CN1638776A - 取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物 - Google Patents
取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物 Download PDFInfo
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- CN1638776A CN1638776A CNA028136608A CN02813660A CN1638776A CN 1638776 A CN1638776 A CN 1638776A CN A028136608 A CNA028136608 A CN A028136608A CN 02813660 A CN02813660 A CN 02813660A CN 1638776 A CN1638776 A CN 1638776A
- Authority
- CN
- China
- Prior art keywords
- chloro
- thiophene
- oxadiazoles
- phenyl
- trifluoromethyl
- 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
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- 150000001875 compounds Chemical class 0.000 claims abstract description 413
- 230000006907 apoptotic process Effects 0.000 claims abstract description 39
- -1 anilino- Chemical class 0.000 claims description 230
- 238000000034 method Methods 0.000 claims description 97
- 150000003839 salts Chemical class 0.000 claims description 83
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 79
- 125000003118 aryl group Chemical group 0.000 claims description 66
- 229940002612 prodrug Drugs 0.000 claims description 64
- 239000000651 prodrug Substances 0.000 claims description 64
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 55
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 49
- 206010028980 Neoplasm Diseases 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 125000001544 thienyl group Chemical group 0.000 claims description 36
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 201000011510 cancer Diseases 0.000 claims description 33
- 238000011282 treatment Methods 0.000 claims description 33
- 125000002541 furyl group Chemical group 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 25
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000004104 aryloxy group Chemical group 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- PDJHJNIKXHBBMQ-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical class C1=CC(C(F)(F)F)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 PDJHJNIKXHBBMQ-UHFFFAOYSA-N 0.000 claims description 16
- 241001465754 Metazoa Species 0.000 claims description 15
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 15
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- 125000005493 quinolyl group Chemical group 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- XJAWNFCAHCKUCE-UHFFFAOYSA-N 5-(3-bromofuran-2-yl)-3-(4-chlorophenyl)-1,2,4-oxadiazole Chemical class C1=CC(Cl)=CC=C1C1=NOC(C2=C(C=CO2)Br)=N1 XJAWNFCAHCKUCE-UHFFFAOYSA-N 0.000 claims description 13
- SYMWZIQCLDZKKV-UHFFFAOYSA-N 5-(3-bromofuran-2-yl)-3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazole Chemical class N1=CC(C(F)(F)F)=CC=C1C1=NOC(C2=C(C=CO2)Br)=N1 SYMWZIQCLDZKKV-UHFFFAOYSA-N 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- ZNEKVNVVSZSFNI-UHFFFAOYSA-N 5-(3-chlorofuran-2-yl)-3-(4-chlorophenyl)-1,2,4-oxadiazole Chemical class C1=COC(C=2ON=C(N=2)C=2C=CC(Cl)=CC=2)=C1Cl ZNEKVNVVSZSFNI-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- HNLXMMPRJSANGA-UHFFFAOYSA-N 5-(3-bromofuran-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole Chemical class N1=CC(Cl)=CC=C1C1=NOC(C2=C(C=CO2)Br)=N1 HNLXMMPRJSANGA-UHFFFAOYSA-N 0.000 claims description 11
- UQRQBELNAZQFGA-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-[5-(trifluoromethyl)pyridin-2-yl]-1,2,4-oxadiazole Chemical class N1=CC(C(F)(F)F)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 UQRQBELNAZQFGA-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- GPZIBFGNDZJFDW-UHFFFAOYSA-N 2-(3-chlorothiophen-2-yl)-5-phenyl-1,3-oxazole Chemical class C1=CSC(C=2OC(=CN=2)C=2C=CC=CC=2)=C1Cl GPZIBFGNDZJFDW-UHFFFAOYSA-N 0.000 claims description 8
- SOBAXKKTMVAOHI-UHFFFAOYSA-N 4-[5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazol-3-yl]aniline Chemical class C1=CC(N)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 SOBAXKKTMVAOHI-UHFFFAOYSA-N 0.000 claims description 8
- BWZGHYWHBKLROX-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-2-phenyl-1,3-oxazole Chemical class C1=CSC(C=2OC(=NC=2)C=2C=CC=CC=2)=C1Cl BWZGHYWHBKLROX-UHFFFAOYSA-N 0.000 claims description 8
- 206010059866 Drug resistance Diseases 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- XRCCCGCVVDVJOA-UHFFFAOYSA-N 1-(3-chlorophenyl)-5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)pyrazole Chemical class C1=CSC(C2=NN(C(C=3C=CC(Cl)=CC=3)=C2)C=2C=C(Cl)C=CC=2)=C1Cl XRCCCGCVVDVJOA-UHFFFAOYSA-N 0.000 claims description 7
- NMHIGRULAVHQEJ-UHFFFAOYSA-N 2-(3-chlorothiophen-2-yl)-5-pyridin-3-yl-1,3,4-oxadiazole Chemical class C1=CSC(C=2OC(=NN=2)C=2C=NC=CC=2)=C1Cl NMHIGRULAVHQEJ-UHFFFAOYSA-N 0.000 claims description 7
- UOBGMNVBDFEORR-UHFFFAOYSA-N 2-(4-chlorophenyl)-5-(3-chlorothiophen-2-yl)-1,3,4-oxadiazole Chemical class C1=CSC(C=2OC(=NN=2)C=2C=CC(Cl)=CC=2)=C1Cl UOBGMNVBDFEORR-UHFFFAOYSA-N 0.000 claims description 7
- VBBXDIVQDMTNME-UHFFFAOYSA-N 2-(4-chlorophenyl)-5-(3-chlorothiophen-2-yl)-1,3-oxazole Chemical class C1=CSC(C=2OC(=NC=2)C=2C=CC(Cl)=CC=2)=C1Cl VBBXDIVQDMTNME-UHFFFAOYSA-N 0.000 claims description 7
- PVWNOEWUPKEKBA-UHFFFAOYSA-N 2-(6-chloropyridin-3-yl)-5-(3-chlorothiophen-2-yl)-1,3-oxazole Chemical class C1=CSC(C=2OC(=NC=2)C=2C=NC(Cl)=CC=2)=C1Cl PVWNOEWUPKEKBA-UHFFFAOYSA-N 0.000 claims description 7
- WMMOEUAWSDCEAR-UHFFFAOYSA-N 2-[5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazol-3-yl]quinolin-8-ol Chemical class N1=C2C(O)=CC=CC2=CC=C1C(N=1)=NOC=1C=1SC=CC=1Cl WMMOEUAWSDCEAR-UHFFFAOYSA-N 0.000 claims description 7
- XMNNIXBSSUBOOW-UHFFFAOYSA-N 2-[5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)pyrazol-1-yl]ethanol Chemical class OCCN1N=C(C2=C(C=CS2)Cl)C=C1C1=CC=C(Cl)C=C1 XMNNIXBSSUBOOW-UHFFFAOYSA-N 0.000 claims description 7
- HOYGOGRMYZCFCS-UHFFFAOYSA-N 2-[5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)pyrazol-1-yl]pyridine Chemical class C1=CSC(C2=NN(C(C=3C=CC(Cl)=CC=3)=C2)C=2N=CC=CC=2)=C1Cl HOYGOGRMYZCFCS-UHFFFAOYSA-N 0.000 claims description 7
- ZJZBMGUJHMQNFG-UHFFFAOYSA-N 3-(4-butoxyphenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CC(OCCCC)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 ZJZBMGUJHMQNFG-UHFFFAOYSA-N 0.000 claims description 7
- QZRBEJJCGIGWEC-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2C=CC(Cl)=CC=2)=C1Cl QZRBEJJCGIGWEC-UHFFFAOYSA-N 0.000 claims description 7
- BZFHZPCDDSDNJC-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-(3-chlorothiophen-2-yl)-1h-pyrazole Chemical class C1=CSC(C=2NN=C(C=2)C=2C=CC(Cl)=CC=2)=C1Cl BZFHZPCDDSDNJC-UHFFFAOYSA-N 0.000 claims description 7
- QLWZGYISUDNRSA-UHFFFAOYSA-N 3-(5-chloropyridin-2-yl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2N=CC(Cl)=CC=2)=C1Cl QLWZGYISUDNRSA-UHFFFAOYSA-N 0.000 claims description 7
- GOXUTDKGBQFDQL-UHFFFAOYSA-N 3-(5-chloropyridin-2-yl)-5-(4-chloro-1,3-thiazol-5-yl)-1,2,4-oxadiazole Chemical class N1=CSC(C=2ON=C(N=2)C=2N=CC(Cl)=CC=2)=C1Cl GOXUTDKGBQFDQL-UHFFFAOYSA-N 0.000 claims description 7
- WANXSMAQHBOXBV-UHFFFAOYSA-N 3-(6-chloropyridin-3-yl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2C=NC(Cl)=CC=2)=C1Cl WANXSMAQHBOXBV-UHFFFAOYSA-N 0.000 claims description 7
- CDJZACAGQJLPMP-UHFFFAOYSA-N 3-[2-(4-chlorophenyl)ethyl]-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(CCC=3C=CC(Cl)=CC=3)N=2)=C1Cl CDJZACAGQJLPMP-UHFFFAOYSA-N 0.000 claims description 7
- BFATVAXLPIRXCM-UHFFFAOYSA-N 4-[5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)pyrazol-1-yl]benzoic acid Chemical class C1=CC(C(=O)O)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C2=C(C=CS2)Cl)=N1 BFATVAXLPIRXCM-UHFFFAOYSA-N 0.000 claims description 7
- PHTFISKCVIYUNK-UHFFFAOYSA-N 5-(3-bromofuran-2-yl)-3-(4-fluorophenyl)-1,2,4-oxadiazole Chemical class C1=CC(F)=CC=C1C1=NOC(C2=C(C=CO2)Br)=N1 PHTFISKCVIYUNK-UHFFFAOYSA-N 0.000 claims description 7
- HBEGOHSMVWAPMK-UHFFFAOYSA-N 5-(3-chlorofuran-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole Chemical class C1=COC(C=2ON=C(N=2)C=2N=CC(Cl)=CC=2)=C1Cl HBEGOHSMVWAPMK-UHFFFAOYSA-N 0.000 claims description 7
- OTOLBHSUPKUGIG-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-2-[4-(trifluoromethyl)phenyl]-1,3-oxazole Chemical class C1=CC(C(F)(F)F)=CC=C1C1=NC=C(C2=C(C=CS2)Cl)O1 OTOLBHSUPKUGIG-UHFFFAOYSA-N 0.000 claims description 7
- KFZOZRPKUBTDAW-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-(4-methylpyridin-2-yl)-1,2,4-oxadiazole Chemical class CC1=CC=NC(C=2N=C(ON=2)C2=C(C=CS2)Cl)=C1 KFZOZRPKUBTDAW-UHFFFAOYSA-N 0.000 claims description 7
- WJQHXYTWTUYTLF-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-(4-nitrophenyl)-1,2,4-oxadiazole Chemical class C1=CC([N+](=O)[O-])=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 WJQHXYTWTUYTLF-UHFFFAOYSA-N 0.000 claims description 7
- ZAZPZYYESPQZOH-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-(5-methylpyridin-2-yl)-1,2,4-oxadiazole Chemical class N1=CC(C)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 ZAZPZYYESPQZOH-UHFFFAOYSA-N 0.000 claims description 7
- WKFOPRUOMXNECV-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole Chemical class C1=NC(C)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 WKFOPRUOMXNECV-UHFFFAOYSA-N 0.000 claims description 7
- GWJGRVCDXDRMPP-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-[4-(trifluoromethyl)phenyl]-1h-1,2,4-triazole Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=NNC(C2=C(C=CS2)Cl)=N1 GWJGRVCDXDRMPP-UHFFFAOYSA-N 0.000 claims description 7
- REXPEWGPDOIUKI-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical class C1=C(Cl)C(C(F)(F)F)=CC(C=2N=C(ON=2)C2=C(C=CS2)Cl)=C1 REXPEWGPDOIUKI-UHFFFAOYSA-N 0.000 claims description 7
- IASFWURAZNQZLD-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-isoquinolin-3-yl-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2N=CC3=CC=CC=C3C=2)=C1Cl IASFWURAZNQZLD-UHFFFAOYSA-N 0.000 claims description 7
- LYOHCNXXNGOPRW-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-quinolin-2-yl-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2N=C3C=CC=CC3=CC=2)=C1Cl LYOHCNXXNGOPRW-UHFFFAOYSA-N 0.000 claims description 7
- HXGORZYFLYKWAK-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-quinolin-3-yl-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2C=C3C=CC=CC3=NC=2)=C1Cl HXGORZYFLYKWAK-UHFFFAOYSA-N 0.000 claims description 7
- RFPXMHVLMPUFTB-UHFFFAOYSA-N 5-(4-bromophenyl)-2-(3-chlorothiophen-2-yl)-1,3-oxazole Chemical class C1=CSC(C=2OC(=CN=2)C=2C=CC(Br)=CC=2)=C1Cl RFPXMHVLMPUFTB-UHFFFAOYSA-N 0.000 claims description 7
- WOCHCATZZPUZEK-UHFFFAOYSA-N 5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)-1-(4-methylsulfonylphenyl)pyrazole Chemical class C1=CC(S(=O)(=O)C)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C2=C(C=CS2)Cl)=N1 WOCHCATZZPUZEK-UHFFFAOYSA-N 0.000 claims description 7
- PMKGATIMUGCKIN-UHFFFAOYSA-N 5-(4-chlorophenyl)-3-(3-chlorothiophen-2-yl)-1-phenylpyrazole Chemical class C1=CSC(C2=NN(C(C=3C=CC(Cl)=CC=3)=C2)C=2C=CC=CC=2)=C1Cl PMKGATIMUGCKIN-UHFFFAOYSA-N 0.000 claims description 7
- NWROARSJRCSHTO-UHFFFAOYSA-N 5-chloro-2-[5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazol-3-yl]aniline Chemical class NC1=CC(Cl)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 NWROARSJRCSHTO-UHFFFAOYSA-N 0.000 claims description 7
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 229960000485 methotrexate Drugs 0.000 claims description 7
- HKEAMTVKVKTPAD-UHFFFAOYSA-N methyl 4-[5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazol-3-yl]benzoate Chemical class C1=CC(C(=O)OC)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 HKEAMTVKVKTPAD-UHFFFAOYSA-N 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 6
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 claims description 6
- RRTQDBUIKQVDOM-UHFFFAOYSA-N 2-(3-chlorothiophen-2-yl)-4-[4-(trifluoromethyl)phenyl]-1,3-oxazole Chemical class C1=CC(C(F)(F)F)=CC=C1C1=COC(C2=C(C=CS2)Cl)=N1 RRTQDBUIKQVDOM-UHFFFAOYSA-N 0.000 claims description 6
- ZAQPGFQYEKLMLQ-UHFFFAOYSA-N 2-[5-(3-chlorothiophen-2-yl)-1h-1,2,4-triazol-3-yl]pyridine Chemical compound C1=CSC(C=2NN=C(N=2)C=2N=CC=CC=2)=C1Cl ZAQPGFQYEKLMLQ-UHFFFAOYSA-N 0.000 claims description 6
- NTXRDPTWTSVZKD-UHFFFAOYSA-N 3-(3-bromothiophen-2-yl)-5-(4-chlorophenyl)-1,2,4-oxadiazole Chemical class C1=CC(Cl)=CC=C1C1=NC(C2=C(C=CS2)Br)=NO1 NTXRDPTWTSVZKD-UHFFFAOYSA-N 0.000 claims description 6
- HMOGXUGCIZYDNN-UHFFFAOYSA-N 3-(4-azidophenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2C=CC(=CC=2)N=[N+]=[N-])=C1Cl HMOGXUGCIZYDNN-UHFFFAOYSA-N 0.000 claims description 6
- QUAPVAKOKOMDPW-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-(3-methylthiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)C=2C=CC(Cl)=CC=2)=C1C QUAPVAKOKOMDPW-UHFFFAOYSA-N 0.000 claims description 6
- GJSVOUIRFVPTIC-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-(4-chloro-1h-pyrazol-5-yl)-1,2,4-oxadiazole Chemical class ClC1=CNN=C1C1=NC(C=2C=CC(Cl)=CC=2)=NO1 GJSVOUIRFVPTIC-UHFFFAOYSA-N 0.000 claims description 6
- OBXMMIYFAUYQFV-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]-1,2,4-oxadiazole Chemical class S1C(C)=NC(C(F)(F)F)=C1C1=NC(C=2C=CC(Cl)=CC=2)=NO1 OBXMMIYFAUYQFV-UHFFFAOYSA-N 0.000 claims description 6
- ZBIZYSIIJRBDSE-UHFFFAOYSA-N 3-(4-methylphenyl)-5-thiophen-2-yl-1,2,4-oxadiazole Chemical class C1=CC(C)=CC=C1C1=NOC(C=2SC=CC=2)=N1 ZBIZYSIIJRBDSE-UHFFFAOYSA-N 0.000 claims description 6
- WJCJBQBWEBYRCZ-UHFFFAOYSA-N 3-[(4-chlorophenoxy)methyl]-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(COC=3C=CC(Cl)=CC=3)N=2)=C1Cl WJCJBQBWEBYRCZ-UHFFFAOYSA-N 0.000 claims description 6
- HZKZEGHBHUTRBW-UHFFFAOYSA-N 3-[(4-chlorophenyl)methyl]-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(CC=3C=CC(Cl)=CC=3)N=2)=C1Cl HZKZEGHBHUTRBW-UHFFFAOYSA-N 0.000 claims description 6
- CCHJKSVJNQMMKO-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-(3-chlorothiophen-2-yl)-1,3-oxazole Chemical class C1=CSC(C=2OC=C(N=2)C=2C=CC(Cl)=CC=2)=C1Cl CCHJKSVJNQMMKO-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
本发明涉及取代的3-芳基-5-芳基-[1,2,4]-噁二唑及其类似物,表示为式I:其中在本文中定义了Ar1、Ar3、A、B和D。本发明还涉及发现具有式I的化合物是半胱氨酰天冬氨酸蛋白酶活化剂和细胞凋亡诱导剂。因而,在多种发生异常细胞失控性生长和传播的临床病症中,本发明的半胱氨酰天冬氨酸蛋白酶活化剂和凋亡诱导剂可用于诱导细胞死亡。
Description
发明背景
发明领域
此发明是属于药物化学领域。特别地,本发明涉及任选地取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物,且涉及这些化合物是半胱氨酰天冬氨酸蛋白酶活化剂和细胞凋亡诱导剂的发现。本发明还涉及这些化合物作为治疗有效的抗癌剂的应用。
相关技术
有机体通过不同名称的已知过程,如调控性细胞死亡、程序化细胞死亡和细胞凋亡来消除不需要的细胞。这种细胞死亡作为动物发育的一个正常方面,以及在组织自身稳定和老化中发生(Glucksmann,A.,Biol.Rev.Cambridge Philos.Soc.26:59-86(1951);Glucksmann,A.,Archives de Biologie 76:419-437(1965);Ellis,et al.Dev.112:591-603(1991);Vaux,et al.Cell 76:777-779(1994))。细胞凋亡调节细胞数量,推动形态发生,清除有害的或相反,反常的细胞和消灭已经履行完它们功能的细胞。另外,细胞凋亡在对各种生理性应激反应,如缺氧或局部缺血的应答中发生(PCT publishedapplication WO/96/20721)。
有许多为细胞经历调节性细胞死亡所共有的形态学变化,包括胞浆和核膜出泡、细胞皱缩(核质和细胞质浓缩)、细胞器再定位和压缩、染色质浓缩和凋亡小体的产生(含细胞内物质的膜包绕的颗粒)(Orrenius,S.,J.Internal Medicine 237:529-536(1995))。
凋亡是通过细胞自杀的内生机制产生的(Wyllie,A.H.,in CellDeath in Biology and Pathology,Bowen and Locksin,eds.,Chapmanand Hall(1981),pp.9-34)。作为或内部或外部信号的结果,细胞激活其内部编码的自杀程序。此自杀程序通过一个精细调节的基因程序的激活执行。(Wyllie,et al.,Int.Rev.Cyt.68:251(1980);Ellis,et al.,Ann.Rev.Cell Bio.7:663(1991))。凋亡细胞和小体通常在分解前被邻近细胞或巨噬细胞识别和清除。正因为这种清除机制,即使大量细胞的清除也不导致炎症(Orrenius,S.,J.Internal Medicine 237:529-536(1995))。
据发现,一组蛋白酶是凋亡中的关键元素(参见,例如,Thornberry,Chemistry and Biology 5:R97-R103(1998);Thornberry,BritishMed.Bull.53:478-490(1996))。对线虫的基因研究揭示,凋亡细胞死亡涉及至少14个基因,其中2个是促凋亡的(促进死亡的)ced(代表异常的细胞死亡,cell death abnormal)基因,ced-3和ced-4。CED-3是与白细胞介素1β转换酶同源的一种半胱氨酸蛋白酶,现在被称做半胱氨酰天冬氨酸蛋白酶-1。当这些数据被全部应用于哺乳动物,且基于进一步的大量研究,发现哺乳动物的凋亡系统表现为包括一个半胱氨酰天冬氨酸蛋白酶的级联或一个行为表现类似半胱氨酰天冬氨酸蛋白酶级联的系统。目前,半胱氨酸蛋白酶的半胱氨酰天冬氨酸蛋白酶家族包括14个不同的成分,将来可能发现更多的成分。所有已知的半胱氨酰天冬氨酸蛋白酶被合成为酶原,在形成活性酶之前需要清除天冬氨酰残基。这样,半胱氨酰天冬氨酸蛋白酶能够以扩大的级联方式激活其他半胱氨酰天冬氨酸蛋白酶。
凋亡和半胱氨酰天冬氨酸蛋白酶被认为是癌症发展中至关紧要的(Apoptosis and Cancer Chemotherapy,Hickman and Dive,eds.,Humana Press(1999))。进一步的证据表明癌细胞,当包含半胱氨酰天冬氨酸蛋白酶时,缺少部分激活半胱氨酰天冬氨酸蛋白酶级联的分子机能。这使癌细胞丧失它们经历细胞自杀的能力,且使细胞变成癌性。在凋亡过程中,已经知道存在控制点,以干涉再现该点会导致激活作用。这些控制点包括CED-9-BCL类和CED-3-ICE类基因家族产物,它们是调节细胞生或死的结果的固有蛋白质,并且其本身相应地执行部分细胞死亡过程(参见,Schmitt,et al.,Biochem.Cell.Biol.75:301-314(1997))。BCL类蛋白质包括BCL-xL和BCL-α,它们表现出半胱氨酰天冬氨酸蛋白酶激活的相反的作用。BCL-xL表现为阻止凋亡蛋白酶级联的激活,而BCL-α加速凋亡蛋白酶级联的激活。
据显示化学治疗(抗癌)药物通过激活静止的半胱氨酰天冬氨酸蛋白酶级联能触发癌细胞经历自杀。这可能是大部分,如果不是全部,已知抗癌药的作用方式的一个至关紧要的方面(Los,et al.,Blood 90:3118-3129(1997);Friesen,et al.,Nat.Med.2:574(1996))。当前的抗肿瘤的药的作用机制经常涉及在细胞循环的特定阶段的攻击。简要地说,细胞循环指这样的阶段,通过这些阶段细胞在它们的寿命期内正常发育。正常地,细胞存在于休眠期称为G0。在增殖期间,细胞发育到一个DNA合成发生的阶段,称为S。之后,细胞分裂,或有丝分裂发生于称为M的阶段。抗肿瘤药物,如阿糖胞苷、羟基脲、6-巯基嘌呤和氨甲蝶呤是S特异性的,而抗肿瘤药物,如长春新碱、长春碱和紫杉酚是M期特异性的。许多缓慢生长的肿瘤,例如结肠癌,最初存在于G0期,而快速增殖的正常组织,例如骨髓,最初存在于S或M期。这样,一种药物,象6-巯基嘌呤在保持对缓慢生长的肿瘤无效的同时可以引起骨髓毒性。肿瘤疾病的化学治疗的另外作用方面对本领域技术人员是已知的(参见,例如,Hardman,et al.,eds.,Goodman and Gilman’s The Pharmacological Basis of Therapeutics,Ninth Edition,McGraw-Hill,New York(1996),pp.1225-1287)。因而,存在对半胱氨酰天冬氨酸蛋白酶级联的激活作用的可能性是明确的,尽管在这么做的确切机制这一点上不清楚。同样清楚地的是不充分的半胱氨酰天冬氨酸蛋白酶级联活性及随之发生的凋亡结果见于各种各样类型的癌症。凋亡的半胱氨酰天冬氨酸蛋白酶级联活化剂和诱导剂的发展是治疗有效的抗癌药物的发展的极值得想望的目标。凋亡的半胱氨酰天冬氨酸蛋白酶级联活化剂和诱导剂还是清除病原体,如人免疫缺陷病毒(HIV)、丙型肝炎和其他病毒性病原体的一种值得想望的疗法。一种疾病进展后的长期持续的静止可以用这些病原体的抗凋亡机制导致持续的病毒颗粒的细胞贮主来解释。据报道被感染的T白血病细胞或外周血单核细胞(PBMCs)中的HIV-1在半胱氨酰天冬氨酸蛋白酶抑制剂Z-VAD-fmk存在下经历增强的病毒复制。此外,Z-VAD-fmk还刺激得自HIV-1感染的无症状个体的活化的PBMCs中内源性病毒生产(Chinnaiyan,A.et.al.,Nature Medicine.3:333.1997)。因此,凋亡可作为限制HIV蔓延的有益的宿主机制,且使用半胱氨酰天冬氨酸蛋白酶/凋亡活化剂的新治疗方法可对从感染个体清除病毒贮主有帮助。类似地,HCV感染也触发抗凋亡机制以逃避宿主的免疫监视,导致病毒的持续和肝癌发生(Tai DI et.al.Hepatology 3:656-64,2000)。因此,凋亡诱导剂可用作对HCV和其他感染性疾病的治疗。而且,由于自身免疫性疾病和某些变性疾病也涉及异常细胞的增殖,所以对这些疾病的治疗处理也可涉及通过给予合适的半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂增强凋亡过程。
发明概述
本发明涉及发现任选地取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物,如在式I所表现,是半胱氨酰天冬氨酸蛋白酶级联的活化剂和细胞凋亡的诱导剂。因而,本发明的一个方面涉及作为细胞凋亡诱导剂的式I的化合物的用途。
本发明的化合物以图I表示:
或它们的可药用盐或前药或互变异构体,其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中
Ar2,是任选地取代的芳基或任选地取代的杂芳基;且
如果价律未被违背,A、B和D独立地是C、CR10、C(R10)R11、N、NR12、O或S,其中R10和R11在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基,且R12在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。
本发明的再一个方面是为了提供一种通过对需要如此治疗的哺乳动物给予式I之一的化合物用于治疗、防止或改善瘤形成和癌症的方法。
本发明范围内化合物的许多种都是新化合物。因此,本发明的第三个方面是为了提供式I的新化合物,并为了提供这些用于治疗、防止或改善瘤形成和癌症的新化合物的用途。
本发明的第四个方面是为了提供一种有助于对诱导凋亡敏感的疾病的治疗的药用组合物,包含有效量的式I之一的化合物和一种或多种药用载体或稀释剂。
本发明的第五方面涉及式I新化合物的制备方法。
发明的详细说明
本发明起于发现任选地取代的3-芳基-5-芳基-[1,2,4]-噁二唑和类似物,如在式I中所示,是有效的和高效的半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂。因而,式I的化合物是对治疗细胞凋亡反应的疾病有帮助的。
特别地,本发明的化合物以式I表示:
或它们的可药用盐或前药或互变异构体,其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中
Ar2,是任选地取代的芳基或任选地取代的杂芳基;且如果价律未被违背,A、B和D独立地是C、CR10、C(R10)R11、N、NR12、O或S,其中R10和R11在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基,且R12在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。优选地,R10、R11和R12是氢、烷基、环烷基或芳基;更优选地,R10、R11和R12是氢、烷基或环烷基。
式I的优选化合物包括其中A是N、B是O、D是N的化合物。另一组式I的优选化合物包括其中A是N、B是NR12、D是N的化合物。
另一组式I的优选化合物包括其中A是N、B是CR10、D是NR12的化合物。另一组式I的优选化合物包括其中A是O、B和D是N的化合物。
另一组式I的优选化合物包括其中A是O、B是N和D是C的化合物。
另一组式I的优选化合物包括其中A是N、B是O、D是C的化合物。
另一组式I的优选化合物包括其中A是C、B是N和D是NR12的化合物。
式I的优选化合物包括其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基的化合物,其中每个都是任选地取代的。更优选地,Ar1是异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基。
式I的优选化合物包括其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吡唑基[1,5-α]嘧啶基、苄基、苯乙基、苯氧甲基、苄基氨基、苯甲酰氨基或亚苄基氨基,其中每个都是任选地取代的。更优选地,Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基。最优选地,Ar3是苯基或吡啶基。
一组本发明的优选化合物以式II表示:
或它们的可药用盐或前药,其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中
Ar2,是任选地取代的芳基或任选地取代的杂芳基。
式II的优选化合物包括其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基;和其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基的化合物,其中每个都是任选地取代的。优选地,Ar1是苯基、吡啶基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的;Ar3是苯基、吡啶基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。更优选地,Ar1是异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的;Ar3是任选地取代的苯基或任选地取代的吡啶基。
对于式II的化合物优选地:
(a)当Ar1是未取代的或取代的噻吩基时,那么Ar3不是被氯基或三氟甲基取代的苯基;
(b)当Ar1是未取代的或取代的异噁唑基时,那么Ar3不是未取代的苯基;
(c)当Ar1是取代的或未取代的吡唑基时,那么Ar3不是三氟甲基吡啶基(pyridinyl);
(d)当Ar1是取代的或未取代的吡咯基时,那么Ar3不是未取代的吡啶基。
优选地在本发明的这方面有用的化合物以式III表示:
或它们的可药用盐或前药,其中:
R1-R8独立地是氢、卤、卤代烷基、芳基、稠合芳基、碳环基、一个杂环基、杂芳基、烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酸基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,其中每个都是任选地取代的;
Q是S、O或NR9,其中R9是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。优选地,R9是氢、烷基、环烷基或芳基;更优选地,R9是氢、烷基或环烷基。
式II的优选化合物包括其中Q是S或O;且其中R3不是一个氢的化合物。
另一组本发明的优选化合物以式IV-IX表示:
或它们的可药用盐或前药,其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中
Ar2,是任选地取代的芳基或任选地取代的杂芳基;和
R12是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基和杂芳基。
式II的优选化合物包括其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基;和其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基的化合物,其中每个都是任选地取代的。优选地,Ar1是苯基、吡啶基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的;Ar3是苯基、吡啶基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。更优选地,Ar1是异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的;Ar3是任选地取代的苯基或任选地取代的吡啶基。优选地,R12是氢、任选地取代的烷基或任选地取代的芳基和杂芳基。
本发明方法中可使用的列举的优选化合物包括,但不限于:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(-1苯基-5-三氟甲基-1H-吡唑-4-基)-3-[3,5-双(三氟甲基)苯基]-[1,2,4]-噁二唑;
5-[1-(4-氯-苯基)-5-三氟甲基-1H-吡唑-4-基]-3-[3,5-双(三氟甲基)苯基]-[1,2,4]-噁二唑;
5-(4-溴-1-乙基-3-甲基-1H-吡唑-5-基)3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(2-甲基-吡咯-3-基)3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,5-双(三氟甲基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-溴-3-甲氧基-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-甲基-5-三氟甲基-异噁唑-4-基)-3-苯基-[1,2,4]-噁二唑;
3-(4-氨基-3,5-二氯-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2,4-二氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-(甲磺酰基氨基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基-苯基)-[1,2,4]-噁二唑;
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-二甲氨基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-羟基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-叠氮基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑;
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氨基-嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(2-甲基-4-三氟甲基-噻唑-5-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑;
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
5-(6-氯-吡啶-3-基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
5-(3-溴-5-吗啉代甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑;
2-(3-氯-噻吩-2-基)-5-苯基-噁唑;
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-苯基-噁唑;
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑;
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑;
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑;
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑;
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑;
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯胺基)[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉;
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲胺;
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯;
5-(3,4,5-三氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑;
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;和
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
或它们的可药用盐或前药。
本发明还涉及在式I-IX范围内的新化合物。本发明列举的新化合物包括,但不限于:
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑;
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2,4-二氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-(甲磺酰基氨基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基苯基)-[1,2,4]-噁二唑;
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-二甲氨基苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-羟基苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-叠氮基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑;
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氨基-嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(2-甲基-4-三氟甲基-噻唑-5-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑;
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
5-(6-氯-吡啶-3-基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
5-(3-溴-5-吗啉代甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑;
2-(3-氯-噻吩-2-基)-5-苯基-噁唑;
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-苯基-噁唑;
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑;
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑;
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑;
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑;
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑;
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯胺基)[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉;
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲胺;
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯;
5-(3,4,5-三氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑;
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;和
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
或它们的可药用盐或前药。
此处所使用术语“烷基”,其本身或作为部分其他基团,涉及直链和支链至多10碳的基团。有利的烷基包括直链的和支链C1-10烷基,更优选C1-6烷基。典型的C1-10烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基,它们是可任选地取代的。
此处所使用术语“链烯基”,其本身或作为部分其他基团,涉及直链和支链2-10个碳原子的基团,除非链的长度受到另外限制,在链中两个碳原子间至少包括一个双键。典型的链烯基包括乙烯、1-丙烯、2-丙烯、2-甲基-1-丙烯、1-丁烯和2-丁烯。
此处所使用术语“炔基”,其本身或作为部分其他基团,涉及直链和支链2-10个碳原子的基团,除非链的长度受到另外限制,其中在链中两个碳原子间至少存在一个三键。典型的炔基包括乙炔基、1-丙炔基、2-丙炔基、2-甲基-1-丙炔基、1-丁炔基和2-丁炔基。
可用的烷氧基包括以一个上面提到的C1-10烷基取代的氧,其可被任选地取代。烷氧基取代基包括但不限于卤、吗啉代、氨基(含烷基氨基和二烷基氨基)和羧基(含它们的酯)。
可用的烷基硫基包括以一个上面提到的C1-10烷基取代的硫,其可被任选地取代。还包括这类烷基硫基的亚砜和砜。
可用的氨基包括-NH2、-NHR15和-NR15R16,其中R15和R16是C1-10烷基或环烷基,或R15和R16是与N结合形成的环形结构,如哌啶,或R15和R16是与N结合形成的环,如哌嗪。该烷基可被任选地取代。
对烷基、链烯基、炔基、环烷基、碳环和杂环基的任选地取代基包括一个或多个卤、羟基、羧基、氨基、硝基、氰基、C1-C6酰氨基、C1-C6酸基、C1-C6烷氧基、芳氧基、烷基硫基、C6-C10芳基、C4-C7环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、饱和及不饱和杂环的或杂芳基。
对烷基、芳基烷基、芳基链烯基、芳基炔基和杂芳基和杂芳基烷基的任选地取代基包括一个或多个卤、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、脲基、氰基、C1-C6酰氨基、羟基、巯基、C1-C6酸基、叠氮基、C1-C6烷氧基或羧基。
本文中使用的术语“芳基”本身或作为其他基团的部分,指单环的、双环的或三环的在环部分含6-14个碳的芳香基。
可用的芳基包括C6-14芳基,优选C6-10芳基。典型的C6-10芳基包括苯基、萘基、菲基(phenanthrenyl)、蒽基(anthracenyl)、茚基(indenyl)、azulenyl、联苯基、biphenylenyl和芴基。
可用的环烷基是C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
可用的饱和或部分饱和的碳环基是如上所述的环烷基,以及环链烯基如环戊烯基、环庚烯基和环辛烯基。
可用的卤或卤素基团包括氟、氯、溴和碘。
本文中使用的术语“芳基烷基”指以任何上述的C6-14芳基取代的上述任何C1-10烷基。优选芳基烷基是苄基、苯乙基或萘基甲基。
本文中使用的术语“芳基链烯基”指以任何上述的C6-14芳基取代的上述任何C2-10链烯基。
本文中使用的术语“芳基炔基”指以任何上述的C6-14芳基取代的上述任何C2-10炔基。
本文中使用的术语“芳氧基”指以一种上述的C6-14芳基取代的氧,其可以是任选地取代的。可用的芳氧基包括苯氧基和4-甲基苯氧基。
本文中使用的术语“芳基烷氧基”指以任何上述芳基取代的C1-10烷氧基,其可以是任选取代的。可用的芳基烷氧基包括苄氧基和苯乙基氧基(phenethyloxy)。
可用的卤代烷基包括以一个或多个氟、氯、溴或碘原子取代的C1-10烷基,例如,氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、氯甲基、氯氟甲基和三氯甲基。
可用的酰氨基(酰胺基)是加入了氨基氮的任何C1-6酰基(烷酰基),例如,乙酰胺基、氯乙酰胺基、丙酰胺基、丁酰胺基、戊酰胺基和己酰胺基,以及芳基取代的C1-6酰氨基,例如苯甲酰胺基和五氟苯甲酰胺基。
可用的酰氧基是加入氧基(-O-)的任何C1-6酰基(烷酰基),例如甲酸基、乙酸基、丙酰氧基、丁酰氧基、戊酰氧基和己酰氧基。
本文中使用的术语杂环指饱和的或部分饱和的3-7元单环或7-10元双环系统,所述杂环由碳原子和单独选自由O、N和S组成的组中的1-4杂原子组成,其中氮和硫杂原子能被任选地氧化,氮能被任选地季铵化,并且包括在苯环中熔合了任何上述定义的杂环的任何双环基团,且如果产生的化合物是稳定的,其中的杂环在碳或一个氮原子能被取代。
可用的饱和的或部分饱和的杂环基包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异苯并二氢吡喃基、苯并二氢吡喃基、吡唑烷基、吡唑啉基、tetronoyl基和tetramonyl基。
本文中使用的术语“杂芳基”指具有5-14环原子的基团;在环状排列中共用6、10或14π电子;且含碳原子和1、2或3个氧、氮或硫杂原子。
可用的杂芳基包括噻吩基(thiophenyl)、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽烯基(thianthrenyl)、呋喃基(furanyl)、吡喃基、异苯并呋喃基、chromenyl、吨基、phenoxanthiinyl、吡咯基(含但不限于2H-吡咯基)、咪唑基、吡唑基、吡啶基(含但不限于2-吡啶基、3-吡啶基和4-吡啶基)、吡嗪基、嘧啶基、哒嗪基、吡咯并[1,2-α]吡啶基(indolizinyl,中氮茚基)、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、phthalzinyl、二氮杂萘基、quinozalinyl、噌啉基、蝶啶基、咔唑基、β-咔唑基、菲啶基、acrindinyl、咱啶基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基(furazanyl)、吩噁嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-α]嘧啶-4-酮、吡唑并[1,5-α]嘧啶基(含但不限于吡唑并[1,5-α]嘧啶-3-基)、1,2苯并异噁唑-3-基、苯并咪唑基、2-羟基吲哚基和2-氧代苯并咪唑基。杂环基在一个环中包括一个氮原子,此氮原子可以是以N-氧化物的形式,例如,吡啶基N-氧化物、吡嗪基N-氧化物和嘧啶基N-氧化物。
本文中使用的术语“杂芳氧基”指以一种上述杂芳基取代的氧,所述杂芳基可被任选地取代。可用的杂芳氧基包括吡啶基氧基、吡嗪基氧基、吡咯基氧基、吡唑基氧基、咪唑基氧基和噻吩基氧基。
本文中使用的术语“杂芳基烷氧基”指以任何上述杂芳基取代的任何上述的C1-10烷氧基,所述杂芳基可被任选地取代。
一些本发明的化合物可以作为立体异构体含旋光异构体而存在。本发明包括所有立体异构体,且包括这些立体异构体的外消旋混合物及依照本领域普通技术人员所熟知的方法可分离的各自对映体。
可药用加成盐的实例包括无机和有机酸加成盐,例如氢氯酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、延胡索酸盐、扁桃酸盐和草酸盐;和无机和有机碱与碱类的加成盐,例如氢氧化钠、三(羟甲基)氨基甲烷(Tris,tromethane)和N-甲基-葡糖胺。
本发明化合物的前药的实例包括含化合物的简单羧酸酯(例如,依照本领域已知方法通过用C1-4醇缩合得到的酯);含化合物的羟基酯(例如,通过用C1-4羧酸、C3-6二酸或它们的酐,如琥珀酸酐和反丁烯二酸酐,依照本领域已知方法缩合得到的酯);含化合物的氨基亚胺(例如依照本领域已知方法通过用C1-4醛或酮缩合得到的氨基亚胺);含化合物的氨基甲酸酯,例如Leu,et.al.,(J.Med.Chem.42:3623-3628(1999))和Greenwald,et.al.,(J.Med.Chem.42:3657-3667(1999))所描述的氨基甲酸酯;和含化合物的醇的缩醛和缩酮(例如依照本领域已知方法用氯甲基甲基酯或氯甲基乙基酯缩合所得到的)。
本发明的化合物可以用本领域技术人员知道的方法或此发明的新方法来制备。具体地,式I-IX的本发明化合物能够按反应流程1所举反应实例来制备。在1,4-二噁烷中3-氯-噻吩-2-羰基氯化物与4-氯苄胺肟反应后通过用BF3OEt2处理,产生产物3-(4-氯-苯基)5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑。另一方面,反应还能在二噁烷/吡啶中或在吡啶中进行,且产生相同的噁二唑产物。
反应流程1
式I-IX的本发明化合物可以按反应流程2所举反应实例来制备。3-溴-呋喃-2-羧酸与亚硫酰氯化物反应产生中间产物(3-溴-呋喃-2-羰基氯化物)后通过在吡啶中用4-三氟甲基-苄胺肟回流产生产物5-(3-溴-呋喃)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑。
反应流程2
式IV的本发明化合物可以按反应流程3所举反应实例来制备。在氯仿中2-溴-1-(3-氯-噻吩-2-基)-乙酮(ethanone)与4-氯-苯甲脒反应产生产物2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-咪唑。
反应流程3
式V的本发明化合物可以按反应流程4所举反应实例来制备。3-氯-噻吩-2-羰基氯化物与4-氯-苯甲亚胺酰肼反应产生产物3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-三唑。
反应流程4
另一方面,式V的本发明化合物可以按反应流程5所举反应实例来制备。在碱例如NaOMe存在下,3-氯-噻吩-2-碳草酸(carboxalicacid)酰肼与4-氯苯甲脒反应产生产物3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-三唑。
反应流程5
式VI的本发明化合物可以按反应流程6所举反应实例来制备。3-氯-噻吩-2-羧酸酰肼与4-三氟甲基苯甲酰氯化物反应产生N-(3-氯-噻吩-2-羰基)-N’-4-三氟甲基苯甲酰-肼,以亚硫酰氯处理后产生5-(3-氯-2-噻吩基)-3-(4-三氟甲基苯甲酰)-[1,3,4]-噁二唑。
反应流程6
式VII的本发明化合物可以按反应流程7所举反应实例来制备。将3-氯-噻吩-2-羰基氯化物在吡啶中与2-氨基苯乙酮氢氯化物加热以产生取代的3-氯-噻吩-2-羧酸(2-氧代-2-苯基-乙基)-胺。用酸例如硫酸处理化合物使3-氯-噻吩-2-羧酸(2-氧代-2-苯基-乙基)-胺转换为终末产物2-(3-氯-噻吩-2-基)-5-苯基-噁唑。
反应流程7
另一方面,式VII的本发明化合物可以按反应流程8所举反应实例来制备。2-氨基-1-(3-氯-噻吩-2-基)-乙酮(ethanone)氢氯化物与多种的苯甲酰氯化物反应产生取代的N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-苯甲酰胺。用酸例如硫酸处理化合物导致环化以得到产物取代的5-(3-氯-噻吩-2-基)-2-苯基-噁唑。
反应流程8
式VIII的本发明化合物可以按反应流程9所举反应实例来制备。3-氯-噻吩-2-甲酰胺与多种2-溴-苯乙酮反应产生取代的2-(3-氯-噻吩-2-基)-4-苯基-噁唑。
反应流程9
式IX的本发明化合物可以按反应流程10所举反应实例来制备。1-(3-氯-噻吩-2-基)-1-乙酮(ethanone)与多种苯甲醛反应得到取代的3-苯基-1-(3-氯-噻吩-2-基)-丙烯酮(propenone)。在碱例如氢氧化钠存在下取代的3-苯基-1-(3-氯-噻吩-2-基)-丙烯酮(propenone)与取代的肼反应产生取代的5-苯基-3-(3-氯-噻吩-2-基)-1-苯基-4,5-二氢-1H-吡唑。用四乙酸铅使该4,5-二氢-吡唑脱氢,用盐酸处理后产生取代的5-苯基-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑。
反应流程10
具有在中间环和Ar2间连接基的本发明化合物可以按反应流程11所举反应实例来制备。3-氯-噻吩-2-羰基氯化物与氨腈反应产生N-氰基-3-氯-噻吩-2-羧酸酰胺,通过用羟基胺处理后得到3-氨基-5-(3-氯-2-噻吩基)-1,2,4-噁二唑。该胺在甲苯中用4-氯苯甲醛回流产生(4-氯-苯亚甲基)-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-胺。
反应流程11
具有可用于识别其生物靶的放射性标记和光敏基团的本发明化合物可以按反应流程12所举反应实例来制备。将硝基化合物还原为氨基化合物,通过碘化作用后得到二碘化合物。碘能够被氚代替,且通过重氮化作用氨基能被转化为叠氮基,得到放射标记的光敏性靶分子。另一方面,其他同位素如C14和其他光敏基团如重氮基也能用于制备放射性标记的光敏性化合物。
反应流程12
本发明的一个重要方面是发现具有式I-IX的化合物是半胱氨酰天冬氨酸蛋白酶活化剂和细胞凋亡诱导剂。因此,这些化合物可用于多种具有异常细胞失控性细胞生长和传播的临床疾病,例如用于癌。
本发明的另一个重要方面是发现在抗药性癌细胞中,例如乳腺和前列腺癌细胞,具有式I-IX的化合物是强力的和高效的半胱氨酰天冬氨酸蛋白酶活化剂和细胞凋亡诱导剂,使得这些化合物能杀死这些抗药性癌细胞。比较而言,大多数普通抗癌药物在同等条件下在杀死抗药性癌细胞方面无效。因此,本发明的化合物可用于治疗抗药性癌,例如动物的乳腺癌。
本发明包括用于调节在活体内细胞凋亡或在活体内肿瘤疾病的治疗方法,包括对需要此治疗的个体给药有效量的一种式I-IX的化合物或该化合物可药用盐或前药,其功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂。
本发明也包括一种治疗方法,该方法包括对动物给药有效量的一种式I-IX的化合物或该化合物可药用盐或前药,其中所说的治疗方法可用于治疗癌,它是以异常细胞失控性生长和传播为特征的一组疾病。这类疾病包括但不限于何杰金病、非何杰金氏淋巴瘤、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、多发性骨髓瘤、神经母细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞性白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌、绒(毛)膜癌、蕈样霉菌病、头颈癌、骨肉瘤、胰腺癌、急性粒细胞性白血病、毛细胞白血病、神经母细胞瘤、横纹肌肉瘤、卡波西肉瘤、泌尿生殖器癌、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多、特发性血小板增多、肾上腺皮质癌、皮肤癌和前列腺癌。
在实施这些治疗方法时,将有效量的组合物给药于显示出一种或多种此类疾病症状的个体,该组合物含制备成口服、静脉内、局部和表面应用的,用于治疗肿瘤疾病和其中涉及半胱氨酰天冬氨酸蛋白酶级联介导的生理反应的其他疾病的,治疗有效浓度的化合物。所述组合物的有效量对改善或消除一种或多种该类疾病的症状是有效的。治疗一种特定疾病的化合物的有效量是足以改善,或在某种程度内减轻,与疾病相关的症状的化合物数量。此数量可以一次剂量给药或可以根据计划给药,由此而起效。此剂量可治愈该类疾病但,典型地,给药是为改善疾病的症状。典型地,需要重复给药以取得所需要的症状改善。
在另一个实施方案中,提供了包括与可药用载体结合的式I-IX化合物或其可药用盐的药物组合物,所述化合物或其可药用盐功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂。
本发明的另一个实施方案涉及有效抑制瘤形成的组合物,包括与至少一种已知化学治疗剂或其一种可药用盐结合的,功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂的式I-IX化合物或其可药用盐或前药。可以用于联合治疗的已知癌化学治疗剂的实例包括,但不限于烷化剂,例如白消安、顺铂、丝裂霉素C和卡铂;抗有丝分裂药,例如秋水仙碱、长春碱、紫杉酚和多西他赛(docetaxel);拓扑异构酶I(topo I)抑制剂,例如喜树碱和托泊替康(topotecan);拓扑异构酶II(topo II)抑制剂,例如阿霉素和鬼臼乙叉苷;RNA/DNA抗代谢物,例如5-阿扎胞苷、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物,例如5-氟-2’-脱氧-尿苷、阿糖胞苷、羟基脲和硫鸟嘌呤;抗体,例如campath、Herceptin_或Rituxan_。可用于联合治疗的其他已知癌化学治疗剂包括美法仑、苯丁酸氮芥、环磷酰胺(cyclophosamide)、异环磷酰胺、长春新碱、米托胍腙(mitoguazone)、表柔比星、阿柔比星(aclarubicin)、博来霉素、米托蒽醌、依利醋铵(elliptinium)、氟达拉滨、奥曲肽、视黄酸、三苯氧胺、Gleeyec_和阿拉诺新(alanosine)。
在实施本发明的方法中,本发明化合物可作为整体药物组合物的部分与至少一种已知化学治疗剂一起给药。另一方面,本发明的化合物可除至少一种已知化学治疗剂之外给药。在一实施方案中,本发明化合物和至少一种已知癌化学治疗剂实质上同时给药,即两化合物在相同时间或相继地给药,只要化合物同时在血液中达到治疗水平。另一个实施方案,本发明化合物和至少一种已知癌化学治疗剂依照它们各自给药方案给药,只要化合物在血液中达到治疗水平。
本发明的另一个实施方案涉及有效抑制肿瘤的组合物,包括所述功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂的式I-IX化合物与至少一种已知治疗用抗体,例如Herceptin_或Rituxan_;生长因子,例如DGF、NGF;细胞因子,例如IL-2、IL-4;或结合于细胞表面的任何分子结合的生物缀合物。抗体和其他分子将式I-IX化合物递送到其靶并使其成为有效抗癌剂。该生物缀合体还能提高治疗用抗体如Herceptin_或Rituxan_的抗癌效应。
类似地,本发明的另一个实施方案涉及有效抑制肿瘤的组合物,包括与放射治疗结合的,所述功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂的式I-IX化合物或其可药用盐或前药。在此实施方案中,当给予放射治疗时,本发明化合物可同时或不同时给药。
另外一个实施方案涉及用于癌手术后治疗有效的组合物,包括功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂的式I-IX化合物或其可药用盐或前药。本发明还涉及通过手术除去癌,然后以一种本文中描述的药物组合物治疗动物治疗癌的方法
在暴露于感染因素后,大范围的免疫机制迅速发挥作用。根据感染的类型,发生T和B淋巴细胞迅速的克隆扩增以对抗感染。感染后效应细胞的清除是保持免疫自身稳定的一种主要机制。效应细胞的清除显现为细胞凋亡的调控。最近确定发生自身免疫病是作为细胞死亡失调的结果。在某些自身免疫病中,免疫系统指挥其强有力的细胞毒效应器机制对抗特定细胞,例如多发性硬化中的少突神经胶质细胞、糖尿病中胰腺的β细胞和桥本甲状腺炎中的甲状腺细胞(Ohsako,S.&Elkon,K.B.,Cell Death Differ.6:13-21(1999))。编码淋巴细胞凋亡受体Fas/APO-1/CD95的基因突变被报道与有缺陷的淋巴细胞凋亡和自身免疫性淋巴组织增生综合征有关,该综合征特点为慢性、组织学良性的脾大、全身淋巴结病、高丙种球蛋白血症和自身抗体形成。(Infante,A.J.,et al.,J.Pediatr.133:629-633(1998)和Vaishnaw,A.K.,et al.,J.Clin.Invest.103:355-363(1999))。已报道在转基因小鼠的发育B细胞中,在T细胞依赖共刺激信号存在下,Bcl-2(具有抗细胞凋亡活性的程序性细胞死亡调节基因bcl-2基因家族成员)的过表达导致发生更改的B细胞库和导致产生病理性自身抗体(Lopez-Hoyos,M.,et al.,Int.J.Mol.Med.1:475-483(1998))。因此,显然很多种自身免疫病是由细胞凋亡过程缺陷所引起。对这类疾病的一个治疗策略是开启正引起自身免疫病的淋巴细胞中的细胞凋亡(O’Reilly,L.A.& Strasser,A.,Inflamm.Res.48:5-21(1999))。
已知Fas-Fas配体(FasL)相互作用是保持免疫自身稳定所需要的。实验性自身免疫性甲状腺炎(EAT),其特征为自身反应性T和B细胞应答和甲状腺的显著淋巴细胞浸润,是研究FasL治疗效应的良好模型。Batteux,F.,et al.,(J.Immunol.162:603-608(1999))报道,通过向发炎的甲状腺中直接注射编码FasL的DNA表达载体,甲状腺淋巴细胞浸润被抑制,且观察到诱导浸润性T细胞死亡。这些结果表明,通过诱导病理性自身反应性浸润性T细胞死亡,甲状腺细胞上FasL表达可对进行性EAT具有治疗作用。
已知双吲哚基马来酰亚胺VIII加强人星形细胞瘤1321N1细胞中和Molt-4T细胞中Fas-介导的细胞凋亡;缺乏双吲哚基马来酰亚胺VIII时,这两种细胞抵抗以抗-Fas抗体介导的细胞凋亡。已报道,用双吲哚基马来酰亚胺VIII加强Fas-介导的细胞凋亡是对活化的而不是对未活化的T细胞有选择性,且是Fas-依赖的。Zhou T.,et al.,(Nat.Med.5:42-48(1999))报道,在Lewis鼠实验性变应性脑炎和Lewis佐剂性关节炎两个模型中,在自身抗原刺激期间,向鼠给予双吲哚基马来酰亚胺VIII防止了T细胞介导的自身免疫病症状的发展。因而,应用Fas依赖的细胞凋亡的增强剂,例如双吲哚基马来酰亚胺VIII,可用治于更有效消除有害细胞和抑制T细胞介导的自身免疫病。因而,有效量的功能为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂的式I-IX化合物或其可药用盐或前药,是对自身免疫病的有效治疗。
牛皮癣是一种特征为鳞状红斑的慢性皮肤病。补骨脂内酯加紫外线A(PUVA)是广泛使用的治疗寻常牛皮癣的有效手段,并且Coven等人在Photodermatol.Photoimmunol.Photomed.15:22-27(1999)中报道,用补骨脂内酯8-MOP或TMP加UVA治疗的淋巴细胞表现出具有细胞凋亡特征的DNA降解模式。Ozawa等人在J.Exp.Med.189:711-718(1999)中报道,诱导T细胞凋亡可能是312-nm UVB消除牛皮癣皮肤损伤的主要机制。低剂量的甲氨蝶呤可用于治疗牛皮癣以恢复临床上正常的皮肤。Heenen等人在Arch.Dermatol.Res.290:240-245(1998)中报道,低剂量的甲氨蝶呤可诱导细胞凋亡,并且该作用方式可解释用甲氨蝶呤治疗牛皮癣期间表皮增生减轻的原因。因此,有效量的起半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂作用的式I-IX化合物或其可药用盐或前药可有效地治疗高增殖性皮肤疾病例如牛皮癣。
滑液细胞增生是类风湿性关节炎(RA)患者的特征。据信RA滑液细胞的过度增殖以及滑液细胞死亡的缺乏可能是滑液细胞增生的原因。Wakisaka等人,Clin.Exp.Immunol.114:119-128(1998),发现虽然RA滑液细胞可通过经由Fas/FasL途径的细胞凋亡来死亡,但是存在于滑膜内的促炎性细胞因子抑制了滑液细胞的凋亡。Wakisaka等人还提出,在RA患者中,促炎性细胞因子的细胞凋亡抑制作用可导致滑液细胞过度生长,并且导致血管翳形成和关节破坏。因此,有效量的起半胱氨酰天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导剂作用的式I-IX化合物或其可药用盐或前药可有效地治疗类风湿性关节炎。
已经有令人信服的证据表明细胞凋亡在促进急性炎性反应的消除中起主要作用。中性白细胞在组成上程序化地经历细胞凋亡,由此限制了其促炎性可能和导致被巨噬细胞与半专门吞噬细胞迅速、特异性和非炎性识别(Savill,J.,J.Leukoc.Biol.61:375-380(1997))。Boirivant等人在Gastroenterology 116:557-565(1999)中报道了从局限性回肠炎、溃疡性结肠炎和其它炎性病症中的发炎区域内分离出的lamina propria T细胞,表现出CD2途径诱导的细胞凋亡下降。另外,对从发炎的局限性回肠炎组织中分离出的细胞进行的研究表明,这种缺陷伴随Bcl-2水平增高。因此,有效量的起半胱氨酰天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导剂作用的式I-IX化合物或其可药用盐或前药可有效地治疗炎症。
在本发明范围内的药物组合物包括其中本发明化合物以有效地实现其预期目的的量包含在内的所有组合物。虽然个体需要不同,但是每一组分的有效量的最理想范围的确定在本领域技术人员的能力范围内。一般可将本发明化合物对动物例如哺乳动物给药,口服剂量为每天0.0025-50mg/kg因凋亡诱导的病症而治疗的哺乳动物体重的化合物或等价量其可药用盐。优选口服施用约0.01-约10mg/kg体重来治疗或预防这样的病症。对于肌内注射,该剂量一般为口服剂量的大约一半。例如,合适的肌内剂量是约0.0025-约25mg/kg体重,最优选为约0.01-约5mg/kg体重。如果已经施用了已知的癌症化疗剂,则以能有效地实现其预期目的的量进行给药。有效地治疗癌症的这样的已知癌症化疗剂的量是本领域技术众所周知的。
单位口服剂量可由约0.01-约50mg,优选约0.1-约10mg本发明化合物组成。单位剂量可作为一个或多个片剂每天给药一次或多次,其中每个片剂含有约0.1-约10mg,适宜地约0.25-50mg本发明化合物或其溶剂化物。
在局部给药用制剂中,本发明化合物可以以约0.01-100mg/g载体的浓度存在。
本发明化合物除了作为未加工化学药品给药以外,还可以作为含有合适的可药用载体的药物制剂的一部分给药,所述可药用载体包括有助于将化合物加工成可药用制剂的赋形剂和辅助剂。优选地,制剂,特别是可口服给药的制剂,和可用于优选给药剂型例如片剂、糖锭剂和胶囊的制剂,以及可直肠给药的制剂例如栓剂,和用于注射或口服给药的适当溶液剂含有约0.01-99%,优选约0.25-75%的活性化合物和赋形剂。
本发明化合物的无毒可药用盐也在本发明范围内。酸加成盐可通过将特定的本发明细胞凋亡诱导剂的溶液与可药用无毒酸的溶液混和来形成,所述无毒酸例如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等。碱加成盐是通过将特定的本发明细胞凋亡诱导剂的溶液与可药用无毒碱的溶液混和而形成的,所述无毒碱例如氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、Tris、N-甲基-葡糖胺等。
可将本发明药物组合物施用给其中能表现出本发明化合物有益作用的任何动物。在这样的动物当中,最重要的是哺乳动物,例如人和兽医动物,但是本发明不限于此。
本发明的药物组合物可通过能实现其预期目的的任意途径给药。例如,可通过非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径进行给药。另外或并行地,可通过口服途径给药。给药剂量取决于受治疗者的年龄、健康状况和体重,如果有的话并行治疗的类型,治疗频率以及所需效果的性质。
本发明药物制剂可通过自身已知的方式,例如常规混和、制粒、糖锭剂制备、溶解或冷冻干燥方法制得。因此,口服使用的药物制剂可这样制得:将活性化合物与固体赋形剂混和,任选将所得混合物磨碎,如果需要或必需的话,加入合适的辅助剂后,将颗粒混合物加工以获得片剂或糖锭剂核芯。
合适的赋形剂特别是填充剂,例如糖类如乳糖或蔗糖、甘露醇或山梨醇;纤维素制备物和/或磷酸钙例如磷酸三钙或磷酸氢钙;以及粘合剂例如使用如玉米淀粉、小麦淀粉、大米淀粉、土豆淀粉的淀粉糊,明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要的话,可加入崩解剂例如上述淀粉以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐如藻酸钠。辅助剂特别是流动调节剂和润滑剂,例如二氧化硅、滑石粉、硬脂酸或其盐例如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。可给糖锭剂核芯提供合适的包衣,如果需要的话,这样的包衣是抗胃液的。对于此,可使用浓的糖溶液,其中可任选含有阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和适当的有机溶剂或溶剂混合物。为了制备抗胃液的包衣,使用合适的纤维素制备物例如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素。可向片剂或糖锭剂包衣中加入染料或色素,例如,以鉴别活性化合物剂量或表明结合活性化合物剂量的特征。
可口服使用的其它药物制剂包括用明胶制成的推入配合型胶囊,以及用明胶和增塑剂例如甘油或山梨醇制成的软的密封胶囊。该推入配合型胶囊可含有颗粒形式的活性化合物,活性化合物颗粒可以与填充剂例如乳糖;粘合剂例如淀粉;和/或润滑剂例如滑石粉或硬脂酸镁,和任选地稳定剂混和。在软胶囊中,优选将活性化合物溶解或悬浮在合适的液体例如脂肪油或液体石蜡中。此外,可加入稳定剂。
可直肠使用的可能药物制剂包括例如由一种或多种活性化合物与栓剂基质组成的栓剂。合适的栓剂基质是例如天然或合成甘油三酯或石蜡烃。此外,还能够使用由活性化合物与基质的混合物组成的直肠用明胶胶囊。可能的基质材料包括例如液体甘油三酯、聚乙二醇或石蜡烃。
合适的非胃肠道给药用制剂包括水溶形式例如水溶性盐形式的活性化合物的水溶液和碱性溶液。此外,可以施用作为适当油注射悬浮液的活性化合物的悬浮液。合适的亲脂性溶剂或载体包括脂肪油例如芝麻油或合成的脂肪酸酯例如油酸乙酯或甘油三酯或聚乙二醇-400(活性化合物溶于PEG-400中)或聚乙二醇化合物(cremophor)或环糊精。水注射悬浮液可含能提高悬浮液粘度的物质,包括例如羧甲基纤维素钠、山梨醇和/或葡聚糖。任选地,悬浮液还可含有稳定剂。
依据本发明的一个方面,本发明化合物在局部且非胃肠道给药用制剂中使用,并且可用于治疗皮肤癌。
本发明局部给药用组合物优选通过选择合适的载体来配制成油性制剂、霜剂、洗剂、软膏剂等。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量醇(大于C12)。优选的载体是活性组分溶于其中的载体。还可以包含软化剂、稳定剂、湿润剂和抗氧化剂,以及如果需要的话着色剂或香料。此外,在这些局部给药用制剂中可使用经皮渗透增强剂。这样的增强剂的合适的实例可见于U.S.专利Nos.3,989,816和4,444,762。
霜剂优选用矿物油、自乳化蜂蜡和水的混合物配制,将溶解在少量油例如杏仁油中的活性成分混和在该混合物中。这样的霜剂的典型实例是包括约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的霜剂。
软膏剂可通过将在植物油例如杏仁油中的活性成分的溶液与温热的软石蜡混和,且让该混合物冷却来配制。这样的软膏剂的典型实例是含约30%重量的杏仁油和约70%重量的白软石蜡的软膏剂。
下列实施例是举例说明,但不是限制本发明的方法和组合物。对于本领域技术人员来说是显而易见的和在临床治疗中通常会遇见的各种病症和参数的其它适当改变和改进在本发明实质和范围内。
实施例1
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
方法A
将3-氯-噻吩-2-羰基氯化物(720mg,4mmol)和4-氯苄胺肟(680mg,4mmol)在1,4-二噁烷(40mL)中的溶液回流1小时,然后逐滴加入BF3OEt2。将该溶液回流5小时并在真空中蒸发,通过柱色谱法(硅胶;乙酸乙酯∶己烷,1∶20)纯化残余物,获得850mg(72%)标题化合物。
1H NMR(CDCl3):8.10(d,J=8.4Hz,2H),7.61(d,J=5.1Hz,1H),7.49(d,J=8.4Hz,2H),7.14(d,J=5.1Hz,1H).
方法B
将3-氯-噻吩-2-羰基氯化物(1.45g,8mmol)和4-氯苄胺肟(1.37g,8mmol)在二噁烷/吡啶(110mL,10∶1)中的溶液回流12小时并冷却至室温。向搅拌的该溶液中加入水(200mL)以产生沉淀物。过滤收集固体并用水(4×20mL)洗涤,干燥获得2.36g无色样品,该样品通过柱色谱法(硅胶;乙酸乙酯∶己烷,1∶10)进一步纯化,获得2.01g(85%)标题化合物。
1H NMR(CDCl3):8.10(d,J=8.4Hz,2H),7.61(d,J=5.1Hz,1H),7.49(d,J=8.4Hz,2H),7.13(d,J=5.1Hz,1H).
实施例2
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑
以类似于实施例1方法A的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(36mg,0.2mmol)和4-甲苯偕胺肟(toluamidoxime)(30mg,0.2mmol)中得到18mg(33%)标题化合物。
1H NMR(CDCl3):8.04(d,J=8.1Hz,2H),7.59(d,J=5.1Hz,1H),7.30(d,J=8.0Hz,2H),7.12(d,J=5.1Hz,1H),2.42(s,3H).
实施例3
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑
以类似于实施例1方法A的方法制备标题化合物。从噻吩-2-羰基氯化物(48.67mg,0.33mmol)和4-甲苯甲酰胺肟(50mg,0.33mmol)中得到42mg(53%)标题化合物。
1H NMR(CDCl3):8.04(d,J=8.4Hz,2H),7.95(d,J=3.6Hz,1H),7.66(d,J=5.1Hz,1H),7.31(d,J=8.7Hz,2H),7.22(m,1H),2.43(s,3H).
实施例4
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑
将3-氯-噻吩-2-羰基氯化物(455mg,2.51mmol)和4-三氟甲基-苄胺肟(513mg,2.51mmol)在1,4-二噁烷(50mL)中的溶液回流1小时,然后逐滴加入BF3OEt2。将该溶液回流5小时并冷却至室温。向搅拌的该溶液中加入水(100mL)以产生沉淀物。过滤收集固体并用二噁烷∶水(1∶1)洗涤,干燥获得687mg(82%)标题化合物。
1H NMR(CDCl3):8.29(d,J=8.1Hz,2H),7.78(d,J=8.4Hz,2H),7.63(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,1H)
实施例5
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑
以类似于实施例4的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(181mg,1mmol)和4-氟苄胺肟(154mg,1mmol)中得到280mg(99%)标题化合物。
1H NMR(CDCl3):8.29(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.63(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,1H).
实施例6
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑
以类似于实施例4的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(181mg,1mmol)和4-硝基苄胺肟(181mg,1mmol)中得到230mg(75%)标题化合物。
1H NMR(CDCl3):8.37(s,4H),7.65(d,J=5.1Hz,1H),7.16(d,J=5.1Hz,1H).
实施例7
5-(3-氯-噻吩-2-基)-3-(2,4-二氯-苯基)-[1,2,4]-噁二唑
以类似于实施例4的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(181mg,1mmol)和2,4-二氯-苄胺肟(205mg,1mmol)中得到208mg(63%)标题化合物。
1H NMR(CDCl3):8.06(m,2H),7.64(d,J=5.4Hz,1H),7.52(t,J=1.8Hz,1H),7.15(d,J=5.1Hz,1H).
实施例8
5-(3-氯-噻吩-2-基)-3-(4-(甲基磺酰氨基)苯基)-[1,2,4]-噁二唑
以类似于实施例4的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(19.9mg,0.11mmol)和4-(甲基-磺酰氨基)苄胺肟(22.9mg,0.11mmol)中得到14mg(43%)标题化合物。
1H NMR(DMSO-d6):10.28(s,1H),8.19(d,J=5.4Hz,1H),8.03(d,J=9.0Hz,2H),7.43-7.38(m,3H),3.11(s,3H).
实施例9
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑
以类似于实施例4的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(90mg,0.5mmol)和苄胺肟(68mg,0.5mmol)中得到30mg(23%)标题化合物。
1H NMR(CDCl3):8.18-8.15(m,2H),7.60(d,J=5.4Hz,1H),7.54-7.48(m,3H),7.13(d,J=5.1Hz,1H).
实施例10
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基苯基)-[1,2,4]-噁二唑
将3-氯-噻吩-2-羰基氯化物(72.4mg,0.4mmol)和4-三氟甲氧基苄胺肟(88mg,0.4mmol)在二噁烷/吡啶(11mL,10∶1)中的溶液回流10小时并冷却至室温。向搅拌的该溶液中加入20mL水以产生沉淀物。过滤收集固体并用二噁烷∶水(1∶3)洗涤,干燥获得103mg(75%)标题化合物。
1H NMR(CDCl3):8.20(d,J=9.0Hz,2H),7.62(d,J=5.4Hz,1H),7.35(bd,J=9.3Hz,2H),7.14(d,J=5.1Hz,1H).
实施例11
5-(3-氯-噻吩-2-基)-3-(4-甲氧基苯基)-[1,2,4]-噁二唑
以类似于实施例10的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(72.4mg,0.4mmol)和4-甲氧基苄胺肟(66.5mg,0.4mmol)中得到88mg(76%)标题化合物。
1H NMR(CDCl3):8.10(d,J=9.0Hz,2H),7.59(d,J=5.1Hz,1H),7.12(d,J=5.1Hz,1H),7.01(d,J=9.0Hz,2H),3.89(s,3H).
实施例12
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基苯基)-[1,2,4]-噁二唑
以类似于实施例10的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(72.4mg,0.4mmol)和3,4-亚甲二氧基苄胺肟(72mg,0.4mmol)中得到100mg(82%)标题化合物。
1H NMR(CDCl3):7.73(dd,J=8.1,1.8Hz,1H),7.60(s,1H),7.59(d,J=5.4Hz,1H),7.13(d,J=5.4Hz,1H),6.92(d,J=7.8Hz,1H),6.06(s,2H).
实施例13
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
以类似于实施例10的方法制备标题化合物。从3-溴-噻吩-2-羰基氯化物(67.7mg,0.3mmol)和4-氯苄胺肟(51mg,0.3mmol)中得到101mg(98%)标题化合物。
1H NMR(CDCl3):8.11(d,J=8.7Hz,2H),7.60(d,J=5.4Hz,1H),7.49(d,J=8.4Hz,2H),7.20(d,J=5.1Hz,1H).
实施例14
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑
将3-氯-噻吩-2-羰基氯化物(72mg,0.40mmol)和4-吡啶基偕胺肟(4-pyridinylamidoxime)(55mg,0.40mmol)在1,4二噁烷(9mL)和吡啶(1mL)中的溶液回流3.5小时。将该溶液冷却至室温,通过加入20mL水使产物沉淀。过滤沉淀物并用冷水洗涤,然后干燥获得31mg(29%)标题化合物。
1H NMR(CDCl3):8.81(d,J=6.05Hz,2H),8.03(dd,J=4.40,1.65Hz,2H),7.64(d,J=5.22Hz,1H),7.15(d,J=5.22Hz,1H).
实施例15
5-(3-氯-噻吩-2-基)-3-(4-二甲基氨基-苯基)-[1,2,4]-噁二唑
以类似于实施例14的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)和4-二甲基氨基-苄胺肟(55mg,0.31mmol)中得到13mg(14%)标题化合物。
1H NMR(CDCl3):8.01(m,2H),7.56(d,J=5.22Hz,1H),7.10(d,J=5.49Hz,1H),6.76(m,2H),3.04(s,2H).
实施例16
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑
将3-氯-噻吩-2-羰基氯化物(79mg,0.44mmol)、3-吡啶基偕胺肟(60mg,0.44mmol)和吡啶(1mL)的溶液回流5小时。将该溶液冷却至室温并通过4mL水稀释以产生白色沉淀。过滤沉淀物并用水洗涤,然后干燥获得68mg(59%)标题化合物。
1H NMR(CDCl3):9.39(dd,J=2.20,0.83Hz,1H),8.78(dd,J=4.95,1.65Hz,1H),8.43(dt,J=7.97,1.92Hz,1H),7.64(d,J=5.22Hz,1H),7.46(ddd,J=7.97,4.81,0.97Hz,1H),7.15(d,J=5.22Hz,1H).
实施例17
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑
以类似于实施例16的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(54mg,0.30mmol)和2-吡啶基偕胺肟(41mg,0.30mmol)中得到45mg(57%)标题化合物。
1H NMR(CDCl3):8.84(d,J=4.12Hz,1H),8.22(d,J=7.97Hz,1H),7.88(td,J=7.76,1.74Hz,1H),7.62(d,J=5.22Hz,1H),7.46(ddd,J=7.62,4.74,1.17Hz,1H),7.14(d,J=5.22Hz,1H).
实施例18
5-(3-氯-噻吩-2-基)-3-(4-羟基-苯基)-[1,2,4]-噁二唑
以类似于实施例16的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(37mg,0.20mmol)和4-羟基-苯基偕胺肟(31mg,0.20mmol)中得到16mg(28%)标题化合物。
1H NMR(CDCl3):9.12(sb,1H),8.05(d,J=5.49Hz,1H),8.00(m,2H),7.32(d,J=5.22Hz,1H),8.22(m,2H).
实施例19
5-(3-氯-噻吩-2-基)-3-(N-氧代-吡啶-4-基)-[1,2,4]-噁二唑
以类似于实施例16的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(73mg,0.40mmol)和N-氧代-4-吡啶基偕胺肟(62mg,0.41mmol)中得到54mg(48%)标题化合物。
1H NMR(60∶40,CD3OD:DMSO-d6):9.16(d,J=7.14Hz,2H),8.83(d,J=7.14Hz,2H),8.81(d,J=5.22Hz,1H),8.07(d,J=5.49Hz,1H).
实施例20
3-(4-氯-苯基)-5-(3-甲基-呋喃-2-基)
将3-甲基-呋喃-2-羧酸(252mg,2mmol)、亚硫酰氯化物(0.5mL)在苯(5mL)中的溶液在60℃搅拌8小时并蒸发至干。将残余物溶解在吡啶(10mL)中,并向溶液中加入4-氯-苄胺肟(340mg,2mmol)。将该溶液回流10小时,然后冷却至室温。将该溶液用水(20mL)稀释以生成沉淀。通过过滤收集固体并用水洗涤,然后干燥获得201mg(39%标题化合物。)
1H NMR(CDCl3):8.12(d,J=8.4Hz,2H),7.62(d,J=1.5Hz,1H),7.48(d,J=8.4Hz,2H),6.50(d,J=1.5Hz,1H).
实施例21
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-甲基-呋喃-2-羧酸(126mg,1mmol)和5-三氟甲基-吡啶-2-偕胺肟(205mg,1mmol)中得到118mg(40%)标题化合物。
1H NMR(CDCl3):9.07(s,1H),8.35(d,J=8.4Hz,1H),8.13(m,1H),7.63(d,J=1.5Hz,1H),6.53(d,J=1.5Hz,1H),2.56(s,3H).
实施例22
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-甲基-2-噻吩羧酸(28.42mg,0.2mmol)和4-氯-苄胺肟(34.1mg,0.2mmol)中得到28mg(51%)标题化合物。
1H NMR(CDCl3):8.10(d,J=8.7Hz,2H),7.52(d,J=4.8Hz,1H),7.48(d,J=8.7Hz,2H),7.03(d,J=4.8Hz,1H),2.71(s,3H).
实施例23
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-溴-呋喃-2-羧酸(74mg,1mmol)和4-氯-苄胺肟(72.7mg,0.43mmol)中得到28mg(22%)标题化合物。
1H NMR(CDCl3):8.11(d,J=9.0Hz,1H),7.67(d,J=2.1Hz,1H),7.42(d,J=9.0Hz,2H),6.75(d,J=1.8Hz,1H).
实施例24
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-溴-呋喃-2-羧酸(38mg,0.2mmol)和4-三氟-甲基苄胺肟(41mg,0.2mmol)中得到11mg(15%)标题化合物。
1H NMR(CDCl3):8.33(d,J=8.7Hz,1H),7.79(d,J=8.7Hz,1H),7.68(d,J=2.1Hz,1H),6.76(d,J=2.1Hz,1H).
实施例25
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑
以类似于实施例16的方法制备标题化合物。从3-氯-噻吩-2-羰基氯化物(49.2mg,0.27mmol)和2-(4-氯-苯基)-N-羟基乙脒(50mg,0.27mmol)中得到28mg(33%)标题化合物。
1H NMR(CDCl3):7.57(d,J=5.1Hz,1H),7.31(s,2H),7.26(s,2H),7.09(d,J=5.1Hz,1H),4.11(s,2H).
实施例26
5-(4-氯-1H-吡唑-3-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从4-氯-1H-吡唑-3-羧酸(34mg,0.26mmol)和4-氯-苄胺肟(45mg,26mmol)中得到11mg(16%)标题化合物。
1H NMR(CD3OD):8.15(d,J=9.0Hz,2H),8.01(brs,1H),7.59(d,J=8.7Hz,2H).
实施例27
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从4-氯-1H-吡唑-3-羧酸(15mg,0.12mmol)和5-三氟-甲基-吡啶-2-偕胺肟(23mg,0.12mmol)中得到3mg(9%)标题化合物。
1H NMR(Acetone-d6):9.15(s,1H),8.46(s,2H),8.24(s,1H).
实施例28
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-氯-呋喃-2-羧酸(116.8mg,0.8mmol)和4-氯-苄胺肟(136mg,0.8mmol)中得到101mg(45%)标题化合物。
1H NMR(CDCl3):8.12(d,J=8.4Hz,2H),7.68(d,J=1.8Hz,1H),7.49(d,J=8.4Hz,2H),6.69(d,J=1.8Hz,1H).
实施例29
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
以类似于实施例20的方法制备标题化合物。从3-氯-呋喃-2-羧酸(14.6mg,0.1mmol)和5-三氟甲基-吡啶-2-偕胺肟(20.5mg,0.1mmol)中得到5.7mg(18%)标题化合物。
1H NMR(CDCl3):9.08(s,1H),8.37(d,J=8.1Hz,1H),8.15(dd,J=8.1Hz,2.4Hz,1H),7.70(d,J=2.1Hz,1H),6.72(d,J=2.1Hz,1H).
实施例30
(4-氯-苯亚甲基)-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-
胺
a)N-氰基-3-氯-噻吩-2-羧酸酰胺:向氨腈(302.4mg,7.2mmol)的10%氢氧化钠水溶液(3mL)中加入在二乙醚(3mL)中的3-氯-噻吩-2-羰基氯化物(1.09g,6mmol)。将其搅拌1小时并用1N HCl酸化以得到沉淀,通过过滤收集沉淀,然后用水洗涤得到807mg(75%)标题化合物。
b)5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基胺:将N-氰基-3-氯-噻吩-2-羧酸酰胺(467.5mg,2.5mmol)、羟基胺基氢氯化物(174mg,2.5mmol)在吡啶(5mL)中的溶液在100℃加热8小时。将该溶液冷却并倒在水(80mL)中,用乙酸乙酯(3×20mL)提取混合物。用水洗涤合并的有机层,1N HCl,用Na2SO4干燥,并浓缩。通过柱色谱法(己烷∶乙酸乙酯,10∶1)纯化未加工的残余物,获得189mg(37%)标题化合物。 1HNMR(CDCl3):7.56(d,J=5.4Hz,1H),7.09(d,J=5.4Hz,1H),4.49(brs,2H).
c)(4-氯-苯亚甲基)-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-胺:将5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基胺(15mg,0.075mmol)、4-氯苯甲醛(12.6mg,0.09mmol)、乙酸(3滴)在甲苯(1.4mL)中的溶液回流16小时。将其蒸发,并通过柱色谱法(己烷∶乙酸乙酯,30∶1)纯化残余物,获得4mg(17%)标题化合物。
1H NMR(CDCl3):9.40(s,1H),8.10(m,2H),7.62(d,J=5.1Hz,1H),7.52(m,2H),7.18(d,J=5.1Hz,1H).
实施例31
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-(3-三氟甲基-苯亚甲基)-胺
以类似于实施例30c的方法制备标题化合物。从5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基胺(15mg,0.075mmol)、3-三氟甲基苯甲醛(15.7mg,0.09mmol)中得到4mg(15%)标题化合物。
1H NMR(CDCl3):9.33(s,1H),8.36(s,1H),8.25(d,J=7.5Hz,1H),7.84(d,J=7.5Hz,1H),7.7.70-7.62(m,2H),7.14(d,J=5.1Hz,1H).
实施例32
3-(4-氨基苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
将5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑和Pd/C(30mg)在乙醇(30mL)中的混合物在氢气下(46psi)振荡6小时。过滤后,浓缩过滤物,并应用小柱色谱法(己烷∶乙酸乙酯,5∶1)获得18mg(25%)标题化合物。
1H NMR(CDCl3):7.98(d,J=8.7Hz,2H),7.60(d,J=5.1Hz,1H),7.14(d,J=5.1Hz,2H),6.78(d,J=8.7Hz,1H).
实施例33
3-(4-叠氮基苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
向3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑(15.5mg,0.05mmol)在乙酸(2mL)和浓硫酸(0.3mL)中的混合物加入在水(0.5mL)中的亚硝酸钠(3.8mg,0.055mmol)。将混合物在0-5℃剧烈搅拌20分钟,然后加入在水(0.5mL)中的叠氮化钠(3.6mg,0.055mmol)。将其在0-5℃搅拌3小时,然后倒入冰水(30mL)中。用乙酸乙酯(3×10mL)提取产物混合物。将有机层用水洗涤,无水硫酸钠上干燥,蒸发。未加工的残余物经闪式谱法纯化获得16mg(100%)标题化合物。
1H NMR(CDCl3):8.18(d,J=8.7Hz,2H),7.63(d,J=5.4Hz,1H),7.18(d,J=8.7Hz,1H),7.16(d,J=5.4Hz,2H).
实施例34
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑
a)N-(3-氯-噻吩-2-羰基)-N’-(4-三氟甲基苯甲酰基)-肼:将3-氯-2-噻吩羧酸肼(70.4mg,0.4mmol)、4-三氟甲基苯甲酰基氯化物(83.6mg,0.4mmol)在吡啶(5mL)中的溶液回流4小时,然后冷却。该溶液用水稀释,通过过滤收集沉淀,然后干燥获得129mg(93%)标题化合物。
b)5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑:将N-(3-氯-噻吩-2-羰基)-N’-(4-三氟甲基苯甲酰基)-肼(75mg,0.22mmol)在亚硫酰(二)氯(8mL)中的溶液回流6小时。将其蒸发至干,柱色谱法后获得58mg(81%)标题化合物。1H NMR(CDCl3):8.26(d,J=8.1Hz,2H),7.80(d,J=8.1Hz,2H),7.56(d,J=5.4Hz,1H),7.11(d,J=5.4Hz,1H).
实施例35
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
a)2,4-二氯-噻唑-5-甲基醛(carbaldehyde):在氩气下冰浴中向四氢噻唑-2,4-二酮(1.98g,16.9mmol)和三氯氧化磷(10.0mL,107mmol)的搅拌溶液中加入超过2分钟N,N-二甲基甲酰胺(1.44mL,18.6mmol)。去除冰浴并在室温搅拌该溶液1小时。将该溶液回流4小时,冷却并倒在160mL碎冰上。用二氯甲烷(4×50mL)提取该溶液,蒸发提取物。通过柱色谱法(二氯甲烷)纯化残余物获得781mg(25%)淡绿色固体。
1H NMR(CDCl3):9.97(s,1H).
b)4-氯-5-[1,3]二氧戊环-2-基-噻唑:将2,4-二氯-噻唑-5-甲基醛(747mg,4.10mmol)、乙二醇(680μL,12.2mmol)、对甲苯亚磺酸一水合物(1.1mg,5.04μmol)和甲苯(15.0mL)的搅拌溶液在氩气下回流5小时。将该溶液冷却至室温并用乙醚(10mL)稀释。用饱和碳酸氢钠水溶液(20mL)、去离子水(20mL)和盐水(20mL)洗涤该溶液。将乙醚层在硫酸钠上干燥、倾析并在50℃浓缩。通过柱色谱法(二氯甲烷)纯化产物获得787mg(85%)无色油状标题化合物。
1H NMR(CDCl3):6.04(s,1H),4.11(m,2H),4.03(m,2H).
c)4-氯-噻唑-5-甲基醛:在冰浴中向4-氯-5-[1,3]二氧戊环-2-基-噻唑(787.2mg,4.32mmol)和四氢呋喃(20.0mL)的搅拌溶液中逐滴加入1.6M正丁基锂己烷(2.7mL,4.32mmol)溶液。将该溶液搅拌1小时,平衡至室温,倒入10%盐酸水溶液(50mL)中。用乙醚(100mL)提取该溶液。向提取物加入10%盐酸水溶液,将生成溶液搅拌6小时。将乙醚层用盐水洗涤,用硫酸钠干燥,倾析并浓缩。通过柱色谱法(二氯甲烷)纯化产物获得245mg(38%)近于纯白的固态标题化合物。
1H NMR(CDCl3):10.11(s,1H),9.01(s,1H).
d)4-氯-噻唑-5-羧酸:将300mL chomium(IV)氧化物(149mg,1.49mmol)去离子水溶液逐滴加入在冰浴中(1.0mL)的4-氯-噻唑-5-甲基醛(205mg,1.37mmol)搅拌溶液中,其后加入硫酸(8滴)。去除冰浴,室温下搅拌该溶液30分钟。向该溶液中加入乙酸乙酯(30mL),用去离子水(4×10mL)和盐水(2×10mL)该溶液。用10%饱和碳酸氢钠溶液(2×20mL)提取乙酸乙酯层。将水提取物用10%盐酸水溶液酸化至pH3,并以1∶1二氯甲烷∶乙酸乙酯溶液(5×15mL)和乙酸乙酯(20mL)提取。将有机提取物在硫酸钠上干燥,倾析并浓缩,获得170mg(75%)白色固态标题化合物。
1H NMR(Acetone-d6):9.20(s,1H).
e)5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑:在氩气下冰浴中向在二氯甲烷(85mL)和二甲基甲酰胺(120μL)中的4-氯-噻唑-5-羧酸(107mg,0.655mmol)的搅拌悬浮液中逐滴加入草酰氯(450μL,0.90mmol)。去除冰浴,将该溶液搅拌3小时,并浓缩溶剂。向残余物中加入5-氯-吡啶-2-偕胺肟(113mg,0.656mmol)和吡啶(5mL),且在氩气下将该溶液回流2小时。将该溶液冷却至室温,用去离子水(25mL)稀释以产生沉淀。过滤沉淀物,并以去离子水(4×5mL)洗涤,在真空中干燥。通过柱色谱法(9∶1,二氯甲烷∶乙酸乙酯)纯化产物后,从乙酸乙酯和己烷中重结晶,获得96.1mg(49%)白色固态标题化合物。 1HNMR(CDCl3):9.00(s,1H),8.82(d,J=2.47Hz,1H),8.21(d,J=7.97Hz,1H),7.95(dd,J=8.52,2.48Hz,1H).
实施例36
5-(3-氯噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
a)5-氯-2-碘-吡啶:在氩气下向2,5-二氯-吡啶(12.2g,82.2mmol)、碘化钠(37.0g,247mmol)和乙腈(170mL)的回流溶液中加入乙酰氯(9.0mL,127mmol),且将该溶液回流5小时。向该溶液中加入过量的碘化钠(24.9g,166mmol),且将该溶液回流16小时。加入过量的碘化钠(12.5g,83.6mmol),且将该溶液回流4.5小时。将溶液冷却至室温,并在10%硫代硫酸钠/10%碳酸钠(300mL)和乙醚(400mL)两者之间分配。用盐水(100mL)洗涤乙醚层,并在无水硫酸钠上干燥。将该溶液倾析,真空干燥,获得16.8g(85%)棕色固态标题化合物。
1H NMR(CDCl3):8.36(d,J=2.75Hz,1H),7.66(d,J=8.79Hz,1H),7.32(dd,J=8.38,2.61Hz,1H).
当通过NMR测定时,在产物中有5mol%其始物质2,5-二氯-吡啶。
b)5-氯-2-氰基-吡啶:在氩气下将5-氯-2-碘-吡啶(16.6g,69.5mmol)、氰化亚铜(8.15g,91.0mmol)和吡啶(120mL)的搅拌溶液回流1.5小时。将该溶液冷却至室温,并倒在氰化钾水溶液(56g/L,500mL)中。用二氯甲烷(4×200mL)提取该溶液。将有机层政治无水硫酸钠上干燥,倾析,并在50℃浓缩。用柱(二氯甲烷)纯化产物,获得6.8g(70%)白色固态标题化合物。
1H NMR(CDCl3):8.69(dd,J=2.47,0.55Hz,1H),7.84(dd,J=8.38,2.34Hz,1H),7.87(dd,J=8.38,0.69Hz,1H).
c)5-氯-吡啶-2-偕胺肟:将5-氯-2-氰基-吡啶(6.751g,48.7mmol)和50%重量含水的羟胺(3.5mL,57mmol)的溶液、乙醇(10mL)和四氢呋喃(50mL)室温搅拌20分钟。并浓缩该溶液。将产物悬浮于己烷(50mL)中并回流5分钟,冷却至室温,过滤获得7.9g(94%)白色固态标题化合物。
1H NMR(DMSO-d6):10.05(s,1H),8.62(dd,J=2.34,0.69Hz,1H),7.94(dd,J=8.66,2.34Hz,1H),7.86(dd,J=8.66,0.69Hz,1H),5.86(s,2H).
d)5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑:以类似于实施例17的方法制备标题化合物。从5-氯-吡啶-2-偕胺肟(3.44g,20.0mmol)和3-氯-噻吩-2-羰基氯化物(3.62g,20.0mmol)中得到5.06g(85%)白色固态标题化合物。
1H NMR(CDCl3):8.78(dd,J=2.47,0.83Hz,1H),8.18(dd,J=8.38,0.69Hz,1H),7.86(dd,J=8.51,2.47Hz,1H),7.64(d,J=5.22Hz,1H),7.14(d,J=5.22Hz,1H).
实施例37
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉
向4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-酚(50mg,0.179mmol)和碳酸钾(25mg,0.179mmol)在无水乙醇(1mL)中的混合物中加入4-(2-氯乙基)吗啉(66.7mg,0.358mmol)。将反应混合物回流1小时,然后冷却至室温以形成沉淀。过滤沉淀物,获得33.3mg(47.3%)褐色固态标题化合物。
1H NMR(DMSO-d6):8.18(d,J=5.7Hz,1H),7.98(d,J=8.7Hz,2H),7.41(d,J=7.41Hz,1H),7.15(d,J=8.7Hz,2H),4.35(m,2H),4.18(m,2H),3.58(m,3H),3.43(m,3H),2.72(m,2H).
实施例38
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲基-胺
通过类似于实施例37的步骤从4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-酚和2-(二甲基氨基)乙基bormide中制备标题化合物。
1H NMR(DMSO-d6):8.18(d,J=5.4Hz,1H),7.98(d,J=9.0Hz,2H),7.41(d,J=5.4Hz,1H),7.15(d,J=8.7Hz,2H),4.14(t,2H),2.61(m,2H),2.48(m,6H).
实施例39
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯
通过类似于实施例37的步骤从4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-酚和溴乙酸甲酯中制备白色固态标题化合物(30.3mg,52.0%)。1H NMR(DMSO-d6):8.18(d,J=5.1Hz,1H),8.00(d,J=8.7Hz,2H),7.42(d,J=5.1Hz,1H),7.15(d,J=9.0Hz,2H),4.90(s,2H),1.2(m,3H).
实施例40
5-(3,4,5-三氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑
如实施例16中的方法从3,4,5-三氯-噻吩-2-羰基氯化物(0.150g,0.600mmol)和4-三氟-甲基-苄胺肟(0.122g,0.600mmol)中制备白色固态标题化合物(0.208g,87%)。
1H NMR(DMSO-d6):8.7(d,J=8.7Hz,2H),7.99(d,J=8.4Hz,2H).
实施例41
5-(3-氯-噻吩-2-基)-3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑
如实施例16中的方法从3-氯-噻吩-2-羰基氯化物(0.150g,0.828mmol)和6-甲氧基-吡啶-3-偕胺肟(0.138g,0.828mmol)中制备白色固态标题化合物(166mg,63%)。
1H NMR(DMSO-d6):8.84(d,J=2.4Hz,1H),8.28(m,1H),8.20(d,J=6.0Hz,1H),7.42(d,J=5.1Hz,1H),7.04(d,J=9.3Hz,1H).
实施例42
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
a)4-丁氧基-苄胺肟:如实施例36c中方法从羟胺(0.195mL)和4-丁氧基苄腈(0.500g,2.85mmol)中制备白色固态标题化合物(0.534g,92%)。
1H NMR(DMSO-d6):9.44(s,1H),7.58(d,J=8.7Hz,2H),6.90(d,J=9.0Hz,2H),5.74(s,2H),3.97(m,2H),1.72(m,2H),1.42(m,2H),0.928(t,3H).
b)3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑:如实施例16中的方法从3-氯-噻吩-2-羰基氯化物(86mg,0.480mmol)和4-丁氧基-苄胺肟(100mg,0.480mmol)中制备褐色固态标题化合物(0.113g,72%)。
1H NMR(Acetone-d6):8.10(d,J=1.8Hz,1H),8.08(d,J=2.1Hz,1H),7.36(d,J=3.9Hz,1H),7.16(d,J=8.7Hz,2H),4.14(t,2H),1.95(m,2H),1.56(m,2H),0.928(t,3H).
实施例43
3-(4-氨基嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
类似于实施例16,从4-氨基嘧啶-5-偕胺肟(50mg,0.33mmol)和3-氯-噻吩-2-羰基氯化物(59mg,0.33mmol)中制备标题化合物,并获得25mg(27%)黄色固体。
1H NMR(CDCl3):9.18(s,1H),8.69(s,1H),7.66(d,J=5.22Hz,1H),7.16(d,J=5.22Hz,1H),5.85(s,1H),3.51(s,1H).
实施例44
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例16,从5-三氟甲基-吡啶-2-偕胺肟(429mg,2.09mmol)和3-氯-噻吩-2-羰基氯化物(378mg,2.09mmol)中制备标题化合物,并获得535mg(77%)白色固体。
1H NMR(CDCl3):9.09(m,1H),8.36(d,J=8.24Hz,1H),8.14(m,1H),7.66(d,J=5.22Hz,1H),7.16(d,J=5.22Hz,1H).
实施例45
5-(3-溴-5-甲酰-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
在氩气下将5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑(599mg,1.84mmol)在四氢呋喃(10mL)中的溶液加入超过20分钟到在干冰/丙酮浴中的1.5M二异丙氨基锂(1.3mL,1.95mmol)和四氢呋喃(10mL)的搅拌溶液中,并将其搅拌1小时。然后向该溶液中逐滴加入无水DMF(1.5mL,19.4mmol),且将该溶液搅拌30分钟。用冰浴替换干冰浴并将该溶液搅拌20分钟。去除冰浴后,该溶液用甲醇(10mL)然后用饱和碳酸氢钠(3mL)淬火。向溶液中加入1N盐酸直至其达到pH3。用二氯甲烷(2×100mL)提取该溶液。将提取物在硫酸钠上干燥,过滤并浓缩。用柱色谱法(二氯甲烷)纯化产物两次,获得393mg(60%)淡黄色固态标题化合物。
1H NMR(DMSO-d6):9.79(s,1H),8.11(dd,J=8.52,2.13Hz,2H),8.05(s,1H),7.70(dd,J=8.24,2.06Hz,2H).
实施例46
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑
a)嘧啶-2-偕胺肟:类似于实施例36c,从2-氰基嘧啶(341mg,3.25mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.65mL,3.25mmol)制备标题化合物,获得293mg(65%)白色固体。
1H NMR(DMSO-d6):10.17(s,1H),8.84(d,J=4.94Hz,2H),7.51(t,J=4.81Hz,1H),5.83(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑:类似于实施例16,从嘧啶-2-偕胺肟(41mg,0.30mmol)和3-氯-噻吩-2-羰基氯化物(51mg,0.28mmol)制备标题化合物,获得35mg(39%)白色固体。
1H NMR(CDCl3):9.02(d,J=4.67Hz,2H),7.65(d,J=5.22Hz,1H),7.49(t,J=4.81Hz,1H),7.15(d,J=5.22Hz,1H).
实施例47
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑
类似于实施例16,从N-氧化物-吡啶-3-偕胺肟(53mg,0.35mmol)和3-氯-噻吩-2-羰基氯化物(63mg,0.35mmol)制备标题化合物,获得38mg(39%)白色固体。1HNMR(CDCl3):8.96(m,1H),8.34(m,1H),8.03(d,J=7.96Hz,1H),7.76(d,J=5.22Hz,1H),7.50(m,1H),7.19(d,J=5.50Hz,1H).
实施例48
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑
a)6-氯-吡啶-3-偕胺肟:类似于实施例36c,从6-氯-3-氰基-吡啶(416mg,3.00mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.8mL,3.3mmol)制备标题化合物,获得275mg(53%)白色固体。
1H NMR(Acetone-d6):9.26(s,1H),8.71(dd,J=2.47,0.82Hz,1H),8.10(dd,J=8.24,2.47Hz,1H),7.47(dd,J=8.40,0.69Hz,1H),5.69(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑:类似于实施例16,从6-氯-吡啶-3-偕胺肟(47mg,0.27mmol)和3-氯-噻吩-2-羰基氯化物(50mg,0.28mmol)制备标题化合物,获得49mg(27%)淡粉色固体。
1H NMR(CDCl3):9.16(d,J=2.20Hz,1H),8.39(dd,J=8.24,2.20Hz,1H),7.65(d,J=5.22Hz,1H),7.49(d,J=8.52Hz,1H),7.15(d,J=5.22Hz,1H).
实施例49
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑
a)4-氯-3-三氟甲基-苄胺肟:类似于实施例36c,从4-氯-3-三氟甲基-苄腈(617mg,3.00mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.8mL,3.3mmol)制备标题化合物,获得528mg(74%)白色固体。
1H NMR(Acetone-d6):9.29(s,1H),8.15(d,J=2.19Hz,1H),8.00(m,1H),7.69(d,J=8.24Hz,1H),5.73(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑:类似于实施例16,从4-氯-3-三氟甲基-苄胺肟(66mg,0.28mmol)和3-氯-噻吩-2-羰基氯化物(50mg,0.28mmol)制备标题化合物,获得68mg(68%)白色固体。
1H NMR(CDCl3):8.49(d,J=1.64Hz,1H),8.28(dd,J=8.52,1.92Hz,1H),7.66(m,2H),7.15(d,J=5.22Hz,1H).
实施例50
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
a)3,4-二氯-苄胺肟:类似于实施例36c,从3,4-二氯-苄腈(516mg,3.00mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.8mL,3.3mmol)制备标题化合物,获得276mg(45%)白色固体。
1H NMR(Acetone-d6):9.21(s,1H),7.89(d,J=2.20Hz,1H),7.70(dd,J=8.52,2.20Hz,1H),7.58(d,J=8.52Hz,1H),5.62(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑:类似于实施例16,从3,4-二氯苄胺肟(57mg,0.28mmol)和3-氯-噻吩-2-羰基氯化物(50mg,0.28mmol)制备标题化合物,获得63mg(69%)白色固体。
1H NMR(CDCl3):8.27(d,J=1.38Hz,1H),8.00(dd,J=8.46,1.52Hz,1H),7.63(d,J=5.50Hz,1H),7.59(d,J=8.24Hz,1H),7.14(d,J=5.22Hz,1H).
实施例51
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例16,从5-三氟甲基-吡啶-2-偕胺肟(516mg,5.52mmol)和3-氯-噻吩-2-羰基氯化物(455mg,2.51mmol)制备标题化合物,获得764mg(92%)近纯白色固体。
1H NMR(CDCl3):9.09(m,1H),8.36(d,J=8.24Hz,1H),8.14(m,1H),7.66(d,J=5.22Hz,1H),7.16(d,J=5.49Hz,1H).
实施例52
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑
a)3-溴-噻吩-2-偕胺肟:类似于实施例36c,从3-溴-2-氰基-噻吩(564mg,3.00mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.8mL,3.3mmol)制备标题化合物,获得383mg(58%)白色固体。
1H NMR(Acetone-d6):9.18(s,1H),7.51(d,J=5.50Hz,1H),7.06(d,J=5.22Hz,1H),5.59(s,2H).
b)3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑:类似于实施例36c,从4-氯-苯甲酰基氯化物(60μL,0.47mmol)和3-溴-噻吩-2-偕胺肟(102mg,0.461mmol)制备标题化合物,获得80mg(51%)白色固体。
1H NMR(CDCl3):8.15(dd,J=9.09,2.06Hz,2H),7.54(dd,J=8.51,2.20Hz,2H),7.50(d,J=5.22Hz,1H),7.18(d,J=5.22Hz,1H).
实施例53
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-苯基)-[1,2,4]-噁二唑
类似于实施例16,从4-三氟甲基-苯甲酰基氯化物(66μL,0.44mmol)和3-溴-噻吩-2-偕胺肟(98mg,0.44mmol)制备标题化合物,获得130mg(78%)白色固体。
1H NMR(CDCl3):8.34(d,J=8.24Hz,2H),7.83(d,J=8.51Hz,2H),7.52(d,J=5.22Hz,1H),7.19(d,J=5.21Hz,1H).
实施例54
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑类似于实施例16,从4-乙酰氨基苄胺肟(55.4mg,0.287mmol)和3-氯-噻吩-2-羰基氯化物(52.4mg,0.289mmol)制备标题化合物,获得33.6mg(37%)淡橙色固体。
1H NMR(CDCl3):8.12(d,J=8.52Hz,2H),7.66(d,J=8.79Hz,2H),7.60(d,J=5.22Hz,1H),7.35(s,1H),7.12(d,J=5.22Hz,1H).
实施例55
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑
类似于实施例16,从3-三氟甲基-苄胺肟(70.3mg,0.344mmol)和3-氯-噻吩-2-羰基氯化物(62mg,0.343mmol)制备标题化合物,获得81.6mg(72%)近纯白色固体。
1H NMR(CDCl3):8.44(s,1H),8.36(d,J=7.69Hz,1H),7.80(d,J=8.51Hz,1H),7.67(d,J=7.96Hz,1H),7.64(d,J=5.21Hz,1H),7.15(d,J=5.22Hz,1H).
实施例56
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑
类似于实施例16,从6-三氟甲基-吡啶-3-偕胺肟(418mg,2.04mmol)和3-氯-噻吩-2-氯化物(369mg,2.04mmol)制备标题化合物,获得538mg(80%)白色固体。
1H NMR(CDCl3):9.49(m,1H),8.63(m,1H),7.85(dd,J=8.24,0.82Hz,1H),7.66(d,J=5.49Hz,1H),7.17(d,J=5.22Hz,1H).
实施例57
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
a)2-氨基-4-氯-苄胺肟:类似于实施例36c,从2-氨基-4-氯-苄腈(458mg,3.00mmol)和0.576M羟胺盐酸盐95%乙醇溶液(5.8mL,3.3mmol)制备标题化合物,获得377mg(68%)淡黄色固体。1H NMR(Acetone-d6):8.99(s,1H),7.42(d,J=8.51Hz,1H),6.77(d,J=1.92Hz,1H),6.56(dd,J=8.52,2.20Hz,1H),6.30(s,2H),5.51(s,2H).
b)3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑:类似于实施例16,从2-氨基-4-氯-苄胺肟(63.2mg,0.336mmol)和3-氯-噻吩-2-羰基氯化物(62mg,0.343mmol)制备标题化合物,获得16.2mg(16%)黄色固体。
1H NMR(CDCl3):8.07(d,J=9.07Hz,1H),7.62(d,J=5.22Hz,1H),7.14(d,J=5.22Hz,1H),6.78(m,2H),5.53(s,2H).
实施例58
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑
a)喹啉-2-偕胺肟:类似于实施例36c,从2-氰基-喹啉(463mg,3.00mmol)和50%重量羟胺(200μL,3.26mmol)制备标题化合物,获得554mg(98%)淡黄色固体。
1H NMR(DMSO-d6):10.23(s,1H),8.34(d,J=8.79Hz,1H),8.06(d,J=8.51Hz,1H),8.00(d,J=8.24Hz,2H),7.80(t,J=7.69Hz,1H),7.62(dd,J=7.97,6.87Hz,1H),6.01(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑:类似于实施例16,从喹啉-2-偕胺肟(64.5mg,0.346mmol)和3-氯-噻吩-2-羰基氯化物(62.5mg,0.345mmol)制备标题化合物,获得31mg(29%)白色固体。 1HNMR(CDCl3):8.36(d,J=8.52Hz,2H),8.30(d,J=8.51Hz,1H),7.92(dd,J=7.97,1.38Hz,1H),7.81(ddd,J=8.45,7.07,1.44Hz,1H),7.65(m,2H),7.15(d,J=5.22Hz,1H).
实施例59
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑
a)异喹啉-3-偕胺肟:类似于实施例36c,从异喹啉-3-腈(364mg,2.36mmol)和50%重量羟胺(160μL,2.61mmol)制备标题化合物,获得439mg(99%)淡黄色固体。
1H NMR(DMSO-d6):9.81(s,1H),9.35(s,1H),8.31(s,1H),8.16(dd,J=8.17,0.75Hz,1H),8.06(d,J=7.97Hz,1H),7.80(ddd,J=8.24,6.87,1.37Hz,1H),7.70(ddd,J=8.11,6.87,1.24Hz,1H),5.97(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑:类似于实施例16,从异喹啉-3-偕胺肟(64.7mg,0.346mmol)和3-氯-噻吩-2-羰基氯化物(62.5mg,0.343mmol)制备标题化合物,获得65.8mg(61%)近纯白色固体。
1H NMR(CDCl3):9.43(s,1H),8.64(s,1H),8.08(d,J=7.42Hz,1H),8.00(d,J=7.97Hz,1H),7.80(td,J=7.49,1.46Hz,1H),7.73(td,J=7.48,1.10Hz,1H),7.63(d,J=5.22Hz,1H),7.15(d,J=5.50Hz,1H).
实施例60
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑
a)4-甲基-吡啶-2-偕胺肟:类似于实施例36c,从4-甲基-吡啶-2-腈(441mg,3.73mmol)和50%重量羟胺(250μL,2.61mmol)制备标题化合物,获得427mg(76%)白色固体。
1H NMR(DMSO-d6):9.85(s,1H),8.41(d,J=4.94Hz,1H),7.68(m,1H),7.24(m,1H),5.81(s,2H),2.34(s,3H).
b)5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑:类似于实施例16,从4-甲基-吡啶-2-偕胺肟(50.5mg,0.334mmol)和3-氯-噻吩-2-羰基氯化物(60.7mg,0.335mmol)制备标题化合物,获得72.7mg(80%)近纯白色固体。
1H NMR(CDCl3):8.68(dd,J=4.95,0.83Hz,1H),8.04(m,1H),7.62(d,J=5.22Hz,1H),7.27(m,1H),7.13(d,J=5.50Hz,1H),2.48(s,3H).
实施例61
5-(2-甲基-4-三氟甲基-噻唑-5-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
类似于实施例16,从4-氯苄胺肟和2-甲基-4-三氟甲基-噻唑-5-羧酸盐制备淡橙色固体标题化合物。
1H NMR(CDCl3):8.08(dd,J=8.52,2.20Hz,1H),7.50(dd,J=8.51,2.13Hz,1H),2.85(s,3H).
实施例62
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑
a)4-氰基-吡啶-2-偕胺肟:类似于实施例36c,从2,4-氰基-吡啶(481mg,3.72mmol)、50%重量羟胺(240μL,3.92mmol)制备标题化合物,获得452mg(75%)白色固体。
1H NMR(DMSO-d6):9.52(s,1H),8.81(dd,J=5.08,0.96Hz,1H),7.18(dd,J=1.51,0.96Hz,1H),7.66(dd,J=5.22,1.65Hz,1H),5.85(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑:类似于实施例16,从4-氰基-吡啶-2-偕胺肟(49.1mg,0.303mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得73.5mg(84%)近纯白色固体。
1H NMR(CDCl3):9.03(d,J=4.94Hz,1H),8.45(m,1H),7.70(dd,J=4.94,1.37Hz,1H),7.67(d,J=5.22Hz,1H),7.16(d,J=5.49Hz,1H).
实施例63
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑
a)4-氰基-苄胺肟:类似于实施例36c,从对苯二腈(384mg,3.00mmol)、50%重量羟胺(200μL,3.26mmol)制备标题化合物,获得196mg(41%)白色固体。
1HNMR(DMSO-d6):10.04(s,1H),7.86(s,4H),6.01(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑:类似于实施例16,从4-氰基-苄胺肟(49.0mg,0.304mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得73.4mg(84%)白色固体。
1H NMR(CDCl3):8.29(dd,J=8.24,1.65Hz,2H),7.81(dd,J=8.24,1.51Hz,2H),7.65(d,J=5.22Hz,1H),7.15(d,J=5.22Hz,1H).
实施例64
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑
a)5-甲基-吡啶-2-偕胺肟:将5-甲基-2-溴-吡啶(505mg,2.93mmol)与氰化亚铜(287mg,3.20mmol)熔化几秒钟。将混合物冷却至室温,用乙酸乙酯(3×5mL)提取。将提取物过滤并浓缩,获得86mg淡绿色固体。向该固体中加入50%重量羟胺(45μL,0.73mmol)、乙醇(5mL),在氩气下回流生成溶液30分钟。将该溶液冷却至室温并浓缩至干。用柱色谱法纯化(95∶5,乙酸乙酯∶甲醇)产物,获得60.7mg(14%)白色固体标题化合物。
1H NMR(Acetone-d6):9.01(s,1H),8.39(dd,J=1.38,0.83Hz,1H),7.81(d,J=7.96Hz,1H),7.59(m,1H),5.69(s,1H),2.35(s,3H).
b)5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑:类似于实施例16,从5-甲基-吡啶-2-偕胺肟(26mg,0.17mmol)和3-氯-噻吩-2-羰基氯化物(31.7mg,0.175mmol)制备标题化合物,获得39.4mg(82%)近纯白色固体。
1H NMR(CDCl3):8.66(m,1H),8.10(d,J=7.97Hz,1H),7.67(m,1H),7.61(d,J=5.22Hz,1H),7.13(d,J=5.22Hz,1H),2.44(s,3H).
实施例65
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑
a)6-甲基-吡啶-3-偕胺肟:类似于实施例36c,从6-甲基-烟腈(nicotinenitrile)(354mg,3.00mmol)、50%重量羟胺(200μL,3.26mmol)制备标题化合物,获得300mg(66%)白色固体。
1H NMR(DMSO-d6):9.74(s,1H),8.72(d,J=2.19Hz,1H),7.89(dd,J=8.10,2.33Hz,1H),7.26(d,J=8.24Hz,1H),5.93(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑:类似于实施例16,从6-甲基-吡啶-3-偕胺肟(45.9mg,0.304mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得60.8mg(72%)近纯白色固体。
1H NMR(CDCl3):9.25(d,J=2.20Hz,1H),8.31(dd,J=7.97,2.20Hz,1H),7.63(d,J=5.49Hz,1H),7.31(d,J=7.97Hz,1H),7.14(d,J=5.22Hz,1H),2.66(s,3H).
实施例66
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑
类似于实施例16,从吡嗪-2-偕胺肟(42.2mg,0.306mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得67.4mg(84%)白色固体。
1HNMR(CDCl3):9.45(d,J=1.37Hz,1H),8.81(dd,J=2.48,1.65Hz,1H),8.77(d,J=2.47Hz,1H),7.66(d,J=4.95Hz,1H),7.16(d,J=5.50Hz,1H).
实施例67
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑
a)4-(甲基羧基)-苄胺肟:类似于实施例36c,从4-(甲基羧基)-苄腈(483mg,3.00mmol)、50%重量羟胺(195μL,3.18mmol)制备标题化合物,获得403mg(69%)白色固体。
1H NMR(DMSO-d6):9.91(s,1H),7.95(dd,J=8.79,1.86Hz,2H),7.82(dd,J=8.79,1.79Hz,2H),5.94(s,2H),3.86(s,3H).
b)5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑:类似于实施例16,从4-(甲基羧基)-苄胺肟(234mg,1.21mmol)和3-氯-噻吩-2-羰基氯化物(218.7mg,1.21mmol)制备标题化合物,获得340mg(88%)白色固体。
1H NMR(CDCl3):8.25(m,2H),8.17(m,2H),7.63(d,J=5.36Hz,1H),7.14(d,J=5.22Hz,1H).
实施例68
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑
a)喹啉-3-偕胺肟:类似于实施例36c,从3-氰基-喹啉(464mg,3.01mmol)和50%重量羟胺(200μL,3.26mmol)制备标题化合物,获得141mg(25%)淡黄色固体。
1H NMR(DMSO-d6):10.01(s,1H),9.22(d,J=1.93Hz,1H),8.58(d,J=1.64Hz,1H),8.01(dd,J=12.09,8.24Hz,2H),7.78(td,J=7.63,1.28Hz,1H),7.65(t,J=7.56Hz,1H),6.11(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑:类似于实施例16,从喹啉-3-偕胺肟(56.9mg,0.304mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得85.0mg(89%)白色固体。
1H NMR(CDCl3):9.64(d,J=2.20Hz,1H),8.95(d,J=1.92Hz,1H),8.20(d,J=8.52Hz,1H),7.98(dd,J=7.97,0.83Hz,1H),7.82(ddd,J=8.52,7.00,1.51Hz,1H),7.65(m,2H),7.17(d,J=5.22Hz,1H).
实施例69
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑
a)8-羟基-喹啉-2-偕胺肟:类似于实施例36c,从8-羟基-喹啉-2-腈(508mg,2.99mmol)和50%重量羟胺(200μL,3.26mmol)制备标题化合物,获得541mg(89%)白色固体。
1H NMR(DMSO-d6):10.07(s,1H),9.98(s,1H),8.25(d,J=8.79Hz,1H),7.96(d,J=8.79Hz,1H),7.45(t,J=7.33Hz,1H),7.38(dd,J=8.24,1.38Hz,2H),7.10(dd,J=7.56,1.51Hz,1H),6.55(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑:类似于实施例16,从喹啉-8-醇-2-偕胺肟(61.8mg,0.304mmol)和3-氯-噻吩-2-羰基氯化物(55mg,0.30mmol)制备标题化合物,获得16.3mg(16%)白色固体。
1H NMR(CDCl3):8.61(s,1H),8.34(d,J=8.52Hz,1H),8.29(d,J=8.52Hz,1H),7.66(d,J=5.22Hz,1H),7.56(t,J=7.97Hz,1H),7.41(dd,J=8.24,1.10Hz,1H),7.26(dd,J=8.24,1.10Hz,1H),7.17(d,J=5.50Hz,1H).
实施例70
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
向在氩气下冰浴中的3-氰基-噻吩-2-羧酸(42.5mg,0.278mmol)和二氯甲烷(1.5mL)的搅拌溶液中加入草酰氯(205μL,0.410mmol)超过2分钟,然后加入2滴二甲亚砜。搅拌该溶液5分钟,去除冰浴,将溶液搅拌1小时。将该溶液浓缩至干,获得白色固体。向该固体中加入5-三氟甲基-吡啶-2偕胺肟(56.4mg,0.275mmol)和吡啶(1.6mL),在室温搅拌所生成溶液10分钟。然后将该溶液回流21小时。将溶液冷却至室温,并通过加入5mL去离子水沉淀产物。过滤沉淀物,用去离子水洗涤,真空干燥获得38.3mg(43%)粉色固体标题化合物。
1H NMR(CDCl3):9.09(m,1H),8.40(d,J=8.25Hz,1H),8.16(dd,J=8.24,2.20Hz,1H),7.80(d,J=5.22Hz,1H),7.52(d,J=5.22Hz,1H).
实施例71
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑
a)5,6-二氯-吡啶-3-腈:向在氩气下冰浴中的5,6-二氯-吡啶-3-羧酸(1.11mg,5.79mmol)和二氯甲烷(1.5mL)的搅拌溶液中加入草酰氯(4.4mL,8.8mmol)超过25分钟,其后加入2滴二甲亚砜。将该溶液搅拌5分钟,去除冰浴,将该溶液搅拌1.5小时。将溶液浓缩获得白色固体。向该固体加入四氢呋喃(5.0mL)和1∶1二氯甲烷∶乙酸乙酯(3×50mL)。将有机层浓缩。向该固体中加入亚硫酰(二)氯(50mL),在氩气下将该溶液回流69小时。将该溶液浓缩,用柱色谱法纯化残余物两次(1∶2,己烷∶乙酸乙酯,然后用1∶1,己烷∶乙酸乙酯),获得268mg(27%)标题化合物。
1H NMR(CDCl3):8.59(d,J=2.20Hz,1H),8.05(d,J=2.20Hz,1H).
b)5,6-二氯-吡啶-3-偕胺肟:类似于实施例36c,从5,6-二氯-吡啶-3-腈(257mg,1.485mmol)和50%重量羟胺(96.0μL,1.57mmol)制备标题化合物,获得234mg(76%)淡黄色固体产物。1H NMR(DMSO-d6):10.11(s,1H),8.66(d,J=2.20Hz,1H),8.29(d,J=1.93Hz,1H),6.12(s,2H).
c)5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑:类似于实施例16,从5,6-二氯-吡啶-3-偕胺肟(101mg,0.491mmol)和3-氯-噻吩-2-羰基氯化物(88.9mg,0.491mmol)制备标题化合物,获得101mg(62%)白色固体。
1H NMR(CDCl3):9.06(d,J=2.20Hz,1H),8.52(d,J=2.20Hz,1H),7.66(d,J=5.22Hz,1H),7.16(d,J=5.22Hz,1H).
实施例72
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例70,从3-溴-呋喃-2-羧酸(381.7mg,2.00mmol)和5-氯-吡啶-2-偕胺肟(343mg,2.00mmol)制备标题化合物,获得353mg(54%)白色固体。
1H NMR(CDCl3):8.81(d,J=2.47Hz,1H),8.22(d,J=8.24Hz,1H),7.90(dd,J=8.25,2.48Hz,1H),7.71(d,J=1.93Hz,1H),6.79(d,J=1.64Hz,1H).
实施例73
5-(3-溴-呋喃溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑
类似于实施例16,从6-三氟甲基-吡啶-3-偕胺肟(508mg,2.48mmol)和3-溴-呋喃-2-羰基氯化物(520mg,2.48mmol)制备标题化合物,获得725mg(81%)淡黄色固体。
1H NMR(CDCl3):9.51(m,1H),8.65(dd,J=8.17,1.99Hz,1H),7.86(d,J=8.10Hz,1H),7.71(d,J=1.92Hz,1H),6.79(d,J=1.92Hz,1H).
实施例74
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例16,从5-三氟甲基-吡啶-2-偕胺肟(480mg,2.34mmol)和3-溴-呋喃-2-羰基氯化物(490mg,2.34mmol)制备标题化合物,获得718mg(85%)淡黄色固体。
1H NMR(CDCl3):9.09(m,1H),8.37(d,J=8.24Hz,1H),8.14(dd,J=8.10,2.34Hz,1H),7.70(d,J=1.92Hz,1H),6.78(d,J=1.92Hz,1H).
实施例75
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑
类似于实施例16,从2-甲基-噻唑-4-偕胺肟(24.6mg,0.156mmol)和3-氯-噻吩-2-羰基氯化物(28.7mg,0.159mmol)制备标题化合物,获得18.2mg(40%)白色固体。
1H NMR(CDCl3):8.03(s,1H),7.61(d,J=5.49Hz,1H),7.13(d,J=5.22Hz,1H),2.84(s,3H).
实施例76
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑
类似于实施例16,从5-硝基-噻唑-2-偕胺肟(17.2mg,0.0914mmol)和3-氯-噻吩-2-羰基氯化物(16.4mg,0.0905mmol)制备标题化合物,获得6.7mg(23%)黄色固体。
1H NMR(CDCl3):8.74(s,1H),7.70(d,J=5.22Hz,1H),7.18(d,J=5.22Hz,1H).
实施例77
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑
类似于实施例16,从7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-偕胺肟(13.8mg,0.0532mmol)和3-氯-噻吩-2-羰基氯化物(9.8mg,0.0541mmol)制备标题化合物,获得9.8mg(48%)近纯白色固体。
1H NMR(CDCl3):8.89(s,1H),7.62(d,J=5.22Hz,1H),7.20(d,J=0.83Hz,1H),7.14(d,J=5.22Hz,1H),2.98(s,3H).
实施例78
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
类似于实施例16,从4-氯苄胺肟(479mg,2.29mmol)和3-溴-呋喃-2-羰基氯化物(390mg,2.29mmol)制备标题化合物,获得570mg(81%)白色固体。
1H NMR(CDCl3):8.13(dd,J=8.80,2.20Hz,2H),7.67(d,J=1.92Hz,1H),7.49(dd,J=8.79,2.20Hz,2H),6.75(d,J=1.92Hz,1H).
实施例79
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑
a)3-(4-氯-苯基)-丙基偕胺肟:类似于实施例36c,从3-(4-氯-苯基)-丙腈(535mg,3.23mmol)和50%重量羟胺(120μL,1.96mmol)制备标题化合物,获得240mg(37%)白色固体产物。
1H NMR(DMSO-d6):8.75(s,1H),7.32(m,2H),7.24(d,J=8.51Hz,1H),6.12(s,2H),2.79(m,2H),2.22(dd,J=8.93,7.00Hz,1H).
b)5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑:类似于实施例16,从3-(4-氯-苯基)-丙基偕胺肟(76.2mg,0.384mmol)和3-氯-噻吩-2-羰基氯化物(69.9mg,0.386mmol)制备标题化合物,获得71.8mg(57%)近纯白色固体。
1H NMR(CDCl3):7.58(d,J=5.22Hz,1H),7.26(m,2H),7.18(m,2H),7.11(d,J=5.22Hz,1H),3.10(s,4H).
实施例80
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑
类似于实施例16,从2-(4-氯苯氧基)-乙基偕胺肟(25.0mg,0.125mmol)和3-氯-噻吩-2-羰基氯化物(23.1mg,0.128mmol)制备标题化合物,获得20.1mg(57%)近纯白色固体。
1H NMR(CDCl3):7.62(d,J=5.22Hz,1H),7.27(m,2H),7.12(d,J=5.22Hz,1H),6.98(dd,J=9.07,2.89Hz,2H),5.23(s,2H).
实施例81
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑
将4-三氟甲氧基-苄脒氢氯化物(102mg,0.42mmol)的3M氢氧化钠溶液(10mL)用二氯甲烷(4×10mL)提取。将合并的有机相在无水硫酸钠上干燥,倾析并浓缩,获得白色粉末(74mg,73%)。将该白色粉末(64mg,0.27mmol)与2-溴-1-(3-氯-噻吩-2-基)-1-乙烯酮(54mg,0.23mmol)和二甲亚砜(2.0mL)结合,并在氩气下在50℃加热1小时。然后将溶液冷却至室温并加入饱和碳酸氢钠(6mL)。将该溶液用二氯甲烷(4×10mL)提取,将合并的有机相在无水硫酸钠上干燥,倾析并浓缩。用闪柱色谱法(13∶2,己烷∶乙酸乙酯)纯化产物,获得27mg(34%)白色固体标题化合物。
1H NMR(CDCl3):9.90(s,1H),8.44(m,1H),7.81(d,J=1.92Hz,1H),7.41(m,3H),7.21(d,J=5.50Hz,1H),6.96(d,J=5.50Hz,1H).
实施例82
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑
类似于实施例81,从三氟甲基-苄胺肟(35mg,0.19mmol)和2-溴-1-(3-溴-噻吩-2-基)-1-乙烯酮(52mg,0.18mmol)制备标题化合物,获得15mg(22%)棕色固体。
1H NMR(CDCl3):10.19(s,1H),7.91(m,3H),7.63(d,J=7.96Hz,2H),7.21(d,J=5.22Hz,1H),7.02(d,J=5.22Hz,1H).
实施例83
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑
类似于实施例81,从三氟甲基-苄胺肟(26mg,0.15mmol)和2-溴-1-(3-氯-噻吩-2-基)-1-乙烯酮(37mg,0.15mmol)制备标题化合物,获得12mg(24%)棕色固体。
1H NMR(CDCl3):10.18(s,1H),7.92(d,J=8.52,Hz,2H),7.73(s,1H),7.64(d,J=8.24Hz,2H),7.21(d,J=5.22Hz,1H),6.97(d,J=5.50Hz,1H).
实施例84
5-(6-氯-吡啶-3-基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑
a)3-氯-噻吩-羰基酰肼:在氩气下冰浴中将3-氯-噻吩-羰基氯化物(647mg,3.57mmol)在二氯甲烷(10mL)中的溶液加入超过5分钟在酰肼(350μL,11.2mmol)二氯甲烷搅拌溶液(10mL)中。去除冰浴,在室温搅拌该溶液2小时。将溶液浓缩,将残余物在水(10mL)和二氯甲烷(8×8mL)之间分配。将合并的二氯甲烷层在无水硫酸钠上干燥,倾析并浓缩。用柱色谱法(43∶57,己烷∶乙酸乙酯)纯化产物,获得502mg(80%)白色固体标题化合物。
1HNMR(CDCl3):8.11(s,1H),7.50(d,J=5.22Hz,1H),6.99(d,J=5.22Hz,1H),4.11(s,2H).
b)6-氯-烟酸N’-(3-氯-噻吩-2-羰基)-酰肼:将3-氯-噻吩-2-羰基酰肼(70mg,0.40mmol)、6-氯烟酰氯化物(76mg,0.43mmol)和二氯甲烷(10mL)溶液搅拌5分钟。向该溶液加入饱和碳酸氢钠溶液(10mL),并将其搅拌5分钟。分离各层,并以二氯甲烷(8×10mL)提取水相。向合并的有机相加入乙酸乙酯(50mL),将其在无水硫酸钠上干燥,倾析并浓缩,获得120mg(96%)白色粉末标题化合物。
1H NMR(DMSO-d6):10.89(s,1H),10.37(s,1H),8.89(d,J=2.19Hz,1H),8.30(dd,J=8.52,2.48Hz,1H),7.93(d,J=5.22Hz,1H),7.72(d,J=8.25Hz,1H),7.22(d,J=5.22Hz,1H).
c)5-(6-氯-吡啶-3-基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑:在氩气下将6-氯-烟酸N’-(3-氯-噻吩-2-羰基)-酰肼:将3-氯-噻吩-2-羰基酰肼(60mg,0.19mmol)和亚硫酰(二)氯(6mL)回流3.5小时,然后冷却至室温,并浓缩。用柱色谱法(5∶2,己烷∶乙酸乙酯)纯化产物,获得33mg(58%)近纯白色粉末标题化合物。
1H NMR(CDCl3):9.13(d,J=2.48Hz,1H),8.39(dd,J=8.52,2.48Hz,1H),7.58(d,J=5.22Hz,1H),7.53(d,J=8.24Hz,1H),7.13(d,J=5.22Hz,1H).
实施例85
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑
a)烟酸N’-(3-氯-噻吩-2-羰基)-酰肼:类似于实施例84b,从3-氯-噻吩-2-羰基酰肼(70mg,0.40mmol)和烟酰氯盐酸盐(348mg,1.96mmol)制备标题化合物,获得76mg(68%)白色固体。1HNMR(DMSO-d6):10.82(s,1H),10.33(s,1H),9.07(s,1H),8.79(d,J=3.84Hz,1H),8.26(d,J=6.87Hz,1H),7.93(d,J=5.22Hz,1H),7.58(dd,J=7.55,4.53Hz,1H),7.23(d,J=4.95Hz,1H).
b)2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑:类似于实施例84c,从烟酸N’-(3-氯-噻吩-2-羰基)-酰肼(52mg,0.18mmol)和亚硫酰(二)氯制备标题化合物,获得17mg(35%)白色固体。
1H NMR(CDCl3):9.38(s,1H),8.82(s,1H),8.44(d,J=7.97Hz,1H),7.57(d,J=5.22Hz,1H),7.51(dd,J=7.83,4.54Hz,1H),7.13(d,J=5.22Hz,1H).
实施例86
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑
a)4-氯-苯甲酸N’-(3-氯-噻吩-2-羰基)-酰肼:类似于实施例84b,从3-氯-噻吩-2-羰基酰肼(70mg,0.40mmol)和4-氯-苯甲酰氯(50.5μL,0.40mmol)制备标题化合物,获得130mg(100%)白色固体。
1H NMR(DMSO-d6):10.66(s,1H),10.30(s,1H),7.93(m,3H),7.61(d,J=8.79Hz,1H),7.22(d,J=5.22Hz,1H).
b)5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑:类似于实施例84c,从4-氯-苯甲酸N’-(3-氯-噻吩-2-羰基)-酰肼(55mg,0.17mmol)和亚硫酰(二)氯制备标题化合物,获得46mg(89%)白色固体。
1H NMR(CDCl3):8.08(d,J=8.24Hz,2H),7.53(m,3H),7.11(d,J=5.22Hz,1H).
实施例87
5-(3-溴-5-吗啉基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁
二唑
和
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二
唑
在氩气下向5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑(60mg,0.170mmol)、氰基氢硼化物(10.5mg,0.167mmol)、乙酸(10.0μL,0.173mmol)和甲醇(2.0mL)的搅拌溶液中加入吗啉(50μL,0.57mmol)。将该溶液搅拌24小时并浓缩至干。用柱色谱法(2∶1,己烷∶乙酸乙酯)纯化产物,获得12mg(17%)5-(3-溴-5-吗啉基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑,为白色固体。
1H NMR(CDCl3):8.12(d,J=8.51Hz,2H),7.49(d,J=8.52Hz,2H),6.60(s,1H),3.74(t,J=4.67Hz,4H),3.67(s,2H),2.56(t,J=4.67Hz,4H)
;还获得12mg(20%)5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑,为白色固体。
1H NMR(CDCl3):8.11(dd,J=8.79,2.20Hz,2H),7.49(dd,J=8.79,2.20Hz,2H),6.67(s,1H),4.77(d,J=6.32Hz,2H),2.09(t,J=6.46Hz,4H).
实施例88
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑
a)3-氯-噻吩-2-羧酸酰肼:向冰浴中冷却的酰肼(0.433mL.13.8mmol)在二氯甲烷(13.8mL)中的溶液中逐滴加入在13.8mL二氯甲烷中的3-氯-噻吩-2-羰基氯化物(1.0g,5.52mmol)。之后将反应溶液缓慢恢复至室温,搅拌1.5小时。将该溶液浓缩,将固体悬浮在去离子水(13.8mL)中。过滤沉淀并真空干燥,获得0.176g(73%)白色固体标题化合物。
1H NMR(DMSO-d6):9.40(s,1H),7.81(d,J=5.4Hz,1H),7.12(d,J=5.4Hz,1H),4.56(s,2H).
b)5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑:向4-三氟甲基-苄脒(0.442g,1.13mmol)乙醇(3mL)溶液中加入在乙醇(2.26mL)的甲醇钠(0.442g,2.26mmol)。将乳浆室温搅拌45分钟并过滤。向乙醇过滤物加入3-氯-噻吩-2-羧酸酰肼,将生成溶液回流12小时,冷却至室温,真空蒸发溶剂。过滤固体,真空干燥,用柱色谱法(梯度8∶1-5∶1己烷∶乙酸乙酯)纯化产物,获得0.141g(37%)标题化合物,为淡黄色固体。
1H NMR(DMSO-d6):8.25(d,J=8.4Hz,2H),7.93(d,J=8.1Hz,2H),7.80(d,J=6.0Hz,1H),7.22(d,J=5.70Hz,1H).
实施例89
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑
通过类似于实施例88b的步骤,从苄脒氢氯化物和3-氯-噻吩-2-羧酸酰肼制备标题化合物,为淡黄色固体(0.141g,37%)。
1H NMR(DMSO-d6):8.04(d,J=9.6Hz,2H),7.80(d,J=6.0Hz,1H),7.55(d,J=7.80Hz,3H),7.19(d,J=5.70Hz,1H).
实施例90
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑
通过类似于实施例88b的步骤,从4-甲基-苄脒氢氯化物和3-氯-噻吩-2-羧酸酰肼制备标题化合物,为黄色固体(0.054g,17%)。
1H NMR(CD3OD):7.80(d,J=7.8Hz,2H),7.52(d,J=6.0Hz,1H),7.22(d,J=8.4Hz,2H),6.97(d,J=5.10Hz,1H),2.30(s,3H).
实施例91
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑
通过类似于实施例88b的步骤,从3-甲基-苄脒氢氯化物和3-氯-噻吩-2-羧酸酰肼制备标题化合物,为黄色固体(0.013g,5.6%)。
1HNMR(CD3OD):7.75(s,1H),7.69(d,J=5.7Hz,1H),7.4(d,J=5.7Hz,1H),7.24(m,2H),6.97(d,J=6.3Hz,1H),3.10(s,3H).
实施例92
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑
通过类似于实施例88b的步骤,从2-脒-吡啶氢氯化物和3-氯-噻吩-2-羧酸酰肼制备标题化合物,为黄色固体(0.025g,11.4%)。
1HNMR(CD3OD):8.58(s,1H),8.07(d,J=8.1Hz,1H),7.84(t,1H),7.49(d,J=5.4Hz,1H),7.36(t,1H),6.98(d,J=7.5Hz,1H).
实施例93
2-(3-氯-噻吩-2-基)-5-苯基-噁唑
a)3-氯-噻吩-2-羧酸(2-氧代-苯基-乙基)-酰胺:向在冰浴中冷却的2-氨基苯乙酮氢氯化物(0.098g,0.552mmol)在吡啶(3mL)中的溶液中加入3-氯-噻吩-2-羰基氯化物(0.100g,0.552mmol)吡啶(1mL)溶液。之后去除冰浴,室温搅拌生成溶液1小时,然后回流30分钟。将反应混合物冷却至室温,过滤沉淀,真空干燥,获得0.104g(69%)褐色固体。 1H NMR(CD3OD):7.94(d,J=9.9Hz,2H),7.62(d,J=5.1Hz,1H),7.53(t,1H),7.43(t,2H),7.01(d,J=6.3Hz,1H),4.82(s,2H).
b)2-(3-氯-噻吩-2-基)-5-苯基-噁唑:向硫酸(1mL)中分批加入3-氯-噻吩-2-羧酸(2-氧代-苯基-乙基)-酰胺(0.075g,0.330mmol),且在氩气下室温搅拌该溶液0.5小时,然后加水(100mL),形成沉淀。过滤沉淀物,将固体溶解于乙酸乙酯中,然后用饱和碳酸氢钠洗涤,MgSO4上干燥,过滤并浓缩,获得0.027g(44%)褐色固体标题化合物。
1H NMR(CD3OD):7.67(d,J=8.4Hz,2H),7.56(d,J=5.4Hz,1H),7.50(s,1H),7.36(t,2H),7.26(d,J=7.2Hz,1H),7.03(d,J=5.4Hz,1H).
实施例94
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑
a)3-氯-噻吩-2-羧酸[2-(4-溴-苯基)-2-氧代-乙基]-酰胺:通过类似于实施例93a的步骤,从3-氯-噻吩-2-羰基氯化物和2-氨基-4’-溴苯乙酮氢氯化物制备化合物,为橙色固体。
1H NMR(DMSO-d6):8.40(s,NH),7.96(d,J=8.7Hz,2H),7.89(d,J=5.1Hz,1H),7.78(d,J=8.7Hz,2H),7.20(d,J=5.1Hz,1H),4.80(d,J=5.4Hz,2H).
b)5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑:通过类似于实施例93b的步骤,从3-氯-噻吩-2-羧酸-[2-(4-溴-苯基)-2-氧代-乙基]-酰胺制备标题化合物,为褐色固体(0.059g,62%)。
1H NMR(DMSO-d6):7.81(s,1H),7.80(d,J=5.1Hz,1H),7.60(s,3H),7.16(d,J=5.4Hz,1H).
实施例95
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑
a)3-氯-噻吩-2-羧酸[2-(4-甲氧基-苯基)-2-氧代-乙基]-酰胺:通过类似于实施例93a的步骤,从3-氯-噻吩-2-羰基氯化物和2-氨基-4’-甲氧基苯乙酮氢氯化物制备标题化合物,为橙色固体。
1H NMR(DMSO-d6):8.30(s,NH),8.02(d,J=9.0Hz,1H),7.89(d,J=6.6Hz,2H),7.20(d,J=6.0Hz,2H),7.10(d,J=8.7Hz,1H),4.80(d,J=5.4Hz,2H),3.86(s,3H).
b)2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑:通过类似于实施例93b的步骤,从3-氯-噻吩-2-羧酸-[2-(4-甲氧基-苯基)-2-氧代-乙基]-酰胺制备标题化合物,为褐色固体(0.023g,24%)。
1H NMR(DMSO-d6):7.75(d,J=5.1Hz,1H),7.59(m,3H),7.13(d,J=5.1Hz,1H),6.95(d,J=8.7Hz,2H),3.68(s,3H).
实施例96
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑
通过类似于实施例93b的步骤,从3-氯-噻吩-2-羧酸-[2-(4-氯-苯基)-2-氧代-乙基]-酰胺制备标题化合物,为褐色固体(0.0058g,43%)。
1H NMR(CD3OD):7.71(d,J=5.1Hz,1H),7.61(m,3H),7.32(d,J=8.5Hz,2H),7.13(d,J=5.1Hz,1H).
实施例97
5-(3-氯-噻吩-2-基)-2-苯基-噁唑
a)N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-苄酰胺:向在冰浴中冷却的2-(3-氯-噻吩-2-基)-2-氧代-1-乙胺氢氯化物(0.05g,0.235mmol)的吡啶(0.5mL)溶液中逐滴加入苯甲酰氯化物(0.02mL,0.235mmol)。在冰浴中搅拌该反应溶液15分钟,加水,并以乙酸乙酯提取。用1N HCl溶液、盐水洗涤提取物,MgSO4上干燥,过滤并浓缩,获得0.047g(72.7%)白色固体。 1HNMR(CD3OD):7.79(m,3H),7.43(m,3H),7.05(d,J=5.4Hz,1H),4.75(d,J=9.3Hz,2H).
b)5-(3-氯-噻吩-2-基)-2-苯基-噁唑:将N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-苄脒(0.048g,0.171mmol)在硫酸(1mL)中的混合物室温搅拌40分钟。将混合物加水并过滤。将固体溶解于乙酸乙酯,用水、饱和碳酸氢钠、盐水和水洗涤。将有机层MgSO4上干燥,过滤并蒸发。用柱色谱法(25∶1-100%CH2Cl2∶MeOH)纯化残余物,获得0.001g(2.2%)标题化合物,为白色固体。
1H NMR(Acetone-d6):7.99(m,2H),2.26(d,J=6.9Hz,2H),7.45(m,3H),7.07(d,J=5.7Hz,1H).
实施例98
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑
a)N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-4-氯-苄酰胺:通过类似于实施例97a的步骤,从2-(3-氯-噻吩-2-基)-2-氧代-1-乙胺氢氯化物(0.05g,0.235mmol)和4-氯-苯甲酰氢氯化物(0.02mL,0.235mmol)制备标题化合物,获得0.048g(72.7%)白色固体。
1H NMR(CD3OD):7.77(m,3H),7.43(d,J=8.4Hz,2H),7.36(t,1H),7.05(d,J=5.4Hz,1H),4.75(d,J=9.3Hz,2H).
b)2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑:通过类似于实施例97b的步骤,从N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-4-氯-苄酰胺(0.050g,0.159mmol)制备标题化合物,获得0.020g(42%)标题化合物,为褐色固体。 1H NMR(DMSO-d6):7.90(d,J=8.4Hz,2H),7.72(t,2H),7.52(d,J=9.0Hz,2H),7.13(d,J=5.4Hz,1H).
实施例99
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑
a)6-氯-N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-烟酰胺:通过类似于实施例98a的步骤,从2-(3-氯-噻吩-2-基)-2-氧代-1-乙胺氢氯化物和6-氯-烟酰氢氯化物制备标题化合物,为白色固体(0.044g,30%)。
1H NMR(CD3OD):8.74(d,J=8.74Hz,1H),8.13(d,J=6.3Hz,1H),7.79(d,J=5.4Hz,1H),7.48(d,J=9.0Hz,1H),7.07(d,J=5.4Hz,1H),4.75(s,2H).
b)2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑:通过类似于实施例98b的步骤,从6-氯-N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-烟酰胺制备标题化合物,为褐色固体(0.026g,69.2%)。
1H NMR(DMSO-d6):8.88(d,J=2.4Hz,1H),8.25(d,J=10.8Hz,1H),7.75(t,2H),7.60(d,J=8.1Hz,1H),7.14(d,J=5.1Hz,1H).
实施例100
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑
a)N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-4-三氟甲基-苄酰胺:通过类似于实施例98a的步骤,从2-(3-氯-噻吩-2-基)-2-氧代-1-乙胺氢氯化物和4-三氟甲基-苯甲酰氢氯化物(0.02mL,0.235mmol)制备标题化合物,为白色固体(0.044g,30%)。 1HNMR(DMSO-d6):9.06(m,1H),7.99(m,3H),7.77(d,J=8.4Hz,2H),7.20(d,J=9.0Hz,1H),4.73(s,2H).
b)5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑:通过类似于实施例98b的步骤,从N-[2-(3-氯-噻吩-2-基)-2-氧代-乙基]-4-三氟甲基-苄酰胺制备标题化合物,为白色固体(0.0056g,11.8%)。 1H NMR(Acetone-d6):8.18(d,J=9.9Hz,2H),7.80(d,J=9.60Hz,2H),7.69(s,1H),7.65(d,J=5.4Hz,1H),7.08(d,J=5.7Hz,1H).
实施例101
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑
将3-氯-噻吩-2-甲酰胺(0.145g,0.898mmol)和4-三氟甲基-苯甲酰甲基溴化物(0.200g,0.749mmol)放入一支密封管,并在150℃加热4小时。将反应混合物用乙酸乙酯淬火,且用柱色谱法(梯度100∶1,20∶1己烷∶二氯甲烷)纯化残余物。用制备性薄层色谱法(100∶1,己烷∶二氯甲烷)纯化产物,获得0.0148g(5.0%)标题化合物,为白色固体。 1H NMR(Acetone-d6):8.58(s,1H),8.01(d,J=8.1Hz,2H),7.71(t,3H),7.10(d,J=5.1Hz,1H),7.08(d,J=5.7Hz,1H).
实施例102
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑
通过类似于实施例101的步骤,从3-氯-噻吩-2-甲酰胺(0.100g,1.03mmol)和4-氯-苯甲酰甲基溴化物(0.200g,0.856mmol)制备标题化合物,为白色固体(0.006g,3.2%)。
1H NMR(Acetone-d6):8.45(s,1H),7.80(d,J=6.6Hz,2H),7.70(d,J=6.0Hz,1H),7.38(d,J=8.1Hz,2H),7.08(d,J=6.0Hz,1H).
实施例103
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑
a)3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮:向1-(3-氯-噻吩-2-基)-1-乙酮(ethanone)(0.450g,2.80mmol)和在乙醇(11.2mL)中的4-氯苯甲醛(0.393g,2.80mmol)溶液中加入0.5M氢氧化钠水溶液(5.6mL)。将反应混合物搅拌2.5小时,用乙酸乙酯(20mL)稀释,用1N HCI、盐水洗涤,MgSO4上干燥,过滤并蒸发,获得淡黄色固体(0.530g,60%)。
1H NMR(Acetone-d6):7.87(d,J=5.4Hz,1H),7.70(m,4H),7.40(d,J=8.4Hz,2H),7.11(d,J=5.4Hz,1H).
b)3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑:向在乙醇(1.5mL)和氢氧化钠(7.0mg,0.176mmol)中的3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮(50mg,0.176mmol)溶液中逐滴加入肼(5μL),将反应混合物在70℃加热16小时。将其浓缩,用色谱法(3∶1,己烷∶乙酸乙酯)纯化残余物,获得5.0g(8.0%)近纯白色固体。
1H NMR(Acetone-d6):7.77(d,J=8.7Hz,2H),7.40(d,J=8.4Hz,3H),7.16(s,1H),6.96(d,J=5.1Hz,1H).
实施例104
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺
a)4-氯-N-氰基-苯甲酰胺:将氨腈(124mg,2.94mmol)在3.0MNaOH(3.0mL)中的溶液加入4-氯-苯甲酰基氯化物(310μL,2.43mmol)乙醚(4.0mL)溶液中,搅拌混合物2.5小时。用10%HCl将该混合物酸化至pH3以形成沉淀。将沉淀物过滤,用水洗涤,真空干燥过夜,获得353mg未加工产物,为白色固体。
b)4-氯-N-(N-羟基-脒)苯甲酰胺:将上述未加工的4-氯-N-氰基-苯甲酰胺(154mg)、50%重量羟胺水溶液和乙醇的溶液室温搅拌2小时。将该溶液浓缩,用柱色谱法(95∶5,乙酸乙酯∶甲醇)纯化标题化合物,获得55.1g标题化合物,为白色固体。
c)4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺:将4-氯-N-(N-羟基-脒)苯甲酰胺(32.8mg,0.179mmol)、3-氯-噻吩-2-羰基氯化物(38.2mg,0.181mmol)和吡啶(2.0mL)的溶液在氩气下室温搅拌10分钟。将该溶液回流1小时,冷却至室温并以水(6mL)稀释以形成沉淀。将沉淀物过滤并真空干燥。用制备性TLC(2∶1,己烷∶乙酸乙酯)纯化产物,获得4.1mg(7%)标题化合物,为白色固体。
1H NMR(CDCl3):9.32(s,1H),8.09(dd,J=8.79,2.06Hz,2H),7.65(d,J=5.49Hz,4H),7.49(dd,J=8.79,2.06Hz,2H),7.09(d,J=5.22Hz,4H).
实施例105
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-4,5二氢-1H-吡唑:向在乙醇(1.5mL)和氢氧化钠(7.0mg,0.176mmol)中的3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮(50mg,0.176mmol)溶液中逐滴加入苯肼(17μL,0.176mmol),将反应溶液在70℃加热3小时。将其浓缩至干,用色谱法(50∶1,己烷∶乙酸乙酯)纯化残余物,获得12.8mg(19.4%)淡黄色油。 1HNMR(CDCl3):7.18(m,9H),6.88(d,J=8.7Hz,2H),6.77(d,J=5.4Hz.1H),6.69(t,1H),5.14(m,1H),3.93(m,1H),3.22(m,1H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑:向5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-4,5二氢-1H-吡唑(11.0mg,0.029mmol)在二氯甲烷(0.2mL)中的溶液逐滴加入四乙酸铅(6.6mg,0.029mmol)在二氯甲烷(0.1mL)中的溶液。将反应混合物室温搅拌15分钟,然后用水(1mL)稀释。用水洗涤有机层,MgSO4上干燥,并蒸发产生油。将所得的油溶解在HCl/乙醇溶液(0.1mL,0.225M)中,在60℃加热10分钟。冷却后加入二氯甲烷,将有机层用碳酸氢钠和水洗涤,MgSO4上干燥并浓缩。用色谱法(50∶1,己烷∶乙酸乙酯)纯化残余物,获得5.9mg(54%)标题化合物,为褐色固体。
1H NMR(CDCl3):7.15(m,11H),6.87(d,J=5.4Hz,1H),4.00(d,J=7.2Hz,1H).
实施例106
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-4,5二氢-1H-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮(50mg,0.176mmol)和甲肼(9μL,0.17mmol)制备标题化合物,为淡黄色油(20.9mg,38%)。
1H NMR(CDCl3):7.24(m,4H),7.09(d,J=6.6Hz,1H),6.75(d,J=6.60Hz,1H),4.08(m,1H),3.83(m,1H),2.98(t,1H),2.67(s,3H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑:类似于实施例105b,从5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-4,5二氢-1H-吡唑(19.0mg,0.061mmol)制备标题化合物,为褐色固体(9.5mg,48%)。 1H NMR(CDCl3):7.30(m,4H),7.09(d,J=5.7Hz,1H),6.83(d,J=6.0Hz,2H),3.78(s,3H).
实施例107
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑
a)5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-4,5二氢-1H-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和3-氯-苯肼制备标题化合物,为淡黄色固体(93.8mg,43%)。
1H NMR(CDCl3):7.29(m,7H),6.92(m,3H),5.25(m,1H),4.08(m,1H),3.83(m,1H).
b)5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑:通过类似于实施例105b的步骤,从5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-4,5二氢-1H-吡唑制备标题化合物,为褐色固体(5.0mg,5.4%)。
1H NMR(CDCl3):7.52(t,1H),7.28(m,8H),7.13(d,J=9.0Hz,1H),7.02(d,J=5.7Hz,1H).
实施例108
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑
a)1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-4,5-二氢-1H-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和4-氯-苯肼制备标题化合物,为淡黄色油(112mg,51.8%)。
1H NMR(CDCl3):7.35(d,J=8.7Hz,2H),7.27(t,3H),7.15(d,J=9.3Hz,2H),6.91(m,3H),5.25(m,1H),4.03(m,1H),3.83(m,1H).
b)1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑:通过类似于实施例105b的步骤,从1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-4,5-二氢-1H-吡唑制备标题化合物,为褐色固体(5.4mg,5.6%)。
1H NMR(CDCl3):7.29(m,10H),7.02(d,J=5.7Hz,1H).
实施例109
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-4,5-二氢-1H-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和2-肼基吡啶制备标题化合物,为淡黄色油(141mg,73.8%)。
1H NMR(CDCl3):8.04(m,1H),7.59(t,1H),7.46(d,J=9.0Hz,1H),7.27(m,6H),6.92(d,J=5.4Hz,1H),6.68(t,1H),4.01(t,1H),3.41(m,1H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑:通过类似于实施例105b的步骤,从5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-4,5-二氢-1H-吡唑制备标题化合物,为褐色固体(5.4mg,5.6%)。
1H NMR(CDCl3):8.35(m,1H),7.83(t,1H),7.71(d,J=10.2Hz,1H),7.30(m,6H),7.02(d,J=6.9Hz,1H).
实施例110
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-4,5-二氢-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和4-肼基苯甲酸制备标题化合物,为淡黄色油(166mg,74%)。
1H NMR(CDCl3):9.02(s,1H),7.92-6.80(m,10H),5.72(m,1H),4.20(m,1H),4.01(t,1H),3.41(m,1H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑:通过类似于实施例105b的步骤,从5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-4,5-二氢-吡唑制备标题化合物,为褐色固体(1.0mg,1.4%)。
1H NMR(CDCl3):7.78(s,1H),7.76(d,J=3.3Hz,2H),7.44(d,J=8.4Hz,2H),7.30(d,J=9.0Hz,2H),7.15(d,J=5.4Hz,1H),6.98(d,J=8.7Hz,2H),5.77(s,1H).
实施例111
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-4,5-二氢-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和4-甲基-磺酰基苯肼制备标题化合物,为淡黄色油(78mg,32%)。
1H NMR(CDCl3):7.69(d,J=9.0Hz,1H),7.33(m,3H),7.22(m,4H),6.92(m,2H),5.38(t,1H),4.15(m,1H),3.46(m,1H),1.29(m,3H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑:通过类似于实施例105b的步骤,从5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-4,5-二氢-吡唑制备标题化合物,为褐色固体(14.2mg,18.0%)。
1H NMR(CDCl3):7.97(m,3H),7.58(m,2H),7.44(d,J=8.7Hz,2H),7.29(m,2H),7.02(d,J=5.4Hz,1H),5.77(s,1H),3.09(s,3H).
实施例112
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑
a)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-4,5-二氢-吡唑:通过类似于实施例105a的步骤,从3-(4-氯-苯基)-1-(3-氯-噻吩-2-基)-丙烯酮和2-羟基乙肼制备标题化合物,为淡黄色油(88mg,73%)。
1H NMR(CDCl3):7.40(m,6H),6.91(d,J=5.1Hz,1H),3.78(m,2H),2.97(m,2H).
b)5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑:通过类似于实施例105b的步骤,从5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-4,5-二氢-吡唑制备标题化合物,为褐色固体(4.8mg,3.6%)。 1HNMR(CDCl3):7.48(m,4H),7.25(d,J=5.4Hz,1H),6.98(t,2H),4.24(m,2H),3.51(m,2H).
实施例113
5-(3-氯-噻吩-2-基)-3-(4-氯苯胺基)[1,2,4]-噁二唑
a)3-氯-噻吩-2-氨腈:向氨腈(0.232g,5.52mmol)的10%氢氧化钠溶液中加入在二乙醚(2mL)中的3-氯-噻吩-2-羰基氯化物(1.0g,5.52mmol)。将该溶液在室温搅拌40分钟并在冰浴中搅拌10分钟,然后将1N HCl逐滴加入。收集沉淀物,用色谱法(梯度4∶1,己烷∶乙酸乙酯∶甲醇)纯化,获得0.561g(56%)褐色固体。
1H NMR(DMSO-d6):7.48(d,J=5.7Hz,1H),6.94(d,J=6.3Hz,1H),5.78(s,1H).
b)N-(4-氯-苯基)-N-(-3-氯-噻吩-2-羰基)-胍:向3-氯-噻吩-2-氨腈(0.207g,1.11mmol)的水(5mL)溶液中加入对氯苯胺,之后用2N HCl调节pH为3。将反应混合物回流3小时以形成白色固体。将其冷却至室温,用氢氧化钠(0.5M)、水、盐水洗涤,MgSO4上干燥,过滤并浓缩。用柱色谱法(10∶0.1,二氯甲烷∶甲醇)纯化,获得0.083g(24%)褐色固体。 1H NMR(CDCl3):7.29(d,J=9.0Hz,2H),7.25(d,J=5.1Hz,1H),7.10(d,J=9.0Hz,2H),6.86(d,J=5.1Hz,1H).
c)5-(3-氯-噻吩-2-基)-3-(4-氯苯胺基)[1,2,4]-噁二唑:向N-(4-氯-苯基)-N-(-3-氯-噻吩-2-羰基)-胍(50.0mg,0.159mmol)的甲醇(1.0mL)溶液中加入盐酸(0.146mL)。沉淀立即产生,通过过滤去除固体。向溶液中加入
NaOCl(0.08mL)和碳酸钾水溶液(0.152mL,1.0M)。室温搅拌反应混合物1小时,通过过滤收集沉淀。用柱色谱法(二氯甲烷)纯化固体,获得0.008g(17.1%)标题化合物,为白色固体。
1H NMR(Acetone-d6):8.02(d,J=5.4Hz,1H),7.53(d,J=8.7Hz,2H),7.23(m,3H).
实施例114
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑
a)3-溴-呋喃-2-羧酸:向冷却至-78℃的二异丙胺锂(26.2mL,1.4M)在四氢呋喃(26mL)中的溶液逐滴加入3-溴-呋喃(5.0g,34.0mmol)在四氢呋喃(26mL)中的溶液。将该溶液在-78℃搅拌30分钟,然后倒在二氧化碳和乙醚的溶液中,并搅拌10分钟。将淤浆倒入水中(注意大量气体发射能产生剧烈反应)并分离水相。用2N HCl将水相酸化为pH3,以乙酸乙酯提取3次。将合并的有机层在MgSO4上干燥,过滤并浓缩。所得固体从己烷和乙酸乙酯重结晶,获得4.21g(64.8%)淡黄色粉末。
1H NMR(CDCl3):7.58(m,1H),6.66(m,1H).
b)5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑:向3-溴-呋喃-2-羧酸(0.700g,3.66mmol)在无水苯(9mL)中的混合物加入亚硫酰(二)氯(0.9mL),将反应混合物在60℃加热6小时。将反应混合物浓缩至干(油),然后与己烷共同蒸发数次以获得半固体。向半固体加入4-氟-苄偕胺肟(0.147g,0.955mmol)和吡啶(2mL),将该溶液回流12小时。在冷却至室温后,将该溶液加水,用乙酸乙酯提取。将有机层在MgSO4上干燥,过滤并浓缩。将该化合物用柱色谱法(3∶1,己烷∶乙酸乙酯)纯化,且用色谱法(3∶1,己烷∶乙酸乙酯)进一步纯化,获得14.3mg(4.8%)淡黄色粉末。
1H NMR(Acetone-d6):8.21(m,2H),8.07(d,J=1.8Hz,1H),7.39(t,2H),7.03(d,J=2.1Hz,1H).
实施例115
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
a)3-氯-呋喃:将在无水THF(40mL)中的新鲜馏得的3-溴-呋喃(19.49g,132.1mmol)与无水乙醚(70mL)的溶液冷却至-78℃,并搅拌20分钟。然后通过另外的漏斗向该溶液逐滴加入在戊烯(66.3mL,2.0M)中正丁基锂。将反应混合物在-78℃搅拌0.5小时,然后向搅拌着的溶液中加入在无水THF(15mL)中的六氯乙烷(31.39g,132.6mmol)。将反应溶液在-78℃再搅拌1小时。去除冰浴,然后将反应物室温搅拌2小时,形成沉淀。将混合物加水,分离,以2N HCl淬火,用水洗涤,MgSO4上干燥,过滤并真空蒸馏(bp:35-40℃),获得6.09g(44.7%)淡黄色液体。
1H NMR(CDCl3):7.36(m,1H),7.30(t,1H),6.33(m,1H).
b)3-氯-呋喃-2-羧酸:类似于实施例114a制备标题化合物,获得4.48g(51.2%)淡黄色粉末。 1HNMR(CDCl3):7.57(d,J=2.1Hz,1H),6.59(d,J=1.8Hz,1H).
c)5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑:从3-氯-呋喃-2-羧酸(0.250g,1.71mmol)和5-氯-吡啶-2-偕胺肟(0.288g,1.68mmol)制备标题化合物,获得101mg(20.9%)淡黄色粉末。 1H NMR(DMSO-d6):8.87(m,1H),8.28(d,J=2.1Hz,1H),8.19(d,J=2.1Hz,1H),8.18(d,J=0.9Hz,1H),7.15(d,J=2.1Hz,1H).
实施例116
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑
按照实施例115c制备标题化合物,为白色固体(190mg,35.5%)。
1H NMR(DMSO-d6):8.29(m,3H),7.99(d,J=8.7Hz,2H),7.16(d,J=1.8Hz,1H).
实施例117
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
按照实施例115c制备标题化合物,为白色固体(1.89g,65.5%)。
1H NMR(DMSO-d6):8.27(d,J=1.8Hz,1H),8.08(d,J=8.7Hz,2H),7.69(d,J=8.7Hz,2H),7.15(d,J=1.8Hz,1H).
实施例118
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑
a)2-碘-5-三氟甲基-吡啶:向2-氯-5-三氟甲基-吡啶(15.0g,82.6mmol)在乙腈(400mL)中的溶液加入碘化钠(43.3g,289.1mmol),将反应混合物在88℃搅拌直至碘化钠溶解。然后向该溶液中加入乙酰氯(8.8mL,12.3mmol),形成沉淀。将反应混合物回流24小时,冷却并浓缩成油。将此油溶解于二氯甲烷,用10%硫代硫酸钠、10%碳酸钠和盐水洗涤,MgSO4上干燥,过滤并浓缩。将残余物用色谱法纯化并以二氯甲烷洗脱,获得10.9g(48.4%)淡黄色固体。
1H NMR(CDCl3):8.68(s,1H),7.88(m,1H),7.49(d,J=9.9Hz,1H).
b)5-三氟甲基-吡啶-2-腈:向2-碘-5-三氟甲基-吡啶(10.9g,40.0mmol)在吡啶(250mL)中的溶液中加入氰化铜(5.37g,60.0mmol),将反应混合物回流2小时。将反应混合物冷却,用氰化钾和水洗涤,MgSO4上干燥,过滤并浓缩为棕色油。用柱色谱法(梯度6∶1-4∶1,己烷∶乙酸乙酯)纯化所得油,获得5.09g(74%)淡黄色粉末。
1H NMR(CDCl3):9.01(s,1H),8.11(m,1H),7.86(d,J=7.5Hz,1H).
c)5-三氟甲基-吡啶-2-偕胺肟:向5-三氟甲基-吡啶-2-腈(5.00g,29.5mmol)在乙醇(100mL)中的溶液加入羟胺(2.0mL),将该溶液回流12小时。然后将其浓缩,获得5.46g(89%)白色固体。
1H NMR(CDCl3):8.83(s,1H),8.05(m,1H),6.99(s,1H).
d)5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑:类似于实施例115c制备标题化合物,为淡黄色粉末。
1H NMR(DMSO-d6):10.2(s,1H),8.17(d,J=5.4Hz,1H),7.89(d,J=8.7Hz,2H),7.41(d,J=5.4Hz,1H),6.94(d,J=8.7Hz,2H).
实施例119
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例115c制备标题化合物,为淡黄色粉末(2.7mg,2.7%)。
1H NMR(CDCl3):8.75(m,1H),8.15(d,J=9.0Hz,1H),7.84(d,J=10.8Hz,1H),7.60(d,J=5.1Hz,1H),7.18(d,J=5.1Hz,1H).
实施例120
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑
向3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑(100mg,0.36mmol)的乙酸(3mL)溶液中加入一氯化碘(175.74mg,1.08mmol)乙酸溶液(1mL)。将其室温搅拌1小时,然后真空浓缩。用柱色谱法(己烷∶乙酸乙酯,8∶1)纯化残余物,获得56mg(30%)标题化合物。 1H NMR(CDCl3):8.45(s,2H),7.63(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,2H),5.01(brs,2H).
实施例121
5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑和类似物作为半胱氨酰天冬氨酸蛋白酶级联活化剂和细胞凋亡诱导剂在实
体瘤细胞中的鉴定
在5%CO2-95%湿度的培养箱内于37℃,让人乳腺癌细胞系T-47D和ZR-75-1在美国模式培养物收集中心设计的培养基组分混合物+10%FCS(Invitrogen Corporation)中生长。在0.1-0.6×106个细胞/ml的细胞密度下,让T-47D和ZR-75-1细胞保持50-80%铺满的细胞密度。以600×g收获细胞,以0.65×106个细胞/mL重悬在适当培养基+10%FCS中。将45μL等份试样的细胞加到96孔微量滴定板的孔中,其中微量滴定板的孔中含有2.5μl 10%DMSO在RPMI-1640培养基溶液中的混合物,所述培养基溶液含有0.16-10μM 5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑或其它测试化合物(终浓度为0.016-10μM)。将22.5μL等份试样的细胞加到384孔微量滴定板的孔中,其中微量滴定板的孔中含有2.5μl 10%DMSO在RPMI-1640培养基溶液中的混合物,并且所述培养基溶液不含测试化合物,以此作为对照样本。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养箱内于37℃培养48小时。培养后,将样本从培养箱中取出,加入25μL含有下列组分的溶液:14μM N-(Ac-DEVD)-N’-乙氧基羰基-R110(SEQ ID No.:1)荧光底物(Maxim,Inc.;WO99/18856)、20%蔗糖(Sigma)、20mM DTT(Sigma)、200mM NaCl(Sigma)、40mM Na PIPES缓冲液pH 7.2(Sigma)和500μg/mL溶血卵磷脂(Calbiochem)。通过搅拌将样本混和,并在室温培养。使用荧光平板读数器(Model SpectraMax Gemini,Molecular Devices),采用485nm的激发波长和530nm的发射波长,在加入底物溶液约1-2分钟后记录初始读数(T=0),以确定对照样本的背底荧光。培养3小时后,如上所述读取样本的荧光(T=3小时)。
计算:
如下所示,使用相对荧光单位值(RFU)来计算样本读数值:
RFU(T=3小时)-对照RFU(T=0)=净RFU(T=3小时)
通过5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑或其它测试化合物的净RFU值与对照样本的净RFU值的比值来确定半胱氨酰天冬氨酸蛋白酶级联激活活性。通过乙状剂量-反应计算(Prism 2.0,GraphPad Software Inc.)确定EC50(nM)。表I中总结了半胱氨酰天冬氨酸蛋白酶活性(比值)和效力(EC50)。
表I.半胱氨酰天冬氨酸蛋白酶活性和效力
实施例 | T-47D比值 EC50(nM) | |
1 | 16.9 | 3614 |
4 | 4.2 | 5354 |
5 | 19.7 | 2145 |
6 | 3.8 | 5000 |
7 | 4.1 | 865 |
因此,经鉴定,5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑(实施例4)和类似物在实体瘤细胞中是有效的半胱氨酰天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导剂。
实施例122
5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑作为
抑制细胞增殖的抗肿瘤化合物的鉴定
如实施例121培养和收获T-47D和SKBr-3细胞。将90μL等份试样的细胞(2.2×104个细胞/mL)加到96孔微量滴定板的孔中,其中微量滴定板的孔中含有10μl 10%DMSO在RPMI-1640培养基溶液中的混合物,所述培养基溶液含有1nM-100μM 5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑(终浓度为0.1nM-10μM)。将90μL等份试样的细胞加到96孔微量滴定板的孔中,其中微量滴定板的孔中含有10μL 10%DMSO在RPMI-1640培养基溶液中的混合物,并且所述培养基溶液不含测试化合物,以此作为最大细胞增殖(AMax)对照样本。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养箱内于37℃培养48小时。培养后,将样本从培养箱中取出,加入20μLCellTiter 96 AQUEOUS One Solution Cell ProliferationTMreagent(Promega)。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养箱内于37℃培养2-4小时。使用吸收平板读数器(Model 1420Wallac Instruments),采用490nm的吸收波长,在加入溶液约1-2分钟后记录初始读数(T=0)。这确定测试化合物可能的的背底吸收。发现在490nm无5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑吸收。培养2-4小时后,如上所述读取样本的吸收(ATest)。
通过向孔中含有10μl 10%DMSO在RPMI-1640培养基溶液的96孔微量滴定板的孔中相应加入90μL等份试样的细胞或90μL培养基,确定初始细胞数的GI50(细胞增殖的50%抑制剂量)基线。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养箱内于37℃培养0.5小时。培养后,将样本从培养箱中取出,加入20μL CellTiter 96 AQUEOUS OneSolution Cell ProliferationTM reagent(Promega)。通过搅拌将样本混和,然后在5%CO2-95%湿度的培养箱内于37℃培养2-4小时。如上所述读取吸收,(AStart)定义在GI50确定中用作基线的初始细胞数的吸收。
计算:
GI50(细胞增殖的50%抑制剂量)
是[(ATest-AStart)/(AMax-AStart)]=0.5的浓度。
表II中总结了GI50(nM)。
表II.癌细胞中的GI50
细胞系 | GI50(nM) | |
实施例5 | 实施例1 | |
T-47D | 300 | 250 |
ZR-75-1 | 400 | 200 |
因此,经鉴定,5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑(实施例4)和3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑(实施例1)是有效的抑制细胞增殖的抗肿瘤化合物。
实施例123
5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑作为
选择性抑制乳腺癌细胞增殖的抗肿瘤化合物的鉴定(GI50)
按照美国模式培养物收集中心推荐的条件培养T-47D、ZR-75-1、MX-1、SK-Br-3、Panc-1、K562、Hela和PC-3细胞。SW620和NCI-H23按照National Cancer Institute提供的条件培养。如在实施例122中方法进行细胞增殖分析和GI50的计算(表III和IV)。
表III.乳腺癌细胞系中的GI50
细胞系 | GI50(nM) | |
实施例5 | 实施例1 | |
T-47D | 300 | 250 |
ZR-75-1 | 400 | 200 |
MX-1 | 400 | 300 |
SK-Br-3 | 20 | 20 |
表IV.非乳腺癌细胞系中的GI50
细胞系 | GI50(nM) | |
实施例5 | 实施例1 | |
PC-3 | >10,000 | >10,000 |
Panc-1 | >10,000 | >10,000 |
SW620 | >10,000 | >10,000 |
NCI-H23 | >10,000 | >10,000 |
K562 | >10,000 | >10,000 |
DLD-1 | 40 | 35 |
因此,经鉴定,5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑(实施例4)和3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑(实施例1)是选择性抑制除结肠癌细胞系DLD-1之外的乳腺癌细胞系生长的抗肿瘤化合物。
实施例124
5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑抑制
MX-1实体瘤细胞系克隆生存
按照美国模式培养物收集中心推荐的条件培养MX-1细胞。在96孔培养板的孔中,接种30,000个细胞,且以指定浓度的化合物在5%CO2-95%湿度的培养箱内于37℃处理48小时。对照孔用与化合物样品等量溶剂(DMSO)处理。在指定的处理时间后,将上清液移到无菌培养管,用磷酸盐缓冲液洗涤各孔,将粘连的细胞胰蛋白酶消化5分钟。将胰蛋白酶消化的细胞加入在培养上清液中,收集细胞(1,200rpm,10分钟),用磷酸盐缓冲液洗涤,并重悬于新鲜培养基中。计数台盼蓝阴性细胞,用新鲜培养基稀释该细胞至1,000个细胞/mL。向24孔培养板的孔中,与1mL新鲜培养基同时加入0.1mL该细胞悬浮液(种植前将细胞悬浮液过22G针数次以形成单个细胞悬浮液)。将培养板在5%CO2-95%湿度的培养箱内于37℃培养7-10天。当其大小达到大于每克隆50个细胞时计数克隆。细胞用磷酸盐缓冲液洗涤,与100%甲醇结合15分钟,然后用0.5%龙胆紫染色15分钟。克隆用水漂洗,计数克隆,生存分数表示为对照克隆的数目的百分数。
结果显示在48小时处理后,5-(3-氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑在IC50大约1050nM时抑制MX-1细胞增殖能力和其克隆形成能力。
虽然已经充分地描述了本发明,但是本领域技术人员应当理解,可在不影响本发明范围或其任何实施方案的情况下,在广泛且等同的病症、制剂和其它参数范围内进行相同实施。本文所引用的所有专利、专利申请和出版物都全文引入本文以供参考。
序列表
<110>Cytovia,Inc.
Cai,Sui Xiong
Zhang,Han-Zhong
Drewe,John A.
Reddy,P.Sanjeeva
Kasibhatla,Shailaja
<120>作为半胱氨酰天冬氨酸蛋白酶活化剂和细胞凋亡诱导剂的取代的3-芳基-5-芳基-[1,2,4]-恶二唑和类似物及其用途
<130>1735.064PC01
<150>US 60/296,479
<151>2001-06-08
<160>1
<170>PatentIn version 3.1
<210>1
<211>4
<212>PRT
<213>人工序列
<220>
<223>生氟底物
<400>1
Asp Glu Val Asp
1
Claims (100)
1.治疗患病动物中对细胞凋亡有反应的疾病的方法,包括向需要这样治疗的动物施用有效量的式I的化合物或其可药用盐或前药或互变异构体,
其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中Ar2是任选地取代的芳基或任选地取代的杂芳基;且
如果价律未被违背,A、B和D独立地是CR10、C(R10)R11、N、NR12、O或S,其中R10和R11在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基,且R12在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。
2.权利要求1的方法,其中所述动物是哺乳动物。
3.权利要求1的方法,其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。
4.权利要求1的方法,其中Ar3是任选地取代的芳基或任选地取代的杂芳基。
5.权利要求4的方法,其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。
6.权利要求1的方法,其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吡唑并[1,5-α]嘧啶基、苄基、苯乙基、苯氧甲基、苄基氨基、苯甲酰氨基或亚苄基氨基,其中每个都是任选地取代的。
7.权利要求1的方法,其中所述化合物具有式II或其可药用盐或前药。
8.权利要求7的方法,其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。
9.权利要求7的方法,其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吡唑并[1,5-α]嘧啶基、苄基、苯乙基、苯氧甲基、苄基氨基、苯甲酰氨基或亚苄基氨基,其中每个都是任选地取代的。
10.权利要求7的方法,其中Ar1是异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的;Ar3是任选地取代的苯基或任选地取代的吡啶基。
11.权利要求7的方法,其中所述化合物具有式III或其可药用盐或前药,
其中:
R1-R8独立地是氢、卤素、卤代烷基、芳基、稠合芳基、碳环基、一个杂环基、一个杂芳基、烷基、链烯基、炔基、芳基烷基、芳基链烯基、芳基炔基、杂芳基烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰氨基、羟基、巯基、酰基氧基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,其中每个都是任选地取代的;且Q是S、O或NR9,其中R9是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。
12.权利要求11的方法,其中所述化合物选自下列化合物组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[3,5-双(三氟甲基)苯基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-溴-3-甲氧基-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(4-氨基-3,5-二氯-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3,4,5-三氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)-3-(2,4-二氯-苯基)-[1,2,4]-噁二唑;或其可药用盐或前药。
13.权利要求11的方法,条件是当Ar1是未取代的或取代的噻吩基时,R1-R8每个都不是氯和三氟甲基。
14.权利要求13的方法,其中所述化合物选自下列化合物组:
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑;
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-(甲磺酰基氨基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-二甲氨基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-羟基-苯基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-叠氮基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-吗啉代甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉;
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲胺;
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯;
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;和
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
15.权利要求7的方法,其中所述化合物选自下列化合物组:
5-(1-苯基-5-三氟甲基-1H-吡唑-4-基)-3-(3,5-双-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-[1-(4-氯-苯基)-5-三氟甲基-1H-吡唑-4-基]-3-(3,5-双-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(4-溴-1-乙基-3-甲基-1H-吡唑-5-基)3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(2-甲基-吡咯-3-基)3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-甲基-5-三氟甲基-异噁唑-4-基)-3-苯基-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氨基-嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(2-甲基-4-三氟甲基-噻唑-5-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑;
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺;
5-(3-氯-噻吩-2-基)-3-(4-氯苯胺基)[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
17.权利要求16的方法,其中所述化合物具有式IV。
18.权利要求17的方法,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑;
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;和
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
或其可药用盐或前药。
19.权利要求16的方法,其中所述化合物具有式V。
20.权利要求19的方法,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑;和
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑;
或其可药用盐或前药。
21.权利要求16的方法,其中所述化合物具有式VI。
22.权利要求21的方法,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑;
5-(6-氯-3-吡啶基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑;和
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
或其可药用盐或前药。
23.权利要求16的方法,其中所述化合物具有式VII。
24.权利要求23的方法,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-5-苯基-噁唑;
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-苯基-噁唑;
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑;
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑;
或其可药用盐或前药。
25.权利要求16的方法,其中所述化合物具有式VIII。
26.权利要求25的方法,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑;和
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
或其可药用盐或前药。
27.权利要求16的方法,其中所述化合物具有式IX。
28.权利要求27的方法,其中所述化合物选自下列组:
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑;
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑;和
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑;
或其可药用盐或前药。
29.权利要求1的方法,其中所述疾病是癌症。
30.权利要求29的方法,其中所述癌症是药物抵抗性癌症。
31.权利要求30的方法,其中所述药物抵抗性癌症是激素依赖或不依赖的乳腺癌,或结肠癌。
32.治疗或预防癌的方法,包括向需要这样治疗的动物施用有效量的式I的化合物或其可药用盐或前药或互变异构体,
其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中Ar2是任选地取代的芳基或任选地取代的杂芳基;且
如果价律未被违背,A、B和D独立地是CR10、C(R10)R11、N、NR12、O或S,其中R10和R11在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基,且R12在各种情况下独立地是氢、任选地取代的烷基、任选地取代的环烷基或任选地取代的芳基。
33.权利要求32的方法,其中所述动物是哺乳动物。
34.权利要求32的方法,其中A是N,B是O和D是N。
35.权利要求32的方法,其中Ar1是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,其中每个都是任选地取代的。
36.权利要求32的方法,其中Ar3是苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吡唑并[1,5-α]嘧啶基、苄基、苯乙基、苯氧甲基、苄基氨基、苯甲酰氨基或亚苄基氨基,其中每个都是任选地取代的。
37.权利要求32的方法,其中所述癌症选自下列组:何杰金病、非何杰金氏淋巴瘤、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、多发性骨髓瘤、神经母细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、子宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞性白血病、原发性脑癌、恶性黑素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌性癌、绒(毛)膜癌、蕈样霉菌病、头颈癌、骨肉瘤、胰腺癌、急性粒细胞性白血病、毛细胞白血病、神经母细胞瘤、横纹肌肉瘤、卡波西肉瘤、泌尿生殖器癌、甲状腺癌、食管癌、恶性高钙血症、子宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多、特发性血小板增多、肾上腺皮质癌、皮肤癌和前列腺癌。
38.权利要求32的方法,其中所述癌症是药物抵抗性癌症。
39.权利要求38的方法,其中所述药物抵抗性癌症是激素依赖或不依赖的乳腺癌,或结肠癌。
40.权利要求29-39中任何一项的方法,另外包括施用至少一种已知的癌症化学治疗剂,或所述化学治疗剂的可药用盐。
41.权利要求40的方法,其中所述已知的癌症治疗剂选自下列组:白消安、顺铂、丝裂霉素C、卡铂、秋水仙碱、长春碱、紫杉醇、多西他赛、喜树碱、托泊替康(topotecan)、阿霉素、鬼臼乙叉苷、5-阿扎胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2’-脱氧-尿苷、阿糖胞苷、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙(mitoguazone)、表柔比星、阿柔比星(aclarubicin)、博来霉素、米托蒽醌、依利醋铵(elliptinium)、氟达拉滨、奥曲肽、视黄酸、三苯氧胺、campath、Gleevec_、Herceptin_或Rituxan_和阿拉诺新(alanosine)。
42.权利要求29-39中任何一项的方法,另外包括用放射治疗治疗所述动物。
43.权利要求29-39中任何一项的方法,其中患所述癌症的所述动物在手术治疗后施用所述化合物。
44.权利要求1的方法,其中所述疾病是自身免疫病。
45.权利要求1的方法,其中所述疾病是感染性病毒疾病。
46.权利要求1的方法,其中所述疾病是类风湿性关节炎。
47.权利要求1的方法,其中所述疾病是炎症性肠病。
48.权利要求1的方法,其中所述疾病是皮肤病。
48.权利要求48的方法,其中所述疾病是牛皮癣。
50.包括可药用载体和具有式II化合物或其可药用盐或前药的药物制剂,
其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中Ar2,是任选地取代的芳基或任选地取代的杂芳基。
52.权利要求51的药物制剂,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[3,5-双(三氟甲基)苯基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-溴-3-甲氧基-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(4-氨基-3,5-二氯-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3,4,5-三氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)-3-(2,4-二氯-苯基)-[1,2,4]-噁二唑;或其可药用盐或前药。
53.权利要求51的药物制剂,条件是当Ar1是未取代的或取代的噻吩基时,R1-R8每个都不是氯和三氟甲基。
54.权利要求53的药物制剂,其中所述化合物选自下列化合物组:
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑;
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-(甲磺酰基氨基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-二甲氨基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-羟基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-呋喃-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-叠氮基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)-苯基]-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-吗啉代甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉;
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲胺;
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯;
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;和
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
55.权利要求50的药物制剂,其中所述化合物选自下列组:
5-(1-苯基-5-三氟甲基-1H-吡唑-4-基)-3-(3,5-双-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-[1-(4-氯-苯基)-5-三氟甲基-1H-吡唑-4-基]-3-[3,5-双(三氟甲基)苯基]-[1,2,4]-噁二唑;
5-(4-溴-1-乙基-3-甲基-1H-吡唑-5-基)3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(2-甲基-吡咯-3-基)3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-甲基-5-三氟甲基-异噁唑-4-基)-3-苯基-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氨基-嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(2-甲基-4-三氟甲基-噻唑-5-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑;
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺;
5-(3-氯-噻吩-2-基)-3-(4-氯苯胺基)[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
57.权利要求56的药物制剂,其中所述化合物具有式IV。
58.权利要求57的药物制剂,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑;
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;和
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
或其可药用盐或前药。
59.权利要求56的药物制剂,其中所述化合物具有式V。
60.权利要求59的药物制剂,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑;和
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑;
或其可药用盐或前药。
61.权利要求6的药物制剂,其中所述化合物具有式VI。
62.权利要求61的药物制剂,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑;
5-(6-氯-3-吡啶基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑;和
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
或其可药用盐或前药。
63.权利要求56的药物制剂,其中所述化合物具有式VII。
64.权利要求63的药物制剂,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-5-苯基-噁唑;
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-苯基-噁唑;
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑;
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑;
或其可药用盐或前药。
65.权利要求56的药物制剂,其中所述化合物具有式VIII。
66.权利要求65的药物制剂,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑;和
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
或其可药用盐或前药。
67.权利要求56的药物制剂,其中所述化合物具有式IX。
68.权利要求57的药物制剂,其中所述化合物选自下列组:
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑;
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑;和
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑;
或其可药用盐或前药。
69.权利要求50-68中任何一项的药物制剂,进一步包括施用至少一种已知的癌症化学治疗剂,或所述化学治疗剂的可药用盐。
70.权利要求69的药物制剂,其中所述已知的癌症治疗剂选自下列组:白消安、顺铂、丝裂霉素C、卡铂、秋水仙碱、长春碱、紫杉酚、多西他赛、喜树碱、托泊替康(topotecan)、阿霉素、鬼臼乙叉苷、5-阿扎胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2’-脱氧-尿苷、阿糖胞苷、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙(mitoguazone)、表柔比星、阿柔比星(aclarubicin)、博来霉素、米托蒽醌、依利醋铵(elliptinium)、氟达拉滨、奥曲肽、视黄酸、三苯氧胺、campath、Gleevec_、Herceptin_或Rituxan_和阿拉诺新(alanosine)。
71.具有式II的化合物或其可药用盐或其前药,
其中:
Ar1是任选地取代的芳基或任选地取代的杂芳基;
Ar3是任选地取代的并从由芳基烷基、芳氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰氨基和Ar2组成的组中选取的,其中Ar2是任选地取代的芳基或任选地取代的杂芳基;条件是:
(a)当Ar1是未取代的或取代的噻吩基时,那么Ar3不是被氯或三氟甲基取代的苯基;
(b)当Ar1是未取代的或取代的异噁唑基时,那么Ar3不是未取代的苯基;
(c)当Ar1是取代的或未取代的吡唑基时,那么Ar3不是三氟甲基取代的吡啶基以及不是三氟甲基取代的苯基;
(d)当Ar1是取代的或未取代的吡咯基时,那么Ar3不是未取代的吡啶基。
72.权利要求71的化合物,其中Ar3是任选地取代的苯基。
74.权利要求73的化合物,其中Q是S或O。
75.权利要求73的化合物,其中R3不是氢。
76.权利要求73的化合物,其中所述的化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-硝基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-苯基-[1,2,4]-噁二唑;
3-(4-甲基-苯基)-5-(噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-(甲磺酰基氨基)苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-三氟甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-亚甲二氧基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-二甲氨基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-羟基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-呋喃-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-甲基-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
3-(4-叠氮基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-溴-5-甲酰基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-乙酰氨基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[4-(甲基羧基)苯基]-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-吗啉代甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-5-羟基甲基-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(4-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
4-(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-吗啉;
(2-{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙基)-二甲胺;
{4-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯氧基}-乙酸甲酯;
3-(4-丁氧基-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;和
3-(4-氨基-3,5-二碘-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
77.权利要求72的化合物,其中所述化合物选自下列组:
5-(4-氯-1H-吡唑-3-基)3-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(2-甲基-4-三氟甲基-噻唑-5-基)-[1,2,4]-噁二唑;和
或其可药用盐或前药。
78.权利要求71的化合物,其中Ar3是任选取代的吡啶基。
79.权利要求78的化合物,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-4-基)-[1,2,4]-噁二唑;
5-(3-甲基-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(4-氯-1H-吡唑-3-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(4-氯-噻唑-5-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氨基-嘧啶-5-基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(N-氧化物-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氰基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(6-甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-氰基-噻吩-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5,6-二氯-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(6-三氟甲基-吡啶-3-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-呋喃-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
5-(3-溴-呋喃-2-基)-3-(5-三氟甲基-吡啶-2-基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)3-(6-甲氧基-吡啶-3-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
80.权利要求71的化合物,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-氯-苄基)-[1,2,4]-噁二唑;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
(4-氯-苯亚甲基)-[5-(3-噻吩-2-基)-[1,2,4]-噁二唑-3基]-胺;
[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3基]-(3-三氟甲基-苯亚甲基)-胺;
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(异喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(吡嗪-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(喹啉-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(8-羟基-喹啉-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(2-甲基-噻唑-4-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(5-硝基-噻唑-2-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(7-甲基-5-三氟甲基-吡唑并[1,5-α]嘧啶-3-基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-[2-(4-氯-苯基)-乙基]-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯氧甲基)-[1,2,4]-噁二唑;
4-氯-N-[5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯甲酰胺;
5-(3-氯-噻吩-2-基)-3-(4-氯-苯胺基)[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)-3-(嘧啶-2-基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
83.权利要求82的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar2是任选地取代的苯基或任选地取代的吡啶基。
84.权利要求83的化合物,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-2-(4-三氟甲氧基-苯基)-1H-咪唑;
5-(3-溴-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;和
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-1H-咪唑;
或其可药用盐或前药。
86.权利要求85的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar3是任选地取代的苯基或任选地取代的吡啶基。
87.权利要求86的化合物,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-苯基-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(4-甲基-苯基)-1H-[1,2,4]-三唑;
5-(3-氯-噻吩-2-基)-3-(3-甲基-苯基)-1H-[1,2,4]-三唑;和
5-(3-氯-噻吩-2-基)-3-(吡啶-2-基)-1H-[1,2,4]-三唑;
或其可药用盐或前药。
89.权利要求88的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar3是任选地取代的苯基或任选地取代的吡啶基。
90.权利要求89的化合物,其中所述化合物选自下列组:
5-(3-氯-噻吩-2-基)-3-(4-三氟甲基-苯基)-[1,3,4]-噁二唑;
5-(6-氯-3-吡啶基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
2-(3-氯-噻吩-2-基)-5-(吡啶-3-基)-[1,3,4]-噁二唑;和
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-[1,3,4]-噁二唑;
或其可药用盐或前药。
92.权利要求91的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar3是任选地取代的苯基或任选地取代的吡啶基。
93.权利要求92的化合物,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-5-苯基-噁唑;
5-(4-溴-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
2-(3-氯-噻吩-2-基)-5-(4-甲氧基-苯基)-噁唑;
5-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-苯基-噁唑;
2-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-噁唑;
2-(6-氯-吡啶-3-基)-5-(3-氯-噻吩-2-基)-噁唑;
5-(3-氯-噻吩-2-基)-2-(4-三氟甲基-苯基)-噁唑;
或其可药用盐或前药。
95.权利要求94的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar2是任选地取代的苯基或任选地取代的吡啶基。
96.权利要求95的化合物,其中所述化合物选自下列组:
2-(3-氯-噻吩-2-基)-4-(4-三氟甲基-苯基)-噁唑;和
4-(4-氯-苯基)-2-(3-氯-噻吩-2-基)-噁唑;
或其可药用盐或前药。
97.权利要求81的化合物,其中所述化合物具有式IX或其可药用盐或前药。
98.权利要求97的化合物,其中:
Ar1是噻吩基、呋喃基、吡咯基,其中每个都是任选地取代的;且Ar2是任选地取代的苯基或任选地取代的吡啶基。
99.权利要求98的化合物,其中所述化合物选自下列组:
3-(4-氯-苯基)-5-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-苯基-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-甲基-1H-吡唑;
5-(4-氯-苯基)-1-(3-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
1,5-双-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(吡啶-2-基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-羧基-苯基)-1H-吡唑;
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(4-甲磺酰基-苯基)-1H-吡唑;和
5-(4-氯-苯基)-3-(3-氯-噻吩-2-基)-1-(2-羟基乙基)-1H-吡唑;
或其可药用盐或前药。
100.选自下组的化合物:
5-(3-溴-噻吩-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(4-氯-3-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3,4-二氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-溴-噻吩-2-基)-5-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;
5-(3-氯-噻吩-2-基)-3-(3-三氟甲基-苯基)-[1,2,4]-噁二唑;
3-(2-氨基-4-氯-苯基)-5-(3-氯-噻吩-2-基)-[1,2,4]-噁二唑;
5-(3,4,5-三氯-噻吩-2-基)3-(4-三氟甲基-苯基)-[1,2,4]-噁二唑;和
5-(3-氯-噻吩-2-基)-3-(2,4-二碘-苯基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
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Cited By (4)
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CN104054719A (zh) * | 2007-08-13 | 2014-09-24 | 孟山都技术有限责任公司 | 用于控制线虫的组合物和方法 |
CN104054719B (zh) * | 2007-08-13 | 2016-09-28 | 孟山都技术有限责任公司 | 用于控制线虫的组合物和方法 |
CN109415356A (zh) * | 2016-06-22 | 2019-03-01 | 伦敦皇家学院 | 4-(5-(4,7-二甲基苯并呋喃-2-基)-1,2,4-噁二唑-3-基)苯甲酸的结晶形式及其制备方法 |
CN106349232A (zh) * | 2016-08-31 | 2017-01-25 | 河北艾林国际贸易有限公司 | 一种噁二唑化合物及其制备方法和应用 |
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WO2002100826A3 (en) | 2003-10-16 |
IL159086A0 (en) | 2004-05-12 |
KR20040004705A (ko) | 2004-01-13 |
RU2003138074A (ru) | 2005-02-20 |
US20050154012A1 (en) | 2005-07-14 |
EP1406632A4 (en) | 2009-11-04 |
EP1406632A2 (en) | 2004-04-14 |
WO2002100826A2 (en) | 2002-12-19 |
US7435750B2 (en) | 2008-10-14 |
US7041685B2 (en) | 2006-05-09 |
JP2005504014A (ja) | 2005-02-10 |
AU2002313633B2 (en) | 2007-03-01 |
MXPA03011196A (es) | 2004-10-28 |
US20030045546A1 (en) | 2003-03-06 |
CA2449544A1 (en) | 2002-12-19 |
ZA200309309B (en) | 2004-11-29 |
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