CN113288892A - 聚adp核糖聚合酶抑制剂在抗冠状病毒中的应用 - Google Patents
聚adp核糖聚合酶抑制剂在抗冠状病毒中的应用 Download PDFInfo
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- CN113288892A CN113288892A CN202110218734.7A CN202110218734A CN113288892A CN 113288892 A CN113288892 A CN 113288892A CN 202110218734 A CN202110218734 A CN 202110218734A CN 113288892 A CN113288892 A CN 113288892A
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- China
- Prior art keywords
- aminocarbonyl
- indazol
- phenyl
- trifluoroacetic acid
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 202
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 178
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- 229910052717 sulfur Inorganic materials 0.000 claims description 131
- -1 hydroxy, carboxy, nitro, amino Chemical group 0.000 claims description 128
- 125000005842 heteroatom Chemical group 0.000 claims description 126
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 115
- 229910052757 nitrogen Inorganic materials 0.000 claims description 107
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 86
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 83
- 125000000623 heterocyclic group Chemical group 0.000 claims description 70
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 150000003254 radicals Chemical class 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims description 31
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 24
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 20
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000011737 fluorine Substances 0.000 claims description 17
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 16
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 16
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
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- 239000000126 substance Substances 0.000 claims description 8
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- 230000000241 respiratory effect Effects 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 0.000 claims description 6
- 206010046306 Upper respiratory tract infection Diseases 0.000 claims description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-O azetidin-1-ium Chemical compound C1C[NH2+]C1 HONIICLYMWZJFZ-UHFFFAOYSA-O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
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- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- DENYZIUJOTUUNY-MRXNPFEDSA-N (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one Chemical compound FC=1C=C2C=3C=4C(CN5[C@@](C4NC3C1)(CCC5)C)=NNC2=O DENYZIUJOTUUNY-MRXNPFEDSA-N 0.000 claims description 4
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- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
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- MWZCHAJAHLWNHS-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-7-yl)indazole-7-carboxamide Chemical class C1CNCC2=CC(N3C=C4C=CC=C(C4=N3)C(=O)N)=CC=C21 MWZCHAJAHLWNHS-UHFFFAOYSA-N 0.000 claims description 4
- ZITYCKWITVUXHF-UHFFFAOYSA-N 2-[4-[(1-pyrimidin-1-ium-2-ylpiperidine-4-carbonyl)amino]phenyl]indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1NC(=O)C(CC1)CCN1C1=NC=CC=[NH+]1 ZITYCKWITVUXHF-UHFFFAOYSA-N 0.000 claims description 4
- DPTMLZNTOJLFQF-UHFFFAOYSA-N 2-[4-[(2-morpholin-4-ylacetyl)amino]phenyl]indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1NC(=O)CN1CCOCC1 DPTMLZNTOJLFQF-UHFFFAOYSA-N 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- VBTUJTGLLREMNW-UHFFFAOYSA-N 5-fluoro-1-[[4-fluoro-3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4-dione Chemical compound FC1=CC=C(CN2C(NC(=O)C3=C(F)C=CC=C32)=O)C=C1C(=O)N(CC1)CCN1C1=NC=CC=N1 VBTUJTGLLREMNW-UHFFFAOYSA-N 0.000 claims description 4
- CWISFANUCRTMOR-UHFFFAOYSA-N 5-fluoro-2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]indazole-7-carboxamide Chemical class C1CN(C)CCN1CC1=CC=C(N2N=C3C(C(N)=O)=CC(F)=CC3=C2)C=C1 CWISFANUCRTMOR-UHFFFAOYSA-N 0.000 claims description 4
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- ZEUOOTVXMGIOAJ-UHFFFAOYSA-N (1-benzylpyrrolidin-1-ium-3-yl)-[[4-(7-carbamoylindazol-2-yl)phenyl]methyl]azanium;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1C[NH2+]C(C1)CC[NH+]1CC1=CC=CC=C1 ZEUOOTVXMGIOAJ-UHFFFAOYSA-N 0.000 claims description 2
- KJJNRGFYNOVFDO-UHFFFAOYSA-N (1-benzylpyrrolidin-1-ium-3-yl)methyl-[[4-(7-carbamoylindazol-2-yl)phenyl]methyl]azanium;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1C[NH2+]CC(C1)CC[NH+]1CC1=CC=CC=C1 KJJNRGFYNOVFDO-UHFFFAOYSA-N 0.000 claims description 2
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- AYERPIGWNOIKSM-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-2-ium-6-yl)indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1[NH2+]CCC2=CC(N3C=C4C=CC=C(C4=N3)C(=O)N)=CC=C21 AYERPIGWNOIKSM-UHFFFAOYSA-N 0.000 claims description 2
- DTQNDVVSMQXWAV-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-2-ium-7-yl)indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1C[NH2+]CC2=CC(N3C=C4C=CC=C(C4=N3)C(=O)N)=CC=C21 DTQNDVVSMQXWAV-UHFFFAOYSA-N 0.000 claims description 2
- CYJGVBUKZAGGCY-UHFFFAOYSA-N 2-(2-chlorophenyl)indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C1=CC=CC=C1Cl CYJGVBUKZAGGCY-UHFFFAOYSA-N 0.000 claims description 2
- HWNODZACISEDHJ-UHFFFAOYSA-N 2-(3-chlorophenyl)indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C1=CC=CC(Cl)=C1 HWNODZACISEDHJ-UHFFFAOYSA-N 0.000 claims description 2
- RHXODLQWBRUVQQ-UHFFFAOYSA-N 2-(4-acetylphenyl)indazole-7-carboxamide Chemical compound C1=CC(C(=O)C)=CC=C1N1N=C2C(C(N)=O)=CC=CC2=C1 RHXODLQWBRUVQQ-UHFFFAOYSA-N 0.000 claims description 2
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- IGFSZCSGLMYWNE-UHFFFAOYSA-N 2-(4-bromophenyl)indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C1=CC=C(Br)C=C1 IGFSZCSGLMYWNE-UHFFFAOYSA-N 0.000 claims description 2
- ZUUTWXXAMVQOFT-UHFFFAOYSA-N 2-(4-chlorophenyl)indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C1=CC=C(Cl)C=C1 ZUUTWXXAMVQOFT-UHFFFAOYSA-N 0.000 claims description 2
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- WQFNCKCVJCNKRS-UHFFFAOYSA-N 2-(4-pyridin-3-ylphenyl)indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1C1=CC=CN=C1 WQFNCKCVJCNKRS-UHFFFAOYSA-N 0.000 claims description 2
- GJIXGANMZPJFEI-UHFFFAOYSA-N 2-(4-pyrrolidin-1-ium-2-ylphenyl)indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1C1CCC[NH2+]1 GJIXGANMZPJFEI-UHFFFAOYSA-N 0.000 claims description 2
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- ICCREFOJWCQSNV-UHFFFAOYSA-N 2-[3-(1,4-diazepane-1-carbonyl)-4-fluorophenyl]indazole-7-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=1)=CC=C(F)C=1C(=O)N1CCCNCC1 ICCREFOJWCQSNV-UHFFFAOYSA-N 0.000 claims description 2
- XVYXQSXNGDZQRV-UHFFFAOYSA-N 2-[3-(piperidin-1-ium-4-ylcarbamoyl)phenyl]indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.N1=C2C(C(=O)N)=CC=CC2=CN1C(C=1)=CC=CC=1C(=O)NC1CC[NH2+]CC1 XVYXQSXNGDZQRV-UHFFFAOYSA-N 0.000 claims description 2
- ATXLFRDCNMDZPB-UHFFFAOYSA-N 2-[3-[(4-methylpiperazine-1,4-diium-1-yl)methyl]phenyl]indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F.C1C[NH+](C)CC[NH+]1CC1=CC=CC(N2N=C3C(C(N)=O)=CC=CC3=C2)=C1 ATXLFRDCNMDZPB-UHFFFAOYSA-N 0.000 claims description 2
- CKRODZGXJOHVJJ-UHFFFAOYSA-N 2-[3-hydroxy-4-[(4-methylpiperazin-1-ium-1-yl)methyl]phenyl]indazole-7-carboxamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1CN(C)CC[NH+]1CC1=CC=C(N2N=C3C(C(N)=O)=CC=CC3=C2)C=C1O CKRODZGXJOHVJJ-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供了一种聚ADP核糖聚合酶抑制剂或其药学上可接受的盐在制备抗病毒剂或在制备治疗由病毒引起的疾病的药物中的应用,其中所述病毒为β冠状病毒属的病毒。本发明还提供了如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐在制备抗病毒剂或在制备由病毒引起的疾病的药物中的应用,所述病毒为HIV、HPV、EBV、IFV和/或冠状病毒科的病毒。本发明所述的聚ADP核糖聚合酶抑制剂包括如式III所示的化合物和/或如式IV所示的化合物或其在药学上可接受的盐在确保用于人体时毒性小、安全性高的情况下,抑制病毒时的有效浓度更低、抗病毒活性更高,从而将其应用于临床治疗冠状病毒引起的疾病时更能够发挥有效的抑制病毒的作用。
Description
本申请要求申请日为2020/2/24的中国专利申请2020101117554的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于生物医药技术领域,尤其涉及以聚ADP核糖聚合酶抑制剂为主要成分的药物及其在药学上可接受的盐,及包含其的药物组合物、套装药盒,在抗冠状病毒引起的疾病中的应用。
背景技术
冠状病毒(Coronavirus,CoV)是一类有包膜的单股正链RNA病毒,能感染人及多种动物,具有呼吸道、胃肠道以及神经系统嗜性,可在家畜和伴侣动物(如猪、牛、鸡、狗、猫)中引起严重疾病,并可导致人罹患从普通感冒到严重的急性呼吸综合征等疾病。国际病毒分类委员会第九次报告根据冠状病毒的进化特点将其分为α、β、γ以及δ四个群,其中,α和β群的宿主以哺乳动物为主,γ和δ群主要发现于鸟类和禽类。
截止2020年2月,目前已知的能感染人的冠状病毒共有七种,包括引起上呼吸道感染症状普通感冒的人冠状病毒229E(HCoV-229E)、NL63(HCoV-NL63)、HKU1(HCoV-HKU1)、OC43(HCoV- OC43)和中东呼吸综合征冠状病毒(Middle eastrespiratory syndromecoronavirus,MERS-CoV),以及严重急性呼吸综合征(Severe acuterespiratorysyndrome,SARS)相关冠状病毒:冠状病毒SARS-CoV (严重急性呼吸综合征冠状病毒)和SARS-CoV-2(严重急性呼吸综合征冠状病毒2型)。每年15%- 30%的人呼吸道感染是由冠状病毒导致的,在新生儿、老年人和其他易感人群中能够引起更严重的疾病,这些人群中下呼吸道感染的发生率更高。其中,高致死率的冠状病毒SARS-CoV和MERS-CoV 的病死率分别高达10%和36%。但是,目前尚无批准的特异性药物治疗冠状病毒引起的感染,即使针对由SARS-CoV、SARS-CoV-2和MERS-CoV感染引起的严重急性呼吸道患者,临床也主要以对症治疗减少患者并发症为主。因此,亟需研制有效的药物来治疗冠状病毒引起的感染。
小分子化合物是抗病毒候选药物研究的热点。探讨已有药物的新用途已成为药物研发的一种重要途径。由于如候选药物已具有关于药理药效测试、功能靶点以及临床安全性等资料,有利于进一步的毒理学评价、药代动力学评价和制剂研发等,可以大大减少研发风险、缩短研发时间和研发成本,有着广阔的应用前景。
目前,临床一线治疗冠状病毒引起的感染,使用的多为广谱抗病毒药,如抗HIV药物洛匹那韦/ 利托那韦(克力芝)、阿比多尔、抗埃博拉病毒药物瑞德西韦等。阿比多尔(又称阿比朵尔,Arbidol) 是一种广谱抗病毒药,主要治疗A、B型流感病毒等引起的上呼吸道感染,在近些年有较多研究证明其对SARS-CoV及MERS-CoV冠状病毒均有一定的抑制活性。2020年2月4日,李兰娟团队最新研究成果在体外细胞实验中显示:阿比多尔在10~30微摩尔浓度下,与药物未处理的对照组比较,能有效抑制冠状病毒达到60倍,并且显著抑制病毒对细胞的病变效应。但从目前的数据判断,10~30 微摩尔的浓度在目前临床治疗中难以达到。《新型冠状病毒肺炎诊疗方案(试行第六版》中,推荐的阿比多尔用量为200mg每次,每天3次。但据“阿比多尔片(玛诺苏)”的药品说明书中描述,受试者单剂量口服阿比多尔200mg、400mg、600mg,达峰浓度分别为614.1±342.5ng/mL、904.2±355.6ng/mL、 975.1±661.0ng/mL,仅相当于1~2微摩尔的水平,远低于体外抑制浓度,推测其仅能发挥有限的体内抗病毒活性。同时药品说明书显示,阿比多尔不良事件发生率约为6.2%,主要表现为恶心、腹泻、头晕和血清转氨酶增高,且在同时需警惕国内阿比多尔制剂的人体生物等效性试验中,部分健康受试者出现心动过缓(服药3小时后部分健康受试者心率小于60次/分,且心率降低在2-24次/分间)的情况。此事件与药物的相关性尚不明确。此外,孕妇及哺乳期妇女、严重肾功能不全者慎用或遵医嘱。药物对于有窦房结病变或功能不全的患者的意义尚不明确,故目前建议该类人群服用本品慎重考虑。根据以上数据推测,即便是现有的被列入推荐治疗的药物,由于其抗病毒活性较低、临床证据不足和安全性问题等,仍不是治疗冠状病毒的最佳选择。
除了阿比多尔以外,其他抗病毒药物也正在进行抗新型冠状病毒的体外筛选和临床试验过程中。但是有证据表明并不是所有的抗病毒药物都对新型冠状病毒有效。其中抗艾滋病药物克力芝对治疗新型冠状病毒感染的肺炎效果不佳,且有毒副作用,不再推荐继续使用。而正在进行临床研究的瑞德西韦,也存在比较严重的肝毒性风险。因此,依据现有证据和经验判断,冠状病毒的治疗有其特殊性,仍需要开发具有自主知识产权的、具有创新作用机理、良好的疗效和安全性的药物。
聚ADP核糖聚合酶(poly(ADP-ribose)polymerases,PARP),在DNA损伤修复与细胞凋亡中发挥着重要作用,也参与感染、免疫调节等在内的一系列细胞过程。该蛋白家族由17个成员组成,包括PARP1、PARP2等。业界研发PARP抑制剂最初是希望通过阻断高度突变的癌细胞中的DNA损伤修复,从而利用“毒性损伤”的积累和“协同致死”效应来发挥抗癌作用。目前,全球已上市的PARP 抑制剂共有4款,分别是奥拉帕利(Olaparib)、尼拉帕利(Niraparib)、卢卡帕利(Rucaparib)、他拉唑帕利(Talazoparib)。同时,国内外也有数个PARP抑制剂进入了临床研究阶段,包括氟唑帕利、美呋哌瑞、希明哌瑞、IMP4297、BGB-290、ABT-888等。
据文献报道,PARP可能与病毒的入侵、整合、复制和衣壳蛋白的形成有着密切的关系。2001年 Hyo Chol Ha等人报道,在HIV病毒的复制过程中,PARP-1酶对HIV-1的复制、整合和转录中起到了关键作用,Proc Natl Acad Sci U S A.2001;98(6):3364–8中提到PARP抑制剂有助于抑制HIV病毒感染;另外有报道称,PARP-1还能通过参与炎症通路NF-KB剌激基因转录表达的过程,抑制PARP- 1的核定位,从而抑制NF-KB转录途径并达到抑制病毒复制的效果。最后,PARP-1可以诱导包括T 细胞在内的免疫细胞的凋亡,因此对PARP-1的抑制有可能阻断艾滋病病毒在宿主细胞中的整合,从而达到治疗艾滋病的效果。类似的发现在HPV、EBV、HSV等中也被证明。Tempera等在2010年证实PARP1抑制剂对EB病毒有抑制作用(JVirol.2010;84(10):4988–97.)。2012年,Grady等证实 PARP1抑制剂对HSV病毒有抑制作用(J Virol.2012;86(15):8259–68.)。2017年,Matthew E.Grunewald 等提出,冠状病毒的衣壳蛋白是ADP核糖基化修饰的,推测部分PARP的亚型参与了冠状病毒衣壳蛋白的形成(Virology.2018,517:62–68),但其中并没有进一步阐释哪些PARP亚型的选择性极为重要,也并未提出PARP抑制剂是否可以抑制病毒的复制或衣壳蛋白的形成。另一方面,2016年,Chad. V.Kuny等发表文章论述了PARP酶在病毒-宿主相互作用中起到的作用。其中PARP13能够降解病毒的逆转录RNA从而阻断病毒复制,PARP10、12、13、14等可以通过干扰素的产生来抑制病毒的复制 (PLoS pathogens,2016,12(3):e1005453)。2019年,MatthewE.Grunewald在文章中提到,PARP酶兼具抗病毒和免疫调节剂的功能,证实PARP12和PARP14的存在可以抑制病毒的入侵和复制(PLoS pathogens,2019,15(5):e1007756)。可见部分PARP酶的亚型反而会抑制病毒感染。目前国内外对PARP 的功能未有定论,PARP抑制剂对各种病毒的抑制作用并不明确。
综上所述,目前急需寻求在确保用药安全性高、副作用小的情况下,抑制病毒时的有效浓度更低、抗病毒活性更高,从而将其应用于临床治疗冠状病毒引起的疾病时更能够发挥有效的抑制病毒的作用的药物。
发明内容
本发明所要解决的技术问题是,为了克服现有技术中用于治疗冠状病毒引起的疾病的药物在所能够发挥作用的有效浓度过高、抗病毒活性不够强从而用于临床时发挥体内抗病毒活性有限等问题,提供了一种聚ADP核糖聚合酶(PARP)抑制剂或其在药学上可接受的盐、及包含其的药物组合物、套装药盒,在抗病毒例如冠状病毒中的应用,所述抗病毒可以是使用本发明的PARP抑制剂作为抗病毒剂,也可以是使用所述PARP抑制剂来治疗由病毒引起的疾病。本发明所述的聚ADP核糖聚合酶抑制剂或其在药学上可接受的盐、及包含其的药物组合物、套装药盒在确保用于人体时毒性小、安全性高的情况下,抑制病毒时的有效浓度更低、抗病毒活性更高,从而将其应用于临床治疗冠状病毒引起的疾病时更能够发挥有效的抑制病毒的作用。
本发明经过大量实验,意外发现聚ADP核糖聚合酶抑制剂或其在药学上可接受的盐能在体外显著抑制冠状病毒的复制。本发明首次证实了聚ADP核糖聚合酶抑制剂或其在药学上可接受的盐能够抑制冠状病毒对宿主细胞的感染及冠状病毒的复制,可将其用于抗冠状病毒感染方面的疾病治疗,对于冠状病毒感染尤其是冠状病毒SARS-CoV-2的防控和治疗具有重要意义。
为了解决上述技术问题,本发明第一方面提供了一种聚ADP核糖聚合酶抑制剂或其药学上可接受的盐在制备抗病毒剂或在制备治疗由病毒引起的疾病的药物中的应用,其中所述病毒为β冠状病毒属的病毒。
本发明中,所述SARS相关冠状病毒即为引起严重急性呼吸综合征(SARS)的冠状病毒。所述由SARS相关冠状病毒引起的疾病是因病毒感染引起的症状或疾病,这个疾病早期主要反映在呼吸道疾病上,临床上表现为发热、乏力、干咳、咳嗽、呼吸加速或急性呼吸窘迫综合征、气促等,少数患者伴有鼻塞、流涕、咽痛等症状。影像学表现为肺部不同程度改变如多发斑点和磨玻璃样阴影,病毒主要传播方式为近距离飞沫传播或接触患者呼吸道分泌物。此外还可能有消化道症状例如腹泻、婴儿和新生儿急性肠胃炎,极少数情况下引起神经系统综合征。再后期可能产生许多并发症包括难以纠正的代谢性酸中毒和出凝血功能障碍、呼吸衰竭、爆发性心肌炎至心力衰竭、肝肾衰竭等多脏器衰竭和脓毒症休克等。重症患者多在发病一周后出现呼吸困难和/或低氧血症,严重者快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和凝血功能障碍及多器官功能衰竭。上述疾病均寄望可使用本发明的PARP抑制剂进行治疗。此外,还有一部分病毒携带者未出现上述症状,也可以使用本发明所述的PARP抑制剂,来抑制病毒复制和传播等从而避免该病毒携带者患病或传播病毒产生新的病例。在某一方案中,所述β冠状病毒属的病毒为引起急性呼吸综合征的病毒例如SARS相关冠状病毒;较佳地,所述SARS相关冠状病毒为SARS-CoV(严重急性呼吸综合征冠状病毒)和/或SARS-CoV-2(严重急性呼吸综合征冠状病毒-2)。
在某一方案中,所述聚ADP核糖聚合酶抑制剂为针对PARP1和/或PARP2的抑制剂。
在某一方案中,所述聚ADP核糖聚合酶抑制剂为物质A、其药学上可接受的盐、其溶剂合物、或、其药学上可接受的盐的溶剂合物;
所述的物质A选自他拉唑帕利、氟唑帕利、希明哌瑞、IMP4297、BGB-290、ABT-888、如 CN1342161A所述的PARP抑制剂、如CN1788000A所述的PARP抑制剂、如CN103242273A所述的 PARP抑制剂、如CN101415686A所述的PARP抑制剂和如CN101578279A所述的PARP抑制剂中的一种或多种;此处仅为示例,并不排除物质A可以选自此处未列出的其他化合物的可能性。
本发明中,所述的“选自……中的一种或多种”包括将所列出的化合物进行联用的情况。在本发明某些实施方案中,将两种或两种以上的化合物进行联用时,会有更好的治疗效果。
在某一方案中,所述的如CN1342161A所述的PARP抑制剂为如式I所示的化合物;
其中,R11为H、卤素、氰基、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含 1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个R11-1取代的C1~C4的烷基、被一个或多个R11-1取代的C2~C4的烯基、被一个或多个R11-1取代的C2~C4的炔基、被一个或多个R11-1取代的C3~C4的环烷基、被一个或多个R11-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个R11-1取代的C6~C10的芳基(所述的“C6~C10的芳基”例如苯基;所述的“被一个R11-1取代的C6~C10的芳基”例如)、被一个或多个R11-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、-C(=O)-R11-2、-C(=O)-O-R11-3或-C(=O)-NR11-4R11-5;
R11-1独立地为卤素、羟基、羧基、硝基、氨基、C1~C4的烷基或被一个或多个NR11-1- 1R11-1-2取代的C1~C4的烷基(所述的“C1~C4的烷基”例如甲基);
R11-1-1和R11-1-2独立地为氢或C1~C4的烷基(例如甲基);
R11-2、R11-3、R11-4和R11-5为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个 R11-2-1取代的C1~C4的烷基、被一个或多个R11-2-1取代的C2~C4的烯基、被一个或多个R11-2-1取代的 C2~C4的炔基、被一个或多个R11-2-1取代的C3~C4的环烷基、被一个或多个R11-2-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个R11-2-1取代的C6~C10的芳基、或、被一个或多个R11-2-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基;
R11-2-1独立地为卤素、羟基、羧基、硝基、氨基或C1~C4的烷基;
Y1为-(CRY1-1RY1-2)(CRY1-3RY1-4)n-或-N=C(RY1-5)-;
n为0或1;
RY1-1、RY1-2和RY1-5独立地为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个 RY1-1-1取代的C1~C4的烷基、被一个或多个RY1-1-1取代的C2~C4的烯基、被一个或多个RY1-1-1取代的 C2~C4的炔基、被一个或多个RY1-1-1取代的C3~C4的环烷基、被一个或多个RY1-1-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个RY1-1-1取代的C6~C10的芳基、或、被一个或多个RY1-1-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基;
RY1-1-1独立地为卤素、羟基、硝基、氨基、C1~C4的烷基或C1~C4的烷氧基;
RY1-3和RY1-4独立地为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2 个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2 个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个RY1-3-1取代的C1~C4的烷基、被一个或多个RY1-3-1取代的C2~C4的烯基、被一个或多个RY1-3-1取代的C2~C4的炔基、被一个或多个RY1-3-1取代的C3~C4的环烷基、被一个或多个RY1-3-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个RY1-3-1取代的C6~C10的芳基、或、被一个或多个RY1-3-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基
RY1-3-1独立地为卤素、羟基、硝基、氨基、C1~C4的烷基或C1~C4的烷氧基;
R12是H或C1~C4的烷基;
X1是O或S;
R14是H、卤素(例如氟、氯或溴)或C1~C4的烷基;
R13是H或C1~C4的烷基。
在某一方案中,所述的如CN1788000A所述的PARP抑制剂为如式II所示的化合物;
其中,X2、Y2及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个RX2-1取代的C6~C10的芳基;
RX2-1独立地为卤素、硝基、羟基、巯基、氨基、C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、-ORX2-1-1或-SRX2-1-2;
RX2-1-1和RX2-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、 N和S中的一种或多种的、3~20元的”杂环基;
R21为H或卤素(例如氟、氯或溴);
Z为-NRZ-1-或-CRZ-2RZ-3-;
当Z为-NRZ-1-时,m为1或2;当Z为-CRZ-2RZ-3-时,m为1;
RZ-1和RZ-2独立地为C1~C20的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S 中的一种或多种的、3~20元的”杂环基、-C(=O)NRZ-1-1RZ-1-2、-C(=O)RZ-1-3(例如)、-C(= O)ORZ-1-4、-C(=S)NRZ-1-5RZ-1-6、-S(=O)2RZ-1-7、被一个或多个RZ-1-8取代的C1~C20的烃基、被一个或多个RZ-1-9取代的C6~C20的芳基、或、被一个或多个RZ-1-10取代的“含1~6个杂原子,杂原子选自O、 N和S中的一种或多种的、3~20元的”杂环基;
RZ-1-1、RZ-1-2、RZ-1-3、RZ-1-4、RZ-1-5、RZ-1-6和RZ-1-7独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-1、RZ-1-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-5、RZ-1-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
RZ-1-8、RZ-1-9和RZ-1-10独立地为C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、 N和S中的一种或多种的、3~20元的”杂环基、卤素、羟基、硝基、氰基、羧基、巯基、脲基、-C(= O)NRZ-1-8-1RZ-1-8-2、-C(=O)RZ-1-8-3、-C(=O)ORZ-1-8-4、-C(=S)NRZ-1-8-5RZ -1-8-6、-S(=O)2RZ-1-8-7、-ORZ-1-8-8、-SRZ-1-8-9、-S(=O)2NRZ-1-8-10RZ-1-8-11、-OC(=O)RZ-1-8-12、-S(=O)NRZ-1-8-13RZ-1-8-14或-C(=O)-NH-C(= O)RZ-1-8-15;
RZ-1-8-1、RZ-1-8-2、RZ-1-8-3、RZ-1-8-4、RZ-1-8-5、RZ-1-8-6、RZ-1-8-7、RZ-1-8-8、RZ-1-8-9、RZ-1-8-10、RZ-1-8-11、 RZ-1-8-12、RZ-1-8-13、RZ-1-8-14和RZ-1-8-15独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-8-1、RZ-1-8-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S 中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-5、RZ-1-8-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S 中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-10、RZ-1-8-11及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S 中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-13、RZ-1-8-14及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S 中的一种或多种的、4~8元的”杂环基;
RZ-3为H、羟基或氨基;
或者,RZ-2、RZ-3及与之相连的碳原子一起形成C3~C7的螺环烷基、或、“含1~3个杂原子,杂原子选自O、N和S中的一种或多种的、3~7元的”杂螺环烷基;
R22和R23都为氢,或者,当Z为-CRZ-2RZ-3-时,R22、R23、RZ-2、RZ-3及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个R22-1取代的C6~C10的芳基;
R22-1独立地为C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、羟基、巯基、氨基、-OR22-1-1、-SR22-1-2或-O-(CH2)p-O-;p为1、2 或3;
R22-1-1和R22-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、 N和S中的一种或多种的、3~20元的”杂环基。
在某一方案中,所述的如CN103242273A所述的PARP抑制剂为如式III所示的化合物;
R31和R32独立地为氢、C1~C4的烷基(例如甲基)、C3~C4的环烷基或“含1~3个杂原子,杂原子选自O和N中的一种或多种的、5元或6元的”杂环烷基;
或者,R31、R32及与之相连的N原子一起形成“含1~3个杂原子,杂原子选自O、N和S中的一种或多种的、5~6元的”杂环烷基、或、被一个或多个R31-1取代的“含1~3个杂原子,杂原子选自O、 N和S中的一种或多种的、5~6元的”杂环烷基;
R31-1为在N上的C1~C4的烷基(例如甲基);
X3为CH、CF或N;
Y3为CH、CF或N;
R33为H或Cl;
R34为H或F。
在某一方案中,所述的如CN101415686A所述的PARP抑制剂为如式IV所示的化合物;
fm为0、1、2或3;
R41独立地为羟基、卤素(例如氟)、氰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基;
A4为CH或N;
fn为0、1、2、3、4、5或6;
Y4为单键、C3-5环烷基、包含一个N原子的4元饱和杂环、包含1、2或3个独立地选自N、O 和S的杂原子的5、6或7元饱和或部分饱和的杂环、包含1、2、3或4个独立地选自O、N和S的杂原子但其中不多于一个为O或S的5元不饱和杂环、包含1、2或3个氮原子的6元不饱和杂环、“6-13元饱和、部分饱和或不饱和的烃环”(例如C6~C10的芳基,又例如苯基)、或、“包含1、2、3 或4个独立地选自N、O和S的杂原子的8-13元不饱和或部分饱和的杂环”;
z为1、2或3
fp为0、1、2、3、4、5或6;
R46和R47独立地为氢或C1-6烷基;
q为0或1;
t为0或1;
R42为氢、C1-6烷基或C3-10环烷基;
v为0或1;
X4为C或S=O;
w为0或1;
x为0、1、2、3、4、5或6;
R48和R49独立地为氢、C1-6烷基、羟基、卤代C1-6烷基、羟基C1-6烷基、氨基、C1-6烷基氨基或二(C1-6烷基)氨基;
a为0或1;
y为0或1;
R43为氢或C1-6烷基;
R44为氢、羟基、氰基、卤素(例如氟、氯或溴)、C1-6烷基、C2-10链烯基、卤代C1-6烷基、羟基 C1-6烷基、C1-6烷基羰基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基羰基、羧基、硝基、R44 -1、或、被一个或多个-(CH2)bR44-2取代的R44-3;
R44-1和R44-3独立地为C6-10芳基、C6-10芳氧基、C6-10芳基羰基、C3-10环烷基、包含一个N原子的 4元饱和杂环、“包含1、2或3个独立地选自N、O和S的原子的5或6元饱和或部分饱和的杂环” (例如)、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-15元不饱和、部分饱和或饱和的杂环”;
b独立地为0、1、2、3、4、5或6;
R44-2独立地为羟基、氧代、氰基、卤素、C1-6烷基、C2-10链烯基、卤代C1-6烷基、C1-6烷基羰基、 C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷氧基羰基、羧基、-NRaRb、-C(=O)NRaRb、S(=O)frRe、 R44-2-1、或、被一个或多个R44-2-2取代的R44-2-3;
Ra和Rb独立地为氢、C1-6烷基、C1-6烷基羰基、卤代C1-6烷基、羟基C1-6烷基、S(O)srRc或S(O)trN(Rd)2;
sr和tr独立地为0、1或2;
Rc为C1-6烷基、Rc-1或被一个或多个Rc-2取代的Rc-3;
Rc-1和Rc-3独立地为C6-10芳基、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“或包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
Rc-2独立地为羟基、氰基、卤素、C1-6烷基、C2-10链烯基或卤代C1-6烷基;
Rd独立地为氢或C1-6烷基;
或者,Ra、Rb及与之相连的N原子一起形成Ra-1或被一个或多个Ra-2取代的Ra-3;
Ra-1和Ra-3独立地为“包含一个N原子的4元饱和杂环”、或、“包含1、2或3个N原子和0或1个O原子的5、6或7元饱和或部分饱和的杂环”;
Ra-2独立地羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-10链烯基或卤代C1-6烷基;
fr为0、1或2;
Re为C1-6烷基、Re-1或被一个或多个Re-2取代的Re-3;
Re-1和Re-3独立地为C6-10芳基、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“或包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
Re-2独立地为羟基、氰基、卤素、C1-6烷基、C2-10链烯基或卤代C1-6烷基;
R44-2-1和R44-2-3独立地为C6-10芳基、C6-10芳基C1-6烷基、“包含一个N原子的4元饱和杂环”、“包含1、2或3个独立地选自N、O和S的原子的5、6或7元饱和或部分饱和的杂环”、“包含1、 2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
R44-2-2独立地为羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-10链烯基、卤代C1-6烷基、氨基、 C1-6烷基氨基和二(C1-6烷基)氨基。
在某一方案中,所述的如式I所示的化合物具有以下定义:
R11-1独立地为卤素、羟基、羧基、硝基、氨基、C1~C4的烷基或被一个或多个NR11-1- 1R11-1-2取代的C1~C4的烷基(所述的“C1~C4的烷基”例如甲基);
R11-1-1和R11-1-2独立地为氢或C1~C4的烷基(例如甲基);
Y1为-(CRY1-1RY1-2)(CRY1-3RY1-4)n-;
n为0或1;
RY1-1和RY1-2独立地为H或C1~C4的烷基;
RY1-3和RY1-4独立地为H或C1~C4的烷基;
R12是H或C1~C4的烷基;
X1是O或S;
R14是H或卤素(例如氟、氯或溴);
R13是H或C1~C4的烷基。
在某一方案中,所述的如式II所示的化合物具有以下定义:
X2、Y2及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个RX2-1取代的C6~C10的芳基;
RX2-1独立地为卤素、硝基、羟基、巯基、氨基、C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、-ORX2-1-1或-SRX2-1-2;
RX2-1-1和RX2-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、 N和S中的一种或多种的、3~20元的”杂环基;
R21为H或卤素(例如氟、氯或溴);
Z为-NRZ-1-;m为1或2;
RZ-1-1、RZ-1-2、RZ-1-3、RZ-1-4、RZ-1-5、RZ-1-6和RZ-1-7独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-1、RZ-1-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-5、RZ-1-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
R22和R23都为氢。
在某一方案中,所述的如式III所示的化合物具有以下定义:
R31为氢、甲基、乙基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基;
R32为氢、甲基、乙基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基;
或者,R31、R32及与之相连的N原子一起形成未取代或取代的吗啉基、哌嗪基、高哌嗪基、硫代吗啉基、哌啶基或四氢吡咯基,其中,所述的取代是指N被甲基取代;
X3为CH、CF或N;
Y3为CH、CF或N;
R33为H;
R34为F。
在某一方案中,所述的如式III所示的化合物具有以下定义:
R31为氢或甲基;
R32为甲基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基;
或者,R31、R32及与之相连的N原子一起形成未取代或取代的吗啉基、哌嗪基、高哌嗪基、硫代吗啉基、哌啶基或四氢吡咯基,其中,所述的取代是指N被甲基取代;
X3为CH、CF或N;
Y3为CH、CF或N;
R33为H;
R34为F。
在某一方案中,所述的如式IV所示的化合物具有以下定义:
fm为0、1、2或3;
R41独立地为羟基、卤素、氰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基;
A4为CH或N;
fn为0;
Y4为包含1、2或3个独立地选自N、O和S的杂原子的5、6或7元饱和或部分饱和的杂环、包含1、2、3或4个独立地选自O、N和S的杂原子但其中不多于一个为O或S的5元不饱和杂环、包含1、2或3个氮原子的6元不饱和杂环、“6-13元饱和、部分饱和或不饱和的烃环”(例如C6~C10的芳基,又例如苯基)、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的8-13元不饱和或部分饱和的杂环”;
z为1或2;
fp为0;
q为0;
t为0;
v为0;
w为0;
x为0;
a为0;
y为0;
R44为卤素或R44-1;
R44-1为C3-10环烷基、包含一个N原子的4元饱和杂环、“包含1、2或3个独立地选自N、O和 S的原子的5或6元饱和或部分饱和的杂环”(例如)、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-15元不饱和、部分饱和或饱和的杂环”。
在某一方案中,所述的如式IV所示的化合物具有以下定义:
fm为0或1;
R41为卤素(例如氟);
R44为氢或卤素(例如氟)。
在某一方案中,所述的如式I所示的化合物为下述任一化合物:
在某一方案中,所述的如式II所示的化合物为下述任一化合物:
其中R选自
在某一方案中,所述的如式III所示的化合物为下述任一化合物:
在某一方案中,所述的如式IV所示的化合物为下述任一化合物:
2-苯基-2H-吲唑-7-甲酰胺;2-(3-氯苯基)-2H-吲唑-7-甲酰胺;和2-{4-[(二甲基氨基)甲基]苯基}-2H- 吲唑-7-甲酰胺;2-{4-[(N,N-二甲基甘氨酰)氨基]苯基}-2H-吲唑-7-甲酰胺;2-苄基-2H-吲唑-7-甲酰胺; 2-(4-氯苯基)-2H-吲唑-7-甲酰胺;2-(2-氯苯基)-2H-吲唑-7-甲酰胺;2-{4-[(4-甲基哌嗪-1-基)甲基]苯基}- 2H-吲唑-7-甲酰胺;2-[4-(吗啉-4-基甲基)苯基]-2H-吲唑-7-甲酰胺;2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-[4-(吡咯烷-1-基甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-(哌啶-1-基甲基)苯基]-2H-吲唑-7- 甲酰胺;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N,N-二甲基甲烷氯化铵;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)甲基]吡啶鎓;2-{4-[1-(甲基氨基)乙基]苯基}-2H-吲唑-7-甲酰胺;N- {4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}环己烷三氟乙酸铵;{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苯基}- N-甲基甲烷三氟乙酸铵;2-苯基-2H-1,2,3-苯并三唑-4-甲酰胺;2-苄基-2H-1,2,3-苯并三唑-4-甲酰胺;2-{3-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸4-({3-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)哌啶鎓;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基甲烷氯化铵;2-{3-氯-4-[(二甲基氨基) 甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-4-甲基哌嗪-1-鎓;2-(4-{[(4-吡咯烷-1-基哌啶-1-基)乙酰基]氨基}苯基)-2H-吲唑-7-甲酰胺;2-{4-[(吡咯烷-1-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(哌啶-1-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(吗啉-4-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;氯化4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基] 苯基}氨基)-2-氧代乙基]吗啉-4-鎓;2-{4-[(乙基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(异丙基氨基) 甲基]苯基}-2H-吲唑-7-甲酰胺;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}丙烷-2-氯化铵;2-(4-{[(2-氟乙基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺;2-(4-{[(2,2-二氟乙基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺; 2-{4-[(环丙基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}-1,4-二氮杂环庚烷-1-鎓;2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)-N,N-二甲基乙烷三氟乙酸铵;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)甲基]哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-N,N’,N’-三甲基乙烷-1,2-二氯化二铵;三氟乙酸4-{4-[7-(氨基羰基)-2H- 吲唑-2-基]苯甲酰基}-1-甲基哌嗪-1-鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基] 氮杂环丁烷鎓;三氟乙酸(2S)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)-1-苄基哌啶鎓;2-{4-[(吡啶-4-基氨基)羰基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(4-苯基哌嗪-1- 基)羰基]苯基}-2H-吲唑-7-甲酰胺;2-(4-{[甲基(喹喔啉-6-基甲基)氨基]羰基}苯基)-2H-吲唑-7-甲酰胺; 2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基) 乙基]吡咯烷鎓;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)乙基]哌啶鎓;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)乙基]吗啉-4-鎓;三氟乙酸4-({4-[7-(氨基羰基)- 2H-吲唑-2-基]苯甲酰基}氨基)-1-甲基哌啶鎓;2-[4-[(4-甲基哌嗪-1-基)甲基]-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-[(甲基氨基)甲基]-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;2-[4-(吡咯烷-1-基甲基)-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4- (哌啶-1-基甲基)-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-[(乙基氨基)甲基]-3-(三氟甲基)苯基]-2H- 吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苄基}-1-甲基哌嗪-1-鎓;双(三氟乙酸)1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]哌啶鎓;双(三氟乙酸)4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]吗啉-4-鎓;双(三氟乙酸)1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]吡咯烷鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-甲基哌啶鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-苄基哌啶鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)- 2H-吲唑-2-基]苄基}-4-苯基哌嗪二鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(二甲基氨基)-2-氧代乙烷三氟乙酸铵;双(三氟乙酸)2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]吡啶鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]吡啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-甲基丙烷-2-三氟乙酸铵;双(三氟乙酸)N′-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-N,N-二甲基乙烷-1,2-二铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-(1,3-噁唑-2-基甲基)甲烷三氟乙酸铵;氯化 7-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;氯化6-[7-(氨基羰基)-2H-吲唑-2-基]-1,2, 3,4-四氢异喹啉鎓;三氟乙酸5-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]氮杂环丁烷鎓;2-(4-{[(氮杂环丁烷-3-基羰基)(甲基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基) 羰基]氮杂环丁烷鎓;2-(4-溴苯基)-5-氟-2H-吲唑-7-甲酰胺;5-氟-2-(4-吡啶-3-基苯基)-2H-吲唑-7-甲酰胺;2-(4-吡啶-3-基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-1-甲基哌嗪-1-鎓;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}哌啶鎓;2-{4-[7-(氨基羰基)-2H-吲唑-2- 基]苯基}-N-甲基乙烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]氮杂环丁烷鎓;2-{5-[(甲基氨基)甲基]吡啶-2-基}-2H-吲唑-7-甲酰胺;5-氟-2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氟-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基丙烷-2-三氟乙酸铵;2-(6-苯基哒嗪-3-基)-2H-吲唑-7-甲酰胺;{4-[7- (氨基羰基)-5-氟-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环己基]甲基}甲烷三氟乙酸铵;5-氯-2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;2-{3-甲氧基-4-[(4-甲基哌嗪-1-基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{3-甲氧基-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氯-2-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-2H-吲唑- 7-甲酰胺;5-氯-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-4-氟-2H-吲唑-2-基] 苯基}-N-甲基甲烷氯化铵;{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}-N-甲基甲烷氯化铵;氯化1-{4- [7-(氨基羰基)-4-氟-2H-吲唑-2-基]苄基}-4-甲基哌嗪-1-鎓;氯化1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基] 苄基}-4-甲基哌嗪-1-鎓;双(三氟乙酸)1-{3-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-甲基哌嗪二鎓;2-[4- (1-羟基-1-甲基乙基)苯基]-2H-吲唑-7-甲酰胺;2-(4-乙酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸3-{[{4- [7-(氨基羰基)-2H-吲唑-2-基]苄基}(甲基)氨基]羰基}-1-甲基哌啶鎓;2-{4-[1-(甲酰基氨基)-1-甲基乙基] 苯基}-2H-吲唑-7-甲酰胺;2-[3-(1,4-二氮杂环庚烷-1-基羰基)苯基]-2H-吲唑-7-甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸(2S)-2-[({4-[7-(氨基羰基)- 2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸(2R)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸 3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶鎓;三氟乙酸(3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;4-氯-2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸(3S)-3-[({4-[7-(氨基羰基)-2H- 吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;(R)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;(S)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;2-{3-氟-4-[(甲基氨基)甲基] 苯基}-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-2H-吲唑-2·基]-2-氟苯基}-N-甲烷三氟乙酸铵;2-{4-[1-甲基-1-(甲基氨基)乙基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]-2-羟基苄基}-4-甲基哌嗪-1-鎓;氯化(3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;氯化(3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;双(三氟乙酸)1-(2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}乙基)-4-甲基哌嗪二鎓;{4-[7-(氨基羰基)-4-羟基-2H-吲唑-2-基]苯基}-N- 甲基甲烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-苯基吡咯烷鎓;(1R,3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;(1R,3R)-3-[({4-[7- (氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;(1S,3R)-3-[({4-[7-(氨基羰基)-2H-吲唑 -2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-2-甲基氮杂环丁烷鎓;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-1-甲基哌啶鎓;9-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-3-氮鎓杂螺[5.5]十一烷三氟乙酸盐;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-4-苯基哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-{3-[({4-[7-(氨基羰基)- 2H-吲唑-2-基]苯基}氨基)羰基]吡啶-2-基}哌嗪-1-鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]喹啉鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]异喹啉鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1- 甲基氮杂环庚烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-2-甲基-1,2,3,4- 四氢异喹啉鎓;三氟乙酸2-{4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶-1-基}嘧啶-1-鎓;氯化1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-4-甲基哌嗪-1-鎓;5-[({4-[7-(氨基羰基)-2H-吲唑-2- 基]苯基}氨基)羰基]-3-氧代八氢吲嗪-2-三氟乙酸铵;三氟乙酸2-{3-[({4-[7-(氨基羰基)-2H-吲唑-2-基] 苯基}氨基)羰基]哌啶-1-基}吡啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4- 甲基吗啉-4-鎓;(1R,4R)-N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-1′-(甲基磺酰基)-1′,2′-二氢螺 [环己烷-1,3′-吲哚]-4-甲酰胺;三氟乙酸1-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]八氢- 1H-异吲哚鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-苄基吗啉-4-鎓;三氟乙酸(3S,4R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-(甲氧基羰基)吡咯烷鎓;双(三氟乙酸)4-{(2S)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓-1-基}哌啶鎓;(1S,3S)-3- [({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;三氟乙酸3-[({4-[7-(氨基羰基)- 2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸2-{4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基} 氨基)羰基]哌啶-1-基}嘧啶-1-鎓;双(三氟乙酸)2-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}吡咯烷鎓-3- 基)吡啶鎓;双(三氟乙酸)3-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}吡咯烷鎓-3-基)吡啶鎓;三氟乙酸 (3S,4S)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,4-二氟吡咯烷鎓;3-{4-[7-(氨基羰基)-2H-吲唑-2- 基]苄基}-6-铵基-3-氮鎓杂双环[3.1.0]己烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-7- 甲基-2,7-二氮鎓杂螺[4.4]壬烷双(三氟乙酸盐);双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}- 3-[4-(二甲基铵基)苯基]吡咯烷鎓;双(三氟乙酸)5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-甲基-1,2, 4,5,6,6a-六氢吡咯并[3,4-b]吡咯二鎓;双(三氟乙酸)3-{[{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}(甲基)铵基]甲基}-1-甲基哌啶鎓;(1R,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-氧杂-5-氮鎓杂双环 [2.2.1]庚烷三氟乙酸盐;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-羟基-2-甲基丙烷-1-三氟乙酸铵;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,3-二氟环丁烷三氟乙酸铵;三氟乙酸4-{4-[7-(氨基羰基)-2H- 吲唑-2-基]苄基}-6-氟-1,4-二氮杂环庚烷-1-鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}- 4-嘧啶-1-鎓-2-基-1,4-二氮杂环庚烷-1-鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)- 1-苄基吡咯烷鎓;双(三氟乙酸)3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1-甲基吡咯烷鎓;双(三氟乙酸)3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1-苄基吡咯烷鎓;2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-7-苄基-2,7-二氮鎓杂螺[4.4]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-8-苄基-2,8-二氮鎓杂螺[5.5]十一烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基] 苄基}-2,6-二氮鎓杂螺[3.3]庚烷双(三氟乙酸盐);7-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,7-二氮鎓杂螺[3.5]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,6-二氮鎓杂螺[3.5]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,8-二氮鎓杂螺[5.5]十一烷双(三氟乙酸盐);2-{4- [7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,8-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H- 吲唑-2-基]苄基}-2,7-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);8-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}- 2,8-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);3-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,9-二氮鎓杂螺 [5.5]十一烷双(三氟乙酸盐);双(三氟乙酸)2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}八氢吡咯并[3,4-c] 吡咯二鎓;双(三氟乙酸)5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}八氢吡咯并[3,4-b]吡咯二鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)八氢环戊二烯并[c]吡咯鎓;N2-{4-[7-(氨基羰基)- 2H-吲唑-2-基]苄基}-N1,N1-二甲基-1-吡啶-2-基乙烷-1,2-双(三氟乙酸)二铵;双(三氟乙酸)7-(氨基羰基)-2-[4-({[2-(2,3-二氢-1H-吲哚-1-基)乙基]铵基}甲基)苯基]-2H-吲唑-1-鎓;双(三氟乙酸)(3S,4S)-1- [2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]-3,4-二氟吡咯烷鎓;三氟乙酸5-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基)-1,3-苯并噻唑-3-鎓;1-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-8-氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);双(三氟乙酸)4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1- 甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-羟基乙烷三氟乙酸铵;三氟乙酸7-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸3-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]氮杂环丁烷鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶鎓;双 (三氟乙酸)(3R,4R)-4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-氟哌啶鎓;双(三氟乙酸)(3S,4R)- 4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-苄基-1-甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基] 苄基}-1-异丁酰基哌啶-4-三氟乙酸铵;双(三氟乙酸)2-[4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶-1-基]-3-甲基吡啶鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-苄基哌啶鎓;5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-5-氮杂-2-氮鎓杂双环[2.2.2]辛烷三氟乙酸盐;(1S,4S)-2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-5- 甲基-2,5-二氮鎓杂双环[2.2.1]庚烷双(三氟乙酸盐);双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(吡啶-2-基甲基)哌嗪二鎓;5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-苄基-5-氮杂-2-氮鎓杂双环 [2.2.2]辛烷三氟乙酸盐;8-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3-苄基-8-氮杂-3-氮鎓杂双环[3.2.1]辛烷三氟乙酸盐;(1S,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-苄基-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)吡咯烷鎓;6-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-氮鎓杂双环[3.1.0]己烷双(三氟乙酸盐);三氟乙酸(3S,4S)-N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-羟基四氢噻吩-3-铵1,1-二氧化物;双(三氟乙酸)4-[({4-[7-(氨基羰基)- 2H-吲唑-2-基]苄基}铵基)甲基]-4-羟基-1-甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-环丙基-2-羟基乙烷三氟乙酸铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环戊基]甲基}甲烷三氟乙酸铵;双(三氟乙酸)2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1,2,3,4-四氢-2,7-二氮杂萘二鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3-[(二甲基铵基)甲基]哌啶鎓;双(三氟乙酸)4-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}哌啶鎓-4-基)硫代吗啉-4-鎓;三氟乙酸1-{4-[7-(氨基羰基)-2H- 吲唑-2-基]苄基}-4-[(甲基磺酰基)氨基]哌啶鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}- 4-(1H-咪唑-3-鎓-1-基甲基)哌啶鎓;7-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-氧杂-7-氮鎓杂螺[4.5]癸烷三氟乙酸盐;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(1-羟基-1-甲基乙基)哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-苄基哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-乙基哌啶鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基} 氨基)羰基]-1-乙基哌啶鎓;2-[3-(1,4-二氮杂环庚烷-1-基羰基)-4-氟苯基]-2H-吲唑-7-甲酰胺三氟乙酸盐;{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苄基}甲基氨基甲酸叔丁酯;三氟乙酸6-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}吡咯烷鎓;6-氟 -2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氟-2-{2-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{3-羟基-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-(4-{[甲酰基(甲基)氨基]甲基}-3-羟基苯基)-2H-吲唑-7-甲酰胺;2-{2-氯-4-[(甲基氨基)甲基]苯基}-5-氟-2H-吲唑-7-甲酰胺;5-氟- 2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{2,5-二氟-4-[(甲基氨基)甲基]苯基}-5-氟-2H-吲唑-7-甲酰胺三氟乙酸盐;2-(4-溴苯基)-2H-吲唑-7-甲酰胺;氯化(3R)-3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸(3R)-3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;2-(1,2,3,4-四氢异喹啉-7-基)-2H-吲唑-7-甲酰胺;(R)-2-[4- ({3-[(二甲基氨基)甲基]哌啶-1-基}甲基)苯基]-2H-吲唑-7-甲酰胺;(S)-2-[4-({3-[(二甲基氨基)甲基]哌啶 -1-基}甲基)苯基]-2H-吲唑-7-甲酰胺;3-({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)-2-(氯甲基)-3-氧代丙烷-1-三氟乙酸铵;5-氟-2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺盐酸盐;2-{4-[(二甲基氨基)甲基]-3-氟苯基}-5-氟-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{4-[(氮杂环丁烷-3-基羰基)氨基]苯基}- 5-氟-2H-吲唑-7-甲酰胺;2-[4-(2,7-二氮杂螺[4.5]癸-2-基甲基)苯基]-2H-吲唑-7-甲酰胺;(1S,4S)-5-{4- [7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(4-氯苄基)-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;(1S,4S)- 5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(3-氯苄基)-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-[(甲基氨基)羰基]哌嗪-1-鎓;N-{4-[7-(氨基羰基)-2H- 吲唑-2-基]苄基}-2-羟基-2-吡啶-3-基乙烷三氟乙酸铵;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-环己基-2-羟基乙烷三氟乙酸铵;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-6-(羟基甲基)-1,4-氧杂氮杂环庚烷-4-鎓;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环丁基]甲基}甲烷三氟乙酸铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环己基]甲基}甲烷三氟乙酸铵;三氟乙酸 1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(5-甲基-1H-苯并咪唑-2-基)哌啶鎓;双(三氟乙酸)2-(1-{4-[7- (氨基羰基)-2H-吲唑-2-基]苄基}-4-羟基哌啶鎓-4-基)吡啶鎓;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2- 基]苄基}-3,3-二氟吡咯烷鎓;2-(4-{[(2R)-2-(氟甲基)吡咯烷-1-基]甲基}苯基)-2H-吲唑-7-甲酰胺;N- {4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-氧代吡咯烷-3-三氟乙酸铵;5-氟-2-(4-甲酰基苯基)-2H-吲唑-7- 甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基氮杂环丁烷鎓;双 (三氟乙酸)1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-3-[(二甲基铵基)甲基]哌啶鎓;三氟乙酸3-[({4- [7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苯基}氨基)羰基]氮杂环丁烷鎓;2-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-2,7-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);4,5-二氟-2-{4-[(甲基氨基)甲基]苯基}-2H- 吲唑-7-甲酰胺三氟乙酸盐;5-氟-2-(3-氟-4-{[(1-甲基氮杂环丁烷-3-基)羰基]氨基}苯基)-2H-吲唑-7-甲酰胺三氟乙酸盐;5-氟-2-(3-氟-4-甲酰基苯基)-2H-吲唑-7-甲酰胺;5-氟-2-(5-氟-2-甲酰基苯基)-2H-吲唑- 7-甲酰胺;{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苯基}-N-{[1-(羟基甲基)环戊基]甲基}甲烷三氟乙酸铵;5-氟-2-[3-氟-4-({[(3R)-1-甲基哌啶-3-基]羰基}氨基)苯基]-2H-吲唑-7-甲酰胺三氟乙酸盐;双(三氟乙酸)1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苄基}-4-甲基哌嗪二鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}铵基)甲基]-1-甲基哌啶鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-5-氟- 2H-吲唑-2-基]-2-氟苄基}铵基)甲基]-1-甲基哌啶鎓;
及其药学上可接受的盐或互变异构体。
在本发明范围内的其他特别的化合物有:
三氟乙酸7-[7-(氨基羰基)-2H-吲唑-2-基]-1-甲基-1,2,3,4-四氢异喹啉鎓;三氟乙酸3-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}-1-乙基哌啶鎓;2-(4-氰基苯基)-5-氟-2H-吲唑-7-甲酰胺;5-氟-2-[4- (1H-四唑-5-基)苯基]-2H-吲唑-7-甲酰胺;2-(4-氨基苯基)-5-氟-2H-吲唑-7-甲酰胺盐酸盐;3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]吡咯烷-1-甲酸叔丁酯;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]吡咯烷鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-甲基吡咯烷鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-乙基吡咯烷鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-丙基吡咯烷鎓;三氟乙酸3- [7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-异丙基吡咯烷鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]- 1-环己基吡咯烷鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-环丁基吡咯烷鎓;4-[7-(氨基羰基)- 2H-吲唑-2-基]-4-甲基哌啶-1-甲酸叔丁酯;三氟乙酸4-[7-(氨基羰基)-2H-吲唑-2-基]-4-甲基哌啶鎓;三氟乙酸2-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}吡咯烷鎓;2-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-5- 氟-2H-吲唑-7-甲酰胺三氟乙酸盐;氯化6-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;氯化2-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}哌啶鎓;5-氟-2-[4-(1H-吡唑-1-基)苯基]-2H-吲唑-7- 甲酰胺;5-氟-2-(3-哌啶-3-基苯基)-2H-吲唑-7-甲酰胺;2-[4-(氨基磺酰基)苯基]-5-氟-2H-吲唑-7-甲酰胺; 5-氟-2-(5,6,7,8-四氢-1,7-二氮杂萘-3-基)-2H-吲唑-7-甲酰胺;5-氟-2-(4-哌嗪-2-基苯基)-2H-吲唑-7-甲酰胺;4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯甲酸甲酯;5-氟-2-(1-甲基哌啶-3-基)-2H-吲唑-7-甲酰胺;5-氟-2-(1-乙基哌啶-3-基)-2H-吲唑-7-甲酰胺;5-氟-2-(1-丙基哌啶-3-基)-2H-吲唑-7-甲酰胺;5-氟- 2-(1-异丙基哌啶-3-基)-2H-吲唑-7-甲酰胺;2-(1-环己基哌啶-3-基)-5-氟-2H-吲唑-7-甲酰胺;5-氟-2-(1- 甲基哌啶-4-基)-2H-吲唑-7-甲酰胺;5-氟-2-(1-乙基哌啶-4-基)-2H-吲唑-7-甲酰胺;5-氟-2-(1-丙基哌啶- 4-基)-2H-吲唑-7-甲酰胺;5-氟-2-(1-异丙基哌啶-4-基)-2H-吲唑-7-甲酰胺;2-(1-环己基哌啶-4-基)-5-氟- 2H-吲唑-7-甲酰胺;2-(1-环丁基哌啶-4-基)-5-氟-2H-吲唑-7-甲酰胺;2-(1-环丁基哌啶-3-基)-2H-吲唑-7- 甲酰胺;2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-N,N-二甲基乙烷三氟乙酸铵;2-[7-(氨基羰基)-5-氟-2H- 吲唑-2-基]-N,N-二乙基乙烷三氟乙酸铵;N-{2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]乙基}丙烷-2-三氟乙酸铵;N-{2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]乙基}环己烷三氟乙酸铵;2-[2-(二环丁基氨基)乙基]-5-氟-2H-吲唑-7-甲酰胺;3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]哌啶-1-甲酸叔丁酯;4-[7-(氨基羰基)-5-氟- 2H-吲唑-2-基]哌啶-1-甲酸叔丁酯;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]哌啶鎓;三氟乙酸4- [7-(氨基羰基)-5-氟-2H-吲唑-2-基]哌啶鎓;3-[7-(氨基羰基)-2H-吲唑-2-基]哌啶-1-甲酸叔丁酯;{2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]乙基}氨基甲酸叔丁酯;2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]乙烷三氟乙酸铵;三氟乙酸3-[7-(氨基羰基)-2H-吲唑-2-基]哌啶鎓;三氟乙酸3-[7-(氨基羰基)-2H-吲唑-2-基]-1-甲基哌啶鎓;三氟乙酸3-[7-(氨基羰基)-2H-吲唑-2-基]-1-乙基哌啶鎓;三氟乙酸3-[7-(氨基羰基)-2H-吲唑- 2-基]-1-丙基哌啶鎓;三氟乙酸3-[7-(氨基羰基)-2H-吲唑-2-基]-1-异丙基哌啶鎓;三氟乙酸3-[7-(氨基羰基)-2H-吲唑-2-基]-1-环己基哌啶鎓;三氟乙酸3-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-1-环丁基哌啶鎓; N-{2-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]乙基}-N-丙基丙烷-1-三氟乙酸铵;
2-(4-哌啶-3-基苯基)-2H-引唑-7-甲酰胺;
2-{4-[(3R)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
2-{4-[(3S)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
5-氟-2-(4-哌啶-3-基苯基)-2H-吲唑-7-甲酰胺;
5-氟-2-{4-[(3S)-哌啶-3-基]苯基}-2H-引唑-7-甲酰胺;
5-氟-2-{4-[(3R)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
5-氟-2-(3-氟-4-哌啶-3-基苯基)-2H-吲唑-7-甲酰胺;
5-氟-2-{3-氟-4-[(3R)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
5-氟-2-{3-氟-4-[(3S)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
2-{4-[(3R)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
2-{4-[(3S)-哌啶-3-基]苯基}-2H-吲唑-7-甲酰胺;
在某一方案中,所述的物质A选自尼拉帕利、他拉唑帕利、氟唑帕利、希明哌瑞、IMP4297、 BGB-290、ABT-888、鲁卡帕尼、奥拉帕利和美呋哌瑞中的一种或多种;
在某一方案中,所述的药学上可接受的盐为盐酸盐。
在某一方案中,所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐以包含其的药物组合物的形式存在。较佳地,所述药物组合物以所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐作为所述药物组合物的唯一活性成份;和/或,所述药物组合物还包含药学上可接受的载体,例如药学上可接受的药用辅料。
在某一方案中,所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐以包含其的套装药盒的形式存在,所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
为了解决上述技术问题,本发明第二方面提供了一种如本发明第一方面所述的如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐在制备抗病毒剂或在制备治疗由病毒引起的疾病的药物中的应用,所述病毒为HIV、HPV、EBV、IFV和/或冠状病毒科优选正冠状病毒亚科的病毒。
在某一方案中,所述药学上可接受的盐为盐酸盐。在本发明某一较佳实施例中,优选所述药学上可接受的盐为盐酸美呋哌瑞。
在某一方案中,所述如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐以包含其的药物组合物的形式存在;较佳地,所述药物组合物以如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐作为所述药物组合物的唯一活性成份;和/或,所述药物组合物还包含药学上可接受的载体,例如药学上可接受的药用辅料。
在某一方案中,所述如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐以包含其的套装药盒的形式存在,所述套装药盒还包括其他抗冠状病毒引起的疾病的药物。
在某一方案中,所述正冠状病毒亚科的病毒为α冠状病毒属、β冠状病毒属、γ冠状病毒属和 /或δ冠状病毒属的病毒,优选为引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如 SARS相关冠状病毒和/或中东呼吸综合征冠状病毒(MERS-CoV)。
较佳地,所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠状病毒HKU1(HCoV-HKU1)、人冠状病毒OC43(HCoV-OC43)、人冠状病毒NL63(HCoV-NL63)和/或小鼠肝炎病毒A59(MHV- A59)。
较佳地,所述SARS相关冠状病毒为SARS-CoV(严重急性呼吸综合征冠状病毒)或SARS-CoV- 2(严重急性呼吸综合征冠状病毒-2)。
在本发明某一较佳实施方案中,所述的冠状病毒包括严重急性呼吸综合征冠状病毒(SARS-CoV) 和严重急性呼吸综合征冠状病毒-2(SARS-CoV-2)。
在本发明某一较佳实施方案中,所述的冠状病毒为严重急性呼吸综合征冠状病毒-2(SARS-CoV- 2)。
此外,为了解决上述技术问题,本发明还提供了一种聚ADP核糖聚合酶抑制剂或其药学上可接受的盐在制备病毒相关的疾病的药物中的应用。
较佳地,所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐如本发明第一方面所述。
较佳地,所述病毒相关的疾病的药物如本发明第二方面所述。
为了解决上述技术问题,本发明还提供了一种如本发明第二方面所述的治疗病毒相关的疾病的药物,所述药物包括如本发明第一方面所述的聚ADP核糖聚合酶抑制剂或其药学上可接受的盐。
为了解决上述技术问题,本发明还提供了一种病毒抑制剂,其包括如本发明第一方面所述的聚 ADP核糖聚合酶抑制剂或其药学上可接受的盐。所述病毒为如本发明第二方面所述的病毒。
为了解决上述技术问题,本发明还提供了一种如本发明第一方面所述的聚ADP核糖聚合酶抑制剂或其药学上可接受的盐在治疗如本发明第二方面所述的病毒相关的疾病中的应用。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全,并且适合于患者使用。所述的“患者”优选哺乳动物,更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of PharmaceuticalSalts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述,是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。所述的“药学上可接受的盐的溶剂合物”包括但不限于本发明化合物的盐酸一水合物。
术语“多个”是指2个、3个、4个或5个。
当任意变量(例如R11-1)在化合物的定义中多次出现时,该变量每一位置出现的定义与其余位置出现的定义无关,它们的含义互相独立、互不影响。因此,若某基团被1个、2个或3个R11-1基团取代,也就是说,该基团可能会被最多3个R11-1取代,该位置R11-1的定义与其余位置R11-1的定义是互相独立的。另外,取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
术语“卤素”是指氟、氯、溴或碘。
术语“烃基”是指具有1至20个碳原子(另有指定除外)的烃化合物的碳原子上除去氢原子所得到的一价部分,它可以是脂族的或脂环族的,并且可以是饱和的或不饱和的(例如部分不饱和的、完全不饱和的)。因而,术语“烃基”包括小类烷基、烯基、炔基、环烷基、环烯基、环炔基等。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。
术语“烯基”是指具有指定的碳原子数的直链或支链烯基。
术语“炔基”是指具有指定的碳原子数的直链或支链炔基。
术语“烷氧基”是指基团-O-RX,其中,RX为如上文所定义的烷基。
术语“环烷基”是指单价饱和的环状烷基基,优选具有3-7个环碳原子、更优选3-6个碳原子的单价饱和的环状烷基,例如环丙基、环丁基、环戊基或环己基。
术语“杂环基”或“杂环”是指杂环化合物的环原子上除去氢原子所得到的一价部分,该部分具有3至20个环原子(另有指定除外),其中1至10个是环杂原子,并且可以是芳香的或非芳香的。优选地,每个环具有3至7个环原子,其中1至4个是环杂原子。
术语“杂环烷基”是指具有杂原子的饱和的单环基团,优选含有1个、2个或3个独立选自N、 O和S的环杂原子的3-7元饱和的单环。杂环烷基的示例为:吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。优选的杂环基为吗啉-4-基、哌啶-1-基、吡咯烷-1-基、硫代吗啉-4-基和1,1-二氧代-硫代吗啉-4-基。
术语“杂芳基”或“杂芳环”是指含有杂原子的芳香基团,优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环或9-10元双环,例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。
本发明中涉及的以本发明所述化合物作为活性成份的药物组合物,均可根据本领域公知的方法制备。可通过将本发明化合物制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的重量含量通常为0.1-99.0%。
所述的药学可接受的载体可为本领域常规的载体,所述的载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料,较佳地包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地,所述的药物组合物包括0.01~99.99%的上述蛋白质和/或上述的抗体药物偶联物,和0.01~99.99%的药用载体,所述百分比为占所述药物组合物的质量百分比。
本发明化合物或含其的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明首次证实了聚ADP核糖聚合酶抑制剂能够抑制冠状病毒对宿主细胞的感染及冠状病毒的复制,且呈剂量依赖性,且无明显的细胞病变作用,可用于抗冠状病毒感染方面的疾病治疗。本发明所述的聚ADP核糖聚合酶抑制剂或其在药学上可接受的盐、及包含其的药物组合物、套装药盒在确保用于人体时毒性小、安全性高的情况下,抑制病毒时的有效浓度更低、抗病毒活性更高,从而将其应用于临床治疗冠状病毒引起的疾病时更能够发挥有效的抑制病毒的作用。在本发明某一较佳实施例中,聚ADP核糖聚合酶抑制剂对病毒的抑制率可达35%(同等条件下阿比多尔对病毒的抑制率仅为21%)。
附图说明
图1为盐酸美呋哌瑞(CVL218)、Olaparib等对SARS-CoV-2的抑制活性结果图。
图2为盐酸美呋哌瑞(CVL218)对SARS-CoV-2的抑制病毒活性和细胞活性图,其中A和B分别为不同批次实验。
图3为Olaparib在Vero-E6细胞中的细胞毒性结果图。
图4显示了试验药物的体外抗SARS-CoV-2活性。(A)使用荧光显微镜观察受SARS-CoV-2感染后14小时后再用CVL218处理后Vero细胞中的病毒核蛋白(NP)表达情况(NP表示核蛋白染色, DAPI表示核DNA染色,其中DAPI为染色剂4',6-二脒基-2-苯基吲哚)。(B)CVL218和瑞德西韦对 SARS-CoV-2体外抑制作用与不同作用时间的关系。分别在“全过程”、“病毒进入时”和“病毒进入后”阶段测定CVL218和瑞德西韦的病毒抑制活性。(C)用Westernblot分析CVL218和瑞德西韦处理感染细胞中的病毒NP的表达。
图5显示了CVL218以时间和剂量依赖的方式减弱CpG诱导的IL-6的产生。
图6显示了CVL218对大鼠(A)和猴子(B)体重的影响。大鼠和猴子分别口服20/60/160mg/kg 和5/20/80mg/kg的CVL218,连续28天,然后停药28天,显示CVL218具有良好的安全性。
图7显示了SARS-CoV-2的核衣壳蛋白N端(N-NTD)与PARP1抑制剂复合物的作用模型结构。(A).SARS-CoV-2-N-NTD与CVL218和olaparib结合的复合物模拟结构(均由AutoDock4.2建模)。(B). 病毒N-NTD和PARP1抑制剂CVL218和Olaparib的相互作用模式。关键残基显示为棍棒。氢键被表示为虚线。
图8显示了大鼠体内CVL218的组织分布特点,肺部浓度最高。大鼠口服20mg/kg后,在3/6/8 h时间点测定不同组织中CVL218的浓度。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。以下实施例中未注明具体条件的实验方法,通常按照常规条件如《分子克隆实验指南》(第三版,科学出版社,2005)等本领域常用工具书中所述的条件,或按试剂生产厂家所建议的条件进行。
(1)主要仪器(名称、编号)见下表1。
表1
仪器名称 | 厂家 | 仪器编号 |
荧光定量PCR仪QuantStudio Dx | ABI | 04-620 |
MagNA Pure LC2.0全自动核酸提取仪 | Roche | - |
二氧化碳培养箱(GALAXYS) | RsBiotech | 04-0303 |
倒置显微镜 | NiKon | 0393 |
(2)实验试剂及病毒株
1)试剂下表2。
表2
名称 | 厂家 | 货号 | 有效期 |
DMSO | 碧云天生物技术 | ST-1276-500ml | - |
DMEM培养基 | Gibco | 12430-054 | 2020-10-30 |
CCK-8试剂盒 | 碧云天生物技术 | C0039 | - |
核酸提取试剂盒 | Roche | 03038505001 | 2021-06 |
2019新型冠状病毒核酸检测试剂盒 | 上海伯杰 | SJ-HX-226-2 | 2021-01-16 |
2)SARS-CoV-2病毒株
①取自江苏省疾病预防控制中心BSL-3实验室。本毒株内部编号为:2019-nCoV-1。
②取自武汉病毒研究所,病毒株保藏号为:IVCAS 6.7512,保藏单位:中国科学院武汉病毒研究所,国家病毒资源库。
经鉴定,上述两种病毒株基因组完全一致,因此同为SARS-CoV-2病毒株,后续实验中使用的病毒株以2019-nCoV-1为主。
(3)药物
扎那米韦、奥司他韦、瑞德西韦、巴利替尼、奥拉帕利和阿比多尔,均由MCE(中国Medchem Express)提供。PARP1抑制剂盐酸美呋哌瑞(CVL218,也可详见专利申请201210028895.0)纯度超过99.0%,由甫康(上海)健康科技有限责任公司提供。
实施例1.盐酸美呋哌瑞(CVL218)体外抗SARS-CoV-2活性检测
1.1实验分组:
1)阿比多尔(Arbidol)组3μM组和30μM组
2)盐酸美呋哌瑞(CVL218)3μM组
3)盐酸美呋哌瑞(CVL218)30μM组
4)扎那米韦(Zanamivir)组
5)奥司他韦(Oseltamivir)组
6)奥拉帕利(Olaparib)3.2μM组
7)巴瑞替尼(Baricitinib)3.2μM组
8)DMSO对照组
9)病毒对照组:仅加入病毒,未加入药物
10)细胞对照组:仅含有细胞,未加入病毒和药物
1.2药物稀释:
每一组药物取15μl 1mM母液,加4985μl细胞维持液(即DMEM培养基),得3μM应用液。 CVL218取3μl 20mM母液,加1997μl细胞维持液,得30μM应用液。DMSO按照对应药物的稀释比例进行稀释。
1.3实验步骤:
1.3.1细胞准备及药物预处理(细胞培养室)
将Vero-E6细胞(购自ATCC细胞库)分别按照1×104细胞/孔接种于96孔培养板中,使用含 10%(v/v)胎牛血清的DMEM培养16小时至80%成片,之后吸弃每一孔的细胞培养液,无菌PBS 洗涤细胞1次,根据实验分组每孔加入上述1.2中细胞维持液稀释好的不同药物(50μl/孔),每组设立4个复孔,放置于37℃,5%CO2孵箱中预处理1h。病毒对照组和细胞对照组只加50μl细胞维持液。
1.3.2病毒感染及培养(BSL-3实验室):
药物预处理1h后,除了细胞对照组之外,每孔加入2μl SARS-CoV-2毒株,使病毒感染复数为 0.05(Multiplicity of infection,MOI=0.05),放置于37℃,5%CO2孵箱中吸附2小时,吸附完成后弃去带有病毒的培养基,根据实验分组重新加入新的含药培养基,于37℃,5%CO2孵箱中培养48h。培养结束后显微镜下观察各实验组的细胞病变情况并记录。吸取每一孔培养上清120μl,置于56℃,灭活30min。灭活完成后,每孔取100μl加入核酸提取试剂的试剂槽裂解液中。试剂槽外表面消毒后转入BSL-2实验室进行病毒核酸提取和基因检测。
1.3.3核酸提取:
参照全自动核酸提取仪和提取试剂盒的操作说明进行病毒核酸RNA提取。
1.3.4荧光定量PCR检测
按照上海伯杰2019新型冠状病毒核酸检测试剂盒说明书配置PCR反应体系,具体反应体系为: qRT-PCR反应液6μl,qRT-PCR酶混合液2μl,引物探针2μl,上述提取的病毒核酸RNA模板2.5 μl;反应参数为:50℃ 10min,95℃ 5min,40cycles of:95℃ 10s,55℃ 40s(在此步收集FAM通道及VIC通道荧光信号);通过检测SARS-CoV-2病毒基因(ORF1ab和N)转录水平以反应病毒的复制水平。根据PCR仪给出的CT值计算值,来表示实验组相对于对照组的相对病毒含量,
1.4实验结果
盐酸美呋哌瑞(CVL218)、奥拉帕利(Olaparib)等化合物及对SARS-CoV-2冠状病毒的抑制效果见图1、图2和表3。各对照组中均未检测有抑制活性。从图1、表3中可以看出,CVL218在Vero- E6细胞中可有效抑制SARS-CoV-2的复制,浓度为3μM的CVL218对病毒的抑制率为35%,高于对照药阿比多尔(Arbidol)的21%,而抗流感病毒药物扎那米韦(Zanamivir)和奥司他韦(Oseltamivir) 对SARS-CoV-2病毒没有抑制活性。当CVL218的浓度达30μM时,其对病毒的抑制率达99%以上。图2中显示CVL218的抗SARS-CoV-2的EC50在不同批次分别为7.67μM和5.12μM(实验步骤如实施例2中所示),呈剂量依赖性。图1、表3中还显示PARP-1抑制剂奥拉帕利(Olaparib)也轻微的抗SARS-CoV-2活性,3.2μM对病毒的抑制率为12%或15.8%左右,而JAK-1抑制剂巴瑞替尼 (Baricitinib)的病毒的抑制率几乎为0%。
综上所述,PARP1抑制剂奥拉帕利(olaparib)和CVL218均表现出对SARS-CoV-2复制的抑制作用;并且,CVL218的抑制率比奥拉帕利更高。值得注意的是,CVL218的抗病毒效力超过了阿比多尔,后者是中国政府颁布的《新型冠状病毒性肺炎诊断和治疗方案(第6版)》中COVID-19的标准治疗方法之一。
表3
实施例2:盐酸美呋哌瑞(CVL218)对Vero-E6细胞的细胞毒性实验
2.1实验分组:
1)盐酸美呋哌瑞(CVL218)组
2)DMSO对照组
3)奥拉帕利(Olaparib)组
4)细胞对照组:仅含有细胞,未添加药物
5)空白对照组(只含培养基不含细胞)
2.2药物稀释:
盐酸美呋哌瑞来源于甫康(上海)健康科技有限责任公司,纯度>99.0%,使用DMSO溶解后按照下表4进行梯度稀释(维持液为DMEM培养基)。DMSO按照同样稀释梯度进行连续稀释。
表4
稀释液 | 组合 | 浓度 |
稀释液1 | 0.05ml盐酸美呋哌瑞原液(20mM)+2.45ml维持液 | 400μM |
稀释液2 | 1ml稀释液1+1ml维持液 | 200μM |
稀释液3 | 1ml稀释液2+1ml维持液 | 100μM |
稀释液4 | 1ml稀释液3+1ml维持液 | 50μM |
稀释液5 | 1ml稀释液4+1ml维持液 | 25μM |
稀释液6 | 1ml稀释液5+1ml维持液 | 12.5μM |
稀释液7 | 1ml稀释液6+1ml维持液 | 6.25μM |
稀释液8 | 1ml稀释液7+1ml维持液 | 3.125μM |
2.3实验步骤:
2.3.1细胞准备及加药培养
将Vero-E6细胞按照1×104细胞/孔接种于96孔培养板中,使用含10%胎牛血清的DMEM培养 16小时至80%成片,之后吸弃每一孔的细胞培养液,无菌PBS洗涤细胞1次,根据实验分组每孔加入细胞维持液稀释好的不同浓度药物(200μl/孔),每组设立3个复孔,放置于37℃,5%CO2孵箱中培养48h。DMSO对照组加入细胞维持液稀释好的对应浓度DMSO,细胞对照组加入200μl细胞维持液。空白对照组只含有细胞维持液不含有细胞。
2.3.2盐酸美呋哌瑞和奥拉帕利(Olaparib)对Vero-E6的毒性检测
倒置显微镜下观察细胞状态并记录,根据CCK-8试剂盒操作说明检测药物对Vero-E6细胞的毒性:在所有实验孔、对照孔中加入20μl CCK-8溶液,将细胞培养板置于37℃,5%CO2孵箱中孵育 1小时,使用多功能酶标仪在450nm波长下测定其吸光度值。根据公式计算:细胞活性抑制率(%) =[1-(药物组-空白对照组)/(细胞对照组-空白对照组)]×100%。
以盐酸美呋哌瑞和奥拉帕利(Olaparib)的药物浓度为横坐标,以细胞增殖抑制率为纵坐标作图。结果如图3圆形实心点所示。由图中可以看出,盐酸美呋哌瑞在Vero-E6细胞中的CC50(50%cytotoxic concentration,使50%细胞死亡时的药物浓度)在92μM左右。其中盐酸美呋哌瑞30μM时细胞无抑制作用,基本没有毒性。可见盐酸美呋哌瑞(CVL218)的安全性较高。Olaparib在Vero-E6细胞中的 CC50(50%cytotoxic concentration,使50%细胞死亡时的药物浓度)在100-300μM左右。
实施例3:
3.1间接免疫荧光检测法
Vero E6细胞分别用5μM、15μM和25μM的CVL218处理,遵循"全过程"处理程序。将感染的细胞用80%丙酮在PBS中固定,并用0.5%的Triton X-100进行渗透,然后用5%的BSA在含有0.05%Tween 20的PBS缓冲液中室温下阻断30分钟。进一步用SARS-CoV核衣壳蛋白兔多克隆抗体 (美国Cambridgebio公司)作为一抗,以1:200的稀释度孵育2小时,然后用Alexa 488标记的山羊抗兔抗体(中国Beyotime公司)以1:500的稀释度孵育作为二抗。用DAPI(中国Beyotime公司)对细胞核进行染色。用荧光显微镜观察免疫荧光。
免疫荧光显微镜检查发现,在SARS-CoV-2感染后14h,CVL218处理的细胞中病毒核蛋白(NP) 的表达量与处理药物浓度呈现剂量反应关系,CVL218处理后的表达量明显低于DSMO处理的细胞 (图4的A)。在25μM的CVL218处理的感染细胞中,没有观察到明显的细胞病变作用。
3.2作用时间研究
为了系统地评估化合物对SARS-CoV-2的抑制活性,我们还进行了添加时间测定(方法),以确定化合物在哪个阶段抑制病毒感染。采用相对高剂量的试验药物(CVL218为20μM,瑞德西韦为10 μM)进行作用时间测定。每孔密度为5×104个细胞的Vero E6细胞在病毒感染的不同阶段用测试药物处理,或用DMSO作为对照。细胞感染病毒的MOI为0.05。"全过程"处理是为了评价最大的抗病毒效果,在整个实验过程中,细胞培养基中的测试药物与病毒感染检测中的描述一致。在"病毒进入时"处理中,在病毒感染前1小时将测试药物加入细胞中,然后在病毒感染过程中,将细胞在药物-病毒混合物中维持2小时。之后,用新鲜的培养基替换含有病毒和检测药物的培养基,直至实验结束。在"病毒进入后"实验中,先向细胞中加入病毒,使其感染2h后,再将含病毒的上清液更换为含药物的培养基,直至实验结束。感染后14h,用qRT-PCR定量检测药物对细胞上清液中病毒的抑制作用,并以DMSO组为参考计算。
结果显示,与DMSO对照组相比,在SARS-CoV-2感染Vero E6细胞的全过程中,CVL218和瑞德西韦都显示出较强的抗病毒活性(图4的B)。作用时间测定的结果表明,CVL218可以部分对抗病毒进入,并显著抑制病毒进入后的复制,而瑞德西韦只能在病毒进入后阶段发挥作用(图4的B、C)。综上所述,CVL218或可作为更有优势的COVID-19潜在治疗药物。
实施例4:CVL218抑制CpG-ODN 1826诱导的PBMCs中IL-6的产生
近来人们发现白细胞介素-6(IL-6)是病毒感染过程中最重要的细胞因子之一(L.Velazquez- Salinas,A.Verdugo-Rodriguez,L.L.Rodriguez,M.V.Borca,The role ofinterleukin 6during viral infections,Frontiers in microbiology 10(2019)1057),新出现的人类和动物临床研究表明, IL-6的过度合成与许多病毒的持续存在有关,如人类免疫缺陷病毒(HIV)(M.M.McFarland- Mancini,H.M.Funk,A.M.Paluch,M.Zhou,P.V.Giridhar,C.A.Mercer,S. C.Kozma,A.F.Drew,Differences in wound healing inmice with deficiency of IL-6versus IL-6 receptor,The journal of immunology184(12)(2010)7219–7228)、口蹄疫病毒(G. A.Palumbo,C.Scisciani,N.Pediconi,L.Lupacchini,D.Alfalate,F.Guerrieri,L.Calv o,D.Salerno,S.Di Cocco,M.Levrero,et al.,IL6 inhibits HBV transcription by targeting the epigenetic control ofthe nuclear cccdna minichromosome,PLoS one 10(11))和泡性口炎病毒(VSV)(L.Velazquez-Salinas,S.J.Pauszek,C.Stenfeldt,E.S.OHearn,J.M.Pacheco,M.V.Borca,A.Verdugo-Rodriguez,J.Arzt,L.L.Rodriguez,Increased virulence of anepidemic strain of vesicular stomatitis virus is associated with interferenceof the innate response in pigs,Frontiers in microbiology 9(2018)1891)。此外,Friend逆转录病毒(FV)小鼠模型的体内研究表明,IL-6阻断可以降低病毒载量,增强病毒特异性CD8+T细胞免疫力(W.Wu,K. K.Dietze,K.Gibbert,K.
S.Lang,M.Trilling,H.Yan,J.Wu,D.Yang,M.Lu,M.Roggendorf,et al.,TLRligand induced IL-6counter-regulates the anti-viral CD8+T cell responseduring an acute retrovirus infection,Scientific reports 5(2015)10501)。这些研究结果支持了一个假说,即IL-6的快速产生可能是导致病毒发病中有害临床表现的可能机制 (J.Zheng,Y.Shi,L.Xiong,W.Zhang,Y.Li,P.G.Gibson,J. L.Simpson,C.Zhang,J.Lu,J.Sai,et al.,The expression of IL-6,tNF-α,and MCP-1in respiratory viralinfection in acute exacerbations of chronic obstructive pulmonary disease,Journal of immunology research 2017)。最近发表的关于SARS-CoV-2感染重症患者临床特征的研究表明,IL-6 明显升高,尤其是在那些ICU患者中,引起过度激活的免疫反应(Y.Zhou,B.Fu,X.Zheng,D.Wang, C.Zhao,Y.Qi,R.Sun,Z.Tian,X.Xu,H.Wei,Aberrantpathogenic GM-CSF+T cells and inflammatory CD14+CD16+monocytes in severepulmonary syndrome patients of a new coronavirus,bioRxiv;J.-J. Zhang,X.Dong,Y.-Y.Cao,Y.-d.Yuan,Y.-b.Yang,Y.-q.Yan,C.A.Akdis,Y.-d.Gao,Allergy;B.Diao,C.Wang,Y.Tan,X.Chen,Y.Liu,L.Ning,L.Chen,M.Li,Y.Liu,G.Wang,et al.,Reduction andfunctional exhaustion of T cells in patients with coronavirus disease 2019(COVID-19),medRxiv;X.C.Huang,Y. Wang,X.Li,L.Ren,J.Zhao,Y.Hu,L.Zhang,G.Fan,J.Xu,Gu,et al.,The lancet 395(10223)(2020)497– 506;Y.B.Li,F.Feng,G.Yang,A.Liu,N.Yang,Q.Jiang,H.Zhang,T.Wang,P.Li,Mao,et al., Immunoglobulin G/M andcytokines detections in continuous sera from patients with novelcoronaviruses (2019-nCoV)infection,Available at SSRN 3543609)。IL-6在SARS-CoV-2感染中的病理作用表明,IL- 6阻断可能为COVID-19的治疗提供可行的疗法。
为了测试CVL218是否能够在体外调节IL-6的产生,我们用CpG-ODN 1826刺激外周血单核细胞(PMBCs)的IL-6产生,CpG-ODN 1826是细胞因子和趋化因子的有效刺激物。用1μM CpG-ODN 1826孵育PBMCs 6小时(方法),与未处理的细胞相比,可诱导IL-6的产生40%(图5)。在CVL218 的存在下,CpG-ODN 1826的刺激作用被抵消。进一步的研究表明,CVL218以时间和剂量依赖的方式抑制CpG诱导的IL-6上调(图5)。更具体地说,用CVL218在1μM和3μM浓度下暴露12小时,分别减弱了50%和72.65%的CpG诱导的IL-6产生。这些结果为CVL218作为治疗SARS-CoV-2感染引起的促炎反应的潜在治疗药物提供了体外证据。
其中,CpG-PDN1826诱导PBMCs产生IL-6的实验步骤如下:外周血单核细胞(北京亦康)在37℃、浓度为5%CO2大气下,在RPMI1640细胞生长培养基(Corning,Cat.10-040-CVR)的96孔板上培养。为了刺激,用1μM CpG-ODN1826(InvivoGen,Cat.tlrl-1826)孵育PBMC细胞。为了测试CVL218是否能抑制IL-6的产生,将1μM和3μM浓度的CVL218分别加入细胞培养基中6和12小时。使用商业试剂盒(Dakewe Biotech,Cat.1110602)通过ELISA测定IL-6的浓度。
实施例5:CVL218在动物体内的代谢及安全性特征
(一)实验步骤
5.1.药代动力学研究
Sprague-Dawley大鼠购自中国上海实验动物中心。实验动物分组饲养在铁丝笼中,每笼不超过6 只,实验条件良好(温度25±2℃;相对湿度50±20%),光暗循环(12小时/12小时)。144只Sprague- Dawley大鼠随机分为4组(18只/性别/组)。以20、40、60和160mg/kg的剂量给药CVL218。对于所有组别,随机选取20只大鼠(10只/性别/组),在第28天进行安乐死,并获得其各种组织和器官的切片,并进行冷冻。10只(5只/性别/组)动物在28天无药期后安乐死,取其各组织器官的切片并冷冻。 6只(3只/性别/组)在获得血样后安乐死。在药代动力学和安全性评价方面,对动物的血药浓度、临床症状、死亡率和体重进行检测
5.2.组织分布研究
将30只Sprague-Dawley大鼠随机分为3个时间点组(3只/性/组)。在CVL218给药后3、6、8h,处死动物,收集脑、心、肺、肝、脾、胃、肾组织。组织样品用冰冷的生理盐水洗涤,用纸巾吸去多余的液体,称重。组织样品液,称量后,在-20±2℃保存,直到用LC-MS-MS测定药物浓度。
5.3.食蟹猴的安全性研究。
健康的雄猴和雌猴,年龄为3-4岁,购自中国广东兰道生物技术公司。动物按照《实验动物护理与使用指南》进行饲养。随机化分组(5只/性别/组),通过鼻胃饲喂CVL218,剂量水平为0(对照)、 5、20、80mg/kg。每天对猴子进行两次观察,以了解其生存能力/死亡率和行为的任何变化、对治疗的反应或健康状况。
5.4.统计学分析
所有数据代表n个值的平均值±标准差(SDs),其中n对应于使用的数据点的数量。数字使用 GraphPad Prism(GraphPad Software,USA)编制。统计学意义采用SPSS(ver.12)计算,如果p值<0.05,则认为两个数值有显著差异。
(二)实验结果与结论
5.5.CVL218在大鼠肺部组织分布最多
大鼠口服不同剂量后不同时间CVL218在不同组织上的浓度见图8和表5。在7个组织(即肺、脾、肝、肾、胃、心、脑)中,我们观察到肺脏的CVL218浓度最高,比血浆高188倍(表6)。观察到肺部的CVL218浓度最高,这与SARS-CoV-2病毒在肺部的病理影响最大,病毒载量高的事实相符,这说明CVL218有可能用于SARS-CoV-2感染引起的肺部病变的适应症。
此外,结果显示CVL218和阿比多尔的药代动力学参数相当,血浆浓度和药物暴露量相似(表7)。大鼠给药后,阿比多尔主要分布在胃和血浆中。相比之下,CVL218在组织中的分布较高,尤其是在肺部而非血浆中的分布高于阿比多尔,说明CVL218的药代动力学特征较好,可能使其成为肺部SARS- CoV-2感染的潜在抗病毒治疗药物。
表5大鼠口服20mg/kg和54mg/kg后,CVL218和阿比多尔的组织分布比较
表6大鼠体内CVL218和阿比多尔的组织与血浆浓度比的比较。阿比多尔的数据来源于X.Liu, K.Pei,X.-h.Chen,K.-s.Bi,Distribution and excretion of arbidolhydrochloride in rats,Chinese journal of new drugs 22(7)(2013)829–833
表7CVL218和阿比多尔分别口服20/40mg/kg和18/54mg/kg后的大鼠药代动力学参数比较。阿比多尔的数据来源于X.Liu,Q.-g.Zhou,H.Li,B.-c.Cai,X.-h.Chen,K.-s.Bi,Pharmacokinetics of arbidol hydrochloride in rats,Chinese pharmacologicalbulletin 28(12)(2012)1747–1750.
5.6.CVL218在动物体内的安全性良好
大鼠连续28天口服20/60/160mg/kg CVL218后,再28天不给药(方法),我们观察到不同剂量和对照组的大鼠和食蟹猴体重无明显差异(图6)。
上述体内数据表明,CVL218在大鼠和猴子体内具有良好的药代动力学和安全性特征,其在治疗靶组织(即肺部)中的高水平分布将有利于SARS-CoV-2感染的治疗。
实施例6:分子对接表明PARP1抑制剂与冠状病毒核帽蛋白N端域之间的相互作用
本实施例中进行了分子对接,研究奥拉帕利和CVL218这两种药物与SARS-CoV-2的N-NTD之间的潜在相互作用模式。
建立PARP1抑制剂CVL218和奥拉帕利与SARS-CoV-2的N蛋白N端域(SARS-CoV-2-N-NTD) 的分子相互作用模型利用对接程序AutoDock4.2生成。用于分子对接的SARS-CoV-2-N-NTD的结构通过同源建模建立。采用AutoGrid程序生成网格图,60×60×60点间距均等为用于评估蛋白质与配体之间的结合能。
结果显示(图7),CVL218和奥拉帕利都能与SARS-CoV-2的N-NTD结合。在氢键形成方面, CVL218表现出比奥拉帕利更强的结合能力。同时,SARS-CoV-2-N-NTD上参与与药物结合的关键残基(即S51、Y109和Y111)在SARS-CoV、HCoV-OC43、小鼠肝炎病毒(MHV)和传染性支气管炎病毒 (IBV)等其他病毒中也是高度保守的,说明不同病毒的N-NTD很可能对PARP抑制剂表现出相似的结合行为,从而抑制病毒的复制。
综上所述,可以知晓PARP1抑制剂可能具有治疗病毒所引起的疾病例如COVID-19的治疗潜力。首先,在冠状病毒的生命周期中,PARP1抑制剂可能通过抑制病毒复制和阻碍核帽蛋白与病毒RNA 的结合来抑制病毒的生长,我们的分子对接结果也可以支持这一点。其次,PARP1抑制剂通过调节IL- 6等促炎因子,在控制炎症反应方面发挥了关键作用,从而为减轻SARS-CoV-2感染引起的细胞因子风暴和炎症反应提供临床潜力。在中国政府颁布的《新型冠状病毒肺炎诊断与治疗方案(试行版7)》中,针对IL-6的单克隆抗体药物托西利珠单抗被推荐用于治疗COVID-19,这也凸显了抗炎症反应在目前SARS-CoV-2治疗中的重要作用。CVL218能有效抑制CpG诱导的PBMCs产生IL-6。这一发现表明CVL218可能也具有IL-6特异性抗炎作用,适用于那些严重的SARS-CoV-2感染患者。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (14)
1.聚ADP核糖聚合酶抑制剂或其药学上可接受的盐在制备抗病毒剂或在制备治疗由病毒引起的疾病的药物中的应用,其中所述病毒为β冠状病毒属的病毒;优选引起急性呼吸综合征的病毒例如SARS相关冠状病毒;更优选SARS-CoV和/或SARS-CoV-2。
2.如权利要求1所述的应用,其特征在于,所述聚ADP核糖聚合酶抑制剂为针对PARPl和/或PARP2的抑制剂。
3.如权利要求1所述的应用,其特征在于,所述聚ADP核糖聚合酶抑制剂为物质A、其药学上可接受的盐;
所述的物质A选自他拉唑帕利、氟唑帕利、希明哌瑞、IMP4297、BGB-290、ABT-888、如式I所示的化合物、如式II所示的化合物、如式III所示的化合物和如式IV所示的化合物中的一种或多种;
其中,所述的如式I所示的化合物为:
其中,R11为H、卤素、氰基、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个R11-1取代的C1~C4的烷基、被一个或多个R11-1取代的C2~C4的烯基、被一个或多个R11-1取代的C2~C4的炔基、被一个或多个R11-1取代的C3~C4的环烷基、被一个或多个R11-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个R11-1取代的C6~C10的芳基(所述的“C6~C10的芳基”例如苯基;所述的“被一个R11-1取代的C6~C10的芳基”例如)、被一个或多个R11-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、-C(=O)-R11-2、-C(=O)-O-R11-3或-C(=O)-NR11-4R11-5;
R11-1独立地为卤素、羟基、羧基、硝基、氨基、C1~C4的烷基或被一个或多个NR11-1-1R11-1-2取代的C1~C4的烷基(所述的“C1~C4的烷基”例如甲基);
R11-1-1和R11-1-2独立地为氢或C1~C4的烷基(例如甲基);
R11-2、R11-3、R11-4和R11-5为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个R11-2-1取代的C1~C4的烷基、被一个或多个R11-2-1取代的C2~C4的烯基、被一个或多个R11-2-1取代的C2~C4的炔基、被一个或多个R11-2-1取代的C3~C4的环烷基、被一个或多个R11-2-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个R11-2-1取代的C6~C10的芳基、或、被一个或多个R11-2-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基;
R11-2-1独立地为卤素、羟基、羧基、硝基、氨基或C1~C4的烷基;
Y1为-(CRY1-1RY1-2)(CRY1-3RY1-4)n-或-N=C(RY1-5)-;
n为0或1;
RY1-1、RY1-2和RY1-5独立地为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个RY1-1-1取代的C1~C4的烷基、被一个或多个RY1-1-1取代的C2~C4的烯基、被一个或多个RY1-1-1取代的C2~C4的炔基、被一个或多个RY1-1-1取代的C3~C4的环烷基、被一个或多个RY1-1-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个RY1-1-1取代的C6~C10的芳基、或、被一个或多个RY1-1-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基;
RY1-1-1独立地为卤素、羟基、硝基、氨基、C1~C4的烷基或C1~C4的烷氧基;
RY1-3和RY1-4独立地为H、C1~C4的烷基、C2~C4的烯基、C2~C4的炔基、C3~C4的环烷基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、C6~C10的芳基、“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基、被一个或多个RY1-3-1取代的C1~C4的烷基、被一个或多个RY1-3-1取代的C2~C4的烯基、被一个或多个RY1 -3-1取代的C2~C4的炔基、被一个或多个RY1-3-1取代的C3~C4的环烷基、被一个或多个RY1-3-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、3~6元的”杂环烷基、被一个或多个RY1-3-1取代的C6~C10的芳基、或、被一个或多个RY1-3-1取代的“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、5~10元的”杂芳基
RY1-3-1独立地为卤素、羟基、硝基、氨基、C1~C4的烷基或C1~C4的烷氧基;
R12是H或C1~C4的烷基;
X1是O或S;
R14是H、卤素(例如氟、氯或溴)或C1~C4的烷基;
R13是H或C1~C4的烷基;
所述的如式II所示的化合物为:
其中,X2、Y2及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个RX2-1取代的C6~C10的芳基;
RX2-1独立地为卤素、硝基、羟基、巯基、氨基、C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、-ORX2-1-1或-SRX2-1-2;
RX2-1-1和RX2-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
R21为H或卤素(例如氟、氯或溴);
Z为-NRZ-1-或-CRZ-2RZ-3-;
当Z为-NRZ-1-时,m为1或2;当Z为-CRZ-2RZ-3-时,m为1;
RZ-1和RZ-2独立地为C1~C20的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、-C(=O)NRZ-1-1RZ-1-2、-C(=O)RZ-1-3(例如)、-C(=O)ORZ-1-4、-C(=S)NRZ-1-5RZ-1-6、-S(=O)2RZ-1-7、被一个或多个RZ-1-8取代的C1~C20的烃基、被一个或多个RZ-1-9取代的C6~C20的芳基、或、被一个或多个RZ-1-10取代的“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
RZ-1-1、RZ-1-2、RZ-1-3、RZ-1-4、RZ-1-5、RZ-1-6和RZ-1-7独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-1、RZ-1-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-5、RZ-1-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
RZ-1-8、RZ-1-9和RZ-1-10独立地为C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、卤素、羟基、硝基、氰基、羧基、巯基、脲基、-C(=O)NRZ-1-8-1RZ-1-8-2、-C(=O)RZ-1-8-3、-C(=O)ORZ-1-8-4、-C(=S)NRZ-1-8-5RZ-1-8-6、-S(=O)2RZ-1-8-7、-ORZ-1-8-8、-SRZ-1-8-9、-S(=O)2NRZ-1-8-10RZ-1-8-11、-OC(=O)RZ-1-8-12、-S(=O)NRZ -1-8-13RZ-1-8-14或-C(=O)-NH-C(=O)RZ-1-8-15;
RZ-1-8-1、RZ-1-8-2、RZ-1-8-3、RZ-1-8-4、RZ-1-8-5、RZ-1-8-6、RZ-1-8-7、RZ-1-8-8、RZ-1-8-9、RZ-1-8-10、RZ -1-8-11、RZ-1-8-12、RZ-1-8-13、RZ-1-8-14和RZ-1-8-15独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-8-1、RZ-1-8-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-5、RZ-1-8-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-10、RZ-1-8-11及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-8-13、RZ-1-8-14及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
RZ-3为H、羟基或氨基;
或者,RZ-2、RZ-3及与之相连的碳原子一起形成C3~C7的螺环烷基、或、“含1~3个杂原子,杂原子选自O、N和S中的一种或多种的、3~7元的”杂螺环烷基;
R22和R23都为氢,或者,当Z为-CRZ-2RZ-3-时,R22、R23、RZ-2、RZ-3及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个R22-1取代的C6~C10的芳基;
R22-1独立地为C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、羟基、巯基、氨基、-OR22-1-1、-SR22-1-2或-O-(CH2)p-O-;p为1、2或3;
R22-1-1和R22-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
所述的如式III所示的化合物为:
R31和R32独立地为氢、C1~C4的烷基(例如甲基)、C3~C4的环烷基或“含1~3个杂原子,杂原子选自O和N中的一种或多种的、5元或6元的”杂环烷基;
或者,R31、R32及与之相连的N原子一起形成“含1~3个杂原子,杂原子选自O、N和S中的一种或多种的、5~6元的”杂环烷基、或、被一个或多个R31-1取代的“含1~3个杂原子,杂原子选自O、N和S中的一种或多种的、5~6元的”杂环烷基;
R31-1为在N上的C1~C4的烷基(例如甲基);
X3为CH、CF或N;
Y3为CH、CF或N;
R33为H或Cl;
R34为H或F;
所述的如式IV所示的化合物为:
fm为0、1、2或3;
R41独立地为羟基、卤素(例如氟)、氰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基;
A4为CH或N;
fn为0、1、2、3、4、5或6;
Y4为单键、C3-5环烷基、包含一个N原子的4元饱和杂环、包含1、2或3个独立地选自N、O和S的杂原子的5、6或7元饱和或部分饱和的杂环、包含1、2、3或4个独立地选自O、N和S的杂原子但其中不多于一个为O或S的5元不饱和杂环、包含1、2或3个氮原子的6元不饱和杂环、“6-13元饱和、部分饱和或不饱和的烃环”(例如C6~C10的芳基,又例如苯基)、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的8-13元不饱和或部分饱和的杂环”;
z为1、2或3
fp为0、1、2、3、4、5或6;
R46和R47独立地为氢或C1-6烷基;
q为0或1;
t为0或1;
R42为氢、C1-6烷基或C3-10环烷基;
v为0或1;
X4为C或S=O;
w为0或1;
x为0、1、2、3、4、5或6;
R48和R49独立地为氢、C1-6烷基、羟基、卤代C1-6烷基、羟基C1-6烷基、氨基、C1-6烷基氨基或二(C1-6烷基)氨基;
a为0或1;
y为0或1;
R43为氢或C1-6烷基;
R44为氢、羟基、氰基、卤素(例如氟、氯或溴)、C1-6烷基、C2-10链烯基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷基羰基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基羰基、羧基、硝基、R44-1、或、被一个或多个-(CH2)bR44-2取代的R44-3;
R44-1和R44-3独立地为C6-10芳基、C6-10芳氧基、C6-10芳基羰基、C3-10环烷基、包含一个N原子的4元饱和杂环、“包含1、2或3个独立地选自N、O和S的原子的5或6元饱和或部分饱和的杂环”(例如)、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-15元不饱和、部分饱和或饱和的杂环”;
b独立地为0、1、2、3、4、5或6;
R44-2独立地为羟基、氧代、氰基、卤素、C1-6烷基、C2-10链烯基、卤代C1-6烷基、C1-6烷基羰基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷氧基羰基、羧基、-NRaRb、-C(=O)NRaRb、S(=O)frRe、R44-2-1、或、被一个或多个R44-2-2取代的R44-2-3;
Ra和Rb独立地为氢、C1-6烷基、C1-6烷基羰基、卤代C1-6烷基、羟基C1-6烷基、S(O)srRc或S(O)trN(Rd)2;
sr和tr独立地为0、1或2;
Rc为C1-6烷基、Rc-1或被一个或多个Rc-2取代的Rc-3;
Rc-1和Rc-3独立地为C6-10芳基、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“或包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
Rc-2独立地为羟基、氰基、卤素、C1-6烷基、C2-10链烯基或卤代C1-6烷基;
Rd独立地为氢或C1-6烷基;
或者,Ra、Rb及与之相连的N原子一起形成Ra-1或被一个或多个Ra-2取代的Ra-3;
Ra-1和Ra-3独立地为“包含一个N原子的4元饱和杂环”、或、“包含1、2或3个N原子和0或1个O原子的5、6或7元饱和或部分饱和的杂环”;
Ra-2独立地羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-10链烯基或卤代C1-6烷基;
fr为0、1或2;
Re为C1-6烷基、Re-1或被一个或多个Re-2取代的Re-3;
Re-1和Re-3独立地为C6-10芳基、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“或包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
Re-2独立地为羟基、氰基、卤素、C1-6烷基、C2-10链烯基或卤代C1-6烷基;
R44-2-1和R44-2-3独立地为C6-10芳基、C6-10芳基C1-6烷基、“包含一个N原子的4元饱和杂环”、“包含1、2或3个独立地选自N、O和S的原子的5、6或7元饱和或部分饱和的杂环”、“包含1、2、3或4个独立地选自N、O和S的杂原子的5元杂芳环,其中不多于一个杂原子为O或S”、“包含1、2或3个氮原子的6元杂芳环”、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-10元不饱和或部分饱和的杂环”;
R44-2-2独立地为羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-10链烯基、卤代C1-6烷基、氨基、C1-6烷基氨基和二(C1-6烷基)氨基。
4.如权利要求3所述的应用,其特征在于,所述的如式I所示的化合物具有以下定义:
R11-1独立地为卤素、羟基、羧基、硝基、氨基、C1~C4的烷基或被一个或多个NR11-1-1R11-1-2取代的C1~C4的烷基(所述的“C1~C4的烷基”例如甲基);
R11-1-1和R11-1-2独立地为氢或C1~C4的烷基(例如甲基);
Y1为-(CRY1-1RY1-2)(CRY1-3RY1-4)n-;
n为0或1;
RY1-1和RY1-2独立地为H或C1~C4的烷基;
RY1-3和RY1-4独立地为H或C1~C4的烷基;
R12是H或C1~C4的烷基;
X1是O或S;
R14是H或卤素(例如氟、氯或溴);
R13是H或C1~C4的烷基;
所述的如式II所示的化合物具有以下定义:
X2、Y2及与之相连的碳原子一起形成C6~C10的芳基(例如苯基)、或、被一个或多个RX2-1取代的C6~C10的芳基;
RX2-1独立地为卤素、硝基、羟基、巯基、氨基、C1~C7的烃基、C6~C20的芳基、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基、-ORX2-1-1或-SRX2-1-2;
RX2-1-1和RX2-1-2独立地为C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
R21为H或卤素(例如氟、氯或溴);
Z为-NRZ-1-;m为1或2;
RZ-1-1、RZ-1-2、RZ-1-3、RZ-1-4、RZ-1-5、RZ-1-6和RZ-1-7独立地为氢、C1~C7的烃基、C6~C20的芳基、或、“含1~6个杂原子,杂原子选自O、N和S中的一种或多种的、3~20元的”杂环基;
或者,RZ-1-1、RZ-1-2及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
或者,RZ-1-5、RZ-1-6及与之相连的碳原子一起形成“含1~2个杂原子,杂原子选自O、N和S中的一种或多种的、4~8元的”杂环基;
R22和R23都为氢;
所述的如式III所示的化合物具有以下定义:
R31为氢、甲基、乙基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基,优选氢或甲基;
R32为氢、甲基、乙基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基,优选甲基、异丙基、环丙基、哌啶-4-基或(R)-四氢呋喃-3-基;
或者,R31、R32及与之相连的N原子一起形成未取代或取代的吗啉基、哌嗪基、高哌嗪基、硫代吗啉基、哌啶基或四氢吡咯基,其中,所述的取代是指N被甲基取代;
X3为CH、CF或N;
Y3为CH、CF或N;
R33为H;
R34为F;
所述的如式IV所示的化合物具有以下定义:
fm为0、1、2或3;
R41独立地为羟基、卤素、氰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基;
A4为CH或N;
fn为0;
Y4为包含1、2或3个独立地选自N、O和S的杂原子的5、6或7元饱和或部分饱和的杂环、包含1、2、3或4个独立地选自O、N和S的杂原子但其中不多于一个为O或S的5元不饱和杂环、包含1、2或3个氮原子的6元不饱和杂环、“6-13元饱和、部分饱和或不饱和的烃环”(例如C6~C10的芳基,又例如苯基)、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的8-13元不饱和或部分饱和的杂环”;
z为1或2;
fp为0;
q为0;
t为0;
v为0;
w为0;
x为0;
a为0;
y为0;
R44为卤素或R44-1;
R44-1为C3-10环烷基、包含一个N原子的4元饱和杂环、“包含1、2或3个独立地选自N、O和S的原子的5或6元饱和或部分饱和的杂环”(例如)、或、“包含1、2、3或4个独立地选自N、O和S的杂原子的7-15元不饱和、部分饱和或饱和的杂环”;
和/或,所述的如式IV所示的化合物具有以下定义:其为如式IV-1所述的化合物,
fm为0或1;
R41为卤素(例如氟);
R44为氢或卤素(例如氟)。
5.如权利要求4所述的应用,其特征在于,所述的如式I所示的化合物为下述任一化合物:
所述的如式II所示的化合物为下述任一化合物:
其中R选自
所述的如式III所示的化合物为下述任一化合物:
所述的如式IV所示的化合物为下述任一化合物:
2-苯基-2H-吲唑-7-甲酰胺;2-(3-氯苯基)-2H-吲唑-7-甲酰胺;和2-{4-[(二甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(N,N-二甲基甘氨酰)氨基]苯基}-2H-吲唑-7-甲酰胺;2-苄基-2H-吲唑-7-甲酰胺;2-(4-氯苯基)-2H-吲唑-7-甲酰胺;2-(2-氯苯基)-2H-吲唑-7-甲酰胺;2-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-[4-(吗啉-4-基甲基)苯基]-2H-吲唑-7-甲酰胺;2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-[4-(吡咯烷-1-基甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-(哌啶-1-基甲基)苯基]-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N,N-二甲基甲烷氯化铵;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)甲基]吡啶鎓;2-{4-[1-(甲基氨基)乙基]苯基}-2H-吲唑-7-甲酰胺;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}环己烷三氟乙酸铵;{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苯基}-N-甲基甲烷三氟乙酸铵;2-苯基-2H-1,2,3-苯并三唑-4-甲酰胺;2-苄基-2H-1,2,3-苯并三唑-4-甲酰胺;2-{3-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸4-({3-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)哌啶鎓;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基甲烷氯化铵;2-{3-氯-4-[(二甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-4-甲基哌嗪-1-鎓;2-(4-{[(4-吡咯烷-1-基哌啶-1-基)乙酰基]氨基}苯基)-2H-吲唑-7-甲酰胺;2-{4-[(吡咯烷-1-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(哌啶-1-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(吗啉-4-基乙酰基)氨基]苯基}-2H-吲唑-7-甲酰胺;氯化4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]吗啉-4-鎓;2-{4-[(乙基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(异丙基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}丙烷-2-氯化铵;2-(4-{[(2-氟乙基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺;2-(4-{[(2,2-二氟乙基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺;2-{4-[(环丙基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}-1,4-二氮杂环庚烷-1-鎓;2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)-N,N-二甲基乙烷三氟乙酸铵;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)甲基]哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-N,N’,N’-三甲基乙烷-1,2-二氯化二铵;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}-1-甲基哌嗪-1-鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]氮杂环丁烷鎓;三氟乙酸(2S)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)-1-苄基哌啶鎓;2-{4-[(吡啶-4-基氨基)羰基]苯基}-2H-吲唑-7-甲酰胺;2-{4-[(4-苯基哌嗪-1-基)羰基]苯基}-2H-吲唑-7-甲酰胺;2-(4-{[甲基(喹喔啉-6-基甲基)氨基]羰基}苯基)-2H-吲唑-7-甲酰胺;2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)乙基]吡咯烷鎓;三氟乙酸1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)乙基]哌啶鎓;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)乙基]吗啉-4-鎓;三氟乙酸4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯甲酰基}氨基)-1-甲基哌啶鎓;2-[4-[(4-甲基哌嗪-1-基)甲基]-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-[(甲基氨基)甲基]-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;2-[4-(吡咯烷-1-基甲基)-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-(哌啶-1-基甲基)-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;2-[4-[(乙基氨基)甲基]-3-(三氟甲基)苯基]-2H-吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苄基}-1-甲基哌嗪-1-鎓;双(三氟乙酸)1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]哌啶鎓;双(三氟乙酸)4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]吗啉-4-鎓;双(三氟乙酸)1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]吡咯烷鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-甲基哌啶鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-苄基哌啶鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-苯基哌嗪二鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(二甲基氨基)-2-氧代乙烷三氟乙酸铵;双(三氟乙酸)2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]吡啶鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]吡啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-甲基丙烷-2-三氟乙酸铵;双(三氟乙酸)N′-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-N,N-二甲基乙烷-1,2-二铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-(1,3-噁唑-2-基甲基)甲烷三氟乙酸铵;氯化7-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;氯化6-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸5-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]氮杂环丁烷鎓;2-(4-{[(氮杂环丁烷-3-基羰基)(甲基)氨基]甲基}苯基)-2H-吲唑-7-甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基)羰基]氮杂环丁烷鎓;2-(4-溴苯基)-5-氟-2H-吲唑-7-甲酰胺;5-氟-2-(4-吡啶-3-基苯基)-2H-吲唑-7-甲酰胺;2-(4-吡啶-3-基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-1-甲基哌嗪-1-鎓;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}哌啶鎓;2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]氮杂环丁烷鎓;2-{5-[(甲基氨基)甲基]吡啶-2-基}-2H-吲唑-7-甲酰胺;5-氟-2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氟-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基丙烷-2-三氟乙酸铵;2-(6-苯基哒嗪-3-基)-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环己基]甲基}甲烷三氟乙酸铵;5-氯-2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;2-{3-甲氧基-4-[(4-甲基哌嗪-1-基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{3-甲氧基-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氯-2-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氯-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-4-氟-2H-吲唑-2-基]苯基}-N-甲基甲烷氯化铵;{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}-N-甲基甲烷氯化铵;氯化1-{4-[7-(氨基羰基)-4-氟-2H-吲唑-2-基]苄基}-4-甲基哌嗪-1-鎓;氯化1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-4-甲基哌嗪-1-鎓;双(三氟乙酸)1-{3-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-甲基哌嗪二鎓;2-[4-(1-羟基-1-甲基乙基)苯基]-2H-吲唑-7-甲酰胺;2-(4-乙酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸3-{[{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}(甲基)氨基]羰基}-1-甲基哌啶鎓;2-{4-[1-(甲酰基氨基)-1-甲基乙基]苯基}-2H-吲唑-7-甲酰胺;2-[3-(1,4-二氮杂环庚烷-1-基羰基)苯基]-2H-吲唑-7-甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸(2S)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸(2R)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶鎓;三氟乙酸(3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;4-氯-2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸(3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;(R)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;(S)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-甲基乙烷氯化铵;2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-2H-吲唑-2·基]-2-氟苯基}-N-甲烷三氟乙酸铵;2-{4-[1-甲基-1-(甲基氨基)乙基]苯基}-2H-吲唑-7-甲酰胺;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]-2-羟基苄基}-4-甲基哌嗪-1-鎓;氯化(3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;氯化(3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;双(三氟乙酸)1-(2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}乙基)-4-甲基哌嗪二鎓;{4-[7-(氨基羰基)-4-羟基-2H-吲唑-2-基]苯基}-N-甲基甲烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-苯基吡咯烷鎓;(1R,3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;(1R,3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;(1S,3R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-2-甲基氮杂环丁烷鎓;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-1-甲基哌啶鎓;9-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-3-氮鎓杂螺[5.5]十一烷三氟乙酸盐;三氟乙酸4-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]-4-苯基哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-{3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶-2-基}哌嗪-1-鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡啶鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]喹啉鎓;三氟乙酸4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]异喹啉鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基氮杂环庚烷鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-2-甲基-1,2,3,4-四氢异喹啉鎓;三氟乙酸2-{4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶-1-基}嘧啶-1-鎓;氯化1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-4-甲基哌嗪-1-鎓;5-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-3-氧代八氢吲嗪-2-三氟乙酸铵;三氟乙酸2-{3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶-1-基}吡啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-甲基吗啉-4-鎓;(1R,4R)-N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-1′-(甲基磺酰基)-1′,2′-二氢螺[环己烷-1,3′-吲哚]-4-甲酰胺;三氟乙酸1-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]八氢-1H-异吲哚鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-苄基吗啉-4-鎓;三氟乙酸(3S,4R)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-4-(甲氧基羰基)吡咯烷鎓;双(三氟乙酸)4-{(2S)-2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]吡咯烷鎓-1-基}哌啶鎓;(1S,3S)-3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]环戊烷三氟乙酸铵;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基吡咯烷鎓;三氟乙酸2-{4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]哌啶-1-基}嘧啶-1-鎓;双(三氟乙酸)2-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}吡咯烷鎓-3-基)吡啶鎓;双(三氟乙酸)3-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}吡咯烷鎓-3-基)吡啶鎓;三氟乙酸(3S,4S)-1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,4-二氟吡咯烷鎓;3-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-6-铵基-3-氮鎓杂双环[3.1.0]己烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-7-甲基-2,7-二氮鎓杂螺[4.4]壬烷双(三氟乙酸盐);双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3-[4-(二甲基铵基)苯基]吡咯烷鎓;双(三氟乙酸)5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-甲基-1,2,4,5,6,6a-六氢吡咯并[3,4-b]吡咯二鎓;双(三氟乙酸)3-{[{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}(甲基)铵基]甲基}-1-甲基哌啶鎓;(1R,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-氧杂-5-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-羟基-2-甲基丙烷-1-三氟乙酸铵;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,3-二氟环丁烷三氟乙酸铵;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-6-氟-1,4-二氮杂环庚烷-1-鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-嘧啶-1-鎓-2-基-1,4-二氮杂环庚烷-1-鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-苄基吡咯烷鎓;双(三氟乙酸)3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1-甲基吡咯烷鎓;双(三氟乙酸)3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1-苄基吡咯烷鎓;2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-7-苄基-2,7-二氮鎓杂螺[4.4]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-8-苄基-2,8-二氮鎓杂螺[5.5]十一烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,6-二氮鎓杂螺[3.3]庚烷双(三氟乙酸盐);7-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,7-二氮鎓杂螺[3.5]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,6-二氮鎓杂螺[3.5]壬烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,8-二氮鎓杂螺[5.5]十一烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,8-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,7-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);8-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2,8-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);3-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,9-二氮鎓杂螺[5.5]十一烷双(三氟乙酸盐);双(三氟乙酸)2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}八氢吡咯并[3,4-c]吡咯二鎓;双(三氟乙酸)5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}八氢吡咯并[3,4-b]吡咯二鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)八氢环戊二烯并[c]吡咯鎓;N2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-N1,N1-二甲基-1-吡啶-2-基乙烷-1,2-双(三氟乙酸)二铵;双(三氟乙酸)7-(氨基羰基)-2-[4-({[2-(2,3-二氢-1H-吲哚-1-基)乙基]铵基}甲基)苯基]-2H-吲唑-1-鎓;双(三氟乙酸)(3S,4S)-1-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)乙基]-3,4-二氟吡咯烷鎓;三氟乙酸5-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}氨基)-1,3-苯并噻唑-3-鎓;1-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-8-氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);双(三氟乙酸)4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-1-甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-羟基乙烷三氟乙酸铵;三氟乙酸7-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸3-[2-({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)-2-氧代乙基]氮杂环丁烷鎓;双(三氟乙酸)4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶鎓;双(三氟乙酸)(3R,4R)-4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-氟哌啶鎓;双(三氟乙酸)(3S,4R)-4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-苄基-1-甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-异丁酰基哌啶-4-三氟乙酸铵;双(三氟乙酸)2-[4-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶-1-基]-3-甲基吡啶鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)哌啶鎓;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-1-苄基哌啶鎓;5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-5-氮杂-2-氮鎓杂双环[2.2.2]辛烷三氟乙酸盐;(1S,4S)-2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-5-甲基-2,5-二氮鎓杂双环[2.2.1]庚烷双(三氟乙酸盐);双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(吡啶-2-基甲基)哌嗪二鎓;5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-苄基-5-氮杂-2-氮鎓杂双环[2.2.2]辛烷三氟乙酸盐;8-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3-苄基-8-氮杂-3-氮鎓杂双环[3.2.1]辛烷三氟乙酸盐;(1S,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-苄基-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;双(三氟乙酸)3-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)吡咯烷鎓;6-({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)-3-氮鎓杂双环[3.1.0]己烷双(三氟乙酸盐);三氟乙酸(3S,4S)-N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-羟基四氢噻吩-3-铵1,1-二氧化物;双(三氟乙酸)4-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}铵基)甲基]-4-羟基-1-甲基哌啶鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-环丙基-2-羟基乙烷三氟乙酸铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环戊基]甲基}甲烷三氟乙酸铵;双(三氟乙酸)2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1,2,3,4-四氢-2,7-二氮杂萘二鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3-[(二甲基铵基)甲基]哌啶鎓;双(三氟乙酸)4-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}哌啶鎓-4-基)硫代吗啉-4-鎓;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-[(甲基磺酰基)氨基]哌啶鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(1H-咪唑-3-鎓-1-基甲基)哌啶鎓;7-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-1-氧杂-7-氮鎓杂螺[4.5]癸烷三氟乙酸盐;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(1-羟基-1-甲基乙基)哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-苄基哌啶鎓;三氟乙酸2-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-乙基哌啶鎓;三氟乙酸3-[({4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}氨基)羰基]-1-乙基哌啶鎓;2-[3-(1,4-二氮杂环庚烷-1-基羰基)-4-氟苯基]-2H-吲唑-7-甲酰胺三氟乙酸盐;{4-[7-(氨基羰基)-4-氯-2H-吲唑-2-基]苄基}甲基氨基甲酸叔丁酯;三氟乙酸6-[7-(氨基羰基)-2H-吲唑-2-基]-1,2,3,4-四氢异喹啉鎓;三氟乙酸2-{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}吡咯烷鎓;6-氟-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;5-氟-2-{2-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺;2-{3-羟基-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-(4-{[甲酰基(甲基)氨基]甲基}-3-羟基苯基)-2H-吲唑-7-甲酰胺;2-{2-氯-4-[(甲基氨基)甲基]苯基}-5-氟-2H-吲唑-7-甲酰胺;5-氟-2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{2,5-二氟-4-[(甲基氨基)甲基]苯基}-5-氟-2H-吲唑-7-甲酰胺三氟乙酸盐;2-(4-溴苯基)-2H-吲唑-7-甲酰胺;氯化(3R)-3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;三氟乙酸(3R)-3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基哌啶鎓;2-(1,2,3,4-四氢异喹啉-7-基)-2H-吲唑-7-甲酰胺;(R)-2-[4-({3-[(二甲基氨基)甲基]哌啶-1-基}甲基)苯基]-2H-吲唑-7-甲酰胺;(S)-2-[4-({3-[(二甲基氨基)甲基]哌啶-1-基}甲基)苯基]-2H-吲唑-7-甲酰胺;3-({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)-2-(氯甲基)-3-氧代丙烷-1-三氟乙酸铵;5-氟-2-{3-氟-4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺盐酸盐;2-{4-[(二甲基氨基)甲基]-3-氟苯基}-5-氟-2H-吲唑-7-甲酰胺三氟乙酸盐;2-{4-[(氮杂环丁烷-3-基羰基)氨基]苯基}-5-氟-2H-吲唑-7-甲酰胺;2-[4-(2,7-二氮杂螺[4.5]癸-2-基甲基)苯基]-2H-吲唑-7-甲酰胺;(1S,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(4-氯苄基)-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;(1S,4S)-5-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-(3-氯苄基)-5-氮杂-2-氮鎓杂双环[2.2.1]庚烷三氟乙酸盐;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-[(甲基氨基)羰基]哌嗪-1-鎓;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-羟基-2-吡啶-3-基乙烷三氟乙酸铵;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-环己基-2-羟基乙烷三氟乙酸铵;三氟乙酸4-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-6-(羟基甲基)-1,4-氧杂氮杂环庚烷-4-鎓;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环丁基]甲基}甲烷三氟乙酸铵;{4-[7-(氨基羰基)-2H-吲唑-2-基]苯基}-N-{[1-(羟基甲基)环己基]甲基}甲烷三氟乙酸铵;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-(5-甲基-1H-苯并咪唑-2-基)哌啶鎓;双(三氟乙酸)2-(1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-4-羟基哌啶鎓-4-基)吡啶鎓;三氟乙酸1-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-3,3-二氟吡咯烷鎓;2-(4-{[(2R)-2-(氟甲基)吡咯烷-1-基]甲基}苯基)-2H-吲唑-7-甲酰胺;N-{4-[7-(氨基羰基)-2H-吲唑-2-基]苄基}-2-氧代吡咯烷-3-三氟乙酸铵;5-氟-2-(4-甲酰基苯基)-2H-吲唑-7-甲酰胺;三氟乙酸3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苯基}氨基)羰基]-1-甲基氮杂环丁烷鎓;双(三氟乙酸)1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-3-[(二甲基铵基)甲基]哌啶鎓;三氟乙酸3-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苯基}氨基)羰基]氮杂环丁烷鎓;2-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}-2,7-二氮鎓杂螺[4.5]癸烷双(三氟乙酸盐);4,5-二氟-2-{4-[(甲基氨基)甲基]苯基}-2H-吲唑-7-甲酰胺三氟乙酸盐;5-氟-2-(3-氟-4-{[(1-甲基氮杂环丁烷-3-基)羰基]氨基}苯基)-2H-吲唑-7-甲酰胺三氟乙酸盐;5-氟-2-(3-氟-4-甲酰基苯基)-2H-吲唑-7-甲酰胺;5-氟-2-(5-氟-2-甲酰基苯基)-2H-吲唑-7-甲酰胺;{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苯基}-N-{[1-(羟基甲基)环戊基]甲基}甲烷三氟乙酸铵;5-氟-2-[3-氟-4-({[(3R)-1-甲基哌啶-3-基]羰基}氨基)苯基]-2H-吲唑-7-甲酰胺三氟乙酸盐;双(三氟乙酸)1-{4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苄基}-4-甲基哌嗪二鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]苄基}铵基)甲基]-1-甲基哌啶鎓;双(三氟乙酸)4-[({4-[7-(氨基羰基)-5-氟-2H-吲唑-2-基]-2-氟苄基}铵基)甲基]-1-甲基哌啶鎓;
及其药学上可接受的盐或互变异构体。
8.如权利要求1-7任一项所述的应用,其特征在于,所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐以包含其的药物组合物的形式存在;
较佳地,所述药物组合物以所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐作为所述药物组合物的唯一活性成份;和/或,所述药物组合物还包含药学上可接受的载体,例如药学上可接受的药用辅料。
9.如权利要求1-8任一项所述的应用,其特征在于,所述聚ADP核糖聚合酶抑制剂或其药学上可接受的盐以包含其的套装药盒的形式存在,所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
10.如权利要求3~6中任一项所述的如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐在制备抗病毒剂或制备治疗由病毒引起的疾病的药物中的应用,所述病毒为HIV、HPV、EBV、IFV和/或冠状病毒科优选正冠状病毒亚科的病毒。
12.如权利要求10或11所述的应用,其特征在于,所述的如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐以包含其的药物组合物的形式存在;
较佳地,所述药物组合物以如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐作为所述药物组合物的唯一活性成份;和/或,所述药物组合物还包含药学上可接受的载体,例如药学上可接受的药用辅料。
13.如权利要求10-12任一项所述的应用,其特征在于,所述如式III所示的化合物和/或如式IV所示的化合物或其药学上可接受的盐以包含其的套装药盒的形式存在,所述套装药盒还包括其他抗冠状病毒引起的疾病的药物。
14.如权利要求10-13任一项所述的应用,其特征在于,所述正冠状病毒亚科的病毒为α冠状病毒属、β冠状病毒属、γ冠状病毒属和/或δ冠状病毒属的病毒,优选为引起上呼吸道感染的冠状病毒、引起急性呼吸综合征的病毒例如SARS相关冠状病毒和/或中东呼吸综合征冠状病毒;
较佳地,所述引起上呼吸道感染的冠状病毒为人冠状病毒229E、人冠状病毒HKU1、人冠状病毒OC43、人冠状病毒NL63和/或小鼠肝炎病毒A59;和/或,所述SARS相关冠状病毒为SARS-CoV或SARS-CoV-2。
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