AU2020100093A4 - Isonicotinic acid derivative and preparation method and application thereof technical field - Google Patents
Isonicotinic acid derivative and preparation method and application thereof technical field Download PDFInfo
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- AU2020100093A4 AU2020100093A4 AU2020100093A AU2020100093A AU2020100093A4 AU 2020100093 A4 AU2020100093 A4 AU 2020100093A4 AU 2020100093 A AU2020100093 A AU 2020100093A AU 2020100093 A AU2020100093 A AU 2020100093A AU 2020100093 A4 AU2020100093 A4 AU 2020100093A4
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- isoxazole
- alkyl
- cancer
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- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims abstract description 4
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 113
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 57
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 56
- 206010028980 Neoplasm Diseases 0.000 description 42
- 201000011510 cancer Diseases 0.000 description 32
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 27
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- -1 2-isethionate Chemical compound 0.000 description 13
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- 206010058467 Lung neoplasm malignant Diseases 0.000 description 11
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- 208000020816 lung neoplasm Diseases 0.000 description 11
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
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- 230000034994 death Effects 0.000 description 9
- 231100000517 death Toxicity 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
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- 239000003814 drug Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
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- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 5
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
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- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 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 description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
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- CITYOBPAADIHAD-UHFFFAOYSA-N (3-phenyl-1,2-oxazol-5-yl)methanol Chemical compound O1C(CO)=CC(C=2C=CC=CC=2)=N1 CITYOBPAADIHAD-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- 239000003146 anticoagulant agent Substances 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
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- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 210000000988 bone and bone Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
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- 201000010536 head and neck cancer Diseases 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
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- 230000009545 invasion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical class NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
An embodiment of the present disclosure mainly relates to an isonicotinic acid derivative, a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof represented by the formula (I), a preparation method thereof, and its use in preparation of anticancer drugs. In formula (I), Z is selected from 0, S, and NR3, wherein R3 is hydrogen or CI-C6 alkyl; R1 is selected from C1 -C 6 alkyl, C1 -C 6 alkoxy, and halogenated C1 -C 6 alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, halogen; R2 is selected from halogen, cyano, nitro, C1 ~ C6 alkyl, C1 ~ C6 alkoxy or halogenated CI-C 6 alkyl; m is an integer from 0-4; n is an integer from 0-5; provided that when Z is selected from NR3 , m is 0, and n is 1, R2 is not halogen. m(R1) (R2 )n (I)
Description
ISONICOTINIC ACID DERIVATIVE AND PREPARATION METHOD AND APPLICATION THEREOF TECHNICAL FIELD
Embodiments of the present disclosure belong to the field of medicinal chemistry and relate to a class of isonicotinic acid derivatives with novel structures, in particular to isonicotinate derivatives and isonicotinamide derivatives containing isoxazole heterocycles, and preparation methods and uses thereof.
BACKGROUND
Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis. It is the second leading cause of death in humans, second only to cardiovascular and cerebrovascular diseases. Cancer can occur in various organs and tissues at any age. According to statistics of the World Health Organization, in 2018, there were approximately 18.1 million new cancer cases and 9.6 million cancer deaths worldwide. There were new cancer cases in Asia (of 8751,000 people) with 48.4% incidence, and cancer death cases (5477,000 people) with 57.3% mortality; There were new cancer cases in Europe (4230000 people) with 23.4% incidence, and cancer death cases (1943,000) with 20.3% mortality; There were new cancer cases in America (3792,000) with 21.0% incidence, and cancer death cases (1371,000) with 14.4% mortality; There were new cancer cases in Africa (1055,000 people) with 5.8% incidence, and cancer death cases (693,000 people) with 7.3% mortality; There were new cancer cases in Oceania (252,000 people) with 1.4% incidence, and cancer death cases (70,000) with 0.7% mortality. From the statistics above, it could be seen that Asia had the highest incidence of cancer and the highest mortality rate. Among them, compared with other countries, incidence and mortality in China ranked first in the world. Of the 18.1 million new cancer patients, China accounted for 3.804 million, and of the 9.6 million cancer deaths, China accounted for 2.296 million. It implied that for every 100 new cancer patients in the world, 21 of which were Chinese. In other words, it meant that an average of 7 people are diagnosed with cancer every minute in our country, and nearly 5 people died from cancers every minute.
The main types of cancer that cause death are: lung cancer, breast cancer, colorectal cancer, prostate cancer, and gastric cancer. Among them, the incidence of lung cancer is 11.6% and the mortality of it is 18.4%; the incidence of breast cancer is 11.6% and the
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2020100093 17 Jan 2020 mortality of it is 6.6%; the incidence of colorectal cancer is 10.2% and the mortality of it is 9.2%; the incidence of gastric cancer is 5.7% and the mortality rate of it is 8.2%. However, in China, the incidence of lung cancer is the highest. For males, gastric cancer, liver cancer, colorectal cancer, and esophageal cancer are high-incidence cancers; for females, breast cancer, colorectal cancer, thyroid cancer, and gastric cancer are also high-incidence cancers.
However, most cancers are discovered in the middle to advanced stages, and the overall effect of treatment is poor. Cancer has posed a huge threat to human survival.
Methods related to cancer treatment include: surgery, radiation therapy and chemotherapy, etc.. Surgical treatment sometimes fails to eradicate cancer cells, which makes them spread and recur. In addition, surgical treatment may lead to serious irrecoverable consequences. For example, cervical and bladder cancer surgeries may cause infertility and sexual dysfunction, etc.; radiation treatment of cancer will damage normal cells; therefore, drug treatment is a better choice. However, the continuous emergence of multidrug resistance has made cancer treatment difficult. In addition, at present, the anticancer drugs used in clinical practice still fail to reach a satisfactory degree of specificity. When patients undergo chemotherapy, normal cells in the body are often killed together, which seriously affects normal physiological functions and is accompanied by many side effects. Therefore, specific anticancer drugs with high activities and low side effects must be developed to meet clinical needs.
Pyridine derivatives have a broad spectrum of biological activities, such as bacteriostatic, anti-inflammatory, activities against cardiovascular diseases, blood lipid lowering, anti-platelet aggregation, activity as plant growth regulator and the like. The patent document CN1953748A also reports that nicotinic acid derivatives have activities to prevent and treat cancers; the patent document CN101210012A reports that nicotinic acid derivatives have activities such as reducing glucose, lowering blood lipids, lowering blood pressure, as well as anticancer, antibacterial, and antiviral activities. In recent years, our group has been mainly engaged in the design and synthesis of compound libraries of small molecule anticancer drugs. Good results have been obtained in previous research work (CN103360382A, CN103664991A, CN103601762A). However, the activity of the above compounds needs to be further improved.
SUMMARY
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2020100093 17 Jan 2020
The purpose of an embodiment of the present disclosure is to provide an isonicotinic acid derivative represented by the formula (I). After activity studies, it has been shown that the isonicotinic acid derivative have strong inhibitory activity against human lung cancer cell line A549, colorectal cancer cell line HCT-116 and breast cancer cell line MCF-7. Therefore, it can be used as candidate compounds or lead compounds of anticancer drugs.
An embodiment of the present disclosure is achieved through the following technical solutions:
an isonicotinic acid derivative represented by formula (I), a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof,
(I) wherein,
Z is selected from the group consisting of O, S, and NR3, wherein R3 is hydrogen or Ci~C6~ alkyl;
Ri is selected from the group consisting of Ci~C6 alkyl, Ci~C6 alkoxy, halogenated C1-C6 alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy and halogen;
R2 is selected from the group consisting of halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkyl;
m is an integer from 0 to 4;
n is an integer from 0 to 5;
provided that when Z is NR3, m is 0 and n is 1, R2 is not a halogen.
According to a preferred technical solution of embodiments of the present disclosure, wherein in formula (I):
Z is O or NH;
Ri is selected from the group consisting of fluorine, chlorine, bromine, Ci~C4 alkyl,
Cj~C4 alkoxy, halogenated Ci~C4 alkyl, and phenoxy;
R2 is selected from the group consisting of fluorine, chlorine, bromine, nitro, Ci~C4
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2020100093 17 Jan 2020 alkyl, Ci~C4 alkoxy, and halogenated Ci~C4 alkyl;
m is an integer of 0, 1, 2; when m is greater than 1, Ri may be the same or different groups;
n is an integer of 0, 1, 2, 3; when n is greater than 1, R2 may be the same or different groups;
provided that when Z is NR3, m is 0 and n is 1, R2 is not fluorine, chlorine, or bromine.
Preferably, wherein in the formula (I), Z is O;
Ri is selected from 2- and / or 6-position substituents on 3-pyridyl, and the substituents are selected from the group consisting of fluorine, chlorine, bromine, Ci~C4 alkyl, and Ci~C4 alkoxy;
R2 is selected from 2- and / or 4- and / or 6-position substituents on 1-phenyl, and the substituents are selected from the group consisting of fluorine, chlorine, bromine, nitro, Cj~C4 alkyl, Ci~C4 alkoxy and halogenated Ci ~ C4 alkyl.
According to embodiments of the present disclosure, the isonicotinic acid derivative represented by the formula (I) is selected from any one of the following compounds:
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2020100093 17 Jan 2020
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2020100093 17 Jan 2020
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The isonicotinic acid derivative represented by formula (I) can be selected to form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid, respectively. Wherein the term pharmaceutically acceptable salt includes, but is not limited to, salts formed with inorganic acids, for example, hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, etc.; and salts formed with organic acids such as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, sulfonate , P-toluenesulfonate, 2-isethionate, benzoate, salicylate, stearate, trifluoroacetic acid, amino acid, alkanoate such as acetate, salts formed with H00C-(CH2)s-C00H, wherein s is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
An embodiment of the present disclosure also provides a pharmaceutical composition
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2020100093 17 Jan 2020 comprising a therapeutically effective amount of at least one selected from the compound of formula (I), the stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof.
According to embodiments of the present disclosure, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient. The excipient may be inert, non-toxic excipients, carriers or diluents, for example, the excipient is selected from one, two or more of the following: disintegrants, glidants, lubricants, fillers, binders, colorants, effervescents, flavoring agents, preservatives, coating materials, etc.
Embodiments of the present disclosure also provide a pharmaceutical preparation comprising at least one selected from the compound represented by formula (I) of embodiments of the present disclosure, the stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof.
According to embodiments of the present disclosure, the preparation is preferably a solid oral preparation, a liquid oral preparation or an injection.
According to embodiments of the present disclosure, the preparation is selected from the group consisting of tablets (dispersed tablets, enteric tablets, chewable tablets, orally disintegrating tablets), capsules, granules, oral solutions, solution-type injections, lyophilized powder injections, large infusions and small infusions.
Embodiments of the present disclosure also provide a use of at least one selected from the isonicotinic acid derivative represented by formula (I), the stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof in preparation of anticancer drugs.
According to embodiments of the present disclosure, the cancer is associated with excessive expression and / or activity of EGFR.
Preferably, the cancer is selected from the group consisting of intestinal cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, and pancreatic cancer.
Further preferably, the cancer is non-small cell lung cancer (NSCLC), bowel cancer, bowel cancer or breast cancer.
An embodiment of the present disclosure also provides a method for preparing the isonicotinic acid derivative represented by formula (I), including the following steps:
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2020100093 17 Jan 2020
(III) (II)
(I) reacting a compound represented by formula (III) with a compound represented by formula (II) to obtain the compound of formula (I);
wherein, each Ri, R2, Z, m, n independently has the definition described above; X is a leaving group;
preferably, X is selected from hydroxyl or Cl;
If protection is required, any functional group in formula (II) and formula (III) may be protected, and thereafter, if necessary, in any order:
(1) removing any protective agent, and (2) forming a pharmaceutically acceptable salt of the compound of formula (I).
According to the preparation method of embodiments of the present disclosure, the reaction is preferably performed under the action of a condensing agent selected from dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI · HC1).
According to embodiments of the present disclosure, an activator is preferably further used with the condensing agent, and the activator is selected from at least one of 1hydroxybenzotriazole (HOBT), N, N-diisopropylethylamine and 4-dimethylaminopyridine (DMAP).
According to the preparation method of embodiments of the present disclosure, the temperature of the reaction is -20 °C to reflux temperature of a solvent used, preferably 0 °C to 30 °C.
According to the preparation method of embodiments of the present disclosure, the reaction is performed in an organic solvent, and the organic solvent is at least one of benzene, toluene, xylene, dichloromethane, chloroform, acetonitrile, dioxane, tetrahydrofuran, and DMF. Tetrahydrofuran is preferred.
According to the preparation method of embodiments of the present disclosure, the
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2020100093 17 Jan 2020 reaction is performed in the presence of a basic catalyst, which is an organic base or an inorganic base, and the organic base is preferably triethylamine, tripropylamine, DMAP, potassium tert-butoxide, etc. ; The inorganic base is preferably potassium carbonate, sodium hydride, or sodium carbonate.
Definition and description of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skilled person in the art to which the subject matter of the claims belongs.
When a numerical range described in the specification and claims of this application is defined as an integer, it should be understood that the two endpoints of the range and each integer in the range are recorded. For example, “integer from 0 to 4” should be understood as each integer of 0, 1, 2, 3, and 4 is recorded. More means three or more.
Halogen refers to F, Cl, Br and I.
Cj~C6 alkyl group refers to an alkyl group with a straight or branched chain having Ιό carbon atoms. Ci-Ce alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, tert-butyl, sec-butyl, pentyl, or neopentyl.
Cj~C6 alkoxy group refers to an -O-Ci~C6 alkyl group, wherein the Ci~C6 alkyl group is as defined above.
Halogenated Ci~C6 alkyl group refers to a group in which any one, two, or more hydrogens of the carbon chain of the Ci~C6 alkyl group is substituted with halogen.
Aryl group refers to a monocyclic or polycyclic aromatic group having 6-20 (preferably 6-14) carbon atoms, and representative aryl groups include: phenyl, naphthyl, anthracenyl, fluorenyl and the like.
Aryloxy group means -O-aryl, wherein aryl is as defined above.
Heteroaryl group refers to a monocyclic or polycyclic aromatic group having 6-20 carbon atoms and 1-4 heteroatoms selected from N, S, and O heteroatoms. Representative heteroaryl groups include thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, indolyl, azanaphthyl, azaanthryl, azafluorenyl and the like.
Heteroaryloxy refers to -O-heteroaryl, wherein heteroaryl is as defined above.
Heterocyclic group refers to a monocyclic or polycyclic non-aromatic group having 3-20
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2020100093 17 Jan 2020 carbon atoms and 1-4 heteroatoms selected from N, S, and O heteroatoms. In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl and oxetanyl; a 5-membered ring such as tetrahydro furanyl, dioxolyl, and pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithioalkyl, thiomorpholinyl, piperazinyl or trithiaalkyl; or a 7membered ring, such as diazacycloheptyl. Optionally, the heterocyclyl may be benzofused. The heterocyclic group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5 or 6-membered bicyclic ring, such as hexahydropyrrole [ 1,2-a] pyrazine-2 (1H) -yl ring.
Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is as defined above.
The term effective amount refers to an amount of at least one compound and / or at least one pharmaceutically acceptable salt that is effective to treat a disease or discomfort in an individual. In the case of cancer, the effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into surrounding organs, for example, inhibit tumors spread into soft tissue or bone; inhibit or prevent the metastasis of the tumor; inhibit or prevent tumor growth; reduce one or more cancer-related symptoms to a certain extent; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. The effective amount can be an amount that reduces disease symptoms by inhibiting EGFR activity. For cancer treatment, the effects of in vivo experiments can be measured by assessing, for example, survival time, time to disease progression (TDP), response rates (RR), duration of response, and / or quality of life.
Those skilled in the art have recognized that the effective amount may vary depending on the route of administration, the dosage of the excipient, and the combination with other drugs.
The term effective amount may also refer to a dose that is effective for inhibiting overexpression of EGFR and / or being overactive for at least one of the compound and / or at least one pharmaceutically acceptable salt thereof.
Beneficial effects
The compound of the disclosure has antitumor and anticancer activities, in particular has
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2020100093 17 Jan 2020 strong inhibitory activities on human lung cancer cell line A549, colorectal cancer cell line HCT116 and breast cancer cell line MCF-7 with high expression of EGFR. The compound YP-1 shows strong activity on three tumor cell lines (A549, HCT116 and MCF-7), among which, compound YP-1 shows strong inhibitory activity on A549 and HCT116 cell lines in vitro, with IC50 values of 4.73 x IO'6 and 3.60 x IO'6 pm, respectively, while the IC50 values of gefitinib on A549 and HCT116 are 21.6 and 17.9 pm, respectively; compound YP-28 on three tumor cell lines (A549, HCT116 and MCF-7) shows strong inhibitory activity, which is similar to that of gefitinib in A549 cell line.
Therefore, the compound of embodiments of the present disclosure has broadspectrum anticancer and antitumor activities and can be used as a candidate drug or a leading compound for treating tumors and cancers.
DETAILED DESCRIPTION
Embodiments of the present disclosure will be further described with reference to the following embodiments. It should be noted that the following embodiments cannot be used as a limitation on the protection scope of embodiments of the present disclosure, and any improvement based on embodiments of the present disclosure do not violate the spirit of embodiments of the present disclosure.
Among them, the synthesis processes of intermediates and target compounds are described by the representatives in the examples, and the synthesis processes of the remaining intermediates and target compounds are the same as the representative compounds.
Instruments and reagents:
AVANCE III nuclear magnetic resonance instrument (400 MHz, DMSO-de, TMS as the internal standard), ion trap liquid mass spectrometer (DECAX-30000 LCQ Deca XP), adjustable wavelength microplate reader (Molecular Devices SPECTRAMAX190). Tunable wavelength microplate reader (Molecular Devices SPECTRAMAX190). The chemical reagents are all commercially available analytical or chemical reagents. RPMI1640 is purchased from Gibco, and thiazole blue [3- (4, 5-dimethylthiazol-2-yl) -2,5diphenyltetrazolium bromide, MTT] is purchased from Sigma. The other reagents are all commercially available and of analytical grades which are not treated before being used
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2020100093 17 Jan 2020 unless special instruction is given. Tetrahydro furan is treated with dry molecular sieve before use.
Example 1 Synthesis of intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II1) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (Π-2):
Using substituted benzaldehyde as a raw material, it is prepared by synthesis of oxime, 1,3-dipolar cycloaddition reaction, methanesulfonyl esterification reaction, azidation, reduction reaction (R2 and n are as defined above), referring to the following process in details:
/ d x if^CHO NH3OH .HCI, Na2CO3 /^_C=NOH n(R2) J ------------------------► n( R2Jqr J H
25°C
NCS / Et3N λ XO MsCI / Et3N * n( R2T-N- I \___/ * °C-reflux Xx0H 0 °C - r. t.
(H-1)
(HI-2)
The detailed preparation processes of intermediate 3-substituted phenyl-5 -hydroxymethyl-isoxazole (II-1) or intermediate 3-substituted phenyl-5-aminomethylisoxazole (II-2) are referring to the three applications of the applicant's earlier applications with publication numbers CN103360382A, CN103664991A, and CN103601762A, of which the entire contents are incorporated herein by reference.
Example 2 Synthesis of the isonicotinic acid derivative represented by formula (I), which is illustrated by the reaction between isonicotinic acid and 3-phenyl-5-hydroxymethylisoxazole:
Synthesis of [(3-phenyl-isoxazol-5-yl) -methyl] -pyridine-3-carboxylate (YP-77)
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2020100093 17 Jan 2020
0.123 g (1 mmol) niacin and 0.206 g (1 mmol) DCC were added to a 50 mL roundbottomed flask, added with 10 mL dry THF, and stirred in an ice bath for 30 minutes. Then, a solution of 0.175 g (1 mmol) 5- hydroxymethyl-3-phenyl-isoxazole and 0.122 g (1 mmol) DMAP in 10 mL THF were slowly added dropwise to the reaction system, and the reaction solution was allowed to naturally rise to room temperature after stirring for 30 minutes in an ice bath. After the completion of the TLC detection reaction, the reaction solution is concentrated in vacuo and the residue is directly separated by column (V (petroleum ether): V (ethyl acetate) = 5:1-2:1) to obtain the target compound [(3-phenyl- isoxazol5-yl) -methyl] -pyridine-3-formate (YP-77).
The compounds in the following table are also synthesized according to the method of example 2. The characterization data of compound Y-77 and the other compounds are:
Table 1- mass spectrometry data of compounds
No. | MS (m/e, 100%) | NO. | MS (m/e, 100%) |
YP-1 | 344 ([M]+, 15) | YP-2 | 376 ([M+18]+, 10) |
YP-3 | 372 ([M]+, 80) | YP-4 | 401 ([M+l]+, 80) |
YP-5 | 386 ([M]+, 45) | YP-6 | 374 ([M]+, 15) |
YP-7 | 374 ([M]+, 60) | YP-8 | 374 ([M]+, 45) |
YP-9 | 412 ([M]+, 75) | YP-10 | 412 ([M]+, 65) |
YP-11 | 362 ([M]+, 60) | YP-12 | 362 ([M]+, 75) |
YP-13 | 381 ([M+2]+, 10) | YP-14 | 379 ([M]+, 10) |
YP-15 | 413 ([M]+, 75) | YP-16 | 424 ([M+l]+, 48) |
YP-17 | 423 ([M]+, 65) | YP-18 | 423 ([M]+, 55) |
YP-19 | 389 ([M]+, 15) | YP-20 | 328 ([M]+, 60) |
YP-21 | 342 ([M]+, 85) | YP-22 | 356 ([M]+, 75) |
YP-23 | 384 ([M]+, 75) | YP-24 | 370 ([M]+, 50) |
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YP-25 | 358 ([M]+, 15) | YP-26 | 358 ([M]+, 75) |
YP-27 | 358 ([M]+, 65) | YP-28 | 396 ([M]+, 15) |
YP-29 | 396 ([M]+, 75) | YP-30 | 346 ([M]+, 70) |
YP-31 | 346 ([M]+, 35) | YP-32 | 363 ([M]+, 100) |
YP-33 | 365 ([M+2]+, 20) | YP-34 | 397 ([M]+, 55) |
YP-35 | 407 ([M]+, 100) | YP-36 | 407 ([M]+, 85) |
YP-37 | 408 ([M+l]+, 85) | YP-38 | 373 ([M]+, 100) |
YP-39 | 344 ([M+l]+, 100) | YP-40 | 358 ([M+l]+, 80) |
YP-41 | 372 ([M+l]+, 80) | YP-42 | 400 ([M+l]+, 90) |
YP-43 | 386 ([M+l]+, 60) | YP-44 | 374 ([M+l]+, 85) |
YP-45 | 374 ([M+l]+, 65) | YP-46 | 374 ([M+l]+, 65) |
YP-47 | 412 ([M+l]+, 55) | YP-48 | 412 ([M+l]+, 65) |
YP-49 | 362 ([M+l]+, 55) | YP-50 | 362 ([M+l]+, 85) |
YP-51 | 379 ([M+l]+, 55) | YP-52 | 379 ([M+l]+, 55) |
YP-53 | 413 ([M+l]+, 85) | YP-54 | 403 ([M+l]+, 85) |
YP-55 | 403 ([M+l]+, 25) | YP-56 | 403 ([M+l]+, 100) |
YP-57 | 389 ([M+l]+, 95) | YP-58 | 328 ([M+l]+, 100) |
YP-59 | 342 ([M+l]+, 100) | YP-60 | 356 ([M+l]+, 100) |
YP-61 | 384 ([M+l]+, 100) | YP-62 | 370 ([M+l]+, 80) |
YP-63 | 358 ([M+l]+, 70) | YP-64 | 358 ([M+l]+, 40) |
YP-65 | 358 ([M+l]+, 100) | YP-66 | 396 ([M+l]+, 80) |
YP-67 | 396 ([M+l]+, 60) | YP-68 | 346 ([M+l]+, 100) |
YP-69 | 346 ([M+l]+, 100) | YP-70 | 363 ([M+l]+, 100) |
YP-71 | 363 ([M+l]+, 100) | YP-72 | 397 ([M+l]+, 80) |
YP-73 | 407 ([M+l]+, 100) | YP-74 | 407 ([M+l]+, 50) |
YP-75 | 407 ([M+l]+, 60) | YP-76 | 373 ([M+l]+, 100) |
YP-77 | 280 ([M]+, 100) | YP-78 | 294 ([M]+, 100) |
YP-79 | 208 ([M]+, 90) | YP-80 | 236 ([M]+, 90) |
YP-81 | 322 ([M]+, 100) | YP-82 | 310 ([M]+, 100) |
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YP-83 | 310 ([M]+, 80) | YP-84 | 310 ([M]+, 60) |
YP-85 | 348 ([M]+, 80) | YP-86 | 348 ([M]+, 80) |
YP-87 | 298 ([M]+, 100) | YP-88 | 298 ([M]+, 80) |
YP-89 | 314 ([M]+, 100) | YP-90 | 314 ([M]+, 100) |
YP-91 | 349 ([M]+, 90) | YP-92 | 359 ([M]+, 100) |
YP-93 | 359 ([M]+, 90) | YP-94 | 359 ([M]+, 60) |
YP-95 | 325 ([M]+, 100) | YP-98 | 307 ([M+l]+, 80) |
YP-97 | 294 ([M+l]+, 100) | YP-100 | 321 ([M+l]+, 90) |
YP-99 | 336 ([M+l]+, 90) | YP-102 | 310 ([M+l]+, 90) |
YP-101 | 310 ([M+l]+, 90) | YP-104 | 348 ([M+l]+, 90) |
YP-103 | 310 ([M+l]+, 90) | YP-106 | 298 ([M+l]+, 100) |
YP-105 | 348 ([M+l]+, 90) | YP-108 | 314 ([M+l]+, 100) |
YP-107 | 298 ([M+l]+, 100) | YP-110 | 349 ([M+l]+, 100) |
YP-109 | 314 ([M+l]+, 100) | YP-112 | 359 ([M+l]+, 80) |
YP-111 | 359 ([M+l]+, 100) | YP-114 | 325 ([M+l]+, 100) |
YP-113 | 359 ([M+l]+, 90) |
Table 2-1 H NMR data of representative compounds in Table 1
NO. | *H NMR (400 MHz, DMSO-</6) |
YP-1 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 7.28 (s, 1H, isoxazole), 7.30 (s, 1H), 7.50-7.53 (m, 4H), 7.89-7.91 (m, 2H). |
YP-2 | 2.37 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.24 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.34 (d, J= 8.0 Hz, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H). |
YP-3 | 1.29 (t, 3H, CH3, J= 7.6 Hz), 2.72 (q, 2H, CH2, J= 7.6 Hz), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.24 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.34 (d, J=8.0Hz, 2H), 7.50 (d, J= 1.2 Hz, 1H), 7.80 (d,J=8.0 Hz, 2H). |
YP-4 | 1.35 (s, 9H, 3CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.24 (s, |
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1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.34 (d, J= 8.0 Hz, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H). | |
YP-5 | 2.15 (s, 6H, 2CH3), 2.31 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.24 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.50 (d, J= 1.2 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H). |
YP-6 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 7.08 (d, J= 8.8 Hz, 2H), 7.21(s,lH, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.84 (d, J= 8.8 Hz, 2H). |
YP-7 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 7.017.08 (m, 2H), 7.42-7.46 (m, 1H), 7.21 (s,lH, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.50 (d, J=0.8 Hz, 1H), 8.17-8.20 (m, 1H). |
YP-8 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 7.21 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.38-7.41 (m, 3H), 7.50 (d, J= 0.8 Hz, 1H), 8.17-8.20 (m, 1H). |
YP-9 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.50 (s, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.72 (d, J= 8.0 Hz, 2H). |
YP-10 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.34 (dd, 7=1.8, 1.6 Hz, 1H), 7.51-7.53 (m, 1H), 7.55 (s, 1H), 7.61 (d, 7=1.8 Hz, 1H), 7.68 (d, 7=1.6 Hz, 1H). |
YP-11 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.30 (d, J= 8.0 Hz, 2H), 7.55 (s, 1H), 7.72 (d, J= 8.0 Hz, 2H). |
YP-12 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.28 (dd, 7=1.2, 1.4 Hz, 1H), 7.49 (d, 7=1.5 Hz, 1H), 7.55 (s, 1H), 7.71-7.73 (m, 1H), 7.76-7.77 (m, 1H). |
YP-13 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 7.29 (d, 7=0.8 Hz, 1H), 7.31 (s, 1H, isoxazole), 7.49 (d, 7=1.2 Hz, 1H), 7.61 (d, 7=8.4 Hz, 2H), 7.94 (d, 7=8.8 Hz, 2H). |
YP-14 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (d, 7= 0.8 Hz, 1H), 7.48-7.52 (m, 2H), 7.54-7.58 (m, 1H), 7.67 (dd,7= 1.2, 1.2 Hz, 1H), 7.72 (dd, 7= 1.6, 1.6 Hz, 1H) |
YP-15 | 3.93 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 7.30 (d, J= 7.2 Hz, 2H), 7.49 (s, 1H, isoxazole), 7.75 (d, J= 8.8 Hz, 2H), 7.85 (s, 1H), 7.87 (s, 1H). |
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YP-16 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 7.29 (d, 7=0.8 Hz, 1H), 7.31 (s, 1H, isoxazole), 7.49 (d, 7=1.2 Hz, 1H), 7.61 (d, 7=8.4 Hz, 2H), 7.94 (d, 7=8.8 Hz, 2H). |
YP-17 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (d,7= 0.8 Hz, 1H), 7.48-7.52 (m, 2H), 7.54-7.58 (m, 1H), 7.67 (dd,7= 1.2, 1.2 Hz, 1H), 7.72 (dd,7= 1.6, 1.6 Hz, 1H). |
YP-18 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8 Hz, 1H), 7.40-7.44 (m, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 7.57 (d, J= 2.2 Hz, 1H), 7.73 (d, 7=2.3 Hz, 1H). |
YP-19 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8 Hz, 1H), 7.55 (s, 1H), 8.05 (d, 7=8.4 Hz, 2H), 8.32 (d, 7=8.8 Hz, 2H). |
YP-20 | 2.57 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 7.29 (s, 1H, isoxazole), 7.52- 7.54 (m, 3H), 7.75 (s, 1H), 7.80 (s, 1H), 7.89-7.91 (m, 2H). |
YP-21 | 2.37 (s, 3H, CH3), 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 7.23 (s, 1H, isoxazole), 7.34 (d, 7=8.0 Hz, 2H), 7.74 (s, 1H), 7.77 (s, 1H), 7.79 (d, 7=2.0 Hz, 2H). |
YP-22 | 1.25 (t, 7=2.6 Hz, 3H, CH3), 2.56 (s, 3H, CH3), 2.60 (q, 7=4.8 Hz, 2H, CH2CH3), 5.58 (s, 2H, isoxazole-CH2), 7.23 (s, 1H, isoxazole), 7.35 (d, 7=8.0 Hz, 2H), 7.46 (s, 1H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
YP-23 | 1.35 (s, 9H, 3CH3), 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 7.23 (s, 1H, isoxazole), 7.38 (d, 7=8.0 Hz, 2H), 7.46 (s, 1H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
YP-24 | 2.34 (s, 3H, CH3), 2.55(s, 3H, CH3), 2.59 (s, 6H, 2CH3), 5.58 (s, 2H, isoxazole-CH2), 7.23 (s, 1H, isoxazole), 6.97 (s, 2H), 7.46 (s, 1H), 8.14 (s, 1H). |
YP-25 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.08 (d, J= 8.8 Hz, 2H), 7.21 (s, 1H, isoxazole), 7.73 (s, 1H), 7.78 (s, 1H), 7.84 (d, J= 8.8 Hz, 2H). |
YP-26 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.05-7.07 (m, 2H), 7.21 (s, 1H, isoxazole), 7.30-7.32 (m, 1H), 7.46 (s, 1H), 8.14 (s, 1H), 8.32 (d, 7=2.4 Hz, 1H). |
YP-27 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 7.05 (d, |
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7=1.8 Hz, H), 7.21 (s, 1H, isoxazole), 7.35-7.40 (m, 3H), 7.46 (s, 1H), 8.14 (s, 1H). | |
YP-28 | 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CTz), 7.21 (s, 1H, isoxazole), 7.46 (s, 1H), 7.68 (d, 7=8.0 Hz, 2H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
YP-29 | 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CTz), 7.21 (s, 1H, isoxazole), 7.34 (dd, 7=1.8, 2.2 Hz, 1H), 7.46 (s, 1H), 7.51-7.53 (m, 1H), 7.61 (d, 7=2.4 Hz, 1H), 7.68 (d, 7=2.4 Hz, 1H), 8.14 (s, 1H). |
YP-30 | 2.56 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 7.31 (s, 1H, isoxazole), 7.59- 7.61 (m, 2H), 7.73 (s, 1H), 7.79 (s, 1H), 7.92-7.94 (m, 2H). |
YP-31 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s,lH, isoxazole), 7.48- 7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
YP-32 | 2.56 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 7.31 (s, 1H, isoxazole), 7.59- 7.61 (m, 2H), 7.73 (s, 1H), 7.79 (s, 1H), 7.92-7.94 (m, 2H). |
YP-33 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.48- 7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
YP-34 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CTz), 7.16 (s, 1H, isoxazole), 7.43 (d, 7=2.6 Hz, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.03 (d, 7=2.2 Hz, 1H), 8.14 (s, 1H). |
YP-35 | 2.51 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CTz), 7.31 (s, 1H, isoxazole), 7.73 (d, J= 6.8 Hz, 2H), 7.75 (s, 1H), 7.79 (s, 1H), 7.87 (d, J= 8.8 Hz, 2H). |
YP-36 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.48- 7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
YP-37 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CTz), 7.16 (s, 1H, isoxazole), 7.40 (dd, 7=2.4, 2.4 Hz, 1H), 7.46 (s, 1H), 7.47 (s, 1H), 7.56 (d, J= 2.4 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 8.01 (s, 1H). |
YP-38 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CTz), 7.16 (s, 1H, isoxazole), 7.46 (s, 1H), 8.05 (d, 7= 6.8 Hz, 2H), 8.15 (s, 1H), 8.32 (d, 7=7.8 Hz, 2H). |
YP-39 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.28 (s, 1H, isoxazole), 7.30 (s, 1H), 7.50-7.53 (m, 4H), 7.89-7.91 (m, 2H). |
YP-40 | 2.37 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.24 (s, 1H, isoxazole), 7.29 (d, 7= 1.2 Hz, 1H), 7.34 |
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(d, J= 8.0 Hz, 2H), 7.50 (d, J= 1.2 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H). | |
YP-41 | 1.29 (t, 3H, CH3, J= 7.6 Hz), 2.72 (q, 2H, CH2, J= 7.6 Hz), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.24 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.34 (d, J= 8.0 Hz, 2H), 7.50 (d, J = 1.2 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H) |
YP-42 | 1.35 (s, 9H, 3CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.24 (s, 1H, isoxazole), 7.29 (d, 7= 1.2 Hz, 1H), 7.34 (d, 7= 8.0 Hz, 2H), 7.50 (d, 7= 1.2 Hz, 1H), 7.80 (d, 7= 8.0 Hz, 2H) |
YP-43 | 2.15 (s, 6H, 2CH3), 2.31 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.24 (s, 1H, isoxazole), 7.29 (d,7= 1.2 Hz, 1H), 7.34 (d,7=8.0 Hz, 2H), 7.50 (d, 7= 1.2 Hz, 1H), 7.80 (d, 7= 8.0 Hz, 2H) |
YP-44 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.08 (d, 7= 8.8 Hz, 2H), 7.21(s, 1H, isoxazole), 7.29 (d,7= 1.2 Hz, 1H), 7.50 (d, 7= 0.8 Hz, 1H), 7.84 (d, 7= 8.8 Hz, 2H) |
YP-45 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.01-7.08 (m, 2H), 7.42-7.46 (m, 1H), 7.21 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.50 (d, J= 0.8 Hz, 1H), 8.17-8.20 (m, 1H). |
YP-46 | 3.82 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 5.56 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.21 (s, 1H, isoxazole), 7.29 (d, J= 1.2 Hz, 1H), 7.38-7.41 (m, 3H), 7.50 (d, 7= 0.8 Hz, 1H), 8.17-8.20 (m, 1H). |
YP-47 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.80 (s, 1H), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.08 (s, 1H, isoxazole), 7.50 (s, 1H), 7.68 (d, 7= 8.0 Hz, 2H), 7.72 (d, 7=8.0 Hz, 2H). |
YP-48 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.34 (dd, 7=1.8, 1.6 Hz, 1H), 7.517.53(m, 1H), 7.55 (s, 1H), 7.61 (d, 7=1.8 Hz, 1H), 7.68 (d, 7=1.6 Hz, 1H). |
YP-49 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.30 (d, 7= 8.0 Hz, 2H), 7.55 (s, 1H), 7.72 (d, 7=8.0 Hz, 2H). |
YP-50 | 3.92 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 6.80 (s, 1H), 7.08 (s, 1H, isoxazole), 7.28 (dd, 7=1.2, 1.4 Hz, 1H), 7.49 |
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(d, 7=1.5 Hz, 1H), 7.55 (s, 1H), Ί.ΊΧ-Ί.Ί3 (m, 1H), 7.76-7.77 (m, 1H). | |
YP-51 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.29 (d, 7=0.8 Hz, 1H), 7.3l(s, 1H, isoxazole), 7.49 (d, 7=1.2 Hz, 1H), 7.61 (d, 7=8.4 Hz, 2H), 7.94 (d, 7=8.8 Hz, 2H) |
YP-52 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8Hz, 1H), 7.48-7.52 (m, 2H), 7.54- 7.58 (m, 1H), 7.67 (dd,7= 1.2, 1.2 Hz, 1H), 7.72 (dd,7= 1.6, 1.6 Hz, 1H) |
YP-53 | 3.93(s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.30 (d, J= 7.2 Hz, 2H), 7.49(s, 1H, isoxazole), 7.75 (d, J= 8.8 Hz, 2H), 7.85 (s, 1H), 7.87 (s, 1H). |
YP-54 | 3.92 (s, 3H, OCH3), 5.59 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.29 (d, 7=0.8 Hz, 1H), 7.31 (s, 1H, isoxazole), 7.49 (d, 7=1.2 Hz, 1H), 7.61 (d, 7=8.4 Hz, 2H), 7.94 (d, 7=8.8 Hz, 2H). |
YP-55 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8 Hz, 1H), 7.48-7.52 (m, 2H), 7.54-7.58 (m, 1H), 7.67 (dd,7= 1.2, 1.2 Hz, 1H), 7.72 (dd,7= 1.6, 1.6 Hz, 1H). |
YP-56 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8 Hz, 1H), 7.40-7.44 (m, 1H), 7.46 (s, 1H), 7.55 (s, 1H), 7.57 (d, J= 2.2 Hz, 1H), 7.73 (d, 7=2.3 Hz, 1H). |
YP-57 | 3.92 (s, 3H, OCH3), 5.62 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.28 (d, J= 0.8 Hz, 1H), 7.55 (s, 1H), 8.05 (d, 7=8.4 Hz, 2H), 8.32 (d, 7=8.8 Hz, 2H). |
YP-58 | 2.57 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.29 (s, 1H, isoxazole), 7.52-7.54 (m, 3H), 7.75 (s, 1H), 7.80 (s, 1H), 7.89-7.91 (m, 2H). |
YP-59 | 2.37 (s, 3H, CH3), 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.23 (s, 1H, isoxazole), 7.34 (d, 7=8.0 Hz, 2H), 7.74 (s, 1H), 7.77 (s, 1H), 7.79 (d, 7=2.0 Hz ,2H). |
YP-60 | 1.25 (t, 7=2.6 Hz, 3H, CH3), 2.56 (s, 3H, CH3), 2.60 (q, 7=4.8 Hz, 2H, CH2CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.23 (s, 1H, isoxazole), 7.35 (d, 7=8.0 Hz, 2H), 7.46 (s, 1H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
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YP-61 | 1.35 (s, 9H, 3CH3), 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.23 (s, 1H, isoxazole), 7.38 (d, 7=8.0 Hz, 2H), 7.46 (s, 1H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
YP-62 | 2.34 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.59 (s, 6H, 2CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.23 (s, 1H, isoxazole), 6.97 (s, 2H), 7.46 (s, 1H), 8.14 (s, 1H). |
YP-63 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.08 (d, J= 8.8 Hz, 2H), 7.21 (s, 1H, isoxazole), 7.73 (s, 1H), 7.78 (s, 1H), 7.84 (d, J= 8.8 Hz, 2H). |
YP-64 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.05-7.07 (m, 2H), 7.21 (s, 1H, isoxazole), 7.30-7.32 (m, 1H), 7.46 (s, 1H), 8.14 (s, 1H), 8.32 (d,7= 2.4 Hz, 1H). |
YP-65 | 2.56 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.05 (d, 7=1.8 Hz, H), 7.21 (s, 1H, isoxazole), 7.35- 7.40 (m, 3H), 7.46 (s, 1H), 8.14 (s, 1H). |
YP-66 | 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.21 (s, 1H, isoxazole), 7.46 (s, 1H), 7.68 (d, 7=8.0 Hz, 2H), 7.74 (d, 7=8.0 Hz, 2H), 8.14 (s, 1H). |
YP-67 | 2.56 (s, 3H, CH3), 5.58 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.21 (s, 1H, isoxazole), 7.34 (dd, 7=1.8, 2.2 Hz, 1H), 7.46 (s, 1H), 7.51- 7.53 (m, 1H), 7.61 (d, 7=2.4 Hz, 1H), 7.68 (d, 7=2.4 Hz, 1H), 8.14 (s, 1H). |
YP-68 | 2.56 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.31 (s, 1H, isoxazole), 7.59-7.61 (m, 2H), 7.73 (s, 1H), 7.79 (s, 1H), 7.92-7.94 (m, 2H). |
YP-69 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.48-7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
YP-70 | 2.56 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.31 (s, 1H, isoxazole), 7.59-7.61 (m, 2H), 7.73 (s, 1H), 7.79 (s, 1H), 7.92-7.94 (m, 2H). |
YP-71 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.48-7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
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YP-72 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.43 (d, 7=2.6 Hz, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.03 (d, 7=2.2 Hz, 1H), 8.14 (s, 1H). |
YP-73 | 2.51 (s, 3H, CH3), 5.60 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.31 (s, 1H, isoxazole), 7.73 (d, J= 6.8 Hz, 2H), 7.75 (s, 1H), 7.79 (s, 1H), 7.87 (d, 7= 8.8 Hz, 2H). |
YP-74 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.48-7.58 (m, 2H), 7.67 (d, 7=8.0 Hz, 1H), 7.73 (m, 2H), 7.79 (s, 1H). |
YP-75 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.40 (dd, 7=2.4, 2.4 Hz, 1H), 7.46 (s, 1H), 7.47 (s, 1H), 7.56 (d, J= 2.4 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 8.01 (s, 1H). |
YP-76 | 2.56 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.46 (s, 1H), 8.05 (d, J= 6.8 Hz, 2H), 8.15 (s, 1H), 8.32 (d, 7=7.8 Hz, 2H). |
YP-77 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.41-7.51 (m, 3H), 7.79- 7.82 (m, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-78 | 2.34 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-79 | 1.28 (t, 7=2.3 Hz, 3H, CH3), 2.65 (q, 7=2.4 Hz, 2H, CH2CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-80 | 1.36 (s, 9H, 3CH3), 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-81 | 2.23 (s, 3H, CH3), 2.62 (s, 6H, 2CH3), 5.63 (s, 2H, isoxazole-CH2), 7.06(s, 2H), 7.16 (s, 1H, isoxazole), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-82 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 7.06 (d, 7=7.2 Hz, 2H), 7.16 (s, 1H, isoxazole), 7.55 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-83 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 7.05-7.07 (m, 2H), 7.16 (s, 1H, isoxazole), 7.30-7.32 (m, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.32 (d, 7=2.4 Hz, |
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1H), 8.90 (d, 7=8.2 Hz, 2H). | |
YP-84 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 7.05 (d, 7=2.0 Hz, 1H), 7.16 (s, 1H, isoxazole), 7.35-7.40 (m, 3H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-85 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.68 (d, 7=8.0 Hz, 2H), 7.74 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-86 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.34 (dd, 7=2.2, 1.8 Hz, 1H), 7.51 (dd, 7=2.2, 1.8 Hz, 1H), 7.61 (dd, 7=2.2, 2.8 Hz, 1H), 7.68 (dd, 7=2.2, 1.8 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-87 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-88 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 (m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-89 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-90 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 (m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-91 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.45 (d, 7= 2.4 Hz, 1H), 7.50 (s, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.06 (d, 7=2.4 Hz, 1H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-92 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-93 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 (m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-94 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.40-7.44(m, 1H), 7.46 (s, 1H), 7.56 (d, 7=2.4 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-95 | 5.63 (s, 2H, isoxazole-CH2), 7.16 (s, 1H, isoxazole), 7.92 (d, 7= 7.8 Hz, 2H), 8.05 (d, J= 7.6 Hz, 2H), 8.38 (d, J= 7.8 Hz, 2H), 9.12 (d, J= 7.8 Hz, 2H), |
YP-97 | 2.34 (s, 3H, CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH- |
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CO), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). | |
YP-98 | 1.28 (t, 7=2.3 Hz, 3H, CH3), 2.65 (q, 7=2.4 Hz, 2H, CH2CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-99 | 1.36 (s, 9H, 3CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.16 (s, 1H, isoxazole), 7.29 (d, 7=8.0 Hz, 2H), 7.70 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-100 | 2.23 (s, 3H, CH3), 2.62 (s, 6H, 2CH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.06 (s, 2H), 7.16 (s, 1H, isoxazole), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-101 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.06 (d, 7=7.2 Hz, 2H), 7.16 (s, 1H, isoxazole), 7.55 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-102 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.05-7.07 (m, 2H), 7.16 (s, 1H, isoxazole), 7.30-7.32 (m, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.32 (d, 7=2.4 Hz, 1H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-103 | 3.85 (s, 3H, OCH3), 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NHCO), 7.05 (d, 7=2.0 Hz, 1H), 7.16 (s, 1H, isoxazole), 7.35-7.40 (m, 3H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-104 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.16 (s, 1H, isoxazole), 7.68 (d, 7=8.0 Hz, 2H), 7.74 (d, 7=8.0 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-105 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.16 (s, 1H, isoxazole), 7.34 (dd, 7=2.2, 1.8 Hz, 1H), 7.51 (dd, 7=2.2, 1.8 Hz, 1H), 7.61 (dd, 7=2.2, 2.8 Hz, 1H), 7.68 (dd, 7=2.2, 1.8 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-106 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-107 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CO), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 |
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(m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). | |
YP-108 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-109 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 (m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-110 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.45 (d, J= 2.4 Hz, 1H), 7.50 (s, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.06(d, 7=2.4 Hz, 1H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-111 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.30 (d, 7=8.0 Hz, 2H), 7.92 (d, 7=8.0 Hz, 2H), 7.95 (d, J= 7.8 Hz, 2H), 8.91 (d, 7=8.2 Hz, 2H). |
YP-112 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.28 (dd, 7=2.0, 2.2 Hz, 1H), 7.49 (d, 7=2.4 Hz, 1H), 7.71-7.75 (m, 1H), 7.77 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-113 | 5.63 (s, 2H, isoxazole-CH2), 6.44 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.40-7.44 (m, 1H), 7.46 (s, 1H), 7.56 (d, 7=2.4 Hz, 1H), 7.73 (d, 7=2.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 2H), 8.90 (d, 7=8.2 Hz, 2H). |
YP-114 | 5.63 (s, 2H, isoxazole-CH2), 6.65 (t, 7=4.6 Hz, 1H, NH-CQ), 7.16 (s, 1H, isoxazole), 7.92 (d, J= 7.8 Hz, 2H), 8.05 (d, J= 7.6 Hz, 2H), 8.38 (d, J= 7.8 Hz, 2H), 9.12 (d, J= 7.8 Hz, 2H), |
Example 3 Biological activity test
The MTT method was used to test the activity against the colorectal cancer cell line HCT-116, human lung cancer cell line A549 and breast cancer cell line MCF-7 using the above specific compounds. The specific test process is as follows:
(1) The lung cancer cell line A549 was laid in a 96-well plate, added with 100 pL medium to culture until the cells grow to 90%. 1 pL drug was added to the wells. Each drug was tested at 8 different concentrations (respectively are the initial concentrations of drugs, 50
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2020100093 17 Jan 2020 μΜ, 5 μΜ, 500 ηΜ, 50 ηΜ, 5 ηΜ, 500 ρΜ, 50 ρΜ). Three wells of replicates of each drug concentration were made in parallel, and after 18 hours of incubation, each well was added with prepared 20 pL of 5 mg / mL MTT solution. After 4 hours, the medium was aspirated and 150 pL DMSO was added to each well. The optical density (OD) of the test compounds were measured at a wavelength of 595 nm. The negative control was DMSO. The inhibition rate was calculated according to the formula.
Negative control OD - Drug OD
Inhibition rate(%)= X 100
Negative control OD
The IC50 value was calculated by GraphPad Prism 5 software.
(2) The screening process of colorectal cancer cell line HCT-116 and breast cancer cell line MCF-7 was the same as that of lung cancer cell line A549.
The test results of the preferred compounds for inhibiting the activity of human lung cancer cells A549, colorectal cancer cell line HCT-116 and breast cancer cell line MCF-7 are shown in Tables 3, 4 and 5 below.
Table 3-Test results of the compounds of formula (I) for inhibiting the activity of human lung cancer cell A549
Compound No. | IC50 (μΜ) | Compound No. | IC50 (μΜ) |
YP-1 | 4.73 | YP-13 | 219.3 |
YP-6 | 694.9 | YP-28 | 27.6 |
Gefitinib | 21.55 |
Table 4-Test results of the compounds of formula (I) for inhibiting the activity of colorectal cancer cell line HCT-116
Compound No. | ICso(pM) | Compound No. | ICso(pM) |
YP-1 | 3.60 | YP-13 | 550.2 |
YP-6 | 295.0 | YP-28 | 273.3 |
Gefitinib | 17.9 |
Table 5- Test results of the compounds of formula (I) for inhibiting the activity of breast cancer cell line MCF-7
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Compound No. | IC50(pM) | Compound No. | IC50(pM) |
YP-1 | 170.8 | YP-13 | 197.3 |
YP-6 | 114.7 | YP-28 | 106.8 |
Gefitinib | 20.68 |
The embodiments of the present disclosure have been described above. However, this disclosure is not limited to the said embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of embodiments of the present disclosure shall be included in the protection scope of embodiments of the present disclosure.
Claims (5)
1. An isonicotinic acid derivative represented by formula (I), a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof,
(I) wherein,
Z is selected from the group consisting of O, S, and NR3, wherein R3 is hydrogen or Ci~C6~ alkyl;
Ri is selected from the group consisting of C j-Ce alkyl, C j-Ce alkoxy, halogenated C j-Ce alkyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy and halogen;
R2 is selected from the group consisting of halogen, cyano, nitro, C j-Ce alkyl, C j-Ce alkoxy, and halogenated C j-Ce alkyl;
m is an integer from 0 to 4;
n is an integer from 0 to 5;
provided that when Z is NR3, m is 0 and n is 1, R2 is not a halogen.
2. The isonicotinic acid derivative, stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (I):
Z is O or NH;
Ri is selected from the group consisting of fluorine, chlorine, bromine, Ci~C4 alkyl, Ci~C4 alkoxy, halogenated Ci~C4 alkyl, and phenoxy;
R2 is selected from the group consisting of fluorine, chlorine, bromine, nitro, Ci~C4 alkyl, Cj~C4 alkoxy, and halogenated Ci~C4 alkyl;
m is an integer of 0,1, 2; when m is greater than 1, Ri may be the same or different groups;
n is an integer of 0, 1, 2, 3; when n is greater than 1, R2 may be the same or different groups;
provided that when Z is NR3, m is 0 and n is 1, R2 is not fluorine, chlorine, or bromine.
3. The isonicotinic acid derivative, stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof according to claims 1 or 2, wherein in formula (I):
Z is O;
Ri is selected from 2- and / or 6-position substituents on 3-pyridyl, and the substituents are selected from the group consisting of fluorine, chlorine, bromine, Ci~C4 alkyl, and Ci~C4
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2020100093 17 Jan 2020 alkoxy;
R2 is selected from 2- and / or 4- and / or 6-position substituents on 1 -phenyl, and the substituents are selected from the group consisting of fluorine, chlorine, bromine, nitro, Cj~C4 alkyl, Ci~C4 alkoxy and halogenated Ci~C4 alkyl.
4. The isonicotinic acid derivative, stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt thereof according to claims 1 or 2, wherein, the isonicotinic acid derivative represented by the formula (I) is selected from any one of the following compounds:
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5. A pharmaceutical composition comprising a therapeutically effective amount of at least one selected from the compounds of the stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.
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