CN116693551A - 二氢吡唑氮杂卓类化合物、含其的药物组合物及其在抗肿瘤中的应用 - Google Patents
二氢吡唑氮杂卓类化合物、含其的药物组合物及其在抗肿瘤中的应用 Download PDFInfo
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- CN116693551A CN116693551A CN202210187178.6A CN202210187178A CN116693551A CN 116693551 A CN116693551 A CN 116693551A CN 202210187178 A CN202210187178 A CN 202210187178A CN 116693551 A CN116693551 A CN 116693551A
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- Prior art keywords
- piperidin
- carboxamide
- compound
- thieno
- difluorophenyl
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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Abstract
本发明公开了一种二氢吡唑氮杂卓类化合物、含其的药物组合物及其在抗肿瘤中的应用,所述二氢吡唑氮杂卓类化合物结构如式I所示。本发明发明人通过多次实验证实,本发明化合物对AKT1有显著的抑制作用,对小鼠神经母细胞瘤细胞Neuro2a等肿瘤细胞株显示出强效的抗增殖作用和促Neuro2a等细胞株强效的诱导分化作用。因此本发明化合物可作为诱导分化调节剂和(或)AKT抑制剂应用于治疗人或动物细胞增殖性相关和分化异常相关的实体瘤或血癌的药物中。
Description
技术领域
本发明涉及药物领域,具体设计作为AKT抑制剂的二氢吡唑氮杂卓类化合物、含其的药物组合物及其在诱导分化和抗肿瘤中的应用。
背景技术
Akt即蛋白激酶B作为一个极有潜力的抗肿瘤靶点而备受关注。Akt处于PI3K/Akt信号转导通路的核心部位,Akt家族的成员有Aktl、Akt2、Akt3三个亚型,具有80%以上的序列同源性,研究发现Akt不同的亚型在结构和功能方面均高度一致,只是在不同的肿瘤中表达的水平有所不同。Akt可直接磷酸化mTOR、Bad和Caspase9蛋白,以及调节ForkHead转录因子家族和NF-κB进而控制转录、翻译、代谢、细胞凋亡、血管新生等众多在肿瘤发生发展过程中至关重要的细胞生物学过程。研究还发现在多数肿瘤中存在Akt过度表达或活性失调的现象,Akt异常与这些肿瘤的发生、发展以及对化疗、放疗产生耐受密切相关,体内和体外药理实验均证明Akt抑制剂可促进癌细胞的程序性死亡。
肿瘤细胞分化异常是肿瘤发生发展的重要过程之一。诱导分化(induction ofdifferentiation)是指恶性肿瘤细胞在体内外分化诱导剂作用下,向正常或接近正常细胞方向分化逆转,从而逆转肿瘤恶性表型的治疗方法。有效的分化诱导剂的发现将改变以往杀伤肿瘤细胞为主的治疗模式,而形成以控制、调整其生物学行为为主的新疗法,最终实现肿瘤的治愈。近20多年来,已发现具有分化作用的化合物达百种以上,其中相当一部分已进入I期、II期临床试验,少数如维甲酸类(RA)、砷剂、γ干扰素(IFN-γ)、神经生长因子(NGF)等已作为分化诱导剂用于临床肿瘤治疗和预防,显示出一定疗效,因此分化诱导剂的研究和应用为肿瘤药物及其药理学研究开辟了一条广阔的途径。近年来,靶向药物在肿瘤分化方面的治疗作用日益突出。Akt在肿瘤分化相关信号通路中占据关键节点,其抑制剂可能具有诱导肿瘤细胞分化的功能。
综上,以AKT抑制剂切入,开发兼具诱导分化治疗作用和增殖抑制作用的小分子药物,有望为肿瘤治疗提供全新作用机制的临床药物。
发明内容
本发明的目的是提供一种抗癌作用强、诱导分化作用强且具有AKT抑制作用的新型二氢吡唑氮杂卓类化合物及其光学异构体或其药学上可接受的盐或溶剂合物。
术语说明:本文所用术语“芳基”是指5到12个碳原子的全碳单环或稠合多环基团,具有完全共轭电子系统。芳环的非限制性实例有:苯环、萘环和蔥环。芳环可以是无取代或取代的。芳环的取代基选自卤素、硝基、氨基、氰基、羟基、Cl~C6烷基、Cl~C6烷氧基、卤代Cl~C6烷基、卤代Cl~C6烷氧基、C3~C6环烷基、卤代C3~C6环烷基。
本文所用术语“杂环芳基”指5到12个碳原子的不饱和的碳环,具有完全共轭电子系统,相当于上述“芳基”中的一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环,也可以是双环,即通过两个环稠合而成。具体的杂环芳基可以是:吡啶基,嘧啶基,吡嗪基,异噁唑基,异噻唑基、吡唑基、噻唑基、噁唑基和咪唑基等。杂环芳基可以是无取代或取代的。杂环芳基的取代基选自卤素、硝基、氨基、氰基、羟基、Cl~C6烷基、Cl~C6烷氧基、卤代Cl~C6烷基、卤代Cl~C6烷氧基、C3~C6环烷基、卤代C3~C6环烷基。
本文所用术语“杂环烷基”指单环或稠合环基团,在环中具有5到9个环原子(基连接成环的原子),其中一个或两个环原子是选自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枙的π电子系统。杂环可以是无取代或取代的。取代的杂环烷基可以是吡咯烷基、哌啶基、哌嗪基、吗啉代基、硫代吗啉代基、高哌嗪基等。杂环的取代基选自卤素、硝基、氨基、氰基、羟基、Cl~C6烷基、Cl~C6烷氧基、卤代Cl~C6烷基、卤代Cl~C6烷氧基、C3~C6环烷基、卤代C3~C6环烷基。
本文所用术语“环烷基”是指具有3~6个碳原子的饱和单环碳环,除非指明不同数目的原子。环烷基包括例如环丙基、环丁基、环戊基、环已基、环庚基和环辛基。“环烷基”还包括取代环烷基。环烷基还可任选在任何可利用碳上被一个或多个选自烷氧基、卤素和卤代烷基,如全氟烷基的取代基取代。
本文所用术语“烷基”是指具有1~6个碳原子的烷基。包括但不限于甲基、乙基、丙基、异丙基、丁基、戊基、庚基。取代基选自卤素、硝基、氨基、氰基、羟基、Cl~C6烷基、Cl~C6烷氧基、卤代Cl~C6烷基、卤代Cl~C6烷氧基、C3~C6环烷基、卤代C3~C6环烷基。
本文所用术语“烷氧基”是指-O-烷基基团,其中烷基如上所定义。本文所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基。烷氧基可被卤素取代一次或多次。
本文所用术语“卤素”表示氟、氯、溴或碘,优选为氟或氯或溴。
术语“药学可接受衍生物”是指所选化合物的盐和溶剂合物。
本文所用术语“溶剂合物”是指由溶质(例如:本发明的通式(I)~通式(VI)化合物)和溶剂形成的可变化学计量的复合物。为了本发明的目的,所述溶剂不能干扰溶质的生物学活性。合适的溶剂的实例包括但不限于水、甲醇、乙醇和乙酸。优选使用的溶剂为药学可接受溶剂。合适的药学可接受溶剂包括但不限于水、乙醇和乙酸。更优选地,所用溶剂为水。
本发明采用如下的技术方案:
本发明所提供的取代哌啶-杂卓类衍生物具有通式(I)结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,
其中:
环A选自无取代或取代的五元或六元芳基,包含1~4个选自O、N、S的五元或六元杂环芳基;
R1选自无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的环烷基、无取代或取代的饱和或不饱和的杂环烷基,任意稠和的芳基、杂环芳基;
R2选自氨基、氰基、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、烯烃取代烷基、C1~C4羰基氧基、卤代的C1~C4烷氧基、 其中n=0-4的整数,Rd选自H、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基、Re选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基、环D选自无取代或取代的五元~八元饱和或不饱和的脂肪含氮杂环、无取代或取代的五元~八元含N杂芳基,所述杂环基、杂芳基中碳原子可以进一步被O、S取代;
R3选自H、卤素、羟基、羟甲基,羟乙基基、羧基、饱和或不饱和的C1~C4烃基、卤代的C1~C4烷基,C1~C4烷氧基、卤代的C1~C4烷氧基、无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的饱和或部分饱和的杂环、无取代或取代的环烷基;
R4选自H、卤素、硝基、氨基、氰基、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基;
m=0-3的整数;
X选自O、NH、S、C(=O);
Y选自碳(CH2)、C(=O)、磺酰基;
所述取代的取代基选自卤素、硝基、氨基、氰基、羟基、C1~C3烷基、卤代的C1~C3烷基、C1~C3烷氧基、卤代的C1-C3烷氧基。
进一步地,本发明优选的化合物具有通式(II)、(II’)所示的结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,
其中:
(R1R2R3R4XYm)如通式(I)结构所定义;
E选自(O,S,NH,NH和NCH3);
T选自CH和N。
更进一步地,本发明优选的化合物具有通式(III)结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,
其中:
R1、R2、R3、R4、X、Y、m如通式(I)结构所定义。
更进一步地,本发明优选的化合物具有通式(IV)结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,
其中:
R1、R2、R3、X、Y如通式(I)结构所定义;
E优选为S。
作为进一步优选,所述X为O或CH;Y为CH2;
所述R1选自取代苯基;取代基为一个或多个卤素(进一步优选为一个或多个F、Cl、Br)、卤代C1~C3烷基(甲基、乙基、丙基或异丙基);
所述R2选自H、3-(二甲基氨基)丙基、烯丙基、3-(1H-咪唑-1-基)丙基、3-羟丙基、3-(吡咯烷-1-基)丙基、3-(哌啶-1-基)丙基、3-吗啉代丙基、3-(4-羟基哌啶-1-基)丙基、2-(甲基氨基)-2-氧代乙基;
所述R3选自H、卤素、C1~C5烷基(优选为甲基、乙基、丙基或异丙基);
所述R3选自H;E为S。
更具体地,本发明通式(IV)结构的优选化合物为:
10-溴-N-(((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑啉[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S)-4-(4-氯苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S)-4-(4-氯-3-三氟甲基苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S)-4-(3-氯-4-三氟甲基苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-氯-N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
1-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
1-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
1-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
1-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
1-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
1-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(二甲基氨基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S,6R)-6-烯丙基-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S,6R)-6-(3-(1H-咪唑-1-基)丙基)-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-羟丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(吡咯烷-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-吗啉代丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(4-羟基哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-氯-N-(((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-乙基-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-(2-羟乙基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
10-溴-N-(((3R,4R)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-羧酰胺
10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-羧酰胺
10-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-羧酰胺
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-甲基-5,6-二氢吡唑并[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺
及其上述化合物的光学异构体或其药学上可接受的盐或溶剂合物。
更具体地,本发明通式(IV)结构的优选化合物为:
另外,本发明优选的化合物具有通式(V)的结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,
其中:
R1、R2、R3、R4、X、Y如通式(I)结构所定义;
更进一步地,本发明优选的化合物具有通式(VI)结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,其中:
R1、R2、R3、X、Y如通式(I)结构所定义;
更具体地,本发明通式(VI)结构的优选化合物为;
1-氯-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺
N-(((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺
N-(((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺
N-(((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺
N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺
及其上述化合物的光学异构体或其药学上可接受的盐或溶剂合物。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述的取代哌啶类-氮杂环类化合物的盐。所述的盐可以是有机酸盐、无机酸盐等,所述的有机酸盐包括枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等;所述的无机酸盐包括氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如,与低级烷基磺酸,如甲磺酸,三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐;与芳基磺酸,如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐,苯磺酸盐;与有机羧酸,如乙酸,富马酸,酒石酸,草酸,马来酸,苹果酸,琥珀酸或柠檬酸等可形成相应的盐;与氨基酸,如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸,如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸),硝酸,碳酸,硫酸或磷酸等也可形成相应的盐。
本发明的第二个目的是提供一种药物组合物,所述药物组合物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分可以是本发明的取代哌啶类-氮杂环类化合物、所述化合物的光学异构体,所述化合物或其光学异构体在药学上可接受的盐、所述化合物或其光学异构体的溶剂合物中的任意一种或任意多种。
所述载体包括药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。本发明药物可以制成片剂,粉剂,粒剂,胶囊,口服液及注射用药等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明还提供通式(I)-通式(VI)所述的化合物、及其光学异构体或其药学上可接受的盐或溶剂合物在制备抗肿瘤药物中的用途。所述的肿瘤为成神经细胞瘤、乳腺癌、肉瘤、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、血癌、神经胶质瘤、头癌、颈癌、甲状腺癌、胰癌、肝癌、卵巢癌、外阴癌子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质癌、皮肤癌、多发性骨髓瘤。
本发明还提供了制备通式(I)及其药学可接受衍生物的方法,通过化合物的两个主要组分,本文称为化合物的胺片段,酸片段的反应来制备通式(I)化合物,部分通式(I)化合物的合成路线如下:
每种通式(I)化合物都可方便地通过分开制备所述化合物的两种构建体,然后再将这些组分组合形成通式(I)化合物。为了方便所述两种构建体在本文中被称为胺片段、酸片段,当在文中以胺片段/酸片段组合出现时,也是指相应的部分。
本发明化合物的酸片段为以通式(VII)为代表的(三元并环芳基)甲酸化合物:
本发明化合物的胺片段为以通式(VIII)为代表的含保护基团取代哌啶化合物:
化合物酸片段(VII)和胺片段(VIII)以如下方案所示的合成路线组合:
其中,PG为常见的胺基保护基,如:Boc(叔丁氧羰基),Cbz(苄氧羰基),Ac(乙酰基)等。
更具体地,以通式(II)和通式(V)为代表进行说明。
本发明通式(II)和通式(V)的酸为以通式中心(i-1)和中心(i-2)为代表的三元并环、五元或六元芳基甲酸化合物:
其中E、T如通式(II)结构所定义,即E选自(O,S,NH,NH和NCH3),T选自CH和N。
其中R3、R4、X、Y、m如通式(I)结构所定义,即:R3选自H、卤素、羟基、羟甲基、羧基、饱和或不饱和的C1~C4烷基、卤代的C1~C4烷基,C1~C4烷氧基、卤代的C1~C4烷氧基、无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的饱和或部分饱和的杂环、无取代或取代的环烷基;R4选自H、卤素、硝基、氨基、氰基、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基;m=0-3的整数;X选自O、N、S、碳;Y选自碳基、磺酰基、碳等。
本发明化合物的胺片段部分为以通式胺片段(ii)为代表的Boc保护的取代哌啶化合物
其中取代基R1、R2如通式(I)结构所定义,即:R1选自无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的环烷基、无取代或取代的饱和或不饱和的杂环烷基,任意稠和的芳基、杂环芳基,
R2选自氨基、氰基、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、C1~C4羧基、卤代的C1~C4烷氧基、 其中n=0-4的整数,Rd选自H、
C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基、Re选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基、环D选自无取代或取代的五元~八元饱和或不饱和的脂肪含氮杂环;
化合物通式酸片段(i)和胺片段(ii)以如下方案所示的合成路线组合
如上述合成路线所示,将通式酸片段(i)与通式胺片段(ii)在缩合剂(EDCI)作用下得到的产物经过酸性条件脱Boc保护,即得到通式(II)和通式(V)化合物。
通式(III)、通式(IV)和通式(VI)化合物的制备方法参照通式(II)和通式(V)化合物的制备方法。
本发明还提供本发明所述的化合物及其光学异构体或其药学上可接受的盐或溶剂合物在制备AKT抑制剂中的应用,特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之,本发明提供取代哌啶类-氮杂环类化合物或其可药用盐单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类:有丝分裂抑制剂(如长春碱、长春地辛和长春瑞宾);微管蛋白分解抑制剂(如泰素);烷基化试剂(如顺铂、卡铂和环磷酰胺);抗代谢物(5-氟尿嘧啶、替如氟、甲氨蝶呤、阿糖胞苷和羟基脲);可插入抗生素(如阿雷素、丝裂霉素和争光霉素);酶(如天门冬氨酶);拓扑异构酶抑制剂(如依托伯苷和喜树碱);生物反应调节剂(如干扰素);蛋白酶体抑制剂(如硼替佐米)。
本发明发明人通过多次实验证实,本发明化合物对AKT1有显著的抑制作用,对小鼠神经母细胞瘤细胞Neuro2a等肿瘤细胞株显示出强效的抗增殖作用和促Neuro2a等细胞株强效的诱导分化作用。因此本发明化合物可作为诱导分化调节剂和(或)AKT抑制剂应用于治疗人或动物细胞增殖性相关和分化异常相关的实体瘤或血癌的药物中。
附图说明
图1为未给药组Neuro2a的促分化图;
图2为化合物1对Neuro2a的促分化图。
具体实施方式
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1.中间体1~3的合成
步骤1.化合物1-2的合成
将5-氯-2-酰氯噻吩(1.00g,5.52mmol)溶于10.0mL四氢呋喃中,依次加入三乙胺(587mg,5.81mmol)和乙二醇单叔丁基醚(686mg,5.80mmol),室温反应4h。TLC薄层层析监测反应完毕后,将反应液倒入水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得浅黄色油状物体1.21g目标产物(化合物1-2),收率83.7%;1H NMR(400MHz,CDCl3)δ7.60(d,J=4.0Hz,1H),6.93(d,J=4.0Hz,1H),4.40-4.32(m,2H),3.69-3.61(m,2H),1.21(s,9H).ESI-MS:m/z=285.0[M+Na]+.
步骤2.化合物1-3的合成
将60%的NaH(274mg,6.85mmol)混悬于10.0mL无水DMF(N,N-二甲基甲酰胺)中,氮气保护下,依次加入乙二醇单叔丁基醚(800mg,6.77mmol)和化合物1-2(1.20g,4.56mmol)。加热至60℃,反应2h。TLC检测反应完全后将反应液倒入200mL水中,用乙酸乙酯萃取三次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析快速纯化得浅黄色油状物体594mg,目标产物(化合物1-3),收率37.5%;1HNMR(400MHz,CDCl3)δ7.53(d,J=4.2Hz,1H),6.24(d,J=4.3Hz,1H),4.36-4.29(m,2H),4.22–4.15(m,2H),3.71(dd,J=5.7,4.3Hz,2H),3.67–3.60(m,2H),1.22(s,9H),1.21(s,9H).ESI-MS:m/z=345.2[M+H]+
步骤3.化合物1-4的合成
将化合物1-3(590mg,1.72mmol)溶于10.0mL甲醇中,氮气保护下,加入50%甲醇钠的甲醇溶液(204mg,1.88mmol)。加热回流,反应2h。冷却至室温后,将反应液倒入水中,用乙酸乙酯萃取三次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析快速纯化得无色油状物体430mg目标产物化合物1-4,收率97%;ESI-MS:m/z=259.1[M+H]+.
步骤4.化合物1-5的合成
将化合物1-4(439mg,1.70mmol)溶于10.0mL四氢呋喃中,加入NBS(N-溴代琥珀酰亚胺,363mg,2.04mmol)。室温反应1h后TLC薄层(色谱)层析监测反应完毕后,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得淡黄色油状液体(516mg,1.53mmol)化合物1-5,收率90.0%,ESI-MS:m/z=359.0[M+Na]+.
步骤5.化合物1-6的合成
将化合物1-5(4.70g,14.0mmol),3-(4,4,5,5-四甲基-1,3,2-二恶英-2-基)-1H吡唑(3.00g,15.5mmol)溶于二氧六环(50.0mL)和水(12.0mL)的混合溶液中,氮气保护下,加入碳酸氢钠(3.00g,35.7mmol)和二(三叔丁基膦)钯(1.00g,1.96mmol),加热至86℃,反应1h。TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得淡黄色固体(3.11g,9.60mmol)化合物1-6,收率68.6%。1HNMR(400MHz,CDCl3)δ7.83(s,1H),7.62(d,J=2.0Hz,1H),6.48(d,J=1.9Hz,1H),4.41–4.33(m,2H),3.88(s,3H),3.84–3.76(m,2H),1.31(s,9H).ESI-MS:m/z=325.1[M+H]+.
步骤6.化合物1-7的合成
将化合物1-6(500mg,1.54mmol)溶于5.00mL甲醇中,缓慢滴加浓盐酸(1.00mL),加热至60℃,反应过夜。TLC检测原料反应完全,将反应液倒入水中,滴加饱和碳酸氢钠溶液至pH=8-9,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品加入10mL DCM(二氯甲烷),室温搅拌0.5h,抽滤,得白色固体(298mg,1.11mmol)化合物1-7,收率72.1%。1H NMR(400MHz,DMSO)δ10.13(s,2H),8.18(s,1H),7.97(d,J=2.3Hz,1H),6.88(d,J=2.3Hz,1H),4.32(t,J=4.4Hz,2H),3.84(t,J=4.4Hz,2H),3.83(s,3H).ESI-MS:m/z=269.1[M+H]+.
步骤7.化合物1-8的合成
将化合物1-7(200mg,0.746mmol)溶于氯仿(3.00mL)和DMA(二甲基乙酰胺,11.00mL)的混合溶液中,冰浴条件下,依次加入吡啶(60.0mg,0.759mmol)和二氯亚砜(268mg,2.25mmol)。继续在冰浴下反应30min后,加热至60℃反应1h。TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得到淡黄色固体(187mg,0.654mmol)化合物1-8,收率87.6%。1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.62(d,J=2.0Hz,1H),6.57(d,J=2.0Hz,1H),4.50(t,J=5.3Hz,2H),3.94(t,J=5.3Hz,2H),3.88(s,3H).ESI-MS:m/z=287.0[M+H]+。
步骤8.化合物1-9的合成
将化合物1-8(87mg,0.304mmol)溶于5.00mLDMF溶液中,依次加入碳酸铯(195mg,0.598mmol)和碘化钾(75.5mg,0.455mmol),室温搅拌过夜。TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得黄色固体(58.52mg,0.234mmol)化合物1-9,收率77%。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.48(d,J=2.1Hz,1H),6.43(d,J=2.1Hz,1H),4.79–4.72(m,2H),4.63–4.56(m,2H),3.87(s,3H).ESI-MS:m/z=251.0[M+H]+。
步骤9.化合物1-10a的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,制备化合物1-10a,收率89.8%;1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.46(s,1H),4.72–4.63(m,2H),4.58(dt,J=5.8,1.8Hz,2H),3.88(s,3H).ESI-MS:m/z=328.7[M+H]+。
步骤10.化合物1-10b的合成
合成步骤参考实施例1步骤9,用类似于化合物1-10a的合成方法,以化合物1-9和N-氯代丁二酰亚胺(NCS)为原料,制备化合物1-10b,收率:87%;ESI-MS:m/z=285[M+H]+。
步骤11.中间体2的合成
将化合物1-10a(125mg,0.382mmol)溶于5.00mLTHF(四氢呋喃)和水的混合溶液(v/v,1:1)中,加入无水氢氧化锂(91.0mg,3.80mmol),加热至60℃,回流过夜。TLC检测原料反应完全后,减压浓缩,向残余物中加入20mL水,用1N的盐酸酸化至pH=2-3,析出大量白色固体,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得产物(中间体2)无需进一步纯化,直接用于下一步。1HNMR(400MHz,DMSO)δ13.26(s,1H),8.28(s,1H),7.62(s,1H),4.76–4.69(m,2H),4.69–4.62(m,2H).ESI-MS:m/z=312.9[M-H]-。
步骤12.中间体1的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物1-9为原料,制备化合物中间体1;ESI-MS:m/z=235.0[M-H]-.
步骤13.中间体3的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,化合物1-10b为原料制备化合物中间体3;ESI-MS:m/z=269.0[M-H]-。
实施例2中间体4~6的合成
步骤1.化合物2-2的合成
将化合物2-1(1.00g,4.30mmol)和双(三苯基膦)氯化钯(120mg,0.171mmol)加入到双颈瓶中,氮气保护下,依次注射8.00mL水、700μL四氢吡咯和(丙炔氧基)三甲基硅烷(650mg,5.07mmol)。油浴100℃反应2h,TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得淡黄色油状液体。(380mg,1.81mmol)化合物2-2,收率42.2%。1H NMR(400MHz,CDCl3)δ7.64(d,J=3.9Hz,1H),7.14(d,J=3.9Hz,1H),4.52(s,2H),4.34(q,J=7.1Hz,2H),1.79(s,1H),1.37(t,J=7.1Hz,3H).ESI-MS:m/z=209.0[M-H]-.
步骤2.化合物2-3的合成
将化合物2-2(2.50g,11.9mmol)溶于50.0mL的甲醇中,加入钯碳(250mg,10%)。氢气置换三次后,于约3.8个大气压(氢气)下,室温氢化反应过夜。过滤,滤液浓缩得到黄色油状液体(2.20g,10.5mmol)化合物2-3,收率88.2%,无需进一步纯化,直接用于下一步。1HNMR(400MHz,CDCl3)δ7.63(d,J=3.8Hz,1H),6.81(dt,J=3.8,0.9Hz,1H),4.32(q,J=7.1Hz,2H),3.71(t,J=6.2Hz,2H),2.95(t,J=7.6Hz,2H),1.95(tt,J=7.6,6.3Hz,2H),1.36(t,J=7.1Hz,3H).ESI-MS:m/z=213.0[M-H]-。
步骤3.化合物2-4的合成
冰浴条件下,将化合物2-3(100mg,0.47mmol)溶于1.00mL的DCM中,氮气保护下分别加入三氯化铝(186.7mg,1.40mmol)、液溴(74.6mg,0.467mmol)的DCM溶液。室温反应2h,TLC监控原料反应完全。反应液倒入水中,用乙酸乙酯萃取三次。合并有机层,分别用饱和硫代硫酸钠和饱和食盐水洗涤,无水硫酸钠干燥,减压回收溶剂,残余物经柱层析纯化得到黄色油状液体(134mg,0.46mmol)化合物2-4,收率97.8%。1H NMR(400MHz,CDCl3)δ7.60(s,1H),4.33(q,J=7.1Hz,2H),3.71(t,J=6.2Hz,2H),2.92(t,J=7.6Hz,2H),1.94(dq,J=7.7,6.3Hz,2H),1.35(t,J=7.1Hz,3H).ESI-MS:m/z=292.8[M+H]+。
步骤4.化合物2-5的合成
将化合物2-4(1.00g,3.42mmol)溶于10.0mLDMF和2.0mL水中,氮气保护下,加入1H-吡唑-3-硼酸频哪酯(794mg,4.08mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(250mg,0.342mmol)和碳酸铯(2.30g,7.06mmol)。反应液加热至100℃,反应5h,TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得黄色固体(258mg,0.914mmol)化合物2-5。收率26.7%;1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.66–7.60(m,1H),6.76(s,2H),6.48(s,1H),4.36(q,J=7.1Hz,2H),3.67(s,2H),3.30(t,J=6.2Hz,2H),2.02(s,2H),1.38(t,J=7.1Hz,3H).ESI-MS:m/z=281.1[M+H]+。
步骤5.化合物2-6的合成
冰浴条件下,将化合物2-5(100mg,0.357mmol)和四溴化碳(130mg,0.392mmol)溶于5mL DCM中,N2置换三次后,缓慢滴加三苯基膦(121.3mg,0.462mmol)的DCM(2.00mL)溶液。继续冰浴反应过夜,TLC检测反应完全。反应液浓缩,残余物通过柱层析纯化得到黄色固体(69.3mg,0.203mmol)化合物2-6,收率56.8%;1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.65(d,J=2.3Hz,1H),6.52(d,J=2.3Hz,1H),5.72(s,1H),4.35(q,J=7.1Hz,2H),3.47(t,J=6.5Hz,2H),3.32–3.21(m,2H),2.33–2.20(m,2H),1.38(t,J=7.1Hz,3H).ESI-MS:m/z=343.0[M+H]+。
步骤6.化合物2-7的合成
合成步骤参考实施例1步骤8,用类似于化合物1-9的合成方法,化合物2-6为原料,制备化合物2-7收率82.9%;1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.49(d,J=2.0Hz,1H),6.54(d,J=2.0Hz,1H),4.62–4.56(m,2H),4.40(q,J=7.1Hz,2H),3.30–3.24(m,2H),2.36(qt,J=7.0,4.0Hz,2H),1.43(t,J=7.2Hz,3H).ESI-MS:m/z=263.1[M+H]+。
步骤7.化合物2-8a的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物2-7和N-溴代丁二酰亚胺(NBS)为原料,制备化合物2-8a,收率95%;1H NMR(400MHz,DMSO)δ8.17(s,1H),7.62(s,1H),4.32–4.30(m,2H),3.82–3.75(m,2H),3.14(t,J=7.0Hz,2H),2.35–2.18(m,2H),1.30(t,J=7.1Hz,3H).ESI-MS:m/z=340.9[M+H]+。
步骤8.化合物2-8b的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物2-7和N-氯代丁二酰亚胺(NCS)为原料,制备化合物2-8b,收率:80%;ESI-MS:m/z=297[M+H]+。
步骤9.中间体4的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物2-7为原料,制备中间体4;ESI-MS:m/z=233.0[M-H]-。
步骤12.中间体5的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物2-8a为原料,制备中间体5;ESI-MS:m/z=311.0[M-H]-。
步骤13.中间体6的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,化合物2-8b为原料制备中间体6;ESI-MS:m/z=267.0[M-H]-。
实施例3中间体7~8的合成
步骤1.化合物3-2的合成
将4-溴-3-羟基苯甲酸甲酯(500mg,2.16mmol)溶于MeCN(10.0mL)中,加入碳酸铯(1.70g,5.22mmol)和1,2-二溴乙烷(3.30g,17.6mmol)。加热回流反应5h,TLC监控原料反应完全,冷却至室温,将反应液倒入到水中淬灭,用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠洗两次后,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得无色油状液体(717.1mg,2.13mmol)化合物3-2。收率98.6%;1H NMR(400MHz,CDCl3)δ7.69(d,J=8.1Hz,1H),7.64–7.57(m,2H),4.46(td,J=6.4,3.3Hz,2H),4.01–3.95(m,3H),3.76(td,J=6.4,3.3Hz,2H).ESI-MS:m/z=336.9[M+H]+。
步骤2.化合物3-3的合成
合成步骤参考实施例1步骤5,用类似于化合物1-6的合成方法,以化合物3-2为原料,制备化合物3-3。收率84.2%;ESI-MS:m/z=325.0[M+H]+。
步骤3.化合物3-4的合成
合成步骤参考实施例1步骤8,用类似于化合物1-9的合成方法,以化合物3-3为原料,制备化合物3-4,收率78.4%;ESI-MS:m/z=245.1[M+H]+。
步骤4.化合物3-5的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物3-4和N-氯代丁二酰亚胺(NCS)为原料,制备化合物3-5,收率89.0%;1H NMR(400MHz,DMSO)δ7.91(d,J=8.2Hz,1H),7.83(dd,J=8.2,1.7Hz,1H),7.78(s,1H),7.71(d,J=1.6Hz,1H),4.60(t,J=5.1Hz,2H),4.51(t,J=5.1Hz,2H),3.89(s,3H).ESI-MS:m/z=279.1[M+H]+.
步骤5.中间体8的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,化合物3-5为原料制备中间体8;ESI-MS:m/z=263.0[M-H]-.
步骤6.中间体7的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物3-4为原料,制备化合物中间体7;ESI-MS:m/z=243.0[M-H]-.
实施例4中间体9~11的合成
步骤1化合物4-2的合成
将化合物4-1(2.1g,11mmol)溶于30mL冰醋酸中,加入铁粉(3.1g,55mmol)。反应液加热至50摄氏度反应1h,TLC检测原料反应完全,且LC-MS监测羟胺中间体转化完全,加饱和碳酸氢钠50ml淬灭,用乙酸乙酯(500mL×3)萃取,合成并有机层,饱和NaCl溶液洗涤两次,无水硫酸钠干燥,滤液浓缩得到黄色油状液体(2.20g,10.5mmol)化合物4-2,收率95%。无需进一步纯化,直接用于下一步。ESI-MS:m/z=158.0[M+H]+。
步骤2化合物4-3的合成
将化合物4-2(1.48g,9.43mmol)和4-二甲氨基吡啶(115mg,0.94mmol)溶于20mL1,4-二氧六环中,加入三乙胺(1.14g,11.3mmol)和二碳酸二叔丁酯(2.47g,11.3mmol)。反应液加热至80摄氏度反应6h,TLC检测原料反应完全,加入100mL水,用乙酸乙酯(300mL×3)萃取,合成并有机层,饱和NaCl溶液洗涤两次,无水硫酸钠干燥,减压回收溶剂,残余物经柱层析纯化得淡黄色固体(1.54g,6mmol)化合物4-3。收率63.6%;1H NMR(400MHz,Chloroform-d)δ7.61(d,J=4.1Hz,1H),6.50(d,J=4.1Hz,1H),3.88(s,3H),1.57(s,9H).ESI-MS:m/z=258.0[M+H]+
步骤3化合物4-4的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物4-3,N-溴代丁二酰亚胺(NBS)为原料,制备化合物4-4,收率80%。ESI-MS:m/z=336.0[M+H]+。
步骤4化合物4-5的合成
合成步骤参考实施例1步骤5,用类似于化合物1-6的合成方法,以化合物4-4原料,制备化合物4-5,收率73.9%。1H NMR(400MHz,Chloroform-d)δ10.66(s,1H),7.93(s,1H),7.67(d,J=2.5Hz,1H),6.57(d,J=2.5Hz,1H),3.91(s,3H),1.60(s,9H).ESI-MS:m/z=324.1[M+H]+.
步骤5化合物4-6和4-7的合成
将化合物4-5(91mg,0.28mmol)溶于4N盐酸乙醇溶液(5mL),室温搅拌3h,TLC检测原料转化完全。减压除去溶剂,得化合物4-6粗品,直接溶于5.0mL无水四氢呋喃中,冰浴条件下,加入三乙胺(85mg,0.84mmol),缓慢滴加氯乙酰氯(97mg,0.84mmol)。室温反应30分钟,TLC监控反应完全,减压除去溶剂,加入30mL水,用乙酸乙酯(40mL×3)萃取,合并有机层,饱和NaCl溶液洗涤两次,无水硫酸钠干燥,减压回收溶剂,残余物经柱层析纯化得白色固体(44mg,0.15mmol)化合物4-7,收率52%。1H NMR(400MHz,DMSO-d6)δ13.33(s,1H),12.58(s,1H),8.17(s,1H),7.93(d,J=1.9Hz,1H),6.93(s,1H),4.68(s,2H),3.85(s,3H).ESI-MS:m/z=300.0[M+H]+.
步骤6化合物4-8的合成
合成步骤参考实施例1步骤8,用类似于化合物1-9的合成方法,以化合物4-7原料,制备化合物4-8,收率48.4%。1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.60(d,J=1.9Hz,1H),6.49(d,J=1.9Hz,1H),4.99(s,2H),3.95(s,3H).ESI-MS:m/z=264.0[M+H]+.
步骤7.化合物4-9a的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物4-8和N-溴代丁二酰亚胺(NBS)为原料,制备化合物4-9a,收率97.7%;1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.03(d,J=5.1Hz,1H),7.80(s,1H),4.99(s,2H),3.89(s,3H).ESI-MS:m/z=342.0[M+H]+.
步骤8.化合物4-9b的合成
合成步骤参考实施例1步骤4,用类似于化合物1-5的合成方法,以化合物4-8和N-氯代丁二酰亚胺(NCS)为原料,制备化合物4-9b,收率:97%;1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),7.96(d,J=5.7Hz,1H),7.80(s,1H),4.98(s,2H),3.88(s,3H).ESI-MS:m/z=298.0[M+H]+.
步骤9.中间体9的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物4-8为原料,制备中间体9;ESI-MS:m/z=248.0[M-H]-。
步骤12.中间体10的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,以化合物4-9a为原料,制备中间体10;ESI-MS:m/z=326.0[M-H]-。
步骤13.中间体11的合成
合成步骤参考实施例1步骤11,用类似于中间体2的合成方法,化合物4-9b为原料制备中间体11;ESI-MS:m/z=282.0[M-H]-。
实施例5中间体12~19的合成
步骤1化合物5-3a的合成(化合物5-3b~5-3g的合成见表1)
将2-硝基乙基氨基甲酸叔丁酯(化合物5-1,380mg,2mmol),((S)-(-)-α,α-二苯基-2-吡咯甲基)三甲基硅基醚(33mg,0.1mmol)((S)-2-(二苯基((三甲基甲硅烷基)氧基)甲基)吡咯烷),苯甲酸(25mg,0.2mmol),溶于无水二氯甲烷(2ml),冰浴条件下,缓慢加入3,4-二氟肉桂醛(化合物5-2a,168mg,1mmol),室温搅拌约24h,将反应体系用二氯甲烷稀释至五倍以上,向反应液中缓慢滴加200微升三氟乙酸,室温反应5小时,随后向反应液中加入1N碳酸氢钠溶液约10ml,室温搅拌10min,然后用乙酸乙酯萃取反应液三次,合并有机相饱和氯化钠洗1次后,无水硫酸钠干燥,柱层析纯化得到淡黄色固体(化合物5-3a)228mg,收率67%;ESI-MS:m/z=341[M+H]+。
表1化合物5-3b~5-3g的合成方法
步骤2中间体12的合成方法(中间体13~18的合成见表2)
将化合物5-3a(170mg,0.5mmol)溶于乙酸乙酯(10ml),加入30mgl0%Pd/C,室温下氢化过夜,反应完成后抽滤,滤液旋干,得油状液体(中间体12)101mg,收率65%;ESI-MS:m/z=313[M+H]+。
表2中间体13~18的合成方法
步骤3化合物5-4的合成方法
合成步骤参考实施例5步骤1,用类似于化合物5-3a的合成方法,以化合物5-1,5-2a,((R)-(-)-α,α-二苯基-2-吡咯甲基)三甲基硅基醚为原料,制备化合物5-4;ESI-MS:m/z=341[M+H]+.
步骤4中间体19的合成方法
合成步骤参考实施例5步骤2,用类似于中间体12的合成方法,以化合物5-4为原料。制备中间体19,ESI-MS:m/z=313[M+H]+。
实施例6中间体20的合成
将2-硝基乙基氨基甲酸叔丁酯(化合物6-1,2.85g,15mmol),((S)-(-)-α,α-二苯基-2-吡咯甲基)三甲基硅基醚(0.36g,1.1mmol),苯甲酸(0.25g,2mmol),溶于无水二氯甲烷(15ml),冰浴条件下,缓慢加入3,4-二氟肉桂醛(化合物6-2,1.68g,10mmol),室温搅拌约18h,生成化合物6-3后直接进行下一步;用二氯甲烷将反应液稀释至100ml,将体系降温到-78℃,向反应液中加入烯丙基三甲基硅烷(5ml,30mmol),接着缓慢滴加三氟化硼乙醚,继续反应10h,向反应液中加入1N碳酸氢钠溶液100ml,室温搅拌10min,乙酸乙酯萃取三次,合并有机相,饱和氯化钠洗涤,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得得到白色固体(中间体20)1.9g,收率50%;ESI-MS:m/z=383[M+H]+。
实施例7中间体21的合成
步骤1化合物7-1的合成
将中间体19(149mg,0.390mmol)溶于乙醇(10.0mL)和水(2.00mL)中,加入铁粉(110mg,1.95mmol)和氯化铵(42.0mg,0.785mmol),加热至回流,机械搅拌3h。TLC监控原料反应完全。反应液旋干乙醇后,残余液倒入100ml饱和碳酸氢钠溶液中,乙酸乙酯萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩得淡黄色油状液体102mg(化合物7-1)。ESI-MS:m/z=296[M-Tert-butyl]+。
步骤2化合物7-2的合成
将中间体2(110mg,0.35mmol),1-羟基苯并三唑(HOBt)(97mg,0.345mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(98.8mg,0.517mmol)溶于无水二氯甲烷(4ml)中,冰浴条件下搅拌10分钟,加入二异丙基乙胺(0.115ml,1.21mmol),继续在冰浴下搅拌15分钟,加入化合物7-1(123mg,0.35mmol),室温搅拌过夜,TLC监测反应完成后,倒入15ml水中,用二氯甲烷萃取反应液3次,合并有机相,用饱和氯化钠洗两次,无水硫酸钠干燥,旋干,柱层析纯化得到淡黄色固体150mg(化合物7-2),收率66%,ESI-MS:m/z=649[M+H]+。
步骤3化合物7-3的合成
将化合物7-2(648mg,1mmol)溶解于5ml四氢呋喃中,缓慢加入硼烷四氢呋喃直至气泡消失,TLC监控原料反应完全,缓慢加入4N NaOH溶液3ml,残余液倒入50ml水中,乙酸乙酯萃取三次,合并有机相,饱和食盐水洗涤两次,无水硫酸钠干燥,浓缩得无色油状液体500mg(化合物7-3),收率75%。ESI-MS:m/z=667[M+H]+。
步骤4中间体21的合成
将化合物7-3(666mg,1mmol)溶解于5mL二氯甲烷溶液中,冰浴条件下加入DIPEA(mg,3mmol),然后缓慢滴加甲基磺酰氯(212mg,1.1mmol),室温搅拌20min,TLC监测反应完成后,倒入15ml水中,用二氯甲烷萃取反应液3次,合并有机相,用饱和氯化钠洗两次,无水硫酸钠干燥,旋干,柱层析纯化得到淡黄色固体600mg(中间体21),收率80.6%,ESI-MS:m/z=745[M+H]+。
实施例8中间体22的合成
步骤1化合物8-1的合成
将中间体20(1.9g,5mmol)溶于40ml混合DCM/CH3CN/H2O(v/v/v=1/1/2)溶剂中,冰浴条件下,依次缓慢加入NaIO4(5.35g,25mmol)、RuCl3单水合物(170mg,lmmol),室温搅拌过夜,滤去黑色不溶物,滤液用稀盐酸溶液调至pH=5,用二氯甲烷萃取三次,合并有机层,饱和氯化钠洗2次后,无水硫酸钠干燥,旋干得无色油状物(化合物8-1)1.8g,收率90%;1HNMR(500MHz,CDC13)δ7.11(dd,J=18.2,8.4Hz,lH),7.05-7.00(m,lH),6.92(dd,J=5.4,3.lHz,lH),4.89(m,lH),4.62(m,2H),3.42(m,lH),3.29(m,lH),2.76(d,J=6.7Hz,2H),1.97(s,2H),1.46(s,9H).
步骤2化合物8-2的合成
将中间体2-3(200mg,O.5mmol)溶于5ml DMF中,冰浴条件下,依次加入HBTU(379mg,lmmol),三乙胺0.25ml,常温反应15min后,向反应液中滴加30%甲胺乙醇溶液(1ml),继续反应3h。反应结束,将体系倒入10ml水中,用乙酸乙酯萃取三次,合并有机相,饱和氯化钠洗2次后,无水硫酸钠干燥,旋干得200mg白色固体(中间体5-2)收率97%,无需纯化直接用于下一步反应。
步骤3中间体22的合成
合成步骤参考实施例7步骤1,类似于化合物7-1的合成方法,以化合物8-2为原料,制备中间体22,收率91%;ESI-MS:m/z=384[M+H]+。
实施例10中间体24~25的合成
步骤1中间体24的合成
合成步骤参考实施例7步骤2,以中间体12和中间体2为原料,制备中间体24,收率63%;ESI-MS:m/z=609[M+H]+。
步骤2中间体25的合成
将三(二亚苄基丙酮)二钯(Pd2(dba)3)(91.6mg,0.1mmol)和10%三叔丁基膦戊正烷溶液(0.8mL,0.4mmol)溶于3mL无水DMF中,N2保护下,室温搅拌3h。向反应液中滴加20mL二氧六环和水的混合溶液(v/v,5:1)稀释,冷却至0℃,加入中间体24(608mg,1mmol)、乙烯硼酐吡啶络合物(265mg,1.1mmol)和碳酸钾(414mg,3mmol),加热至70℃,搅拌过夜。原料反应完全后,反应液倒入水(50mL)中,用EA萃取(30mL×3),合并有机层,饱和NaCl溶液(30mL×2)洗涤,无水硫酸钠干燥,减压回收溶剂,残余物经柱层析纯化得白色固体(278mg,0.5mmol)中间体25。ESI-MS:m/z=557[M+H]+。
实施例11中间体26的合成
步骤1化合物10-2的合成
将化合物10-1(328.44mg,4mmol)溶于5ml四氢呋喃中,加入3,4-二氢-2H-吡喃(328.44mg,4mmol)和40微升三氟乙酸。油浴80摄氏度搅拌过夜,TLC监测反应完成后,倒入15ml水中,用EA萃取反应液3次,合并有机相,用饱和氯化钠洗两次,无水硫酸钠干燥,旋干,柱层析纯化得到淡黄色固体400mg化合物10-2,收率60.25%,ESI-MS:m/z=167[M+H]+。
步骤2化合物10-3的合成
将化合物10-2(1g,6.024mmol)溶于10ml的无水四氢呋喃中,将反应液降温至-40摄氏度,滴加正丁基锂(424mg,7.23mmol,3ml)(2.5mol/L in haxane),继续在此温度下搅拌1h,随后滴加2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(1.23g,6.626mmol),室温搅拌,TLC监测反应完毕后,滴加饱和氯化铵溶液淬灭,调pH=5-6,EA萃取,合并有机相,用饱和氯化钠洗两次,无水硫酸钠干燥,旋干,得黄色油状液体1.557g化合物10-3,收率88.5%,直接用于下一步,ESI-MS:m/z=293[M+H]+。
步骤3化合物中间体10-4的合成
将化合物10-3(200mg,0.685mmol)溶于2ml甲醇,冰浴下逐渐加入2ml的4N盐酸甲醇溶液中,搅拌过夜后TLC点板,反应结束后,将反应液旋干。得到淡黄色油状物170mg中间体10-4,ESI-MS:m/z=127[M+H]+。
步骤4化合物10-5的合成
合成步骤参考实施例1步骤5,用类似于化合物1-6的合成方法,以化合物1-5和10-4为原料,制备化合物10-5。
步骤5化合物10-6的合成
合成步骤参考实施例1步骤6,用类似于化合物1-7的合成方法,以化合物10-5为原料,制备化合物10-6。
步骤6化合物10-7的合成
合成步骤参考实施例1步骤7,用类似于化合物1-8的合成方法,以化合物10-6为原料,制备化合物10-7。
步骤7化合物10-8的合成
合成步骤参考实施例1步骤8,用类似于化合物1-9的合成方法,以化合物10-7为原料,制备化合物10-8。
步骤8中间体26的合成
合成步骤参考实施例1步骤10,用类似于中间体2的合成方法,以化合物10-8为原料,制备中间体26。
实施例12 10-溴-N-(((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物1)的合成
向得到的中间体24中加入2ml 4N盐酸乙醇溶液,室温搅拌两小时后TLC点板,反应完毕后旋干,加入饱和碳酸氢钠,乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥硅胶柱层析纯化得到白色固体产物(化合物1),收率87%。1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),9.41(s,1H),8.76(d,J=8.8Hz,1H),8.08(s,1H),7.62(s,1H),7.44–7.27(m,2H),7.18–7.09(m,1H),4.77–4.65(m,2H),4.59(dtd,J=13.5,11.0,9.8,6.2Hz,2H),4.43(dtd,J=15.6,11.5,10.0,4.2Hz,1H),3.39(d,J=11.8Hz,2H),3.17(td,J=11.6,4.0Hz,1H),2.95(q,J=10.0,9.1Hz,2H),2.16–2.05(m,1H),2.01(d,J=12.5Hz,1H).ESI-MS:m/z=509.0[M+H]+.
实施例13.10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑啉[1,5-d]噻吩[3,2-f][1,4]氧杂氮卓-2-甲酰胺(化合物2)的合成
将中间体3(92.4mg,0.35mmol),1-羟基苯并三唑(HOBt)(97mg,0.345mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI(98.8mg,0.517mmol)溶于无水二氯甲烷(4ml)中,冰浴条件下搅拌10分钟,加入二异丙基乙胺(0.115ml,1.21mmol),继续在冰浴下搅拌15分钟,加入中间体12(110mg,0.35mmol),室温搅拌过夜,反应完成后,倒入15ml水中,用二氯甲烷萃取反应液3次,合并有机相,用饱和氯化钠洗2次,无水硫酸钠干燥,旋干,柱层析纯化得到淡黄色固体;向得到的淡黄色固体中加入2ml 4N盐酸乙醇溶液,室温搅拌两小时后TLC点板,反应完毕后旋干,加入饱和碳酸氢钠,乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥硅胶柱层析纯化得到白色固体产物(化合物2),收率88.2%;收率34%,1H NMR(500MHz,DMSO-d6)δ9.46(d,J=10.6Hz,1H),9.34(d,J=12.0Hz,1H),8.75(d,J=8.9Hz,1H),8.01(s,1H),7.59(s,1H),7.34(dt,J=10.7,8.5Hz,1H),7.31–7.24(m,1H),7.09(dt,J=9.6,2.9Hz,1H),4.65(t,J=4.2Hz,2H),4.61–4.51(m,2H),4.48–4.30(m,1H),3.41–3.31(m,2H),3.14(td,J=11.6,4.1Hz,1H),3.00–2.85(m,2H),2.05(dd,J=13.0,3.6Hz,1H),1.99(q,J=4.9Hz,1H).ESI-MS:m/z=465.0[M+H]+.
实施例14.N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物3)的合成
合成步骤参考实施例13,以中间体12和中间体1为原料,制备化合物3,收率34%,1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.73(s,1H),9.05(d,J=8.9Hz,1H),8.50(d,J=4.8Hz,1H),8.21(s,1H),7.52–7.43(m,1H),7.33(dd,J=8.3,4.5Hz,2H),6.50(s,1H),4.62(d,J=4.4Hz,2H),4.55(t,J=3.9Hz,2H),3.35(d,J=6.5Hz,2H),3.20(dd,J=11.2,4.2Hz,1H),3.00(d,J=12.5Hz,1H),2.93(d,J=12.0Hz,2H),2.15(q,J=12.9Hz,1H),1.98–1.87(m,1H).ESI-MS:m/z=431.0[M+H]+.
实施例15.10-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物4)的合成
合成步骤参考实施例13,以中间体14和中间体3为原料,制备化合物4,收率34%,1H NMR(500MHz,DMSO-d6)δ9.46(d,J=10.6Hz,1H),9.34(d,J=11.0Hz,1H),8.71(d,J=9.0Hz,1H),8.00(s,1H),7.59(s,1H),7.31(td,J=8.0,6.3Hz,1H),7.16–7.04(m,2H),7.01(td,J=8.6,2.6Hz,1H),4.71–4.61(m,2H),4.60–4.51(m,2H),4.48–4.38(m,1H),3.36(dt,J=12.2,3.1Hz,2H),3.14(td,J=11.7,4.2Hz,1H),3.01–2.86(m,2H),2.12–1.93(m,2H).ESI-MS:m/z=447.0[M+H]+.
实施例16.10-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物5)的合成
合成步骤参考实施例13,以中间体14和中间体2为原料,制备化合物5,收率45%,1H NMR(500MHz,DMSO-d6)δ9.52(d,J=10.6Hz,1H),9.38(d,J=11.2Hz,1H),8.69(d,J=8.7Hz,1H),8.03(s,1H),7.59(s,1H),7.36–7.28(m,1H),7.18–7.05(m,2H),7.01(td,J=8.6,2.5Hz,1H),4.66(t,J=5.3Hz,2H),4.61–4.49(m,2H),4.44(ddt,J=16.3,11.4,5.7Hz,1H),3.35(dd,J=11.1,3.5Hz,2H),3.14(td,J=11.8,3.8Hz,1H),2.92(dt,J=22.4,11.1Hz,2H),2.06(td,J=12.9,3.5Hz,1H),2.01–1.94(m,1H).ESI-MS:m/z=491.0[M+H]+.
实施例17.N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物6)的合成
合成步骤参考实施例13,以中间体12和中间体1为原料,制备化合物6,收率48%,1H NMR(500MHz,Methanol-d4)δ7.55(s,1H),7.42(d,J=2.0Hz,1H),6.96–6.87(m,2H),6.73(tt,J=9.1,2.3Hz,1H),6.41(d,J=2.1Hz,1H),4.66–4.60(m,2H),4.60–4.53(m,2H),4.24(td,J=11.1,4.5Hz,1H),3.31–3.23(m,1H),3.19–3.11(m,1H),2.91(td,J=11.8,3.8Hz,1H),2.73(td,J=12.8,2.8Hz,1H),2.65(dd,J=12.4,10.9Hz,1H),1.97–1.90(m,1H),1.86–1.71(m,1H).ESI-MS:m/z=430.9[M+H]+.
实施例18.10-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑啉[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物7)的合成
合成步骤参考实施例13,以中间体12和中间体2为原料,制备化合物7,收率43%,1H NMR(400MHz,DMSO-d6)δ9.50(d,J=10.5Hz,1H),9.37(d,J=11.6Hz,1H),8.76(d,J=8.8Hz,1H),8.06(s,1H),7.59(s,1H),7.07(tt,J=9.4,2.4Hz,1H),6.98(h,J=4.1Hz,2H),4.74–4.64(m,2H),4.63–4.51(m,2H),4.42(qd,J=11.4,4.3Hz,1H),3.37(td,J=7.9,7.5,4.3Hz,2H),3.19(td,J=11.6,4.2Hz,1H),2.93(p,J=11.0,10.5Hz,2H),2.16–2.03(m,1H),2.02(s,1H).ESI-MS:m/z=509.0[M+H]+.
实施例19.10-溴-N-(((3S,4S)-4-(4-氯苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物8)的合成
合成步骤参考实施例13,以中间体15和中间体2为原料,制备化合物8,收率50%,1H NMR(400MHz,Methanol-d4)δ8.08(d,J=5.2Hz,1H),7.64(d,J=7.7Hz,2H),7.56(dd,J=8.1,5.2Hz,2H),7.49(d,J=5.2Hz,1H),4.71–4.64(m,2H),4.63–4.53(m,3H),3.69–3.50(m,3H),3.28–3.14(m,2H),2.22(s,1H),2.16(d,J=11.5Hz,1H).ESI-MS:m/z=507[M+H]+.
实施例20.10-溴-N-(((3S,4S)-4-(4-氯-3-三氟甲基苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物9)的合成
合成步骤参考实施例13,以中间体16和中间体2为原料,制备化合物9,收率51%,1H NMR(500MHz,DMSO-d6)δ9.39(d,J=10.7Hz,1H),9.20(d,J=11.4Hz,1H),8.70(d,J=8.8Hz,1H),8.01(s,1H),7.74(d,J=2.1Hz,1H),7.69(d,J=8.3Hz,1H),7.61(s,1H),7.56(dd,J=8.3,2.1Hz,1H),4.71–4.63(m,2H),4.62–4.52(m,2H),4.47(tdd,J=11.7,8.6,4.3Hz,1H),3.40–3.35(m,2H),3.23(td,J=11.0,5.8Hz,1H),2.94(dd,J=24.0,11.9Hz,2H),2.05(td,J=10.4,9.4,3.4Hz,2H).ESI-MS:m/z=575.0[M+H]+.
实施例21.10-溴-N-(((3S,4S)-4-(3-氯-4-三氟甲基苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物10)的合成
合成步骤参考实施例13,以中间体17和中间体2为原料,制备化合物10,收率51%,1H NMR(500MHz,DMSO-d6)δ8.07(s,1H),7.70(d,J=8.0Hz,1H),7.60(s,1H),7.45(d,J=5.8Hz,2H),4.63(dd,J=6.3,3.3Hz,2H),4.59–4.46(m,3H),3.65–3.59(m,1H),3.59–3.52(m,1H),3.48(q,J=7.0Hz,1H),3.19(dt,J=24.1,12.4Hz,2H),2.21(d,J=14.4Hz,1H),2.12(t,J=13.1Hz,1H).ESI-MS:m/z=575.0[M+H]+.
实施例22.10-溴-N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物11)的合成
合成步骤参考实施例13,以中间体18和中间体2为原料,制备化合物11,收率56%,1H NMR(500MHz,DMSO-d6)δ9.39(d,J=10.9Hz,1H),9.24(d,J=11.4Hz,1H),8.75(d,J=8.9Hz,1H),8.08(s,1H),7.61(s,1H),7.21(dd,J=9.1,6.5Hz,2H),4.69–4.54(m,4H),4.39(ddt,J=16.2,11.4,5.8Hz,1H),3.41–3.33(m,2H),3.16(td,J=11.5,4.4Hz,1H),2.98–2.89(m,2H),2.09–1.96(m,2H).ESI-MS:m/z=527[M+H]+.
实施例23.10-氯-N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物12)的合成
合成步骤参考实施例13,以中间体18和中间体3为原料,制备化合物12,收率49%,1H NMR(500MHz,DMSO-d6)δ9.51(d,J=10.7Hz,1H),9.37(d,J=11.1Hz,1H),8.86(d,J=8.8Hz,1H),8.06(s,1H),7.61(s,1H),7.22(dd,J=9.1,6.6Hz,2H),4.67(dt,J=4.8,2.3Hz,2H),4.64–4.54(m,2H),4.45–4.36(m,1H),3.41–3.33(m,2H),3.20(td,J=11.7,4.0Hz,1H),2.94(s,2H),2.13–1.98(m,2H).ESI-MS:m/z=483[M+H]+.
实施例24.1-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物13)的合成
合成步骤参考实施例13,以中间体15和中间体2为原料,制备化合物13,收率77.2%;1H NMR(500MHz,DMSO-d6)δ9.48(s,1H),9.40(s,1H),8.79(d,J=8.8Hz,1H),8.03(s,1H),7.61(s,1H),7.44–7.24(m,2H),7.12(s,1H),4.54–4.41(m,1H),4.31–4.19(m,J=4.4Hz,2H),3.38(d,J=11.9Hz,2H),3.21–3.10(m,1H),3.02(t,J=6.9Hz,2H),2.93(q,J=12.5,12.1Hz,2H),2.31–2.16(m,2H),2.11–1.99(m,2H).ESI-MS:m/z=507.1[M+H]+.
实施例25.1-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物14)的合成
合成步骤参考实施例13,以中间体13和中间体5为原料,制备化合物14,收率Yield:86.1%,1H NMR(500MHz,DMSO-d6)δ9.48(d,J=8.8Hz,1H),9.38(d,J=10.0Hz,1H),8.81(d,J=8.9Hz,1H),8.04(s,1H),7.60(s,1H),7.06(ddd,J=9.3,7.2,2.1Hz,1H),6.98(d,J=6.6Hz,2H),4.47(qd,J=11.6,4.4Hz,1H),4.31–4.16(m,2H),3.36(d,J=11.4Hz,2H),3.19(td,J=11.6,4.2Hz,1H),3.01(t,J=7.0Hz,2H),2.92(q,J=10.9Hz,2H),2.28–2.14(m,2H),2.11–1.98(m,2H).ESI-MS:m/z=507.1[M+H]+.
实施例26.1-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物15)的合成
合成步骤参考实施例13,以中间体12和中间体6为原料,制备化合物15,收率77.7%;1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.38(s,1H),7.07(td,J=10.1,9.0,3.7Hz,2H),6.99(dd,J=8.1,5.3Hz,1H),4.22(dd,J=7.4,4.2Hz,2H),4.20–4.12(m,1H),3.52(dd,J=12.2,4.3Hz,1H),3.19(d,J=13.0Hz,1H),3.06(t,J=6.9Hz,2H),2.75(td,J=11.9,11.5,3.5Hz,2H),2.70–2.58(m,1H),2.26–2.23(m,2H),1.94(dd,J=13.6,3.5Hz,1H),1.81–1.70(m,1H).ESI-MS:m/z=463.0[M+H]+.
实施例27.N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物16)的合成
合成步骤参考实施例13,以中间体12和中间体4为原料,制备化合物16,收率86.6%;1H NMR(400MHz,Chloroform-d)δ7.33(d,J=18.2Hz,2H),7.06(q,J=8.6Hz,2H),6.98(t,J=6.2Hz,1H),6.26(s,1H),6.03(d,J=8.2Hz,1H),4.49–4.27(m,2H),4.20(dd,J=11.3,7.1Hz,1H),3.47(dd,J=12.2,4.3Hz,1H),3.15(d,J=11.7Hz,1H),3.11(t,J=6.3Hz,2H),2.71(t,J=12.1Hz,2H),2.59(t,J=11.2Hz,1H),2.19(p,J=5.6Hz,2H),1.94(s,1H),1.68(tt,J=12.3,6.2Hz,1H).ESI-MS:m/z=429.0[M+H]+.
实施例28.1-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物17)的合成
合成步骤参考实施例13,以中间体14和中间体5为原料,制备化合物17,收率89.3%;1H NMR(500MHz,DMSO-d6)δ9.46(d,J=8.6Hz,1H),9.35(d,J=10.7Hz,1H),8.74(d,J=8.9Hz,1H),8.01(s,1H),7.60(s,1H),7.32(q,J=7.8Hz,1H),7.09(dd,J=17.0,9.0Hz,2H),7.01(td,J=8.6,2.2Hz,1H),4.49(qd,J=11.6,4.4Hz,1H),4.35–4.13(m,2H),3.39–3.31(m,2H),3.14(td,J=11.6,4.1Hz,1H),3.01(t,J=7.0Hz,2H),2.97–2.84(m,2H),2.27–2.12(m,2H),2.10–1.99(m,2H).ESI-MS:m/z=489.0[M+H]+.
实施例29.1-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物18)的合成
合成步骤参考实施例13,以中间体14和中间体6为原料,制备化合物18,收率92.2%;1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),9.44(d,J=10.0Hz,1H),8.78(d,J=8.9Hz,1H),8.02(s,1H),7.58(s,1H),7.31(q,J=7.8Hz,1H),7.09(dd,J=14.2,9.0Hz,2H),7.03–6.96(m,1H),4.48(qd,J=11.6,4.4Hz,1H),4.25(p,J=10.3Hz,2H),3.35(d,J=11.9Hz,2H),3.15(td,J=11.8,3.6Hz,1H),3.06–3.04(m,2H),2.92(q,J=11.2Hz,2H),2.16(dp,J=13.5,7.5,7.0Hz,2H),2.09–1.94(m,2H).ESI-MS:m/z=445.1[M+H]+.
实施例30.N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑啉[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺(化合物19)的合成
合成步骤参考实施例13,以中间体14和中间体4为原料,制备化合物19,收率78.6%;1H NMR(500MHz,DMSO-d6)δ9.45(d,J=9.3Hz,1H),9.36(d,J=9.9Hz,1H),9.03(d,J=8.9Hz,1H),8.25(s,1H),7.41(d,J=1.7Hz,1H),7.30(dq,J=14.1,7.9,6.2Hz,1H),7.18–7.08(m,2H),6.98(td,J=8.7,2.2Hz,1H),6.59(d,J=1.6Hz,1H),4.49(qd,J=11.8,4.6Hz,1H),4.44–4.37(m,2H),3.35(d,J=11.7Hz,2H),3.23(td,J=11.6,4.1Hz,1H),3.17–3.08(m,2H),2.96(q,J=10.9Hz,2H),2.17–2.08(m,2H),2.06–1.95(m,2H).ESI-MS:m/z=411.1[M+H]+.
步骤31.1-氯-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺(化合物20)的合成
合成步骤参考实施例13,以中间体13和中间体7为原料,制备化合物20,收率88.2%;1H NMR(500MHz,DMSO)δ9.47(d,J=9.6Hz,1H),9.38(d,J=11.6Hz,1H),8.83(d,J=8.9Hz,1H),7.78(d,J=8.1Hz,1H),7.72(s,1H),7.59(dd,J=8.2,1.9Hz,1H),7.51(d,J=1.8Hz,1H),7.05(ddd,J=9.3,6.9,2.4Hz,1H),7.04–6.95(m,2H),4.59(ddt,J=14.8,9.8,5.0Hz,1H),4.53(q,J=4.5,3.8Hz,2H),4.46(dd,J=6.4,4.7Hz,2H),3.38(t,J=3.5Hz,2H),3.22(td,J=11.3,4.8Hz,1H),2.95(q,J=11.1Hz,2H),2.12–2.04(m,1H),2.03(s,1H).ESI-MS:m/z=459.1[M+H]+.
实施例32.N-(((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺(化合物21)的合成
合成步骤参考实施例13,以中间体12和中间体7为原料,制备化合物21,收率89.0%;1H NMR(500MHz,MeOD)δ8.01–7.93(m,2H),7.41(dd,J=8.2,1.6Hz,1H),7.35(d,J=1.6Hz,1H),7.33–7.26(m,1H),7.20–7.15(m,2H),7.14(d,J=2.4Hz,1H),4.83–4.75(m,2H),4.63(td,J=11.3,3.9Hz,1H),4.57–4.52(m,2H),3.61(dd,J=12.1,4.3Hz,1H),3.55(d,J=12.2Hz,1H),3.27–3.20(m,2H),3.17(d,J=11.9Hz,1H),2.19(d,J=14.3Hz,1H),2.11(d,J=12.7Hz,1H).ESI-MS:m/z=425.1[M+H]+
实施例33.N-(((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺(化合物21)的合成
合成步骤参考实施例13,以中间体14和中间体7为原料,制备化合物22,收率94.5%;1H NMR(500MHz,DMSO)δ9.56(d,J=10.7Hz,1H),9.46(q,J=11.0Hz,1H),8.70(d,J=8.8Hz,1H),7.89(d,J=8.4Hz,1H),7.51(d,J=1.9Hz,1H),7.40(dd,J=8.3,1.8Hz,1H),7.35(d,J=1.7Hz,1H),7.30(p,J=8.7,8.0Hz,1H),7.15–7.04(m,2H),6.99(td,J=8.6,2.5Hz,1H),6.93(d,J=2.0Hz,1H),4.64–4.59(m,2H),4.59–4.54(m,1H),4.43(s,2H),3.36(dq,J=11.8,5.9,4.6Hz,2H),3.19(td,J=11.7,3.9Hz,1H),2.94(p,J=11.2Hz,2H),2.12–2.02(m,1H),1.99(d,J=14.8Hz,1H).ESI-MS:m/z=407.1[M+H]+.
实施例34.N-(((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺(化合物23)的合成
合成步骤参考实施例13,以中间体14和中间体7为原料,制备化合物23,收率68.2%;1H NMR(500MHz,MeOD)δ7.93(d,J=8.4Hz,1H),7.91–7.86(m,1H),7.40(dd,J=8.3,1.8Hz,1H),7.35(d,J=1.7Hz,1H),7.07(d,J=2.5Hz,1H),7.00(h,J=4.3Hz,2H),6.80(tt,J=9.0,2.3Hz,1H),4.77–4.71(m,2H),4.64(td,J=11.5,4.2Hz,1H),4.55–4.48(m,2H),3.61(dd,J=12.3,4.4Hz,1H),3.58–3.52(m,1H),3.25(ddd,J=24.1,12.5,9.1Hz,2H),3.16(d,J=12.0Hz,1H),2.21(d,J=14.1Hz,1H),2.17–2.04(m,1H)ESI-MS:m/z=425.1[M+H]+.
实施例35.N-(((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺(化合物24)的合成
合成步骤参考实施例13,以中间体18和中间体7为原料,制备化合物24,收率68.2%;1H NMR(500MHz,DMSO-d6)δ9.39(d,J=10.9Hz,1H),9.24(d,J=11.4Hz,1H),8.75(d,J=8.9Hz,1H),8.08(s,1H),7.61(s,1H),7.21(dd,J=9.1,6.5Hz,2H),4.69–4.54(m,4H),4.39(ddt,J=16.2,11.4,5.8Hz,1H),3.41–3.33(m,2H),3.16(td,J=11.5,4.4Hz,1H),2.98–2.89(m,2H),2.09–1.96(m,2H).ESI-MS:m/z=443[M+H]+.
实施例36.10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(二甲基氨基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物25)的合成
将中间体22(mg,mmol)溶解于3mlDMF溶液中,加入你N,N-二甲基胺(mg,mmol),升温至90℃,搅拌2h,TLC监测反应完成后,冷却至室温,倒入15ml水中,乙酸乙酯萃取三次,合并有机相,用饱和氯化钠洗两次,无水硫酸钠干燥,旋干,柱层析纯化得到淡黄色固体mg,收率%,将淡黄色固体(mg,mmol)溶解于3ML 4N HCl-1,4二氧六环溶液中,室温搅拌1小时后,TLC点板,反应完毕后旋干,加入饱和碳酸氢钠,乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥硅胶柱层析纯化得到白色固体产物(化合物25),收率%;ESI-MS:m/z=594[M+H]+。
实施例37.N-((3S,4S,6R)-6-烯丙基-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物26)的合成
合成步骤参考实施例12,以化合物7-2为原料制备化合物26,收率58%,1H NMR(500MHz,Methanol-d4)δ8.11(s,1H),7.47(s,1H),7.28–7.18(m,2H),7.12(s,1H),5.85(ddt,J=17.1,10.2,7.0Hz,1H),5.40(dd,J=17.0,1.5Hz,1H),5.30(dd,J=10.1,1.5Hz,1H),4.76–4.63(m,2H),4.63–4.51(m,2H),4.44(td,J=11.4,4.7Hz,1H),3.79(s,1H),3.40(td,J=12.3,4.9Hz,2H),2.81–2.68(m,2H),2.12(dd,J=5.0,2.4Hz,1H),1.32–1.27(m,2H).ESI-MS:m/z=549[M+H]+。
实施例38.N-((3S,4S,6R)-6-(3-(1H-咪唑-1-基)丙基)-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物27)的合成
合成步骤参考实施例34,以中间体22和咪唑为原料,制备化合物27,收率%ESI-MS:m/z=617[M+H]+。
实施例39 10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-羟丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]thieno[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物28)的合成
合成步骤参考实施例12,以化合物7-3为原料制备化合物28,收率%ESI-MS:m/z=567[M+H]+
实施例40 10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(吡咯烷-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物29)的合成
合成步骤参考实施例34,以中间体22和吡咯为原料,制备化合物29,收率%,1HNMR(500MHz,Methanol-d4)δ8.14(s,1H),7.47(s,1H),7.34(t,J=9.2Hz,1H),7.18(d,J=13.1Hz,2H),4.65(s,2H),4.60–4.50(m,2H),4.45(d,J=10.9Hz,1H),3.78–3.74(m,1H),3.73–3.70(m,1H),3.58–3.54(m,1H),3.40(d,J=7.9Hz,2H),3.27–3.23(m,2H),3.15(s,1H),2.75(s,2H),2.24–2.19(m,2H),2.18(s,2H),2.06(s,2H),2.02–1.99(m,2H),1.95–1.88(m,2H).ESI-MS:m/z=620[M+H]+
实施例41.10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物30)的合成
合成步骤参考实施例34,以中间体22和哌啶为原料,制备化合物30,收率%ESI-MS:m/z=634[M+H]+
实施例42.10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-吗啉代丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]thieno[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物31)的合成
合成步骤参考实施例34,以中间体22和吗啉为原料,制备化合物31,收率%ESI-MS:m/z=636[M+H]+
实施例43.10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(4-羟基哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物32)的合成
合成步骤参考实施例34,以中间体22和4-羟基哌啶为原料,制备化合物32,收率%ESI-MS:m/z=650[M+H]+
实施例44.10-溴-N-(((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物33)的合成
合成步骤参考实施例13,以中间体22和中间体2为原料,制备化合物33,收率%ESI-MS:m/z=580[M+H]+
实施例45.10-氯-N-(((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物34)的合成
合成步骤参考实施例13,以中间体22和中间体3为原料,制备化合物34,收率66%1H NMR(500MHz,Methanol-d4)δ8.06(s,1H),7.46(s,1H),7.33–7.09(m,3H),4.64(dq,J=4.4,2.1Hz,2H),4.57(dq,J=5.1,2.1Hz,2H),4.41(td,J=11.5,4.9Hz,1H),4.09(dd,J=9.8,5.1Hz,1H),3.44(dd,J=13.0,4.9Hz,1H),3.40–3.33(m,2H),3.02(dd,J=16.2,9.9Hz,1H),2.78(s,3H),2.76–2.71(m,1H),2.23(ddd,J=14.8,12.9,5.1Hz,1H),2.05(ddd,J=14.8,3.9,1.8Hz,1H).ESI-MS:m/z=536[M+H]+
实施例46.N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-乙基-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物35)的合成
步骤1化合物11-1的合成
合成步骤参考实施例5步骤2,以中间体6-1为原料制备化合物11-1,收率80.6%。
步骤2化合物35的合成
合成步骤参考实施例12,以化合物11-1为原料制备化合物35,收率43.2%。1HNMR(400MHz,DMSO-d6)δ9.50(s,1H),9.41(s,1H),9.01(d,J=10.4Hz,1H),7.78–7.71(m,1H),7.37–7.29(m,3H),7.15–7.09(m,1H),4.57(t,J=4.4Hz,2H),4.52–4.49(m,2H),4.40(d,J=7.5Hz,1H),3.39–3.31(m,2H),3.25(t,J=11.8Hz,1H),2.97(dt,J=25.3,12.1Hz,2H),2.68(qd,J=7.6,2.6Hz,2H),2.08(q,J=12.8,11.9Hz,1H),2.02–1.92(m,1H),1.16(t,J=7.4Hz,3H).
实施例47.N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-(2-羟乙基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物36)合成
步骤1化合物12-1的合成
合成步骤参考实施例7步骤3,以中间体25为原料制备中化合物12-1,收率。
步骤2化合物36的合成
合成步骤参考实施例12,以化合物12-1为原料制备化合物36,收率45%。1H NMR(500MHz,DMSO-d6)δ9.15(d,J=10.9Hz,1H),9.05(d,J=9.1Hz,2H),7.74(s,1H),7.37–7.28(m,3H),7.14(dt,J=9.0,2.9Hz,1H),4.59–4.54(m,2H),4.53–4.46(m,2H),4.38(dtd,J=11.2,8.0,7.1,4.4Hz,1H),3.58(s,1H),3.36–3.33(m,1H),3.27(td,J=8.9,8.4,4.7Hz,1H),3.06–2.90(m,2H),2.89(s,1H),2.82(dq,J=18.6,7.2Hz,2H),2.73(s,1H),2.00(dd,J=9.2,3.4Hz,2H).
实施例48.10-溴-N-(((3R,4R)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物37)的合成
合成步骤参考实施例13,以中间体19和中间体2为原料,制备化合物37,收率%,1HNMR(500MHz,DMSO-d6)δ9.46(s,1H),9.38–9.23(m,1H),8.68(dt,J=9.0,2.2Hz,1H),8.03(d,J=1.4Hz,1H),7.60(s,1H),7.36(dt,J=10.8,8.5Hz,1H),7.29(ddd,J=12.1,7.8,2.1Hz,1H),7.15–7.06(m,1H),4.73–4.65(m,2H),4.62–4.51(m,2H),4.39(ddd,J=7.0,4.7,2.4Hz,1H),3.43–3.34(m,2H),3.11(td,J=11.6,4.4Hz,1H),3.00–2.85(m,2H),1.99(d,J=11.0Hz,2H).ESI-MS:m/z=509[M+H]+
实施例49.N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-甲酰胺(化合物38)的合成
合成步骤参考实施例13,以中间体9和中间体2为原料,制备化合物38,收率%ESI-MS:m/z=444[M+H]+
实施例50.10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂-2-甲酰胺(化合物39)的合成
合成步骤参考实施例13,以中间体11和中间体12为原料,制备化合物39,收率%ESI-MS:m/z=479[M+H]+
实施例51.10-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-甲酰胺(化合物40)的合成
合成步骤参考实施例13,以中间体10和中间体12为原料,制备化合物40,收率%.1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.51(s,1H),7.19(dt,J=7.7,5.4Hz,1H),7.09(tdd,J=9.4,5.6,3.0Hz,2H),4.85(d,J=11.2Hz,2H),4.45(dd,J=10.5,6.3Hz,1H),3.55(d,J=4.6Hz,1H),3.46(d,J=12.6Hz,1H),3.10(dtd,J=11.8,8.3,7.3,3.7Hz,3H),2.15–2.11(m,1H),1.98(d,J=12.9Hz,1H).ESI-MS:m/z=522[M+H]+
实施例52N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-甲基-5,6-二氢吡唑并[1,5-d]噻吩[3,2-f][1,4]氧氮杂卓-2-甲酰胺(化合物41)的合成
合成步骤参考实施例13,以中间体12和中间体25为原料,制备化合物39,收率%ESI-MS:m/z=479[M+H]+
本发明公开的化合物对神经母细胞的生长抑制作用,促分化作用,以及对AKT1激酶抑制活性。
以临床促分化剂13-cisRA为阳性对照,采用细胞突触伸长变化表型筛选法对常见的肿瘤细胞株(神经母细胞株)的分化比例,平均突触长度和最大突触长度进行评价,采用MTT法测定化合物对其的体外抑制作用(IC50),同时利用商品化的AKT1试剂盒,评价AKT1酶抑制活性(IC50)。
本发明化合物抗肿瘤活性的药理实验方法与结果如下:
首先是体外肿瘤诱导分化活性的测定及初步的构效关系研究,选用神经母细胞株对所合成的化合物进行了体外肿瘤诱导分化活性的测定。
实验材料
细胞株:小鼠神经母细胞瘤细胞(Neuro2a)
培养基:RPMI1640+胎牛血清
药物配置方法:将药物溶于DMSO中制成50mM的储备液,并按一定比例稀释得到5个不同浓度
肿瘤细胞体外培养:
将所选取的Neuro2a,于37℃、5%CO2细胞培养箱中孵育,待细胞密度长到70-90%时传代(贴壁细胞用Duck‘sEDTA消化后传代),用于以后实验所需。
取适量NB细胞Neruo2a接种于6孔培养板中,细胞培养箱中培养过夜,待细胞贴壁生长后,分别给予终浓度0.5μM不同的化合物,以DMSO(1%)为空白对照,作用48h后拍照。并通过ImageJ软件中的NeuonJ插件计算细胞突触伸长变化,重复3次实验。采用分化比例(突触数量/细胞数量)、平均突触长度和最大突触长度评价分化强弱。所有数据除以对照组统计数据进行归一化处理。
分化比例的计算公式为:分化比例=(实验组轴突细胞数量/实验组细胞总数)/(对照组轴突细胞数量/对照组细胞总数);平均神经突长度=(实验组平均神经突长度)/(对照组平均神经突长度);最大神经突长度=(实验组最大神经突长度)/(对照组最大神经突长度)。
其次是受试化合物对Neuro2a细胞增殖抑制活性的测试方法:
取对数生长期的细胞,接种于96孔培养板中;肿瘤细胞均为4×103细胞/孔。每孔加入含10%血清的完全培养基,在20%氧气的培养箱中培养过夜。待细胞贴壁后,加入梯度浓度的受试化合物,于常氧培养箱中再培养3天,以评价候选化合物物对细胞增殖的抑制能力。酶标仪检测各孔OD值(检测波长:490nm),所得数据由于计算IC50。
细胞抑制率的计算公式为:细胞抑制率(%)=(对照组OD值-用药组OD值)/对照组OD值×100%,用Bliss法求出半数抑制浓度IC50值,由Graphpad5.0软件处理得到。
最后是受试化合物对AKT1酶抑制率的测试方法:
选用Mobility shift assay实验方法来检测化合物对AKT1的抑制活性。
化合物溶解在100%DMSO中,配制成10mM储存液,于氮气柜中避光储存。化合物浓度梯度的配制:受试化合物测试起始浓度为1000nM,10倍稀释或3倍稀释,6个浓度,单孔测试。在384孔板中稀释成100倍终浓度的溶液。然后用Echo550转移250nl到384反应板中备用。阴性对照孔和阳性对照孔中分别加250nl的100%DMSO。在化合物孔和阳性对照孔分别加10μl的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μl的1×Kinase buffer。1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate 6的混合溶液。加入15μl的25/15倍终浓度的ATP和底物的混合溶液,起始反应。将384孔板1000rpm离心30秒,振荡混匀后室温孵育30分钟。加入30μl终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。用Caliper EZ Reader读取转化率。
抑制率计算公式为:Inhibition%=(Conversion%_max-Conversion%_sample)/(Conversion%_max-Conversion%_min)*100,其中,Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值代表没有酶活孔的转化率读数;Conversion%_max:阳性对照孔均值,代表没有化合物抑制孔的转化率读数。
IC50计算公式为:Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。其中,以浓度的log值作为X轴,采用分析软件GraphPad Prism5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
表1部分化合物对肿瘤细胞增殖以及Akt1激酶的IC50(μM)
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表2部分化合物对Neuro2a的促分化活性
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a.Diff rate=Differentiation rate:the number of axons/cells;normalized to control
b.Avg neurite=Average neurite length;normalized to control
c.Max neurite=maximum neurite length;normalized to control
图1为未给药组的Neuro2a细胞分化情况,图2为给药组(化合物1)的Neuro2a细胞分化情况。通过对比,可以从表型上发现化合物1能够明显促进Neuro2a细胞的突触生长。说明以化合物1为代表的本发明化合物具备促进Neuro2a细胞的分化。
Claims (10)
1.通式(1)所示化合物:
及其光学异构体或其药学上可接受的盐或溶剂合物,其中:
环A选自无取代或取代的五元或六元芳基,包含0~4个选自O、N、S的五元或六元芳基;
R1选自无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的环烷基、无取代或取代的饱和或不饱和的杂环烷基,任意稠和的芳基、杂环芳基;
R2选自H、氨基、氰基、C1~C4烷基、卤代C1~C4烷基、烯烃取代烷基、C1~C4烷氧基、C1~C4羰基氧基、卤代的C1~C4烷氧基、 其中:n=0-4的整数;Rd选自H、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基;Re选自C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基;环D选自无取代或取代的五元~八元饱和或不饱和的脂肪含氮杂环基、无取代或取代的五元~八元含N杂芳基,所述杂环基、杂芳基中碳原子可以进一步被O、S取代;
R3选自H、卤素、羟基、羟甲基、羟乙基、羧基、饱和或不饱和的C1~C4烃基、卤代的C1~C4烷基,C1~C4烷氧基、卤代的C1~C4烷氧基、无取代或取代的芳基、无取代或取代的杂环芳基、无取代或取代的饱和或部分饱和的杂环、无取代或取代的环烷基;
R4选自H、卤素、硝基、氨基、氰基、C1~C4烷基、卤代C1~C4烷基、C1~C4烷氧基、卤代的C1~C4烷氧基;
m=0-3的整数;
X选自O、NH、S、C(=O);
Y选自CH2、C(=O)、磺酰基;
所述取代的取代基选自卤素、硝基、氨基、氰基、羟基、C1-C3烷基、卤代的C1-C3烷基、C1-C3烷氧基、卤代的C1-C3烷氧基。
2.根据权利要求1所述的化合物,其特征在于,所述的化合物具有通式(II)、(II’)所示的结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,其中:
E选自O,S,N,NH或NCH3;
T选自CH、NH或N。
3.根据权利要求2所述的化合物,其特征在于,所述的化合物具有通式(III)、(III’)所示的结构:
及其光学异构体或其药学上可接受的盐或溶剂合物。
4.根据权利要求3所述的化合物,其特征在于,所述的化合物具有通式(IV)、(IV’)所示的结构:
及其光学异构体或其药学上可接受的盐或溶剂合物,其中:
E为S。
5.根据权利要求4所述的化合物,其特征在于,所述X为O或CH;Y为CH2;
所述R1选自取代苯基;取代基为一个或多个卤素、卤代C1~C3烷基;
所述R2选自H、3-(二甲基氨基)丙基、烯丙基、3-(1H-咪唑-1-基)丙基、3-羟丙基、3-(吡咯烷-1-基)丙基、3-(哌啶-1-基)丙基、3-吗啉代丙基、3-(4-羟基哌啶-1-基)丙基、2-(甲基氨基)-2-氧代乙基;
所述R3选自H、卤素、C1~C5烷基;
所述R3选自H;E为S。
6.根据权利要求4所述的化合物,其特征在于,所述的化合物选自:
10-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (1)
10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (2)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (3)
10-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (4)
10-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (5)
N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (6)
10-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢吡唑啉并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (7)
10-溴-N-((3S,4S)-4-(4-氯苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (8)
10-溴-N-((3S,4S)-4-(4-氯-3-三氟甲基苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (9)
10-溴-N-((3S,4S)-4-(3-氯-4-(三氟甲基)苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (10)
10-溴-N-((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (11)
10-氯-N-((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (12)
1-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (13)
1-溴-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (14)
1-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩[3,2-c]氮杂环庚烷-9-甲酰胺 (15)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (16)
1-溴-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (17)
1-氯-N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (18)
N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-6,7-二氢-5H-吡唑并[1,5-a]噻吩并[3,2-c]氮杂环庚烷-9-甲酰胺 (19)
1-氯-N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺 (20)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺 (21)
N-((3S,4S)-4-(3-氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺 (22)
N-((3S,4S)-4-(3,5-二氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺 (23)
N-((3S,4S)-4-(3,4,5-三氟苯基)哌啶-3-基)-5,6-二氢苯并[f]吡唑并[1,5-d][1,4]氧氮杂卓-9-甲酰胺 (24)
10-溴-N-((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(二甲基氨基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (25)
N-((3S,4S,6R)-6-烯丙基-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (26)
N-((3S,4S,6R)-6-(3-(1H-咪唑-1-基)丙基)-4-(3,4-二氟苯基)哌啶-3-基)-10-溴-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (27)
10-溴-N-((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-羟丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (28)
10-溴-N-((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(吡咯烷-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (29)
10-溴-N-((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (30)
10-溴-N-(((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-吗啉代丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (31)
10-溴-N-((3S,4S,6R)-4-(3,4-二氟苯基)-6-(3-(4-羟基哌啶-1-基)丙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (32)
10-溴-N-((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (33)
10-氯-N-((3S,4S,6S)-4-(3,4-二氟苯基)-6-(2-(甲基氨基)-2-氧代乙基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (34)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-乙基-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (35)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-(2-羟乙基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (36)
10-溴-N-((3R,4R)-4-(3,4-二氟苯基)哌啶-3-基)-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (37)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-甲酰胺 (38)
10-氯-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-甲酰胺 (39)
10-溴-N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-5-氧代-5,6-二氢-4H-吡唑并[1,5-d]噻吩并[3,2-f][1,4]二氮杂卓-2-甲酰胺 (40)
N-((3S,4S)-4-(3,4-二氟苯基)哌啶-3-基)-10-甲基-5,6-二氢吡唑并[1,5-d]噻吩并[3,2-f][1,4]氧氮杂卓-2-甲酰胺 (41)
及其上述化合物的光学异构体或其药学上可接受的盐或溶剂合物。
7.一种药物组合物,其特征在于,所述药物组合物包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂,所述的活性组分选自权利要求1~6中任一项所述的化合物、所述化合物的光学异构体、所述化合物或其光学异构体在药学上可接受的盐、所述化合物或其光学异构体的溶剂合物中的任意一种或任意多种。
8.由权利要求7所述的药物组合物制得的制剂,所述制剂为片剂,粉剂,粒剂,胶囊,口服液及注射剂。
9.权利要求1-5任一项所述的化合物在制备抗肿瘤药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述的肿瘤选自,成神经细胞瘤、乳腺癌、肉瘤、肺癌、前列腺癌、结肠癌、直肠癌、肾癌、胰腺癌、血癌、神经胶质瘤、头癌、颈癌、甲状腺癌、胰癌、肝癌、卵巢癌、外阴癌子宫颈癌、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质癌、皮肤癌、多发性骨髓瘤。
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