CN116354938B - 一类喹唑啉衍生物与其类似物的制备方法及应用 - Google Patents
一类喹唑啉衍生物与其类似物的制备方法及应用 Download PDFInfo
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- CN116354938B CN116354938B CN202111622304.8A CN202111622304A CN116354938B CN 116354938 B CN116354938 B CN 116354938B CN 202111622304 A CN202111622304 A CN 202111622304A CN 116354938 B CN116354938 B CN 116354938B
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- Prior art keywords
- quinazoline
- pyrazol
- diamine
- methyl
- difluorophenyl
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属药物合成领域,涉及一类新型喹唑啉衍生物与其类似物物,及其制备方法和作为治疗剂特别是作为TRK抑制剂的用途。如通式(I)的化合物及其几何异构体或其药学上可接受的盐和它们的制备方法。优选的化合物具有作为蛋白激酶抑制剂,特别是TRK激酶抑制剂的活性。
Description
技术领域
本发明属药物合成领域,涉及一类新型喹唑啉衍生物及其类似物,及其制备方法和作为TRK抑制剂的用途。
背景技术
恶性肿瘤已经成为严重危害人类健康的疾病之一。人类与癌症的抗争史已有近一个世纪之久。抗肿瘤药物的研发正在逐步由非选择性的化疗药物向具有高选择性的靶向药物转变。自伊马替尼上市以来,以激酶为靶点的抗肿瘤药物研发就步入了快车道。随着精准医疗概念的提出,针对特定生物标志物来划分肿瘤类型已经是大势所趋。而靶向特定生物标志物来医治肿瘤的疗法,已经收获了大量成功的临床经验。
大约有17%-20%的肿瘤是由NTRK基因融合引起的,NTRK是编码TRK蛋白的DNA序列。TRK全称是原肌球蛋白受体激酶,是细胞表面受体酪氨酸激酶(Receptor tyrosinekinase,RTK)家族的一员。TRK共有三种亚型,分别是由NTRK1基因编码的TRKA,由NTRK2编码的TRKB以及由NTRK3编码的TRKC。TRK是一类跨膜受体蛋白,其包括一个与配体结合的胞外域,一个跨膜域,以及一个具有激酶活性的胞内域。受体酪氨酸激酶的胞内激酶域在结构上是相对保守的,TRK三种亚型在激酶域的同源性在71.9%至78.3%之间,而三种亚型的主要差异在于活化它们的天然配体不同。激动TRKA的天然配体主要是:神经生长因子(NGF)、神经营养蛋白-7(NT-7)和神经营养蛋白-6(NT-6);激动TRKB的天然配体有:脑源性神经营养因子(BDNF)和神经营养蛋白4/5;而激动TRKC的天然配体则是神经营养蛋白-3(NT-3)。前期的科学研究表明,TRK作为一个神经生长因子受体,可以通过磷酸化下游蛋白来调节细胞的增殖,分化,迁移和凋亡。在人类的恶性肿瘤中,TRK可以通过多种机制被持续的活化。其中,最具代表性的机制当属NTRK的基因融合。NTRK的基因融合是指其3,末端序列在染色体内或者染色体间发生重组,然后其5,末端序列与其它基因(伴侣基因)相互链接,从而形成一个新的突变蛋白。这种蛋白会导致TRK的持续活化,并最终诱导肿瘤的形成。研究者们已经在多种肿瘤中发现了NTRK的基因融合行为,如在结肠癌(CRC)中,人们发现了存在TPM3-NTRK1的基因融合;而在分泌性中胚层先天纤维肉瘤和婴儿纤维肉瘤中,发现了ETV6-NTRK3的基因融合。除基因融合外,NTRK基因的持续活化,转录和翻译过程中产生的剪接变体以及TRK蛋白的过表达也是诱发肿瘤的关键因素。目前,人们已经在神经胶质瘤、急性髓细胞白血病(AML)、肺癌、乳腺癌等多种癌症中发现了TRK相关蛋白的异常行为,并证明了其与癌症的发生发展紧密相关。由NTRK基因融合导致的TRK蛋白异常活化,已经被证明是引起肿瘤的关键因素。而令人遗憾的是,NTRK的基因融合通常会导致TRK蛋白胞外域的遗失,这意味着,诸如单克隆抗体等靶向蛋白胞外域的抑制剂对于NTRK基因融合型癌症将不再有效。因此,小分子TRK抑制剂应是解决NTRK基因融合型癌症的唯一有效手段。
发明内容:
本发明的目的在于提供一种新型喹唑啉衍生物及其类似物,及其制备方法和作为治疗剂特别是作为TRK抑制剂的用途。
为实现上述目的,本发明采用技术方案为:
一种喹唑啉衍生物,衍生物为通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐;通式(I)所示化合物如下:
其中,R1选自氢,C1-C4烷基,C3-C6环烷基,C1-C4卤代烷基,C1-C4卤代烷氧基、未取代或被1-4个Ra所取代的苯环或吡啶环;
Ra选自氢,卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基或C1-C4卤代烷氧基;
R2,R3可相同或不同选自氢,卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基或C1-C4卤代烷氧基;
Ar选自未取代或被1-3个Rb所取代的苯环,吡啶环或嘧啶环;
Rb选自卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基或C1-C4卤代烷氧基;
X和Y可相同或不同选自C原子或N原子。
优选,所述衍生物通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐;通式(I)中,
R1选自氢,C1-C4烷基,C3-C6环烷基,C1-C4卤代烷基,C1-C4卤代烷氧基,苯基或吡啶基;
R2,R3可相同或不同选自氢,卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基,C1-C4卤代烷氧基;
Ar选自未取代或被1-3个Rb所取代的苯环,吡啶环或嘧啶环;
Rb选自卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基,C1-C4卤代烷氧基;
X和Y可相同或不同选自C原子或N原子。
进一步优选,所述衍生物通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐;通式(I)中,
R1选自氢,C1-C4烷基,C3-C6环烷基,C1-C4卤代烷基,C1-C4卤代烷氧基或苯基;
R2,R3可相同或不同选自氢,卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基,C1-C4卤代烷氧基;
Ar是含有1-3个Rb取代的苯环;
Rb选自卤素,硝基,氨基,氰基,C1-C4烷基,C1-C4烷氧基,C1-C4卤代烷基,C1-C4卤代烷氧基;
X和Y选自C。
再进一步优选,所述衍生物通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐;通式(I)中,
R1选自氢,甲基,乙基,环丙基或苯基;
R2,R3可相同或不同选自氢,甲基,卤素或三氟甲基;
Ar是含有1-3个Rb取代的苯环;
Rb选自氢,甲基,甲氧基,卤素,氰基,三氟甲基或三氟甲氧基;
X和Y选自C。
更优选,所述衍生物为:
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-甲基苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-甲氧基苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氯苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-溴苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氰基苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-三氟甲基苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-三氟甲氧基苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(3-氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(2-氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,5-二氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,6-二氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,4-二氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,5-二氟苯基)喹唑啉-2,4-二胺
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,4,5-三氟苯基)喹唑啉-2,4-二胺
N4-(5-环丙基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺
N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺
N4-(5-乙基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺
N4-(5-乙基-1H-吡唑-3-基)-N2-(2,4-氟苯基)喹唑啉-2,4-二胺
N4-(5-苯基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺
N4-(5-苯基-1H-吡唑-3-基)-N2-(2,4-氟苯基)喹唑啉-2,4-二胺
7-氟-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-氟-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-氯-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-氯-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-溴-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-溴-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-甲基-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-甲基-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-三氟甲基-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
7-三氟甲基-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-氟-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-氟-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-氯-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-氯-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-溴-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-甲基-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-甲基-N2-(2,4-二氟苯基)-N4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
6-三氟甲基-N2-(2,4-二氟苯基)-N4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
或,上述化合物的异构体或其药学上可接受的盐。
一种通式(I)所示衍生物的制备方法,所述通式(I)所示衍生物制备反应如下:
以各种取代的邻氨基芳基甲酸1为起始原料,与尿素在高温下共熔融得到中间体2,中间体2经过氯代试剂全氯代得到中间体3,中间体3在碱性条件下与各种取代的3-氨基吡唑发生亲核取代反应得到中间体4,中间体4在酸性条件下或在金属钯的催化条件下与芳基卤代烷反应得到终产物5.
进一步的说,以各种取代的邻氨基芳基甲酸1为起始原料,与尿素在高温下共熔融得到中间体2,反应温度为150~300℃,优选180~220℃;环合后的产物2与氯代试剂发生取代反应得到中间体3,反应溶剂可为乙腈,丙酮,二甲基亚砜,N,N-二甲基甲酰胺,四氢呋喃,1,4-二氧六环等,优选N,N-二甲基甲酰胺,反应温度为130~250℃,优选150~180℃,氯代试剂可为氯化亚砜,三氯氧磷,三氯化磷,五氯化磷等,优选三氯氧磷;中间体(氯代产物)3可在碱存在的条件下与各种取代的3-氨基吡唑反应得到中间体4,反应溶剂可为二氯甲烷,三氯甲烷,丙酮,乙腈,四氢呋喃,1,4二氧六环,二甲基亚砜,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,N,N-二甲基乙酰胺等,优选N,N-二甲基甲酰胺,反应温度为-20~80℃,优选-5~10℃,所用的碱可为碳酸钾,碳酸钠,碳酸氢钠,碳酸铯,乙酸钾,三乙胺,二乙胺,N,N-二异丙基乙胺,吡啶等,优选N,N-二异丙基乙胺;中间体4在酸催化的条件下与各种取代的芳基卤代烷反应得到终产物5,反应温度为80~180℃,优选105~135℃,反应溶剂可为甲醇,乙醇,异丙醇,正丁醇,正丙醇,异丁醇,叔丁醇,水等,优选乙醇;反应中的酸可为盐酸,氢溴酸,氢碘酸,稀硫酸或是酸性气体的饱和溶液,比如氯化氢的饱和乙酸乙酯溶液,氯化氢的饱和甲醇溶液,氯化氢的饱和1,4-二氧六环溶液等;优选氯化氢的饱和1,4二氧六环溶液。中间体4或可经过钯催化的偶联反应制得终产物5,反应温度为90~150℃,优选100~120℃,反应溶剂可为二甲基亚砜,甲苯,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,1,4-二氧六环,四氢呋喃等,催化剂可为乙酸钯,Pd(dba)2,四三苯基磷钯,PdCl2(dppf)2等,优选乙酸钯,配体可为三苯基磷,Xphos,Xtanphos等,优选Xphos,碱可为乙酸钾,碳酸钾,碳酸钠,碳酸氢钠,氢化钠,叔丁醇钾,叔丁醇钠,碳酸铯,甲醇钠,乙醇钠等,优选叔丁醇钾。
一种通式(I)所述的衍生物对的应用,所述通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐在制备预防或治疗与TRK激酶的表达或活性有关的疾病的药物中的应用。
进一步的,所述通式(I)所示的化合物,及其几何异构体或其药学上可接受的盐在制备预防或抗肿瘤药物中的应用。
一种药用组合物,组合物为活性成分和药学上可接受的赋形剂;其中,活性成分含通式(I)所示的化合物及其几何异构体或药学上可接受的盐,活性成分占组合物质量的0.1-99%。
进一步的,所述的药用组合物在制备预防或治疗与TRK激酶的表达或活性有关的疾病的药物中的应用。
再进一步,所述的药用组合物在制备预防或抗肿瘤药物中的应用。
本发明所具有的优点:
本发明着眼于NTRK基因融合型肿瘤,获得通式(I)所示结构的化合物,所得化合物均未见文献报道,且在结构上具备一定的新颖性;本发明所涉及到的化合物对于蛋白激酶TRK具有强效的抑制作用,用以治疗由NTRK基因融合所引起的肿瘤或与TRK表达异常相关的其它疾病;同时本发明部分化合物对于TRK三种亚型的抑制作用与上市药物拉罗替尼及恩曲替尼相当。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定;所用试剂均为分析纯或化学纯,本发明部分通式(I)所示化合物取代基如表1所示,其中,X和Y选自C。
表1实施例的结构式
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下述为实施例1的具体制备方式,其它实施例的制备方法与实施例1类似,具体的合成路线如下:
喹唑啉-2,4-二酚(7)的制备
在茄型瓶中加入邻氨基苯甲酸(10g,0.073mol)和尿素(43.84g,0.73mol),加热至共熔融,维持反应大于12h,将反应液冷却至室温。向反应液中加入200mL水,搅拌0.5h,用冰醋酸调pH<4,有固体析出。减压过滤,水洗滤饼三次,滤饼干燥即所得产物,无需进一步纯化直接用于下一步反应,收率95%。
2,4-二氯喹唑啉(8)的制备
将喹唑啉-2,4-二酚(11.18g,0.069mol)溶于100mL无水的N,N-二甲基甲酰胺中,冰浴条件下缓慢加入三氯氧磷(32.16mL,0.35mol),回流反应8h。TLC检测,原料反应完毕,将反应液倾入1L冰水中,有固体析出。减压过滤,水洗滤饼三次,滤饼干燥即所得产物,无需进一步纯化直接用于下一步反应,收率92%。
2-氯-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺(9)的制备
将2,4-二氯喹唑啉(0.50g,2.53mmol)溶于5mL无水的N,N-二甲基甲酰胺中,冰浴条件下依次加入N,N-二异丙基乙胺(0.53mL,3.03mmol)和3-氨基-5-甲基吡唑(0.29g,3.03mmol),维持冰浴条件下反应4h,TLC检测,原料反应完毕。将反应液倾入50mL水中,有固体析出。减压过滤,用5℃的二氯甲烷淋洗滤饼三次,滤饼干燥即所得产物,无需进一步纯化,直接用于下一步反应,收率79%。
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-甲基苯基)喹唑啉-2,4-二胺(实施例1(10))的制备
将2-氯-N-(5-甲基-1H-吡唑-3-基)喹唑啉-4-胺(0.10g,0.39mmol)溶于2mL无水乙醇,加入4-甲基苄胺(60uL,0.47mmol)和催化量的1,4-二氧六环的饱和氯化氢溶液。将反应液转移至厚壁耐压瓶中,120℃反应12h。TLC检测反应完毕,将反应液冷却至室温,旋除溶剂,柱层析纯化。展开剂极性:1%~5%甲醇的二氯甲烷溶液。纯化所得固体再用少量无水二氯甲烷重结晶,即得实施例1。收率58%。1H NMR(600MHz,DMSO-d6)δ12.25(s,1H),8.55–7.84(m,2H),7.62(s,1H),7.40(d,J=6.6Hz,1H),7.27(s,3H),7.13(d,J=7.6Hz,2H),4.57(s,2H),2.27(s,3H),2.20(s,3H).HRMS(ESI,m/z)calcd for C20H20N6[M+H]+,345.1828;found 345.1819.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-甲氧基苯基)喹唑啉-2,4-二胺(实施例2)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-甲氧基苄胺,即得实施例2.1H NMR(600MHz,DMSO-d6)δ12.12(s,1H),8.35–8.03(m,2H),7.53(s,1H),7.39(d,J=8.4Hz,1H),7.31(s,3H),6.97(d,J=8.5Hz,1H),6.88(d,J=7.7Hz,3H),4.50(d,J=6.0Hz,2H),3.71(s,3H),2.20(s,3H).HRMS(ESI,m/z)calcd for C20H20N6O[M+H]+,361.1777;found 361.1779.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺(实施例3)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-氟苄胺,即得实施例3.1H NMR(600MHz,DMSO-d6)δ12.22(s,1H),10.28(s,1H),8.37(s,1H),7.98–7.53(m,2H),7.45–7.35(m,3H),7.15(t,J=8.8Hz,3H),4.59(d,J=5.8Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C19H17FN6[M+H]+,349.1577;found 349.1577.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氯苯基)喹唑啉-2,4-二胺(实施例4)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-氯苄胺,即得实施例4.1H NMR(600MHz,DMSO-d6)δ12.35(s,1H),10.87(s,1H),8.50–7.76(m,2H),7.77–7.54(m,1H),7.39(s,5H),7.31–7.10(m,1H),4.61(d,J=5.7Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C19H17ClN6[M+H]+,365.1281;found 365.1271.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-溴苯基)喹唑啉-2,4-二胺(实施例5)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-溴苄胺,即得实施例5.1H NMR(600MHz,DMSO-d6)δ12.22(s,1H),8.36(s,1H),7.88–7.55(m,2H),7.51(d,J=8.3Hz,2H),7.34(s,3H),7.16(s,1H),4.57(d,J=5.9Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C19H17BrN6[M+H]+,409.0776;found 409.0781.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-氰基苯基)喹唑啉-2,4-二胺(实施例6)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-氰基苄胺,即得实施例6.1H NMR(600MHz,DMSO-d6)δ12.39(s,1H),8.59–7.96(m,2H),7.81(d,J=8.1Hz,2H),7.63–7.11(m,5H),4.74(d,J=5.7Hz,2H),2.16(s,3H).HRMS(ESI,m/z)calcdfor C20H17N7[M+H]+,356.1624;found 356.1628.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-三氟甲基苯基)喹唑啉-2,4-二胺(实施例7)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-三氟甲基苄胺,即得实施例7.1H NMR(600MHz,DMSO-d6)δ12.38(s,1H),8.58–8.29(m,0H),7.81–7.64(m,3H),7.57(s,2H),7.51–7.15(m,2H),4.73(d,J=4.7Hz,1H),2.18(s,3H).HRMS(ESI,m/z)calcd for C20H17F3N6[M+H]+,399.1545;found 399.1540.
N4-(5-甲基-1H-吡唑-3-基)-N2-(4-三氟甲氧基苯基)喹唑啉-2,4-二胺(实施例8)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为4-三氟甲氧基苄胺,即得实施例8.1H NMR(600MHz,DMSO-d6)δ12.38(s,1H),8.65–7.83(m,2H),7.79–7.41(m,4H),7.39–7.13(m,3H),4.67(d,J=5.1Hz,2H),2.21(s,3H).HRMS(ESI,m/z)calcd forC20H17F3N6O[M+H]+,415.1494;found 415.1483.
N4-(5-甲基-1H-吡唑-3-基)-N2-(3-氟苯基)喹唑啉-2,4-二胺(实施例9)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为3-氟苄胺,即得实施例9.1H NMR(600MHz,DMSO-d6)δ12.18(s,1H)10.15(s,1H),8.32(s,1H),7.55(t,J=7.3Hz,2H),7.40–7.30(m,2H),7.24–7.16(m,2H),7.11(t,J=7.4Hz,1H),7.04(t,J=8.4Hz,1H),4.61(s,2H),2.21(s,3H).HRMS(ESI,m/z)calcd for C19H17FN6[M+H]+,349.1577;found 349.1579.
N4-(5-甲基-1H-吡唑-3-基)-N2-(2-氟苯基)喹唑啉-2,4-二胺(实施例10)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为2-氟苄胺,即得实施例10.1H NMR(600MHz,DMSO-d6)δ12.33(s,1H),10.97(s,1H),8.58–8.32(m,1H),8.26–8.13(m,1H),7.72(s,1H),7.45(s,2H),7.35–7.19(m,3H),7.18–7.13(m,1H),4.69(s,2H),2.19(s,3H).HRMS(ESI,m/z)calcd for C19H17FN6[M+H]+,349.1577;found 349.1577.
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,5-二氟苯基)喹唑啉-2,4-二胺(实施例11)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为2,5-二氟苄胺,即得实施例11.1H NMR(600MHz,DMSO-d6)δ12.14(s,1H),10.25(s,1H),8.38(s,1H),7.73–7.66(m,1H),7.58(s,1H),7.40–7.34(m,2H),7.31–7.20(m,2H),7.18–7.10(m,2H),4.63(d,J=4.6Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C19H16F2N6[M+H]+,367.1483;found367.1482.
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例12)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例12.1H NMR(600MHz,DMSO-d6)δ12.37(s,1H),8.57–8.10(m,2H),7.80–7.57(m,1H),7.51–7.14(m,4H),7.04(d,J=7.5Hz,1H),4.65(s,2H),2.21(s,3H).HRMS(ESI,m/z)calcd for C19H16F2N6[M+H]+,367.1483;found 367.1478.
N4-(5-甲基-1H-吡唑-3-基)-N2-(2,6-二氟苯基)喹唑啉-2,4-二胺(实施例13)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为2,6-二氟苄胺,即得实施例13.1H NMR(600MHz,DMSO-d6)δ12.72(s,1H),8.48(s,1H),7.64(s,2H),7.48–7.39(m,2H),7.22(s,1H),7.16–7.07(m,2H),4.67(s,2H),2.23(s,3H).HRMS(ESI,m/z)calcd for C19H16F2N6[M+H]+,367.1483;found 367.1488.
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,4-二氟苯基)喹唑啉-2,4-二胺(实施例14)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为3,4-二氟苄胺,即得实施例14.1H NMR(600MHz,DMSO-d6)δ12.25(s,1H),11.01–9.89(m,0H),8.40(s,1H),7.82–7.46(m,2H),7.45–7.33(m,3H),7.26–7.13(m,2H),4.58(d,J=4.1Hz,2H),2.21(s,1H).HRMS(ESI,m/z)calcd for C19H16F2N6[M+H]+,367.1483;found 367.1473.
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,5-二氟苯基)喹唑啉-2,4-二胺(实施例15)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为3,5-二氟苄胺,即得实施例15.1H NMR(600MHz,DMSO-d6)δ12.29(s,1H),10.68(s,1H),8.48(s,1H),7.83–7.52(m,2H),7.39(s,1H),7.20(s,1H),7.09(t,J=7.8Hz,3H),4.63(d,J=4.6Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C19H16F2N6[M+H]+,367.1483;found 367.1477.
N4-(5-甲基-1H-吡唑-3-基)-N2-(3,4,5-三氟苯基)喹唑啉-2,4-二胺(实施例16)的制备
参考制备实施例1的方法,将d步骤中4-甲基苄胺原料等比例替换为3,4,5-二氟苄胺,即得实施例16.1H NMR(600MHz,DMSO-d6)δ12.33(s,1H),8.58–7.88(m,2H),7.75–7.53(m,1H),7.48–7.13(m,4H),4.60(d,J=5.8Hz,3H),2.21(s,3H).HRMS(ESI,m/z)calcd forC19H15F3N6[M+H]+,385.1389;found 385.1388.
N4-(5-环丙基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺(实施例17)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为4-氟苄胺,即得实施例17.1H NMR(600MHz,DMSO-d6)δ12.36(s,1H),8.55–7.73(m,2H),7.59(s,1H),7.40(s,3H),7.15(t,J=8.8Hz,3H),4.61(d,J=4.5Hz,2H),1.86(s,1H),0.89(s,2H),0.76–0.40(m,2H).HRMS(ESI,m/z)calcd for C21H19FN6[M+H]+,375.1733;found 375.1735.
N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例18)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例18.1HNMR(600MHz,DMSO-d6)δ12.45(s,1H),8.71–7.90(m,2H),7.80–7.59(m,1H),7.53–7.17(m,4H),7.05(s,1H),4.67(s,2H),1.86(s,1H),0.91(d,J=5.8Hz,2H),0.78–0.42(m,2H).HRMS(ESI,m/z)calcd for C21H18F2N6[M+H]+,393.1639;found 393.1642.
N4-(5-乙基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺(实施例19)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-乙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为4-氟苄胺,即得实施例19.1H NMR(600MHz,DMSO-d6)δ12.25(s,1H),10.91–9.85(m,1H),8.40(s,1H),7.74–7.51(m,2H),7.47–7.33(m,3H),7.14(t,J=8.8Hz,3H),4.64–4.55(m,2H),2.57(s,2H),1.23(s,3H).HRMS(ESI,m/z)calcd for C20H19FN6[M+H]+,363.1733;found 363.1729.
N4-(5-乙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例20)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-乙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例20.1H NMR(600MHz,DMSO-d6)δ12.37(s,1H),8.57–7.96(m,0H),7.77–7.64(m,1H),7.43(s,2H),7.25(t,J=9.0Hz,2H),7.04(t,J=6.6Hz,1H),4.65(s,2H),2.57(s,2H),1.23(s,3H).HRMS(ESI,m/z)calcd for C20H18F2N6[M+H]+,381.1639;found 381.1630.
N4-(5-苯基-1H-吡唑-3-基)-N2-(4-氟苯基)喹唑啉-2,4-二胺(实施例21)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-苯基吡唑,将d步骤中4-甲基苄胺原料等比例替换为4-氟苄胺,即得实施例19.1H NMR(600MHz,DMSO-d6)δ13.01(s,1H),8.51–8.27(m,1H),8.06–7.69(m,3H),7.61(s,1H),7.48–7.38(m,5H),7.34(s,1H),7.22–7.13(m,3H),4.63(s,2H).HRMS(ESI,m/z)calcd forC24H19FN6[M+H]+,411.1733;found 411.1735.
N4-(5-苯基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例22)的制备
参考制备实施例1的方法,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-苯基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例22.1H NMR(600MHz,DMSO-d6)δ12.45(s,1H),8.71–7.90(m,2H),7.80–7.59(m,1H),7.53–7.17(m,4H),7.05(s,1H),4.67(s,2H),1.86(s,1H),0.91(d,J=5.8Hz,2H),0.78–0.42(m,2H).HRMS(ESI,m/z)calcd for C24H18F2N6[M+H]+,429.1639;found 429.1642.
7-氟-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例23)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-氟苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例23.1H NMR(600MHz,DMSO-d6)δ12.08(s,1H),10.52–9.95(m,1H),8.44(s,1H),7.50(s,2H),7.23(s,1H),7.09–6.90(m,3H),4.57(s,2H),2.17(s,3H).HRMS(ESI,m/z)calcd for C19H15F3N6[M+H]+,385.1389;found 385.1392.
7-氟-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例24)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-氟苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例24.1H NMR(600MHz,DMSO-d6)δ12.74–12.10(m,1H),10.50–9.94(m,1H),8.47–8.26(m,1H),7.49(s,1H),7.27–7.18(m,1H),7.10–6.90(m,3H),4.58(d,J=5.9Hz,2H)1.87(s,1H),0.90(s,2H),0.76–0.42(m,2H).HRMS(ESI,m/z)calcd for C21H17F3N6[M+H]+,411.1545;found 411.1549.
7-氯-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例25)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-氯苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例25.1H NMR(600MHz,DMSO-d6)δ12.09(s,1H),10.07(s,1H),8.46–8.24(m,1H),7.99–7.36(m,2H),7.33–7.19(m,2H),7.18–6.89(m,2H),4.56(d,J=4.9Hz,2H),2.19(s,3H).HRMS(ESI,m/z)calcd for C19H15ClF2N6[M+H]+,401.1093;found 401.1098.
7-氯-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例26)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-氯苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例26.1H NMR(600MHz,DMSO-d6)δ12.15(s,1H),10.51–9.92(m,1H),8.37(s,1H),7.55(s,1H),7.30(s,1H),7.23(t,J=9.0Hz,1H),7.15–6.86(m,2H),4.58(d,J=5.8Hz,2H),1.87(s,1H),0.90(s,2H),0.78–0.44(m,2H).HRMS(ESI,m/z)calcd for C21H17ClF2N6[M+H]+,427.1250;found 427.1259.
7-溴-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例27)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-溴苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例27.1H NMR(600MHz,DMSO-d6)δ12.38(s,1H),11.43–9.76(m,1H),8.60–7.72(m,2H),7.70–7.21(m,4H),7.05(s,1H),4.63(s,2H),2.19(s,3H).HRMS(ESI,m/z)calcd for C19H15BrF2N6[M+H]+,445.0588;found445.0583.
7-溴-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例28)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-溴苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例28.1H NMR(600MHz,DMSO-d6)δ12.72–12.00(m,1H),10.57–9.98(m,1H),8.41–8.11(m,1H),8.09–7.33(m,3H),7.33–7.12(m,2H),7.02(s,1H),4.57(d,J=5.8Hz,2H),1.87(s,1H),0.98–0.80(m,2H),0.81–0.44(m,2H).HRMS(ESI,m/z)calcd for C21H17BrF2N6[M+H]+,471.0744;found 471.0754.
7-甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例29)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-甲基苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例29.1H NMR(600MHz,DMSO-d6)δ12.43(s,1H),8.45(s,2H),7.67–7.14(m,4H),7.05(t,J=7.0Hz,1H),4.66(s,2H),2.42(s,3H),2.20(s,3H).HRMS(ESI,m/z)calcd for C20H18F2N6[M+H]+,381.1639;found 381.1644.
7-甲基-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例30)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-甲基苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例30.1H NMR(600MHz,DMSO-d6)δ12.83–11.98(m,1H),10.39–9.72(m,1H),8.30–8.03(m,1H),7.58–6.86(m,6H),4.57(d,J=5.9Hz,2H),2.36(s,3H),1.85(s,1H),0.89(s,2H),0.65(s,2H).HRMS(ESI,m/z)calcd forC22H20F2N6[M+H]+,407.1796;found 407.1804.
7-三氟甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例31)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-三氟甲基苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例31.1HNMR(600MHz,DMSO-d6)δ12.14(s,1H),10.70–10.20(m,1H),8.63–8.41(m,1H),7.74–7.39(m,3H),7.35–7.20(m,2H),7.02(s,1H),4.59(s,2H),2.22(s,3H).HRMS(ESI,m/z)calcdfor C20H15F5N6[M+H]+,435.1357;found 435.1356.
7-三氟甲基-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例32)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-4-三氟甲基苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例32.1H NMR(600MHz,DMSO-d6)δ12.77–12.15(m,1H),10.71–10.14(m,1H),8.65–8.40(m,1H),7.65(s,1H),7.60–7.37(m,2H),7.35–7.13(m,2H),7.04(s,1H),4.60(d,J=5.5Hz,2H),1.88(s,1H),0.93(s,2H),0.82–0.52(m,2H).HRMS(ESI,m/z)calcd for C22H17F5N6[M+H]+,461.1513;found461.1514.
6-氟-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例33)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-氟苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例33.1H NMR(600MHz,DMSO-d6)δ12.75(s,1H),8.53(s,1H),7.68–7.39(m,3H),7.36–7.11(m,3H),4.67(s,2H),2.23(s,3H).HRMS(ESI,m/z)calcd for C19H15F3N6[M+H]+,385.1389;found385.1383.
6-氟-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例34)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-氟苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例34.1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),11.49(s,1H),8.80–8.04(m,2H),8.02–7.64(m,2H),7.41(s,1H),7.36–7.28(m,1H),7.05(s,1H),4.91–4.60(m,2H),1.84(s,1H),0.93(d,J=6.7Hz,2H),0.80–0.43(m,2H).HRMS(ESI,m/z)calcd for C21H17F3N6[M+H]+,411.1545;found 411.1537.
6-氯-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例35)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-氯苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例35.1H NMR(600MHz,DMSO-d6)δ12.09(s,1H),10.54–9.99(m,1H),8.64–8.33(m,1H),7.61–7.19(m,5H),7.02(s,1H),4.57(d,J=4.5Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd forC19H15ClF2N6[M+H]+,401.1093;found 401.1101.
6-氯-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例36)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-氯苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例36.1H NMR(600MHz,DMSO-d6)δ12.77–12.09(m,1H),10.52–10.03(m,1H),8.56(s,1H),7.98(s,0.5H,tautomerism),7.69–7.16(m,5H),7.10–6.51(m,1.5H,tautomerism),4.58(d,J=5.8Hz,2H),1.86(s,1H),1.00–0.82(m,2H),0.80–0.53(m,2H).HRMS(ESI,m/z)calcd for C21H17ClF2N6[M+H]+,427.1250;found427.1251.
6-溴-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例37)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-溴苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例37.1H NMR(600MHz,DMSO-d6)δ12.77–12.11(m,1H),10.58–10.04(m,1H),8.75–8.43(m,1H),8.19–7.40(m,3H),7.32–7.20(m,2H),7.02(s,1H),4.58(d,J=6.4Hz,2H),1.87(s,1H),0.96–0.85(m,2H),0.80–0.43(m,2H).HRMS(ESI,m/z)calcd for C21H17BrF2N6[M+H]+,471.0744;found 471.0752.
6-甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例38)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-甲基苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例38.1H NMR(600MHz,DMSO-d6)δ12.89–12.04(m,1H),10.54–9.84(m,1H),8.34–8.03(m,1H),7.85–7.37(m,3H),7.32–7.19(m,2H),7.03(s,1H),4.59(d,J=5.2Hz,2H),2.37(s,3H),2.20(s,3H).HRMS(ESI,m/z)calcd for C20H18F2N6[M+H]+,381.1639;found 381.1627.
6-甲基-N4-(5-环丙基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例39)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-甲基苯甲酸,将c步骤中3-氨基-5-甲基吡唑等比例替换为3-氨基-5-环丙基吡唑,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例39.1H NMR(600MHz,DMSO-d6)δ12.79–12.03(m,1H),10.51–9.75(m,1H),8.17(s,1H),7.96–7.30(m,3H),7.28–7.19(m,2H),7.03(s,1H),4.58(d,J=6.0Hz,2H),2.37(s,3H),1.86(s,1H),0.89(s,1H),0.67(s,2H).HRMS(ESI,m/z)calcd for C22H20F2N6[M+H]+,407.1796;found407.1805.
6-三氟甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-(2,4-二氟苯基)喹唑啉-2,4-二胺(实施例40)的制备
参考制备实施例1的方法,将a步骤中邻氨基苯甲酸等比例替换为2-氨基-5-甲基苯甲酸,将d步骤中4-甲基苄胺原料等比例替换为2,4-二氟苄胺,即得实施例40.1H NMR(600MHz,DMSO-d6)δ12.77–12.04(m,1H),10.74–10.35(m,1H),8.91(s,1H),7.82–7.58(m,2H),7.56–7.32(m,2H),7.24(s,1H),7.02(s,1H),4.60(s,2H),2.22(s,3H).HRMS(ESI,m/z)calcd for C20H15F5N6[M+H]+,435.1357;found 435.1335.
实施例41:本发明部分产物的体外酶抑制活性研究
实验材料:
TecanF500酶标仪。
KinEASETM-STK试剂盒(包含生物素化的多肽底物S2,Eu3+标记的只针对特异性磷酸化位点的单抗,Sa-XL665标记的链霉亲和素,激酶反应缓冲溶液(KinEASE酶反应缓冲液)),384浅孔板,TRKA全长蛋白。
TRKA蛋白浓度0.111ng/μl,MgCl2,乙二胺四乙酸(EDTA),二硫苏糖醇(DL-Dithiothreitol,DTT),DMSO。
实验方法:
第一步:激酶反应。首先将上述实施例制备化合物样品用DMSO配成20mM的溶液,之后根据测试需要,再用激酶反应缓冲溶液稀释成100μM、10μM、1μM等浓度。然后将TRKA激酶(浓度为0.111ng/μL)、ATP(4μM)、生物素标记的多肽底物TK(1μM)和上述配置后化合物样品(4μL)加入到10μL激酶反应缓冲溶液(含有MgCl2 5mM和DTT 1mM)中,在室温下孵育40分钟,激酶将底物TK磷酸化。之后加入10μL的含有EDTA的检测试剂(试剂盒自带),来检测磷酸化产物。
第二步:检测磷酸化产物。稀土元素铕(Eu3+)标记的抗体识别磷酸化底物,XL665标记的链霉亲和素与底物上的生物素结合。Eu3+是荧光供体,XL665是荧光受体,当Eu3+与XL665接近,Eu3+能量转移给XL665,产生HTRF信号。
结果评定方法:荧光信号是由Eu3+的620nm和XL665的665nm荧光吸收信号产生的。所以每一个孔板反应的HTRF信号(665/620)比值被计算。结果被表征为Delta F(DF%):
计算抑制率(%activity):在不加化合物样品的情况下,激酶活性的DF%被定义为100%。当加入化合物样品后,激酶活性率:
计算IC50:在加入化合物的情况下,激酶活性的DF%被绘制成Y-轴,化合物的浓度对数值被绘制成X-轴。IC50值是通过数据拟合成S-型计量反应曲线获得。
表2部分实施例化合物得IC50值。
由上述表2中数据可见,实施例中的化合物均对TRKA表现出了抑制作用,其中,部分化合物具有很强的抑制活性,IC50<10nM;由此可见本发明化合物均系TRK抑制剂,进而可见本发明化合物有希望治疗NTRK基因融合型癌症或与TRK信号通路相关的其他疾病;综上所述本发明化合物具有广泛的抑制TRKA的激酶活性,部分化合物活性与拉罗替尼或恩曲替尼相当,对NTRK基因融合型肿瘤及其他与TRK信号通路相关的疾病具有潜在的治疗价值。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显而易见的,且它们都包含在本发明范围。
Claims (6)
1.一种喹唑啉衍生物或其药学上可接受的盐,其特征在于:
所示化合物如下:
实施例12:N 4-(5-甲基-1H-吡唑-3-基)-N 2-(2,4-二氟苯基)喹唑啉-2,4-二胺
实施例17:N 4-(5-环丙基-1H-吡唑-3-基)-N 2-(4-氟苯基)喹唑啉-2,4-二胺
实施例18:N 4-(5-环丙基-1H-吡唑-3-基)-N 2-(2,4-二氟苯基)喹唑啉-2,4-二胺
实施例20:N 4-(5-乙基-1H-吡唑-3-基)-N 2-(2,4-氟苯基)喹唑啉-2,4-二胺
实施例25:7-氯-N 2-(2,4-二氟苯基)-N 4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
实施例29:7-甲基-N 2-(2,4-二氟苯基)-N 4-(5-甲基-1H-吡唑-3-基)喹唑啉-2,4-二胺
实施例30:7-甲基-N 2-(2,4-二氟苯基)-N 4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
实施例32:7-三氟甲基-N 2-(2,4-二氟苯基)-N 4-(5-环丙基-1H-吡唑-3-基)喹唑啉-2,4-二胺
。
2.一种权利要求1所述的衍生物的应用,其特征在于:权利要求1所述化合物或其药学上可接受的盐在制备预防或治疗与TRK激酶的表达或活性有关的疾病的药物中的应用。
3.按权利要求2所述的衍生物的应用,其特征在于:权利要求1所述化合物或其药学上可接受的盐在制备预防或抗肿瘤药物中的应用。
4.一种药用组合物,其特征在于:组合物为活性成分和药学上可接受的赋形剂;其中,活性成分含权利要求1中的化合物或药学上可接受的盐,活性成分占组合物质量的0.1-99%。
5.权利要求4所述的药用组合物的应用,其特征在于:所述的药用组合物在制备预防或治疗与TRK激酶的表达或活性有关的疾病的药物中的应用。
6.按权利要求5所述的药用组合物的应用,其特征在于:所述的药用组合物在制备预防或抗肿瘤药物中的应用。
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CN1486312A (zh) * | 2000-12-21 | 2004-03-31 | ��̩��˹ҩ��ɷ�����˾ | 可用作蛋白激酶抑制剂的吡唑化合物 |
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