CN103038231B - Hec1活性调节剂及其方法 - Google Patents
Hec1活性调节剂及其方法 Download PDFInfo
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- CN103038231B CN103038231B CN201180024772.3A CN201180024772A CN103038231B CN 103038231 B CN103038231 B CN 103038231B CN 201180024772 A CN201180024772 A CN 201180024772A CN 103038231 B CN103038231 B CN 103038231B
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- ethyl ketone
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- 238000000034 method Methods 0.000 title abstract description 15
- 101001112162 Homo sapiens Kinetochore protein NDC80 homolog Proteins 0.000 title description 3
- 102100023890 Kinetochore protein NDC80 homolog Human genes 0.000 title description 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
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- 238000011282 treatment Methods 0.000 claims description 9
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
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- 125000001072 heteroaryl group Chemical group 0.000 description 10
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- 239000003112 inhibitor Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 8
- 230000000394 mitotic effect Effects 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
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- 239000002253 acid Substances 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
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Abstract
提供调节Hec1/Nek2相互作用的化合物,组合物和方法。特别优选地,化合物破坏Nek2/Hec1结合,并且因此用作肿瘤疾病的化疗剂。
Description
本申请要求2010年3月17日提交的序列号为61/314798的我们同时待审的美国临时申请的优先权。
技术领域
本发明的领域是与HEC1活性调节相关的各种化合物、组合物和方法,尤其是其涉及抑制肿瘤细胞增殖。
背景技术
虽然与有丝分裂调节相关的机理在概念上是试图减缓肿瘤细胞生长的有吸引力的靶点,但是具有高特异活性和选择性以及理想药理学特征的药物是难以得到的。例如,纺锤体可以是相对高活性的纺锤体抑制剂(如:紫杉烷、长春花生物碱等)的靶标,但鉴于该抑制剂经常是非特异性的,对于药物干预许多纺锤体抑制剂是无法接受的。
为了改进治疗的特异性,用于纺锤体和着丝点调节或有丝分裂检查点控制的组分可以被挑选出来,其显示功能上与癌症相关。例如:Hec1是纺锤体检查点信号转导的关键组分,它在癌症中高表达,并有助于在细胞分裂期间确保正确的染色体分离。Hec1与各种其它着丝点组分相互作用,包括Nuf2,Spc24,Spc25和Zwint-1,以及有丝分裂激酶Nek2和极光激酶B。在众多种类的癌症和癌细胞株中,Hec1过度表达是普遍的,并且经常可作为原发型乳腺癌和其他癌症的预后指标。基于Hec1在癌细胞生长中的显著重要性,RNAi被用于减少Hec1表达,并显示至少在动物模型方面具有很大的前景。然而,体内给予对肿瘤具有高特异性的siRNA经常是有问题的。
最近,已经开发了干预Nek2/Hec1相互作用的各种小分子抑制剂。由于Nek2是有丝分裂中Hec1的调控组分,废除Hec1/Nek2功能期望导致染色体错分离(mis-segregation)和细胞死亡。已经报道了数个有前景的化合物(见 J. Med. Chem., 2009, 52 (6), pp 1757–1767, Cancer Res. 2008 Oct 15;68(20):8393-9),其具有显著的细胞杀伤活性,并直接靶向Hec1/Nek2途径。这和所有本文讨论的其他外在材料以引用的方式全盘并入。在并入的参考文献中的术语的定义或使用与本文提供的该术语的定义不一致或者相反时,适用本文提供的术语定义,而不适用参考文献中的术语定义。然而,尽管在至少一些例子中,观测到的活性是有希望的,但无论如何与溶解度、毒性和相对高的半数抑制浓度相关的问题仍然存在。
因此,依然需要用于Hec1抑制的改进的化合物、组合物和方法,尤其是当其涉及这些化合物在癌症治疗中的用途时。
发明内容
本发明主题涉及用于Hec1抑制的各种化合物、组合物和方法。更特别地,预期的化合物将包括根据式I的那些。
其中R1,R2,R3,R4和R5如下进一步描述。更特别优选的化合物将具有根据式II和III的结构(以下还更详细地描述各自的基团)。
本发明主题的一方面,预期的化合物是Hec1抑制剂,和/或可以以破坏Hec1/Nek2相互作用为特征。因此,本文所述的化合物特别适合用作破坏有丝分裂途径的治疗药剂。所以,从另一个角度考虑,特别预期的组合物包括含有一个或多个预期化合物的药物组合物,当该组合物给予患者时,预期化合物的浓度有效破坏患者的Hec1/Nek2结合。
因此,本发明主题的另一方面,破坏Nek2/Hec1相互作用的方法是预期的,该方法包括用有效破坏Nek2/Hec1结合的量的一个或多个本文所述的化合物接触Nek2/Hec1复合体的步骤。尽管所有接触方式通常是预期的,通常优选接触Nek2/Hec1复合体的步骤在哺乳动物体内进行,接触步骤还可以与干预微管形成或降解的药剂组合进行。
根据以下优选实施方案的详述以及附图(其中相同的编号代表相同的组分),本发明主题的各种目的、特征、方面和优势将变得更加明显。
附图简述
图1A和1B是说明选定化合物对肿瘤细胞(1A)和正常细胞(1B)的细胞毒效应的表格。
图2A-2D是描述由选定化合物引起的破坏Hec1/Nek2相互作用(2A,2B),Nek2降解(2C)和Nek2不稳定性(2D)的免疫印迹照片。
图3是说明预期化合物影响有丝分裂细胞百分比的表格。
图4是说明预期化合物对蛋白激酶高特异性的表格。
图5A和5B是描述选定化合物对裸鼠肿瘤体积的体内作用的图表。
详细描述
预期化合物
本发明人已经发现根据式I的某些化合物可以被制备,并且其作为干扰Hec1的部分具有有利性能。特别优选的化合物将包括根据式I的那些。
在特别优选的方面,R1 是氢,烷基,烯基,炔基,烷氧基,芳基,卤素,硝基,氰基,环烷基,杂环烷基,环烯基,杂环烯基,ORa,SRa,NRaRb, –S(O)2Ra,–S(O)2NRaRb,–C(O)Ra, –C(O)NRaRb,–NRaC(O)Rb,–NRaS(O)2Rb,–N=CRaRb或者–NRaC(O)NHRb;Ra 和R b独立地是氢,烷基,烯基,炔基,芳基,芳氧基,烷氧基,羟基,杂芳基,环烷基,杂环烷基,环烯基或者杂环烯基,或者Ra和Rb,与其相结合的氮原子一起,是杂芳基,杂环烷基或者杂环烯基;R2 , R3 和R4 独立地是氢,C1–C6烷基,卤素或者ORa;R5 是烷基,苯基烷基,杂芳基烷基,苯基烯基,杂芳基烯基,苯基,杂芳基,杂环烷基或者杂环烯基;其中R1,R2,R3,R4,R5,Ra和Rb中的每一个独立地任选被取代。次优选的化合物包括那些,其中(I)R1和R2 是甲基且当R3是氢时,R5不是噻唑基,N-甲基咪唑基,吡嗪基,吡啶基,吗啉基,苯基或者二甲氧基苯基;(II)当R1,R2和R3是甲基时,R5不是噻唑基,N-甲基咪唑基,吡嗪基,吡啶基,吗啉基,苯基,甲氧基苯基,二羟基苯基,羟基甲氧基苯基,三氟甲基苯基或者二甲氧基苯基;及(III)当R1和R2是甲基且当R3是羟基或者甲氧基时,R5不是苯基。
特别优选的是,R1是烷氧基,SRa,ORa或者–S(O)2Ra,Ra是烷基或者任选取代的芳基,R2,R3和R4独立地是氢或者C1–C6烷基,及R5是任选取代的杂芳基。其中更优选的化合物是这样的化合物,其中R1是烷氧基,SRa,ORa或者–S(O)2Ra,其中Ra是烷基或者任选取代的芳基,其中R2和R3是C1–C6烷基,其中R5是任选取代的(如:卤代的)吡啶基。最优选地,R1是ORa,其中Ra是任选取代的芳基,R2和R3是C1–C6烷基,且R5是任选取代的吡啶基。
因此,从不同角度看,具有根据式II的结构的化合物也是优选的。
在化合物中,其中X1 和X2 独立地是H,烷基,烯基,炔基,卤素,硝基,氰基,环烷基,杂环烷基,环烯基,杂环烯基,ORa,NRaRb,–S(O)2Ra,–S(O)2NRaRb,–C(O)Ra,–C(O)NRaRb,–NRaC(O)Rb,–NRaS(O)2Rb,–N=CRaRb或者–NRaC(O)NHRb;Y 是CH2,CHRa,CRaRb,O,NH,NRa,S,SO或者SO2;R1 , R2 和R3 独立地是H,烷基,烷氧基或者卤素;n是0,1,或者2;其中A是任选取代的芳基或者任选取代的杂芳基,最优选如下所示的化合物:
其中X1和X2的每一个独立地任选被取代,其中Rc和Rd独立地是Ra。这些化合物中,进一步优选Y是O,S或者SO2,和/或A是任选取代的吡啶基。最有代表性地,在这些化合物中X1和X2独立地是H,烷基和烷氧基,且n是0或者1。关于剩余基团,适用提供于式I的同样的考虑。
还优选的化合物具有根据式III的结构
其中X1 ,X2 和X3 独立地是H,烷基,烯基,炔基,卤素,硝基,氰基,环烷基,杂环烷基,环烯基,杂环烯基,ORa,NRaRb,–S(O)2Ra,–S(O)2NRaRb,–C(O)Ra,–C(O)NRaRb,–NRaC(O)Rb,–NRaS(O)2Rb,–N=CRaRb或者–NRaC(O)NHRb;Y是CH2,CHRa,CRaRb,O,NH,NRa,S,SO或者SO2;R1 ,R2 和R3 独立地是H,烷基,烷氧基或者卤素;n是0,1或2;其中X1 和X2的每一个独立地任选被取代;其中Rc 和Rd 独立地是Ra,其中A和Het独立且优选地是芳香族的和任选取代的芳基或者杂芳基。在其他合适的选择中,通常优选
。
关于剩余基团,适用式I所注的同样的考虑。根据式II特别优选的化合物包括那些,其中A是任选取代的吡啶基,和/或Y是O,S或者SO2。
考虑到以上和进一步的实验数据(见下文),特别优选的化合物将具有如下所示的结构
。
本文所用的术语“烷基”是指烃基,其可以是直链,环形或者支链。术语“烯基”是指具有至少一个双键的烷基。当存在多于一个双键时,预期双键可以是共轭的或者非共轭的。本文所用的术语“炔基”是指具有至少一个三键的烷基。预期的炔基可以进一步包括另一个三键或双键,其与首个三键可以共轭或者非共轭。本文所用的术语“烷氧基”是指O-烷基基团,其中“烷基”如上定义。
本文所用的“环烷基”是指具有3到14个碳原子的非芳香族的一价单环或多环基,每个环基可以是饱和或非饱和的,可以是不被取代或被一个或多个本文定义的合适取代基所取代,其可以与一个或多个芳基,杂芳基,环烷基或者杂环烷基稠合,这些基团本身可以不被取代或被一个或多个取代基所取代。环烷基的例子包括环丙基,环庚基,环辛基,环癸基,环丁基,金刚烷基,降蒎烷基,十氢化萘基,降冰片基(norbornyl),环己基和环戊基。
本文所用的“杂环烷基”是指具有1-5个选自氮,氧和硫的杂原子的非芳香族的一价单环或多环基,可以不被取代或被一个或多个本文定义的取代基所取代,并且其可以与一个或多个芳基,杂芳基,环烷基或者杂环烷基稠合,这些基团本身可以不被取代或被一个或多个取代基取代。杂环烷基的例子包括环氧乙烷基,吡咯烷基,哌啶基,四氢吡喃和吗啉基。
本文所用的“芳基”(Ar)是指通常包括5至18个碳环成员的芳香族单环或多环基,其可以不被取代或者被一个或多个本文定义的合适的取代基所取代,可以与一个或多个环烷基,杂环烷基或杂芳基稠合,这些基团本身可以不被取代,或者被一个或多个合适的取代基取代。因此,术语“芳基”包括苄基(Bzl)。例子包括苯基,联苯基,1,2,3,4-四氢萘基,奈基,蒽基和菲基。
本文所用的“杂芳基”是指通常含有4至18个环成员(包括选自氮,氧和硫的1-5个杂原子)的芳香族单环或多环基,其可以不被取代,或者被一个或多个以下定义的取代基所取代,其可以与一个或多个环烷基,杂环烷基或者芳基稠合,这些基团本身可以不被取代或者被一个或多个合适的取代基所取代。例子包括噻吩基,呋喃基,噻唑基,三唑基,咪唑基,异噁唑基,噁二唑基,四唑基,吡啶基,吡咯基,噻二唑基,噁二唑基,氧杂噻二唑基, 噻三唑基,嘧啶基,异喹啉基,喹啉基,萘啶基(napthyridinyl), 邻苯二甲酰亚胺基,苯并咪唑基和苯并噁唑基。
本文所用的术语“杂环”或者“杂环的”是指芳香族和非芳香族的杂环基团,通常4-10个原子形成环并且包含一个或多个杂原子(通常为O,S或N)。非芳香族杂环基团包括其环系统中只有4个原子的基团,但是芳香族杂环基团在其环系统中通常具有至少5个原子。非芳香族杂环基团的例子包括吡咯烷基,四氢呋喃基,四氢噻吩基,四氢吡喃基,四氢噻喃基,哌啶基,吗啉代,硫代吗啉代,噻噁烷基,哌嗪基,氮杂环丁烷基,氧杂环丁烷基,硫杂环丁烷基,高哌啶基,环氧己烷基,硫杂环庚烷基,氧氮杂基,二氮杂基,硫氮杂基,1,2,3,6-四氢吡啶基,2-吡咯啉基,3-吡咯啉基,二氢吲哚基,2H-吡喃基,4H-吡喃基,二氧己环基,1,3-二氧戊环基,吡唑啉基,二噻烷基,二硫戊环基,二氢吡喃基,二氢噻吩基,二氢呋喃基, 吡唑烷基,咪唑啉基,咪唑烷基,3-氮杂双环[3.i.0]己烷基,3H-吲哚基和喹嗪基。
芳香族杂环基团的例子包括吡啶基,咪唑基,嘧啶基,吡唑基,三唑基,吡嗪基,四唑基,呋喃基,噻吩基,异噁唑基,噻唑基,噁唑基,异噻唑基,吡咯基,喹啉基,异喹啉基,吲哚基,苯并咪唑基,异苯并呋喃基(is
benzofuranyl),噌啉基,吲唑基,吲嗪基,酞嗪基,哒嗪基,三嗪基,异吲哚基,蝶啶基,嘌呤基,噁二唑基,噻二唑基,呋咱基,苯并呋咱基,苯并噻吩基,喹唑啉基,苯并噻唑基,苯并噁唑基,喹喔啉基,萘啶基和呋喃并吡啶基。预期的4-10元杂环可以是C-连接或N-连接的(适当情况下)。例如,吡咯衍生的基团可以是吡咯-i-基(N-连接)或吡咯-3-基(C-连接)。
如本文更进一步所用,本文所用的术语“取代的”是指用功能基团替代或者修饰分子中的原子(基团)或者化学基团(如:NH2或者OH)以产生取代的分子,特别预期的功能基团包括亲核基团(如:-NH2,-OH,-SH,-NC等),亲电子基团(如:C(O)OR,C(O)OH等),极性基团(如:-OH),非极性基团(如:芳基,烷基,烯基,炔基等),离子基团(如:-NH3 +)和卤素(如:-F,-Cl)及其所有化学上合理的组合。例如,分子是烷基时,被取代基是氢基,功能基团是羟基,H原子被OH基团取代形成取代烷基。另一个例子中,分子是氨基酸时,被改性基团是氨基,功能基团是烷基,氨基被烷基化形成N-取代的氨基酸。
例如:适当的取代基包括卤素(氯代,碘代,溴代或氟代);C1-6-烷基;C1-6-烯基;C1-6-炔基,羟基,C1-6 烷氧基;氨基;硝基;硫醇;硫醚;亚胺;氰基;酰胺基;膦酸酯基(phosphonato);膦;羧基;羰基;氨基羰基;硫代羰基;磺酰基;磺酰胺(sulfonamine);磺酰胺(sulfonamide); 酮;醛;酯;氧(=O);卤代烷基(如:三氟甲基);可以是单环或稠合或非稠合多环的碳环环烷基(如:环丙基,环丁基,环戊基或者环己基),或者可以是单环或稠合或非稠合多环的杂环烷基(如:吡咯烷基,哌啶基,哌嗪基,吗啉基或者噻嗪基);碳环或杂环,单环或稠合或非稠合多环的芳基(如:苯基,萘基,吡咯基,吲哚基,呋喃基,苯硫基,咪唑基,噁唑基,异噁唑基,噻唑基,三唑基,四唑基,吡唑基,吡啶基,喹啉基,异喹啉基,吖啶基,吡嗪基,哒嗪基,嘧啶基,苯并咪唑基,苯并噻吩基或者苯并呋喃基);氨基(伯,仲或叔);硝基;硫醇;硫醚,O-低级烷基(O-lower alky);O-芳基,芳基;芳基-低级烷基;CO2CH3;CONH2;OCH2CONH2;NH2;SO2NH2;OCHF2;CF3;OCF3等。应该进一步指出的是本文预期的所有取代基可以进一步任选被一个或者多个上述指出的取代基所取代。特别优选的取代基包括羟基,卤素,氧代(oxo),烷基(特别是低级烷基),酰基,磺酰基,巯基,烷基硫代,烷氧基,环烷基,杂环烷基, 芳基,杂芳基,羧基,氨基,烷基氨基,二烷基氨基,氨基甲酰基,芳氧基,杂芳氧基,芳基硫代,杂芳基硫代。
而且,应该理解的是根据本发明主题的化合物可以包括一个或者多个不对称中心,因此可以以不同的对映体形式存在,预期化合物的所有对映体形式在本文是特别预期的。同样地,当预期化合物显示旋光性和/或有立体异构体时,所有的旋光性和/或异构体形式在本文是预期的。同样地,当双键来区别Z-型与E-型(或者顺-与反-)时,两个异构体都是被预期的。而且,应当指出,根据本发明主题的化合物也可以是同位素标记的。适当的同位素的例子为2H,3H,13C,14C,15N,18O,17O,18F或者36Cl。本发明主题的某些同位素标记的化合物,例如包含14C 或者3H的那些,在药物和/或基质组织分布分析中可能是有用的。另一方面,非放射性同位素(如:2H或13C)取代可以提供某些源于更大代谢稳定性的治疗优势,例如提高体内半衰期或者降低剂量需求,该取代因此可以在一些情况中是优选的。
预期化合物可以制备为药学上可接受的盐,其特别包括可以存在于预期化合物中的酸性或碱性基团的盐。例如,当预期化合物实际上是碱性的时,应该注意的是这样的化合物可以和多种无机酸和有机酸形成多种盐。适当的酸将提供药理学上可接受的阴离子,包括氯化物,溴化物,碘化物,硝酸盐,硫酸盐,硫酸氢盐,磷酸盐,酸式磷酸盐,异烟酸盐,醋酸盐,乳酸盐,水杨酸盐,柠檬酸盐,酸式柠檬酸盐,酒石酸盐,泛酸盐,酒石酸氢盐,抗坏血酸盐,琥珀酸盐,马来酸盐,龙胆酸盐, 富马酸盐,葡糖酸盐,葡萄糖醛酸盐,糖酸盐,甲酸盐,苯甲酸盐,谷氨酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,对甲苯磺酸盐和双羟萘酸盐[1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐)] 阴离子。同样地,当预期化合物实际上是酸性的时,应该注意的是这些化合物可以与多种药理学上可接受的阳离子形成碱盐,特别适当的阳离子包括碱金属或者碱土金属离子(如:钠和钾离子)。
在另一预期的方面,本文所述的化合物可以制备为前药,只要这个前药增加药物(或者前药的代谢产物)在靶器官、靶细胞和/或Hec1中的浓度,那么前药的所有已知方式和类型均被考虑适合本文使用。例如,当预期化合物具有游离氨基,酰氨基,羟基,硫代或者羧基时,预期这些基团可用于共价和可释放地结合将药物转化为前药的部分。因此,前药特别包括其中预期化合物与另一个可裂解部分形成酯,酰胺或者二硫化物键的那些。这些部分可以帮助药物的器官或细胞特异性传递,因此特别包括受体配体及其类似物,抗体片段或者其它高亲和力配体(Kd<106M)。
例如,羧基能衍生形成酰胺或者烷基酯,其可以包括醚,胺-和/或羧酸基团。游离羟基可利用半琥珀酸盐,磷酸酯,二甲基氨基醋酸盐和磷酰氧基甲氧基羰基来衍生化,如D. Fleisher, R.
Bong, B. H. Stewart, Advanced Drug Delivery 40 Reviews (1996) 19, 115所述。还包括羟基和氨基的氨基甲酸酯前药,以及羟基的碳酸酯前药和硫酸酯。将羟基衍生为(酰氧基)甲基和(酰氧基)乙醚,其中酰基可以是烷基酯(任选取代的),或者其中酰基是氨基酸酯,也是预期的(这种类型的前药描述于R. P. Robinson et al., J. Medicinal
Chemistry (1996) 39:p.10)。
在另一预期的方面,应该理解根据本发明主题的化合物也可以是作为代谢物(前药或非前药形式的)有效的,所有这样的代谢物在本文是特别预期的。例如,适当的代谢物包括羟基化形式,氧化形式,葡糖醛酸化形式,硫酸化形式等。而且,还要注意的是代谢物可能比最初给药形式更有效。
预期组合物和制剂
基于化合物作为Hec1调节剂的活性,本发明人预期根据本发明主题的化合物和组合物可用于预防和/或治疗Hec1功能紊乱和/或过度表达相关的各种疾病,事实上用于对预期化合物的给药有积极响应的所有疾病。本文所用的术语“Hec1功能紊乱”是指任何Hec1异常,特别是当涉及到其与Nek2功能和纺锤体检验点信号转导的相关性时。这些异常可能是由于突变(如:增加或降低与结合配偶体(partner)的亲和力),暂时或者永久的过度表达(如:被不适当或突变的启动子激活),活化剂的不可逆结合或更紧固结合,通过非生理分子的不适当激活等的一个或多个因素。因此,特别预期的疾病包括肿瘤疾病,特别是癌变肿瘤疾病(如:乳腺癌,鳞状细胞癌,膀胱癌,胃癌,胰腺癌,头癌,颈癌,食道癌,前列腺癌,结肠直肠癌,肺癌,肾癌,宫颈癌或者甲状腺癌)。非癌变的肿瘤疾病包括良性皮肤增生(如:银屑病)或者良性前列腺增生(如:良性前列腺肥大(BPH))。
因此,本发明人还预期许多包括本文所述的化合物的药物组合物,通常预期根据本发明主题的化合物可以配制为药物组合物,该药物组合物含有治疗有效量的预期化合物(或者其药学上可接受的盐,水合物或者前药)和药学上可接受的载体。
利用大量已知的方案,可以确定本文所述的化合物的活性、毒性和其它药理学和药效动力参数。同样地,可以通过在多种细胞株中的MTS分析确定细胞毒性,并且可以通过免疫共沉淀或者酵母双杂交系统监控Hec1-Nek2相互作用的破坏。可以通过监控不同阶段种群(如:sub-G1,G0/G1,S等)进行细胞周期分析,并可以利用本领域众所周知的荧光免疫方法进行中期染色体错位定量。利用多种动物模型,特别是异种移植模型,可以确定体内活性。附表和规范化数据中提供了示例性的结果。因此,本发明人预期包括药学上可接受的载体和本文预期化合物的药物组合物,其中当给予患者该组合物时,所述化合物以有效破坏病人体内Hec1/Nek2结合的浓度存在。本发明人也已经发现,根据本发明主题的许多化合物在口服给药后是生物可利用的,并且在口服给药或静脉(i.v.)给药很长时间后,可以在血清中检测到(见下文)。
最优选地,预期化合物与一个或多个无毒的药学可接受的载体一起配制,优选配制为用于口服的固体或液体形式,或用于肠胃外注射。因此,应当理解根据本发明主题的药物组合物可以采用多种途径给予人和其它动物,包括口服给药,直肠给药,肠胃外给药,腹腔给药,阴道给药或者局部给药。
例如,合适的注射用药物组合物优选包括药学上可接受的无菌水溶液或非水溶液,分散液,乳剂或悬浮液,以及使用前再制成无菌注射溶液或者分散液的无菌粉末。合适的水性和非水性载体,稀释剂,溶剂或者媒介物的例子包括水,乙醇,多元醇(如:甘油,丙二醇、聚乙二醇等)及其合适的混合物,油,和注射用有机酯(如:油酸乙酯)。预期组合物也可以包含多种非活性成分,包括防腐剂,润湿剂,乳化剂和/或分散剂。包含抗菌剂和/或抗真菌剂(如:尼泊金,苯酚山梨酸,氯丁醇等)可以确保无菌。在合适情况下,可以包括渗透活性剂(如:糖,氯化钠等)。
可选择地,预期组合物可以配制成口服给药用固体剂型,并且因此可以是胶囊,片剂,药丸,粉末和颗粒剂。在优选的固体剂型中,预期化合物与药学上可接受的赋形剂或者载体(如:柠檬酸钠或磷酸二钙),填充物或者增量剂(如:淀粉,乳糖,蔗糖,葡萄糖,甘露醇或者硅酸),粘合剂(如:羧甲基纤维素,海藻酸盐,明胶,聚乙烯吡咯烷酮,蔗糖等),湿润剂(如:甘油),崩解剂(如:琼脂,碳酸钙,马铃薯或者木薯淀粉,海藻酸,某些硅酸盐,或者碳酸钠),溶液阻滞剂(如:石蜡),吸收促进剂(如:季铵化合物),湿润剂(如:鲸蜡醇,单硬脂酸甘油酯),和吸收剂(如:高岭土或膨润土),和润滑剂(如:滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,十二烷基硫酸钠)中的至少一种混合。
类似类型的固体组合物也可在软和硬填充明胶胶囊中作为填充物使用,其中胶囊使用诸如乳糖或牛奶糖(milk sugar),以及高分子量聚乙二醇等的赋形剂。片剂,锭剂,胶囊,药丸和颗粒剂的固体剂型可以使用包衣和壳(例如肠溶包衣及其它制药领域众所周知的包衣)来制备。预期组合物可以进一步配制为只释放活性成分,或优选地,在肠道的某一部分,任选地,以延迟的方式。可以使用的包埋组合物的例子包括聚合物质和蜡。如果适当的话,预期化合物也可以是微囊的形式,含有上述赋形剂的一种或多种。
口服给药的液体剂型包括药学上可接受的乳剂,溶液,悬浮液,糖浆剂和酏剂。除活性化合物外,液体剂型可以包含本领域普遍使用的惰性稀释剂(如:水,或其它溶剂,增溶剂),乳化剂(如:乙醇,异丙醇,碳酸乙酯,乙酸乙酯,苄醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,二甲基甲酰胺),油(特别是棉籽油,花生油,玉米油,胚芽油,橄榄油,蓖麻油和芝麻油),甘油,四氢糠醇,聚乙二醇和脱水山梨糖醇的脂肪酸酯,及其混合物。除惰性稀释剂外,口服组合物还可以包括如润湿剂,乳化和悬浮剂,甜味剂,调味剂,和香味剂的佐剂。
根据本发明主题的化合物也可以以脂质体的形式给药,该脂质体可以是单层的,寡层的,或者多层的。预期的脂质体形式的组合物可以进一步含有稳定剂,防腐剂,赋形剂等。用于脂质体形成的优选脂质包括天然和合成的磷脂和磷脂酰胆碱(卵磷脂)。形成脂质体的方法是本领域众所周知的。参见,例如Prescott,
Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33 et seq。
预期化合物在根据本发明主题的药物组合物中的实际剂量水平可以改变,以获得对于具体患者,组合物及给药方式有效实现期望的治疗响应的预期化合物的量。因此,所选择的剂量水平将取决于多种因素,包括具体化合物的活性,给药途径,治疗病症的严重性,以及被治疗病人的状况和之前病史。然而,这是在本领域技术范畴内的,即以低于实现期望的治疗效果所需水平的化合物的剂量开始,并逐渐增加剂量直到实现期望的效果。通常,口服给予哺乳类患者每天每千克体重约0.01mg至约500mg,更优选约0.5mg至约50mg的剂量水平的预期化合物。如需要,为了给药目的,可将有效日剂量分为多个剂量,例如每天2-4个分剂量。因此,预期制剂特别包括适于口服给药,肠胃外给药,作为乳膏或滴眼液或其它液体局部制剂给药的那些。
此外,初步数据显示多种Hec1抑制剂表现出与选定的化疗抑制剂的协同效应。在其它化疗抑制剂中,包括紫杉醇,长春新碱和长春花碱的化合物显示出协同效应,并且还期望具有与微管蛋白形成或聚合抑制剂,以及前微管蛋白抑制剂的协同效应。因此,适当的化疗抑制剂特别包括一个或多个干扰微管形成或降解的药物。因此,任何影响细胞分裂的药物和任何抗代谢药与本文预期的Hec1抑制剂组合都被视为是有益的。相反,蒽环类(如:阿霉素)显示与Hec1抑制剂最多只有累加效应,没有协同效应。
还应当理解的是,预期的药物组合物还可以包括附加的药学活性化合物,特别预期的附加的药学活性化合物包括抗肿瘤药,其可以作用于DNA复制,细胞周期,细胞代谢,血管再生,或者诱导细胞凋亡。另外合适的活性药剂包括免疫活性药剂(如:抗炎药,免疫抑制剂,类固醇,干扰素(α,β,γ)及其片段,和那些选择性增加或抑制Th1和/或Th2细胞因子表达的分子)。其它适当的活性药剂包括抗菌剂和抗病毒剂,刺激或改变代谢的药物,神经活性药物,和/或止痛药。当然,应当认识到,附加的药学活性化合物可以包括在相同的药物组合物中,或者可以分开给药,本领域的普通技术人员将容易确定附加的药学活性化合物的适当共同给药的时间表和路线。
实施例
/
实验
4-
芳基
-2-
酰氨基噻唑的示例性合成
预期的4-芳基-2-酰氨基噻唑可以通过多种合成途径制备,以下提供的只是给出示例性指导。虽然以下方案可用于制备本文所述的大多数化合物,但是其他化合物可能需要超出一般方案的小修改,这对于本领域技术人员来说是显而易见的。
上述方案阐明了合成4-芳基-2-氨基噻唑E的方法。结构A的芳香族化合物,包括取代的苯,嘧啶,或其他杂环化合物(5-,6-,或7-元)在AlCl3存在下与乙酰氯反应,生成乙酰化的芳烃B。B溴化得到α-Br-乙酰化的芳烃C,使其与硫脲反应生成在C-4位上具有一个芳基取代基的氨基噻唑D。然后,如此制备的氨基噻唑与不同的酸反应得到最终的4-芳基-2-酰氨基噻唑E。
Ar1的乙酰化:
可以通过利用上述方案所示的不同试剂完成Ar1的乙酰化。
乙酰基Ar1的溴化:
合适的溴化剂包括在多种溶剂,包括醚,THF,卤化烃,酯等中的Br2,HBr,NBS,TBABr3,CuBr2等。
氨基噻唑的酰胺化:
合适的偶联剂包括CDI,EDC,CDC等。
X通常是Cl或Br;碱通常是Et3N,Me3N,DIPEA,K2CO3,Na2CO3,DMAP等。可选择的,4-芳基-2-酰氨基噻唑可按照以下制备:
可选择的,也可以按照以下来进行偶联:
向4-芳基噻唑-2-胺(1.0当量)于CH2Cl2中的溶液中加入三乙胺(3.0当量)或DMAP(3.0当量),随后加入芳氧基氯(aryloxy chloride)(1.5当量)或芳氧基氯盐酸盐(1.5当量)。将反应混合物在室温下搅拌过夜。溶液减压浓缩,加入热水。将所得沉淀物过滤,真空干燥,得到相应的4-芳基-2-酰氨基噻唑。对于合成的具体例子,见下文。
示例性的氨基噻唑和相关中间体的合成
2- 溴 -1- 均三甲苯基乙酮( 2-bromo-1-mesitylethanone )。向 1-均三甲苯基乙酮(1.02
g,6.27 mmol)于EtOAc(50 mL)中的溶液中加入溴化铜(II)(CuBr2,2.85
g,12.8 mmol)。反应混合物加热回流90分钟。使溶液冷却,将所得固体过滤,用EtOAc洗涤。滤液减压浓缩得粗2-溴-1-均三甲苯基乙酮(1.67g),为黄色油状物:1H NMR (500 MHz, CDCl3)
δ 6.87 (2 H, s), 4.27 (2 H, s), 2.31 (3
H, s), 2.22 (6 H, s)。
化合物 4- 均三甲苯基噻唑 -2- 胺。将2-溴-1-均三甲苯基乙酮(2.43 g,10.1 mmol)和硫脲(0.810 g,10.6 mmol)溶于95%乙醇(20mL)。反应混合物加热回流2.0小时。溶液减压浓缩,残余物在异丙醇中重结晶,得到预期的4-均三甲苯基噻唑-2-胺(2.36g),为白色固体:1H NMR (500 MHz, CD3OD)
δ 7.00 (2 H, s), 6.67 (1 H, s), 2.31(3 H,
s), 2.19 (6 H, s)。
化合物 4-( 对甲苯基 ) 噻唑 -2- 胺。将2-溴-1-(对甲苯基)乙酮(5.00 g,23.5 mmol)和硫脲(1.97 g,25.9 mmol)于95%EtOH(33.5mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(1.0 mL)。过滤所得沉淀物,用热水洗涤。过滤固体,真空干燥得4-(对甲苯基)噻唑-2-胺(4.40g),为白色固体,产率99%。1H NMR
(500 MHz, CDCl3) δ 7.66 (d, J
= 8.0 Hz, 2 H), 7.18 (d, J = 7.5 Hz, 2 H), 6.66 (s, 1 H), 5.25 (bs, 2
H), 2.36 (s, 6 H)。
化合物 5- 甲基 -4-( 对甲苯基 ) 噻唑 -2- 胺。将2-溴-1-(对甲苯基)丙-1-酮(6.88 g,30.3 mmol)和硫脲(2.54 g,33.4 mmol)于95%EtOH(43 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得5-甲基-4-(对甲苯基)噻唑-2-胺(6.10g),为白色固体,产率99%。1H NMR
(500 MHz, CDCl3) δ 7.40 (d, J
= 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 3.18 (bs, 2 H), 2.37 (s, 3
H), 2.35 (s, 3 H)。
化合物 2- 溴 -1-(4- 甲氧基 -2,6- 二甲基苯基 ) 乙酮。向1-(4-甲氧基-2,6-二甲基苯基)乙酮(5.7 g,32 mmol)于乙腈(64mL)中的溶液中加入四丁基三溴化铵(TBABr3,15.4 g,32.0 mmol)。室温下搅拌反应80分钟。溶液减压浓缩,加水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩得2-溴-1-(4-甲氧基-2,6-二甲基苯基)乙酮(9.14g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4- 甲氧基 -2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-甲氧基-2,6-二甲基苯基)乙酮(8.65 g,33.6 mmol)和硫脲(2.56 g,33.6 mmol)于95%EtOH(48mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(5.0mL)。过滤所得沉淀,并在甲苯中重结晶(50mL)。过滤固体,真空干燥,得4-(4-甲氧基-2,6-二甲基苯基)噻唑-2-胺(5.9g),为白色固体,产率66%:1H NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H), 6.27(s, 1 H), 4.91 (bs, 2 H), 3.79 (s, 3
H), 2.15 (s, 6 H)。
化合物 2- 溴 -1-(2,4,6- 三甲基吡啶 -3- 基 ) 乙酮氢溴酸盐。向1-(2,4,6-三甲基吡啶-3-基)乙酮(5.0 g,30.6 mmol)于33%HBr醋酸溶液(10.2mL)中的溶液中逐滴加入溴(1.57 ml,30.6
mmol)的醋酸溶液(10.2mL)。70℃下搅拌反应2.0小时。溶液冷却至室温,并用醚洗涤。残余物减压干燥,得2-溴-1-(2,4,6-三甲基吡啶-3-基)乙酮氢溴酸盐,其被直接用于下一步,无需进一步纯化。
化合物 4-(2,4,6- 三甲基吡啶 -3- 基 ) 噻唑 -2- 胺。将2-溴-1-(2,4,6-三甲基吡啶-3-基)乙酮氢溴酸盐(9.00 g,27.9 mmol)和硫脲(2.12 g, 27.9 mmol)于95%EtOH(39.8mL)中的混合物加热回流120分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(5.0mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(2,4,6-三甲基吡啶-3-基)噻唑-2-胺(3.80g),为黄色固体,产率62%:1H NMR
(500 MHz, CDCl3) δ 6.87 (s, 1 H),
6.31 (s, 1 H), 5.07 (bs, 2 H), 2.49 (s, 3 H), 2.38 (s, 3 H), 2.14 (s, 3 H)。
化合物 2- 溴 -1-(4- 乙氧基 -2,6- 二甲基苯基 ) 乙酮。向1-(4-乙氧基-2,6-二甲基苯基)乙酮(4.00 g,20.8 mmol)于乙腈(41.6mL)中的溶液中加入四丁基三溴化铵(TBABr3,10.0 g,20.8 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-乙氧基-2,6-二甲基苯基)乙酮(6.40g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4- 乙氧基 -2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-乙氧基-2,6-二甲基苯基)乙酮(6.35 g,23.4 mmol)和硫脲(1.78 g,23.4 mmol)于95%EtOH(33.5mL)中的混合物加热回流60分钟。浓缩溶液,加入水(50mL)和饱和Na2CO3水溶液(5.0mL)。过滤所得沉淀物,并在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(4-乙氧基-2,6-二甲基苯基)噻唑-2-胺(4.18g),为白色固体,产率72%:1H NMR (500 MHz, DMSO-d6 )
δ 6.84 (s, 2 H), 6.60 (s, 2 H), 6.27(s, 1
H), 3.99 (q, J = 6.5 Hz, 2 H), 2.06 (s, 6 H), 1.31 (t, J = 6.95 Hz, 3 H)。
化合物 4- 乙酰基 -3,5- 二甲基苯基三氟甲磺酸盐。将1-(4-羟基-2,6-二甲基苯基)乙酮(3.30 g,20.1 mmol),三乙胺(4.07 g,40.2 mmol)于无水CH2Cl2(20.1mL)中的溶液冷却至0℃,然后逐滴加入三氟甲磺酸酐(4.0 mL,24
mmol)。完成添加后,将反应混合物温热至室温,搅拌1小时。在溶液中加入水,用乙酸乙酯(60mL)萃取。分离有机层,用MgSO4(s)干燥,减压浓缩。残余物通过快速硅胶色谱纯化,得4-乙酰基-3,5-二甲基苯基三氟甲磺酸基(5.0g),为黄色油状物,产率85%。
化合物 1-(3,5- 二甲基 -[1,1 ’ - 联苯 ]-4- 基 ) 乙酮。向4-乙酰基-3,5-二甲基苯基三氟甲磺酸盐(1.00 g,3.38 mmol),KF(0.65 g,11 mmol)和苯基硼酸(0.49 g, 4.0 mmol)于THF(4.0mL)中的溶液中加入三环己基膦(11.4 mg, 0.04
mmol)和Pd(OAc)2 (7.6 mg,0.03 mmol)。室温N2下搅拌反应混合物5.0小时。反应混合物通过硅藻土(Celite)小垫片过滤,用乙酸乙酯(40mL)洗涤滤饼。滤液减压浓缩,残余物通过快速硅胶色谱纯化,得1-(3,5-二甲基-[1,1’-联苯]-4-基)乙酮(0.68g),产率90%:1H NMR
(500 MHz, CDCl3) δ 7.56 (d, J
= 8.0 Hz, 2 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.35 (m, 1 H), 7.25 (s, 2 H),
2.52 (s, 3 H), 2.33 (s, 6 H)。
化合物 2- 溴 -1-(3,5- 二甲基 -[1,1 ’ - 联苯 ]-4- 基 ) 乙酮。向1-(3,5-二甲基-[1,1'-联苯]-4-基)乙酮 (1.89 g,8.43 mmol)于乙腈(16.9 mL)中的溶液中加入四丁基三溴化铵(TBABr3,4.07 g,8.43 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(3,5-二甲基-[1,1'-联苯]-4-基)乙酮 (3.2 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(3,5- 二甲基 -[1,1'- 联苯 ]-4- 基 ) 噻唑 -2- 胺。将2-溴-1-(3,5-二甲基-[1,1'-联苯]-4-基)乙酮 (2.56 g, 8.44
mmol)和硫脲 (0.64 g, 8.44 mmol)于95% EtOH (12.1 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和 Na2CO3水溶液 (1.0 mL)。过滤所得沉淀物,在甲苯(10 mL)中重结晶。过滤固体,真空干燥,得4-(3,5-二甲基-[1,1'-联苯]-4-基)噻唑-2-胺 (0.66 g) ,为黄色固体,产率 28% : 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 1 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.32
(m, 1 H), 7.25 (s, 2 H), 6.34 (s, 1 H), 5.03 (bs, 2 H), 2.24 (s, 6 H)。
化合物 1-(4- 氯 -2,6- 二甲基苯基 ) 乙酮。无水氯化铜(II) (98.9 g, 0.74 mol)与亚硝酸叔丁酯
(94.8 g, 0.83 mol)在乙腈(1.02 L)中混合。将溶液冷却至0℃,缓慢加入1-(4-氨基-2,6-二甲基苯基)乙酮 (100 g, 0.61 mol),历时5.0分钟。完成添加后,将反应混合物温热至室温,倒入盐酸水溶液(20%, 1.0 L)中。用EtOAc (800 mL)萃取溶液,分离有机层,用水(1.0mL)洗涤,用MgSO4 (s)干燥,减压浓缩。蒸馏液体,得1-(4-氯-2,6-二甲基苯基)乙酮(85.0 g),为黄色油状物,产率76%: 1H
NMR (500 MHz, CDCl3) δ 7.02 (s, 2 H),
2.45 (s, 3 H), 2.22 (s, 6 H)。
化合物 2- 溴 -1-(4- 氯 -2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮 (5.0 g, 27
mmol)于乙腈 (54.8 mL)中的溶液中加入四丁基三溴化铵(TBABr3,
13.2 g, 27.4 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,无水 MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-氯-2,6-二甲基苯基)乙酮 (7.2 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4- 氯 -2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-氯-2,6-二甲基苯基)乙酮 (6.54 g, 25.0 mmol)和硫脲(1.90
g, 25.0 mmol)于95% EtOH (35.7 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水 (50 mL),然后加入饱和Na2CO3 水溶液(4.0 mL)。过滤所得沉淀物,在甲苯(30 mL)中重结晶。过滤固体,真空干燥,得4-(4-氯-2,6-二甲基苯基)噻唑-2-胺 (4.30 g) ,为白色固体,产率72%: 1H
NMR (500 MHz, DMSO-d6 ) δ 7.16
(s, 2 H), 6.43 (s, 1 H), 2.10 (s, 6 H)。
化合物 N-(4-(2- 溴乙酰基 )-3,5- 二甲基苯基 ) 乙酰胺。向N-(4-乙酰基-3,5-二甲基苯基)乙酰胺 (5.00 g, 24.4
mmol)于乙腈(48.7 mL)中的溶液中加入四丁基三溴化铵
(TBABr3,11.7 g,24.4 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得N-(4-(2-溴乙酰基)-3,5-二甲基苯基)乙酰胺 (7.00 g),其被直接用于下一步,无需进一步纯化。
化合物 N-(4-(2- 氨基噻唑 -4- 基 )-3,5- 二甲基苯基 ) 乙酰胺。将N-(4-(2-溴乙酰基)-3,5-二甲基苯基)乙酰胺 (7.34 g, 25.8 mmol) 和硫脲
(1.97 g, 25.9 mmol) 于95% EtOH (36.9
mL)中的混合物加热回流120分钟。将溶液浓缩,加入水(100
mL)和饱和Na2CO3 水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(50 mL)中重结晶。过滤固体,真空干燥,得N-(4-(2-氨基噻唑-4-基)-3,5-二甲基苯基)乙酰胺(5.83 g),为黄色固体,产率86%: 1H NMR (500 MHz, DMSO-d6 ) δ 9.80 (s, 1 H), 7.26 (s, 2 H), 6.90 (bs, 2 H), 6.30 (s, 1
H), 2.06 (s, 6 H), 2.02 (s, 3 H)。
化合物 2- 溴 -1-(2,4,6- 三异丙基苯基 ) 乙酮。向1-(2,4,6-三异丙基苯基)乙酮 (10.0 g, 65.3 mmol) 于乙腈(81
mL)中的溶液中加入四丁基三溴化铵(TBABr3, 19.6 g, 40.6
mmol)。室温下搅拌反应3.0小时。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(2,4,6-三异丙基苯基)乙酮(13.2 g), 其被直接用于下一步,无需进一步纯化。
化合物 4-(2,4,6- 三异丙基苯基 ) 噻唑 -2- 胺。将2-溴-1-(2,4,6-三异丙基苯基)乙酮 (13.9 g, 42.7
mmol) 和硫脲(3.24 g, 42.6 mmol)于95% EtOH (60.9 mL)中的混合物加热回流过夜。将溶液浓缩,加入水(100mL),饱和Na2CO3 水溶液(10 mL),用乙酸乙酯萃取。用盐水洗涤有机层,用无水 MgSO4(s)干燥,减压浓缩,用硅胶柱色谱(33% EtOAc/己烷为洗脱剂)纯化,得4-(2,4,6-三异丙基苯基)噻唑-2-胺(3.28 g),为白色固体,产率25%: 1H
NMR (500 MHz, CDCl3) δ 7.03 (s, 2 H),
6.22 (s, 1 H), 4.75 (bs, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27–1.14 (m, 18 H)。
化合物 1-(2,6- 二甲基 -4- 苯氧基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(4.50 g, 24.6
mmol), K3PO4 (10.5 g, 49.3 mmol)和苯酚 (2.78 g, 29.5 mmol)于甲苯(49.3
mL)中的溶液中加入2-(二-叔丁基膦基)联苯 (221 mg, 0.74
mmol) 和Pd(OAc)2 (233 mg, 1.04 mmol)。在100℃ 在N2下加热反应2.0小时。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50
mL)洗涤滤饼,合并后的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(2,6-二甲基-4-苯氧基苯基)乙酮,为黄色油状物,产率68%: 1H NMR (500 MHz, CDCl3) δ 7.35 (t, J = 8.0 Hz, 2 H), 7.12 (t, J = 7.5
Hz ,1 H), 7.00 (d, J = 7.5 Hz, 2 H), 6.65 (s, 2 H), 2.48 (s, 3 H), 2.22
(s, 6 H)。
化合物 2- 溴 -1-(2,6- 二甲基 -4- 苯氧基苯基 ) 乙酮。向1-(2,6-二甲基-4-苯氧基苯基)乙酮(3.60 g, 15.0
mmol)于乙腈(30 mL)中的溶液中加入四丁基三溴化铵(TBABr3,
7.95 g, 15.0 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(2,6-二甲基-4-苯氧基苯基)乙酮(4.8 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(2,6- 二甲基 -4- 苯氧基苯基 ) 噻唑 -2- 胺。将2-溴-1-(2,6-二甲基-4-苯氧基苯基)乙酮(5.18 g, 16.2 mmol)和硫脲(1.24
g, 16.3 mmol)于95% EtOH (23.2 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3 水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(2,6-二甲基-4-苯氧基苯基)噻唑-2-胺(2.84 g),为黄色固体,产率59%: 1H
NMR (500 MHz, CDCl3) δ 7.33
(t, J = 7.5 Hz, 2 H), 7.26 (t, J = 7.5 Hz ,1 H), 7.10 (d, J
= 7.3, 2 H), 6.72 (s, 2 H), 6.30 (s, 1 H), 5.18 (bs, 2 H), 2.14 (s, 6 H)。
化合物 2- 溴 -1-(4- 异丙氧基 -2,6- 二甲基苯基 ) 乙酮。向1-(4-异丙氧基-2,6-二甲基苯基)乙酮(4.3 g, 20.9
mmol)于乙腈(41.7 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 11.1 g, 22.9 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-异丙氧基-2,6-二甲基苯基)乙酮(5.9 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4- 异丙氧基 -2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-异丙氧基-2,6-二甲基苯基)乙酮(5.18 g, 18.2 mmol)和硫脲(1.38
g, 18.2 mmol)于95% EtOH (26 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3 水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(4-异丙氧基-2,6-二甲基苯基)噻唑-2-胺(3.44 g),为黄色固体,产率72.2%: 1H
NMR (500 MHz, CDCl3) δ 6.60 (s, 2 H), 6.26
(s, 1 H), 4.97 (bs, 2 H), 4.54 (m, 1 H), 2.13 (s, 6 H), 1.32 (d, J = 6.1 Hz, 6
H)。
化合物 2- 溴 -1-(4-( 环戊基氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(环戊基氧基)-2,6-二甲基苯基)乙酮(4.60 g, 19.8
mmol)于乙腈(39.6 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 10.5 g, 21.8 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-(环戊基氧基)-2,6-二甲基苯基)乙酮(6.2 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-( 环戊基氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(环戊基氧基)-2,6-二甲基苯基)乙酮(6.16 g, 19.8 mmol) 和硫脲(1.51
g, 19.8 mmol)于95% EtOH (28.3 mL)中的混合物加热回流90分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3 水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(4-(环戊基氧基)-2,6-二甲基苯基)噻唑-2-胺(4.2 g),为白色固体,产率73.7%: 1H
NMR (500 MHz, CDCl3) δ 6.58
(s, 2 H), 6.24(s, 1 H), 4.75 (m, 1 H), 2.13 (s, 6 H), 1.88–1.78 (m, 6 H), 1.62–1.59
(m, 2 H)。
化合物 1-(4-(4- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(10.0 g, 54.8
mmol), K3PO4 (23.2 g, 110 mmol) 和4-甲氧基苯酚 (8.16 g, 65.7
mmol) 于甲苯(78.2 mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(349 mg, 0.82 mmol),Pd(OAc)2
(259 mg, 1.15 mmol)。 在100℃在N2下加热反应5.0小时。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物在MeOH 中重结晶,得1-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(11.1 g),为白色固体,产率75.0%: 1H NMR (500 MHz, CDCl3) δ 6.96 (m, 2 H), 6.88 (m, 2 H), 6.57 (s, 2 H), 3.81 (s, 3
H), 2.46 (s, 3 H), 2.20 (s, 6 H)。
化合物 2- 溴 -1-(4-(4- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(3.80 g, 14.1
mmol)于乙腈(28.1 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 7.46 g, 15.5 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(5.25 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(4- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(4.90 g, 14.0 mmol)和硫脲(1.07
g, 14.1 mmol) 于95% EtOH (20.0 mL)中的混合物加热回流100分钟。将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)噻唑-2-胺(3.10 g),为黄色固体,产率68%: 1H NMR (500 MHz, CDCl3) δ 6.98 (m, 2 H), 6.88 (m, 2 H), 6.64 (s, 2 H), 6.27 (s, 1
H), 5.40 (bs, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H)。
化合物 1-(4-(4- 氟苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(4.50 g, 24.6
mmol), K3PO4 (10.5 g, 49.3 mmol), 4-氟苯酚(3.31 g, 29.5 mmol)于甲苯(49.3
mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(314
mg, 0.74 mmol), Pd(OAc)2 (233 mg, 1.04 mmol)。在100℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(100mL)洗涤滤饼,合并后的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(4-(4-氟苯氧基)-2,6-二甲基苯基)乙酮(4.40 g) ,为黄色油状物,产率68%: 1H
NMR (500 MHz, CDCl3) δ 7.03
(m, 2 H), 6.98 (m, 2 H), 6.60 (s, 2 H), 2.47 (s, 3 H), 2.22 (s, 6 H)。
化合物 2- 溴 -1-(4-(4- 氟苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(4-氟苯氧基)-2,6-二甲基苯基)乙酮(4.40 g, 17.0
mmol)于乙腈(34.1 mL)中的溶液中加入四丁基三溴化铵(TBABr3,
9.04 g, 18.8 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-(4-氟苯氧基)-2,6-二甲基苯基)乙酮(5.8 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(4- 氟苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(4-氟苯氧基)-2,6-二甲基苯基)乙酮(5.74 g, 17.0 mmol)和硫脲(1.30
g, 17.1 mmol)于95% EtOH (24.3 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(100 mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-(4-氟苯氧基)-2,6-二甲基苯基)噻唑-2-胺(4.50 g),为黄色固体,产率84%: 1H NMR (500 MHz, CDCl3) δ 7.05–6.97 (m, 4 H),
6.66 (s, 2 H), 6.28 (s, 1 H), 5.95 (bs, 2 H), 2.14 (s, 6 H)。
化合物 2- 溴 -1-(4- 异丁氧基 -2,6- 二甲基苯基 ) 乙酮。向1-(4-异丁氧基-2,6-二甲基苯基)乙酮(4.3 g, 19.5
mmol)于乙腈(39 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 9.41 g, 19.5 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得1-(4-异丁氧基-2,6-二甲基苯基)乙酮(6.1 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4- 异丁氧基 -2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-异丁氧基-2,6-二甲基苯基)乙酮(5.84 g, 19.5 mmol)和硫脲(1.49
g, 19.6 mmol)于95% EtOH (28 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(4-异丁氧基-2,6-二甲基苯基)噻唑-2-胺(4.4 g),为白色固体,产率82%: 1H
NMR (500 MHz, CDCl3) δ 6.61 (s, 2 H),
6.24 (s, 1 H), 3.70 (d, J = 6.5 Hz, 2 H), 2.15 (s, 6 H), 2.07 (m, 1 H),
1.01 (d, J = 6.7 Hz, 6 H)。
化合物 1-(4-( 苯并 [d][1,3] 二氧杂环戊烯 -5- 基氧基 )-2,6- 二甲基苯基 ) 乙酮。 向1-(4-氯-2,6-二甲基苯基)乙酮 (5.0 g, 27.4
mmol), K3PO4 (11.6 g, 54.7 mmol),芝麻酚(4.54 g, 32.9 mmol)于甲苯(54.8
mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(349
mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol)。在100℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并后的滤液减压浓缩。残余物在MeOH中重结晶,得1-(4-(苯并[d][1,3]二氧杂环戊烯-5-基氧基)-2,6-二甲基苯基)乙酮(4.80 g),为白色固体,产率62%: 1H
NMR (500 MHz, CDCl3) δ 6.77 (d, J
= 8.5 Hz, 1 H), 6.59 (s, 2 H), 6.56 (s, 1 H), 6.48 (m, 1 H), 5.98 (s, 2 H),
2.46 (s, 3 H), 2.21 (s, 6 H)。
化合物 1-(4-( 苯并 [d][1,3] 二氧杂环戊烯 -5- 基氧基 )-2,6- 二甲基苯基 )-2- 溴乙酮。向1-(4-(苯并[d][1,3]二氧杂环戊烯-5-基氧基)-2,6-二甲基苯基)乙酮(4.80 g, 16.9
mmol)于乙腈(33.8 mL)中的溶液中加入四丁基三溴化铵(TBABr3,
8.14 g, 16.9 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得 1-(4-(苯并[d][1,3]二氧杂环戊烯-5-基氧基)-2,6-二甲基苯基)-2-溴乙酮(6.70 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-( 苯并 [d][1,3] 二氧杂环戊烯 -5- 基氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将1-(4-(苯并[d][1,3]二氧杂环戊烯-5-基氧基)-2,6-二甲基苯基)-2-溴乙酮(6.13 g, 16.9
mmol)和硫脲(1.29 g, 16.9 mmol)于95% EtOH (24.1 mL)中的混合物加热回流90分钟。 将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-(苯并[d][1,3]二氧杂环戊烯-5-基氧基)-2,6-二甲基苯基)噻唑-2-胺(5.50 g),为黄色固体,产率96%: 1H NMR (500 MHz, CDCl3) δ 6.75 (d, J = 8.5 Hz, 1 H), 6.66 (s, 2 H), 6.58
(m, 1 H), 6.49 (m, 1 H), 6.28 (s, 1 H), 5.98 (s, 2 H), 5.05 (bs, 2 H), 2.13 (s,
6 H)。
化合物 1-(4-(3,5- 二甲基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(5.0 g, 27.4
mmol), K3PO4 (11.6 g, 54.7 mmol), 3,5-二甲基苯酚(4.01 g, 32.8 mmol)于甲苯(54.8
mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(349
mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol)。在100℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(4-(3,5-二甲基苯氧基)-2,6-二甲基苯基)乙酮(6.3 g),为黄色固体,产率86%: 1H
NMR (500 MHz, CDCl3) δ 6.76
(s, 1 H), 6.63 (s, 2 H), 6.62 (s, 2 H), 2.48 (s, 3 H), 2.29 (s, 6 H), 2.22 (s,
6 H)。
化合物 2- 溴 -1-(4-(3,5- 二甲基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(3,5-二甲基苯氧基)-2,6-二甲基苯基)乙酮(6.30 g, 23.5
mmol)于乙腈(47.0 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 11.9 g, 24.7 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-(3,5-二甲基苯氧基)-2,6-二甲基苯基)乙酮(8.3 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(3,5- 二甲基苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(3,5-二甲基苯氧基)-2,6-二甲基苯基)乙酮(8.15 g, 23.5 mmol) 和硫脲(1.79
g, 23.5 mmol)于95% EtOH (33.5 mL)中的混合物加热回流120分钟。将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-(3,5-二甲基苯氧基)-2,6-二甲基苯基)噻唑-2-胺(4.50 g),为黄色固体,产率59%: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1 H), 6.68 (s, 2 H), 6.64 (s, 2 H), 6.26 (s, 1
H), 2.29 (s, 6 H), 2.16 (s, 6 H)。
化合物 1-(4-(3- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(5.00 g, 27.4
mmol), K3PO4 (11.6 g, 54.7 mmol), 3-甲氧基苯酚(4.08 g, 32.9 mmol)于甲苯(54.8
mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(349
mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol)。在100℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(4-(3-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(5.4 g),为黄色油状物,产率73%: 1H
NMR (500 MHz, CDCl3) δ 7.24
(m, 1 H), 6.68–6.66 (m, 3 H), 6.57–6.56 (m, 2 H), 3.79 (s, 3 H), 2.48 (s, 3 H), 2.22 (s, 6
H)。
化合物 2- 溴 -1-(4-(3- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(3-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(5.40 g, 20.0
mmol)于乙腈(40.0 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 10.1 g, 21.0 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(4-(3-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(7.00 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(3- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(3-甲氧基苯氧基)-2,6-二甲基苯基)乙酮(6.98 g, 20.0 mmol)和硫脲(1.52
g, 20.0 mmol)于95% EtOH (28.5 mL)中的混合物加热回流5.0小时。将溶液浓缩,加入水(50mL)和饱和Na2CO3 水溶液(1.0 mL),用乙酸乙酯 (100 ml)萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得4-(4-(3-甲氧基苯氧基)-2,6-二甲基苯基)噻唑-2-胺(4.30 g),为深棕色油状物,其被直接用于下一步,无需进一步纯化。
化合物 1-(2,6- 二甲基 -4-(4-( 三氟甲基 ) 苯氧基 ) 苯基 ) 乙酮。向1-氯-4-(三氟甲基)苯(6.60 g, 36.6 mmol), K3PO4 (12.9 g,
60.9 mmol), 1-(4-羟基-2,6-二甲基苯基)乙酮(5.00 g, 30.5
mmol)于甲苯(60.9 mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(388 mg, 0.91 mmol)和Pd(OAc)2
(288 mg, 1.28 mmol)。在100℃在N2下加热反应120分钟。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(2,6-二甲基-4-(4-(三氟甲基)苯氧基)苯基)乙酮(1.8 g),为黄色油状物,产率19%: 1H
NMR (500 MHz, CDCl3) δ 7.58 (d, J
= 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.70 (s, 2 H), 2.50 (s, 3 H),
2.25 (s, 6 H)。
化合物 2- 溴 -1-(2,6- 二甲基 -4-(4-( 三氟甲基 ) 苯氧基 ) 苯基 ) 乙酮。向1-(2,6-二甲基-4-(4-(三氟甲基)苯氧基)苯基)乙酮(1.80 g, 5.84
mmol)于乙腈(11.7 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 2.82 g, 5.84 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(2,6-二甲基-4-(4-(三氟甲基)苯氧基)苯基)乙酮(2.16 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(2,6- 二甲基 -4-(4-( 三氟甲基 ) 苯氧基 ) 苯基 ) 噻唑 -2- 胺。将2-溴-1-(2,6-二甲基-4-(4-(三氟甲基)苯氧基)苯基)乙酮(2.20 g, 5.68 mmol)和硫脲(0.43
g, 5.68 mmol)于95% EtOH (8.1 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(1.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(2,6-二甲基-4-(4-(三氟甲基)苯氧基)苯基)噻唑-2-胺(1.30 g),为黄色固体,产率63%: 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 2 H), 7.05 (d, J =
8.5 Hz, 2 H), 6.76 (s, 2 H), 6.32 (s, 1 H), 5.03 (s, 2 H), 2.17 (s, 6 H)。
化合物 1-(4-(4- 乙基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-氯-2,6-二甲基苯基)乙酮(5.0 g, 27.4
mmol), K3PO4 (11.6 g, 54.7 mmol), 4-乙苯(4.01 g, 32.8 mmol)于甲苯(54.8
mL)中的溶液中加入2-二-叔丁基膦基-2',4',6'-三异丙基联苯(349
mg, 0.82 mmol)和Pd(OAc)2 (259 mg, 1.15 mmol)。在100℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(4-(4-乙基苯氧基)-2,6-二甲基苯基)乙酮(6.0 g),为黄色油状物,产率82%: 1H
NMR (500 MHz, CDCl3) δ 7.17
(d, J = 8.5 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 6.63 (s, 2 H),
2.64 (q, J = 7.5 Hz, 2 H), 2.47 (s, 3 H), 2.21 (s, 6 H), 1.25 (t, J
= 7.5 Hz, 3 H)。
化合物 2- 溴 -1-(4-(4- 乙基苯氧基 )-2,6- 二甲基苯基 ) 乙酮。向1-(4-(4-乙基苯氧基)-2,6-二甲基苯基)乙酮(6.00 g, 22.4
mmol)于乙腈(44.7 mL)中的溶液中加入四丁基三溴化铵
(TBABr3, 10.8 g, 22.4 mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得 2-溴-1-(4-(4-乙基苯氧基)-2,6-二甲基苯基)乙酮(8.2 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(4- 乙基苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-(4-乙基苯氧基)-2,6-二甲基苯基)乙酮(7.70 g, 22.2 mmol)和硫脲(1.69
g, 22.2 mmol)于95% EtOH (31.7 mL)中的混合物加热回流180分钟。将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-(4-乙基苯氧基)-2,6-二甲基苯基)噻唑-2-胺(6.30 g),为黄色固体,产率88%: 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 7.5 Hz, 2 H), 6.95 (d, J =
8.5, 2 H), 6.71 (s, 2 H), 6.29 (s, 1 H), 5.45 (bs, 2 H), 2.64 (q, J =
7.5 Hz, 2 H), 2.14 (s, 6 H), 1.25 (t, J = 8.0 Hz, 3 H)。
化合物 2- 溴 -1-(3,5- 二氟 -4- 甲氧基苯基 ) 乙酮。向含有1-(3,5-二氟-4-甲氧基苯基)乙酮(5.0 g, 26.9
mmol, 1.0当量)的CH3CN溶液(56mL)中加入TBABr3
(12.95 g, 26.9 mmol, 1.0当量)。将反应混合物在室温下搅拌16小时。溶液减压浓缩,残余物重溶于EtOAc
(50 mL)。用饱和NaHCO3 水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(洗脱液:2.0%
EtOAc 的乙烷溶液)纯化,得2-溴-1-(3,5-二氟-4-甲氧基苯基)乙酮(5.05 g, 19.0
mmol),为白色固体,产率71%: 1H NMR (DMSO-d6 ,
500 MHz) δ 7.76–7.81
(m, 2 H), 4.91 (s, 2 H), 4.07 (s, 3 H)。
化合物 4-(3,5- 二氟 -4- 甲氧基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(3,5-二氟-4-甲氧基苯基)乙酮(2.0 g, 7.5 mmol, 1.0当量)和硫脲(0.57 g, 7.5 mmol, 1.0当量)的EtOH (20.0 mL)中的反应混合物加热回流3.0小时。残余物用饱和NaHCO3水溶液 (20
mL)碱化,用EtOAc (3 × 30
mL)萃取。分离有机层,用MgSO4(s)干燥,减压浓缩。所得固体用己烷洗涤,得4-(3,5-二氟-4-甲氧基苯基)噻唑-2-胺(1.54 g, 6.4 mmol),为白色固体,产率84%: 1H
NMR (DMSO-d6, 500 MHz) δ 7.49–7.54 (m, 2 H), 7.12–7.14
(m, 3 H), 3.92 (s, 3 H); ESI-MS: m/z 243.0 (M + H)+。
化合物 1-(2,6- 二氟 -4- 甲氧基苯基 ) 乙酮。 将氯化铝(10.0 g, 69.4 mmol, 5.0当量) 和乙酰氯(2.0 mL, 28 mmol, 2.0当量)于CH2Cl2 (50.0 mL)中的混合物在0℃下搅拌30分钟。反应混合物中缓慢加入1,3-二氟-5-甲氧基-苯(2.0 g, 13.9
mmol, 1.0当量)的CH2Cl2溶液(10.0 mL),所得溶液在室温下搅拌另外2.0小时。溶液用饱和NaHCO3水溶液(20
mL)碱化至pH 8–9。分离有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(15%
EtOAc的己烷溶液作为洗脱液)纯化,得1-(2,6-二氟-4-甲氧基苯基)乙酮(1.5 g, 8.1 mmol),为黄色油状物,产率58%: 1H
NMR (CDCl3, 500 MHz) δ 6.46–6.48 (m, 2 H), 3.83 (s, 3 H), 2.56 (s, 3 H); ESI-MS: m/z
187.0 (M + H)+。
化合物 2- 溴 -1-(2,5- 二氟 -4- 甲氧基苯基 ) 乙酮。向含有1-(2,6-二氟-4-甲氧基苯基)乙酮(1.5 g, 8.1
mmol, 1.0当量)的CH3CN溶液(20 mL)中加入TBABr3
(3.88 g, 8.1 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(2.0% EtOAc的己烷溶液作为洗脱液)纯化,得2-溴-1-(2,5-二氟-4-甲氧基苯基)乙酮(5.05 g, 19.1
mmol),为黄色油状物,产率84%: 1H NMR (CDCl3,
500 MHz) δ 6.50–6.52
(m, 2 H), 4.34 (s, 2 H), 3.85 (s, 3 H)。
化合物 4-(2,6- 二氟 -4- 甲氧基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(2,5-二氟-4-甲氧基苯基)乙酮(1.5 g, 5.7 mmol, 1.0当量)和硫脲(430.8 mg, 5.7 mmol, 1.0当量)的反应混合物于EtOH (15.0 mL)中加热回流6.0小时。残余物用饱和NaHCO3水溶液 (20
mL)碱化,用EtOAc (3 × 30
mL)萃取。分离有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得4-(2,6-二氟-4-甲氧基苯基)噻唑-2-胺(928.6 mg, 3.8
mmol),为白色固体,产率68%: 1H NMR (CDCl3, 500 MHz) δ 6.68 (s, 1 H), 6.50–6.52
(m, 2 H), 5.07 (brs, 2 H), 3.81 (s, 3 H); ESI-MS: m/z 243.7 (M + H)+。
化合物 1-(4-(2- 羟基丙氧基 )-2,6- 二甲基苯基 ) 乙酮。压力玻璃容器中装入1-(4-羟基-2,6-二甲基苯基)乙酮(500 mg, 3.1
mmol, 1.0当量)和2-甲基环氧乙烷 (0.22 mL, 3.1 mmol, 1.0当量) 的50%NaOH水溶液(5.0 mL),140℃搅拌4.0小时。用H2O (20 mL)稀释混合物,用EtOAc
萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(30% EtOAc的己烷溶液作为洗脱液)纯化,得1-(4-(2-羟基丙氧基)-2,6-二甲基苯基)乙酮(445.9 mg, 2.1 mmol),为黄色油状物,产率66%: 1H
NMR (CDCl3, 500 MHz) δ 6.57
(s, 2 H), 4.10–4.20 (brs, 1 H), 3.90–3.93 (m, 2 H), 3.75–3.79
(m, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 1.25–1.28
(m, 3 H); ESI-MS: m/z 223.4 (M + H)+。
化合物 2- 溴 -1-(4-(2- 羟基丙氧基 )-2,6- 二甲基苯基 ) 乙酮。向含有1-(4-(2-羟基丙氧基)-2,6-二甲基苯基)乙酮(445.9 mg, 2.0
mmol, 1.0当量)的CH3CN溶液(6.0 mL)中加入TBABr3
(967.3 mg, 2.0 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶剂减压浓缩,残余物在EtOAc (50mL)中再溶解。用饱和NaHCO3水溶液(30mL)洗涤溶液,用MgSO4干燥,减压浓缩。得2-溴-1-(4-(2-羟基丙氧基)-2,6-二甲基苯基)乙酮(547.8 mg, 1.8
mmol),为棕色油状物,产率91%: 1H NMR (CDCl3, 500 MHz) δ 6.60 (s, 2 H), 4.25 (s, 2 H), 4.10–4.20 (brs, 1 H), 3.91–3.94
(m, 2 H), 3.79–3.80 (s, 1 H), 2.24 (s, 6 H), 1.27–1.29 (m, 3 H)。
化合物 1-(4-(2- 氨基噻唑 -4- 基 )-3,5- 二甲基苯氧基 ) 丙 -2- 醇。将含有2-溴-1-(2,5-二氟-4-甲氧基苯基)乙酮(547.8 mg, 1.8 mmol, 1.0当量)和硫脲(138.5 mg, 1.8 mmol, 1.0当量)的反应混合物在EtOH (3.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (30 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(30% EtOAc的己烷溶液作为洗脱液)纯化,得1-(4-(2-氨基噻唑-4-基)-3,5-二甲基苯氧基)丙-2-醇(332.5 mg, 1.2 mmol),为黄色油状物,产率66%:
1H NMR (CDCl3, 500 MHz) δ 6.62 (s, 2 H),
6.26 (s, 1 H), 4.95 (brs, 2 H), 4.10–4.20
(brs, 1 H), 3.91–3.94(m, 2 H),
3.75–3.79 (m, 1 H), 2.15 (s, 6 H), 1.26–1.28 (m, 3 H); ESI-MS: m/z 279.7 (M + H)+。
化合物 1-(4-(2,3- 二羟丙氧基 )-2,6- 二甲基苯基 ) 乙酮。压力玻璃容器中装入1-(4-羟基-2,6-二甲基苯基)乙酮(2.00 g, 12.2
mmol, 1.0当量)和3-氯丙烷-1,2-二醇(1.02 mL, 12.2
mmol, 1.0当量)的50%
NaOH水溶液(20.0 mL),140℃加热16小时。用H2O
(20 mL)稀释混合物,用EtOAc萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(30% EtOAc的己烷溶液作为洗脱液)纯化,得1-(4-(2,3-二羟丙氧基)-2,6-二甲基苯基)乙酮(1.66 g, 7.0 mmol),为黄色油状物,产率57%: 1H
NMR (CDCl3, 500 MHz) δ 6.57
(s, 2 H), 4.10–4.11 (m, 1 H), 4.08–4.09 (m, 2 H), 4.01–4.02
(m, 1 H), 3.74–3.75 (m, 1 H), 2.58–2.59 (brs, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.05–2.10 (brs, 1 H); ESI-MS: m/z 239.9 (M + H)+。
化合物 2- 溴 -1-(4-(2,3- 二羟丙氧基 )-2,6- 二甲基苯基 ) 乙酮。向含有1-(4-(2,3-二羟丙氧基)-2,6-二甲基苯基)乙酮(1.0 g, 4.2
mmol, 1.0当量)的CH3CN溶液(10.0 mL)中加入TBABr3
(2.04 g, 4.2 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4干燥,减压浓缩。得2-溴-1-(4-(2,3-二羟丙氧基)-2,6-二甲基苯基)乙酮(741.9 mg, 2.3 mmol),为黄色固体,产率56%: 1H
NMR (CDCl3, 500 MHz) δ 6.60
(s, 2 H), 4.25 (s, 2 H), 4.10–4.11 (m, 1 H),
4.03–4.04 (m, 2 H), 3.82–3.85 (m, 1 H), 3.75–3.76
(m, 1 H), 2.24 (s, 6 H)。
化合物 3-(4-(2- 氨基噻唑 -4- 基 )-3,5- 二甲基苯氧基 ) 丙烷 -1,2- 二醇。将含有2-溴-1-(4-(2,3-二羟丙氧基)-2,6-二甲基苯基)乙酮(741.9 mg, 2.3 mmol, 1.0当量)和硫脲(178.1 mg, 2.3 mmol, 1.0当量) 的反应混合物于EtOH (10.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (30 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用 MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(30.0% EtOAc的己烷溶液作为洗脱液)纯化,得3-(4-(2-氨基噻唑-4-基)-3,5-二甲基苯氧基)丙烷-1,2-二醇(694.1 mg, 2.4
mmol),为黄色固体,产率>99%: 1H NMR (CDCl3,
500 MHz) δ 6.76 (s, 2 H), 5.31–5.32 (m, 1 H), 3.99–4.00
(m, 1 H), 3.79–3.87 (m, 1H), 3.78–3.79 (m, 1 H), 3.43–3.44 (m,
2 H), 3.37 (brs, 2 H), 2.15 (s, 6 H); ESI-MS: m/z 295.6 (M + H)+。
化合物 1-(4-(2- 甲氧基乙氧基 )-2,6- 二甲基苯基 ) 乙酮。压力玻璃容器中装入1-(4-羟基-2,6-二甲基苯基)乙酮(500 mg, 3.1
mmol, 1.0当量)和1-氯-2-甲氧基乙烷(0.28 mL, 3.1
mmol, 1.0当量)的50%NaOH水溶液(5.0 mL),140℃加热16小时。用 H2O
(20 mL)稀释残余物,用EtOAc (3 × 30
mL)萃取。分离有机层,用MgSO4干燥,减压浓缩,得1-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)乙酮(430.9 mg, 1.9
mmol),为黄色油状物,产率64%: 1H NMR (CDCl3, 500 MHz) δ 6.58 (s, 2 H), 4.09–4.10
(m, 2 H), 3.72–3.74 (m, 2 H), 3.44 (s, 3 H), 2.45 (s, 3
H), 2.23 (s, 6 H); ESI-MS: m/z 223.6 (M + H)+。
化合物 2- 溴 -1-(4-(2- 甲氧基乙氧基 )-2,6- 二甲基苯基 ) 乙酮。向含有1-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)乙酮(400 mg, 1.8
mmol, 1.0当量)的CH3CN溶液(6.0mL)中加入TBABr3
(867.7 mg, 1.8 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4(s)干燥,减压浓缩。得2-溴-1-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)乙酮(322.9 mg, 1.1 mmol),为黄色固体,产率60%: 1H
NMR (CDCl3, 500 MHz) δ 6.61
(s, 2 H), 4.25 (s, 2 H), 4.09–4.11 (m, 2 H),
3.73–3.75 (m, 2 H), 3.45 (s, 3 H), 2.24 (s, 6
H)。
化合物 4-(4-(2- 甲氧基乙氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)乙酮(322.9 mg, 1.1 mmol, 1.0当量)和硫脲(81.61 mg, 1.1 mmol, 1.0当量) 的反应混合物于EtOH (3.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (20 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(30% EtOAc的己烷溶液作为洗脱液)纯化,得4-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)噻唑-2-胺(281.0 mg, 1.0
mmol),为黄色固体,产率94%: 1H NMR (DMSO-d6 ,
500 MHz) δ 6.76 (s, 2 H), 5.31–5.33 (m, 1 H), 4.09–4.11
(m, 2 H), 3.64–3.65 (m, 2 H), 3.30 (s, 3 H), 2.12 (s, 6
H); ESI-MS: m/z 279.7 (M + H)+。
化合物 1-(4-(3- 甲氧基丙氧基 )-2,6- 二甲基苯基 ) 乙酮。压力玻璃容器中装入1-(4-羟基-2,6-二甲基苯基)乙酮(800 mg, 4.9
mmol, 1.0当量)和1-氯-3-甲氧基丙烷(528.97 mg, 4.9
mmol, 1.0当量)的50%NaOH水溶液(10.0 mL),140℃搅拌16小时。用H2O
(20 mL)稀释残余物,用EtOAc (3 × 30
mL)萃取。分离有机层,用 MgSO4(s)干燥,减压浓缩,得1-(4-(3-甲氧基丙氧基)-2,6-二甲基苯基)乙酮(987.8 mg, 4.2
mmol),为黄色油状物,产率86%: 1H NMR (DMSO-d6 ,
500 MHz) δ 6.56 (s, 2 H), 4.02–4.04 (m, 2 H), 3.53–3.55
(m, 2 H), 3.36 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.02–2.04 (m, 3H); ESI-MS: m/z 237.7 (M + H)+。
化合物 2- 溴 -1-(4-(3- 甲氧基丙氧基 )-2,6- 二甲基苯基 ) 乙酮。向含有1-(4-(3-甲氧基丙氧基)-2,6-二甲基苯基)乙酮(987.8 mg, 4.2
mmol, 1.0当量)的CH3CN溶液(15.0 mL)中加入TBABr3
(2.02 g, 4.2 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4干燥,减压浓缩。获得2-溴-1-(4-(3-甲氧基丙氧基)-2,6-二甲基苯基)乙酮(1.23 g, 3.9 mmol),为黄色油状物,产率93%: 1H
NMR (CDCl3, 500 MHz) δ 6.58
(s, 2 H), 4.24–4.35 (m, 2 H), 4.03–4.05 (m, 2 H), 3.53–3.55
(m, 2 H), 3.35 (s, 3 H), 2.24 (s, 6 H), 2.01–2.06
(m, 2 H)。
化合物 4-(4-(3- 甲氧基丙氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(4-(3-甲氧基丙氧基)-2,6-二甲基苯基)乙酮(500.0 mg, 1.6 mmol, 1.0当量)和硫脲(126.8 mg, 1.6 mmol, 1.0当量) 的反应混合物于EtOH (10.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3
(30 mL)水溶液洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(30% EtOAc的己烷溶液作为洗脱液)纯化,得4-(4-(3-甲氧基丙氧基)-2,6-二甲基苯基)噻唑-2-胺(328.9 mg, 1.1
mmol),为黄色固体,产率71%: 1H NMR (CDCl3,
500 MHz) δ 9.35 (brs, 1 H), 9.00 (brs, 1 H), 6.64
(s, 2 H), 6.22 (s, 1 H), 4.04–4.05 (m, 2 H),
3.54–3.56 (m, 2 H), 3.37 (s, 3 H), 2.19 (s, 6
H), 2.03–2.06 (m, 2 H); ESI-MS m/z 293.8 (M + H)+。
化合物 1-(2,6- 二甲基 -4-( 苯硫基 ) 苯基 ) 乙酮。将1-(4-碘-2,6-二甲基苯基)乙酮(1.5 g, 5.5
mmol, 1.0当量), 苯硫酚(0.60
mL, 8.2 mmol, 1.5当量), 氧化铜(I)(39.2 mg, 0.3 mmol, 0.05当量)和氢氧化钾(614.1 mg, 11.0 mmol, 2.0当量)于DMF (4.4 mL)和H2O
(1.1 mL)中的混合物加热回流20小时。用H2O
(10 mL)淬灭混合物,用乙醚 (2 × 20
mL)萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得1-(2,6-二甲基-4-(苯硫基)苯基)乙酮(931 mg, 3.6
mmol),为黄色油状物,产率66%: 1H NMR (CD3OD, 500 MHz) δ 7.34–7.35 (m, 5 H), 6.97
(s, 2 H), 2.46 (s, 3 H), 2.17 (s, 6 H); ESI-MS: m/z 257.0 (M + H)+。
化合物 2- 溴 -1-(2,6- 二甲基 -4-( 苯硫基 ) 苯基 ) 乙酮。向含有1-(2,6-二甲基-4-(苯硫基)苯基)乙酮(816.3 mg, 3.2
mmol, 1.0当量)的CH3CN溶液(15.0 mL)中加入TBABr3
(1.54 g, 3.2 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得2-溴-1-(2,6-二甲基-4-(苯硫基)苯基)乙酮(591.7 mg, 1.6 mmol),为黄色油状物,产率55%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.36–7.42 (m, 5 H), 7.01 (s, 2 H), 4.75 (s, 2 H), 2.13 (s, 6
H)。
化合物 4-(2,6- 二甲基 -4-( 苯硫基 ) 苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(2,6-二甲基-4-(苯硫基)苯基)乙酮(591.7 mg, 1.8
mmol, 1.0当量)和硫脲(134.3
mg, 1.8 mmol, 1.0当量) 的反应混合物于EtOH (15.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(5.0% EtOAc的己烷溶液作为洗脱液)纯化,得4-(2,6-二甲基-4-(苯硫基)苯基)噻唑-2-胺(483.7 mg, 1.6 mmol),为黄色固体,产率88%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.33–7.38 (m, 2 H), 7.29–7.33
(m, 3 H), 7.06 (brs, 2 H), 6.89 (s, 2 H), 6.38 (s, 1 H), 2.07 (s, 6 H); ESI-MS:
m/z 313.8 (M + H)+。
化合物 1-(2,6- 二甲基 -4-( 对甲苯硫基 ) 苯基 ) 乙酮。 将1-(4-碘-2,6-二甲基苯基)乙酮(1.5 g, 5.5 mmol, 1.0当量), 4-甲基苯硫酚(1.02 g, 8.2 mmol, 1.5当量),氧化铜(I)(39.2 mg, 0.3 mmol, 0.05当量)和氢氧化钾(614.1 mg, 11.0 mmol, 2.0当量)于DMF (4.4 mL)和H2O
(1.1 mL)中的混合物加热回流20小时。用H2O
(10 mL)淬灭混合物,用醚 (2 × 20
mL)萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得1-(2,6-二甲基-4-(对甲苯硫基)苯基)乙酮(1.16 g, 4.3
mmol),为黄色油状物,产率79%: 1H NMR (CD3OD, 500 MHz) δ 7.29 (d, J = 8.0 Hz, 2 H), 7.20 (d, J =
8.0 Hz, 2 H), 6.88 (s, 2 H), 2.45 (s, 3 H), 2.35 (s, 3 H), 2.15 (s, 6 H);
ESI-MS: m/z 271.8 (M + H)+。
化合物 2- 溴 -1-(2,6- 二甲基 -4-( 对甲苯硫基 ) 苯基 ) 乙酮。向含有1-(2,6-二甲基-4-(对甲苯硫基)苯基)乙酮(1.0 g, 3.7
mmol, 1.0当量)的CH3CN溶液 (20.0 mL)中加入TBABr3
(1.79 g, 3.7 mmol, 1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30
mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得2-溴-1-(2,6-二甲基-4-(对甲苯硫基)苯基)乙酮(394.8 mg, 1.1 mmol),为黄色油状物,产率31%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.33
(d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 6.92 (s, 2 H),
4.76 (s, 2 H), 2.32 (s, 3 H), 2.11 (s, 6 H)。
化合物 4-(2,6- 二甲基 -4-( 对甲苯硫基 ) 苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(2,6-二甲基-4-(对甲苯硫基)苯基)乙酮(394.8 mg, 1.1
mmol, 1.0当量)和硫脲(86.04
mg, 1.1 mmol, 1.0当量) 的反应混合物于EtOH (10.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(5.0% EtOAc的己烷溶液作为洗脱液)纯化,得4-(2,6-二甲基-4-(对甲苯硫基)苯基)噻唑-2-胺(371.9 mg, 1.1 mmol),为黄色固体,产率>99%:
1H NMR (DMSO-d6 , 500 MHz) δ 7.27 (d, J = 8.0 Hz, 2 H), 7.21 (d, J =
8.0 Hz, 2 H), 6.97 (s, 2 H), 6.87 (s, 2 H), 6.36 (s, 1 H), 2.30 (s, 3 H), 2.05
(s, 6 H); ESI-MS: m/z 327.0 (M + H)+。
化合物 1-(4-(4- 甲氧基苯硫基 )-2,6- 二甲基苯基 ) 乙酮。将1-(4-碘-2,6-二甲基苯基)乙酮(1.5 g, 5.5
mmol, 1.0当量), 对甲氧基苯硫酚(1.01
mL, 8.2 mmol, 1.5当量), 氧化铜(I)(39.2 mg, 0.3 mmol, 0.05当量)和氢氧化钾(614.1 mg, 11.0 mmol, 2.0当量)于DMF (4.4 mL)和H2O
(1.1 mL)中的混合物加热回流20小时。用H2O
(10 mL)淬灭混合物,用醚(2 × 20
mL)萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(1.41 g, 4.9 mmol),为黄色油状物,产率90%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.39
(d, J = 8.5 Hz, 2 H), 6.96 (d, J = 8.5 Hz, 2 H), 6.79 (s, 2 H),
3.82 (s, 3 H), 2.43 (s, 3 H), 2.13 (s, 6 H); ESI-MS: m/z 287.6 (M + H)+。
化合物 2- 溴 -1-(4-(4- 甲氧基苯硫基 )-2,6- 二甲基苯基 ) 乙酮。 向含有1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(1.0 g, 3.5 mmol, 1.0当量)的CH3CN溶液(20.0
mL)中加入TBABr3 (1.684 g, 3.5 mmol,
1.0当量)。室温下搅拌反应混合物16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(3.0% EtOAc的己烷溶液作为洗脱液)纯化,得2-溴-1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(1.06 g, 2.9
mmol),为黄色油状物,产率83%: 1H NMR (DMSO-d6 ,
500 MHz) δ 7.44 (d, J = 8.7 Hz, 2 H), 7.03
(d, J = 8.7 Hz, 2 H), 6.83 (s, 2 H), 4.71 (s, 2 H), 3.80 (s, 3 H), 2.10
(s, 6 H)。
化合物 4-(4-(4- 甲氧基苯硫基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(1.06 g, 2.9 mmol, 1.0当量)和硫脲(221.5 mg, 2.9 mmol, 1.0当量)的反应混合物于EtOH (20.0 mL)中加热回流16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱(5.0% EtOAc的己烷溶液作为洗脱液)纯化,得4-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)噻唑-2-胺(890.9 mg, 2.6
mmol),为黄色固体,产率90%: 1H NMR (DMSO-d6 ,
500 MHz) δ 7.40 (d, J = 8.7 Hz, 2 H), 7.00
(d, J = 8.7 Hz, 2 H), 6.86–6.87
(m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M + H)+。
化合物 2- 溴 -1-(4-(4- 甲氧基苯磺酰基 )-2,6- 二甲基苯基 ) 乙酮。将2-溴-1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(1.0 g, 2.7 mmol, 1.0当量)和间氯过氧苯甲酸(1.69 g, 6.8 mmol, 2.5当量)于二氯甲烷(10.0 mL)中的混合物室温下搅拌16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩,得2-溴-1-(4-(4-甲氧基苯磺酰基)-2,6-二甲基苯基)乙酮(1.09 g, 2.7 mmol),为白色固体,产率>99%:
1H NMR (CDCl3, 500 MHz) δ 7.85–7.90 (m, 2 H), 7.57–7.60
(m, 2 H), 6.97–6.90 (m, 2 H), 4.21 (s, 2 H), 3.85 (s, 3
H), 2.30 (s, 6 H)。
化合物 4-(4-(4- 甲氧基苯磺酰基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。将含有2-溴-1-(4-(4-甲氧基苯磺酰基)-2,6-二甲基苯基)乙酮(1.33 g, 3.4 mmol, 1.0当量)和硫脲(254.8 mg, 3.4 mmol, 1.0当量)于EtOH (5.0 mL)中的反应混合物加热回流1.0小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。用己烷洗涤所得固体,得4-(4-(4-甲氧基苯磺酰基)-2,6-二甲基苯基)噻唑-2-胺(839.2 mg, 2.2 mmol),为黄色固体,产率65%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.89
(d, J = 8.9 Hz, 2 H), 7.61 (s, 2 H), 7.13 (d, J = 8.9 Hz, 2 H),
6.95 (brs, 2 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 375.6
(M + H)+。
化合物 2- 溴 -1-(4-(4- 甲氧基苯基亚磺酰基 )-2,6- 二甲基苯基 ) 乙酮。将2-溴-1-(4-(4-甲氧基苯硫基)-2,6-二甲基苯基)乙酮(500.0 mg, 1.3 mmol, 1.0当量), 醋酸酐(0.14 mL, 1.5 mmol, 1.1当量),
30%过氧化氢(55.86 mg, 1.6 mmol, 1.2当量)和硅胶(273.75 mg, 230–400目)于二氯甲烷(10.0 mL)中的混合物在室温下搅拌16小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩,得2-溴-1-(4-(4-甲氧基苯基亚磺酰基)-2,6-二甲基苯基)乙酮(235.4 mg, 0.6 mmol),为浅黄色油状物,产率48%: 1H
NMR (DMSO-d6 , 500 MHz) δ 7.65
(d, J = 8.8 Hz, 2 H), 7.41 (s, 2 H), 7.09 (d, J = 8.8 Hz, 2 H),
4.78 (s, 2 H), 3.79 (s, 3 H), 2.21 (s, 6 H)。
化合物 N -(4-(4-(4- 甲氧基苯基亚磺酰基 )-2,6- 二甲基苯基 ) 噻唑 -2- 基 ) 异烟酰胺。将含有2-溴-1-(4-(4-甲氧基苯基亚磺酰基)-2,6-二甲基苯基)乙酮(235.4 mg, 0.6
mmol, 1.0当量)和硫脲(47.0
mg, 0.60 mmol, 1.0当量) 的反应混合物于EtOH (5.0 mL)中加热回流1.0小时。溶液减压浓缩,残余物在EtOAc (50 mL)中再溶解。用饱和NaHCO3水溶液(30 mL)洗涤溶液,用MgSO4干燥,减压浓缩。用己烷洗涤所得固体,得N-(4-(4-(4-甲氧基苯基亚磺酰基)-2,6-二甲基苯基)噻唑-2-基)异烟酰胺(236.7 mg, 0.70 mmol),为黄色固体,产率>99%:
1H NMR (DMSO-d6 , 500 MHz) δ 7.64 (d, J = 8.9 Hz, 2 H), 7.34 (s, 2 H), 7.09
(d, J = 8.9 Hz, 2 H), 6.90 (brs, 2 H), 6.39 (s, 1 H), 3.79 (s, 3 H),
2.13 (s, 6 H); ESI-MS m/z 359.0 (M + H)+。
化合物 5- 甲基 -4- 苯基噻唑 -2- 胺。 将2-溴-1-苯基丙-1-酮(3.00 g, 19.5
mmol)和硫脲(1.56 g, 20.5 mmol)于95% EtOH (30 mL)中的混合物加热回流60分钟。将溶液浓缩,与水(100mL)和饱和Na2CO3水溶液(5.0 mL)混合。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得5-甲基-4-苯基噻唑-2-胺(4.07 g),为黄色固体,产率77%: 1H
NMR (500 MHz, DMSO-d6 ) δ 8.85
(s, 2 H), 7.54–7.49 (m, 5 H), 2.28 (s, 3 H)。
化合物 2- 溴 -1-(4- 甲氧基苯基 ) 丙 -1- 酮。 向1-(4-甲氧基苯基)丙-1-酮(5.01 g, 30.2 mol)于EtOAc
(120 mL)中的溶液中加入溴化酮(II)(CuBr2, 13.6 g, 6.8 mmol)。反应混合物加热回流90分钟。使溶液冷却,滤出所得固体,并用EtOAc
洗涤。滤液减压浓缩,得粗2-溴-1-(4-甲氧基苯基)丙-1-酮(10.4 g),为黄色油状物: 1H
NMR (500 MHz, CDCl3) δ 8.02
(2 H, m), 6.96 (2 H, m), 5.28-5.25 (m, 1 H), 3.89 (s, 3 H), 1.89 (d, 3 H)。
化合物 4-(4- 甲氧基苯基 )-5- 甲基噻唑 -2- 胺。 将2-溴-1-(4-甲氧基苯基)丙-1-酮(10.4 g, 36.1 mmol)和硫脲(2.76
g, 36.2 mmol)于95% EtOH (70 mL)中的混合物加热回流60分钟。将溶液浓缩,与水(100mL)和饱和Na2CO3水溶液(5.0 mL)混合。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-甲氧基苯基)-5-甲基噻唑-2-胺(6.16 g),为黄色固体,产率78%: 1H
NMR (500 MHz, DMSO-d6 ) δ 8.90
(s, 2 H), 7.46–7.44 (m, 2 H), 7.09–7.07 (m, 2 H), 3.81 (s, 3 H), 2.47 (s, 3 H)。
化合物 2- 溴 -1-(2,4,6- 三甲氧基苯基 ) 乙酮。向1-(2,4,6-三甲氧基苯基)乙酮(5.0 g, 23.3 mmol)于EtOAc
(100 mL)中的溶液中加入溴化铜(II)(CuBr2, 10.4 g, 46.7
mmol)。反应混合物加热回流90分钟。使溶液冷却,滤出所得固体,用EtOAc洗涤。滤液减压浓缩,得粗2-溴-1-(2,4,6-三甲氧基苯基)乙酮(2.70 g),为黄色油状物: 1H-NMR (500 MHz, CDCl3) δ 6.11 (m, 2 H), 4.36 (m, 2 H), 3.86 (s, 3 H), 3.82 (s, 6
H)。
化合物 4-(2,4,6- 三甲氧基苯基 ) 噻唑 -2- 胺。将2-溴-1-(2,4,6-三甲氧基苯基)乙酮(2.49 g, 8.6
mmol)和硫脲(0.67 g, 8.7 mmol)于95% EtOH (16 mL)中的混合物加热回流60分钟。将溶液浓缩,与水(100mL)和饱和Na2CO3水溶液(5.0 mL)混合。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(2,4,6-三甲氧基苯基)噻唑-2-胺(1.75 g),为黄色固体,产率>99%: 1H
NMR (500 MHz, DMSO-d6 ) δ 9.00
(s, 2 H), 6.78 (s,1 H), 6.36 (s, 2 H), 3.84 (s, 3 H), 3.79 (s, 6 H)。
化合物 2- 溴 -1-(4- 甲氧基苯基 ) 乙酮。 向1-(4-甲氧基苯基)乙酮(15.2 g, 0.10 mol)于EtOAc
(250 mL)中的溶液中加入溴化铜(II)(CuBr2, 45.1 g, 0.20 mol)。反应混合物加热回流90分钟。使溶液冷却,滤出所得固体,用EtOAc
洗涤。滤液减压浓缩,得粗2-溴-1-(4-甲氧基苯基)乙酮(15.8 g),为黄色油状物: 1H NMR (500 MHz, CDCl3) δ 7.98 (m, 2 H), 6.97 (m, 2 H), 4.41 (s, 3 H), 3.89 (s, 6
H)。
化合物 4-(4- 甲氧基苯基 ) 噻唑 -2- 胺。将2-溴-1-(4-甲氧基苯基)乙酮(5.00 g, 21.8
mmol)和硫脲(1.72 g, 22.6 mmol)于95% EtOH (40 mL)中的混合物加热回流60分钟。将溶液浓缩,与水(100mL)和饱和Na2CO3水溶液(5.0 mL)混合。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(4-甲氧基苯基)噻唑-2-胺(5.24 g),为黄色固体,产率>99%: 1H
NMR (500 MHz, DMSO-d6 ) δ 7.72
(d, 2 H), 6.99 (s, 2 H), 6.92–6.91 (m, 2 H),
6.82 (s, 1 H), 3.76 (s, 3 H)。
化合物 2- 溴 -1-(2,4- 二甲氧基苯基 ) 乙酮。 将1-(2,4-二甲氧基苯基)乙酮(10.0 g, 54.4 mmol)于EtOAc
(220 mL)中的溶液中加入溴化铜(II)(CuBr2, 24.3 g, 0.11 mol)。反应混合物加热回流90分钟。使溶液冷却,滤出所得固体,用EtOAc
洗涤。滤液减压浓缩,得粗2-溴-1-(2,4-二甲氧基苯基)乙酮(14.5 g),为黄色油状物: 1H NMR (500 MHz, CDCl3) δ 7.91 (m, 2 H), 6.52 (m, 2 H), 4.57 (s, 3 H), 3.98 (s, 3
H), 3.85 (s, 3 H)。
化合物 4-(2,4- 二甲氧基苯基 ) 噻唑 -2- 胺。 将2-溴-1-(2,4-二甲氧基苯基)乙酮(14.5 g, 55.8
mmol)和硫脲(4.32 g, 56.7 mmol)于95% EtOH (110 mL)中的混合物加热回流60分钟。将溶液浓缩,与水(100mL)和饱和Na2CO3
(5.0 mL)水溶液混合。过滤所得沉淀物,在甲苯中重结晶。过滤固体,真空干燥,得4-(2,4-二甲氧基苯基)噻唑-2-胺(10.9 g),为黄色固体,产率62%: 1H
NMR (500 MHz, DMSO-d6 ) δ 8.60
(s, 2 H), 7.53 (s, 1 H), 6.97 (s, 1 H), 6.69 (s, 1 H), 6.67–6.63 (m,1 H), 3.86 (s, 3 H), 3.80 (s, 3 H)。
化合物 2- 氯 -1-(2,4,6- 三氟苯基 ) 乙酮。 向1,3,5-三氟苯(6.0 mL, 58
mmol)于二氯乙烷(14.0 mL)中的机械搅拌溶液中小心逐步加入AlCl3
(15.5 g, 116 mmol),历时15分钟。观察到猛烈暴沸和HCl气体逸出。混合物小心加热回流,逐滴加入氯乙酰氯(5.5
mL, 69 mmol),历时45分钟。反应混合物再加热回流6.0小时。冷却溶液,小心倒在冰水浆上(200mL),用醚(3 × 50 mL)萃取水溶液。用10% HCl水溶液 (2 × 30 mL), 1.0 N
NaOH水溶液 (3 × 30
mL)和盐水(25 mL)洗涤合并的醚层。用MgSO4干燥溶液,减压浓缩,得2-氯-1-(2,4,6-三氟苯基)乙酮(5.28 g),为黄色固体,产率51%: 1H NMR (500 MHz, CDCl3) δ 6.79–6.76 (m, 2 H),
4.50 (s, 2 H)。
化合物 4-(2,4,6- 三氟苯基 ) 噻唑 -2- 胺。将 2-氯-1-(2,4,6-三氟苯基)乙酮(9.04 g, 43.5
mmol)和硫脲(3.51 g, 46.1 mmol)于95% EtOH (50 mL)中的混合物加热回流过夜。将溶液浓缩,与水(100mL)和饱和Na2CO3水溶液(5.0 mL)混合。过滤固体,真空干燥,得4-(2,4,6-三氟苯基)噻唑-2-胺(9.71 g),为粉白色固体,产率97%: 1H
NMR (500 MHz, DMSO-d6 ) δ 7.26–7.22 (m, 2 H), 7.09 (s, 2 H), 6.77 (s, 1 H)。
化合物 1-(2,6- 二甲基 -4-( 苯基氨基 ) 苯基 ) 乙酮。向1-(4-氨基-2,6-二甲基苯基)乙酮(3.26 g, 20.0
mmol), K3PO4 (9.2 g, 40 mmol)和1-碘苯(4.08 g, 20.0
mmol)于DMF (35.0 mL)中的溶液中加入CuI (761.8 mg, 40 mmol)。在110℃在N2下加热反应过夜。溶液冷却至室温,通过硅藻土小垫片过滤。用乙酸乙酯(50mL)洗涤滤饼,合并的滤液减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(2,6-二甲基-4-(苯基氨基)苯基)乙酮,为红棕色糖浆: 1H
NMR (500 MHz, CDCl3) δ 7.30
(d, J = 8.2 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 2 H), 6.99 (d, J
= 4.2 Hz, 1 H), 6.71 (s, 1 H), 2.47 (s, 3 H) , 2.18 (s, 6 H); ESI-MS: m/z 239.5
(M + H)+。
化合物 1-(4-(4- 溴苯氨基 )-2,6- 二甲基苯基 )-2- 溴乙酮。 向1-(2,6-二甲基-4-(苯氨基)苯基)乙酮(2.10 g, 8.78 mmol)于乙腈(50
mL)中的溶液中加入四丁基三溴化铵 (TBABr3, 4.24 g, 8.78
mmol)。室温下搅拌反应60分钟。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,无水MgSO4(s)干燥,减压浓缩,得1-(4-(4-溴苯氨基)-2,6-二甲基苯基)-2-溴乙酮(2.01 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(4-(4- 溴苯氨基 )-2,6- 二甲基苯基 ) 噻唑 -2- 胺。1-(4-(4-溴苯氨基)-2,6-二甲基苯基)-2-溴乙酮(1.6 g, 4.0
mmol)和硫脲(0.79 g, 7.2 mmol)于乙腈(30 mL)中的溶液加热回流90分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(1.0 mL),用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得产物(1.1g),其被直接用于下一步,无需进一步纯化。
化合物 3- 氯 -5- 甲基 - 苯胺。向含有1-氯-3-甲基-5-硝基苯(5.0 g, 29 mmol)的乙醇溶液(75mL)中加入SnCl2∙2H2O (32.8 g, 146 mmol)。反应混合物回流3.0小时。溶液真空浓缩,残余物在NaOH水溶液中再溶解,过滤,用 EtOAc 萃取。收集有机层,用盐水洗涤,用MgSO4干燥,减压浓缩。残余物通过硅胶柱色谱纯化,得3-氯-5-甲基-苯胺(4.0 g),为淡黄色固体,产率97%: 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1 H), 3.66 (bs, 2
H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M + H)+。
化合物 N -(3- 氯 -5- 甲基 - 苯基 )- 乙酰胺。将醋酸酐(6.7
mL)和3-氯-5-甲基-苯胺(5.0 g, 35 mmol)混合,静置2.0小时。将反应混合物冷却至室温,得N-(3-氯-5-甲基-苯基)-乙酰胺(5.1 g),为淡黄色固体,产率79%: 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1 H), 7.19 (s, 1 H), 7.12 (s, 1 H), 6.91 (s, 1
H), 2.31 (s, 3 H), 2.16 (s, 3 H)。
化合物 N-(4- 乙酰基 -3- 氯 -5- 甲基 - 苯基 )- 乙酰胺。向含有N-(3-氯-5-甲基-苯基)乙酰胺(5.0 g, 27 mmol)和乙酰氯(2.9 ml, 40.8 mmol)的干CS2溶液(30 mL)中缓慢加入氯化铝(9.1 g, 68 mmol)。反应混合物加热回流30分钟,冷却至室温,静置4.0小时。轻轻倒出CS2,剩余的糖浆倒入冰HCl中。收集所得固体,在EtOH中再溶解,用炭脱色。过滤溶液,滤液真空浓缩,得N-(4-乙酰基-3-氯-5-甲基苯基)乙酰胺(5.2 g),为淡黄色固体,产率85%: 1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 2.52 (s, 3
H), 2.24 (s, 3 H), 2.18 (s, 3 H)。
化合物 1-(4- 氨基 -2- 氯 -6- 甲基苯基 ) 乙酮。将含有N-(4-乙酰基-3-氯-5-甲基苯基)乙酰胺(0.53 g, 2.3
mmol)和浓盐酸(1.6 mL)的乙醇溶液(4.0mL)加热回流15小时。溶液中加入10%NaOH水溶液,收集所得固体,得1-(4-氨基-2-氯-6-甲基苯基)乙酮(0.37 g),为淡黄色固体,产率88%: 1H
NMR (500 MHz, CDCl3) δ 6.46 (d, J = 1.77 Hz, 1 H), 6.34 (s, 1 H), 3.85 (bs, 2 H),
2.49 (s, 3 H), 2.14 (s, 3 H): ESI-MS: m/z 183.4 (M + H)+。
化合物 1-(2- 氯 -4- 碘 -6- 甲基 - 苯基 )- 乙酮。 -10℃下,向含有KI (2.5 g, 15 mmol) 和亚硝酸叔丁酯(2.00
mL, 16.9 mmol)的CH3CN溶液(20mL)中加入1-(4-氨基-2-氯-6-甲基-苯基)乙酮(2.3 g, 12.5 mmol)的CH3CN
(13 mL)溶液。反应混合物温热至室温,倒入HCl水溶液(20%,
23 mL)。用EtOAc (20 mL)萃取溶液,分离有机层,用H2O (23 mL)洗涤,用MgSO4(s)干燥,减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-(2-氯-4-碘-6-甲基苯基)乙酮(1.28 g),为黄色油状物,产率35%: 1H
NMR (500 MHz, CDCl3) δ 7.58 (s, 1 H),
7.49 (s, 1 H), 2.51 (s, 3 H), 2.21 (s, 3 H)。
化合物 1-[2- 氯 -4-(4- 甲氧基 - 苯氧基 )-6- 甲基 - 苯基 ]- 乙酮。向1-(2-氯-4-碘-6-甲基苯基)乙酮(1.1 g, 3.7 mmol), K3PO4 (1.6 g,
7.4 mmol)和4-甲氧基苯酚(0.55
g, 4.44 mmol)于DMF (55 mL)中的溶液加入四丁基溴化铵(0.12 g, 0.37 mmol)和碘化铜(I)(70
mg, 0.37 mmol)。反应加热回流22小时。用EtOAc
(10 mL)萃取溶液,分离有机层,用H2O (11 mL)洗涤,用MgSO4(s)干燥,减压浓缩。残余物通过快速硅胶柱色谱纯化,得1-[2-氯-4-(4-甲氧基苯氧基)-6-甲基苯基]乙酮,为黄色油状物,产率19%: 1H
NMR (500 MHz, CDCl3) δ 6.97
(m, 2 H), 6.90 (m ,2 H), 6.73 (d, J = 2.19 Hz, 1 H), 6.67 (d, J = 1.99 Hz, 1
H), 3.81 (s, 3 H), 2.52 (s, 3 H) , 2.20 (s, 3 H)。
化合物 2- 溴 -1-[2- 氯 -4-(4- 甲氧基苯氧基 )-6- 甲基苯基 ] 乙酮。向1-[2-氯-4-(4-甲氧基苯氧基)-6-甲基苯基]乙酮(0.20 g, 0.69 mmol)于乙腈(6.0
mL)中的溶液中加入TBABr3 (0.33 g, 0.69 mmol)。室温下搅拌反应30分钟。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(2,6-二甲基-4-苯氧基苯基)乙酮,其被直接用于下一步,无需进一步纯化。
化合物 4-[2- 氯 -4-(4- 甲氧基苯氧基 )-6- 甲基 - 苯基 ]- 噻唑 -2- 基胺。 将2-溴-1-(2,6-二甲基-4-苯氧基苯基)乙酮和硫脲(63 mg, 0.83
mmol)于95% EtOH (3.0 mL)中的混合物加热回流60分钟。将溶液浓缩,加入水(50mL)和饱和NaHCO3水溶液(5.0
mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-[2-氯-4-(4-甲氧基苯氧基)-6-甲基苯基]噻唑-2-基胺(0.10 g),为黄色固体,产率42%: 1H NMR (500 MHz, CDCl3) δ 6.98 (m, 2 H), 6.90 (m, 2 H), 6.83 (d, J = 2.4 Hz, 1 H),
6.73 (d, J = 2.3 Hz, 1 H), 6.41 (s, 1 H), 4.97 (brs, 2 H) , 3.81 (s, 3 H), 2.16
(s, 3 H)。
化合物 2- 溴 -1-(2,6- 二甲基 -4-( 甲硫基 ) 苯基 ) 乙酮。向1-(4-(环戊基氧基)-2,6-二甲基苯基)乙酮(3.30 g, 17.0 mmol)于乙腈(34.0
mL)中的溶液中加入四丁基三溴化铵 (TBABr3, 8.19 g, 17.0
mmol)。将反应在室温下搅拌过夜。溶液减压浓缩,加入水,用乙酸乙酯萃取。用盐水洗涤有机层,用无水MgSO4(s)干燥,减压浓缩,得2-溴-1-(2,6-二甲基-4-(甲硫基)苯基)乙酮(5.2 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(2,6- 二甲基 -4-( 甲硫基 ) 苯基 ) 噻唑 -2- 胺。将2-溴-1-(2,6-二甲基-4-(甲硫基)苯基)乙酮(4.64 g, 17.0
mmol)和硫脲(1.29 g, 17.0 mmol)于95% EtOH (24.3 mL)中的混合物加热回流120分钟。将溶液浓缩,加入水(50mL)和饱和Na2CO3水溶液(4.0 mL)。过滤所得沉淀物,在甲苯(30mL)中重结晶。过滤固体,真空干燥,得4-(2,6-二甲基-4-(甲硫基)苯基)噻唑-2-胺(1.9 g),为淡黄色固体,产率45%: 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 2 H), 6.26 (s, 1 H), 2.47 (s, 3 H), 2.15 (s, 6
H)。
化合物 2- 溴 -1-(2,6- 二甲基 -4-( 甲磺酰基 ) 苯基 ) 乙酮。在0℃下向 2-溴-1-(2,6-二甲基-4-(甲硫基)苯基)乙酮(4.92 g, 0.653
mol)于CH2Cl2 (36 mL)中的溶液中加入mCPBA (70%, 11.1 g, 1.63 mol)。室温下搅拌混合物7.0小时。过滤溶液,滤液中加入饱和NaHCO3水溶液(50 mL)。用无水MgSO4(s)干燥有机层,减压浓缩,得2-溴-1-(2,6-二甲基-4-(甲磺酰基)苯基)乙酮(7.6 g),其被直接用于下一步,无需进一步纯化。
化合物 4-(2,6- 二甲基 -4-( 甲磺酰基 ) 苯基 ) 噻唑 -2- 胺。2-溴-1-(2,6-二甲基-4-(甲磺酰基)苯基)乙酮(7.60 g, 24.9 mmol)和硫脲(1.90
g, 25.0 mmol)于95% EtOH (35.6 mL)中的混合物加热回流90分钟。将溶液浓缩,加入水(100mL)和饱和Na2CO3水溶液(5.0 mL)。过滤所得沉淀物,在甲苯(20mL)中重结晶。过滤固体,真空干燥,得4-(2,6-二甲基-4-(甲磺酰基)苯基)噻唑-2-胺(3.28 g),为黄色固体,产率47%: 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 2 H), 6.34 (s, 1 H), 5.19 (m, 1 H), 3.04 (s, 3
H), 2.26 (s, 6 H)。
化合物 2- 氨基 -N-(4-(4-(4- 甲氧基苯氧基 )-2,6- 二甲基苯基 ) 噻唑 -2- 基 ) 异烟酰胺。将N-(4-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基) 噻唑-2-基)-2-硝基异烟酰胺(0.20 g, 0.40 mmol) 和Pd/C
(0.15 g, 10% w/w)于乙醇(10 mL)中的混合物在H2下搅拌过夜。反应通过硅藻土过滤,减压浓缩,得2-氨基-N-(4-(4-(4-甲氧基苯氧基)-2,6-二甲基苯基)噻唑-2-基)异烟酰胺,为黄色固体,产率59%: 1H-NMR
(500 MHz, DMSO-d6) δ 7.88–7.89 (m, 1 H), 7.10–7.11
(m, 2 H), 6.95–6.97 (m, 2 H), 6.62 (s, 1 H), 5.76 (s, 1
H), 3.29 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 446.6 [M + H]+。
化合物 N-(4- 均三甲苯基噻唑 -2- 基 )-2- 吗啉代异烟酰胺。将2-氯-N-(4-均三甲苯基噻唑-2-基)异烟酰胺(500.0 mg, 1.4 mmol, 1.0当量)和吗啉(1.5 mL, 16.8 mmol, 12当量)于甲基吡咯烷酮(15.0 mL)中的混合物在150℃下搅拌16小时。混合物倒入冰冷的H2O
(20.0 mL)中,过滤所得固体,得N-(4-均三甲苯基噻唑-2-基)-2-吗啉代异烟酰胺(358.6 mg, 0.90
mmol),为黄色固体,产率63%: 1H NMR (DMSO-d6, 500
MHz) δ 8.30 (d, J = 5.1 Hz, 2 H), 7.50 (s, 1
H), 7.22 (d, J = 5.1 Hz, 2 H), 7.10 (s, 1 H), 6.92 (s, 2 H), 3.70–3.73 (m, 4 H), 3.53–3.55
(m, 4 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 409.3 (M + H)+。
化合物 N-(4- 均三甲苯基噻唑 -2- 基 )-2-(4- 甲基哌嗪 -1- 基 ) 异烟酰胺。将2-氯-N-(4-均三甲苯基噻唑-2-基)异烟酰胺(300.0 mg, 0.8
mmol, 1.0当量)和1-甲基哌嗪(1.12 mL, 10.1 mmol, 12当量)于甲基吡咯烷酮(9.0 mL)中的混合物在150℃下搅拌16小时。将混合物倒入冰冷的H2O
(15.0 mL)中,过滤所得固体,得N-(4-均三甲苯基噻唑-2-基)-2-(4-甲基哌嗪-1-基)异烟酰胺(95.6 mg, 0.20
mmol),为黄色固体,产率27%: 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J = 5.1 Hz, 1 H), 7.12 (s, 1 H), 6.83–6.86 (m, 3 H), 6.78 (s, 1 H), 3.63–3.65 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 3 H), 2.04 (s, 6
H); ESI-MS: m/z 422.1 (M + H)+。
化合物 N-(4- 均三甲苯基噻唑 -2- 基 )-2-( 哌啶 -1- 基 ) 异烟酰胺。将2-氯-N-(4-均三甲苯基噻唑-2-基)异烟酰胺(200 mg, 0.60
mmol, 1.0当量)和哌啶(0.70
mL, 6.7 mmol, 12当量)于甲基吡咯烷酮(6.0 mL)中的混合物在150℃下搅拌16小时。将混合物倒入冰冷的H2O
(10.0 mL)中,过滤所得固体。固体通过硅胶柱色谱(15% EtOAc的己烷溶液作为洗脱液)纯化,得N-(4-均三甲苯基噻唑-2-基)-2-(哌啶-1-基)异烟酰胺(87.2 mg, 0.20
mmol),为黄色固体,产率38%: 1H NMR (CDCl3,
500 MHz) δ 8.29 (d, J = 5.1 Hz, 1 H), 7.15 (s, 1
H), 6.83–6.90 (m, 3 H), 6.79 (s, 1 H), 3.61–3.63 (m, 4 H), 2.31 (s, 3 H), 2.08 (s, 6 H), 1.57–1.67 (m, 6 H); ESI-MS: m/z 407.2 (M + H)+。
化合物 2-( 二甲氨基 )-N-(4- 均三甲苯基噻唑 -2- 基 ) 异烟酰胺。将2-氯-N-(4-均三甲苯基噻唑-2-基)异烟酰胺(200 mg, 0.60 mmol, 1.0当量), 碳酸铯 (2.73 g, 0.6 mmol, 15当量)和2.0 M二甲胺的THF (3.4 mL, 6.7
mmol, 12当量)溶液于DMF
(6.0 mL)中的混合物加热回流16小时。将混合物倒入冰冷的H2O
(10.0 mL)中,用EtOAc萃取。收集有机层,用MgSO4(s)干燥,减压浓缩。残余物通过硅胶柱色谱(15% EtOAc的己烷溶液作为洗脱液)纯化,得2-(二甲氨基)-N-(4-均三甲苯基噻唑-2-基)异烟酰胺(5.5 mg, 0.10
mmol),为黄色固体,产率3.0%: 1H NMR (CDCl3, 500 MHz)
δ 8.32 (d, J = 5.1 Hz, 1 H), 7.02 (s, 1
H), 6.92 (s, 2 H), 6.85 (d, J = 5.1 Hz, 1 H), 6.80 (s, 1 H), 3.16 (s, 6 H),
2.31 (s, 3 H), 2.09 (s, 6 H); ESI-MS: m/z 367.1 (M + H)+。
化合物 N-(4-(4- 苄基 -2,6- 二甲基苯基 ) 噻唑 -2- 基 ) 异烟酰胺。将苄基溴化锌(II)(4.0
mL, 2.0 mmol)的THF溶液加入N-(4-(4-碘-2,6-二甲基苯基)噻唑-2-基)异烟酰胺(435 mg, 1.0 mmol)和四三苯基膦钯(57.8
mg, 0.10 mmol) 于THF (5.0 mL)中的脱气溶液中。在N2下将反应混合物加热回流16小时,然后倒入饱和NaHCO3水溶液中。用乙酸乙酯萃取混合物,用盐水洗涤,用MgSO4干燥,减压浓缩。残余物通过快速硅胶柱色谱纯化,得N-(4-(4-苄基-2,6-二甲基苯基)噻唑-2-基)异烟酰胺: 1H
NMR (500 MHz, CDCl3) δ 8.70
(d, J = 4.9 Hz, 2 H), 7.67 (d, J = 4.9 Hz, 2 H), 7.33 (d, J = 8.6 Hz, 2 H),
7.10–7.26 (m, 3 H), 6.80 (s, 1 H), 6.24 (s, 1
H), 3.86 (s, 2 H), 2.04 (s, 6 H); ESI-MS: m/z 399.9 (M + H)+。
化合物 N-(4-(4-(4- 甲氧基苄基 )-2,6- 二甲基苯基 ) 噻唑 -2- 基 ) 异烟酰胺。将4-甲氧基苄基溴化锌(II)(4.0 mL, 2.0 mmol)的THF溶液加入N-(4-(4-碘-2,6-二甲基苯基)噻唑-2-基)异烟酰胺(435 mg, 1.0
mmol)和四三苯基膦钯(57.8 mg, 0.10 mmol)于THF (5.0 mL)中的脱气溶液中。在N2下将反应混合物加热回流16小时,然后倒入饱和NaHCO3水溶液中。用乙酸乙酯萃取混合物,用盐水洗涤,用MgSO4干燥,减压浓缩。残余物通过快速硅胶柱色谱纯化,得N-(4-(4-(4-甲氧基苄基)-2,6-二甲基苯基)噻唑-2-基)异烟酰胺: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 5.2 Hz, 2 H), 7.66 (d, J = 4.9 Hz, 2 H),
7.11 (d, J = 8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80
(s, 2 H), 3.78 (s, 2 H), 1.98(s, 6 H); ESI-MS: m/z 399.9 (M + H)+。
示例性化合物和理化数据
产率: 67%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.23 (d, 2 H), 8.02 (d, 2 H), 7.09 (s,
1 H), 6.92 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 348.0 (M + H)+。
产率: 62%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.41 (s, 1 H), 9.15 (d, 1 H), 8.14 (d,
1 H), 7.17 (s, 1 H), 6.89 (s, 2 H), 2.25 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z
325.1 (M + H)+。
产率: 8.6%; 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 5.5 Hz, 2 H), 7.65–7.63 (m, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.17 (s, 1 H),
7.14 (d, J = 7.5 Hz, 2 H), 2.34 (s, 6 H); ESI-MS: m/z 295.9 (M + H)+。
产率: 63%; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H),
7.55 (d, J = 8.5 Hz, 2 H), 7.17 (s, 1 H), 7.12 (d, J = 8.0 Hz, 2 H), 2.34 (s, 6
H); ESI-MS: m/z 317.9 (M – H)–。
产率: 62%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.72 (s, 1 H), 9.50 (d, 1 H), 8.21 (m,
1 H), 7.13 (s, 1 H), 6.94 (s, 2 H), 2.27 (s, 3 H), 2.06 (s, 6 H); ESI-MS: m/z
324.5 (M + H)+。
产率: 40%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.36 (s, 1 H), 8.82 (brs, 1 H), 7.06
(s, 1 H), 6.93 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 329.3 (M +
H)+。
产率: 74%; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, 1 H), 8.73–8.72
(m, 1 H), 8.15–8.14 (m, 1 H), 7.42–7.41 (m, 2 H), 7.35 (m, 1 H), 6.87–6.85 (m, 2 H), 3.82 (s, 3 H), 2.51 (s, 6 H); ESI-MS: m/z
325.3 [M + H]+。
产率: 87%; 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1 H), 8.82–8.81
(m, 1 H), 8.39–8.36 (m, 1 H), 7.80–7.79 (m, 1 H), 7.48–7.46
(m, 1 H),7.43–7.39 (m, 1 H), 6.58–6.55 (m, 2 H), 3.92 (s, 3 H), 3.86 (s, 3 H); ESI-MS: m/z
341.4 [M + H]+。
产率: >99%; 1H NMR (500 MHz, CDCl3) δ 10.55 (s, 1 H), 8.65–8.64
(m, 1 H), 8.30–8.29 (m, 1 H), 7.93 (m, 1 H), 7.60–7.58 (m, 2 H), 7.54–7.53
(m, 1 H), 6.99–6.98 (m, 2 H), 3.86 (s, 3 H), 2.54 (s, 3
H); ESI-MS: m/z 325.6 [M + H]+。
产率: >99%; 1H NMR (500 MHz, DMSO-d6 )
δ 11.98 (s, 1 H), 8.78–8.77 (m, 1 H), 8.19–8.17
(m, 1 H), 8.11–8.09 (m, 1 H), 7.89–7.87 (m, 2 H), 7.74–7.71
(m, 1 H), 7.58 (m, 1 H), 7.00–6.99 (m, 2 H),
3.79 (s, 3 H), 2.54 (s, 3 H); ESI-MS: m/z 310.0 [M – H]–。
产率: 89%; 1H NMR (500 MHz, DMSO-d6 )
δ 11.9 (s, 1 H), 8.79–8.78 (m, 1 H), 8.20–8.19
(m, 1 H), 8.12–8.07 (m, 1 H), 7.75–7.74 (m, 2 H), 7.61 (s, 1 H), 6.68–6.63 (m, 2 H), 3.92 (s, 3 H), 3.82 (s, 3 H); ESI MS: m/z
340.3 [M – H]–。
产率 90%: 1H NMR (500 MHz, DMSO-d6 )
δ 11.9 (s, 1 H), 8.76–8.77 (m, 1 H), 8.18–8.19
(m, 1 H), 8.10 (m, 1 H), 7.69–7.73 (m, 3 H),
7.45–7.48 (m, 1 H), 7.36–7.38 (m, 1 H), 2.50 (s, 3 H); ESI-MS: m/z 295.4 [M + H]+。
产率78%: 1H NMR (500 MHz, DMSO-d6 )
δ 9.24 (d, 1 H), 8.79 (t, 1 H), 8.44 (d,
1 H), 7.75 (s, 1 H), 7.58–7.60 (m, 1 H),
7.26 (s, 2 H), 3.85 (s, 6 H), 3.69 (s, 3 H); ESI-MS: m/z 372.5 [M + H]+。
产率81%: 1H NMR (500 MHz, DMSO-d6 )
δ 9.23 (d, 1 H), 8.80 (t, 1 H), 8.44 (d,
1 H), 8.00–8.03 (m, 1 H), 7.58–7.60 (m, 1 H), 7.46 (d, 1 H), 6.90–6.98 (m, 2 H), 3.82 (s, 3 H); ESI-MS: m/z 330.0 [M + H]+。
产率 53%: 1H NMR (500 MHz, CDCl3) δ 11.01 (s, 1 H), 7.82–7.86
(m, 1 H), 7.27 (d, 1 H), 6.63–6.84 (m, 6 H),
3.80 (s, 3 H), 3.76 (s, 3 H), 2.77 (t, 2 H), 2.29 (t, 3 H); ESI-MS: m/z 387.0
[M + H]+。
产率 45%: 1H NMR (500 MHz, CDCl3) δ 10.87 (s, 1 H), 7.83–7.87
(m, 1 H), 7.15–7.27 (m, 5 H), 7.95 (d, 2 H), 6.62–6.73 (m, 2 H), 3.80 (s, 3 H), 2.86 (t, 2 H), 2.36 (t, 2
H); ESI-MS: m/z 356.0 [M + H]+。
产率 77%: 1H NMR (500 MHz, DMSO-d6 )
δ 12.04 (s, 1 H), 8.79 (d, 2 H), 8.02–8.21 (m, 3 H), 7.74 (t, 1 H), 7.49 (d, 2 H), 6.90–6.97 (m, 2 H), 3.82 (s, 3 H); ESI-MS: m/z 330.0 [M + H]+。
产率75%: 1H NMR (500 MHz, DMSO-d6 )
δ 12.04 (s, 1 H), 8.78 (s, 1 H), 8.18 (d,
1 H), 8.11 (t, 1 H), 7.78–7.82 (m, 2 H),
7.28 (s, 2 H), 3.86 (s, 6 H), 3.69 (s, 3 H); ESI-MS: m/z 372.0 [M + H]+。
产率84%: 1H NMR (500 MHz, DMSO-d6 )
δ 8.82 (d, 2 H), 7.99–8.03 (m, 3 H), 7.48 (d, 1 H), 6.91–6.98 (m, 2 H), 3.83 (s, 3 H); ESI-MS: m/z 330.0 [M + H]+。
产率 82%: 1H NMR (500 MHz, DMSO-d6 )
δ 8.79 (d, 2 H), 8.00–8.01 (m, 2 H), 7.71 (s, 1 H), 7.26 (s, 2 H), 3.85 (s, 6
H), 3.70 (s, 3 H); ESI-MS: m/z 372.0 [M + H]+。
产率: 6.7%; 1H NMR (500 MHz, CDCl3) δ 10.96 (bs, 1 H), 9.11 (bs, 1 H), 8.75 (bs, 1 H), 8.14
(d, J = 8.0 Hz, 1 H), 7.60 (d, J = 7.5 Hz, 2 H), 7.34 (s, 1 H), 7.15 (s, 1 H),
7.12 (d, J = 7.5 Hz, 2 H), 2.33 (s, 6 H); ESI-MS: m/z 293.7 (M – H)–。
产率: 83%; 1H NMR (500 MHz, CDCl3) δ 11.24 (s, 1 H), 8.68 (d, J = 4.5 Hz, 1 H), 8.31 (d, J =
8.0 Hz, 1 H), 7.95 (m, 1 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.54 (m, 1 H), 7.24 (m,
2 H), 7.17 (s, 1 H), 2.39 (s, 6 H); ESI-MS: m/z 295.6 (M + H)+。
产率: 36%; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.5 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H),
7.20 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 2.51 (s, 3 H), 2.27 (s, 3
H); ESI-MS: m/z 332.0 (M – H)–。
产率: 56%; 1H NMR (500 MHz, CDCl3) δ 8.99 (s, 1 H), 8.63 (d, J = 5.0 Hz, 1 H), 8.01 (d, J =
7.9 Hz, 1 H), 7.29–7.21 (m, 3 H),
7.03 (d, J = 7.8 Hz, 2 H), 2.49 (s, 3 H), 2.29 (s, 3 H); ESI-MS: m/z 310.3 (M +
H)+.
产率: 79%; 1H NMR (500 MHz, CDCl3)
δ 11.11 (s, 1 H), 8.64 (d, J = 4.5 Hz, 1
H), 8.29 (d, J = 7.5 Hz,1 H), 7.93 (t, J = 8.0 Hz, 1 H), 7.55–7.51 (m, 3 H), 7.25 (d, J = 7.5 Hz,1 H), 2.54 (s, 3 H),
2.40 (s, 3 H); ESI-MS: m/z 309.0 (M – H)–。
产率: 37%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.59 (s, 1 H), 8.60 (s, 1 H), 7.69–7.76 (m, 2 H), 7.04 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3
H), 2.06 (s, 6 H); ESI-MS: m/z 327.1 (M – H)–
产率: 54%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.89 (d, 2 H), 8.00 (d, 2 H), 7.57 (d,
1 H), 7.44–7.46 (m, 1 H), 7.26 (d, 1 H), 7.11 (s, 3
H), 3.81 (s, 3 H); ESI-MS: m/z 327.9 (M + H)+。
产率: 44%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.25 (s, 1 H), 8.91 (s, 1 H), 8.45–8.48 (m, 1 H), 7.65–7.67
(m, 1 H), 7.57 (d, 1 H), 7.44–7.46 (m, 1 H),
7.26 (d, 1 H), 7.10 (s, 2 H), 3.81 (s, 3 H); ESI-MS: m/z 328.0 (M + H)+。
产率: 37%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.82 (d, 1 H), 8.23 (d, 1 H), 8.08 (d,
1 H), 7.74–7.75 (m, 1 H), 7.57 (d, 1 H), 7.44–7.46 (m, 1 H), 7.23 (d, 1 H), 7.10 (s, 2 H), 3.81 (s, 3
H); ESI-MS: m/z 328.1 (M + H)+。
产率: 94%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.98 (s, 1 H), 9.23 (m, 1 H), 8.80 (m,
1 H), 8.46–8.43 (m, 1 H), 7.90–7.88 (m, 2 H), 7.61–7.56
(m, 1 H), 7.02–7.00 (m, 2 H), 3.80 (s, 3 H); ESI-MS:
m/z 310.0 [M – H]–。
产率: 99%; 1H NMR (500 MHz, DMSO-d6 )
δ 7.82–7.80
(m, 2 H), 7.60–7.58 (m, 2 H), 7.41–7.40 (m, 2 H), 7.30–7.29
(m, 2 H), 7.22–7.19 (m, 1 H), 2.54 (s, 3 H); ESI-MS:
m/z 320.0 [M + H]+。
产率: 66%; 1H NMR (500 MHz, CD3OD) δ 8.18–8.17 (m, 2 H),
7.92–7.90 (m, 2 H), 7.60–7.58 (m, 2 H), 7.01–7.00
(m, 2 H), 3.84 (s, 3 H), 2.50 (s, 2 H); ESI-MS m/z 349.5 [M + H]+。
产率: 85%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.3 (s, 1 H), 7.99–7.97 (m, 1 H), 7.64 (s, 1 H), 7.24 (m, 1 H), 6.91 (m, 2
H), 6.90 (m, 1 H), 6.66–6.61 (m, 2 H),
3.89 (s, 3 H), 3.80 (s, 3 H), 3.75–3.74(m,
5 H); ESI-MS: m/z 385.1 [M + H]+。
产率: 76%; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1 H), 7.56–7.55
(m, 2 H), 7.43–7.40 (m, 2 H), 7.34–7.33 (m, 1 H), 7.26–7.22
(m, 1 H), 3.77 (s, 3 H), 3.47 (s, 2 H), 2.49 (s, 3 H); ESI-MS: m/z 339.2 [M +
H]+。
产率: 69%; 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 5.5 Hz, 2 H), 7.55 (d, J = 6.0 Hz, 2 H),
6.77 (s, 1 H), 6.32 (s, 2 H), 3.73 (s, 3 H), 1.91 (s, 6 H); ESI-MS: m/z 340.0
(M + H)+。
产率: 54%; 1H NMR (500 MHz, CDCl3) δ 8.57 (d, J = 5.0 Hz, 2 H), 7.46 (d, J = 5.5 Hz, 2 H),
7.25 (d, J = 4.5 Hz, 2 H), 7.02 (d, J = 7.5 Hz, 2 H), 2.51 (s, 3 H), 2.28 (s, 3
H); ESI-MS: m/z 309.9 (M + H)+。
产率: 51%; 1H NMR (500 MHz, CDCl3) δ 8.79 (d, J = 5.5 Hz, 2 H), 7.70 (d, J = 5.5 Hz, 2 H),
6.86 (s, 1 H), 6.77 (s, 1 H), 2.45 (s, 3 H), 2.23 (s, 3 H), 2.03 (s, 3 H);
ESI-MS: m/z 324.5 (M + H)+。
产率: 18%; 1H NMR (500 MHz, CDCl3) δ 11.22 (s, 1 H), 8.65 (d, J = 4.5 Hz, 1 H), 8.31 (d, J =
7.5 Hz, 1 H), 7.96 (t, J = 7.5 Hz, 1 H), 7.54 (m, 1 H), 6.92 (s, 1 H), 6.85 (s,
1 H), 2.52 (s, 3 H), 2.37 (s, 3 H), 2.133 (s, 3 H); ESI-MS: m/z 325.0 (M + H)+。
产率: 18%; 1H NMR (500 MHz, CDCl3) δ 9.11 (s, 1 H), 8.77 (s, 1 H), 8.17 (d, J = 7.5 Hz, 1 H),
7.42 (m, 1 H), 6.85 (s, 1 H), 6.78 (s, 1 H), 2.45 (s, 3 H), 2.27 (s, 3 H), 2.02
(s, 3 H); ESI-MS: m/z 325.1 (M + H)+。
产率: 54%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.75 (s, 1 H), 9.61 (s, 1 H), 8.28–8.30 (m, 1 H), 7.58 (d, 1 H), 7.46–7.48 (m, 1 H), 7.29 (d, 1 H), 7.12 (s, 3 H), 3.82 (s, 3
H); ESI-MS: m/z 329.4 (M + H)+。
产率: 44%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.49 (d, 1 H), 9.19 (d, 1 H), 8.22–8.23 (m, 1 H), 7.58 (d, 1 H), 7.45–7.47 (m, 1 H), 7.27 (d, 1 H), 7.12 (s, 3 H), 3.82 (s, 3
H); ESI-MS: m/z 328.9 (M + H)+。
产率: 37%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.58 (d, 1 H), 7.73–7.75 (m, 1 H), 7.60 (d, 1 H), 7.55 (d, 1 H), 7.42–7.44 (m, 1 H), 7.18 (d, 1 H), 7.09 (m, 3 H); ESI-MS: m/z
333.0 (M + H)+。
产率: 37%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.49 (s, 1 H), 8.75 (s, 1 H), 7.56 (s,
1 H), 7.43–7.45 (m 1 H), 7.24 (d, 1 H), 7.11 (m, 3
H), 3.81 (s, 3 H); ESI-MS: m/z 333.9 (M + H)+。
产率: 32%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.63 (s, 1 H), 7.91 (s, 1 H), 7.54 (s,
1 H), 7.41–7.43 (m, 1 H), 7.08–7.18 (m, 4 H), 6.93 (s, 1 H), 3.80 (s, 3 H); ESI-MS: m/z
316.9 (M + H)+。
产率: 88%; 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 6.0 Hz, 2 H), 7.58(d, J = 6.0 Hz, 2 H),
6.78 (s, 1 H), 6.37 (s, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 1.94 (s, 6 H), 1.41(t,
J = 7.0 Hz, 3 H); ESI-MS: m/z 353.6 (M + H)+。
产率: 78%; 1H NMR (500 MHz, CDCl3) δ 8.58 (m, 2 H), 7.53–7.44
(m, 5 H), 7.37 (m, 1 H), 7.03 (s, 2 H), 6.86 (s, 1 H), 2.02 (s, 6 H); ESI-MS:
m/z 385.7 (M + H)+。
产率: 89%; 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J = 6.0 Hz, 2 H), 7.57 (m, 2 H), 6.81 (m, 3 H),
1.92 (s, 6 H); ESI-MS: m/z 343.8 (M + H)+。
产率: 38%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.28 (d, 2 H), 8.09 (d, 2 H), 7.88 (d,
2 H), 7.31 (d, 2 H), 7.04–7.08 (m, 3 H);
ESI-MS: m/z 322.0 (M + H)+。
产率: 75%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.89 (d, 2 H), 8.01–8.06 (m, 2 H), 7.89 (d, 2 H), 7.32 (d, 2 H), 7.05–7.09 (m, 3 H); ESI-MS: m/z 297.6 (M + H)+。
产率: 48%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.49 (s, 1 H), 9.18 (d, 1 H), 8.23 (d,
1 H), 7.86–7.91 (m, 2 H), 7.33 (d, 2 H), 7.06–7.09 (m, 3 H); ESI-MS: m/z 192.5 (M – 106, aminothiazole)。
产率: 49%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.82 (d, 1 H), 8.24 (d, 1 H), 8.07–8.10 (m, 1 H), 7.88 (d, 2 H), 7.73–7.75 (m, 1 H), 7.30 (d, 2 H), 7.05–7.08 (m, 3 H); ESI-MS: m/z 297.7 (M + H)+。
产率: 49%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.26 (d, 1 H), 8.91 (d, 1 H), 8.47 (d,
1 H), 7.89 (d, 2 H), 7.65–7.67 (m, 1 H),
7.32 (d, 2 H), 7.05–7.08 (m, 3 H);
ESI-MS: m/z 297.6 (M + H)+。
产率: 48%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.24–8.30
(m, 2 H), 8.04–8.11 (m, 2 H), 7.63 (d, 1 H), 7.00–7.20 (m, 4 H), 6.67 (s, 1 H); ESI-MS: m/z 335.7 (M + H)+。
产率: 67%; 1H NMR (DMSO-d6 , 500
MHz) δ 13.10 (s, 1 H), 8.82 (d, J = 5.6 Hz, 2
H), 8.00 (d, J = 5.6 Hz, 2 H), 7.88 (s, 1 H), 7.70–7.72 (m, 2 H), 3.96 (s, 3 H); ESI-MS m/z 348.0 (M + H)+。
产率: 40%; 1H NMR (500 MHz, DMSO-d6 )
δ 10.49 (bs, 1 H), 8.54 (d, J = 6.5 Hz, 2
H), 7.94 (s, 2 H), 6.88 (s, 1 H), 6.74 (s, 2 H), 3.76 (s, 3 H), 2.10 (s, 6 H);
ESI-MS: m/z 354.8 (M + H)+。
产率: 73%; 1H NMR (500 MHz, DMSO-d6 )
δ 9.87 (s, 1 H), 9.40 (s, 1 H), 8.39 (d,
J = 6.0 Hz, 2 H), 7.49 (d, J = 6.5 Hz, 2 H), 7.32 (s, 2 H), 6.92 (s, 1 H), 2.06
(s, 6 H), 2.04 (s, 3 H); ESI-MS: m/z 381.8 (M + H)+。
产率: 62%; 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 5.5 Hz, 2 H), 7.83 (d, J = 6.0 Hz, 2 H),
7.06 (s, 2 H), 6.82 (s, 1 H), 2.94 (m, 1 H), 2.64 (m, 2 H), 1.29 (d, J = 7.0
Hz, 6 H), 1.13 (d, J = 7.0 Hz, 12 H); ESI-MS: m/z 407.9 (M + H)+。
产率: 39%; 1H NMR (500 MHz, DMSO-d6 )
δ 13.03 (bs, 1 H), 9.86 (s, 1 H), 8.80
(d, J = 5.5 Hz, 2 H), 7.99 (d, J = 5.5 Hz, 2 H), 7.34 (s, 2 H), 7.13 (s, 1 H),
2.06 (s, 6H); ESI-MS: m/z 385.7 (M + H)+。
产率: 23%; 1H NMR (500 MHz, CDCl3) δ 11.32 (bs, 1 H), 8.57 (m, 2 H), 7.80 (t, J = 5.5 Hz, 1
H), 6.80 (s, 1 H), 6.71 (s, 2 H), 2.23 (s, 3 H), 1.96 (s, 6 H); ESI-MS: m/z
341.9 (M + H)+。
产率: 49%; 1H NMR (DMSO-d6 , 500
MHz) δ 13.13 (s, 1 H), 8.81 (d, J = 5.9 Hz, 2
H), 8.00 (d, J = 5.9 Hz, 2 H), 7.46 (s, 1 H), 6.86–6.88 (m, 2 H), 3.83 (s, 3 H); ESI-MS: m/z 348.7 (M + H)+。
产率: 30%; 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J = 5.5 Hz, 2 H), 7.99 (d, J = 5.5 Hz, 2 H),
7.41 (t, J = 8.0 Hz, 2 H), 7.19 (s, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.04 (d, J
= 8.2 Hz, 2 H), 6.78 (s, 2 H), 2.07 (s, 6 H); ESI-MS: m/z 401.8 (M + H)+。
产率: 80%; 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 6.0 Hz, 2 H), 7.55 (d, J = 6.0 Hz, 2 H),
6.77 (s, 1 H), 6.30 (s, 2 H), 4.43 (m, 1 H), 1.89 (s, 6 H), 1.31(d, J = 6.0 Hz,
6 H); ESI-MS: m/z 368.1 (M + H)+。
产率: 62%; 1H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 6.0 Hz, 2 H), 7.60 (d, J = 6.0 Hz, 2 H),
6.78 (s, 1 H), 6.37 (s, 2 H), 4.68 (m, 1 H), 1.95 (s, 6 H), 1.80–1.92 (m, 6 H), 0.85 (m, 2 H); ESI-MS: m/z 394.1 (M + H)+。
产率: 4.0%; 1H NMR (CDCl3, 500 MHz) δ 8.80 (d, J = 5.9 Hz, 2 H), 7.69 (d, J = 5.9 Hz, 2 H),
6.81 (s, 1 H), 6.55 (s, 2 H), 4.19–4.25
(brs, 1 H), 4.10–4.15 (m, 1 H),
3.91–3.98 (m, 1 H), 3.78–3.82 (m, 1 H), 2.05 (s, 6 H), 1.28 (s, 3 H); ESI-MS: m/z
384.7 (M + H)+。
产率: 95%; 1H NMR (500 MHz, CDCl3) δ 8.73 (m, 2 H), 7.62 (m, 2 H), 6.90–6.96 (m, 4 H), 6.80 (s, 1 H), 6.45 (s, 2 H), 3.83 (s, 3
H), 1.92 (s, 6 H); ESI-MS: m/z 431.7 (M + H)+。
产率: 17%; 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 5.5 Hz, 2 H), 7.60 (d, J = 5.5 Hz, 2 H),
7.04 (m, 2 H), 6.94 (m, 2 H), 6.81 (s, 1 H), 6.43 (s, 2 H), 1.92 (s, 6 H);
ESI-MS: m/z 420.2 (M + H)+。
产率: 12%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.78 (d, J = 4.5 Hz, 2 H), 7.98 (d, J =
4.5 Hz, 2 H), 7.15 (s, 1 H), 6.69 (s, 2 H), 4.95–4.96
(m, 1 H), 4.68–4.69 (m, 1 H), 3.97–3.98 (m, 1 H), 3.84–3.85
(m, 1 H), 3.78–3.79 (m, 1 H), 2.06 (s, 6 H); ESI-MS:
m/z 400.7 (M + H)+。
产率: 99%; 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J = 6.0 Hz, 2 H), 7.56 (d, J = 6.0 Hz, 2 H),
6.77 (s, 1 H), 6.33 (s, 2 H), 3.62 (d, J = 6.5 Hz, 2 H), 2.08 (m, 1 H), 1.91
(s, 6 H), 1.05 (d, J = 6.7 Hz, 6 H); ESI-MS: m/z 381.1 (M + H)+。
产率: 92%; 1H NMR (500 MHz, CDCl3) δ 8.73 (m, 2 H), 7.62 (m, 2 H), 6.81 (s, 1 H), 6.78 (d, J
= 8.5 Hz, 1 H), 6.43–6.52 (m, 4 H),
6.00 (s, 2 H), 1.93 (s, 6 H); ESI-MS: m/z 445.9 (M + H)+。
产率: 94%; 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J = 5.1 Hz, 2 H), 7.78 (d, J = 5.6 Hz, 2 H),
6.84 (s, 1 H), 6.78 (s, 1 H), 6.64 (s, 2 H), 6.61 (s, 2 H), 2.31 (s, 6 H), 2.02
(s, 6 H); ESI-MS: m/z 429.8 (M + H)+。
产率: 51%; 1H NMR (500 MHz, CDCl3) δ 8.75 (m, 2 H), 7.62 (m, 2 H), 7.25 (m, 1 H), 6.82 (s, 1
H), 6.69 (m, 1 H), 6.56 (d, 1 H), 6.51 (m, 2 H), 6.47 (s, 2 H), 3.81 (s, 3 H),
1.94 (s, 6 H); ESI-MS: m/z 431.6 (M + H)+。
产率: 87%; 1H NMR (500 MHz, CDCl3) δ 8.76 (m, 2 H), 7.64 (m, 2 H), 7.58 (d, J = 8.5 Hz, 2 H),
7.01 (d, J = 8.5 Hz, 2 H), 6.86 (s, 1 H), 6.57 (s, 2 H), 1.98 (s, 6 H); ESI-MS:
m/z 469.7 (M + H)+。
产率: 85%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.80–8.81
(m, 2 H), 7.98–7.99 (m, 2 H), 7.16–7.21 (m, 3 H), 6.99–7.06
(m, 2 H), 6.59 (s, 2 H), 3.76 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 431.5 [M +
H]+。
产率: 89%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.80–8.81
(m, 2 H), 7.98–7.99 (m, 2 H), 7.18–7.22 (m, 3 H), 6.94–6.95
(m, 2 H), 6.73 (s, 2 H), 2.30 (s, 3 H), 2.06 (s, 6 H); ESI-MS: m/z 414.9 [M – H]–。
产率: 91%; 1H NMR (500 MHz, CDCl3) δ 8.78 (d, J = 6.0 Hz, 2 H), 8.67 (m, 2 H), 7.18 (d, J =
8.0 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 6.83 (s, 1 H), 6.56 (s, 2 H), 2.65 (m,
2 H), 1.98 (s, 6 H), 1.26 (t, J = 7.5 Hz, 3 H); ESI-MS: m/z 429.6 (M + H)+。
产率: 61%; 1H NMR (500 MHz, CDCl3) δ 8.76 (m, 2 H), 7.52 (m, 2 H), 7.11 (s, 2 H), 6.80 (s, 1
H), 1.84 (s, 6 H); ESI-MS: m/z 435.6 (M + H)+。
产率: 63%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.77 (d, J = 5.4 Hz, 2 H), 7.98 (d, J =
5.4 Hz, 2 H), 7.38–7.40 (m, 2 H),
7.31–7.35 (m, 3 H), 7.11 (s, 3 H), 2.07 (s, 6
H); ESI-MS: m/z 418.8 (M + H)+。
产率: 84%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.78 (d, J = 5.2 Hz, 2 H), 7.98 (d, J =
5.2 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.10 (s, 1
H), 7.02 (s, 2 H), 2.36 (s, 3 H), 2.04 (s, 6 H); ESI-MS: m/z 432.5 (M + H)+。
产率: 64%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.79 (d, J = 5.0 Hz, 2 H), 7.98 (d, J =
5.0 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.12 (s, 1 H), 7.02 (d, J = 8.4 Hz, 2
H), 6.92 (s, 2 H), 3.79 (s, 3 H), 2.02 (s, 6 H); ESI-MS: m/z 448.1 (M + H)+。
产率: 62%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.8 (s, 1 H), 8.54–8.58 (m, 2 H), 7.55–7.56
(m, 1 H), 7.14 (s, 1 H), 6.96–7.03 (m, 4 H),
6.67 (s, 2 H), 3.76 (s, 3 H), 2.40 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 445.7
[M + H]+。
产率: 60%; 1H NMR (500 MHz, CDCl3) δ 8.79 (d, J = 4.5 Hz, 2 H), 7.85 (d, J = 4.5 Hz, 2 H),
7.39 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.83 (s, 1 H), 2.05 (s, 6
H); ESI-MS: m/z 479.2 (M + H)+。
产率: 58%; 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J = 4.5 Hz, 2 H), 8.02 (d, J = 4.5 Hz, 2 H),
7.47 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.89 (s, 1 H), 6.85 (s, 1
H), 6.24 (s, 1 H), 2.04 (s, 6 H); ESI-MS: m/z 479.3 (M + H)+。
产率: 94%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.82 (s, 1 H), 8.71–8.72 (m, 1 H), 8.39–8.40
(m, 1 H), 7.01–7.03 (m, 2 H), 6.96–6.99 (m, 2 H), 6.64–6.67
(m, 3 H), 3.75 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 476.8 [M + H]+。
产率: 94%; 1H NMR (500 MHz, CDCl3) δ 8.66–8.68 (m, 2 H),
7.49–7.50 (m, 2 H), 6.77 (s, 1 H), 6.57 (s, 2
H), 2.42 (s, 3 H), 1.87 (s, 6 H); ESI-MS: m/z 355.6 (M + H)+。
产率: 39%; 1H NMR (500 MHz, CDCl3) δ 8.80–8.81 (m, 2 H),
7.98–8.00 (m, 2 H), 7.70 (s, 2 H), 7.30 (s, 1
H), 3.30 (s, 1 H), 2.20 (s, 6 H); ESI-MS: m/z 387.6 (M + H)+。
产率: 61%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.79 (s, 2 H), 7.97 (d, J = 6.0 Hz, 2
H), 7.91 (d, J = 8.9 Hz, 2 H), 7.69 (s, 2 H), 7.27 (s, 1 H), 7.15 (d, J = 8.9
Hz, 2 H), 3.84 (s, 3 H), 2.16 (s, 6H); ESI-MS: m/z 480.6 (M + H)+。
产率: 43%; 1H NMR (DMSO-d6 , 500
MHz) δ 13.1 (brs, 1 H), 8.80 (d, J = 6.0 Hz, 2
H), 7.97 (d, J = 6.0 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 7.42 (s, 2 H), 7.23
(s, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 2.13 (s, 6H); ESI-MS: m/z
464.7 (M + H)+。
产率: 24%; 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 2H), 7.70 (d, J = 5.1 Hz, 2 H), 6.97 (m, 2 H),
6.92 (m, 3 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.61 (d, J = 2.3, 1 H), 3.83 (s, 3
H), 2.02 (s, 3 H); ESI-MS: m/z 452.4 (M + H)+。
4-芳基-2-酰氨基噻唑合成的一般程序II。向芳基羧酸(1.5当量)于二氯甲烷中的悬浮液中加入1,1’-羰基二咪唑(CDI,
3.0当量)。室温搅拌2.0小时后,溶液中加入4-芳基噻唑-2-胺 (q.0当量)。室温下搅拌反应混合物过夜。将溶液浓缩,残余物在二氯甲烷中再溶解。用盐水洗涤溶液,MgSO4干燥,减压浓缩得相应的4-芳基-2-酰氨基噻唑。
产率: 77%; 1H NMR (500 MHz, CD3OD) δ 8.75–8.76 (m, 2 H),
7.96–7.99 (m, 2 H), 6.90–6.92 (m, 3 H), 2.29 (s, 3 H), 2.08 (s, 6 H); ESI-MS: m/z
324.0 [M + H]+。
产率: 77%; 1H NMR (500 MHz, CDCl3) δ 11.7 (s, 1 H), 8.61–8.62
(m, 2 H), 7.51–7.53 (m, 2 H), 7.41–7.43 (m, 2 H), 7.26–7.30
(m, 2 H), 7.20–7.22 (m, 1 H), 2.54 (s, 3 H); ESI-MS:
m/z 295.3 [M + H]+。
产率: 15%; 1H NMR (500 MHz, CDCl3) δ 11.7 (s, 1 H), 9.03 (s, 1 H), 8.68–8.69 (m, 1 H), 8.06–8.08
(m, 1 H), 7.45–7.47 (m, 2 H), 7.22–7.31 (m, 4 H), 2.54 (s, 3 H); ESI-MS: m/z 295.9 [M + H]+。
产率: 12%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.9 (s, 1 H), 8.80–8.81 (m, 2 H), 7.99–8.00
(m, 2 H), 7.61–7.63 (m, 2 H), 7.02–7.04 (m, 2 H), 3.80 (s, 3 H), 2.49 (s, 3 H); ESI-MS: m/z
326.0 [M + H]+。
产率: 12%; 1H NMR (500 MHz, DMSO-d6 )
δ 13.0 (s, 1 H), 8.78 (s, 2 H), 7.98–8.00 (m, 3 H), 6.98 (s, 1 H), 6.29 (s, 2 H), 3.82 (s, 3
H), 3.68 (s, 3 H); ESI-MS: m/z 369.9 [M – H]–。
产率: 50%; 1H NMR (500 MHz, CDCl3) δ 11.7 (s, 1 H), 8.61–8.62
(m, 2 H), 7.51–7.53 (m, 2 H), 7.41–7.43 (m, 2 H), 7.26–7.30
(m, 2 H), 7.20–7.22 (m, 1 H), 2.54 (s, 3 H); ESI-MS:
m/z 310.1 [M – H]–。
产率: 10%; 1H NMR (500 MHz, DMSO-d6 )
δ 12.97 (s, 1H), 8.81–8.82 (m, 2 H), 8.00–8.07
(m, 3 H), 7.59 (s, 1 H), 6.64–6.68 (m, 2 H),
3.92 (s, 3 H), 3.81 (s, 3 H); ESI-MS: m/z 340.3 [M – H]–。
产率: 95%; 1H NMR (500 MHz, CDCl3) δ 8.33–8.34 (m, 1 H),
7.47–7.54 (m, 4 H), 7.11 (s, 1 H), 6.79–6.80 (m, 2 H), 3.81 (s, 3 H); ESI-MS: m/z 345.7 [M + H]+。
产率: 83%; 1H NMR (500 MHz, CDCl3) δ 8.52–8.53 (m, 1 H),
7.69–7.70 (m, 1 H), 7.59–7.60 (m, 1 H), 7.28–7.47
(m, 2 H), 7.16 (s, 1 H), 6.93–6.97 (m, 1 H),
3.93 (s, 3 H); ESI-MS: m/z 363.7 [M + H]+。
产率: 87%; 1H NMR (500 MHz, CDCl3) δ 8.49–8.50 (m, 1 H),
7.74 (m, 1 H), 7.62 (m, 1 H), 6.83 (s, 1 H), 6.72 (m, 2 H), 2.26 (s, 3 H),
1.97(s, 6 H); ESI-MS: m/z 357.7 [M + H]+。
产率: 63%; 1H NMR (500 MHz, CDCl3) δ 8.60–8.61 (m, 1 H),
7.91–7.96 (m, 2 H), 6.87 (s, 1 H), 6.58 (m, 2
H), 3.81 (s, 3 H), 2.11(s, 6 H); ESI-MS: m/z 373.9 [M + H]+。
产率: 95%; 1H NMR (500 MHz, CDCl3) δ 8.53–8.54 (m, 1 H),
7.74–7.84 (m, 2 H), 6.83 (s, 1 H), 6.48 (m, 2
H), 3.98–4.02 (m, 2 H), 2.01(s, 6 H), 1.41–1.44 (m, 3 H); ESI-MS: m/z 387.9 [M + H]+。
产率: 68%; 1H NMR (500 MHz, CDCl3) δ 8.36–8.38 (m, 1 H),
7.72 (s, 1 H), 7.42 (s, 1 H), 6.84 (s, 1 H), 6.48 (s, 2 H), 3.78 (s, 3 H), 2.03
(s, 6 H); ESI-MS: m/z 357.5 [M + H]+。
产率: 94%; 1H NMR (500 MHz, CDCl3) δ 8.39–8.40 (m, 1 H),
7.78 (s, 1 H), 7.48 (s, 1 H), 6.85 (s, 1 H), 6.50 (s, 2 H), 3.98–4.01 (q, 2 H), 2.05(s, 6 H), 1.42–1.44 (t, 3 H); ESI-MS: m/z 371.8 [M + H]+。
产率: 75%; 1H NMR (500 MHz, CDCl3) δ 8.15–8.16 (d, 2 H),
7.78–7.79 (d, 2 H), 6.83 (s, 1 H), 6.80 (s, 2
H), 2.23 (s, 3 H), 2.01 (s, 6 H); ESI-MS: m/z 340.1 [M + H]+。
产率: 43%; 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 2 H), 8.04 (s, 2 H), 6.85 (s, 1 H), 6.60 (s, 2
H), 3.80 (s, 3 H), 2.12 (s, 6 H); ESI-MS: m/z 355.8 [M + H]+。
产率: 18%; 1H NMR (500 MHz, CDCl3) δ 9.01 (s, 1 H), 8.66 (s, 1 H), 6.82 (s, 1 H), 6.59 (s, 2
H), 3.81 (s, 3 H), 2.13 (s, 6 H); ESI-MS: m/z 345.6 [M + H]+。
产率: 46%; 1H NMR (500 MHz, CDCl3) δ 8.78–8.79 (m, 2 H),
7.73–7.74 (m, 2 H), 7.26–7.28 (m, 1 H), 6.76–6.79
(m, 1 H), 6.67–6.70 (m, 2 H); ESI-MS: m/z 335.5 [M +
H]+。
产率: 21%; 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1 H), 8.59–8.60
(m, 1 H), 7.54–7.55 (m, 1 H), 6.81–6.83 (m, 2 H), 2.30 (s, 3 H), 2.01 (s, 6 H); ESI-MS: m/z
357.8 [M + H]+。
产率: 42%; 1H NMR (500 MHz, DMSO-d6 )
δ 8.63–8.64
(m, 1 H), 8.11 (s, 1 H), 7.98–7.99 (m, 1 H),
7.12 (s, 1 H), 6.93 (m, 2 H), 2.50 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 357.9
[M + H]+。
产率: 40%; 1H NMR (500 MHz, CDCl3) δ 8.38–8.39 (m, 1 H),
7.55–7.56 (m, 1 H), 7.41 (s, 1 H), 6.91–6.93 (m, 2 H), 6.86 (s, 1 H), 5.30 (s, 1 H), 4.00 (s, 3
H), 2.32 (s, 3 H), 2.12 (s, 6 H); ESI-MS: m/z 355.0 [M + H]+。
产率: 63%; 1H NMR (500 MHz, CDCl3) δ 7.31 (s, 1 H), 7.06 (s, 1 H), 6.81 (s, 1 H), 6.76 (s, 2
H), 4.00 (s, 3 H), 2.32 (s, 3 H), 1.98 (s, 6 H); ESI-MS: m/z 387.9 [M + H]+。
产率: 70%; 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 2 H), 6.80 (s, 1 H), 6.73 (s, 2 H), 2.29 (s, 3
H), 1.94 (s, 6 H); ESI-MS: m/z 392.0 [M + H]+。
产率: 61%; 1H-NMR (500 MHz, CDCl3) δ 8.81 (s, 1 H), 8.37 (s, 1 H), 7.80–7.77 (m, 1 H), 6.91 (s, 2 H), 6.80 (s, 1 H), 2.30 (s, 3
H), 2.26 (s, 3 H), 2.11 (s, 6 H); ESI-MS: m/z 381.2 [M + H]+。
产率: 67%; 1H-NMR (500 MHz, CDCl3) δ 7.11 (s, 2 H), 6.81 (s, 1 H), 6.68 (s, 1 H), 2.30 (s, 3
H), 1.91 (s, 6 H); ESI-MS: m/z 360.0 [M + H]+。
产率: 65%; 1H-NMR (500 MHz, DMSO-d6 )
δ 8.52–8.53
(m, 2 H), 7.35–7.36 (m, 2 H), 6.99 (s, 1 H), 6.91 (s, 1
H), 3.84 (s, 1 H), 2.25 (s, 3 H), 2.02 (s, 6 H); ESI-MS: m/z 338.1 [M + H]+。
产率: 70%; 1H-NMR (500 MHz, CDCl3) δ 8.38–8.40 (m, 1 H),
7.66–7.67 (m, 2 H), 7.43 (s, 1 H), 6.98–7.00 (m, 2 H), 6.91–6.93
(m, 2 H), 6.84 (s, 1 H), 6.54 (s, 1 H), 3.83 (s, 3 H), 2.0 (s, 6 H); ESI-MS:
m/z 450.0 [M + H]+。
产率: 83%; 1H-NMR (500 MHz, CDCl3) δ 8.40 (m, 1 H), 7.78 (s, 1 H), 7.50 (s, 1 H), 6.84 (s, 1
H), 6.53 (s, 2 H), 4.52–4.56 (m, 1 H),
2.06 (s, 6 H), 1.33 (s, 6 H); ESI-MS: m/z 385.8 [M + H]+。
产率: 34% yield; 1H NMR (DMSO-d6 ,
500 MHz) δ 12.48 (brs, 1 H), 8.82–8.83 (m, 1 H), 8.60–8.61
(m, 1 H), 8.04–8.05 (m, 1 H), 7.76–7.79 (m, 1 H), 7.49–7.51
(m, 1 H), 7.00–7.03 (m, 2 H), 6.92 (s, 2 H), 2.26 (s, 3
H), 2.05 (s, 6 H); ESI-MS: m/z 350.7 (M + H)+。
产率: 25%; 1H NMR (DMSO-d6 , 500
MHz) δ 13.20 (brs, 1 H), 8.36 (s, 1 H), 8.19
(s, 1 H), 7.87–7.88 (m, 1 H), 7.72–7.83 (m, 1 H), 7.00 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3
H), 2.07 (s, 6 H); ESI-MS: m/z 363.9 (M + H)+。
产率: 38% yield; 1H NMR (DMSO-d6 ,
500 MHz) δ 13.20 (brs, 1 H), 8.66 (s, 1 H), 8.26
(s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.02 (s, 1 H),
6.93 (s, 2 H), 2.36 (s, 3 H), 2.07 (s, 6 H); ESI-MS: m/z 363.9 (M + H)+。
产率: 41%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.78 (s, 1 H), 8.11 (d, J = 8.4 Hz, 1
H), 7.96 (d, J = 8.4 Hz, 1 H), 7.07 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3 H),
2.07 (s, 6 H); ESI-MS: m/z 364.9 (M + H)+。
产率: 19%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.79–8.80
(m, 12H), 7.98–7.99 (m, 2 H), 7.08 (s, 1 H), 6.70 (s, 2
H), 4.08–4.10 (m, 2 H), 3.65–3.66 (m, 2 H), 3.31 (s, 3 H), 2.06 (s, 6 H); ESI-MS: m/z
384.6 (M + H)+。
产率: 58%; 1H NMR (DMSO-d6 , 500
MHz) δ 8.78–8.79
(m, 2 H), 7.98–7.99 (m, 2 H), 7.05 (s, 1 H), 6.69 (s, 2
H), 4.00–4.02 (m, 2 H), 3.46–3.48 (m, 2 H), 3.25 (s, 3 H), 2.06 (s, 6 H), 1.93–1.95 (m, 2 H); ESI-MS: m/z 398.8 (M + H)+。
产率: 69%; 1H NMR (500 MHz, CDCl3) δ 8.46–8.48 (m, 1 H),
8.39–8.43 (m, 2 H), 8.32–8.33 (m, 1 H), 7.02–7.05
(m, 2 H), 6.93–6.95 (m, 3 H), 6.70 (s, 2 H), 3.84 (s, 3
H), 2.19 (s, 3 H), 2.16 (s, 3 H); ESI-MS: m/z 447.8 [M + H]+。
产率: 65%; 1H-NMR (500 MHz, DMSO-d6 )
δ 13.1 (s, 1 H), 8.46–8.47 (m, 1H), 7.93–7.94
(m, 1 H), 7.78 (s, 1 H), 7.42–7.44 (m, 2 H),
7.19 (s, 1 H), 7.01–7.03 (m, 2 H),
6.91 (s, 2 H), 3.79 (s, 3 H), 2.02 (s, 6 H); ESI-MS: m/z 465.4 [M + H]+。
示例性化合物和抑制活性
下表列出选定化合物的示例性结果,其利用细胞暴露于含有所示化合物的生长培养基中的方法,阐明对选定癌细胞的抗增殖作用。抗增殖作用以微摩尔终浓度的IC50值表示。
选定化合物的示例性生物活性
下面数据提供了关于某些化合物体内和体外生物活性的示例性指导。当化合物以编号引用时,所述编号对应于上表列出的化合物。
细胞毒性和抗增殖活性:来自建立细胞株(例如:来自如MDA-MB-231,MDA-MB-468,Hela和K562的细胞株)的细胞在DMEM培养基(Sigma, D5523)中的10%FBS(Hylcone)中培养。细胞在37℃含有5% CO2和95%空气的潮湿气氛下生长。将细胞接种于96孔组织培养板中。
细胞(T0)孵育过夜后,开始化合物处理。以3倍稀释的八个点制备10μM 至4.6 nM 的化合物。将化合物加入板上孔中,一式三份,然后将板孵育96小时。也包括DMSO(化合物稀释剂)并将其加入到板上对照孔中。然后利用CellTiter
96® Aqueous非放射性细胞增殖分析系统(Promega) 通过MTS分析测定细胞活力。利用酶标仪(Molecular
Devices, Vmax)读取光密度,结果用于推导浓度-响应曲线。所有数据代表一式三份实验的结果,为三次单独测定的均值,偏差小于±20%。利用线性回归软件(GraphPad Prism 5; GraphPad Software Inc.)分析结果。
IC50值是指引起50%生长抑制的浓度。测定GI50值(生长抑制活性)以强调在时间0时的细胞计数的修正;因此,供试药物的抑制%为:[1- (T - T0)/(C - T0)] x 100;这些值用于绘制浓度-响应曲线,然后用线性回归软件(GraphPad Prism 5)分析。
如可从图 1A所见,选定化合物对多种实体瘤细胞和白血病细胞具有显著的细胞毒性和抗增殖作用。相反,如可从图 1B所得,相同化合物对几个正常细胞株没有显示显著的细胞毒性和抗增殖作用。这里,WI-38是人正常肺成纤维细胞株,RPTEC是肾近端小管上皮细胞,HuVec是人脐静脉内皮细胞,HAoSMC是人大动脉平滑肌细胞。
选定化合物破坏Hec1/Nek2相互作用,激发Nek2降解,并增加Nek2蛋白不稳定性:将细胞重悬于冰冷的裂解缓冲液250(50 mM Tris-HCl, pH 7.4, 250 mM NaCl, 0.3% Nonidet P-40,
10 mM NaF, 补充有蛋白酶抑制剂),进行三次冻融循环,并在室温下在14000rpm离心2分钟。上清液用于裂解物分析或免疫沉淀反应。对于免疫沉淀反应,上清液和抗Hec1抗体mAb1 9G3或鼠多克隆抗Nek2孵育1小时,然后和蛋白A-琼脂糖小珠孵育另外1小时。收集小珠,用含有高渗NaCl的裂解缓冲液洗涤5次,在SDS加样缓冲液中煮沸用于免疫印迹分析。免疫印迹于Immobilon-P膜(Millipore Corp., Bedford, MA)后,用抗-Hec1抗体或者抗-Nek2抗体(Genetex, Irvine, CA)探测印迹。利用ECL化学发光试剂盒(Amersham Biosciences)显影印迹。其它的细节可见于别处(Phosphorylation
of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful
chromosome segregation。J Biol Chem。2002 Dec 20;277(51):49408-16。Epub 2002 Oct 16)。
图 2A 和 2B描述了这个实验的示例性结果,其中很显然选定的供试化合物显著地破坏Hec1/Nek2的相互作用。图 2C显示K562细胞与1mcM的供试化合物孵育24小时后Nek2减少的典型结果,图2D描述了显示K562细胞暴露于1 mcM终浓度的选定化合物的处理后,Nek2随时间的蛋白质不稳定性。
选定化合物诱导异常有丝分裂:细胞在盖玻片上生长,用PEMG缓冲液[80
mM 哌嗪-N,N-双(2-乙磺酸) (PIPES), pH 6.8, 5 mM EGTA, 1 mM MgCl2和4 M甘油]或者磷酸盐缓冲盐水(PBS)轻柔洗涤。然后,用100%甲醇在–20℃或4%多聚甲醛的PEMG溶液或PBS缓冲液固定细胞,并用0.4% Triton-X 100渗透细胞。细胞用PBS中的5%正常山羊血清(NGS)封闭,在含5%NGS的PBS中与一级抗体孵育(室温1-2小时)。二级抗体和Alexa 488或594 (Invitrogen, Carlsbad, CA)结合。和二级抗体孵育后,应用4 ,6-二脒基-2-苯基吲哚 (DAPI)染色,并用Prolong gold 抗褪色试剂 (Invitrogen)将细胞固定在盖玻片上。用配有数码相机和SPOT数字图像软件(version 4, Diagnostic Instruments, Inc)的Nikon H550L显微镜捕捉图像。用Image-Pro
Plus (MediaCybernetics, Bethesda, MD) 或者Adobe
Photoshop软件(Adobe Systems, Mountain View, CA)进行进一步的图像分析或定量。进一步的细节描述于别处(Hec1 contributes to mitotic centrosomal
microtubule growth for proper spindle assembly through interaction with Hice1。Mol Biol Cell。2009
Nov;20(22):4686-95。Epub 2009 Sep 23)。
图 3是描述选定化合物对有丝分裂的作用的表格。更具体地,结果以48小时内有丝分裂细胞中的染色体错位的百分比来表示。如可获知的,供试化合物明显影响大量细胞内的有丝分裂。
选定化合物是高选择性的激酶抑制剂:通过对供试化合物存在下的基质的[33P]掺入量定量来测定供试化合物的激酶活性抑制。在供试化合物(在终浓度为4%的DMSO中稀释)或DMSO对照存在下,用MgATP启动标准激酶分析,通过加入3%磷酸终止,用unifilter采集器(PerkinElmer, Boston, MA, U.S.A.)采集至滤板上,用TopCount计数。对于激酶活性抑制的初步筛选,在两个浓度(10mM和1mM)一式两份评估每个供试化合物。结果是重复测定的平均值,用抑制百分比(化合物处理比DMSO对照)表示。可利用的激酶分析如下:VEGFR2, PDGFR-β, FGFR1, Flt3, c-Met, CHK1, CHK2, Cdk1/细胞周期蛋白B, 极光激酶A, 极光激酶B, B-Raf, B-Raf (V600E), C-Raf和mTOR。在多数激酶分析中使用的ATP浓度等于或低于每个酶ATP的Km值。
尽管预期化合物在非常低的IC50下有显著的作用,但是从图 4的表格可以看出,其抑制曲线是高度选择性的。
生物利用度:选定化合物按已知的程序通过口服或者注射给予大鼠。例如,化合物82以制剂的形式以2 mg/kg的浓度静脉注射,该制剂含有5%DMSO,10%氢化蓖麻油和85%WFI。下表列出示例性的药代动力学数据。
化合物82还以制剂的形式以20 mg/kg的浓度口服给药,该制剂含有1%甲基-纤维素。下表列出示例性的药代动力学数据。
同样,采用另外相同的制剂和给药途径获得化合物42和95的PK数据。下表示例性地阐明了结果。
以下各表显示化合物42 静注和口服的结果:
。
以下各表显示化合物95静注和口服的结果:
。
选定的化合物在小鼠异种移植模型中是有效的:程序改编自早前发表的方案(Small molecule
targeting the Hec1Nek2 mitotic pathway suppresses tumor cell growth in culture
and in animal。Cancer Res。2008
Oct 15;68(20):8393-9)。更具体地,雌性BALB/c裸(nu/nu)鼠(5–8周)购于Lasco(台湾)。动物在特异性无病原体条件下饲养,食物和水随意供应。涉及动物的居所和所有程序依据DCB的IACUC批准的草案执行。对于MDA-MB-468和MDA-MB-231细胞的皮下植入,将细胞(分别为 1
x107基质凝胶中/动物和0.5 x107 /动物)皮下注入右腋下区域。肿瘤植入10天后,小鼠用媒介物A(5% DMSO,10% 氢化蓖麻油,85% H2O)或者配制在媒介物A中的候选化合物(7.5-150 mg/kg体重)处理(总计i.v.,QD/21周期或 p.o.,QD/28周期)。利用数显卡尺进行每个肿瘤的垂直直径测量,用公式(Lx W
x W)/2计算肿瘤体积,其中L和W分别代表长和宽。每周测量体重3次。每个处理组的平均肿瘤生长抑制与媒介对照组的进行比较,利用公式[1-(T/C)
x100%]计算肿瘤生长抑制值。
由图 5A 和 5B的图表明显可见预期化合物对裸鼠中肿瘤体积的体内影响。虽然肿瘤减小,但是在所有例子中体重保持恒定(未显示数据)。
在不偏离本发明构思的情况下,可以有除已描述的那些外的更多的修改方案,这一点对于本领域技术人员是显而易见的。因此,除在所附权利要求的精神之内,本发明主题不受限制。而且,在解释说明书和权利要求时,应该以符合上下文的最宽泛的可能方式解释所有的术语。特别是,当涉及元素,组分或步骤时,术语“包括(comprises)”和“包括(comprising)”应当以非排他的方式解释,表明引用的元素、组分或步骤可以存在,或被利用,或与其它未特别提及的元素、组分或步骤组合。当说明书权利要求涉及选自由A,B,C……和N组成的组的某物的至少一个时,该文字应该被解释为只需要所述组中的一个元素,不是A加N,或B加N,等。
Claims (9)
1.具有根据式I的结构的化合物
R1是ORa,SRa或-S(O)2Ra;其中Ra是烷基或者被烷基、卤代烷基、烷氧基和/或卤素任选取代的苯基;
R2和R3是C1-C6烷基;
R4是氢或C1-C6烷基;和
R5是任选被卤素取代的吡啶基。
2.权利要求1的化合物,其中Ra是任选被卤代烷基、烷氧基和/或卤素取代的苯基,R2和R3是C1-C6烷基,且其中R5是任选被卤素取代的吡啶基。
3.权利要求1的化合物,具有根据式II的结构
其中X1和X2独立地是H,烷基,卤素;
Y是O,S或SO2;
R2、R3是C1-C6烷基,R4是H;
n是0;
是和
其中中的Ra,Rb,Rc和Rd独立地为氢或卤素。
4.具有根据式III的结构的化合物
其中X1,X2和X3独立地是H,烷基,卤素,或ORa;
Y是O,S,或SO2;
R1和R2是烷基,R3是氢;
n是0;
当X1和X2为烷基或ORa时,其中的每一个独立地任选被烷基或烷氧基取代;
是和
其中中的Ra,Rb,Rc和Rd独立地为氢或卤素。
5.权利要求4的化合物,其中X1和X2中的至少一个是任选被烷氧基取代的ORa。
6.权利要求1的化合物,具有选自下述的结构
7.药物组合物,包括药学上可接受的载体和根据权利要求1的化合物,其中当给予患者该组合物时,该化合物的浓度有效破坏患者中的Hecl/Nek2结合。
8.权利要求7的药物组合物,进一步包括干扰微管形成或降解的药物。
9.根据权利要求1或6的化合物在制备治疗与Hecl功能紊乱和/或过度表达相关的癌变肿瘤疾病的药物中的用途。
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