CN111263756A - Rad51抑制剂 - Google Patents
Rad51抑制剂 Download PDFInfo
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- CN111263756A CN111263756A CN201880058652.7A CN201880058652A CN111263756A CN 111263756 A CN111263756 A CN 111263756A CN 201880058652 A CN201880058652 A CN 201880058652A CN 111263756 A CN111263756 A CN 111263756A
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Abstract
本申请涉及RAD51的抑制剂,及其使用方法,诸如用于治疗或预防涉及线粒体缺陷的病症。
Description
相关申请的交叉参考
本申请要求2017年7月11日提交的美国临时申请号62/530,972的权益。上述申请的全部教导通过引用并入本文。
发明领域
本申请涉及RAD51的抑制剂,及其使用方法,诸如用于治疗各种病症如癌症、自身免疫性疾病、免疫缺陷或神经变性疾病。
发明背景
同源重组(HR)在DNA修复中具有多种作用,包括DNA双链断裂(DSB)的修复和从由DNA交联剂形成的复制阻断损伤中恢复。HR通过定位DNA的同源片段并从同源模板复制缺失的遗传信息来修复DSB。许多研究也表明HR在维持基因组稳定性中是至关重要的(Thompson和Schild,“Homologous recombinational repair of DNA ensures mammalianchromosome stability,”Mutat.Res.,477:131-153,2001;Godthelp等人,“MammalianRad51C contributes to DNA cross-link resistance,sister chromatid cohesion andgenomic stability,”Nucleic Acids Res.,30:2172-2182,2002;Tebbs等人,“Correctionof chromosomal instability and sensitivity to diverse mutagens by a clonedcDNA ofthe XRCC3 DNA repair gene,”Proc.Natl.Acad.Sci.USA,92:6354-6358,1995;Takata等人,“Chromosome instability and defective recombinational repair inknockout mutants of the five Rad51 paralogs,”Mol.Cell Biol.,21:2858-2866,2001;Liu等人,“Involvement of Rad51C in two distinct protein complexes ofRad51 paralogs in human cells,”Nucleic Acids Res.,30:1009-1015,2002;Cui等人,“The XRCC2 and XRCC3 repair genes are required for chromosome stability inmammalian cells,”Mutat.Res.,434:75-88,1999;Thompson和Schild,“Homologousrecombinational repair of DNA ensures mammalian chromosome stability,”Mutat.Res.,477:131-153,2001)。
RAD51是真核生物基因。由该基因编码的蛋白是RAD51蛋白家族的成员,其有助于DNA双链断裂的修复。RAD51家族成员与细菌RecA、古细菌RadA和酵母Rad51同源。该蛋白在从酵母到人类的大多数真核生物中高度保守。在人类中,RAD51是339个氨基酸的蛋白,其在双链断裂(DSB)修复期间在DNA同源重组中起重要作用。RAD51催化断裂序列和其未破坏的同源物之间的链转移,以允许损伤区域的再合成(参见同源重组模型)。
研究已经证明对与促进HRDNA修复的蛋白中的细胞缺陷相关的某些DNA损伤疗法敏感。这种敏感对于DNA交联化疗药物(30-100倍)和电离辐射(3-5倍)特别显著(Godthelp等人,“Mammalian Rad51C contributes to DNA cross-link resistance,sisterchromatid cohesion and genomic stability,”Nucleic Acids Res.,30:2172-2182,2002;Tebbs等人,“Correction of chromosomal instability and sensitivity todiverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene,”Proc.Natl.Acad.Sci.USA,92:6354-6358,1995;Takata等人,“Chromosome instabilityand defective recombinational repair inknockout mutants of the five Rad51paralogs,”Mol.Cell Biol.,21:2858-2866,2001;Liu等人,“XRCC2 and XRCC3,new humanRad51-family members,promote chromosome stability andprotect against DNAcross-links and other damages,”Mol.Cell,1:783-793,1998)。
最近若干小组证明,HR可以被部分抑制,以使细胞对DNA损伤治疗敏感。XRCC3(RAD51旁系同源蛋白)的抑制已使用对应于另一种旁系同源蛋白的合成肽证明。该肽使中国仓鼠卵巢(CHO)细胞对顺铂敏感,并抑制了对DNA损伤应答的亚核RAD51中心的形成(Connell等人,CancerRes.,64:3002-3005,2004)。其它研究人员已经抑制了RAD51蛋白本身的表达(Russell等人,CancerRes.,63:7377-7383,2003;Hansen等人,Int.J.Cancer,105:472-479,2003;Ohnishi等人,Biochem.Biophys.Res.Commun.,245:319-324,1998;Ito等人,J.Gene Med.,7(8):1044-1052,2005;Collins等人,Nucleic Acids Res.,29:1534-1538,2001)或通过过表达衍生自BRCA2的显性负性BRC肽片段阻断其功能(Chen等人,J.Biol.Chem.,274:32931-32935,1999)。
考虑到对某些DNA损伤疗法增加的敏感性和HRDNA修复相关蛋白中的细胞缺陷之间的联系,需要抑制RAD51的其它化合物。
发明概述
申请人现在已经发现了为RAD51的有效抑制剂的新化合物(参见实施例1-18)。
本发明提供了一种由结构式I表示的化合物:
或其药学上可接受的盐。每个变量的定义提供如下。
本发明还提供了包含如本文所述的化合物和药学上可接受的载体或稀释剂的药物组合物。
本发明还提供了治疗癌症、自身免疫性疾病、免疫缺陷或神经变性疾病的方法,所述方法包括向有需要的受试者施用有效量的本文公开的化合物或其药学上可接受的盐或相应的药物组合物。
本文还提供了一种或多种所公开的化合物或其药学上可接受的盐或本文所公开的药物组合物用于制备治疗癌症、自身免疫性疾病、免疫缺陷或神经变性疾病的药物的用途。
在本文提供的另一个实施方案中,所公开的化合物或其药学上可接受的盐或本文公开的药物组合物用于治疗癌症、自身免疫性疾病、免疫缺陷或神经变性疾病。
在另一个实施方案中,本发明提供了治疗患有癌症的受试者的方法,所述方法包括向有需要的受试者施用有效量的本文公开的化合物或其药学上可接受的盐或相应的药物组合物,其中所述癌症选自淋巴瘤、白血病和浆细胞肿瘤。
本文还提供了一种或多种所公开的化合物或其药学上可接受的盐或本文所公开的药物组合物用于制备治疗癌症的药物的用途,其中所述癌症选自淋巴瘤、白血病和浆细胞肿瘤。
在另一个实施方案中,本文提供的公开的化合物或其药学上可接受的盐或本文公开的药物组合物用于治疗癌症,其中所述癌症选自淋巴瘤、白血病和浆细胞肿瘤。
详述
在第一实施方案中,本发明提供了由结构式I表示的化合物:
或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代。或者,噻唑环是未取代的;
X1、X2、X3和X4独立地是N或CR5,条件是X1、X2、X3和X4中不多于两个是N;
R1是-ORa;-NH2、-N((C1-C5)烷基)2;-NRa(C1-C5)烷基;-NRa-(C3-C6)环烷基、-NRa-苯基;-NRa-单环3-7元杂环;-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接)或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R1表示的-(C3-C6)环烷基或由R1表示的基团中的(C3-C6)环烷基任选地被卤素或-ORa取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-(C1-C4)烷基;-NH2、-NO2、-ORa;-(CH2)mC(O)NH2;-(CH2)mNRaC(O)NH2;-(CH2)mC(O)NRa(C1-C4)烷基;-(CH2)mC(O)NRa(C2-C4)烯基;-(CH2)mC(O)NRa-(C3-C6)环烷基;-(CH2)mC(O)NRa-苯基;-(CH2)mC(O)NRa-单环3-7元杂环;-(CH2)mC(O)NRa-5-10元杂芳环;-(CH2)mNRa(C1-C4)烷基;-(CH2)mNRa(C2-C4)烯基;-(CH2)mNRa-(C3-C6)环烷基;-(CH2)mNRa-苯基;-(CH2)mNRa-单环3-7元杂环;-(CH2)mNRa-5-10元杂芳环;-(CH2)mNRaC(O)(C1-C4)烷基;-(CH2)mNRaC(O)(C2-C4)烯基;-(CH2)mNRaC(O)-(C3-C6)环烷基;-(CH2)mNRaC(O)-苯基;-(CH2)mNRaC(O)-单环3-7元杂环;-(CH2)mNRaC(O)-5-10元杂芳环;-(CH2)mNRaC(O)O(C1-C4)烷基;-(CH2)mNRaC(O)O(C2-C4)烯基;-(CH2)mNRaC(O)O-(C3-C6)环烷基;-(CH2)mNRaC(O)O-苯基;-(CH2)mNRaC(O)O-单环3-7元杂环;-(CH2)mNRaC(O)O-5-10元杂芳环;-(CH2)mNRaC(O)NRa(C1-C4)烷基;-(CH2)mNRaC(O)NRa(C2-C4)烯基;-(CH2)mNRaC(O)NRa-(C3-C6)环烷基;-(CH2)mNRaC(O)NRa-苯基;-(CH2)mNRaC(O)NRa-单环3-7元杂环;-(CH2)mNRaC(O)NRa-5-10元杂芳环;-(CH2)mNRaC(S)(C1-C4)烷基;-(CH2)mNRaC(S)(C2-C4)烯基;-(CH2)mNRaC(S)-(C3-C6)环烷基;-(CH2)mNRaC(S)-苯基;-(CH2)mNRaC(S)-单环3-7元杂环;-(CH2)mNRaC(S)-5-10元杂芳环;-(CH2)mNRaC(S)NRa(C1-C4)烷基;-(CH2)mNRaC(S)NRa(C2-C4)烯基;-(CH2)mNRaC(S)NRa-(C3-C6)环烷基;-(CH2)mNRaC(S)NRa-苯基;-(CH2)mNRaC(S)NRa-单环3-7元杂环;-(CH2)mNRaC(S)NRa-5-10元杂芳环;-(CH2)mNRaS(O)2-(C1-C4)烷基;-(CH2)mNRaS(O)2-(C2-C4)烯基;-(CH2)mNRaS(O)2-(C3-C6)环烷基;-(CH2)mNRaS(O)2-苯基;-(CH2)mNRaS(O)2-单环3-7元杂环;-(CH2)mNRaS(O)2-5-10元杂芳环;单环3-10元杂环;5-10元杂芳环;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R2表示的-(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-ORa或-N3取代;其中由R2表示的杂环或由R2表示的基团中的杂环任选地被=O、-CH3、卤代甲基、卤代甲氧基、苯基或苄基取代;其中由R2表示的杂芳环或由R2表示的基团中的杂芳环任选地被卤素、-CH3、卤代甲基或卤代甲氧基取代;
R4是-H;-NH2;-NO2;-NRa(C1-C4)烷基;-NRaC(O)(C1-C4)烷基;-NRaC(O)O(C1-C4)烷基;-NRaC(O)NRa(C1-C4)烷基;-NRaC(S)NRa(C1-C4)烷基;-NRaS(O)2(C1-C4)烷基;-NRaS(O)2NRa(C1-C4)烷基;-NRaS(O)2-苯基;-OC(O)NRa(C1-C4)烷基;-NRaC(S)O(C1-C4)烷基;-NRa-单环5或6元含氮杂芳环;-NRaC(S)-N-单环4-7元含氮杂环;-NRaC(S)NRa-单环3-7元杂环;-NRaC(S)NRa-单环5或6元含氮杂芳环;单环5或6元含氮杂环;或任选地被=O或-NRa(C1-C4)烷基取代的-NRa-(C3-C6)环烯基;
其中由R4表示的(C1-C4)烷基或在由R4表示的基团中的(C1-C4)烷基任选地被-ORa、苯基、-C(O)NRaRa或-NRaRa取代;其中由R4表示的杂环或在由R4表示的基团中的杂环任选地被-CH3、卤代甲基、卤代甲氧基或-ORa取代;
各R5独立地是-H、-(C1-C4)烷基、-O(C1-C4)烷基、卤素、-CN、卤代甲基、卤代甲氧基、-OCH2CH2R1、-C(O)O(C1-C4)烷基、-S(O)2NH2或-SO2NRa(C1-C4)烷基;
各Ra独立地是-H或-CH3;
m是0或1。
在第二实施方案中,本发明提供了由结构式II表示的化合物:
或其药学上可接受的盐,其中R3是-H、卤素、-C(O)O(C1-C4)烷基、-S(O)2NH2或-SO2NRa(C1-C4)烷基;且剩余变量如第一实施方案中定义。
在第三实施方案中本发明提供了由结构式III表示的化合物:
或其药学上可接受的盐,其中R3是-H、卤素、-C(O)O(C1-C4)烷基、-S(O)2NH2或-SO2NRa(C1-C4)烷基;且剩余变量如第一实施方案中定义。
在第四实施方案中,本发明提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代。或者,噻唑环是未取代的;
R1是-NH2、-NRa(C1-C5)烷基、-NRa-(C3-C6)环烷基、-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接)或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R1表示的-(C3-C6)环烷基或由R1表示的基团中的(C3-C6)环烷基任选地被-ORa取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-(C1-C4)烷基;-(CH2)mC(O)NH2;-(CH2)mC(O)NRa(C1-C4)烷基;-ORa;-(CH2)mNRaC(O)NRaRa;-(CH2)mNRa(C1-C4)烷基;-(CH2)mNRaC(O)(C1-C4)烷基;-(CH2)mNRaC(O)O(C1-C4)烷基;-(CH2)mNRaC(O)O(C2-C4)烯基;-(CH2)mNRaC(O)NRa(C1-C4)烷基;-(CH2)mNRaC(O)-(C3-C6)环烷基;-(CH2)mNRaC(O)NRa-(C3-C6)环烷基;-(CH2)mNRaC(O)-苯基;-(CH2)mNRaC(O)O-苯基;-(CH2)mNRa-单环3-7元杂环;-(CH2)mNRa-单环5-6元杂芳环;-(CH2)mNRaC(O)-单环3-7元杂环;-(CH2)mNRaC(O)-单环5-6元杂芳环;-(CH2)mNRaC(O)O-单环3-7元杂环;-(CH2)mNRaC(O)O-单环5-6元杂芳环;单环3-7元杂环;单环5-6元杂芳环;-(CH2)m-NRaC(O)NRa-单环3-7元杂环;-(CH2)m-NRaC(O)NRa-单环5-6元杂芳环;-NRaC(S)NRa(C1-C4)烷基;-(CH2)mNRaS(O)2-(C1-C4)烷基;-CH2NRaS(O)2-苯基;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R2表示的-(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-ORa或-N3取代;其中由R2表示的单环3-7元杂环或由R2表示的基团中的单环3-7元杂环任选地被=O、-CH3、卤代甲基、卤代甲氧基、苯基或苄基取代;其中由R2表示的5-6元杂芳环或由R2表示的基团中的5-6元杂芳环任选地被卤素、-CH3、卤代甲基或卤代甲氧基取代;
R3是-H、卤素或-SO2NRa(C1-C4)烷基;
R4是-H;-NH2;-NRa(C1-C4)烷基;-NRaC(O)(C1-C4)烷基;-NRaC(O)O(C1-C4)烷基;-NRaC(O)NRa(C1-C4)烷基;-NRaC(S)NRa(C1-C4)烷基;-NRaS(O)2(C1-C4)烷基;-NRaS(O)2NRa(C1-C4)烷基;-NRaS(O)2-苯基;-OC(O)NRa(C1-C4)烷基;或任选地被甲基取代的单环5或6元含氮杂环;其中由R4表示的(C1-C4)烷基或在由R4表示的基团中的(C1-C4)烷基任选地被-ORa或苯基取代;
各Ra独立地是-H或-CH3;
且剩余变量如第一实施方案中定义。
在第五实施方案中,本发明提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
R1是-NH2、-NHCH3、-NHCH2CH3、-N(CH3)2、-NHC(CH3)3、-NHCH2CH2NH2、-NHCH2CH2NHCH3、-NHCH2CH2N(CH3)2、-NHCH2CH2CH2NH2、-NHCH2CH2CH2NHCH3、-NHCH2CH2CH2N(CH3)2、-NHCH2C(O)OCH3、-NHCH(CH(CH3)2)C(O)OCH3、-NHCH2-苯基、-NHCH2-吡啶基、-NHCH2CH2OH、-NHCH2CH2OCH3、-NHCH2C(CH3)2CH2OH、-NHCH(CH3)CH2OH、-NHCH2CH2OCH2CH2OH、-NHCH(CH2OH)C(O)OCH3、-NHCH(CH2OH)2、-NH-环己基(其中环己基任选地被-OH取代);N-吗啉基、N-哌啶基、N-哌嗪基、N-吡咯烷基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-CH2OH、-CH2NHC(O)CH3、-CH2NHC(O)OCH3、-CH2NHC(O)CH2CH3、-CH2NHC(O)CH2CH2OH、-CH2NHC(O)CH2CH2OCH3,-CH2NHC(O)OCH2CH3、-CH2NHC(O)CH(CH3)2、-CH2NHC(O)OCH(CH3)2、-CH2NHC(O)C(CH3)3、-CH2NHC(O)-苯基、-CH2NHC(O)-哌啶基、-CH2NHC(O)-吡啶基、-CH2NHC(O)-嘧啶基、-CH2NHC(O)CH2-苯基、-CH2NHC(O)CH2-吡啶基、-CH2NHC(O)OCH2-苯基、-CH2NHS(O)2CH3、-CH2NHS(O)2-苯基、-CF3、-C(O)NH2、-C(O)NHCH3、-C(O)NHCH2-苯基、-OH、-NHCH2CH3、-NHCH2CF3、-NHCH(CH3)CF3、-NHCH2CH(OH)CH3、被甲基取代的-NH-氧杂环丁烷基、-NHC(O)CH3、-NHC(O)CH2CH3、-N(CH3)C(O)CH3、-NHC(O)CH(CH3)2、-NHC(O)-环丙基、-NHC(O)-吡咯烷基、-NHC(O)-苯基、-NHC(O)-CH2-CH2-苯基、-NHC(O)NH-CH2CH2NH2、-NHC(O)N(CH3)2、-NHC(O)NH-CH2CH2NHCH3、-NHC(O)NH-氮杂环丁烷基、-NHC(O)NH-环己基(其中环己基任选地被NH2或-N(CH3)2取代-)、-NHC(O)NHCH2-氮杂环庚烷基、-NHC(O)NHCH2-氮杂环丁烷基、-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代)、-NHC(O)NH-CH(CH3)-苯基、-NHC(O)N(CH3)-CH2-苯基、-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基、-NHC(O)NH-CH2-咪唑基、-NHC(O)NH-CH2-吡唑基、-NHC(O)NH-CH2-吡啶基、-NHC(O)NH-CH2-嘧啶基、-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代)、-NHC(O)N(CH3)-CH2-吡咯烷基、-NHC(O)NH-CH2-噻唑基、-NHC(O)OCH3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH3、-NHC(O)OCH2CH2NH2、-NHC(O)OCH2C(CH3)=CH2、-NHC(O)OCH=CH(CH3)、-NHC(O)OCH2CH2OH、-NHC(O)OCH2CH2OCH3、-NHC(O)O-CH2-环己基、-NHC(O)O-CH2-咪唑基、-NHC(O)O-CH2-苯基、-NHC(O)O-CH(CH3)-苯基、-NHC(O)O-CH2-CH2-苯基、-NHC(O)O-CH2-吡啶基、-NHC(O)O-CH2-吡咯烷基、-NHC(O)O-CH2-CH2-噻唑基、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-NH-噻唑基、-NH-咪唑基(被甲基取代)、-NHS(O)2CH3、-NHS(O)2-苯基、-NHS(O)2-CH2-苯基、-N(CH3)S(O)2CH3、咪唑基、吡唑基、三唑基、任选地被苄基取代的任选地被甲基、苯基或苄基取代的任选地被苄基取代的
R3是-H、-F或-SO2NHC(CH3)3;
R4是-H、-NH2、-NHCH2CH(OH)CH3、-NHCH2C(CH3)2OH、-NHC(O)CH3、-NHC(O)CH2CH(CH3)2、-NHC(O)OCH3、-NHC(O)OC(CH3)3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、、-NHC(O)OCH2CH(CH3)2、-NHC(O)NHCH(CH3)2、-NHC(O)N(CH3)CH(CH3)2、-N(CH3)C(O)NHCH(CH3)2、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-NHS(O)2CH3、-NHS(O)2CH2CH3、-NHS(O)2CH2CH2OCH3、-NHS(O)2-苯基、-NHS(O)2NHCH3、-OC(O)NHCH(CH3)2或任选地被一个或两个甲基取代的
且剩余变量如第一实施方案中定义。
在第六实施方案中提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
R1是-NH(C1-C4)烷基;-N-单环5或6元含氮杂环(其中杂环的氮原子与硫原子连接);或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
R2是-H;-CH2ORa;-C(O)NRaRa;-ORa;-(CH2)mNHC(O)(C1-C4)烷基;-NHC(O)NRaRa;-NH(C1-C4)烷基;-NHC(O)(C1-C4)烷基;-NHC(O)NH(C1-C4)烷基;-NHC(O)O(C1-C4)烷基;-NHC(O)O(C2-C4)烯基;-NHC(O)-(C3-C6)环烷基;-NHC(O)OCH2-(C3-C6)环烷基;-NHC(O)NH-(CH2)n-(C3-C6)环烷基;-NRaC(O)-(CHRa)n-苯基;-NRaC(O)O-(CHRa)n-苯基;-NRaC(O)NRa-(CHRa)n-苯基;-NRaC(S)NRa-(CH2)-苯基;任选地被-CH3取代的-NH-单环3-7元杂环;-NH-单环5-6元杂芳环;-NHC(O)-单环3-7元杂环;-NHC(O)-单环5-6元杂芳环;-(CH2)mNHC(O)-(CH2)n-单环5或6元含氮杂环或杂芳环;任选地被CH3取代的-NHC(O)O-(CH2)n-单环5或6元含氮杂环或杂芳环;单环5或6元含氮杂芳环;-NRaC(O)NRa-(CH2)n-单环3-7元杂环;-NRaC(O)NRa-(CH2)n-单环5或6元含氮杂芳环;-NRaC(S)NRa(C1-C4)烷基;-NRaC(S)NRa-(CHRa)n-苯基;-NRaS(O)2-(C1-C4)烷基;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-ORa或-N3取代;
R3是-H或卤素;
R4是-H、-NRaC(O)O(C1-C4)烷基、-OC(O)NRa(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基,任选地被苯基取代;
各Ra独立地是-H或-CH3;
m是0或1;和
n是0、1或2;
且剩余变量如第一实施方案中定义。
在第七实施方案中,本发明提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
R1是-N(CH3)2、-NHC(CH3)3、-N-哌嗪基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-CH2OH、-CH2NHC(O)CH(CH3)2、-CH2NHC(O)-吡啶基、-CH2NHC(O)CH2-吡啶基、-C(O)NH2、-C(O)NHCH3、-OH、-NHCH2CH3、-NHCH2CF3、-NHCH(CH3)CF3、-NHCH2CH(OH)CH3、被甲基取代的-NH-氧杂环丁烷基、-NHC(O)CH3、-NHC(O)CH2CH3、-NHC(O)CH(CH3)2、-NHC(O)-环丙基、-NHC(O)-吡咯烷基、-NHC(O)-苯基、-NHC(O)-CH2-CH2-苯基、-NHC(O)NH-CH2CH2NH2、-NHC(O)N(CH3)2、-NHC(O)NH-CH2CH2NHCH3、-NHC(O)NH-氮杂环丁烷基、-NHC(O)NH-环己基(其中环己基任选地被-NH2或-N(CH3)2取代)、-NHC(O)NHCH2-氮杂环庚烷基、-NHC(O)NHCH2-氮杂环丁烷基、-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代)、-NHC(O)NH-CH(CH3)-苯基、-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基、-NHC(O)NH-CH2-吡啶基、-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代)、-NHC(O)N(CH3)-CH2-吡咯烷基、-NHC(O)OCH3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH3、-NHC(O)OCH2CH2NH2、-NHC(O)OCH2C(CH3)=CH2、-NHC(O)OCH=CH(CH3)、-NHC(O)OCH2CH2OH、-NHC(O)OCH2CH2OCH3、-NHC(O)O-CH2-环己基、-NHC(O)O-CH2-苯基、-NHC(O)O-CH(CH3)-苯基、-NHC(O)O-CH2-CH2-苯基、-NHC(O)O-CH2-吡啶基、-NHC(O)O-CH2-吡咯烷基、-NHC(O)O-CH2-CH2-噻唑基、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-N(CH3)S(O)2CH3、咪唑基、吡唑基、三唑基;
R3是-H或-F;
R4是-H、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH(CH3)2、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基或-OC(O)NHCH(CH3)2;
且剩余变量如第一实施方案中定义。
在第八实施方案中,本发明提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
R1是-NH(C1-C4)烷基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-NHC(O)(C1-C4)烷基;-NHC(O)O(C1-C4)烷基;-NHC(O)O(C2-C4)烯基;-NHC(O)OCH2-(C3-C6)环烷基;-NHC(O)NH-(CH2)n-(C3-C6)环烷基;-NRaC(O)-(CHRa)n-苯基;-NRaC(O)O-(CHRa)n-苯基;-NRaC(O)NRa-(CHRa)n-苯基;-NRaC(S)NRa-(CHRa)n-苯基;任选地被-CH3取代的-NHC(O)O-(CH2)n-单环5或6元含氮杂环或杂芳环;-NRaC(O)NRa-(CH2)n-单环5或6元含氮杂环或杂芳环;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被-ORa取代;其中由R2表示的(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被-NRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被-ORa或-N3取代;
R3是-H或卤素;
R4是-H、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;
各Ra独立地是-H或-CH3;和
n是0、1或2;
且剩余变量如第一实施方案中定义。
在第九实施方案中,本发明提供了根据结构式I、II或III的化合物或其药学上可接受的盐,其中:
R1是-N(CH3)2、-NHC(CH3)3或7-氮杂二环[2.2.1]庚烷基;
R2是-H;-NHC(O)CH3;-NHC(O)CH2CH3;-NHC(O)CH(CH3)2;-NHC(O)-苯基;-NHC(O)-CH2-CH2-苯基;-NHC(O)NH-环己基(其中环己基任选地被-NH2或-N(CH3)2取代);-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代);-NHC(O)NH-CH(CH3)-苯基;-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基;-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代);-NHC(O)OCH3;-NHC(O)OCH(CH3)2;-NHC(O)OCH2CH3;-NHC(O)OCH2C(CH3)=CH2;-NHC(O)OCH=CH(CH3);-NHC(O)OCH2CH2OCH3;-NHC(O)O-CH2-环己基;-NHC(O)O-CH2-苯基;-NHC(O)O-CH(CH3)-苯基;-NHC(O)O-CH2-CH2-苯基;-NHC(O)O-CH2-吡啶基;-NHC(O)O-CH2-CH2-噻唑基;或-NHC(S)NHCH2-苯基;
R3是-H或-F;
R4是-H、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2;
且剩余变量如第一实施方案中定义。
在第十实施方案中,本发明提供了由结构式IV或V表示的化合物:
或其药学上可接受的盐,其中噻唑环任选地被-F或-Cl取代。或者,噻唑环是未取代的;R3是-H、卤素、-C(O)O(C1-C4)烷基、-S(O)2NH2或-SO2NRa(C1-C4)烷基;且剩余变量如第一实施方案中定义。
在第十一实施方案中,本发明提供了根据结构式IV或V的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代。或者,噻唑环是未取代的;
R1是-NRaRa、-NRa(C1-C5)烷基或-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基或单环5-6元杂芳环取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-NH2、-NO2、-NRaC(O)(C1-C4)烷基、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;
R3是-H或-S(O)2NRa(C1-C4)烷基;
R4是-H、-NH2、-NO2、-NRaC(O)(C1-C4)烷基、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;和
各Ra独立地是-H或-CH3;
且剩余变量如第一实施方案中定义。
在第十二实施方案中,本发明提供了根据结构式IV或V的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代。或者,噻唑环是未取代的;
R1是-NHCH3、-NHCH2CH3、-N(CH3)2、-NHC(CH3)3、-NHCH2CH2OH、-NHCH(CH3)CH2OH、-NHCH2C(CH3)2CH2OH、-NHCH2CH2OCH3、-NHCH2C(O)OCH3、-NHCH2CH2OCH2CH2OH、-NHCH(CH2OH)2、-NHCH2CH2NH2、-NHCH2CH2NHCH3、-NHCH2CH2N(CH3)2、-NHCH2CH2CH2NH2、-NHCH2CH2CH2NHCH3、-NHCH2CH2CH2N(CH3)2、-NHCH2-苯基、-NHCH2-吡啶基、-NH-环丁基或-N-吡咯烷基;
R2是-H、-NH2、-NO2、-NHC(O)CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2,;
R3是-H或-S(O)2NHC(CH3)3;和
R4是-H、-NH2、-NO2、-NHC(O)CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2;
且剩余变量如第一实施方案中定义。
术语"药学上可接受的盐"是指在合理的医学判断范围内适用于与人和低等动物的组织接触而没有不适当的毒性、刺激和过敏反应并且与合理的效益/风险比相称的药学上可接受的盐。药学上可接受的盐是本领域公知的。例如,S.M.Berge等人在J.Pharm.Sci.,1977,66,1-19中描述了药学上可接受的盐。
包括在本教导中的有本文公开的化合物的药学上可接受的盐。具有碱性基团的化合物可与药学上可接受的酸形成药学上可接受的盐。本文所述化合物的适合的药学上可接受的酸加成盐包括无机酸(如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸)和有机酸(如乙酸、苯磺酸、苯甲酸、乙磺酸、甲磺酸、琥珀酸和三氟乙酸)的盐。具有酸性基团的本教导的化合物(如羧酸)可与药学上可接受的碱形成药学上可接受的盐。合适的药学上可接受的碱性盐包括铵盐、碱金属盐(如钠盐和钾盐)和碱土金属盐(如镁盐和钙盐)。
定义
本文所用的术语"卤(代)"是指卤素,包括氟、氯、溴和碘。
单独使用或作为较大部分如"烷氧基"或"卤代烷基"等的一部分使用的术语"烷基"是指饱和脂族直链或支链一价烃基。除非另有说明,否则烷基通常具有1-5个碳原子,即(C1-C5)烷基。本文所用的"(C1-C5)烷基"是指具有1-5个碳原子的直链或支链排列的基团。实例包括甲基、乙基、正丙基、异丙基等。
术语"烷氧基"是指通过氧连接原子连接的烷基,由-O-烷基表示。例如,"(C1-C4)烷氧基"包括甲氧基、乙氧基、丙氧基和丁氧基。
术语"卤代烷基"和"卤代烷氧基"是指视情况被一个或多个卤素原子取代的烷基或烷氧基。
"亚烷基"是饱和的脂族支链或直链二价烃基。除非另有说明,否则亚烷基通常具有2-6个碳原子,即(C2-C6)亚烷基。
术语"烯基"是指包含至少一个双键的支链或直链一价烃基。烯基可以是单不饱和或多不饱和的,并且可以E或Z构型存在。除非另有说明,否则烯基通常具有2-6个碳原子,即(C2-C6)烯基。例如,"(C2-C4)烯基"是指具有2-4个碳原子的直链或支链排列的基团。
术语"环烷基"是指单环饱和烃环系。例如,C3-6环烷基包括环丙基、环丁基、环戊基和环己基。除非另有说明,否则"环烷基"具有三至七个环碳原子。
术语"环烯基"是指包含碳-碳双键并具有3至7个环碳原子的非芳族单环系。
术语"杂环基"或"杂环"是指包含1-4个选自N、O或S的环杂原子的饱和或不饱和的非芳族3-12元环基团,所述环杂原子可以相同或不同。它可以是单环、双环或三环(例如稠合或桥接的双环或三环)。杂环基任选地包含一个或多个双键和/或任选地与一个或多个芳环稠合(例如四氢萘啶、吲哚酮、二氢吡咯并三唑、咪唑并嘧啶、喹啉酮、二氧杂螺癸烷)。
"3-7元单环杂环"是指具有3-7个以单环排列的原子的基团。术语"杂环基"旨在包括所有可能的异构体形式。3-7元单环杂环的实例包括但不限于氮杂环丁烷基、吗啉基、硫代吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、哌嗪基、乙内酰脲基、戊内酰胺基、氧杂环丙烷基、氧杂环丁烷基、二氢咪唑、二氢呋喃基、二氢吡喃基、二氢吡啶基、二氢嘧啶基、二氢噻吩基(dihydrothienyl)、二氢噻吩基(dihydrothiophenyl)、二氢噻喃基、四氢咪唑、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢嘧啶基、四氢噻吩基和四氢噻喃基。
双环杂环基团的实例包括二氢吲哚基、二氢异吲哚基、二氢苯并咪唑基、二氢苯并噻吩基、二氢苯并呋喃基、二氢异苯并呋喃基、二氢苯并三唑基、二氢苯并噻唑基、二氢苯并噁唑基、二氢喹啉基、四氢喹啉基、二氢异喹啉基、四氢异喹啉基、二氢吲唑基、二氢吖啶基、四氢吖啶基、二氢苯并异噁唑基、色满、色烯、异色满和异色烯。
术语"桥接双环基团"是指包括共享至少三个相邻环原子的两个环的环系。"含氮桥接双环基团"是具有环氮原子的桥接双环基团。实例包括氮杂双环[3.2.1]辛烷、氮杂双环[2.2.1]庚烷、氮杂双环[3.1.0]己烷等。
术语"稠合双环基团"是指包括共享两个相邻环原子的两个环的环系。
"含氮杂环基环"是指含氮杂环通过环氮原子与化合物的剩余部分连接。例如,N-哌啶基是指哌啶基通过哌啶基中的环氮环原子与化合物的剩余部分连接。
术语"杂芳基"、"杂芳族"、"杂芳基环"、"杂芳基基团"、"杂芳族环"和"杂芳族基团"在本文中可互换使用。"杂芳基"当单独使用或作为在如"杂芳烷基"或"杂芳基烷氧基"的较大部分中的一部分使用时,是指具有五至十个选自碳和至少一个(通常1至4个,更通常1或2个)杂原子(例如氧、氮或硫)的环原子的芳族环基团。"杂芳基"包括单环和多环,其中单环杂芳环与一个或多个其它芳环或杂芳环稠合。"杂芳基"包括单环和双环系。
"单环5-6元杂芳基"是指具有五个或六个选自碳和至少一个(通常1至3个,更通常1或2个)杂原子(例如氧、氮或硫)的环原子的单环芳族环系。单环5-6元杂芳基的实例包括呋喃基(例如2-呋喃基、3-呋喃基)、咪唑基(例如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基(例如3-异噁唑基、4-异噁唑基、5-异噁唑基)、噁二唑基(例如2-噁二唑基、5-噁二唑基)、噁唑基(例如2-噁唑基、4-噁唑基、5-噁唑基)、吡唑基(例如3-吡唑基、4-吡唑基)、吡咯基(例如1-吡咯基、2-吡咯基、3-吡咯基)、吡啶基(例如2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(例如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基(例如3-哒嗪基)、噻唑基(例如2-噻唑基、4-噻唑基、5-噻唑基)、异噻唑基、三唑基(例如2-三唑基、5-三唑基)、四唑基(例如四唑基)、噻吩基(例如2-噻吩基、3-噻吩基)。
双环芳族杂芳基的实例包括咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、异苯并呋喃基、吲哚基、苯并三唑基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、吲唑基、异吲哚基、吖啶基或苯并异噁唑基。
术语"亚苯基"是指基于二取代苯环的基团(C6H4)。
如果基团被描述为"取代的",则非氢取代基置换取代基的碳或氮上的氢。因此,例如,取代的烷基是其中至少一个非氢取代基代替烷基取代基上的氢取代基的烷基。为了说明,单氟烷基是被氟取代基取代的烷基,二氟烷基是被两个氟取代基取代的烷基。应当认识到,如果在取代基上存在多于一个取代,则每个非氢取代基可以相同或不同(除非另有说明)。如本文所用,许多部分(例如烷基、亚烷基、环烷基、亚环烷基、芳基、亚芳基、杂芳基、亚杂芳基、杂环基或亚杂环基)被称为"取代的"或"任选取代的"。当部分被这些术语之一修饰时,除非另有说明,否则其表示本领域技术人员已知的可进行取代的部分的任何部分可以被取代,其包括一个或多个取代基。如果存在多于一个取代基,则独立地选择每个取代基。这种取代方法是本领域公知的和/或由本公开教导的。任选的取代基可以是适于连接到该部分的任何取代基。本领域普通技术人员将认识到,所提供的化合物和定义不包括不允许的取代基模式(例如,被5个不同基团取代的甲基等)。本领域普通技术人员清楚地知晓这种不允许的取代模式。
合适的取代基是对化合物抑制RAD51的能力没有明显不利影响的那些。当没有具体列举合适的取代基时,示例性的取代基包括但不限于:卤素、-CN、烷基、烷氧基、卤代甲基、卤代甲氧基、(C1-C5)烷基、卤代(C1-C5)烷基、(C1-C5)烷氧基、-NO2、-ORc’、-NRa’Rb’、-S(O)iRa’、-NRaS(O)iRb’、-S(O)iNRa’Rb’、-C(=O)ORa’、-OC(=O)ORa’、-C(=S)ORa’、-O(C=S)Ra’、-C(=O)NRa’Rb’、-NRa’C(=O)Rb’、-C(=S)NRa’Rb’、-NRa’C(=S)Rb’、-NRa’(C=O)ORb’、-O(C=O)NRa’Rb’、-NRa’(C=S)ORb’、-O(C=S)NRa’Rb’、-NRa’(C=O)NRa’Rb’、-NRa’(C=S)NRa’Rb’、-C(=S)Ra’、-C(=O)Ra’、(C3-C6)环烷基、单环杂芳基和苯基,其中所述(C3-C6)环烷基、单环杂芳基和苯基取代基任选且独立地被-CH3、卤代甲基、卤素、甲氧基或卤代甲氧基取代。每个Ra’和每个Rb’独立地选自-H和(C1-C5)烷基,其中由Ra’或Rb’表示的(C1-C5)烷基任选地被羟基或(C1-C3)烷氧基取代;Rc’是-H、卤代(C1-C5)烷基或(C1-C5)烷基,其中由Rc表示的(C1-C5)烷基任选地被羟基或(C1-C3)烷氧基取代;且i是0、1或2。=O也是烷基、环烷基、环烯基和杂环基的合适取代基。
具有一个或多个手性中心的化合物可以各种立体异构形式存在。立体异构体是仅在其空间排列上不同的化合物。立体异构体包括所有非对映体、对映体和差向异构形式以及其外消旋体和混合物。术语"几何异构体"是指具有至少一个双键的化合物,其中双键可以顺式(也称为syn或entgegen(E)或反式(也称为anti或zusammen(Z))形式以及它们的混合物存在。当所公开的化合物通过结构命名或描述而不表明立体化学时,应当理解,该名称或结构涵盖一种或多种可能的立体异构体或几何异构体或所涵盖的立体异构体或几何异构体的混合物。
当几何异构体通过名称或结构描述时,应当理解,命名或描述的异构体比另一种异构体存在的程度更大,即命名或描述的几何异构体的纯度大于50%,如纯度为至少60%、70%、80%、90%、99%或99.9%重量。几何异构体纯度通过将混合物中命名或描述的几何异构体的重量除以混合物中所有几何异构体的总重量来确定。
外消旋混合物是指50%的一种对映体和50%的相应对映体。当具有一个手性中心的化合物被命名或描述而不指出手性中心的立体化学时,应当理解,该名称或结构涵盖化合物的两种可能的对映体形式(例如,两种对映体纯的、对映体富集的或外消旋的)。当具有两个或更多个手性中心的化合物被命名或描述而不指出手性中心的立体化学时,应当理解,该名称或结构涵盖化合物的所有可能的非对映异构形式(例如,非对映体纯的、非对映体富集的和一种或多种非对映体的等摩尔的混合物(例如,外消旋混合物)。
对映体和非对映体混合物可通过公知的方法如手性相气相色谱法、手性相高效液相色谱法、使化合物结晶为手性盐络合物或使化合物在手性溶剂中结晶而拆分成它们的组分对映体或立体异构体。对映体和非对映体也可通过公知的不对称合成方法从非对映体纯或对映体纯的中间体、试剂和催化剂获得。
当化合物由表示单一对映异构体的名称或结构指定时,除非另有说明,否则该化合物为至少60%、70%、80%、90%、99%或99.9%光学纯(也称为"对映体纯")。光学纯度是所命名或描述的对映体的混合物的重量除以两种对映体的混合物的总重量。
当所公开的化合物的立体化学通过结构命名或描述时,并且所命名或描述的结构涵盖多于一种立体异构体(例如,以非对映体对形式)时,应当理解,包括所涵盖的立体异构体之一或所涵盖的立体异构体的任何混合物。还应当理解,所命名或描述的立体异构体的立体异构体纯度为至少60%、70%、80%、90%、99%或99.9重量%。在这种情况下,立体异构体纯度通过将该名称或结构所涵盖的立体异构体的混合物的总重量除以所有立体异构体的混合物的总重量来确定。
药物组合物
本文公开的化合物是RAD51抑制剂。本发明的药物组合物包含一种或多种RAD51抑制剂或其药学上可接受的盐和药学上可接受的载体或稀释剂。
"药学上可接受的载体"和"药学上可接受的稀释剂"是指有助于配制和/或给予受试者活性剂和/或被受试者吸收的物质,并且可以包括在本公开的组合物中而不引起对受试者的显著不利的毒理学作用。药学上可接受的载体和/或稀释剂的非限制性实例包括水、NaCl、标准盐水溶液、乳酸化林格氏溶液、标准蔗糖、标准葡萄糖、粘结剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(如林格氏溶液)、醇、油、明胶、碳水化合物如乳糖、直链淀粉或淀粉、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷和着色剂等。可以将这些制剂灭菌,并且如果需要,可以与辅剂混合,所述辅剂如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂和/或芳香物质等,其不会有害地与本文提供的化合物反应或干扰其活性。本领域普通技术人员将认识到,其它药物赋形剂也适用于所公开的化合物。
本教导的药物组合物任选地包括用于其的一种或多种药学上可接受的载体和/或稀释剂,如乳糖、淀粉、纤维素和右旋糖。还可以包括其它赋形剂,如调味剂;甜味剂;和防腐剂,如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯和对羟基苯甲酸丁酯。合适赋形剂的更完整列表可在Handbook of Pharmaceutical Excipients(第5版,Pharmaceutical Press(2005))中找到。本领域技术人员知道如何制备适用于各种类型给药途径的制剂。选择和制备合适制剂的常规程序和成分描述于例如Remington’sPharmaceutical Sciences(2003-第20版)和1999年出版的The United StatesPharmacopeia:The National Formulary(USP 24 NF19)中。载体、稀释剂和/或赋形剂在与药物组合物的其它成分相容的意义上是"可接受的",并且对其接受者无害。
治疗方法
本发明提供了治疗患有可通过抑制RAD51改善的疾病的受试者的方法,该方法通过向受试者施用有效量的一种或多种所公开的化合物或其药学上可接受的盐或相应的药物组合物来进行。
本发明还提供了通过向有需要的受试者施用有效量的一种或多种所公开的化合物或其药学上可接受的盐或其药物组合物来治疗癌症、自身免疫性疾病、免疫缺陷或神经变性疾病的方法。
在一个实施方案中,可通过本发明的方法和组合物治疗的癌症包括膀胱癌、血癌、骨癌、骨髓癌、脑癌、乳腺癌、结肠癌、食道癌、胃肠癌、牙龈癌、头癌、肾癌、肝癌、肺癌、鼻咽癌、颈癌、卵巢癌、前列腺癌、皮肤癌、胃癌、睾丸癌、舌癌或子宫癌。此外,癌症可以具体地为以下组织学类型,但其不限于这些:恶性赘生物;癌;未分化癌;巨细胞和纺锤体细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;组合肝细胞癌和胆管癌;小梁状腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;恶性类癌瘤;细支气管肺泡癌;乳头状腺癌;嗜铬癌;嗜酸性癌;嗜氧性腺癌;嗜碱细胞癌;透明细胞腺癌;粒状细胞癌;滤泡性腺癌;乳头状和滤泡性腺癌;未包囊硬化癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;大汗腺癌;皮脂腺腺癌;盯聍腺腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;乳腺佩吉特病;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;恶性胸腺瘤;恶性卵巢基质瘤;恶性卵泡膜瘤;恶性粒状细胞肿瘤;恶性雄母细胞瘤;支持细胞癌;恶性莱迪希细胞肿瘤;恶性脂质细胞肿瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;骨肉瘤;恶性黑色素瘤;无黑色素黑素瘤;浅表播散黑色素瘤;巨大色素痣中的恶性黑素瘤;上皮样细胞黑素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎横纹肌肉瘤;腺泡状横纹肌肉瘤;基质肉瘤;恶性混合肿瘤;缪勒氏混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;恶性间充质瘤;恶性Brenner肿瘤;恶性叶状瘤肿瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺肿;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤;恶性血管周皮细胞瘤;淋巴管肉瘤;骨肉瘤;近关节骨肉瘤;软骨肉瘤;恶性成软骨细胞瘤;间充质软骨肉瘤;骨巨细胞瘤;尤文氏肉瘤;恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉质纤维肉瘤;恶性松果体瘤;脊索瘤;恶性胶质瘤;室管膜瘤;星形细胞瘤;原浆型星形细胞瘤;纤维型星形细胞瘤;成星形细胞瘤;成胶质细胞瘤;少突神经胶质瘤;少突胶质细胞瘤;原始神经外胚层;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经营养瘤;恶性粒状细胞肿瘤;恶性淋巴瘤;霍奇金病;霍奇金病;副肉芽肿;恶性淋巴瘤,小淋巴细胞性淋巴瘤;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;蕈样真菌病;其它特定的非霍奇金淋巴瘤;恶性组织细胞增多病;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱性白血病;嗜酸性白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤;和毛细胞白血病。
另一个实施方案是治疗选自淋巴瘤、白血病和浆细胞肿瘤的癌症的方法。
在该实施方案的一个方面,所述癌症是淋巴瘤,并且所述淋巴瘤选自非霍奇金淋巴瘤;伯基特氏淋巴瘤;小淋巴细胞性淋巴瘤;淋巴浆细胞淋巴瘤;MALT淋巴瘤;滤泡性淋巴瘤;弥漫性大B细胞淋巴瘤;和T细胞淋巴瘤的淋巴瘤。
在该实施方案的另一方面,所述癌症是白血病,所述白血病选自急性成淋巴细胞性白血病(ALL);伯基特氏白血病;B细胞白血病;B细胞急性成淋巴细胞性白血病;慢性淋巴细胞性白血病(CLL);急性髓性白血病(AML);慢性髓性白血病(CML);和T细胞急性成淋巴细胞性白血病(T-ALL)。
在该实施方案的另一个方面,所述癌症是浆细胞肿瘤,并且所述浆细胞肿瘤选自多发性骨髓瘤;浆细胞骨髓瘤;浆细胞白血病;和浆细胞瘤。
在另一个实施方案中,所述方法是治疗癌症的方法,并且所述癌症选自上皮细胞癌;结肠癌;肝癌;胃癌;肠癌;食道癌;乳腺癌;卵巢癌;头颈癌;肺癌;和甲状腺癌。
在另一个实施方案中,所述方法是治疗自身免疫性疾病的方法,并且所述自身免疫性疾病选自红斑狼疮;Wiskott-Aldrich综合征;自身免疫性淋巴组织增生综合征;重症肌无力;类风湿性关节炎(RA);狼疮肾炎;多发性硬化;系统性红斑狼疮;盘状狼疮;亚急性皮肤红斑狼疮;皮肤红斑狼疮,包括冻疮红斑狼疮;慢性关节炎;干燥综合征;炎性慢性鼻窦炎;结肠炎;乳糜泻;炎性肠病;巴雷特食管;炎性胃炎;自身免疫性肾炎;自身免疫性血管炎;自身免疫性肝炎;自身免疫性心炎;自身免疫性脑炎;自身免疫性糖尿病;自身免疫性糖尿病性肾炎;和自身免疫介导的血液疾病。
"受试者"是哺乳动物,优选人,但也可以是需要兽医治疗的动物,例如伴侣动物(例如狗、猫等)、农场动物(例如牛、羊、猪、马等)和实验室动物(例如大鼠、小鼠、豚鼠等)。
在某些实施方案中,本文公开的方法还包括,除了有效量的所公开的RAD51抑制剂之外,还向正在进行癌症治疗的受试者共施用有效量的DNA损伤剂。术语"DNA损伤剂"指直接或间接损伤DNA的任何试剂,同源重组可以修复该损伤。所述DNA损伤剂选自:暴露于DNA损伤性化学品;暴露于化疗剂;暴露于放化疗法;和暴露于电离或紫外辐射。DNA损伤性化疗剂的具体实例包括烷化剂、亚硝基脲、抗代谢物、植物生物碱、植物提取物和放射性同位素。化疗剂的具体实例还包括DNA损伤性药物,例如5-氟尿嘧啶(5-FU)、卡培他滨、S-1(特加氟,5-氯-2,4-二羟基吡啶和氧嗪酸)、5-乙炔基尿嘧啶、阿糖胞苷(ara-C)、5-氮胞苷(5-AC)、2’,2’-二氟-2’-脱氧胞苷(dFdC)、嘌呤抗代谢物(巯基嘌呤、氮杂硫代嘌呤、硫鸟嘌呤)、吉西他滨盐酸盐(Gemzar)、喷司他丁、别嘌呤醇、2-氟-阿拉伯糖基-腺嘌呤(2F-ara-A)、羟基脲、硫氮芥(双氯乙基硫醚(bischloroetyhylsulfide))、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替哌、AZQ、丝裂霉素C、二氢卫矛醇、二溴卫矛醇、烷基磺酸酯(白消安),亚硝基脲(BCNU、CCNU、4-甲基CCNU或ACNU)、甲基苄肼、氮烯咪胺、蝴蝶霉素、蒽环类如多柔比星(阿霉素;ADR)、柔红霉素(Cerubicine)、伊达比星(依达霉素)和表柔比星(Ellence)、蒽环类似物如米托蒽醌、放线菌素D、非插入式拓扑异构酶抑制剂如表鬼臼毒素(依托泊苷或VP16,替尼泊苷或VM-26)、鬼臼毒素、博来霉素(Bleo)、派来霉素、与核酸形成加合物的化合物包括铂衍生物,例如顺铂(CDDP)、顺铂的反式类似物、卡铂、异丙铂、四铂和奥沙利铂,以及喜树碱、托泊替康、伊立替康(CPT-11)和SN-38。核酸损伤治疗的具体实例包括辐射,例如紫外线(UV)、红外(IR)或α-、β-或γ辐射,以及环境冲击,例如高温。
在某些实施方案中,确定受试者具有提高的DNA损伤过程或DNA编辑酶水平和/或活性。"DNA编辑酶"是指通常催化DNA片段的突变、交换或切除的酶,特别是能够产生或促进点突变、DNA单链断裂、DNA双链断裂或蛋白-DNA加合物产生的酶。在该实施方案的一个方面中,DNA编辑酶选自活化诱导胞苷脱氨酶(AID或AICDA)、APOBEC2、APOBEC3A、APOBEC3C、APOBEC3D、APOBEC3F、APOBEC3G、APOBEC3H、APOBEC4、1型拓扑异构酶、2型拓扑异构酶、重组活化基因1(RAG1)和重组活化基因2(RAG2)。
在某些实施方案中,已经确定从受试者获得的血细胞具有可检测水平的活化诱导胞苷脱氨酶(AID)。
在某些实施方案中,已经确定从受试者获得的B细胞具有可检测水平的活化诱导胞苷脱氨酶(AID)。
在某些实施方案中,活化诱导胞苷脱氨酶(AID)的可检测水平在统计学上显著高于在来自健康受试者的未活化B细胞或正常非免疫细胞中表达的AID水平。
在某些实施方案中,本发明提供了使用本发明的化合物或其药学上可接受的盐或药物组合物的方法。本发明的化合物或其药学上可接受的盐或药物组合物可用于多种治疗应用,包括治疗和/或减轻多种疾病和病症,包括例如癌症、自身免疫性疾病、免疫缺陷或神经变性疾病。所述方法包括向有需要的受试者施用有效量的一种或多种本发明的化合物或其药学上可接受的盐或其药物组合物。
给药方法和剂型
给予受试者以提供"有效量"的化合物的精确量将取决于给药模式、疾病的类型和严重程度,并取决于受试者的特征,例如一般健康状况、年龄、性别、体重和对药物的耐受性。技术人员将能够根据这些和其它因素确定适当的剂量。当与其他治疗剂组合施用时,例如当与抗癌剂组合施用时,任何另外的治疗剂的"有效量"将取决于所用药物的类型。合适的剂量是已知的批准的治疗剂,并且可以由本领域技术人员根据受试者的病症、所治疗的病症的类型和所使用的本发明化合物的量通过遵循例如文献中报道的和Physician'sDeskReference(第57版,2003)中推荐的剂量来调整。
术语"有效量"是指当施用于受试者时,与对照相比,导致有益或期望的结果,包括临床结果的量,例如抑制、压制或减轻受试者中被治疗的病症的症状。例如,治疗有效量可以单位剂型给予(例如,每天0.1mg至约50g,或者每天1mg至约5克;并且在另一个实施方案中,每天10mg至1克)。
本文所用的术语"施用"、"施予"、"给予"等是指可用于将组合物递送至生物作用的期望部位的方法。这些方法包括但不限于关节内(在关节中)、静脉内、肌内、肿瘤内、皮内、腹膜内、皮下、口服、局部、鞘内、吸入、透皮、直肠等。可与本文所述的药剂和方法一起使用的施用技术可见于例如Goodman和Gilman,The Pharmacological Basis ofTherapeutics,当前版本;Pergamon;和Remington,Pharmaceutical Sciences(当前版本),MackPublishing Co.Easton,Pa。
此外,所公开的RAD51抑制剂可与其它治疗剂共同施用。本文所用的术语"共同给药"、"联合给药"及其语法上的等同体,是指包括向单个受试者给予两种或更多种治疗剂,并且旨在包括其中通过相同或不同的给药途径或者在相同或不同的时间给予所述药剂的治疗方案。在一些实施方案中,本文所述的所述一种或多种化合物将与其它药剂共同施用。这些术语包括向受试者施用两种或更多种药剂,使得两种药剂和/或它们的代谢物同时存在于受试者中。它们包括在分开的组合物中同时给药、在分开的组合物中在不同时间给药和/或在其中存在两种试剂的组合物中给药。因此,在一些实施方案中,本文所述的化合物和其它药剂在单一组合物中施用。在一些实施方案中,本文所述的化合物和其它试剂在组合物中混合。
具体的施用模式和剂量方案将由主治临床医师考虑病例的细节(例如,受试者、疾病、涉及的疾病状态、具体的治疗)来选择。治疗可以包括在几天至几个月或甚至几年的期间内每日或每日多次或少于每日(例如每周或每月等)的剂量。然而,本领域普通技术人员查看作为指导的使用所公开的RAD51抑制剂用于治疗RAD51介导的疾病的批准组合物的剂量,将立即认识到适当的和/或等效的剂量。
如本领域技术人员所理解的,本文教导的化合物或相应的药物组合物可以以多种形式施用给患者,这取决于所选择的施用途径。本发明的化合物可以例如通过口服、肠胃外、口腔、舌下、鼻、直肠、贴剂、泵或经皮给药来施用,并且相应地配制药物组合物。肠胃外施用包括静脉内、腹膜内、皮下、肌内、经上皮、经鼻、肺内、鞘内、直肠和局部施用模式。肠胃外给药可以通过在选定的时间内连续输注。
本发明的药物组合物被配制成与其预期的给药途径相容。在一个实施方案中,根据常规方法将组合物配制成适于静脉内、皮下、肌内、口服、鼻内或局部施用于人的药物组合物。在优选的实施方案中,药物组合物被配制用于静脉内施用。
通常,对于口服治疗性施用,本教导的化合物可以与赋形剂合并,并且以可吸收片剂、口含片剂、锭剂、胶囊、酏剂、混悬剂、糖浆剂、纸囊剂等的形式使用。
通常对于肠胃外施用,本教导的化合物的溶液通常可以在与表面活性剂如羟丙基纤维素适当混合的水中制备。分散体也可以在甘油、液体聚乙二醇、DMSO和它们的混合物中(有或没有醇)以及在油中制备。在普通的储存和使用条件下,这些制剂包含防腐剂以防止微生物的生长。
通常,对于注射用途,本文所述的用于临时制备无菌注射溶液或分散体的化合物的无菌水溶液或分散体和无菌粉末是合适的。
示例
合成方案
实施例1
流程1.1
中间体化合物2
将4-硝基苯基)硼酸(23.00g,137.78mmol,1.00eq.)、2-溴噻唑(25.54g,155.69mmol,14.03mL,1.13eq.)、Na2CO3(36.51g,344.45mmol,2.50eq.)和Pd(dppf)Cl2.CH2Cl2(6.75g,8.27mmol,0.06eq.)在甲苯(250.00mL)/H2O(100.00mL)/二噁烷(250.00mL)中的混合物脱气并用N2吹扫3次。将混合物在N2气氛下在80℃下搅拌12小时,并且LCMS显示反应完成。浓缩混合物,残余物通过柱色谱法纯化(石油醚:乙酸乙酯=50:1至5:1),得到2-(4-硝基苯基)噻唑(14.00g,67.89mmol,56.00%收率),为黄色固体。1H NMR(400MHz,氯仿-d)δ=8.35-8.29(m,2H),8.21-8.12(m,2H),7.99(d,J=3.2Hz,1H),7.50(d,J=3.2Hz,1H)。
中间体化合物3
向2-(4-硝基苯基)噻唑(6g,29.10mmol,1eq.)在DMF(50mL)中的溶液中加入NBS(15.54g,87.29mmol,3eq.)。将混合物在80℃下搅拌15分钟,LCMS显示反应完成。将混合物倒入水(1L)中并过滤。滤饼用MeOH(50mL)洗涤并干燥,得到5-溴-2-(4-硝基苯基)噻唑(7.3g,粗品),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.35(br s,2H),8.18(br s,2H),8.07-7.88(m,1H)。
通用方法A:中间体化合物4
将N-[3-(叔丁基氨磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]乙酰胺(5g,12.62mmol,1eq.)、5-溴-2-(4-硝基苯基)噻唑(4.32g,15.14mmol,1.2eq.)、Na2CO3(4.01g,37.85mmol,3eq.)和Pd(dppf)Cl2(923.16mg,1.26mmol,0.1eq.)在二噁烷(50mL)和H2O(10mL)中的混合物脱气并用N2吹扫3次。随后将混合物在N2气氛下在80℃下搅拌12小时,并且LCMS显示反应完成。将混合物浓缩,用H2O(50mL)稀释并用EtOAc(40mL X 3)萃取。合并的有机层用盐水(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到N-[3-(叔丁基氨磺酰基)-4-[2-(4-硝基苯基)噻唑-5-基]苯基]乙酰胺(8.9g,粗品),为黑褐色油,无需进一步纯化即可直接使用。ESI[M+H]=475.1
通用方法B:中间体化合物5
在80℃下将N-[3-(叔丁基氨磺酰基)-4-[2-(4-硝基苯基)噻唑-5-基]苯基]乙酰胺(800mg,1.69mmol,1eq.)、NH4Cl(450.87mg,8.43mmol,294.68ul,5eq.)和Fe(470.76mg,8.43mmol,5eq.)在EtOH(20mL)、THF(20mL)和H2O(10mL)中的混合物搅拌2小时并且LCMS显示反应完成。将混合物过滤,将滤液用H2O(20mL)稀释,并用EtOAc(20mL X 3)萃取。合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过柱色谱法纯化(石油醚:乙酸乙酯=10:1~1:2),得到N-[4-[2-(4-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺(0.6g,1.35mmol,80.06%收率),为黄色固体。ESI[M+H]=445.1
通用方法C:中间体化合物6
在0℃下将N-[4-[2-(4-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺(1.3g,2.92mmol,1eq.)、DMAP(35.72mg,292.42μmol,0.1eq.)和吡啶(1.16g,14.62mmol,1.18mL,5eq.)在DCM(20mL)中的混合物中加入氯甲酸异丙酯(716.72mg,5.85mmol,811.68ul,2eq.)。随后在N2气氛下在20℃下将混合物搅拌1小时。TLC(石油醚:乙酸乙酯=1:1,Rf=0.3)表明反应完成。将反应混合物用1N HCl(50mL)和饱和Na2CO3水溶液(50mL)洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过柱色谱法纯化(石油醚:乙酸乙酯=1:1),得到N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(1.5g,2.83mmol,96.67%收率),为黄色固体。
中间体化合物7
N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(1.5g,2.83mmol,1eq.)溶于HCl/MeOH(4M,17.65mL,24.97eq.)中,将混合物在30℃下搅拌2小时。LCMS显示反应完成。浓缩混合物,并将残余物溶于饱和Na2CO3水溶液(50mL)中并用EtOAc(50mL X 3)萃取。合并的有机相经Na2SO4干燥,过滤并浓缩,得到中间体化合物7(1.3g,2.66mmol,94.12%收率),为黄色固体,其无需进一步纯化即可直接使用。ESI[M+H]=489.1
中间体化合物8
在0℃下向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(0.5g,1.02mmol,1eq.)、DMAP(12.50mg,102.33μmol,0.1eq.)和吡啶(404.71mg,5.12mmol,412.97ul,5eq.)在DCM(10mL)中的混合物中加入氯代甲酸4-硝基苯酯(412.52mg,2.05mmol,2eq.),随后在N2气氛下在20℃下将混合物搅拌2小时。LCMS显示反应完成。该混合物无需任何纯化即可用于下一步。ESI[M+H]=654.1
通用方法D:中间体化合物9
在80℃下将(2S)-2-(羟基甲基)吡咯烷-1-甲酸叔丁酯(60mg,298.12μmol,3.90eq.)、DIEA(25mg,193.43μmol,33.69ul,2.53eq.)和N-[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]氨基甲酸(4-硝基苯基)酯(50mg,76.48μmol,1eq.)在MeCN(2mL)中的混合物搅拌1小时。LCMS显示反应完成。混合物用EtOAc(4mL)和THF(1mL)稀释,用H2O(5mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到(2S)-2-[[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]氨基甲酰基氧基甲基]吡咯烷-1-甲酸叔丁酯(80mg,粗品),为黄色胶,其直接使用。ESI[M+H]=716.2
通用方法E:化合物A1
向(2S)-2-[[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]氨基甲酰基氧基甲基]吡咯烷-1-甲酸叔丁酯(80mg,111.75μmol,1eq.)在DCM(1mL)中的溶液中滴加TFA(1mL)并且混合物在15℃下搅拌1小时。LCMS显示反应完成。将混合物浓缩并且残余物通过制备型HPLC纯化(柱:Luna C18100*305u;流动相:[水(0.1%TFA)-ACN];B%:20%-60%,10min),得到化合物A1(4.54mg,6.10μmol,5.46%收率,98.064%纯度,TFA,为棕色固体。1H NMR(400MHz,甲醇-d4)δ=8.41(d,J=2.2Hz,1H),7.91-7.84(m,3H),7.75(dd,J=2.0,8.4Hz,1H),7.57(d,J=8.8Hz,2H),7.50(d,J=8.4Hz,1H),5.02-4.93(m,1H),4.50(dd,J=3.3,12.6Hz,1H),4.35(dd,J=7.8,12.5Hz,1H),3.95(dq,J=3.4,8.1Hz,1H),3.42-3.33(m,2H),2.31-2.02(m,3H),1.93-1.81(m,1H),1.32(d,J=6.4Hz,6H),1.12(s,9H)。ESI[M+H]=616.2
通用方法F:化合物A2
向苯基甲胺(14.47g,135.06mmol,14.72mL,3eq.)和DIEA(23.27g,180.08mmol,31.37mL,4eq.)在DCM(500mL)中的溶液中加入在DCM(500mL)中的N-[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]氨基甲酸4-硝基苯酯(29.43g,45.02mmol,1eq.)。将混合物在20℃下搅拌15分钟,LCMS显示反应完成。将混合物用1N HCl(500mL)和饱和Na2CO3水溶液(500mL)洗涤。然后有机相经Na2SO4干燥,过滤并浓缩。将残余物通过硅胶色谱法纯化,用石油醚:乙酸乙酯=3∶1洗脱,得到化合物A2(10.23g,15.47mmol,34.37%收率,94.09%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.29(d,J=2.4Hz,1H),7.93-7.84(m,3H),7.74(dd,J=2.2,8.6Hz,1H),7.59(d,J=8.8Hz,2H),7.45(d,J=8.3Hz,1H),7.40-7.32(m,4H),7.27(dt,J=2.7,5.7Hz,1H),5.07-4.95(m,1H),4.44(s,2H),1.33(d,J=6.4Hz,6H),1.15(s,9H)。ESI[M+H]=622.2
流程1.2
中间体化合物10
中间体化合物10由中间体化合物3通过通用方法A(同上)制备
1H NMR(400MHz,DMSO-d6)δ=9.85(s,1H),8.36-8.31(m,2H),8.22-8.16(m,2H),8.10(s,1H),7.24-7.16(m,2H),6.84(dd,J=2.0,8.4Hz,1H),5.35(s,2H),2.02(s,3H)。
中间体化合物11
在0℃下向N-[3-氨基-4-[2-(4-硝基苯基)噻唑-5-基]苯基]乙酰胺(2.00g,5.64mmol,1.00eq.)在H2O(5mL)和AcOH(15mL)中的混合物中加入浓HCl(20.00mL),随后加入NaNO2(2.00g,28.99mmol,1.57mL,5.14eq.)在H2O(5mL)中的溶液。将混合物在0℃下搅拌2.5小时(混合物1)。将CuCl2(758.79mg,5.64mmol,1.00eq.)在SO2的AcOH(15g在20mL中)和H2O(5mL)溶液中的另一混合物在20℃下搅拌1小时(混合物2)。随后将混合物2冷却至0℃,并将混合物1逐滴加入。将反应混合物在0℃下再搅拌0.5小时。HPLC显示反应完成。将混合物倒入冰水混合物(70mL)中,并通过过滤收集所得沉淀,随后用水(10mLX 3)洗涤并干燥,得到5-乙酰氨基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰氯(2.50g,粗品),为黑褐色固体,其直接使用。
中间体化合物12
向哌嗪-1-甲酸叔丁酯(191.41mg,1.03mmol,3.00eq.)和DMAP(4.19mg,34.26μmol,0.10eq.)在DCM(1.00mL)中的溶液中滴加5-乙酰氨基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰氯(150.00mg,342.56μmol,1.00eq.)在THF(5.00mL)中的溶液。将混合物在25℃下搅拌1小时,并且LCMS显示反应完成。将混合物倒入0.5N HCl(6mL)中,并用EtOAc/THF(3mL/1mL X 3)萃取。合并的有机层用盐水(3mL X 2)洗涤,经Na2SO4干燥,过滤并浓缩,得到4-[5-乙酰氨基-2-[2-(4-硝基苯基)噻唑-5-基]苯基]磺酰基哌嗪-1-甲酸叔丁酯(200.00mg,粗品),无需任何纯化。ESI[M+Na]=610.2
中间体化合物13
中间体化合物13由中间体化合物12通过通用方法B(同上)制备
通用方法G:中间体化合物14
在80℃下将2-异硫氰酸根合丙烷(261.23mg,2.58mmol,274.98ul,10.00eq.)和4-[5-乙酰氨基-2-[2-(4-氨基苯基)噻唑-5-基]苯基]磺酰基哌嗪-1-甲酸叔丁酯(180.00mg,258.21μmol,1.00eq.)在EtOH(3.00mL)中的混合物搅拌2小时,LCMS显示反应完成。将混合物浓缩并将残余物通过制备型TLC纯化(石油醚:乙酸乙酯=1:2),得到4-[5-乙酰氨基-2-[2-[4-(异丙基氨基硫代甲酰氨基)苯基]噻唑-5-基]苯基]磺酰基哌嗪-1-甲酸叔丁酯(90.00mg,粗品),为黄色固体。ESI[M+H]=659.3
化合物A3
化合物A3由中间体化合物14通过通用方法E(同上)制备。
1H NMR(400MHz,DMSO-d6)δ=10.54(s,1H),9.70(br s,1H),8.75(br s,2H),8.42(d,J=1.8Hz,1H),8.00-7.80(m,5H),7.68(d,J=8.6Hz,2H),7.61(d,J=8.4Hz,1H),4.39(br d,J=6.4Hz,1H),3.12(br s,4H),3.05-2.97(m,4H),2.11(s,3H),1.18(d,J=6.6Hz,6H)。ESI[M+H]=558.9
通用方法H:化合物A4
在N2下将4-(5-溴噻唑-2-基)苯胺(80.00mg,313.57μmol,1.00eq.)、N-[3-(叔丁基氨磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]乙酰胺(149.13mg,376.28μmol,1.20eq.)、Pd(PPh3)2Cl2(22.01mg,31.36μmol,0.10eq.)和K2CO3(86.68mg,627.14μmol,2.00eq.)在EtOH(900.00ul)、甲苯(900.00ul)和H2O(300.00ul)中的混合物加热至80℃,持续16小时。LCMS显示反应完成。将混合物用EtOAc(20mL)稀释,并用H2O(7mL)洗涤。用EtOAc(7mL X 2)萃取水相。合并的有机相经Na2SO4干燥,过滤,真空浓缩,并通过酸性制备型HPLC纯化,得到化合物A4(90.00mg,143.73μmol,45.84%收率,71%纯度),为黄色固体。1H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),8.39(d,J=2.2Hz,1H),7.81(dd,J=2.0,8.6Hz,1H),7.73(s,1H),7.65(br d,J=6.6Hz,2H),7.45(d,J=8.3Hz,1H),7.09(s,1H),6.76-6.64(m,2H),2.08(s,3H),1.07(s,9H)。ESI[M+H]=445.2
通用方法I:化合物A5
向N-[3-(叔丁基氨磺酰基)-4-[2-(4-羟基苯基)噻唑-5-基]苯基]乙酰胺(50.00mg,112.22μmol,1.00eq.)在Py(2.00mL)中的溶液中加入2-异氰酸根合丙烷(28.65mg,336.66μmol,32.93ul,3.00eq.)并将混合物在80℃下搅拌16小时。LCMS显示反应完成。浓缩混合物,并通过酸性制备型HPLC纯化残余物,得到化合物A5(3.68mg,6.84μmol,6.09%收率,98.6%纯度),为棕色固体。1H NMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.98(d,J=8.8Hz,2H),7.91-7.84(m,2H),7.50(d,J=8.3Hz,1H),7.24(d,J=8.8Hz,2H),3.78(brd,J=7.9Hz,1H),2.17(s,3H),1.22(d,J=6.6Hz,6H),1.13(s,9H)。ESI[M+H]=530.9
流程1.3
通用方法J:中间体化合物34
向N-[4-[5-[4-溴-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(100.00mg,181.00μmol,1.00eq.)在二噁烷(3.00mL)中的溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(183.85mg,724.00μmol,4.00eq.)、Na2CO3(38.37mg,362.00μmol,2.00eq.)和Pd(dppf)Cl2.CH2Cl2(14.78mg,18.10μmol,0.10eq.),将混合物在80℃下搅拌16小时。LCMS显示反应完成。混合物用水(30mL)稀释并用EtOAc(30mL X 3)萃取。将合并的有机相干燥,过滤并浓缩。残余物通过制备型TLC纯化(PE:EtOAc=2:1),得到中间体化合物34(90.00mg,150.11μmol,82.93%收率),为黄色固体。ESI[M+H]=600.3
化合物A6
化合物A6由中间体化合物34通过通用方法A(同上)制备。
1H NMR(400MHz,甲醇-d4)δ=9.05(s,1H),8.60(d,J=2.0Hz,1H),8.13(d,J=1.2Hz,1H),8.04(dd,J=2.0,7.9Hz,1H),8.00(s,1H),7.96-7.92(m,2H),7.75(d,J=8.1Hz,1H),7.61(d,J=8.7Hz,2H),5.01(td,J=6.2,12.5Hz,1H),1.34(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=540.2
通用方法K:化合物A7
在0℃下向N-甲基丙烷-2-胺(124.33mg,1.70mmol,177.61ul,10.00eq.)在DCM(2.00mL)中的溶液中加入DIPEA(109.85mg,849.95μmol,148.45ul,5.00eq.)和碳酸双(三氯甲酯)(227.00mg,764.96μmol,4.50eq.)。将混合物在0℃下搅拌0.5小时,随后加入在DMF(2.00mL)中的2-[2-(4-氨基苯基)噻唑-5-基]-N-叔丁基-5-(2-氧代吡咯烷-1-基)苯磺酰胺(80.00mg,169.99μmol,1.00eq.)。将混合物在80℃下再搅拌0.5小时,LCMS显示反应完成。将混合物浓缩并将残余物通过酸性制备型HPLC纯化,得到化合物A7(4.83mg,8.27μmol,4.87%收率,97.6%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.66(d,J=2.2Hz,1H),7.92-7.80(m,4H),7.60-7.49(m,3H),4.54(td,J=6.7,13.5Hz,1H),3.99(t,J=7.1Hz,2H),2.90(s,3H),2.65(t,J=8.0Hz,2H),2.22(quin,J=7.6Hz,2H),1.19(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=570.2
实施例2
除非另有说明,否则以下化合物通过通用方法D和E(实施例1中所示)通过使中间体8与不同的醇反应来合成。
化合物B1
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=2.0Hz,1H),7.93–7.86(m,3H),7.75(dd,J=2.0,8.3Hz,1H),7.61–7.57(m,2H),7.49(d,J=8.8Hz,1H),5.00(td,J=6.2,12.6Hz,1H),4.32–4.22(m,2H),3.87–3.76(m,2H),1.34(d,J=6.4Hz,6H),1.16(s,9H)。ESI[M+H]=577.2
化合物B2
1H NMR(400MHz,甲醇-d4)δ=8.37(d,J=2.2Hz,1H),7.90–7.82(m,3H),7.70(dd,J=2.2,8.4Hz,1H),7.56(d,J=8.6Hz,2H),7.45(d,J=8.4Hz,1H),5.04–4.93(m,1H),4.34–4.26(m,2H),3.66(dd,J=3.9,5.4Hz,2H),3.40(s,3H),1.31(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=591.2
化合物B3
1H NMR(400MHz,甲醇-d4)δ=8.69(d,J=5.3Hz,1H),8.39(d,J=2.2Hz,1H),8.25(dt,J=1.5,7.8Hz,1H),7.91–7.81(m,4H),7.77–7.66(m,2H),7.57(d,J=8.8Hz,2H),7.48(d,J=8.3Hz,1H),5.43(s,2H),4.97(quin,J=6.2Hz,1H),1.31(d,J=6.1Hz,6H),1.12(s,9H)。ESI[M+H]=624.0
化合物B4
1H NMR(400MHz,甲醇-d4)δ=8.81(d,J=7.0Hz,2H),8.40(d,J=2.2Hz,1H),8.02(d,J=6.6Hz,2H),7.91–7.83(m,3H),7.77–7.72(m,1H),7.57(d,J=8.8Hz,2H),7.50(d,J=8.3Hz,1H),5.53(s,2H),4.98(quin,J=6.2Hz,1H),1.31(d,J=6.1Hz,6H),1.12(s,9H)。ESI[M+H]=624.1
化合物B5
1H NMR(400MHz,甲醇-d4)δ=8.38(d,J=2.2Hz,1H),7.90–7.83(m,3H),7.72(dd,J=2.2,8.3Hz,1H),7.57(d,J=8.8Hz,2H),7.45(d,J=8.3Hz,1H),5.05(s,1H),5.01–4.93(m,2H),4.61(s,2H),1.81(s,3H),1.31(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=587.1
化合物B6
1H NMR(400MHz,甲醇-d4)δ=8.46(d,J=2.0Hz,1H),7.94–7.84(m,4H),7.59(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,1H),7.35–7.25(m,4H),7.23–7.15(m,1H),5.00(td,J=6.2,12.6Hz,1H),3.04(t,J=7.6Hz,2H),2.80–2.66(m,2H),1.33(d,J=5.9Hz,6H),1.16(s,9H)。ESI[M+H]=621.1
化合物B7
1H NMR(400MHz,甲醇-d4)δ=8.43(d,J=1.5Hz,1H),7.94–7.85(m,3H),7.77(dd,J=2.0,8.3Hz,1H),7.59(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,1H),5.00(spt,J=6.2Hz,1H),4.52(dd,J=3.4,12.7Hz,1H),4.37(dd,J=7.8,12.7Hz,1H),3.97(dq,J=3.4,8.0Hz,1H),3.46–3.35(m,2H),2.35–2.23(m,1H),2.21–2.01(m,2H),1.89(qd,J=8.4,12.9Hz,1H),1.34(d,J=6.4Hz,6H),1.14(s,9H)。ESI[M+H]=616.2
化合物B8
1H NMR(400MHz,甲醇-d4)δ=8.37(s,1H),7.91–7.85(m,3H),7.70(br d,J=8.6Hz,1H),7.58(d,J=8.6Hz,2H),7.45(d,J=8.2Hz,1H),7.36–7.25(m,4H),7.22(qd,J=4.2,8.7Hz,1H),4.98(td,J=6.3,12.5Hz,1H),4.39(t,J=6.8Hz,2H),3.01(t,J=6.8Hz,2H),1.35–1.29(m,6H),1.14(s,9H)。ESI[M+H]=637.2
化合物B9
1H NMR(400MHz,甲醇-d4)δ=8.89(s,1H),8.75(br d,J=5.5Hz,1H),8.49(br d,J=8.6Hz,1H),8.39(d,J=1.8Hz,1H),7.96–7.85(m,4H),7.73(br d,J=7.9Hz,1H),7.58(d,J=8.6Hz,2H),7.49(d,J=8.4Hz,1H),5.42(s,2H),4.98(td,J=6.2,12.3Hz,1H),1.32(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=624.2
化合物B10
1H NMR(400MHz,甲醇-d4)δ=8.38(d,J=2.0Hz,1H),7.91–7.82(m,3H),7.70(brd,J=7.3Hz,1H),7.57(d,J=8.6Hz,2H),7.45(d,J=8.4Hz,1H),5.02–4.92(m,1H),3.98(d,J=6.4Hz,2H),1.87–1.63(m,6H),1.39–1.19(m,9H),1.16–0.94(m,11H)。ESI[M+H]=629.2
化合物B11
1H NMR(400MHz,甲醇-d4)δ=8.39(s,1H),7.92–7.85(m,3H),7.82(d,J=3.1Hz,1H),7.75(br d,J=6.6Hz,1H),7.66(d,J=3.3Hz,1H),7.58(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,1H),5.51(s,2H),5.02–4.91(m,1H),1.31(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=630.1
化合物B12
1H NMR(400MHz,甲醇-d4)δ=8.38(d,J=1.8Hz,1H),7.96–7.84(m,3H),7.73(dd,J=2.0,8.3Hz,1H),7.58(d,J=8.7Hz,2H),7.48(d,J=8.3Hz,1H),5.98–5.81(m,1H),5.75–5.63(m,1H),4.99(td,J=6.3,12.5Hz,1H),4.61(d,J=6.4Hz,2H),1.76(d,J=6.1Hz,3H),1.33(d,J=6.2Hz,6H),1.16(s,9H)。ESI[M+H]=587.2
化合物B13
1H NMR(400MHz,甲醇-d4)δ=8.41(d,J=2.0Hz,1H),7.96–7.83(m,3H),7.77(dd,J=2.1,8.4Hz,1H),7.59(d,J=8.7Hz,2H),7.51(d,J=8.3Hz,1H),5.00(td,J=6.2,12.5Hz,1H),4.50–4.43(m,2H),3.31(br s,2H),1.33(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=576.1
化合物B14
1H NMR(400MHz,甲醇-d4)δ=8.42(s,1H),7.94–7.86(m,3H),7.75(br d,J=8.3Hz,1H),7.65–7.50(m,5H),5.49(s,2H),5.00(td,J=6.3,12.5Hz,1H),1.34(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=613.2
化合物B15
1H NMR(400MHz,DMSO-d6)δ=10.25(s,1H),9.84(s,1H),8.33(d,J=2.2Hz,1H),7.87(d,J=8.8Hz,2H),7.81(s,1H),7.67(dd,J=2.2,8.4Hz,1H),7.60(d,J=8.8Hz,2H),7.42(dt,J=8.1,14.1Hz,5H),7.35–7.29(m,1H),7.14–7.09(m,1H),5.85(q,J=6.6Hz,1H),4.92(td,J=6.2,12.5Hz,1H),1.57(d,J=6.6Hz,3H),1.27(d,J=6.2Hz,6H),1.08(s,9H)。ESI[M+H]=637.2
化合物B16
1H NMR(400MHz,甲醇-d4)δ=8.43(d,J=1.96Hz,1H),7.87-7.94(m,3H),7.77(brd,J=8.44Hz,1H),7.60(d,J=8.68Hz,2H),7.52(d,J=8.44Hz,1H),5.00(td,J=6.28,12.50Hz,1H),4.52(dd,J=3.36,12.53Hz,1H),4.37(br dd,J=7.83,10.88Hz,1H),3.97(dq,J=3.30,8.03Hz,1H),3.36-3.44(m,2H),2.05-2.34(m,3H),1.84-1.94(m,1H),1.34(d,J=6.24Hz,6H),1.14(s,9H)。ESI[M+H]=616.2
化合物B17
1H NMR(400MHz,甲醇-d4)δ=8.41(d,J=2.2Hz,1H),7.91–7.84(m,3H),7.75(dd,J=2.0,8.4Hz,1H),7.57(d,J=8.8Hz,2H),7.50(d,J=8.4Hz,1H),5.02–4.93(m,1H),4.50(dd,J=3.3,12.6Hz,1H),4.35(dd,J=7.8,12.5Hz,1H),3.95(dq,J=3.4,8.1Hz,1H),3.42–3.33(m,2H),2.31–2.02(m,3H),1.93–1.81(m,1H),1.32(d,J=6.4Hz,6H),1.12(s,9H)。ESI[M+H]=616.2
化合物B18
1H NMR(400MHz,甲醇-d4)δ=8.44(d,J=2.08Hz,1H),7.88-7.94(m,3H),7.78(dd,J=1.90,8.38Hz,1H),7.61(d,J=8.68Hz,2H),7.53(d,J=8.44Hz,1H),5.01(td,J=6.21,12.53Hz,1H),4.42-4.49(m,1H),4.33(dd,J=7.21,12.59Hz,1H),3.42-3.55(m,2H),3.01-3.11(m,1H),1.91-2.06(m,3H),1.58-1.76(m,3H),1.35(d,J=6.24Hz,6H),1.14(s,9H)。ESI[M+H]=630.2
化合物B19
1H NMR(400MHz,甲醇-d4)δ=8.43(d,J=2.2Hz,1H),7.87–7.94(m,3H),7.77(dd,J=8.3,2.0Hz,1H),7.60(d,J=8.7Hz,2H),7.53(d,J=8.4Hz,1H),5.00(dt,J=12.5,6.3Hz,1H),4.42–4.48(m,1H),4.29–4.36(m,1H),3.41–3.53(m,2H),3.01–3.10(m,1H),1.92–2.06(m,3H),1.58–1.75(m,3H),1.34(d,J=6.2Hz,6H),1.13(s,9H)。SI[M+H]=630.2
实施例3
除非另有说明,否则以下化合物通过通用方法D和E(实施例1中所示)通过使中间体8与不同的胺反应来合成。
化合物C1
1H NMR(400MHz,DMSO-d6)δ=9.84(s,1H),8.96(s,1H),8.24(d,J=2.3Hz,1H),7.86(d,J=8.7Hz,2H),7.80(s,1H),7.63–7.55(m,3H),7.41–7.32(m,5H),7.28–7.20(m,1H),7.07(s,1H),6.76(d,J=7.8Hz,1H),4.98–4.80(m,2H),1.42(d,J=6.8Hz,3H),1.27(d,J=6.2Hz,6H),1.08(s,9H)。ESI[M+H]=636.3
化合物C2
1H NMR(400MHz,甲醇-d4)δ=8.25(d,J=2.3Hz,1H),7.87–7.91(m,3H),7.68–7.72(m,1H),7.60(d,J=8.7Hz,2H),7.33–7.45(m,5H),7.23–7.29(m,1H,),4.94–5.03(m,2H),1.51(d,J=6.8Hz,3H),1.33(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=636.2
化合物C3
1H NMR(400MHz,DMSO-d6)δ=9.84(s,1H),9.39(s,1H),9.23–9.15(m,2H),8.25(d,J=2.4Hz,1H),7.85(d,J=8.8Hz,2H),7.79(s,1H),7.67–7.56(m,4H),7.39(d,J=8.4Hz,1H),7.07(s,1H),6.97(t,J=6.0Hz,1H),4.90(quin,J=6.3Hz,1H),4.39(d,J=5.5Hz,2H),1.26(d,J=6.2Hz,6H),1.05(s,9H)。ESI[M+H]=624.2
化合物C4
1H NMR(400MHz,甲醇-d4)δ=9.23(br s,1H),8.31(d,J=2.2Hz,1H),8.08–8.02(m,1H),8.01–7.95(m,1H),7.86(t,J=4.3Hz,3H),7.70(dd,J=2.2,8.4Hz,1H),7.57(d,J=8.6Hz,2H),7.43(d,J=8.4Hz,1H),4.97(td,J=6.2,12.5Hz,1H),4.77(s,2H),1.30(d,J=6.2Hz,6H),1.11(s,9H)。ESI[M+H]=624.2
化合物C5
1H NMR(400MHz,甲醇-d4)δ=9.07(s,1H),8.82(s,2H),8.28(d,J=2.2Hz,1H),7.91–7.84(m,3H),7.71(dd,J=2.3,8.3Hz,1H),7.57(d,J=8.8Hz,2H),7.44(d,J=8.4Hz,1H),4.97(td,J=6.1,12.5Hz,1H),4.46(s,2H),1.31(d,J=6.4Hz,6H),1.12(s,9H)。ESI[M+H]=624.2
化合物C6
1H NMR(400MHz,甲醇-d4)δ=8.84(br s,1H),8.75(br d,J=5.1Hz,1H),8.60(brd,J=8.2Hz,1H),8.33(d,J=2.2Hz,1H),8.04(dd,J=6.0,7.7Hz,1H),7.91–7.82(m,3H),7.67(dd,J=2.3,8.3Hz,1H),7.56(d,J=8.6Hz,2H),7.43(d,J=8.2Hz,1H),5.02–4.95(m,1H),4.61(s,2H),1.30(d,J=6.2Hz,6H),1.10(s,9H)。ESI[M+H]=623.4
化合物C7
1H NMR(400MHz,甲醇-d4)δ=8.25(d,J=2.2Hz,1H),7.90–7.84(m,3H),7.69(dd,J=2.3,8.5Hz,1H),7.58(d,J=8.8Hz,2H),7.43(d,J=8.4Hz,1H),5.04–4.92(m,1H),3.91(quin,J=6.6Hz,1H),1.32(d,J=6.2Hz,6H),1.20(d,J=6.6Hz,6H),1.13(s,9H)。ESI[M+H]=574.1
化合物C8
1H NMR(400MHz,甲醇-d4)δ=8.22(d,J=2.2Hz,1H),7.91–7.83(m,3H),7.69(dd,J=2.2,8.4Hz,1H),7.57(d,J=8.8Hz,2H),7.44–7.32(m,5H),7.28–7.21(m,1H),5.02–4.91(m,2H),1.50(d,J=6.8Hz,3H),1.31(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=636.2
化合物C9
1H NMR(400MHz,甲醇-d4)δ=8.38(d,J=2.2Hz,1H),7.90–7.83(m,3H),7.70(dd,J=2.2,8.4Hz,1H),7.57(d,J=8.6Hz,2H),7.45(d,J=8.4Hz,1H),4.98(td,J=6.1,12.5Hz,1H),3.79–3.68(m,1H),3.59–3.47(m,2H),3.40–3.32(m,1H),3.30–3.25(m,1H),2.24–1.96(m,3H),1.89–1.75(m,1H),1.32(d,J=6.4Hz,6H),1.11(s,9H)。ESI[M+H]=615.2
化合物C10
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=2.32Hz,1H),7.88-7.93(m,2H),7.87(s,1H),7.72(dd,J=2.32,8.31Hz,1H),7.59(d,J=8.68Hz,2H),7.47(d,J=8.31Hz,1H),5.00(td,J=6.28,12.50Hz,1H),3.72-3.79(m,1H),3.53-3.57(m,2H),3.36-3.42(m,1H),3.27-3.32(m,1H),2.00-2.26(m,3H),1.75-1.90(m,1H),1.34(d,J=6.24Hz,6H),1.13(s,9H)。ESI[M+H]=615.2
化合物C11
1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.4Hz,1H),7.93–7.85(m,3H),7.71(dd,J=2.4,8.3Hz,1H),7.60(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,1H),5.06–4.95(m,1H),3.08(d,J=6.4Hz,2H),1.86–1.68(m,5H),1.52(ttd,J=3.5,7.3,14.5Hz,1H),1.33(d,J=5.9Hz,9H),1.15(s,9H),1.07–0.93(m,2H)。ESI[M+H]=628.2
化合物C12
1H NMR(400MHz,甲醇-d4)δ=8.36(d,J=2.4Hz,1H),7.91–7.82(m,3H),7.70(dd,J=2.4,8.4Hz,1H),7.57(d,J=8.8Hz,2H),7.45(d,J=8.4Hz,1H),4.98(td,J=6.3,12.4Hz,1H),3.61(t,J=5.6Hz,2H),3.35–3.31(m,2H),2.98(s,6H),1.31(d,J=6.4Hz,6H),1.11(s,9H)。ESI[M+H]=603.2
化合物C13
1H NMR(400MHz,甲醇-d4)δ=8.34(d,J=2.2Hz,1H),7.92–7.82(m,3H),7.67(dd,J=2.2,8.4Hz,1H),7.57(d,J=8.6Hz,2H),7.44(d,J=8.4Hz,1H),4.97(td,J=6.3,12.4Hz,1H),4.46–4.32(m,1H),3.56–3.47(m,2H),3.39–3.32(m,2H),2.45–2.32(m,1H),2.15–2.00(m,1H),1.31(d,J=6.4Hz,6H),1.11(s,9H)。ESI[M+H]=601.3
化合物C14
1H NMR(400MHz,甲醇-d4)δ=8.37(d,J=1.8Hz,1H),7.93–7.86(m,3H),7.71(dd,J=1.9,8.3Hz,1H),7.60(d,J=8.6Hz,2H),7.46(d,J=8.3Hz,1H),5.03–4.98(m,1H),3.65–3.46(m,10H),3.27(br s,2H),1.33(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=644.2
化合物C15
1H NMR(400MHz,甲醇-d4)δ=8.40(d,J=2.3Hz,1H),7.93–7.85(m,3H),7.73(dd,J=2.3,8.3Hz,1H),7.59(d,J=8.7Hz,2H),7.47(d,J=8.4Hz,1H),5.00(td,J=6.2,12.5Hz,1H),3.46(d,J=5.5Hz,2H),3.40(br d,J=12.8Hz,1H),3.28–3.19(m,1H),3.03–2.93(m,1H),2.01–1.86(m,3H),1.75–1.47(m,3H),1.34(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=629.3
化合物C16
1H NMR(400MHz,甲醇-d4)δ=8.38(d,J=2.32Hz,1H),7.90(d,J=8.80Hz,2H),7.74(d,J=2.4Hz,1H),7.73(dd,J=2.32,8.31Hz,1H),7.59(d,J=8.68Hz,2H),7.47(d,J=8.44Hz,1H),5.00(td,J=6.24,12.47Hz,1H),3.81(br d,J=5.26Hz,2H),3.62(t,J=5.75Hz,2H),3.39(t,J=5.62Hz,2H),3.11-3.21(m,2H),2.00-2.24(m,4H),1.33(d,J=6.24Hz,6H),1.14(s,9H)。ESI[M+H]=629.3
化合物C17
1H NMR(400MHz,甲醇-d4)δ=8.32(d,J=2.2Hz,1H),7.91–7.82(m,3H),7.66(dd,J=2.4,8.6Hz,1H),7.57(d,J=8.8Hz,2H),7.42(d,J=8.3Hz,1H),4.97(td,J=6.2,12.6Hz,1H),3.41(br d,J=12.7Hz,2H),3.18(d,J=6.6Hz,2H),3.04–2.92(m,2H),1.99(br d,J=13.6Hz,2H),1.92–1.80(m,1H),1.51–1.36(m,2H),1.31(d,J=6.1Hz,6H),1.11(s,9H)。ESI[M+H]=629.2
化合物C18
1H NMR(400MHz,甲醇-d4)δ=8.33(s,1H),7.90–7.82(m,3H),7.65(br d,J=7.5Hz,1H),7.57(br d,J=8.3Hz,2H),7.43(br d,J=8.3Hz,1H),5.01–4.94(m,1H),3.43–3.32(m,2H),3.20(br d,J=6.1Hz,2H),2.92(brt,J=12.5Hz,1H),2.74(brt,J=12.1Hz,1H),2.08–1.87(m,3H),1.73(br d,J=11.8Hz,1H),1.31(br d,J=6.1Hz,7H),1.11(s,9H)。ESI[M+H]=629.2
化合物C19
1H NMR(400MHz,甲醇-d4)δ=8.24(d,J=2.2Hz,1H),7.81–7.73(m,3H),7.57(dd,J=2.3,8.4Hz,1H),7.47(d,J=8.6Hz,2H),7.34(d,J=8.4Hz,1H),4.91–4.85(m,1H),3.36–3.26(m,2H),3.24(s,1H),3.20–3.15(m,2H),2.95(dd,J=8.1,11.7Hz,1H),2.51(spt,J=7.5Hz,1H),2.14–2.03(m,1H),1.71(qd,J=8.1,13.2Hz,1H),1.22(d,J=6.2Hz,6H),1.02(s,9H)。ESI[M+H]=615.2
实施例4
除非另有说明,否则以下化合物通过通用方法E和G(实施例1中所示)通过使中间体11与不同的胺反应来合成。
化合物D1
1H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),9.55(br s,1H),8.31(d,J=8.8Hz,1H),8.18(s,1H),7.91–7.77(m,4H),7.70(s,1H),7.64(d,J=8.8Hz,2H),7.41(d,J=8.3Hz,1H),7.18–7.07(m,3H),7.03(br d,J=6.1Hz,2H),4.37(br s,1H),3.92–3.80(m,1H),3.43(br s,3H),2.96–2.80(m,2H),2.09(s,3H),1.17(d,J=6.6Hz,6H)。ESI[M+H]=652.2
化合物D2
1H NMR(400MHz,DMSO-d6)δ=10.39(s,1H),9.55(br s,1H),8.25(d,J=1.8Hz,1H),8.14(d,J=9.6Hz,1H),7.93–7.77(m,5H),7.64(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,1H),4.37(br s,1H),3.58(br s,1H),3.43(s,3H),2.08(s,3H),1.89(br dd,J=6.4,13.4Hz,1H),1.17(d,J=6.6Hz,6H),0.83–0.69(m,6H)。ESI[M+H]=604.2
化合物D3
1H NMR(400MHz,DMSO-d6)δ=10.40(s,1H),9.56(br s,1H),8.43(d,J=4.2Hz,1H),8.28(d,J=2.2Hz,1H),8.19(t,J=6.2Hz,1H),7.89–7.78(m,6H),7.64(d,J=8.8Hz,2H),7.49(d,J=8.4Hz,1H),7.38(d,J=7.9Hz,1H),7.33–7.26(m,1H),4.38(br s,1H),4.15(d,J=6.2Hz,2H),2.09(s,3H),1.16(d,J=6.6Hz,6H)。ESI[M+H]=581.2
化合物D4
1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),9.56(br s,1H),8.20(d,J=2.0Hz,1H),7.89–7.80(m,5H),7.63(d,J=8.8Hz,2H),7.52(d,J=8.4Hz,1H),7.39(t,J=6.5Hz,1H),4.42–4.33(m,1H),3.05(s,2H),2.70(d,J=6.4Hz,2H),2.09(s,3H),1.17(d,J=6.6Hz,6H),0.70(s,6H)。ESI[M+H]=576.3
化合物D5
1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),9.56(br s,1H),8.35(d,J=2.2Hz,1H),7.90–7.79(m,5H),7.63(d,J=8.8Hz,2H),7.50(d,J=8.2Hz,1H),7.26(d,J=7.7Hz,1H),4.38(br d,J=6.6Hz,1H),3.32–3.24(m,1H),3.12–2.97(m,2H),2.08(s,3H),1.17(d,J=6.4Hz,6H),0.94(d,J=6.4Hz,3H)。ESI[M+H]=548.2
化合物D6
1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),9.55(br s,1H),8.24(d,J=2.0Hz,1H),7.92–7.76(m,5H),7.62(d,J=8.8Hz,2H),7.50(d,J=8.2Hz,1H),7.35(br d,J=4.6Hz,1H),4.36(br d,J=7.1Hz,1H),2.43(d,J=4.9Hz,3H),2.07(s,3H),1.15(d,J=6.6Hz,6H)。ESI[M+H]=503.8
化合物D7
1H NMR(400MHz,DMSO-d6)δ=10.49–10.34(m,1H),9.67–9.48(m,1H),8.36(s,1H),7.97–7.79(m,5H),7.65(d,J=8.8Hz,2H),7.49(dd,J=8.2,17.6Hz,2H),4.39(br d,J=7.5Hz,1H),3.29–3.17(m,1H),2.81(br d,J=7.5Hz,1H),2.10(s,3H),1.67(brt,J=14.2Hz,4H),1.18(d,J=6.6Hz,8H),1.08–0.94(m,2H)。ESI[M+H]=587.9
化合物D8
1H NMR(400MHz,甲醇-d4)δ=8.47–8.39(m,1H),7.96–7.86(m,4H),7.59(d,J=8.4Hz,3H),4.66–4.40(m,1H),3.54–3.48(m,4H),3.05–2.98(m,4H),2.18(s,3H),1.25(d,J=6.6Hz,6H)。ESI[M+H]=559.8
化合物D9
1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),9.56(br s,1H),8.29(d,J=2.2Hz,1H),7.90–7.79(m,5H),7.63(d,J=8.8Hz,2H),7.53–7.47(m,2H),4.46–4.30(m,1H),2.90–2.74(m,2H),2.08(s,3H),1.17(d,J=6.6Hz,6H),0.95(t,J=7.2Hz,3H)。ESI[M+H]=517.9
化合物D10
1H NMR(400MHz,DMSO-d6)δ=10.44(s,1H),9.55(br s,1H),8.23(d,J=2.0Hz,1H),7.92–7.77(m,5H),7.60(d,J=8.6Hz,2H),7.53(d,J=8.4Hz,1H),4.36(br d,J=6.8Hz,1H),2.60(s,6H),2.08(s,3H),1.15(d,J=6.4Hz,6H)。ESI[M+H]=517.9
化合物D11
1H NMR(400MHz,甲醇-d4)δ=8.42(s,1H),7.96–7.84(m,4H),7.57(br d,J=8.2Hz,2H),7.50(d,J=7.9Hz,1H),4.52(br s,1H),3.55–3.44(m,4H),3.23–3.18(m,1H),2.16(s,3H),1.23(d,J=6.6Hz,6H)。ESI[M+H]=563.9
化合物D12
1H NMR(400MHz,DMSO-d6)δ=10.45(s,1H),9.61(br s,1H),8.68(d,J=6.2Hz,2H),8.45(t,J=6.3Hz,1H),8.36(s,1H),7.88(brt,J=4.3Hz,5H),7.72–7.60(m,4H),7.58–7.56(m,1H),4.40(br s,1H),4.23(br d,J=6.0Hz,2H),2.11(s,3H),1.21–1.16(m,6H)。ESI[M+H]=580.8
化合物D13
1H NMR(400MHz,DMSO-d6)δ=10.46(s,1H),9.58(br s,1H),8.32(s,1H),7.92–7.79(m,5H),7.64(d,J=8.6Hz,2H),7.55(s,1H),4.39(br d,J=6.2Hz,1H),3.10–3.01(m,4H),2.11(s,3H),1.82–1.75(m,4H),1.18(d,J=6.4Hz,6H)。ESI[M+H]=543.9
化合物D14
1H NMR(400MHz,DMSO-d6)δ=10.46(s,1H),9.58(br s,1H),8.32(d,J=2.2Hz,1H),7.96–7.80(m,5H),7.63(d,J=8.8Hz,2H),7.56(d,J=8.4Hz,1H),4.39(br d,J=6.2Hz,1H),2.91(br s,4H),2.10(s,3H),1.38(br s,6H),1.20–1.16(m,6H)。ESI[M+H]=557.9
化合物D15
1H NMR(400MHz,DMSO-d6)δt=10.40(s,1H),9.54(s,1H),8.25(s,1H),7.96–7.77(m,6H),7.62(d,J=8.4Hz,2H),7.48(d,J=8.2Hz,1H),4.37(s,1H),3.68(br s,1H),3.53–3.51(m,2H),3.43(s,3H),2.07(s,3H),1.20(br s,1H),1.15(d,J=6.6Hz,6H)。ESI[M+H]=591.8
化合物D16
1H NMR(400MHz,DMSO-d6)δ=10.58–10.47(m,1H),9.73(br s,1H),9.44(br s,1H),8.49–8.29(m,1H),8.02–7.97(m,1H),7.92–7.80(m,4H),7.69(d,J=8.6Hz,2H),7.60–7.53(m,1H),4.39(br d,J=6.6Hz,1H),3.20–3.07(m,4H),2.76(br s,6H),2.11(s,3H),1.21–1.14(m,6H)。ESI[M+H]=560.9
化合物D17
1H NMR(400MHz,DMSO-d6)δ=10.48(s,1H),9.64(br s,1H),8.42(d,J=2.0Hz,1H),7.93–7.85(m,3H),7.81(dd,J=2.2,8.4Hz,1H),7.76–7.65(m,5H),7.57(d,J=8.4Hz,1H),4.46–4.32(m,1H),3.01(q,J=6.5Hz,2H),2.82(br d,J=5.5Hz,2H),2.11(s,3H),1.18(d,J=6.6Hz,6H)。ESI[M+H]=533.1
化合物D18
1H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),9.54(br s,1H),8.28(s,1H),7.87–7.81(m,5H),7.69(d,J=3.3Hz,1H),7.60(br d,J=6.0Hz,2H),7.46(d,J=8.4Hz,1H),7.10(d,J=9.0Hz,1H),4.36(br s,1H),3.28–3.13(m,2H),2.88(br s,1H),2.06(s,3H),1.81–1.69(m,1H),1.15(br d,J=4.4Hz,6H),0.71–0.60(m,6H)。ESI[M+H]=575.9
化合物D19
1H NMR(400MHz,DMSO-d6)δ=10.43(s,1H),9.57(br s,1H),8.30(s,1H),8.20–8.14(m,1H),7.90–7.79(m,5H),7.64(d,J=8.6Hz,2H),7.50(d,J=8.2Hz,1H),7.28–7.14(m,5H),4.39(br s,1H),4.03(d,J=5.7Hz,2H),2.11(s,3H),1.18(d,J=6.4Hz,6H)。ESI[M+H]=580.1
化合物D20
1H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),9.54(br s,1H),8.19(s,1H),8.05(s,1H),7.91–7.75(m,5H),7.62(br d,J=8.6Hz,2H),7.48(d,J=8.2Hz,1H),4.35(s,1H),3.62(br d,J=5.7Hz,2H),3.49(s,3H),2.07(s,3H),1.15(d,J=6.6Hz,6H)。ESI[M+H]=561.8
化合物D21
1H NMR(400MHz,DMSO-d6)δt=10.40(s,1H),9.54(br s,1H),8.28(s,1H),8.22(d,J=8.4Hz,1H),7.88–7.79(m,5H),7.62(br d,J=8.8Hz,2H),7.49(d,J=8.2Hz,1H),4.36(br s,1H),3.74–3.66(m,1H),3.46(s,3H),2.07(s,3H),1.20(br d,J=7.3Hz,3H),1.15(d,J=6.4Hz,6H)。ESI[M+H]=575.9
化合物D22
1H NMR(400MHz,DMSO-d6)δ=10.46(s,1H),9.61(br s,1H),8.40(d,J=2.2Hz,1H),8.00–7.92(m,1H),7.91–7.82(m,4H),7.66–7.59(m,2H),7.56(d,J=8.4Hz,1H),4.38(br d,J=6.8Hz,1H),3.84(br s,2H),2.13–2.07(m,3H),1.58(br d,J=6.8Hz,4H),1.34(br d,J=6.8Hz,4H),1.16(d,J=6.6Hz,6H)。ESI[M+H]=569.9
化合物D23
1H NMR(400MHz,DMSO-d6)δ=10.48(s,1H),9.69(br s,1H),8.39(d,J=1.8Hz,1H),8.31(br s,2H),7.96(br d,J=7.9Hz,1H),7.91–7.85(m,3H),7.84–7.79(m,1H),7.75–7.65(m,3H),7.55(d,J=8.4Hz,1H),4.39(br d,J=6.2Hz,1H),2.90–2.81(m,4H),2.50(s,3H),2.11(s,3H),1.69(quin,J=7.3Hz,2H),1.18(d,J=6.4Hz,6H)。ESI[M+H]=561.3
化合物D24
1H NMR(400MHz,DMSO-d6)δ=10.48(s,1H),9.71(br s,1H),8.37(d,J=1.8Hz,1H),7.98(br d,J=7.7Hz,1H),7.91–7.81(m,4H),7.74–7.62(m,6H),7.54(d,J=8.4Hz,1H),4.52–4.30(m,1H),2.87(q,J=6.5Hz,2H),2.81–2.70(m,2H),2.11(s,3H),1.74–1.59(m,2H),1.18(d,J=6.6Hz,6H)。ESI[M+H]=547.2
化合物D25
1H NMR(400MHz,DMSO-d6)δ=10.45(s,1H),9.67(br s,1H),9.38(br s,1H),8.36(s,1H),7.94(br d,J=7.7Hz,1H),7.88–7.82(m,3H),7.78(br d,J=8.2Hz,1H),7.72–7.63(m,3H),7.52(d,J=8.2Hz,1H),4.36(br d,J=6.6Hz,1H),3.03–2.92(m,2H),2.84(q,J=6.3Hz,2H),2.68(d,J=4.4Hz,6H),2.08(s,3H),1.78–1.65(m,2H),1.15(d,J=6.4Hz,6H)。ESI[M+H]=575.2
化合物D26
1H NMR(400MHz,DMSO-d6)δ=10.42(s,1H),9.58(br s,1H),8.29(d,J=2.2Hz,1H),7.93–7.81(m,5H),7.68–7.57(m,3H),7.53(d,J=8.4Hz,1H),4.47–4.37(m,2H),3.44–3.39(m,2H),3.38–3.29(m,4H),3.03–2.93(m,2H),2.10(s,3H),1.18(d,J=6.6Hz,6H)。ESI[M+H]=578.2
化合物D27
1H NMR(400MHz,DMSO-d6)δ=10.42(s,1H),9.58(br s,1H),8.28(d,J=2.2Hz,1H),7.92–7.82(m,5H),7.68–7.58(m,3H),7.54–7.50(m,1H),4.40(br d,J=6.6Hz,1H),4.00(s,3H),3.26(t,J=5.8Hz,2H),3.02–2.93(m,2H),2.10(s,3H),1.20–1.16(m,6H)。ESI[M+H]=548.2
化合物D28
1H NMR(400MHz,DMSO-d6)δ=10.43(s,1H),9.59(br s,1H),8.29(d,J=2.2Hz,1H),7.98–7.79(m,5H),7.70–7.61(m,2H),7.53(d,J=8.4Hz,1H),7.44(t,J=5.8Hz,1H),4.69–4.47(m,2H),3.33(t,J=6.6Hz,2H),2.91–2.80(m,2H),2.10(s,3H),1.18(d,J=6.4Hz,6H)。ESI[M+H]=534.2
化合物D29
1H NMR(400MHz,DMSO-d6)δ=10.50(s,1H),9.72(br s,1H),8.41(d,J=2.2Hz,2H),7.98(d,J=7.7Hz,1H),7.91–7.86(m,3H),7.84–7.77(m,2H),7.72–7.67(m,2H),7.57(d,J=8.4Hz,1H),4.48–4.27(m,1H),3.12–3.01(m,2H),2.95(br s,2H),2.56–2.52(m,3H),2.11(s,3H),1.18(d,J=6.4Hz,6H)。ESI[M+H]=547.2
化合物D30
通用方法G。1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=1.8Hz,1H),7.95–7.82(m,4H),7.57(d,J=8.8Hz,2H),7.49(d,J=8.3Hz,1H),4.53(br s,1H),2.17(s,3H),1.24(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=546.0
流程4.1
化合物D31
化合物D31使用通用方法A和G中给出的条件来制备。
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=1.1Hz,1H),8.14(s,1H),8.03–7.91(m,1H),7.77(d,J=8.6Hz,1H),7.66(br d,J=8.4Hz,2H),7.49(br d,J=8.4Hz,2H),4.62–4.40(m,1H),2.16(s,3H),1.26(s,9H),1.22(d,J=6.6Hz,6H)。ESI[M+H]=546.2
实施例5
除非另有说明,否则以下化合物通过通用方法C(实施例1中所示)通过使中间体7与不同的磺酰氯反应来合成。
化合物E1
1H NMR(400MHz,甲醇-d4)δ=7.97(d,J=2.2Hz,1H),7.88–7.78(m,5H),7.63–7.46(m,5H),7.43–7.35(m,2H),4.97(quin,J=6.1Hz,1H),1.30(d,J=6.6Hz,6H),1.02(s,9H)。ESI[M+H]=629.5
化合物E2
1H NMR(400MHz,甲醇-d4)δ=7.99(d,J=2.2Hz,1H),7.91–7.85(m,3H),7.57(d,J=8.3Hz,2H),7.47–7.42(m,1H),7.40–7.36(m,1H),7.35–7.25(m,5H),5.04–4.93(m,1H),4.50(s,2H),1.31(d,J=6.6Hz,6H),1.15(s,9H)。ESI[M+H]=643.5
化合物E3
将N-[3-(叔丁基氨磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]乙酰胺(285.99mg,721.62μmol,1.20eq.)、N-[4-(5-溴噻唑-2-基)-3-(叔丁基氨磺酰基)苯基]乙酰胺(260.00mg,601.35μmol,1.00eq.)、Na2CO3(159.34mg,1.50mmol,2.50eq.)和Pd(PPh3)4(138.98mg,120.27μmol,0.20eq.)在甲苯(1.50mL)/EtOH(3.00mL)/H2O(1.50mL)中的混合物脱气并用N2吹扫3次,随后在N2气氛、80℃下将混合物搅拌12小时。LCMS显示反应完成。将反应混合物浓缩,用H2O(5mL)稀释,并用EtOAc(10mL X 3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过制备型HPLC纯化(TFA条件;5-P1B,柱:YMC-Actus Triart C18 150*305u;流动相:[水(0.1%TFA)-€];B%:40%-70%,12min),得到化合物E3(65.75mg,101.09μmol,16.81%收率,95.6%纯度),为浅黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.44(dd,J=2.2,12.8Hz,2H),8.01(dd,J=2.2,8.4Hz,1H),7.98(s,1H),7.92(dd,J=2.4,8.4Hz,1H),7.79(d,J=8.4Hz,1H),7.54(d,J=8.4Hz,1H),2.18(d,J=3.1Hz,6H),1.29(s,9H),1.12(s,9H)。ESI[M+H]=622.3
流程5.1
中间体化合物19
中间体化合物19通过通用方法A(实施例1中所示)制备。
ESI[M+H]=298.8/296.8
化合物E4
向5-氨基-N-叔丁基-2-(4,4,5,5-四甲基-1,3,2–二氧杂硼杂环戊烷-2-基)苯磺酰胺(150.00mg,423.41μmol,1.00eq.)在EtOH(2.00mL)、甲苯(1.00mL)和H2O(1.00mL)中的溶液中加入N-[4-(5-溴噻唑-2-基)苯基]乙酰胺(150.99mg,508.09μmol,1.20eq.)、Pd(PPh3)4(48.93mg,42.34μmol,0.10eq.)和Na2CO3(134.63mg,1.27mmol,3.00eq.)。在N2下将混合物在80℃下搅拌16小时,并且LCMS显示反应完成。将混合物浓缩并将残余物通过酸性制备型HPLC纯化,得到化合物E4(47.72mg,107.34μmol,25.35%收率,100%纯度),为黄色固体。1H NMR(400MHz,DMSO-d6)δ=10.16(s,1H),7.90–7.83(m,2H),7.74–7.67(m,3H),7.32(d,J=2.4Hz,1H),7.15(d,J=8.2Hz,1H),6.81(s,1H),6.74(dd,J=2.4,8.2Hz,1H),5.83(br s,1H),2.07(s,3H),1.06(s,9H)。ESI[M+H]=445.2
化合物E5
化合物E5通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.19(s,1H),9.72(br s,1H),8.36(d,J=2.0Hz,1H),7.90(d,J=8.6Hz,3H),7.84(s,1H),7.77–7.69(m,3H),7.46(d,J=8.2Hz,1H),7.16(s,1H),4.38(br d,J=5.3Hz,1H),2.10–2.06(m,3H),1.19(d,J=6.6Hz,6H),1.10(s,9H)。ESI[M+H]=546.3
流程5.2
中间体化合物21
中间体化合物21通过通用方法A(实施例1中所示)制备。
ESI[M+H]=392.1/390.1
化合物E6
化合物E6由中间体21通过通用方法H制备。
1H NMR(400MHz,甲醇-d4)δ=8.03(s,1H),7.63(d,J=3.5Hz,4H),7.53(d,J=8.3Hz,1H),7.46–7.43(m,1H),6.86(br d,J=11.0Hz,1H),2.14(s,3H),1.27(s,9H)。ESI[M+H]=445.2
化合物E7
化合物E7由化合物E6通过通用方法G制备。
1H NMR(400MHz,甲醇-d4)δ=8.42(d,J=2.6Hz,1H),8.13(s,1H),7.85(dd,J=2.2,8.3Hz,1H),7.75(d,J=8.3Hz,1H),7.65(s,4H),4.53(br s,1H),2.14(s,3H),1.31–1.24(m,15H)。ESI[M+H]=546.3
流程5.3
化合物E8
向5-氨基-2-(5-溴噻唑-2-基)-N-叔丁基-苯磺酰胺(95.00mg,243.39μmol,1.00eq.)在EtOH(2.00mL)、甲苯(1.00mL)和H2O(1.00mL)中的溶液中加入N-[3-(叔丁基氨磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]乙酰胺(106.10mg,267.73μmol,1.10eq.)、Pd(PPh3)4(28.13mg,24.34μmol,0.10eq.)和Na2CO3(64.49mg,608.48μmol,2.50eq.)。将混合物在N2下在80℃下搅拌16小时,LCMS显示反应完成。将混合物过滤并浓缩,并将残余物通过制备型HPLC纯化,得到化合物E8(11.00mg,17.04μmol,7.00%收率,89.79%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.43(s,1H),7.90(s,2H),7.56–7.50(m,2H),7.46(s,1H),6.86(br d,J=10.5Hz,1H),2.17(s,3H),1.28(s,9H),1.10(s,9H)。ESI[M+H]=580.2
化合物E9
化合物E9由化合物E8通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.45(s,2H),7.99(s,1H),7.92(br d,J=10.1Hz,1H),7.87–7.83(m,1H),7.79–7.75(m,1H),7.54(d,J=8.3Hz,1H),4.52(s,1H),2.17(s,3H),1.31–1.24(m,15H),1.12(s,9H)。ESI[M+H]=681.3
流程5.4
中间体化合物22
中间体化合物22由中间体化合物3通过通用方法B(实施例1中所示)制备。
ESI[M+H]=257.0/255.0
化合物E11
化合物E11由化合物A4通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=1.8Hz,1H),7.95–7.82(m,4H),7.57(d,J=8.8Hz,2H),7.49(d,J=8.3Hz,1H),4.53(br s,1H),2.17(s,3H),1.24(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=531.1
流程5.5
中间体化合物23
中间体化合物23由中间体化合物3通过通用方法A(实施例1中所示)制备。
ESI[M+H]=433.1
中间体化合物24
向5-氨基-N-叔丁基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰胺(150.00mg,346.80μmol,1.00eq.)在i-PrOH(5.00mL)中的溶液中加入2-溴噻唑(170.65mg,1.04mmol,93.76ul,3.00eq.)和TsOH(179.16mg,1.04mmol,3.00eq.)。将混合物在80℃下搅拌16小时,LCMS显示反应完成。将混合物浓缩并将残余物通过制备型TLC纯化(PE:EtOAc=1:1),得到中间体化合物24(100.00mg,粗品),为黄色固体。ESI[M+H]=516.0
化合物E12
化合物E12由中间体24通过通用方法B(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.66(br s,1H),8.47(s,1H),7.88–7.79(m,1H),7.72(s,1H),7.65(d,J=8.6Hz,2H),7.43(d,J=8.4Hz,1H),7.30(d,J=3.7Hz,1H),7.10(s,1H),7.00(d,J=3.7Hz,1H),6.70(br d,J=7.9Hz,2H),1.09(s,9H)。ESI[M+H]=486.1
化合物E13
化合物E13由化合物E12通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.69(s,1H),9.55(br s,1H),8.49(d,J=2.2Hz,1H),7.91–7.77(m,5H),7.61(d,J=8.6Hz,2H),7.47(d,J=8.4Hz,1H),7.31(d,J=3.7Hz,1H),7.15(s,1H),7.01(d,J=3.7Hz,1H),4.37(br d,J=6.6Hz,1H),1.16(d,J=6.6Hz,6H),1.09(s,9H)。ESI[M+H]=587.2
流程5.6
化合物E14
化合物E14由中间体化合物22通过通用方法A(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=7.97(s,1H),7.80(s,1H),7.69(d,J=8.3Hz,2H),7.64–7.54(m,2H),7.26(s,1H),6.74(d,J=8.3Hz,3H),3.24(br s,3H),1.92(br s,3H),1.05(s,9H)。ESI[M+H]=459.2
化合物E15
化合物E15由化合物E14通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=9.56(br s,1H),7.98(d,J=2.0Hz,1H),7.91–7.80(m,4H),7.66–7.56(m,4H),7.28(s,1H),4.37(br dd,J=6.6,13.2Hz,1H),3.23(br s,3H),1.90(br s,3H),1.16(d,J=6.6Hz,6H),1.04(s,9H)。ESI[M+H]=559.9
流程5.7
中间体化合物25
向5-氨基-N-叔丁基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰胺(50.00mg,115.60μmol,1.00eq.)在n-BuOH(2.00mL)中的溶液中加入2-溴-1-甲基-咪唑(55.84mg,346.80μmol,3.00eq.)和TsOH.H2O(65.97mg,346.80μmol,3.00eq.)并将混合物在125℃下搅拌6小时。将混合物浓缩并且残余物通过制备型HPLC纯化(TFA条件),得到中间体化合物25(45mg,粗品),为黄色固体。ESI[M+H]=513.1
化合物E16
化合物E16由中间体化合物25通过通用方法B(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.07(br s,1H),7.89(s,1H),7.74(s,1H),7.64(d,J=8.3Hz,2H),7.56–7.50(m,1H),7.44(br d,J=7.9Hz,1H),7.35(s,1H),7.24(br s,1H),7.11(s,1H),6.64(d,J=8.8Hz,2H),3.64(s,3H),1.06(s,9H)。ESI[M+H]=483.1
化合物E17
化合物E17由化合物E16通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.10(br s,1H),9.60(br s,1H),7.94–7.82(m,5H),7.66(br d,J=8.3Hz,2H),7.57(d,J=8.8Hz,1H),7.45(br d,J=8.3Hz,1H),7.36(s,1H),7.26(s,1H),7.17(s,1H),4.38(br s,1H),3.64(s,3H),1.18(d,J=6.6Hz,6H),1.06(s,9H)。ESI[M+H]=584.0
流程5.8
中间体化合物26
向5-氨基-N-叔丁基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰胺(300.00mg,693.61μmol,1.00eq.)在n-BuOH(5.00mL)中的溶液中加入TsOH.H2O(395.82mg,2.08mmol,3.00eq.)并将混合物在130℃下搅拌18小时。LCMS显示反应完成。将混合物浓缩并且残余物通过制备型HPLC纯化(TFA条件),得到中间体化合物26(140.00mg,291.35μmol,42.00%收率,95%纯度),为黄色固体。1H NMR(400MHz,氯仿-d)δ=8.23(br d,J=8.8Hz,2H),8.05(d,J=8.3Hz,2H),7.93(s,1H),7.79(s,1H),7.39(d,J=8.3Hz,1H),7.23(br d,J=8.3Hz,1H),6.95–6.81(m,2H),3.58(s,3H)。
化合物E18
化合物E18由中间体化合物26通过通用方法B(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.29(br s,1H),7.83(s,1H),7.78(s,1H),7.66(d,J=8.3Hz,2H),7.56(d,J=8.3Hz,1H),7.46–7.38(m,4H),7.29(s,1H),6.68(br d,J=7.5Hz,2H),3.66(s,3H)。ESI[M+H]=427.2
化合物E19
化合物E19由化合物E18通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.17(br s,1H),9.62(br s,1H),7.93–7.76(m,5H),7.67(br d,J=8.8Hz,2H),7.59(d,J=8.3Hz,1H),7.51–7.40(m,3H),7.38(s,1H),7.28(s,1H),4.40(br s,1H),3.65(s,3H),1.19(d,J=6.6Hz,6H)。ESI[M+H]=528.2
化合物E20
化合物E20由化合物E14通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=9.89(s,1H),8.01(s,1H),7.95–7.82(m,3H),7.62(br d,J=8.6Hz,4H),7.32(s,1H),4.93(td,J=6.2,12.5Hz,1H),3.34–3.30(m,3H),1.94(br s,3H),1.28(d,J=6.2Hz,6H),1.07(s,9H)。ESI[M+H]=544.9
流程5.9
中间体化合物20
向N-[4-(5-溴噻唑-2-基)-3-(叔丁基氨磺酰基)苯基]乙酰胺(100.00mg,231.29μmol,1.00eq.)在EtOH(2.00mL),、甲苯(1.00mL)和H2O(1.00mL)中的溶液中加入5-氨基-N-叔丁基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(90.13mg,254.42μmol,1.10eq.)、Pd(PPh3)4(26.73mg,23.13μmol,0.10eq.)和Na2CO3(61.29mg,578.22μmol,2.50eq.)。将混合物在N2下在80℃下搅拌16小时,LCMS显示反应完成。将混合物过滤并浓缩并且残余物通过制备型HPLC纯化(TFA条件),得到中间体化合物20(25.00mg,36.58μmol,15.82%收率,84.83%纯度),为黄色固体。ESI[M+H]=580.2
化合物E21
化合物E21由中间体化合物20通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.40(s,2H),8.02–7.95(m,2H),7.78(br d,J=8.4Hz,2H),7.51(d,J=8.4Hz,1H),4.52(br s,1H),2.17(s,3H),1.30–1.21(m,15H),1.12(s,9H)。ESI[M+H]=681.3
实施例6
流程6.1
中间体化合物28
中间体化合物28由中间体27通过通用方法A(实施例1中所示)制备。
ESI[M+H]=257.9/255.7
中间体化合物29
中间体化合物29由中间体化合物28通过通用方法A(实施例1中所示)制备。
ESI[M+H]=446.1
实施例7
除非另有说明,否则以下化合物通过通用方法C(实施例1中所示)通过使中间体5与不同的酰氯反应来合成。
化合物G1
1H NMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.92–7.84(m,4H),7.59(br d,J=8.8Hz,2H),7.50(d,J=8.3Hz,1H),3.95(d,J=6.6Hz,2H),2.18(s,3H),2.05–1.95(m,1H),1.14(s,9H),1.00(d,J=6.6Hz,6H)。ESI[M+H]=545.2
化合物G2
1H NMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.92–7.84(m,4H),7.58(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,1H),3.76(s,3H),2.17(s,3H),1.14(s,9H)。ESI[M+H]=503.3
化合物G3
1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=1.8Hz,1H),7.91–7.85(m,4H),7.58(d,J=8.8Hz,2H),7.50(d,J=8.3Hz,1H),4.21(q,J=7.0Hz,2H),2.18(s,3H),1.32(t,J=7.0Hz,3H),1.14(s,9H)。ESI[M+H]=517.2
化合物G4
1H NMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.93(d,J=8.8Hz,2H),7.89–7.85(m,2H),7.72(d,J=8.8Hz,2H),7.50(d,J=8.3Hz,1H),2.30–2.25(m,2H),2.18(s,3H),1.14(s,10H),1.03(d,J=6.6Hz,6H)。ESI[M+H]=529.2
化合物G5
1H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),10.10(s,1H),8.39(s,1H),7.90(d,J=8.4Hz,2H),7.84–7.78(m,2H),7.46(d,J=8.4Hz,1H),7.29(br d,J=8.6Hz,2H),7.15(s,1H),3.05(s,3H),2.07(s,3H),1.05(s,9H)。[M+H]=523.0
化合物G6
1H NMR(400MHz,DMSO-d6)δ=10.66(s,1H),10.41(s,1H),8.41(s,1H),7.86–7.79(m,6H),7.65–7.53(m,3H),7.46(d,J=8.2Hz,1H),7.23(br d,J=8.2Hz,2H),7.15(s,1H),2.09(s,3H),1.06(s,9H)。ESI[M+H]=585.0
化合物G7
1H NMR(400MHz,DMSO-d6)δ=10.42(s,1H),10.17(s,1H),8.42(s,1H),7.92(d,J=8.6Hz,2H),7.87–7.82(m,2H),7.49(d,J=8.4Hz,1H),7.33(d,J=8.8Hz,2H),7.19(s,1H),3.18(q,J=7.2Hz,2H),2.10(s,3H),1.21(t,J=7.3Hz,3H),1.07(s,9H)。ESI[M+H]=537.3
化合物G8
1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),10.15(s,1H),8.42(s,1H),7.95–7.88(m,2H),7.85-7.84(m,2H),7.49(d,J=8.3Hz,1H),7.35–7.29(m,J=8.4Hz,2H),7.17(s,1H),3.68(t,J=5.9Hz,2H),3.46–3.43(m,2H),3.18(s,3H),2.10(s,3H),1.08(s,9H)。ESI[M+H]=567.1
化合物G9
1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=2.0Hz,1H),7.99–7.85(m,4H),7.50(d,J=8.2Hz,1H),7.29(d,J=8.6Hz,2H),2.60(s,3H),2.18(s,3H),1.14(s,9H)。ESI[M+H]=538.1
化合物G10
化合物G10由中间体5通过通用方法I(实施例1中所示)制备。
1HNMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.91–7.84(m,4H),7.50(d,J=8.8Hz,3H),3.94–3.82(m,1H),2.18(s,3H),1.20(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=530.2
化合物G11
在20℃下将N-[4-[2-(4-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺(50.00mg,112.47μmol,1.00eq.)、吡啶(25.00mg,316.04μmol,25.51ul,2.81eq.)和Boc2O(40.00mg,183.28μmol,42.11ul,1.63eq.)在THF(2.00mL)和t-BuOH(2.00mL)中的混合物搅拌14小时。LCMS显示反应完成。将混合物浓缩并且残余物通过制备型HPLC纯化(YMC-Actus Triart C18 150*305u;流动相:[水(10mM NH4HCO3)-€];B%:55%-75%,12min),得到N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸叔丁酯(20.01mg,35.05μmol,31.16%收率,95.41%纯度),为黄色固体。1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),9.70–9.63(m,1H),8.42(d,J=2.2Hz,1H),7.88–7.82(m,4H),7.59(d,J=8.8Hz,2H),7.48(d,J=8.4Hz,1H),7.18(s,1H),2.10(s,3H),1.50–1.49(m,9H),1.08(s,9H)。ESI[M+H]=545.4
实施例8
流程8.1
中间体化合物30
向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,40.93μmol,1.00eq.)在吡啶(2.00mL)中的溶液中加入(2S)-1-叔丁氧基羰基吡咯烷-2-甲酸(44.05mg,204.66μmol,5.00eq.)和EDCI(9.42mg,49.12μmol,1.20eq.)并将混合物在20℃下搅拌0.5小时。LCMS显示反应完成。将混合物倾入1M HCl(10mL)并用DCM(10mL X 3)萃取。有机相经Na2SO4干燥,过滤并浓缩,得到(2S)-2-[[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]氨基甲酰基]吡咯烷-1-甲酸叔丁酯(30.00mg,粗品),为黄色油,其无需任何纯化使用。ESI[M+H]=686.2
化合物H1
化合物H1由中间体化合物30通过通用方法E(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.55(d,J=2.3Hz,1H),7.96–7.88(m,4H),7.63–7.56(m,3H),5.00(td,J=6.2,12.5Hz,1H),4.47(dd,J=6.8,8.6Hz,1H),3.55–3.48(m,1H),3.46–3.40(m,1H),2.63–2.53(m,1H),2.28–2.11(m,3H),1.34(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=586.2
化合物H2
化合物H2通过与化合物H1相同的方法合成
1H NMR(400MHz,甲醇-d4)δ=8.54(d,J=2.2Hz,1H),7.95–7.91(m,2H),7.90(s,2H),7.61(s,1H),7.60–7.56(m,2H),5.07–4.95(m,1H),4.50–4.42(m,1H),3.54–3.48(m,1H),3.46–3.39(m,2H),2.65–2.54(m,1H),2.20–2.13(m,2H),1.34(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=586.2
除非另有说明,否则以下化合物通过通用方法C(实施例1中所示)通过使中间体化合物7与不同的酰氯反应来合成。
化合物H3
1H NMR(400MHz,甲醇-d4)δ=8.49(d,J=2.2Hz,1H),7.94–7.87(m,4H),7.59(d,J=8.7Hz,2H),7.51(d,J=8.3Hz,1H),5.06–4.95(m,1H),1.87–1.77(m,1H),1.34(d,J=6.2Hz,6H),1.15(s,9H),1.05–0.99(m,2H),0.96–0.89(m,2H)。ESI[M+H]=557.1
化合物H4
1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=2.1Hz,1H),7.91–7.85(m,4H),7.57(d,J=8.7Hz,2H),7.49(d,J=8.3Hz,1H),5.04–4.92(m,1H),2.45(q,J=7.5Hz,2H),1.32(d,J=6.2Hz,6H),1.23(t,J=7.6Hz,3H),1.14(s,9H)。ESI[M+H]=545.1
化合物H5
1H NMR(400MHz,甲醇-d4)δ=8.36(s,1H),7.88–7.82(m,3H),7.71(br d,J=7.3Hz,1H),7.55(br d,J=8.6Hz,2H),7.47–7.39(m,3H),7.39–7.28(m,3H),5.20(s,2H),4.96(td,J=6.4,12.5Hz,1H),1.29(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=623.1
化合物H6
1H NMR(400MHz,甲醇-d4)δ=8.35(s,1H),7.89–7.82(m,3H),7.69(br d,J=8.2Hz,1H),7.55(br d,J=8.6Hz,2H),7.44(d,J=8.4Hz,1H),4.96(td,J=6.3,12.6Hz,1H),4.21(q,J=7.1Hz,2H),1.33–1.27(m,9H),1.12(s,9H)。ESI[M+H]=561.1
化合物H7
1H NMR(400MHz,甲醇-d4)δ=8.35(s,1H),7.90–7.83(m,3H),7.70(br d,J=8.4Hz,1H),7.56(d,J=8.6Hz,2H),7.45(d,J=8.4Hz,1H),4.96(quin,J=6.2Hz,1H),3.76(s,3H),1.29(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=547.1
化合物H8
1H NMR(400MHz,甲醇-d4)δ=8.37(s,1H),7.91–7.82(m,3H),7.70(br d,J=8.2Hz,1H),7.57(br d,J=8.6Hz,2H),7.45(d,J=8.4Hz,1H),5.04–4.91(m,2H),1.32(dd,J=3.6,6.1Hz,12H),1.14(s,9H)。ESI[M+H]=575.2
化合物H9
1H NMR(400MHz,甲醇-d4)δ=8.70–8.67(m,1H),8.06–7.95(m,3H),7.94–7.85(m,3H),7.65–7.48(m,6H),5.02–4.93(m,1H),1.32(d,J=6.2Hz,6H),1.16(s,9H)。ESI[M+H]=593.2
化合物H10
1H NMR(400MHz,甲醇-d4)δ=8.49(d,J=2.2Hz,1H),7.92–7.86(m,4H),7.57(d,J=8.7Hz,2H),7.50(d,J=8.3Hz,1H),4.98(td,J=6.3,12.5Hz,1H),2.67(spt,J=6.8Hz,1H),1.32(d,J=6.2Hz,6H),1.23(d,J=7.0Hz,6H),1.14(s,9H)。ESI[M+H]=559.2
化合物H11
1H NMR(400MHz,甲醇-d4)δ=8.09(d,J=2.2Hz,1H),7.92–7.84(m,3H),7.63–7.44(m,4H),4.98(td,J=6.2,12.5Hz,1H),3.06(s,3H),1.31(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=567.1
实施例9
化合物I1
在0℃下向N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,37.69μmol,1.00eq.)在THF(200.00ul)中的混合物中加入BH3-Me2S(10M,18.85ul,5.00eq.),随后在N2气氛下在70℃下将混合物搅拌2小时。LCMS显示反应完成。混合物通过在0℃下加入MeOH(5mL)来猝灭,随后将其浓缩,残余物通过制备型HPLC纯化(TFA条件),得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(乙基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(3.92mg,7.59μmol,20.13%收率,100%纯度),为浅黄色固体。1H NMR(400MHz,甲醇-d4)δ=7.84(d,J=8.6Hz,2H),7.76(s,1H),7.54(br d,J=8.6Hz,2H),7.36(d,J=2.2Hz,1H),7.24(d,J=8.4Hz,1H),6.78(dd,J=2.1,8.5Hz,1H),4.96(td,J=6.2,12.3Hz,1H),3.18(q,J=7.1Hz,2H),1.29(d,J=6.4Hz,6H),1.25(t,J=7.2Hz,3H),1.10(s,9H)。ESI[M+H]=517.1
化合物I2
将N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,40.93μmol,1.00eq.)溶解于H2SO4(40.14mg,409.30μmol,21.82ul,10.00eq.)的H2O(1.00mL)溶液。将混合物冷却至-5℃,随后加入在H2O(500.00ul)中的NaNO2(3.39mg,49.12μmol,2.67ul,1.20eq.),将混合物在0℃下搅拌30分钟。随后加入H2O(500.00ul),将混合物在26℃下搅拌1.5小时。LCMS显示反应完成。将混合物浓缩并且残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-羟基-苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(3.04mg,6.02μmol,14.71%收率,97%纯度),为棕色固体。1H NMR(400MHz,甲醇-d4)δ=7.85(d,J=8.6Hz,2H),7.78(s,1H),7.61–7.51(m,3H),7.35(d,J=8.2Hz,1H),7.05–6.96(m,1H),4.97–4.93(m,1H),1.29(d,J=6.2Hz,6H),1.10(s,9H)。ESI[M+H]=490.1
化合物I3
在0℃下向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,40.93μmol,1.00eq.)和NaBH3CN(5.14mg,81.86μmol,2.00eq.)在DCM(2.00mL)中的溶液中加入纯TFA(2.00mL),将混合物在0℃下搅拌5分钟。随后在0℃下加入2,2,2-三氟乙醛(10.03mg,102.33μmol,2.50eq.),将混合物在20℃下搅拌30分钟。LCMS显示反应完成。用饱和NaHCO3水溶液(10mL)洗涤混合物,用DCM(20mL X 3)萃取水相。将合并的有机相干燥,过滤并浓缩。残余物通过制备型HPLC纯化(TFA条件),得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2,2,2-三氟乙基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(4.68mg,8.20μmol,20.03%收率,100%纯度),为浅黄色固体。1H NMR(400MHz,甲醇-d4)δ=7.77(d,J=8.7Hz,2H),7.69(s,1H),7.47(br d,J=8.7Hz,2H),7.43(d,J=2.4Hz,1H),7.22(d,J=8.4Hz,1H),6.86(dd,J=2.5,8.4Hz,1H),4.88(td,J=6.2,12.5Hz,1H),3.83(q,J=9.2Hz,2H),1.22(d,J=6.2Hz,6H),1.02(s,9H)。ESI[M+H]=571.1
流程9.1
中间体化合物31
向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(840.00mg,1.72mmol,1.00eq.)在€(30.00mL)中的溶液中加入叔丁腈(354.55mg,3.44mmol,407.53ul,2.00eq.)和CuBr2(191.98mg,860.00μmol,40.25ul,0.50eq.),随后在N2下在60℃下将混合物加热1小时。LCMS显示反应完成。用水(50mL)稀释混合物并用EtOAc(50mL X 3)萃取。将合并的有机相干燥,过滤并浓缩。残余物通过硅胶柱色谱法纯化(石油醚/乙酸乙酯=8:1),得到中间体化合物31(350.00mg,633.48μmol,36.83%收率),为黄色固体。ESI[M+H]=554.0/552.0
化合物I4
在N2下在110℃下将N-[4-[5-[4-溴-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸酯异丙酯(30.00mg,54.30μmol,1.00eq.)、3-甲基氧杂环丁-3-胺(23.65mg,271.49μmol,5.00eq.)、Pd2(dba)3(4.97mg,5.43μmol,0.10eq.)、Xphos(3.88mg,8.14μmol,0.15eq.)和t-BuONa(5.74mg,59.73μmol,1.10eq.)在甲苯(2.00mL)中的混合物搅拌16小时。LCMS显示反应完成。用水(30mL)洗涤混合物并用EtOAc(30mL X 3)萃取水相。将合并的有机相干燥,过滤并浓缩。残余物通过制备型TLC(PE:EtOAc=1:1)和制备型HPLC(TFA条件)纯化,得到化合物I4(2.78mg,4.94μmol,9.10%收率,99.36%纯度),为棕色固体。1H NMR(400MHz,甲醇-d4)δ=7.88(d,J=8.7Hz,2H),7.80(s,1H),7.58(d,J=8.6Hz,2H),7.30(d,J=8.3Hz,1H),7.23(d,J=2.4Hz,1H),6.67(dd,J=2.4,8.3Hz,1H),5.00(td,J=6.2,12.5Hz,1H),4.82(d,J=6.0Hz,2H),4.63(d,J=6.0Hz,2H),1.71(s,3H),1.33(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=559.2
流程9.2
中间体化合物32
中间体化合物32由中间体化合物22通过通用方法C(实施例1中所示)制备。
ESI[M+H]=343.1/341.1
化合物I5
化合物I5由中间体化合物32通过通用方法A(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.64(d,J=1.8Hz,1H),8.05(dd,J=1.8,7.9Hz,1H),7.96(s,1H),7.91(d,J=8.8Hz,2H),7.67(d,J=7.9Hz,1H),7.58(d,J=8.6Hz,2H),4.98(td,J=6.3,12.5Hz,1H),2.96(s,3H),1.31(d,J=6.2Hz,6H),1.15–1.02(m,9H)。ESI[M+H]=531.2
流程9.3
化合物I6
化合物I6由中间体化合物32通过通用方法A(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=9.88(s,1H),8.60(d,J=2.0Hz,1H),8.27(br s,1H),8.13(dd,J=2.0,7.8Hz,1H),7.99–7.86(m,3H),7.65(dd,J=8.3,18.1Hz,4H),7.28(s,1H),4.93(quin,J=6.4Hz,1H),1.28(d,J=5.9Hz,6H),1.05(s,9H)。ESI[M+H]=517.1
中间体化合物33
向化合物I6(70.00mg,135.49μmol,1.00eq.)在甲苯(2.00mL)中的溶液中加入1,1-二甲氧基-N,N-二甲基-甲胺(48.44mg,406.48μmol,53.82ul,3.00eq.)。将混合物在110℃下搅拌1小时,LCMS显示反应完成。将混合物浓缩,得到中间体化合物33(70.00mg,粗品),为黄色固体。ESI[M+H]=572.2
化合物I7
向中间体化合物33(70.00mg,122.44μmol,1.00eq.)在AcOH(2.00mL)中的溶液中加入NH2NH2.H2O(9.38mg,183.66μmol,9.11ul,98%纯度,1.50eq.)。将混合物在90℃下搅拌1小时,LCMS显示反应完成。将混合物浓缩并且残余物通过酸性制备型HPLC纯化,得到化合物I7(1.90mg,3.51μmol,2.87%收率,100%纯度),为浅黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.89(d,J=1.8Hz,1H),8.54(s,1H),8.29(dd,J=1.8,7.9Hz,1H),7.97(s,1H),7.91(d,J=8.6Hz,2H),7.69(d,J=7.9Hz,1H),7.58(d,J=8.6Hz,2H),4.98(td,J=6.3,12.6Hz,1H),1.31(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=541.1
实施例10
化合物J1
化合物J1由中间体化合物32通过通用方法A制备
1H NMR(400MHz,甲醇-d4)δ=8.19(s,1H),7.91-7.86(m,3H),7.64-7.51(m,4H),4.97(quin,J=6.2Hz,1H),4.73(s,2H),1.31(d,J=6.2Hz,6H),1.10(s,9H)。ESI[M+H]=504.1
流程10.1
中间体化合物35
中间体化合物35由中间体化合物34通过通用方法A(实施例1中所示)制备。
ESI[M+H]=782.4
化合物J2
化合物J2由中间体化合物34通过通用方法E(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.63(s,1H),8.07(dd,J=1.6,7.9Hz,1H),7.96(s,1H),7.92(br d,J=8.7Hz,2H),7.77(d,J=2.1Hz,1H),7.65-7.58(m,3H),6.82(d,J=2.1Hz,1H),5.00(td,J=6.3,12.5Hz,1H),1.33(d,J=6.2Hz,6H),1.15(s,9H)。ESI[M+H]=540.3
化合物J3
在0℃下向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(25.00mg,51.16μmol,1.00eq.)和NaBH3CN(6.43mg,102.32μmol,2.00eq.)在DCM(2.00mL)中的溶液中加入纯TFA(2.00mL),将混合物在0℃下搅拌0.1小时。在0℃下加入三氟丙酮(14.33mg,127.90μmol,11.46ul,2.50eq.),将混合物在20℃下搅拌1小时。LCMS显示反应完成。反应混合物用饱和NaHCO3水溶液(10mL)洗涤,有机相用DCM(20mL X 3)萃取。将合并的有机相干燥,过滤并浓缩。残余物通过制备型HPLC纯化(TFA条件),得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-[(2,2,2-三氟-1-甲基-乙基)氨基]苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(3.97mg,6.75μmol,13.19%收率,99.40%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=7.88(d,J=8.7Hz,2H),7.81(s,1H),7.58(d,J=8.7Hz,2H),7.54(d,J=2.4Hz,1H),7.32(d,J=8.3Hz,1H),6.97(dd,J=2.6,8.4Hz,1H),5.00(tt,J=6.3,12.5Hz,1H),4.31(td,J=6.7,13.4Hz,1H),1.44(d,J=6.8Hz,3H),1.33(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=585.4
流程10.3
中间体化合物36由中间体化合物7通过通用方法C(实施例1中所示)制备。
ESI[M+H]=593.2/595.2
化合物J4
向中间体化合物36(15.00mg,25.29μmol,1.00eq.)在DMF(150.00ul)中的溶液中加入K2CO3(10.49mg,75.87μmol,3.00eq.)。将混合物在60℃下搅拌2小时,LCMS显示反应完成。将混合物浓缩并且残余物通过制备型HPLC纯化(TFA条件),得到化合物J3(1.07mg,1.88μmol,7.45%收率,98%纯度),为白色固体。1H NMR(400MHz,甲醇-d4)δ=8.65(d,J=2.4Hz,1H),7.93-7.77(m,4H),7.56(dd,J=4.0,8.6Hz,3H),5.02-4.92(m,1H),3.99(t,J=7.1Hz,2H),2.65(t,J=8.0Hz,2H),2.29-2.15(m,2H),1.31(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=557.4
流程10.4
中间体化合物38
向(6-氨基-3-吡啶基)硼酸(200.00mg,1.45mmol,1.00eq.)在二噁烷(5.00mL)、甲苯(5.00mL)和H2O(2.00mL)中的溶液中加入Pd(dppf)Cl2.CH2Cl2(118.41mg,145.00μmol,0.10eq.)、Na2CO3(461.06mg,4.35mmol,3.00eq.)和2,5-二溴噻唑(528.35mg,2.18mmol,1.50eq.)。将混合物在N2下在80℃下搅拌16小时,LCMS显示反应完成。将混合物浓缩并将残余物通过制备型TLC纯化(PE:EtOAc=1:2),得到5-(5-溴噻唑-2-基)吡啶-2-胺(100.00mg,粗品),为黄色固体。ESI[M+H]=257.7/255.7
中间体化合物39由中间体化合物38通过通用方法A(实施例1中所示)制备。
ESI[M+H]=446.1
化合物J5
化合物J5由中间体化合物39通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.38(br d,J=19.0Hz,2H),8.82(s,1H),8.41(s,1H),8.27(br d,J=8.8Hz,1H),7.97(br d,J=9.0Hz,1H),7.89-7.80(m,2H),7.48(br d,J=8.4Hz,1H),7.17(s,1H),5.01-4.85(m,1H),2.08(s,3H),1.25(br d,J=6.0Hz,6H),1.07(s,9H)。ESI[M+H]=532.1
化合物J6
化合物J6由中间体化合物32通过通用方法A(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.42(s,1H),8.01-7.87(m,4H),7.79(d,J=7.9Hz,1H),7.59(d,J=8.6Hz,2H),4.98(td,J=6.0,12.5Hz,1H),1.32(d,J=6.2Hz,6H),1.11(s,9H)。ESI[M+H]=542.1
流程10.5
化合物40的制备
通用方法C,N-[3-(叔丁基氨磺酰基)-4-[2-(4-硝基苯基)噻唑-5-基]苯基]-4-氯-丁酰胺。ESI[M+H]=537.0
化合物41的制备
在80℃下将N-[3-(叔丁基氨磺酰基)-4-[2-(4-硝基苯基)噻唑-5-基]苯基]-4-氯-丁酰胺(100.00mg,186.20μmol,1.00eq.)和Cs2CO3(75.00mg,542.65μmol,2.91eq.)在DMF(2.00mL)中的混合物搅拌8小时,LCMS显示反应完成。用水H2O(10mL)稀释混合物并用EtOAc(10mL)萃取。有机相经Na2SO4干燥,过滤并浓缩,得到N-叔丁基-2-[2-(4-硝基苯基)噻唑-5-基]-5-(2-氧代吡咯烷-1-基)苯磺酰胺(100.00mg,粗品),为黑褐色固体,其直接使用。ESI[M+H]=501.1
化合物42的制备
通用方法B,2-[2-(4-氨基苯基)噻唑-5-基]-N-叔丁基-5-(2-氧代吡咯烷-1-基)苯磺酰胺。ESI[M+H]=471.1
化合物J7
化合物J7由中间体化合物42通过通用方法I(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=8.67-8.58(m,2H),7.86-7.73(m,4H),7.59-7.49(m,3H),7.26(s,1H),6.14(d,J=7.5Hz,1H),3.90(t,J=6.9Hz,2H),3.77(qd,J=6.6,13.5Hz,1H),2.59-2.54(m,2H),2.11(quin,J=7.3Hz,2H),1.17-1.05(m,15H)。ESI[M+H]=556.1
流程10.6
化合物43的制备
在0℃下向NaH(11.72mg,293.06μmol,60%纯度,2.00eq.)在THF(1.00mL)中的溶液中加入在THF(1.00mL)中的N-[4-(5-溴噻唑-2-基)苯基]氨基甲酸异丙酯(50.00mg,146.53μmol,1.00eq.),随后加入在THF(1.00mL)中的MeI(41.60mg,293.06μmol,18.25ul,2.00eq.)。将混合物在20℃下搅拌1小时,LCMS显示反应完成。混合物用饱和NH4Cl水溶液(5mL)猝灭并用EtOAc(5mL X 3)萃取。有机相经Na2SO4干燥,过滤并浓缩,得到N-[4-(5-溴噻唑-2-基)苯基]-N-甲基-氨基甲酸异丙酯(65.00mg,粗品),为黄色油。ESI[M+H]=357.0/355.0
化合物J8
通用方法A,N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氧代吡咯烷-1-基)苯基]噻唑-2-基]苯基]-N-甲基-氨基甲酸异丙酯。1H NMR(400MHz,甲醇-d4)δ=8.67(s,1H),8.00-7.96(m,2H),7.93(s,1H),7.86(br d,J=8.6Hz,1H),7.58(d,J=8.4Hz,1H),7.43(br d,J=8.6Hz,2H),4.94(br d,J=6.2Hz,1H),4.00(brt,J=6.8Hz,2H),3.33(s,3H),2.66(brt,J=7.9Hz,2H),2.29-2.19(m,2H),1.26(br d,J=6.2Hz,6H),1.15(s,9H)。ESI[M+H]=571.2
流程10.7
化合物45的制备
通用方法H,4-(5-溴噻唑-2-基)-2-氟-苯胺。ESI[M+H]=275.0/273.0
化合物46的制备
通用方法A,2-[2-(4-氨基-3-氟-苯基)噻唑-5-基]-N-叔丁基-5-(2-氧代吡咯烷-1-基)苯磺酰胺。ESI[M+H]=489.2
化合物J9
通用方法C,N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氧代吡咯烷-1-基)苯基]噻唑-2-基]-2-氟-苯基]氨基甲酸异丙酯。1H NMR(400MHz,甲醇-d4)δ=8.66(d,J=2.0Hz,1H),8.08(brt,J=8.2Hz,1H),7.90(s,1H),7.84(dd,J=2.2,8.4Hz,1H),7.78-7.69(m,2H),7.55(d,J=8.4Hz,1H),5.00(quin,J=6.3Hz,1H),3.99(t,J=7.1Hz,2H),2.65(t,J=8.0Hz,2H),2.22(quin,J=7.6Hz,2H),1.32(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=575.2
流程10.8
化合物J10
向2-甲基氧杂环丙烷(19.60mg,337.41μmol,23.61ul,1.50eq.)在二噁烷(1.00mL)中的混合物中加入LiClO4(5M,1.00mL,22.23eq.)在THF中的溶液和N-[4-[2-(4-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺(100.00mg,224.94μmol,1.00eq.)。将混合物在100℃下搅拌6小时,LCMS显示反应完成。混合物用H2O(3mL)稀释并用DCM(3mL X 3)萃取。合并的有机层经Na2SO4干燥,过滤并浓缩。残余物通过制备型TLC纯化,得到N-[3-(叔丁基氨磺酰基)-4-[2-[4-(2-羟基丙基氨基)苯基]噻唑-5-基]苯基]乙酰胺(40.00mg,75.60μmol,33.61%收率,95%纯度),为黄色油。1H NMR(400MHz,甲醇-d4)δ=8.50(d,J=2.2Hz,1H),7.93-7.87(m,2H),7.81-7.75(m,2H),7.53(d,J=8.4Hz,1H),6.83(d,J=8.8Hz,2H),4.04-3.92(m,1H),3.29-3.11(m,2H),2.19(s,3H),1.27-1.24(m,3H),1.17(s,9H)。ESI[M+H]=503.1
化合物J11
化合物J11由化合物J10通过通用方法K(实施例1中所示)制备。
通用方法K,N-[3-(叔丁基氨磺酰基)-4-[2-[4-(2-羟基丙基氨基)苯基]噻唑-5-基]苯基]乙酰胺。1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=2.2Hz,1H),8.02-7.97(m,2H),7.91-7.85(m,2H),7.75-7.70(m,2H),7.51(d,J=8.4Hz,1H),4.94-4.89(m,1H),4.27(t,J=8.6Hz,1H),3.77(dd,J=7.2,8.9Hz,1H),2.18(s,3H),1.53(d,J=6.2Hz,3H),1.15(s,9H)。ESI[M+H]=529.1
流程10.9
化合物J12
向N-[4-[2-(4-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺(50.00mg,112.47μmol,1.00eq.)在EtOH(900.00ul)和H2O(100.00ul)中的溶液中加入2,2-二甲基氧杂环丙烷(810.00mg,11.23mmol,1.00mL,99.87eq.)。混合物在100℃下加热1小时,LCMS显示反应完成。将混合物浓缩并且残余物通过制备型HPLC纯化(TFA条件),得到N-[3-(叔丁基氨磺酰基)-4-[2-[4-[(2-羟基-2-甲基-丙基)氨基]苯基]噻唑-5-基]苯基]乙酰胺(60.00mg,粗品),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.46(d,J=1.8Hz,1H),7.87(br d,J=6.4Hz,1H),7.82(s,1H),7.72(d,J=8.8Hz,2H),7.49(d,J=8.4Hz,1H),6.77(d,J=8.6Hz,2H),3.17(s,2H),2.17(s,3H),1.27(s,6H),1.14(s,9H)。ESI[M+H]=517.1
化合物J13
化合物J13由化合物J12通过通用方法K(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.48(s,1H),7.99(d,J=8.8Hz,2H),7.90-7.85(m,2H),7.72(d,J=8.8Hz,2H),7.50(d,J=8.2Hz,1H),3.94(s,2H),2.17(s,3H),1.56(s,6H),1.14(s,9H)。ESI[M+H]=543.2
流程10.10
化合物48的制备
通用方法A,3-(5-溴噻唑-2-基)苯胺。ESI[M+H]=255.0/257.0
化合物49的制备
通用方法A,N-[4-[2-(3-氨基苯基)噻唑-5-基]-3-(叔丁基氨磺酰基)苯基]乙酰胺。ESI[M+H]=445.0
化合物J14
化合物J14由中间体化合物49通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.48(d,J=2.0Hz,1H),8.10(s,1H),7.92-7.85(m,2H),7.62(d,J=7.5Hz,1H),7.56-7.48(m,2H),7.42-7.35(m,1H),4.97(td,J=6.3,12.6Hz,1H),2.17(s,3H),1.31(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=531.2
流程10.11
化合物50的制备
通用方法C,N-叔丁基-5-(甲磺酰氨基)-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰胺。ESI[M+H]=511.1
化合物51的制备
通用方法B,2-[2-(4-氨基苯基)噻唑-5-基]-N-叔丁基-5-(甲磺酰氨基)苯磺酰胺。ESI[M+H]=481.2
化合物J15
化合物J15由中间体化合物51通过通用方法I(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.09(d,J=2.2Hz,1H),7.88-7.81(m,3H),7.55-7.43(m,4H),3.90(td,J=6.7,13.3Hz,1H),1.20(s,3H),1.18(s,6H),1.14(s,9H)。ESI[M+H]=566.1
流程10.12
化合物53的制备
通用方法J,2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺。1H NMR(400MHz,氯仿-d)δ=7.30(dd,J=0.9,7.5Hz,1H),7.21(s,1H),6.71(d,J=7.9Hz,1H),4.01(br s,2H),3.90(s,3H),1.34(s,12H)
化合物54的制备
通用方法H,4-(5-溴噻唑-2-基)-2-甲氧基-苯胺。ESI[M+H]=285.2/287.2
化合物55的制备
通用方法A,2-[2-(4-氨基-3-甲氧基-苯基)噻唑-5-基]-N-叔丁基-5-(2-氧代吡咯烷-1-基)苯磺酰胺。ESI[M+H]=501.2
化合物J16
化合物J16由中间体化合物55通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.67(d,J=2.2Hz,1H),8.06(d,J=8.4Hz,1H),7.89(s,1H),7.85(dd,J=2.2,8.6Hz,1H),7.61(s,1H),7.57(d,J=8.5Hz,1H),7.51(d,J=8.6Hz,1H),5.05-4.94(m,1H),4.03-3.95(m,5H),2.66(t,J=8.0Hz,2H),2.23(quin,J=7.5Hz,2H),1.32(d,J=6.2Hz,6H),1.15(s,9H)。ESI[M+H]=587.1
流程10.13
化合物57的制备
通用方法J,2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺。1H NMR(400MHz,甲醇-d4)δ=7.43-7.29(m,2H),6.65(d,J=7.8Hz,1H),2.13(s,3H),1.31(s,12H)。
化合物58的制备
通用方法H,4-(5-溴噻唑-2-基)-2-甲基-苯胺。1H NMR(400MHz,DMSO-d6)δ=7.76(s,1H),7.54-7.32(m,2H),6.64(d,J=8.2Hz,1H),5.53(s,2H),2.09(s,3H)。
化合物59的制备
通用方法A,2-[2-(4-氨基-3-甲基-苯基)噻唑-5-基]-N-叔丁基-5-(2-氧代吡咯烷-1-基)苯磺酰胺。ESI[M+H]=485.1
化合物J17
化合物J17由中间体化合物59通过通用方法C(实施例1中所示)制备。
1HNMR(400MHz,DMSO-d6)δ=8.90(s,1H),8.64(d,J=2.4Hz,1H),7.87(s,1H),7.80-7.74(m,3H),7.59(t,J=9.1Hz,2H),7.24(s,1H),4.90(spt,J=6.2Hz,1H),3.91(t,J=7.0Hz,2H),2.61-2.54(m,2H),2.30(s,3H),2.15-2.08(m,2H),1.27(d,J=6.2Hz,6H),1.10(s,9H)。ESI[M+H]=571.1
流程10.14
化合物60的制备
通用方法A,2-[2-(4-氨基苯基)噻唑-5-基]-N-叔丁基-5-[甲基(甲基磺酰基)氨基]苯磺酰胺。ESI[M+H]=495.2
化合物J18
化合物J18由中间体化合物60通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.23(d,J=2.2Hz,1H),7.91-7.86(m,3H),7.70(dd,J=2.4,8.1Hz,1H),7.58(t,J=8.1Hz,3H),4.98(td,J=6.2,12.6Hz,1H),3.39(s,3H),2.96(s,3H),1.31(d,J=6.1Hz,6H),1.13(s,9H)。ESI[M+H]=581.1
化合物J18
通用方法I,1-[4-[5-[2-(叔丁基氨磺酰基)-4-[甲基(甲基磺酰基)氨基]苯基]噻唑-2-基]苯基]-3-异丙基-脲。1HNMR(400MHz,甲醇-d4)δ=8.23(d,J=2.6Hz,1H),7.90-7.84(m,3H),7.71(dd,J=2.6,8.3Hz,1H),7.60(d,J=8.3Hz,1H),7.50(d,J=8.8Hz,2H),3.90(quin,J=6.5Hz,1H),3.40(s,3H),2.96(s,3H),1.19(d,J=6.6Hz,6H),1.13(s,9H)。ESI[M+H]=580.2
流程10.15
化合物61的制备
通用方法C,N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸2-氯乙酯。ESI[M+H]=551.1/553.0
化合物J19
向N-[4-[5-[4-乙酰氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸2-氯乙酯(70.00mg,127.02μmol,1.00eq.)在DMF(1.00mL)中的溶液中加入K2CO3(52.67mg,381.06μmol,3.00eq.)和NaI(57.12mg,381.06μmol,3.00eq.)。将混合物在60℃下搅拌3小时,LCMS显示反应完成。将混合物浓缩并且残余物通过酸性制备型HPLC纯化,得到N-[3-(叔丁基氨磺酰基)-4-[2-[4-(2-氧代噁唑烷-3-基)苯基]噻唑-5-基]苯基]乙酰胺(27.79mg,53.95μmol,42.47%收率,99.9%纯度),为白色固体。1H NMR(400MHz,DMSO-d6)δ=10.38(s,1H),8.39(s,1H),7.96(d,J=8.8Hz,2H),7.86-7.78(m,2H),7.69(d,J=8.8Hz,2H),7.47(d,J=8.4Hz,1H),7.18(s,1H),4.44(t,J=7.9Hz,2H),4.15-4.04(m,2H),2.07(s,3H),1.05(s,9H)。ESI[M+H]=515.3
流程10.16
化合物102的制备
通用方法C,(4-(5-(4-(3-(3-氨基苄基)脲基)-2-(N-(叔丁基)氨磺酰基)苯基)噻唑-2-基)苯基)氨基甲酸异丙酯。ESI[M+H]=637.2
化合物J20
将N-[4-[5-[4-[(3-氨基苯基)甲基氨基甲酰基氨基]-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(0.05g,78.52μmol,1eq.)溶于浓HCl(0.5mL)和水(500.00ul),随后冷却至0℃。以一定的速率滴加NaNO2(8.13mg,117.78μmol,6.40ul,1.5eq.)在水(0.5mL)中的水溶液,使得温度不超过5℃。将混合物在0℃下搅拌0.5小时。在0~5℃下加入NaN3(7.66mg,117.78μmol,1.5eq.)和NaOAc(96.62mg,1.18mmol,15eq.)在水(4mL)中的溶液,在该温度下将混合物再搅拌0.5小时。用EtOAc(30mL X 3)萃取该水溶液,将有机相干燥,过滤并浓缩。残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[4-[(3-叠氮基苯基)甲基氨基甲酰基氨基]-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(12.57mg,18.85μmol,24.01%收率,99.39%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.2Hz,1H),7.90-7.83(m,3H),7.72(dd,J=2.2,8.4Hz,1H),7.57(d,J=8.6Hz,2H),7.43(d,J=8.4Hz,1H),7.38-7.33(m,1H),7.16(d,J=7.7Hz,1H),7.06(s,1H),6.97(br d,J=7.9Hz,1H),4.97(td,J=6.3,12.6Hz,1H),4.41(s,2H),1.31(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=663.4。
化合物J21
化合物J21由中间体化合物32通过通用方法A(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=9.86(s,1H),8.56(s,1H),7.86(d,J=8.6Hz,2H),7.81(s,1H),7.65(br d,J=8.6Hz,1H),7.59(br d,J=8.4Hz,2H),7.49(d,J=8.4Hz,1H),7.39-7.34(m,2H),7.33-7.27(m,3H),7.19(s,1H),4.90(td,J=6.0,12.4Hz,1H),4.42(s,2H),3.88(brt,J=7.9Hz,2H),3.40(brt,J=7.9Hz,2H),1.26(d,J=6.4Hz,6H),1.08(s,9H)。ESI[M+H]=648.2
流程10.17
化合物103的制备
通用方法A,5-(3-苄基-2-氧代咪唑烷-1-基)-N-(叔丁基)-2-(2-(4-硝基苯基)噻唑-5-基)苯磺酰胺。ESI[M+H]=591.9
化合物104的制备
通用方法B,2-(2-(4-氨基苯基)噻唑-5-基)-5-(3-苄基-2-氧代咪唑烷-1-基)-N-(叔丁基)苯磺酰胺。ESI[M+H]=561.9
化合物J22
化合物J22由中间体化合物104通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.61(d,J=2.0Hz,1H),7.99-7.87(m,3H),7.83-7.76(m,1H),7.64-7.50(m,3H),7.43-7.28(m,5H),4.52(s,3H),3.96(brt,J=7.8Hz,2H),3.57-3.43(m,2H),1.27(d,J=6.4Hz,6H),1.18(s,9H)。ESI[M+H]=663.2
流程10.18
化合物105的制备
通用方法C,N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氯乙氧基羰基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯。ESI[M+H]=595.3
化合物J23
向N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氯乙氧基羰基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,33.61μmol,1.00eq.)在DMF(1.00mL)中的溶液中加入Cs2CO3(32.85mg,100.82μmol,3.00eq.),将混合物在60℃下搅拌1小时。将混合物过滤,滤液通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氧代噁唑烷-3-基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(10.15mg,18.17μmol,54.06%收率,100%纯度),为白色固体。1H NMR(400MHz,DMSO-d6)δ=9.88(s,1H),8.51(d,J=2.3Hz,1H),7.98-7.79(m,3H),7.71(dd,J=2.3,8.4Hz,1H),7.65-7.57(m,3H),7.31(s,1H),5.02-4.85(m,1H),4.51(t,J=7.9Hz,2H),4.16(t,J=7.9Hz,2H),1.29(d,J=6.2Hz,6H),1.11(s,9H)。ESI[M+H]=559.1
流程10.19
化合物106的制备
通用方法C,N-[4-[5-[2-(叔丁基氨磺酰基)-4-(3-氯丙氧基羰基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯。ESI[M+H]=609.2
化合物J24
在80℃下将N-[4-[5-[2-(叔丁基氨磺酰基)-4-(3-氯丙氧基羰基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(30.00mg,49.25μmol,1.00eq.)和K2CO3(6.81mg,49.25μmol,1.00eq.)在DMF(500.00ul)中的混合物搅拌2小时。将混合物过滤,滤液通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氧代-1,3-氧杂氮杂环己烷-3-基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(2.17mg,3.79μmol,7.70%收率),为白色固体。1HNMR(400MHz,甲醇-d4)δ=8.22(d,J=2.0Hz,1H),7.93-7.86(m,3H),7.70-7.64(m,1H),7.58(dd,J=5.4,8.3Hz,3H),4.98(td,J=6.3,12.4Hz,1H),4.49(t,J=5.3Hz,2H),3.84(t,J=6.0Hz,2H),2.26(quin,J=5.6Hz,2H),1.31(d,J=6.4Hz,6H),1.12(s,9H)。ESI[M+H]=573.1
流程10.20
化合物J25
向2-甲基氧杂环丙烷(29.72mg,511.65μmol,35.80ul,5.00eq.)在AcOH(500.00ul)中的混合物中加入N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(50.00mg,102.33μmol,1.00eq.),将混合物在60℃下搅拌2小时。混合物用H2O(1mL)稀释并用DCM(1mL X 3)萃取。合并的有机层用H2O(1mL)、饱和NaHCO3水溶液洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-羟基丙基氨基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(7.32mg,13.35μmol,26.06%收率,99.7%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=7.86(d,J=8.8Hz,2H),7.78(s,1H),7.57(d,J=8.6Hz,2H),7.47-7.40(m,1H),7.26(d,J=8.4Hz,1H),6.88-6.82(m,1H),5.03-4.93(m,1H),4.03-3.90(m,1H),3.72-3.55(m,1H),3.22-3.08(m,1H),1.31(d,J=6.2Hz,6H),1.26-1.22(m,3H),1.12(s,9H)。ESI[M+H]=547.2
化合物J26
通用方法K,(4-(5-(2-(N-(叔丁基)氨磺酰基)-4-(5-甲基-2-氧代噁唑烷-3-基)苯基)噻唑-2-基)苯基)氨基甲酸异丙酯。1H NMR(400MHz,DMSO-d6)δ=9.86(s,1H),8.46(d,J=2.4Hz,1H),7.87(d,J=8.8Hz,2H),7.83(s,1H),7.65(dd,J=2.4,8.6Hz,1H),7.58(dd,J=8.7,13.8Hz,3H),7.26(s,1H),4.97-4.77(m,2H),4.22(t,J=8.6Hz,1H),3.73(dd,J=7.3,8.6Hz,1H),1.43(d,J=6.2Hz,3H),1.26(d,J=6.4Hz,6H),1.07(s,9H)。ESI[M+H]=573.2
流程10.21
化合物107的制备
向N-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(200.00mg,409.32μmol,1.00eq.)在ACN(5.00mL)中的溶液中加入2-苄基氧杂环丙烷(219.67mg,1.64mmol,215.37ul,4.00eq.)和三(三氟甲基磺酰基氧基)合镱(253.88mg,409.32μmol,1.00eq.),将混合物在60℃下搅拌小时4小时。将混合物浓缩并且残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-[(2-羟基-3-苯基-丙基)氨基]苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(75.00mg,120.42μmol,29.42%收率),为黄色固体。ESI[M+H]=623.1
化合物J27
化合物J27由中间体化合物107通过通用方法K(实施例1中所示)制备。
通用方法K,(4-(5-(4-(5-苄基-2-氧代噁唑烷-3-基)-2-(N-(叔丁基)氨磺酰基)苯基)噻唑-2-基)苯基)氨基甲酸异丙酯。1H NMR(400MHz,DMSO-d6)δ=9.88(s,1H),8.41(s,1H),7.94-7.80(m,3H),7.67-7.59(m,3H),7.55(d,J=8.4Hz,1H),7.34(d,J=4.6Hz,4H),7.29(br d,J=17.4Hz,2H),5.08-4.97(m,1H),4.92(td,J=6.3,12.4Hz,1H),4.20(t,J=8.9Hz,1H),3.88(brt,J=7.9Hz,1H),3.11(d,J=6.2Hz,2H),1.27(d,J=6.2Hz,6H),1.08(s,9H)。ESI[M+H]=649.2
化合物J28
通用方法A,(4-(5-(4-(3-苄基-2-氧代吡咯烷-1-基)-2-(N-(叔丁基)氨磺酰基)苯基)噻唑-2-基)苯基)氨基甲酸异丙酯。1H NMR(400MHz,DMSO-d6)δ=9.86(s,1H),8.64(d,J=2.2Hz,1H),7.91-7.84(m,3H),7.78(dd,J=2.3,8.4Hz,1H),7.59(dd,J=8.6,19.4Hz,3H),7.34-7.19(m,6H),4.92(spt,J=6.2Hz,1H),3.83-3.65(m,2H),3.15(dd,J=4.2,13.6Hz,1H),3.02(dq,J=4.2,9.1Hz,1H),2.76(dd,J=9.4,13.5Hz,1H),2.16-2.07(m,1H),1.89-1.78(m,1H),1.28(d,J=6.2Hz,6H),1.11(s,9H)。ESI[M+H]=647.2
流程10.22
化合物108的制备
通用方法K,5-苯基噁唑烷-2-酮。ESI[M+H]=164.1
化合物J29
将N-[4-[5-[4-溴-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸酯(40.00mg,72.40μmol,1.00eq.)、5-苯基噁唑烷-2-酮(40.05mg,245.44μmol,3.39eq.)、Pd2(dba)3(6.63mg,7.24μmol,0.10eq.)、K3PO4(46.11mg,217.20μmol,3.00eq.)和Xantphos(4.19mg,7.24μmol,0.10eq.)在二噁烷(3.00mL)中的混合物脱气并用N2吹扫3次,在N2气氛下在100℃下搅拌16小时。将混合物倾入水(30mL)中并用EtOAc(30mL X 3)萃取水相。将合并的有机相干燥,过滤并浓缩,残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[2-(叔丁基氨磺酰基)-4-(2-氧代-5-苯基-噁唑烷-3-基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(28.54mg,44.96μmol,62.10%收率,100%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=9.42(br s,1H),8.64(br s,1H),7.88(br s,2H),7.75(br d,J=7.5Hz,1H),7.62-7.54(m,1H),7.57(br d,J=7.7Hz,2H),7.54-7.49(m,1H),7.51(br s,1H),7.46(br d,J=7.5Hz,3H),5.79(brt,J=7.7Hz,1H),5.00-4.93(m,1H),4.58(br t,J=8.8Hz,1H),4.09(br t,J=8.2Hz,1H),1.31(br d,J=6.0Hz,6H),1.15(s,9H)。ESI[M+H]=635.1
实施例11
除非另有说明,否则以下化合物通过通用方法A(实施例1中所示)通过使中间体32与不同的硼酸酯反应来合成。
化合物K1
1H NMR(400MHz,甲醇-d4)δ=8.67(s,1H),8.08(d,J=7.9Hz,1H),7.96(s,1H),7.90(d,J=8.6Hz,2H),7.67(d,J=7.9Hz,1H),7.58(d,J=8.6Hz,2H),7.41-7.30(m,4H),7.29-7.21(m,1H),4.97(td,J=6.4,12.3Hz,1H),4.61(s,2H),1.31(d,J=6.4Hz,6H),1.10(s,9H)。ESI[M+H]=607.1
化合物K2
1H NMR(400MHz,甲醇-d4)δ=8.08(d,J=8.8Hz,1H),7.96-7.86(m,3H),7.76-7.65(m,2H),7.59(d,J=8.8Hz,2H),7.49-7.42(m,2H),7.41-7.29(m,3H),5.23(s,2H),5.00(td,J=6.2,12.6Hz,1H),1.33(d,J=6.4Hz,6H),1.11(s,9H)。ESI[M+H]=623.2
实施例12
流程12.1
化合物127的制备
在40℃下将N-[4-(5-溴噻唑-2-基)-3-(叔丁基氨磺酰基)苯基]乙酰胺(200.00mg,462.58μmol,1.00eq.)在HCl/MeOH(5.00mL,4M)中的混合物搅拌20分钟,随后浓缩。残余物在EtOAc(10mL)和饱和NaHCO3水溶液(10mL)之间分配。将有机层干燥,过滤并浓缩,得到5-氨基-2-(5-溴噻唑-2-基)-N-叔丁基-苯磺酰胺(200.00mg,粗品),为黄色油,其直接使用。ESI[M+H]=389.9/391.9
化合物128的制备
通用方法C,(4-(5-溴噻唑-2-基)-3-(N-(叔丁基)氨磺酰基)苯基)氨基甲酸异丙酯。ESI[M+H]=475.9/477.9
化合物129的制备
通用方法A,(4-(5-(4-氨基苯基)噻唑-2-基)-3-(N-(叔丁基)氨磺酰基)苯基)氨基甲酸异丙酯。ESI[M+H]=489.1
化合物L1
化合物L1由中间体化合物129通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.19(s,1H),9.86(s,1H),8.37(s,1H),8.28(s,1H),7.81(s,1H),7.78-7.73(m,2H),7.68-7.63(m,2H),7.57(d,J=8.6Hz,2H),4.94(spt,J=6.2Hz,1H),4.15(q,J=7.1Hz,2H),1.30-1.23(m,9H),1.20(s,9H)。ESI[M+H]=561.2
化合物L2
化合物L2由中间体化合物129通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.19(s,1H),9.80(s,1H),8.37(s,1H),8.28(s,1H),7.81(s,1H),7.76(s,2H),7.68-7.63(m,2H),7.59-7.53(m,2H),5.00-4.85(m,2H),1.28(t,J=6.4Hz,12H),1.20(s,9H)。ESI[M+H]=575.2
化合物L3
向N-[4-[5-(4-氨基苯基)噻唑-2-基]-3-(叔丁基氨磺酰基)苯基]氨基甲酸异丙酯(30.00mg,61.40μmol,1.00eq.)和K2CO3(20.00mg,144.71μmol,2.36eq.)在THF(2.00mL)和H2O(500.00ul)中的混合物中加入CbzCl(15.00mg,87.93μmol,1.43eq.)。将混合物在15℃下搅拌1小时并随后浓缩。残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[4-(苄基氧基羰基氨基)苯基]噻唑-2-基]-3-(叔丁基氨磺酰基)苯基]氨基甲酸异丙酯(30.92mg,49.45μmol,80.54%收率,99.596%纯度),为浅黄色固体。1H NMR(400MHz,DMSO-d6)δ=10.19(s,1H),10.01(s,1H),8.37(s,1H),8.29(s,1H),7.81(s,1H),7.76(s,2H),7.70-7.65(m,2H),7.58(d,J=8.8Hz,2H),7.47-7.33(m,5H),5.18(s,2H),5.02-4.84(m,1H),1.28(d,J=6.2Hz,6H),1.20(s,9H)。ESI[M+H]=623.2
流程12.2
化合物131的制备
向5-氨基-N-叔丁基-2-[2-(4-硝基苯基)噻唑-5-基]苯磺酰胺(100.00mg,231.20μmol,1.00eq.)在THF(3.00mL)中的溶液中加入K2CO3(63.91mg,462.41μmol,2.00eq.)和氯甲酸苄酯(197.20mg,1.16mmol,164.34ul,5.00eq.)。将混合物在20℃下搅拌0.5小时,随后浓缩并通过制备型TLC纯化(SiO2,石油醚:EtOAc=2:1),得到N-[3-(叔丁基氨磺酰基)-4-[2-(4-硝基苯基)噻唑-5-基]苯基]氨基甲酸苄酯(90.00mg),为黄色固体。
化合物132的制备
通用方法B,(4-(2-(4-氨基苯基)噻唑-5-基)-3-(N-(叔丁基)氨磺酰基)苯基)氨基甲酸苄酯。ESI[M+H]=537.2
化合物L4
化合物L4由中间体化合物132通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.41(d,J=1.7Hz,1H),7.95(d,J=8.7Hz,2H),7.90(s,1H),7.79-7.71(m,1H),7.60(d,J=8.6Hz,2H),7.50-7.45(m,3H),7.43-7.34(m,3H),5.25(s,2H),4.56(br s,1H),1.27(d,J=6.6Hz,6H),1.16(s,9H)。ESI[M+H]=638.2
流程12.3
化合物133的制备
通用方法C,(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-硝基苯基)噻唑-5-基)苯基)氨基甲酸乙酯。ESI[M+H]=505.0
化合物134的制备
通用方法B,(4-(2-(4-氨基苯基)噻唑-5-基)-3-(N-(叔丁基)氨磺酰基)苯基)氨基甲酸乙酯。ESI[M+H]=475.0
化合物L5
化合物L5由中间体化合物134通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.18(br s,1H),9.58(br s,1H),8.35(br s,1H),7.88(br d,J=10.1Hz,4H),7.76-7.59(m,3H),7.49(br s,1H),7.18(br s,1H),4.39(brs,1H),4.18(br s,2H),1.27(br d,J=7.0Hz,3H),1.19(br s,6H),1.09(br s,9H)。ESI[M+H]=576.2
流程12.4
化合物135的制备
通用方法C,N-(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-硝基苯基)噻唑-5-基)苯基)苯甲酰胺。ESI[M+H]=537.3
化合物136的制备
通用方法B,N-(4-(2-(4-氨基苯基)噻唑-5-基)-3-(N-(叔丁基)氨磺酰基)苯基)苯甲酰胺。
化合物L6
化合物L6由中间体化合物136通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.69(1H,s),7.89-8.10(6H,m),7.49-7.62(6H,m),4.54(1H,br s),1.25(6H,d,J=6.4Hz),1.16(9H,s)。ESI[M+H]=608.2
流程12.5
化合物137的制备
通用方法C,(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-硝基苯基)噻唑-5-基)苯基)氨基甲酸基甲酯。ESI[M+H]=491.0
化合物138的制备
通用方法B,(4-(2-(4-氨基苯基)噻唑-5-基)-3-(N-(叔丁基)氨磺酰基)苯基)氨基甲酸甲酯。ESI[M+H]=461.0
化合物L7
化合物L7由中间体化合物138通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.17(s,1H),9.58(br s,1H),8.34(s,1H),7.93-7.80(m,4H),7.74-7.61(m,3H),7.50(d,J=8.3Hz,1H),7.17(s,1H),4.40(br d,J=5.9Hz,1H),3.72(s,3H),1.19(d,J=6.5Hz,6H),1.10(s,9H)。ESI[M+H]=562.2
化合物L8
化合物L8由中间体化合物7通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=10.05(br s,1H),9.87(s,1H),8.49-8.36(m,2H),7.92-7.76(m,4H),7.62(br d,J=8.6Hz,2H),7.49(d,J=8.3Hz,1H),7.40-7.33(m,4H),7.29(br d,J=3.1Hz,1H),7.18(s,1H),5.03-4.87(m,1H),4.77(br d,J=5.0Hz,2H),1.28(d,J=6.1Hz,6H),1.11(s,9H)。ESI[M+H]=638.2
化合物L9
化合物L9由中间体化合物7通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.47(s,1H),7.99-7.81(m,4H),7.58(d,J=8.6Hz,2H),7.49(d,J=8.2Hz,1H),7.41-7.29(m,4H),7.28-7.21(m,1H),4.83(br s,2H),2.17(s,3H),1.13(s,9H)。ESI[M+H]=594.2
流程12.6
化合物139的制备
通用方法C,(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-硝基苯基)噻唑-5-基)苯基)氨基甲酸4-硝基苯酯。ESI[M+H]=597.9
化合物140的制备
通用方法F,5-(3-苄基脲基)-N-(叔丁基)-2-(2-(4-硝基苯基)噻唑-5-基)苯磺酰胺。ESI[M+H]=566.1
化合物141的制备
通用方法B,2-(2-(4-氨基苯基)噻唑-5-基)-5-(3-苄基脲基)-N-(叔丁基)苯磺酰胺。ESI[M+H]=536.3
化合物L10
化合物L10由中间体化合物141通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,DMSO-d6)δ=9.56(br s,1H),9.15(s,1H),8.28(d,J=2.2Hz,1H),7.88(d,J=8.7Hz,2H),7.85–7.80(m,2H),7.68–7.61(m,3H),7.42(d,J=8.3Hz,1H),7.38–7.30(m,4H),7.26(dt,J=2.6,6.1Hz,1H),7.09(s,1H),6.77(brt,J=5.9Hz,1H),4.45–4.36(m,1H),4.33(d,J=5.7Hz,2H),1.19(d,J=6.5Hz,6H),1.08(s,9H)。ESI[M+H]=637.3
实施例13
除非另有说明,否则以下化合物通过通用方法F、B、G和E(实施例1中所示)通过使中间体化合物139与不同的胺和醇合成。
化合物M1
1H NMR(400MHz,DMSO-d6)δ=9.57(br s,1H),8.95(s,1H),8.39(d,J=2.2Hz,1H),7.91-7.81(m,5H),7.64(d,J=8.7Hz,2H),7.44(d,J=8.4Hz,1H),7.40-7.34(m,2H),7.29(br d,J=6.6Hz,3H),7.02(s,1H),4.59(s,2H),4.40(br d,J=6.7Hz,1H),2.95(s,3H),1.19(d,J=6.6Hz,6H),1.07(s,9H)。ESI[M+H]=651.3
化合物M2
1H NMR(400MHz,甲醇-d4)δ=8.80(d,J=6.5Hz,2H),8.36(d,J=2.2Hz,1H),8.06(d,J=6.4Hz,2H),7.94(d,J=8.6Hz,2H),7.89(s,1H),7.73(dd,J=2.3,8.4Hz,1H),7.61(d,J=8.6Hz,2H),7.47(d,J=8.3Hz,1H),4.73(s,2H),4.56(br s,1H),1.27(d,J=6.5Hz,6H),1.13(s,9H)。ESI[M+H]=638.3
化合物M3
1H NMR(400MHz,DMSO-d6)δ=9.61(br s,1H),9.44(s,1H),8.83-8.66(m,2H),8.31-8.22(m,2H),7.94-7.76(m,5H),7.64(br d,J=8.4Hz,3H),7.42(br d,J=8.3Hz,2H),7.08(s,2H),4.52-4.33(m,3H),1.18(d,J=6.5Hz,6H),1.06(s,9H)。ESI[M+H]=638.2
化合物M4
1H NMR(400MHz,DMSO-d6)δ=9.57(br s,1H),9.48(s,1H),8.64(br d,J=5.3Hz,1H),8.27(d,J=2.2Hz,1H),8.07(brt,J=7.5Hz,1H),7.89-7.81(m,4H),7.67-7.57(m,4H),7.54(br d,J=6.4Hz,1H),7.41(d,J=8.4Hz,1H),7.09(s,1H),7.00(brt,J=5.6Hz,1H),4.52(br d,J=5.5Hz,2H),4.37(br s,1H),1.16(d,J=6.4Hz,6H),1.05(s,9H)。ESI[M+H]=638.1
化合物M5
1H NMR(400MHz,DMSO-d6)δ=9.60(br s,1H),9.34(s,1H),9.10(s,1H),8.78(s,2H),8.28(d,J=2.1Hz,1H),7.92-7.82(m,4H),7.69-7.61(m,3H),7.45-7.39(m,1H),7.10(s,1H),7.03-6.95(m,1H),4.45-4.33(m,3H),1.19(d,J=6.6Hz,6H),1.08(s,9H)。ESI[M+H]=639.2
化合物M6
1H NMR(400MHz,DMSO-d6)δ=9.60(br s,1H),9.43(s,1H),8.31(d,J=2.1Hz,1H),7.94-7.82(m,4H),7.75(d,J=3.2Hz,1H),7.71-7.62(m,4H),7.44(d,J=8.4Hz,1H),7.20-7.09(m,2H),4.63(br d,J=5.9Hz,2H),4.40(br d,J=6.2Hz,1H),1.19(d,J=6.5Hz,6H),1.09(s,9H)。ESI[M+H]=644.1
化合物M7
1H NMR(400MHz,甲醇-d4)δ=8.22(d,J=2.2Hz,1H),7.91(d,J=8.8Hz,2H),7.85(s,1H),7.68(dd,J=2.4,8.4Hz,1H),7.56(d,J=8.6Hz,2H),7.45-7.32(m,5H),7.28-7.21(m,1H),4.93(q,J=6.8Hz,1H),4.53(br s,1H),1.49(d,J=7.1Hz,3H),1.24(d,J=6.6Hz,6H),1.11(s,9H)。ESI[M+H]=651.2
化合物M8
1H NMR(400MHz,甲醇-d4)δ=8.35(d,J=2.0Hz,1H),7.91(d,J=8.6Hz,2H),7.86(s,1H),7.70(br d,J=8.4Hz,1H),7.57(d,J=8.6Hz,2H),7.47-7.41(m,3H),7.36(t,J=7.4Hz,2H),7.32-7.26(m,1H),5.87(q,J=6.6Hz,1H),4.53(br s,1H),1.59(d,J=6.6Hz,3H),1.24(d,J=6.6Hz,6H),1.12(s,9H)。ESI[M+H]=652.2
实施例14
流程14.1
化合物142的制备
通用方法G,N-(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-(3-异丙基硫脲基)苯基)噻唑-5-基)苯基)乙酰胺。ESI[M+H]=546.4
化合物143的制备
在30℃下将N-[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙基氨基硫代甲酰基氨基)苯基]噻唑-5-基]苯基]乙酰胺(1g,1.83mmol,1eq.)在HCl/MeOH(4M,50mL)中的混合物搅拌1小时,随后浓缩。用DCM(30mL)稀释残余物并用饱和Na2CO3水溶液(20mL)洗涤。有机相经Na2SO4干燥,过滤并浓缩,得到1-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]-3-异丙基-硫脲(900mg,粗品),为黄色固体。ESI[M+H]=504.0
化合物144的制备
通用方法C,(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-(3-异丙基硫脲基)苯基)噻唑-5-基)苯基)氨基甲酸4-硝基苯酯。
化合物N1
化合物145的制备
通用方法F,N-(叔丁基)-5-(3-(4-羟基苄基)脲基)-2-(2-(4-(3-异丙基硫脲基)苯基)噻唑-5-基)苯磺酰胺。1H NMR(400MHz,甲醇-d4)δ=8.30-8.25(m,1H),7.96-7.89(m,2H),7.86(s,1H),7.70(br d,J=6.6Hz,1H),7.57(br d,J=8.3Hz,2H),7.42(br d,J=8.3Hz,1H),7.17(br d,J=8.3Hz,2H),6.75(br d,J=8.3Hz,2H),4.54(br s,1H),4.30(s,2H),1.24(br d,J=6.6Hz,6H),1.13(s,9H)。ESI[M+H]=653.2
除非另有说明,否则以下化合物类似于化合物N1通过使中间体144与不同的胺反应来合成。
化合物N2
1H NMR(400MHz,DMSO-d6)δ=9.58(br s,1H),9.35(br s,1H),9.15(s,1H),8.31-8.23(m,1H),7.94-7.77(m,4H),7.69-7.59(m,3H),7.42(br d,J=8.3Hz,1H),7.15-7.07(m,2H),6.72(br s,3H),6.63(br d,J=8.6Hz,1H),4.46-4.31(m,1H),4.24(br d,J=5.4Hz,2H),1.23-1.13(m,6H),1.08(s,9H)。ESI[M+H]=653.2
化合物N3
1H NMR(400MHz,甲醇-d4)δ=8.26(s,1H),7.96-7.85(m,3H),7.69(br d,J=8.3Hz,1H),7.58(br d,J=8.8Hz,2H),7.42(d,J=8.3Hz,1H),7.21(br d,J=7.0Hz,1H),7.10(brt,J=7.7Hz,1H),6.83-6.74(m,2H),4.54(br s,1H),4.37(s,2H),1.24(d,J=6.6Hz,6H),1.13(s,9H)。ESI[M+H]=653.1
化合物N4
1H NMR(400MHz,DMSO-d6)δ=9.58(br s,1H),9.02(s,1H),8.27(s,1H),7.93-7.79(m,4H),7.64(br d,J=8.4Hz,3H),7.57(s,3H),7.41(br d,J=8.2Hz,1H),7.11(s,1H),6.51(br s,1H),4.40(br d,J=5.6Hz,1H),4.18(br d,J=4.2Hz,2H),1.18(br d,J=6.5Hz,6H),1.08(s,9H)。ESI[M+H]=627.2
化合物N5
1H NMR(400MHz,DMSO-d6)δ=11.89(br s,1H),9.57(br s,1H),9.25(s,1H),8.28(s,1H),7.93-7.77(m,4H),7.64(br d,J=8.3Hz,3H),7.42(br d,J=8.4Hz,1H),7.10(s,1H),6.94(br s,2H),6.69(brt,J=5.0Hz,1H),4.48-4.20(m,3H),1.18(br d,J=6.5Hz,6H),1.08(s,9H)。ESI[M+H]=627.1
化合物N6
1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.4Hz,1H),7.92(d,J=8.6Hz,2H),7.86(s,1H),7.70(dd,J=2.4,8.4Hz,1H),7.64(s,1H),7.57(d,J=8.6Hz,2H),7.43(d,J=8.4Hz,1H),7.02(s,1H),4.53(br s,1H),4.36(s,2H),1.24(d,J=6.6Hz,6H),1.12(s,9H)。ESI[M+H]=627.2
实施例15
流程15.1
化合物145的制备
通用方法A,N-[4-[5-[4-[(叔丁氧基羰基氨基)甲基]-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯。ESI[M+H]=603.3
化合物146的制备
在15℃下将N-[4-[5-[4-[(叔丁氧基羰基氨基)甲基]-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(2.20g,3.65mmol,1.00eq.)在HCl/MeOH(20.00mL)中的溶液搅拌1小时并随后浓缩,得到N-[4-[5-[4-(氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(2.00g,粗品,HCl),为黄色固体。
化合物147的制备
向N-[4-[5-[4-(氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(40.00mg,74.20μmol,1.00eq.,HCl)、1-叔丁氧基羰基哌啶-4-甲酸(25.52mg,111.30μmol,1.50eq.)和DIEA(47.95mg,371.00μmol,64.62ul,5.00eq.)在DCM(2.00mL)中的混合物中加入HATU(36.68mg,96.46μmol,1.30eq.)。将混合物在20℃下搅拌1小时,随后用0.5N HCl(5mL)、饱和Na2CO3水溶液(5mL)洗涤,经Na2SO4干燥,过滤并浓缩,得到4-[[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙氧基羰基氨基)苯基]噻唑-5-基]苯基]甲基氨基甲酰基]哌啶-1-甲酸叔丁酯(50mg,粗品),为黄色油。ESI[M+H]=714.1
化合物O1
化合物O1由中间体化合物147通过通用方法E(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.09(s,1H),7.91-7.86(m,3H),7.60-7.50(m,4H),4.98(td,J=6.0,12.5Hz,1H),4.54-4.46(m,2H),3.46(br d,J=13.2Hz,2H),3.11-3.01(m,2H),2.69-2.58(m,1H),2.11-1.89(m,4H),1.31(d,J=6.6Hz,6H),1.07(s,9H)。ESI[M+H]=614.2
以下化合物通过使用类似于用于合成化合物O1的程序使中间体146与不同的酸反应来合成。
化合物O2
1H NMR(400MHz,甲醇-d4)δ=8.11(s,1H),7.92-7.81(m,3H),7.60-7.46(m,4H),5.02-4.92(m,1H),4.50(s,2H),3.68(t,J=6.1Hz,2H),3.35(s,3H),2.52(t,J=5.9Hz,2H),1.31(d,J=6.1Hz,6H),1.09(s,9H)。ESI[M+H]=589.2
化合物O3
1H NMR(400MHz,甲醇-d4)δ=8.12(s,1H),7.96-7.83(m,3H),7.59(br d,J=8.2Hz,3H),7.55-7.49(m,1H),5.07-4.91(m,1H),4.51(s,2H),3.86(t,J=6.2Hz,2H),2.50(t,J=6.2Hz,2H),1.32(d,J=6.1Hz,6H),1.11(s,9H)。ESI[M+H]=575.1
化合物O4
1H NMR(400MHz,甲醇-d4)δ=8.10(s,1H),7.92-7.85(m,3H),7.62-7.43(m,4H),7.35-7.18(m,5H),4.97(td,J=6.2,12.6Hz,1H),4.47(s,2H),3.34-3.24(m,2H),1.31(d,J=6.1Hz,6H),1.07(s,9H)。ESI[M+H]=621.1
化合物O5
1H NMR(400MHz,甲醇-d4)δ=8.81(br d,J=6.0Hz,2H),8.07(br d,J=6.0Hz,2H),8.01(s,1H),7.93-7.87(m,3H),7.63-7.51(m,4H),5.00(td,J=6.2,12.5Hz,1H),4.55(s,2H),4.02(s,2H),1.34(d,J=6.2Hz,6H),1.07(s,9H)。ESI[M+H]=622.2
化合物O6
1H NMR(400MHz,甲醇-d4)δ=8.85(s,1H),8.78(d,J=5.8Hz,1H),8.57(br d,J=7.9Hz,1H),8.11-7.98(m,2H),7.88(d,J=7.9Hz,3H),7.57(br d,J=8.1Hz,3H),7.54-7.49(m,1H),5.03-4.93(m,1H),4.53(s,2H),3.93(s,2H),1.31(d,J=6.1Hz,6H),1.05(s,9H)。ESI[M+H]=622.2
化合物O7
1H NMR(400MHz,甲醇-d4)δ=8.88(br d,J=5.3Hz,2H),8.20(s,1H),8.14(d,J=5.5Hz,2H),7.93-7.85(m,3H),7.67(br d,J=7.7Hz,1H),7.61-7.54(m,3H),4.98(td,J=6.2,12.4Hz,1H),4.73(s,2H),1.31(d,J=6.2Hz,6H),1.09(s,9H)。ESI[M+H]=608.2
化合物O8
1H NMR(400MHz,甲醇-d4)δ=9.29(s,1H),9.21(s,2H),8.20(s,1H),7.88(br d,J=6.0Hz,3H),7.67(br d,J=7.8Hz,1H),7.62-7.52(m,3H),5.06-4.92(m,1H),4.75-4.69(m,2H),1.31(d,J=6.1Hz,6H),1.09(s,9H)。ESI[M+H]=609.1
实施例16
除非另有说明,否则以下化合物通过通用方法C(实施例1中所示)通过使中间体146与不同的酰氯反应合成。
化合物P1
1H NMR(400MHz,甲醇-d4)δ=8.13(s,1H),7.96-7.86(m,3H),7.65-7.51(m,4H),5.00(td,J=6.2,12.3Hz,1H),4.50(s,2H),2.32(q,J=7.6Hz,2H),1.34(d,J=6.2Hz,6H),1.20(brt,J=7.6Hz,3H),1.15-1.09(m,9H)。ESI[M+H]=559.2
化合物P2
1H NMR(400MHz,甲醇-d4)δ=8.11(s,1H),7.95-7.83(m,3H),7.63-7.47(m,4H),5.00-4.95(m,1H),4.47(s,2H),2.68-2.43(m,1H),1.32(br d,J=6.2Hz,6H),1.17(br d,J=6.8Hz,6H),1.09(s,9H)。ESI[M+H]=573.2
化合物P3
1H NMR(400MHz,甲醇-d4)δ=8.11(br s,1H),7.89(br s,3H),7.65-7.44(m,4H),5.00-4.94(m,1H),4.47(s,2H),1.32(br d,J=6.0Hz,6H),1.24(s,9H),1.09(s,9H)。ESI[M+H]=587.3
化合物P4
1H NMR(400MHz,DMSO-d6)δ=9.88(br s,1H),9.23(br s,1H),8.05(br s,1H),7.88(br dd,J=9.2,18.6Hz,5H),7.67-7.43(m,7H),7.22(s,1H),4.98-4.86(m,1H),4.58(br s,2H),1.27(br d,J=6.2Hz,6H),1.02(s,9H)。ESI[M+H]=607.2
化合物P5
1H NMR(400MHz,甲醇-d4)δ=8.23(br s,1H),7.97-7.79(m,3H),7.67(br d,J=7.5Hz,1H),7.62-7.52(m,3H),4.97(br dd,J=6.0,12.1Hz,1H),4.39(s,2H),2.96(s,3H),1.32(br d,J=6.0Hz,6H),1.12(s,9H)。ESI[M+H]=581.2
化合物P6
1H NMR(400MHz,甲醇-d4)δ=8.10(br s,1H),7.96-7.78(m,5H),7.69-7.45(m,6H),7.45-7.35(m,1H),5.02-4.94(m,1H),4.20(s,2H),1.32(br d,J=5.5Hz,6H),1.10(s,9H)。ESI[M+H]=643.2
化合物P7
1H NMR(400MHz,甲醇-d4)δ=8.12(br s,1H),7.94-7.85(m,3H),7.65-7.46(m,4H),5.03-4.94(m,1H),4.40(br s,2H),3.68(s,3H),1.32(br d,J=6.0Hz,6H),1.12(s,9H)。ESI[M+H]=561.2
化合物P8
1H NMR(400MHz,甲醇-d4)δ=8.12(br s,1H),7.95-7.84(m,3H),7.63-7.46(m,4H),5.05-4.93(m,1H),4.39(br s,2H),4.12(q,J=6.7Hz,2H),1.32(br d,J=6.2Hz,6H),1.26(br t,J=6.8Hz,3H),1.11(s,9H)。ESI[M+H]=575.2
化合物P9
1H NMR(400MHz,甲醇-d4)δ=8.13(br s,1H),7.89(br d,J=5.3Hz,3H),7.65–7.47(m,4H),4.97(br dd,J=6.1,12.5Hz,2H),4.39(br s,2H),1.32(br d,J=6.0Hz,6H),1.25(br d,J=6.0Hz,6H),1.11(br s,9H)。ESI[M+H]=589.2
实施例17
化合物Q1
在0℃下向N-[4-[5-[4-(氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(75.00mg,69.56μmol,1.00eq.,HCl)在DCM(3.00mL)中的溶液中加入DMAP(849.80ug,6.96μmol,0.10eq.)和Ac2O(8.52mg,83.47μmol,7.82ul,1.20eq.)。将混合物在15℃下搅拌0.5小时,随后浓缩并且残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[4-(乙酰氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(5.27mg,9.67μmol,13.90%收率,99.9%纯度),为黄色固体。1H NMR(400MHz,甲醇-d4)δ=8.11(s,1H),7.92-7.86(m,3H),7.63-7.50(m,4H),4.98(quind,J=6.3,12.4Hz,1H),4.48(s,2H),2.03(s,3H),1.32(d,J=6.2Hz,6H),1.11(s,9H)。ESI[M+H]=545.2
化合物Q2
向N-[4-[5-[4-(氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(20.00mg,37.10μmol,1.00eq.,HCl)在THF(3.00mL)中的溶液中加入K2CO3(10.26mg,74.20μmol,2.00eq.)和氯甲酸苄酯(31.64mg,185.50μmol,26.37ul,5.00eq.)。将混合物在20℃下搅拌2小时,随后浓缩并且残余物通过酸性制备型HPLC纯化,得到N-[4-[5-[4-(苄基氧基羰基氨基甲基)-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]氨基甲酸异丙酯(17.54mg,27.27μmol,73.50%收率,99%纯度),为灰色固体。1H NMR(400MHz,甲醇-d4)δ=8.14(br s,1H),7.89(br s,3H),7.66-7.45(m,4H),7.42-6.99(m,5H),5.12(br s,2H),4.97(br dd,J=6.3,12.2Hz,1H),4.42(br s,2H),1.32(br d,J=6.0Hz,6H),1.10(brs,9H)。ESI[M+H]=637.2
流程17.1
化合物164的制备
通用方法A,5-(3-苄基-1-甲基脲基)-N-(叔丁基)-2-(2-(4-硝基苯基)噻唑-5-基)苯磺酰胺。ESI[M+H]=580.3
化合物165的制备
通用方法B,2-(2-(4-氨基苯基)噻唑-5-基)-5-(3-苄基-1-甲基脲基)-N-(叔丁基)苯磺酰胺。ESI[M+H]=550.0
化合物Q3
化合物Q3由中间体化合物165通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.12(s,1H),7.98-7.92(m,3H),7.63-7.59(m,4H),7.33(d,J=4.4Hz,4H),7.28-7.21(m,1H),4.56(br s,1H),4.40(s,2H),3.37(s,3H),1.27(d,J=6.5Hz,6H),1.13(s,9H)。ESI[M+H]=651.2
流程17.2
化合物166的制备
通用方法A,5-(3-苄基-1,3-二甲基脲基)-N-(叔丁基)-2-(2-(4-硝基苯基)噻唑-5-基)苯磺酰胺。ESI[M+H]=593.9
化合物167的制备
通用方法B,2-(2-(4-氨基苯基)噻唑-5-基)-5-(3-苄基-1,3-二甲基脲基)-N-(叔丁基)苯磺酰胺。ESI[M+H]=564.1
化合物Q4
化合物Q4由中间体化合物167通过通用方法G(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=7.98-7.86(m,4H),7.58(br d,J=8.6Hz,2H),7.51(d,J=8.4Hz,1H),7.40-7.31(m,3H),7.30-7.22(m,3H),4.53(br s,1H),4.45(s,2H),3.28(s,3H),2.65(s,3H),1.24(d,J=6.6Hz,6H),1.08(s,9H)。ESI[M+H]=665.2
流程17.3
化合物182的制备
通用方法C,(4-(5-(4-乙酰氨基-2-(N-(叔丁基)氨磺酰基)苯基)噻唑-2-基)苯基)氨基甲酸4-硝基苯酯。ESI[M+H]=610.2
化合物183的制备
通用方法F,N-(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-(3-异丙基脲基)苯基)噻唑-5-基)苯基)乙酰胺。ESI[M+H]=530.2
化合物184的制备
在30℃下将N-[3-(叔丁基氨磺酰基)-4-[2-[4-(异丙基氨基甲酰基氨基)苯基]噻唑-5-基]苯基]乙酰胺(100mg,188.80μmol,1eq.)在HCl/MeOH(4M,2mL)中的混合物搅拌1小时。将混合物浓缩,随后用EtOAc(50mL)稀释并用饱和Na2CO3水溶液(5mL)洗涤。有机层经Na2SO4干燥,过滤并浓缩,得到1-[4-[5-[4-氨基-2-(叔丁基氨磺酰基)苯基]噻唑-2-基]苯基]-3-异丙基-脲(0.08g,粗品),为黄色固体。ESI[M+H]=488.2
化合物Q5
化合物Q5由中间体化合物184通过通用方法C(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=2.2Hz,1H),7.83-7.91(m,3H),7.73(dd,J=8.4Hz,J=2.1Hz,1H),7.50-7.57(m,2H),7.48(d,J=8.3Hz,1H),4.97-5.06(m,1H),3.92(quin,J=6.5Hz,1H),1.34(d,J=6.2Hz,6H),1.21(d,J=6.5Hz,6H),1.16(s,9H)。ESI[M+H]=574.2
流程17.4
化合物185的制备
通用方法C,(3-(N-(叔丁基)氨磺酰基)-4-(2-(4-(3-异丙基脲基)苯基)噻唑-5-基)苯基)氨基甲酸4-硝基苯酯。ESI[M+H]=653.1
化合物Q6
化合物Q6由中间体化合物185通过通用方法F(实施例1中所示)制备。
1H NMR(400MHz,甲醇-d4)δ=8.25(d,J=1.8Hz,1H),7.79–7.87(m,3H),7.66(dd,J=8.3Hz,J=1.3Hz,1H),7.49(br d,J=8.8Hz,2H),7.41(d,J=8.3Hz,1H),3.90(br dd,J=10.1Hz,J=6.1Hz,2H),1.19(dd,J=6.1Hz,J=2.2Hz,12H),1.12(s,9H)。ESI[M+H]=573.2
实施例18
通用流程18.1
化合物187的制备
通用方法J,3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺。ESI[M+H]=234.2
化合物188的制备
通用方法H,4-(5-溴噻唑-2-基)-3-甲基-苯胺。ESI[M+H]=269.0/271.0
化合物189的制备
通用方法C,N-[4-(5-溴噻唑-2-基)-3-甲基-苯基]氨基甲酸异丙酯。ESI[M+H]=355.0/357.0
以下化合物使用类似于用于中间体化合物189的合成中的程序用不同的溴化物来合成。
1H NMR(400MHz,甲醇-d4)δ=7.75(s,1H),7.72(s,1H),7.68–7.65(m,2H),4.97(spt,J=6.3Hz,1H),5.03–4.91(m,1H),2.31(s,3H),1.31(d,J=6.2Hz,6H)。ESI[M+H]=355.0/357.0
ESI[M+H]=370.7/372.7
ESI[M+H]=358.9/360.9
ESI[M+H]=358.8/360.8
通用流程18.2
化合物195的制备
通用方法C,(4-溴-3-甲氧基苯基)氨基甲酸异丙酯。ESI[M+H]=288.0/290.0
化合物196的制备
通用方法J,N-[3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]氨基甲酸异丙酯。ESI[M+H]=336.2
化合物197的制备
通用方法H,N-[4-(5-溴噻唑-2-基)-3-甲氧基-苯基]氨基甲酸异丙酯。ESI[M+H]=371.0/373.0
除非另有说明,否则以下化合物通过通用方法A(实施例1中所示)使用中间体化合物M6作为左手侧,使用不同的溴化物作为右手侧来合成。
化合物R1
1H NMR(400MHz,甲醇-d4)δ=8.40(d,J=2.0Hz,1H),7.94(s,1H),7.78–7.62(m,2H),7.52–7.39(m,3H),5.09–4.95(m,2H),2.59(s,3H),1.34(dd,J=4.4,6.4Hz,12H),1.17(s,9H)。ESI[M+H]=589.2
化合物R2
1H NMR(400MHz,甲醇-d4)δ=8.37(d,J=2.2Hz,1H),7.86(s,1H),7.82–7.74(m,2H),7.72–7.63(m,2H),7.45(d,J=8.3Hz,1H),5.03–4.94(m,2H),2.33(s,3H),1.32(d,J=6.1Hz,12H),1.13(s,9H)。ESI[M+H]=589.2
化合物R3
1H NMR(400MHz,甲醇-d4)δ=8.37(d,J=2.2Hz,1H),8.05(d,J=8.4Hz,1H),7.86(s,1H),7.69(dd,J=2.0,8.4Hz,1H),7.59(d,J=1.8Hz,1H),7.52–7.41(m,2H),5.05–4.94(m,2H),3.97(s,3H),1.32(dd,J=1.1,6.2Hz,12H),1.14(s,9H)。ESI[M+H]=605.3
化合物R4
1H NMR(400MHz,甲醇-d4)δ=8.37(d,J=2.0Hz,1H),8.08(brt,J=8.2Hz,1H),7.87(s,1H),7.78–7.67(m,3H),7.44(d,J=8.4Hz,1H),5.05–4.95(m,2H),1.32(dd,J=1.5,6.4Hz,12H),1.13(s,9H)。ESI[M+H]=593.2
化合物R5
1H NMR(400MHz,DMSO-d6)δ=10.10(s,1H),9.92(s,1H),8.35(d,J=1.5Hz,1H),8.20(d,J=8.8Hz,1H),7.87(s,1H),7.67(dd,J=1.5,8.3Hz,1H),7.53(s,1H),7.44(d,J=8.3Hz,1H),7.16(br d,J=7.8Hz,1H),7.08(s,1H),4.94(qd,J=6.3,9.6Hz,2H),3.96(s,3H),1.28(d,J=6.4Hz,12H),1.09(s,9H)。ESI[M+H]=605.2
使用中间体化合物M5作为左手侧。
化合物R6
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=1.8Hz,1H),7.92(s,1H),7.73(br d,J=8.3Hz,1H),7.66(d,J=8.3Hz,1H),7.50–7.41(m,5H),7.40–7.30(m,3H),5.22(s,2H),4.97(td,J=6.5,12.5Hz,1H),2.56(s,3H),1.31(d,J=6.6Hz,6H),1.14(s,9H)。ESI[M+H]=637.4
化合物R7
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=2.2Hz,1H),8.05(d,J=8.6Hz,1H),7.86(s,1H),7.77–7.68(m,1H),7.60(d,J=1.5Hz,1H),7.53–7.41(m,4H),7.40–7.28(m,3H),5.22(s,2H),5.06–4.94(m,1H),3.98(s,3H),1.32(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=653.1
化合物R8
1H NMR(400MHz,甲醇-d4)δ=8.38(s,1H),8.11–8.03(m,1H),7.87(s,1H),7.78–7.70(m,3H),7.48–7.41(m,3H),7.40–7.29(m,3H),5.22(s,2H),5.00(td,J=6.4,12.5Hz,1H),1.32(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=641.2
化合物R9
1H NMR(400MHz,甲醇-d4)δ=8.39(d,J=2.2Hz,1H),8.10(d,J=8.8Hz,1H),7.97(s,1H),7.75(dd,J=2.2,8.4Hz,1H),7.56(d,J=1.5Hz,1H),7.49–7.41(m,3H),7.41–7.27(m,3H),7.13(dd,J=1.9,8.7Hz,1H),5.22(s,2H),5.06–4.92(m,1H),4.05(s,3H),1.32(d,J=6.2Hz,6H),1.14(s,9H)。ESI[M+H]=653.1
使用中间体化合物M4作为左手侧。
化合物R10
1H NMR(400MHz,甲醇-d4)δ=8.28(d,J=2.2Hz,1H),7.91(s,1H),7.73(dd,J=2.2,8.3Hz,1H),7.66(d,J=8.3Hz,1H),7.47–7.41(m,3H),7.37–7.30(m,4H),7.29–7.21(m,1H),5.00–4.95(m,1H),4.42(s,2H),2.56(s,3H),1.31(d,J=6.1Hz,6H),1.14(s,9H)。ESI[M+H]=636.4
化合物R11
1H NMR(400MHz,DMSO-d6)δ=9.17(s,1H),8.45(s,1H),8.29(d,J=2.2Hz,1H),7.91–7.83(m,2H),7.66(dd,J=2.3,8.4Hz,1H),7.56(d,J=1.7Hz,1H),7.51(dd,J=1.7,8.4Hz,1H),7.42(d,J=8.4Hz,1H),7.38–7.31(m,4H),7.29–7.23(m,1H),7.14(s,1H),6.80(t,J=5.9Hz,1H),4.91(spt,J=6.2Hz,1H),4.34(d,J=5.9Hz,2H),3.91(s,3H),1.26(d,J=6.2Hz,6H),1.09(s,9H)。ESI[M+H]=652.2
化合物R12
1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.2Hz,1H),8.07(brt,J=8.3Hz,1H),7.86(s,1H),7.78–7.69(m,3H),7.43(d,J=8.4Hz,1H),7.36–7.29(m,4H),7.28–7.22(m,1H),5.00(td,J=6.3,12.5Hz,1H),4.41(s,2H),1.32(d,J=6.2Hz,6H),1.13(s,9H)。ESI[M+H]=640.3
化合物R13
1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.2Hz,1H),8.11(d,J=8.8Hz,1H),7.95(s,1H),7.74(dd,J=2.4,8.4Hz,1H),7.55(d,J=1.5Hz,1H),7.44(d,J=8.6Hz,1H),7.38–7.30(m,4H),7.29–7.22(m,1H),7.11(dd,J=1.9,8.7Hz,1H),4.99(td,J=6.2,12.5Hz,1H),4.42(s,2H),4.05(s,3H),1.32(d,J=6.4Hz,6H),1.13(s,9H)。ESI[M+H]=652.2
化合物R14
1H NMR(400MHz,甲醇-d4)δ=8.27(d,J=2.2Hz,1H),8.11(t,J=8.6Hz,1H),7.93(d,J=2.2Hz,1H),7.72(dd,J=2.3,8.3Hz,1H),7.61(br d,J=13.7Hz,1H),7.42(d,J=8.4Hz,1H),7.37–7.31(m,4H),7.29–7.22(m,2H),4.99(td,J=6.2,12.7Hz,1H),4.42(s,2H),1.31(d,J=6.2Hz,6H),1.12(s,9H)。ESI[M+H]=640.1
生物学筛选
实施例19
化合物初步筛选
1.材料和供应
该实验所需的塑料制品和消耗品包括:细胞培养基;蒸发缓冲介质;100%DMSO;96孔U型底无菌培养板;250mL瓶;1.5mL不透明的琥珀色Epi管;Epi管架;300mL储器;25mL储器;25mL血清移液器吸头;5mL血清移液器吸头;P1000移液器吸头;和P200移液器吸头。
该实验所需的设备包括:Viaflo384液体处理器;Eppendorf血清移液器;EppendorfP1000移液器;和EppendorfP200移液器。
Daudi Cell Culture也是该实验所需的。
最后,需要待测试的化合物(例如,本发明的化合物)。
2.程序
所有步骤都在生物安全柜内的无菌环境中进行。
通过在板盖的右上角书写实验编号、板编号、日期和首字母,制备96孔U型底板。使用无菌300ml储器和25ml血清移液器,以25ml增量将蒸发缓冲介质移液至储器中。使用液体处理器,将150μl蒸发缓冲介质从储器中移液至96孔U型底板的A和H行以及1和12列中。计数细胞培养物以获得每毫升的细胞密度和培养物生存力。使用细胞密度信息,使用5mL血清移液器从培养物获得1,000,000个细胞到Epi管内。将来自培养物的细胞密度信息用于计算测定在96孔U形底板中每个可用培养孔的130μl培养基中接种1250个细胞所需的细胞数目和培养基体积。B至F行用于细胞(总共50个孔),G行留作空培养基对照。将计算结果高估10mL以考虑300ml储器中的死体积。一旦计算出培养基体积,就使用25mL血清移液器将适当体积的培养基以25mL增量吸入250mL瓶中。将250ml瓶盖紧,并置于37℃水浴中2分钟。在培养基温热的同时,将10mL新鲜培养基从500mL培养基瓶中吸入无菌的25mL储器中。使用Eppendorf多通道移液器,将130μl培养基从25mL储器中移入96孔U型底板的G行中。一旦250mL瓶的培养基被温热,将所需体积的培养物移入瓶中,并用25mL血清移液器轻轻混合以不产生气泡,然后将瓶的内容物移入新的300mL储器中。使用液体处理器,将130μl培养物从300mL储器移入96孔U型底板的B-F行。一旦加入培养物,将板置于37℃培养箱中直到化合物主板准备就绪。
通过在板盖的右上角写上主板名称来制备两个96孔U型底板。标记一个DMSO主板和另一个培养基主板。从实验室冰箱获得感兴趣的化合物,并放入具有盖子的25孔储存盒中,并将盒放置在一边。在解冻后但在使用前将化合物涡旋。使用自动多通道移液器,将20μl100%DMSO移入DMSO主板的孔B3-B11至G3-G11中。对于主板上的每种化合物,将50μl该化合物移入第2行的适当孔中(参考板图以确定适当孔)。从第2行吸取20μl并与第3行混合,开始制备系列稀释液,重复直至达到第11行。使用液体处理器,将194μl Daudi培养基分配到培养基主板的孔B2-B11至G2-G11中。使用液体处理器,从DMSO主板吸取6μl,并分配到培养基主板中,混合100μl两次。
然后将来自主板的化合物加入培养板。将培养板从培养箱中取出,并放置在生物安全柜内。使用液体处理器,从主板的孔B2-B11至G2-G11吸出20μl,并分配到培养板的孔B2-B11至G2-G11中。对每个培养板继续该设置。一旦培养板获得了它们的20μl的化合物稀释液,将它们放回培养箱中,直到在实验的第7天读取。
筛选数据
表1
Claims (27)
1.由以下结构式表示的化合物:
或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代;
X1、X2、X3和X4独立地是N或CR5,条件是X1、X2、X3和X4中不多于两个是N;
R1是-ORa;-NH2、-N((C1-C5)烷基)2;-NRa(C1-C5)烷基;-NRa-(C3-C6)环烷基、-NRa-苯基;-NRa-单环3-7元杂环;-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接)或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R1表示的-(C3-C6)环烷基或由R1表示的基团中的(C3-C6)环烷基任选地被卤素或-ORa取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-(C1-C4)烷基;-NH2、-NO2、-ORa;-(CH2)mC(O)NH2;-(CH2)mNRaC(O)NH2;-(CH2)mC(O)NRa(C1-C4)烷基;-(CH2)mC(O)NRa(C2-C4)烯基;-(CH2)mC(O)NRa-(C3-C6)环烷基;-(CH2)mC(O)NRa-苯基;-(CH2)mC(O)NRa-单环3-7元杂环;-(CH2)mC(O)NRa-5-10元杂芳环;-(CH2)mNRa(C1-C4)烷基;-(CH2)mNRa(C2-C4)烯基;-(CH2)mNRa-(C3-C6)环烷基;-(CH2)mNRa-苯基;-(CH2)mNRa-单环3-7元杂环;-(CH2)mNRa-5-10元杂芳环;-(CH2)mNRaC(O)(C1-C4)烷基;-(CH2)mNRaC(O)(C2-C4)烯基;-(CH2)mNRaC(O)-(C3-C6)环烷基;-(CH2)mNRaC(O)-苯基;-(CH2)mNRaC(O)-单环3-7元杂环;-(CH2)mNRaC(O)-5-10元杂芳环;-(CH2)mNRaC(O)O(C1-C4)烷基;-(CH2)mNRaC(O)O(C2-C4)烯基;-(CH2)mNRaC(O)O-(C3-C6)环烷基;-(CH2)mNRaC(O)O-苯基;-(CH2)mNRaC(O)O-单环3-7元杂环;-(CH2)mNRaC(O)O-5-10元杂芳环;-(CH2)mNRaC(O)NRa(C1-C4)烷基;-(CH2)mNRaC(O)NRa(C2-C4)烯基;-(CH2)mNRaC(O)NRa-(C3-C6)环烷基;-(CH2)mNRaC(O)NRa-苯基;-(CH2)mNRaC(O)NRa-单环3-7元杂环;-(CH2)mNRaC(O)NRa-5-10元杂芳环;-(CH2)mNRaC(S)(C1-C4)烷基;-(CH2)mNRaC(S)(C2-C4)烯基;-(CH2)mNRaC(S)-(C3-C6)环烷基;-(CH2)mNRaC(S)-苯基;-(CH2)mNRaC(S)-单环3-7元杂环;-(CH2)mNRaC(S)-5-10元杂芳环;-(CH2)mNRaC(S)NRa(C1-C4)烷基;-(CH2)mNRaC(S)NRa(C2-C4)烯基;-(CH2)mNRaC(S)NRa-(C3-C6)环烷基;-(CH2)mNRaC(S)NRa-苯基;-(CH2)mNRaC(S)NRa-单环3-7元杂环;-(CH2)mNRaC(S)NRa-5-10元杂芳环;-(CH2)mNRaS(O)2-(C1-C4)烷基;-(CH2)mNRaS(O)2-(C2-C4)烯基;-(CH2)mNRaS(O)2-(C3-C6)环烷基;-(CH2)mNRaS(O)2-苯基;-(CH2)mNRaS(O)2-单环3-7元杂环;-(CH2)mNRaS(O)2-5-10元杂芳环;单环3-10元杂环;5-10元杂芳环;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R2表示的-(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-ORa或-N3取代;其中由R2表示的杂环或由R2表示的基团中的杂环任选地被=O、-CH3、卤代甲基、卤代甲氧基、苯基或苄基取代;其中由R2表示的杂芳环或由R2表示的基团中的杂芳环任选地被卤素、-CH3、卤代甲基或卤代甲氧基取代;
R4是-H;-NH2;-NO2;-NRa(C1-C4)烷基;-NRaC(O)(C1-C4)烷基;-NRaC(O)O(C1-C4)烷基;-NRaC(O)NRa(C1-C4)烷基;-NRaC(S)NRa(C1-C4)烷基;-NRaS(O)2(C1-C4)烷基;-NRaS(O)2NRa(C1-C4)烷基;-NRaS(O)2-苯基;-OC(O)NRa(C1-C4)烷基;-NRaC(S)O(C1-C4)烷基;-NRa-单环5或6元含氮杂芳环;-NRaC(S)-N-单环4-7元含氮杂环;-NRaC(S)NRa-单环3-7元杂环;-NRaC(S)NRa-单环5或6元含氮杂芳环;单环5或6元含氮杂环;或任选地被=O或-NRa(C1-C4)烷基取代的-NRa-(C3-C6)环烯基;
其中由R4表示的(C1-C4)烷基或在由R4表示的基团中的(C1-C4)烷基任选地被-ORa、苯基、-C(O)NRaRa或-NRaRa取代;其中由R4表示的杂环或在由R4表示的基团中的杂环任选地被-CH3、卤代甲基、卤代甲氧基或-ORa取代;
各R5独立地是-H、-(C1-C4)烷基、-O(C1-C4)烷基、卤素、-CN、卤代甲基、卤代甲氧基、-OCH2CH2R1、-C(O)O(C1-C4)烷基、-S(O)2NH2或-SO2NRa(C1-C4)烷基;
各Ra独立地是-H或-CH3;
m是0或1。
4.权利要求1-3中任一项的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代;
R1是-NH2、-NRa(C1-C5)烷基、-NRa-(C3-C6)环烷基、-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接)或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R1表示的-(C3-C6)环烷基或由R1表示的基团中的(C3-C6)环烷基任选地被-ORa取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-(C1-C4)烷基;-(CH2)mC(O)NH2;-(CH2)mC(O)NRa(C1-C4)烷基;-ORa;-(CH2)mNRaC(O)NRaRa;-(CH2)mNRa(C1-C4)烷基;-(CH2)mNRaC(O)(C1-C4)烷基;-(CH2)mNRaC(O)O(C1-C4)烷基;-(CH2)mNRaC(O)O(C2-C4)烯基;-(CH2)mNRaC(O)NRa(C1-C4)烷基;-(CH2)mNRaC(O)-(C3-C6)环烷基;-(CH2)mNRaC(O)NRa-(C3-C6)环烷基;-(CH2)mNRaC(O)-苯基;-(CH2)mNRaC(O)O-苯基;-(CH2)mNRa-单环3-7元杂环;-(CH2)mNRa-单环5-6元杂芳环;-(CH2)mNRaC(O)-单环3-7元杂环;-(CH2)mNRaC(O)-单环5-6元杂芳环;-(CH2)mNRaC(O)O-单环3-7元杂环;-(CH2)mNRaC(O)O-单环5-6元杂芳环;单环3-7元杂环;单环5-6元杂芳环;-(CH2)m-NRaC(O)NRa-单环3-7元杂环;-(CH2)m-NRaC(O)NRa-单环5-6元杂芳环;-NRaC(S)NRa(C1-C4)烷基;-(CH2)mNRaS(O)2-(C1-C4)烷基;-CH2NRaS(O)2-苯基;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa、-NRaRa、-(C3-C6)环烷基、苯基、单环3-7元杂环或单环5-6元杂芳环取代;其中由R2表示的-(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-ORa或-N3取代;其中由R2表示的单环3-7元杂环或由R2表示的基团中的单环3-7元杂环任选地被=O、-CH3、卤代甲基、卤代甲氧基、苯基或苄基取代;其中由R2表示的5-6元杂芳环或由R2表示的基团中的5-6元杂芳环任选地被卤素、-CH3、卤代甲基或卤代甲氧基取代;
R3,当存在时,是-H、卤素或-SO2NRa(C1-C4)烷基;
R4是-H;-NH2;-NRa(C1-C4)烷基;-NRaC(O)(C1-C4)烷基;-NRaC(O)O(C1-C4)烷基;-NRaC(O)NRa(C1-C4)烷基;-NRaC(S)NRa(C1-C4)烷基;-NRaS(O)2(C1-C4)烷基;-NRaS(O)2NRa(C1-C4)烷基;-NRaS(O)2-苯基;-OC(O)NRa(C1-C4)烷基;或任选被甲基取代的单环5或6元含氮杂环;其中由R4表示的(C1-C4)烷基或在由R4表示的基团中的(C1-C4)烷基任选地被-ORa或苯基取代;
各Ra独立地是-H或-CH3;和
m是0或1。
5.权利要求4的化合物或其药学上可接受的盐,其中:
R1是-NH2、-NHCH3、-NHCH2CH3、-N(CH3)2、-NHC(CH3)3、-NHCH2CH2NH2、-NHCH2CH2NHCH3、-NHCH2CH2N(CH3)2、-NHCH2CH2CH2NH2、-NHCH2CH2CH2NHCH3、-NHCH2CH2CH2N(CH3)2、-NHCH2C(O)OCH3、-NHCH(CH(CH3)2)C(O)OCH3、-NHCH2-苯基、-NHCH2-吡啶基、-NHCH2CH2OH、-NHCH2CH2OCH3、-NHCH2C(CH3)2CH2OH、-NHCH(CH3)CH2OH、-NHCH2CH2OCH2CH2OH、-NHCH(CH2OH)C(O)OCH3、-NHCH(CH2OH)2、-NH-环己基(其中环己基任选地被-OH取代);N-吗啉基、N-哌啶基、N-哌嗪基、N-吡咯烷基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-CH2OH、-CH2NHC(O)CH3、-CH2NHC(O)OCH3、-CH2NHC(O)CH2CH3、-CH2NHC(O)CH2CH2OH、-CH2NHC(O)CH2CH2OCH3,-CH2NHC(O)OCH2CH3、-CH2NHC(O)CH(CH3)2、-CH2NHC(O)OCH(CH3)2、-CH2NHC(O)C(CH3)3、-CH2NHC(O)-苯基、-CH2NHC(O)-哌啶基、-CH2NHC(O)-吡啶基、-CH2NHC(O)-嘧啶基、-CH2NHC(O)CH2-苯基、-CH2NHC(O)CH2-吡啶基、-CH2NHC(O)OCH2-苯基、-CH2NHS(O)2CH3、-CH2NHS(O)2-苯基、-CF3、-C(O)NH2、-C(O)NHCH3、-C(O)NHCH2-苯基、-OH、-NHCH2CH3、-NHCH2CF3、-NHCH(CH3)CF3、-NHCH2CH(OH)CH3、被甲基取代的-NH-氧杂环丁烷基、-NHC(O)CH3、-NHC(O)CH2CH3、-N(CH3)C(O)CH3、-NHC(O)CH(CH3)2、-NHC(O)-环丙基、-NHC(O)-吡咯烷基、-NHC(O)-苯基、-NHC(O)-CH2-CH2-苯基、-NHC(O)NH-CH2CH2NH2、-NHC(O)N(CH3)2、-NHC(O)NH-CH2CH2NHCH3、-NHC(O)NH-氮杂环丁烷基、-NHC(O)NH-环己基(其中环己基任选地被-NH2或-N(CH3)2取代)、-NHC(O)NHCH2-氮杂环庚烷基、-NHC(O)NHCH2-氮杂环丁烷基、-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代)、-NHC(O)NH-CH(CH3)-苯基、-NHC(O)N(CH3)-CH2-苯基、-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基、-NHC(O-NH-CH2-咪唑基、-NHC(O)NH-CH2-吡唑基、-NHC(O)NH-CH2-吡啶基、-NHC(O)NH-CH2-嘧啶基、-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代)、-NHC(O)N(CH3)-CH2-吡咯烷基、-NHC(O)NH-CH2-噻唑基、-NHC(O)OCH3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH3、-NHC(O)OCH2CH2NH2、-NHC(O)OCH2C(CH3)=CH2、-NHC(O)OCH=CH(CH3)、-NHC(O)OCH2CH2OH、-NHC(O)OCH2CH2OCH3、-NHC(O)O-CH2-环己基、-NHC(O)O-CH2-咪唑基、-NHC(O)O-CH2-苯基、NHC(O)O-CH(CH3)-苯基、-NHC(O)O-CH2-CH2-苯基、-NHC(O)O-CH2-吡啶基、-NHC(O)O-CH2-吡咯烷基、-NHC(O)O-CH2-CH2-噻唑基、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-NH-噻唑基、-NH-咪唑基(被甲基取代)、-NHS(O)2CH3、-NHS(O)2-苯基、-NHS(O)2-CH2-苯基、-N(CH3)S(O)2CH3、咪唑基、吡唑基、三唑基、任选地被苄基取代的任选地被甲基、苯基或苄基取代的任选地被苄基取代的
R3是-H、-F或-SO2NHC(CH3)3;
R4是-H、-NH2、-NHCH2CH(OH)CH3、-NHCH2C(CH3)2OH、-NHC(O)CH3、-NHC(O)CH2CH(CH3)2、-NHC(O)OCH3、-NHC(O)OC(CH3)3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、、-NHC(O)OCH2CH(CH3)2、-NHC(O)NHCH(CH3)2、-NHC(O)N(CH3)CH(CH3)2、-N(CH3)C(O)NHCH(CH3)2、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-NHS(O)2CH3、-NHS(O)2CH2CH3、-NHS(O)2CH2CH2OCH3、-NHS(O)2-苯基、-NHS(O)2NHCH3、-OC(O)NHCH(CH3)2或任选地被一个或两个甲基取代的
6.权利要求4的化合物或其药学上可接受的盐,其中:
R1是-NH(C1-C4)烷基;-N-单环5或6元含氮杂环(其中杂环的氮原子与硫原子连接);或-N-5-8元含氮桥接双环杂环基(其中桥接双环杂环基的氮原子与硫原子连接);
R2是-H;-CH2ORa;-C(O)NRaRa;-ORa;-(CH2)mNHC(O)(C1-C4)烷基;-NHC(O)NRaRa;-NH(C1-C4)烷基;-NHC(O)(C1-C4)烷基;-NHC(O)NH(C1-C4)烷基;-NHC(O)O(C1-C4)烷基;-NHC(O)O(C2-C4)烯基;-NHC(O)-(C3-C6)环烷基;-NHC(O)OCH2--C3-C6)环烷基;-NHC(O)NH-(CH2)n-(C3-C6)环烷基;-NRaC(O)-(CHRa)n-苯基;-NRaC(O)O-(CHRa)n-苯基;-NRaC(O)NRa-(CHRa)n-苯基;-NRaC(S)NRa-(CH2)-苯基;任选地被-CH3取代的-NH-单环3-7元杂环;-NH-单环5-6元杂芳环;-NHC(O)-单环3-7元杂环;-NHC(O)-单环5-6元杂芳环;-(CH2)mNHC(O)-(CH2)n-单环5或6元含氮杂环或杂芳环;任选地被-CH3取代的-NHC(O)O-(CH2)n-单环5或6元含氮杂环或杂芳环;单环5或6元含氮杂芳环;-NRaC(O)NRa-(CH2)n-单环3-7元杂环;-NRaC(O)NRa-(CH2)n-单环5或6元含氮杂芳环;-NRaC(S)NRa(C1-C4)烷基;-NRaC(S)NRa-(CHRa)n-苯基;-NRaS(O)2-(C1-C4)烷基;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被卤素、-ORa或-NRaRa取代;其中由R2表示的(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被-NRaRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被卤素、-ORa或-N3取代;
R3是-H或卤素;
R4是-H、-NRaC(O)O(C1-C4)烷基、-OC(O)NRa(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基,任选地被苯基取代;
各Ra独立地是-H或-CH3;
m是0或1;和
n是0、1或2。
7.权利要求6的化合物或其药学上可接受的盐,其中:
R1是-N(CH3)2、-NHC(CH3)3、-N-哌嗪基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-CH2OH、-CH2NHC(O)CH(CH3)2、-CH2NHC(O)-吡啶基、-CH2NHC(O)CH2-吡啶基、-C(O)NH2、-C(O)NHCH3、-OH、-NHCH2CH3、-NHCH2CF3、-NHCH(CH3)CF3、-NHCH2CH(OH)CH3、被甲基取代的-NH-氧杂环丁烷基、-NHC(O)CH3、-NHC(O)CH2CH3、-NHC(O)CH(CH3)2、-NHC(O)-环丙基、-NHC(O)-吡咯烷基、-NHC(O)-苯基、-NHC(O)-CH2-CH2-苯基、-NHC(O)NH-CH2CH2NH2、-NHC(O)N(CH3)2、-NHC(O)NH-CH2CH2NHCH3、-NHC(O)NH-氮杂环丁烷基、-NHC(O)NH-环己基(其中环己基任选地被-NH2或-N(CH3)2取代)、-NHC(O)NHCH2-氮杂环庚烷基、-NHC(O)NHCH2-氮杂环丁烷基、-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代)、-NHC(O)NH-CH(CH3)-苯基、-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基、-NHC(O)NH-CH2-吡啶基、-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代)、-NHC(O)N(CH3)-CH2-吡咯烷基、-NHC(O)OCH3、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH3、-NHC(O)OCH2CH2NH2、-NHC(O)OCH2C(CH3)=CH2、-NHC(O)OCH=CH(CH3)、-NHC(O)OCH2CH2OH、-NHC(O)OCH2CH2OCH3、-NHC(O)O-CH2-环己基、-NHC(O)O-CH2-苯基、-NHC(O)O-CH(CH3)-苯基、-NHC(O)O-CH2-CH2-苯基、-NHC(O)O-CH2-吡啶基、-NHC(O)O-CH2-吡咯烷基、-NHC(O)O-CH2-CH2-噻唑基、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基、-N(CH3)S(O)2CH3、咪唑基、吡唑基、三唑基;
R3是-H或-F;
R4是-H、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2、-NHC(O)OCH2CH(CH3)2、-NHC(S)NHCH(CH3)2、-NHC(S)NHCH2-苯基或-OC(O)NHCH(CH3)2。
8.权利要求4的化合物或或其药学上可接受的盐,其中:
R1是-NH(C1-C4)烷基或7-氮杂二环[2.2.1]庚烷基;
R2是-H、-NHC(O)(C1-C4)烷基;-NHC(O)O(C1-C4)烷基;-NHC(O)O(C2-C4)烯基;-NHC(O)OCH2-(C3-C6)环烷基;-NHC(O)NH-(CH2)n-(C3-C6)环烷基;-NRaC(O)-(CHRa)n-苯基;-NRaC(O)O-(CHRa)n-苯基;-NRaC(O)NRa-(CHRa)n-苯基;-NRaC(S)NRa-(CHRa)n-苯基;被-CH3任选取代的-NHC(O)O-(CH2)n-单环5或6元含氮杂环或杂芳环;-NRaC(O)NRa-(CH2)n-单环5或6元含氮杂环或杂芳环;
其中由R2表示的(C1-C4)烷基或由R2表示的基团中的(C1-C4)烷基任选地被-ORa取代;其中由R2表示的(C3-C6)环烷基或由R2表示的基团中的(C3-C6)环烷基任选地被-NRa取代;其中由R2表示的苯基或由R2表示的基团中的苯基任选地被-ORa或-N3取代;
R3是-H或卤素;
R4是-H、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;
各Ra独立地是-H或-CH3;和
n是0、1或2。
9.权利要求8的化合物或其药学上可接受的盐,其中:
R1是-N(CH3)2、-NHC(CH3)3或7-氮杂二环[2.2.1]庚烷基;
R2是-H;-NHC(O)CH3;-NHC(O)CH2CH3;-NHC(O)CH(CH3)2;-NHC(O)-苯基;-NHC(O)-CH2-CH2-苯基;-NHC(O)NH-环己基(其中环己基任选地被-NH2或-N(CH3)2取代);-NHC(O)NH-CH2-苯基(其中苯基任选地被-OH或N3取代);-NHC(O)NH-CH(CH3)-苯基;-N(CH3)C(O)NH-CH2-苯基、-N(CH3)C(O)N(CH3)-CH2-苯基;-NHC(O)NH-CH2-吡咯烷基(其中吡咯烷基任选地被-CH3取代);-NHC(O)OCH3;-NHC(O)OCH(CH3)2;-NHC(O)OCH2CH3;-NHC(O)OCH2C(CH3)=CH2;-NHC(O)OCH=CH(CH3);-NHC(O)OCH2CH2OCH3;-NHC(O)O-CH2-环己基;-NHC(O)O-CH2-苯基;-NHC(O)O-CH(CH3)-苯基;-NHC(O)O-CH2-CH2-苯基;-NHC(O)O-CH2-吡啶基;-NHC(O)O-CH2-CH2-噻唑基;或-NHC(S)NHCH2-苯基;
R3是-H或-F;
R4是-H、-NHC(O)OCH2CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2。
11.权利要求10的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代;
R1是-NRaRa、-NRa(C1-C5)烷基或-N-单环4-7元含氮杂环(其中杂环的氮原子与硫原子连接);
其中由R1表示的(C1-C5)烷基或由R1表示的基团中的(C1-C5)烷基任选地被-ORa、-OC(C1-C3)亚烷基-OH、-CO(O)CH3、-NRaRa、-(C3-C6)环烷基、苯基或单环5-6元杂芳环取代;其中由R1表示的苯基或由R1表示的基团中的苯基任选地被卤素、-CH3、卤代甲基、卤代甲氧基、-OH或-NH2取代;
R2是-H、-NH2、-NO2、-NRaC(O)(C1-C4)烷基、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;
R3是-H或-S(O)2NRa(C1-C4)烷基;
R4是-H、-NH2、-NO2、-NRaC(O)(C1-C4)烷基、-NRaC(O)O(C1-C4)烷基或-NRaC(S)NRa(C1-C4)烷基;和
各Ra独立地是-H或-CH3。
12.权利要求11的化合物或其药学上可接受的盐,其中:
噻唑环任选地被-F或-Cl取代;
R1是-NHCH3、-NHCH2CH3、-N(CH3)2、-NHC(CH3)3、-NHCH2CH2OH、-NHCH(CH3)CH2OH、-NHCH2C(CH3)2CH2OH、-NHCH2CH2OCH3、-NHCH2C(O)OCH3、-NHCH2CH2OCH2CH2OH、-NHCH(CH2OH)2、-NHCH2CH2NH2、-NHCH2CH2NHCH3、-NHCH2CH2N(CH3)2、-NHCH2CH2CH2NH2、-NHCH2CH2CH2NHCH3、-NHCH2CH2CH2N(CH3)2、-NHCH2-苯基、-NHCH2-吡啶基、-NH-环丁基或-N-吡咯烷基;
R2是-H、-NH2、-NO2、-NHC(O)CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2;
R3是-H或-S(O)2NHC(CH3)3;和
R4是-H、-NH2、-NO2、-NHC(O)CH3、-NHC(O)OCH(CH3)2或-NHC(S)NHCH(CH3)2。
13.一种药物组合物,其包含药学上可接受的载体或稀释剂和权利要求1-12中任一项的化合物或其药学上可接受的盐。
14.一种治疗癌症、自身免疫性疾病、免疫缺陷或神经变性疾病的方法,所述方法包括给予有需要的受试者有效量的权利要求1-12中任一项的化合物或其药学上可接受的盐或权利要求13的药物组合物。
15.权利要求14的方法,其中所述方法是治疗癌症的方法,并且所述癌症选自淋巴瘤、白血病和浆细胞肿瘤。
16.权利要求15的方法,其中所述癌症是选自非霍奇金淋巴瘤;伯基特氏淋巴瘤;小淋巴细胞性淋巴瘤;淋巴浆细胞淋巴瘤;MALT淋巴瘤;滤泡性淋巴瘤;弥漫性大B细胞淋巴瘤;和T细胞淋巴瘤的淋巴瘤。
17.权利要求15的方法,其中所述癌症是选自急性成淋巴细胞性白血病(ALL);伯基特氏白血病;B细胞白血病;B细胞急性成淋巴细胞性白血病;慢性淋巴细胞性白血病(CLL);急性髓性白血病(AML);慢性髓性白血病(CML);和T细胞急性成淋巴细胞性白血病(T-ALL)的白血病。
18.权利要求15的方法,其中所述癌症是选自多发性骨髓瘤;浆细胞骨髓瘤;浆细胞白血病;和浆细胞瘤的浆细胞肿瘤。
19.权利要求14的方法,其中所述方法是治疗癌症的方法,所述癌症选自上皮细胞癌;结肠癌;肝癌;胃癌;肠癌;食道癌;乳腺癌;卵巢癌;头颈癌;肺癌;和甲状腺癌。
20.权利要求14的方法,其中所述方法是治疗自身免疫性疾病的方法,所述自身免疫性疾病选自红斑狼疮;Wiskott-Aldrich综合征;自身免疫性淋巴组织增生综合征;重症肌无力;类风湿性关节炎(RA);狼疮肾炎;多发性硬化;系统性红斑狼疮;盘状狼疮;亚急性皮肤红斑狼疮;皮肤红斑狼疮,包括冻疮红斑狼疮;慢性关节炎;干燥综合征;炎性慢性鼻窦炎;结肠炎;乳糜泻;炎性肠病;巴雷特食管;炎性胃炎;自身免疫性肾炎;自身免疫性血管炎;自身免疫性肝炎;自身免疫性心炎;自身免疫性脑炎;自身免疫性糖尿病;自身免疫性糖尿病性肾炎;和自身免疫介导的血液疾病。
21.权利要求14-20中任一项的方法,其还包括向受试者共施用有效量的DNA损伤剂的步骤。
22.权利要求21的方法,其中所述DNA损伤剂选自:暴露于DNA损伤性化学品;暴露于化疗剂;暴露于放化疗;和暴露于电离或紫外辐射。
23.权利要求14-22中任一项的方法,其中确定受试者具有提高的DNA破坏过程或DNA编辑酶的水平和/或活性。
24.权利要求23的方法,其中所述DNA编辑酶选自活化诱导胞苷脱氨酶(AID或AICDA)、APOBEC2、APOBEC3A、APOBEC3C、APOBEC3D、APOBEC3F、APOBEC3G、APOBEC3H、APOBEC4、1型拓扑异构酶、2型拓扑异构酶、重组活化基因1(RAG1)和重组活化基因2(RAG2)。
25.权利要求14-24中任一项所述的方法,其中已经确定从受试者获得的血细胞具有可检测水平的活化诱导胞苷脱氨酶(AID)。
26.权利要求14-24中任一项所述的方法,其中已经确定从受试者获得的B细胞具有可检测水平的活化诱导胞苷脱氨酶(AID)。
27.权利要求25或26所述的方法,其中活化诱导胞苷脱氨酶(AID)的可检测水平在统计学上显著高于在来自健康受试者的未活化B细胞或正常非免疫细胞中表达的AID水平。
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