CN103896796B - 作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物 - Google Patents
作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物 Download PDFInfo
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- CN103896796B CN103896796B CN201410129040.6A CN201410129040A CN103896796B CN 103896796 B CN103896796 B CN 103896796B CN 201410129040 A CN201410129040 A CN 201410129040A CN 103896796 B CN103896796 B CN 103896796B
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
一种作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物。本发明提供了式I’的化合物或其可药用的盐,其中R1、R2、R3、R5、B1、X和n如本文所定义。本发明还涉及制备本发明化合物的方法以及其治疗用途。本发明进一步提供了一种药理学活性剂的组合和药物组合物。
Description
本申请为2010年5月26日提交的申请号为PCT/EP2010/057247、发明名称为“作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物”的国际申请的分案申请,该国际申请于2012年1月19日进入中国国家阶段,申请号为201080032688.1。
发明背景
内源性心房钠尿肽(ANP)(也被称为心房尿肽因子(ANF))在哺乳动物体内具有利尿、促尿钠排泄和血管松弛功能。天然的ANF肽被代谢灭活,特别是被降解酶代谢灭活,该酶被认为是相当于中性肽链内切酶(NEP)EC3.4.24.11的酶,其还负责例如脑啡肽类的代谢灭活。
中性肽链内切酶(EC3.4.24.11;脑啡肽酶;心房肽酶(atriopeptidase);NEP)是一种在疏水性残基的氨基侧裂解多种肽底物的含锌的金属蛋白酶[见PharmacolRev,第45卷,第87页(1993)]。这种酶的底物非限制性地包括心房钠尿肽(ANP,也被称为ANF)、脑利钠肽(BNP)、met-和leu-脑啡肽、缓激肽、神经激肽A、内皮素-1和P物质。ANP是一种有效的血管松弛剂和促尿钠排泄剂[见JHypertens,第19卷,第1923页(2001)]。给正常个体输入ANP导致可再现的尿钠排泄和利尿作用的显著增强,包括钠排泄分数、尿流量和肾小球滤过率的增加[见JClinPharmacol,第27卷,第927页(1987)]。然而,ANP在循环中的半衰期短,并且已经表明肾皮质膜中的NEP是降解这种肽的主要酶[见Peptides,第9卷,第173页(1988)]。因此,NEP的抑制剂(中性肽链内切酶抑制剂,NEPi)应当能增加ANP的血浆水平,并且预期其可诱导促尿钠排泄和利尿作用。
这种酶参与多种生物活性寡肽类的分解,在疏水性氨基酸残基的氨基侧裂解肽键。被代谢的肽包括心房钠尿肽(ANP)、铃蟾肽、缓激肽、与降钙素基因相关的肽、内皮素、脑啡肽类、神经降压肽、P物质和血管活性肠肽。这些肽中的一些具有有效的血管舒张和神经激素功能、利尿和促尿钠排泄活性或调节行为效应。
发明概述:
本发明的目的是提供可用作中性肽链内切酶抑制剂,例如作为哺乳动物体内ANF降解酶的抑制剂,从而通过抑制ANF降解成活性较低的代谢物来延长和增强哺乳动物体内ANF的利尿、促尿钠排泄和血管舒张剂性质的新化合物。
因此,本发明的化合物特别是可用于治疗对中性肽链内切酶(NEP)EC3.4.24.11的抑制有响应的情况和病症。
因此,通过抑制中性肽链内切酶EC.3.4.24.11,本发明的化合物可增强生物活性肽的生物学作用。因此,本发明的化合物特别是可用于治疗多种病症,包括高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全(糖尿病或非糖尿病性)、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、肾病综合征、肾小球肾炎、硬皮病、肾小球硬化、原发性肾病的蛋白尿、肾血管性高血压、糖尿病性视网膜病和晚期肾病(ESRD)、内皮机能障碍、舒张期功能障碍、肥厚型心肌病、糖尿病性心肌病、室上和室性心律失常、心房颤动(AF)、心脏纤维化、心房扑动、有害的血管重构、斑块稳定、心肌梗死(MI)、肾纤维化、多囊性肾病(PKD)、肺动脉高血压、肾衰竭(包括水肿和盐潴留)、周期性水肿、梅尼埃病、高醛固酮血症(原发性和继发性)和高钙尿症、腹水。此外,因为增强ANF作用的能力,这些化合物还可用于治疗青光眼。作为抑制中性肽链内切酶E.C.3.4.24.11能力的另一个结果,本发明的化合物在其它一些治疗领域中具有活性,包括例如月经失调、早产、先兆子痫、子宫内膜异位和生殖病症(尤其是男性和女性不育、多囊卵巢综合征、植入物衰竭)的治疗。本发明的化合物还应能治疗哮喘、阻塞性睡眠呼吸暂停、炎症、白血病、疼痛、癫痫症、情感障碍如抑郁和精神病情况如痴呆和老年意识错乱、肥胖和胃肠道病症(尤其是腹泻和肠易激综合征)、伤口愈合(尤其是糖尿病和静脉溃疡以及压疮)、脓毒性休克、胃酸分泌的调节、高肾素血症的治疗、囊性纤维化、再狭窄、2型糖尿病、代谢综合征、糖尿病并发症和动脉粥样硬化、雄性和雌性性功能障碍。在一个优选的实施方案中,本发明的化合物可用于治疗心血管病症。
本发明涉及如本文所述的化合物、其使用方法以及其用途。本发明化合物的实例包括式I’和I至VIIC中任意一项的化合物或其可药用的盐以及实施例的化合物。
因此,本发明提供了式(I’)的化合物:
或其可药用的盐,其中:
R1是H、C1-7烷基、羟基、C1-7烷氧基、卤素、-SH、-S-C1-7烷基或NRaRb;
R2每次出现时独立地是C1-7烷基、卤素、NO2、CN、C1-7烷酰基氨基、C3-7环烷基、羟基、C1-7烷氧基、卤代C1-7烷基、-NRaRb、C6-10芳基、杂芳基或杂环基;其中Ra和Rb每次出现时独立地是H或C1-7烷基;
R3是A1-C(O)X1或A2-R4;
R4是C6-10芳基或杂芳基,其可以是单环或二环,并且其可任选地被一个或多个独立地选自羟基、羟基C1-7烷基、硝基、-NRaRb、-C(O)C1-7烷基、C(O)-O-C1-7烷基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C2-7链烯基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代;或者R4是一种杂环基,其可任选地被一个或多个独立地选自氧代、羟基、羟基C1-7烷基、氨基、C(O)-O-C1-7烷基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代;
R5是H、卤素、羟基、C1-7烷氧基、卤素、C1-7烷基或卤代-C1-7烷基;
X和X1独立地是OH、-O-C1-7烷基、-NRaRb、-NHS(O)2-C1-7烷基、-NHS(O)2-苄基或-O-C6-10芳基;其中烷基任选地被一个或多个独立地选自C6-10芳基、杂芳基、杂环基、C(O)NH2、C(O)NH-C1-6烷基和C(O)N(C1-6烷基)2的取代基取代;
B1是-C(O)NH-或-NHC(O)-;
A1是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C3-7环烷基、C1-7烷氧基、羟基和O-乙酸酯的取代基取代;其中两个偕烷基可任选地合并形成C3-7环烷基;或者
A1是直链或支链C1-7亚链烯基;或者
A1是其中一个或多个碳原子被选自O、NRc的杂原子替代的直链C1-4亚烷基;并且A1任选地被一个或多个独立地选自卤素和C1-7烷基的取代基取代;其中Rc每次出现时独立地是H、C1-7烷基、-C(O)-O-C1-7烷基或-CH2C(O)OH;或者
A1是苯基或杂芳基;其各自任选地被一个或多个独立地选自C1-7烷基、C3-7环烷基、卤代-C1-7烷基、羟基、C1-7烷氧基、卤素、-NRaRb、-OCH2CO2H和-OCH2C(O)NH2的取代基取代;或者
A1是C3-7环烷基;
A1是-C1-4亚烷基-C6-10-芳基-、-C1-4亚烷基-杂芳基-或-C1-4亚烷基-杂环基-,其中A1可以采取任何方向;
A2是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C1-7烷氧基、羟基、O-乙酸酯和C3-7环烷基的取代基取代;
n是0、1、2、3、4或5;
其中各杂芳基是一种包含5-10个选自碳原子和1至5个杂原子的环原子的单环或二环的芳族环,并且
各杂环基是一种包含4-7个选自碳原子和1-5个杂原子的环原子的单环饱和或部分不饱和但非芳族的部分,其中杂芳基或杂环基的各杂原子独立地选自O、N和S。
因此,本发明提供了式(I)的化合物:
或其可药用的盐,其中:
R1是H或C1-7烷基;
R2每次出现时独立地是C1-7烷基、卤素、NO2、CN、C1-7烷酰基氨基、C3-7环烷基、羟基、C1-7烷氧基、卤代C1-7烷基、-NRaRb、C6-10芳基、杂芳基或杂环基;其中Ra和Rb每次出现时独立地是H或C1-7烷基;
R3是A1-C(O)X1或A2-R4;
R4是C6-10芳基或杂芳基,其可以是单环或二环,并且其可任选地被一个或多个独立地选自羟基、羟基C1-7烷基、氨基、C(O)-O-C1-7烷基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代;或者R4是一种杂环基,其可任选地被一个或多个独立地选自氧代、羟基、羟基C1-7烷基、氨基、C(O)-O-C1-7烷基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代;
R5是H、卤素、羟基、C1-7烷氧基、卤素、C1-7烷基或卤代-C1-7烷基;
X和X1独立地是OH、-O-C1-7烷基、NRaRb或-O-C6-10芳基;其中烷基任选地被一个或多个独立地选自C6-10芳基、杂芳基、杂环基、C(O)NH2、C(O)NH-C1-6烷基和C(O)N(C1-6烷基)2的取代基取代;
B1是-C(O)NH-或-NHC(O)-;
A1是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C3-7环烷基、C1-7烷氧基、羟基和O-乙酸酯的取代基取代;其中两个偕烷基可任选地合并形成C3-7环烷基;或者
A1是苯基或杂芳基;其各自任选地被一个或多个独立地选自C1-7烷基、C3-7环烷基、卤代-C1-7烷基、羟基、C1-7烷氧基、卤素、-NRaRb、-OCH2CO2H和-OCH2C(O)NH2的取代基取代;或者
A1是C3-7环烷基;
A1是-C1-4亚烷基-C6-10-芳基-、-C1-4亚烷基-杂芳基-或-C1-4亚烷基-杂环基-,其中A1可以采取任何方向;
A2是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C1-7烷氧基、羟基、O-乙酸酯和C3-7环烷基的取代基取代;
n是0、1、2、3、4或5;
其中各杂芳基是一种包含5-10个选自碳原子和1至5个杂原子的环原子的单环或二环的芳族环,并且
各杂环基是一种包含4-7个选自碳原子和1-5个杂原子的环原子的单环饱和或部分不饱和但非芳族的部分,其中杂芳基或杂环基的各杂原子独立地选自O、N和S。
在另一个实施方案中,本发明涉及一种通过给个体施用治疗有效量式I’和I至VIIC中任意一项的化合物或其可药用的盐来治疗个体中对中性肽链内切酶EC3.4.24.11(NEP)的抑制有响应的病症或疾病的方法,从而使得个体中对中性肽链内切酶EC3.4.24.11(NEP)的抑制有响应的病症或疾病得以治疗。
在另一个实施方案中,本发明涉及一种治疗高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全(糖尿病或非糖尿病性)、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、肾病综合征、肾小球肾炎、硬皮病、肾小球硬化、原发性肾病的蛋白尿、肾血管性高血压、糖尿病性视网膜病和晚期肾病(ESRD)、内皮机能障碍、舒张期功能障碍、肥厚型心肌病、糖尿病性心肌病、室上和室性心律失常、心房颤动(AF)、心脏纤维化、心房扑动、有害的血管重构、斑块稳定、心肌梗死(MI)、肾纤维化、多囊性肾病(PKD)、肺动脉高血压、肾衰竭(包括水肿和盐潴留)、周期性水肿、梅尼埃病、高醛固酮血症(原发性和继发性)和高钙尿症、腹水、青光眼、月经失调、早产、先兆子痫、子宫内膜异位、生殖病症(尤其是男性和女性不育、多囊卵巢综合征、植入物衰竭)、哮喘、阻塞性睡眠呼吸暂停、炎症、白血病、疼痛、癫痫症、情感障碍如抑郁和精神病情况如痴呆和老年意识错乱、肥胖和胃肠道病症(尤其是腹泻和肠易激综合征)、伤口愈合(尤其是糖尿病和静脉溃疡以及压疮)、脓毒性休克、胃酸分泌功能障碍、高肾素血症、囊性纤维化、再狭窄、2型糖尿病、代谢综合征、糖尿病并发症和动脉粥样硬化、雄性和雌性性功能障碍的方法;其包括给个体施用治疗有效量式I’和I至VIIC中任意一项的化合物或其可药用的盐,从而使个体得以治疗。
在另一个实施方案中,本发明涉及包含式I’和I至VIIC中任意一项的化合物或其可药用的盐和一种或多种可药用载体的药物组合物。
在另一个实施方案中,本发明涉及包括式I’和I-VIC中任意一项的化合物或其可药用的盐以及一种或多种治疗活性剂的药物组合的组合。
在另一个实施方案中,本发明涉及一种通过给个体施用治疗有效量式I’和I至VIIC中任意一项的化合物或其可药用的盐,从而使得中性肽链内切酶EC3.4.24.11被抑制来抑制个体体内中性肽链内切酶EC3.4.24.11的方法。
发明详述:
本发明的化合物
下文在提到式I或I’的化合物时,同样适用于式IA至VIIC中任意一项的化合物。
下文在提到本发明的实施方案时,同样适用于式I或I’的化合物和式IA至VIIC中任意一项的化合物,只要该实施方案存在即可。
本文对本发明的各种实施方案进行了描述。将意识到,可以将各实施方案中指定的特征与另一些实施方案中提供的其它指定特征相结合。
在一个实施方案中,本发明提供了式I或I’的化合物或其可药用的盐,其中:
R1是H或C1-7烷基;
R2每次出现时独立地是C1-7烷基、卤素、C3-7环烷基、羟基、C1-7烷氧基、卤代C1-7烷基、-NRaRb、C6-20芳基、杂芳基或杂环基;其中Ra和Rb每次出现时独立地是H或C1-7烷基;
R3是A1-C(O)X1或A2-R4;
R4是C6-20芳基或杂芳基,其可以是单环或二环并且可任选地被一个或多个独立地选自羟基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代;
R5是H;
X和X1独立地是OH、-O-C1-7烷基或NRaRb;
B1是-C(O)NH-或-NHC(O)-;
A1是直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C3-7环烷基、C1-7烷氧基、羟基和O-乙酸酯的取代基取代;其中两个偕烷基可任选地合并形成C3-7环烷基;或者
A1是苯基或杂芳基;其各自任选地被一个或多个独立地选自C1-7烷基、C3-7环烷基、卤代-C1-7烷基、羟基、C1-7烷氧基、卤素、-NRaRb、-OCH2CO2H和-OCH2C(O)NH2的取代基取代;
A2是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C1-7烷氧基、羟基、O-乙酸酯和C3-7环烷基的取代基取代;
n是0、1、2、3、4或5;
其中各杂芳基是一种包含5-10个选自碳原子和1至5个杂原子的环原子的单环或二环的芳族环,并且
各杂环基是一种包含4-7个选自碳原子和1-5个杂原子的环原子的单环饱和或部分不饱和但非芳族的部分,其中杂芳基或杂环基的各杂原子独立地选自O、N和S。
式I或I’的某些化合物包括其中携带联苯基的碳上的立体化学是(R)的式IA的化合物:
或其可药用的盐,其中X、R1、R2、B1、R3和n具有上面式I或I’中的定义。
在一个实施方案中,本发明涉及其中n是1、2、3、4或5;R2是卤素并且被连接到间位并且其它任选的R2基团独立地是C1-7烷基、NO2、CN、卤素、C3-7环烷基、羟基、C1-7烷氧基、卤代-C1-7烷基、NRbRc、C6-10芳基、杂芳基或杂环基的式I或I’的化合物或其可药用的盐。这一实施方案可以用式IB和IC的化合物或其可药用的盐来说明:
其中X、R1、R2、B1、R3具有上面式I或I’中的定义;p是0、1、2、3或4且R2a是卤素。
某些式I或I’的化合物包括式II的化合物:
或其可药用的盐,其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义。
在另一个实施方案中,本发明涉及其中携带联苯基的碳的立体化学是(R)的式II的化合物。这一实施方案用式IIA化合物或其可药用的盐来说明:
其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义。
某些式I、I’或II的化合物包括式IIB或IIC的化合物:
或其可药用的盐,其中X、X1、A1、R1、R2具有上面式I或I’中的定义;p是0、1、2、3或4且R2a是卤素。
某些式I或I’的化合物包括式III的化合物:
或其可药用的盐,其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义。
在另一个实施方案中,本发明涉及其中携带联苯基的碳的立体化学是(R)的式III的化合物。这一实施方案可以用式IIIA的化合物或其可药用的盐来说明:
其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义。
某些式III的化合物包括式IIIB或IIIC的化合物:
或其可药用的盐,其中X、X1、A1、R1、R2具有上面式I或I’中的定义;p是0、1、2、3或4且R2a是卤素。
在另一些实施方案中,本发明提供了其中A1是任选地被一个或多个独立地选自卤素、C1-7烷氧基、羟基、O-乙酸酯和C3-7环烷基的取代基取代的直链C1-7亚烷基;其中两个偕烷基可任选地合并形成C3-7环烷基的式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物。
另一个实施方案包括式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐,其中A1是-CH2-、-CH2CH2-、-CH2CH2CH2-或A1具有下式:
其中Rc1、Rc2、Rd1、Rd2、Re1、Re2、Re3和Re4独立地是H、卤素、C3-7环烷基或C1-7烷基;或者,Rc1和Rc2或Rd1和Rd2可以和与其相连的氮一起形成C3-7环烷基。在这种实施方案的一个方面,A1是下面的基团之一:
另一个实施方案包括式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐,其中A1具有下式:
其中Rf1、Rf2、Rf3和Rf4独立地是H、卤素、O-乙酸酯或C1-7烷基。在另一个实施方案中,A1是下面的基团之一:
在另一个实施方案中,本发明提供了其中A1是C3-7环烷基的式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物。这一实施方案的实例是式I’、I至IC、II至IIC和III至IIIC中任意一项的化合物,其中A1选自下面的基团:
在另一个实施方案中,本发明提供了其中A1是直链或支链C2-7亚链烯基的式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物。C2-7亚链烯基的一个实例是反式CH=CH。
在另一个实施方案中,本发明提供了式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物,其中A1是其中一个或多个碳原子被选自O、NRc的杂原子替换的直链C1-4亚烷基;且A1任选地被一个或多个独立地选自卤素和C1-7烷基的取代基取代;其中Rc每次出现时独立地是H、C1-7烷基、-C(O)OC1-7烷基或CH2C(O)OH。另一个实施方案包括其中A1是下面基团之一的式I’、I至IC、II至IIC和III至IIIC的化合物:
在另一个实施方案中,本发明提供了的式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物,其中A1是任选地被取代的苯基或杂芳基,其中任选的取代基如式I或I’中所定义。
上面实施方案的某些化合物包括中A1是5-员环杂芳基的式I’、I至IC、II至IIC和III至IIIC中任意一项的化合物或其可药用的盐。这一实施方案用式IV化合物或其可药用的盐来说明:
其中X、X1、B1、R1、R2和n具有上面式I或I’中的定义并且Y1、Y2和Y3独立地是N、NH、S、O或CH并和与其相连的环原子一起形成一种5-员杂芳基环。
在这一实施方案的一个方面,本发明涉及式IVA的化合物或其可药用的盐:
其中X、X1、B1、R1、R2、Y1、Y2、Y3和n具有上面式I、I’或IV中的定义。
在这一实施方案的一个方面,Y1、Y2和Y3和与其相连的环原子一起形成一种选自呋喃、噻吩、吡咯、吡唑、唑、噻唑、二唑、噻二唑和三唑的5-员杂芳基环。另一个实施方案包括其中所述5-员杂芳基是下面的基团之一的式IV或VIA的化合物或其可药用的盐:
在另一个实施方案中,本发明涉及其中n是1、2、3、4或5;R2是位于间位上的卤素并且其它任选的R2基团独立地是C1-7烷基、NO2、CN、卤素、C3-7环烷基、羟基、C1-7烷氧基、卤代-C1-7烷基、NRbRc、C6-10芳基、杂芳基或杂环基的式IV或IVA的化合物。
在上面实施方案的另一些方面,本发明涉及其中A1是在氮原子上与酰胺B1相连的5-员杂芳基环的式I’、I至IC、II至IIC或III至IIIC的化合物或其可药用的盐。这一实施方案用式V或VA的化合物或其可药用的盐来说明:
其中X、X1、B1、R1、R2和n具有上面式I或I’中的定义并且各Y4独立地是N、S、O或CH。在另一个实施方案中,本发明涉及其中n是1、2、3、4或5;R2是位于间位上的卤素并且其它任选的R2基团独立地是C1-7烷基、NO2、CN、卤素、C3-7环烷基、羟基、C1-7烷氧基、卤代-C1-7烷基、NRbRc、C6-10芳基、杂芳基或杂环基的式V或VA的化合物。
在上面实施方案的另一个方面,本发明提供了式I’、I至IC、II至IIC和III至IIIC中任意一项或其中所述的任何类和亚类中的化合物或其可药用的盐或溶剂化物,其中A1是苯基或6-员环杂芳基,其中苯基和杂芳基任选地被C1-7烷基、C3-7环烷基、卤代-C1-7烷基、羟基、C1-7烷氧基、卤素、NRaRb、-OCH2CO2H或-OCH2C(O)NH2取代。这一实施方案的一个方面包括其中A1与酰胺B1和以对位排列方式与C(O)X1部分相连的式I’、I至IC、II至IIC和III至IIIC中任意一项的化合物或其可药用的盐。这一实施方案的另一方面包括其中A1与酰胺B1和以间位排列方式与C(O)X1部分相连的式I’、I至IC、II至IIC和III至IIIC中任意一项的化合物。这一实施方案的化合物包括式VI的化合物或其可药用的盐:
其中X、X1、B1、R1、R2和n具有上面式I或I’中的定义且W1、W2、W3和W4独立地是N或CRe,其中各Re独立地是H、C1-7烷基、C3-7环烷基、卤代-C1-7烷基、羟基、C1-7烷氧基、卤素、-NRaRb、-OCH2CO2H或-OCH2C(O)NH2。在这一实施方案的一个方面,A1是苯基、吡啶或嘧啶。
在另一个实施方案中,本发明涉及式VIA的化合物或其可药用的盐:
其中X、X1、B1、R1、R2、W1、W2、W3和W4以及n具有上面式I、I’或VI中的定义。
另一个实施方案包括其中A1是下面基团之一的式VI或VIA的化合物或其可药用的盐:
在另一个实施方案中,本发明涉及其中n是1、2、3、4或5;R2是位于间位上的卤素并且其它任选的R2基团独立地是C1-7烷基、NO2、CN、卤素、C3-7环烷基、羟基、C1-7烷氧基、卤代-C1-7烷基、NRbRc、C6-10芳基、杂芳基或杂环基的式VI或VIA的化合物或其可药用的盐。
在前面实施方案的一个方面,本发明涉及其中B1是-C(O)NH-的式I’、I至IC、IV至IVC、V至VC和VI至VIC中任意一项的化合物或其可药用的盐。在另一个实施方案中,B1是-NHC(O)-。
上面实施方案的某些化合物包括其中A1是-C1-4亚烷基-C6-10-芳基-、-C1-4亚烷基-杂芳基-或-C1-4亚烷基-杂环基-、-C6-10芳基-C1-4-亚烷基-、-杂芳基-C1-4亚烷基或-杂环基-C1-4亚烷基-的式I’、I至IC、II至IIC和III至IIIC中任意一项的化合物或其可药用的盐。在这一实施方案的一个方面,A1是-C1-4亚烷基-C6-10-芳基-、-C1-4亚烷基-杂芳基-或-C1-4亚烷基-杂环基-,其中亚烷基部分与B1酰胺基团相连且芳基、杂芳基或杂环基部分与C(O)X1相连。在这一实施方案的另一个方面,A1是-CH2-苯基-或-苯基-CH2-。在这一实施方案的另一个方面,A1是-CH2-杂芳基或-杂芳基-CH2-。在另一个实施方案中,A1是-CH2-杂环基或-杂环基-CH2-。A1的代表性实例如下:
式I或I’的某些化合物包括式VII的化合物或其可药用的盐:
其中X、A2、R1、R2、R4和n具有上面式I或I’中的定义。另一个实施方案包括式VIIA的化合物或其可药用的盐:
其中X、A2、R1、R2、R4和n具有上面式I或I’中的定义。
式VII或VIIA的某些化合物具有式VIIB或VIIC:
或其可药用的盐,其中X、A2、R1、R2、R4具有上面式I或I’中的定义;p是0、1、2、3或4且R2a是卤素。
这一实施方案的另一方面包括其中A2是(CH2)p且p是0、1、2、3的式VII至VIIC中任意一项的化合物或其可药用的盐。在这一实施方案的一个方面,p是0,因此A2是键。在这一实施方案的另一个方面,A2是CH2或CH2-CH2。
在这一实施方案的另一方面,本发明提供了其中R4是任选地被取代的C6-10芳基的式VII至VIIC中任意一项的化合物或其可药用的盐。芳基的代表性实例是苯并咪唑酮、苯并异噻唑酮或苯基。在这一实施方案的另一方面,R4是苯基。苯基环上的取代基包括例如卤素(例如F、Cl)、羟基、卤代-C1-7烷基(例如CF3)、-NHS(O)2-C1-7烷基、杂芳基、C1-7烷氧基或C1-7烷基。
在这一实施方案的另一方面,本发明提供了其中R4是任选地被取代的二环杂芳基的式VII至VIIC中任意一项的化合物或其可药用的盐。
在这一实施方案的另一方面,本发明提供了其中R4是任选地被取代的5-或6-员杂芳基的式VII至VIIC中任意一项的化合物或其可药用的盐。在这一实施方案的一个方面,R4是一种选自吡嗪基、吡啶基、嘧啶基、氧代-吡喃基(例如吡喃酮、任选地被取代的吡喃-4-酮、吡喃-2-酮如3-羟基-吡喃-4-酮、3-羟基-吡喃-2-酮)和氧代-吡啶基(例如吡啶酮、任选地被取代的吡啶-4-酮或吡啶-2-酮例如3-羟基-1-甲基-吡啶-4-酮或1-苄基-吡啶-2-酮)或嘧啶酮(即氧代-嘧啶基)的6-员环杂芳基。在这一实施方案的另一个方面,R4是一种选自唑、吡咯、吡唑、异唑、三唑、四唑、二唑(例如1--3,4-二唑、1--2,4-二唑)、二唑酮(例如二唑-2-酮)、噻唑、异噻唑、噻吩、咪唑和噻二唑的5-员环杂芳基。R4的其它代表性实例有唑酮、噻唑酮、二唑酮、三唑酮、唑酮、咪唑酮、吡唑酮。在另一个实施方案中,C6-10芳基和杂芳基上任选的取代基选自羟基、C1-7烷基、C1-7烷氧基、卤素、卤代-C1-7烷基或苄基。
在上面实施方案的另一个方面,本发明提供了其中R4是二环杂芳基的式VII至VIIC中任意一项的化合物或其可药用的盐。另一个实施方案包括其中R4是吲哚、苯并噻唑或苯并咪唑的式VII至VIIC中任意一项的化合物或其可药用的盐。R4的代表性实例如下:
在上面实施方案的另一个方面,本发明提供了式VII至VIIC中任意一项的化合物或其可药用的盐,其中R4是一种饱和或部分饱和的单环杂环基,该杂环基包含至少一个选自氮、硫和氧的杂原子,并且该杂环基任选地被一个或多个独立地选自氧代、羟基、C1-7烷氧基、卤素、C1-7烷基、卤代-C1-7烷基、C6-10芳基、杂芳基、-NHSO2-C1-7烷基和苄基的取代基取代。在这一实施方案一个特定的方面,R4是吡咯烷或咪唑烷,其中该杂环可通过碳或氮与羰基(C(O)-A2)部分相连并且该杂环基任选地被氧代取代。
在一个实施方案中,本发明提供了其中R1是H的式I’、I至IC、II至IIC、III至IIIC、IV、IVA、V、VA、VI、VIA和VII至VIIC中任意一项的化合物或其可药用的盐。
在另一个实施方案中,本发明提供了其中各R2独立地是卤素、C1-7烷基、C1-7烷氧基、羟基、卤代-C1-7烷基且n是0、1或2的式I’、I至IC、II至IIC、III至IIIC、IV、IVA、V、VA、VI、VIA和VII至VIIC中任意一项的化合物或其可药用的盐。在另一个实施方案中,n是1、2、3、4或5,R2是位于间位上的卤素且其它任选的R2基团独立地是卤素、C1-7烷基、C1-7烷氧基、羟基或卤代烷基。在另一个实施方案中,本发明提供了其中n是1或2,R2是间-氯或间-氟且其它任选的R2基团是卤素、C1-7烷基、C1-7烷氧基、羟基或卤代烷基的式I’、I至IC、II至IIC、III至IIIC、IV、IVA、V、VA、VI、VIA和VII至VIIC中任意一项的化合物或其可药用的盐。
在另一个实施方案中,本发明提供了其中X和X1独立地是OH或-O-C1-7烷基(例如-O-乙基、-O-甲基或-O-正丁基)的式I’、I至IC、II至IIC、III至IIIC、I、IVA、V、VA、VI、VIA和VII至VIIC中任意一项的化合物或其可药用的盐。在这一实施方案的一个特定方面,X和X1是OH。在这一实施方案的另一个方面,X和X1独立地是-O-C1-7烷基,其中烷基被C6-10芳基、杂芳基、杂环基、C(O)NH2、C(O)NH-C1-6烷基或C(O)N(C1-6烷基)2取代。X或X1的代表性实例是-O-CH2-C(O)N(CH3)2、-O-CH2-CH2-吗啉、-O-CH2-间二氧杂环戊烯酮或-O-苄基。在这一实施方案的另一方面,X和X1是-O-C6-10芳基。-O-C6-10芳基的代表性实例是-O-(2,3-二氢-1H-茚)。
在另一个实施方案中,X、X1、B1、A1、A2、R2、R1和R4基团是下面实施例部分中X、X1、A1、A2、B1、R2、R1和R4基团所定义的那些基团。
在另一个实施方案中,本发明的各化合物是下面实施例部分中所列的那些化合物或其可药用的盐。
定义
为了解释本说明书,除非特别说明,否则将适用下面的定义,并且在适用的情况中,以单数使用的术语也将包括复数并且反之亦然。
本文所用的术语“烷基”是指包含1至20个碳原子的全饱和的分枝或无分枝的(或直链或线形)烃部分。该烷基优选地包含1至7个碳原子,并且更优选地包含1至4个碳原子。烷基的代表性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正-庚基。术语“C1-7烷基”是指具有1至7个碳原子的烃。此外,术语烷基包括“未被取代的烷基”和“被取代的烷基”。术语“亚烷基”是指其中烷基如之前所定义的二价烷基基团。
术语“链烯基”是指具有至少一个碳-碳双键的分枝或无分枝的烃。术语“C2-7链烯基”是指具有2至7个碳原子并包含至少一个碳-碳双键的烃。链烯基的代表性实例有乙烯基、丙-1-烯基、烯丙基、丁烯基、异丙烯基或异丁烯基。术语“亚链烯基”是指其中链烯基如之前所定义的二价链烯基基团。
本文所用的术语“卤代烷基”是指被一个或多个本文所定义的卤素基团取代的如本文所定义的烷基。优选地,卤代烷基可以是单卤代烷基、二卤代烷基或多卤代烷基,包括全卤代烷基。单卤代烷基可在烷基内具有一个碘、溴、氯或氟。二卤代烷基和多卤代烷基可在烷基内具有两个或多个相同的卤素原子或不同卤素基团的组合。多卤代烷基优选包含最多12个、或10个、或8个、或6个、或4个、或3个、或2个卤素基团。卤代烷基的代表性实例有氟代甲基、二氟甲基、三氟甲基、氯代甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基是指氢原子都被卤素原子代替的烷基。术语“卤代-C1-7烷基”是指具有1至7个碳原子并且被一个或多个卤素基团取代的烃。
本文所用的术语“烷氧基”是指其中烷基如本文上面所定义的烷基-O-。烷氧基的代表性实例非限制性地包括甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基、环丙氧基-、环己氧基-等。烷氧基优选具有约1-7个,更优选约1-4个碳。
本文所用的术语“环烷基”是指3-12个碳原子,优选3-8个或3-7个碳原子的饱和或不饱和但非芳族的单环、二环或三环烃基团。对于二环或三环环烷基系统而言,所有的环都是非芳族的。实例性的单环烃基包括环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基。实例性的二环烃基包括冰片基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基。实例性的三环烃基包括金刚烷基。术语“C3-7环烷基”是指具有3至7个碳原子的环状烃基。术语“环烷基烷基”是指被环烷基取代的烷基。
术语“芳基”是指在环部分具有6-10个碳原子的单环或二环芳族烃基团。术语“芳基”也指其中芳族环与环烷基环稠合的基团,其中连接的基团位于芳族环上或稠合的环烷基环上。芳基的代表性实例有苯基、萘基、六氢茚基、茚满基或四氢萘基。术语“C6-10芳基”是指在环部分具有6至10个碳原子的芳族烃基团。
术语“芳基烷基”是被芳基取代的烷基。芳基烷基的代表性实例是苄基或苯基-CH2CH2-。该术语也包括被取代的芳基烷基部分。
术语“杂芳基”包括包含5-10个选自碳原子和1至5个杂原子的环成员并且各杂原子独立地选自O、N或S的单环或二环杂芳基,其中S和N可以被氧化成各种氧化状态。对于二环杂芳基系统而言,该系统完全是芳族的(即所有的环都是芳族的)。
典型的单环杂芳基包括噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、-2,3-二唑基、-2,4-二唑基、-2,5-二唑基、-3,4-二唑基、噻-2,3-二唑基、噻-2,4-二唑基、噻-2,5-二唑基、噻-3,4-二唑基、3-、4-或5-异噻唑基、2-、4-或5-唑基、3-、4-或5-异唑基、3-或5-1,2,4-三唑基、4-或5-1,2,3-三唑基、四唑基、2-、3-或4-吡啶基、3-或4-哒嗪基、3-、4-或5-吡嗪基、2-吡嗪基、2-、4-或5-嘧啶基。
术语“杂芳基”还指其中杂芳族环与一个或多个芳基、环脂族或杂环基环稠合的基团,其中连接基团或连接点位于杂芳族环或稠合的芳基环上。二环杂芳基的代表性实例有吲哚基、异吲哚基、吲唑基、吲嗪基、嘌呤基、喹嗪基、喹啉基、异喹啉基、噌啉基、酞嗪基、萘啶基、喹唑啉基、喹喔啉基、噻吩并[2,3-b]呋喃基、呋喃并[3,2-b]吡喃基、5H-吡啶并[2,3-d]嗪基、1H-吡唑并[4,3-d]唑基、4H-咪唑并[4,5-d]噻唑基、吡嗪并[2,3-d]哒嗪基、咪唑并[2,1-b]噻唑基、咪唑并[1,2-b][1,2,4]三嗪基、7-苯并[b]噻吩基、苯并唑基、苯并咪唑基、苯并噻唑基、苯并庚英基(benzoxapinyl)、苯并嗪基、1H-吡咯并[1,2-b][2]苯并吖庚英基(benzazapinyl)、苯并呋喃基、苯并噻吩基、苯并三唑基、吡咯并[2,3-b]吡啶基、吡咯并[3,2-c]吡啶基、吡咯并[3,2-c]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[4,5-b]吡啶基、咪唑并[4,5-c]吡啶基、吡唑并[4,3-d]吡啶基、吡唑并[4,3-c]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[3,4-d]吡啶基、吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡咯并[1,2-b]哒嗪基、咪唑并[1,2-c]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[4,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、嘧啶并[5,4-d]嘧啶基、吡嗪并[2,3-b]吡嗪基或嘧啶并[4,5-d]嘧啶基。
当杂芳基部分被羟基取代时,本发明还涉及其氧代互变异构体。例如,被羟基取代的二唑也包括氧代-二唑或者也被称为二唑酮。该互变异构化如下所示:
本文所用的术语“杂环基”或“杂环”是指任选地被取代的、饱和或不饱和的非芳族(部分不饱和的)环,其是4-、5-、6-或7-员单环,并且包含至少一个选自O、S和N的杂原子,其中N和S也可任选地被氧化成各种氧化状态。对于二环和三环杂环基环系而言,非芳族环系被定义为是一种非全饱和的或部分不饱和的环系。因此,二环和三环杂环基环系包括其中稠合环中的一个是芳族的,但是另一个(其它的)是非芳族的杂环基环系。在一个实施方案中,杂环基部分表示一种包含5-7个环原子并任选地包含另一个选自O、S或N的杂原子的饱和单环。该杂环基团可以在杂原子或碳原子上进行连接。该杂环基可包括稠合或桥连的环以及螺环的环。杂环的实例包括二氢呋喃基、二氧戊环基、二恶烷基、二噻烷基、哌嗪基、吡咯烷、二氢吡喃基、氧硫杂环戊烷基、二硫戊环、氧硫杂环己烷基、硫代吗啉代、环氧乙烷基、环乙亚胺基、氧杂环丁烷基、氧杂环庚烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、哌啶基、吗啉代、哌嗪基、吖庚英基、庚英基、氧氮杂环庚烷基、氧硫杂环己基、硫杂环庚烷基、氮杂环庚烷基、二氧杂环庚烷基和二氮杂环庚烷基。
术语“羟基烷基”是指其中烷基被一个或多个羟基取代的如上所述的烷基。
术语“卤素”包括氟、溴、氯和碘。术语“全卤化的”通常是指一种其中所有氢都被卤素原子代替的部分。
术语“杂原子”包括除碳或氢外的任何元素的原子。优选的杂原子是氮、氧、硫和磷。在另一个实施方案中,杂原子是氮、氧或硫。
应当注意到,本发明一些化合物的结构包括不对称碳原子。因此,应当清楚,除非说明,否则本发明范围内包括由该类不对称性产生的异构体(例如,所有的对映异构体和非对映异构体)。该类异构体可以通过经典的分离技术和立体化学控制的合成以基本纯的形式获得。此外,本申请中所讨论的结构和其它化合物以及部分也包括其所有互变异构体。
本文所用的术语“异构体”是指具有相同分子式,但是原子的排列和构型不同的不同化合物。对于本发明所给出的化合物而言,本文所用的术语“旋光异构体”和“立体异构体”还涉及可以存在的各种立体异构构型中的任何一种并且包括几何异构体。应当清楚的是,取代基可以连接在碳原子的手性中心上。本发明包括所述化合物的对映异构体、非对映异构体或外消旋体。“对映异构体”是一对彼此成不可重叠的镜像的立体异构体。一对对映异构体的1:1的混合物是一种“外消旋的”混合物。在适用的情况中,用该术语来称呼一种外消旋混合物。“非对映异构体”是具有至少两个不对称原子,但是彼此不成镜像的立体异构体。根据Cahn-lngold-PrelogR-S系统来指定绝对立体化学。当一种化合物是纯对映异构体时,可以用R或S来说明各手性碳的立体化学。可以根据其在钠D线的波长下旋转平面偏振光的方向(右旋或左旋)来将绝对构型未知的被拆分了的化合物指定为(+)或(-)。本文所述的某些化合物包含一个或多个不对称中心或轴,因此,可以产生对映异构体、非对映异构体和可以根据绝对立体化学被定义为(R)-或(S)-的其它立体异构形式。本发明意指包括所有该类可能的异构体,包括外消旋混合物、光学纯的形式和中间体混合物。(R)-和(S)-旋光异构体可以用手性合成子或手性试剂来进行制备,或者可以用常规技术进行拆分。如果化合物包含双键,则取代基可以是E或Z构型。如果化合物包含被二取代的环烷基,则该环烷基取代基可以具有顺式-或反式-构型。也包括所有的互变异构形式。
本发明化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。如果可能的话,具有不饱和键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。
因此,如本文所用的那样,本发明的化合物可以以可能的异构体、旋转异构体、阻转异构体、互变异构体中的一种形式或其混合物的形式存在,例如为基本纯的几何(顺式或反式)异构体、非对映异构体、旋光异构体(对映体)、外消旋体或其混合物形式。
可以根据组分的理化性质将所得的任何异构体混合物分离成纯或基本纯的几何或旋光异构体、非对映异构体、外消旋体,例如通过色谱法和/或分级结晶来进行分离。
可以用已知的方法将任何所得终产物或中间体的外消旋体拆分成旋光对映体,例如通过对用光学活性的酸或碱获得的其非对映异构的盐进行分离,然后释放光学活性的酸性或碱性化合物来进行拆分。因此,特别是可以用一种碱性部分来将本发明化合物拆分成其旋光对映体,例如,通过对用光学活性的酸例如酒石酸、二苯甲酰基酒石酸、二乙酰基酒石酸、二-O,O'-对-甲苯甲酰基酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸形成的盐进行分级结晶来进行拆分。外消旋产物也可以用手性色谱,例如使用手性吸附剂的高压液相色谱来进行拆分。
本文所用的术语“可药用的盐”是指保留了本发明化合物的生物学有效性和性质,但是在生物学或其它方面不会不受欢迎的盐。在许多情况中,本发明的化合物能凭借存在的氨基和/或羧基或与其类似的基团形成酸式和/或碱式盐。可药用的酸加成盐可以用无机酸和有机酸来形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、羟苯酰苯酸盐(hibenzate)、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、蔗糖酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐和三氟乙酸盐。可由其形成盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可由其形成盐的有机酸包括例如乙酸、丙酸、羟乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对-甲苯磺酸、水杨酸等。可以用无机碱和有机碱形成可药用的碱加成盐。可由其形成盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等;特别优选的是铵盐、钾盐、钠盐、钙盐和镁盐。可由其形成盐的有机碱包括例如伯、仲和叔胺、包括天然存在的被取代的胺在内的被取代的胺、环胺、离子交换树脂等,特别是如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言,该类盐可以通过使这些化合物的游离酸形式与化学计量数量的适宜碱(如Na、Ca、Mg或K氢氧化物、碳酸盐、碳酸氢盐等)反应,或者通过使这些化合物的游离碱形式与化学计量数量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。在适用的情况中,一般优选非水性介质如醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington'sPharmaceuticalSciences”,第20版,MackPublishingCompany,Easton,Pa.,(1985);和“药用盐手册:性质、选择和应用(HandbookofPharmaceuticalSalts:Properties,Selection,andUse)”,StahlandWermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
本文给出的任何结构式也意指表示这些化合物未被标记的形式以及同位素标记的形式。例如,本文任何结构式中“H”所表示的任何氢意指表示氢的所有同位素形式(例如1H、2H或D、3H);本文任何结构式中“C”所表示的任何碳意指表示碳的所有同位素形式(例如11C、13C、14C);“N”所表示的任何氮意指表示氮的所有同位素形式(例如14N、15N)。被包括在本发明中的同位素的其它实例包括氧、硫、磷、氟、碘和氯的同位素,如18F、31P、32P、35S、36Cl、125I。本发明包括各种同位素标记的本文所定义的化合物,例如其中存在放射性同位素如3H、13C和14C的那些化合物。在一个实施方案中,本文结构式中的原子以其天然丰度存在。在另一个实施方案中,一个或多个氢原子可以在2H方面富集;或/和一个或多个原子可以在11C、13C或14C方面富集;或/和一个或多个氮可以在14N方面富集。该类同位素标记的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、探测或成像技术(如包括药物或底物分布测定在内的正电子发射断层扫描术(PET)或单光子发射计算体层摄影术(SPECT)),或可用于患者的放疗中。18F标记的化合物对PET或SPECT研究而言是特别理想的。本发明同位素标记的化合物及其前体药物通常可通过用容易获得的同位素标记的试剂代替非同位素标记的试剂,实施流程或下述实施例和制备例中所公开的操作来进行制备。
此外,重同位素,特别是氘(即,2H或D)富集可提供一些治疗优点,这些优点是由代谢稳定性更高例如体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当清楚的是,本文中的氘被看做式I’和I至VIIC化合物中任何一种化合物的取代基。可以用同位素富集因子来定义该类重同位素,特别是氘的浓度。本文所用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该类化合物对各指定的氘原子而言具有至少3500(各指定氘原子上52.5%的氘混入)、至少4000(60%的氘混入)、至少4500(67.5%的氘混入),至少5000(75%的氘混入),至少5500(82.5%的氘混入)、至少6000(90%的氘混入)、至少6333.3(95%的氘混入)、至少6466.7(97%的氘混入)、至少6600(99%的氘混入)或至少6633.3(99.5%的氘混入)的同位素富集因子。
同位素富集的式I’或I至VIIC的化合物通常可用本领域技术人员已知的常规技术或与所附实施例和制备例中所述那些方法类似的方法,用适宜的同位素富集的试剂代替之前所用的非同位素富集的试剂来进行制备。
本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、d6-丙酮、d6-DMSO的那些溶剂化物。
包含能作为氢键供体和/或受体的基团的本发明化合物,即式I’和I至VIIC中任意一项的化合物可能能与适宜的共结晶形成剂形成共结晶。这些共结晶可以通过已知的成共结晶操作,由式I’和I至VIIC中任意一项的化合物来进行制备。该类操作包括研磨、加热、共升华、共熔化、或在式I’和I至VIIC中任意一项的化合物溶液中与共结晶形成剂在结晶条件下接触和分离由此形成的共结晶。适宜的共结晶形成剂包括WO2004/078163中所述的那些物质。因此,本发明进一步提供了包含式I’和I至VIIC中任意一项化合物的共结晶。
如本领域普通技术人员已知的那样(例如参见,Remington'sPharmaceuticalSciences,第18版,MackPrintingCompany,1990,第1289-1329页),本文所用的术语“可药用的载体”包括任何和所有溶剂、分散介质、包衣、表面活性剂、抗氧剂、防腐剂(例如,抗细菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐类、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等及其组合。除非载体与活性成分不相容,否则考虑其在治疗或药物组合物中的应用。
术语本发明化合物的“治疗有效量”是指将引起个体的生物学或医学响应,例如降低或抑制酶或蛋白活性、或改善症状、缓解病症、减缓或延迟疾病进程、或预防疾病等的本发明化合物的量。在一个非限制性实施方案中,术语“治疗有效量”是指当被施用于个体时,对(1)至少部分缓解、抑制、预防和/或改善(i)由中性肽链内切酶EC3.4.24.11介导的或(ii)与中性肽链内切酶EC3.4.24.11活性有关的或(iii)特征在于中性肽链内切酶EC3.4.24.11活性异常的情况或病症或疾病;或(2)降低或抑制中性肽链内切酶EC3.4.24.11的活性;或(3)降低或抑制中性肽链内切酶EC3.4.24.11的表达而言有效的本发明化合物的量。在另一个非限制性实施方案中,术语“治疗有效量”是指当被施用给细胞或组织或非细胞的生物学材料或培养基时,对于至少部分降低或抑制中性肽链内切酶EC3.4.24.11的活性或至少部分降低或抑制中性肽链内切酶EC3.4.24.11的表达而言有效的本发明化合物的量。
本文所用的术语“个体”是指动物。该动物优选地是哺乳动物。个体还指例如灵长类动物(例如,人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟类等。在一个优选的实施方案中,该个体是人。
本文所用的术语“抑制”是指给出的情况、症状或病症或疾病的降低或遏制,或者生物学活性或过程的基准活性显著降低。
在一个实施方案中,本文所用的术语任何疾病或病症的“治疗”是指疾病或病症的改善(即,疾病发展或其至少一种临床症状的减缓或抑制或降低)。在另一个实施方案中,“治疗”是指缓解或改善包括患者不能辨别的那些参数在内的至少一种身体参数。在另一个实施方案中,“治疗”是指对疾病或病症进行身体上(例如稳定可辨别的症状)、生理上(例如稳定身体参数)或者身体上和生理上的调控。在另一个实施方案中,“治疗”是指阻止或延迟疾病或病症的开始或发展或进行。
除非在本文中特别说明或者与上下文明显相悖,否则本文所用的术语“一个”、“一种”、“该”以及本发明上下文(尤其是权利要求书)中所用的类似术语被理解为覆盖了单数和复数。
术语“高血压”是指一种其中血管内的血液压力高于血液在体内循环时的正常压力的情况。当持续一段时间内收缩压超过150mmHg或舒张压超过90mmHg时,会对机体造成损害。例如,收缩压过高可能使得任何地方的血管破裂,并且当其在脑中发生时,发生中风。高血压还可造成血管增厚和变窄,其最终导致动脉粥样硬化。
包括与高血压有关的2型糖尿病在内的术语“2型糖尿病”是指一种其中由于胰岛β-细胞功能受损使得胰腺不能分泌足够的胰岛素和/或其中对产生的胰岛素不敏感(胰岛素耐受性)的疾病。空腹血糖通常低于126mg/dL,而前驱糖尿病例如是一种特征在于下面情况之一的情况:空腹葡萄糖受损(110-125mg/dL)和葡萄糖耐受性受损(空腹葡萄糖水平低于126mg/dL并且餐后葡萄糖水平位于140mg/dL至199mg/dL之间)。2型糖尿病可能伴有或不伴有高血压。糖尿病在例如非裔美国人(AfricanAmerican)、拉丁美洲/说西班牙语的美籍人(Latino/HispanicAmerican)、印第安人(NativeAmerican)、印第安人(NativeAmerican)、亚裔美国人(AsianAmerican)和太平洋岛民(PacificIslanders)中频发。胰岛素耐受性的标记物包括HbA1C、HOMAIR、测量胶原片段、尿中的TGF-β、PAI-1和肾素原。
除非在本文特别说明或者与上下文明显相悖,否则本文所述的所有方法都可以以任何适宜的次序进行。本文提供的任何和全部实施例或举例性的语言(例如“如”)仅仅是为了更好地对本发明进行说明,并不会对本发明的保护范围构成限制。
本发明的化合物以游离形式、其盐形式或其前体药物衍生物的形式被获得。
当在同一个分子中同时包含碱性基团和酸性基团时,本发明化合物也可以形成内盐,例如,两性离子分子。
本发明还提供了在体内转化成本发明化合物的本发明化合物的前体药物。前体药物是一种有活性或无活性的化合物,在该前体药物被施用于个体后,通过体内的生理学作用,例如水解、代谢等被化学修饰成本发明化合物。制备和使用前体药物时涉及的适应性和技术是本领域技术人员众所周知的。前体药物在概念上可被分成非排他性的两类:生物前体性前体药物和载体性前体药物。见药物化学实践(ThePracticeofMedicinalChemistry),第31-32章(Wermuth编辑,AcademicPress,SanDiego,Calif.,2001)。生物前体性前体药物通常是与相应的活性药物化合物相比无活性或具有低活性的化合物,其包含一个或多个保护基团并且通过代谢或水解被转化成活性形式的化合物。活性药物形式和所释放的任何代谢产物都具有可接受的低毒性。载体性前体药物是包含一种转运部分的药物化合物,例如改善吸收和/或定位传递于作用部位的药物化合物。对于该类载体性前体药物而言,位于药物部分和转运部分之间的键理想地是一种共价键,该前体药物是无活性的或者比所述药物化合物的活性低,并且所释放出来的任何转运部分都是可接受的无毒的。对于想要用转运部分来增强吸收的前体药物来说,转运部分通常应被迅速释放。在另一些情况中,希望利用一种提供缓慢释放的部分,例如某些聚合物或其它部分,如环糊精。例如,可以用载体性前体药物来改善一种或多种下面的性质:增加亲脂性、增加药理学作用的持续时间、增加部位特异性、降低毒性和不良反应、和/或在药物配制方面得到改善(例如,稳定性、水溶性、抑制不希望的感官性能或理化性能)。例如,可以通过(a)用亲脂性羧酸(例如具有至少一个亲脂性部分的羧酸)酯化羟基,或(b)用亲脂性醇(例如具有至少一个亲脂性部分的醇,例如脂族醇)酯化羧酸来增加亲脂性。
实例性的前体药物有例如,游离羧酸的酯类和硫醇的S-酰基衍生物以及醇类或酚类的O-酰基衍生物,其中酰基具有本文所定义的含义。优选的是可在生理性条件下通过溶剂分解被转化成母体羧酸的可药用的酯衍生物,例如,低级烷基酯、环烷基酯、低级链烯基酯、苄基、单-或二-取代的低级烷基酯,如ω-(氨基、单-或二-低级烷基氨基、羧基、低级烷氧基羰基)-低级烷基酯、α-(低级烷酰氧基、低级烷氧基羰基或二-低级烷基氨基羰基)-低级烷基酯,如现有技术中常用的新戊酰氧基甲基酯等。此外,胺类以芳基羰氧基甲基取代的衍生物的形式被掩蔽,其在体内被酯酶裂解释放出游离药物和甲醛(Bundgaard,J.Med.Chem.2503(1989))。此外,包含酸性NH基团,如咪唑、亚胺、吲哚等的药物用N-乙酰氧基甲基掩蔽(Bundgaard,DesignofProdrugs,Elsevier(1985))。羟基以酯和醚的形式被掩蔽。EP039,051(Sloan和Little)公开了曼尼西碱异羟肟酸前体药物、其制备以及应用。
此外,包括其盐在内的本发明的化合物也可以以其水合物的形式获得,或者包括它们结晶用的其它溶剂。
一般合成
本发明的化合物可以用下面的流程、实施例所述的方法和使用现有技术中公认的技术来合成。本文所述的所有化合物都以化合物的形式被包括在本发明中。本发明的化合物可以根据流程1-4中所述的方法的至少一种来合成。
在本文的范围内,除非在上下文中特别说明,否则仅将不是本发明化合物所需的特定终产物的组分的容易除去的基团称为“保护基团”。在例如标准参考著作,如J.F.W.McOmie,“有机化学中的保护基团(ProtectiveGroupsinOrganicChemistry)”,PlenumPress,伦敦和纽约,1973,T.W.Greene和P.G.M.Wuts,“有机合成中的保护基团(ProtectiveGroupsinOrganicSynthesis)”,第三版,Wiley,纽约,1999中描述了用该类保护基团对官能团进行的保护、保护基团本身以及其裂解反应。
具有至少一个成盐基团的本发明化合物的盐可以以本身已知的方式制备。例如,具有酸性基团的本发明化合物的盐例如可以通过用金属化合物如适宜有机羧酸的碱金属盐,例如2-乙基己酸的钠盐、用有机碱金属或碱土金属化合物如相应的氢氧化物、碳酸盐或碳酸氢盐如氢氧化钠或氢氧化钾、碳酸钠或碳酸钾、碳酸氢钠或碳酸氢钾、用相应的钙化合物或用氨或适宜的有机胺处理本发明化合物来形成,优选地使用化学计量数量或仅少量过量的成盐试剂。本发明化合物的酸加成盐是以常规方式获得的,例如通过用酸或适宜的阴离子交换试剂处理该化合物来获得。包含酸性和碱性成盐基团,例如游离羧基和游离氨基的本发明化合物的内盐例如可以通过将盐例如酸加成盐中和至等电点,例如用弱碱中和来形成,或者可以通过用离子交换剂处理来形成。
可以用常规方式将盐转化成游离化合物;例如,可以通过用适宜的酸处理来对金属盐和铵盐进行转化,酸加成盐例如可以通过用适宜的碱性剂处理来进行转化。
可以用本身已知的方式将可根据本发明获得的异构体混合物分离成各异构体;例如,可以通过在多相溶剂混合物之间进行分配、重结晶和/或色谱分离,例如用硅胶色谱进行分离或通过例如使用反向柱的高压液相色谱来对非对映异构体进行分离,和例如可以通过用光学纯的成盐试剂形成盐和对由此获得的非对映异构体混合物进行分离,例如通过分级结晶、使用旋光柱材料的色谱法进行分离来对外消旋体进行分离。
可以根据标准方法,例如用色谱法、分配法、(重)结晶等对中间体和终产物进行后处理和/或纯化。
下面的描述一般适用于本文上下文所述的所有过程。
上述所有步骤都可以在本身已知的反应条件(包括特定提及的那些条件)下进行,在不存在或通常在存在溶剂或稀释剂(包括例如对所用试剂而言为惰性并能溶解它们的溶剂或稀释剂)、在不存在或存在催化剂、缩合剂或中和剂,例如离子交换剂,如阳离子交换剂例如H+形式的阳离子交换剂的情况下进行,根据反应和/或反应物的性质,在降低、正常或升高的温度下,例如在约-100℃至约190℃,包括例如在大约-80℃至大约150℃,例如-80至-60℃、室温、-20至40℃下或在回流温度下、在大气压或密封容器中进行,在适宜的情况中,在减压下进行,和/或在惰性气氛下,例如在氩气或氮气气氛下进行。
在反应的所有阶段,都可以将所形成的异构体混合物分离成各异构体,例如非对映异构体或对映异构体,或者将其分离成任何所需的异构体混合物,例如外消旋体或非对映异构体混合物,例如与“另外的处理步骤”下所述的方法类似地来进行分离。
除非在方法的描述中特别标明,否则可选择的适用于任何特定反应的溶剂包括明确提及的那些溶剂,例如水;酯类,如低级烷基-低级链烷酸酯类,例如乙酸乙酯;醚类,如脂族醚类,例如乙醚;或环状醚类,例如四氢呋喃或二恶烷;液体芳族烃类,如苯或甲苯;醇类,如甲醇、乙醇或1-或2-丙醇;腈类,如乙腈;卤化烃类,如二氯甲烷或氯仿;酰胺类,如二甲基甲酰胺或二甲基乙酰胺;碱类,如杂环氮碱,例如吡啶或N-甲基吡咯烷-2-酮;羧酸酐,如低级链烷酸酐,例如乙酸酐;环状、直链或支链烃类,如环己烷、己烷或异戊烷、甲基环己烷,或这些溶剂的混合物,例如水溶液。该类溶剂混合物也可用于后处理,例如通过色谱法或分配进行的后处理中。
包括其盐在内的所述化合物也可以以水合物的形式获得,或者它们的结晶可包括结晶用的溶剂。可存在不同的结晶形式。
本发明还涉及其中用在该方法的任何阶段可获得的中间体化合物作为起始材料和进行其余加工步骤的那些处理形式,或者其中在反应条件下形成起始材料或起始材料以衍生物形式例如以被保护形式或盐形式进行应用或者在加工条件下制备可用本发明方法获得的化合物并在原位对其进一步进行处理的那些处理形式。
合成本发明化合物所用的所有起始材料、构造块、试剂、酸、碱、脱水剂、溶剂和催化剂都可以商业获得或者可以用本领域普通技术人员已知的有机合成方法来制备(Houben-Weyl,第4版,1952,有机合成方法(MethodsofOrganicSynthesis),Thieme,第21卷)。
本发明式I’和I至VIIC中任意一项的化合物可以用下面部分中所述的操作来制备。
缩写:
本发明式II的化合物可以通过其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义;P1和P2是非限制性地选自甲基、乙基、异丙基、叔丁基、甲氧基苄基或苄基的适宜保护基团的中间体A至C的水解来进行制备。
本发明式III的化合物可以通过其中X、X1、A1、R1、R2和n具有上面式I或I’中的定义;P1和P2可以是非限制性地选自甲基、乙基、异丙基、叔丁基、甲氧基苄基或苄基的适宜保护基团的中间体D、E或F的水解来进行制备。
本发明式VII的化合物可以通过其中A2、R1、R2、R4和n具有上面式I或I’中的定义;P1可以是非限制性地选自甲基、乙基、异丙基、叔丁基、甲氧基苄基或苄基的适宜保护基团的中间体G的水解来进行制备。
可以用非限制性地选自NaOH、KOH或LiOH的碱或非限制性地选自TFA或HCl的酸通过用标准方法来水解中间体A至G。当P1或P2是苄基或甲氧基苄基时,优选的去保护方法是在氢气下、在存在催化剂例如但不限于钯碳的情况下进行氢化。
中间体A、B、C或G可以用下面的方法来制备,该方法包括:使其中X、P1、R1、R2和n如之前所述的中间体H或I:
与其中X1、A1、A2、R4和P2如之前所述的中间体J、K或L缩合。
可应用的已知缩合方法非限制性地包括用试剂如亚硫酰氯或草酰氯将中间体J、K或L转化成其相应的酰卤,或者用试剂如ClC(O)O-异丁基或2,4,6-三氯苯甲酰氯将中间体J、K或L转化成混合酸酐,然后使该酰卤或混合酸酐与中间体H或I在存在或不存在碱如叔胺(例如三乙胺、DIPEA或N-甲基吗啉)或吡啶衍生物(例如吡啶、4-(二甲基氨基)吡啶或4-吡咯烷-1-基吡啶)的情况下反应。或者,可以用偶合剂如DCC、EDCI、PyBOP或BOP在存在或不存在试剂如1-羟基苯并三唑、1-羟基-7-氮杂苯并三唑或五氟苯酚的情况下使中间体J、K或L与H或I偶合。
其中R4是四唑的中间体G可以根据流程1来合成:
其中A2、R1、R2、R4、P1、P2和n如之前所定义。
在步骤1a中,使用非限制性地选自DCC、EDCI、PyBOP或BOP的标准偶合剂,在存在或不存在试剂如1-羟基苯并三唑、1-羟基-7-氮杂苯并三唑或五氟苯酚的情况下,使中间体I与适宜的羧酸反应;然后在步骤1c中用非限制性地选自NaOH、KOH或LiOH的碱或者非限制性地选自TFA或HCl的酸,或者在氢气下用催化剂例如但不限于钯碳进行氢化除去P2保护基团。或者,使中间体I在存在非限制性地选自吡啶、三乙胺或二异丙基乙基胺的碱的情况下与适宜的酸酐反应(步骤1b);然后用与JournalofMedicinalChemistry1998,41,1513所述方法类似的方法将该羧酸转化成四唑(步骤1b)。
中间体D、E或F可以用下面的方法来进行制备,该方法包括:使其中X、P1、R1、R2和n如上面所定义的中间体M;
与其中X1、A1和P2具有上面所定义的含义的中间体Q或S缩合。
可以应用已知的缩合方法,包括但不限于用试剂如亚硫酰氯或草酰氯将中间体M或N转化成酰卤,或者用试剂如ClC(O)O-异丁基或2,4,6-三氯苯甲酰氯将中间体M或N转换成混合酸酐,然后使该酰氯或混合酸酐与中间体Q或S在不存在或存在碱如叔胺(例如三乙胺、DIPEA或N-甲基吗啉)或吡啶衍生物(例如吡啶、4-(二甲基氨基)吡啶或4-吡咯烷-1-基吡啶)的情况下反应;或者,可以用试剂如DCC、EDCI、PyBOP或BOP在存在或不存在试剂如1-羟基苯并三唑、1-羟基-7-氮杂苯并三唑或五氟苯酚的情况下使中间体M或N与中间体Q或S偶合。
中间体M或N可以根据下面流程2中描述的一般合成操作来进行制备:
其中R1、R2、X和n如上面所定义并且其中m=0或1;P1是非限制性地选自氢、甲基、乙基、丙基、叔丁基、甲氧基甲基、叔丁基二甲基硅烷基、四氢呋喃基、苄基、烯丙基或苯基的保护基团;R5是例如氢、甲基、乙基、异丙基、苄基或苯基;R6和R7独立地是氢、甲基、乙基、异丙基、苄基或苯基。Y非限制性地选自氯、溴、碘、苯并三唑氧基、吡啶N,N-二甲基氨基吡啶五氟苯氧基、苯氧基、4-氯苯氧基、-OCO2Me、-OCO2Et、叔丁氧基羰基或-OCC(O)O-异丁基。
在步骤(2a)中,可以用标准方法如使用亚硫酰氯、草酰氯来制备相应的酰卤;或者可以用标准方法来制备混合酸酐或者可以应用酰基吡啶阳离子,如在不存在或存在吡啶衍生物(例如吡啶、4-(二甲基氨基)吡啶、4-吡咯烷-1-基吡啶)的情况下与叔胺(例如三乙胺、DIPEA、N-甲基吗啉)一起使用新戊酰氯、在不存在或存在吡啶衍生物(例如吡啶、4-(二甲基氨基)吡啶、4-吡咯烷-1-基吡啶)的情况下与叔胺(例如三乙胺、DIPEA、N-甲基吗啉)一起使用2,4,6-三氯苯甲酰氯、或者在不存在或存在吡啶衍生物(例如吡啶、4-(二甲基氨基)吡啶、4-吡咯烷-1-基吡啶)的情况下与叔胺(例如三乙胺、DIPEA、N-甲基吗啉)一起使用ClC(O)O-i-Bu;或者可以应用用于制备活性酯的标准方法,如在存在偶合剂(例如DCC、EDCI)或BOP的情况下使用1-羟基苯并三唑、1-羟基-7-氮杂苯并三唑或五氟苯酚。
在步骤(2b)中,可以使用用于制备N-酰基唑烷酮(m=0)的标准方法。在AldrichchimicaActa1997,第30卷,第3–12页和其中的参考资料中概述了这种化学过程的说明性实例;或者可以使用用于制备N-酰基嗪烷酮(m=1)的标准方法。在OrganicandBiomolecularChemistry2006,第4卷,第14期,第2753–2768页中概述了这种化学过程的说明性实例。
在步骤(2c)中,可以使用烷基化的标准方法。在ChemicalReviews1996,96(2),835-876和其中的参考资料中对其说明性实例进行了概述。
在步骤(2d)中,可以使用用于裂解N-酰基唑烷酮或N-酰基嗪烷酮的标准方法,在AldrichchimicaActa1997,第30卷,第3–12页和其中的参考资料中概述了这种化学过程的说明性实例。
中间体H或I可以根据流程3和4中描述的一般操作来进行制备:
其中R1、R2、X和n如上面所定义且其中P3是非限制性地选自叔丁基、苄基、三苯基氧膦基、叔丁氧基羰基、苄氧基羰基、烯丙氧基羰基、乙酰基或三氟乙酰基的保护基团。
在步骤(3a)中,可以使用用于引入胺部分的标准方法,如使用:通过用亚硫酰氯(或ClCO2R8)、NaN3(或TMSN3)和R9OH(其中R8和R9是氢、甲基、乙基、叔丁基、烯丙基、苄基或4-甲氧基苄基)形成相应的酰基叠氮化物来同时或分步处理;或者通过用DPPA和R9OH(其中R9如上面所定义)形成相应的酰基叠氮化物来同时或分步处理;或者使用转化成相应羧酰胺的标准方法,然后用NH3等价物处理和用LTA或高价碘试剂(例如PIDA、PIFA、PhI(OH)OTs、PhIO)和R9OH(其中R9如上面所定义)同时或分步处理;或者使用转化成相应羧酰胺的标准方法和用Br2和MOH(其中M如本文所定义,例如Na、K、Ba或Ca)同时或分步处理;或者使用转化成相应羧酰胺的标准方法和用MOZ或NaBrO2(其中Z如本文所定义,例如Cl或Br)进行处理;或者使用转化成相应羧酰胺的标准方法和用Pb(OAc)4和R9OH(其中R9如上面所定义)进行处理;或者使用转化成相应异羟肟酸的标准方法,然后用H2NOH或H2NOTMS进行处理和用Ac2O、Boc2O、R10COCl、R10SO2Cl、R10PO2Cl(其中R10如本文所定义,例如Me、Et、tBu或苯基)、亚硫酰氯、EDCI、DCC或1-氯-2,4-二硝基苯在不存在或存在碱(例如吡啶、Na2CO3aq、三乙胺、DIPEA)的情况下进行处理和用R9OH在存在碱(例如DBU、ZOH、DIPEA)(其中R9和Z如上面所定义)的情况下进行处理。
在步骤(3b)中,可以应用除去P3保护基团的标准方法,如使用NaOH、KOH或LiOH的碱水解、使用TFA或HCl的酸水解,或者在氢气下使用钯碳进行氢化。
流程4描述了中间体H或I的另一种合成方法:
其中LG是非限制性地选自Cl、Br、I、OMs、OTs或OTf的离去基团。
在步骤(4a)中,可以使用用于Arndt-Eistert同系化的标准方法。在“β-氨基酸的对映选择合成(Enantioselectivesynthesisofβ-aminoacids),第2版”,JohnWiley和Sons,Inc.,NJ(2005)中直接或类似地概述了这一化学过程的说明性实例。
在步骤(4b)中,可以使用用于烷基化的标准方法,如在存在碱如LDA、NHMDS、LHMDS或KHMDS的情况下使用R1LG。
在步骤(4c)中,可以使用用于对羧酸进行保护的标准方法,如使用TMSCHN2(对于甲酯而言)、P1LG/碱(例如K2CO3、NaHCO3、Cs2CO3或K3PO4)、亚硫酰氯(或草酰氯)/R9OH、DCC(或EDCI)/DMAP/R9OH、BOP/R9OK(或R9ONa)、(R9O)2CHNMe2、CDI/DBU/R9OH(其中R9具有如上面所定义的含义)或异丁烯/H2SO4(对于叔丁基酯而言)。
在步骤(4d)中,可以使用用于Suzuki偶合反应的标准方法,如使用钯(或镍)类物质[例如Pd(PPh3)4、PdCl2(dppf)、Pd(OAc)2/膦(例如PPh3、dppf、PCy3、P(tBu)3、XPhos)、Pd/C、Pd2(dba)3/膦(例如PPh3、dppf、PCy3、P(tBu)3、XPhos)、Ni(COD)2/膦(或dppe、dppb、PCy3)、Ni(dppf)Cl2]、碱(例如KF、CsF、K3PO4、Na2CO3、K2CO3、Cs2CO3、NaOH、KOH、NaO-t-Bu、KO-t-Bu)和(R2)n-PhB(OH)2[或(R2)n-PhBF3K]。
在步骤(4e)中,可以使用用于除去P3保护基团的标准方法,如使用NaOH、KOH或LiOH的碱水解、使用TFA或HCl的酸水解,或者在氢气下用钯碳进行氢化。
或者,中间体H或I可以直接或类似地按照TetrahedronLetters,2008,第49卷,第33期,第4977-4980页中概括的合成路线和用OrganicLetters,2002,第4卷,第22期,第3803–3805页中概括的方法将所得的硼酸转化成取代的联苯来进行制备。
或者,中间体H或I可以直接或类似地按照Tetrahedron:Asymmetry,2006,第17卷,第2期,第205-209页中概括的合成路线来进行制备。
或者,中间体H或I可以通过Mannich反应法来进行制备。在“β-氨基酸的对映选择合成(Enantioselectivesynthesisofβ-aminoacids),第2版”,JohnWiley和Sons,Inc.,NJ(2005)中直接或类似地概述了这一化学过程的说明性实例。
或者,中间体H或I可以通过烯醇化物加成来制备。在“β-氨基酸的对映选择合成(Enantioselectivesynthesisofβ-aminoacids),第2版”,JohnWiley和Sons,Inc.,NJ(2005)中直接或类似地概述了这一化学过程的说明性实例。
或者,中间体H或I可以通过氮杂-Michael反应法来制备。在“β-氨基酸的对映选择合成(Enantioselectivesynthesisofβ-aminoacids),第2版”,JohnWiley和Sons,Inc.,NJ(2005)中直接或类似地概述了这一化学过程的说明性实例。
或者,中间体H或I可以直接或类似地按照Synlett,2006,第4期,第539-542页中概括的合成路线来进行制备。
在于2010年4月16日申请的申请人案卷号为PAT053600-US-USP3的US专利申请中也描述了中间体J、K和L的合成,该申请被引入本文作为参考。
本发明进一步包括其中用在任何阶段获得的中间体产物作为起始材料并进行剩余步骤、或者其中在反应条件下在原位形成起始材料、或者反应组分以其盐或光学纯的对映体形式进行应用的本发明方法的任何变型。
也可以根据本身通常已知的方法将本发明的化合物和中间体彼此转化。
在另一方面,本发明提供了一种包含本发明化合物或其可药用盐和一种或多种可药用载体的药物组合物。该药物组合物可被配制为用于特定施用途径如口服施用、胃肠外施用和直肠施用等。此外,本发明的药物组合物还可以被制备为固体形式(包括胶囊、片剂、丸剂、颗粒、粉剂或栓剂)或液体形式(包括溶液、混悬液或乳剂)。该药物组合物可以被进行常规药用操作如灭菌和/或可以包含常规惰性稀释剂、润滑剂或缓冲剂以及助剂,如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
该药物组合物典型地是片剂和明胶胶囊,其包含活性成分和
a)稀释剂,例如,乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如,硅石、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇;对于片剂而言,还有
c)粘合剂,例如,硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要的话,还包含
d)崩解剂,例如,淀粉类、琼脂、藻酸或其钠盐、或泡腾混合物;和/或
e)吸收剂、着色剂、矫味剂和甜味剂。
可以根据现有技术已知的方法对片剂包膜衣或肠衣。
口服施用的适宜组合物包括片剂、糖锭剂、水性或油性混悬液、可分散的粉剂或颗粒、乳剂、硬或软胶囊或糖浆或酏剂形式的有效量的本发明化合物。用于口服施用的组合物是根据药物组合物制备领域任何已知的方法来进行制备的,并且该类组合物可包含一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的物质以提供美观和适口的药物制剂。片剂包含与适于制备片剂的无毒可药用赋形剂混合的活性成分。这些赋形剂有例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂和崩解剂,例如,玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂未被包衣或用用于延迟其在胃肠道中的崩解和吸收的已知技术进行了包衣,从而提供长久的持续作用。例如,可以使用延时材料如甘油单硬脂酸酯或甘油二硬脂酸酯。用于口服应用的制剂可以以其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊形式或其中活性成分与水或油性介质例如花生油、液体石蜡或橄榄油混合的软明胶胶囊形式呈现。
一些可注射的组合物是等渗的水性溶液或混悬液,栓剂有利地是由脂肪乳或混悬液制备的。所述组合物可以被灭菌和/或包含助剂,如防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、用于调节渗透压的盐和/或缓冲剂。此外,它们还可包含其它有治疗价值的物质。所述组合物是根据常规混合、制粒或包衣方法来制备的,并且包含约0.1-75%或约1-50%的活性成分。
用于经皮应用的适宜组合物包括有效量的本发明化合物和载体。载体包括用于帮助通过主体皮肤的药理学可接受的可吸收溶剂。例如,经皮装置为包含背衬成员、包含所述化合物和任选的载体的储库、任选的用于以受控和预定的速率在长期内向主体皮肤传递化合物的控速屏障、和将该装置固定在皮肤上的工具。
用于局部应用例如应用于皮肤和眼睛的适宜组合物包括水溶液、混悬液、软膏、霜剂、凝胶或可喷雾制剂,例如,用于通过气雾剂等传递。该类局部传递系统特别适于皮肤应用。因此,它们特别适用于局部应用,包括现有技术中众所周知的化妆品制剂。该类制剂可包含增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。
如本文所用的那样,局部应用还涉及吸入剂或鼻内应用。它们方便地以干粉形式(单独地、以混合物的形式例如与乳糖的干混合物、或以混合组分颗粒例如与磷脂的混合组分颗粒形式)由干粉吸入器进行传递或在使用或不使用适宜抛射剂的情况下由加压的容器、泵、喷雾器、雾化器或喷洒器以喷雾剂形式呈递。
因为水可能会促进活性化合物分解,因此,本发明进一步提供了包含本发明化合物作为活性成分的无水药物组合物和剂型。
本发明的无水药物组合物和剂型可以用无水或低含水量的成分和低水分或低湿度条件来制备。可以制备无水药物组合物并以维持其无水状态的方式对其进行储存。因此,优选用已知可阻止与水分接触的材料对无水组合物进行包装,从而使得它们被包括在适宜的制剂药盒中。适宜包装的实例非限制性地包括密封的箔、塑料制品、单位剂量容器(例如,小瓶)、凸泡包装和条状包装(strippacks)。
本发明进一步提供了包含一种或多种降低作为活性成分的本发明化合物的降解速率的物质的药物组合物和剂型。在本文被称为“稳定剂”的该类物质非限制性地包括抗氧剂如抗坏血酸、pH缓冲剂或盐缓冲剂等。
游离或可药用盐形式的式I’和I至VIIC中任意一项的化合物表现出有价值的药理学性质,例如中性肽链内切酶EC3.4.24.11调节性质,例如如下一部分中提供的体外和体内试验中所表明的性质,因此,表明它们可用于治疗。
本发明的化合物或其可药用的盐可用于治疗选自下列的适应症:心血管病症,如高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、周期性水肿、梅尼埃病、高醛固酮血症(原发性和继发性)和高钙尿症、腹水、青光眼、月经失调、早产、先兆子痫、子宫内膜异位和生殖病症(尤其是男性和女性不育、多囊卵巢综合征、植入物衰竭)、哮喘、阻塞性睡眠呼吸暂停、炎症、白血病、疼痛、癫痫症、情感障碍如抑郁和精神病情况如痴呆和老年意识错乱、肥胖和胃肠道病症(尤其是腹泻和肠易激综合征)、伤口愈合(尤其是糖尿病和静脉溃疡以及压疮)、脓毒性休克、胃酸分泌的调节、高肾素血症的治疗、囊性纤维化、再狭窄、2型糖尿病、糖尿病并发症和动脉粥样硬化、雄性和雌性性功能障碍。
因此,作为另一个实施方案,本发明提供了式I’和I至VIIC中任意一项的化合物或其可药用的盐的用途。在另一个实施方案中,所述治疗选自可以通过抑制中性肽链内切酶EC3.4.24.11来改善的疾病。在另一个实施方案中,所述疾病选自上述列表,适宜地选自高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、2型糖尿病和糖尿病并发症,并且最适宜地是心血管病症,如高血压、包括水肿在内的肾功能不全和充血性心力衰竭。
在另一个实施方案中,本发明提供了一种治疗可以通过抑制中性肽链内切酶EC3.4.24.11来改善的疾病的方法,其包括施用治疗有效量的式I’、I、IA、II、IIA、III、IIIA、IV、IVA、V、VA、VI、VIA和VII至VIIC中任意一项的化合物或其可药用的盐。在另一个实施方案中,该疾病选自上述列表,适宜地是高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、2型糖尿病和糖尿病并发症,并且最适宜地是心血管病症、如高血压、包括水肿在内的肾功能不全和充血性心力衰竭。
对于约50-70kg的个体而言,本发明的药物组合物或组合可以为约1-1000mg活性成分的单位剂量,或者为约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg活性成分。化合物、其药物组合物或组合的治疗有效量取决于个体的种属、体重、年龄和个体情况、所治疗的病症或疾病或其严重程度。普通的医师、临床医师或兽医可容易地确定预防、治疗或抑制病症或疾病进程所需的各活性成分的有效量。
可在使用哺乳动物,例如小鼠、大鼠、狗、猴或离体器官、组织或其制剂进行的体外和体内试验中证明上面所列举的剂量性质。本发明的化合物可以以溶液,例如优选水溶液的形式进行体外应用和以肠、胃肠外形式(有利地为静脉内形式),例如,以混悬液或水溶液的形式进行体内应用。体外剂量可以为约10-3摩尔至10-9摩尔浓度。根据施用途径,体内治疗有效量范围可以为约0.1-500mg/kg,或约1-100mg/kg。
可以用下面的体外和体内方法和/或现有技术中进行了充分描述的下面的体外和体内方法来对本发明化合物的活性进行评估。见“一种用于对人血管舒缓素7的蛋白酶抑制剂描述的以荧光寿命为基础的测定(Afluorescencelifetime-basedassayforproteaseinhibitorprofilingonhumankallikrein7)”DoeringK,MederG,HinnenbergerM,WoelckeJ,MayrLM,HassiepenUBiomolScreen.2009年1月;14(1):1-9。
特别是可以如下那样来测定重组的人中性肽链内切酶(NEP,EC3.4.24.11)的体外抑制:
将重组的人中性肽链内切酶(在昆虫细胞中表达并用标准方法纯化,终浓度为7pM)用各种浓度的试验化合物在包含150mMNaCl和0.05%(w/v)CHAPS的10mM磷酸钠缓冲液(pH7.4)中在室温下预培养1小时。通过加入合成的肽底物Cys(PT14)-Arg-Arg-Leu-Trp-OH至0.7μM的终浓度来开始该酶反应。底物水解导致用FLT读数器测量(如Doering等(2009)所述)的PT14的荧光寿命(FLT)增加。在室温下培养1小时(t=60min)后,测定化合物对酶活性的作用。用非线性回归分析软件,由抑制百分比—抑制剂浓度图计算IC50值,该值相当于使不存在抑制剂情况下测得的FLT值降低50%的抑制剂浓度。
使用该试验测定法(如上所述),根据下面提供的表1,本发明化合物表现出抑制功效。
表1化合物的抑制活性
实施例# | 人NEP IC50(nM) |
实施例3-25 | 18 |
实施例3-26 | 15 |
实施例3-27 | 15 |
实施例5-1 | 38 |
实施例5-4 | 7 |
实施例5-7 | 4 |
实施例5-11 | 3 |
实施例5-12 | 67 |
实施例5-36 | 42 |
实施例5-37 | 2.3 |
实施例5-39 | 0.7 |
实施例5-46 | 0.5 |
实施例5-47 | 2.7 |
实施例5-55 | 0.7 |
实施例6-1 | 75 |
实施例9-1 | 56 |
实施例11-1 | 1.1 |
实施例11-11 | 0.5 |
实施例11-14 | 0.07 |
实施例12-1 | 0.2 |
实施例14-1 | 0.8 |
实施例15-1 | 1.2 |
本发明的化合物可以与至少一种其它治疗剂同时施用或前后施用。本发明的化合物可以通过相同或不同的施用途径独立施用,或者可以在相同的药物组合物中一起施用。
在一个实施方案中,本发明提供了一种作为用于在治疗中同时、独立或顺序应用的联合制剂形式的产品,其包含式I’和I至VIIC中任意一项的化合物或其可药用的盐和至少一种其它治疗剂。在一个实施方案中,所述治疗是治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况。以联合制剂形式提供的产品包括在同一种药物组合物中包含式I’和I至VIIC的化合物以及其它治疗剂的组合物,或式I’和I至VIIC中任意一项的化合物或其可药用的盐和其它治疗剂为独立形式,例如药盒形式的组合物。
在一个实施方案中,本发明提供了一种包含式I’和I至VIIC中任意一项的化合物或其可药用的盐和另一种(些)治疗活性剂的药物组合物。该药物组合物可任选地包含如上所述的可药用的赋形剂。
在一个实施方案中,本发明提供了一种包含两种或多种独立的药物组合物的药盒,所述组合物中的至少一种包含式I’和I至VIIC中任意一项的化合物或其可药用的盐。在一个实施方案中,该药盒包含用于单独保留所述组合物的工具,如容器、分开的瓶子或分开的箔袋。该类药盒的一个实例是通常用于包装片剂、胶囊等的凸泡包装。
本发明的药盒可用于施用不同的剂型,例如口服和胃肠外剂型,用于以不同的剂量间隔施用独立的组合物,或用于相互滴定独立的组合物。为了有助于顺从性,本发明的药盒通常包含施用指导。
在本发明的组合治疗中,本发明的化合物或其可药用的盐和其它治疗剂可由相同或不同的制造商制造和/或配制。此外,本发明的化合物或其可药用的盐和其它治疗剂可:(i)在该组合产品被发放给医师之前(例如在药盒包含本发明化合物和其它治疗剂的情况中);(ii)在临施用前由医师自己(或在医师的指导下);(iii)由患者自身(例如在本发明化合物和其它治疗剂顺序施用期间)集合到一种联合治疗中。
因此,本发明提供了式I’和I至VIIC中任意一项的化合物或其可药用的盐在制备治疗与中性肽链内切酶EC3.4.24.11.活性有关的疾病或情况的药物中的用途,其中药物被制备成用于与其它治疗剂一起施用。本发明还提供了其它治疗剂在制备治疗与中性肽链内切酶EC3.4.24.11.活性有关的疾病或情况的药物中的用途,其中药物被制备成用于与式I’和I至VIIC中任意一项的化合物或其可药用的盐一起施用。
本发明还提供了用于治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的方法中的式I’和I至VIIC中任意一项的化合物或其可药用的盐,其中式I’和I至VIIC中任意一项的化合物或其可药用的盐被制备成用于与其它治疗剂一起施用。本发明还提供了用于治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的方法中的其它治疗剂,其中该其它治疗剂被制备为用于与式I’和I至VIIC中任意一项的化合物或其可药用的盐一起施用。本发明还提供了用于治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的方法中的式I’和I至VIIC中任意一项的化合物或其可药用的盐,其中式I’和I至VIIC中任意一项的化合物或其可药用的盐与其它治疗剂一起施用。本发明还提供了用于治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的方法中的其它治疗剂,其中其它治疗剂与式I’和I至VIIC中任意一项的化合物或其可药用的盐一起施用。
本发明还提供了式I’和I至VIIC中任意一项的化合物或其可药用的盐在制备治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的药物中的用途,其中患者之前(例如在24小时内)已经用其它治疗剂进行了治疗。本发明还提供了其它治疗剂在制备治疗与中性肽链内切酶EC3.4.24.11活性有关的疾病或情况的药物中的用途,其中患者之前(例如在24小时内)已经用式I’和I至VIIC中任意一项的化合物或其可药用的盐进行了治疗。
在一个实施方案中,该其它治疗剂选自:HMG-Co-A还原酶抑制剂、血管紧张素受体阻滞剂(ARB,血管紧张素II受体拮抗剂)、血管紧张素转化酶(ACE)抑制剂、钙通道阻滞剂(CCB)、内皮素拮抗剂、肾素抑制剂、利尿剂、ApoA-I拟似物、抗糖尿病药、减肥药、醛固酮受体阻滞剂、内皮素受体阻滞剂、醛固酮合酶抑制剂(ASI)、CETP抑制剂或5型磷酸二酯酶(PDE5)抑制剂。
术语与第二种活性剂或治疗“联合”包括将本发明化合物(例如,式I’或I-VIIC的化合物或者本文所述的其它化合物)与第二种活性剂或治疗共同施用;首先施用本发明化合物,然后施用第二种活性剂或治疗;以及首先施用第二种活性剂或治疗,然后施用本发明化合物。
术语“第二种活性剂”包括现有技术中已知可治疗、预防或减轻本文所述疾病或病症的症状的任何活性剂,所述疾病或病症是例如对中性肽链内切酶的抑制有响应的病症或疾病,例如高血压、肺动脉高压、单纯收缩期高血压、顽固性高血压、外周血管疾病、心力衰竭、充血性心力衰竭、左心室肥大、心绞痛、肾功能不全(糖尿病或非糖尿病性)、肾衰竭(包括水肿和盐潴留)、糖尿病性肾病、非糖尿病性肾病、肾病综合征、肾小球肾炎、硬皮病、肾小球硬化、原发性肾病的蛋白尿、肾血管性高血压、糖尿病性视网膜病和晚期肾病(ESRD)、内皮机能障碍、舒张期功能障碍、肥厚型心肌病、糖尿病性心肌病、室上和室性心律失常、心房颤动(AF)、心脏纤维化、心房扑动、有害的血管重构、斑块稳定、心肌梗死(MI)、肾纤维化、多囊性肾病(PKD)、肺动脉高血压、肾衰竭(包括水肿和盐潴留)、周期性水肿、梅尼埃病、高醛固酮血症(原发性和继发性)和高钙尿症、腹水、青光眼、月经失调、早产、先兆子痫、子宫内膜异位、生殖病症(尤其是男性和女性不育、多囊卵巢综合征、植入物衰竭)、哮喘、阻塞性睡眠呼吸暂停、炎症、白血病、疼痛、癫痫症、情感障碍如抑郁和精神病情况如痴呆和老年意识错乱、肥胖和胃肠道病症(尤其是腹泻和肠易激综合征)、伤口愈合(尤其是糖尿病和静脉溃疡以及压疮)、脓毒性休克、胃酸分泌功能障碍、高肾素血症、囊性纤维化、再狭窄、2型糖尿病、代谢综合征、糖尿病并发症和动脉粥样硬化、雄性和雌性性功能障碍。
第二种活性剂的实例包括HMG-Co-A还原酶抑制剂、血管紧张素II受体拮抗剂、血管紧张素转化酶(ACE)抑制剂、钙通道阻滞剂(CCB)、内皮素拮抗剂、肾素抑制剂、利尿剂、ApoA-I拟似物、抗糖尿病药、减肥药、醛固酮受体阻滞剂、内皮素受体阻滞剂、醛固酮合酶抑制剂(ASI)和CETP抑制剂。
术语“HMG-Co-A还原酶抑制剂”(也被称为β-羟基-β-甲基戊二酰基-辅酶-A还原酶抑制剂)包括可用于降低包括胆固醇在内的血液脂质水平的活性剂。其实例包括阿伐他汀、西立伐他汀、康帕丁、达伐他汀、二氢康帕丁、Fluindostatin、氟伐他汀、洛伐他汀、匹伐他汀、美伐他汀、普伐他汀、Rivastatin、辛伐他汀和Velostatin,或其可药用的盐。
术语“ACE-抑制剂”(也被称为血管紧张素转化酶抑制剂)包括阻止血管紧张素I酶降解成血管紧张素II的分子。可以用该类化合物来调节血压和治疗充血性心力衰竭。其实例包括阿拉普利、贝那普利、贝那普利拉、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、Enaprilat、福辛普利、咪达普利、赖诺普利、Moveltopril、培哚普利、喹那普利、雷米普利、螺普利、替莫普利和群多普利,或其可药用的盐。
术语“内皮素拮抗剂”包括波生坦(参见EP526708A)、替唑生坦(参见WO96/19459),或其可药用的盐。
术语“肾素抑制剂”包括地特吉仑(化学名:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-二甲基乙氧基)羰基]-L-丙基-L-苯基丙氨酰基-N-[2-羟基-5-甲基-1-(2-甲基丙基)-4-[[[2-甲基-1-[[(2-吡啶基甲基)氨基]羰基]丁基]氨基]羰基]己基]-N-α-甲基-L-组氨酰胺);特拉吉仑(化学名:[R-(R*,S*)]-N-(4-吗啉基羰基)-L-苯基丙氨酰基-N-[1-(环己基甲基)-2-羟基-3-(1-甲基乙氧基)-3-氧代丙基]-S-甲基-L-半胱氨酰胺);阿利吉仑(化学名:(2S,4S,5S,7S)-5-氨基-N-(2-氨基甲酰基-2,2-二甲基乙基)-4-羟基-7-{[4-甲氧基-3-(3-甲氧基丙氧基)苯基]甲基}-8-甲基-2-(丙烷-2-基)壬酰胺)和占吉仑(化学名:[1S-[1R*[R*(R*)],2S*,3R*]]-N-[1-(环己基甲基)-2,3-二羟基-5-甲基己基]-α-[[2-[[(4-甲基-1-哌嗪基)磺酰基]甲基]-1-氧代-3-苯基丙基]-氨基]-4-噻唑丙酰胺)或其盐酸盐,或如Speedel研制的SPP630、SPP635和SPP800、或式(A)和(B)的RO66-1132和RO66-1168:
或其可药用的盐。
如果没有特定指出,则术语“阿利吉仑”被理解为是指游离碱形式以及其盐形式,尤其是其可药用的盐,最优选其半富马酸盐。
血管紧张素II受体拮抗剂或其可药用的盐被理解为是一种与血管紧张素II受体的AT1-受体亚型结合但是不导致该受体活化的活性成分。由于抑制AT1受体,这些拮抗剂例如可用作抗高血压药或用于治疗充血性心力衰竭。
AT1受体拮抗剂类包括具有不同结构特征的化合物,尤其优选的是非肽类。例如,可提及的有选自缬沙坦、氯沙坦、坎地沙坦、依普沙坦、伊贝沙坦、沙普立沙坦、他索沙坦、替米沙坦、具有下式的被命名为E-1477的化合物
具有下式的被命名为SC-52458的化合物
和具有下式的被命名为ZD-8731的化合物
或这些化合物各自可药用的盐的化合物。
优选的AT1-受体拮抗剂是已经被市售的那些活性剂,最优选缬沙坦或其可药用的盐。
术语“钙通道阻滞剂(CCB)”包括二氢吡啶类(DHP)和非-DHP类(例如,地尔硫卓型和维拉帕米型CCB)。其实例包括氨氯地平、非洛地平、ryosidine、依拉地平、拉西地平、尼卡地平、硝苯地平、尼古地平、尼鲁地平、尼莫地平、尼索地平、尼群地平和尼伐地平,并且优选地是选自氟桂利嗪、普尼拉明、地尔硫卓、芬地林、加洛帕米、咪拉地尔、阿尼帕米、噻帕米和维拉帕米、或其可药用的盐的非DHP代表。CCB可用作抗高血压药、抗心绞痛药或抗心律失常药。
术语“利尿剂”包括噻嗪衍生物(例如,氯噻嗪、氢氯噻嗪、甲氯噻嗪和氯噻酮)。
术语“ApoA-I拟似物”包括D4F肽类(例如,式D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F)
术语“抗糖尿病药”包括促进胰腺β-细胞分泌胰岛素的胰岛素分泌增强剂。其实例包括双胍衍生物(例如,甲福明)、磺酰脲类(SU)(例如,甲苯磺丁脲、氯磺丙脲、妥拉磺脲、醋磺己脲、4-氯-N-[(1-吡咯烷基氨基)羰基]-苯磺酰胺(Glycopyramide)、优降糖(格列苯脲)、格列齐特、间氨磺丁脲、磺胺丁脲、格列波脲(glibonuride)、格列吡嗪、格列喹酮、格列派特(glisoxepid)、格列噻唑、Glibuzole、格列己脲、格列嘧啶、格列平脲、苯磺丁脲和Tolylcyclamide)或其可药用的盐。另一些实例包括苯丙氨酸衍生物(例如,下式的那格列奈[N-(反式-4-异丙基环己基羰基)-D-苯丙氨酸](参见EP196222和EP526171)
瑞格列奈[(S)-2-乙氧基-4-{2-[[3-甲基-1-[2-(1-哌啶基)苯基]丁基]氨基]-2-氧代乙基}苯甲酸](参见EP589874、EP147850A2,特别是第61页的实施例11、和EP207331A1);(2S)-2-苄基-3-(顺式-六氢-2-异二氢吲哚基羰基)-丙酸钙二水合物(例如,米格列奈(参见EP507534));和格列美脲(参见EP31058)。另一些实例包括DPP-IV抑制剂、GLP-1和GLP-1激动剂。
DPP-IV负责灭活GLP-1。更具体地讲,DPP-IV产生一种GLP-1受体拮抗剂,从而缩短对GLP-1的生理学响应。GLP-1是胰腺胰岛素分泌的主要刺激物并且对葡萄糖处置具有直接益处。
该DPP-IV抑制剂可以是肽类或优选地是非肽类的。DPP-IV抑制剂在例如WO98/19998、DE19616486A1、WO00/34241和WO95/15309中进行了一般和具体公开,在各情况中特别是在化合物权利要求和加工实施例的终产品中进行了公开,这些公开物的终产品主题、药物制剂和权利要求书被引入本申请作为参考。优选的分别是在WO98/19998的实施例3和WO00/34241的实施例1中具体公开的那些化合物。
GLP-1是例如W.E.Schmidt等人在Diabetologia,28,1985,704-707中和在US5,705,483中描述的促胰岛素蛋白。
术语“GLP-1激动剂”包括特别是在US5,120,712、US5,118666、US5,512,549、WO91/11457和由C.Orskov等人在J.Biol.Chem.264(1989)12826中公开的GLP-1(7-36)NH2的变型和类似物。另一些实例包括其中Arg36的羧基-末端酰胺官能团被GLP-1(7-36)NH2分子的第37位上的Gly代替的GLP-1(7-37)以及其变型和类似物,包括GLN9-GLP-1(7-37)、D-GLN9-GLP-1(7-37)、乙酰基LYS9-GLP-1(7-37)、LYS18-GLP-1(7-37)和特别是GLP-1(7-37)OH、VAL8-GLP-1(7-37)、GLY8-GLP-1(7-37)、THR8-GLP-1(7-37)、MET8-GLP-1(7-37)和4-咪唑丙酰基-GLP-1。特别优选的是Greig等人在Diabetologia1999,42,45-50中所述的GLP激动剂类似物Exendin-4。
“抗糖尿病药”的定义中还包括恢复受损的胰岛素受体功能以降低胰岛素耐受性并因此增强胰岛素敏感性的胰岛素敏感性增强剂。其实例包括降血糖的噻唑烷二酮衍生物(例如,格列酮、(S)-((3,4-二氢-2-(苯基-甲基)-2H-1-苯并吡喃-6-基)甲基-噻唑烷-2,4-二酮(恩格列酮)、5-{[4-(3-(5-甲基-2-苯基-4-唑基)-1-氧代丙基)-苯基]-甲基}-噻唑烷-2,4-二酮(达格列酮)、5-{[4-(1-甲基-环己基)甲氧基)-苯基]甲基}-噻唑烷-2,4-二酮(环格列酮)、5-{[4-(2-(1-吲哚基)乙氧基)苯基]甲基}-噻唑烷-2,4-二酮(DRF2189)、5-{4-[2-(5-甲基-2-苯基-4-唑基)-乙氧基)]苄基}-噻唑烷-2,4-二酮(BM-13.1246)、5-(2-萘基磺酰基)-噻唑烷-2,4-二酮(AY-31637)、二{4-[(2,4-二氧代-5-噻唑烷基)甲基]苯基}甲烷(YM268)、5-{4-[2-(5-甲基-2-苯基-4-唑基)-2-羟基乙氧基]苄基}-噻唑烷-2,4-二酮(AD-5075)、5-[4-(1-苯基-1-环丙烷羰基氨基)-苄基]-噻唑烷-2,4-二酮(DN-108)5-{[4-(2-(2,3-二氢吲哚-1-基)乙氧基)苯基]甲基}-噻唑烷-2,4-二酮、5-[3-(4-氯-苯基])-2-丙炔基]-5-苯基磺酰基)噻唑烷-2,4-二酮、5-[3-(4-氯苯基])-2-丙炔基]-5-(4-氟苯基-磺酰基)噻唑烷-2,4-二酮、5-{[4-(2-(甲基-2-吡啶基-氨基)-乙氧基)苯基]甲基}-噻唑烷-2,4-二酮(罗格列酮)、5-{[4-(2-(5-乙基-2-吡啶基)乙氧基)苯基]-甲基}噻唑烷-2,4-二酮(吡格列酮)、5-{[4-((3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基)-苯基]-甲基}-噻唑烷-2,4-二酮(曲格列酮)、5-[6-(2-氟-苄氧基)萘-2-基甲基]-噻唑烷-2,4-二酮(MCC555)、5-{[2-(2-萘基)-苯并唑-5-基]-甲基}噻唑烷-2,4-二酮(T-174)和5-(2,4-二氧代噻唑烷-5-基甲基)-2-甲氧基-N-(4-三氟甲基-苄基)苯甲酰胺(KRP297))。
另外的抗糖尿病药包括胰岛素发信号途径调节剂,如蛋白酪氨酸磷酸酶(PTPases)的抑制剂、抗糖尿病的非小分子拟态(mimetic)化合物和谷酰胺-果糖-6-磷酸酰氨基转移酶(GFAT)的抑制剂;影响失调的肝葡萄糖生成的化合物,如葡萄糖-6-磷酸酶(G6Pase)的抑制剂、果糖-1,6-二磷酸酶(F-1,6-Bpase)的抑制剂、糖原磷酸化酶(GP)的抑制剂、胰高血糖素受体拮抗剂和磷酸烯醇丙酮酸羧基激酶(PEPCK)的抑制剂;丙酮酸盐脱氢酶激酶(PDHK)抑制剂;胃排空的抑制剂;胰岛素;GSK-3的抑制剂;类视色素X受体(RXR)激动剂;Beta-3AR的激动剂;解偶联蛋白(UCPs)的激动剂;非格列酮型PPARγ激动剂;双重PPARα/PPARγ激动剂;含钒的抗糖尿病化合物;肠降血糖素激素,如胰高血糖素样肽-1(GLP-1)和GLP-1激动剂;β-细胞咪唑啉受体拮抗剂;米格列醇;α2-肾上腺素能拮抗剂;以及其可药用的盐。
术语“减肥药”包括脂酶抑制剂(例如,奥利斯特)和食欲抑制剂(例如,西布曲明和苯丁胺)。
醛固酮合酶抑制剂或其可药用的盐被理解为是具有抑制醛固酮产生性质的活性成分。醛固酮合酶(CYP11B2)是一种催化肾上腺皮质中醛固酮产生的最后一步,即11-脱氧皮质酮转化成醛固酮的线粒体细胞色素P450酶。已知用所谓的醛固酮合酶抑制剂抑制醛固酮产生是治疗低钾血、高血压、充血性心力衰竭、心房颤动或肾衰竭的成功变型。本领域技术人员根据标准测定试验(例如,US2007/0049616)可容易地测定该醛固酮合酶抑制活性。
醛固酮合酶抑制剂的种类包括甾族和非甾族醛固酮合酶抑制剂,最优选非甾族醛固酮合酶抑制剂。
优选可商业获得的醛固酮合酶抑制剂或已经被卫生当局批准的那些醛固酮合酶抑制剂。
醛固酮合酶抑制剂的种类包括具有不同结构特征的化合物。例如,可提及的有选自非甾族芳香酶抑制剂阿那曲唑、法倔唑(包括其(+)-对映异构体)以及甾族芳香酶抑制剂依西美坦的化合物或可适用情况中其各自可药用的盐。
最优选的非甾族醛固酮合酶抑制剂是下式的法倔唑盐酸盐的(+)-对映异构体(US专利4617307和4889861),
或者如果适宜的话,其可药用的盐。
一种优选的甾族醛固酮拮抗剂是下式的伊普利酮(参见EP122232A)
或螺内酯;或者在各情况中,如果适宜的话,其可药用的盐。
用于所述组合中的醛固酮合酶抑制剂是在例如US2007/0049616中,特别是在化合物权利要求和加工实施例的终产物中进行了一般和具体公开的化合物和类似物,这一公开物的药物制剂和权利要求书被引入本申请作为参考。适用于本发明的优选的醛固酮合酶抑制剂非限制性地包括4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-甲基苯甲腈;5-(2-氯-4-氰基苯基)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-甲酸(4-甲氧基苄基)甲基酰胺;4’-氟-6-(6,7,8,9-四氢-5H-咪唑并[1,5-a]氮杂-5-基)联苯-3-甲腈;5-(4-氰基-2-甲氧基苯基)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-甲酸丁酯;4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-2-甲氧基苯甲腈;5-(2-氯-4-氰基苯基)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-甲酸4-氟苄基酯;5-(4-氰基-2-三氟甲氧基苯基)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-甲酸甲酯;5-(4-氰基-2-甲氧基苯基)-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-甲酸2-异丙氧基乙基酯;4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-2-甲基苯甲腈;4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-3-氟苯甲腈;4-(6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)-2-甲氧基苯甲腈;3-氟-4-(7-亚甲基-6,7-二氢-5H-吡咯并[1,2-c]咪唑-5-基)苯甲腈;顺式-3-氟-4-[7-(4-氟-苄基)-5,6,7,8-四氢-咪唑并[1,5-a]吡啶-5-基]苯甲腈;4’-氟-6-(9-甲基-6,7,8,9-四氢-5H-咪唑并[1,5-a]氮杂-5-基)联苯-3-甲腈;4’-氟-6-(9-甲基-6,7,8,9-四氢-5H-咪唑并[1,5-a]氮杂-5-基)联苯-3-甲腈或各种情况中其(R)或(S)对映异构体;或者如果适宜的话,其可药用的盐。
术语醛固酮合酶抑制剂还包括在WO2008/076860、WO2008/076336、WO2008/076862、WO2008/027284、WO2004/046145、WO2004/014914、WO2001/076574中公开的化合物和类似物。
此外,醛固酮合酶抑制剂还包括在US专利申请US2007/0225232、US2007/0208035、US2008/0318978、US2008/0076794、US2009/0012068、US20090048241以及PCT申请WO2006/005726、WO2006/128853、WO2006128851、WO2006/128852、WO2007065942、WO2007/116099、WO2007/116908、WO2008/119744中和在欧洲专利申请EP1886695中公开的化合物和类似物。适用于本发明的优选的醛固酮合酶抑制剂非限制性地包括8-(4-氟苯基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)-2-氟苯甲腈;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)-2,6-二氟苯甲腈;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)-2-甲氧基苯甲腈;3-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)苯甲腈;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)酞腈;4-(8-(4-氰基苯基)-5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)苯甲腈;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)苯甲腈;4-(5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪-8-基)萘-1-甲腈;由Speedel研制的8-[4-(1H-四唑-5-基)苯基]-5,6-二氢-8H-咪唑并[5,1-c][1,4]嗪,或者在各种情况中,其(R)或(S)对映异构体;或者如果适宜的话,其可药用的盐。
术语“内皮素受体阻滞剂”包括波生坦。
术语“CETP抑制剂”是指抑制胆固醇酯转移蛋白(CETP)介导的各种胆固醇酯和甘油三酯由HDL向LDL和VLDL转运的化合物。本领域技术人员根据标准测定试验(例如,US专利6,140,343)可容易地测定该类CETP抑制活性。其实例包括在US专利6,140,343和US专利6,197,786中公开的化合物(例如,[2R,4S]4-[(3,5-二-三氟甲基-苄基)-甲氧基羰基-氨基]-2-乙基-6-三氟甲基-3,4-二氢-2H-喹啉-1-甲酸乙基酯(Torcetrapib);在US专利6,723,752中公开的化合物(例如,(2R)-3-{[3-(4-氯-3-乙基-苯氧基)-苯基]-[[3-(1,1,2,2-四氟-乙氧基)-苯基]-甲基]-氨基}-1,1,1-三氟-2-丙醇);在序号为10/807,838的US专利申请中公开的化合物;在US专利5,512,548中公开的多肽衍生物;分别在J.Antibiot.,49(8):815-816(1996)和Bioorg.Med.Chem.Lett.;6:1951-1954(1996)中公开的玫瑰酮内酯衍生物和包含磷酸酯的胆固醇酯类似物。此外,CETP抑制剂还包括在WO2000/017165、WO2005/095409和WO2005/097806中公开的那些化合物。
优选的PDE5抑制剂是昔多芬。
特别感兴趣的第二种活性剂包括内皮素拮抗剂、肾素抑制剂、血管紧张素II受体拮抗剂、钙通道阻滞剂、利尿剂、抗糖尿病药如DPPIV抑制剂和醛固酮合酶抑制剂。
本发明的举例说明:
用于合成本发明化合物的所有的起始材料、构造块、试剂、酸、碱、脱水剂、溶剂和催化剂可商业获得或者可以用本领域普通技术人员已知的有机合成方法来制备(Houben-Weyl第4版,1952,有机合成方法(MethodsofOrganicSynthesis),Thieme,第21卷)。此外,本发明化合物也可以用如下面实施例中所示的本领域普通技术人员已知的有机合成方法来制备。
用下面的实施例对本发明进行说明,不应将其解释为是对本发明的限制。温度是以摄氏度为单位给出的。如果没有特别提及,则所有的蒸发都是在减压下进行的,优选在约15mmHg至100mmHg(=20-133mbar)下进行。终产物、中间体和起始材料的结构是用标准分析方法,例如微量分析和光谱特征例如MS、IR、NMR确认的。所用缩写是现有技术中常用的那些缩写。发现实施例5-1至15-3的化合物对NEP具有约0.01nM至约10,000nM的IC50值。
用于测量保留时间的条件如下:
HPLC条件A:
柱:40℃下,INERTSILC8-3,3μmx33mmx3.0mm
流速:2ml/min
流动相:A)5mMHCOONH4水溶液,B)MeOH/CH3CN(1/1,v/v)
梯度:2min内从5%A至95%B的线性梯度
检测:200-400nm下的DAD-UV
HPLC条件B:
柱:40℃下,INERTSILC8-3,3μmx33mmx3.0mm
流速:2ml/min
流动相:A)5mMHCOONH4水溶液,B)MeOH/CH3CN(1/1,v/v)
梯度:2min内从40%A至95%B的线性梯度
检测:200-400nm下的DAD-UV
HPLC条件C:
柱:40℃下,INERTSILC8-3,3μmx33mmx3.0mm
流速:2ml/min
流动相:A)(5mMNH4 +HCOO-)/水,B)MeOH/CH3CN(1/1,v/v)
梯度:2min内从5至95%B的线性梯度
检测:200-400nm下的DAD-UV
HPLC条件D:
柱:40℃下,INERTSILC8-3,3μmx33mmx3.0mm
流速:2ml/min
流动相:A)0.1%甲酸水溶液,B)MeOH/CH3CN(1/1,v/v)
梯度:2min内从5%B至95%B的线性梯度
检测:200-400nm下的DAD-UV
HPLC条件E:
柱:40℃下,InertsilC8-3,3μmx33mmx3.0mm
流速:2ml/min
流动相:A)甲醇/乙腈(1/1,v/v),B)5mMHCOONH4水溶液
梯度:2min内从40%B至95%A的线性梯度
检测:214nm下的UV
用二维NMR测定相对立体化学。在反应条件下,出乎意料地是,携带联苯基-甲基的立体中心外消旋。因此,根据携带联苯基-甲基的立体中心的相对立体化学和绝对立体化学来测定绝对立体化学。
实施例1-1:(R)-4-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸的合成
在室温下,向(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯(230.1mg,0.600mmol)中加入HCl在1,4-二恶烷中的溶液(3.00mL,12.00mmol)。在搅拌1小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-联苯-4-基-丁酸乙酯盐酸盐。将(R)-3-氨基-4-联苯-4-基-丁酸乙酯盐酸盐、琥珀酸酐(72.1mg,0.720mmol)和DIPEA(0.126mL,0.720mmol)在二氯甲烷(4mL)中的溶液搅拌1小时。将该反应用10%柠檬酸水溶液淬熄并用二氯甲烷萃取。将有机层分离出来并减压浓缩。将所得残余物用CN-改性的硅胶快速柱色谱(洗脱剂:庚烷/EtOAc=100:0至0:100)和RP-HPLC(SunFireC18,H2O(0.1%TFA)/CH3CN)进行纯化,从而得到(R)-4-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(148.2mg)。HPLC保留时间=1.64分钟(条件A);MS(m+1)=384.1;1HNMR(400MHz,乙腈-d3)δppm1.21(t,J=7.07Hz,3H),2.31-2.39(m,2H),2.40-2.56(m,4H),2.77-2.92(m,2H),4.08(q,J=7.24Hz,2H),4.33-4.48(m,1H),6.62(d,J=8.34Hz,1H),7.30(d,J=8.08Hz,2H),7.32-7.39(m,1H),7.41-7.49(m,2H),7.54-7.60(m,2H),7.60-7.67(m,2H),10.02(br.s.,1H)。
实施例1-2:(R)-4-(1-(3'-氯联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸的合成
将(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(400mg,1.13mmol)、琥珀酸酐(136mg,1.36mmol)和DIPEA(0.237mL,1.36mmol)在二氯甲烷(5mL)中的溶液搅拌2.5小时。将该反应用1MHCl水溶液淬熄并用二氯甲烷萃取。将有机层分离出来并减压浓缩。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而得到(R)-4-(1-(3'-氯联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(255mg)。HPLC保留时间=1.15分钟(条件B);MS(m+1)=418.0;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.08Hz,3H),2.46-2.58(m,4H),2.64-2.67(m,2H),2.87(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.99(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),4.12-4.24(m,2H),4.47-4.55(m,1H),6.50(brd,J=8.8Hz,1H),7.24-7.37(m,4H),7.43-7.46(m,1H),7.48-7.52(m,2H),7.55-7.56(m,1H)。
手性HPLC保留时间=3.59min。柱:DaicelCHIRALPAKAD-H(4.6x100mm);流速=1ml/min.;洗脱剂:EtOH(包含0.1%TFA)/庚烷=4/6。
下面的化合物是用与实施例1-2所述操作类似的操作制备的:
实施例1-3:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),1.86-1.97(m,2H),2.25-2.28(m,2H),2.34(t,J=7.0Hz,2H),2.50(ABX的A,Jab=16.2Hz,Jax=5.6Hz,1H),2.56(ABX的B,Jab=16.2Hz,Jbx=5.1Hz,1H),2.88(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.98(ABX的B,Jab=13.6Hz,Jbx=7.1Hz,1H),4.12-4.23(m,2H),4.50-4.58(m,1H),6.32(brd,J=8.8Hz,1H),7.25-7.37(m,4H),7.43-7.46(m,1H),7.49-7.52(m,2H),7.55-7.56(m,1H)。
实施例1-4:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),1.86-1.97(m,2H),2.25-2.28(m,2H),2.34(t,J=7.0Hz,2H),2.54(ABX的A,Jab=16.1Hz,Jax=5.6Hz,1H),2.58(ABX的B,Jab=16.1Hz,Jbx=5.2Hz,1H),2.88(ABX的A,Jab=13.5Hz,Jax=7.6Hz,1H),2.97(ABX的B,Jab=13.5Hz,Jbx=7.0Hz,1H),3.78(s,3H),4.12-4.23(m,2H),4.50-4.59(m,1H),6.34(brd,J=8.6Hz,1H),6.88-6.91(m,1H),6.96-7.04(m,2H),7.23(d,J=8.3Hz,2H),7.44-7.47(m,2H)。
实施例1-5:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),1.86-1.97(m,2H),2.25-2.36(m,4H),2.49-2.61(m,2H),2.88(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.97(ABX的B,Jab=13.6Hz,Jbx=6.8Hz,1H),3.79(s,3H),4.12-4.23(m,2H),4.50-4.59(m,1H),6.34-6.36(m,1H),6.89(d,J=8.6Hz,1H),7.21-7.28(m,3H),7.43(d,J=8.1Hz,2H)。
实施例1-6:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.47-2.67(m,6H),2.89(ABX的A,Jab=13.7Hz,Jax=7.8Hz,1H),3.00(ABX的B,Jab=13.7Hz,Jbx=6.7Hz,1H),4.12-4.24(m,2H),4.49-4.57(m,1H),6.51(brd,J=8.6Hz,1H),6.97-7.07(m,2H),7.24-7.26(m,2H),7.36-7.43(m,3H)。
实施例1-7:1HNMR(400MHz,DMSO-d6)δppm1.16(t,J=7.1Hz,3H),2.23-2.27(m,2H),2.34-2.38(m,2H),2.40-2.47(m,2H),2.77(d,J=6.6Hz,2H),3.99-4.06(m,2H),4.21-4.30(m,1H),7.14-7.19(m,1H),7.29(d,J=8.4Hz,2H),7.46-7.52(m,3H),7.63(d,J=8.4Hz,2H),7.91(d,J=8.3Hz,1H),12.04(s,1H)。
实施例1-8:1HNMR(400MHz,氯仿-d)δppm2.41-2.45(m,2H),2.50-2.64(m,4H),2.81-2.87(m,1H),2.95-3.00(m,1H),4.49-4.56(m,1H),5.12(AB的A,J=12.1Hz,1H),5.18(AB的B,J=12.1Hz,1H),6.39(d,J=8.1Hz,1H),7.18-7.54(m,13H)。
实施例1-9:1HNMR(400MHz,DMSO-d6):δppm1.22-1.25(t,J=7.07Hz,3H),2.61-2.63(m,2H),2.91(d,J=7.07Hz,2H),4.09(q,J=7.07Hz,2H),4.52-4.59(m,1H),7.32-7.34(m,3H),7.04(t,J=7.83Hz,1H),7.52-7.56(m,3H),7.59(t,J=2.02Hz,1H)。
实施例1-10:1HNMR(400MHz,氯仿-d)δppm2.03-2.13(m,2H),2.44(t,J=6.3Hz,2H),2.64(t,J=6.6Hz,2H),2.70(dd,J=16.2,5.6Hz,1H),2.78(dd,J=16.2,5.1Hz,1H),2.83-2.98(m,5H),3.04(dd,J=13.9,6.8Hz,1H),4.57-4.69(m,1H),6.51(d,J=8.8Hz,1H),6.79(dd,J=8.1,2.3Hz,1H),6.90(d,J=1.8Hz,1H),7.18(d,J=8.1Hz,1H),7.26-7.31(m,3H),7.34(t,J=7.7Hz,1H),7.43(dt,J=7.3,1.5Hz,1H),7.49(d,J=8.1Hz,2H),7.54(t,J=1.8Hz,1H),9.34(br.s.,1H)。
实施例1-11:(R)-4-(1-(2',5'-二氯联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸的合成
在室温下,向(R)-3-(叔丁氧基羰基氨基)-4-(2',5'-二氯联苯-4-基)丁酸乙酯(1.09g,2.33mmol)中加入4MHCl在1,4-二恶烷中的溶液(5.81mL,23.3mmol)。在搅拌2小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-(2',5'-二氯联苯-4-基)丁酸乙酯盐酸盐。接下来,将该产物、琥珀酸酐(280mg,2.80mmol)和DIPEA(0.489mL,2.80mmol)在二氯甲烷(15mL)中的溶液搅拌2小时。将该反应用1MHCl水溶液淬熄并用二氯甲烷萃取。将有机层分离出来并减压浓缩。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而以白色固体形式的得到(R)-4-(1-(2',5'-二氯联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(553mg);HPLC保留时间=1.02分钟(条件B);MS(m+1)=452.14;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.47-2.67(m,6H),2.89(ABX的A,Jab=13.7Hz,Jax=7.8Hz,1H),3.00(ABX的B,Jab=13.7Hz,Jbx=6.7Hz,1H),4.12-4.24(m,2H),4.49-4.57(m,1H),6.53(brd,J=8.8Hz,1H),7.23-7.26(m,3H),7.32-7.40(m,4H)。
下面的化合物是用与实施例1-11中所述操作类似的操作制备的:
实施例1-12:1HNMR(400MHz,DMSO-d6)δppm0.87(t,J=7.5Hz,3H),1.49-1.61(m,2H),2.22-2.29(m,2H),2.32-2.39(m,2H),2.45(dd,J=6.9,3.4Hz,2H),2.78(d,J=6.6Hz,2H),3.94(t,J=6.6Hz,2H),4.21-4.33(m,1H),7.29(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.58-7.65(m,3H),7.69(t,J=1.9Hz,1H),7.92(d,J=8.3Hz,1H)。
实施例1-13:1HNMR(400MHz,氯仿-d)δppm0.94(t,J=7.3Hz,3H),1.32-1.44(m,2H),1.56-1.67(m,2H),2.43-2.59(m,4H),2.65(t,J=6.4Hz,2H),2.85(dd,J=13.6,8.1Hz,1H),2.99(dd,J=13.6,6.6Hz,1H),4.03-4.18(m,2H),4.43-4.56(m,1H),6.57(d,J=8.6Hz,1H),7.25(d,J=8.3Hz,2H),7.28-7.32(m,1H),7.35(t,J=7.7Hz,1H),7.41-7.46(m,1H),7.48(d,J=8.1Hz,2H),7.55(t,J=1.8Hz,1H)。
实施例1-14:1HNMR(400MHz,氯仿-d)δppm2.17(s,3H),2.44(t,J=6.2Hz,2H),2.48-2.57(m,1H),2.57-2.73(m,3H),2.87(dd,J=13.6,7.6Hz,1H),2.98(dd,J=13.9,7.1Hz,1H),4.47-4.58(m,1H),4.84(s,2H),6.32(d,J=8.6Hz,1H),7.23(d,J=8.1Hz,2H),7.30(d,1H),7.35(t,J=7.7Hz,1H),7.44(d,J=7.3Hz,1H),7.49(d,J=8.1Hz,2H),7.54(s,1H)。
实施例1-15:1HNMR(400MHz,氯仿-d)δppm2.48-2.59(m,3H),2.61-2.71(m,3H),2.91-3.06(m,8H),4.53-4.63(m,1H),4.67(d,J=14.7Hz,1H),5.03(d,J=14.7Hz,1H),7.30(dt,J=7.8,1.8Hz,1H),7.32-7.38(m,3H),7.45(dt,J=7.6,1.5Hz,1H),7.50(d,J=8.1Hz,2H),7.55(t,J=1.8Hz,1H),8.08(d,J=9.3Hz,1H)。
实施例1-16:1HNMR(400MHz,DMSO-d6)δppm2.20-2.32(m,2H),2.32-2.41(m,2H),2.42-2.50(m,1H),2.57(dd,J=15.4,5.6Hz,1H),2.80(d,J=36.1Hz,2H),3.15(br.s.,2H),3.31-3.50(m,4H),3.52-4.05(m,4H),4.25-4.40(m,3H),7.31(d,J=8.3Hz,2H),7.39-7.43(m,1H),7.48(t,J=7.8Hz,1H),7.60-7.67(m,3H),7.70(t,J=1.8Hz,1H),8.02(d,J=8.6Hz,1H),10.06(br.s.,1H),12.17(br.s.,1H)。
实施例1-17:(R)-4-(1-(5'-氯-2'-氟联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸的合成
将(R)-3-氨基-4-(5’-氯-2’-氟联苯-4-基)丁酸乙酯盐酸盐(293mg,0.777mmol)、琥珀酸酐(93mg,0.932mmol)和DIPEA(0.204mL,1.165mmol)在二氯甲烷(4mL)中的溶液搅拌1.5小时。将该反应用1MHCl水溶液淬熄并用二氯甲烷萃取。将有机层分离出来并减压浓缩。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而得到(R)-4-(1-(5'-氯-2'-氟联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(294mg)。HPLC保留时间=1.03分钟(条件B);MS(m+1)=436.2;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.07Hz,3H),2.46-2.58(m,4H),2.64-2.68(m,2H),2.87(ABX的A,Jab=13.64Hz,Jax=7.83Hz,1H),2.99(ABX的B,Jab=13.64Hz,Jbx=6.57Hz,1H),4.11-4.22(m,2H),4.47-4.56(m,1H),6.60(brd,J=8.59Hz,1H),7.05-7.10(m,1H),7.23-7.27(m,3H),7.39-7.41(m,1H),7.44-7.46(m,2H)。
下面的化合物是用与实施例1-17所述操作类似的操作制备的:
实施例1-20:1HNMR(400MHz,CDCl3)δppm1.15(t,J=7.07Hz,3H),2.24-2.34(m,4H),2.74(dd,J=8.59,13.39Hz),2.88(dd,J=6.32,13.39Hz),3.34(s,3H),3.75(d,J=2.78Hz,1H),4.04(dd,J=7.07,13.89Hz,2H),4.33-4.43(m,1H),7.31(d,J=8.08Hz,2H),7.38-7.43(m,1H),7.48(t,J=7.83Hz,1H),7.63(d,J=3.34Hz),7.71(t,J=1.77Hz,1H),7.95(d,J=9.35Hz,1H)。
实施例2-1:(R)-3-(3-羧基-丙酰基氨基)-4-(4'-氟-联苯-4-基)-丁酸乙酯的合成
将(R)-4-(1-(4-溴苯基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(50mg,0.129mmol)、4-氟苯基硼酸(27.2mg,0.194mmol)、Pd(Ph3P)4(14.96mg,0.013mmol)和Na2CO3水溶液(0.129mL,0.259mmol)在甲苯(1mL)中的混合物在氮气下在95℃下进行搅拌。在搅拌13小时后,将该溶液冷却至环境温度,然后用1MHCl水溶液淬熄。将产物用乙酸乙酯萃取,用盐水洗涤,用MgSO4干燥,过滤,减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-3-(3-羧基-丙酰基氨基)-4-(4'-氟-联苯-4-基)-丁酸乙酯(29.2mg)。HPLC保留时间=1.26分钟(条件B);MS(m+1)=402.2;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7Hz,3H),2.47-2.67(m,6H),2.87(ABX的A,Jab=13.7Hz,Jax=7.9Hz,1H),2.99(ABX的B,Jab=13.7Hz,Jbx=6.6Hz,1H),4.12-4.23(m,2H),4.47-4.55(m,1H),6.52(brd,J=8.6Hz,1H),7.08-7.14(m,2H),7.24(d,J=8.4Hz,2H),7.46-7.55(m,4H)。
下面的化合物是用与实施例2-1所述操作类似的操作制备的:
实施例2-2:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7Hz,3H),2.47-2.67(m,6H),2.84-3.02(m,2H),4.12-4.24(m,2H),4.47-4.55(m,1H),6.52(brd,J=9.3Hz,1H),7.24-7.26(m,2H),7.39-7.41(m,2H),7.48-7.51(m,4H)。
实施例2-3:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7Hz,3H),2.43-2.65(m,6H),2.84-3.02(m,2H),3.67(s,3H),4.12-4.23(m,2H),4.47-4.55(m,1H),6.30(brd,J=8.6Hz,1H),7.00-7.05(m,1H),7.26-7.29(m,3H),7.34-7.41(m,2H),7.51(d,J=8.3Hz,2H)。
实施例2-4:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7Hz,3H),2.44-2.65(m,6H),2.85-3.02(m,2H),3.67(s,3H),4.11-4.23(m,2H),4.48-4.56(m,1H),6.30(brd,J=9.6Hz,1H),7.11-7.22(m,2H),7.25-7.33(m,3H),7.40-7.45(m,1H),7.48-7.50(m,2H)。
实施例2-5:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.44-2.65(m,6H),2.86-3.02(m,2H),3.68(s,3H),4.12-4.23(m,2H),4.49-4.57(m,1H),6.31(brd,J=8.8Hz,1H),7.24-7.34(m,5H),7.37-7.39(m,2H),7.45-7.47(m,1H)。
实施例2-6:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7Hz,3H),2.44-2.66(m,6H),2.84-3.01(m,2H),3.68(s,3H),3.81(s,3H),4.11-4.23(m,2H),4.48-4.56(m,1H),6.26(brd,J=8.8Hz,1H),6.97-7.04(m,2H),7.22(d,J=8.1Hz,2H),7.29-7.33(m,2H),7.46-7.48(m,2H)。
实施例2-7:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.26(s,3H),2.44-2.69(m,6H),2.85-3.01(m,2H),3.68(s,3H),4.12-4.23(m,2H),4.48-4.57(m,1H),6.30(brd,J=8.6Hz,1H),7.21-7.26(m,8H)。
实施例2-8:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.44-2.69(m,6H),2.86-3.03(m,2H),3.68(s,3H),4.12-4.23(m,2H),4.48-4.57(m,1H),6.31(brd,J=8.8Hz,1H),6.90-7.01(m,1H),7.05-7.08(m,1H),7.25-7.27(m,2H),7.36-7.43(m,3H)。
实施例2-9:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),2.41-2.65(m,9H),2.84-3.00(m,2H),3.67(s,3H),4.11-4.23(m,2H),4.47-4.55(m,1H),6.29(brd,J=8.9Hz,1H),7.16-7.39(m,6H),7.50-7.53(m,2H)。
实施例2-10:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.43-2.65(m,6H),2.84-3.02(m,2H),3.67(s,3H),4.12-4.23(m,2H),4.46-4.55(m,1H),6.33(brd,J=8.8Hz,1H),6.76-6.80(m,1H),7.06-7.12(m,2H),7.26-7.27(m,2H),7.48(d,J=8.0Hz,2H)。
实施例2-11:1HNMR(400MHz,氯仿-d)δppm1.27-1.30(m,6H),2.44-2.57(m,4H),2.62-2.74(m,4H),2.84-3.00(m,2H),3.67(s,3H),4.13-4.23(m,2H),4.47-4.55(m,1H),6.30(brd,J=7.6Hz,1H),7.17-7.26(m,3H),7.33-7.41(m,3H),7.52(d,J=7.8Hz,2H)。
实施例2-12:1HNMR(400MHz,氯仿-d)δppm1.30(t,J=7.1Hz,3H),2.41-2.65(m,6H),2.67-2.92(m,1H),3.00-3.05(m,1H),3.68(s,3H),4.14-4.22(m,2H),4.48-4.56(m,1H),6.33(brd,J=8.6Hz,1H),7.32(d,J=8.3Hz,2H),7.56-7.62(m,3H),7.89-7.91(m,1H),8.18-8.20(m,1H),8.44(t,J=8.0Hz,1H)。
实施例2-13:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.44-2.65(m,6H),2.86-2.91(m,1H),2.98-3.03(m,1H),3.67(s,3H),4.13-4.22(m,2H),4.47-4.56(m,1H),6.33(brd,J=8.8Hz,1H),7.29(d,J=8.2Hz,2H),7.53(d,J=8.2Hz,2H),7.56-7.60(m,2H),7.75(d,J=7.6Hz,1H),7.81(s,1H)。
实施例2-14:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),2.43-2.65(m,6H),2.84-2.89(m,1H),2.96-3.01(m,1H),3.67(s,3H),3.86(s,3H),4.11-4.23(m,2H),4.47-4.55(m,1H),6.30(brd,J=8.8Hz,1H),6.87-6.90(m,1H),7.10-7.11(m,1H),7.15-7.17(m,1H),7.24-7.26(m,2H),7.34(t,J=7.8Hz,2H),7.51-7.53(m,2H)。
实施例2-15:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.43-2.58(m,4H),2.61-2.65(m,2H),2.84-2.91(m,1H),2.98-3.03(m,1H),3.68(s,3H),4.12-4.24(m,2H),4.47-4.55(m,1H),6.34(brd,J=8.8Hz,1H),7.30(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.51-7.63(m,2H),7.78-7.81(m,1H),7.85(brs,1H)。
实施例2-16:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.43-2.57(m,4H),2.61-2.64(m,2H),2.87(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.99(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.68(s,3H),4.12-4.23(m,2H),4.46-4.55(m,1H),6.34(brd,J=8.6Hz,1H),7.05(dt,J=8.3and2.0Hz,1H),7.15-7.19(m,1H),7.26-7.28(m,3H),7.35-7.36(m,1H),7.45(d,J=8.1Hz,2H)。
实施例2-17:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.43-2.69(m,6H),2.90(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.99(ABX的B,Jab=13.6Hz,Jbx=6.8Hz,1H),3.68(s,3H),4.12-4.23(m,2H),4.49-4.57(m,1H),6.31(brd,J=8.6Hz,1H),7.20-7.26(m,4H),7.32(d,J=7.6Hz,1H),7.44-7.47(m,1H),7.53-7.57(m,1H),7.73(d,J=7.6Hz,2H)。
实施例2-18:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),2.44-2.65(m,6H),2.91(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),3.01(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.68(s,3H),4.12-4.24(m,2H),4.48-4.57(m,1H),6.34(brd,J=8.6Hz,1H),7.32(d,J=8.1Hz,2H),7.41-7.56(m,2H),7.62-7.66(m,1H),7.75-7.77(m,1H),7.81-7.84(m,2H)。
实施例2-19:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),1.35(t,J=6.9Hz,3H),2.44-2.53(m,4H),2.44-2.53(m,4H),2.86(ABX的A,Jab=13.6Hz,Jax=8.1Hz,1H),2.98(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),3.67(s,3H),3.99-4.23(m,4H),4.48-4.56(m,1H),6.27(brd,J=8.6Hz,1H),6.94-7.04(m,2H),7.20-7.22(m,2H),7.27-7.33(m,2H),7.41-7.52(m,2H)。
实施例2-20:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),1.43(s,9H),2.36-2.56(m,6H),2.84-3.01(m,4H),4.11-4.22(m,2H),4.47-4.56(m,1H),6.30-6.35(m,1H),7.25-7.27(m,2H),7.51-7.54(m,2H)。
实施例2-21:(R)-4-(4-乙氧基-1-(5'-氟-2'-甲氧基联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁酸的合成
向(R)-4-(1-(4-溴苯基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸叔丁酯、中间体9(100mg,0.23mmol)和5-氟-2-甲氧基苯基硼酸(57.6mg,0.34mmol)在甲苯(1mL)和EtOH(0.1mL)中的溶液中加入Pd(PPh3)4(26.1mg,0.023mmol)和Na2CO3(47.9mg,0.45mmol)。在将其在氮气下在95℃下搅拌18小时后,将溶液冷却至环境温度,然后用1MHCl水溶液淬熄。将该混合物用乙酸乙酯稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=100:0至30:70),从而得到(R)-4-(4-乙氧基-1-(5'-氟-2'-甲氧基联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁酸叔丁酯(65mg)。HPLC保留时间=1.44分钟(条件B);MS(m+1)=488.3;1HNMR(400MHz,氯仿-d)δppm1.32(t,J=7.1Hz,3H),1.48(s,9H),2.41-2.48(m,2H),2.51-2.63(m,4H),2.90(dd,J=13.6,6Hz,1H),3.02(dd,J=13.6,6Hz,1H),3.81(s,3H),4.14-4.29(m,2H),4.49-4.63(m,1H),6.44(d,J=8.6Hz,1H),6.89-6.97(m,1H),6.98-7.05(m,1H),7.05-7.11(m,1H),7.27(d,J=8.1Hz,2H),7.49(d,J=8.1Hz,2H)。
将(R)-4-(4-乙氧基-1-(5'-氟-2'-甲氧基联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁酸叔丁酯(65mg,0.13mmol)在4MHCl的1,4-二恶烷溶液(671μL,2.68mmol)中的溶液在室温下进行搅拌。在搅拌1小时后,将该反应混合物减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-4-(4-乙氧基-1-(5'-氟-2'-甲氧基联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁酸(23mg)。HPLC保留时间=1.66分钟(条件D);MS(m+1)=432.3;1HNMR(400MHz,DMSO-d6)δppm1.17(t,J=7.1Hz,3H),2.21-2.32(m,2H),2.32-2.40(m,2H),2.40-2.48(m,2H),2.77(d,J=6.8Hz,2H),3.74(s,3H),4.03(q,J=7.1Hz,2H),4.19-4.33(m,1H),7.04-7.20(m,3H),7.23(d,J=8.1Hz,2H),7.43(d,J=8.1Hz,2H),7.93(d,J=8.3Hz,1H)。
下面的化合物是用与实施例2-21所述操作类似的操作制备的:
实施例2-22:1HNMR(400MHz,CD3OD)δppm1.23(t,J=7.1Hz,3H),2.36-2.58(m,6H),2.85(d,J=7.1Hz,2H),3.76(s,3H),4.10(q,J=7.1Hz,2H),4.40-4.57(m,1H),7.01(d,J=8.6Hz,1H),7.17-7.30(m,4H),7.39(d,J=8.1Hz,2H)。
实施例2-23:1HNMR(400MHz,DMSO-d6)δppm1.16(t,J=7.2Hz,1H),2.23-2.30(m,2H),2.34-2.40(m,2H),2.40-2.45(m,2H),2.75(dd,J=6.6,3.3Hz,2H),4.02(q,J=7.2Hz,2H),4.19-4.30(m,1H),6.87-6.94(m,1H),6.93-7.02(m,1H),7.07(dd,J=9.7,3.2Hz,1H),7.22(d,J=8.1Hz,2H),7.49(d,J=8.1Hz,2H),7.94(d,J=8.1Hz,1H),9.52(s,1H)。
实施例2-24:1HNMR(400MHz,DMSO-d6)δppm1.16(t,J=7.1Hz,3H),2.22-2.32(m,2H),2.34-2.41(m,2H),2.43(dd,J=6.8,3.3Hz,2H),2.68-2.82(m,2H),4.02(q,J=7.1Hz,2H),4.17-4.35(m,1H),6.80-6.89(m,1H),6.93(d,J=7.1Hz,1H),7.09-7.17(m,1H),7.17-7.29(m,3H),7.46(d,J=8.3Hz,2H),7.93(d,J=8.1Hz,1H),9.46(br.s.,1H)。
实施例3-1:(R)-6-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基甲酰基)嘧啶-4-甲酸的合成
在室温下,向(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯(300mg,0.782mmol)中加入4MHCl在1,4-二恶烷中的溶液(3.92mL,15.65mmol)。在搅拌1小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-联苯-4-基-丁酸乙酯盐酸盐。接下来,向嘧啶-4,6-二甲酸(325mg,1.935mmol)、(R)-3-氨基-4-联苯-4-基-丁酸乙酯盐酸盐(250mg,0.774mmol)、WSC盐酸盐(148mg,0.774mmol)和HOAt(105mg,0.774mmol)在DMF(4mL)和H2O(1mL)中的混悬液中加入DIPEA(0.135mL,0.774mmol)。在搅拌14小时后,将该反应用H2O淬熄,将产物用EtOAc萃取,用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。
将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-6-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基甲酰基)嘧啶-4-甲酸(84.8mg)。HPLC保留时间=1.32分钟(条件B);MS(m+1)=434.1;1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.0Hz,3H),2.65(ABX的A,Jab=15.4Hz,Jax=5.8Hz,1H),2.73(ABX的B,Jab=15.4Hz,Jbx=7.9Hz)2.91(ABX的A,Jab=13.6Hz,Jax=6.1Hz,1H),3.01(ABX的B,Jab=13.6Hz,Jbx=8.2Hz,1H),4.01(q,J=7.0Hz,2H),4.59-4.68(m,1H),7.29-7.35(m,3H),7.41-7.45(m,2H),7.55-7.63(m,4H),8.32(d,J=1.35Hz,1H),9.19(d,J=9.1Hz,1H),9.50(d,J=1.35Hz,1H),14.11(brs,1H)。
下面的化合物是用与实施例3-1所述操作类似的操作制备的:
实施例3-2:1HNMR(400MHz,DMSO-d6)δppm1.14(t,J=7.1Hz,3H),2.57(d,J=7.1Hz,2H),2.83-2.92(m,2H),4.03(q,J=7.1Hz,2H),4.43-4.52(m,1H),7.29-7.36(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.30(d,J=8.4Hz,1H),8.64(brs,1H)。
实施例3-4:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.55(d,J=6.9Hz,2H),2.82-2.92(m,2H),4.00(q,J=7.1Hz,2H),4.43-4.52(m,1H),7.29-7.35(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),7.93-7.96(m,1H),8.10(d,J=2.3Hz,1H),8.25(d,J=8.3Hz,1H),12.53(d,J=6.1Hz,1H)。
实施例3-5:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.55(d,J=7.6Hz,2H),2.81-2.92(m,2H),4.02(q,J=7.1Hz,2H),4.43-4.52(m,1H),7.29-7.36(m,3H),7.42-7.46(m,2H),7.57-7.65(m,4H),7.78-7.81(m,1H)7.92(d,J=2.3Hz,1H),8.16(d,J=8.1Hz,1H),11.92(s,1H)。
实施例3-6:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7Hz,3H),2.55-2.67(m,2H),2.83-2.94(m,2H),4.02(q,J=7Hz,2H),4.46-4.55(m,1H),6.82(s,1H),7.28-7.35(m,3H),7.42-7.46(m,2H),7.59(d,J=8.3Hz,2H),7.63(d,J=7.0Hz,2H),8.13(s,1H),8.89(d,J=8.6Hz,1H),9.56(s,1H)。
实施例3-7:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7Hz,3H),2.56-2.58(m,2H),2.83-2.94(m,2H),4.02(q,J=7Hz,2H),4.46-4.55(m,1H),7.19(s,2H),7.30-7.35(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.22(d,J=8.1Hz,1H),8.60(s,1H)。
实施例3-9:(R)-3-(4-丁氧基-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸苄酯的合成
将(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯盐酸盐(150mg,0.360mmol)、4-丁氧基-4-氧代丁酸(107mg,0.540mmol,纯度为88%)、EDCI(104mg,0.540mmol)、DIPEA(0.094ml,0.540mmol)和HOAt(73.6mg,0.540mmol)在DMF(2ml)中的混合物在室温下搅拌1小时。将该反应混合物用水稀释,然后将沉淀出来的固体收集在漏斗上,用H2O洗涤并减压干燥得到粗品。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至0:100),从而得到(R)-3-(4-丁氧基-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸苄酯(178.9mg);HPLC保留时间=1.47分钟(条件B);MS(m+1)=536.42;1HNMR(400MHz,氯仿-d)δppm0.90-0.94(m,3H),1.31-1.40(m,2H),1.56-1.63(m,2H),2.39-2.42(m,2H),2.48-2.62(m,4H),2.84(ABX的A,Jab=13.6Hz,Jax=8.1Hz,1H),2.97(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),4.07(t,J=6.7Hz,2H),4.48-4.56(m,1H),5.12(AB的A,J=12.1Hz,1H),5.18(AB的B,J=12.1Hz,1H),6.27(brd,J=7.7Hz,1H),7.20(d,J=8.3Hz,1H),7.29-7.39(m,7H),7.42-7.47(m,3H),7.54-7.55(m,1H)。
下面的化合物是用与实施例3-8所述操作类似的操作制备的:
实施例3-10:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),1.58-1.64(m,4H),2.14-2.18(m,2H),2.28-2.32(m,2H),2.49(ABX的A,Jab=16.2Hz,Jax=5.3Hz,1H),2.53(ABX的B,Jab=16.2Hz,Jbx=5.3Hz,1H),2.87(ABX的A,Jab=13.6Hz,Jax=8.1Hz,1H),2.99(ABX的B,Jab=13.6Hz,Jbx=6.8Hz,1H),3.65(s,3H),4.11-4.23(m,2H),4.48-4.56(m,1H),6.18(brd,J=8.8Hz,1H),7.26-7.37(m,4H),7.43-7.52(m,3H),7.56(brt,J=1.8Hz,1H)。
实施例3-11:1HNMR(400MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H),2.40-2.51(m,4H),2.77-2.83(m,1H),2.91-2.97(m,3H),4.08-4.20(m,2H),4.46-4.54(m,1H),6.22-6.24(m,1H),7.18-7.23(m,3H),7.29-7.37(m,2H),7.43-7.49(m,3H),7.55-7.57(m,2H),8.44(d,J=4.8Hz,1H),8.48(s,1H)。
实施例3-12:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),1.53-2.20(m,9H),2.46-2.57(m,3H),2.86(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.98(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.65(s,3H),4.11-4.23(m,2H),4.47-4.55(m,1H),6.23(brd,J=8.6Hz,1H),7.24-7.26(m,2H),7.31-7.35(m,1H),7.41-7.45(m,2H),7.51-7.59(m,4H)。
实施例3-13:1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.2Hz,3H),1.36-1.51(m,4H),1.84-1.94(m,2H),1.98-2.06(m,3H),2.24-2.32(m,1H),2.50(ABX的A,Jab=16.2Hz,Jax=5.3Hz,1H),2.53(ABX的B,Jab=16.2Hz,Jbx=5.1Hz,1H),2.86(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.98(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.66(s,3H),4.11-4.23(m,2H),4.46-4.55(m,1H),6.19(brd,J=8.8Hz,1H),7.24-7.26(m,2H),7.31-7.36(m,1H),7.41-7.45(m,2H),7.51-7.58(m,4H)。
实施例3-14:1HNMR(400MHz,氯仿-d)δppm1.26(t,J=7.2Hz,3H),2.41-2.51(m,4H),2.62-2.66(m,2H),2.84(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.92(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.06-3.10(m,2H),4.08-4.19(m,2H),4.46-4.55(m,1H),6.78(d,J=8.9Hz,1H),7.10-7.12(m,1H),7.16(d,J=7.8Hz,1H),7.20-7.22(m,2H),7.29-7.31(m,1H),7.35(t,J=7.7Hz,1H),7.42-7.47(m,3H),7.54-7.59(m,2H),8.48(d,J=1.0Hz,1H)。
实施例3-16:1HNMR(400MHz,氯仿-d)δppm1.24(t,J=7.1Hz,3H),2.38-2.42(m,2H),2.49-2.61(m,4H),2.82-3.00(m,2H),4.12(q,J=7.1Hz,2H),4.47-4.56(m,1H),5.12(AB的A,J=12.3Hz,1H),5.18(AB的B,J=12.3Hz,1H),6.26(brd,J=8.6Hz,1H),7.20(d,J=8.3Hz,2H),7.29-7.46(m,10H),7.54-7.54(m,1H)。
实施例3-17:1HNMR(400MHz,氯仿-d)δppm1.23(t,J=7.2Hz,3H),1.86-1.92(m,2H),2.14-2.18(m,2H),2.24-2.28(m,2H),2.50-2.63(m,2H),2.82-2.99(m,2H),4.11(q,J=7.2Hz,2H),4.53-4.54(m,1H),5.12(AB的A,J=12.1Hz,1H),5.18(AB的B,J=12.1Hz,1H),6.12-6.14(m,1H),7.19-7.54(m,13H)。
实施例3-18:1HNMR(400MHz,氯仿-d)δppm1.26(t,J=7.2Hz,3H),1.67(s,9H),2.46-2.57(m,2H),2.74-2.96(m,4H),3.41-3.45(m,2H),4.09-4.17(m,2H),4.50-4.59(m,1H),6.95(brd,J=8.6Hz,1H),7.18(d,J=8.1Hz,2H),7.27-7.42(m,7H),7.51(t,J=1.8Hz,1H),7.61-7.65(m,1H),7.86-7.93(m,1H)。
实施例3-19:1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),1.43(s,9H),2.37-2.40(m,2H),2.50-2.59(m,4H),2.98(d,J=7.3Hz,2H),4.13-4.21(m,2H),4.48-4.56(m,1H),6.35(brd,J=8.8Hz,1H),7.22-7.44(m,6H),7.54-7.54(m,1H)。
实施例3-20:(R)-4-(3'-氨基联苯-4-基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯的合成
将(R)-3-(4-甲氧基-4-氧代丁烷酰氨基)-4-(3'-硝基联苯-4-基)丁酸乙酯(123mg,0.278mmol)和Pd/C(59.2mg,0.028mmol)在EtOH(2ml)中的混悬液在氢气下、在室温下搅拌5.5小时。将该反应混合物过滤并将该溶液浓缩,从而得到(R)-4-(3'-氨基联苯-4-基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯(105mg);HPLC保留时间=0.84分钟(条件B);MS(m+1)=413.1;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),2.41-2.65(m,6H),2.85-3.00(m,2H),3.67(s,3H),4.11-4.22(m,2H),4.46-4.54(m,1H),6.31(brd,J=8.8Hz,1H),6.71-6.74(m,1H),6.95-7.02(m,2H),7.21-7.25(m,3H),7.48-7.50(m,2H)。
下面的化合物是用与实施例3-20所述操作类似的操作制备的:
实施例3-22:1HNMR(400MHz,氯仿-d)δppm2.03-2.11(m,2H)2.48-2.62(m,4H),2.81-2.90(m,7H),2.95-3.00(m,1H),4.49-4.58(m,1H),5.07-5.18(m,2H),6.23(brd,J=8.6Hz,1H),6.79-6.82(m,1H),6.92(s,1H),7.15-7.20(m,3H),7.29-7.45(m,10H),7.52-7.53(m,1H)。
实施例3-23:(S)-1-(2-((R)-1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-2-氧代乙基)吡咯烷-2-甲酸苄酯三氟乙酸盐的合成
在室温下,向(S)-1-(2-叔丁氧基-2-氧代乙基)吡咯烷-2-甲酸苄酯(200mg,0.626mmol)和三乙基硅烷(0.250ml,1.565mmol)在DCM(3ml)中的溶液中加入TFA(0.965ml,12.52mmol)。在搅拌24小时后,将该反应浓缩得到粗品。
向该粗品、(R)-3-氨基-4-(联苯-4-基)丁酸乙酯盐酸盐(266mg,0.832mmol、WSC.HCl(0.180g,0.939mmol)和HOAt(128mg,0.939mmol)在DMF(4ml)中的混悬液中加入DIPEA(0.328ml,1.878mmol)。在搅拌4小时后,将该反应用H2O和EtOAc稀释。将产物用EtOAc萃取,用盐水洗涤,用Na2SO4干燥,过滤,浓缩。将该粗品用柱色谱处理两次(庚烷/EtOAc=100:0至0:100)。然后,将所得产物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而以灰黄色固体形式得到(S)-1-(2-((R)-1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-2-氧代乙基)吡咯烷-2-甲酸苄酯三氟乙酸盐(28.5mg);HPLC保留时间=1.84分钟(条件D);MS(m+1)=529.3;1HNMR(400MHz,氯仿-d)δppm1.25-1.28(m,3H),1.74-1.85(m,2H),1.91-1.98(m,1H),2.09-2.19(m,1H),2.35-2.41(m,1H),2.46(ABX的A,Jab=15.7Hz,Jax=6.6Hz,1H),2.59(ABX的B,Jab=13.7Hz,Jbx=5.7Hz,1H),2.78-2.83(m,1H),2.86(ABX的A,Jab=13.8Hz,Jax=8.1Hz,1H),2.99(ABX的B,Jab=13.7Hz,Jbx=6.4Hz,1H),3.08(AB的A,J=16.5Hz,1H),3.35(AB的B,J=16.5Hz,1H),3.41(dd,J=9.1和5.1Hz,1H),4.11-4.20(m,2H),4.46-4.55(m,1H),5.10(AB的A,J=12.4Hz,1H),5.13(AB的B,J=12.4Hz,1H),7.26-7.27(m,2H),7.31-7.38(m,6H),7.40-7.44(m,2H),7.49-7.56(m,4H),7.74(brd,J=8.6Hz,1H)。
实施例3-24:(R)-4-(3'-乙酰氨基联苯-4-基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯的合成
将(R)-4-(3'-氨基联苯-4-基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯(70.5mg,0.171mmol)、Et3N(0.027ml,0.205mmol)和Ac2O(0.019ml,0.205mmol)在DCM(1.7ml)中的溶液在室温下搅拌65小时。将该反应混合物用水稀释。将产物在分相器中用DCM萃取并浓缩得到粗品(98mg)。将该粗品用硅胶快速柱色谱进行纯化(洗脱剂:DCM/MeOH=10:1),从而得到(R)-4-(3'-乙酰氨基联苯-4-基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯(71.5mg);HPLC保留时间=1.45分钟(条件D);MS(m+1)=455.4;1HNMR(400MHz,CD3CN,旋转异构体的混合物,主要旋转异构体的数据)δppm1.21(t,J=7.1Hz,3H),2.07(s,3H),2.31-2.34(m,2H),2.40-2.51(m,4H),2.82-2.84(m,2H),3.58(s,3H),4.07(q,J=7.1Hz,2H),4.34-4.43(m,1H),6.46(brd,J=8.9Hz,1H),7.28-7.39(m,4H),7.52-7.54(m,3H),7.80(s,1H),8.37(brs,1H)。
实施例3-25:(R)-3-(4-丁氧基-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸的合成
将(R)-3-(4-丁氧基-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸苄酯(178.9mg,0.334mmol)和Pd/C(71.0mg,0.033mmol)在EtOAc(3ml)中的混悬液在氢气下、在室温下搅拌1.5小时。将该反应混合物过滤,浓缩,从而得到粗品。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而以白色固体形式得到(R)-3-(4-丁氧基-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸(90.7mg);HPLC保留时间=1.27分钟(条件B);MS(m+1)=446.24;1HNMR(400MHz,氯仿-d)δppm0.91(t,J=7.5Hz,3H),1.31-1.40(m,2H),1.55-1.62(m,2H),2.43-2.47(m,2H),2.52-2.69(m,4H),2.93(ABX的A,Jab=13.7Hz,Jax=7.7Hz,1H),3.00(ABX的B,Jab=13.7Hz,Jbx=6.8Hz,1H),4.07(t,J=6.7Hz,2H),4.49-4.57(m,1H),6.31(brd,J=8.6Hz,1H),7.26-7.37(m,4H),7.43-7.46(m,1H),7.49-7.52(m,2H),7.55(brt,J=1.8Hz,1H)。
手性HPLC保留时间=4.33min。柱:DaicelCHIRALPAKIA(4.6x100mm);流速=1ml/min.;洗脱剂:在10min内,EtOH(包含0.1%TFA)/庚烷=10/90至70/30(线性梯度)。
下面的化合物是用与实施例3-24所述操作类似的操作制备的:
实施例3-26:1HNMR(400MHz,氯仿-d)δppm1.23(t,J=7.1Hz,3H),1.86-1.93(m,2H),2.57(ABX的A,Jab=16.3Hz,Jax=5.7Hz,1H),2.64(ABX的B,Jab=16.3Hz,Jbx=5.2Hz,1H),2.94(ABX的A,Jab=13.7Hz,Jax=7.6Hz,1H),2.99(ABX的B,Jab=13.7Hz,Jbx=7.2Hz,1H),4.10(q,J=7.1Hz,2H),4.51-4.60(m,1H),6.17(brd,J=8.6Hz,1H),7.26-7.37(m,4H),7.43-7.45(m,1H),7.49-7.52(m,2H),7.55(brt,J=1.8Hz,1H)。
实施例3-27:1HNMR(400MHz,氯仿-d)δppm2.07(quint,J=7.4Hz,2H),2.51-2.63(m,4H),2.82-3.02(m,8H),4.50-4.59(m,1H),6.28(d,J=8.6Hz,1H),6.78-6.81(m,1H),6.91(d,J=1.8Hz,1H),7.26-7.36(m,6H),7.41-7.44(m,1H),7.47-7.50(m,2H),7.53-7.54(m,1H)。
实施例3-28:1HNMR(400MHz,氯仿-d)δppm1.24(t,J=7.2Hz,3H),2.44-2.69(m,6H),2.93(ABX的A,Jab=13.7Hz,Jax=7.8Hz,1H),3.00(ABX的B,Jab=13.7Hz,Jbx=6.7Hz,1H),4.12(q,J=7.2Hz,2H),4.49-4.57(m,1H),6.35(brd,J=8.6Hz,1H),7.26-7.37(m,4H),7.43-7.46(m,1H),7.49-7.52(m,2H),7.55(brt,J=1.6Hz,1H)。
实施例3-29:(R)-3-(4-(苄氧基)-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸的合成
将琥珀酸单苄酯(71.1mg,0.342mmol)、EDCI(65.5mg,0.342mmol)和HOAt(46.5mg,0.342mmol)在DMF(1ml)中的溶液在室温下搅拌1小时,将其加入到(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸(66mg,0.228mmol)和DIPEA(0.080ml,0.456mmol)在DMF(2ml)和水(2ml)的混合溶剂中的溶液中。将该反应混合物搅拌3小时,然后用H2O稀释。将产物用EtOAc萃取两次。将所合并的有机层用盐水洗涤,用Na2SO4干燥,过滤,浓缩,从而得到粗品。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而以白色固体形式得到(R)-3-(4-(苄氧基)-4-氧代丁烷酰氨基)-4-(3'-氯联苯-4-基)丁酸(42.4mg);HPLC保留时间=1.22分钟(条件B);MS(m+1)=480.35;1HNMR(400MHz,氯仿-d)δppm2.44-2.75(m,6H),2.86-2.99(m,2H),4.48-4.56(m,1H),5.11(s,2H),6.29(brd,J=8.6Hz,1H),6.97-7.07(m,10H),7.25-7.36(m,2H),7.42-7.50(m,2H),7.54(brt,J=1.6Hz,1H)。
实施例3-30:4-(联苯-4-基)-3-(1-(羧基甲基)环戊烷甲酰氨基)丁酸的合成
向4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯(110mg,0.267mmol)中加入4MHCl在1,4-二恶烷中的溶液(0.668ml,2.67mmol)。在搅拌1小时后,将该反应混合物浓缩,从而得到3-氨基-4-联苯-4-基-丁酸叔丁酯盐酸盐粗品。
接下来,向预先搅拌了1.5小时的EDCI(51.2mg,0.267mmol)、1-羟基-7-氮杂苯并三唑(36.4mg,0.267mmol)和6:1的1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酸和2-(1-(苄氧基羰基)环戊基)乙酸的混合物(65.6mg,0.214mmol)在DMF(1ml)中的溶液中加入3-氨基-4-联苯-4-基-丁酸叔丁酯盐酸盐粗品和DIPEA(0.093ml,0.535mmol)。在搅拌2.5小时后,将反应混合物用H2O稀释,并将产物用EtOAc萃取。将有机层用盐水洗涤,用Na2SO4干燥,过滤,浓缩。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至0:100),从而得到3-(1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酰氨基)-4-(联苯-4-基)丁酸叔丁酯粗品(38mg)。
接下来,向3-(1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酰氨基)-4-(联苯-4-基)丁酸叔丁酯粗品(38mg)在DCM(0.7ml)中的溶液中加入TFA(0.263ml,3.42mmol)。在搅拌1小时后,将该反应混合物浓缩,从而得到3-(1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酰氨基)-4-(联苯-4-基)丁酸粗品(39mg)。
接下来,将该粗品(39mg)和Pd/C(16.6mg,7.8μmol)在EtOH(1ml)中的混悬液在氢气下、在室温下搅拌4小时。将该反应混合物过滤,浓缩,从而得到粗品。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,从而得到4-(联苯-4-基)-3-(1-(羧基甲基)环戊烷甲酰氨基)丁酸(12.7mg);HPLC保留时间=1.16分钟(条件B);MS(m+1)=410.1;1HNMR(400MHz,DMSO-d6)δppm1.39-1.53(m,6H),1.83-1.98(m,2H),2.34-2.45(m,2H),2.53(s,2H),2.73-2.86(m,2H),4.21-4.33(m,1H),7.27(d,J=8.1Hz,2H),7.32-7.37(m,2H),7.43-7.46(m,2H),7.55-7.58(m,2H),7.62-7.64(m,2H),7.84(brd,J=8.9Hz,1H)。
实施例3-31:(R)-4-(3'-氯联苯-4-基)-3-(2-氧代-2,3-二氢唑-5-甲酰氨基)丁酸乙酯的合成
向(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基唑-5-甲酰氨基)丁酸乙酯(中间体14,103mg,0.23mmol)在二恶烷(3mL)中的溶液中加入4NHCl的二恶烷溶液(0.29mL,1.16mmol)。将该混合物在室温下搅拌2小时。将该混合物浓缩,用水和EtOAc稀释。将有机层用盐水洗涤,用MgSO4干燥,过滤,浓缩。将50%的该粗品用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),从而以白色固体形式得到(R)-4-(3’-氯联苯-4-基)-3-(2-氧代-2,3-二氢唑-5-甲酰氨基)丁酸乙酯(38mg)。HPLC保留时间=1.66分钟(条件A);MS(m+1)=429.4;1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.51-2.69(m,2H),2.95(dd,1H),3.05(dd,1H),4.19(q,2H),4.58-4.75(m,1H),6.83(d,J=8.8Hz,1H),7.26-7.33(m,4H),7.35(t,J=7.7Hz,1H),7.45(dt,J=7.6,1.5Hz,1H),7.51(d,J=8.3Hz,2H),7.56(t,J=1.8Hz,1H),8.45(br.s.,1H)。
实施例3-32:(R)-4-(3'-氯联苯-4-基)-3-(2-氧代-2,3-二氢噻唑-5-甲酰氨基)丁酸乙酯的合成
向(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基噻唑-5-甲酰氨基)丁酸乙酯(中间体13,170mg,0.37mmol)在二恶烷(5mL)中的溶液中加入4MHCl的二恶烷溶液(0.5mL,2.00mmol)。将该混合物在室温下搅拌3小时。将该混合物浓缩。将该粗品的一部分用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),从而以白色固体形式得到(95mg)(R)-4-(3'-氯联苯-4-基)-3-(2-氧代-2,3-二氢噻唑-5-甲酰氨基)丁酸乙酯。HPLC保留时间=1.82分钟(条件D);MS(m+1)=445.2。1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.46-2.70(m,2H),2.78-2.97(m,1H),3.07(dd,J=13.0,6.2Hz,1H),4.11-4.28(m,2H),4.51-4.69(m,1H),6.64(d,J=8.1Hz,1H),7.19-7.42(m,5H),7.44(d,J=6.1Hz,1H),7.48-7.62(m,3H),9.54(br.s.,1H)。
实施例3-33:(R)-4-(3'-氯联苯-4-基)-3-(5-氧代-4,5-二氢-1,3,4-二唑-2-甲酰氨基)丁酸乙酯的合成
在室温下,向(R)-4-(3'-氯联苯-4-基)-3-(2-肼基-2-氧代乙酰氨基)丁酸乙酯(中间体12,289mg,0.72mmol)在THF(8.5mL)中的溶液中加入CDI(139mg,0.86mmol)。在室温下搅拌18小时后,将该反应用H2O和1MHCl淬熄,将粗品用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-4-(3'-氯联苯-4-基)-3-(5-氧代-4,5-二氢-1,3,4-二唑-2-甲酰氨基)丁酸乙酯(100mg)。HPLC保留时间=1.67分钟(条件A);MS(m+1)=430.2;1HNMR(400MHz,DMSO-d6)δppm1.14(t,J=7.1Hz,3H),2.52-2.70(m,2H),2.84(dd,J=13.7,8.4Hz,1H),2.90(dd,J=13.7,8.4Hz,1H),4.02(q,J=7.1Hz,2H),4.42-4.58(m,1H),7.30(d,J=8.1Hz,2H),7.37-7.43(m,1H),7.47(t,J=7.8Hz,1H),7.57-7.66(m,3H),7.70(t,J=1.9Hz,1H),8.98(d,J=8.8Hz,1H),12.94(s,1H)。
实施例3-34:(R)-3-(3-羧基甲基-脲基)-4-(3'-氯-联苯-4-基)-丁酸乙酯的合成
向2-氨基乙酸叔丁酯(19.08mg,0.145mmol)和DIEA(18.8mg,0.145mmol)在DMF(1mL)中的溶液中加入中间体45(50mg,0.145mmol)并将该混合物在室温下搅拌2小时。减压除去溶剂,从而得到(R)-3-(3-叔丁氧基羰基甲基-脲基)-4-(3'-氯-联苯-4-基)-丁酸乙酯。
接下来,向上面的二酯(70mg,0.147mmol)在二氯甲烷(2mL)中的溶液中加入TFA(4mL)并将该混合物在室温下搅拌18小时。减压除去溶剂并将残余物用制备型HPLC进行纯化,用35%MeCN/水至100%MeCN(+0.1%TFA)梯度洗脱。将适当的级分冻干得到标题化合物;HPLC保留时间1.42分钟(条件C);MS419.1(M+1);1HNMR(400MHz,DMSO-d6):δppm1.17(t,J=7.07Hz,3H),2.41(d,J=7.07Hz,2H),2.77-2.79(m,2H),3.66-3.68(m,2H),4.04(q,J=7.07Hz,2H),4.08-4.15(m,1H),6.13(t,J=5.81Hz,1H),6.24(d,J=8.59Hz,1H),7.28-7.30(m,2H),7.39-7.42(m,1H),7.48(t,J=7.83Hz,1H),7.62-7.64(m,3H),7.71(t,J=1.77Hz,1H),12.42(s,1H)。
实施例4-1:(R)-4-联苯-4-基-3-(2-1H-四唑-5-基-乙酰基氨基)-丁酸乙酯的合成
在室温下,向(R)-4-联苯-4-基-3-叔丁氧基羰基氨基-丁酸乙酯(100mg,0.261mmol)在DCM(3mL)中的溶液中加入TFA(1mL,12.98mmol)并将该混合物在室温下搅拌0.5小时。将该混合物减压浓缩,从而得到(R)-3-氨基-4-联苯-4-基-丁酸乙酯三氟乙酸盐。HPLC保留时间=1.50分钟(条件C);MS(m+1)=384。
接下来,在室温下,向(R)-3-氨基-4-联苯-4-基-丁酸乙酯三氟乙酸盐(0.074g,0.261mmol)在DCM(10mL)中的混悬液中加入1H-四唑-5-乙酸(0.050g,0.392mmol)。在冰浴温度下,向该混合物中加入二(2-氧代-3-唑烷基)次膦酰氯(0.100g,0.392mmol),然后迅速加入DIPEA(0.137ml,0.783mmol)。将该反应混合物缓慢加温至室温并搅拌一夜。将该反应用DCM萃取。将所合并的有机层用饱和NaHCO3、饱和NH4Cl、盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩,从而得到(R)-4-联苯-4-基-3-(2-1H-四唑-5-基-乙酰基氨基)-丁酸乙酯。HPLC保留时间=1.04分钟(条件E);MS(m+1)=394。
实施例4-2:(R)-4-(联苯-4-基)-3-(6-(甲基磺酰氨基)烟酰氨基)丁酸乙酯的合成
在室温下,向(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(103mg,0.32mmol)和6-(甲基磺酰氨基)烟酸(中间体15,84mg,0.39mmol)在CH2Cl2(2mL)和DMF(2mL)中的溶液中加入TEA(0.18mL,1.29mmol)和HATU(159mg,0.42mmol)。将该混合物在室温下搅拌2小时。将该混合物用饱和NaHCO3淬熄,用EtOAc稀释。将有机层用水、盐水洗涤六次,用MgSO4干燥,过滤,浓缩。将该粗品用RP-HPLC纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),从而以白色固体形式得到(R)-4-(联苯-4-基)-3-(6-(甲基磺酰氨基)烟酰氨基)丁酸乙酯(4.1mg)。HPLC保留时间=1.61分钟(条件A);MS(m+1)=482.3。1HNMR(400MHz,氯仿-d)δppm1.22(t,J=7.2Hz,3H),2.56(t,J=4.8Hz,2H),2.84-2.92(m,1H),3.05(dd,J=13.6,6.1Hz,1H),3.16(s,3H),4.08-4.18(m,2H),4.57-4.71(m,1H),7.03(d,J=8.3Hz,1H),7.10(d,J=8.3Hz,1H),7.22(d,J=8.3Hz,2H),7.26-7.31(m,1H),7.33-7.40(m,2H),7.44-7.54(m,5H),7.98(dd,J=8.8,2.3Hz,1H),8.52(s,1H)。
下面的化合物是用与实施例4-2所述操作类似的操作制备的:
实施例4-3:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.52-2.67(m,2H),2.88(dd,J=13.3,8.0Hz,1H),2.95(dd,J=13.3,8.0Hz,1H),3.05(s,3H),4.02(q,J=7.1Hz,2H),4.46-4.65(m,1H),7.23(d,J=8.8Hz,2H),7.34(d,J=8.1Hz,2H),7.36-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.59-7.66(m,3H),7.69(t,J=1.8Hz,1H),7.75(d,J=8.6Hz,2H),8.31(d,J=8.3Hz,1H),10.07(s,1H)。
实施例4-4:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),1.28(t,J=7.5Hz,3H),2.59(d,J=7.1Hz,2H),2.81-2.94(m,2H),2.97(q,J=7.6Hz,2H),4.03(q,J=7.1Hz,2H),4.40-4.55(m,1H),7.32(d,J=8.1Hz,2H),7.36-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.58-7.65(m,3H),7.69(t,J=1.9Hz,1H),8.18(s,1H),8.52(d,J=8.3Hz,1H)。
实施例4-5:1HNMR(400MHz,CD3OD)δppm1.24(t,J=7.1Hz,3H),2.38-2.60(m,6H),2.78-2.94(m,2H),4.10(q,J=7.1Hz,2H),4.42-4.55(m,1H),7.32(d,J=8.3Hz,2H),7.40(t,J=7.83Hz,1H),7.50-7.53(m,4H),7.60(t,J=1.89Hz,1H)。
实施例4-6:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.2Hz,3H),1.25(t,J=7.6Hz,3H),2.53-2.65(m,2H),2.80(q,J=7.6Hz,2H),2.84-2.96(m,2H),4.02(q,J=7.1Hz,2H),4.42-4.60(m,1H),7.31(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.59(s,1H),7.60-7.65(m,3H),7.69(t,J=1.9Hz,1H),8.48(d,J=8.6Hz,1H)。
实施例4-7:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.52-2.65(m,2H),2.85(dd,J=13.6,5.8Hz,1H),2.91(dd,J=13.6,5.8Hz,1H),4.02(q,J=7.1Hz,2H),4.38-4.60(m,1H),5.89(s,1H),7.31(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.58-7.65(m,3H),7.69(t,J=1.8Hz,1H),8.10(d,J=8.6Hz,1H)。
实施例4-8:1HNMR(400MHz,CD3OD)δppm1.22(t,J=7.2Hz,3H),2.56-2.72(m,2H),2.95(d,J=7.3Hz,2H),4.11(q,J=7.2Hz,2H),4.53-4.73(m,1H),7.28-7.36(m,3H),7.39(t,J=7.8Hz,1H),7.48-7.55(m,3H),7.58(t,J=1.8Hz,1H)。
实施例4-9:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.53-2.71(m,2H),2.85(dd,J=13.7,8.3Hz,1H),2.96(dd,J=13.7,8.3Hz,1H),4.02(q,J=7.1Hz,2H),4.45-4.63(m,1H),6.93(dd,J=9.9,2.3Hz,1H),7.30(d,J=8.1Hz,2H),7.36-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.61(d,J=8.3Hz,3H),7.69(t,J=1.8Hz,1H),7.75(d,J=9.9Hz,1H),8.45(d,J=9.1Hz,1H),13.41(d,J=2.0Hz,1H)。
实施例4-10:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.60(d,J=7.6Hz,2H),2.90(d,J=6.8Hz,2H),4.02(q,J=7.2Hz,2H),4.39-4.53(m,1H),7.11(s,1H),7.32(d,J=8.1Hz,2H),7.37-7.43(m,1H),7.47(t,J=7.8Hz,1H),7.60-7.66(m,3H),7.70(t,J=1.9Hz,1H),8.72(d,J=8.3Hz,1H),11.76(br.s.,1H)。
实施例4-11:1HNMR(400MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H),2.47-2.69(m,2H),2.90(dd,J=13.6,7.8Hz,1H),3.06(dd,J=13.6,6.6Hz,1H),3.06(宽s,1H)4.07-4.28(m,2H),4.52-4.74(m,1H),7.21-7.37(m,5H),7.38-7.44(m,1H),7.48(d,J=8.1Hz,2H),7.53(t,J=1.6Hz,1H),9.50(br.s.,1H)。
实施例4-12:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.1Hz,3H),2.59(d,J=7.3Hz,2H),2.76-3.03(m,2H),4.03(q,J=7.1Hz,2H),4.39-4.66(m,1H),7.02(d,1H),7.28-7.54(m,4H),7.54-7.80(m,4H),8.05(dd,J=8.6,2.3Hz,1H),8.45(d,J=8.3Hz,1H),8.61(br.s.,1H)。
实施例4-13:(R)-4-(5'-氟-2'-甲氧基联苯-4-基)-3-(唑-5-甲酰氨基)丁酸乙酯的合成
向唑-5-甲酸(70mg,0.61mmol)在DMF(1.5mL)和DCM(1.5mL)的溶液中加入(R)-3-氨基-4-(5'-氟-2'-甲氧基联苯-4-基)丁酸乙酯盐酸盐(中间体10,150mg,0.41mmol)、HATU(233mg,0.61mmol)和TEA(284μL,2.04mmol)。在搅拌2小时后,将该反应用H2O淬熄,将该混合物用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-4-(5'-氟-2'-甲氧基联苯-4-基)-3-(唑-5-甲酰氨基)丁酸乙酯(157mg)。HPLC保留时间=1.50分钟(条件A);MS(m+1)=427.4;1HNMR(400MHz,氯仿-d)δppm1.19(t,J=7.2Hz,3H),2.46-2.62(m,2H),2.86(dd,J=13.6,8.1Hz,1H),3.02(dd,J=13.6,6.1Hz,1H),3.67(s,3H),4.05-4.15(m,2H),4.52-4.69(m,1H),6.76-6.82(m,1H),6.83-6.96(m,2H),7.11-7.21(m,3H),7.37(d,J=8.1Hz,2H),7.61(s,1H),7.80(s,1H)。
下面的化合物是用与实施例4-13所述操作类似的操作制备的:
实施例4-14:1HNMR(400MHz,CD3OD)δppm1.21(t,J=7.1Hz,3H),2.61-2.68(m,2H),2.95(d,J=7.1Hz,2H),3.74(s,3H),4.10(q,J=7.1Hz,2H),4.60-4.73(m,1H),6.43(s,1H),6.98-7.06(m,3H),7.27(d,J=8.1Hz,2H),7.38-7.48(m,2H),8.78(d,J=8.8Hz,1H)。
实施例4-15:5-[(R)-1-(3'-氯-联苯-4-基甲基)-2-乙氧基羰基-乙基氨基甲酰基]-1H-吡唑-3-甲酸的合成
向中间体17-1(130mg,0.367mmol)、1H-吡唑-3,5-二甲酸(74.5mg,0.477mmol)、EDCI(91mg,0.477mmol)和HOBt(64.5mg,0.477mmol)在DMF(3mL)中的混合物中加入三乙胺(149mg,0.203mmol)并将该混合物在室温下搅拌18小时。通过过滤除去任何不溶的物质并将滤液用HPLC进行色谱处理,用10%MeCN/水至100%MeCN(+0.1%TFA)梯度洗脱。将适当的级分冻干得到标题化合物;HPLC保留时间1.31分钟(条件C);MS456.2(M+1);1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.07Hz,3H),2.54-2.67(m,2H),2.84-2.97(m,2H),4.02(q,J=7.07Hz,2H),4.54(m,1H),7.11(s,宽峰,1H),7.32(d,J=8.08Hz,2H),7.39(m,1H),7.46(t,1H),7.62(d,J=8.08Hz,3H),7.69(s,1H),8.41(s,宽峰,1H)。
下面的化合物是用与实施例4-15所述操作类似的操作制备的。
实施例4-16:1HNMR(400MHz,DMSO-d6):δppm1.11(t,J=7.07Hz,3H),2.59-2.79(m,2H),2.87-2.92(m,1H),2.98-3.04(m,1H),4.01(q,J=7.33Hz,2H),4.57-4.66(m,1H),7.30-7.32(m,2H),7.37-7.40(m,1H),7.45(t,J=7.58Hz,1H),7.59-7.61(m,3H),7.68(t,J=1.77Hz,1H),8.16(s,1H),9.10(d,J=9.35Hz,1H),9.31(s,1H)。
实施例4-17:(R)-4-(3'-氯-联苯-4-基)-3-[(3-羟基-异唑-5-羰基)-氨基]-丁酸乙酯
向中间体16-1(40.6mg,0.315mmol)和HATU(144mg,0.378mmol)在DMF(2mL)中的溶液中加入吡啶(74.7mg,0.76mL,0.944mmol)并将该混合物在室温下搅拌15分钟。然后,加入中间体17-1并继续搅拌2小时。通过过滤除去任何不溶物并将滤液用HPLC进行色谱处理,用10%MeCN/水至100%MeCN(+0.1%TFA)梯度洗脱。将适当的级分冻干得到标题化合物。HPLC保留时间1.36分钟(条件C);MS429.1(M+1);1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.07Hz,3H),2.60(dd,J=6.95,3.66Hz,2H),2.81-2.95(m,2H),4.02(q,J=7.24Hz,2H),4.49(d,J=7.83Hz,1H),6.49(s,1H),7.31(d,J=8.34Hz,2H),7.37-7.43(m,1H),7.47(t,J=7.83Hz,1H),7.59-7.66(m,3H),7.70(t,J=1.89Hz,1H),8.83(d,J=8.84Hz,1H)。
下面的化合物是用与实施例4-17所述操作类似的操作制备的
实施例4-18:1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.07Hz,3H),2.60(dd,J=6.95,2.65Hz,2H),2.82-2.96(m,2H),4.02(q,J=7.07Hz,2H),4.45-4.58(m,1H),7.31(d,J=8.34Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.83Hz,1H),7.58-7.65(m,3H),7.69(t,J=1.77Hz,1H),7.72(s,1H),8.55(s,1H),8.63(d,J=8.59Hz,1H)。
实施例4-19:1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.07Hz,3H),2.54-2.75(m,2H),2.76-3.02(m,2H),4.02(q,J=7.07Hz,2H),4.29-4.70(m,1H),6.49(s,1H),6.96-7.23(m,1H),7.30(d,J=8.08Hz,2H),7.44-7.58(m,3H),7.64(d,J=8.08Hz,2H),8.83(d,J=8.59Hz,1H),11.68(s,1H)。
实施例4-20:(R)-3-[(5-羧基甲基-呋喃-2-羰基)-氨基]-4-(3'-氯-联苯-4-基)-丁酸乙酯和
实施例4-21:(R)-3-[(5-羧基甲基-呋喃-2-羰基)-氨基]-4-(3'-氯-联苯-4-基)-丁酸
该反应是与实施例4-15类似地用中间体16-1和中间体44来进行的,从而得到(R)-4-(3'-氯-联苯-4-基)-3-[(5-甲氧基羰基甲基-呋喃-2-羰基)-氨基]-丁酸乙酯。HPLC保留时间1.38分钟(条件C)。
接下来,向上面的二酯(235mg,0.486mmol)在EtOH(5mL)中的溶液中加入1NNaOH(0.486mL)并将该混合物在室温下搅拌4小时。减压除去溶剂并加入水(4mL)。将该溶液用1NHCl酸化并将该混合物用EtOAc萃取。将有机相用硫酸钠干燥并减压除去溶剂。将残余物用制备型HPLC进行纯化,用10%MeCN/水至100%MeCN(+0.1%TFA)梯度洗脱。将适当的级分冻干得到标题化合物。(R)-3-[(5-羧基甲基-呋喃-2-羰基)-氨基]-4-(3'-氯-联苯-4-基)-丁酸乙酯。HPLC保留时间1.35分钟(条件C);MS470.0(M+1);1HNMR(400MHz,DMSO-d6)δppm1.13(t,J=7.07Hz,3H),2.50-2.64(m,2H),2.81-2.95(m,2H),3.74(s,2H),4.01(q,J=7.07Hz,2H),4.51(m,1H),6.99(d,J=3.28Hz,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.62(d,J=8.08Hz,3H),7.69(t,1H),8.24(d,J=8.84Hz,1H)。(R)-3-[(5-羧基甲基-呋喃-2-羰基)-氨基]-4-(3'-氯-联苯-4-基)-丁酸。HPLC保留时间0.94分钟(条件C);MS442.0(M+1);1HNMR(400MHz,DMSO-d6)δppm2.44-2.58(m,2H),2.81-2.94(m,2H),3.74(s,2H),4.48(m,1H),6.39(d,J=3.28Hz,1H),6.99(d,J=3.54Hz,1H),7.30(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.62(d,J=8.34Hz,3H),7.70(t,J=1.77Hz,1H),8.22(d,J=8.84Hz,1H)。
实施例4-22:(R)-4-(3'-氯-联苯-4-基)-3-[(2H-四唑-5-羰基)-氨基]-丁酸乙酯
在室温下,向中间体16-1在DCM(8ml)中的溶液中加入2-(4-甲氧基-苄基)-2H-四唑-5-碳酰氯,然后加入TEA(0.293ml,2.100mmol)。将该反应在室温下搅拌5min。将该反应用盐水淬熄并用DCM萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将残余物用柱色谱进行纯化(15%至40%EtOAc/庚烷)。将所得残余物在TFA(5ml,64.9mmol)中在80℃下加热0.5小时。将该反应减压浓缩,从而得到(R)-4-(3'-氯-联苯-4-基)-3-[(2H-四唑-5-羰基)-氨基]-丁酸乙酯。
HPLC保留时间=1.31分钟(条件B);MS(m+1)=414.1;1HNMR(400MHz,DMSO-d6)δppm1.11(t,J=7.1Hz,3H),2.63(dd,J=15.4,5.6Hz,1H),2.72(dd,J=15.4,8.3Hz,1H),2.86-2.99(m,2H),4.02(q,J=7.1Hz,2H),4.55-4.67(m,1H),7.32(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.60(d,J=8.1Hz,3H),7.68(t,J=1.8Hz,1H),9.37(d,J=8.8Hz,1H)。
下面的化合物是用与实施例4-22所述操作类似的操作制备的:
实施例4-23:1HNMR(400MHz,DMSO-d6)δppm1.12(t,J=7.2Hz,3H),2.59-2.67(m,J=15.4,5.6Hz,1H),2.72(dd,J=15.4,8.3Hz,1H),2.85-3.01(m,2H),4.02(q,J=7.1Hz,2H),4.55-4.67(m,1H),7.11-7.19(m,1H),7.32(d,J=8.3Hz,2H),7.42-7.51(m,3H),7.61(d,J=8.3Hz,2H),9.34(d,J=8.8Hz,1H)。
实施例4-24:1HNMR(400MHz,DMSO-d6)δppm1.95-2.06(m,2H),2.75-2.92(m,6H),2.95(dd,J=13.5,5.9Hz,1H),3.06(dd,J=13.6,8.1Hz,1H),4.64-4.76(m,1H),6.78(dd,J=8.1,2.3Hz,1H),6.88(d,J=1.5Hz,1H),7.17(d,J=8.1Hz,1H),7.34-7.41(m,3H),7.46(t,J=7.8Hz,1H),7.59-7.65(m,3H),7.70(t,J=1.8Hz,1H),8.43(d,J=8.8Hz,1H)。
实施例4-25:2-((R)-1-联苯-4-基甲基-2-乙氧基羰基-乙基氨基)-唑-4-甲酸乙基酯
在冰浴上,向(R)-4-联苯-4-基-3-脲基-丁酸乙酯(169mg,0.518mmol)在EtOH(5ml)中的混悬液中加入溴代丙酮酸乙酯(0.098ml,0.777mmol)。使该反应缓慢加温至室温并将其在回流下搅拌一夜。将该反应浓缩,将残余物吸收于EtOAc和H2O中。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩,从而得到2-((R)-1-联苯-4-基甲基-2-乙氧基羰基-乙基氨基)-唑-4-甲酸乙酯。HPLC保留时间=1.42分钟(条件B);MS(m+1)=423。
实施例4-26:(R,E)-4-(4-(苄氧基)-1-(3'-氯联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁-2-烯酸乙酯的合成
在室温下,向(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯(87.6mg,0.183mmol)中加入HCl在1,4-二恶烷中的溶液(0.456mL,1.825mmol)。在搅拌3小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯盐酸盐。将(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯盐酸盐、富马酸单乙酯(33.4mg,0.220mmol)、EDCI(63.3mg,0.330mmol)、DIPEA(0.058ml,0.330mmol)和HOAt(44.9mg,0.330mmol)在DMF(1.8ml)中的混合物在室温下搅拌3小时。将该反应混合物用水稀释,然后将产物用EtOAc进行萃取。将有机层用NH4OH、1MHCl水溶液和盐水洗涤,用Na2SO4干燥,过滤,浓缩,从而得到粗品。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至0:100),从而得到(R,E)-4-(4-(苄氧基)-1-(3'-氯联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁-2-烯酸乙酯(72.9mg);HPLC保留时间=1.40分钟(条件B);MS(m+1)=506.3;1HNMR(400MHz,氯仿-d)δppm1.31(t,J=7.1Hz,3H),2.58(ABX的A,Jab=16.4Hz,Jax=5.3Hz,1H),2.6(ABX的B,Jab=16.4Hz,Jbx=5.1Hz,1H),2.88(ABX的A,Jab=13.6Hz,Jax=8.1Hz,1H),3.03(ABX的B,Jab=13.6Hz,Jbx=6.3Hz,1H),4.24(q,J=7.1Hz,2H),4.56-4.64(m,1H),5.12(AB的A,J=12.1Hz,1H),5.18(AB的B,J=12.1Hz,1H),6.57(brd,J=9.1Hz,1H),6.77(AB的A,J=15.4Hz,1H),6.81(AB的B,J=15.4Hz,1H),7.19(brd,J=8.1Hz,2H),7.29-7.47(m,10H),7.53-7.54(m,1H)。
实施例4-27:(R)-4-(3'-氯联苯-4-基)-3-(2-(乙氧基羰基氨基)乙酰氨基)丁酸乙酯的合成
将(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(173mg,0.488mmol)、2-(乙氧基羰基氨基)乙酸(86mg,0.488mmol)、EDCI(140mg,0.732mmol)、DIPEA(0.128ml,0.732mmol)和HOAt(100mg,0.732mmol)在DMF(2.5ml)中的混合物在室温下搅拌1小时。将该反应混合物用水稀释,然后将沉淀出来的固体收集在漏斗上,用H2O洗涤,减压干燥,从而得到粗品。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至0:100),从而得到(R)-4-(3'-氯联苯-4-基)-3-(2-(乙氧基羰基氨基)乙酰氨基)丁酸乙酯(161mg);HPLC保留时间=1.16分钟(条件B);MS(m+1)=447.3;1HNMR(400MHz,氯仿-d)δppm1.25(t,J=7.07Hz,3H),1.29(t,J=7.07Hz,3H),2.50(ABX的A,Jab=16.2Hz,Jax=5.3Hz,1H),2.54(ABX的B,Jab=16.2Hz,Jbx=5.3Hz,1H),2.89(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.99(ABX的B,Jab=13.6Hz,Jbx=6.6Hz,1H),3.80(bed,J=5.8Hz,2H),4.12-4.23(m,4H),4.48-4.56(m,1H),5.15(brs,1H),6.64(brd,J=8.8Hz,1H),7.25-7.27(m,2H),7.29-7.38(m,2H),7.43-7.46(m,1H),7.49-7.52(m,2H),7.55-7.56(m,1H)。
下面的化合物是用与实施例4-27所述操作类似的操作制备的:
实施例4-29:1HNMR(400MHz,氯仿-d)δppm1.31(t,J=7.2Hz,3H),2.64(ABX的A,Jab=16.8Hz,Jax=5.1HZ,1H),2.68(ABX的B,Jab=16.8Hz,Jbx=5.1Hz,1H),2.97(ABX的A,Jab=13.7Hz,Jax=8.1HZ,1H),3.08(ABX的B,Jab=13.7Hz,Jbx=6.7Hz,1H),4.25(q,J=7.2Hz,2H),4.58-4.67(m,1H),6.66(d,J=8.8Hz,1H),6.80(AB的A,J=15.4Hz,1H),6.97(AB的B,J=15.4Hz,1H),7.27-7.37(m,4H),7.43-7.45(m,1H),7.51(d,J=8.3Hz,2H),7.55-7.56(m,1H)。
实施例4-30:1HNMR(400MHz,CD3OD)δppm1.21(t,J=7.2Hz,3H),1.34(t,J=7.6Hz,3H),2.68(d,J=6.8Hz,2H),2.84-2.87(m,2H),2.98-3.00(m,2H),4.10(q,J=7.1Hz,2H),4.66-4.78(m,1H),7.27-7.37(m,6H),7.41-7.47(m,1H),7.54(s,1H)。
实施例4-31:1HNMR(400MHz,CD3OD)δppm1.20(t,J=7.1Hz,3H),2.28(s,3H),2.62(d,J=7.1Hz,2H),2.93(dd,J=13.6,6.8Hz,1H),3.00(dd,J=13.6,7.3Hz,1H),4.09(q,J=7.1Hz,2H),4.60-4.76(m,1H),6.45(s,1H),7.24-7.40(m,4H),7.42-7.51(m,3H),7.54(t,J=1.8Hz,1H)。
实施例4-32:1HNMR(400MHz,CD3OD)δppm1.20(t,J=7.2Hz,3H),2.58-2.66(m,2H),2.68(s,3H),2.94(dd,J=14.2,7.8Hz,1H),2.99(dd,J=13.6,6.8Hz,1H),4.09(q,J=7.2Hz,2H),4.58-4.76(m,1H),7.27-7.31(m,1H),7.33(d,J=8.3Hz,2H),7.37(t,J=7.8Hz,1H),7.46-7.49(m,1H),7.51(d,J=8.1Hz,2H),7.55(t,J=1.9Hz,1H),8.06(s,1H),8.49(d,J=8.6Hz,1H)。
实施例4-33:1HNMR(400MHz,CD3OD)δppm1.21(t,J=7.1Hz,3H),2.60-2.70(m,2H),2.72(s,3H),2.97(dd,J=13.6,8.1Hz,1H),3.03(dd,J=13.9,6.6Hz,1H),4.11(q,J=7.2Hz,2H),4.67-4.81(m,1H),7.27-7.33(m,1H),7.33-7.41(m,3H),7.48-7.52(m,1H),7.54(d,J=8.3Hz,2H),7.57(t,J=1.8Hz,1H),8.70(d,J=8.3Hz,1H),8.92(s,2H)。
实施例4-34:1HNMR(400MHz,CD3OD)δppm1.21(t,J=7.2Hz,3H),2.43(s,3H),2.63(d,J=6.6Hz,2H),2.94(dd,J=13.9,7.1Hz,1H),2.99(dd,J=13.6,7.6Hz,1H),4.10(q,J=7.1Hz,2H),4.62-4.74(m,1H),7.26-7.30(m,1H),7.30-7.39(m,3H),7.43-7.51(m,3H),7.53(t,J=1.8Hz,1H),8.15(s,1H)。
实施例4-35:1HNMR(400MHz,CD3OD)δppm1.20(t,J=7.1Hz,3H),2.64(dd,J=15.4,7.3Hz,1H),2.70(dd,J=15.9,6.3Hz,1H),2.99(d,J=7.3Hz,2H),4.10(q,J=7.2Hz,2H),4.65-4.79(m,1H),7.14(dd,J=10.2,8.7Hz,1H),7.30(ddd,J=8.8,4.1,2.8Hz,1H),7.32-7.37(m,2H),7.37-7.46(m,3H),7.67(s,1H),8.28(s,1H),8.62(d,J=8.6Hz,1H)。
实施例4-36:1HNMR(400MHz,CD3OD)δppm1.20(t,J=7.2Hz,3H),1.33(t,J=7.7Hz,3H),2.66(d,J=6.8Hz,2H),2.83(q,J=7.6Hz,2H),2.98(d,J=7.1Hz,2H),4.10(q,J=7.1Hz,2H),4.65-4.79(m,1H),7.14(dd,J=10.2,8.7Hz,1H),7.30(ddd,J=8.8,4.1,2.8Hz,1H),7.32-7.37(m,2H),7.37-7.46(m,3H),7.54(s,1H),8.49(d,J=8.8Hz,1H)。
实施例4-37:1HNMR(400MHz,氯仿-d)δppm1.33(t,J=7.1Hz,3H),2.22(s,3H),2.57-2.72(m,2H),2.99(dd,J=13.6,8.1Hz,1H),3.16(dd,J=13.6,6.3Hz,1H),4.15-4.33(m,2H),4.60-4.82(m,1H),5.55(s,1H),6.10(s,1H),7.15(d,J=8.8Hz,1H),7.34(d,J=8.1Hz,3H),7.39(t,J=7.7Hz,1H),7.48(dt,J=7.6,1.5Hz,1H),7.54(d,J=8.1Hz,2H),7.58(t,J=1.8Hz,1H),7.72(s,1H)。
实施例5-1:(R)-4-(联苯-4-基)-3-(3-羧基丙酰氨基)丁酸的合成
在室温下,向(R)-4-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(61.2mg,0.160mmol)在THF(1.6mL)和甲醇(0.2mL)中的溶液中加入1MNaOH水溶液(0.638mL,0.638mmol)。在搅拌45分钟后,将该反应用0.1MHCl水溶液淬熄并用乙酸乙酯萃取。将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩,从而得到(R)-4-(联苯-4-基)-3-(3-羧基丙酰氨基)丁酸(54.9mg)。HPLC保留时间=1.33分钟(条件A);MS(m+1)=356.1;1HNMR(400MHz,CD3OD)δppm2.40-2.56(m,6H),2.83-2.94(m,2H),4.43-4.50(m,1H),7.29-7.32(m,3H),7.41(t,2H,J=7.7Hz),7.53-7.60(m,4H)。
下面的化合物是用与实施例5-1所述操作类似的操作制备的:
实施例5-2:1HNMR(400MHz,CD3OD)δppm2.38-2.42(m,2H),2.45-2.54(m,4H),2.82-2.94(m,2H),4.42-4.48(m,1H),7.12-7.16(m,2H),7.31(d,J=8.4Hz,2H),7.41(d,J=8.6Hz,2H),7.54(d,J=8.1Hz,2H),7.58(d,J=8.6Hz,2H)。
实施例5-3:1HNMR(400MHz,CD3OD)δppm2.39-2.42(m,2H),2.45-2.54(m,4H),2.85(ABX的A,Jab=13.6Hz,Jax=7.6HZ,1H),2.91(ABX的B,Jab=13.6Hz,Jbx=6.2HZ,1H),4.42-4.48(m,1H),7.12-7.16(m,2H),7.31(AB的A,J=8.2Hz,2H),7.52(AB的B,J=8.2Hz,2H),7.58-7.62(m,2H)。
实施例5-4:1HNMR(400MHz,CD3OD)δppm2.39-2.44(m,2H),2.46-2.55(m,4H),2.86(ABX的A,Jab=13.6Hz,Jax=7.6HZ,1H),2.92(ABX的B,Jab=13.6Hz,Jbx=6.3HZ,1H),4.42-4.49(m,1H),7.01-7.06(m,1H),7.32(brd,J=8.1Hz,2H),7.39-7.45(m,2H),7.55(d,J=8.1Hz,2H)。
实施例5-5:1HNMR(400MHz,CD3OD)δppm2.40-2.43(m,2H),2.46-2.56(m,4H),2.87(ABX的A,Jab=13.5Hz,Jax=7.7HZ,1H),2.93(ABX的B,Jab=13.5Hz,Jbx=6.2HZ,1H),4.43-4.50(m,1H),7.13-7.18(m,1H),7.20-7.24(m,1H),7.31-7.35(m,3H),7.44-7.48(m,3H),7.99(brd,J=8.3Hz,1H)。
实施例5-6:1HNMR(400MHz,CD3OD)δppm2.39-2.43(m,2H),2.45-2.57(m,4H),2.87(ABX的A,Jab=13.6Hz,Jax=7.6HZ,1H),2.94(ABX的B,Jab=13.6Hz,Jbx=6.1HZ,1H),4.44-4.51(m,1H),7.28-7.35(m,7H),7.46(brd,J=7.9Hz,1H)。
实施例5-7:1HNMR(400MHz,CD3OD)δppm2.40-2.52(m,6H),2.83-2.92(m,2H),3.77(s,3H),4.44-4.47(m,1H),6.96-7.05(m,2H),7.23-7.30(m,4H),7.39-7.41(m,2H)。
实施例5-8:1HNMR(400MHz,CD3OD)δppm2.21(s,3H),2.41-2.55(m,6H),2.82-2.94(m,2H),3.77(s,3H),4.45-4.48(m,1H),7.15-7.28(m,8H)。
实施例5-9:1HNMR(400MHz,DMSO-d6)δppm2.56(dd,J=5.81,15.92Hz,1H),2.66(dd,J=7.07,15.92Hz,1H),2.90(dd,J=6.06,13.64Hz,1H),3.00(dd,J=8.08,13.64Hz,1H),4.53-4.64(m,1H),7.30(d,J=8.34Hz,2H),7.33(t,J=7.58,1H),7.56(d,J=8.34Hz,2H),7.62(d,J=7.07Hz,2H),7.95(dd,J=1.26,5.05Hz,1H),9.01-9.07(m,2H),9.33(d,J=1.52Hz,1H),12.28(s,1H)。
实施例5-10:1HNMR(400MHz,DMSO-d6)δppm2.36-2.49(m,2H),2.75-2.86(m,2H),3.83(s,2H),4.19-4.31(m,1H),7.26(d,J=8.3Hz,2H),7.31-7.38(m,1H),7.45(t,J=7.6Hz,2H),7.56(d,J=8.3Hz,2H),7.61-7.67(m,2H),8.40(d,J=8.1Hz,1H),12.26(br.s.,1H),16.02(br.s.,1H)。
实施例5-11:1HNMR(400MHz,DMSO-d6)δppm2.46-2.59(m,2H),2.86-2.88(m,2H),4.41-4.49(m,1H),7.29-7.36(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.26(d,J=8Hz,1H),8.64(brs,2H),12.24(br.s.,1H)。
实施例5-12:1HNMR(400MHz,DMSO-d6)δppm2.54-2.70(m,2H),2.88-3.03(m,2H),4.56-4.65(m,1H),7.29-7.34(m,3H),7.41-7.45(m,2H),7.55-7.63(m,4H),8.33(s,1H),9.15(d,J=9.1Hz,1H),9.49(s,1H),12.30(brs,1H),14.11(brs,1H)。
实施例5-13:1HNMR(400MHz,CD3OD)δppm2.38-2.57(m,6H),2.87(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.95(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),4.44-4.51(m,1H),7.06-7.14(m,2H),7.31-7.37(m,5H),7.48(dd,J=8.8和5.1Hz,1H)。
实施例5-14:1HNMR(400MHz,CD3OD)δppm2.39(s,3H),2.39-2.55(m,6H),2.85(ABX的A,Jab=13.5Hz,Jax=7.5HZ,1H),2.90(ABX的B,Jab=13.5Hz,Jbx=6.4Hz,1H),4.42-4.49(m,1H),7.13(brd,J=7.3Hz,1H),7.26-7.30(m,3H),7.36-7.40(m,2H),7.52(d,J=8.3Hz,2H)。
实施例5-15:1HNMR(400MHz,CD3OD)δppm2.38-2.55(m,6H),2.86(ABX的A,Jab=13.6Hz,Jax=7.8HZ,1H),2.93(ABX的B,Jab=13.6Hz,Jbx=6.1HZ,1H),4.42-4.49(m,1H),6.86-6.92(m,1H),7.19-7.25(m,2H),7.33-7.35(m,2H),7.55-7.58(m,2H)。
实施例5-16:1HNMR(400MHz,CD3OD)δppm1.27(t,J=7.6Hz,3H),2.39-2.55(m,6H),2.70(q,J=7.6Hz,2H),2.85(ABX的A,Jab=13.6Hz,Jax=7.5HZ,1H),2.90(ABX的B,Jab=13.6Hz,Jbx=6.4HZ,1H),4.42-4.49(m,1H),7.16(brd,J=7.6Hz,1H),7.28-7.33(m,3H),7.38-7.42(m,2H),7.52-7.54(m,2H)。
实施例5-17:1HNMR(400MHz,DMSO-d6)δppm2.47-2.50(m,2H),2.82-2.91(m,2H),4.40-4.49(m,1H),7.29(d,J=8.3Hz,2H),7.31-7.36(m,1H),7.42-7.46(m,2H),7.59(d,J=8.4Hz,2H),7.63-7.65(m,2H),7.95(brd,J=2.3Hz,1H),8.11(brd,J=2.3Hz,1H),8.25-8.27(m,1H),12.24(brs,1H),12.48(brs,1H)。
实施例5-18:1HNMR(400MHz,CD3OD)δppm2.38-2.55(m,6H),2.86(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.92(ABX的B,Jab=13.6Hz,Jbx=6.3Hz,1H),4.43-4.50(m,1H),7.26(brd,J=7.3Hz,1H),7.35(d,J=8.1Hz,2H),7.51-7.58(m,4H),7.64(brd,J=7.8Hz,1H)。
实施例5-19:1HNMR(400MHz,CD3OD)δppm2.39-2.42(m,2H),2.45-2.56(m,4H),2.88(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.95(ABX的B,Jab=13.6Hz,Jbx=6.2Hz,1H),4.44-4.51(m,1H),6.86-6.89(m,1H),7.38-7.41(m,2H),7.63-7.70(m,3H),8.02-8.04(m,1H),8.18-8.21(m,1H),8.45(brt,J=1.9Hz,1H)。
实施例5-20:1HNMR(400MHz,CD3OD)δppm2.39-2.56(m,6H),2.87(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.93(ABX的B,Jab=13.6Hz,Jbx=6.3Hz,1H),4.43-4.50(m,1H),7.36(d,J=8.3Hz,2H),7.58-7.62(m,4H),7.85-7.87(m,2H)。
实施例5-21:1HNMR(400MHz,CD3OD)δppm2.39-2.54(m,6H),2.85(ABX的A,Jab=13.6Hz,Jax=7.5Hz,1H),2.91(ABX的B,Jab=13.6Hz,Jbx=6.3HZ,1H),3.84(s,3H),4.42-4.49(m,1H),6.86-6.89(m,1H),7.11-7.17(m,2H),7.29-7.34(m,3H),7.52-7.54(m,2H)。
实施例5-22:1HNMR(400MHz,DMSO-d6)δppm2.43-2.46(m,2H),2.81-2.91(m,2H),4.40-4.49(m,1H),6.33(d,J=9.6Hz,1H),7.28-7.35(m,3H),7.42-7.46(m,2H),7.58(d,J=8.1Hz,2H),7.63-7.65(m,2H),7.81(dd,J=9.6,2.8Hz,1H),7.93(brs,1H),8.14(d,J=8.3Hz,1H),11.92(brs,1H),12.19(brs,1H)。
实施例5-23:1HNMR(400MHz,CD3OD)δppm2.39-2.42(m,2H),2.44-2.55(m,4H),2.86(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.93(ABX的B,Jab=13.6Hz,Jbx=6.3HZ,1H),4.43-4.50(m,1H),7.36(d,J=8.3Hz,2H),7.58-7.63(m,3H),7.66-7.69(m,1H),7.91-7.94(m,1H),7.97(brt,J=1.5Hz,1H)。
实施例5-24:1HNMR(400MHz,DMSO-d6)δppm2.50-2.61(m,2H),2.83-2.94(m,2H),4.43-4.52(m,1H),6.82(s,1H),7.28-7.35(m,3H),7.44(t,J=7.7Hz,2H),7.58-7.65(m,4H),8.12(s,1H),8.86(d,J=8.3Hz,1H),9.55(s,1H),12.25(brs,1H)。
实施例5-25:1HNMR(400MHz,DMSO-d6)δppm1.66-2.47(m,10H),2.71-2.83(m,2H),3.31-3.46(m,3H),4.18-4.49(m,2H),7.26-7.28(m,2H),7.32-7.36(m,1H),7.43-7.47(m,2H),7.57-7.66(m,4H),7.86(d,J=8.3Hz,1H),12.31(brs,2H)。
实施例5-26:1HNMR(400MHz,DMSO-d6)δppm1.80-2.03(m,3H),2.27-2.31(m,1H),2.39-2.52(m,2H),2.75-2.81(m,1H),2.85-2.89(m,1H),2.95-3.03(m,1H),3.41-3.78(m,2H),3.90-3.99(m,1H),4.14-4.20(m,1H),4.28-4.35(m,1H),7.28-7.37(m,3H),7.44-7.48(m,2H),7.58-7.65(m,2H),8.45(brs,1H),12.34(brs,1H)。
实施例5-27:1HNMR(400MHz,CD3OD)δppm2.38-2.54(m,6H),2.86(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.93(ABX的B,Jab=13.6Hz,Jbx=6.2HZ,1H),4.42-4.49(m,1H),7.13-7.17(m,1H),7.31-7.37(m,3H),7.46-7.47(m,1H),7.54-7.57(m,2H)。
实施例5-28:1HNMR(400MHz,CD3OD)δppm1.49-1.71(m,6H),2.01-2.11(m,2H),2.14-2.21(m,1H),2.44-2.56(m,3H),2.83(ABX的A,Jab=13.6Hz,Jax=8.0Hz,1H),2.91(ABX的B,Jab=13.6Hz,Jbx=6.3HZ,1H),4.43-4.51(m,1H),7.28-7.32(m,3H),7.38-7.42(m,2H),7.52(d,J=8.1Hz,2H),7.56-7.59(m,2H),7.71(brd,J=8.6Hz,1H)。
实施例5-29:1HNMR(400MHz,CD3OD)δppm2.39-2.42(m,2H),2.45-2.56(m,4H),2.87(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.94(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),4.44-4.51(m,1H),7.23(AB的A,J=8.0Hz,2H),7.28(AB的B,J=8.0Hz,2H),7.35(d,J=7.6Hz,1H),7.50-7.53(m,1H),7.60-7.63(m,1H),7.75(d,J=7.8Hz,1H)。
实施例5-30:1HNMR(400MHz,DMSO-d6)δppm2.45-2.56(m,2H),2.83-2.93(m,2H),4.43-4.52(m,1H),7.18(s,2H),7.29-7.35(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.19(d,J=8.1Hz,1H),8.60(s,2H),12.21(brs,1H)。
实施例5-31:1HNMR(400MHz,CD3OD)δppm2.39-2.43(m,2H),2.46-2.57(m,4H),2.90(ABX的A,Jab=13.6Hz,Jax=7.8Hz,1H),2.97(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),4.45-4.52(m,1H),7.37-7.39(m,2H),7.49-7.53(m,3H),7.57-7.59(m,1H),7.70-7.74(m,1H),7.80-7.82(m,1H)。
实施例5-32:1HNMR(400MHz,CD3OD)δppm1.33-1.49(m,4H),1.68-1.72(m,1H),1.79-1.83(m,1H),1.96-2.01(m,2H),2.05-2.13(m,1H),2.17-2.25(m,1H),2.43-2.55(m,2H),2.80-2.95(m,2H),4.42-4.49(m,1H),7.28-7.32(m,3H),7.38-7.43(m,2H),7.52-7.59(m,4H)。
实施例5-33:1HNMR(400MHz,DMSO-d6)δppm2.48-2.55(m,2H),2.84-2.96(m,2H),4.44-4.53(m,1H),6.94(brs,1H),7.30-7.35(m,3H),7.42-7.46(m,2H),7.57-7.64(m,4H),8.17-8.60(brm,5H),12.27(brs,1H)。
实施例5-34:1HNMR(400MHz,CD3OD)δppm1.30(t,J=7.0Hz,3H),2.39-2.56(m,6H),2.82-2.93(m,2H),4.02(q,J=7.0Hz,2H),4.42-4.49(m,1H),6.96-7.03(m,2H),7.23-7.28(m,4H),7.44(d,J=8.4Hz,2H)。
实施例5-35:1HNMR(400MHz,CD3OD)δppm2.14(s,3H),2.39-2.43(m,2H),2.45-2.56(m,4H),2.82-2.94(m,2H),4.02(q,J=7.0Hz,2H),4.42-4.49(m,1H),7.30-7.38(m,4H),7.49-7.55(m,3H),7.80(brs,1H)。
实施例5-36:1HNMR(400MHz,CD3OD)δppm2.39-2.55(m,6H),2.85(ABX的A,Jab=13.6Hz,Jax=7.5HZ,1H),2.90(ABX的B,Jab=13.6Hz,Jbx=6.3HZ,1H),4.42-4.49(m,1H),6.86-6.92(m,1H),7.31(d,J=8.1Hz,2H),7.53-7.55(m,2H)。
实施例5-37:(R)-4-(1-羧基-3-(5'-氟-2'-甲氧基联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸的合成
向(R)-4-(4-乙氧基-1-(5'-氟-2'-甲氧基联苯-4-基)-4-氧代丁烷-2-基氨基)-4-氧代丁酸(83mg,0.192mmol)在MeOH(2mL)中的溶液中加入1NNaOH(4mL,4mmol)。在室温下搅拌2小时后,将该混合物减压浓缩除去MeOH并用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干得到(R)-4-(1-羧基-3-(5'-氟-2'-甲氧基联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸(58mg)。HPLC保留时间=1.46分钟(条件D);MS(m+1)=404.2;1HNMR(400MHz,CD3OD)δppm2.36-2.59(m,6H),2.84(dd,J=13.4,6.3Hz,1H),2.91(dd,J=13.4,6.3Hz,1H),3.75(s,3H),4.34-4.56(m,1H),6.95-7.08(m,3H),7.26(d,J=8.1Hz,2H),7.42(d,J=8.3Hz,2H)。
下面的化合物是用与实施例5-37所述操作类似的操作制备的:
实施例5-38:1HNMR(400MHz,CD3OD)δppm2.65(d,J=7.1Hz,2H),2.91-3.07(m,2H),3.26(s,3H),4.70(m,1H),7.04(d,J=8.8Hz,1H),7.26-7.33(m,1H),7.33-7.44(m,3H),7.47-7.56(m,3H),7.57(t,J=1.9Hz,1H),8.02(dd,J=8.8,2.5Hz,1H),8.55(d,J=1.78Hz,1H)。
实施例5-39:1HNMR(400MHz,CD3OD)δppm2.36-2.60(m,6H),2.84(dd,J=13.4,6.1Hz,1H),2.91(dd,J=13.4,6.1Hz,1H),3.77(s,3H),4.34-4.58(m,1H),7.03(d,J=8.6Hz,1H),7.18-7.31(m,4H),7.39(d,J=8.1Hz,2H)。
实施例5-40:1HNMR(400MHz,DMSO-d6)δppm2.51-2.70(m,2H),2.79-2.99(m,2H),3.05(s,3H),4.41-4.62(m,1H),7.22(d,J=8.8Hz,2H),7.33(d,J=8.1Hz,2H),7.36-7.43(m,1H),7.46(t,J=7.8Hz,1H),7.56-7.66(m,3H),7.69(t,J=1.8Hz,1H),7.76(d,J=8.6Hz,2H),8.30(d,J=8.3Hz,1H),10.09(s,1H),12.24(s,1H)。
实施例5-41:1HNMR(400MHz,DMSO-d6)δppm1.28(t,J=7.6Hz,3H),2.51-2.60(m,2H),2.84-2.94(m,2H),2.97(q,J=7.6Hz,2H),4.36-4.56(m,1H),7.32(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.60-7.66(m,3H),7.70(t,J=1.8Hz,1H),8.23(s,1H),8.60(d,J=8.3Hz,1H),12.30(br.s.,1H)。
实施例5-42:1HNMR(400MHz,DMSO-d6)δppm2.23-2.31(m,2H),2.31-2.43(m,4H),2.76(d,J=6.6Hz,2H),4.16-4.30(m,1H),6.87-7.02(m,2H),7.07(dd,J=9.6,3.0Hz,1H),7.21(d,J=8.3Hz,2H),7.50(d,J=8.1Hz,2H),7.90(d,J=8.1Hz,1H),9.51(br.s.,1H)。
实施例5-43:1HNMR(400MHz,CD3OD)δppm2.33-2.60(m,6H),2.85(dd,J=13.7,6.1Hz,1H),2.94(dd,J=13.7,6.1Hz,1H),3.45(s,3H),4.35-4.57(m,1H),7.14(t,J=7.8Hz,1H),7.21-7.34(m,3H),7.38(dd,J=8.0,1.6Hz,1H),7.47(d,J=8.3Hz,2H)。
实施例5-44:1HNMR(400MHz,CD3OD)δppm2.64(d,J=5.8Hz,2H),3.01(d,J=6.8Hz,2H),4.51-4.74(m,1H),7.00(br.s.,1H),7.25-7.35(m,3H),7.40(t,J=7.6Hz,2H),7.53(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,2H),8.21(br.s.,1H)。
实施例5-45:1HNMR(400MHz,CD3OD)δppm2.38-2.55(m,6H),2.85(dd,J=13.6,6.3,Hz,1H),2.93(dd,J=13.6,6.3,Hz,1H),4.40-4.56(m,1H),7.27-7.37(m,3H),7.40(t,J=7.8Hz,1H),7.54-7.56(m,3H),7.60(t,J=1.8Hz,1H)。
实施例5-46:1HNMR(400MHz,DMSO-d6)δppm2.51-2.63(m,2H),2.84(dd,J=13.6,8.3Hz,1H),2.89(dd,J=13.6,8.3Hz,1H),4.40-4.55(m,1H),7.30(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.58-7.66(m,3H),7.70(t,J=1.9Hz,1H),8.95(d,J=8.6Hz,1H),12.93(s,1H)。
实施例5-47:1HNMR(400MHz,DMSO-d6)δppm1.25(t,J=7.6Hz,3H),2.51-2.59(m,2H),2.80(q,J=7.6Hz,2H),2.84-2.94(m,2H),4.41-4.56(m,1H),7.31(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.59(s,1H),7.63(d,J=8.3Hz,3H),7.70(t,J=1.9Hz,1H),8.45(d,J=8.6Hz,1H),12.27(br.s.,1H)。
实施例5-48:1HNMR(400MHz,CD3OD)δppm1.33(t,J=7.6Hz,3H),2.64(d,J=6.8Hz,2H),2.84(q,J=7.6Hz,2H),2.98(d,J=7.01Hz,2H),3.72(s,3H),4.62-4.75(m,1H),6.94-7.06(m,3H),7.27(d,J=8.1Hz,2H),7.40(d,J=8.3Hz,2H),7.54(s,1H)。
实施例5-49:1HNMR(400MHz,DMSO-d6)δppm2.51-2.62(m,2H),2.84(dd,J=13.7,7.9Hz,1H),2.91(dd,J=13.7,7.9Hz,1H),3.73(s,3H),4.42-4.55(m,1H),7.05-7.19(m,3H),7.25(d,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),7.73(s,1H),8.55(s,1H),8.63(d,J=8.6Hz,1H)。
实施例5-50:1HNMR(400MHz,CD3OD)δppm2.69(d,J=6.8Hz,2H),2.95-3.10(m,2H),4.68-4.79(m,1H),7.21-7.33(m,1H),7.33-7.47(m,4H),7.49-7.65(m,4H),7.76-7.97(m,2H),8.20-8.42(m,1H)。
实施例5-51:1HNMR(400MHz,CD3OD)δppm2.62(d,J=6.6Hz,2H),2.96(d,J=7.3Hz,2H),4.54-4.68(m,1H),7.28-7.36(m,3H),7.40(t,J=7.7Hz,2H),7.56(dd,J=17.2,7.8Hz,4H)。
实施例5-52:1HNMR(400MHz,CD3OD)δppm2.34-2.45(m,2H),2.45-2.59(m,4H),2.86(dd,J=13.4,6.0Hz,1H),2.93(dd,J=13.4,6.0Hz,1H),4.40-4.55(m,1H),7.19-7.26(m,1H),7.34(d,J=8.1Hz,2H),7.46-7.49(m,1H),7.51(t,J=8.0Hz,1H),7.56(d,J=8.3Hz,2H),7.61(d,J=7.8Hz,1H)。
实施例5-53:1HNMR(400MHz,DMSO-d6)δppm2.04-2.26(m,2H),2.31-2.46(m,2H),2.69-2.88(m,2H),2.94-3.21(m,2H),4.18-4.37(m,1H),7.28(d,J=7.1Hz,2H),7.35-7.43(m,1H),7.43-7.54(m,2H),7.63(d,J=8.2Hz,3H),7.70(t,J=1.9Hz,1H),7.98(dd,J=8.3,2.3Hz,1H),12.22(br.s.,1H)。
实施例5-54:1HNMR(400MHz,CD3OD)δppm2.57(s,3H),2.68(d,J=6.6Hz,2H),2.92-3.08(m,2H),4.64-4.74(m,1H),7.25-7.33(m,1H),7.33-7.44(m,3H),7.44-7.55(m,3H),7.57(t,J=1.8Hz,1H)。
实施例5-55:1HNMR(400MHz,CD3OD)δppm2.64(d,J=6.3Hz,2H),2.97(d,J=7.1Hz,2H),3.74(s,3H),4.58-4.73(m,1H),6.43(s,1H),6.96-7.08(m,3H),7.27(d,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),8.71(d,J=8.3Hz,1H)。
实施例5-56:1HNMR(400MHz,DMSO-d6)δppm2.52-2.67(m,2H),2.80-2.96(m,2H),4.38-4.54(m,1H),5.90(br.s.,1H),7.30(d,J=8.1Hz,2H),7.35-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.61(d,J=8.3Hz,3H),7.69(t,J=1.9Hz,1H),8.08(br.s.,1H)。
实施例5-57:1HNMR(400MHz,CD3OD)δppm2.48-2.55(m,1H),2.64(d,J=6.8Hz,1H),2.88-3.00(m,2H),4.32-4.69(m,1H),7.26-7.35(m,3H),7.41(t,J=7.5Hz,2H),7.49-7.65(m,4H)。
实施例5-58:1HNMR(400MHz,CD3OD)δppm2.62(d,J=6.6Hz,2H),2.92-3.01(m,2H),4.59-4.64(m,1H),7.28-7.43(m,4H),7.48-7.56(m,3H),7.59(t,J=1.9Hz,1H)。
实施例5-59:1HNMR(400MHz,CD3OD)δppm2.64(d,J=6.6Hz,2H),3.01(d,J=7.1Hz,2H),4.63-4.75(m,1H),7.05(d,J=8.1Hz,1H),7.26-7.32(m,1H),7.35(d,J=8.3Hz,2H),7.37-7.43(m,2H),7.44(d,J=1.0Hz,1H),7.48(dd,J=8.1,1.77Hz,1H),7.52-7.60(m,4H)。
实施例5-60:1HNMR(400MHz,CD3OD)δppm2.30-2.44(m,2H),2.44-2.64(m,4H),2.87(dd,J=13.7,6.4Hz,1H),2.95(dd,J=13.7,6.4Hz,1H),4.42-4.53(m,1H),7.27-7.52(m,8H)。
实施例5-61:1HNMR(400MHz,DMSO-d6)δppm2.22-2.32(m,2H),2.32-2.44(m,4H),2.76(d,J=6.6Hz,2H),4.16-4.29(m,1H),6.82-6.88(m,1H),6.89-6.97(m,1H),7.08-7.17(m,1H),7.17-7.28(m,3H),7.47(d,J=8.1Hz,2H),7.90(d,J=8.1Hz,1H),9.47(br.s.,1H),12.14(br.s.,1H)。
实施例5-62:1HNMR(400MHz,DMSO-d6)δppm2.22-2.31(m,2H),2.33-2.42(m,4H),2.72-2.85(m,2H),3.72(s,3H),4.16-4.34(m,1H),6.92(ddd,J=9.4,3.79,1.8Hz,1H),7.21-7.33(m,4H),7.34-7.45(m,1H),7.92(d,J=8.1Hz,1H),12.14(br.s.,2H)。
实施例5-63:1HNMR(400MHz,DMSO-d6)δppm2.42-2.48(m,2H),2.85(d,J=6.8Hz,2H),4.30-4.46(m,1H),6.99(s,1H),7.30(d,J=8.1Hz,2H),7.36-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.63(d,J=8.1Hz,3H),7.67-7.77(m,2H),10.13(br.s.,1H),10.22(br.s.,1H),12.26(br.s.,1H)。
实施例5-64:1HNMR(400MHz,CD3OD)δppm2.35-2.60(m,6H),2.85(dd,J=13.7,6.4Hz,1H),2.93(dd,J=13.7,6.4Hz,1H),3.65(s,3H),4.37-4.58(m,1H),7.05-7.18(m,3H),7.30(d,J=8.1Hz,2H),7.44(d,J=8.3Hz,2H)。
实施例5-65:1HNMR(400MHz,CD3OD)δppm2.38-2.56(m,6H),2.85(dd,J=13.4,7.3Hz,1H),2.89(dd,J=13.4,7.3Hz,1H),4.40-4.52(m,1H),7.26-7.35(m,3H),7.36-7.46(m,2H),7.52-7.61(m,3H)。
实施例5-66:1HNMR(400MHz,CD3OD)δppm2.31-2.58(m,6H),2.68-2.99(m,2H),3.63(s,3H),4.33-4.56(m,1H),6.92-7.18(m,3H),7.30-7.38(m,1H),7.38-7.46(m,2H)。
实施例5-67:1HNMR(400MHz,DMSO-d6)δppm2.51-2.65(m,2H),2.86(dd,J=13.7,8.1Hz,1H),2.95(dd,J=13.7,8.1Hz,1H),4.42-4.61(m,1H),6.89-6.99(m,1H),7.30(d,J=8.3Hz,2H),7.37-7.42(m,1H),7.42-7.51(m,1H),7.62(d,J=8.1Hz,3H),7.69(t,J=1.8Hz,1H),7.76(d,J=9.9Hz,1H),8.41(d,J=9.1Hz,1H),12.26(br.s.,1H),13.40(s,1H)。
实施例5-68:1HNMR(400MHz,DMSO-d6)δppm2.51-2.57(m,2H),2.90(d,J=6.8Hz,2H),4.34-4.52(m,1H),7.15(s,1H),7.31(d,J=8.1Hz,2H),7.39(dd,J=7.6,1.77Hz,1H),7.47(t,J=7.8Hz,1H),7.59-7.66(m,3H),7.70(t,J=1.8Hz,1H),8.74(d,J=8.6Hz,1H)。
实施例5-69:1HNMR(400MHz,CD3OD)δppm2.61(d,J=6.6Hz,2H),2.89-3.02(m,2H),4.53-4.71(m,1H),7.16-7.37(m,4H),7.39(t,J=7.8Hz,1H),7.45-7.57(m,3H),7.59(t,J=1.8Hz,1H),8.20(d,1H)。
实施例5-70:1HNMR(400MHz,DMSO-d6)δppm2.41-2.57(m,2H),2.73-2.96(m,2H),4.35-4.46(m,1H),7.30(d,J=8.3Hz,2H),7.35-7.44(m,1H),7.47(t,J=7.8Hz,1H),7.57-7.67(m,4H),7.70(t,J=1.9Hz,1H),8.23(d,J=8.3Hz,1H),11.14(s,1H),12.29(br.s.,1H)。
实施例5-71:1HNMR(400MHz,CD3OD)δppm2.58(dd,J=6.8,1.8Hz,2H),2.95(dd,J=7.0,3.4Hz,2H),4.53-4.66(m,1H),7.27-7.36(m,3H),7.36-7.43(m,2H),7.49-7.57(m,3H)7.59(t,J=1.7Hz,1H)。
实施例5-72:1HNMR(400MHz,CD3OD)δppm2.60-2.71(m,2H),3.03(dd,J=6.9,4.7Hz,2H),3.28(s,3H),4.65-4.76(m,1H),7.06(d,J=8.8Hz,1H),7.23-7.38(m,3H),7.38-7.47(m,2H),7.50-7.64(m,5H),8.03(dd,J=8.8,2.3Hz,1H),8.17(d,1H),8.56(br.s.,1H)。
实施例5-73:1HNMR(400MHz,DMSO-d6)δppm2.43-2.59(m,2H),2.82-2.95(m,2H),4.04-4.16(m,1H),7.30(d,J=8.3Hz,2H),7.34(t,J=7.3Hz,1H),7.45(t,J=7.6Hz,2H),7.59(d,J=8.1Hz,3H),7.64(d,J=8.6Hz,2H),8.03(s,1H),12.45(br.s.,2H)。
实施例6-1:(R)-3-(联苯-4-基甲基)-4-(2-羧基乙基氨基)-4-氧代丁酸的合成
在室温下,向(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸(22.1mg,0.060mmol)在THF(0.6mL)和甲醇(0.1mL)中的溶液中加入1MNaOH水溶液(0.12mL,0.12mmol)。在搅拌3小时后,再加入1MNaOH水溶液(0.12mL,0.12mmol)。将该反应混合物搅拌30分钟并用0.5mL1MHCl水溶液以及0.5mL盐水淬熄。将该混合物用乙酸乙酯萃取两次,将有机层减压浓缩,从而得到(R)-3-(联苯-4-基甲基)-4-(2-羧基乙基氨基)-4-氧代丁酸(16.4mg)。HPLC保留时间=1.04分钟(条件A);MS(m+1)=356.1;1HNMR(400MHz,DMSO-d6)δppm2.13-2.31(m,3H),2.59-2.65(m,1H),2.81-2.90(m,2H),3.12-3.27(m,2H),7.26(d,2H,J=8Hz),7.34(t,1H,J=7.4Hz),7.45(t,2H,J=7.7Hz),7.57(d,2H,J=8.1Hz),7.63-7.65。
实施例7-1:(R)-3-联苯-4-基甲基-N-羧基甲基-琥珀酰胺酸的合成
将(R)-3-(联苯-4-基甲基)-4-(2-叔丁氧基-2-氧代乙基氨基)-4-氧代丁酸叔丁酯(40mg,0.088mmol)和TFA(0.5mL,6.49mmol)在DCM(1.5mL)中的溶液在室温下搅拌2小时。将该反应减压浓缩,将所得残余物混悬于DCM(0.5mL)和庚烷(2mL)中,在漏斗上对其进行收集,得到(R)-3-联苯-4-基甲基-N-羧基甲基-琥珀酰胺酸(9.6mg)。HPLC保留时间=1.26分钟(条件A);MS(m+1)=342.0;1HNMR(400MHz,CD3OD)δppm2.39(dd,J=16.67,5.31Hz,1H),2.63-2.82(m,2H),2.98-3.14(m,2H),3.84和3.95(AB,2H,J=17.8Hz),7.26-7.33(m,3H),7.40(t,J=7.71Hz,2H),7.56(dd,J=19.96,8.08Hz,4H)。
下面的化合物是用与实施例7-1所述操作类似的操作制备的:
实施例7-2:1HNMR(400MHz,DMSO-d6)δppm1.51-1.58(m,2H),2.12-2.21(m,3H),2.49-2.65(m,2H),2.81-2.89(m,2H),2.94-3.08(m,2H),7.26(d,2H,J=8.1Hz),7.32-7.36(m,1H),7.43-7.46(m,2H),7.57(d,2H,J=8.0Hz),7.63-7.65(m,2H)。
实施例8-1:(R)-4-(2-联苯-4-基甲基-3-羧基-丙酰基氨基)-2-甲基-戊酸的合成
向进行着搅拌的2-联苯-4-基甲基-琥珀酸4-叔丁基酯(100mg,0.29mmol)在DMF(10mL)中的溶液中加入HOBt(45mg,0.29mmol)和EDCI(56mg,0.29mmol)并将该混合物在室温下搅拌10分钟,然后加入(2R,4R)-4-氨基-2-甲基-戊酸乙酯三氟乙酸盐(47mg,0.29mmol)和三乙胺(89mg,0.87mmol)并将该混合物在室温下搅拌5小时。将该混合物用水淬熄并用乙酸乙酯萃取。将有机层用水、盐水洗涤,用硫酸镁干燥并过滤。减压除去溶剂,从而得到(2R,4R)-7-联苯-4-基甲基-2,4-二甲基-6-氧代-壬二酸9-叔丁酯1-乙酯。
接下来,向(2R,4R)-7-联苯-4-基甲基-2,4-二甲基-6-氧代-壬二酸9-叔丁酯1-乙酯的EtOH溶液(4mL)中加入1MNaOH水溶液(4mL)并将该混合物在室温下搅拌30分钟。用1MHCl水溶液将该混合物酸化至pH2-3并用乙酸乙酯萃取。减压除去溶剂并将残余物用制备型HPLC进行纯化,用10-100%MeCN/水(0.1%TFA)梯度洗脱。将适当的级分冻干,得到(R)-4-(2-联苯-4-基甲基-3-羧基-丙酰基氨基)-2-甲基-戊酸。HPLC保留时间=1.13分钟(条件C);MS398.2(M+1);1H-NMR(400MHz,DMSO-d6)δppm0.93(m,6H),1.23(m,1H),1.59(m,1H),2.17(m,1H),2.63(m,1H),2.82(m,1H),3.72(m,1H),7.27(m,2H),7.33(m,1H),7.45(m,2H),7.56(m,2H),7.62(m,2H),7.71(m,1H),12.07(s,1H)。
实施例9-1:(R)-4-联苯-4-基-3-[(1H-四唑-5-羰基)-氨基]-丁酸的合成
向(R)-3-[(1-苄基-1H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯和(R)-3-[(2-苄基-2H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯的混合物(180mg,0.383mmol)的EtOH(1mL)和THF(1mL)溶液中加入1MLiOH水溶液(2mL)。在搅拌0.5小时后,将该反应混合物用1MHCl水溶液酸化。将该混合物用乙酸乙酯萃取,用Na2SO4干燥并减压浓缩。将残余物溶解于MeOH中并用10%Pd/C在室温下氢化3小时,然后在40℃下氢化2小时。将反应混合物浓缩并用反相HPLC进行纯化,从而得到(R)-4-联苯-4-基-3-[(1H-四唑-5-羰基)-氨基]-丁酸。HPLC保留时间=1.18分钟(条件D);MS(m+1)=352;1HNMR(400MHz,DMSO-d6)δppm2.56(dd,J=5.81,15.92Hz,1H),2.67(dd,J=7.58,15.92Hz,1H),2.85-2.99(m,2H),4.55-4.64(m,1H),7.26-7.35(m,3H),7.43(dd,J=7.83,7.83Hz,2H),7.56(d,J=8.08Hz,2H),7.62(d,J=7.07Hz,2H),9.28(d,8.84Hz,1H),12.28(s,1H)。
实施例10-1:(R)-4-联苯-4-基-3-(3-1H-四唑-5-基-丙酰基氨基)-丁酸
在室温下,向(R)-4-联苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四唑-5-基]-丙酰基氨基}-丁酸乙酯(137mg,0.297mmol)在DCM(8mL)中的溶液中加入DBU(1.507mL,10.00mmol)并将该混合物在室温下搅拌2小时。将该反应用DCM萃取。将所合并的有机层用饱和NH4Cl、盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将所得残余物用快速柱色谱进行纯化(硅胶,2%至10%EtOH/DCM),从而得到(R)-4-联苯-4-基-3-(3-1H-四唑-5-基-丙酰基氨基)-丁酸乙酯(37mg)。在室温下,向所得酯的EtOH(2mL)溶液中加入1MNaOH水溶液(1mL,1.0mmol)并将该混合物在室温下搅拌1小时。向该反应中加入1mL1MHCl水溶液至pH=4,并将该混合物用反相HPLC进行纯化[30%至60%乙腈-H2O(0.1%TFA)],从而得到(R)-4-联苯-4-基-3-(3-1H-四唑-5-基-丙酰基氨基)-丁酸。HPLC保留时间=1.24分钟(条件C);MS(m+1)=380;1HNMR(400MHz,DMSO-d6)δppm2.37(dd,J=6.7,2.1Hz,2H),2.53(t,J=7.6Hz,2H),2.69-2.82(m,2H),3.02(t,J=7.7Hz,2H),4.17-4.29(m,1H),7.22(d,J=8.3Hz,2H),7.34(tt,J=7.3,1.3Hz,1H),7.42-7.48(m,2H),7.57(d,J=8.3Hz,2H),7.64(dd,J=8.2,1.1Hz,2H),8.00(d,J=8.1Hz,1H),12.21(br.s.,1H),15.92(br.s.,1H)。
手性HPLC保留时间=5.64min。柱:DaicelCHIRALCELOJ-H(4.6x100mm);流速=1ml/min.;洗脱剂:EtOH(包含0.1%TFA)/庚烷=2/8。
实施例11-1:(R)-4-(1-羧基-3-(3'-氯联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸的合成
在室温下,向(R)-4-(1-(联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(110mg,0.263mmol)在THF(2mL)和甲醇(0.2mL)中的溶液中加入1MNaOH水溶液(1.053mL,1.053mmol)。在搅拌1小时后,将该反应用0.1MHCl水溶液淬熄,将该溶液用DCM(15ml)稀释并将其搅拌1.5小时。将沉淀出来的固体收集在漏斗上,依次用水、DCM、庚烷和DCM洗涤并将其减压干燥,从而得到(R)-4-(1-羧基-3-(3'-氯联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸(66mg)。HPLC保留时间=0.87分钟(条件B);MS(m+1)=390.0;1HNMR(400MHz,CD3OD)δppm2.39-2.55(m,6H),2.86(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.92(ABX的B,Jab=13.6Hz,Jbx=6.2Hz,1H),4.42-4.49(m,1H),7.30-7.34(m,3H),7.40(t,J=7.4Hz,1H),7.51-7.56(m,3H),7.60(t,J=1.8Hz,1H)。
下面的化合物是用与实施例11-1所述操作类似的操作制备的:
实施例11-2:1HNMR(400MHz,CD3OD)δppm1.76-1.83(m,2H),2.15-2.21(m,4H),2.49(ABX的A,Jab=15.7Hz,Jax=7.3Hz,1H),2.53(ABX的B,Jab=15.7Hz,Jbx=6.1Hz,1H),2.83(ABX的A,Jab=13.6Hz,Jax=8.3Hz,1H),2.93(ABX的B,Jab=13.6Hz,Jbx=5.8Hz,1H),4.46-4.53(m,1H),7.30-7.33(m,3H),7.39(t,,J=7.8Hz,1H),7.51-7.55(m,3H),7.59-7.60(m,1H)。
实施例11-3:1HNMR(400MHz,CD3OD)δppm1.77-1.84(m,2H),2.16-2.23(m,4H),2.39-2.42(m,2H),2.49(ABX的A,Jab=15.6Hz,Jax=7.5Hz,1H),2.53(ABX的B,Jab=15.6Hz,Jbx=6.1Hz,1H),2.83(ABX的A,Jab=13.6Hz,Jax=6.1Hz,1H),2.91(ABX的B,Jab=13.6Hz,Jbx=6.3Hz,1H),3.75(s,3H),4.46-4.53(m,1H),6.97-7.04(m,2H),7.26(d,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H)。
实施例11-4:1HNMR(400MHz,CD3OD)δppm1.77-1.84(m,2H),2.16-2.24(m,4H),2.49(ABX的A,Jab=15.6Hz,Jax=7.5Hz,1H),2.54(ABX的B,Jab=15.6Hz,Jbx=6.1Hz,1H),2.83(ABX的A,Jab=13.6Hz,Jax=8.2Hz,1H),2.91(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),3.77(s,3H),4.45-4.52(m,1H),7.03(d,J=8.6Hz,1H),7.24-7.28(m,3H),7.39-7.41(m,2H)。
实施例11-5:1HNMR(400MHz,CD3OD)δppm1.49-1.56(m,4H),2.13(t,J=6.8Hz,2H),2.23(t,J=6.9Hz,2H),2.45-2.56(m,2H),2.80-2.86(m,1H),2.91-2.96(m,1H),4.46-4.53(m,1H),7.31-7.33(m,3H),7.40(t,J=8.0Hz,1H),7.52-7.55(m,3H),7.59(brt,J=1.8Hz,1H)。
实施例11-6:1HNMR(400MHz,CD3OD)δppm2.39-2.57(m,4H),2.80(ABX的A,Jab=13.6Hz,Jax=8.1Hz,1H),2.89(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),3.04(t,J=7.1Hz,2H),3.75(s,3H),4.40-4.47(m,1H),7.27-7.29(m,2H),7.32-7.35(m,1H),7.41(t,J=7.8Hz,1H),7.51-7.54(m,3H),7.59-7.60(m,1H),7.83-7.84(m,1H),8.28(brd,J=7.1Hz,1H),8.55(d,J=5.6Hz,1H),8.62(s,1H)。
实施例11-7:1HNMR(400MHz,CD3OD)δppm2.47(ABX的A,Jab=15.7Hz,Jax=7.7HZ,1H),2.54(ABX的B,Jab=15.7Hz,Jbx=5.8Hz,1H),2.64-2.75(m,2H),2.80(ABX的A,Jab=13.7Hz,Jax=8.3Hz,1H),2.92(ABX的B,Jab=13.7Hz,Jbx=5.9Hz,1H),3.17-3.21(m,2H),4.43-4.50(m,1H),7.28-7.35(m,3H),7.39-7.43(m,1H),7.51-7.54(m,3H),7.59(brt,J=1.9Hz,1H),7.69-7.75(m,2H),8.29-8.32(m,1H),8.61(d,J=4.6Hz,1H)。
实施例11-8:1HNMR(400MHz,氯仿-d)δppm1.82-1.89(m,2H),2.29(t,J=7.3Hz,2H),2.56(ABX的A,Jab=16.4Hz,Jax=5.6Hz,1H),2.64(ABX的B,Jab=16.4Hz,Jbx=5.1Hz,1H),2.95(ABX的A,Jab=13.8Hz,Jax=7.6Hz,1H),2.99(ABX的B,Jab=13.8Hz,Jbx=7.2Hz,1H),3.30(s,3H),3.38(t,J=5.9Hz,2H),4.10(q,J=7.1Hz,2H),4.52-4.57(m,1H),6.59(brd,J=8.6Hz,1H),7.26-7.37(m,4H),7.42-7.45(m,1H),7.48-7.52(m,2H),7.55(brt,J=1.6Hz,1H)。
实施例11-9:1HNMR(400MHz,CD3CN+D2O)δppm2.43-2.56(m,2H),2.71-2.91(m,4H),3.21-3.34(m,2H),4.39-4.46(m,1H),7.27(d,J=8.3Hz,2H),7.34-7.49(m,7H),7.55-7.56(m,1H),7.65-7.70(m,2H)。
实施例11-10:1HNMR(400MHz,CD3OD)δppm2.38-2.41(m,2H),2.47-2.58(m,4H),2.85-2.90(m,1H),2.99-3.04(m,1H),4.48-4.55(m,1H),7.32-7.44(m,5H),7.53-7.56(m,1H),7.62-7.63(m,1H)。
实施例11-11:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.44-2.52(m,2H),2.83-2.85(d,J=6.82Hz,2H),4.29-4.38(m,1H),7.28-7.30(d,J=8.34Hz,2H),7.40-7.43(t,J=7.83Hz,1H),7.62-7.65(m,3H),7.71-7.72(t,J=1.77Hz,1H),9.42-9.45(m,1H),12.32(s,1H)。
实施例11-12:1HNMR(400MHz,DMSO-d6)δppm2.54-2.59(m,1H),2.64-2.70(m,1H),2.88-2.93(m,1H),2.98-3.03(m,1H),4.56-4.63(m,1H),7.30-7.32(m,2H),7.37-7.40(m,1H),7.43-7.47(t,J=7.83Hz,1H),7.59-7.61(m,3H),7.67-7.68(t,J=2.02Hz,1H),8.32(d,J=1.26Hz,1H),9.17-9.19(d,J=9.09Hz,1H),9.50(d,J=1.52Hz,1H),12.34(s,1H),14.14(s,1H)。
实施例11-13:1HNMR(400MHz,DMSO-d6)δppm2.46-2.60(m,2H),2.84-2.96(m,2H),4.51(m,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.46(t,1H),7.62(d,J=8.34Hz,3H),7.69(t,1H)。
实施例11-14:1HNMR(400MHz,DMSO-d6)δppm)2.75-2.99(m,1H),4.47(d,J=7.58Hz,1H),6.49(s,1H),7.30(d,J=8.34Hz,1H),7.37-7.43(m,1H),7.47(t,J=7.83Hz,1H),7.63(d,J=8.08Hz,2H),7.70(t,J=1.77Hz,1H),8.80(d,J=8.59Hz,1H),11.69(s,1H),12.04-12.58(m,1H)。
实施例11-15:1HNMR(400MHz,DMSO-d6)δppm2.81-2.96(m,2H),4.42-4.55(m,1H),7.31(d,J=8.34Hz,2H),7.36-7.43(m,1H),7.47(t,J=7.83Hz,1H),7.63(d,J=8.34Hz,4H),7.69(t,J=1.77Hz,1H),7.72(s,1H),8.54(s,1H),8.60(d,J=8.59Hz,1H),12.29(br.s.,1H)。
实施例11-16:1HNMR(400MHz,DMSO-d6)δppm2.53-2.64(m,2H),2.84-2.93(m,2H),4.41-4.59(m,1H),7.00(d,J=2.02Hz,1H),7.31(d,J=8.08Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.83Hz,1H),7.58-7.65(m,3H),7.70(t,J=1.77Hz,1H),8.72(d,J=1.77Hz,1H),8.95(d,J=8.59Hz,1H),12.31(br.s.,1H)。
实施例11-17:1HNMR(400MHz,DMSO-d6)δppm2.46-2.60(m,2H),2.83-2.98(m,2H),4.52(m,1H),6.61(d,J=2.27Hz,1H),7.31(d,J=8.34Hz,2H),7.37-7.42(m,1H),7.46(t,1H),7.62(d,J=8.34Hz,3H),7.69(t,1H),7.74(d,J=2.02Hz,1H),8.13(d,J=8.84Hz,1H)。
实施例11-18:1HNMR(400MHz,DMSO-d6)δppm2.48-2.62(m,2H),2.84-2.96(m,2H),4.52(m,1H),7.16(d,J=3.54Hz,1H),7.27(d,J=3.79Hz,1H),7.31(d,J=8.34Hz,2H),7.38-7.41(m,1H),7.47(t,1H),7.63(d,J=8.34Hz,3H),7.70(t,1H),8.59(d,J=8.59Hz,1H)。
实施例11-19:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.54-2.67(m,2H),2.88-2.92(m,1H),2.99-3.05(m,1H),4.53-4.62(m,1H),7.31-7.33(m,2H),7.37-7.39(m,1H),7.43-7.47(t,J=7.58Hz,1H),7.60-7.62(m,3H),7.68(m,1H),7.86-7.87(d,J=4.55Hz,1H),8.30(s,1H),8.62-8.63(d,J=4.80Hz,1H),8.80-8.83(d,J=9.09Hz,1H)。
实施例11-20:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.50-2.53(m,1H),2.56-2.59(t,J=6.32Hz,1H),2.90-2.98(m,2H),4.51-4.58(m,1H),7.33-7.35(d,J=8.34Hz,2H),7.39-7.42(m,1H),7.45-7.49(t,J=7.83Hz,1H),7.61-7.65(m,3H),7.69-7.70(t,J=1.77Hz,1H),7.90-7.91(dd,J=1.77Hz,5.05Hz,1H),8.38-8.39(m,1H),8.83-8.85(dd,J=0.76Hz,5.05Hz,1H),8.91-8.93(d,J=8.34Hz,1H)。
实施例11-21:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.45-2.55(m,1H),2.59-2.67(m,1H),2.88-2.93(m,1H),2.99-3.05(m,1H),4.51-4.61(m,1H),7.32-7.34(d,J=8.08Hz,2H),7.37-7.40(m,1H),7.44-7.48(t,J=7.58Hz,1H),7.60-7.62(t,J=7.83Hz,2H),7.69(s,1H),7.77(s,1H),8.86-8.87(d,J=4.04Hz,1H),9.06(s,1H)。
实施例11-22:1HNMR(400MHz,DMSO-d6):δppm2.49-2.53(m,2H),2.90-2.92(d,J=6.82Hz,2H),4.42-4.51(m,1H),6.72-6.73(d,J=2.27Hz,2H),7.32-7.34(m,2H),7.39-7.42(m,1H),7.45-7.49(t,J=7.83Hz,1H),7.62-7.66(m,3H),7.70-7.71(t,J=1.77Hz,1H),8.27-8.29(d,J=8.08Hz,1H),11.96(s,1H),12.33(s,1H),12.75(s,1H)。
实施例11-23:1HNMR(400MHz,DMSO-d6):1HNMR(400MHz,DMSO-d6):δppm2.44-2.55(m,2H),2.79-2.89(m,2H),4.29-4.38(m,1H),7.27-7.29(d,J=8.08Hz,2H),7.39-7.42(m,1H),7.45-7.49(t,J=8.08Hz,1H),7.62-7.64(d,J=8.08Hz,3H),7.70-7.71(m,1H),8.85-8.87(d,J=9.09Hz,1H),12.30(s,1H)。
实施例11-24:1HNMR(400MHz,DMSO-d6)δppm2.46-2.60(m,2H),2.84-2.96(m,2H),4.51(m,1H),7.15(m,2H),7.44-7.52(m,3H),7.62(d,J=8.34Hz,2H),8.38(d,宽峰,J=7.58Hz,1H)。
实施例11-25:1HNMR(400MHz,DMSO-d6):δppm2.54-2.59(m,1H),2.64-2.70(m,1H),2.88-2.93(m,1H),2.98-3.03(m,1H),4.56-4.65(m,1H),7.13-7.18(m,1H),7.30-7.32(d,J=8.34Hz,2H),7.45-7.48(m,3H),7.60-7.62(d,J=8.34Hz,2H),8.31-8.32(d,J=1.26Hz,1H),8.17-8.19(d,J=9.09Hz,1H),8.49(d,J=1.26Hz,1H),12.32(s,1H),14.10(s,1H)。
实施例11-26:1HNMR(400MHz,DMSO-d6)δppm2.52-2.62(m,2H),2.83-2.92(m,2H),4.47(d,J=7.07Hz,1H),6.49(s,1H),7.11-7.21(m,1H),7.30(d,J=8.34Hz,2H),7.42-7.55(m,3H),7.64(d,J=8.34Hz,2H),8.80(d,J=8.59Hz,1H),11.68(br.s.,1H),12.30(br.s.,1H)。
实施例11-27:1HNMR(400MHz,DMSO-d6)δppm2.51-2.57(m,1H),2.64-2.70(m,1H),2.84-2.89(dd,J=6.06Hz,1H),2.96-3.01(dd,J=7.83Hz,1H),3.72(s,3H),4.54-4.63(m,1H),6.96-7.00(m,1H),7.06-7.08(dd,J=0.76Hz,1H),7.22-7.24(m,3H),7.28-7.32(m,1H),7.35-7.38(m,2H),8.33-8.34(d,J=1.26Hz,1H),9.16-9.18(d,J=9.09Hz,1H),9.49(d,J=1.52Hz,1H),12.31(s,1H),14.13(s,1H)。
实施例11-28:1HNMR(400MHz,DMSO-d6)δppm2.52-2.60(m,2H),2.73(s,1H),2.89(s,1H),2.81-2.95(m,2H),3.74(s,3H),4.50(m,1H),7.00(t,1H),7.08(d,J=8.34Hz,1H),7.15(s,宽峰,1H),7.23-7.26(m,3H),7.29-7.33(m,1H),7.38(d,J=8.08Hz,2H),8.39(d,宽峰,J=7.07Hz,1H)。
实施例11-29:1HNMR(400MHz,CD3OD)δppm1.33(t,J=7.6Hz,3H),2.66(d,J=6.8Hz,2H),2.84(q,J=7.6Hz,2H),2.98(dd,J=13.6,8.1Hz,1H),3.03(dd,J=13.6,6.6Hz,1H),4.64-4.76(m,1H),7.24-7.37(m,6H),7.40-7.45(m,1H),7.53(s,1H)。
实施例11-30:1HNMR(400MHz,DMSO-d6)δppm2.40-2.51(m,2H),2.79-2.90(m,2H),4.29-4.38(m,1H),6.47(d,J=15.7Hz,1H),6.88(d,J=15.7Hz1H),7.28-7.30(m,2H),7.39-7.41(m,1H),7.47(t,J=8.0Hz,1H),7.62-7.65(m,2H),7.70-7.71(m,1H),8.54(d,J=8.1Hz,1H),7.31(d,J=8.3HZ,2H),7.40-7.43(m,1H),7.47-7.50(m,1H),7.62-7.65(m,3H),7.69-7.71(m,1H),8.54(d,J=8.1Hz,1H)。
实施例11-31:1HNMR(400MHz,DMSO-d6)δppm2.22(s,3H),2.43-2.49(m,1H),2.52-2.60(m,1H),2.84(dd,J=13.6,6.1Hz,1H),2.94(dd,J=13.6,8.1Hz,1H),4.39-4.58(m,1H),6.33(s,1H),7.30(d,J=8.3Hz,2H),7.36-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.61(d,J=8.3Hz,3H),7.69(t,J=1.9Hz,1H),8.02(d,J=7.8Hz,1H)。
实施例11-32:1HNMR(400MHz,DMSO-d6)δppm2.51-2.56(m,2H),2.89(d,J=6.8Hz,2H),3.31(s,3H),4.33-4.57(m,1H),7.31(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.60-7.66(m,3H),7.69(t,J=1.8Hz,1H),8.15(s,1H),8.50(d,J=8.3Hz,1H),12.24(br.s.,1H)。
实施例11-33:1HNMR(400MHz,DMSO-d6)δppm2.52-2.60(m,2H),2.66(s,3H),2.93(d,J=6.8Hz,2H),4.43-4.63(m,1H),7.33(d,J=8.1Hz,2H),7.36-7.42(m,1H),7.46(t,J=7.8Hz,1H),7.58-7.66(m,3H),7.69(t,J=1.8Hz,1H),8.74(d,J=8.3Hz,1H),8.98(s,2H),12.28(br.s.,1H)。
实施例11-34:1HNMR(400MHz,MeOD)δppm2.15(s,3H),2.67(d,J=6.6Hz,2H),2.98(dd,J=13.9,8.3Hz,1H),3.03(dd,J=14.1,6.8Hz,1H),4.62-4.77(m,1H),5.57(s,1H),6.16(s,1H),7.27-7.32(m,1H),7.32-7.41(m,3H),7.46-7.54(m,3H),7.56(t,J=1.8Hz,1H),7.65(s,1H),8.55(d,J=8.6Hz,1H)。
实施例11-35:1HNMR(400MHz,CD3OD)δppm2.42(s,3H),2.63(d,J=6.3Hz,2H),2.99(d,J=7.1Hz,2H),4.59-4.73(m,1H),7.25-7.30(m,1H),7.30-7.37(m,3H),7.41-7.50(m,3H),7.53(t,J=1.8Hz,1H),8.15(s,1H)。
实施例11-36:1HNMR(400MHz,DMSO-d6)δppm2.51-2.61(m,2H),2.87(dd,J=13.1,5.6Hz,1H),2.94(dd,J=13.4,7.6Hz,1H),4.41-4.60(m,1H),7.29-7.38(m,3H),7.45(ddd,J=8.7,4.2,2.8Hz,1H),7.49(d,J=6.8Hz,2H),7.56(dd,J=6.8,2.5Hz,1H),7.71(s,1H),8.53(s,1H),8.59(d,J=8.6Hz,1H),12.26(br.s.,1H)。
实施例11-37:1HNMR(400MHz,CD3OD)δppm1.32(t,J=7.6Hz,3H),2.66(d,J=6.8Hz,2H),2.83(q,J=7.6Hz,2H),2.98(dd,J=13.6,7.8Hz,1H),3.03(dd,J=14.7,6.8Hz,1H),4.61-4.80(m,1H),7.13(dd,J=18.9,10.1Hz,1H),7.25-7.32(m,1H),7.32-7.37(m,2H),7.37-7.45(m,3H),7.54(s,1H)。
实施例11-38:1HNMR(400MHz,DMSO-d6)δppm1.15(t,J=7.73Hz,3H),2.39(d,J=6.8Hz,2H),2.79(d,J=6.8Hz,2H),3.46-3.56(m,2H),3.91-4.01(m,2H),4.21-4.29(m,1H),7.14-7.17(m,1H),7.28(d,J=8.3Hz,2H),7.39-7.42(m,1H),7.48(t,J=7.83Hz,1H),7.61-7.64(m,3H),7.69-7.70(m,1H),7.84(d,J=8.4Hz,1H),12.23(brs,1H)。
实施例11-39:1HNMR(400MHz,甲醇-d4)δppm2.39-2.56(m,6H),2.87(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.94(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),4.43-4.50(m,1H),7.15-7.20(m,1H),7.31-7.35(m,3H),7.45-7.48(m,3H)。
实施例11-40:1HNMR(400MHz,DMSO-d6)δppm2.24-2.37(m,4H),2.73(dd,1H,J=7.83,13.4Hz),2.88(dd,1H,J=7.33,13.4Hz),3.93(s,1H),4.26-4.36(m,1H),5.35(bs,1H),7.33(d,2H,J=8.08Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.34Hz),7.70(t,1H,J=2.02Hz),7.73(d,1H,J=9.09Hz),12.26(bs,2H)。
实施例11-41:1HNMR(400MHz,DMSO-d6)δppm2.21-2.33(m,4H),2.65-2.81(m,2H),4.02(d,1H,J=4.04Hz),4.24-4.32(m,1H),5.56(bs,1H),7.27(d,2H,J=8.34Hz),7.37-7.42(m,1H),7.47(t,1H,J=7.83Hz),7.58(d,2H,J=8.34Hz),7.60-7.64(m,1H),7.69(t,1H,J=1.77Hz),7.96(d,1H,J=8.84Hz),12.03(bs,1H),12.60(bs,1H)。
实施例11-42:1HNMR(400MHz,DMSO-d6)δppm2.22-2.37(m,4H),2,74(dd,1H,J=8.34,13.4Hz),2.86(dd,1H,J=6.82,13.4Hz),3.34(s,3H),3.62(d,1H,J=2.78Hz),4.34-4.44(m,1H),7.31(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.34Hz),7.71(s,1H),7.89(d,1H,J=9.35Hz)。
实施例11-43:1HNMR(400MHz,DMSO-d6)δppm2.17-2.37(m,4H),2.64-2.81(m,2H),3.37(s,3H),3.77(d,1H,J=4.04Hz),4.25-4.34(m,1H),7.25(d,2H,J=8.08Hz),7.38-7.42(m,1H),7.47(t,1H,J=7.83Hz),7.56-7.64(m,3H),7.68(t,1H,J=1.77Hz),8.05(d,1H,J=8.84Hz),12.05(bs,1H),12.89(bs,1H)。
实施例11-44:1HNMR(400MHz,DMSO-d6)δppm2.20-2.39(m,4H),2.65-2.87(m,2H),4.37-4.56(m,1H),4.91(d,0.5H,J=2.78Hz),5.04(d,0.5H,J=3.03Hz),7.29(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.47(t,1H,J=7.83Hz),7.58-7.65(m,3H),7.69(t,1H,J=1.77Hz),8.27(d,1H,J=8.59Hz),12.05(bs,1H),13.57(bs,1H)。
实施例11-45:1HNMR(400MHz,DMSO-d6)δppm1.10(d,J=7.1Hz,3H),2.17-2.37(m,4H),2.57-2.78(m,3H),4.19-4.31(m,J=9.2,9.2,4.5,4.3Hz,1H),7.30(d,J=8.1Hz,2H),7.37-7.42(m,1H),7.47(t,J=7.8Hz,1H),7.57-7.65(m,3H),7.70(t,J=1.8Hz,1H),7.86(d,J=8.8Hz,1H),12.21(br.s.,2H)。
实施例11-46:1HNMR(400MHz,DMSO-d6)δppm2.45(dd,J=6.6,3.5Hz,1H),2.82(d,J=7.1Hz,1H),3.88(dd,J=20.2,15.2Hz,1H),4.03(s,1H),4.29-4.41(m,1H),7.29(d,J=8.3Hz,1H),7.37-7.43(m,1H),7.48(t,J=8.0Hz,1H),7.62(d,J=8.3Hz,2H),7.70(t,J=1.8Hz,1H),7.89(d,J=8.8Hz,1H),11.65-13.45(m,1H)。
实施例11-47/48:(R)-3-[(S)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸和(R)-3-[(R)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸
在室温下,向(R)-3-[2-(叔丁氧基羰基-乙氧基羰基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸乙酯(290mg,0.504mmol)在THF(3ml)和MeOH(0.5ml)中的溶液中加入2MNaOH(1.009ml,2.017mmol)。将该反应在室温下搅拌一夜。将该混合物浓缩至干燥,将该粗品吸收于DCM(3.00ml)中,向其中加入TFA(3.89ml,50.4mmol)并将该混合物在室温下搅拌2hr。将该反应浓缩以进行HPLC纯化。用反相HPLC进行处理[10分钟内从25至50%ACN-H2O(0.1%TFA),SunfireC18柱],得到(R)-3-[(S)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸和(R)-3-[(R)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸。
(R)-3-[(S)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸:1HNMR(400MHz,DMSO-d6)δppm1.28(d,J=7.1Hz,3H),2.40(dd,J=15.7,8.3Hz,1H),2.51-2.56(m,1H),2.76(dd,J=13.4,8.1Hz,1H),2.87(dd,J=13.4,5.3Hz,1H),3.43-3.52(m,3H),3.67(q,J=6.7Hz,1H),4.25-4.36(m,1H),7.30(d,J=8.3Hz,2H),7.38-7.43(m,1H),7.48(t,J=7.8Hz,1H),7.59-7.65(m,3H),7.70(t,J=1.8Hz,1H),8.41(d,J=8.3Hz,1H)。HRMS:C21H23ClN2O5的计算值:418.1295;实测值:m/z418.1307。LCMS(条件A):419(M+1);保留时间=0.93min;(R)-3-[(R)-2-(羧基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸:1HNMR(400MHz,DMSO-d6)δppm1.17(d,J=6.8Hz,3H),2.41-2.49(m,0H),2.51-2.57(m,1H),2.73(dd,J=13.4,9.1Hz,1H),2.91(dd,J=13.4,4.8Hz,1H),3.55-3.67(m,2H),3.67-3.74(m,1H),4.26-4.40(m,1H),7.29(d,J=8.3Hz,2H),7.39-7.44(m,0H),7.48(t,J=7.8Hz,0H),7.59-7.65(m,3H),7.69(t,J=1.8Hz,1H),8.43(d,J=8.6Hz,1H)。HRMS:C21H23ClN2O5的计算值:418.1295;实测值:m/z418.1305。LCMS(条件A):419(M+1);保留时间=0.99min。
下面的化合物是用与实施例11-47/48所述操作类似的操作制备的:
实施例11-49:1HNMR(400MHz,DMSO-d6)δppm2.39-2.50(m,2H),2.77-2.89(m,2H),3.61-3.71(m,2H),3.81(s,2H),4.26-4.35(m,1H),7.31(d,J=8.3HZ,2H),7.40-7.43(m,1H),7.47-7.50(m,1H),7.62-7.65(m,3H),7.69-7.70(m,1H),8.49(d,J=7.3Hz,1H)。
实施例12-1:(R)-4-(1-羧基-3-(3'-氯联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸的合成
在室温下,向(R)-4-(1-(2',5'-二氯联苯-4-基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(106mg,0.234mmol)在THF(2ml)和MeOH(0.1ml)中的溶液中加入1MNaOH水溶液(1.406mL,1.406mmol)。在搅拌4.5小时后,将该反应用0.1MHCl水溶液(3ml)淬熄,将产物用EtOAc萃取。将所合并的有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将该粗品用DCM研磨。将沉淀收集在漏斗上,用DCM洗涤,减压干燥,从而以白色固体形式得到(R)-4-(1-羧基-3-(3'-氯联苯-4-基)丙烷-2-基氨基)-4-氧代丁酸(64.0mg);HPLC保留时间=1.24分钟(条件A);MS(m+1)=424.07;1HNMR(400MHz,CD3OD)δppm2.38-2.42(m,2H),2.45-2.57(m,4H),2.87(ABX的A,Jab=13.6Hz,Jax=7.6Hz,1H),2.95(ABX的B,Jab=13.6Hz,Jbx=6.1Hz,1H),4.44-4.51(m,1H),7.30-7.37(m,6H),7.47(d,J=8.4Hz,1H)。
实施例13-1:(R)-4-(1-(联苯-4-基)-3-羧基丙烷-2-基氨基甲酰基)吡啶甲酸的合成
实施例13-2:(R)-2-(1-(联苯-4-基)-3-羧基丙烷-2-基氨基甲酰基)异烟酸的合成
向(R)-3-氨基-4-(联苯-4-基)丁酸乙酯盐酸盐(200mg,0.625mmol)、2,4-吡啶二甲酸水合物(151mg,0.813mmol)、EDCI(132mg,0.688mmol)和1-羟基-7-氮杂苯并三唑(94mg,0.688mmol)在DMF(6ml)中的溶液中加入DIPEA(0.164ml,0.938mmol)。将该反应混合物搅拌3小时。然后,将该反应混合物用H2O稀释。将沉淀出来的固体收集在漏斗上并减压干燥。向该粗品在THF(8ml)和MeOH(1ml)中的溶液中加入1MNaOH水溶液(2.5ml,2.5mmol)。在搅拌1小时后,将该反应用5%柠檬酸和盐水洗涤,将产物用EtOAc萃取。将有机层用盐水洗涤,用Na2SO4干燥,过滤,浓缩。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%TFA)至100%MeCN梯度洗脱,分别以白色固体形式得到(R)-4-(1-(联苯-4-基)-3-羧基丙烷-2-基氨基甲酰基)吡啶甲酸和(R)-2-(1-(联苯-4-基)-3-羧基丙烷-2-基氨基甲酰基)异烟酸(实施例13-1:33mg;实施例13-2:36mg)。实施例13-1,HPLC保留时间=1.50分钟(条件D);MS(m+1)=405.1;1HNMR(400MHz,DMSO-d6)δppm2.53-2.62(m,2H),2.88-2.97(m,2H),4.50-4.59(m,1H),7.31-7.35(m,3H),7.42-7.45(m,2H),7.57-7.64(m,4H),7.89(dd,J=5,1.6Hz,1H),8.83(dd,J=5,0.8Hz,1H),8.37(dd,J=1.6,0.8Hz),8.89(d,J=8.3Hz,1H)。实施例13-2,HPLC保留时间=1.24分钟(条件A);MS(m+1)=405.1;1HNMR(400MHz,DMSO-d6)δppm2.52-2.68(m,2H),2.91(ABX的A,Jab=13.6Hz,Jax=6.1Hz,1H),3.01(ABX的B,Jab=13.6Hz,Jbx=8.1Hz,1H),4.56-4.65(m,1H),7.29-7.34(m,3H),7.41-7.45(m,2H),7.55-7.64(m,4H),7.99(dd,J=5,1.6Hz,1H),8.34(dd,J=1.6,0.8Hz,1H),8.84(dd,J=5,0.8Hz,1H),8.90(d,J=9.1Hz,1H),12.26(brs,1H),13.87(brs,1H)。
下面的化合物是用与实施例13-1和13-2所述操作类似的操作制备的:
实施例13-3:1HNMR(400MHz,DMSO-d6)δppm2.55(d,J=6.6Hz,2H),2.91(ABX的A,Jab=13.6Hz,Jax=6.3Hz,1H),2.96(ABX的B,Jab=13.6Hz,Jbx=7.6Hz,1H),4.46-4.55(m,1H),6.86(brs,2H),7.02(d,J=4.8Hz,1H),7.28-7.36(m,3H),7.42-7.46(m,2H),7.58-7.65(m,4H),8.39(d,J=9.1Hz,1H),8.45(d,J=4.8Hz,1H)。
实施例14-1:(R)-3-(3-羧基甲基-脲基)-4-(3'-氯-联苯-4-基)-丁酸的合成
向中间体16-1(90mg,0.254mmol)和异氰酰乙酸乙酯(39.4mg,0.305mmol)在DMF(3mL)中的溶液中加入吡啶(2.93g,37.1mmol)并将该混合物在室温下搅拌2小时。减压除去溶剂并将残余物直接用于下一步。
接下来,将上面的残余物溶解于EtOH(1mL)中并加入1NNaOH(3mL,3mmol)。将该混合物在室温下搅拌2小时,然后用1NHCl酸化。将该混合物用EtOAc萃取,将有机相用水、盐水洗涤,然后用硫酸钠干燥。减压除去溶剂,将残余物用制备型HPLC进行纯化,用10%MeCN/水至100%MeCN(+0.1%TFA)梯度洗脱。将适当的级分冻干得到标题化合物;HPLC保留时间0.98分钟(条件C);MS391.3(M+1);1HNMR(400MHz,DMSO-d6):δppm2.34(d,J=7.33Hz,2H),2.79(d,J=6.57Hz,2H),3.67(d,J=5.56Hz,2H),4.04-4.12(m,1H),6.15(t,J=5.81Hz,1H),6.23(d,J=8.34Hz,1H),7.28-7.30(m,2H),7.39-7.42(m,1H),7.48(t,J=7.83Hz,1H),7.62-7.65(m,3H),7.71(t,J=1.77Hz,1H),12.32(s,br,2H)。
实施例15-1:(R)-4-(3'-氯-联苯-4-基)-3-[(2H-四唑-5-羰基)-氨基]-丁酸
在室温下,向起始材料在MeOH(5ml)中的混悬液中加入NaOH(2mL,6.00mmol)并将该混合物搅拌至反应结束。将该反应混合物酸化至pH<4,用HPLC进行纯化(15%至60%的乙腈-H2O,含0.1%TFA),从而得到(R)-4-(3'-氯-联苯-4-基)-3-[(2H-四唑-5-羰基)-氨基]-丁酸(80mg)。
HPLC保留时间=0.95分钟(条件B);MS(m+1)=386.1;1HNMR(400MHz,DMSO-d6)δppm2.52-2.61(m,1H),2.61-2.72(m,1H),2.84-2.99(m,2H),4.51-4.64(m,1H),7.31(d,J=8.1Hz,2H),7.36-7.41(m,1H),7.46(t,J=7.8Hz,1H),7.61(d,J=8.3Hz,3H),7.68(t,J=1.9Hz,1H),9.31(d,J=8.8Hz,1H),12.32(br.s.,1H)。
下面的化合物是用与实施例15-1所述操作类似的操作制备的:
实施例15-2:1HNMR(400MHz,DMSO-d6)δppm2.52-2.72(m,2H),2.86-3.00(m,2H),4.52-4.65(m,1H),7.11-7.20(m,1H),7.31(d,J=8.1Hz,2H),7.43-7.51(m,3H),7.61(d,J=8.3Hz,2H),9.28(d,J=8.8Hz,1H),12.29(br.s.,1H)。
实施例15-3:1HNMR(400MHz,DMSO-d6)δppm2.52-2.60(m,J=15.9,5.8Hz,1H),2.67(dd,J=15.9,7.8Hz,1H),2.87(dd,J=13.6,5.8Hz,1H),2.95(dd,J=13.6,8.3Hz,1H),3.73(s,3H),4.52-4.64(m,1H),7.00(td,J=7.4,1.1Hz,1H),7.08(d,J=9.1Hz,1H),7.22-7.27(m,3H),7.28-7.34(m,1H),7.37(d,J=8.3Hz,2H),9.30(d,J=8.8Hz,1H),12.28(br.s.,1H)。
实施例16-1:N-[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-琥珀酰胺酸
将[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-氨基甲酸叔丁酯(150mg,0.321mmol)用4MHCl的二恶烷溶液处理。在室温下搅拌1小时后,将该反应混合物真空浓缩。向残余物的DCM(2mL)溶液加入琥珀酸酐(48.2mg,0.482mmol)和三乙胺(0.112mL,0.803mmol)。在室温下搅拌2小时后,将反应混合物用EtOAc稀释并用1MHCl和盐水洗涤。将有机层用Na2SO4干燥,浓缩。将残余物用反相HPLC进行纯化(SunFireC18,0.1%TFA的H2O/CH3CN溶液),从而得到N-[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-琥珀酰胺酸(63mg)。HPLC保留时间=1.32分钟(条件A);MS(m+1)=467;1HNMR(400Mz,DMSO-d6)δppm2.22-2.29(m,2H),2.32-2.54(m,4H),2.77(d,2H,J=6.82Hz),3.17(s,3H),4.31(dt,1H,J=7.33,13.9Hz),7.28(d,2H,J=8.08Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.62(d,3H,J=8.34Hz),7.70(t,1H,J=2.02Hz),7.89(d,1H,J=8.34Hz),11.70(s,1H),12.04(s,1H)。
下面的化合物是用与实施例16-1所述操作类似的操作制备的:
实施例16-2:1HNMR(400MHz,DMSO-d6)δppm0.96(t,3H,J=7.33Hz),1.66(dd,2H,J=7.33,15.2Hz),2.25(t,2H,J=7.07Hz),2.31-2.45(m,4H),2.76(d,2H,J=6.82Hz),3.25-3.32(m,2H),4.30(dd,1H,J=7.83,14.7Hz),7.28(d,2H,J=8.34Hz),7.38-7.43(m,1H),7.48(t,1H,J=7.83Hz),7.63(d,3H,J=8.08Hz),7.70(t,1H,J=1.77Hz),7.89(d,1H,J=8.34Hz),11.61(s,1H),12.04(s,1H)。
实施例16-3:1HNMR(400MHz,DMSO-d6)δppm2.24-2.31(m,2H),2.34-2.40(m,2H),2.44(d,2H,J=6.82Hz),2.78(d,2H,J=6.82Hz),4.26-4.36(m,1H),4.67(s,2H),7.25-7.33(m,4H),7.34-7.43(m,4H),7.48(t,1H,J=7.58Hz),7.63(d,3H,J=8.34Hz),7.70(t,1H,J=1.77Hz),7.92(d,1H,J=8.34Hz),11.60(s,1H),12.05(s,1H)。
实施例16-4:1HNMR(400MHz,DMSO-d6)δppm2.19-2.29(m,4H),2.36(dd,2H,J=6.57,6.57Hz),2.72(dd,1H,J=7.83,13.6Hz),2.81(dd,1H,J=5.31,13.6Hz),4.17-4.27(m,1H),6.83(s,1H),7.28(d,3H,J=8.34Hz),7.38-7.43(m,1H),7.47(t,1H,J=7.83Hz),7.58-7.65(m,3H),7.69(t,1H,J=1.77Hz),7.78(d,1H,J=8.34Hz),12.05(s,1H)。
实施例16-5:N-[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-琥珀酰胺酸丁酯的合成
向N-[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-琥珀酰胺酸(50mg,0.107mmol)在正丁醇(2mL)中的溶液中加入亚硫酰氯(9.38μL,0.128mmol)。将该反应混合物加温至50℃并搅拌1小时。在冷却至室温后,将该反应混合物浓缩并用反相HPLC进行纯化(SunFireC18,0.1%TFA的H2O/CH3CN溶液),从而得到N-[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-琥珀酰胺酸丁酯(32mg)。HPLC保留时间=1.56分钟(条件A);MS(m+1)=523;1HNMR(400Mz,DMSO-d6)δppm0.86(t,3H,J=7.33Hz),1.22-1.34(m,2H),1.45-1.55(m,2H),2.23-2.33(m,2H),2.35-2.44(m,3H),2.45-2.55(m,3H),2.71-2.83(m,1H),3.18(s,3H),3.96(t,2H,J=6.57Hz),4.27-4.38(m,1H),7.28(d,2H,J=8.08Hz),7.37-7.43(m,1H),7.48(t,1HJ=7.83Hz),7.62(d,3H,J=8.34Hz),7.70(s,1H),7.91(d,1H,J=8.34Hz),11.71(s,1H)。
实施例17:(R)-3-(2-乙酰基唑-5-甲酰氨基)-4-(3'-氯联苯-4-基)丁酸
在-78℃下,向(R)-4-(3'-氯联苯-4-基)-3-(2-(丙-1-烯-2-基)唑-5-甲酰氨基)丁酸(60mg,0.14mmol)在DCM(2mL)和MeOH(2mL)中的溶液中用臭氧鼓泡30秒。在30秒后,除去臭氧并用氧气鼓泡10分钟。在用氧气鼓泡10分钟后,除去-78℃浴,将该反应用聚合物负载的三苯基膦淬熄并将该反应在室温下搅拌2小时。在2小时后,将该反应过滤以除去聚合物负载的三苯基膦氧化物,收集滤液并将其减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC18,H2O(0.1%TFA)/CH3CN),然后冻干,从而得到(R)-3-(2-乙酰基唑-5-甲酰氨基)-4-(3'-氯联苯-4-基)丁酸(13mg)。HPLC保留时间=1.67分钟(条件D);MS(m+1)=427.0;1HNMR(400MHz,DMSO-d6)δppm2.53-2.59(m,2H),2.60(s,3H),2.87(dd,J=10.9,3.3Hz,1H),2.94(dd,J=10.9,5.1Hz,1H),4.46-4.60(m,1H),7.31(d,J=8.1Hz,2H),7.36-7.43(m,1H),7.47(t,J=7.8Hz,1H),7.62(d,J=8.3Hz,3H),7.69(t,J=1.9Hz,1H),7.94(s,1H),8.86(d,J=8.6Hz,1H),12.31(br.s.,1H)。
起始材料或中间体是用下面的方式制备的:
中间体1:(R)-4-(4-溴苯基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯
在室温下,向(R)-4-(4-溴苯基-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯(2.02g,5.23mmol)中加入4MHCl的1,4-二恶烷溶液(13.1mL,52.3mmol)。在搅拌1小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-溴苯基-4-基-丁酸乙酯盐酸盐。向(R)-3-氨基-4-溴苯基-4-基-丁酸乙酯盐酸盐的溶液中加入位于二氯甲烷(20mL)中的琥珀酸酐(0.707g,7.06mmol)和DIPEA(2.06mL,11.8mmol)并将其搅拌4小时。将该反应用0.1MHCl水溶液淬熄。将产物用乙酸乙酯萃取并用盐水洗涤。将有机层用Na2SO4干燥,过滤,减压浓缩,从而得到(R)-4-(1-(4-溴苯基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(2.26g)。在室温下、在氮气下,向所得残余物(2.26g)在甲苯(25mL)和MeOH(25mL)中的溶液中分批加入位于己烷(5.85ml,11.70mmol)中的TMSCHN2。将该反应混合物搅拌1.5小时,然后用AcOH(0.5mL;8.78mmol)淬熄并将该溶液搅拌10分钟。将该溶液浓缩,将所得残余物用40g硅胶通过快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到(R)-4-(4-溴苯基)-3-(4-甲氧基-4-氧代丁烷酰氨基)丁酸乙酯(1.92g)。HPLC保留时间=1.04分钟(条件B);MS(ES+)=400(m+1),402.0(m+3;100%);1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),2.40-2.53(m,4H),2.60-2.64(m,2H),2.79(ABX的A,Jab=13.7Hz,Jax=7.85Hz,1H),2.90(ABX的B,Jab=13.7Hz,Jbx=6.65Hz,1H),3.68(s,3H),4.10-4.22(m,2H),4.39-4.47(m,1H),6.29(brd,J=8.6Hz,1H),7.06(d,J=8.4Hz,2H),7.40-7.42(m,2H)。
中间体2:(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯
将(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯(1.5g,3.88mmol)、苯基硼酸(0.710g,5.82mmol)、Pd(Ph3P)4(0.449g,0.388mmol)和Na2CO3水溶液(3.88mL,7.77mmol)在甲苯(25mL)中的混合物在95℃下、在氮气下搅拌14小时。将该反应混合物冷却至室温并用盐水淬熄。将该混合物用乙酸乙酯萃取两次,将所合并的有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至50:50),从而得到(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯(1.30g);HPLC保留时间=1.61分钟(条件B);MS(ES+)=328.0(m-tBu+2);284.1(m-Boc+2;100%);1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H),2.48(ABX的A,Jab=16.1Hz,Jax=5.9Hz,1H),2.53(ABX的B,Jab=16.0Hz,Jbx=5.3Hz,1H),2.83-3.00(m,2H),4.14-4.19(m,3H),5.06(brs),7.26-7.27(m,2H),7.31-7.35(m,2H),7.43(t,J=7.6Hz,2H)7.52-7.58(m,4H)。
下面的中间体是用与中间体2所述操作类似的操作制备的:
中间体3:(R)-4-(1-(联苯-4-基)-4-叔丁氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸
在室温下,向(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯(26.4mg,0.064mmol)中加入4MHCl的1,4-二恶烷溶液(0.321ml,1.283mmol)。将该反应混合物搅拌45分钟并减压浓缩。向所得残余物在二氯甲烷(0.4mL)中的溶液中加入琥珀酸酐(7.70mg,0.077mmol)和DIPEA(0.013mL,0.077mmol)。将该反应混合物在室温下搅拌14小时并减压浓缩。将所得残余物用RP-HPLC进行纯化(SunFireC-18,H2O(0.1%TFA)/CH3CN),从而得到(R)-4-(1-(联苯-4-基)-4-叔丁氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸(9.5mg)。HPLC保留时间=1.70分钟(条件A);MS(ES+)=412.1(m+1);356.0(m-tBu+2;100%);1HNMR(400MHz,氯仿-d)δppm1.48(s,9H),2.36-2.51(m,4H),2.64-2.67(m,2H),2.87(ABX的A,Jab=13.5Hz,Jax=5.7Hz,1H),2.97(Jab=13.5Hz,Jbx=6.2Hz,1H),7.24-7.26(m,2H),7.31-7.35(m,1H),7.43(t,J=7.75Hz,2H),7.53(d,J=8.0Hz,2H),7.57(d,J=7.6HZ,2H)。
下面的中间体是用与中间体3所述操作类似的操作制备的:
中间体4:(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯
将(R)-2-(联苯-4-基甲基)-4-叔丁氧基-4-氧代丁酸(100mg,0.294mmol)、DPPA(0.076mL,0.353mmol)和Et3N(0.049mL,0.353mmol)在甲苯(1.5mL)中的溶液在100℃下在氮气下搅拌2小时。加入tBuOH(0.281ml,2.94mmol)并将该混合物在相同的温度下回流5小时。将该反应冷却至室温并除去溶剂。向所得残余物中加入乙酸乙酯并将有机层用5%柠檬酸水溶液、H2O、饱和NaHCO3水溶液和盐水洗涤。将有机层用Na2SO4干燥,过滤,减压浓缩。将所得残余物用40g硅胶通过快速柱色谱进行纯化(庚烷/EtOAc=100:0至50:50),从而得到相应的异氰酸酯(35.7mg)。将所得异氰酸酯溶解于tBuOH(0.3mL)中并将该溶液在80℃下搅拌20小时。将该反应混合物浓缩,将残余物用12g硅胶通过快速柱色谱进行纯化(庚烷/EtOAc=100:0至70:30),从而得到(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯(26.4mg,22%)。HPLC保留时间=1.74分钟(条件B);MS(ES+)=356.0(m-tBu+2),300.0(m-tBux2+3;100%);1HNMR(400MHz,氯仿-d)δppm1.41(s,9H),1.47(s,9H),2.36(ABX的A,Jab=15.6Hz,Jax=6.2Hz,1H),2.44(ABX的B,Jab=15.5Hz,Jbx=5.45Hz)2.82-2.97(m,2H),4.15(brs)5.09(brd)7.6-7.35(m,3H)7.41-7.45(m,2H),7.51-7.56(m,4H)。
中间体5:(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯
在室温下、在氮气下,向(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸(9.98g,27.9mmol)和NaHCO3(4.68g,55.7mmol)在DMF(45mL)中的混悬液中加入碘乙烷(6.75mL,84mmol)。在搅拌71小时后,将该反应用H2O(300mL)淬熄,然后收集沉淀出来的固体,用H2O(500mL)洗涤,从而得到(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯(10.25g,94%)。HPLC保留时间=1.48分钟(条件B);MS(ES+)=329.9(m-tBu+2);286.0(m-Boc+2;100%);1HNMR(400MHz,氯仿-d)δppm1.27(t,J=7.2Hz,3H),1.40(s,9H),2.43(ABX的A,Jab=15.8Hz,Jax=5.7Hz,1H),2.50(ABX的B,Jab=15.8Hz,Jbx=5.4Hz,1H),2.74-2.90(m,2H),4.11(brs),4.15(q,J=7.1Hz,2H),5.04(brd)7.07(d,J=8.3Hz,2H),7.40-7.43(m,2H)。
下面的中间体是用与中间体5所述操作类似的操作制备的:
中间体5-2:(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸苄酯
在室温下、在氮气下,向(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸(5.02g,14.01mmol)和NaHCO3(3.53g,42.0mmol)在DMF(20mL)中的混悬液中加入苄基溴(5.10mL,42mmol)。在搅拌46小时后,将该反应用H2O稀释(200mL),然后,收集沉淀出来的固体,用H2O(500mL)、然后用庚烷(200ml)洗涤,从而得到(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸苄酯(5.61g,89%)。HPLC保留时间=1.56分钟(条件B);MS(ES+)=392.1(m-tBu+2);348.1(m-Boc+2;100%);1HNMR(400MHz,氯仿-d)δppm1.39(s,9H),2.48(ABX的A,Jab=15.9Hz,Jax=5.6Hz,1H),2.54(ABX的B,Jab=15.9Hz,Jbx=5.3Hz,1H),2.72-2.88(m,2H),4.11(brs,1H),5.02(brs,1H),5.10(AB的A,J=12.1Hz,1H),5.16(AB的A,J=12.1Hz,1H),7.00(d,J=8.1Hz,2H),7.34-7.39(m,7H)。
中间体6:(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸
在室温下,向(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸叔丁酯(40mg,0.094mmol)在DCM(0.5mL)中的溶液中加入TFA(0.15mL)。将该混合物搅拌2小时,然后减压浓缩,从而得到(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸(33.5mg,96%)。HPLC保留时间=1.20分钟(条件A);MS(m+1)=370.1;1HNMR(400MHz,氯仿-d)δppm2.21-2.29(m,1H),2.38-2.45(m,1H),2.62-2.66(m,1H),2.75-3.00(m,4H),3.29-3.37(m,1H),3.45-3.53(m,4H),6.12(brs,1H),7.23(d,J=8Hz,2H),7.32-7.35(m,1H),7.41-7.45(m,2H),7.53(d,J=8.1Hz,2H),7.56-7.59(m,2H)。
中间体7:(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸叔丁酯
将(R)-2-(联苯-4-基甲基)-4-叔丁氧基-4-氧代丁酸(142mg,0.417mmol)、3-氨基-丙酸甲酯盐酸盐(76mg,0.542mmol)、WSC盐酸盐(120mg,0.626mmol)、1-羟基-7-氮杂苯并三唑(85mg,0.626mmol)和DIPEA(0.219ml,1.251mmol)在DMF(4mL)中的溶液在室温下、在氮气下搅拌13小时。将该反应用H2O淬熄。将产物用乙酸乙酯萃取,用1MHCl水溶液,然后用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用12g硅胶通过快速柱色谱进行纯化(庚烷/EtOAc=70:30至0:100),从而得到(R)-3-(联苯-4-基甲基)-4-(3-甲氧基-3-氧代丙基氨基)-4-氧代丁酸叔丁酯(164mg,91%)。HPLC保留时间=1.59分钟(条件A);MS(ES+)=425.4(m);369.4(m-tBu+1;100%);1HNMR(400MHz,氯仿-d)δppm2.24-2.44(m,2H),2.67-2.79(m,3H),2.89-2.96(m,1H),3.28-3.36(m,1H),3.45-3.53(m,1H),7.23(d,J=5.8Hz,2H),7.33(t,J=7.35Hz,1H),7.41-7.44(m,2H),7.51(d,J=8.1Hz,2H),7.58(d,J=7.4Hz,2H)。
下面的中间体是用与中间体7所述操作类似的操作制备的:
中间体8:(R)-3-[(1-苄基-1H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯和(R)-3-[(2-苄基-2H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯
将(R)-4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸乙酯(117mg,0.305mmol)用4MHCl的二恶烷溶液(2mL)处理。在搅拌0.5小时后,将该反应混合物减压浓缩。向所得残余物和Et3N(0.106mL,0.763mmol)在DCM(3mL)中的溶液中加入苄基-H-四唑-5-碳酰氯(1-和2-苄基异构体的混合物,82mg,0.366mmol,根据J.Med.Chem.1986,29,538-549制得的)。在搅拌10分钟后,加入Et3N(0.106mL,0.763mmol)和该酰氯(82mg,0.366mmol)。在搅拌0.5小时后,将该反应混合物用乙酸乙酯稀释,用H2O和盐水洗涤,用Na2SO4干燥并减压浓缩。将残余物用硅胶柱色谱进行纯化,从而得到(R)-3-[(1-苄基-1H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯和(R)-3-[(2-苄基-2H-四唑-5-羰基)-氨基]-4-联苯-4-基-丁酸乙酯。HPLC保留时间=1.51分钟(条件D);MS=470.0(m+1);1HNMR(400MHz,CDCl3)δppm1.27(t,J=7.07,7.07Hz,3H),2.57-2.70(m,2H),3.00(dd,J=7.58,13.77Hz,1H),3.12(dd,J=6.57,13.77Hz,1H),4.12-4.23(m,2H),4.71-4.80(m,1H),5.80(s,2H),7.27-7.45(m,9H),7.52(d,J=8.34Hz,2H),7.56(d,J=8.46Hz,2H),7.75(d,J=7.33Hz,1H)。
中间体9:(R)-4-联苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四唑-5-基]-丙酰基氨基}-丁酸乙酯
在室温下,向(R)-4-联苯-4-基-3-叔丁氧基羰基氨基-丁酸乙酯(400mg,1.04mmol)在DCM(10mL)中的溶液中加入TFA(2.009mL,26.1mmol)并将该混合物在室温下搅拌1小时。将该混合物减压浓缩。在冰浴温度下,向位于DCM(10mL)中的所得TFA盐中加入琥珀酸酐(125mg,1.25mmol),然后加入TEA(0.363mL,2.61mmol)。将该反应在室温下搅拌16小时。将该混合物减压浓缩。将所得残余物用快速柱色谱进行纯化(硅胶,2%至5%EtOH/DCM),得到(R)-4-联苯-4-基-3-(3-羧基-丙酰基氨基)-丁酸乙酯(200mg)。HPLC保留时间=1.53分钟(条件C);MS=384(m+1)。
接下来,在室温下,向(R)-4-联苯-4-基-3-(3-羧基-丙酰基氨基)-丁酸乙酯(200mg,0.522mmol)在THF(10mL)中的溶液中加入EDCHCl(120mg,0.626mmol)和HOBT(96mg,0.626mmol)。将该反应在室温下搅拌10分钟,然后加入3-氨基丙腈(0.046ml,0.626mmol)和TEA(0.087ml,0.626mmol)。在1小时后,加入0.5当量的EDCHCl、HOBT和3-氨基丙腈并搅拌16小时。将该反应混合物用盐水淬熄并用乙酸乙酯萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将所得残余物用快速柱色谱进行纯化(硅胶,2%至5%EtOH/DCM),从而得到(R)-4-联苯-4-基-3-[3-(2-氰基-乙基氨基甲酰基)-丙酰基氨基]-丁酸乙酯(218mg,收率为96%)。HPLC保留时间=0.77分钟(条件E);MS=436(m+1)。
接下来,在室温下,向(R)-4-联苯-4-基-3-[3-(2-氰基-乙基氨基甲酰基)-丙酰基氨基]-丁酸乙酯(204mg,0.468mmol)在THF(10mL)中的溶液中加入Ph3P(307mg,1.17mmol)并将该混合物在室温下搅拌10分钟。然后,在冰浴温度下,向该混合物中加入DIAD(0.228ml,1.171mmol)和三甲基硅烷基叠氮化物(0.155ml,1.171mmol)。将所得混合物缓慢加温至室温并搅拌16小时。将该反应混合物减压浓缩。将所得残余物用快速柱色谱进行纯化(硅胶,1%至3%EtOH/DCM),从而得到(R)-4-联苯-4-基-3-{3-[1-(2-氰基-乙基)-1H-四唑-5-基]-丙酰基氨基}-丁酸乙酯(137mg,64%收率)。HPLC保留时间=1.61分钟(条件C);MS=461(m+1)。
中间体10:(R)-2-(联苯-4-基甲基)-4-叔丁氧基-4-氧代丁酸
在0℃下,在5分钟内,向进行着搅拌的(R)-4-((S)-4-苄基-2-氧代唑烷-3-基)-3-(联苯-4-基甲基)-4-氧代丁酸叔丁酯(1.20g,2.402mmol)在THF(20mL)和水(5mL)的混合溶剂中的溶液中加入H2O2水溶液(0.960mL,9.61mmol)和LiOH水溶液(4.80ml,4.80mmol)。在搅拌1.5小时后,在0℃下,将该反应用饱和Na2SO3水溶液(10mL)淬熄并将其在相同的温度下搅拌10分钟。在搅拌0.5小时后,将该反应混合物加温至环境温度。然后,向该混合物中加入饱和NaHCO3水溶液和盐水。将产物用乙酸乙酯萃取,用1MHCl水溶液洗涤,用MgSO4干燥,过滤,减压浓缩。将所得残余物用120g硅胶通过快速柱色谱进行纯化(庚烷/EtOAc=75:25至0:100),从而得到(R)-2-(联苯-4-基甲基)-4-叔丁氧基-4-氧代丁酸(765mg,93%)。HPLC保留时间=1.63分钟(条件D);MS=338.6(m-1);1HNMR(400MHz,氯仿-d)δppm1.43(s,9H),2.41(ABX的A,Jab=16.67Hz,Jax=4.55Hz,1H),2.52-2.67(ABX的B,Jab=16.75Hz,Jbx=8.45Hz,1H),2.74-2.89(m,1H),3.06-3.22(m,2H),7.22-7.29(m,2H),7.30-7.37(m,1H),7.43(t,J=7.58Hz,2H),7.53(d,J=8.1Hz,2H),7.57(d,J=7.8Hz,2H)。
中间体11:(R)-4-((S)-4-苄基-2-氧代唑烷-3-基)-3-(联苯-4-基甲基)-4-氧代丁酸叔丁酯的合成
将进行着搅拌的(S)-4-苄基-3-(3-(联苯-4-基)丙酰基)唑烷-2-酮(中间体12:5.01g,13.00mmol)在THF(180mL)中的溶液冷却至-73.8℃并在5分钟内加入1M的六甲基二甲硅烷基氨基化钠的THF溶液(14.30mL,14.30mmol)。在30分钟后,在5分钟内滴加溴乙酸叔丁酯(2.495mL,16.90mmol)在THF(20mL)中的溶液。将该溶液在-74℃下搅拌1小时,将该反应用饱和NH4Cl水溶液(100mL)淬熄并将其加温至环境温度。将沉淀出来的固体滤出并用乙酸乙酯(50mL)洗涤。将有机相分离出来,用盐水洗涤,用MgSO4干燥并减压浓缩。将所得残余物混悬于MeOH(70mL)中,然后过滤以收集固体(5.9g),该固体为所需产物和起始材料的混合物。将该混合物用120g硅胶通过快速柱色谱进行纯化(庚烷/EtOAc=90:10至50:50),从而得到(R)-4-((S)-4-苄基-2-氧代唑烷-3-基)-3-(联苯-4-基甲基)-4-氧代丁酸叔丁酯(2.40g,37%)。HPLC保留时间=1.74分钟(条件B);MS=499.4(m+);443.4(m-tBu+1;100%);1HNMR(400MHz,氯仿-d)δppm1.41(s,9H),2.42(dd,J=16.67,4.04Hz,1H),2.71(ddd,J=16.55,13.26,9.60Hz,2H),2.87(dd,J=16.93,10.86Hz,1H),3.04(dd,J=13.14,6.32Hz,1H),3.32(dd,J=13.39,3.03Hz,1H),3.92(t,J=8.34Hz,1H),4.07(dd,J=8.97,2.15Hz,1H),4.48-4.58(m,2H),7.20-7.30(m,3H),7.30-7.36(m,5H),7.42(t,J=7.58Hz,2H),7.52(d,J=8.1Hz,2H),7.56(d,J=7.8Hz,2H)。
中间体12:(S)-4-苄基-3-(3-(联苯-4-基)丙酰基)唑烷-2-酮
在-71.6℃下、在氮气下,历经10分钟,向1.6M的n-BuLi在己烷中的溶液(12.1mL,19.3mmol)中滴加(S)-(-)-4-苄基-2-唑烷酮(3.26g,18.4mmol)在无水THF(80mL)中的溶液。在加入的同时,将该溶液加温至-60.5℃并将其在干冰/MeOH浴上搅拌1小时。在-71.6℃下,历经5分钟向其中滴加位于无水THF(20mL)中的3-(联苯-4-基)丙酰氯(中间体13:5.46g,22.31mmol)。在加入的同时,将该溶液加温至-56.5℃。将其在相同的温度下搅拌10分钟后,使该反应混合物加温至室温并继续搅拌3小时。将该反应混合物过滤,将所收集的沉淀用20mL(10mLx2)MeOH、然后用150mLH2O洗涤得到所需产物(4.26g)。将母液中的产物用乙酸乙酯萃取,用盐水洗涤,用MgSO4干燥,过滤,减压浓缩。将所得残余物混悬于80mLMeOH中,将该混悬液过滤并用20mLMeOH(1.79g)洗涤。将两部分级分混合,从而得到(S)-4-苄基-3-(3-(联苯-4-基)丙酰基)唑烷-2-酮(6.05g,2步的收率为85%)。保留时间=1.77分钟(条件A);MS(m+1)=387.3;1HNMR(400MHz,氯仿-d)δppm2.77(dd,J=13.39,9.35Hz,1H),2.99-3.15(m,2H),3.20-3.43(m,3H),4.09-4.24(m,2H),4.68(dddd,J=9.76,6.73,3.47,3.28Hz,1H),7.18(d,J=7.07Hz,2H),7.23-7.37(m,6H),7.42(t,J=7.58Hz,2H),7.53(d,J=8.1Hz,2H),7.57(d,J=7.8Hz,2H)。
中间体13:3-(联苯-4-基)丙酰氯
将3-(4-联苯基)丙酸(5g,22.10mmol)和SOCl2(4.03ml,55.2mmol)的混合物在氮气下在85℃下回流1.5小时。将该反应混合物减压浓缩,从而得到3-(联苯-4-基)丙酰氯(5.46g)。将该物质在不进行进一步纯化的情况下用于下一步。
中间体14:(2R,4R)-4-氨基-2-甲基-戊酸乙酯三氟乙酸盐
向进行着搅拌的2-(三苯基亚正膦基)-丙酸乙酯(3.11g,8.57mmol)在二氯甲烷(20mL)中的溶液中加入3,3-二甲基-N-((R)-1-甲基-2-氧代-乙基)-丁酰胺(J.Med.Chem.41,6(1998)(1.35g,7.79mmol)在二氯甲烷(20mL)中的溶液并将该混合物在室温下搅拌2小时。减压除去溶剂并将残余物用柱色谱进行纯化,用10-50%庚烷/EtOAc梯度洗脱,从而得到(E)-(R)-4-叔丁氧基羰基氨基-2-甲基-戊-2-烯酸乙酯。1H-NMR(400MHz,CDCl3)δppm1.22(d,J=6.44Hz,3H),1.30(t,3H),1.43(s,9H),1.91(s,3H),4.19(q,2H),6.51(d,宽峰,J=7.45Hz,1H)。
接下来,将(E)-(R)-4-叔丁氧基羰基氨基-2-甲基-戊-2-烯酸乙酯(1.83g,7.11mmol)在乙酸乙酯(75mL)中的溶液用10%Pt/C(183mg)在1atm下氢化18小时。通过用硅藻土过滤除去催化剂并减压除去溶剂。将残余物用手性HPLC进行纯化,从而得到(2R,4R)-4-叔丁氧基羰基氨基-2-甲基-戊酸乙酯,1H-NMR(400MHz,CDCl3)δppm1.13(t,3H),1.18(m,3H),1.26(t,3H),1.43(s,9H),1.81(s,1H),2.50(m,1H),3.72(m宽峰,1H),4.14(m,2H),4.33(m宽峰,1H)。
接下来,将(2R,4R)-4-叔丁氧基羰基氨基-2-甲基-戊酸乙酯(142mg,0.548mmol)加入到三氟乙酸(5mL)中。在10分钟后,减压除去溶剂。加入二氯甲烷并减压除去溶剂,从而得到(2R,4R)-4-氨基-2-甲基-戊酸乙酯三氟乙酸盐。将该物质直接用于随后的偶合反应。
中间体15:2-联苯-4-基甲基-琥珀酸1-甲酯
向(三苯基亚正膦基)-乙酸甲酯(2.26g,6.77mmol)在二氯甲烷(25mL)中的溶液中加入溴代乙酸叔丁酯(1.32g,6.77mmol)并将该混合物在室温下搅拌48小时。减压除去溶剂并将残余物用柱色谱进行纯化,用80-100%庚烷/EtOAc梯度洗脱,从而得到2-(三苯基亚正膦基)-琥珀酸4-叔丁酯1-甲酯。MS449.3(M+1)。
接下来,将2-(三苯基亚正膦基)-琥珀酸4-叔丁酯1-甲酯(700mg,1.561mmol)和联苯-4-甲醛(278mg,1.419mmol)在甲苯(20mL)中的混合物回流4天。减压除去溶剂并将残余物用柱色谱进行纯化,用0-30%庚烷/EtOAc梯度洗脱,从而以油状物形式得到2-[1-联苯-4-基-亚甲-(Z)-基]-琥珀酸4-叔丁酯1-甲酯,1H-NMR(400MHz,CDCl3);δppm1.47(s,9H),3.52(s,2H),3.84(s,3H),7.37(t,1H),7.46(t,4H),7.62(t,4H),7.89(s,1H)。
将2-[1-联苯-4-基-亚甲-(Z)-基]-琥珀酸4-叔丁酯1-甲酯(410mg,1.163mmol)在乙酸乙酯(20mL)中的溶液用Pt/C(40mg)在1atm下氢化18小时。通过用硅藻土过滤除去催化剂并减压除去溶剂,从而得到2-联苯-4-基甲基-琥珀酸4-叔丁酯1-甲酯。用手性HPLC对该对映异构体进行分离。
接下来,将2-联苯-4-基甲基-琥珀酸4-叔丁酯1-甲酯(160mg,0.451mmol)加入到三氟乙酸(5mL)中。在10分钟后,减压除去溶剂。加入二氯甲烷并减压除去溶剂,从而得到2-联苯-4-基甲基-琥珀酸1-甲酯。将该物质直接用于随后的偶合反应。
中间体16-1:(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐的合成
在室温下,向(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸乙酯(3.33g,7.97mmol)中加入4MHCl的1,4-二恶烷溶液(19.9mL,18.0mmol)。在搅拌0.5小时后,将该反应混合物减压浓缩得到(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(2.90g)。HPLC保留时间=0.70分钟(条件B);MS(m+1)=318.26;1HNMR(400MHz,氯仿-d)δppm1.19-1.24(m,3H),2.73-2.78(m,1H),2.84-2.91(m,1H),3.05-3.11(m,1H),3.50-3.54(m,1H),3.92(brs,1H),4.14-4.17(m,2H),7.29-7.53(m,8H),8.73(br.s.,3H)。
下面的中间体是用与中间体16-1所述操作类似的操作制备的:
中间体16-7:(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯盐酸盐
在室温下,向(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸苄酯(3.561g,7.42mmol)中加入4MHCl的1,4-二恶烷溶液(18.55mL,74.2mmol)。在搅拌4小时后,将该反应混合物减压浓缩得到(R)-3-氨基-4-(3’-氯联苯-4-基)丁酸苄酯盐酸盐(3.11g)。HPLC保留时间=1.07分钟(条件B);MS(m+1)=380.1;1HNMR(400MHz,氯仿-d)δppm2.81(ABX的A,Jab=17.4Hz,Jax=4.5Hz,1H),2.93(ABX的B,Jab=17.4Hz,Jbx=7.6Hz,1H),3.03-3.09(m,1H),3.50(dd,J=4.9和13.5Hz,1H),3.98(brs,1H),5.09(s,2H),7.24-7.22(m,9H),7.35-7.38(m,1H),7.42(d,J=8.1Hz,2H),7.48-7.49(m,1H),8.78(brs,3H)。
中间体17-1:(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸乙酯的合成
将(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯(4.89g,12.66mmol)、3-氯苯基硼酸(2.97g,18.99mmol)、Pd(PPh3)4(1.463g,1.266mmol)和2MNa2CO3水溶液(12.66ml,25.3mmol)在1,2-二甲氧基乙烷(100ml)中的混合物在95℃下在氮气下搅拌3小时。将该反应混合物冷却至室温并用盐水淬熄。将两相分开。用乙酸乙酯对该混合物的水层萃取两次。将所合并的有机层用盐水洗涤,用MgSO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至70:30)得到(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸乙酯(3.33g);HPLC保留时间=1.44分钟(条件B);MS(ES+)=318.26(m-BOC+2;100%);1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.2Hz,3H),1.41(s,9H),2.47(ABX的A,Jab=15.8Hz,Jax=5.9Hz,1H),2.52(ABX的B,Jab=15.8Hz,Jbx=5.4Hz,1H),2.83-2.89(m,1H),2.95-3.00(m,1H),4.17(q,J=7.2Hz,2H),4.18(brs,1H),5.07(brs,1H),7.26-7.37(m,4H),7.43-7.51(m,3H),7.55(brt,J=1.8Hz,1H)。
下面的中间体是用与中间体17-1所述操作类似的操作制备的:
中间体17-2:(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸苄酯
将(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸苄酯(2.00g,4.46mmol)、3-氯苯基硼酸(1.046g,6.69mmol)、Pd(PPh3)4(0.515g,0.446mmol)和Na2CO3水溶液(4.46ml,8.92mmol)在甲苯(30ml)中的混合物在氮气下在95℃下搅拌19小时。将该反应混合物冷却至环境温度并用盐水和EtOAc稀释。将产物用EtOAc萃取两次,用盐水洗涤,用MgSO4干燥,过滤,浓缩。将残余物用90g硅胶通过快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=100:0至65:35),从而得到(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸苄酯(1.03g);HPLC保留时间=1.74分钟(条件B);MS(ES+)=380.2(m-BOC+2;100%);1HNMR(400MHz,氯仿-d)δppm1.40(s,9H),2.52(ABX的A,Jab=15.9Hz,Jax=5.8Hz,1H),2.58(ABX的B,Jab=15.9Hz,Jbx=5.6Hz,1H),2.81-2.98(m,2H),4.19(brs,1H),5.07(brd,1H),5.12(AB的A,J=12.3Hz,1H),5.17(AB的A,J=12.3Hz,1H),7.20-7.22(m,2H),7.28-7.39(m,7H),7.42-7.47(m,3H),7.53-7.54(m,1H)。
中间体18:(S)-1-(2-叔丁氧基-2-氧代乙基)吡咯烷-2-甲酸苄酯的合成
向(S)-吡咯烷-2-甲酸苄酯盐酸盐(700mg,2.90mmol)和K2CO3(1201mg,8.69mmol)在DMF(7ml)中的混悬液中加入溴代乙酸叔丁酯(0.535ml,3.62mmol)。搅拌71小时后,向该反应混合物中加入K2CO3水溶液(1.5gK2CO3/40mlH2O)。将产物用EtOAc萃取。将有机层用水洗涤两次并用盐水洗涤一次,用K2CO3干燥,过滤,浓缩,从而得到(S)-1-(2-叔丁氧基-2-氧代乙基)吡咯烷-2-甲酸苄酯(458mg);HPLC保留时间=1.38分钟(条件D);MS(m+1)=320.2;1HNMR(400MHz,氯仿-d)δppm1.44(s,9H),1.81-2.03(m,3H),2.13-2.14(m,1H),2.82-2.88(m,1H),3.13-3.17(m,1H),3.46(AB的A,J=17.3Hz,1H),3.49(AB的B,J=17.3Hz,1H),3.73(dd,J=8.8和4.8Hz,1H),5.15(AB的A,J=12.4Hz,1H),5.17(AB的B,J=12.4Hz,1H),7.29-7.38(m,5H)。
中间体19:(R)-3-(叔丁氧基羰基氨基)-4-(2',5'-二氯联苯-4-基)丁酸乙酯的合成
将(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯(1.005g,2.60mmol)、2,5-二氯苯基硼酸(0.745g,3.90mmol)、Pd(PPh3)4(0.301g,0.260mmol)和2MNa2CO3水溶液(2.60ml,5.20mmol)在1,2-二甲氧基乙烷(20ml)中的混合物在95℃下在氮气下搅拌3小时。将该反应混合物冷却至室温并用盐水稀释。将两相进行分离。用乙酸乙酯(2x100ml)从水层中萃取产物两次。将所合并的有机层用盐水洗涤,用MgSO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至70:30),从而得到(R)-3-(叔丁氧基羰基氨基)-4-(2',5'-二氯联苯-4-基)丁酸乙酯(1.09g);HPLC保留时间=1.50分钟(条件B);MS(ES+)=352.00(m-BOC+2;100%);1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H),1.41(s,9H),2.45-2.58(m,2H),2.85-3.00(m,2H),4.17(t,J=7.1Hz,2H),4.20(brs,1H),5.06-5.08(m,1H),7.23-7.28(m,3H),7.31-7.40(m,4H)。
中间体20:(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸盐酸盐的合成
将(R)-3-(叔丁氧基羰基氨基)-4-(3'-氯联苯-4-基)丁酸苄酯(152mg,0.317mmol)和1MNaOH水溶液(1.583ml,1.583mmol)在MeOH(0.3ml)和THF(3ml)的混合溶剂中的溶液搅拌2小时。将该反应用1MHCl水溶液(2.5ml)淬熄。将产物用EtOAc萃取。将有机层用Na2SO4干燥,过滤,浓缩,从而得到粗品。
向该粗品中加入4MHCl的1,4-二恶烷溶液(1.583ml,6.33mmol)。在搅拌1小时后,收集沉淀出来的固体并减压干燥,从而以白色固体形式得到(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸盐酸盐(60.2mg);HPLC保留时间=0.52分钟(条件B);MS(m+1)=290.22;1HNMR(400MHz,CD3OD)δppm2.58-2.74(m,2H),2.99-3.11(m,2H),3.80-3.85(m,1H),7.34-7.45(m,4H),7.54-7.57(m,1H),7.62-7.65(m,3H)。
中间体21:1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酸和2-(1-(苄氧基羰基)环戊基)乙酸的混合物的合成
将2-氧杂螺环[4.4]壬烷-1,3-二酮(3g,19.46mmol)和苄醇(2.023ml,19.46mmol)在甲苯(2ml)中的溶液在100℃下搅拌19小时。将该反应混合物冷却至环境温度并浓缩,从而得到6:1的1-(2-(苄氧基)-2-氧代乙基)环戊烷甲酸和2-(1-(苄氧基羰基)环戊基)乙酸的混合物(4.89g);1HNMR(400MHz,氯仿-d)δppm1.60-1.78(m,6H),2.19-2.24(m,2H),2.75(s,2H),5.11(s,2H,主要的异构体),5.13(s,2H,次要的异构体),7.30-7.37(m,5H)。
中间体22:4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯的合成
将4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸(250mg,0.703mmol)、tBuOH(0.135ml,1.407mmol)、EDCI(270mg,1.407mmol)和4-二甲基氨基吡啶(86.0mg,0.704mmol)在DCM(7ml)中的溶液在室温下、在氮气下搅拌62小时。将该反应用水淬熄,将有机层分离出来并浓缩。将残余物用硅胶快速柱色谱进行纯化,从而得到4-(联苯-4-基)-3-(叔丁氧基羰基氨基)丁酸叔丁酯(110mg);HPLC保留时间=1.77分钟(条件B);MS(ES+)=412.1(m+1),300.0(m-tBux2+3;100%);1HNMR(400MHz,氯仿-d)δppm1.41(s,9H),1.47(s,9H),2.36(ABX的A,Jab=15.5Hz,Jax=6.2Hz,1H),2.44(ABX的B,Jab=15.5Hz,Jbx=5.6Hz)2.82-2.94(m,2H),4.11-4.17(m,1H),5.08-5.10(m,1H),7.25-7.34(m,3H)7.41-7.44(m,2H),7.51-7.58(m,4H)。
中间体23:3-氨基-4-(3'-氯-3-氟联苯-4-基)丁酸乙酯的合成
将锌(479mg,7.33mmol)和1,2-二溴乙烷(0.032ml,0.366mmol)在THF(8ml)中的混悬液在70℃下在氮气下加热,然后加入几滴溴代乙酸乙酯。在搅拌20分钟后,一次性加入2-(3'-氯-3-氟联苯-4-基)乙腈(300mg,1.221mmol)在THF(2ml)中的溶液。历经50分钟滴加剩余的溴代乙酸酯(溴代乙酸乙酯的总量:4.88mmol)。将其在相同温度下搅拌15分钟后,将该反应混合物冷却至环境温度。向该反应混合物中加入三乙酰氧基硼氢化钠(2588mg,12.22mmol)和AcOH(8ml)。将该反应混合物搅拌13小时,浓缩,从而得到粗品。将该粗品用EtOAc稀释,加入2MNa2CO3水溶液至pH10。将产物用EtOAc萃取。将有机层用K2CO3干燥,过滤,浓缩,从而得到粗品。将所得残余物用制备型HPLC进行纯化,用20%MeCN/水(0.1%NH4OH)至100%MeCN梯度洗脱,从而以油状物形式得到3-氨基-4-(3'-氯-3-氟联苯-4-基)丁酸乙酯(148mg);HPLC保留时间=0.85分钟(条件B);MS(m+1)=336.13;1HNMR(400MHz,氯仿-d)δppm1.27(t,J=7.1Hz,3H),2.36(ABX的A,Jab=15.9Hz,Jax=8.8Hz,1H),2.52(ABX的B,Jab=15.9Hz,Jbx=4.0Hz,1H),2.71-2.76(m,1H),2.82-2.87(m,1H),3.51-3.57(m,1H),4.15(d,J=7.1Hz,2H),7.24-7.39(m,5H),7.42-7.44(m,1H),7.54-7.55(m,1H)。
中间体24:2-(3'-氯-3-氟联苯-4-基)乙腈的合成
将4-溴-2-氟苄基氰(3.50g,16.35mmol)、3-氯苯硼酸(2.68g,17.17mmol)、Pd(OAc)2(0.110g,0.491mmol)、K2CO3(5.65g,40.9mmol)和溴化四丁基铵(5.80g,17.99mmol)在水(14ml)中的混悬液在氮气下在70℃下搅拌1小时。将该反应混合物冷却至室温并用EtOAc稀释。对两相进行分离。将有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。将所得残余物用硅胶快速柱色谱进行纯化(庚烷/EtOAc=100:0至70:30),从而得到2-(3'-氯-3-氟联苯-4-基)乙腈(3.52g);HPLC保留时间=1.17分钟(条件B);1HNMR(400MHz,氯仿-d)δppm3.81(s,2H),7.29-7.45(m,5H),7.50-7.55(m,2H)。
中间体25:(R)-4-(1-(4-溴苯基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸叔丁酯
向4-叔丁氧基-4-氧代丁酸(2.38g,13.64mmol)在DMF(30mL)和DCM(30mL)中的溶液中加入(R)-3-氨基-4-(4-溴苯基)丁酸乙酯盐酸盐(4g,12.4mmol)、HATU(5.19g,13.64mmol)和TEA(6.91mL,49.6mmol)。将其在室温下搅拌2小时后,将该反应用H2O淬熄,将粗品用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩,从而得到(R)-4-(1-(4-溴苯基)-4-乙氧基-4-氧代丁烷-2-基氨基)-4-氧代丁酸叔丁酯(4.0g)。HPLC保留时间=1.70分钟(条件A);MS(m+1)=444.1。
中间体26:(R)-3-氨基-4-(5'-氟-2'-甲氧基-联苯-4-基)-丁酸乙酯盐酸盐
向(R)-4-(4-溴苯基)-3-(叔丁氧基羰基氨基)丁酸乙酯(3.12g,8.08mmol)和5-氟-2-甲氧基苯基硼酸(2.2g,12.93mmol)在甲苯(52mL)中的溶液中加入PdCl2(dppf)·CH2Cl2加合物(0.66g,0.81mmol)和2MNa2CO3水溶液(8.1mL,16.16mmol)。将其在95℃下在氮气下搅拌4小时后,将溶液冷却至环境温度,然后用冰水淬熄。将粗品用乙酸乙酯稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=100:0至50:50),从而得到(R)-3-(叔丁氧基羰基氨基)-4-(5'-氟-2'-甲氧基联苯-4-基)丁酸乙酯(2.86g)。HPLC保留时间=1.80分钟(条件A);MS(m+1)=432.2;1HNMR(400MHz,氯仿-d)δppm1.31(t,J=7.1Hz,3H),1.45(s,9H),2.45-2.65(m,2H),2.83-2.94(m,1H),2.94-3.09(m,1H),3.80(s,3H),4.20(q,J=7.2Hz,2H),4.24-4.33(m,1H),5.11(br.s.,1H),6.90-6.96(m,1H),7.00(dd,J=7.8,3.3Hz,1H),7.06(dd,J=9.2,3.2Hz,1H),7.27(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H)。
将(R)-3-(叔丁氧基羰基氨基)-4-(5'-氟-2'-甲氧基联苯-4-基)丁酸乙酯(2.86g,6.62mmol)在4MHCl的1,4-二恶烷溶液(33.1ml,132mmol)中的溶液在室温下搅拌。在搅拌1小时后,将该反应混合物减压浓缩,从而得到(R)-3-氨基-4-(5'-氟-2'-甲氧基联苯-4-基)丁酸乙酯盐酸盐(2.44g)。HPLC保留时间=1.46分钟(条件A);MS(m+1)=332.3;1HNMR(400MHz,氯仿-d)δppm1.15(t,J=6.4Hz,3H),2.66-2.77(m,1H),2.78-2.91(m,1H),2.94-3.10(m,1H),3.42-3.53(m,1H),3.67(s,3H),3.83-3.96(m,1H),4.07(q,J=6.8Hz,2H),6.77-6.84(m,1H),6.87-6.96(m,2H),7.23(d,J=7.1Hz,2H),7.38(d,J=7.1Hz,2H),8.64(br.s.,2H)。
中间体27:(R)-4-(3'-氯联苯-4-基)-3-(2-乙氧基-2-氧代乙酰氨基)丁酸乙酯
在室温下,向(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(500mg,1.57mmol)在DMF(11mL)中的溶液中加入TEA(0.23mL,1.65mmol)和2-氯-2-氧代乙酸乙酯(0.18mL,1.57mmol)。将其在室温下搅拌1小时后,将反应用H2O淬熄并将粗品用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=70:30至50:50),从而得到(R)-4-(3'-氯联苯-4-基)-3-(2-乙氧基-2-氧代乙酰氨基)丁酸乙酯(550mg)。HPLC保留时间=1.88分钟(条件A);MS(m+1)=418.3。
中间体28:(R)-4-(3'-氯联苯-4-基)-3-(2-肼基-2-氧代乙酰氨基)丁酸乙酯
在-20℃下,向(R)-4-(3'-氯联苯-4-基)-3-(2-乙氧基-2-氧代乙酰氨基)丁酸乙酯(450mg,1.08mmol)在MeOH(24mL)中的溶液中加入50%wt的肼(0.068ml,1.08mmol)在MeOH(10mL)中的溶液。将其在室温下搅拌18小时后,将该反应混合物减压浓缩,从而得到(R)-4-(3'-氯联苯-4-基)-3-(2-肼基-2-氧代乙酰氨基)丁酸乙酯(412mg)。HPLC保留时间=1.76分钟(条件A);MS(m+1)=404.1。
中间体29:(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基噻唑-5-甲酰氨基)丁酸乙酯
向2-甲氧基噻唑-5-甲酸(80mg,0.50mmol)和(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(160mg,0.45mmol)在DMF(5mL)中的溶液中加入HATU(207mg,0.55mmol)和TEA(276mg,2.73mmol)。将混合物在室温下搅拌2小时。将该混合物用1NHCl中和并用水和EtOAc稀释。将有机层用盐水洗涤,用MgSO4干燥,过滤,浓缩。将粗品用快速柱色谱进行纯化,用30%EtOAc/庚烷至70%EtOAc/庚烷梯度洗脱,从而得到(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基噻唑-5-甲酰氨基)丁酸乙酯(170mg)。HPLC保留时间=1.97分钟(条件D);MS(m+1)=459.1。1HNMR(400MHz,氯仿-d)δppm1.29(t,J=7.1Hz,3H),2.49-2.69(m,2H),2.93(dd,J=13.6,8.1Hz,1H),3.10(dd,J=13.5,6.2Hz,1H),4.09(s,3H),4.00-4.15(m,2H),4.53-4.69(m,1H),6.78(d,J=8.6Hz,1H),7.25-7.32(m,3H),7.35(t,J=7.71Hz,1H),7.44(dt,J=7.6,1.5Hz,1H),7.48-7.54(m,3H),7.55(t,J=1.8Hz,1H)。
中间体30:(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基唑-5-甲酰氨基)丁酸乙酯
向2-甲氧基唑-5-甲酸(中间体16,98mg,0.69mmol)和(R)-3-氨基-4-(3'-氯联苯-4-基)丁酸乙酯盐酸盐(210mg,0.57mmol)在DMF(10mL)和CH2Cl2(4mL)中的溶液中加入HATU(272mg,0.72mmol)和TEA(0.50mL,3.58mmol)。将该混合物在室温下搅拌2小时。将该混合物用水淬熄并用EtOAc稀释。将有机层用水洗涤3次,用盐水洗涤,用MgSO4干燥,过滤,浓缩。将粗品用快速柱色谱进行纯化,用30%EtOAc/庚烷至70%EtOAc/庚烷进行洗脱,从而得到(R)-4-(3'-氯联苯-4-基)-3-(2-甲氧基唑-5-甲酰氨基)丁酸乙酯(122mg)。HPLC保留时间=1.89分钟(条件A);MS(m+1)=443.2;1HNMR(400MHz,氯仿-d)δppm1.28(t,J=7.1Hz,3H),2.52-2.66(m,2H),2.94(dd,1H),3.08(dd,J=13.6,6.3Hz,1H),4.12(s,3H),4.14-4.23(m,2H),4.60-4.71(m,1H),6.81(d,J=8.8Hz,1H),7.25-7.32(m,3H),7.35(t,J=7.7Hz,1H),7.42(s,1H),7.43-7.47(m,1H),7.48-7.54(m,2H),7.55(t,J=1.6Hz,1H)。
中间体31:6-(甲基磺酰氨基)烟酸
向在冰浴上冷却的、含有TEA(0.96mL,6.90mmol)的6-氨基烟酸甲酯(1.0g,6.57mmol)在CH2Cl2(50mL)中的溶液中缓慢加入MsCl(0.54mL,6.90mmol)。将混合物在室温下搅拌2小时。然后,将该混合物浓缩。将粗品溶解于MeOH(20mL)中并向其中加入1NNaOH(30mL,30mmol)。将混合物在室温下搅拌18小时。将混合物用1NHCl(32mL,32mmol)淬熄。将混合物浓缩以除去MeOH以及一些水。将粗品用CH2Cl2稀释并用1NNaOH(30mL)碱化。将水层用CH2Cl2萃取。将水层用浓HCl酸化至pH试纸表明其pH至1。将混合物用EtOAc稀释并用EtOAc对水层进行萃取。将所合并的有机层用盐水洗涤,用MgSO4干燥,过滤,浓缩,从而以黄色固体形式得到6-(甲基磺酰氨基)烟酸(421mg)。HPLC保留时间=0.40分钟(条件D);MS(m+1)=217.2。
中间体32:2-甲氧基唑-5-甲酸
向2-氯唑-5-甲酸乙酯(510mg,2.90mmol)在无水MeCN(10mL)和无水MeOH(10mL)中的溶液中加入NaOMe(628mg,11.62mmol)。将该混合物在回流下搅拌2小时。向该混合物中再加入一些MeOH。将该混合物再回流4小时。将混合物浓缩并重新溶解于MeOH(10mL)中。向该混合物中加入1NNaOH(10ml)。将混合物在室温下搅拌3小时。将混合物用浓HCl淬熄,调节pH至pH试纸表明pH为7。将该混合物浓缩并用水稀释。将水层用浓HCl酸化并用EtOAc稀释。将有机层用水、盐水洗涤,用MgSO4干燥,过滤,浓缩,从而得到2-甲氧基唑-5-甲酸(290mg)。HPLC保留时间=0.58分钟(条件D);MS(m+1)=144.0。
中间体33:5-氧代-4,5-二氢-1,2,4-二唑-3-甲酸乙酯
在室温下,向2-(羟基氨基)-2-亚氨基乙酸乙酯(2g,15.14mmol)在二恶烷(15.00mL)中的溶液中加入CDI(2.7g,16.65mmol)和DBU(2.5ml,16.65mmol)。在80℃下搅拌1小时后,将该反应用1NHCl淬熄并将该混合物用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩,从而得到5-氧代-4,5-二氢-1,2,4-二唑-3-甲酸乙酯(2.4g)。HPLC保留时间=0.72分钟(条件D);MS159.1(M+1)。
中间体34:5-氧代-4,5-二氢-1,2,4-二唑-3-甲酸
在室温下,向5-氧代-4,5-二氢-1,2,4-二唑-3-甲酸乙酯(2.4g,15.14mmol)在MeOH(2mL)中的溶液中加入1NNaOH水溶液(4mL,4mmol)。将其在室温下搅拌5小时后,将该反应用1NHCl(5mL,5mmol)淬熄,将该混合物减压浓缩以除去MeOH。将该混合物用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩得到5-氧代-4,5-二氢-1,2,4-二唑-3-甲酸(1.9g)。
中间体35:2-氧代-2,3-二氢唑-4-甲酸
该中间体是根据Okonya,J.F.;Hoffman,R.V.;Johnson,M.C.;J.Org.Chem.2002,67,1102-1108来进行制备的。
中间体36:3-羟基异噻唑-5-甲酸
向3-羟基异噻唑-5-甲酸甲酯(300mg,1.73mmol)在MeOH(2mL)中的溶液中加入1NNaOH(6mL,6mmol)。将其在室温下搅拌2小时后,将该混合物减压浓缩除去MeOH并用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩得到3-羟基异噻唑-5-甲酸(250mg)。
中间体37:2-乙烯基唑-5-甲酸乙酯
在室温下,向三丁基(乙烯基)氢化锡(1.1mL,3.83mmol)和2-氯唑-5-甲酸乙酯(546mg,3.11mmol)在二恶烷(37mL)中的溶液中加入Pd(PPh3)2Cl2(222mg,0.32mmol)。将其在氮气下在100℃下搅拌4小时后,将该溶液冷却至环境温度,然后用H2O淬熄。将该混合物用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩。将所得残余物用快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=90:10至80:20),从而得到2-乙烯基唑-5-甲酸乙酯(470mg)。HPLC保留时间=0.39分钟(条件B);MS(m+1)=168.2;1HNMR(400MHz,CD3OD)δppm1.38(t,J=7.1Hz,3H),4.38(q,J=7.2Hz,2H),5.88(d,J=11.4Hz,1H),6.39(d,J=17.7Hz,1H),6.69(dd,J=17.6,11.2Hz,1H),7.83(s,1H)。
中间体38:2-乙基唑-5-甲酸乙酯
在室温下,向2-乙烯基唑-5-甲酸乙酯(470mg,2.81mmol)在MeOH(7mL)中的溶液中加入10%wt.Pd/C(100mg,0.094mmol)。将其在室温下在氢气囊下搅拌1小时后,将该混合物过滤以除去Pd/C。收集滤液并将其浓缩,从而得到2-乙基唑-5-甲酸乙酯(470mg)。HPLC保留时间=1.09分钟(条件A);MS(m+1)=170.3;1HNMR(400MHz,CD3OD)δppm1.35(t,J=7.6Hz,3H),1.36(t,J=7.2Hz,3H),2.87(q,J=7.7Hz,2H),4.35(q,J=7.2Hz,2H),7.71(s,1H)。
中间体39:2-乙基唑-5-甲酸
向2-乙基唑-5-甲酸酯(470mg,2.81mmol)在MeOH(10mL)中的溶液中加入1NNaOH(6mL,6mmol)。将其在室温下搅拌18小时后,将该混合物减压浓缩除去MeOH并将其用EtOAc稀释。将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩得到2-乙基唑-5-甲酸(244mg)。1HNMR(400MHz,CD3OD)δppm1.36(t,J=7.7Hz,3H),2.89(q,J=7.6Hz,2H),5.15(br.s.,1H),7.69(s,1H)。
中间体40:2-乙烯基噻唑-5-甲酸乙酯
在室温下,向三丁基(乙烯基)氢化锡(0.92mL,3.14mmol)和2-溴噻唑-5-甲酸乙酯(0.38mL,2.54mmol)在二恶烷(33mL)中的溶液中加入Pd(PPh3)2Cl2(182mg,0.26mmol)。将其在100℃下在氮气下搅拌4小时后,将该溶液冷却至环境温度,然后用H2O淬熄。将该混合物用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩。将所得残余物用硅胶快速柱色谱进行纯化(洗脱剂:庚烷/EtOAc=90:10至80:20),从而得到2-乙烯基噻唑-5-甲酸乙酯(418mg)。HPLC保留时间=0.45分钟(条件B);MS(m+1)=184.1;1HNMR(400MHz,CD3OD)δppm1.37(t,J=7.2Hz,3H),4.35(q,J=7.1Hz,2H),5.71(d,J=10.9Hz,1H),6.24(d,J=17.4Hz,1H),6.93(dd,J=17.4,10.9Hz,1H),8.29(s,1H)。
中间体41:2-乙基噻唑-5-甲酸乙酯
在室温下,向2-乙烯基噻唑-5-甲酸乙酯(400mg,2.18mmol)在MeOH(7mL)中的溶液中加入10%wt.Pd/C(267mg,0.25mmol)。将其在室温下在氢气囊下搅拌1小时后,将该混合物过滤以除去Pd/C。将滤液浓缩,从而得到2-乙基噻唑-5-甲酸乙酯(404mg)。HPLC保留时间=0.60分钟(条件B);MS(m+1)=186.3;1HNMR(400MHz,CD3OD)δppm1.35(t,J=7.3Hz,2H),1.39(t,J=7.20Hz,2H),3.07(q,J=7.58Hz,2H),4.35(q,J=7.16Hz,2H),8.22(s,1H)。
中间体42:2-乙基噻唑-5-甲酸
向2-乙基噻唑-5-甲酸乙酯(400mg,2.159mmol)在MeOH(10mL)中的溶液中加入1NNaOH(6mL,6mmol)。将其在室温下搅拌18小时后,将该混合物减压浓缩以除去MeOH。将该混合物用EtOAc稀释,将有机层用盐水洗涤,用Na2SO4干燥,过滤并减压浓缩得到2-乙基噻唑-5-甲酸(282.4mg)。HPLC保留时间=0.78分钟(条件D);MS(m+3)=160.4;1HNMR(400MHz,CD3OD)δppm1.40(t,J=7.6Hz,3H),3.07(q,J=7.6Hz,2H),5.08(br.s.,1H),8.20(s,1H)。
中间体43:3-羟基-异唑-5-甲酸
向3-羟基-异唑-5-甲酸甲酯(286mg,2.0mmol)在甲醇(7mL)中的溶液中加入1NNaOH(4.0mL,4.0mmol)并将该混合物在室温下搅拌18小时。减压除去溶剂并向残余物中加入4.0mL1NHCl。将所得溶液冻干得到产物,将其用于随后的反应中。
中间体44:5-甲氧基羰基甲基-呋喃-2-甲酸
向5-甲氧基羰基甲基-呋喃-2-甲酸甲酯(250mg,1.26mmol)在甲醇(5mL)中的溶液中加入1NNaOH(2.78mL,2.78mmol)并将该混合物在室温下搅拌18小时。减压除去溶剂并向残余物中加入2.78mL1NHCl。将所得溶液冻干,从而得到5-羧基甲基-呋喃-2-甲酸。
接下来,向上面的二酸(220mg,1.29mmol)在甲醇(8mL)中的溶液中加入Amberlyst-15树脂(50mg)并将该混合物在室温下搅拌18小时。将树脂滤除并减压除去溶剂得到产物,将其用于随后的反应中。1HNMR(400MHz,氯仿-d)δppm3.75(s,3H),3.82(s,2H),6.45(d,J=3.54Hz,1H),7.29(d,J=3.54Hz,1H),10.17(s,宽峰,1H)。
中间体45:(R)-4-(3'-氯-联苯-4-基)-3-异氰酰基-丁酸乙酯
在0℃下,向剧烈搅拌着的8%碳酸氢钠水溶液(3mL)和二氯甲烷(3mL)的混合物中加入三光气(28.1mg,0.095mmol)并将该混合物在0℃下搅拌5分钟,然后加入中间体17-1(100mg,0.284mmol)并将其再继续搅拌15分钟。将有机层分离出来并用硫酸钠干燥。减压除去溶剂得到标题化合物。将其用于随后的反应中。
中间体46:2-(4-甲氧基-苄基)-2H-四唑-5-碳酰氯
在室温下,向1H-四唑-5-甲酸乙酯钠盐(500mg,3.05mmol)在DMF(5ml)中的溶液中加入4-甲氧基苄基氯(747μl,5.48mmol)和TEA(1500μl,10.76mmol)。将该反应混合物在室温下搅拌一夜。向该反应中加入水并用EtOAc萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将残余物用柱色谱进行纯化(10%至30%EtOAc/庚烷)。在室温下,向进行了纯化的残余物在EtOH(2ml)中的溶液中加入NaOH(2ml,2.000mmol)并将该混合物在室温下搅拌。在搅拌1小时后,将该混合物减压浓缩以除去EtOH,在酸化至pH<5后,用EtOAc萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩,从而得到2-(4-甲氧基-苄基)-2H-四唑-5-甲酸。
接下来,在室温下,向2-(4-甲氧基-苄基)-2H-四唑-5-甲酸在甲苯(15ml)中的混合物中加入SOCl2(1ml,13.70mmol)并将该混合物在80℃下加热3小时。将该反应混合物减压浓缩得到粗品,将其在不进行进一步纯化的情况下应用。
中间体47:(R)-3-氨基-4-(3'-氯-联苯-4-基)-丁酸茚满-5-基酯
在室温下,向boc-(R)-3-氨基-4-(4-溴-苯基)-丁酸(500mg,1.396mmol)在THF(12ml)中的混悬液中加入5-二氢化茚醇(187mg,1.396mmol)和Ph3P(403mg,1.535mmol)。在冰浴上,向该混合物中加入DIAD(0.326ml,1.675mmol)并将该混合物由冰浴至室温搅拌过夜。将该反应减压浓缩并用柱色谱进行纯化(5%至20%EtOAc/庚烷),从而得到450mg固体。在室温下,向所得固体(200mg,0.422mmol)在DMF(5ml)中的溶液中加入3-氯苯基硼酸(79mg,0.506mmol)、磷酸钾(134mg,0.632mmol)和Pd(PPh3)4(48.7mg,0.042mmol)。将该反应在100℃下搅拌一夜。将该反应用盐水淬熄并用EtOAc萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将残余物用柱色谱进行纯化(5%至30%EtOAc/庚烷)。在室温下,向位于DCM(1ml)中的所得残余物(143mg,0.283mmol)中加入TFA(1mL,12.98mmol)并将该混合物在室温下搅拌2小时。将该混合物浓缩得到粗品盐,将其在不进行进一步纯化的情况下直接使用。HPLC保留时间=1.27分钟(条件B);MS(m+1)=406。
中间体48:(R)-4-联苯-4-基-3-脲基-丁酸乙酯
在0℃下,向(R)-3-氨基-4-联苯-4-基-丁酸乙酯(200mg,0.625mmol)在THF(10ml)中的混悬液中加入氯甲酸苯酯(0.087ml,0.688mmol)和吡啶(0.126ml,1.563mmol)。将该混合物在0℃下搅拌5分钟,然后将其加温至室温。用LCMS对该反应进行监测直至反应结束。将该反应用EtOAc萃取。将所合并的有机层用1NHCl、H2O、饱和NaHCO3水溶液和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩得到粗品残余物。
接下来,在室温下,向所得残余物(0.252g,0.625mmol)在DMSO(1.5ml)中的溶液中加入氢氧化铵(0.027ml,0.688mmol)。将该反应在室温下进行搅拌。30分钟时,LCMS表明含有大量起始材料,仅有少量所需产物,因此,再加入一些氢氧化铵并将该反应在室温下搅拌过夜直至反应结束。将该反应用EtOAc萃取。将所合并的有机层用H2O、1NHCl、H2O、1NNaOH和盐水洗涤并用无水硫酸钠干燥,过滤并减压浓缩。将残余物用柱色谱进行纯化(2%至6%EtOH/DCM),从而得到(R)-4-联苯-4-基-3-脲基-丁酸乙酯(169mg)。HPLC保留时间=1.04分钟(条件B);MS(m+1)=327。
中间体49:(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-羟基-丁酸甲酯盐酸盐
将(R)-3-(4-溴-苯基)-2-叔丁氧基羰基氨基-丙酸(4.0g,11.6mmol)、3-氯苯基硼酸(2.36g,15.11mmol)、Pd(PPh3)4(0.067g,0.058mmol)和2MNa2CO3水溶液(8.0mL)在1,2-二甲氧基乙烷(70mL)中在N2气氛下回流2.5小时。在冷却至室温后,将该反应混合物用EtOAc稀释并用1MHCl和盐水洗涤。将有机层用Na2SO4干燥并浓缩。将残余物用快速柱色谱进行纯化(硅胶,DCM/10%MeOH的DCM溶液=100:0至0:100),从而得到(R)-2-叔丁氧基羰基氨基-3-(3'-氯-联苯-4-基)-丙酸(包含杂质)。HPLC保留时间=1.56分钟(条件A):MS(m+1)=376。
将其溶解于1,2-二甲氧基乙烷(40mL)和Et3N(1.46mL,10.5mmol)中并加入氯甲酸乙酯(1.00mL,10.5mmol)。将其在室温下搅拌0.5小时后,通过过滤除去所产生的沉淀。向滤液中缓慢加入NaBH4(0.44g,11.6mmol)的H2O(5mL)溶液。在搅拌2小时后,将该反应混合物用EtOAc稀释并用H2O和盐水洗涤。将有机层用Na2SO4干燥,浓缩并通过快速柱色谱进行纯化(硅胶,洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到[(R)-2-(3'-氯-联苯-4-基)-1-羟基甲基-乙基]-氨基甲酸叔丁酯(2.8g)。HPLC保留时间=1.26分钟(条件A):MS(m+1-Boc)=262。1H-NMR(400MHz,DMSO-d6)δppm1.43(s,9H),2.90(d,2H,J=7.33Hz),3.60(dd,1H,J=5.05,10.86Hz),3.72(dd,1H,J=3.79,11.12Hz),3.91(bs,1H),4.75(bs,1H),7.29-7.34(m,3H),7.37(t,1H,J=7.83Hz),7.44-7.48(m,1H),7.51(d,2H,J=8.08Hz),7.57(t,1H,J=1.77Hz)。
接下来,向[(R)-2-(3'-氯-联苯-4-基)-1-羟基甲基-乙基]-氨基甲酸叔丁酯(2.0g,5.53mmol)的DCM(30mL)溶液中加入Dess-Martinperiodinane(2.81g,6.63mmol)。将其在室温下搅拌2小时后,将该反应混合物用EtOAc稀释并用饱和NaHCO3水溶液和盐水洗涤。将有机层用Na2SO4干燥并浓缩。将残余物通过快速柱色谱进行纯化(硅胶,洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到[(R)-2-(3'-氯-联苯-4-基)-1-甲酰基-乙基]-氨基甲酸叔丁酯(1.05g)。HPLC保留时间=1.27分钟(条件A):MS(m+1)=360。
将其溶解于MeOH(20mL)和AcOH(0.199mL,3.47mmol)中。向该溶液中缓慢加入KCN(0.226g,3.47mmol)的H2O(4mL)溶液。将其在室温下搅拌一夜后,将该反应混合物用EtOAc稀释并用饱和NaHCO3水溶液、H2O和盐水洗涤。将有机层用Na2SO4干燥并浓缩。在室温下,将其用4MHCl的二恶烷溶液(20mL)和MeOH(10mL)处理。在搅拌一夜后,将该反应混合物浓缩。将残余物溶解于MeOH中并用SOCl2(0.211mL,2.89mmol)处理。将其在50℃下搅拌5小时后,将反应混合物浓缩至干。将残余物溶解于THF(10mL)中并用饱和NaHCO3水溶液(5mL)以及Boc2O(0.631g,2.89mmol)处理。将其在室温下搅拌2小时后,将该反应混合物用EtOAc稀释并用盐水洗涤。将有机层用MgSO4干燥并浓缩。将残余物通过快速柱色谱进行纯化(硅胶,洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-羟基-丁酸甲酯(0.61g)。HPLC保留时间=1.01,1.06分钟(条件B):MS(m+1-Boc)=320。1H-NMR(400MHz,CDCl3)δppm1.40(s,9H),2.77-3.05(m,2H),3.63(s,0.7H),3.77(s,2.3H),4.11(s,0.8H),4.25-4.40(m,1.2H),4.78-4.95(m,1H),7.27-7.40(m,4H),7.42-7.58(m,4H)。
将(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-羟基-丁酸甲酯(113mg,0.269mmol)用4MHCl的二恶烷溶液(2mL)处理。将其在室温下搅拌1小时后,将该反应混合物浓缩。将残余物在不进行进一步纯化的情况下用于下一步。HPLC保留时间=1.22、1.29分钟(条件A):MS(m+1)=320。中间体50:(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-甲氧基-丁酸甲酯盐酸盐
向(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-羟基-丁酸甲酯(610mg,1.45mmol)在CH3CN(20mL)中的溶液中加入碘甲烷(0.545mL,8.72mmol)和氧化银(1.35g,5.81mmol)。将其在室温下搅拌16小时后,再加入一些碘甲烷(0.545mL,8.72mmol)和氧化银(1.35g,5.81mmol)并搅拌3天。将该反应混合物用硅藻土垫过滤并将滤液用盐水洗涤。将有机层用MgSO4干燥并浓缩。将残余物通过快速柱色谱进行纯化(硅胶,洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-甲氧基-丁酸甲酯(500mg)。HPLC保留时间=1.20、1.25分钟(条件B):MS(m+1-Boc)=334。1H-NMR(400MHz,CDCl3)δppm1.37,1.41(s,9H),2.72-3.03(m,2H),3.43,3.71(s,3H),3.63-3.82(m,1H),4.27-4.41(m,1H),4.68-5.04(m,1H),7.28-7.40(m,4H),7.41-7.61(m,4H)。
将(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-甲氧基-丁酸甲酯(200mg,0.461mmol)用4MHCl的二恶烷溶液(3mL)处理。将其在室温下搅拌1小时后,将该反应混合物浓缩。将残余物在不进行进一步纯化的情况下用于下一步。HPLC保留时间=1.26、1.33分钟(条件A):MS(m+1)=334。
中间体51:(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-甲氧基-丁酸乙酯盐酸盐
向(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-甲氧基-丁酸甲酯(500mg,1.15mmol)在MeOH(5mL)中的溶液中加入2MNaOH水溶液(5mL)。将其在室温下搅拌2小时后,将该反应混合物用2MHCl酸化并用EtOAc萃取。将有机层用Na2SO4干燥并浓缩。将残余物溶解于EtOH(5mL)中并用SOCl2(0.252mL,3.26mmol)处理。将其在55℃下搅拌后,将该反应混合物浓缩。将残余物在不进行进一步纯化的情况下用于下一步。HPLC保留时间=1.49分钟(条件A):MS(m+1)=348.2。
中间体52:(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-氟-丁酸甲酯盐酸盐
在0℃下,向(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-羟基-丁酸甲酯(220mg,0.524mmol)中加入DAST(0.083mL,0.629mmol)。将该反应混合物逐渐加温至室温并搅拌1小时。再加入一些DAST(0.083mL,0.629mmol)并将其在室温下搅拌2小时。将该反应混合物用EtOAc稀释并用饱和NaHCO3水溶液和盐水洗涤。将有机层用Na2SO4干燥并浓缩。将残余物通过快速柱色谱进行纯化(硅胶,洗脱剂:庚烷/EtOAc=100:0至0:100),从而得到(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-氟-丁酸甲酯(63mg)。HPLC保留时间=1.36分钟(条件B):MS(m+1-Boc)=322。1H-NMR(400MHz,CDCl3)δppm1.39(s,9H),2.84-2.95(m,2H),3.06(bs,0.5H),3.69(s,3H),4.43-4.61(m,1H),4.72-4.80(m,0.5H),5.00(s,0.5H),5.12(s,0.5H),7.28-7.34(m,3H),7.37(t,1H,J=7.58Hz),7.42-7.47(m,1H),7.48-7.53(m,1H),7.55(t,1H,J=2.02Hz)。19F-NMR(377MHz,CDCl3)δppm-204.18。
将(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-2-氟-丁酸甲酯(60mg,0.142mmol)用4MHCl的二恶烷溶液处理(1.5mL)。将其在室温下搅拌1小时后,将该反应混合物浓缩。将残余物在不进行进一步纯化的情况下用于下一步。HPLC保留时间=0.88分钟(条件B):MS(m+1)=322。
中间体53-1:[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-氨基甲酸叔丁酯
将(R)-3-叔丁氧基羰基氨基-4-(3'-氯-联苯-4-基)-丁酸乙酯(250mg,0.598mmol)用2MNaOH水溶液(1mL)在THF(1mL)和EtOH(2mL)中进行处理。在搅拌1小时后,将该反应混合物用1MHCl酸化并用EtOAc萃取。将有机层用盐水洗涤,用Na2SO4干燥并将其真空浓缩。向残余物在DMF(2mL)中的溶液中加入甲磺酰胺(85mg,0.897mmol)、EDC(172mg,0.897mmol)、HOAt(98mg,0.718mmol)和Et3N(0.125mL,0.897mmol)。将其在室温下搅拌一夜后,将该反应混合物用EtOAc稀释,用1MHCl和盐水洗涤。将有机层用Na2SO4干燥并浓缩。将残余物通过快速柱色谱进行纯化(硅胶,洗脱剂:DCM/10%MeOH的DCM溶液=100:0至0:100),从而得到[(R)-1-(3'-氯-联苯-4-基甲基)-3-甲烷磺酰基氨基-3-氧代-丙基]-氨基甲酸叔丁酯(244mg)。HPLC保留时间=1.30分钟(条件B);MS(m+1)=467;1HNMR(400Mz,DMSO-d6)δppm1.30(s,9H),2.41-2.48(m,2H),2.70-2.78(m,2H),3.18(s,3H),3.99-4.11(m,1H),7.28(d,2H,J=8.34Hz),7.38-7.44(m,1H),7.48(t,1H,J=7.83Hz),7.59-7.66(m,3H),7.69(s,1H)。
下面的化合物是用与实施例53-1所述操作类似的操作制备的:
中间体54-1:(R)-3-[2-(叔丁氧基羰基-乙氧基羰基甲基-氨基)-丙酰基氨基]-4-(3’-氯-联苯-4-基)-丁酸乙酯
在室温下,向2-(叔丁氧基羰基-乙氧基羰基甲基-氨基)-丙酸TFA盐(197mg,0.714mmol)在THF(10ml)中的混悬液中加入EDCI(219mg,1.142mmol)和HOBT(164mg,1.071mmol)。将该混合物在室温下搅拌10分钟,然后加入(R)-3-氨基-4-(3’-氯-联苯-4-基)-丁酸乙酯(202mg,0.571mmol)在THF和TEA(0.199ml,1.428mmol)中的溶液。将该混合物在室温下搅拌。用反相HPLC进行处理[历经10min,30至90%ACN-H2O(0.1%TFA),X-Bridge苯基柱]得到标题化合物(290mg,收率为71%)。LCMS(条件B):575(M+1);保留时间=1.52分钟。
中间体54-2:2-(叔丁氧基羰基-乙氧基羰基甲基-氨基)-丙酸
在室温下,向H-DL-Ala-OBzl.对-甲苯磺酸盐(2.88g,8.20mmol)在THF(80ml)中的溶液中加入TEA(3.43ml,24.60mmol),然后加入溴代乙酸乙酯(1.096ml,9.84mmol)。将该反应在室温下搅拌一夜。在反应液中有一些白色固体。将该反应混合物中的白色固体滤除并浓缩以进行纯化。用快速柱色谱进行纯化(硅胶,2至4%EtOH/DCM),以油状物形式得到标题化合物(1.7g,收率为78%)。LCMS(条件B):266(M+1);保留时间=0.70分钟。
接下来,在0℃下,向2-(乙氧基羰基甲基-氨基)-丙酸苄酯(1.7g,6.41mmol)在DCM(80ml)中的溶液中加入BOC-酸酐(2.232ml,9.61mmol),然后加入TEA(2.68ml,19.22mmol)。将该反应混合物缓慢加温至室温并将其搅拌一夜。将该反应用盐水淬熄并用DCM萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并浓缩得到粗品。用快速柱色谱进行纯化(硅胶,5至10%丙酮/庚烷),以油状物形式得到标题化合物(1.66g,收率为71%)。LCMS(条件B):366(M+1);保留时间=1.13分钟。
接下来,将2-(叔丁氧基羰基-乙氧基羰基甲基-氨基)-丙酸苄酯在EtOAc中的溶液在H2气囊下用催化剂湿的10%Pd/C氢化1小时。将该反应液过滤以除去催化剂并将其浓缩得到粗品,将其用于下面的反应。
中间体55:(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-甲基-丁酸乙酯三氟乙酸盐
在-78℃下,向(R)-3-叔丁氧基羰基氨基-4-(3’-氯-联苯-4-基)-丁酸乙酯(300mg,0.718mmol)在THF(10ml)中的溶液中加入LiHMDS/THF(1M)(1.579ml,1.579mmol)。将该反应混合物在-78℃下搅拌50分钟,然后,向该混合物中加入甲基碘(0.054ml,0.861mmol),将该反应缓慢加温至室温并搅拌一夜。将该反应用饱和NH4Cl淬熄并用EtOAc萃取。将所合并的有机层用盐水洗涤并用无水硫酸钠干燥,过滤并浓缩得到粗品。用反相HPLC进行纯化[历经10分钟,20至90%ACN-H2O(0.1%TFA),SunfireC18]得到(R)-3-叔丁氧基羰基氨基-4-(3’-氯-联苯-4-基)-2-甲基-丁酸乙酯。LCMS(条件B):432(M+1);保留时间=1.55分钟。在室温下,向(R)-3-叔丁氧基羰基氨基-4-(3’-氯-联苯-4-基)-2-甲基-丁酸乙酯(240mg,0.556mmol)在DCM(2ml)中的溶液中加入TFA(1.070ml,13.89mmol)并将该混合物在室温下搅拌。1小时后反应结束,将该混合物浓缩,从而得到(R)-3-氨基-4-(3'-氯-联苯-4-基)-2-甲基-丁酸乙酯三氟乙酸盐。LCMS(条件B):332(M+1);保留时间=1.00分钟。
可以看到,本发明的化合物可用作中性肽链内切酶(EC3.4.24.11)活性的抑制剂并因此可用于治疗与中性肽链内切酶(EC3.4.24.11)活性有关的疾病和情况,例如本文所公开的疾病。
应当清楚的是,仅以举例的方式对本发明进行了描述,可以对本发明进行修改,这些修改仍然在本发明的主旨和范围内。
Claims (14)
1.式IC的化合物:
或其可药用的盐,其中:
R1是H;
R2a是氯或氟并且R2是卤素、C1-7烷基、C1-7烷氧基、羟基或卤代-C1-7烷基;
R3是A1-C(O)X1;
X和X1独立地是OH、-O-C1-7烷基、-NRaRb、-NHS(O)2-C1-7烷基、-NHS(O)2-苄基或-O-C6-10芳基;其中烷基任选地被一个或多个独立地选自C6-10芳基、杂芳基、杂环基、C(O)NH2、C(O)NH-C1-6烷基和C(O)N(C1-6烷基)2的取代基取代;其中Ra和Rb每次出现时独立地是H或C1-7烷基;
B1是-C(O)NH-或-NHC(O)-;
A1是键或直链或支链C1-7亚烷基;其任选地被一个或多个独立地选自卤素、C3-7环烷基、C1-7烷氧基、羟基和O-乙酸酯的取代基取代;其中两个偕烷基可任选地合并形成C3-7环烷基;或者
A1是直链或支链C1-7亚链烯基;或者
A1是其中一个或多个碳原子被选自O、NRc的杂原子替代的直链C1-4亚烷基;并且A1任选地被一个或多个独立地选自卤素和C1-7烷基的取代基取代;其中Rc每次出现时独立地是H、C1-7烷基、-C(O)-O-C1-7烷基或-CH2C(O)OH;
p是0或1;
其中各杂芳基是一种包含5-10个选自碳原子和1至5个杂原子的环原子的单环或二环的芳族环,并且
各杂环基是一种包含4-7个选自碳原子和1-5个杂原子的环原子的单环饱和或部分不饱和但非芳族的部分,其中杂芳基或杂环基的各杂原子独立地选自O、N和S。
2.具有式IIC的权利要求1的化合物:
或其可药用的盐。
3.具有式IIIC的权利要求1的化合物:
或其可药用的盐。
4.权利要求1至3中任意一项的化合物或其可药用的盐,其中A1是任选地被取代的直链或支链C1-7亚烷基。
5.权利要求1至3中任意一项的化合物或其可药用的盐,其中A1是CH2CH2。
6.权利要求1至3中任意一项的化合物或其可药用的盐,其中X和X1独立地是OH或-O-C1-7烷基。
7.权利要求1至3中任意一项的化合物或其可药用的盐,其中R2a是间-氯。
8.一种药物组合物,其包含权利要求1至7中任意一项的化合物或其可药用的盐和一种或多种可药用的载体。
9.一种组合产品,其包含:权利要求1至7中任意一项的化合物或其可药用的盐,和一种或多种选自下列的治疗活性剂:血管紧张素受体阻滞剂和血管紧张素转化酶抑制剂。
10.权利要求1至7中任意一项的化合物或其可药用的盐在制备用于在需要其的个体中治疗与中性肽链内切酶EC.3.4.24.11.活性有关的病症或疾病的药物中的用途。
11.权利要求10的用途,其中所述病症或疾病选自高血压、外周血管疾病、心力衰竭、左心室肥大、肾功能不全、肾衰竭、非糖尿病性肾病、肾病综合征、硬皮病、肾小球硬化、原发性肾病的蛋白尿、晚期肾病、内皮机能障碍、舒张期功能障碍、肥厚型心肌病、室上和室性心律失常、心房颤动、心脏纤维化、心房扑动、有害的血管重构、斑块稳定、心肌梗死、肾纤维化、多囊性肾病、周期性水肿、梅尼埃病、高醛固酮血症、高钙尿症、腹水、青光眼、月经失调、早产、先兆子痫、子宫内膜异位、生殖病症、哮喘、阻塞性睡眠呼吸暂停、炎症、白血病、疼痛、癫痫症、精神病情况、痴呆、老年意识错乱、肥胖和胃肠道病症、伤口愈合、脓毒性休克、胃酸分泌功能障碍、高肾素血症、囊性纤维化、再狭窄、代谢综合征、糖尿病并发症和动脉粥样硬化。
12.权利要求11的用途,其中所述病症或疾病选自肺动脉高压、肾血管性高血压、糖尿病性肾病、糖尿病性视网膜病、糖尿病性心肌病和抑郁。
13.权利要求11的用途,其中所述病症或疾病选自单纯收缩期高血压、顽固性高血压和充血性心力衰竭。
14.权利要求11的用途,其中所述病症或疾病选自心绞痛、肾小球肾炎、情感障碍、2型糖尿病和雄性和雌性性功能障碍。
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