CN108191871B - 新型布鲁顿酪氨酸激酶抑制剂及其制备方法和应用 - Google Patents
新型布鲁顿酪氨酸激酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN108191871B CN108191871B CN201810002152.3A CN201810002152A CN108191871B CN 108191871 B CN108191871 B CN 108191871B CN 201810002152 A CN201810002152 A CN 201810002152A CN 108191871 B CN108191871 B CN 108191871B
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- C—CHEMISTRY; METALLURGY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明涉及一种可逆的布鲁顿酪氨酸激酶抑制剂,包括式(Ⅰ)的化合物及其立体异构体,水合物,溶剂化物,药学上可接受的盐,共晶或者前药,以及此类化合物的制备方法和使用这些新型化合物抑制BTK激酶活性和突变型BTK激酶活性的方法和用途。
Description
技术领域
本发明属于药物化学领域,具体涉及一种新型布鲁顿酪氨酸激酶的可逆性抑制剂化合物,以及此类化合物的制备方法和使用这些新型化合物抑制BTK激酶活性和突变型BTK激酶活性的方法和用途。
背景技术
Btk是一种在造血细胞(包括骨髓细胞和B细胞,但不是T细胞)中表达的非受体Tec家族细胞质酪氨酸激酶,在B细胞成熟和激活过程中有着重要的作用,在B细胞恶性肿瘤细胞内高表达。Btk抑制剂ibrutinib已经在一系列B细胞恶性肿瘤中证明了临床疗效,包括慢性淋巴细胞白血病(CLL),复发性或难治性套细胞淋巴瘤(MCL)及巨球蛋白血症(WM)等。BTK抑制剂除了可以抗B细胞淋巴瘤和白血病,还可以抑制B细胞自身抗体和细胞因子的产生。在自身免疫性疾病中,B细胞呈递自身抗原,促进T细胞活化分泌致炎症因子造成组织损伤,同时又激活B细胞产生大量抗体,触发自身免疫反应。T和B细胞相互作用形成正反馈调节链,导致自身免疫反应失控,加重组织病理损伤。研究显示,体内存在着调节性B细胞,可通过分泌白细胞介素10(IL-10)或转化生长因子β1(TGF-β1)及其他机制,负向调控免疫应答,抑制免疫介导的炎症反应。所以,B细胞可以作为自身免疫性疾病,比如类风湿性关节炎(rheumatoid arthritis,RA)、***性红斑狼疮(systemic lupus erythematosus,SLE)等的药物靶点。
Btk(ibrutinib)的共价不可逆结合机制虽然是临床有效的,但也导致了一系列的毒副作用,在临床上具有心房纤颤、腹泻、皮疹、关节痛和出血,临床数据显示停药后有些患者易发生进行性疾病(Progressive Disease,PD),比如Richter综合征(Richter Syndrom,RS)。另外随着ibrutinib广泛使用,其在患者中的耐药性也显现,其产生原因主要是BTK481位点的半胱氨酸突变为丝氨酸(C481S),Cys481的突变阻断了Btk与ibrutinib及其他抑制剂的共价不可逆结合反应,使得BTK抑制剂(ibrutinib)对突变型BTK抑制效果大幅降低,产生耐药性。
虽然依鲁替尼治疗效果显著,但是临床上的B细胞淋巴瘤患者除了一部分患者在后期产生抗药耐受外,还有相当一部分患者对其治疗不敏感,比如在MCL中约有1/3患者对其治疗无应答,DLBCL中的应答率也不高,鉴于以上问题,医生和患者都需要额外的治疗选项。
因此本发明提供一种不同于依鲁替尼,选择性地非共价可逆的BTK抑制剂,非共价结构能够抑制BTK C481S突变及野生型BTK抑制。本发明报道了一种优选的非共价BTK抑制剂,其目的在于提供一种疗效好,耐受性好或者毒副作用低的BTK抑制剂,及其在制备自身免疫性病症、炎性病症和癌症组成的病症药物中的用途。所述炎性疾病包括类风湿性关节炎,特应性皮炎等,所述自生免疫性疾病包括***性红斑狼疮。所述癌症为白血病或淋巴瘤等。
目前关于非共价可逆的BTK抑制剂报道有:
WO-2017103611公开了一种可逆的Btk抑制剂,其通式结构如下:
WO-2017046604公开了一种可逆的Btk抑制剂,其通式结构如下:
发明内容
本发明涉及一种可逆的布鲁顿酪氨酸激酶抑制剂,具有下式结构:
一种可逆的布鲁顿酪氨酸激酶抑制剂,包括式(Ⅰ)的化合物及其立体异构体,水合物,溶剂化物,药学上可接受的盐,共晶或者前药:
Q选自R1,-COR2,-SOR3,-SO2R4,-NHCONH(R5),-NHCOR6,-(CH2)nCONHR7其中R1,R2,R3,R4,R5,R6,R7为取代或者未被取代的C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,C5~C6芳基,5~6元杂芳基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代的C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
n=1~3;
当A为不存在时,Q为-COR2;
R8为氢,取代或者未被取代的C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,C5~C6芳基,5~6元杂芳基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代的C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
作为选择,当R8和Q为邻位,且R8选自C1~C6烷基时,可以选择地与他们所连接的碳原子与苯环一起形成被羰基取代的苯并五元或者六元环;
B环选自取代或者未被取代的5~6元芳环或杂芳环,所述杂芳基中包含0-3个杂原子N、S或O,所述取代基为甲基,乙基,异丙基,羟基,氨基,氰基,硝基,异氰基,卤素,三氟甲基;
L选自O,S,CONH或者CH2;
D环选自取代或者未被取代的5~6元芳环或杂芳环,所述杂芳基中包含0-3个杂原子N、S或O,所述取代基为甲基,乙基,异丙基,羟基,氨基,氰基,硝基,异氰基,卤素,三氟甲基;
本发明优选方案,一种通式(II)所示的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药,其中根据权利要求1所述的可逆的布鲁顿酪氨酸激酶抑制剂,其特征在于具有以下结构:
其中X为C-H或者N;
本发明优选方案,一种通式(II)所示的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药,其中L为O或CONH,当L为CONH时NH连接至中X邻位的碳原子上;
本发明优选方案一种通式(II)所示的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药,其中当X为C-H时,L为O;当X为N时,L为CONH;当L为CONH时NH连接至中吡啶邻位的碳原子上;
本发明提供一种通式(III),(IV),(V),(VI),(VII)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药:
其中Q1选自R1,-COR2,-SOR3,-SO2R4,;
Q2选自R1,-COR2,-NHCONH(R5),-NHCOR6,-(CH2)nCONHR7;
Q3,Q4,Q5选自-COR2;
R1,R2,R3,R4,R5,R6,R7为取代或者未被取代的C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,C5~C6芳基,5~6元杂芳基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代的C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
n=1~3;
R8为氢,取代或者未被取代的C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,C5~C6芳基,5~6元杂芳基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代的C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
作为选择,当R8和Q为邻位,且R8选自C1~C6烷基时,可以选择地与他们所连接的碳原子与苯环一起形成被羰基取代的苯并五元或者六元环;
本发明优选方案,本发明提供一种通式(III),(IV),(V),(VI),(VII)所示的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药:
其中Q1选自R1,-COR2;
Q2选自R1,-COR2,-NHCONH(R5),-NHCOR6,-(CH2)nCONHR7;
Q3,Q4,Q5选自-COR2;
其中R1,R2,R3,R4为取代或者未被取代的C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,C5~C6芳基,5~6元杂芳基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
n=1;
R5选自取代或者未被取代的芳基,杂芳基,所述取代基为C1~C6烷基,羟基,氨基,氰基,卤素,=O,三氟甲基;所述杂环烷基或杂芳基中包含0-3个杂原子N、S或O;
R6选自取代或者未被取代的芳基,杂芳基,所述杂芳基中包含0-3个杂原子N、S或O;所述取代基为1-3个C1~C6烷基,C3~C6环烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;
R7选自取代的芳基,所述取代基为C1~C6烷基,C3~C6环烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;
R8选自氢,取代或者未被取代的C1~C6烷基,C3~C6环烷基;所述取代基为1~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代的C1~C6烷基,羟基,氨基,氰基,硝基,异氰基,卤素,=O,三氟甲基;
作为选择,当R8和Q为邻位时,且R8选自C1~C6烷基时,可以选择他们所连接的碳原子与苯环一起形成被氧代的苯并五元或者六元环;
本发明优选方案,本发明涉及化合物选自,但不限于:
本发明优选方案,本发明涉及化合物选自,但不限于:
本发明优选方案,本发明涉及化合物选自,但不限于:
根据本发明的具体实施方案,本发明的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药,其中所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合,优选的,所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、肉桂酸盐、乳酸盐、丙二酸盐、琥珀酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或者它们的组合
本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药在治疗布鲁顿氏酪氨酸激酶的抑制在制备药物制剂的应用,特别是在用于制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用
本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药在制备自由自身免疫性病症、炎性病症和癌症药物中的用途。
本发明的的优选,本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药在类风湿性关节炎中的用途。
本发明的的优选,本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药在***性红斑狼疮的用途。
本发明的的优选,本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药在特应性皮炎的用途。
本发明的的优选,本发明还提供了所述的化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐、共晶或前药病症在白血病或淋巴瘤中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指含1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、正辛基及其各种支链异构体;所述的烷基可以任选进一步被0至4个选自F、Cl、Br、I、羟基、硝基、氰基、异氰基、羟基烷基、碳环基、杂环基、取代或者未被取代的5~6元芳环或杂芳环,所述杂芳基中包含0-3个杂原子N、S或O,所述取代基为甲基,乙基,异丙基,羟基,氨基,氰基,卤素,三氟甲基。
“杂环基”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至6元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。所述取代基为0~4个C1~C6烷基,C3~C6环烷基,3~6元杂环烷基,羟基取代C1~C6烷基,羟基,氨基,氰基,卤素,=O,三氟甲基;非限制地实施例包括以下结构
“碳环基”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系,优选3~6元环体系
术语“卤素”意谓F、Cl、Br或I;
如本文中所使用,术语“氧代”意谓以双键与碳原子键结,从而形成羰基的氧
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。通常,药学上适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的羟基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的羟基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
将本发明活性成分制备成药物制剂,可以根据活性成分的物化性质和实际的用药需求,制备不同的制剂形式,如溶液剂、固体制剂等。
本发明的一方面涉及具有通式结构(I),(II),(III),(IV),(V),(VI)或(VII)式,在制备治疗响应于对布鲁顿氏酪氨酸激酶的抑制的病症药物中的用途;
进一步地涉及具有通式结构(I),(II),(III),(IV),(V),(VI)或(VII)式,在制备自由自身免疫性病症、炎性病症和癌症药物中的用途;进一步地涉及具有通式结构(I),(II),(III),(IV),(V),(VI)或(VII)式,在制备自由治疗,类风湿关节炎,***性红斑狼疮,特征性皮炎药物中的用途;
在一些实施方案中,Btk抑制剂可用于治疗可通过抑制(即,降低)Btk酶活性来减轻的疾病和病症。“疾病”意谓疾病或疾病症状。因而,本发明提供治疗有需要的受试者的自身免疫性病症、炎性病症和癌症的方法。此类方法包括向受试者施用治疗有效量的Btk抑制剂。
术语“自身免疫性病症”包括涉及对天然抗原的不当免疫反应的疾病或病症,诸如急性播散性脑脊髓炎(ADEM)、阿狄森氏病(Addison's disease)、斑秃、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、大疱性类天疱疮(BP)、腹腔病、皮肌炎、1型糖尿病、古德帕斯彻氏综合征(Goodpasture's syndrome)、格雷夫斯氏病(Graves'disease)、格林-巴利综合征(Guillain-Barré syndrome,GBS)、桥本氏病(Hashimoto'sdisease)、特发性血小板减少性紫癜、红斑狼疮、混合型***病、多发性硬化、重症肌无力、寻常天疱疮、恶性贫血、多发性肌炎、原发性胆汁性肝硬化、肖格伦综合征(syndrome)、颞动脉炎和韦格纳氏肉芽肿(Wegener's granulomatosis)。术语“炎性病症”包括涉及急性或慢性炎症的疾病或病症,诸如过敏、哮喘、***炎、肾小球肾炎、骨盆炎性疾病(PID)、炎性肠病(IBD,例如克罗恩氏病、溃疡性结肠炎)、再灌注损伤、类风湿性关节炎、移植物排斥反应和血管炎。在一些实施方案中,本发明提供一种治疗类风湿性关节炎或狼疮的方法。
术语“癌症”包括涉及异常细胞生长和/或增殖的疾病或病症,诸如神经胶质瘤、甲状腺癌、乳腺癌、肺癌(例如小细胞肺癌、非小细胞肺癌)、胃癌、胃肠道间质瘤、胰腺癌、胆管癌、卵巢癌、子宫内膜癌、***癌、肾细胞癌、淋巴瘤(例如退行性大细胞淋巴瘤)、白血病(例如急性骨髓性白血病、T细胞白血病、慢性淋巴细胞性白血病)、多发性骨髓瘤、恶性间皮瘤、恶性黑色素瘤和结肠癌(例如高微卫星不稳定性结肠直肠癌)。在一些实施方案中,本发明提供一种治疗白血病或淋巴瘤的方法。
在某些实施方案中,本发明化合物用于医学中。在一些实施方案中,本发明化合物
本发明的化合物可用作激酶抑制剂。在某些实施方案中,本发明化合物为选择性抑制Btk野生型BTK激酶和突变型BTK-C481S。
在一些实施例中Btk抑制剂对野生型BTK激酶的IC50小于400nM,在一些实施例中Btk抑制剂对突变型BTK-C481S的IC50小于400nM。在一些实施方案中,Btk抑制剂对野生型BTK激酶的IC50小于10nM。在一些实施方案中,Btk抑制剂对突变型BTK-C481S的IC50为10nM至10uM。
为了开发适用的BTK抑制剂,可在体外鉴别BTK-C481S抑制激酶活性检测。可利用本领域中已知的方法和/或本文中所提供的那些方法来测定抑制剂化合物的活性。
本发明提供的布鲁顿酪氨酸激酶抑制剂对野生型BTK和C481S突变型BTK具有较强且几乎等效的抑制活性,这对解决现有BTK抑制剂的耐药性具有极其重要的意义。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
下面的缩写具有如下所示的意义:
DMF表示N,N-二甲基甲酰胺;
NBS表示N-溴代丁二酰亚胺;
DCM表示二氯甲烷;
TEA表示三乙胺;
TFA表示三氟乙酸;
THF表示四氢呋喃;
EA表示乙酸乙酯;
PE表示石油醚;
MeOH表示甲醇;
TBSCl表示叔丁基二甲基氯硅烷;
HBTU表示苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐;
TLC表示点样硅胶板;
KOAc表示乙酸钾;
Ac2O表示乙酸酐
BPO表示过氧化苯甲酰;
Pd(pph3)4表示三苯基磷钯;
Pd(dppf)Cl2表示[1,1'-双(二苯基膦基)二茂铁]二氯化钯;
EDCI表示1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
HOBT表示1-羟基苯并***;
STAB表示三乙酰氧基硼氢化钠;
FAM表示羧基荧光素;
ATP表示腺嘌呤核苷三磷酸。
实施例1:4-(8-氨基-3-((1R,3S,4S)-2-(2-氯嘧啶-4-羰基)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
合成步骤如下所示:
步骤1:(1R,3R,4S)-3-(((3-氯吡嗪-2-基)甲基)胺甲酰基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
在氮气保护下,向装有(3-氯吡嗪-2-基)甲胺(3.43g,24mmol),(1R,3R,4S)-2-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚烷-3-羧酸(5.80g,20mmol),HOBt(4.21g,31.2mmol)和TEA(4.37g,43.2mmol)的30mL DMF溶液中(0℃)逐份加EDCI(5.97g,31.2mmol),该反应混合物在室温下搅拌反应过夜,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(50mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=5/1~3/1)纯化得到8.0g目标化合物,为棕色固体。
步骤2:(1R,3S,4S)-3-(8-氯咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
冰盐浴下,向装有(1R,3R,4S)-3-(((3-氯吡嗪-2-基)甲基)胺甲酰基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(6.3g,17.18mmol)的DMF/EA(7.5mL/50mL)混合溶液中慢慢滴加POCl3(12.6mL,103.08mmol),加毕,该反应混合物在室温下搅拌2h,TLC显示原料反应完全以后,将反应液慢慢加入Na2CO3(6mol/L)的溶液中,保持pH大于8,分出有机相,水相用EA(20mL x 3)萃取,合并上述有机相用无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=3/1)纯化得到5.6g目标化合物,为黄色固体。
步骤3:(1R,3S,4S)-3-(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
冰盐浴下,向装有(1R,3S,4S)-3-(8-氯咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(4.95g,14.19mmol)的50mL DMF溶液中逐份加入NBS(2.66g,14.9mmol),该反应混合物在冰盐浴下搅拌1h,TLC显示原料反应完成以后,将反应液慢慢加入到NaHCO3(1mol/L)溶液中淬灭反应,用EA(20mL×3)萃取,有机相用饱和NaCl洗涤,无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=5/1)纯化得到5.2g目标化合物,为淡黄色固体。
步骤4:(1R,3S,4S)-3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
室温下,向装有(1R,3S,4S)-3-(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(4.4g,10.29mmol)的高压反应釜中加入15mL 2-BuOH和30mL氨水,该反应混合物在90℃搅拌反应15h,TLC显示原料反应完全以后,将反应液真空浓缩得到固体粗产品,用EA/PE(5/1)打浆得纯品3.2g目标化合物,为淡黄色固体。
步骤5:(1R,3S,4S)-3-(8-氨基-1-(4-(吡啶-2-基氨甲酰基)苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯的制备
氮气保护下,向装有(1R,3S,4S)-3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(3.5g,8.57mmol),N-(吡啶-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酰胺(3.33g,10.28mmol),Na2CO3(1.82g,17.14mmol)的dioxane/EtOH/water(36mL/12mL/12mL)混合溶液中,加入Pd(PPh3)4(496.89mg,0.43mmol),反应混合物在90℃下搅拌反应过夜,TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(40mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后柱层析(DCM/MeOH=60/1)纯化得2.8g目标化合物,为淡黄色固体。
步骤6:4-(8-氨基-3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
向装有(1R,3S,4S)-3-(8-氨基-1-(4-(吡啶-2-基氨甲酰基)苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(2.98g,5.68mmol)的DCM(20mL)溶液中,加入TFA(3.5mL),该反应混合物在室温下搅拌反应过夜,TLC显示原料反应完全以后,反应体系浓缩,用Na2CO3(3mol/L)调pH至8,用DCM/MeOH(10/1)萃取,有机相无水Na2SO4干燥,真空蒸发后通过柱层析(DCM/MeOH=60/1~10/1)纯化得到2.0g目标化合物,为白色固体。
步骤7:4-(8-氨基-3-((1R,3S,4S)-2-(2-氯嘧啶-4-羰基)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
在氮气保护下,向装有2-氯-4-嘧啶甲酸(16mg,0.10mmol)、4-(8-氨基-3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(43mg,0.10mmol)和TEA(20mg,0.20mmol)的1mL THF溶液中加入HBTU(57mg,0.15mmol),该反应混合物在室温下搅拌反应过夜,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(5mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过硅胶板(DCM/EA=1/1)纯化得到21mg目标化合物,为黄色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.43-1.51(1H,m),1.78-1.83(3.5H,m),1.97-2.00(0.5H,m),2.31-2.34(0.5H,m),2.66-2.69(1H,m),2.75-2.77(0.5H,m),4.78(0.5H,s),4.92(0.5H,s),5.22(0.5H,s),5.47(0.5H,s),6.08-6.17(2H,m),7.09-7.20(2H,m),7.54-7.58(1.5H,m),7.70-7.76(2H,m),7.84-7.89(1H,m),7.98(0.5H,d,J=4.8Hz),8.11-8.17(2.5H,m),8.21-8.24(0.5H,m),8.41(1H,d,J=4.0Hz),8.66(0.5H,d,J=4.8Hz),8.94(0.5H,d,J=4.8Hz),10.85(1H,s).
EM(计算值):565.2;MS(ESI)m/e(M+1H)+:566.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例2:4-(8-氨基-3-((1R,3S,4S)-2-(2,3-二羟基丙基)-2-氮杂双环[2.2.1]庚-3-基)咪唑并[1,5-α]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
在氮气保护下,向装有4-(8-氨基-3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(43mg,0.10mmol)的1mL甲醇溶液中加入缩水甘油(15mg,0.20mmol),该反应混合物在70℃下搅拌5h,反应体系直接旋干,然后后通过硅胶板(DCM/MeOH=20/1)纯化得到13mg目标化合物,为黄色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.24-1.26(1H,m),1.42-1.50(1H,m),1.66-1.68(2H,m),1.86-1.96(2H,m),2.38-2.50(2.3H,m),2.87-2.92(0.7H,m),3.27-3.32(2H,m),3.42-3.48(2H,m),3.72(1H,s),4.50-4.52(1H,m),4.89-4.91(1H,m),6.13-6.18(2H,m),7.08-7.12(1H,m),7.17-7.20(1H,m),7.67-7.78(3H,m),7.84-7.88(1H,m),8.14(2H,d,J=8.4Hz),8.22(1H,d,J=8.4Hz),8.41(1H,dd,J=4.8Hz,1.2Hz),10.83(1H,s).
EM(计算值):499.2;MS(ESI)m/e(M+1H)+:500.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例3:4-(-氨基-3-((1R,3S,4S)-2-(氧杂环丁烷-3-基)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-α]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
装有3-氧杂环丁酮(14mg,0.20mmol)和4-(8-氨基-3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚烷-3-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(43mg,0.10mmol)的1mL 1,2-二氯乙烷溶液于室温下搅拌1h,然后向反应液中加入STAB(42mg,0.20mmol),该反应混合物在室温下继续搅拌反应2h,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(5mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过硅胶板(DCM/EA=2/1)纯化得到27mg目标化合物,为浅黄色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.29(1H,d,J=9.2Hz),1.39-1.42(1H,m),1.56-1.65(3H,m),2.15(1H,d,J=9.2Hz),2.42(1H,s),3.49(1H,s),3.95(1H,s),4.14-4.17(1H,m),4.28-4.32(2H,m),4.48-4.54(2H,m),6.13(2H,brs),7.10(1H,d,J=4.8Hz),7.17-7.20(1H,m),7.76(2H,d,J=8.0Hz),7.85-7.89(1H,m),8.00(1H,d,J=5.2Hz),8.17(2H,d,J=8.0Hz),8.23(1H,d,J=8.4Hz),8.41(1H,d,J=4.4Hz),10.87(1H,s).
EM(计算值):481.2;MS(ESI)m/e(M+1H)+:482.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例4~16
采用以下化合物为原料,以实施例1或实施例3的制备方法,制备得到以下化合物,所述化合物的结构以及核磁表征数据见表1,表1是本申请实施例4~16制备的化合物结构以及结构分析数据汇总。
以上试剂均通过直接采购得到
表1实施例4~16制备的化合物结构以及结构分析数据
实施例17:1-((1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷吡啶-2-基)丙烷-1,2-二酮的制备
合成步骤如下所示:
步骤1:(1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯的制备
氮气保护下,向装有(1R,3S,4S)-3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(4.08g,10.00mmol)、4,4,5,5-四甲基-2-(4-苯氧基苯基)-1,3,2-二氧硼戊环(4.44g,15.00mmol)、Na2CO3(2.12g,20.00mmol)的dioxane/EtOH/water(36mL/12mL/12mL)混合溶液中,加入Pd(PPh3)4(0.58g,0.50mmol),该反应混合物在90℃下搅拌反应过夜,向反应溶液中加入水淬灭,用EA(50mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过柱层析(PE/EA=2/1)纯化得到3.81g目标化合物,为淡黄色固体。
步骤2:3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚-3-基)-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-8-胺的制备
向装有(1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(3.8g,7.64mmol)的DCM(50mL)溶液中,加入TFA(10mL),该反应混合物在室温下搅拌反应过夜,TLC显示原料反应完全以后,反应体系浓缩,用Na2CO3(3mol/L)调pH至8,用DCM/MeOH(10/1)萃取,有机相无水Na2SO4干燥,真空蒸发后通过柱层析(DCM/MeOH=20/1)纯化得到2.8g目标化合物,为浅黄色固体。
步骤3:1-((1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷吡啶-2-基)丙烷-1,2-二酮的制备
在氮气保护下,向装有丙酮酸(10mg,0.11mmol)、3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚-3-基)-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-8-胺(40mg,0.10mmol)和TEA(20mg,0.20mmol)的1mL THF溶液中加入HBTU(57mg,0.15mmol),该反应混合物在室温下搅拌反应过夜,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(5mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过硅胶板(DCM/EA=1/1)纯化得到33mg目标化合物,为类白色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.34-1.36(0.5H,m),1.46-1.48(0.5H,m),1.60-1.62(0.5H,m),1.75-1.79(3H,m),1.80-2.00(2H,m),2.31(1.5H,s),2.55-2.59(1H,m),2.67-2.68(1H,m),4.57(0.5H,s),4.73(0.5H,s),5.03(0.5H,s),5.24(0.5H,s),6.02-6.11(2H,m),7.08-7.13(5H,m),7.15-7.19(1H,m),7.41-7.44(2H,m),7.54-7.59(2H,m),7.73(0.5H,d,J=5.2Hz),7.86(0.5H,d,J=5.2Hz).
EM(计算值):467.2;MS(ESI)m/e(M+1H)+:468.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例18:1-((1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷吡啶-2-基)丙烷-1,3-二醇的制备
装有1,3-二羟基丙酮(18mg,0.20mmol)和3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚-3-基)-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-8-胺(40mg,0.10mmol)的1mL 1,2-二氯乙烷溶液于室温下搅拌1h,然后向反应液中加入STAB(42mg,0.20mmol),该反应混合物在室温下继续搅拌反应过夜。加水淬灭反应,EA萃取(5mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥。真空蒸发后通过硅胶板(DCM/EA=2/1)纯化得到5mg目标化合物,为黄色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.44-1.46(1H,m),1.63-1.66(2H,m),1.71-1.73(1H,m),1.91-1.94(1H,m),2.35(1H,s),2.55-2.56(2H,m),3.07-3.10(1H,m),3.47-3.57(4H,m),3.83(1H,s),4.47(1H,dd,J=8.8Hz,3.2Hz),4.59-4.62(1H,m),6.07(2H,brs),7.04(1H,d,J=5.2Hz),7.11-7.13(4H,m),7.17-7.20(1H,m),7.41-7.45(2H,m),7.60(2H,d,J=8.8Hz),7.78(1H,d,J=4.8Hz).
EM(计算值):471.2;MS(ESI)m/e(M+1H)+:472.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例19:1-((1R,3S,4S)-3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-氮杂双环[2.2.1]庚烷吡啶-2-基)丙烷-2-酮的制备
在氮气保护下,向装有3-((1R,3S,4S)-2-氮杂双环[2.2.1]庚-3-基)-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-8-胺(40mg,0.10mmol)和溴丙酮(14mg,0.10mmol)的1mLCH3CN溶液中加入K2CO3(28mg,0.2mmol),该反应混合物在60℃下搅拌反应一天,TLC显示原料反应完全以后,体系过滤,滤液真空蒸发后通过硅胶板(DCM/MeOH=15/1)纯化得到30mg目标化合物,为白色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.31-1.34(1H,m),1.40-1.43(1H,m),1.59-1.66(2H,m),1.87-1.91(1H,m),1.97(3H,s),2.12-2.18(1H,m),2.33-2.38(1H,m),3.36(0.4H,s),3.41(0.6H,s),3.52(1H,s),3.56(0.6H,s),3.60(0.4H,s),3.71(1H,s),5.97(2H,brs),6.95(1H,d,J=4.8Hz),7.08-7.12(4H,m),7.15-7.21(1H,m),7.40-7.46(2H,m),7.57-7.62(2H,m),7.96-8.02(1H,m).
EM(计算值):453.2;MS(ESI)m/e(M+1H)+:454.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例20~23
采用以下化合物为原料,以实施例17或实施例19的制备方法,制备得到以下化合物,所述化合物的结构以及核磁表征数据见表2,表2是本申请实施例20~23制备的化合物结构以及结构分析数据汇总。
以上试剂均通过直接采购得到
表2实施例20~23制备的化合物结构以及结构分析数据
实施例24:4-(3-(3-乙酰基苯基)-8-氨基咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
合成步骤如下所示:
步骤1:1-(3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)乙酮的制备
氮气保护下,向装有3'-溴苯乙酮(19.9g,100.0mmol)、联硼酸频那醇酯(25.4g,100.0mmol)、AcOK(19.6g,200.0mmol)的300mL dioxane溶液中,加入Pd(dppf)Cl2(3.7g,5.0mmol)。该反应混合物在80℃下搅拌反应4h。向反应溶液中加水淬灭,用EA(200mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过柱层析(PE/EA =10/1)纯化得到20.6g目标化合物,为类白色固体。
步骤2:N-((3-氯吡嗪-2-基)甲基)甲酰胺的制备
将乙酸酐(40mL)和甲酸(80mL)的混合溶液于60℃搅拌反应2h,然后向反应体系中加入3-氯吡嗪-2-甲胺二盐酸盐(21.6g,100.0mmol)。加毕,该反应混合物60℃继续搅拌反应2h,TLC显示原料反应完全以后,反应体系浓缩至油状物,将其慢慢加入Na2CO3(6mol/L)的溶液中,保持pH大于8。用EA(200mL x 3)萃取,合并上述有机相用无水Na2SO4充分干燥,真空蒸发后得到15.6g目标化合物,为棕色固体。
步骤3:8-氯咪唑并[1,5-a]吡嗪的制备
冰盐浴下,向装有N-((3-氯吡嗪-2-基)甲基)甲酰胺(15.0g,87.7mmol)的DMF/EA(25mL/150mL)混合溶液中慢慢滴加POCl3(26.8g,175.4mmol),加毕,该反应混合物在室温下搅拌2h,TLC显示原料反应完全以后,将反应液慢慢加入Na2CO3(6mol/L)的溶液中,保持pH大于8,分出有机相,水相用EA(100mL x 3)萃取,合并上述有机相用无水Na2SO4充分干燥,真空蒸发后得到11.0g目标化合物,为黄色固体。
步骤4:1,3-二溴-8-氯咪唑并[1,5-a]吡嗪的制备
冰盐浴下,向装有8-氯咪唑并[1,5-a]吡嗪(10.0g,65.3mmol)的100mL DMF溶液中逐份加入NBS(23.2g,130.6mmol),该反应混合物在室温下搅拌过夜,TLC显示原料反应完成以后,将反应液慢慢加入到NaHCO3(1mol/L)溶液中淬灭反应,用EA(100mL×3)萃取,有机相用饱和NaCl洗涤,无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=5/1)纯化得到16.4g目标化合物,为黄色固体。
步骤5:1,3-二溴咪唑并[1,5-a]吡嗪-8-胺的制备
室温下,向装有1,3-二溴-8-氯咪唑并[1,5-a]吡嗪(15g,48.2mmol)的高压反应釜中加入100mL 2-BuOH和200mL氨水,该反应混合物在90℃搅拌反应15h,TLC显示原料反应完全以后,将反应液真空浓缩得到固体粗产品,用EA/PE(5/1)打浆得纯品11.7g目标化合物,为淡黄色固体。
步骤6:1-(3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-苯基)乙酮的制备
在氮气保护下,向装有1,3-二溴咪唑并[1,5-a]吡嗪-8-胺(292mg,1.0mmol),1-(3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)乙酮(246mg,1.0mmol)和Na2CO3(212mg,2.0mmol)的dioxane/EtOH/water(3mL/1mL/1mL)混合溶液中,加入Pd(dppf)Cl2(73mg,0.1mmol)。该反应混合物在90℃下搅拌反应4h。TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(5mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发得固体粗产品,用EA/PE(1/2)打浆得到280mg目标化合物,为棕色固体。
步骤7:4-(3-(3-乙酰基苯基)-8-氨基咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
在氮气保护下,向装有1-(3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-苯基)乙酮(280mg,0.85mmol),N-(吡啶-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酰胺(247mg,0.76mmol)和Na2CO3(212mg,2.0mmol)的dioxane/EtOH/water(3mL/1mL/1mL)混合溶液中,加入Pd(dppf)Cl2(73mg,0.1mmol)。该反应混合物在90℃下搅拌反应4h。TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(5mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过硅胶板(DCM/EA=1/1)纯化得到135mg目标化合物,为类白色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ2.69(3H,s),6.33(2H,brs),7.18-7.21(2H,m),7.74-7.78(1H,m),7.84-7.89(4H,m),8.09-8.15(2H,m),8.19-8.25(3H,m),8.39-8.43(2H,m),10.90(1H,s).
EM(计算值):448.2;MS(ESI)m/e(M+1H)+:449.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例25:4-(8-氨基-3-(3-(1-羟乙基)苯基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
向装有4-(3-(3-乙酰基苯基)-8-氨基咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺(45mg,0.10mmol)的2mL甲醇溶液中加入NaBH4(15mg,0.4mmol),该反应混合物在室温下搅拌反应0.5h,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(5mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过硅胶板(DCM/MeOH=20/1)纯化得到21mg目标化合物,为白色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.40(3H,d,J=6.4Hz),4.84-4.87(1H,m),5.34(1H,d,J=4.0Hz),6.29(2H,brs),7.17-7.21(2H,m),7.49-7.57(2H,m),7.72-7.90(6H,m),8.19-8.29(3H,m),8.42-8.43(1H,m),10.95(1H,s).
EM(计算值):450.2;MS(ESI)m/e(M+1H)+:451.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例26~38
采用以下化合物为原料,以实施例24或实施例25的制备方法,制备得到以下化合物,所述化合物的结构以及核磁表征数据见表3,表3是本申请实施例26~38制备的化合物结构以及结构分析数据汇总。
以上试剂均通过直接采购或定制合成得到
表3实施例26~38制备的化合物结构以及结构分析数据
实施例39:1-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-(羟基甲基)苯基)-3-(对甲苯基)脲的制备
合成步骤如下所示
步骤1:1-溴-2-(溴甲基)-3-硝基苯的制备
室温下,向装有2-溴-6-硝基甲苯(21.6g,100.0mmol)和BPO(2.4g,10.0mmol)的30mL CH3CN溶液中加入NBS(17.8g,100.0mmol),该反应混合物在室温下搅拌反应4h,TLC显示原料反应完全以后,加水淬灭反应,EA萃取(30mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=10/1)纯化得到24.0g目标化合物,为黄色固体。
步骤2:乙酸2-溴-6-硝基苄酯的制备
将装有1-溴-2-(溴甲基)-3-硝基苯(20.0g,67.8mmol)和AcOK(13.3g,135.6mmol)的200mL DMF溶液于80℃搅拌反应4h。TLC显示原料反应完全以后,加水淬灭反应,EA萃取(100mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后得到14.5g目标化合物,为黄色固体。
步骤3:2-溴-6-硝基苯甲醇的制备
将装有乙酸2-溴-6-硝基苄酯(12.0g,43.8mmol),氢氧化钠水溶液(3M,50mL)和50mL乙醇的混合溶液于室温搅拌反应过夜。TLC显示原料反应完全以后,加水稀释反应,EA萃取(50mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后得到9.5g目标化合物,为黄色固体。
步骤4:((2-溴-6-硝基苄基)氧基)(叔丁基)二甲基硅烷的制备
室温下,向装有2-溴-6-硝基苯甲醇(9.0g,38.8mmol)和咪唑(5.3g,77.6mmol)的100mLDCM溶液中滴加TBSCl(5.8g,38.5mmol)加毕后该反应混合物在室温下搅拌反应5h。TLC显示原料反应完全以后,加水淬灭反应,DCM萃取(50mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后得到11.4g目标化合物,为黄色固体。
步骤5:3-溴-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯胺的制备
向装有((2-溴-6-硝基苄基)氧基)(叔丁基)二甲基硅烷(11.0g,31.8mmol)和NH4Cl(8.5g,159.0mmol)的EtOH/水(100mL/20mL)溶液中加入铁粉(8.9g,159.0mmol),体系于80℃搅拌反应4h。TLC显示原料反应完全以后,加水稀释反应,EA萃取(100mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后得到9.5g目标化合物,为黄色固体。
步骤6:1-(3-溴-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲的制备
将装有3-溴-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯胺(9.0g,28.5mmol)和对甲苯异氰酸酯(3.8g,28.5mmol)的100mL CH3CN溶液于室温搅拌反应过夜。TLC显示原料反应完全以后,加水淬灭反应,EA萃取(100mL×4),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过柱层析(DCM/MeOH=20/1)纯化得到6.9g目标化合物,为浅黄色固体。
步骤7:1-(2-(((叔丁基二甲基硅烷基)氧基)甲基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-3-(对甲苯基)脲的制备
氮气保护下,向装有1-(3-溴-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲(4.5g,10.0mmol)、联硼酸频那醇酯(2.5g,10.0mmol)、AcOK(2.0g,20.4mmol)的50mL dioxane溶液中,加入Pd(dppf)Cl2(0.4g,0.5mmol)。该反应混合物在80℃下搅拌反应4h。向反应溶液中加水淬灭,用EA(200mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发得到的粗品再用PE打浆得4.5g目标化合物,为棕色固体。
步骤8:1-(3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲的制备
在氮气保护下,向装有1-(2-(((叔丁基二甲基硅烷基)氧基)甲基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-3-(对甲苯基)脲(4.0g,8.1mmol),1,3-二溴咪唑并[1,5-a]吡嗪-8-胺(2.4g,8.2mmol)和Na2CO3(1.7g,16.2mmol)的dioxane/water(40mL/15mL)混合溶液中,加入Pd(dppf)Cl2(0.3g,0.4mmol)。该反应混合物在90℃下搅拌反应4h。TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(50mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过柱层析(DCM/MeOH=20/1)纯化得到200mg目标化合物,为黄色固体。
步骤9:1-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲的制备
在氮气保护下,向装有1-(3-(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲(190mg,0.33mmol),4,4,5,5-四甲基-2-(4-苯氧基苯基)-1,3,2-二氧硼戊环(97mg,0.33mmol)和Na2CO3(69mg,0.65mmol)的dioxane/water(4mL/1.5mL)混合溶液中,加入Pd(dppf)Cl2(15mg,0.02mmol)。该反应混合物在90℃下搅拌反应4h。TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(5mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过硅胶板(DCM/MeOH=20/1)纯化得到25mg目标化合物,为黄色固体。
步骤10:1-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-(羟基甲基)苯基)-3-(对甲苯基)脲的制备
将1-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-(((叔丁基二甲基硅烷基)氧基)甲基)苯基)-3-(对甲苯基)脲(20mg,0.03mmol)的HCl/EA溶液(4M,4mL)于室温下搅拌反应过夜。TLC显示原料反应完全以后,加水稀释反应并用Na2CO3调节体系至弱碱性,DCM萃取(5mL×5),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过硅胶板(DCM/MeOH=10/1)纯化得到10mg目标化合物,为浅黄色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ2.25(3H,s),4.46(2H,d,J=4.8Hz),5.44(1H,t,J=5.0Hz),6.21(2H,brs),7.05-710(3H,m),7.13-7.21(6H,m),7.28(1H,d,J=4.8Hz),7.37-7.46(5H,m),7.69(2H,d,J=8.8Hz),8.09(1H,d,J=8.4Hz),8.53(1H,s),9.43(1H,s).
EM(计算值):556.2;MS(ESI)m/e(M+1H)+:557.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例40:1-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-(羟基甲基)苯基)-3-(对甲苯基)脲的制备
以3-溴-苯乙酮为原料,以实施例39之步骤7,8,9的方法制备可得
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ2.68(3H,s),6.24(2H,brs),7.13-7.21(6H,m),7.43-7.47(2H,m),7.69-7.77(3H,m),7.82(1H,d,J=5.2Hz),8.08-8.13(2H,m),8.37(1H,s).
EM(计算值):420.2;MS(ESI)m/e(M+1H)+:421.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例41:2-(3-(8-氨基-1-(4-苯氧基苯基)咪唑并[1,5-a]吡嗪-3-基)-2-甲基苯基)-N-(对甲苯基)乙酰胺的制备
以订制合成的2-(3-溴-2-甲基苯基)-N-(对甲苯基)乙酰胺为原料,以实施例39之步骤7,8,9的方法制备可得
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ2.13(3H,s),2.24(3H,s),3.82(2H,s),6.20(2H,brs),7.05-7.20(9H,m),7.34-7.37(2H,m),7.42-7.50(5H,m),7.70(2H,d,J=8.8Hz),10.12(1H,s).
EM(计算值):539.2;MS(ESI)m/e(M+1H)+:590.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例42:4-(8-氨基-3-(环丙烷羰基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
合成步骤如下所示
步骤1:(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)(环丙基)甲酮的制备
在氮气保护下,将1,3-二溴-8-氯咪唑并[1,5-a]吡嗪(311mg,1.0mmol)的THF(5mL)溶液冷却至-70℃,然后在此温度下滴加正丁基锂(2.5M in THF,0.4mL,0.1mmol),加毕后继续搅拌0.5h,再将N-甲氧基-N-甲基环丙烷甲酰胺(129mg,1.0mmol)的THF(1mL)溶液滴加到上述反应体系中,加毕后该反应混合物继续在-70℃下搅拌1h。反应体系倒入饱和NH4Cl水溶液中,EA萃取(10mL×3),有机相用饱和食盐水反洗,无水Na2SO4充分干燥,真空蒸发后通过柱层析(PE/EA=2/1)纯化得到180mg目标化合物,为棕色固体。
步骤2:(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)(环丙基)甲酮的制备
室温条件下,向装有(1-溴-8-氯咪唑并[1,5-a]吡嗪-3-基)(环丙基)甲酮(150mg,0.5mmol)的高压反应釜中加入2mL 2-BuOH和4mL氨水,该反应混合物在90℃搅拌反应过夜,TLC显示原料反应完全以后,将反应液真空浓缩得到固体粗产品,用EA/PE(3/1)打浆得纯品105mg目标化合物,为淡黄色固体。
步骤3:4-(8-氨基-3-(环丙烷羰基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
在氮气保护下,向装有(8-氨基-1-溴咪唑并[1,5-a]吡嗪-3-基)(环丙基)甲酮(56mg,0.2mmol),N-(吡啶-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酰胺(65mg,0.2mmol)和Na2CO3(42mg,0.4mmol)的dioxane/EtOH/water(1.5mL/0.5mL/0.5mL)混合溶液中,加入Pd(dppf)Cl2(7mg,0.01mmol)。该反应混合物在90℃下搅拌反应4h。TLC显示原料反应完全以后,向反应溶液中加入水淬灭,用EA(5mL×3)萃取,有机相用饱和食盐水反洗,无水Na2SO4干燥,真空蒸发后通过硅胶板(DCM/EA =1/1)纯化得到29mg目标化合物,为白色固体。
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.20(4H,d,J=6.0Hz),1.30(1H,s),6.55(2H,brs),7.26(1H,dd,J=5.4Hz,7.0Hz),7.57(1H,d,J=4.4Hz),7.90-7.96(3H,m),8.27-8.31(3H,m),8.49(1H,d,J=4.0Hz),8.80(1H,d,J=4.8Hz),10.99(1H,s).
EM(计算值):398.1;MS(ESI)m/e(M+1H)+:399.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
实施例43:4-(8-氨基-3-((1S)-2-(2-氯嘧啶-4-羰基)八氢环戊[c]吡咯-1-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的制备
采用(1S)-2-(叔丁氧基羰基)八氢环戊二烯并[c]吡咯-1-羧酸及实施例1中相应化合物为原料,以实施例1的方法制备可得
采用核磁共振以及质谱对产物结构进行表征,结果如下:
1H NMR(400MHz,d6-DMSO)δ1.45-2.02(7H,m),2.79-2.90(1H,m),3.05-3.10(1H,m),3.57-3.69(1H,m),3.98-4.18(1H,m),5.46-5.64(1H,m),6.07-6.18(3H,m),7.07-7.20(2H,m),7.40-7.49(0.5H,m),7.67(0.5H,d,J=8.4Hz),7.76-7.79(2H,m),7.84-7.89(1H,m),7.95(0.5H,d,J=5.2Hz),8.13-8.17(2H,m),8.22(0.5H,dd,J=8.4Hz,0.8Hz),8.40-8.42(1H,m),8.68(0.5H,d,J=5.2Hz),8.94(0.5H,d,J=5.2Hz).
EM(计算值):579.2;MS(ESI)m/e(M+1H)+:580.2。
可见本申请制备得到的化合物与上述反应式中的化合物结构一致。
试验例1:体外野生型BTK抑制激酶活性试验
1:试验原理:
微流体芯片技术的迁移率检测技术(Mobility-Shift Assay),该技术将毛细管电泳的基本理念应用到微流体环境中,用于实验的底物是带有荧光标记的多肽,在反应体系中酶的作用下,底物转变为产物,其所带的电荷也发生了相应的变化,Mobility-ShiftAssay正是利用底物和产物所带电荷的不同,将二者进行分离,并分别进行检测,检测结果由转化率表达出来。2:试验方法:
(1)配置待测样品:用100%DMSO稀释至反应终浓度的50倍即25umol/L;
(2)稀释:25umol/L为起始浓度,然后以4倍浓度稀释,稀释10个浓度梯度;
(3)阳性对照和阴性对照孔中分别加入100%DMSO;
(4)将配好的10个浓度的化合物分别用1倍激酶缓冲液稀释10倍;其中激酶缓冲液中包含浓度为50mmol/L,pH为7.5的羟乙基哌嗪乙硫磺酸、0.01%的十二烷基聚乙二醇醚、10mmol/L的氯化镁、2mmol/L的二硫苏糖醇;
(5)配制2.5倍酶溶液:将激酶加入1倍激酶缓冲液,形成2.5倍酶溶液;
(6)配制2.5倍的底物溶液:将FAM标记的多肽和ATP加入1倍激酶缓冲液,形成2.5倍底物溶液;
(7)向384孔板中加入酶溶液:384孔反应板中已有5μl的10%DMSO溶解的5倍化合物,然后再加入10μl的2.5倍酶溶液,室温下孵育10分钟;
(8)向384孔板中加入底物溶液:在384孔反应板中加入10μl的2.5倍底物溶液;
(9)激酶反应和终止:28℃下孵育1h,然后加25μl终止液终止反应;其中终止液中包含浓度为100mmol/L,pH为7.5的羟乙基哌嗪乙硫磺酸、0.015%的十二烷基聚乙二醇醚、0.2%的3号表面试剂、20mmol/L的乙二胺四乙酸;
(10)Caliper读取数据Caliper上读取转化率数据;
(11)抑制率计算从Caliper上复制转化率数据。
把转化率转化成抑制率数据,其中max是指DMSO对照的转化率,min是无酶活对照的转化率。
Percent inhibition=(max-conversion)/(max-min)*100.
试验例2:体外突变型BTK-C481S抑制激酶活性试验
1:试验方法:
1)待测化合物溶于DMSO中以1mM为起始浓度,然后以3倍浓度稀释,10个浓度梯度;将DMSO溶解的待测化合物、BTK-C481S蛋白、底物Ploy E4Y1和ATP分别用1×buffer稀释成2.5倍反应液,1×buffer:40mM Tris,7.5;20mM MgCl2;0.1mg/ml BSA;2mM MnCl2,50μM DTT
2)分别向384孔板中加入含4%DMSO的2.5倍待测化合物1.25μL、2.5倍酶溶液1.25μL,室温下孵育30分钟;再加入2.5μL PolyE4Y1/ATP反应液,室温孵育60分钟;
3)向384孔板中加入5μL ADP-Glo Reagent,室温下孵育40分钟;
4)向384孔板中加入10μL Kinase Detection Reagent,室温下孵育30分钟;
5)Envision Plate-Reader读数
2:实验验证:
实验中有溶媒组(含激酶、ATP、多肽底物和1%DMSO)作为100%phosphorylationcontrol;含有激酶、ATP和1%DMSO反应组作为0%phosphorylation control(不含多肽底物);实验中使用参照化合物PCI32765购自Haoyuan Chemexpress Co.,Ltd.。
3:结果:
Envision Plate-reader读数得出对应的每孔化学发光值RLU。待测化合物原始数据为RLUDrug、100%phosphorylation control对照组数据为RLU100、0%phosphorylationcontrol对照组数据为RLU0;对RLUDrug进行预处理、即扣除背景值RLU0,然后进行归一化:
%Enzyme Activity=(RLUDrug-RLU0)/(RLU100-RLU0)*100%
采用Graph Pad Prism version 5.0.对待测化合物单个浓度对BTK-C481S激酶相对剩余活性(%Enzyme Activity)数值进行非线性回归曲线拟合,得出IC50值
表4实施例化合物对野生型BTK激酶及突变型BTK-C481S抑制活性结果
从表中数据可以看出,实施例15、17、19、23、24、36对野生型BTK及突变型BTK-C481S激酶活性都具有较高的抑制作用。其中,实施例19与实施例23的表现尤其突出:两个化合物的野生型BTK激酶抑制作用与阳性对照物依鲁替尼大致相当;同时,它们的突变型BTK-C481S激酶抑制作用要好于阳性对照物GDC-0853。因此,本发明所设计的化合物可用作BTK抑制剂,且可同时抑制野生型BTK及突变型BTK-C481S,从而克服因突变产生的耐药性。具有广阔的抗恶性肿瘤的应用前景。
Claims (5)
3.权利要求1或2中任一项所述的化合物在制备治疗响应于对布鲁顿氏酪氨酸激酶的抑制的病症药物中的用途。
4.权利要求1或2中任一项所述的化合物在制备自由自身免疫性病症、炎性病症和癌症药物中的用途。
5.根据权利要求4所述的用途, 选自类风湿性关节炎,***性红斑狼疮,特应性皮炎,白血病或淋巴瘤。
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