CN112574176B - 一种杂芳基类化合物及其应用 - Google Patents
一种杂芳基类化合物及其应用 Download PDFInfo
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- CN112574176B CN112574176B CN202011000203.2A CN202011000203A CN112574176B CN 112574176 B CN112574176 B CN 112574176B CN 202011000203 A CN202011000203 A CN 202011000203A CN 112574176 B CN112574176 B CN 112574176B
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Abstract
本发明公开了一种杂芳基类化合物及其应用。本发明提供了一种如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐。其具有较好的肿瘤抑制活性,特别是对人慢性淋巴细胞白血病、肺腺癌、乳腺癌、卵巢癌、乳腺癌或者胰腺癌;且对耐药的乳腺癌、肺癌、卵巢癌或白血病都有较好的抑制活性。
Description
技术领域
本发明涉及一种杂芳基类化合物及其应用。
背景技术
慢性淋巴细胞性白血病(CLL)起源于B淋巴细胞,B淋巴细胞在活化和成熟阶段不同,其来源于具有不同免疫球蛋白链可变(IgVH)基因突变的经历过抗原的B细胞(Chiorazzi Net al.,N.Engl.J.Med.,2005,352,804-15)。与具有未突变基因的患者相比具有突变IgHV基因的患者具有更好的预后效果(Damle RN et al.,Blood 1999,94,1840-7;Hamblin TJ et al.,Blood,1999,94,1848-54)。全球基因表达谱研究表明,在突变和未突变的白血病B细胞中部分区别但总体重叠的表达谱,表明了共同的表型(Klein Uet.al.,J.Exp.Med.,2001,194,1625-38;Rosenwald A et al.,J.Exp.Med.,2001,194,1639-47)。
基因表达谱研究表明CLL细胞中孤儿受体激酶酪氨酸激酶(RTK)ROR1的43.8倍的增加(Klein U et.al.,J.Exp.Med.,2001,194,1625-38)。ROR1是与肌肉特异性激酶(MUSK)和Trk神经营养因子(Trk neurotrophin)受体相关的孤儿受体的RTK家族成员(Glass DJ,etal.,Cell,1996,85,513-23;Masiakowski Pet al.,J.Biol.Chem.,1992,267,26181-90;Valenzuela DM et al.,Neuron,1995,15,573-84)。ROR受体是参与信号转导、细胞-细胞相互作用、调节细胞增殖、分化、细胞代谢和存活的细胞表面受体(Masiakowski P et al.,Biol.Chem.,1992,267,26181-90;Yoda A et al.,J.Recept.Signal Iransduct.Res.,2003,23,1-15)。它们在不同物种如人、小鼠、果蝇和秀丽隐杆线虫(C.elegans)之间在进化上具有高度保守性,表现出重要的生物学功能。
人体ROR1基因具有2814bp的编码区,具有预测的937个氨基酸序列和105kDa的蛋白质大小,包括Ig样结构域、Kringle结构域、酪氨酸激酶结构域和富含脯氨酸结构域(YodaA et al.,J.Recept.Signal Transduct.Res.,2003,23,1-15)。ROR1位于染色体区Ip31.3上(http://ensembl.org),该染色体区是在血液恶性肿瘤中染色体畸变不常见的区域。人体在ROR1在心脏、肺和肾脏中以基因水平表达,但在胎盘、胰腺和骨骼肌中表达较少(ReddyUR et al.,Oncogene,1996,13,1555-9)。重要的是,正常成年人组织和器官中几乎完全没有ROR1蛋白表达。ROR1最初从神经细胞系克隆(Masiakowski Pet al.,J.Biol.Chem.,1992,267,26181-90),且随后将缺少整个细胞外结构域但包含跨膜结构域的较短形式从胎脑库(fetal brain library)中分离。已经报道了在胎儿和成年人中枢神经系统、人类白血病、淋巴瘤细胞系和源自神经外胚层的多种人类癌症中的截短的ROR1(t-Ror1)基因(ReddyUR et al.,Oncogene,1996,13,1555-9)。还描述了包含内因子7的短部分的外显子1-7的较短转录物,预测长度为393个氨基酸,分子量为44kDa(Ensembl ID:ENSG0000185483)。
慢性淋巴细胞性白血病(CLL)患者的基因谱和蛋白质表达研究已显示ROR1的表达增加,而来自健康供体的成熟白细胞不表达该蛋白(DaneshManesh,AH et al.,Int.,J.Cancer,2008,123,1190-5)。在CLL细胞中用siRNA使ROR1沉默导致凋亡,而来自正常供体的B细胞的siRNA处理没有导致凋亡(Choudhury,A et al.,Brit.J.Haematol.,2010,151,327-35)。
急性骨髓性白血病(AML)干细胞(CD34+)可能潜在地解释了对许多细胞毒性药物的耐性。在外体测定中,对抗ROR1的嵌合体(UC99961)以剂量依赖性方式抑制ROR1+AML干细胞而不是ROR-AML细胞且不是正常CD34+干细胞的集落形式。结果表明,靶向ROR可能代表根除AML以及潜在的其它难治疗性癌症,如干细胞驱动的恶性肿瘤干细胞的重要组成部分(Balaian L et al.,Blood,ASH Annual Meeting,2012,Abstract 2560)。在急性淋巴母细胞性白血病(ALL)中,ROR1以与导致AKR、ERK和MEK的激酶的前B细胞受体(pre-BCR)信号转导平衡的方式上调调节。siRNA转染诱导ALL细胞的生长受损和凋亡(Biocca V.et al.,Cancer Cell,22,656-667,2012)。
人乳腺癌细胞,但不是正常乳腺上皮细胞,也表达了ROR1。激素受体阴性肿瘤患者以及细胞分化程度低的患者(即预后差的患者)的ROR1表达强度较高。ROR1的沉默损害了人体乳腺癌细胞在体外生长和在免疫缺陷小鼠中的生长。结果支持了这样一个概念,ROR1在乳腺癌中具有生物学和临床学意义,可能是疗法的潜在靶点(Zang,S.,et al.,Plos one,7(3):e31127,2012)。
在人体肺癌细胞中,ROR1过度表达,ROR1激酶活性在增殖P13K/AKT和凋亡性p38信号传导之间维持有利的促存活平衡,这部分是过度ROR1激酶依赖性src激酶活性以及激酶非依赖低维持EGFR/ERBB3磷酸化和PI3K激活。ROR1敲低在体外和体内有效抑制肺癌细胞的生长,不管EGFR状态如何,包括对EGFR酪氨酸激酶抑制剂吉非替尼具有抗性的那些细胞。这些数据也表面ROR1在肺癌中的重要生物学作用和用于靶向疗法的结构(Yamaguchi etal.,Cancer Cell,21,348-361,2012)。意外的是,CLL细胞表现出ERBB2的过度表达和src/PI3K、AKT/mTOR/CREB脱磷酸化(自身未公布的观测结果)。
在另一项研究中,许多实体肿瘤组织(肺、卵巢、胰腺)表达ROR1,但正常的细胞对应物不表达。ROR1表达与高级组织学和AKT和CREB的激活相关。使用shRNA使ROR1沉默诱导胰腺和卵巢癌细胞的凋亡和ROR1蛋白以及活化的AKT和CREB的下调(Zhan S.,et al.,American Jouranl of Pathology,181:1903-1910,2012)。
已经表明黑素瘤细胞表达ROR1,在凋亡之前ROR1 siRNA诱导mRNA和蛋白质水平的ROR1下调。通过ROR1定向单克隆抗体靶向黑素瘤细胞的ROR1诱导了显著凋亡,不需要免疫细胞或补体。有抗体诱导的凋亡程度在细胞之间变化(Hodjat-Farsangi M.,et al.,PlosOne,8,e61167,2013)。此外,最近研究表明,ROR1在3T3-L1细胞中的脂肪形成和葡萄糖体内平衡中起重要作用(Sanchez-Solana B.,Laborda J.,Baladron V.,MolecularEndocrinology 26:110-127,2012)。因此,调控WNT途径(如通过调节ROR1)来改变脂肪细胞的组成可能构成对抗肥胖相关代谢并发症的有吸引力的药物开发目标(ChristodoulidiesC.,Lagthu C.,Sethi J.K.,Vidal-Puig A.,Trends Endocrinol.Metab.,2009,Jan:20(1):16-24)。
上述数据用于说明调节ROR1活性以治疗失调和疾病的有效性,所述失调和疾病不仅包括慢性淋巴细胞性白血病(CLL),还包括其它血液恶性肿瘤以及实体肿瘤和肥胖相关的代谢并发症。
ROR1的抗体抑制剂已经在文献中描述:例如PCT Int.Appl.WO2011079902,酪氨酸激酶样孤儿受体1(ROR1)小分子抑制剂也有报道于文献中,例如PCTInt.Appl.WO2018011138,WO2016124553。但是,该WO2018011138,WO2016124553中提供的化合物仅公开了其对于慢性淋巴细胞性白血病(CLL)患者的周边血单核细胞(PBMC)具有一定的抑制活性。但是经研究发现,其对于其它癌细胞的抑制作用研究不足,药代性质,毒理特点还有改进的空间。
发明内容
本发明所要解决的技术问题是针对现有技术中ROR1抑制剂不足的缺陷,而提供了一种杂芳基类化合物、中间体、其制备方法及应用。本发明的杂芳基类化合物,可以用作哺乳动物中酪氨酸激酶样孤儿受体1(ROR1)抑制剂;其用于治疗,如人体激酶活性的调节有益的病症,包括各种过度增生性疾病,如血液肿瘤如慢性淋巴细胞性白血病,急性骨髓性白血病,急性淋巴母细胞白血病或套细胞淋巴瘤,以及实体肿瘤如肺、卵巢、乳腺或胰腺肿瘤,其它还包括肥胖相关的代谢并发症、自身免疫疾病和炎性病症。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐;
其中,表示咪唑环中的不饱和键;
X和Y独立地为
R4独立地为H、F、Cl、Br、I、或未取代或被一个或多个R4a取代的C1-C4烷基;当所述的取代为多个时,相同或不同;
R2独立地为C1-C6烷基;
n为0、1、2、3或4;
W独立地为连接键、-O-(C1-C3亚烷基)-、-S-(C1-C3亚烷基)-或-N(RW1)-(C1-C3亚烷基)-;
RW1独立地为H或C1-C4烷基;
R3独立地为-C(=O)-NR3aR3a’或-NR3b-C(=O)-R3b’;
R3a、R3a’、R3b和R3b’独立地为H或C1-C6烷基;
R1独立地为
R5和R5’独立地为H或C1-C6烷基;
o、p1和q1独立地为1、2或3;p2和q2独立地为1或2;
L1独立地为-SO2-或C1-C3亚烷基;
L2独立地为C1-C3亚烷基;
Ra和Rb独立地为未取代或被一个或多个Ra1取代的Cl-C6烷基、未取代或被一个或多个Ra2取代的C3~C6环烷基、未取代或被一个或多个Ra3取代的C2~C9杂环烷基、未取代或被一个或多个Ra4取代的C6~C10芳基、或、未取代或被一个或多个Ra5取代的C2~C9杂芳基;所述的C2~C9杂环烷基中,杂原子选自N、O或S中的一种或多种,杂原子数为1~3个;所述的C2~C9杂芳基中,杂原子选自N、O或S中的一种或多种,杂原子数为1~4个;当所述的取代为多个时,相同或不同;
Ra1、Ra2、Ra3、Ra4和Ra5独立地为H、F、Cl、Br、I、未取代或被一个或多个R1a-1取代的Cl-C6烷基、未取代或被一个或多个R1a-2取代的Cl-C6烷基-O-、-N(Rb2)SO2-Rb2’或-N(Rb3Rb3’);当所述的取代为多个时,相同或不同;
Rc独立地为
Rb1、Rb1’、Rb1”、Rb2’、Rc2、Rc2’、Rc2”、Rc3’和Rc4独立地为Cl-C6烷基;Rb2、Rb3、Rb3’和Rc3独立地为H或Cl-C6烷基;
Rc1独立地为H、F、Cl、Br、I、未取代或被一个或多个Rc1-1取代的Cl-C6烷基、或未取代或被一个或多个Rc1-2取代的Cl-C6烷基-O-;当所述的取代为多个时,相同或不同;
R4a、R1a-1、R1a-2、Rc1-1和Rc1-2独立地为F、Cl、Br或I;
带“*”碳原子表示为非手性碳原子或手性碳原子,当为手性碳原子时,为S构型、R构型或它们的混合物。
本发明中,所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中某些取代基的定义可如下所述,未提及的取代基的定义均如上任一方案所述。
本领域技术人员可以理解,包含互变异构体:/>
在本发明的某一方案中,所述的未取代或被一个或多个R4a取代的C1-C4烷基里的C1-C4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本发明的某一方案中,R4a、R1a-1、R1a-2、Rc1-1和Rc1-2独立地为F或Cl。
在本发明的某一方案中,R2独立地为C1-C6烷基里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,n为0或1,例如0。
在本发明的某一方案中,W可位于环的邻位、间位或对位;较佳地为间位或对位;更佳地为对位。
在本发明的某一方案中,W独立地为-O-(C1-C3亚烷基)-、-S-(C1-C3亚烷基)-或-N(RW1)-(C1-C3亚烷基)-里的C1-C3亚烷基独立地为亚甲基(-CH2-),亚乙基(例如-CH2CH2-或-CH(CH3)-),亚异丙基(例如-CH(CH3)CH2-或-C(CH3)2-);较佳地为-(CH2)-或者-(CH2)2-。
在本发明的某一方案中,RW1独立地为C1-C4烷基里的C1-C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)较佳地为甲基。
在本发明的某一方案中,R3a、R3a’、R3b和R3b’独立地为C1-C6烷基里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,R5和R5’独立地为C1-C6烷基里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,o为1或2。
在本发明的某一方案中,p为1或2。
在本发明的某一方案中,q为1或2。
在本发明的某一方案中,L1和L2独立地为C1-C3亚烷基里的C1-C3亚烷基独立地为亚甲基(-CH2-),亚乙基(例如-CH2CH2-或-CH(CH3)-),亚异丙基(例如-CH(CH3)CH2-或-C(CH3)2-);较佳地为-(CH2)-或者-(CH2)2-。
在本发明的某一方案中,所述的未取代或被一个或多个Ra1取代的Cl-C6烷基里的Cl-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,所述的未取代或被一个或多个Ra2取代的C3~C6环烷基里的C3~C6环烷基独立地为环丙基、环丁基、环戊基或环己基,例如环丙基。
在本发明的某一方案中,所述的未取代或被一个或多个Ra3取代的C2~C9杂环烷基里的C2~C9杂环烷基独立地为C3~C6杂环烷基,其中的杂原子为N,杂原子数为1或2个;例如,哌嗪基(又例如)。
在本发明的某一方案中,所述的未取代或被一个或多个Ra4取代的C6~C10芳基里的C6~C10芳基独立地为苯基或萘基。
在本发明的某一方案中,所述的未取代或被一个或多个Ra5取代的C2~C9杂芳基里的C2~C9杂芳基独立地为吡啶基(又例如),苯并呋喃基(又例如)或吲唑基(又例如/>)。
在本发明的某一方案中,Ra1、Ra2、Ra3、Ra4和Ra5独立地为未取代或被一个或多个R1a-1取代的Cl-C6烷基、未取代或被一个或多个R1a-2取代的Cl-C6烷基-O-里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,Rb1、Rb1’、Rb1”、Rb2’、Rc2、Rc2’、Rc2”、Rc3’、Rc4、Rb2、Rb3、Rb3’和Rc3独立地为Cl-C6烷基里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,Rc1独立地为未取代或被一个或多个Rc1-1取代的Cl-C6烷基、或未取代或被一个或多个Rc1-2取代的Cl-C6烷基-O-里的C1-C6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C1~C4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基),较佳地为甲基。
在本发明的某一方案中,所述的被一个或多个R4a取代的C1-C4烷基可为三氟甲基或二氟甲基。
在本发明的某一方案中,R4独立地为H或Cl。
在本发明的某一方案中,W独立地为-O-(C1-C3亚烷基)-;较佳地为-O-(CH2)-。
在本发明的某一方案中,R3独立地为-C(=O)-NR3aR3a’;较佳地为-C(=O)-NHCH3。
在本发明的某一方案中,-W-R3独立地为
在本发明的某一方案中,独立地为/>
在本发明的某一方案中,独立地为哌啶基,例如 (又例如/>)。
在本发明的某一方案中,L1独立地为-SO2-。
在本发明的某一方案中,L1独立地为C1-C3亚烷基;较佳地为亚甲基。
在本发明的某一方案中,L2为C1-C3亚烷基;较佳地为亚甲基。
在本发明的某一方案中,独立地为/>
在本发明的某一方案中,为/>
在本发明的某一方案中,-N(Rb2)SO2-Rb2’和独立地为-N(CH3)SO2-CH3。
在本发明的某一方案中,为/>
在本发明的某一方案中,为/>
在本发明的某一方案中,所述的未取代或被一个或多个Ra4取代的C6~C10芳基选自:
较佳地为
在本发明的某一方案中,所述的未取代或被一个或多个Ra5取代的C2~C9杂芳基选自: 较佳地为/>
在本发明的某一方案中,R1为
在本发明的某一方案中,R1独立地为较佳地为在本发明的某一方案中,R1独立地为/>较佳地为
在本发明的某一方案中,R1为其中,Rc独立地为/>较佳地为/> 较佳地为/>在本发明的某一方案中,R1为/>其中,Rc独立地为/>较佳地为较佳地为/>在本发明的某一方案中,R1为/>其中,Rc独立地为/>较佳地为较佳地为/>
在本发明的某一方案中,R1为其中,Rc独立地为/>较佳地为/>较佳地为/>
在本发明的某一方案中,Ra独立地为未取代或被一个或多个Ra4取代的C6~C10芳基。
在本发明的某一方案中,Rb独立地为未取代或被一个或多个Ra1取代的Cl-C6烷基、未取代或被一个或多个Ra2取代的C3~C6环烷基、或未取代或被一个或多个Ra4取代的C6~C10芳基。
在本发明的某一方案中,为/>本领域技术人员可以理解,当化合物价允许时,/>可以互变异构的形式存在;例如,可以为互变异构:/>可为互变异构:/>
在本发明的某一方案中,为/>较佳地为(或互变异构:/>)。
在本发明的某一方案中,不为/>
在本发明的某一方案中,为/>
在本发明的某一方案中,X和Y独立地为或者,Y独立地为/>X独立地为/>即为/>所述的/>可为(或互变异构:/>)或/>(或互变异构:/>);所述的/>可为/>(例如/>)/>
所述的较佳地为/>(或互变异构:/>)或(或互变异构:/>);所述的/>较佳地为/>(或互变异构:/>)、/>(或互变异构:/>)(或互变异构:/>)。
在本发明的某一方案中,所述的如式I所示的杂芳基类化合物为如式Ia所示:
其中,R1为Rc独立地为/>
R2、R3、R4a、Ra、Rb、R5、R5’、L1、L2、Rc2、Rc2’、Rc2”、Rc3、Rc3’、Rc4、W、o、p1、q1、p2、q2和n的定义均如上所述。
在本发明的某一方案中,所述的如式I所示的杂芳基类化合物为如式Ib所示:
其中,X和Y独立地为或者,Y独立地为/>X独立地为/>或R1、R2、R3、R4、W和n的定义均如上所述。
在本发明的某一方案中,当带“*”碳原子为手性碳时,可为构型R或S构型,更佳地为R构型。
在本发明的某一方案中,所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中,所述的如式I所示的杂芳基类化合物选自如下结构:
由此,在本说明书通篇中,本领域技术人员可对所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中所述基团及其取代基进行选择,以提供稳定的如式I所示的杂芳基类化合物、其立体异构体、互变异构体、药学上可接受的盐或前药,包括但不限于本发明的实施例中所述的化合物。
本发明所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成,其步骤和条件可参考本领域类似反应的步骤和条件,特别是根据本文说明进行合成。起始原料通常是来自商业来源,例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。
本发明中,所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐,也可以通过已制备得到的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐,采用本领域常规方法,经外周修饰进而得到其他所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式I所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
本发明中,所述的如式I所示的杂芳基类化合物的制备方法,其包括如下步骤:在有机溶剂中,在还原剂存在下,将如式1所示的化合物与如式2所示的化合物进行如下所示的缩合反应,得到所述的如式I所示的杂芳基类化合物即可;
其中,X、Y、R1、R2、n、W和R3的定义如上所述。
所述的缩合反应的条件和操作可为本领域该类反应中常规的条件和操作,例如参考Yang,D,et al.,Synthesis,2005,47-56中的反应的条件和操作。其中,所述的有机溶剂可为乙醇;所述的还原剂可为硫代硫酸钠;所述的缩合反应的温度可为70±5℃。
所述的制备方法还可包括如下步骤,在有益溶剂中,将如式3所示的化合物与如式4所示的化合物进行如下所示的取代反应,得到所述的如式1所示的化合物即可;
其中,X、Y和R1的定义如上所述。
所述的取代反应的条件和操作可为本领域该类反应中常规的条件和操作。其中,所述的有机溶剂可为异丙醇;所述的取代反应的温度可为70±5℃。
用于制备如式I中化合物的必要原料或试剂可以商购获得,或者通过本领域已知的合成方法制备。
药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸,根据常规方法处理来制备药学上可接受的盐。
成盐实例包括:与无机酸成盐,如盐酸、氢溴酸、硫酸、硝酸、磷酸;和有机酸所形成的盐,如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柃檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏糠酸、2-萘磺酸、丙酸、水杨酸、琥铂酸、酒石酸、对甲苯磺酸或三甲基乙酸。
如式I所示的杂芳基类化合物可能具有一个或多个手性碳原子,因此可以分离得到光学纯度异构体,例如纯的对映异构体,或者外消旋体,或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体,如手性结晶成盐,或者手性制备柱分离得到。
各种合成步骤可以交替或顺次的进行以得到最终的目标产物。
本发明提供了一种药物组合物,其包含所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐,和,至少一种药用辅料。所述的药物组合物进一步可包括一种或多种另外的活性成分。举例来说,这种药物组合物可以包含一种或多种另外的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐。作为另外一种选择或除此之外,所述药物组合物还可以例如包含除如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐以外的一种或多种活性成分。
所述药物组合物中的各组分可同时使用或分开使用(例如顺序使用);当所述药物组合中的各组分同时使用时,所述药物组合物中的各组分可均匀混合(即各组分的混合物)。
所述药物组合物中的各组分可以制备成一个单一的药物组合物同时使用,也可以将各组分分别制成单个独立的药物组合物(例如以套装的形式),这些单个独立的药物组合物可同时使用或分开使用(例如顺序使用)。
在所述的药物组合物中,所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐的用量可为治疗有效量。
在所述的药物组合物中,所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐,和,所述的另外的活性成分可以同时或者分开施用(例如顺序施用)。
本发明还提供了所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物在制备激酶(例如酪氨酸激酶样孤儿受体1(ROR1))抑制剂中的应用。
本发明还提供了所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物在制备用于预防和/或治疗肿瘤药物中的应用;所述的药物可通过调节ROR1活性预防和/或治疗肿瘤;所述的肿瘤可为恶性肿瘤增生失调(又称恶性增生型失调),例子包括但不限于,血癌,如慢性淋巴细胞性白血病,急性骨髓性白血病,急性淋巴母细胞性白血病或者细胞淋巴瘤,以及实体肿瘤,例如,肺癌,卵巢癌,乳腺癌或者胰腺癌。所述的肿瘤的细胞可为人慢性髓系白血病细胞K562(又称人慢性淋巴白血病细胞K562)、人急性淋巴细胞白血病Jurkat细胞、人原髓细胞白血病细胞HL-60、人肺腺癌细胞A549、人肺腺癌细胞H1299、人三阴性乳腺癌MDA-MB-231细胞、人三阴性乳腺癌MDA-MB-468细胞、人卵巢癌细胞A2780、人卵巢癌细胞OVCAR-3、人卵巢癌细胞SK-OV-3、人脐静脉内皮细胞HUVEC、人乳腺癌阿霉素耐药株MDA-MB-231/Adr、人肺癌紫杉醇耐药株A549/Taxol、人卵巢癌紫杉醇耐药株A2780/Taxol和人白细胞长春新碱耐药株HL60/VCR中的一种或多种。
在某一方案中,所述的肿瘤还可为前列腺癌。
在某一方案中,所述的肿瘤的细胞为人套细胞系淋巴瘤细胞株Z138、人弥漫大B淋巴瘤细胞WSU-DLCL2、人弥漫大B淋巴瘤细胞DOHH-2、人前列腺癌细胞株PC-3、人前列腺癌细胞株DU145、人套细胞淋巴瘤细胞株Jeko-1和人胰腺癌细胞株BXPC-3中的一种或多种。
本发明还提供了一种用于预防和/或治疗哺乳动物(如用于人)中,与酪氨酸激酶样孤儿受体1的活性调节或混乱状况有关的疾病(如恶性增生型失调,肥胖相关代谢并发症,自身免疫性疾病或炎症)的方法,通过对需要此种治疗的哺乳动物(尤其是人类)喂服有效量的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐或者如上所述的药物组合物。
本发明还提供了一种用于预防和/或治疗癌症的方法,其包括给受试者施用有效剂量的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物。
本发明还提供了一种治疗剂,其包括所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物。
本发明的化合物可以用局部或全身给药,例如,用于肠内给药,比如直肠或口服用药,或用于肠胃外给药至哺乳动物(尤其指人)。本发明的化合物也可在肠胃外给药,例如,通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。
本发明所述化合物、药物组合物或药物的有效量取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式。
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定,最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
可作为药学上可接受辅料的物质包括,但并不限于,离子交换剂,铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸脂,蜡,聚乙烯-聚氧丙烯-阻断聚合体,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如,常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定,可能需要特殊装置来施用或给予药物,例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Specialflask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性,并且可提供获得所需药物释放曲线的方法。因此,添加到药物中的赋形剂类型可视各种因素而定,例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(EuropeanPharmacopoeia,EP)和英国药典(British pharmacopoeia,BP);美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物,例如《非活性组分指南》(Inactive Ingredient Guide,1996);Ash和Ash编写的《药物添加剂手册》(Hand book ofPharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY;etc.)。
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造,例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述,本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分,这些非活性成分会促进活性分子被加工成用于医药用途的制剂。
本发明的药物组合物可以用局部或全身给药,例如,用于肠内给药,比如直肠或口服用药,或用于肠胃外给药至哺乳动物(尤其指人),并且包括根据本发明的化合物、其立体异构体或其药学上可接受的盐作为活性成分的治疗有效量,连同药学上可接受的赋形剂,如药学上可接受的载体。活性成份的治疗有效量如上下文所定义,并且取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式对于肠内给药,如口服药,本发明化合物可以配制成广泛的多种剂型。
所述药物组合物和剂型可以包含一种或多种本发明的化合物、其立体异构体或其一种或多种药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体的形式的制剂包括粉剂、片剂、丸剂、锭剂、胶囊剂、扁嚢剂、栓剂和可分散的颗粒剂。固体载体可以还是作为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或者包封材料的一种或多种物质。在粉剂中,载体通常是细碎的固体,其是与细碎的活性组分的混合物。在片剂中,活性组分通常与具有必要粘合能力的载体以合适的比例混合并按照所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精,淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡,可可脂等。活性化合物的制剂可以包括作为载体的包封材料,提供胶囊,其中有或没有载体的活性组分被与其结合的载体包围。
适于口服给药的其它形式包括液体形式制剂,包括乳液、糖浆剂、酏剂、水溶液、水性悬浊液、或意图在使用前不久转化成液体形式制剂的固体形式制剂。乳液可以在溶液中制备,例如丙二醇水溶液中,或者可以含有乳化剂,如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶。水溶液可以通过将活性组分溶解在水中并加入合适的着色剂、香料、稳定剂和增稠剂来制备。水性混悬液可以通过将细小颗粒的活性成分用粘合剂如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素和其它常用的悬浮剂分散在水中制备。固体形式的制剂包括溶液剂、混悬剂和乳液,除了活性组分外,还可以含有着色剂、香料、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
用于直肠给药的示例性组合包括栓剂,其可以包含例如适合的非刺激性赋形剂,例如可可脂、合成甘油酯或聚乙二醇,其在常温下是固体,但是在直肠腔中融化和/或溶解以释放药物。
本发明的化合物也可在肠胃外给药,例如,通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。
因此,对于肠胃外给药,本发明的药物组合物可以是无菌可注射或可输注射剂制剂的形式,例如,作为无菌水性或油性混悬液。该混悬液可以根据本领域已知的技术使用合适的分散剂或润湿剂(例如吐温80)和悬浮剂来配制。无菌可注射或可输注制剂也可以是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或混悬液。例如,药物组合物可以是1,3-丁二醇中的溶液。可以用于本发明药物组合物中的可接受的媒介和溶剂的其它实例包括但不限于甘露醇、水、林格溶液和等渗氯化钠溶液。此外,无菌非挥发性油通常用作溶剂或悬浮介质。为此目的可以使用任何温和的非挥发性油,包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油脂衍生物可用于制备注射剂,同样还有天然的药学上可接受的油,例如橄榄油或蓖麻油,特别是其聚氧乙基化形式。这些油溶液或混悬液也可含有长链醇稀释剂或分散剂。用于肠胃外使用的溶液也可以包括合适的稳定剂,如果需要,可以包含缓冲物质。合适的稳定剂包括抗氧化剂,例如单独或组合的硫酸氢钠,亚硫酸钠或抗坏血酸、柃檬酸以及其盐和EDTA钠盐。肠胃外溶液也可以包含防腐剂,如苯扎氯铵、对羟基苯甲酸或对羟基苯甲酸丙酯和氯丁醇。
对于吸入或鼻腔给药,合适的药物制剂室颗粒、气溶胶、粉末、雾或小滴液,例如平均尺寸为直径约10微米或更小。例如,可以在盐水中制备溶液形式的用于吸入的组合物,使用苄醇或其它适合的防腐剂,用于提高生物利用度的吸收促进剂,氟碳和/或本领域已知的其它增溶剂或分散剂。
本发明的药物组合物也可以局部给药至皮肤或粘膜。对于局部应用,药物组合物可以是例如为洗剂、凝胶、糊剂、酊剂、透皮贴剂、用于经粘膜递送的凝胶。
所述药物组合物可以用包含悬浮或溶解在载体中的活性成分的合适的软膏制剂。用于局部给予本发明化合物的载体包括但不限于矿物油、液体石油、白色石油、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,药物组合物可以配制成包含悬浮或溶剂在载体中的活性化合物的合适的洗剂或乳剂。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、鲸蜡醇、2-辛基十二烷醇、苄醇和水。本发明的药物组合物也可以通过直肠栓剂制剂或合适的灌肠制剂中局部施用于下肠道。合适的药物赋形剂(如载体)和制备药物剂型的方法描述于药物制剂领域的标准参考教科书中(Remington'sPharmaceutical Sciences,Mack Publishing Company)
药物组合物可以包含约1%至约95%,优选约20%至约90%的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐,以及至少一种药学上可接受的赋形剂。
通常,本发明的化合物将以治疗有效量通过用于类似效用的药剂的任何接受的给药方式给予。合适的日剂量通常为1至1000毫克,例如每天1-500毫克,或每天1-50毫克,取决于许多因素,例如治疗疾病的严重程度、患者年龄和相对健康状况、使用化合物的效力、给药途径和形式以及给药所针对的适应症等。治疗这些疾病的技术领域的普通技术人员将能够在没有过度实验,依赖个人知识和本申请的公开情况下,确定对于给定疾病本发明化合物的有效治疗量。本发明的化合物可以作为药物制剂给予,包括适合于肠内或肠胃外给药的制剂。优选的给药方式一般是口服,使用方便的日剂量方案,其可根据患者病情程度进行调整。
适当的制剂视所需的给药途径而定。例如,对于静脉注射来说,组合物可配制于水溶液中,必要时使用生理上相容的缓冲剂,包括例如用于调整制剂pH值的磷酸盐、组氨酸或柠檬酸盐,以及诸如氯化钠或右旋糖的张度剂。对于经粘膜或鼻给药来说,可首选半固体、液体制剂或者贴片、可能含有渗透增强剂;所述渗透剂通常为本领域所已知。对于口服给药来说,化合物可配制成液体或固体剂型并作为速释或控释/缓释制剂。用于个体口服摄取的合适剂型包括片剂、药丸、糖衣药丸、硬壳和软壳胶囊、液体、凝胶、糖浆、膏剂、悬浮液和乳液。化合物也可以被配制在直肠组合物中,诸如栓剂或保留灌肠剂,例如含有常规的栓剂基质如可可脂或其它甘油酯。
固体口服剂型可使用赋形剂获得,所述赋形剂包括填充剂、崩解剂、粘合剂(干和湿)、溶解延缓剂、润滑剂、助流剂、抗粘剂、阳离子性交换树脂、湿润剂、抗氧化剂、防腐剂、着色剂和调味剂。这些赋形剂可为合成或天然来源。所述赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/月桂基硫酸钠、甘露糖醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨糖醇、淀粉、硬脂酸或其盐、糖(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆(tragacanth mucilage)、植物油(氢化)和蜡。乙醇和水可用作造粒助剂。在某些情况下,需要用例如掩味膜、抗胃酸膜或延缓释放膜来涂覆片剂。常常将天然和合成的聚合物与着色剂、糖和有机溶剂或水组合用于涂覆片剂,从而产生糖衣药丸。当胶囊优于片剂时,可以用兼容的硬壳或软壳胶囊形式递送其药物粉末、悬浮液或溶液。
在一些实施方案中,本发明的化合物可局部给药,例如通过皮肤贴片、半固体或液体制剂,如凝胶、(微)乳液、软膏、溶液、(纳米/微米级)悬浮液或泡沫。药物的皮肤和下层组织渗透可通过以下方式来调节:例如使用渗透增强剂;使用亲脂性、亲水性和两亲性赋形剂的适当选择和组合,包括水、有机溶剂、蜡、油、合成和天然的聚合物、表面活性剂、乳化剂;通过调整pH值;和使用络合剂。例如离子电渗疗法(iontophoresi)的其它技术也可以用于调节本发明的化合物的皮肤渗透。例如在需要以最小全身性暴露局部给药的情形下,将首选透皮或局部给药。
对于通过吸入给药或鼻给药来说,根据本发明使用的化合物以溶液、悬浮液、乳液或半固体气溶胶的形式从加压包或喷雾器中方便地给药,通常借助于推进剂,例如衍生自甲烷和乙烷的卤化碳、二氧化碳或任何其它合适的气体。对于局部气溶胶来说,如丁烷、异丁烯和戊烷等烃是适用的。在加压气溶胶的情况下,适当的剂量单位可通过提供阀门传递计量来测定。可配制用于吸入器或吹入器中的具有例如明胶的胶囊和药筒。这些通常含有化合物与合适粉末基质(如乳糖或淀粉)的粉末混合物。
用于通过注射非经肠给药而配制的组合物通常是无菌的并且可以用单位剂型提供,例如安瓿瓶、注射器、注射笔、或多剂量容器,后者通常含有防腐剂。组合物可采用在油性或水性载体中的悬浮液、溶液或乳液等形式,并且可含有配制试剂,例如缓冲剂、张度剂、粘度增强剂、表面活性剂、悬浮剂和分散剂、抗氧化剂、生物相容性聚合物、鳌合剂和防腐剂。视注射部位而定,所述载体可含有水、合成或植物油和/或有机共溶剂。在某些情况下,例如对于冻干产物或浓缩物,会在给药之前将非经肠制剂重组或加以稀释。提供本发明的化合物的控释或缓释的贮库制剂(depot formulation)可包括纳米/微米级微粒或者纳米/微米级或非微细化晶体的可注射悬浮液。本领域其它熟知的基质,聚(乳酸)、聚(乙醇酸)或其共聚物等聚合物可被用作控释/缓释基质。可以以需要切口的植入物和泵的形式提供其它的贮库型(depot)给药系统。
用于静脉注射的本发明化合物的合适的载体为本领域所熟知并且包括含有碱(如氢氧化钠)的水基溶液,用于形成离子化合物;作为张度剂的蔗糖或氯化钠;例如含有磷酸盐或组氨酸的缓冲剂。可添加如聚乙二醇的共溶剂。这些水基体系能有效溶解本发明的化合物并且在全身性给药后产生低毒性。在不破坏溶解性和毒性特征的情况下,可大大改变溶液体系的组分的比例。此外,可改变组分的特性。举例来说,可使用诸如聚山梨醇酯或泊洛沙姆(poloxamer)的低毒性表面活性剂,也可使用聚乙二醇或其它共溶剂,可添加诸如聚乙烯毗略烷酮的生物相容性聚合物,并且可用其它糖和多元醇来替代右旋糖。
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中,可以将本发明的化合物制备为用于口服的药剂。
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定,例如通过测LD50(使群体50%致死的剂量)和ED50(对群体的50%治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数,可表示为LD50/ED50。优选显示高治疗指数的药剂。
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED50的循环浓度的范围内。剂量可在这个范围内变化,视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法,考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平;即最小有效浓度(minimal effective concentration,MEC)。各化合物的MEC将有所不同,但可以例如从体外(invitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。
所施予的药剂或组合物的量可视各种因素而定,包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。
在需要时,本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说,所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞,如在小瓶中。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物,将其置于适当容器中,并且加上用于治疗指定病状的标签。
“药学上可接受的”是指可用于制备药物组合的情形,通常是安全的和无毒的,且非生物学以及其它方面所不期望,并且包括对于兽用和用于人的药物用途的可接受的情形。
术语“赋形剂”是指药学上可接受的化学物质,例如药学领域的普通技术人员已知的用于帮助给予药用的试剂。它是可以用于制备药物组分的化合物,通常是安全的、无毒的,且是生物学或者其它方面所不可期望的,其包括对于兽用和人用药物可接受的赋形剂。通常的赋形剂包括粘合剂、表面活性剂、稀释剂、崩解剂和润滑剂。
术语“有效治理量”是指当给予受试者来治疗疾病状态时足以实现疾病状态的这种治理的所用化合物的量。“有效治理量”将根据化合物、所治疗的疾病状态、所治疗疾病的严重程度、受试者的年龄和相对健康、给药途径和方式、主治医疗或兽医的判断等而变化。
本专利所用“治理”或“治理中”是获得有益或期望结果,包括临床结果。有益或期望的临床结果包括但不限于一个或多个症状或病症的减轻或改善、疾病程度的减少、疾病状态的稳定化(如不恶化),预防疾病传播、延迟或减缓疾病进展、疾病状态的改善或缓解,以及部分或全部好转,无论是可检测或不可检测的情形。相比对应没有治疗的预期生存期,该术语也可指延长生存期。
术语哺乳动物是指人或任何哺乳动物,如灵长类动物、农场动物、宠物动物或者实验动物。这些动物的实例有猴、母牛、羊、马、猪、狗、猫、兔、小鼠和大鼠等。哺乳动物优选于人。
术语“恶性过度增殖性失调”是指由异常和不受控制的细胞分裂而引起的任何恶性生长或肿瘤,其可能通过淋巴系统或血液循环系统扩散到身体的其它部分,包括实体肿瘤和血源性肿瘤。示例性癌症包括肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、肛门直肠癌、阑尾癌、儿童小脑星形细胞瘤、基底细胞癌、胆道癌、肝外胆管癌、肝内胆管癌、泌尿膀胱癌、骨和关节癌、骨肉瘤和恶性纤维组织细胞瘤、脑肿瘤、脑干胶质瘤、小脑星形细胞瘤、大脑星形细胞瘤、恶性胶质瘤、室管膜瘤、成神经细胞瘤、视觉通路和下丘脑神经胶质瘤、乳腺癌、支气管腺瘤/类癌、神经系统癌症、神经系统淋巴瘤、中枢神经系统癌症、中枢神经系统淋巴瘤、子宫颈癌、儿童期癌症、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性骨髓增殖性失调、结肠癌、结直肠癌、皮肤T细胞淋巴瘤、淋巴样肿瘤、
蕈样肉芽肿,Sezary综合征、子宫内膜癌、食道癌、颅外生殖细胞瘤、性腺外生殖细胞瘤、眼癌、视网膜母细胞瘤、胆囊癌、胃癌、胃肠类肿瘤、胃肠道间质瘤、生殖细胞癌、卵巢生殖细胞瘤、妊娠滋养细胞瘤胶质瘤、头颈癌,肝癌、霍奇金淋巴瘤、咽喉癌、卡波西肉瘤、肾癌、急性淋巴母细胞性白血病、急性骨髓性白血病、毛细胞白血病、唇和口腔癌、肺癌、非小细胞肺癌、小细胞肺癌、非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、瓦尔登斯特伦巨球蛋白血症、眼内黑素瘤、Merkel细胞癌、恶性间皮瘤、转移性鳞状颈癌、舌癌、多发性内分泌肿瘤综合症、骨髓增生异常综合症、骨髓增生异常/骨髓增殖疾病、鼻咽癌、成神经细胞瘤、口咽癌、卵巢癌、卵巢上皮癌、卵巢低恶性潜在肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状腺癌、阴茎癌、嗜铬细胞瘤、松果体母细胞瘤和幕上原始神经外胚层肿瘤、垂体瘤、浆细胞肿瘤、多发性骨髓瘤、胸膜肺母细胞瘤、前列腺癌、横纹肌肉瘤、唾液腺癌、尤文氏肿瘤肉瘤家族,软组织肉瘤、子宫癌、子宫肉瘤、皮肤癌(非黑素瘤)、皮肤癌(黑素瘤)、小肠癌、鳞状细胞癌、睾丸癌、咽喉癌、胸腺瘤、胸腺癌和胸腺瘤、甲状腺癌、肾盂和输尿管和其它泌尿器官的移行细胞癌、妊娠滋养细胞肿瘤、尿道癌、外阴癌和威尔姆氏肿瘤。
术语“自身免疫失调”是指对身体中通常存在的物质和组织不适当的免疫反应引起的任何失调。这种反应可能限于某些器官或涉及不同地方的特点组织。示例性自身免疫失调是急性脑脊髓炎(ADEM)、艾迪生病、无丙种球蛋白血症、斑秃、肌萎缩性侧索硬化、强直性脊柱炎、抗磷脂性综合症、抗合成酶综合症、特应性变态反应。特应性皮炎、自身免疫再生性障碍贫血、自身免疫心肌病、自身免疫肠病、自身免疫溶血性贫血、自身免疫肝炎、自身免疫内耳疾病、自身免疫淋巴细胞增殖综合症、自身免疫神经周围病、自身免疫胰腺炎、自身免疫多内分泌综合症、自身免疫黄体性皮炎、自身免疫血小板减少性紫癜、自身免疫荨麻疹、自身免疫葡萄膜炎、Balo疾病/Balo同心硬化,Behcet’s病、Berger’s病、Bickerstaff’s脑炎、Blau综合症、大疱性类天疱疮、Castleman’s病、乳糜病、查加斯病、慢性炎性脱髓鞘性多发性神经病、慢性复发性多病性骨髓炎、慢性阻塞性肺病、Churg-Strauss综合症,癫痕性类天疱疮、柯根综合症、冷凝集素病、补体成分2缺乏症、接触性皮炎、颅动脉炎、CREST综合症、克罗恩病(两种特发性肠病IBD之一),Cusshing’s综合症、皮肤白细胞破碎性脉管炎、Dego’s病、Dercum’s病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤系统性硬化症、Dressler’s综合症、药物诱导的狼疮,盘状红斑狼疮、湿疹、子宫内膜异位症、附着点炎相关性关节炎、嗜曙红细胞筋膜炎、嗜曙红细胞性胃肠炎、获得性大疱性表皮松解症、结节性红斑、胎儿成红细胞增多病、原发性混合型冷球形蛋白血症、伊万氏综合症、进行性肌肉骨化症、纤维化肺泡炎(或特发性肺纤维化)、胃炎、胃肠类天疱疮、肾小球肾炎、古德帕斯特综合症、格雷夫斯病、格林-巴利综合症、Hashimoto’s脑病、Hashimoto’s甲状腺炎、Henoch-Schonlein紫癜、妊娠疱疹(又称妊娠类天疱疮)、化脓性汗腺炎、Hughes-Stovin综合症、低丙球蛋白血症、特发性炎性脱髓鞘病、特发性肺纤维化、特发性血小板减少性紫癜、IgA肾病、包涵体肌炎、慢性炎脱性髓鞘多神经病、间质性膀胱炎、青少年特发性关节炎(又称青少年类风湿关节炎)、Kawasaki’s病、Lambert-Eaton肌无力综合症、白细胞破碎性脉管炎、扁平苔藓、硬化性苔藓、线性IgA病、类狼疮肝炎(又称自身免疫肝炎)、红斑狼疮、Majeed综合症、Meniere’s病、显微镜多血管炎、混合性结缔组织病、硬斑病、急性苔藓痘疮糠疹,多发性硬化、重症肌无力、肌炎、多发性睡病、视神经脊髓炎、神经肌强直、眼癫痕性类天疱疮、斜视眼肌阵挛综合症、Ord氏甲状腺炎、回纹型风湿症、PANDAS(与链球菌有关的儿科自身免疫神经精神失调)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿、Parry Romberg综合症、Parsonage-Turner综合症、扁平不睫状体炎、寻常性天疱疮、恶性贫血、静脉周围性脑脊髓炎、POEMS综合症、结节性多动脉炎、风湿性多肌痛、多肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎性神经病、牛皮癣、牛皮癣性关节炎、坏疽性脓皮病、纯红细胞发育不良、拉斯穆森脑炎、雷诺现象、复发性多软骨炎、赖特综合症、不宁腿综合症、腹膜后纤维化、类风湿关节炎、风湿热、结节病、精神分裂症、施密特综合症(APS的另一种形式)、施奈茨勒综合症、巩膜炎、硬皮病、血清病、Sjogren综合症、脊柱关节炎、僵人综合症、亚急性细菌性心内膜炎、Susac’s综合症、Sweet’s综合症、交感性眼炎、系统性红斑狼疮、Takayasu’s动脉炎、巨细胞动脉炎、血小板减少症、Tolosa-Hunt综合症、横贯性脊髓炎、溃疡性结肠炎(两种特发性肠病IBD之一)、与混合型结缔组织疾病不同的未分化结缔组织疾病、未分化的脊柱关节病、荨麻疹性脉管炎、脉管炎、白癜风和魏格纳肉芽肿病。
术语“炎性失调”是指于炎症相关的病例状态,通常由白细胞浸润引起。炎性失调可能是急性或慢性的。示例性的炎症失调包括炎性皮肤疾病,包括但不限于牛皮癣和特应性皮炎,系统性硬皮病和硬化症,与炎性肠病(IBD)相关的反应(如克罗恩病和溃疡性结肠炎);缺血性再灌注失调,包括手术组织再灌注损伤,心肌缺血病症如心肌梗塞、心动停止、心脏手术后的再灌注和经皮腔内冠状动脉血管成型术后的缩窄、中风和腹部主动脉瘤,继发于中风的脑水肿,颅外伤,低血容性休克,窒息,成人呼吸窘迫综合症、急性肺损伤、白塞氏病、皮肌炎、多肌炎、多发性硬化症、皮炎、脑膜炎、脑炎、葡萄膜炎、骨关节炎、狼疮性肾炎、自身免疫疾病如类风湿性关节炎、Sjogren’s综合症、脉管炎、涉及白细胞渗出的疾病、中枢神经系统炎症性失调、继发于白血病或外伤的多器官损伤综合症、酒精性肝炎、细菌性肺炎、抗原-抗体复合物介导的疾病包括肾小球炎、败血症、结节病。对组织或器官移植的免疫病理性反应,肺的炎症,包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性全细支气管炎、超敏性肺炎、特发性肺纤维化(IPF)和囊性纤维化等。
术语“于肥胖相关的代谢并发症”通常是指由于肥胖引起的代谢并发症,通常称为代谢综合症,该综合症的特征在于血浆脂质失调(致动脉粥样化血脂异常),升高的血压、升高的血浆葡萄糖和血栓形成前状态。该代谢综合症的临床后果是例如冠心病和中风、II型糖尿病以及并发症、脂肪肝和胆固醇性胆结石。
非另外说明,应当应用本文所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-C6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
在本文中,取代基中定义的数值范围如0至4、1-4、1至3等表明该范围内的整数,如1-6为1、2、3、4、5、6。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
术语“包括”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。
一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地,当该基团被1个以上所述取代基取代时,所述取代基之间是相互独立,即,所述的1个以上的取代基可以是互不相同的,也可以是相同的。除非其他方面表明,一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1~C6烷基”或“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基;“C1-4烷基”特指独立公开的甲基、乙基、C3烷基(即丙基,包括正丙基和异丙基)、C4烷基(即丁基,包括正丁基、异丁基、仲丁基和叔丁基)。
术语“卤素”选自于F,Cl,Br或I,尤其指F或Cl。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”(通式CnH2n+1)意指包括具有指定碳原子数目的支链和直链的饱和脂族烃基;例如,C1-C16的烷基。如在“C1~C6烷基”中定义为包括在直链或者支链结构中具有1、2、3、4、5、或者6个碳原子的基团。其中,丙基为C3烷基(包括同分异构体,例如正丙基或异丙基);丁基为C4烷基(包括同分异构体,例如正丁基、仲丁基、异丁基或叔丁基);戊基为C5烷基(包括同分异构体,例如正戊基、1-甲基-丁基、1-乙基-丙基、2-甲基-1-丁基、3-甲基-1-丁基、异戊基、叔戊基或新戊基);己基为C6烷基(包括同分异构体,例如正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基)。此外,庚基为C7烷基(包括同分异构体,例如正庚基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基)。辛基为C8烷基(包括同分异构体,例如正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基)。壬基为C9烷基(包括同分异构体,例如正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基)。奎基为C10烷基(包括同分异构体,例如正奎基、3,3-二乙基己基、2,2-二乙基己基)。在某一实施方案中,所述的“烷基”优选含有1至6个碳原子的直链或支链的烷基。在某一实施方案中,所述的“烷基”是指C1-C6烷基。在某一实施方案中,所述的“烷基”是指C1-C4烷基。
在本申请中,作为基团或是其它基团的一部分,除非另有规定,术语“环烷基”意指仅由碳原子和氢原子组成的饱和的单环、多环或者桥接碳环取代基,且其可经由任何适宜的碳原子通过单键与分子的其余部分连接;当为多环时,可为并环连接或螺环连接(即,碳原子上的两个偕氢被亚烷基取代)的桥环体系或螺环体系。环烷基取代基可以经任何适宜的碳原子连接在中心分子上。在一些实施例中,具有3-16个碳原子的环可以表示为C3-C16环烷基。在一些实施例中,C3~C6的环烷基包括环丙基(C3)、环丁基(C4)、环戊基(C5)及环己基(C6)。在一些实施例中,C3~C10的环烷基的实例包括上述C3~C6环烷基基团连同环庚基(C7)、环辛基(C8)、环壬基(C9)及环癸基(C10)。
在本申请中,作为基团或是其它基团的一部分,术语“杂环烷基”意指由2-6个碳原子(优选2-5个碳原子)以及1-4个选自氮、氧和硫的杂原子组成的稳定的3元至7元饱和环状基团。示例性3-元杂环基基团包括但不限于,氮杂环丙基、环氧乙烷基以及硫杂环丙烷基,或者其立体异构体;示例性4-元杂环基基团包括但不限于,氮杂环丁烷基,环氧丙烷基,硫杂环丁烷基,或者其同分异构体和立体异构体;示例性5-元杂环基基团包括但不限于,四氢呋喃基,四氢噻吩基,吡咯烷基,噻唑烷基,异噻唑烷基,噁唑烷基,异噁唑烷基,咪唑烷基,吡唑烷基,二氧戊环基,氧杂硫呋喃基,二硫呋喃基,或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于,哌啶基,四氢吡喃基,硫化环戊烷基,吗啉基,硫代吗啉基,二噻烷基,二噁烷基,哌嗪基,三嗪烷基,或者其同分异构体和立体异构体;示例性7-元杂环基基团包括但不限于,氮杂环庚烷基,氧杂环庚烷基,硫杂环庚烷基,以及二氮杂环庚基,或者其同分异构体和立体异构体。在某一方案中,“杂环烷基”为C3~C5杂环烷基,其中杂原子选自N、O和S中的一种或多种,杂原子数为1、2或3个。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”是指具有6-14个环原子以及提供在芳香族环系统中的零个杂原子单环的或多环的(例如,二环的或三环的)4n+2芳香族环系统(例如,在循环阵列中具有6,10,或14个共享的p电子)的基团(“C6-C14芳基”)。上述芳基单元的实例包括苯基、萘基、菲基、或者蒽基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”是指具有碳原子以及提供在该芳香族环系统中的1-3个杂原子(其中每个杂原子独立地选自氮、氧以及硫)的4-16元单环的或二环的4n+2芳香族环系统(例如,在循环阵列中具有6或10个共享的p电子)的基团(“4-16元杂芳基”)。在包含一个或多个氮原子的杂芳基基团中,连接点可以是碳或氮原子,只要化合价允许。
在一些实施例中,所述的杂芳基为杂原子选自N、O和S中的一种或多种,杂原子数为1-4个的5-10元杂芳基。在一些实施例中,所述的杂芳基为杂原子选自N、O和S中的一种或多种,杂原子数为1~3个的4-6元杂芳基,较佳地为5-6元杂芳基。
示例性5-元杂芳基基团包括但不限于:吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、噁二唑基、噻二唑基、呋咱基、噁三唑基或四唑基。示例性6-元杂芳基基团包括但不限于:吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基或四嗪基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当所列举的基团中没有明确指明其具有取代基时,这种基团仅指未被取代。例如当“C1~C4烷基”前没有“取代或未取代的”的限定时,仅指“C1~C4烷基”本身或“未取代的C1~C4烷基”。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中,当烷基基团清楚地表示为连接基团时,则该烷基基团代表连接的亚烷基基团,例如,基团“卤代-C1~C6烷基”中的C1-C6烷基应当理解为C1~C6亚烷基。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH2-),亚乙基{包括-CH2CH2-或-CH(CH3)-},亚异丙基{包括-CH(CH3)CH2-或-C(CH3)2-}等等。
除非另有规定,本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义,则以本文定义为准。
应该理解,在本发明中使用的单数形式,如“一种”,包括复数指代,除非另有规定。此外,术语“包括”是开放性限定并非封闭式,即包括本发明所指明的内容,但并不排除其他方面的内容。
除非另有说明,本发明采用质谱、元素分析的传统方法,各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明,本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下,标准技术被用于化学合成、化学分析、发光器件性能检测。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“…独立地为”应做广义理解,是指所描述的各个个体之间是相互独立的,可以独立地为相同或不同的具体基团。更详细地,描述方式“…独立地为”既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响;也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解,根据本领域中使用的惯例,本申请描述基团的结构式中所使用的是指,相应的基团通过该位点与化合物中的其它片段、基团进行连接。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明提供的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐具有较好的肿瘤抑制活性,特别是对人慢性淋巴细胞白血病、肺腺癌、乳腺癌、卵巢癌、乳腺癌或者胰腺癌;且对耐药的乳腺癌、肺癌、卵巢癌或白血病都有较好的抑制活性。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
所有化合物,试剂以及溶剂都从商业购买,使用均没有进一步纯化除非特别说明。
缩写解释:
ACN:乙腈;DCE:1,2-二氯乙烷;DCM:二氯甲烷;DIPEA:N,N-二异丙基乙胺;DMF:N,N-二甲基甲酰胺;DMSO:二甲亚砜;EtOAc:乙酸乙酯;EtOH:乙醇;ESI:电喷雾质谱;HPLC:高效液相色谱;iPrOH:异丙醇;MeOH:甲醇;MS:质谱;NCS:N-氯代琥珀酰亚胺;NMR:核磁共振;TFA:三氟乙酸;MTBE:甲基叔丁基醚;eq.:等当量。
1H NMR数据报道均包括溶剂信息,以以下形式报道:化学位移(δppm),多重性,耦合常数和积分。多重性的表述:s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰.所有1H NMR均采集于Bruker spectrometer at frequencies of 400MHz,溶剂为氘代氯仿或者氘代二氯亚砜.质谱采集于Waters ACQUITY UPLC/Xevo G2 QTOF SYSTEM.液相色谱采集于Agilent 1290Infinity LC System.
中间体1:2-(4-甲酰基苯氧基)-氮-甲基乙酰胺
通用方法A:于碳酸钾(20.6g,2eq)和2-氯-氮-甲基乙酰胺(8g,1eq)的乙腈(100ml)悬浊液中加入4-甲醛苯酚(9.8g,1.1eq),混合液在60℃下搅拌12小时。反应液然后冷却到室温,之后浓缩除去绝大部分溶剂。残渣加入二氯甲烷(100ml),然后过滤,将滤液浓缩,然后用硅胶柱分离纯化,洗脱液(乙酸乙酯:正庚烷=3:2),得到白色固体化合物2-(4-甲酰基苯氧基)-氮-甲基乙酰胺(I-1,12g,83%)。
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.12(q,J=4.7Hz,1H),7.95–7.82(m,2H),7.21–7.09(m,2H),4.61(s,2H),2.67(d,J=4.6Hz,3H).MS:ESI(+):[M+H]+:194.1。
中间体2:1-(4-甲氧基苄基)哌啶-4-胺
通用方法B:于500ml的封管中加入4-甲氧基苯甲醛(6g,1eq)和4-(叔丁氧羰基-氨基)哌啶(10g,1eq),然后加入二氯乙烷(100ml)溶液,最后缓慢加入NaBH(OAc)3(17g,1.5eq),反应液在室温下搅拌12小时。反应完全后,用饱和碳酸氢钠溶液(100ml)淬灭反应,混合液继续搅拌10分钟,然后用二氯甲烷(150ml)稀释。将有机相分离,依次用饱和碳酸氢钠水溶液,饱和食盐水洗涤,最后用无水硫酸钠干燥,过滤,浓缩得到黄色油状粗品。
上述粗品溶于二氯甲烷(100ml),然后加入盐酸/异丙醇溶液(5N,10ml)。混合液在室温下搅拌2小时,然后浓缩,残渣用甲基叔丁基醚打浆,然后过滤得到目标产物的盐酸盐。将盐酸盐溶于水,用10%碳酸钠水溶液中和,调至pH=8,水相用二氯甲烷萃取,二氯甲烷溶液浓缩得到油状目标产物I-2(1-(4-甲氧基苄基)哌啶-4-胺(8g,83%))。
1H NMR(400MHz,DMSO-d6)δ7.22–7.13(m,2H),6.90–6.82(m,2H),3.72(s,3H),3.35(s,2H),2.75(ddt,J=11.4,6.9,3.9Hz,3H),1.90(td,J=11.8,2.4Hz,2H),1.80–1.66(m,2H),1.37(qd,J=11.8,3.8Hz,2H);MS:ESI(+)[M+H]+:221.2.
中间体3:4,5-二氯-3-硝基吡啶-2-胺
4,5-二氯吡啶-2-胺(5g,31mmol)分成小量多次的加入浓硫酸(30ml)维持内部温度小于30℃。反应液用冰浴冷却到5℃,然后缓慢滴加发烟硝酸(3g),反应液在冰浴中搅拌3小时。然后将反应液倒入冰水混合物(200ml),继续搅拌10分钟至冰完全融化,过滤,滤饼用冰水(100ml)打浆,过滤,水洗至中性(pH=7)。滤饼溶于乙酸乙酯,然后有机相用饱和食盐水洗涤,用无水硫酸钠干燥,过滤,浓缩干燥得5g固体。
上述固体于室温下溶于浓硫酸(50ml),然后升温至40℃并继续搅拌2.5小时。然后冷却到室温,倒入冰水混合物(200g)并持续搅拌,至冰完全融化,黄色悬浊液过滤,用冰水洗涤至中性(pH=7)。固体溶于乙酸乙酯,然后依次用氢氧化钠水溶液(0.5N),饱和食盐水洗涤,用无水硫酸钠干燥,过滤,浓缩干燥得目标化合物I-3(4,5-二氯-3-硝基吡啶-2-胺3.5g(70%)).
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.40(s,2H).MS:ESI(+):[M+H]+:208.0。
中间体4:5-氯-N4-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:于1-(4-甲氧基苄基)哌啶-4-胺(I-2,5g,1eq)和4,5-二氯-3-硝基吡啶-2-胺(I-3,4.8g,1eq)的异丙醇(30ml)悬浊液中加入DIPEA(13ml,3eq),混合液在70℃下搅拌12h.然后冷却到室温,悬浊液过滤,然后用少量异丙醇冲洗,拉干滤饼溶剂,真空干燥得到黄色目标化合物5-氯-N4-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-4,5.8g,65%)。
1H NMR(400MHz,DMSO-d6)δ8.45(s,2H),7.56–7.48(m,2H),7.03–6.98(m,2H),4.17(d,J=4.8Hz,2H),3.78(s,3H),3.22(s,1H),2.96(q,J=11.7Hz,2H),2.14–2.07(m,2H),1.97(q,J=14.8,13.6Hz,2H).MS:ESI(+):[M+H]+:392.2。
中间体9:1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-胺
通用方法B:相关化合物6-甲氧基尼古丁甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ8.01(d,J=2.4Hz,1H),7.59(dd,J=8.5,2.4Hz,1H),6.77(d,J=8.4Hz,1H),3.83(s,3H),3.37(s,2H),2.76–2.57(m,3H),1.92(td,J=11.7,2.5Hz,2H),1.77–1.63(m,2H),1.37–1.22(m,2H).MS:ESI(+):[M+H]+:222.2。
中间体10:1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-胺
通用方法B:相关化合物5-甲氧基尼古丁甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.38(d,J=3.0Hz,1H),7.77(d,J=8.6Hz,1H),7.58(dd,J=8.7,3.0Hz,1H),4.35(s,2H),3.52–3.39(m,2H),3.30(s,1H),3.13(t,J=11.8Hz,2H),2.22-1.93(m,4H);MS:ESI(+):[M+H]+:222.1。
中间体11:1-(4-(三甲基硅烷基)苄基)哌啶-4-胺
通用方法B:相关化合物4-(三甲基硅烷基)苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ7.60(s,4H),4.22(d,J=5.1Hz,2H),3.23(s,1H),3.00(q,J=11.7Hz,2H),2.03(dt,J=37.2,14.1Hz,5H),0.26(s,9H).MS:ESI(+):[M+H]+:263.2。
中间体12:1-(2,5-二氟-4-甲氧基苄基)哌啶-4-胺
通用方法B:相关化合物2,5-二氟-4-甲氧基苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ7.75(dd,J=11.8,6.9Hz,1H),7.25(dd,J=11.3,7.3Hz,1H),4.20(d,J=3.6Hz,2H),3.88(s,4H),3.26(s,2H),3.06(q,J=12.4,11.7Hz,2H),2.23–1.91(m,5H).MS:ESI(+):[M+H]+:257.2。
中间体13:1-(2-氟-4-甲氧基苄基)哌啶-4-胺
通用方法B:相关化合物2-氟-4-甲氧基苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ8.51(d,J=5.0Hz,2H),7.59(dd,J=12.2,2.0Hz,1H),7.38(dt,J=8.6,1.4Hz,1H),7.23(t,J=8.7Hz,1H),4.19(d,J=4.7Hz,2H),3.86(s,3H),3.22(s,1H),2.99(q,J=11.7Hz,2H),2.22–1.90(m,5H).MS:ESI(+):[M+H]+:239.2。
中间体14:1-(2,5-二氟苄基)哌啶-4-胺
通用方法B:相关化合物2,5-二氟苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ8.50(d,J=5.1Hz,2H),7.79(dd,J=8.8,5.4Hz,1H),7.40(td,J=6.3,1.8Hz,2H),4.28(d,J=4.2Hz,2H),3.27(s,1H),3.11(q,J=11.6Hz,2H),2.16–1.98(m,4H).MS:ESI(+):[M+H]+:227.2。
中间体15:1-(3-氟-4-甲氧基苄基)哌啶-4-胺
通用方法B:相关化合物3-氟-4-甲氧基苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.13(d,J=1.0Hz,1H),7.97(s,1H),7.73(d,J=8.5Hz,1H),7.65(dd,J=8.7,1.5Hz,1H),4.35(d,J=4.9Hz,2H),4.07(s,3H),3.21(d,J=13.1Hz,1H),3.00(q,J=11.2Hz,2H),2.10(d,J=14.5Hz,2H),1.99(td,J=14.0,13.3,6.8Hz,2H).MS:ESI(+):[M+H]+:239.2。
中间体16:1-(3,5-二氟-4-甲氧基苄基)哌啶-4-胺
通用方法B:相关化合物3,5-二氟-4-甲氧基苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ8.49–8.43(m,2H),7.51(d,J=8.8Hz,2H),4.22(d,J=4.6Hz,2H),3.96(s,3H),3.37(d,J=12.3Hz,2H),3.22(d,J=13.6Hz,2H),3.08–2.90(m,2H),2.19–1.96(m,4H).MS:ESI(+):[M+H]+:257.2。
中间体17:1-(2,4-二氟苄基)哌啶-4-胺
通用方法B:相关化合物2,4-二氟苯甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。
1H NMR(400MHz,DMSO-d6)δ8.48(d,J=5.4Hz,2H),7.88(td,J=8.6,6.5Hz,1H),7.40(td,J=9.8,2.6Hz,1H),7.23(td,J=8.5,2.6Hz,1H),4.27(d,J=3.8Hz,2H),3.42(d,J=12.3Hz,2H),3.27(d,J=13.4Hz,1H),3.13–3.01(m,2H),2.12(d,J=13.3Hz,2H),2.00(qd,J=13.3,4.0Hz,2H).MS:ESI(+):[M+H]+:227.2。
中间体18:1-((4-甲氧基苯基)磺酰基)哌啶-4-胺
于4-(叔丁氧羰基-氨基)哌啶(1eq)的二氯甲烷溶液中加入4-甲氧基苯磺酰氯(1eq),然后加入三乙胺(2eq),混合液在室温下搅拌20小时,然后用水淬灭反应,分离有机相。有机相中加入盐酸异丙醇溶液(4eq)并在室温下搅拌3小时,然后加入碳酸钠水溶液(10%w/w),并搅拌20分钟,至pH~8。分离有机相,然后用无水硫酸钠干燥,过滤,浓缩得到白色目标化合物。
1H NMR(400MHz,DMSO-d6)δ7.68–7.64(m,2H),7.17–7.13(m,2H),3.86(s,3H),3.41(dd,J=10.8,4.6Hz,3H),2.42–2.31(m,2H),1.79–1.66(m,2H),1.40(q,J=10.4,9.8Hz,1H),1.24(tdd,J=13.4,10.1,3.9Hz,2H).MS:ESI(+):[M+H]+:271.2。
中间体19:1-(环丙基磺酰基)哌啶-4-胺
参照I-18合成:相关化合物:环丙基磺酰氯,4-(叔丁氧羰基-氨基)哌啶和三乙胺。
1H NMR(400MHz,DMSO-d6)δ8.39(d,J=5.1Hz,2H),3.63(dt,J=13.3,3.7Hz,2H),3.17(ddp,J=16.1,10.6,6.1,5.1Hz,1H),2.91(td,J=12.3,2.5Hz,2H),2.57(tt,J=7.9,4.8Hz,1H),2.06–1.95(m,2H),1.61(qd,J=12.0,4.2Hz,2H),1.04–0.95(m,2H),0.95–0.88(m,2H).MS:ESI(+):[M+H]+:205.1。
中间体20:1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺
通用方法B:相关化合物1-甲基-1氢-吲哚氮唑-5-甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.41(s,2H),8.13(d,J=1.0Hz,1H),7.97(s,1H),7.73(d,J=8.5Hz,1H),7.65(dd,J=8.7,1.5Hz,1H),4.35(d,J=4.9Hz,2H),4.07(s,3H),3.21(d,J=13.1Hz,1H),3.00(q,J=11.2Hz,2H),2.10(d,J=14.5Hz,2H),1.99(td,J=14.0,13.3,6.8Hz,2H).MS:ESI(+):[M+H]+:245.2中间体21:1-(苯并呋喃-5-基亚甲基)哌啶-4-胺
通用方法B:相关化合物苯并呋喃-5-甲醛(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.08(d,J=2.2Hz,1H),7.91(d,J=1.8Hz,1H),7.69(d,J=8.4Hz,1H),7.57(dd,J=8.5,1.8Hz,1H),7.04(dd,J=2.2,0.9Hz,1H),4.34(d,J=4.9Hz,2H),3.40(s,1H),3.23(s,2H),3.02(q,J=11.6Hz,2H),2.11(d,J=13.9Hz,2H),2.00(tt,J=13.1,6.7Hz,2H).MS:ESI(+):[M+H]+:231.2。
中间体22:N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺
通用方法B:相关化合物N-(4-甲酰基苯基)-N-甲基甲基磺酰胺(1eq),4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.44(d,J=5.3Hz,2H),7.67(dd,J=9.1,2.6Hz,2H),7.50-7.46(m,2H),4.24(d,J=5.0Hz,2H),3.35(s,1H),3.26(s,5H),2.98(s,5H),2.16-2.09(m,2H),2.07-1.93(m,2H).MS:ESI(+):[M+H]+:298.2。
中间体23:N1-(4-甲氧基苄基)-N1-亚甲基乙烷-1,2-二胺
通用方法B:相关化合物4-甲氧基苯甲醛(1eq),叔丁氧羰基(2-(甲基胺)乙基)(1eq)和三乙酰基硼氢化钠(1.5eq).
1H NMR(400MHz,DMSO-d6)δ8.56–8.50(m,2H),7.64–7.51(m,2H),7.04–6.96(m,2H),4.32(d,J=37.7Hz,2H),3.78(s,3H),3.38(s,4H),2.67(s,3H).MS:ESI(+):[M+H]+:195.2。
中间体24:1-(甲基磺酰基)哌啶-4-胺
参照I-18合成:相关化合物:4-(叔丁氧羰基-氨基)哌啶(1eq),甲基磺酰氯(1eq)和三乙胺(2eq)。
1H NMR(400MHz,Chloroform-d)δ4.47(s,1H),3.75(d,J=12.0Hz,2H),3.57(s,1H),2.78(s,5H),2.12–1.99(m,2H),1.56–1.46(m,2H).MS:ESI(+):[M+H]+:179.1。
中间体25:4-氯-3-氟-2-硝基苯胺
于3-氟-2-硝基苯胺(1g,6.4mmol,1eq)的乙腈(10ml)溶液中加入NCS(1.3g,1.5eq),反应液在50℃下搅拌5小时。反应液浓缩,然后用硅胶柱分离纯化,用乙酸乙酯/正庚烷(1:4)洗脱,浓缩干燥得到棕色固体4-氯-3-氟-2-硝基苯胺I-25(0.2g,17%),以及6-氯-3-氟-2-硝基苯胺I-26(0.28g,23%).
1H NMR(400MHz,DMSO-d6)δ7.65(dd,J=8.8,5.4Hz,1H),6.84(s,2H),6.70(dd,J=11.0,8.8Hz,1H);MS:ESI(+)[M+1]+191.0。
中间体26:6-氯-3-氟-2-硝基苯胺
参照化合物I-25.
1H NMR(400MHz,Chloroform-d)δ7.30(dd,J=9.2,7.2Hz,1H),6.56(dd,J=9.2,2.1Hz,1H);MS:ESI(+)[M+1]+191.0。
中间体27:5-氯-N4-(1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-胺(I-9,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,Chloroform-d)δ8.81(d,J=8.0Hz,1H),8.02(d,J=2.4Hz,1H),7.81(s,1H),7.56(dd,J=8.5,2.4Hz,1H),6.72(dd,J=8.6,0.7Hz,1H),4.42–4.28(m,1H),3.93(s,3H),3.43(s,2H),2.77(d,J=11.5Hz,2H),2.18(t,J=11.0Hz,2H),2.04(dt,J=12.9,4.0Hz,2H),1.61(dtd,J=13.4,10.0,3.6Hz,3H);MS:ESI(+)[M+1]+394.0。
中间体28:5-氯-N4-(1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-胺(I-10,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ8.19(dd,J=2.7,1.0Hz,1H),7.88(s,1H),7.77(d,J=8.3Hz,1H),7.58(s,2H),7.35–7.34(m,1H),3.81(s,4H),3.52(s,2H),2.70(d,J=12.4Hz,2H),2.12(t,J=11.0Hz,2H),1.88(d,J=12.3Hz,2H),1.55(q,J=9.5Hz,2H);MS:ESI(+)[M+1]+393.0。
中间体29:5-氯-3-硝基-N4-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)吡啶-2,4-二胺
通用方法C:相关化合物1-(4-(三甲基硅烷基)苄基)哌啶-4-胺(I-11,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.81–7.72(m,1H),7.57(s,2H),7.49–7.42(m,2H),7.27(d,J=7.7Hz,2H),3.91–3.72(m,1H),3.44(s,2H),2.68(d,J=11.1Hz,2H),2.06(t,J=11.1Hz,2H),1.87(d,J=12.3Hz,2H),1.63–1.47(m,2H),0.23(s,9H);MS:ESI(+)[M+1]+434.0。
中间体30:5-氯-N4-(1-(2,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(2,5-二氟-4-甲氧基苄基)哌啶-4-胺(I-12,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J=8.3Hz,1H),7.58(s,2H),7.21(dd,J=11.8,6.9Hz,1H),7.08(dd,J=11.3,7.3Hz,1H),3.84(s,4H),3.44(d,J=1.5Hz,2H),2.69(d,J=11.4Hz,2H),2.09(t,J=10.9Hz,2H),1.88(d,J=12.2Hz,2H),1.55(q,J=9.8Hz,2H).MS:ESI(+)[M+1]+428.0。
中间体31:5-氯-N4-(1-(2-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(2-氟-4-甲氧基苯基)哌啶-4-胺(I-13,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.77(d,J=8.4Hz,1H),7.58(s,2H),7.14–7.01(m,3H),3.82(s,4H),2.67(d,J=10.9Hz,2H),2.05(t,J=10.9Hz,2H),1.88(d,J=12.2Hz,2H),1.56(t,J=9.9Hz,2H);MS:ESI(+)[M+1]+410.0。
中间体32:5-氯-N4-(1-(2,5-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(2,5-二氟苄基)哌啶-4-胺(I-14,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J=8.4Hz,1H),7.57(s,2H),7.23(dq,J=9.1,4.3Hz,2H),7.15(td,J=8.8,8.2,4.2Hz,1H),3.83(s,1H),3.52(s,2H),2.71(d,J=11.0Hz,2H),2.14(t,J=11.0Hz,2H),1.89(d,J=12.4Hz,2H),1.59(dd,J=12.3,8.9Hz,2H).MS:ESI(+)[M+1]+398.0。
中间体33:5-氯-N4-(1-(3-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(3-氟-4-甲氧基苯基)哌啶-4-胺(I-15,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.77(d,J=8.4Hz,1H),7.58(s,2H),7.15–7.01(m,3H),3.82(s,4H),3.39(s,2H),2.67(d,J=11.2Hz,2H),2.05(t,J=10.5Hz,2H),1.88(d,J=12.3Hz,2H),1.63–1.47(m,2H);MS:ESI(+)[M+1]+410.0。
中间体34:5-氯-N4-(1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(3,5-二氟-4-甲氧基苄基)哌啶-4-胺(I-16,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,Chloroform-d)δ8.81(d,J=8.0Hz,1H),7.81(s,1H),6.91–6.84(m,2H),6.78(s,2H),4.44–4.28(m,1H),3.98(d,J=1.0Hz,3H),2.76(d,J=11.7Hz,2H),2.19(t,J=11.1Hz,2H),2.11–1.97(m,2H),1.68–1.61(m,2H).MS:ESI(+)[M+1]+428.0。
中间体35:5-氯-N4-(1-(2,4-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(2,4-二氟苄基)哌啶-4-胺(I-17,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J=8.3Hz,1H),7.57(s,2H),7.43(td,J=8.6,6.8Hz,1H),7.24–7.14(m,1H),7.09–7.02(m,1H),3.87–3.76(m,1H),3.49(s,2H),2.69(d,J=11.7Hz,2H),2.11(t,J=11.1Hz,2H),1.88(d,J=12.3Hz,2H),1.61–1.47(m,2H).MS:ESI(+)[M+1]+398.0。
中间体36:5-氯-N4-(1-((4-甲氧基苄基)磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-((4-甲氧基苯基)磺酰基)哌啶-4-胺(I-18,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.69–7.65(m,2H),7.57(d,J=8.5Hz,1H),7.53(s,2H),7.19–7.13(m,2H),4.36(d,J=4.2Hz,1H),3.86(s,3H),3.46(d,J=11.9Hz,2H),2.44–2.34(m,2H),1.96(d,J=13.0Hz,2H),1.71–1.55(m,2H).MS:ESI(+)[M+1]+442.0。
中间体37:5-氯-N4-(1-(环丙基磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(环丙基磺酰基)哌啶-4-胺(I-19,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.65(d,J=8.5Hz,1H),7.55(s,2H),3.97–3.82(m,1H),3.55(d,J=12.6Hz,2H),3.01–2.90(m,2H),2.64–2.54(m,1H),1.99(dd,J=13.3,3.7Hz,2H),1.69–1.56(m,2H),1.02–0.96(m,2H),0.95–0.90(m,2H).MS:ESI(+)[M+1]+376.0。
中间体38:5-氯-N4-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺(I-20,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,Chloroform-d)δ8.82(d,J=7.9Hz,1H),7.93(d,J=0.9Hz,1H),7.80(s,1H),7.61(s,1H),7.42–7.32(m,2H),6.79(s,2H),4.44–4.27(m,1H),4.07(s,3H),3.61(s,2H),2.81(d,J=11.8Hz,2H),2.28–2.13(m,2H),2.10–1.98(m,2H),1.67–1.59(m,2H).MS:ESI(+)[M+1]+416.0。
中间体39:N4-(1-(苯并呋喃-5-基亚甲基)哌啶-4-基)-5-氯-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(苯并呋喃-5-基亚甲基)哌啶-4-胺(I-21,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.96(d,J=2.2Hz,1H),7.88(s,1H),7.78(d,J=8.3Hz,1H),7.59(s,2H),7.56–7.50(m,2H),7.24(dd,J=8.4,1.7Hz,1H),6.92(dd,J=2.2,1.0Hz,1H),3.91–3.77(m,1H),3.54(s,2H),2.71(d,J=11.5Hz,2H),2.09(t,J=10.9Hz,2H),1.88(d,J=11.9Hz,2H),1.63–1.48(m,2H).MS:ESI(+)[M+1]+402.0。
中间体40:N-(4-((4-((2-氨-5-氯-3-硝基吡啶-4-基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺
通用方法C:相关化合物N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-22,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,Chloroform-d)δ8.82(d,J=8.0Hz,1H),7.81(s,1H),7.33(s,4H),6.79(s,2H),4.49–4.23(m,1H),3.50(s,2H),3.32(s,3H),2.85(s,3H),2.78(d,J=11.0Hz,2H),2.20(t,J=11.0Hz,2H),2.09–1.99(m,2H),1.63(dtd,J=13.3,10.0,3.6Hz,3H).MS:ESI(+)[M+1]+469.0。
中间体41:5-氯-N4-(2-((4-甲氧基苄基)(亚甲基)氨)乙基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物N1-(4-甲氧基苄基)-N1-亚甲基乙烷-1,2-二胺(I-23,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.72(s,1H),7.35(s,2H),7.26(d,J=8.1Hz,2H),6.88(d,J=8.5Hz,2H),3.74(s,3H),3.65–3.45(m,4H),3.12(qd,J=7.3,3.3Hz,2H).MS:ESI(+)[M+1]+366.1。
中间体42:5-氯-N4-(1-(甲基磺酰基)哌啶--4-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物1-(甲基磺酰基)哌啶-4-胺(I-24,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ6.90(d,J=7.9Hz,1H),3.46(dt,J=12.5,3.9Hz,2H),3.38(d,J=7.9Hz,1H),2.84(s,3H),2.79(td,J=11.8,2.8Hz,2H),1.89–1.73(m,2H),1.49–1.40(m,2H).MS:ESI(+):[M+H]+:350.1。
中间体43:(R)-5-氯-N4-(1-甲基哌啶-3-基)-3-硝基吡啶-2,4-二胺
通用方法C:相关化合物(R)-1-甲基哌啶-3-胺(1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.58(s,2H),4.16(s,1H),2.48–2.31(m,3H),2.19(s,3H),2.10(s,1H),1.58–1.42(m,4H).MS:ESI(+)[M+1]+286.2。
中间体44:N2-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺
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通用方法C:相关化合物2-氯-3-硝基吡啶-4-胺(1eq),1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,Chloroform-d)δ7.74(d,J=5.7Hz,1H),7.26–7.20(m,2H),6.88–6.84(m,2H),5.87(d,J=5.7Hz,1H),4.27–4.11(m,1H),3.80(s,3H),3.46(s,2H),2.79(d,J=12.3Hz,2H),2.22(t,J=10.8Hz,2H),2.04(dd,J=12.8,3.8Hz,2H),1.62(dtd,J=13.7,10.2,3.7Hz,2H).MS:ESI(+):[M+H]+:358.2。
中间体45:N2-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基吡啶-2,4-二胺
通用方法C:相关化合物2-氯-5-硝基吡啶-4-胺(1eq),1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)和二异丙基乙胺(3eq)。
1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.39(s,2H),7.26–7.24(m,2H),3.79(d,J=1.5Hz,4H),3.44(s,2H),2.83(d,J=11.4Hz,2H),2.06–2.00(m,2H),1.86(d,J=12.9Hz,2H),1.53–1.44(m,2H).MS:ESI(+):[M+H]+:358.2。
中间体46:N4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺
于4,6-二氯-5-硝基嘧啶(0.5g)的四氢呋喃(10mL)溶液中加入1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq),升温至55℃并继续搅拌12小时。反应然后冷却至室温,于此反应液中加入氨甲醇溶液并继续搅拌12小时。然后悬浊液过滤干燥得到目标化合物N4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺(I-46)。
1H NMR(400MHz,DMSO-d6)δ9.04(d,J=7.6Hz,1H),8.59(d,J=13.8Hz,2H),7.98(s,1H),7.21(d,J=8.2Hz,3H),6.88(d,J=8.5Hz,2H),4.14(dp,J=14.6,6.2,5.2Hz,1H),3.74(s,3H),3.40(s,2H),2.71(d,J=11.5Hz,2H),2.10(t,J=11.1Hz,2H),1.87(dd,J=12.8,4.2Hz,2H),1.70–1.51(m,2H).MS:ESI(+):[M+H]+:359.2。
中间体47:N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺
通用方法D:于1-(4-甲氧基苄基)哌啶-4-胺(I-2,0.1g,1eq)和3-氟-2-硝基苯胺(71mg,1eq)的DMF(2ml)溶液中加入碳酸钾(0.1g,1.5eq),反应液升温至100℃并搅拌2小时。然后冷却至室温,深棕色反应液倒入二氯甲烷/水混合液中,摇匀,静置分相,有机相分离,浓缩。经硅胶柱分离纯化,洗脱液乙酸乙酯/正庚烷1:2,得到棕色固体I-47。
1H NMR(400MHz,Chloroform-d)δ7.25–7.21(m,2H),7.04(t,J=8.2Hz,1H),6.89–6.83(m,2H),6.01–5.95(m,1H),5.90(dd,J=8.1,1.3Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J=11.0Hz,2H),2.21(t,J=11.0Hz,2H),2.13–1.94(m,2H),1.72–1.52(m,4H).MS:ESI(+):[M+H]+:357.3。
中间体48:6-氯-N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺
通用方法D:相关化合物1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq),4-氯-3-氟-2-硝基苯胺(I-25,1eq)和碳酸钾。
1H NMR(400MHz,Chloroform-d)δ7.23(d,J=8.6Hz,2H),7.19(d,J=9.1Hz,1H),6.90–6.83(m,2H),5.97(d,J=9.2Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J=10.0Hz,2H),2.30–2.12(m,2H),2.03(d,J=12.5Hz,2H),1.67(d,J=13.0Hz,2H).MS:ESI(+):[M+H]+:391.3。
中间体49:4-氯-N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺
通用方法D:1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq),6-氯-3-氟-2-硝基苯氨(I-26,1eq)和碳酸钾。
1H NMR(400MHz,Chloroform-d)δ7.22–7.17(m,2H),7.15(d,J=8.8Hz,1H),6.86–6.82(m,2H),6.18(d,J=8.8Hz,1H),3.80(s,3H),3.59–3.47(m,1H),3.42(s,2H),2.75(d,J=11.6Hz,2H),2.06(t,J=11.3Hz,2H),1.96–1.80(m,2H),1.54–1.38(m,2H).MS:ESI(+):[M+H]+:391.3。
中间体51:6-氯-2-硝基-N1-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)苯基-1,3-二胺
通用方法C:相关化合物1-(4-(三甲基硅烷基)苄基)哌啶-4-胺(I-11,1eq),4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷/三乙胺1:8。
1H NMR(400MHz,Chloroform-d)δ8.49(d,J=7.2Hz,1H),7.51–7.44(m,2H),7.31(d,J=7.6Hz,2H),7.19(d,J=9.2Hz,1H),6.74(s,2H),5.97(d,J=9.2Hz,1H),3.52(s,3H),2.81(d,J=9.4Hz,2H),2.24(t,J=10.5Hz,2H),2.11–1.98(m,2H),1.66(d,J=29.2Hz,2H),0.26(s,9H);MS:ESI(+)[M+1]+433.2。
中间体52:6-氯-N1-(1-(2,5-二氟苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺
通用方法D:相关化合物1-(2,5-二氟苯基)哌啶-4-胺(I-14,1eq),4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:8。
1H NMR(400MHz,Chloroform-d)δ8.48(d,J=7.2Hz,1H),7.20(d,J=9.2Hz,1H),7.17–7.09(m,1H),7.04–6.87(m,2H),6.74(s,2H),5.97(d,J=9.2Hz,1H),3.57(s,2H),3.47(s,1H),2.83(d,J=11.8Hz,2H),2.31(t,J=11.0Hz,2H),2.06(d,J=12.9Hz,2H),1.75–1.61(m,2H);MS:ESI(+)[M+1]+397.2。
中间体53:6-氯-N1-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-2-硝基苯基-1,3-二胺
通用方法D:相关化合物1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺(I-20,1eq),4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:2。
1H NMR(400MHz,Chloroform-d)δ8.49(d,J=7.2Hz,1H),7.94(d,J=0.9Hz,1H),7.62(s,1H),7.41(dd,J=8.6,1.5Hz,1H),7.36(d,J=8.7Hz,1H),7.19(d,J=9.1Hz,1H),5.97(d,J=9.2Hz,1H),4.07(s,3H),3.63(s,2H),3.48(s,1H),2.81(d,J=11.7Hz,2H),2.25(t,J=11.6Hz,2H),2.04(d,J=13.3Hz,2H),1.72–1.61(m,2H);MS:ESI(+)[M+1]+415.2。
中间体54:N-(4-((4-((3-氨-6-氯-2-硝基苯基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺
通用方法D:N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-22,1eq)和4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:1;
1H NMR(400MHz,Chloroform-d)δ8.49(d,J=7.1Hz,1H),7.39–7.29(m,4H),7.20(d,J=9.1Hz,1H),6.75(s,2H),5.98(d,J=9.4Hz,1H),3.52(s,3H),3.33(s,3H),2.85(s,3H),2.78(d,J=11.5Hz,2H),2.25(t,J=11.2Hz,2H),2.04(d,J=13.1Hz,2H),1.66(d,J=29.1Hz,2H);MS:ESI(+)[M+1]+468.2。
通用方法E:芳香胺(1eq),醛(1eq)和新配制的1M Na2S2O4(3eq)水溶液在乙醇溶液中于封管中在70℃搅拌12小时。然后冷却至室温,反应液倒入5%的氨水中继续搅拌30分钟,悬浊液过滤,滤饼用水洗,真空拉干,滤饼置于乙腈悬浊液中于70℃下搅拌30分钟,然后冷却至室温,过滤,滤饼干燥得到目标化合物。
实施例1
化合物1:2-(4-(6-氯-7-((1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)胺)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-27,50mg,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,25mg,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.17–8.02(m,4H),7.92(s,1H),7.66(dd,J=8.5,2.4Hz,1H),7.17–7.07(m,2H),6.81(d,J=8.4Hz,1H),5.81(d,J=8.8Hz,1H),5.04–4.85(m,1H),4.57(s,2H),3.84(s,3H),3.47(s,2H),2.86(d,J=11.1Hz,2H),2.68(d,J=4.6Hz,3H),2.15(t,J=11.5Hz,2H),1.98(d,J=8.7Hz,3H),1.67(q,J=10.7,9.9Hz,2H).MS:ESI(+)[M+1]+536.0。
实施例2
化合物2:2-(4-(6-氯-7-((1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-28,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.24(s,1H),8.08(d,J=8.6Hz,3H),7.92(s,1H),7.48–7.31(m,2H),7.21–7.06(m,2H),5.84(d,J=8.6Hz,1H),4.98(s,1H),4.57(s,2H),3.83(s,3H),3.65(s,2H),2.94(s,2H),2.68(d,J=4.6Hz,3H),2.31(d,J=20.6Hz,2H),2.02(d,J=11.6Hz,2H),1.72(d,J=12.2Hz,2H);MS:ESI(+)[M+1]+536.0。
实施例3
化合物3:2-(4-(6-氯-7-((1-(4-(三甲基硅烷基)苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-3-硝基-N4-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)吡啶-2,4-二胺(I-29,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ7.95–7.77(m,3H),7.67(s,1H),7.25(d,J=7.5Hz,2H),7.09(d,J=7.6Hz,2H),6.95–6.80(m,2H),5.53(d,J=8.8Hz,1H),4.73(d,J=10.9Hz,1H),4.32(s,2H),3.27(s,3H),2.63(d,J=11.0Hz,2H),2.44(d,J=4.6Hz,3H),1.91(t,J=11.4Hz,2H),1.75(d,J=11.3Hz,2H),1.44(td,J=12.8,9.3Hz,2H);MS:ESI(+)[M+1]+576.9。
实施例4
化合物4:2-(4-(6-氯-7-((1-(二氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(2,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-30,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.07(d,J=8.8Hz,3H),7.92(s,1H),7.26(dd,J=11.8,6.8Hz,1H),7.19–7.02(m,3H),5.81(d,J=8.9Hz,1H),4.95(d,J=9.6Hz,1H),4.57(s,2H),3.85(s,3H),3.50(s,2H),2.87(d,J=11.2Hz,2H),2.68(d,J=4.6Hz,3H),2.19(t,J=11.4Hz,2H),1.98(d,J=10.9Hz,2H),1.68(q,J=11.8,11.3Hz,2H);MS:ESI(+)[M+1]+571.0。
实施例5
化合物5:2-(4-(6-氯-7-((1-(2-氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(2-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-31,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.08(d,J=8.5Hz,3H),7.92(s,1H),7.12(d,J=8.7Hz,4H),5.82(s,1H),4.98(s,1H),4.57(s,2H),3.84(s,3H),3.53(d,J=40.5Hz,1H),2.88(s,1H),2.68(d,J=4.6Hz,3H),2.14(s,1H),2.05–1.95(m,2H),1.71(s,2H);MS:ESI(+)[M+1]+553.0。
实施例6
化合物6:2-(4-(6-氯-7-((1-(2,5-二氟苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(2,5-二氟苯基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-32,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.08(dd,J=11.2,4.3Hz,3H),7.91(s,1H),7.73(d,J=469.0Hz,10H),7.27(tq,J=11.8,4.5,4.0Hz,2H),7.18(td,J=8.8,8.3,4.4Hz,1H),7.14–7.08(m,2H),5.81(d,J=8.9Hz,1H),5.05–4.88(m,1H),4.57(s,2H),3.59(s,2H),2.89(d,J=11.0Hz,2H),2.68(d,J=4.6Hz,3H),2.30–2.18(m,2H),2.08(s,3H),1.99(dd,J=10.0,5.5Hz,3H),1.77–1.63(m,2H),1.24(d,J=3.3Hz,2H);MS:ESI(+)[M+1]+541.0。
实施例7
化合物7:2-(4-(6-氯-7-((1-(3-氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(3-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-33,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.07(d,J=8.7Hz,3H),7.91(s,1H),7.21–7.04(m,5H),5.78(d,J=8.9Hz,1H),4.96(d,J=11.0Hz,1H),4.57(s,2H),3.83(s,3H),3.46(s,2H),2.86(d,J=11.1Hz,2H),2.68(d,J=4.6Hz,3H),2.14(t,J=11.2Hz,2H),1.99(d,J=11.5Hz,2H),1.68(q,J=11.6Hz,2H);MS:ESI(+)[M+1]+553.0。
实施例8
化合物8:2-(4-(6-氯-7-((1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-34,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.14–8.02(m,3H),7.92(s,1H),7.20–7.02(m,4H),5.82(d,J=8.9Hz,1H),5.05–4.88(m,1H),4.57(s,2H),3.91(s,3H),3.50(s,2H),2.86(d,J=11.1Hz,2H),2.68(d,J=4.6Hz,3H),2.18(t,J=11.5Hz,2H),2.00(d,J=11.7Hz,2H),1.71(q,J=11.8Hz,2H);MS:ESI(+)[M+1]+570.9。
实施例9
化合物9:2-(4-(6-氯-7-((1-(2,4-二氟苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(2,4-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-35,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.08(dd,J=11.4,4.5Hz,3H),7.91(s,1H),7.48(q,J=8.3Hz,1H),7.22(td,J=9.8,2.6Hz,1H),7.16–7.05(m,3H),5.80(d,J=8.8Hz,1H),4.95(d,J=11.0Hz,1H),4.57(s,2H),3.56(s,2H),2.88(d,J=11.2Hz,2H),2.68(d,J=4.6Hz,3H),2.26–2.14(m,2H),1.99(d,J=11.7Hz,2H),1.67(q,J=11.7,11.3Hz,2H);MS:ESI(+)[M+1]+541.0。
实施例10
化合物10:2-(4-(6-氯-7-((1-((4-甲氧基苯基)磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-((4-甲氧基苯基)磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-36,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.09(d,J=5.3Hz,1H),7.92(d,J=9.2Hz,3H),7.80–7.72(m,2H),7.29–7.20(m,2H),7.05(d,J=8.8Hz,2H),6.03(d,J=8.8Hz,1H),4.86(d,J=8.6Hz,1H),4.57(s,2H),3.90(s,3H),3.71(d,J=11.4Hz,2H),2.69(d,J=4.7Hz,3H),2.38(t,J=11.7Hz,2H),2.06(d,J=12.0Hz,2H),1.82–1.65(m,2H);MS:ESI(+)[M+1]+584.9。
实施例11
化合物11:2-(4-(6-氯-7-((1-(环丙基磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(环丙基磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-37,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.15–8.04(m,3H),7.94(s,1H),7.17–7.07(m,2H),6.02(d,J=8.8Hz,1H),5.17–5.01(m,1H),4.56(s,2H),3.73(d,J=12.0Hz,2H),3.05(dd,J=13.2,10.8Hz,2H),2.67(d,J=4.6Hz,4H),2.12(d,J=11.2Hz,2H),1.75(qd,J=12.1,4.1Hz,2H),1.04(ddt,J=9.8,6.0,3.5Hz,2H),1.01–0.94(m,2H);MS:ESI(+)[M+1]+519.0。
实施例12
化合物12:2-(4-(6-氯-7-((1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-38,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.12–8.05(m,3H),8.00(d,J=0.9Hz,1H),7.91(s,1H),7.66(s,1H),7.60(d,J=8.6Hz,1H),7.41(dd,J=8.6,1.5Hz,1H),7.15–7.09(m,2H),5.79(d,J=8.8Hz,1H),5.04–4.89(m,1H),4.57(s,2H),4.04(s,3H),3.62(s,2H),2.90(d,J=11.2Hz,2H),2.69(d,J=4.6Hz,3H),2.17(t,J=11.6Hz,2H),1.99(d,J=10.6Hz,3H),1.68(q,J=11.8Hz,2H);MS:ESI(+)[M+1]+559.0。
实施例13
化合物13:2-(4-(7-((1-(苯并呋喃-5-基亚甲基)哌啶-4-基)氨)-6-氯-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N4-(1-(苯并呋喃-5-基亚甲基)哌啶-4-基)-5-氯-3-硝基吡啶-2,4-二胺(I-39,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.13–8.05(m,3H),7.98(d,J=2.2Hz,1H),7.92(s,1H),7.61(s,1H),7.55(d,J=8.5Hz,1H),7.35–7.27(m,1H),7.16–7.08(m,2H),6.95(dd,J=2.2,0.9Hz,1H),5.80(d,J=8.8Hz,1H),5.04–4.87(m,1H),4.57(s,2H),3.62(s,2H),2.90(d,J=11.2Hz,2H),2.69(d,J=4.6Hz,3H),2.18(s,2H),2.00(d,J=11.9Hz,2H),1.69(q,J=11.6Hz,2H);MS:ESI(+)[M+1]+545.0。
实施例14
化合物14:2-(4-(6-氯-7-((1-(4-(N-甲基甲基磺酰胺)苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N-(4-((4-((2-氨-5-氯-3-硝基吡啶-4-基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-40,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.18–7.99(m,3H),7.97–7.85(m,1H),7.45–7.30(m,4H),7.19–7.06(m,2H),5.81(d,J=8.7Hz,1H),4.98(s,1H),4.62–4.50(m,2H),3.53(d,J=6.1Hz,2H),3.26–3.19(m,3H),2.96–2.82(m,5H),2.68(q,J=4.5Hz,3H),2.17(s,2H),2.00(d,J=11.8Hz,3H),1.70(d,J=12.0Hz,2H);MS:ESI(+)[M+1]+612.0。
实施例15
化合物15:2-(4-(6-氯-7-((2-((4-甲氧基苄基)(亚甲基)氨)乙基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(2-((4-甲氧基苄基)(亚甲基)氨)乙基)-3-硝基吡啶-2,4-二胺(I-41,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ7.73–7.65(m,2H),7.61(s,1H),7.20–7.17(m,2H),6.82(d,J=8.1Hz,2H),6.69(d,J=8.2Hz,2H),6.49(s,2H),5.82(s,1H),4.62(d,J=3.9Hz,3H),4.49(d,J=8.1Hz,2H),3.77(d,J=5.7Hz,4H),3.27(s,2H),2.74(dd,J=4.8,2.0Hz,5H),2.06(q,J=7.1Hz,1H),1.92(s,3H);MS:ESI(+):[M+H]+:509.0。
实施例16
化合物16:2-(4-(6-氯-7-((1-(甲基磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-(甲基磺酰基)哌啶--4-基)-3-硝基吡啶-2,4-二胺(I-42,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.10(dd,J=8.7,6.5Hz,3H),7.94(s,1H),7.17–7.05(m,2H),6.01(d,J=8.9Hz,1H),5.06(q,J=10.3Hz,1H),4.56(s,2H),3.68(d,J=12.1Hz,2H),2.97(s,5H),2.67(d,J=4.6Hz,3H),2.12(d,J=11.7Hz,2H),1.75(qd,J=12.2,4.1Hz,2H);MS:ESI(+):[M+H]+:493.0。
实施例17
化合物17:(R)-2-(4-(6-氯-7-((1-甲基哌啶-3-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物(R)-5-氯-N4-(1-甲基哌啶-3-基)-3-硝基吡啶-2,4-二胺(I-43,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.17–8.03(m,3H),7.95(s,1H),7.23–7.00(m,2H),5.84(d,J=9.2Hz,1H),5.28–5.14(m,1H),4.56(s,2H),2.68(d,J=4.6Hz,4H),2.33(s,2H),2.23(s,3H),2.08(s,1H),1.82–1.48(m,4H);MS:ESI(+)[M+1]+429.0。
实施例18
化合物18:2-((5-(6-氯-7-((1-甲基哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)吡啶-2-基)氧基)-N-甲基乙酰胺
通用方法E:相关化合物5-氯-N4-(1-甲基哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-5,1eq)和2-((5-甲酰基吡啶-2-基)氧基)-N-甲基乙酰胺(I-6,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.41(d,J=2.6Hz,1H),8.29–8.21(m,1H),8.16(dd,J=9.6,2.5Hz,1H),7.93(s,1H),6.58(d,J=9.5Hz,1H),6.01(d,J=8.4Hz,1H),4.98(s,1H),4.60(s,2H),2.65(d,J=4.5Hz,5H),2.16–1.89(m,5H),1.80(d,J=12.4Hz,2H);MS:ESI(+):[M+H]+:430.0。
实施例19
化合物19:2-(4-(4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-咪唑[4,5-c]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N2-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-44,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.12–8.04(m,3H),7.69(d,J=5.8Hz,1H),7.37(s,2H),7.13(d,J=8.8Hz,2H),6.98(s,2H),6.76(d,J=5.2Hz,1H),4.56(s,2H),3.78(s,3H),2.68(d,J=4.6Hz,3H),2.00(dt,J=13.0,7.1Hz,4H),1.76(s,2H).MS:ESI(+)[M+1]+501.3。
实施例20
化合物20:2-(4-(6-((1-(4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-c]吡啶-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N2-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基吡啶-2,4-二胺(I-45,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.35(s,1H),8.08(s,1H),8.03(d,J=8.5Hz,2H),7.23–7.20(m,2H),7.11(d,J=8.6Hz,2H),6.91–6.87(m,2H),6.42(s,1H),4.55(s,2H),3.40(s,2H),2.78(d,J=11.5Hz,1H),2.67(d,J=4.6Hz,3H),2.04–1.99(m,3H),1.91(d,J=12.2Hz,2H),1.44(d,J=13.6Hz,2H);MS:ESI(+)[M+1]+501.0。
实施例21
化合物21:2-(4-(6-((1-(4-甲氧基苄基)哌啶-4-基)氨)-9氢-嘌呤-8-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺(I-46,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。
1H NMR(400MHz,DMSO-d6)δ8.15–8.07(m,2H),8.04(s,1H),7.89(s,1H),7.26–7.20(m,2H),6.95(d,J=8.5Hz,2H),6.93–6.86(m,2H),4.48(s,2H),3.74(s,3H),3.40(s,2H),2.81(d,J=11.1Hz,2H),2.68(d,J=4.5Hz,4H),2.02(dd,J=13.2,5.8Hz,4H),1.88(d,J=12.3Hz,2H),1.57(q,J=11.3,10.9Hz,2H);MS:ESI(+)[M+1]+502.0。
实施例22
化合物22:2-(4-(4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1H-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-47,1eq)and 2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(250:1:2)。
1H NMR(400MHz,Chloroform-d)δ8.00(t,J=9.3Hz,2H),7.25(d,J=8.2Hz,2H),7.02(ddd,J=23.9,11.7,8.2Hz,4H),6.88–6.84(m,2H),6.64(s,1H),6.30(d,J=8.4Hz,1H),4.55–4.52(m,2H),3.81(s,3H),3.49(s,3H),3.28(dtd,J=15.8,8.5,7.9,6.3Hz,1H),2.94–2.87(m,5H),2.79(q,J=7.2Hz,4H),2.21–2.10(m,4H),1.66–1.58(m,2H);MS:ESI(+):[M+H]+:500.1。
实施例23
化合物23:2-(4-(5-氯-4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物6-氯-N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-48,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(200:1:2).
1H NMR(400MHz,Chloroform-d)δ8.07–7.93(m,2H),7.26(d,J=6.8Hz,3H),7.02(t,J=9.7Hz,3H),6.87(d,J=8.1Hz,2H),6.64(s,1H),6.30(d,J=8.4Hz,1H),4.55(s,2H),3.81(s,3H),3.50(d,J=8.8Hz,3H),2.95(dd,J=9.9,6.0Hz,5H),2.16(dd,J=35.9,12.0Hz,4H),1.70–1.59(m,2H);MS:ESI(+)[M+1]+534.1。
实施例24
化合物24:2-(4-(7-氯-4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物4-氯-N1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-49,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(200:1:2)。
1H NMR(400MHz,Chloroform-d)δ7.86(d,J=8.3Hz,2H),7.16(d,J=8.4Hz,2H),7.01(d,J=8.5Hz,1H),6.86–6.81(m,2H),6.79–6.74(m,2H),6.70–6.54(m,2H),4.68(d,J=40.5Hz,1H),4.41(s,2H),4.28(d,J=40.9Hz,1H),3.71(s,3H),3.43(s,2H),2.82(dd,J=15.1,7.8Hz,5H),2.14(td,J=11.2,10.0,4.7Hz,2H),2.01(d,J=10.0Hz,2H),1.51(d,J=34.4Hz,2H);MS:ESI(+)[M+1]+534.1。
实施例25
化合物32:2-(4-(5-氯-4-((1-(4-(三甲基硅烷基)苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物6-氯-2-硝基-N1-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)苯-1,3-二胺(I-51,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(200:1:2)。
1H NMR(400MHz,Chloroform-d)δ7.58–7.52(m,2H),7.50(d,J=7.6Hz,2H),7.32(d,J=7.6Hz,2H),7.13(d,J=8.7Hz,1H),7.05(dd,J=8.8,7.2Hz,3H),6.61(s,1H),4.71(s,2H),4.58(s,2H),4.23(tt,J=12.3,4.2Hz,1H),3.53(s,2H),3.03(d,J=11.4Hz,2H),2.94(d,J=4.9Hz,3H),2.71–2.53(m,2H),2.01(t,J=12.3Hz,2H),1.85–1.76(m,2H),0.27(s,9H);MS:ESI(+):[M+H]+:576.22。
实施例26
化合物33:2-(4-(5-氯-4-((1-(2,5-二氟苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物6-氯-N1-(1-(2,5-二氟苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-52,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(200:1:2)。
1H NMR(400MHz,Chloroform-d)δ7.57–7.49(m,2H),7.15(dd,J=11.9,7.1Hz,2H),7.07–6.91(m,5H),6.63(s,1H),4.72(s,2H),4.58(s,2H),4.22(tt,J=12.4,4.3Hz,1H),3.58(d,J=1.5Hz,2H),3.02(d,J=11.3Hz,2H),2.94(d,J=5.0Hz,3H),2.62(qd,J=12.5,3.9Hz,2H),2.12–2.05(m,2H),1.88–1.78(m,2H);MS:ESI(+):[M+H]+:540.2。
实施例27
化合物34:2-(4-(5-氯-4-((1-((1-甲基-1氢-吲哚-5-基)亚甲基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物6-氯-N1-(1-((1-甲基-1氢-吲哚-5-基)亚甲基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-53,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq).硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(100:1:1)。
1H NMR(400MHz,Chloroform-d)δ7.95(d,J=0.9Hz,1H),7.61(t,J=1.1Hz,1H),7.56–7.52(m,2H),7.45–7.37(m,2H),7.13(d,J=8.7Hz,1H),7.06–7.02(m,3H),6.62(s,1H),4.71(s,2H),4.58(s,2H),4.23(tt,J=12.4,4.3Hz,1H),4.08(s,3H),3.63(s,2H),3.03(d,J=11.4Hz,2H),2.94(d,J=4.9Hz,3H),2.61(qd,J=12.5,4.0Hz,2H),2.07–1.97(m,3H),1.84–1.77(m,2H),1.28–1.22(m,1H);MS:ESI(+):[M+H]+:558.2。
实施例28
化合物35:2-(4-(5-氯-4-((1-(4-(N-甲基甲基磺酰氨)苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺
通用方法E:相关化合物N-(4-((4-((3-氨-6-氯-2-硝基苯基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-54,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(100:1:1)。
1H NMR(400MHz,Chloroform-d)δ7.60–7.51(m,2H),7.41–7.31(m,4H),7.13(d,J=8.7Hz,1H),7.09–6.98(m,3H),6.64(s,1H),4.72(s,2H),4.58(s,2H),4.24(tt,J=12.2,4.3Hz,1H),3.51(s,2H),3.33(s,3H),3.05–2.97(m,2H),2.94(d,J=5.0Hz,3H),2.86(s,3H),2.63(ddt,J=21.1,12.5,7.2Hz,2H),2.07–1.98(m,3H),1.88–1.76(m,2H),1.30–1.23(m,2H);MS:ESI(+):[M+H]+:611.2。
生物学测定以及效果实施例:
效果实施例1
实验材料:
1.细胞株及培养条件:
2.商业可获得的试剂:RPMI-1640(批号:1970736)、DMEM(批号:2027913)及L-15培养基(批号:AD18274267)均购自Gibco公司;CCK8细胞活力检测试剂盒(批号:EG20190416)由南京恩晶生物科技有限公司提供。
3.实验方法:CCK8法检测受试物对各细胞体外增殖活性的影响:取对数生长期细胞进行实验。细胞经消化、计数、制成1×105个/mL的细胞悬液,接种于96孔板中(100μL/孔),置于37℃,5%CO2培养箱中培养24小时;每孔加入含相应浓度的受试物,同时设立阴性对照组及空白组,每组3复孔;将板置于培养箱中培养72h后,显微镜下观察各组细胞形态,每孔加入10μL CCK8溶液,在细胞培养箱内继续孵育4小时,450nm下测定吸光值,并计算增殖抑制率。
表1列出了部分化合物对所列肿瘤细胞体外活性的结果。
表1:8种受试物对各肿瘤细胞体外增殖活性IC50(μM)汇总。
效果实施例2
实验材料:
1.细胞株及培养条件:
/>
2.受试药物及试剂:
RPMI-1640、DMEM及MEM培养基购自Gibco公司;
CCK8细胞活力检测试剂盒由南京恩晶生物科技有限公司提供,批号:EG20190416。
3.仪器:
生物洁净安全柜,苏州净化设备有限公司,型号:BHC-1300A/B2;
二氧化碳培养箱,日本三洋SANYO,型号:MCO-15AC;
荧光倒置生物显微镜,南京江南永新光学有限公司,型号:XD-202;
酶标仪,Thermo scientific,型号,MUTISKAN MK3。
4.实验方法:
CCK8法检测受试物对各细胞体外增殖活性的影响:
取对数生长期细胞进行实验。细胞经消化、计数、制成1×105个/mL的细胞悬液,接种于96孔板中(100μL/孔),置于37℃,5%CO2培养箱中培养24小时;每孔加入含相应浓度的受试物,同时设立阴性对照组及空白组,每组3复孔;将板置于培养箱中培养72h后,显微镜下观察各组细胞形态,每孔加入10μL CCK8溶液,在细胞培养箱内继续孵育2-4小时,450nm下测定吸光值,并计算增殖抑制率。
表2:受试物对各肿瘤细胞体外增殖活性IC50汇总(单位:μM)。
受试物 | PC-3 | BXPC-3 | DU145 | Z138 | jeko-1 | WSU-DLCL2 | DOHH-2 |
H1 | 0.5170 | 0.7916 | 2.160 | 0.5871 | 0.6107 | 0.6881 | 0.5182 |
H2 | 0.9415 | 0.6669 | 4.815 | 0.6749 | 1.218 | 0.9718 | 0.4933 |
H3 | 0.7477 | 0.5965 | 3.224 | 0.4697 | 0.5995 | 0.4980 | 0.4189 |
H4 | 0.6275 | 0.7150 | 1.892 | 0.5177 | 1.385 | 0.4994 | 0.3142 |
H5 | 0.2333 | 0.3433 | 1.392 | 0.3913 | 0.4913 | 0.3035 | 0.2605 |
12 | 0.06689 | 0.1165 | 0.5598 | 0.1524 | 0.2179 | 0.1048 | 0.08596 |
23 | 9.745 | 7.019 | 58.81 | 13.74 | 9.530 | 12.51 | 20.77 |
效果实施例3化合物对裸鼠异种移植肿瘤生长的影响
试验中采用的对照化合物H1为WO2016124553实施例中的化合物。
取生长旺盛期的肿瘤,在无菌条件下,肿瘤细胞接种于BALB/c裸小鼠右侧腋窝皮下,细胞接种量为5×106。裸小鼠移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至100mm3左右时挑选生长状态良好且肿瘤大小均一性较好荷瘤裸鼠分组给药。给药结束后脱颈处死裸鼠,手术剥取瘤块称重,抗肿瘤活性的评价指标为抑瘤率(%),计算公式为:抑瘤率(%)=(模型组瘤重-给药组瘤重/模型组瘤重*100%),结果如表3所示。
表3化合物对人前列腺癌PC-3裸鼠异种移植肿瘤生长的影响(Mean±SD,n=8)
组别 | 剂量 | 起始动物数 | 终末动物数 | 瘤重(g) | 抑瘤率(%) |
模型组 | 10ml/kg生理盐水 | 8 | 8 | 1.231±0.058 | - |
对照化合物H1 | 50mg/kg | 8 | 8 | 0.648±0.062** | 50.4 |
化合物12 | 50mg/kg | 8 | 8 | 0.420±0.037** | 70.1 |
与模型组比较,*p<0.05,**p<0.01。
根据上述数据可知,两种化合物对人前列腺癌PC-3裸鼠异种移植瘤生长有明显的抑制作用。对PC-3异种移植瘤的抗肿瘤活性从强到弱顺序为:化合物12>化合物H1。
效果实施例4
受试药物:化合物H5,化合物12,化合物23。
药物配置:
溶媒:5%DMSO、25%聚乙二醇(PEG400)、70%生理盐水。
动物:
来源、种系、品系:ICR小鼠,由南通大学提供(实验动物生产许可证:SCXK(苏)2016-0010);实验动物使用许可证:SYXK(苏)2017-0035。
日龄:采购时4-6周,开始给药时6-8周
体重:18-20g
性别:雌雄各半
实验方法:
实验动物雌雄各半,随机分成三组,即化合物H5(4500mg/kg),化合物12(4500mg/kg),化合物23(4500mg/kg)。每组10只动物,雌雄各半。各组动物单次灌胃给药,给药体积为0.2ml/10g体重。给药后观察动物状态,记录死亡数,存活动物继续观察。
实验结果:
化合物H5、化合物12、化合物23对小鼠的急性毒性动物存活情况的影响见表4。化合物H5、化合物12、化合物23对急性毒性动物体重情况的影响见表5。
表4:化合物H5、化合物12、化合物23对小鼠的急性毒性动物存活情况的影响
表5:化合物H5、化合物12、化合物23对小鼠的急性毒性实验小鼠体重的影响(g)
组别 | 单次给药剂量 | 给药前体重 | 给药后一周体重 |
化合物H 5 | 4500mg/kg | 22.4±0.6 | 24.8±0.8 |
化合物12 | 4500mg/kg | 22.3±0.3 | 24.4±0.5 |
化合物23 | 4500mg/kg | 21.9±0.2 | 24.5±1.0 |
结论:
化合物H5的半数致死剂量(LD50)为4500mg/kg左右;化合物12和化合物23的半数致死剂量(LD50)大于4500mg/kg。
Claims (9)
1.一种如式I所示的杂芳基类化合物或药学上可接受的盐;
其中,
选自:/>
n为0;
W位于环的对位;
W为-O-(C1-C3亚烷基)-;
R3为-C(=O)-NR3aR3a’;
R3a为H,R3a’为C1-C6烷基;
R1为为/>
L2为C1-C3亚烷基;
当为/>时,Rc为/>
当为/>时,Rc为/>
Rc2、Rc2’、Rc2”、Rc3、Rc3’和Rc4独立地为Cl-C6烷基。
2.如权利要求1所述的如式I所示的杂芳基类化合物或药学上可接受的盐,其特征在于,
W为-O-(C1-C3亚烷基)-里的C1-C3亚烷基为-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-或-C(CH3)2-;
和/或,R3a’为C1-C6烷基里的C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;
和/或,L2为C1-C3亚烷基里的C1-C3亚烷基为-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-或-C(CH3)2-;
和/或,Rc2、Rc2’、Rc2”、Rc3’、Rc4’和Rc3独立地为Cl-C6烷基里的C1-C6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
3.如权利要求2所述的如式I所示的杂芳基类化合物或药学上可接受的盐,其特征在于,
W中,所述的-O-(C1-C3亚烷基)-为-O-(CH2)-;
和/或,-C(=O)-NR3aR3a’为-C(=O)-NHCH3;
和/或,L2为亚甲基;
和/或,为/>
和/或,为-N(CH3)SO2-CH3。
4.如权利要求1所述的如式I所示的杂芳基类化合物或药学上可接受的盐,其特征在于,
-W-R3为
和/或,为/>
和/或,为/>
和/或,为/>
5.如权利要求1-4中任一项所述的如式I所示的杂芳基类化合物或药学上可接受的盐,其特征在于,所述的如式I所示的杂芳基类化合物选自如下结构:
6.一种药物组合物,其特征在于,其包括如权利要求1-5中任一项所述的如式I所示的杂芳基类化合物或药学上可接受的盐,和,至少一种药用辅料。
7.一种如权利要求1-5中任一项所述的如式I所示的杂芳基类化合物或药学上可接受的盐、或者如权利要求6所述的药物组合物在制备用于预防和/或治疗肿瘤的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述的肿瘤为急性淋巴细胞白血病、肺腺癌、三阴性乳腺癌、卵巢癌、淋巴瘤、前列腺癌和胰腺癌中的一种或多种。
9.如权利要求8所述的应用,其特征在于,所述淋巴瘤为弥漫大B淋巴瘤。
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