CN116874468A - 具有2-吡啶取代甲酰胺结构的小分子化合物的合成和应用 - Google Patents
具有2-吡啶取代甲酰胺结构的小分子化合物的合成和应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- A61P9/12—Antihypertensives
Abstract
本发明涉及一类ASK1激酶的小分子抑制剂,具体涉及一种具有2‑吡啶取代甲酰胺结构的小分子化合物的合成和应用,及其药物组合物和在制备ASK1小分子抑制剂,或预防和/或治疗与ASK1相关疾病,尤其是肝脏疾病、肺部疾病、肿瘤、心血管疾病、肾脏疾病和代谢性疾病的药物中的用途。
Description
技术领域
本发明本发明属于医药技术领域,具体涉及一种具有2-吡啶取代甲酰胺结构的小分子化合物的合成和应用,及其药物组合物及其用于预防或治疗凋亡信号调节激酶I(ASKl,也称为MAP3K5,MAPKKK5,MEKK5)介导的疾病或病症的用途,尤其是肝脏疾病、肺部疾病、心血管疾病、肾脏疾病和代谢性疾病的药物中的应用。
背景技术
ASK1激酶,全称细胞凋亡信号调节激酶I(Apoptosis Signal RegulatingKinase1),属于MAP3K家族成员,位于Jun N末端激酶(JNK)和p38的上游。大量实验证明,ASK1在哺乳动物细胞应激反应和诱导细胞凋亡相关疾病中发挥了重要作用。
ASK1激酶抑制剂对于治疗常见的肝脏疾病,例如非酒精性脂肪肝、非酒精性脂肪肝炎、慢性肝病、代谢性肝病、肝纤维化、原发性硬化性胆管炎、肝脏缺血-再灌注损伤、原发性胆汁肝硬化、糖尿病相关的肝脏疾病等疾病,具有潜在治疗前景。生物学和医学相关研究还表明,ASK1激酶激酶抑制剂具有治疗肺部疾病(例如肺动脉高压、肺纤维化)的疗效。此外,抑制ASK1激酶也具有治疗肾脏疾病(血管球性肾炎、糖尿病肾病、高血压性肾病)、肿瘤的可行性。抑制ASK1激酶活性在糖尿病小鼠模型中,具有显著的治疗效果;使用ASK1小分子抑制剂GS-444217可以降低糖尿病的参数指标。因此,ASK1是治疗上述疾病的潜在靶点,开发新型ASK1抑制剂对缓解甚至治愈这些疾病具有重要意义。
目前,已经有一些文献报道的部分ASK1抑制剂具有分子水平活性低,靶点选择性差,动物药效量效关系不明显,化合物的类药性差等潜在问题。另外,部分化合物具有化学稳定性和体内代谢稳定性的潜在问题。还有一些ASK1激酶小分子抑制剂水溶性太强,动物口服药物后体内暴露量偏低,相应的药物在动物体内的药代动力学性质欠佳,导致化合物的体内药效有待提高。
因此,本领域仍然需要研发一种效果更好的ASK1激酶小分子抑制剂。
发明内容
本发明的目的在于提供一类结构新颖的ASK1激酶的小分子抑制剂。
本发明的目的还在于提供上述化合物的合成方法和用途。
本发明第一方面提供了一种式(I)所述的具有2-吡啶取代甲酰胺结构的小分子化合物,或其对映异构体、外消旋体或其混合物,或其药学上可接受的盐、水合物或者溶剂合物,
其中,
R1表示不同取代位置的卤素、氘原子、氰基、羟基、氨基、硝基、氧基、烷基、取代或未取代的含N、O或S原子的5-12元杂芳环、取代或未取代的含N、O或S原子的5-13元饱和杂环,取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的C3-C6环烷基,取代或未取代的C1-C4烷基乙炔基、取代或未取代的C1-C4烷基氨基、取代或未取代的C1-C4烷基羰基氨基、取代或未取代的C1-C4烷氧基羰基氨基、取代或未取代的C1-C4磺酰基、取代或未取代的C1-C4烷基-S-、取代或未取代的C2-C10酰基、取代或未取代的C1-C4烷基羰基、取代或未取代的C1-C4烷基氨基羰基,或其组合;
表示不同N原子位置的喹啉环或含有两个氮原子的6元杂环;
X表示N、CH或C=O;
a,b表示含N杂环上酰胺取代的位置。
R2表示H或甲基;
R3表示取代或未取代的含1-4个N、O或S的杂原子的5-6元杂芳环,所述的取代基团上的一个或多个氢原子被选自下组的基团取代:卤素、氘原子、氰基、羟基、氨基、硝基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C6烷氧基;其中,所述的取代基团中相应的取代基团上的一个或多个氢原子被选自下组的基团取代:羟基、氨基、羧基。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂化合物、N-氧化物、同位素标记的化合物、代谢物或前药。所述化合物具体选自以下结构式中的一种:
本发明还提供了一种ASK1抑制剂,所述的抑制剂包括所述的化合物,或其对映异构体、非对映异构体、外消旋体及其混合物,或其药学上可接受的盐、结晶水合物或者溶剂合物。
本发明还提供了一种药物组合物,包括:(A)治疗有效量的所述的化合物,及其对映异构体、非对映异构体、外消旋体及其混合物,以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或多种;和(B)药学上可接受的载体。
优选的,所述药物组合物还包含药学上可接受的辅料,所述辅料选自粘合剂、填充剂、稀释剂、崩解剂、混悬剂、助悬剂、缓释剂或控制剂、冻干保护剂、包衣剂、肠溶材料、润滑剂、助流剂、抗粘剂、甜味剂、风味剂、增塑剂、遮光剂、增溶剂、保湿剂、溶剂、渗透压调节剂、着色剂、色素、表面活性剂、乳化剂、水溶性基质、脂溶性基质、油脂性基质、致孔剂、凝胶剂、防腐剂、缓冲剂、螯合剂以及抗氧剂中的一种,或其多种组合。
提供了本发明的药物组合物在制备用于预防或治疗凋亡信号调节激酶1(ASK1)介导的疾病或病症的药物中的用途。
本发明还提供了一种所述的化合物在制备治疗与ASK1激酶的活性或表达量相关的疾病的药物中的应用。
优选的,所述与ASK1激酶的活性或表达量相关的疾病选自肝脏疾病、肺部疾病、心血管疾病、肾脏疾病、代谢性疾病和肿瘤疾病中的一种。
优选的,所述肝脏疾病选自非酒精性脂肪肝、非酒精性脂肪肝炎、慢性肝病、代谢性肝病、肝纤维化、原发性硬化性胆管炎、肝脏缺血-再灌注损伤、原发性胆汁肝硬化以及糖尿病相关的肝脏疾病中的一种;
所述肺部疾病为肺动脉高压或者肺纤维化;
所述心血管疾病为心脏功能衰竭;
所述肾脏疾病选自血管球性肾炎、糖尿病肾病以及高血压性肾病中的一种;
所述代谢性疾病为二型糖尿病或者一型糖尿病;
所述肿瘤疾病选自肝癌,肺癌,乳腺癌,胃癌,结直肠癌,食管癌,***,卵巢癌,膀胱癌以及胰腺癌中的一种。
本发明还提供了一种所述的化合物的合成方法,其合成路线如下:
优选的,所述合成路线中的I-1通过一步反应制备,所述步骤一具体为:胺S1与相应的酰氯S2在适当溶剂,例如四氢呋喃、2-甲基四氢呋喃、二氯甲烷、或者N、N-二甲基甲酰胺等中混合。加入碱(三乙基胺、二异丙基乙基胺、或N-甲基吗啉等),在室温、适当低温条件(-10℃至0℃)或适当升高温度条件下(例如40-50℃),反应得到终产物I-1;步骤二具体为将I-1溶解于DMF,加NaH,碘甲烷,室温、低温条件或升高温度条件下搅拌反应,制备终产物I-2。
实施方式
定义
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然详细一下术语对本领域技术人员很好理解,但仍然阐述以下定义以更好的解释本发明。
如本文中所使用,术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的,且不排除其它未列举的元素或方法步骤。
如本文中所使用,术语“氢”是指氕(H)、氘(D)、氚(T)。
如本文中所使用,术语“烷基”定义为线下或支化饱和脂肪族烃。C1-12烷基是指具有1至12,例如1至6个碳原子(C1-6烷基)或1至4个碳原子(C1-4烷基)。例如,如本文中所使用,术语“C1-6烷基”指1至6个碳原子的线下或支化的基团(例如甲基、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、新戊基或正己基),其人选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文所使用,术语“烯基”意指线下的或支化的单价烃基,其包含一个或多个双键,且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3戊烯基。当本发明的化合物含有烯基时,所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意比例混合物形式存在。
如本文所使用,术语“炔基”表示包含一个或多个三键的单价烃基,例如具有2、3、4、5或6个碳原子,例如乙炔基或丙炔基。
如本文中所使用,术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、或双环,包括螺环、稠合或桥连***(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)),其人选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如,术语“C3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基),其任选地被1或多个(诸如1至3个)适合的取代基取代,例如甲基取代的环丙基。
如本文中所使用,术语“杂环基”指饱和或部分不饱和的一价单环或双环基团,其在环中具有2、3、4、5、6、7、8或9个碳原子或一个或多个(例如一个、两个、三个或四个)选自C(=O)、O、S、S(=O)、S(=O)2和NRa的含杂原子的基团,其中Ra表示氢原子
如本文所使用,术语“5-12元杂芳环”个环成员的单环芳族基团,且所述环成员中饱和至少1个(例如1、2、3或4个)选自N、O、S的杂原子,例如“5-6元杂芳基”、5元杂芳基、6元杂芳基等。其具体实例包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、咪唑基、吡唑基、1,2,3-***基、1,2,4-***基、1,2,3-恶二唑、1,2,4-恶二唑、1,2,5-恶二唑、1,3,4-恶二唑、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、2H-1,2-恶嗪基、4H-1,2-恶嗪基、6H-1,2-恶嗪基、4H-1,3-恶嗪基、6H-1,3-恶嗪基、4H-1,4-恶嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基等。
如本文所使用,术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文所使用,术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
除非另外指明,否则如本文中所使用,取代基的连接点可来自取代基的任意适宜位置。
本发明还包括所有药学上可接受的同位素标记的化合物,其与本发明的化合物相同,除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素(例如氘(2H)氚(3H)):碳的同位素(例如11C、13C及14C);氯的同位素(例如36Cl);氟的同位素(例如18F);碘的同位素(例如123I及125I);氮的同位素(例如13N及15N);氧的同位素(例如15O、17O及18O);磷的同位素(例如32P);硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(3H)及碳-14(14C)因①掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述与随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些,例如,D2O、丙酮-d6或DMSO-d6。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成,实例包括天冬氨酸盐、葡萄糖酸盐、乳酸盐、棕榈酸盐、盐酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、钠盐、钙盐、钾盐、胆碱盐及其它类似的盐。
本发明的化合物可以溶剂合物(优选水合物)的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化合物计量比存在。
术语“约”是指在所述数值的±10%范围内,优选±5%范围内,更优选±2%范围内。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按质量计算。
实验实施例1:化合物的合成
合成中间体01:6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-胺(12-4-41)
步骤一:将6-氨基吡啶甲酸甲酯(500mg,3.289mmol),溶于25mL甲醇中,在氩气环境下,缓慢滴加水合肼(318.75μL,6.578mmol),升高温度至75℃回流3h。反应完全后,降至室温,无水硫酸钠干燥,旋蒸浓缩。得白色固体目标化合物粗品475mg(12-3-41),产率95%。
步骤二:将6-氨基-吡啶甲酰肼(475mg,3.125mmol),溶于30mL的甲苯中,加入N,N-二甲基甲酰胺二甲基缩醛(104.74μL,9.375mmol)和异丙胺(157.5μL,21.875mmol)。冷却至0℃,滴加醋酸(45.1μL,9.375mmol)。氩气环境下,升高温度至95℃回流10h,降至室温,旋转蒸发仪浓缩后,溶于10mL纯净水中,85℃下继续反应10h。反应结束后,加入20mL***洗涤,20mL二氯甲烷洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化(石油醚/乙酸乙酯=20/1),目标化合物纯品243.485mg白色固体(12-4-41),产率51.26%。1H NMR(400MHz,DMSO-d6):δ8.78(s,1H),7.52(dd,J=8.1,7.6Hz,1H),7.23–7.13(m,1H),6.58–6.47(m,1H),δ5.53(dt,J=13.5,6.7Hz,1H).,1.43(d,J=6.7Hz,6H).
终产物1:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)异喹啉-4-甲酰胺(1,12-168-41)
将中间体01(12-4-41,70.2mg,0.346mmol)和异喹啉-4-羧酸(50mg,0.289mmol),溶于5mL的二氯甲烷中,冷却至0℃,加入三乙胺(280μL,2.02mmol)和1-丙基磷酸酐(688μL,2.310mmol)。氩气环境下,升高温度至40℃回流7h。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物10mg(1,12-168-41),产率25.8%。1H NMR(400MHz,CD3OD):δ9.48–9.32(m,1H),8.79(dd,J=15.6,3.6Hz,1H),8.44(t,J=8.9Hz,1H),8.23(tt,J=17.0,8.6Hz,1H),7.94(dt,J=15.3,7.7Hz,1H),7.88–7.75(m,1H),7.60–7.55(m,1H),7.21(dd,J=12.9,6.8Hz,1H),6.66(d,J=8.4Hz,1H),5.51(dt,J=13.5,6.7Hz,1H),1.52(t,J=4.8Hz,6H)。
终产物2:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-4-甲酰胺(2,12-161-41)
将中间体01(12-4-41,70.2mg,0.346mmol)和喹啉-4-羧酸(50mg,0.289mmol),溶于5mL的二氯甲烷中,冷却至0℃,加入三乙胺(280μL,2.02mmol)和1-丙基磷酸酐(688μL,2.310mmol)。氩气环境下,升高温度至40℃回流7h。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋干浓缩,柱层析纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物54.1mg(2,12-161-41),产率52.3%。1H NMR(400MHz,CD3OD):δ9.01(d,J=4.4Hz,1H),8.80(s,1H),8.45(d,J=8.3Hz,1H),8.26(d,J=8.4Hz,1H),8.15(d,J=8.5Hz,1H),8.09(t,J=8.0Hz,1H),7.94(d,J=7.7Hz,1H),7.87(t,J=7.7Hz,1H),7.78–7.73(m,1H),7.71(d,J=7.3Hz,1H),5.76(dt,J=13.5,6.8Hz,1H),1.48(d,J=6.7Hz,6H)。
终产物3:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)异喹啉-1-甲酰胺(3,12-68-41)
将异喹啉-1-羧酸(50mg,0.289mmol),溶于5mL的二氯甲烷中,加入碳二亚胺盐酸盐(55.4mg,0.289mmol)和N-羟基琥珀酰亚胺(34.1mg,0.289mmol)。氩气环境下,加入中间体01(12-4-41,59mg,0.289mmol),升高温度至40℃回流7h。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物24.5mg(3,12-68-41),产率23.7%。1H NMR(400MHz,CDCl3):δ10.73(s,1H),9.61(dd,J=
6.7,3.0Hz,1H),8.52(t,J=5.4Hz,2H),7.99(s,1H),7.93–7.81(m,3H),7.75–
7.67(m,2H),5.73(s,1H),1.56(s,6H)。
终产物4:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹喔啉-2-甲酰胺(4,12-13-42)
将喹喔啉-2-羧酸(81.78mg,0.47mmol),溶于6mL的二氯甲烷中,加入0.06mL的N,N-二甲基甲酰胺二甲基缩醛。冷却至0℃,氩气环境下,滴加草酰氯(80μL,0.93mmol),室温搅拌2h。酰氯制备完成后,旋干,真空干燥除去反应溶剂和过量草酰氯,加入中间体01(12-4-41,62.93mg,0.31mmol)的二氯甲烷溶液(6mL),再滴加三乙胺(85.8μL,0.62mmol),室温搅拌1h。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物21.42mg(4,12-13-42),产率42.84%。1H NMR(400MHz,CDCl3):δ9.72(s,1H),8.45(d,J=8.2Hz,1H),8.39(s,1H),8.18(d,J=8.1Hz,1H),8.13(d,J=7.7Hz,1H),8.00(d,J=7.6Hz,1H),7.88(dd,J=16.2,8.9Hz,3H),7.20(s,1H),5.53(dt,J=13.3,6.7Hz,1H),1.58(d,J=6.7Hz,6H)。
终产物5:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)-4-氧代-1,4-二氢喹唑啉-2-甲酰胺(5,12-163-41)
将4-氧代-1,4-二氢喹唑啉-2-羧酸(40mg,0.210mmol)和中间体01(12-4-41,51.2mg,0.252mmol),溶于5mL的二氯甲烷中,冷却至0℃,加入三乙胺(206μL,1.472mmol)和1-丙基磷酸酐(500μL,1.682mmol)。氩气环境下,升高温度至40℃回流7h。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物32mg(5,12-163-41),产率40.5%。1H NMR(400MHz,CD3OD)δ8.86(s,1H),8.43(d,J=8.3Hz,1H),8.31(d,J=7.9Hz,1H),8.08(t,J=8.0Hz,1H),7.98–7.89(m,3H),7.66(dd,J=9.8,4.2Hz,1H),5.69–5.62(m,1H),1.63(s,3H),1.62(s,3H).
终产物6:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(6,12-70-41)
将喹啉-2-羧酸(50mg,0.289mmol),溶于5mL的二氯甲烷中,加入碳二亚胺盐酸盐(55.4mg,0.289mmol)和N-羟基琥珀酰亚胺(34.1mg,0.289mmol)。氩气环境下,加入中间体01(12-4-41,59mg,0.289mmol),升高温度至40℃回流7h,反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋转蒸发仪浓缩,反相硅胶柱纯化(二氯甲烷/甲醇=80/1),得白色固体目标化合物27.5mg(6,12-70-41),产率26.57%。.1H NMR(400MHz,CDCl3)δ8.49(d,J=8.2Hz,2H),8.36(s,3H),8.11(d,J=8.4Hz,1H),7.90(t,J=10.2Hz,3H),7.63(t,J=7.5Hz,1H),5.23(s,1H),1.63(s,6H)。
终产物7:8-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(7,21-25-41)
将8-溴喹啉-2-羧酸(50mg,0.2mmol)、中间体01(12-4-41,40.3mg,0.2mmol)加入到50mL茄型烧瓶中,加入无水二氯甲烷5mL。冷却至0℃,加入三乙胺(140.5mg,1.4mmol),再缓慢加入T3P(50%乙酸乙酯,504.9mg,0.8mmol),室温搅拌过夜。反应结束后,用二氯甲烷稀释,用水和碳酸氢钠溶液洗涤,有机层无水硫酸钠干燥,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物35.7mg(7,21-25-41),产率40.9%。1H NMR(400MHz,CDCl3):δ10.86(s,1H),8.45(d,J=8.2Hz,1H),8.37(dt,J=12.8,6.4Hz,3H),8.11–8.03(m,2H),7.88(d,J=24.2Hz,2H),7.48(t,J=7.8Hz,1H),5.81–5.67(m,1H),1.59(d,J=6.8Hz,6H).
终产物8:7-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(8,21-26-41)
将7-溴喹啉-2-羧酸(50mg,0.2mmol)、中间体01(12-4-41,40.3mg,0.2mmol)加入到50mL茄型烧瓶中,加入无水二氯甲烷5mL。冷却至0℃,加入三乙胺(140.5mg,1.4mmol),再缓慢加入T3P(50%乙酸乙酯,504.9mg,0.8mmol),室温搅拌过夜。反应结束后,用二氯甲烷稀释,用水和碳酸氢钠溶液洗涤,有机层无水硫酸钠干燥,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物48.3mg(8,21-26-41),产率55.2%。1H NMR(400MHz,CDCl3):δ10.51(s,1H),8.46(d,J=8.2Hz,1H),8.37(d,J=8.4Hz,2H),8.32(d,J=8.6Hz,1H),8.29(s,1H),8.00(d,J=7.6Hz,1H),7.89(t,J=8.0Hz,1H),7.76(d,J=8.7Hz,1H),7.70(dd,J=8.7,1.7Hz,1H),5.62–5.47(m,1H),1.60(d,J=6.7Hz,6H)。
终产物9:6-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(9,21-18-41)
将6-溴喹啉-2-羧酸(50mg,0.2mmol)、中间体01(12-4-41,40.3mg,0.2mmol)加入到50mL茄型烧瓶中,加入无水二氯甲烷5mL。冷却至0℃,加入三乙胺(140.5mg,1.4mmol),再缓慢加入T3P(50%乙酸乙酯,504.9mg,0.8mmol),室温搅拌过夜。反应结束后,用二氯甲烷稀释,用水和碳酸氢钠溶液洗涤,有机层无水硫酸钠干燥,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物48.5mg(9,21-18-41),产率55.5%。1H NMR(400MHz,CDCl3):δ10.55(s,1H),8.46(d,J=8.2Hz,1H),8.37(d,J=8.5Hz,1H),8.26(d,J=8.5Hz,1H),8.05(d,J=1.5Hz,1H),7.98(dd,J=8.0,5.7Hz,2H),7.89(d,J=15.9Hz,1H),7.85–7.81(m,1H),5.54(dt,J=13.4,6.7Hz,1H),1.59(d,J=6.7Hz,6H)。
终产物10:5-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(10,21-19-41)
将5-溴喹啉-2-羧酸(50mg,0.2mmol)、中间体01(12-4-41,40.3mg,0.2mmol)加入到50mL茄型烧瓶中,加入无水二氯甲烷5mL。冷却至0℃,加入三乙胺(140.5mg,1.4mmol),再缓慢加入T3P(50%乙酸乙酯,504.9mg,0.8mmol),室温搅拌过夜。反应结束后,用二氯甲烷稀释,用水和碳酸氢钠溶液洗涤,有机层无水硫酸钠干燥,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物56.2mg(10,21-19-41),产率64.3%。1H NMR(400MHz,CDCl3):δ10.57(s,1H),8.73(d,J=8.7Hz,1H),8.45(d,J=3.0Hz,1H),8.35(s,1H),8.08(d,J=8.5Hz,1H),7.98(s,1H),7.91–7.87(m,1H),7.63(t,J=8.0Hz,1H),5.61–5.42(m,1H),1.59(d,J=6.7Hz,6H)。
终产物11:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)-8-(1-甲基-1,2,3,6-四氢吡啶-4-基)喹啉-2-甲酰胺(11,21-59-36)
将8-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(07,21-25-41,40mg,0.09mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(22.5mg,0.1mmol)、碳酸钠(48.5mg,0.45mmol)、四三苯基膦钯(10.6mg,0.009mmol)加入到50mL茄型烧瓶中,加入1,2-二甲氧基乙烷和水各2mL,80℃反应2h。旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物42mg(11,21-59-36),产率100%。1H NMR(400MHz,CDCl3):δ10.38(s,1H),8.42(d,J=8.2Hz,1H),8.33(d,J=6.1Hz,3H),7.90(t,J=7.9Hz,1H),7.80(dd,J=11.6,7.8Hz,2H),7.64(d,J=6.5Hz,1H),7.56(t,J=7.6Hz,1H),5.92(s,1H),5.34–5.24(m,1H),3.30(s,2H),2.92–2.86(m,4H),2.45(s,3H),1.50(d,J=6.7Hz,6H).
终产物12:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)-7-(1-甲基-1,2,3,6-四氢吡啶-4-基)喹啉-2-甲酰胺(12,21-36-36)
将7-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(08,21-26-41,30mg,0.07mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(16.8mg,0.075mmol)、碳酸钠(72.7mg,0.69mmol)、四三苯基膦钯(7.9mg,0.0073mmol)加入到50mL茄型烧瓶中,加入1,2-二甲氧基乙烷和水各2mL,80℃反应2h。旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物40.1mg(12,21-36-36),产率100%。1HNMR(400MHz,CDCl3):δ10.61(s,1H),8.45(dd,J=8.2,0.9Hz,1H),8.34(s,1H),8.29(s,2H),8.01(d,J=1.4Hz,1H),7.95(d,J=7.0Hz,1H),7.88(t,J=7.9Hz,1H),7.80(d,J=8.6Hz,1H),7.72(dd,J=8.6,1.8Hz,1H),6.29(t,J=3.5Hz,1H),5.59–5.47(m,1H),3.25(d,J=2.6Hz,2H),2.79(s,2H),2.76(d,J=2.2Hz,2H),2.46(s,3H),1.58(d,J=6.7Hz,6H)。
终产物13:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)喹啉-2-甲酰胺(13,21-45-36)
将6-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(09,21-18-41,40mg,0.09mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(22.5mg,0.1mmol)、碳酸钠(48.5mg,0.45mmol)、四三苯基膦钯(10.6mg,0.009mmol)加入到50mL茄型烧瓶中,加入1,2-二甲氧基乙烷和水各2mL,80℃反应2h。旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物33.6mg(13,21-45-36),产率82.3%。1H NMR(400MHz,CDCl3):δ10.62(s,1H),8.45(d,J=7.5Hz,1H),8.33(s,1H),8.30(d,J=4.7Hz,1H),8.01(d,J=8.9Hz,1H),7.96(d,J=6.9Hz,1H),7.89–7.85(m,2H),7.76(d,J=1.8Hz,1H),6.29(t,J=3.5Hz,1H),5.62–5.50(m,1H),3.17(d,J=3.0Hz,2H),2.71(d,J=3.8Hz,4H),2.40(s,3H),1.58(d,J=6.7Hz,6H)。
终产物14:N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)-5-(1-甲基-1,2,3,6-四氢吡啶-4-基)喹啉-2-甲酰胺(14,21-46-36)
将5-溴-N-(6-(4-异丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(10,21-19-41,40mg,0.09mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(22.5mg,0.1mmol)、碳酸钠(48.5mg,0.45mmol)、四三苯基膦钯(10.6mg,0.009mmol)加入到50mL茄型烧瓶中,加入1,2-二甲氧基乙烷和水各2mL,80℃反应2h。旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物20.6mg(14,21-46-36),产率50.5%。1H NMR(400MHz,CDCl3):δ10.65(s,1H),8.58(d,J=8.8Hz,1H),8.47–8.43(m,1H),8.33(s,1H),8.30(d,J=8.7Hz,1H),7.98(d,J=3.1Hz,1H),7.88(t,J=7.9Hz,1H),7.70(dd,J=8.5,7.1Hz,1H),7.43(dd,J=7.1,1.0Hz,1H),5.76–5.72(m,1H),5.62–5.49(m,1H),3.21(d,J=2.8Hz,2H),2.77(t,J=5.6Hz,2H),2.57(d,J=1.8Hz,2H),2.46(s,3H),1.59(d,J=6.7Hz,6H)。
终产物15:N-(6-(4-环丙基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(15,24-57-31)
步骤一:将6-氨基吡啶甲酸甲酯(250mg,1.6mmol)加入到100mL茄型烧瓶中,加入水合肼(3mL),氩气保护,120℃回流搅拌1h。反应结束后,旋转蒸发仪浓缩,固体干燥。得到白色固体粗品,250.8mg,产率100%。得到的粗品加入到100mL茄型烧瓶中,用甲苯溶解,加入1,1-二甲氧基-N,N-二甲基甲胺(573.7mg,4.8mmol)和环丙胺(635.4mg,11.2mmol),冷却至0℃,加入冰醋酸(289.2mg,4.8mmol),氩气保护,95℃回流20h。旋转蒸发仪浓缩旋干,旋干后加适量水,再次用旋转蒸发仪浓缩,浓缩之后的残渣用10倍量的水溶解,85℃搅拌过夜。反应结束后,用***萃取两次,留下水层,水层用二氯甲烷萃取三次,二氯甲烷层用无水硫酸钠干燥,旋转蒸发仪浓缩,硅胶柱纯化。目标化合物163mg(22-55-33),白色固体,产率50.7%。1H NMR(400MHz,CDCl3):δ8.14(s,1H),7.53(t,J=8.0Hz,1H),7.46(d,J=7.2Hz,1H),6.58(d,J=8.0Hz,1H),3.86(m,1H),1.05(q,J=6.8Hz,2H),0.89–0.82(m,2H);13C NMR(101MHz,DMSO-d6):δ163.43,158.62,147.84,143.63,138.10,111.22,109.80,25.86,6.05;ESI-HRMS(m/z)[M+H]+,C10H11N5,计算值:202.1014,实测值:202.1093。
步骤二:将喹啉-2-羧酸(30mg,0.17mmol)、(6-(4-环丙基-4H-1,2,4-***-3-基)吡啶-2-胺(35mg,0.17mmol)加入到50mL茄型烧瓶中,加入无水吡啶3mL。氩气保护,再缓慢加入三氯氧磷(106.1mg,0.7mmol),室温搅拌2h。反应结束后,用水淬灭,乙酸乙酯萃取三次。乙酸乙酯层用无水硫酸钠干燥。有机溶剂旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物47mg(15,24-57-31),白色偏粉固体,产率76.3%。1H NMR(400MHz,CDCl3):δ10.75(s,1H),8.55(dd,J=8.0,0.8Hz,1H),8.41(s,2H),8.31(s,1H),8.17(d,J=8.4Hz,1H),7.99(dd,J=7.6,0.8Hz,1H),7.95(t,J=8.0Hz,2H),7.82(m,1H),7.68(m,1H),4.02–3.92(m,1H),1.24(m,2H),1.01(m,2H);ESI-HRMS(m/z)[M+Na]+,C20H16N6O,计算值:379.1386,实测值:3791286。
终产物16:N-(6-(1-环丁基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(16,24-61-34)
步骤一:将6-氨基吡啶甲酸甲酯(250mg,1.6mmol)加入到100mL茄型烧瓶中,加入水合肼(3mL),氩气保护,120℃回流搅拌1h。反应结束后,旋转蒸发仪浓缩,固体干燥。得到白色固体粗品,250.8mg,产率100%。得到的粗品加入到100mL茄型烧瓶中,用甲苯溶解,加入1,1-二甲氧基-N,N-二甲基甲胺(573.7mg,4.8mmol)和环丁胺(800mg,11.2mmol),冷却至0℃,加入冰醋酸(289.2mg,4.8mmol),氩气保护,95℃回流20h。旋转蒸发仪浓缩旋干,旋干后加适量水,再次用旋转蒸发仪浓缩,浓缩之后的残渣用10倍量的水溶解,85℃搅拌过夜。反应结束后,用***萃取两次,留下水层,水层用二氯甲烷萃取三次,二氯甲烷层用无水硫酸钠干燥,旋转蒸发仪浓缩,硅胶柱纯化。目标化合物224mg(21-149-37),黄色固体,产率65.1%。1H NMR(400MHz,CDCl3):δ8.36(s,1H),7.57–7.52(m,1H),7.49(dd,J=7.6,0.8Hz,1H),6.58(dd,J=7.6,0.8Hz,1H),5.53–5.41(m,1H),2.60–2.51(m,2H),2.32–2.28(m,2H),1.88–1.78(m,2H);13C NMR(101MHz,DMSO-d6):δ159.18,151.04,145.34,143.62,138.06,111.19,108.53,49.64,30.79,14.34;ESI-HRMS(m/z)[M+Na]+calcd for C11H13N5,238.1171,found 238.1061.
步骤二:将喹啉-2-羧酸(30mg,0.17mmol)、6-(4-环丁基-4H-1,2,4-***-3-基)吡啶-2-胺(37mg,0.17mmol)加入到50mL茄型烧瓶中,加入无水吡啶3mL。氩气保护,再缓慢加入三氯氧磷(106.1mg,0.7mmol),室温搅拌2h。反应结束后,用水淬灭,乙酸乙酯萃取三次。乙酸乙酯层用无水硫酸钠干燥。有机溶剂旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物47mg(16,24-61-34),白色固体,产率74.9%。1H NMR(400MHz,CDCl3):δ10.40(s,1H),9.80(s,1H),8.51(d,J=8.0Hz,2H),8.28–8.23(m,1H),8.21–8.16(m,1H),8.04(d,J=7.2Hz,1H),7.99–7.89(m,3H),5.53(m,1H),2.76–2.64(m,2H),2.48–2.37(m,2H),2.05–1.98(m,2H);ESI-HRMS(m/z)[M+H]+calcd for C21H18N6O,371.1542,found371.1628.
终产物17:N-(6-(1-环戊基-4H-1,2,4-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(17,24-58-31)
步骤一:将5-氨基烟酸甲酯(550mg,3.6mmol)加入到100mL茄型烧瓶中,加入无水甲醇15mL。再加入水合肼(326.5mg,6.5mmol),氩气保护,65℃回流搅拌过夜。反应结束后,旋转蒸发仪浓缩,固体干燥。得到白色固体粗品,550.8mg,产率100%。得到的粗品加入到100mL茄型烧瓶中,用甲苯溶解,加入1,1-二甲氧基-N,N-二甲基甲胺(1629.8mg,8.9mmol)和环戊胺(1627mg,19.1mmol),冷却至0℃,加入冰醋酸(491.4mg,8.9mmol),氩气保护,95℃回流20h。旋转蒸发仪浓缩旋干,旋干后加适量水,再次用旋转蒸发仪浓缩,浓缩之后的残渣用10倍量的水溶解,85℃搅拌过夜。反应结束后,用***萃取两次,留下水层,水层用二氯甲烷萃取三次,二氯甲烷层用无水硫酸钠干燥,旋转蒸发仪浓缩,硅胶柱纯化。目标化合物110mg(23-143-36),白色固体,产率17.6%。1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.59–7.50(m,2H),6.58(dd,J=8.0,1.2Hz,1H),5.63–5.50(m,1H),2.30–2.18(m,2H),1.92–1.69(m,6H);13C NMR(101MHz,CDCl3):δ157.70,152.11,145.85,142.26,138.86,114.79,109.37,57.62,33.98,24.03.ESI-HRMS(m/z)[M+H]+calcd for C12H15N5,230.1327,found230.1408.
步骤二:将喹啉-2-羧酸(22.7mg,0.13mmol)、6-(4-环戊基-4H-1,2,4-***-3-基)吡啶-2-胺(30mg,0.13mmol)加入到50mL茄型烧瓶中,加入无水吡啶3mL。氩气保护,再缓慢加入三氯氧磷(80.4mg,0.5mmol),室温搅拌2h。反应结束后,用水淬灭,乙酸乙酯萃取三次。乙酸乙酯层用无水硫酸钠干燥。有机溶剂旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物48mg(17,24-58-31),白色固体,产率96.4%。1H NMR(400MHz,CDCl3)δ10.75(s,1H),8.52(dd,J=8.4,0.8Hz,1H),8.43(s,1H),8.41(s,1H),8.13(d,J=8.4Hz,1H),8.04(dd,J=7.6,0.8Hz,1H),7.99–7.92(m,2H),7.84(m,1H),7.69(m,1H),5.71–5.58(m,1H),2.41(m,2H),2.02–1.88(m,6H);ESI-HRMS(m/z)[M+Na]+calcd for C22H20N6O,407.1699,found407.1606.
终产物18:(S)-8-溴-N-(6-(4-(1-羟基丙-2-基)-4H-1.24-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(18,21-159-42)
步骤一:将6-氨基吡啶酰肼(500mg,3.3mmol)加入到100mL茄型烧瓶中,用乙腈溶解,冷却到15℃加入1,1-二甲氧基-N,N-二甲基甲胺(1.57g,13.2mmol),氩气保护,90℃搅拌反应4h。反应结束后,冷却到室温,加入(R)-2-氨基丙醇(1.24g,16.4mmol),再次冷却到15℃,加入冰醋酸(394.7mg,6.6mmol),氩气保护,90℃搅拌反应过夜。反应结束后,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物575.1mg(21-130-39),产率79.5%。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.51(t,J=8.0Hz,1H),7.17(d,J=7.2Hz,1H),6.51(d,J=8.0Hz,1H),6.17(s,2H),5.47–5.35(m,1H),3.65–3.59(m,2H),1.42(d,J=6.8Hz,3H);13CNMR(101MHz,DMSO-d6):δ159.17,151.33,145.84,143.32,138.17,111.68,108.56,64.37,45.29,17.71;ESI-HRMS(m/z)[M+H]+calcd for C10H13N5O,220.1120,found 220.1195.
步骤二:将8-溴喹啉-2-羧酸(62.1mg,0.25mmol)加入到50mL茄型烧瓶中,加入无水甲苯4mL。缓慢滴加二氯亚砜(39.1mg,0.33mmol),80℃回流2h。反应结束后,旋转蒸发仪浓缩干燥。残渣溶于无水甲苯,加入(S)-2-(3-(6-氨基吡啶-2-基)-4H-1,2,4-***-4-基)丙-1-醇(30mg,0.14mmol)、DIPEA(35.4mg,0.27mmol)80℃回流2h。反应结束后,旋转蒸发仪浓缩,残渣用二氯甲烷稀释,饱和碳酸氢钠水溶液洗涤,有机层用无水硫酸钠干燥,旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物12mg(18,21-159-42),白色偏黄固体,产率19.0%。1HNMR(400MHz,CD3OD):δ9.63(s,1H),8.65(t,J=8.4Hz,2H),8.44(d,J=8.4Hz,1H),8.26(dd,J=7.6,1.2Hz,1H),8.20–8.13(m,1H),8.09(dd,J=8.4,1.2Hz,1H),8.00(d,J=7.2Hz,1H),7.67–7.63(m,1H),5.88–5.77(m,1H),4.09(dd,J=12.0,3.6Hz,1H),3.96(dd,J=12.0,5.6Hz,1H),1.74(d,J=7.2Hz,3H);ESI-HRMS(m/z)[M+H]+calcd for C20H17BrN6O2,453.0596,found453.0659.
终产物19:(R)-8-溴-N-(6-(4-(1-羟基丙-2-基)-4H-1.24-***-3-基)吡啶-2-基)喹啉-2-甲酰胺(19,21-155-36)
步骤一:将6-氨基吡啶酰肼(100mg,0.66mmol)加入到100mL茄型烧瓶中,用乙腈溶解,冷却到15℃加入1,1-二甲氧基-N,N-二甲基甲胺(313.2mg,2.6mmol),氩气保护,90℃搅拌反应4h。反应结束后,冷却到室温,加入(S)-2-氨基丙醇(247.9mg,3.3mmol),再次冷却到15℃,加入冰醋酸(78.9mg,1.3mmol),氩气保护,90℃搅拌反应过夜。反应结束后,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物38mg(20-141-42),产率26.4%。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.55–7.48(m,1H),7.17(d,J=7.2Hz,1H),6.51(dd,J=8.4,0.8Hz,1H),6.16(d,J=5.2Hz,1H),5.46–5.36(m,1H),3.70–3.54(m,2H),1.42(d,J=6.8Hz,3H);13C NMR(101MHz,DMSO-d6):δ159.12,151.31,145.89,143.29,138.12,111.63,108.48,64.39,53.28,17.71;ESI-HRMS(m/z)[M+H]+calcd for C10H13N5O,220.1120,found220.1183.
步骤二:将8-溴喹啉-2-羧酸(30mg,0.12mmol)、(R)-2-(3-(6-氨基吡啶-2-基)-4H-1,2,4-***-4-基)丙-1-醇(26.1mg,0.12mmol)加入到50mL茄型烧瓶中,加入无水吡啶3mL。氩气保护,再缓慢加入三氯氧磷(73.0mg,0.5mmol),室温搅拌2h。反应结束后,用水淬灭,乙酸乙酯萃取三次。乙酸乙酯层用无水硫酸钠干燥。有机溶剂旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物6.2mg(19,21-155-36),白色固体,产率11.4%。1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),9.11(s,1H),8.58(d,J=8.8Hz,1H),8.25(dd,J=7.6,1.2Hz,1H),8.11(dd,J=8.0,1.2Hz,1H),8.02(dd,J=8.0,1.2Hz,1H),7.96(d,J=8.4Hz,1H),7.82–7.73(m,2H),7.67–7.61(m,1H),6.24–6.15(m,1H),4.68(m,2H),1.68(d,J=7.2Hz,3H).
终产物20:N-(6-(1-异丙基-1H-吡唑-5-基)吡啶-2-基)喹啉-2-甲酰胺(20,21-127-36)
步骤一:将6-溴吡啶-2-胺(100mg,0.58mmol)加入到100mL茄型烧瓶中,加入1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)-1H-吡唑(273mg,1.16mmol),Xphos-Pd-G2(45.4mg,0.058mmol)和碳酸钠(612.68mg,5.78mmol),最后溶于1,4-二氧六环和水中(5:1),100℃搅拌反应2h。反应结束后,加水稀释,二氯甲烷萃取水层三次,收集二氯甲烷层,用无水硫酸钠干燥,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物60mg(14-163-41),产率51.3%。1H NMR(400MHz,CDCl3):δ7.53(d,J=1.6Hz,1H),7.50(dd,J=8.4,7.6Hz,1H),6.87(dd,J=7.2,0.8Hz,1H),6.48(dd,J=8.4,0.8Hz,1H),6.43(d,J=2.0Hz,1H),5.32(m,1H),4.59(s,2H),1.50(d,J=6.4Hz,6H);13C NMR(101MHz,CDCl3):δ157.99,148.66,141.03,138.48,138.18,113.91,107.56,106.26,50.79,22.89;ESI-HRMS(m/z)[M+H]+calcd forC11H14N4,203.1218,found 203.1297.
步骤二:将喹啉-2-羧酸(25.7mg,0.15mmol)、6-(1-异丙基-1H-吡唑-5-基)吡啶-2-胺(30mg,0.15mmol)加入到50mL茄型烧瓶中,加入无水吡啶3mL。氩气保护,再缓慢加入三氯氧磷(91.03mg,0.59mmol),室温搅拌2h。反应结束后,用2M盐酸溶液酸化至析出固体,析出的固体用布氏漏斗过滤,清水洗涤,最后干燥。目标化合物54mg(20,21-127-36),白色偏黄固体,产率75.6%。1H NMR(400MHz,CDCl3):δ10.80(s,1H),8.46(dd,J=8.4,0.8Hz,1H),8.41(s,2H),8.19(d,J=8.8Hz,1H),7.93(dd,J=8.4,0.8Hz,1H),7.90–7.81(m,2H),7.72–7.65(m,1H),7.60(d,J=2.0Hz,1H),7.34(dd,J=7.6,0.8Hz,1H),6.54(d,J=2.0Hz,1H),5.36(m,1H),1.61(d,J=6.8Hz,6H);ESI-HRMS(m/z)[M+H]+calcd for C21H19N5O,358.1590,found 358.1699.
终产物21:(R)-N-(6-(1-(1-羟基丙-2-基)-1H-吡唑-5-基)吡啶-2-基)喹啉-2-甲酰胺(21,21-174-39)
步骤一:将6-氨基吡啶酰肼(100mg,0.66mmol)加入到100mL茄型烧瓶中,用乙腈溶解,冷却到15℃加入1,1-二甲氧基-N,N-二甲基甲胺(313.2mg,2.6mmol),氩气保护,90℃搅拌反应4h。反应结束后,冷却到室温,加入(S)-2-氨基丙醇(247.9mg,3.3mmol),再次冷却到15℃,加入冰醋酸(78.9mg,1.3mmol),氩气保护,90℃搅拌反应过夜。反应结束后,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物38mg(20-141-42),产率26.4%。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.55–7.48(m,1H),7.17(d,J=7.2Hz,1H),6.51(dd,J=8.4,0.8Hz,1H),6.16(d,J=5.2Hz,1H),5.46–5.36(m,1H),3.70–3.54(m,2H),1.42(d,J=6.8Hz,3H);13C NMR(101MHz,DMSO-d6):δ159.12,151.31,145.89,143.29,138.12,111.63,108.48,64.39,53.28,17.71;ESI-HRMS(m/z)[M+H]+calcd for C10H13N5O,220.1120,found220.1183.
步骤二:将喹啉-2-羧酸(30mg,0.17mmol),溶于5mL的二氯甲烷中,加入碳二亚胺盐酸盐(33.2mg,0.17mmol)和N-羟基琥珀酰亚胺(33.2mg,0.17mmol)。氩气环境下,加入(R)-2-(3-(6-氨基吡啶-2-基)-4H-1,2,4-***-4-基)丙-1-醇(38.0mg,0.17mmol),升高温度至40℃回流过夜。反应结束后,加入20mL饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,旋蒸浓缩,柱层析纯化,得白色固体目标化合物19.9mg(21,21-174-39),产率31.3%。1H NMR(400MHz,DMSO-d6):δ8.94(s,1H),8.47(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),8.04(d,J=7.6Hz,1H),7.87–7.80(m,2H),7.75–7.68(m,1H),7.40–7.34(m,1H),7.10(d,J=6.8Hz,1H),6.42(d,J=7.6Hz,1H),6.06–5.96(m,1H),4.66(m,2H),1.60(d,J=7.2Hz,3H);ESI-HRMS(m/z)[M+H]+calcd for C20H18N6O2,375.1491,found 375.1565.
终产物22:(S)-N-(6-(1-(1-羟基丙-2-基)-1H-吡唑-5-基)吡啶-2-基)喹啉-2-甲酰胺(22,22-92-40)
步骤一:将6-氨基吡啶酰肼(500mg,3.3mmol)加入到100mL茄型烧瓶中,用乙腈溶解,冷却到15℃加入1,1-二甲氧基-N,N-二甲基甲胺(1.57g,13.2mmol),氩气保护,90℃搅拌反应4h。反应结束后,冷却到室温,加入(R)-2-氨基丙醇(1.24g,16.4mmol),再次冷却到15℃,加入冰醋酸(394.7mg,6.6mmol),氩气保护,90℃搅拌反应过夜。反应结束后,旋转蒸发仪浓缩,正相硅胶柱纯化。目标化合物575.1mg(21-130-39),产率79.5%。1H NMR(400MHz,DMSO-d6):δ8.68(s,1H),7.51(t,J=8.0Hz,1H),7.17(d,J=7.2Hz,1H),6.51(d,J=8.0Hz,1H),6.17(s,2H),5.47–5.35(m,1H),3.65–3.59(m,2H),1.42(d,J=6.8Hz,3H);13CNMR(101MHz,DMSO-d6):δ159.17,151.33,145.84,143.32,138.17,111.68,108.56,64.37,45.29,17.71;ESI-HRMS(m/z)[M+H]+calcd for C10H13N5O,220.1120,found 220.1195.
步骤二:将喹啉-2-羧酸(70.9mg,0.41mmol)加入到50mL茄型烧瓶中,加入无水甲苯4mL。缓慢滴加二氯亚砜(65mg,0.55mmol),80℃回流2h。反应结束后,旋转蒸发仪浓缩干燥。残渣溶于无水甲苯,加入(S)-2-(3-(6-氨基吡啶-2-基)-4H-1,2,4-***-4-基)丙-1-醇(50mg,0.23mmol)、DIPEA(59mg,0.46mmol)80℃回流2h。反应结束后,旋转蒸发仪浓缩,残渣用二氯甲烷稀释,饱和碳酸氢钠水溶液洗涤,有机层用无水硫酸钠干燥,旋转蒸发仪浓缩,硅胶柱层析纯化。目标化合物23mg(22,22-92-40),白色偏黄固体,产率26.7%。1H NMR(400MHz,DMSO-d6):δ10.78(s,1H),8.80(s,1H),8.64(d,J=8.4Hz,1H),8.31(d,J=8.4Hz,1H),8.25(d,J=8.8Hz,1H),8.18(d,J=8.4Hz,1H),8.10(d,J=8.0Hz,1H),8.06(t,J=8.0Hz,1H),7.88(m,2H),7.74(t,J=8.0Hz,1H),5.39(m,1H),3.74–3.65(m,2H),1.50(d,J=7.2Hz,3H);ESI-HRMS(m/z)[M+H]+calcd for C20H18N6O2,375.1491,found 375.1553.
选用相应的原料,可以合成下述各个化合物:
表1
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实验实施例2:ASK1的ADP Glo激酶测定筛选方法:ADP-GLO发光法激酶检方式,它检测激酶反应中所形成的ADP,ADP被转化成ATP,然后ATP再被Ultra-Glo荧光素酶转化成光。
仪器:多功能酶标仪(2104Multilabel Reader,PerkinElmer,USA);生化培养箱,购自Biochemical incubator公司;超声波纳升液体处理***购自Echo公司。
材料:ADP-GloTM试剂盒(Promega USA);ASK1激酶,购自Eurofins公司。原理:在激酶反应后,先将剩余的ATP被ADP-Glo试剂完全消耗掉,然后再将ADP转化成ATP,并将ATP的能量传递给荧光素,使得Ultra-GloTM荧光素酶转化成光,发光信号与激酶活性成正相关。ADP-GloTM可以检测任何生成的ADP的酶的活性,不需要抗体参与以及放射性标记。
样品处理:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响ADP-GloTM试剂范围之内。
ASK1和底物用HTRF激酶缓冲溶液(1X Kinase buffer,25mM MgCl2,4mM DTT,20mMHEPES,PH7.5,0.01%Triton x-100)稀释。将40μL化合物从源板转移到新的384孔板作为中间板,通过Echo将50nl化合物转移至测定板。在1x激酶缓冲液中制备ASK1溶液,其浓度为每种试剂最终浓度的2倍,向测定板的每个孔中加入2.5μL激酶溶液,在1x激酶反应缓冲液中制备MBP底物和ATP的底物溶液,浓度为最终浓度的4倍,测定中所需的每种试剂的浓度。向测定板的每个孔中加入2.5μL底物溶液以开始反应,摇动盘子,在37℃下孵育60分钟,加入5μL ADP-Glo试剂,在37℃下孵育180分钟,然后加入10μL激酶检测试剂,在室温下平衡30分钟,将ADP转化为ATP并引进荧光素酶和荧光素来检查ATP。收集Envision上的数据。将RLU值转换百分比抑制值,在XLFit excel加载项5.4.0.8版中拟合数据,以获得IC50值,使用的公式为:Y=底部+(顶部-底部)/(1+(IC50/X)^山坡)。
表2
(表格中,*表示IC50>2001nM;**为501-2000nM;***表示IC50为50-500nM;****表示<50nM,*****表示<20nM)。
Claims (8)
1.一种具有2-吡啶取代甲酰胺结构的小分子化合物,或其对映异构体、外消旋体或其混合物,或其药学上可接受的盐、水合物或者溶剂合物,其特征在于:所述化合物的结构通式如式(I):
,
其中,
R1表示不同取代位置的卤素、氘原子、氰基、羟基、氨基、硝基、氧基、烷基、取代或未取代的含N、O或S原子的5-12元杂芳环、取代或未取代的含N、O或S原子的5-13元饱和杂环,取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的C3-C6环烷基,取代或未取代的C1-C4烷基乙炔基、取代或未取代的C1-C4烷基氨基、取代或未取代的C1-C4烷基羰基氨基、取代或未取代的C1-C4烷氧基羰基氨基、取代或未取代的C1-C4磺酰基、取代或未取代的C1-C4烷基-S-、取代或未取代的C2-C10酰基、取代或未取代的C1-C4烷基羰基、取代或未取代的C1-C4烷基氨基羰基,或其组合;
表示不同N原子位置的喹啉环或含有两个氮原子的6元杂环;
X表示N、CH或C=O;
a,b表示含N杂环上酰胺取代的位置;
R2表示H或甲基;
R3表示取代或未取代的含1-4个N、O或S的杂原子的5-6元杂芳环,所述的取代基团上的一个或多个氢原子被选自下组的基团取代:卤素、氘原子、氰基、羟基、氨基、硝基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C6烷氧基;其中,所述的取代基团中相应的取代基团上的一个或多个氢原子被选自下组的基团取代:羟基、氨基、羧基。
2.一种具有2-吡啶取代甲酰胺结构的小分子化合物,或其对映异构体、外消旋体或其混合物,或其药学上可接受的盐、水合物或者溶剂合物,其特征在于:所述化合物具体选自以下结构式中的一种:
。
3.一种ASK1抑制剂,其特征在于:所述的抑制剂包括权利要求1或2中任一所述的化合物,或其对映异构体、非对映异构体、外消旋体及其混合物,或其药学上可接受的盐、结晶水合物或者溶剂合物。
4. 一种药物组合物,其特征在于:包括:(A) 治疗有效量的如权利要求1或2所述的化合物,及其对映异构体、非对映异构体、外消旋体及其混合物,以及其药学上可接受的盐、结晶水合物及溶剂合物中的一种或多种;和(B) 药学上可接受的载体。
5.一种根据权利要求1或2所述的化合物在制备治疗与ASK1激酶的活性或表达量相关的疾病的药物中的应用。
6.根据权利要求5所述的应用,其特征在于:所述与ASK1激酶的活性或表达量相关的疾病选自肝脏疾病、肺部疾病、心血管疾病、肾脏疾病、代谢性疾病和肿瘤疾病中的一种。
7.一种根据权利要求1或2所述的化合物的合成方法,其特征在于:其合成路线如下:
。
8.根据权利要求7所述的化合物的合成方法,其特征在于:所述合成路线中的I-1通过一步反应制备,步骤一具体为:胺S1与相应的酰氯S2在溶剂中混合,加入碱,在室温、低温条件或升高温度条件下,反应得到终产物I-1;步骤二具体为将I-1溶解于DMF,加NaH,碘甲烷,室温、低温条件或升高温度条件下搅拌反应,制备终产物I-2。
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