CN114195735A - 1,2, 3-thiadiazole compound and use thereof - Google Patents
1,2, 3-thiadiazole compound and use thereof Download PDFInfo
- Publication number
- 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
- Authority
- 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.)
- Pending
Links
- -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
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- 229940126086 compound 21 Drugs 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125961 compound 24 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
- 229940125851 compound 27 Drugs 0.000 claims description 4
- 229940127204 compound 29 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125877 compound 31 Drugs 0.000 claims description 4
- 229940125878 compound 36 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 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
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- RJSYPKWVIJGNLO-UHFFFAOYSA-N CCOClOC Chemical compound CCOClOC RJSYPKWVIJGNLO-UHFFFAOYSA-N 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- NSHIYIMHYBAIEY-UHFFFAOYSA-N ethyl hypochlorite Chemical compound CCOCl NSHIYIMHYBAIEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001613 neoplastic effect Effects 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 140
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- 239000011734 sodium Substances 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- 239000007858 starting material Substances 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000012216 screening Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003831 tetrazolyl group Chemical group 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000004867 thiadiazoles Chemical class 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical class C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- CQMJEZQEVXQEJB-UHFFFAOYSA-N 1-hydroxy-1,3-dioxobenziodoxole Chemical class C1=CC=C2I(O)(=O)OC(=O)C2=C1 CQMJEZQEVXQEJB-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical class C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical class CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
The invention belongs to the technical field of medicines, relates to a 1,2, 3-thiadiazole compound and application thereof, and particularly relates to a 5-phenyl-4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole compound and application thereof as a tumor cell proliferation inhibitor in preparation of antitumor drugs. The structure of the compound and the pharmaceutically acceptable salt and hydrate thereof is shown as a general formula M, wherein R is1‑R10As described in the claims and specification.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a 1,2, 3-thiadiazole compound and application thereof, and particularly relates to a 5-phenyl-4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole compound and application thereof as a tumor cell proliferation inhibitor in preparation of antitumor drugs.
Background
Malignant tumor is a serious disease seriously threatening the health and life of human beings, and is the first cause of death in China. The search and discovery of new drugs for the treatment and prevention of tumors is a major issue facing today.
Thiadiazole compounds have a variety of biological activities including anti-insect, herbicidal, plant growth regulating, antibacterial, anti-inflammatory, anti-tumor, anti-tubercular and enzyme inhibitory effects (see: Jun Suzuki, et al J. pesticide. Sci.,2013,36(3), 392-. In the field of research on antitumor drugs, thiadiazole compounds have also been reported in which 4-aryl-5- (3,4, 5-trimethoxyphenyl) -1,2, 3-thiadiazole and 5-aryl-4- (3,4, 5-trimethoxyphenyl) -1,2, 3-thiadiazole have good activity (see: Maojiang Wu, et al. Bioorganic & Medicinal Chemistry Letters,2007,17, 869-.
The invention synthesizes a series of 1,2, 3-thiadiazole compounds with reference to the prior art, and the compounds have obvious antitumor activity.
Disclosure of Invention
The invention aims to prepare a 1,2, 3-thiadiazole compound with good antitumor activity, namely a 5-phenyl-4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole compound; the prepared compound shows good results in vitro anti-tumor activity tests.
The present invention relates to compounds of general formula M defined below and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5while being hydrogen, R6、R7、R9、R10Each independently is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl; r8Are independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R is6～R10Not hydrogen at the same time.
(2)R1～R5Independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, halogen, hydroxyl, amino, nitro, hydrazine, cyano, aldehyde and carboxyl, and when not simultaneously hydrogen, R is not hydrogen6～R10Independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl.
The present invention preferably relates to compounds of general formula M as defined below and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5while being hydrogen, R6、R7、R9、R10Each independently is hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl; r8Are independently hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C3 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R is6～R10Not hydrogen at the same time.
(2)R1～R5Independently selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde and carboxyl, and when not simultaneously hydrogen, R is not hydrogen6～R10Independently hydrogen, C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazine, cyano, aldehyde group, carboxyl.
The present invention preferably relates to compounds of general formula M as defined below and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5while being hydrogen, R6、R7、R9、R10Each independently is hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl; r8Is independently hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethoxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R is6～R10Not hydrogen at the same time.
(2)R1～R5Independently selected from hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde and carboxyl, and when not simultaneously hydrogen, R is6～R10Independently hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl.
The present invention preferably relates to compounds of general formula M as defined below and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5simultaneously being hydrogen, R6、R7、R9Is hydrogen, halogen or C1-C4Oxy radical, R8、R10Is hydrogen;
(2)R1～R5independently hydrogen or halogen; r6～R10Independently hydrogen, halogen or C1-C4 alkoxy.
The compound also comprises pharmaceutically acceptable non-toxic salts and hydrates thereof formed by the compound shown in the structural formula, and the pharmaceutically acceptable non-toxic salts comprise salts formed by the compound and acid. The acid can be inorganic acid of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or organic acid selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid. The number of crystal water of the hydrate is any real number in 0-16. Preferred partial compounds of the present invention have the following structure:
compound 1
5-phenyl-4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 2
5-phenyl-4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 3
5-phenyl-4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 4
5- (2-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 5
5- (2-fluorophenyl) -4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 6
5- (2-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 7
5- (2-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 8
5- (2-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 9
5- (2-fluorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 10
5- (2-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 11
5- (2-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 12
5- (2-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 13
5- (3-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 14
5- (3-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 15
5- (3-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 16
5- (3-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 17
5- (3-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 18
5- (3-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 19
5- (3-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 20
5- (4-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 21
5- (4-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 22
5- (4-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 23
5- (4-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 24
5- (4-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 25
5- (4-fluorophenyl) -4- (4- (3, 4-dimethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 26
5- (4-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 27
5- (2-chlorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 28
5- (2-chlorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 29
5- (2-chlorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 30
5- (2-chlorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 31
5- (2-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 32
5- (2-chlorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 33
5- (2-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 34
5- (3, 4-dichlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 35
5- (4-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 36
5- (4-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
The 5-aryl-4- (4-arylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole compound can be synthesized according to the following reaction route:
(1) preparation of Compound II
Sequentially adding various substituted benzaldehyde, DBU, IBX, DMSO and ethyl diazoacetate into a reaction bottle, and stirring and reacting for 1-20 hours at 0-70 ℃ in a nitrogen atmosphere. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, then the appropriate amount of water was added and extracted with dichloromethane. And (4) evaporating the solvent under reduced pressure, and carrying out column chromatography separation and purification to obtain the compound II.
(2) Preparation of Compound III
Dissolving the compound II and Lawson reagent (2,4-Bis (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphetane) in toluene, adding into a reaction flask, and reacting at 20-110 ℃ for 1-20 hours. And (3) after the reaction is finished, evaporating toluene under reduced pressure, and carrying out column chromatography separation and purification to obtain a compound III.
(3) Preparation of Compound V
Sequentially adding a compound IV and trimethylaluminum into anhydrous dichloromethane under the nitrogen atmosphere, stirring for reacting for 0.1-1.0 hour, adding a compound III, and continuously reacting for 8-24 hours at 0-40 ℃. After the reaction, the reaction solution was slowly dropped into ice water, the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. And (4) evaporating the solvent under reduced pressure, and carrying out column chromatography separation and purification to obtain the compound V.
The series of compounds or pharmaceutically acceptable salts thereof provided by the invention have obvious antitumor activity and can be used for preparing antitumor drugs. The tumor is as follows: gastric cancer, lung cancer, liver cancer, cervical cancer, breast cancer and leukemia.
Detailed Description
The invention will be understood by the following examples, but the content of the invention is not limited to the examples.
Unless otherwise stated, the reagents used in the present invention are commercially available, and the NMR spectra were determined on a Bruker ARX Fourier transform NMR spectrometer and the mass spectra were determined on a BrukeeEsqure2000, Shimadzu GCMS-QP5050A type mass spectrometer.
Example 1: preparation of 5-phenyl-4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 1)
Compound IV (1.2equiv) and trimethylaluminum (1.5equiv) were added to anhydrous dichloromethane in this order under a nitrogen atmosphere, and after stirring for 15mins, compound III (1equiv) was added, and the reaction was continued at room temperature for 16 hours. After the reaction, the reaction solution was slowly dropped into ice water, the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. And (3) evaporating the solvent under reduced pressure, and carrying out column chromatography separation and purification to obtain the compound 1. Yellow solid; 60.7 percent of yield; mp 46.9-48.6 deg.C;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 for C19H17FN4NaOS[M+Na]+391.1005,found 391.1009.
example 2: preparation of 5-phenyl-4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 2)
Compound 2 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Deep red solid; 52.4 percent of yield; 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,found 433.1309.
example 3: preparation of 5-phenyl-4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 3)
Compound 3 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. A Brown black solid; 47.4 percent of yield; 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；HRMS calcd for C21H22N4NaO3S[M+Na]+403.1310,found 433.1311.
example 4: preparation of 5- (2-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 4)
The same procedure as in example 1 was repeated, except that the corresponding starting materials were usedThe process of (1) to prepare compound 4. White solid; 57.4 percent of yield; 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.
example 5: preparation of 5- (2-fluorophenyl) -4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 5)
Compound 5 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 59.4 percent of yield; 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.
example 6: preparation of 5- (2-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 6)
Compound 6 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Light yellow solid; 54.2 percent of yield; 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.
example 7: preparation of 5- (2-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 7)
Compound 7 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Light yellow solid; 58.2 percent of yield; 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 for C20H19FN4NaOS[M+Na]+405.1161,found 405.1176.
example 8: preparation of 5- (2-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 8)
Compound 8 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Light yellow solid; 56.3 percent of yield; 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.
example 9: preparation of 5- (2-fluorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 9)
Compound 9 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 49.5 percent of yield; 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.
example 10: preparation of 5- (2-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 10)
Compound 10 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 47.5 percent of yield; 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,found 421.1121.
example 11: preparation of 5- (2-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 11)
Compound 11 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Deep red solid; 51.4 percent of yield; mp 46.2-7-47.1 deg.C;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,found 451.1221.
example 12: preparation of 5- (2-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 12)
Compound 12 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 55.5 percent of yield; 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.
example 13: preparation of 5- (3-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 13)
Compound 13 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 59.1 percent of yield; 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.
example 14: preparation of 5- (3-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 14)
Compound 14 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 60.1 percent of yield; mp 69.3-70.7 deg.C;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.
example 15: preparation of 5- (3-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 15)
Compound 15 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 61.1 percent of yield; 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.
example 16: preparation of 5- (3-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 16)
Compound 16 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 64.1 percent of yield; 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 for C20H19FN4NaO2S[M+Na]+421.1110,found 421.1130.
example 17: preparation of 5- (3-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 17)
Compound 17 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 59.7 percent of yield; 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.
example 18: preparation of 5- (3-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 18)
Compound 18 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 50.6 percent of yield; mp 35.2-37.1 deg.C;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.
example 19: preparation of 5- (3-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 19)
Compound 19 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 42.5 percent of yield; mp 46.8-48.2 deg.C;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 for C21H21FN4NaO3S[M+Na]+451.1216,found 451.1211.
example 20: preparation of 5- (4-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 20)
Compound 20 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. 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.
example 21: preparation of 5- (4-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 21)
Compound 21 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 59.1 percent of yield; mp 37.1-39.1 deg.C;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,found 425.0629.
example 22: preparation of 5- (4-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 22)
Compound 22 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 60.6 percent of yield; 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.
example 23: preparation of 5- (4-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 23)
Compound 23 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 64.8 percent of yield; 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.
example 24: preparation of 5- (4-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 24)
Compound 24 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 67.1 percent of yield; 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).13C NMR(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.
example 25: preparation of 5- (4-fluorophenyl) -4- (4- (3, 4-dimethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 25)
Compound 25 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 66.1 percent of yield; mp 82.9-85.0 deg.C;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.
example 26: preparation of 5- (4-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 26)
Compound 26 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Light brown solid; 53.7 percent of yield; mp 55.5-57.2 deg.C;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.
example 27: preparation of 5- (2-chlorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 27)
Compound 27 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 62.5 percent of yield; 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 calcd for C19H16Cl2N4NaOS[M+Na]+441.0320,found 441.0324.
example 28: preparation of 5- (2-chlorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (Compound 28)
Compound 28 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Deep red solid; 61.4 percent of yield; 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 calcd for C20H19ClN4NaOS[M+Na]+421.0866,found 421.0891.
example 29: preparation of 5- (2-chlorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 29)
Compound 29 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Red solid; 54.4 percent of yield; 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,found 437.0837
example 30: preparation of 5- (2-chlorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 30)
Compound 30 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Light yellow solid; 57.7 percent of yield; 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.
example 31: preparation of 5- (2-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 31)
Compound 31 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 42.5 percent of yield; mp 57.9-59.1 deg.C;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.
example 32: preparation of 5- (2-chlorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 32).
Compound 32 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 66.5 percent of yield; 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 for C21H21ClN4NaO3S[M+Na]+467.0921,found 467.0926.
example 33: preparation of 5- (2-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 33)
Compound 33 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 68.5 percent of yield; 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.
example 34: preparation of 5- (3, 4-dichlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 34)
Compound 34 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 68.2 percent of yield; 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).13C NMR(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.
example 35: preparation of 5- (4-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 35)
Compound 35 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Yellow solid; 63.1 percent of yield; 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.
example 36: preparation of 5- (4-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole (compound 36)
Compound 36 was prepared in the same manner as in example 1, except that the corresponding starting materials were used. Brown solid; 63.5 percent of yield; 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.
example 37:
in vitro antitumor Activity test of Compounds of the invention
In vitro activity test methods and results are as follows: wherein, the clinical commonly used antitumor drug adriamycin (DOX) is a positive experimental group.
In vitro screening test for antitumor Activity-1
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human gastric cancer cell line SGC cell line
Acting time: 72h
The inhibition rate of each compound on tumor growth (10. mu.g/mL) is shown in Table-1.
In vitro screening test for antitumor Activity-2
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human lung adenocarcinoma A549 cell line
Acting time: 72h
The inhibition rate of each compound on tumor growth (10. mu.g/mL) is shown in Table-1.
In vitro screening test for antitumor Activity-3
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human cervical cancer cell line Hela cell line
Acting time: 72h
The inhibition rate of each compound on tumor growth (10. mu.g/mL) is shown in Table-1.
In vitro screening test for antitumor Activity-4
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human leukemia cell HL-60 cell line
Acting time: 72h
The inhibition rate of each compound on tumor growth (10. mu.g/mL) is shown in Table-1.
Antitumor Activity in vitro screening test-5
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: adriamycin resistant strain MCF-7/ADR cell line of human breast cancer cells
Acting time: 72h
The inhibition rate of each compound on tumor growth (10. mu.g/mL) is shown in Table-1.
Normal cell in vitro activity screening assay-6
The screening method comprises the following steps: reduction of tetrazolium salts (MTT)
Cell lines: human normal liver cell HL-7702 cell line
Acting time: 72h
The inhibition rate (10. mu.g/mL) of each compound on the growth of human normal liver cells is shown in Table-1.
Example 38: in vivo anti-tumor Activity testing of Compounds of the invention in animals
The compound 12 and the compound 19 with better in vitro activity are selected to carry out the test of the antitumor activity in animals, the used model is a mouse S-180 sarcoma model, and the positive control drug is clinical common antitumor drug Fluorouracil (Fluorouracil).
The experimental method comprises the following steps: selecting 18-22 g female Kunming mouse and S-180 tumor with good growth for 7-11 days, making tumor tissue into cell suspension, inoculating to the right axillary part of mouse, and inoculating to the subcutaneous part of the right axillary part of mouse, wherein the cell suspension is about 1.0-2.0 × 106Cells/mouse, randomly divided into cages 24 hours after inoculation, and administered by intraperitoneal injection for 7 days continuously. Animals were sacrificed 24 hours after drug withdrawal, the body weight and tumor weight were weighed, the average tumor weight of each group was calculated, and the tumor inhibition rate was determined according to the following formula and subjected to t-test.
The tumor inhibition rate is ═ [ (average tumor weight in placebo-average tumor weight in treated group)/(average tumor weight in placebo) ] × 100%
The experimental results are shown in Table-2
TABLE-1
TABLE-2
Claims (10)
1. A compound of formula M and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5while being hydrogen, R6、R7、R9、R10Each independently is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl; r8Are independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R is6～R10Not hydrogen at the same time;
(2)R1～R5independently selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, halogen, hydroxyl, amino, nitro, hydrazine, cyano, aldehyde and carboxyl, and when not simultaneously hydrogen, R is not hydrogen6～R10Independently hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl.
2. A compound of general formula M according to claim 1 and pharmaceutically acceptable salts, hydrates thereof:
(1) when R1-R5 are hydrogen at the same time, R6, R7, R9 and R10 are hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde and carboxyl respectively and independently; r8 is independently hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C3 alkyloxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R6-R10 are not hydrogen at the same time;
(2) R1-R5 are independently selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde and carboxyl, and when not hydrogen at the same time, R6-R10 are independently selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkyloxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazine, cyano, aldehyde and carboxyl.
3. A compound of general formula M according to claim 1 and pharmaceutically acceptable salts, hydrates thereof:
(1)R1～R5while being hydrogen, R6、R7、R9、R10Each independently is hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl; r8Is independently hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethoxy, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde group, carboxyl; provided that R is6～R10Not hydrogen at the same time;
(2)R1～R5independently selected from hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde and carboxyl, and when not simultaneously hydrogen, R is6～R10Independently hydrogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, hydrazino, cyano, aldehyde, carboxyl.
4. A compound of general formula M according to claim 1 and pharmaceutically acceptable salts, hydrates thereof:
(1) R1-R5 are hydrogen at the same time, R6, R7 and R9 are hydrogen, halogen or C1-C4 oxy, and R8 and R10 are hydrogen;
(2)R1～R5independently hydrogen or halogen; r6～R10Independently hydrogen, halogen or C1-C4 alkoxy.
5. The following compounds and pharmaceutically acceptable salts, hydrates thereof:
compound 1
5-phenyl-4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 2
5-phenyl-4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 3
5-phenyl-4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 4
5- (2-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 5
5- (2-fluorophenyl) -4- (4- (3-fluorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 6
5- (2-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 7
5- (2-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 8
5- (2-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 9
5- (2-fluorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 10
5- (2-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 11
5- (2-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 12
5- (2-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 13
5- (3-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 14
5- (3-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 15
5- (3-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 16
5- (3-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 17
5- (3-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 18
5- (3-fluorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 19
5- (3-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 20
5- (4-fluorophenyl) -4- (4-phenylpiperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 21
5- (4-fluorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 22
5- (4-fluorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 23
5- (4-fluorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 24
5- (4-fluorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 25
5- (4-fluorophenyl) -4- (4- (3, 4-dimethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 26
5- (4-fluorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 27
5- (2-chlorophenyl) -4- (4- (3-chlorophenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 28
5- (2-chlorophenyl) -4- (4- (3-methylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 29
5- (2-chlorophenyl) -4- (4- (3-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 30
5- (2-chlorophenyl) -4- (4- (3-trifluoromethylphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 31
5- (2-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 32
5- (2-chlorophenyl) -4- (4- (2, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 33
5- (2-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 34
5- (3, 4-dichlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 35
5- (4-chlorophenyl) -4- (4- (4-methoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole
Compound 36
5- (4-chlorophenyl) -4- (4- (3, 5-dimethoxyphenyl) piperazinyl-1-carbonyl) -1,2, 3-thiadiazole.
6. A process for the preparation of compounds of general formula M and pharmaceutically acceptable salts, hydrates thereof, according to claim 1, characterized in that:
wherein R is1-R10As claimed in claim 1.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and pharmaceutically acceptable salts, hydrates thereof.
8. The use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts and hydrates thereof, for the manufacture of a medicament for the treatment of neoplastic diseases.
9. The use of the pharmaceutical composition of claim 7 in the preparation of an anti-tumor medicament.
10. The use according to claim 8 or 9, wherein the tumor is gastric cancer, lung cancer, liver cancer, cervical cancer, breast cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010908505.3A CN114195735A (en) | 2020-09-02 | 2020-09-02 | 1,2, 3-thiadiazole compound and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010908505.3A CN114195735A (en) | 2020-09-02 | 2020-09-02 | 1,2, 3-thiadiazole compound and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114195735A true CN114195735A (en) | 2022-03-18 |
Family
ID=80644277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010908505.3A Pending CN114195735A (en) | 2020-09-02 | 2020-09-02 | 1,2, 3-thiadiazole compound and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114195735A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829697A (en) * | 2003-06-04 | 2006-09-06 | 安万特医药股份有限公司 | Aryl-heteroaromatic products, compositions containing same and use thereof |
| CN102690247A (en) * | 2011-03-25 | 2012-09-26 | 上海长恒生物医药科技有限公司 | Furan compound, preparation method and application of same |
-
2020
- 2020-09-02 CN CN202010908505.3A patent/CN114195735A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829697A (en) * | 2003-06-04 | 2006-09-06 | 安万特医药股份有限公司 | Aryl-heteroaromatic products, compositions containing same and use thereof |
| CN102690247A (en) * | 2011-03-25 | 2012-09-26 | 上海长恒生物医药科技有限公司 | Furan compound, preparation method and application of same |
Non-Patent Citations (3)
| Title |
|---|
| CHAO WANG 等: "Design, synthesis and anticancer activity of 5-aryl-4-(4-arylpiperazine-1-carbonyl)-1,2,3- thiadiazoles as microtubule-destabilizing agents", vol. 106, pages 3 * |
| 余元勋等主编: "中国分子白血病学", vol. 1, 安徽科学技术出版社, pages: 256 - 258 * |
| 尚海 等: "微管蛋白抑制剂的研究进展", vol. 45, no. 09, pages 1078 - 1088 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI113765B (en) | Process for the preparation of novel antiproliferative 5-substituted quinazoline compounds | |
| EA005377B1 (en) | TETRAHYDROIMIDAZO[1,2-h][1,7]NAPHTHYRIDINE COMPOUNDS | |
| WO2013123840A1 (en) | Antitumor aza-benzo[f]azulen derivative, method for preparing same, and use thereof | |
| CN111704646B (en) | Steroid compound and preparation method and application thereof | |
| CN103601762A (en) | Ferrocene derivatives, preparation method and use thereof | |
| CA2652074C (en) | Substituted carboxamides as group 1 metabotropic receptor antagonists | |
| JP2008544952A (en) | Dibenzocycloheptane compounds and drugs containing these compounds | |
| US20230219935A1 (en) | 4-(n-methyl) aminopiperidine myricetin derivative containing dithiocarbamate, preparation method and application | |
| CN114195735A (en) | 1,2, 3-thiadiazole compound and use thereof | |
| CN105367495B (en) | Piperlongumine containing seven membered lactams rings is similar to object and its preparation and application | |
| JPH03505204A (en) | Tricyclic 3-oxo-propanenitrile derivative and method for its preparation | |
| CN108794474B (en) | Evodiamine derivative with multi-target antitumor activity and preparation method and application thereof | |
| KR940006633B1 (en) | Optically active tienotriazolodiazepine compounds | |
| US4112112A (en) | Pyrrolo[2,1-b] [3]benzazepines useful for producing a skeletal muscle relaxing or tranquilizing effect | |
| CN102010418B (en) | High-camptothecin compounds and use thereof as medicaments | |
| PL128998B1 (en) | Process for preparing novel 2-amino-3-benzoylphenylacetamides and their derivatives | |
| US6211189B1 (en) | Amino-spiro-quinazoline compounds | |
| CN110172058B (en) | 7-azaspiro [5.6] dodecane-10-one compound and preparation method and application thereof | |
| US20100311784A1 (en) | Stereoselective process and crystalline forms of a camptothecin | |
| US20160102095A1 (en) | Pyrazolo[1,5-a]pyrimidine derivative and use of anti-tumor thereof | |
| US20210395266A1 (en) | In-flow photooxygenation of aminothienopyridinones generates novel ptp4a3 phosphatase inhibitors | |
| CN107365322B (en) | A kind of novel rutaecarpin analog derivative, preparation method and the usage | |
| CN112939864B (en) | Spiro [ benzo [ c ] aza-1, 1' -cyclohexyl ] -3-ones | |
| CN115572247B (en) | Vitamin K 3 Derivatives and medical use thereof | |
| PT94928A (en) | METHOD FOR THE PREPARATION OF NEW OXAZOLO-PYRIDINE DERIVATIVES |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |