CN116507611A - 新型衣壳组装抑制剂 - Google Patents
新型衣壳组装抑制剂 Download PDFInfo
- Publication number
- CN116507611A CN116507611A CN202180074857.6A CN202180074857A CN116507611A CN 116507611 A CN116507611 A CN 116507611A CN 202180074857 A CN202180074857 A CN 202180074857A CN 116507611 A CN116507611 A CN 116507611A
- Authority
- CN
- China
- Prior art keywords
- chemical formula
- pyrimidin
- methylsulfonyl
- compound
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 210000000234 capsid Anatomy 0.000 title claims abstract description 38
- 239000003112 inhibitor Substances 0.000 title description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims description 166
- 150000001875 compounds Chemical class 0.000 claims description 158
- -1 phenylamino, piperazinyl Chemical group 0.000 claims description 158
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000009385 viral infection Effects 0.000 claims description 11
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 10
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 208000036142 Viral infection Diseases 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000006251 butylcarbonyl group Chemical group 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 241000700721 Hepatitis B virus Species 0.000 claims description 5
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
- KINFFJSIKAMKHL-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound BrC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O KINFFJSIKAMKHL-UHFFFAOYSA-N 0.000 claims description 4
- CMAHSWPDOLATED-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound BrC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O CMAHSWPDOLATED-UHFFFAOYSA-N 0.000 claims description 4
- VJIXVTJDISQNBE-UHFFFAOYSA-N COC(N=CC=C1)=C1C(NCCNC1=NC(S(C)(=O)=O)=NC(NC(C=CC(F)=C2)=C2Cl)=C1)=O Chemical compound COC(N=CC=C1)=C1C(NCCNC1=NC(S(C)(=O)=O)=NC(NC(C=CC(F)=C2)=C2Cl)=C1)=O VJIXVTJDISQNBE-UHFFFAOYSA-N 0.000 claims description 4
- BHVLNAILRGHNJS-UHFFFAOYSA-N COC1=NC=CC=C1C(=O)N1CCN(CC1)C1=NC(=NC(=C1)NC1=CC=C(C=C1)N1CCOCC1)SC Chemical compound COC1=NC=CC=C1C(=O)N1CCN(CC1)C1=NC(=NC(=C1)NC1=CC=C(C=C1)N1CCOCC1)SC BHVLNAILRGHNJS-UHFFFAOYSA-N 0.000 claims description 4
- KUCSZCNUZZMBTQ-UHFFFAOYSA-N COC1=NC=CC=C1C(N(CC1)CCN1C1=NC(S(C)=O)=NC(NC(C=C2)=CC=C2N2CCOCC2)=C1)=O Chemical compound COC1=NC=CC=C1C(N(CC1)CCN1C1=NC(S(C)=O)=NC(NC(C=C2)=CC=C2N2CCOCC2)=C1)=O KUCSZCNUZZMBTQ-UHFFFAOYSA-N 0.000 claims description 4
- XZNLBDQUWHNNSO-UHFFFAOYSA-N ClC1=C(C=CC(=C1)F)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound ClC1=C(C=CC(=C1)F)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O XZNLBDQUWHNNSO-UHFFFAOYSA-N 0.000 claims description 4
- NJCSQQGQXLCGKB-UHFFFAOYSA-N ClC1=C(C=CC(=C1)F)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound ClC1=C(C=CC(=C1)F)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O NJCSQQGQXLCGKB-UHFFFAOYSA-N 0.000 claims description 4
- YXWWIIKCZJEAAF-UHFFFAOYSA-N FC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound FC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O YXWWIIKCZJEAAF-UHFFFAOYSA-N 0.000 claims description 4
- NFMXPTUHNMXFML-UHFFFAOYSA-N FC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound FC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O NFMXPTUHNMXFML-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- QXGOKOHSRYHFDU-UHFFFAOYSA-N IC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound IC1=CC=C(C=C1)NC1=CC(=NC(=N1)S(=O)C)NCCNC(C1=C(N=CC=C1)OC)=O QXGOKOHSRYHFDU-UHFFFAOYSA-N 0.000 claims description 4
- IBABHABKLFACIL-UHFFFAOYSA-N IC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O Chemical compound IC1=CC=C(C=C1)NC1=CC(=NC(=N1)SC)NCCNC(C1=C(N=CC=C1)OC)=O IBABHABKLFACIL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- 150000004985 diamines Chemical class 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 241000711549 Hepacivirus C Species 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- AFOGRMGCGWHLPW-UHFFFAOYSA-N CS(C1=NC(N2CC3(CNC3)C2)=CC(NC(C=C2)=CC(Cl)=C2F)=N1)(=O)=O Chemical compound CS(C1=NC(N2CC3(CNC3)C2)=CC(NC(C=C2)=CC(Cl)=C2F)=N1)(=O)=O AFOGRMGCGWHLPW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Chemical group 0.000 claims 1
- 239000011630 iodine Chemical group 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- 230000003612 virological effect Effects 0.000 abstract description 7
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-UHFFFAOYSA-N 0.000 abstract description 4
- 208000035473 Communicable disease Diseases 0.000 abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- 238000006243 chemical reaction Methods 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
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- 238000002604 ultrasonography Methods 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
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- 210000002845 virion Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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Abstract
本发明涉及一种一系列的新型苯基氨基嘧啶衍生物,涉及其抑制衣壳组装以及通过其预防或者治疗病毒感染疾病的用途。
Description
技术领域
本发明涉及一种一系列的新型苯基氨基嘧啶衍生物,涉及其抑制衣壳组装以及通过其预防或者治疗病毒感染疾病的用途。
背景技术
慢性乙型肝炎病毒(chronic hepatitis B virus;HBV)是全世界主要的健康问题,可以引起肝硬化(cirrhosis)或者肝癌之类的严重的健康问题。依据WHO的最新报告,推测2015年当时全世界有2亿5700万人以被慢性HBV感染的状态生活着,其中134万人因肝炎相关并发症而导致死亡。目前为止,作为认可其能够治疗HBV的物质,具有干扰素(interferons;IFNs、非聚乙二醇化或者聚乙二醇化)以及核苷酸类似物(nucleos(t)ideanalogues;拉米夫定(lamivudine)、阿德福韦(adefovir)、恩替卡韦片(entecavir)、泰诺福韦(tenofovir)等)。IFNs治疗方法是抑制HBV复制以及诱导肝疾病的缓解(remission),核苷酸类似物药物是抑制反转录酶(reverse transcriptase)以及DNA聚合酶(polymerase)活性。即便如此,目前利用抗病毒剂难以完全去除(complete elimination)HBV,而且频繁发生由长时间的使用引起的耐药性。为了克服这种不满意的医学要求,需要发掘出具有新的分子靶向且有效安全的抗HBV药物。
HBV病毒基因组(viral genome)是被由核心蛋白形态组装的HBV衣壳包裹,HBV衣壳不仅保护DNA,而且与前基因组RNA(pregenomicRNA;pgRNA)衣壳化(encapsidation)有关联。另外,调节病毒基因组的传输(transport)以及核释放(nuclear release),与cccDNA一起参与到表观遗传调控(epigenetic regulation)中,调节(modulate)宿主基因表达、pgRNA的反转录以及核衣壳(nucleocapsids)的再利用(recycling)。因此,广泛研究着基于HBV复制周期(replication cycle)的衣壳蛋白靶向抗-HBV制剂的发掘。
若干研究团队和制药公司正在开发衣壳组装调节剂。Bay-41-4109、非杂芳基二氢嘧啶(heteroaryldihydropyrimidine;HAP)类似物作为最初进入临床试验的衣壳组装抑制剂,诱导衣壳的畸变(aberrant formation)以及衣壳蛋白聚合(aggregation)。作为衣壳蛋白的错误组装(incorrect assembly)的结果,在HepG2.2.15细胞中观察到与HBV DNA还原一起,HBV核心蛋白的蛋白酶体介导的降解(proteasome mediated degradation)。GLS-4是具有与BAY-41-4109相同的作用机理的第二代HAP类似物,与用于防止由GLS-4导致的CYP诱导的利托那韦(ritonavir;RTV)一起,在II期临床试验(phase II clinical trials)中进行着研究。最近,同一批研究团队报告了HEC72702,其即便在CYP酶的低诱导、Herg k+通道的低抑制以及相比2减少2至3倍的体外(in vitro)功效(potency)下,也显示提高的口服生物利用度(oral bioavailability)。与其他衣壳组装调节剂一起,开发出具有与HAPs不同的作用机理的AT130、NVR3-778以及JNJ-632。例如,即便在结合衣壳蛋白的情况下,NVR3-778的处理虽然始终促进正常大小的衣壳组装过程,但是诱导了空的衣壳的形成。有报告指出JNJ-632是新型的氨基磺酰基苯甲酰胺(sulfamoylbenzamide)衣壳组装调节剂,目前在II期临床试验中研究着作为其最佳化的类似物JNJ-6379。最近,本发明人作为药物重新定位战略(drug repositioning strategy)中可口服使用的衣壳组装抑制剂,报告了FDA认证的作为抗真菌剂(antifungal drug)的环匹酮胺(ciclopirox)。
发明内容
技术问题
本发明人为了发掘出通过抑制衣壳组装,从而能够抑制病毒感染的新型小分子化合物而努力研究的结果,确认到一系列的苯基氨基嘧啶衍生物抑制潜在的衣壳组装,从而具有抑制病毒感染,例如乙型肝炎病毒感染的活性,由此完成了本发明。
发明效果
根据本发明新合成的分子内存在的苯基氨基嘧啶衍生物显示抑制衣壳组装的效果,因此能够活用在与此相关的疾病,例如HBV、HCV、HIV等的病毒感染疾病的预防或者治疗中。
具体实施方式
以下进行具体说明。一方面,在本发明中公开的每个说明以及实施形态也可以各自应用在其他说明以及实施形态中。即,在本发明中公开的各种要素的所有组合属于本发明的范畴中。另外,不应视为通过以下说明的具体叙述,限制本发明的范畴。
本发明的第一形态提供一种由以下化学式1表示的化合物或者其药学上可接受的盐。
【化学式1】
在所述化学式1中,
m为0、1或者2;
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R2为氢、卤素、氨基、-NH-(CH2)P-NHCO-R5、或者未被取代或者被R6取代的C6-10芳基、C6-10芳氨基、3-10元杂环基或者3-10元杂环氨基;
R5为叔丁基、C6-10芳基或者5-10元杂芳基;
R6为未被取代或者被叔丁基羰基取代的氨基、直接或者通过-CO-连接的叔丁基、C6-10芳基或者5-10元杂芳基;
p为1至4的整数;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
本发明的术语“杂芳基”以及“杂环基”各自为包括选自由O、N或者S构成的组中的一种以上的杂元素的不饱和或者饱和环结构的取代基,所述杂元素可以为氮,但不限于此。例如,在本发明的化合物中,杂芳基或者杂环基可以是包括1至3个氮原子的环结构的取代基,但不限于此。
例如,在所述化学式1中,R1可以是甲基,但不限于此。
例如,在所述化学式1中,可以是R2为氢、卤素、氨基、-NH-(CH2)2-NHCO-R5或者未被取代或者被R6取代的苯基氨基、哌嗪基、哌啶基或者哌啶氨基,R5为叔丁基、苯基或者吡啶基,R6为直接或者通过-CO-连接的叔丁基、苯基或者吡啶基,但不限于此。
具体地,在所述化学式1中,R2可以是氢、氯、氨基、未被取代或者被丁基羰基取代的哌嗪基、哌啶氨基、氨基哌啶基、被选自氟或者氯中的1至3个卤素取代的苯基氨基、(甲氧基吡啶基)羰基哌嗪基、(甲氧基吡啶基)羰基氨基乙基氨基、被选自氟或者氯中的1或者2个卤素取代的苯基羰基氨基乙基氨基、未被取代或者被丁基羰基取代的(1R,4R)-2,5-二氮杂二环[2.2.1]庚基、未被取代或者被丁基羰基取代的(1S,4S)-2,5-二氮杂二环[2.2.1]庚基、未被取代或者被丁基羰基取代的2,6-二氮杂螺[3.3]庚基、或者未被取代或者被丁基羰基或者丁基羰基氨基取代的3-氮杂二环[3.1.0]庚基,但不限于此。
例如,在所述化学式1中,R3可以是氢、吗啉基、氰基、甲基、三氟甲基或者选自由氟、氯、溴以及碘构成的组中1至3个取代基,但不限于此。
例如,在所述化学式1中,R4可以是氢、苄基或者苯基乙基,但不限于此。
具体地,所述化合物可以是,
1.2-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(2-methoxy-N-(2-(2-(methylthio)-6-(4-morpholinophenylamino)pyrimidin-4-ylamino)ethyl)nicotinamide)、
2.5-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(5-methoxy-N-(2-(2-(methylthio)-6-(4-morpholinophenylamino)pyrimidin-4-ylamino)ethyl)nicotinamide)、
3.4-氟-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(4-fluoro-N-(2-(2-(methylthio)-6-(4-morpholinophenylamino)pyrimidin-4-ylamino)ethyl)benzamide)、
4.2,4-二氯-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(2,4-dichloro-N-(2-(2-(methylthio)-6-(4-morpholinophenylamino)pyrimidin-4-ylamino)ethyl)benzamide)、
5.2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(2-methoxy-N-(2-(2-(methylsulfinyl)-6-(4-morpholinophenylamino)pyrimidi n-4-ylamino)ethyl)nicotinamide)、
6.5-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(5-methoxy-N-(2-(2-(methylsulfinyl)-6-(4-morpholinophenylamino)pyrimidi n-4-ylamino)ethyl)nicotinamide)、
7.4-氟-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(4-fluoro-N-(2-(2-(methylsulfinyl)-6-(4-morpholinophenylamino)pyrimidin-4-ylamino)ethyl)benzamide)、
8.2,4-二氯-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(2,4-dichloro-N-(2-(2-(methylsulfinyl)-6-(4-morpholinophenylamino)pyrimi din-4-ylamino)ethyl)benzamide)、
9.2-甲氧基-N-(2-(2-(甲硫基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺
(2-methoxy-N-(2-(2-(methylthio)-6-(phenylamino)pyrimidin-4-ylamino)ethy l)nicotinamide)、
10.N-(2-(6-(4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-fluorophenylamino)-2-(methylthio)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
11.N-(2-(6-(4-氯苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-chlorophenylamino)-2-(methylthio)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
12.N-(2-(6-(4-溴苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-bromophenylamino)-2-(methylthio)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
13.N-(2-(6-(4-碘苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-iodophenylamino)-2-(methylthio)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
14.N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(3,4-difluorophenylamino)-2-(methylthio)pyrimidin-4-ylamino)ethy l)-2-methoxynicotinamide)、
15.N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(2-chloro-4-fluorophenylamino)-2-(methylthio)pyrimidin-4-ylamin o)ethyl)-2-methoxynicotinamide)、
16.2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(2-methoxy-N-(2-(2-(methylsulfinyl)-6-(phenylamino)pyrimidin-4-ylamino)ethyl)nicotinamide)、
17.N-(2-(6-(4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-fluorophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylamino)ethy l)-2-methoxynicotinamide)、
18.N-(2-(6-(4-氯苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-chlorophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylamino)eth yl)-2-methoxynicotinamide)、
19.N-(2-(6-(4-溴苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-bromophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylamino)eth yl)-2-methoxynicotinamide)、
20.N-(2-(6-(4-碘苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(4-iodophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
21.N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(3,4-difluorophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
22.N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(3,4-difluorophenylamino)-2-(methylsulfonyl)pyrimidin-4-ylamino)ethyl)-2-methoxynicotinamide)、
23.N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(2-chloro-4-fluorophenylamino)-2-(methylsulfinyl)pyrimidin-4-ylami no)ethyl)-2-methoxynicotinamide)、
24.N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(N-(2-(6-(2-chloro-4-fluorophenylamino)-2-(methylsulfonyl)pyrimidin-4-ylam ino)ethyl)-2-methoxynicotinamide)、
25.6-氯-N-(4-氟苄基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺(N-(2-(6-(2-chloro-4-fluorophenylamino)-2-(methylsulfonyl)pyrimidin-4-ylam ino)ethyl)-2-methoxynicotinamide)、
26.6-氯-N-(4-氟苯乙基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺(6-chloro-N-(4-fluorophenethyl)-2-(methylthio)-N-(4-morpholinophenyl)pyri midin-4-amine)、
27.N4-(4-氟苄基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺(N4-(4-fluorobenzyl)-2-(methylthio)-N4-(4-morpholinophenyl)pyrimidine-4,6-diamine)、
28.N4-(4-氟苯乙基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺(N4-(4-fluorophenethyl)-2-(methylthio)-N4-(4-morpholinophenyl)pyrimidine-4,6-diamine)、
29.(2-甲氧基吡啶基-3-基)(4-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮((2-methoxypyridin-3-yl)(4-(2-(methylthio)-6-(4-morpholinophenylamino)pyr imidin-4-yl)piperazin-1-yl)methanone)、
30.(2-甲氧基吡啶基-3-基)(4-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮((2-methoxypyridin-3-yl)(4-(2-(methylsulfinyl)-6-(4-morpholinophenylamino)pyrimidin-4-yl)piperazin-1-yl)methanone)、
31.6-氯-N-(2,4-氯氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(6-chloro-N-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidin-4-amine)、
32.6-氯-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(6-chloro-2-(methylsulfonyl)-N-(3,4,5-trifluorophenyl)pyrimidin-4-amine)、
33.N4,N6-双(4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺(N4,N6-bis(4-fluorophenyl)-2-(methylsulfonyl)pyrimidine-4,6-diamine)、
34.2-(甲磺酰基)-N4,N6-双(3,4,5-三氟苯基)嘧啶基-4,6-二胺(2-(methylsulfonyl)-N4,N6-bis(3,4,5-trifluorophenyl)pyrimidine-4,6-diamine)、
35.N4,N6-双(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺(N4,N6-bis(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)pyrimidine-4,6-diamin e)、
36.叔丁基4-(6-(4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-fluorophenylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate)、
37.叔丁基4-(6-(4-氟苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-fluorobenzylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-ca rboxylate)、
38.叔丁基4-(6-(4-氯苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-chlorophenylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate)、
39.叔丁基4-(6-(4-氯苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-chlorobenzylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate)、
40.叔丁基4-(6-(4-溴苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-bromophenylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate)、
41.叔丁基4-(6-(4-碘苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(4-iodophenylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-car boxylate)、
42.叔丁基4-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(6-(3,4-difluorophenylamino)-2-(methylsulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate)、
43.叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苯基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(2-(methylsulfonyl)-6-(3,4,5-trifluorophenylamino)pyrimidin-4-yl)piperazine-1-carboxylate)、
44.叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苄基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯(tert-butyl4-(2-(methylsulfonyl)-6-(3,4,5-trifluorobenzylamino)pyrimidin-4-yl)piperazine-1-carboxylate)、
45.N-(4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(N-(4-fluorophenyl)-2-(methylsulfonyl)-6-(piperazin-1-yl)pyrimidin-4-amine)、
46.2-(甲磺酰基)-6-(哌嗪基-1-基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(2-(methylsulfonyl)-6-(piperazin-1-yl)-N-(3,4,5-trifluorophenyl)pyrimidin-4-amine)、
47.N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(N-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)-6-(piperazin-1-yl)pyrimidin-4-amine)、
48.N-(3-溴-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(N-(3-bromo-4-fluorophenyl)-2-(methylsulfonyl)-6-(piperazin-1-yl)pyrimidin-4-amine)、
49.2-(甲磺酰基)-N4-(哌啶基-4-基)-N6-(3,4,5-三氟苯基)嘧啶基-4,6-二胺(2-(methylsulfonyl)-N4-(piperidin-4-yl)-N6-(3,4,5-trifluorophenyl)pyrimidine-4,6-diamine)、
50.N4-(3-氯-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺(N4-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)-N6-(piperidin-4-yl)pyrimidin e-4,6-diamine)、
51.N4-(3-溴-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺(N4-(3-bromo-4-fluorophenyl)-2-(methylsulfonyl)-N6-(piperidin-4-yl)pyrimidin e-4,6-diamine)、
52.6-(4-氨基哌啶-1-基)-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(6-(4-aminopiperidin-1-yl)-2-(methylsulfonyl)-N-(3,4,5-trifluorophenyl)pyrimidin-4-amine)、
53.6-(4-氨基哌啶-1-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(6-(4-aminopiperidin-1-yl)-N-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)pyrimidin-4-amine)、
54.6-(4-氨基哌啶-1-基)-N-(3-溴-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(6-(4-aminopiperidin-1-yl)-N-(3-bromo-4-fluorophenyl)-2-(methylsulfonyl)pyrimidin-4-amine)、
55.6-((1R,4R)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)pyrimidin-4-amine)、
56.N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶基-4-胺(N-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)-6-(2,6-diazaspiro[3.3]hepta n-2-yl)pyrimidin-4-amine)、
57.6-((1S,4S)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(3-chloro-4-fluorophenyl)-2-(methylsulfonyl)pyrimidin-4-amine)或者
58.(1R,5S,6s)-3-(6-(3-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)-3-氮杂二环[3.1.0]己烷-6-胺((1R,5S,6s)-3-(6-(3-chloro-4-fluorophenylamino)-2-(methylsulfonyl)pyrimidi n-4-yl)-3-azabicyclo[3.1.0]hexan-6-amine),但不限于此。
本发明的化合物可以以药学上可接受的盐的形态存在。作为盐使用药学上可接受的、通过游离酸(free acid)形成的酸加成盐。本发明的术语“药学上可接受的盐”是指作为对患者比较没有毒性且具有无害的有效作用的浓度,该盐所具有的的副作用不抑制由化学式1表示的化合物的有益功效的所述化合物的任意的所有有机或者无机附加盐。
酸加成盐是通过通常的方法,例如将化合物溶解到过量的酸水溶液中,并利用水混合性有机溶剂,例如甲醇、乙醇、丙醇或者乙腈,使该盐沉淀,由此制备得到。可以加热等摩尔量的化合物以及水中的酸或者醇(例如,二醇单甲醚),接着蒸发干燥所述混合物或者通过吸入过滤析出的盐。
此时,作为游离酸可以使用有机酸和无机酸,作为无机酸可以使用盐酸、磷酸、硫酸、硝酸、锡酸等,作为有机酸可以使用甲磺酸、p-甲苯磺酸、乙酸、三氟乙酸、马来酸(maleic acid)、琥珀酸、草酸、苯甲酸、酒石酸、富马酸(fumaric acid)、扁桃酸、丙酸(propionic acid)、柠檬酸(citric acid)、乳酸(lactic acid)、乙醇酸(glycolic acid)、葡萄糖酸(gluconic acid)、半乳糖醛酸、谷氨酸、戊二酸(glutaric acid)、葡萄糖醛酸(glucuronic acid)、天门冬氨酸、抗坏血酸、羧酸、香草酸、氢碘酸(hydroiodic acid)等,而且不限于此。
另外,可以使用碱来制备药学上可接受的金属盐。碱金属盐或者碱土金属盐是例如将化合物溶解到过量的碱金属氢氧化物或者碱土金属氢氧化物溶液中,过滤不溶解化合物盐之后,蒸发、干燥滤液来得到。此时,作为金属盐,尤其是制备钠、钾或者钙盐对于制药方面来说是合适的,但不限于此。另外,与其对应的银盐可以是将碱金属或者碱土金属盐与适当的银盐(例如,硝酸银)反应来得到。
除非另有说明,否则本发明的化合物的药学上可接受的盐包括在所述化学式1的化合物中可能存在的酸性或者碱性基的盐。例如,作为药学上可接受的盐,可以包括羟基的钠、钙以及钾盐等,作为氨基的其他药学上可接受的盐,具有氢溴化物、硫酸盐、氢硫酸盐、磷酸盐、氢磷酸盐、二氢磷酸盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐(mesylate)以及p-甲苯磺酸盐(tosylate)等,可以通过本领域中公知的盐的制备方法来制备。
作为本发明的苯基氨基嘧啶衍生物化合物的盐,作为药学上可接受的盐,只要是显示与苯基氨基嘧啶衍生物化合物等同的药理活性的苯基氨基嘧啶衍生物化合物的盐,则不受限制而可以全部使用。
另外,根据本发明的由所述化学式1表示的化合物,不仅包括其药学上可接受的盐,还无限制地包括可以由此制备得到的水合物等的溶剂化物以及可能的所有非对映异构体。由所述化学式1表示的化合物的溶剂化物以及非对映异构体可以是使用本领域中公知的方法,从由化学式1表示的化合物制备得到。
进一步地,根据本发明的由所述化学式1表示的化合物可以制成结晶形态或者非晶形态,当制成结晶形态时,可以任意水合或者溶剂化。在本发明中,不仅包括由所述化学式1表示的化合物的化学计量学上的水合物,还可以包括各种量的含水的化合物。根据本发明的由所述化学式1表示的化合物的溶剂化物包括化学计量学上的溶剂化物以及非化学计量学上的溶剂化物全部。
本发明的第二形态提供一种制备方法,其作为由以下化学式1表示的化合物或者其药学上可接受的盐的制备方法,所述方法包括:使由以下化学式2-1表示的化合物与由化学式3表示的胺衍生物发生反应,从而制备由化学式4-1表示的化合物的第1步骤;以及当R4不是氢时,选择性地,使由化学式4-1表示的化合物与由化学式5表示的卤化盐衍生物发生反应,从而制备由化学式6表示的化合物的第2步骤:
【化学式1】
【化学式2-1】
【化学式3】
【化学式4-1】
【化学式5】
R4-X3
【化学式6】
在所述化学式1、2-1、3、4-1、5以及6中,
X1至X3各自独立为卤素;
X为X1或者
m为0、1或者2;
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R2为氢、卤素、氨基、-NH-(CH2)P-NHCO-R5、或者未被取代或者被R6取代的C6-10芳基、C6-10芳氨基、3-10元杂环基或者3-10元杂环氨基;
R5为叔丁基、C6-10芳基或者5-10元杂芳基;
R6为未被取代或者被叔丁基羰基取代的氨基、直接或者通过-CO-连接的叔丁基、C6-10芳基或者5-10元杂芳基;
p为1至4的整数;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
所述第1步骤可以由以下反应式1表示。以下反应可以是在乙醇等的有机溶剂中与DIPEA(二异丙基乙胺;N,N-Diisopropylethylamine)一起在140至180℃下反应0.5至5小时来进行,但不限于此。在所述反应中,可以使用微波反应器,但不限于此。
【反应式1】
所述第2步骤可以由以下反应式2表示。以下反应可以是在ACN(乙腈;acetonitrile)等的有机溶剂中在TBAF(四丁基氟化铵;tetrabutylammonium fluoride)的存在下,与K2CO3等的碱一起在50至100℃下反应5至24小时来进行,但不限于此。
【反应式2】
本发明的制备方法还可以包括:使由化学式6表示的化合物与氢氧化铵发生反应,从而制备由化学式7表示的化合物的第3-1步骤。
【化学式7】
在所述化学式7中,
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢或者C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
所述第3-1步骤可以由以下反应式3表示。以下反应可以是在丁醇和氢氧化铵混合溶液中在140至180℃下反应3至12小时来进行,但不限于此。在所述反应中,可以使用微波反应器,但不限于此。
【反应式3】
另外,本发明还可以包括:
使由化学式6表示的化合物与由化学式8至15中的任一个表示的Boc-保护的二胺衍生物发生反应,从而制备各自由化学式16或者化学式23表示的化合物的第3-2步骤;以及
使由化学式16或者化学式17表示的化合物与由化学式24表示的酰卤衍生物发生反应,从而制备各自由化学式25或者化学式26表示的化合物的第4-1步骤,或者
将由化学式17或者化学式23表示的化合物的烷硫基利用烷基磺酰基进行氧化之后去保护,从而制备由化学式27至化学式33表示的化合物的第4-2步骤。
【化学式8】
NH2-(CH2)p-NH-Boc
【化学式9】
【化学式10】
【化学式11】
【化学式12】
【化学式13】
【化学式14】
【化学式15】
【化学式16】
【化学式17】
/>
【化学式18】
【化学式19】
【化学式20】
【化学式21】
【化学式22】
【化学式23】
【化学式24】R-COX4
【化学式25】
【化学式26】
【化学式27】
【化学式28】
【化学式29】
【化学式30】
【化学式31】
【化学式32】
【化学式33】
在所述化学式8至化学式33中,n为0至4的整数;
p为1至4的整数;
q为0、1或者2,;
r为1或者2;
X4为卤素;
R1为C1-4烷基;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
R为C6-10芳基或者5-10元杂芳基
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
所述第3-2步骤可以由以下反应式4表示。以下反应可以是在THF(四氢呋喃;tetrahydrofuran)等的有机溶剂中与TEA(三乙胺;triethylamine)一起在140至200℃下反应0.5至5小时来进行,但不限于此。
【反应式4-1】
【反应式4-2】
所述第4-1步骤可以由以下反应式5表示。以下反应可以是将反应物溶解到DCM(二氯甲烷;dichloromethane)等的有机溶剂中,并在10℃以下的低温下进行搅拌的同时,添加TFA(三氟乙酸;trifluoroacetic acid)的DCM溶液,反应10分钟至3小时进行去保护,将收获的有机物在DCM和TEA中与化学式16的酰卤衍生物进行反应,从而在常温下反应0.5至4小时来进行,但不限于此。
【反应式5】
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所述4-2步骤可以由以下反应式6表示。以下反应可以是将反应物与溶解到DCM等的有机溶剂中的mCPBA(间氯过氧苯甲酸;meta-Chloroperoxybenzoic acid)进行混合,从而在常温下反应0.5至4小时来进行,但不限于此。然后,去保护可以是与所述反应式5类似,但不限于此。
【反应式6-1】
【反应式6-2】
进一步地,本发明的制备方法还可以包括:与mCPBA发生反应,从而将烷硫基利用亚磺酰基或者磺酰基进行氧化的第5步骤,但不限于此。
所述第5步骤可以与所述4-2步骤类似,但不限于此。
本发明的第三形态提供一种制备方法,其作为由以下化学式1表示的化合物或者其药学上可接受的盐的制备方法,所述方法包括:
使由以下化学式2-2表示的化合物与由化学式3表示的胺衍生物发生反应,从而制备由化学式4表示的化合物的第1步骤;以及
由化学式4-2表示的化合物与由化学式9表示的Boc-保护的二胺衍生物发生反应,从而制备由化学式34表示的化合物的第2步骤。
【化学式1】
【化学式2-2】
【化学式3】
【化学式4-2】
【化学式9】
【化学式34】
在所述化学式1、2-2、3、4-2、9以及34中,
X1以及X2各自独立为卤素;
m为2;
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R2为
R6为-CO-叔丁基;
q为0、1或者2;
r为1或者2;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢;
所述杂环基是未被取代或者被选自卤素或者氨基中的一种以上取代。
所述第1步骤可以由以下反应式7表示。以下反应可以是将反应物在THF等的有机溶剂下,与TEA一起在常温下反应10分钟至2小时来进行,但不限于此。
【反应式7】
所述第2步骤可以由以下反应式8表示。以下反应可以与所述反应式4类似,但不限于此。
【反应式8】
本发明的第四形态提供一种包括所述第一形态的化合物或者其药学上可接受的盐的、衣壳组装(capsid assembly)抑制用组合物。
本发明的术语“第一形态的化合物”以及“药学上可接受的盐”为如上所述。
本发明的术语“衣壳(capsid)”是指包裹遗传物质(genitic material)的病毒的蛋白质外壳,由被称作原体(protomer)的蛋白质构成的若干低聚物(反复)结构的亚单元构成。将与个别蛋白质相应或者不相应的、可观察的三维形态学亚单元称为壳微粒(capsomere)。构成衣壳的蛋白质被称为衣壳蛋白或者病毒外壳蛋白(viral coatproteins;VCP)。衣壳和衣壳中包括的基因组被称为核衣壳(nucleocapsid)。所述衣壳根据结构而分类的范围较广,大部分的病毒具有螺旋形(herical)或者二十面体(icosahedral)结构的衣壳。噬菌体(bacteriophages)等的若干病毒通过弹性(elasticity)和静电学(electrostatics)的制约而发展为更加复杂的结构。衣壳面(capsid surface)可以由一个以上的蛋白质构成,例如,口蹄病(foot-and-mouth disease)病毒衣壳具有由3个蛋白质VP1-3构成的面。当病毒感染细胞并开始自我复制时,使用细胞的蛋白质生合成机制,合成新的衣壳亚单元。被衣壳包裹的遗传物质可以是RNA或者DNA,但不限于此。
例如,被病毒感染的宿主细胞本来是需要快速复制生成数千个相同的病毒。当不在被感染的细胞内部或者处于感染细胞的过程中时,病毒以(i)遗传物质,即,使病毒工作的蛋白质结构加密的DNA或者RNA的长分子;(ii)作为包裹所述遗传物质并进行保护的蛋白质外壳的衣壳;以及选择性地(iii)由脂质外皮构成的独立颗粒或者病毒粒子(virions)形态存在。
本发明的第五形态提供一种作为有效成分含有所述第一形态的化合物或者其药学上可接受的盐的、抗病毒组合物。
本发明的术语“第一形态的化合物”以及“药学上可接受的盐”为如上所述。
本发明的第六形态提供一种作为有效成分含有所述第一形态的化合物或者其药学上可接受的盐的、用于预防或者治疗病毒感染疾病的药学组合物。
本发明的术语“第一形态的化合物”以及“药学上可接受的盐”为如上所述。
本发明的术语“预防”是指通过给药本发明的组合物,抑制或者延迟病毒感染疾病的发生、扩散以及复发的所有行为,“治疗”是指通过给药本发明的组合物,使所述疾病的症状好转或者向有益的方向转变的所有行为。
本发明的药学组合物通过抑制衣壳形成,能够预防或者治疗通过病毒感染引起的疾病。
所述病毒感染疾病是由乙型肝炎病毒(hepatitis B virus;HBV)、丙型肝炎病毒(hepatitis C virus;HCV)或者人体免疫缺陷病毒(human immunodeficiency virus;HIV)引起的感染疾病。
优选为,根据本发明的药学组合物,可以以组合物的总重量为基准,作为有效成分含有0.1至75重量%,更加优选为1至50重量%的由化学式1表示的化合物或者其药学上可接受的盐。
本发明的组合物还可以包括药学上可接受的载体、稀释剂或者赋形剂,按照各自的使用目的,通过通常的方法剂型化为散剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳液、糖浆、气溶胶等的口服剂型;灭菌注射液的注射剂等各种形态,可以通过口服给药或者包括静脉内、腹腔内、皮下、直肠、局部给药等的各种路径来给药。作为可以在这种组合物中包括的合适的载体、赋形剂或者稀释剂的示例,可以举出乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、非晶纤维素、聚乙烯吡咯烷酮、水、甲基羟苯酸酯、丙基羟苯酸酯、滑石、硬脂酸镁以及矿物油等。另外,本发明的组合物还可以包括填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂以及防腐剂等。
用于口服给药的固态制剂,包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这种固态制剂在所述组合物中混合至少一种赋形剂,例如淀粉、碳酸钙、蔗糖、乳糖、明胶等来剂型化。另外,除了单纯的赋形剂之外,还可以使用硬脂酸镁、滑石之类的润滑剂。
作为口服用液态制剂,可以示例悬浮剂、内溶液剂、乳剂、糖浆剂等,除了作为通常使用的单纯的稀释剂的水、液态石蜡之外,可以包括各种赋形剂,例如润湿剂、甜味剂、芳香剂、保存剂等。
作为用于非口服给药的制剂,包括灭菌的水溶液剂、非水性溶剂、悬浮剂、乳剂、冷冻干燥制剂、栓剂。作为非水性溶剂、悬浮剂,可以使用丙二醇、聚乙二醇、橄榄油之类的植物油;油酸乙酯之类的可注射的酯等。作为栓剂的基剂,可以使用维太素(witepsol)、聚乙二醇(macrogol)、吐温61、可可脂、三月硅酸甘油醋、甘油胶冻等。一方面,注射剂中可以包括溶解剂、等渗溶液、悬浮剂、乳化剂、稳定剂、防腐剂等之类的现有的添加剂。
此时,本发明的组合物以药学上有效的量给药。本发明的术语“药学上有效的量”是指按照可以在医学治疗上使用的合理的受益/危害比率,适合治疗疾病且不引起副作用程度的量,有效容量基准可以根据包括患者的健康状态、疾病的种类、疾病的严重程度、药物的活性、对药物的敏感度、给药方法、给药时间、给药路径以及排放比率、治疗时间、配制或者同时使用的药物的因素以及其他药学上周知的因素来决定。本发明的组合物可以作为个别治疗剂给药或者与其他治疗剂一同给药,可以与现有的治疗剂依次或者同时给药,可以单次或者多次给药。重要的是考虑所述全部因素,在没有副作用的情况下,以能够以最少量得到最大效果的量给药,其可以是由本领域技术人员容易决定。
例如,所述给药量可以根据给药路径、症状的程度、性别、体重、年龄等而进行增减,因此所述给药量不通过任何的方法来限定本发明的范围。
具体地,在本发明的组合物中,化合物的有效量可以根据患者的年龄、性别、体重而不同,一般可以是每1kg体重给药1至100mg,优选为5至60mg,且每日或者隔天给药或者每日分1至3次给药。然而,所述给药量可以根据给药路径、症状的程度、性别、体重、年龄等而进行增减,因此所述给药量不通过任何的方法来限定本发明的范围。
本发明的第四形态提供一种病毒感染疾病的治疗方法,所述方法包括向需要所述第三形态的药学组合物的个体给药所述组合物的步骤。
本发明的术语“第三形态的药学组合物”以及“病毒感染疾病”为如上所述。
本发明的术语“个体”是指感染了所述病毒感染疾病或者可以感染所述病毒感染疾病的包括人类在内的猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、老鼠、兔子或者天竺鼠的所有动物,通过向个体给药本发明的药学组合物,能够有效预防或者治疗所述疾病。本发明的药学组合物可以与现有的治疗剂一起给药。
本发明的术语“给药”是指通过任意的合适方法向患者提供预定的物质,作为本发明的组合物的给药路径,可以通过能够到达目的组织的任何的一般路径来给药。可以腹腔内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、局部给药、鼻内给药、肺内给药、直肠内给药,但不限于此。另外,本发明的药学组合物还可以通过可使活性物质移动至靶向细胞的任意的装置来给药。作为优选的给药方式以及制剂,具有静脉注射剂、皮下注射剂、皮内注射剂、肌肉注射剂、点滴注射剂等。注射剂可以是利用生理性盐水、注射液等的水性溶剂;植物油、高级脂肪酸酯(例如,油酸乙酯等)、醇类(例如,乙醇、苄醇、丙二醇、甘油等)等的非水性溶剂等来制备,可以包括用于防止变质的稳定剂(例如,抗坏血酸、亚硫酸氢钠、焦亚硫酸钠、BHA、生育酚、EDTA等)、乳化剂、用于调节pH的缓冲剂、用于阻止微生物发育的保存剂(例如,硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苄醇等)等的药学载体。
在本发明中,与有效成分结合来使用的“治疗上有效的量”是指在预防或者治疗对象疾病中有效的苯基氨基嘧啶衍生物化合物或者其药学上可接受的盐的量。
本发明的药学组合物根据想要预防或者治疗的疾病的种类,作为有效成分除了包括苯基氨基嘧啶衍生物化合物或者其药学上可接受的盐之外,还可以包括在公知的各个疾病的预防或者治疗中使用的公知的药物。例如,当使用在预防或者治疗病毒感染疾病中时,作为有效成分除了包括苯基氨基嘧啶衍生物化合物或者其药学上可接受的盐之外,还可以包括公知的药物,为了该疾病的治疗,可以与公知的其他治疗一起使用。
用于实施发明的形态
以下,通过实施例进一步详细说明本发明。这些实施例仅是用于进一步详细说明本发明,本发明的范围不受这些实施例的限制。
实施例1.化合物的合成1
试剂以及反应条件:
(a)4-吗啉代苯胺、DIPEA、EtOH、160℃、3h、m.w.;
(b)N-Boc-乙二胺、TEA、THF、160℃、3h、m.w.;
(c)20%TFAin DCM、0℃、1h;
(d)R2-COCl、TEA、DCM、rt、2h;
(e)mCPBA、DCM、100℃、0.2h、m.w.
将4,6-二氯-2(甲硫基)嘧啶(化合物1)与溶解4-吗啉代苯胺(2eq.)和DIPEA(2eq.)的乙醇溶液(2mL)混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物2。
接着,将所述化合物2溶解到THF(2mL)中,并与TEA(2eq.)以及N-Boc-乙二胺(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物3。
接着,将所述化合物3溶解到DCM(1mL)之后,在0℃下搅拌的同时,缓慢加入TFA:DCM=1:3混合溶液(4mL),并搅拌1小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NaHCO3水溶液和乙酸乙酯进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将收获的有机物溶解到DCM(10mL)和TEA(2eq.)之后,添加与各自的R2-基团相应的R2-COCl(2eq.),在常温下反应2小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物4a至化合物4d。
最后,将所述化合物4a至化合物4d各自添加到溶解mCPBA(2eq.)的DCM溶液(2mL)之后,利用微波反应器在100℃下反应0.2小时。利用NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物5a至化合物5d。
实施例2:化合物的合成2
试剂以及反应条件:
(a)R3-苯胺、DIPEA、EtOH、m.w.、160℃、3h;
(b)N-Boc-乙二胺、TEA、THF、180℃、3h;
(c)20% TFA in DCM、0℃、1h;
(d)2-甲氧基烟酰氯、TEA、DCM、r.t.、2h;
(e)mCPBA、MeOH、r.t.、0.5h
将化合物1混合到溶解有与各自的R3-基团相应的R3-苯胺(2eq.)和DIPEA(2eq.)的EtOH溶液(2mL)之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物6a至化合物6g。
接着,将所述化合物6a至化合物6g各自溶解到THF(2mL)中,并与TEA(2eq.)以及N-Boc-乙二胺(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物7a至化合物7g。
接着,将所述化合物7a至化合物7g溶解到DCM(1mL)之后,在0℃下搅拌的同时,缓慢加入TFA:DCM=1:3混合溶液(4mL),并搅拌1小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NaHCO3水溶液和乙酸乙酯进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将收获的有机物溶解到DCM(10mL)和TEA(2eq.)之后,添加2-甲氧基烟酰氯(2eq.),在常温下反应2小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物8a至化合物8g。
最后,将所述化合物8a至化合物8g各自添加到溶解mCPBA(2eq.)的DCM溶液(2mL)之后,利用微波反应器在100℃下反应0.2小时。利用NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物9a至化合物9g。
实施例3:化合物的合成3
试剂以及反应条件:
(a)4-吗啉代苯胺、DIPEA、EtOH、160℃、3h、m.w.;
(b)R4-Br、K2CO3、TBAF、ACN、70℃、12h;
(c)NH4OH(20%aq.)、n-BuOH、m.w.、160℃、6h;
(d)N-Boc-哌嗪、TEA、THF、m.w.、160℃、3h;
(e)20% TFA in DCM、0℃、1h;
(f)2-甲氧基烟酰氯、TEA、THF、r.t.、1h;
(e)mCPBA、DCM、100℃、0.2h、m.w.
将化合物1混合到溶解4-吗啉代苯胺(2eq.)和DIPEA(2eq.)的EtOH溶液(2mL)之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物2。
接着,将所述化合物2溶解到ACN(10mL)中,并与K2CO3(2eq.)、TBAF(0.05eq.)以及与各自的R4-基团相应的R4-Br(2eq.)一起溶解之后,在70℃下反应12小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物10a以及化合物10b。
接着,将所述化合物10a以及化合物10b各自与NH4OH(20%aq.):n-BuOH=1:1混合溶液(1mL)一起混合之后,利用微波反应器在160℃下反应6小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NH4Cl水溶液和乙酸乙酯进行后处理(work-up)。提取有机层之后,利用Na2SO4进行干燥并浓缩,然后利用硅胶闪蒸塔色谱法提纯,从而收获化合物11a以及化合物11b。
与此分开地,将所述化合物2溶解到THF(2mL)中,并与TEA(2eq.)以及N-Boc-哌嗪(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物12。
接着,将所述化合物12溶解到DCM(1mL)之后,在0℃下搅拌的同时,缓慢加入TFA:DCM=1:3混合溶液(4mL),并搅拌1小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NaHCO3水溶液和乙酸乙酯进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将收获的有机物溶解到DCM(10mL)和TEA(2eq.)之后,添加2-甲氧基烟酰氯(2eq.),在常温下反应2小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物13。
最后,将所述化合物13添加到溶解mCPBA(2eq.)的DCM溶液(2mL)之后,利用微波反应器在100℃下反应0.2小时。利用NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物14。
实施例4:化合物的合成4
试剂以及反应条件:
(a)R3-苯胺、DIPEA、EtOH、m.w.、160℃、3h;
(b)R3-苯胺、CuI(I)、H2O、160℃、m.w.、1.5h;
(e)mCPBA、MeOH、r.t.、0.5h
将化合物1混合到溶解有与各自的R3-基团相应的R3-苯胺(2eq.)和DIPEA(2eq.)的EtOH溶液(2mL)之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物15a以及化合物15b。
与此分开地,将化合物1与水(1mL)、CuI(I)(0.05eq.)以及与各自的R3-基团相应的R3-苯胺(2eq.)混合之后,利用微波反应器在160℃下反应1.5小时。确认到反应结束之后,利用饱和NH4Cl水溶液和乙酸乙酯进行后处理(work-up)。提取有机层之后,利用Na2SO4进行干燥并浓缩,然后利用硅胶闪蒸塔色谱法提纯,从而收获化合物17a至化合物17c。
最后,将所述化合物15a以及化合物15b、化合物17a至化合物17c添加到各自溶解有mCPBA(2eq.)的DCM溶液(2mL)之后,利用微波反应器在100℃下反应0.2小时。利用NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物16a以及化合物16b、化合物18a至化合物18c。
实施例5:化合物的合成5
试剂以及反应条件:
(a)R3-苯胺、TEA、THF、r.t.、1h;
(d)N-Boc-哌嗪、TEA、THF、160℃、m.w.、3h;
将4,6-二氯-2-(甲磺酰基)嘧啶(化合物20)混合到溶解有与各自的R3-基团相应的R3-苯胺(2eq.)和TEA(2eq.)的THF溶液(2mL)之后,在常温下反应1小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物21a至化合物21i。
接着,将所述化合物21a至化合物21i溶解到THF(2mL)中,并与TEA(2eq.)以及N-Boc-乙二胺(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物22a至化合物22i。
实施例6:化合物的合成6
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试剂以及反应条件:
(a)R3-苯胺、DIPEA、EtOH、m.w.、160℃、3h;
(b)N-Boc-哌嗪、TEA、THF、m.w.、160℃、3h;
(c)4-氨基-1-Boc-哌啶、TEA、THF、m.w.、160℃、3h;
(d)4-(N-Boc-氨基)哌啶、TEA、THF、m.w.、160℃、3h;
(e)mCPBA、DMF、r.t.、2h
(c)20%TFA in DCM、0℃、1h;
将化合物1混合到溶解有与各自的R3-基团相应的R3-苯胺(2eq.)和DIPEA(2eq.)的EtOH溶液(2mL)之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物6b、化合物15b、化合物23a以及化合物23b。
接着,将所述化合物6b、化合物15b、化合物23a以及化合物23b各自溶解到THF(2mL)中,并与TEA(2eq.)以及N-Boc-哌嗪(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物24a至化合物24d。
另外,除了将所述化合物15b、化合物23a以及化合物23b与4-氨基-1-Boc-哌啶(2eq.)进行反应来代替与N-Boc-哌嗪的反应之外,通过与上面类似的方法进行反应,从而收获化合物24e至化合物24g。
进一步地,除了将所述化合物15b、化合物23a以及化合物23b与4-(N-Boc-氨基)哌啶(2eq.)进行反应来代替与N-Boc-哌嗪的反应之外,通过与上面类似的方法进行反应,从而收获化合物24h至化合物24j。
接着,将所述化合物24a至化合物24j各自添加到溶解有mCPBA(2eq.)的DCF溶液(2mL)之后,在常温下反应2小时。利用真空泵去除有机溶剂,并利用饱和NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物25a至化合物25j。
最后,将所述化合物25a至化合物25j各自溶解到DCM溶液(1mL)之后,在0℃下搅拌的同时,缓慢加入TFA:DCM=1:3混合溶液(4mL),并搅拌1小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NaHCO3水溶液和乙酸乙酯进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物26a至化合物26j。
实施例7:化合物的合成7
试剂以及反应条件:
(a)3-氯-4-氟苯胺(R3-苯胺)、DIPEA、EtOH、m.w.、160℃、3h;
(b)(1R,4R)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯、TEA、THF、m.w.、160℃、3h;
(c)叔丁基2,6-二氮杂螺[3.3]庚烷-2-羧酸酯、TEA、THF、m.w.、160℃、3h;
(d)(1s,4s)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯、TEA、THF、m.w.、160℃、3h;
(e)exo-6-(boc-氨基)-3-氮杂二环[3.1.0]己烷、TEA、THF、m.w.、160℃、3h;
(f)mCPBA、DCM、r.t.、2h;
(e)20% TFA in DCM、0℃、1h
将化合物1混合到溶解有3-氯-4-氟苯胺(R3-苯胺)(2eq.)和DIPEA(2eq.)的EtOH溶液(2mL)之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物23a。
接着,将所述化合物23a溶解到THF(2mL)中,并与TEA(2eq.)以及(1R,4R)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯(2eq.)一起混合之后,利用微波反应器在160℃下反应3小时。确认到反应结束之后,将全部溶液进行浓缩,并利用硅胶闪蒸塔色谱法提纯,从而收获化合物4925-1。
另外,除了将所述化合物23a与叔丁基2,6-二氮杂螺[3.3]庚烷-2-羧酸酯(2eq.)进行反应来代替与(1R,4R)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯的反应之外,通过与上面类似的方法进行反应,从而收获化合物4941-1。
另外,除了将所述化合物23a与(1s,4s)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯(2eq.)进行反应来代替与(1R,4R)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯的反应之外,通过与上面类似的方法进行反应,从而收获化合物4942-1。
进一步地,除了将所述化合物23a与exo-6-(boc-氨基)-3-氮杂二环[3.1.0]己烷(2eq.)进行反应来代替与(1R,4R)-叔丁基2,5-二氮杂二环[2.2.1]庚烷-2-羧酸酯的反应之外,通过与上面类似的方法进行反应,从而收获化合物4943-1。
接着,将所述化合物4925-1、化合物4941-1、化合物4942-1以及化合物4943-1各自添加到溶解有mCPBA(2eq.)的DCF溶液(2mL)之后,在常温下反应2小时。利用真空泵去除有机溶剂,并利用饱和NaHCO3水溶液和DCM进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物4925-2、化合物4941-2、化合物4942-2以及化合物4943-2。
最后,将所述化合物4925-2、化合物4941-2、化合物4942-2以及化合物4943-2各自溶解到DCM溶液(1mL)之后,在0℃下搅拌的同时,缓慢加入TFA:DCM=1:3混合溶液(4mL),并搅拌1小时。确认到反应结束之后,将全部溶液进行浓缩,然后利用饱和NaHCO3水溶液和乙酸乙酯进行后处理(work-up),提取有机层之后,利用Na2SO4进行干燥并浓缩。将浓缩的有机物利用硅胶闪蒸塔色谱法提纯,从而收获化合物4925、化合物4941、化合物4942以及化合物4943。
实施例8:新型化合物的鉴别
利用1H NMR以及质量分析仪鉴别根据所述实施例1至7合成的一系列的化合物,以下与化合物名称一起示出该结果。以下化合物的序号与在所述反应式内表示的序号相一致。
化合物4a:2-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-3139)
1H NMR(CDCl3,400MHz):δ7.53(d,J=8.2Hz,1H),7.41(d,J=1.8Hz,1H),7.30(dd,J=8.4,2.0Hz,2H),7.15(d,J=8.5Hz,2H),6.93(d,J=8.9Hz,2H),6.68(s,1H),5.52(s,1H),3.86-3.91(m,5H),3.63-3.68(m,2H),3.58(br.s.,2H),3.16-3.20(m,4H),2.82ppm(s,3H);
MS(ESI):[M+H]+=495.99.
化合物4b:5-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-3345)
1H NMR(CDCl3,400MHz):δ8.55(d,J=1.5Hz,1H),8.42(d,J=3.1Hz,1H),7.61(dd,J=2.7,1.8Hz,1H),7.12-7.17(m,J=8.9Hz,2H),6.88-6.92(m,J=8.9Hz,2H),6.34(s,1H),5.30(s,1H),4.88(br.s.,1H),3.90(s,3H),3.86-3.89(m,4H),3.63(br.s.,5H),3.14-3.17(m,4H),2.48ppm(s,3H);
MS(ESI):[M+H]+=495.92.
化合物4c:4-氟-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(LDD-3157)
1H NMR(CDCl3,400MHz):δ8.13(dd,J=8.8,5.3Hz,1H),7.83(dd,J=8.8,5.3Hz,1H),7.10-7.(m,3H),7.07(t,J=8.6Hz,1H),5.28(d,J=3.8Hz,1H),2.50-2.53ppm(m,3H);
MS(ESI):[M+H]+=482.97.
化合物4d:2,4-二氯-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(LDD-3155)
1H NMR(CDCl3,400MHz):δ7.48(d,J=8.2Hz,1H),7.39(d,J=2.1Hz,1H),7.28(d,J=2.1Hz,1H),7.14(d,J=8.9Hz,3H),6.90(d,J=8.9Hz,2H),6.47(s,1H),5.29(s,1H),3.84-3.89(m,5H),3.59-3.64(m,2H),3.56(br.s.,2H),3.12-3.17ppm(m,5H);
MS(ESI):[M-H]-=532.64.
化合物5a:2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-3140)
1H NMR(CDCl3,400MHz:δ8.47(dd,J=7.6,2.3Hz,1H),8.29(dd,J=4.8,2.1Hz,1H),8.18(t,J=6.3Hz,1H),7.11-7.17(m,J=8.4Hz,2H),7.06(dd,J=7.4,4.8Hz,1H),6.89-6.94(m,J=8.0Hz,2H),6.74(br.s.,1H),5.60(t,J=4.2Hz,1H),5.55(s,1H),4.07(s,3H),3.86-3.91(m,4H),3.67(q,J=5.8Hz,2H),3.51(br.s.,2H),3.17(br.s.,4H),2.87ppm(s,3H);
MS(ESI):[M+H]+=512.04.
化合物5b:5-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-3366)
1H NMR(CDCl3,400MHz):δ8.77(s,1H),8.36(d,J=2.7Hz,1H),7.82(br.s.,1H),7.69-7.71(m,1H),7.11-7.15(m,2H),6.89-6.92(m,J=8.9Hz,2H),5.51(s,1H),3.87-3.90(m,7H),3.63-3.71(m,2H),3.53(br.s.,2H),3.14-3.19(m,4H),2.86ppm(s,3H);
MS(ESI):[M+H]+=512.13.
化合物5c:4-氟-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(LDD-3160)
1H NMR(CDCl3,400MHz):δ8.77(s,1H),8.36(d,J=2.7Hz,1H),7.82(br.s.,1H),7.69-7.71(m,1H),7.11-7.15(m,2H),6.89-6.92(m,J=8.9Hz,2H),5.51(s,1H),3.87-3.90(m,7H),3.63-3.71(m,2H),3.53(br.s.,2H),3.14-3.19(m,4H),2.86ppm(s,3H);
MS(ESI):[M+H]+=512.13.
化合物5d:2,4-二氯-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺(LDD-3156)
1H NMR(CDCl3,400MHz):δ7.53(d,J=8.2Hz,1H),7.41(d,J=1.8Hz,1H),7.30(dd,J=8.4,2.0Hz,2H),7.15(d,J=8.5Hz,2H),6.93(d,J=8.9Hz,2H),6.68(s,1H),5.52(s,1H),3.86-3.91(m,5H),3.63-3.68(m,2H),3.58(br.s.,2H),3.16-3.20(m,4H),2.82ppm(s,3H);
MS(ESI):[M+H]+=548.19.
化合物8a:2-甲氧基-N-(2-(2-(甲硫基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-3343)
1H NMR(CDCl3,400MHz):δ8.48(dd,J=7.6,2.1Hz,1H),8.27(dd,J=4.9,2.1Hz,1H),8.15(t,J=6.0Hz,1H),7.31-7.37(m,2H),7.22-7.26(m,2H),7.09-7.14(m,1H),7.05(dd,J=7.6,4.9Hz,1H),6.47(s,1H),5.55(s,1H),5.13(t,J=5.3Hz,1H),4.05(s,3H),3.64-3.71(m,2H),3.53-3.62ppm(m,2H);
[M-H]-=408.95.
化合物8b:N-(2-(6-(4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3346)
1H NMR(CDCl3,400MHz):δ8.44-8.51(m,1H),8.25-8.30(m,1H),8.15(t,J=4.7Hz,1H),7.18-7.25(m,2H),6.99-7.10(m,3H),6.36(s,1H),5.39(s,1H),5.13(t,J=5.6Hz,1H),4.05(s,3H),3.67(q,J=5.9Hz,2H),3.50-3.61(m,2H),2.49ppm(s,3H);
[M-H]-=226.73.
化合物8c:N-(2-(6-(4-氯苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3380)
1H NMR(CDCl3,400MHz):δ8.48(ddd,J=7.6,2.1,0.8Hz,1H),8.28(dq,J=4.8,0.8Hz,1H),7.29(d,J=8.5Hz,2H),7.22(d,J=8.9Hz,2H),6.44(s,1H),5.50(s,1H),5.20(t,J=5.6Hz,1H),4.05(s,3H),3.63-3.71(m,2H),3.52-3.61(m,2H),2.49ppm(s,3H);
[M+H]+=445.15.
化合物8d:N-(2-(6-(4-溴苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3381)
1H NMR(CDCl3,400MHz):δ8.46-8.52(m,1H),8.26-8.31(m,1H),8.16(t,J=5.2Hz,1H),7.40-7.47(m,2H),7.14-7.21(m,2H),6.45(s,1H),5.51(s,1H),5.22(t,J=5.5Hz,1H),4.05(s,3H),3.67(q,J=5.9Hz,2H),3.52-3.62(m,2H),2.49ppm(s,3H);
[M+H]+=491.90.
化合物8e:N-(2-(6-(4-碘苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3382)
1H NMR(CDCl3,400MHz):δ8.45-8.51(m,1H),8.27(dt,J=4.9,1.2Hz,1H),8.16(t,J=5.6Hz,1H),7.57-7.65(m,2H),7.02-7.11(m,3H),6.45(s,1H),5.53(s,1H),5.22(t,J=5.5Hz,1H),4.05(s,3H),3.67(q,J=5.9Hz,2H),3.52-3.62(m,2H),2.49ppm(s,3H);
[M+H]+=537.17.
化合物8f:N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3399)
1H NMR(CDCl3,400MHz):δ8.48(dd,J=7.5,2.0Hz,1H),8.28(dd,J=4.9,2.1Hz,1H),8.14-8.21(m,1H),7.28-7.33(m,1H),7.05-7.14(m,2H),6.90-6.96(m,1H),6.43(s,1H),5.47(s,1H),5.24(t,J=5.5Hz,1H),4.06(s,3H),3.67(q,J=6.2Hz,2H),3.53-3.61(m,2H),2.50ppm(s,3H);
[M+H]+=447.24.
化合物8g:N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3401)
1H NMR(CDCl3,400MHz):δ8.48(dd,J=7.5,2.0Hz,1H),8.28(dd,J=4.1,2.0Hz,1H),8.17(t,J=5.3Hz,1H),7.78(dd,J=9.2,5.5Hz,1H),7.17(dd,J=8.2,2.7Hz,1H),7.06(dd,J=7.3,4.9Hz,1H),6.99(td,J=8.5,2.7Hz,1H),6.52(s,1H),5.40(s,1H),5.24-5.32(m,1H),4.06(s,3H),3.68(q,J=5.7Hz,2H),3.54-3.64(m,2H),2.49ppm(s,3H);
[M+H]+=463.22.
化合物9a:2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺(LDD-4098)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=2.06,7.56Hz,1H),8.29(dd,J=2.06,5.04Hz,1H),8.19(t,J=5.95Hz,1H),7.36-7.41(m,2H),7.24(d,J=8.01Hz,3H),7.16-7.21(m,1H),7.07(dd,J=4.81,7.56Hz,1H),6.87(s,1H),5.77(s,1H),5.66(t,J=4.81Hz,1H),4.08(s,3H),3.65-3.71(m,3H),3.56(br.s.,2H),2.89(s,3H);
[M+H]+=426.98.
化合物9b:N-(2-(6-(4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-4099)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=2.06,7.56Hz,1H),8.29(dd,J=2.06,4.81Hz,1H),8.19(t,J=5.04Hz,1H),7.19-7.24(m,2H),7.05-7.10(m,3H),6.80(s,1H),5.69(t,J=5.50Hz,1H),5.62(s,1H),4.08(s,3H),3.67(q,J=6.03Hz,2H),3.54(br.s.,2H),2.88(s,3H);
[M+H]+=444.98.
化合物9c:N-(2-(6-(4-氯苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-4100)
1H NMR(CDCl3,400MHz):δ8.45(dd,J=2.06,7.56Hz,1H),8.27(dd,J=2.06,4.81Hz,1H),8.18(t,J=5.72Hz,1H),7.29-7.33(m,2H),7.16-7.21(m,J=8.70Hz,2H),7.05(dd,J=4.81,7.56Hz,1H),6.88(br.s.,1H),5.72-5.77(m,2H),4.06(s,3H),3.63-3.69(m,2H),3.54(br.s.,2H),2.86(s,3H);
[M+H]+=460.94.
化合物9d:N-(2-(6-(4-溴苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-4101)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=1.83,7.56Hz,1H),8.29(dd,J=1.95,4.92Hz,1H),8.21(t,J=6.07Hz,1H),7.46-7.50(m,3H),7.16(d,J=8.70Hz,3H),7.08(dd,J=4.81,7.56Hz,1H),6.89(br.s.,1H),5.77(s,2H),4.08(s,4H),3.65-3.71(m,3H),3.56(br.s.,2H),2.88(s,3H);
[M+H]+=506.79.
化合物9e:N-(2-(6-(4-碘苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3414)
1H NMR(CDCl3,400MHz):δ8.48(dd,J=2.14,7.63Hz,1H),8.29(dd,J=2.14,4.88Hz,1H),8.20(t,J=5.49Hz,1H),7.64-7.70(m,2H),7.08(dd,J=4.73,7.48Hz,1H),7.02-7.06(m,J=8.55Hz,2H),6.82(s,1H),5.73-5.81(m,2H),4.08(s,3H),3.69(q,J=6.10Hz,2H),3.57(br.s.,2H),2.88(s,3H);
[M+H]+=533.09.
化合物9f:N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3416)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=7.5,2.0Hz,1H),8.29(dd,J=4.7,2.0Hz,1H),8.22(t,J=6.0Hz,1H),7.11-7.19(m,1H),7.08(dd,J=7.6,4.9Hz,1H),6.94-7.01(m,1H),5.84(t,J=5.2Hz,1H),5.74(s,1H),4.09(s,2H),3.64-3.71(m,2H),3.56(br.s.,1H),2.88ppm(s,2H);
[M+H]+=463.22.
化合物9g:N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3417)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=7.5,2.0Hz,1H),8.30(dd,J=4.7,2.0Hz,1H),8.20-8.28(m,1H),7.14-7.22(m,1H),7.09(dd,J=7.8,4.7Hz,1H),6.95-7.01(m,1H),5.79(br.s.,1H),5.35ppm(s,1H);
[M+H]+=479.16.
化合物9h:N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3418)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=7.3,1.8Hz,1H),8.29(dd,J=4.9,2.1Hz,1H),8.17-8.26(m,1H),7.61-7.69(m,1H),7.21(dd,J=7.9,2.7Hz,1H),7.02-7.10(m,2H),6.77(s,1H),5.78(t,J=4.3Hz,1H),5.61(s,1H),4.08(s,3H),3.66-3.72(m,2H),3.54-3.61(m,2H),2.89ppm(s,3H);
[M+H]+=479.15.
化合物9i:N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺(LDD-3419)
1H NMR(CDCl3,400MHz):δ8.47(dd,J=7.5,2.0Hz,1H),8.30(dd,J=4.9,1.8Hz,1H),8.22(br.s.,1H),7.62(td,J=7.6,2.6Hz,1H),7.22(dd,J=7.9,3.1Hz,1H),7.02-7.10(m,3H),6.73(br.s.,1H),5.90(br.s.,1H),5.68(br.s.,1H),5.36(s,1H),4.10(s,3H),3.67-3.72(m,2H),3.60(br.s.,2H),3.25ppm(s,3H);
[M+H]+=495.17.
化合物10a:6-氯-N-(4-氟苄基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺(LDD-3303)
1H NMR(CDCl3,400MHz):δ7.17-7.24(m,2H),6.88-7.00(m,6H),5.80(s,1H),5.11(s,2H),3.85-3.92(m,4H),3.17-3.24(m,4H),2.51ppm(s,3H);
[M+H]+=444.99.
化合物10b:6-氯-N-(4-氟苯乙基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺(LDD-3316)
1H NMR(CDCl3,400MHz):δ7.10-7.17(m,2H),6.93-7.02(m,6H),5.77(s,1H),4.05-4.12(m,2H),3.86-3.94(m,4H),3.20-3.26(m,4H),2.91-2.98(m,2H),2.58ppm(s,3H);
[M+H]+=458.91.
化合物11a:N4-(4-氟苄基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺(LDD-3304)
1H NMR(CDCl3,400MHz):δ7.22(dd,J=8.5,5.5Hz,2H),6.91-6.98(m,4H),6.85-6.89(m,2H),5.11(s,2H),4.91(s,1H),4.32(s,2H),3.83-3.90(m,4H),3.14-3.20(m,4H),2.47ppm(s,3H);
[M+H]+=426.01.
化合物11b:N4-(4-氟苯乙基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺(LDD-3319)
1H NMR(CDCl3,400MHz):δ7.11-7.16(m,2H),6.91-7.05(m,6H),4.87(s,1H),4.33(s,2H),4.03-4.11(m,2H),3.85-3.92(m,4H),3.18-3.24(m,3H),2.90-2.98(m,2H),2.57ppm(s,3H);
[M+H]+=439.98.
化合物13:(2-甲氧基吡啶基-3-基)(4-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮(LDD-3368)
1H NMR(CDCl3,400MHz):δ8.23(dd,J=5.0,2.0Hz,1H),7.61(dd,J=7.2,2.0Hz,1H),7.13-7.21(m,J=8.2Hz,2H),6.96(dd,J=7.2,5.0Hz,1H),6.88-6.94(m,J=8.5Hz,2H),6.44(br.s.,1H),5.44(s,1H),3.97(s,3H),3.76-3.91(m,6H),3.55-3.64(m,4H),3.23-3.40(m,2H),3.16(br.s.,4H),2.49ppm(s,3H);
[M+H]+=522.13.
化合物14:(2-甲氧基吡啶基-3-基)(4-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮(LDD-3369)
1H NMR(CDCl3,400MHz):δ8.21-8.26(m,1H),7.62(dd,J=6.9,2.6Hz,1H),7.13-7.21(m,2H),6.91-7.00(m,3H),6.79(s,1H),5.62(s,1H),3.97(s,3H),3.80-3.93(m,6H),3.61(br.s.,5H),3.32(br.s.,2H),3.15-3.23(m,4H),2.88ppm(s,3H);
[M+H]+=538.20.
化合物16a:6-氯-N-(2,4-氯氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(LDD-3379)
1H NMR(CDCl3,400MHz):δ7.64(br.s.,1H),7.13(br.s.,1H),6.98-7.04(m,2H),6.62(s,1H),3.33ppm(s,3H);
[M+H]+=320.22.
化合物16b:6-氯-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(LDD-3582)
1H NMR(CDCl3,400MHz):δ7.11(dd,J=7.7,6.5Hz,2H),6.77(s,1H),3.34ppm(s,3H);
[M+H]+=426.01;
[M-H]-=335.81.
化合物18a:N4,N6-双(4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺(LDD-3365)
1H NMR(CDCl3,400MHz):δ7.17-7.23(m,4H),7.04-7.11(m,4H),6.80(s,2H),5.85(s,1H),3.27ppm(s,3H);
[M+H]+=376.88.
化合物18b:2-(甲磺酰基)-N4,N6-双(3,4,5-三氟苯基)嘧啶基-4,6-二胺(LDD-3580)
1H NMR(CDCl3,400MHz):δ7.03(dd,J=8.7,6.0Hz,4H),6.88(s,2H),6.02(s,1H),3.29ppm(s,3H);
[M+H]+=448.83.
化合物18c:N4,N6-双(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺(LDD-3581)
1H NMR(CDCl3,400MHz):δ7.39(dd,J=6.9,2.1Hz,2H),7.14-7.20(m,4H),6.81(s,2H),5.91(s,1H),3.28ppm(s,3H);
[M+H]+=444.75.
化合物22a:叔丁基4-(6-(4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3403)
1H NMR(CDCl3,400MHz):δ7.22-7.26(m,2H),7.09-7.15(m,2H),6.79(s,1H),5.68(s,1H),3.48-3.60(m,8H),3.26(s,3H),1.47ppm(s,9H);
[M-H]-=450.27.
化合物22b:叔丁基4-(6-(4-氟苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3409)
1H NMR(CDCl3,400MHz):δ7.28-7.31(m,2H),7.05(t,J=8.7Hz,2H),5.37(s,1H),4.46(d,J=5.8Hz,2H),3.57(br.s.,4H),3.51(d,J=5.8Hz,4H),3.22(s,3H),1.48ppm(s,9H);
[M-H]-=464.13.
化合物22c:叔丁基4-(6-(4-氯苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3447)
1H NMR(CDCl3,400MHz):δ7.36-7.39(m,2H),7.21-7.24(m,2H),6.80(s,1H),5.79(s,1H),3.59(br.s.,4H),3.50-3.54(m,4H),3.26(s,3H),1.48ppm(s,9H);
[M-H]-=466.10.
化合物22d:叔丁基4-(6-(4-氯苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3477)
1H NMR(CDCl3,400MHz):δ7.32-7.35(m,2H),7.24-7.27(m,2H),5.44(br.s.,1H),5.36(s,1H),4.47(d,J=5.5Hz,2H),3.57(br.s.,4H),3.48-3.53(m,4H),3.21(s,3H),1.48ppm(s,9H);
[M-H]-=480.00.
化合物22e:叔丁基4-(6-(4-溴苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3448)
1H NMR(CDCl3,400MHz):δ7.48-7.52(m,2H),7.16-7.20(m,2H),6.91(s,1H),5.81(s,1H),3.58(br.s.,4H),3.49-3.54(m,4H),3.25(s,3H),1.48ppm(s,9H);
[M-H]-=511.95.
化合物22f:叔丁基4-(6-(4-碘苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3449)
1H NMR(CDCl3,400MHz):δ7.68-7.71(m,2H),7.04-7.08(m,2H),6.86(s,1H),5.83(s,1H),3.59(br.s.,4H),3.50-3.54(m,4H),3.25(s,3H),1.48ppm(s,9H);
[M-H]-=557.97.
化合物22g:叔丁基4-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3451)
1H NMR(CDCl3,400MHz):δ7.16-7.22(m,2H),6.98-7.03(m,1H),6.75(s,1H),5.74(s,1H),3.60(br.s.,4H),3.51-3.55(m,4H),3.26(s,3H),1.48ppm(s,9H);
[M-H]-=468.11.
化合物22h:叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苯基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3505)
1H NMR(CDCl3,400MHz):δ6.99-7.05(m,2H),6.77(s,1H),5.80(s,1H),3.63(br.s.,4H),3.52-3.57(m,4H),3.27(s,3H),1.49ppm(s,9H);
[M-H]-=485.99.
化合物22i:叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苄基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯(LDD-3450)
1H NMR(CDCl3,400MHz):δ6.93-6.98(m,2H),5.40(br.s.,1H),5.36(s,1H),4.48(d,J=5.7Hz,2H),3.57(br.s.,4H),3.49-3.54(m,4H),3.21(s,3H),1.48ppm(s,9H);
[M-H]-=500.10.
化合物26a:N-(4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(LDD-3404)
1H NMR(CDCl3,400MHz):δ7.20-7.24(m,2H),7.07-7.13(m,2H),6.73-6.79(m,1H),5.67(s,1H),3.54(br.s.,4H),3.24(s,3H),2.90-2.94ppm(m,4H);
[M+H]+=352.03.
化合物26b:2-(甲磺酰基)-6-(哌嗪基-1-基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(LDD-3629)
1H NMR(DMSO-d6,400MHz):δ10.10(s,1H),7.54(d,J=6.2Hz,1H),7.56(d,J=6.4Hz,1H),6.13(s,1H),3.70(br.s.,4H),3.31(s,3H),3.09ppm(br.s.,4H);
[M+H]+=387.87.
化合物26c:N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(LDD-3666)
1H NMR(DMSO-d6,400MHz):δ9.80(s,1H),7.89(dd,J=6.8,2.6Hz,1H),7.46(ddd,J=9.0,4.3,2.7Hz,1H),7.36(t,J=9.0Hz,1H),5.99(s,1H),3.44-3.51(m,4H),3.27(s,3H),2.73-2.78ppm(m,4H);
[M-H]-=383.88.
化合物26d:N-(3-溴-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺(LDD-3682)
1H NMR(DMSO-d6,400MHz):δ9.70(s,1H),8.00(dd,J=6.4,2.8Hz,1H),7.49(ddd,J=8.9,4.4,2.8Hz,1H),7.33(t,J=8.7Hz,1H),5.95(s,1H),3.45-3.49(m,4H),3.27(s,3H),2.74-2.77ppm(m,4H);
[M+H]+=431.86.
化合物26e:2-(甲磺酰基)-N4-(哌啶基-4-基)-N6-(3,4,5-三氟苯基)嘧啶基-4,6-二胺(LDD-3644)
1H NMR(DMSO-d6,400MHz):δ9.87(br.s.,1H),7.84(br.s.,1H),7.46-7.54(m,2H),5.93(br.s.,1H),4.08(br.s.,2H),3.29(s,3H),2.97-3.06(m,2H),2.04(d,J=12.8Hz,2H),1.55-1.67ppm(m,2H);
[M+H]+=401.90.
化合物26f:N4-(3-氯-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺(LDD-3678)
1H NMR(DMSO-d6,400MHz):δ9.58(br.s.,1H),7.83(br.s.,1H),7.59(br.s.,1H),7.34-7.42(m,2H),5.84(br.s.,1H),3.31(br.s.,3H),2.94(d,J=12.6Hz,2H),1.81(d,J=9.6Hz,2H),1.25-1.35ppm(m,2H);
[M+H]+=399.81.
化合物26g:N4-(3-溴-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺(LDD-3683)
1H NMR(DMSO-d6,400MHz):δ9.56(br.s.,1H),7.93(br.s.,1H),7.54-7.63(m,1H),7.42-7.48(m,1H),7.33(t,J=8.8Hz,1H),5.83(br.s.,1H),3.81(br.s.,1H),3.24(s,3H),2.94(d,J=12.4Hz,2H),1.81(d,J=11.2Hz,2H),1.29ppm(d,J=8.9Hz,2H);
[M+H]+=445.86.
化合物26h:6-(4-氨基哌啶-1-基)-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺(LDD-3705)
1H NMR(DMSO-d6,400MHz):δ9.98(s,1H),7.51-7.56(m,2H),6.05(s,1H),3.61(br.s.,4H),3.29(s,3H),2.94ppm(br.s.,4H);
[M-H]-=399.96.
化合物26i:6-(4-氨基哌啶-1-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(LDD-3677)
1H NMR(DMSO-d6,400MHz):δ9.70(br.s.,1H),7.89(dd,J=6.8,2.6Hz,1H),7.42-7.47(m,1H),7.36(t,J=9.0Hz,1H),6.00(s,1H),4.10(br.s.,2H),3.27(s,3H),3.04(ddd,J=13.5,11.2,2.7Hz,2H),2.80-2.89(m,1H),1.78(dd,J=12.6,3.0Hz,2H),1.13-1.24ppm(m,2H);
[M+H]+=399.80.
化合物26j:6-(4-氨基哌啶-1-基)-N-(3-溴-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(LDD-3684)
1H NMR(DMSO-d6,400MHz):δ9.67(br.s.,1H),8.00(dd,J=6.3,2.6Hz,1H),7.48(ddd,J=9.0,4.2,2.6Hz,1H),7.30-7.36(m,1H),5.99(s,1H),4.10(br.s.,2H),3.27(s,3H),2.99-3.09(m,2H),2.82-2.91(m,1H),1.78(d,J=15.4Hz,2H),1.14-1.26ppm(m,2H);
[M-H]-=443.82.
化合物4925:6-((1R,4R)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(LDD-4925)
1H NMR(DMSO-d6,400MHz):δ1.64-1.83(m,2H)2.72-2.79(m,1H)2.90(d,J=8.24Hz,1H)3.03-3.12(m,1H)3.27(s,3H)3.45(m,1H)3.63-3.74(m,1H)4.30-4.40(br.s.,0.25H)4.85-4.94(br.s.,0.5H)5.54-5.65(br.s.,0.5H)5.80-5.90(br.s.,0.25H)7.36(t,J=9.04Hz,1H)7.44(ddd,J=9.04,4.24,2.52Hz,1H)7.89(dd,J=6.75,2.63Hz,1H)9.66-9.72(m,1H);
室温下的化合物的1H NMR光谱显示出一些信号加倍,这表明在DMSO-d6中的2个旋转构象异构体的比率约为1:1
[M+H]+=398.5.
化合物4941:N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶基-4-胺(LDD-4941)
1H NMR(METHANOL-d4,400MHz):δ3.25(s,3H)4.31(s,4H)4.35(s,4H)5.66(s,1H)7.18(t,J=9.04Hz,1H)7.46(ddd,J=9.16,4.12,2.75Hz,1H)7.80(dd,J=6.64,2.52Hz,1H);
[M+H]+=398.5.
化合物4942:6-((1S,4S)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺(LDD-4942)
1H NMR(CHLOROFORM-d,400MHz):δ1.84(br.s.,2H)2.90-3.05(m,1H)3.05-3.16(m,2H)3.26(s,3H)3.39(br.s.,1H)3.88(br.s.,1H)5.11(br.s.,1H)5.41(br.s.,1H)6.79(s,1H)7.14-7.19(m,2H)7.34-7.40(m,1H);
[M+H]+=398.4.
化合物4943:(1R,5S,6s)-3-(6-(3-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)-3-氮杂二环[3.1.0]己烷-6-胺(LDD-4943)
1H NMR(ACETONE-d6,400MHz):δ1.88(br.s.,2H)2.33(q,J=2.14Hz,1H)3.23(s,3H)3.44-3.68(m,2H)3.83(br.s.,2H)5.74(s,1H)7.26(t,J=9.04Hz,1H)7.55(ddd,J=9.16,4.12,2.75Hz,1H)7.92(dd,J=6.64,2.75Hz,1H);
[M+H]+=398.4.
实验例1:HBV核心蛋白的表达以及提纯
Cp149(氨基酸1-149)是HBV核心蛋白的截断型(truncated form)。将其在大肠杆菌(Escherichia coli)中表达,并提纯表达的蛋白质。将重组Cp149在37℃下在LB培养基中进行培养的大肠杆菌BL21(E.coli BL21;DE3)中进行表达。在培养物达到0.7至0.8的OD600时,利用0.5mM的异丙基-β-D-硫代半乳糖吡喃糖苷(isopropyl-β-d-thiogalactopyranoside)诱导表达,并将培养物冷却至16℃。16小时之后,回收所述细胞,在液体氮中急速冷冻(flash-frozen),在-80℃下进行保存。为了提纯Cp149,使解冻(thawed)细胞在裂解缓冲液(lysis buffer;20mM Tris-HCl pH 9.0、200mM NaCl、10mM咪唑啉、10μg/mL DNaseI、1mM苯甲基磺酰氟)中再悬浮,并利用超声波进行处理。将上层液装到Ni-NTA亲和树脂(affinity resin)中,并利用在裂解缓冲液中溶解的20mM至500mM的咪唑啉梯度,洗脱(eluted)蛋白质。利用凝血酶去除组氨酸标签之后,利用HiTrap Q阴离子交换色谱法(17115401,GE Healthcare)进一步提纯蛋白质。
实验例2:体外(in vitro)HBV衣壳组装的免疫印迹分析
为了决定对体外Cp149组装(assembly)的效果,向含Cp149的悬浮液添加本发明的化合物。Cp149的最终浓度为1mg/mL,以0.1至10μM浓度添加本发明的化合物。将所述悬浮液与以2:1比率添加的反应缓冲液(150mM HEPES pH 7.5、15mM NaCl)进行混合。在37℃下进行体外组装1小时,通过利用抗-HBV核心抗体(1:2000、B0586、Dako)的免疫印迹分析,检测HBV衣壳。
实验例3:体外HBV衣壳组装的蔗糖密度梯度分析
将在抑制化合物的存在以及不存在的情况下,通过组装形成的Cp149结构物应用到蔗糖密度梯度分析(sucrose density gradient analysis)中。将试料(150μL)放入溶解到Ph7.5的150mM HEPES中的由800μL的50%(wt/vol,以下同样适用)蔗糖、800μL的40%蔗糖、800μL的30%蔗糖、800μL的20%蔗糖以及650μL的10%蔗糖构成的蔗糖密度梯度上(laid)。在250000×g以及20℃下离心分离1.5小时之后,从上部到底部为止回收10个400μL分馏(fractions),利用15%SDS-PAGE分析各个分馏。利用考马斯亮蓝R-250(CoomassieBrilliant Blue R-250)染色所述凝胶或者将所述凝胶应用到利用抗-HBV核心抗体的免疫印迹分析中。利用ImageJ软件分析个别条带的密度。
实验例4:细胞存活率
在96孔板中以每个孔2×104细胞的密度分株HepG2.2.15细胞。利用表示的化合物进行处理之后,去除培养基,并在37℃下,在EZ-CYTOX溶液(EZ-5000、DoGenBio)中培养细胞1小时。然后,测定在450nm下的吸光度。
实验例5:细胞内HBV衣壳组装的分析
在6孔板中以每个孔5×105细胞的密度分株Huh-7细胞,并利用pCDNA3-Core(genotype C)质粒DNA进行转染(transfected)。12小时之后,将所述细胞与表示的化合物培育36小时。然后,将该细胞在冰块上利用裂解缓冲液(1%NP40)裂解10分钟,在15000×g中进行离心分离,去除细胞碎片(debris)和核。将上层液放到溶解到1×PBS的由1mL的40%(wt/vol,以下同样适用)蔗糖以及1.5mL的20%蔗糖构成的蔗糖梯度上,在400000×g以及20℃下离心分离8小时,从而使HBV衣壳沉淀。使球体在50μL的1×PBS中再悬浮,并进行超声波处理(1s per stroke×3times),从而将试料分离到1%琼脂糖凝胶上。将所述凝胶在10×SSC上利用毛细管转移(capillary transfer)转移至硝酸纤维膜上,并通过利用抗-HBV核心抗体(1:2000、B0586、Dako)的免疫印迹分析,检测HBV核心颗粒。
实验例6:用于测定细胞内HBV DNA的定量(quantitative)PCR
利用表示的化合物处理细胞之后,提取向培养基分泌的HBV DNA以及细胞内HBVDNA,并提纯,然后利用定量PCR进行定量。为了分离分泌的HBV DNA,回收培养基,并在15000×g中进行离心分离,从而去除碎片。利用磷酸盐缓冲生理盐水(phosphate-bufferedsaline;PBS)以1:1稀释所述培养基,并添加1M的NaOH溶液以使最终浓度成为0.1M。将所述混合物在37℃下培育1小时。添加2M的Tris-HCl溶液(pH7.5)至最终浓度为0.2M,并在98℃下进行培育,从而使蛋白质变性。在15000×g中进行离心分离,从而去除所述蛋白质沉淀,并将上层液与HBV DNA引物和探针组一起应用到PCR中:Forward:5'-TCCTCTTCATCCTGCTGCTATG-3',Reverse:5'-CGTGCTGGTAGTTGATGTTCCT-3',Probe:5'-TATTGGTTCTTCTGGACTA-3'。
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本发明所属技术领域的技术人员可以从以上说明中理解到本发明在不改变其技术构思或者必要特定的情况下,可以实施为其他具体形态。针对此,应理解以上叙述的实施例在所有方面属于示例,而不用于限定。应解释为相比所述具体实施方式,从专利权利要求书的含义、范围以及其等价概念导出的所有变更或者变形的形态包含在本发明的范围中。
Claims (16)
1.一种由以下化学式1表示的化合物或者其药学上可接受的盐:
【化学式1】
在所述化学式1中,
m为0、1或者2;
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R2为氢、卤素、氨基、-NH-(CH2)P-NHCO-R5、或者未被取代或者被R6取代的C6-10芳基、C6-10芳氨基、3-10元杂环基或者3-10元杂环氨基;
R5为叔丁基、C6-10芳基或者5-10元杂芳基;
R6为未被取代或者被叔丁基羰基取代的氨基、直接或者通过-CO-连接的叔丁基、C6-10芳基或者5-10元杂芳基;
p为1至4的整数;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
2.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
R1为甲基。
3.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
R2为氢、卤素、氨基、-NH-(CH2)2-NHCO-R5或者未被取代或者被R6取代的苯基氨基、哌嗪基、哌啶基、哌啶氨基、(1R,4R)-2,5-二氮杂二环[2.2.1]庚基、(1S,4S)-2,5-二氮杂二环[2.2.1]庚基、2,6-二氮杂螺[3.3]庚基或者3-氮杂二环[3.1.0]庚基,
R5为叔丁基、苯基或者吡啶基,
R6为未被取代或者被叔丁基羰基取代的氨基、直接或者通过-CO-连接的叔丁基、苯基或者吡啶基。
4.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
R2为氢、氯、氨基、未被取代或者被丁基羰基取代的哌嗪基、哌啶氨基、氨基哌啶基、被选自氟或者氯中的1至3个卤素取代的苯基氨基、(甲氧基吡啶基)羰基哌嗪基、(甲氧基吡啶基)羰基氨基乙基氨基、被选自氟或者氯中的1或者2个卤素取代的苯基羰基氨基乙基氨基、未被取代或者被丁基羰基取代的(1R,4R)-2,5-二氮杂二环[2.2.1]庚基、未被取代或者被丁基羰基取代的(1S,4S)-2,5-二氮杂二环[2.2.1]庚基、未被取代或者被丁基羰基取代的2,6-二氮杂螺[3.3]庚基、或者未被取代或者被丁基羰基或者丁基羰基氨基取代的3-氮杂二环[3.1.0]庚基。
5.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
R3为氢、吗啉基、氰基、甲基、三氟甲基或者选自由氟、氯、溴以及碘构成的组中的1至3个取代基。
6.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
R4为氢、苄基或者苯基乙基。
7.根据权利要求1所述的化合物或者其药学上可接受的盐,其中,
所述化合物为,
1. 2-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
2. 5-甲氧基-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
3. 4-氟-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺、
4. 2,4-二氯-N-(2-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺、
5. 2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
6. 5-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
7. 4-氟-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺、
8. 2,4-二氯-N-(2-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基氨基)乙基)苯甲酰胺、
9. 2-甲氧基-N-(2-(2-(甲硫基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
10. N-(2-(6-(4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
11. N-(2-(6-(4-氯苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
12. N-(2-(6-(4-溴苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
13. N-(2-(6-(4-碘苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
14. N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
15. N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲硫基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
16. 2-甲氧基-N-(2-(2-(甲基亚磺酰基)-6-(苯基氨基)嘧啶基-4-基氨基)乙基)烟酰胺、
17. N-(2-(6-(4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
18. N-(2-(6-(4-氯苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
19. N-(2-(6-(4-溴苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
20. N-(2-(6-(4-碘苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
21. N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
22. N-(2-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
23. N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲基亚磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
24. N-(2-(6-(2-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基氨基)乙基)-2-甲氧基烟酰胺、
25. 6-氯-N-(4-氟苄基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺、
26. 6-氯-N-(4-氟苯乙基)-2-(甲硫基)-N-(4-吗啉代苯基)嘧啶基-4-胺、
27. N4-(4-氟苄基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺、
28. N4-(4-氟苯乙基)-2-(甲硫基)-N4-(4-吗啉代苯基)嘧啶基-4,6-二胺、
29.(2-甲氧基吡啶基-3-基)(4-(2-(甲硫基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮、
30.(2-甲氧基吡啶基-3-基)(4-(2-(甲基亚磺酰基)-6-(4-吗啉代苯基氨基)嘧啶基-4-基)哌嗪基-1-基)甲酮、
31.6-氯-N-(2,4-氯氟苯基)-2-(甲磺酰基)嘧啶基-4-胺、
32.6-氯-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺、
33.N4,N6-双(4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺、
34.2-(甲磺酰基)-N4,N6-双(3,4,5-三氟苯基)嘧啶基-4,6-二胺、
35.N4,N6-双(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4,6-二胺、
36.叔丁基4-(6-(4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
37.叔丁基4-(6-(4-氟苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
38.叔丁基4-(6-(4-氯苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
39.叔丁基4-(6-(4-氯苄基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
40.叔丁基4-(6-(4-溴苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
41.叔丁基4-(6-(4-碘苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
42.叔丁基4-(6-(3,4-氯氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
43.叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苯基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
44.叔丁基4-(2-(甲磺酰基)-6-(3,4,5-三氟苄基氨基)嘧啶基-4-基)哌嗪基-1-羧酸酯、
45.N-(4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺、
46.2-(甲磺酰基)-6-(哌嗪基-1-基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺、
47.N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺、
48.N-(3-溴-4-氟苯基)-2-(甲磺酰基)-6-(哌嗪基-1-基)嘧啶基-4-胺、
49.2-(甲磺酰基)-N4-(哌啶基-4-基)-N6-(3,4,5-三氟苯基)嘧啶基-4,6-二胺、
50.N4-(3-氯-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺、51.N4-(3-溴-4-氟苯基)-2-(甲磺酰基)-N6-(哌啶基-4-基)嘧啶基-4,6-二胺、52.6-(4-氨基哌啶-1-基)-2-(甲磺酰基)-N-(3,4,5-三氟苯基)嘧啶基-4-胺、53.6-(4-氨基哌啶-1-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺、
54.6-(4-氨基哌啶-1-基)-N-(3-溴-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺、
55.6-((1R,4R)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺、
56.N-(3-氯-4-氟苯基)-2-(甲磺酰基)-6-(2,6-二氮杂螺[3.3]庚烷-2-基)嘧啶基-4-胺、
57.6-((1S,4S)-2,5-二氮杂二环[2.2.1]庚烷-2-基)-N-(3-氯-4-氟苯基)-2-(甲磺酰基)嘧啶基-4-胺或者
58.(1R,5S,6s)-3-(6-(3-氯-4-氟苯基氨基)-2-(甲磺酰基)嘧啶基-4-基)-3-氮杂二环[3.1.0]己烷-6-胺。
8.一种制备方法,其作为由以下化学式1表示的化合物或者其药学上可接受的盐的制备方法,所述方法包括:
使由以下化学式2-1表示的化合物与由化学式3表示的胺衍生物发生反应,从而制备由化学式4-1表示的化合物的第1步骤;以及
当R4不是氢时,选择性地,使由化学式4-1表示的化合物与由化学式5表示的卤化盐衍生物发生反应,从而制备由化学式6表示的化合物的第2步骤:
【化学式1】
【化学式2-1】
【化学式3】
【化学式4-1】
【化学式5】
R4-X3
【化学式6】
在所述化学式1、2-1、3、4-1、5以及6中,
X1至X3各自独立为卤素;
X为X1或者
m为0、1或者2;
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R2为氢、卤素、氨基、-NH-(CH2)P-NHCO-R5、或者未被取代或者被R6取代的C6-10芳基、C6-10芳氨基、3-10元杂环基或者3-10元杂环氨基;
R5为叔丁基、C6-10芳基或者5-10元杂芳基;
R6为直接或者通过-CO-连接的叔丁基、C6-10芳基或者5-10元杂芳基;
p为1至4的整数;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
9.根据权利要求8所述的制备方法,其中,
所述方法还包括:
使由化学式6表示的化合物与氢氧化铵发生反应,从而制备由化学式7表示的化合物的第3-1步骤:
【化学式7】
在所述化学式7中,
n为0至4的整数;
Y为C(H)或者N;
R1为C1-4烷基;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢或者C6-10芳基-C1-4烷基;
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
10.根据权利要求8所述的制备方法,其中,
所述方法还包括:
使由化学式6表示的化合物与由化学式8至15中的任一个表示的Boc-保护的二胺衍生物发生反应,从而制备各自由化学式16或者化学式23表示的化合物的第3-2步骤;以及
使由化学式16或者化学式17表示的化合物与由化学式24表示的酰卤衍生物发生反应,从而制备各自由化学式25或者化学式26表示的化合物的第4-1步骤,或者
将由化学式17或者化学式23表示的化合物的烷硫基利用烷基磺酰基进行氧化之后去保护,从而制备由化学式27至化学式33表示的化合物的第4-2步骤:
【化学式8】
NH2-(CH2)p-NH-Boc
【化学式9】
【化学式10】
【化学式11】
【化学式12】
【化学式13】
【化学式14】
【化学式15】
【化学式16】
【化学式17】
【化学式18】
【化学式19】
【化学式20】
【化学式21】
【化学式22】
【化学式23】
【化学式24】
R-COX4
【化学式25】
【化学式26】
【化学式27】
【化学式28】
【化学式29】
【化学式30】
【化学式31】
【化学式32】
【化学式33】
在所述化学式8至化学式33中,n为0至4的整数;
p为1至4的整数;
q为0、1或者2,;
r为1或者2;
R1为C1-4烷基;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢、C6-10芳基-C1-4烷基;
R为C6-10芳基或者5-10元杂芳基
所述芳基、杂芳基以及杂环基是未被取代或者被选自卤素、C1-4烷基、C1-4烷氧基或者氨基中的一种以上取代。
11.根据权利要求8至10中任一项所述的制备方法,其中,
所述方法还包括:
与mCPBA发生反应,从而将烷硫基利用亚磺酰基或者磺酰基进行氧化的第5步骤。
12.一种制备方法,其作为由以下化学式1表示的化合物或者其药学上可接受的盐的制备方法,所述方法包括:
使由以下化学式2-2表示的化合物与由化学式3表示的胺衍生物发生反应,从而制备由化学式4表示的化合物的第1步骤;以及
由化学式4-2表示的化合物与由化学式9表示的Boc-保护的二胺衍生物发生反应,从而制备由化学式34表示的化合物的第2步骤:
【化学式1】
【化学式2-2】
【化学式3】
【化学式4-2】
【化学式9】
【化学式34】
在所述化学式1、2-2、3、4-2、9以及34中,
X1以及X2各自独立为卤素;
m为2;
n为0至4的整数;
R1为C1-4烷基;
R2为
R6为-CO-叔丁基;
q为0、1或者2;
r为1或者2;
R3为氢、3-10元杂环基、氰基、C1-4烷基、C1-4卤烷基或者1至3个卤素;
R4为氢;
所述杂环基是未被取代或者被选自卤素或者氨基中的一种以上取代。
13.一种衣壳组装抑制用组合物,其包括权利要求1至7中任一项所述的化合物或者其药学上可接受的盐。
14.一种抗病毒组合物,其作为有效成分含有权利要求1至7中任一项所述的化合物或者其药学上可接受的盐。
15.一种用于预防或者治疗病毒感染疾病的药学组合物,其作为有效成分含有权利要求1至7中任一项所述的化合物或者其药学上可接受的盐。
16.根据权利要求15所述的药学组合物,其中,
所述病毒感染疾病为由乙型肝炎病毒、丙型肝炎病毒或者人体免疫缺陷病毒引起的感染疾病。
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