CN115894482A - Ret抑制剂及其制备方法与应用 - Google Patents
Ret抑制剂及其制备方法与应用 Download PDFInfo
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- CN115894482A CN115894482A CN202211397468.XA CN202211397468A CN115894482A CN 115894482 A CN115894482 A CN 115894482A CN 202211397468 A CN202211397468 A CN 202211397468A CN 115894482 A CN115894482 A CN 115894482A
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- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000003112 inhibitor Substances 0.000 title abstract description 21
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 title abstract description 7
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- 238000006467 substitution reaction Methods 0.000 claims description 24
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- 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
本发明提供RET抑制剂及其制备方法与应用,所述RET抑制剂具有式I的结构式,本发明化合物对RET具有高选择性的抑制活性,且对RET融合和突变都有很好的抑制活性。
Description
技术领域
本发明属于医药技术领域,尤其涉及RET抑制剂及其制备方法与应用。
背景技术
转染重排(Re-arranged during transfection,RET)是属于钙黏蛋白超家族的受体型酪氨酸激酶之一,其激活涉及细胞增殖和存活的多个下游途径。
研究表明RET参与甲状腺癌、乳腺癌和肺腺癌的发生、发展及局部淋巴结的转移,已有资料表明RET可以作为潜在的有价值的抗肿瘤新靶点。
目前针对RET通路设计的靶向治疗药物可分为非特异性多靶点抑制剂(MKIs)和特异性RET抑制剂,其中非特异性多靶点抑制剂包括卡博替尼、凡德替尼(Vandetanib)和仑伐替尼等,特异性RET抑制剂主要包括普拉替尼BLU-667和塞尔帕替尼(Selpercatinib)。
尽管目前已有不少的多靶点抑制剂的药物已上市并成为肺癌患者们的靶向治疗药物,但根据临床的评估数据显示,多靶点抑制剂总体呈现的数据和效果还是差强人意的。甚至目前已上市的第二代特异性RET抑制剂也无可避免的存在“脱靶效应”及靶外产生的毒性和耐药性等问题。
基于目前靶向RET抑制剂存在的缺点和问题,亟需特异性更优的靶向RET药物。因此,设计和开发出更多对RET具有高度选择性的新型高效抑制剂极为关键和重要。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明第一个方面提出RET抑制剂,其对RET具有高选择性的抑制剂,且对RET融合和突变都有很好的抑制活性。
本发明的第二个方面提出了RET抑制剂的制备方法。
本发明的第三个方面提出了包含RET抑制剂的药物组合物。
本发明的第四个方面提出了RET抑制剂在制备药物中的用途。
本发明的第五个方面提出了RET抑制剂用于预防或治疗RET相关疾病。
根据本发明的第一个方面,提出了式I所示的化合物,或式I所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,
其中,X1、X2、X3、X4各自独立选自CR5或N,且X1、X2、X3、X4中的1或2个为N;
G独立选自4~10元杂环烷基、5~12元桥杂环基或5~12元螺杂环基;
E独立选自-O-、-(C=O)-、-(C=O)CR5-、-(C=O)NR5-、-(C=S)NR5-、-(S=O)2-、-(S=O)2NR5-、-NR5(C=O)-、-NR5(C=O)O-、-NR5(C=O)NR5-、-NR5-或-(C=O)O-;
M独立选自-C0~C4亚烷基-(6~10元芳基)、-C0~C4亚烷基-(5~10元杂芳基)、-C2~C8烯基-(6~10元芳基)、-C2~C8烯基-(5~10元杂芳基)、-C2~C8炔基-(6~10元芳基)、-C2~C8炔基-(5~10元杂芳基)、-C0~C4亚烷基-(3~10元环烷基)、-C0~C4亚烷基-(4~10元杂环基)、-C0~C4亚烷基-(5~12元桥环基)、-C0~C4亚烷基-(5~12元桥杂环基)、-C0~C4亚烷基-(5~12元螺环基)、-C0~C4亚烷基-(5~12元螺杂环基)、-(6~10元芳基)-C0~C4亚烷基或-(5~10元杂芳基)-C0~C4亚烷基,其中所述的亚烷基、环烷基、杂环基、桥环基、桥杂环基、螺环基、螺杂环基、芳基、杂芳基任选为非取代,或被一个或多个选自F、Cl、Br、OH、CF3、NR5、氧代、烷氧基、环烷叉基、杂环叉基、羟基烷基、烷基、环烷基或杂环基的取代基所取代;
R1独立选自H、D、CN、F、Cl、Br、烷基或环烷基,其中所述的烷基和环烷基任选为非取代,或各自独立任选地被一个或多个选自F、Cl、Br、CN、NH2、OH或NO2的取代基所取代;
R2独立选自F、Cl、Br、NH2、OH、C1~C4烷基、取代氨基或取代C1~C4烷基;
R3独立选自OH、非取代或羟基取代的C1~C6烷基、非取代或羟基取代的C1~C6烷氧基或5元杂芳基,其中所述的5元杂芳基任选为非取代,或独立任选地被一个或多个选自F、Cl、Br、烷基、环烷基、杂环基、桥环基、桥杂环基、螺环基、螺杂环基、芳基烷基或杂芳基烷基的取代基取代;
R4、R5独立选自H、D、F、Cl、Br、C1~C6烷基或C1~C6烷氧基;
当C为0的情况表示该基团不存在。
在本发明的一些优选的实施方式中,R3独立选自OH、C1~C6烷基、羟基C1~C6烷基、C1~C6烷氧基、羟基C1~C6烷氧基或5元杂芳基,其中所述的5元杂芳基任选为非取代,或独立任选地被一个或多个选自F、Cl、Br、C1~C4烷基、羟基C1~C6烷基、3~10元环烷基、4~10元杂环基、5~12元桥环基、5~12元桥杂环基、5~12元螺环基、5~12元螺杂环基、芳基C1~C4烷基或杂芳基C1~C4烷基的取代基取代。
在本发明的一些更优选的实施方式中,M独立选自-C0~C4亚烷基-(6~10元芳基)、-C0~C4亚烷基-(5~10元杂芳基)、-C2~C8烯基-(6~10元芳基)、-C2~C8烯基-(5~10元杂芳基)、-C2~C8炔基-(6~10元芳基)、-C2~C8炔基-(5~10元杂芳基)、-C0~C4亚烷基-(3~10元环烷基)、-C0~C4亚烷基-(4~10元杂环基)、-C0~C4亚烷基-(5~12元桥环基)或-C0~C4亚烷基-(5~12元桥杂环基),其中所述的亚烷基、环烷基、杂环基、桥环基、桥杂环基、芳基、杂芳基任选为非取代,或被一个或多个选自F、Cl、Br、OH、CF3、NR5、氧代或C1~C6烷氧基的取代基所取代。
在本发明的一些更优选的实施方式中,所述化合物具有式II的结构,或式II结构的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,
X1、X2、X3、X4、G、R1、R2、R3的定义分别如前述。
在本发明的一些更优选的实施方式中,式I化合物选自:
根据本发明的第二个方面,提出了式I化合物的制备方法,包括以下步骤:
式I-A化合物与式I-B化合物发生偶联反应制得式I化合物;
其中,X1、X2、X3、X4、G、E、M、R1、R2、R3、R4的定义分别如前述。
在本发明的一些实施方式中,当式I化合物中R2独立选自F、Cl、Br时,式I化合物的制备方法包括以下步骤:
式I-C化合物与式I-D化合物进行偶联反应制得式I-E化合物;
式I-E化合物脱保护得式I-F化合物;
式I-F化合物进行取代反应制得式I化合物。
在本发明的一些优选的实施方式中,当式I化合物中R2独立选自F、Cl、Br时,式I化合物的制备方法还包括式I-F化合物进行取代反应制得式I-G化合物的步骤,再制得式I化合物
根据本发明的第三个方面,提出了一种药物组合物,包括所述的式I化合物、式II化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,以及任选地,药学上可接受的辅料。
根据本发明的第四个方面,提出了所述的式I化合物、式II化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药或所述的药物组合物在制备用于预防或治疗RET相关疾病的药物中的用途。
在本发明的一些实施方式中,RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
根据本发明的第五个方面,提出了所述的式I化合物、式II化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药或所述的药物组合物用于预防或治疗RET相关疾病。
在本发明的一些实施方式中,RET相关疾病包括癌症、肠易激综合征和/或与肠易激综合征相关的疼痛。
定义
除非另有说明,本发明对于基团或者术语所提供的初始定义适用于整篇说明书的该基团或者术语;对于本发明没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换。
“多个”是指两个或更多的数量,因而本发明中描述的被多个基团取代,是指被两个或更多的基团取代,具体的取代基个数,受到被取代基团的可取代位点个数及空间位阻的影响,通常是指被两个、三个、四个、五个或六个基团取代,进一步优选被两个或三个基团取代。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~C4烷基”是指包含1~4个碳原子的烷基。
本发明中所述的“烷基”是指具有指定数目的碳原子的饱和烃基。例如,C1~C8烷基是指具有1至8个碳原子,例如优选具体1至4个碳原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团也可任选地被一个或多个如本发明所定义的取代基取代。烷基的具体实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明中所述的“亚烷基”是指具有指定数目个碳原子的二价饱和脂肪族烃基。例如,“Ca~Cb亚烷基”是指具有a至b个碳原子的亚烷基基团。亚烷基基团可以是直链或支链的。例如,“C1~C6亚烷基”意在包括亚甲基、亚乙基、亚丙基、2-甲基亚丙基、二甲基亚乙基、亚戊基等。因此,术语“亚丙基”可以通过下列结构例举:同样地,术语“二甲基亚丙基”可以例如通过下列结构的任一种例举:
本发明中所述的“烯基”是指具有指定数目个碳原子且具有至少1个碳碳双键(>C=C<)的直链或支链不饱和烃基基团。例如,Ca~Cb烯基是指具有a至b个碳原子的含烯基的不饱和烃基,烯基的具体实例包括乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
本发明中所述的“炔基”是指含有至少一个碳碳三键的直链或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如,C2~C6炔基的具体实例包括乙炔基、丙炔基等。
本本发明中所述的“环烷基”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(包括稠合)的饱和或部分饱和的环状基团。环烷基基团的实例包括环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基、环己烯基,以及多环烷基环,例如双环丙基、双环己基、双环戊基、双环辛基等,其中,多环烷基环中的各个环可以与同一个碳原子相连,例如也可以分别与相邻和/或间隔的不同碳原子相连,例如
本发明中所述的“桥环”是指由两个或两个以上环状结构彼此共用两个非相邻碳原子所形成的饱和或部分饱和的环状结构。因此,本发明所述的“5~12元桥环基”包括“5~12元饱和桥环基”和“5~12元部分饱和桥环基”,优选5~10元桥环基。“桥环基”的具体实例包括:等。术语“桥环”还包括金刚烷,包括但不限于以下结构
本发明中所述的“螺环”是指由两个或两个以上环状结构彼此共用一个环原子所形成的饱和或部分饱和且没有环杂原子的环状结构。本发明所述的“5~12元螺环基”包括“5~12元饱和螺环基”和“5~12元部分饱和螺环基”,具体实例包括:等。
本发明中所述的“杂环”是指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环的基团、优选3至9个环原子的一价饱和或部分不饱和单环或二环的基团,其任选包含1、2或3个选自N、O和/或S的环杂原子,其余的环原子是碳。二环表示由共有两个环原子的两个环组成的。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。上述定义所述的“非芳香性”是指该基团独立存在时不具有芳香性。本发明不限制该基团通过环内或环外不饱和键与其他结构相连、或者通过单键与其他不饱和结构相连、或者在特定的条件下(如特殊溶剂中)而使其具有芳香性。本发明的杂环基包括“4~10元杂环烷基”、“5~12元桥杂环基”、“5~12元螺杂环基”。
本发明中所述的“桥杂环”是指由两个或两个以上环状结构彼此共用两个非相邻碳原子所形成的、含有至少一个环原子为杂原子的、饱和或部分饱和的环状结构。所述桥杂环一般包含CO、N、O、S、NO、SO、S(O)2,优选独立地包含1~3个CO、N和/或O,更优选独立地包含1个O和/或1个N。本发明所述“5~12元桥杂环基”包括“5~12元饱和桥杂环基”和“5~12元部分饱和桥杂环基”,优选5~10元桥杂环基、6~8元桥杂环基、7~8元桥杂环基、6~8元饱和桥杂环基、6~8元含氮桥杂环基、6~8元饱和含氮桥杂环基等。桥杂环的具体实例包括:等。
本发明中所述的“螺杂环”是指由两个或两个以上环状结构彼此共用一个环原子所形成的、含有至少一个环原子为杂原子的、饱和或部分饱和的环状结构。所述杂原子一般选自CO、N、O、S、NO、SO、S(O)2,优选独立地包含1~3个CO、N和/或O,更优选独立地包含1个CO和1个N。本发明所述“5~12元螺杂环基”包括“5~12元饱和螺杂环基”和“5~12元部分饱和螺杂环基”,优选7~12元螺杂环基、7~11元螺杂环基、8~11元螺杂环基、8~11元饱和螺杂环基、9~11元饱和螺杂环基、9~11元饱和螺杂环基、9~11元含氮螺杂环基、9~11元含氮饱和螺杂环基。螺杂环的具体实例包括但不仅限于: 等。
本发明中所述的“芳基”是指具有多个碳原子的芳烃基团。芳基通常包含单环、二环或三环芳基。此外,本发明所用的术语“芳基”是指可以是单个芳环或由多个芳环稠合在一起的的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基等。
本发明中所述的“杂芳基”是指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子等。通常指包含多个环原子的、其中一个或多个环原子选自O、N、S等杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂芳基例如有:吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。
术语“环烷叉基”表示从3~7元饱和的单环碳环中的同一个碳原子上去除两个氢原子形成的二价的饱和的单环碳体系。在一些实施方案中,环烷叉基表示C3~C6环烷叉基;在另一些实施方案中,环烷叉基表示C3~C5环烷叉基。环烷叉基的实例包括但不限于,环丙叉基、环戊叉基、环丁叉基、环己叉基,等。
术语“杂环叉基”表示从3~7元饱和的单环杂环中的同一个碳原子上去除两个氢原子形成的二价的饱和的单环杂环体系,其中该体系中至少包含1个碳原子,包含1个、2个或3个选自O、N、S的杂原子。在一些实施方案中,杂环叉基表示3~6元杂环叉基;在另一些实施方案中,杂环叉基表示3~5元杂环叉基。杂环叉基的实例包括但不限于,环氧乙烷叉基、氮杂环丙烷叉基、氧杂环丁烷叉基、氧杂环戊烷叉基、氮杂环丁烷叉基,等。
术语“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。
术语“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物。尤其是,N-氧化物可用L.W.Deady的方法制备,其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1~C4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1~C8磺酸化物和芳香磺酸化物。
术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1~C24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
术语“RET相关癌症”是指与RET基因、RET激酶(在本发明中也称为RET激酶蛋白或RET激酶)或其中任何一者的表达或活性或水平相关或具有失调的癌症。本发明描述了RET相关癌症的非限制性示例。所述RET基因、RET激酶或者其中任何一者的表达或活性或水平的失调是RET基因中的一个或多个点突变。
短语“RET基因、RET激酶或其中任何一者的表达或活性或水平失调”是指基因突变(例如导致融合蛋白表达的RET基因易位,导致与野生型RET蛋白相比包含至少一个氨基酸缺失的RET蛋白表达的RET基因中的缺失,或导致具有一个或多个点突变的RET蛋白表达的RET基因中的突变,或导致与野生型RET蛋白相比RET蛋白中的至少一个氨基酸缺失的RET蛋白的RET mRNA的可变剪接形式),或RET基因扩增,所述基因扩增导致RET蛋白过表达或由细胞RET基因过表达导致的自分泌活性,导致细胞中RET蛋白的激酶结构域的活性的致病性增加(例如,RET蛋白的激酶结构域的组成性激活)。作为另一个示例,RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是编码RET蛋白的RET基因中的突变,所述RET蛋白与不包含该突变的RET基因编码的蛋白质相比,具有组成型活性或具有增加的活性。例如,RET基因、RET激酶或其中任何一者的表达或活性或水平失调可以是基因或染色体易位的结果,其导致融合蛋白的表达,所述融合蛋白包含第一包含功能性激酶结构域的RET部分和伴侣蛋白的第二部分(即不是RET)。在一些示例中,RET基因、RET蛋白或表达或活性的失调可以是一个RET基因与另一个RET基因的基因翻译的结果。
RET激酶、RET基因或其中任何(例如一种或多种)的表达或活性或水平的失调可能有助于肿瘤发生。例如,RET激酶、RET基因失调或者其中任何一者的表达或活性或水平的失调可以是RET激酶、RET基因或RET激酶结构域的易位、过表达、激活、扩增或突变。易位可以包括涉及RET激酶结构域的易位,突变可以包括涉及RET配体结合位点的突变,并且扩增可以是RET基因。其他失调可包括RET mRNA剪接变体和RET自分泌/旁分泌信号传导,这也可能有助于肿瘤发生。
在一些实施方式中,RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶中的一个或多个缺失(例如4位氨基酸的缺失)、插入或点突变。在一些实施方式中,RET基因、RET激酶或其中任何一者的表达或活性或水平的失调包括RET激酶的一个或多个残基的缺失,导致RET激酶结构域的组成型活性。
术语“肠易激综合征”包括腹泻主导型、便秘主导型或交替排便模式、功能性胃气胀、功能性便秘、功能性腹泻、非特异性功能性肠病、功能性腹痛综合征、慢性特发性便秘、功能性食管病、功能性胃十二指肠病、功能性肛门直肠疼痛、炎性肠病,等。
本发明的药物组合物适用于多种给药途径,因而可制成药学上可接受的任一剂型。例如,上述药物组合物可以经口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,所述药物组合物可制成口服制剂,例如可以制成常规的口服固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,上述药物组合物也可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中的常规方法生产,配置注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。用于直肠给药时,所述药物组合物可制成栓剂等。用于经肺给药时,所述药物组合物可制成吸入制剂、气雾剂、粉雾剂或喷雾剂等。
药学上可接受的辅料是指无毒性、与活性成分相容且其他方面生物学性质上适用于生物体的物质。特定辅料的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。药学上可接受的辅料其实例包括但不限于药学领域常规的溶剂、稀释剂、分散剂、助悬剂、表面活性剂、等渗剂、增稠剂、乳化剂、粘合剂、润滑剂、稳定剂、水合剂、乳化加速剂、缓冲剂、吸收剂、着色剂、离子交换剂、脱模剂、涂布剂、矫味剂、和抗氧化剂等。必要时,还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
包含本发明所述化合物的组合物可以配制成单位剂型,每个剂量包含约5至约1,000mg(1g),更通常约100mg至约500mg的活性成分。术语“单位剂量形式”指适合作为单一剂量用于人体对象或其他患者的物理上离散的单位,每个单位包含预定量的活性材料(即如本发明提供的通式I的化合物)和合适的药用赋形剂,所述预定量经计算能够产生所需的治疗效果。
在一些实施方式中,本发明提供的组合物含有约5mg至约50mg的活性成分。本领域普通技术人员将理解,这体现了包含约5mg至约10mg,约10mg至约15mg,约15mg至约20mg,约20mg至约25mg,约25mg mg至约30mg,约30mg至约35mg,约35mg至约40mg,约40mg至约45mg或约45mg至约50mg活性成分的化合物或组合物。
在一些实施方式中,本发明提供的组合物含有约50mg至约500mg的活性成分。本领域普通技术人员将会理解,这体现了包含约50mg至约100mg,约100mg至约150mg,约150mg至约200mg,约200mg至约250mg,约250mg至约300mg,约350mg至约400mg或约450mg至约500mg活性成分的化合物或组合物。
在一些实施方式中,本发明提供的组合物含有约500mg至约1,000mg的活性成分。本领域普通技术人员将理解,这体现了包含约500mg至约550mg,约550mg至约600mg,约600mg至约650mg,约650mg至约700mg,约700至约750mg,约750mg至约800mg,约800mg至约850mg,约850mg至约900mg,约900mg至约950mg或约950mg至约1,000mg活性成分的化合物或组合物。
在本本发明所述的任何方法的一些实施方式中,式I或式II的化合物(或其药学上可接受的盐或溶剂合物)与治疗有效量的至少一种其他治疗剂联用,所述至少一种其他治疗剂选自一种或多种其他疗法或治疗(例如化学治疗)试剂。
其他治疗剂的非限制性示例包括:其它RET靶向治疗剂(即其他RET激酶抑制剂:不是本发明所述化合物的RET抑制剂),受体酪氨酸激酶靶向的治疗剂,信号转导途径抑制剂,检查点抑制剂,凋亡途径调节剂(例如Obataclax);细胞毒性化学治疗剂,血管生成靶向治疗剂,免疫靶向剂和放射疗法。
在一些实施方式中,其他RET靶向治疗剂是显示RET抑制活性的多激酶抑制剂。
RET靶向治疗剂的非限制性示例包括阿拉替尼,阿帕替尼,卡博替尼(XL-184),多维替尼,乐伐替尼,莫泰沙尼,尼达尼布,普纳替尼,雷格拉非尼,斯塔替尼(sitravatinib)(MGCD516),舒尼替尼,索拉非尼,瓦他拉尼,凡德他尼,AUY-922(5-(2,4-二羟基-5-异丙基-苯基)-N-乙基-4-[4-(吗啉代甲基)苯基]异噁唑-3-甲酰胺),BLU6864,BLU-667,DCC-2157,NVP-AST487(1-[4-[(4-乙基哌嗪-1-基)甲基]-3-(三氟甲基)苯基]-3-[4-[6-(甲氨基)嘧啶-4-基]氧苯基]脲),PZ-1,RPI-1(1,3-二氢-5,6-二甲氧基-3-[(4-羟基苯基)亚甲基]-H-吲哚-2-酮),RXDX-105(1-(3-(6,7-二甲氧基喹唑啉-4-基)氧基)苯基)-3-(5-(1,1,1-三氟-2-甲基丙-2-基)异噁唑-3-基)脲),SPP86(1-异丙基-3-(苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺)和TG101209(N-(1,1-二甲基乙基)-3-[[5-甲基-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-4-嘧啶基]氨基]苯磺酰胺)。
其它治疗剂包括RET抑制剂,如在例如下述中所述的那些:美国专利号7,504,509;8,299,057;8,399,442;8,067,434;8,937,071;9,006,256;和9,035,063;美国公开号2014/0121239;20160176865;2011/0053934;2011/0301157;2010/0324065;2009/0227556;2009/0130229;2009/0099167;2005/0209195;国际公开号WO 2014/184069;WO 2014/072220;WO2012/053606;WO 2009/017838;WO 2008/031551;WO 2007/136103;WO 2007/087245;WO2007/057399;WO 2005/051366;WO 2005/062795;和WO 2005/044835;和J.Med.Chem.2012,55(10),4872-4876,其全部通过引用全文纳入本发明。
本发明还提供了治疗癌症的方法,包括向有需要的患者给予治疗癌症的药物组合,其包括(a)通式I的化合物或其药学上可接受的盐或溶剂合物,(b)其他治疗剂,和(c)任选的至少一种药学上可接受的运载体,以同时、分开或顺序用于治疗癌症,其中通式I的化合物或其药学上可接受的盐或溶剂合物的量和其他治疗剂的量在治疗癌症方面共同有效。
本发明所述的化合物和组合物可单独施用或与其它化合物(包括其它RET调节化合物)或其它治疗剂组合施用。在一些实施方案中,本发明的化合物或组合物可与一种或多种选自以下的化合物组合施用:卡博替尼(COMETRIQ)、凡德他尼(CALPRESA)、索拉非尼(NEXAVAR)、舒尼替尼(SUTENT)、雷格拉非尼(STAVARGA)、普纳替尼(ICLUSIG)、贝伐单抗(阿瓦斯汀)、克唑替尼(XALKORI)或吉非替尼(IRESSA)。本发明的化合物或组合物可通过相同或不同给药途径与其它治疗剂同时或相继施用。本发明的化合物可与其它治疗剂一起包含在单一制剂中或在单独的制剂中。
在一些实施方式中,本发明的化合物可用于与一种或多种其他治疗剂或疗法组合治疗肠易激综合征(IBS),所述其它治疗剂或疗法通过相同或不同作用机制起作用而在肠易激综合征治疗中有效。根据本领域技术人员已知的标准药学实践,所述至少一种其他治疗剂可以与通式I的化合物或其药学上可接受的盐或溶剂合物作为相同或分开的剂型的一部分、经由相同或不同的给予途径、以及根据相同或不同的给予时间表而给予。用于治疗肠易激综合征(IBS)的其他治疗剂的非限制性示例包括益生菌,纤维增补剂(例如洋车前草,甲基纤维素),止泻药(例如洛哌丁胺),胆汁酸结合剂(例如考来烯胺,考来替泊,考来维仑),抗胆碱能药和抗痉挛药(例如莨菪碱,双环胺),抗抑郁药(例如三环类抗抑郁药如丙咪嗪或去甲替林或选择性5-羟色胺再摄取抑制剂(SSRI)如氟西汀或帕罗西汀),抗生素(例如利福昔明),阿洛司琼和鲁比前列酮。
本发明所述的癌症(例如RET相关癌症)是血液学癌症。在本发明所述的任何方法或用途的一些实施方式中,癌症(例如RET相关癌症)是实体瘤。在本发明所述的任何方法或用途的一些实施方式中,癌症(例如RET相关癌症)是肺癌(例如,小细胞肺癌或非小细胞肺癌),乳头状甲状腺癌,甲状腺髓样癌,分化型甲状腺癌,复发性甲状腺癌,难治性分化型甲状腺癌,肺腺癌,细支气管肺癌,2A或2B型多发性内分泌肿瘤(分别为MEN2A或MEN2B),嗜铬细胞瘤,甲状旁腺增生,乳腺癌,结直肠癌(例如转移性结肠直肠癌),乳头状肾细胞癌,胃肠粘膜的神经节细胞瘤病,炎性肌纤维母细胞瘤或宫颈癌。在本文所述的任何方法或用途的一些实施方式中,癌症(例如RET相关癌症)选自:急性淋巴细胞白血病(ALL),急性髓性白血病(AML),青少年癌症,肾上腺皮质癌,肛门癌、阑尾癌,星形细胞瘤,非典型性畸胎瘤/横纹肌样瘤,基底细胞癌,胆管癌,膀胱癌,骨癌,脑干胶质瘤,脑肿瘤,乳腺癌,支气管肿瘤,伯基特淋巴瘤,类癌瘤,未知原发癌,心脏肿瘤,宫颈癌,儿童癌症,脊索瘤,慢性淋巴细胞白血病(CLL),慢性骨髓性白血病(CML),慢性骨髓增殖性肿瘤,结肠癌,结肠直肠癌,颅咽管瘤,皮肤T细胞淋巴瘤,胆管癌,原位导管癌,胚胎性肿瘤,子宫内膜癌,室管膜瘤,食道癌,成感觉神经细胞瘤,尤因肉瘤,颅外生殖细胞肿瘤,性腺外生殖细胞瘤,肝外胆管癌,眼癌,输卵管癌,骨纤维组织细胞瘤,胆囊癌,胃癌,胃肠类癌瘤,胃肠道间质瘤(GIST),生殖细胞瘤,妊娠滋养细胞疾病,神经胶质瘤,多毛细胞瘤,多毛细胞白血病,头颈癌,心脏癌,肝细胞癌,组织细胞增多症,霍奇金淋巴瘤,下咽癌,眼内黑色素瘤,胰岛细胞瘤,胰腺神经内分泌瘤,卡波西肉瘤,肾癌,朗格汉斯细胞组织细胞增多症,喉癌,白血病,唇和口腔癌,肝癌,肺癌,淋巴瘤,巨球蛋白血症,骨恶性纤维组织细胞瘤,骨癌,黑色素瘤,梅克尔细胞癌,间皮瘤,转移性鳞状颈癌,中线状癌,口癌,多发性内分泌瘤综合征,多发性骨髓瘤,真菌病蕈样肉芽肿,骨髓增生异常综合征,骨髓增生异常/骨髓增殖性肿瘤,髓性白血病,骨髓性白血病,多发性骨髓瘤,骨髓增殖性肿瘤,鼻腔和鼻窦癌,鼻咽癌,成神经细胞瘤,非霍奇金淋巴瘤,非小细胞肺癌,口部癌,口腔癌,唇癌,口咽癌,骨肉瘤,卵巢癌,胰腺癌,乳头状瘤病,副神经节瘤,鼻旁窦和鼻腔癌,甲状旁腺癌,阴茎癌,咽癌,嗜铬细胞瘤,垂体癌,浆细胞瘤,胸膜肺胚细胞瘤,妊娠和乳腺癌,原发性中枢神经系统淋巴瘤,原发腹膜癌,前列腺癌,直肠癌,肾细胞癌,视网膜母细胞瘤,横纹肌肉瘤,唾液腺癌,肉瘤,塞扎里综合征,皮肤癌,小细胞肺癌,小肠癌,软组织肉瘤,鳞状细胞癌,鳞状颈癌,胃癌,T细胞淋巴瘤,睾丸癌,咽喉癌,胸腺瘤和胸腺癌,甲状腺癌症,肾盂和输尿管的移行细胞癌,未知原发癌,尿道癌,子宫癌,子宫肉瘤,阴道癌,外阴癌和威尔姆氏瘤。
在一些实施方案中,本发明所述RET相关癌症选自肺癌,乳头状甲状腺癌,甲状腺髓样癌,分化的甲状腺癌,复发性甲状腺癌,难治性分化型甲状腺癌,2A或2B型多发性内分泌瘤(分别为MEN2A或MEN2B),嗜铬细胞瘤,甲状旁腺增生,乳腺癌,结直肠癌,乳头状肾细胞癌,胃肠粘膜神经节细胞瘤和宫颈癌。在一些实施方案中,所述RET相关癌症是RET融合体肺癌或甲状腺髓样癌。
本发明所述的肠易激综合征(IBS)包括腹泻主导型、便秘主导型或交替型、功能性腹胀、功能性便秘、功能性腹泻、不特异的功能性肠紊乱、功能性腹痛综合征、慢性特发性便秘、功能性食管疾病、功能性胃十二指肠疾病、功能性肛门直肠疼痛和炎性肠病。
本发明的有益效果为:本发明化合物对RET具有高选择性的抑制活性,且对RET融合和突变都有很好的抑制活性。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例中无特殊说明,反应的温度为室温,室温是指20~25℃。所有温度以℃(摄氏度)表示。
1.中间体的合成
以部分中间体为例,可采用以下方法合成得到:
1.1中间体式I-A1化合物的合成:
6-溴-2-氟-4-羟基吡唑并[1,5-a]吡啶-3-碳腈与式I-A1-1化合物进行偶联反应制得式I-A1-2化合物,式I-A1-2化合物进行取代反应制得式I-A1化合物。
1.2中间体式I-A2化合物的合成:
2-氨基-6-溴-4-羟基吡唑并[1,5-a]吡啶-3-碳腈与式I-A1-1化合物进行偶联反应制得式I-A2-1化合物,式I-A2-1化合物进行取代反应制得式I-A2化合物。
1.3中间体式I-B1化合物、式I-D1化合物的合成:
2-氟-5-溴吡啶与G-Boc衍生物在Cs2CO3、DMSO下反应后调节pH制得式I-D1-1化合物,式I-D1-1化合物进行取代反应制得式I-D1化合物,式I-D1化合物与联硼酸频那醇酯在钯催化剂下反应制得式I-B1化合物。
1.4中间体1-氨基-3-溴-5-甲氧基吡啶-1-三甲基苯磺酸铵(1-amino-3-bromo-5-methoxypyridin-1-ium2,4,6-trimethylbenzenesulfonate)的合成
称取2,4,6-三甲基苯磺酸(3000g,14.98mol),加入甲叔醚36L,加入HO-NH-Boc(2015.35g,15.136mol),降温至0℃,滴加1670.8gTEA,控温<5℃,有白色固体产生,搅拌过夜。TLC监控(正己烷/EA=2:1,RF0=0.8,RF1=0.5),过滤用甲叔醚洗涤滤饼,得到的滤液旋蒸到差不多干,正庚烷打浆,得到4.3kg N-Boc-O-(2,4,6-三甲基苯磺酰基)羟胺。
称取20mL TFA,分批加入N-Boc-O-(2,4,6-三甲基苯磺酰基)羟胺(10g,31.67mmol),0℃下搅拌2h,TLC监控(正己烷/EA=3:1,RF1=0.8,RF2=0.6),倒入250mL冰水,搅拌10min,析出大量白色固体,过滤用水洗至滤液中性,得到7g 2,4,6-三甲基苯磺酰基)羟胺。
量取18L DCM溶解2,4,6-三甲基苯磺酰基)羟胺(2600g,12.077mol),降温至0℃,分批加入3-溴-5-甲氧基吡啶(2.28kg,12.198mol)。低温搅拌过夜。析出大量固体,加入甲叔醚18L,搅拌1h。过滤,用甲叔醚洗涤滤饼,得到3.93kg 1-氨基-3-溴-5-甲氧基吡啶-1-三甲基苯磺酸铵,产率86.71%
1.5中间体4-溴-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-bromo-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成
5L三口瓶中加入2,2,2-三氟乙基对甲苯磺酸酯(240g,0.944mol),2.4L THF,搅拌溶清,氩气保护,降温至-65℃,滴加正丁基锂(1140mL,2.832mol),控温-55~-65℃,滴加完毕反应半小时,期间TLC监控(EA/PE=1:20,RF0=0.35,RF1=0.5),加入500mL水,控温0℃以下,加入稀盐酸调酸性放置过夜,旋蒸大部分THF,加入3L EA萃取,乳化严重,抽滤破乳,收集有机相旋蒸,柱层析分离得到黄色液体170g,产率55.6%。
5L三口瓶加入1-氨基-3-溴-5-甲氧基吡啶-1-三甲基苯磺酸铵(346.05g,0.922mol),K2CO3(531.08g,3.842mol),2L DMF,氩气保护,降至内温0℃,滴加上一步反应产物2,2-二氟乙烯基-4-甲基苯磺酸酯(180g,0.768mol),滴加完毕自然升至室温搅拌1h,1h就升至90℃,加热反应过夜。后处理加水10L,搅拌有固体析出,过滤,滤饼用水洗涤,溶解拌样,柱层析分离共得到33g 4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶,产率17.52%(TLC的上点是需要的产物,中点是往O那边环化的产物,用EA/PE:65:1冲)。
往500mL三口瓶中加入4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶(23.5g,96mmol)和240mL DMF,氩气保护,降温至内温0℃以下,滴加三氯氧磷(73.5g,479mmol),滴加完毕自然升至室温,搅拌过夜。TLC监控(PE/EA=4:1,RF2=0.9,RF3=0.2,UV254nm)。用水淬灭POCl3,放热明显,过滤抽干旋蒸除水,得到米黄色固体22.1g,产率84.4%。
往1L三口瓶中加入上述米黄色固体产物(11.8g,0.0432mol),NH2-OH-HCl(3g,0.0432mol)和200mL EtOH,升温至80℃回流搅拌2h,TLC监控(EA/PE=1:2,RF3=0.5,RF4=0.6),后处理加入水有固体析出,抽滤滤液旋蒸,得到11.67g(Z)-4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶-3-碳醛肟,产率93.73%。
5L三口瓶中加入(Z)-4-溴-2-氟-6-甲氧基吡唑[1,5-a]吡啶-3-碳醛肟(24.5g,90.7mmol),DCE 2.5L,搅拌下降温至-5℃,滴加BBr3(73.5mL,0.91mol),控制温度低于-5℃,滴加完毕恢复室温搅拌10min,升温55℃加热反应过夜。TLC监控(PE/EA=2:1,RF5=0.7,RF6=0.1),用水淬灭BBr3,控制淬灭温度不超过10℃(淬灭时产生HBr气体,需搭设尾气吸收装置),淬灭后浓缩除去DCE,加入水和EA萃取,有机相除水干燥后浓缩得到粗品,粗品于50mL(PE/EA=10:1)打浆,过滤滤饼用石油醚洗涤,得到20.5g棕色固体,产率88.26%。
1H NMR(500MHz,DMSO-d6)δ11.94(s,1H),8.71(d,J=1.4Hz,1H),6.97(d,J=1.4Hz,1H)
1.6中间体6-溴-2-氟-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(6-bromo-2-fluoro-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
5L三口瓶中加入2,2,2-三氟乙基对甲苯磺酸酯(240g,0.944mol),2.4L THF,搅拌溶清,氩气保护,降温至-65℃,滴加正丁基锂(1140mL,2.832mol),控温-55~-65℃,滴加完毕反应半小时,期间TLC监控(EA/PE=1:20,RF0=0.35,RF1=0.5),加入500mL水,控温0℃以下,加入稀盐酸调酸性放置过夜,旋蒸大部分THF,加入3L EA萃取,乳化严重,抽滤破乳,收集有机相旋蒸,柱层析分离得到黄色液体170g,产率55.6%。
5L三口瓶加入1-氨基-3-溴-5-甲氧基吡啶-1-三甲基苯磺酸铵(346.05g,0.922mol),K2CO3(531.08g,3.842mol),2L DMF,氩气保护,降至内温0℃,滴加上一步反应得到的黄色液体(180g,0.768mol),滴加完毕自然升至室温搅拌1h,1h就升至90℃,加热反应过夜。后处理加水10L,搅拌有固体析出,过滤,滤饼用水洗涤,溶解拌样,柱层析分离共得到往O那边环化的产物,下点。
往500mL三口瓶中加入上一步反应产物(24g,98mmol)和250mL DMF,氩气保护,降温至内温-5~-10℃以下,滴加三氯氧磷(75.1g,490mmol),滴加完毕自然升至45℃,搅拌3h。LCMS监控。用水淬灭POCl3,放热明显,过滤抽干旋蒸除水,得到白色固体26g。
往三口瓶中加入上一步反应产物(25g,91.5mol),NH2-OH-HCl(7g,101mol)和350mL EtOH,升温至80℃回流搅拌4h。LCMS监控,后处理加入水有固体析出,抽滤滤饼用水洗涤,滤饼除水干燥后得到25g产物。
向反应瓶加入上一步反应产物(23.0g,0.08mol),500mL DCM,降温至0℃,滴加SOCl2,放烟,加完后撤去冰水浴,自然升至室温搅拌,过程LCMS监控,反应完毕反应液加入冰水淬灭,用DCM萃取,除水干燥,旋蒸得到固体21g。
5L三口瓶中加入上一步反应产物(18.5g,68.5mmol),1L DCE,搅拌下降温至-5℃,滴加BBr3(85g,0.34mol),控制温度低于0℃,滴加完毕恢复室温搅拌10min。TLC监控(PE/EA=1:1),用水淬灭BBr3,控制淬灭温度不超过10℃(淬灭时产生HBr气体,需搭设尾气吸收装置),淬灭后浓缩除去DCE,加入水和EA萃取,有机相除水干燥后浓缩干得到粗品,粗品于50mL(PE/EA=10:1)打浆,过滤滤饼用石油醚洗涤,得到16g粗品(纯度82%)。粗品溶于EA和THF,加入饱和亚硫酸氢钠洗涤,减少副产物含量,得到13g较纯产品(纯度86%)。
1H NMR(500MHz,DMSO-d6)δ10.43(s,1H),8.26(d,J=1.9Hz,1H),7.83–7.60(m,1H)
1.7中间体2-氨基-6-溴-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(2-amino-6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
单口瓶中加入1-氨基-3-溴-5-甲氧基吡啶-1-三甲基苯磺酸铵(250g,0.6183mol),加入1250mL DMF,加入碳酸钾(256.36g,1.8549mol),降至0℃,分批加入乙基2-氰基亚氨代乙酸酯盐酸盐(181g,1.2367mol),室温搅拌2h,TLC监控(PE/EA=1/1)。反应结束加入3V水和1.5eq碳酸钾的冰醋酸,有固体析出,静置一夜。过滤,THF溶解固体,旋蒸得到80g粗品。
加入上一步反应产物(17g,63.65mmmol),300mL DCE,加入AlCl3(50.9g,381.89mmol)。80℃下回流搅拌,TLC监控(EA/Hexane=1/1)反应结束后后处理加入适量THF然后缓缓把反应液加入水中淬灭,有固体析出,过滤,收集滤饼,滤饼用THF回流溶清后,垫硅藻土过滤,滤液加入活性炭,搅拌过滤,滤饼用甲叔醚打浆,得到黄色固体3.1g。
1H NMR(500MHz,DMSO-d6)δ11.24(s,1H),8.34(s,1H),6.87(s,1H),6.22(d,J=4.9Hz,2H)
实施例1
化合物4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:4-溴-2-氟-6-((4-甲氧基苄基)氧基)吡唑[1,5-a]吡啶-3-碳腈(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
500mL单口瓶加入4-溴-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(14.5g,56.6mmol,1.0eq),4-甲氧基氯苄(10.6g,67.9mmol,1.2eq),K2CO3(15.6g,0.1mol,2.0eq),250mL DMF,65℃下搅拌3h。TLC监控(PE/EA=4:1)反应结束后将反应液倒入500mL水中,加入300mL EA萃取,有机相除水干燥后旋蒸。固体加入100mL MTBE打浆,过滤,滤饼用MTBE洗涤,得到19.5g固体。将打浆后的固体用THF溶清浓缩时析晶,趁热过滤,滤饼用MTBE洗涤,得到15.2g棕色晶状固体,产率70%。
1H NMR(500MHz,DMSO-d6)δ8.87(d,J=1.3Hz,1H),7.55–7.49(m,1H),7.45(d,J=8.3Hz,2H),7.04–6.92(m,2H),5.32(s,2H),3.77(s,3H).
步骤2:2-氟-6-(4-甲氧基苄基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡唑[1,5-a]吡啶-3-碳腈
(2-fluoro-6-((4-methoxybenzyl)oxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
室温下加入4-溴-2-氟-6-((4-甲氧基苄基)氧基)吡唑[1,5-a]吡啶-3-碳腈(5.62g,0.0145mol,1.0eq),加入联硼酸频那醇酯(5.71g,0.02248mol,1.2eq),Pd2(dba)3(1.43g,0.00145mol,0.1eq),加入X-phos(1.43g,0.0030mol,0.2eq),120mL甲苯,三乙胺(4.56g,0.045mol,3.0eq),氮气交换多次,于85℃加热搅拌。硅藻土过滤,甲苯洗涤,滤液浓缩干,用100mL异丙醇打浆2h,过滤,滤饼用异丙醇洗涤,滤饼加入100mL EA,加热75℃左右,过滤用EA洗涤滤饼,滤液浓缩干,再用PE打浆淋洗,过滤得到白色固体4.91g。
1H NMR(500MHz,Chloroform-d)δ8.36(s,1H),7.47(d,J=8.5Hz,2H),7.10(s,1H),6.95(d,J=8.6Hz,2H),5.24(s,2H),3.82(s,3H),1.37(s,12H).
步骤3:1-(5-溴吡啶-2-基)氮杂环丁烷-3-醇(1-(5-bromopyridin-2-yl)azetidin-3-ol)的合成:
室温下,于500mL单口瓶中依次加入N-Boc-3-羟基氮杂环丁烷(15g,0.086mol,1.0eq),EtOH(75mL,5V),之后将其降温到0℃搅拌,之后在此温度下缓慢滴加6.8mol/L的HCl/EtOH(150mL,1.02mol,11.9eq),滴加完毕后置于室温搅拌2.5h,TLC监测反应完全。浓缩后得11.6g黄色液体,直接用其进行下一步反应。
室温下,于500mL单口瓶中依次加入上述所得的黄色液体(9.377g,0.085mol,1.5eq),2-氟-5-溴吡啶(10g,0.051mol,1.0eq),Cs2CO3(27.770g,0.085mol,1.5eq),DMSO(125mL,12.5V),之后将其置于100℃油浴中搅拌2.5h,TLC监测反应完全。将反应液加水和无水Na2CO3调节pH至8~9,加EA萃取,有机相用无水Na2SO4干燥后,柱层析分离得白色固体1-(5-溴吡啶-2-基)氮杂环丁烷-3-醇(11.1g,收率85%)。
步骤4:3-氟-4-(三异丙基硅基)乙炔基)苯酚(3-fluoro-4-((triisopropylsilyl)ethynyl)phenol)的合成:
室温下,于50mL单口瓶中依次加入4-溴-3-氟苯酚(200mg,1.047mmol,1.0eq),Ac2O(161mg,1.571mmol,1.5eq),吡啶(166mg,2.094mmol,2.0eq),之后将其置于100℃油浴中搅拌3h,TLC监测反应完全。将反应液加水和稀盐酸调节pH至3~4,之后加EA萃取2次,收集有机相,有机相用饱和NaHCO3调至碱性,萃取分离有机相,之后将有机相水洗2次后,收集此时的有机相用无水Na2SO4干燥后,浓缩得淡黄色液体(185mg,收率75%)。
室温下,于100mL三口瓶中依次加入上步反应所得淡黄色液体(5.690g,24.42mmol,1.0eq),CuI(279mg,1.46mmol,0.06eq),Pd(pph3)4(1.693g,1.46mmol,0.06eq),N2置换多次后,依次加入三异丙基硅基乙炔(13.359g,73.25mmol,3.0eq),N2置换多次,之后加入Et3N(3.953g,39.07mmol,1.6eq),再次N2置换多次,之后将其置于70℃油浴中搅拌21h后,TLC监测反应完全。将反应液抽滤(用硅藻土垫),滤液加饱和食盐水和EA萃取,有机相用无水Na2SO4干燥后,柱层析分离得黄色液体(7.6g,收率92%)。
0℃下,于50mL单口瓶中依次加入上一步反应所得黄色液体(1.933g,5.87mmol,1.0eq),NaOH(347mg,8.67mmol,1.5eq),MeOH(10mL,5V),H2O(2mL,1V),之后在该温度下搅拌1.5h,TLC监测反应完全。将反应液加饱和NaCl水溶液和EA萃取,有机相用无水Na2SO4干燥后,柱层析分离得黄色液体(1.5g,收率88%)
步骤5:5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(5-bromo-2-(3-(3-fluoro-4-((triisopropylsilyl)ethynyl)phenoxy)azetidin-1-yl)pyridine)的合成:
室温下,于250mL三口瓶中依次加入3-氟-4-(三异丙基硅基)乙炔基)苯酚(9.1g,0.031mol,1.0eq),1-(5-溴吡啶-2-基)氮杂环丁烷-3-醇(9.3g,0.040mol,1.3eq),pph3(24.5g,0.093mol,3.0eq),插入温度计,N2置换三次,之后加入THF(60mL,6.5V),再次N2置换三次,之后将其置于60℃油浴中搅拌,待反应液温度达到60℃时,缓慢滴加DIAD(18.9g,0.093mol,3.0eq)(控制滴加速度,使反应液温度保持在60~70℃之间),滴加完毕后在60℃油浴下搅拌16h,TLC监测反应完全。将反应液柱层析分离,除去极性最大和最小得杂质后,得到的黄色油状物在-10℃下于正己烷中结晶,过滤,旋干滤饼,得到白色固体7.5g,收率47%。
1H NMR(400MHz,Chloroform-d)δ8.20(dd,J=2.4,0.7Hz,1H),7.56(dd,J=8.8,2.4Hz,1H),7.41(dd,J=8.8,8.1Hz,1H),6.58–6.47(m,2H),6.26(dd,J=8.8,0.7Hz,1H),5.08(tt,J=6.2,4.1Hz,1H),4.44(ddd,J=9.1,6.2,1.1Hz,2H),4.07(ddd,J=9.1,4.1,1.0Hz,2H),1.15(s,21H).
步骤6:4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈
(4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氟-6-(4-甲氧基苄基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡唑[1,5-a]吡啶-3-碳腈(1.4g,0.004618mol,1.0eq),5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(2.33g,0.004618mol,1.0eq),加入碳酸钾(0.96g,0.006928mol,1.5eq),加入14mL水和42mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.54g,于80℃加热搅拌,TLC监控(PE/EA=2/1)。反应结束浓缩,转移至室温,加入水和EA萃取,水相再用EA萃取一次,合并有机相除水干燥,柱层析分离得到700mg产物。
加入上步反应产物(0.7g,1.0eq),加入10mL DCM,搅拌,滴加1mL TFA,室温下搅拌。TLC监控(PE/THF=1/1)。反应结束用水和DCM萃取,柱层析纯化得到300mg产物。
称取上步反应产物(150mg,0.25mmol,1.0eq),6mL THF,TBAF·3H2O(196mg,0.75mmol,3.0eq),室温搅拌过夜,TLC监控(PE/THF=1/1),加入水和EA萃取,分液,有机相除水干燥,柱层析纯化得到13mg产物,收率11.7%。
1H NMR(500MHz,DMSO-d6)δ11.62(d,J=34.5Hz,1H),8.66(s,1H),8.42(s,1H),7.88(dd,J=8.7,2.0Hz,1H),7.51(t,J=8.5Hz,1H),7.12(s,1H),6.92(d,J=9.6Hz,1H),6.79(d,J=8.5Hz,1H),6.58(d,J=8.7Hz,1H),5.26(s,1H),4.56–4.45(m,2H),4.34(s,1H),3.97(dd,J=9.4,3.2Hz,2H)
实施例2
化合物4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:1-(5-溴吡啶)-2-哌嗪(1-(5-bromopyridin-2-yl)piperazine)的合成:
于500mL单口瓶中加入1-Boc-哌嗪(47g,0.25mol,1.5eq),加入DMSO(200mL,6.7V),加入碳酸铯(82g,0.25mol,1.5eq),15min后加入5-溴-2氟吡啶(30g,0.17mol,1.0eq),氮气保护,100℃加热,回流4小时。TLC监控反应完全后过滤多余的碳酸铯,乙酸乙酯洗涤滤渣2次,加入EA、水(各300mL,10V)萃取,多次萃取直至水相TLC无产物点,分液,无水硫酸钠干燥,旋蒸得到70g粗品,加入正己烷冷冻打浆得到41g白色固体产物,滤液旋干过柱得到9g白色固体产物,共得到50g产物,收率86%。
取上一步反应产物(20g,0.06mol,1.0eq)中加入6.7mol/L盐酸乙醇(60mL,6.8eq),室温搅拌至反应完全。直接旋干后得到26g白色固体粗品。加入20g无水碳酸钠,20mL三乙胺,200mL饱和食盐水和200mL乙酸乙酯,搅拌半小时后萃取分液,干燥,过滤后旋干有机相得到13g淡黄色固体产物,收率92%。
步骤2:6-(三异丙基硅基)乙基)烟醛(6-((triisopropylsilyl)ethynyl)nicotinaldehyde)的合成:
往1L三口瓶中加入2-溴-5-醛基吡啶(33g,0.18mol,1.0eq),三异丙基硅基乙炔(42g,0.23mol,1.3eq),三苯基膦(2.4g,9mmol,0.05eq),CuI(1.7g,9mmol,0.05eq),三乙胺(182g,1.8mol,10eq),350mL THF,氮气置换5次,加入醋酸钯(2.0g,9mmol,0.05eq),升温60℃反应搅拌过夜。TLC监控(PE/EA=5/1)。反应结束后,冷却过滤,滤饼用少量EA洗涤,收集滤液除水干燥,浓缩,柱层析分离得到40g棕黄色油状物。
步骤3:1-(5-溴吡啶-2-基)-4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪(1-(5-bromopyridin-2-yl)-4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)piperazine)的合成:
往500mL单口瓶中加入6-(三异丙基硅基)乙基)烟醛(6.0g,27mmol,1.0eq),1-(5-溴吡啶)-2-哌嗪(9.0g,32.2mmol,1.2eq),120mL DCE,室温搅拌2h,分批加入NaBH(OAc)3(15.6g,81mmol,3eq),加完室温反应2h,TLC监控(PE/EA=1:1,RF产物=0.7).后处理加入冰的饱和氯化铵溶液250mL淬灭。用100mL DCM萃取,有机相除水干燥,柱层析得到5.6g产物。
步骤4:2-氟-6-羟基-4-(6-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(2-fluoro-6-hydroxy-4-(6-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氟-6-(4-甲氧基苄基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡唑[1,5-a]吡啶-3-碳腈(3.0g,0.00709mol,1.0eq),1-(5-溴吡啶-2-基)-4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪(3.79g,0.01063mol,1.5eq),加入碳酸钾(1.47g,0.01063mol,1.5eq),加入22.5mL水和67.5mL1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.3g,于80℃加热搅拌,TLC监控(PE/EA=3/2),转移至室温,加入水和EA萃取,水相再用EA萃取一次,合并有机相除水干燥,柱层析分离得到泡沫状固体1.37g,收率30.6%。
加入上一步反应产物(1.36g,1.8645mol,1.0eq),加入20mL DCM,搅拌,滴加20mLTFA,室温下搅拌。TLC监控(PE/EA=1/2)(用NaHCO3淬灭)。在HPLC看还有6%原料。缓慢加入NaHCO3溶液,调pH=7~8,有固体析出。用EA溶解,分液水相再用EA萃取,合并有机相除水干燥,浓缩至浓稠加入PE析晶,过滤用PE洗涤,得到黄色固体978mg,产率85.7%。
步骤5:4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氟-6-羟基-4-(6-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(150mg,0.2462mol,1.0eq),8mL THF,TBAF·3H2O(193mg,0.73786mol,3.0eq),室温搅拌2h,TLC监控(PE/EA=1/2),加入水萃取,水相再用EA萃取一次,粗品浓缩,刮大板提纯83mg,产率73%。
1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),8.64(s,1H),8.52(s,1H),8.42(d,J=2.0Hz,1H),7.85(dd,J=8.9,2.3Hz,1H),7.77(d,J=7.9Hz,1H),7.55(d,J=7.9Hz,1H),7.11(s,1H),6.93(d,J=8.9Hz,1H),4.28(s,1H),3.29(s,6H),1.36(s,4H)
实施例3
化合物4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)-2-氟-6-羟基吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:4-(三异丙基硅基)乙炔基)苯甲醛(4-((triisopropylsilyl)ethynyl)benzaldehyde)的合成:
于250mL三颈瓶中加入4-溴苯甲醛(8g,0.0432mol,1.0eq),加入四(三苯基膦)钯(2g,0.0017mol,0.04eq),碘化铜(0.45g,0.0024mol,0.05eq),除空气,氮气保护,注射加入THF(100mL,12V),注射加入三乙胺(30g,0.2970mol,7eq),注射加入三异丙基硅基乙炔(10g,0.0548mol,1.3eq),60℃回流过夜。监控反应完全后,萃取分液后再加入2mol/L盐酸洗涤,分液干燥过滤后旋干过柱,得到含杂质点的淡黄色液体产物15g。
步骤2:1-(5-溴吡啶-2-基)-4-((三异丙基硅基)乙炔基)苄基)哌嗪(1-(5-bromopyridin-2-yl)-4-(4-((triisopropylsilyl)ethynyl)benzyl)piperazine)的合成:
于250mL三颈瓶中加入1-(5-溴吡啶)-2-哌嗪(10.5g,0.04337mol,1.2eq),加入4-(三异丙基硅基)乙炔基)苯甲醛(10.4g,0.03630mol,1.0eq),加入DCM(100mL,10V),氮气保护,室温搅拌一小时后加入NaBH(OAc)3(15g,0.07077mol,2.0eq),氮气保护,TLC监控反应完全后,萃取分液干燥过滤旋干得到22g粗品,加入正己烷冷冻后结晶过滤洗涤得到12g淡黄色固体产物,收率65%。
步骤3:1-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-4-(4-(三异丙基硅基)乙炔基)苄基)哌嗪(1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-4-(4-((triisopropylsilyl)ethynyl)benzyl)piperazine)的合成:
往50mL单口瓶加入1-(5-溴吡啶-2-基)-4-((三异丙基硅基)乙炔基)苄基)哌嗪(2g,3.9mmol),联硼酸酯(1.976g,7.8mmol),NaOAc(1.9g,27.3mmol),20mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(0.4g),升温80℃搅拌,TLC监控(PE/EA=2:1,RF4=0.9,RF5=0.5),反应完成后将反应液倒入100mL水中,用EA萃取,取有机相。柱层析分离得到1.2g黄色固体。
步骤4:4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)-2-氟-6-羟基吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-((4-甲氧基苄基)氧基)吡唑[1,5-a]吡啶-3-碳腈(50mg,0.13mmmol,1.0eq),加入1-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-4-(4-(三异丙基硅基)乙炔基)苄基)哌嗪(112mg,0.20mmol,1.5eq),碳酸钠(28mg,0.27mmol,2.0eq),0.5mL水和1.5mL 1,4-二氧六环,氮气置换,加入10mg三苯基膦钯。氮气保护下升温至100℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物。
加入上一步反应产物(876g,1.0eq),加入10mL DCM,搅拌,滴加1mL TFA,室温下搅拌。TLC监控(PE/EA=1/2)。旋蒸溶剂。柱层析分离,杂质有一点,用正庚烷打浆,过滤,得到320mg。
称取上一步反应产物(100mg,0.1643mmol,1.0eq),8mL THF,TBAF·3H2O(129mg,0.4914mmol,3.0eq),室温搅拌6h,TLC监控(PE/EA=1/1),加入水萃取,水相再用EA萃取一次,除水干燥,浓缩。刮大板提纯得50mg淡黄固体。
1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),8.64(s,1H),8.43(d,J=2.3Hz,1H),7.85(dd,J=8.8,2.5Hz,1H),7.45(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.11(s,1H),6.93(d,J=8.9Hz,1H),4.13(s,1H),3.56(d,J=12.2Hz,6H),2.47(s,4H)
实施例4
化合物4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(4-bromo-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(2.56g,10mmol),30mL DMF,碳酸钾(4.15g,30mmol),甲基环氧丙烷(2.16g,30mmol),密封于80℃下搅拌,补加4.95g碳酸钾和12g甲基环氧丙烷,TLC监控(PE/EA=2:1,RF6=0.5,RF7=0.55),降温,过滤用EA洗涤滤饼,用水/EA调节pH至5~6,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到类白色固体1.632g,收率45.4%。
步骤2:4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取1-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-4-(4-(三异丙基硅基)乙炔基)苄基)哌嗪(110mg,0.335mmol),加入4-(三异丙基硅基)乙炔基)苯甲醛(281mg,0.503mmol),碳酸钾(140mg,1mmol),加入28mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至84℃,TLC监控(PE/EA=1:1,RF7=0.5,RF5=0.9,RF产物=0.15)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物泡沫状黄色固体270mg。
25mL单口瓶中加入上一步反应产物(270mg,0.4mmol),TBAF(311mg,1.2mmol)和10mL THF,常温搅拌1h,TLC监控(纯EA,RFA=0.5,RF产品=0.45),反应完全后加入10mL饱和食盐水,用EA萃取,取有机相除水干燥,柱层析分离得到170mg白色固体。
1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.58(d,J=2.1Hz,1H),8.01(dd,J=9.0,2.3Hz,1H),7.45(d,J=7.5Hz,3H),7.36(d,J=8.0Hz,2H),6.93(d,J=9.0Hz,1H),4.77(s,1H),4.17(s,1H),4.07(s,2H),3.60–3.57(m,4H),3.54(s,2H),2.47(d,J=4.6Hz,4H),1.30(s,6H)
实施例5
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-羟基吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-6-溴-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(1g,4mmol,1.0eq),5mL水,15mL 1,4-二氧六环,碳酸钾(0.84g,8mmol,2.0eq),1-二氟甲基-吡咯-4-硼酸频哪醇酯(1.9g,8mmol,2.0eq),氮气保护。加入400mg Pd(PPh3)4,氮气置换,密封于100℃下搅拌,TLC监控(PE/EA=1:1)。反应结束。降温,加入水,用稀盐酸调节pH至酸性,搅拌30min,过滤,滤饼用MTBE打浆,过滤得到灰绿色固体950mg,产率82.8%。
步骤2:2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(2-amino-3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate)的合成:
称取2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-羟基吡唑[1,5-a]吡啶-3-碳腈(0.83g,2.9mmol,1.0eq),12mL DMF,N-苯基双三氟甲基磺酰亚胺(1.5g,4.3mmol,1.5eq),滴加DIPEA(0.74g,5.7mmol,2.0eq),室温下搅拌,TLC监控(PE/EA=1:1)。后处理加入水,过滤得到1.1g黑色固体,柱层析提纯得到500mg黄色固体。
步骤3:2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基苄基)哌嗪-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.257mmol,1.0eq),加入1-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-4-(4-(三异丙基硅基)乙炔基)苄基)哌嗪(198.58mg,0.355mmol,1.5eq),碳酸钠(38mg,0.355mmol,1.5eq),加入40mg三苯基膦钯和1mL水,3mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后垫硅藻土过滤,滤液用水和EA萃取分液,有机层浓缩柱层析分离得到产物100mg。
25mL单口瓶中加入上一步反应产物(100mg,1.0eq),TBAF·3H2O(300mg,3.0eq)和5mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后旋蒸干,加入EA和水,用EA萃取,取有机相除水干燥,刮大板分离得到产物10mg固体。
1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.87(s,1H),8.42(s,1H),8.34(d,J=2.1Hz,1H),7.84(s,1H),7.77(dd,J=8.8,2.3Hz,1H),7.69(s,1H),7.46(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),6.93(d,J=8.9Hz,1H),6.30(s,2H),4.13(s,1H),3.60(s,4H),3.56(s,2H)
实施例6
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基基苄基)哌嗪-1-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluoropyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate)的合成:
称取6-溴-2-氟-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(2.56g,10mmol),15mL水,45mL 1,4-二氧六环,碳酸钾(2.76g,20mmol),1-二氟甲基-吡咯-4-硼酸频哪醇酯(6.24g,30mmol),氮气置换,密封于80℃下搅拌,TLC监控(PE/EA=1:1),降温。加入水和EA,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到黄色固体2.12g,收率72.3%。
称取上一步反应产物(2.12g,7.2303mmol),30mL DMF,PhN(Tf)2(3.87g,10.845mmol),DIPEA(1.868g,14.4606mmol),室温下搅拌,TLC监控(PE/EA=3:1)。后处理加入水和EA,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到黄色油状物,久置固体析出,确认是产物,正庚烷打浆,得到黄色固体2.00g,收率65.1%。
步骤2:6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙基苄基)哌嗪-1-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylbenzyl)piperazin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.23514mmol),加入1-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-4-(4-(三异丙基硅基)乙炔基)苄基)哌嗪(197mg,0.35272mmol),碳酸钾(97mg,0.70542mmol),加入20mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物白色固体168mg。
25mL单口瓶中加入上一步反应产物(168mg,0.23698mmol),TBAF·3H2O(186mg,0.71095mmol)和15mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后加入EA和水,用EA萃取,取有机相除水干燥,柱层析分离得到产物89mg白色固体。
1H NMR(500MHz,DMSO-d6)δ9.19(s,1H),8.77(s,1H),8.65–8.60(m,1H),8.26(s,1H),8.08(s,1H),8.07–8.03(m,1H),7.89(d,J=59.1Hz,1H),7.45(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),6.94(d,J=9.0Hz,1H),4.13(s,1H),3.59(s,4H),3.55(s,2H),2.48(d,J=4.8Hz,4H)
实施例7
化合物4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(2-羟丙基-2-基)氧基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-((2-hydroxypropan-2-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:2-氟-6-(4-甲氧基苄基)氧基)-4-(6-(6-((三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(2-fluoro-6-((4-methoxybenzyl)oxy)-4-(6-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氟-6-(4-甲氧基苄基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡唑[1,5-a]吡啶-3-碳腈(3.0g,0.00709mol,1.0eq),1-(5-溴吡啶-2-基)-4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪(3.79g,0.01063mol,1.5eq),加入碳酸钾(1.47g,0.01063mol,1.5eq),加入22.5mL水和67.5mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.3g,于80℃加热搅拌,TLC监控(PE/EA=3/2),转移至室温,加入水和EA萃取,水相再用EA萃取一次,合并有机相除水干燥,柱层析分离得到泡沫状固体1.37g,收率30.6%。
步骤2:2-氟-6-羟基-4-(6-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(2-fluoro-6-hydroxy-4-(6-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
加入2-氟-6-(4-甲氧基苄基)氧基)-4-(6-(6-((三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(1.36g,1.8645mol,1.0eq),加入20mL DCM,搅拌,滴加2mL TFA,室温下搅拌。TLC监控(PE/EA=1/2)(用NaHCO3淬灭)。在HPLC看还有6%原料。缓慢加入NaHCO3溶液,调pH=7~8,有固体析出。用EA溶解,分液水相再用EA萃取,合并有机相除水干燥,浓缩至浓稠加入PE析晶,过滤用PE洗涤,得到黄色固体978mg,产率85.7%。
步骤3:4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(2-羟丙基-2-基)氧基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-((2-hydroxypropan-2-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氟-6-羟基-4-(6-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(235mg,0.38573mol,1.0eq),15mL DMF,碳酸钾(160mg,1.15719mmol,3.0eq),甲基环氧丙烷(0.556g,7.7146mmol,20eq),密封于84℃下搅拌,TLC监控(PE/EA=1:2),降温,用水/EA萃取,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到产品,产品在洗脱剂中浓缩至有固体析出,加入正庚烷打浆,过滤得到淡黄色固体100mg,收率49.5%。
1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.58(d,J=2.1Hz,1H),8.52(s,1H),8.01(dd,J=8.9,2.3Hz,1H),7.78(d,J=7.9Hz,1H),7.55(d,J=7.9Hz,1H),7.44(s,1H),6.93(d,J=9.0Hz,1H),4.77(s,1H),4.32(s,1H),4.06(s,2H),3.59(s,6H),2.48(d,J=7.1Hz,4H),1.30(s,6H)。
实施例8
化合物4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-氰基-2-氟-4-(6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-6-基三氟甲基磺酸酯(3-cyano-2-fluoro-4-(6-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl trifluoromethanesulfonate)的合成:
称取2-氟-6-羟基-4-(6-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(430mg,0.6615mmol,1.0eq),20mL DMF,DIPEA(171mg,1.323mmol,2.0eq),N-苯基双三氟甲基磺酰亚胺(354mg,0.9922mmol,1.5eq),室温下搅拌,TLC监控(PE/EA=1/1),反应完毕加水和EA萃取分液,水相再用EA萃取,合并有机相除水干燥后柱层析提纯,得到642mg,产率112.6%。
步骤2:4-(6-(4-(6-乙炔基吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-4-(6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-6-基三氟甲基磺酸酯(150mg,0.20219mmol,1.0eq),1-甲基吡唑-4-硼酸嚬哪醇酯(210mg,1mmol,5.0eq),加入碳酸钠(100mg,0.9435mmol,4.0eq),56mg三苯基膦钯,3mL水和9mL 1,4-二氧六环,氩气置换多次,110℃反应,TLC监控(纯EA),加入水和EA萃取,水相再用EA萃取一次,合并有机相除水干燥,柱层析分离得到188mg粗品。
称取上一步反应产物(145mg,0.21567mmol,1.0eq),加入35~40mL THF,TBAF·3H2O(169mg,0.6470mmol,3.0eq),室温下反应,LCMS显示反应完毕,用水和EA萃取,有机相除水干燥后用柱层析提纯一次,再刮大板到40mg产物。
1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.61(d,J=2.1Hz,1H),8.53(s,1H),8.23(s,1H),8.03(dd,J=8.9,2.4Hz,1H),7.94(s,1H),7.91(s,1H),7.78(d,J=7.9Hz,1H),7.55(d,J=7.9Hz,1H),6.95(d,J=9.0Hz,1H),4.28(s,1H),3.94(s,3H),3.59(d,J=6.1Hz,6H),2.45(d,J=30.0Hz,4H)
实施例9
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基吡啶)哌嗪-1-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylpyridin)piperazin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
取3-氰基-2-氟-4-(6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)哌嗪-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-6-基三氟甲基磺酸酯(160mg,0.21567mmol,1.0eq),1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑(158mg,0.64701mmol,3.0eq),碳酸钠(68mg,0.64701mmol,3.0eq),63mg三苯基膦,9mL 1,4-二氧六环,3mL水。氩气置换多次,110℃升温反应2h。TLC监控(PE/EA=1/1),加入EA和水,萃取分液,水相再用EA萃取,合并有机相浓缩,柱层析提纯后于正庚烷打浆,得到269mg固体(理论产物162mg),进行下一步。
称取上一步反应产物(162mg,0.2291mmol,1.0eq),加入30mL THF,TBAF·3H2O(180mg,0.6875mmol,3.0eq),室温下反应,LCMS显示反应完毕,用水和EA萃取,有机相除水干燥后用柱层析提纯一次,再刮大板得到80mg。
1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),8.77(s,1H),8.62(d,J=2.2Hz,1H),8.52(s,1H),8.26(s,1H),8.09–8.02(m,2H),7.89(d,J=59.0Hz,1H),7.80–7.74(m,1H),7.55(d,J=7.9Hz,1H),6.94(d,J=9.0Hz,1H),4.28(s,1H),3.59(s,6H),2.48(s,4H)
实施例10
化合物4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(2-(3-(3-fluoro-4-((triisopropylsilyl)ethynyl)phenoxy)azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)的合成:
往单口瓶加入5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(5.04g,10.0mmol),联硼酸酯(5.08g,20.0mmol,2.0eq),NaOAc(4.92g,60mmol,6.0eq),55mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(1.00g),升温80℃搅拌,TLC监控(PE/EA=2:1),反应完成后将反应液垫硅藻土过滤,EA洗涤滤饼,用EA和饱和食盐水萃取,取有机相。柱层析过快速柱(PE/EA=2:1+1%三乙胺)分离得到6.04g油状物。
步骤2:4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(100mg,0.30474mmol),加入(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(252mg,0.4571mmol),碳酸钾(63mg,0.4571mmol),加入20mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至84℃,TLC监控(PE/EA=1:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物泡沫状黄色固体227mg。
单口瓶中加入上一步反应产物(227mg,0.33814mmol),TBAF(265mg,1.01443mmol)和15mL THF,常温搅拌1h,TLC监控(PE/EA=1/1),反应完全后加入10mL饱和食盐水,用EA萃取,取有机相除水干燥,柱层析分离得到产物162mg白色泡沫状固体。
1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.57(d,J=1.8Hz,1H),8.03(dd,J=8.7,2.2Hz,1H),7.51(t,J=8.5Hz,1H),7.44(s,1H),6.92(dd,J=11.4,2.0Hz,1H),6.79(dd,J=8.6,2.0Hz,1H),6.58(d,J=8.7Hz,1H),5.26(s,1H),4.71(s,1H),4.50(dd,J=9.1,6.5Hz,2H),4.34(s,1H),4.08(s,2H),3.98(dd,J=9.4,3.3Hz,2H),1.31(s,6H)
实施例11
化合物2-氨基-4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:2-氨基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-6-溴-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(0.75g,0.002964mol,1.0eq),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-1H-吡唑(0.80g,0.003843mol,1.3eq),加入碳酸钾(0.61g,0.004414mol,1.5eq),加入5mL水和15mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.2g,于110℃加热搅拌,TLC监控(EA/MeOH=9/1)。加入80mL水,调pH至3-4,搅拌30min,过滤,用甲叔醚洗涤滤饼得到固体0.6g,收率80%。
步骤2:2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(2-amino-3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate)的合成:
称取2-氨基-4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(1.1g,0.004331mol,1.0eq),30mL DMF,DIPEA(1.1g,0.008511mol,2.0eq),N-苯基双三氟甲基磺酰亚胺(2.3g,0.006438mmol,1.5eq),室温下搅拌,TLC监控(EA/MeOH=9/1),反应完毕加水有固体析出,搅拌1h,过滤,用MTBE洗涤滤饼,滤液柱层析纯化得到500mg。
步骤3:2-氨基-4-(6-(3-(4-乙炔基-3-氟苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(3-(4-ethynyl-3-fluorophenoxy)azetidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
往单口瓶加入5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(5.04g,10mmol),联硼酸酯(5.08g,20mmol),NaOAc(4.92g,60mmol),55mLDMSO。氩气置换多次后加入催化剂三苯基膦钯(1g),氩气置换多次。升温80℃搅拌过夜,TLC监控(PE/EA=2:1),用水和EA萃取,有机层除水干燥,柱层析分离得到6.04g油状物。
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(0.1g,0.0002589mol,1.0eq),上一步反应产物(0.21g,0.0003814mol,1.5eq),加入碳酸钠(0.08g,0.0007548mol,3.0eq),加入1mL水和3mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.04g,于110℃加热搅拌,TLC监控(EA)。加入水,调节pH至酸性,过滤,得到200mg黑色固体。
加入上一步反应产物(0.2g,0.0003035mol,1.0eq),加入20mL THF,200mh四丁基氟化铵,室温下搅拌过夜。TLC监控(Hexane/THF=1/3)。反应结束旋蒸干,用水和EA萃取,有机层除水干燥,旋蒸,爬大板纯化得到100mg。
1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.36–8.29(m,1H),8.27(s,1H),8.00(s,1H),7.77(dd,J=8.6,2.2Hz,1H),7.55–7.47(m,2H),6.94(d,J=9.5Hz,1H),6.81(d,J=8.6Hz,1H),6.58(d,J=8.5Hz,1H),6.23(s,2H),5.28(s,1H),4.52(dd,J=9.2,6.5Hz,2H),4.34(s,1H),3.98(dd,J=9.7,3.4Hz,2H),3.86(s,3H)
实施例12
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-(4-乙炔基-3-氟苯氧基)环丁基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-(4-ethynyl-3-fluorophenoxy)cyclobutyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
往单口瓶加入5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(5.04g,10mmol),联硼酸酯(5.08g,20mmol),NaOAc(4.92g,60mmol),55mLDMSO。氩气置换多次后加入催化剂三苯基膦钯(1g),氩气置换多次。升温80℃搅拌过夜,TLC监控(PE/EA=2:1),用水和EA萃取,有机层除水干燥,柱层析分离得到6.04g油状物。
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.257mmol,1.0eq),加入上一步反应产物(196mg,0.355mmol,1.5eq),碳酸钠(38mg,0.355mmol,1.5eq),加入40mg三苯基膦钯和1mL水,3mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后垫硅藻土过滤,滤液用水和EA萃取分液,有机层浓缩柱层析分离得到产物77mg。
25mL单口瓶中加入上一步反应产物(77mg,1.0eq),TBAF·3H2O(246mg,3.0eq)和3mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后旋蒸干,加入EA和水,用EA萃取,取有机相除水干燥,刮大板分离得到产物33mg黄色固体。
1H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.88(s,1H),8.42(s,1H),8.33(s,1H),7.79(d,J=6.5Hz,1H),7.68(s,1H),7.51(t,J=8.4Hz,1H),6.94(d,J=11.4Hz,1H),6.80(dd,J=8.6,2.5Hz,1H),6.59(d,J=8.5Hz,1H),6.29(s,1H),5.28(s,1H),4.58–4.47(m,2H),4.34(s,1H),3.98(d,J=9.1Hz,2H)
实施例13
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-(6-乙炔基吡啶-3-基)氧基)氮杂环丁-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-((6-ethynylpyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:6-((三异丙基硅基)乙炔基)吡啶-3-醇(6-((triisopropylsilyl)ethynyl)pyridin-3-ol)的合成:
往单口瓶中加入6-溴-3-羟基吡啶(20g,1.0eq),加入DMAP(1g),200mL Ac2O,加热60℃反应2h,TLC监控(PE/EA=9/1)。反应结束后,将反应液倒入100mL水中,搅拌30min,用NaHCO3洗至中性。用EA萃取,旋蒸,柱层析分离得到24.5g白色固体,产率98.67%。1H NMR(500MHz,Chloroform-d)δ8.14(d,J=2.7Hz,1H),7.39(d,J=8.5Hz,1H),7.22(dd,J=8.6,2.8Hz,1H),1.09(s,21H)
称取上一步反应产物(20g,90mmol,1.0eq),加入三异丙基硅乙炔(21.9g,130mmol,1.3eq),CuI(0.88g,5mmol,0.05eq),三乙胺(93.7g,0.92mol,10eq),200mL THF,氩气保护,置换多次。加2.1g醋酸钯,氩气置换多次。升温80℃搅拌过夜。TLC监控(PE/EA=9/1),反应结束后硅藻土过滤,滤饼EA洗涤,滤液旋蒸,柱层析分离得到14.6g,收率49.7%。
单口瓶加入上一步反应产物(10g,31.5mmol,1.0eq),NaOH(2.52g,63mmol,2.0eq)提前溶解于20mL H2O,20mL THF,MeOH(10mL,1V),放热明显,搅拌过夜。TLC监测(PE/EA=9/1),反应完全旋蒸一部分溶剂,用EA萃取,冰醋酸调节pH至5~6,再用3次EA萃取,除水干燥,旋蒸得到淡黄色粘稠固体。加10mL MTBE,90mL正庚烷打浆,1.5h后过滤,得到15.5g白色固体,产率84.8%。
步骤2:5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(3-(6-(三异丙基硅基)乙炔基)吡啶-3-基)氧基)氮杂环丁-1-基)吡啶(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(3-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)oxy)azetidin-1-yl)pyridine)的合成:
室温下,于250mL三口瓶中依次加入6-((三异丙基硅基)乙炔基)吡啶-3-醇(7g,0.025mol,1.0eq),1-(5-溴吡啶-2-基)氮杂环丁烷-3-醇(11.6g,0.051mol,2.0eq),pph3(20g,0.076mol,3.0eq),100mL THF。N2置换三次,之后将其置于55℃油浴中搅拌,待反应液温度达到55℃时,缓慢滴加DEAD(13.3g,0.076mol,3.0eq)(控制滴加速度,滴加时放热,沸腾),滴加完毕后在60℃油浴下搅拌16h,TLC监测(PE/EA=9/1)反应完全。将反应液旋蒸干,柱层析分离,得到黄色液体(13g,收率105%)。
往单口瓶加入上一步反应产物(10g,20.6mmol),联硼酸酯(10.45g,41.2mmol),NaOAc(10.12g,123.4mmol),100mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(2g),氩气置换多次。升温80℃搅拌过夜,TLC监控(PE/EA=2:1),用水和EA萃取,有机层除水干燥,柱层析分离得到2g灰色液体。
步骤3:2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-(6-乙炔基吡啶-3-基)氧基)氮杂环丁-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-((6-ethynylpyridin-3-yl)oxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.257mmol,1.0eq),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(3-(6-(三异丙基硅基)乙炔基)吡啶-3-基)氧基)氮杂环丁-1-基)吡啶(189.43mg,0.355mmol,1.5eq),碳酸钠(38mg,0.355mmol,1.5eq),加入40mg三苯基膦钯和1mL水,3mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后垫硅藻土过滤,滤液用水和EA萃取分液,有机层浓缩柱层析分离得到产物100mg。
单口瓶中加入上一步反应产物(100mg,1.0eq),加入20mL THF,200mg四丁基氟化铵,室温下搅拌过夜。TLC监控(Hexane/THF=1/3)。反应结束旋蒸干,用水和EA萃取,有机层除水干燥,旋蒸,爬大板纯化得到16mg。
1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.31(d,J=1.8Hz,1H),8.28(d,J=2.8Hz,1H),8.27(s,1H),8.00(s,1H),7.78(dd,J=8.5,2.3Hz,1H),7.59–7.50(m,2H),7.37(dd,J=8.6,2.8Hz,1H),6.58(d,J=8.5Hz,1H),6.24(s,2H),5.34(s,1H),4.53(dd,J=9.1,6.5Hz,2H),4.18(s,1H),4.01(dd,J=9.5,3.3Hz,2H),3.86(s,3H)
实施例14
化合物4-(6-(4-(4-乙炔基苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylphenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:1-(5-溴-2-吡啶)-4-羟基哌啶(1-(5-bromopyridin-2-yl)piperidin-4-ol)的合成:
250mL单口瓶中加入4-羟基哌啶-1-羧酸叔丁酯(20g,1.0eq),40mL乙醇,40mL盐酸乙醇,搅拌过夜。TLC监控(PE/EA=1/1)。反应结束后旋蒸溶剂,固体过滤用EA洗涤滤饼,得到13g固体。
单口瓶中加入2-氟-5-溴吡啶(7.1g,40.2mmol,1.0eq),上一步反应产物(7.2g,52.3mmol,1.3eq),70mL DMSO,碳酸铯(17g,52.3mmol,1.3eq),升温100℃反应过夜,TLC监控(PE/EA=1/1)。反应结束把反应液加入到100mL水,搅拌30min,过滤,滤饼用PE打浆,过滤干燥得到7.2g黄色固体。
步骤2:5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(5-bromo-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)piperidin-1-yl)pyridine)的合成:
往250mL三口瓶中加入1-(5-溴-2-吡啶)-4-羟基哌啶(18.7g,72.9mmol,2.0eq),4-((三异丙基硅基)乙炔基)苯酚(10g,36.4mmol,1.0eq),三苯基膦(19.1g,72.9mmol,2.0eq),100mL THF,氩气置换。升温至55℃。滴加DIPEA(12.7g,72.9mmol,2.0eq),滴加放热明显,沸腾。滴毕,反应一小时,TLC监控(PE/EA=40/1),反应结束浓缩反应液,柱层析分离得到13g产物。1H NMR(500MHz,Chloroform-d)δ8.19(d,J=2.1Hz,1H),7.52(dd,J=9.0,2.4Hz,1H),7.41(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),6.58(d,J=9.0Hz,1H),4.55(dt,J=6.9,3.5Hz,1H),3.83(ddd,J=11.9,7.5,3.4Hz,2H),3.46(ddd,J=12.6,7.6,3.5Hz,2H),2.07–1.98(m,2H),1.85(ddd,J=16.7,7.6,3.7Hz,2H),1.13(s,22H)
步骤3:5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)piperidin-1-yl)pyridine)的合成:
250mL三口瓶中加入5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(10g,19mmol,1.0eq),联硼酸频那醇酯(9.89g,39mmol,2.0eq),100mL DMSO,氩气保护。2g Pd(PPh3)4,氩气置换多次,升温至80℃搅拌过夜。TLC监控(PE/EA=9/1)。反应结束反应液加入150mL水中,用EA萃取,收集有机相旋蒸,柱层析分离得到8.3g淡黄色油状物,产率69.17%。
步骤4:4-(6-(4-(4-乙炔基苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylphenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-((4-甲氧基苄基)氧基)吡唑[1,5-a]吡啶-3-碳腈(120mg,0.31898mmol,1.0eq),5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(268mg,0.47848mmol,1.5eq),K2CO3(66mg,0.47838mmol,1.5eq),加入24mg Pd(PPh3)4,5mL水,5mL二氧六环。氩气置换多次,升温80℃反应。TLC监控(THF/PE=1/1)。反应结束后EA和水萃取,有机相浓缩,柱层析分离得到232mg产物,产率99.6%。
称取上一步反应产物(232mg,0.31782mmol,1.0eq),15mL DCM,缓慢加入约0.5mLTFA于RT反应,TLC监控(PE/EA=1/1)。剩余少量原料,补加0.5mL TFA,再监控,反应结束。加入水和EA萃取,用NaHCO3调节pH至7~8,分液,得到的有机相浓缩,柱层析分离得到90mg产物,产率46.4%。
称取上一步反应产物(90mg+30mg,0.19678mmol,1.0eq),20mL THF,TBAF·3H2O(154mg+46mg,0.59033mmol,3.0eq),室温下反应。TLC监控(THF/PE=1/1),加入盐水和EA萃取,分液,有机相浓缩,柱层析分离得到65mg产物。
1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.44(d,J=2.0Hz,1H),7.86(dd,J=8.9,2.3Hz,1H),7.41(d,J=8.6Hz,2H),7.13(s,1H),7.05–6.97(m,3H),6.87(s,1H),4.71(s,1H),4.10–4.01(m,2H),3.99(s,1H),3.47–3.37(m,2H),2.01(s,2H),1.68–1.59(m,2H)
实施例15
化合物4-(6-(4-(4-乙炔基苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylphenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(100mg,0.30474mmol,1.0eq),5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(301mg,0.45712mmol,1.5eq),K2CO3(128mg,0.45712mmol,1.5eq),加入22mg Pd(PPh3)4,5mL水,15mL二氧六环。氩气置换多次,升温80℃反应。TLC监控(THF/PE=1/1)。反应结束后EA和水萃取,有机相浓缩,柱层析分离得到260mg产物,产率125%。
称取上一步反应产物(260mg,0.388mmol,1.0eq),10mL THF,TBAF·3H2O(299mg,1.1mmol,3.0eq),室温下反应。TLC监控(THF/PE=1/1),加入饱和盐水萃取,分液,有机相除水干燥,浓缩,柱层析分离得到130mg产物。
1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.59(d,J=2.1Hz,1H),8.01(dd,J=9.0,2.4Hz,1H),7.46(s,1H),7.41(d,J=8.6Hz,2H),7.04–6.95(m,3H),4.71(s,1H),4.08(s,2H),4.04(s,2H),4.00(s,1H),3.43(t,J=9.9Hz,2H),2.01(s,2H),1.71–1.57(m,2H),1.31(s,6H)
实施例16
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基苯氧基)哌啶-1-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynylphenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.23514mmol),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(198mg,0.35272mmol,1.5eq),碳酸钾(97mg,0.70542mmol),加入20mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物110mg。
称取上一步反应产物(110mg,0.15mmol,1.0eq),TBAF·3H2O(121mg,0.46mmol,3.0eq)和10mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后加入EA和水,用EA萃取,取有机相除水干燥,柱层析分离得到产物50mg淡绿色固体。
1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.78(s,1H),8.65(d,J=2.2Hz,1H),8.27(s,1H),8.10(s,1H),8.06(dd,J=8.8,2.6Hz,1H),7.89(d,J=59.0Hz,1H),7.41(d,J=8.7Hz,2H),7.06–6.95(m,3H),4.72(s,1H),4.06(d,J=13.8Hz,2H),3.99(s,1H),3.49–3.40(m,2H),2.00(d,J=13.6Hz,2H),1.69–1.59(m,2H)
实施例17
化合物4-(6-(4-(4-乙炔基-3-氟苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynyl-3-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-氰基-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(3-cyano-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate)的合成:
称取6-溴-2-氟-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(2.0g,7.8mmol,1.0eq),10mL水,30mL 1,4-二氧六环,碳酸钠(1.6g,15.6mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-1H-吡唑(4.8g,23.4mmol,3.0eq),450mg Pd(PPh3)4,氮气置换,密封于110℃下搅拌,TLC监控(PE/EA=1:1),降温。旋蒸掉多余溶剂,加入甲醇和EA溶解后,柱层析提纯得到褐色固体1.7g,收率84%。
称取上一步产物(1.5g,5.8mmol,1.0eq),20mL DMF,PhN(Tf)2(3.1g,8.75mmol,1.5eq),DIPEA(1.5g,11.6mmol,2.0eq),室温下搅拌,TLC监控(PE/EA=1:1)。后处理加入饱和盐水和EA,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到黄色固体1.50g,收率66%。
步骤2:5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(5-bromo-2-(3-(3-fluoro-4-((triisopropylsilyl)ethynyl)phenoxy)piperidin-1-yl)pyridine)的合成:
室温下,于三口瓶中依次加入3-氟-4-(三异丙基硅基)乙炔基)苯酚(7.3g,0.025mol,1.0eq),1-(5-溴-2-吡啶)-4-羟基哌啶(8.3g,0.032mol,1.3eq),pph3(19.6g,0.075mol,3.0eq),插入温度计,N2置换三次,之后加入THF(70mL),再次N2置换三次,之后将其置于60℃油浴中搅拌,待反应液温度达到60℃时,缓慢滴加DIAD(15.2g,0.075mol,3.0eq)(控制滴加速度,使反应液温度保持在60~70℃之间),滴加完毕后在60℃油浴下搅拌过夜,TLC监测(EA/hexane=1/10)。反应完全,将反应液柱层析分离,除去极性最大和最小得杂质后,得到的黄色油状物在-10℃下于正己烷中结晶,过滤,旋干滤饼,得到白色固体8.2g。
步骤3:5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(3-(3-fluoro-4-((triisopropylsilyl)ethynyl)phenoxy)piperidin-1-yl)pyridine)的合成:
三口瓶中加入5-溴-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(3g,5.463mmol,1.0eq),联硼酸频那醇酯(4.299g,16.93mmol,3.0eq),KOAc(1.329g,13.544mmol,2.4eq),30mL 1,4-二氧六环,氩气保护。加入600mg Pd(dppf)2ch,氩气置换多次,升温至120℃搅拌过夜。TLC监控(EA/Hexane=1/4)。反应结束抽滤,滤饼用EA洗涤,收集滤液。滤液加入150mL饱和盐水中,用EA萃取,收集有机相除水干燥后,旋蒸,柱层析(每5mL洗脱剂中加入0.2mL三乙胺),分离得到2.9g白色固体。
步骤4:4-(6-(4-(4-乙炔基-3-氟苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynyl-3-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(0.1g,0.0002569mol,1.0eq),5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(0.22g,0.0003802mol,1.5eq),加入碳酸钠(0.08g,0.0007737mol,3.0eq),加入1mL水和3mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯0.04g,氮气置换多次。于80℃加热搅拌,TLC监控(THF/Hexane=1/3)。反应结束后加入水,过滤,滤饼用THF溶解,旋蒸得到250mg粗品,柱层析分离得到170mg固体,直接用于下一步。
加入上一步反应产物(0.17g,0.0002466mol,1.0eq),加入10mL THF,200mg四丁基氟化铵,室温下搅拌过夜。TLC监控(Hexane/THF=3/2)。反应结束旋蒸干,用水和EA萃取,有机层除水干燥,旋蒸,爬大板纯化得到68mg产物。
1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.62(d,J=2.2Hz,1H),8.24(s,1H),8.08–8.00(m,1H),7.95(s,1H),7.91(s,1H),7.45(t,J=8.5Hz,1H),7.06–6.99(m,2H),6.86(d,J=8.2Hz,1H),4.76(s,1H),4.29(s,1H),4.06(d,J=14.2Hz,2H),3.94(s,3H),3.42(td,J=9.7,8.8,5.0Hz,3H),2.01(s,3H),1.63(d,J=8.8Hz,2H)
实施例18
化合物2-氨基-4-(6-(4-(4-乙炔基-3-氟苯氧基)哌啶-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(4-(4-ethynyl-3-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(50mg,0.1294mmol,1.0eq),5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(111mg,0.1901mmol,1.5eq),加入碳酸钠(40mg,0.3774mmol,3.0eq),加入1mL水和3mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯20mg,于110℃加热搅拌过夜。TLC监控(EA/Hexane=1/1)。反应结束加2mL水,用稀盐酸调酸性,过滤后得到含水的固体150mg,直接用于下一步。
加入上一步反应产物(150mg),加入30mL THF,150mg四丁基氟化铵,室温下搅拌。TLC监控(Hexane/THF=1/1)。反应结束用水和EA萃取,有机层除水干燥,旋蒸,爬大板纯化得到80mg。
1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.36–8.32(m,1H),8.27(s,1H),8.01(s,1H),7.76(d,J=6.5Hz,1H),7.55(s,1H),7.46(t,J=8.5Hz,1H),7.04(d,J=11.8Hz,1H),7.00(d,J=8.8Hz,1H),6.88(d,J=6.4Hz,1H),6.22(s,1H),4.77(s,1H),4.29(s,1H),4.07(d,J=13.2Hz,2H),3.86(s,3H),3.46–3.38(m,3H),2.03(s,2H),1.65(d,J=9.1Hz,2H)
实施例19
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(4-乙炔基-3-氟苯氧基)哌啶-1-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(4-ethynyl-3-fluorophenoxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(50mg,0.118mmol,1.0eq),5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(3-(3-氟-4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(101mg,0.176mmol,1.5eq),加入碳酸钠(19mg,0.178mmol,1.5eq),加入0.5mL水和1.5mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯20mg,于110℃加热搅拌过夜。TLC监控(EA/Hexane=1/1)。加入饱和食盐水和EA,萃取分液,有机层除水干燥,旋蒸,柱层析分离得到61mg黄色固体。
加入上一步反应产物(61mg),加入2mL THF,202mg四丁基氟化铵,室温下搅拌过夜。TLC监控(Hexane/THF=1/1)。反应结束旋蒸干,用水和EA萃取,有机层除水干燥,旋蒸,爬大板纯化得到75mg产物。
1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.88(s,1H),8.42(s,1H),8.36(s,1H),7.78(d,J=8.8Hz,1H),7.70(s,1H),7.46(t,J=8.5Hz,1H),7.02(dd,J=16.3,10.6Hz,2H),6.88(d,J=8.6Hz,1H),6.30(s,2H),4.77(s,1H),4.29(s,1H),4.07(d,J=13.4Hz,2H),3.45(s,2H),2.03(s,2H),1.65(d,J=8.9Hz,2H)
实施例20
化合物4-(6-(3-(4-乙炔基苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(3-(4-ethynylphenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:4-((三异丙基硅基)乙炔基)苯酚(4-((triisopropylsilyl)ethynyl)phenol)的合成:
往单口瓶中加入对溴苯酚(16.5g,1.0eq),加入DMAP(600mg),40mL Ac2O,加热60℃反应2h,TLC监控(PE/EA=10/1)。反应结束后,将反应液倒入100mL水中,搅拌30min,用NaHCO3洗至中性。用EA萃取,旋蒸,柱层析分离得到20.1g无色液体。1H NMR(500MHz,Chloroform-d)δ7.41–7.34(m,2H),6.76(d,J=8.6Hz,2H),1.13(s,21H)
称取上一步反应产物(37g,170mmol,1.0eq),加入三异丙基硅乙炔(62.8g,340mmol,2.0eq),CuI(8g,6.9mmol,0.04eq),三乙胺(174g,1.7mol,10eq),370mL THF,氩气保护,置换多次。加8g三苯基膦钯,氩气置换多次。升温60℃搅拌过夜。TLC监控(PE/EA=50/1),反应结束后过滤,滤液旋蒸,柱层析分离得到46.1g黄色液体,产率84.6%。
500mL单口瓶加入上一步反应产物(46g,0.14mol,1.0eq),100mL THF,50mL MeOH。取NaOH(11.6g,0.29mol,2.0eq)溶于100mL水中,分批加入NaOH(aq),冰水降温。加入完毕室温搅拌30min,TLC监控(PE/EA=50/1),用稀盐酸调pH至5~6,浓缩用EA萃取,柱层析分离得到30g黄色固体。
步骤2:5-溴-2-(3-(4-(三异丙基硅基)乙炔基)苯氧基)氮杂环丁-1-基)吡啶(5-bromo-2-(3-(4-((triisopropylsilyl)ethynyl)phenoxy)azetidin-1-yl)pyridine)的合成:
往250mL三口瓶中加入4-((三异丙基硅基)乙炔基)苯酚(12g,0.044mol,1.0eq),1-(5-溴吡啶-2-基)氮杂环丁烷-3-醇(18g,0.078mol,1.78eq),三苯基膦(19.1g,72.9mmol,2.0eq),100mL THF,氩气置换。升温至55℃。滴加DIPEA(12.7g,72.9mmol,2.0eq),滴加放热明显,沸腾。滴毕,反应一小时,TLC监控(PE/EA=40/1),反应结束浓缩反应液,柱层析分离得到13g产物。
步骤3:5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(3-(4-(三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(3-(4-((triisopropylsilyl)ethynyl)phenoxy)azetidin-1-yl)pyridine)的合成:
称取5-溴-2-(3-(4-(三异丙基硅基)乙炔基)苯氧基)氮杂环丁-1-基)吡啶(10g,20.6mmol,1.0eq),联硼酸酯(10.5g,41.2mmol,2.0eq),NaOAc(10.1g,0.123mmol,6.0eq),100mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(0.2g),升温80℃搅拌6h,TLC监控(PE/EA=4:1),反应完成后将反应液倒入200mL水中,用EA萃取,取有机相。柱层析分离得到5.6g黄色油状物。
步骤4:4-(6-(3-(4-乙炔基苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(4-(6-(3-(4-ethynylphenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(3-(4-(三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(128mg,0.50mmmol,1.0eq),加入4-溴-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(399mg,0.750mmol,1.5eq),碳酸钾(207mg,1.5mmol,3.0eq),5mL水和15mL 1,4-二氧六环,氮气置换,加入31mg三苯基膦钯。氮气保护下升温至80℃,TLC监控(PE/THF=1:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物400mg。
称取上一步反应产物(500mg,0.86mmol,1.0eq),10mL THF,TBAF·3H2O(674mg,2.6mmol,3.0eq),室温搅拌过夜,TLC监控(PE/THF=1/1),加入饱和食盐水萃取,分液,有机相除水干燥,柱层析纯化得到黄色油状物,加入2mL甲叔醚和6mL正庚烷,旋蒸部分溶剂,有固体析出,过滤,得到80mg黄色固体。
1H NMR(500MHz,DMSO-d6)δ11.61(d,J=44.2Hz,1H),8.64(s,1H),8.41(s,1H),7.87(d,J=8.5Hz,1H),7.44(d,J=8.4Hz,2H),7.11(s,1H),6.90(d,J=8.5Hz,2H),6.57(d,J=8.6Hz,1H),5.22(s,1H),4.53–4.42(m,2H),4.03(s,1H),3.96(dd,J=9.1,3.1Hz,2H)
实施例21
化合物4-(6-(4-(4-乙炔基苯氧基)氮杂环丁烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-(4-ethynylphenoxy)azetidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(100mg,0.30mmmol,1.0eq),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(3-(4-(三异丙基硅基)乙炔基)苯氧基)氮杂环丁烷-1-基)吡啶(250mg,0.45mmol,1.5eq),碳酸钾(125mg,0.9mmol,3.0eq),5mL水和15mL 1,4-二氧六环,氮气置换,加入20mg三苯基膦钯。氮气保护下升温至80℃,TLC监控(PE/THF=1:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到黄色油状产物260mg。
称取上一步反应产物(26mg,0.4mmol,1.0eq),10mL THF,TBAF·3H2O(312mg,1.2mmol,3.0eq),室温搅拌1h,TLC监控(PE/THF=1/1),加入饱和食盐水,EA萃取,分液,有机相除水干燥,柱层析纯化得到白色产物70mg。
1H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.56(s,1H),8.09(d,J=7.6Hz,1H),7.45(d,J=5.7Hz,4H),6.92(d,J=8.5Hz,3H),6.65(d,J=8.2Hz,1H),5.24(s,1H),4.62–4.46(m,3H),4.17–3.96(m,4H),1.31(s,6H)
实施例22
化合物4-(6-(4-(6-乙炔基吡啶-3-基)氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-氰基-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(3-cyano-2-fluoro-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yltrifluoromethanesulfonate)的合成:
称取6-溴-2-氟-4-羟基吡唑并[1,5-a]吡啶-3-碳腈(256mg,1mmol,1.0eq),5mL水,15mL 1,4-二氧六环,碳酸钾(2.76g,2mmol,2.0eq),1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯(417g,1.5mmol,1.5eq),氮气置换,加入52mg三苯基膦钯,氮气置换。密封于80℃下搅拌,TLC监控(PE/EA=1:1),降温。加入水和EA,萃取分液,水相用EA反萃取,合并有机相除水干燥,柱层析提纯得到黄色油状物272mg,收率83.1%。
称取上一步反应产物(272mg,0.83099mmol),10mL DMF,PhN(Tf)2(446mg,1.24648mmol),DIPEA(0.215g,1.66198mmol),室温下搅拌,TLC监控(PE/EA=1:1)。后处理加入水和MTBE,萃取分液,有机相除水干燥,柱层析提纯得到白色固体300mg。
步骤2:5-溴-2-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)氧基)哌啶-1-基)吡啶(5-bromo-2-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)oxy)piperidin-1-yl)pyridine)的合成:
往250mL三口瓶中加入1-(5-溴-2-吡啶)-4-羟基哌啶(13.1g,0.051mmol,2.0eq),6-((三异丙基硅基)乙炔基)吡啶-3-醇(7g,0.025mmol,1.0eq),三苯基膦(20g,76mmol,3.0eq),100mL THF,氩气置换。升温至55℃。滴加DIPEA(13.3g,76mmol,3.0eq),滴加放热明显,沸腾。滴毕,反应1h,TLC监控(PE/EA=4/1),反应结束浓缩反应液,柱层析分离得到14.4g橙色油状液体。
步骤3:5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((6-((三异丙基硅基)乙炔基)吡啶-3-基)氧基)哌啶-1-基)吡啶(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)oxy)piperidin-1-yl)pyridine)的合成:
三口瓶中加入5-溴-2-(4-(6-(三异丙基硅基)乙炔基)吡啶-3-基)氧基)哌啶-1-基)吡啶(13.3g,25.9mmol,1.0eq),联硼酸频那醇酯(13.1g,51.7mmol,2.0eq),130mLDMSO,氩气保护。2.66g Pd(PPh3)4,氩气置换多次,升温至80℃搅拌过夜。TLC监控(PE/EA=4/1)。反应结束反应液加入150mL水中,用EA萃取,收集有机相旋蒸,柱层析分离得到9.2g淡黄色固体。
步骤4:4-(6-(4-(6-乙炔基吡啶-3-基)氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.21768mmol),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((6-((三异丙基硅基)乙炔基)吡啶-3-基)氧基)哌啶-1-基)吡啶(184mg,0.32653mmol,1.5eq),碳酸钾(90mg,0.65304mmol,3.0eq),5mL水,15mL 1,4-二氧六环,氮气置换,加入30mg三苯基膦钯,氮气置换,氮气保护下升温至80℃,TLC监控(THF/PE=1:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物190mg黄色固体。
25mL单口瓶中加入上一步反应产物(190mg,0.255mmol,1.0eq),TBAF·3H2O(200mg,0.7651mmol,3.0eq)和15mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后加入EA和20mL饱和盐水,用EA萃取,取有机相除水干燥,柱层析分离得到产物67mg黄色固体。1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.63(d,J=2.1Hz,1H),8.36(s,1H),8.31(d,J=2.0Hz,1H),8.05(dd,J=9.0,2.4Hz,1H),7.99(s,1H),7.96(s,1H),7.53–7.46(m,2H),7.02(d,J=9.0Hz,1H),4.81(dd,J=7.8,4.1Hz,1H),4.50(dt,J=11.2,6.7Hz,1H),4.14(s,1H),4.07(d,J=13.8Hz,2H),3.99(d,J=11.4Hz,2H),3.55–3.47(m,2H),3.44(t,J=9.9Hz,2H),2.10–1.95(m,6H),1.71–1.60(m,2H)
实施例23
化合物4-(6-(4-(4-乙炔基苯氧基)哌啶-1-基)吡啶-3-基)-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(4-((6-ethynylphenoxy-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-2-fluoro-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.21768mmol),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)哌啶-1-基)吡啶(183mg,0.32653mmol,1.5eq),碳酸钾(90mg,0.65305mmol,3.0eq),加入30mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物白色固体170mg。
25mL单口瓶中加入上一步反应产物(170mg,0.22849mmol,1.0eq),TBAF·3H2O(183mg,0.68548mmol,3.0eq)和25mL THF,常温搅拌1h,TLC监控(THF/PE=1/2),反应完全后加入EA和水,用EA萃取,取有机相除水干燥,柱层析分离得到粗品,再用正庚烷打浆得到34mg产物。1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.63(s,1H),8.36(s,1H),8.05(d,J=6.9Hz,1H),7.98(d,J=16.3Hz,2H),7.41(d,J=8.5Hz,2H),7.01(d,J=8.5Hz,3H),4.72(s,1H),4.50(dd,J=13.2,9.0Hz,1H),4.06(d,J=13.4Hz,2H),3.99(s,3H),3.55–3.48(m,2H),3.46–3.41(m,2H),2.18–1.92(m,6H),1.63(d,J=9.3Hz,2H)
实施例24
化合物(S)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈((S)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:(S)-1-(5-溴-吡啶-2-基)-吡咯烷-3-醇((S)-1-(5-Bromopyridin-2-yl)pyrrolidin-3-ol)的合成:
250mL单口瓶中加入2-氟-5-溴吡啶(13.5g,76.7mmol,1.0eq),(S)-3-吡咯烷醇(8.69g,99.7mmol,1.3eq),碳酸铯(37.49g,0.12mol,1.5eq),加入135mL DMSO,于60℃下反应。TLC监控(PE/EA=4/1),过滤,收集滤液,倒入300mL水中,加入EA萃取,有机相除水干燥,柱层析纯化得到15g白色固体,产率80.4%。
步骤2:(S)-5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶((S)-5-bromo-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)pyrrolidin-1-yl)pyridine)的合成:
250mL三口瓶中加入4-((三异丙基硅基)乙炔基)苯酚(7g,25.5mmol,1.0eq),(S)-1-(5-溴-吡啶-2-基)-吡咯烷-3-醇(12.4g,51.0mmol,2.0eq),PPh3(20.1g,76.5mmol,3.0eq),加入100mL THF,置换但其多次后置于60℃下反应,滴加DEAD(13.4g,76.5mmol,3.0eq),控制滴加温度60~65℃,滴加完毕后反应1.5h,TLC监控(PE/EA=20/1)。反应结束后旋蒸THF,柱层析分离得到7.3g纯产物,产率57.3%。
步骤3:(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶((S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)pyrrolidin-1-yl)pyridine)的合成:
往三口瓶中加入(S)-5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(6g,12mmol,1.0eq),联硼酸酯(6.1g,24mmol,2.0eq),NaOAc(5.9g,72.1mmol,6.0eq),100mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(0.7g),氩气置换多次。升温80℃搅拌过夜,TLC监控(PE/EA=20:1),反应结束后用水和EA萃取,有机层除水干燥,柱层析分离得到5.0g灰白色固体。
步骤4:(S)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈((S)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-羟基吡唑并[1,5-a]吡啶-3-碳腈(120mg,0.4687mmol,1.0eq),加入(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(384mg,0.70304mmol,1.5eq),碳酸钾(194mg,1.40608mmol,3.0eq),加入29mg三苯基膦钯和5mL水,15mL1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=1:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物300mg。
称取上一步反应产物(300mg,0.5036mmol,1.0eq),TBAF·3H2O(395mg,1.5107mmol,3.0eq)和20mL THF,常温搅拌1h,TLC监控(THF/PE=2/1),反应完全后加入EA和水,用EA萃取,取有机相除水干燥,柱层析分离得到产物180mg灰色固体,PE再次打浆得到90mg灰色固体。1H NMR(500MHz,DMSO-d6)δ8.63(s,1H),8.40(d,J=2.1Hz,1H),7.84(dd,J=8.8,2.4Hz,1H),7.42(d,J=8.7Hz,2H),7.12(s,1H),6.99(d,J=8.7Hz,2H),6.61(d,J=8.8Hz,1H),5.22(s,1H),4.29–4.20(m,1H),4.01(s,1H),3.79(dd,J=12.2,4.3Hz,1H),3.66(dd,J=16.1,10.4Hz,2H),3.53(q,J=9.6Hz,1H),2.38–2.30(m,1H),2.24(d,J=6.3Hz,1H)
实施例25
化合物(S)-4-(3-(4-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈((S)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(100mg,0.30475mmol,1.0eq),加入(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(250mg,0.45712mmol,1.5eq),碳酸钾(126mg,0.91425mmol,3.0eq),加入20mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物200mg黄色油状物。
称取上一步反应产物(190mg,0.28447mmol,1.0eq),TBAF·3H2O(223mg,0.85342mmol,2.0eq)和30mL THF,常温搅拌1h,TLC监控(THF/PE=2/1),反应完全后用EA和饱和盐水萃取,柱层析分离得到产物94mg类白色固体。1H NMR(500MHz,DMSO-d6)δ8.73(s,1H),8.59–8.53(m,1H),7.99(dd,J=8.8,2.2Hz,1H),7.42(d,J=8.8Hz,3H),6.99(d,J=8.6Hz,2H),6.61(d,J=8.8Hz,1H),5.23(s,1H),4.71(s,1H),4.07(s,2H),4.01(s,1H),3.80(dd,J=12.1,4.3Hz,1H),3.67(dd,J=15.4,10.9Hz,2H),3.56(s,1H),2.38–2.31(m,1H),2.24(d,J=5.6Hz,1H),1.31(s,6H)
实施例26
化合物(S)-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟吡唑并[1,5-a]吡啶-3-碳腈((S)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.28mmol,1.0eq),加入(S)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(306mg,0.56mmol,2.0eq),碳酸钾(77mg,0.56mmol,2.0eq),加入79mg三苯基膦钯和0.5mL水,2mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物150mg。。
称取上一步反应产物(150mg,0.22mmol,1.0eq),TBAF·3H2O(136mg,0.43mmol,2.0eq)和4mL THF,常温搅拌1h,TLC监控(THF/PE=2/1),反应完全后旋蒸掉THF,柱层析分离得到产物CP002-064 80mg淡黄色固体。
1H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.77(s,1H),8.61(s,1H),8.26(s,1H),8.08(s,1H),8.05(d,J=11.2Hz,1H),7.94(s,1H),7.83(s,1H),7.42(d,J=8.6Hz,2H),6.99(d,J=8.7Hz,2H),6.63(d,J=9.0Hz,1H),5.23(s,1H),4.01(s,1H),3.83–3.77(m,1H),3.72–3.64(m,2H),3.54(d,J=7.9Hz,2H),2.34(s,1H),2.24(s,1H)
实施例27
化合物(R)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈((R)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:(R)-1-(5-溴-吡啶-2-基)-吡咯烷-3-醇((R)-1-(5-Bromopyridin-2-yl)pyrrolidin-3-ol)的合成:
250mL单口瓶中加入2-氟-5-溴吡啶((15g,95.4mmol,1.0eq)),(R)-3-吡咯烷醇(9.7g,0.11mol,1.3eq),碳酸铯(42.5g,0.13mol,1.5eq),加入150mL DMSO,于60℃下反应。TLC监控(PE/EA=4/1),过滤,收集滤液,倒入300mL水中,加入EA萃取,有机相除水干燥,柱层析纯化得到18g白色固体,产率86.87%。
步骤2:(R)-5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶((R)-5-bromo-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)pyrrolidin-1-yl)pyridine)的合成:
250mL单口瓶中加入4-((三异丙基硅基)乙炔基)苯酚(8g,29.1mmol,1.0eq),(R)-1-(5-溴-吡啶-2-基)-吡咯烷-3-醇(14.2g,58.3mmol,2.0eq),PPh3(2.9g,87.4mmol,3.0eq)和100mL THF,氮气置换多次,升温至60℃滴加DEAD(15.2g,87.4mmol,3.0eq),控制滴加温度60~65℃,滴加完毕后60℃下搅拌1,5h,TLC监控(PE/EA=50/1)。反应结束后旋蒸THF,柱层析纯化得到8.4g产物,产率51.1%。
步骤3:(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶((R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-((triisopropylsilyl)ethynyl)phenoxy)pyrrolidin-1-yl)pyridine)的合成:
往单口瓶加入(S)-5-溴-2-(4-(4-(三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(7.5g,15mmol,1.0eq),联硼酸酯(7.6g,30mmol,2.0eq),NaOAc(7.4g,90mmol,6.0eq),100mL DMSO。氩气置换多次后加入催化剂三苯基膦钯(0.87g),氩气置换多次。升温80℃搅拌过夜,TLC监控(PE/EA=2:1),反应结束后用水和EA萃取,有机层除水干燥,柱层析分离得到5.1g灰白色固体。
步骤4:(R)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈((R)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(100mg,0.30475mmol,1.0eq),加入(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(250mg,0.45712mmol,1.5eq),碳酸钾(126mg,0.91425mmol,3.0eq),加入25mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物200mg黄色油状物。
25mL单口瓶中加入上一步反应产物(200mg,0.2994mmol,1.0eq),TBAF·3H2O(234mg,0.8983mmol,2.0eq)和30mL THF,常温搅拌1h,TLC监控(THF/PE=2/1),反应完全后用EA和饱和盐水萃取,柱层析分离得到产物粗品淡黄色固体,用THF/PE打浆得到类白色固体71mg。1H NMR(500MHz,DMSO-d6)δ8.73(s,1H),8.56(d,J=2.1Hz,1H),8.00(dd,J=8.8,2.3Hz,1H),7.42(d,J=8.9Hz,3H),6.99(d,J=8.7Hz,2H),6.61(d,J=8.9Hz,1H),5.23(s,1H),4.71(s,1H),4.07(s,2H),4.01(s,1H),3.80(dd,J=12.2,4.4Hz,1H),3.67(dd,J=15.6,10.7Hz,2H),3.54(q,J=9.7Hz,1H),2.36–2.30(m,1H),2.24(s,1H),1.31(s,6H)
实施例28
化合物(R)-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-(4-乙炔基苯氧基)吡咯烷-1-基)吡啶-3-基)-2-氟吡唑并[1,5-a]吡啶-3-碳腈((R)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-(4-ethynylphenoxy)pyrrolidin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.23mmol,1.0eq),加入(R)-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((三异丙基硅基)乙炔基)苯氧基)吡咯烷-1-基)吡啶(190mg,0.35mmol,1.5eq),碳酸钾(95mg,0.69mmol,3.0eq),加入20mg三苯基膦钯和5mL水,15mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物黄色固体130mg。
称取上一步反应产物(150mg,0.22mmol,1.0eq),TBAF·3H2O(136mg,0.43mmol,2.0eq)和4mL THF,常温搅拌1h,TLC监控(THF/PE=2/1),反应完全后旋蒸掉THF,柱层析分离得到产物80mg淡黄色固体。1H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.77(s,1H),8.61(s,1H),8.26(s,1H),8.08(s,1H),8.05(d,J=10.7Hz,1H),7.95(s,1H),7.42(d,J=8.5Hz,2H),6.99(d,J=8.5Hz,2H),6.63(d,J=8.9Hz,1H),5.23(s,1H),4.01(s,1H),3.79(s,1H),3.69(d,J=14.2Hz,2H),3.54(d,J=7.6Hz,1H),2.26–2.19(m,2H)
实施例29
化合物4-(6-(4-乙炔基苄基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(6-(4-ethynylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈,加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(314mg,0.549mmol),碳酸钾(152mg,1.097mmol),加入48mg三苯基膦钯和2mL水,5mL 1,4-二氧六环,氮气保护下升温至80℃,TLC监控(THF/Hexane=1:1)。反应结束后旋蒸,用THF溶解,柱层析分离得到黄色固体296mg。
加入上一步反应产物(296mg),TBAF(1040mg)和10mL THF,常温搅拌1h,TLC监控(THF/Hexane=2:1),反应完全后柱层析分离得到产物173mg淡黄色固体。1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.64(d,J=2.1Hz,1H),8.06(dd,J=8.9,2.4Hz,1H),7.47(s,1H),7.41(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H),6.77(d,J=8.9Hz,1H),4.72(s,1H),4.09(d,J=4.1Hz,3H),3.70(d,J=5.8Hz,4H),3.59–3.49(m,4H),2.55(d,J=6.4Hz,1H),1.58(d,J=8.4Hz,1H),1.32(s,6H)
实施例30
化合物4-(6-(4-乙炔基苄基)-3,6-二氮杂二环[3.1.1]庚-3-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(6-(4-ethynylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-(5-溴吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(3-(5-bromopyridin-2-yl)-6-(4-((triisopropylsilyl)ethynyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane)的合成:
于三颈瓶中加入4-(三异丙基硅基)乙炔基)苯甲醛(265mg,0.926mmol,1.0eq),加入3-(5-溴吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(353mg,1.389mmol,1.5eq),加入DCM10mL,氮气保护,室温搅拌一小时后加入NaBH(OAc)3(785mg,3.704mmol,4.0eq),氮气保护,TLC监控反应完全后,加入水和EA萃取分液,除水干燥后柱层析分离得到黄色粘稠物310mg。
步骤2:3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-6-(4-((triisopropylsilyl)ethynyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane)
往单口瓶加入3-(5-溴吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(293mg,0.558mmol),联硼酸酯(425mg,1.675mmol,3.0eq),KOAc(132mg,1.340mmol,2.4eq),10mL 1,4-二氧六环。氩气置换多次后加入催化剂Pd(dppf)2CH(59mg),升温120℃搅拌,TLC监控(Hexane/EA=1:1),反应完成后将反应液垫硅藻土过滤,EA洗涤滤饼,用EA和饱和食盐水萃取,取有机相。柱层析分离得到244mg黄色油状物。
步骤3:4-(6-(4-乙炔基苄基)-3,6-二氮杂二环[3.1.1]庚-3-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(6-(4-ethynylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(110mg,0.283mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(242mg,0.424mmol,1.5eq),碳酸钾(117mg,0.848mmol,3.0eq)和2mL水,5mL 1,4-二氧六环,氮气置换,加入55mg三苯基膦钯,氮气保护下升温至80℃,TLC监控(PE/EA=2:1)。反应结束后垫硅藻土过滤,滤饼用EA充分洗涤,用饱和食盐水和EA萃取分液,有机层除水干燥,浓缩,柱层析分离得到产物灰色固体108mg。
加入上一步反应产物(82mg),TBAF·3H2O(302mg)和5mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后柱层析分离得到粗品85mg白色固体。用(EA/Hexane=2:8)打浆,得到52mg白色固体。1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.67(s,1H),8.25(s,1H),8.09(d,J=8.9Hz,1H),7.97(s,1H),7.92(s,1H),7.41(d,J=8.0Hz,2H),7.35(d,J=7.9Hz,2H),6.79(d,J=9.1Hz,1H),4.10(s,1H),3.95(s,3H),3.70(d,J=12.5Hz,4H),3.55(d,J=19.0Hz,4H),2.18(s,1H),1.57(d,J=8.4Hz,1H)
实施例31
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(6-(4-乙炔基苄基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-(4-ethynylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.2822mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(242mg,0.423mmol,1.5eq),碳酸钾(117mg,0.847mmol,3.0eq)和2mL水,5mL 1,4-二氧六环,氮气置换,加入48mg三苯基膦钯,氮气保护下升温至60℃,TLC监控(hexane/THF=1:1)。反应结束后旋蒸,THF溶解除水,过柱后得到289mg蓝绿色固体。
加入上一步反应产物(289mg),TBAF·3H2O(1065mg)和10mL THF,常温搅拌,TLC监控(THF/hexane=2:1),反应完全后柱层析分离得到98mg。1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.78(s,1H),8.69(d,J=2.1Hz,1H),8.28(s,1H),8.14–8.06(m,2H),7.90(d,J=59.1Hz,1H),7.41(d,J=8.1Hz,2H),7.35(d,J=8.0Hz,2H),6.79(d,J=9.0Hz,1H),4.10(s,1H),3.76–3.65(m,4H),3.57(s,4H),2.56(d,J=6.0Hz,1H),1.58(d,J=8.4Hz,1H)
实施例32
化合物4-(6-(6-乙炔基吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑基[1,5-a]吡啶-3-碳腈(4-(6-(6-((6-ethynylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:3-(5-溴吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane)
250mL单口瓶中加入2-氟-5-溴吡啶(5.3g,0.3mol,1.0eq),加入DMSO(50mL),加入碳酸铯(14.7g,0.045mol,1.5eq),加入6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(9g,0.045mol,1.5eq),氮气保护,100℃加热,回流4小时。TLC监控反应完全后过滤多余的碳酸铯,乙酸乙酯洗涤滤渣2次,加入EA、水萃取,多次萃取直至水相TLC无产物点,分液,无水硫酸钠干燥,过柱得到9.3g白色固体产物。
取上一步反应产物(502mg,1.0eq)中加入2.5mL乙醇,滴加6.7mol/L盐酸乙醇5mL,室温搅拌至反应完全。直接旋干后得到白色固体粗品。加入无水碳酸钠调节pH至7~8,加盐至不在溶解,呈饱和状态,加入30mL乙酸乙酯,搅拌半小时后萃取分液,干燥,过滤后旋干有机相得到353mg白色固体产物
步骤2:3-(5-溴吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(3-(5-bromopyridin-2-yl)-6-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane)的合成:
于三颈瓶中加入6-(三异丙基硅基)乙基)烟醛(2.8g,0.00974mmol,1.0eq),加入3-(5-溴吡啶-2-基)-3,6-二氮杂二环[3.1.1]庚烷(3.0g,0.0118mmol,1.2eq),加入DCM50mL,氮气保护,室温搅拌一小时后加入NaBH(OAc)3(4.1g,0.01935mmol,2.0eq),氮气保护,TLC监控反应完全后,加入水和EA萃取分液,除水干燥后柱层析分离得到5.0g黄色油状物,产率90%。
步骤3:3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-6-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane)的合成:
往单口瓶加入3-(5-溴吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(3.8g,7.23mmol),联硼酸酯(3.7g,14.57mmol,2.0eq),KOAc(2.1g,21.4mmol,3.0eq),70mL 1,4-二氧六环。氩气置换多次后加入催化剂Pd(dppf)Cl2(40mg),升温100℃搅拌,TLC监控(Hexane/EA=1:1),反应完成后将反应液垫硅藻土过滤,EA洗涤滤饼,用EA和饱和食盐水萃取,取有机相。柱层析分离得到2.2g黄色油状物,产率50%。
步骤4:4-(6-(6-乙炔基吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑基[1,5-a]吡啶-3-碳腈(4-(6-(6-((6-ethynylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取4-溴-2-氟-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-碳腈(120mg,0.3657mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(270mg,0.4717mmol,1.3eq),碳酸钾(150mg,0.4717mmol,1.3eq),加入40mg三苯基膦钯和2mL水,6mL 1,4-二氧六环,氮气保护下升温至100℃,TLC监控(THF/hexane=1:1)。反应结束后过滤,保留滤渣,滤液用水和EA萃取分液,滤渣和有机层柱层析分离得到产物190mg。
25mL单口瓶中加入上一步反应产物(190mg),TBAF(300mg)和10mL THF,常温搅拌1h,TLC监控(THF/hexane=3:1),反应完全后柱层析分离得到产物76mg。用20mLTHF+10mLhexane打浆得到60mg。1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.65(d,J=2.0Hz,1H),8.51(s,1H),8.07(dd,J=8.9,2.2Hz,1H),7.77(d,J=7.7Hz,1H),7.50(d,J=7.9Hz,1H),7.47(s,1H),6.78(d,J=8.9Hz,1H),4.72(s,1H),4.25(s,1H),4.09(s,2H),3.72(d,J=13.6Hz,4H),3.60(s,2H),3.55(d,J=12.3Hz,2H),2.55(s,1H),1.58(d,J=8.4Hz,1H),1.32(s,6H)
实施例33
化合物4-(6-(6-乙炔基吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(4-(6-(6-((6-ethynylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-2-氟-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.3083mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(265mg,0.4630mmol,1.5eq),碳酸钾(130mg,0.9407mmol,3.0eq)和2mL水,6mL 1,4-二氧六环,氮气置换,加入48mg三苯基膦钯,氮气保护下升温至100℃,TLC监控(hexane/THF=2:3)。反应结束后加入200mL水,垫硅藻土过滤,洗涤固体,THF溶解固体后和有机相一起合并除水,旋蒸得到240mg产物,过柱后得到140mg产物。
加入上一步反应产物(140mg),TBAF·3H2O(200mg)和10mL THF,常温搅拌,TLC监控(THF/hexane=3:2),反应完全后柱层析分离得到粗品100mg。用Hexane打浆,得到67mg黄色固体。1H NMR(500MHz,DMSO-d6)δ11.66(s,0H),9.12(s,1H),8.67(d,J=2.1Hz,1H),8.51(s,1H),8.24(s,1H),8.09(dd,J=8.9,2.4Hz,1H),7.96(s,1H),7.92(s,1H),7.77(d,J=7.9Hz,1H),7.50(d,J=7.9Hz,1H),6.79(d,J=8.9Hz,1H),5.41–5.33(m,1H),4.25(s,1H),3.95(s,3H),3.82–3.70(m,4H),3.66–3.48(m,4H),2.44(s,1H),1.58(d,J=8.4Hz,1H)
实施例34
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-((6-乙炔基吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-ethynylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.2822mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(210mg,0.3669mmol,1.3eq),碳酸钾(120mg,0.8683mmol,3.0eq)和2mL水,6mL 1,4-二氧六环,氮气置换,加入48mg三苯基膦钯,氮气保护下升温至100℃,TLC监控(hexane/THF=1:1)。反应结束后加入40mL水,垫硅藻土过滤,洗涤固体,THF溶解固体后和有机相一起合并除水,过柱后得到200mg产物。
称取上一步反应产物(200mg),TBAF·3H2O(300mg)和5mL THF,常温搅拌,TLC监控(THF/hexane=1:1),反应完全后柱层析分离得到粗品120mg。用Hexane打浆,得到20mg黄色固体。1H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.78(s,1H),8.70(d,J=2.1Hz,1H),8.51(s,1H),8.28(s,1H),8.12(d,J=5.1Hz,2H),7.95(s,1H),7.84(s,0H),7.77(d,J=6.4Hz,1H),7.50(d,J=7.9Hz,1H),6.80(d,J=8.9Hz,1H),4.25(s,1H),3.72(t,J=8.4Hz,4H),3.60(s,2H),3.56(d,J=11.5Hz,2H),2.56(d,J=5.9Hz,1H),1.58(d,J=8.4Hz,1H)
实施例35
化合物2-氨基-4-(6-(4-乙炔基苄基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(6-(4-ethynylbenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.284mmol,1.0eq),3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(4-(三异丙基硅基)乙炔基)苄基)-3,6-二氮杂二环[3.1.1]庚烷(244mg,0.426mmol,1.5eq),加入碳酸钾(118mg,0.832mmol,3.0eq),加入2mL水和5mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯48mg,于80℃加热搅拌过夜。TLC监控(EA/Hexane=5/1)。反应结束后旋蒸,THF溶解除水,过柱后得到108mg淡黄色固体。
加入上一步反应产物(108mg),加入10mL THF,418mg四丁基氟化铵,室温下搅拌。TLC监控(EA)。反应结束旋蒸,柱层析纯化得到132mg产物。1H NMR(500MHz,Chloroform-d)δ8.41(s,1H),8.33(s,1H),7.80(d,J=8.1Hz,1H),7.73(s,1H),7.61(s,1H),7.45(d,J=7.5Hz,2H),7.38(s,2H),7.31(s,1H),6.69(d,J=8.5Hz,1H),4.52(s,2H),3.97(s,3H),3.86(s,3H),3.67(d,J=28.9Hz,3H),3.05(s,1H),1.26(s,1H),0.87(d,J=6.1Hz,1H)
实施例36
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(6-(6-乙炔基吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(6-((6-ethynylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.2840mmol),加入3-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-6-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,6-二氮杂二环[3.1.1]庚烷(240mg,0.4143mmol,1.5eq),碳酸钾(80mg,0.5789mmol,2.0eq)和2mL水,6mL 1,4-二氧六环,氮气置换,加入48mg三苯基膦钯,氮气保护下升温至100℃,TLC监控(hexane/THF=1:1)。反应结束后加入40mL水,垫硅藻土过滤,洗涤固体,THF溶解固体后和有机相一起合并除水,过柱后得到240mg产物。
加入上一步反应产物(240mg),TBAF·3H2O(300mg)和10mL THF,常温搅拌,TLC监控(THF/hexane=1:1),反应完全后柱层析分离得到粗品190mg。用3mL THF+15mL Hexane打浆,得到80mg。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.89(s,1H),8.52(s,1H),8.45–8.39(m,2H),7.96(s,0H),7.86–7.82(m,1H),7.78(d,J=8.0Hz,1H),7.71(d,J=13.7Hz,1H),7.50(d,J=8.0Hz,1H),6.79(d,J=8.8Hz,1H),6.31(s,2H),4.25(s,1H),3.74(d,J=11.0Hz,4H),3.60(d,J=17.9Hz,4H),2.56(s,1H),1.61(d,J=8.4Hz,1H)
实施例37
化合物2-氨基-4-(6-(3-((6-乙炔基吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛基-8-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(3-((6-ethynylpyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:8-(5-溴吡啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷(8-(5-bromopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane)的合成:
于单口瓶中加入2-氟-5-溴吡啶(5.9g,1.0eq),加入DMSO(5mL),加入碳酸铯(16.7g,1.5eq),加入3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯盐酸盐(9.4g,1.5eq),氮气保护,100℃加热,回流4小时。TLC监控反应完全后加入EA、水萃取,多次萃取直至水相TLC无产物点,分液,无水硫酸钠干燥,过柱得到1.6g白色固体产物。
取上一步反应产物(1.6g,1.0eq)中加入20mL乙醇,滴加6.7mol/L盐酸乙醇16mL,室温搅拌至反应完全。直接旋干后加入水溶解,加入少量三乙胺。加入无水碳酸钠调节pH至7~8,加盐至不在溶解,呈饱和状态,加入乙酸乙酯,搅拌半小时后萃取分液2次,干燥,过滤后旋干有机相得到1.2g黄色固体产物。
步骤2:8-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-3-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛烷(8-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3-((6-((triisopropylsilyl)ethynyl)pyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octane)的合成:
于三颈瓶中加入8-(5-溴吡啶-2-基)-3,8-二氮杂二环[3.2.1]辛烷(1.1g,4.1mmol,1.1eq),加入6-(三异丙基硅基)乙基)烟醛(1.1g,3.3826mmol,1.0eq),加入DCM10mL,氮气保护,室温搅拌1h后加入NaBH(OAc)3(1.2g,5.662mmol,1.5eq),氮气保护,TLC监控反应完全后,加入水和EA萃取分液,除水干燥后柱层析分离得到淡黄色油状物2.01g。
取上一步反应产物(1.8g,3.336mmol),联硼酸酯(1.7g,6.694mmol,2.0eq),KOAc(1g,10.2mmol,3.0eq),50mL 1,4-二氧六环。氩气置换多次后加入催化剂Pd(dppf)Cl2(0.54g),升温120℃搅拌,TLC监控(Hexane/EA=4:1),反应完成后将反应液用水和EA萃取,柱层析分离得到1.6g黄色油状物。
步骤3:2-氨基-4-(6-3-((6-乙炔基吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛基-8-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(3-((6-ethynylpyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.3106mmol,1.0eq),8-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)-3-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛烷(200mg,0.3409mmol,1.2eq),加入碳酸钾(130mg,0.9407mmol,3.0eq),加入2mL水和6mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯48mg,于100℃加热搅拌过夜。TLC监控(THF/Hexane=3/2)。反应结束后加入水,调pH<7,过滤,THF溶解滤渣,合并有机层,过柱后得到140mg。
加入上一步反应产物(140mg),加入3mL THF,200mg四丁基氟化铵,室温下搅拌。TLC监控(THF/Hexane=3:2)。反应结束直接柱层析纯化得到120mg,正己烷打浆得到50mg白色固体。1H NMR(500MHz,Chloroform-d)δ8.53(s,1H),8.32(s,2H),7.73(s,1H),7.69(d,J=8.6Hz,1H),7.62(s,2H),7.45(d,J=7.7Hz,1H),7.31(s,1H),6.68(d,J=8.6Hz,1H),4.58(s,2H),4.53(s,2H),3.97(s,3H),3.48(s,2H),3.14(s,1H),2.58(d,J=38.9Hz,4H),2.03(d,J=19.8Hz,4H)
实施例38
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(3-((6-乙炔基吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(3-((6-ethynylpyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.2842mmol,1.0eq),8-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)-3-(6-(三异丙基硅基)乙炔基)吡啶-3-基)甲基)-3,8-二氮杂二环[3.2.1]辛烷(200mg,0.3409mmol,1.5eq),加入碳酸钠(120mg,0.8683mmol,3.0eq),加入2mL水和6mL 1,4-二氧六环,氮气置换多次,加入三苯基膦钯48mg,于100℃加热搅拌过夜。TLC监控(THF/Hexane=1/1)。加入水,有固体析出,THF溶解固体合并有机相旋蒸,柱层析分离得到150mg产物。
加入上一步反应产物(150mg),加入5mL THF,300mg四丁基氟化铵,室温下搅拌过夜。TLC监控(Hexane/THF=1/1)。反应结束直接柱层析纯化得到110mg,用正己烷打浆得到50mg固体。1H NMR(500MHz,Chloroform-d)δ8.53(s,1H),8.38(s,1H),8.32(s,1H),8.06(s,1H),7.91(s,1H),7.69(d,J=7.9Hz,1H),7.63(d,J=7.4Hz,1H),7.50–7.42(m,1H),7.33(d,J=19.0Hz,1H),7.17(d,J=60.5Hz,1H),6.67(d,J=8.7Hz,1H),4.58(s,2H),4.54(s,2H),3.48(s,2H),3.13(s,1H),2.63(d,J=10.1Hz,2H),2.53(d,J=10.6Hz,2H),2.06(d,J=6.9Hz,2H),2.00(s,2H)
实施例39
化合物6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(6-乙炔基吡啶-3-基)氧基)哌啶-1-基)吡啶-3-基)-2-氟吡唑[1,5-a]吡啶-3-碳腈(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-((6-ethynylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)-2-氟吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(100mg,0.23mmol),加入5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)-2-(4-((6-((三异丙基硅基)乙炔基)吡啶-3-基)氧基)哌啶-1-基)吡啶(198mg,0.35mmol,1.5eq),碳酸钾(97mg,0.70mmol),5mL水,15mL 1,4-二氧六环,氮气置换,加入20mg三苯基膦钯,氮气置换,氮气保护下升温至80℃,TLC监控(PE/EA=4:1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物200mg黄色液体。
称取上一步反应产物(200mg,0.28mmol,1.0eq),TBAF·3H2O(221mg,0.84mmol,3.0eq)和10mL THF,常温搅拌1h,TLC监控(THF/PE=1/1),反应完全后加入EA和20mL饱和盐水,用EA萃取,取有机相除水干燥,柱层析分离得到产物36mg黄色固体。1H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.78(s,1H),8.65(d,J=2.0Hz,1H),8.31(d,J=2.1Hz,1H),8.27(s,1H),8.10(s,1H),8.07(dd,J=5.9,2.7Hz,1H),7.89(d,J=59.0Hz,1H),7.54–7.47(m,2H),7.03(d,J=8.9Hz,1H),4.81(s,1H),4.14(s,1H),4.07(d,J=13.3Hz,2H),3.48–3.41(m,2H),2.03(s,2H),1.69–1.62(m,2H)
实施例40
化合物2-氨基-4-(6-(2-(4-乙炔基苯基)乙酰基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(6-(2-(4-ethynylphenyl)acetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:2-(4-((三异丙基硅基)乙炔基)苯基)乙酸(2-(4-((triisopropylsilyl)ethynyl)phenyl)acetic acid)的合成:
于250mL三颈瓶中加入4-溴苯乙酸甲酯(8.4g,0.037mol,1.0eq),加入四(三苯基膦)钯(2.5g,0.002mol,0.06eq),碘化铜(0.4g,0.002mol,0.06eq),除空气,氮气保护,注射加入DMF 60mL,注射加入三乙胺(5.9g,0.059mol,1.6eq),注射加入三异丙基硅基乙炔(20.1g,0.11mol,3.0eq),70℃回流过夜。TLC监控(EA/Hexane=1:8,),监控反应完全后,垫硅藻土过滤,EA和饱和盐水萃取,分液后干燥旋干过柱,得到含杂质点的绿色液体产物13.1g。
将上一步反应产物(13.1g,0.04mol,1.0eq),MeOH 50mL,NaOH(3.2g,0.079mol,2.0eq)加入单口瓶中,加入13mL水,搅拌,点板仍有大量原料,补加80mL MeOH,搅拌过夜,点板反应完全,反应液用稀盐酸调pH至酸性,加入EA萃取,有机相除水干燥后,旋蒸得到12.3g黄色液体粗品,过柱得到8.7g黄色油状物。
步骤2:1-(4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)哌嗪-1-基)-2-(4-(三异丙基硅基)乙炔基)苯基)乙烷-1-酮(1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)-2-(4-((triisopropylsilyl)ethynyl)phenyl)ethan-1-one)的合成:
于250mL三颈瓶中加入2-(4-((三异丙基硅基)乙炔基)苯基)乙酸(1.8g,5.687mmol,1.0eq),加入1-(5-溴-2-吡啶)-4-羟基哌啶(1.515g,6.156mmol,1.1eq),HOBt(0.845g,6.256mmol,1.1eq),加入DMF5mL,氮气保护,加入EDCI(1.308g,6.824mmol,1.2eq),室温搅拌后TLC监控(EA/Hexane=1/1),反应完成后EA和水萃取分液干燥,柱层析得到3.1g淡黄色固体。
往单口瓶加入上一步反应产物(1.6g,2.96mmol),联硼酸酯(2.3g,8.879mmol,3.0eq),KOAc(0.7g,7.103mmol,2.4eq),30mL 1,4-二氧六环。氩气置换多次后加入催化剂Pd(dppf)2Cl2(0.3g),升温100℃搅拌,TLC监控,反应完成后垫硅藻土过滤,滤饼用EA冲洗,加入饱和盐水萃取,取有机相,除水干燥。柱层析分离得到300mg黄色液体。
步骤3:2-氨基-4-(6-(2-(4-乙炔基苯基)乙酰基)-3,6-二氮杂二环[3.1.1]庚烷-3-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(6-(2-(4-ethynylphenyl)acetyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.311mmol),加入1-(4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)哌嗪-1-基)-2-(4-(三异丙基硅基)乙炔基)苯基)乙烷-1-酮(274mg,0.466mmol,1.5eq),碳酸钾(129mg,0.932mmol),和2mL水,5mL 1,4-二氧六环,氮气保护下加入48mg三苯基膦钯,升温至80℃,TLC监控(THF/Hexane=1/1)。反应结束后用水和EA萃取分液,有机层浓缩柱层析分离得到产物白色固体530mg。
加入上一步反应产物(53mg),TBAF(221mg)和20mL THF,常温搅拌1h,TLC监控(THF/Hexane=4/1),反应完全后直接柱层析分离得到粗品产物87mg白色固体。正己烷打浆得到44mg白色固体。1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.34(d,J=1.9Hz,1H),8.26(s,1H),8.00(s,1H),7.78(dd,J=8.7,2.3Hz,1H),7.54(s,1H),7.43(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),6.96(d,J=8.9Hz,1H),6.23(d,J=4.8Hz,2H),4.11(s,1H),3.86(s,3H),3.82(s,2H),3.64(s,4H),3.57(s,4H)
实施例41
化合物2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(5-乙炔基吡啶酰)哌嗪-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(5-ethynylpicolinoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
步骤1:5-(三异丙基硅基)乙炔基)吡啶甲酸(5-((triisopropylsilyl)ethynyl)picolinic acid)的合成:
往1L三口瓶中加入5-溴吡啶-2-羧酸甲酯(8g,0.03703mol,1.0eq),三异丙基硅基乙炔(8.8g,0.04825mol,1.3eq),三苯基膦钯(1.7g,0.001471mol,0.04eq),CuI(0.35g,0.001838mmol,0.05eq),三乙胺(37g,0.3656mol,10eq),60mL THF,氮气置换5次,升温60℃反应搅拌过夜。TLC监控(hexane/EA=4/1)。反应结束后,冷却垫硅藻土过滤,滤饼用少量EA洗涤,收集滤液用EA和水萃取,期间把pH调至酸性,有机层除水干燥,浓缩,柱层析分离得到14g产物。
将MeOH 60mL,NaOH(4g,0.1mol,3.0eq)溶于40mL水,冷却后加入上一步反应产物(12g,0.0378mol,1.0eq),搅拌过夜,点板(EA/Hexane=1/4),反应完全,反应液用稀盐酸调pH至酸性,加入EA萃取,有机相除水干燥后,旋蒸得到12.4g粗品,过柱得到9.8g白色固体。
步骤2:4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)哌嗪-1-基)(5-(三异丙基硅基)乙炔基)吡啶-2-基)甲酮((4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)(5-((triisopropylsilyl)ethynyl)pyridin-2-yl)methanone)的合成:
于三颈瓶中加入5-(三异丙基硅基)乙炔基)吡啶甲酸(1.32g,4.942mmol,1.0eq),加入1-(5-溴-2-吡啶)-4-羟基哌啶(1.32g,5.369mmol,1.1eq),HOBt(0.75g,5.551mmol,1.1eq),加入DMF 50mL,氮气保护,加入EDCI(1.14g,5.947mmol,1.2eq),室温搅拌过夜后TLC监控(EA/Hexane=1/4),反应完成后EA和水萃取分液干燥,柱层析得到2.2g产品。
往单口瓶加入上一步反应产物(2.3g,4.36mmol),联硼酸酯(2.2g,8.663mmol,2.0eq),KOAc(1.3g,13.25mmol,3.0eq),40mL dioxane。氩气置换多次后加入催化剂Pd(dppf)Cl2(700mg),升温100℃搅拌,TLC监控(Hexane/EA=4:1),反应完成后将反应液垫硅藻土过滤,EA洗涤滤饼,用EA和饱和食盐水萃取,取有机相。柱层析分离得到2.6g棕黄色油状物。
步骤3:2-氨基-6-(1-(二氟甲基)-1H-吡唑-4-基)-4-(6-(4-(5-乙炔基吡啶酰)哌嗪-1-基)吡啶-3-基)吡唑[1,5-a]吡啶-3-碳腈(2-amino-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-(6-(4-(5-ethynylpicolinoyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-(二氟甲基)-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(120mg,0.2840mmol),加入4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷烷-2-基)吡啶-2-基)哌嗪-1-基)(5-(三异丙基硅基)乙炔基)吡啶-2-基)甲酮(220mg,0.3828mmol,1.3eq),碳酸钾(120mg,0.8683mmol,3.0eq)和2mL水,6mL 1,4-二氧六环,氮气置换,加入48mg三苯基膦钯,氮气保护下升温至100℃,TLC监控(hexane/THF=1:1)。反应结束后加入40mL水,调pH至酸性,垫硅藻土过滤,洗涤固体,THF溶解固体后和有机相一起合并除水,过柱后得到110mg产物。
加入上一步反应产物(110mg),TBAF·3H2O(200mg)和3mL THF,常温搅拌,TLC监控(THF/hexane=1:1),反应完全后柱层析分离得到粗品用20mL THF+20mL Hexane打浆,得到22mg产物。1H NMR(500MHz,DMSO-d6)δ8.97(s,1H),8.88(s,1H),8.72(s,1H),8.42(s,1H),8.38(d,J=1.9Hz,1H),8.06(dd,J=8.1,1.8Hz,1H),7.84(s,1H),7.81(dd,J=8.8,2.2Hz,1H),7.73–7.65(m,2H),6.98(d,J=8.8Hz,1H),6.30(s,2H),4.56(s,1H),3.78(d,J=21.6Hz,4H),3.61(d,J=24.7Hz,4H)
实施例42
化合物2-氨基-4-(6-(4-(5-乙炔基吡啶酰基)哌嗪-1-基)吡啶-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-碳腈(2-amino-4-(6-(4-(5-ethynylpicolinoyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile)的合成:
称取2-氨基-3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑[1,5-a]吡啶-4-基三氟甲基磺酸酯(80mg,0.20710mmol),加入4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶-2-基)哌嗪-1-基)(5-(三异丙基硅基)乙炔基)吡啶-2-基)甲酮(170mg,0.2958mmol,1.2eq),碳酸钾(90mg,0.6812mmol,3.0eq)和2mL水,6mL 1,4-二氧六环,氮气置换,加入32mg三苯基膦钯,氮气保护下升温至100℃,TLC监控(hexane/THF=1:1)。反应结束后加入40mL水,调pH至酸性,垫硅藻土过滤,洗涤固体,THF溶解固体后和有机相一起合并除水,过柱后得到75mg产物。
25mL单口瓶中加入上一步反应产物(75mg),TBAF·3H2O(100mg)和2mL THF,常温搅拌,TLC监控(THF/hexane=3:1),反应完全后柱层析分离得到40mg产物。1H NMR(500MHz,DMSO-d6)δ8.78(s,1H),8.72(s,1H),8.36(s,1H),8.27(s,1H),8.11–8.04(m,1H),8.00(s,1H),7.80(d,J=8.6Hz,1H),7.67(d,J=7.8Hz,1H),7.54(s,1H),6.98(d,J=8.7Hz,1H),6.23(d,J=5.0Hz,2H),4.56(s,1H),3.86(s,3H),3.77(d,J=27.2Hz,4H),3.60(d,J=17.0Hz,4H)
试验例1
本试验例对上述化合物进行体外酶学抑制活性测试,具体过程为:
1、实验目的:用HTRF方法测试系列化合物对Ret wt、VEGFR2、CCDC6-RET、RetV804M这4个激酶的抑制活性,并求出IC50值。
2、所用实验试剂及耗材如下:
1)HTRF KinEASE-TK kit(Cisbio,62TK0PEC);2)Ret wt(Invitrogen,PV3082);3)VEGFR2(invitrogeon,PV3660);4)CCDC6-RET(Signalchem,R02-19BG-10);5)Ret V804M(Signalchem,R02-12GG-10);6)MgCl2(Sigma,M1028);7)ATP(Promega,V910B);8)DTT(Invitrogen,P2325);9)DMSO(Sigma,D8418);10)384孔板,(白色,小体积,圆形底部,Greiner,784075);11)384孔聚丙烯微孔板,Clear,Flatt Bottom,Bar Code(Labcyte,P-05525-BC);12)96孔板polypropylene plate(Nunc,249944);13)平板振动筛(Thermo,4625-1CECN/THZ Q);14)离心机(Eppendorf,5810R);15)Envision 2104multi-labelReader(PerkinElmer,2104-10-1);16)Echo(Labcyte,550)
3、实验步骤:
3.1制备1x激酶反应缓冲液:
1倍体积的5X激酶反应缓冲液和4倍体积的水;5mM MgCl2;1mM DTT;1mM MnCl2
3.2用Echo 550反应板(784075,Greiner)每孔转移10nl稀释好的化合物;
3.3用封板膜封住反应板,1000g离心1分钟;
3.4用1X的酶反应缓冲液配制准备2X激酶;
3.5向反应板中每孔加入5μl激酶(步骤3中配制);
3.6 1000g离心30秒,用封板膜封住板子,室温反应40分钟;
3.7用HTRF检测缓冲液配制4X Sa-XL 665(250nM);
3.8每孔加入5μl Sa-XL 665和5μLTK-antibody-Cryptate;
3.9 1000g离心30秒,室温反应1小时;
3.10用Envision 2104读615nm(Cryptate)和665nm(XL665)的荧光信号。
4、数据计算
4.1计算每孔的比率(Ratio_665/615nm)
4.2抑制率计算如下:
4.3计算IC50并绘制化合物的抑制曲线:
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度):用Graphpad 6.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值;Y:抑制率(%inhibition)
结果如表1所示:
表1化合物体外酶学不同靶点的抑制活性
从表1可看出,本发明实施例化合物对RET-WT、RET-V804M和CCDC6-RET均具有好的抑制效果,其IC50值范围分别为0~5.0nM、0~7.0nM和0~2.0nM。
试验例2
本试验例对上述化合物进行体外细胞学抑制活性测试,具体过程为:
1、实验目的:用CellTiter-GloTM发光活细胞检测系统测试系列化合物对BAF3-KIF5B-RET-WT和BAF3-KIF5B-RET-V804M这2种细胞的抑制活性,并求出IC50值。
2、所用实验试剂及耗材如下:
1)CellTiter-GloTM试剂;2)1640细胞培养液;牛胎血清(FBS);DMSO;96孔板;加样槽;
3、实验步骤
3.1在DMSO中制备1000X cpd溶液;3.2用培养基将化合物稀释至最终浓度20X;3.3向98μL培养基中加入2μL 1000X cpds溶液;3.4旋转悬浮细胞并重新悬浮在生长培养基中,然后用细胞计数器计数;
3.5将95μL的细胞悬浮液放入96孔板中;3.6向96孔板中添加5μL 20X cpd溶液,每孔DMSO终浓度为0.1%;3.7在37℃、5%CO2下孵育72小时;3.8测量前,将96孔板平衡至室温;3.9向每个孔中添加50μL CellTiter试剂;3.10仪器测量前,使用仪器SHAKE功能振荡混匀2分钟,以诱导细胞裂解;3.11在室温下孵育10分钟以稳定发光信号;3.12在Paradigm上记录;4、计算
4.1使用以下公式计算相对于载体(DMSO)处理的对照孔的抑制率(Inh%):
Inhibition Rate(Inh%)=100-(RLU compound-RLU blank)/(RLU control-RLUblank)*100%
4.2根据公示计算出细胞存存活率后,再用Prism7.0程序计算出IC50值。
结果如表2所示:
表2化合物体外细胞学不同靶点的抑制活性
从表2可看出,以LOXO-292作为参考对象,实验涉及的大部分本发明专利化合物对细胞BAF3-KIF5B-RET-WT和BAF3-KIF5B-RET-V804M具有很好的抑制作用,其中,实施例18、19、11、35、12对野生型RET及V840M均具有较突出的抑制活性。
试验例3
本试验例对上述化合物进行体外细胞学抑制活性测试,具体过程为:
1、实验目的:用CellTiter-GloTM发光活细胞检测系统测试系列化合物对Ba/F3-KIF5B-RET-G810R,Ba/F3-KIF5B-RET-G810S,Ba/F3-KIF5B-RET-G810C这3种细胞的抑制活性,并求出IC50值。
2、所用实验试剂及耗材如下:
1)CellTiter-GloTM试剂;2)1640细胞培养液;3)牛胎血清(FBS);4)DMSO;5)96孔板;6)加样槽;
3、实验步骤
3.1在DMSO中制备1000X cpd溶液;3.2用培养基将化合物稀释至最终浓度20X;3.3向98μL培养基中加入2μL 1000X cpds溶液;3.4旋转悬浮细胞并重新悬浮在生长培养基中,然后用细胞计数器计数;3.5将95μL的细胞悬浮液放入96孔板中;3.6向96孔板中添加5μL20X cpd溶液,每孔DMSO终浓度为0.1%;3.7在37℃、5%CO2下孵育72小时;3.8测量前,将96孔板板平衡至室温;3.9向每个孔中添加50μL CellTiter试剂;3.10仪器测量前,使用仪器SHAKE功能振荡混匀2分钟,以诱导细胞裂解;3.11在室温下孵育10分钟;3.12在Paradigm上记录;
4、计算
4.1使用以下公式计算相对于载体(DMSO)处理的对照孔的抑制率(Inh%):
Inhibition Rate(Inh%)=100-(RLU compound-RLU blank)/(RLU control-RLUblank)*100%
4.2根据公示计算出细胞存存活率后,再用Prism7程序计算出IC50值。
结果如表3所示:
表3化合物体外细胞学对不同靶点的抑制活性
从表3可看出,以LOXO-292作为参考对象,实验涉及的本发明专利化合物对细胞Ba/F3-KIF5B-RET-G810R、Ba/F3-KIF5B-RET-G810S和Ba/F3-KIF5B-RET-G810C均具有很好的抑制作用,尤其针对Ba/F3-KIF5B-RET-G810S表现出最为优异的抑制效果,其IC50值范围为3.1~19.6nM。由此可初步推论,该化合物RET溶剂前沿突变G810R、G810S和G810C基因具有较强的抑制活性。
试验例4
本试验例对上述化合物进行体外酶学抑制活性测试,具体过程为:
1、实验目的:用HTRF方法测试系列化合物对RET G810S和RET G810C这2个激酶的抑制活性,并求出IC50值。
2、所用实验试剂及耗材如下:
1)HTRF KinEASE-TK kit(Cisbio,62TK0PEC);2)RET G810S(ProQinase);3)RETG810C(ProQinase);4)LOXO-292;5)MgCl2(Sigma,M1028);6)DTT(Invitrogen,P2325);7)384孔板,(白色,小体积,圆形底部,Greiner,784075);8)384孔聚丙烯微孔板,(Labcyte,P-05525-BC);9)96孔板(Nunc,249944);10)平板振动筛(Thermo,4625-1CECN/THZ Q);11)离心机(Eppendorf,5810R);12)Envision 2104multi-label Reader(PerkinElmer,2104-10-1);13)Echo(Labcyte,550)
3、实验步骤:
3.1制备1x激酶反应缓冲液:
1倍体积的5X激酶反应缓冲液和4倍体积的水;5mM MgCl2;1mM DTT;1mM MnCl2
3.2用Echo 650反应板每孔转移10ml稀释好的化合物;3.3用封板膜封住反应板,1000g离心1分钟;
3.4用1X的酶反应缓冲液配制准备2X激酶;3.5向反应板(784075,Greiner)中每孔加入5μl激酶(步骤3中配制);3.6 1000g离心60秒,室温反应10分钟;3.7在1x激酶缓冲液中制备2X TK底物和ATP混合物;3.8向反应板(784075,Greiner)中每孔加入5μl 2X TK-Substrate and ATP混合物,开始反应;3.9 1000g离心60秒,用封板膜封住板子,室温反应40分钟;3.10制备检测试剂;3.11在板的每个孔中加入10μl检测试剂(3.10中制备);3.121000g离心60秒,用封板膜封住板子,室温反应60分钟;3.13用Envision 2104读615nm(Cryptate)和665nm(XL665)的荧光信号。
4、数据计算
4.1计算每孔的比率(Ratio_665/615nm)
4.2抑制率计算如下:
4.3计算IC50并绘制化合物的抑制曲线:
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度):用Graphpad 6.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值;Y:抑制率(%inhibition)
结果如表4所示,
表4化合物体外酶学不同靶点的抑制活性
从表4可看出,以LOXO-292做为参照对象,实验结果表明本发明实施例化合物对RET溶剂前沿耐药突变基因G810R和G810S具有较强的抑制活性和较好的抑制作用,其IC50值范围分别为:3.66~52.18nM,0.25~5.21nM。
上面对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
1.式I所示的化合物,或式I所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,
其中,X1、X2、X3、X4各自独立选自CR5或N,且X1、X2、X3、X4中的1或2个为N;
G独立选自4~10元杂环烷基、5~12元桥杂环基或5~12元螺杂环基;
E独立选自-O-、-(C=O)-、-(C=O)CR5-、-(C=O)NR5-、-(C=S)NR5-、-(S=O)2-、-(S=O)2NR5-、-NR5(C=O)-、-NR5(C=O)O-、-NR5(C=O)NR5-、-NR5-或-(C=O)O-;
M独立选自-C0~C4亚烷基-(6~10元芳基)、-C0~C4亚烷基-(5~10元杂芳基)、-C2~C8烯基-(6~10元芳基)、-C2~C8烯基-(5~10元杂芳基)、-C2~C8炔基-(6~10元芳基)、-C2~C8炔基-(5~10元杂芳基)、-C0~C4亚烷基-(3~10元环烷基)、-C0~C4亚烷基-(4~10元杂环基)、-C0~C4亚烷基-(5~12元桥环基)、-C0~C4亚烷基-(5~12元桥杂环基)、-C0~C4亚烷基-(5~12元螺环基)、-C0~C4亚烷基-(5~12元螺杂环基)、-(6~10元芳基)-C0~C4亚烷基或-(5~10元杂芳基)-C0~C4亚烷基,其中所述的亚烷基、环烷基、杂环基、桥环基、桥杂环基、螺环基、螺杂环基、芳基、杂芳基任选为非取代,或被一个或多个选自F、Cl、Br、OH、CF3、NR5、氧代、烷氧基、环烷叉基、杂环叉基、羟基烷基、烷基、环烷基或杂环基的取代基所取代;
R1独立选自H、D、CN、F、Cl、Br、烷基或环烷基,其中所述的烷基和环烷基任选为非取代,或各自独立任选地被一个或多个选自F、Cl、Br、CN、NH2、OH或NO2的取代基所取代;
R2独立选自F、Cl、Br、NH2、OH、C1~C4烷基、取代氨基或取代C1~C4烷基;
R3独立选自OH、非取代或羟基取代的C1~C6烷基、非取代或羟基取代的C1~C6烷氧基或5元杂芳基,其中所述的5元杂芳基任选为非取代,或独立任选地被一个或多个选自F、Cl、Br、烷基、环烷基、杂环基、桥环基、桥杂环基、螺环基、螺杂环基、芳基烷基或杂芳基烷基的取代基取代;
R4、R5独立选自H、D、F、Cl、Br、C1~C6烷基或C1~C6烷氧基;
当C为0的情况表示该基团不存在。
3.根据权利要求1所述的化合物,其特征在于:R3独立选自OH、C1~C6烷基、羟基C1~C6烷基、C1~C6烷氧基、羟基C1~C6烷氧基或5元杂芳基,其中所述的5元杂芳基任选为非取代,或独立任选地被一个或多个选自F、Cl、Br、C1~C4烷基、3~10元环烷基、4~10元杂环基、5~12元桥环基、5~12元桥杂环基、5~12元螺环基、5~12元螺杂环基、芳基C1~C4烷基或杂芳基C1~C4烷基的取代基取代。
9.一种药物组合物,包括如权利要求1~5任一项所述的式I化合物、权利要求4所述的式II化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药,以及任选地,药学上可接受的辅料。
10.权利要求1~5任一项所述的式I化合物、权利要求4所述的式II化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药或所述的药物组合物在制备用于预防或治疗RET相关疾病的药物中的用途。
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