CN110734437A - 吡唑并嘧啶化合物和药物组合物及其应用 - Google Patents
吡唑并嘧啶化合物和药物组合物及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,公开了吡唑并嘧啶化合物和药物组合物及其应用,该吡唑并嘧啶化合物具有式(I)所示结构。本发明提供的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药对TRK激酶表现出优异的抑制活性,同时,在动物水平上表现出良好的抗肿瘤活性。
Description
技术领域
本发明涉及生物医药领域,具体涉及一种吡唑并嘧啶化合物、一种含有该吡唑并嘧啶化合物的药物组合物、前述吡唑并嘧啶化合物及药物组合物的应用。
背景技术
NTRK/TRK(Tropomyosin receptor kinase)为祌经营养因子酪氨酸受体,隶属于受体酪氨酸激酶家族。TRK家族主要包括3个成员,NTRK1/TRKA,NTRK2/TRKB和NTRK3/TRKC。完整的TRK激酶包括胞外区、跨膜区和胞内区三个部分。TRK激酶的胞外区与相应的配体结合之后,能够引起激酶构型变化,形成二聚体。TRK激酶的胞内区发生自体磷酸化从而激活自身的激酶活性,进而进一步激活下游的信号转导通路(如MAPK,AKT,PKC等),产生相应的生物学功能;其中NGF(神经生长因子)结合TRKA,BDNF(衍生的神经营养因子)结合TRKB,以及NT3(神经营养因子3)结合TRKC。
TRK激酶在神经的发育过程中发挥重要的生理功能,包括神经元轴突的生长与功能维持、记忆的发生发展以及保护神经元免受伤害等等。同时,大量的研究表明TRK信号转导通路的活化与肿瘤的发生发展密切相关,在神经细胞瘤、前列腺癌、乳腺癌等中都发现了活化的TRK信号蛋白。
近几年来多种TRK融合蛋白的发现,更显示了其促进肿瘤发生的生物学功能。最早的TPM3-TRKA融合蛋白是在结肠癌细胞中发现的,在检测的临床病人中约有1.5%的发生率。后来在不同类型的临床肿瘤病人样本如肺癌,头颈癌、乳腺癌、甲状腺癌、神经胶质瘤等中发现了不同类型的TRK融合蛋白,如CD74-NTRK1,MPRIP-NTRK1,QKI-NTRK2,ETV6-NTRK3,BTB1-NTRK3等。这些不同的NTRK融合蛋白在不需要配体结合的情况下,自身处于高度活化的激酶活性状态,因而能够持续性的磷酸化下游的信号途径,诱导细胞增殖,促进肿瘤的发生、发展。
因此,近几年来,TRK融合蛋白己经成为一个有效的抗癌靶点和研究热点,例如WO2010048314、WO2012116217、WO2011146336、W02010033941、WO2018077246等均公开了具有不同结构类型的TRK激酶抑制剂。
此外,持续给药后出现的靶标突变是肿瘤产生耐药性的重要原因,近期临床上已经出现了TRK突变的病例,如TRKA G595R和G667C的突变(Russo M等.Cancer Discovery,2016,6(1),36-44)、TRKC G623R的突变(Drilon A.等Annals of Oncology 2016,27(5),920-926),而寻找新的TRK激酶抑制剂有望解决TRK突变引起的肿瘤耐药性问题。
另外,含氮芳杂环通常具有较好的成药性,典型的例子是ALK激酶抑制剂克唑替尼(Cui J.等.J.Med.Chem.2011,54,6342–6363)。WO2007147647和WO2007025540也分别公开了吡唑取代的吡唑并吡啶化合物和吡唑取代的咪唑并哒嗪化合物作为ALK激酶抑制剂及其在疾病治疗中的应用。
发明内容
本发明的目的之一是为了提供一种新的具有优异的抗肿瘤活性的吡唑并嘧啶化合物。
现有技术中提供的典型化合物A和典型化合物B虽然对ALK激酶具有良好的抑制活性,但是,以典型化合物A和典型化合物B为代表的结构类似物对TRK激酶的抑制效果却并不佳。本发明的发明人通过大量的科学研究发现,具有本发明式(I)所示结构的吡唑并嘧啶化合物对TRK激酶表现出优异的抑制活性,且其抑制活性明显优于现有技术的典型化合物A和典型化合物B。更为重要的是,本发明的该类含有苯基的吡唑并嘧啶化合物在动物水平上的抗肿瘤活性同样明显优于典型化合物A和典型化合物B,从而表现出较现有技术更为优异的肿瘤治疗效果。
为了实现上述目的,本发明的第一方面提供一种具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,
其中,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、卤素、由1-6个卤素取代的C1-12的烷基;
R6为H、C1-12的烷基或卤素,
R7为选自以下式(1)、式(2)或式(3)的基团,
在上述式(1)、式(2)和式(3)中,R11、R21和R31各自独立地为H、C1-12的烷基、羰基、苄基、由1-6个选自卤素的卤原子取代的C1-12的烷基、C1-12的烷基羟基、取代或未取代的C3-12的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-12的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自卤素、羟基、硝基和巯基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、氰基、C1-12的烷基、由1-6个选自卤素的原子取代的C1-12的烷基中的至少一种。
本发明的第二方面提供一种药物组合物,其包含药学上可接受的载体、赋形剂或稀释剂,以及作为活性成分的本发明第一方面所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药。
本发明的第三方面提供本发明第一方面所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
本发明的第四方面提供本发明第二方面所述的药物组合物在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
本发明的第五方面提供本发明第一方面中所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,或者本发明第二方面中所述的药物组合物在制备用于预防和/或治疗肿瘤的药物中的应用。
本发明提供的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药对TRK激酶表现出优异的抑制活性,同时,在动物水平上表现出良好的抗肿瘤活性。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
如前所述,本发明的第一方面提供一种具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,
其中,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、卤素、由1-6个卤素取代的C1-12的烷基;
R6为H、C1-12的烷基或卤素,
R7为选自以下式(1)、式(2)或式(3)的基团,
在上述式(1)、式(2)和式(3)中,R11、R21和R31各自独立地为H、C1-12的烷基、乙酰基、苄基、由1-6个选自卤素的卤原子取代的C1-12的烷基、C1-12的烷基羟基、取代或未取代的C3-12的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-12的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自卤素、羟基、硝基和巯基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、氰基、C1-12的烷基、由1-6个选自卤素的原子取代的C1-12的烷基中的至少一种。
“C1-12的烷基”表示碳原子总数为1-12的烷基,包括直链或支链烷基,例如可以为碳原子总数为1、2、3、4、5、6、7、8、9、10、11或12的直链烷基或者支链烷基。
“由1-6个选自卤素的卤原子取代的C1-12的烷基”表示碳原子总数为1-12的烷基,包括直链或支链烷基,并且该C1-12的烷基中的1-6个H由选自卤素的卤原子取代,例如该C1-12的烷基中的1、2、3、4、5或6个H由选自氟、氯、溴、碘中的任意一个或者多个卤原子取代。
“C1-12的烷基羟基”表示碳原子总数为1-12的烷基,包括直链或支链烷基,并且该C1-12的烷基中的至少一个H由羟基取代。
“取代或未取代的C3-12的环烷基”表示碳原子总数为3-12的环烷基,形成环的碳原子数可以为3-12中的任意一个,并且形成环的碳原子上可以含有烷基取代基,该烷基取代基中含有的碳原子数包括在前述碳原子总数范围内。C3-12的环烷基例如可以为三元环、四元环、五元环、六元环、七元环、八元环、九元环、十元环、十一元环或十二元环,并且,C3-12的环烷基中的H可以任意地被取代基取代或者未取代,若被取代,其中的取代基各自独立地选自卤素、羟基、硝基和巯基中的至少一种。
“取代或未取代的含有1-4个选自O、N和S的杂原子的C3-12的杂环烷基中的至少一种”表示碳原子总数为3-12的杂环烷基,1-4个选自O、N和S的杂原子与碳原子一起形成环。
优选情况下,在式(I)中,R1、R2、R3、R4和R5各自独立地选自H、氟、氯、溴、由1-6个选自氟、氯和溴的卤素取代的C1-8的烷基;
R6为H、C1-8的烷基或卤素。
更优选情况下,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、氯、由1-6个选自氟和氯的卤素取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素。
优选情况下,在式(I)中,R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-8的烷基、乙酰基、苄基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基、C1-8的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯、溴、羟基和硝基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、氰基、C1-6的烷基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基中的至少一种。
更优选情况下,在式(I)中,R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-6的烷基、乙酰基、苄基、由1-6个选自氟和氯的卤原子取代的C1-6的烷基、C1-6的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯和羟基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-6个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
根据第一种优选的具体实施方式,在式(I)中,R1、R2、R3、R4和R5各自独立地选自H、氟、氯、溴、由1-6个选自氟、氯和溴的卤素取代的C1-8的烷基;
R6为H、C1-8的烷基或卤素;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-8的烷基、乙酰基、苄基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基、C1-8的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯、溴、羟基和硝基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、氰基、C1-6的烷基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基中的至少一种。
根据第二种优选的具体实施方式,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、氯、由1-6个选自氟和氯的卤素取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-6的烷基、乙酰基、苄基、由1-6个选自氟和氯的卤原子取代的C1-6的烷基、C1-6的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯和羟基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、氰基、由1-6个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
根据第三种优选的具体实施方式,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、由1-3个氟原子取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-6的烷基、乙酰基、苄基、由1-3个氟原子取代的C1-6的烷基、C1-6的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-3个O和N原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯和羟基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-3个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
根据第四种优选的具体实施方式,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、由1-3个氟原子取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为以下基团中的至少一种:
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-3个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
根据第五种优选的具体实施方式,在式(I)中,R1、R2、R3、R4和R5各自独立地选自H、氟、由1-3个氟原子取代的C1-6的烷基;
R6为甲基;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为以下基团中的至少一种:
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-3个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
根据第六种优选的具体实施方式,本发明的所述吡唑并嘧啶化合物为权利要求5所示的化合物中的至少一种,或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药。
需要说明的是,在本发明列举的具体化合物中,例如前述权利要求5所示的化合物中,未标示手性中心具体构型的化合物,即表示为外消旋体。
本发明对制备具有式(I)所示结构的吡唑并嘧啶化合物的方法没有特别的限定,例如可以采用如下制备方法获得:
上述制备方法中涉及的是Suzuki偶联反应,对所述偶联反应的反应条件没有特别的限定,本领域技术人员可以根据有机合成领域内的公知常识以及本发明实施例部分提供的具体实例获得适宜的反应条件。
如前所述,本发明的第二方面提供一种药物组合物,其包含药学上可接受的载体、赋形剂或稀释剂,以及作为活性成分的本发明第一方面所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药。
如前所述,本发明的第三方面提供本发明的第一方面中所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
如前所述,本发明的第四方面提供本发明的第二方面中所述的药物组合物在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
如前所述,本发明的第五方面提供本发明的第一方面中所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,或者本发明第二方面所述的药物组合物在制备用于预防和/或治疗肿瘤的药物中的应用。
优选情况下,所述肿瘤为乳腺癌、大肠癌、肺癌、甲状腺癌、皮肤癌、白血病、唾液腺肿瘤、神经内分泌肿瘤、淋巴瘤、脑肿瘤、成神经细胞瘤、卵巢癌、胰腺癌、间皮瘤、食管癌、肺肉瘤、成神经管细胞瘤、成胶质细胞瘤、结肠癌、肝癌、成视网膜细胞瘤、肾癌、膀胱癌、骨肉瘤、胃癌、子宫癌、外阴癌、小肠癌、前列腺癌、胆管癌、输尿管癌、肾上腺皮质癌或头颈部癌症中的至少一种。
以下将通过实例对本发明进行详细描述。以下实例中,在没有特别说明的情况下,使用的各种原料均来自商购。
实施例1:化合物1的制备
步骤1):N-(2,5-二氟苄基)吡唑并[1,5-a]嘧啶-5-胺
在厚壁耐压瓶中加入5-氯吡唑并[1,5-a]嘧啶(19.6mmol),(2,5-二氟苯基)甲胺(19.6mmol),无水正丁醇(15mL)和N,N-二异丙基乙胺(DIPEA 55mmol)。将淡黄色悬浮液密封并在油浴(160℃)中加热过夜。将反应冷却至环境温度,转移至100ml梨形瓶中减压浓缩尽量除去正丁醇和N,N-二异丙基乙胺(DIPEA)得黄色油状粗品,粗品经柱层析纯化(TLC,石油醚:丙酮=5:1)得淡黄色固体。
步骤2):N-(2,5-二氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的合成:
将N-(2,5-二氟苄基)吡唑并[1,5-a]嘧啶-5-胺(13.5mmol),加入到200mL的梨形瓶中,向其中加入乙腈(50mL)。在室温,磁力搅拌条件下,加入N-碘代丁二酰亚胺(NIS,14.85mmol)。室温反应1h,TLC监测(石油醚:丙酮=5:1)。减压尽量出去乙腈后用250mL乙酸乙酯稀释,并转移到分液漏斗中。用1mol/L的NaOH溶液洗3次,饱和食盐水洗两次,用无水硫酸钠干燥,浓缩得红色油状粗品,粗品经柱层析纯化(TLC,石油醚:丙酮=5:1)得淡黄色固体。
步骤3):N-(2,5-二氟苄基)-3-(1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺的合成:
将N-(2,5-二氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺(0.52mmol),1-Boc-吡唑-4-硼酸频哪醇酯(0.78mmol),无水碳酸钾(2.08mmol),四(三苯基膦)钯(0.052mmol)加入到100ml反应管中,氩气置换3次,加入10ml无水DMF,2ml水。100℃,氩气氛围下反应2h,TLC监测(石油醚:丙酮=2:1)。反应完毕后,冷却至50℃,硅藻土过滤,滤液加水并用乙酸乙酯萃取。有机相用饱和食盐水洗两次,用无水硫酸钠干燥,浓缩得黑色油状粗品,粗品经柱层析纯化(TLC,石油醚:丙酮=2:1)得淡黄色固体。1H NMR(400MHz,DMSO-d6)δ12.70(br,1H),8.51(d,J=7.6Hz,1H),8.16–8.05(m,2H),8.00–7.88(m,2H),7.33–7.24(m,2H),7.22–7.12(m,1H),6.36(d,J=7.6Hz,1H),4.69(d,J=6.0Hz,2H).
实施例2:化合物2的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-甲基基吡唑-4-硼酸频那醇酯替换。1H NMR(600MHz,DMSO-d6)δ8.49(d,J=7.2Hz,1H),8.12(t,J=6.0Hz,1H),8.06(s,1H),7.91(s,1H),7.77(s,1H),7.41–7.22(m,2H),7.21–7.09(m,1H),6.33(d,J=7.2Hz,1H),4.65(d,J=6.0Hz,2H),3.85(s,3H).
实施例3:化合物3的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑替换。1H NMR(600MHz,DMSO-d6)δ8.60(d,J=7.2Hz,1H),8.46(s,1H),8.36–8.17(m,3H),7.89(t,J=59.4Hz,1H),7.44–7.28(m,2H),7.26–7.15(m,1H),6.45(d,J=7.2Hz,1H),4.73(d,J=6.0Hz,2H).
实施例4:化合物4的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑替换。1H NMR(400MHz,DMSO-d6)δ8.51(d,J=7.6Hz,1H),8.14(t,J=6.0Hz,1H),8.09(s,1H),7.98(s,1H),7.80(s,1H),7.36–7.24(m,2H),7.21–7.12(m,1H),6.37(d,J=7.6Hz,1H),4.69(d,J=6.0Hz,2H),4.56–4.42(m,1H),1.45(d,J=6.8Hz,6H).
实施例5:化合物5的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-环丙基吡唑-4-硼酸频那醇酯替换。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.2Hz,1H),8.15(t,J=6.0Hz,1H),8.07(s,1H),7.94(s,1H),7.77(s,1H),7.42–7.20(m,2H),7.19–7.11(m,1H),6.34(d,J=7.2Hz,1H),4.65(d,J=6.0Hz,2H),3.68(p,J=8.4Hz,1H),1.05–0.88(m,4H).
实施例6:化合物6的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-乙醇替换。1H NMR(600MHz,DMSO-d6)δ8.55(d,J=7.2Hz,1H),8.24–8.09(m,2H),8.02(s,1H),7.86(s,1H),7.41–7.28(m,2H),7.24–7.11(m,1H),6.40(d,J=7.2Hz,1H),4.97((t,J=5.6Hz,1H),4.72(d,J=6.0Hz,2H),4.21(t,J=5.6Hz,2H),3.81(q,J=5.6Hz,2H).
实施例7:化合物7的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.2Hz,1H),8.14(t,J=6.0Hz,1H),8.12(s,1H),8.10(s,1H)7.95(s,1H),7.36–7.24(m,2H),7.16–7.10(m,1H),6.34(d,J=7.2Hz,1H),5.58(p,J=7.2Hz,1H),5.02–4.81(m,4H),4.66(d,J=6.0Hz,2H)。
实施例8:化合物8的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯替换。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.6Hz,1H),8.13(t,J=5.6Hz,1H),8.09(s,1H),7.99(s,1H),7.82(s,1H),7.35–7.10(m,3H),6.35(d,J=7.6Hz,1H),4.67(d,J=5.6Hz,2H),4.44–4.34(s,1H),4.06–3.93(m,2H),3.55–3.46(m,2H),2.06–1.81(m,4H).
实施例9:化合物9的制备
制备方法同实施例1,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-甲基吡唑-3-硼酸频那醇酯替换。1H NMR(600MHz,DMSO-d6)δ8.52(d,J=7.2Hz,1H),8.15(t,J=6.0Hz,1H),8.09(s,1H),7.63(d,J=2.4Hz,1H),7.37–7.23(m,2H),7.19–7.04(m,1H),6.66(d,J=2.4Hz,1H),6.34(d,J=7.2Hz,1H),4.64(d,J=6.0Hz,2H),3.83(s,3H).
实施例10:化合物10的制备
步骤1):N-(3-氟苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤1的方法,不同之处在于,2,5-二氟苄胺由相同摩尔量的3-氟苄胺替换。
步骤2):N-(3-氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤2的方法。
步骤3):制备方法同实施例1的步骤3,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑替换。1H NMR(400MHz,DMSO-d6)δ8.54(d,J=7.6Hz,1H),8.41(s,1H),8.29–8.18(m,3H),7.85(t,J=59.4Hz,1H),7.45–7.36(m,1H),7.33–7.22(m,2H),7.14–7.05(m,1H),6.40(d,J=7.6Hz,1H),4.68(d,J=6.0Hz,2H).
实施例11:化合物11的制备
制备方法同实例10,不同之处在于,1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑由相同摩尔量的1-甲基吡唑-3-硼酸频那醇酯替换。1H NMR(600MHz,DMSO-d6)δ8.49(d,J=7.2Hz,1H),8.13(t,J=6.0Hz,1H),8.07(s,1H),7.61(d,J=2.4Hz,1H),7.42–7.32(m,1H),7.29–7.19(m,2H),7.10–7.00(m,1H),6.66(d,J=2.4Hz,1H),6.32(d,J=7.2Hz,1H),4.62(d,J=6.0Hz,2H),3.81(s,3H).
实施例12:化合物12的制备
步骤1):N-(4-氟苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤1的方法,不同之处在于,2,5-二氟苄胺由相同摩尔量的4-氟苄胺替换。
步骤2):N-(4-氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑替换。1H NMR(600MHz,DMSO-d6)δ8.51(d,J=7.2Hz,1H),8.40(s,1H),8.23–8.13(m,3H),7.94–7.74(m,1H),7.46(t,J=6.6Hz,2H),7.16(t,J=8.4Hz,2H),6.35(d,J=7.2Hz,1H),4.62(d,J=5.4Hz,2H).
实施例13:化合物13的制备
步骤1):N-(2-氟苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤1的方法,不同之处在于,2,5-二氟苄胺由相同摩尔量的2-氟苄胺替换。
步骤2):N-(2-氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑替换。1H NMR(600MHz,DMSO-d6)δ8.52(d,J=7.2Hz,1H),8.42(s,1H),8.25–8.19(m,3H),7.94–7.74(m,1H),7.48(t,J=7.2Hz,1H),7.32(q,J=7.2Hz,1H),7.21(t,J=9.6Hz,1H),7.17(t,J=7.2Hz,1H),6.37(d,J=7.2Hz,1H),4.68(d,J=5.4Hz,2H).
实施例14:化合物14的制备
步骤1):N-(3-氟-5-(三氟甲基)苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤1的方法,不同之处在于,2,5-二氟苄胺由相同摩尔量的3-氟-5-(三氟甲基)苄胺替换。
步骤2):N-(3-氟-5-(三氟甲基)苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于,1-Boc-吡唑-4-硼酸频哪醇酯由相同摩尔量的1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑替换。1H NMR(600MHz,DMSO-d6)δ8.54(d,J=7.2Hz,1H),8.38(s,1H),8.31(s,1H),8.23–8.19(m,1H),8.17–8.14(m,1H),7.91–7.71(m,1H),7.70–7.68(m,1H),7.65–7.62(m,1H),7.57–7.54(m,1H),6.38(d,J=7.2Hz,1H),4.74(d,J=5.4Hz,2H).
实施例15:化合物15的制备
步骤1):N-(2-氟-3-(三氟甲基)苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实施例1中的步骤1的方法,不同之处在于,2,5-二氟苄胺由相同摩尔量的2-氟-3-(三氟甲基)苄胺替换。
步骤2):N-(2-氟-3-(三氟甲基)苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为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。1H NMR(600MHz,DMSO-d6)δ8.56(d,J=7.2Hz,1H),8.35(s,1H),8.26(s,1H),8.21(d,J=1.8Hz,1H),8.14–8.12(m,1H),7.86(d,J=44.4Hz,1H),7.75(t,J=7.2Hz,1H),7.53(d,J=11.4Hz,1H),7.45(d,J=8.4Hz,1H),6.40(dd,J=7.2,1.8Hz,1H),4.73(d,J=5.4Hz,2H).
实施例16:化合物16的制备
步骤1):N-(3,5-二氟苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为3,5-二氟苄胺。
步骤2):N-(3,5-二氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-环丙基吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.2Hz,1H),8.16(t,J=6.0Hz,1H),8.07(s,1H),7.92(s,1H),7.76(s,1H),7.22–7.08(m,3H),6.34(d,J=7.2Hz,1H),4.65(d,J=6.0Hz,2H),3.69(p,J=6.0Hz,1H),1.10–0.90(m,4H).
实施例17:化合物17的制备
步骤1):N-(2,6-二氟苄基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为2,6-二氟苄胺。
步骤2):N-(2,6-二氟苄基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基基吡唑-4-硼酸频那醇酯。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=7.6Hz,1H),8.10(s,1H),8.08(s,1H),7.97(t,J=5.6Hz,1H),7.90(s,1H),7.54–7.32(m,1H),7.22–7.12(m,2H),6.31(d,J=7.6Hz,1H),4.73(d,J=5.6Hz,2H),3.91(s,3H).
实施例18:化合物18的制备
步骤1):(R)-N-(1-苯乙基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为R(+)-α-甲基苄胺。
步骤2):(R)-N-(1-苯乙基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.59(d,J=7.2Hz,1H),8.23–8.13(m,2H),7.76(s,1H),7.63–7.54(m,2H),7.50–7.41(m,2H),7.38–7.30(m,1H),6.78(s,1H),6.46(d,J=7.2Hz,1H),5.42–5.30(m,1H),3.96(s,3H),1.64(d,J=7.2Hz,3H).
实施例19:化合物19的制备
制备方法同实施例18,不同之处在于将1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑改为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。1H NMR(600MHz,DMSO-d6)δ8.61(d,J=7.6Hz,1H),8.45(s,1H),8.37–8.23(m,3H),7.98(t,J=59.4Hz,1H),7.62–7.54(m,2H),7.50–7.41(m,2H),7.37–7.29(m,1H),6.50(d,J=7.6Hz,1H),5.35–5.23(m,1H),1.64(d,J=7.2Hz,3H).
实施例20:化合物20的制备
步骤1):(R)-N-(1-(3,5-二氟苯基)乙基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为(R)-1-(3,5-二氟苯基)乙胺盐酸盐。
步骤2):(R)-N-(1-(3,5-二氟苯基)乙基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基基吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.55–8.45(m,1H),8.12–8.07(m,1H),8.06–8.02(m,1H),7.84–7.77(m,1H),7.74–7.68(m,1H),7.26–7.14(m,2H),7.10–7.00(m,1H),6.39–6.30(m,1H),5.22–5.13(m,1H),3.86(s,3H),1.56–1.44(s,3H).
实施例21:化合物21的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-乙基基吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.8Hz,1H),8.11(d,J=7.2Hz,1H),8.07(s,1H),7.86(s,1H),7.74(s,1H),7.25–7.16(m,2H),7.11–7.03(m,1H),6.36(d,J=7.8Hz,1H),5.29–5.09(m,1H),4.16(q,J=7.2Hz 2H),1.51(d,J=7.2Hz,3H),1.41(t,J=7.2Hz,3H).
实施例22:化合物22的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-异丙基基吡唑-4-硼酸频那醇酯。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.08–8.00(m,2H),7.86(s,1H),7.71(s,1H),7.22–7.12(m,2H),7.08–7.00(m,1H),6.33(d,J=7.2Hz,1H),5.19(t,J=6.6Hz,1H),4.50(p,J=6.6Hz,1H),1.49(d,J=7.2Hz,3H),1.43(dd,J=6.6,2.4Hz,6H).
实施例23:化合物23的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-环丙基吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.11–8.06(m,1H),8.05–8.02(m,1H),7.88–7.83(m,1H),7.74–7.68(m,1H),7.21–7.12(m,2H),7.09–7.03(m,1H),6.33(d,J=6.6Hz,1H),5.22–5.12(m,1H),3.72–3.66(m,1H),1.49(d,J=5.4Hz,3H),0.98(d,J=7.2Hz,4H).
实施例24:化合物24的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-乙醇。1H NMR(600MHz,DMSO-d6)δ8.50(d,J=7.8Hz,1H),8.09(d,J=7.2Hz,1H),8.07(s,1H),7.91(s,1H),7.75(s,1H),7.25–7.16(m,2H),7.11–7.03(m,1H),6.35(d,J=7.8Hz,1H),5.25–5.15(m,1H),4.96(t,J=5.6Hz,1H),4.17(t,J=5.6,2H),3.78(q,J=5.6,2H),1.51(d,J=7.2Hz,3H).
实施例25:化合物25的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.49(d,J=7.2Hz,1H),8.15–8.02(m,3H),7.92–7.87(m,1H),7.25–7.15(m,2H),7.09–7.01(m,1H),6.34(d,J=6.6Hz,1H),5.65–5.55(s,1H),5.25–5.15(m,1H),5.00–4.85(m,4H),1.49(s,3H).
实施例26:化合物26的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-(四氢呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.09–8.03(m,2H),7.94(s,1H),7.77(s,1H),7.17(d,J=8.4Hz,2H),7.04(t,J=9.6Hz,1H),6.33(d,J=7.8Hz,1H),5.24–5.14(m,1H),5.07–4.99(m,1H),4.06–3.98(m,2H),3.95–3.82(m,2H),2.45–2.34(m,1H),2.32–2.17(m,1H),1.49(d,J=7.2Hz,3H).
实施例27:化合物27的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.09–8.02(m,2H),7.89(s,1H),7.75(s,1H),7.17(d,J=7.8Hz,2H),7.04(d,J=2.4Hz,1H),6.34(d,J=7.2Hz,1H),5.18(d,J=6.6Hz,1H),4.44–4.34(m,1H),4.00(d,J=12.0Hz,2H),3.49(t,J=10.4Hz,2H),1.97(t,J=9.6Hz,4H),1.49(d,J=7.2Hz,3H).
实施例28:化合物28的制备
在茄形瓶中加入(R)-N-(1-(3,5-二氟苯基)乙基)-3-(1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺(100.0mg,0.3mmol),1,2-环氧环戊烷(25.2mg,0.3mmol),无水DMF(10mL)和碳酸铯(195.5mg,0.6mmol)。在油浴(100℃)中加热回流过夜。反应完全后将反应冷却至环境温度,减压浓缩尽量除去DMF得黄色油状粗品,粗品经柱层析纯化(TLC,石油醚:丙酮=2:1,Rf=0.3)得淡黄色固体。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.06(s,1H),8.04(d,J=7.2Hz,1H),7.95–7.85(m,1H),7.84–7.79(m,1H),7.16(d,J=6.6Hz,2H),7.08–7.02(m,1H),6.32(d,J=7.2Hz,1H),5.26–5.19(m,1H),5.16–5.06(m,1H),4.45–4.35(m,1H),4.31–4.29(m,1H),2.25–2.10(m,1H),2.08–1.92(m,1H),1.88–1.76(m,1H),1.57–1.48(m,3H).
实施例29:化合物29的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为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。1H NMR(400MHz,DMSO-d6)δ8.55(d,J=7.6Hz,1H),8.34(s,1H),8.25–8.18(m,2H),8.14(s,1H),7.85(t,J=59.4Hz,1H),7.22–7.13(m,2H),7.10–6.99(m,1H),6.42(d,J=7.6Hz,1H),5.27–5.14(m,1H),1.53(d,J=6.8Hz,3H).
实施例30:化合物30的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑。1H NMR(400MHz,DMSO-d6)δ8.52(d,J=7.6Hz,1H),8.10(d,J=6.8Hz,1H),8.08(s,1H),7.64(d,J=2.4Hz,1H),7.23–7.13(m,2H),7.11–7.01(m,1H),6.58(d,J=2.4Hz,1H),6.37(d,J=7.6Hz,1H),5.26–5.14(m,1H),3.85(s,3H),1.52(d,J=6.8Hz,3H).
实施例31:化合物31的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1-BOC-3-甲基吡唑-5-硼酸。1H NMR(400MHz,DMSO-d6)δ12.18(br,1H),8.50(d,J=7.2Hz,1H),8.20–8.00(m,2H),7.14(d,J=8.4Hz,2H),7.04(t,J=9.0Hz,1H),6.36(d,J=7.2Hz,1H),6.25–6.17(m,1H),5.20–5.05(m,1H),2.21(s,3H),1.49(d,J=6.6Hz,3H).
实施例32:化合物32的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为(1-(叔丁氧基羰基)-1H-吡唑-5-基)硼酸。1H NMR(400MHz,DMSO-d6)δ12.64(br,1H),8.55(d,J=7.6Hz,1H),8.29–8.09(m,2H),7.68–7.44(br,1H),7.25–7.16(m,2H),7.11–7.03(m,1H),6.65–6.52(br,1H),6.41(d,J=7.6Hz,1H),5.39–5.20(m,1H),1.53(d,J=7.2Hz,3H).
实施例33:化合物33的制备
制备方法同实施例20,不同之处在于将1-甲基基吡唑-4-硼酸频那醇酯改为1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.57(d,J=7.2Hz,1H),8.25–8.17(m,1H),8.09–8.02(m,1H),7.09(d,J=9.6Hz,3H),6.44(d,J=7.2Hz,1H),6.09–6.01(m,1H),5.10–5.00(m,1H),3.65(s,3H),2.13(s,3H),1.46(d,J=6.6Hz,3H).
实施例34:化合物34的制备
步骤1):(R)-N-(1-(3-氟苯基)乙基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为(R)-1-(3-氟苯基)乙胺。
步骤2):(R)-N-(1-(3-氟苯基)乙基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3。1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),8.47(d,J=7.2,1.5Hz,1H),8.08(d,J=6.4Hz,1H),8.02(d,J=7.2Hz,1H),7.90(br,2H),7.45–7.23(m,3H),7.08–7.01(m,1H),6.34(d,J=7.2Hz,1H),5.31–5.16(m,1H),1.53(d,J=7.2Hz,3H).
实施例35:化合物35的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为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。1H NMR(400MHz,CDCl3)δ8.16(d,J=7.2Hz,1H),8.10–7.90(m,3H),7.73–7.61(m,1H),7.59–7.24(m,2H),7.14–7.03(m,1H),6.98–6.86(m,1H),6.11(d,J=7.2Hz,1H),5.80–5.69(m,1H),5.25–5.07(m,1H),1.57(d,J=6.8Hz,3H).
实施例36:化合物36的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.50–8.43(m,1H),8.10–8.05(m,1H),8.04–8.00(m,1H),7.82–7.77(m,1H),7.74–7.69(m,1H),7.42–7.35(m,1H),7.33–7.26(m,2H),7.07–6.99(m,1H),6.37–6.29(m,1H),5.25–5.10(m,1H),3.86(s,3H),1.54–1.46(m,3H).
实施例37:化合物37的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-乙基吡唑-4-硼酸频哪醇酯。1H NMR(400MHz,DMSO-d6)δ8.45(d,J=7.2Hz,1H),8.04(d,J=6.4Hz,1H),8.02(s,1H),7.83(s,1H),7.72(s,1H),7.43–7.19(m,3H),7.11–6.93(m,1H),6.33(d,J=7.2Hz,1H),5.24–5.01(m,1H),4.13(q,J=7.2Hz,2H),1.50(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H).
实施例38:化合物38的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=7.6Hz,1H),8.13–8.01(m,2H),7.90(s,1H),7.76(s,1H),7.45–7.35(m,1H),7.34–7.25(m,2H),7.10–7.00(m,1H),6.36(d,J=7.6Hz,1H),5.30–5.15(m,1H),4.58–4.45(m,1H),1.53(d,J=6.8Hz,3H),1.47(d,J=6.8Hz,6H).
实施例39:化合物39的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.45(d,J=7.2Hz,1H),8.07(d,J=6.6Hz,1H),8.03(s,1H),7.86(s,1H),7.71(s,1H),7.45–7.34(m,1H),7.31–7.20(m,2H),7.08–6.99(m,1H),6.33(d,J=7.2Hz,1H),5.30–5.06(m,1H),3.69(p,J=8.4,4.5Hz,1H),1.50(d,J=7.2Hz,3H),1.02–0.96(m,4H).
实施例40:化合物40的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-乙醇。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=7.6Hz,1H),8.11–8.02(m,2H),7.91(s,1H),7.77(s,1H),7.47–7.24(m,3H),7.09–7.00(m,1H),6.35(d,J=7.6Hz,1H),5.28–5.13(m,1H),4.98(t,J=5.6Hz,1H),4.18(t,J=5.6Hz,2H),3.79(q,J=5.6Hz,2H),1.52(d,J=6.8Hz,3H).
实施例41:化合物41的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.52–8.42(m,1H),8.15–8.00(m,3H),7.93–7.85(m,1H),7.45–7.20(m,3H),7.07–6.98(m,1H),6.38–6.28(m,1H),5.65–5.55(m,1H),5.25–5.15(m,1H),5.05–4.80(m,4H),1.50(s,3H).
实施例42:化合物42的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(四氢呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=7.6Hz,1H),8.13–8.04(m,2H),7.98(s,1H),7.82(s,1H),7.45–7.23(m,3H),7.10–7.00(m,1H),6.37(d,J=7.6Hz,1H),5.30–5.16(m,1H),5.12–5.01(m,1H),4.13–3.82(m,4H),2.49–2.38(m,1H),2.35–2.19(m,1H),1.53(d,J=6.8Hz,3H).
实施例43:化合物43的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=7.6Hz,1H),8.11–8.02(m,2H),7.91(s,1H),7.78(s,1H),7.44–7.24(m,3H),7.10–7.00(m,1H),6.36(d,J=7.6Hz,1H),5.28–5.15(m,1H),4.50–4.34(m,1H),4.10–3.98(m,2H),3.61–3.47(m,2H),2.06–1.90(m,4H),1.53(d,J=6.8Hz,3H).
实施例44:化合物44的制备
将(R)-N-(1-(3-氟苯基)乙基)-3-(1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺(实施例34制备,0.31mmol),碳酸铯(1.24mmol),1,2-环氧环戊烷(0.34mmol)放入50ml梨型瓶中,加入10ml DMF,回流反应过夜,冷却到室温后用100ml乙酸乙酯稀释,饱和食盐水洗3次,有机相用无水硫酸钠干燥。滤除无水硫酸钠,减压出去乙酸乙酯得黄色粗品,粗品用丙酮洗2次得黄色固体。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=7.2,1H),8.10(d,J=6.4Hz,1H),8.06(s,1H),7.92(s,1H),7.79(s,1H),7.47–7.21(m,3H),7.11–6.95(m,1H),6.35(d,J=7.2Hz,1H),5.32–5.16(m,1H),5.14–5.04(m,1H),4.39(m,1H),4.31–4.21(m,1H),2.19(m,1H),2.08–1.92(m,2H),1.81(m,2H),1.66–1.55(m,1H),1.50(d,J=7.2Hz,3H).
实施例45:化合物45的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基吡唑-3-硼酸频那醇酯。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=7.6Hz,1H),8.10–8.01(m,2H),7.61(d,J=2.4Hz,1H),7.40–7.31(m,1H),7.30–7.20(m,2H),7.05–7.95(m,1H),6.59(d,J=2.4Hz,1H),6.33(d,J=7.6Hz,1H),5.26–5.14(m,1H),3.82(s,3H),1.50(d,J=6.8Hz,3H).
实施例46:化合物46的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-BOC-3-甲基吡唑-5-硼酸。1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.51(d,J=7.6Hz,1H),8.24–8.06(m,2H),7.44–7.35(m,1H),7.34–7.25(m,2H),7.11–6.99(m,1H),6.39(d,J=7.6Hz,1H),6.31(s,1H),5.31–5.12(m,1H),2.25(s,3H),1.53(d,J=6.8Hz,3H).
实施例47:化合物47的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,3-二甲基-1H-吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.46(d,J=7.6Hz,1H),8.04(d,J=6.0Hz,1H),7.91(s,1H),7.62(s,1H),7.41–7.32(m,1H),7.30–7.20(m,2H),7.04–6.95(m,1H),6.34(d,J=7.6Hz,1H),5.16–5.04(m,1H),3.76(s,3H),2.21(s,3H),1.46(d,J=6.8Hz,3H).
实施例48:化合物48的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,5-二甲基-1H-吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.46(d,J=7.6Hz,1H),7.95(d,J=7.0Hz,1H),7.89(s,1H),7.51(s,1H),7.39–7.30(m,1H),7.25–7.13(m,2H),7.05–6.96(m,1H),6.32(d,J=7.6Hz,1H),5.21–5.07(m,1H),3.72(s,3H),2.26(s,3H),1.46(d,J=6.8Hz,3H).
实施例49:化合物49盐酸盐的制备
步骤1):(R)-4-(4-(5-((1-(3-氟苯基)乙基)氨基)吡唑并[1,5-a]嘧啶-3-基)-1H-吡唑-1-基叔丁酯基)哌啶-1-甲酸叔丁酯的制备:
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯。
步骤2):(R)-N-(1-(3-氟苯基)乙基)-3-(1-(哌啶-4-基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺盐酸盐的制备:
将(R)-4-(4-(5-((1-(3-氟苯基)乙基)氨基)吡唑并[1,5-a]嘧啶-3-基)-1H-吡唑-1-基叔丁酯基)哌啶-1-甲酸叔丁酯放入50ml梨型瓶中,加入5ml盐酸的甲醇溶液,室温反应过夜,旋干得棕色固体粗品,丙酮洗2次的黄色固体。1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.47(d,J=7.6Hz,1H),8.30(s,1H),8.08(s,1H),7.92(s,1H),7.81(s,1H),7.47–7.28(m,3H),7.12–6.99(m,1H),6.42(d,J=7.6Hz,1H),5.29–5.10(m,1H),4.60–4.44(m,1H),3.51–3.32(m,2H),3.20–3.02(m,2H),2.38–2.12(m,4H),1.51(d,J=6.8Hz,3H).
实施例50:化合物50的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-H-吡唑-3-硼酸频哪酯。1H NMR(600MHz,DMSO-d6)δ12.59(br,1H),8.49(d,J=7.6Hz,1H),8.25–8.03(m,2H),7.52(br,1H),7.41–7.16(m,3H),7.06–6.95(m,1H),6.55(br,1H),6.35(d,J=7.6Hz,1H),5.35–5.17(m,1H),1.49(d,J=6.8Hz,3H).
实施例51:化合物51的制备
制备方法同实施例34,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.53(d,J=7.6Hz,1H),8.18(d,J=6.6Hz,1H),8.00(s,1H),7.40–7.30(m,1H),7.25–7.13(m,2H),7.06–6.96(m,1H),6.42(d,J=7.6Hz,1H),6.04(s,1H),5.11–5.01(m,1H),3.61(s,3H),2.11(s,3H),1.45(d,J=6.8Hz,3H).
实施例52:化合物52的制备
步骤1):(R)-N-(1-(2,5-二氟苯基)乙基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为(R)-1-(2,5-二氟苯基)乙胺盐酸盐。
步骤2):(R)-N-(1-(3-氟苯基)乙基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3。1H NMR(600MHz,DMSO-d6)δ12.86(s,1H),8.61(d,J=7.6Hz,1H),8.25–8.17(m,2H),7.98(br,2H),7.44–7.30(m,2H),7.27–7.18(m,1H),6.47(d,J=7.6Hz,1H),5.61–5.51(m,1H),1.64(d,J=6.6Hz,3H).
实施例53:化合物53的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.11(d,J=6.6Hz,1H),8.03(s,1H),7.80(s,1H),7.70(s,1H),7.37–7.27(m,1H),7.24–7.19(m,1H),7.11–7.06(m,1H),6.34(d,J=7.2Hz,1H),5.45–5.32(m,1H),3.84(s,3H),1.51(d,J=7.2Hz,3H).
实施例54:化合物54的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为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。1H NMR(600MHz,DMSO-d6)δ8.66(d,J=7.2Hz,1H),8.42(s,1H),8.37(d,J=6.6Hz,1H),8.32(s,1H),8.24(s,1H),8.05–7.85(m,1H),7.42–7.29(m,2H),7.22(d,J=8.4Hz,1H),6.52(d,J=7.8Hz,1H),5.52(s,1H),1.64(d,J=6.6Hz,3H).
实施例55:化合物55的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.11(d,J=6.6Hz,1H),8.04(s,1H),7.86(s,1H),7.70(s,1H),7.36–7.15(m,2H),7.14–7.06(m,1H),6.34(d,J=7.2Hz,1H),5.52–5.31(m,1H),3.66(p,J=6.0Hz,1H),1.51(d,J=7.2Hz,3H),1.09–0.94(m,4H).
实施例56:化合物56的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.61(d,J=7.6Hz,1H),8.24(d,J=7.2Hz,1H),8.19(s,1H),8.03(s,1H),7.88(s,1H),7.43–7.37(m,1H),7.36–7.30(m,1H),7.26–7.19(m,1H),6.48(d,J=7.6Hz,1H),5.59–5.49(m,1H),4.54–4.45(m,1H),4.21–4.07(m,2H),3.70–3.59(m,2H),2.19–1.98(m,4H),1.64(d,J=7.2Hz,3H).
实施例57:化合物57的制备
将(R)-N-(1-(2,5-二氟苯基)乙基)-3-(1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺(实施例52制备,0.29mmol),碳酸铯(1.17mmol),1,2-环氧环戊烷(0.32mmol)放入50ml梨型瓶中,加入10ml DMF,回流反应过夜,冷却到室温后用100ml乙酸乙酯稀释,饱和食盐水洗3次,有机相用无水硫酸钠干燥。滤除无水硫酸钠,减压出去乙酸乙酯得黄色粗品,粗品用丙酮洗2次得黄色固体。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.11(d,J=6.6Hz,1H),8.05(s,1H),7.89(s,1H),7.75(s,1H),7.36–7.16(m,2H),7.15–7.02(m,1H),6.34(d,J=7.2Hz,1H),5.48–5.37(m,1H),5.13–5.00(m,1H),4.37–4.28(m,1H),4.28–4.16(m,1H),2.24–2.14(m,1H),2.03–1.89(m,2H),1.85–1.73(m,2H),1.66–1.55(m,1H),1.50(d,J=7.2Hz,3H).
实施例58:化合物58的制备
将(R)-N-(1-(2,5-二氟苯基)乙基)-3-(1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺(实施例52制备,0.29mmol)放入50ml梨型瓶中,加入5ml二氯甲烷溶解,磁力搅拌下加入TEA(0.58mmol)乙酰氯(0.35mmol),室温反应过夜,TLC监测(石油醚:丙酮=5:1)。加水淬灭并用乙酸乙酯萃取。有机相用饱和食盐水洗3次,用无水硫酸钠干燥,浓缩得黄色粗品,粗品经柱层析纯化(TLC,石油醚:丙酮=5:1)得淡黄色固体。1H NMR(600MHz,DMSO-d6)δ8.55–8.51(m,2H),8.28–8.23(m,3H),7.34–7.17(m,2H),7.13–7.04(m,1H),6.39(d,J=7.2Hz,1H),5.51–5.33(m,1H),2.65(s,3H),1.52(d,J=7.2Hz,3H).
实施例59:化合物59的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-乙基基吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.61(d,J=7.2Hz,1H),8.24(d,J=6.6Hz,1H),8.17(s,1H),7.97(s,1H),7.84(s,1H),7.46–7.29(m,2H),7.26–7.17(m,1H),6.47(d,J=7.2Hz,1H),5.59–5.46(m,1H),4.26(q,J=7.8Hz,2H),1.64(d,J=7.2Hz,3H),1.53(t,J=7.2Hz,3H).
实施例60:化合物60的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-乙醇。1H NMR(600MHz,DMSO-d6)δ8.47(d,J=7.2Hz,1H),8.10(d,J=6.6Hz,1H),8.04(s,1H),7.86(s,1H),7.73(s,1H),7.35–7.14(m,2H),7.12–7.03(m,1H),6.33(d,J=7.2Hz,1H),5.52–5.32(m,1H),4.92(t,J=6.0Hz,1H),4.12(t,J=6.0Hz,2H),3.75(dt,J=6.0Hz,2H),1.50(d,J=7.2Hz,3H).
实施例61:化合物61的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(2-甲氧基乙基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.61(d,J=7.6Hz,1H),8.24(d,J=6.6Hz,1H),8.19(s,1H),8.00(s,1H),7.89(s,1H),7.45–7.32(m,2H),7.26–7.18(m,1H),6.48(d,J=7.6Hz,1H),5.63–5.44(m,1H),4.38(t,J=5.4Hz,2H),3.84(t,J=5.4Hz,2H),3.51(s,3H),1.64(d,J=6.6Hz,3H).
实施例62:化合物62的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-基)丙烷-2-醇。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.09(d,J=6.6Hz,1H),8.06(s,1H),7.87(s,1H),7.76(s,1H),7.31–7.19(m,2H),7.13–7.04(m,1H),6.34(d,J=7.2Hz,1H),5.47–5.36(m,1H),4.73(s,1H),4.00(s,2H),1.51(d,J=7.2Hz,3H),1.09(s,6H).
实施例63:化合物63的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.10(d,J=6.6Hz,1H),8.05(s,1H),7.87(s,1H),7.72(s,1H),7.31–7.23(m,1H),7.22–7.18(m,1H),7.12–7.08(m,1H),6.34(d,J=7.8Hz,1H),5.50–5.35(m,1H),4.51–4.43(m,1H),1.50(d,J=7.2Hz,3H),1.47–1.38(m,6H).
实施例64:化合物64的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-环丁基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.12(d,J=6.6Hz,1H),8.05(s,1H),7.92(s,1H),7.75(s,1H),7.34–7.17(m,2H),7.15–7.04(m,1H),6.34(d,J=7.2Hz,1H),5.47–5.35(m,1H),4.79(p,J=8.4Hz,1H),2.49–2.38(m,4H),1.89–1.78(m,2H),1.51(d,J=7.2Hz,3H).
实施例65:化合物65的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-(四氢呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.2Hz,1H),8.11(d,J=6.6Hz,1H),8.06(s,1H),7.93(s,1H),7.77(s,1H),7.35–7.17(m,2H),7.12–7.05(m,1H),6.34(d,J=7.2Hz,1H),5.41(s,1H),5.06–4.87(m,1H),4.15–3.95(m,2H),3.94–3.82(m,2H),2.46–2.37(m,1H),2.33–2.21(m,1H),1.51(d,J=7.2Hz,3H).
实施例66:化合物66的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-THP-4-吡唑硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.49(d,J=7.8Hz,1H),8.14(d,J=5.4Hz,1H),8.09(d,J=2.4Hz,1H),8.01(d,J=5.4Hz,1H),7.80(s,1H),7.28–7.23(m,1H),7.21–7.15(m,1H),7.12–7.06(m,1H),6.35(d,J=7.8Hz,1H),5.44–5.33(m,2H),3.98(t,J=10.2Hz,1H),3.70–3.64(m,1H),2.14–1.90(m,3H),1.76–1.67(m,1H),1.63–1.55(m,2H),1.51(d,J=7.2Hz,3H).
实施例67:化合物67的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-苄基-1H-吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.48(d,J=7.8Hz,1H),8.11(d,J=6.6Hz,1H),8.06(s,1H),7.95(s,1H),7.79(s,1H),7.39–7.34(m,2H),7.33–7.29(m,1H),7.26–7.22(m,2H),7.21–7.18(m,1H),7.16–7.11(m,1H),7.06–7.01(m,1H),6.34(d,J=7.8Hz,1H),5.41–5.36(m,1H),5.33(s,2H),1.49(d,J=7.2Hz,3H).
实施例68:化合物68的制备
步骤1):(R)-4-(4-(5-((1-(2,5-二氟苯基)乙基)氨基)吡唑并[1,5-a]嘧啶-3-基)-1H-吡唑-1-基叔丁酯基)哌啶-1-甲酸叔丁酯的制备:
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯。
步骤2):(R)-N-(1-(2,5-二氟苯基)乙基)-3-(1-(哌啶-4-基)-1H-吡唑-4-基)吡唑并[1,5-a]嘧啶-5-胺盐酸盐的制备:
将(R)-4-(4-(5-((2,5-二氟苯基)乙基)氨基)吡唑并[1,5-a]嘧啶-3-基)-1H-吡唑-1-基叔丁酯基)哌啶-1-甲酸叔丁酯放入50ml梨型瓶中,加入5ml盐酸的甲醇溶液,室温反应过夜,旋干得棕色固体粗品,丙酮洗2次的黄色固体。1H NMR(600MHz,DMSO-d6)δ9.31(s,1H),9.02(s,1H),8.48(d,J=7.2Hz,1H),8.28(d,J=6.6Hz,1H),8.08(s,1H),7.90(s,1H),7.81(s,1H),7.42–7.22(m,2H),7.17–7.06(m,1H),6.39(d,J=6.0Hz,1H),5.44–5.37(m,1H),4.50–4.46(m,1H),3.51–3.35(m,2H),3.17–2.97(m,2H),2.27–2.15(m,4H),1.51(d,J=6.9Hz,3H).
实施例69:化合物69的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,3-二甲基-1H-吡唑-4-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.53–8.47(m,1H),8.13–8.07(m,1H),7.96–7.91(m,1H),7.70–7.65(m,1H),7.34–7.28(m,1H),7.23–7.16(m,1H),7.12–7.06(m,1H),6.36(d,J=7.2Hz,1H),5.36–5.29(m,1H),3.77(s,3H),2.23(s,3H),1.49(d,J=6.6Hz,3H).
实施例70:化合物70的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,5-二甲基-1H-吡唑-4-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.63(d,J=7.6Hz,1H),8.14(d,J=7.2Hz,1H),8.06(s,1H),7.63(s,1H),7.41–7.35(m,1H),7.34–7.28(m,1H),7.26–7.20(m,1H),6.49(d,J=7.6Hz,1H),5.55–5.44(m,1H),3.86(s,3H),2.41(s,3H),1.61(d,J=7.2Hz,3H).
实施例71:化合物71的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-H-吡唑-3-硼酸频哪酯。1H NMR(600MHz,DMSO-d6)δ12.59(br,1H),8.52(d,J=7.8Hz,1H),8.23–8.10(m,2H),7.53(br,1H),7.34–7.18(m,2H),7.11–7.06(m,1H),6.57–6.50(m,1H),6.38(d,J=7.2Hz,1H),5.49–5.42(m,1H),1.51(d,J=7.2Hz,3H).
实施例72:化合物72的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-BOC-3-甲基吡唑-5-硼酸。1H NMR(600MHz,DMSO-d6)δ12.20(br,1H),8.51(d,J=7.8Hz,1H),8.23–8.15(m,1H),8.13–8.04(m,1H),7.28–7.23(m,1H),7.23–7.17(m,1H),7.11–7.06(m,1H),6.37(d,J=7.8Hz,1H),6.28(s,1H),5.42–5.34(m,1H),2.21(s,3H),1.51(d,J=7.2Hz,3H).
实施例73:化合物73的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基吡唑-3-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.64(d,J=7.6Hz,1H),8.26(d,J=7.2Hz,1H),8.18(s,1H),7.74(s,1H),7.42–7.31(m,1H),7.25–7.18(m,1H),6.68(s,1H),6.49(d,J=7.6Hz,1H),5.60–5.50(m,1H),3.95(s,3H),1.63(d,J=7.2Hz,3H).
实施例74:化合物74的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基-1H-吡唑-5-硼酸频哪醇酯。1H NMR(600MHz,DMSO-d6)δ8.72(d,J=7.6Hz,1H),8.37(d,J=6.6Hz,1H),8.22(s,1H),7.49(s,1H),7.43–7.35(m,1H),7.34–7.28(m,1H),7.26–7.19(m,1H),6.59(d,J=7.6Hz,1H),6.46(s,1H),5.52–5.42(m,1H),3.88(s,3H),1.61(d,J=6.6Hz,3H).
实施例75:化合物75的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑。1H NMR(600MHz,DMSO-d6)δ8.70(d,J=7.6Hz,1H),8.37(d,J=6.6Hz,1H),8.19(s,1H),7.43–7.36(m,1H),7.32–7.27(m,1H),7.26–7.20(m,1H),6.58(d,J=7.6Hz,1H),6.23(s,1H),5.48–5.38(m,1H),3.80(s,3H),2.26(s,3H),1.61(d,J=6.6Hz,3H).
实施例76:化合物76的制备
步骤1):N-(1-(2,5-二氟苯基)乙基)吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤1的方法,不同之处在于将2,5-二氟苄胺改为1-(2,5-二氟苯基)乙胺盐酸盐。
步骤2):N-(1-(3-氟苯基)乙基)-3-碘吡唑并[1,5-a]嘧啶-5-胺的制备,采用实例1中的步骤2的方法。
步骤3):制备方法同实施例1中步骤3。不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为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。1H NMR(600MHz,DMSO-d6)δ8.53(d,J=7.2Hz,1H),8.29(d,J=6.6Hz,1H),8.26(s,1H),8.19(s,1H),8.11(s,1H),7.82(t,J=60.0Hz,1H),7.30–7.15(m,2H),7.13–7.02(m,1H),6.39(d,J=7.2Hz,1H),5.45–5.33(m,1H),1.51(d,J=6.0Hz,3H).
实施例77:化合物77的制备
制备方法同实施例52,不同之处在于将1-Boc-吡唑-4-硼酸频哪醇酯改为1-甲基吡唑-3-硼酸频那醇酯。1H NMR(600MHz,DMSO-d6)δ8.51(d,J=7.2Hz,1H),8.15(d,J=6.6Hz,1H),8.05(s,1H),7.63–7.60(m,1H),7.28–7.18(m,2H),7.11–7.04(m,1H),6.58–6.53(m,1H),6.36(d,J=7.2Hz,1H),5.47–5.34(m,1H),3.82(s,3H),1.50(d,J=6.6Hz,3H).
测试例1:体外生化水平抑制蛋白激酶(PK)活性实验
材料与方法:TRKA、TRKB和TRKC等激酶,来源于Carna Biosciences 08-186,08-187,08-197;HTRF KinEASE TK kit(Cisbio公司62TK0PEC);384孔板(Greiner公司);ATP(Life technologies PV3227),MgCl2(sigma)公司;PHERAstar FS多功能酶标仪(BMG公司);低速离心机(StaiteXiangyi公司);恒温箱(Binder公司)。
选取的对照化合物为WO2007147647中公开的典型化合物A和WO2007025540中公开的典型化合物B,结构如下:
化合物溶解及保存:根据溶解性,用二甲基亚砜(DMSO)将受试化合物配置成10mmol/L的母液,分装后-20℃保存;
化合物工作液的配制:测试前将分装的化合物从冰箱取出,用纯DMSO稀释到100×所需浓度;然后用去离子水将化合物稀释至4×所需浓度;
1.33×酶缓冲液(Enzymatic buffer)的配制:将5×酶缓冲液(来源于HTRF试剂盒)用去离子水稀释到1.33×,并且加入1.33×终浓度的相应成分:1.33mmol/L二硫苏糖醇(DTT)、1.33mmol/L MnCl2、6.65mmol/L MgCl2和39.9nmol/L SEB;
激酶工作液的配制:用1.33×酶缓冲液将TRKA、TRKB和TRKC稀释到2×所需浓度分别为0.404ng/μL、0.304ng/μL和0.236ng/μL;
底物工作液的配制:用1.33×酶缓冲液将TK Substrate–biotin(来源于HTRF试剂盒)和ATP(10mM)稀释为4×所需终浓度的混合液;TRKA、TRKB和TRKC的ATP终浓度分别为:3.727μmol/L、2.56μmol/L和2.526μmol/L。TK Substrate–biotin(来自HTRF KinEASE TKkit)终浓度均为:0.2μmol/L。
检测工作液的配制:用HTRF测试缓冲液将16.67μmol/L的抗生蛋白链菌-XL665(Streptavidin-XL665)稀释到4×所需终浓度,然后与等体积的抗体-铕隐酸盐(Antibody-Cryptate)混合(均来源于HTRF试剂盒)。
酶反应步骤:向低体积384微孔板的每个孔中加入4μL的激酶工作液,同时加入4μL的1.33×酶缓冲液作为阴性对照(Negative);向孔加入2μl的化合物工作液,同时加入2μL的8%DMSO水溶液作为零化合物浓度对照(即阳性对照,Positive);于25℃,孵育5min;向孔中加入2μL底物工作液启动酶反应,于37℃,振荡反应30min。
HTRF试剂检测步骤:向孔加入8μL的检测工作液终止反应;25℃反应1h;
HTRF信号的读取:采用PHERAstar FS读数检测信号,仪器相应设置如下:
Optic module
积分延迟(Integration delay,lag time)50μs
积分时间(Integration time)400μs
闪光次数(Number of flashes)200
对于每孔读出的原始数据,比值=665nm/620nm;
抑制率的计算:
IC50值的计算:以化合物浓度的对数为横坐标,抑制率为纵坐标,在GraphPadPrism 5中,拟合非线性曲线:log(inhibitor)vs.response--Variable slope,求出酶活抑制率为50%时的待测化合物浓度即IC50。
实验结果:TRKA、TRKB和TRKC激酶活性半数抑制浓度(IC50,nM)
本发明提供结构如式(I)所示化合物以及对照化合物对TRKA激酶的半数抑制浓度(IC50)见表1:
表1:化合物的TRKA激酶抑制活性
本发明提供的部分结构如式(I)所示化合物以及对照化合物对TRKB激酶的半数抑制浓度(IC50)见表2:
表2:化合物的TRKB激酶抑制活性
化合物编号 | IC<sub>50</sub>,nM |
52 | 27.0 |
53 | 28.4 |
54 | 14.7 |
55 | 11.5 |
56 | 13.0 |
57 | 9.1 |
58 | 32.7 |
59 | 23.1 |
60 | 17.9 |
61 | 35.4 |
62 | 27.9 |
63 | 37.9 |
64 | 21.1 |
65 | 63.0 |
66 | 14.9 |
69 | 21.9 |
70 | 83.0 |
71 | 34.2 |
72 | 41.3 |
73 | 22.2 |
74 | 253.2 |
75 | 116.1 |
典型化合物A | >1000 |
典型化合物B | >1000 |
测试例2:大鼠体内药物代谢研究
将化合物30、化合物35以聚乙二醇400水溶液(70%)形式大鼠给药。对于口服给药,大鼠给予5mg/kg的剂量。口服组给药后15、30、45min、1、2、4、6、8、10、24h各采集血样约0.3mL至肝素化的Eppendorf管中,于冰上暂存至离心。全血经8000rpm离心5min后收集血浆,转移血浆至96孔板中,于-20℃保存至LC-MS/MS检测。
采用软件WinNonlin软件的非室模型计算大鼠给药后的药代动力学参数。
达峰浓度Cmax:采用实测值;
药时曲线下面积AUC0-t值:采用梯形法计算;AUC0-∞=AUC0-t+Ct/ke,Ct为最后一个可测得时间点的血药浓度,ke为消除速率常数;
消除半衰期t1/2=0.693/ke;
绝度生物利用度F=Doseiv*AUC0-t,ig/Doseig*AUC0-t,iv×100%。
表3列出了口服给药后,化合物30和化合物35在大鼠体内的药代动力学参数。结果表明,化合物30和化合物35具有良好的药代动力学性质,包括理想的清除率(CL)、半衰期(t1/2)、峰浓度(Cmax)和暴露量(AUC0-t)。
表3:化合物30和化合物35在大鼠体内的药代动力学数据
上述结果表明,本发明提供的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药对TRK激酶表现出优异的抑制活性,同时,能够在动物水平上表现出良好的抗肿瘤活性。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (10)
1.一种具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,
其中,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、卤素、由1-6个卤素取代的C1-12的烷基;
R6为H、C1-12的烷基或卤素,
R7为选自以下式(1)、式(2)或式(3)的基团,
在上述式(1)、式(2)和式(3)中,R11、R21和R31各自独立地为H、C1-12的烷基、乙酰基、苄基、由1-6个选自卤素的卤原子取代的C1-12的烷基、C1-12的烷基羟基、取代或未取代的C3-12的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-12的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自卤素、羟基、硝基和巯基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、氰基、C1-12的烷基、由1-6个选自卤素的原子取代的C1-12的烷基中的至少一种;
优选地,
在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、氯、溴、由1-6个选自氟、氯和溴的卤素取代的C1-8的烷基;
R6为H、C1-8的烷基或卤素;优选地,
在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、氯、由1-6个选自氟和氯的卤素取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素。
2.根据权利要求1所述的化合物,其中,在式(I)中,R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-8的烷基、乙酰基、苄基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基、C1-8的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯、溴、羟基和硝基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-6个选自氟、氯和溴的卤原子取代的C1-8的烷基中的至少一种;优选地,
在式(I)中,R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-6的烷基、乙酰基、苄基、由1-6个选自氟和氯的卤原子取代的C1-6的烷基、C1-6的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-4个选自O、N和S的杂原子的C3-10的杂环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯和羟基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-6个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
3.根据权利要求1所述的化合物,其中,在式(I)中,
R1、R2、R3、R4和R5各自独立地选自H、氟、由1-3个氟原子取代的C1-6的烷基;
R6为H、C1-6的烷基或卤素;
R7为选自所述式(1)、式(2)或式(3)的基团,且在式(1)、式(2)和式(3)中,
R11、R21和R31各自独立地为H、C1-6的烷基、乙酰基、苄基、由1-3个氟原子取代的C1-6的烷基、C1-6的烷基羟基、取代或未取代的C3-10的环烷基、取代或未取代的含有1-3个O和N原子的C3-10的环烷基中的至少一种,其中,R11、R21和R31中的取代基各自独立地选自氟、氯和羟基中的至少一种;
R12、R13、R22、R23、R32和R33各自独立地为H、C1-6的烷基、由1-3个选自氟、氯和溴的卤原子取代的C1-6的烷基中的至少一种。
6.一种药物组合物,其包含药学上可接受的载体、赋形剂或稀释剂,以及作为活性成分的权利要求1-5中任意一项所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药。
7.权利要求1-5中任意一项所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
8.权利要求6所述的药物组合物在制备用于预防和/或治疗TRK酪氨酸激酶受体介异的疾病的药物中的应用。
9.权利要求1-5中任意一项所述的具有式(I)所示结构的吡唑并嘧啶化合物或其药学上可接受的盐,或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物,或其前药,或者权利要求6所述的药物组合物在制备用于预防和/或治疗肿瘤的药物中的应用。
10.根据权利要求9所述的应用,其中,所述肿瘤为乳腺癌、大肠癌、肺癌、甲状腺癌、皮肤癌、白血病、唾液腺肿瘤、神经内分泌肿瘤、淋巴瘤、脑肿瘤、成神经细胞瘤、卵巢癌、胰腺癌、间皮瘤、食管癌、肺肉瘤、成神经管细胞瘤、成胶质细胞瘤、结肠癌、肝癌、成视网膜细胞瘤、肾癌、膀胱癌、骨肉瘤、胃癌、子宫癌、外阴癌、小肠癌、前列腺癌、胆管癌、输尿管癌、肾上腺皮质癌或头颈部癌症的至少一种。
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CN114315900A (zh) * | 2020-09-30 | 2022-04-12 | 美迪西普胜医药科技(上海)有限公司 | 3-芳基吡唑并嘧啶类衍生物及其应用 |
CN114315900B (zh) * | 2020-09-30 | 2023-09-05 | 美迪西普胜医药科技(上海)有限公司 | 3-芳基吡唑并嘧啶类衍生物及其应用 |
WO2022095910A1 (zh) * | 2020-11-04 | 2022-05-12 | 浙江同源康医药股份有限公司 | 用作激酶抑制剂的化合物及其应用 |
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