CN105503730B - 吡唑类衍生物及其制备方法与应用 - Google Patents
吡唑类衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN105503730B CN105503730B CN201510997646.6A CN201510997646A CN105503730B CN 105503730 B CN105503730 B CN 105503730B CN 201510997646 A CN201510997646 A CN 201510997646A CN 105503730 B CN105503730 B CN 105503730B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- nmr
- cdcl
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 67
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 140
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- 238000005406 washing Methods 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 31
- 238000001035 drying Methods 0.000 claims description 31
- 239000012074 organic phase Substances 0.000 claims description 31
- 229920006395 saturated elastomer Polymers 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 22
- 229910002027 silica gel Inorganic materials 0.000 claims description 22
- 238000011068 loading method Methods 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- -1 aliphatic ketones Chemical class 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012312 sodium hydride Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 5
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 186
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 49
- 238000004611 spectroscopical analysis Methods 0.000 description 49
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 46
- 239000007787 solid Substances 0.000 description 32
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 241000700721 Hepatitis B virus Species 0.000 description 20
- 239000007788 liquid Substances 0.000 description 18
- 239000007858 starting material Substances 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- SKVGLOFWEJFQKU-UHFFFAOYSA-N (3-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=CC(F)=C1 SKVGLOFWEJFQKU-UHFFFAOYSA-N 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 101710142246 External core antigen Proteins 0.000 description 9
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 8
- 208000002672 hepatitis B Diseases 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000004237 preparative chromatography Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000003752 polymerase chain reaction Methods 0.000 description 6
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 229940125844 compound 46 Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 4
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 229940125851 compound 27 Drugs 0.000 description 4
- 229940126540 compound 41 Drugs 0.000 description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940127271 compound 49 Drugs 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- FEKUXLUOKFSMRO-UHFFFAOYSA-N (4-fluorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(F)C=C1 FEKUXLUOKFSMRO-UHFFFAOYSA-N 0.000 description 2
- BTWNEJOURYOHME-UHFFFAOYSA-N 1,3-thiazol-2-ylhydrazine Chemical compound NNC1=NC=CS1 BTWNEJOURYOHME-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- BFWYZZPDZZGSLJ-UHFFFAOYSA-N 4-(aminomethyl)aniline Chemical compound NCC1=CC=C(N)C=C1 BFWYZZPDZZGSLJ-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical group NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 2
- 0 CCN(C)c(c(*)c1)n[n]1-c1cc(F)ccc1 Chemical compound CCN(C)c(c(*)c1)n[n]1-c1cc(F)ccc1 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 229940127009 HBV antigen inhibitor Drugs 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 239000012414 tert-butyl nitrite Substances 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VFZYLSYYMHFPSY-UHFFFAOYSA-N (2-fluoroanilino)azanium;chloride Chemical compound Cl.NNC1=CC=CC=C1F VFZYLSYYMHFPSY-UHFFFAOYSA-N 0.000 description 1
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- FQHCPFMTXFJZJS-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine;hydrochloride Chemical compound Cl.COC1=CC=C(NN)C=C1 FQHCPFMTXFJZJS-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- AIMREYQYBFBEGQ-UHFFFAOYSA-N 2-methyl-2-nitropropane Chemical compound CC(C)(C)[N+]([O-])=O AIMREYQYBFBEGQ-UHFFFAOYSA-N 0.000 description 1
- YONFQPJFIKYVLO-UHFFFAOYSA-N 3-hydrazinylbenzoic acid;hydrochloride Chemical compound Cl.NNC1=CC=CC(C(O)=O)=C1 YONFQPJFIKYVLO-UHFFFAOYSA-N 0.000 description 1
- XHLQMKQBCHYRLC-UHFFFAOYSA-N 4-hydrazinylbenzoic acid;hydron;chloride Chemical compound Cl.N[NH2+]C1=CC=C(C([O-])=O)C=C1 XHLQMKQBCHYRLC-UHFFFAOYSA-N 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- MMODWSCTJGUVNT-UHFFFAOYSA-N CC(C)Cc(c(C(CN(C)c1ccncc1)=O)c1)n[n]1-c1cc(F)ccc1 Chemical compound CC(C)Cc(c(C(CN(C)c1ccncc1)=O)c1)n[n]1-c1cc(F)ccc1 MMODWSCTJGUVNT-UHFFFAOYSA-N 0.000 description 1
- OLWZEZQOKXHMPH-UHFFFAOYSA-N CC(C)Cc(c(C(N(C)CC(CC1)CCN1C(OC(C)(C)C)=O)=O)c1)n[n]1-c1cc(F)ccc1 Chemical compound CC(C)Cc(c(C(N(C)CC(CC1)CCN1C(OC(C)(C)C)=O)=O)c1)n[n]1-c1cc(F)ccc1 OLWZEZQOKXHMPH-UHFFFAOYSA-N 0.000 description 1
- OMLKFIQGFQKOPK-UHFFFAOYSA-N CC(C)Cc(c(C(N(C)Cc(cccc1)c1F)=O)c1)n[n]1C1=NC=CC1=C Chemical compound CC(C)Cc(c(C(N(C)Cc(cccc1)c1F)=O)c1)n[n]1C1=NC=CC1=C OMLKFIQGFQKOPK-UHFFFAOYSA-N 0.000 description 1
- UTBSNYMKSTTWJO-UHFFFAOYSA-N CC(C)Cc(c(C(NCc(cc1)ccc1O)=O)c1)n[n]1-c1ncc[s]1 Chemical compound CC(C)Cc(c(C(NCc(cc1)ccc1O)=O)c1)n[n]1-c1ncc[s]1 UTBSNYMKSTTWJO-UHFFFAOYSA-N 0.000 description 1
- WKPPUJQBYHESAW-UHFFFAOYSA-N CC(C)Cc(c(C(NCc1ccccc1)=O)c1)n[n]1-c1cccc(F)c1 Chemical compound CC(C)Cc(c(C(NCc1ccccc1)=O)c1)n[n]1-c1cccc(F)c1 WKPPUJQBYHESAW-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- ZWWXDCOPVYATOQ-UHFFFAOYSA-N amino-(4-nitrophenyl)azanium;chloride Chemical compound [Cl-].N[NH2+]C1=CC=C([N+]([O-])=O)C=C1 ZWWXDCOPVYATOQ-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- XCUBVSAYUSFHNN-UHFFFAOYSA-N hydron;(2-nitrophenyl)hydrazine;chloride Chemical compound [Cl-].[NH3+]NC1=CC=CC=C1[N+]([O-])=O XCUBVSAYUSFHNN-UHFFFAOYSA-N 0.000 description 1
- GMXFZBZOVZOYNQ-UHFFFAOYSA-N hydron;(3-methoxyphenyl)hydrazine;chloride Chemical compound Cl.COC1=CC=CC(NN)=C1 GMXFZBZOVZOYNQ-UHFFFAOYSA-N 0.000 description 1
- BKOYKMLGFFASBG-UHFFFAOYSA-N hydron;(3-nitrophenyl)hydrazine;chloride Chemical compound Cl.NNC1=CC=CC([N+]([O-])=O)=C1 BKOYKMLGFFASBG-UHFFFAOYSA-N 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- MVSMBIBGGPSEHQ-UHFFFAOYSA-N o-[(4-methoxyphenyl)methyl]hydroxylamine Chemical compound COC1=CC=C(CON)C=C1 MVSMBIBGGPSEHQ-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- KLKBCNDBOVRQIJ-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CN)CC1 KLKBCNDBOVRQIJ-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种吡唑类衍生物及其制备方法和应用。所述化合物具有式I所示的结构。本发明还涉及含有式I结构化合物的药物组合物以及提供上述化合物在制备抗HBV药物中的应用。
Description
技术领域
本发明属于医药技术领域，具体涉及吡唑类衍生物及其制备方法与制药用途。
背景技术
乙型病毒性肝炎(viral hepatitis type B)，简称乙肝(Hepatitis B)，是由乙型肝炎病毒(HBV)所致的重大传染性疾病，长期发展可导致急慢性病毒性肝炎、重型肝炎、肝硬化和原发性肝细胞癌(hepatocellular carcinoma,HCC)。据世界卫生组织(WHO)报道，全球近20亿人曾感染过HBV，其中约3.5亿人为慢性HBV感染者，平均每年约有100万人死于HBV感染所致的急、慢性肝炎及相关并发症。目前用于预防和治疗慢性乙型肝炎(CHB)的药物主要有疫苗、干扰素、免疫调节药以及DNA聚合酶抑制剂。但是由于它们存在耐药性、副作用、停药后反弹和不能彻底的清除乙肝病毒等缺点，因此发现和研究新的安全、高效、低毒和抗耐药性的非核苷类乙肝病毒抑制剂显得至关重要。
杂环化合物是发现药物活性先导物的重要源泉。取代吡唑作为结构独特的一类杂环“优势结构”，具有广泛的生物活性。它可以作为构成药效团的基本结构母核，以适合药物特殊作用靶点的空间要求；还可以作为活性取代基或环系的组成部分而产生相应的生物活性；另外杂环具有较好的体内代谢稳定性及生物相容性，对发现高效广谱、生物利用度好的新型抗HBV药物具有重要意义。
本发明基于噻唑类乙肝病毒抑制剂药效团模型和活性构象，采用分子杂合和电子等排药物设计策略，设计合成了一系列吡唑类化合物，此类化合物在现有技术中未见相关报道。
发明内容
针对现有技术的不足，本发明提供了吡唑类衍生物及其制备方法。本发明还提供了上述化合物作为非核苷类HBV抑制剂的活性筛选结果及其应用。
本发明的技术方案如下：
一.吡唑类衍生物
本发明涉及的吡唑类衍生物，具有如下通式I所示的结构：
其中，
R1为含取代基的苯环或芳杂环；
R2为烷基、苄基或不同链长度的酯基；
X为NH、S或CH2；
R3为羧基、酯基或不同取代基的酰胺。
根据本发明优选的，通式I中，R1为不同取代基的苯环或噻唑环；R2为饱和烷基、苄基或丁酸乙酯；X为O、NH或CH2；R3为甲酸、甲酸乙酯、环丙酰胺、不同取代基的苯酰胺、不同取代基的苄酰胺。
进一步优选的，吡唑类衍生物是具有下列结构的化合物之一：
表1.化合物1-50的结构式
二.吡唑类衍生物的制备方法
本发明吡唑类衍生物的制备方法为下列之一：
1.吡唑类衍生物的制备方法，步骤如合成路线1：以乙氧甲叉氰乙酸乙酯Ia为初始原料，首先在醋酸和水的混合溶液中经过醋酸钠的催化与不同的芳香肼反应得到中间体Ib粗品，然后Ib与溴化亚铜、2-甲基-2-硝基丙烷经重氮化反应得到中间体Ic，Ib或Ic与不同取代基发生亲核取代反应生成不同的目标化合物Id；接着，在碱性条件下发生水解反应生成中间体Ie，Ie与不同取代的胺发生酰化反应得到目标产物If。
合成路线1如下：
试剂及条件:(i)醋酸钠，醋酸，水，回流；(ii)溴化亚铜，乙腈,50℃；(iii)氢化钠、碳酸钾或碳酸铯，不同的胺、醇或卤代烷，N,N-二甲基甲酰胺，30-80℃；(iv)氢氧化钠，乙醇，水，四氢呋喃，50℃；(v)不同的胺，二氯甲烷，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，1-羟基苯并三唑；
其中，
R1为含取代基的苯环或芳杂环；
R2为烷基、苄基或不同链长度的酯基；
X为NH或S；
R3为不同取代基的酰胺；
所述的不同的胺为环丙胺，2,4-二氟苄胺；
本发明所述的吡唑类衍生物的制备方法，具体制备步骤如下：
(1)取25mL圆底烧瓶，将不同取代基的肼盐酸盐Ia1.59mmol溶于3mL乙酸中，加入1mL水，醋酸钠3.49mmol回流4h；反应结束后冷却至室温，加入20mL冰水中；乙酸乙酯萃取三次，合并有机相，30mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品Ib；
(2)取25mL圆底烧瓶，将中间体Ib 0.8mmol溶于乙腈5mL中，加入溴化亚铜，冷却至0℃，缓慢加入亚硝酸叔丁酯2.17mmol，50℃搅拌过夜。反应结束后冷却至室温，加50mL水淬灭；乙酸乙酯萃取三次，合并有机相，50mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品Ic；
(3)取25mL圆底烧瓶，将中间体Ib 1.12mmol溶于5mL DMF中，加入碳酸钾、碳酸铯或者氢化钠，室温搅拌5min；加入不同的卤代烷1.35mmol，室温搅拌过夜。反应结束后加入50mL水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗三次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品Id；
取25mL圆底烧瓶，将中间体Ic 0.64mmol溶于5mL DMF中，加入60％NaH 0.77mmol，室温搅拌5分钟；缓慢加入不同的硫醇等试剂，室温搅拌过夜。反应结束后加入50mL水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗三次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品Id；
(4)取25mL圆底烧瓶，将中间体Id 0.74mmol溶于2mL乙醇、2mL水和2mL四氢呋喃的混合溶液中，50℃加热反应过夜。反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL氯化铵水溶液中和反应，乙酸乙酯萃取三次，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到纯品Ie；
(5)取25mL圆底烧瓶，将中间体Ie 0.19mmol溶于5mL二氯甲烷中，然后低温下缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐0.25mmol和1-羟基苯并三唑0.25mmol，搅拌10分钟；加入不同的胺，室温反应过夜。反应结束后加入30mL水，乙酸乙酯萃取三次，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品If。
2.吡唑类衍生物的制备方法，步骤如合成路线2：以碳酸二乙酯IIa为初始原料，首先在醋酸和四氢呋喃的混合溶液中经过氢化钠的催化与不同的脂肪酮得到中间体IIb粗品，然后IIb与N,N-二甲基甲酰胺缩二甲醇反应得到中间体IIc，IIc与不同肼盐酸盐发生成环反应生成不同的目标化合物IId；接着，在碱性条件下发生水解反应生成中间体IIe，IIe与不同取代的胺发生酰化反应得到目标产物IIf；
合成路线2如下：
试剂及条件:(i)四氢呋喃，氢化钠，60℃；(ii)100℃；(iii)乙醇，三乙胺；(iv)氢氧化钠，乙醇，水，四氢呋喃，50℃；(v)N,N-二甲基甲酰胺，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，三乙胺，室温；
其中，
R1为含取代基的苯环或芳杂环；
R2为烷基；
R3为不同取代的苯基、苄基、苯胺或酚；
本发明所述的吡唑类衍生物的制备方法，具体制备步骤如下：
(1)取50mL圆底烧瓶，低温下将60％氢化钠11.98mmol溶于15mL四氢呋喃溶液中，缓慢滴加不同的脂肪酮IIa 1.59mmol溶于混合溶液中，室温搅拌半小时；低温下继续滴加碳酸二乙酯14.98mmol于混合溶液中，60℃反应4小时。反应结束后冷却至室温，加入50mL冰水中，加入1.5mL醋酸中和反应，乙酸乙酯萃取三次，合并有机相，30mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩得到粗品IIb；
(2)取25mL圆底烧瓶，将中间体IIb 5.81mmol溶于5mL N,N-二甲基甲酰胺缩二甲醇中100℃搅拌过夜；反应结束后减压蒸馏得到粗品IIc；
(3)取25mL圆底烧瓶，将1.59mmol不同取代基的肼盐酸盐溶于6mL乙醇中，加入1.90mmol中间体IIc于混合溶液中，缓慢滴加三乙胺7.93mmol，室温搅拌过夜。反应结束后冷却至室温，减压蒸馏除去部分乙醇，加入50mL水中；乙酸乙酯萃取三次，合并有机相，30mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品IId；
(4)取25mL圆底烧瓶，将中间体IId 0.69mmol溶于3mL乙醇、3mL水和3mL四氢呋喃的混合溶液中，50℃加热反应过夜。反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL氯化铵水溶液，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次20mL，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到纯品IIe；
(5)取25mL圆底烧瓶，将中间体IIe 0.38mmol溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯0.46mmol，搅拌10分钟；加入不同的胺及三乙胺0.76mmol，室温反应1小时；反应结束后加入30mL水，乙酸乙酯萃取三次，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品IIf。
三.吡唑类衍生物的应用
本发明公开了吡唑类衍生物抗HBV活性筛选结果及其作为抗HBV抑制剂的应用。通过实验证明本发明的吡唑类衍生物可作为经典的HBV非核苷类抑制剂应用。具体地说，可以作为HBV抑制剂用于制备抗乙肝药物。因此，本发明还提供吡唑类衍生物在制备抗HBV的药物中的应用。
四.吡唑类衍生物的抗HBV活性和毒性实验
对上述新合成的化合物(化合物的结构式见表1)运用酶联免疫法(ELISA)检测样品药物达到抑制病毒HBeAg和HBsAg分泌的50％时的浓度数值为IC50；运用MTT法检测样品药物导致50％细胞毒性死亡的数值浓度为CC50值；用聚合酶链反应(PCR)检测药物抑制HBVDNA复制量的50％时的浓度数值IC50，以拉米夫定作为阳性对照药。它们的抗HBV活性和毒性数据列于表2中。由表2看出新合成的化合物部分呈现出较好抑制病毒HBeAg和HBsAg分泌活性，大部分细胞毒性较低。
本发明的吡唑类衍生物是一类结构新颖的非核苷类HBV抑制剂，可作为抗HBV的先导化合物。
本发明的吡唑类衍生物可作为非核苷类HBV抑制剂应用。具体地说，作为HBV抑制剂用来制备抗乙肝药物。
一种抗HBV药物组合物，包括本发明的吡唑类衍生物和一种或多种药学上可接受载体或赋形剂。
本发明公开了吡唑类衍生物、其制备方法、抗HBV活性筛选结果及其作为抗HBV抑制剂的首次应用。实验证明本发明的吡唑类衍生物可作为HBV抑制剂用于制备抗乙肝药物。
具体实施方式
通过下述实例有助于理解本发明，但是不能限制本发明的内容，在下列实例中，所有目标化合物的编号与表1相同。
合成路线：
实施例1.化合物44的制备方法
取25mL圆底烧瓶，将3-氟苯肼盐酸盐(5g,30.52mmol)溶于45mL乙酸中，加入15mL水，醋酸钠(5.68g,33.58mmol)，回流4h。反应结束后冷却至室温，加入200mL冰水中；乙酸乙酯萃取三次(50mL x 3)，合并有机相，50mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝1：20)分离获取淡黄色固体3-氨基-1-(3-氟苯)-1H-吡唑-4-甲酸乙酯(44)6.93g，熔点为130–131℃，收率为91％。
化合物44波谱数据：1H-NMR(400MHz,CDCl3)δppm:7.79(s,1H),7.51～7.45(m,1H),7.37～7.30(m,2H),7.13～7.08(m,1H),5.36(s,1H),4.31(q,2H,J＝7.1Hz),1.37(t,3H,J＝7.1Hz)；13C-NMR(100MHz,CDCl3):164.47,164.39,161.92,149.15,140.97,139.15,139.04,131.10,131.01,118.88,188.85,115.11,114.90,111.41,111.17,96.57,59.78,14.49；EI-MS:250.4[M+H]+.
实施例2.化合物1的制备
取25mL圆底烧瓶，将化合物44(280mg,1.12mmol)溶于5mL DMF中，加入碳酸钾(466mg,3.36mmol)，室温搅拌5min；加入溴化苄(230mg,1.35mmol)，室温搅拌过夜。反应结束后加入50mL水，乙酸乙酯萃取三次(25mL x 3)，合并有机相，饱和食盐水洗三次(50mL x3)，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝1：30)分离获取浅黄色油状液体1280mg，收率为73％。
化合物1的波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.81(s,1H),7.43～7.4536(m,2H),7.32～7.27(m,1H),7.25～7.22(m,3H),7.12～7.07(m,1H)7.04(dd,2H,J1＝2.0Hz,J2＝7.6Hz),6.52(s,1H),4.29(q,2H,J＝7.2Hz),4.03(s,1H),1.34(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.72,164.00,161.53,151.71,141.21,140.87,140.77,137.81,130.42,130.33,128.66,127.66,127.19,120.37,120.34,115.28,115.07,112.51,112.27,99.11,77.34,77.23,77.03,76.71,59.84,49.79,14.45；EI-MS:340.5[M+H]+.
实施例3.化合物2的制备
将化合物1(250mg,0.74mmol)溶于2mL乙醇、2mL水和2mL四氢呋喃的混合溶液中，50℃加热反应过夜。反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到白色固体化合物2100mg，收率为32％。
化合物2波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.89(s,1H),7.45～7.40(m,1H),7.35～7.33(m,1H),7.33～7.24(m,4H),7.14～7.09(m,1H),7.02(dd,2H,J1＝2.0Hz,J2＝7.6Hz),6.57(s,1H),4.07(s,1H)；13C-NMR(100MHz,CDCl3):169.57,163.95,161.48,152.18,141.89,140.59,140.49,137.58,130.46,130.37,128.74,127.77,127.04,120.76,120.73,115.65,115.44,112.90,112.66,97.91,77.35,77.23,77.03,76.71,49.50；EI-MS:312.4[M+H]+.
实施例4.化合物3的制备
取25mL圆底烧瓶，将化合物3(60mg,0.19mmol)溶于5mL二氯甲烷中，然后低温下缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(43mg,0.25mmol)和1-羟基苯并三唑(39mg,0.25mmol)，搅拌10分钟；加入不同的胺，室温反应过夜。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝1：8)分离获取白色固体化合物340mg，收率为60％。
化合物3波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.58(s,1H),7.42～7.36(m,2H),7.31～7.29(m,1H),7.26～7.20(m,3H),7.11～7.07(m,1H),7.04(dd,2H,J1＝2.0Hz,J2＝8.0Hz),5.87(s,1H),4.01(s,2H),2.82～2.76(m,1H),0.88～0.82(m,2H),0.62～0.58(m,2H)；13C-NMR(100MHz,CDCl3):163.99,161.52,151.35,140.92,140.82,137.97,137.59,130.39,130.30,129.17,128.53,127.67,127.44,127.26,120.24,120.21,115.19,114.98,112.38,112.13,100.82,49.66,29.70,22.39,6.82；EI-MS:351.6[M+H]+.
实施例5.化合物4的制备
操作同实施例2，所不同的是将溴化苄换成碘乙烷。油状液体，收率72％。
化合物4波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.81(s,1H),7.46～7.39(m,2H),7.38～7.34(m,1H),7.11～7.06(m,1H),6.00(s,1H),4.30(q,2H,J＝7.2Hz),2.87(q,2H,J＝7.2Hz),1.37(t,3H,J＝7.1Hz),1.08(t,3H,J＝7.1Hz)；13C-NMR(100MHz,CDCl3):164.87,164.00,161.53,152.33,141.21,141.01,130.38,130.29,120.07,120.04,115.05,114.84,112.16,111.92,98.58,77.37,77.25,77.05,76.73,59.76,40.92,15.55,14.50；EI-MS:278.2[M+H]+.
实施例6.化合物5的制备
操作同实施例2，所不同的是将溴化苄换成碘甲烷。油状液体，收率38％。
化合物5波谱分析数据1H-NMR(400MHz,CDCl3)δppm:7.80(s,1H),7.47～7.32(m,3H),7.12～7.07(m,1H),4.30(q,2H,J＝7.2Hz),2.95(s,3H),1.36(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.88,163.96,153.23,141.10,140.85,130.36,130.27,120.53,120.50,115.21,115.00,112.59,112.35,97.75,59.78,32.74,14.49；EI-MS:264.3[M+H]+.
实施例7.化合物7的制备
操作同实施例2，不同的是将溴化苄换成溴代环丁烷，将碳酸钾换成碳酸铯。油状液体，收率27％。
化合物7波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.80(s,1H),7.46～7.41(m,1H),7.38～7.30(m,2H),7.12～7.07(m,1H),6.29(s,1H),4.31(q,2H,J＝7.2Hz),3.49(s,1H),2.07～1.99(m,2H),1.89～1.79(m,2H),1.67～1.59(m,1H),1.47～1.42(m,1H),1.37(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.89,163.94,161.48,150.98,141.17,141.08,140.98,130.36,130.27,120.08,120.05,115.06,114.85,112.17,111.93,98.32,59.77,50.93,32.26,14.51,14.19；EI-MS:304.4[M+H]+.
实施例8.化合物8的制备
操作同实施例2，不同的是将溴化苄换成溴代环戊烷，将碳酸钾换成碳酸铯。油状液体，收率47％。
化合物8波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.82(s,1H),7.45～7.37(m,3H),7.11～7.06(m,1H),5.99(s,1H),4.30(q,2H,J＝7.2Hz),3.44(d,1H,J＝4.4Hz),1.67～1.59(m,4H),1.47～1.40(m,4H),1.36(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.83,163.98,161.52,151.93,141.20,141.10,130.36,130.27,119.98,119.94,114.98,114.77,112.06,111.81,99.34,77.35,77.24,77.03,76.72,59.76,56.96,33.49,23.41,14.48,EI-MS:318.4[M+H]+.
实施例9.化合物9的制备
操作同实施例2，操作同实施例2，不同的是将溴化苄换成溴代丁酸乙酯，将碳酸钾换成氢化钠。油状液体，收率44％。
化合物9波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.84(s,1H),7.48～7.42(m,1H),7.38～7.36(m,1H),7.33～7.29(m,1H),7.15～7.10(m,1H),6.44(d,1H,J＝10.4Hz),4.30(q,2H,J＝7.2Hz),4.13～4.03(m,2H),3.73～3.67(m,1H),1.73～1.62(m,3H),1.38(t,3H,J＝7.2Hz),1.17(t,3H,J＝7.2Hz),0.87(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):171.87,164.33,164.09,161.62,150.51,141.46,140.51,140.41,130.71,130.62,120.30,120.27,115.58,115.37,112.46,112.22,99.93,77.35,77.23,77.03,76.71,61.24,59.95,58.71,26.31,14.46,14.06,9.37,EI-MS:364.5[M+H]+.
实施例10.化合物6的制备
取25mL圆底烧瓶，将中间体3-氨基-1-(3-氟苯基)-1H-吡唑-4-碳酸乙酯(200mg,0.8mmol)溶于5mL乙腈中，加入溴化亚铜，冷却至0℃，缓慢加入亚硝酸叔丁酯(223mg,2.17mmol)，50℃搅拌过夜。反应结束后冷却至室温，加50mL水淬灭；乙酸乙酯萃取三次(25mL x 3)，合并有机相，50mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝1：30)分离获取黄色固体3-溴-1-(3-氟苯基)-1H-吡唑-4-碳酸乙酯195mg，收率72％。
化合物6波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.14(s,1H),7.52～7.4(m,1H),7.36(dd,1H,J1＝2.0Hz,J2＝7.6Hz),7.32～7.28(m,1H),7.23～7.18(m,1H),4.37(q,2H,J＝7.2Hz),1.37(t,3H,J＝7.2Hz),1.40(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):163.69,161.62,161.22,143.43,139.60,139.50,130.39,130.31,121.85,121.81,117.78,116.50,116.29,115.55,113.98,113.73,77.34,77.23,77.03,76.71,60.71,14.33,EI-MS:313.3[M+H]+.
实施例11.化合物10的制备
取25mL圆底烧瓶，将中间体3-溴-1-(3-氟苯基)-1H-吡唑-4-碳酸乙酯(200mg,0.64mmol)溶于5mL DMF中，加入60％NaH(31mg,0.77mmol)，室温搅拌5分钟；缓慢加入不同的硫醇等试剂，室温搅拌过夜。反应结束后加入50mL水，乙酸乙酯萃取三次(25mL x 3)，合并有机相，饱和食盐水洗三次(50mL x 3)，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取油状液体85mg，收率38％。
化合物10波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.14(s,1H),7.49～7.43(m,1H),7.33～7.27(m,2H),7.19～7.15(m,1H),4.37(q,2H,J＝7.2Hz),4.13～4.03(m,2H),3.30～3.28(m,1H),1.73～1.50(m,5H),1.40(t,3H,J＝7.2Hz),1.21～1.15(m,5H),EI-MS:349.5[M+H]+.
实施例12.化合物11的制备
取25mL圆底烧瓶，将中间体异丁酰乙酸乙酯(1.33g,8.39mmol)溶于11mL N,N-二甲基甲酰胺缩二甲醇中100℃搅拌过夜。反应结束后减压蒸馏得到粗品。将中间体溶于11mL乙醇，加入1.1mL三乙胺，3-氟苯肼盐酸盐化合物(1.36g,8.39mmol)，室温反应2小时。反应结束后，加入150mL水，乙酸乙酯萃取三次(50mL x 3)，合并有机相，饱和食盐水洗三次(50mL x 3)，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝30：1)分离获取油状液体832mg，收率36％。
化合物11波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.03(s,1H),7.50～7.45(m,1H),7.23～7.11(m,3H),4.33(q,2H,J＝7.2Hz),3.31～3.24(m,1H),1.41～1.37(m,9H).13C-NMR(100MHz,CDCl3):163.86,163.20,161.38,152.90,143.31,140.79,140.69,130.48,130.39,122.42,122.38,116.41,116.20,114.54,114.30,111.98,77.35,77.24,77.04,76.72,60.11,26.42,20.09,14.41,EI-MS:277.4[M+H]+.
实施例13.化合物12的制备
取50mL圆底烧瓶，将中间体碳酸二乙酯(1.77g,14.98mmol)溶于15mL THF中，低温下加入60％NaH(480mg,11.98mmol)，室温搅拌30分钟；缓慢加4-甲基-2-戊酮(1g,9.98mmol)，60℃加热反应4h。反应结束后冷却至室温，加入50mL醋酸水溶液猝灭，乙酸乙酯萃取三次(25mL x 3)，合并有机相，50mL饱和碳酸氢钠水溶液洗一次，50mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩得粗品4-甲基丁酰乙酸乙酯，直接进行下一步。
取25mL圆底烧瓶，将上步得到的粗品4-甲基丁酰乙酸乙酯(1g,5.81mmol)溶于5mLN,N-二甲基甲酰胺缩二甲醇中100℃搅拌过夜。反应结束后减压蒸馏得到黄色油状液体。
取25mL圆底烧瓶，将上步中间体(335mg，1.47mmol)溶于6mL乙醇，加入三乙胺(622mg，6.14mmol)，3-氟苯肼盐酸盐化合物(200mg,1.23mmol)，室温反应2小时。反应结束后，减压蒸馏除去部分乙醇，加入50mL水，乙酸乙酯萃取三次(25mL x 3)，合并有机相，50mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚＝30：1)分离获取油状液体135mg，收率38％。
化合物12波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.05(s,1H),7.50～7.45(m,1H),7.21～7.14(m,3H),4.34(q,2H,J＝7.2Hz),2.94(d,2H,J＝7.6Hz),1.89～1.78(m,1H),1.38(t,3H,J＝7.2Hz),0.76(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.90,163.55,161.43,147.59,142.37,140.70,140.60,130.56,130.47,122.08,122.05,116.13,115.92,114.21,113.97,113.18,77.35,77.24,77.03,76.71,60.04,33.31,28.85,22.21,14.40,EI-MS:291.4[M+H]+.
实施例14.化合物13的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为2-氟苯肼盐酸盐。油状液体，收率58％。
化合物13光谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.09(s,1H),7.52～7.46(m,1H),7.44～7.39(m,1H),7.31～7.24(m,2H),4.33(q,2H,J＝7.2Hz),2.79(d,2H,J＝7.6Hz),1.90～1.80(m,1H),1.38(t,3H,J＝7.2Hz),0.75(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.53,158.33,155.82,149.02,142.73,131.29,131.21,129.52,127.18,127.06,124.77,124.73,116.91,116.72,112.65,77.36,77.24,77.04,76.72,59.99,33.53,33.51,28.68,22.20,14.40；EI-MS:291.4[M+H]+.
实施例15.化合物14的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为4-氟苯肼盐酸盐。油状液体，收率56％。
化合物14波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.03(s,1H),7.38～7.35(m,2H),7.21～7.17(m,2H),4.32(q,2H,J＝7.2Hz),2.88(d,2H,J＝7.2Hz),1.87～1.80(m,1H),1.38(t,3H,J＝7.2Hz),0.75(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.75,163.60,161.27,147.65,142.11,135.42,135.39,128.41,128.32,116.37,116.14,112.86,77.34,77.23,77.02,76.71,59.97,33.34,28.76,22.20,14.39；EI-MS:291.4[M+H]+.
实施例16.化合物15的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为4-硝基苯肼盐酸盐。油状液体，收率37％。
化合物15波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.39(dd,2H,J1＝2.0Hz,J2＝6.8Hz),8.09(s,1H),7.64(dd,2H,J1＝2.0Hz,J2＝6.8Hz),7.27(s,1H),4.34(q,2H,J＝7.2Hz),3.01(d,2H,J＝7.2Hz),1.85～1.78(m,1H),1.39(t,3H,J＝7.2Hz),0.75(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.28,147.78,147.34,144.53,143.15,126.68,124.82,114.13,77.35,77.24,77.04,76.72,60.23,33.36,29.09,22.18,14.38；EI-MS:318.5[M+H]+.
实施例17.化合物16的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为3-甲氧基苯肼盐酸盐。油状液体，收率47％。
化合物16波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.39(t,1H,J＝8.4Hz),7.00(dd,1H,J1＝1.6Hz,J2＝8.4Hz),6.98(dd,1H,J1＝1.6Hz,J2＝8.4Hz),6.92(t,1H,J＝2.0Hz),4.32(q,2H,J＝7.2Hz),3.85(s,3H),2.92(d,2H,J＝7.2Hz),1.89～1.82(m,1H),1.38(t,3H,J＝7.2Hz),0.76(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.69,160.20,147.55,141.98,140.27,129.92,118.58,114.93,112.81,112.12,77.35,77.24,77.03,76.72,59.95,55.58,33.38,28.74,22.24,14.41；EI-MS:303.5[M+H]+.
实施例18.化合物17的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为2-硝基苯肼盐酸盐。油状液体，收率52％。
化合物17波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.10(dd,1H,J1＝0.8Hz,J2＝8.0Hz),8.05(s,1H),7.78(dt,1H,J1＝1.2Hz,J2＝7.6Hz),7.68(dt,1H,J1＝1.2Hz,J2＝7.6Hz),7.54(dd,1H,J1＝0.8Hz,J2＝7.6Hz),4.33(q,2H,J＝7.2Hz),2.83(d,2H,J＝7.6Hz),1.89～1.79(m,1H),1.38(t,3H,J＝7.2Hz),0.81(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.34,148.59,146.03,143.16,133.50,132.53,130.42,129.77,125.64,113.52,77.36,77.05,76.73,60.08,33.45,28.43,22.23,14.36；EI-MS:318.5[M+H]+.
实施例19.化合物18的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为4-甲氧基苯肼盐酸盐。油状液体，收率32％。
化合物18波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.03(s,1H),7.29(dd,2H,J1＝2.4Hz,J2＝6.8Hz),6.99(dd,2H,J1＝2.4Hz,J2＝6.8Hz),4.32(q,2H,J＝7.2Hz),3.87(s,1H),2.86(d,2H,J＝7.2Hz),1.90～1.80(m,1H),1.37(t,3H,J＝7.2Hz),0.75(d,6H,J＝6.8Hz),EI-MS:303.5[M+H]+.
实施例20.化合物19的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为3-羧基苯肼盐酸盐。白色固体，收率52％。
化合物19波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:9.80(s,1H),8.21(dd,1H,J1＝1.6Hz,J2＝7.2Hz),8.15(s,1H),8.10(s,1H),4.34(q,2H,J＝7.2Hz),2.94(d,2H,J＝7.6Hz),1.88～1.81(m,1H),1.39(t,3H,J＝7.2Hz),0.76.13C-NMR(100MHz,CDCl3):170.08,163.55,147.77,142.47,139.57,131.49,130.79,130.52,129.68,127.88,113.25,77.35,77.24,77.03,76.71,60.12,33.36,28.94,22.23,14.40；EI-MS:317.5[M+H]+.
实施例21.化合物20的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为4-羧基苯肼盐酸盐。白色固体，收率50％。
化合物20波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:9.84(s,1H),8.27(d,2H,J＝8.8Hz),8.11(s,1H),7.56(d,2H,J＝8.8Hz),4.34(q,2H,J＝7.2Hz),2.99(d,2H,J＝7.2Hz),1.86～1.79(m,1H),1.39(t,3H,J＝7.2Hz),0.75(d,6H,J＝6.8Hz)；EI-MS:317.5[M+H]+.
实施例22.化合物45的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为3-硝基苯肼盐酸盐。油状液体，收率45％。
化合物45波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.35～8.33(m,2H),8.09(s,1H),7.80(d,1H,J＝8.0Hz),7.72(t,1H,J＝8.0Hz),4.34(q,2H,J＝7.2Hz),2.98(d,2H,J＝7.2Hz),1.90～1.79(m,1H),1.39(t,3H,J＝7.2Hz),0.77(d,6H,J＝6.8Hz).13C-NMR(100MHz,CDCl3):163.32,148.58,147.76,142.95,140.41,132.02,130.33,123.52,121.32,113.81,77.35,77.24,77.04,76.72,60.21,33.36,29.09,22.22,14.39；EI-MS:318.5[M+H]+.
实施例23.化合物21的制备
操作同实施例13，不同的是将12的原料3-氟苯肼盐酸盐替换为2-噻唑肼。白色固体，收率25％。
化合物21波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.02(s,1H),7.60(d,1H,J＝3.2Hz),7.18(d,1H,J＝3.6Hz),4.33(q,2H,J＝7.2Hz),3.51(d,2H,J＝7.2Hz),2.16～2.06(m,1H),1.38(t,3H,J＝7.2Hz),0.94(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.14,161.89,148.96,143.46,140.40,117.18,115.17,60.25,33.02,28.89,22.13,14.35；EI-MS:280.3[M+H]+.
实施例24.化合物46的制备
取25mL圆底烧瓶，将化合物12(200mg,0.69mmol)溶于3mL乙醇、3mL水和3mL四氢呋喃的混合溶液中，加入氢氧化钠(165mg,4.13mmol)，50℃加热反应过夜。反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL氯化铵水溶液中和反应，乙酸乙酯萃取三次(15mL x3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到白色固体120mg，收率：66％。
化合物46波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.02(s,1H),7.60(d,1H,J＝3.2Hz),7.18(d,1H,J＝3.6Hz),4.33(q,2H,J＝7.2Hz),3.51(d,2H,J＝7.2Hz),2.16～2.06(m,1H),1.38(t,3H,J＝7.2Hz),0.94(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.14,161.89,148.96,143.46,140.40,117.18,115.17,60.25,33.02,28.89,22.13,14.35；EI-MS:280.3[M+H]+.
实施例25.化合物22的制备
取25mL圆底烧瓶，将化合物46(100mg,0.38mmol)溶于10mL二氯甲烷中，然后低温下缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(95mg,0.5mmol)和1-羟基苯并三唑(67mg,0.5mmol)，搅拌10分钟；室温反应过夜。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取白色固体，收率55％。
化合物22波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.39(s,1H),8.11(d,1H,J＝8.4Hz),7.60～7.44(m,4H),7.28～7.21(m,3H),2.96(d,2H,J＝7.6Hz),1.94～1.84(m,1H),0.78(d,6H,J＝6.8Hz)；EI-MS:380.4[M+H]+.
实施例26.化合物23的制备
取25mL圆底烧瓶，将化合物46(100mg,0.38mmol)溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(174mg,0.46mmol)，搅拌10分钟；加入4-氟苄胺(48mg,0.38mmol)及三乙胺(77mg,0.76mmol)，室温反应1小时。反应结束后加入30mL水)，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取白色固体137mg，收率：97％。
化合物23波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::7.79(s,1H),7.49～7.44(m,1H),7.31(dd,2H,J1＝5.6Hz,J2＝8.8Hz),7.19(dd,2H,J1＝2.0Hz,J2＝8.0Hz),7.15～7.12(m,1H),6.24(s,1H),4.56(d,2H,J＝6.0Hz),2.98(d,2H,J＝7.6Hz),1.87～1.76(m,1H),0.75(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):163.91,163.47,163.33,161.44,161.02,146.43,140.77,140.67,138.42,134.31,134.28,130.56,130.47,129.50,129.42,121.95,121.91,116.09,115.88,115.73,115.71,115.49,114.08,113.84,77.36,77.25,77.04,76.73,42.69,33.15,28.78,22.19；EI-MS:370.4[M+H]+.
实施例27.化合物24的制备
取25mL圆底烧瓶，将化合物46(100mg,0.38mmol)溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(174mg,0.46mmol)，搅拌10分钟；加入三乙胺(77mg,0.76mmol)，60℃加热反应5小时。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取白色固体40mg，收率：33％。
化合物24波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::7.64(s,1H),7.46(dd,1H,J1＝8.0Hz,J2＝14.4Hz),7.22(d,1H,J＝8.4Hz),7.18～7.14(m,2H),3.52(q,4H,J＝7.2Hz),2.80(d,2H,J＝7.2Hz),1.74～1.64(m,1H),1.24(t,6H,J＝7.2Hz),0.76(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):165.25,163.90,161.43,144.25,142.86,141.00,140.90,138.04,130.45,130.36,121.70,121.66,116.93,115.72,115.51,113.83,113.59,77.36,77.04,76.73,33.26,28.63,22.17；EI-MS:318.5[M+H]+.
实施例28.化合物25的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为苄胺。白色固体80mg，收率：60％。
化合物25波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::7.79(s,1H),7.79～7.44(m,1H),7.36～7.27(m,5H),7.20～7.12(m,3H),6.21(s,1H),4.61(d,2H,J＝4.4Hz),2.99(d,2H,J＝7.2Hz),1.88～1.78(m,1H),0.75(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):163.90,163.27,161.42,146.40,140.74,140.64,138.40,130.55,130.46,128.79,127.85,127.58,121.96,121.93,116.07,115.86,114.09,113.85,77.35,77.24,77.04,76.72,43.45,33.15,28.77,22.20；EI-MS:352.5[M+H]+.
实施例29.化合物26的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为4-氟苯胺。白色固体65mg，收率：48％。
化合物26波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::8.00(s,1H),7.78(s,1H),7.56～7.53(m,2H),7.51～7.45(m,1H),7.21(dd,2H,J1＝2.0Hz,J2＝8.0Hz),7.16(dd,1H,J1＝2.0Hz,J2＝9.2Hz),7.04(t,2H,J＝8.4Hz),2.99(d,2H,J＝7.2Hz),1.89～1.82(m,1H),0.75(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.91,161.52,161.43,160.73,158.30,147.24,140.40,140.30,138.37,133.79,133.76,130.66,130.57,122.42,122.34,122.04,122.00,116.36,116.15,115.96,115.81,115.59,114.17,113.93,77.36,77.24,77.04,76.72,33.19,28.74,22.21.
实施例30.化合物27的制备
取25mL圆底烧瓶，将化合物21(1.5g,5.37mmol)溶于14mL乙醇、14mL水和14mL四氢呋喃的混合溶液中，加入氢氧化钠(1.29g,32.2mmol)，50℃加热反应过夜。反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL乙酸乙酯和50mL水萃取，取水相，加入30mL稀盐酸中和反应，乙酸乙酯萃取三次(30mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到白色固体1.18g，收率：87％。
化合物27波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::12.79(s,1H),8.11(s,1H),7.76(d,1H,J＝3.6Hz),7.67(d,1H,J＝3.2Hz),3.45(d,2H,J＝7.2Hz),2.07～2.00(m,1H),0.88(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):164.30,161.71,148.11,144.06,140.95,119.37,115.92,32.70,28.69,22.34；EI-MS:252.4[M+H]+.
实施例31.化合物28的制备
取25mL圆底烧瓶，将化合物27(70mg,0.28mmol)溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(127mg,0.33mmol)，搅拌10分钟；加入4-氟苄胺(35mg,0.33mmol)及三乙胺(56mg,0.56mmol)，室温反应1小时。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取白色固体72mg，收率：72％。
化合物28波谱分析数据：1H-NMR(400MHz,CDCl3)δppm::7.80(s,1H),7.60(d,1H,J＝3.6Hz),7.32～7.29(m,2H),7.17(d,1H,J＝3.6Hz),7.02(t,2H,J＝8.4Hz),6.29(s,1H),4.55(d,2H,J＝5.6Hz),3.50(d,2H,J＝7.2Hz),2.12～2.05(m,1H),0.92(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.45,162.82,161.74,161.01,147.53,140.43,139.87,134.12,134.09,133.82,129.55,129.47,117.72,117.17,115.71,115.49,114.43,77.37,77.05,76.74,42.77,32.92,28.86,22.12；EI-MS:359.4[M+H]+.
实施例32.化合物29的制备
取25mL圆底烧瓶，将化合物27(100mg,0.4mmol)溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(182mg,0.48mmol)，搅拌10分钟；加入三乙胺(81mg,0.8mmol)，室温反应1小时。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取白色固体60mg，收率：40％。
化合物29波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.75(dd,1H,J1＝0.8Hz,J2＝4.4Hz),8.47(dd,1H,J1＝1.2Hz,J2＝8.4Hz),7.28(d,1H,J＝3.6Hz),3.55(d,2H,J＝7.2Hz),2.22～2.16(m,1H),0.96(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):161.05,158.58,152.21,151.84,143.11,140.89,140.67,135.05,129.55,120.89,118.11,108.90,77.35,77.23,77.03,76.71,33.41,28.98,22.12；EI-MS:370.3[M+H]+.
实施例33.化合物30的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为4-甲氧基苄氧胺。白色固体，收率：48％。
化合物30波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.67(s,1H),7.74(s,1H),7.48～7.43(m,1H),7.35(d,2H,J＝8.8Hz),7.19～7.10(m,1H),6.90(d,2H,J＝8.4Hz),4.92(s,2H),3.81(s,3H),2.93(d,2H,J＝7.6Hz),1.82～1.75(m,1H),0.74(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):163.88,161.40,160.07,146.97,140.59,140.49,138.74,131.04,130.56,130.47,127.40,121.92,121.89,116.12,115.91,114.04,114.01,113.80,112.79,78.19,77.38,77.06,76.74,55.29,33.17,28.71,22.17；EI-MS:398.4[M+H]+.
实施例34.化合物31的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为4-氟苯肼盐酸盐，三乙胺为3个当量。白色固体，收率：45％。
化合物31波谱分析数据：1H-NMR(400MHz,DMSO)δppm:10.08(s,1H),8.27(s,1H),7.87(s,1H),7.61(q,1H,J＝6.8Hz),7.48(d,1H,J＝9.6Hz),7.38(t,2H,J＝8.0Hz),7.00(t,2H,J＝8.8Hz),6.80～6.77(m,2H),2.96(d,2H,J＝7.6Hz),1.65～1.58(m,1H),0.64(d,6H,J＝6.4Hz)；13C-NMR(100MHz,DMSO):163.66,163.27,161.21,157.48,155.16,146.79,146.27,141.13,141.03,139.60,131.59,131.50,122.73,116.28,116.08,115.71,115.49,114.40,114.07,113.88,113.80,40.65,40.44,40.24,40.03,39.82,39.61,39.40,32.86,28.40,22.43；EI-MS:371.4[M+H]+.
实施例35.化合物32的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为4-吡啶甲胺。白色固体，收率：61％。
化合物32波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.53(s,1H),7.89(s,1H),7.47(q,1H,J＝6.4Hz),7.28～7.14(m,5H),6.81(s,1H),4.60(d,2H,J＝6.0Hz),2.99(t,2H,J＝7.2Hz),1.84～1.78(m,1H),0.75(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.89,163.63,161.42,149.90,147.96,146.73,140.67,140.58,138.52,130.60,130.51,122.29,121.93,121.90,116.16,115.95,115.37,114.07,113.83,77.37,77.05,76.73,42.13,33.12,28.76,22.18；EI-MS:353.4[M+H]+.
实施例36.化合物33的制备
操作同实施例26，不同的是将23的原料4-氟苄胺替换为1-BOC-4-氨甲基哌啶。白色固体，收率：60％。
化合物33波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.81(s,1H),7.50～7.44(m,1H),7.20～7.13(m,3H),6.16(t,1H,J＝6.0Hz),4.13(d,2H,J＝12.8Hz),3.30(d,2H,J＝5.2Hz),2.97(d,2H,J＝7.6Hz),2.70(t,2H,J＝12.4Hz),1.84～1.72(m,4H),1.46(s,9H),1.23～1.13(m,2H),0.75(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):163.88,163.61,161.41,154.82,146.23,140.77,140.67,138.33,130.54,130.45,121.93,121.90,116.05,115.96,115.84,114.06,113.82,79.41,77.36,77.25,77.05,76.73,44.80,43.61,36.57,33.11,29.88,28.74,28.46,22.17；EI-MS:459.6[M+H]+.
实施例37.化合物34的制备
取25mL圆底烧瓶，将化合物44(100mg,0.4溶于5mL N,N-二甲基甲酰胺中，加入三乙胺(122mg,1.2mmol)，然后低温下缓慢加入对硝基酰氯(104mg,0.56mmol)，60℃加热反应过夜。反应结束后加入30mL水，乙酸乙酯萃取三次(15mL x 3)，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱(乙酸乙酯：石油醚)分离获取目标化合物。
化合物34波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:9.59(s,1H),8.32(d,2H,J＝8.4Hz),8.04(d,3H,J＝6.8Hz),7.42～7.27(m,3H),7.07(t,1H,J＝8.0Hz),7.35(q,2H,J＝7.2Hz),1.38(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.03,163.98,163.02,161.52,150.40,141.29,141.19,140.66,139.71,137.77,130.52,130.43,128.90,124.15,118.52,118.49,115.44,115.23,110.87,110.62,105.62,77.36,77.04,76.72,60.96,14.33；EI-MS:399.3[M+H]+.
实施例38.化合物35的制备
操作同实施例37，不同的是将34的原料对硝基酰氯替换为対硝基磺酰氯。
化合物35波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.28(s,1H),7.94(s,1H),7.71～7.66(m,2H),7.38～7.32(m,1H),6.99～6.94(m,1H),4.25(q,2H,J＝7.2Hz),3.11(s,3H),3.06(s,3H),1.34(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.31,163.57,161.14,158.37,153.68,142.73,141.02,140.92,129.49,129.40,119.14,119.11,113.14,112.93,111.26,111.01,100.97,77.36,77.04,76.72,59.63,40.53,34.31,14.45；EI-MS:305.4[M+H]+.
实施例39.化合物36的制备
操作同实施例31，不同的是将28的原料替换为2-氟苄胺。白色固体，熔点101-102℃，收率：49％。
化合物35波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.80(s,1H),7.59(d,1H,J＝3.2Hz),7.40(t,1H,J＝7.2Hz),7.38～7.25(m,1H),7.16(d,1H,J＝3.6Hz),7.14～7.04(m,2H),6.24(s,1H),4.65(d,2H,J＝5.6Hz),3.48(d,2H,J＝7.2Hz),2.12～2.02(m,1H),0.90(d,6H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):162.81,162.35,161.79,159.90,147.34,140.40,139.99,130.39,130.35,129.45,129.37,125.28,125.14,124.40,124.37,117.87,117.14,115.55,115.33,37.59,37.55,32.93,28.84,22.06；EI-MS:359.5[M+H]+.
实施例40.化合物37的制备
操作同实施例31，不同的是将28的原料替换为4-氟苯胺。白色固体，熔点126-127℃，收率：28％。
化合物37波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.37(t,1H,J＝8.0Hz),7.95(s,1H),7.71(s,1H),7.62(d,1H,J＝3.6Hz),7.20(d,1H,J＝3.6Hz),7.17～7.07(m,3H),3.56(d,2H,J＝7.2Hz),2.18～2.11(m,1H),0.96(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):161.70,160.77,153.83,151.42,147.92,140.45,140.06,126.37,126.27,124.70,124.66,124.52,124.44,122.05,118.05,117.39,114.97,114.78(d),33.02,28.92,22.11；EI-MS:345.4[M+H]+.
实施例41.化合物38的制备
操作同实施例31，不同的是将28的原料替换为4-三氟甲基苄胺。白色固体，熔点163-164℃，收率：83％。
化合物38波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.81(s,1H),7.61(s,1H),7.59(d,2H,J＝7.2Hz),7.44(d,2H,J＝8.0Hz),7.17(d,1H,J＝3.6Hz),6.35(s,1H),4.64(d,2H,J＝6.0Hz),3.51(d,2H,J＝7.2Hz),2.12～2.05(m,1H),0.92(d,6H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):162.97,161.69,147.71,142.43,140.44,139.76,127.88(d),125.70,125.66,117.50,117.22,77.34,77.03,76.71,42.95,32.93,28.86,22.09；EI-MS:409.5[M+H]+.
实施例42.化合物39的制备
操作同实施例31，不同的是将28的原料替换为2,4-二氟苄胺。白色固体，熔108107-164℃，收率：92％。
化合物39波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.80(s,1H),7.59(d,1H,J＝3.2Hz),7.42～7.36(m,1H),7.16(d,1H,J＝3.2Hz),6.87～6.79(m,2H),6.27(s,1H),4.59(d,2H,J＝5.6Hz),3.48(d,2H,J＝7.2Hz),2.10～2.03(m,1H),0.90(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):163.77,163.65,162.87,162.35,162.23,161.75,161.30,161.18,159.87,159.75,147.39,140.40,139.91,131.34,131.28,131.24,131.19,121.40,121.36,121.25,121.21,117.70,117.16,111.56,111.52,111.34,111.31,104.16,103.91,103.66,77.34,77.03,76.71,37.01,36.98,32.91,28.83,22.05；EI-MS:377.5[M+H]+.
实施例43.化合物40的制备
操作同实施例31，不同的是将28的原料替换为4-甲氧基苄胺。白色固体，熔点111-113℃，收率：96％。
化合物40波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.77(s,1H),7.59(d,1H,J＝3.2Hz),7.26(d,2H,J＝8.4Hz),7.16(d,1H,J＝2.8Hz),6.87(d,2H,J＝8.4Hz),6.12(s,1H),4.52(d,2H,J＝5.2Hz),3.80(s,3H),3.51(d,2H,J＝7.6Hz),2.13～2.04(m,1H),0.93(d,6H,J＝6.8Hz)；13C-NMR(100MHz,CDCl3):162.69,161.81,159.16,147.41,140.40,139.91,130.30,129.26(d),117.94,117.10,114.19,77.36,77.04,76.72,55.32,43.05,32.93,28.86,22.12；EI-MS:371.5[M+H]+.
实施例44.化合物41的制备
操作同实施例31，不同的是将28的原料替换为3-氟苄胺。白色固体，熔点117-119℃，收率：79％。
化合物41波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.81(s,1H),7.59(d,1H,J＝3.6Hz),7.29(q,1H,J＝7.6Hz),7.17(d,1H,J＝3.2Hz),7.10(d,1H,J＝7.6Hz),7.03(d,1H,J＝9.6Hz),6.97(t,1H,J＝7.6Hz),6.28(s,1H),4.58(d,2H,J＝5.6Hz),3.51(d,2H,J＝7.2Hz),2.12～2.06(m,1H),0.92(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):164.27,162.88,161.82,161.73,147.62,140.93,140.86,140.43,139.83,130.32,130.23,123.23,123.20,117.64,117.18,114.71,114.57,114.49,114.36,77.35,77.03,76.72,42.94,32.93,28.87,22.11；EI-MS:359.6[M+H]+.
实施例45.化合物41的制备
操作同实施例31，不同的是将28的原料替换为4-氨基苄胺。白色固体，熔点126-128℃，收率：79％。
化合物41波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.75(s,1H),7.59(d,1H,J＝3.2Hz),7.15(d,2H,J＝3.2Hz),7.13(d,1H,J＝8.0Hz),6.65(d,2H,J＝8.0Hz),6.06(s,1H),4.46(d,2H,J＝5.6Hz),3.50(d,2H,J＝7.2Hz),3.42(s,2H),2.14～2.06(m,1H),0.92(d,6H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):162.64,161.84,147.32,145.97,140.38,139.95,129.28,127.97,118.04,117.08,115.29,77.37,77.05,76.73,43.26,32.92,28.86,22.13；EI-MS:356.5[M+H]+.
实施例46.化合物42的制备
操作同实施例31，不同的是将28的原料替换为4-氨基苄胺。白色固体，熔点122-124℃，收率：55％。
化合物42波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:9.31(s,1H),8.70(s,1H),8.24(s,1H),7.73(s,1H),7.63(s,1H),7.12(d,2H,J＝7.6Hz),6.72(d,2H,J＝7.6Hz),4.33(d,2H,J＝4.0Hz),3.48(d,2H,J＝7.2Hz),2.01～1.98(m,1H),0.84(d,6H,J＝6.0Hz)；13C-NMR(100MHz,CDCl3):162.28,161.91,156.71,146.58,141.59,140.91,130.26,129.05,119.07,118.51,115.48,42.01,40.62,40.41,40.20,40.00,39.79,39.58,39.37,32.53,28.71,22.37；EI-MS:357.4[M+H]+.
实施例47.化合物47的制备
操作同实施例1，不同的是将44的原料替换为2-噻唑肼。白色固体，收率：35％。
化合物47波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:7.75(s,1H),7.53(d,1H,J＝3.6Hz),7.14(s,2H),7.05(d,2H,J＝3.6Hz),4.30(q,2H,J＝7.2Hz),1.36(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):164.00,162.38,150.38,142.70,139.70,114.54,95.46,77.35,77.24,77.04,76.72,59.82,14.52；EI-MS:239.0[M+H]+.
实施例48.化合物48的制备
操作同实施例2，不同的是将1的原料替换为化合物47，将碳酸钾替换为氢化钠。白色固体，收率：35％。
化合物48的波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.77(s,1H),7.84(s,1H),7.46(d,1H,J＝3.6Hz),7.35～7.24(m,5H),7.03(d,1H,J＝3.6Hz),5.08(d,2H,J＝6.0Hz),4.25(q,2H,J＝7.2Hz),1.32(t,3H,J＝7.2Hz)；13C-NMR(100MHz,CDCl3):163.10,162.71,150.23,145.53,139.32,139.10,128.63,127.43,127.33,114.68,97.00,77.35,77.03,76.72,59.96,49.40,14.46；EI-MS:657.2[2M+H]+.
实施例49.化合物49的制备
操作同实施例3，不同的是将2的原料替换为化合物48。白色固体，收率：70％。
化合物49的波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:12.19(s,1H),8.67(t,1H,J＝6.4Hz),7.84(s,1H),7.67(d,1H,J＝3.6Hz),7.54(d,1H,J＝3.6Hz),7.34～7.22(m,5H),5.05(d,2H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):163.86,162.81,150.02,146.01,139.99,139.87,129.02,127.66,127.63,117.11,97.64,48.39,40.63,40.42,40.21,40.00,39.79,39.58,39.38；EI-MS:299.5[M-H]-.
实施例50.化合物50的制备
操作同实施例4，不同的是将3的原料替换为化合物49，将环丙胺替换为2,4-二氟苄胺。白色固体，收率：70％。
化合物50波谱分析数据：1H-NMR(400MHz,CDCl3)δppm:8.37(s,1H),7.61(s,1H),7.49(d,1H,J＝3.6Hz),7.34～7.23(m,6H),7.05(d,1H,J＝3.2Hz),6.84～6.77(m,2H),6.14(s,1H),4.79(s,2H),4.52(d,2H,J＝6.4Hz)；13C-NMR(100MHz,CDCl3):162.83,148.76,142.24,139.47,138.72,131.28,131.22,131.12,128.56,127.37,127.31,121.62,114.90,111.50,111.46,111.29,111.25,104.12,103.87,103.62,101.05,77.36,77.24,77.04,76.72,49.36,37.04；EI-MS:426.2[M+H]+.
实施例51.目标化合物的体外抗HBV细胞活性筛选试验
测试原理
HBV转染的肝癌细胞HepG2.2.15细胞株，在进行细胞培养时能够分泌HBV病毒颗粒(包含HBsAg、HBeAg和DNA)。在抗HBV目标化合物的干预下，细胞分泌HBsAg的和HBeAg的含量和产生的DNA会有所变化，因此检测细胞分泌到培养上清中的HBsAg的和HBeAg的含量以及产生的HBV DNA，参照未加药对照组的含量，可以反映样品药物的抗病毒活性作用。以拉米夫定为阳性对照药，用酶联免疫法(ELISA)检测样品药物达到抑制病毒HBsAg的和HBeAg分泌的50％时的浓度数值为IC50；用聚合酶链反应(PCR)检测药物抑制HBV DNA复制量的50％时的浓度数值IC50；运用CCK-8检测样品药物导致50％细胞毒性死亡的数值浓度为CC50值；并计算出待测化合物的“选择系数”(selectivity index)，计算公式：SI＝CC50/IC50。
测试方法
(1)细胞毒性实验
配成实验所需样品储备浓度(100μmol/L)，每个样品用HepG2.2.15细胞培养液配置成做5个稀释浓度(100μmol/L、10μmol/L、1μmol/L、0.1μmol/L、0.01μmol/L)，设立空白对照并以拉米夫定作为的阳性对照药。加入96孔板细胞培养板，每浓度3复孔，每4天换同浓度药液并设无药细胞对照组，共培养9天。用CCK-8法检测细胞存活率，确定药物对HepG2.2.15细胞的毒性。
(2)抑制HBeAg和HBsAg抗原分泌实验
HepG2 2.2.15细胞在96孔细胞培养板中培养24小时后，加入所配不同浓度含药培养液，继续培养8天(每4天换液一次)，收集上清液，用HBsAg和HBeAg诊断试剂盒(ELISA)检测HBsAg和HBeAg。
(3)抑制HBV DNA合成实验(PCR方法)
HepG2 2.2.15细胞在96孔细胞培养板中培养24小时后，加入所配不同浓度含药培养液，继续培养8天(每4天换液一次)，收集上清液，用探针法进行PCR检测。
化合物的活性列于表2中。由表2可以看出，化合物36和39显示出了较显著的抑制抗原分泌的活性可以作为HIV抑制剂的先导化合物加以利用。但其基本上没有抑制DNA合成活性，只有化合物26表现较弱的活性(71μmol/L)。
表2.吡唑类衍生物抗HBV的毒性(HepG22.2.15细胞)、活性和选择系数
注：aIC50:保护50％感染HBV的HepG22.2.15细胞免于细胞病变的化合物浓度；bCC50:使50％未感染HBV的细胞发生病变的化合物浓度；cSI选择性系数:CC50/IC50的比值。
Claims (5)
1.吡唑类衍生物，其特征在于是下述结构的化合物之一：
2.如权利要求1所述的化合物的制备方法，其特征在于方法如下：
以碳酸二乙酯IIa为初始原料，首先在醋酸和四氢呋喃的混合溶液中经过氢化钠的催化与不同的脂肪酮得到中间体IIb粗品，然后IIb与N,N-二甲基甲酰胺缩二甲醇反应得到中间体IIc，IIc与不同肼盐酸盐发生成环反应生成不同的目标化合物IId；接着，在碱性条件下发生水解反应生成中间体IIe，IIe与不同取代的胺发生酰化反应得到目标产物IIf；
合成路线如下：
试剂及条件:(i)四氢呋喃，氢化钠，60℃；(ii)100℃；(iii)乙醇，三乙胺；(iv)氢氧化钠，乙醇，水，四氢呋喃，50℃；(v)N,N-二甲基甲酰胺，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，三乙胺，室温；
其中，
R1为3-氟苯基、2-氟苯基、3-甲氧基苯基、2-硝基苯基、3-羧基苯基、4-甲氧基苯基、3-硝基苯基和2-噻唑苯基；
R2为异丁烷基；
R3为苯甲基、4-氟苯基、4-氟苯甲基、4-甲氧基苯甲基、4-氟氨基、4-吡啶甲基、2-氟苯甲基、2,4-二氟苯甲基和3-氟苯甲基。
3.如权利要求2所述的化合物的制备方法，其特征在于具体步骤如下：
(1)取50mL圆底烧瓶，低温下将60％氢化钠11.98mmol溶于15mL四氢呋喃溶液中，缓慢滴加不同的脂肪酮IIa 1.59mmol溶于混合溶液中，室温搅拌半小时；低温下继续滴加碳酸二乙酯14.98mmol于混合溶液中，60℃反应4小时；反应结束后冷却至室温，加入50mL冰水中，加入1.5mL醋酸中和反应，乙酸乙酯萃取三次，合并有机相，30mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩得到粗品IIb；
(2)取25mL圆底烧瓶，将中间体IIb 5.81mmol溶于5mL N,N-二甲基甲酰胺缩二甲醇中100℃搅拌过夜；反应结束后减压蒸馏得到粗品IIc；
(3)取25mL圆底烧瓶，将1.59mmol不同取代基的肼盐酸盐溶于6mL乙醇中，加入1.90mmol中间体IIc于混合溶液中，缓慢滴加三乙胺7.93mmol，室温搅拌过夜；反应结束后冷却至室温，减压蒸馏除去部分乙醇，加入50mL水中；乙酸乙酯萃取三次，合并有机相，30mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品IId；
(4)取25mL圆底烧瓶，将中间体IId 0.69mmol溶于3mL乙醇、3mL水和3mL四氢呋喃的混合溶液中，50℃加热反应过夜；反应结束后用旋转蒸发仪除去四氢呋喃和乙醇，加入30mL氯化铵水溶液，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次20mL，无水硫酸钠干燥；浓缩，石油醚洗，重结晶得到纯品IIe；
(5)取25mL圆底烧瓶，将中间体IIe 0.38mmol溶于5mL N,N-二甲基甲酰胺中，然后低温下缓慢加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯0.46mmol，搅拌10分钟；加入不同的胺及三乙胺0.76mmol，室温反应1小时；反应结束后加入30mL水，乙酸乙酯萃取三次，合并有机相，20mL饱和食盐水洗一次，无水硫酸钠干燥；浓缩，干法上样，快速制备色谱硅胶柱分离获取纯品IIf。
4.权利要求1所述的吡唑类衍生物在制备抗HBV的药物中的应用。
5.一种抗HBV药物组合物，包含权利要求1所述吡唑类衍生物和一种或多种药学上可接受载体或赋形剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510997646.6A CN105503730B (zh) | 2015-12-25 | 2015-12-25 | 吡唑类衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510997646.6A CN105503730B (zh) | 2015-12-25 | 2015-12-25 | 吡唑类衍生物及其制备方法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105503730A CN105503730A (zh) | 2016-04-20 |
| CN105503730B true CN105503730B (zh) | 2018-06-22 |
Family
ID=55712100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510997646.6A Active CN105503730B (zh) | 2015-12-25 | 2015-12-25 | 吡唑类衍生物及其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105503730B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102109148B1 (ko) * | 2018-06-28 | 2020-05-11 | 영남대학교 산학협력단 | N-아릴피라졸 화합물 및 이의 제조방법 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632004B (zh) * | 2016-10-10 | 2019-03-08 | 山东大学 | 吡啶酮类衍生物及其制备方法与应用 |
| CN108033925A (zh) * | 2017-12-27 | 2018-05-15 | 温州大学 | 一种苯并三氮唑化合物及其制备方法 |
| US11560370B1 (en) | 2018-10-22 | 2023-01-24 | Assembly Biosciences, Inc. | 5-membered heteroaryl carboxamide compounds for treatment of HBV |
| CN112574188B (zh) * | 2019-09-29 | 2022-05-06 | 苏州爱科百发生物医药技术有限公司 | 一种吡唑类化合物及其应用 |
| AR123849A1 (es) * | 2020-10-19 | 2023-01-18 | Adama Makhteshim Ltd | Compuestos útiles para la preparación de pirazolopirimidinonas |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007147336A1 (en) * | 2006-06-13 | 2007-12-27 | Shanghai Institue Of Materia Medica, Chinese Academy Of Sciences | Heterocyclic non-nucleoside compounds, their peparation, pharmaceutical composition and their use as antiviral agents |
| CN102199133A (zh) * | 2010-03-24 | 2011-09-28 | 中国科学院上海药物研究所 | 2’，2-双噻唑非核苷类化合物及其制备方法、药物组合物和作为肝炎病毒抑制剂的用途 |
| CN102271515A (zh) * | 2008-10-31 | 2011-12-07 | 健泰科生物技术公司 | 吡唑并嘧啶jak抑制剂化合物和方法 |
| TW201305140A (zh) * | 2011-06-17 | 2013-02-01 | Daiichi Sankyo Co Ltd | 新穎聯芳基醚衍生物 |
| WO2015140051A1 (en) * | 2014-03-19 | 2015-09-24 | Boehringer Ingelheim International Gmbh | Heteroaryl sik inhibitors |
-
2015
- 2015-12-25 CN CN201510997646.6A patent/CN105503730B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007147336A1 (en) * | 2006-06-13 | 2007-12-27 | Shanghai Institue Of Materia Medica, Chinese Academy Of Sciences | Heterocyclic non-nucleoside compounds, their peparation, pharmaceutical composition and their use as antiviral agents |
| CN102271515A (zh) * | 2008-10-31 | 2011-12-07 | 健泰科生物技术公司 | 吡唑并嘧啶jak抑制剂化合物和方法 |
| CN102199133A (zh) * | 2010-03-24 | 2011-09-28 | 中国科学院上海药物研究所 | 2’，2-双噻唑非核苷类化合物及其制备方法、药物组合物和作为肝炎病毒抑制剂的用途 |
| TW201305140A (zh) * | 2011-06-17 | 2013-02-01 | Daiichi Sankyo Co Ltd | 新穎聯芳基醚衍生物 |
| WO2015140051A1 (en) * | 2014-03-19 | 2015-09-24 | Boehringer Ingelheim International Gmbh | Heteroaryl sik inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| Isothiafludine, a novel non-nucleoside compound,inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation;Li YANG等;《Acta Pharmacologica Sinica》;20130203;第35卷;第410-418页 * |
| N-(1,4-二取代吡唑基)-杂环酰胺类化合物的合成及抗植病真菌生物活性;吴志兵，等;《农药》;20130131;第52卷(第1期);第11-14页 * |
| Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors;James S. Scott等;《Bioorganic & Medicinal Chemistry Letters》;20120905;第22卷;第6756-6761页 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102109148B1 (ko) * | 2018-06-28 | 2020-05-11 | 영남대학교 산학협력단 | N-아릴피라졸 화합물 및 이의 제조방법 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105503730A (zh) | 2016-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105503730B (zh) | 吡唑类衍生物及其制备方法与应用 | |
| RU2647853C2 (ru) | Способы получения определенных 2-(пиридин-3-ил)тиазолов | |
| DK2855466T3 (en) | Process for preparing certain 2- (pyridin-3-yl) thiazoles | |
| JP6435054B2 (ja) | Ｂ型肝炎ウイルス感染の治療及び予防のための新規２−オキソ−６，７−ジヒドロベンゾ［ａ］キノリジン−３−カルボン酸誘導体 | |
| CN107501257B (zh) | 二氢嘧啶-三氮唑类衍生物及其制备方法与应用 | |
| CN101903372B (zh) | 作为食欲肽受体拮抗剂的杂芳基衍生物 | |
| JP4939527B2 (ja) | 抗ウィルス剤の機能を有する両複素環連結化合物、その応用および当該化合物を含有する組成物 | |
| KR20180073689A (ko) | Ret의 저해제 | |
| CN1071917A (zh) | 用作人类免疫缺陷病毒逆转录酶拮抗剂的喹唑啉衍生物 | |
| US6441018B2 (en) | Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity | |
| CN1829709A (zh) | 对抗黄病毒的双环咪唑衍生物 | |
| JP2023103364A (ja) | 化合物、その薬学的に許容される塩又は立体異性体、及びその使用 | |
| KR101472944B1 (ko) | 2＇,2-비스티아졸 비뉴클레오시드 화합물, 이의 제조방법, 이를 포함하는 약학 조성물 및 이의 간염 바이러스 억제제로서의 용도 | |
| CA2530310C (en) | Substituted diketopiperazines and their use as oxytocin antagonists | |
| JPH04230277A (ja) | ２−アミノアルキル−５−アリールアルキル−１，３−ジオキサン誘導体、その製造方法およびそれを含有する医薬 | |
| CN109021015B (zh) | 二氢嘧啶-磷酰胺类衍生物及其制备方法与应用 | |
| CN113698390B (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
| WO2007019674A1 (en) | Viral polymerase inhibitors | |
| CN106632004B (zh) | 吡啶酮类衍生物及其制备方法与应用 | |
| JP5539322B2 (ja) | Ｃｂ−１リガンドとしての１，５−ジフェニル−ピロリジン−２−オン化合物 | |
| CN114853761A (zh) | 一种含有二氢嘧啶的双功能衍生物及其用途 | |
| CN117088861A (zh) | 2-取代芳基-恶唑啉-4-酮衍生物及其用途 | |
| CN118103363A (zh) | 新型衣壳组装抑制剂 | |
| CN116675687A (zh) | 一种含羧酸的二氢嘧啶类衍生物及其制备方法与应用 | |
| CN104016977B (zh) | 一种取代噻二嗪二酮类衍生物及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |