CN114195735A - 1,2,3-噻二唑类化合物及其用途 - Google Patents
1,2,3-噻二唑类化合物及其用途 Download PDFInfo
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- CN114195735A CN114195735A CN202010908505.3A CN202010908505A CN114195735A CN 114195735 A CN114195735 A CN 114195735A CN 202010908505 A CN202010908505 A CN 202010908505A CN 114195735 A CN114195735 A CN 114195735A
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- CN
- China
- Prior art keywords
- carbonyl
- piperazinyl
- compound
- fluorophenyl
- thiadiazole compound
- 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.)
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- -1 1,2, 3-thiadiazole compound Chemical class 0.000 title claims abstract description 70
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 15
- 150000001299 aldehydes Chemical class 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000004677 hydrates Chemical class 0.000 claims description 13
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 12
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 12
- 230000000259 anti-tumor effect Effects 0.000 claims description 11
- 125000003172 aldehyde group Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 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 claims description 5
- 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 claims description 5
- 229940125797 compound 12 Drugs 0.000 claims description 5
- 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 claims description 4
- 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 claims 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 claims description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims 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 claims description 4
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims description 4
- OJWYYSVOSNWCCE-UHFFFAOYSA-N 2-methoxyethyl hypofluorite Chemical compound COCCOF OJWYYSVOSNWCCE-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- 229940126639 Compound 33 Drugs 0.000 claims description 4
- XZJKQEQKZAYDRM-UHFFFAOYSA-N N,N-diaminonitramide Chemical compound [N+](=O)([O-])N(N)N XZJKQEQKZAYDRM-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
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- 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 claims description 4
- 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 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
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- 229940125904 compound 1 Drugs 0.000 claims description 3
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- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
本发明属于医药技术领域，涉及一种1,2,3‑噻二唑类化合物及其用途，确切地说，涉及5‑苯基‑4‑(4‑苯基哌嗪基‑1‑羰基)‑1,2,3‑噻二唑类化合物及其作为肿瘤细胞增殖抑制剂在制备抗肿瘤的药物方面的应用。本发明的化合物及其药学上可接受的盐、水合物的结构如通式M所述，其中，R1‑R10如权利要求和说明书所述。
Description
技术领域
本发明属于医药技术领域，涉及一种1,2,3-噻二唑类化合物及其用途，确切地说，涉及5-苯基-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑类化合物及其作为肿瘤细胞增殖抑制剂在制备抗肿瘤的药物方面的应用。
背景技术
恶性肿瘤是严重威胁人类健康与生命的重大疾病，在中国为第一致死病因。寻找和发现治疗与预防肿瘤的新药是当前面临的重大课题。
噻二唑类化合物具有多种生物活性，包括抗虫、除草、调节植物生长、抗菌、抗炎、抗肿瘤、抗结核和酶抑制作用(参见：Jun Suzuki,et al.J.Pestic.Sci.,2013,36(3),392-401；Triloknadh Settypalli,et al.Chemistry Select,2019,4,1627-1634；AnamariaCristina,et al.Molecules,2018,23,2425；Maria Shafique,et al.MolecularDiversity,2018,22(4),957-968；Yasser M.Omar,et al.Bioorganic Chemistry,2018,80,461-471)。在抗肿瘤药物研究方面，噻二唑类化合物也有报道，其中4-芳基-5-(3,4,5-三甲氧基苯基)-1,2,3-噻二唑与5-芳基-4-(3,4,5-三甲氧基苯基)-1,2,3-噻二唑活性良好(参见：Maojiang Wu,et al.Bioorganic&Medicinal Chemistry Letters,2007,17,869-873；Boga Ramesh Babu,et al.Biochemistry,1997,36,7209-7216)。
本发明参考现有技术合成了一系列1,2,3-噻二唑类化合物化合物，该类化合物具有明显的抗肿瘤活性。
发明内容
本发明的目的在于制备具有良好抗肿瘤活性的1,2,3-噻二唑类化合物，即5-苯基-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑类化合物；所制备的化合物在体外抗肿瘤活性测试中显现良好的结果。
本发明涉及定义如下的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、C1-C6烷基、卤代C1-C6烷基、C2-C6烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢。
(2)R1～R5独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、卤素、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
本发明优选涉及定义如下的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、C1-C3烷基、卤代C1-C3烷基、C2-C3烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢。
(2)R1～R5独立地选自氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
本发明优选涉及定义如下的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、甲基、乙基、三氟甲基、三氟乙基、乙氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢。
(2)R1～R5独立地选自氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
本发明优选涉及定义如下的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢，R6、R7、R9为氢、卤素或C1-C4氧基，R8、R10为氢；
(2)R1～R5独立地为氢或卤素；R6～R10独立地为氢、卤素或C1-C4烷氧基。
本发明的化合物还包括上述结构式所示化合物所形成的在药学上可接受的无毒盐及其水合物，这些药学上可接受的无毒盐包括该化合物与酸所形成的盐。所述的酸可以为盐酸、硫酸、氢溴酸、磷酸的无机酸或选自乙酸、柠檬酸、草酸、酒石酸、苯甲酸、苹果酸的有机酸。所述水合物的结晶水数目为0～16中的任意实数。本发明优选的部分化合物结构如下：
化合物1
5-苯基-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物2
5-苯基-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物3
5-苯基-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物4
5-(2-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物5
5-(2-氟苯基)-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物6
5-(2-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物7
5-(2-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物8
5-(2-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物9
5-(2-氟苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物10
5-(2-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物11
5-(2-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物12
5-(2-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物13
5-(3-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物14
5-(3-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物15
5-(3-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物16
5-(3-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物17
5-(3-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物18
5-(3-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物19
5-(3-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物20
5-(4-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物21
5-(4-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物22
5-(4-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物23
5-(4-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物24
5-(4-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物25
5-(4-氟苯基)-4-(4-(3,4-二甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物26
5-(4-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物27
5-(2-氯苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物28
5-(2-氯苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物29
5-(2-氯苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物30
5-(2-氯苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物31
5-(2-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物32
5-(2-氯苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物33
5-(2-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物34
5-(3,4-二氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物35
5-(4-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物36
5-(4-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
本发明的5-芳基-4-(4-芳基哌嗪基-1-羰基)-1,2,3-噻二唑类化合物可以按照以下反应路线合成得到：
(1)化合物II的制备
依次将各种取代苯甲醛、DBU、IBX、DMSO、重氮乙酸乙酯依次加入反应瓶中，在氮气氛围下于0-70℃下搅拌反应1-20小时。反应完毕，用饱和碳酸氢钠溶液淬灭，然后加入适量水，用二氯甲烷萃取。减压蒸除溶剂，柱层析分离纯化即可得到化合物II。
(2)化合物III的制备
将化合物II、劳森试剂(2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane)溶于甲苯加入反应瓶中，于20-110℃下反应1-20小时。反应完毕，减压蒸除甲苯，柱层析分离纯化即可得到化合物III。
(3)化合物V的制备
在氮气氛围下向无水二氯甲烷中依次加入化合物IV与三甲基铝，搅拌反应0.1-1.0小时后加入化合物III，继续在0-40℃下反应8-24小时。反应完毕，将反应液慢慢滴入冰水中，用稀盐酸调节pH至中性，用二氯甲烷萃取。减压蒸除溶剂，柱层析分离纯化即可得到化合物V。
本发明提供的系列化合物或其药学上可接受的盐具有明显的抗肿瘤活性，可用于制备抗肿瘤药物。所述的肿瘤为：胃癌、肺癌、肝癌、***、乳腺癌、白血病。
具体实施方式
通过下述实例将有助于理解本发明，但本发明的内容并不限于所举实例。
除特别声明外，本发明所用试剂均为市售来源，核磁共振谱由Bruker ARX傅立叶变换核磁共振波谱仪测定，质谱由BrukeeEsqure2000、Shimadzu GCMS-QP5050A型质谱仪测定。
实施例1：5-苯基-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物1)的制备
在氮气氛围下向无水二氯甲烷中依次加入化合物IV(1.2equiv)与三甲基铝(1.5equiv)，搅拌反应15mins后加入化合物III(1equiv)，继续在室温下搅拌反应16小时。反应完毕，将反应液慢慢滴入冰水中，用稀盐酸调节pH至中性，用二氯甲烷萃取。减压蒸除溶剂，柱层析分离纯化即可得到化合物1。Yellow solid；yield:60.7％；mp 46.9-48.6℃；1H NMR(600MHz,CDCl3)δ7.52(2H,m),7.41(3H,m),7.12(1H,q),6.55(1H,dd,J＝1.92Hz,J＝8.85Hz),6.50(1H,m),6.46(1H,m),3.92(2H,t,J＝5.27Hz),3.33(2H,t,J＝5.11Hz),3.19(2H,t,J＝5.22Hz),2.87(2H,t,J＝5.34Hz).13C NMR(150MHz,CDCl3)δ162.71(d,J＝246.79Hz),160.35,154.66,151.26(d,J＝10.11Hz),150.53,129.93,129.31(d,J＝8.09Hz),128.52(2C),128.03(2C),125.22,110.81(d,J＝2.02Hz),105.95(d,J＝21.24Hz),102.46(d,J＝24.78Hz),48.09,47.85,45.72,41.06；HRMS calcd forC19H17FN4NaOS[M+Na]+391.1005,found 391.1009.
实施例2：5-苯基-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物2)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物2。Deep red solid；yield:52.4％；mp 36.3-37.9℃；1H NMR(600MHz,CDCl3)δ7.59(2H,m),7.49(3H,t),6.77(1H,d,J＝8.15Hz),6.51(1H,dd,J＝2.72Hz,J＝8.49Hz),6.40(1H,d,J＝3.03H),4.02(2H,t,J＝5.11Hz),3.80(3H,s),3.75(3H,s),3.39(2H,t,J＝5.18Hz),3.10(2H,t,J＝5.20Hz),2.78(2H,t,J＝4.95Hz).13C NMR(150MHz,CDCl3)δ161.43,155.12,154.02,151.83,146.48,141.33,130.90,129.59(2C),129.02(2C),126.31,111.87,106.51,106.04,55.87,55.61,50.52,50.25,47.26,42.48；HRMS calcd for C21H22N4NaO3S[M+Na]+433.1310,found433.1309.
实施例3：5-苯基-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物3)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物3。Brown blacksolid；yield:47.4％；mp 50.7-52.2℃；1H NMR(600MHz,CDCl3)δ7.58(2H,m),7.48(3H,d,J＝7.13Hz),6.05(1H,t,J＝2.21Hz),6.02(2H,d,J＝2.21Hz),3.98(2H,t,J＝5.09Hz),3.76(6H,s),3.38(2H,t,J＝5.43Hz),3.24(2H,t,J＝5.43Hz),2.92(2H,t,J＝5.43Hz).13C NMR(150MHz,CDCl3)δ160.49(2C),160.35,154.50,151.61,150.62,129.92,128.53(2C),128.01(2C),125.24,94.72(2C),91.40,54.26(2C),51.42,49.87,45.85,41.18；HRMScalcd for C21H22N4NaO3S[M+Na]+403.1310,found 433.1311.
实施例4：5-(2-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑(化合物4)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物4。White solid；yield:57.4％；mp 62.1-63.4℃；1H NMR(600MHz,CDCl3)δ7.56(1H,m),7.42(1H,m),7.20(4H,m),6.85(3H,t),3.92(2H,t,J＝5.47Hz),3.94(2H,t,J＝5.31Hz),3.23(2H,t,J＝5.32Hz),3.03(2H,t,J＝5.14Hz).13C NMR(150MHz,CDCl3)δ160.18,157.85(d,J＝258.93Hz),152.30,149.76,148.03(d,J＝2.28Hz),131.74(d,J＝8.60Hz),129.74,128.27(2C),124.11(d,J＝3.29Hz),119.75,115.80(2C),115.48(d,J＝22.25Hz),113.84(d,J＝14.16Hz),48.68,48.47,46.13,41.29；HRMS calcd for C19H17FN4NaOS[M+Na]+391.1005,found 391.1012.
实施例5：5-(2-氟苯基)-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物5)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物5。Yellow solid；yield:59.4％；mp 53.2-55.6℃；1H NMR(600MHz,CDCl3)δ7.62(1H,m),7.49(1H,m),7.25(3H,m),6.67(1H,dd,J＝1.92Hz,J＝8.85Hz),6.59(2H,m),4.00(2H,t,J＝5.25Hz),3.60(2H,t,J＝5.34Hz),3.31(2H,t,J＝5.43Hz),3.13(2H,t,J＝5.19Hz).13C NMR(150MHz,CDCl3)δ162.75(d,J＝250.84Hz),160.17,157.81(d,J＝254.88Hz),152.17,151.37(d,J＝8.60Hz),148.34(d,J＝2.28Hz),131.77(d,J＝7.08Hz),129.81,129.32(d,J＝9.10Hz),124.12(d,J＝3.03Hz),115.49(d,J＝20.23Hz),113.79(d,J＝13.15Hz),110.80(d,J＝2.28Hz),105.90(d,J＝21.24Hz),102.45(d,J＝23.26Hz),48.14,47.86,45.90,41.09；HRMS calcd for C19H16F2N4NaOS[M+Na]+409.0911,found 409.0916.
实施例6：5-(2-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物6)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物6。Light yellowsolid；yield:54.2％；mp 70.9-72.9℃；1H NMR(600MHz,CDCl3)δ7.62(1H,m),7.50(1H,m),7.27(2H,m),7.19(1H,t,J＝8.55Hz),6.88(2H,d,J＝7.31Hz),6.79(1H,d,J＝8.85Hz),4.01(2H,t,J＝5.21Hz),3.60(2H,t,J＝5.12Hz),3.31(2H,t,J＝5.32Hz),3.13(2H,t,J＝5.34Hz).13C NMR(150MHz,CDCl3)δ160.17,157.80(d,J＝254.88Hz),152.16,150.78,148.36(d,J＝2.28Hz),134.06,131.78(d,J＝8.09Hz),129.82,129.20,124.12(d,J＝3.29Hz),119.40,115.58,115.49(d,J＝22.25Hz),113.79(d,J＝14.16Hz),113.65,48.23,47.98,45.91,41.10；HRMS calcd for C19H16ClFN4NaOS[M+Na]+425.0615,found 425.0623.
实施例7：5-(2-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物7)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物7。Light yellowsolid；yield:58.2％；mp 34.7-36.5℃；1H NMR(600MHz,CDCl3)δ7.63(1H,m),7.50(1H,m),7.28(1H,m),7.24(1H,d,J＝7.66Hz),7.19(1H,t,J＝7.86Hz),6.79(3H,s),4.04(2H,s),3.62(2H,s),3.31(2H,s),3.13(2H,s),2.33(3H,s).13C NMR(150MHz,CDCl3)δ160.18,157.93(d,J＝245.90Hz),152.26,148.08,138.14,131.75(d,J＝9.22Hz),129.72,128.88(d,J＝7.17Hz),128.15,124.12(d,J＝4.09Hz),120.95,116.84,115.48(d,J＝23.55Hz),113.81(d,J＝13.03Hz),113.06,48.88(2C),46.04,41.21,20.70；HRMS calcd forC20H19FN4NaOS[M+Na]+405.1161,found 405.1176.
实施例8：5-(2-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物8)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物8。Light yellowsolid；yield:56.3％；mp 131.2-133.4℃；1H NMR(600MHz,CDCl3)δ7.62(1H,m),7.48(1H,m),7.26(2H,m),7.19(1H,d,J＝8.83Hz),6.53(1H,dd,J＝2.38Hz,J＝8.15Hz),6.46(2H,m),4.00(2H,t,J＝5.26Hz),3.79(3H,s),3.57(2H,t,J＝5.11Hz),3.29(2H,t,J＝5.31Hz),3.10(2H,t,J＝5.32Hz).13C NMR(150MHz,CDCl3)δ161.20,160.62,158.86(d,J＝251.17Hz),153.30,152.14,149.06(d,J＝3.26Hz),132.77(d,J＝10.07Hz),130.75,129.98,125.13(d,J＝3.85Hz),116.49(d,J＝21.62Hz),114.83(d,J＝14.22Hz),109.44,105.37,103.26,55.23,49.57,49.35,47.07,42.25；HRMS calcd for C20H19FN4NaO2S[M+Na]+421.1110,found 421.1125.
实施例9：5-(2-氟苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物9)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物9。Brown solid；yield:49.5％；mp 42.9-43.5℃；1H NMR(600MHz,CDCl3)δ7.62(1H,m),7.50(1H,m),7.39(1H,t,J＝8.25Hz),7.28(1H,m),7.24(1H,m),7.16(1H,d,J＝7.66Hz),7.13(1H,s),7.11(1H,d,J＝8.55Hz),4.04(2H,t,J＝5.37Hz),3.65(2H,t,J＝5.37Hz),3.36(2H,t,J＝5.47Hz),3.19(2H,t,J＝5.21Hz).13C NMR(150MHz,CDCl3)δ161.20,158.83(d,J＝245.70Hz),153.14,150.82,149.52(d,J＝3.04Hz),132.83(d,J＝9.21Hz),131.54,130.88,129.80,125.16(d,J＝3.09Hz),123.22,119.69,117.13(d,J＝3.09Hz),116.52(d,J＝21.50Hz),114.81(d,J＝13.31Hz),113.07(d,J＝4.09Hz),49.33,49.14,46.91,42.17；HRMS calcd for C20H16F4N4NaOS[M+Na]+459.0879,found 459.0882.
实施例10：5-(2-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物10)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物10。Brown solid；yield:47.5％；mp 53.7-55.2℃；1H NMR(600MHz,DMSO)δ7.67(1H,m),7.62(1H,m),7.48(1H,t,J＝9.61Hz),7.41(1H,t,J＝7.91Hz),6.89(2H,d,J＝7.91Hz),6.83(2H,d,J＝8.48Hz),3.84(2H,t,J＝5.65Hz),3.68(3H,s),3.41(2H,t,J＝5.21Hz),3.07(2H,t,J＝5.15Hz),2.79(2H,t,J＝5.01Hz).13C NMR(150MHz,DMSO)δ160.81,158.87(d,J＝249.79Hz),153.93,148.22,148.20,145.32,133.70(d,J＝9.21Hz),131.21,130.09(d,J＝7.17Hz),126.03(d,J＝3.58Hz),118.63(2C),116.96(d,J＝22.01Hz),114.77(2C),54.64,50.53,50.24,47.03,42.21；HRMS calcd for C20H19FN4NaO2S[M+Na]+421.1110,found421.1121.
实施例11：5-(2-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物11)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物11。Deep red solid；yield:51.4％；mp 46.2-7-47.1℃；1H NMR(600MHz,CDCl3)δ7.64(1H,m),7.50(1H,m),7.26(2H,m),6.79(1H,d,J＝9.51Hz),6.53(1H,d,J＝8.83Hz),6.48(1H,s),4.03(2H,t,J＝5.07Hz),3.82(3H,s),3.76(3H,s),3.57(2H,t,J＝5.23Hz),3.15(2H,t,J＝5.10Hz),2.96(2H,t,J＝4.95Hz).13C NMR(150MHz,CDCl3)δ161.29,158.93(d,J＝245.70Hz),154.05,153.44,148.56,146.53,141.45,132.74(d,J＝8.70Hz),130.65,125.15(d,J＝3.07Hz),116.49(d,J＝21.50Hz),114.87(d,J＝13.31Hz),111.92,106.58,106.01,55.91,55.63,50.64,50.33,47.42,42.51；HRMS calcd for C21H21FN4NaO3S[M+Na]+451.1216,found451.1221.
实施例12：5-(2-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物12)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物12。Brown solid；yield:55.5％；mp 91.5-93.7℃；1H NMR(600MHz,CDCl3)δ7.62(1H,t,J＝7.47Hz),7.49(1H,m),7.25(2H,m),6.07(3H,d,J＝5.77Hz),3.99(2H,t,J＝5.28Hz),3.77(6H,s),3.56(2H,t,J＝5.16Hz),3.28(2H,t,J＝4.85Hz),3.08(2H,t,J＝5.21Hz).13C NMR(150MHz,CDCl3)δ161.50(2C),160.16,157.82(d,J＝245.75Hz),152.25,151.68,148.03,131.76(d,J＝9.21Hz),129.72,124.11(d,J＝2.56Hz),115.47(d,J＝21.50Hz),113.79(d,J＝14.84Hz),94.69(2C),91.37,54.26(2C),48.56,48.36,45.99,41.18；HRMS calcd for C21H21FN4NaO3S[M+Na]+451.1216,found 451.1223.
实施例13：5-(3-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑(化合物13)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物13。Yellow solid；yield:59.1％；mp 92.3-94.4℃；1H NMR(600MHz,CDCl3)δ7.45(1H,m),7.38(1H,d,J＝7.69Hz),7.34(1H,dd,J＝2.31Hz,J＝9.23Hz),7.27(2H,t,J＝8.46Hz),7.19(1H,m),6.91(3H,m),4.02(2H,t,J＝5.40Hz),3.46(2H,t,J＝5.28Hz),3.27(2H,t,J＝5.42Hz),3.02(2H,t,J＝5.24Hz).13C NMR(150MHz,CDCl3)δ161.79(d,J＝254.88Hz),159.93,153.25(d,J＝3.03Hz),151.00,149.63,130.21(d,J＝10.11Hz),128.27(2C),127.08(d,J＝7.08Hz),123.96(d,J＝2.53Hz),119.86,116.87(d,J＝21.24Hz),115.85(2C),115.14(d,J＝23.26Hz),48.82,48.49,46.05,41.34；HRMS calcd for C19H17FN4NaOS[M+Na]+391.1005,found 391.1014.
实施例14：5-(3-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物14)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物14。Yellow solid；yield:60.1％；mp 69.3-70.7℃；1H NMR(600MHz,CDCl3)δ7.39(1H,q),7.31(1H,d,J＝8.46Hz),7.27(1H,d,J＝9.23Hz),7.12(2H,m),6.79(2H,t),6.69(1H,d,J＝8.46Hz),3.94(2H,t,J＝5.12Hz),3.40(2H,t,J＝5.21Hz),3.21(2H,t,J＝5.23Hz),2.98(2H,t,J＝5.43Hz).13C NMR(150MHz,CDCl3)δ161.79(d,J＝258.93Hz),159.93,153.53(d,J＝3.03Hz),150.86,150.68,134.06,130.22(d,J＝8.09Hz),129.21,127.04,123.99(d,J＝3.41Hz),119.50,116.91(d,J＝22.25Hz),115.64,115.18(d,J＝24.27Hz),113.66,48.35,48.00,45.86,41.19；HRMS calcd for C19H16N4NaOS[M+Na]+425.0615,found 425.0620.
实施例15：5-(3-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物15)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物15。Yellow solid；yield:61.1％；mp 119.8-121.0℃；1H NMR(600MHz,CDCl3)δ7.45(1H,m),7.38(1H,m),7.34(1H,m),7.17(2H,m),6.72(3H,m),4.01(2H,t,J＝5.20Hz),3.44(2H,t,J＝5.35Hz),3.25(2H,t,J＝5.41Hz),3.01(2H,t,J＝5.22Hz),2.31(3H,s).13C NMR(150MHz,CDCl3)δ161.78(d,J＝253.89Hz),159.93,153.19(d,J＝3.01Hz),151.02,149.69,138.03,130.21(d,J＝8.70Hz),128.08,127.08(d,J＝8.70Hz),123.95(d,J＝3.58Hz),120.74,116.86(d,J＝20.99Hz),116.71,115.12(d,J＝23.70Hz),112.93,48.88,48.57,46.07,41.37,20.68；HRMS calcd for C20H19FN4NaOS[M+Na]+405.1161,found 405.1176.
实施例16：5-(3-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物16)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物16。Yellow solid；yield:64.1％；mp 123.6-124.8℃；1H NMR(600MHz,CDCl3)δ7.45(1H,m),7.38(1H,d,J＝8.15Hz),7.34(1H,m),7.19(2H,m),6.50(1H,dd,J＝2.34Hz,J＝8.25Hz),6.47(1H,dd,J＝2.32Hz,J＝8.13Hz),6.42(1H,t),4.00(2H,t,J＝5.21Hz),3.78(3H,s),3.44(2H,t,J＝5.17Hz),3.27(2H,t,J＝5.24Hz),3.02(2H,t,J＝5.22Hz).13C NMR(150MHz,CDCl3)δ161.79(d,J＝251.18Hz),159.92,159.58,153.27,153.25,150.98,130.21(d,J＝8.29Hz),128.97,127.07(d,J＝8.29Hz),123.95(d,J＝3.41Hz),116.88(d,J＝21.33Hz),115.14(d,J＝23.10Hz),108.44,104.46,102.29,54.20,48.68,48.36,45.98,41.29；HRMS calcd forC20H19FN4NaO2S[M+Na]+421.1110,found 421.1130.
实施例17：5-(3-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物17)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物17。Yellow solid；yield:59.7％；mp 46.3-47.6℃；1H NMR(600MHz,CDCl3)δ7.56(1H,m),7.49(1H,d,J＝7.47Hz),7.45(1H,m),7.30(1H,m),6.98(2H,d,J＝8.49Hz),6.94(2H,d,J＝9.17Hz),4.12(2H,t,J＝5.21Hz),3.87(3H,s),3.55(2H,s),3.25(2H,t,J＝4.75Hz),3.01(2H,s).13C NMR(150MHz,CDCl3)δ161.81(d,J＝262.08Hz),159.92,153.64,153.19,151.05,143.86,130.21(d,J＝7.68Hz),127.11(d,J＝9.21Hz),123.97(d,J＝3.33Hz),118.17(2C),116.86(d,J＝21.50Hz),115.14(d,J＝23.55Hz),113.52(2C),54.52,50.29,50.03,46.21,41.78；HRMS calcd for C20H19FN4NaO2S[M+Na]+421.1110,found 421.1121.
实施例18：5-(3-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物18)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物18。Brown solid；yield:50.6％；mp 35.2-37.1℃；1H NMR(600MHz,CDCl3)δ7.46(1H,q),7.38(1H,d,J＝8.15Hz),7.34(1H,d,J＝9.51Hz),7.20(1H,m),6.78(1H,d,J＝8.49Hz),6.52(1H,dd,J＝2.72H,J＝8.49Hz),6.44(1H,d,J＝2.04Hz),4.03(2H,t,J＝5.09Hz),3.81(3H,s),3.75(3H,s),3.44(2H,t,J＝5.43Hz),3.13(2H,t,J＝5.09Hz),2.88(2H,t,J＝4.75Hz).13C NMR(150MHz,CDCl3)δ161.81(d,J＝245.70Hz),159.99,153.03,152.86,151.16,145.47,140.25,130.24(d,J＝8.19Hz),127.13(d,J＝9.21Hz),123.93(d,J＝3.07Hz),116.86(d,J＝20.50Hz),115.10(d,J＝23.55Hz),110.89,105.49,105.13,54.86,54.59,49.67,49.26,46.32,41.54；HRMS calcd for C21H21FN4NaO3S[M+Na]+451.1216,found 451.1216.
实施例19：5-(3-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物19)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物19。Brown solid；yield:42.5％；mp 46.8-48.2℃；1H NMR(600MHz,CDCl3)δ7.46(1H,m),7.38(1H,m),7.34(1H,m),7.20(1H,m),6.05(3H,q),3.99(2H,t,J＝5.43Hz),3.76(6H,s),3.43(2H,t,J＝5.43Hz),3.25(2H,t,J＝5.47Hz),3.00(2H,t,J＝4.75Hz).13C NMR(150MHz,CDCl3)δ161.78(d,J＝257.98Hz),160.49(2C),159.94,153.27,151.57,150.95,130.23(d,J＝8.19Hz),127.05(d,J＝9.43Hz),123.95(d,J＝3.58Hz),116.90(d,J＝21.50Hz),115.12(d,J＝23.70Hz),94.72(2C),91.45,54.25(2C),48.66,48.37,45.93,41.26；HRMS calcd forC21H21FN4NaO3S[M+Na]+451.1216,found 451.1211.
实施例20：5-(4-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑(化合物20)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物20。Yellow solid；yield:70.1％；mp 53.5-54.8℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.28(2H,m),7.17(2H,t,J＝8.83Hz),6.91(3H,m),4.01(2H,t,J＝5.31Hz),3.46(2H,t,J＝5.27Hz),3.27(2H,t,J＝5.14Hz),3.04(2H,t,J＝5.22Hz).13C NMR(150MHz,CDCl3)δ163.10(d,J＝253.89Hz),160.13,153.83,150.62,149.60,130.19(d,J＝9.21Hz)(2C),128.28(2C),121.40(d,J＝3.28Hz),119.91,115.87(d,J＝4.61Hz)(2C),115.70(2C),48.88,48.57,46.07,41.34；HRMS calcd for C19H17FN4NaOS[M+Na]+391.1005,found 391.1014.
实施例21：5-(4-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物21)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物21。Yellow solid；yield:59.1％；mp 37.1-39.1℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.18(3H,t,J＝7.60Hz),6.86(2H,t),6.76(1H,d,J＝9.02Hz),4.00(2H,t,J＝5.01Hz),3.47(2H,t,J＝5.32Hz),3.28(2H,t,J＝5.22Hz),3.06(2H,t,J＝5.14Hz).13C NMR(150MHz,CDCl3)δ163.12(d,J＝242.74Hz),160.12,154.10,150.68,150.48,134.07,130.22(d,J＝9.10Hz)(2C),129.21,121.36(d,J＝4.55Hz),119.50,115.85,115.68(d,J＝10.11Hz)(2C),113.64,48.37,48.04,45.88,41.18；HRMS calcd for C19H16ClFN4NaOS[M+Na]+425.0615,found425.0629.
实施例22：5-(4-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物22)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物22。Yellow solid；yield:60.6％；mp 112.6-114.9℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.16(3H,q),6.72(3H,m),4.00(2H,t,J＝5.39Hz),3.44(2H,t,J＝5.23Hz),3.25(2H,t,J＝5.14Hz),3.02(2H,t,J＝5.33Hz),2.31(3H,s).13C NMR(150MHz,CDCl3)δ163.08(d,J＝255.91Hz),160.11,153.74,150.65,149.69,138.03,130.17(d,J＝8.29Hz)(2C),128.09,121.40(d,J＝3.85Hz),120.75,116.71,115.77(d,J＝21.99Hz)(2C),112.95,48.90,48.64,46.09,41.37,20.68；HRMS calcd for C20H19FN4NaOS[M+Na]+405.1161,found 405.1183.
实施例23：5-(4-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物23)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物23。Yellow solid；yield:64.8％；mp 81.6-82.7℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.18(3H,m),6.50(1H,dd,J＝2.32Hz,J＝8.21Hz),6.47(1H,dd,J＝2.37Hz,J＝8.43Hz),6.42(1H,t),4.00(2H,t,J＝5.29Hz),3.78(3H,s),3.45(2H,t,J＝5.37Hz),3.27(2H,t,J＝5.44Hz),3.03(2H,t,J＝5.27Hz).13C NMR(150MHz,CDCl3)δ163.10(d,J＝251.18Hz),160.12,159.59,153.83,151.00,150.61,130.18(d,J＝8.89Hz)(2C),128.98,121.39(d,J＝3.26Hz),115.78(d,J＝22.51Hz)(2C),108.45,104.45,102.31,54.20,48.72,48.41,46.01,41.29；HRMS calcd for C20H19FN4NaO2S[M+Na]+421.1110,found 421.1121.
实施例24：5-(4-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物24)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物24。Yellow solid；yield:67.1％；mp 62.3-63.7℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.18(2H,t,J＝8.81Hz),6.85(4H,m),4.00(2H,s),3.77(3H,s),3.45(2H,s),3.14(2H,s),2.91(2H,s).13CNMR(150MHz,CDCl3)δ163.10(d,J＝253.89Hz),160.11,153.70,153.60,150.68,143.92,130.19(d,J＝10.24Hz)(2C),121.42(d,J＝3.58Hz),118.14(2C),115.77(d,J＝22.52Hz)(2C),116.52(2C),54.52,50.27,50.05,46.24,41.48；HRMS calcd for C20H19FN4NaO2S[M+Na]+421.1110,found 421.1119.
实施例25：5-(4-氟苯基)-4-(4-(3,4-二甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物25)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物25。Yellow solid；yield:66.1％；mp 82.9-85.0℃；1H NMR(600MHz,CDCl3)δ7.61(2H,m),7.17(2H,t,J＝8.55Hz),7.03(1H,d,J＝8.55Hz),6.70(2H,d,J＝43.67Hz),6.48(1H,s),4.01(2H,s),3.45(2H,s),3.21(2H,s),2.98(2H,s),2.23(3H,s),2.19(3H,s).13C NMR(150MHz,CDCl3)δ164.13(d,J＝261.69Hz),161.56,154.78,151.68,148.89,137.48,131.21(d,J＝8.97Hz)(2C),130.34(2C),122.43(d,J＝3.82Hz),118.96,116.81(d,J＝20.76Hz)(2C),114.68,50.52,50.31,47.13,42.38,20.16,18.85；HRMS calcd for C21H21FN4NaOS[M+Na]+419.1318,found 419.1327.
实施例26：5-(4-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物26)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物26。Light brownsolid；yield:53.7％；mp 55.5-57.2℃；1H NMR(600MHz,CDCl3)δ7.53(2H,m),7.10(2H,t,J＝8.83Hz),5.97(3H,m),3.91(2H,t,J＝5.09Hz),3.69(6H,s),3.36(2H,t,J＝5.09Hz),3.18(2H,t,J＝4.75Hz),2.94(2H,t,J＝5.09Hz).13C NMR(150MHz,CDCl3)δ163.09(d,J＝250.23Hz),160.50(2C),160.13,153.83,151.57,150.57,130.17(d,J＝8.53Hz)(2C),121.37(d,J＝5.21Hz),115.78(d,J＝22.27Hz)(2C),94.73(2C),91.44,54.26(2C),48.69,48.41,45.95,41.26；HRMS calcd for C21H21FN4NaO3S[M+Na]+451.1216,found 451.1218.
实施例27：5-(2-氯苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物27)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物27。Brown solid；yield:62.5％；mp 96.3-97.4℃；1H NMR(600MHz,CDCl3)δ7.53(2H,m),7.44(1H,m),7.37(1H,m),7.18(1H,d,J＝8.07Hz),6.86(2H,d,J＝8.55Hz),6.77(1H,t),3.91(2H,t,J＝5.11Hz),3.64(2H,t,J＝5.11Hz),3.23(2H,t,J＝5.11Hz),3.08(2H,t,J＝5.11Hz).13C NMR(150MHz,CDCl3)δ159.51,153.17,152.19,150.77,134.04,131.78(2C),130.72,129.33,129.18,126.39,124.71,119.34,115.52,113.58,48.27,47.86,45.88,41.08；HRMS calcdfor C19H16Cl2N4NaOS[M+Na]+441.0320,found 441.0324.
实施例28：5-(2-氯苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物28)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物28。Deep red solid；yield:61.4％；mp 89.2-90.7℃；1H NMR(600MHz,CDCl3)δ7.52(2H,m),7.43(1H,m),7.38(1H,m),7.16(1H,t,J＝7.66Hz),6.72(3H,m),3.91(2H,t,J＝5.33Hz),3.61(2H,t,J＝5.29Hz),3.20(2H,t,J＝5.17Hz),3.04(2H,t,J＝5.26Hz),2.32(3H,s).13C NMR(150MHz,CDCl3)δ159.50,153.31,151.85,149.77,138.01,131.82,130.69,130.68,129.31,128.08,126.38,124.75,120.63,116.66,112.86,48.84,48.47,46.11,41.27,20.70；HRMS calcdfor C20H19ClN4NaOS[M+Na]+421.0866,found 421.0891.
实施例29：5-(2-氯苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物29)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物29。Red solid；yield:54.4％；mp 60.5-62.3℃；1H NMR(600MHz,CDCl3)δ7.52(2H,m),7.43(1H,m),7.38(1H,m),7.18(1H,d,J＝8.55Hz),6.51(1H,d,J＝7.66Hz),6.46(1H,d,J＝8.55Hz),6.44(1H,s),3.91(2H,t,J＝5.33Hz),3.79(3H,s),3.62(2H,t,J＝5.29Hz),3.21(2H,t,J＝5.17Hz),3.05(2H,t,J＝5.26Hz).13C NMR(150MHz,CDCl3)δ159.58,159.50,153.26,151.90,151.04,131.81,130.69(2C),129.32,128.96,126.38,124.73,108.42,104.38,102.25,54.21,48.67,48.29,45.99,41.17；HRMS calcd for C20H19ClN4NaO2S[M+Na]+437.0815,found437.0837
实施例30：5-(2-氯苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物30)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物30。Light yellowsolid；yield:57.7％；mp 42.9-42.6℃；1H NMR(600MHz,CDCl3)δ7.53(2H,m),7.44(1H,m),7.38(2H,m),7.14(1H,d,J＝8.25Hz),7.09(1H,s),7.05(1H,d,J＝9.43Hz),3.94(2H,t,J＝5.18Hz),3.67(2H,t,J＝5.31Hz),3.28(2H,t,J＝5.27Hz),3.14(2H,t,J＝5.41Hz).13C NMR(150MHz,CDCl3)δ160.54,154.16,153.33,150.93,132.82,131.76,131.74,131.51,130.35,129.76,127.42,125.74,125.04,119.55,116.95(d,J＝4.09Hz),112.97(d,J＝3.58Hz),49.33,49.14,46.91,42.17；HRMS calcd for C20H16ClF3N4NaOS[M+Na]+475.0583,found 475.0613.
实施例31：5-(2-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物31)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物31。Brown solid；yield:42.5％；mp 57.9-59.1℃；1H NMR(600MHz,CDCl3)δ7.53(2H,m),7.44(1H,m),7.39(1H,m),6.85(4H,d,J＝8.49Hz),3.93(2H,s),3.78(3H,s),3.62(2H,s),3.10(2H,s),2.94(2H,s).13C NMR(150MHz,CDCl3)δ159.50,153.56,153.32,151.81,143.98,131.85,130.70,130.67,129.32,126.39,124.75,118.11(2C),113.53(2C),54.53,50.27,49.86,46.20,41.34；HRMS calcd for C20H19ClN4NaO2S[M+Na]+437.0815,found 437.0817.
实施例32：5-(2-氯苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物32)的制备。
除了使用相应的原料外，以实施例1相同的方法制备化合物32。Brown solid；yield:66.5％；mp 96.8-97.9℃；1H NMR(600MHz,CDCl3)δ7.53(2H,m),7.44(1H,m),7.39(1H,m),6.78(1H,d,J＝8.83Hz),6.52(1H,dd,J＝3.06Hz,J＝8.86Hz),6.44(1H,d,J＝3.06H),3.94(2H,t,J＝5.19Hz),3.81(3H,s),3.76(3H,s),3.60(2H,t,J＝5.13Hz),3.06(2H,t,J＝5.19Hz),2.90(2H,t,J＝4.85Hz).13C NMR(150MHz,CDCl3)δ159.59,153.44,153.01,151.40,145.49,140.41,131.88,130.67(2C),129.33,126.40,124.78,110.86,105.50,105.94,54.86,54.59,49.67,49.26,46.32,41.54；HRMS calcd forC21H21ClN4NaO3S[M+Na]+467.0921,found 467.0926.
实施例33：5-(2-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物33)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物33。Brown solid；yield:68.5％；mp 44.7-46.2℃；1H NMR(600MHz,CDCl3)δ7.52(2H,m),7.43(1H,m),7.38(1H,m),6.05(3H,s),3.90(2H,t,J＝5.22Hz),3.77(6H,s),3.61(2H,t,J＝5.02Hz),3.20(2H,t,J＝4.91Hz),3.04(2H,t,J＝5.05Hz).13C NMR(150MHz,CDCl3)δ160.49(2C),159.50,153.26,151.91,151.68,131.82,130.70,130.69,129.32,126.39,124.73,94.67(2C),91.36,54.26(2C),48.64,48.29,45.98,41.17；HRMS calcd for C21H21ClN4NaO3S[M+Na]+467.0921,found 467.0922.
实施例34：5-(3,4-二氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物34)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物34。Brown solid；yield:68.2％；mp 87.7-89.2℃；1H NMR(600MHz,CDCl3)δ7.71(1H,d,J＝2.12Hz),7.55(1H,d,J＝8.49Hz),7.47(1H,dd,J＝2.38Hz,J＝8.15Hz),6.06(3H,s),3.99(2H,t,J＝5.08Hz),3.77(6H,s),3.49(2H,t,J＝5.20Hz),3.28(2H,t,J＝4.95Hz),3.09(2H,t,J＝5.01Hz).13CNMR(150MHz,CDCl3)δ161.55(2C),160.64,153.68,152.61,152.13,135.45,133.83,131.43,130.87,128.22,126.13,95.81(2C),92.56,55.31(2C),49.85,49.51,47.09,42.40；HRMS calcd for C21H20Cl2N4NaO3S[M+Na]+501.0531,found 501.0548.
实施例35：5-(4-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物35)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物35。Yellow solid；yield:63.1％；mp 43.1-45.4℃；1H NMR(600MHz,CDCl3)δ7.55(2H,d,J＝7.51Hz),7.46(2H,d,J＝8.33Hz),6.85(4H,t,J＝8.83Hz),4.02(2H,s),3.77(3H,s),3.65(2H,s),3.16(2H,s),2.94(2H,s).13C NMR(150MHz,CDCl3)δ160.00,153.65,153.63,150.82,143.82,136.26,129.35(2C),128.77(2C),123.73,118.26(2C),113.56(2C),54.53,50.19,50.18,46.22,41.47；HRMS calcd for C20H19ClN4NaO2S[M+Na]+437.0815,found 437.0824.
实施例36：5-(4-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑(化合物36)的制备
除了使用相应的原料外，以实施例1相同的方法制备化合物36。Brown solid；yield:63.5％；mp 43.5-45.2℃；1H NMR(600MHz,CDCl3)δ7.55(2H,d,J＝7.81Hz),7.45(2H,d,J＝8.49Hz),6.06(3H,s),3.99(2H,t,J＝5.12Hz),3.77(6H,s),3.45(2H,t,J＝5.29Hz),3.27(2H,t,J＝4.85Hz),3.05(2H,t,J＝5.11Hz).13C NMR(150MHz,CDCl3)δ160.51(2C),160.01,153.80,151.53,150.72,136.26,129.32(2C),128.77(2C),123.68,94.79(2C),91.55,54.27(2C),48.77,48.51,45.94,41.26；HRMS calcd for C21H21ClN4NaO3S[M+Na]+467.0921,found 467.0930.
实施例37：
本发明的化合物的体外抗肿瘤活性测试
体外活性测试方法和结果如下：其中，临床常用的抗肿瘤药物阿霉素(DOX)为阳性实验组。
抗肿瘤活性体外筛选试验-1
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人胃癌细胞株SGC cell line
作用时间：72h
各化合物对肿瘤生长的抑制率(10μg/mL)见表-1。
抗肿瘤活性体外筛选试验-2
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人肺腺癌A549 cell line
作用时间：72h
各化合物对肿瘤生长的抑制率(10μg/mL)见表-1。
抗肿瘤活性体外筛选试验-3
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人***细胞株Hela cell line
作用时间：72h
各化合物对肿瘤生长的抑制率(10μg/mL)见表-1。
抗肿瘤活性体外筛选试验-4
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人白血病细胞HL-60 cell line
作用时间：72h
各化合物对肿瘤生长的抑制率(10μg/mL)见表-1。
抗肿瘤活性体外筛选试验-5
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人乳腺癌细胞阿霉素耐药株MCF-7/ADR cell line
作用时间：72h
各化合物对肿瘤生长的抑制率(10μg/mL)见表-1。
正常细胞体外活性筛选试验-6
筛选方法：四氮唑盐(micoculturetetrozolium,MTT)还原法
细胞株：人正常肝脏细胞HL-7702 cell line
作用时间：72h
各化合物对人正常肝脏细胞生长的抑制率(10μg/mL)见表-1。
实施例38：本发明的化合物的动物体内抗肿瘤活性测试
选择体外活性较好的化合物12和化合物19进行了动物体内抗肿瘤活性测试，所用模型为小鼠S-180肉瘤模型，阳性对照药物为临床常用的抗肿瘤药物氟尿嘧啶(Fluorouracil)。
实验方法：选用18-22克雌性昆明小鼠及生长良好的7-11天的S-180瘤种，将瘤组织制成细胞悬液，接种至小鼠右侧腋部皮下，约1.0-2.0×106细胞/只，接种24小时后随机分笼，腹腔注射给药连续7天。停药后24小时处死动物，称体重、瘤重，计算各组平均瘤重，按如下公式求出肿瘤抑制率并进行t检验。
肿瘤抑制率＝[(空白对照组平均瘤重-治疗组平均瘤重)/(空白对照组平均瘤重)]×100％
实验结果见表-2
表-1
表-2
Claims (10)
1.通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、C1-C6烷基、卤代C1-C6烷基、C2-C6烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢；
(2)R1～R5独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、卤素、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
2.权利要求1的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、C1-C3烷基、卤代C1-C3烷基、C2-C3烷基氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢；
(2)R1～R5独立地选自氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、C1-C3烷基、卤代C1-C3烷基、C1-C3烷基氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
3.权利要求1的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢时，R6、R7、R9、R10各自独立地为氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；R8为各自独立地为氢、甲基、乙基、三氟甲基、三氟乙基、乙氧基、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基；其前提是R6～R10不同时为氢；
(2)R1～R5独立地选自氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基，且不同时为氢时，R6～R10独立地为氢、甲基、乙基、三氟甲基、三氟乙基、甲氧基、乙氧基、氟、氯、溴、碘、羟基、氨基、硝基、肼基、氰基、醛基、羧基。
4.权利要求1的通式M的化合物及其药学上可接受的盐、水合物：
(1)R1～R5同时为氢，R6、R7、R9为氢、卤素或C1-C4氧基，R8、R10为氢；
(2)R1～R5独立地为氢或卤素；R6～R10独立地为氢、卤素或C1-C4烷氧基。
5.如下的化合物及其药学上可接受的盐、水合物：
化合物1
5-苯基-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物2
5-苯基-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物3
5-苯基-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物4
5-(2-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物5
5-(2-氟苯基)-4-(4-(3-氟苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物6
5-(2-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物7
5-(2-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物8
5-(2-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物9
5-(2-氟苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物10
5-(2-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物11
5-(2-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物12
5-(2-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物13
5-(3-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物14
5-(3-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物15
5-(3-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物16
5-(3-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物17
5-(3-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物18
5-(3-氟苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物19
5-(3-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物20
5-(4-氟苯基)-4-(4-苯基哌嗪基-1-羰基)-1,2,3-噻二唑
化合物21
5-(4-氟苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物22
5-(4-氟苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物23
5-(4-氟苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物24
5-(4-氟苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物25
5-(4-氟苯基)-4-(4-(3,4-二甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物26
5-(4-氟苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物27
5-(2-氯苯基)-4-(4-(3-氯苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物28
5-(2-氯苯基)-4-(4-(3-甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物29
5-(2-氯苯基)-4-(4-(3-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物30
5-(2-氯苯基)-4-(4-(3-三氟甲基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物31
5-(2-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物32
5-(2-氯苯基)-4-(4-(2,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物33
5-(2-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物34
5-(3,4-二氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物35
5-(4-氯苯基)-4-(4-(4-甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑
化合物36
5-(4-氯苯基)-4-(4-(3,5-二甲氧基苯基)哌嗪基-1-羰基)-1,2,3-噻二唑。
6.权利要求1所述的通式M的化合物及其药学上可接受的盐、水合物的制备方法，其特征在于：
其中，R1-R10如权利要求1所述。
7.药物组合物，包含权利要求1-5任何一项所述的化合物及其药学上可接受的盐、水合物。
8.权利要求1-5任何一项所述的化合物及其药学上可接受的盐、水合物的制备抗肿瘤药物中的应用。
9.权利要求7所述的药物组合物在制备抗肿瘤药物中的应用。
10.如权利要求8或9所述的应用，其特征在于，所述的肿瘤为胃癌、肺癌、肝癌、***、乳腺癌或白血病。
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| CN1829697A (zh) * | 2003-06-04 | 2006-09-06 | 安万特医药股份有限公司 | 芳基－杂芳族化合物、含有它们的组合物及其用途 |
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| CN102690247A (zh) * | 2011-03-25 | 2012-09-26 | 上海长恒生物医药科技有限公司 | 呋喃类化合物、其制备方法及所述呋喃类化合物的应用 |
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