CN113912595A - 一类含有噻唑或噻二唑结构的化合物及其应用 - Google Patents
一类含有噻唑或噻二唑结构的化合物及其应用 Download PDFInfo
- Publication number
- CN113912595A CN113912595A CN202111188298.XA CN202111188298A CN113912595A CN 113912595 A CN113912595 A CN 113912595A CN 202111188298 A CN202111188298 A CN 202111188298A CN 113912595 A CN113912595 A CN 113912595A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- ring
- iii
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 184
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 title abstract description 9
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 title abstract 3
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 4
- -1 cyano, nitro, amino, hydroxyl Chemical group 0.000 claims description 121
- 125000003118 aryl group Chemical group 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000004185 ester group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 4
- 125000002560 nitrile group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 3
- WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical group C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 claims description 3
- AWPNFXRMNNPKDW-UHFFFAOYSA-N 4-phenylthiadiazole Chemical group S1N=NC(C=2C=CC=CC=2)=C1 AWPNFXRMNNPKDW-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 3
- 229940114124 ferulic acid Drugs 0.000 claims description 3
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 3
- 235000001785 ferulic acid Nutrition 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 3
- 229940107700 pyruvic acid Drugs 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 208000030172 endocrine system disease Diseases 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims description 2
- 208000014951 hematologic disease Diseases 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- 159000000007 calcium salts Chemical class 0.000 claims 1
- 150000002169 ethanolamines Chemical class 0.000 claims 1
- 159000000003 magnesium salts Chemical class 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 159000000000 sodium salts Chemical group 0.000 claims 1
- 101000841466 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 8 Proteins 0.000 abstract description 17
- 102100029088 Ubiquitin carboxyl-terminal hydrolase 8 Human genes 0.000 abstract description 17
- 230000006798 recombination Effects 0.000 abstract description 3
- 238000005215 recombination Methods 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 103
- 239000007787 solid Substances 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 60
- 238000000034 method Methods 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- 230000008569 process Effects 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 125000005605 benzo group Chemical group 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
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- 230000002401 inhibitory effect Effects 0.000 description 6
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical class ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- 239000000758 substrate Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 5
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
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- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 4
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- 101150065749 Churc1 gene Proteins 0.000 description 4
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
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- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- CMIBWIAICVBURI-UHFFFAOYSA-N tert-butyl 3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)C1 CMIBWIAICVBURI-UHFFFAOYSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-UHFFFAOYSA-N tert-butyl n-pyrrolidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNC1 DQQJBEAXSOOCPG-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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Abstract
本发明公开了一类含有噻唑或噻二唑结构的化合物及其应用，属于医药技术领域。本发明利用药效团拆分及重组等手段对先导化合物进行结构优化，得到一系列含有噻唑或噻二唑结构的新型骨架的USP8抑制剂，丰富了USP8抑制剂的结构多样性。
Description
技术领域
本发明属于医药技术领域，具体涉及一类含有噻唑或噻二唑结构的化合物及其在制备泛素特异性蛋白酶USP8的抑制剂中的应用。
背景技术
泛素化是一种重要的翻译后修饰过程，通过将泛素转移到底物蛋白上，可以实现对蛋白稳定性和活性的调节，并且泛素化过程还与蛋白的功能定位以及蛋白-蛋白相互作用的正常发挥密切相关(Han J et al.Bioorganic Chemistry,2020,101:103962)。像其他翻译后修饰一样，泛素化是一个可逆的过程。去泛素化酶可以去除底物中的泛素，保护底物不被降解。USP8属于泛素特异性蛋白酶(USPs)家族中的一员，研究表明USP8基因突变或者蛋白的过表达与多种腺癌、胃癌等的发生密切相关。例如对库欣病等垂体腺瘤患者基因测序，发现USP8的体细胞突变导致胞内EGFR去泛素化程度增加，使EGFR在细胞膜上大量积累。而高EGFR水平反过来促使血浆ACTH增加，从而诱导垂体腺瘤的发生(Martin Reinckeet.al.Nat.Genet.2015,47:31–38)。目前治疗非小细胞肺癌的首选药物是受体酪氨酸激酶抑制剂，如吉非替尼和厄洛替尼。但由于EGFR二次突变和/或Met基因扩增，会导致许多患者产生耐药性。而USP8小分子抑制剂通过减少EGFR的表达，抑制了吉非替尼耐药的癌细胞增殖，而对正常细胞无影响(Kim,Y.et.al.Oncogene 2018,37,5387-5402.)。因此，USP8有望成为一种有效的肿瘤治疗靶标，针对其开展化学干预，抑制USP8异常的去泛素化活性，可为肿瘤治疗提供新的途径。
基于已报道的一类含硫脲结构的USP8小分子抑制剂(CN111138358A)，为进一步提高化合物抑制活性，并改善其不良理化性质。申请人采用骨架跃迁与药效团拆分及重组等手段，获得了一类含有噻唑或噻二唑结构的新型化合物，丰富了USP8抑制剂的结构多样性。
发明内容
本发明利用药效团拆分及重组等手段对先导化合物进行结构优化，得到一系列含有噻唑或噻二唑结构的新型骨架的USP8抑制剂，并且活性、选择性以及理化性质相较于之前报道的硫脲类结构的USP8抑制剂均有大幅度的提升。
为了实现上述发明目的，本发明采用以下技术方案：
通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐，
式(Ⅰ)中，
X选自
其中n、i各自独立选自0、1或2，m选自1、2或3，n1、n2、m1、m2各自独立选自1、2或3；
R1、R2各自独立地选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素、酯基中的一个或多个；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、氰基、氨基、羟基、羧基、酯基中的一个或多个；
式(Ⅱ)中，
X为C或N，当X为C时，Z为H，A片段为取代芳香环，其中取代基选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素或酯基中的一个或多个；当X为N时，A片段不存在，Z选自取代芳香环，其中取代基选自氢原子、烷基、烷氧基、三氟甲基、腈基、硝基、氨基、羟基、卤素或酯基中的一个或多个；
Y选自
其中n、i各自独立选自0、1或2，m选自1、2或3，n1、n2、m1、m2各自独立选自1、2或3；
R2选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素或酯基中的一个或多个；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、氰基、氨基、羟基、羧基或酯基中的一个或多个；
式(Ⅲ)中，
A片段选自苯基噻唑环、苯基噻二唑环或苯并噻唑环；
X为-C(O)-、-S(O)2-或不存在；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、腈基、氨基、羟基、羧基或酯基中的一个或多个。
本发明所述的通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物的药学上可接受的盐，是指通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成碱加成盐，所述酸包括：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；所述碱加成盐包括：钠盐、钾盐、铵盐、钙盐、铝盐、镁盐或其他金属盐，乙二胺、乙醇胺或其他常见碱加成盐。
通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物可通过以下路线合成。
第一类化合物的合成：
第二类化合物的合成(苯基噻唑类)：
第二类化合物的合成(苯基噻二唑类)：
第三类化合物的合成：
由化合物I-1制备化合物I-2的过程，通过芳香磺酰氯与取代芳香胺反应，溶剂优先采用水，所用缚酸剂为氢氧化钠；由化合物I-3制备化合物I-4的过程，通过酰胺缩合反应得到，缩合剂优选为HATU，碱为N,N-二异丙基乙胺，溶剂优选N,N-二甲基甲酰胺；由化合物I-5制备化合物I-6的过程，为碱性条件的亲核取代反应，选用碱为碳酸钾，溶剂为丙酮或N,N-二甲基甲酰胺；由化合物I-6制备化合物I-7的过程，同化合物I-4；由化合物I-5制备化合物I-8的过程，通过4-Boc-氨基哌啶与芳香卤化物的亲核取代反应得到，选用碱为碳酸钾，溶剂为丙酮或N,N-二甲基甲酰胺；由化合物I-8制备化合物I-9的过程，为脱Boc保护基反应，采用6mol/L盐酸水溶液与1，4-二氧六环的混合体系脱除；由化合物I-9制备化合物I-10的过程，同化合物I-4。
由化合物II-1制备化合物II-2的过程，通过卤素与硫氰酸钾反应生成异硫氰酸酯，溶剂为甲醇或乙醇；由化合物II-2制备化合物II-3的过程，通过异硫氰酸酯合成噻唑环得到，溶剂优选33％氢溴酸乙酸溶液。
由化合物II-4制备化合物II-5的过程，利用2-溴苯乙酮与硫脲反应，溶剂为乙醇；由化合物II-5制备化合物II-6的过程，同化合物I-4。由化合物II-3制备化合物II-7的过程，同化合物I-6；由II-7制备化合物II-8的过程，同化合物I-4；由化合物II-3制备化合物II-9的过程，同化合物I-8；由化合物II-9制备化合物II-10的过程，同化合物I-9；由化合物II-10制备化合物II-11的过程，同化合物I-4。化合物II-14、II-17、II-20的制备过程与化合物II-11的过程类似。由化合物II-21制备化合物II-22的过程，为取代苯甲酸与硫代氨基脲的反应，三氯氧磷为催化剂；由化合物II-22制备化合物II-23的过程，同化合物I-4。由化合物II-22制备化合物II-24的过程，为氨基被卤素取代反应，反应试剂溴化铜，亚硝酸异戊酯，溶剂为乙腈；由化合物II-24制备化合物II-25的过程，同化合物I-6；由化合物II-25制备化合物II-26的过程，同化合物I-4。
由化合物III-1制备化合物III-2的过程，同化合物I-4；由化合物III-2制备化合物III-3的过程，为卤素与氨基的偶联反应，碱为N,N-二异丙基乙胺，溶剂为二甲亚砜；由化合物III-3制备化合物III-4的过程，为硝基还原反应，由铁粉/浓盐酸催化，溶剂为乙醇；由化合物III-4制备化合物III-5的过程，为氨基与酰氯或磺酰氯反应所得，缚酸剂为吡啶，溶剂为二氯甲烷；化合物III-9的制备过程，同化合物III-4；由化合物III-9制备化合物III-10的过程，为氨基与卤素偶联反应，碱为碳酸铯，溶剂为1,4-二氧六环。
所述通式(Ⅰ)、(Ⅱ)、(Ⅲ)化合物的药学上可接受的盐可通过与等化学当量或过量酸(无机酸或有机酸)在合适的溶剂或溶剂组合物中反应制得。所述酸包括但不限于氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。所述溶剂包括但不限于甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯或四氢呋喃，或任意几种混合溶剂。
本发明提供了一种药物组合物，其包括药物有效量的活性组分和药学上可接受的辅料；所述活性组分包括通式(Ⅰ)、(Ⅱ)、(Ⅲ)化合物和药学上可接受的盐中的一种或多种。所述药物组合物中，所述辅料包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、颗粒剂、胶囊和针剂(溶液或悬浮液)等，优选片剂、胶囊、液体、悬浮液和针剂(溶液或悬浮液)。
本发明所述化合物在临床上的给药方式可采用口服、注射等方式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1-1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
本发明还提供了所示通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物在制备USP8抑制剂中的应用。
本发明还提供通式(Ⅰ)、(Ⅱ)、(Ⅲ)所示化合物在用于治疗USP8介导的免疫抑制相关疾病中的应用。
本发明所述的USP8介导的免疫抑制相关疾病包括癌症、神经变性疾病、血液系统疾病、内分泌系统疾病。其中癌症优选但不局限于非小细胞肺癌、肝癌、胃癌、胆管癌、乳腺癌、胰腺癌、宫颈癌、垂体瘤、多发性骨髓瘤、白血病、黑色素瘤、胶质瘤；神经系统变性疾病优选但不局限于帕金森症、阿尔兹海默症；血液系统疾病优选但不局限于范可尼贫血；内分泌系统疾病优选但不局限于库欣病。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
术语“芳香环”指含有1-12个碳原子的单环或稠合多环或联苯基团，具有完全的共轭π电子系统。芳香环的非限制性实例有苯基、萘基和联苯，芳香环可以是取代的或未取代的。
术语“芳杂环”指含有1-6个原子的单环体系，体系含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，并具有完全的共轭π电子系统。未取代的芳杂环非限制性实例包括吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、噻二唑、吡唑、吡啶、嘧啶、四唑和三嗪。芳杂环可以是取代的或未取代的。
术语“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个。
术语“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
术语“三氟甲基”表示-CF3基团。
术语“硝基”表示-NO2基团。
术语“氨基”表示-NH2基团。
术语“氰基”表示-CN基团。
术语“羧基”表示-COOH基团。
术语“羟基”表示-OH基团。
术语“酯基”表示-COOCH3等甲酸酯基团。
术语“卤素”表示氟、氯、溴或碘。优选为氟、氯、溴。
具体实施方式
为了进一步阐释本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
4-甲氧基-2-(噻吩-2-磺酰胺基)苯甲酸(I-2)
将化合物I-1(0.5g,2.7mmol)，噻吩-2-磺酰氯(0.49g,2.7mmol)，氢氧化钠(0.13g,3.24mmol)以及水(20ml)加入到三颈瓶中，室温下快速搅拌5h，逐渐有大量灰色固体析出。反应液抽滤，用1mol/L盐酸洗涤滤饼，烘干，得灰色固体0.7g，收率77％。1H NMR(300MHz,DMSO-d6):δ＝8.02-8.00(t,1H,J1＝3.8Hz,J2＝1.2Hz,Ar-H),7.93-7.90(d,1H,J＝8.8Hz,Ar-H),7.75(s,1H,Ar-H),7.19-7.18(s,1H,Ar-H),7.12-7.11(d,1H,J＝2.4Hz,Ar-H),6.79-6.76(dd,1H,J1＝8.9Hz,J2＝2.5Hz,Ar-H),3.85(s,3H,OCH3)ppm.HRMS(ESI),[M+H]+calculated for C12H11NO5S2 314.0152,found 314.0158。
N-(苯并[d]噻唑-2-基)-4-甲氧基-2-(噻吩-2-磺酰氨基)苯甲酰胺(L01)
将化合物I-2(0.2g,0.64mmol)，HATU(0.3g,0.77mmol),N,N-二异丙基乙胺(0.26g,1.92mmol)，N,N-二甲基甲酰胺(1mL)加入到三颈瓶中，氮气保护条件下0℃搅拌30min，加入苯并[d]噻唑-2-胺(96mg，0.64mmol),氮气保护下70℃反应6h，待反应结束后，反应液冷却至室温，缓慢加入到5mL的1mol/L盐酸中，逐渐析出淡黄色固体。抽滤，滤饼烘干后，经硅胶柱层析纯化得淡黄色固体0.1g，收率50％。1H NMR(300MHz,DMSO-d6):δ＝8.15-8.12(d,1H,J＝8.9Hz,Ar-H),8.04-8.01(d,1H,J＝7.9Hz,Ar-H),7.95-7.93(d,1H,J＝4.1Hz,Ar-H),7.76-7.74(d,1H,J＝7.7Hz,Ar-H),7.67-7.66(d,1H,J＝2.8Hz,Ar-H),7.55-7.50(t,1H,J1＝8.0Hz,J2＝7.5Hz,Ar-H),7.41-7.37(t,1H,J1＝8.0Hz,J2＝7.1Hz,Ar-H),7.15-7.12(t,1H,J1＝4.7Hz,J2＝4.1Hz,Ar-H),7.08-7.07(d,1H,J＝2.3Hz,Ar-H),6.86(s,1H,Ar-H),3.85(s,3H,OCH3)ppm.HRMS(ESI),[M+H]+calculated for C19H15N3O4S3446.0298,found 446.0193。
实施例2
N-(苯并[d]噻唑-2-基)-4-甲氧基-2-(吡啶-3-磺酰氨基)苯甲酰胺(L02)
用吡啶-3-磺酰氯(0.5g,2.8mmol)代替噻吩-2-磺酰氯之外，以与化合物L01相同的方法合成得到淡黄色固体90mg，收率61％。1H NMR(300MHz,DMSO-d6):δ＝9.00(s,1H,Ar-H),8.84-8.82(d,1H,J＝4.8Hz,Ar-H),8.26-8.24(d,1H,J＝8.2Hz,Ar-H),8.09-8.06(d,2H,J＝7.1Hz,Ar-H),7.80-7.79(d,1H,J＝5.1Hz,Ar-H),7.65-7.54(m,2H,Ar-H),7.46-7.41(t,1H,J1＝7.7Hz,J2＝7.5Hz,Ar-H),7.01(s,1H,Ar-H),6.93-6.89(d,1H,J＝9.6Hz,Ar-H),3.87(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C20H16N4O4S2 439.0540,found 439.0503。
实施例3
4-三氟甲基-2-(萘-1-磺酰胺基)苯甲酸(I-4)
将化合物I-3(0.36g,1.76mmol)，萘-1-磺酰氯(0.4g,1.76mmol)，氢氧化钠(84mg,2.1mmol)，水(10ml)加入到三颈瓶中，室温下快速搅拌3h，逐渐有大量白色固体析出。反应液抽滤，用1mol/L盐酸洗涤滤饼，烘干，得白色固体0.5g，收率72％。1H NMR(300MHz,DMSO-d6):δ＝8.78-8.75(d,1H,J＝8.4Hz,Ar-H),8.25-8.23(d,1H,J＝7.4Hz,Ar-H),8.14-8.11(d,1H,J＝8.4Hz,Ar-H),8.03-8.01(d,1H,J＝7.6Hz,Ar-H),7.96-7.93(d,1H,J＝8.2Hz,Ar-H),7.66-7.56(m,4H,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C18H12F3NO4S396.0512,found 396.0548。
N-(苯并[d]噻唑-2-基)-4-三氟甲基-2-(萘-1-磺酰氨基)苯甲酰胺(L04)
将化合物I-4(0.26g,0.66mmol)代替化合物2外，以与化合物L01相同的方法合成得到灰白色固体0.15g，收率68％。1H NMR(300MHz,DMSO-d6):δ＝9.18-9.15(d,1H,J＝8.9Hz,Ar-H),8.23-8.21(d,1H,J＝7.2Hz,Ar-H),8.12-8.09(d,1H,J＝8.5Hz,Ar-H),8.05-8.03(d,2H,J＝8.2Hz,Ar-H),7.97-7.88(m,3H,Ar-H),7.62-7.50(m,2H,Ar-H),7.47-7.30(m,3H,Ar-H),6.93-6.90(d,1H,J＝8.9Hz,Ar-H)ppm.HRMS(ESI),[M-H]-calculated forC25H16F3N3O3S2526.0512,found 526.0504。
实施例4
4-苯基噻唑-2-胺(II-2)
将化合物II-1(2g,10.05mmol)，硫脲(0.84g,11.16mmol)，乙醇(20ml)加入到三颈瓶中，反应液澄清，加热回流3h，TLC监测反应完全，待反应结束后，将反应液减压蒸除溶剂，乙醇加水重结晶得黄色固体1.6g，收率90％。
N-(4-苯基噻唑-2-基)-4-三氟甲基-2-(萘-1-磺酰氨基)苯甲酰胺(L06)
用化合物II-2(0.2g,1.14mmol)代替苯并噻唑-2-胺以外，以与化合物L04相同的方法合成得到米黄色固体0.4g，收率85％。1H NMR(300MHz,DMSO-d6):δ＝8.40-8.37(dd,1H,J1＝7.3Hz,J2＝1.3Hz,Ar-H),8.22(s,1H,Ar-H),8.18-8.14(m,4H,Ar-H),7.97-7.95(d,1H,J＝8.2Hz,Ar-H),7.86-7.82(m,1H,Ar-H),7.57-7.55(m,1H,Ar-H),7.52-7.47(m,4H,Ar-H),7.40-7.33(m,3H,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C27H18F3N3O3S2554.0815,found 554.0815。
实施例5
N-(4-苯基噻唑-2-基)-4-甲氧基-2-(噻吩-2-磺酰氨基)苯甲酰胺(L09)
用化合物II-2(0.11g,0.64mmol))代替苯并噻唑-2-胺以外，以与化合物L01相同的方法合成得到淡黄色固体0.1g，收率60％。1H NMR(300MHz,DMSO-d6):δ＝8.13-8.10(d,1H,J＝8.7Hz,Ar-H),7.99-7.97(t,3H,J1＝5.1Hz,J2＝1.4Hz,Ar-H),7.77(s,1H,Ar-H),7.71-7.70(d,1H,J＝3.7Hz,Ar-H),7.53-7.46(m,2H,Ar-H),7.40-7.35(t,1H,J1＝6.9Hz,J2＝6.5Hz,Ar-H),7.16-7.13(t,1H,J1＝4.5Hz,J2＝4.2Hz,Ar-H),7.06(s,1H,Ar-H),6.88-6.86(d,1H,J＝8.6Hz,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C21H17N3O4S3470.0308,found 470.0373。
实施例6
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((2-(三氟甲基)苯基)磺酰氨基)苯甲酰胺(L11)
用2-(三氟甲基)苯磺酰氯(0.5g,2.04mmol)代替噻吩-2-磺酰氯之外，以与化合物L09相同的方法合成得到淡黄色固体0.2g，收率70％。1H NMR(300MHz,DMSO-d6):δ＝8.26-8.24(d,1H,J＝7.0Hz,Ar-H),8.13-8.10(d,1H,J＝8.9Hz,Ar-H),8.02-7.87(m,5H,Ar-H),7.76(s,1H,Ar-H),7.50-7.45(t,1H,J1＝7.7Hz,J2＝7.3Hz,Ar-H),7.39-7.34(m,1H,Ar-H),6.95-6.94(d,1H,J＝2.3Hz,Ar-H),6.83-6.80(m,1H,Ar-H),3.80(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C24H18F3N3O4S2 532.0618,found 532.0614。
实施例7
4-溴-2-(吡啶-3-磺酰氨基)苯甲酸(II-4)
将化合物II-3(0.3g,1.39mmol))，吡啶-3-磺酰氯(0.25g,1.39mmol)，氢氧化钠(67mg,1.67mmol)，水(15ml)加入到三颈瓶中，逐渐有橙黄色固体析出。待反应结束后，抽滤，滤饼用甲醇打浆后抽滤，得淡黄色固体纯品0.3g，收率61％。1H NMR(300MHz,DMSO-d6):δ＝9.02(s.1H,Ar-H),8.88-8.87(d,1H,J＝3.7Hz,Ar-H),8.27-8.25(d,1H,J＝5.6Hz,Ar-H),7.87-7.84(d,1H,J＝8.5Hz,Ar-H),7.70-7.65(m,2H,Ar-H),7.44-7.41(d,1H,J＝8.6Hz,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C12H9BrN2O4S 354.9393,found354.9390。
N-(4-苯基噻唑-2-基)-4-溴-2-(吡啶-3-磺酰氨基)苯甲酰胺(L12)
用化合物II-4(0.3g,0.84mmol)代替中间体I-4之外，以与化合物L06相同的方法合成得到淡黄色固体0.12g，收率72％。1H NMR(300MHz,DMSO-d6):δ＝8.94-8.80(m,2H,Ar-H),8.28-8.16(m,1H,Ar-H),8.00-7.97(d,1H,J＝8.4Hz,Ar-H),7.88-7.76(m,2H,Ar-H),7.70-7.59(m,1H,Ar-H),7.53-7.39(m,4H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated forC21H15BrN4O3S2 512.9696,found 512.9690。
实施例8
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((4-溴苯基)磺酰氨基)苯甲酰胺(L14)
用4-溴苯磺酰氯(0.3g,1.17mmol)代替噻吩-2-磺酰氯之外，以与化合物L09相同的方法合成得到浅灰色固体0.13g，收率75％。1H NMR(300MHz,DMSO-d6):δ＝8.05-7.97(m,3H,Ar-H),7.77-7.75(d,5H,J＝4.1Hz,Ar-H),7.51-7.46(t,2H,J1＝7.2Hz,J2＝7.8Hz,Ar-H),7.52-7.47(t,2H,J1＝7.7Hz,J2＝7.2Hz,Ar-H),7.40-7.37(d,1H,J＝7.3Hz,Ar-H),6.92-6.91(d,1H,J＝2.5Hz,Ar-H),6.88-6.84(dd,1H,J1＝8.9Hz,J2＝2.5Hz Ar-H),3.82(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C23H18BrN3O4S2 541.9849,found541.9839。
实施例9
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((4-(4-甲基吡啶-3-基)苯基)磺酰胺基)苯甲酰胺(L15)
将化合物L14(0.2g,0.36mmol)，4-甲基吡啶-3-硼酸频那醇酯(0.15g,0.72mmol)，碳酸钾(0.1g,0.72mmol)，四三苯基膦钯(20mg,0.018mmol)，1,4-二氧六环(2ml)，水(1ml)加入到三颈瓶中，反应需氮气保护，70-80℃反应过夜，TLC监测原料L14反应完全。反应液抽滤，滤液用二氯甲烷萃取，将有机层用无水硫酸钠除水，减压蒸除溶剂。柱层析纯化得米黄色固体0.15g，收率75％。1H NMR(300MHz,DMSO-d6):δ＝8.49-8.47(d,1H,J＝5.1Hz,Ar-H),8.40(s,1H,Ar-H),8.09-8.06(d,1H,J＝8.9Hz,Ar-H),7.98-7.89(m,4H,Ar-H),7.76(s,1H,Ar-H),7.69-7.58(m,6H,Ar-H),7.51-7.46(t,2H,J1＝7.6Hz,J2＝7.3Hz,Ar-H),7.38(s,1H,Ar-H),7.01-7.00(d,1H,J＝2.4Hz,Ar-H),3.84(s,3H,OCH3),2.2(s,3H,CH3-Ar)ppm.HRMS(ESI),[M-H]-calculated for C29H24N4O4S2 555.1166,found 555.1428。
实施例10
2-(吡啶-3-磺酰氨基)-4-(三氟甲基)苯甲酸(II-6)
用吡啶-3-磺酰氯(0.43g,2.44mmol)代替萘-1磺酰氯之外，以与化合物I-4相同的方法合成得到浅灰色固体0.6g，收率82％。1H NMR(300MHz,DMSO-d6):δ＝8.97(s,1H,Ar-H),8.85(s,1H,Ar-H),8.21-8.10(m,2H,Ar-H),7.71-7.55(m,3H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C13H9F3N2O4S 345.0162,found 345.0149。
5-苯基-1,3,4-噻二唑-2-胺(II-8)
将苯甲酸(0.43g,2.44mmol)，硫代氨基脲(1.8g,19.67mmol)，三氯氧磷(20ml)加入到三颈瓶中，75℃反应5小时，TLC监测反应完全。待反应液冷却至室温，在冰浴的条件下向反应液中缓慢滴加1mol/L盐酸溶液淬灭三氯氧磷。后用乙酸乙酯萃取，将有机层用无水硫酸钠除水，减压蒸出溶剂。柱层析纯化得白色固体1.9g，收率88％。1H NMR(300MHz,DMSO-d6):δ＝7.83-7.81(t,2H,J1＝3.7Hz,J2＝3.5Hz,Ar-H),7.57-7.55(t,3H,J1＝2.9Hz,J2＝2.4Hz,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C8H7N3S 178.0434,found 178.0419。
N-(5-苯基-1,3,4-噻二唑-2-基)-4-三氟甲基-2-(吡啶-3-磺酰氨基)苯甲酰胺(L17)
用中间体II-8(0.1g,0.578mmol)代替中间体II-2之外，以与化合物L09相同的方法合成得到淡黄色固体0.1g，收率65％。1H NMR(300MHz,DMSO-d6):δ＝8.86(s,1H,Ar-H),8.78-8.77(d,1H,J＝4.6Hz,Ar-H),8.12-8.10(d,1H,J＝7.9Hz,Ar-H),8.01-8.00(m,3H,Ar-H),7.67-7.51(m,6H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C21H14F3N5O3S2504.0417,found 504.0362。
实施例11
N-(5-苯基-1,3,4-噻二唑-2-基)-4-溴-2-(吡啶-3-磺酰氨基)苯甲酰胺(L19)
用中间体II-8(0.17g,0.95mmol)代替中间体II-2之外，以与化合物L12相同的方法合成得到米白色固体0.60g，收率90％。1H NMR(300MHz,DMSO-d6):δ＝8.92(s,1H,Ar-H),8.82-8.80(d,1H,J＝4.8Hz,Ar-H),8.18-8.15(m,1H,Ar-H),8.05-8.02(m,1H,Ar-H),7.86-7.82(m,1H,Ar-H),7.64-7.59(m,4H,Ar-H),7.52-7.48(m,2H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C20H14BrN5O3S2 513.9648,found 513.9640。
实施例12
N-(5-苯基-1,3,4-噻二唑-2-基)-4-三氟甲基-2-([1,1'-联苯]-4-磺酰氨基)苯甲酰胺(L22)
用中间体II-8(0.1g,0.59mmol)代替中间体II-2之外，以与化合物L07相同的方法合成得到灰色固体0.15g，收率72％。1H NMR(300MHz,DMSO-d6):δ＝8.11-8.08(m,2H,Ar-H),7.92-7.91(m,4H,Ar-H),7.73-7.67(m,7H,Ar-H),7.55-7.54(m,4H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C28H19F3N4O3S2 579.0778,found 579.0776。
实施例13
2-(4-(2-硝基苯基)哌嗪-1-基)苯并[d]噻唑(III-3)
将化合物III-2(0.62g,2.8mmol)，邻氟硝基苯(0.3g,2.34mmol)，二甲亚砜(5ml)，N,N-二异丙基乙胺(0.6g,4.70mmol)加入到三颈瓶中，氮气保护下100℃反应4h，待反应结束后，反应液冷却至室温，用1mol/L盐酸水洗，用二氯甲烷萃取。将有机层用无水硫酸钠除水，减压蒸出溶剂，得黄色固体0.8g，收率91％。1H NMR(300MHz,DMSO-d6):δ＝7.91-7.88(dd,1H,J1＝8.1Hz,J2＝1.4Hz,Ar-H),7.85-7.82(d,1H,J＝7.8Hz,Ar-H),7.69-7.64(t,1H,J1＝7.2Hz,J2＝6.8Hz,Ar-H),7.54-7.51(d,1H,J＝8.0Hz,Ar-H),7.46-7.44(d,1H,J＝8.1Hz,Ar-H),7.36-7.31(t,1H,J1＝8.1Hz,J2＝7.2Hz,Ar-H),7.26-7.21(t,1H,J1＝8.1Hz,J2＝7.3Hz,Ar-H),7.16-7.11(t,1H,J1＝7.8Hz,J2＝7.4Hz,Ar-H),3.76-3.72(m,4H,NCH 2CH2N),3.22-3.19(m,4H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated for C17H16N4O2S341.1067,found 341.1077。
2-(4-(苯并[d]噻唑-2-基)哌嗪-1-基)苯胺(III-4)
将化合物III-3(0.8g,2.35mmol)，还原铁粉(0.66g,11.75mmol)，乙醇(15ml)加入到三颈瓶中，向其中加入几滴浓盐酸，加热回流反应3h。待反应结束后，趁热过滤除掉铁粉，将滤液减压蒸出溶剂，加乙酸乙酯溶解，用饱和碳酸氢钠溶液调PH至中性或弱碱性，将乙酸乙酯减压蒸出溶剂，柱层析纯化得淡黄色固体0.6g，收率80％。1H NMR(300MHz,DMSO-d6):δ＝7.83-7.80(dd,1H,J1＝7.1Hz,J2＝0.8Hz,Ar-H),7.52-7.50(d,1H,J＝7.5Hz,Ar-H),7.35-7.29(m,1H,Ar-H),7.14-7.09(m,1H,Ar-H),6.97-6.94(dd,1H,J1＝7.8Hz,J2＝1.3Hz,Ar-H),6.90-6.84(m,1H,Ar-H),7.46-7.44(dd,1H,J1＝7.9Hz,J2＝1.4Hz,Ar-H),6.62-6.56(m,1H,Ar-H),3.78-3.74(m,4H,NCH 2CH2N),2.98-2.95(m,4H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated for C17H18N4S 311.1325,found 341.1299。
N-(2-(4-(苯并[d]噻唑-2-基)哌嗪-1-基)苯基)-2-甲基苯甲酰胺(L24)
将化合物III-4(0.2g,0.58mmol)，吡啶(0.14g,1.54mmol)，二氯甲烷(2ml)加入到三颈瓶中，将邻甲基苯甲酰氯(90mg,0.58mmol)缓慢滴加到反应体系中。待反应结束后，反应液加入甲醇淬灭，经柱层析纯化得到乳黄色固体0.18g，收率78％。1H NMR(300MHz,CDCl3-d3):δ＝8.89(s,1H,NH),7.76-7.73(d,1H,J＝7.8Hz,Ar-H),7.68-7.65(d,1H,J＝7.6Hz,Ar-H),7.56-7.54(d,1H,J＝7.3Hz,Ar-H),7.43-7.41(d,2H,J＝6.5Hz,Ar-H),7.36-7.34(d,3H,J＝6.9Hz,Ar-H),7.29-7.23(m,2H,Ar-H),7.21-7.15(m,2H,Ar-H),3.88-3.80(m,4H,NCH 2CH2N),3.13-3.12(m,4H,NCH2CH2 N),2.62(s,3H,CH3Ar)ppm.HRMS(ESI),[M-H]-calculated for C25H24N4OS 429.1744,found 429.1675。
实施例14
N-(2-(4-(苯并[d]噻唑-2-基)哌嗪-1-基)苯基)-3-(三氟甲基)苯磺酰胺(L26)
用3-三氟甲基苯磺酰氯(0.15g,0.6mmol))代替邻甲苯甲酰氯之外，以与化合物L24相同的方法合成得到米白色固体0.12g，收率76％。1H NMR(300MHz,CDCl3-d3):δ＝9.54(s,1H,NH),8.11-8.08(d,3H,J＝10.5Hz,Ar-H),7.90-7.80(m,2H,Ar-H),7.51-7.49(d,1H,J＝8.0Hz,Ar-H),7.40-7.29(m,2H,Ar-H),7.21-7.09(m,4H,Ar-H),3.62-3.59(t,4H,NCH 2CH2N),2.66-2.64(t,4H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated forC24H21F3N4O2S2 519.1131,found 519.1150。
实施例15
N-(2-(4-(苯并[d]噻唑-2-基)哌嗪-1-基)苯基)-4-苯基噻唑-2-胺(L28)
将化合物III-4(0.24g,0.71mmol)，2-溴-4-苯基噻唑(0.17g,0.71mmol)，碳酸铯(0.7g,2.13mmol)，醋酸钯(8mg,0.035mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(25mg,0.04mmol)，1,4-二氧六环(3ml)加入到三颈瓶中，氮气保护，加热回流反应过夜。待反应结束后，反应液抽滤，将滤液减压蒸出溶剂，经柱层析纯化得灰白色固体0.14g，收率73％。1HNMR(300MHz,DMSO-d6):δ＝7.94-7.91(d,3H,J＝7.3Hz.Ar-H),7.72(s,2H,Ar-H),7.50-7.37(m,4H,Ar-H),7.13-7.04(m,1H,Ar-H),3.29-3.24(m,4H,NCH 2CH2N),3.02-3.01(m,4H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated for C26H23N5S3 470.1468,found 470.1499。
实施例16
N-(2-(4-(4-苯基噻唑-2-基)哌嗪-1-基)苯基)-4-苯基噻唑-2-胺(L30)
用2-溴-4-苯基噻唑(0.5g,2.09mmol)代替2-溴苯并噻唑之外，以与化合物L27相同的方法合成得到灰白色固体0.11g，收率56％。1H NMR(300MHz,DMSO-d6):δ＝9.32(s,1H,NH),8.42-8.39(d,1H,J＝8.2Hz,Ar-H),7.95-7.90(t,4H,J1＝8.6Hz,J2＝7.8Hz,Ar-H),7.48-7.38(m,6H,Ar-H),7.37-7.35(m,2H,Ar-H),7.27-7.19(m,2H,Ar-H),7.09-7.04(t,1H,J1＝7.7Hz,J2＝7.5Hz,Ar-H),3.76-3.70(m,4H,NCH 2CH2N),3.06-3.04(m,4H,NCH2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C28H25N5S2 496.1624,found 496.1676。
实施例17
N-(2-(4-(苯并[d]噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L31)
中间体II-6(0.25g,0.73mmol)与化合物III-2(0.16g,0.73mmol)进行酰胺缩合反应，合成方法与化合物L17类似，得到淡黄色固体0.13g，收率62％。1H NMR(300MHz,DMSO-d6):δ＝10.58(s,1H,NH),8.91-8.90(d,1H,J＝1.8Hz,Ar-H),8.87-8.85(dd,1H,J1＝4.8Hz,J2＝1.5Hz,Ar-H),8.19-8.15(m,1H,Ar-H),7.87-7.84(d,1H,J＝7.1Hz,Ar-H),7.73-7.64(m,3H,Ar-H),7.54-7.52(d,1H,J＝7.5Hz,Ar-H),7.39-7.33(m,2H,Ar-H),7.19-7.13(m,1H,Ar-H),3.77-3.74(m,4H,NCH 2CH2N),3.64-3.59(m,2H,NCH2CH2 N),3.36-3.30(m,2H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated for C24H20F3N5O3S2 548.1033,found548.1038。
实施例18
N-(2-(4-(苯并[d]噻唑-2-基)哌嗪-1-羰基)-5-甲氧基苯基)-[1,1'-联苯]-4-磺酰胺(L33)
用[1,1'-联苯]-4-磺酰氯(0.3g,1.19mmol)代替4-三氟甲基苯磺酰氯之外，以与化合物L31相同的方法合成得到淡黄色固体0.12g，收率54％。1H NMR(300MHz,Acetone-d6):δ＝9.30(s,1H,NH),8.49-8.46(dd,1H,J1＝8.4Hz,J2＝1.4Hz,Ar-H),8.06-8.03(d,1H,J＝7.9Hz,Ar-H),7.98-7.91(m,3H,Ar-H),7.75-7.72(m,2H,Ar-H),7.64-7.63(m,2H,Ar-H),7.57-7.50(m,2H,Ar-H),7.46-7.35(m,3H,Ar-H),7.21-7.20(d,1H,J＝2.4Hz,Ar-H),6.83-6.79(dd,1H,J1＝8.7Hz,J2＝2.5Hz,Ar-H),3.89(s,3H,OCH3),3.00-2.83(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C31H28N4O4S2 585.1625,found 585.1628.
实施例19
2-溴-5-苯基-1,3,4-噻二唑(II-9)
将溴化铜(0.87g,3.90mmol)，亚硝酸异戊酯(0.45g,3.90mmol)，乙腈(30ml)加入到三颈瓶中，室温搅拌15min后，加入化合物II-8(0.3g,1.70mmol)，继续室温搅拌2h。待反应结束后，减压蒸除溶剂，加入乙酸乙酯稀释后，用1mol/L盐酸水洗(10mlx3)，将有机层用无水硫酸钠除水，减压蒸除溶剂，得黄色固体0.3g，收率81％。1H NMR(300MHz,DMSO-d6):δ＝7.83-7.81(t,2H,J1＝3.7Hz,J2＝3.5Hz,Ar-H),7.57-7.55(t,3H,J1＝2.9Hz,J2＝2.4Hz,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C8H5BrN2S 240.9430,found 240.9442。
N-(2-(4-(5-苯基-1,3,4-噻二唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L35)
用II-9(0.37g,1.54mmol)代替2-溴苯并噻唑之外，以与化合物L31相同的方法合成得到淡黄色固体0.22g，收率79％。1H NMR(300MHz,DMSO-d6):δ＝8.97-8.96(d,1H,J＝2.3Hz,Ar-H),8.93-8.91(dd,1H,J1＝4.8Hz,J2＝1.5Hz,Ar-H),8.24-8.20(m,1H,Ar-H),7.90-7.87(m,2H,Ar-H),7.75-7.69(m,3H,Ar-H),7.57-7.56(m,3H,Ar-H),7.45(s,1H,Ar-H),3.83-3.75(m,4H,NCH 2CH2N),3.64-3.59(m,2H,NCH2CH2 N),3.41-3.37(m,2H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated for C25H21F3N6O3S2 575.1142,found 575.1145。
实施例20
N-(2-(4-(5-苯基-1,3,4-噻二唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)-[1,1'-联苯]-4-磺酰胺(L36)
用[1,1'-联苯]-4-磺酰氯(0.23g,0.6mmol)代替吡啶-3-磺酰氯之外，以与化合物L35相同的方法合成得到淡黄色固体0.18g，收率53％。1H NMR(300MHz,DMSO-d6):δ＝9.87(s,1H,NH),7.95-7.94(d,4H,J＝2.8Hz,Ar-H),7.87-7.84(dd,2H,J1＝7.9Hz,J2＝2.3Hz,Ar-H),7.79-7.76(d,2H,J＝7.2Hz,Ar-H),7.61-7.55(m,3H,Ar-H),7.53-7.50(d,2H,J＝7.7Hz,Ar-H),7.47-7.44(m,1H,Ar-H),7.39-7.36(d,1H,J＝8.5Hz,Ar-H),6.91-6.88(dd,1H,J1＝8.6Hz,J2＝2.4Hz,Ar-H),6.84-6.83(d,1H,J＝2.4Hz,Ar-H),3.78(s,3H,OCH3),3.61-3.40(m,8H,NCH 2CH 2N)ppm。
实施例21
2-溴苯基噻唑(II-13)
将II-11(2.0g,10.05mmol)，硫氰酸钾(1.08g,11.05mmol)，无水乙醇(20ml)加入到三颈瓶中，加热至回流反应2h。待反应结束后，趁热过滤掉生成的溴化钾，将滤液减压蒸除溶剂，得乳白色晶体1.9g，将其溶于乙酸(20ml)中，向反应液中缓慢滴加20ml 33％氢溴酸乙酸溶液，滴加完毕升温至回流，TLC监测反应情况。待反应结束后，将反应液冷却至室温，析出大量淡黄色固体，抽滤，将滤饼用饱和碳酸氢钠溶液洗涤(5mlx3)，将其烘干，得淡黄色固体1g，收率60％。1H NMR(300MHz,DMSO-d6):δ＝8.19(s,1H,Ar-H),7.95-7.92(m,2H,Ar-H),7.52-7.43(m,2H,Ar-H)ppm。
1-(4-苯基噻唑-2-基)哌啶-4-胺(II-15)
将化合物II-14(2.5g)，1,4-二氧六环(15ml)，6mol/L盐酸(15ml)加入到圆底烧瓶中，40℃反应1h。待反应结束后，用饱和碳酸氢钠溶液将反应液PH调至中性或弱碱性，加二氯甲烷萃取。将有机层减压蒸除溶剂，得白色固体2g，收率86％。1H NMR(300MHz,DMSO-d6):δ＝7.90-7.87(m,2H,Ar-H),7.44-7.39(t,2H,J1＝7.7Hz,J2＝7.2Hz,Ar-H),7.33-7.31(m,2H,Ar-H),4.05-4.01(m,2H),3.60(s,1H),3.20-3.13(m,2H),2.07-2.03(m,2H),1.68-1.63(m,2H)ppm.HRMS(ESI),[M+H]+calculated for C14H17N3S 260.1216,found 260.1227。
N-(1-(4-苯基噻唑-2-基)哌啶-4-基)-2-(吡啶-3-磺酰氨基)-4-(三氟甲基)苯甲酰胺(L37)
将中间体II-6(0.2g,0.58mmol)，N,N-二甲基甲酰胺(2ml)加入到三颈瓶中，0℃下氮气保护加入HATU(0.27g,0.70mmol)，N,N-二异丙基乙胺(0.23g,1.74mmol)搅拌30min后，加入化合物II-15(0.15g,0.58mmol)，室温反应5h，TLC监测反应情况。待反应结束后，将反应液倒入5V体积1mol/L盐酸中，有淡黄色固体析出，抽滤，将滤饼烘干经柱层析纯化得米黄色固体0.14g，收率75％。1H NMR(300MHz,DMSO-d6):δ＝8.82-8.76(m,2H,Ar-H),7.86-7.83(m,3H,Ar-H),7.66-7.61(m,4H,Ar-H),7.38-7.26(m,4H,Ar-H),3.99-3.95(m,2H),3.60(s,1H),3.20-3.15(m,2H),2.91-2.88(m,2H),1.99-1.86(m,2H)ppm.HRMS(ESI),[M+H]+calculated for C27H24F3N5O3S2 588.1346,found 588.1341。
实施例22
N-(1-(苯并[d]噻唑-2-基)哌啶-4-基)-4-甲氧基-2-((4-(5-甲基噻吩-2-基)苯基)磺酰氨基)苯甲酰胺(L40)
用(5-甲基噻吩-2-基)苯磺酰氯代替吡啶-3-磺酰氯之外，以与化合物L37相同的方法合成得到黄色固体0.14g，收率58％。1H NMR(300MHz,DMSO-d6):δ＝11.95(s,1H,NHCO),7.84-7.78(m,2H,Ar-H),7.75-7.67(m,4H,Ar-H),7.53-7.50(t,2H,J1＝4.5Hz,J2＝3.5Hz,Ar-H),7.37-7.31(t,1H,J1＝7.7Hz,J2＝7.5Hz,Ar-H),7.16-7.11(t,1H,J1＝7.7Hz,J2＝7.6Hz,Ar-H),7.07-7.02(m,1H,Ar-H),6.91-6.90(d,1H,J＝3.3Hz,Ar-H),6.77-6.73(dd,1H,J1＝8.8Hz,J2＝2.6Hz,Ar-H),4.09-4.05(m,2H),3.81(s,3H,OCH3),3.41-3.33(m,1H),2.50(s,3H,CH3Ar),1.94-1.89(m,2H),1.64-1.54(m,2H)ppm.HRMS(ESI),[M-H]-calculatedfor C31H30N4O4S3617.1356,found 617.1279。
实施例23
N-(1-(苯并[d]噻唑-2-基)哌啶-4-基)-4-三氟甲基-2-(吡啶-3-磺酰氨基)苯甲酰胺(L41)
用1-(苯并[d]噻唑-2-基)哌啶-4-胺(0.2g,0.86mmol)代替化合物II-15之外，以与化合物L37相同的方法合成得到淡黄色固体0.16g，收率73％。1H NMR(300MHz,DMSO-d6):δ＝11.35(s,1H,NHCO),8.95-8.88(m,2H,Ar-H),8.20(s,1H,Ar-H),7.94-7.93(m,2H,Ar-H),7.69-7.68(m,4H,Ar-H),7.46-7.44(d,1H,J＝6.8Hz,Ar-H),7.28-7.26(d,1H,J＝6.5Hz,Ar-H),4.20-4.16(m,4H),3.60-3.52(m,1H),2.02-2.00(m,2H),1.72-1.70(m,2H)ppm.HRMS(ESI),[M+H]+calculated for C25H22F3N5O3S2 562.1189,found 562.1193。
实施例24
N-(2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L42)
用中间体II-16(0.5g,6.28mmol)代替中间体II-9之外，以与化合物L35相同的方法合成得到乳白色固体0.11g，收率74％。1H NMR(300MHz,DMSO-d6):δ＝8.91-8.89(t,1H,J1＝2.5Hz,J2＝2.3Hz,Ar-H),8.86-8.85(d,1H,J＝3.5Hz,Ar-H),8.18-8.07(m,2H,Ar-H),7.90-7.88(d,1H,J＝7.1Hz,Ar-H),7.68-7.66(m,3H,Ar-H),7.42-7.35(m,4H,Ar-H),3.56-3.54(m,4H,NCH 2CH2N),3.10-3.06(m,4H,NCH 2CH2N)ppm。HRMS(ESI),[M+H]+calculated forC26H22F3N5O3S2 574.1189,found 574.1195。
实施例25
N-(2-(4-(4-(对甲苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L43)
用2-溴-4-(对甲苯基)噻唑(0.3g,1.18mmol)代替中间体II-16之外，以与化合物L42相同的方法合成得到白色固体0.18g，收率80％。1H NMR(300MHz,DMSO-d6):δ＝10.54(s,1H,NH),8.91-8.90(d,1H,J＝2.1Hz,Ar-H),8.86-8.84(dd,1H,J1＝4.8Hz,J2＝1.4Hz,Ar-H),8.18-8.14(m,1H,Ar-H),7.79-7.77(d,2H,J＝8.1Hz,Ar-H),7.68-7.63(m,3H,Ar-H),7.40(s,1H,Ar-H),7.28(s,1H,Ar-H),7.24-7.21(d,2H,J＝8.0Hz,Ar-H),3.76-3.51(m,8H,NCH 2CH 2N),2.34(s,3H,CH3Ar)ppm.HRMS(ESI),[M+H]+calculated for C27H24F3N5O3S2588.1346,found588.1364。
实施例26
N-(2-(4-(4-(3,4-二甲苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L45)
用2-溴-4-(3,4-二甲苯基)噻唑(0.5g,1.87mmol)代替中间体II-16之外，以与化合物L42相同的方法合成得到白色固体0.21g，收率74％。1H NMR(300MHz,DMSO-d6):δ＝8.96-8.92(m,2H,Ar-H),8.25-8.23(d,1H,J＝7.5Hz,Ar-H),7.73-7.62(m,5H,Ar-H),7.43(s,1H,Ar-H),7.29(s,1H,Ar-H),7.23-7.20(d,1H,J＝7.8Hz,Ar-H),3.79-3.38(m,8H,NCH 2CH 2N),2.31(s,3H,CH3Ar),2.29(s,3H,CH3Ar)ppm.HRMS(ESI),[M+H]+calculated forC28H26F3N5O3S2 601.1429,found 602.1510。
实施例27
N-(2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L46)
用2-溴-4-(4-三氟甲基苯基)噻唑(0.3g,0.97mmol)代替中间体II-16之外，以与化合物L42相同的方法合成得到白色固体0.14g，收率71％。1H NMR(300MHz,DMSO-d6):δ＝10.56(s,1H,NH),8.92-8.91(d,1H,J＝2.1Hz,Ar-H),8.87-8.85(m,1H,Ar-H),8.18-8.09(m,3H,Ar-H),7.80-7.78(d,2H,J＝8.3Hz,Ar-H),7.69-7.63(m,3H,Ar-H),7.61(s,1H,Ar-H),7.39(s,1H,Ar-H),3.77-3.60(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC27H21F6N5O3S2 642.1063,found 642.1076。
实施例28
N-(5-硝基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)吡啶-3-磺酰胺(L48)
利用类似化合物L46的方法合成得到米白色固体，收率72％。1H NMR(300MHz,DMSO-d6):δ＝8.96(s,1H,Ar-H),8.86-8.85(d,1H,J＝4.7Hz,Ar-H),8.21-8.18(dd,1H,J1＝8.0Hz,J2＝1.7Hz,Ar-H),8.12-8.09(m,3H,Ar-H),8.02-8.01(d,1H,J＝1.9Hz,Ar-H),7.79-7.77(d,2H,J＝7.9Hz,Ar-H),7.69-7.64(m,2H,Ar-H),7.60(s,1H,Ar-H),3.77(s,2H,NCH 2CH2N),3.67(s,2H,NCH 2CH2N),3.32(s,2H,NCH2CH 2N),3.19(s,2H,NCH2CH 2N)ppm.HRMS(ESI),[M-H]-calculated for C26H21F3N6O5S2 617.0894,found 617.0862。
实施例29
N-(5-氨基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)吡啶-3-磺酰胺(L49)
将化合物L48(0.15g,0.24mmol)，10％钯碳(30mg)，四氢呋喃(10ml)加入圆底烧瓶中，向反应体系中通入氢气，室温下反应6h，TLC监测反应完全。待反应结束后，过滤掉钯碳，将滤液减压蒸除溶剂，得白色固体0.10g，收率90％。1H NMR(300MHz,DMSO-d6):δ＝9.86(s,1H,NH),8.91(s,1H,Ar-H),8.83-8.81(m,1H,Ar-H),8.17-8.09(m,3H,Ar-H),7.80-7.77(d,2H,J＝8.2Hz,Ar-H),7.67-7.62(m,1H,Ar-H),7.60(s,1H,Ar-H),7.18-7.15(d,1H,J＝8.4Hz,Ar-H),7.04-7.02(d,1H,J＝8.4Hz,Ar-H),6.74-6.62(m,1H,Ar-H),6.40-6.37(d,1H,J＝8.4Hz,Ar-H),3.56-3.52(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC26H23F3N6O3S2 589.1298,found 589.1164。
实施例30
N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L50)
用中间体I-2(0.2g,0.64mmol)代替中间体II-6之外，以与化合物L42相同的方法合成得到米白色固体0.17g，收率74％。1H NMR(300MHz,DMSO-d6):δ＝9.94(s,1H,NH),7.98-7.97(dd,1H,J1＝5.0Hz,J2＝1.4Hz,Ar-H),7.91-7.88(m,2H,Ar-H),7.62-7.60(dd,1H,J1＝3.8Hz,J2＝1.4Hz,Ar-H),7.42-7.40(m,1H,Ar-H),7.36-7.33(m,3H,Ar-H),7.20-7.18(m,1H,Ar-H),6.89-6.85(dd,1H,J1＝8.6Hz,J2＝2.5Hz,Ar-H),6.74-6.73(d,1H,J＝2.5Hz,Ar-H),3.74(s,1H,OCH3),3.56-3.40(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC25H24N4O4S3 541.1033,found 541.1032。
实施例31
N-(5-甲氧基-2-(4-(4-(4-甲氧基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L52)
用2-溴-4-(4-甲氧基苯基)噻唑(0.2g,0.74mmol)代替中间体II-16之外，以与化合物L50相同的方法合成得到淡黄色固体90mg，收率58％。1H NMR(300MHz,DMSO-d6):δ＝9.94(s,1H,NH),7.99-7.97(d,1H,J＝4.6Hz,Ar-H),7.83-7.81(d,2H,J＝8.6Hz,Ar-H),7.62-7.61(d,1H,J＝3.0Hz,Ar-H),7.36-7.34(d,1H,J＝8.5Hz,Ar-H),7.21-7.19(m,2H,Ar-H),7.01-6.98(d,2H,J＝8.8Hz,Ar-H),6.89-6.86(d,1H,J＝8.4Hz,Ar-H),6.74(s,1H,Ar-H),3.81(s,3H,OCH3),3.75(s,3H,OCH3),3.57(d,4H,NCH 2CH2N),2.92(s,2H,NCH2CH 2N),2.72(s,2H,NCH2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H26N4O5S3 571.1138,found 571.1152。
实施例32
N-(5-甲氧基-2-(4-(4-(4-硝基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L54)
用2-溴-4-(4-硝基苯基)噻唑(0.5g,1.75mmol)代替中间体II-16之外，以与化合物L50相同的方法合成得到淡黄色固体0.4g，收率70％。1H NMR(300MHz,DMSO-d6):δ＝9.92(s,1H,NH),8.31-8.28(d,2H,J＝8.7Hz,Ar-H),8.17-8.14(d,2H,J＝8.7Hz,Ar-H),7.98-7.97(d,1H,J＝4.6Hz,Ar-H),7.74(s,1H,Ar-H),7.61-7.60(d,1H,J＝3.4Hz,Ar-H),7.36-7.33(d,1H,J＝8.6Hz,Ar-H),7.20-7.17(t,1H,J1＝4.3Hz,J2＝4.2Hz,Ar-H),6.88-6.85(d,1H,J＝6.7Hz,Ar-H),6.74-6.73(d,1H,J＝1.9Hz,Ar-H),3.74(s,3H,OCH3),3.60-3.43(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H23N5O6S3 586.0883,found586.0821。
实施例33
N-(5-甲氧基-2-(4-(4-(4-氨基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L55)
将化合物L54硝基还原得到L55，合成方法与化合物L49类似，收率84％。1H NMR(300MHz,DMSO-d6):δ＝7.98-7.96(t,1H,J1＝J2＝3.8Hz,Ar-H),7.61-7.60(m,1H,Ar-H),7.57(s,1H,Ar-H),7.55(s,1H,Ar-H),7.35-7.33(d,1H,J＝8.5Hz,Ar-H),7.20-7.17(t,1H,J1＝4.8Hz,J2＝3.8Hz,Ar-H),6.92(s,1H,Ar-H),6.88-6.85(dd,1H,J1＝8.6,J2＝2.4Hz,Ar-H),6.76-6.75(d,1H,J＝2.3Hz,Ar-H),6.60-6.57(d,2H,J＝8.5Hz,Ar-H),3.75(s,3H,OCH3),3.70-3.53(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H23N5O4S3556.1142,found 556.1224。
实施例34
N-(5-甲氧基-2-(4-(4-(4-氰基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L57)
用2-溴-4-(4-氰基苯基)噻唑(0.2g,0.75mmol)代替中间体II-16之外，以与化合物L50相同的方法合成得到淡黄色固体0.14g，收率70％。1H NMR(300MHz,DMSO-d6):δ＝9.93(s,1H,NH),8.09-8.06(d,2H,J＝7.9Hz,Ar-H),7.98-7.96(d,1H,J＝4.1Hz,Ar-H),7.90-7.87(d,2H,J＝8.4Hz,Ar-H),7.66-7.55(m,2H,Ar-H),7.35-7.32(d,1H,J＝8.9Hz,Ar-H),7.19(s 1H,Ar-H),6.88-6.85(d,1H,J＝8.3Hz,Ar-H),6.73(s,1H,Ar-H),3.74(s,3H,OCH3),3.70-3.50(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H23N5O4S3566.0985,found566.0979。
实施例35
2-((5-氯噻吩)-2-磺酰氨基)-4-甲氧基苯甲酸(II-19)
用2-氯-噻吩-2-磺酰氯(2g,11.97mmol)代替噻吩-2-磺酰氯之外，以与中间体I-2相同的方法合成得到淡黄色固体2.7g，收率79％。1H NMR(300MHz,DMSO-d6):δ＝11.50(s,1H,NH),7.94-7.91(d,1H,J＝8.9Hz,Ar-H),7.65-7.64(d,1H,J＝4.1Hz,Ar-H),7.26-7.25(d,1H,J＝4.1Hz,Ar-H),7.07-7.06(d,1H,J＝2.4Hz,Ar-H),6.82-6.78(dd,1H,J1＝8.9,J2＝2.5Hz,Ar-H),3.44(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C12H10ClNO5S2345.9616,found345.9599。
5-氯-N-(5-甲氧基-2-(4-(4-(间甲苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L58)
用中间体II-19(0.32g,0.92mmol)代替中间体II-6之外，以与化合物L44相同的方法合成得到淡黄色固体0.14g，收率70％。1H NMR(300MHz,DMSO-d6):δ＝10.14(s,1H,NH),7.71-7.66(t,1H,J1＝7.8,J2＝7.1Hz,Ar-H),7.50-7.49(d,1H,J＝3.9Hz,Ar-H),7.37-7.26(m,4H,Ar-H),7.15-7.12(d,1H,J＝7.5Hz,Ar-H),6.92-6.89(d,1H,J＝8.2Hz,Ar-H),6.75(s,1H,Ar-H),3.76(s,3H,OCH3),3.62-3.57(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H25ClN4O4S3 589.0799,found 589.0802。
实施例36
5-氯-N-(5-甲氧基-2-(4-(4-(4-氯苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L59)
用2-溴-4-(4-氯苯基)噻唑(0.3g,1.10mmol)代替2-溴-4-(3-甲苯基)噻唑之外，以与化合物L57相同的方法合成得到淡黄色固体0.18g，收率74％。1H NMR(300MHz,DMSO-d6):δ＝9.54(s,1H,NH),7.97-7.94(d,2H,J＝7.9Hz,Ar-H),7.53-7.48(m,4H,Ar-H),7.32-7.25(m,2H,Ar-H),7.18-7.17(d,1H,J＝3.3Hz,Ar-H),6.91-6.89(d,1H,J＝6.9Hz,Ar-H),3.93(s,3H,OCH3),3.79-3.75(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC25H22Cl2N4O4S3 609.0253,found 609.0275。
实施例37
5-氯-N-(5-甲氧基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L60)
用2-溴-4-(4-三氟甲基苯基)噻唑(0.3g,0.97mmol)代替2-溴-4-(3-甲苯基)噻唑之外，以与化合物L57相同的方法合成得到淡黄色固体0.17g，收率72％。1H NMR(300MHz,DMSO-d6):δ＝10.13(s,1H,NH),8.12-8.09(d,2H,J＝8.2Hz,Ar-H),7.80-7.77(d,2H,J＝8.5Hz,Ar-H),7.60(s,1H,Ar-H),7.51-7.49(d,1H,J＝4.1Hz,Ar-H),7.38-7.35(d,1H,J＝8.6Hz,Ar-H),7.28-7.26(d,1H,J＝4.1Hz,Ar-H),6.93-6.89(dd,1H,J1＝8.6,J2＝2.5Hz,Ar-H),6.76-6.75(d,1H,J＝2.4Hz,Ar-H),3.77(s,3H,OCH3),3.59-3.55(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H22ClF3N4O4S3 643.0517,found 643.0429。
实施例38
5-氯-N-(5-甲氧基-2-(4-(4-(4-羟基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L61)
用2-溴-4-(4-羟基苯基)噻唑(0.3g,1.16mmol)代替2-溴-4-(3-甲苯基)噻唑之外，以与化合物L57相同的方法合成得到淡黄色固体0.12g，收率65％。1H NMR(300MHz,DMSO-d6):δ＝9.57(s,1H,OH),7.72-7.69(d,2H,J＝8.6Hz,Ar-H),7.50-7.49(d,1H,J＝4.1Hz,Ar-H),7.36-7.34(d,1H,J＝8.6Hz,Ar-H),7.27-7.26(d,1H,J＝4.1Hz,Ar-H),7.07(s,1H,Ar-H),6.91-6.88(d,1H,J＝6.5Hz,Ar-H),6.81-6.76(m,3H,Ar-H),3.77(s,3H,OCH3),3.64-3.54(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H23ClN4O5S3591.0592,found591.0512。
实施例39
4-溴-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)苯磺酰胺(II-18)
以与化合物L50类似的方法制备得到浅灰色固体。1H NMR(300MHz,DMSO-d6):δ＝9.93(s,1H,OH),7.92-7.89(d,2H,J＝7.3Hz,Ar-H),7.86-7.84(d,2H,J＝8.6Hz,Ar-H),7.75-7.73(d,2H,J＝8.6Hz,Ar-H),7.46-7.41(t,2H,J1＝7.8,J2＝7.3Hz,Ar-H),7.37-7.31(m,3H,Ar-H),6.88-6.84(dd,1H,J1＝8.6,J2＝2.5Hz,Ar-H),6.67-6.66(d,1H,J＝2.4Hz,Ar-H),3.74(s,3H,OCH3),3.56-3.40(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculatedfor C27H25BrN4O4S2 613.0574,found 613.0588。
3'-氨基-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)-[1,1'-联苯]-4-磺酰胺(L62)
将中间体II-18(0.2g,0.33mmol)以及3-氨基苯硼酸频那醇酯(0.14g,0.65mmol)以与化合物L15相同的方法合成得到浅灰色固体0.12g，收率77％。1H NMR(300MHz,DMSO-d6):δ＝7.90-7.85(t,4H,J1＝8.6Hz,J2＝7.6Hz,Ar-H),7.79-7.76(d,2H,J＝8.6Hz,Ar-H),7.45-7.40(t,2H,J1＝7.7Hz,J2＝7.3Hz,Ar-H),7.36-7.31(m,3H,Ar-H),7.15-7.10(t,1H,J1＝7.9Hz,J2＝7.8Hz,Ar-H),6.90(s,1H,Ar-H),6.85-6.81(m,2H,Ar-H),6.71-6.64(d,1H,J＝2.3Hz,Ar-H),6.67-6.64(d,1H,J＝8.2Hz,Ar-H),3.71(s,3H,OCH3),3.70-3.50(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C33H31N5O4S2 626.1890,found626.1777。
实施例40
3'-羟基-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)-[1,1'-联苯]-4-磺酰胺(L63)
用3-羟基苯硼酸频那醇酯(0.14g,0.65mmol)代替3-氨基苯硼酸频那醇酯之外，以与化合物L62相同的方法合成得到米白色固体0.11g，收率55％。1H NMR(300MHz,DMSO-d6):δ＝9.85(s,1H,NH),9.68(s,1H,OH),7.90-7.82(m,6H,Ar-H),7.45-7.40(t,2H,J1＝7.7Hz,J2＝7.2Hz,Ar-H),7.34-7.25(m,4H,Ar-H),7.14-7.08(t,2H,J1＝8.9,J2＝7.9Hz,Ar-H),6.86-6.81(m,2H,Ar-H),6.72-6.71(d,1H,J＝2.4Hz,Ar-H),3.71(s,3H,OCH3),3.63-3.38(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C33H30N4O5S2 627.1731,found627.1698。
实施例41
4'-(N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)氨磺酰基)-[1,1'-联苯]-3-羧酸(L66)
用3-羧酸苯硼酸频那醇酯(0.15g,0.60mmol)代替3-氨基苯硼酸频那醇酯之外，以与化合物L62相同的方法合成得到米白色固体0.12g，收率60％。收率84％。1H NMR(300MHz,DMSO-d6):δ＝9.89(s,1H,NH),8.25(s,1H,Ar-H),8.02-7.86(m,8H,Ar-H),7.64-7.59(t,1H,J1＝7.8Hz,J2＝7.7Hz,Ar-H),7.45-7.40(t,2H,J1＝7.7Hz,J2＝7.2Hz,Ar-H),7.34-7.30(m,3H,Ar-H),6.85-6.82(dd,1H,J1＝8.6Hz,J2＝2.4Hz,Ar-H),6.75-6.74(d,1H,J＝2.3Hz,Ar-H),3.72(s,3H,OCH3),3.60-3.38(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C34H30N4O6S2 655.1680,found 655.1686。
实施例42
N-(5-甲氧基-2-(3-((4-(4-(三氟甲基)苯基)噻唑-2-基)氨基)吡咯烷-1-羰基)苯基)噻吩-2-磺酰胺(L68)
与化合物L37的制备类似，得到浅灰色固体，收率71％。1H NMR(300MHz,Acetone-d6):δ＝8.14(s,2H,Ar-H),7.96-7.76(m.3H,Ar-H),7.56-7.54(d,2H,J＝8.6Hz,Ar-H),7.29-7.27(d,2H,J＝6.6Hz,Ar-H),7.23-7.21(d,1H,J＝5.6Hz,Ar-H),6.81(s,1H,Ar-H),3.90(s,3H,OCH3),3.61-3.58(m,2H,NCH(CH2)CH 2N),2.87-2.85(m,2H,NCHCH2CH 2N),2.84-2.80(m,1H,NCH(CH2)CH2N),2.08-2.05(m,2H,NCH(CH2)CH 2CH2N)ppm.HRMS(ESI),[M+H]+calculated for C26H23F3N4O4S3 609.0907,found 609.0880。
实施例43
N-(5-甲氧基-2-(5-(4-(对甲苯基)噻唑-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)苯基)噻吩-2-磺酰胺(L69)
用2,5-二氮杂双环[2.2.1]庚烷代替哌嗪环，以与化合物L51相同的方法合成得到浅灰色固体，收率76％。1H NMR(300MHz,Acetone-d6):δ＝8.04-8.03(d,2H,J＝2.5Hz,Ar-H),7.81-7.61(m,3H,Ar-H),7.58-7.52(m,1H,Ar-H),7.34-7.25(m,3H,Ar-H),7.1-7.03(m,1H,Ar-H),6.86-6.79(m,3H,Ar-H),4.91-4.84(m,2H,CHCH 2NCO),3.77(s,3H,OCH3),3.74-3.70(m,2H,NCH 2CHN),3.59(s,1H,NCH(CH2)CH2),3.37(s,1H,NCH(CH2)CH2),2.40(s,3H,CH3Ar),2.22-2.21(m,2H,CHCH 2CH)ppm.HRMS(ESI),[M+H]+calculated for C27H26N4O4S3567.1189,found 567.1253.
实施例44
N-(5-甲氧基-2-(5-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)苯基)噻吩-2-磺酰胺(L70)
以与化合物L69类似的方法合成得到浅灰色固体，收率70％。1H NMR(300MHz,Acetone-d6):δ＝8.15-8.12(d,2H,J＝8.0Hz,Ar-H),7.84-7.81(d,2H,J＝8.3Hz,Ar-H),7.58-7.46(m,4H,Ar-H),7.21(s,1H,Ar-H),6.97(s,1H,Ar-H),6.77(s,1H,Ar-H),3.94-3.90(m,3H,CHCH 2NCO),3.87(s,3H,OCH3),3.52(s,1H,NCH(CH2)CH2),2.98-2.82(m,2H,NCH 2),2.32-2.30(m,2H,CHCH 2CH)ppm.HRMS(ESI),[M+H]+calculated forC27H23F3N4O4S3621.0907,found 621.0964.
实施例45
2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(II-23)
将原料II-20(0.3g,0.97mmol)，2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(0.38g,1.45mmol)，N,N-二甲基甲酰胺(3ml)，碳酸钾(0.4g,2.9mmol)，110℃反应过夜，待反应结束后，将反应液冷却至室温，将其倒入5倍体积水中，用二氯甲烷萃取(8ml x 3)，将有机层合并，减压蒸除溶剂，经柱层析纯化得到淡黄色固体0.23g，收率71％。1H NMR(300MHz,DMSO-d6):δ＝8.09-8.06(d,2H,J＝8.1Hz,Ar-H),7.78-7.76(d,2H,J＝8.3Hz,Ar-H),7.53(s,1H,Ar-H),3.85(s,4H,CH2(CH 2)2NCO),3.36-3.34(m,4H,NCH2CCH2),1.77-1.73(t,4H,J1＝5.4Hz,J2＝5.2Hz,CCH2CH2)ppm.HRMS(ESI),[M+H]+calculated forC22H26F3N3O2S454.1771,found 454.1886。
N-(5-甲氧基-2-(2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羰基)苯基)噻吩-2-磺酰胺(L72)
将化合物II-23脱Boc保护后，得到化合物II-24，用II-24(0.2g,0.56mmol)代替II-17之外，以与化合物L50相同的方法合成得到淡黄色固体0.10g，收率68％。1H NMR(300MHz,Acetone-d6):δ＝8.20-8.17(d,2H,J＝8.0Hz,Ar-H),8.02-8.00(d,1H,J＝5.0Hz,Ar-H),7.87-7.84(d,2H,J＝8.2Hz,Ar-H),7.63-7.62(d,1H,J＝3.2Hz,Ar-H),7.56-7.53(d,1H,J＝8.6Hz,Ar-H),7.36-7.33(d,1H,J＝5.6Hz,Ar-H),7.28-7.22(m,2H,Ar-H),6.85-6.81(dd,1H,J1＝8.3Hz,J2＝2.1Hz,Ar-H)4.37(s,4H,CH2(CH 2)2NCO),3.90(s,3H,OCH3),3.52(s,4H,NCH 2CCH2),1.98(s,4H,CCH 2CH2)ppm.HRMS(ESI),[M+H]+calculated forC29H27F3N4O4S3 649.1220,found 649.1228。
实施例46
N-(5-(三氟甲基)-2-(2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羰基)苯基)吡啶-3-磺酰胺(L73)
用中间体II-6代替中间体I-2之外，以与化合物L73相同的方法合成得到淡黄色固体，收率61％。1H NMR(300MHz,Acetone-d6):δ＝9.08-9.07(d,1H,J＝1.5Hz,Ar-H),8.94-8.87(dd,1H,J1＝8.3Hz,J2＝4.6Hz,Ar-H),8.31-8.28(d,2H,J＝8.2Hz,Ar-H),8.09-8.03(t,2H,J1＝9.9Hz,J2＝8.2Hz,Ar-H),7.92(s,1H,Ar-H),7.86-7.83(d,1H,J＝8.2Hz,Ar-H),7.76-7.72(m,2H,Ar-H),7.64-7.60(m,2H,Ar-H),4.25-4.08(m,4H,CH2(CH 2)2NCO),3.76-3.71(m,4H,NCH 2CCH2),1.54-1.52(s,4H,CCH 2CH2)ppm.HRMS(ESI),[M+H]+calculated forC30H25F6N5O3S2 682.1376,found 682.1388。
实施例47
4-甲氧基-2-(噻吩-2-磺酰氨基)-N-(1-(4-(4-(三氟甲基)苯基)噻唑-2-基)吡咯烷-3-基)苯甲酰胺(L74)
用3-(Boc-氨基)吡咯烷代替1-Boc-3-氨基吡咯烷之外，以与化合物L68相同的方法制备得到淡黄色固体，收率69％。1H NMR(300MHz,Acetone-d6):δ＝8.32(s,2H,Ar-H),7.88-7.72(m.2H,Ar-H),7.66-7.58(d,3H,J＝8.6Hz,Ar-H),7.30-7.26(d,2H,J＝6.7Hz,Ar-H),7.25-7.23(d,1H,J＝5.9Hz,Ar-H),6.79-6.77(m,1H,Ar-H),3.91(s,3H,OCH3),3.69-3.66(m,1H,NHCH(CH2)CH2),3.11-2.90(m,2H,NCH 2CH(CH2)NH),2.84-2.71(m,2H,NCH 2CH2CHNH),1.96-1.73(m,2H,NCH2CH 2CHNH)ppm.HRMS(ESI),[M+H]+calculated forC26H23F3N4O4S3609.0907,found 609.0980。
实施例48
USP8小分子抑制剂酶活测试方法以及USP7、USP2选择性测试方法
本实施例利用底物Ubiquitin-Rho-110建立了靶向USP8的高通量筛选体系。使用DMSO将底物粉末溶解到浓度200μM。然后配置筛选所用实验缓冲液，成分包括50mM Tris-HCl，pH 7.5，1mM EDTA，100mM NaCl和0.05％(w/v)CHAPS。将USP8蛋白、USP2蛋白和USP7蛋白用实验缓冲液分别稀释到1nM、2nM、1nM，分别取2.5μL加入到384孔板中。接着加入2.5μL化合物稀释缓冲液。之后，再分别加入5μL 200nM底物，室温孵育。设置Envision酶标仪激发波长为480nM，发射波长为580nM，40分钟后读取反应产物荧光强度，利用Graphpad Prism5.0软件拟合求得IC50。结果如表1所示。
表1本发明部分化合物对USP8的抑制活性IC50
注：“++++”表示IC50＜5μM，“+++”表示IC50＜20μM，“+++”表示IC50＜50μM，“+”表示IC50＞50μM。
实施例49
细胞存活实验测定化合物对MCF-7细胞系增殖抑制作用。
本实施例选择MCF-7细胞株，选择多个重点化合物处理细胞，进行细胞增殖抑制的检测。细胞均以3×104mL-1的密度培养于96孔透明板中，用化合物或相同体积的DMSO处理细胞，处理3天后，利用CellTiter-Glo试剂，用Envision多孔微型板检测仪测定各个孔的荧光强度，指示细胞活力。半增殖抑制浓度GI50值经GraphPad Prism 5.0软件拟合求得。结果见表2所示。
表2本发明部分化合物对MCF-7的增殖抑制活性GI50
| Compound | GI<sub>50</sub>(μM) |
| L05 | 9.21 |
| L06 | 23.11 |
| L07 | 7.15 |
| L08 | 16.20 |
| L10 | 22.12 |
| L11 | 9.16 |
| L14 | 5.91 |
| L16 | 10.46 |
| L17 | 28.47 |
| L19 | 31.54 |
| L22 | 5.45 |
| L21 | 25.55 |
| L34 | 18.41 |
| L50 | 23.47 |
| L52 | 15.19 |
| L57 | 30.20 |
由上表可知，本发明的化合物在MCF-7细胞上表现出了较好的增殖抑制效果。
Claims (7)
1.通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐，
式(Ⅰ)中，
X选自
其中n、i各自独立选自0、1或2，m选自1、2或3，n1、n2、m1、m2各自独立选自1、2或3；
R1、R2各自独立地选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素、酯基中的一个或多个；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、氰基、氨基、羟基、羧基、酯基中的一个或多个；
式(Ⅱ)中，
X为C或N，当X为C时，Z为H，A片段为取代芳香环，其中取代基选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素或酯基中的一个或多个；当X为N时，A片段不存在，Z选自取代芳香环，其中取代基选自氢原子、烷基、烷氧基、三氟甲基、腈基、硝基、氨基、羟基、卤素或酯基中的一个或多个；
Y选自
其中n、i各自独立选自0、1或2，m选自1、2或3，n1、n2、m1、m2各自独立选自1、2或3；
R2选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素或酯基中的一个或多个；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、氰基、氨基、羟基、羧基或酯基中的一个或多个；
式(Ⅲ)中，
A片段选自苯基噻唑环、苯基噻二唑环或苯并噻唑环；
X为-C(O)-、-S(O)2-或不存在；
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环，其中取代基选自烷基、三氟甲基、卤素、腈基、氨基、羟基、羧基或酯基中的一个或多个。
2.根据权利要求1所述通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐，其特征在于：所述药学上可接受的盐是指通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成碱加成盐，所述酸选自氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；所述碱加成盐选自钠盐、钾盐、铵盐、钙盐、铝盐、镁盐、乙二胺盐或乙醇胺盐。
3.根据权利要求1所述通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐，其特征在于：所述化合物选自以下化合物式中的一个：
4.一种药物组合物，包括药物有效量的活性组分和药学上可接受的辅料，其特征在于：所述活性组分包括权利要求1所述的通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐中的一种或多种。
5.权利要求1所述通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐在制备USP8抑制剂中的应用。
6.权利要求1所述通式(Ⅰ)、(Ⅱ)、(Ⅲ)的化合物或其药学上可接受的盐在制备USP8介导的相关疾病的治疗药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述USP8介导的相关疾病包括癌症、神经变性疾病、血液系统疾病、内分泌系统疾病。
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| US20190202929A1 (en) * | 2016-09-20 | 2019-07-04 | Sara Buhrlage | Compositions and methods for identification, assessment, prevention, and treatment of aml using usp10 biomarkers and modulators |
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