,發展能克服C797S突變的***EGFR抑制劑具有重要的意義與臨床價值。
本申請發明人經廣泛、深入的研究,設計、合成了一系列結構新穎的小分子化合物,對臨床常見的EGFR激酶多種突變體,包括含有C797S突變的突變體具有很好抑制作用。
本發明提供如下所示化合物:
(A)
或上述化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物。
其中取代基和符號的定義下面詳細說明。
本發明的一個目的是提供一類具有抑制EGFR激酶活性的化合物及其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物。
本發明的另一個目的是提供上述化合物的製備方法。
本發明的另一個目的是提供包含上述化合物的藥物組合物。
本發明的另一個目的是提供上述化合物及包含上述化合物的藥物組合物在製備用於EGFR激酶介導的癌症或其他疾病的預防及/或治療的藥物中的用途。
本發明的另一個目的是提供一種治療癌症的方法,該方法包括向受試者施用有效量的本發明化合物或組合物。
發明詳述
本文描述了各種具體實施方案、方式和實施例,包括為了理解所要求保護的本發明而採用的示例性實施方式和定義。儘管以下詳細描述給出了具體的較佳實施方案,但是本領域技術人員將理解,這些實施方式僅是示例性的,並且本發明可以以其他方式實踐。為了確定侵權的目的,本發明的範圍將涉及所附申請專利範圍中的任何一個或複數個,包括其等同物,以及等同於所述的那些要素或限制。
本發明是藉由下面的技術方案實現的。
在本發明的第一方面,本發明提供了以下通式(A)的化合物:
(A)
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(17)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(18),,,,,,,,,,,,;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R4
、R5
各自獨立地選自:
氫、氟、氯、溴、C1-C6含氟烷基(例如,三氟甲基),氰基,硝基,C1-C6烷基(例如,甲基,乙基或異丙基),C1-C6烷氧基(例如,甲氧基或乙氧基),C3-C6環烷基(例如,環丙基),
或者,R4
、R5
和與它們相連的碳原子一起,形成含一個N、O或S原子的5元環。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,
(14),,,,,,,,,,,,;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,C3-C6環烷基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,
(12),,,,,,,,,,,,;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,氟,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,甲基,乙基,異丙基,環丙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,呱嗪-1-基,N-甲基呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基,,,,;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R4
為氫,R5
選自氫、氟、氯、溴、三氟甲基,氰基,硝基,甲基,乙基,異丙基,甲氧基,乙氧基或環丙基,
或者,R4
、R5
和與它們相連的碳原子一起,形成,或。
在本發明的第二方面,本發明提供了以下式(I)所示化合物:
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16),,,,,,,,,,,,,
(17)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(18)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R5
選自氫、氟、氯、溴、C1-C6含氟烷基,氰基,硝基,C1-C6烷基,C1-C6烷氧基,C3-C6環烷基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
(14),,,,,,,,,,,,;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1, 5-二乙基-3-吡唑基,1, 5-二異丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1, 3-二甲基-4-吡唑基,1-甲基-3-乙基-4-吡唑基,1-甲基-3-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1,3-二乙基-4-吡唑基,1-乙基-3-異丙基-4-吡唑基,1-異丙基-3-甲基-4-吡唑基,1-異丙基-3-乙基-4-吡唑基,1,3-二異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,C3-C6環烷基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(呱啶-4-)呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(N-乙基呱啶-4-)呱嗪基,4-(N-正丙基呱啶-4-)呱嗪基,4-(N-異丙基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,4-(N-甲基-氮雜環丁烷-3-基)呱嗪基,4-(N-乙基-氮雜環丁烷-3-基)呱嗪基,4-(N-正丙基-氮雜環丁烷-3-基)呱嗪基,4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-(呱嗪-1-)呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,
(12),,,,,,,,,,,,;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1, 5-二甲基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-乙基-3-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,氟,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,甲基,乙基,異丙基,環丙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,呱嗪-1-基,N-甲基呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基,,,,;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫,氟,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基;且Z3
和Z4
之一選自以下,另一個為氫、氟、甲基、乙基、異丙基、環丙基、乙烯基、苄基或環丙基亞甲基:
氟,2-羥基乙基氨基,2-N, N-二甲基氨基乙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,呱嗪-1-基,N-甲基呱嗪基,4-(N-甲基呱啶-4-)呱嗪基,4-(氮雜環丁烷-3-基)呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-氰基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基,,,,;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為甲基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基或4-(N-甲基呱嗪-1-)呱啶基;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R2
選自甲基,三氟甲基,乙基,異丙基,環丙基,R3
選自氫,甲基,乙基,異丙基,環丙基。
在一些實施方案中,R5
選自氫、氟、氯、溴、三氟甲基,氰基,硝基,甲基,乙基,異丙基,甲氧基,乙氧基,環丙基。
在本發明的第三方面,本發明提供了以下式(II-1)或(II-2)所示化合物:或
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
各X獨立地選自NH,O,S;
各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基;
2),其中Z2
,Z3
,Z4
,Z5
與1)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
3),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z2
,Z4
,Z5
與1)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
5),其中Z1
,Z3
,Z5
與1)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
2),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-羥基呱啶基,
(9)苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
2),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,三氟甲氧基,乙烯基,N-甲基呱嗪基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-羥基呱啶基,苄基,環丙基亞甲基;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基、三氟甲氧基,Z4
為氫、甲基、乙基、乙烯基、苄基、環丙基亞甲基或4-羥基呱啶基,Z3
為氫、N-甲基呱嗪基、 3-(N, N-二甲基氨基)四氫吡咯基、4-N, N-二甲基氨基呱啶基或4-(N-甲基呱嗪-1-)呱啶基,Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫;
2),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為4-(N-甲基呱嗪-1-)呱啶基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,C1-C6烷基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基。
在本發明的第四方面,本發明提供了以下通式(A)的化合物:
(A)
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(17)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R4
、R5
各自獨立地選自:
氫、氟、氯、溴、C1-C6含氟烷基(例如,三氟甲基),氰基,硝基,C1-C6烷基(例如,甲基),C1-C6烷氧基(例如,甲氧基),C3-C6環烷基(例如,環丙基),
或者,R4
、R5
和與它們相連的碳原子一起,形成含一個N、O或S原子的5元環。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R4
為氫,R5
選自氟、氯、溴、三氟甲基,氰基,硝基,甲基,甲氧基或環丙基,
或者,R4
、R5
和與它們相連的碳原子一起,形成,或。
在本發明的第五方面,本發明提供了以下式(I)所示化合物:
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(17)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R5
選自氟、氯、溴、C1-C6含氟烷基,氰基,硝基,C1-C6烷基,C1-C6烷氧基,C3-C6環烷基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基;且Z3
和Z4
之一選自以下,另一個為氫、甲基、乙基、乙烯基、苄基或環丙基亞甲基:
N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為甲基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基或4-(N-甲基呱嗪-1-)呱啶基;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R2
選自甲基,三氟甲基,乙基,異丙基,環丙基,R3
選自甲基,乙基,異丙基,環丙基。
在一些實施方案中,R5
選自氟、氯、溴、三氟甲基,氰基,硝基,甲基,甲氧基,環丙基。
在本發明的第六方面,本發明提供了以下式(II-1)或(II-2)所示化合物:或
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
各X獨立地選自NH,O,S;
各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基;
2),其中Z2
,Z3
,Z4
,Z5
與1)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
3),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z2
,Z4
,Z5
與1)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
5),其中Z1
,Z3
,Z5
與1)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
2),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,
(9)苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
2),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,三氟甲氧基,乙烯基,N-甲基呱嗪基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,苄基,環丙基亞甲基;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基、三氟甲氧基,Z4
為氫、甲基、乙基、乙烯基、苄基或環丙基亞甲基,Z3
為N-甲基呱嗪基、 3-(N, N-二甲基氨基)四氫吡咯基、4-N, N-二甲基氨基呱啶基或4-(N-甲基呱嗪-1-)呱啶基;
2),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為4-(N-甲基呱嗪-1-)呱啶基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,C1-C6烷基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基。
在本發明的第七方面,本發明提供了以下通式(A)的化合物:
(A)
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(17)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R4
、R5
各自獨立地選自:
氫、氟、氯、溴、C1-C6含氟烷基(例如,三氟甲基),氰基,硝基,
或者,R4
、R5
和與它們相連的碳原子一起,形成含一個N、O或S原子的5元環。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R4
為氫,R5
選自氟、氯、溴、三氟甲基,氰基或硝基,
或者,R4
、R5
和與它們相連的碳原子一起,形成,或。
在本發明的第八方面,本發明提供了以下式(I)所示化合物:
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-乙醯基-4-呱啶基,N-丙醯基-4-呱啶基,N-異丙醯基-4-呱啶基,N-環丙基甲醯基-4-呱啶基,N-甲基磺醯基-4-呱啶基,N-乙基磺醯基-4-呱啶基,N-丙基磺醯基-4-呱啶基,N-異丙基磺醯基-4-呱啶基,N-環丙基磺醯基-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-乙醯氨基環己基,4-丙醯氨基環己基,4-異丙基甲醯氨基環己基,4-甲基磺醯氨基環己基,4-乙基磺醯氨基環己基,4-丙基磺醯氨基環己基,4-異丙基磺醯氨基環己基,4-環丙基磺醯氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1-(N-甲基-4-呱啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-呱啶基)-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基,
(16)Z3
與Z4
可以形成含氧的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
(17)Z3
與Z4
可以形成含氮的取代或未取代的五-七元環;取代基可以選自與Z1相同的上述取代基,
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基;
R5
選自氟、氯、溴、C1-C6含氟烷基,氰基,硝基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C1-C6含氟烷基,C3-C8環烷基,C1-C6含雜原子烷基,C3-C8含雜原子環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-(N-甲基呱嗪基)乙基,2-(N-乙醯基呱嗪基)乙基,2-嗎啡啉基乙基,2-硫啡啉基乙基,2-呱啶基乙基,2-羥基乙基,3-羥基丙基,2-甲氧基乙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,N-羥乙基-4-呱啶基,N-氰甲基-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,3-N,N-二甲基氨基環戊基,3-N,N-二乙基基氨基環戊基,3-N,N-二丙基氨基環戊基,3-N,N-異丙基氨基環戊基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基,4-羥基環己基,4-甲氧基環己基,4-乙氧基環己基,4-異丙氧基環己基;
3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-異丙基-3-吡咯基,1-環丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-羥乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1-羥乙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-異噁唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
5),其中Z2
,Z3
,Z4
,Z5
與4)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
與4)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
與4)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
與4)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
與4)中定義相同, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自與Z1
相同的上述取代基;
10), 其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫,Ry
選自與Z1
相同的上述取代基;
11),其中Z1
,Z2
,Z5
與4)中定義相同,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自與Z1
相同的上述取代基。
在一些實施方案中,R1
選自:
1)氫,C1-C6烷基,C3-C8環烷基;
2)2-N, N-二甲基氨基乙基,3-N, N-二甲基氨基丙基,2-N, N-二乙基氨基乙基,3-N, N-二乙基氨基丙基,2-羥基乙基,3-羥基丙基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-丙基-4-呱啶基,N-異丙基-4-呱啶基,4-氨基環己基,4-N,N-二甲基氨基環己基,4-N,N-二乙基氨基環己基,4-N,N-二丙基氨基環己基,4-N,N-二異丙基氨基環己基;
3)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-異丙基-3-吡唑基,1-環丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-異丙基-4-吡唑基,1-環丙基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
4),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,
(7)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,
(8)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(9)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(10)4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,
(11)環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基;
5),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
6),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
8),其中Z1
,Z3
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
9),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基, 且Z1
,Z2
,Z5
可以同時為氫,Rx
選自氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基;
10), 其中Z1
,Z2
,Z5
各自獨立地選自氫,氟,氯,溴,碘,C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6含氟烷氧基,且Z1
,Z2
,Z5
可以同時為氫,Ry
為C1-C6烷基;
11),其中Z1
,Z2
,Z5
各自獨立地選自氫,C1-C6烷基,且Z1
,Z2
,Z5
可以同時為氫, Rz
、R各自獨立地選自C1-C6烷基。
在一些實施方案中,R1
選自:
1)環丙基,2-N, N-二甲基氨基乙基,2-羥基乙基,N-甲基-4-呱啶基,4-氨基環己基,1-甲基-3-吡唑基,1-甲基-4-吡唑基,1, 3-二甲基-5-吡唑基,1-甲基-4-咪唑基;
2),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基,乙烯基,N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,苄基,環丙基亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫,甲氧基,乙氧基,異丙氧基,三氟甲基,三氟甲氧基;且Z3
和Z4
之一選自以下,另一個為氫、甲基、乙基、乙烯基、苄基或環丙基亞甲基:
N-甲基呱嗪基,嗎啡啉基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-羥基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,N-甲基-4-呱啶基,2-(N, N-二甲基氨基)乙醯胺基,環丙基磺醯胺基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,4-甲基-1-呱嗪亞甲基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,N-甲基呱嗪-1-甲醯基,環丙胺基磺醯基,N-甲基呱嗪-1-磺醯基;
3),其中Z2
,Z3
,Z4
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z2
,Z3
,Z4
,Z5
不同時為氫;
4),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為甲基、N-(N-甲基-3-四氫吡咯基)氨基、N-甲基-N-(N-甲基-3-四氫吡咯基)氨基、N-甲基呱嗪基或4-(N-甲基呱嗪-1-)呱啶基;
5),其中Z1
,Z2
,Z4
,Z5
為氫;
6),其中Z1
,Z3
,Z5
各自獨立地選自氫、甲氧基、N-甲基呱嗪基,且Z1
,Z3
,Z5
不同時為氫;
7),其中Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基,Rx
為2-(N, N-二甲基氨基)乙醯基;
8), 其中Z1
,Z2
,Z5
各自獨立地選自氫、氟、氯、甲基、甲氧基、三氟甲基、三氟甲氧基,Ry
為甲基;
9),其中Z1
,Z2
,Z5
為氫, Rz
、R為甲基。
在一些實施方案中,R2
、R3
各自獨立地選自C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基,三氟甲基,乙基,異丙基,環丙基。
在一些實施方案中,R2
選自甲基,三氟甲基,乙基,異丙基,環丙基,R3
選自甲基,乙基,異丙基,環丙基。
在一些實施方案中,R5
選自氟、氯、溴、三氟甲基,氰基,硝基。
在本發明的第九方面,本發明提供了以下式(II-1)或(II-2)所示化合物:或
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物,
其中:
各X獨立地選自NH,O,S;
各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)2-N, N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基呱嗪基)乙氧基,2-(N-乙醯基呱嗪基)乙氧基,2-嗎啡啉基乙氧基,2-硫啡啉基乙氧基,2-呱啶基乙氧基,3-N, N-二甲基氨基丙氧基,3-N, N-二乙基氨基丙氧基,3-N, N-二異丙基氨基丙氧基,3-(N-甲基呱嗪基)丙氧基,3-(N-乙醯基呱嗪基)丙氧基,3-嗎啉基丙氧基,3-硫啡啉基丙氧基,3-呱啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,單鹵素取代苯基甲氧基,偕二鹵素取代苯基甲氧基,雜二鹵素取代苯基甲氧基,
(4)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,N-(N-甲基-4-呱啶基)呱嗪基,N-(N-乙基-4-呱啶基)呱嗪基,N-叔丁氧羰基呱嗪基,N-乙醯基呱嗪基,N-丙醯基呱嗪基,N-異丁醯基呱嗪基,N-環丙基甲醯基呱嗪基,N-甲磺醯基呱嗪基,N-乙基磺醯基呱嗪基,N-正丙基磺醯基呱嗪基,N-異丙基磺醯基呱嗪基,N-環丙基磺醯基呱嗪基,2-氧代-呱嗪-4-基,
(5)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(6)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(7)咪唑基,4-甲基-1-咪唑基,
(8)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-乙醯基呱嗪-1-)呱啶基,4-(N-叔丁氧羰基呱嗪-1-)呱啶基,4-(N-甲磺醯基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(9)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-乙醯基-4-呱啶基,N-叔丁氧羰基-4-呱啶基,N-甲磺醯基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(10)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,2-嗎啡啉基乙基氨基,2-(N-甲基呱嗪基)乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,3-嗎啉基丙基氨基,3-(N-甲基呱嗪基)丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(11)氨基亞甲基,N, N-二甲基氨基亞甲基,N, N-二乙基氨基亞甲基,4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(12)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,環丙基胺基甲醯基,環丁基胺基甲醯基,環戊基胺基甲醯基,環己基胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,環丙基胺基乙醯基,環丁基胺基乙醯基,環戊基胺基乙醯基,環己基胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(13)羥基甲醯基,甲氧基甲醯基,乙氧基甲醯基,丙氧基甲醯基,異丙氧基甲醯基,正丁氧基甲醯基,異丁氧基甲醯基,叔丁氧基甲醯基,
(14)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基,4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基,
(15)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基,環丙基氨基甲醯氨基,環丁基氨基甲醯氨基,環戊基氨基甲醯氨基,呱啶基-1-甲醯氨基,4-羥基呱啶基-1-甲醯氨基,4-N, N-二甲基呱啶基-1-甲醯氨基,4-N, N-二乙基呱啶基-1-甲醯氨基,四氫吡咯基-1-甲醯氨基,3-N, N-二甲基四氫吡咯基-1-甲醯氨基,3-N, N-二乙基四氫吡咯基-1-甲醯氨基,N-甲基呱嗪基-1-甲醯氨基,N-乙基呱嗪基-1-甲醯氨基,N-乙醯基呱嗪基-1-甲醯氨基,N-叔丁氧羰基呱嗪基-1-甲醯氨基,N-(2-羥基乙基)呱嗪基-1-甲醯氨基,N-(2-氰基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基,N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基,N-(3-羥基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基,N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基,嗎啉基-1-甲醯氨基,3, 5-二甲基嗎啉基-1-甲醯氨基,4-(四氫吡咯基)呱啶基-1-甲醯氨基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基,4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基,N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基;
2),其中Z2
,Z3
,Z4
,Z5
與1)中定義相同,且Z2
,Z3
,Z4
,Z5
不同時為氫;
3),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫;
4),其中Z1
,Z2
,Z4
,Z5
與1)中定義相同,且Z1
,Z2
,Z4
,Z5
可以同時為氫;
5),其中Z1
,Z3
,Z5
與1)中定義相同,且Z1
,Z3
,Z5
不同時為氫;
R2
、R3
各自獨立地選自:
氫、C1-C6烷基,C1-C6含氟烷基,C3-C6環烷基,C3-C6含氟環烷基。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6環烷基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,N-環丙基呱嗪基,N-(2-羥基乙基)呱嗪基,N-(2-N, N-二甲基氨基乙基)呱嗪基,N-(2-N, N-二乙基氨基乙基)呱嗪基,N-(2-氰基乙基)呱嗪基,N-氰甲基呱嗪基,N-(3-羥基丙基)呱嗪基,N-(3-N, N-二甲基氨基丙基)呱嗪基,N-(3-N, N-二乙基氨基丙基)呱嗪基,
(4)嗎啡啉基,2, 6-二甲基嗎啡啉基,硫啡啉基,
(5)四氫吡咯基,3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)咪唑基,4-甲基-1-咪唑基,
(7)呱啶基,4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-羥基呱啶基,4-甲氧基呱啶基,4-乙氧基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,4-(N-(2-羥基乙基)呱嗪-1-)呱啶基,4-(N-(2-氰基乙基)呱嗪-1-)呱啶基,4-(N-(3-羥基丙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基,4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基,4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基,4-(四氫吡咯-1-)呱啶基,4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基,4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基,
(8)呱啶-4-基,N-甲基-4-呱啶基,N-乙基-4-呱啶基,N-異丙基-4-呱啶基,N-(2-羥基乙基)-4-呱啶基,N-(2-N, N-二甲基氨基乙基)-4-呱啶基,N-(2-N, N-二乙基氨基乙基)-4-呱啶基,N-(2-氰基乙基)-4-呱啶基,N-(3-羥基丙基)-4-呱啶基,N-(3-N, N-二甲基氨基丙基)-4-呱啶基,N-(3-N, N-二乙基氨基丙基)-4-呱啶基,N-(3-氰基丙基)-4-呱啶基,N-氰基亞甲基-4-呱啶基,
(9)氨基,N, N-二甲基氨基,N, N-二乙基氨基,N, N-二正丙基氨基,N, N-二異丙基氨基,2-N, N-二甲基氨基乙基氨基,3-N, N-二甲基氨基丙基氨基,3-N, N-二乙基氨基丙基氨基,3-N, N-二異丙基氨基丙基氨基,N-甲基呱啶-4-氨基,N-乙基呱啶-4-氨基,N-正丙基呱啶-4-氨基,N-異丙基呱啶-4-氨基,乙醯胺基,丙醯胺基,2-(N, N-二甲基氨基)乙醯胺基,2-羥基乙醯胺基,2-甲氧基乙醯胺基,甲磺醯胺基,乙磺醯胺基,正丙基磺醯胺基,異丙基磺醯胺基,環丙基磺醯胺基,N-甲基-N-(N-甲基-3-四氫吡咯基)氨基,N-(N-甲基-3-四氫吡咯基)氨基,N-甲基-N-(2-N, N-二甲基氨基)乙基氨基,
(10)4-甲基-1-呱嗪亞甲基,4-乙基-1-呱嗪亞甲基,4-丙基-1-呱嗪亞甲基,4-異丙基-1-呱嗪亞甲基,4-(2-羥基乙基)-1-呱嗪亞甲基,4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基,呱啶-1-亞甲基,4-(N, N-二甲基氨基)-1-呱啶亞甲基,4-羥基呱啶-1-亞甲基,四氫吡咯-1-亞甲基,3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基,苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
(11)氨基甲醯基,甲胺基甲醯基,N, N-二甲基氨基甲醯基,乙胺基甲醯基,氨基乙醯基,甲胺基乙醯基,2-(N, N-二甲基氨基)乙醯基,乙胺基乙醯基,
四氫吡咯-1-甲醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基,
嗎啡啉基-4-甲醯基,硫啡啉基-4-甲醯基,2, 6-二甲基嗎啡啉基-4-甲醯基,
呱啶基-1-甲醯基,4-羥基呱啶基-1-甲醯基,4-(N, N-二甲基氨基)呱啶基-1-甲醯基,4-(N, N-二乙基氨基)呱啶基-1-甲醯基,4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基,4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基,
N-甲基呱嗪-1-甲醯基,N-乙基呱嗪-1-甲醯基,N-異丙基呱嗪-1-甲醯基,N-(2-羥基乙基)呱嗪-1-甲醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基,4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基,4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基,
(12)羥基磺醯基,氨基磺醯基,甲胺基磺醯基,乙胺基磺醯基,丙胺基磺醯基,異丙胺基磺醯基,環丙胺基磺醯基,環丁胺基磺醯基,環戊胺基磺醯基,環己胺基磺醯基,
四氫吡咯-1-磺醯基,3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基,3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基,
嗎啡啉基-4-磺醯基,硫啡啉基-4-磺醯基,2 6-二甲基嗎啡啉基-4-磺醯基,
呱啶基-1-磺醯基,4-羥基呱啶-1-磺醯基,4-(N, N-二甲基氨基)呱啶基-1-磺醯基,4-(N, N-二乙基氨基)呱啶基-1-磺醯基,
N-甲基呱嗪-1-磺醯基,N-乙基呱嗪-1-磺醯基,N-異丙基呱嗪-1-磺醯基,N-(2-羥基乙基)呱嗪-1-磺醯基,N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基,N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基,
(13)氨基甲醯氨基,甲氨基甲醯氨基,乙氨基甲醯氨基,丙氨基甲醯氨基,異丙氨基甲醯氨基;
2),其中Z1
,Z3
,Z4
,Z5
與1)中定義相同,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
(1)氫,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷氧基,C2-C6烯基,
(3)呱嗪基,N-甲基呱嗪基,N-乙基呱嗪基,N-正丙基呱嗪基,N-異丙基呱嗪基,
(5)3-(N, N-二甲基氨基)四氫吡咯基,3-(N, N-二乙基氨基)四氫吡咯基,
(6)4-N, N-二甲基氨基呱啶基,4-N, N-二乙基氨基呱啶基,4-N, N-二異丙基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,
(9)苄基,環丙基亞甲基,環丁基亞甲基,環戊基亞甲基,環己基亞甲基,
2),其中Z1
,Z3
,Z4
,Z5
各自獨立地選自氫,C1-C6烷基,C1-C6烷氧基,4-(N-甲基呱嗪-1-)呱啶基,4-(N-乙基呱嗪-1-)呱啶基,4-(N-異丙基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫。
在一些實施方案中,各R1
獨立地選自:
1),其中:
Z1
,Z2
,Z3
,Z4
,Z5
各自獨立地選自以下,且Z1
,Z2
,Z3
,Z4
,Z5
不同時為氫:
氫,甲基,乙基,甲氧基,三氟甲氧基,乙烯基,N-甲基呱嗪基,3-(N, N-二甲基氨基)四氫吡咯基,4-N, N-二甲基氨基呱啶基,4-(N-甲基呱嗪-1-)呱啶基,苄基,環丙基亞甲基;
較佳地,Z1
,Z2
,Z5
各自獨立地選自氫、甲氧基、三氟甲氧基,Z4
為氫、甲基、乙基、乙烯基、苄基或環丙基亞甲基,Z3
為N-甲基呱嗪基、 3-(N, N-二甲基氨基)四氫吡咯基、4-N, N-二甲基氨基呱啶基或4-(N-甲基呱嗪-1-)呱啶基;
2),其中:
Z1
,Z3
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基、4-(N-甲基呱嗪-1-)呱啶基,且Z1
,Z3
,Z4
,Z5
不同時為氫;
較佳地,Z1
,Z4
,Z5
各自獨立地選自氫、甲基、乙基、甲氧基,Z3
為4-(N-甲基呱嗪-1-)呱啶基。
在一些實施方案中,R2
、R3
各自獨立地選自氫,C1-C6烷基。
在一些實施方案中,R2
、R3
各自獨立地選自甲基。
在一些實施方案中,該藥學上可接受的鹽為無機酸鹽或有機酸鹽,其中,該無機酸鹽為鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、碳酸氫鹽和碳酸鹽、硫酸鹽或磷酸鹽,該有機酸鹽為甲酸鹽、乙酸鹽、丙酸鹽、苯甲酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、α-酮戊二酸鹽、α-甘油磷酸鹽、烷基磺酸鹽或芳基磺酸鹽;較佳地,該烷基磺酸鹽為甲基磺酸鹽或乙基磺酸鹽;該芳基磺酸鹽為苯磺酸鹽或對甲苯磺酸鹽。
除非特殊說明,上述基團和取代基具有藥物化學領域的普通含義。
術語“C1-C6烷基”指的是任意的含有1-6個碳原子的直鏈或支鏈基團,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
術語“C1-C3烷基”指的是任意的含有1-3個碳原子的直鏈或支鏈基團,例如甲基、乙基、正丙基、異丙基等。
術語“含氧烷基”是指是指烷基骨架被一個或複數烷氧基取代所成的基團,例如,甲氧基乙基,甲氧基乙氧基甲基等。
例如,C1-C6含氧烷基是指是指C1-C6烷基骨架被一個或複數C1-C6烷氧基取代所成的基團,例如,甲氧基乙基,甲氧基乙氧基甲基等。類似地,C1-C3含氧烷基是指是指C1-C3烷基骨架被一個或複數C1-C6烷氧基取代所成的基團。
術語“C2-C6烯基”指的是任意的含有2-6個碳原子,且含有至少一個碳碳雙鍵的直鏈或支鏈基團,例如乙烯基、1-丙烯基、2-丙烯基等。
術語“C3-C8環烷基”是指具有飽和環的3-8元單環系統的烴,C3
-C8
環烷基可以為環丙基、環丁基、環戊基、環己基等。
術語“C3-C6環烷基”是指具有飽和環的3-6元單環系統的烴,C3
-C6
環烷基可以為環丙基、環丁基、環戊基、環己基等。
術語“氰基”指的是-CN殘基。
術語“硝基”指的是-NO2
基團。
術語“烷氧基”、“環基氧基”及其衍生物指的是任意上述烷基(例如C1
-C6
烷基、C1
-C3
烷基等)、環烷基(例如C3
-C6
環烷基),其藉由氧原子(-O-)連接到分子的其餘部分。
術語"雜芳基"是指芳族的雜環,通常為具有1至3個選自N、O或S的雜原子的5-、6-、7-、8-元的雜環;雜芳基環可以任選地進一步稠合或連接於芳族和非芳族的碳環和雜環。該雜芳基的非限制性的實例為例如吡啶基、吡嗪基、嘧啶基、噠嗪基、吲哚基、咪唑基、噻唑基、異噻唑基、噻噁唑基、吡咯基、苯基-吡咯基、呋喃基、苯基-呋喃基、噁唑基、異噁唑基、吡唑基、噻吩基、苯並呋喃基、苯並噻吩基、苯並1,3-二氧戊環(苯並二噁茂)、異二氫吲哚基、苯並咪唑基、吲唑基、喹啉基、異喹啉基、1,2,3-***基、1-苯基-1,2,3-***基、2,3-二氫吲哚基、2,3-二氫苯並呋喃基、2,3-二氫苯並噻吩基、苯並吡喃基、2,3-二氫苯並噁嗪基、2,3-二氫喹喔啉基等。
術語“雜環基”(也稱作“雜環烷基”)指的是3-、4-、5-、6-和7-元飽和或部分不飽和碳環,其中一個或複數碳原子被雜原子例如氮、氧和硫替代。雜環基的非限制性實例是,例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、嗎啡啉基、四氫吡咯基、硫嗎啉基等。
例如,“6元雜環基”指的是6-元飽和或部分不飽和碳環,其中一個或複數碳原子被雜原子例如氮、氧和硫替代。6元雜環基的非限制性實例是,例如吡喃、呱啶、呱嗪、嗎啉、嗎啡啉基、硫嗎啉基等。
“5元雜環基”指的是5-元飽和或部分不飽和碳環,其中一個或複數碳原子被雜原子例如氮、氧和硫替代。5元雜環基的非限制性實例是,例如吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、1,3-二氧戊環等。
術語“任選被取代的雜環基”指的是上述“雜環基”被一個或複數“C1-C6烷基”、“C1-C3烷基”、“C3-C6環烷基”等取代。
“含氟烷基”是指烷基骨架被一個或複數氟基取代所成的基團,例如,單氟甲基,二氟乙基,三氟甲基等。
術語“C1-C6含氟烷基”是指C1-C6烷基骨架被一個或複數氟基取代所成的基團,例如,單氟甲基,二氟乙基,三氟甲基等。
類似地,術語“C1-C3含氟烷基”是指C1-C3烷基骨架被一個或複數氟基取代所成的基團,例如,單氟甲基,二氟乙基,三氟甲基等。
術語“C1-C6含雜原子烷基”是指C1-C6烷基骨架中的一個或複數碳原子被一個或複數例如氮、氧和硫的雜原子替代所成的基團,例如,、、等。
術語“C3-C8含雜原子環烷基”是指C3-C8環烷基骨架中的一個或複數碳原子被一個或複數例如氮、氧和硫的雜原子替代所成的基團,例如吡咯烷、咪唑烷、吡唑烷、噻唑烷、呱啶、呱嗪、嗎啉、嗎啡啉基、硫嗎啉基等。
術語“C1-C6醯基”指的是-C(=O)-H和-C(=O)-C1-C5烷基,例如甲醯基、乙醯基、丙醯基、丁醯基等。
術語“磺醯基”指的是和-S(=O)2
-。
術語“C1-C6烷基磺醯基”指的是-S(=O)2
-C1-C6烷基,例如甲磺醯基、乙磺醯基、丙磺醯基、丁磺醯基等。
術語“烷氧基”、“環基氧基”及其衍生物指的是任意上述烷基(例如C1
-C6
烷基、C1
-C3
烷基等)、環烷基(例如C3
-C6
環烷基),其藉由氧原子(-O-)連接到分子的其餘部分。
從所有上述描述中,對本領域技術人員顯而易見的是,其名稱是複合名稱的任意基團,例如“含氟含氧烷基”,應該指的是常規地從其衍生的部分例如從被氟基取代的含氧烷基來構建,其中烷基如上文所定義。類似地,還有“含氟烷氧基”。又例如,“芳基氨基”,應該指的是常規地從其衍生的部分例如從被芳基取代的氨基來構建,其中芳基如上文所定義。類似地,可以理解“雜芳氨基”的含義。類似地,可以理解“羥基磺醯基”、“氨基磺醯基”等的含義。
同樣,任意術語例如烷基氨基、二烷基氨基、烷氧基羰基、烷氧基羰基氨基、雜環基羰基、雜環基羰基氨基、環烷基氧基羰基、烷氧基甲醯基等包括基團,其中烷基、烷氧基、芳基、C3
-C7
環烷基和雜環基部分如上文所定義。
通式中,術語“R4
、R5
和與它們相連的碳原子一起,形成,或”指的是形成通式、、、、或。
術語“各R1
獨立地選自”表示每個R1
代表的基團可以相同,也可以不同。例如,“通式或中,各R1
獨立地選自氫或甲基”,其含義為,式(II-1)中的R1
選自氫或甲基,式(II-2)中的R1
選自氫或甲基。
術語“R2
、R3
各自獨立地選自”表示每個R2
、每個R3
或者R2
和R3
代表的基團可以相同,也可以不同。例如,“通式或中,R2
、R3
各自獨立地選自氫或甲基”,其含義為,式(II-1)中的R2
選自氫或甲基,式(II-1)中的R3
選自氫或甲基,式(II-2)中的R2
選自氫或甲基,式(II-2)中的R3
選自氫或甲基。
根據本發明和除非另有提供,任意上述基團可以任選地在其任意自由位置上被一個或複數基團取代,例如被1-6個基團取代,該基團獨立地選自: 鹵素原子、硝基、氧代(=O)、氰基、C1-C6 烷基、多氟化烷基、多氟化烷氧基、烯基、炔基、羥基烷基、羥基烷基氨基、羥基雜環基、芳基、芳基-烷基、雜芳基、雜芳基-烷基、雜環基、雜環基-烷基、C3-C7環烷基、環烷基-烷基、烷基-芳基、烷基-雜芳基、烷基-雜環基、烷基-環烷基、烷基-芳基-烷基、烷基-雜芳基-烷基、烷基-雜環基-烷基、烷基-環烷基-烷基、烷基-雜環基-雜環基、雜環基-雜環基、雜環基-烷基-雜環基、雜環基-烷基氨基、烷基-雜環基-烷基-氨基、羥基、烷氧基、芳氧基、雜環基氧基、烷基-雜環基氧基、亞甲二氧基、烷基羰基氧基、芳基羰基氧基、環烯基氧基、雜環基羰基氧基、亞烷基氨基氧基、羧基、烷氧基羰基、芳氧基羰基、環烷基氧基羰基、雜環基氧基羰基、氨基、脲基、烷基氨基、氨基-烷基氨基、二烷基氨基、二烷基氨基-雜環基、二烷基氨基-烷基氨基、芳基氨基、芳基烷基氨基、二芳基氨基、雜環基氨基、烷基-雜環基氨基、烷基-雜環基羰基、甲醯基氨基、烷基羰基氨基、芳基羰基氨基、雜環基羰基氨基、烷基-雜環基羰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、雜環基氨基羰基、烷氧基羰基氨基、烷氧基羰基氨基-烷基氨基、烷氧基羰基雜環基-烷基氨基、烷氧基-芳基-烷基、羥基氨基-羰基、烷氧基亞氨基、烷基磺醯基氨基、芳基磺醯基氨基、雜環基磺醯基氨基、甲醯基、烷基羰基、芳基羰基、環烷基羰基、雜環基羰基、烷基磺醯基、芳基磺醯基、氨基磺醯基、烷基氨基磺醯基、二烷基氨基磺醯基、芳基氨基磺醯基、雜環基氨基磺醯基、芳硫基、烷硫基、膦酸酯基和烷基膦酸酯基。
進而,如果適合,上述取代基各自可以進一步被一個或複數上述舉出的基團取代。
術語“含氧的取代或未取代的五-七元環”或“含氮的取代或未取代的五-七元環”指的是5-、6-或7-元飽和或部分不飽和碳環,其中一個或複數碳原子被氧或氮替代。非限制性實例是,例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、四氫吡咯基、六亞甲基亞胺等。
術語“取代或未取代的含1~2個雜原子的3-7元環”指的是3-、4-、5-、6-或7-元飽和或部分不飽和碳環,其中一個或2個碳原子被例如氮、氧和硫的雜原子替代。非限制性實例是,例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、四氫吡咯基、六亞甲基亞胺等。
如本文所使用,除非另外說明,術語“前藥”是指可以在生物學條件(體外或體內)下水解、氧化或進行其他反應以提供本發明的化合物的衍生物。前藥僅在生物學條件下經過該反應成為活性化合物,或者它們在它們不反應的形式中不具有活性。通常可以使用公知的方法製備前藥,例如Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff編, 第5版)中描述的那些方法。
如本文所使用,術語“式(A)、(I)、(II-1)或(II-2)的化合物的藥學上可接受的鹽”的例子是由形成藥學上可以接受的陰離子的有機酸形成的有機酸加合鹽,包括但不限於甲酸鹽、乙酸鹽、丙酸鹽、苯甲酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、α-酮戊二酸鹽、α-甘油磷酸鹽、烷基磺酸鹽或芳基磺酸鹽;較佳地,該烷基磺酸鹽為甲基磺酸鹽或乙基磺酸鹽;該芳基磺酸鹽為苯磺酸鹽或對甲苯磺酸鹽。也可形成合適的無機鹽,包括但不限於鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、碳酸氫鹽和碳酸鹽、硫酸鹽或磷酸鹽等。
藥學上可接受的鹽可使用本領域熟知的標準程式獲得,例如,藉由將足量的鹼性化合物和提供藥學上可以接受的陰離子的合適的酸反應。
本文使用的術語“治療”一般是指獲得需要的藥理及/或生理效應。該效應根據完全或部分地預防疾病或其症狀,可以是預防性的;及/或根據部分或完全穩定或治癒疾病及/或由於疾病產生的副作用,可以是治療性的。本文使用的“治療”涵蓋了對患者疾病的任何治療,包括:(a)預防易感染疾病或症狀但還沒診斷出患病的患者所發生的疾病或症狀;(b)抑制疾病的症狀,即阻止其發展;或(c)緩解疾病的症狀,即,導致疾病或症狀退化。
按照本發明的一種具體技術方案,該化合物、其立體異構體、其前藥、 或者其藥學上可接受的鹽或藥學上可接受的溶劑合物,其中該化合物為下面實施例中該化合物之一。
另一方面,本發明提供了藥物組合物,其包含上述任一技術方案所述的化合物、其立體異構體、其前藥、或者其藥學上可接受的鹽或藥學上可接受的溶劑合物,和任選的藥學上可接受的載體、稀釋劑或賦形劑。
在一些實施方案中,該藥物組合物進一步包含EGFR單抗。
在一些實施方案中,該EGFR單抗為西妥昔單抗或其生物類似物。
術語“生物類似物”指的是序列與西妥昔單抗相同,理化性質以及生物活性、臨床安全性有效性也與西妥昔一致的抗體產品。
製備各種含有一定量的活性成分的藥物組合物的方法是已知的,或根據本發明的揭露內容對於本領域技術人員是顯而易見的。如REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed.(1995)所述,製備該藥物組合物的方法包括摻入適當的藥學賦形劑、載體、稀釋劑等。
以已知的方法製造本發明的藥物製劑,包括常規的混合、溶解或凍乾方法。本發明的化合物可以製成藥物組合物,並向患者以適於選定的施用方式的各種途徑施用,例如,口服或腸胃外(藉由靜脈內、肌內、局部或皮下途徑)。
因此,本發明的化合物結合藥學上可以接受的載體(如惰性稀釋劑或可同化的可食用的載體)可以全身施用,例如,口服。它們可以封閉在硬或軟殼的明膠膠囊中,可以壓為片劑。對於口服治療施用,活性化合物可以結合一種或多種賦形劑,並以可吞咽的片劑、頰含片劑、含片、膠囊劑、酏劑、懸浮劑、糖漿、圓片等的形式使用。這種組合物和製劑應該包含至少0.1%的活性化合物。這種組合物和製劑的比例當然可以變化,可以占給定的單位劑型重量的大約1%至大約99%。在這種治療有用的組合物中,活性化合物的量使得能夠獲得有效劑量水準。
片劑、含片、丸劑、膠囊劑等也可以包含:黏合劑,如黃蓍膠、***膠、玉米澱粉或明膠;賦形劑,如磷酸氫二鈣;崩解劑,如玉米澱粉、馬鈴薯澱粉、藻酸等;潤滑劑,如硬脂酸鎂;和甜味劑,如蔗糖、果糖、乳糖或阿司帕坦;或調味劑,如薄荷、冬青油或櫻桃香味。當單位劑型是膠囊時,除了上面類型的材料,它還可以包含液體載體,如植物油或聚乙二醇。各種其他材料可以存在,作為包衣,或以其他方式改變固體單位元劑型的物理形式。例如,片劑、丸劑或膠囊劑可以用明膠、蠟、蟲膠或糖等包衣。糖漿或酏劑可以包含活性化合物,蔗糖或果糖作為甜味劑,對羥苯甲酸甲酯或對羥苯甲酸丙酯作為防腐劑,染料和調味劑(如櫻桃香料或桔子香料)。當然,用於製備任何單位劑型的任何材料應該是藥學上可以接受的且以應用的量基本上無毒。此外,活性化合物可以摻入緩釋製劑和緩釋裝置中。
活性化合物也可以藉由輸注或注射來靜脈內或腹膜內施用。可以製備活性化合物或其鹽的水溶液,任選地混和無毒的表面活性劑。也可以製備在甘油、液體聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散劑。在普通的儲存和使用條件下,這些製劑包含防腐劑以防止微生物生長。
適於注射或輸注的藥物劑型可以包括包含適於無菌的可注射或可輸注的溶液或分散劑的即時製劑的活性成分(任選封裝在脂質體中)的無菌水溶液或分散劑或無菌粉末。在所有情況下,最終的劑型在生產和儲存條件下必須是無菌的、液體的和穩定的。液體載體可以是溶劑或液體分散介質,包括,例如水、乙醇、多元醇(例如,甘油、丙二醇、液體聚乙二醇等)、植物油、無毒的甘油酯及其合適的混合物。可以維持合適的流動性,例如,藉由脂質體的形成,藉由在分散劑的情況下維持所需的粒子大小,或藉由表面活性劑的使用。可以藉由各種抗細菌劑和抗真菌劑(如對羥苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)產生預防微生物的作用。在許多情況下,較佳包括等滲劑,如糖、緩衝劑或氯化鈉。藉由使用延緩吸收劑的組合物(例如,單硬脂酸鋁和明膠)可以產生可注射的組合物的延長吸收。
藉由將合適的溶劑中的需要量的活性化合物與需要的上面列舉的各種其他成分結合,然後進行過濾滅菌,製備無菌可注射溶液。在用於製備無菌注射溶液的無菌粉末的情況下,較佳的製備方法是真空乾燥和冷凍乾燥技術,這會產生活性成分加上任何另外需要的以前無菌過濾溶液中存在的成分的粉末。
有用的固體載體包括粉碎的固體(如滑石、黏土、微晶纖維素、二氧化矽、氧化鋁等)。有用的液體載體包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物,本發明的化合物可以任選在無毒的表面活性劑的幫助下以有效含量溶解或分散在其中。可以加入佐劑(如香味)和另外的抗微生物劑來最佳化對於給定用途的性質。
增稠劑(如合成的聚合物、脂肪酸、脂肪酸鹽和酯、脂肪醇、改性纖維素或改性無機材料)也可和液體載體用於形成可塗覆的糊劑、凝膠、軟膏、肥皂等,直接用於使用者的皮膚上。
化合物或其活性鹽或衍生物的治療需要量,不僅取決於選擇的特定的鹽,而且取決於施藥方式、待治療的疾病的本質和患者的年齡和狀態,最終取決於在場醫師或臨床醫生的決定。
上述製劑可以以單位劑型存在,該單位劑型是含有單位元劑量的物理分散單元,適於向人體和其它哺乳動物體給藥。單位劑型可以是膠囊或片劑,或是很多膠囊或片劑。根據所涉及的具體治療,活性成分的單位劑量的量可以在大約0.1到大約1000毫克或更多之間進行變化或調整。
此外,還包括各種藥物新劑型如乳脂質體、微球和奈米球的應用,如使用微粒分散體系包括聚合物膠束(polymeric micelles)、奈米乳(nanoemulsion)、亞微乳(submicroemuls微囊(microcapsule)、 微球(microsphere)、脂質體(liposomes)和 類脂囊泡(niosomes)(又稱非離子表面活性劑囊泡)等製備的藥劑。
另一方面,本發明還提供了上述任一技術方案該化合物的製備方法,包括下面步驟:
反應條件:(a)酸性或鹼性條件下胺類化合物對雜芳基氯代物的親核取代反應;(b)金屬鈀催化的雜芳基氯代物與胺類化合物的碳氮鍵形成的偶聯反應,或酸性條件下胺類化合物對雜芳基氯代物的親核取代反應;
其中,該雜芳基氯代物包含以下類型(P代表保護基團,例如:苄氧羰基 (Cbz)、叔丁氧羰基(BOC)、9-芴甲氧羰基(FMOC)、苄基(Bn)、對甲氧基苄基(PMB)、苯磺醯基、對甲基苯磺醯基、2-(三甲基矽基)乙氧甲基(SEM)、乙醯基(Ac)、三苯甲基衍生物保護基):
該胺類化合物選自取代或未被取代的五元或六元雜環胺、苯胺及其衍生物、C1-C6烷基氨、C3-C7環烷基氨、C1-C6含氧烷基氨、C3-C7含氧環烷基氨,詳見之前所述;
該金屬鈀催化劑選自醋酸鈀、四(三苯基膦)鈀、雙三苯基磷二氯化鈀、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀、三(二亞苄基丙酮)二鈀;該鹼性條件指以下任意物質存在的條件下:三乙胺、二異丙基乙基胺、吡啶、碳酸氫鈉、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鋰、氫氧化鈉、氫氧化鉀、氫化鈉、氫化鉀;該酸性條件指以下任意物質存在的條件下:乙酸、三氟乙酸、鹽酸、甲磺酸、對甲苯磺酸、樟腦磺酸。
另一方面,本發明還提供了上述任一技術方案該化合物的製備方法,包括下面步驟:
反應條件:
(a)酸性或鹼性條件下的親核取代反應;
(b)金屬鈀催化的偶聯反應,或酸性條件下的親核取代反應;
其中:
該金屬鈀催化劑選自醋酸鈀、四(三苯基膦)鈀、雙三苯基磷二氯化鈀、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀、三(二亞苄基丙酮)二鈀;
該鹼性條件指以下任意物質存在的條件:三乙胺、二異丙基乙基胺、吡啶、碳酸氫鈉、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鋰、氫氧化鈉、氫氧化鉀、氫化鈉、氫化鉀;
該酸性條件指以下任意物質存在的條件:乙酸、三氟乙酸、鹽酸、甲磺酸、對甲苯磺酸、樟腦磺酸;
R1
、R2
、R3
、R4
和R5
的定義詳見之前所述。
另一方面,本發明提供了藥物組合物,其包含上述任一技術方案所述的化合物、其立體異構體、其前藥、或者其藥學上可接受的鹽或藥學上可接受的溶劑合物,和任選的藥學上可接受的載體、稀釋劑或賦形劑。
在一些實施方案中,該藥物組合物進一步包含EGFR單抗。
在一些實施方案中,該EGFR單抗為西妥昔單抗或其生物類似物。
另一方面,本發明還提供了上述任一技術方案該化合物其立體異構體、其前藥、或者其藥學上可接受的鹽或藥學上可接受的溶劑合物及包含該化合物的藥物組合物在製備用於EGFR激酶介導的癌症及其他疾病的預防及/或治療的藥物的用途,尤其是在製備用於預防及/或治療肺癌(較佳非小細胞肺癌)的藥物中的用途,特別是在製備用於預防及/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌(較佳非小細胞肺癌)的藥物中的用途,最佳在製備用於預防及/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌(較佳非小細胞肺癌)的藥物中的用途。
另一方面,本發明還提供了預防和/治療EGFR激酶介導的癌症及其他疾病的方法,其包括給予有需要的受試者預防及/或治療有效量的上述化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者上述藥物組合物。
在一些實施方案中,該方法用於預防及/或治療肺癌(較佳非小細胞肺癌)。
在一些實施方案中,該方法用於預防及/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌(較佳非小細胞肺癌)。
在一些實施方案中,該方法用於預防及/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌(較佳非小細胞肺癌)。
另一方面,本發明還提供了上述化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者上述藥物組合物,其用於預防及/或治療EGFR激酶介導的癌症及其他疾病,較佳用於預防及/或治療肺癌(較佳非小細胞肺癌),更佳用於預防及/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌(較佳非小細胞肺癌),最佳用於預防及/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌(較佳非小細胞肺癌)。
在本發明中,“受試者”指脊椎動物。在某些實施方案中,脊椎動物指哺乳動物。哺乳動物包括,但不限於,牲畜(諸如牛)、寵物(諸如貓、犬、和馬)、靈長類動物、小鼠和大鼠。在某些實施方案中,哺乳動物指人。
在本發明中,“有效量”指在必需的劑量和時間上有效實現期望的治療或預防效果的量。本發明的物質/分子的“治療有效量”可根據諸如個體的疾病狀態、年齡、性別和體重及該物質/分子在個體中引發期望應答的能力等因素而變化。治療有效量還涵蓋該物質/分子的治療有益效果勝過任何有毒或有害後果的量。 “預防有效量”指在必需的劑量和時間上有效實現期望的預防效果的量。通常而非必然,由於預防劑量是在疾病發作之前或在疾病的早期用於受試者的,因此預防有效量會低於治療有效量。在癌症的情況中,藥物的治療有效量可減少癌細胞數;縮小腫瘤體積;抑制(即一定程度的減緩,較佳停止)癌細胞浸潤到周圍器官中;抑制(即一定程度的減緩,較佳停止)腫瘤轉移;一定程度的抑制腫瘤生長;及/或一定程度的減輕與癌症有關的一種或多種症狀。
實驗部分
就如下涉及的實施例而言,使用本文所述的方法或本領域眾所周知的其他方法合成本發明的化合物。
通用純化和分析方法:
在矽膠GF254預塗覆板(青島海洋化工廠)上進行薄層色譜。在中壓下經矽膠(300-400目,煙臺市芝罘區黃務矽膠開發試劑廠)進行柱色譜分離或藉由使用ISCO Combiflash Rf200快速純化系統,用預裝的矽膠筒(ISCO或Welch)進行柱色譜分離。成分藉由UV光(波長254 nm)和藉由碘蒸氣顯影。當必要時,將化合物藉由製備型HPLC經Waters Symmetry C18 (19 x 50 mm, 5 µm)柱或經Waters X Terra RP 18 (30 x 150 mm, 5 μm)柱純化,使用裝配有996 Waters PDA檢測器的Waters製備型HPLC 600和Micromass mod. ZMD單四級質譜(電噴霧離子化,陽離子模式)檢測。方法1:相A: 0.1% TFA/MeOH 95/5;相B: MeOH/H2
O 95/5。梯度:10至90% B進行8 min,保持90% B 2 min;流速20 mL/min。方法2:相A: 0.05% NH4
OH/MeOH 95/5;相B: MeOH/H2
O 95/5。梯度:10至100% B進行8 min,保持100% B 2 min;流速20 mL/min。
1
H-NMR譜在600 MHz的Bruker Avance 600核磁共振波譜儀進行記錄。化學位移(δ)以百萬分率(ppm)進行報導且偶合常數(J)以Hz計。將四甲基矽烷信號用作參比(δ = 0 ppm)。以下縮寫用於峰裂分: s =單;br. s. =寬信號;d =雙;t =三;m =多重;dd =雙雙。
電噴霧(ESI)質譜經Finnigan LCQ離子阱獲得。
除非另外說明,所有最終化合物均是均質的(純度不低於95%),由高效液相色譜(HPLC)所確定。用於評價化合物純度的HPLC-UV-MS分析藉由組合離子阱MS設備與HPLC系統SSP4000 (Thermo Separation Products)來進行,該HPLC系統裝配有自動進樣器LC Pal (CTC Analytics)和UV6000LP二極體陣列檢測器(UV檢測215-400 nm)。用Xcalibur 1.2軟體(Finnigan)進行設備控制、資料獲取和處理。HPLC色譜法在室溫和1 mL/min流速下進行,其使用Waters X Terra RP 18柱(4.6 x 50 mm;3.5 μm)。流動相A是乙酸銨5 mM緩衝液(採用乙酸得到pH 5.5):乙腈 90:10,流動相B乙酸銨5 mM緩衝液(採用乙酸得到pH 5.5):乙腈 10:90;梯度為0至100% B進行7分鐘,然後在再平衡前保持100% B達2分鐘。
試劑純化參考Purification of Laboratory Chemicals(Perrin, D. D., Armarego, W. L. F. and Perrins Eds, D. R.; Pergamon Press: Oxford, 1980)一書進行。石油醚是60-90 ℃餾分、乙酸乙酯、甲醇、二氯甲烷均為分析純。
下面藉由具體實施例詳細描述本發明的實施方式,但是無論如何它們不能解釋為對本發明的限制。
化合物可分為以下三大類:
其中,R1
、R2
、R3
、R5
如前所述,X = NH、O或S。
合成程序中涉及的部分原料及中間體描述如下:
1.,由2-氟-4-羥基苯乙酮(cas:98619-07-9,畢得,上海)經鈀碳、氫氣還原得3-氟-4-乙基苯酚,再硝化得到3-氟-4-乙基-6-硝基苯酚,進一步與碘甲烷(cas:74-88-4,西亞試劑,山東)反應得到3-氟-4-乙基-6-硝基苯甲醚,再與N-甲基呱嗪(cas:109-01-3,安耐吉,上海)反應到3-(N-甲基呱嗪基)-4-乙基-6-硝基苯甲醚,最後還原硝基而得。
3-氟-4-乙基-6-硝基苯甲醚還原硝基可得。
以下中間體經類似的方法獲得:所涉及的原料為:3-N,N-二甲基氨基吡咯烷(cas:64021-83-6,TCI,上海),4-二甲氨基呱啶(cas:50533-97-6,韶遠,上海),1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇),乙醇胺(cas:141-43-5,阿拉丁,上海), N,N-二甲基乙二胺(cas:108-00-9,畢得,上海), N,N,N’-三甲基乙二胺(cas:142-25-6,畢得,上海),2-氧雜-6-氮雜螺[3.3]庚烷(cas:174-78-7,畢得,上海),2-甲基-2,6-二氮雜螺[3.3]庚烷(cas:1203567-11-6,畢得,上海),4-(呱啶-4-基)呱嗪-1-甲酸叔丁酯(cas:205059-24-1,畢得,上海),1-(1-甲基呱啶-4-基)呱嗪(cas:23995-88-2,百靈威,上海),2-甲基-2,7-二氮雜螺[3.5]壬烷二鹽酸鹽(cas:1610028-42-6,畢得,上海),1-(1-甲基氮雜環丁烷-3-基)呱嗪(cas:864350-81-2,百靈威,上海),1-叔丁氧羰基-3-(1-呱嗪基)氮雜環丁烷(cas:178311-48-3,畢得,上海)。
2.,由1-氟-5-甲氧基-2-甲基-4-硝基苯(cas:314298-13-0,畢得,上海)與N-甲基呱嗪(cas:109-01-3,安耐吉,上海)反應到1-(N-甲基呱嗪基)-5-甲氧基-2-甲基-4-硝基苯,再還原硝基而得。以下中間體經類似的方法獲得:
所涉及的原料為:3-N,N-二甲基氨基吡咯烷(cas:64021-83-6,TCI,上海),4-二甲氨基呱啶(cas:50533-97-6,韶遠,上海),1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇),5-氟-2-硝基苯甲醚(cas:448-19-1,畢得,上海),2-乙氧基-4-氟-1-硝基苯(cas:28987-44-2,畢得,上海),對氟硝基苯(cas:350-46-9,畢得,上海),4-(1-吡咯烷)呱啶(cas:5004-07-9,韶遠,上海),嗎啉(cas:110-91-8,安耐吉,上海),N,N,N'-三甲基乙二胺(cas:142-25-6,安耐吉,上海),4-羥基呱啶(cas:5382-16-1,安耐吉,上海),1-甲基-3-氨基吡咯烷(cas:13220-27-4,書亞,上海),N,N'-二甲基-3-氨基吡咯烷(cas:64021-83-6,TCI,上海),2-甲氧基-3-硝基-6-氯吡啶(cas:40851-91-0,畢得,上海),2-氟-5-硝基吡啶(cas:456-24-6,畢得,上海),2-氯-4-甲氧基-5-硝基吡啶(cas:607373-83-1,畢得,上海),2-氯-4-甲氧基-5-硝基嘧啶(cas:282102-07-2,畢得,上海),3,4,5-三氟硝基苯(cas:66684-58-0,畢得,上海),2,3,4-三氟硝基苯(cas:771-69-7,畢得,上海)。
3.,由3-氟-5-羥基吡啶(cas:209328-55-2,畢得,上海)硝化得3-氟-5-羥基-6-硝基吡啶,再與碘甲烷(cas:74-88-4,西亞試劑,山東)反應得到3-氟-5-甲氧基-6-硝基吡啶,進一步與N-甲基呱嗪(cas:109-01-3,安耐吉,上海)反應得到,再還原硝基而得。
4.,由2,6-二氯-3-硝基吡啶與甲醇鈉(cas:124-41-4,安耐吉,上海)反應得2-甲氧基-3-硝基-6-氯吡啶,再與1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇)反應得,再還原氨基而得。由2,6-二氯-3-硝基-5-甲基吡啶經相似的方法獲得。
5.,由與液溴(cas:7726-95-6,國藥集團,上海)反應得到,再與乙烯基頻哪醇硼酸酯(cas:75927-49-0,畢得,上海)反應得,再還原硝基與雙鍵而得。
6.,由1-溴-2-氟-4-三氟甲氧基苯(cas:168971-68-4,畢得,上海)硝化得到2-三氟甲氧基-4-氟-5溴硝基苯,再與1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇)反應得,再還原硝基與脫溴而得。
7.,由與乙烯基頻哪醇硼酸酯(cas:75927-49-0,畢得,上海)反應得,再還原硝基與雙鍵而得。
8.,由還原硝基而得。
9.,由2-氟-4-甲氧基苯甲醛(cas:331-64-6)硝化得到2-氟-4-甲氧基-5-硝基苯甲醛,再還原得2-氟-4-甲氧基-5-硝基苯甲醇,進一步溴代為2-氟-4-甲氧基-5-硝基苄溴,再與苯硼酸(cas:98-80-6,安耐吉,上海)反應得到1-苄基-2-氟-4-甲氧基-5-硝基苯,再與1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇)反應得到,再還原硝基而得。將苯硼酸換為環丙基硼酸(cas:411235-57-9,畢得,上海),經類似的方法可得。
10.,由4-甲氧基-3-硝基苯甲酸(cas:89-41-8,畢得,上海)與N-甲基呱嗪(cas:109-01-3,安耐吉,上海)反應分到,再還原硝基而得;以下中間體經類似的方法獲得:
所涉及的原料為:3-甲氧基-4-硝基苯甲酸(cas:5081-36-7,畢得,上海),對硝基苯磺醯氯(cas:98-74-8,阿拉丁,上海),間硝基苯甲酸(cas:121-92-6,安耐吉,上海),1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇),N-甲基呱嗪(cas:109-01-3,安耐吉,上海),環丙基氨(cas:765-30-0,安耐吉,上海)。
11.,由4-叔丁氧羰基氨基苯胺(cas:71026-66-9,畢得,上海)與環丙基磺醯氯(cas:139631-62-2,安耐吉,上海)反應得,再脫去叔丁氧羰基而得。
12.,由間溴硝基苯(cas:585-79-5,安耐吉,上海)與4-羥基呱啶(cas:5382-16-1,安耐吉,上海)反應得到,再還原硝基而得;
以下中間體經類似方法獲得:
所涉及原料為:4-溴-2-硝基苯甲醚(cas:33696-00-3,書亞,上海),4-羥基呱啶(cas:5382-16-1,安耐吉,上海),1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇),N-甲基呱嗪(cas:109-01-3,安耐吉,上海),4-氰基呱啶(cas:4395-98-6,百靈威,上海),1-叔丁氧羰基呱嗪(cas:57260-71-6,畢得,上海),4-(吡咯烷-1-基)呱啶(cas:5004-07-9,畢得,上海)。
13.,由2-硝基-4-甲基-5-氯苯酚(cas:100278-74-8,畢得,上海)與碘甲烷( cas:74-88-4,西亞試劑,山東)反應得到2-硝基-4-甲基-5-氯苯甲醚,再與4-吡啶硼酸(cas:1692-15-5,書亞,上海)反應得到,進一步與碘甲烷( cas:74-88-4,西亞試劑,山東)反應得到,最後還原硝基與吡啶環而得;將碘甲烷換為溴代異丙烷(cas:75-26-3,麥克林,上海),經相似的方法可得。
14.,由對硝基苯乙醇(cas:100-27-6,畢得,上海)與1,3-二溴-5,5-二甲基海因(cas:77-48-5,畢得,上海)反應得2-溴-4-硝基苯乙醇,再與甲基磺醯氯(cas:124-63-0,西亞試劑,山東)得到2-溴-4-硝基苯乙醇甲磺酸酯,繼續與甲基烯丙基胺反應(cas:627-37-2,安耐吉,上海)得到,再進一步經Heck反應轉化為,最後還原硝基與雙鍵而得。
15.,由6-氟-3,4-二氫-2H-異喹啉-1-酮(cas:214045-84-8,畢得,上海)與碘甲烷( cas:74-88-4,西亞試劑,山東)反應得到2-甲基-6-氟-3,4-二氫-2H-異喹啉-1-酮,再與發煙硝酸(cas:7697-37-2,滬試,上海)反應得到2-甲基-6-氟-7-硝基-3,4-二氫-2H-異喹啉-1-酮,進一步還原羰基得到2-甲基-6-氟-7-硝基-1,2,3,4-四氫異喹啉,最後還原硝基而得;由6-氯-3,4-二氫-2H-異喹啉-1-酮(cas:22246-02-2,畢得,上海)經相似的方法獲得;,由3-(三氟甲氧基)苯乙腈(cas:108307-56-8,畢得,上海)還原得2-(3-三氟甲氧基苯基)乙胺,再與氯甲酸乙酯(cas:541-41-3,西亞試劑,山東)得2-(3-三氟甲氧基苯基)乙基氨基甲酸酯,進一步在三氟甲磺酸酐(cas:358-23-6,安耐吉,上海)作用下得到6-三氟甲氧基-3,4-二氫-2H-異喹啉-1-酮,再經相似的方法獲得;由間三氟甲基苯乙腈(cas:2338-76-3,畢得,上海)經相似的方法可得;2-甲基-6-氟-7-硝基-3,4-二氫-2H-異喹啉-1-酮與甲醇(cas:67-56-1,滬試,上海)反應得到2-甲基-6-甲氧基-7-硝基-3,4-二氫-2H-異喹啉-1-酮,再經相似的方法可以得到。
16.,由6-硝基喹喔啉(cas:6639-87-8,畢得,上海)、鹽酸羥胺(cas:5470-11-1,安耐吉,上海)反應得到5-氨基-6-硝基喹喔啉,再轉化為5-氯-6-硝基喹喔啉,進一步與甲磺醯甲胺(cas:1184-85-6,畢得,上海)反應得到,最後還原硝基而得。以下中間體經類似的方法獲得:
所涉及的原料為:甲胺(cas:74-89-5,安耐吉,上海),乙胺(cas:75-04-7,阿拉丁,上海),異丙基胺(cas:75-31-0,安耐吉,上海),環丙基胺(cas:765-30-0,安耐吉,上海),三氟甲磺醯氯(cas:421-83-0,阿拉丁,上海),乙基磺醯氯(cas:594-44-5,安耐吉,上海),異丙基磺醯氯(cas:10147-37-2,TCI,上海),環丙基磺醯氯(cas:139631-62-2,安耐吉,上海),甲基磺醯胺(cas:3144-09-0,畢得,上海),異丙基磺醯胺(cas:81363-76-0,畢得,上海)。
17. 1,3-二甲基-5-氨基吡唑(cas:3524-32-1,百靈威,北京)。
18. 1-甲基-3-氨基吡唑(cas:1904-31-0,畢得,上海)。
19. 1-甲基-4-氨基吡唑(cas:69843-13-6,畢得,上海)。
20. 1-甲基-4-氨基咪唑(cas:79578-98-6,畢得,上海)。
21. 1-甲基-4-氨基呱啶(cas:41838-46-4,安耐吉,上海)。
22. N,N-二甲基乙二胺(cas:108-00-9,韶遠,上海)。
23. 乙醇胺(cas:141-43-5,阿拉丁,上海)。
24. 反式-1,4-環己二胺(cas:2615-25-0,安耐吉,上海)。
25.,由3-硝基-4-甲氧基苯胺(cas:577-72-0,畢得,上海)與溴乙醯溴(cas:598-21-0,安耐吉,上海)反應所得進一步與二甲胺(cas:124-40-3,邁瑞爾,上海)反應得到,再還原硝基而得。
26.,cas:1116229-84-5,畢得,上海。
27. 3-(4-甲基呱嗪-1-亞甲基)-5-三氟甲基苯胺(cas:853296-94-3,艾康,江蘇)。
28. 3-三氟甲基-4-(4-甲基呱嗪-1-亞甲基)-苯胺(cas:694499-26-8,書亞,上海)。
29.,由對硝基苯甲醛(cas:555-16-8,畢得,上海)與N-甲基呱嗪(cas:109-01-3,安耐吉,上海)反應得,再還原硝基而得。以下中間體經類似的方法獲得:
涉及的原料為:3-甲氧基-4-硝基苯甲醛(cas:80410-57-7,畢得,上海),4-甲氧基-3-硝基苯甲醛(cas:31680-08-7,畢得,上海),間硝基苯甲醛(cas:99-61-6,畢得上海),N-甲基呱嗪(cas:109-01-3,安耐吉,上海)。
30. 3-氨基-6-甲基吡啶(cas:3430-14-6,安耐吉,上海)。
31. 4-氨基吡啶(cas:504-24-5,安耐吉,上海)。
32. 2,4-二氯-5-溴嘧啶(cas:36082-50-5,畢得,上海)。
33. 2,4,5-三氯嘧啶(cas:5750-76-5,安耐吉,上海)。
34. 2,4-二氯-5-氟嘧啶(cas:2927-71-7,畢得,上海)。
35. 2,4-二氯-5-三氟甲基嘧啶(cas:3932-97-6,畢得,上海)。
36. 2,4-二氯-5-氰基嘧啶(cas:3177-24-0,畢得,上海)。
37. 2,4-二氯-5-硝基嘧啶(cas:49845-33-2,艾康,上海)。
38. 2,4-二氯噻吩並[3,2-d]嘧啶(cas:16234-14-3,南京藥石,江蘇)。
39. 2,4-二氯呋喃並[3,2-d]嘧啶(cas:956034-07-4,艾康,上海)。
40.,由2,4-二氯吡咯並[3,2-d]嘧啶(cas:63200-54-4,南京藥石,江蘇)與2-(三甲基矽基)乙氧甲基氯(CAS:76513-69-4,一飛,上海)反應而得。
41.,(cas:1268394-21-3,艾康,上海)。
42. 2,4-二氯噻吩並[2,3-d]嘧啶(cas:18740-39-1,南京康滿林,江蘇)。
43.,由2,4-二氯-7H-吡咯並[2,3-d]嘧啶(cas:90213-66-4,書亞,上海)與2-(三甲基矽基)乙氧甲基氯(CAS:76513-69-4,一飛,上海)反應而得。
44. 2,4-二氯呋喃並[2,3-d]嘧啶(cas:1000577-84-3,畢得,上海)。
45. 2,4-二氯-5-環丙基嘧啶(cas:1190379-86-2,畢得,上海)。
46. 2,4-二氯-5-甲基嘧啶(cas:1780-31-0,畢得,上海)。
47. 2,4-二氯-5-甲氧基嘧啶(cas:19646-07-2,畢得,上海)。
48. 2,4-二氯嘧啶(cas:3934-20-1,畢得,上海)
49. 2,4-二氯-5-乙基嘧啶(cas:34171-40-9,畢得,上海)
50. 2,4-二氯-5-異丙基嘧啶(cas:514843-12-0,畢得,上海)
51. 2,4-二氯-5-乙氧基嘧啶(cas:280582-25-4,畢得,上海)
52. 1-乙基-3-氨基吡唑(cas:55361-49-4,畢得,上海)
53. 1-異丙基-3-氨基吡唑(cas:857267-04-0,畢得,上海)
54. 1,5-二甲基-3-氨基吡唑(cas:35100-92-6,畢得,上海)
55. 1-乙基-4-氨基吡唑(cas:876343-24-7,畢得,上海)
56. 1-異丙基-4-氨基吡唑(cas:97421-16-4,畢得,上海)
57. 1-乙基-3-甲基-4-氨基吡唑(cas:947763-34-0,畢得,上海)
58.,由1-溴-2-甲基-4-甲氧基-5-硝基苯(cas:89978-56-3,九鼎化學,上海)經氧化為2-溴-4-硝基-5-甲氧基苯甲酸,再與1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇)縮合得到,進一步與乙烯三氟硼酸鉀(cas:13682-77-4,畢得,上海)偶聯得到,再經還原而得。
59.,由1-溴-2-氟-4-甲氧基-5-硝基苯(cas:1352244-77-9,畢得,上海)與1-甲基-4-(4-呱啶基)呱嗪(cas:53617-36-0,艾康,江蘇)反應得到,再與異丙烯基硼酸頻哪醇酯(cas:126726-62-3,畢得,上海)偶聯得到,進一步還原而得。以下中間體經相似的方法獲得:
所涉及的原料為:3-溴-4-氟硝基苯(cas:701-45-1,畢得,上海),環丙基硼酸頻哪醇酯(cas:126689-01-8,畢得,上海),乙烯基硼酸頻哪醇酯(cas:75927-49-0,畢得,上海)。
60.,由2-氧代-7-氮雜螺[3.5]壬烷-7-甲酸叔丁酯(cas:203661-69-2,畢得,上海)與二甲胺(cas:124-40-3,阿拉丁,上海)反應得到,脫去叔丁氧羰基後與(1)中3-氟-4-乙基-6-硝基苯甲醚反應得到,再還原硝基而得。
下面藉由具體實施例詳細描述本發明的實施方式,但是無論如何它們不能解釋為對本發明的限制。
化合物I-1的合成:
第一步:將化合物2(504 mg,2 mmol)溶於DMF(5 mL)中,0℃下分批次加入NaH(60%含量,分散於液體石蠟,160 mg,4 mmol),5分鐘後加入化合物1(501 mg,2.2 mmol),自熱升溫反應1小時,TLC及LCMS檢測反應完畢。加水100 mL,有固體析出,過濾,抽乾,得化合物3,直接用於下一步。
第二步:化合物3(44 mg,0.1 mmol)、化合物4(30.4 mg,0.1 mmol)及甲磺酸(19 µL,0.3 mmol)於t
-BuOH(2 mL)中100℃加熱4 h,TLC及LCMS檢測反應完畢。冷卻後將反應混合物濃縮,經矽膠柱純化(以二氯甲烷/甲醇洗脫),再經製備型HPLC(以含0.35%三氟乙酸的水和甲醇為流動相)純化得化合物I-1。
化合物II-1-1的合成:
第一步:化合物6由化合物5與化合物2經製備化合物3相同的方法而得。
第二步:化合物6(42.1 mg,0.1 mmol)、化合物4(30.4 mg,0.1 mmol)、2-二環己基磷-2,4,6-三異丙基聯苯(7.2 mg,0.015 mmol),三(二亞苄基丙酮)二鈀(9.2 mg,0.01 mmol)及碳酸鉀(,41.4 mg,0.3 mmol)分散於t
-BuOH(2 mL)中,置換氮氣後將反應體系液置於預熱至100℃的油浴中加熱攪拌,6小時後 TLC及LCMS檢測反應完畢。冷卻後將反應混合物濃縮,經矽膠柱純化(以二氯甲烷/甲醇洗脫),再經製備型HPLC(以含0.35%三氟乙酸的水和甲醇為流動相)純化得化合物II-1-1。
化合物II-1-18的製備:
第一步:化合物8由化合物7與化合物2經製備化合物3相同的方法而得。
第二步:化合物9由化合物8與化合物4經製備化合物II-1-1相同的方法而得。
第三步:化合物9(30 mg,0.037 mmol)於TFA/DCM(1/2 mL)中室溫下攪拌2小時後TLC及LCMS檢測反應完畢,濃縮,殘留物溶於甲醇(2 mL),加入25%氨水(1 mL),室溫反應4小時後LCMS檢測反應完全。以二氯甲烷(50 mL)稀釋,飽和食鹽水(30 mL)洗滌1次,分液,有機相經無水Na2
SO4
乾燥,過濾,濃縮後經矽膠柱純化(以二氯甲烷/甲醇洗脫),再經製備型HPLC(以含0.35%三氟乙酸的水和甲醇為流動相)純化得化合物II-1-18。
其餘化合物經類似的方法獲得。
下表列出具體化合物及結構鑒定資料:
序號 | 結構 | 核磁共振氫譜和(或)質譜數據 |
I-1 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.7 Hz, 1H), 8.90 (d,J = 1.7 Hz, 1H), 8.79 (d,J = 9.5 Hz, 1H), 8.28 (s, 1H), 8.10 (d,J = 9.4 Hz, 1H), 7.92 – 7.70 (m, 1H), 7.00 (s, 1H), 6.83 (d,J = 8.9 Hz, 1H), 3.91 (s, 3H), 3.87 – 3.74 (m, 2H), 3.48 (s, 3H), 3.43 – 3.33 (m, 8H), 3.28 – 3.26 (m, 1H), 3.20 (s, 3H), 2.97 – 2.90 (m, 2H), 2.88 (s, 3H), 2.23 – 2.13 (m, 2H), 2.01 – 1.89 (m, 2H). MS (ESI)m/z : 711 [M+H]+ . | |
I-2 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.65 – 8.50 (m, 1H), 8.27 (s, 1H), 8.07 (d,J = 9.3 Hz, 1H), 7.36 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.70 – 3.48 (m, 8H), 3.47 (s, 3H), 3.36 – 3.33 (m, 2H), 3.28 – 3.23 (m, 1H), 3.18 (s, 3H), 2.96 (s, 3H), 2.95 – 2.87 (m, 2H), 2.26 – 2.19 (m, 2H), 2.05 (s, 3H), 2.01 – 1.90 (m, 2H). MS (ESI)m/z : 725 [M+H]+ . | |
I-3 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.60 – 8.42 (m, 1H), 8.28 (s, 1H), 8.11 – 7.97 (m, 1H), 7.39 (s, 1H), 6.85 (s, 1H), 3.85 (s, 3H), 3.72 – 3.53 (m, 8H), 3.47 (s, 3H), 3.37 – 3.34 (m, 1H), 3.26 – 3.21 (m, 2H), 3.17 (s, 3H), 2.97 (s, 3H), 2.95 – 2.88 (m, 2H), 2.56 – 2.36 (m, 2H), 2.34 – 2.18 (m, 2H), 2.13 – 1.89 (m, 2H), 1.04 – 0.73 (m, 3H). MS (ESI)m/z : 739 [M+H]+ . | |
I-4 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.80 – 8.45 (m, 1H), 8.35 – 8.18 (m, 1H), 8.16 – 7.97 (m, 1H), 7.60 – 7.47 (m, 1H), 6.50 – 6.23 (m, 1H), 4.64 – 4.40 (m, 2H), 3.88 (s, 3H), 3.77 – 3.52 (m, 9H), 3.48 (s, 3H), 3.49 – 3.43 (m, 2H), 3.18 (s, 3H), 2.96 (s, 3H), 2.95 – 2.92 (m, 1H), 2.33 – 2.10 (m, 2H), 1.91 – 1.62 (m, 2H). MS (ESI)m/z : 712 [M+H]+ . | |
I-5 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.96 – 8.89 (m, 1H), 8.75 – 8.46 (m, 1H), 8.37 – 8.21 (m, 1H), 8.19 – 7.85 (m, 1H), 7.44 (s, 1H), 3.95 (s, 3H), 3.86 – 3.73 (m, 2H), 3.65 – 3.52 (m, 8H), 3.50 (s, 3H), 3.38 – 3.33 (m, 1H), 3.20 (s, 3H), 2.95 (s, 3H), 2.93 – 2.86 (m, 2H), 2.12 – 2.04 (m, 2H), 2.05 – 1.90 (m, 3H), 1.86 – 1.59 (m, 2H). MS (ESI)m/z : 726 [M+H]+ . | |
I-6 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.47 (s, 1H), 8.34 – 8.27 (m, 1H), 8.03 (d,J = 9.4 Hz, 1H), 7.70 (s, 1H), 3.93 (s, 3H), 3.78 – 3.61 (m, 8H), 3.58 – 3.52 (m, 2H), 3.47 (s, 3H), 3.45 – 3.38 (m, 1H), 3.17 (s, 3H), 3.05 – 3.00 (m, 2H), 2.99 (s, 3H), 2.50 – 2.29 (m, 2H), 2.22 (d,J = 11.8 Hz, 2H), 2.05 – 1.91 (m, 2H), 1.01 – 0.73 (m, 3H). MS (ESI)m/z : 740 [M+H]+ . | |
I-7 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.76 (d,J = 9.7 Hz, 1H), 8.24 (s, 1H), 7.93 (d,J = 9.5 Hz, 1H), 7.51 (d,J = 8.8 Hz, 1H), 7.00 (dd,J = 8.8, 2.8 Hz, 1H), 6.98 (s, 1H), 3.92 – 3.81 (m, 2H), 3.46 (s, 3H), 3.36 – 3.31 (m, 6H), 3.20 (s, 3H), 3.19 – 3.09 (m, 2H), 2.97 – 2.93 (m, 1H), 2.90 (t,J = 12.2 Hz, 2H), 2.85 (s, 3H), 2.17 – 2.05 (m, 2H), 1.83 – 1.72 (m, 2H). MS (ESI)m/z : 765 [M+H]+ . | |
I-8 | MS (ESI)m/z : 793 [M+H]+ . | |
I-9 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 2.0 Hz, 1H), 8.86 (d,J = 1.8 Hz, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.93 – 7.80 (m, 1H), 7.78 (s, 1H), 7.13 – 6.99 (m, 1H), 6.94 – 6.81 (m, 1H), 5.40 (d,J = 17.7 Hz, 1H), 5.02 (d,J = 11.3 Hz, 1H), 3.53 – 3.48 (m, 2H), 3.46 (s, 3H), 3.36 – 3.31 (m, 8H), 3.18 (s, 3H), 3.15 – 3.07 (m, 1H), 2.91 (s, 3H), 2.81 – 2.73 (m, 2H), 2.23 – 2.14 (m, 2H), 1.98 – 1.87 (m, 2H). MS (ESI)m/z : 791 [M+H]+ . | |
I-10 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.54 (s, 1H), 8.35 – 8.22 (m, 1H), 8.09 – 7.93 (m, 1H), 7.59 (s, 1H), 6.86 (s, 1H), 3.85 (s, 3H), 3.72 – 3.51 (m, 8H), 3.48 (s, 3H), 3.30 – 3.26 (m, 1H), 3.25 – 3.19 (m, 2H), 3.18 (s, 3H), 2.95 (s, 3H), 2.93 – 2.76 (m, 2H), 2.44 – 2.25 (m, 2H), 2.24 – 2.17 (m, 2H), 2.02 – 1.82 (m, 2H), 0.73 – 0.51 (m, 1H), 0.34 – 0.14 (m, 2H), -0.05 – -0.24 (m, 2H). MS (ESI)m/z : 765 [M+H]+ . | |
I-11 | 1 H NMR (600 MHz, MeOD) δ 9.02 – 8.90 (m, 1H), 8.86 (d,J = 6.2 Hz, 1H), 8.46 – 8.18 (m, 2H), 8.01 (s, 1H), 7.35 (s, 1H), 7.15 – 6.96 (m, 3H), 6.94 – 6.74 (m, 3H), 3.84 (s, 3H), 3.80 – 3.58 (m, 10H), 3.43 (s, 3H), 3.39 – 3.33 (m, 2H), 3.19 (s, 1H), 3.13 (s, 3H), 3.09 – 3.02 (m, 2H), 3.01 (s, 3H), 2.88 – 2.69 (m, 2H), 2.24 – 2.09 (m, 2H), 1.94 – 1.76 (m, 2H). MS (ESI)m/z : 801 [M+H]+ . | |
I-12 | 1 H NMR (600 MHz, MeOD) δ 8.97 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.68 – 8.59 (m, 1H), 8.23 (s, 1H), 8.00 (d,J = 9.3 Hz, 1H), 7.46 (s, 1H), 6.78 (s, 1H), 3.85 (s, 3H), 3.65 – 3.56 (m, 2H), 3.47 (s, 3H), 3.37 – 3.33 (m, 2H), 3.29 – 3.22 (m, 2H), 3.19 (s, 3H), 3.16 – 3.06 (m, 2H), 3.00 (s, 3H), 2.06 (s, 3H). MS (ESI)m/z : 642 [M+H]+ . | |
I-13 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.73 – 8.51 (m, 1H), 8.21 (s, 1H), 7.99 (d,J = 9.1 Hz, 1H), 7.38 (s, 1H), 6.75 (s, 1H), 3.83 (s, 3H), 3.46 (s, 3H), 3.38 – 3.33 (m, 1H), 3.29 – 3.22 (m, 2H), 3.19 (s, 3H), 2.94 (s, 6H), 2.87 – 2.72 (m, 2H), 2.29 – 2.17 (m, 2H), 2.05 (s, 3H), 1.98 – 1.88 (m, 2H). MS (ESI)m/z : 670 [M+H]+ . | |
I-14 | 1 H NMR (600 MHz, MeOD) δ 8.97 (d,J = 1.7 Hz, 1H), 8.90 (d,J = 1.7 Hz, 1H), 8.72 – 8.56 (m, 1H), 8.24 (s, 1H), 8.09 – 7.94 (m, 1H), 7.31 (s, 1H), 6.73 (s, 1H), 4.11 – 3.97 (m, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 3.46 – 3.38 (m, 2H), 3.19 (d,J = 3.6 Hz, 3H), 3.18 – 3.11 (m, 2H), 2.99 (s, 6H), 2.59 – 2.42 (m, 1H), 2.31 – 2.18 (m, 1H), 2.08 (s, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-15 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.66 – 8.40 (m, 1H), 8.25 (s, 1H), 7.99 (d,J = 9.4 Hz, 1H), 7.49 (s, 1H), 6.82 (s, 1H), 3.84 (s, 3H), 3.68 – 3.55 (m, 2H), 3.45 (s, 3H), 3.35 – 3.33 (m, 2H), 3.33 – 3.30 (m, 2H), 3.17 (s, 3H), 3.16 – 3.13 (m, 2H), 2.98 (s, 3H), 2.43 (d,J = 8.5 Hz, 2H), 0.97 – 0.72 (m, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-16 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.67 – 8.46 (m, 1H), 8.25 (s, 1H), 8.00 (d,J = 8.7 Hz, 1H), 7.40 (s, 1H), 6.82 (s, 1H), 3.83 (s, 3H), 3.46 (s, 3H), 3.37 – 3.34 (m, 1H), 3.22 – 3.14 (m, 5H), 2.94 (s, 6H), 2.89 – 2.80 (m, 2H), 2.58 – 2.37 (m, 2H), 2.29 – 2.14 (m, 2H), 2.07 – 1.81 (m, 2H), 1.09 – 0.75 (m, 3H). MS (ESI)m/z : 684 [M+H]+ . | |
I-17 | 1 H NMR (600 MHz, MeOD) δ 9.01 – 8.96 (m, 1H), 8.94 – 8.87 (m, 1H), 8.67 – 8.43 (m, 1H), 8.26 (s, 1H), 8.09 – 7.92 (m, 1H), 7.33 (s, 1H), 6.80 (s, 1H), 4.14 – 3.98 (m, 1H), 3.84 (s, 3H), 3.47 (s, 3H), 3.46 – 3.41 (m, 2H), 3.31 (s, 2H), 3.17 (s, 3H), 2.98 (s, 6H), 2.69 – 2.47 (m, 2H), 2.47 – 2.37 (m, 1H), 2.36 – 1.97 (m, 1H), 1.13 – 0.69 (m, 3H). MS (ESI)m/z : 670 [M+H]+ . | |
I-18 | 1 H NMR (600 MHz, MeOD) δ 9.01 – 8.95 (m, 1H), 8.93 – 8.88 (m, 1H), 8.75 – 8.65 (m, 1H), 8.20 (s, 1H), 8.11 (d,J = 9.2 Hz, 1H), 7.74 (d,J = 8.6 Hz, 1H), 7.01 (s, 1H), 6.81 (d,J = 8.9 Hz, 1H), 3.91 (s, 3H), 3.86 – 3.77 (m, 2H), 3.48 (s, 3H), 3.46 – 3.42 (m, 2H), 3.33 – 3.30 (m, 8H), 3.19 (s, 3H), 3.14 – 3.06 (m, 1H), 2.93 (s, 3H), 2.28 – 2.20 (m, 2H), 2.06 – 1.92 (m, 2H). MS (ESI)m/z : 667 [M+H]+ . | |
I-19 | 1 H NMR (600 MHz, MeOD) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.56 – 8.42 (m, 1H), 8.21 (s, 1H), 8.09 (d,J = 9.3 Hz, 1H), 7.28 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 3.78 – 3.56 (m, 8H), 3.46 (s, 3H), 3.44 – 3.37 (m, 1H), 3.31 (s, 3H), 3.16 (s, 3H), 3.01 (s, 3H), 2.95 – 2.84 (m, 2H), 2.37 – 2.21 (m, 2H), 2.05 – 1.93 (m, 4H). MS (ESI)m/z : 681 [M+H]+ . | |
I-20 | 1 H NMR (600 MHz, MeOD) δ 8.92 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 1.8 Hz, 1H), 8.46 – 8.28 (m, 1H), 8.14 (s, 1H), 8.03 – 7.93 (m, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 3.76 (s, 3H), 3.69 – 3.52 (m, 8H), 3.38 (s, 3H), 3.35 – 3.29 (m, 1H), 3.16 – 3.10 (m, 2H), 3.08 (s, 3H), 2.92 (s, 3H), 2.87 – 2.70 (m, 2H), 2.48 – 2.23 (m, 2H), 2.22 – 2.13 (m, 2H), 2.01 – 1.79 (m, 2H), 0.90 – 0.65 (m, 3H). MS (ESI)m/z : 695 [M+H]+ . | |
I-21 | 1 H NMR (600 MHz, MeOD) δ 9.00 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.54 – 8.41 (m, 1H), 8.23 (s, 1H), 8.07 (d,J = 9.3 Hz, 1H), 7.72 (s, 1H), 3.93 (s, 3H), 3.68 – 3.53 (m, 10H), 3.47 (s, 3H), 3.36 – 3.33 (m, 1H), 3.16 (s, 3H), 3.04 – 2.99 (m, 2H), 2.97 (s, 3H), 2.43 – 2.28 (m, 2H), 2.24 – 2.15 (m, 2H), 2.01 – 1.92 (m, 2H), 0.91 – 0.73 (m, 3H). MS (ESI)m/z : 696 [M+H]+ . | |
I-22 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.54 (d,J = 9.3 Hz, 1H), 8.21 (s, 1H), 7.92 (d,J = 9.3 Hz, 1H), 7.52 (s, 1H), 7.07 (s, 1H), 3.63 – 3.50 (m, 8H), 3.44 (s, 3H), 3.28 – 3.23 (m, 1H), 3.21 – 3.18 (m, 2H), 3.17 (s, 3H), 2.95 (s, 3H), 2.83 – 2.74 (m, 2H), 2.59 – 2.46 (m, 2H), 2.27 – 2.18 (m, 2H), 1.99 – 1.89 (m, 2H), 0.93 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 749 [M+H]+ . | |
I-23 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.7 Hz, 1H), 8.87 (d,J = 1.8 Hz, 1H), 8.63 – 8.43 (m, 1H), 8.22 (s, 1H), 7.86 (d,J = 9.4 Hz, 1H), 7.77 (s, 1H), 7.02 (s, 1H), 6.85 (dd,J = 17.7, 11.0 Hz, 1H), 5.37 (d,J = 17.7 Hz, 1H), 4.99 (d,J = 11.0 Hz, 2H), 3.73 – 3.48 (m, 10H), 3.45 (s, 3H), 3.25 – 3.21 (m, 1H), 3.17 (s, 3H), 2.95 (s, 3H), 2.81 – 2.71 (m, 2H), 2.25 – 2.16 (m, 2H), 2.00 – 1.89 (m, 2H). MS (ESI)m/z : 747 [M+H]+ . | |
I-24 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.58 (d,J = 9.3 Hz, 1H), 8.14 (d,J = 9.3 Hz, 1H), 8.10 (d,J = 4.2 Hz, 1H), 7.72 – 7.64 (m, 1H), 6.99 – 6.91 (m, 1H), 6.75 (d,J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.84 – 3.78 (m, 2H), 3.49 (s, 3H), 3.43 – 3.31 (m, 8H), 3.23 – 3.19 (m, 2H), 3.15 (s, 3H), 3.01 – 2.96 (m, 1H), 2.89 (s, 3H), 2.22 – 2.14 (m, 2H), 1.97 – 1.88 (m, 2H). MS (ESI)m/z : 651 [M+H]+ . | |
I-25 | 1 H NMR (600 MHz, MeOD) δ 8.94 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.7 Hz, 1H), 8.28 (d,J = 9.2 Hz, 1H), 8.07 (s, 1H), 8.06 – 8.04 (m, 1H), 7.21 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.69 – 3.50 (m, 8H), 3.39 (s, 3H), 3.30 – 3.27 (m, 1H), 3.24 – 3.16 (m, 2H), 3.08 (s, 3H), 2.92 (s, 3H), 2.86 – 2.76 (m, 2H), 2.24 – 2.11 (m, 2H), 1.95 – 1.88 (m, 2H), 1.84 (s, 3H). MS (ESI)m/z : 665 [M+H]+ . | |
I-26 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.41 (d,J = 9.3 Hz, 1H), 8.11 (s, 1H), 8.10 – 8.09 (m, 1H), 7.43 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 3.46 (s, 3H), 3.39 – 3.33 (m, 8H), 3.22 – 3.15 (m, 4H), 3.13 (s, 3H), 2.95 – 2.91 (m, 1H), 2.90 – 2.84 (m, 2H), 2.82 (s, 3H), 2.14 – 2.04 (m, 2H), 1.94 – 1.74 (m, 2H), 0.87 – 0.73 (m, 3H). MS (ESI)m/z : 679 [M+H]+ . | |
I-27 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 9.02 – 8.96 (m, 1H), 8.95 – 8.86 (m, 1H), 8.81 – 8.64 (m, 1H), 8.63 – 8.34 (m, 2H), 8.03 – 7.74 (m, 1H), 7.29 – 7.06 (m, 1H), 6.71 (s, 1H), 6.47 (s, 1H), 3.91 – 3.87 (m, 2H), 3.76 (s, 3H), 3.60 – 3.44 (m, 5H), 3.33 (s, 3H), 3.18 (s, 3H), 3.14 – 2.88 (m, 4H), 2.80 (s, 3H), 2.75 (t,J = 12.6 Hz, 2H), 2.11 – 1.98 (m, 2H), 1.71 – 1.59 (m, 2H). MS (ESI)m/z : 658 [M+H]+ . | |
I-28 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.63 – 8.46 (m, 1H), 8.38 (s, 1H), 8.09 – 7.80 (m, 1H), 7.61 – 7.27 (m, 1H), 6.73 (s, 1H), 3.81 (s, 3H), 3.72 (p,J = 6.6 Hz, 1H), 3.44 (s, 3H), 3.28 – 3.18 (m, 9H), 3.16 (s, 3H), 2.97 (s, 1H), 2.86 – 2.75 (m, 5H), 2.13 – 2.06 (m, 2H), 2.03 – 1.75 (m, 5H). MS (ESI)m/z : 672 [M+H]+ . | |
I-29 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 – 8.89 (m, 1H), 8.90 – 8.74 (m, 1H), 8.53 – 8.31 (m, 2H), 8.09 – 7.80 (m, 1H), 7.68 – 7.34 (m, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.72 (p,J = 6.6 Hz, 1H), 3.44 (s, 3H), 3.34 – 3.20 (m, 7H), 3.16 – 3.10 (m, 5H), 3.03 – 2.94 (m, 1H), 2.87 – 2.78 (m, 5H), 2.42 – 2.13 (m, 2H), 2.15 – 2.05 (m, 2H), 1.93 – 1.76 (m, 2H), 0.65 (s, 3H). MS (ESI)m/z : 686 [M+H]+ . | |
I-30 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 9.89 (s, 1H), 9.14 (s, 1H), 9.01 – 8.94 (m, 1H), 8.95 – 8.86 (m, 1H), 8.73 (d,J = 9.4 Hz, 1H), 7.81 (d,J = 9.4 Hz, 1H), 7.23 (d,J = 8.5 Hz, 1H), 6.81 (s, 1H), 6.62 (d,J = 8.8 Hz, 1H), 4.16 – 3.89 (m, 10H), 3.78 (s, 3H), 3.45 – 3.42 (m, 1H), 3.36 (s, 3H), 3.21 (s, 3H), 2.86 (s, 3H), 2.84 – 2.78 (m, 2H), 2.22 – 2.04 (m, 2H), 1.80 – 1.65 (m, 2H). MS (ESI)m/z : 678 [M+H]+ . | |
I-31 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.51 (s, 1H), 9.18 (s, 1H), 8.95 – 8.87 (m, 2H), 8.82 (d,J = 9.3 Hz, 1H), 8.13 (s, 1H), 8.03 (d,J = 9.2 Hz, 1H), 7.79 (s, 1H), 6.58 (s, 1H), 3.86 (s, 3H), 3.80 – 3.63 (m, 8H), 3.52 (s, 3H), 3.33 – 3.26 (m, 2H), 3.27 – 3.22 (m, 1H), 3.19 (s, 3H), 2.91 (s, 3H), 2.79 – 2.72 (m, 2H), 2.22 – 2.15 (m, 2H), 2.02 – 1.95 (m, 2H), 1.91 (s, 3H). MS (ESI)m/z : 692 [M+H]+ . | |
I-32 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.23 (s, 1H), 9.84 (s, 1H), 9.16 (s, 1H), 9.03 – 8.97 (m, 1H), 8.96 – 8.87 (m, 1H), 8.59 (d,J = 9.4 Hz, 1H), 7.71 (d,J = 9.4 Hz, 1H), 7.21 (s, 1H), 6.88 (s, 1H), 3.76 (s, 3H), 3.70 – 3.59 (m, 8H), 3.36 (s, 3H), 3.25 (s, 1H), 3.21 (s, 3H), 3.17 – 3.12 (m, 4H), 2.84 (s, 3H), 2.49 – 2.40 (m, 2H), 2.15 – 2.05 (m, 2H), 1.81 – 1.72 (m, 2H), 0.92 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 706 [M+H]+ . | |
I-33 | 1 H NMR (600 MHz, MeOD) δ 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.63 – 8.55 (m, 1H), 8.42 (s, 1H), 8.08 (d,J = 9.2 Hz, 1H), 7.84 – 7.77 (m, 1H), 7.06 – 7.01 (m, 1H), 6.76 (s, 1H), 3.90 (s, 3H), 3.82 – 3.76 (m, 2H), 3.43 (s, 3H), 3.43 – 3.38 (m, 2H), 3.35 – 3.28 (m, 8H), 3.15 (s, 3H), 3.06 – 3.01 (m, 1H), 2.92 (s, 3H), 2.21 (d,J = 12.6 Hz, 2H), 1.99 (tt,J = 12.1, 6.2 Hz, 2H). MS (ESI)m/z : 701 [M+H]+ . | |
I-34 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.7 Hz, 1H), 8.92 (d,J = 1.7 Hz, 1H), 8.54 – 8.32 (m, 2H), 8.13 – 7.96 (m, 1H), 7.38 (s, 1H), 6.80 (s, 1H), 3.84 (s, 3H), 3.73 – 3.52 (m, 8H), 3.42 (s, 3H), 3.35 – 3.33 (m, 1H), 3.31 – 3.24 (m, 2H), 3.14 (s, 3H), 2.98 (s, 3H), 2.95 – 2.88 (m, 2H), 2.32 – 2.18 (m, 2H), 2.08 – 1.97 (m, 2H), 1.93 (s, 3H). MS (ESI)m/z : 715 [M+H]+ . | |
I-35 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 2.0 Hz, 1H), 8.88 (d,J = 2.0 Hz, 1H), 8.50 – 8.27 (m, 2H), 7.97 (s, 1H), 7.46 (s, 1H), 6.80 (s, 1H), 3.81 (s, 3H), 3.60 – 3.42 (m, 8H), 3.40 (s, 3H), 3.22 – 3.17 (m, 2H), 3.17 – 3.13 (m, 1H), 3.11 (s, 3H), 2.93 – 2.91 (m, 3H), 2.91 – 2.85 (m, 2H), 2.41 – 2.18 (m, 2H), 2.19 – 2.12 (m, 2H), 1.97 – 1.86 (m, 2H), 0.97 – 0.30 (m, 3H). MS (ESI)m/z : 729 [M+H]+ . | |
I-36 | MS (ESI)m/z : 641 [M+H]+ . | |
I-37 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.01 – 8.98 (m, 1H), 8.97 – 8.92 (m, 1H), 8.81 (d,J = 9.1 Hz, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.50 (s, 1H), 6.79 (s, 1H), 4.55 – 4.49 (m, 1H), 3.37 (s, 3H), 3.23 (s, 3H), 3.19 – 3.08 (m, 4H), 3.02 – 2.90 (m, 1H), 2.83 (s, 3H), 2.05 (s, 3H), 1.94 – 1.87 (m, 4H), 1.26 – 1.22 (m, 6H). MS (ESI)m/z : 669 [M+H]+ . | |
I-38 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.88 – 9.70 (m, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 8.04 – 7.93 (m, 1H), 7.39 (d,J = 8.8 Hz, 1H), 6.77 (d,J = 2.6 Hz, 1H), 6.57 (d,J = 8.8, 2.7 Hz, 1H), 3.95 – 3.90 (m, 2H), 3.79 (s, 3H), 3.61 – 3.54 (m, 2H), 3.38 (s, 3H), 3.25 (s, 3H), 3.23 – 3.17 (m, 2H), 3.05 – 2.94 (m, 2H), 2.90 (s, 3H). MS (ESI)m/z : 628 [M+H]+ . | |
I-39 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.78 – 9.68 (m, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 8.00 – 7.93 (m, 1H), 7.41 (d,J = 8.7 Hz, 1H), 6.75 (d,J = 2.5 Hz, 1H), 6.55 (d,J = 8.7, 2.5 Hz, 1H), 4.09 – 4.02 (m, 2H), 3.95 – 3.85 (m, 2H), 3.59 – 3.52 (m, 2H), 3.38 (s, 3H), 3.24 (s, 3H), 3.22 – 3.15 (m, 2H), 3.00 – 2.93 (m, 2H), 2.89 (s, 3H), 1.25 (t,J = 6.9 Hz, 3H). MS (ESI)m/z : 642 [M+H]+ . | |
I-40 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.35 (s, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 8.10 (d,J = 9.5 Hz, 1H), 7.45 – 7.41 (m, 3H), 6.90 – 6.87 (m, 2H), 3.39 (s, 3H), 3.25 (s, 3H), 3.11 – 3.06 (m, 4H), 2.49 – 2.46 (m, 4H), 2.24 (s, 3H). MS (ESI)m/z : 598 [M+H]+ . | |
I-41 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.98 – 7.88 (m, 1H), 7.36 – 7.26 (m, 1H), 6.70 – 6.66 (m, 1H), 6.51 – 6.46 (m, 1H), 3.77 (s, 3H), 3.66 (d,J = 12.2 Hz, 2H), 3.37 (s, 3H), 3.24 (s, 3H), 2.82 – 2.68 (m, 2H), 2.58 – 2.52 (m, 4H), 2.17 – 2.09 (m, 1H), 1.98 – 1.90 (m, 2H), 1.72 – 1.65 (m, 4H), 1.58 – 1.50 (m, 2H). MS (ESI)m/z : 682 [M+H]+ . | |
I-42 | MS (ESI)m/z : 656 [M+H]+ . | |
I-43 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 9.01 – 8.95 (m, 1H), 8.95 – 8.89 (m, 2H), 8.87 – 8.80 (m, 1H), 8.31 (s, 1H), 8.03 – 7.88 (m, 1H), 7.23 (d,J = 8.5 Hz, 1H), 6.38 – 6.31 (m, 1H), 6.19 (dd,J = 8.5, 2.3 Hz, 1H), 4.10 – 4.00 (m, 1H), 3.78 (s, 3H), 3.69 – 3.62 (m, 1H), 3.57 – 3.48 (m, 2H), 3.37 (s, 3H), 3.32 – 3.26 (m, 1H), 3.23 (s, 3H), 2.90 (s, 6H), 2.49 – 2.44 (m, 1H), 2.28 – 2.19 (m, 1H). MS (ESI)m/z : 642 [M+H]+ . | |
I-44 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.90 – 8.84 (m, 1H), 8.73 (s, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 8.06 (d,J = 9.4 Hz, 1H), 7.72 – 7.62 (m, 1H), 7.15 – 7.10 (m, 1H), 6.96 – 6.90 (m, 1H), 3.87 – 3.79 (m, 4H), 3.68 – 3.56 (m, 2H), 3.38 (s, 3H), 3.36 – 3.27 (m, 2H), 3.23 (s, 3H), 2.05 – 1.95 (m, 2H), 1.78 – 1.65 (m, 2H). MS (ESI)m/z : 629 [M+H]+ . | |
I-45 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 9.01 – 8.94 (m, 3H), 8.76 (s, 1H), 8.35 (s, 1H), 8.07 – 7.97 (m, 1H), 7.32 (d,J = 8.7 Hz, 1H), 6.74 (d,J = 2.5 Hz, 1H), 6.51 (dd,J = 8.7, 2.5 Hz, 1H), 3.82 – 3.79 (m, 4H), 3.79 (s, 3H), 3.38 (s, 3H), 3.23 (s, 3H), 3.19 (t,J = 4.9 Hz, 4H). MS (ESI)m/z : 615 [M+H]+ . | |
I-46 | MS (ESI)m/z : 630 [M+H]+ . | |
I-47 | MS (ESI)m/z : 656 [M+H]+ . | |
I-48 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.03 – 8.98 (m, 1H), 8.96 – 8.93 (m, 1H), 8.88 (d,J = 9.4 Hz, 1H), 8.76 (s, 1H), 8.73 (s, 1H), 8.43 (s, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.85 (d,J = 8.1 Hz, 1H), 7.12 (s, 1H), 6.96 (d,J = 8.2 Hz, 1H), 3.87 (s, 3H), 3.52 (s, 9H), 3.40 (s, 3H), 3.25 (s, 3H), 3.20 – 2.98 (m, 4H), 2.90 (s, 3H), 2.20 – 1.97 (m, 2H), 1.72 – 1.57 (m, 2H). MS (ESI)m/z : 739 [M+H]+ . | |
I-49 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 9.5 Hz, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.22 (d,J = 9.3 Hz, 1H), 7.95 (d,J = 8.5 Hz, 2H), 7.62 (d,J = 8.5 Hz, 2H), 3.84 – 3.65 (m, 2H), 3.59 – 3.46 (m, 2H), 3.41 (s, 3H), 3.25 (s, 3H), 3.20 – 3.11 (m, 2H), 2.80 (s, 3H), 2.58 – 2.45 (m, 2H). MS (ESI)m/z : 662 [M+H]+ . | |
I-50 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 9.00 (d, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 9.3 Hz, 1H), 8.73 (s, 1H), 8.48 (s, 1H), 8.17 (d,J = 9.3 Hz, 1H), 7.84 (d,J = 8.4 Hz, 2H), 7.73 (d,J = 2.7 Hz, 1H), 7.64 (d,J = 8.4 Hz, 2H), 3.39 (s, 3H), 3.23 (s, 3H), 2.09 – 2.03 (m, 1H), 0.51 – 0.42 (m, 2H), 0.40 – 0.32 (m, 2H). MS (ESI)m/z : 619 [M+H]+ . | |
I-51 | MS (ESI)m/z : 619 [M+H]+ . | |
I-52 | MS (ESI)m/z : 642 [M+H]+ . | |
I-53 | MS (ESI)m/z : 612 [M+H]+ . | |
I-54 | MS (ESI)m/z : 680 [M+H]+ . | |
I-55 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.93 – 8.90 (m, 1H), 8.77 (s, 1H), 8.34 (s, 1H), 8.05 – 7.92 (m, 1H), 7.69 (d,J = 8.3 Hz, 1H), 6.51 (d,J = 8.4 Hz, 1H), 4.45 – 4.36 (m, 2H), 3.84 (s, 3H), 3.62 – 3.53 (m, 2H), 3.40 (s, 3H), 3.25 (s, 3H), 3.21 – 3.09 (m, 4H), 2.90 (s, 3H). MS (ESI)m/z : 629 [M+H]+ . | |
I-56 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 9.01 – 8.96 (m, 1H), 8.94 – 8.92 (m, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.30 – 8.24 (m, 1H), 8.14 – 7.96 (m, 1H), 7.84 – 7.69 (m, 1H), 6.82 (d,J = 8.8 Hz, 1H), 3.49 – 3.42 (m, 4H), 3.25 (s, 3H), 3.18 (s, 3H), 2.45 – 2.37 (m, 4H), 2.23 (s, 3H). MS (ESI)m/z : 599 [M+H]+ . | |
I-57 | MS (ESI)m/z : 682 [M+H]+ . | |
I-58 | MS (ESI)m/z : 629 [M+H]+ . | |
I-59 | MS (ESI)m/z : 629 [M+H]+ . | |
I-60 | MS (ESI)m/z : 630 [M+H]+ . | |
I-61 | MS (ESI)m/z : 643 [M+H]+ . | |
I-62 | MS (ESI)m/z : 629 [M+H]+ . | |
I-63 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 9.10 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 9.3 Hz, 1H), 8.82 (s, 1H), 8.55 – 8.51 (m, 2H), 8.22 (d,J = 9.3 Hz, 1H), 7.81 (d,J = 8.8 Hz, 1H), 3.43 (s, 3H), 3.25 (s, 3H), 2.65 (s, 3H). MS (ESI)m/z : 515 [M+H]+ . | |
I-64 | MS (ESI)m/z : 501 [M+H]+ . | |
I-65 | MS (ESI)m/z : 518 [M+H]+ . | |
I-66 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.15 – 10.02 (m, 1H), 9.20 (d,J = 9.3 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.84 (s, 1H), 8.39 (s, 1H), 8.11 (d,J = 9.3 Hz, 1H), 7.58 (d,J = 2.2 Hz, 1H), 6.30 (s, 1H), 3.79 (s, 3H), 3.41 (s, 3H), 3.25 (s, 3H). MS (ESI)m/z : 504 [M+H]+ . | |
I-67 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.73 – 9.51 (m, 1H), 9.19 (s, 1H), 9.06 – 8.99 (m, 1H), 8.98 – 8.94 (m, 1H), 8.88 – 8.71 (m, 1H), 8.40 – 8.34 (m, 1H), 8.19 (d,J = 9.3 Hz, 1H), 7.95 – 7.81 (m, 1H), 7.52 – 7.30 (m, 1H), 3.85 – 3.55 (m, 3H), 3.39 (s, 3H), 3.24 (s, 3H). MS (ESI)m/z : 504 [M+H]+ . | |
I-68 | MS (ESI)m/z : 504 [M+H]+ . | |
I-69 | MS (ESI)m/z : 521 [M+H]+ . | |
I-70 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.29 – 9.11 (m, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.24 (t,J = 5.8 Hz, 1H), 4.73 (t,J = 5.4 Hz, 1H), 3.59 – 3.51 (m, 4H), 3.40 (s, 3H), 3.26 (s, 3H). MS (ESI)m/z : 468 [M+H]+ . | |
I-71 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 9.00 (d,J = 1.9 Hz, 1H), 8.95 (s, 1H), 8.88 – 8.76 (m, 1H), 8.32 (s, 1H), 8.22 – 8.11 (m, 1H), 7.76 – 7.48 (m, 1H), 3.65 – 3.55 (m, 2H), 3.41 (s, 3H), 3.29 – 3.21 (m, 5H), 2.96 – 2.64 (m, 6H). MS (ESI)m/z : 495 [M+H]+ . | |
I-72 | MS (ESI)m/z : 521 [M+H]+ . | |
I-73 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.50 – 9.36 (m, 1H), 9.04 – 8.98 (m, 1H), 8.99 – 8.93 (m, 1H), 8.89 – 8.79 (m, 1H), 8.43 – 8.28 (m, 2H), 8.25 – 8.15 (m, 1H), 3.42 (s, 3H), 3.26 (s, 3H), 2.76 – 2.62 (m, 1H), 0.89 – 0.73 (m, 2H), 0.62 – 0.53 (m, 2H). MS (ESI)m/z : 464 [M+H]+ . | |
I-74 | MS (ESI)m/z : 598 [M+H]+ . | |
I-75 | MS (ESI)m/z : 628 [M+H]+ . | |
I-76 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 8.14 (d,J = 9.4 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.60 – 7.51 (m, 1H), 7.35 (t,J = 8.1 Hz, 1H), 7.09 (d,J = 8.1 Hz, 1H), 3.78 – 3.66 (m, 1H), 3.56 – 3.48 (m, 2H), 3.43 (s, 3H), 3.25 (s, 3H), 3.23 – 3.20 (m, 2H), 1.95 – 1.84 (m, 2H), 1.72 – 1.61 (m, 2H). MS (ESI)m/z : 599 [M+H]+ . | |
I-77 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.87 (d,J = 8.4 Hz, 1H), 8.75 – 8.69 (m, 2H), 8.41 (s, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.40 – 7.30 (m, 1H), 7.22 (d,J = 8.9 Hz, 1H), 3.86 (s, 3H), 3.77 – 3.62 (m, 1H), 3.51 – 3.44 (m, 2H), 3.42 (s, 3H), 3.34 – 3.27 (m, 2H), 3.25 (s, 3H), 1.95 – 1.82 (m, 2H), 1.75 – 1.62 (m, 2H). MS (ESI)m/z : 629 [M+H]+ . | |
I-78 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 8.11 (d,J = 9.3 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.19 – 7.16 (m, 1H), 7.13 (t,J = 8.0 Hz, 1H), 6.68 (dd,J = 8.2, 2.3 Hz, 1H), 3.76 – 3.67 (m, 2H), 3.63 – 3.46 (m, 5H), 3.41 (s, 3H), 3.25 (s, 3H), 3.20 – 2.92 (m, 4H), 2.86 (s, 3H), 2.72 – 2.57 (m, 2H), 2.04 – 1.91 (m, 2H), 1.68 – 1.51 (m, 2H). MS (ESI)m/z : 681 [M+H]+ . | |
I-79 | MS (ESI)m/z : 711 [M+H]+ . | |
I-80 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.32 – 10.20 (m, 1H), 9.80 (s, 1H), 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.71 (s, 1H), 8.44 (s, 1H), 8.15 (d,J = 9.3 Hz, 1H), 7.82 (s, 1H), 7.70 (dd,J = 8.1, 2.1 Hz, 1H), 7.36 (t,J = 7.8 Hz, 1H), 7.07 (d,J = 7.5 Hz, 1H), 3.41 (s, 3H), 3.39 – 3.31 (m, 4H), 3.25 (s, 3H), 3.18 – 2.94 (m, 4H), 2.83 (s, 3H). MS (ESI)m/z : 626 [M+H]+ . | |
I-81 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.18 – 10.08 (m, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.05 (d,J = 9.4 Hz, 1H), 7.94 (s, 1H), 7.27 (d,J = 8.4, 2.1 Hz, 1H), 7.18 (d,J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.50 – 3.42 (m, 4H), 3.40 (s, 3H), 3.25 (s, 3H), 3.14 – 3.02 (m, 4H), 2.83 (s, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-82 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 9.02 (d,J = 1.8 Hz, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.94 – 8.87 (m, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.13 (d,J = 9.3 Hz, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.32 (s, 1H), 3.83 (s, 2H), 3.42 (s, 3H), 3.25 (s, 3H), 3.21 – 2.94 (m, 4H), 2.82 (s, 3H), 2.76 – 2.57 (m, 4H). MS (ESI)m/z : 680 [M+H]+ . | |
I-83 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.92 – 8.87 (m, 1H), 8.72 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.76 (s, 1H), 7.24 – 7.20 (m, 1H), 7.16 (d,J = 8.4 Hz, 1H), 4.02 – 3.89 (m, 2H), 3.84 (s, 3H), 3.40 (s, 3H), 3.25 (s, 3H), 3.24 – 3.08 (m, 4H), 2.80 (s, 3H), 2.77 – 2.58 (m, 4H). MS (ESI)m/z : 642 [M+H]+ . | |
I-84 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 9.03 (d,J = 10.4 Hz, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.73 (s, 1H), 8.43 (s, 1H), 8.15 (d,J = 9.3 Hz, 1H), 7.70 (d,J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.33 (t,J = 7.8 Hz, 1H), 7.07 (d,J = 7.5 Hz, 1H), 3.99 (s, 2H), 3.41 (s, 3H), 3.26 (s, 3H), 3.23 – 2.89 (m, 4H), 2.83 (s, 3H), 2.82 – 2.60 (m, 4H). MS (ESI)m/z : 612 [M+H]+ . | |
I-85 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 9.4 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.96 (d,J = 9.4 Hz, 1H), 7.89 (s, 1H), 7.45 (d,J = 8.8, 2.6 Hz, 1H), 7.13 (d,J = 8.9 Hz, 1H), 4.10 (s, 2H), 3.81 (s, 3H), 3.40 (s, 3H), 3.25 (s, 3H), 2.86 (s, 6H). MS (ESI)m/z : 630 [M+H]+ . | |
I-86 | MS (ESI)m/z : 656 [M+H]+ . | |
I-87 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.33 – 10.20 (m, 1H), 9.37 (s, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.71 – 8.67 (m, 1H), 8.38 (s, 1H), 8.10 (d,J = 9.6 Hz, 1H), 7.45 (d,J = 7.8 Hz, 1H), 7.29 (d,J = 11.2 Hz, 1H), 4.44 – 4.36 (m, 1H), 4.25 – 4.14 (m, 1H), 3.77 – 3.65 (m, 1H), 3.40 (s, 3H), 3.37 – 3.31 (m, 1H), 3.25 (s, 3H), 3.15 – 3.04 (m, 2H), 2.93 (s, 3H). MS (ESI)m/z : 587 [M+H]+ . | |
I-88 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.20 (s, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 9.4 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.04 (d,J = 9.4 Hz, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 4.48 – 4.37 (m, 1H), 4.28 – 4.16 (m, 1H), 3.77 – 3.66 (m, 1H), 3.40 (s, 3H), 3.38 – 3.31 (m, 1H), 3.25 (s, 3H), 3.21 – 3.08 (m, 2H), 2.94 (s, 3H). MS (ESI)m/z : 603 [M+H]+ . | |
I-89 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.89 – 8.79 (m, 1H), 8.78 – 8.73 (m, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.19 – 8.12 (m, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 4.26 – 4.07 (m, 1H), 4.05 – 3.94 (m, 1H), 3.81 (s, 3H), 3.72 – 3.63 (m, 1H), 3.39 (s, 3H), 3.31 (s, 1H), 3.23 (s, 3H), 3.20 – 3.09 (m, 1H), 3.07 – 2.99 (m, 1H), 2.89 (s, 3H). MS (ESI)m/z : 599 [M+H]+ . | |
I-90 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 2.0 Hz, 1H), 8.88 (d,J = 9.5 Hz, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.10 (d,J = 9.5 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 4.47 – 4.37 (m, 1H), 4.30 – 4.14 (m, 1H), 3.78 – 3.65 (m, 2H), 3.40 (s, 3H), 3.25 (s, 3H), 3.21 – 3.12 (m, 2H), 2.94 (s, 3H). MS (ESI)m/z : 653 [M+H]+ . | |
I-91 | MS (ESI)m/z : 637 [M+H]+ . | |
I-92 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.18 (s, 1H), 8.99 (d,J = 1.7 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.90 – 8.83 (m, 1H), 8.76 – 8.71 (m, 1H), 8.35 (s, 1H), 8.06 – 8.00 (m, 1H), 7.24 (s, 1H), 7.18 (s, 1H), 4.48 – 4.35 (m, 1H), 4.28 – 4.16 (m, 1H), 3.81 – 3.65 (m, 1H), 3.40 (s, 3H), 3.38 – 3.31 (m, 1H), 3.26 (s, 3H), 3.20 – 3.13 (m, 1H), 3.09 – 3.02 (m, 1H), 2.95 (s, 3H), 2.20 (s, 3H). MS (ESI)m/z : 583 [M+H]+ . | |
I-93 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 9.07 – 8.90 (m, 3H), 8.70 – 8.57 (m, 1H), 8.38 (s, 1H), 8.09 (d,J = 9.4 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.35 – 7.28 (m, 1H), 6.96 (d,J = 8.1 Hz, 1H), 3.39 (s, 3H), 3.24 (s, 3H), 2.91 – 2.76 (m, 3H), 2.42 – 2.28 (m, 2H), 2.24 (s, 3H), 2.19 – 2.04 (m, 2H), 1.15 – 1.04 (m, 3H). MS (ESI)m/z : 597 [M+H]+ . | |
I-94 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.91 (d,J = 1.9 Hz, 1H), 8.82 (d,J = 1.9 Hz, 1H), 8.80 (d,J = 8.7 Hz, 1H), 8.19 (s, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.59 (s, 1H), 6.74 (s, 1H), 4.17 – 4.06 (m, 1H), 3.84 – 3.75 (m, 4H), 3.26 – 3.18 (m, 4H), 3.16 (s, 3H), 3.13 – 3.00 (m, 3H), 2.86 – 2.74 (m, 6H), 2.65 (s, 3H), 2.09 – 2.03 (m, 5H), 1.88 – 1.75 (m, 2H), 1.02 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 739 [M+H]+ . | |
I-95 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 – 8.90 (m, 1H), 8.90 – 8.81 (m, 1H), 8.68 – 8.58 (m, 1H), 8.24 (s, 1H), 8.00 (d,J = 9.4 Hz, 1H), 7.56 (s, 1H), 6.83 (s, 1H), 4.20 – 4.07 (m, 1H), 3.83 (s, 3H), 3.82 – 3.74 (m, 1H), 3.50 – 3.37 (m, 4H), 3.30 – 3.27 (m, 2H), 3.26 – 3.17 (m, 2H), 3.14 (s, 3H), 3.11 – 3.04 (m, 1H), 2.95 – 2.87 (m, 2H), 2.87 (s, 3H), 2.67 – 2.62 (m, 5H), 2.57 – 2.46 (m, 1H), 2.45 – 2.35 (m, 1H), 2.19 – 2.09 (m, 2H), 1.98 – 1.81 (m, 2H), 1.00 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 753 [M+H]+ . | |
I-96 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.9 Hz, 1H), 8.84 (d,J = 1.8 Hz, 1H), 8.65 (d,J = 9.3 Hz, 1H), 8.24 (s, 1H), 7.88 (d,J = 9.3 Hz, 1H), 7.56 (s, 1H), 7.05 (s, 1H), 4.19 – 4.06 (m, 1H), 3.83 – 3.72 (m, 1H), 3.27 – 3.15 (m, 8H), 3.00 – 2.91 (m, 1H), 2.82 (s, 3H), 2.78 – 2.72 (m, 2H), 2.65 (s, 5H), 2.63 – 2.56 (m, 1H), 2.56 – 2.44 (m, 1H), 2.16 – 2.04 (m, 2H), 1.88 – 1.74 (m, 2H), 1.01 (t,J = 7.1 Hz, 3H), 0.92 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 807 [M+H]+ . | |
I-97 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.72 – 8.64 (m, 1H), 8.21 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.64 (s, 1H), 6.78 (s, 1H), 4.19 – 4.05 (m, 1H), 3.83 (s, 3H), 3.81 – 3.76 (m, 1H), 3.34 – 3.28 (m, 1H), 3.18 – 3.12 (m, 5H), 2.93 (s, 6H), 2.86 – 2.78 (m, 2H), 2.58 – 2.43 (m, 1H), 2.44 – 2.31 (m, 1H), 2.22 – 2.11 (m, 2H), 1.97 – 1.81 (m, 2H), 1.01 (t,J = 7.2 Hz, 3H), 0.84 – 0.71 (m, 3H). MS (ESI)m/z : 698 [M+H]+ . | |
I-98 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.71 – 8.58 (m, 1H), 8.22 (s, 1H), 7.98 (d,J = 9.2 Hz, 1H), 7.57 (d,J = 4.6 Hz, 1H), 6.80 (d,J = 1.4 Hz, 1H), 4.19 – 4.07 (m, 1H), 4.05 – 3.96 (m, 1H), 3.84 (s, 3H), 3.82 – 3.72 (m, 1H), 3.45 – 3.36 (m, 2H), 3.33 – 3.25 (m, 1H), 3.16 (s, 3H), 3.13 – 3.03 (m, 1H), 3.01 – 2.93 (m, 6H), 2.56 – 2.44 (m, 2H), 2.44 – 2.33 (m, 1H), 2.26 – 2.11 (m, 1H), 1.01 (t,J = 7.2 Hz, 3H), 0.90 – 0.71 (m, 3H). MS (ESI)m/z : 684 [M+H]+ . | |
I-99 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.62 (d,J = 9.2 Hz, 1H), 8.26 (s, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.45 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.52 – 3.48 (m, 2H), 3.47 (s, 3H), 3.41 – 3.32 (m, 8H), 3.24 – 3.19 (m, 2H), 3.09 – 3.01 (m, 1H), 2.95 – 2.90 (m, 2H), 2.88 (s, 3H), 2.19 – 2.13 (m, 2H), 2.05 (s, 3H), 1.96 – 1.85 (m, 2H), 1.42 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 739 [M+H]+ . | |
I-100 | 1 H NMR (600 MHz, MeOD) δ 8.94 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.44 – 8.34 (m, 1H), 8.23 (s, 1H), 8.02 – 7.97 (m, 1H), 7.31 (s, 1H), 6.79 (s, 1H), 3.79 (s, 3H), 3.57 (s, 8H), 3.48 – 3.42 (m, 2H), 3.41 (s, 3H), 3.33 – 3.28 (m, 1H), 3.18 – 3.13 (m, 2H), 2.93 (s, 3H), 2.89 – 2.79 (m, 2H), 2.40 – 2.27 (m, 2H), 2.21 – 2.14 (m, 2H), 1.96 – 1.85 (m, 2H), 1.36 (t,J = 7.4 Hz, 3H), 0.87 – 0.69 (m, 3H). MS (ESI)m/z : 753 [M+H]+ . | |
I-101 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 1.9 Hz, 1H), 8.87 – 8.86 (m, 1H), 8.47 (d,J = 9.8 Hz, 1H), 8.27 (s, 1H), 7.89 (d,J = 9.3 Hz, 1H), 7.49 (s, 1H), 7.05 (s, 1H), 3.55 – 3.46 (m, 8H), 3.43 (s, 3H), 3.25 – 3.10 (m, 5H), 2.92 (s, 3H), 2.82 – 2.72 (m, 2H), 2.49 (q,J = 7.5 Hz, 2H), 2.22 – 2.15 (m, 2H), 1.94 – 1.84 (m, 2H), 1.40 (t,J = 7.4 Hz, 3H), 0.89 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 807 [M+H]+ . | |
I-102 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.54 – 8.44 (m, 1H), 8.26 (s, 1H), 8.02 (d,J = 9.1 Hz, 1H), 7.37 (s, 1H), 6.80 (s, 1H), 3.82 (s, 3H), 3.52 – 3.47 (m, 2H), 3.46 (s, 3H), 3.21 – 3.12 (m, 3H), 2.92 (s, 6H), 2.87 – 2.79 (m, 2H), 2.47 – 2.35 (m, 2H), 2.24 – 2.14 (m, 2H), 1.98 – 1.85 (m, 2H), 1.40 (t,J = 7.4 Hz, 3H), 0.95 – 0.73 (m, 3H). MS (ESI)m/z : 698 [M+H]+ . | |
I-103 | MS (ESI)m/z : 684 [M+H]+ . | |
I-104 | MS (ESI)m/z : 751 [M+H]+ . | |
I-105 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.58 – 8.44 (m, 1H), 8.24 (s, 1H), 8.02 (d,J = 9.2 Hz, 1H), 7.41 (s, 1H), 6.83 (s, 1H), 3.83 (s, 3H), 3.59 – 3.36 (m, 11H), 3.27 – 3.13 (m, 3H), 2.94 – 2.87 (m, 5H), 2.86 – 2.82 (m, 1H), 2.50 – 2.36 (m, 2H), 2.22 – 2.09 (m, 2H), 1.98 – 1.83 (m, 2H), 1.21 – 1.09 (m, 2H), 0.92 – 0.76 (m, 3H), 0.72 – 0.67 (m, 1H), 0.67 – 0.59 (m, 1H). MS (ESI)m/z : 765 [M+H]+ . | |
I-106 | 1 H NMR (600 MHz, MeOD) δ 8.92 (d,J = 1.9 Hz, 1H), 8.82 (d,J = 1.9 Hz, 1H), 8.52 (d,J = 9.2 Hz, 1H), 8.23 (s, 1H), 7.86 (d,J = 9.3 Hz, 1H), 7.48 (s, 1H), 7.03 (s, 1H), 3.45 (s, 3H), 3.43 – 3.30 (m, 8H), 3.18 – 3.11 (m, 2H), 3.10 – 3.03 (m, 1H), 2.85 (s, 3H), 2.79 – 2.69 (m, 2H), 2.55 – 2.45 (m, 2H), 2.19 – 2.07 (m, 2H), 1.92 – 1.79 (m, 2H), 1.29 – 1.19 (m, 1H), 1.18 – 1.10 (m, 2H), 0.91 (t,J = 7.5 Hz, 3H), 0.74 – 0.60 (m, 2H). MS (ESI)m/z : 819 [M+H]+ . | |
I-107 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.55 – 8.41 (m, 1H), 8.25 (d,J = 5.3 Hz, 1H), 8.00 (d,J = 9.2 Hz, 1H), 7.35 (s, 1H), 6.79 (s, 1H), 3.81 (s, 3H), 3.49 (s, 3H), 3.35 – 3.30 (m, 1H), 3.23 – 3.10 (m, 2H), 2.92 (s, 6H), 2.87 – 2.74 (m, 3H), 2.52 – 2.29 (m, 2H), 2.26 – 2.14 (m, 2H), 1.98 – 1.83 (m, 2H), 1.22 – 1.10 (m, 2H), 0.96 – 0.78 (m, 3H), 0.74 – 0.68 (m, 1H), 0.66 – 0.61 (m, 1H). MS (ESI)m/z : 710 [M+H]+ . | |
I-108 | 1 H NMR (600 MHz, MeOD) δ 8.93 (d,J = 1.8 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.52 – 8.33 (m, 1H), 8.20 (s, 1H), 8.01 – 7.89 (m, 1H), 7.25 (s, 1H), 6.76 – 6.71 (m, 1H), 4.02 – 3.93 (m, 1H), 3.78 (s, 3H), 3.45 (s, 3H), 3.40 – 3.35 (m, 2H), 3.14 – 3.03 (m, 1H), 2.92 (s, 6H), 2.84 – 2.76 (m, 1H), 2.47 – 2.42 (m, 1H), 2.41 – 2.32 (m, 2H), 2.24 – 2.08 (m, 1H), 1.30 – 1.03 (m, 3H), 0.93 – 0.71 (m, 3H), 0.69 – 0.56 (m, 2H). MS (ESI)m/z : 696 [M+H]+ . | |
I-109 | MS (ESI)m/z : 695 [M+H]+ . | |
I-110 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 (d,J = 1.9 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.59 – 8.46 (m, 1H), 8.14 (s, 1H), 7.96 (d,J = 9.3 Hz, 1H), 7.47 (s, 1H), 6.80 (s, 1H), 4.13 – 4.00 (m, 1H), 3.79 (s, 3H), 3.77 – 3.68 (m, 1H), 3.56 – 3.47 (m, 6H), 3.26 – 3.24 (m, 1H), 3.23 – 3.16 (m, 2H), 3.10 (s, 3H), 2.94 – 2.85 (m, 5H), 2.52 – 2.42 (m, 1H), 2.42 – 2.32 (m, 1H), 2.22 – 2.06 (m, 2H), 1.99 – 1.82 (m, 2H), 0.94 (t,J = 7.2 Hz, 3H), 0.86 – 0.71 (m, 3H). MS (ESI)m/z : 709 [M+H]+ . | |
I-111 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.89 (d,J = 1.9 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.53 – 8.41 (m, 1H), 8.18 (s, 1H), 7.86 (d,J = 9.4 Hz, 1H), 7.48 (s, 1H), 7.06 – 6.98 (m, 1H), 4.14 – 4.00 (m, 1H), 3.79 – 3.71 (m, 1H), 3.68 – 3.51 (m, 8H), 3.28 – 3.24 (m, 1H), 3.19 – 3.13 (m, 2H), 3.10 (s, 3H), 2.94 (s, 3H), 2.75 (t,J = 11.6 Hz, 2H), 2.62 – 2.45 (m, 2H), 2.30 – 2.12 (m, 2H), 1.98 – 1.82 (m, 2H), 0.97 – 0.88 (m, 6H). MS (ESI)m/z : 763 [M+H]+ . | |
I-112 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.66 – 8.50 (m, 1H), 8.15 (s, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.48 (s, 1H), 6.78 (s, 1H), 4.16 – 4.04 (m, 1H), 3.80 (s, 3H), 3.78 – 3.73 (m, 1H), 3.34 – 3.30 (m, 2H), 3.29 – 3.25 (m, 1H), 3.20 – 3.14 (m, 2H), 3.13 (s, 3H), 2.91 (s, 6H), 2.87 – 2.74 (m, 2H), 2.56 – 2.45 (m, 1H), 2.45 – 2.34 (m, 1H), 2.19 – 2.09 (m, 2H), 1.98 – 1.80 (m, 2H), 0.97 (t,J = 7.2 Hz, 3H), 0.90 – 0.72 (m, 3H). MS (ESI)m/z : 654 [M+H]+ . | |
I-113 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.65 – 8.41 (m, 1H), 8.17 (s, 1H), 8.03 – 7.90 (m, 1H), 7.34 (d,J = 4.2 Hz, 1H), 6.77 (d,J = 2.3 Hz, 1H), 4.17 – 4.04 (m, 1H), 4.05 – 3.94 (m, 1H), 3.79 (s, 3H), 3.79 – 3.70 (m, 1H), 3.52 – 3.38 (m, 2H), 3.29 – 3.24 (m, 1H), 3.16 – 3.08 (m, 4H), 3.00 – 2.90 (m, 6H), 2.56 – 2.34 (m, 3H), 2.27 – 2.10 (m, 1H), 1.05 – 0.94 (m, 3H), 0.85 (s, 3H). MS (ESI)m/z : 640 [M+H]+ . | |
I-114 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.74 (d,J = 9.4 Hz, 1H), 8.11 (s, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.58 (s, 1H), 6.75 (s, 1H), 3.83 (s, 3H), 3.52 – 3.47 (m, 1H), 3.45 (s, 3H), 3.31 – 2.97 (m, 10H), 2.94 – 2.83 (m, 2H), 2.84 – 2.71 (m, 5H), 2.16 – 2.05 (m, 2H), 2.04 (s, 3H), 1.88 – 1.78 (m, 2H), 1.42 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 695 [M+H]+ . | |
I-115 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.64 (d,J = 9.3 Hz, 1H), 8.16 (s, 1H), 8.02 (d,J = 9.3 Hz, 1H), 7.60 (s, 1H), 6.80 (s, 1H), 3.84 (s, 3H), 3.53 – 3.47 (m, 1H), 3.46 (s, 3H), 3.28 – 2.94 (m, 10H), 2.92 – 2.79 (m, 4H), 2.78 (s, 3H), 2.50 – 2.31 (m, 2H), 2.15 – 1.97 (m, 2H), 1.89 – 1.69 (m, 2H), 1.42 (t,J = 7.4 Hz, 3H), 0.90 – 0.68 (m, 3H). MS (ESI)m/z : 709 [M+H]+ . | |
I-116 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.68 (d,J = 9.4 Hz, 1H), 8.17 (s, 1H), 7.91 (d,J = 9.4 Hz, 1H), 7.59 (s, 1H), 7.05 (s, 1H), 3.54 – 3.48 (m, 1H), 3.45 (s, 3H), 3.25 – 3.00 (m, 10H), 2.93 – 2.82 (m, 2H), 2.79 (s, 3H), 2.76 – 2.70 (m, 2H), 2.59 – 2.47 (m, 2H), 2.13 – 2.02 (m, 2H), 1.85 – 1.71 (m, 2H), 1.42 (t,J = 7.4 Hz, 3H), 0.93 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 763 [M+H]+ . | |
I-117 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.48 – 8.38 (m, 1H), 8.17 (s, 1H), 8.00 (d,J = 9.3 Hz, 1H), 7.41 (s, 1H), 6.79 (s, 1H), 3.82 (s, 3H), 3.56 (d,J = 12.1 Hz, 2H), 3.43 (s, 4H), 3.31 (s, 1H), 3.29 – 3.24 (m,J = 4.2, 3.4 Hz, 2H), 3.19 – 3.07 (m, 6H), 2.95 (s, 3H), 2.35 (s, 2H), 1.37 (t,J = 7.4 Hz, 3H), 0.76 (s, 3H). MS (ESI)m/z : 654 [M+H]+ . | |
I-118 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.8 Hz, 1H), 8.51 – 8.32 (m, 1H), 8.17 (s, 1H), 8.05 – 7.93 (m, 1H), 7.28 (s, 1H), 6.79 – 6.74 (m, 1H), 4.03 – 3.94 (m, 1H), 3.81 (s, 3H), 3.49 – 3.45 (m, 1H), 3.43 (s, 3H), 3.41 – 3.36 (m, 2H), 3.32 – 3.30 (m, 1H), 3.14 (dd,J = 14.3, 7.3 Hz, 1H), 3.10 – 3.05 (m, 1H), 2.94 (s, 6H), 2.50 – 2.41 (m, 1H), 2.36 (s, 2H), 2.23 – 2.10 (m, 1H), 1.37 (t,J = 7.4 Hz, 3H), 1.06 – 0.66 (m, 3H). MS (ESI)m/z : 640 [M+H]+ . | |
I-119 | MS (ESI)m/z : 707 [M+H]+ . | |
I-120 | 1 H NMR (600 MHz, MeOD) δ 8.97 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.51 – 8.42 (m, 1H), 8.17 (s, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.41 (s, 1H), 6.82 (s, 1H), 3.82 (s, 3H), 3.51 – 3.44 (m, 8H), 3.47 (s, 3H), 3.21 – 3.16 (m, 2H), 2.91 (s, 3H), 2.90 – 2.86 (m, 2H), 2.85 – 2.80 (m, 1H), 2.47 – 2.31 (m, 2H), 2.17 (d,J = 11.6 Hz, 2H), 1.97 – 1.85 (m, 2H), 1.27 – 1.12 (m, 3H), 0.88 – 0.75 (m, 3H), 0.72 – 0.62 (m, 2H). MS (ESI)m/z : 721 [M+H]+ . | |
I-121 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 2.0 Hz, 1H), 8.63 (d,J = 9.6 Hz, 1H), 8.18 (s, 1H), 7.91 (d,J = 9.3 Hz, 1H), 7.55 (s, 1H), 7.07 (s, 1H), 3.48 (s, 3H), 3.28 – 3.13 (m, 8H), 2.97 – 2.92 (m, 1H), 2.92 – 2.86 (m, 2H), 2.82 (s, 3H), 2.80 – 2.71 (m, 2H), 2.58 – 2.52 (m, 2H), 2.14 – 2.08 (m, 2H), 1.86 – 1.79 (m, 2H), 1.33 – 1.27 (m, 1H), 1.22 – 1.14 (m, 2H), 0.95 (t,J = 7.5 Hz, 3H), 0.75 – 0.64 (m, 2H). MS (ESI)m/z : 775 [M+H]+ . | |
I-122 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.63 – 8.51 (m, 1H), 8.17 (s, 1H), 8.03 (d,J = 9.4 Hz, 1H), 7.47 (s, 1H), 6.80 (s, 1H), 3.84 (s, 3H), 3.50 (s, 3H), 3.16 (t,J = 13.8 Hz, 2H), 2.93 (s, 6H), 2.89 – 2.85 (m, 1H), 2.85 – 2.79 (m, 2H), 2.49 – 2.36 (m, 2H), 2.24 – 2.12 (m, 2H), 1.90 (q,J = 11.8, 4.1 Hz, 2H), 1.37 – 1.23 (m, 1H), 1.22 – 1.12 (m, 2H), 0.94 – 0.78 (m, 3H), 0.77 – 0.63 (m, 2H). MS (ESI)m/z : 666 [M+H]+ . | |
I-123 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 1.8 Hz, 1H), 8.55 – 8.40 (m, 1H), 8.14 (s, 1H), 7.99 (d,J = 9.4 Hz, 1H), 7.35 (s, 1H), 6.81 – 6.73 (m, 1H), 4.03 – 3.93 (m, 1H), 3.81 (s, 3H), 3.46 (s, 3H), 3.40 – 3.34 (m, 2H), 3.12 – 3.02 (m, 1H), 2.93 (s, 6H), 2.86 – 2.77 (m, 1H), 2.52 – 2.43 (m, 1H), 2.44 – 2.34 (m, 2H), 2.21 – 2.12 (m, 1H), 1.26 – 1.08 (m, 3H), 0.90 – 0.77 (m, 3H), 0.72 – 0.59 (m, 2H). MS (ESI)m/z : 652 [M+H]+ . | |
I-124 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.25 (s, 1H), 8.20 – 8.06 (m, 2H), 7.13 (s, 1H), 6.68 (s, 1H), 3.77 (s, 3H), 3.61 – 3.42 (m, 11H), 3.23 – 3.18 (m, 1H), 3.19 – 3.09 (m, 2H), 2.91 (s, 3H), 2.84 – 2.73 (m, 2H), 2.21 – 2.08 (m, 2H), 1.95 – 1.81 (m, 2H), 1.65 (br s, 3H). MS (ESI)m/z : 779 [M+H]+ . | |
I-125 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.08 – 8.98 (m, 1H), 8.98 – 8.92 (m, 1H), 8.33 (s, 1H), 8.28 – 8.24 (m, 1H), 8.13 (d,J = 10.6 Hz, 1H), 7.42 (s, 1H), 6.84 – 6.71 (m, 1H), 4.01 – 3.85 (m, 1H), 3.82 (s, 3H), 3.67 – 3.61 (m, 1H), 3.57 (s, 3H), 3.30 – 3.03 (m, 9H), 2.98 – 2.87 (m, 2H), 2.85 – 2.80 (m, 3H), 2.33 – 2.21 (m, 1H), 2.12 – 2.05 (m, 2H), 1.91 – 1.72 (m, 2H), 1.36 – 1.23 (m, 1H), 0.80 – 0.57 (m, 3H). MS (ESI)m/z : 793 [M+H]+ . | |
I-126 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.28 (s, 1H), 8.13 (d,J = 9.3 Hz, 1H), 8.01 (d,J = 9.2 Hz, 1H), 7.31 (s, 1H), 6.93 (s, 1H), 3.65 – 3.52 (m, 8H), 3.50 (s, 3H), 3.25 – 3.22 (m, 1H), 3.08 – 2.97 (m, 2H), 2.92 (s, 3H), 2.72 – 2.59 (m, 2H), 2.38 – 2.27 (m, 1H), 2.20 – 2.13 (m, 2H), 2.14 – 2.07 (m, 1H), 1.92 – 1.76 (m, 2H), 0.80 – 0.68 (m, 3H). MS (ESI)m/z : 847 [M+H]+ . | |
I-127 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.02 (d,J = 1.8 Hz, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.28 (s, 1H), 8.25 – 8.11 (m, 2H), 7.24 (s, 1H), 6.72 (s, 1H), 3.80 (s, 3H), 3.56 (s, 3H), 3.17 – 3.00 (m, 3H), 2.92 (s, 6H), 2.83 – 2.70 (m, 2H), 2.35 – 2.23 (m, 1H), 2.21 – 2.11 (m, 2H), 2.10 – 1.95 (m, 1H), 1.92 – 1.80 (m, 2H), 0.88 – 0.51 (m, 3H). MS (ESI)m/z : 738 [M+H]+ . | |
I-128 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.42 (d,J = 9.3 Hz, 1H), 8.26 (s, 1H), 7.87 (d,J = 8.6 Hz, 1H), 7.46 (s, 1H), 6.75 (s, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 3.07 – 3.03 (m, 1H), 2.96 (d,J = 2.4 Hz, 6H), 2.53 – 2.39 (m, 1H), 2.28 (s, 1H), 2.21 – 2.10 (m, 2H), 2.04 – 1.97 (m, 1H), 1.82 – 1.74 (m, 1H), 1.68 – 1.51 (m, 2H), 0.76 – 0.59 (m, 3H). MS (ESI)m/z : 724 [M+H]+ . | |
I-129 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.18 (s, 1H), 8.17 – 8.15 (m, 1H), 7.20 (s, 1H), 6.71 (s, 1H), 3.79 (s, 3H), 3.53 (s, 3H), 3.49 – 3.31 (m, 8H), 3.21 – 3.13 (m, 2H), 3.13 – 3.06 (m, 1H), 2.89 (s, 3H), 2.86 – 2.78 (m, 2H), 2.17 – 2.08 (m, 2H), 1.92 – 1.82 (m, 2H), 1.66 (s, 3H). MS (ESI)m/z : 735 [M+H]+ . | |
I-130 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.18 – 8.04 (m, 2H), 7.25 (s, 1H), 6.74 (s, 1H), 3.79 (s, 3H), 3.54 (s, 3H), 3.53 – 3.32 (m, 8H), 3.16 – 3.04 (m, 3H), 2.89 (s, 3H), 2.86 – 2.77 (m, 2H), 2.29 – 2.18 (m, 1H), 2.17 – 2.08 (m, 2H), 2.04 – 1.91 (m, 1H), 1.89 – 1.78 (m, 2H), 0.82 – 0.28 (m, 2H). MS (ESI)m/z : 749 [M+H]+ . | |
I-131 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.20 (s, 1H), 8.09 (d,J = 9.2 Hz, 1H), 8.03 (d,J = 9.2 Hz, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 3.71 – 3.52 (m, 8H), 3.49 (s, 3H), 3.26 – 3.21 (m, 1H), 3.04 – 2.97 (m, 2H), 2.92 (s, 3H), 2.71 – 2.58 (m, 2H), 2.37 – 2.26 (m, 1H), 2.22 – 2.11 (m, 2H), 2.11 – 2.00 (m, 1H), 1.90 – 1.76 (m, 2H), 0.81 – 0.64 (m, 3H). MS (ESI)m/z : 803 [M+H]+ . | |
I-132 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.15 (d,J = 9.1 Hz, 1H), 8.08 (d,J = 9.2 Hz, 1H), 7.17 (s, 1H), 6.69 (s, 1H), 3.77 (s, 3H), 3.53 (s, 3H), 3.27 – 3.22 (m, 1H), 3.09 – 2.97 (m, 2H), 2.89 (s, 6H), 2.80 – 2.65 (m, 2H), 2.33 – 2.18 (m, 1H), 2.17 – 2.09 (m, 2H), 2.05 – 1.75 (m, 3H), 0.67 (d,J = 64.2 Hz, 3H). MS (ESI)m/z : 694 [M+H]+ . | |
I-133 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.7 Hz, 1H), 8.97 (d,J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.17 – 8.10 (m, 2H), 7.19 (d,J = 8.6 Hz, 1H), 6.73 – 6.65 (m, 1H), 4.01 – 3.92 (m, 1H), 3.79 (s, 3H), 3.57 (s, 3H), 3.38 – 3.30 (m, 3H), 3.26 – 3.18 (m, 1H), 3.08 – 3.01 (m, 1H), 2.94 (s, 3H), 2.93 – 2.91 (m, 2H), 2.52 – 2.39 (m, 1H), 2.33 – 2.21 (m, 1H), 2.19 – 2.12 (m, 1H), 2.12 – 1.88 (m, 1H), 0.81 – 0.42 (m, 3H). MS (ESI)m/z : 680 [M+H]+ . | |
I-134 | 1 H NMR (600 MHz, MeOD) δ 8.95 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.43 – 8.33 (m, 1H), 8.22 (s, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.23 (s, 1H), 6.73 (s, 1H), 3.77 (s, 3H), 3.71 – 3.48 (m, 8H), 3.40 (s, 3H), 3.40 – 3.37 (m, 1H), 3.35 – 3.28 (m, 1H), 3.25 – 3.18 (m, 2H), 2.93 (s, 3H), 2.87 – 2.77 (m, 2H), 2.22 – 2.12 (m, 2H), 2.04 – 1.81 (m, 5H), 1.59 (d,J = 6.6 Hz, 3H), 1.21 (d,J = 6.8 Hz, 3H). MS (ESI)m/z : 753 [M+H]+ . | |
I-135 | 1 H NMR (600 MHz, MeOD) δ 9.00 – 8.98 (m, 1H), 8.92 (d,J = 1.7 Hz, 1H), 8.43 – 8.35 (m, 1H), 8.26 (s, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.40 (s, 1H), 6.82 (s, 1H), 3.83 (s, 3H), 3.58 – 3.41 (m, 11H), 3.26 – 3.14 (m, 3H), 2.91 (s, 3H), 2.91 – 2.86 (m, 2H), 2.45 – 2.28 (m, 2H), 2.23 – 2.10 (m, 2H), 1.99 – 1.85 (m, 2H), 1.64 (d,J = 6.7 Hz, 3H), 1.26 (d,J = 6.9 Hz, 3H), 0.94 – 0.61 (m, 3H). MS (ESI)m/z : 767 [M+H]+ . | |
I-136 | MS (ESI)m/z : 821 [M+H]+ . | |
I-137 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.44 – 8.32 (m, 1H), 8.26 (s, 1H), 8.10 – 7.98 (m, 1H), 7.29 (s, 1H), 6.78 (s, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 3.44 – 3.40 (m, 1H), 3.33 – 3.29 (m, 1H), 3.18 – 3.08 (m, 2H), 2.91 (s, 6H), 2.83 – 2.76 (m, 2H), 2.41 – 2.26 (m, 2H), 2.21 – 2.11 (m, 2H), 1.88 (s, 2H), 1.63 (d,J = 6.7 Hz, 3H), 1.25 (d,J = 6.9 Hz, 3H), 0.76 (t,J = 7.3 Hz, 3H). MS (ESI)m/z : 712 [M+H]+ . | |
I-138 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.50 – 8.35 (m, 1H), 8.26 (s, 1H), 8.02 (d,J = 8.8 Hz, 1H), 7.36 (d,J = 2.9 Hz, 1H), 6.77 (d,J = 2.5 Hz, 1H), 4.03 – 3.96 (m, 1H), 3.83 (s, 3H), 3.46 (s, 3H), 3.45 – 3.42 (m, 1H), 3.41 – 3.37 (m, 2H), 3.34 – 3.31 (m, 1H), 3.13 – 3.05 (m, 1H), 3.01 – 2.92 (m, 6H), 2.52 – 2.44 (m, 1H), 2.42 – 2.27 (m, 2H), 2.23 – 2.13 (m, 1H), 1.65 (d,J = 6.7 Hz, 3H), 1.26 (d,J = 6.9 Hz, 3H), 0.78 (br s, 3H). MS (ESI)m/z : 698 [M+H]+ . | |
I-139 | MS (ESI)m/z : 709 [M+H]+ . | |
I-140 | MS (ESI)m/z : 723 [M+H]+ . | |
I-141 | MS (ESI)m/z : 777 [M+H]+ . | |
I-142 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.40 – 8.30 (m, 1H), 8.19 (s, 1H), 8.04 (d,J = 9.4 Hz, 1H), 7.32 (s, 1H), 6.77 (s, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 3.43 – 3.40 (m, 1H), 3.33 – 3.30 (m, 1H), 3.19 – 3.06 (m, 2H), 2.91 (s, 6H), 2.84 – 2.75 (m, 2H), 2.42 – 2.26 (m, 2H), 2.21 – 2.12 (m, 2H), 1.94 – 1.82 (m, 2H), 1.62 (d,J = 6.7 Hz, 3H), 1.25 (d,J = 6.9 Hz, 3H), 0.91 – 0.63 (m, 3H). MS (ESI)m/z : 668 [M+H]+ . | |
I-143 | 1 H NMR (600 MHz, MeOD) δ 9.00 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.46 – 8.31 (m, 1H), 8.19 (s, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.33 (s, 1H), 6.79 – 6.74 (m, 1H), 4.02 – 3.95 (m, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.45 – 3.41 (m, 1H), 3.41 – 3.37 (m, 2H), 3.29 – 3.25 (m, 1H), 3.14 – 3.04 (m, 1H), 2.96 (s, 6H), 2.51 – 2.43 (m, 1H), 2.42 – 2.29 (m, 2H), 2.23 – 2.11 (m, 1H), 1.63 (d,J = 6.7 Hz, 3H), 1.26 (d,J = 7.0 Hz, 3H), 0.90 – 0.67 (m, 3H). MS (ESI)m/z : 654 [M+H]+ . | |
I-144 | MS (ESI)m/z : 753 [M+H]+ . | |
I-145 | MS (ESI)m/z : 767 [M+H]+ . | |
I-146 | MS (ESI)m/z : 821 [M+H]+ . | |
I-147 | MS (ESI)m/z : 712 [M+H]+ . | |
I-148 | MS (ESI)m/z : 698 [M+H]+ . | |
I-149 | MS (ESI)m/z : 709 [M+H]+ . | |
I-150 | MS (ESI)m/z : 723 [M+H]+ . | |
I-151 | MS (ESI)m/z : 777 [M+H]+ . | |
I-152 | MS (ESI)m/z : 668 [M+H]+ . | |
I-153 | MS (ESI)m/z : 654 [M+H]+ . | |
I-154 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.77 – 8.65 (m, 1H), 8.22 (s, 1H), 7.96 (d,J = 9.4 Hz, 1H), 7.51 (s, 1H), 6.83 (s, 1H), 3.84 (s, 3H), 3.74 – 3.67 (m, 1H), 3.62 – 3.39 (m, 8H), 3.37 – 3.34 (m, 5H), 3.26 – 3.16 (m, 1H), 2.99 – 2.91 (m, 5H), 2.28 – 2.17 (m, 2H), 2.10 (s, 3H), 2.04 – 1.90 (m, 2H), 1.31 – 1.16 (m, 1H), 1.08 – 0.91 (m, 1H), 0.49 – 0.36 (m, 1H), 0.34 – 0.21 (m, 1H). MS (ESI)m/z : 751 [M+H]+ . | |
I-155 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.72 – 8.56 (m, 1H), 8.24 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.57 (s, 1H), 6.85 (s, 1H), 3.85 (s, 3H), 3.73 – 3.65 (m, 1H), 3.51 – 3.33 (m, 8H), 3.33 (s, 3H), 3.27 – 3.19 (m, 2H), 3.15 – 3.09 (m, 1H), 3.00 – 2.90 (m, 2H), 2.89 (s, 3H), 2.59 – 2.47 (m, 1H), 2.47 – 2.37 (m, 1H), 2.24 – 2.11 (m, 2H), 1.97 – 1.84 (m, 2H), 1.27 – 1.18 (m, 1H), 1.04 – 0.94 (m, 1H), 0.90 – 0.75 (m, 3H), 0.46 – 0.35 (m, 1H), 0.32 – 0.22 (m, 1H). MS (ESI)m/z : 765 [M+H]+ . | |
I-156 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.67 (d,J = 9.4 Hz, 1H), 8.24 (s, 1H), 7.86 (d,J = 9.4 Hz, 1H), 7.57 (s, 1H), 7.06 (s, 1H), 3.75 – 3.64 (m, 1H), 3.39 – 3.23 (m, 11H), 3.20 – 3.14 (m, 2H), 3.07 – 2.93 (m, 1H), 2.84 (s, 3H), 2.80 – 2.73 (m, 2H), 2.63 – 2.50 (m, 2H), 2.16 – 2.09 (m, 2H), 1.92 – 1.79 (m, 2H), 1.29 – 1.22 (m, 1H), 1.02 – 0.88 (m, 4H), 0.44 – 0.33 (m, 1H), 0.33 – 0.19 (m, 1H). MS (ESI)m/z : 819 [M+H]+ . | |
I-157 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.90 – 8.74 (m, 1H), 8.48 (s, 1H), 8.31 (d,J = 2.2 Hz, 2H), 7.90 (d,J = 8.7 Hz, 1H), 7.40 (s, 1H), 6.82 (s, 1H), 3.78 (s, 3H), 3.65 – 3.54 (m, 1H), 3.38 (s, 3H), 3.33 – 3.23 (m, 1H), 3.12 (d,J = 10.7 Hz, 2H), 2.84 (s, 6H), 2.78 (t,J = 11.9 Hz, 2H), 2.55 (t,J = 7.3 Hz, 1H), 2.47 (t,J = 7.2 Hz, 1H), 2.16 – 2.00 (m, 2H), 1.88 – 1.77 (m, 2H), 1.28 – 1.17 (m, 1H), 1.01 – 0.96 (m, 1H), 0.95 – 0.84 (m, 3H), 0.47 – 0.37 (m, 1H), 0.31 – 0.21 (m, 1H). MS (ESI)m/z : 710 [M+H]+ . | |
I-158 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.76 – 8.62 (m, 1H), 8.20 (s, 1H), 7.94 (dd,J = 9.2, 1.9 Hz, 1H), 7.62 (d,J = 4.7 Hz, 1H), 6.80 (s, 1H), 4.04 – 3.97 (m, 1H), 3.84 (s, 3H), 3.71 – 3.64 (m, 1H), 3.44 – 3.36 (m, 2H), 3.33 (s, 3H), 3.30 – 3.26 (m, 1H), 3.15 – 3.04 (m, 1H), 3.00 – 2.94 (m, 6H), 2.56 – 2.37 (m, 3H), 2.25 – 2.12 (m, 1H), 1.30 – 1.23 (m, 1H), 1.01 – 0.94 (m, 1H), 0.87 – 0.74 (m, 3H), 0.43 – 0.34 (m, 1H), 0.34 – 0.25 (m, 1H). MS (ESI)m/z : 696 [M+H]+ . | |
I-159 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.70 (d,J = 10.5 Hz, 1H), 8.17 (s, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.54 (s, 1H), 6.86 (s, 1H), 3.87 (s, 3H), 3.77 – 3.68 (m, 1H), 3.65 – 3.42 (m, 8H), 3.41 – 3.35 (m, 5H), 3.31 – 3.21 (m, 1H), 3.05 – 2.91 (m, 5H), 2.29 – 2.17 (m, 2H), 2.12 (s, 3H), 2.07 – 1.92 (m, 2H), 1.28 – 1.12 (m, 1H), 1.05 – 0.95 (m, 1H), 0.53 – 0.39 (m, 1H), 0.38 – 0.25 (m, 1H). MS (ESI)m/z : 707 [M+H]+ . | |
I-160 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.53 (s, 1H), 6.87 (s, 1H), 3.85 (s, 3H), 3.72 – 3.66 (m, 1H), 3.65 – 3.44 (m, 8H), 3.35 (s, 3H), 3.30 – 3.21 (m, 3H), 3.03 – 2.90 (m, 5H), 2.58 – 2.48 (m, 1H), 2.49 – 2.40 (m, 1H), 2.29 – 2.15 (m, 2H), 2.06 – 1.89 (m, 2H), 1.23 – 1.07 (m, 1H), 1.04 – 0.94 (m, 1H), 0.94 – 0.75 (m, 3H), 0.46 – 0.35 (m, 1H), 0.32 – 0.23 (m, 1H). MS (ESI)m/z : 721 [M+H]+ . | |
I-161 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.62 (d,J = 9.1 Hz, 1H), 8.18 (s, 1H), 7.89 (d,J = 9.3 Hz, 1H), 7.57 (s, 1H), 7.15 – 7.02 (m, 1H), 3.71 – 3.64 (m, 1H), 3.63 – 3.43 (m, 8H), 3.35 (s, 3H), 3.27 – 3.15 (m, 3H), 2.93 (s, 3H), 2.86 – 2.76 (m, 2H), 2.66 – 2.49 (m, 2H), 2.28 – 2.15 (m, 2H), 2.02 – 1.87 (m, 2H), 1.26 – 1.11 (m, 1H), 1.04 – 0.90 (m, 4H), 0.46 – 0.34 (m, 1H), 0.30 – 0.21 (m, 1H). MS (ESI)m/z : 775 [M+H]+ . | |
I-162 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.67 – 8.49 (m, 1H), 8.21 (s, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.43 (s, 1H), 6.84 (s, 1H), 3.84 (s, 3H), 3.73 – 3.67 (m, 1H), 3.35 (s, 3H), 3.31 – 3.30 (m, 1H), 3.25 – 3.15 (m, 2H), 2.94 (s, 6H), 2.86 (t,J = 11.6 Hz, 2H), 2.57 – 2.41 (m, 2H), 2.27 – 2.12 (m, 2H), 2.00 – 1.83 (m, 2H), 1.19 – 1.10 (m, 1H), 1.04 – 0.94 (m, 1H), 0.95 – 0.72 (m, 3H), 0.47 – 0.35 (m, 1H), 0.32 – 0.22 (m, 1H). MS (ESI)m/z : 666 [M+H]+ . | |
I-163 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.7 Hz, 1H), 8.94 – 8.89 (m, 1H), 8.69 – 8.51 (m, 1H), 8.18 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.44 (d,J = 3.9 Hz, 1H), 6.81 (s, 1H), 4.10 – 3.97 (m, 1H), 3.85 (s, 3H), 3.72 – 3.63 (m, 1H), 3.49 – 3.40 (m, 2H), 3.37 – 3.35 (m, 1H), 3.32 (s, 3H), 3.20 – 3.08 (m, 1H), 2.98 (s, 6H), 2.59 – 2.39 (m, 3H), 2.30 – 2.17 (m, 1H), 1.21 – 1.12 (m, 1H), 1.02 – 0.94 (m, 1H), 0.93 – 0.77 (m, 3H), 0.47 – 0.34 (m, 1H), 0.34 – 0.22 (m, 1H). MS (ESI)m/z : 652 [M+H]+ . | |
I-164 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.7 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.64 – 8.35 (m, 1H), 8.21 – 8.07 (m, 1H), 8.07 – 7.95 (m, 1H), 7.47 – 7.40 (m, 1H), 6.37 – 6.18 (m, 1H), 4.58 – 4.40 (m, 2H), 3.82 (s, 3H), 3.68 – 3.56 (m, 8H), 3.50 – 3.46 (m, 1H), 3.43 (s, 3H), 3.12 (s, 3H), 2.93 (s, 3H), 2.91 – 2.84 (m, 2H), 2.27 – 2.07 (m, 2H), 1.84 – 1.62 (m, 2H). MS (ESI)m/z : 668 [M+H]+ . | |
I-165 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.7 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.68 – 8.52 (m, 1H), 8.22 (d,J = 6.0 Hz, 1H), 8.17 – 7.96 (m, 1H), 7.46 (s, 1H), 3.96 (s, 3H), 3.88 – 3.73 (m, 2H), 3.69 – 3.53 (m, 8H), 3.52 (s, 3H), 3.33 – 3.28 (m, 1H), 3.21 (s, 3H), 2.95 (s, 3H), 2.94 – 2.87 (m, 2H), 2.23 – 2.07 (m, 2H), 2.02 (s, 3H), 1.86 – 1.62 (m, 2H). MS (ESI)m/z : 682 [M+H]+ . | |
I-166 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.54 (d,J = 9.4 Hz, 1H), 8.21 (s, 1H), 7.99 (d,J = 9.4 Hz, 1H), 7.45 (d,J = 8.6 Hz, 1H), 7.03 – 6.95 (m, 2H), 3.95 – 3.88 (m, 2H), 3.68 – 3.53 (m, 8H), 3.45 (s, 3H), 3.38 – 3.34 (m, 1H), 3.17 (s, 3H), 2.97 (s, 3H), 2.92 (t,J = 12.4 Hz, 2H), 2.31 – 2.18 (m, 2H), 2.01 – 1.80 (m, 2H). MS (ESI)m/z : 721 [M+H]+ . | |
I-167 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.61 – 8.44 (m, 1H), 8.19 (s, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.60 (s, 1H), 6.84 (s, 1H), 3.84 (s, 3H), 3.45 (s, 3H), 3.44 – 3.32 (m, 8H), 3.18 (s, 3H), 3.16 – 3.13 (m, 3H), 2.94 – 2.86 (m, 5H), 2.38 – 2.23 (m, 2H), 2.18 – 2.08 (m, 2H), 1.97 – 1.76 (m, 2H), 0.75 – 0.52 (m, 1H), 0.36 – 0.11 (m, 2H), -0.08 – -0.30 (m, 2H). MS (ESI)m/z : 721 [M+H]+ . | |
I-168 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 (d,J = 1.8 Hz, 1H), 8.82 (d,J = 1.8 Hz, 1H), 8.48 – 8.37 (m, 1H), 8.18 (s, 1H), 7.99 (d,J = 9.4 Hz, 1H), 7.46 (s, 1H), 7.07 – 6.98 (m, 3H), 6.90 – 6.79 (m, 3H), 3.84 (s, 3H), 3.77 – 3.68 (m, 2H), 3.66 – 3.56 (m, 8H), 3.41 (s, 3H), 3.29 – 3.24 (m, 1H), 3.12 (s, 3H), 3.02 – 2.92 (m, 5H), 2.86 – 2.67 (m, 2H), 2.18 – 2.03 (m, 2H), 1.89 – 1.70 (m, 2H). MS (ESI)m/z : 757 [M+H]+ . | |
I-169 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.67 – 8.51 (m, 1H), 8.15 (s, 1H), 8.02 (d,J = 9.3 Hz, 1H), 7.33 (s, 1H), 6.74 (s, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 3.34 – 3.30 (m, 1H), 3.26 – 3.18 (m, 2H), 3.15 (s, 3H), 2.92 (s, 6H), 2.83 – 2.61 (m, 2H), 2.24 – 2.15 (m, 2H), 2.00 (br s, 3H), 1.94 – 1.85 (m, 2H). MS (ESI)m/z : 626 [M+H]+ . | |
I-170 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.51 – 8.38 (m, 1H), 8.15 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.32 (s, 1H), 6.76 (s, 1H), 3.79 (s, 3H), 3.41 (s, 3H), 3.33 – 3.28 (m, 1H), 3.17 – 3.08 (m, 5H), 2.89 (s, 6H), 2.85 – 2.71 (m, 2H), 2.48 – 2.25 (m, 2H), 2.18 – 2.08 (m, 2H), 1.92 – 1.78 (m, 2H), 0.92 – 0.70 (m, 3H). MS (ESI)m/z : 640 [M+H]+ . | |
I-171 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.62 – 8.42 (m, 1H), 8.13 (s, 1H), 7.98 (d,J = 9.6 Hz, 1H), 7.35 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.62 – 3.53 (m, 2H), 3.41 (s, 3H), 3.31 – 3.27 (m, 2H), 3.24 – 3.17 (m, 2H), 3.13 (s, 3H), 3.11 – 3.04 (m, 2H), 2.96 (s, 3H), 1.97 (s, 3H). MS (ESI)m/z : 598 [M+H]+ . | |
I-172 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.7 Hz, 1H), 8.66 – 8.52 (m, 1H), 8.18 (s, 1H), 8.02 (d,J = 9.3 Hz, 1H), 7.53 (s, 1H), 6.82 (s, 1H), 3.85 (s, 3H), 3.65 – 3.54 (m, 2H), 3.46 (s, 3H), 3.36 – 3.31 (m, 2H), 3.21 – 3.17 (m, 2H), 3.16 (s, 3H), 3.15 – 3.08 (m, 2H), 2.98 (s, 3H), 2.52 – 2.32 (m, 2H), 0.96 – 0.71 (m, 3H). MS (ESI)m/z : 612 [M+H]+ . | |
I-173 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.55 – 8.40 (m, 1H), 8.15 (br s, 1H), 8.07 – 7.96 (m, 1H), 7.20 (s, 1H), 6.68 (d,J = 1.7 Hz, 1H), 4.03 – 3.96 (m, 1H), 3.80 (s, 3H), 3.43 (s, 3H), 3.41 – 3.38 (m, 1H), 3.37 – 3.32 (m, 2H), 3.33 – 3.31 (m, 1H), 3.13 (s, 3H), 2.95 (s, 6H), 2.53 – 2.43 (m, 1H), 2.24 – 2.17 (m, 1H), 2.00 (br s, 3H). MS (ESI)m/z : 612 [M+H]+ . | |
I-174 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.7 Hz, 1H), 8.91 (d,J = 1.7 Hz, 1H), 8.61 – 8.43 (m, 1H), 8.18 (s, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.36 (s, 1H), 6.79 (s, 1H), 4.06 – 3.99 (m, 1H), 3.84 (s, 3H), 3.46 (s, 3H), 3.44 – 3.40 (m, 2H), 3.36 – 3.33 (m, 1H), 3.16 (s, 3H), 3.14 – 3.09 (m, 1H), 2.98 (s, 6H), 2.55 – 2.48 (m, 1H), 2.50 – 2.38 (m, 2H), 2.30 – 2.14 (m, 1H), 0.99 – 0.78 (m, 3H). MS (ESI)m/z : 626 [M+H]+ . | |
I-175 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.88 (d,J = 1.7 Hz, 1H), 8.84 (d,J = 1.8 Hz, 1H), 8.39 – 8.18 (m, 1H), 8.11 – 7.89 (m, 2H), 7.31 (d,J = 8.5 Hz, 1H), 6.35 – 6.04 (m, 1H), 4.56 – 4.36 (m, 2H), 3.75 (s, 3H), 3.68 – 3.52 (m, 8H), 3.50 – 3.44 (m, 1H), 3.38 (s, 3H), 3.01 (s, 3H), 2.88 (s, 3H), 2.85 – 2.72 (m, 2H), 2.21 – 2.06 (m, 2H), 1.78 – 1.58 (m, 2H). MS (ESI)m/z : 652 [M+H]+ . | |
I-176 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.8 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.32 (d,J = 9.3 Hz, 1H), 8.15 – 7.98 (m, 2H), 7.35 (s, 1H), 3.88 (s, 3H), 3.78 – 3.64 (m, 2H), 3.57 – 3.37 (m, 11H), 3.22 – 3.16 (m, 1H), 3.11 (s, 3H), 2.88 (s, 3H), 2.86 – 2.73 (m, 2H), 2.08 – 1.99 (m, 2H), 2.00 – 1.84 (m, 3H), 1.75 – 1.52 (m, 2H). MS (ESI)m/z : 666 [M+H]+ . | |
I-177 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.24 – 8.16 (m, 1H), 8.10 (d,J = 4.8 Hz, 1H), 8.04 (d,J = 9.1 Hz, 1H), 7.58 (s, 1H), 3.87 (s, 3H), 3.73 – 3.53 (m, 8H), 3.47 – 3.39 (m, 5H), 3.35 – 3.29 (m, 1H), 3.08 (s, 3H), 2.93 (s, 3H), 2.92 – 2.83 (m, 2H), 2.34 – 2.22 (m, 1H), 2.18 – 2.09 (m, 2H), 2.09 – 2.01 (m, 1H), 1.96 – 1.75 (m, 2H), 0.77 – 0.55 (m, 3H). MS (ESI)m/z : 680 [M+H]+ . | |
I-178 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.7 Hz, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.32 (d,J = 9.2 Hz, 1H), 8.13 (d,J = 4.7 Hz, 1H), 8.06 (d,J = 9.1 Hz, 1H), 7.37 (d,J = 9.0 Hz, 1H), 6.95 (s, 1H), 6.90 (d,J = 8.6 Hz, 1H), 3.97 – 3.85 (m, 2H), 3.69 – 3.53 (m, 8H), 3.45 (s, 3H), 3.13 (s, 3H), 2.97 (s, 3H), 2.88 (t,J = 13.1 Hz, 2H), 2.28 – 2.18 (m, 2H), 1.95 – 1.71 (m, 2H). MS (ESI)m/z : 705 [M+H]+ . | |
I-179 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 – 8.99 (m, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.19 (d,J = 4.9 Hz, 1H), 8.12 (d,J = 9.2 Hz, 1H), 8.01 (d,J = 9.2 Hz, 1H), 7.35 (s, 1H), 7.03 (s, 1H), 3.86 – 3.68 (m, 8H), 3.49 – 3.45 (m, 1H), 3.43 (s, 3H), 3.11 (s, 3H), 3.11 – 3.06 (m, 2H), 3.02 (s, 3H), 2.82 – 2.65 (m, 2H), 2.53 – 2.36 (m, 1H), 2.38 – 2.23 (m, 2H), 2.19 (s, 1H), 2.03 – 1.87 (m, 2H), 0.87 – 0.60 (m, 3H). MS (ESI)m/z : 733 [M+H]+ . | |
I-180 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.28 (d,J = 9.3 Hz, 1H), 8.16 (d,J = 4.3 Hz, 1H), 7.91 (d,J = 9.2 Hz, 1H), 7.70 (s, 1H), 6.98 (s, 1H), 6.72 (dd,J = 17.7, 11.0 Hz, 1H), 5.21 (d,J = 17.7 Hz, 1H), 4.85 (d,J = 11.0 Hz, 1H), 3.67 – 3.48 (m, 8H), 3.43 (s, 3H), 3.27 – 3.19 (m, 3H), 3.13 (s, 3H), 2.96 (s, 3H), 2.72 (td,J = 11.8, 2.2 Hz, 2H), 2.23 – 2.12 (m, 2H), 2.03 – 1.80 (m, 2H). MS (ESI)m/z : 731 [M+H]+ . | |
I-181 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 – 8.89 (m, 1H), 8.90 – 8.84 (m, 1H), 8.24 – 8.11 (m, 1H), 8.08 – 8.01 (m, 1H), 7.99 (d,J = 9.1 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 3.74 (s, 3H), 3.70 – 3.51 (m, 8H), 3.37 (s, 3H), 3.34 – 3.26 (m, 1H), 3.08 – 3.03 (m, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 2.75 (dt,J = 25.4, 11.7 Hz, 2H), 2.27 – 2.04 (m, 3H), 1.97 – 1.73 (m, 3H), 0.55 – 0.33 (m, 1H), 0.24 – 0.00 (m, 2H), -0.13 – -0.41 (m, 2H). MS (ESI)m/z : 705 [M+H]+ . | |
I-182 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.29 (d,J = 9.2 Hz, 1H), 8.13 (d,J = 4.7 Hz, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.12 – 6.95 (m, 3H), 6.89 – 6.77 (m, 3H), 3.84 (s, 3H), 3.74 – 3.61 (m, 2H), 3.59 – 3.46 (m, 8H), 3.42 (s, 3H), 3.23 – 3.15 (m, 1H), 3.09 (s, 3H), 2.99 – 2.88 (m, 5H), 2.82 – 2.66 (m, 2H), 2.11 – 1.98 (m, 2H), 1.85 – 1.68 (m, 2H). MS (ESI)m/z : 741 [M+H]+ . | |
I-183 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.23 (s, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.57 (d,J = 9.3 Hz, 1H), 8.47 (s, 1H), 8.27 (d,J = 3.7 Hz, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 3.78 (s, 3H), 3.35 (s, 3H), 3.31 – 3.25 (m, 1H), 3.18 (s, 3H), 3.15 – 3.08 (m, 2H), 2.82 (s, 6H), 2.71 – 2.61 (m, 2H), 2.18 – 2.03 (m, 2H), 1.91 (s, 3H), 1.83 – 1.71 (m, 2H). MS (ESI)m/z : 610 [M+H]+ . | |
I-184 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.57 – 9.41 (m, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.62 (s, 1H), 8.46 (d,J = 9.1 Hz, 1H), 8.31 (d,J = 3.9 Hz, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.41 (s, 1H), 6.74 (s, 1H), 3.78 (s, 3H), 3.33 (s, 3H), 3.30 – 3.23 (m, 1H), 3.16 (s, 3H), 3.09 – 2.97 (m, 2H), 2.82 (s, 6H), 2.77 – 2.65 (m, 2H), 2.41 – 2.29 (m, 1H), 2.27 – 2.15 (m, 1H), 2.13 – 2.05 (m, 2H), 1.86 – 1.63 (m, 2H), 0.88 – 0.61 (m, 3H). MS (ESI)m/z : 624 [M+H]+ . | |
I-185 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.41 (d,J = 9.9 Hz, 1H), 8.21 – 7.99 (m, 2H), 7.37 (s, 1H), 6.76 (s, 1H), 3.84 (s, 3H), 3.69 – 3.56 (m, 2H), 3.47 (s, 3H), 3.36 – 3.32 (m, 2H), 3.24 – 3.18 (m, 2H), 3.14 (s, 3H), 3.13 – 3.05 (m, 2H), 2.99 (s, 3H), 1.93 (s, 3H). MS (ESI)m/z : 582 [M+H]+ . | |
I-186 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.27 (d,J = 9.1 Hz, 1H), 8.14 (d,J = 4.8 Hz, 1H), 8.09 (d,J = 9.1 Hz, 1H), 7.35 (s, 1H), 6.81 (s, 1H), 3.85 (s, 3H), 3.65 – 3.53 (m, 2H), 3.46 (s, 3H), 3.30 – 3.26 (m, 2H), 3.17 – 3.10 (m, 7H), 2.98 (s, 3H), 2.47 – 2.31 (m, 1H), 2.28 – 2.09 (m, 1H), 0.90 – 0.50 (m, 3H). MS (ESI)m/z : 596 [M+H]+ . | |
I-187 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.37 (d,J = 9.5 Hz, 1H), 8.10 (d,J = 7.9 Hz, 2H), 7.21 (s, 1H), 6.69 (s, 1H), 4.05 – 3.96 (m, 1H), 3.83 (s, 3H), 3.48 (d,J = 2.9 Hz, 3H), 3.47 – 3.44 (m, 1H), 3.42 – 3.34 (m, 2H), 3.20 – 3.13 (m, 3H), 3.11 (t,J = 8.7 Hz, 1H), 3.03 – 2.94 (m, 6H), 2.57 – 2.44 (m, 1H), 2.30 – 2.16 (m, 1H), 1.96 (s, 3H). MS (ESI)m/z : 596 [M+H]+ . | |
I-188 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.7 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.34 – 8.22 (m, 1H), 8.19 – 8.04 (m, 2H), 7.23 (d,J = 5.9 Hz, 1H), 6.76 (s, 1H), 4.07 – 3.97 (m, 1H), 3.83 (s, 3H), 3.47 (s, 3H), 3.44 – 3.38 (m, 2H), 3.29 – 3.25 (m, 1H), 3.12 (s, 3H), 3.10 – 3.05 (m, 1H), 3.03 – 2.94 (m, 6H), 2.56 – 2.33 (m, 2H), 2.31 – 2.14 (m, 2H), 0.93 – 0.60 (m, 3H). MS (ESI)m/z : 610 [M+H]+ . | |
I-189 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.59 (s, 1H), 9.24 (s, 1H), 8.85 (s, 2H), 8.83 (d,J = 9.7 Hz, 1H), 8.50 (s, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.83 (s, 1H), 3.91 (s, 3H), 3.80 – 3.60 (m, 8H), 3.61 – 3.51 (m, 2H), 3.48 (s, 3H), 3.35 – 3.27 (m, 1H), 3.16 (s, 3H), 3.00 – 2.82 (m, 5H), 2.22 – 2.11 (m, 2H), 2.12 – 1.94 (m, 5H). MS (ESI)m/z : 693 [M+H]+ . | |
I-190 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.94 (s, 1H), 9.17 (s, 1H), 9.01 (s, 1H), 8.96 (s, 1H), 8.52 (d,J = 9.4 Hz, 1H), 7.72 (d,J = 9.4 Hz, 1H), 7.57 (s, 1H), 3.83 (s, 3H), 3.68 – 3.50 (m, 8H), 3.47 – 3.43 (m, 2H), 3.37 (s, 3H), 3.28 – 3.26 (m, 1H), 3.22 (s, 3H), 2.93 – 2.89 (m, 2H), 2.87 (s, 3H), 2.47 – 2.34 (m, 2H), 2.18 – 2.09 (m, 2H), 1.86 – 1.76 (m, 2H), 0.92 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 707 [M+H]+ . | |
I-191 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.13 – 9.05 (m, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.89 – 8.79 (m, 1H), 8.56 (d,J = 9.2 Hz, 1H), 7.80 (d,J = 9.3 Hz, 1H), 7.71 – 7.64 (m, 1H), 6.83 (s, 1H), 3.82 (s, 3H), 3.66 – 3.41 (m, 11H), 3.26 – 3.16 (m, 6H), 2.98 – 2.88 (m, 5H), 2.39 – 2.28 (m, 1H), 2.26 – 2.11 (m, 3H), 1.97 – 1.79 (m, 2H), 0.49 – 0.33 (m, 1H), 0.14 – 0.01 (m, 2H), -0.27 – -0.48 (m, 2H). MS (ESI)m/z : 732 [M+H]+ . | |
I-192 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.08 (s, 1H), 9.85 (s, 1H), 9.14 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.64 (d,J = 9.4 Hz, 1H), 7.73 (d,J = 9.4 Hz, 1H), 7.20 (s, 1H), 6.82 (s, 1H), 3.77 (s, 3H), 3.36 (s, 3H), 3.29 – 3.23 (m, 3H), 3.20 (s, 3H), 2.88 – 2.83 (m, 6H), 2.80 – 2.71 (m, 2H), 2.20 – 2.13 (m, 2H), 2.08 (s, 3H), 1.92 – 1.77 (m, 2H). MS (ESI)m/z : 637 [M+H]+ . | |
I-193 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.42 (s, 1H), 9.17 (s, 1H), 8.93 – 8.84 (m, 2H), 8.67 (d,J = 9.4 Hz, 1H), 8.17 (s, 1H), 8.00 (d,J = 9.4 Hz, 1H), 7.79 (s, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 3.50 (s, 3H), 3.35 – 3.21 (m, 2H), 3.17 (s, 3H), 2.84 (s, 6H), 2.81 – 2.78 (m, 1H), 2.77 – 2.63 (m, 4H), 2.21 – 2.07 (m, 2H), 2.01 – 1.90 (m, 2H), 0.75 – 0.48 (m, 3H). MS (ESI)m/z : 651 [M+H]+ . | |
I-194 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.54 (s, 1H), 9.15 (s, 1H), 8.94 – 8.84 (m, 3H), 8.19 – 7.99 (m, 2H), 7.85 (s, 1H), 6.64 (s, 1H), 3.87 (s, 3H), 3.72 – 3.64 (m, 2H), 3.51 (s, 3H), 3.34 – 3.26 (m, 2H), 3.18 (s, 3H), 3.17 – 3.01 (m, 4H), 2.90 (s, 3H), 1.96 (s, 3H). MS (ESI)m/z : 609 [M+H]+ . | |
I-195 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.50 (s, 1H), 9.08 (d,J = 14.5 Hz, 1H), 8.96 – 8.78 (m, 3H), 8.12 (s, 1H), 8.07 – 8.00 (m, 1H), 7.76 (s, 1H), 6.57 (s, 1H), 3.90 – 3.80 (m, 3H), 3.50 (s, 3H), 3.43 – 3.32 (m, 2H), 3.18 (s, 3H), 3.11 – 3.04 (m, 1H), 2.96 – 2.88 (m, 6H), 2.82 – 2.68 (m, 2H), 2.45 – 2.37 (m, 1H), 2.35 – 2.26 (m, 1H), 2.01 – 1.92 (m, 3H). MS (ESI)m/z : 623 [M+H]+ . | |
I-196 | 1 H NMR (600 MHz, Chloroform-d ) δ 11.40 (d,J = 3.3 Hz, 1H), 9.12 (d,J = 6.8 Hz, 1H), 8.88 (d,J = 7.5 Hz, 2H), 8.77 – 8.62 (m, 1H), 8.22 (s, 1H), 8.05 – 7.97 (m, 1H), 7.73 (s, 1H), 6.67 (s, 1H), 3.90 – 3.80 (m, 3H), 3.49 (s, 3H), 3.43 – 3.29 (m, 4H), 3.16 (s, 3H), 3.12 – 3.06 (m, 1H), 2.90 (d,J = 8.6 Hz, 6H), 2.47 – 2.16 (m, 4H), 0.56 (t,J = 8.3 Hz, 3H). MS (ESI)m/z : 637 [M+H]+ . | |
I-197 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 – 8.94 (m, 1H), 8.94 – 8.88 (m, 1H), 8.50 – 8.20 (m, 2H), 8.07 – 7.79 (m, 1H), 7.52 (s, 1H), 6.43 – 6.07 (m, 1H), 4.56 – 4.36 (m, 2H), 3.86 (s, 3H), 3.66 – 3.49 (m, 8H), 3.46 – 3.43 (m, 1H), 3.42 (s, 3H), 3.14 (s, 3H), 2.94 (s, 3H), 2.93 – 2.89 (m, 2H), 2.23 – 2.10 (m, 2H), 1.80 – 1.65 (m, 2H). MS (ESI)m/z : 702 [M+H]+ . | |
I-198 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 – 8.93 (m, 1H), 8.91 – 8.83 (m, 1H), 8.51 – 8.38 (m, 1H), 7.94 – 7.75 (m, 1H), 7.45 (s, 1H), 3.93 (s, 3H), 3.83 – 3.70 (m, 2H), 3.66 – 3.48 (m, 8H), 3.46 – 3.39 (m, 3H), 3.33 – 3.28 (m, 1H), 3.17 (s, 3H), 2.93 (s, 3H), 2.92 – 2.82 (m, 2H), 2.05 (t,J = 16.1 Hz, 3H), 1.99 – 1.82 (m, 2H), 1.77 – 1.66 (m, 2H). MS (ESI)m/z : 716 [M+H]+ . | |
I-199 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.51 – 8.21 (m, 2H), 8.12 – 7.93 (m, 1H), 7.87 – 7.66 (m, 1H), 3.92 (s, 3H), 3.74 – 3.57 (m, 8H), 3.51 – 3.47 (m, 2H), 3.43 (s, 3H), 3.37 – 3.33 (m, 1H), 3.14 (s, 3H), 3.03 – 2.99 (m, 2H), 2.97 (s, 3H), 2.39 – 2.17 (m, 4H), 2.06 – 1.89 (m, 2H), 1.02 – 0.34 (m, 3H). MS (ESI)m/z : 730 [M+H]+ . | |
I-200 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.57 – 8.45 (m, 1H), 8.39 (s, 1H), 7.96 – 7.85 (m, 1H), 7.43 (d,J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.93 (d,J = 10.9 Hz, 1H), 3.94 – 3.82 (m, 2H), 3.66 – 3.47 (m, 8H), 3.40 (s, 3H), 3.30 – 3.26 (m, 1H), 3.15 (s, 3H), 2.96 (s, 3H), 2.90 (ddd,J = 12.7, 9.9, 3.0 Hz, 2H), 2.28 – 2.18 (m, 2H), 1.93 – 1.83 (m, 2H). MS (ESI)m/z : 755 [M+H]+ . | |
I-201 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.44 (s, 1H), 8.40 – 8.21 (m, 1H), 7.99 – 7.79 (m, 1H), 7.44 (s, 1H), 7.05 (s, 1H), 3.77 – 3.61 (m, 8H), 3.41 (s, 3H), 3.40 – 3.36 (m, 1H), 3.20 – 3.16 (m, 2H), 3.14 (s, 3H), 3.00 (s, 3H), 2.90 – 2.67 (m, 2H), 2.55 – 2.39 (m, 2H), 2.33 – 2.15 (m, 2H), 2.07 – 1.88 (m, 2H), 1.03 – 0.71 (m, 3H). MS (ESI)m/z : 783 [M+H]+ . | |
I-202 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.44 (s, 1H), 8.39 – 8.17 (m, 1H), 7.87 – 7.75 (m, 1H), 7.68 (s, 1H), 6.99 (s, 1H), 6.88 – 6.67 (m, 1H), 5.43 – 5.04 (m, 2H), 3.82 – 3.60 (m, 8H), 3.42 (s, 3H), 3.39 – 3.34 (m, 2H), 3.34 – 3.32 (m, 1H), 3.14 (s, 3H), 3.00 (s, 3H), 2.83 – 2.70 (m, 2H), 2.33 – 2.19 (m, 2H), 2.07 – 1.90 (m, 2H). MS (ESI)m/z : 781 [M+H]+ . | |
I-203 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.40 (s, 2H), 7.95 (s, 1H), 7.55 (s, 1H), 6.80 (s, 1H), 3.81 (s, 3H), 3.67 – 3.47 (m, 8H), 3.40 (s, 3H), 3.31 – 3.28 (m, 1H), 3.19 – 3.11 (m, 2H), 3.09 (s, 3H), 2.93 (s, 3H), 2.91 – 2.81 (m, 2H), 2.30 – 1.98 (m, 4H), 1.96 – 1.79 (m, 2H), 0.51 – 0.23 (m, 1H), 0.20 – -0.08 (m, 2H), -0.02 – -0.69 (m, 2H). MS (ESI)m/z : 755 [M+H]+ . | |
I-204 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.89 – 8.84 (m, 1H), 8.81 – 8.77 (m, 1H), 8.48 – 8.28 (m, 2H), 8.05 – 7.87 (m, 1H), 7.57 (s, 1H), 7.07 – 6.90 (m, 3H), 6.83 (s, 1H), 6.80 – 6.49 (m, 2H), 3.84 (s, 3H), 3.57 – 3.40 (m, 8H), 3.35 (s, 3H), 3.17 – 3.12 (m, 1H), 3.10 (s, 3H), 3.04 – 2.99 (m, 1H), 2.91 (s, 3H), 2.88 – 2.81 (m, 1H), 2.81 – 2.64 (m, 2H), 2.13 – 1.95 (m, 2H), 1.84 – 1.65 (m, 2H). MS (ESI)m/z : 791 [M+H]+ . | |
I-205 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.58 – 8.27 (m, 2H), 8.12 – 7.93 (m, 1H), 7.33 (s, 1H), 6.74 (s, 1H), 3.82 (s, 3H), 3.43 (s, 3H), 3.38 – 3.34 (m, 1H), 3.28 – 3.20 (m, 2H), 3.14 (s, 3H), 2.94 (s, 6H), 2.85 – 2.73 (m, 2H), 2.26 – 2.16 (m, 2H), 2.09 – 1.70 (m, 5H). MS (ESI)m/z : 660 [M+H]+ . | |
I-206 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.62 – 8.26 (m, 2H), 8.10 – 7.86 (m, 1H), 7.40 (s, 1H), 6.79 (s, 1H), 3.83 (s, 3H), 3.43 (s, 3H), 3.37 – 3.33 (m, 1H), 3.21 – 3.09 (m, 5H), 2.99 – 2.91 (m, 6H), 2.82 (t,J = 11.0 Hz, 2H), 2.45 – 2.10 (m, 4H), 2.00 – 1.83 (m, 2H), 1.07 – 0.25 (m, 3H). MS (ESI)m/z : 674 [M+H]+ . | |
I-207 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.60 – 8.45 (m, 1H), 8.40 (s, 1H), 8.05 – 7.93 (m, 1H), 7.46 (s, 1H), 6.76 (s, 1H), 3.84 (s, 3H), 3.64 – 3.54 (m, 2H), 3.43 (s, 3H), 3.36 – 3.32 (m, 2H), 3.28 – 3.20 (m, 2H), 3.15 (s, 3H), 3.12 – 3.05 (m, 2H), 2.99 (s, 3H), 2.10 – 1.74 (m, 3H). MS (ESI)m/z : 632 [M+H]+ . | |
I-208 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.51 – 8.29 (m, 2H), 8.06 – 7.89 (m, 1H), 7.51 (s, 1H), 6.81 (s, 1H), 3.85 (s, 3H), 3.67 – 3.54 (m, 2H), 3.44 (s, 3H), 3.31 – 3.26 (m, 2H), 3.21 – 3.11 (m, 7H), 2.99 (s, 3H), 2.58 – 2.08 (m, 2H), 1.14 – 0.33 (m, 3H). MS (ESI)m/z : 646 [M+H]+ . | |
I-209 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.92 (d,J = 1.7 Hz, 1H), 8.56 – 8.24 (m, 2H), 8.08 – 7.87 (m, 1H), 7.27 (s, 1H), 6.70 (s, 1H), 4.08 – 3.99 (m, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.42 – 3.33 (m, 3H), 3.14 (s, 4H), 3.05 – 2.95 (m, 6H), 2.57 – 2.44 (m, 1H), 2.32 – 2.19 (m, 1H), 2.13 – 1.59 (m, 3H). MS (ESI)m/z : 646 [M+H]+ . | |
I-210 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.54 – 8.39 (m, 1H), 8.37 – 8.20 (m, 1H), 8.11 – 7.86 (m, 1H), 7.33 (s, 1H), 6.78 (s, 1H), 4.08 – 3.96 (m, 1H), 3.84 (s, 3H), 3.59 – 3.38 (m, 6H), 3.13 (s, 3H), 3.11 – 3.06 (m, 1H), 2.98 (s, 6H), 2.62 – 2.09 (m, 4H), 1.16 – 0.39 (m, 3H). MS (ESI)m/z : 660 [M+H]+ . | |
I-211 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.80 (d,J = 9.4 Hz, 1H), 8.30 (s, 1H), 8.11 (d,J = 9.4 Hz, 1H), 7.86 (d,J = 8.6 Hz, 1H), 7.06 (d,J = 2.4 Hz, 1H), 6.89 (dd,J = 8.9, 2.5 Hz, 1H), 4.17 (dq,J = 14.6, 7.3 Hz, 1H), 3.93 (s, 3H), 3.91 – 3.81 (m, 3H), 3.45 (s, 4H), 3.38 – 3.35 (m, 2H), 3.21 (s, 7H), 3.13 – 3.07 (m, 1H), 2.94 (s, 3H), 2.31 – 2.19 (m, 2H), 2.02 (qd,J = 12.2, 3.9 Hz, 2H), 1.04 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 725 [M+H]+ . | |
I-212 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.62 – 8.47 (m, 1H), 8.26 (s, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.80 (s, 1H), 4.17 – 4.06 (m, 1H), 3.90 (s, 3H), 3.82 – 3.75 (m, 1H), 3.64 – 3.49 (m, 10H), 3.28 (p,J = 1.6 Hz, 1H), 3.13 (s, 3H), 3.05 – 2.98 (m, 2H), 2.93 (s, 3H), 2.49 – 2.32 (m, 2H), 2.22 – 2.13 (m, 2H), 1.99 – 1.88 (m, 2H), 0.97 (t,J = 7.1 Hz, 3H), 0.89 – 0.73 (m, 3H). MS (ESI)m/z : 754 [M+H]+ . | |
I-213 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.71 – 8.58 (m, 1H), 8.24 (s, 1H), 7.98 (d,J = 9.4 Hz, 1H), 7.73 (s, 1H), 6.83 (s, 1H), 4.13 (dq,J = 14.5, 7.3 Hz, 1H), 3.84 (s, 3H), 3.77 (dq,J = 13.9, 7.0 Hz, 1H), 3.46 – 3.29 (m, 8H), 3.23 – 3.18 (m, 2H), 3.14 (s, 3H), 3.08 – 3.00 (m, 1H), 2.97 – 2.86 (m, 2H), 2.85 (s, 3H), 2.47 (dd,J = 14.6, 6.7 Hz, 1H), 2.28 – 2.16 (m, 1H), 2.16 – 2.07 (m, 2H), 1.94 – 1.74 (m, 2H), 1.01 (t,J = 7.2 Hz, 3H), 0.57 – 0.48 (m, 1H), 0.20 – 0.00 (m, 2H), -0.12 – -0.32 (m, 2H). MS (ESI)m/z : 779 [M+H]+ . | |
I-214 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.68 (d,J = 9.4 Hz, 1H), 8.26 (s, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.75 (d,J = 8.8 Hz, 1H), 7.01 (d,J = 2.4 Hz, 1H), 6.86 – 6.75 (m, 1H), 3.90 (s, 3H), 3.87 – 3.80 (m, 2H), 3.58 – 3.34 (m, 9H), 3.30 – 3.15 (m, 6H), 3.12 – 3.04 (m, 1H), 2.93 (s, 3H), 2.28 – 2.17 (m, 2H), 2.04 – 1.93 (m, 2H), 1.43 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 725 [M+H]+ . | |
I-215 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.65 (d,J = 9.5 Hz, 1H), 8.23 (s, 1H), 8.05 (d,J = 9.3 Hz, 1H), 7.70 (d,J = 8.9 Hz, 1H), 6.97 (d,J = 2.5 Hz, 1H), 6.78 (dd,J = 8.9, 2.5 Hz, 1H), 3.87 (s, 3H), 3.84 – 3.75 (m, 2H), 3.49 (s, 3H), 3.47 – 3.34 (m, 4H), 3.28 – 3.15 (m, 6H), 3.13 – 3.05 (m, 1H), 2.91 (s, 3H), 2.87 (td,J = 8.0, 4.0 Hz, 1H), 2.30 – 2.14 (m, 2H), 2.02 – 1.87 (m, 2H), 1.23 – 1.07 (m, 2H), 0.75 – 0.63 (m, 2H). MS (ESI)m/z : 737 [M+H]+ . | |
I-216 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.68 (m, 1H), 8.20 (s, 1H), 8.10 – 7.96 (m, 1H), 7.56 (d,J = 8.5 Hz, 1H), 6.32 (d,J = 8.7 Hz, 1H), 4.53 – 4.44 (m, 2H), 3.87 (s, 3H), 3.51 (s, 3H), 3.29 – 3.11 (m, 6H), 3.09 – 3.04 (m, 1H), 2.97 – 2.86 (m, 5H), 2.83 (s, 3H), 2.16 – 2.04 (m, 2H), 1.72 – 1.61 (m, 2H), 1.23 – 1.16 (m, 2H), 0.77 – 0.62 (m, 2H). MS (ESI)m/z : 738 [M+H]+ . | |
I-217 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.86 (d,J = 1.8 Hz, 1H), 8.63 (s, 1H), 8.23 (s, 1H), 8.00 – 7.85 (m, 1H), 7.45 (s, 1H), 3.93 (s, 3H), 3.83 – 3.70 (m, 2H), 3.51 (s, 3H), 3.46 – 3.30 (m, 8H), 3.16 – 3.07 (m, 1H), 2.96 – 2.83 (m, 6H), 2.11 – 1.94 (m, 5H), 1.72 – 1.57 (m, 2H), 1.28 – 1.13 (m, 2H), 0.78 – 0.60 (m, 2H). MS (ESI)m/z : 752 [M+H]+ . | |
I-218 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.59 – 8.45 (m, 1H), 8.27 (s, 1H), 8.02 (d,J = 9.3 Hz, 1H), 7.77 (s, 1H), 3.93 (s, 3H), 3.68 – 3.41 (m, 13H), 3.29 (d,J = 14.8 Hz, 1H), 3.01 (t,J = 12.6 Hz, 2H), 2.94 (s, 3H), 2.89 – 2.84 (m, 1H), 2.49 – 2.33 (m, 2H), 2.24 – 2.14 (m, 2H), 1.94 (dt,J = 12.1, 3.0 Hz, 2H), 1.22 – 1.13 (m, 2H), 0.97 – 0.77 (m, 3H), 0.76 – 0.63 (m, 2H). MS (ESI)m/z : 766 [M+H]+ . | |
I-219 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.60 – 8.52 (m, 1H), 8.27 (s, 1H), 7.83 (d,J = 9.5 Hz, 1H), 7.77 (s, 1H), 7.01 (s, 1H), 6.88 (dd,J = 17.7, 11.0 Hz, 1H), 5.39 (d,J = 17.8 Hz, 1H), 5.02 – 5.01 (m, 1H), 3.48 (s, 3H), 3.45 – 3.35 (m, 8H), 3.10 – 3.03 (m, 1H), 2.89 (d,J = 4.9 Hz, 6H), 2.74 (t,J = 11.9 Hz, 2H), 2.18 – 2.08 (m, 2H), 1.95 – 1.84 (m, 2H), 1.24 – 1.12 (m, 2H), 0.76 – 0.63 (m, 2H). MS (ESI)m/z : 817 [M+H]+ . | |
I-220 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.62 – 8.39 (m, 1H), 8.22 (s, 1H), 7.97 (d,J = 9.1 Hz, 1H), 7.60 (s, 1H), 6.82 (s, 1H), 3.82 (s, 3H), 3.53 – 3.39 (m, 11H), 3.21 – 3.13 (m, 3H), 2.90 – 2.88 (m, 3H), 2.88 – 2.80 (m, 3H), 2.39 – 2.32 (m, 1H), 2.23 (s, 1H), 2.19 – 2.08 (m, 2H), 1.94 – 1.81 (m, 2H), 1.21 – 1.11 (m, 2H), 0.73 – 0.63 (m, 2H), 0.63 – 0.46 (m, 1H), 0.30 – 0.11 (m, 2H), -0.04 – -0.36 (m, 2H). MS (ESI)m/z : 791 [M+H]+ . | |
I-221 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.65 – 8.38 (m, 1H), 8.29 – 8.14 (m, 1H), 8.06 – 7.91 (m, 1H), 7.24 (s, 1H), 6.73 (s, 1H), 3.79 (s, 3H), 3.48 (s, 3H), 3.33 – 3.30 (m, 1H), 3.25 – 3.19 (m, 2H), 2.91 (s, 6H), 2.87 – 2.82 (m, 1H), 2.79 – 2.68 (m, 2H), 2.25 – 2.12 (m, 2H), 1.99 (br s, 3H), 1.94 – 1.82 (m, 2H), 1.23 – 1.08 (m, 2H), 0.75 – 0.54 (m, 2H). MS (ESI)m/z : 696 [M+H]+ . | |
I-222 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.68 – 8.54 (m, 1H), 8.23 (s, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.33 (s, 1H), 6.72 (d,J = 1.6 Hz, 1H), 4.08 – 3.99 (m, 1H), 3.84 (s, 3H), 3.51 (s, 3H), 3.50 – 3.46 (m, 1H), 3.45 – 3.36 (m, 2H), 3.18 – 3.08 (m, 1H), 2.99 (s, 6H), 2.92 – 2.83 (m, 1H), 2.54 – 2.46 (m, 1H), 2.29 – 2.18 (m, 1H), 2.07 (br s, 3H), 1.24 – 1.13 (m, 2H), 0.77 – 0.63 (m, 2H). MS (ESI)m/z : 682 [M+H]+ . | |
I-223 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 – 8.93 (m, 1H), 8.83 – 8.81 (m, 1H), 8.79 (d,J = 9.5 Hz, 1H), 8.21 (d,J = 2.0 Hz, 1H), 7.97 (dd,J = 9.4, 2.0 Hz, 1H), 7.86 (d,J = 7.8 Hz, 1H), 7.05 (s, 1H), 6.88 (d,J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.85 – 3.80 (m, 2H), 3.73 – 3.67 (m, 1H), 3.57 – 3.32 (m, 10H), 3.28 – 3.12 (m, 3H), 3.11 – 3.04 (m, 1H), 2.93 (s, 3H), 2.28 – 2.17 (m, 2H), 2.02 (td,J = 14.3, 7.1 Hz, 2H), 1.32 – 1.21 (m, 1H), 1.00 (ddd,J = 9.2, 6.2, 2.3 Hz, 1H), 0.42 (ddd,J = 9.6, 5.1, 2.2 Hz, 1H), 0.33 – 0.20 (m, 1H). MS (ESI)m/z : 737 [M+H]+ . | |
I-224 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.9 Hz, 1H), 8.87 – 8.81 (m, 1H), 8.74 (d,J = 9.4 Hz, 1H), 8.18 (s, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.78 (d,J = 8.8 Hz, 1H), 7.03 (d,J = 2.5 Hz, 1H), 6.86 (dd,J = 8.9, 2.5 Hz, 1H), 4.14 (dq,J = 14.6, 7.4 Hz, 1H), 3.90 (s, 3H), 3.88 – 3.83 (m, 2H), 3.83 – 3.77 (m, 1H), 3.63 – 3.48 (m, 4H), 3.45 – 3.31 (m, 6H), 3.27 – 3.23 (m, 1H), 3.20 (s, 3H), 2.97 (s, 3H), 2.35 – 2.22 (m, 2H), 2.06 (td,J = 12.3, 3.9 Hz, 2H), 1.06 – 0.99 (m, 3H). MS (ESI)m/z : 681 [M+H]+ . | |
I-225 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.8 Hz, 1H), 8.79 (d,J = 41.4 Hz, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.68 – 7.59 (m, 1H), 6.38 (d,J = 8.5 Hz, 1H), 4.61 – 4.50 (m, 2H), 4.23 – 4.10 (m, 1H), 3.89 (s, 3H), 3.86 – 3.80 (m, 1H), 3.69 – 3.48 (m, 8H), 3.45 – 3.41 (m, 1H), 3.19 (s, 3H), 3.03 – 2.93 (m, 5H), 2.31 – 2.10 (m, 2H), 1.86 – 1.71 (m, 2H), 1.03 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 682 [M+H]+ . | |
I-226 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.8 Hz, 1H), 8.84 – 8.70 (m, 1H), 8.21 (s, 1H), 8.09 – 7.92 (m, 1H), 7.52 (s, 1H), 4.19 – 4.08 (m, 1H), 3.97 (s, 3H), 3.90 – 3.78 (m, 3H), 3.56 – 3.37 (m, 8H), 3.23 – 3.17 (m, 4H), 2.96 – 2.87 (m, 5H), 2.07 (s, 3H), 2.02 (d,J = 18.1 Hz, 2H), 1.78 – 1.61 (m, 2H), 1.04 (t,J = 7.1 Hz, 3H). MS (ESI)m/z : 696 [M+H]+ . | |
I-227 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.71 – 8.55 (m, 1H), 8.21 (s, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.88 (s, 1H), 4.13 (dq,J = 14.5, 7.3 Hz, 1H), 3.94 (s, 3H), 3.81 (dq,J = 13.9, 7.0 Hz, 1H), 3.69 – 3.48 (m, 10H), 3.35 – 3.32 (m, 1H), 3.17 (s, 3H), 3.05 (q,J = 11.9 Hz, 2H), 2.96 (s, 3H), 2.55 – 2.45 (m, 1H), 2.45 – 2.38 (m, 1H), 2.26 – 2.13 (m, 2H), 2.05 – 1.91 (m, 2H), 1.00 (t,J = 7.2 Hz, 3H), 0.90 – 0.74 (m, 3H). MS (ESI)m/z : 710 [M+H]+ . | |
I-228 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.60 – 8.42 (m, 1H), 8.25 (s, 1H), 7.86 (d,J = 9.4 Hz, 1H), 7.78 (s, 1H), 7.05 – 6.99 (m, 1H), 6.92 (dd,J = 17.7, 11.1 Hz, 1H), 5.43 (d,J = 17.6 Hz, 1H), 5.07 (d,J = 11.1 Hz, 1H), 4.18 – 4.08 (m, 1H), 3.82 – 3.77 (m, 1H), 3.74 – 3.58 (m, 8H), 3.42 – 3.37 (m, 2H), 3.35 – 3.32 (m, 1H), 3.15 (s, 3H), 3.00 (s, 3H), 2.83 – 2.71 (m, 2H), 2.34 – 2.20 (m, 2H), 2.09 – 1.93 (m, 2H), 0.99 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 761 [M+H]+ . | |
I-229 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.68 – 8.47 (m, 1H), 8.18 (s, 1H), 7.99 (d,J = 9.5 Hz, 1H), 7.68 (s, 1H), 6.84 (s, 1H), 4.12 (dq,J = 14.5, 7.3 Hz, 1H), 3.83 (s, 3H), 3.76 (dq,J = 13.8, 6.9 Hz, 1H), 3.64 – 3.39 (m, 8H), 3.25 – 3.17 (m, 3H), 3.13 (s, 3H), 2.99 – 2.85 (m, 5H), 2.46 (dd,J = 14.7, 6.7 Hz, 1H), 2.30 – 2.21 (m, 1H), 2.20 – 2.12 (m, 2H), 1.98 – 1.83 (m, 2H), 0.98 (t,J = 7.2 Hz, 3H), 0.56 (s, 1H), 0.25 – 0.04 (m, 2H), -0.13 – -0.32 (m, 2H). MS (ESI)m/z : 735 [M+H]+ . | |
I-230 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.8 Hz, 1H), 8.80 – 8.68 (m, 1H), 8.15 (s, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.50 (s, 1H), 6.75 (s, 1H), 4.17 – 4.08 (m, 1H), 3.83 (s, 3H), 3.82 – 3.78 (m, 1H), 3.35 – 3.33 (m, 1H), 3.30 – 3.22 (m, 2H), 3.17 (s, 3H), 2.94 (s, 6H), 2.86 – 2.75 (m, 2H), 2.28 – 2.16 (m, 2H), 2.09 (s, 3H), 1.99 – 1.88 (m, 2H), 1.01 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 640 [M+H]+ . | |
I-231 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.87 (d,J = 1.8 Hz, 1H), 8.72 (d,J = 9.1 Hz, 1H), 8.17 (s, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.56 (s, 1H), 6.78 (s, 1H), 4.20 – 4.07 (m, 1H), 3.85 (s, 3H), 3.84 – 3.79 (m, 1H), 3.65 – 3.58 (m, 2H), 3.34 – 3.31 (m, 2H), 3.30 – 3.23 (m, 2H), 3.17 (s, 3H), 3.15 – 3.08 (m, 2H), 3.00 (s, 3H), 2.10 (s, 3H), 1.00 (t,J = 7.0 Hz, 3H). MS (ESI)m/z : 612 [M+H]+ . | |
I-232 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.00 (d,J = 9.4 Hz, 1H), 7.53 (s, 1H), 6.82 (s, 1H), 4.07 (dq,J = 14.4, 7.3 Hz, 1H), 3.82 (s, 3H), 3.69 (dq,J = 13.9, 7.0 Hz, 1H), 3.60 – 3.51 (m, 2H), 3.31 – 3.20 (m, 5H), 3.19 – 3.04 (m, 4H), 2.92 (s, 3H), 2.60 – 2.53 (m, 1H), 2.51 – 2.43 (m, 1H), 1.07 – 0.97 (m, 3H), 0.95 – 0.78 (m, 3H). MS (ESI)m/z : 626 [M+H]+ . | |
I-233 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.78 – 8.52 (m, 1H), 8.19 (s, 1H), 8.07 – 7.95 (m, 1H), 7.34 (d,J = 2.2 Hz, 1H), 6.73 (d,J = 2.6 Hz, 1H), 4.20 – 4.10 (m, 1H), 4.08 – 3.99 (m, 1H), 3.84 (s, 3H), 3.83 – 3.79 (m, 1H), 3.56 – 3.48 (m, 1H), 3.47 – 3.38 (m, 2H), 3.22 – 3.13 (m, 4H), 3.00 (s, 6H), 2.58 – 2.48 (m, 1H), 2.28 – 2.20 (m, 1H), 2.14 (d,J = 7.0 Hz, 3H), 1.00 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 626 [M+H]+ . | |
I-234 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.52 – 8.35 (m, 1H), 8.21 (s, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.76 (s, 1H), 3.93 (s, 3H), 3.66 – 3.53 (m, 8H), 3.51 – 3.48 (m, 2H), 3.46 (s, 3H), 3.36 – 3.31 (m, 2H), 3.25 – 3.11 (m, 1H), 3.06 – 2.98 (m, 2H), 2.96 (s, 3H), 2.43 – 2.26 (m, 2H), 2.26 – 2.16 (m, 2H), 2.02 – 1.88 (m, 2H), 1.41 (t,J = 7.4 Hz, 3H), 0.93 – 0.68 (m, 3H). MS (ESI)m/z : 710 [M+H]+ . | |
I-235 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 8.04 (d,J = 9.2 Hz, 1H), 7.58 (s, 1H), 6.85 (s, 1H), 3.85 (s, 3H), 3.67 – 3.51 (m, 8H), 3.50 – 3.48 (m, 1H), 3.47 (s, 3H), 3.29 – 3.25 (m, 1H), 3.23 – 3.12 (m, 3H), 2.95 (s, 3H), 2.93 – 2.80 (m, 2H), 2.35 – 2.11 (m, 4H), 2.00 – 1.87 (m, 2H), 1.40 (t,J = 7.4 Hz, 3H), 0.72 – 0.36 (m, 1H), 0.32 – 0.10 (m, 2H), -0.04 – -0.37 (m, 2H). MS (ESI)m/z : 735 [M+H]+ . | |
I-236 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.55 – 8.33 (m, 1H), 8.24 – 8.16 (m, 1H), 8.05 (d,J = 9.1 Hz, 1H), 7.34 (s, 1H), 6.81 (s, 1H), 3.83 (s, 3H), 3.46 (s, 3H), 3.21 – 3.15 (m, 2H), 2.95 – 2.92 (m, 5H), 2.88 – 2.78 (m, 2H), 2.53 – 2.29 (m, 2H), 2.23 – 2.13 (m, 2H), 2.01 – 1.86 (m, 2H), 1.40 (t,J = 7.4 Hz, 3H), 1.00 – 0.66 (m, 3H). MS (ESI)m/z : 626 [M+H]+ . | |
I-237 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.70 (d,J = 9.3 Hz, 1H), 8.20 (s, 1H), 8.11 (d,J = 9.3 Hz, 1H), 7.80 (d,J = 8.8 Hz, 1H), 7.01 (s, 1H), 6.82 (d,J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.85 – 3.75 (m, 2H), 3.52 (s, 3H), 3.46 – 3.32 (m, 6H), 3.28 – 3.07 (m, 4H), 3.04 – 2.99 (m, 1H), 2.91 (s, 3H), 2.90 – 2.86 (m, 1H), 2.27 – 2.09 (m, 2H), 2.02 – 1.88 (m, 2H), 1.30 – 1.10 (m, 2H), 0.82 – 0.61 (m, 2H). MS (ESI)m/z : 693 [M+H]+ . | |
I-238 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.5 Hz, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 8.02 (d,J = 9.4 Hz, 1H), 7.69 (s, 1H), 6.85 (s, 1H), 3.86 (s, 3H), 3.51 (d,J = 2.9 Hz, 3H), 3.30 – 3.08 (m, 11H), 2.99 – 2.92 (m, 1H), 2.89 – 2.85 (m, 2H), 2.82 (s, 3H), 2.44 – 2.21 (m, 2H), 2.16 – 2.04 (m, 2H), 1.91 – 1.78 (m, 2H), 1.23 – 1.15 (m, 2H), 0.77 – 0.65 (m, 2H), 0.64 – 0.53 (m, 1H), 0.29 – 0.06 (m, 2H), -0.03 – -0.36 (m, 2H). MS (ESI)m/z : 747 [M+H]+ . | |
I-239 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.81 – 8.60 (m, 1H), 8.14 (s, 1H), 8.09 – 7.92 (m, 1H), 7.69 – 7.50 (m, 1H), 6.37 (d,J = 8.6 Hz, 1H), 4.60 – 4.45 (m, 2H), 3.88 (s, 3H), 3.73 – 3.67 (m, 1H), 3.59 – 3.45 (m, 8H), 3.35 (s, 3H), 3.35 – 3.32 (m, 1H), 2.98 – 2.94 (m, 2H), 2.93 (s, 3H), 2.25 – 2.10 (m, 2H), 1.82 – 1.64 (m, 2H), 1.26 – 1.13 (m, 1H), 1.07 – 0.92 (m, 1H), 0.51 – 0.37 (m, 1H), 0.35 – 0.21 (m, 1H). MS (ESI)m/z : 694 [M+H]+ . | |
I-240 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.86 – 8.72 (m, 1H), 8.18 (s, 1H), 8.01 – 7.85 (m, 1H), 7.51 (s, 1H), 3.97 (s, 3H), 3.85 – 3.75 (m, 2H), 3.72 – 3.66 (m, 1H), 3.51 – 3.31 (m, 11H), 3.19 – 3.05 (m, 1H), 2.92 – 2.88 (m, 2H), 2.87 (s, 3H), 2.06 (s, 3H), 2.04 – 1.94 (m, 2H), 1.78 – 1.53 (m, 2H), 1.35 – 1.18 (m, 1H), 1.10 – 0.94 (m, 1H), 0.52 – 0.39 (m, 1H), 0.39 – 0.24 (m, 1H). MS (ESI)m/z : 708 [M+H]+ . | |
I-241 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.66 – 8.50 (m, 1H), 8.23 (s, 1H), 8.04 (d,J = 9.1 Hz, 1H), 7.84 (s, 1H), 3.95 (s, 3H), 3.77 – 3.66 (m, 1H), 3.62 – 3.41 (m, 10H), 3.32 (s, 3H), 3.29 – 3.26 (m, 1H), 3.12 – 3.01 (m, 2H), 2.94 (s, 3H), 2.55 – 2.33 (m, 2H), 2.28 – 2.08 (m, 2H), 2.02 – 1.88 (m, 2H), 1.20 – 1.08 (m, 1H), 1.02 – 0.92 (m, 1H), 0.90 – 0.70 (m, 3H), 0.49 – 0.35 (m, 1H), 0.31 – 0.22 (m, 1H). MS (ESI)m/z : 722 [M+H]+ . | |
I-242 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.65 – 8.39 (m, 1H), 8.13 (s, 1H), 7.93 (d,J = 9.4 Hz, 1H), 7.61 (s, 1H), 6.81 (s, 1H), 3.79 (s, 3H), 3.67 – 3.61 (m, 1H), 3.53 (s, 8H), 3.26 (s, 3H), 3.24 – 3.22 (m, 1H), 3.18 (t,J = 12.8 Hz, 2H), 2.90 (s, 3H), 2.88 – 2.80 (m, 2H), 2.45 – 2.34 (m, 1H), 2.33 – 2.23 (m, 1H), 2.22 – 2.10 (m, 2H), 1.96 – 1.80 (m, 2H), 1.18 – 1.05 (m, 1H), 1.00 – 0.71 (m, 1H), 0.66 – 0.47 (m, 1H), 0.40 – 0.29 (m, 1H), 0.23 – 0.04 (m, 3H), -0.09 – -0.28 (m, 2H). MS (ESI)m/z : 747 [M+H]+ . | |
I-243 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 – 8.91 (m, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.74 – 8.57 (m, 1H), 8.15 (s, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.41 (s, 1H), 6.76 (s, 1H), 3.82 (s, 3H), 3.75 – 3.60 (m, 1H), 3.34 (s, 3H), 3.31 – 3.27 (m, 2H), 3.27 – 3.24 (m, 1H), 2.93 (s, 6H), 2.86 – 2.76 (m, 2H), 2.25 – 2.15 (m, 2H), 2.08 (s, 3H), 1.99 – 1.85 (m, 2H), 1.22 – 1.08 (m, 1H), 1.03 – 0.94 (m, 1H), 0.47 – 0.37 (m, 1H), 0.33 – 0.24 (m, 1H). MS (ESI)m/z : 652 [M+H]+ . | |
I-244 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.67 (d,J = 9.3 Hz, 1H), 8.13 (s, 1H), 7.95 (d,J = 9.2 Hz, 1H), 7.52 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.72 – 3.64 (m, 1H), 3.65 – 3.55 (m, 2H), 3.38 – 3.33 (m, 5H), 3.32 – 3.31 (m, 1H), 3.25 (t,J = 14.4 Hz, 2H), 3.14 – 3.06 (m, 2H), 2.98 (s, 3H), 2.08 (s, 3H), 1.26 – 1.11 (m, 1H), 1.02 – 0.89 (m, 1H), 0.46 – 0.35 (m, 1H), 0.30 – 0.23 (m, 1H). MS (ESI)m/z : 624 [M+H]+ . | |
I-245 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.92 – 8.80 (m, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.96 (d,J = 9.4 Hz, 1H), 7.49 (s, 1H), 6.81 (s, 1H), 3.80 (s, 3H), 3.63 – 3.52 (m, 3H), 3.38 (s, 3H), 3.26 (d,J = 10.6 Hz, 2H), 3.18 – 3.05 (m, 4H), 2.91 (s, 3H), 2.60 – 2.51 (m, 2H), 1.17 – 1.07 (m, 1H), 1.02 – 0.83 (m, 4H), 0.49 – 0.38 (m, 1H), 0.31 – 0.20 (m, 1H). MS (ESI)m/z : 638 [M+H]+ . | |
I-246 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 2.0 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.76 – 8.57 (m, 1H), 8.17 (s, 1H), 7.99 (d,J = 9.4 Hz, 1H), 7.37 (d,J = 2.2 Hz, 1H), 6.73 (d,J = 2.1 Hz, 1H), 4.10 – 3.95 (m, 1H), 3.84 (s, 3H), 3.73 – 3.64 (m, 1H), 3.56 – 3.46 (m, 1H), 3.46 – 3.38 (m, 2H), 3.35 (s, 3H), 3.20 – 3.09 (m, 1H), 3.06 – 2.94 (m, 6H), 2.57 – 2.47 (m, 1H), 2.30 – 2.20 (m, 1H), 2.11 (s, 3H), 1.24 – 1.11 (m, 1H), 1.08 – 0.90 (m, 1H), 0.52 – 0.37 (m, 1H), 0.33 – 0.22 (m, 1H). MS (ESI)m/z : 638 [M+H]+ . | |
I-247 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.52 (d,J = 9.2 Hz, 1H), 8.13 (d,J = 9.2 Hz, 1H), 8.09 (d,J = 4.3 Hz, 1H), 7.64 (d,J = 8.5 Hz, 1H), 6.94 (d,J = 2.4 Hz, 1H), 6.72 (dd,J = 8.9, 2.4 Hz, 1H), 3.89 (s, 3H), 3.86 – 3.79 (m, 2H), 3.52 (s, 3H), 3.48 – 3.35 (m, 4H), 3.30 – 3.10 (m, 6H), 3.09 – 3.03 (m, 1H), 2.91 (s, 3H), 2.89 – 2.81 (m, 1H), 2.24 – 2.14 (m, 2H), 2.01 – 1.84 (m, 2H), 1.26 – 1.09 (m, 2H), 0.75 – 0.58 (m, 2H). MS (ESI)m/z : 677 [M+H]+ . | |
I-248 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.34 (d,J = 9.3 Hz, 1H), 8.15 – 8.05 (m, 2H), 7.29 (s, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.63 – 3.40 (m, 11H), 3.27 – 3.18 (m, 3H), 2.94 (s, 3H), 2.89 – 2.69 (m, 3H), 2.26 – 2.12 (m, 2H), 2.02 – 1.84 (m, 5H), 1.23 – 1.04 (m, 2H), 0.74 – 0.56 (m, 2H). MS (ESI)m/z : 691 [M+H]+ . | |
I-249 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.28 (d,J = 9.2 Hz, 1H), 8.20 – 8.01 (m, 2H), 7.33 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 3.61 – 3.49 (m, 8H), 3.49 (s, 3H), 3.26 – 3.19 (m, 1H), 3.19 – 3.05 (m, 2H), 2.94 (s, 3H), 2.91 – 2.70 (m, 3H), 2.38 (s, 1H), 2.28 – 2.04 (m, 3H), 2.01 – 1.79 (m, 2H), 1.23 – 1.06 (m, 2H), 0.91 – 0.73 (m, 3H), 0.73 – 0.57 (m, 2H). MS (ESI)m/z : 705 [M+H]+ . | |
I-250 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.32 (d,J = 9.3 Hz, 1H), 8.14 (d,J = 4.2 Hz, 1H), 7.99 (d,J = 9.2 Hz, 1H), 7.47 (s, 1H), 7.04 (s, 1H), 3.62 – 3.37 (m, 11H), 3.20 – 3.06 (m, 3H), 2.91 (s, 3H), 2.86 – 2.79 (m, 1H), 2.73 (q,J = 11.4 Hz, 2H), 2.53 – 2.42 (m, 1H), 2.41 – 2.26 (m, 1H), 2.23 – 2.11 (m, 2H), 1.93 – 1.81 (m, 2H), 1.22 – 1.10 (m, 2H), 0.87 (t,J = 7.5 Hz, 3H), 0.71 – 0.61 (m, 2H). MS (ESI)m/z : 759 [M+H]+ . | |
I-251 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.34 (d,J = 9.4 Hz, 1H), 8.14 – 8.03 (m, 2H), 7.53 (s, 1H), 6.82 (s, 1H), 3.85 (s, 3H), 3.50 (s, 3H), 3.44 – 3.31 (m, 8H), 3.19 – 3.10 (m, 2H), 3.09 – 2.99 (m, 1H), 2.87 (s, 3H), 2.86 – 2.77 (m, 3H), 2.37 – 2.23 (m, 1H), 2.20 – 2.01 (m, 3H), 1.91 – 1.75 (m, 2H), 1.21 – 1.05 (m, 2H), 0.81 – 0.63 (m, 2H), 0.61 – 0.50 (m, 1H), 0.34 – 0.09 (m, 2H), -0.07 – -0.24 (m, 2H). MS (ESI)m/z : 731 [M+H]+ . | |
I-252 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.7 Hz, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.31 (d,J = 9.2 Hz, 1H), 8.16 – 8.04 (m, 2H), 7.31 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 3.38 – 3.33 (m, 1H), 3.18 – 3.08 (m, 2H), 2.93 (s, 6H), 2.86 – 2.72 (m, 3H), 2.45 – 2.36 (m, 1H), 2.29 – 2.21 (m, 1H), 2.20 – 2.14 (m, 2H), 1.93 – 1.84 (m, 2H), 1.26 – 1.11 (m, 2H), 0.91 – 0.74 (m, 3H), 0.74 – 0.61 (m, 2H). MS (ESI)m/z : 650 [M+H]+ . | |
I-253 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.49 – 8.32 (m, 1H), 8.22 (s, 1H), 8.07 (d,J = 9.2 Hz, 1H), 7.79 (s, 1H), 3.93 (s, 3H), 3.59 – 3.43 (m, 14H), 3.25 – 3.18 (m, 1H), 3.03 – 2.97 (m, 2H), 2.92 (s, 3H), 2.37 – 2.25 (m, 2H), 2.22 – 2.13 (m, 2H), 2.01 – 1.86 (m, 2H), 1.65 (d,J = 6.7 Hz, 3H), 1.28 (d,J = 6.9 Hz, 3H), 0.87 – 0.64 (m, 3H). MS (ESI)m/z : 724 [M+H]+ . | |
I-254 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.02 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.45 – 8.31 (m, 1H), 8.22 (s, 1H), 8.05 (d,J = 9.3 Hz, 1H), 7.55 (s, 1H), 6.84 (s, 1H), 3.85 (s, 3H), 3.71 – 3.54 (m, 8H), 3.46 (s, 3H), 3.45 – 3.42 (m, 1H), 3.39 – 3.34 (m, 1H), 3.18 (t,J = 13.4 Hz, 2H), 2.98 (s, 3H), 2.88 (t,J = 11.9 Hz, 2H), 2.34 – 2.16 (m, 4H), 2.01 – 1.86 (m, 2H), 1.65 (d,J = 6.7 Hz, 3H), 1.27 (d,J = 6.9 Hz, 3H), 0.69 – 0.40 (m, 1H), 0.31 – 0.07 (m, 2H), -0.07 – -0.39 (m, 2H). MS (ESI)m/z : 749 [M+H]+ . | |
I-255 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.40 (d,J = 9.0 Hz, 1H), 8.21 (s, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.46 (s, 1H), 6.81 (s, 1H), 3.85 (s, 3H), 3.62 – 3.55 (m, 2H), 3.52 – 3.41 (m, 5H), 3.30 – 3.26 (m, 1H), 3.19 – 3.10 (m, 4H), 2.99 (s, 3H), 2.46 – 2.23 (m, 2H), 1.65 (d,J = 6.6 Hz, 3H), 1.28 (d,J = 6.9 Hz, 3H), 0.85 – 0.62 (m, 3H). MS (ESI)m/z : 640 [M+H]+ . | |
I-256 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.02 (d,J = 1.8 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.33 (d,J = 9.2 Hz, 1H), 8.29 (s, 1H), 8.22 (d,J = 9.2 Hz, 1H), 7.53 (d,J = 8.8 Hz, 1H), 6.91 (d,J = 2.5 Hz, 1H), 6.56 (d,J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.79 – 3.71 (m, 2H), 3.59 (s, 3H), 3.52 – 3.39 (m, 4H), 3.30 – 3.14 (m, 6H), 3.13 – 3.07 (m, 1H), 2.93 (s, 3H), 2.25 – 2.15 (m, 2H), 2.00 – 1.89 (m, 2H). MS (ESI)m/z : 765 [M+H]+ . | |
I-257 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 1.9 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.31 (s, 1H), 8.22 (d,J = 9.0 Hz, 1H), 8.15 (d,J = 9.1 Hz, 1H), 7.63 (s, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.57 – 3.38 (m, 10H), 3.26 – 3.19 (m, 1H), 2.99 – 2.89 (m, 5H), 2.32 – 2.19 (m, 1H), 2.18 – 2.11 (m, 2H), 2.09 – 1.96 (m, 1H), 1.97 – 1.82 (m, 2H), 0.76 – 0.50 (m, 3H). MS (ESI)m/z : 794 [M+H]+ . | |
I-258 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.31 (s, 1H), 8.20 (d,J = 9.2 Hz, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.63 (s, 1H), 6.98 – 6.88 (m, 1H), 6.66 (dd,J = 17.8, 11.0 Hz, 1H), 5.19 – 5.08 (m, 1H), 4.83 – 4.75 (m, 1H), 3.63 – 3.43 (m, 11H), 3.26 – 3.16 (m, 3H), 2.94 (s, 3H), 2.74 – 2.62 (m, 2H), 2.23 – 2.12 (m, 2H), 1.94 – 1.84 (m, 2H). MS (ESI)m/z : 845 [M+H]+ . | |
I-259 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 1.8 Hz, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 2H), 7.39 (s, 1H), 6.77 (s, 1H), 3.81 (s, 3H), 3.73 – 3.49 (m, 11H), 3.30 – 3.24 (m, 1H), 3.15 – 3.05 (m, 2H), 2.96 (s, 3H), 2.88 – 2.73 (m, 2H), 2.29 – 2.12 (m, 3H), 2.01 – 1.81 (m, 3H), 0.60 – 0.32 (m, 1H), 0.29 – 0.07 (m, 2H), -0.09 – -0.31 (m, 2H). MS (ESI)m/z : 819 [M+H]+ . | |
I-260 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.38 (d,J = 9.2 Hz, 1H), 8.28 (s, 1H), 8.13 (d,J = 9.2 Hz, 1H), 7.52 (s, 1H), 6.75 (s, 1H), 3.84 (s, 3H), 3.58 (s, 3H), 3.58 – 3.51 (m, 2H), 3.30 – 3.24 (m, 2H), 3.16 – 3.04 (m, 4H), 2.98 (s, 3H), 2.34 – 2.07 (m, 2H), 0.74 – 0.53 (m, 3H). MS (ESI)m/z : 710 [M+H]+ . | |
I-261 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 1.8 Hz, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.28 (d,J = 9.2 Hz, 1H), 8.26 – 8.18 (m, 2H), 7.51 (d,J = 8.8 Hz, 1H), 6.90 (d,J = 2.5 Hz, 1H), 6.60 – 6.51 (m, 1H), 3.85 (s, 3H), 3.81 – 3.72 (m, 2H), 3.59 (s, 3H), 3.53 – 3.42 (m, 4H), 3.32 – 3.23 (m, 4H), 3.19 – 3.10 (m, 3H), 2.94 (s, 3H), 2.26 – 2.17 (m, 2H), 2.00 – 1.89 (m, 2H). MS (ESI)m/z : 721 [M+H]+ . | |
I-262 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.04 (d,J = 1.9 Hz, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.20 – 8.08 (m, 2H), 7.60 (s, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.58 – 3.44 (m, 8H), 3.43 – 3.38 (m, 2H), 3.28 – 3.21 (m, 1H), 2.98 – 2.91 (m, 5H), 2.28 – 2.10 (m, 3H), 2.01 – 1.81 (m, 3H), 0.74 – 0.50 (m, 3H). MS (ESI)m/z : 750 [M+H]+ . | |
I-263 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.23 (s, 1H), 8.18 (d,J = 9.3 Hz, 1H), 7.99 (d,J = 9.2 Hz, 1H), 7.63 (s, 1H), 6.92 (s, 1H), 6.64 (dd,J = 17.8, 11.0 Hz, 1H), 5.17 – 5.06 (m, 1H), 4.82 – 4.72 (m, 1H), 3.64 – 3.44 (m, 11H), 3.24 – 3.14 (m, 3H), 2.94 (s, 3H), 2.72 – 2.64 (m, 2H), 2.22 – 2.13 (m, 2H), 1.94 – 1.83 (m, 2H). MS (ESI)m/z : 801 [M+H]+ . | |
I-264 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 1.9 Hz, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.22 (s, 1H), 8.20 – 8.09 (m, 2H), 7.38 (s, 1H), 6.76 (s, 1H), 3.81 (s, 3H), 3.68 – 3.48 (m, 11H), 3.27 – 3.21 (m, 1H), 3.15 – 3.05 (m, 2H), 2.95 (s, 3H), 2.89 – 2.72 (m, 2H), 2.26 – 2.14 (m, 3H), 1.97 – 1.81 (m, 3H), 0.62 – 0.31 (m, 1H), 0.26 – 0.08 (m, 2H), -0.05 – -0.26 (m, 2H). MS (ESI)m/z : 775 [M+H]+ . | |
I-265 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 1.9 Hz, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.22 – 8.12 (m, 3H), 7.14 (s, 1H), 6.66 (s, 1H), 3.80 (s, 3H), 3.56 (s, 3H), 3.30 – 3.26 (m, 1H), 3.17 – 3.07 (m, 2H), 2.93 (s, 6H), 2.79 – 2.67 (m, 2H), 2.20 – 2.12 (m, 2H), 1.92 – 1.83 (m, 2H), 1.67 (br s, 3H). MS (ESI)m/z : 680 [M+H]+ . | |
I-266 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.39 (d,J = 9.2 Hz, 1H), 8.18 (s, 1H), 8.14 (d,J = 9.2 Hz, 1H), 7.44 (s, 1H), 6.70 (s, 1H), 3.83 (s, 3H), 3.64 – 3.52 (m, 5H), 3.30 – 3.24 (m, 2H), 3.21 – 3.13 (m, 2H), 3.03 (t,J = 12.5 Hz, 2H), 2.98 (s, 3H), 1.73 (s, 3H). MS (ESI)m/z : 652 [M+H]+ . | |
I-267 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.04 (d,J = 1.8 Hz, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.17 (d,J = 9.1 Hz, 1H), 8.13 (d,J = 9.2 Hz, 1H), 7.27 (s, 1H), 6.75 (s, 1H), 3.82 (s, 3H), 3.61 – 3.55 (m, 5H), 3.30 – 3.23 (m, 2H), 3.13 – 3.04 (m, 4H), 2.97 (s, 3H), 2.36 – 1.86 (m, 2H), 0.75 – 0.49 (m, 3H). MS (ESI)m/z : 666 [M+H]+ . | |
I-268 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.32 (d,J = 9.2 Hz, 1H), 8.18 (s, 1H), 8.14 (dd,J = 9.3, 2.2 Hz, 1H), 7.27 (d,J = 2.7 Hz, 1H), 6.65 (s, 1H), 4.02 – 3.93 (m, 1H), 3.82 (s, 3H), 3.58 (d,J = 4.1 Hz, 3H), 3.43 – 3.36 (m, 1H), 3.36 – 3.25 (m, 2H), 3.08 – 2.99 (m, 1H), 2.96 (d,J = 6.0 Hz, 6H), 2.52 – 2.38 (m, 1H), 2.25 – 2.11 (m, 1H), 1.86 – 1.68 (m, 3H). MS (ESI)m/z : 666 [M+H]+ . | |
I-269 | MS (ESI)m/z : 701 [M+H]+ . | |
I-270 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.74 – 8.36 (m, 1H), 8.14 – 7.98 (m, 1H), 7.90 – 7.72 (m, 1H), 7.60 (s, 1H), 3.92 (s, 3H), 3.59 – 3.46 (m, 13H), 3.28 – 3.23 (m, 1H), 3.17 (s, 3H), 2.97 – 2.93 (m, 2H), 2.91 (s, 3H), 2.51 – 2.29 (m, 2H), 2.20 – 2.14 (m, 2H), 1.95 – 1.85 (m, 2H), 1.83 – 1.72 (m, 1H), 1.26 – 1.15 (m, 2H), 0.96 – 0.84 (m, 3H), 0.82 – 0.69 (m, 2H). MS (ESI)m/z : 702 [M+H]+ . | |
I-271 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.56 – 8.35 (m, 1H), 7.95 – 7.80 (m, 2H), 7.69 (s, 1H), 7.06 (s, 1H), 6.94 – 6.81 (m, 1H), 5.53 – 5.38 (m, 1H), 5.17 – 5.03 (m, 1H), 3.48 (s, 3H), 3.45 – 3.31 (m, 10H), 3.16 (s, 3H), 3.09 – 3.01 (m, 1H), 2.90 (d,J = 3.4 Hz, 3H), 2.83 – 2.72 (m, 2H), 2.21 – 2.11 (m, 2H), 1.96 – 1.84 (m, 2H), 1.83 – 1.74 (m, 1H), 1.26 – 1.15 (m, 2H), 0.90 – 0.71 (m, 2H). MS (ESI)m/z : 753 [M+H]+ . | |
I-272 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.88 – 8.49 (m, 1H), 8.05 (s, 1H), 7.79 (d,J = 35.9 Hz, 1H), 7.28 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 3.50 (s, 3H), 3.43 – 3.32 (m, 2H), 3.30 – 3.23 (m, 1H), 3.19 (s, 3H), 2.95 (s, 6H), 2.87 – 2.80 (m, 2H), 2.26 – 2.19 (m, 2H), 2.20 – 2.04 (m, 3H), 2.00 – 1.88 (m, 2H), 1.80 – 1.72 (m, 1H), 1.31 – 1.22 (m, 1H), 1.21 – 1.13 (m, 1H), 0.94 – 0.79 (m, 1H), 0.77 – 0.67 (m, 1H). MS (ESI)m/z : 632 [M+H]+ . | |
I-273 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.82 – 8.29 (m, 1H), 8.21 – 7.91 (m, 1H), 7.90 – 7.64 (m, 1H), 7.40 – 7.24 (m, 1H), 6.86 (s, 1H), 3.84 (s, 3H), 3.50 (s, 3H), 3.39 – 3.32 (m, 1H), 3.26 – 3.20 (m, 2H), 3.18 (s, 3H), 2.95 (s, 6H), 2.92 – 2.80 (m, 2H), 2.67 – 2.34 (m, 2H), 2.26 – 2.17 (m, 2H), 2.00 – 1.88 (m, 2H), 1.80 – 1.71 (m, 1H), 1.27 – 1.15 (m, 2H), 1.11 – 0.64 (m, 5H). MS (ESI)m/z : 646 [M+H]+ . | |
I-274 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.89 – 8.59 (m, 1H), 8.26 – 7.92 (m, 1H), 7.86 – 7.64 (m, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.09 – 3.98 (m, 1H), 3.85 (s, 3H), 3.57 – 3.49 (m, 4H), 3.48 – 3.41 (m, 2H), 3.27 – 3.13 (m, 4H), 3.00 (s, 6H), 2.60 – 2.47 (m, 1H), 2.31 – 2.22 (m, 1H), 2.20 – 2.08 (m, 3H), 1.86 – 1.63 (m, 1H), 1.31 – 1.24 (m, 1H), 1.20 – 1.13 (m, 1H), 0.91 – 0.81 (m, 1H), 0.77 – 0.67 (m, 1H). MS (ESI)m/z : 618 [M+H]+ . | |
I-275 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.83 – 8.38 (m, 1H), 8.18 – 7.91 (m, 1H), 7.89 – 7.65 (m, 1H), 7.28 (s, 1H), 6.84 (s, 1H), 4.12 – 3.97 (m, 1H), 3.85 (s, 3H), 3.56 – 3.43 (m, 5H), 3.41 – 3.34 (m, 1H), 3.18 (s, 4H), 2.99 (s, 6H), 2.63 – 2.39 (m, 3H), 2.30 – 2.16 (m, 1H), 1.84 – 1.71 (m, 1H), 1.33 – 1.23 (m, 1H), 1.22 – 1.13 (m, 1H), 1.12 – 0.78 (m, 4H), 0.76 – 0.68 (m, 1H). MS (ESI)m/z : 632 [M+H]+ . | |
I-276 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.68 – 8.31 (m, 1H), 8.08 (d,J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.21 (s, 1H), 6.77 (s, 1H), 3.82 (s, 3H), 3.73 – 3.51 (m, 8H), 3.43 (s, 3H), 3.32 (d,J = 8.9 Hz, 1H), 3.27 – 3.19 (m, 2H), 3.15 (s, 3H), 2.97 (s, 3H), 2.90 – 2.76 (m, 2H), 2.29 (s, 3H), 2.25 – 2.16 (m, 2H), 2.11 – 1.79 (m, 5H). MS (ESI)m/z : 661 [M+H]+ . | |
I-277 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.62 – 8.21 (m, 1H), 8.16 – 7.97 (m, 1H), 7.81 (s, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 3.83 (s, 3H), 3.75 – 3.54 (m, 8H), 3.46 – 3.41 (m, 3H), 3.34 – 3.32 (m, 1H), 3.21 – 3.11 (m, 5H), 2.98 (s, 3H), 2.84 (q,J = 11.1, 10.6 Hz, 2H), 2.45 – 2.34 (m, 2H), 2.30 (s, 3H), 2.24 – 2.18 (m, 2H), 2.01 – 1.86 (m, 2H), 1.14 – 0.45 (m, 3H). MS (ESI)m/z : 675 [M+H]+ . | |
I-278 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.46 – 8.18 (m, 1H), 8.15 – 8.00 (m, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 3.91 (s, 3H), 3.66 – 3.51 (m, 8H), 3.52 – 3.47 (m, 2H), 3.45 (s, 3H), 3.34 – 3.32 (m, 1H), 3.15 (s, 3H), 2.99 – 2.88 (m, 5H), 2.40 – 2.26 (m, 4H), 2.24 – 2.12 (m, 3H), 2.00 – 1.83 (m, 2H), 1.02 – 0.52 (m, 3H). MS (ESI)m/z : 676 [M+H]+ . | |
I-279 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.56 – 8.21 (m, 1H), 8.11 – 8.00 (m, 1H), 7.81 (s, 1H), 7.25 (s, 1H), 6.81 (s, 1H), 3.82 (s, 3H), 3.44 (s, 3H), 3.37 – 3.33 (m, 1H), 3.19 – 3.09 (m, 5H), 2.94 (s, 6H), 2.86 – 2.77 (m, 2H), 2.52 – 2.32 (m, 2H), 2.30 (s, 3H), 2.22 – 2.16 (m, 2H), 1.99 – 1.85 (m, 2H), 1.19 – 0.45 (m, 3H). MS (ESI)m/z : 620 [M+H]+ . | |
I-280 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.44 (d,J = 44.5 Hz, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.23 (s, 1H), 6.94 – 6.66 (m, 1H), 4.13 – 3.96 (m, 1H), 3.83 (s, 3H), 3.51 – 3.40 (m, 5H), 3.34 – 3.31 (m, 1H), 3.21 – 3.10 (m, 4H), 2.98 (s, 6H), 2.61 – 2.39 (m, 2H), 2.35 – 2.15 (m, 5H), 1.24 – 0.42 (m, 3H). MS (ESI)m/z : 606 [M+H]+ . | |
I-281 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.41 (d,J = 9.3 Hz, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.69 (s, 1H), 7.42 (s, 1H), 7.13 – 7.08 (m, 1H), 4.04 (s, 3H), 3.72 – 3.48 (m, 8H), 3.44 (s, 3H), 3.28 – 3.22 (m, 1H), 3.20 – 3.10 (m, 5H), 2.95 (s, 3H), 2.84 – 2.73 (m, 2H), 2.61 – 2.51 (m, 1H), 2.50 – 2.42 (m, 1H), 2.27 – 2.16 (m, 2H), 2.01 – 1.86 (m, 2H), 0.94 (t,J = 7.6 Hz, 3H). MS (ESI)m/z : 745 [M+H]+ . | |
I-282 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.73 – 8.50 (m, 1H), 8.06 (d,J = 9.4 Hz, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 4.02 (s, 3H), 3.84 (s, 3H), 3.46 (s, 3H), 3.35 – 3.32 (m, 1H), 3.25 – 3.15 (m, 5H), 2.94 (s, 6H), 2.91 – 2.81 (m, 2H), 2.59 – 2.39 (m, 2H), 2.29 – 2.15 (m, 2H), 2.00 – 1.86 (m, 2H), 1.05 – 0.80 (m, 3H). MS (ESI)m/z : 636 [M+H]+ . | |
I-283 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.69 – 8.51 (m, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.65 (s, 1H), 7.37 (s, 1H), 6.88 (s, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.65 – 3.56 (m, 2H), 3.47 (s, 3H), 3.35 – 3.31 (m, 2H), 3.24 – 3.12 (m, 7H), 3.00 (s, 3H), 2.59 – 2.35 (m, 2H), 0.96 – 0.81 (m, 3H). MS (ESI)m/z : 608 [M+H]+ . | |
I-284 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.82 – 8.75 (m, 3H), 8.35 – 8.34 (m, 1H), 7.94 – 7.87 (m, 1H), 7.35 – 7.30 (m, 1H), 6.84 (s, 1H), 3.76 (s, 3H), 3.36 (s, 3H), 3.33 (s, 5H), 3.28 – 3.23 (m, 5H), 3.22 (s, 3H), 3.09 – 3.02 (m, 2H), 2.90 (s, 3H), 2.86 – 2.78 (m, 2H), 2.19 – 2.11 (m, 2H), 1.85 – 1.74 (m, 2H), 0.99 – 0.87 (m, 6H). MS (ESI)m/z : 753 [M+H]+ . | |
I-285 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.82 – 8.70 (m, 3H), 8.34 (s, 1H), 7.95 – 7.88 (m, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 3.77 (s, 3H), 3.65 (s, 8H), 3.44 – 3.39 (m, 3H), 3.38 (s, 3H), 3.23 (s, 3H), 2.90 (s, 3H), 2.84 – 2.73 (m, 2H), 2.22 – 2.13 (m, 2H), 2.09 – 2.02 (m, 1H), 1.91 – 1.81 (m, 2H), 0.78 – 0.62 (m, 2H), 0.45 – 0.32 (m, 2H). MS (ESI)m/z : 751 [M+H]+ . | |
I-286 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 – 8.86 (m, 2H), 8.80 (d,J = 1.9 Hz, 1H), 8.20 (s, 1H), 7.94 (d,J = 9.3 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.10 (d,J = 8.6 Hz, 1H), 3.45 (s, 3H), 3.41 – 3.32 (m, 4H), 3.30 – 3.17 (m, 9H), 3.05 – 2.99 (m, 1H), 2.98 – 2.89 (m, 2H), 2.86 (s, 3H), 2.66 (s, 3H), 2.61 (t,J = 8.1 Hz, 2H), 2.19 – 2.06 (m, 2H), 1.92 (q,J = 12.3 Hz, 2H), 1.06 (t,J = 7.6 Hz, 3H). MS (ESI)m/z : 709 [M+H]+ . | |
I-287 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.74 – 8.58 (m, 1H), 8.12 (s, 1H), 7.95 (d,J = 9.4 Hz, 1H), 7.14 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.47 (s, 3H), 3.46 – 3.41 (m, 2H), 3.31 – 3.04 (m, 11H), 2.96 – 2.90 (m, 1H), 2.85 (t,J = 11.8 Hz, 2H), 2.79 (s, 3H), 2.18 – 2.05 (m, 3H), 1.94 – 1.77 (m, 2H), 0.70 – 0.51 (m, 2H), 0.35 – 0.19 (m, 2H). MS (ESI)m/z : 707 [M+H]+ . | |
I-288 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.77 – 8.58 (m, 1H), 8.15 (s, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.54 (s, 1H), 6.84 (s, 1H), 3.82 (s, 3H), 3.45 (s, 3H), 3.31 – 3.15 (m, 11H), 3.15 – 3.06 (m, 3H), 2.97 – 2.90 (m, 1H), 2.90 – 2.83 (m, 2H), 2.79 (s, 3H), 2.15 – 2.03 (m, 2H), 1.89 – 1.77 (m, 2H), 1.00 – 0.82 (m, 6H). MS (ESI)m/z : 709 [M+H]+ . | |
I-289 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 – 8.89 (m, 2H), 8.80 (d,J = 1.8 Hz, 1H), 8.11 (s, 1H), 7.95 (d,J = 9.4 Hz, 1H), 7.42 – 7.28 (m, 2H), 7.09 (d,J = 8.6 Hz, 1H), 3.45 (s, 3H), 3.31 – 3.11 (m, 13H), 3.02 – 2.95 (m, 1H), 2.94 – 2.86 (m, 2H), 2.83 (s, 3H), 2.61 (q,J = 7.6 Hz, 2H), 2.15 – 2.05 (m, 2H), 1.95 – 1.84 (m, 2H), 1.07 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 665 [M+H]+ . | |
I-290 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.17 (s, 1H), 8.93 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.02 (s, 1H), 6.85 (s, 1H), 5.31 (d,J = 17.8 Hz, 1H), 4.93 (t,J = 8.7 Hz, 1H), 3.46 (s, 3H), 3.40 – 3.26 (m, 10H), 3.18 (s, 3H), 3.04 – 2.94 (m, 1H), 2.87 (s, 3H), 2.82 – 2.72 (m, 2H), 2.18 – 2.09 (m, 2H), 1.94 – 1.81 (m, 2H). MS (ESI)m/z : 758 [M+H]+ . | |
I-291 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.75 – 8.36 (m, 1H), 8.15 – 7.84 (m, 1H), 7.78 – 7.62 (m, 1H), 7.22 (s, 1H), 6.87 (s, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 3.44 – 3.29 (m, 8H), 3.21 – 3.09 (m, 6H), 3.08 – 2.99 (m, 1H), 2.89 – 2.81 (m, 5H), 2.21 – 2.07 (m, 2H), 1.91 – 1.81 (m, 2H), 1.76 – 1.69 (m, 1H), 1.25 – 1.20 (m, 1H), 1.17 – 1.12 (m, 1H), 1.11 – 0.85 (m, 6H), 0.85 – 0.80 (m, 1H), 0.74 – 0.68 (m, 1H). MS (ESI)m/z : 715 [M+H]+ . | |
I-292 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 2.0 Hz, 1H), 8.91 (d,J = 2.0 Hz, 1H), 8.81 – 8.48 (m, 1H), 8.11 – 7.93 (m, 1H), 7.84 – 7.64 (m, 1H), 6.84 (s, 1H), 6.79 (s, 1H), 3.82 (s, 3H), 3.52 – 3.46 (m, 5H), 3.31 – 3.11 (m, 11H), 3.00 – 2.89 (m, 1H), 2.84 – 2.78 (m, 5H), 2.19 – 2.06 (m, 3H), 1.92 – 1.82 (m, 2H), 1.80 – 1.67 (m, 1H), 1.27 – 1.21 (m, 1H), 1.19 – 1.10 (m, 1H), 0.87 – 0.81 (m, 1H), 0.78 – 0.60 (m, 3H), 0.55 – 0.15 (m, 2H). MS (ESI)m/z : 713 [M+H]+ . | |
I-293 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.79 – 8.64 (m, 1H), 8.00 (d,J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.27 (d,J = 2.6 Hz, 1H), 7.21 (dd,J = 8.4, 2.6 Hz, 1H), 7.12 (d,J = 8.5 Hz, 1H), 3.48 (s, 3H), 3.34 – 3.21 (m, 8H), 3.18 (s, 3H), 3.17 – 3.13 (m, 2H), 3.00 – 2.93 (m, 1H), 2.82 (s, 3H), 2.81 – 2.76 (m, 2H), 2.63 – 2.53 (m, 2H), 2.18 – 2.07 (m, 2H), 1.89 – 1.82 (m, 2H), 1.78 – 1.65 (m, 1H), 1.29 – 1.21 (m, 1H), 1.19 – 1.09 (m, 1H), 1.07 – 0.96 (m, 3H), 0.91 – 0.82 (m, 1H), 0.74 – 0.64 (m, 1H). MS (ESI)m/z : 671 [M+H]+ . | |
I-294 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.65 (d,J = 9.3 Hz, 1H), 8.18 (s, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.76 (d,J = 8.7 Hz, 1H), 6.80 (dd,J = 8.9, 2.5 Hz, 1H), 3.90 (s, 3H), 3.86 – 3.79 (m, 2H), 3.54 – 3.34 (m, 9H), 3.30 – 3.16 (m, 6H), 3.14 – 3.05 (m, 1H), 2.93 (s, 3H), 2.26 – 2.16 (m, 2H), 2.04 – 1.92 (m, 2H), 1.43 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 681 [M+H]+ . | |
I-295 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.9 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.67 (d,J = 9.5 Hz, 1H), 8.17 (s, 1H), 7.90 – 7.81 (m, 2H), 7.00 (s, 1H), 6.91 (dd,J = 17.7, 11.0 Hz, 1H), 5.36 (d,J = 17.7 Hz, 1H), 4.98 (d,J = 11.1 Hz, 1H), 3.53 – 3.47 (m, 1H), 3.45 (s, 3H), 3.43 – 3.37 (m, 1H), 3.29 – 2.96 (m, 10H), 2.87 – 2.79 (m, 4H), 2.76 – 2.68 (m, 2H), 2.13 – 1.99 (m, 2H), 1.88 – 1.74 (m, 2H), 1.42 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 761 [M+H]+ . | |
I-296 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.89 (d,J = 1.9 Hz, 1H), 8.87 – 8.78 (m, 2H), 8.15 (s, 1H), 7.97 – 7.90 (m, 1H), 7.68 (d,J = 4.9 Hz, 1H), 6.29 (d,J = 8.4 Hz, 1H), 4.45 – 4.37 (m, 2H), 4.17 – 4.07 (m, 1H), 3.85 (s, 3H), 3.82 – 3.74 (m, 1H), 3.29 – 3.02 (m, 11H), 2.98 (d,J = 14.1 Hz, 1H), 2.91 – 2.85 (m, 2H), 2.80 (s, 3H), 2.08 – 1.97 (m, 2H), 1.73 – 1.58 (m, 2H), 1.03 (t,J = 7.1 Hz, 3H). MS (ESI)m/z : 726 [M+H]+ . | |
I-297 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.95 (d,J = 1.8 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.88 – 8.76 (m, 1H), 8.74 – 8.69 (m, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 7.86 – 7.59 (m, 1H), 7.42 (s, 1H), 4.11 – 4.05 (m, 1H), 3.93 (s, 3H), 3.89 – 3.81 (m, 2H), 3.72 – 3.66 (m, 1H), 3.38 (s, 3H), 3.22 (s, 3H), 3.14 – 2.54 (m, 11H), 2.04 (s, 3H), 1.84 – 1.60 (m, 2H), 1.42 – 1.20 (m, 2H), 1.00 (t,J = 7.1 Hz, 3H). MS (ESI)m/z : 740 [M+H]+ . | |
I-298 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.9 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.64 (d,J = 9.3 Hz, 1H), 8.26 (s, 1H), 7.85 – 7.77 (m, 2H), 7.03 – 6.99 (m, 1H), 6.93 (dd,J = 17.8, 11.1 Hz, 1H), 5.38 (d,J = 17.7 Hz, 1H), 5.01 (d,J = 11.0 Hz, 1H), 4.14 (dq,J = 14.5, 7.3 Hz, 1H), 3.79 (dq,J = 14.1, 7.1 Hz, 1H), 3.41 – 3.31 (m, 8H), 3.16 (s, 3H), 2.99 (d,J = 11.4 Hz, 2H), 2.89 – 2.84 (m, 4H), 2.79 – 2.72 (m, 2H), 2.17 – 2.08 (m, 2H), 1.92 – 1.82 (m, 2H), 1.03 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 805 [M+H]+ . | |
I-299 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.91 (d,J = 1.9 Hz, 1H), 8.85 – 8.78 (m, 2H), 8.18 (s, 1H), 7.96 (d,J = 9.3 Hz, 1H), 7.62 (s, 1H), 6.71 (s, 1H), 4.16 – 4.07 (m, 1H), 3.82 (s, 3H), 3.81 – 3.76 (m, 1H), 3.34 – 3.28 (m, 1H), 3.26 – 3.19 (m, 2H), 3.17 (s, 3H), 2.93 (s, 6H), 2.82 – 2.74 (m, 2H), 2.23 – 2.13 (m, 2H), 2.06 (s, 3H), 1.91 (qdd,J = 11.5, 6.2, 4.1 Hz, 2H), 1.02 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 684 [M+H]+ . | |
I-300 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.80 (d,J = 9.3 Hz, 1H), 8.22 (s, 1H), 8.00 (d,J = 9.3 Hz, 1H), 7.67 (s, 1H), 6.76 (s, 1H), 4.19 – 4.07 (m, 1H), 3.85 (s, 3H), 3.84 – 3.77 (m, 1H), 3.66 – 3.53 (m, 2H), 3.36 – 3.31 (m, 2H), 3.29 – 3.22 (m, 2H), 3.18 (s, 3H), 3.14 – 3.04 (m, 2H), 3.00 (s, 3H), 2.08 (s, 3H), 1.02 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-301 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 21.5 Hz, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.97 (d,J = 9.3 Hz, 1H), 7.49 (s, 1H), 6.80 (s, 1H), 4.06 (dq,J = 14.5, 7.3 Hz, 1H), 3.80 (s, 3H), 3.69 (dq,J = 13.9, 7.0 Hz, 1H), 3.57 – 3.48 (m, 2H), 3.27 – 3.19 (m, 5H), 3.17 – 3.10 (m, 2H), 3.09 – 2.97 (m, 2H), 2.91 (s, 3H), 2.59 – 2.53 (m, 1H), 2.48 – 2.38 (m, 1H), 0.98 (t,J = 7.2 Hz, 3H), 0.91 – 0.79 (m, 3H). MS (ESI)m/z : 670 [M+H]+ . | |
I-302 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.91 (d,J = 1.5 Hz, 1H), 8.85 – 8.78 (m, 2H), 8.19 (s, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.58 (s, 1H), 6.72 (s, 1H), 4.19 – 4.07 (m, 1H), 4.05 – 3.97 (m, 1H), 3.83 (s, 3H), 3.82 – 3.76 (m, 1H), 3.49 – 3.40 (m, 1H), 3.41 – 3.33 (m, 2H), 3.17 (s, 3H), 3.14 – 3.06 (m, 1H), 2.98 (d,J = 5.5 Hz, 6H), 2.53 – 2.43 (m, 1H), 2.20 (dq,J = 14.2, 7.5 Hz, 1H), 2.09 (s, 3H), 1.03 (t,J = 7.1 Hz, 3H). MS (ESI)m/z : 670 [M+H]+ . | |
I-303 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.8 Hz, 1H), 8.85 (d,J = 9.3 Hz, 1H), 8.81 (d,J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.94 – 7.85 (m, 1H), 7.00 (s, 1H), 3.90 (s, 3H), 3.82 – 3.75 (m, 2H), 3.70 – 3.65 (m, 1H), 3.38 (s, 3H), 3.31 – 3.19 (m, 5H), 3.19 – 2.96 (m, 4H), 2.95 – 2.88 (m, 2H), 2.87 (s, 3H), 2.21 – 2.12 (m, 2H), 1.99 – 1.90 (m, 2H), 1.24 – 1.17 (m, 1H), 1.05 – 0.93 (m, 1H), 0.49 – 0.37 (m, 1H), 0.34 – 0.22 (m, 1H). MS (ESI)m/z : 693 [M+H]+ . | |
I-304 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.9 Hz, 1H), 8.82 (d,J = 1.8 Hz, 1H), 8.73 (d,J = 9.7 Hz, 1H), 8.16 (s, 1H), 7.91 – 7.72 (m, 2H), 7.01 (s, 1H), 6.95 (dd,J = 17.8, 11.0 Hz, 1H), 5.39 (d,J = 17.7 Hz, 1H), 5.01 (d,J = 11.0 Hz, 1H), 3.68 – 3.63 (m, 1H), 3.34 (s, 3H), 3.28 – 2.99 (m, 10H), 2.83 – 2.78 (m, 4H), 2.76 – 2.71 (m, 2H), 2.11 – 2.01 (m, 2H), 1.87 – 1.79 (m, 2H), 1.25 – 1.20 (m, 1H), 1.03 – 0.97 (m, 1H), 0.45 – 0.38 (m, 1H), 0.33 – 0.25 (m, 1H). MS (ESI)m/z : 773 [M+H]+ . | |
I-305 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 (d,J = 1.9 Hz, 1H), 8.86 – 8.75 (m, 2H), 8.12 (s, 1H), 7.94 – 7.81 (m, 1H), 7.70 – 7.61 (m, 1H), 6.28 (d,J = 8.5 Hz, 1H), 4.48 – 4.38 (m, 2H), 3.84 (s, 3H), 3.68 – 3.62 (m, 1H), 3.37 (s, 3H), 3.36 – 3.34 (m, 1H), 3.31 – 3.14 (m, 7H), 3.07 – 3.01 (m, 1H), 2.89 – 2.84 (m, 2H), 2.83 (s, 3H), 2.10 – 2.02 (m, 2H), 1.73 – 1.61 (m, 2H), 1.33 – 1.27 (m, 1H), 1.06 – 0.95 (m, 1H), 0.48 – 0.35 (m, 1H), 0.35 – 0.25 (m, 1H). MS (ESI)m/z : 738 [M+H]+ . | |
I-306 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.87 – 8.81 (m, 1H), 8.77 (s, 1H), 8.32 (d,J = 12.6 Hz, 2H), 7.75 (s, 1H), 7.43 (s, 1H), 4.10 – 3.85 (m, 7H), 3.71 – 3.59 (m, 4H), 3.40 (s, 3H), 3.08 – 2.81 (m, 4H), 2.77 – 2.70 (m, 5H), 2.05 (s, 3H), 1.95 – 1.80 (m, 2H), 1.56 – 1.37 (m, 2H), 1.31 – 1.20 (m, 1H), 1.07 – 0.96 (m, 1H), 0.50 – 0.37 (m, 1H), 0.30 – 0.23 (m, 1H). MS (ESI)m/z : 752 [M+H]+ . | |
I-307 | MS (ESI)m/z : 817 [M+H]+ . | |
I-308 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.9 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.71 – 8.57 (m, 1H), 8.19 (s, 1H), 7.92 (d,J = 9.3 Hz, 1H), 7.76 (s, 1H), 6.81 (s, 1H), 3.82 (s, 3H), 3.73 – 3.62 (m, 1H), 3.38 – 3.22 (m, 11H), 3.18 – 3.09 (m, 2H), 3.03 – 2.95 (m, 1H), 2.88 – 2.76 (m, 5H), 2.49 – 2.42 (m, 1H), 2.33 – 2.21 (m, 1H), 2.15 – 2.05 (m, 2H), 1.90 – 1.75 (m, 2H), 1.30 – 1.16 (m, 1H), 1.04 – 0.91 (m, 1H), 0.64 – 0.47 (m, 1H), 0.41 – 0.31 (m, 1H), 0.32 – 0.23 (m, 1H), 0.20 – 0.01 (m, 2H), -0.12 – -0.30 (m, 2H). MS (ESI)m/z : 791 [M+H]+ . | |
I-309 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 – 8.89 (m, 1H), 8.82 (d,J = 1.8 Hz, 1H), 8.81 – 8.77 (m, 1H), 8.18 (s, 1H), 7.94 (d,J = 9.3 Hz, 1H), 7.67 (s, 1H), 6.75 (s, 1H), 3.84 (s, 3H), 3.72 – 3.64 (m, 1H), 3.63 – 3.53 (m, 2H), 3.36 (s, 3H), 3.35 – 3.31 (m, 2H), 3.29 – 3.19 (m, 2H), 3.09 (t,J = 12.5 Hz, 2H), 2.99 (s, 3H), 2.09 (s, 3H), 1.29 – 1.24 (m, 1H), 1.01 – 0.93 (m, 1H), 0.45 – 0.35 (m, 1H), 0.35 – 0.26 (m, 1H). MS (ESI)m/z : 668 [M+H]+ . | |
I-310 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.90 – 8.76 (m, 1H), 8.48 (s, 1H), 8.32 (d,J = 2.9 Hz, 2H), 7.94 (d,J = 9.4 Hz, 1H), 7.47 (s, 1H), 6.82 (s, 1H), 3.80 (s, 3H), 3.65 – 3.59 (m, 1H), 3.57 – 3.48 (m, 2H), 3.38 (s, 3H), 3.31 – 3.21 (m, 2H), 3.19 – 3.05 (m, 4H), 2.91 (s, 3H), 2.59 – 2.52 (m, 1H), 2.49 – 2.42 (m, 1H), 1.26 – 1.15 (m, 1H), 1.00 – 0.95 (m, 1H), 0.94 – 0.85 (m, 3H), 0.46 – 0.35 (m, 1H), 0.31 – 0.16 (m, 1H). MS (ESI)m/z : 682 [M+H]+ . | |
I-311 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.91 (d,J = 2.0 Hz, 1H), 8.84 – 8.80 (m, 1H), 8.80 (d,J = 1.9 Hz, 1H), 8.14 (s, 1H), 7.90 (d,J = 9.3 Hz, 1H), 7.61 (s, 1H), 6.70 (s, 1H), 3.80 (s, 3H), 3.69 – 3.63 (m, 1H), 3.36 (s, 3H), 3.31 – 3.26 (m, 1H), 3.25 – 3.13 (m, 2H), 2.92 (s, 6H), 2.76 (t,J = 11.6 Hz, 2H), 2.22 – 2.14 (m, 2H), 2.06 (s, 3H), 1.97 – 1.85 (m, 2H), 1.33 – 1.19 (m, 1H), 1.03 – 0.91 (m, 1H), 0.45 – 0.37 (m, 1H), 0.35 – 0.27 (m, 1H). MS (ESI)m/z : 696 [M+H]+ . | |
I-312 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.8 Hz, 1H), 8.85 – 8.76 (m, 2H), 8.15 (s, 1H), 7.91 (d,J = 9.3 Hz, 1H), 7.56 – 7.52 (m, 1H), 6.71 (d,J = 2.1 Hz, 1H), 4.04 – 3.97 (m, 1H), 3.82 (d,J = 1.7 Hz, 3H), 3.69 – 3.63 (m, 1H), 3.51 – 3.43 (m, 1H), 3.40 – 3.34 (m, 5H), 3.15 – 3.06 (m, 1H), 2.98 (d,J = 4.2 Hz, 6H), 2.52 – 2.43 (m, 1H), 2.24 – 2.16 (m, 1H), 2.10 (s, 3H), 1.29 – 1.24 (m, 1H), 1.04 – 0.93 (m, 1H), 0.44 – 0.35 (m, 1H), 0.34 – 0.26 (m, 1H). MS (ESI)m/z : 682 [M+H]+ . | |
I-313 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 2.0 Hz, 1H), 8.61 – 8.47 (m, 1H), 8.09 (d,J = 9.3 Hz, 1H), 7.77 (s, 1H), 7.31 – 7.23 (m, 1H), 6.77 (s, 1H), 3.85 – 3.81 (m, 5H), 3.46 (s, 3H), 3.42 – 3.33 (m, 4H), 3.31 – 3.19 (m, 4H), 3.16 (s, 3H), 3.07 – 3.00 (m, 1H), 2.97 – 2.89 (m, 2H), 2.87 (s, 3H), 2.28 (s, 3H), 2.16 – 2.11 (m, 2H), 1.87 – 1.78 (m, 2H). MS (ESI)m/z : 647 [M+H]+ . | |
I-314 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.24 (d,J = 8.7 Hz, 1H), 7.96 (d,J = 9.2 Hz, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.04 (s, 1H), 3.41 (s, 3H), 3.38 – 3.20 (m, 8H), 3.14 (s, 3H), 3.11 – 3.04 (m, 2H), 3.00 – 2.93 (m, 1H), 2.85 (s, 3H), 2.75 – 2.68 (m, 2H), 2.51 – 2.42 (m, 1H), 2.36 – 2.32 (m, 1H), 2.31 (s, 3H), 2.15 – 2.07 (m, 2H), 1.87 – 1.76 (m, 2H), 0.92 – 0.83 (m, 3H). MS (ESI)m/z : 729 [M+H]+ . | |
I-315 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.42 (d,J = 9.1 Hz, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.37 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.66 – 3.51 (m, 2H), 3.44 (s, 3H), 3.32 – 3.25 (m, 2H), 3.18 – 3.11 (m, 7H), 2.99 (s, 3H), 2.44 – 2.36 (m, 1H), 2.34 – 2.24 (m, 4H), 0.85 – 0.70 (m, 3H). MS (ESI)m/z : 592 [M+H]+ . | |
I-316 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.59 – 8.49 (m, 1H), 8.11 (d,J = 9.3 Hz, 1H), 7.73 (s, 1H), 7.32 – 7.21 (m, 1H), 6.77 (s, 1H), 6.57 – 6.47 (m, 1H), 3.89 – 3.79 (m, 5H), 3.46 (s, 3H), 3.42 – 3.32 (m, 4H), 3.30 – 3.17 (m, 4H), 3.16 (s, 3H), 3.04 – 2.97 (m, 1H), 2.92 (t,J = 12.2 Hz, 2H), 2.87 (s, 3H), 2.73 – 2.66 (m, 2H), 2.16 – 2.10 (m, 2H), 1.87 – 1.78 (m, 2H), 1.37 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 661 [M+H]+ . | |
I-317 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.46 (br s,J = 34.6 Hz, 1H), 8.13 – 8.04 (m, 1H), 7.81 – 7.72 (m, 1H), 7.19 (s, 1H), 6.76 (s, 1H), 3.82 (s, 3H), 3.46 – 3.35 (m, 9H), 3.26 – 3.17 (m, 2H), 3.15 (s, 3H), 3.12 – 3.06 (m, 1H), 2.89 (s, 3H), 2.81 – 2.74 (m, 2H), 2.72 – 2.67 (m, 2H), 2.19 – 2.11 (m, 2H), 1.98 – 1.80 (m, 4H), 1.38 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 675 [M+H]+ . | |
I-318 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.39 (br s, 1H), 8.12 – 8.00 (m, 1H), 7.83 – 7.67 (m, 1H), 7.24 (s, 1H), 6.80 (s, 1H), 3.83 (s, 3H), 3.44 (s, 3H), 3.36 – 3.23 (m, 10H), 3.16 – 3.08 (m, 5H), 3.01 – 2.94 (m, 1H), 2.83 (s, 3H), 2.81 – 2.75 (m, 2H), 2.72 – 2.67 (m, 2H), 2.49 – 2.19 (m, 2H), 2.13 – 2.07 (m, 2H), 1.87 – 1.77 (m, 2H), 1.38 (t,J = 7.4 Hz, 3H), 1.03 – 0.62 (m, 3H). MS (ESI)m/z : 689 [M+H]+ . | |
I-319 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.47 – 8.37 (m, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.20 (d,J = 2.6 Hz, 1H), 7.10 (dd,J = 8.5, 2.6 Hz, 1H), 7.00 (d,J = 8.6 Hz, 1H), 3.41 (s, 3H), 3.39 – 3.36 (m, 1H), 3.23 – 3.05 (m, 12H), 2.88 – 2.82 (m, 1H), 2.78 (s, 3H), 2.73 – 2.68 (m, 4H), 2.55 – 2.36 (m, 2H), 2.10 – 2.01 (m, 2H), 1.83 – 1.73 (m, 2H), 1.38 (t,J = 7.5 Hz, 4H), 1.00 – 0.91 (m, 3H). MS (ESI)m/z : 659 [M+H]+ . | |
I-320 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.31 (br s, 1H), 8.06 (d,J = 9.0 Hz, 1H), 7.86 – 7.76 (m, 1H), 7.54 (s, 1H), 3.91 (s, 3H), 3.52 – 3.40 (m, 6H), 3.39 – 3.23 (m, 7H), 3.14 (s, 3H), 3.08 – 3.02 (m, 1H), 2.92 – 2.86 (m, 2H), 2.84 (s, 3H), 2.70 (q,J = 7.4 Hz, 2H), 2.37 – 2.23 (m, 1H), 2.18 – 2.03 (m, 3H), 1.88 – 1.77 (m, 2H), 1.38 (t,J = 7.5 Hz, 3H), 0.93 – 0.52 (m, 3H). MS (ESI)m/z : 690 [M+H]+ . | |
I-321 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.22 (d,J = 9.1 Hz, 1H), 7.95 (d,J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.35 (s, 1H), 7.03 (s, 1H), 3.41 (s, 3H), 3.38 – 3.17 (m, 8H), 3.13 (s, 3H), 3.11 – 3.04 (m, 2H), 2.97 – 2.91 (m, 1H), 2.85 (s, 3H), 2.70 (q,J = 7.4 Hz, 4H), 2.50 – 2.39 (m, 1H), 2.35 – 2.25 (m, 1H), 2.14 – 2.05 (m, 2H), 1.87 – 1.76 (m, 2H), 1.39 (t,J = 7.5 Hz, 3H), 0.91 – 0.78 (m, 3H). MS (ESI)m/z : 743 [M+H]+ . | |
I-322 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.38 (s, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.81 (s, 1H), 7.34 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.66 – 3.57 (m, 2H), 3.45 (s, 3H), 3.31 – 3.26 (m, 2H), 3.20 – 3.11 (m, 7H), 2.99 (s, 3H), 2.70 (q,J = 7.4 Hz, 2H), 2.42 – 2.19 (m, 2H), 1.38 (t,J = 7.4 Hz, 3H), 0.92 – 0.62 (m, 3H). MS (ESI)m/z : 606 [M+H]+ . | |
I-323 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.46 – 8.33 (m, 1H), 8.10 – 8.01 (m, 1H), 7.82 – 7.72 (m, 1H), 7.28 (s, 1H), 6.80 (s, 1H), 3.83 (s, 3H), 3.44 (s, 3H), 3.35 – 3.32 (m, 1H), 3.19 – 3.12 (m, 5H), 2.93 (s, 6H), 2.84 – 2.78 (m, 2H), 2.69 (q,J = 7.5 Hz, 2H), 2.42 – 2.25 (m, 2H), 2.20 – 2.14 (m, 2H), 1.95 – 1.86 (m, 2H), 1.38 (t,J = 7.5 Hz, 3H), 0.92 – 0.74 (m, 3H). MS (ESI)m/z : 634 [M+H]+ . | |
I-324 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.41 (br s, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.84 – 7.74 (m, 1H), 7.26 (s, 1H), 6.79 (d,J = 2.1 Hz, 1H), 4.07 – 3.96 (m, 1H), 3.84 (s, 3H), 3.46 (s, 3H), 3.42 – 3.38 (m, 2H), 3.31 – 3.27 (m, 1H), 3.14 (s, 3H), 3.12 – 3.07 (m, 1H), 2.97 (d,J = 2.1 Hz, 6H), 2.71 – 2.67 (m, 2H), 2.52 – 2.45 (m, 1H), 2.43 – 2.25 (m, 2H), 2.25 – 2.15 (m, 1H), 1.38 (t,J = 7.5 Hz, 3H), 0.94 – 0.67 (m, 3H). MS (ESI)m/z : 620 [M+H]+ . | |
I-325 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.57 – 8.42 (m, 1H), 8.11 (d,J = 9.3 Hz, 1H), 7.83 – 7.67 (m, 1H), 7.27 (d,J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.60 – 6.44 (m, 1H), 3.86 – 3.79 (m, 5H), 3.49 – 3.36 (m, 7H), 3.31 – 3.23 (m, 4H), 3.15 (s, 3H), 3.12 – 3.03 (m, 2H), 2.98 – 2.91 (m, 2H), 2.89 (s, 3H), 2.19 – 2.07 (m, 2H), 1.90 – 1.78 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.39 (d,J = 6.8 Hz, 3H). MS (ESI)m/z : 675 [M+H]+ . | |
I-326 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.46 – 8.25 (m, 1H), 8.11 – 8.01 (m, 1H), 7.83 – 7.74 (m, 1H), 7.24 (s, 1H), 6.79 (s, 1H), 3.82 (s, 3H), 3.43 (s, 3H), 3.31 – 3.16 (m, 7H), 3.14 (s, 3H), 3.13 – 3.06 (m, 4H), 2.98 – 2.88 (m, 1H), 2.81 (s, 3H), 2.80 – 2.73 (m, 2H), 2.47 – 2.16 (m, 2H), 2.13 – 2.01 (m, 2H), 1.84 – 1.73 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.40 (d,J = 6.8 Hz, 3H), 1.00 – 0.48 (m, 3H). MS (ESI)m/z : 689 [M+H]+ . | |
I-327 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.40 – 8.18 (m, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.91 – 7.74 (m, 1H), 7.54 (s, 1H), 3.49 – 3.40 (m, 5H), 3.34 – 3.15 (m, 8H), 3.14 (s, 3H), 3.11 – 3.06 (m, 1H), 3.01 – 2.94 (m, 1H), 2.91 – 2.83 (m, 2H), 2.80 (s, 3H), 2.36 – 2.10 (m, 2H), 2.10 – 2.03 (m, 2H), 1.84 – 1.74 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.40 (d,J = 6.8 Hz, 3H), 0.73 (s, 3H). MS (ESI)m/z : 703 [M+H]+ . | |
I-328 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.40 – 8.18 (m, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.91 – 7.74 (m, 1H), 7.54 (s, 1H), 3.49 – 3.40 (m, 5H), 3.34 – 3.15 (m, 8H), 3.14 (s, 3H), 3.11 – 3.06 (m, 1H), 3.01 – 2.94 (m, 1H), 2.91 – 2.83 (m, 2H), 2.80 (s, 3H), 2.36 – 2.10 (m, 2H), 2.10 – 2.03 (m, 2H), 1.84 – 1.74 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.40 (d,J = 6.8 Hz, 3H), 0.73 (s, 3H). MS (ESI)m/z : 704 [M+H]+ . | |
I-329 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.39 (d,J = 9.0 Hz, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.85 (s, 1H), 7.39 (s, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.70 – 3.51 (m, 2H), 3.45 (s, 3H), 3.31 – 3.21 (m, 2H), 3.16 – 3.11 (m, 7H), 3.08 (q,J = 6.8 Hz, 1H), 2.98 (s, 3H), 2.42 – 2.15 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.40 (d,J = 6.8 Hz, 3H), 0.87 – 0.65 (m, 3H). MS (ESI)m/z : 620 [M+H]+ . | |
I-330 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.51 – 8.21 (m, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.27 (s, 1H), 6.80 (s, 1H), 3.83 (s, 3H), 3.44 (s, 3H), 3.35 – 3.32 (m, 1H), 3.17 – 3.06 (m, 6H), 2.93 (s, 6H), 2.85 – 2.75 (m, 2H), 2.48 – 2.21 (m, 2H), 2.22 – 2.15 (m, 2H), 1.95 – 1.83 (m, 2H), 1.42 (d,J = 6.8 Hz, 3H), 1.40 (d,J = 6.7 Hz, 3H), 0.97 – 0.50 (m, 3H). MS (ESI)m/z : 648 [M+H]+ . | |
I-331 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.46 – 8.26 (m, 1H), 8.13 – 7.97 (m, 1H), 7.80 (s, 1H), 7.25 (s, 1H), 6.79 (d,J = 2.8 Hz, 1H), 4.05 – 3.96 (m, 1H), 3.84 (s, 3H), 3.45 (s, 3H), 3.42 – 3.38 (m, 2H), 3.30 – 3.27 (m, 1H), 3.14 (s, 3H), 3.12 – 3.05 (m, 2H), 2.97 (d,J = 2.0 Hz, 6H), 2.51 – 2.43 (m, 1H), 2.42 – 2.25 (m, 2H), 2.24 – 2.16 (m, 1H), 1.42 (d,J = 6.7 Hz, 3H), 1.40 (d,J = 6.8 Hz, 3H), 0.97 – 0.57 (m, 3H). MS (ESI)m/z : 634 [M+H]+ . | |
I-332 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.71 (d,J = 8.0 Hz, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 6.80 (s, 1H), 4.01 (s, 3H), 3.83 (s, 3H), 3.47 (s, 3H), 3.30 – 3.00 (m, 13H), 2.96 – 2.87 (m, 1H), 2.84 – 2.74 (m, 5H), 2.14 – 2.07 (m, 5H), 1.89 – 1.76 (m, 2H). MS (ESI)m/z : 677 [M+H]+ . | |
I-333 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.74 – 8.56 (m, 1H), 8.08 (d,J = 9.4 Hz, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 6.84 (s, 1H), 4.02 (s, 3H), 3.84 (s, 3H), 3.47 (s, 3H), 3.30 – 2.97 (m, 13H), 2.91 – 2.76 (m, 6H), 2.57 – 2.38 (m, 2H), 2.13 – 2.03 (m, 2H), 1.85 – 1.72 (m, 2H), 1.04 – 0.86 (m, 3H). MS (ESI)m/z : 691 [M+H]+ . | |
I-334 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.61 – 8.50 (m, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.55 – 3.49 (m, 2H), 3.47 (s, 3H), 3.37 – 3.23 (m, 8H), 3.17 (s, 3H), 3.09 – 3.00 (m, 1H), 2.96 – 2.88 (m, 2H), 2.83 (s, 3H), 2.47 – 2.27 (m, 2H), 2.16 – 2.03 (m, 2H), 1.94 – 1.78 (m, 2H), 0.89 (s, 3H). MS (ESI)m/z : 692 [M+H]+ . | |
I-335 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.8 Hz, 1H), 8.69 (d,J = 9.3 Hz, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 6.82 (s, 1H), 4.06 – 3.98 (m, 4H), 3.85 (s, 3H), 3.47 (s, 3H), 3.45 – 3.40 (m, 2H), 3.35 – 3.32 (m, 1H), 3.18 (s, 3H), 3.17 – 3.11 (m, 1H), 2.98 (s, 6H), 2.56 – 2.43 (m, 3H), 2.28 – 2.16 (m, 1H), 1.00 – 0.88 (m, 3H). MS (ESI)m/z : 622 [M+H]+ . | |
I-336 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 9.3 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.06 (d,J = 9.4 Hz, 1H), 7.60 (s, 1H), 7.36 (s, 1H), 6.80 (s, 1H), 4.24 – 4.15 (m, 2H), 3.84 (s, 3H), 3.48 (s, 3H), 3.30 – 3.22 (m, 5H), 3.21 (s, 3H), 3.18 – 2.68 (m, 11H), 2.18 (s, 3H), 2.10 – 2.04 (m, 2H), 1.85 – 1.72 (m, 2H), 1.55 (t,J = 6.9 Hz, 3H). MS (ESI)m/z : 691 [M+H]+ . | |
I-337 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 9.6 Hz, 1H), 8.05 (d,J = 9.4 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 6.86 (s, 1H), 4.22 – 4.13 (m, 2H), 3.84 (s, 3H), 3.48 (s, 3H), 3.36 – 3.22 (m, 3H), 3.20 (s, 3H), 3.18 – 3.15 (m, 2H), 3.14 – 2.87 (m, 4H), 2.87 – 2.78 (m, 4H), 2.76 (s, 3H), 2.60 – 2.53 (m, 2H), 2.13 – 2.01 (m, 2H), 1.87 – 1.75 (m, 2H), 1.55 (t,J = 6.9 Hz, 3H), 1.03 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 705 [M+H]+ . | |
I-338 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.9 Hz, 1H), 8.79 (d,J = 9.4 Hz, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 4.22 – 4.14 (m, 2H), 3.93 (s, 3H), 3.53 – 3.46 (m, 5H), 3.26 – 3.21 (m, 1H), 3.20 (s, 3H), 3.18 – 2.79 (m, 10H), 2.75 (s, 3H), 2.55 – 2.46 (m, 2H), 2.09 – 2.03 (m, 2H), 1.83 – 1.73 (m, 2H), 1.54 (t,J = 6.9 Hz, 3H), 1.01 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 706 [M+H]+ . | |
I-339 | MS (ESI)m/z : 633 [M+H]+ . | |
I-340 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.49 – 8.15 (m, 1H), 8.14 – 7.99 (m, 1H), 7.96 – 7.80 (m, 1H), 7.34 – 7.17 (m, 1H), 6.76 (s, 1H), 6.67 (d,J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.63 – 3.37 (m, 11H), 3.27 – 3.16 (m, 3H), 3.14 (s, 3H), 2.92 (s, 3H), 2.83 – 2.73 (m, 2H), 2.21 – 2.13 (m, 2H), 2.05 – 1.71 (m, 5H). MS (ESI)m/z : 647 [M+H]+ . | |
I-341 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.42 – 8.11 (m, 1H), 8.11 – 7.97 (m, 1H), 7.96 – 7.83 (m, 1H), 7.30 (s, 1H), 6.79 (s, 1H), 6.66 (d,J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.58 – 3.40 (m, 11H), 3.20 – 3.10 (m, 6H), 2.91 (s, 3H), 2.85 – 2.76 (m, 2H), 2.21 – 2.10 (m, 2H), 1.94 – 1.80 (m, 2H), 1.42 – 1.35 (m, 2H), 1.07 – 0.33 (m, 3H). MS (ESI)m/z : 661 [M+H]+ . | |
I-342 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.31 – 8.08 (m, 1H), 8.07 – 7.94 (m, 1H), 7.93 – 7.80 (m, 1H), 7.24 (s, 1H), 6.81 (s, 1H), 6.65 (d,J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.47 (s, 3H), 3.39 – 3.18 (m, 9H), 3.12 (s, 3H), 3.09 – 3.02 (m, 2H), 3.01 – 2.94 (m, 1H), 2.84 – 2.77 (m, 5H), 2.14 – 2.07 (m, 2H), 1.86 – 1.77 (m, 2H), 1.30 – 0.43 (m, 6H). MS (ESI)m/z : 675 [M+H]+ . | |
I-343 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.30 – 8.07 (m, 1H), 8.05 – 7.93 (m, 1H), 7.91 – 7.81 (m, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.64 (d,J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 3.44 – 3.38 (m, 2H), 3.31 – 3.22 (m, 8H), 3.13 (s, 3H), 3.02 – 2.93 (m, 1H), 2.82 (s, 3H), 2.80 – 2.74 (m, 2H), 2.15 – 2.07 (m, 2H), 2.04 – 1.90 (m, 1H), 1.89 – 1.80 (m, 2H), 1.05 – -0.04 (m, 4H). MS (ESI)m/z : 673 [M+H]+ . | |
I-344 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.34 – 8.15 (m, 1H), 8.02 (d,J = 9.2 Hz, 1H), 7.93 – 7.84 (m, 1H), 7.25 (d,J = 2.5 Hz, 1H), 7.12 (dd,J = 8.4, 2.7 Hz, 1H), 7.07 – 6.95 (m, 1H), 6.67 (d,J = 7.2 Hz, 1H), 3.46 (s, 3H), 3.44 – 3.32 (m, 8H), 3.14 – 3.05 (m, 6H), 2.87 (s, 3H), 2.79 – 2.72 (m, 2H), 2.56 – 2.30 (m, 2H), 2.19 – 2.09 (m, 2H), 1.90 – 1.80 (m, 2H), 1.06 – 0.63 (m, 3H). MS (ESI)m/z : 631 [M+H]+ . | |
I-345 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.94 (d,J = 1.8 Hz, 1H), 8.88 – 8.81 (m, 1H), 8.46 – 8.37 (m, 2H), 7.98 – 7.72 (m, 1H), 7.11 – 6.89 (m, 1H), 6.74 (s, 1H), 3.81 (s, 3H), 3.49 – 3.42 (m, 5H), 3.25 – 3.09 (m, 9H), 2.93 (s, 1H), 2.87 – 2.75 (m, 6H), 2.14 – 2.08 (m, 2H), 2.07 – 1.90 (m, 2H), 1.88 – 1.82 (m, 2H), 0.63 – 0.28 (m, 3H), 0.20 – -0.09 (m, 3H). MS (ESI)m/z : 700 [M+H]+ . | |
I-346 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.92 (d,J = 1.8 Hz, 1H), 8.83 – 8.78 (m, 1H), 8.65 – 8.48 (m, 1H), 8.41 (s, 1H), 8.07 – 7.87 (m, 1H), 7.52 – 7.19 (m, 2H), 7.16 – 6.99 (m, 1H), 3.64 – 3.32 (m, 11H), 3.24 – 3.16 (m, 5H), 3.14 – 3.07 (m, 1H), 2.97 – 2.84 (m, 5H), 2.64 – 2.36 (m, 2H), 2.22 – 2.09 (m, 2H), 1.99 – 1.86 (m, 2H), 1.19 – 0.77 (m, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-347 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 9.78 – 9.66 (m, 1H), 9.11 – 8.98 (m, 2H), 8.50 (s, 1H), 8.17 – 8.05 (m, 2H), 7.52 – 7.40 (m, 1H), 7.05 – 6.92 (m, 1H), 3.88 – 3.79 (m, 3H), 3.75 – 3.28 (m, 15H), 3.24 – 3.20 (m, 3H), 3.14 – 2.97 (m, 2H), 2.89 (s, 3H), 2.84 – 2.75 (m, 1H), 2.27 – 1.91 (m, 2H), 1.84 – 1.63 (m, 2H), 1.57 – 1.30 (m, 1H), 1.16 – 1.05 (m, 3H), 0.89 – 0.64 (m, 4H). MS (ESI)m/z : 729 [M+H]+ . | |
I-348 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.40 (d,J = 9.3 Hz, 1H), 7.99 (d,J = 9.2 Hz, 1H), 7.85 (s, 1H), 7.13 – 7.06 (m, 1H), 6.73 (t,J = 8.6 Hz, 1H), 3.54 – 3.46 (m, 2H), 3.41 (s, 3H), 3.34 – 3.18 (m, 6H), 3.14 (s, 3H), 3.12 – 2.91 (m, 3H), 2.82 (s, 3H), 2.80 – 2.72 (m, 3H), 2.69 (q,J = 7.6 Hz, 2H), 2.11 – 1.98 (m, 2H), 1.84 – 1.70 (m, 2H), 1.38 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 667 [M+H]+ . | |
I-349 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.35 (d,J = 9.2 Hz, 1H), 8.15 (d,J = 9.1 Hz, 1H), 7.87 (s, 1H), 6.97 (d,J = 10.7 Hz, 2H), 3.43 (s, 3H), 3.40 – 3.23 (m, 8H), 3.18 – 3.13 (m, 5H), 3.06 (t,J = 11.8 Hz, 2H), 3.01 – 2.95 (m, 1H), 2.85 (s, 3H), 2.71 (q,J = 7.4 Hz, 2H), 2.06 – 1.96 (m, 2H), 1.82 – 1.71 (m, 2H), 1.39 (d,J = 7.5 Hz, 3H). MS (ESI)m/z : 667 [M+H]+ . | |
I-350 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 2.0 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.33 (d,J = 12.0 Hz, 1H), 8.18 – 8.05 (m, 1H), 7.89 (d,J = 9.6 Hz, 1H), 7.53 – 7.46 (m, 1H), 6.90 – 6.79 (m, 1H), 3.91 – 3.84 (m, 3H), 3.49 – 3.43 (m, 3H), 3.43 – 3.18 (m, 8H), 3.14 (s, 3H), 3.12 – 2.88 (m, 5H), 2.88 – 2.85 (m, 3H), 2.75 – 2.69 (m, 2H), 2.09 – 2.00 (m, 2H), 1.99 – 1.79 (m, 2H), 1.66 – 1.47 (m, 2H), 1.40 (t,J = 7.4 Hz, 3H), 0.70 – 0.46 (m, 3H). MS (ESI)m/z : 717 [M+H]+ . | |
I-351 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.81 (d,J = 9.4 Hz, 1H), 8.33 (s, 1H), 8.10 (d,J = 9.4 Hz, 1H), 7.96 (s, 1H), 7.08 – 7.04 (m, 1H), 3.91 (s, 3H), 3.50 (s, 3H), 3.21 (s, 3H), 3.20 – 3.14 (m, 2H), 3.13 – 3.00 (m, 2H), 2.88 – 2.80 (m, 1H), 2.06 – 1.95 (m, 2H), 1.92 – 1.76 (m, 2H). MS (ESI)m/z : 638 [M+H]+ . | |
I-352 | 1 H NMR (600 MHz, Chloroform-d ) δ 9.61 (s, 1H), 9.01 (d,J = 9.1 Hz, 1H), 8.87 – 8.79 (m, 3H), 8.32 (s, 1H), 8.13 (d,J = 9.3 Hz, 1H), 8.10 – 8.02 (m, 1H), 7.63 (s, 1H), 6.83 (d,J = 8.7 Hz, 1H), 6.56 (dd,J = 8.6, 2.8 Hz, 1H), 3.89 (s, 3H), 3.51 (s, 3H), 3.24 – 3.10 (m, 11H). MS (ESI)m/z : 614 [M+H]+ . | |
I-353 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.91 – 8.81 (m, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 7.22 (t,J = 8.7 Hz, 1H), 6.91 – 6.82 (m, 1H), 3.65 – 3.36 (m, 11H), 3.25 (s, 3H), 3.13 – 2.89 (m, 3H), 2.81 – 2.71 (m, 5H), 2.09 – 1.99 (m, 2H), 1.77 – 1.66 (m, 2H). MS (ESI)m/z : 717 [M+H]+ . | |
I-354 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.01 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.90 – 8.78 (m, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.14 (d,J = 9.3 Hz, 1H), 7.40 – 7.30 (m, 2H), 3.93 – 3.28 (m, 11H), 3.23 (s, 3H), 3.15 – 3.11 (m, 2H), 3.01 (t,J = 11.8 Hz, 3H), 2.78 (s, 3H), 2.01 – 1.92 (m, 2H), 1.69 – 1.56 (m, 2H). MS (ESI)m/z : 717 [M+H]+ . | |
I-355 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 – 8.92 (m, 1H), 8.81 – 8.74 (m, 1H), 8.72 – 8.69 (m, 1H), 8.61 – 8.54 (m, 1H), 8.39 (s, 1H), 8.05 – 7.99 (m, 1H), 7.63 – 7.55 (m, 1H), 6.94 – 6.85 (m, 1H), 3.87 – 3.74 (m, 3H), 3.69 – 3.42 (m, 8H), 3.38 (s, 3H), 3.23 (s, 3H), 3.20 – 2.93 (m, 4H), 2.83 (s, 3H), 2.80 – 2.71 (m, 1H), 2.42 – 2.18 (m, 2H), 2.13 – 1.80 (m, 2H), 1.66 – 1.22 (m, 2H), 0.90 – 0.74 (m, 3H). MS (ESI)m/z : 767 [M+H]+ . | |
I-356 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 29.4 Hz, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 7.93 (d,J = 8.9 Hz, 1H), 7.25 – 7.17 (m, 1H), 6.91 – 6.78 (m, 1H), 3.61 – 3.42 (m, 6H), 3.37 (s, 3H), 3.24 (s, 3H), 3.20 – 2.86 (m, 5H), 2.81 – 2.71 (m, 5H), 2.12 – 1.98 (m, 2H), 1.78 – 1.65 (m, 2H). MS (ESI)m/z : 673 [M+H]+ . | |
I-357 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 9.8 Hz, 1H), 8.95 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 8.10 (d,J = 9.2 Hz, 1H), 7.23 (d,J = 11.9 Hz, 2H), 3.48 (s, 3H), 3.38 – 3.18 (m, 13H), 3.15 – 3.09 (m, 2H), 3.03 – 2.94 (m, 1H), 2.83 (s, 3H), 2.10 – 1.96 (m, 2H), 1.84 – 1.72 (m, 2H). MS (ESI)m/z : 673 [M+H]+ . | |
I-358 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 – 8.92 (m, 1H), 8.89 – 8.83 (m, 1H), 8.70 – 8.61 (m, 1H), 8.21 (d,J = 2.8 Hz, 1H), 8.06 (dd,J = 9.1, 5.1 Hz, 1H), 7.85 (d,J = 4.9 Hz, 1H), 6.88 – 6.74 (m, 1H), 3.88 (dd,J = 12.6, 5.0 Hz, 3H), 3.70 – 3.51 (m, 2H), 3.48 – 3.44 (m, 3H), 3.42 – 3.27 (m, 6H), 3.18 (s, 3H), 3.14 – 2.97 (m, 4H), 2.90 – 2.85 (m, 4H), 2.37 – 2.18 (m, 2H), 2.15 – 1.99 (m, 1H), 1.99 – 1.89 (m, 1H), 1.70 – 1.48 (m, 2H), 0.87 – 0.66 (m, 3H). MS (ESI)m/z : 723 [M+H]+ . | |
I-359 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 9.30 (s, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.94 (s, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.72 – 8.60 (m, 1H), 8.34 (s, 1H), 7.88 (d,J = 9.4 Hz, 1H), 7.18 (t,J = 8.5 Hz, 1H), 6.88 – 6.77 (m, 1H), 3.87 – 3.59 (m, 8H), 3.55 – 3.48 (m, 2H), 3.45 – 3.36 (m, 1H), 3.03 (s, 3H), 2.91 (s, 3H), 2.80 – 2.70 (m, 2H), 2.24 – 2.13 (m, 2H), 1.88 – 1.76 (m, 2H). MS (ESI)m/z : 703 [M+H]+ . | |
I-360 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 9.82 (s, 1H), 9.05 (d,J = 1.9 Hz, 1H), 9.03 (s, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.72 – 8.61 (m, 1H), 8.43 (s, 1H), 8.11 (d,J = 9.2 Hz, 1H), 7.36 – 7.28 (m, 2H), 3.80 – 3.24 (m, 9H), 3.22 – 3.12 (m, 2H), 3.05 (s, 3H), 3.04 – 2.98 (m, 2H), 2.89 (s, 3H), 2.11 – 2.01 (m, 2H), 1.74 – 1.67 (m, 2H). MS (ESI)m/z : 703 [M+H]+ . | |
I-361 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 9.07 – 9.00 (m, 2H), 8.98 – 8.94 (m, 1H), 8.59 (d,J = 8.2 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.06 – 7.97 (m, 1H), 7.67 – 7.59 (m, 1H), 6.91 – 6.82 (m, 1H), 3.82 – 3.79 (m, 3H), 3.71 – 3.53 (m, 8H), 3.51 – 3.38 (m, 2H), 3.35 – 3.23 (m, 2H), 3.04 (s, 3H), 2.86 (s, 3H), 2.81 – 2.72 (m, 1H), 2.36 – 2.04 (m, 2H), 1.99 – 1.85 (m, 2H), 1.69 – 1.42 (m, 2H), 0.81 – 0.68 (m, 3H). MS (ESI)m/z : 753 [M+H]+ . | |
I-362 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.30 (d,J = 9.3 Hz, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.74 (d,J = 2.9 Hz, 1H), 7.45 (dd,J = 9.0, 3.0 Hz, 1H), 7.24 (d,J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.79 – 3.69 (m, 1H), 3.49 (s, 3H), 3.46 – 3.37 (m, 1H), 3.34 – 3.31 (m, 1H), 3.18 (s, 3H), 3.16 – 3.11 (m, 1H), 3.09 – 2.96 (m, 1H), 2.32 (s, 3H), 2.00 – 1.91 (m, 1H), 1.88 – 1.78 (m, 1H), 1.76 – 1.70 (m, 1H), 1.69 – 1.60 (m, 1H). MS (ESI)m/z : 565 [M+H]+ . | |
I-363 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.42 (d,J = 9.3 Hz, 1H), 8.06 (d,J = 9.2 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.23 (dd,J = 9.0, 2.8 Hz, 1H), 7.15 (d,J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.66 – 3.57 (m, 1H), 3.49 (s, 3H), 3.38 – 3.32 (m, 1H), 3.29 – 3.24 (m, 1H), 3.17 (s, 3H), 3.00 – 2.91 (m, 1H), 2.91 – 2.83 (m, 1H), 2.71 (q,J = 7.4 Hz, 2H), 1.90 – 1.82 (m, 1H), 1.81 – 1.75 (m, 1H), 1.67 – 1.60 (m, 1H), 1.59 – 1.53 (m, 1H), 1.38 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 579 [M+H]+ . | |
I-364 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.8 Hz, 1H), 8.43 (d,J = 9.3 Hz, 1H), 8.03 (d,J = 9.2 Hz, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 7.08 (s, 2H), 3.86 (s, 3H), 3.58 – 3.49 (m, 1H), 3.46 (s, 3H), 3.27 – 3.19 (m, 2H), 3.15 (s, 3H), 3.07 (p,J = 6.8 Hz, 1H), 2.84 – 2.69 (m, 2H), 1.84 – 1.66 (m, 2H), 1.60 – 1.44 (m, 2H), 1.39 (dd,J = 12.2, 6.8 Hz, 6H). MS (ESI)m/z : 593 [M+H]+ . | |
I-365 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.61 (d,J = 9.3 Hz, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.91 (s, 1H), 7.79 (d,J = 2.9 Hz, 1H), 7.41 (dd,J = 9.0, 3.0 Hz, 1H), 7.25 (d,J = 9.0 Hz, 1H), 3.93 (s, 3H), 3.77 – 3.65 (m, 1H), 3.53 (s, 3H), 3.50 – 3.44 (m, 1H), 3.44 – 3.37 (m, 1H), 3.20 (s, 3H), 3.19 – 3.14 (m, 1H), 3.14 – 3.03 (m, 1H), 2.00 – 1.90 (m, 1H), 1.90 – 1.81 (m, 1H), 1.79 – 1.75 (m, 1H), 1.74 – 1.67 (m, 1H), 1.66 – 1.59 (m, 1H), 1.29 – 1.22 (m, 1H), 1.21 – 1.13 (m, 1H), 0.93 – 0.81 (m, 1H), 0.79 – 0.71 (m, 1H). MS (ESI)m/z : 591 [M+H]+ . | |
I-366 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 1.9 Hz, 1H), 8.75 (d,J = 9.4 Hz, 1H), 8.06 (d,J = 9.3 Hz, 2H), 7.81 (s, 1H), 7.20 (dd,J = 8.8, 2.9 Hz, 1H), 7.14 (d,J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.76 – 3.68 (m, 1H), 3.55 – 3.41 (m, 5H), 3.22 (s, 3H), 3.19 – 3.12 (m, 1H), 3.13 – 3.04 (m, 1H), 2.02 – 1.92 (m, 1H), 1.91 – 1.84 (m, 1H), 1.77 – 1.61 (m, 2H). MS (ESI)m/z : 581 [M+H]+ . | |
I-367 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.89 (d,J = 1.7 Hz, 1H), 8.74 (d,J = 9.5 Hz, 1H), 8.62 – 8.48 (m, 1H), 8.22 (d,J = 3.2 Hz, 1H), 8.13 (d,J = 9.3 Hz, 1H), 7.22 – 7.11 (m, 2H), 3.98 (s, 3H), 3.63 – 3.56 (m, 2H), 3.52 (s, 3H), 3.36 – 3.33 (m, 2H), 3.26 – 3.16 (m, 4H), 2.00 – 1.73 (m, 4H). MS (ESI)m/z : 569 [M+H]+ . | |
I-368 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 (d,J = 1.9 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.79 (d,J = 9.3 Hz, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 8.04 (d,J = 9.3 Hz, 1H), 7.30 (dd,J = 8.8, 3.0 Hz, 1H), 7.18 (d,J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.93 – 3.84 (m, 1H), 3.67 – 3.61 (m, 1H), 3.60 – 3.54 (m, 1H), 3.50 (s, 3H), 3.45 – 3.38 (m, 1H), 3.37 – 3.34 (m, 1H), 3.23 (s, 3H), 2.15 – 2.04 (m, 1H), 2.03 – 1.95 (m, 1H), 1.92 – 1.84 (m, 1H), 1.82 – 1.75 (m, 1H). MS (ESI)m/z : 585 [M+H]+ . | |
I-369 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.9 Hz, 1H), 8.74 – 8.59 (m, 1H), 8.53 (s, 1H), 8.50 – 8.32 (m, 1H), 8.08 (d,J = 8.9 Hz, 1H), 7.32 (dd,J = 8.9, 2.9 Hz, 1H), 7.20 (d,J = 8.9 Hz, 1H), 3.96 (s, 3H), 3.90 – 3.79 (m, 1H), 3.68 – 3.53 (m, 2H), 3.49 (s, 3H), 3.41 – 3.34 (m, 2H), 3.19 (s, 3H), 2.13 – 1.90 (m, 2H), 1.88 – 1.70 (m, 2H). MS (ESI)m/z : 619 [M+H]+ . | |
I-370 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.56 (d,J = 9.4 Hz, 1H), 8.48 – 8.35 (m, 1H), 8.31 (s, 1H), 8.20 (d,J = 9.2 Hz, 1H), 7.17 (d,J = 8.1 Hz, 1H), 7.13 (d,J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.70 – 3.61 (m, 4H), 3.60 – 3.46 (m, 2H), 3.27 – 3.11 (m, 2H), 2.06 – 1.89 (m, 2H), 1.87 – 1.70 (m, 2H). MS (ESI)m/z : 639 [M+H]+ . | |
I-371 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.59 (d,J = 9.3 Hz, 1H), 8.45 – 8.39 (m, 2H), 8.18 (d,J = 9.3 Hz, 1H), 7.24 (dd,J = 8.8, 2.9 Hz, 1H), 7.15 (d,J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.83 – 3.72 (m, 1H), 3.64 (s, 3H), 3.63 – 3.50 (m, 2H), 3.36 – 3.33 (m, 1H), 3.30 – 3.24 (m, 1H), 2.09 – 2.03 (m, 1H), 2.01 – 1.93 (m, 1H), 1.91 – 1.83 (m, 1H), 1.82 – 1.72 (m, 1H). MS (ESI)m/z : 683 [M+H]+ . | |
I-372 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.83 (d,J = 9.3 Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.09 (d,J = 9.3 Hz, 1H), 7.22 (dd,J = 8.8, 2.8 Hz, 1H), 7.15 (d,J = 8.8 Hz, 1H), 3.97 (s, 3H), 3.89 – 3.79 (m, 1H), 3.66 – 3.47 (m, 7H), 3.42 – 3.32 (m, 2H), 3.28 – 3.21 (m, 1H), 2.10 – 1.95 (m, 2H), 1.90 – 1.83 (m, 1H), 1.81 – 1.70 (m, 1H), 1.45 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 599 [M+H]+ . | |
I-373 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.66 (d,J = 9.4 Hz, 1H), 8.53 – 8.42 (m, 1H), 8.21 (d,J = 3.3 Hz, 1H), 8.11 (d,J = 9.2 Hz, 1H), 7.22 (dd,J = 8.8, 2.9 Hz, 1H), 7.15 (d,J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.83 – 3.66 (m, 1H), 3.61 – 3.48 (m, 5H), 3.39 – 3.33 (m, 1H), 3.25 – 3.18 (m, 1H), 2.95 – 2.82 (m, 1H), 2.08 – 2.00 (m, 1H), 1.90 – 1.80 (m, 2H), 1.79 – 1.71 (m, 1H), 1.26 – 1.15 (m, 2H), 0.86 – 0.72 (m, 2H). MS (ESI)m/z : 595 [M+H]+ . | |
I-374 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.7 Hz, 1H), 8.85 (d,J = 2.1 Hz, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 8.15 – 8.04 (m, 2H), 7.24 (dd,J = 8.9, 2.8 Hz, 1H), 7.15 (d,J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.87 – 3.75 (m, 1H), 3.65 – 3.57 (m, 2H), 3.54 (s, 3H), 3.44 – 3.35 (m, 2H), 2.95 – 2.91 (m, 1H), 2.10 – 1.96 (m, 2H), 1.88 – 1.75 (m, 2H), 1.24 – 1.19 (m, 2H), 0.77 – 0.71 (m, 2H). MS (ESI)m/z : 611 [M+H]+ . | |
I-375 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.87 (d,J = 9.2 Hz, 1H), 8.85 (d,J = 1.8 Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 8.09 (d,J = 9.3 Hz, 1H), 7.22 (dd,J = 8.9, 2.8 Hz, 1H), 7.15 (d,J = 8.8 Hz, 1H), 3.97 (s, 3H), 3.89 – 3.76 (m, 1H), 3.63 – 3.54 (m, 5H), 3.37 (s, 2H), 2.99 – 2.91 (m, 1H), 2.07 – 1.95 (m, 2H), 1.87 – 1.75 (m, 2H), 1.26 – 1.18 (m, 2H), 0.80 – 0.74 (m, 2H). MS (ESI)m/z : 655 [M+H]+ . | |
I-376 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.88 (d,J = 1.9 Hz, 1H), 8.74 (d,J = 9.2 Hz, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.10 (d,J = 9.3 Hz, 1H), 7.24 (dd,J = 8.8, 2.9 Hz, 1H), 7.17 (d,J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.87 – 3.77 (m, 1H), 3.64 – 3.47 (m, 7H), 3.40 – 3.36 (m, 1H), 2.07 – 1.98 (m, 2H), 1.87 – 1.74 (m, 2H), 1.70 (d,J = 6.6 Hz, 3H), 1.30 (d,J = 6.9 Hz, 3H). MS (ESI)m/z : 657 [M+H]+ . | |
I-377 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.95 – 8.93 (m, 1H), 8.92 (d,J = 1.9 Hz, 2H), 8.81 (d,J = 1.9 Hz, 1H), 8.62 – 8.51 (m, 1H), 8.24 (s, 1H), 8.03 (d,J = 9.4 Hz, 1H), 7.26 (dd,J = 8.8, 2.9 Hz, 1H), 7.15 (d,J = 8.9 Hz, 1H), 4.19 – 4.11 (m, 1H), 3.98 (s, 3H), 3.93 – 3.87 (m, 1H), 3.85 – 3.79 (m, 1H), 3.73 – 3.63 (m, 2H), 3.49 – 3.40 (m, 2H), 3.22 (s, 3H), 2.14 – 2.03 (m, 2H), 1.94 – 1.81 (m, 2H), 1.08 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 599 [M+H]+ . | |
I-378 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 9.6 Hz, 1H), 8.85 (d,J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.09 (d,J = 9.4 Hz, 1H), 7.20 – 7.10 (m, 2H), 4.24 – 4.08 (m, 1H), 3.96 (s, 3H), 3.89 – 3.73 (m, 2H), 3.63 – 3.51 (m, 2H), 3.29 – 3.13 (m, 5H), 2.10 – 1.87 (m, 2H), 1.83 – 1.69 (m, 2H), 1.09 (t,J = 7.2 Hz, 3H). MS (ESI)m/z : 643 [M+H]+ . | |
I-379 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 – 8.91 (m, 2H), 8.81 (d,J = 1.8 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.23 (dd,J = 8.8, 2.9 Hz, 1H), 7.14 (d,J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.92 – 3.83 (m, 1H), 3.75 – 3.61 (m, 3H), 3.45 – 3.33 (m, 5H), 2.17 – 1.99 (m, 2H), 1.95 – 1.80 (m, 2H), 1.36 – 1.22 (m, 1H), 1.08 – 0.96 (m, 1H), 0.53 – 0.42 (m, 1H), 0.41 – 0.31 (m, 1H). MS (ESI)m/z : 611 [M+H]+ . | |
I-380 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.99 – 8.95 (m, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.73 – 8.65 (m, 1H), 8.39 (s, 2H), 8.01 (d,J = 9.4 Hz, 1H), 7.94 – 7.67 (m, 1H), 7.16 (d,J = 7.0 Hz, 1H), 3.83 (s, 3H), 3.56 – 3.50 (m, 3H), 3.46 – 3.41 (m, 2H), 3.39 (s, 3H), 3.15 – 3.01 (m, 1H), 1.95 – 1.75 (m, 2H), 1.68 – 1.50 (m, 2H), 1.29 – 1.21 (m, 1H), 1.06 – 0.94 (m, 1H), 0.53 – 0.40 (m, 1H), 0.33 – 0.25 (m, 1H). MS (ESI)m/z : 655 [M+H]+ . | |
I-381 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.03 (d,J = 9.4 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.83 (d,J = 1.9 Hz, 1H), 8.24 (s, 1H), 8.02 (d,J = 9.4 Hz, 1H), 7.22 (s, 1H), 7.18 – 7.14 (m, 1H), 7.05 (d,J = 7.9 Hz, 1H), 6.77 – 6.70 (m, 1H), 3.77 – 3.72 (m, 2H), 3.65 – 3.59 (m, 2H), 3.47 (s, 3H), 3.24 – 3.22 (m, 4H), 3.15 – 3.06 (m, 2H), 2.77 – 2.69 (m, 2H), 2.18 – 2.09 (m, 4H), 2.01 – 1.95 (m, 2H), 1.80 – 1.72 (m, 2H). MS (ESI)m/z : 652 [M+H]+ . | |
I-382 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.90 – 8.83 (m, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.43 – 7.32 (m, 1H), 7.02 – 6.94 (m, 1H), 6.75 (dd,J = 8.9, 2.9 Hz, 1H), 3.75 (s, 3H), 3.54 – 3.47 (m, 4H), 3.43 – 3.37 (m, 7H), 3.24 (s, 3H), 3.07 – 3.03 (m, 1H), 2.06 – 1.92 (m, 4H), 1.88 – 1.80 (m, 2H), 1.64 – 1.52 (m, 2H). MS (ESI)m/z : 682 [M+H]+ . | |
I-383 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.53 – 10.11 (m, 1H), 9.12 – 9.06 (m, 1H), 9.01 (d,J = 1.9 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.42 (s, 1H), 8.13 (d,J = 9.3 Hz, 1H), 7.67 – 7.62 (m, 1H), 6.32 – 6.24 (m, 1H), 4.08 (q,J = 7.3 Hz, 2H), 3.41 (s, 3H), 3.25 (s, 3H), 1.38 (t,J = 7.3 Hz, 3H). MS (ESI)m/z : 518 [M+H]+ . | |
I-384 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.24 – 10.05 (m, 1H), 9.36 – 9.14 (m, 1H), 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.84 – 8.78 (m, 1H), 8.39 (s, 1H), 8.09 (d,J = 9.4 Hz, 1H), 7.65 (d,J = 2.4 Hz, 1H), 6.39 – 6.29 (m, 1H), 4.42 (p,J = 6.7 Hz, 1H), 3.41 (s, 3H), 3.26 (s, 3H), 1.41 (d,J = 6.7 Hz, 6H)。 MS (ESI)m/z : 532 [M+H]+ . | |
I-385 | 1 H NMR (600 MHz, Chloroform-d ) δ 10.06 (s, 1H), 9.80 (s, 1H), 9.23 (d,J = 2.0 Hz, 1H), 9.03 (d,J = 2.0 Hz, 1H), 8.72 (d,J = 9.3 Hz, 1H), 8.37 (d,J = 9.3 Hz, 1H), 8.35 (s, 1H), 6.21 (s, 1H), 3.81 (s, 3H), 3.53 (s, 3H), 3.19 (s, 3H), 2.33 (s, 3H). MS (ESI)m/z : [M+H]+ . | |
I-386 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.45 (s, 1H), 9.33 – 9.17 (m, 1H), 9.00 (d, 1H), 8.98 – 8.93 (m, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.15 (d,J = 9.3 Hz, 1H), 7.96 – 7.85 (m, 1H), 7.53 – 7.29 (m, 1H), 4.17 – 3.76 (m, 2H), 3.38 (s, 3H), 3.23 (s, 3H), 1.41 – 1.07 (m, 3H). MS (ESI)m/z : 518 [M+H]+ . | |
I-387 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.14 (s, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.71 – 8.55 (m, 1H), 8.44 – 8.28 (m, 1H), 8.08 – 7.97 (m, 1H), 7.89 – 7.74 (m, 1H), 7.51 (s, 1H), 4.10 – 3.79 (m, 2H), 3.38 (s, 3H), 3.23 (s, 3H), 2.07 (s, 3H), 1.39 – 1.09 (m, 3H). MS (ESI)m/z : 532 [M+H]+ . | |
I-388 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.43 (s, 1H), 9.04 – 8.92 (m, 2H), 8.67 – 8.55 (m, 2H), 8.41 – 8.26 (m, 1H), 8.14 (s, 1H), 7.54 – 7.29 (m, 2H), 4.54 – 4.09 (m, 1H), 3.38 (s, 3H), 3.23 (s, 3H), 1.52 – 1.08 (m, 6H). MS (ESI)m/z : 532 [M+H]+ . | |
I-389 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.83 – 8.73 (m, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 7.95 (d,J = 9.4 Hz, 1H), 7.43 (d,J = 8.3 Hz, 1H), 7.01 (d,J = 11.8 Hz, 1H), 3.78 (s, 3H), 3.38 (s, 3H), 3.23 (s, 3H), 2.43 (q,J = 7.5 Hz, 2H), 0.97 (t,J = 7.6 Hz, 3H). MS (ESI)m/z : 576 [M+H]+ . | |
I-390 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 1.8 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.72 – 8.62 (m, 1H), 8.23 (s, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.39 (s, 1H), 6.74 (s, 1H), 4.29 (t,J = 5.1 Hz, 2H), 3.85 (s, 3H), 3.47 (s, 3H), 3.43 (t,J = 5.0 Hz, 2H), 3.19 (s, 3H), 2.51 (q,J = 7.6 Hz, 2H), 0.99 – 0.87 (m, 3H). MS (ESI)m/z : 617 [M+H]+ . | |
I-391 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.91 – 9.69 (m, 1H), 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.90 – 8.79 (m, 2H), 8.32 (s, 1H), 7.95 – 7.81 (m, 1H), 7.02 (s, 1H), 6.38 (s, 1H), 3.79 (s, 3H), 3.57 (t,J = 6.4 Hz, 2H), 3.38 (s, 3H), 3.34 (t,J = 6.4 Hz, 2H), 3.23 (s, 3H), 2.90 (s, 6H), 2.39 – 2.32 (m, 2H), 0.98 (s, 3H). MS (ESI)m/z : 644 [M+H]+ . | |
I-392 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.20 – 9.12 (m, 2H), 9.02 (d,J = 1.9 Hz, 1H), 8.98 (d,J = 1.8 Hz, 1H), 8.46 (s, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.37 (s, 1H), 6.93 (s, 1H), 3.83 (s, 3H), 3.38 (s, 3H), 3.25 (s, 4H), 3.22 (s, 3H), 2.83 (s, 6H), 2.61 (s, 3H), 2.45 – 2.29 (m, 2H), 0.84 – 0.71 (m, 3H). MS (ESI)m/z : 658 [M+H]+ . | |
I-393 | MS (ESI)m/z : 655 [M+H]+ . | |
I-394 | MS (ESI)m/z : 668 [M+H]+ . | |
I-395 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.96 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.11 – 8.07 (m, 1H), 7.94 (d,J = 9.4 Hz, 1H), 7.49 (s, 1H), 6.80 – 6.72 (m, 2H), 5.76 (d,J = 17.5 Hz, 1H), 5.34 (d,J = 11.2 Hz, 1H), 4.37 – 4.33 (m, 1H), 3.77 (s, 3H), 3.32 (s, 3H), 3.18 (s, 3H), 3.01 – 2.93 (m, 2H), 2.74 – 2.61 (m, 6H), 2.45 (s, 4H), 2.36 – 2.30 (m, 2H), 2.29 – 2.23 (m, 1H), 1.86 – 1.78 (m, 2H), 1.60 – 1.50 (m, 2H), 0.83 – 0.76 (m, 3H). MS (ESI)m/z : 725 [M+H]+ . | |
I-396 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.81 – 8.73 (m, 2H), 8.66 (s, 1H), 8.37 (s, 1H), 7.98 (d,J = 9.3 Hz, 1H), 7.47 (s, 1H), 6.79 (s, 1H), 3.80 (s, 3H), 3.72 – 3.62 (m, 4H), 3.60 – 3.50 (m, 1H), 3.38 (s, 3H), 3.34 – 3.26 (m, 2H), 3.24 (s, 3H), 3.15 (d,J = 8.4 Hz, 4H), 3.10 – 3.00 (m, 2H), 2.82 (s, 3H), 2.49 – 2.37 (m, 4H), 2.08 – 1.92 (m, 2H), 0.95 – 0.83 (m, 3H). MS (ESI)m/z : 739 [M+H]+ . | |
I-397 | MS (ESI)m/z : 697 [M+H]+ . | |
I-398 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.83 (s, 1H), 8.74 – 8.69 (m, 2H), 8.37 (s, 1H), 7.96 (d,J = 9.2 Hz, 1H), 7.41 (s, 1H), 6.81 (s, 1H), 4.58 – 4.39 (m, 2H), 4.30 – 4.06 (m, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.23 (s, 3H), 3.17 – 2.98 (m, 9H), 2.93 (s, 3H), 2.45 – 2.34 (m, 2H), 0.91 – 0.80 (m, 3H). MS (ESI)m/z : 711 [M+H]+ . | |
I-399 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.00 (d,J = 2.0 Hz, 1H), 8.99 – 8.94 (m, 2H), 8.90 (s, 1H), 8.75 – 8.57 (m, 1H), 8.40 (s, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.38 (s, 1H), 6.85 (s, 1H), 3.79 (s, 3H), 3.77 – 3.68 (m, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 2.93 – 2.81 (m, 4H), 2.72 (s, 3H), 2.71 (s, 3H), 2.44 – 2.35 (m, 2H), 2.32 – 2.20 (m, 2H), 2.09 – 1.96 (m, 2H), 1.82 – 1.68 (m, 4H), 0.84 (s, 3H). MS (ESI)m/z : 724 [M+H]+ . | |
I-400 | MS (ESI)m/z : 696 [M+H]+ . | |
I-401 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 9.13 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.85 (s, 1H), 8.71 – 8.63 (m, 1H), 8.36 (s, 1H), 7.98 (d,J = 9.4 Hz, 1H), 7.41 (d,J = 8.7 Hz, 1H), 6.85 – 6.73 (m, 1H), 6.56 (d,J = 8.8 Hz, 1H), 3.90 – 3.86 (m, 2H), 3.80 (s, 3H), 3.51 (d,J = 129.0 Hz, 9H), 3.05 (s, 3H), 2.90 (s, 3H), 2.88 – 2.80 (m, 2H), 2.22 – 2.14 (m, 2H), 1.82 – 1.72 (m, 2H). MS (ESI)m/z : 697 [M+H]+ . | |
I-402 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 9.12 (s, 1H), 9.03 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.67 (s, 1H), 8.64 – 8.57 (m, 1H), 8.37 (s, 1H), 7.94 (d,J = 9.3 Hz, 1H), 7.36 (s, 1H), 6.75 (s, 1H), 3.79 (s, 3H), 3.73 – 3.28 (m, 10H), 3.22 – 3.19 (m, 1H), 3.18 (s, 3H), 3.05 (s, 3H), 2.91 (s, 3H), 2.77 – 2.70 (m, 2H), 2.20 – 2.11 (m, 2H), 1.86 – 1.76 (m, 2H). MS (ESI)m/z : 711 [M+H]+ . | |
I-403 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.17 (s, 1H), 9.03 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.79 (s, 1H), 8.62 – 8.50 (m, 1H), 8.40 (s, 1H), 7.93 (d,J = 9.4 Hz, 1H), 7.39 (s, 1H), 6.80 (s, 1H), 3.79 (s, 3H), 3.74 – 3.21 (m, 9H), 3.15 – 3.09 (m, 2H), 3.05 (s, 3H), 2.92 (s, 3H), 2.84 – 2.74 (m, 2H), 2.42 – 2.35 (m, 2H), 2.20 – 2.13 (m, 2H), 1.87 – 1.77 (m, 2H), 0.87 – 0.73 (m, 3H). MS (ESI)m/z : 725 [M+H]+ . | |
I-404 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 9.03 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.64 (s, 1H), 8.60 – 8.51 (m, 1H), 8.35 (s, 1H), 7.93 – 7.87 (m, 1H), 7.67 (s, 1H), 3.85 (s, 3H), 3.79 – 3.57 (m, 8H), 3.49 – 3.40 (m, 2H), 3.32 – 3.20 (m, 1H), 3.04 (s, 3H), 2.90 (s, 3H), 2.88 – 2.82 (m, 2H), 2.43 – 2.33 (m, 2H), 2.19 – 2.07 (m, 2H), 1.85 – 1.74 (m, 2H), 0.91 – 0.74 (m, 3H). MS (ESI)m/z : 726 [M+H]+ . | |
I-405 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 9.11 (s, 1H), 9.01 (d,J = 1.8 Hz, 1H), 8.94 (s, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.64 – 8.55 (m, 1H), 8.33 (s, 1H), 7.82 (d,J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.08 (s, 1H), 3.85 – 3.23 (m, 9H), 3.15 – 3.09 (m, 2H), 3.03 (s, 3H), 2.90 (s, 3H), 2.79 – 2.69 (m, 2H), 2.56 – 2.52 (m, 2H), 2.19 – 2.12 (m, 2H), 1.85 – 1.75 (m, 2H), 0.98 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 779 [M+H]+ . | |
I-406 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.08 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.83 (s, 1H), 8.67 – 8.51 (m, 1H), 8.37 (s, 1H), 7.95 – 7.79 (m, 1H), 7.40 – 7.29 (m, 1H), 6.85 (s, 1H), 3.77 (s, 3H), 3.72 – 3.48 (m, 8H), 3.47 – 3.36 (m, 1H), 3.27 – 3.20 (m, 1H), 3.10 – 3.06 (m, 2H), 3.05 (s, 3H), 2.92 (s, 3H), 2.89 – 2.80 (m, 2H), 2.24 – 2.11 (m, 2H), 1.92 – 1.78 (m, 2H), 1.00 – 0.90 (m, 6H). MS (ESI)m/z : 739 [M+H]+ . | |
I-407 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.13 – 9.06 (m, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 2.0 Hz, 1H), 8.87 – 8.81 (m, 1H), 8.63 – 8.51 (m, 1H), 8.35 (s, 1H), 7.91 – 7.82 (m, 1H), 6.98 – 6.87 (m, 1H), 6.75 (s, 1H), 3.78 (s, 3H), 3.73 – 3.47 (m, 8H), 3.46 – 3.38 (m, 2H), 3.26 – 3.21 (m, 1H), 3.04 (s, 3H), 2.91 (s, 3H), 2.83 – 2.73 (m, 2H), 2.25 – 2.14 (m, 2H), 2.09 – 2.01 (m, 1H), 1.95 – 1.80 (m, 2H), 0.73 – 0.62 (m, 2H), 0.41 – 0.31 (m, 2H). MS (ESI)m/z : 737 [M+H]+ . | |
I-408 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 9.06 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.64 (s, 1H), 8.60 – 8.53 (m, 1H), 8.35 (s, 1H), 7.89 (d,J = 9.2 Hz, 1H), 7.53 (s, 1H), 6.80 (s, 1H), 3.78 (s, 3H), 3.70 – 3.40 (m, 8H), 3.38 – 3.30 (m, 1H), 3.12 – 3.06 (m, 2H), 3.03 (s, 3H), 2.90 (s, 3H), 2.81 – 2.72 (m, 2H), 2.34 – 2.25 (m, 2H), 2.18 – 2.10 (m, 2H), 1.82 – 1.69 (m, 2H), 0.68 – 0.52 (m, 1H), 0.27 – 0.14 (m, 2H), -0.09 – -0.19 (m, 2H). MS (ESI)m/z : 751 [M+H]+ . | |
I-409 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 9.48 (s, 1H), 9.03 (d,J = 1.9 Hz, 1H), 8.99 – 8.94 (m, 2H), 8.81 – 8.67 (m, 1H), 8.36 (s, 1H), 8.05 (d,J = 9.3 Hz, 1H), 7.44 – 7.37 (m, 2H), 6.97 (d,J = 8.5 Hz, 1H), 3.72 – 3.40 (m, 8H), 3.33 – 3.21 (m, 1H), 3.08 – 3.00 (m, 5H), 2.87 (s, 3H), 2.74 – 2.63 (m, 2H), 2.49 – 2.47 (m, 2H), 2.16 – 2.05 (m, 2H), 1.82 – 1.69 (m, 2H), 0.98 – 0.89 (m, 3H). MS (ESI)m/z : 695 [M+H]+ . | |
I-410 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.18 (s, 1H), 9.03 (d,J = 1.9 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.79 (s, 1H), 8.60 – 8.47 (m, 1H), 8.39 (s, 1H), 7.92 (d,J = 9.3 Hz, 1H), 7.39 (s, 1H), 6.80 (s, 1H), 3.79 (s, 3H), 3.32 – 3.25 (m, 1H), 3.13 – 3.07 (m, 2H), 3.05 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H), 2.80 – 2.73 (m, 2H), 2.39 (q,J = 7.5 Hz, 2H), 2.17 – 2.05 (m, 2H), 1.85 – 1.75 (m, 2H), 0.84 – 0.77 (m, 3H). MS (ESI)m/z : 670 [M+H]+ . | |
I-411 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 9.07 (s, 1H), 9.05 – 9.00 (m, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.56 (s, 1H), 8.37 (s, 1H), 7.94 (d,J = 9.3 Hz, 1H), 7.47 (s, 1H), 6.85 – 6.63 (m, 2H), 3.81 (s, 3H), 3.57 – 3.49 (m, 2H), 3.27 – 3.19 (m, 2H), 3.14 – 3.09 (m, 2H), 3.06 – 2.99 (m, 5H), 2.91 (s, 3H), 2.44 – 2.37 (m, 2H), 0.92 – 0.73 (m, 3H). MS (ESI)m/z : 642 [M+H]+ . | |
I-412 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 9.10 (s, 1H), 9.03 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.70 (s, 1H), 8.60 – 8.53 (m, 1H), 8.36 (s, 1H), 7.91 (d,J = 9.2 Hz, 1H), 7.34 (s, 1H), 6.78 (s, 1H), 3.79 (s, 3H), 3.36 – 3.30 (m, 2H), 3.23 – 3.18 (m, 2H), 3.12 – 3.06 (m, 1H), 3.04 (s, 3H), 2.88 (s, 3H), 2.87 (s, 3H), 2.45 – 2.38 (m, 2H), 2.37 – 2.30 (m, 1H), 2.22 – 2.08 (m, 1H), 0.89 – 0.78 (m, 3H). MS (ESI)m/z : 656 [M+H]+ . | |
I-413 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 9.23 (s, 1H), 9.01 (d,J = 1.7 Hz, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.86 – 8.78 (m, 1H), 8.56 (d,J = 9.2 Hz, 1H), 8.36 (s, 1H), 7.98 (d,J = 9.2 Hz, 1H), 7.39 (d,J = 8.6 Hz, 1H), 6.78 (s, 1H), 6.52 (d,J = 8.6 Hz, 1H), 3.90 – 3.83 (m, 2H), 3.80 (s, 3H), 3.73 – 3.45 (m, 8H), 3.42 – 3.33 (m, 1H), 3.29 (hept,J = 6.8 Hz, 1H), 2.89 (s, 3H), 2.87 – 2.78 (m, 2H), 2.20 – 2.11 (m, 2H), 1.80 – 1.70 (m, 2H), 1.38 (d,J = 6.8 Hz, 6H). MS (ESI)m/z : 725 [M+H]+ . | |
I-414 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.17 (s, 1H), 9.01 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.55 – 8.46 (m, 2H), 8.36 (s, 1H), 7.93 (d,J = 9.3 Hz, 1H), 7.36 (s, 1H), 6.73 (s, 1H), 3.78 (s, 3H), 3.75 – 3.44 (m, 8H), 3.38 – 3.24 (m, 2H), 3.16 – 3.12 (m, 2H), 2.89 (s, 3H), 2.75 – 2.67 (m, 2H), 2.16 – 2.09 (m, 2H), 1.95 (s, 3H), 1.84 – 1.73 (m, 2H), 1.38 (d,J = 6.8 Hz, 6H). MS (ESI)m/z : 739 [M+H]+ . | |
I-415 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 9.27 (s, 1H), 9.00 (d,J = 1.9 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.71 (s, 1H), 8.46 – 8.40 (m, 1H), 8.38 (s, 1H), 7.91 (d,J = 9.2 Hz, 1H), 7.38 (s, 1H), 6.77 (s, 1H), 3.77 (s, 3H), 3.60 (d,J = 116.1 Hz, 8H), 3.42 – 3.34 (m, 1H), 3.28 (hept,J = 6.7 Hz, 1H), 3.09 – 3.03 (m, 2H), 2.90 (s, 3H), 2.80 – 2.71 (m, 2H), 2.31 (s, 2H), 2.17 – 2.10 (m, 2H), 1.84 – 1.74 (m, 2H), 1.36 (d,J = 6.7 Hz, 6H), 0.79 – 0.65 (m, 3H). MS (ESI)m/z : 753 [M+H]+ . | |
II-1-1 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.7 Hz, 1H), 8.98 (d,J = 1.7 Hz, 1H), 8.35 – 8.24 (m, 2H), 8.15 (d,J = 9.2 Hz, 1H), 7.40 – 7.26 (m, 2H), 6.85 (d,J = 2.4 Hz, 1H), 6.62 – 6.50 (m, 1H), 3.89 – 3.81 (m, 5H), 3.60 – 3.41 (m, 11H), 3.28 – 3.21 (m, 1H), 3.12 (s, 3H), 3.08 – 3.01 (m, 2H), 2.96 (s, 3H), 2.32 – 2.19 (m, 2H), 2.04 – 1.83 (m, 2H). MS (ESI)m/z : 689 [M+H]+ . | |
II-1-2 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.25 (d,J = 5.5 Hz, 1H), 8.21 – 8.15 (m, 1H), 8.10 (d,J = 9.2 Hz, 1H), 7.29 (d,J = 5.5 Hz, 1H), 7.16 (s, 1H), 6.72 (s, 1H), 3.79 (s, 3H), 3.54 (s, 8H), 3.41 (s, 3H), 3.26 – 3.22 (m, 1H), 3.22 – 3.15 (m, 2H), 3.09 (s, 3H), 2.93 (s, 3H), 2.81 – 2.73 (m, 2H), 2.24 – 2.12 (m, 2H), 1.97 – 1.89 (m, 2H), 1.78 (br s, 3H). MS (ESI)m/z : 703 [M+H]+ . | |
II-1-3 | 1 H NMR (600 MHz, MeOD) δ 9.00 – 8.97 (m, 1H), 8.96 – 8.92 (m, 1H), 8.25 (d,J = 5.6 Hz, 1H), 8.21 – 8.13 (m, 1H), 8.08 (d,J = 8.9 Hz, 1H), 7.30 (d,J = 5.5 Hz, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 3.79 (s, 3H), 3.64 – 3.47 (m, 8H), 3.42 (s, 3H), 3.26 – 3.19 (m, 1H), 3.10 (s, 2H), 3.07 (s, 3H), 2.92 (s, 3H), 2.87 – 2.72 (m, 2H), 2.49 – 2.20 (m, 2H), 2.20 – 2.12 (m, 2H), 1.95 – 1.81 (m, 2H), 1.02 – 0.50 (m, 3H). MS (ESI)m/z : 717 [M+H]+ . | |
II-1-4 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.38 – 8.20 (m, 2H), 8.16 – 8.01 (m, 1H), 7.45 – 7.34 (m, 1H), 7.33 – 7.22 (m, 1H), 6.49 – 5.96 (m, 1H), 4.56 – 4.40 (m, 2H), 3.83 (s, 3H), 3.52 – 3.43 (m, 8H), 3.34 – 3.31 (m, 1H), 3.28 (s, 3H), 3.09 (s, 3H), 2.90 (s, 3H), 2.90 – 2.84 (m, 2H), 2.17 – 2.08 (m, 2H), 1.80 – 1.60 (m, 2H). MS (ESI)m/z : 690 [M+H]+ . | |
II-1-5 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.88 (br s, 1H), 9.60 (br s, 1H), 9.06 (s, 2H), 8.35 (d,J = 5.3 Hz, 1H), 8.22 – 8.05 (m, 2H), 7.41 – 7.36 (m, 1H), 7.34 (d,J = 5.4 Hz, 1H), 3.82 (s, 3H), 3.75 – 3.62 (m, 2H), 3.53 – 3.20 (m, 8H), 3.20 – 3.03 (m, 6H), 2.82 (s, 3H), 2.78 – 2.68 (m, 2H), 1.92 (s, 3H), 1.86 – 1.25 (m, 5H). MS (ESI)m/z : 704 [M+H]+ . | |
II-1-6 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.9 Hz, 1H), 8.95 – 8.92 (m, 1H), 8.24 (d,J = 5.5 Hz, 1H), 8.12 – 8.05 (m, 1H), 8.05 – 8.01 (m, 1H), 7.48 (s, 1H), 7.29 (d,J = 5.4 Hz, 1H), 3.85 (s, 3H), 3.71 – 3.57 (m, 8H), 3.48 – 3.39 (m, 5H), 3.38 – 3.33 (m, 1H), 3.05 (s, 3H), 2.94 (s, 3H), 2.91 – 2.79 (m, 2H), 2.29 – 2.15 (m, 2H), 2.18 – 2.11 (m, 2H), 1.94 – 1.82 (m, 2H), 1.04 – 0.30 (m, 3H). MS (ESI)m/z : 718 [M+H]+ . | |
II-1-7 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 8.7 Hz, 2H), 8.28 (d,J = 5.5 Hz, 1H), 8.16 (d,J = 8.8 Hz, 1H), 8.07 (d,J = 9.3 Hz, 1H), 7.35 (d,J = 5.5 Hz, 1H), 7.29 (d,J = 8.9 Hz, 1H), 6.88 (s, 1H), 6.77 (s, 1H), 3.93 – 3.80 (m, 2H), 3.77 – 3.49 (m, 8H), 3.41 (s, 3H), 3.38 – 3.33 (m, 1H), 3.11 (s, 3H), 2.97 (s, 3H), 2.89 – 2.77 (m, 2H), 2.29 – 2.20 (m, 2H), 1.97 – 1.81 (m, 2H). MS (ESI)m/z : 743 [M+H]+ . | |
II-1-8 | 1 H NMR (600 MHz, MeOD) δ 8.94 – 8.92 (m, 1H), 8.92 – 8.91 (m, 1H), 8.25 (d,J = 5.6 Hz, 1H), 8.01 – 7.85 (m, 2H), 7.31 (d,J = 5.5 Hz, 1H), 7.24 (s, 1H), 6.94 (s, 1H), 3.73 – 3.54 (m, 8H), 3.35 (s, 3H), 3.33 – 3.30 (m, 1H), 3.03 (s, 3H), 3.02 – 2.98 (m, 2H), 2.93 (s, 3H), 2.72 – 2.58 (m, 2H), 2.38 – 2.23 (m, 1H), 2.23 – 2.11 (m, 2H), 2.10 – 1.92 (m, 1H), 1.91 – 1.79 (m, 2H), 0.83 – 0.63 (m, 3H). MS (ESI)m/z : 771 [M+H]+ . | |
II-1-9 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.33 (d,J = 5.6 Hz, 1H), 8.01 – 7.95 (m, 1H), 7.94 – 7.86 (m, 1H), 7.54 (s, 1H), 7.38 (d,J = 5.5 Hz, 1H), 6.96 (s, 1H), 6.62 – 6.49 (m, 1H), 5.16 (s, 1H), 4.89 (s, 1H), 3.65 – 3.51 (m, 8H), 3.43 (s, 3H), 3.28 – 3.19 (m, 3H), 3.11 (s, 3H), 2.96 (s, 3H), 2.79 – 2.62 (m, 2H), 2.26 – 2.14 (m, 2H), 1.97 – 1.87 (m, 2H). MS (ESI)m/z : 769 [M+H]+ . | |
II-1-10 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.22 (d,J = 5.4 Hz, 1H), 8.18 – 8.08 (m, 1H), 8.07 – 7.94 (m, 1H), 7.37 (s, 1H), 7.28 (d,J = 5.5 Hz, 1H), 6.74 (s, 1H), 3.77 (s, 3H), 3.65 – 3.47 (m, 8H), 3.41 (s, 3H), 3.24 – 3.20 (m, 1H), 3.10 – 3.03 (m, 5H), 2.91 (s, 3H), 2.82 – 2.69 (m, 2H), 2.16 (dt,J = 9.5, 3.3 Hz, 2H), 1.92 – 1.77 (m, 2H), 0.62 – 0.31 (m, 1H), 0.27 – 0.06 (m, 2H), -0.08 – -0.39 (m, 2H). MS (ESI)m/z : 742 [M+H]+ . | |
II-1-11 | 1 H NMR (600 MHz, MeOD) δ 8.94 – 8.89 (m, 1H), 8.89 – 8.80 (m, 1H), 8.28 (d,J = 5.6 Hz, 1H), 8.24 – 8.12 (m, 1H), 8.10 – 8.03 (m, 1H), 7.43 – 7.26 (m, 2H), 7.15 – 6.98 (m, 3H), 6.95 – 6.73 (m, 3H), 3.82 (s, 3H), 3.79 – 3.48 (m, 10H), 3.41 (s, 3H), 3.37 – 3.34 (m, 1H), 3.06 (s, 3H), 2.99 (s, 3H), 2.96 – 2.80 (m, 2H), 2.78 – 2.61 (m, 2H), 2.18 – 2.02 (m, 2H), 1.87 – 1.71 (m, 2H). MS (ESI)m/z : 779 [M+H]+ . | |
II-1-12 | 1 H NMR (600 MHz, MeOD) δ 9.03 (d,J = 1.8 Hz, 1H), 8.99 (d,J = 1.9 Hz, 1H), 8.29 (d,J = 5.5 Hz, 1H), 8.26 – 8.20 (m, 1H), 8.15 – 8.09 (m, 1H), 7.35 (d,J = 5.5 Hz, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 3.85 (s, 3H), 3.62 (t,J = 11.4 Hz, 2H), 3.48 (s, 3H), 3.34 – 3.28 (m, 2H), 3.27 – 3.18 (m, 2H), 3.14 (s, 3H), 3.13 – 3.06 (m, 2H), 3.01 (s, 3H), 1.83 (br s, 3H). MS (ESI)m/z : 620 [M+H]+ . | |
II-1-13 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.28 (d,J = 5.5 Hz, 1H), 8.25 – 8.20 (m, 1H), 8.16 – 8.10 (m, 1H), 7.32 (d,J = 5.1 Hz, 1H), 7.19 (s, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 3.46 (s, 3H), 3.24 – 3.17 (m, 2H), 3.12 (s, 3H), 2.94 (s, 6H), 2.84 – 2.69 (m, 3H), 2.23 – 2.16 (m, 2H), 1.97 – 1.72 (m, 5H). MS (ESI)m/z : 648 [M+H]+ . | |
II-1-14 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.35 – 8.26 (m, 1H), 8.26 – 8.17 (m, 1H), 8.16 – 8.10 (m, 1H), 7.32 (d,J = 5.4 Hz, 1H), 7.20 – 7.12 (m, 1H), 6.69 (s, 1H), 4.04 – 3.98 (m, 1H), 3.82 (s, 3H), 3.48 (s, 3H), 3.45 – 3.37 (m, 4H), 3.18 – 3.14 (m, 1H), 3.12 (s, 3H), 2.99 (s, 3H), 2.98 (s, 3H), 2.55 – 2.45 (m, 1H), 2.25 – 2.18 (m, 1H), 1.73 (br s, 3H). MS (ESI)m/z : 634 [M+H]+ . | |
II-1-15 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.29 (d,J = 5.5 Hz, 1H), 8.24 – 8.16 (m, 1H), 8.12 – 8.05 (m, 1H), 7.36 – 7.27 (m, 2H), 6.80 (s, 1H), 3.84 (s, 3H), 3.59 (t,J = 10.1 Hz, 2H), 3.47 (s, 3H), 3.30 – 3.25 (m, 2H), 3.17 – 3.07 (m, 7H), 2.98 (s, 3H), 2.46 – 2.25 (m, 1H), 2.18 – 1.92 (m, 1H), 0.72 (br s, 3H). MS (ESI)m/z : 634 [M+H]+ . | |
II-1-16 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.98 (d,J = 1.9 Hz, 1H), 8.28 (d,J = 5.5 Hz, 1H), 8.26 – 8.15 (m, 1H), 8.15 – 8.03 (m, 1H), 7.33 (d,J = 5.4 Hz, 1H), 7.25 (s, 1H), 6.78 (s, 1H), 3.82 (s, 3H), 3.46 (s, 3H), 3.36 – 3.32 (m, 2H), 3.17 – 3.07 (m, 5H), 2.93 (s, 6H), 2.85 – 2.72 (m, 2H), 2.45 – 2.28 (m, 1H), 2.23 – 2.15 (m, 2H), 1.94 – 1.83 (m, 2H), 0.76 (br s, 3H). MS (ESI)m/z : 662 [M+H]+ . | |
II-1-17 | 1 H NMR (600 MHz, MeOD) δ 9.06 – 9.02 (m, 1H), 9.01 – 8.98 (m, 1H), 8.30 (d,J = 5.5 Hz, 1H), 8.26 – 8.18 (m, 1H), 8.13 – 8.06 (m, 1H), 7.35 (d,J = 5.5 Hz, 1H), 7.25 (d,J = 8.7 Hz, 1H), 6.78 (s, 1H), 4.09 – 3.98 (m, 1H), 3.85 (s, 3H), 3.50 (s, 3H), 3.47 – 3.39 (m, 2H), 3.32 – 3.23 (m, 1H), 3.13 (s, 3H), 3.10 – 3.06 (m, 1H), 3.00 (s, 3H), 2.99 (s, 3H), 2.58 – 2.47 (m, 1H), 2.27 – 2.19 (m, 1H), 1.12 – 0.50 (m, 3H). MS (ESI)m/z : 648 [M+H]+ . | |
II-1-18 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.6 Hz, 1H), 8.42 (d,J = 9.2 Hz, 1H), 8.08 (d,J = 9.2 Hz, 1H), 7.64 (d,J = 3.0 Hz, 1H), 7.50 – 7.40 (m, 1H), 6.93 (s, 1H), 6.67 – 6.59 (m, 1H), 6.41 (d,J = 3.1 Hz, 1H), 3.84 (s, 3H), 3.83 – 3.78 (m, 2H), 3.63 – 3.47 (m, 7H), 3.46 – 3.33 (m, 4H), 3.24 – 3.09 (m, 6H), 2.95 (s, 3H), 2.28 – 2.17 (m, 2H), 2.04 – 1.93 (m, 2H). MS (ESI)m/z : 672 [M+H]+ . | |
II-1-19 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.37 (d,J = 9.2 Hz, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.64 (d,J = 3.1 Hz, 1H), 7.27 (s, 1H), 6.80 (s, 1H), 6.40 (d,J = 3.1 Hz, 1H), 3.82 (s, 3H), 3.68 – 3.54 (m, 8H), 3.52 (s, 3H), 3.50 – 3.45 (m, 1H), 3.29 – 3.25 (m, 2H), 3.15 (s, 3H), 2.98 (s, 3H), 2.88 (t,J = 11.9 Hz, 2H), 2.26 – 2.19 (m, 2H), 2.00 – 1.93 (m, 2H), 1.87 (br s, 3H). MS (ESI)m/z : 686 [M+H]+ . | |
II-1-20 | 1 H NMR (600 MHz, MeOD) δ 9.01 – 8.97 (m, 1H), 8.96 – 8.91 (m, 1H), 8.31 (d,J = 9.0 Hz, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.63 (d,J = 3.2 Hz, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 6.39 (d,J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.76 – 3.59 (m, 8H), 3.52 (s, 3H), 3.41 – 3.35 (m, 1H), 3.23 – 3.17 (m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.94 – 2.79 (m, 2H), 2.41 – 2.31 (m, 1H), 2.28 – 2.18 (m, 2H), 2.16 – 2.10 (m, 1H), 2.05 – 1.88 (m, 2H), 0.85 – 0.56 (m, 3H). MS (ESI)m/z : 670 [M+H]+ . | |
II-1-21 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.8 Hz, 1H), 8.27 (d,J = 9.0 Hz, 1H), 8.01 (d,J = 9.2 Hz, 1H), 7.66 (d,J = 3.1 Hz, 1H), 7.61 (s, 1H), 6.42 (d,J = 3.0 Hz, 1H), 3.91 (s, 3H), 3.72 – 3.53 (m, 11H), 3.50 – 3.42 (m, 2H), 3.37 – 3.33 (m, 1H), 3.14 (s, 3H), 3.01 – 2.88 (m, 5H), 2.40 – 2.24 (m, 1H), 2.23 – 2.15 (m, 2H), 2.13 – 2.03 (m, 1H), 2.01 – 1.86 (m, 2H), 0.84 – 0.45 (m, 3H). MS (ESI)m/z : 701 [M+H]+ . | |
II-1-22 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.18 (d,J = 9.2 Hz, 1H), 7.91 (d,J = 9.2 Hz, 1H), 7.69 (d,J = 3.0 Hz, 1H), 7.37 (s, 1H), 7.06 (s, 1H), 6.47 (d,J = 3.0 Hz, 1H), 3.70 – 3.56 (m, 8H), 3.52 (s, 3H), 3.32 – 3.27 (m, 1H), 3.19 – 3.12 (m, 5H), 2.98 (s, 3H), 2.84 – 2.72 (m, 2H), 2.50 – 2.38 (m, 1H), 2.29 – 2.19 (m, 3H), 2.01 – 1.86 (m, 2H), 0.76 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 754 [M+H]+ . | |
II-1-23 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.8 Hz, 1H), 8.91 (d,J = 2.0 Hz, 1H), 8.08 (d,J = 9.2 Hz, 1H), 7.79 (d,J = 9.2 Hz, 1H), 7.67 (d,J = 3.0 Hz, 1H), 7.58 (s, 1H), 7.03 – 6.88 (m, 1H), 6.61 (dd,J = 17.7, 11.1 Hz, 1H), 6.45 (d,J = 3.1 Hz, 1H), 5.10 (d,J = 17.8 Hz, 1H), 4.72 (d,J = 11.2 Hz, 1H), 3.56 – 3.39 (m, 11H), 3.26 – 3.20 (m, 2H), 3.18 – 3.10 (m, 4H), 2.91 (s, 3H), 2.81 – 2.66 (m, 2H), 2.27 – 2.10 (m, 2H), 1.95 – 1.82 (m, 2H). MS (ESI)m/z : 752 [M+H]+ . | |
II-1-24 | 1 H NMR (600 MHz, MeOD) δ 9.00 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.43 (d,J = 9.3 Hz, 1H), 8.19 (d,J = 2.2 Hz, 1H), 8.12 (d,J = 9.2 Hz, 1H), 7.41 (d,J = 8.7 Hz, 1H), 6.95 – 6.87 (m, 2H), 6.68 – 6.61 (m, 1H), 3.92 – 3.86 (m, 2H), 3.85 (s, 3H), 3.68 – 3.45 (m, 11H), 3.35 – 3.33 (m, 1H), 3.14 (s, 3H), 3.13 – 3.05 (m, 2H), 2.97 (s, 3H), 2.31 – 2.21 (m, 2H), 2.04 – 1.87 (m, 2H). MS (ESI)m/z : 673 [M+H]+ . | |
II-1-25 | 1 H NMR (600 MHz, MeOD) δ 9.00 (d,J = 1.7 Hz, 1H), 8.98 – 8.90 (m, 1H), 8.43 – 8.29 (m, 1H), 8.19 (d,J = 2.2 Hz, 1H), 8.10 (d,J = 9.3 Hz, 1H), 7.23 (s, 1H), 6.99 – 6.89 (m, 1H), 6.79 (s, 1H), 3.82 (s, 3H), 3.79 – 3.60 (m, 8H), 3.48 (s, 3H), 3.45 – 3.38 (m, 1H), 3.29 – 3.23 (m, 2H), 3.13 (s, 3H), 3.01 (s, 3H), 2.90 – 2.79 (m, 2H), 2.31 – 2.20 (m, 2H), 2.07 – 1.85 (m, 5H). MS (ESI)m/z : 687 [M+H]+ . | |
II-1-26 | 1 H NMR (600 MHz, MeOD) δ 9.01 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.8 Hz, 1H), 8.37 – 8.27 (m, 1H), 8.20 (d,J = 2.2 Hz, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.29 (s, 1H), 7.01 – 6.90 (m, 1H), 6.82 (s, 1H), 3.83 (s, 3H), 3.79 – 3.62 (m, 8H), 3.48 (s, 3H), 3.45 – 3.38 (m, 1H), 3.23 – 3.16 (m, 2H), 3.12 (s, 3H), 3.01 (s, 3H), 2.94 – 2.79 (m, 2H), 2.51 – 2.35 (m, 1H), 2.31 – 2.23 (m, 2H), 2.23 – 2.13 (m, 1H), 2.03 – 1.91 (m, 2H), 0.98 – 0.54 (m, 3H). MS (ESI)m/z : 701 [M+H]+ . | |
II-1-27 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.8 Hz, 1H), 8.64 – 8.29 (m, 1H), 8.17 – 7.95 (m, 1H), 7.60 (d,J = 3.0 Hz, 1H), 7.50 – 7.41 (m, 1H), 6.37 (d,J = 3.0 Hz, 1H), 6.30 – 6.16 (m, 1H), 4.56 – 4.43 (m, 2H), 3.85 (s, 3H), 3.64 – 3.38 (m, 12H), 3.15 (s, 3H), 2.98 – 2.88 (m, 5H), 2.24 – 2.06 (m, 2H), 1.79 – 1.61 (m, 2H). MS (ESI)m/z : 673 [M+H]+ . | |
II-1-28 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.64 – 8.29 (m, 1H), 8.21 – 7.94 (m, 1H), 7.62 (d,J = 3.0 Hz, 1H), 7.38 (s, 1H), 6.38 (d,J = 3.0 Hz, 1H), 3.93 (s, 3H), 3.86 – 3.77 (m, 1H), 3.74 – 3.65 (m, 1H), 3.59 (s, 3H), 3.53 – 3.32 (m, 6H), 3.27 – 3.11 (m, 6H), 2.96 – 2.83 (m, 4H), 2.77 – 2.65 (m, 1H), 2.16 – 1.95 (m, 4H), 1.91 – 1.83 (m, 1H), 1.56 – 1.22 (m, 2H). MS (ESI)m/z : 687 [M+H]+ . | |
II-1-29 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.97 (d,J = 2.3 Hz, 1H), 8.93 (d,J = 2.3 Hz, 1H), 8.31 (d,J = 9.5 Hz, 1H), 7.98 (d,J = 9.1 Hz, 1H), 7.65 (t,J = 2.7 Hz, 1H), 7.32 (dd,J = 9.0, 2.3 Hz, 1H), 6.93 (s, 1H), 6.84 (d,J = 8.9 Hz, 1H), 6.43 (t,J = 2.7 Hz, 1H), 3.92 – 3.81 (m, 2H), 3.64 – 3.46 (m, 11H), 3.29 – 3.25 (m, 1H), 3.14 (s, 3H), 2.95 (d,J = 2.3 Hz, 3H), 2.91 – 2.81 (m, 2H), 2.26 – 2.17 (m, 2H), 1.92 – 1.78 (m, 2H). MS (ESI)m/z : 726 [M+H]+ . | |
II-1-30 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 (d,J = 2.0 Hz, 1H), 8.84 (d,J = 1.9 Hz, 1H), 8.32 (d,J = 9.2 Hz, 1H), 8.01 (d,J = 9.3 Hz, 1H), 7.65 (t,J = 2.2 Hz, 1H), 7.37 (s, 1H), 7.08 – 6.99 (m, 3H), 6.91 – 6.80 (m, 3H), 6.41 (d,J = 2.7 Hz, 1H), 3.83 (s, 3H), 3.73 – 3.61 (m, 1H), 3.54 – 3.35 (m, 12H), 3.12 – 3.06 (m, 4H), 3.01 – 2.95 (m, 1H), 2.93 – 2.88 (m, 4H), 2.79 – 2.64 (m, 2H), 2.10 – 1.94 (m, 2H), 1.78 – 1.68 (m, 2H). MS (ESI)m/z : 762 [M+H]+ . | |
II-1-31 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.38 (d,J = 9.1 Hz, 1H), 8.03 (d,J = 9.2 Hz, 1H), 7.62 (d,J = 2.9 Hz, 1H), 7.23 (s, 1H), 6.74 (s, 1H), 6.39 (d,J = 3.0 Hz, 1H), 3.80 (s, 3H), 3.52 (s, 3H), 3.38 – 3.33 (m, 1H), 3.25 – 3.20 (m, 2H), 3.15 (s, 3H), 2.94 (s, 6H), 2.84 – 2.75 (m, 2H), 2.26 – 2.15 (m, 2H), 2.02 – 1.82 (m, 5H). MS (ESI)m/z : 631 [M+H]+ . | |
II-1-32 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.8 Hz, 1H), 8.34 (d,J = 9.2 Hz, 1H), 8.01 (d,J = 9.2 Hz, 1H), 7.63 (d,J = 3.0 Hz, 1H), 7.32 (s, 1H), 6.79 (s, 1H), 6.40 (d,J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.53 (s, 3H), 3.36 – 3.32 (m, 1H), 3.17 – 3.11 (m, 5H), 2.93 (s, 6H), 2.87 – 2.76 (m, 2H), 2.44 – 2.33 (m, 1H), 2.25 – 2.13 (m, 3H), 1.93 – 1.84 (m, 2H), 0.85 – 0.61 (m, 3H). MS (ESI)m/z : 645 [M+H]+ . | |
II-1-33 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 2.0 Hz, 1H), 8.36 (d,J = 9.2 Hz, 1H), 8.02 (dd,J = 9.2, 2.5 Hz, 1H), 7.63 (d,J = 2.7 Hz, 1H), 7.29 (s, 1H), 6.76 (s, 1H), 6.40 (d,J = 2.8 Hz, 1H), 3.82 (d,J = 2.1 Hz, 3H), 3.61 (t,J = 10.3 Hz, 2H), 3.52 (d,J = 2.1 Hz, 3H), 3.36 – 3.32 (m, 2H), 3.26 – 3.20 (m, 2H), 3.15 (d,J = 2.0 Hz, 3H), 3.10 (t,J = 12.6 Hz, 2H), 3.00 (d,J = 2.1 Hz, 3H), 1.87 (s, 3H). MS (ESI)m/z : 603 [M+H]+ . | |
II-1-34 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.94 (d,J = 1.9 Hz, 1H), 8.31 (d,J = 9.2 Hz, 1H), 8.00 (d,J = 9.1 Hz, 1H), 7.65 (d,J = 3.1 Hz, 1H), 7.38 (s, 1H), 6.81 (s, 1H), 6.41 (d,J = 3.1 Hz, 1H), 3.84 (s, 3H), 3.66 – 3.58 (m, 2H), 3.53 (s, 3H), 3.31 – 3.26 (m, 2H), 3.22 – 3.13 (m, 7H), 2.99 (s, 3H), 2.47 – 2.31 (m, 1H), 2.24 – 2.09 (m, 1H), 0.81 – 0.61 (m, 3H). MS (ESI)m/z : 617 [M+H]+ . | |
II-1-35 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.39 (d,J = 9.1 Hz, 1H), 8.01 (d,J = 9.4 Hz, 1H), 7.63 (d,J = 3.1 Hz, 1H), 7.20 (d,J = 4.1 Hz, 1H), 6.71 (s, 1H), 6.40 (d,J = 3.0 Hz, 1H), 4.05 – 3.97 (m, 1H), 3.81 (s, 3H), 3.53 (d,J = 2.4 Hz, 3H), 3.48 – 3.43 (m, 1H), 3.43 – 3.36 (m, 2H), 3.15 (s, 3H), 3.14 – 3.09 (m, 1H), 2.99 (d,J = 3.4 Hz, 6H), 2.58 – 2.46 (m, 1H), 2.29 – 2.15 (m, 1H), 1.94 (s, 3H). MS (ESI)m/z : 617 [M+H]+ . | |
II-1-36 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.41 – 8.28 (m, 1H), 7.99 (d,J = 9.3 Hz, 1H), 7.65 (d,J = 3.0 Hz, 1H), 7.29 (d,J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.41 (d,J = 3.0 Hz, 1H), 4.08 – 3.98 (m, 1H), 3.82 (s, 3H), 3.54 (s, 3H), 3.45 – 3.38 (m, 2H), 3.37 – 3.32 (m, 1H), 3.14 (s, 3H), 3.12 – 3.04 (m, 1H), 2.98 (d,J = 5.3 Hz, 6H), 2.53 – 2.46 (m, 1H), 2.44 – 2.35 (m, 1H), 2.30 – 2.15 (m, 2H), 0.84 – 0.69 (m, 3H). MS (ESI)m/z : 631 [M+H]+ . | |
II-1-37 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.9 Hz, 1H), 8.64 – 8.31 (m, 1H), 8.17 (d,J = 2.3 Hz, 1H), 8.14 – 8.02 (m, 1H), 7.46 (dd,J = 9.2, 4.4 Hz, 1H), 7.03 – 6.76 (m, 1H), 6.46 – 6.15 (m, 1H), 4.60 – 4.44 (m, 2H), 3.87 (s, 3H), 3.54 (s, 11H), 3.43 – 3.36 (m, 1H), 3.14 (s, 3H), 3.00 – 2.86 (m, 5H), 2.27 – 2.12 (m, 2H), 1.84 – 1.66 (m, 2H). MS (ESI)m/z : 674 [M+H]+ . | |
II-1-38 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.8 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.45 – 8.31 (m, 1H), 8.19 (d,J = 2.2 Hz, 1H), 8.16 – 8.01 (m, 1H), 7.40 (s, 1H), 7.00 – 6.79 (m, 1H), 3.93 (s, 3H), 3.86 – 3.70 (m, 2H), 3.63 – 3.42 (m, 11H), 3.30 – 3.26 (m, 1H), 3.15 (s, 3H), 2.93 (s, 3H), 2.85 (dt,J = 26.2, 12.1 Hz, 2H), 2.21 – 1.85 (m, 5H), 1.77 – 1.42 (m, 2H). MS (ESI)m/z : 688 [M+H]+ . | |
II-1-39 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.09 – 9.00 (m, 1H), 8.97 (d,J = 1.7 Hz, 1H), 8.36 – 8.19 (m, 2H), 8.07 (d,J = 9.3 Hz, 1H), 7.59 (s, 1H), 7.02 – 6.89 (m, 1H), 3.91 (s, 3H), 3.82 – 3.62 (m, 8H), 3.56 – 3.48 (m, 5H), 3.46 – 3.41 (m, 1H), 3.12 (s, 3H), 3.06 – 2.92 (m, 5H), 2.42 – 2.28 (m, 1H), 2.27 – 2.18 (m, 2H), 2.15 – 2.03 (m, 1H), 2.02 – 1.85 (m, 2H), 0.90 – 0.52 (m, 3H). MS (ESI)m/z : 702 [M+H]+ . | |
II-1-40 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.8 Hz, 1H), 8.95 (d,J = 1.7 Hz, 1H), 8.33 (d,J = 9.3 Hz, 1H), 8.20 (d,J = 2.1 Hz, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.36 (d,J = 8.9 Hz, 1H), 7.01 – 6.88 (m, 3H), 3.91 – 3.82 (m, 2H), 3.61 – 3.38 (m, 11H), 3.23 – 3.17 (m, 1H), 3.13 (s, 3H), 2.92 (s, 3H), 2.91 – 2.82 (m, 2H), 2.28 – 2.10 (m, 2H), 1.89 – 1.72 (m, 2H). MS (ESI)m/z : 727 [M+H]+ . | |
II-1-41 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.00 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.23 (d,J = 2.1 Hz, 1H), 8.16 (d,J = 9.2 Hz, 1H), 7.97 (d,J = 9.1 Hz, 1H), 7.37 (s, 1H), 7.05 (s, 1H), 6.97 (d,J = 2.2 Hz, 1H), 3.76 – 3.53 (m, 8H), 3.48 – 3.42 (m, 3H), 3.38 – 3.32 (m, 1H), 3.16 – 3.08 (m, 5H), 2.98 (s, 3H), 2.75 (dt,J = 17.6, 12.0 Hz, 2H), 2.51 – 2.40 (m, 1H), 2.28 – 2.16 (m, 3H), 1.98 – 1.84 (m, 2H), 0.83 (t,J = 7.4 Hz, 3H). MS (ESI)m/z : 755 [M+H]+ . | |
II-1-42 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.24 (d,J = 2.2 Hz, 1H), 8.09 (d,J = 10.0 Hz, 1H), 7.90 (d,J = 9.3 Hz, 1H), 7.60 (s, 1H), 7.05 – 6.93 (m, 2H), 6.63 (dd,J = 17.3, 11.4 Hz, 1H), 5.26 – 5.16 (m, 1H), 4.86 – 4.80 (m, 1H), 3.75 – 3.59 (m, 8H), 3.49 – 3.45 (m, 3H), 3.37 – 3.34 (m, 1H), 3.29 – 3.22 (m, 2H), 3.12 (s, 3H), 2.99 (s, 3H), 2.80 – 2.64 (m, 2H), 2.23 (t,J = 14.3 Hz, 2H), 2.01 – 1.87 (m, 2H). MS (ESI)m/z : 753 [M+H]+ . | |
II-1-43 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.01 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.46 – 8.25 (m, 1H), 8.20 (d,J = 2.2 Hz, 1H), 8.08 (d,J = 9.3 Hz, 1H), 7.47 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 3.84 (s, 3H), 3.50 (s, 3H), 3.48 – 3.34 (m, 8H), 3.20 – 3.11 (m, 6H), 2.89 (s, 3H), 2.86 – 2.73 (m, 2H), 2.41 – 2.30 (m, 1H), 2.22 – 2.00 (m, 3H), 1.95 – 1.71 (m, 2H), 0.74 – 0.49 (m, 1H), 0.40 – 0.09 (m, 2H), -0.02 – -0.25 (m, 2H). MS (ESI)m/z : 727 [M+H]+ . | |
II-1-44 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.93 (d,J = 1.7 Hz, 1H), 8.88 (d,J = 1.8 Hz, 1H), 8.39 – 8.25 (m, 1H), 8.20 (d,J = 2.2 Hz, 1H), 8.06 (d,J = 9.3 Hz, 1H), 7.40 – 7.27 (m, 1H), 7.11 – 7.01 (m, 3H), 6.96 – 6.79 (m, 4H), 3.83 (s, 3H), 3.75 – 3.54 (m, 10H), 3.45 (s, 3H), 3.31 – 3.25 (m, 1H), 3.08 (s, 3H), 3.02 – 2.90 (m, 5H), 2.84 – 2.66 (m, 2H), 2.20 – 2.00 (m, 2H), 1.86 – 1.73 (m, 2H). MS (ESI)m/z : 763 [M+H]+ . | |
II-1-45 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.02 (d,J = 1.7 Hz, 1H), 8.97 (d,J = 1.8 Hz, 1H), 8.27 (dd,J = 7.4, 4.2 Hz, 2H), 8.10 (d,J = 9.1 Hz, 1H), 8.02 (s, 1H), 7.38 (d,J = 5.5 Hz, 1H), 7.32 (dd,J = 9.1, 2.9 Hz, 1H), 7.20 (d,J = 8.9 Hz, 1H), 3.94 (s, 3H), 3.77 – 3.66 (m, 1H), 3.50 (s, 3H), 3.48 – 3.42 (m, 1H), 3.39 – 3.30 (m, 1H), 3.18 (s, 3H), 3.17 – 3.12 (m, 1H), 3.09 – 3.00 (m, 1H), 2.02 – 1.94 (m, 1H), 1.85 – 1.65 (m, 3H). MS (ESI)m/z : 607 [M+H]+ . | |
II-1-46 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 9.02 (d,J = 1.9 Hz, 1H), 8.96 (d,J = 1.9 Hz, 1H), 8.26 (d,J = 9.2 Hz, 1H), 7.99 (d,J = 9.2 Hz, 1H), 7.84 (d,J = 2.9 Hz, 1H), 7.72 (d,J = 3.0 Hz, 1H), 7.30 (dd,J = 8.9, 2.9 Hz, 1H), 7.20 (d,J = 8.9 Hz, 1H), 6.49 (d,J = 3.0 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 3H), 3.43 – 3.32 (m, 2H), 3.25 (s, 3H), 3.18 – 3.07 (m, 1H), 3.03 – 2.94 (m, 1H), 2.82 – 2.68 (m, 1H), 1.90 – 1.80 (m, 1H), 1.67 – 1.43 (m, 3H). MS (ESI)m/z : 590 [M+H]+ . | |
II-2-1 | 1 H NMR (600 MHz, MeOD) δ 8.87 (d,J = 1.9 Hz, 1H), 8.78 (d,J = 1.8 Hz, 1H), 8.56 (d,J = 9.3 Hz, 1H), 7.93 (d,J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.34 (d,J = 5.8 Hz, 1H), 7.20 (d,J = 5.8 Hz, 1H), 6.72 (s, 1H), 3.75 (s, 3H), 3.59 – 3.34 (m, 11H), 3.31 – 3.27 (m, 1H), 3.21 – 3.13 (m, 2H), 3.12 (s, 3H), 2.98 – 2.92 (m, 2H), 2.91 (s, 3H), 2.20 – 2.08 (m, 2H), 2.00 – 1.89 (m, 5H). MS (ESI)m/z : 703 [M+H]+ . | |
II-2-2 | 1 H NMR (600 MHz, MeOD) δ 8.99 (d,J = 1.8 Hz, 1H), 8.93 (d,J = 1.9 Hz, 1H), 8.47 (d,J = 9.2 Hz, 1H), 8.10 (d,J = 9.2 Hz, 1H), 7.58 (d,J = 5.8 Hz, 1H), 7.50 (s, 1H), 7.40 (d,J = 5.8 Hz, 1H), 6.86 (s, 1H), 3.84 (s, 3H), 3.68 – 3.52 (m, 8H), 3.47 (s, 3H), 3.37 – 3.33 (m, 1H), 3.28 – 3.19 (m, 2H), 3.15 (s, 3H), 3.02 – 2.93 (m, 5H), 2.52 – 2.41 (m, 1H), 2.38 – 2.29 (m, 1H), 2.27 – 2.15 (m, 2H), 2.09 – 1.93 (m, 2H), 1.03 – 0.78 (m, 3H). MS (ESI)m/z : 717 [M+H]+ . | |
II-2-3 | 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 9.02 (d,J = 1.9 Hz, 1H), 8.97 (d,J = 1.9 Hz, 1H), 8.57 (br s, 1H), 8.16 (s, 1H), 8.05 (d,J = 9.2 Hz, 1H), 7.86 (s, 1H), 7.57 (d,J = 5.9 Hz, 1H), 7.37 (d,J = 6.1 Hz, 1H), 3.85 (s, 3H), 3.78 – 3.18 (m, 14H), 3.17 (s, 3H), 2.88 (s, 3H), 2.85 – 2.74 (m, 2H), 2.41 – 2.25 (m, 1H), 2.23 – 2.14 (m, 1H), 2.16 – 2.03 (m, 2H), 1.86 – 1.65 (m, 2H), 0.94 – 0.63 (m, 3H). MS (ESI)m/z : 718 [M+H]+ . | |
II-2-4 | MS (ESI)m/z : 771 [M+H]+ . | |
II-2-5 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.9 Hz, 1H), 8.40 (d,J = 9.3 Hz, 1H), 8.09 (d,J = 9.2 Hz, 1H), 7.57 (s, 1H), 7.05 (d,J = 3.6 Hz, 1H), 6.79 (s, 1H), 6.68 (d,J = 3.6 Hz, 1H), 3.83 (s, 3H), 3.53 – 3.39 (m, 11H), 3.27 – 3.22 (m, 2H), 3.18 – 3.12 (m, 4H), 2.95 – 2.88 (m, 5H), 2.18 – 2.14 (m, 2H), 1.97 – 1.86 (m, 5H). MS (ESI)m/z : 686 [M+H]+ . | |
II-2-6 | MS (ESI)m/z : 700 [M+H]+ . | |
II-2-7 | 1 H NMR (600 MHz, MeOD) δ 8.96 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.8 Hz, 1H), 8.25 (d,J = 9.2 Hz, 1H), 8.03 (d,J = 9.1 Hz, 1H), 7.88 (s, 1H), 7.03 (d,J = 3.5 Hz, 1H), 6.69 (d,J = 3.6 Hz, 1H), 3.88 (s, 3H), 3.70 – 3.49 (m, 8H), 3.43 (s, 5H), 3.34 – 3.28 (m, 1H), 3.10 (s, 3H), 3.01 – 2.86 (m, 5H), 2.36 – 2.22 (m, 1H), 2.19 – 2.10 (m, 2H), 2.11 – 2.04 (m, 1H), 1.98 – 1.81 (m, 2H), 0.78 – 0.57 (m, 3H). MS (ESI)m/z : 701 [M+H]+ . | |
II-2-8 | 1 H NMR (600 MHz, MeOD) δ 8.97 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 1.8 Hz, 1H), 8.35 (d,J = 9.2 Hz, 1H), 7.97 (d,J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.08 (d,J = 3.6 Hz, 1H), 7.04 (s, 1H), 6.69 (d,J = 3.6 Hz, 1H), 3.44 (s, 3H), 3.43 – 3.31 (m, 8H), 3.15 (s, 3H), 3.13 – 3.02 (m, 3H), 2.87 (s, 3H), 2.79 – 2.69 (m, 2H), 2.52 – 2.40 (m, 1H), 2.34 – 2.24 (m, 1H), 2.17 – 2.09 (m, 2H), 1.90 – 1.78 (m, 2H), 0.84 (t,J = 7.5 Hz, 3H). MS (ESI)m/z : 754 [M+H]+ . | |
II-2-9 | 1 H NMR (600 MHz, MeOD) δ 8.95 – 8.91 (m, 1H), 8.87 (d,J = 1.7 Hz, 1H), 8.18 (d,J = 9.2 Hz, 1H), 7.85 (d,J = 9.1 Hz, 1H), 7.78 (s, 1H), 7.05 (d,J = 3.4 Hz, 1H), 6.95 (s, 1H), 6.70 (d,J = 3.5 Hz, 1H), 6.64 (dd,J = 17.7, 11.1 Hz, 1H), 5.17 (d,J = 17.7 Hz, 1H), 4.77 (d,J = 11.0 Hz, 1H), 3.63 – 3.47 (m, 8H), 3.40 (s, 3H), 3.24 – 3.18 (m, 3H), 3.11 (s, 3H), 2.92 (s, 3H), 2.73 – 2.63 (m, 2H), 2.21 – 2.13 (m, 2H), 1.94 – 1.83 (m, 2H). MS (ESI)m/z : 752 [M+H]+ . | |
II-2-10 | MS (ESI)m/z : 726 [M+H]+ . | |
II-2-11 | MS (ESI)m/z : 762 [M+H]+ . | |
II-2-12 | 1 H NMR (600 MHz, MeOD) δ 8.98 (d,J = 1.9 Hz, 1H), 8.91 (d,J = 1.9 Hz, 1H), 8.48 (d,J = 9.2 Hz, 1H), 8.08 (d,J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.05 (d,J = 3.5 Hz, 1H), 6.75 (s, 1H), 6.67 (d,J = 3.5 Hz, 1H), 3.85 (s, 3H), 3.64 – 3.56 (m, 2H), 3.46 (s, 3H), 3.38 – 3.31 (m, 2H), 3.25 – 3.19 (m, 2H), 3.17 (s, 3H), 3.12 – 3.05 (m, 2H), 2.98 (s, 3H), 1.92 (s, 3H). MS (ESI)m/z : 603 [M+H]+ . | |
II-2-13 | MS (ESI)m/z : 631 [M+H]+ . | |
II-2-14 | MS (ESI)m/z : 617 [M+H]+ . | |
II-2-15 | MS (ESI)m/z : 617 [M+H]+ . | |
II-2-16 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.98 (d,J = 1.9 Hz, 1H), 8.90 (d,J = 2.0 Hz, 1H), 8.63 – 8.50 (m, 1H), 8.07 (d,J = 9.4 Hz, 1H), 7.83 – 7.68 (m, 1H), 7.05 (d,J = 3.7 Hz, 1H), 6.79 (d,J = 6.1 Hz, 1H), 6.65 (d,J = 3.7 Hz, 1H), 3.86 (s, 3H), 3.52 – 3.45 (m, 3H), 3.21 – 3.17 (m, 3H), 3.16 – 3.08 (m, 3H), 2.94 (d,J = 3.3 Hz, 6H), 2.85 – 2.81 (m, 2H), 2.20 – 2.17 (m, 2H), 1.92 – 1.88 (m, 2H), 0.89 – 0.78 (m, 3H). MS (ESI)m/z : 645 [M+H]+ . | |
II-2-17 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.96 (d,J = 1.9 Hz, 1H), 8.86 (d,J = 1.9 Hz, 1H), 8.78 – 8.73 (m, 1H), 8.05 (d,J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.03 (d,J = 3.7 Hz, 1H), 6.81 (s, 1H), 6.58 (d,J = 3.6 Hz, 1H), 3.88 (s, 3H), 3.48 (s, 3H), 3.40 – 3.38 (m, 3H), 3.20 (s, 3H), 3.10 – 3.05 (m, 2H), 2.97 (s, 6H), 2.49 – 2.18 (m, 4H), 0.91 – 0.88 (m, 3H). MS (ESI)m/z : 631 [M+H]+ . | |
II-2-18 | MS (ESI)m/z : 673 [M+H]+ . | |
II-2-19 | MS (ESI)m/z : 687 [M+H]+ . | |
II-2-20 | MS (ESI)m/z : 701 [M+H]+ . | |
II-2-21 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.90 – 8.82 (m, 1H), 8.77 – 8.65 (m, 2H), 8.01 (d,J = 8.1 Hz, 1H), 7.84 (d,J = 9.2 Hz, 1H), 7.24 (d,J = 5.9 Hz, 1H), 7.16 (d,J = 5.9 Hz, 1H), 6.98 (s, 1H), 6.83 (d,J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.75 – 3.68 (m, 2H), 3.52 – 3.34 (m, 9H), 3.27 – 3.12 (m, 6H), 3.10 – 3.04 (m, 1H), 2.95 (s, 3H), 2.22 (d,J = 13.1 Hz, 2H), 2.05 (q,J = 10.8 Hz, 2H). MS (ESI)m/z : 689 [M+H]+ . | |
II-2-22 | 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.99 (d,J = 1.9 Hz, 1H), 8.92 (d,J = 1.8 Hz, 1H), 8.52 (d,J = 9.3 Hz, 1H), 8.13 (d,J = 9.2 Hz, 1H), 7.98 (d,J = 8.6 Hz, 1H), 7.08 (d,J = 3.6 Hz, 1H), 7.03 (s, 1H), 6.81 – 6.76 (m, 1H), 6.65 (d,J = 3.6 Hz, 1H), 3.90 (s, 3H), 3.83 – 3.73 (m, 2H), 3.61 – 3.34 (m, 9H), 3.30 – 3.27 (m, 1H), 3.26 – 3.13 (m, 6H), 3.11 – 3.04 (m, 1H), 2.93 (s, 3H), 2.26 – 2.18 (m, 2H), 2.06 – 1.95 (m, 2H). MS (ESI)m/z : 672 [M+H]+ . | |
II-2-23 | MS (ESI)m/z : 590 [M+H]+ . |
生物活性測試。
化合物對激酶穩轉細胞系的生長抑制活性。
化合物對激酶EGFR各種突變體的活性藉由其抑制激酶穩轉的BaF3
細胞系的生長進行評價。具體試驗方法如下:
1)培養基:DMEM (Dulbecco's modified eagle medium) 或RPMI1640 (含10% 胎牛血清,100 μg/mL氨苄青黴素,100 μg/mL鏈黴素)。
2)試劑:MTS反應液 (含2 mg/mL的MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt); 100 μg/mL的PES (phenazine methosulfate)。
3)化合物測試:將細胞接入96-孔培養板,細胞液體積為90 μL,然後加入各梯度濃度化合物10 μL,最高濃度為10 μM,依次按1/3逐級稀釋,共設置8個濃度點,體系中含0.1% DMSO(二甲基亞碸)。混勻化合物的細胞板置於細胞培養箱中(37 ℃;5% CO2
)培養48 h,再加入20 μL的MTS反應液,混勻後置於細胞培養箱中(37 ℃;5% CO2
)孵育1-4 h;採用酶標儀(VARIOSKAN FLASH, Thermo)測量490 nm波長下的OD值。每組實驗設置兩個平行,以終濃度為0.1% DMSO為陰性對照,以不含細胞及化合物的培養基為空白對照。細胞生長抑制率由如下公式計算:
細胞抑制率%=1-(OD實驗組-OD空白組)/(OD陰性組-OD空白組)*100%
4)IC50
值計算:根據測量的細胞抑制率利用GradPad Prism 5軟體計算化合物作用於細胞的半抑制濃度。
下表列出化合物對激酶穩轉細胞系的生長抑制活性:
注:++++代表IC50
≤ 50 nM;+++代表50 nM < IC50
≤ 500 nM;++代表500 nM < IC50
≤ 2500 nM。
序號 | Δ19Del | L858R | Δ19Del/ T790M | L858R/ T790M | Δ19Del/ T790M/ C797S | L858R/ T790M/ C797S |
I-1 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-2 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-3 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-4 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-6 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-7 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-9 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-10 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-11 | ++ | +++ | ++ | ++ | ++ | ++ |
I-12 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-13 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-14 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-15 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-16 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-17 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-18 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-19 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-20 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-21 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-22 | +++ | +++ | ++++ | +++ | ++++ | ++++ |
I-23 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-24 | +++ | +++ | +++ | +++ | +++ | +++ |
I-25 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-26 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-27 | ++ | +++ | ++ | ++ | ++ | ++ |
I-28 | +++ | +++ | +++ | +++ | +++ | +++ |
I-29 | +++ | +++ | +++ | +++ | +++ | ++++ |
I-30 | ++ | ++ | ++ | +++ | +++ | ++ |
I-31 | +++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-32 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-33 | +++ | ++++ | ++++ | ++++ | ++++ | +++ |
I-34 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-35 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-37 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-38 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-39 | ++ | ++ | +++ | +++ | ++++ | ++++ |
I-40 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-41 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-43 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-44 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-45 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-48 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-49 | +++ | +++ | +++ | +++ | +++ | +++ |
I-50 | +++ | +++ | +++ | ++++ | ++ | +++ |
I-55 | +++ | +++ | +++ | +++ | +++ | +++ |
I-56 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-63 | ++++ | +++ | ++++ | ++++ | +++ | +++ |
I-66 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-67 | ++++ | +++ | ++++ | ++++ | +++ | ++++ |
I-73 | ++ | ++ | +++ | +++ | ++ | ++ |
I-76 | +++ | ++ | +++ | ++++ | +++ | ++++ |
I-77 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-78 | +++ | +++ | +++ | ++++ | +++ | ++++ |
I-80 | +++ | +++ | +++ | ++++ | ++ | +++ |
I-81 | +++ | ++ | +++ | +++ | ++ | +++ |
I-82 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-83 | +++ | +++ | ++ | +++ | ++ | ++ |
I-84 | +++ | ++++ | +++ | ++++ | +++ | +++ |
I-85 | +++ | +++ | +++ | +++ | +++ | +++ |
I-87 | ++++ | ++++ | +++ | +++ | ++++ | ++++ |
I-89 | ++ | +++ | +++ | +++ | ++ | +++ |
I-90 | +++ | ++ | ++ | ++ | ++ | +++ |
I-92 | +++ | +++ | +++ | +++ | +++ | ++++ |
I-93 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-94 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-95 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-96 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-97 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-98 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-99 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-100 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-101 | +++ | +++ | ++++ | +++ | ++++ | ++++ |
I-102 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-105 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-106 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-108 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-110 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-111 | +++ | +++ | +++ | ++++ | ++++ | +++ |
I-112 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-113 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-114 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-115 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-116 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-117 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-118 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-120 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-121 | +++ | +++ | +++ | +++ | +++ | +++ |
I-122 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-123 | +++ | +++ | +++ | ++++ | ++++ | +++ |
I-124 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-125 | ++ | +++ | +++ | +++ | ++++ | +++ |
I-126 | ++ | ++ | +++ | ++ | +++ | +++ |
I-127 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-128 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-129 | ++ | ++ | +++ | ++ | +++ | +++ |
I-130 | +++ | +++ | ++++ | +++ | +++ | +++ |
I-131 | ++ | ++ | +++ | ++ | +++ | +++ |
I-132 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-133 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-134 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-135 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-137 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-138 | +++ | +++ | +++ | ++++ | ++++ | +++ |
I-142 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-143 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-154 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-155 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-156 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-157 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-158 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-159 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-160 | ++++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-161 | +++ | +++ | +++ | +++ | +++ | +++ |
I-162 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-163 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-164 | ++ | +++ | ++ | +++ | +++ | +++ |
I-166 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-167 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-168 | ++ | ++ | +++ | ++ | ++ | ++ |
I-169 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-170 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-171 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-172 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-173 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-174 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-175 | ++ | ++ | ++ | ++ | +++ | ++ |
I-177 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-178 | +++ | +++ | ++ | ++ | +++ | ++ |
I-179 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-180 | ++++ | ++++ | +++ | ++++ | ++++ | +++ |
I-181 | ++++ | ++++ | +++ | ++++ | ++++ | +++ |
I-182 | ++ | ++ | ++ | ++ | ++ | ++ |
I-183 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-184 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-185 | +++ | ++++ | +++ | +++ | ++++ | +++ |
I-186 | +++ | ++++ | +++ | +++ | ++++ | ++++ |
I-187 | ++++ | +++ | +++ | +++ | +++ | +++ |
I-188 | +++ | ++++ | ++++ | +++ | ++++ | +++ |
I-190 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-191 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-192 | ++++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-193 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-194 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-195 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-196 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-197 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-199 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-200 | +++ | +++ | +++ | +++ | +++ | +++ |
I-201 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-202 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-203 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-204 | ++ | ++ | ++ | ++ | ++ | ++ |
I-205 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-206 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-207 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-208 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-209 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-210 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-211 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-212 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-213 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-214 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-215 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-216 | ++ | ++ | ++ | ++ | +++ | +++ |
I-218 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-219 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-220 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-221 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-222 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-223 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-224 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-225 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-226 | ++ | ++ | +++ | +++ | ++ | ++ |
I-227 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-228 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-229 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-230 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-231 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-232 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-233 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-234 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-235 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-236 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-237 | +++ | +++ | +++ | +++ | +++ | +++ |
I-238 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-239 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-240 | ++ | ++ | ++ | ++ | ++ | ++ |
I-241 | ++++ | ++++ | ++++ | ++++ | ++++ | +++ |
I-242 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-243 | ++++ | ++++ | ++++ | ++++ | +++ | +++ |
I-244 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-245 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-246 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-247 | +++ | +++ | ++ | ++ | +++ | ++ |
I-248 | ++++ | ++++ | +++ | ++++ | ++++ | +++ |
I-249 | ++++ | ++++ | +++ | ++++ | ++++ | +++ |
I-250 | +++ | +++ | ++ | +++ | +++ | ++ |
I-251 | +++ | +++ | ++ | +++ | +++ | ++ |
I-252 | ++++ | ++++ | +++ | ++++ | ++++ | +++ |
I-253 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-254 | +++ | +++ | ++++ | +++ | +++ | +++ |
I-255 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-256 | ++ | ++ | ++ | +++ | +++ | +++ |
I-257 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-258 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-259 | ++ | ++ | ++ | ++ | +++ | +++ |
I-260 | ++ | ++ | +++ | +++ | ++++ | +++ |
I-261 | ++ | ++ | +++ | +++ | +++ | +++ |
I-262 | ++ | ++ | +++ | ++ | +++ | +++ |
I-263 | ++ | ++ | +++ | ++ | +++ | +++ |
I-264 | ++ | ++ | ++ | ++ | +++ | +++ |
I-265 | ++ | ++ | ++ | ++ | +++ | +++ |
I-266 | ++ | ++ | ++ | ++ | ++ | +++ |
I-267 | +++ | +++ | +++ | +++ | +++ | +++ |
I-268 | ++ | ++ | ++ | ++ | +++ | +++ |
I-269 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-270 | +++ | ++++ | +++ | +++ | ++++ | ++++ |
I-271 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-272 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-273 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-274 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-275 | ++++ | ++++ | ++++ | +++ | ++++ | ++++ |
I-276 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-277 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-278 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-279 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-280 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-281 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-282 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-283 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-284 | +++ | ++ | +++ | +++ | ++++ | ++++ |
I-285 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-286 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-287 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-288 | +++ | ++++ | +++ | +++ | +++ | +++ |
I-289 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-290 | ++ | ++ | +++ | +++ | +++ | +++ |
I-291 | +++ | +++ | +++ | +++ | +++ | ++ |
I-292 | +++ | +++ | ++++ | ++++ | +++ | +++ |
I-293 | +++ | +++ | ++++ | ++++ | +++ | +++ |
I-294 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-295 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-296 | +++ | +++ | +++ | +++ | ++ | +++ |
I-297 | ++ | +++ | +++ | +++ | ++ | ++ |
I-298 | +++ | +++ | ++++ | +++ | ++++ | ++++ |
I-299 | ++++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-300 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-301 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-302 | +++ | +++ | ++++ | ++++ | +++ | ++++ |
I-303 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-304 | +++ | +++ | ++++ | ++++ | +++ | +++ |
I-305 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-306 | ++ | +++ | +++ | +++ | ++ | ++ |
I-307 | ++ | ++ | +++ | +++ | +++ | +++ |
I-308 | +++ | +++ | ++++ | ++++ | ++++ | +++ |
I-309 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-310 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-311 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-312 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-313 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-314 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-315 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-316 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-317 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-318 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-319 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-320 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-321 | +++ | +++ | ++++ | +++ | ++++ | +++ |
I-322 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-323 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-324 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-325 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-326 | +++ | +++ | +++ | +++ | +++ | +++ |
I-327 | ++++ | ++++ | ++++ | ++++ | +++ | +++ |
I-328 | +++ | +++ | ++++ | ++++ | +++ | +++ |
I-329 | +++ | +++ | ++++ | ++++ | +++ | +++ |
I-330 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-331 | +++ | +++ | ++++ | +++ | ++++ | ++++ |
I-332 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-333 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-334 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-335 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-336 | +++ | +++ | +++ | +++ | ++ | +++ |
I-337 | ++++ | +++ | ++++ | +++ | +++ | +++ |
I-338 | +++ | +++ | +++ | +++ | ++ | +++ |
I-340 | ++++ | ++++ | ++++ | ++++ | +++ | +++ |
I-341 | ++++ | ++++ | ++++ | ++++ | +++ | ++++ |
I-342 | +++ | +++ | +++ | +++ | ++ | ++ |
I-343 | +++ | +++ | +++ | +++ | +++ | +++ |
I-344 | ++++ | ++++ | +++ | ++++ | +++ | ++++ |
I-345 | +++ | +++ | +++ | +++ | +++ | +++ |
I-346 | ++++ | ++++ | ++++ | ++++ | +++ | ++++ |
I-347 | ++ | +++ | ++ | +++ | +++ | +++ |
I-348 | +++ | +++ | ++++ | +++ | +++ | +++ |
I-349 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-350 | +++ | +++ | +++ | +++ | +++ | +++ |
I-351 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-352 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-353 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-354 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-355 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-356 | +++ | ++++ | +++ | ++++ | ++++ | +++ |
I-357 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-358 | ++ | +++ | +++ | +++ | +++ | +++ |
I-359 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-360 | +++ | ++++ | +++ | ++++ | +++ | +++ |
I-361 | ++ | ++ | ++ | +++ | ++ | ++ |
I-362 | +++ | ++++ | +++ | +++ | ++++ | ++++ |
I-363 | ++++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-364 | ++++ | +++ | ++++ | +++ | +++ | ++++ |
I-365 | +++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-366 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-367 | ++ | ++ | ++ | ++ | +++ | +++ |
I-368 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-369 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-370 | ++ | +++ | ++ | +++ | ++++ | ++++ |
I-371 | ++ | +++ | +++ | +++ | ++++ | ++++ |
I-372 | +++ | ++++ | +++ | ++++ | ++++ | ++++ |
I-373 | ++ | +++ | ++ | ++ | +++ | ++ |
I-374 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-375 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-376 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-377 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-378 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-379 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-380 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-381 | +++ | +++ | ++++ | ++++ | +++ | ++++ |
I-382 | +++ | +++ | +++ | ++++ | +++ | ++++ |
I-383 | +++ | +++ | +++ | +++ | +++ | ++++ |
I-384 | ++ | ++ | +++ | +++ | +++ | +++ |
I-385 | ++ | ++ | ++ | ++ | +++ | ++++ |
I-386 | +++ | +++ | +++ | +++ | ++++ | +++ |
I-387 | ++ | ++ | ++ | +++ | +++ | +++ |
I-388 | +++ | +++ | +++ | ++++ | ++++ | ++++ |
I-389 | ++ | ++ | ++ | ++ | ++ | +++ |
I-390 | ++ | +++ | +++ | +++ | +++ | ++++ |
I-391 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-392 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-396 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-398 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-399 | +++ | +++ | +++ | +++ | ++++ | ++++ |
I-401 | +++ | +++ | +++ | ++++ | +++ | +++ |
I-402 | ++++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-403 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-404 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-405 | +++ | +++ | ++++ | +++ | +++ | +++ |
I-406 | +++ | +++ | +++ | +++ | +++ | +++ |
I-407 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-408 | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-409 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-410 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-411 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-412 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
I-413 | +++ | +++ | +++ | +++ | +++ | +++ |
I-414 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
I-415 | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
II-1-1 | ++ | ++ | ++ | ++ | +++ | ++ |
II-1-2 | +++ | +++ | +++ | +++ | ++++ | +++ |
II-1-3 | +++ | +++ | +++ | +++ | ++++ | ++++ |
II-1-4 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-6 | ++ | ++ | ++ | +++ | +++ | +++ |
II-1-8 | ++ | ++ | +++ | +++ | +++ | +++ |
II-1-9 | ++ | ++ | +++ | +++ | ++++ | +++ |
II-1-10 | ++ | +++ | +++ | ++ | +++ | +++ |
II-1-11 | ++ | ++ | +++ | ++ | ++ | ++ |
II-1-12 | ++ | ++ | ++ | +++ | +++ | +++ |
II-1-13 | ++ | ++ | +++ | +++ | ++++ | +++ |
II-1-14 | ++ | ++ | ++ | +++ | +++ | ++ |
II-1-15 | ++ | ++ | ++ | ++ | +++ | +++ |
II-1-16 | ++ | +++ | +++ | +++ | ++++ | +++ |
II-1-17 | +++ | +++ | +++ | +++ | +++ | +++ |
II-1-19 | ++ | ++ | ++ | +++ | ++ | ++ |
II-1-20 | ++ | +++ | ++ | +++ | +++ | ++ |
II-1-21 | +++ | +++ | +++ | ++ | +++ | +++ |
II-1-22 | +++ | ++ | +++ | +++ | +++ | +++ |
II-1-23 | +++ | +++ | +++ | +++ | ++++ | +++ |
II-1-24 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-25 | +++ | +++ | +++ | +++ | ++++ | +++ |
II-1-26 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
II-1-27 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-28 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-29 | ++ | ++ | ++ | ++ | +++ | ++ |
II-1-31 | ++ | ++ | ++ | ++ | +++ | ++ |
II-1-32 | ++ | ++ | ++ | +++ | +++ | +++ |
II-1-33 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-34 | ++ | ++ | +++ | ++ | +++ | ++ |
II-1-35 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-36 | ++ | ++ | ++ | ++ | ++ | ++ |
II-1-39 | ++ | ++ | +++ | +++ | ++++ | +++ |
II-1-40 | ++ | ++ | +++ | ++ | ++ | ++ |
II-1-41 | ++ | +++ | ++ | ++ | +++ | +++ |
II-1-42 | +++ | +++ | +++ | +++ | +++ | +++ |
II-1-43 | ++ | +++ | ++ | +++ | +++ | +++ |
II-1-44 | ++ | ++ | +++ | ++ | ++ | ++ |
II-1-45 | ++ | +++ | +++ | +++ | ++++ | +++ |
II-2-1 | ++ | ++ | ++ | ++ | +++ | ++ |
II-2-4 | ++ | ++ | ++ | ++ | ++ | ++ |
II-2-5 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
II-2-7 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
II-2-8 | +++ | +++ | ++++ | +++ | ++++ | ++++ |
II-2-9 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
II-2-12 | +++ | +++ | ++++ | ++++ | ++++ | ++++ |
II-2-17 | ++ | ++ | +++ | +++ | ++++ | +++ |
II-2-22 | +++ | ++ | +++ | ++++ | ++++ | +++ |
II-2-23 | +++ | +++ | +++ | +++ | ++++ | ++++ |
其餘化合物同樣對上述激酶穩轉細胞系的生長具有優良的抑制活性。
Claims (3)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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CN202010450437 | 2020-05-25 | ||
CN202010450437.0 | 2020-05-25 | ||
CN202010825263 | 2020-08-17 | ||
CN202010825263.1 | 2020-08-17 | ||
CN202110524157.4 | 2021-05-13 | ||
CN202110524157.4A CN113717156B (zh) | 2020-05-25 | 2021-05-13 | Egfr抑制剂、其制备方法及用途 |
Publications (2)
Publication Number | Publication Date |
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TW202144337A TW202144337A (zh) | 2021-12-01 |
TWI831011B true TWI831011B (zh) | 2024-02-01 |
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