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CN101857589B - Pyrazol-benzimidazoles derivative and application thereof - Google Patents

Pyrazol-benzimidazoles derivative and application thereof Download PDF

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CN101857589B
CN101857589B CN 201010194593 CN201010194593A CN101857589B CN 101857589 B CN101857589 B CN 101857589B CN 201010194593 CN201010194593 CN 201010194593 CN 201010194593 A CN201010194593 A CN 201010194593A CN 101857589 B CN101857589 B CN 101857589B
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benzimidazol
chloro
pyrimidine
pyrazol
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CN101857589A (en
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吉民
郑友广
郑明�
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Southeast University
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Abstract

本发明公开了一类吡唑-苯并咪唑类衍生物及其应用,吡唑-苯并咪唑类衍生物具有式(I)结构。药理实验表明,此类化合物或其药学上可接受的盐对多种肿瘤细胞的增殖具有抑制作用。

Figure DSA00000142843300011
其中:A环为取代或非取代的嘧啶或吡嗪,所述取代基为卤素、硝基、氰基、巯基或氨基;R1为烷基、卤代烷基、烷氧基、烷硫基、烷砜基、苯硫基、环烷基酰胺取代的苯硫基、环烷基酰胺取代的苯氧基、酰基或酯基;R2为氢、卤素或-NR3R4,R4或R3独立地选自氢、烷基、环烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为烷基或羟烷基。The invention discloses a class of pyrazole-benzimidazole derivatives and applications thereof. The pyrazole-benzimidazole derivatives have a structure of formula (I). Pharmacological experiments show that these compounds or their pharmaceutically acceptable salts have inhibitory effects on the proliferation of various tumor cells.
Figure DSA00000142843300011
Wherein: Ring A is substituted or unsubstituted pyrimidine or pyrazine, and the substituent is halogen, nitro, cyano, mercapto or amino; R is alkyl, haloalkyl, alkoxy, alkylthio, alkane Sulfone group, phenylthio group, phenylthio group substituted by cycloalkylamide, phenoxy group substituted by cycloalkylamide, acyl group or ester group; R 2 is hydrogen, halogen or -NR 3 R 4 , R 4 or R 3 are independently selected from hydrogen, alkyl, cycloalkyl, or R 4 and R 3 together form a substituted or unsubstituted heteroalicyclic group, wherein the substituent is an alkyl or hydroxyalkyl group.

Description

吡唑-苯并咪唑类衍生物及其应用Pyrazole-benzimidazole derivatives and their applications

技术领域 technical field

本发明本发明属于药物化学领域,具体涉及一种Aurora激酶抑制剂的合成制备技术,即吡唑苯并咪唑类衍生物及其用途。The present invention belongs to the field of medicinal chemistry, and specifically relates to a synthesis and preparation technology of an Aurora kinase inhibitor, that is, pyrazole benzimidazole derivatives and applications thereof.

背景技术 Background technique

蛋白激酶(Protein Kinases)包括蛋白丝氨酸/苏氨酸激酶(STK)和蛋白酪氨酸激酶(Protein Tyrosine Kinase,PTK)。其中,一种参与有丝分裂的丝氨酸/苏氨酸激酶新家族-Aurora家族被逐渐认识,它们分为3类:Aurora-A、Aurora-B和Aurora-C,主要调节中心体和微管的功能,确保中心体的正确分离和胞浆的完整分裂。Protein Kinases include protein serine/threonine kinase (STK) and protein tyrosine kinase (Protein Tyrosine Kinase, PTK). Among them, a new family of serine/threonine kinases involved in mitosis - Aurora family is gradually recognized, they are divided into three categories: Aurora-A, Aurora-B and Aurora-C, which mainly regulate the functions of centrosomes and microtubules, Ensures proper centrosome separation and complete cytoplasmic division.

Aurora激酶的功能涉及有丝分裂的各项重要事件,包括中心粒周期、纺锤体变化、染色体分离以及胞质分裂等等。在正常细胞中,Aurora激酶依靠各种形式的调控手段在特异的时间、空间表达和活化,作用于各种底物分子,从而实现不同的生物学功能。近年来,人们在大量的实验中发现很多参与Aurora激酶调控作用的分子,主要包括三类:(1)Aurora激酶的上游调控分子,如TPX2、P53、PP1等,它们或者影响Aurora的激酶活性,或指导Aurora的定位;(2)Aurora激酶的伙伴分子,如INCENP、survivin等,它们既是磷酸化的底物,也是具有反馈性激活作用,Aurora激酶的亚细胞定位依赖其伙伴分子,反之亦然,只有完整的复合物才能执行正常功能;(3)Aurora激酶的下游底物分子,如Eg5、TACC、Damlp、H3、MgcRacGAP、vimentin等,它们可以被Aurora激酶磷酸化,分别调节中心体、纺锤体、染色体或者细胞骨架的变化。The functions of Aurora kinases are involved in various important events of mitosis, including centriole cycle, spindle change, chromosome segregation, cytokinesis and so on. In normal cells, Aurora kinases are expressed and activated in specific time and space by various means of regulation, and act on various substrate molecules to achieve different biological functions. In recent years, people have found many molecules involved in the regulation of Aurora kinases in a large number of experiments, mainly including three categories: (1) upstream regulatory molecules of Aurora kinases, such as TPX2, P53, PP1, etc., which may affect the kinase activity of Aurora, Or guide the localization of Aurora; (2) Partner molecules of Aurora kinase, such as INCENP, survivin, etc., they are not only substrates for phosphorylation, but also have a feedback activation effect, and the subcellular localization of Aurora kinase depends on its partner molecules, and vice versa , only complete complexes can perform normal functions; (3) downstream substrate molecules of Aurora kinases, such as Eg5, TACC, Damlp, H3, MgcRacGAP, vimentin, etc., which can be phosphorylated by Aurora kinases to regulate centrosome, spindle Changes in the body, chromosomes, or cytoskeleton.

有丝分裂出错是基因组不稳定的原因,和肿瘤发生密切相关。肿瘤细胞中许多有丝分裂调控因子出现了遗传表达,因此这些蛋白家族可以作为药物治疗靶点。其中,Aurora激酶是这类靶点中的一个蛋白家族。Aurora激酶家族是有丝分裂的关键调控因子,用于维持基因组的稳定。在肿瘤中,这种苏氨酸/丝氨酸激酶经常发生过量表达。例如,肿瘤中AuroraA经常发生扩增,表明这种蛋白在肿瘤形成或恶化中具有重要作用。Aurora蛋白激酶调控有丝分裂的多个步骤,包括中心体复制、两极有丝分裂纺锤体的形成、有丝分裂纺锤体染色体排列、和最重要的是精确监控纺锤体检查点本身。Mitotic errors are the cause of genome instability and are closely related to tumorigenesis. Many mitotic regulators are genetically expressed in tumor cells, so these protein families can serve as drug targets. Among them, Aurora kinases are a family of proteins among such targets. The Aurora kinase family is a key regulator of mitosis for genome stability. In tumors, this threonine/serine kinase is frequently overexpressed. For example, AuroraA is frequently amplified in tumors, suggesting a role for this protein in tumor formation or progression. Aurora protein kinases regulate multiple steps in mitosis, including centrosome duplication, formation of bipolar mitotic spindles, mitotic spindle chromosome alignment, and most importantly, precise monitoring of the spindle checkpoint itself.

Aurora A基因定位于染色体20q13.2部位内,在人类肿瘤中经常检测出这一染色体部位。实际上,一些研究表明,在许多肿瘤中,均发现Aurora A位点的扩增及伴随AuroraA蛋白的过表达。在小鼠异种移植研究中发现,肿瘤细胞中Aurora A的过表达促进集落形成、中心体扩增及肿瘤生长。然而,在普通细胞中Aurora A的过表达并不能诱导细胞转变,这表明Aurora A还需要额外的致癌因素,例如活化Ras-信号以促进转变。Meraldi等研究表明,紧随着Aurora A过表达的中心体扩增是完成胞质分裂的失败的间接因素,产生有两个中心体的四倍体细胞。目前,还不清楚Aurora A的激酶活化如何在这些过表达效应起着关键作用,因为Aurora A激酶死亡的过表达引起相似数量的四倍体化。在一些研究中也发现四倍体化紧随着野生型Aurora A的过表达,但是,引人侧目的是四倍体化并未发现紧随着Aurora A激酶死亡的过表达。这表示集落形成和肿瘤生长需要Aurora A激酶活化,以及在含有Aurora A扩增的肿瘤中Aurora A的序列分析没有鉴定出任何激酶非活化突变。核苷酸位点19(Phe31Ile)可能调控Aurora A蛋白稳定的多态性并肿瘤敏感性相关。The Aurora A gene is located on chromosome 20q13.2, which is frequently detected in human tumors. In fact, some studies have shown that in many tumors, the amplification of Aurora A locus and the overexpression of AuroraA protein are found. Overexpression of Aurora A in tumor cells promotes colony formation, centrosome expansion, and tumor growth in mouse xenograft studies. However, overexpression of Aurora A in normal cells did not induce cellular transformation, suggesting that Aurora A also requires additional oncogenic factors, such as activation of Ras-signaling, to promote transformation. Meraldi et al. show that centrosome expansion following Aurora A overexpression is an indirect factor in the failure to complete cytokinesis, resulting in tetraploid cells with two centrosomes. At present, it is unclear how the kinase activation of Aurora A plays a key role in these overexpression effects, because overexpression of Aurora A kinase death causes a similar amount of tetraploidization. Tetraploidization was also found to be followed by overexpression of wild-type Aurora A in some studies, however, strikingly, tetraploidization was not found to be followed by overexpression of Aurora A kinase death. This indicates that Aurora A kinase activation is required for colony formation and tumor growth, and that sequence analysis of Aurora A in tumors containing Aurora A amplification did not identify any kinase-inactivating mutations. Nucleotide position 19 (Phe31Ile) may regulate the stable polymorphism of Aurora A protein and correlate with tumor sensitivity.

AuroraB定位于17p13.1基因区域,这一区域在人类细胞中是易变的。AuroraA信使RNA及其自身蛋白在肿瘤中频繁过表达,同时也有报道一些肿瘤类型中蛋白表达和病重之间的相互关系。除了Aurora B与肿瘤之间有直接的联系外,还应注意到CPC蛋白,它与Aurora A相互协调且受Aurora B的调控,此蛋白在肿瘤中也过表达或上调。尽管Aurora B与肿瘤有着较强的联系且在有丝分裂过程中起着十分重要的作用,但是体外研究并未发现其转化且体内也并非广泛致肿瘤。另一重要的例外是在表达p53突变细胞中,当Aurora B过表达时,将增加致肿瘤行为。此研究表明,Aurora B自身不可能成为正式的癌基因,但是可与其他致癌突变协同作用促进致癌过程。于此观念相一致的,AuroraA增强Ras介导转化,当除去Aurora B将抑制Ras转化。Aurora B可作为抗癌靶点可以通过以下研究进一步加强,即除去Aurora B的癌细胞对烷化剂和电离辐射等治疗的细胞毒效应更加敏感。AuroraB localizes to the 17p13.1 gene region, which is variable in human cells. AuroraA messenger RNA and its own protein are frequently overexpressed in tumors, and a correlation between protein expression and disease severity has also been reported in some tumor types. In addition to the direct link between Aurora B and tumors, it should be noted that the CPC protein, which is coordinated with and regulated by Aurora A, is also overexpressed or upregulated in tumors. Although Aurora B has a strong association with tumors and plays a very important role in the mitotic process, in vitro studies have not found its transformation and it is not widely tumorigenic in vivo. Another important exception is the increased tumorigenic behavior of Aurora B when overexpressed in p53 mutant cells. This study shows that Aurora B cannot become a formal oncogene by itself, but can cooperate with other oncogenic mutations to promote the carcinogenesis process. Consistent with this notion, AuroraA enhances Ras-mediated transformation, while removal of Aurora B inhibits Ras transformation. The usefulness of Aurora B as an anticancer target can be further strengthened by the study that Aurora B-depleted cancer cells are more sensitive to the cytotoxic effects of treatments such as alkylating agents and ionizing radiation.

Aurora激酶抑制剂从结构上可以大致分为以下几大类:嘧啶类(如VX-680)、喹唑啉类(AZD1152)、吡唑-苯并咪唑类(AT-9283)、四氢吡咯并吡唑类(PHA-739358)、苯并氮杂卓类(MLN5237)等。这些抑制剂的结构中都具有一个或多个杂原子氮,并且母核大多为含氮原子杂环以模拟ATP中的腺嘌呤部分。这些化合物中,有些对特异性的Aurora激酶具有专一的抑制作用,而有些则对两个或多个Aurora激酶靶点具有选择性抑制作用。Aurora kinase inhibitors can be roughly divided into the following categories from the structure: pyrimidines (such as VX-680), quinazolines (AZD1152), pyrazole-benzimidazoles (AT-9283), tetrahydropyrrolo Pyrazoles (PHA-739358), Benzazepines (MLN5237), etc. The structures of these inhibitors all have one or more nitrogen heteroatoms, and the mother nucleus is mostly a nitrogen-containing heterocycle to simulate the adenine part in ATP. Some of these compounds have specific inhibitory effects on specific Aurora kinases, while others have selective inhibitory effects on two or more Aurora kinase targets.

发明内容 Contents of the invention

技术问题:本发明的目的是提供一种对肿瘤细胞的增殖具有抑制能力的吡唑-苯并咪唑类衍生物,Technical problem: The purpose of the present invention is to provide a kind of pyrazole-benzimidazole derivatives capable of inhibiting the proliferation of tumor cells,

本发明的另一目的是提供一种含有上述吡唑苯并咪唑类衍生物的组合物。Another object of the present invention is to provide a composition containing the above-mentioned pyrazole benzimidazole derivatives.

本发明还有一个目的是提供上述吡唑苯并咪唑类衍生物的在医药学上的用途。Another object of the present invention is to provide the medical application of the above-mentioned pyrazole benzimidazole derivatives.

技术方案:本发明的吡唑-苯并咪唑类衍生物为式(I)结构的化合物或其药学上可接受的盐:Technical solution: The pyrazole-benzimidazole derivatives of the present invention are compounds of formula (I) or pharmaceutically acceptable salts thereof:

Figure BSA00000142843500021
Figure BSA00000142843500021

其中:in:

A环为取代或非取代的嘧啶或吡嗪,所述取代基为卤素、硝基、氰基、巯基或氨基;R1为烷基、卤代烷基、烷氧基、烷硫基、烷砜基、苯硫基、环烷基酰胺取代的苯硫基、环烷基酰胺取代的苯氧基、酰基或酯基;Ring A is substituted or unsubstituted pyrimidine or pyrazine, and the substituents are halogen, nitro, cyano, mercapto or amino; R is alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfone , phenylthio, phenylthio substituted by cycloalkylamide, phenoxy substituted by cycloalkylamide, acyl or ester group;

R2为氢、卤素或-NR3R4,R4或R3独立地选自氢、烷基、环烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为烷基或羟烷基。R 2 is hydrogen, halogen or -NR 3 R 4 , R 4 or R 3 are independently selected from hydrogen, alkyl, cycloalkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, Wherein the substituent is an alkyl group or a hydroxyalkyl group.

所述化合物或其药学上可接受的盐中,In the compound or a pharmaceutically acceptable salt thereof,

A环为取代或非取代的嘧啶,所述取代基为卤素、硝基、氰基、巯基或氨基;Ring A is a substituted or unsubstituted pyrimidine, and the substituents are halogen, nitro, cyano, mercapto or amino;

R1为烷基、烷硫基、烷砜基、环丙酰胺取代的苯硫基、环丙酰胺取代的苯氧基;R 1 is an alkyl group, an alkylthio group, an alkylsulfone group, a phenylthio group substituted by cyclopropanamide, or a phenoxy group substituted by cyclopropanamide;

R2为氢、卤素或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为C1-4烷基或C1-4羟烷基。R 2 is hydrogen, halogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C1-4 alkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, wherein the substituent It is C1-4 alkyl or C1-4 hydroxyalkyl.

所述化合物或其药学上可接受的盐中,In the compound or a pharmaceutically acceptable salt thereof,

A环为嘧啶或卤代嘧啶;Ring A is pyrimidine or halogenated pyrimidine;

R1为C1-4烷基、C1-4烷硫基、C1-4烷砜基、环丙酰胺取代的苯硫基;R 1 is C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylsulfone, cyclopropanamide substituted phenylthio;

R2为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为甲基、乙基、羟甲基或羟乙基。R 2 is hydrogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C1-4 alkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, wherein the substituent is methyl radical, ethyl, hydroxymethyl or hydroxyethyl.

所述化合物或其药学上可接受的盐中,In the compound or a pharmaceutically acceptable salt thereof,

A环为卤代嘧啶;Ring A is a halogenated pyrimidine;

R1为C1-2烷基、C1-2烷硫基、C1-2烷砜基、

Figure BSA00000142843500031
R 1 is C 1-2 alkyl, C 1-2 alkylthio, C 1-2 alkylsulfone,
Figure BSA00000142843500031

R2为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成杂脂环基。R 2 is hydrogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C1-4 alkyl, or R 4 and R 3 together form a heteroalicyclic group.

所述化合物或其药学上可接受的盐中,In the compound or a pharmaceutically acceptable salt thereof,

A环为氯代嘧啶;Ring A is chloropyrimidine;

R1为甲基、乙基、甲硫基、乙硫基、甲砜基、乙砜基、

Figure BSA00000142843500032
R is methyl, ethyl, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl,
Figure BSA00000142843500032

R2为氢、二乙胺基、吗啉基、哌嗪基、哌啶基或吡咯烷基。R 2 is hydrogen, diethylamino, morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl.

所述化合物或其药学上可接受的盐中,所述的化合物为选自下组的一个或多个:In the compound or a pharmaceutically acceptable salt thereof, the compound is one or more selected from the following group:

6-氯-2-甲基-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine;

6-氯-2-(甲硫基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(morpholinemethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

N-{4-[4-氯-6-(3-(5-(吗啉甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(morpholinemethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide;

6-氯-2-甲基-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine;

6-氯-2-(甲硫基)-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

N-{4-[4-氯-6-(3-(5-(哌啶甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(piperidinylmethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide;

6-氯-2-甲基-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]嘧啶4-胺;6-Chloro-2-methyl-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]pyrimidine 4-amine;

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲硫基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylthio)pyrimidin-4-amine;

N-{4-[4-氯-6-(3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫基]苯}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-thio]benzene} Cyclopropanamide;

6-氯-2-甲基-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine ;

6-氯-2-(甲硫基)-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-chloro-2-(methylthio)-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine;

N-{4-[4-氯-6-(3-(5-(二乙胺甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(diethylaminomethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2- Sulfur]phenyl}cyclopropylcarboxamide;

6-氯-2-(甲砜基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylsulfonyl)-N-{3-[5-(morpholinomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲砜基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidin-4-amine;

或6-氯-2-(甲砜基)-N-{3-[5-(二乙胺基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺。Or 6-chloro-2-(methylsulfonyl)-N-{3-[5-(diethylamino)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine.

吡唑-苯并咪唑类衍生物的应用,所述化合物或其药学上可接受的盐应用于药物组合物,以及药学上可接受的稀释剂或载体,或应用在制备抗癌药物中。The application of pyrazole-benzimidazole derivatives, the compound or its pharmaceutically acceptable salt is used in pharmaceutical composition, and pharmaceutically acceptable diluent or carrier, or used in the preparation of anticancer drugs.

所述的癌为白血病、结肠癌、宫颈癌或乳腺癌。Said cancer is leukemia, colon cancer, cervical cancer or breast cancer.

有益效果:本发明提供了一类表现出对肿瘤细胞的增殖具有抑制能力的吡唑-苯并咪唑类衍生物,提供一种含有上述吡唑苯并咪唑类衍生物的组合物。提供上述吡唑苯并咪唑类衍生物的在医药学上的用途。Beneficial effects: the present invention provides a class of pyrazole-benzimidazole derivatives exhibiting the ability to inhibit the proliferation of tumor cells, and provides a composition containing the above-mentioned pyrazole-benzimidazole derivatives. The pharmaceutical application of the above-mentioned pyrazole benzimidazole derivatives is provided.

对慢性髓细胞白血病(K562)、人急性单核细胞白血病细胞株(U937)的增殖具有显著的抑制作用。上述这些化合物可应用于抗肿瘤药物的制备。It has significant inhibitory effect on the proliferation of chronic myeloid leukemia (K562) and human acute monocytic leukemia cell line (U937). The above-mentioned compounds can be applied to the preparation of antitumor drugs.

具体实施方式 Detailed ways

式(I)结构的化合物或其药学上可接受的盐:A compound of formula (I) or a pharmaceutically acceptable salt thereof:

其中:in:

A环为取代或非取代的嘧啶或吡嗪,所述取代基为卤素、硝基、氰基、巯基或氨基;A环优选为取代或非取代的嘧啶,所述取代基为卤素、硝基、氰基、巯基或氨基;A环更优选为嘧啶或卤代嘧啶;A环进一步优选为卤代嘧啶;A环最优选为氯代嘧啶。Ring A is substituted or unsubstituted pyrimidine or pyrazine, and the substituents are halogen, nitro, cyano, mercapto or amino; ring A is preferably substituted or unsubstituted pyrimidine, and the substituents are halogen, nitro , cyano, mercapto or amino; ring A is more preferably pyrimidine or halogenated pyrimidine; ring A is more preferably halogenated pyrimidine; ring A is most preferably chloropyrimidine.

R1为烷基、卤代烷基、烷氧基、烷硫基、烷砜基、苯硫基、环烷基酰胺取代的苯硫基、环烷基酰胺取代的苯氧基、酰基或酯基;R1优选为烷基、烷硫基、烷砜基、环丙酰胺取代的苯硫基、环丙酰胺取代的苯氧基;R1更优选为C1-4烷基、C1-4烷硫基、C1-4烷砜基、环丙酰胺取代的苯硫基;R1进一步优选为C1-2烷基、C1-2烷硫基、C1-2烷砜基、

Figure BSA00000142843500042
R is alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfone, phenylthio, cycloalkylamide substituted phenylthio, cycloalkylamide substituted phenoxy, acyl or ester; R 1 is preferably alkyl, alkylthio, alkylsulfone, cyclopropanamide-substituted phenylthio, cyclopropanamide-substituted phenoxy; R is more preferably C 1-4 alkyl, C 1-4 alkane Sulfuryl, C 1-4 alkylsulfone, cyclopropanamide substituted phenylthio; R is further preferably C 1-2 alkyl, C 1-2 alkylthio, C 1-2 alkylsulfone,
Figure BSA00000142843500042

R1最优选为甲基、乙基、甲硫基、乙硫基、甲砜基、乙砜基、 R is most preferably methyl, ethyl, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl,

R2为氢、卤素或-NR3R4,R4或R3独立地选自氢、烷基、环烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为烷基或羟烷基;R2优选为氢、卤素或-NR4R3,R4或R3优选独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基优选为C1-4烷基或C1-4羟烷基;进一步的,R2为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,其中取代基为甲基、乙基、羟甲基或羟乙基;R2更优选为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成杂脂环基;R2最优选为氢、二乙胺基、吗啉基、哌嗪基、哌啶基或吡咯烷基。R 2 is hydrogen, halogen or -NR 3 R 4 , R 4 or R 3 are independently selected from hydrogen, alkyl, cycloalkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, Wherein the substituent is alkyl or hydroxyalkyl; R 2 is preferably hydrogen, halogen or -NR 4 R 3 , R 4 or R 3 is preferably independently selected from C1-4 alkyl, or R 4 and R 3 are combined to form Substituted or unsubstituted heteroalicyclic group, wherein the substituent is preferably C1-4 alkyl or C1-4 hydroxyalkyl; further, R 2 is hydrogen or -NR 4 R 3 , R 4 or R 3 are independently selected From C1-4 alkyl, or R4 and R3 combine to form a substituted or unsubstituted heteroalicyclic group, wherein the substituent is methyl, ethyl, hydroxymethyl or hydroxyethyl; R2 is more preferably hydrogen Or -NR 4 R 3 , R 4 or R 3 are independently selected from C1-4 alkyl, or R 4 and R 3 together form a heteroalicyclic group; R 2 is most preferably hydrogen, diethylamino, morpholine group, piperazinyl, piperidinyl or pyrrolidinyl.

在所述的化合物或这些化合物与药学上可以接受的酸所成的盐中,这些化合物选自下面所列特定化合物中的一个或多个:In the compounds or the salts of these compounds and pharmaceutically acceptable acids, these compounds are selected from one or more of the specific compounds listed below:

6-氯-2-甲基-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine;

6-氯-2-(甲硫基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(morpholinemethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

N-{4-[4-氯-6-(3-(5-(吗啉甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(morpholinemethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide;

6-氯-2-甲基-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine;

6-氯-2-(甲硫基)-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

N-{4-[4-氯-6-(3-(5-(哌啶甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(piperidinylmethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide;

6-氯-2-甲基-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]嘧啶-4-胺;6-Chloro-2-methyl-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]pyrimidin-4-amine;

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲硫基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylthio)pyrimidin-4-amine;

N-{4-[4-氯-6-(3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫基]苯}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-thio]benzene} Cyclopropanamide;

6-氯-2-甲基-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine ;

6-氯-2-(甲硫基)-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-chloro-2-(methylthio)-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine;

N-{4-[4-氯-6-(3-(5-(二乙胺甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(diethylaminomethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2- Sulfur]phenyl}cyclopropylcarboxamide;

6-氯-2-(甲砜基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylsulfonyl)-N-{3-[5-(morpholinomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -amine;

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲砜基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidin-4-amine;

或6-氯-2-(甲砜基)-N-{3-[5-(二乙胺基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺。Or 6-chloro-2-(methylsulfonyl)-N-{3-[5-(diethylamino)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine.

本发明化合物可应用于制备抗癌药物方面,其中所述的癌如白血病、结肠癌或乳腺癌等实体瘤癌症。The compound of the present invention can be applied to the preparation of anticancer drugs, wherein said cancer is solid tumor cancer such as leukemia, colon cancer or breast cancer.

“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括:"Pharmaceutically acceptable salts" means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:

(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等,优选对甲苯磺酸或盐酸。(1) Salt formation with acid, obtained by reacting the free base of the parent compound with inorganic or organic acids, such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc., organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid , Methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid, etc., preferably p-toluenesulfonic acid or hydrochloric acid.

(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属离子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。(2) The acidic proton present in the parent compound is replaced by a metal ion or a salt formed by coordination with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethanolamine, diethanolamine, three Ethanolamine, tromethamine, N-methylglucamine, etc.

所述的化合物或它们与药学上可以接受的酸所成的盐为原料,制备成临床上可使用的用于治疗白血病等肿瘤的药物。The compounds or their salts with pharmaceutically acceptable acids are used as raw materials to prepare clinically usable medicines for treating leukemia and other tumors.

本发明的又一目的在于提供一种药物组合物,其特征在于所述药物组合物包括化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。Another object of the present invention is to provide a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

将本发明的化合物以前药的形式给药。前药是指经过生物体内转化后才具有药理作用的化合物。可使用前药改变本发明化合物的物理化学性质或药物动力学方面性质。当本发明的化合物含有可连接改变性质基团的适当基团或取代基团时,形成前药。The compounds of the invention are administered in the form of prodrugs. Prodrugs refer to compounds that have pharmacological effects after in vivo transformation. Prodrugs may be used to alter the physicochemical or pharmacokinetic properties of the compounds of the invention. Prodrugs are formed when compounds of the invention contain suitable groups or substituent groups to which property-altering groups can be attached.

1.化学1. Chemistry

除非另外说明,在说明书和权力要求中使用的以下术语具有下面讨论的含义:Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below:

“烷基”表示1-20个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-20”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时,称其为无取代的低级烷基。更优选的是,烷基是有1-10个碳原子的中等大小的烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是,烷基为有1-4个碳原子的低级烷基,例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当时取代烷基时,该取代基优选是一或多个,更优选1-3个,最优选1或2个取代基,它们独立地优选自以下的基团:卤素、羟基、低级烷氧基、芳基、芳氧基、杂芳环、杂脂环基和酯基。"Alkyl" means a saturated aliphatic group of 1-20 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as "1-20", refers to the group, here is an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are called lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group. More preferably, the alkyl group is a medium-sized alkyl group having 1-10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl Base etc. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like. Alkyl groups can be substituted or unsubstituted. When substituting an alkyl group, the substituent is preferably one or more, more preferably 1-3, most preferably 1 or 2 substituents, which are independently preferably selected from the following groups: halogen, hydroxyl, lower alkoxy , aryl, aryloxy, heteroaromatic, heteroalicyclic and ester groups.

“环烷基”表示全部为碳的单环或稠合的环(“稠合”环意味着系统中的每个环与系统中的其他环共享毗邻的一对碳原子)基团,含有3-12个碳原子,进一步含有3-9个碳原子,优选5、6或7个碳原子,更优选5或6个碳原子,其中一个或多个环不具有完全连接的π电子系统,任选包含一个或多个双键和/或三键形式的不饱和状态。环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基可为取代的和未取代的。当被取代时,取代基优选为一个或多个各自选自以下的基团,包括:烷基、芳基、杂芳基、杂脂环基、羟基、烷氧基、芳氧基、巯基、烷巯基、氰基、卤素、羰基、硫代羰基、C-酰氨基、N-酰氨基、硝基和氨基。"Cycloalkyl" means an all carbon monocyclic or fused ring ("fused" ring means that each ring in the system shares adjacent pairs of carbon atoms with other rings in the system) group containing 3 - 12 carbon atoms, further containing 3-9 carbon atoms, preferably 5, 6 or 7 carbon atoms, more preferably 5 or 6 carbon atoms, wherein one or more rings do not have a fully connected π-electron system, any An unsaturated state in the form of one or more double and/or triple bonds is selected. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted. When substituted, the substituent is preferably one or more groups each selected from the group consisting of: alkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, Alkylmercapto, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, nitro and amino.

“杂脂环基”表示单环或稠合环基团,在环中具有5-18个、优选5-12个,更优选5-9个环原子,其中一个或两个环原子选自N、O或S(O)m(其中m是0至2的整数)的杂原子,其余环原子是C。这些环可以具有一条或多条双键,但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、吗啉子基、哌嗪子基、硫代吗啉子基、高哌嗪子基等。杂脂环基可以是取代的或未取代的。当被取代时,取代基优选为一个或多个、更优选为一个、两个或三个,进而更优选为一个或两个,独立地选自以下基团,包括:烷基、三卤烷基、卤素、羟基、烷氧基、巯基、烷基硫基、氰基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、硝基、N-磺酰氨基、S-磺酰氨基。优选的杂芳基任选地被一个或两个取代基取代,取代基独立地选自卤素、低级烷基、三卤烷基、氰基、酯基或硝基。"Heteroalicyclic" means a monocyclic or fused ring group having 5-18, preferably 5-12, more preferably 5-9 ring atoms in the ring, one or two of which are selected from N , O or S(O) m (wherein m is an integer from 0 to 2), the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heteroalicyclic groups include pyrrolidinyl, piperidino, morpholino, piperazino, thiomorpholino, homopiperazino, and the like. A heteroalicyclic group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, even more preferably one or two, independently selected from the group consisting of: alkyl, trihaloalkane Halogen, hydroxyl, alkoxy, mercapto, alkylthio, cyano, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thio Carbamoyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino. Preferred heteroaryl groups are optionally substituted with one or two substituents independently selected from halogen, lower alkyl, trihaloalkyl, cyano, ester or nitro.

“羟基”表示-OH基团。"Hydroxy" means a -OH group.

“羟烷基”表示具有-OH基取代基的烷基,其中烷基的概念如上述所。"Hydroxyalkyl" means an alkyl group having an -OH substituent, wherein the concept of an alkyl group is as defined above.

“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基),其中烷基和环烷基定义如上。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。"Alkoxy" means -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

“巯基”表示-SH基团"Mercapto" means -SH group

“酰基”表示-C(O)-R’基团,其中R’是选自以下基团:氢,未取代的低级烷基、三卤甲基、未取代的环烷基、任选地被一或多个、优选被1、2或3个选自未取代的低级烷基、三卤甲基、未取代的低级烷氧基和卤素取代的芳基。"Acyl" means a -C(O)-R' group, where R' is a group selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, optionally One or more, preferably 1, 2 or 3 aryl groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy and halogen.

“硫代酰基”表示-C(S)-R’,其中R’定义同上。"Thioacyl" means -C(S)-R', wherein R' is as defined above.

“酯基”表示-C(O)O-R’基团,其中R’定义同上,但是R’不能是氢。"Ester" means a -C(O)O-R' group where R' is as defined above, but R' cannot be hydrogen.

“卤素”表示氟、氯、溴或碘,优选氟、氯或溴。"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

“三卤甲基”表示-CX3基团,其中X是如上所定义的卤素。"Trihalomethyl" means a -CX3 group where X is halogen as defined above.

“氰基”表示-CN基团。"Cyano"means a -CN group.

“氨基”表示-NH2基团。"Amino" means a -NH2 group.

“硝基”表示-NO2基团。"Nitro" means a -NO2 group.

“卤代烷基”表示烷基被一个或多个相同或不同的卤原子取代,优选如上所定义的低级烷基被一个或多个相同或不同的卤原子取代,其中烷基定义如上,例如-CH2Cl、-CF3、-CH2CF3、-CH2CCl3等。“卤代烷氧基”表示烷氧基被一个或多个相同或不同的卤原子取代,其中烷氧基定义如上,例如-OCH2Cl、-OCF3、-OCH2CF3、-OCH2CCl3等。"Haloalkyl" means that an alkyl group is substituted by one or more same or different halogen atoms, preferably lower alkyl as defined above is substituted by one or more same or different halogen atoms, wherein alkyl is as defined above, for example -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CCl 3 , etc. "Haloalkoxy" means that alkoxy is substituted by one or more same or different halogen atoms, wherein alkoxy is as defined above, such as -OCH 2 Cl, -OCF 3 , -OCH 2 CF 3 , -OCH 2 CCl 3 wait.

“N-甲基哌嗪基”指的是具有以下化学结构的基团。"N-methylpiperazinyl" refers to a group having the following chemical structure.

Figure BSA00000142843500071
Figure BSA00000142843500071

“哌啶基”指的是具有以下化学结构的基团。"Piperidinyl" refers to a group having the following chemical structure.

Figure BSA00000142843500072
Figure BSA00000142843500072

“吗啉基”指的是具有以下化学结构的基团。"Morpholinyl" refers to a group having the following chemical structure.

Figure BSA00000142843500073
Figure BSA00000142843500073

“吡咯烷基”指的是具有以下化学结构的基团。"Pyrrolidinyl" refers to a group having the following chemical structure.

“二乙胺基”指的是具有以下化学结构的基团。"Diethylamino group" refers to a group having the following chemical structure.

Figure BSA00000142843500082
Figure BSA00000142843500082

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生和不发生的场合。例如,“杂芳基任选地被一个或两个取代基取代”意味着杂芳基的取代基可以但不必是一个,该说明包括杂芳基被一个取代基取代的情形和杂芳基被两个取代基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "heteroaryl is optionally substituted with one or two substituents" means that the substituents of heteroaryl may be but need not be one, and the description includes the case where heteroaryl is substituted by one substituent and the case where heteroaryl is substituted by The case where two substituents are substituted.

2.一般合成方法2. General synthesis method

本发明中所提到的化合物总体制备方法为:The general preparation method of the compound mentioned in the present invention is:

以3,4-二硝基苯甲酸为起始原料,经二氯亚砜氯代制得酰氯,然后与仲胺反应得其酰胺产物3,化合物3经硼氢化钠和三氟化硼-乙醚还原得中间体4,然后在钯碳和常压氢气条件下,硝基还原为氨基化合物5,化合物5与4-硝基吡唑3-甲酸在EDCI条件下成酰胺,然后在冰醋酸回流关环,得重要中间体6,化合物6经钯碳常压氢气还原得中间体7,最后于氯代嘧啶衍生物反应得目标产物。Using 3,4-dinitrobenzoic acid as the starting material, the acid chloride was obtained by chlorination with thionyl chloride, and then reacted with a secondary amine to obtain its amide product 3, and compound 3 was treated with sodium borohydride and boron trifluoride-ether Reduction to obtain intermediate 4, and then under the conditions of palladium carbon and normal pressure hydrogen, the nitro group is reduced to amino compound 5, compound 5 and 4-nitropyrazole 3-carboxylic acid form amides under EDCI conditions, and then reflux in glacial acetic acid Ring, the important intermediate 6 was obtained, the compound 6 was reduced by palladium carbon hydrogen at normal pressure to obtain the intermediate 7, and finally reacted with the chloropyrimidine derivative to obtain the target product.

Figure BSA00000142843500083
Figure BSA00000142843500083

3.生物评价方法3. Biological evaluation method

抑制细胞增殖测定方法采取常用的MTT法:活细胞线粒体中的琥珀酸脱氢酶能使外源性溴化3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑(MTT)还原为难溶的蓝紫色结晶物甲臜(Formazan)并沉积在细胞中,而死细胞无此功能。甲臜的多少可通过酶联免疫检测仪在570nm波长处检测其光吸收值(OD值),因而为甲臜生成量在通常情况下与活细胞成正比,因此可根据OD值推算出活细胞数量,了解药物抑制或杀伤细胞的能力。The commonly used MTT method is adopted for the determination of inhibition of cell proliferation: succinate dehydrogenase in the mitochondria of living cells can make exogenous brominated 3-(4,5-dimethylthiazole-2)-2,5-diphenyl Tetrazolium (MTT) is reduced to insoluble blue-purple crystal formazan (Formazan) and deposited in cells, while dead cells do not have this function. The amount of formazan can be detected by an enzyme-linked immunosorbent assay at a wavelength of 570nm (OD value), so the amount of formazan produced is usually proportional to the living cells, so the living cells can be calculated based on the OD value Quantities, to understand the drug's ability to inhibit or kill cells.

该测定方法可用于测定不同的本发明目标化合物对一种或多种癌细胞增殖的抑制能力,利用本领域熟知的方法,可以对任意癌细胞使用相似的测定方法。This assay method can be used to determine the ability of different target compounds of the present invention to inhibit the proliferation of one or more cancer cells. Using methods well known in the art, a similar assay method can be used for any cancer cell.

给出下列制备和实施例,使本领域技术人员能够更清楚地理解和实施本发明。它们不应解释为限制本发明的范围,仅仅是其例证和代表。The following preparations and examples are given to enable those skilled in the art to understand and practice the present invention more clearly. They should not be construed as limiting the scope of the invention, but merely as illustrations and representations thereof.

合成实施例Synthetic example

实施例1Example 1

中间体7的合成Synthesis of intermediate 7

Figure BSA00000142843500091
Figure BSA00000142843500091

(3,4-二硝基苯)吗啉-4-基甲酮(3a)(3,4-Dinitrophenyl)morpholin-4-ylmethanone (3a)

在1L三口烧瓶中,加入3,4-二硝基苯甲酸(50g,235mmol),以500mLTHF溶解,滴加0.5mLDMF,然后加入22.5mL二氯亚砜,机械搅拌,回流反应6h。反应结束后,将反应液降至0℃,在此条件下,0.5h内,滴加50mL三乙胺。滴加完毕,在0-5℃条件下,滴加36mL吗啉,然后升至室温,过夜反应。反应结束后,将反应液倒入1250mL冰水中,有固体析出,室温搅拌0.5h。过滤,水洗涤滤饼,直至滤液为中性,烘干得土黄色固体62.3g,收率94.4%,mp 163-165℃.In a 1L three-neck flask, add 3,4-dinitrobenzoic acid (50g, 235mmol), dissolve in 500mLTHF, add 0.5mL DMF dropwise, then add 22.5mL thionyl chloride, stir mechanically, and reflux for 6h. After the reaction, the reaction solution was lowered to 0°C, and under this condition, 50 mL of triethylamine was added dropwise within 0.5 h. After the dropwise addition was completed, 36 mL of morpholine was added dropwise at 0-5° C., then raised to room temperature, and reacted overnight. After the reaction was completed, the reaction solution was poured into 1250 mL of ice water, solids were precipitated, and stirred at room temperature for 0.5 h. Filter, wash the filter cake with water until the filtrate is neutral, and dry to obtain 62.3g of khaki solid, yield 94.4%, mp 163-165°C.

IR(KBr,cm-1):2861.60,1633.08,1526.82,1442.61,1368.42,1282.21,1113.78,1025.56,919.30,869.17.IR (KBr, cm -1 ): 2861.60, 1633.08, 1526.82, 1442.61, 1368.42, 1282.21, 1113.78, 1025.56, 919.30, 869.17.

(3,4-二硝基苯)哌啶-4-基甲酮(3b)(3,4-Dinitrophenyl)piperidin-4-ylmethanone (3b)

具体实验操作同化合物7a的合成,投入3,4-二硝基苯甲酸(50g,235mmol),得土黄色固体60.5g,收率92.3%,mp 128-130℃.The specific experimental operation was the same as the synthesis of compound 7a, and 3,4-dinitrobenzoic acid (50g, 235mmol) was added to obtain 60.5g of a khaki solid, with a yield of 92.3%, mp 128-130°C.

IR(KBr,cm-1):3025.90,2941.74,1633.08,1530.83,1442.61,1364.41,1284.21,911.28,843.11.IR (KBr, cm -1 ): 3025.90, 2941.74, 1633.08, 1530.83, 1442.61, 1364.41, 1284.21, 911.28, 843.11.

(3,4-二硝基苯)二乙胺-4-基甲酮(3d)(3,4-Dinitrophenyl)diethylamine-4-ylmethanone (3d)

具体实验操作同化合物7a的合成,投入3,4-二硝基苯甲酸(50g,235mmol),得土黄色固体57.5g,收率91.6%,mp 70℃.The specific experimental operation was the same as the synthesis of compound 7a, and 3,4-dinitrobenzoic acid (50g, 235mmol) was added to obtain 57.5g of khaki solid, yield 91.6%, mp 70°C.

IR(KBr,cm-1):3094.03,2973.80,1629.07,1532.83,1490.73,1360.40,1105.76,899.25,843.11.IR (KBr, cm -1 ): 3094.03, 2973.80, 1629.07, 1532.83, 1490.73, 1360.40, 1105.76, 899.25, 843.11.

4-(3,4-二硝基苄基)吗啉(4a)4-(3,4-Dinitrobenzyl)morpholine (4a)

在1L三口烧瓶中,加入NaHB4(16.8g,445mmol),然后加入600mL THF,将温度降至0℃,Ar气保护条件下,滴加三氟化硼-乙醚溶液(55.6mL,445mmol)。滴加完毕后,加入化合物3a(59.55g,210mmol),升至室温,反应5h。反应结束后,将温度降至0℃,滴加500mL甲醇。滴加完毕后,室温搅拌过夜。然后蒸干溶剂,将残余物溶于500mL乙酸乙酯和500mL饱和NaHCO3溶液中,萃取,水层以250mL乙酸乙酯萃取,合并有机层,依次水洗,饱和食盐水洗涤,无水MgSO4干燥。过滤,真空蒸干溶剂,残余物以200mL甲醇重结晶,得黄色固体47.7g,收率85.1%,mp 109-110℃.In a 1L three-neck flask, NaHB 4 (16.8g, 445mmol) was added, then 600mL THF was added, the temperature was lowered to 0°C, and boron trifluoride-ether solution (55.6mL, 445mmol) was added dropwise under the protection of Ar gas. After the dropwise addition was completed, compound 3a (59.55 g, 210 mmol) was added, raised to room temperature, and reacted for 5 h. After the reaction, the temperature was lowered to 0° C., and 500 mL of methanol was added dropwise. After the dropwise addition was completed, the mixture was stirred overnight at room temperature. Then the solvent was evaporated, the residue was dissolved in 500mL ethyl acetate and 500mL saturated NaHCO solution, extracted, the aqueous layer was extracted with 250mL ethyl acetate, the organic layers were combined, washed successively with water, washed with saturated brine, and dried over anhydrous MgSO . After filtration, the solvent was evaporated to dryness in vacuo, and the residue was recrystallized from 200 mL of methanol to obtain 47.7 g of a yellow solid, yield 85.1%, mp 109-110°C.

IR(KBr,cm-1):2961.78,1861.60,1526.82,1368.42,1348.37,1111.78,863.16;1H-NMR(CDCl3-d6,300MHz)δ(ppm):2.48(t,J=4.59Hz,4H,2×morpholine-CH2),3.62(s,2H,CH2),3.75(t,J=4.5Hz,4H,2×morpholine-CH2),7.73(d,J=8.22Hz,1H,Ar-H),6.92(d,J=8.37Hz,1H,Ar-H).IR (KBr, cm -1 ): 2961.78, 1861.60, 1526.82, 1368.42, 1348.37, 1111.78, 863.16; 1 H-NMR (CDCl 3 -d 6 , 300MHz) δ (ppm): 2.48(t, J=4.59Hz, 4H, 2×morpholine-CH 2 ), 3.62 (s, 2H, CH 2 ), 3.75 (t, J=4.5Hz, 4H, 2×morpholine-CH 2 ), 7.73 (d, J=8.22Hz, 1H, Ar-H), 6.92 (d, J=8.37Hz, 1H, Ar-H).

4-(3,4-二硝基苄基)哌啶(4b)4-(3,4-Dinitrobenzyl)piperidine (4b)

具体实验操作同化合物4a的合成,投入化合物3b(58.6g,210mmol),得黄色固体45.7g,收率82.1%。The specific experimental operation was the same as the synthesis of compound 4a, and compound 3b (58.6 g, 210 mmol) was added to obtain 45.7 g of yellow solid, with a yield of 82.1%.

4-(3,4-二硝基苄基)哌啶(4d)4-(3,4-Dinitrobenzyl)piperidine (4d)

具体实验操作同化合物4a的合成,投入化合物3d(56.1g,210mmol),得黄色固体46.1g,收率86.7%。The specific experimental operation was the same as the synthesis of compound 4a, and compound 3d (56.1 g, 210 mmol) was added to obtain 46.1 g of yellow solid, with a yield of 86.7%.

4-(吗啉甲基)苯-1,2-二胺(5a)4-(morpholinomethyl)benzene-1,2-diamine (5a)

在1L圆底烧瓶中,投入化合物4a(26.9g,101mmol),800mL乙醇溶解,然后加入10%钯碳(2.1g),将烧瓶中的气体排空,通入氢气,室温条件下,常压氢气还原36h。反应结束后,过滤钯碳,真空蒸干滤液,得红棕色固体19.8g,收率93.3%,,mp 124-125℃.In a 1L round bottom flask, drop into compound 4a (26.9g, 101mmol), dissolve in 800mL of ethanol, then add 10% palladium carbon (2.1g), the gas in the flask is evacuated, and hydrogen gas is introduced, at room temperature, under normal pressure Hydrogen reduction for 36h. After the reaction, filter palladium carbon, and vacuum evaporate the filtrate to obtain 19.8 g of reddish-brown solid, yield 93.3%, mp 124-125°C.

IR(KBr,cm-1):3394.58,3306.42,2925.71,2865.60,2801.48,1625.06,1590.98,1516.79,1288.22,1105.78,1001.50,863.16,825.06;1H-NMR(CDCl3-d6,500MHz)δ(ppm):2.27(s,4H,2×morpholine-CH2),3.28(s,2H,CH2),3.55(t,J=4.5Hz,4H,2×morpholine-CH2),4.35(d,J=26.5Hz,4H,2×NH2),6.27-6.29(dd,J1=2.0Hz,J2=2.0Hz,1H,Ar-H),6.42(d,J=8.0Hz,1H,Ar-H),6.47(d,J=2.0Hz,1H,Ar-H);ESI-MS m/z:208.0[M+H]+,230.0[M+Na]-.IR (KBr, cm -1 ): 3394.58, 3306.42, 2925.71, 2865.60, 2801.48, 1625.06, 1590.98, 1516.79, 1288.22, 1105.78, 1001.50, 863.16, 825.06; 1 H-NMR ( CD6Cl 3 - ppm): 2.27(s, 4H, 2×morpholine-CH 2 ), 3.28(s, 2H, CH 2 ), 3.55(t, J=4.5Hz, 4H, 2×morpholine-CH 2 ), 4.35(d, J=26.5Hz, 4H, 2×NH 2 ), 6.27-6.29 (dd, J 1 =2.0Hz, J 2 =2.0Hz, 1H, Ar-H), 6.42 (d, J=8.0Hz, 1H, Ar -H), 6.47 (d, J=2.0Hz, 1H, Ar-H); ESI-MS m/z: 208.0[M+H] + , 230.0[M+Na] - .

4-(哌啶甲基)苯-1,2-二胺(5b)4-(piperidinylmethyl)benzene-1,2-diamine (5b)

具体实验操作同化合物5a的合成,投入化合物4b(26.7g,101mmol),得红棕色固体19.2g,收率92.3%。The specific experimental operation was the same as the synthesis of compound 5a, and compound 4b (26.7 g, 101 mmol) was added to obtain 19.2 g of reddish-brown solid with a yield of 92.3%.

4-甲苯基-1,2-二胺(5c)4-Tolyl-1,2-diamine (5c)

具体实验操作同化合物5a的合成,投入4-甲基-1,2-二硝基苯(18.4g,101mmol),得红棕色固体11.6g,收率94.3%。1H-NMR(CDCl3-d6,500MHz)δ(ppm):2.05(s,3H,CH3),4.26(d,J=48.1Hz,4H,2×NH2),6.16-6.18(dd,J1=1.25Hz,J2=1.25Hz,1H,Ar-H),6.32(d,J=1.7Hz,1H,Ar-H),6.37(d,J=7.65Hz,1H,Ar-H);ESI-MS m/z:123.3[M+H]+.The specific experimental operation was the same as the synthesis of compound 5a, and 4-methyl-1,2-dinitrobenzene (18.4 g, 101 mmol) was added to obtain 11.6 g of reddish-brown solid with a yield of 94.3%. 1 H-NMR (CDCl 3 -d 6 , 500MHz) δ (ppm): 2.05 (s, 3H, CH 3 ), 4.26 (d, J=48.1Hz, 4H, 2×NH 2 ), 6.16-6.18 (dd , J 1 =1.25Hz, J 2 =1.25Hz, 1H, Ar-H), 6.32(d, J=1.7Hz, 1H, Ar-H), 6.37(d, J=7.65Hz, 1H, Ar-H ); ESI-MS m/z: 123.3[M+H] + .

4-(二乙胺甲基)苯-1,2-二胺(5d)4-(Diethylaminomethyl)benzene-1,2-diamine (5d)

具体实验操作同化合物5a的合成,投入化合物4d(25.5g,101mmol),得红棕色固体18.8g,收率96.6%。The specific experimental operation was the same as the synthesis of compound 5a, and compound 4d (25.5 g, 101 mmol) was added to obtain 18.8 g of reddish-brown solid, with a yield of 96.6%.

5-(吗啉甲基)-2-(4-硝基-1H-吡唑-3-基)-1H-苯并咪唑(6a)5-(morpholinemethyl)-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (6a)

在250mL圆底烧瓶中,投入化合物5a(11.5g,55.5mmol),4-硝基-1H-吡唑-3-甲酸(7.85g,50.0mmol)、EDCI(10.65g,55.5mmol)及HOBt(7.5g,55.5mmol),用125mL干燥DMF溶解,室温条件下反应24h。真空蒸干溶剂,残余物以200mL冰醋酸溶解,回流反应3h。真空蒸干溶剂,将残余物倒入饱和NaHCO3溶液中,过滤所得固体,水洗滤饼,直至中性。真空烘干,得淡黄色固体8.36g,收率52.1%,mp 238-240℃.In a 250mL round bottom flask, drop into compound 5a (11.5g, 55.5mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (7.85g, 50.0mmol), EDCI (10.65g, 55.5mmol) and HOBt ( 7.5g, 55.5mmol), dissolved in 125mL dry DMF, and reacted at room temperature for 24h. The solvent was evaporated to dryness in vacuo, and the residue was dissolved in 200 mL of glacial acetic acid, and refluxed for 3 h. The solvent was evaporated in vacuo, the residue was poured into saturated NaHCO 3 solution, the resulting solid was filtered, and the filter cake was washed with water until neutral. Vacuum drying gave 8.36 g of light yellow solid, yield 52.1%, mp 238-240°C.

IR(KBr,cm-1):3384.51,2877.32,1496.51,1419.37,1392.38,1311.38,1108.89,863.97;1H-NMR(DMSO-d6,500MHz)δ(ppm):2.39(s,4H,2×morpholine-CH2),3.57-3.60(m,6H,2×morpholine-CH2and CH2),7.25(s,1H,Ar-H),7.59(s,2H,Ar-H),8.78(s,1H,Ar-H),12.78(s,1H,imidazole-NH),14.47(s,1H,pyrazole-NH);ESI-MS m/z:329.2[M+H]+,327.0[M-H]-.IR (KBr, cm -1 ): 3384.51, 2877.32, 1496.51, 1419.37, 1392.38, 1311.38, 1108.89, 863.97; 1 H-NMR (DMSO-d 6 , 500MHz) δ (ppm): 2.39(s, 4H, 2× morpholine-CH 2 ), 3.57-3.60(m, 6H, 2×morpholine-CH 2 and CH 2 ), 7.25(s, 1H, Ar-H), 7.59(s, 2H, Ar-H), 8.78(s , 1H, Ar-H), 12.78(s, 1H, imidazole-NH), 14.47(s, 1H, pyrazole-NH); ESI-MS m/z: 329.2[M+H] + , 327.0[MH] - .

5-(哌啶甲基)-2-(4-硝基-1H-吡唑-3-基)-1H-苯并咪唑(6b)5-(piperidinylmethyl)-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (6b)

具体实验操作同化合物6a的合成,投入化合物5b(11.4g,55.5mmol),得淡黄色固体8.97g,收率49.6%,mp 168-170℃.The specific experimental operation was the same as the synthesis of compound 6a, and compound 5b (11.4g, 55.5mmol) was added to obtain 8.97g of light yellow solid, yield 49.6%, mp 168-170°C.

IR(KBr,cm-1):2937.74,1663.16,1478.70,1450.63,1386.47,1282.21,1149.87,1093.73,821.05.IR (KBr, cm -1 ): 2937.74, 1663.16, 1478.70, 1450.63, 1386.47, 1282.21, 1149.87, 1093.73, 821.05.

5-甲基-2-(4-硝基-1H-吡唑-3-基)-1H-苯并咪唑(6c)5-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (6c)

具体实验操作同化合物6a的合成,投入化合物5c(6.77g,55.5mmol),得淡黄色固体6.96g,收率57.3%。The specific experimental operation was the same as the synthesis of compound 6a, and compound 5c (6.77 g, 55.5 mmol) was added to obtain 6.96 g of light yellow solid with a yield of 57.3%.

5-(哌啶甲基)-2-(4-硝基-1H-吡唑-3-基)-1H-苯并咪唑(6d)5-(piperidinylmethyl)-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (6d)

具体实验操作同化合物6a的合成,投入化合物5d(10.7g,55.5mmol),得淡黄色固体10.1g,收率57.8%。The specific experimental operation was the same as the synthesis of compound 6a, and compound 5d (10.7 g, 55.5 mmol) was added to obtain 10.1 g of light yellow solid with a yield of 57.8%.

3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-胺(7a)3-[5-(morpholinomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-amine (7a)

500mL圆底烧瓶中,加入化合物6a(8.36g,25.5mmol),0.86g 10%钯碳,以300mL乙醇溶解,将烧瓶中的气体排空,通入氢气,室温条件下,常压氢气还原24h。反应结束后,过滤钯碳,真空蒸干滤液,得浅红色固体7.31g,收率96.2%,直接投入下一步。In a 500mL round-bottomed flask, add compound 6a (8.36g, 25.5mmol), 0.86g 10% palladium carbon, dissolve in 300mL ethanol, empty the gas in the flask, feed hydrogen, and reduce with hydrogen at normal pressure for 24h at room temperature . After the reaction, the palladium carbon was filtered, and the filtrate was evaporated to dryness in vacuo to obtain 7.31 g of a light red solid with a yield of 96.2%, which was directly put into the next step.

3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-胺(7b)3-[5-(Piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-amine (7b)

具体实验操作同化合物7a的合成,投入化合物6b(8.97g,27.5mmol),得淡黄色固体7.98g,收率97.2%,直接投入下一步。The specific experimental operation was the same as the synthesis of compound 7a, and compound 6b (8.97g, 27.5mmol) was added to obtain 7.98g of light yellow solid with a yield of 97.2%, which was directly put into the next step.

3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-胺(7c)3-(5-Methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-amine (7c)

具体实验操作同化合物7a的合成,投入化合物6c(6.77g,27.8mmol),得淡黄色固体5.71g,收率96.3%,直接投入下一步。The specific experimental operation was the same as the synthesis of compound 7a, and compound 6c (6.77g, 27.8mmol) was added to obtain 5.71g of light yellow solid with a yield of 96.3%, which was directly put into the next step.

3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-胺(7d)3-[5-(Diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-amine (7d)

具体实验操作同化合物7a的合成,投入化合物6d(8.63g,27.5mmol),得淡黄色固体7.51g,收率96.2%,直接投入下一步。The specific experimental operation was the same as the synthesis of compound 7a, and compound 6d (8.63g, 27.5mmol) was added to obtain 7.51g of light yellow solid with a yield of 96.2%, which was directly put into the next step.

实施例2Example 2

6-氯-2-甲基-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-001)6-chloro-2-methyl-N-{3-[5-(morpholine methyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine ( AM-001)

Figure BSA00000142843500121
Figure BSA00000142843500121

在50mL圆底烧瓶中,投入化合物7a(0.894g,3mmol)、4,6-二氯-2-甲基嘧啶(0.41g,2.5mmol)、碘化钠(0.45g,3mmol)及N,N-二异丙基乙胺(0.52mL,3mmol),以10mL DMF溶解,Ar气保护,90℃条件下反应4h。反应结束后,将反应液倒入100mL冰水中,搅拌0.5h。过滤析出的固体,用硅胶层析分离(展开剂为二氯甲烷∶甲醇=30∶1),得类白色固体0.55g,收率43.1%,mp 244℃.In a 50mL round bottom flask, drop compound 7a (0.894g, 3mmol), 4,6-dichloro-2-methylpyrimidine (0.41g, 2.5mmol), sodium iodide (0.45g, 3mmol) and N, N - Diisopropylethylamine (0.52mL, 3mmol), dissolved in 10mL DMF, protected by Ar gas, reacted at 90°C for 4h. After the reaction, the reaction solution was poured into 100 mL of ice water and stirred for 0.5 h. The precipitated solid was filtered and separated by silica gel chromatography (developing solvent: dichloromethane:methanol=30:1) to obtain 0.55 g of off-white solid, yield 43.1%, mp 244°C.

IR(KBr,cm-1):2933.24,1735.65,1610.30,1438.66,1400.09,1284.38,1132.03,1112.74,1068.39,981.61,941.11,889.04,792.61,688.47;1H-NMR(DMSO-d6,300MHz)δ(ppm):2.51(s,7H,2×morpholine-CH2and CH3),3.69(s,6H,2×morpholine-CH2and-CH2-),7.05(s,1H,Ar-H),7.47(t,3H,Ar-H),8.47(s,1H,Ar-H),10.17(s,1H,-NH-),13.06(s,1H,imidazole-NH),13.44(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):28.93,45.48,52.45,53.19,61.77,62.26,63.80,65.57,102.17,111.13,118.12,120.50,121.24,123.74,130.91,132.04,133.62,142.85,147.73,158.00,159.63,167.89;ESI-MS m/z:425.2[M+H]+,423.2[M-H]-.IR (KBr, cm -1 ): 2933.24, 1735.65, 1610.30, 1438.66, 1400.09, 1284.38, 1132.03, 1112.74, 1068.39, 981.61, 941.11, 889.04, 792.61, 688.47; DM 1 H-d0 MHz ( 6 ) (ppm): 2.51(s, 7H, 2×morpholine-CH 2 and CH 3 ), 3.69(s, 6H, 2×morpholine-CH 2 and-CH 2 -), 7.05(s, 1H, Ar-H) , 7.47(t, 3H, Ar-H), 8.47(s, 1H, Ar-H), 10.17(s, 1H, -NH-), 13.06(s, 1H, imidazole-NH), 13.44(s, 1H , pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 28.93, 45.48, 52.45, 53.19, 61.77, 62.26, 63.80, 65.57, 102.17, 111.13, 118.12, 120.50, 121.24, 123.7 , 130.91, 132.04, 133.62, 142.85, 147.73, 158.00, 159.63, 167.89; ESI-MS m/z: 425.2[M+H] + , 423.2[MH] - .

实施例3Example 3

6-氯-2-(甲硫基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-002)6-Chloro-2-(methylthio)-N-{3-[5-(morpholinemethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -Amine (AM-002)

Figure BSA00000142843500122
Figure BSA00000142843500122

具体实验操作同化合物AM-001的合成,投入化合物7a(0.894g,3mmol)和4,6-二氯-2-甲硫基嘧啶(0.48g,2.5mmol)到10mL DMF中,得白色固体0.56g,收率73.3%,mp 225℃.The specific experimental operation is the same as the synthesis of compound AM-001, and compound 7a (0.894g, 3mmol) and 4,6-dichloro-2-methylthiopyrimidine (0.48g, 2.5mmol) are put into 10mL DMF to obtain a white solid 0.56 g, yield 73.3%, mp 225℃.

IR(KBr,cm-1):2972.46,1610.30,1556.30,1432.78,1356.07,1276.67,1207.24,1058.74,970.03,852.40,680.76;1H-NMR(DMSO-d6,500MHz)δ(ppm):2.55(t,6H,3×morpholine-CH2),3.81-3.91(d,5H,morpholine-CH2and-CH3),4.44(s,2H,-CH2-),6.93(s,1H,Ar-H),7.48-7.77(m,3H,Ar-H),8.35(s,1H,Ar-H),10.21(s,1H,-NH-),11.23(s,1H,imidazole-NH),13.46(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,75MHz)δ(ppm):13.69,50.53,54.86,59.57,63.15,111.50,118.47,120.82,171,97;ESI-MS m/z:457.27[M+H]+.IR (KBr, cm -1 ): 2972.46, 1610.30, 1556.30, 1432.78, 1356.07, 1276.67, 1207.24, 1058.74, 970.03, 852.40, 680.76; 1 H-NMR (DMSO-d 6 , 500MHz) δ (ppm): 2.55 t, 6H, 3×morpholine-CH 2 ), 3.81-3.91 (d, 5H, morpholine-CH 2 and-CH 3 ), 4.44 (s, 2H, -CH 2 -), 6.93 (s, 1H, Ar- H), 7.48-7.77 (m, 3H, Ar-H), 8.35 (s, 1H, Ar-H), 10.21 (s, 1H, -NH-), 11.23 (s, 1H, imidazole-NH), 13.46 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 75MHz) δ (ppm): 13.69, 50.53, 54.86, 59.57, 63.15, 111.50, 118.47, 120.82, 171, 97; ESI-MS m/z: 457.27[M+H] + .

实施例4Example 4

N-{4-[4-氯-6-(3-(5-(吗啉甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺(AM-003)N-{4-[4-chloro-6-(3-(5-(morpholinemethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide (AM-003)

具体实验操作同化合物AM-001的合成,投入化合物7a(0.894g,3mmol)和N-[4-(4,6-二氯嘧啶-2-硫)苯基]环丙甲酰胺(0.85g,2.5mmol)到10mL DMF中,得白色固体0.55g,收率36.5%,mp 198℃.The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7a (0.894g, 3mmol) and N-[4-(4,6-dichloropyrimidine-2-thio)phenyl]cyclopropylcarboxamide (0.85g, 2.5mmol) into 10mL DMF, to obtain white solid 0.55g, yield 36.5%, mp 198 ℃.

IR(KBr,cm-1):3257.23,2956.39,2813.68,1668.15,1554.73,1402.02,1353.81,1274.74,1201.45,1114.67,960.39,850.47,819.61,678.83;1H-NMR(DMSO-d6,300MHz)δ(ppm):0.87(s,4H,2×cyclopropyl-CH2),1.86(s,1H,cyclopropyl-CH),2.37(s,4H,2×morpholine-CH2),3.55(s,6H,2×morpholine-CH2and-CH2-),7.01(s,1H,Ar-H),7.16(s,2H,Ar-H),7.41(s,1H,Ar-H),7.58-7.66(m,3H,Ar-H),7.76(d,J=8.13Hz,2H,Ar-H),10.34(d,2H,2×-NH-),12.99(d,2H,imidazole-NH and pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):7.47,14.78,53.10,54.83,62.77,62.89,66.12,101.75,110.93,111.59,117.98,118.96,119.95,120.26,120.81,121.77,123.13,124.09,130.61,131.06,132.69,133.56,136.54,140.64,142.03,142.73,147.13,157.40,158.83,172.21;ESI-MS m/z:602.47[M+H]+.IR (KBr, cm -1 ): 3257.23, 2956.39, 2813.68, 1668.15, 1554.73, 1402.02, 1353.81, 1274.74, 1201.45, 1114.67, 960.39, 850.47, 819.61, 678.83; DM 1 H-d0 MHz ( 6 ) MHz (ppm): 0.87(s, 4H, 2×cyclopropyl-CH 2 ), 1.86(s, 1H, cyclopropyl-CH), 2.37(s, 4H, 2×morpholine-CH 2 ), 3.55(s, 6H, 2 ×morpholine-CH 2 and-CH 2 -), 7.01(s, 1H, Ar-H), 7.16(s, 2H, Ar-H), 7.41(s, 1H, Ar-H), 7.58-7.66(m , 3H, Ar-H), 7.76 (d, J=8.13Hz, 2H, Ar-H), 10.34 (d, 2H, 2×-NH-), 12.99 (d, 2H, imidazole-NH and pyrazole-NH ); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 7.47, 14.78, 53.10, 54.83, 62.77, 62.89, 66.12, 101.75, 110.93, 111.59, 117.98, 118.96, 119.95, 120.26, 120.87, , 123.13, 124.09, 130.61, 131.06, 132.69, 133.56, 136.54, 140.64, 142.03, 142.73, 147.13, 157.40, 158.83, 172.21; ESI-MS m/z: 602.47[M+H] + .

实施例5Example 5

6-氯-2-甲基-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-004)6-chloro-2-methyl-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine ( AM-004)

Figure BSA00000142843500132
Figure BSA00000142843500132

具体实验操作同化合物AM-001的合成,投入化合物7b(0.888g,3mmol)和4,6-二氯-2-甲基嘧啶(0.45g,2.5mmol)到10mL DMF中,得白色固体0.56g,收率73.3%,mp198-200℃.The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7b (0.888g, 3mmol) and 4,6-dichloro-2-methylpyrimidine (0.45g, 2.5mmol) in 10mL DMF to obtain 0.56g of white solid , yield 73.3%, mp198-200℃.

IR(KBr,cm-1):3190.20,2945.75,1576.94,1394.49,1368.42,1284.21,1129.82,977.44,933.33,887.22;1H-NMR(DMSO-d6,300MHz)δ(ppm):1.21-1.74(t,6H,3×piperidine-CH2),2.87(d,2H,morpholine-CH2),4.32(s,2H,-CH2-),7.03(d,J=21.6Hz,1H,Ar-H),7.40(s,1H,Ar-H),7.52(d,J=7.83Hz,1H,Ar-H),7.70-7.91(m,1H,Ar-H),8.47(s,1H,Ar-H),10.09(s,1H,-NH-),13.16(s,1H,imidazole-NH),13.42(s,1H,pyrazole-NH);ESI-MSm/z:423.16[M+H]+.IR (KBr, cm -1 ): 3190.20, 2945.75, 1576.94, 1394.49, 1368.42, 1284.21, 1129.82, 977.44, 933.33, 887.22; 1 H-NMR (DMSO-d 6 , 300MHz) δ (ppm): 1.21-1.74 ( t, 6H, 3×piperidine-CH 2 ), 2.87 (d, 2H, morpholine-CH 2 ), 4.32 (s, 2H, -CH 2 -), 7.03 (d, J=21.6Hz, 1H, Ar-H ), 7.40(s, 1H, Ar-H), 7.52(d, J=7.83Hz, 1H, Ar-H), 7.70-7.91(m, 1H, Ar-H), 8.47(s, 1H, Ar- H), 10.09(s, 1H, -NH-), 13.16(s, 1H, imidazole-NH), 13.42(s, 1H, pyrazole-NH); ESI-MSm/z: 423.16[M+H] + .

实施例6Example 6

6-氯-2-(甲硫基)-N-{3-[5-(哌啶甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-005)6-Chloro-2-(methylthio)-N-{3-[5-(piperidinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -Amine (AM-005)

具体实验操作同化合物AM-001的合成,投入化合物7b(0.888g,3mmol)和4,6-二氯-2-甲硫基嘧啶(0.48g,2.5mmol)到10mL DMF中,得白色固体0.28g,收率26.7%,mp 223℃.The specific experimental operation was the same as the synthesis of compound AM-001, and compound 7b (0.888g, 3mmol) and 4,6-dichloro-2-methylthiopyrimidine (0.48g, 2.5mmol) were put into 10mL DMF to obtain a white solid 0.28 g, yield 26.7%, mp 223℃.

IR(KBr,cm-1):2931.32,1606.44,1556.30,1432.87,1353.81,1274.74,1207.24,1118.53,970.03,850.47,809.97,682.69;1H-NMR(DMSO-d6,300MHz)δ(ppm):1.40-1.51(d,6H,3×piperidine-CH2),2.39(s,4H,2×piperidine-CH2),2.56(s,2H,-CH2-),3.57(s,3H,-CH3),6.94(s,1H,Ar-H),7.17(s,1H,Ar-H),7.43(s,1H,Ar-H),7.67(s,1H,Ar-H),8.33(s,1H,Ar-H),10.29(s,1H,-NH-),12.94(s,1H,imidazole-NH),13.35(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):13.68,21.09,23.85,25.30,53.68,63.00,101.12,110.86,111.51,117.93,118.92,120.77,123.10,124.10,131.40,132.70,133.59,142.07,142.79,146.99,157.35,159.06,171.96;ESI-MSm/z:455.3[M+H]+.IR (KBr, cm -1 ): 2931.32, 1606.44, 1556.30, 1432.87, 1353.81, 1274.74, 1207.24, 1118.53, 970.03, 850.47, 809.97, 682.69; 1 H-NMR (DMSO-d 6 , 300mMHz) δ( 1.40-1.51(d, 6H, 3×piperidine-CH 2 ), 2.39(s, 4H, 2×piperidine-CH 2 ), 2.56(s, 2H, -CH 2 -), 3.57(s, 3H, -CH 3 ), 6.94(s, 1H, Ar-H), 7.17(s, 1H, Ar-H), 7.43(s, 1H, Ar-H), 7.67(s, 1H, Ar-H), 8.33(s , 1H, Ar-H), 10.29 (s, 1H, -NH-), 12.94 (s, 1H, imidazole-NH), 13.35 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 ,125MHz)δ(ppm):13.68,21.09,23.85,25.30,53.68,63.00,101.12,110.86,111.51,117.93,118.92,120.77,123.10,124.10,131.40,132.70,133.59,142.07,142.79,146.99,157.35, 159.06, 171.96; ESI-MSm/z: 455.3[M+H] + .

实施例7Example 7

N-{4-[4-氯-6-(3-(5-(哌啶甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺(AM-006)N-{4-[4-chloro-6-(3-(5-(piperidinylmethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-sulfur ]phenyl}cyclopropylcarboxamide (AM-006)

Figure BSA00000142843500142
Figure BSA00000142843500142

具体实验操作同化合物AM-001的合成,投入化合物7b(0.888g,3mmol)和N-[4-(4,6-二氯嘧啶-2-硫)苯基]环丙甲酰胺(0.85g,2.5mmol)到10mL DMF中,得白色固体0.25g,收率13.1%。The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7b (0.888g, 3mmol) and N-[4-(4,6-dichloropyrimidine-2-thio)phenyl]cyclopropylcarboxamide (0.85g, 2.5mmol) into 10mL of DMF to obtain 0.25g of white solid with a yield of 13.1%.

IR(KBr,cm-1):3234.09,2942.88,1567.87,1554.37,1403.95,1357.66,1274.74,1201.45,1114.87,958.46,821.54;1H-NMR(DMSO-d6,300MHz)δ(ppm):0.84-1.03(m,5H,2×cyclopropyl-CH2and cyclopropyl-CH),1.17(s,2H,-CH2-),1.69(s,4H,2×piperidine-CH2),1.88-1.98(t,2H,piperidine-CH2),2.72-2.88(d,2H,piperidine-CH2),4.33(s,2H,piperidine-CH2),6.98(s,1H,Ar-H),7.24-7.34(d,2H,Ar-H),7.50-7.85(m,6H,Ar-H),10.26(s,1H,-NH-),10.54(s,1H,-NH-),13.13(s,2H,imidazole-NH and pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):7.45,14.74,51.82,111.44,118.38,120.37,120.93121.71,136.53,140.65,142.75,172.21;ESI-MS m/z:600.4[M+H]+.IR (KBr, cm -1 ): 3234.09, 2942.88, 1567.87, 1554.37, 1403.95, 1357.66, 1274.74, 1201.45, 1114.87, 958.46, 821.54; 1 H-NMR (DMSO-d 6 , 300MHz) δ (4ppm-): 0.8 1.03(m, 5H, 2×cyclopropyl-CH 2 and cyclopropyl-CH), 1.17(s, 2H, -CH 2 -), 1.69(s, 4H, 2×piperidine-CH 2 ), 1.88-1.98(t, 2H, piperidine-CH 2 ), 2.72-2.88(d, 2H, piperidine-CH 2 ), 4.33(s, 2H, piperidine-CH 2 ), 6.98(s, 1H, Ar-H), 7.24-7.34(d , 2H, Ar-H), 7.50-7.85(m, 6H, Ar-H), 10.26(s, 1H, -NH-), 10.54(s, 1H, -NH-), 13.13(s, 2H, imidazole -NH and pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 7.45, 14.74, 51.82, 111.44, 118.38, 120.37, 120.93121.71, 136.53, 140.65, 142.75, 172.21; ESI -MS m/z: 600.4[M+H] + .

实施例8Example 8

6-氯-2-甲基-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]嘧啶-4-胺(AM-007)6-Chloro-2-methyl-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]pyrimidin-4-amine (AM-007)

具体实验操作同化合物AM-001的合成,投入化合物7c(0.639g,3mmol)和4,6-二氯-2-甲基嘧啶(0.45g,2.5mmol)到10mLDMF中,得白色固体0.58g,收率69.2%,mp>250℃.The specific experimental operation was the same as the synthesis of compound AM-001, and compound 7c (0.639g, 3mmol) and 4,6-dichloro-2-methylpyrimidine (0.45g, 2.5mmol) were put into 10mL of DMF to obtain 0.58g of a white solid. Yield 69.2%, mp>250°C.

IR(KBr,cm-1):3160.81,2921.67,2424.12,1579.44,1438.66,1400.09,1328.73,1132.03,985.46,889.04,796.47,686.55;1H-NMR(DMSO-d6,300MHz)δ(ppm):2.50(s,3H,-CH3),2.51(s,3H,-CH3),7.05(d,J=8.88Hz,2H,Ar-H),7.36(t,J=7.77Hz,1H,Ar-H),7.62(t,J=8.10Hz,1H,Ar-H),8.47(s,1H,Ar-H),10.22(s,1H,-NH-),12.85(s,1H,imidazole-NH),13.26(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):13.99,20.67,21.20,21.26,25.47,59.67,102.15,110.89,111.16,118.05,118.30,120.34,121.13,123.15,123.99,130.55,131.04,131.54,131.91,133.79,140.93,143.12,146.78,147.14,157.98,159.54,167.89;ESI-MS m/z:340.11[M+H]+.IR (KBr, cm -1 ): 3160.81, 2921.67, 2424.12, 1579.44, 1438.66, 1400.09, 1328.73, 1132.03, 985.46, 889.04, 796.47, 686.55; 1 H-NMR (DMSO-d 6 , 300mMHz) δ( 2.50(s, 3H, -CH 3 ), 2.51(s, 3H, -CH 3 ), 7.05(d, J=8.88Hz, 2H, Ar-H), 7.36(t, J=7.77Hz, 1H, Ar -H), 7.62(t, J=8.10Hz, 1H, Ar-H), 8.47(s, 1H, Ar-H), 10.22(s, 1H, -NH-), 12.85(s, 1H, imidazole- NH), 13.26 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 13.99, 20.67, 21.20, 21.26, 25.47, 59.67, 102.15, 110.89, 111.16, 118.05 , 118.30, 120.34, 121.13, 123.15, 123.99, 130.55, 131.04, 131.54, 131.91, 133.79, 140.93, 143.12, 146.78, 147.14, 157.98, 159.54, 167.89]; 1 : ESI-MS m/

实施例9Example 9

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲硫基)嘧啶-4-胺(AM-008)6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylthio)pyrimidin-4-amine (AM -008)

具体实验操作同化合物AM-001的合成,投入化合物7c(0.639g,3mmol)和4,6-二氯-2-甲硫基嘧啶(0.48g,2.5mmol)到10mL DMF中,得白色固体0.49g,收率52.7%,mp>250℃.The specific experimental operation is the same as the synthesis of compound AM-001, and compound 7c (0.639g, 3mmol) and 4,6-dichloro-2-methylthiopyrimidine (0.48g, 2.5mmol) are put into 10mL DMF to obtain a white solid 0.49 g, yield 52.7%, mp>250℃.

IR(KB r,cm-1):3193.59,2925.53,1610.30,1556.30,1434.80,1371.16,1276.67,1209.17,1118.53,970.03,850.47,809.97,682.69;1H-NMR(DMSO-d6,300MHz)δ(ppm):2.50(s,3H,-CH3),2.55(s,3H,-CH3),6.92-7.06(t,J=8.28Hz,2H,Ar-H),7.37(d,1H,Ar-H),7.59(d,1H,Ar-H),8.33(s,1H,Ar-H),10.32(s,1H,-NH-),12.86(s,1H,imidazole-NH),13.27(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):13.69,21.29,101.04,110.94,111.19,118.11,118.35,120.59,123.21,124.06,130.60,131.55,131.98,133.81,140.92,143.11,146.63,146.98,157.43,158.98,171.97;ESI-MS m/z:372.08[M+H]+.IR (KB r, cm -1 ): 3193.59, 2925.53, 1610.30, 1556.30, 1434.80, 1371.16, 1276.67, 1209.17, 1118.53, 970.03, 850.47, 809.97, 682.69; 1 H-NMR (DM30-d 6 MHz) ppm): 2.50 (s, 3H, -CH 3 ), 2.55 (s, 3H, -CH 3 ), 6.92-7.06 (t, J=8.28Hz, 2H, Ar-H), 7.37 (d, 1H, Ar -H), 7.59 (d, 1H, Ar-H), 8.33 (s, 1H, Ar-H), 10.32 (s, 1H, -NH-), 12.86 (s, 1H, imidazole-NH), 13.27 ( s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 13.69, 21.29, 101.04, 110.94, 111.19, 118.11, 118.35, 120.59, 123.21, 124.06, 130.60, 131.55, 131.98, 133.81, 140.92, 143.11, 146.63, 146.98, 157.43, 158.98, 171.97; ESI-MS m/z: 372.08[M+H] + .

实施例10Example 10

N-{4-[4-氯-6-(3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫基]苯}环丙甲酰胺(AM-009)N-{4-[4-chloro-6-(3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-thio]benzene} Cyclopropanamide (AM-009)

Figure BSA00000142843500161
Figure BSA00000142843500161

具体实验操作同化合物AM-001的合成,投入化合物7c(0.639g,3mmol)和N-[4-(4,6-二氯嘧啶-2-硫)苯基]环丙甲酰胺(0.85g,2.5mmol)到10mL DMF中,得白色固体0.48g,收率37.5%,mp>250℃.The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7c (0.639g, 3mmol) and N-[4-(4,6-dichloropyrimidine-2-thio)phenyl]cyclopropylcarboxamide (0.85g, 2.5mmol) into 10mL DMF to give 0.48g of white solid, yield 37.5%, mp>250°C.

IR(KBr,cm-1):3249.52,3185.88,2923.60,1664.29,1556.30,1432.87,1403.95,1369.23,1272.81,1201.45,1116.60,962.32,850.47,813.83,680.76;1H-NMR(DMSO-d6,300MHz)δ(ppm):0.82-0.89(m,5H,cyclopropyl-CH2and CH),2.50(s,3H,CH3),6.96-7.04(t,J=8.19Hz,2H,Ar-H),7.27(d,1H,Ar-H),7.52-7.61(t,J=8.55Hz,4H,Ar-H),7.76(d,J=8.55Hz,2H,Ar-H),10.42(d,2H,2×-NH-),12.82(s,1H,imidazole-NH),12.97(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):7.44,13.86,14.01,14.76,20.67,21.19,21.27,21.98,59.67,101.67,110.91,111.16,118.06,118.30,119.92,120.23,121.76,123.20,124.03,130.60,131.49,131.95,133.74,136.52,140.63,140.79,143.00,146.60,146.96,157.42,158.80,172.20;ESI-MS m/z:517.12[M+H]+.IR (KBr, cm -1 ): 3249.52, 3185.88, 2923.60, 1664.29, 1556.30, 1432.87, 1403.95, 1369.23, 1272.81, 1201.45, 1116.60, 962.32, 850.47 , 813.83 , 680 H.7 )δ (ppm): 0.82-0.89 (m, 5H, cyclopropyl-CH 2 and CH), 2.50 (s, 3H, CH 3 ), 6.96-7.04 (t, J=8.19Hz, 2H, Ar-H), 7.27(d, 1H, Ar-H), 7.52-7.61(t, J=8.55Hz, 4H, Ar-H), 7.76(d, J=8.55Hz, 2H, Ar-H), 10.42(d, 2H , 2×-NH-), 12.82 (s, 1H, imidazole-NH), 12.97 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 7.44, 13.86 ,14.01,14.76,20.67,21.19,21.27,21.98,59.67,101.67,110.91,111.16,118.06,118.30,119.92,120.23,121.76,123.20,124.03,130.60,131.49,131.95,133.74,136.52,140.63,140.79,143.00 , 146.60, 146.96, 157.42, 158.80, 172.20; ESI-MS m/z: 517.12[M+H] + .

实施例11Example 11

6-氯-2-甲基-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-010)6-Chloro-2-methyl-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine (AM-010)

Figure BSA00000142843500171
Figure BSA00000142843500171

具体实验操作同化合物AM-001的合成,投入化合物7d(0.852g,3mmol)和4,6-二氯-2-甲基嘧啶(0.45g,2.5mmol)到10mL DMF中,得白色固体0.56g,收率73.3%,mp198-200℃.The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7d (0.852g, 3mmol) and 4,6-dichloro-2-methylpyrimidine (0.45g, 2.5mmol) in 10mL DMF to obtain 0.56g of white solid , yield 73.3%, mp198-200℃.

IR(KBr,cm-1):3166.16,2965.79,1574.94,1434.59,1394.49,1370.43,1283.21,1129.82,977.44,887.22;1H-NMR(DMSO-d6,300MHz)δ(ppm):0.98-1.03(t,6H,2×diethylamine-CH3),1.21-1.45(d,1H,diethylamine-CH2),1.90(s,1H,diethylamine-CH2),3.67(s,3H,-CH3),7.04(s,1H,Ar-H),7.20(d,J=8.16Hz,1H,Ar-H),7.46-7.66(d,2H,Ar-H),8.46(s,1H,Ar-H),10.21(s,1H,-NH-),12.91(s,1H,imidazole-NH),13.29(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,75MHz)δ(ppm):16.38,25.50,28.95,45.98,57.12,68.61,68.83,69.74,102.42,110.89,111.18,117.91,118.63,120.62,121.24,122.84,123.82,130.71,132.62,134.06,141.97,142.86,147.18,158.01,159.61,169.91,172.08;ESI-MS m/z:460.05[M+Na]+.IR (KBr, cm -1 ): 3166.16, 2965.79, 1574.94, 1434.59, 1394.49, 1370.43, 1283.21, 1129.82, 977.44, 887.22; 1 H-NMR (DMSO-d 6 , 300MHz) δ (ppm): 0.98-1.03( t, 6H, 2×diethylamine-CH 3 ), 1.21-1.45 (d, 1H, diethylamine-CH 2 ), 1.90 (s, 1H, diethylamine-CH 2 ), 3.67 (s, 3H, -CH 3 ), 7.04 (s, 1H, Ar-H), 7.20 (d, J=8.16Hz, 1H, Ar-H), 7.46-7.66 (d, 2H, Ar-H), 8.46 (s, 1H, Ar-H), 10.21 (s, 1H, -NH-), 12.91 (s, 1H, imidazole-NH), 13.29 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 75MHz) δ (ppm): 16.38,25.50,28.95,45.98,57.12,68.61,68.83,69.74,102.42,110.89,111.18,117.91,118.63,120.62,121.24,122.84,123.82,130.71,132.62,134.06,141.97,142.86,147.18,158.01,159.61, 169.91, 172.08; ESI-MS m/z: 460.05[M+Na] + .

实施例12Example 12

6-氯-2-(甲硫基)-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AM-011)6-chloro-2-(methylthio)-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-Amine (AM-011)

Figure BSA00000142843500172
Figure BSA00000142843500172

具体实验操作同化合物AM-001的合成,投入化合物7d(0.852g,3mmol)和4,6-二氯-2-甲硫基嘧啶(0.48g,2.5mmol)到10mL DMF中,得白色固体0.28g,收率26.7%,mp 179-180℃.The specific experimental operation was the same as the synthesis of compound AM-001, and compound 7d (0.852g, 3mmol) and 4,6-dichloro-2-methylthiopyrimidine (0.48g, 2.5mmol) were put into 10mL of DMF to obtain a white solid 0.28 g, yield 26.7%, mp 179-180℃.

IR(KBr,cm-1):3186.20,2969.80,1607.02,1552.88,1430.58,1368.42,1274.19,1204.01,1115.79,969.42,811.03;1H-NMR(DMSO-d6,300MHz)δ(ppm):1.02-1.07(d,6H,J=8.16Hz,2×diethylamine-CH3),2.50-2.57(m,4H,2×diethylamine-CH2),2.61(s,3H,-CH3),3.68(s,2H,-CH2-),6.99(s,1H,Ar-H),7.24(s,1H,Ar-H),7.48(s,1H,Ar-H),7.73(s,1H,Ar-H),8.39(s,1H,Ar-H),10.36(s,1H,-NH-),12.93(s,1H,imidazole-NH),13.33(s,1H,pyrazole-NH);ESI-MS m/z:443.3[M+H]+.IR (KBr, cm -1 ): 3186.20, 2969.80, 1607.02, 1552.88, 1430.58, 1368.42, 1274.19, 1204.01, 1115.79, 969.42, 811.03; 1 H-NMR (DMSO-d 6 , 300MHz) δ (ppm-): 1. 1.07(d, 6H, J=8.16Hz, 2×diethylamine-CH 3 ), 2.50-2.57(m, 4H, 2×diethylamine-CH 2 ), 2.61(s, 3H,-CH 3 ), 3.68(s, 2H, -CH 2 -), 6.99(s, 1H, Ar-H), 7.24(s, 1H, Ar-H), 7.48(s, 1H, Ar-H), 7.73(s, 1H, Ar-H ), 8.39(s, 1H, Ar-H), 10.36(s, 1H, -NH-), 12.93(s, 1H, imidazole-NH), 13.33(s, 1H, pyrazole-NH); ESI-MS m /z: 443.3[M+H] + .

实施例13Example 13

N-{4-[4-氯-6-(3-(5-(二乙胺甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺(AM-012)N-{4-[4-chloro-6-(3-(5-(diethylaminomethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2- Sulfur]phenyl}cyclopropylcarboxamide (AM-012)

Figure BSA00000142843500181
Figure BSA00000142843500181

具体实验操作同化合物AM-001的合成,投入化合物7d(0.852g,3mmol)和N-[4-(4,6-二氯嘧啶-2-硫)苯基]环丙甲酰胺(0.85g,2.5mmol)到10mL DMF中,得白色固体0.25g,收率13.1%,mp 176-180℃.The specific experimental operation is the same as the synthesis of compound AM-001, and input compound 7d (0.852g, 3mmol) and N-[4-(4,6-dichloropyrimidine-2-thio)phenyl]cyclopropylcarboxamide (0.85g, 2.5mmol) into 10mL DMF, to give white solid 0.25g, yield 13.1%, mp 176-180°C.

IR(KBr,cm-1):3242.30,1663.16,1588.97,1552.88,1438.60,1400.50,1274.19,1200.00,1113.78,957.39,835.09;1H-NMR(DMSO-d6,300MHz)δ(ppm):0.87(s,5H,2×cyclopropyl-CH2and CH),1.17(d,6H,J=7.17Hz,2×diethylamine-CH3),1.90(s,2H,-CH2-),2.88(s,4H,2×diethylamine-CH2),6.98(s,1H,Ar-H),7.31(s,2H,Ar-H),7.52-7.60(t,3H,Ar-H),7.76(d,J=8.73Hz,3H,Ar-H),10.28(s,1H,-NH-),10.51(s,1H,-NH-),13.10(s,2H,imidazole-NH and pyrazole-NH);ESI-MS m/z:588.4[M+H]+.IR (KBr, cm -1 ): 3242.30, 1663.16, 1588.97, 1552.88, 1438.60, 1400.50, 1274.19, 1200.00, 1113.78, 957.39, 835.09; 1 H-NMR (DMSO-d 6 , 300MHz) δ (ppm): 0.87 s, 5H, 2×cyclopropyl-CH 2 and CH), 1.17 (d, 6H, J=7.17Hz, 2×diethylamine-CH 3 ), 1.90 (s, 2H, -CH 2 -), 2.88 (s, 4H , 2×diethylamine-CH 2 ), 6.98(s, 1H, Ar-H), 7.31(s, 2H, Ar-H), 7.52-7.60(t, 3H, Ar-H), 7.76(d, J= 8.73Hz, 3H, Ar-H), 10.28(s, 1H, -NH-), 10.51(s, 1H, -NH-), 13.10(s, 2H, imidazole-NH and pyrazole-NH); ESI-MS m/z: 588.4[M+H] + .

实施例14Example 14

6-氯-2-(甲砜基)-N-{3-[5-(吗啉甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AN-001)6-Chloro-2-(methylsulfonyl)-N-{3-[5-(morpholinomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -Amine (AN-001)

Figure BSA00000142843500182
Figure BSA00000142843500182

50mL圆底烧瓶中,投入化合物7a(0.894g,3mmol)和4,6-二氯-2-甲砜基嘧啶(0.68g,3mmol),以30mL叔丁醇溶解,Ar气保护下,回流反应1h。反应结束后,真空蒸干溶剂,残余物以50mL乙酸乙酯和50mL饱和NaCO3溶液溶解,分层。有机层依次以水和饱和食盐水洗涤,无水MgSO4干燥。真空蒸干溶剂,乙酸乙酯重结晶,得类白色固体0.38g,收率26.2%,mp>250℃.In a 50mL round bottom flask, put compound 7a (0.894g, 3mmol) and 4,6-dichloro-2-thiamphenicol pyrimidine (0.68g, 3mmol), dissolve it in 30mL tert-butanol, and reflux under the protection of Ar 1h. After the reaction, the solvent was evaporated to dryness in vacuo, and the residue was dissolved in 50 mL ethyl acetate and 50 mL saturated NaCO 3 solution, and the layers were separated. The organic layer was washed successively with water and brine, and dried over anhydrous MgSO 4 . The solvent was evaporated to dryness in vacuo, and recrystallized from ethyl acetate to obtain 0.38 g of off-white solid, yield 26.2%, mp>250°C.

IR(KBr,cm-1):3315.09,2958.31,2859.96,1608.37,1581.37,1434.80,1317.16,1147.46,1116.60,968.11,852.40,763.68,680.76;1H-NMR(DMSO-d6,500MHz)δ(ppm):2.39-2.51(d,4H,2×morpholine-CH2),3.44(s,3H,-CH3),3.58(s,6H,2×morpholine-CH2and-CH2-),7.21(d,J=7.65Hz,1H,Ar-H),7.44(s,1H,Ar-H),7.61-7.69(t,2H,Ar-H),10.92(d,1H,-NH-),13.00(d,1H,imidazole-NH),13.38(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,75MHz)δ(ppm):13.69,50.53,54.86,59.57,63.15,102.17,111.50,118.47,120.82,171,97;ESI-MS m/z:487.35[M+H]+;Anal.Calcd for C20H21ClN8O3S·1/4H2O(%):C 48.72,H 4.41,N 22.73;Found:C 48.58,H 4.35,N 22.47.IR (KBr, cm -1 ): 3315.09, 2958.31, 2859.96, 1608.37, 1581.37, 1434.80, 1317.16, 1147.46, 1116.60, 968.11, 852.40, 763.68, 680.76; 1 H-NMR (DM5-0d 6 MHz) ): 2.39-2.51 (d, 4H, 2×morpholine-CH 2 ), 3.44 (s, 3H, -CH 3 ), 3.58 (s, 6H, 2×morpholine-CH 2 and-CH 2 -), 7.21 ( d, J=7.65Hz, 1H, Ar-H), 7.44(s, 1H, Ar-H), 7.61-7.69(t, 2H, Ar-H), 10.92(d, 1H, -NH-), 13.00 (d, 1H, imidazole-NH), 13.38 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 75MHz) δ (ppm): 13.69, 50.53, 54.86, 59.57, 63.15, 102.17, 111.50, 118.47, 120.82, 171, 97; ESI-MS m/z: 487.35 [M+H] + ; Anal. Calcd for C 20 H 21 ClN 8 O 3 S 1/4H 2 O (%): C 48.72 , H 4.41, N 22.73; Found: C 48.58, H 4.35, N 22.47.

实施例15Example 15

6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲砜基)嘧啶-4-胺(AN-002)6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidin-4-amine (AN -002)

Figure BSA00000142843500191
Figure BSA00000142843500191

具体实验操作同化合物AN-001的合成,投入化合物7c(0.639g,3mmol)和4,6-二氯-2-甲砜基嘧啶(0.68g,3mmol),)到30mL叔丁醇中,得类白色固体0.34g,收率28.1%,mp>250℃.The specific experimental operation is the same as the synthesis of compound AN-001, drop compound 7c (0.639g, 3mmol) and 4,6-dichloro-2-thiamphenicol pyrimidine (0.68g, 3mmol),) into 30mL of tert-butanol, to obtain Off-white solid 0.34g, yield 28.1%, mp>250℃.

IR(KBr,cm-1):3345.94,2925.53,1608.73,1583.30,1434.80,1396.23,1334.52,1299.81,1141.67,1116.60,1141.67,966.18,854.32,761.76,678.83;1H-NMR(DMSO-d6,300MHz)δ(ppm):2.50(s,3H,-CH3),3.40(s,3H,-CH3),7.06(s,1H,Ar-H),7.30-7.40(t,J=8.13Hz,1H,Ar-H),7.55-7.64(t,2H,Ar-H),8.46(s,1H,Ar-H),10.84(s,1H,-NH-),12.91(s,1H,imidazole-NH),13.37(s,1H,pyrazole-NH);13C-NMR(DMSO-d6,125MHz)δ(ppm):21.25,108.51,111.00,111.24,118.14,120.14,121.13,123.29,124.15,130.66,131.50,132.08,140.89,143.06,146.42,157.71,159.65,165.14;ESI-MSm/z:404.06[M+H]+.IR (KBr, cm -1 ): 3345.94, 2925.53, 1608.73, 1583.30, 1434.80, 1396.23, 1334.52, 1299.81, 1141.67, 1116.60, 1141.67, 966.18 , 854.32 , 761.76, 678 H.83 )δ (ppm): 2.50 (s, 3H, -CH 3 ), 3.40 (s, 3H, -CH 3 ), 7.06 (s, 1H, Ar-H), 7.30-7.40 (t, J=8.13Hz, 1H, Ar-H), 7.55-7.64(t, 2H, Ar-H), 8.46(s, 1H, Ar-H), 10.84(s, 1H, -NH-), 12.91(s, 1H, imidazole- NH), 13.37 (s, 1H, pyrazole-NH); 13 C-NMR (DMSO-d 6 , 125MHz) δ (ppm): 21.25, 108.51, 111.00, 111.24, 118.14, 120.14, 121.13, 123.29, 124.15, 130.66 , 131.50, 132.08, 140.89, 143.06, 146.42, 157.71, 159.65, 165.14; ESI-MSm/z: 404.06[M+H] + .

实施例16Example 16

6-氯-2-(甲砜基)-N-{3-[5-(二乙胺基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺(AN-004)6-Chloro-2-(methylsulfonyl)-N-{3-[5-(diethylamino)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine-4 -Amine (AN-004)

Figure BSA00000142843500192
Figure BSA00000142843500192

具体实验操作同化合物AN-001的合成,投入化合物7d(0.87g,3mmol)和4,6-二氯-2-甲砜基嘧啶(0.68g,3mmol),)到30mL叔丁醇中,得类白色固体0.34g,收率22.1%。1H-NMR(DMSO-d6,500MHz)δ(ppm):3.07(s,5H,2×cyclopropyl-CH2and CH),3.31(s,3H,-CH3),3.36-3.61(m,5H,2×cyclopropyl-CH2and CH),7.46-7.56(m,3H,Ar-H),7.76-7.94(m,2H,Ar-H),13.33(d,1H,imidazole-NH),13.54(s,1H,pyrazole-NH);ESI-MS m/z:475.3[M+H]+.The specific experimental operation is the same as the synthesis of compound AN-001, drop compound 7d (0.87g, 3mmol) and 4,6-dichloro-2-thiamphenicol pyrimidine (0.68g, 3mmol),) into 30mL tert-butanol, to obtain Off-white solid 0.34g, yield 22.1%. 1H-NMR (DMSO-d6, 500MHz) δ (ppm): 3.07(s, 5H, 2×cyclopropyl-CH2and CH), 3.31(s, 3H, -CH3), 3.36-3.61(m, 5H, 2×cyclopropyl -CH2and CH), 7.46-7.56(m, 3H, Ar-H), 7.76-7.94(m, 2H, Ar-H), 13.33(d, 1H, imidazole-NH), 13.54(s, 1H, pyrazole- NH); ESI-MS m/z: 475.3[M+H] + .

生物学实施例biological example

采用下列实验甑别具有最佳程度的所需活性的那些化合物。Those compounds with the optimum degree of desired activity were identified using the following assay.

抑制肿瘤细胞增殖测定方法(MTT法)Inhibition of tumor cell proliferation assay method (MTT method)

测定胺常规采用溴化四氮唑蓝(MTT)法。活细胞线粒体中的琥珀酸脱氢酶能使外源性溴化四氮唑蓝还原为难溶的蓝紫色结晶物(Formazan)并沉积在细胞中,而死细胞无此功能。三联裂解液能溶解细胞中的紫色结晶物,用酶联免疫检测仪在570nm波长处检测其光吸收值,可间接反映活细胞数量。因而,采用MTT法可测定目标化合物抑制细胞的增殖能力,同时利用本领域熟知的方法,可以对任意癌细胞使用相似的测定方法。1试剂和仪器Determination of amines routinely adopt blue tetrazolium bromide (MTT) method. Succinate dehydrogenase in the mitochondria of living cells can reduce exogenous blue tetrazolium bromide to insoluble blue-purple crystals (Formazan) and deposit them in cells, while dead cells have no such function. The triple lysate can dissolve the purple crystals in the cells, and the light absorption value is detected at a wavelength of 570nm by an enzyme-linked immunosorbent detector, which can indirectly reflect the number of living cells. Therefore, the ability of the target compound to inhibit cell proliferation can be determined by using the MTT method, and a similar determination method can be used for any cancer cell by using methods well known in the art. 1 Reagents and instruments

RPMI 1640培养基(RPMI 1640+10%小牛血清或胎牛血清+HEPES 3.5g/l+NaHCO32.2g/l+青霉素0.13g/l+链霉素0.15g/l);MTT(Sigma);胰蛋白酶(Invitrogen);三联溶解试剂。RPMI 1640 medium (RPMI 1640+10% calf serum or fetal bovine serum+HEPES 3.5g/l+NaHCO 3 2.2g/l+penicillin 0.13g/l+streptomycin 0.15g/l); MTT (Sigma); Protease (Invitrogen); Triple Lysis Reagent.

CO2培养箱、无菌操作台、酶标仪、离心机、移液枪、移液管、离心管、96孔板等。 CO2 incubator, sterile operating table, microplate reader, centrifuge, pipette gun, pipette, centrifuge tube, 96-well plate, etc.

2细胞株2 cell lines

慢性髓细胞白血病(K562)、人急性单核细胞白血病细胞株(U937)Chronic myeloid leukemia (K562), human acute monocytic leukemia cell line (U937)

3实验方法3 Experimental methods

3.1细胞培养3.1 Cell culture

人非小细胞肺癌细胞株(A549)用含10%小牛血清的RPMI 1640培养基,于37℃,5%CO2的培养箱中培养。人急性单核细胞白血病细胞株(U937)用含10%胎牛血清的RPMI 1640培养基,于37℃,5%CO2的培养箱中培养。Human non-small cell lung cancer cell line (A549) was cultured in RPMI 1640 medium containing 10% calf serum at 37°C in an incubator with 5% CO 2 . Human acute monocytic leukemia cell line (U937) was cultured in RPMI 1640 medium containing 10% fetal bovine serum in an incubator at 37°C and 5% CO 2 .

3.2细胞接种3.2 Cell inoculation

取处于指数生长期,状态良好的细胞,收集细胞离心,弃上清。用含10%小牛血清的RPMI 1640(或DMEM)培养液配成细胞悬液,然后计数。取细胞悬液接种于96孔板上,100μl/孔(每孔含5000个肿瘤细胞)。将培养板转入恒温CO2培养箱中,在37℃,5%CO2及饱和湿度条件下培养24小时。Take the cells that are in the exponential growth phase and in good condition, collect the cells and centrifuge, and discard the supernatant. Prepare cell suspension with RPMI 1640 (or DMEM) culture medium containing 10% calf serum, and then count. The cell suspension was inoculated on a 96-well plate, 100 μl/well (each well contained 5000 tumor cells). The culture plate was transferred to a constant temperature CO 2 incubator and incubated at 37°C, 5% CO 2 and saturated humidity for 24 hours.

3.3化合物配制3.3 Compound preparation

待测化合物先用DMSO配制成20mmol/L浓度,加入待测化合物,使其终浓度为10-5mol/L用于初筛,每组设3个复孔,培养基补足至200ul。阴性对照为等体积培养基,同时设相应浓度的DMSO溶媒对照,空白对照不含细胞和药物。共同于37℃,5%CO2的培养箱中培养72小时。The compound to be tested was first prepared with DMSO to a concentration of 20mmol/L, and the compound to be tested was added to make the final concentration 10 -5 mol/L for primary screening. Three replicate wells were set up in each group, and the medium was replenished to 200ul. The negative control is an equal volume of medium, and a corresponding concentration of DMSO vehicle control is set at the same time, and the blank control does not contain cells and drugs. Cultivate together in an incubator at 37°C, 5% CO 2 for 72 hours.

3.4染色3.4 Dyeing

将5mg/ml的MTT加入96孔板中,20μL/孔,置于培养箱中孵育4小时,再加入含20%SDS的三联裂解液50μL/孔,置于培养箱中过夜。Add 5 mg/ml MTT into 96-well plate, 20 μL/well, and incubate in the incubator for 4 hours, then add 50 μL/well of triple lysis solution containing 20% SDS, and place in the incubator overnight.

3.5测定3.5 Determination

酶标仪设定波长为570nm,参考波长为630nm,测定96孔板每孔吸光值,记录结果并计算细胞生长抑制率,以判断受试药物的抗肿瘤活性。The wavelength of the microplate reader was set at 570nm, and the reference wavelength was 630nm. The absorbance value of each well of the 96-well plate was measured, and the results were recorded and the cell growth inhibition rate was calculated to determine the antitumor activity of the test drug.

3.6复筛3.6 Re-screening

在初筛浓度为10-5mol/L时,3次细胞抑制率≥50%的化合物用于复筛,将20mmol/L再做5个稀释度,孔中终浓度依次为5×10-5mol/L、2×10-5mol/L、10-5mol/L、5×10-6mol/L和2×10-6mol/L。培养72小时,同样每组设3个复孔,并按照初筛方法,测定96孔板每孔吸光值,记录结果并计算细胞生长抑制率。When the initial screening concentration is 10 -5 mol/L, the compound with a cell inhibition rate ≥ 50% for 3 times is used for the secondary screening, and 20mmol/L is used for 5 dilutions, and the final concentration in the well is 5×10 -5 mol/L, 2×10 -5 mol/L, 10 -5 mol/L, 5×10 -6 mol/L and 2×10 -6 mol/L. After culturing for 72 hours, three replicate wells were set up for each group, and the absorbance value of each well of the 96-well plate was measured according to the primary screening method, and the results were recorded and the cell growth inhibition rate was calculated.

3.7细胞生长抑制率以及IC50的计算3.7 Cell growth inhibition rate and calculation of IC50

Figure BSA00000142843500211
Figure BSA00000142843500211

同时根据各浓度的生长抑制率,采用GraphPad Prism 5.0软件计算IC50值。At the same time, according to the growth inhibition rate of each concentration, the IC 50 value was calculated by GraphPad Prism 5.0 software.

4实验结果4 Experimental results

4.1细胞生长抑制率4.1 Cell growth inhibition rate

在浓度为10-5mol/L时,AM系列目标化合物对不同肿瘤细胞的生长抑制率分别见表1。At a concentration of 10 -5 mol/L, the growth inhibition rates of AM series target compounds on different tumor cells are shown in Table 1, respectively.

表1AM和AN系列目标化合物对不同肿瘤细胞的生长抑制率(10μM)Table 1 AM and AN series of target compounds to the growth inhibition rate of different tumor cells (10μM)

Figure BSA00000142843500212
Figure BSA00000142843500212

Figure BSA00000142843500213
Figure BSA00000142843500213

Figure BSA00000142843500221
Figure BSA00000142843500221

a:浓度=10μMa: Concentration = 10 μM

4.2细胞生长半数抑制浓度(IC50μmol/L)4.2 Half inhibitory concentration of cell growth (IC 50 μmol/L)

AM系列目标化合物对不同肿瘤细胞生长的半数抑制浓度(IC50μmol/L)见表2。See Table 2 for the half maximal inhibitory concentration (IC 50 μmol/L) of AM series target compounds on the growth of different tumor cells.

表2AM和系列目标化合物对不同肿瘤细胞生长的半数抑制浓度(IC50μmol/L)Table 2 AM and series of target compounds on the growth of different tumor cell half maximal inhibitory concentration (IC 50 μmol/L)

Figure BSA00000142843500231
Figure BSA00000142843500231

Figure BSA00000142843500232
Figure BSA00000142843500232

Figure BSA00000142843500241
Figure BSA00000142843500241

A-IC50<1.0μmol/L;A-IC 50 <1.0μmol/L;

B-1.0<IC50<5.0μmol/L;B-1.0< IC50 <5.0μmol/L;

C-5.0<IC50<10.0μmol/L;C-5.0< IC50 <10.0μmol/L;

5.实验结论5. Experimental conclusion

本发明实施例中制备的具有式(I)结构的化合物对慢性髓细胞白血病(K562)、人急性单核细胞白血病细胞株(U937)的增殖具有显著的抑制作用。上述这些化合物可应用于抗肿瘤药物的制备。The compound with the structure of formula (I) prepared in the examples of the present invention has significant inhibitory effect on the proliferation of chronic myeloid leukemia (K562) and human acute monocytic leukemia cell line (U937). The above-mentioned compounds can be applied to the preparation of antitumor drugs.

Claims (8)

1.式(I)结构的化合物或其药学上可接受的盐:1. A compound of formula (I) structure or a pharmaceutically acceptable salt thereof:
Figure FDA00003502637300011
Figure FDA00003502637300011
其中:in: A环为取代或非取代的嘧啶,所述取代基为卤素、硝基、氰基、巯基或氨基;Ring A is a substituted or unsubstituted pyrimidine, and the substituents are halogen, nitro, cyano, mercapto or amino; R1为C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷砜基、C3-6环烷基酰胺取代的苯硫基、C3-6环烷基酰胺取代的苯氧基;R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfone, C 3-6 cycloalkylamide Phenylthio, C 3-6 cycloalkylamide substituted phenoxy; R2为氢、卤素或-NR3R4,R4或R3独立地选自氢、C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,所述杂脂环基是吡咯烷基、哌啶基、吗啉基、哌嗪基、硫代吗啉基或高哌嗪基,其中取代基为C1-4烷基或C1-4羟烷基。R 2 is hydrogen, halogen or -NR 3 R 4 , R 4 or R 3 are independently selected from hydrogen, C 1-4 alkyl, or R 4 and R 3 together form a substituted or unsubstituted heteroalicyclic group, The heteroalicyclic group is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or homopiperazinyl, wherein the substituent is C 1-4 alkyl or C 1-4 hydroxy alkyl.
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A环为取代或非取代的嘧啶,所述取代基为卤素、硝基、氰基、巯基或氨基;Ring A is a substituted or unsubstituted pyrimidine, and the substituents are halogen, nitro, cyano, mercapto or amino; R1为C1-4烷基、C1-4烷硫基、C1-4烷砜基、环丙酰胺取代的苯硫基、环丙酰胺取代的苯氧基;R 1 is C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylsulfone, phenylthio substituted by cyclopropanamide, phenoxy substituted by cyclopropanamide; R2为氢、卤素或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,所述杂脂环基是吡咯烷基、哌啶基、吗啉基、哌嗪基、硫代吗啉基或高哌嗪基,其中取代基为C1-4烷基或C1-4羟烷基。R 2 is hydrogen, halogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C 1-4 alkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, said The heteroalicyclic group is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or homopiperazinyl, wherein the substituent is C 1-4 alkyl or C 1-4 hydroxyalkyl . 3.根据权利要求2所述的化合物或其药学上可接受的盐,其中3. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein A环为嘧啶或卤代嘧啶;Ring A is pyrimidine or halogenated pyrimidine; R1为C1-4烷基、C1-4烷硫基、C1-4烷砜基、环丙酰胺取代的苯硫基;R 1 is C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylsulfone, cyclopropanamide substituted phenylthio; R2为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成取代或非取代的杂脂环基,所述杂脂环基是吡咯烷基、哌啶基、吗啉基、哌嗪基、硫代吗啉基或高哌嗪基,其中取代基为甲基、乙基、羟甲基或羟乙基。R 2 is hydrogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C 1-4 alkyl, or R 4 and R 3 are combined to form a substituted or unsubstituted heteroalicyclic group, the heteroaliphatic The cyclic group is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or homopiperazinyl, wherein the substituent is methyl, ethyl, hydroxymethyl or hydroxyethyl. 4.根据权利要求3所述的化合物或其药学上可接受的盐,其中4. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein A环为卤代嘧啶;Ring A is a halogenated pyrimidine; R1为C1-2烷基、C1-2烷硫基、C1-2烷砜基、
Figure FDA00003502637300021
R 1 is C 1-2 alkyl, C 1-2 alkylthio, C 1-2 alkylsulfone,
Figure FDA00003502637300021
R2为氢或-NR4R3,R4或R3独立地选自C1-4烷基,或者R4和R3合起来形成杂脂环基,所述杂脂环基是吡咯烷基、哌啶基、吗啉基、哌嗪基、硫代吗啉基或高哌嗪基。R 2 is hydrogen or -NR 4 R 3 , R 4 or R 3 is independently selected from C 1-4 alkyl, or R 4 and R 3 are combined to form a heteroalicyclic group, and the heteroalicyclic group is pyrrolidine group, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or homopiperazinyl.
5.根据权利要求4所述的化合物或其药学上可接受的盐,其中5. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein A环为氯代嘧啶;Ring A is chloropyrimidine; R1为甲基、乙基、甲硫基、乙硫基、甲砜基、乙砜基、
Figure FDA00003502637300022
R is methyl, ethyl, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl,
Figure FDA00003502637300022
R2为氢、二乙胺基。R 2 is hydrogen, diethylamino.
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述的化合物为选自下组的一个或多个:6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is one or more selected from the group consisting of: 6-氯-2-甲基-N-{3-[5-(吗啉-4-基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine; 6-氯-2-(甲硫基)-N-{3-[5-(吗啉-4-基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl }pyrimidin-4-amine; N-{4-[4-氯-6-(3-(5-(吗啉-4-基甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine -2-thio]phenyl}cyclopropylcarboxamide; 6-氯-2-甲基-N-{3-[5-(哌啶-1-基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(piperidin-1-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine; 6-氯-2-(甲硫基)-N-{3-[5-(哌啶-1-基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylthio)-N-{3-[5-(piperidin-1-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl }pyrimidin-4-amine; N-{4-[4-氯-6-(3-(5-(哌啶-1-基甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(piperidin-1-ylmethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine -2-thio]phenyl}cyclopropylcarboxamide; 6-氯-2-甲基-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]嘧啶-4-胺;6-Chloro-2-methyl-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]pyrimidin-4-amine; 6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲硫基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylthio)pyrimidin-4-amine; N-{4-[4-氯-6-(3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫基]苯}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2-thio]benzene} Cyclopropanamide; 6-氯-2-甲基-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-methyl-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidin-4-amine ; 6-氯-2-(甲硫基)-N-{3-[5-(二乙胺甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-chloro-2-(methylthio)-N-{3-[5-(diethylaminomethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine; N-{4-[4-氯-6-(3-(5-(二乙胺甲基)-1H-苯并咪唑-2-基)-1H-吡唑-4-氨基)嘧啶-2-硫]苯基}环丙甲酰胺;N-{4-[4-chloro-6-(3-(5-(diethylaminomethyl)-1H-benzimidazol-2-yl)-1H-pyrazole-4-amino)pyrimidine-2- Sulfur]phenyl}cyclopropylcarboxamide; 6-氯-2-(甲砜基)-N-{3-[5-(吗啉-4-基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺;6-Chloro-2-(methylsulfonyl)-N-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl }pyrimidin-4-amine; 6-氯-N-[3-(5-甲基-1H-苯并咪唑-2-基)-1H-吡唑-4-基]-2-(甲砜基)嘧啶-4-胺;6-Chloro-N-[3-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidin-4-amine; 或6-氯-2-(甲砜基)-N-{3-[5-(二乙胺基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基}嘧啶-4-胺。Or 6-chloro-2-(methylsulfonyl)-N-{3-[5-(diethylamino)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}pyrimidine- 4-amine. 7.根据权利要求1~6中任意一项的化合物或其药学上可接受的盐在制备抗癌药物中的应用。7. Use of the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof in the preparation of anticancer drugs. 8.根据权利要求7所述的应用,其中所述的癌为白血病、结肠癌、宫颈癌或乳腺癌。8. The use according to claim 7, wherein said cancer is leukemia, colon cancer, cervical cancer or breast cancer.
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