CN114751899A - 一种二芳基脲类mTOR激酶抑制剂及其药物组合物和应用 - Google Patents
一种二芳基脲类mTOR激酶抑制剂及其药物组合物和应用 Download PDFInfo
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- CN114751899A CN114751899A CN202210435526.7A CN202210435526A CN114751899A CN 114751899 A CN114751899 A CN 114751899A CN 202210435526 A CN202210435526 A CN 202210435526A CN 114751899 A CN114751899 A CN 114751899A
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- urea
- triazin
- oxo
- dihydroisobenzofuran
- phenyl
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Abstract
本发明涉及医药技术领域,具体涉及一类末端苯并内酯取代的二芳基脲类mTOR抑制剂及其药物组合物和应用,其中,末端苯并内酯取代的二芳基脲类mTOR抑制剂包括具有通式(Ⅰ)的取代三嗪类化合物,其立体异构体,水合物或药学上可接受的盐,所述通式(Ⅰ)结构如下:
Description
技术领域
本发明涉及医药技术领域,具体地说,涉及一种二芳基脲类mTOR激酶抑制剂及其药物组合物和应用。
背景技术
恶性肿瘤是当今世界直接危及人类生命的一种最常见、最严重的疾病,其是机体在各种致癌因素作用下,局部组织的细胞失去基因调控,导致其克隆性异常增生而形成的新生物。传统的化疗和放疗由于缺乏特异性,取得疗效的同时也往往给患者带来较大的毒副作用(Nature2019,575(7782),299-309)。选择肿瘤细胞特异的靶点,应用针对该靶点的药物进行治疗,从而避免对正常细胞的伤害,取得高效低毒的治疗模式,是当前抗肿瘤药物的重要发展方向。
PI3K/AKT/mTOR信号通路影响恶性肿瘤细胞的增殖、存活、转录、翻译和代谢等过程,因此针对该通路中的PI3K、mTOR等激酶的有机小分子激酶抑制剂已成为小分子靶向抗肿瘤药物研发的热点之一。磷脂酰肌醇-3激酶(PI3K)主要是通过酪氨酸激酶受体、G蛋白偶联受体等被激活;激活的PI3K磷酸化第二信使磷脂酰肌醇4,5-二磷酸(PIP2),生成磷脂酰肌醇3,4,5-三磷酸(PIP3);PIP3可激活丝氨酸/苏氨酸激酶(AKT),并进一步激活下游包括雷帕霉素靶蛋白(mTOR)在内的多个底物,进而影响细胞的增殖、存活、代谢、细胞周期调控和凋亡等过程。mTOR同样是PI3K/AKT/mTOR信号通路的关键位点,mTOR与不同种类型的蛋白结合形成不同的蛋白复合体,即mTOR复合物1(mTORC1)和mTOR复合物2(mTORC2)。其中,哺乳动物中mTOR的两种亚型mTORC1和mTORC2均可被AKT激活,而mTORC2可再激活AKT,形成正反馈。张力蛋白磷酸酶(PTEN)可使PIP3去磷酸化生成PIP2,从而抑制PI3K信号通路的表达,起到负反馈的作用。在已知的肿瘤类型中,约有50%的实体瘤出现PI3K/AKT/mTOR信号转导通路激活,靶向信号通路下游信号蛋白mTOR的抑制剂已成为抗肿瘤药物研发的热门领域。迄今为止,多种mTOR抑制剂被相继报道。
mTOR抑制剂主要分为四类:变构mTOR抑制剂(第一代)、ATP竞争mTOR抑制剂(第二代)、PI3K/mTOR双靶点抑制剂(第二代)和其他新型mTOR抑制剂(第三代)。第一代mTOR抑制剂主要是雷帕霉素及其衍生物(Rapalogs),其主要靶向mTOR和FKBP12,作用机制为雷帕霉素与FKBP12结合形成复合物,再与mTOR的FRB结构域结合,改变mTOR的构象,从而抑制mTORC1的激酶活性。然而,Rapalogs在部分癌症临床治疗中未达到预期疗效,长期使用该药物后,由mTORC1至AKT的负反馈会激活该信号的上游通路,从而产生耐药性。Rapalogs还存在结构复杂、合成难度大、稳定性差和生物利用度低等不足。第二代mTOR抑制剂是小分子ATP类似物,包括ATP竞争性mTOR抑制剂和PI3K/mTOR双重抑制剂。ATP竞争性mTOR抑制剂直接作用于mTOR激酶结构域中的ATP结合位点,对mTOR具有高度选择性,因此也被称为选择性mTOR激酶抑制剂(TORKIs)。相比Rapalogs,TORKIs分子量小易于合成,同时阻断mTORC1和mTORC2,且与mTORC1/C2的ATP结合位点结合稳定。TORKIs还能够通过mTORC2抑制AKT第473位丝氨酸磷酸化而抑制该负反馈效应。与PI3K/mTOR双重抑制剂相比,TORKIs能抑制mTORC1/C2而不抑制其他激酶,降低PI3K/mTOR抑制剂的毒性作用。过去相继报道了多种选择性mTOR抑制剂,有PQR620、Wyeth-BMCL-200910075-9b及PKI-179等。
然而,TORKIs在使用时仍不可避免地导致诸如腹泻、贫血、中性粒细胞减少等副作用,严重限制了TORKIs的临床应用,迄今未有选择性mTOR抑制剂上市使用,多数候选药物仍处于临床试验阶段,具有较好的市场前景。目前,本申请人一直致力于mTOR抑制剂的研究,前期申请CN113045559A一种二芳基脲类PI3Kα/mTOR双靶点抑制剂及其药物组合物和应用,其目标是考虑到多数肿瘤的发生与PI3Kα亚型的扩增与突变密切相关,因此合成了一种能够抑制PI3Kα和mTOR双激酶的化合物,但此前的研究中并未考虑对PI3Kβ、PI3Kγ、PI3Kδ等激酶的抑制活性问题,并且也未考虑中间产物的产率问题。因不同亚型的PI3K激酶有着不同的组织分布和生理功能,非选择性抑制必定会导致非靶点相关副作用。此外,中间产物的产率问题直接关系制作成本;因此,本发明的目的是进一步开发成本低、疗效佳、毒性小的选择性mTOR抑制剂。
发明内容
本发明旨在提供一类二芳基脲类mTOR激酶抑制剂及其药物组合物和应用,以便选择有效性和选择性更好的化合物用于癌症的治疗。
为了实现上述目的,根据本发明的一个方面,提供了一类二芳基脲类mTOR激酶抑制剂,又名二芳基脲苯并呋喃酮类选择性mTOR抑制剂,包括具有通式(Ⅰ)的取代三嗪类化合物,其立体异构体,水合物或药学上可接受的盐,所述通式(Ⅰ)结构如下:
其中,所述通式(Ⅰ)中:X选自H、C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C4-C7杂环基、含一个或多个取代基的C4-C7杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基,X上所述的取代基选自氟、氯、溴、碘、羟基、氨基、酰胺、羧酸、羧酸酯、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基。
R1和R2分别选自H、C1-C4烷基、含一个或多个取代基的C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C1-C4烷基酰基、C1-C4烷基磺酰基、C3-C6杂环基、含一个或多个取代基的C3-C6杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基,R1或R2上所述的取代基选自氟、氯、溴、碘、羟基、氨基、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基。
进一步地,在一些实施方案中,上述通式(Ⅰ)中R1和R2分别独立地选自如下结构:
X选自如下结构:
在本发明的通式(Ⅰ)中与碳相连的氢可以被替换为氢的同位素氘,通俗来说,烷基可被氘代烷基替代,烷氧基可被氘代环氧基替代,苯环被氘代苯环替代,芳环可被氘代芳环替代。
进一步地,在一些实施方案中,本发明所述的二芳基脲类mTOR激酶抑制剂包含以下其中之一的结构:
(1)(S)-1-(4-(4-(3-甲基吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(2)(R)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(3)1-(4-(4-(4-(二甲基氨基)哌啶-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(4)(S)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(5)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(6)1-(4-(4-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(7)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((R)-3-甲基吗啉基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(8)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(9)1-(4-(4-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(10)1-(4-(4-吗啉代-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(11)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(2,2-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(12)1-(4-(4-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(13)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((3R,5S)-3,5-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(14)1-(4-(4-((3R,5S)-3,5-二甲基吗啉)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(15)1-(4-(4-((2S,6R)-2,6-二甲基吗啉)-6-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(16)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,6R)-2,6-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(17)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((S)-3-乙基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(18)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-甲基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(19)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(20)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(21)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-乙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(22)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(23)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(24)1-(4-(4-吗啉-6-硫吗啉-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(25)1-(4-(4-(3-氧杂-8-氮杂双环[3.1.1]庚烷-6-基)-6-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(26)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(27)1-(4-(4-吗啉-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(28)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲。
一种具有通式(Ⅰ)的取代三嗪类化合物的制备方法:以三聚氯氰(A)为原料,原料(A)的两个氯原子与吗啉或其他含氮杂环通过取代反应,引入R1或R2基团得到中间体(B),中间体(B)与4-氨基苯硼酸频哪醇酯发生Suzuki偶联反应,得到中间体(C),中间体(C)的氨基端与不同的含氨基片段通过脲基连接,得到具有通式(Ⅰ)结构的目标化合物(D)。
上述方法的反应式如下:
在上述制备步骤中式A至D中取代基R1、R2、X的定义与通式(Ⅰ)中的取代基R1、R2、X相同。
根据本发明的另一方面,提供了一种药物组合物,其包含至少一种药学上可接受的辅料、辅助剂或载体,以及有效治疗剂量的至少一种上述的二芳基脲类mTOR激酶抑制剂。
根据本发明的另一方面,提供了一种上述的二芳基脲类mTOR激酶抑制剂或上述的药物组合物来制备用于在预防和/或治疗和/或辅助治疗mTOR激酶过度活化引起的增殖性疾病、代谢性疾病、神经系统性疾病及结节性硬化症的药物中的应用。
进一步地,在其中一些实施方案中,本发明上述应用中所述增殖性疾病包括结直肠癌、胃癌、乳腺癌、肺癌、肝癌、前列腺癌、胰腺癌、甲状腺癌、膀胱癌、肾癌、脑瘤、颈癌、CNS的癌症、恶性胶质瘤、骨髓增生病、白血病或淋巴癌。
所述代谢性疾病为糖尿病。
根据本发明的另一方面,提供了一种上述的二芳基脲类mTOR激酶抑制剂或包含二芳基脲类mTOR激酶抑制剂的药物组合物在制备用于体外抑制癌症细胞生长的药物中的应用。
有益效果
与现有技术相比,本发明可以获得包括以下的技术效果:
本发明所述化合物均可有效抑制mTOR激酶,多个化合物具有优于阳性对照PF-05212384的mTOR抑制活性。本发明该类化合物结构新颖、抗肿瘤活性显著,可潜在用于相关肿瘤的治疗。因此,本发明所述化合物具有积极且可预见的抗增殖性疾病,尤其是抗肿瘤的临床应用价值,并具有很好的开发前景。
本发明所述化合物具有成本低、疗效佳、毒性小的特点。本发明的化合物在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行详细的说明,但如下实施例仅是用以理解本发明,而不能限制本发明,本发明可以由权利要求限定和覆盖的多种不同方式实施。
为了实现背景技术部分所指出的提供更多有效性和选择性更好的化合物以用于恶性肿瘤的治疗,在本发明中提供了一种二芳基脲类mTOR激酶抑制剂。这种二芳基脲类mTOR抑制剂包括具有通式(Ⅰ)的取代三嗪类化合物,其立体异构体,水合物或药学上可接受的盐。其中,通式(Ⅰ)结构如下:
其中,所述通式(Ⅰ)中:X选自H、C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C4-C7杂环基、含一个或多个取代基的C4-C7杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基,取代基选自氟、氯、溴、碘、羟基、氨基、酰胺、羧酸、羧酸酯、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基。
R1和R2可分别选自H、C1-C4烷基、含一个或多个取代基的C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C1-C4烷基酰基、C1-C4烷基磺酰基、C3-C6杂环基、含一个或多个取代基的C3-C6杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基,取代基选自氟、氯、溴、碘、羟基、氨基、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基;
进一步地,在一些实施方案中,上述通式(Ⅰ)中R1和R2可分别独立地选自如下结构:
X选自如下结构:
在本发明的通式(Ⅰ)中与碳相连的氢可以被替换为氢的同位素氘,通俗来说,烷基可被氘代烷基替代,烷氧基可被氘代环氧基替代,苯环被氘代苯环替代,芳环可被氘代芳环替代。
本发明所提供一种二芳基脲类mTOR激酶抑制剂、包含其的药物组合物具有抑制mTOR激酶的作用,因此能够在制备治疗或预防mTOR激酶过度活化引起的增殖性疾病、代谢性疾病、神经系统性疾病及结节性硬化症的药物中的应用。
本发明的二芳基脲类mTOR激酶抑制剂可以包括取代三嗪类化合物药学上可接受的盐。药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式。药学上可接受的盐包括,但不仅限于,碱性基团例如胺(氨)基的无机或有机酸盐类。本发明药学上可接受的盐可以由母体化合物合成,即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remington’s Pharmaceutical Sciences,17th ed.,MackPublishing Company,Easton,Pa.,1985,p.1418和Journal ofPharmaceuticalScience,66,2(1977)中。
本发明中化合物碱性基团可与酸成盐,这些酸成盐的例子包括:与无机酸,尤其氢卤酸(如氢氯酸、氢溴酸、氢碘酸)、硝酸、硫酸、磷酸、碳酸等形成的盐;低级烷基磺酸,如甲磺酸,三氟甲磺酸形成的盐;与芳基磺酸,如苯磺酸或对甲苯磺酸形成的盐;与有机酸,如乙酸、富马酸、酒石酸、草酸、柠檬酸、马来酸、苹果酸或琥珀酸形成的盐;与氨基酸,如天冬氨酸或谷氨酸形成的盐。
本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。一般来说,溶剂化物或水合物的形式与非溶剂化的或非水合的形式等同,并涵盖在本发明的范围内。本发明中的某些化合物有可能存在多晶体或无定形的形式。总的来说,所有的物理形式具有同等的用途,并且涵盖在本发明的范围内。
另外,除非其它方面表明,本发明所描述的本发明的二芳基脲类mTOR激酶抑制剂中取代三嗪化合物的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
除非其它方面表明,本发明二芳基脲类mTOR激酶抑制剂中嘧啶化合物的所有互变异构形式都包含在本发明的范围之内。另外,除非其它方面表明,本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
下面将详细描述本发明的示例性实施方案。然而,这些实施方案仅为说明目的,并不旨在限制本发明的范围。
如本文所使用的,如果为提供具体的限定,本发明的术语具有下述含义。
术语“烷基”为包括1-20个碳原子饱和直链或支链的单价烃基,其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是,烷基基团含有1-10个碳原子,另外一些实施例是,烷基基团含有1-8个碳原子,另外一些实施例是,烷基基团含有1-6个碳原子,另外一些实施例是,烷基基团含有1-4个碳原子。烷基基团更进一步的实例包括,但并不限于甲基(Me,-CH3)、乙基(Et,-CH2CH3)、正丙基(n-Pr,-CH2CH2CH3)、异丙基(i-Pr,-CH(CH3)2)、正丁基(n-Bu,-CH2CH2CH2CH3)、异丁基(i-Bu,-CH2CH(CH3)2)、仲丁基(s-Bu,-CH(CH3)CH2CH3)、叔丁基(t-Bu,-C(CH3)3)等等。术语“烷基”和其前缀“烷”在此处使用,都包含直链和支链的饱和碳链。
术语“烷氧基”涉及到烷基的部分与前述“烷基”的定义相同,其是通过氧原子连接到“烷基”主要的碳链上形成的。
术语“卤代烷基”或“卤代烷氧基”是表示“烷基”或“烷氧基”可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基和烷氧基基团具有如本发明前述的含义,这样的实例包括但并不限于三氟甲基、三氟甲氧基等。
术语“羟基烷基”或“羟基烷氧基”是表示“烷基”或“烷氧基”可以被一个或多个羟基所取代的情况。其中“烷基”和“烷氧基”基团具有如本发明前述的含义,这样的实例包括但并不限于羟甲基、1-羟乙基、羟丙基、1,2-二羟基丙基、羟甲氧基、1-羟乙氧基等。
术语“卤素”、“卤原子”或“卤素原子”包括氟、氯、溴、碘。
术语“杂环基”可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括但并不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、噻噁烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、哌啶基、高哌啶基、环氧丙基、氮杂环庚基、氧杂环庚基、硫杂环庚基、N-吗啉基、2-吗啉基、3-吗啉基、硫代吗啉基、N-哌嗪基、2-哌嗪基、3-哌嗪基、高哌嗪基、4-甲氧基-哌啶-1-基、1,2,3,6-四氢吡啶-1-基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡咯啉-1-基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,6-噻二嗪烷、1,1-二氧-2-基、喹嗪基和N-吡啶基尿素。并且所述杂环基可以是取代或非取代的,其中取代基可以是但并不限于氧代(=O)、羟基、氨基、卤素、氰基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(=O)、烷基-C(=O)、羧基烷氧基等。
术语“稠合双环”、“稠环”、“稠合双环基”或“稠环基”表示饱和或不饱和的稠环体系,涉及到非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环或者是碳环或者是杂脂环族,这样的实例包括但并不限于2,3,3a,4,7,7a-六氢-1H-茚基、7-氮杂双环[2.2.1]庚烷基、稠合双环[3.3.0]辛烷基、稠合双环[3.1.0]己烷基、1,2,3,4,4a,5,8,8a-八氢萘基,这些都包含在稠合双环的体系之内。并且所述稠合双环基可以是取代或非取代的,其中取代基可以是但并不限于卤素、羟基、氨基、氰基、芳基、杂芳基、烷氧基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基等。
术语“稠合杂双环基”表示饱和或不饱和的稠环体系,涉及到非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N、O、P、S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到像SO、SO2、PO、PO2的基团,这样的实例包括但并不限于六氢-2H-[1,4]二氧噁[2,3-c]吡咯基等。并且所述稠合杂双环基可以是取代或非取代的,其中取代基可以是但并不限于卤素、羟基、氨基、氰基、芳基、杂芳基、烷氧基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基等。
本发明所提供的上述二芳基脲苯并呋喃酮类选择性mTOR抑制剂中取代三嗪化合物可以通过多种方式制备,本领域技术人员可在本申请中所提供的结构式的启发下寻找适当的方式进行制备。为了便于理解,在本发明创造中提供了关于上述通式(Ⅰ)的制备方法。
一种制备具有通式(Ⅰ)的取代三嗪化合物的方法:以三聚氯氰(A)为原料,原料(A)的两个氯原子与吗啉或其他含氮杂环通过取代反应,引入R1或R2基团得到中间体(B),中间体(B)与4-氨基苯硼酸频哪醇酯发生Suzuki偶联反应,得到中间体(C),中间体(C)的氨基端与不同的含氨基片段通过脲基连接,得到具有通式(Ⅰ)结构的目标化合物(D)。
上述方法的反应式如下:
在上述制备步骤中式A至D中取代基R1、R2、X的定义与通式(Ⅰ)中的取代基R1、R2、X相同。
同时,在本发明的一种实施方式中还提供了一种药物组合物,这种药物组合物包含至少一种药学上可接受的辅料、辅助剂或载体,以及有效治疗剂量的至少一种上述的二芳基脲苯并呋喃酮类选择性mTOR抑制剂。
术语“有效治疗剂量”指的是在给予需要这样的治疗的哺乳动物时,足以有效治疗的通式化合物的量。治疗有效量将依赖于所用的治疗药剂的特定活性、患者的年龄、生理状况、其它疾病状态的存在和营养状况而变化。此外,患者可能正接受的其它药物治疗将影响要给予的治疗药剂的治疗有效量的确定。
术语“治疗”意味着对于哺乳动物体内疾病的任何治疗,包括:(i)防止疾病,即造成疾病的临床症状不发展;(ii)抑制疾病,即阻止临床症状的发展;和/或(iii)减轻疾病,即造成临床症状的消退。
术语“药学上可接受的辅料、辅助剂或载体”包括任何和全部的溶剂、分散介质、包衣、抗细菌和抗真菌药剂、等渗和吸收延迟剂等。这样的介质和药剂用于药学活性物质在本领域是众所周知的。除非任何常规介质或药剂与活性成分不相容,其在治疗组合物中的应用是可预期的。补充的活性成分也可以并入组合物中。
该组合物优选被配制成单位剂型。术语“单位剂型”指的是适于用作给予人类受试者和其他哺乳动物的单一剂量的物理离散单位,每一单位含有计算出用以产生所需要的治疗有效的活性物质的预定的量以及相关的合适的药用赋形剂(如片剂、胶囊、安瓿)。mTOR激酶抑制剂中嘧啶化合物在广泛的剂量范围内是有效的并且通常给予有效药物量。优选地,对于口服给药,每个剂量单位包含10mg至2g的mTOR激酶抑制剂中嘧啶化合物,更优选为10至700mg,而对于肠胃外给药,优选为10至700mg的mTOR激酶抑制剂中嘧啶化合物,更优选约50至200mg。然而,应当明了,实际给予的mTOR激酶抑制剂中嘧啶化合物的量将由医师根据有关的情况来确定,包括要治疗的病症,选择的给药途径,给予的实际化合物以及其相对活性,各个患者的年龄、体重、以及反应,患者症状的严重性等。
为了制备固体组合物如片剂,将主要的活性组分与药物赋形剂(或载体)进行混合以形成固体预配制组合物,其包含本发明的化合物的均匀混合物。当称这些预配制组合物为均匀的时候,它是指活性组分被均匀分散在整个组合物中,以致组合物可以容易地被细分成相同有效的单位剂型如片剂、丸剂以及胶囊剂。
本发明的片剂或丸剂可以被涂布或用其它方式被复合以提供一种具有延长作用优点的剂型,或保护片剂或丸剂免受胃中酸性条件的作用。例如,片剂或丸剂可以包括内剂量和外剂量成分,后者具有在前者之上的外皮的形式。可以用肠溶层来分隔两种成分,其中肠溶层用来阻止在胃中的崩解以及允许内成分完整进入十二指肠或被延迟释放。各种材料可以用于这样的肠溶层或涂层,上述材料包括许多高分子酸以及高分子酸与这样的材料如虫胶、十六烷醇、以及醋酸纤维素的混合物。
用于吸入法或吹入法的组合物包括在药学上可接受的含水溶剂或有机溶剂、或其混合物中的溶液和悬浮液,以及散剂。液体或固体组合物可以包含如上文所述的适宜的药用赋形剂。优选地,通过口服或鼻呼吸途径给予这些组合物以获得局部或全身效应。可以通过使用惰性气体来雾化在优选的药学可接受的溶剂中的组合物。可以直接从雾化装置吸入雾化溶液,或雾化装置可以连接于面罩帐状物、或间歇正压呼吸机。可以由以适当方式递送剂型的装置,优选口服或鼻途径,给予溶液、混悬剂、或散剂组合物。
在另一个方面,本发明还提供了一种上述的二芳基脲类mTOR激酶抑制剂或上述的药物组合物来制备用于在预防和/或治疗和/或辅助治疗mTOR激酶作用的增殖性疾病的药物中的应用。其中,mTOR激酶作用的增殖性疾病为癌症。这种癌症包括实体癌症和血液性癌症的形式。优选的,该mTOR激酶作用的增殖性疾病为结直肠癌、胃癌、乳腺癌、肺癌、肝癌、前列腺癌、胰腺癌、甲状腺癌、膀胱癌、肾癌、脑瘤、颈癌、CNS的癌症、恶性胶质瘤、骨髓增生病、白血病和淋巴癌。
在另一个方面,本发明还提供了一种上述的mTOR激酶抑制剂或上述的药物组合物在制备用于体外抑制癌症细胞生长的药物中的应用。
下面将结合实施例1-28对本发明做进一步的描述,然而,这些实施例不应作为对本发明的范围的限制。
下面所描述的实施例中除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Alfa Aesar Chemical Company、百灵威科技有限公司、阿拉丁试剂有限公司、北京偶合科技有限公司等,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从汕头西陇化工厂、广州化学试剂厂、天津致远化学试剂有限公司和青岛海洋化工厂等购买得到。
下面所描述的实施例中色谱柱使用硅胶柱,硅胶(200-300目)购于青岛海洋化工厂。核磁共振光谱以CDC13或DMSO-d6为溶剂(以ppm为单位),用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),m(multiplet,多重峰),br(broadened,宽峰),dd(doublet ofdoublets,四重峰),dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
下面所描述的实施例中低分辨率质谱(MS)数据通过配备G1311B四元泵和G1316BTCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的,G1329B自动采样器和G1315C DAD检测器应用于分析,ESI源应用于LC-MS光谱仪。
下面所描述的实施例中注射体积是通过样品浓度来确定;流速为0.5mL/min;HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为异丙醇/正己烷(40:60)。
下面描述的实施例为了便于表述,部分原料会以其简称进行描述,这些简称与其全称对照说明如下:DCM为CH2Cl2,即二氯甲烷;CDC13为氘代氯仿;PE为石油醚;EtOAc与EA均为乙酸乙酯;MeOH与CH3OH均为甲醇;Pd(PPh3)4为四三苯基膦钯;DIPEA为N,N-二异丙基乙胺;DMSO-d6为六氘代二甲亚砜;DME为乙二醇二甲醚;Na2SO4为硫酸钠。
实施例1:(S)-1-(4-(4-(3-甲基吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法包括以下步骤:
步骤1:4-(4,6-二氯-1,3,5-三嗪-2-基)吗啉的合成
称取原料三聚氯氰(10.84mmol)放入100mL双颈瓶中,加入DCM溶解,再加入DIPEA(10.84mmol),真空氮气循环三次后在低温-78℃下冷却10分钟,通过恒压滴液漏斗缓慢添加吗啉(10.84mmol)并保持低温反应1h,TLC监测反应完毕,反应液直接真空浓缩硅胶拌样,硅胶柱层析纯化(PE:EA=5:1)既得产物。白色粉末,收率:78.13%。HRMS(ESI)calcd.forC7H8Cl2N4O[M+H]+:235.0153,found:235.0159;
步骤2:(S)-4-(4-氯-6-吗啉代-1,3,5-三嗪-2-基)-3-甲基吗啉的合成
于50mL双颈瓶中依次加入4-(4,6-二氯-1,3,5-三嗪-2-基)吗啉(1.08mmol)、DIPEA(1.13mmol)、吗啉(1.08mmol),用DCM溶解,将反应置换上氮气,在0℃下反应3h。TLC监测原料反应完全后,移去氮气,向反应混合物加入水和DCM(3×20mL)萃取,合并有机层,然后用无水Na2SO4干燥有机相,蒸发除去溶剂,硅胶柱层析(PE:EA=10:1)纯化。白色固体,收率:87.5%。核磁数据为1H NMR(400MHz,Chloroform-d)δ4.67(s,1H),4.33(d,J=14.8Hz,1H),3.94(dd,J=11.5,3.7Hz,1H),3.79(t,J=5.7Hz,4H),3.71(t,J=4.7Hz,5H),3.63(dd,J=11.5,3.3Hz,1H),3.48(td,J=11.9,3.0Hz,1H),3.25(ddd,J=13.7,12.3,3.8Hz,1H),1.30(d,J=6.9Hz,3H).HRMS(ESI)calcd.for C12H18ClN5O2[M+H]+:300.1227,found:300.1221;
步骤3:(S)-4-(4-(3-甲基吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯胺的合成
向50mL单颈瓶中依次加入(S)-4-(4-氯-6-吗啉代-1,3,5-三嗪-2-基)-3-甲基吗啉(2.13mmol),4-氨基苯硼酸频哪醇酯(2.34mmol),四(三苯基膦)钯(0.1mmol),碳酸钾(5.32mmol),用DME(10mL)和水(2mL)溶解。将反应置换上氮气,100℃回流反应12h,TLC跟踪反应完毕,冷却至室温,加入EA(50mL×3)和水萃取,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱层析(DCM:MeOH=50:1)纯化。黄色固体,收率:88.6%。核磁数据为1HNMR(600MHz,DMSO-d6)δ8.05(d,J=8.6Hz,2H),6.58(d,J=8.6Hz,2H),5.71(s,2H),4.75(s,1H),4.37(s,1H),3.90(d,J=11.0Hz,1H),3.71(s,5H),3.64(s,4H),3.57(s,1H),3.41(d,J=11.1Hz,1H),3.15(s,1H),1.21(d,J=6.8Hz,3H);13C NMR(151MHz,DMSO-d6)δ169.9,165.1,164.7,152.7,130.2,123.9,113.2,70.8,66.7,66.5,46.0,14.4.HRMS(ESI)calcd.for C18H24N6O2[M+H]+:357.2039,found:357.2039。
步骤4:(S)-1-(4-(4-(3-甲基吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲的合成
在50mL单颈瓶中加入5-氨基异苯并呋喃-1(3H)-酮(0.66mmol),用1,4-二氧六环(5mL)溶解,混合物降温至0-4℃添加三光气(0.66mmol),110℃回流12h,TLC跟踪反应完毕。反应液除去溶剂得异氰酸酯中间体,残余物用DCM(5mL)溶解,添加中间体7(0.66mmol),在室温下反应12h。TLC跟踪反应完毕,硅胶柱层析(DCM/MeOH=20:1)纯化。白色固体,收率:24%。核磁数据为1HNMR(600MHz,DMSO-d6)δ9.32(s,1H),9.17(s,1H),8.29(s,2H),7.91(s,1H),7.75(s,1H),7.58(s,2H),7.53(s,1H),5.36(s,2H),4.60(dd,J=212.4,94.5Hz,2H),3.94–3.70(m,6H),3.66(s,4H),3.57(s,1H),3.44(s,1H),3.23–3.15(m,1H),1.24(s,3H);13C NMR(151MHz,DMSO-d6)δ175.6,174.2,169.9,169.5,157.2,154.4,150.4,147.6,135.7,134.3,131.1,124.1,123.2,122.8,115.8,75.5,74.7,71.5,71.2,50.9,48.5,43.4.HRMS(ESI)calcd.for C27H29N7O5[M+H]+:532.2308,found:532.2300。
实施例2:(R)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为(R)-2-羟甲基吗啉,其他步骤及操作同实施例1;白色固体,收率:17%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.17(s,1H),8.34-8.28(m,2H),7.90(s,1H),7.76(d,J=8.4Hz,1H),7.58(s,2H),7.52(d,J=9.3Hz,1H),5.36(s,2H),4.83(s,2H),4.77-4.43(m,2H),3.90(d,J=51.7Hz,5H),3.67(s,4H),3.47(d,J=58.4Hz,4H),3.01(s,1H),2.76(s,1H);13C NMR(151MHz,DMSO-d6)δ170.8,169.4,168.9,164.9,164.7,163.8,152.4,149.7,145.6,142.8,130.9,129.5,126.3,119.3,118.4,117.9,111.0,76.0,73.8,69.9,66.5,56.5,55.3.HRMS(ESI)calcd.for C27H29N7O6[M+H]+:548.2258,found:548.2253。
实施例3:1-(4-(4-(4-(二甲基氨基)哌啶-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为4-二甲基氨基哌啶,其他步骤及操作同实施例1。白色固体,收率:27%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.35(s,1H),9.19(s,1H),8.28(d,J=7.2Hz,2H),7.90(s,1H),7.75(s,1H),7.57(s,2H),7.51(s,1H),5.35(s,2H),4.76(d,J=126.1Hz,2H),3.79(s,4H),3.65(s,4H),2.91(s,2H),2.37(ddq,J=11.5,7.8,3.7Hz,1H),2.18(s,6H),1.81(s,2H),1.30(d,J=11.3Hz,2H);13C NMR(151MHz,DMSO-d6)δ170.8,169.4,165.2,164.6,152.4,149.7,145.6,142.8,131.1,129.5,126.3,119.3,118.4,118.0,111.0,70.0,66.5,62.02,43.7,42.5,41.8,28.4.HRMS(ESI)calcd.for C29H34N8O4[M+H]+:559.2781,found:559.2776。
实施例4:(S)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为(S)-2-羟甲基吗啉,其他步骤及操作通于实施例1。白色固体,收率:19%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.17(s,1H),8.32-8.29(m,2H),7.90(s,1H),7.76(d,J=8.4Hz,1H),7.58(s,2H),7.53(s,1H),5.36(s,2H),4.83(s,2H),4.69(s,2H),3.87(d,J=63.3Hz,5H),3.67(t,J=4.8Hz,4H),3.45(d,J=34.0Hz,4H),3.01(s,1H),2.77(s,1H);13C NMR(151MHz,DMSO-d6)δ170.8,169.4,165.1,152.4,149.7,145.6,142.9,130.8,129.5,126.3,119.3,118.4,118.0,111.0,76.5,70.0,66.0,66.1,62.8,55.4,43.8.HRMS(ESI)calcd.for C27H29N7O6[M+H]+:548.2258,found:548.2255。
实施例5:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,其他步骤及操作同实施例1。白色固体,收率:43%。核磁数据为1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),9.78(s,1H),8.26(s,2H),7.91(s,1H),7.76(s,1H),7.62(s,1H),7.54(s,1H),5.36(s,2H),4.85(s,1H),4.64(d,J=30.0Hz,6H),3.80(s,4H),3.68(s,4H),1.95(d,J=33.5Hz,4H);13C NMR(151MHz,DMSO-d6)δ170.8,168.3,164.1,152.6,149.7,145.7,143.5,129.9,126.4,119.1,118.3,117.7,110.8,71.6,70.0,66.4,63.5,54.8,27.0.HRMS(ESI)calcd.for C28H29N7O5[M+H]+:544.2308,found:544.2308。
实施例6:1-(4-(4-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为8-氧杂-3-氮杂双环[3.2.1]辛烷,其他步骤及操作同实施例1。白色固体,收率:64%。核磁数据为1H NMR(600MHz,Chloroform-d)δ9.91(s,1H),9.66(s,1H),8.28(s,2H),7.91(s,1H),7.75(s,1H),7.59(s,2H),7.55(s,1H),5.36(s,2H),4.49(s,1H),4.41(s,2H),4.27(s,1H),3.84(s,4H),3.70-3.64(m,4H),3.11(d,J=38.9Hz,2H),1.83(s,2H),1.65(s,2H);13C NMR(151MHz,DMSO-d6)δ170.8,168.7,165.6,164.3,152.6,149.7,145.7,143.2,130.2,129.7,126.3,119.1,118.3,117.8,110.8,73.4,70.0,66.5,49.3,27.8.HRMS(ESI)calcd.for C28H29N7O5[M+H]+:544.2308,found:544.2308。
实施例7:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((R)-3-甲基吗啉基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲
合成方法:将实施例1步骤1中取代杂环片段改为(R)-3-甲基吗啉,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,其他步骤及操作类似于实施例1。白色固体,收率:17%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.18(s,1H),8.30(s,2H),7.91(s,1H),7.76(d,J=8.4Hz,1H),7.59(s,2H),7.53(s,1H),5.37(s,2H),4.71(d,J=117.9Hz,4H),3.91(s,1H),3.71(s,1H),3.61(d,J=16.2Hz,5H),3.43(td,J=11.9,2.9Hz,1H),3.18(d,J=9.9Hz,1H),1.93(d,J=38.6Hz,4H),1.24(s,3H);13C NMR(151MHz,DMSO-d6)δ170.8,169.7,164.9,152.4,149.7,145.6,142.8,131.0,129.5,126.3,119.3,118.4,118.0,111.0,71.2,70.7,70.0,66.7,54.8,46.2,38.6,26.9,14.5.HRMS(ESI)calcd.forC29H31N7O5[M+H]+:558.2465,found:558.2467。
实施例8:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为(1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷,其他步骤及操作同实施例1。白色固体,收率:40%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.18(s,1H),8.30(s,2H),7.91(s,1H),7.77(d,J=8.4Hz,1H),7.59(d,J=8.6Hz,2H),7.53(s,1H),5.37(s,2H),4.81(s,2H),4.62(s,2H),3.63(s,8H),1.97(s,4H),1.90(s,4H);13C NMR(151MHz,DMSO-d6)δ170.8,169.9,163.8,152.4,149.7,145.6,142.8,130.9,129.5,126.3,119.3,118.4,117.9,111.0,71.5,71.2,70.0,54.8,54.5,27.0.HRMS(ESI)calcd.for C30H31N7O5[M+H]+:570.2465,found:570.2462。
实施例9:1-(4-(4-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法如下:
步骤1:合成8-(4-吗啉-6-(4-(3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲)苯基)-1,3,5-三嗪-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯,其结构式如下:
将实施例1步骤2中取代杂环片段改为3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯,其他步骤及操作同实施例1。白色固体,收率:40%;核磁数据为1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),9.18(s,1H),8.31(s,2H),7.91(s,1H),7.77(s,1H),7.59(s,2H),7.52(s,1H),5.37(s,2H),4.92(s,1H),4.75(s,1H),3.78(d,J=42.9Hz,6H),3.67(s,4H),3.10(s,1H),2.96(s,1H),1.90(s,2H),1.70(s,2H),1.41(s,9H).HRMS(ESI)calcd.for C33H38N8O6[M+H]+:643.2993,found:643.2995。
步骤2:合成1-(4-(4-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲
将8-(4-吗啉-6-(4-(3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲)苯基)-1,3,5-三嗪-2-基)-3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯溶于重蒸的DCM(2ml),冷却至0℃,缓慢滴加三氟乙酸(0.018ml),移至室温下搅拌2h。TLC监测反应完全。蒸发除去溶剂,通过硅胶柱色谱法纯化(DCM/MeOH=10/1)。白色固体,收率:15%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.96(s,1H),8.33(s,2H),7.93(s,1H),7.76(s,1H),7.60(d,J=28.0Hz,3H),5.37(s,2H),5.00(s,1H),4.81(s,1H),4.29-4.01(m,4H),3.68(s,9H),2.15-2.02(m,4H);13CNMR(151MHz,DMSO-d6)δ170.9,169.9,165.1,163.6,152.6,149.7,145.9,143.3,130.4,129.6,119.3,118.3,118.0,117.8,70.0,66.5,51.4,47.1,26.0.HRMS(ESI)calcd.for C28H30N8O4[M+H]+:543.2468,found:543.2473。
实施例10:1-(4-(4-吗啉代-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为哌嗪,其他步骤及操作同实施例1。白色固体,收率:30%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.92(s,1H),9.73(s,1H),8.96(s,1H),8.31(d,J=8.7Hz,2H),7.92(s,1H),7.76(s,1H),7.62(d,J=8.5Hz,2H),7.57(s,1H),5.36(s,2H),3.94(dd,J=125.4,67.5Hz,8H),3.66(s,4H),3.18(d,J=16.2Hz,4H);13CNMR(151MHz,DMSO-d6)δ170.9,169.7,165.1,152.6,149.6,145.9,143.3,130.5,129.6,126.3,119.3,118.3,117.9,110.9,70.0,66.5,49.1,43.1.HRMS(ESI)calcd.for C26H28N8O4[M+H]+:517.2312,found:517.2303。
实施例11:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(2,2-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为2,2-二甲基吗啉,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,其他步骤及操作同实施例1。白色固体,收率:13%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),9.75(s,1H),8.17(s,1H),7.91(s,1H),7.73(s,1H),7.52(s,2H),7.50(s,1H),5.26(s,2H),4.83(s,1H),4.64(d,J=28.0Hz,6H),3.70(s,2H),3.66(s,2H),3.10(s,2H),1.95(d,J=31.6Hz,4H),1.53(s,6H);13C NMR(151MHz,DMSO-d6)δ170.8,164.4,163.1,162.0,152.1,142.3,141.4,140.4,131.0,129.3,126.4,121.5,119.5,118.1,114.7,74.4,69.2,69.0,59.5,55.7,55.3,43.5,27.3,25.3.HRMS(ESI)calcd.for C30H33N7O5[M+H]+:572.2621,found:572.2625。
实施例12:1-(4-(4-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2的取代杂环片段改为2,5-双(羟甲基)吡咯烷,其他步骤及操作类似实施例1。白色固体,收率:23%。核磁数据为1H NMR(600MHz,DMSO-d6)δ10.06(s,1H),9.87(s,1H),8.15(d,J=8.4Hz,2H),7.80(s,1H),7.76(s,1H),7.56(d,J=8.6Hz,2H),7.52(s,1H),5.33(s,2H),4.53(s,2H),3.84(dd,J=66.4Hz,4H),3.68(dd,J=124.2Hz,4H),3.22(d,J=12.8Hz,4H),3.13(s,2H),1.62(s,2H),1.47(s,2H);13C NMR(151MHz,DMSO-d6)δ169.3,165.0,163.9,161.5,153.1,141.6,142.5,140.5,132.1,129.5,127.4,121.7,119.6,118.1,114.9,69.1,65.9,63.5,60.6,45.9,26.6.HRMS(ESI)calcd.for C28H31N7O6[M+H]+:562.2414,found:562.2416。
实施例13:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((3R,5S)-3,5-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为(3R,5S)-3,5-二甲基吗啉,其他步骤及操作类似于实施例1。白色固体,收率:15%。核磁数据为1HNMR(600MHz,DMSO-d6)δ9.92(s,1H),9.67(s,1H),8.17(s,2H),7.81(s,1H),7.75(s,1H),7.64(s,2H),7.56(s,1H),5.22(s,1H),4.91(s,1H),4.69(d,J=31.4Hz,6H),3.75(s,4H),3.62(s,2H),1.89(d,J=31Hz,4H),1.29(s,6H);13C NMR(151MHz,DMSO-d6)δ169.3,166.5,161.2,160.9,153.1,142.6,142.5,140.5,132.1,128.5,127.4,121.7,119.6,118.1,114.7,71.2,69.6,69.1,55.3,47.5,26.8,20.3.HRMS(ESI)calcd.for C30H33N7O5[M+H]+:572.2621,found:572.2623。
实施例14:(4-(4-((3R,5S)-3,5-二甲基吗啉)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,其结构式如下:
合成方法:将实施例1步骤2中取代杂环片段改为(3R,5S)-3,5-二甲基吗啉,其他步骤及操作类似于实施例1。白色固体,收率:18%。1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),9.26(s,1H),8.27-8.16(m,2H),7.86(s,1H),7.69(d,J=7.2Hz,1H),7.61(s,2H),7.56(s,1H),5.38(s,2H),3.81(d,J=63Hz,4H),3.66(t,J=4.4Hz,4H),3.38(d,J=32.2Hz,4H),3.31(s,2H),1.62(s,6H);13C NMR(151MHz,DMSO-d6)δ168.3,164.6,163.5,162.1,153.1,142.6,142.5,141.5,131.1,129.3,126.5,121.6,119.8,118.1,114.7,71.2,68.9,65.1,48.5,45.6,21.7。HRMS(ESI)calcd.for C28H31N7O5[M+H]+:546.2465,found:546.2469。
实施例15:1-(4-(4-((2S,6R)-2,6-二甲基吗啉)-6-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2的取代杂环片段改为(2S,6R)-2,6-二甲基吗啉,其他步骤及操作类似实施例1。白色固体,收率:22%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),9.42(s,1H),8.34-8.25(m,2H),7.79(s,1H),7.67(d,J=7.2Hz,1H),7.60(s,2H),7.54(s,1H),5.37(s,2H),3.83(d,J=61Hz,4H),3.55(t,J=4.6Hz,4H),3.42(d,J=32.0Hz,4H),3.39(s,2H),1.71(s,6H);13C NMR(151MHz,DMSO-d6)δ169.3,164.6,163.5,162.1,153.1,142.6,142.5,141.5,131.1,128.3,126.5,122.3,119.7,117.1,114.7,72.2,68.9,65.1,46.8,42.7,20.9.HRMS(ESI)calcd.for C28H31N7O5[M+H]+:546.2465,found:546.2466。
实施例16:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,6R)-2,6-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为(2S,6R)-2,6-二甲基吗啉,其他步骤及操作类似于实施例1。白色固体,收率:28%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.82(s,1H),9.36(s,1H),8.29-8.18(m,2H),7.88(s,1H),7.76(d,J=7.2Hz,1H),7.67(s,2H),7.59(s,1H),5.35(s,2H),3.81(d,J=64Hz,4H),3.48(t,J=4.8Hz,4H),3.39(d,J=32.5Hz,2H),3.31(s,2H),1.93(s,4H),1.68(s,6H);13C NMR(151MHz,DMSO-d6)δ170.3,165.0,162.8,161.7,153.1,142.6,142.5,140.5,132.1,129.5,127.4,121.7,119.6,118.1,115.7,71.3,70.5,69.6,69.0,55.3,54.3,27.2,18.2.HRMS(ESI)calcd.for C30H33N7O5[M+H]+:572.2621,found:572.2625。
实施例17:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((S)-3-乙基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为(S)-3-乙基吗啉,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,其他步骤及操作类似于实施例1。白色固体,收率:24%。核磁数据为1HNMR(600MHz,DMSO-d6)δ9.96(s,1H),9.78(s,1H),8.12(s,1H),7.89(s,1H),7.77(s,1H),7.58(s,2H),7.51(s,1H),5.29(s,2H),4.80(s,1H),4.55(d,J=29.0Hz,6H),3.72(s,2H),3.69(s,2H),3.42(s,2H),3.07(s,1H),1.92(d,J=32Hz,4H),1.71(s,2H),1.13(s,3H);13C NMR(151MHz,DMSO-d6)δ170.3,163.8,162.4,161.8,153.1,142.6,142.5,140.5,132.1,129.5,127.4,121.7,119.8,118.1,114.8,70.7,69.6,69.1,66.1,58.0,55.3,42.9,27.3,22.8,14.4.HRMS(ESI)calcd.for C30H33N7O5[M+H]+:572.2621,found:572.2620。
实施例18:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-甲基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-甲基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:33%。核磁数据为1H NMR(600MHz,DMSO-d6)δ10.01(s,1H),9.96(s,1H),8.26(s,2H),7.91(s,1H),7.74(s,1H),7.60(s,1H),7.49(s,1H),5.33(s,1H),4.88(s,1H),4.61(d,J=30.0Hz,6H),3.86(s,4H),3.62(s,4H),1.88(d,J=33.5Hz,4H),1.78(s,3H);13C NMR(151MHz,DMSO-d6)δ169.6,164.3,163.6,161.9,153.1,147.9,143.1,140.4,132.1,129.5,125.8,122.8,119.6,118.9,112.7,77.7,69.3,65.3,55.9,46.5,27.4,21.9.HRMS(ESI)calcd.for C29H31N7O5[M+H]+:558.2465,found:558.2469。
实施例19:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-异丙基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:19%。核磁数据为1H NMR(600MHz,DMSO-d6)δ10.04(s,1H),9.87(s,1H),8.19(s,2H),7.89(s,1H),7.73(s,1H),7.59(s,1H),7.51(s,1H),5.67(s,1H),4.82(s,1H),4.55(d,J=28.0Hz,6H),3.78(s,4H),3.67(s,4H),2.69(s,1H),1.89(d,J=32Hz,4H),1.34(s,6H);13C NMR(151MHz,DMSO-d6)δ170.2,164.4,163.6,161.9,153.1,146.5,143.0,140.4,132.1,129.5,125.1,122.1,119.6,118.7,113.5,86.1,69.2,65.9,55.8,44.9,31.0,26.5,20.0.HRMS(ESI)calcd.for C31H35N7O5[M+H]+:586.2778,found:586.2775。
实施例20:1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-环丙基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:25%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),9.65(s,1H),8.31(s,2H),8.09(s,1H),7.89(s,1H),7.70(s,1H),7.61(s,1H),5.76(s,1H),4.89(s,1H),4.57(d,J=30.0Hz,6H),3.91(s,4H),3.72(s,4H),2.11(d,J=33.5Hz,4H),1.55(s,1H),1.17(s,2H),1.12(s,2H);13C NMR(151MHz,DMSO-d6)δ171.2,166.3,162.6,161.9,153.1,146.3,143.0,140.4,132.1,128.3,126.0,123.9,119.6,116.7,114.3,82.6,69.2,65.9,55.8,44.4,26.5,17.9,6.2.HRMS(ESI)calcd.for C31H33N7O5[M+H]+:584.2621,found:584.2625。
实施例21:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-乙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-乙基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:28%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.68(s,1H),9.34(s,1H),8.31(s,2H),7.99(s,1H),7.81(d,J=8.2Hz,1H),7.66(d,J=8.4Hz,2H),7.57(s,1H),5.78(s,1H),4.79(s,2H),4.60(s,2H),3.61(s,8H),2.27(s,2H),1.98(s,4H),1.82(s,4H),1.34(s,3H);13C NMR(151MHz,DMSO-d6)δ168.6,165.0,160.8,153.1,145.3,142.8,140.4,132.1,129.5,125.8,124.9,119.6,118.7,112.9,82.0,68.8,55.8,27.4,27.1,11.9.HRMS(ESI)calcd.forC32H35N7O5[M+H]+:598.2778,found:598.2776。
实施例22:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-环丙基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:22%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),9.69(s,1H),8.28(s,2H),7.96(s,1H),7.87(d,J=8.3Hz,1H),7.63(d,J=8.2Hz,2H),7.57(s,1H),5.71(s,1H),4.79(s,2H),4.60(s,2H),3.83(s,8H),2.12(s,4H),1.96(s,4H),1.27(s,1H),1.15(s,2H),1.09(s,2H);13C NMR(151MHz,DMSO-d6)δ170.2,165.7,160.8,153.1,146.3,143.0,140.4,132.1,129.5,126.0,124.0,119.6,118.7,113.3,84.6,69.2,55.8,27.4,13.7,8.8.HRMS(ESI)calcd.for C33H35N7O5[M+H]+:610.2778,found:610.2775。
实施例23:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤4中缩合杂环片段改为5-氨基-3-异丙基异苯并呋喃-1(3H)-酮,其他步骤及操作类似于实施例1。白色固体,收率:35%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),9.71(s,1H),8.25(s,2H),7.86(s,1H),7.76(d,J=8.5Hz,1H),7.61(d,J=8.1Hz,2H),7.51(s,1H),5.73(s,1H),4.75(s,2H),4.64(s,2H),3.81(s,8H),2.83(s,1H),2.21(s,4H),2.06(s,4H),1.19(s,6H);13CNMR(151MHz,DMSO-d6)δ170.3,165.7,160.8,153.1,146.5,143.0,140.4,132.1,129.5,126.1,124.0,119.6,118.7,114.9,86.1,69.2,56.9,30.9,27.5,19.8.HRMS(ESI)calcd.for C33H37N7O5[M+H]+:612.2934,found:612.2936。
实施例24:1-(4-(4-吗啉-6-硫吗啉-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为硫吗啉,其他步骤及操作类似于实施例1。白色固体,收率:48%。核磁数据为1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),9.26(s,1H),8.17(d,J=8.3Hz,2H),7.87(s,1H),7.74(d,J=8.2Hz,1H),7.61(d,J=8.4Hz,2H),7.48(d,J=8.1Hz,1H),5.37(s,2H),3.92(s,8H),3.59(s,8H);13C NMR(151MHz,DMSO-d6)δ170.7,168.1,165.0,164.2,153.1,142.8,142.6,140.4,132.1,129.5,127.4,121.9,119.6,118.1,115.7,69.1,65.9,48.1,46.7,28.2.HRMS(ESI)calcd.for C26H27N7O4S[M+H]+:534.1923,found:534.1925。
实施例25:1-(4-(4-(3-氧杂-8-氮杂双环[3.1.1]庚烷-6-基)-6-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为3-氧杂-8-氮杂双环[3.1.1]庚烷,其他步骤及操作类似于实施例1。白色固体,收率:38%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.43(s,1H),9.16(s,1H),8.13(s,2H),7.94(s,1H),7.83(d,J=8.8Hz,1H),7.63(d,J=8.2Hz,2H),7.57(s,1H),5.32(s,2H),4.78(s,2H),4.64(s,2H),3.73(s,8H),1.94(s,2H),1.83(s,4H);13C NMR(151MHz,DMSO-d6)δ170.7,168.7,161.2,159.4,153.0,142.8,142.6,140.4,139.2,130.6,128.9,127.4,121.9,119.9,118.1,116.8,115.7,69.2,69.1,68.1,55.8,54.7,33.2,28.9,22.4.HRMS(ESI)calcd.for C29H29N7O5[M+H]+:556.2308,found:556.2305。
实施例26:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为8-氧杂-5-氮杂螺环[3.5]壬烷,其他步骤及操作类似于实施例1。白色固体,收率:24%。核磁数据为1H NMR(600MHz,DMSO-d6)δ10.01(s,1H),9.88(s,1H),8.29–8.17(m,2H),7.93(s,1H),7.80(d,J=7.2Hz,1H),7.68(s,2H),7.57(s,1H),5.38(s,2H),3.93(d,J=66Hz,2H),3.76(s,2H),3.61(t,J=4.0Hz,2H),3.57(s,2H),3.48(d,J=31.0Hz,2H),3.36(s,2H),1.96(s,4H),1.71(s,2H),1.69(s,2H),1.60(s,1H),1.54(s,1H);13C NMR(151MHz,DMSO-d6)δ170.7,166.8,163.0,161.6,153.1,142.8,142.6,140.4,132.1,128.3,127.4,121.9,119.6,118.1,116.8,71.6,69.2,69.1,66.5,64.0,58.0,43.0,32.9,28.9,18.8.HRMS(ESI)calcd.for C31H33N7O5[M+H]+:584.2621,found:584.2623。
实施例27:1-(4-(4-吗啉-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤2中取代杂环片段改为8-氧杂-5-氮杂螺环[3.5]壬烷,其他步骤及操作类似于实施例1。白色固体,收率:45%。核磁数据为1H NMR(600MHz,DMSO-d6)δ9.79(s,1H),9.37(s,1H),8.12–8.03(m,2H),7.73(s,1H),7.68(d,J=6.8Hz,1H),7.61(s,2H),7.44(s,1H),5.29(s,2H),3.71(d,J=61Hz,2H),3.66(s,2H),3.52(t,J=4.3Hz,2H),3.47(s,2H),3.39(d,J=35.0Hz,2H),3.21(s,2H),1.73(s,2H),1.68(s,2H),1.63(s,1H),1.46(s,1H);13C NMR(151MHz,DMSO-d6)δ170.8,166.9,165.5,162.1,153.1,142.8,142.6,140.4,132.1,129.5,127.4,121.9,119.6,118.1,115.7,71.6,69.1,66.5,65.9,64.0,46.7,36.9,32.7,19.4.HRMS(ESI)calcd.for C29H31N7O5[M+H]+:558.2465,found:558.2467。
实施例28:1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲,结构式如下:
合成方法:将实施例1中步骤1中取代杂环片段改为3-氧杂-8-氮杂双环[3.2.1]辛烷,步骤2中取代杂环片段改为2,5-双(羟甲基)吡咯烷,其他步骤及操作类似于实施例1。白色固体,收率:17%。核磁数据为1HNMR(600MHz,DMSO-d6)δ10.07(s,1H),9.77(s,1H),8.19(d,J=8.3Hz,2H),7.91(s,1H),7.82(s,1H),7.64(d,J=8.1Hz,2H),7.38(s,1H),5.41(s,2H),4.67(s,2H),3.90(dd,J=66.4Hz,4H),3.76(dd,J=124.2Hz,4H),3.41(d,J=11Hz,2H),3.16(s,2H),1.93(s,2H),1.53(s,2H),1.42(s,2H),1.38(s,2H);13C NMR(151MHz,DMSO-d6)δ170.4,166.6,161.3,161.2,153.1,142.6,142.5,140.5,133.1,129.5,127.4,121.7,119.6,118.1,115.7,69.6,69.1,63.7,60.6,54.4,32.2,30.7.HRMS(ESI)calcd.forC30H33N7O6[M+H]+:588.2571,found:588.2576。
通过以下实验来说明本发明通式(I)代表的化合物所具有的有益效果和应用。
体外mTOR激酶抑制测试:
本发明化合物抑制mTOR激酶活性,由此抑制细胞信号通路的转导,从而影响细胞周期和细胞增殖。此类化合物对mTOR激酶的抑制作用通过下述Lance Ultra荧光试验方法评价。
检测原理:Lance Ultra荧光试验是一种均质的非放射性的检测方法,它是通过检测激酶反应后体系中ATP的含量来定量测定纯化激酶的活性。ATP含量的测定是通过由Mg2+、ATP和氧催化萤火虫荧光素(beetle luciferin)发生氧化后产生的光强度来定量的。在反应体系中加入一定量的ATP,激酶反应需要消耗ATP,剩余的ATP可以与Kinase Glo试剂中的萤火虫荧光素酶发生反应后发光,从而可以定量检测剩余的ATP的量,间接测定反应激酶的活性。
检测方法:首先准备好1×kinase buffer,其中含有50mM HEPES,PH 7.5,1mMEGTA,0.01%Tween-20;用100%DMSO对化合物溶解并进行梯度稀释,转移10nL稀释后的化合物到检测板中,同时配制不含化合物的Control组和不含激酶的空白对照组。1×kinasebuffer加入mTOR配制激酶溶液,取5μL加入到检测板中涡旋混匀。另外准备1×kinasereactionbuffer含有4E-BP1(Thr 37/46,PE)多肽以及ATP底物,取5μL加入到孔板启动来反应,在室温条件下反应1h后,将含EDTA和Eu-anti-P-4E-BP1(Thr 37/46,PE)抗体PBS缓冲液,取10μL加入到孔板中,室温条件下孵育60min,对孔板进行读数并统计数据计算化合物对mTOR激酶的抑制率。将抑制率和相对应的浓度代入GraphPadPrism软件进行曲线拟合,计算出IC50值。
细胞活性实验:
通过MTT比色法进行细胞抗增殖活性检测。MTT是一种黄色的盐,化合物名称是3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐。MTT作用于活细胞线粒体中的呼吸链,由于死细胞中琥珀酸脱氢酶消失,不能将MTT还原,因此,MTT是用来检测细胞存活、生长的基本方法。
MTT比色法原理:以活细胞代谢物为还原剂,MTT噻唑蓝为颜色对比。MTT在琥珀酸脱氢酶和细胞色素C的作用下tetrazolium环开裂,还原生成的甲臜formazan结晶可在含50%的N,N-二甲基甲酰胺和20%的十二甲基磺酸钠(pH=4.7)的MTT溶解液中溶解。然后通过多功能酶标仪温度设置为37℃,在490nm波长处测定96孔板每孔的光吸收值,可间接反映活细胞数量。在一定活细胞数量范围内,形成蓝紫色晶体甲臜的量与活细胞数呈正相关。细胞生长抑制率可以用下面的公式计算:
其中OD实验、OD对照与OD空白分别表示给药组的平均吸光度、对照组的平均吸光度和空白组的平均吸光度。分析软件:GraphPadPrism。
实验方法:于96孔板中培养细胞,在5%CO2细胞培养箱中37℃孵育24小时,向96孔板中加入递增浓度的化合物并与细胞孵育48小时,总体积为20μLMTT每孔加入(2.5mg/mL),孵育4h,然后除去培养基,向孔中加入120μLDMSO溶解甲臜晶体,用酶标仪在490nm处测定吸光度值,使用GraphPadPrism 8.4.2软件计算IC50,并将上述化合物在MCF-7癌细胞上进行体外细胞抗增殖活性检测。
激酶试验结果见表1,从下表1中活性数据可知,本发明所述化合物均可有效抑制mTOR激酶,对其具有较好的抑制活性,即大多化合物mTOR激酶的抑制活性(IC50)均在纳摩尔水平(1-999nm),且与Ⅲ期临床候选药物PF-05212384相比,本发明中多个化合物具有优于阳性对照PF-05212384的mTOR抑制活性,如实施例1、实施例2、实施例4、实施例5、实施例8、实施例11、实施例13、实施例14、实施例18、实施例20、实施例21、实施例25和实施例26。为了验证化合物对mTOR的选择性,挑选了5个mTOR激酶抑制活性优异的化合物进行PI3K各亚型激酶抑制活性测试,结果见表2所示,与PF-05212384相比,5个化合物均对mTOR具有较好的选择性,其中实施例1、实施例2和实施例4对PI3K各亚型激酶抑制活性呈中等程度,实施例5对PI3K各亚型激酶抑制活性较弱(PI3Kα:354nM,PI3Kβ:782nM,PI3Kγ:1943nM,PI3Kδ:1829nM),对mTOR的抑制活性为1.7nM,具有一定的mTOR选择性。值得注意的是,实施例8对PI3K各亚型抑制活性显著降低(>10μM),而其mTOR抑制活性1.2nM,是高度选择性的mTOR抑制剂。在MCF-7癌细胞上测试化合物的抗增殖活性结果如表2所示,大多数化合物对MCF-7癌细胞均显示出优于PF-05212384的高抗癌活性。值得注意的是,对mTOR激酶具有高抑制活性的化合物对MCF-7癌细胞也显示出高抗癌活性,特别是实施例1、实施例5、实施例8、实施例13和实施例14,其抗MCF-7癌细胞增殖活性均小于1uM。以上结果表明,本发明所述化合物具有积极且可预见的抗增殖性疾病,尤其是抗肿瘤的临床应用价值,并具有很好的开发前景。
表1目标化合物mTOR激酶体外抑制活性
表2所选化合物对I类PI3Ks的活性
表3目标化合物对MCF-7细胞的抗增殖活性
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种二芳基脲类mTOR激酶抑制剂,其特征在于,包括具有通式(Ⅰ)的取代三嗪类化合物,其立体异构体,水合物或药学上可接受的盐,所述通式(Ⅰ)结构如下:
其中,所述通式(Ⅰ)中:X选自H、C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C4-C7杂环基、含一个或多个取代基的C4-C7杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基;X上所述的取代基选自氟、氯、溴、碘、羟基、氨基、酰胺、羧酸、羧酸酯、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基;
R1和R2分别选自H、C1-C4烷基、含一个或多个取代基的C1-C4烷基、C1-C4烷氧基、含一个或多个取代基的C1-C4烷氧基、C1-C4烷基酰基、C1-C4烷基磺酰基、C3-C6杂环基、含一个或多个取代基的C3-C6杂环基、C4-C8稠合杂双环基或含一个或多个取代基的C4-C8稠合杂双环基;R1或R2上所述取代基选自氟、氯、溴、碘、羟基、氨基、氰基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、羟基C1-C4烷氧基或C1-C4烷氧基C1-C4烷基。
3.根据权利要求1所述的二芳基脲类mTOR激酶抑制剂,其特征在于,所述的水合物或药学上可接受的盐,是指取代三嗪类化合物药学上可接受的盐,包括母体化合物中的碱性基团转换成盐的形式、碱性基团与酸成盐的形式,以及溶剂化物或水合物的形式。
4.根据权利要求1所述的二芳基脲类mTOR激酶抑制剂,其特征在于,包括如下结构中的任一:
(1)(S)-1-(4-(4-(3-甲基吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(2)(R)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(3)1-(4-(4-(4-(二甲基氨基)哌啶-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(4)(S)-1-(4-(4-(2-(羟甲基)吗啉代)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(5)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(6)1-(4-(4-(8-氧杂-3-氮杂双环[3.2.1]辛烷-3-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(7)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((R)-3-甲基吗啉基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(8)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(9)1-(4-(4-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(10)1-(4-(4-吗啉代-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(11)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(2,2-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(12)1-(4-(4-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(13)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((3R,5S)-3,5-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(14)1-(4-(4-((3R,5S)-3,5-二甲基吗啉)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(15)1-(4-(4-((2S,6R)-2,6-二甲基吗啉)-6-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(16)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,6R)-2,6-二甲基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(17)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((S)-3-乙基吗啉)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(18)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-甲基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(19)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(20)1-(4-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-吗啉代-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(21)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-乙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(22)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-环丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(23)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基)-3-(3-异丙基-1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(24)1-(4-(4-吗啉-6-硫吗啉-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(25)1-(4-(4-(3-氧杂-8-氮杂双环[3.1.1]庚烷-6-基)-6-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-1,3,5-三嗪-2-基)苯基-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(26)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(27)1-(4-(4-吗啉-6-(8-氧杂-5-氮杂螺环[3.5]壬烷-5-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲;
(28)1-(4-(4-((1R,5S)-3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-((2S,5R)-2,5-双(羟甲基)吡咯烷-1-基)-1,3,5-三嗪-2-基)苯基)-3-(1-氧代-1,3-二氢异苯并呋喃-5-基)脲。
5.一种药物组合物,包含至少一种药学上可接受的辅料、辅助剂或载体,以及有效治疗剂量的至少一种权利要求1-4中的二芳基脲类mTOR激酶抑制剂。
6.一种根据权利要求1-4任意一项所述的二芳基脲类mTOR激酶抑制剂或根据权利要求5所述的药物组合物在制备用于预防和/或治疗和/或辅助治疗mTOR激酶过度活化引起的增殖性疾病、代谢性疾病、神经系统性疾病及结节性硬化症疾病的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述增殖性疾病包括结直肠癌、胃癌、乳腺癌、肺癌、肝癌、前列腺癌、胰腺癌、甲状腺癌、膀胱癌、肾癌、脑瘤、颈癌、CNS癌症、恶性胶质瘤、骨髓增生病、白血病或淋巴癌。
8.一种根据权利要求1-4任意一项所述的二芳基脲类mTOR激酶抑制剂或根据权利要求5所述的药物组合物在制备用于体外抑制癌症细胞生长的药物中的应用。
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