CN114957235A - 苯并噻嗪酮衍生物及其制备方法和用途 - Google Patents
苯并噻嗪酮衍生物及其制备方法和用途 Download PDFInfo
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- CN114957235A CN114957235A CN202210582930.7A CN202210582930A CN114957235A CN 114957235 A CN114957235 A CN 114957235A CN 202210582930 A CN202210582930 A CN 202210582930A CN 114957235 A CN114957235 A CN 114957235A
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- compound
- alkyl
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- nitro
- halogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 87
- MJNPHLBKHKJDEF-UHFFFAOYSA-N 2h-1$l^{4},2-benzothiazine 1-oxide Chemical class C1=CC=C2S(=O)NC=CC2=C1 MJNPHLBKHKJDEF-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 25
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 20
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 14
- 239000000651 prodrug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- -1 hydroxy, carboxy Chemical group 0.000 claims description 68
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 64
- 230000015572 biosynthetic process Effects 0.000 claims description 58
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 3
- 239000002532 enzyme inhibitor Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 6
- 230000001738 genotoxic effect Effects 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- FNMGRVLXWOVONV-UHFFFAOYSA-N 1,3-thiazin-4-one Chemical compound O=C1C=CSC=N1 FNMGRVLXWOVONV-UHFFFAOYSA-N 0.000 description 71
- 239000007787 solid Substances 0.000 description 71
- 238000006243 chemical reaction Methods 0.000 description 69
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 58
- 238000003786 synthesis reaction Methods 0.000 description 56
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 229940125782 compound 2 Drugs 0.000 description 18
- 239000007858 starting material Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 14
- 229940126115 compound 4f Drugs 0.000 description 14
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229940126214 compound 3 Drugs 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- BJDZBXGJNBMCAV-UHFFFAOYSA-N 2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC(C(N=2)=O)=C1SC=2N(CC1)CCN1CC1CCCCC1 BJDZBXGJNBMCAV-UHFFFAOYSA-N 0.000 description 7
- UNIAOYFPHLKRMT-UHFFFAOYSA-N 2,5-dichloro-4-methyl-3-nitrobenzoic acid Chemical compound CC1=C(Cl)C=C(C(O)=O)C(Cl)=C1[N+]([O-])=O UNIAOYFPHLKRMT-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- PSRPKTROFCUEOD-UHFFFAOYSA-N 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC([N+]([O-])=O)=C1Cl PSRPKTROFCUEOD-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 2
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 2
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 2
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
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- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- GTUIRORNXIOHQR-VIFPVBQESA-N 2-[(3s)-3-methyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl]-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one Chemical compound O1[C@@H](C)COC11CCN(C=2SC3=C([N+]([O-])=O)C=C(C=C3C(=O)N=2)C(F)(F)F)CC1 GTUIRORNXIOHQR-VIFPVBQESA-N 0.000 description 2
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
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- JYFJNCCRKBBRKZ-UHFFFAOYSA-N chembl194764 Chemical compound C=1C=CC=C(F)C=1CCN1C(=O)C(CC)=C(C)N=C1C1=CC=CC=C1O JYFJNCCRKBBRKZ-UHFFFAOYSA-N 0.000 description 2
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Abstract
Description
技术领域
本发明属于化学医药领域,具体涉及苯并噻嗪酮衍生物及其制备方法和用途。
背景技术
结核病(tuberculosis,TB)是由结核分枝杆菌引起的一种慢性致死性疾病,是危害人类健康和导致人类死亡的重大传染性疾病。2017年全球的结核病潜伏感染人群约为17亿,潜伏感染率为23%。全球新发结核病患者约1000万,死亡患者约140万,结核病发病率为133/10万。全球结核病防治形势和严峻。特别是多重耐药结核菌(MDR-TB)和广泛耐药结核病(XDR-TB)的流行给结核病防治带来了严重挑战。因此,研发具有新型骨架、新颖作用机制的抗结核药物以治疗与控制结核病,尤其是耐药结核尤为迫切。
DprE1酶抑制剂可以阻断DPR异构化为DPA,从而切断了构成结核分枝杆菌细胞壁重要组成部分的阿拉伯杂多糖的生物合成通路,是开发治疗结核病的研究重点。其特异性的抑制剂主要为BTZ共价抑制剂。BTZ抑制剂在生物体内的还原产物与DprE1的半胱氨酸上的活性巯基加成,生成加合物,因此表现出高活性。然而由于其潜在的基因毒性,迟迟未能进入临床。
目前的研究方向是对抑制剂或治疗结核病的药物进行结构修饰和改造,以期找到避免基因毒性同时能保持相当活性的新抑制剂或新药物。以期望这些改进能够让这些抑制剂或药物进入临床研究,带来更好的临床治疗效果。
发明内容
本发明提供了苯并噻嗪酮衍生物及其制备方法和用途。
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C8烷基、硝基、卤素、羧基、氨基、氰基、三氟甲基;
X选自-NR5-、-CR6R7-;
R5选自-C(O)R8、被0~3个R9取代的5~10元不饱和杂环基;
R8选自5~10元不饱和环烷基、5~10元不饱和杂环基;
R9选自C1~C8烷基、3~10元饱和环烷基、被0~3个R10取代的5~10元不饱和环烷基;
R10选自C1~C8烷基、C1~C8烷氧基、卤素、羟基、羧基;
R6、R7分别独立选自氢、被0~3个R11取代的5~10元不饱和杂环基;或者R6、R7连接形成被0~3个R12取代的5~10元不饱和杂环;
R11选自C1~C8烷基、3~10元饱和环烷基、被0~3个R13取代的5~10元不饱和环烷基、被0~3个R13取代的5~10元不饱和杂环基;
R13选自C1~C8烷基、C1~C8烷氧基、卤素;
R12选自C1~C8烷基、5~10元不饱和环烷基、5~10元不饱和杂环基、被0~3个R14取代的3~10元饱和杂环基、被0~3个R14取代的3~10元饱和环烷基;
R14选自叔丁氧羰基、被0~3个R15取代的C1~C8烷基、3~10元饱和环烷基;
R15选自3~10元饱和环烷基;
所述不饱和杂环基的杂原子为N、O、S,杂原子的个数为1~3个。
进一步地,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
X选自-NR5-、-CR6R7-;
R8选自噻吩基、吡啶基、苯基;
R9选自C1~C4烷基、4~6元饱和环烷基、被0~1个R10取代的苯基;
R10选自卤素;
R11选自C1~C4烷基、4~6元饱和环烷基、被0~1个R13取代的苯基、噻吩基、吡啶基、嘧啶基;
R13选自C1~C3烷基、C1~C3烷氧基、卤素;
R14选自叔丁氧羰基、被0~1个R15取代的C1~C3烷基、5元饱和环烷基;
R15选自6元饱和环烷基。
进一步地,所述化合物如式II所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R8选自噻吩基、吡啶基、苯基;
R9选自C1~C4烷基、4~6元饱和环烷基、被0~1个R10取代的苯基;
R10选自卤素。
进一步地,所述化合物如式III所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R11选自C1~C4烷基、4~6元饱和环烷基、被0~1个R13取代的苯基、噻吩基、吡啶基、嘧啶基;
R13选自C1~C3烷基、C1~C3烷氧基、卤素。
进一步地,所述化合物如式IV所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R14选自叔丁氧羰基、被0~1个R15取代的C1~C3烷基、5元饱和环烷基;
R15选自6元饱和环烷基。
进一步地,所述化合物如式II-A所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R8选自噻吩基、吡啶基、苯基;
或者,所述化合物如式II-B所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R9选自C1~C4烷基、4~6元饱和环烷基、被0~1个R10取代的苯基;
R10选自卤素。
进一步地,所述化合物如式III-A所示:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
R11选自C1~C4烷基、4~6元饱和环烷基、被0~1个R13取代的苯基、噻吩基、吡啶基、嘧啶基;
R13选自C1~C3烷基、C1~C3烷氧基、卤素。
进一步地,所述化合物为如下化合物之一:
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备DprE1酶抑制剂和/或抑制结核分枝杆菌的药物中的用途;
优选地,所述药物为预防和/或治疗结核病的药物。
本发明还提供了一种药物,它是以前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药为活性成分,加上药学上可接受的辅料或辅助性成分制备而成的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~C8烷基”是指包含1~8个碳原子的烷基;“C1~C8烷氧基”是指包含1~8个碳原子的烷氧基。
“烷基”是指具有指定数目的碳原子的饱和烃链。例如,C1~C8烷基是指具有1至8个碳原子,即有1、2、3、4、5、6、7或8个碳原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基等。
“卤素”为氟、氯、溴或碘。
“3~10元饱和环烷基”是指具有3至10个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和的环状基团。“3~10元饱和杂环基”是指饱和环烷基中碳原子至少被一个杂原子取代;其中杂原子指氮原子、氧原子、硫原子。“5~10元不饱和环烷基”是指具有5至10个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的不饱和的环状基团。“5~10元不饱和杂环基”是指不饱和环烷基中碳原子至少被一个杂原子取代;其中杂原子指氮原子、氧原子、硫原子。
本发明提供了一类新的用于抗结核的化合物,本发明化合物对结核分枝杆菌的活性有显著的抑制作用,且该化合物对结核分枝杆菌有良好的选择性。同时,本发明化合物的基因毒性显著降低,安全性提高。本发明化合物可用于制备抗结核分枝杆菌的药物以及预防或治疗结核病的药物,具有良好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物对TA100菌株药物浓度-致突变曲线。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1、7-甲基-8-硝基-2-(4-(噻吩-2-羰基)哌嗪-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮(化合物1a)的制备
化合物1a的合成路线如下:
1、中间体1的制备
2-溴-4-甲基-3-硝基-5-(三氟甲基)苯甲酸(3g,9.2mmol)悬浮于15mL氯化亚砜(SOCl2)中,加入2滴DMF,于55℃加热2小时,得澄清透明溶液。减压浓缩脱除溶剂,用二氯甲烷旋蒸脱除溶剂反复三次,以完全除去过量氯化亚砜。残余物用15mL乙腈(ACN)溶解,一次性加入到KSCN(2.7g,27.5mmol)的15mL乙腈悬浊液中,搅拌反应2小时,然后加入N-Boc-哌嗪(1.7g,9.2mmol),室温搅拌反应过夜。向反应液中加入4g碳酸钾搅拌,用水稀释反应液,乙酸乙酯萃取。有机相减压浓缩后拌样过柱,40%乙酸乙酯的石油醚溶液洗脱,最后得870mg黄色固体中间体1,产率20.1%。
2、中间体2的制备
中间体1(870mg,1.83mmol)加入到10mL 4N HCl/二氧六环溶液中,室温搅拌反应2小时,LCMS显示反应完全,减压浓缩得到740mg黄色固体中间体2,产率98%。
3、化合物1a的制备
中间体2(0.1mmol),噻吩-2-甲酸(0.1mmol)和三乙胺(0.2mmol)加入单口瓶中,加入5mL二氯甲烷溶解,然后加入EDCI(0.2mmol),室温搅拌反应2小时。反应进行完全后,用水稀释反应液,二氯甲烷萃取,有机相水洗,无水硫酸钠干燥,过滤,旋蒸脱除溶剂后用乙醇结晶,得到浅黄色固体(化合物1a),产率64%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.48-7.46(m,1H),7.30-7.29(m,1H),7.05-7.03(m,1H),4.30-3.86(br,8H),2.48(s,3H).ESI-MSm/z 485.1[M+1]+.
实施例2、7-甲基-2-(4-烟酰基哌嗪-1-基)-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物1b)
参照化合物1a的合成方法,将原料噻吩-2-甲酸替换为烟酸,得淡黄色固体(化合物1b),产率35%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),8.81-8.73(m,2H),7.99(d,J=7.6Hz,1H),7.60-7.57(m,1H),3.95-3.55(br,8H),2.49(s,3H).ESI-MS m/z 480.0[M+1]+.
实施例3、2-(4-苯甲酰基哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物1c)
参照化合物1a的合成方法,将原料噻吩-2-甲酸替换为苯甲酸,得浅黄色固体(化合物1c),产率75%。1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.51-7.44(m,5H),4.15-3.60(br,8H),2.56(d,J=0.8Hz,1H).ESI-MS m/z 479.0[M+1]+.
实施例4、5-甲基-8-硝基-2-(4-(噻吩-2-羰基)哌嗪-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物1a’)
化合物1a’的合成路线如下:
1、中间体3的制备
1g 2-氯-3-硝基-5-三氟甲基苯甲酸悬浮于12mL SOCl2中,加入一滴DMF,于60℃下加热反应两小时,旋蒸脱除SOCl2,反复用干燥二氯甲烷旋蒸脱除残余SOCl2三次,得到半固体的酰氯。将酰氯溶解于2mL乙腈中,0-10℃下滴加到12mL 13%的氨水溶液中,滴加完毕搅拌反应20min,然后将反应液倾入适量冰水中,固体析出,过滤、水洗,干燥后得800mg白色固体中间体3。
2、中间体4的制备
10℃下,中间体3(600mg,2.23mmol)加入NaOH(180mg,4.46mmol),CS2(509mg,6.7mmol)和DMSO(15mL)配成的溶液中,加完搅拌反应20min,得到深棕色悬浮液,然后加MeI(348mg,2.45mmol),于10-20℃搅拌反应30min,用适量冰水稀释,有黄色沉淀析出,过滤,固体用水、甲基叔丁基醚洗涤,干燥后得300mg浅黄色固体中间体4。
3、中间体6的制备
氮气保护下、冰盐浴下将无水THF(7mL)加入含有中间体4(97mg,0.3mmol)的反应瓶中,加完滴加MeMgCl(3M,0.17mL),滴加完毕于0℃搅拌反应3小时,然后一次性加入2,3-二氯-5,6-二氰对苯醌(DDQ)(114mg,0.51mmol),0℃搅拌反应1小时,LCMS检测发现所有的加成中间体5(5’)都氧化成了6(6’)(两个mass为337的产物峰),反应液用甲基叔丁基醚/水稀释,分离有机相,水洗,醚相减压浓缩得到棕色油状物,经制备HPLC纯化得到极性较大的异构体18mg和极性较小的异构体23mg,交叉部分产物未收集。极性较大的为中间体6’,极性较小的为中间体6。
4、中间体1’的制备
常温下,将N-Boc-哌嗪(280mg,1.5mmol)溶于20mL无水乙醇中,加入装有中间体6(500mg,1eq)和三乙胺(3eq)的反应瓶中,于40℃下反应过夜,反应完成后,用水稀释反应液,乙酸乙酯萃取。有机相减压浓缩后拌样过柱,得430mg黄色固体中间体1’,产率60%。
5、中间体2’的制备
中间体2’按照实施例1中间体2类似的合成方法得到。
6、化合物1a’的制备
参照化合物1a的合成方法,原料为中间体2’和噻吩-2-甲酸,得浅黄色固体(化合物1a’),产率70%。1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.54-7.53(m,1H),7.36-7.35(m,1H),7.12-7.10(m,1H),4.00-3.92(m,8H),2.88(s,3H).ESI-MS m/z 485.1[M+1]+.
实施例5、2-(4-苯甲酰基哌嗪-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物1c’)
以中间体2’为原料,参照化合物1a’的合成方法,将原料噻吩-2-甲酸替换为苯甲酸,得浅黄色固体(化合物1c’),产率68%。1H NMR(400MHz,CDCl3)δ8.70(s,1H),7.52-7.44(m,5H),3.95-3.62(br,8H),2.88-2.87(d,J=0.4Hz,3H).ESI-MS m/z 479.0[M+1]+.
实施例6、7-甲基-8-硝基-2-(4-(3-(噻吩-2-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2a)
化合物2a的合成路线如下:
1、中间体7的制备
采用与实施例1中间体1类似的合成方法,将N-Boc-哌嗪替换为哌啶-4-羧酸叔丁酯,反应得到中间体7。
2、中间体8的制备
将中间体7(1.3g,2.75mmol)溶解于30mL DCM中,加入30mL三氟醋酸,室温搅拌反应2小时。减压浓缩,用二氯甲烷旋蒸脱除溶剂反复三次,以完全除去过量三氟醋酸。加入10mL石油醚/乙酸乙酯混合溶剂沉淀产品,过滤,固体用正己烷洗涤,真空干燥,得中间体8。
3、化合物2a的制备
中间体8(42mg,0.1mmol),N-羟基噻吩-2-甲脒(15.6mg,0.11mmol),三乙胺(20.2mg,0.2mmol)溶解于5mL DMA中,室温下加入HATU(45.6mg,0.12mmol),搅拌反应1小时。然后用水稀释反应液,乙酸乙酯萃取,有机相水洗,无水硫酸钠干燥,过滤,减压浓缩得到关环前的中间体。用二氧六环5mL溶解该中间体,然后于70℃加热关环反应31小时。反应完全后减压脱除溶剂,制备色谱纯化得到类白色固体(化合物2a)34mg,产率65%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.78-7.77(m,1H),7.51(d,J=4.8Hz,1H),7.16-7.14(m,1H),5.05-4.20(br,2H),3.62-3.55(m,2H),3.45-3.40(m,1H),2.53(s,3H),2.34-2.30(m,2H),2.15-2.07(m,2H).ESI-MS m/z 524.1[M+1]+.
实施例7、7-甲基-8-硝基-2-(4-(3-苯基-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2b)
参照化合物2a的合成方法,制备得类白色固体(化合物2b),产率61%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.07-8.05(m,2H),7.51-7.45(m,3H),5.01-4.25(br,2H),3.65-3.58(m,2H),3.47-3.42(m,1H),2.53(s,3H),2.34-2.31(m,2H),2.16-2.09(m,2H).ESI-MS m/z 518.2[M+1]+.
实施例8、7-甲基-8-硝基-2-(4-(3-(吡啶-3-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2c)
参照化合物2a的合成方法,反应得到类白色固体(化合物2c),产率55%。1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.87(s,1H),8.75(d,J=4.0Hz,1H),8.33(d,J=7.6Hz,1H),7.45-7.41(m,1H),5.10-4.60(br,1H),3.63-3.56(m,2H),3.48-3.46(m,1H),2.54(s,3H),2.37-2.33(m,2H),2.17-2.11(m,2H).ESI-MS m/z 519.0[M+1]+.
实施例9、7-甲基-8-硝基-2-(4-(3-(吡啶-2-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2d)
参照化合物2a的合成方法,反应得到类白色固体2d,产率46%。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.83(d,J=4.0Hz,1H),8.14(d,J=7.6Hz,1H),7.90-7.86(m,1H),7.48-7.45(m,1H),5.10-4.20(br,2H),3.62-3.49(m,3H),2.56(s,3H),2.40-2.33(m,2H),2.21-2.18(m,2H).ESI-MS m/z 519.1[M+1]+.
实施例10、2-(4-(3-(3-氟苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2e)
参照化合物2a的合成方法,反应得到类白色固体(化合物2e),产率51%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.86(d,J=8.0Hz,1H),7.76(d,J=9.2Hz,1H),7.48-7.43(m,1H),7.23-7.18(m,1H),5.10-4.00(br,2H),3.64-3.57(m,2H),3.47-3.43(m,1H),2.53(s,3H),2.35-2.31(m,2H),2.15-2.07(m,2H).ESI-MS m/z 536.0[M+1]+.
实施例11、7-甲基-8-硝基-2-(4-(3-(吡啶-4-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2f)
参照化合物2a的合成方法,反应得到类白色固体(化合物2f),产率53%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.77(d,J=5.2Hz,2H),7.92(d,J=5.6Hz,2H),5.15-4.10(br,2H),3.62-3.55(m,2H),3.50-3.45(m,1H),2.53(s,3H),2.36-2.33(m,2H),2.15-2.07(m,2H).ESI-MS m/z 519.2[M+1]+.
实施例12、7-甲基-8-硝基-2-(4-(3-(对甲苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2g)
参照化合物2a的合成方法,反应得到类白色固体(化合物2g),产率63%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.94(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),5.10-4.15(br,2H),3.64-3.57(m,2H),3.46-3.41(m,1H),2.53(s,3H),2.41(s,3H),2.34-2.31(m,2H),2.16-2.08(m,2H).ESI-MS m/z 532.2[M+1]+.
实施例13、2-(4-(3-(3-氯苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2h)
参照化合物2a的合成方法,反应得到类白色固体(化合物2h),产率65%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.06(t,J=1.6Hz,1H),7.95(d,J=7.6Hz,1H),7.50-7.40(m,2H),5.20-4.12(br,2H),3.64-3.57(m,2H),3.47-3.43(m,1H),2.53(s,3H),2.35-2.31(m,2H),2.15-2.10(m,2H).ESI-MS m/z 552.0[M+1]+.
实施例14、2-(4-(3-(2-氟苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2i)
参照化合物2a的合成方法,反应得到类白色固体(化合物2i),产率59%。1HNMR(400MHz,CDCl3)δ8.90(s,1H),8.08-8.04(m,1H),7.56-7.50(m,1H),7.33-7.24(m,2H),5.15-4.05(br,2H),3.67-3.60(m,2H),3.53-3.48(m,1H),2.56(s,3H),2.39-2.35(m,2H),2.20-2.11(m,2H).ESI-MS m/z 536.0[M+1]+.
实施例15、2-(4-(3-(2-氯苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2j)
参照化合物2a的合成方法,反应得到类白色固体(化合物2j),产率45%。1H NMR(400MHz,CDCl3)δ8.90(s,1H),7.93(d,J=7.6Hz,1H),7.56(d,J=8.0Hz,1H),7.49-7.39(m,2H),5.06-4.10(br,2H),3.68-3.62(m,2H),3.53-3.49(m,1H),2.56(s,3H),2.39-2.36(m,2H),2.17-2.14(m,2H).ESI-MS m/z 552.0[M+1]+.
实施例16、2-(4-(3-(3-甲氧基苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2k)
参照化合物2a的合成方法,反应得到类白色固体(化合物2k),产率70%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.59(d,J=7.6Hz,1H),7.51(s,1H),7.34-7.30(t,J=8.0Hz,1H),7.00-6.97(m,1H),4.90-4.10(br,2H),3.81(s,3H),3.58-3.51(m,2H),3.41-3.36(m,1H),2.47(s,3H),2.28-2.25(m,2H),2.10-2.03(m,2H).ESI-MS m/z 548.0[M+1]+.
实施例17、7-甲基-8-硝基-2-(4-(3-(间甲苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2l)
参照化合物2a的合成方法,反应得到类白色固体(化合物2l),产率71%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.81(s,1H),7.79(d,J=8.0Hz,1H),7.32-7.24(m,2H),4.85-4.10(br,2H),3.58-3.52(m,2H),3.41-3.36(m,1H),2.47(s,3H),2.36(s,3H),2.29-2.25(m,2H),2.11-2.03(m,2H).ESI-MS m/z 532.2[M+1]+.
实施例18、2-(4-(3-(2-甲氧基苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2m)
参照化合物2a的合成方法,反应得到类白色固体(化合物2m),产率75%。1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.01(dd,J=7.6,1.6Hz,1H),7.53-7.49(m,1H),7.12-7.07(m,2H),5.25-4.20(br,2H),4.00(s,3H),3.68-3.61(m,2H),3.51-3.46(m,1H),2.56(d,J=0.8Hz,3H),2.37-2.33(m,2H),2.19-2.12(m,2H).ESI-MS m/z 548.0[M+1]+.
实施例19、7-甲基-8-硝基-2-(4-(3-(嘧啶-2-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2n)
参照化合物2a的合成方法,反应得到类白色固体(化合物2n),产率49%。1H NMR(400MHz,CDCl3)δ8.91(d,J=4.8Hz,2H),8.81(s,1H),7.41(t,J=5.0Hz,1H),5.15-4.00(br,2H),3.51-3.43(m,3H),2.47(s,3H),2.35-2.31(m,2H),2.17-2.12(m,2H).ESI-MS m/z520.0[M+1]+.
实施例20、2-(4-(3-环己基-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2o)
参照化合物2a的合成方法,反应得到类白色固体(化合物2o),产率50%。1H NMR(400MHz,CDCl3)δ8.80(s,1H),5.30-4.00(br,2H),3.51-3.45(m,2H),3.32-3.25(m,1H),2.74-2.67(m,1H),2.47(d,J=0.8Hz,3H),2.22-2.18(m,2H),2.01-1.92(m,4H),1.78-1.74(m,2H),1.67-1.64(m,1H),1.53-1.43(m,2H),1.37-1.17(m,3H).ESI-MS m/z 524.2[M+1]+.
实施例21、2-(4-(3-环戊基-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2p)
参照化合物2a的合成方法,反应得到类白色固体(化合物2p),产率61%。1H NMR(400MHz,CDCl3)δ8.80(s,1H),5.15-4.00(br,2H),3.51-3.44(m,2H),3.31-3.24(m,1H),3.17-3.09(m,1H),2.47(s,3H),2.21-2.18(m,2H),2.01-1.96(m,4H),1.79-1.70(m,4H),1.66-1.60(m,2H).ESI-MS m/z 510.2[M+1]+.
实施例22、2-(4-(3-环丁基-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2q)
参照化合物2a的合成方法,反应得到类白色固体(化合物2q),产率60%。1H NMR(400MHz,CDCl3)δ8.80(s,1H),5.15-4.00(br,2H),3.62-3.54(m,1H),3.52-3.45(m,2H),3.33-3.26(m,1H),2.47(s,3H),2.33-2.27(m,4H),2.23-2.19(m,2H),2.09-1.90(m,4H).ESI-MS m/z 496.1[M+1]+.
实施例23、2-(4-(3-(叔丁基)-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2r)
参照化合物2a的合成方法,反应得到类白色固体(化合物2r),产率61%。1H NMR(400MHz,CDCl3)δ8.89(s,1H),5.10-4.00(br,2H),3.60-3.53(m,2H),3.40-3.35(m,1H),2.56(s,3H),2.30-2.27(m,2H),2.10-2.05(m,2H),1.38(s,9H).ESI-MS m/z 498.1[M+1]+.
实施例24、2-(4-(3-异丁基-1,2,4-噁二唑-5-基)哌啶-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2s)
参照化合物2a的合成方法,反应得到类白色固体(化合物2s),产率63%。1H NMR(400MHz,CDCl3)δ8.80(s,1H),5.10-4.00(br,2H),3.53-3.46(m,2H),3.32-3.26(m,1H),2.53(d,J=7.2Hz,2H),2.47(d,J=1.2Hz,3H),2.23-2.19(m,2H),2.08-1.93(m,3H),0.90(d,J=6.8Hz,6H).ESI-MS m/z 498.1[M+1]+.
实施例25、5-甲基-8-硝基-2-(4-(3-(噻吩-2-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2a’)
化合物2a’的合成路线如下:
1、中间体7’的制备
参照中间体1’的合成方法,反应得到中间体7’。
2、中间体8’的制备
参照中间体8的合成方法,反应得到中间体8’。
3、化合物2a’的制备
参照化合物2a的合成方法,起始原料为中间体8’,反应得到类白色固体(化合物2a’),产率43%。1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.79-7.78(d,J=2.8Hz,1H),7.52-7.29(m,1H),7.15-7.16(m,1H),4.73-4.4(br,2H),3.58-3.52(m,2H),3.44-3.38(m,1H),2.9(s,3H),2.34-2.30(m,2H),2.12-2.01(m,2H).ESI-MS m/z 524.1[M+1]+.
实施例26、5-甲基-8-硝基-2-(4-(3-(吡啶-3-基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2c’)
参照化合物2a’的合成方法,反应得到类白色固体(化合物2c’),产率48%.1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.76(d,J=1.6Hz,1H),8.69(s,1H),8.36-8.33(m,1H),7.52-7.42(m,1H),5.21-4.33(br,2H),3.72-3.49(m,2H),3.46-3.42(m,1H),2.88(s,3H),2.37-2.32(m,2H),2.17-2.07,(m,2H).ESI-MS m/z 519.0[M+1]+.
实施例27、2-(4-(3-(3-氯苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2h’)
参照化合物2a’的合成方法,反应得到类白色固体(2h’),产率46%.1HNMR(400MHz,CDCl3)δ8.69(s,1H),8.07(t,J=3.2Hz,1H),7.96(d,J=10.1Hz,1H),7.52-7.41(m,2H),5.23-4.50(br,2H),3.60-3.40(m,3H),2.88(s,3H),2.36-2.31(m,2H),2.16-2.06(m,2H).ESI-MS m/z 552.0[M+1]+.
实施例28、2-(4-(3-(2-氟苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2i’)
参照化合物2a’的合成方法,反应得到类白色固体(2i’),产率53%。1HNMR(400MHz,CDCl3)δ8.79(s,1H),8.06-8.04(m,1H),7.54-7.52(m,1H),7.24-7.22(m,2H),5.02-4.48(br,2H),3.60-3.57(m,2H),3.50-3.43(m,1H),2.88(s,3H),2.37-2.33(m,2H),2.16-2.08(m,2H).ESI-MS m/z 536.0[M+1]+.
实施例29、5-甲基-8-硝基-2-(4-(3-(间甲苯基)-1,2,4-噁二唑-5-基)哌啶-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2l’)
参照化合物2a’的合成方法,反应得到类白色固体(化合物2l’),产率47%。1H NMR(400MHz,CDCl3)δ8.71(s,1H),7.91-7.89(m,2H),7.39-7.31(m,2H),4.88-4.41(br,2H),3.60-3.52(m,2H),3.46-3.40(m,1H),2.88(s,3H),2.42(s,3H),2.33-2.16(m,2H),2.12-2.01(m,2H).ESI-MS m/z 532.2[M+1]+.
实施例30、2-(4-(3-环己基-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2o’)
参照化合物2a’的合成方法,反应得到类白色固体(化合物2o’),产率55%。1H NMR(400MHz,CDCl3)δ8.69(s,1H),4.83-4.10(br,2H),3.53-3.48(m,2H),3.32-3.29(m,1H),2.87(s,3H),2.79-2.74(m,1H),2.27-2.21(m,2H),2.04-2.00(m,4H),1.84-1.74(m,3H),1.71-1.49(m,2H),1.37-1.10(m,3H).ESI-MS m/z 524.2[M+1]+.
实施例31、2-(4-(3-环戊基-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2p’)
参照化合物2a’的合成方法,反应得到类白色固体(化合物2p’),产率47%。1H NMR(400MHz,CDCl3)δ8.74(s,1H),5.01-4.00(br,2H),3.55-3.44(m,2H),3.39-3.26(m,1H),3.19-3.03(m,1H),2.85(s,3H),2.34-2.28(m,2H),2.16-2.03(m,4H),1.89-1.77(m,4H),1.69-1.63(m,2H).ESI-MS m/z 510.2[M+1]+.
实施例32、2-(4-(3-环丁基-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2q’)
参照化合物2a’的合成方法,反应得到类白色固体(化合物2q’),产率53%。1H NMR(400MHz,CDCl3)δ8.69(s,1H),4.96-4.10(br,2H),3.72-3.64(m,1H),3.60-3.49(m,2H),3.40-3.31(m,1H),2.89(s,3H),2.45-2.39(m,4H),2.32-2.21(m,2H),2.11-1.90(m,4H).
实施例33、2-(4-(3-(叔丁基)-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2r’)
参照化合物2a’的合成方法,反应得到淡黄色固体(化合物2r’),产率44%。1H NMR(400MHz,CDCl3)δ8.69(s,1H),5.10-4.20(br,2H),3.61-3.49(m,2H),3.40-3.31(m,1H),2.89(s,3H),2.28-2.24(m,2H),2.08-2.01(m,2H),1.36(s,9H).ESI-MS m/z 498.1[M+1]+.
实施例34、2-(4-(3-异丁基-1,2,4-噁二唑-5-基)哌啶-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物2s’)
参照化合物2a’的合成方法,反应得到淡黄色固体(化合物2s’),产率46%。1H NMR(400MHz,CDCl3)δ8.69(s,1H),5.09-4.10(br,2H),3.55-3.50(m,2H),3.34-3.31(m,1H),2.87(s,3H),2.60(d,J=1.6Hz,2H),2.32-2.21(m,2H),2.19-1.99(m,3H),0.98(m,6H).ESI-MS m/z 498.1[M+1]+.
实施例35、2-(4-(3-(3-氟苯基)-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3a)
化合物3a的合成路线如下:
1、中间体9的制备
中间体2(243mg,0.62mmol)和Et3N(2.5eq)加入15mL DCM中搅拌溶解,冰浴下加入溴氰(1.2eq),搅拌反应1小时,TLC显示反应进行完全。用水稀释反应液,DCM萃取产品,水洗,无水硫酸钠干燥,过滤,滤液减压浓缩得232mg黄色固体产品中间体9,产率94%。
2、化合物3a的制备
中间体9(20mg,0.05mmol)和N-羟基间氟苯甲脒(9.3mg,0.06mmol)溶解于5mL二氯甲烷中,加入1N ZnCl2四氢呋喃溶液(0.06ml,0.06mmol),于室温下搅拌反应5小时,有固体在反应过程中逐渐析出。反应液浓缩脱除溶剂,加入9mL四氢呋喃和3mL 4N盐酸/二氧六环溶液溶解,于60~70℃加热反应7小时,直至反应完全。减压浓缩脱除溶剂,乙醇溶解,滴加氨水至pH>9。加水沉淀产品,过滤,固体水洗,乙醇洗涤,真空干燥得到浅黄色固体(化合物3a)25mg,产率93%。1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.79(d,J=8.0Hz,1H),7.70(d,J=8.8Hz,1H),7.46-7.41(m,1H),7.21-7.17(m,1H),4.10(br s,4H),3.88-3.84(m,4H),2.56(s,3H).ESI-MS m/z537.2[M+1]+.
实施例36、7-甲基-8-硝基-2-(4-(3-苯基-1,2,4-噁二唑-5-基)哌嗪-1-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3b)
参照化合物3a的合成方法,反应得到淡黄色固体(化合物3b),产率28%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.99(d,J=6.8Hz,2H),7.49-7.44(m,3H),4.11(br s,4H),3.86(s,4H),2.55(s,3H).ESI-MS m/z 519.2[M+1]+.
实施例37、2-(4-(3-环戊基-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3c)
参照化合物3a的合成方法,反应得到淡黄色固体(化合物3c),产率61%。1H NMR(400MHz,CDCl3)δ8.67(s,1H),4.00(br s,4H),3.71-3.68(m,4H),2.93-2.91(m,1H),2.45(s,3H),1.90-1.86(m,2H),1.73-1.58(m,6H).ESI-MS m/z 511.2[M+1]+.
实施例38、2-(4-(3-环己基-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3d)
参照化合物3a的合成方法,反应得到淡黄色固体(化合物3d),产率35%。1H NMR(400MHz,CDCl3)δ8.87(s,1H),4.06(br s,4H),3.77-3.75(m,4H),2.65-2.57(m,1H),2.55(s,3H),1.97-1.94(m,2H),1.82-1.79(m,2H),1.72-1.69(m,1H),1.53-1.47(m,2H),1.37-1.25(m,3H).ESI-MS m/z 525.2[M+1]+.
实施例39、2-(4-(3-环丁基-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3e)
参照化合物3a的合成方法,反应得到类白色固体(化合物3e),产率61%。1H NMR(400MHz,CDCl3)δ8.90(s,1H),4.08(br s,4H),3.82-3.79(m,4H),3.54-3.45(m,1H),2.57(s,3H),2.39-2.30(m,4H),2.15-1.97(m,2H).ESI-MS m/z 497.2[M+1]+.
实施例40、2-(4-(3-(叔丁基)-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3f)
参照化合物3a的合成方法,反应得到类白色固体(化合物3f),产率56%。1H NMR(400MHz,CDCl3)δ8.81(s,1H),3.99(br s,4H),3.71-3.69(m,4H),2.48(d,J=0.8Hz,3H),1.25(s,9H).ESI-MS m/z 499.1[M+1]+.
实施例41、2-(4-(3-异丁基-1,2,4-噁二唑-5-基)哌嗪-1-基)-7-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3g)
参照化合物3a的合成方法,反应得到类白色固体(化合物3g),产率58%。1H NMR(400MHz,CDCl3)δ8.90(s,1H),4.09(br s,4H),3.81-3.78(m,4H),2.57(s,3H),2.45(d,J=7.2Hz,2H),2.14-2.07(m,1H),1.00(d,J=6.8Hz,6H).ESI-MS m/z 499.0[M+1]+.
实施例42、2-(4-(3-环戊基-1,2,4-噁二唑-5-基)哌嗪-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3c’)
化合物3c’的合成路线如下:
1、中间体9’的制备
参照中间体9的合成方法,反应得到中间体9’。
2、化合物3c’的制备
以中间体9’为原料,参照化合物3a的合成方法,反应得到类白色固体(化合物3c’),产率56%。1H NMR(400MHz,CDCl3)δ8.71(s,1H),4.05(br s,4H),3.77-3.75(m,4H),3.06-3.00(m,1H),2.88(s,3H),2.03-1.96(m,2H),1.85-1.81(m,4H),1.79-1.65(m,2H).ESI-MS m/z 511.2[M+1]+.
实施例43、2-(4-(3-环丁基-1,2,4-噁二唑-5-基)哌嗪-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3e’)
参照化合物3c’的合成方法,反应得到类白色固体(化合物3e’),产率45%。13C NMR(101MHz,CDCl 3)δ173.84,170.45,169.51,161.07,147.45,141.75,132.99,130.13,129.91,129.81,129.50,124.93(t,J=6.1Hz),124.13,121.40,45.43,31.55,26.69,18.97,18.32(d,J=2.6Hz).ESI-MS m/z497.2[M+1]+.
实施例44、2-(4-(3-(叔丁基)-1,2,4-噁二唑-5-基)哌嗪-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3f’)
参照化合物3c’的合成方法,反应得到类白色固体(化合物3f’),产率59%。1H NMR(400MHz,CDCl3)δ8.71(s,1H),4.04(br s,4H),3.77-3.74(m,4H),2.88(d,J=0.8Hz,3H),1.32(s,9H).ESI-MS m/z 499.1[M+1]+.
实施例45、2-(4-(3-异丁基-1,2,4-噁二唑-5-基)哌嗪-1-基)-5-甲基-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物3g’)
参照化合物3c’的合成方法,反应得到类白色固体(化合物3g’),产率44%。1HNMR(400MHz,CDCl3)δ8.71(s,1H),4.05(br s,4H),3.78-3.75(m,4H),2.87(d,J=1.2Hz 3H),2.44-2.42(d,J=7.2Hz,2H),2.12-2.07(m,1H),0.99-0.98(d,J=6.4Hz,6H).ESI-MS m/z499.0[M+1]+.
实施例46、8-硝基-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4a)
参照中间体1的合成方法,起始原料为2-氯-3-硝基-5-三氟甲基苯甲酸,反应得到淡黄色固体(化合物4a),产率42%。1H NMR(400MHz,CDCl3)δ9.11(d,J=2.1Hz,1H),8.77(d,J=2.1Hz,1H),7.68-7.64(m,2H),7.43(dd,J=5.2,2.0Hz,3H),4.29(s,4H),3.18(s,2H),2.16(s,2H),1.93(td,J=13.3,4.6Hz,2H).ESI-MS m/z 491.1[M+1]+.
实施例47、2-(3-甲基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-8-硝基-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4b)
参照中间体1的合成方法,起始原料为2-氯-3-硝基-5-三氟甲基苯甲酸,反应得到淡黄色固体(化合物4b),产率44%。1H NMR(400MHz,CDCl3)δ9.10(d,J=2.1Hz,1H),8.76(d,J=2.1Hz,1H),4.35-3.39(m,4H),2.76(s,2H),2.05(s,2H),2.02(s,3H),1.82(td,J=13.0,4.6Hz,2H).ESI-MS m/z 429.1[M+1]+.
实施例48、7-甲基-8-硝基-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-6-(三氟甲基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4c)
参照中间体1的合成方法,起始原料为2-氯-3-硝基-4-甲基-5-三氟甲基苯甲酸反应得到淡黄色固体(化合物4c),产率39%。1H NMR(400MHz,CDCl3)δ8.88(s,1H),7.68-7.63(m,2H),7.43(d,J=1.9Hz,2H),7.42(d,J=2.1Hz,1H),3.89(d,J=146.6Hz,4H),3.17(s,2H),2.54(d,J=1.5Hz,3H),2.14(d,J=13.7Hz,2H),1.90(ddd,J=13.8,12.1,4.7Hz,2H).ESI-MS m/z505.1[M+1]+.
实施例49、6-氯-7-甲基-2-(3-甲基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4d)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4d),产率35%。1H NMR(400MHz,CDCl3)δ8.63(s,1H),2.74(s,2H),2.49(s,3H),2.01(s,7H),1.78(ddd,J=13.9,12.1,4.7Hz,4H).ESI-MS m/z 409.0[M+1]+.
实施例50、6-氟-7-甲基-8-硝基-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4e)
参照中间体1的合成方法,起始原料为2,5-二氟-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4e),产率33%。1H NMR(400MHz,CDCl3)δ8.34(d,J=9.1Hz,1H),7.68-7.63(m,2H),7.42(dd,J=5.2,2.0Hz,3H),4.12(s,2H),3.57(s,2H),3.17(s,2H),2.43(d,J=2.2Hz,3H),2.13(d,J=13.8Hz,2H),1.89(ddd,J=13.9,12.1,4.7Hz,2H).ESI-MS m/z455.1[M+1]+.
实施例51、6-氯-7-甲基-8-硝基-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4f)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4f),产率35%。1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.66–7.63(m,2H),7.42(dd,J=5.3,2.0Hz,3H),4.08(s,4H),3.16(s,2H),2.49(s,3H),2.13(d,J=13.8Hz,2H),1.94-1.85(m,2H).ESI-MS m/z 471.1[M+1]+.
实施例52、6-氯-7-甲基-8-硝基-2-(3-(噻吩-2-基)-1-氧代-2,8-二氮杂螺[4.5]癸-2-烯-8-基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4g)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4g),产率41%。1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.42(dd,J=5.1,1.2Hz,1H),7.19(dd,J=3.6,1.2Hz,1H),7.07(dd,J=5.1,3.6Hz,1H),3.65(s,4H),3.17(s,2H),2.50(s,3H),2.13(d,J=13.9Hz,2H),1.94-1.84(m,2H).ESI-MS m/z 477.0[M+1]+.
实施例53、4-(8-(6-氯-7-甲基-8-硝基-4-氧代-4H-苯并[e][1,3]噻嗪-2-基)-1-氧代-2,8-二氮杂螺[4.5]癸-2-烯-3-基)哌啶-1-羧酸叔丁酯的制备(化合物4h)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4h),产率46%。1H NMR(400MHz,CDCl3)δ8.63(s,1H),2.82(t,J=12.8Hz,2H),2.72(s,2H),2.49(s,3H),2.06–1.98(m,3H),1.89–1.67(m,6H),1.58–1.48(m,6H),1.46(s,9H).ESI-MS m/z 578.2[M+1]+.
实施例54、4-(8-(6-氟-7-甲基-8-硝基-4-氧代-4H-苯并[e][1,3]噻嗪-2-基)-1-氧代-2,8-二氮杂螺[4.5]癸-2-烯-3-基)哌啶-1-羧酸叔丁酯的制备(化合物4i)
参照中间体1的合成方法,起始原料为2,5-二氟-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4i),产率:46%。1H NMR(400MHz,CDCl3)δ8.34(d,J=9.1Hz,1H),4.12(s,2H),2.82(t,J=12.7Hz,2H),2.72(s,2H),2.42(d,J=2.1Hz,3H),2.00(d,J=13.7Hz,2H),1.57-1.48(m,6H),1.46(s,9H).ESI-MS m/z 562.2[M+1]+.
实施例55、6-氯-2-(3-(1-(环己基甲基)哌啶-4-基)-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-7-甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4j)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4j),产率31%。1H NMR(400MHz,CDCl3)δ3.58(s,2H),2.90(dt,J=12.3,3.4Hz,2H),2.72(s,2H),2.49(s,3H),2.41(ddt,J=11.7,8.0,4.0Hz,1H),2.12(d,J=7.0Hz,2H),1.98(q,J=11.1Hz,4H),1.77(ddd,J=18.2,11.6,4.6Hz,11H),1.47(ddp,J=10.8,7.3,3.9Hz,2H),1.21(dddd,J=19.5,10.6,7.6,2.8Hz,4H),0.86(dd,J=11.8,2.9Hz,2H).ESI-MS m/z 574.2[M+1]+.
实施例56、2-(3-(4-(环己基甲基)环己基)-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-6-氟-7-甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4k)
参照中间体1的合成方法,起始原料为2,5-二氟-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4k),产率28%。1H NMR(400MHz,CDCl3)δ8.33(d,J=9.1Hz,1H),3.59(s,2H),2.90(d,J=11.3Hz,2H),2.71(s,2H),2.42(d,J=2.1Hz,3H),2.39(dd,J=11.5,3.8Hz,1H),2.12(d,J=7.1Hz,2H),2.08-.93(m,4H),1.85-.65(m,13H),1.31–1.12(m,4H),0.92-.81(m,2H).ESI-MS m/z 558.3[M+1]+.
实施例57、6-氯-2-(3-(1-环戊基哌啶-4-基)-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-7-甲基-8-硝基-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4l)
参照中间体1的合成方法,起始原料为2,5-二氯-4-甲基-3-硝基苯甲酸,反应得到淡黄色固体(化合物4l),产率32%。1H NMR(400MHz,CDCl3)δ8.62(s,1H),3.57(s,2H),3.07(d,J=11.1Hz,2H),2.71(s,2H),2.52(d,J=8.3Hz,1H),2.49(s,3H),2.47-2.43(m,1H),2.02(q,J=11.2,10.3Hz,4H),1.95-1.71(m,10H),1.62-1.31(m,6H).ESI-MS m/z 546.2[M+1]+.
实施例58、6,7,8-三氟-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4m)
参照中间体1的合成方法,起始原料为2,3,4,5-四氟苯甲酰氯,反应得到淡黄色固体(化合物4m),产率51%。1H NMR(400MHz,CDCl3)δ8.14(ddd,J=9.9,7.3,2.2Hz,1H),7.69-7.63(m,2H),7.42(qd,J=4.4,1.3Hz,3H),5.06(s,2H),3.68(s,2H),3.17(s,2H),2.14(d,J=13.9Hz,2H),1.91(ddd,J=13.9,12.0,4.7Hz,2H).ESI-MS m/z 432.1[M+1]+.
实施例59、5-氟-2-(3-苯基-1-氧代-2,8-二氮螺环[4.5]癸-2-烯-8-基)-4H-苯并[e][1,3]噻嗪-4-酮的制备(化合物4n)
参照中间体1的合成方法,起始原料为2,6-二氟苯甲酸,反应得到淡黄色固体(化合物4n),产率47%。1H NMR(400MHz,CDCl3)δ7.67-7.63(m,2H),7.49–7.39(m,4H),7.17-7.09(m,2H),3.65(s,2H),3.16(s,2H),2.10(d,J=13.5Hz,2H),1.89(ddd,J=13.8,11.8,4.7Hz,2H).ESI-MS m/z 396.1[M+1]+.
以下通过具体试验例证明本发明的有益效果。
试验例1、本发明化合物药效实验
1、化合物体外抗结核分枝杆菌(H37Rv)活性测试
结核分枝杆菌于含0.05%吐温80、0.2%甘油和10%OADC的Middlebrook7H9培养基生长至对数期晚期。离心,重悬于磷酸盐缓冲液,过滤,在7H11培养基上培养计算CFU数。
在96微孔板中加入100μL由Middlebrook 7H12连续2倍稀释的化合物,加入结核分枝杆菌(106cfu/mL)100μL,37℃下培养。第七天,每孔加入20μL 0.01%Alamar Blue和12.5μL 20%的Tween 80。24小时后再次在激发波长530nm,发射波长590nm下测定每孔的荧光,记录MIC值。MIC定义为引起对照孔荧光减弱90%以上的最低药物浓度。
化合物对结核分枝杆菌H37Rv的抑制活性如表1所示:各符号表示的MIC值范围为:A<0.1μM,0.1μM≤B<1μM,1μM≤C<10μM,D>10μM。
表1.化合物抗结核分枝杆菌活性结果
表1结果显示:大多数化合物在体外具有明显抑制结核分枝杆菌H37Rv的活性,其中1a’、1c’、4a、4b和4c抑菌活性与阳性对照PBTZ169相当,4f体外抑菌活性优于阳性对照PBTZ169。
2、化合物4f抗菌谱测试
对照品:左氧氟沙星。
化合物4f对其他细菌的最低抑菌浓度结果如表2所示:
表2.化合物4f抗菌谱测试结果
结果显示:化合物4f对所试的临床分离菌大肠埃希菌Esbls-、肺炎克雷伯菌Esbls-、铜绿假单胞菌、阴沟肠杆菌、大肠埃希菌ATCC25922、金黄色葡萄球菌均无抗菌活性,说明化合物4f对结核分枝杆菌选择性良好。
试验例2、本发明化合物安全性研究
初步基因毒性考察
本试验采用Mini-Ames实验,其目的在于:在有或无哺乳动物代谢活化系统(+S9或-S9)存在的条件下,对比PBTZ169对两种鼠伤寒沙门氏营养缺陷型菌株(TA98和TA100)基因组组氨酸位点的致突变作用。选择化合物4f进行了基因毒性测试。从表3和表4中看出:在有无代谢活化系统(±S9)的条件下,在所有测试浓度下,对于TA98和TA100两种菌株均未见背景菌苔减少,表明所测化合物无细菌毒性。而在致突变性方面PBTZ169和化合物4f则具有显著差异。
表3.pBTZ169 Mini-Ames试验结果
表4.本发明化合物4f Mini-Ames试验结果
对比这几个受试药物的实验结果发现:在当前测试浓度条件下,PBTZ169和化合物4f对TA98菌株没有显著的致基因突变作用;而对于TA100菌株,PBTZ169和化合物4f致突变性具有明显的差异(图1)。TA100菌株对PBTZ169更敏感,剂量依赖性更强,高浓度下致突变作用尤为显著;化合物4f则在回复突变剂量上,以及浓度依耐性上均优于PBTZ169。化合物4f的基因毒性相较于PBTZ169显著降低。
综上,本发明提供了一类新的用于抗结核的化合物,本发明化合物对结核分枝杆菌的活性有显著的抑制作用,且该化合物对结核分枝杆菌有良好的选择性。同时,本发明化合物的基因毒性显著降低,安全性提高。本发明化合物可用于制备抗结核分枝杆菌的药物以及预防或治疗结核病的药物,具有良好的应用前景。
Claims (10)
1.式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药:
其中,
R1、R2、R3、R4分别独立选自氢、C1~C8烷基、硝基、卤素、羧基、氨基、氰基、三氟甲基;
X选自-NR5-、-CR6R7-;
R5选自-C(O)R8、被0~3个R9取代的5~10元不饱和杂环基;
R8选自5~10元不饱和环烷基、5~10元不饱和杂环基;
R9选自C1~C8烷基、3~10元饱和环烷基、被0~3个R10取代的5~10元不饱和环烷基;
R10选自C1~C8烷基、C1~C8烷氧基、卤素、羟基、羧基;
R6、R7分别独立选自氢、被0~3个R11取代的5~10元不饱和杂环基;或者R6、R7连接形成被0~3个R12取代的5~10元不饱和杂环;
R11选自C1~C8烷基、3~10元饱和环烷基、被0~3个R13取代的5~10元不饱和环烷基、被0~3个R13取代的5~10元不饱和杂环基;
R13选自C1~C8烷基、C1~C8烷氧基、卤素;
R12选自C1~C8烷基、5~10元不饱和环烷基、5~10元不饱和杂环基、被0~3个R14取代的3~10元饱和杂环基、被0~3个R14取代的3~10元饱和环烷基;
R14选自叔丁氧羰基、被0~3个R15取代的C1~C8烷基、3~10元饱和环烷基;
R15选自3~10元饱和环烷基;
所述不饱和杂环基的杂原子为N、O、S,杂原子的个数为1~3个。
2.根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药,其特征在于:
R1、R2、R3、R4分别独立选自氢、C1~C3烷基、硝基、卤素、三氟甲基;
X选自-NR5-、-CR6R7-;
R8选自噻吩基、吡啶基、苯基;
R9选自C1~C4烷基、4~6元饱和环烷基、被0~1个R10取代的苯基;
R10选自卤素;
R11选自C1~C4烷基、4~6元饱和环烷基、被0~1个R13取代的苯基、噻吩基、吡啶基、嘧啶基;
R13选自C1~C3烷基、C1~C3烷氧基、卤素;
R14选自叔丁氧羰基、被0~1个R15取代的C1~C3烷基、5元饱和环烷基;
R15选自6元饱和环烷基。
9.权利要求1~8任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药在制备DprE1酶抑制剂和/或抑制结核分枝杆菌的药物中的用途;
优选地,所述药物为预防和/或治疗结核病的药物。
10.一种药物,其特征在于:它是以权利要求1~8任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其水合物、或其前药为活性成分,加上药学上可接受的辅料或辅助性成分制备而成的制剂。
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WO2003020719A1 (fr) * | 2001-09-03 | 2003-03-13 | Takeda Chemical Industries, Ltd. | Derives de 1,3-benzothiazinone et leur utilisation |
CN103508980A (zh) * | 2012-06-14 | 2014-01-15 | 四川大学 | 苯并噻嗪-4-酮衍生物及其制备方法和用途 |
CN108456204A (zh) * | 2017-02-17 | 2018-08-28 | 四川大学 | 苯并噻嗪衍生物及其制备方法和用途 |
CN111303075A (zh) * | 2020-04-08 | 2020-06-19 | 苏州大学 | 苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 |
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WO2003020719A1 (fr) * | 2001-09-03 | 2003-03-13 | Takeda Chemical Industries, Ltd. | Derives de 1,3-benzothiazinone et leur utilisation |
CN103508980A (zh) * | 2012-06-14 | 2014-01-15 | 四川大学 | 苯并噻嗪-4-酮衍生物及其制备方法和用途 |
CN108456204A (zh) * | 2017-02-17 | 2018-08-28 | 四川大学 | 苯并噻嗪衍生物及其制备方法和用途 |
CN111303075A (zh) * | 2020-04-08 | 2020-06-19 | 苏州大学 | 苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 |
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