CN102558172B - 5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物,其制备方法和用途 - Google Patents
5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物,其制备方法和用途 Download PDFInfo
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- CN102558172B CN102558172B CN201010615647.7A CN201010615647A CN102558172B CN 102558172 B CN102558172 B CN 102558172B CN 201010615647 A CN201010615647 A CN 201010615647A CN 102558172 B CN102558172 B CN 102558172B
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Abstract
本发明公开5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物和它们的制备方法、用途,以及包含此化合物的药物组合物。更具体地,本发明公开了结构式I、II或III表示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物和它们的制备方法,并提供了该化合物及含有该化合物的药物组合物作为多靶点酪氨酸蛋白激酶抑制剂用于肿瘤疾病等与酪氨酸蛋白激酶特别是c-Src有关的疾病的治疗。
Description
技术领域
本发明涉及医药技术领域,具体涉及5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物和它们的制备方法,本发明还涉及5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物及含有该化合物的药物组合物作为多靶点酪氨酸蛋白激酶抑制剂用于乳腺癌、卵巢癌、恶性黑色素瘤、皮肤鳞癌、结肠癌、肺癌、肝癌、胰腺癌、急性髓性白血病、***癌等与酪氨酸激酶特别是c-Src有关的疾病的治疗。
背景技术
恶性肿瘤是一种严重威胁人类健康的常见病和多发病,以细胞或变异细胞异常增殖和向周围组织转移为特点,人类因恶性肿瘤而引起的死亡居于所有疾病死亡率的第二位,仅次于心脑血管疾病。肿瘤的治疗方法有手术治疗、放射治疗和药物治疗(化学治疗)等,但是很大程度上仍以化学治疗为主,尤其是针对肿瘤发生机制中的关键酶设计的靶向性抗肿瘤药物的问世,使得化学治疗能成功地治愈病人或明显地延长病人的寿命。
近年来,酪氨酸蛋白激酶(Proteintyrosinekinase,PTK)作为靶向性抗肿瘤药物的靶标,已引起药物学家广泛的兴趣。酪氨酸蛋白激酶是信号传递过程中的重要因子,参与一系列细胞功能,与细胞生长、分化、增殖密切相关[MicroscResTech.2003Jan1;60(1):70-75],它可以催化ATP的γ磷酸基转移到许多重要蛋白质的酪氨酸残基上,使酚羟基磷酸化。许多癌症基因的表达产物也都具有PTK活性,很多恶性转化细胞中的PTK活性远远高于正常细胞。因此若能抑制PTK活性,就有可能阻断肿瘤细胞的生长。PTK已经成为引人注目的抗肿瘤药物新靶点[CurrDrugTargets.2003,Feb;4(2):113-121]。
靶向PTK的抗肿瘤药在最近十年取得了长足进步,Gleevec、Iressa和Erlotinib先后被美国FDA批准上市,充分证明了受体酪氨酸激酶是一个有效的抗肿瘤药物靶点,而且多靶点酪氨酸激酶抑制(multipletargetedtyrosinekinaseinhibition)也成为非常富有前景的肿瘤治疗新策略[EuropeanJ.Cancer.2006,Jun;42,1351-1356]。因为绝大部分肿瘤都不是依靠一条信号传导途径来维持其生长和存活,所以,多靶点药物可以抑制多重信号传导途径或一条信号传导途径的多步骤,不但具有协同作用,而且不易诱导肿瘤细胞产生耐药性。这一分子靶向肿瘤药物治疗的新概念也获得了成功的临床证据,如新近被FDA批准上市的治疗肾细胞肿瘤和胃肠道间质瘤的药物BAY43-9006(Sorafenib)就是同时靶向c-Raf和VEGFR-2、β-PDGFR等多种酪氨酸激酶的多靶点药物。另一个被FDA批准用于胃肠道间质瘤治疗的新酪氨酸激酶抑制SU11248(Sutent)也是同时抑制VEGFR、α-PDGFR等多条酪氨酸激酶通路,为其他实体瘤的治疗提供了新的研究思路[EuropeanJ.Cancer.2006,Jun;42,1351-1356]。
文献报道的氨酸激酶抑制剂多是嘧啶或喹唑啉结构的衍生物,本发明的1,6-二氮杂萘-7-碳酰胺衍生物是一类新结构的多重激酶抑制剂,表现出对c-Src、KDR、EGFR、ErbB2等激酶的抑制活性,而且有效抑制一系列肿瘤细胞系如MDA-MB-435、SK-BR-3、A375、A431、HT-29、A-549、BEL-7402、BXPC3、HL-60、PC-3的细胞生长。
与本发明相关的专利文献如下列出:
WO98/13350中披露了一系列喹啉类血管内皮生长因子抑制剂。其中也包括1,8-二氮杂萘类衍生物,例如该专利中的实施例53:2-乙酰氨基-5-(2-氟-5-羟基-4-甲基苯胺)-1,8-二氮杂萘。
WO99/32450中披露了4-羟基喹啉-2-羧酸胺衍生物用于治疗疱疹病毒感染。
WO98/11073中披露了8-羟基喹啉-7-羧酸胺衍生物用于治疗疱疹病毒感染。
WO02/30931中披露了8-羟基-1,6-二氮杂萘-7-碳酰胺类化合物用于治疗HIV-1病毒感染。
CN2008102000645.4中披露了5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物用于治疗乳腺癌、结肠癌、卵巢癌、***癌。
发明内容
本发明的一个目的是公开一类具有全新结构、强效抗肿瘤活性的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物。
本发明的另一目的是提供上述5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物的制备方法。
本发明的还一目的是提供上述5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物在医药领域的用途,它们可以作为多靶点酪氨酸蛋白激酶抑制剂用于肿瘤,包括乳腺癌、卵巢癌、恶性黑色素瘤、皮肤鳞癌、结肠癌、肺癌、肝癌、胰腺癌、急性髓性白血病、***癌与酪氨酸激酶特别是c-Src有关的疾病的治疗。
本发明的再一目的是提供一种包含治疗有效量的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物的药物组合物。
根据本发明,所述的具有抗肿瘤活性的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物如下面的结构通式I、II或III所示:
其中,
A为:(1)苯环;(2)C8-C10骈合成的双碳环,其中一个是苯环,另一个为饱和的或者不饱和的环;(3)8~10个原子骈合成的环,并含有0-3个选自N、O和S中的杂原子,其中一个是芳环或者杂芳环,另一个为饱和的或者不饱和的碳环或杂环;(4)含有1~3个选自N、O和S中的杂原子的五元或六元杂芳环;或(5)含有0~3个选自N、O和S中的杂原子的三元至七元脂肪环;
L是:(1)直接键;(2)C1-C6烷基;(3)C2-C6烯基;(4)(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基);或(5)(C0-C6烷基)-M-(C0-C6烷基),其中M为N(Ra)、-SO2-、OC(=O)或C(=O)O;其中,(3)中的烯基和(2)、(4)、(5)中的烷基可以被1-3个各自独立的取代基取代,所述取代基选自下列原子或基团:C1-C6烷基、C1-C6烷氧基C1-C6烷基、C3-C8环烷基、卤素、氨基、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa和-OCORb;
X各自独立地为N、NH、O或S;
Y为(1)C1-C6烷基;(2)C2-C6烯基;(3)(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基);(4)(C0-C6烷基)-M-(C0-C6烷基),其中M为N(Ra)、-SO2-、OC(=O)或C(=O)O;或(5)(C0-C6烷基)-(C6-C10芳基)-(C0-C6烷基);其中,(2)中的烯基和(1)、(3)、(4)中的烷基可以被1-3个各自独立的取代基取代,所述取代基选自下列原子或基团之中:C1-C6烷基、C1-C6烷氧基C1-C6烷基、C3-C8环烷基、卤素、氨基、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa和-OCORb;
R1、R2、R3、R4和R6各自独立地为氢、卤素、羟基、巯基、-CF3、-CN、-NO2或者未取代或各自独立地被1-3个取代基取代的下列基团:C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C3-C8环烷氧基、C6-C10芳基氧基、C1-C6烷氧基羰基、氨基、苯基、苄基、萘基、C5-C10杂芳环基或C3-C7饱和杂环基;所述取代基选自下列原子或基团之中:C1-C6烷基、C1-C6烷氧基C1-C6烷基、杂环基、C1-C6烷基取代的杂环基、杂环基羰基、C1-C6烷基杂环基、C6-C10芳基、C3-C8环烷基、卤素、巯基、羟基、-CF3、-CN、-NO2、-NRaRb、-NRaCORb、-NRaCOORb、-NRaSO2Rb、-COORb、-CORb、-CONRaRb、-SO2Rb、-SO2NRaRb、-ORa和-OCORb,且NRaRb可共同组成环胺;所述杂环为包括1-3个选自N、O和S中的杂原子的三元至七元脂肪环;
R5为氢、羟基或者未取代或被1-3个各自独立的取代基取代的下列基团:C1-C6烷基、C1-C6烷氧基C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、苯基、苄基、萘基、C5-C10芳香性杂环基或C4-C7饱和杂环基;所述杂环包括1-3个选自N、O和S中的杂原子;所述取代基选自下列原子或基团:C1-C6烷基、C1-C6烷氧基C1-C6烷基、卤素、氨基、硝基、巯基、羟基、-CN和-CF3;
Ra为氢、C1-C6烷基、C3-C8环烷基或C6-C10芳烃基;
Rb为氢、羟基或者未取代或被1-3个各自独立地取代基取代的下列基团:C1-C6烷基、C1-C6烷氧基C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、苯基、苯酚基、苄基、萘基、C5-C10芳香性杂环基或C4-C7饱和杂环基;所述杂环包括1-3个选自N、O和S中的杂原子;所述取代基选自下列原子或基团:C1-C6烷基、C1-C6烷氧基C1-C6烷基、卤素、氨基、硝基、巯基、羟基、-CN和-CF3。
本发明的结构通式I、II或III表示的化合物中优选的化合物可以用结构通式IV、V或VI表示:
其中,R1、R2、R6、L、X和Y的定义与通式I、II或III中相同,并进一步优选:
R1和R2各自独立地为氢、卤素、-CN、-CF3、-NO2、羟基、氨基、C1-C6烷基氨基、C1-C6烷基羰基氨基、C1-C6烷基杂环基氨基、C6-C10芳基氨基、C6-C10芳基磺酰胺基烷基、C1-C6烷氧基、C3-C8环烷氧基、C6-C10芳基氧基、C1-C6烷基杂环基C1-C6烷氧基、C5-C10杂芳环基、杂环基C1-C6烷氧基、杂环基羰基C1-C6烷氧基或C6-C10芳基C1-C6烷氧基;其中的杂环基是指含有1~3个选自N、O和S中的杂原子的三元至七元脂肪环;
R6为氢、卤素、-CN、-COOCH3、
L为C1-C6烷基或-SO2-;
X为NH;
Y为C1-C6烷基、(C1-C6烷基)-(C6-C10芳基)-(C1-C6烷基)或C3-C6环烷基。
更优选地,通式I所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物,具体地,为下述化合物:
L为-CH2-,R6为Br,R7为
L为-SO2-,R6为Br,R7为
L为-CH2-,R6为-CN,R7为
L为-CH2-,R6为-COOCH3,R7为
L为-CH2-,R6为
L为-CH2-,R6为R7为
即为下表所列的化合物:
更优选地,通式II所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类二聚体化合物,具体地,为下述化合物:
Y为R6为Br,R8为
Y为R6为Br,R8为
Y为R6为R8为
即为下表所列的化合物:
更优选地,通式III所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类二聚体化合物,具体地,为下述化合物:
R6为Br、-X-Y-X-为
即为下表所列的化合物:
本发明结构通式I、II或III表示的化合物通过下面的方法制备:
其中,R6、X和Y的定义与通式I、II、III中相同,并优选为表中所示的基团。R7为其中,A、R1、R2、R3和R4的定义与通式I、II、III中相同。
反应试剂和条件:(a)异丙醇,回流,68%;(b)二氯亚砜,回流;(c)硼氢化钠,四氢呋喃,0℃,两步产率38%;(d)TsNHCH2COOCH3,DEAD(偶氮二甲酸二乙酯),三苯基膦,四氢呋喃,0℃;(e)甲醇钠,甲醇,0℃~室温,两步产率65%;(f)NBS(N-溴代丁二酰亚胺),二氯甲烷,室温,产率85%;(g)胺,甲苯,回流24小时,产率88%;(h)TsCl,三乙胺,二氯甲烷,产率90%;(i)1,4-反式环己二胺,四氢呋喃,回流,产率75%-85%;(j)LiOH溶液/甲醇,或NaOH溶液/THF,回流,产率90%-100%;(k)EDCI,DMAP,二氯甲烷,磺酰胺,产率60%-85%;(l)三氟醋酸/二氯甲烷;(m)CuI,Pd(PPh3)Cl2,K2CO3,丙炔酸甲酯,四氢呋喃,回流,产率70%-85%;(n)EDCI,HOAt,DIPEA,胺,二氯甲烷,产率70%-90%。
(1)化合物S1-S21和S43、S44的合成方法如下:将化合物1吡啶2,3-二酸酐选择性酯化得到化合物2,产率68%。化合物2氯代得到得到化合物3;化合物3以酰氯形式选择性还原得到化合物4,产率为38%。化合物4通过Mitsunobo反应得到化合物5。化合物5在甲醇钠下关环得到1,6-二氮杂萘羰酸甲酯6,两步产率65%。化合物6与含R6的化合物(如N-碘代丁二酰亚胺或N-溴代丁二酰亚胺)反应得到5-R6-1,6-二氮杂萘羰酸甲酯7,产率85%。化合物7与含R7的胺酰胺化得到1,6-二氮杂萘羰酰胺化合物8,产率88%。化合物8的8位羟基用Ts保护以90%产率得到化合物9。化合物9的合成路线见参考文献WO2002030426和WO2002030930。化合物9与1,4-反式环己二发生芳基亲核取代反应得到一系列5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物S1-S21和S43、S44,产率75%-85%。
(2)化合物S22-S30的合成方法如下:化合物7与TsCl和三乙胺在二氯甲烷中回流5小时得到化合物10,化合物10与单Boc保护的反式1,4-环己二胺在K2CO3和四氢呋喃中加热回流8小时得到化合物11,化合物11在1NNaOH溶液/THF中60度下10h生成化合物12。化合物12在EDCI、DMAP和二氯甲烷中,常温下与相应的磺酰胺反应12h得到化合物13。化合物13在20%的三氟醋酸/二氯甲烷中脱除Boc生成5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物S22-S30。
(3)化合物S33-S42的合成方法如下:化合物9与反式1,4-环己二胺在三乙胺、四氢呋喃中加热回流8小时得到化合物14,化合物14在氯化钯、三苯基膦、碘化亚铜、碳酸钾和THF中回流与丙炔酸甲酯反应得到化合物15,化合物15在20%三氟醋酸/二氯甲烷中脱去Boc得到5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物S33-S42。
(4)化合物S46-S51的合成方法如下:化合物12在EDCI、HOAt、DIPEA和二氯甲烷中,常温下与相应的胺反应12h得到化合物16。化合物16在20%的三氟醋酸/二氯甲烷中脱除Boc生成5,8-二取代-1,6-二氮杂萘-7-羰酰胺类二聚体化合物S46-S51。
通过对多种肿瘤细胞株筛选,申请人发现:上述结构通式I、II或III表示的化合物在10μM内对下列细胞有高效的抑制活性:MDA-MB-435、SkBr-3、A375、A431、HT29、A-549、BEL-7402、BXPC3、HL-60、PC-3。
因此,结构通式I、II或III表示的化合物能够有效的治疗MDA-MB-435、SkBr-3、A375、A431、HT29、A-549、BEL-7402、BXPC3、HL-60、PC-3肿瘤细胞恶性增殖引起的疾病。
制剂学上允许的含有结构通式I、II或III表示的化合物的药物组合物同样能起到有效的治疗MDA-MB-435、SkBr-3、A375、A431、HT29、A-549、BEL-7402、BXPC3、HL-60、PC-3肿瘤细胞恶性增殖引起的疾病。
本发明的化合物在CN2008102000645.4的基础上,增加了通式I中取代基R6、L和R7的结构类型,也增加了二聚体的结构类型,这些化合物进一步增强了对c-Src、KDR、EGFR、ErbB2、Flt-1等酪氨酸激酶的抑制活性,并且能够有效抑制更广系列肿瘤细胞系如MDA-MB-435、SK-BR-3、A375、A431、HT-29、A-549、BEL-7402、BXPC3、HL-60、PC-3的细胞生长。
具体实施方式
制备实施例:
下面结合制备实施例对本发明作进一步描述,但不限制本发明。
化合物的1H-NMR光谱数据测量使用VarianMercury-300MHz或VarianMercury-400MHz核磁共振,元素分析使用VarioEL测定仪,熔点用Buchi-510毛细管法测定,温度未经校正。红外光谱由Bio-RadFTS-185红外光谱仪测定;质谱EI-MS用FinniganMAT95质谱仪,ESI-MS使用FinniganLCQDeca质谱仪测定。比旋光由P-1030(A012360639)自动旋光仪测定。快速柱层析在硅胶H(10-40μM)上进行。试剂纯化参照PurificationoflaboratoryChemicals;D.D.Perrin;W.L.F.ArmaregoandD.R.PerrinEds.,PergamonPress:Oxiford,1980。
吡啶-2,3-二甲酸-2-异丙酯(2)
将化合物1吡啶2,3-二酸酐(48.1g,0.32mol)溶解在100mL的2-异丙醇中加热回流16小时,然后将溶液冷却到-20℃得到白色固体化合物2(44.4g,68%)。熔点:140-141℃;1HNMR(CDCl3,300MHz):δ8.87(d,J=4.2Hz,1H),8.35(d,J=7.8Hz,1H),7.55(dd,J=5.1,8.1Hz,1H),5.36(septet(七重峰),J=6.3Hz,1H),1.41(d,J=6.3Hz,6H)。
3-羟基甲基-吡啶-2-甲酸异丙酯(4)
将化合物2(52.7g,0.25mol)溶解在400mL的二氯亚砜中加热回流至溶液成均相,然后旋干溶剂。加2×50mL无水THF旋蒸,去除残留的二氯亚砜。将所得到的红色液体溶于400mL无水THF中冷却到0℃,分批加入硼氢化钠(28.6g,0.76mol),0℃下搅拌4个小时,将反应溶液小心的倒入冰水中,3×200mL二氯甲烷萃取,加无水Na2SO4干燥。柱层析(石油醚∶乙酸乙酯=3∶2)得到黄色固体化合物4(18.8g,38%)。1HNMR(CDCl3,300MHz):δ8.69(dd,J=1.5,4.7Hz,1H),7.88(dd,J=1.5,7.7Hz,1H),7.46(dd,J=4.7,7.8Hz,1H),5.35(septet,J=6.4Hz,1H),4.81(m,2H),1.45(d,J=6.3Hz,6H).EI-MSm/z:195(M)+。
3-{[甲氧羰基甲基-(甲苯-4-磺酰基)-氨基]-甲基}-吡啶-2-羧酸异丙酯(5)
将化合物4(1.734g,8.89mmol),2-对甲苯磺酰胺基乙酸甲酯(TsNHCH2COOCH3)(2.163g,8.89mmol),以及三苯基膦(3.499g,13.338mmol)溶解在100mL无水THF中,冷却到0℃,充氮气保护。DEAD(2.165mL,13.338mmol)溶解在10mL无水THF中,逐滴加入DEAD。撤去冰浴,搅拌两小时后旋干得到红色油状液体化合物5直接用于下步反应。
8-羟基-1,6-二氮杂萘-7-羧酸甲酯(6)
将上步反应得到的化合物5(8.89mmol)溶解在50mL无水甲醇里,冷却到0℃。缓慢加入甲醇钠(1.681g,31.123mmol)。撤去冰浴,搅拌3个小时。旋掉溶剂,加20mL水,20mL乙酸乙酯,有机相用饱和碳酸钠反萃。合并水相,调pH到7,维持水相pH到7,用二氯甲烷萃取5次。有机相用无水硫酸钠干燥,柱层析(石油醚∶乙酸乙酯=2∶1)得到灰白色固体化合物6(0.62g,二步产率65%)。熔点:179-180℃;1HNMR(CDCl3,300MHz):δ11.79(s,1H),9.20(s,1H),8.85(s,1H),8.32(d,J=8.2Hz,1H),7.71(dd,J=4.1,8.2Hz,1H),4.12(s,3H)。
5-溴-8-羟基-1,6-二氮杂萘-7-羧酸甲酯(7-1)
常温下将NBS(30mg,0.167mmol)加入到化合物6(34mg,0.167mmol)的1mLCH2Cl2溶液中,搅拌1小时。过滤,干燥得到白色固体化合物7-1(30mg,产率85%);1HNMR(d6-DMSO,300MHz):δ9.26(dd,J=1.5,4.2Hz,1H),8.59(dd,J=1.6,8.4Hz,1H),8.00(dd,J=4.2,8.4Hz,1H),3.94(s,3H)。
N-(2-氯-苄基)-5-溴-8-羟基-1,6-二氮杂萘-7-羧酸胺(8-1)
将化合物7-1和2-氯苄胺在甲苯中氮气保护下加热回流20小时,冷却至室温。过滤,固体用甲醇洗,得到黄色固体化合物8-1,产率:75-85%;1HNMR(300MHz,CDCl3):δ9.21(d,J=4.2Hz,1H),8.54(d,J=8.4Hz,1H),8.28(m,1H),7.74(dd,J=4.2,8.4Hz,1H),7.46(m,2H),7.19(m,1H),4.80(d,J=6Hz,2H)。
甲苯-4-磺酸5-溴-7-(2-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(9-1)
将对甲苯磺酰氯、化合物8-1、三乙胺在氯仿中50℃搅拌5小时后依次用饱和氯化铵,饱和食盐水洗,干燥。柱层析得到白色固体化合物9-1,产率:85-95%;1HNMR(CDCl3):δ9.04(d,1H,J=4.2Hz),8.57(d,1H,J=8.7Hz),8.08(m,1H),7.91(d,2H,J=8.1Hz),7.68(dd,1H,J=4.2,8.4Hz),7.47(m,1H),7.39(m,1H),7.33(d,2H,J=8.4Hz),7.27(m,1H),7.24(m,1H),4.61(d,J=6.0Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2-氯-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S1)
将化合物9-1,三乙胺和1,4-反式环己二胺在四氢呋喃中加热回流8小时,旋干THF,加入二氯甲烷,依次用饱和Na2CO3水溶液、饱和氯化铵水溶液、饱和食盐水洗,无水Na2SO4干燥。柱层析得到黄色固体化合物S1,产率:75-85%。1HNMR(CDCl3,300MHz):δ9.59(d,1H,J=7.8Hz),8.94(d,1H,J=4.2Hz),8.40(m,2H),7.59(dd,1H,J=4.2,7.8Hz),7.45-7.38(m,2H),7.25-7.22(m,2H),4.82(m,1H),4.73(d,2H,J=6.6Hz),2.71(m,1H),2.17(m,2H),1.90(m,2H),1.43-1.25(m,4H);EI-MSm/z:487(M)+,489(M+2)+。
N-(3-氯-苄基)-5-溴-8-羟基-1,6-二氮杂萘-7-羧酸胺(S2-1)
化合物S2-1的制备方法与化合物8-1的制备方法类似,除了用对3-氯苄胺代替2-氯苄胺。黄色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.20(d,J=4.2Hz,1H),8.55(d,J=8.4Hz,1H),8.20(m,1H),7.73(dd,J=4.2,8.4Hz,1H),7.38(s,1H),7.30(m,1H),7.22(m,3H),4.68(d,J=6.3Hz,2H)。
甲苯-4-磺酸5-溴-7-(3-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S2-2)
化合物S2-2的制备方法与化合物9-1的制备方法类似,除了用化合物S2-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(CDCl3):δ9.04(d,1H,J=4.2Hz),8.57(d,1H,J=8.4Hz),8.01(m,1H),7.92(d,2H,J=8.4Hz),7.69(dd,1H,J=4.2,8.4Hz),7.36-7.28(m,6H),4.61(d,2H,J=6.6Hz),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-氯-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S2)
化合物S2的制备方法与化合物S1的制备方法类似,除了用化合物S2-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.59(d,1H,J=8.1Hz),8.93(d,1H,J=3.9Hz),8.43-8.33(m,2H),7.58(dd,1H,J=3.9,8.1Hz),7.35(s,1H),7.25-7.21(m,3Hz),4.96(m,1H),4.60(d,2H,J=6.3Hz),2.75(m,1H),2.17(m,2H),1.90(m,2H),1.47-1.24(m,4H);EI-MSm/z:487(M)+,489(M+2)+。
N-(4-(2-(4-甲基哌嗪-1-基))乙氧-苄基)-5-溴-8-羟基-1,6-二氮杂萘-7-羧酸胺(S3-1)
化合物S3-1的制备方法与化合物8-1的制备方法类似,除了用对4-(2-(4-甲基哌嗪-1-基))乙氧基苄胺代替2-氯苄胺。黄色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.17(d,J=8.7Hz,1H),8.51(d,J=10.2Hz,1H),8.13(t,J=6Hz,1H),7.71(dd,J=8.7,10.2Hz,1H),7.3(d,J=8.4Hz,2H),6.87(d,J=8.4Hz,2H),4.61(d,J=6Hz,2H),4.09(t,J=5.1Hz,2H),2.99(m,10H),2.56(s,3H)。
甲苯-4-磺酸5-溴-7-(4-(2-(4-甲基哌嗪-1-基))乙氧-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S3-2)
化合物S3-2的制备方法与化合物9-1的制备方法类似,除了用化合物S3-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.97(d,J=4.2Hz,1H),8.53(d,J=10.2Hz,1H),7.9(d,J=8.1Hz,2H),7.66(dd,J=4.2,10.2Hz,1H),7.3(m,4H),6.86(d,J=9.7Hz,2H),4.54(d,J=6Hz,2H),4.1(t,J=5.1Hz,2H),2.95(m,8H),2.89(t,J=5.1Hz,2H),2.64(s,3H),2.46(s,3H);MS-ESIm/z:656(M+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-(4-(2-(4-甲基哌嗪-1-基))乙氧-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S3)
化合物S3的制备方法与化合物S1的制备方法类似,除了用化合物S3-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.65(d,J=8.1Hz,1H),8.94(d,J=2.4Hz,1H),8.4(d,J=8.4Hz,1H),8.25(t,1H),7.58(dd,J=2.4,8.4Hz,1H),7.29(d,J=8.7Hz2H),6.89(d,J=9Hz,2H),4.96(m,1H),4.56(d,J=9Hz,2H),4.10(t,J=6.3Hz,2H),2.79(m,3H),2.62(brs,4H),2.48(brs,4H),2.29(s,3H),2.17(d,J=12.6Hz,2H),1.92(d,J=12.6Hz,2H),1.29-1.44(m,4H);MS-EIm/z:595(M)+,597(M+2)+。
N-(4-(5-吗啉)戊氧-苄基)-5-溴-8-羟基-1,6-二氮杂萘-7-羧酸胺(S4-1)
化合物S4-1的制备方法与化合物8-1的制备方法类似,除了用对4-(5-吗啉)戊氧基苄胺代替2-氯苄胺。黄色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.19(d,J=2.7Hz,1H),8.53(d,J=8.4Hz,1H),8.11(t,J=6Hz,1H),7.72(dd,J=2.7,8.4Hz,1H),731(d,J=8.7Hz,2H),6.89(d,J=9Hz,2H),4.62(d,J=6Hz,2H),3.96(t,J=6.3Hz,2H),3.72(t,J=6.3Hz,4H),2.45(t,J=6.6Hz,4H),2.37(t,J=6.6Hz,2H),1.80(m,2H),1.51-1.62(m,4H)。
甲苯-4-磺酸5-溴-7-(4-(5-吗啉)戊氧-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S4-2)
化合物S4-2的制备方法与化合物9-1的制备方法类似,除了用化合物S4-1代替化合物8-1。白色固体,产率:81.5%。1HNMR(300MHz,CDCl3):9.01(d,J=2.7Hz,1H),8.55(d,J=6.9Hz,1H),7.92(d,J=8.7Hz,2H),7.85(t,J=6Hz,1H),7.66(dd,J=2.7,6.9Hz,1H),7.27-7.34(m,4H),6.87(d,J=8.7Hz,2H),4.54(d,J=6Hz,2H),3.95(t,J=6.6Hz,2H),3.77(t,J=4.8Hz,4H),2.53(m,4H),2.41-2.47(m,5H),1.76-1.85(m,2H),1.53-1.65(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-(5-吗啉)戊氧-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S4)
化合物S4的制备方法与化合物S1的制备方法类似,除了用化合物S4-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.67(d,J=8.4Hz,1H),8.94(d,J=5.4Hz,1H),8.41(d,J=8.4Hz,1H),8.25(t,J=6Hz,1H),7.58(dd,J=5.4,8.4Hz,1H),7.29(d,J=8.4Hz,2H),6.87(d,J=8.7Hz,2H),4.99(m,1H),4.56(d,J=6Hz,2H),3.96(t,J=6.3Hz,2H),3.72(t,J=4.5Hz,4H),2.91(m,1H),2.44(m,4H),2.36(t,2H),2.22(m,2H),2.02(m,2H),1.76-1.85(m,2H),1.41-1.59(m,4H);MS-EIm/z:624(M)+,626(M+2)+;13CNMR(100MHz,CDCl3):δ167.6158.4150.6144.9144.7136.3130.4128.9126.5124.3123.9114.667.866.958.953.753.450.142.533.733.029.126.223.9;HR-EIMS计算值:C32H41BrN6O3(M)+:624.2424,实测值:624.2428。
以下化合物S5-1~S21-1的制备方法与化合物8-1的制备方法类似,粗产物直接投下步反应。
甲苯-4-磺酸5-溴-7-(4-(噻吩-2-基)苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S5-2)
化合物S5-2的制备方法与化合物9-1的制备方法类似,除了用化合物S5-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.04(d,J=3.9Hz,1H),8.57(d,J=8.4Hz,1H),7.92-8(m,2H),7.68(dd,J=3.9,8.4Hz,1H),7.61(d,J=8.4Hz,2H),7.4(d,J=8.4Hz,2H),7.26-7.34(m,4H),7.08(m,1H),4.64(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-(噻吩-2-基)苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S5)
化合物S5的制备方法与化合物S1的制备方法类似,除了用化合物S5-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.65(d,J=8.4Hz,1H),8.95(d,J=3.9Hz,1H),8.42(d,J=8.1Hz,1H),8.34(t,J=6.3Hz,1H),7.61(m,3H),7.4(d,J=7.8Hz,2H),7.26-7.31(m,2H),7.08(m,1H),4.99(m,1H),4.65(d,J=6.3Hz,2H),2.76(m,1H),2.19(d,J=12.3Hz,2H),1.91(d,J=11.7Hz,2H),1.26-1.45(m,4H);MS-EIm/z:535(M)+,537(M+2)+;Anal.计算值:C26H26BrN5OS·CH3COOH:C56.38,H5.07,N11.74,实测值:C56.67,H5.00,N11.70。
甲苯-4-磺酸5-溴-7-((吡啶-2-基)甲基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S6-2)
化合物S6-2的制备方法与化合物9-1的制备方法类似,除了用化合物S6-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.05(d,J=4.2Hz,1H),8.57-8.60(m,2H),8.51(t,J=5.7Hz,1H),7.9(d,J=8.1Hz,2H),7.68(dd,1H),7.36(d,1H),7.29(m,2H),7.21(m,1H),4.69(d,J=5.7Hz,2H),2.43(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-((吡啶-2-基)甲基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S6)
化合物S6的制备方法与化合物S1的制备方法类似,除了用化合物S6-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.6(d,J=8.4Hz,1H),8.94(d,J=3.9Hz,1H),8.73(m,1H),8.61(d,J=4.8Hz,1H),8.43(d,J=10.2Hz,1H),7.68(t,1H),7.58(dd,J=3.9,10.2Hz,1H),7.36(d,J=7.8Hz,1H),7.2(t,2H),4.95(m,1H),4.77(d,J=6Hz,2H),2.74(m,1H),2.16(d,J=13.5Hz,2H),1.9(d,J=12.6Hz,2H),1.23-1.43(m,4H);MS-EIm/z:454(M)+,456(M+2)+;Anal.计算值:C21H23BrN6O·1/2CF3COOH·CH3OH:C50.74,H5.09,N15.44,实测值:C50.81,H4.95,N15.29。
甲苯-4-磺酸5-溴-7-(3-三氟甲基-4-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S7-2)
化合物S7-2的制备方法与化合物9-1的制备方法类似,除了用化合物S7-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.01(d,J=4.2Hz,1H),8.57(d,J=8.1Hz,1H),8.09(t,J=6.3Hz,1H),7.91(d,J=8.4Hz,2H),7.67-7.7(m,2H),7.47-7.56(m,2H),7.31(d,2H),4.68(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-三氟甲基-4-氯-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S7)
化合物S7的制备方法与化合物S1的制备方法类似,除了用化合物S7-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.54(d,J=8.1Hz,1H),8.95(d,J=3.9Hz,1H),8.41(m,2H),7.68(s,1H),7.6(dd,J=8.1,3.9Hz,1H),7.48(m,2H),4.97(m,1H),4.64(d,J=6.9Hz,2H),2.74(m,1H),2.17(d,J=14.4Hz,2H),1.9(d,J=12Hz,2H),1.26-1.43(m,4H);MS-EIm/z:555(M)+,557(M+2)+;Anal.计算值:C23H22BrClF3N5O·1/4CH3OH:C49.44,H4.10,N12.40,实测值:C49.74,H4.32,N12.06。
甲苯-4-磺酸5-溴-7-(2-氯-5-三氟甲基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S8-2)
化合物S8-2的制备方法与化合物9-1的制备方法类似,除了用化合物S8-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.02(d,J=4.2Hz,1H),8.56(d,J=8.4Hz,1H),8.15(t,J=6.3Hz,1H),7.9(d,J=8.4Hz,2H),7.75(s,1H),7.67(dd,J=8.4,8.4Hz,1H),7.5(t,2H),7.31(d,J=8.1Hz,2H),4.75(d,J=6.3Hz,2H),2.45(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2-氯-5-三氟甲基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S8)
化合物S8的制备方法与化合物S1的制备方法类似,除了用化合物S8-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.52(d,J=8.4Hz,1H),8.96(d,J=3.9Hz,1H),8.42-8.46(m,2H),7.67(s,1H),7.61(dd,J=8.4,3.9Hz,1H),7.51(m,2H),4.97(m,1H),4.64(d,J=6.3Hz,2H),2.76(m,1H),2.18(d,J=12.3Hz,2H),1.91(d,J=10.5Hz,2H),1.26-1.46(m,4H);13CNMR(100MHz,CDCl3):δ168.0150.7145.0144.9137.1136.4130.0129.5129.2126.8125.8125.4125.0124.5124.4123.2122.377.377.277.076.753.850.040.735.233.231.6;MS-EIm/z:555(M)+,557(M+2)+;Anal.计算值:C23H22BrClF3N5O·1/5CF3COOH·3/5C6H14:C51.37,H4.89,N11.09,实测值:C51.30,H4.97,N11.07。
甲苯-4-磺酸5-溴-7-(3,4,5-三甲氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S9-2)
化合物S9-2的制备方法与化合物9-1的制备方法类似,除了用化合物S9-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.98(d,J=4.5Hz,1H),8.57(d,J=8.4Hz,1H),7.93(m,3H),7.67(dd,J=4.5,8.4Hz,1H),7.32(d,J=8.1Hz,2H),6.66(s,2H),4.62(d,J=6Hz,2H),3.87(s,6H),3.84(s,3H),2.47(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3,4,5-三甲氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S9)
化合物S9的制备方法与化合物S1的制备方法类似,除了用化合物S9-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.61(d,J=7.8Hz,1H),8.95(d,J=6Hz,1H),8.42(d,J=8.7Hz,1H),8.30(t,J=6.3Hz,1H),7.6(dd,J=6,8.7Hz,1H),6.61(s,2H),4.97(m,1H),4.57(d,J=6.3Hz,2H),3.87(s,6H),3.84(s,3H),2.77(m,1H),2.18(d,J=12.9Hz,2H),1.92(d,J=12.9Hz,2H),1.25-1.48(m,4H);MS-EIm/z:543(M)+,545(M+2)+;Anal.计算值:C25H30BrN5O4·1/4CF3COOH:C53.46,H5.32,N12.22,实测值:C53.52,H5.45,N11.93。
甲苯-4-磺酸5-溴-7-(3,4-二氟-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S10-2)
化合物S10-2的制备方法与化合物9-1的制备方法类似,除了用化合物S10-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.02(d,J=4.2Hz,1H),8.57(d,J=10.2Hz,1H),8.02(t,J=6.3Hz,1H),7.92(d,J=5.4Hz,2H),7.69(dd,J=4.2,10.2Hz,1H),7.33(d,J=7.8Hz,2H),7.11-7.25(m,3H),4.6(d,J=6.3Hz,2H),2.47(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3,4-二氟-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S10)
化合物S10的制备方法与化合物S1的制备方法类似,除了用化合物S10-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.59(d,J=8.7Hz,1H),8.95(d,J=5.7Hz,1H),8.43(d,J=6.6Hz,2H),8.36(t,J=6Hz,1H),7.61(dd,J=5.7,6.6Hz,1H),7.09-7.22(m,3H),4.99(m,1H),4.58(d,J=6Hz,2H),2.86(m,1H),2.19(m,2H),1.98(m,2H),1.40(m,4H);MS-EIm/z:489(M)+,491(M+2)+;Anal.计算值:C22H22BrF2N5O:C53.89,H4.52,N14.28,实测值:C53.81,H4.61,N14.06。
甲苯-4-磺酸5-溴-7-(3,5-二三氟甲基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S11-2)
化合物S11-2的制备方法与化合物9-1的制备方法类似,除了用化合物S11-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.02(d,J=4.5Hz,1H),8.58(d,J=8.7Hz,1H),8.19(t,J=6.3Hz,1H),7.91(d,J=8.4Hz,2H),7.87(s,2H),7.81(s,1H),7.69(dd,J=4.5,8.7Hz,1H),7.31(d,J=7.8Hz,2H),4.79(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3,5-二三氟甲基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S11)
化合物S11的制备方法与化合物S1的制备方法类似,除了用化合物S11-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ:9.52(d,J=8.4Hz,1H),8.96(d,J=2.4Hz,1H),8.42-8.49(m,2H),7.79-7.82(m,3H),7.62(dd,J=8.4,2.4Hz,1H),4.98(m,1H),4.74(d,J=6.3Hz,2H),2.78(m,1H),2.19(d,J=13.2Hz,2H),1.92(d,J=11.4Hz,2H),1.25-1.43(m,4H);MS-EIm/z:589(M)+,591(M+2)+;Anal.计算值:C24H22BrF6N5O·1/6C6H14:C49.33,H3.94,N11.69,实测值:C49.33,H3.91,N11.71。
甲苯-4-磺酸5-溴-7-(4-(4-甲基苯磺酰胺)甲基-苄基)氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S12-2)
化合物S12-2的制备方法与化合物9-1的制备方法类似,除了用化合物S12-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.00(d,J=3.9Hz,1H),8.56(d,J=8.4Hz,1H),7.91-7.93(m,3H),7.76(d,J=7.8Hz,2H),7.68(dd,J=3.9,8.4Hz,1H),7.30-7.33(m,6H),7.19(d,J=7.8Hz,2H),4.59-4.61(m,3H),4.12(d,J=6.3Hz,2H),2.47(s,3H),2.43(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-(4-甲基苯磺酰胺)甲基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S12)
化合物S12的制备方法与化合物S1的制备方法类似,除了用化合物S12-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.51(d,J=5.7Hz,1H),8.95(d,J=4.2Hz,1H),8.41(d,J=10.2Hz,1H),8.27(t,J=6Hz,1H),7.76(d,J=8.1Hz,2H),7.59(dd,J=4.2,10.2Hz,1H),7.29-7.33(m,4H),7.18(d,J=7.8Hz,2H),4.92(m,1H),4.12(d,J=6Hz,2H),3.52(br,1H),2.74(m,1H),2.43(s,3H),2.16(d,J=12.3Hz,2H),1.89(d,J=12.3Hz,2H),1.25-1.41(m,4H);MS-EIm/z:636(M)+,638(M+2)+;HR-EIMS计算值:C30H33BrN6O3S(M)+:636.1518,实测值:636.1526。
甲苯-4-磺酸5-溴-7-((噻吩-2-基)甲基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S13-2)
化合物S13-2的制备方法与化合物9-1的制备方法类似,除了用化合物S13-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.05(d,J=2.4Hz,1H),8.57(d,J=8.7Hz,1H),7.94(d,J=8.1Hz,2H),7.68(dd,J=2.4,8.7Hz,1H),7.34(d,J=8.1Hz,2H),7.25-7.27(m,1H),7.07(m,1H),6.99(m,1H),4.77(d,J=4.5Hz,2H),2.48(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-((噻吩-2-基)甲基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S13)
化合物S13的制备方法与化合物S1的制备方法类似,除了用化合物S13-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.6(d,J=7.8Hz,1H),8.95(d,J=4.5Hz,1H),8.42(d,J=8.4Hz,1H),8.32(t,J=6Hz,1H),7.59(dd,J=4.5Hz,8.4Hz,1H),7.23-7.25(m,1H),7.07(m,1H),6.98(m,1H),4.98(m,1H),4.80(d,J=6Hz,2H),2.81(m,1H),2.19(d,J=11.4Hz,2H),1.94(d,J=12.3Hz,2H),1.31-1.49(m,4H);MS-EIm/z:459(M)+,461(M+2)+;Anal.计算值:C20H22BrN5O·1/2H2O:C51.68,H5.08,N14.70,实测值:C51.71,H4.85,N14.46。
甲苯-4-磺酸5-溴-7-((吲哚-5-基-1-H)甲基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S14-2)
化合物S14-2的制备方法与化合物9-1的制备方法类似,除了用化合物S14-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.05(d,J=4.5Hz,1H),8.55(d,J=8.4Hz,1H),8.21(m,1H),7.95(d,J=8.4Hz,2H),7.87(t,J=5.7Hz,1H),7.65-7.69(m,2H),7.21-7.42(m,4H),6.56(m,1H),4.68(d,J=5.7Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-((吲哚-5-基-1-H)甲基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S14)
化合物S14的制备方法与化合物S1的制备方法类似,除了用化合物S14-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3)δ9.7(d,J=9Hz,1H),8.94(d,J=3.9Hz,1H),8.41(d,J=7.8Hz,1H),8.29(t,J=5.1Hz,1H),8.19(m,1H),7.66(s,1H),7.57(dd,J=3.9,7.8Hz,1H),7.4(d,J=7.8Hz,1H),7.23-7.26(m,1H),6.55(m,1H),4.97(m,1H),4.73(d,J=5.1Hz,2H),2.8(m,1H),2.2(d,J=14.7Hz,2H),1.95(d,J=12.9Hz,2H),1.36-1.46(m,4H);MS-EIm/z:492(M)+,494(M+2)+;Anal.计算值:C21H23BrN6O·2/5CF3COOH·3/4CH3OH:C54.50,H5.08,N14.93,实测值:C54.56,H4.84,N14.66。
甲苯-4-磺酸5-溴-7-((萘-1-基)甲基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S15-2)
化合物S15-2的制备方法与化合物9-1的制备方法类似,除了用化合物S15-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.01(d,J=4.2Hz,1H),8.53(d,J=8.7Hz,1H),8.13(d,J=8.1Hz,1H),7.96(d,J=8.1Hz,2H),7.84-7.93(m,1H),7.66(dd,J=4.2Hz,8.7Hz,2H),7.45-7.6(m,4H),7.33(d,J=8.1Hz,2H),5.09(d,J=5.4Hz,2H),2.45(s,3H);MS-ESIm/z:562(M+H)+,564(M+2+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-((萘-1-基)甲基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S15)
化合物S15的制备方法与化合物S1的制备方法类似,除了用化合物S15-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.69(d,J=8.1Hz,1H),8.95(d,J=4.2Hz,1H),8.4(d,J=8.7Hz,1H),8.29(t,J=6Hz,1H),8.12(d,J=7.5Hz,1H),7.82-7.91(m,2H),7.44-7.6(m,5H),5.10(d,J=6Hz,2H),4.98(m,1H),2.82(m,1H),2.21(d,J=12Hz,2H),1.96(d,J=11.4Hz,2H),1.29-1.52(m,4H);MS-EIm/z:503(M)+,505(M+2)+;Anal.计算值:C26H26BrN5O·1/5CF3COOH·2/5C6H14:C61.58,H5.71,N12.47,实测值:C61.61,H5.62,N12.53。
甲苯-4-磺酸5-溴-7-(3-三氟甲基-4-甲氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S16-2)
化合物S16-2的制备方法与化合物9-1的制备方法类似,除了用化合物S16-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.01(d,J=5.7Hz,1H),8.57(d,J=6.9Hz,1H),7.91-7.97(m,3H),7.68(dd,J=5.7,6.9Hz,1H),7.57(m,2H),7.33(d,J=5.7Hz,2H),7.00(d,J=9.3Hz,1H),4.6(d,J=6Hz,2H),3.9(s,3H),2.47(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-三氟甲基-4-甲氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S16)
化合物S16的制备方法与化合物S1的制备方法类似,除了用化合物S16-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.6(d,J=8.4Hz,1H),8.95(d,J=4.2Hz,1H),8.42(d,J=8.4Hz,1H),8.31(t,J=6.3Hz,1H),7.51-7.61(m,3H),6.99(d,J=8.7Hz,1H),4.97(m,1H),4.59(d,J=6.3Hz,2H),3.9(s,3H),2.78(m,1H),2.18(d,J=12.3Hz,2H),1.92(d,J=13.2Hz,2H),1.25-1.48(m,4H);13CNMR(100MHz,CDCl3):δ167.8156.7150.6145.0136.3132.6130.4126.6126.6126.5124.9124.4124.3123.6122.2118.9118.6112.256.053.750.042.035.033.2;MS-EIm/z:551(M)+,553(M+2)+;Anal.计算值:C24H25BrF3N5O2·1/5C6H14:C53.14,H4.92,N12.29,实测值:C53.04,H4.83,N12.31。
甲苯-4-磺酸5-溴-7-(2-甲氧基-5-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S17-2)
化合物S17-2的制备方法与化合物9-1的制备方法类似,除了用化合物S17-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.07(d,J=4.5Hz,1H),8.56(d,J=8.7Hz,1H),8.1(t,J=6.6Hz,1H),7.90(d,J=8.1Hz,2H),7.68(dd,J=4.5,8.7Hz,1H),7.30-7.34(m,3H),7.21-7.26(m,1H),6.82(d,J=9Hz,1H),4.54(d,J=6.6Hz,2H),3.91(s,3H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2-甲氧基-5-氯-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S17)
化合物S17的制备方法与化合物S1的制备方法类似,除了用化合物S17-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.59(d,J=8.1Hz,1H),8.94(d,J=3Hz,1H),8.4-8.49(m,2H),7.58(dd,J=3Hz,1H),7.2-7.29(m,2H),6.81(d,J=8.7Hz,1H),4.95(m,1H),4.59(d,J=6.3Hz,2H),3.9(s,3H),2.77(m,1H),2.17(d,J=11.7Hz,2H),1.91(d,J=14.1Hz,2H),1.25-1.47(m,4H);MS-EIm/z:517(M)+,519(M+2)+;Anal.计算值:C23H25BrClN5O2·3/20C6H14:C53.98,H5.14,N13.17,实测值:C53.87,H5.12,N12.97。
甲苯-4-磺酸5-溴-7-(4-苯氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S18-2)
化合物S18-2的制备方法与化合物9-1的制备方法类似,除了用化合物S18-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):δ9.03(d,J=4.2Hz,1H),8.65(d,J=8.4Hz,1H),7.93(m,3H),7.68(dd,J=4.2,8.4Hz,1H),7.31-7.37(m,6H),7.10(t,J=6Hz,1H),6.98-7.03(m,4H),4.60(d,J=6Hz,2H),2.47(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-苯氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S18)
化合物S18的制备方法与化合物S1的制备方法类似,除了用化合物S18-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.65(d,J=7.8Hz,1H),8.94(d,J=3.9Hz,1H),8.42(d,J=8.7Hz,1H),8.31(t,J=6Hz,1H),7.59(dd,J=3.9,8.7Hz,1H),7.26-7.36(m,5H),7.10(t,J=6.9Hz,1H),6.98-7.03(m,3H),4.99(m,1H),4.61(d,J=6Hz,2H),2.77(m,1H),2.18(d,J=12.9Hz,2H),1.91(d,J=12.3Hz,2H),1.25-1.49(m,4H);MS-EIm/z:545(M)+,547(M+2)+;HR-EIMS计算值:C28H28BrN5O2(M)+:545.1426,实测值:545.1427;Anal.计算值:C28H28BrN5O2:C61.58,H5.13,N12.71,实测值:C61.54,H5.16,N12.82。
甲苯-4-磺酸5-溴-7-(3-氯-4-环己烷氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S19-2)
化合物S19-2的制备方法与化合物9-1的制备方法类似,除了用化合物S19-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):δ9.04(d,J=4.2Hz,1H),8.57(d,J=8.7Hz,1H),7.91-7.94(m,3H),7.68(dd,J=4.2,8.7Hz,1H),7.37(s,1H),7.33(d,J=8.1Hz,2H),7.19-7.22(m,1H),6.93(d,1H),4.52(d,J=6Hz,2H),4.29(m,1H),2.47(s,3H),1.92-1.96(m,2H),1.79-1.83(m,2H),1.62-1.65(m,2H),1.34-1.39(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-氯-4-环己烷氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S19)
化合物S19的制备方法与化合物S1的制备方法类似,除了用化合物S19-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.63(d,J=8.4Hz,1H),8.95(d,J=2.7Hz,1H),8.42(d,J=10.2Hz,1H),8.28(t,J=7.8Hz,1H),7.59(dd,J=2.7,10.2Hz,1H),7.37(s,1H),7.19(d,J=8.1Hz,2H),6.93(d,J=8.4Hz,2H),4.98(m,1H),4.3(d,J=7.8Hz,2H),4.26(m,1H),2.87(m,1H),2.19(m,2H),1.5-1.69(m,6H),1.25-1.41(m,10H);MS-ESIm/z:588(M+H)+,586(M-2+H)+;HR-ESIMS计算值:C28H33BrClN5O2(M+Na)+:608.1404,实测值:608.1401;Anal.计算值:C28H33BrClN5O2·1/4C6H14:C58.23,H6.05,N11.51,实测值:C58.27,H6.33,N11.70。
甲苯-4-磺酸5-溴-7-(3-三氟甲基-4-环己烷氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S20-2)
化合物S20-2的制备方法与化合物9-1的制备方法类似,除了用化合物S20-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):δ9.02(d,J=4.5Hz,1H),8.57(d,J=8.4Hz,1H),7.93(m,3H),7.68(dd,J=4.5,8.4Hz,1H),7.49-7.55(m,2H),7.33(d,J=8.4Hz,2H),6.98(d,1H),4.58(d,J=6.3Hz,2H),4.41(m,1H),2.47(s,3H),1.87-1.9(m,2H),1.77-1.81(m,2H),1.63-1.69(m,2H),1.38-1.43(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-三氟甲基-4-环己烷氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S20)
化合物S20的制备方法与化合物S1的制备方法类似,除了用化合物S20-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.61(d,J=8.4Hz,1H),8.95(d,J=2.7Hz,1H),8.42(d,J=8.7Hz,1H),8.29(t,J=6.3Hz,1H),7.59(dd,J=2.7,8.7Hz,1H),7.55(s,1H),7.46(d,J=6.3Hz,1H),6.97(d,J=8.4Hz,1H),4.98(m,1H),4.57(d,J=6.3Hz,2H),4.39(m,1H),2.83(m,1H),2.19(m,2H),1.86-1.97(m,5H),1.51-1.54(m,3H),1.25-1,45(m,10H);13CNMR(100MHz,CDCl3)δ167.7155.2150.6145.0144.9136.3132.3129.7126.7126.6124.4124.3123.6114.375.753.750.042.134.833.231.225.523.0;MS-ESIm/z:620(M+H)+,622(M+2+H)+;Anal.计算值:C29H33BrF3N5O2:C56.13,H5.36,N11.29,实测值:C55.84,H5.37,N11.20。
甲苯-4-磺酸5-溴-7-(4-环丙烷甲氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S21-2)
化合物S21-2的制备方法与化合物9-1的制备方法类似,除了用化合物S21-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):δ9.03(d,J=4.2Hz,1H),8.56(d,J=10.2Hz,1H),7.93(d,J=8.4Hz,2H),7.85(t,J=5.7Hz,1H),7.67(dd,J=4.2,10.2Hz,1H),7.26-7.36(m,4H),6.9(d,J=8.4Hz,2H),4.54(d,J=5.7Hz,2H),3.8(d,2H),2.47(s,3H),1.25(m,1H),0.64(m,2H),0.35(m,2H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-环丙烷甲氧基-苄基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S21)
化合物S21的制备方法与化合物S1的制备方法类似,除了用化合物S21-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.64(d,J=8.1Hz,1H),8.94(d,J=4.2Hz,1H),8.4(d,J=8.4Hz,1H),8.24(t,J=5.7Hz,1H),7.57(dd,J=4.2,8.4Hz,1H),7.29(d,J=8.7Hz,2H),6.89(d,J=8.4Hz,2H),4.96(m,1H),4.56(d,J=5.7Hz,2H),3.79(d,2H),2.76(m,1H),2.17(d,J=11.7Hz,2H),1.91(d,J=11.7Hz,2H),1.23-1.48(m,5H),0.63(m,2H),0.34(m,2H);13CNMR(100MHz,CDCl3)δ167.6158.3150.5145.0144.9136.3130.5129.0126.5124.3124.2123.9114.772.853.750.042.535.133.210.23.1;MS-ESIm/z:526(M+H)+,524(M-2+H)+;Anal.计算值:C26H30BrN5O2:C59.54,H5.77,N13.35,实测值:C59.56,H5.85,N13.05。
甲苯-4-磺酸5-溴-7-甲氧甲酰-1,6-二氮杂萘-8-羧酸酯(10)
化合物10的制备方法与化合物9-1的制备方法类似,除了用化合物7-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):δ9.06(dd,1H,J=1.5,4.2Hz),8.60(dd,1H,J=1.5,8.7Hz),7.86(d,2H,J=8.4Hz),7.72(dd,1H,J=4.2,8.4Hz),7.34(d,2H,J=8.4Hz),3.83(s,3H),2.47(s,3H);EI-MSm/z:436(M)+。
叔丁基(1r,4r)-4-(7-(甲氧碳酰基)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(11)
化合物11的制备方法与化合物S1的制备方法类似,除了用化合物10代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ8.95(dd,1H,J=1.5,4.2Hz),8.88(d,1H,J=7.5Hz),8.47(dd,1H,J=1.5,8.4Hz),7.64(dd,1H,J=4.2,8.4Hz),4.92(m,1H),4.42(m,1H),3.97(s,3H),3.47(m,1H),2.20(m,2H),2.05(m,2H),1.44(s,9H),1.43-1.23(m,4H);EI-MSm/z:478(M)+,480(M+2)+。
5-溴-8-((1r,4r)-4-叔丁氧羰基氨基环己氨基)-1,6-二氮杂萘-7-羧酸(12)
化合物12由化合物11在1NNaOH溶液/THF中,60度下,10h水解制得。黄绿色固体,产率:75-85%。熔点:122-126℃;1HNMR(300MHz,CDCl3):δ8.96(dd,1H,J=1.5,4.2Hz),8.88(d,1H,J=7.5Hz),8.45(dd,1H,J=1.5,8.4Hz),7.64(dd,1H,J=4.2,8.4Hz),4.96(m,1H),4.41(m,1H),3.47(m,1H),2.21(m,2H),2.08(m,2H),1.44(s,9H),1.43-1.23(m,4H);EI-MSm/z:464(M)+,466(M+2)+。
叔丁基(1r,4r)-4-(7-(4-甲氧基苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S22-1)
化合物12在EDCI、DMAP和二氯甲烷中,常温下与对甲氧基苯磺酰胺反应12h得到化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.27(s,1H),9.22(m,1H),8.93(d,J=6Hz,1H),8.44(d,J=6.9Hz,1H),8.12(d,J=9Hz,2H),7.64(dd,J=6,6.9Hz,1H),7.02(d,J=9Hz,2H),4.99(brs,1H),4.39(brs,1H),3.89(s,3H),3.46(brs,1H),2.14(d,J=12.3Hz,2H),2.05(d,J=11.4Hz,2H),1.45(s,9H),1.26-1.39(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-甲氧基苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S22)
化合物S22-1在20%的三氟醋酸/二氯甲烷中脱除Boc生成化合物S22。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.1(d,J=6.9Hz,1H),9.0(d,J=5.4Hz,1H),8.39(d,J=8.4Hz,1H),7.83(d,J=8.7Hz,2H),7.77(dd,J=5.4,8.4Hz,1H),6.99(d,J=9Hz,2H),4.59(brs,1H),3.81(s,3H),3.05(m,1H),2.06(d,J=12Hz,2H),1.95(d,J=13.8Hz,2H),1.39-1.51(m,2H),1.21-1.33(m,2H);MS-EIm/z:171ArSO2 +,362(M-HSO2)+;MS-ESIm/z:556(M+Na-2)+,558(M+Na)+;Anal.计算值:C22H24BrN5O4S·5/4H2O:C47.44,H4.80,N12.57,实测值:C47.19,H4.88,N12.93。
叔丁基(1r,4r)-4-(7-(4-氯苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S23-1)
化合物S23-1的制备方法与化合物S22-1的制备方法类似,除了用对氯苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.31(s,1H),9.18(m,1H),8.94(d,J=3.9Hz,1H),8.45(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,2H),7.65(dd,J=3.9,8.4Hz,1H),7.54(d,J=8.7Hz,2H),4.99(brs,1H),4.39(brs,1H),3.46(brs,1H),2.14(d,J=12Hz,2H),2.06(d,J=10.5Hz,2H),1.45(s,9H),1.26-1.39(m,4H);MS-ESIm/z:640(M+H)+,638(M-2+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-(4-氯苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S23)
化合物S23的制备方法与化合物S22的制备方法类似,除了用化合物S23-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.17(d,J=8.1Hz,1H),8.99(d,J=2.7Hz,1H),8.37(d,J=9.9Hz,1H),7.88(d,J=8.7Hz,2H),7.75(dd,J=2.7,9.9Hz,1H),7.52(d,J=8.4Hz,2H),4.58(brs,1H),3.05(t,1H),2.05(d,J=11.1Hz,2H),1.96(d,J=10.5Hz,2H),1.45(m,2H),1.24(m,2H);13CNMR(100MHz,d6-DMSO):δ170.0151.5144.4142.0135.8134.9132.7129.0127.8125.1124.7124.552.548.831.728.9;MS-ESIm/z:540(M+H)+,538(M-2+H)+;Anal.计算值:C21H21BrClN5O3S·5/4H2O:C44.93,H4.22,N12.48,实测值:C44.79,H4.25,N12.70。
叔丁基(1r,4r)-4-(7-(3-氯苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S24-1)
化合物S24-1的制备方法与化合物S22-1的制备方法类似,除了用间氯苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.32(s,1H),9.19(d,1H),8.94(d,J=5.4Hz,1H),8.45(d,J=6.6Hz,1H),8.16(s,1H),8.08(d,J=7.5Hz,1H),7.59-7.67(m,2H),7.51(t,2H),5.0(brs,1H),4.38(brs,1H),3.45(brs,1H),2.15(d,J=12Hz,2H),2.06(d,J=8.7Hz,2H),1.45(s,9H),1.29-1.4(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-氯苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S24)
化合物S24的制备方法与化合物S22的制备方法类似,除了用化合物S24-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.08(brs,1H),9.02(d,J=4.2Hz,1H),8.4(d,J=8.7Hz,1H),7.9(s,1H),7.76-7.85(m,2H),7.49-7.59(m,2H),4.59(brs,1H),3.04(t,1H),2.06(d,J=10.8Hz,2H),1.96(d,J=11.4Hz,2H),1.44(m,2H),1.25(m,2H);13CNMR(100MHz,d6-DMSO):δ151.6144.3135.9132.6130.6130.1126.9125.7125.2125.052.648.731.628.9;MS-ESIm/z:540(M+H)+,538(M-2+H)+;Anal.计算值:C21H21BrClN5O3S·5/3H2O:C44.34,H4.31,N12.31,实测值:C44.56,H4.34,N12.03。
叔丁基(1r,4r)-4-(7-(3,5-二氟苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S25-1)
化合物S25-1的制备方法与化合物S22-1的制备方法类似,除了用3,5-二氟苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3)δ10.33(s,1H),9.18(d,1H),8.96(d,J=5.4Hz,1H),8.46(d,J=8.7Hz,1H),7.73(m,2H),7.67(dd,J=5.4,8.7Hz,1H),7.09(t,1H),5.03(brs,1H),4.38(brs,1H),3.46(brs,1H),2.16(d,J=12Hz,2H),2.07(d,J=11.4Hz,2H),1.45(s,9H),1.31-1.38(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3,5-二氟苯磺酰胺基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S25)
化合物S25的制备方法与化合物S22的制备方法类似,除了用化合物S25-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.00(m,2H),8.38(d,J=6.3Hz,1H),7.45-7.81(m,4H),7.5(m,2H),7.39(m,1H),4.56(brs,1H),3.06(t,1H),2.08(d,J=10.5Hz,2H),1.94(d,J=10.5Hz,2H),1.44(m,2H),1.25(m,2H);13CNMR(100MHz,d6-DMSO)δ170.4162.8162.7160.3160.2151.4149.6144.3141.7135.8132.8125.2124.7124.4110.5110.3105.752.548.831.628.9;MS-EIm/z:177ArSO2 +,362(M-HSO2)+;Anal.计算值:C21H20BrF2N5O3S·1/10C6H14:C47.26,H3.93,N12.76,实测值:C47.14,H3.93,N12.64。
叔丁基(1r,4r)-4-(7-(2,5-二氯噻吩-3-基磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S26-1)
化合物S26-1的制备方法与化合物S22-1的制备方法类似,除了用2,5-二氯噻吩-3-基磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3)δ10.45(s,1H),9.16(d,1H),8.96(d,J=6Hz,1H),8.47(d,J=9.9Hz,1H),7.67(dd,J=6,9.9Hz,1H),7.4(s,1H),5.03(brs,1H),4.38(brs,1H),3.47(brs,1H),2.17(d,J=12.6Hz,2H),2.07(d,J=15Hz,2H),1.45(s,9H),1.31-1.41(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2,5-二氯噻吩-3-基磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S26)
化合物S26的制备方法与化合物S22的制备方法类似,除了用化合物S26-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.12(d,J=8.1Hz,1H),9.01(d,J=4.2Hz,1H),8.39(d,J=6.9Hz,1H),7.76-7.8(m,3H),7.24(s,1H),4.59(brs,1H),3.05(t,1H),2.08(d,J=11.1Hz,2H),1.96(d,J=10.5Hz,2H),1.39-1.51(m,2H),1.24-1.34(m,2H);MS-ESIm/z:578(M+H)+;Anal.计算值:C19H18BrCl2N5O3S2·1/10CF3COOH·1/20C6H14:C39.36,H3.18,N11.77,实测值:C39.40,H3.47,N11.65。
叔丁基(1r,4r)-4-(7-(4-三氟甲基苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S27-1)
化合物S27-1的制备方法与化合物S22-1的制备方法类似,除了用4-三氟甲基苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.35(s,1H),9.17(d,1H),8.94(d,J=4.2Hz,1H),8.45(d,J=8.7Hz,1H),8.32(d,J=8.4Hz,2H),7.84(d,J=8.1Hz,2H),7.65(dd,J=4.2,8.7Hz,1H),5.01(brs,1H),4.39(brs,1H),3.46(brs,1H),2.14(d,J=11.7Hz,2H),2.06(d,J=10.8Hz,2H),1.45(s,9H),1.29-1.39(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-三氟甲基苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S27)
化合物S27的制备方法与化合物S22的制备方法类似,除了用化合物S27-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.01-9.05(m,2H),8.39(d,J=9.9Hz,1H),8.07(d,J=8.4Hz,2H),7.85(d,J=8.1Hz,2H),7.78(dd,J=9.9Hz,1H),4.58(brs,1H),3.06(brs,1H),2.06(d,J=12Hz,2H),1.95(d,J=13.8Hz,2H),1.39-1.5(m,2H),1.24-1.32(m,2H);MS-ESIm/z:574(M+H)+,572(M-2+H)+;Anal.计算值:C22H21BrF3N5O3S·5/4CH3OH·1/2CF3COOH:C43.51,H3.99,N10.46,实测值:C43.71,H4.20,N10.33。
叔丁基(1r,4r)-4-(7-(4-乙酰氨基苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S28-1)
化合物S28-1的制备方法与化合物S22-1的制备方法类似,除了用4-乙酰氨基苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.27(s,1H),9.16(d,1H),8.93(d,J=3.9Hz,1H),8.44(d,J=8.7Hz,1H),8.12(d,J=9Hz,2H),7.71(d,J=8.7Hz,2H),7.64(dd,J=3.9,8.7Hz,1H),7.52(brs,1H),4.97(brs,1H),4.41(brs,1H),3.44(brs,1H),2.22(s,3H),2.11(d,J=11.4Hz,2H),2.02(d,J=12Hz,2H),1.45(s,9H),1.28-1.41(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-乙酰氨基苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S28)
化合物S28的制备方法与化合物S22的制备方法类似,除了用化合物S28-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ10.5(s,1H),9.15(brs,1H),9.01(d,J=3.9Hz,1H),8.38(d,J=8.4Hz,1H),7.86(d,J=8.7Hz,2H),7.79(dd,J=3.9,8.4Hz,1H),7.73(d,J=8.7Hz,2H),4.61(brs,1H),3.01(t,1H),2.08(s,3H),1.94-2.05(m,4H),1.38-1.5(m,2H),1.2-1.28(m,2H);13CNMR(100MHz,d6-DMSO):δ169.1151.7144.3136.0128.3125.4125.1118.152.748.831.628.924.2;MS-ESIm/z:561(M+H)+,563(M+H+2)+。
叔丁基(1r,4r)-4-(7-(2-氯苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S29-1)
化合物S29-1的制备方法与化合物S22-1的制备方法类似,除了用2-氯苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ10.62(s,1H),9.07(d,1H),8.93(d,J=4.2Hz,1H),8.47(d,J=6.9Hz,1H),8.37(m,1H),7.65(dd,J=4.2,6.9Hz,1H),7.48-7.59(m,3H),4.98(brs,1H),4.36(brs,1H),3.42(brs,1H),2.11(d,J=12.3Hz,2H),2.03(d,J=10.8Hz,2H),1.44(s,9H),1.25-1.38(m,4H);MS-ESIm/z:640(M+H)+,638(M-2+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-(2-氯苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S29)
化合物S29的制备方法与化合物S22的制备方法类似,除了用化合物S29-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.06(brs,1H),8.46(d,J=8.1Hz,1H),8.16(d,J=4.2Hz,1H),7.89(brs,2H),7.63(m,2H),7.37(brs,1H),7.21(brs,1H),7.04(brs,1H),4.64(brs,1H),3.55(brs,1H),3.04(brs,1H),2.06(d,J=13.2Hz,2H),1.94(d,J=13.8Hz,2H),1.27-1.47(m,4H);MS-EIm/z:175ArSO2 +,362(M-HSO2)+;Anal.计算值:C21H21BrClN5O3S·1/5CF3COOH·3/4H2O:C44.69,H3.98,N12.18,实测值:C44.95,H4.22,N11.90。
叔丁基(1r,4r)-4-(7-(2-甲氧基-4-甲基-5-氯-苯磺酰胺基甲酰)-5-溴-1,6-二氮杂萘-8-氨基)环己氨基甲酸酯(S30-1)
化合物S30-1的制备方法与化合物S22-1的制备方法类似,除了用2-甲氧基-4-甲基-5-氯-苯磺酰胺代替对甲氧基苯磺酰胺。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3)δ10.56(s,1H),9.17(brs,1H),8.94(d,J=4.2Hz,1H),8.46(d,J=8.4Hz,1H),8.1(s,1H),7.65(dd,J=4.2,8.4Hz,1H),6.85(s,1H),4.98(brs,1H),4.36(brs,1H),3.95(s,3H),3.43(brs,1H),2.42(s,3H),2.01-2.14(m,4H),1.45(s,9H),1.27-1.37(m,4H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2-甲氧基-4-甲基-5-氯-苯磺酰基)-5-溴-1,6-二氮杂萘-7-羧酸胺(S30)
化合物S30的制备方法与化合物S22的制备方法类似,除了用化合物S30-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,d6-DMSO):δ9.05(brs,1H),8.4(d,J=7.2Hz,1H),7.79-7.84(m,2H),7.18-7.23(m,3H),4.54(brs,1H),3.82(s,3H),3.01(brs,1H),2.38(s,3H),2.06(d,J=9.9Hz,2H),1.97(d,J=12.3Hz,2H),1.39-1.47(m,2H),1.24-1.36(m,2H);MS-ESIm/z:584(M+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-(4-氟-苄基)-5-氰基-1,6-二氮杂萘-7-羧酸胺(S31)
化合物S31的制备方法与化合物S1的制备方法类似,黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.60(d,1H,J=8.1Hz),9.30(dd,1H,J=1.5,4.2Hz),8.40(dd,1H,J=1.2,8.7Hz),8.33(m,1H),7.58(dd,1H,J=4.2,8.4Hz),7.30(s,4H),4.96(m,1H),4.59(d,2H,J=6.0Hz),2.77(m,1H),2.17(m,2H),1.94(m,2H),1.43-1.24(m,4H);EI-MSm/z:418(M)+。
8-((1r,4r)-4-氨基环己氨基)-7-(4-氟-苄基氨基甲酰)-1,6-二氮杂萘-5-甲酸甲酯(S32)
化合物S32的制备方法与化合物S1的制备方法类似,黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.58(d,1H,J=8.1Hz),9.29(dd,1H,J=1.2,4.5Hz),8.40(dd,1H,J=1.2,8.7Hz),8.33(m,1H),7.58(dd,1H,J=4.2,8.4Hz),7.30(s,4H),4.96(m,1H),4.59(d,2H,J=6.0Hz),3.89(s,3H),2.77(m,1H),2.17(m,2H),1.94(m,2H),1.43-1.24(m,4H);EI-MSm/z:451(M)+。
甲苯-4-磺酸5-碘-7-(3-三氟甲基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S33-2)
化合物S33-2的制备方法与化合物9-1的制备方法类似,除了用化合物S33-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.97(d,J=3.3Hz,1H),8.41(d,J=8.4Hz,1H),8.1(t,J=6Hz,1H),7.91(d,J=8.1Hz,2H),7.45-7.68(m,5H),7.4(d,J=8.4Hz,2H),7.26-7.34(m,4H),7.31(d,J=8.4Hz,2H),4.71(d,J=6Hz,2H),2.45(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-三氟甲基-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S33-3)
化合物S33-3的制备方法与化合物S1的制备方法类似,除了用化合物S33-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.63(d,J=7.8Hz,1H),8.88(d,J=5.7Hz,1H),8.41(t,J=6.6Hz,1H),8.25(d,J=8.4Hz,1H),7.45-7.62(m,5H),4.95(m,1H),4.7(d,J=6.6Hz,2H),4.39(brs,1H),3.47(m,1H),2.19(d,J=14.4Hz,2H),2.06(d,J=12Hz,2H),1.45(s,9H),1.23-1.45(m,4H)。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(3-三氟甲基苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S33-4)
将化合物S33-3(84mg,1.25mmol),丙炔酸甲酯(100ul,6mmol),氯化钯(1mg,0.05mmol),三苯基膦(2.6mg,0.01mmol),碘化亚铜(2.0mg,0.01mmol)和碳酸钾(34mg,0.25mmol)溶于5mLTHF中,氮气保护,加热回流14小时。反应体系冷却,旋干THF,加入20mL二氯甲烷,饱和食盐水洗两次,有机相用无水硫酸钠干燥。硅胶柱层析(石油醚∶乙酸乙酯=4∶1)得到黄绿色固体化合物S33-475mg,产率:97%。1HNMR(300MHz,CDCl3):δ10.41(d,J=10.8Hz,1H),8.92(d,J=4.2Hz,1H),8.66(m,1H),8.52(d,J=8.4Hz,1H),7.46-7.62(m,5H),5.11(m,1H),4.69(d,2H),4.4(brs,1H),3.88(s,3H),3.5(m,1H),2.24(d,J=12.6Hz,2H),2.1(d,J=11.7Hz,2H),1.45(s,9H),1.24-1.45(m,4H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3-三氟甲基苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S33)
化合物S33由化合物S33-4在20%的三氟醋酸/二氯甲烷室温反应2小时脱Boc得到。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.38(d,J=8.1Hz,1H),8.93(d,J=6Hz,1H),8.67(t,J=6.3Hz,1H),8.51(d,J=8.1Hz,1H),7.45-7.61(m,5H),5.14(m,1H),4.68(d,2H),3.88(s,3H),2.77(m,1H),2.23(d,J=11.4Hz,2H),1.93(d,J=12.3Hz,2H),1.3-1.47(m,4H);MS-EIm/z:525(M)+,526(M+1)+;Anal.计算值:C27H26F3N5O3·1/4CF3COOH:C59.62,H4.78,N12.64,实测值:C59.50,H4.90,N12.63。
甲苯-4-磺酸5-碘-7-(3,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S34-2)
化合物S34-2的制备方法与化合物9-1的制备方法类似,除了用化合物S34-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.97(d,J=3.9Hz,1H),8.39(d,J=8.7Hz,1H),8.08(t,J=6.3Hz,1H),7.91(d,J=8.4Hz,2H),7.66(dd,J=3.9,8.7Hz),7.41-7.48(m,2H),7.32(d,J=8.4Hz,2H),7.23-7.25(m,1H),4.61(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3,4-二氯-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S34-3)
化合物S34-3的制备方法与化合物S1的制备方法类似,除了用化合物S34-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.60(d,J=8.1Hz,1H),8.88(d,J=5.7Hz,1H),8.37(t,J=5.7Hz,1H),8.25(d,J=8.4Hz,1H),7.57(dd,J=5.7,8.4Hz,1H),7.4-7.46(m,2H),7.2-7.23(m,1H),4.95(m,1H),4.59(d,J=5.7Hz,2H),4.39(br,1H),3.47(m,1H),2.18(d,J=13.5Hz,2H),2.06(d,J=12.6Hz,2H),1.45(s,9H),1.27-1.29(m,4H);MS-ESIm/z:670(M+H)+,672(M+2+H)+。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(3,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S34-4)
化合物S34-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S34-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3):10.37(d,J=8.1Hz,1H),8.92(d,J=2.1Hz,1H),8.63(t,J=6.6Hz,1H),8.51(d,J=8.1Hz,1H),7.59(dd,J=2.1,8.1Hz,1H),7.4-7.46(m,2H),7.2-7.23(m,1H),5.1(m,1H),4.57(d,J=6.6Hz,2H),4.42(br,1H),3.88(s,3H),3.48(m,1H),2.24(d,J=12Hz,2H),2.09(d,J=10.8Hz,2H),1.45(s,9H),1.25-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S34)
化合物S34的制备方法与化合物S33的制备方法类似,除了用化合物S34-4代替化合物S33-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.36(d,J=8.1Hz,1H),8.93(d,J=6Hz,1H),8.64(t,J=6.3Hz,1H),8.51(d,J=6.9Hz,1H),7.59(dd,J=6,6.9Hz,1H),7.4-7.46(m,2H),7.2-7.22(m,1H),5.1(m,1H),4.57(d,J=6.3Hz,2H),3.88(s,3H),2.79(m,1H),2.23(d,J=12.3Hz,2H),1.95(d,J=12.3Hz,2H),1.25-1.52(m,4H);MS-EIm/z:525(M)+,527(M+2)+;Anal.计算值:C26H25Cl2N5O3·1/5CF3COOH·3/10C6H14:C58.90,H5.15,N12.18,实测值:C59.04,H5.12,N12.30。
甲苯-4-磺酸5-碘-7-(2,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S35-2)
化合物S35-2的制备方法与化合物9-1的制备方法类似,除了用化合物S35-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3)8.97(d,J=4.5Hz,1H),8.40(d,J=8.4Hz,1H),8.12(t,J=6.3Hz,1H),7.90(d,J=8.1Hz,2H),7.66(dd,J=4.5,8.4Hz,1H),7.43(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),7.22-7.25(m,1H),4.68(d,J=6.3Hz,2H),2.47(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(2,4-二氯-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S35-3)
化合物S35-3的制备方法与化合物S1的制备方法类似,除了用化合物S35-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.58(d,J=8.4Hz,1H),8.87(d,J=3.9Hz,1H),8.42(t,J=6.9Hz,1H),8.25(d,J=8.4Hz,1H),7.57(dd,J=3.9,8.4Hz,1H),7.36-7.41(m,2H),7.22-7.26(m,1H),4.94(m,1H),4.68(d,J=6.9Hz,2H),4.37(br,1H),3.46(m,1H),2.17(d,J=12Hz,2H),2.05(d,J=13.5Hz,2H),1.44(s,9H),1.25-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(2,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S35-4)
化合物S35-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S35-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3)δ10.37(d,J=8.1Hz,1H),8.92(d,J=3.9Hz,1H),8.61(t,J=6.3Hz,1H),7.35-7.41(m,2H),7.21-7.26(m,1H),5.10(m,1H),4.68(d,J=6.3Hz,2H),4.39(br,1H),3.88(s,3H),3.48(m,1H),2.23(d,J=12.3Hz,2H),2.08(d,J=12.9Hz,2H),1.45(s,9H),1.25-1.38(m,4H);MS-EIm/z:625(M)+,627(M+2)+。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(2,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S35)
化合物S35的制备方法与化合物S33的制备方法类似,除了用化合物S35-4代替化合物S33-4。黄绿色固体,产率:70-85%。IR(film)vmax=3427,2920,2202,1709,1643,1606,1576,1500,1358,1230,1138,822cm-1;1HNMR(300MHz,CDCl3)δ10.35(d,J=6.9Hz,1H),8.93(s,1H),8.62(t,J=5.7Hz,1H),8.52(d,J=6.9Hz,1H),7.58(dd,J=6.9Hz,1H),7.34-7.41(m,2H),7.21-7.24(m,1H),5.14(m,1H),4.67(d,J=5.7Hz,2H),3.88(s,3H),2.88(m,1H),2.25(s,2H),2.01(s,2H),1.42-1.52(m,4H);MS-EIm/z:525(M)+,527(M+2)+;Anal.计算值:C26H25Cl2N5O3·1/5CF3COOH·CH3OH:C56.62,H5.06,N12.05,实测值:C56.73,H4.87,N11.81。
甲苯-4-磺酸5-碘-7-(3-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S36-2)
化合物S36-2的制备方法与化合物9-1的制备方法类似,除了用化合物S36-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):9.00(d,J=3.9Hz,1H),8.40(d,J=8.4Hz,1H),8.04(t,J=6.3Hz,1H),7.92(d,J=8.4Hz,2H),7.66(dd,J=3.9,8.4Hz,1H),7.37(s,1H),7.29-7.34(m,5H),4.62(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(3-氯-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S36-3)
化合物S36-3的制备方法与化合物S1的制备方法类似,除了用化合物S36-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.64(d,J=6.6Hz,1H),8.87(d,J=3.6Hz,1H),8.36(t,J=6.3Hz,1H),8.25(d,J=8.4Hz,1H),7.57(dd,J=3.6,8.4Hz,1H),7.36(s,1H),7.25-7.28(m,3H),4.96(m,1H),4.62(d,J=6.3Hz,2H),4.38(br,1H),3.47(m,1H),2.19(d,J=12Hz,2H),2.07(d,J=12.3Hz,2H),1.45(s,9H),1.26-1.4(m,4H);MS-ESIm/z:636(M+H)+。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(3-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S36-4)
化合物S36-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S36-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3):δ10.42(d,J=6.6Hz,1H),8.92(d,J=5.7Hz,1H),8.61(t,J=6.3Hz,1H),8.52(d,J=8.4Hz,1H),7.58(dd,J=5.7,8.4Hz,1H),7.36(s,1H),7.23-7.28(m,3H),5.09(m,1H),4.61(d,J=6.3Hz,2H),4.39(br,1H),3.87(s,3H),3.50(m,1H),2.24(d,J=13.5Hz,2H),2.09(d,J=14.4Hz,2H),1.45(s,9H),1.25-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S36)
化合物S36的制备方法与化合物S33的制备方法类似,除了用化合物S36-4代替化合物S33-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.40(d,J=7.5Hz,1H),8.93(d,J=3.9Hz,1H),8.63(t,J=6.6Hz,1H),8.51(d,J=8.1Hz,1H),7.59(dd,J=3.9,8.1Hz,1H),7.36(s,1H),7.26-7.28(m,3H),5.13(m,1H),4.61(d,J=6.6Hz,2H),3.88(s,3H),2.77(m,1H),2.23(d,J=12Hz,2H),1.93(d,J=12.6Hz,2H),1.25-1.44(m,4H);13CNMR(100MHz,CDCl3):δ167.9154.3150.1145.9141.8140.5134.4133.9129.9128.4127.6127.4125.7124.7124.4121.483.582.153.852.949.942.334.933.0;MS-EIm/z:491(M)+,493(M+2)+;Anal.计算值:C26H26ClN5O3·1/10C6H14:C63.81,H5.52,N13.99,实测值:C63.98,H5.49,N13.99。
甲苯-4-磺酸5-碘-7-(4-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S37-2)
化合物S37-2的制备方法与化合物9-1的制备方法类似,除了用化合物S37-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.97(d,J=4.2Hz,1H),8.39(d,J=9Hz,1H),8.00(t,J=6.3Hz,1H),7.91(d,J=8.1Hz,2H),7.65(dd,J=4.2,9Hz),7.3-7.33(m,6H),4.61(d,J=6.3Hz,2H),2.46(s,3H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-氯-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S37-3)
化合物S37-3的制备方法与化合物S1的制备方法类似,除了用化合物S37-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.64(d,J=8.1Hz,1H),8.87(d,J=3.9Hz,1H),8.33(t,J=6Hz,1H),8.24(d,J=9Hz,1H),7.56(dd,J=3.9,9Hz,1H),7.31(s,4H),4.95(m,1H),4.60(d,J=6Hz,2H),4.37(br,1H),3.49(m,1H),2.18(d,J=12.9Hz,2H),2.06(d,J=13.8Hz,2H),1.44(s,9H),1.26-1.39(m,4H);MS-ESIm/z:636(M+H)+。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(4-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S37-4)
化合物S37-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S37-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3)10.43(d,J=8.4Hz,1H),8.92(d,J=5.7Hz,1H),8.59(t,J=6.3Hz,1H),8.51(d,J=8.4Hz,1H),7.59(dd,J=5.7,8.4Hz,1H),7.32(s,4H),5.11(m,1H),4.59(d,J=6.3Hz,2H),4.40(br,1H),3.88(s,3H),3.50(m,1H),2.24(d,J=12.3Hz,2H),2.09(d,J=12.3Hz,2H),1.45(s,9H),1.26-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(4-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S37)
化合物S37的制备方法与化合物S33的制备方法类似,除了用化合物S37-4代替化合物S33-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.41(d,J=8.7Hz,1H),8.93(d,J=4.2Hz,1H),8.60(t,J=6.3Hz,1H),8.51(d,J=8.4Hz,1H),7.59(dd,J=4.2,8.4Hz,1H),7.32(s,4H),5.13(m,1H),4.59(d,J=6.3Hz,2H),3.88(s,3H),3.53(br,1H),2.80(m,1H),2.23(d,J=12Hz,2H),1.96(d,J=14.1Hz,2H),1.33-1.48(m,4H);MS-EIm/z:491(M)+,493(M+2)+;Anal.计算值:C26H26ClN5O3:C63.48,H5.33,N14.24,实测值:C63.11,H5.33,N13.87。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}-3-丙二酸甲酯(S38)
化合物S38由化合物S34-4在20%的三氟醋酸/二氯甲烷中40度反应2小时得到。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.74(d,J=9Hz,1H),9.69(d,J=8.7Hz,1H),8.89(d,J=4.2Hz,1H),8.76(t,J=6.3Hz,1H),7.56-7.62(m,1H),7.40-7.43(m,2H),7.26-7.30(m,1H),5.21(m,1H),4.61(d,J=6.3Hz,2H),3.93(s,2H),3.57(s,3H),2.78(m,1H),2.23(d,J=13.5Hz,2H),1.94(d,J=12.3Hz,2H),1.25-1.49(m,4H);MS-EIm/z:543(M)+,545(M+2)+。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(2,4-二氯-苄基氨基甲酰)-1,6-二氮杂萘基]}-3-丙二酸甲酯(S39)
化合物S39的制备方法与化合物S38的制备方法类似,除了用化合物S35-4代替化合物S34-4。黄绿色固体,产率:70-85%。IR(film)vmax=3423,2926,1678,1647,1508,1207,1138,800cm-1;1HNMR(300MHz,CDCl3):δ10.72(br,1H),9.69(d,J=9.3Hz,1H),8.89(s,1H),8.70(t,J=6Hz,1H),7.59(m,1H),7.39-7.42(m,2H),7.22-7.26(m,1H),5.19(m,1H),4.71(d,J=6Hz,2H),3.97(s,2H),3.59(s,3H),2.76(m,1H),2.22(d,J=11.4Hz,2H),1.93(d,J=13.5Hz,2H),1.25-1.48(m,4H);13CNMR(100MHz,CDCl3):δ192.0169.9168.4149.5147.6141.9134.6134.1133.7131.8130.1129.3127.2126.3125.3121.854.152.449.948.640.635.033.029.6;MS-EIm/z:543(M)+,545(M+2)+。
甲苯-4-磺酸5-碘-7-(3-三氟甲基-4-氯-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S40-2)
化合物S40-2的制备方法与化合物9-1的制备方法类似,除了用化合物S40-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.95(d,J=4.2Hz,1H),8.39(d,J=8.7Hz,1H),8.11(t,J=6.6Hz,1H),7.90(d,J=7.8Hz,2H),7.71(s,1H),7.66(dd,J=4.2,8.7Hz),7.47-7.56(m,2H),7.31(d,J=8.4Hz,2H),4.68(d,J=6.6Hz,2H),2.46(s,3H);MS-ESIm/z:662(M+H)+。
8-((1r,4r)-4-氨基环己氨基)-N-(3-三氟甲基-4-氯-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S40-3)
化合物S40-3的制备方法与化合物S1的制备方法类似,除了用化合物S40-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.58(d,J=8.1Hz,1H),8.88(d,J=4.8Hz,1H),8.41(t,J=6.6Hz,1H),8.25(d,J=9.9Hz,1H),7.68(s,1H),7.58(dd,J=4.8,9.9Hz,1H),7.46-7.52(m,2H),4.96(m,1H),4.65(d,J=6.6Hz,2H),4.39(br,1H),3.48(m,1H),2.18(d,J=12.6Hz,2H),2.06(d,J=13.8Hz,2H),1.44(s,9H),1.23-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(3-三氟甲基-4-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S40-4)
化合物S40-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S40-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3):10.35(d,J=8.4Hz,1H),8.93(d,J=4.2Hz,1H),8.67(t,J=6.6Hz,1H),8.51(d,J=8.1Hz,1H),7.68(s,1H),7.60(dd,J=4.2,8.1Hz,1H),7.46-7.52(m,2H),5.11(m,1H),4.63(d,J=6.6Hz,2H),4.42(br,1H),3.88(s,3H),3.49(m,1H),2.24(d,J=10.2Hz,2H),2.09(d,J=13.8Hz,2H),1.45(s,9H),1.25-1.38(m,4H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3-三氟甲基-4-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S40)
化合物S40的制备方法与化合物S33的制备方法类似,除了用化合物S40-4代替化合物S33-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.32(d,J=8.4Hz,1H),8.94(d,J=6Hz,1H),8.68(t,J=6Hz,1H),8.52(d,J=6.3Hz,1H),7.69(s,1H),7.60(dd,J=6,6.3Hz,1H),7.46-7.53(m,2H),5.14(m,1H),4.63(d,J=6Hz,2H),3.88(s,3H),2.81(m,1H),2.24(d,J=12.3Hz,2H),1.96(d,J=13.5Hz,2H),1.33-1.51(m,4H);MS-EIm/z:559(M)+,561(M+2)+;Anal.计算值:C27H25ClF3N5O3·1/3H2O:C57.30,H4.57,N12.37,实测值:C57.55,H4.78,N12.07。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(3-三氟甲基-4-氯-苄基氨基甲酰)-1,6-二氮杂萘基]}-3-丙二酸甲酯(S41)
化合物S41的制备方法与化合物S38的制备方法类似,除了用化合物S40-4代替化合物S34-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.72(d,J=8.4Hz,1H),9.68(d,J=8.7Hz,1H),8.91(d,J=3.9Hz,1H),8.83(t,J=6.9Hz,1H),7.80(s,1H),7.56-7.63(m,2H),7.48(d,J=8.4Hz,2H),5.20(m,1H),4.66(d,J=6.9Hz,2H),3.92(s,2H),3.54(s,3H),2.83(m,1H),2.25(d,J=11.1Hz,2H),1.98(d,J=11.4Hz,2H),1.38-1.49(m,4H);MS-EIm/z:577(M)+,579(M+2)+;Anal.计算值:C27H27ClF3N5O4·1/3C6H14:C57.41,H5.26,N11.54,实测值:C57.34,H5.11,N11.24。
甲苯-4-磺酸5-碘-7-(4-环己烷氧基-苄基氨基甲酰)-1,6-二氮杂萘-8-羧酸酯(S42-2)
化合物S42-2的制备方法与化合物9-1的制备方法类似,除了用化合物S42-1代替化合物8-1。白色固体,产率:85-95%。1HNMR(300MHz,CDCl3):8.98(d,J=4.2Hz,1H),8.38(d,J=8.4Hz,1H),7.92(d,J=8.1Hz,2H),7.87(t,J=6.3Hz,1H),7.65(dd,J=4.2,8.4Hz),7.3-7.34(m,4H),6.89(d,J=8.4Hz,2H),4.54(d,J=63Hz,2H),4.25(m,1H),2.47(s,3H),1.96-2.01(m,2H),1.79-1.83(m,2H),1.31-1.53(m,6H)。
8-((1r,4r)-4-氨基环己氨基)-N-(4-环己烷氧基-苄基)-5-碘-1,6-二氮杂萘-7-羧酸胺(S42-3)
化合物S42-3的制备方法与化合物S1的制备方法类似,除了用化合物S42-2代替化合物9-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.43(d,J=8.1Hz,1H),8.87(d,J=4.2Hz,1H),8.22-8.27(m,2H),7.55(dd,J=4.2Hz,1H),7.26-7.3(m,2H),6.89(d,J=9Hz,2H),4.94(m,1H),4.56(d,J=6.6Hz,2H),4.39(br,1H),4.23(m,1H),3.49(m,1H),2.16-2.20(m,2H),1.97-2.09(m,4H),1.78(m,2H),1.45(s,9H),1.26-1.49(m,10H)。
3-{5-[8-((1r,4r)-4-(叔丁氧羰基氨)环己氨基)-7-(4-环己烷氧基-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S42-4)
化合物S42-4的制备方法与化合物S33-4的制备方法类似,除了用化合物S42-3代替化合物S33-3。黄绿色固体,产率:75-95%。1HNMR(300MHz,CDCl3):10.54(d,J=8.1Hz,1H),8.91(d,J=4.2Hz,1H),8.47-8.52(m,2H),7.57(dd,J=4.2Hz,1H),7.26-7.29(m,2H),6.89(d,J=8.7Hz,2H),5.11(m,1H),4.55(d,J=6Hz,2H),4.40(br,1H),4.23(m,1H),3.87(s,3H),3.51(m,1H),1.79-2.26(m,8H),1.46(s,9H),1.25-1.38(m,10H)。
3-{5-[8-((1r,4r)-4-氨基环己氨基)-7-(4-环己烷氧基-苄基氨基甲酰)-1,6-二氮杂萘基]}丙炔酸甲酯(S42)
化合物S42的制备方法与化合物S33的制备方法类似,除了用化合物S42-4代替化合物S33-4。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):δ10.50(d,J=8.1Hz,1H),8.93(d,J=6Hz,1H),8.48-8.51(m,2H),7.57(dd,J=6Hz,1H),7.26-7.29(m,2H),6.89(d,J=8.7Hz,2H),5.13(m,1H),4.54(d,J=6Hz,2H),4.24(m,1H),3.87(s,3H),2.95(m,1H),1.78-2.29(m,8H),1.25-1.49(m,10H);MS-ESIm/z:556(M+1)+;Anal.计算值:C32H37N5O4·3/10CF3COOH:C66.38,H6.37,N11.87,实测值:C66.72,H5.99,N11.55。
化合物S43
化合物S43的制备方法与化合物S1的制备方法类似。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.72(brs,2H),8.82(d,J=4.2Hz,2H),8.35(d,J=8.4Hz,2H),8.22(m,2H),7.50(dd,J=4.2,8.4Hz,2H),7.35(m,4H),7.03(t,J=8.5Hz,4H),4.57(d,J=6Hz,4H),4.35(t,J=6.6Hz,4H),2.15(t,J=6.6Hz,2H);MS-EIm/z:788(M)+,790(M+2)+。
化合物S44
化合物S44的制备方法与化合物S1的制备方法类似。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):δ9.63(d,J=8.7Hz,2H),8.96(d,J=4.2Hz,2H),8.42(m,4H),7.70(s,2H),7.62(dd,J=3.9Hz,2H),7.50(m,4H),5.12(m,2H),4.66(d,J=6Hz,4H),2.23-2.25(m,4H),1.25(m,4H);MS-ESIm/z:999(M+H)+,1001(M+2+H)+。
化合物S45
合物S45的制备方法与化合物S33的制备方法类似。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):8.95(s,2H),8.72(t,J=6.3Hz,2H),8.53(d,J=6.9Hz,2H),7.71(s,2H),7.62(dd,J=6.9Hz,2H),7.50(m,4H),5.29(m,2H),4.65(d,J=6.3Hz,4H),3.89(s,6H),3.50(m,2H),2.30-2.32(m,4H),1.25(m,4H);MS-ESIm/z:1003(M+H)+,1005(M+2+H)+。
化合物S46-1
化合物12与HOAt、EDCI、DIPEA在二氯甲烷中,常温下与1,4-二苄胺反应12h得到化合物S46-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CDCl3):9.67(d,J=8.4Hz,2H),8.93(d,J=5.7Hz,2H),8.41(d,J=6.9Hz,2H),8.31(t,J=6.3Hz,2H),7.58(dd,J=5.7,6.9Hz,2H),7.38(s,4H),4.94(m,2H),4.63(d,J=63Hz,4H),3.48(m,2H),2.19(d,J=12.3Hz,4H),2.06(d,J=12.6Hz,4H),1.45(s,18H),1.25-1.40(m,8H);MS-ESIm/z:1299(M-H)+。
化合物S46
化合物S46的制备方法与化合物S22的制备方法类似,除了用化合物S46-1代替化合物S22-1。黄绿色固体,产率:75-85%。1HNMR(300MHz,CD3OD):8.94(s,2H),8.42(d,J=8.4Hz,2H),7.68(m,2H),7.35(s,4H),4.53(s,4H),3.14(m,4H),2.24-2.28(m,4H),2.05-2.1(m,4H),1.35-1.58(m,8H);MS-ESIm/z:831(M+H)+,833(M+2+H)+;HR-ESIMS计算值:C38H42Br2N10O2(M+Na)+:851.1757,实测值:851.1740。
化合物S47-1
化合物S47-1的制备方法与化合物S46-1的制备方法类似,除了用1,6-己二胺代替1,4-二苄胺。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):9.68(d,J=8.1Hz,2H),8.92(d,J=3.9Hz,2H),8.40(d,J=8.7Hz,2H),8.01(t,J=5.7Hz,2H),7.57(dd,J=3.9,8.7Hz,2H),4.91(m,2H),4.37(m,2H),3.39-3.49(m,6H),2.17(d,J=11.4Hz,4H),2.05(d,J=11.4Hz,4H),1.68(m,6H),1.44(s,18H),1.21-1.39(m,10H);MS-ESIm/z:1011(M+H)+。
化合物S47
化合物S47的制备方法与化合物S22的制备方法类似,除了用化合物S47-1代替化合物S22-1。黄绿色固体,产率:70-85%。1HNMR(300MHz,CD3OD):8.99(d,J=6Hz,2H),8.50(d,J=8.4Hz,2H),7.73(dd,J=6,8.4Hz,2H),4.96(m,2H),3.40(t,J=6.6Hz,4H),3.16(m,2H),2.29(d,J=12Hz,4H),2.09(d,J=11.4Hz,4H),1.64-1.71(m,4H),1.37-1.59(m,12H);MS-ESIm/z:811(M+H)+。
化合物S48-1
化合物S48-1的制备方法与化合物S46-1的制备方法类似,除了用1,3-丙二胺代替1,4-二苄胺。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):9.69(d,J=6.9Hz,2H),8.92(d,J=4.2Hz,2H),839(d,J=8.4Hz,2H),8.26(t,J=5.7Hz,2H),7.57(dd,J=4.2,8.4Hz,2H),4.91(m,2H),4.39(m,2H),3.45-3.59(m,6H),2.18(d,J=11.7Hz,4H),2.06(d,J=10.5Hz,4H),1.44(s,18H),1.21-1.34(m,10H);MS-ESIm/z:969(M+H)+。
化合物S48
化合物S48的制备方法与化合物S22的制备方法类似,除了用化合物S48-1代替化合物S22-1。黄绿色固体,产率:70-85%。1HNMR(300MHz,CD3OD):8.92(d,J=3Hz,2H),8.31(d,J=8.4Hz,2H),7.66(dd,J=3,8.4Hz,2H),4.83(m,2H),3.52(t,J=6Hz,4H),3.14(m,2H),2.26(d,J=12Hz,4H),2.07(d,J=11.4Hz,4H),1.95(m,2H),1.39-1.61(m,8H);13CNMR(100MHz,CD3OD):δ170.0153.0146.4145.8138.0128.2126.7126.6125.954.651.338.733.930.9;MS-ESIm/z:769(M+H)+。
化合物S49-1
化合物S49-1的制备方法与化合物S46-1的制备方法类似,除了用1,4-丁二胺代替1,4-二苄胺。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):9.68(d,J=7.8Hz,2H),8.91(d,J=3.9Hz,2H),8.14(d,J=8.4Hz,2H),8.04(t,J=6Hz,2H),7.57(dd,J=3.9,8.4Hz,2H),4.92(m,2H),4.39(m,2H),3.48(m,6H),2.17(d,J=12.6Hz,4H),2.05(d,J=11.4Hz,4H),1.77(brs,4H),1.44(s,18H),1.23-1.39(m,8H);MS-ESIm/z:983(M+H)+。
化合物S49
化合物S49的制备方法与化合物S22的制备方法类似,除了用化合物S49-1代替化合物S22-1。黄绿色固体,产率:70-85%。1HNMR(300MHz,CD3OD):8.97(d,J=2.7Hz,2H),8.48(d,J=9.6Hz,2H),7.73(dd,J=2.7,9.6Hz,2H),4.92(m,2H),3.45(m,4H),3.15(m,2H),2.27(d,J=11.7Hz,4H),2.08(d,J=12.6Hz,4H),1.75(brs,4H),1.36-1.62(m,8H);MS-ESIm/z:783(M+H)+。
化合物S50-1
化合物S50-1的制备方法与化合物S46-1的制备方法类似,除了用反式1,4-环己二胺代替1,4-二苄胺。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):9.70(d,J=8.4Hz,2H),8.93(d,J=5.7Hz,2H),8.43(d,J=10.5Hz,2H),7.85(d,J=8.1Hz,2H),7.58(dd,J=5.7,10.5Hz,2H),4.93(m,2H),4.38(m,1H),3.96(m,1H),3.48(m,2H),2.18(d,J=7.8Hz,8H),2.06(d,J=11.1Hz,4H),1.45(s,18H),1.25-1.39(m,12H);MS-ESIm/z:1009(M+H)+。
化合物S50
化合物S50的制备方法与化合物S22的制备方法类似,除了用化合物S50-1代替化合物S22-1。黄绿色固体,产率:70-85%。1HNMR(300MHz,CD3OD):9.02(d,J=4.2Hz,2H),8.54(d,J=10.2Hz,2H),7.76(dd,J=4.2,10.2Hz,2H),4.97(m,2H),3.92(m,4H),3.18(m,2H),2.31(d,J=11.7Hz,4H),2.12(m,8H),1.43-1.67(m,12H);13CNMR(100MHz,CD3OD):δ169.2153.2146.5145.8138.2128.3127.0126.8126.054.751.349.749.533.032.330.1;MS-ESIm/z:809(M+H)+。
化合物S51-1
化合物S51-1的制备方法与化合物S46-1的制备方法类似,除了用哌嗪代替1,4-二苄胺。黄绿色固体,产率:70-85%。1HNMR(300MHz,CDCl3):8.94(d,J=12.3Hz,2H),8.44(dd,J=8.1Hz,2H),7.65(m,2H),6.43(brs,2H),4.47(m,2H),4.00(s,2H),3.91(brs,2H),3.58-3.64(m,4H),3.48(brs,2H),2.10(t,J=12.9Hz,10H),1.44(s,18H),1.25-1.38(m,6H);MS-ESIm/z:981(M+H)+。
化合物S51
化合物S51的制备方法与化合物S22的制备方法类似,除了用化合物S51-1代替化合物S22-1。黄绿色固体,产率:70-85%。1HNMR(300MHz,CD3OD):9.05(d,J=12Hz,2H),8.54(dd,J=8.1Hz,2H),7.80(m,2H),4.05(s,2H),3.93(brs,2H),3.69(brs,2H),3.60(s,2H),3.52(brs,2H),3.17(m,2H),2.16(d,J=12.9Hz,8H),1.43-1.57(m,8H);13CNMR(100MHz,CD3OD):δ170.1169.9154.8145.3139.4138.5129.6129.3126.9126.154.051.048.643.232.831.3;MS-ESIm/z:781(M+H)+。
实验实施例1:5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物对人癌细胞株的体外增殖抑制作用
细胞株:人乳腺癌细胞株MDA-MB-435,人卵巢癌细胞株SK-BR-3,人恶性黑色素瘤细胞株A375,人皮肤鳞癌细胞株A431,人结肠癌细胞株HT-29、人肺癌细胞株A-549,人肝癌细胞株BEL-7402,人胰腺癌细胞株BXPC3,人急性髓性白血病细胞株HL-60,人***癌细胞株PC-3购自美国标准生物品收藏中心。
方法:磺酰罗单明B(sulforhodamineB,SRB)法,具体如下:将一定数量处于对数生长期的不同种类的肿瘤细胞分别接种于96孔培养板,培养24h细胞贴壁后,加入不同浓度的本发明的受试化合物,每个浓度设三复孔,并设定相应浓度的DMSO溶液对照及无细胞调零孔。用药物处理细胞72h后,倾去培养液,加入100μL冰预冷的10%的三氯乙酸溶液,于4℃固定细胞1h,用蒸馏水洗涤5次,空气中自然干燥。然后加入100μLSRB(4mg/mL)(Sigma,StLouis,MO,USA)溶液,室温中染色15min,去染色液,用1%冰醋酸洗涤5次,空气干燥。最后加入150μL10mM的Tris溶液(pH10.5),可调波长式微孔板酶标仪515nm波长下测定OD值。以下列公式计算药物对细胞生长的抑制率:抑制率(%)=(OD对照-OD加药)/OD对照×100%。
结果:本发明的多个化合物对多种肿瘤细胞株显示良好的抗肿瘤活性。部分化合物在10μM浓度下对MDA-MB-435、SK-BR-3、A375、A431、HT-29、A-549、BEL-7402、BXPC3、HL-60、PC-3等肿瘤细胞体外增殖抑制率达到了90%。具体数据见表1-10。
表1对肿瘤细胞生长的抑制率%
表2对肿瘤细胞生长的抑制率%
表3对肿瘤细胞生长的抑制率%
表4对肿瘤细胞生长的抑制率%
表5对肿瘤细胞生长的抑制率%
表6对肿瘤细胞生长的抑制率%
表7对肿瘤细胞生长的抑制率%
表8对肿瘤细胞生长的抑制率%
表9对肿瘤细胞生长的抑制率%
表10对肿瘤细胞生长的抑制率%
本发明的多个化合物对多种肿瘤细胞株显示良好的抗肿瘤活性,在10μM浓度下对MDA-MB-435,SK-BR-3,A375,A431,HT-29、A-549、BEL-7402、BXPC3、HL-60、PC-3等肿瘤细胞株的抑制率达到了90%。
基于结构通式I、II或III表示的化合物对多种肿瘤细胞有良好的抑制活性,申请人进一步对5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物的抗肿瘤机理进行了研究。申请人采用酶联免疫吸附测定(ELISA)发现5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物在10μM下对多种酪氨酸激酶(EGFR,ErbB2,c-Src,KDR,Flt-1)有很好的抑制活性。
实施例2:5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物及其二聚体化合物对5种蛋白酪氨酸激酶的抑制作用
蛋白酪氨酸激酶:c-Src、EGFR为本实验室利用昆虫杆状病毒表达***表达,用Ni-NTA柱亲和纯化获得的有活性的胞内激酶区酪氨酸激酶蛋白,并经检测符合实验要求,-70℃分装,保存。KDR,Flt-1购自Upstate公司(Waltham,MA,USA);ErbB2购自Calbiochem公司(Darmstadt,Germany)。
实验方法:酪氨酸激酶活性测试采用酶联免疫吸附测定(ELISA)方法,具体如下:首先将酶反应底物Poly(Glu,Tyr)4:1(20μg/mL,37℃过夜)包被酶标板,洗板后烘干备用。进行反应时,每孔先加入用反应缓冲液稀释的ATP溶液80μL(ATP的终浓度为5μM),然后加入梯度浓度的受试化合物或DMSO溶剂对照10μL,最后分别加入用反应缓冲液稀释的酪氨酸激酶10μL以启动反应,置37℃摇床反应1h。反应结束后,T-PBS洗板三次。然后每孔加入100μLPY99抗体(抗体用含BSA5mg/ml的T-PBS稀释),37℃摇床反应0.5h。T-PBS洗板三次。加入辣根过氧化物酶标记羊抗鼠的IgG100μL/孔(抗体用含BSA5mg/mL的T-PBS稀释),37℃摇床反应0.5h。T-PBS洗板三次。然后加入2mg/mL的OPD显色液100μL/孔,25℃避光反应1-10min。加入2MH2SO450μL/孔中止反应,用可调波长式微孔板酶标仪读数,波长为492nm。样品的抑制率通过下列公式求得:
实验重复3次以上,用Logit法计算化合物抑制PTK的IC50值和SD值。
结果:研究发现多个化合物对受试酪氨酸激酶(包括EGFR,ErbB2,c-Src,KDR,Flt-1)有不同程度的抑制活性,部分化合物在10μM浓度下对c-Src、KDR激酶抑制率高达90%,甚至优于阳性对照药。提示本发明的化合物有效作用于上述酪氨酸激酶,是结构新颖的多靶点酪氨酸激酶抑制剂。详细数据见表11。表中空格表示未进行相关测试,无相关数据。
表11化合物在10μM下对酪氨酸激酶(EGFR,ErbB2,c-Src,KDR,Flt-1)的抑制率
从表11的实验结果可以看出,本发明的化合物有效作用于上述酪氨酸激酶,是结构新颖的多靶点酪氨酸激酶抑制剂。很多化合物对Src、KDR激酶在10μM下抑制率高达90%,甚至优于阳性对照药。
Claims (8)
1.结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物:
其中,
A为苯环;
L是C1-C6烷基;
X各自独立地为NH;
Y为(1)C1-C6烷基;(3)(C0-C6烷基)-(C3-C6环烷基)-(C0-C6烷基);或(5)(C0-C6烷基)-(C6-C10芳基)-(C0-C6烷基);
R1、R2、R3和R4各自独立地为氢、卤素或-CF3;
R5为氢或C1-C6烷基;
R6独立地为卤素或者未取代或各自独立地被取代基取代的下列基团:C2-C6炔基;所述取代基选自-CORb;
Rb为氢或者未取代的下列基团:C1-C6烷基或C1-C6烷氧基。
2.根据权利要求1所述的结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物,其特征在于,进一步用结构通式V或VI表示:
其中,R1、R2、R6、L、X和Y的定义与权利要求1中相同。
3.根据权利要求2所述的结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物,其特征在于,结构通式V或VI中:
R1和R2各自独立地为氢、卤素或-CF3;
R6为卤素或L为C1-C6烷基;
X为NH;
Y为C1-C6烷基、(C1-C6烷基)-(C6-C10芳基)-(C1-C6烷基)或C3-C6环烷基。
4.一种5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物,其特征在于,具体为以下化合物:
其中,
Y为R6为Br,R8为
Y为R6为Br,R8为
Y为R6为R8为或者,
其中,
R6为Br,-X-Y-X-为
5.权利要求1至3中任一项所述的结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物或权利要求4所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物在制备酪氨酸蛋白激酶抑制剂的药物中的用途。
6.权利要求1至3中任一项所述的结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物或权利要求4所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物在制备抑制肿瘤的药物中的用途。
7.根据权利要求6所述的用途,其中,所述肿瘤包括乳腺癌、卵巢癌、恶性黑色素瘤、皮肤鳞癌、结肠癌、肺癌、肝癌、胰腺癌、急性髓性白血病和***癌。
8.一种药物组合物,其包含治疗有效量的权利要求1至3中任一项所述的结构通式II或III所示的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物或权利要求4所述的5,8-二取代-1,6-二氮杂萘-7-羰酰胺类化合物的二聚体化合物。
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