CN113999234B - 一种免疫调节剂 - Google Patents
一种免疫调节剂 Download PDFInfo
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- CN113999234B CN113999234B CN202110847309.4A CN202110847309A CN113999234B CN 113999234 B CN113999234 B CN 113999234B CN 202110847309 A CN202110847309 A CN 202110847309A CN 113999234 B CN113999234 B CN 113999234B
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Abstract
本发明公开了一种免疫调节剂,具体涉及一类抑制IL‑17A的化合物及其作为免疫调节剂在制备药物中的用途。本发明公开了式I所示的化合物、或其立体异构体在制备抑制IL‑17A类药物中的用途,为临床上筛选和/或制备与IL‑17A活性相关的疾病的药物提供了一种新的选择。
Description
技术领域
本发明涉及一种免疫调节剂及其在制备药物中的用途。
背景技术
IL-17(白细胞介素-17)是促炎性细胞因子,在诱导其他炎性细胞因子、趋化因子和粘附因子中发挥作用。IL-17家族由参与急性和慢性炎症反应的细胞因子组成,包括IL-17A(CTLA-8)、IL-17B、IL-17C、IL-17D、IL-17E(IL-25)和IL-17F。IL-17A由TH17细胞表达,其参与炎症和自身免疫性疾病的病理发生。人类IL-17A是分子量约为17000道尔顿的糖蛋白。IL-17A通过IL-17受体复合物(IL-17RA和IL-17RC)将信号传送至细胞内(Wright,etal.Journal of immunology,2008,181:2799-2805)。IL-17A的主要功能是通过促炎和嗜中性粒细胞迁移细胞因子和趋化因子(包括IL-6,G-CSF,TNF-α,IL-1,CXCL1,CCL2,CXCL2)的上调来协调局部组织炎症,以及基质金属蛋白酶来允许活化的T细胞穿透细胞外基质。有研究表明IL-17A在严重哮喘和慢性阻塞性肺疾病(COPD)中发挥重要作用,那些患者通常对目前可用的药物无响应或响应不良(Al-Ramli et al.J Allergy Clin Immunol,2009,123:1185-1187)。IL-17A水平上调涉及许多疾病,包括类风湿性关节炎(RA)、骨侵蚀、腹膜内脓肿、炎性肠病、同种异体移植物排斥反应、牛皮癣、动脉粥样硬化、哮喘和多发性硬化症(Gaffen,SL et al.Arthritis Research&Therapy,2004,6:240-247)。
靶向IL-17A与IL-17RA的结合是治疗IL-17A介导的自身免疫性炎性疾病的有效策略。通过IL-17A中和抗体治疗动物在自身免疫性脑脊髓炎中降低疾病发病率和严重性(Komiyama Y et al.J.Immunol.,2006,177:566-573)。已有IL-17A抗体的临床试验在IL-7A介导的炎性疾病(包括哮喘、牛皮癣、类风湿性关节炎、强直性脊柱炎和多发性硬化症)上显示出良好的结果。IL-17A抗体(Novartis的Cosentyx/secukinumab)在2015年1月已被FDA批准用于牛皮癣的治疗。
尽管存在多种IL-17A抗体,但很少有对具有口服生物利用度的IL-17的小分子特异性抑制剂进行研究。鉴于产生抗体的成本考虑和给药途径的限制,开发IL-17A小分子抑制剂药物具有良好的研发前景。
发明内容
本发明提供了一种式I所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,
每个RA分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
R1选自-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-C(O)R11、-C0~2亚烷基-C(O)NR11R12、-C0~2亚烷基-C(O)OR11、-C0~2亚烷基-S(O)R11、-C0~2亚烷基-S(O)NR11R12、-C0~2亚烷基-S(O)OR11、-C0~2亚烷基-S(O)2R11、-C0~2亚烷基-S(O)2NR11R12、-C0~2亚烷基-S(O)2OR11、-C0~2亚烷基-P(O)R11R12、-C0~2亚烷基-P(O)(OR11)R12、-C0~2亚烷基-P(O)(OR11)(OR12);其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1a取代;
R11、R12分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1a取代;
每个R1a分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR1b、-C0~2亚烷基-C(O)R1b、-C0~2亚烷基-C(O)NR1bR1c、-C0~2亚烷基-NR1bR1c、-C0~2亚烷基-NR1bC(O)R1c、-C0~4亚烷基-S(O)2R1bR1c、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1b取代;
R1b、R1c分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
R2选自氢、-C1~6烷基、-C0~2亚烷基-(3~10元环烷基);
R3选自-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环)、-C0~2亚烷基-(5~12元桥环)、-C0~2亚烷基-(5~12元桥杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个、三个或四个独立的R31取代;
每个R31分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环)、-C0~2亚烷基-(5~12元桥环)、-C0~2亚烷基-(5~12元桥杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个、三个或四个独立的R32取代;
或者,两个R31可以相连形成3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个、三个或四个独立的R32取代;
每个R32分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
R4选自氢、卤素、氰基、=O、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR7、-C0~2亚烷基-OC(O)R7、-C0~2亚烷基-OC(O)NR7R8、-C0~2亚烷基-OS(O)R7、-C0~2亚烷基-OS(O)NR7R8、-C0~2亚烷基-OS(O)2R7、-C0~2亚烷基-OS(O)2NR7R8、-C0~2亚烷基-OP(O)(OH)R7、-C0~2亚烷基-OP(O)(OH)NR7R8、-C0~2亚烷基-C(O)R7、-C0~2亚烷基-C(O)OR7、-C0~2亚烷基-C(O)NR7R8、-C0~2亚烷基-S(O)R7、-C0~2亚烷基-S(O)NR7R8、-C0~2亚烷基-S(O)2R7、-C0~2亚烷基-S(O)2NR7R8、-C0~2亚烷基-P(O)(OH)R7、-C0~2亚烷基-P(O)(OH)NR7R8、-C0~2亚烷基-NR7R8、-C0~2亚烷基-NR7C(O)R8、-C0~2亚烷基-NR7C(O)OR8、-C0~2亚烷基-NR9C(O)NR7R8、-C0~2亚烷基-NR7S(O)R8、-C0~2亚烷基-NR7S(O)OR8、-C0~2亚烷基-NR9S(O)NR7R8、-C0~2亚烷基-NR7S(O)2R8、-C0~2亚烷基-NR7S(O)2OR8、-C0~2亚烷基-NR9S(O)2NR7R8、-C0~2亚烷基-NR9P(O)(OH)R7、-C0~2亚烷基-NR9P(O)(OH)NR7R8、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)或其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R41取代;
每个R41分别独立选自氢、卤素、氰基、羰基、硝基、氧代、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR42、-C0~2亚烷基-OC(O)R42、-C0~2亚烷基-C(O)R42、-C0~2亚烷基-C(O)OR42、-C0~2亚烷基-C(O)NR42R43、-C0~2亚烷基-NR42R43、-C0~2亚烷基-NR42C(O)R43、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R44取代;
或者,两个R41可以相连形成3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个、三个或四个独立的R44取代;
R42、R43分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R47取代;
每个R44分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR45、-C0~2亚烷基-OC(O)R45、-C0~2亚烷基-C(O)R45、-C0~2亚烷基-C(O)OR45、-C0~2亚烷基-C(O)NR45R46、-C0~2亚烷基-NR45R46、-C0~2亚烷基-NR45C(O)R46、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
R45、R46分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R47取代;
每个R47分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
R5、R6分别独立选自氢、C1~6烷基、-C0~2亚烷基-O(C1~6烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(3~10元环烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(3~10元杂环烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(5~10元芳环)、-C0~2亚烷基-O(C0~2亚烷基)-(5~10元芳杂环)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环可进一步被一个、两个或三个独立的R51取代;
或者,R5、R6相连形成3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR52、-C0~2亚烷基-OC(O)R52、-C0~2亚烷基-C(O)R52、-C0~2亚烷基-C(O)OR52、-C0~2亚烷基-C(O)NR52R53、-C0~2亚烷基-NR52R53、-C0~2亚烷基-NR52C(O)R53、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R54取代;
R52、R53分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
每个R54分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
R7、R8、R9分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环)、-C0~2亚烷基-(5~12元桥环)、-C0~2亚烷基-(5~12元桥杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R71取代;
每个R71分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR72、-C0~2亚烷基-OC(O)R72、-C0~2亚烷基-C(O)R72、-C0~2亚烷基-C(O)OR72、-C0~2亚烷基-C(O)NR72R73、-C0~2亚烷基-NR72R73、-C0~2亚烷基-NR72C(O)R73、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R74取代;
R72、R73分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R74取代;
每个R74分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
进一步地,
每个RA分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)。
进一步地,
R3a、R3b分别独立选自3~10元环烷基、3~10元杂环烷基、5~10元芳环、5~10元芳杂环、5~12元螺环、5~12元螺杂环、5~12元桥环、5~12元桥杂环;其中环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个、三个或四个独立的R31取代;
C环选自5~6元芳环、5~6元芳杂环;其中芳环、芳杂环可进一步被一个、两个或三个独立的RC1取代;
每个RC1分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基);
D环选自3~6元环烷烃、3~6元杂环烷烃;其中环烷烃、杂环烷烃可进一步被一个、两个或三个独立的RD1取代;
每个RD1分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-O(卤素取代的C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
X选自O、S、NRx1或CRx2Rx3;
Rx1选自氢、-C1~6烷基、-C0~2亚烷基-(3~10元环烷基);
Rx2、Rx3分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
n选自0、1、2或3;
每个R31分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环)、-C0~2亚烷基-(5~12元桥环)、-C0~2亚烷基-(5~12元桥杂环)。
进一步地,
R4选自-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)、-C0~2亚烷基-(5~6元芳环)、-C0~2亚烷基-(5~6元芳杂环);其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R41取代;
每个R41分别独立选自氢、卤素、氰基、羰基、硝基、氧代、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR42、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)、-C0~2亚烷基-(5~6元芳环)、-C0~2亚烷基-(5~6元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R44取代;
R42选自氢、C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)、-C0~2亚烷基-(5~6元芳环)、-C0~2亚烷基-(5~6元芳杂环);
每个R44分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-C(O)NR45R46;
R45、R46分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)、-C0~2亚烷基-(5~6元芳环)、-C0~2亚烷基-(5~6元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R47取代;
每个R47分别独立选自氢、氢、C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基)、-C0~2亚烷基-(5~6元芳环)、-C0~2亚烷基-(5~6元芳杂环)。
进一步地,
R5、R6分别独立选自氢、C1~6烷基、3~6元环烷基、3~6元杂环烷基;其中烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-C(O)R52、-C0~2亚烷基-C(O)OR52、-C0~2亚烷基-C(O)NR52R53;
R52、R53分别独立选自氢、C1~6烷基。
进一步地,
R5、R6相连形成3~6元环烷基、3~6元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-C(O)R52、-C0~2亚烷基-C(O)OR52、-C0~2亚烷基-C(O)NR52R53;
R52、R53分别独立选自氢、C1~6烷基。
进一步地,
R7、R8分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R71取代;
每个R71分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR72、-C0~2亚烷基-OC(O)R72、-C0~2亚烷基-C(O)R72、-C0~2亚烷基-C(O)OR72、-C0~2亚烷基-C(O)NR72R73、-C0~2亚烷基-NR72R73、-C0~2亚烷基-NR72C(O)R73;
R72、R73分别独立选自氢、C1~6烷基。
进一步地,在本发明的一些具体实施方案中,式I所述的化合物具体为:
本发明还提供了前述化合物、或其立体异构体、或其药学上可接受的盐在制备治疗IL-17A介导的疾病的药物中的用途。
进一步地,所述IL-17A介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
本发明还提供了一种药物组合物,它是以前述化合物、或其立体异构体、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗IL-17A介导的疾病的药物中的用途。
本发明所定义的IL-17A介导的疾病是IL-17A在该疾病的病理发生中起重要作用的疾病。IL-17A的主要功能是协调局部组织炎症,从而在各种疾病中起作用。IL-17A介导的疾病包括炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。。
“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种,受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期,中期或晚期阶段的细胞。癌症包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌和前列腺癌。在一些实施方案中,式I的化合物用于治疗选自结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌的癌症。在一些实施方案中,癌症选自黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌。在一些实施方案中,所治疗的癌症是转移性癌症。
自身免疫性疾病是由身体对体内正常存在的物质和组织的免疫反应引起的。自身免疫疾病的例子包括心肌炎、狼疮性肾炎、原发性胆汁性肝硬化、牛皮癣、1型糖尿病、格雷夫氏病、腹腔疾病、克罗恩病、自身免疫性中性白细胞减少症、幼年型关节炎、类风湿性关节炎、纤维肌痛、吉兰巴利综合征、多发性硬化症和自身免疫性视网膜病变。本发明的一些实施方案涉及治疗自身免疫疾病如牛皮癣或多发性硬化症。
炎症疾病包括以组织病理性炎症为特征的多种病症。炎性疾病的例子包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。本发明的一些实施方案涉及炎性疾病哮喘的治疗。免疫系统通常涉及炎症性疾病,在过敏反应和一些肌病中都有表现,许多免疫系统疾病导致异常炎症。IL-17A介导的疾病也包括自身免疫性炎症性疾病。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~4烷基”是指包含1~4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1~6烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1~C6烷氧基。
“环烷基”、“环烷烃”是指具有碳原子且没有环杂原子且具有单个环或多个环(包括稠合、并和)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时,适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团,诸如环己烯基。环烷基基团的实例包括例如,金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。例如
“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基基团。例如,(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如,(C2-C6)炔基意在包括乙炔基、丙炔基等。
“卤素”为氟、氯、溴或碘。
“卤素烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1~4卤素烷基指氢原子被一个或多个卤素原子取代的包含1~4个碳原子的烷基。
“杂环”、“杂环烷基”、“杂环烷烃”指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“芳杂环”指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“立体异构体”包括对映异构体和非对映异构体;
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明,反应在氮气氛围下进行。实施例中无特殊说明,溶液是指水溶液。实施例中无特殊说明,反应的温度为室温。实施例中无特殊说明,M是摩尔每升。
溶剂、试剂缩写说明:
THF:四氢呋喃;MeOH:甲醇;NMP:N-甲基吡咯烷酮;
DCM:二氯甲烷;EtOAc:乙酸乙酯;DMF:二甲基甲酰胺;
PE:石油醚;ACN或MeCN:乙腈;DEM:二乙氧基甲烷;
CDI:N,N'-羰基二咪唑;n-BuLi:正丁基锂;
DIPEA:N,N-二异丙基乙胺;TEA:三乙胺;
Cbz:苄氧羰基;Boc:叔丁氧羰基;EA:醋酸乙酯;
NBS:N-溴代丁二酰亚胺;DMP:戴斯-马丁氧化剂;
HCl:盐酸;H2SO4:硫酸;DMAP:4-二甲氨基吡啶;
TFA:三氟乙酸;Pd/C:钯碳催化剂;
HBTU:苯并三唑-1-四甲基六氟磷酸酯;
HATU:2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯;
EDCI:1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐;
HOAT:N-羧基-7-氮杂苯并三氮唑;
HOBT:1-羟基苯并三唑;DMAP:4-二甲氨基吡啶;
LiHMDS:双三甲基硅基胺基锂。
中间体Z-1的制备
步骤1,Z-1-a的制备
(2S)-2-((((苄氧基)羰基)氨基)-3-环丁基-3-(1-甲基环丙基)丙酸(1.2g,3.62mmol)的THF(30mL)溶液中加入CDI(653mg,3.62mmol),反应混合液室温氮气保护下搅拌1小时,然后冷却至-78℃备用。
另取一圆底烧瓶氮气保护下加入THF(10mL)和DIPEA(2.5mL,15mmol),冷却溶液至0℃,加入n-BuLi(2.5M己烷溶液,6.2mL,15.5mmol),10min后,反应液冷却至-78℃,逐滴加入叔丁基乙酸酯(1.81g,15mmol),滴毕继续保温反应1小时。所得烯醇溶液经双头针缓慢滴加入上述-78℃的大反应瓶中,滴完继续-78℃搅拌1小时。反应完成后,-78℃加冷的饱和氯化铵水溶液淬灭反应,加水稀释,用乙酸乙酯萃取,合并的有机相依次用1N HCl水溶液,水和饱和氯化铵洗涤,用无水硫酸钠干燥,过滤后浓缩,粗品经硅胶柱分离纯化得Z-1-a(1.4g,3.26mmol,收率90%)。MS(ESI)m/z=430[M+1]+。
步骤2,Z-1的制备
向Z-1-a(1.4g,3.26mmol)的MeOH(12mL)溶液中加入2,6-二甲基吡啶(25mg,0.2mmol),和NBS(568mg,3.19mmol)。反应混合液室温搅拌两小时。反应完成后,加入乙酸乙酯稀释,依次用50%的饱和食盐水(饱和食盐水和水1比1混合)和100%的饱和食盐水洗涤,然后无水硫酸钠干燥,旋干后得中间体的粗品。将粗品溶解在甲苯/TFA(25mL/2.5mL)的混合溶液中,加热至80℃并在此温度下搅拌反应2小时。反应完成后,旋干反应液,粗品用硅胶柱分离纯化得中间体Z-1(705mg,1.73mmol,53%收率)。MS(ESI)m/z=408[M+1]+。
中间体Z-2到Z-4的制备
参照中间体Z-1步骤1到步骤2的制备方法,用表中相应起始Cbz保护的氨基酸代替步骤1中的(2S)-2-((((苄氧基)羰基)氨基)-3-环丁基-3-(1-甲基环丙基)丙酸,其余操作相同,可得到表中相应结构的中间体Z-2到Z-4。
中间体Z-5的制备
步骤1,Z-5-a的制备
-78℃下,向(R)-4-苯基-2-唑烷酮(285mg,1.74mmol)的无水THF(15mL)溶液中逐滴加入n-BuLi(2.5M的己烷溶液,0.69mL,1.74mmol),此温度下继续搅拌1小时,然后加入(1E)-3,3,3-三氟-1-硝基丙-1-烯(300mg,1.93mmol)的THF(5mL)溶液,反应液在-78℃下继续搅拌45min。反应完成后,加饱和氯化铵水溶液淬灭反应,缓慢升至室温,混合液用乙酸乙酯萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩旋干后,粗品用硅胶柱分离纯化(PE/EtOAc=7/3,v/v)得到Z-5-a(471mg,1.55mmol,80%收率)。
步骤2,Z-5-b的制备
向Z-5-a(471mg,1.55mmol)的甲醇溶液中加入Pd(OH)2(49mg),氢气置换后氢气保护下室温搅拌过夜。反应完成后,滤除Pd(OH)2,滤液减压旋干后,干燥得Z-5-b(385mg,1.41mmol)。MS(ESI)m/z=275[M+1]+。
步骤3,Z-5-c的制备
Z-5-b(385mg,1.41mmol)溶解在乙二胺(5mL)(新蒸馏纯化的)中,混合液升温至120℃,并在此温度下搅拌过夜。反应完成后,旋除乙二胺,残余物溶解在1N HCl中,用石油醚和乙酸乙酯(8/1,v/v)混合液洗涤。分离得到的水相,用6M的NaOH调节pH至14,然后加乙酸乙酯萃取,有机相用饱和食盐水洗涤,无水硫酸镁干燥,旋干后得Z-5-c(279mg,1.12mmol)。MS(ESI)m/z=249[M+1]+。
步骤4,Z-5的制备
向Z-5-c(279mg,1.12mmol)的THF/甲醇1:1(10mL)中加入Pd(OH)2(35mg),氢气置换后,在氢气压(60bar)下室温搅拌48小时。反应完成后,滤除靶催化剂,滤液旋干后用硅胶柱分离纯化(CHCl3/MeOH/NH4OH 12:4:1)得Z-5(115mg,0.9mmol,80%收率)。MS(ESI)m/z=129[M+1]+。
中间体Z-6的制备
步骤1,Z-6-a的制备
向3-氨基-5-甲基-6-氯哒嗪(100g,696.5mmol)的NMP(800mL)溶液中加入吡啶(112mL,1.39mol),混合液冷却到15℃左右,新戊酰氯(111mL,905mmol)缓慢滴加入反应混合液,滴加过程监控反应液温度。滴毕维持15度左右继续搅拌1小时,后缓慢升至35℃后搅拌15min,后冷却至15℃,逐滴加入水(1.2L),混合液冷却至5℃,继续搅拌1小时。过滤此浑浊反应液,收集滤饼,滤饼经冷水洗涤并真空干燥后得Z-6-a(139.5g,612.92mmol,88%收率)。MS(ESI)m/z=228[M+1]+。
步骤2,Z-6-b的制备
向反应烧瓶中加入Z-6-a(70g,307mmol)、N,N-二甲基甲酰胺二乙基缩醛(205mL,1.2mol)和DMF(26mL)。氮气保护下,混合液逐渐升温至120℃,并在此温度下搅拌6小时。然后将反应液自然冷却至室温,并在室温下搅拌1.5小时,逐渐由黄色晶状物在溶液中形成。经过滤收集,乙二醚洗涤,真空干燥后得Z-6-b(47.81g,169mmol,收率55%)。MS(ESI)m/z=283[M+1]+。
步骤3,Z-6-c的制备
向Z-6-b(30g,106mmol)的THF/H2O(180mL/180mL)的混合液中加入NaIO4(79.4g,371mmol),反应液室温下剧烈搅拌1小时,然后过滤,滤饼用乙酸乙酯洗涤几遍,收集滤液。滤液用乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,旋干后,粗品用硅胶柱分离纯化得Z-6-c(18.46g,76.39mmol)。MS(ESI)m/z=242[M+1]+。
步骤4,Z-6-d的制备
零度下,Z-6-c(5g,20.69mmol)和氯甲基甲醚(1.56mL,20.69mmol)的THF(50mL)溶液缓慢的滴加入4,4'-二叔丁基苯并(275mg,1.03mmol)和Li(1.0g,145mmol)的THF(100mL)溶液中,滴毕,反应混合液室温搅拌1.5小时。然后小心的用水淬灭反应,继续室温搅拌直至Li金属固体消失不见。反应混合液用乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,旋干得粗品,用硅胶柱分离纯化得Z-6-d(3.27g,11.38mmol)。MS(ESI)m/z=288[M+1]+。
步骤5,Z-6-e的制备
向Z-6-d(3.27g,11.38mmol)的DCM(120mL)溶液中加入戴斯-马丁氧化剂(6.27g,14.77mmol),氮气保护下,反应混合液室温搅拌3小时。反应完成后,加入硫代硫酸钠和饱和NaHCO3水溶液搅拌1小时,淬灭反应。混合液分层后,分离有机相,依次用硫代硫酸钠水溶液、饱和NaHCO3和饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干后,粗品Z-6-e未经纯化直接用于下一步反应。MS(ESI)m/z=286[M+1]+。
步骤6,Z-6-f的制备
上述Z-6-e粗品溶解于异丙醇(40mL)中,加入中间体Z-5(1.89g,14.79mmol),混合液升温至70℃搅拌2小时,然后室温搅拌过夜。反应液旋干,粗品溶解在甲醇(50mL)内,分批次加入NaBH3CN(3.93g,62.56mmol),所得悬浊液继续室温搅拌5分钟,然后加入乙酸(1.15g,19.22mmol),反应混合液升温至40℃,并搅拌30min。反应液旋干,残余物用DCM稀释并加饱和NaHCO3水溶液搅拌中和,混合液用DCM萃取,合并的有机相依次用饱和NaHCO3水溶液和饱和食盐水洗涤,无水硫酸钠干燥,旋干后得Z-6-f粗品,未经纯化直接用于下一步反应。MS(ESI)m/z=398[M+1]+。
步骤7,Z-6-g的制备
粗品Z-6-f溶解于MeOH(50mL)中然后加热至60℃,分批次加入CDI(4.93g,27.33mmol),反应混合液在60℃搅拌1小时后,冷却至室温,加入5N NaOH水溶液(6mL,30mmol)。混合液用乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干后,粗品用硅胶柱分离纯化,收集极性较大的第二个异构体得Z-6-g(1.50g,3.53mmol)。MS(ESI)m/z=424[M+1]+。
步骤8,Z-6的制备
Z-6-g(1.50g,3.53mmol)溶于MeOH(5mL),缓慢加入5N HCl水溶液(14mL,70mmol)。反应混合液升温至110℃并搅拌30min。冷却后,反应液浓缩,并加甲醇共蒸发一次,残余物用乙酸乙酯稀释,加5NaOH水溶液调至碱性,再用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,过滤旋干后得Z-6粗品(1.3g,90%纯度)。MS(ESI)m/z=340[M+1]+。
中间体Z-7的制备
步骤1,Z-7-a的制备
向MeOH(120mL),原甲酸三甲酯(7.5mL)和H2SO4(6.39mL)的混合液中加入1-(4-硝基苯基)乙酮(5.0g,30.28mmol),然后加入1H-1-羟基-5-甲基-1,2,3-苯并恶唑硫醇3,3-二氧化物(9.56g,30.43mmol),反应混合液室温下搅拌3小时,反应完成后,旋除一半溶剂,加入水,加乙酸乙酯萃取,合并的有机相经干燥后旋干,粗品用硅胶柱分离纯化,得Z-7-a(2.54g,13.02mmol,收率:43%)。
步骤2,Z-7-b的制备
向Z-7-a(2.54g,13.02mmol)的乙醇(30mL)溶液中加入Pd/C(300mg),氢气置换几次后,在氢气氛围下搅拌2小时,反应完成后,滤除Pd/C,滤液浓缩干燥后得中间体粗品,MS(ESI)m/z=166[M+1]+,直接用于下一步反应。粗品溶解在DCM(25mL)中,依次加入TEA(1.99mL,14.32mmol)和Ac2O(1.59mL,16.92mmol)。反应混合液室温搅拌3小时,反应完成后,旋干溶剂,粗品用硅胶柱分离纯化,得Z-7-b(1.89g,9.11mmol,两步收率:70%),MS(ESI)m/z=208[M+1]+。
步骤3,Z-7-c的制备
-20℃下,向硝酸(2mL)的溶液中加入Z-7-b(600mg,2.9mmol),保持低温搅拌15min,然后将反应液倒入冰水混合物中,加入DCM搅拌直至并完全溶化。混合物用DCM萃取,合并的有机相用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后得粗品,经柱色谱分离纯化得Z-7-c(555mg,2.2mmol,收率:76%)。MS(ESI)m/z=253[M+1]+。
步骤4,Z-7-d的制备
Z-7-c(810mg,3.21mmol)溶解于异丙醇(10mL)中,加入中间体Z-5(593mg,4.17mmol),混合液升温至75℃搅拌2小时,然后室温搅拌过夜。旋干反应液,得到的粗品溶解在甲醇(15mL)内,加入NaBH3CN(1.11g,17.66mmol),所得悬浊液继续室温搅拌10分钟,然后加入乙酸(328mg,5.46mmol),混合液升温至40℃,并继续搅拌30min。反应完成后,旋干溶剂,残余物用DCM稀释并加饱和NaHCO3水溶液搅拌中和,混合液用DCM萃取,合并的有机相依次用饱和NaHCO3水溶液、饱和食盐水洗涤,无水硫酸钠干燥,旋干后得Z-7-d粗品,未经纯化直接用于下一步反应。MS(ESI)m/z=379[M+1]+。
步骤5,Z-7-e的制备
粗品Z-7-d溶解于MeOH(15mL)中,然后升温至60℃,分批次加入CDI(1.45g,8.03mmol),反应混合液在60℃搅拌1小时后,冷却至室温,加入5N NaOH水溶液(2.0mL,10mmol)。混合液用乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并旋干后,粗品用硅胶柱色谱分离纯化,收集第二个异构体得Z-7-e(476mg,1.22mmol)两步收率38%。MS(ESI)m/z=391[M+1]+。
步骤6,Z-7-f的制备
向Z-7-e(476mg,1.22mmol)的甲醇(8mL)溶液中加入K2CO3(337mg,2.44mmol),混合液室温下搅拌3小时,旋除甲醇后,反应体系加水稀释,DCM萃取,合并的有机相依次用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后得Z-7-f(395mg,1.13mmol),未经纯化直接用于下一步反应。MS(ESI)m/z=349[M+1]+。
步骤7,Z-7的制备
向Z-7-f(395mg,1.13mmol)的乙醇(10mL)溶液中加入Pd/C(300mg),氢气置换几次后,在氢气氛围下搅拌3小时,反应完成后,滤除Pd/C,滤液浓缩干燥后得中间体Z-7(292mg,0.92mmol,收率82%)。MS(ESI)m/z=319[M+1]+。
嘧啶并吡唑实施例通用制备路线A
步骤1,相应的手性氨基酸(氨基用Boc或者Cbz等常用基团保护的)和N,O-二甲基羟胺为起始原料做成weinrab酰胺,用合适的有机碱,例如DIPEA或者TEA为碱,DMF或者THF或DCM等为溶剂。HOBT为缩合剂经常规方法得A-1;步骤2,将A-1中weinrab酰胺转换为多一个碳的氰基,用乙腈为氰基来源,用n-BuLi或HMDSLi或甲基锂-溴化锂络合物为碱,THF为溶剂,零下78度制得A-2;步骤3,A-2和水合肼在乙醇中回流,可得关环产物A-3;步骤4,用A-3和2-溴丙二醛为原料,在酸性条件下(盐酸或者对甲苯磺酸或者醋酸为酸),醇类溶剂(乙醇或者正丁醇),相应条件下关环,制备得含嘧啶并吡唑杂环的A-4;步骤5,以叔丁基异氰和A-4为原料,经偶联的方法(醋酸钯加CyJohnPhos催化体系,碳酸钠做碱,三乙基硅试剂,DMF做溶剂)制的相应的醛A-5;步骤6,A-5与(R)-3,3,3-三氟丙烷-1,2-二胺为原料经还原胺化(NaBH3CN或者三乙酰氧基硼氢化钠为还原剂,乙酸/异丙醇体系或者乙酸/DEM体系为溶剂)的方法,得A-6;步骤7,A-6与CDI在甲醇中加热至60度反应关环后,用NaOH水溶液处理并纯化后得A-7;步骤8,常规脱除氨基保护基的方法,例如TFA或者HCl/二氧己环脱除Boc,或者Pd/C或者PdCl2氢化脱除Cbz得A-8;步骤9,常规缩合方法,HBTU/DIPEA/DCM体系,或HATU/DIPEA/DCM或HOAt/EDCI/DIPEA/DCM或EDCI/DMAP/DCM,将A-8和相应杂环羧酸缩合可得相应目标化合物TM。
实施例1
步骤1,1-1的制备
向Z-6(0.2g,90%purity,0.53mmol)的THF(5mL)溶液中加入Z-1(238mg,0.58mmol)和Na2CO3(150mg,1.14mmol).。反应液升至70℃并在氮气保护下搅拌过夜。反应完成后,滤除固体,加DCM洗涤几次,收集滤液旋干后得粗品,用硅胶柱分离纯化得1-1(240mg,0.37mmol,收率70%)。MS(ESI)m/z=649[M+1]+。
步骤2,1-2的制备
向1-1(240mg,0.37mmol)的MeOH(8mL)溶液中加入Pd/C(30mg),氢气置换几次后,在氢气保护下室温搅拌过夜。反应完成后,滤除Pd/C,滤液浓缩后,经硅胶柱分离纯化得1-2(105mg,0.22mmol,收率59%)。MS(ESI)m/z=481[M+1]+。
步骤3,1的制备
向1-2(100mg,0.2mmol)的THF(5mL)溶液中加入HBTU(95mg,0.25mmol),DIPEA(55mg,0.42mmol)和1-甲基-1H-吡唑-5-羧酸(32mg,0.25mmol)。反应混合液室温搅拌2小时。反应完成后,旋除溶剂,粗品用Pre.HPLC分离纯化得化合物1(93mg,0.15mmol,收率72%)。MS(ESI)m/z=589[M+1]+。
实施例2到实施例4
参照实施例步骤1到步骤3的制备方法,在步骤1中,用表中相应起始原料替代Z-1,在步骤3中,用表中4-甲基呋咱-3-羧酸替代1-甲基-1H-吡唑-5-羧酸,其余操作相同,可得表中相应实施例化合物2到4。
实施例5
参照实施例1步骤3的制备方法,用4-甲基呋咱-3-羧酸替代步骤中的1-甲基-1H-吡唑-5-羧酸,其余操作方法相同。可得实施例5。MS(ESI)m/z=591[M+1]+。
实施例6
步骤1,6-1的制备
在Boc-D-环己基甘氨酸(1g,3.9mmol)在DCM(20mL)中的冰冷却溶液中,加入N,O-二甲基羟胺HCl盐(0.46g,4.6mmol),HOBT(0.7g,5.1mmol),和TEA(1.1mL),然后加入EDCI(1g,5.1mmol)。使反应混合物升温至室温,然后搅拌过夜。加入EtOAc(300mL)萃取。所得有机相用柠檬酸水溶液,NaHCO3水溶液和NaCl水溶液洗涤。分离有机层,用MgSO4干燥,然后蒸发,得到为无色油的6-1(1.05g,3.51mmol),无需进一步纯化直接用于下一步反应。MS(ESI)m/z=301[M+1]+。
步骤2,6-2的制备
在氮气保护下,于-78℃向MeCN(1.84g,44.95mmol)的无水THF(20mL)溶液中缓慢滴加LiHMDS(1M的THF溶液,12mL,12.0mmol),滴加完毕后,混合物在-70℃下搅拌3h,然后在-70℃,将6-1(900mg,3.0mmol)加入反应体系。将反应液缓慢升至室温并搅拌30分钟。反应完成后,加饱和NH4Cl溶液淬灭,然后用EA萃取3次。有机层用饱和盐水洗涤并用无水Na2SO4干燥。浓缩后获得的粗产物经柱色谱法分离和纯化获得6-2(546mg,1.95mmol,产率:65%)。MS(ESI)m/z=281[M+1]+。
步骤3,6-3的制备
将中间体6-2(640mg,2.28mmol)和水合肼(172mg,3.42mmol)混合在在乙醇(15ml)中,混合物加热至回流过夜。冷却后,旋干反应液,粗品经柱色谱法分离和纯化得6-3(538mg,1.38mmol,收率:80%)。MS(ESI)m/z=295[M+1]+。
步骤4,6-4的制备
向6-3(200mg,0.68mmol)和2-溴丙二醛(113mg,0.75mmol)的乙醇(10mL)混合物中加入乙酸(3mL)。将混合物在70℃下搅拌1小时。反应完成后,将反应浓缩至干。将残余物溶于乙酸乙酯,并加入饱和碳酸氢钠溶液。萃取有机相,并用硫酸钠干燥,然后浓缩至干。然后将残余物通过柱色谱法纯化得到6-4(181mg,0.44mmol,收率:65%),MS(ESI)m/z=409[M+1]+。
步骤5,6-5的制备
将6-4(450mg,1.1mmol),异氰酸叔丁酯(110mg,1.32mmol),三乙基硅烷(383mg,3.3mmol),CyJohnPhos(2-(二环己基膦基)联苯)(19mg,0.055mmol)和碳酸钠(117mg,1.1mmol)悬浮在DMF(8mL)中,并将混合物用氮气脱气5分钟。加入Pd(AcO)2(9mg,0.038mmol),并将混合物在65℃在氮气保护下加热过夜。反应完毕,将混合物冷却至室温,用水(200mL)和乙酸乙酯(40mL)稀释,过滤,用乙酸乙酯(2×50mL)萃取,然后用水(5×25mL)洗涤,用硫酸钠干燥。过滤并浓缩。粗品经柱色谱法分离和纯化得6-5(114mg,0.32mmol,收率:29%)。MS(ESI)m/z=359[M+1]+。
步骤6,6-6的制备
6-5(170mg,0.47mmol)溶解于异丙醇(5mL)中,加入(R)-3,3,3-三氟丙烷-1,2-二胺(79mg,0.62mmol),混合液升温至70℃搅拌2小时,然后室温搅拌过夜。旋干反应液,得到的粗品溶解在甲醇(5mL)内,加入NaBH3CN(164mg,2.61mmol),所得悬浊液继续室温搅拌5分钟,然后加入乙酸(48mg,0.8mmol),反应混合液升温至40℃,并搅拌30min。反应液旋干,残余物用DCM稀释并加饱和NaHCO3水溶液搅拌中和,混合液用DCM萃取,合并的有机相依次用饱和NaHCO3水溶液、饱和食盐水洗涤,无水硫酸钠干燥,旋干后得6-6粗品,未经纯化直接用于下一步反应。MS(ESI)m/z=471[M+1]+。
步骤7,6-7的制备
粗品6-6溶解于MeOH(5mL)中然后加热至60℃,分批次加入CDI(167mg,1.18mmol),反应混合液在60℃搅拌1小时后,冷却至室温,加入5N NaOH水溶液(0.3mL,1.5mmol)。混合液用乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤旋干后,粗品用硅胶柱分离纯化得6-7(115mg,0.23mmol)两步收率49%。MS(ESI)m/z=497[M+1]+。
步骤8,6-8的制备
向6-7(115mg,0.23mmol)的乙酸乙酯(5mL)溶液中加入HCl/二氧己环(2.5M,0.4mL,1mmol),反应混合液室温搅拌2小时,反应完成后,旋干反应液,干燥后得6-8(120mg,75%纯度,粗品),未经纯化直接用于下一步反应。MS(ESI)m/z=397[M+1]+。
步骤9,实施例6的制备
向1-甲基-1H-吡唑-5-羧酸(17mg,0.132mmol)的DCM(5mL)溶液中加入HBTU(51mg,0.132mmol)、DIPEA(44mg,0.34mmol)和中间体1-8(60mg,0.113mmol,75%纯度)。反应混合液室温搅拌2小时。反应完成后,旋干反应液,粗品经Pre.HPLC分离纯化得化合物6(32mg,0.063mmol)。MS(ESI)m/z=505[M+1]+。
实施例7到实施例11
参考通用制备路线A和实施例6中步骤1到步骤9的制备方法,将步骤1中的Boc-D-环己基甘氨酸换成下列表中相应的带不同保护基的氨基酸,将步骤8中氨基脱保护的方法,根据起始原料中实际使用的保护基进行相应改变,例如,Cbz保护的氨基酸,步骤8中改用Pd/C氢化的方法脱除。其余方法一致,可得表中相应实施例。
实施例12
参照实施例6中步骤9的合成方法,将其中的1-甲基-1H-吡唑-5-羧酸换成4-甲基呋咱-3-羧酸,其余方法不变,可得化合物12,MS(ESI)m/z=507[M+1]+。
实施例13
参照实施例6中步骤9的合成方法,将其中的1-甲基-1H-吡唑-5-羧酸换成4-甲基异恶唑-3-羧酸,其余方法不变,可得化合物13,MS(ESI)m/z=506[M+1]+。
实施例14
步骤1,14-1的制备
向100mL单口瓶中加入中间体Z-7(80mg,0.25mmol)和(S)-2-((((苄氧基)羰基)氨基)-3,3-二环丙基丙酸(84mg,0.27mmol),加入DCM(5mL),得淡棕色澄清溶液。搅拌下依次加入DIPEA(65mg,0.5mmol),HOAt(45mg,0.3mmol)和EDCI(63mg,0.32mmol),室温下搅拌3小时,LCMS显示酰化完成。反应液用水(20mL)洗,干燥后旋干,残余物柱层析纯化(PE:EA=2:1),得120mg黄色固体,将此中间体溶于HOAc(5mL)中,60℃下搅拌过夜。LCMS显示关环反应完成,旋去HOAc,残余物加饱和NaHCO3(aq)和EA(20mL)溶解,分出EA层后,水层继续用EA(20mL)萃取2次,合并EA层干燥后旋干,得14-1(107mg,1.08mmol,产率:73%),直接用于下一步反应。MS m/z:586[M+1]+。
步骤2,14-2的制备
向100mL单口瓶中加入中间体14-2(107mg,1.08mmol),加入DCM(5mL)溶解。冰浴下依次加入PdCl2(17mg,0.057mmol)和TEA(14mg,0.133mmol),搅拌下滴入Et3SiH(0.15mL,0.95mmol),滴完后缓慢升至室温下反应过夜。LCMS显示反应完成,过滤除去不溶物,滤液旋干,得14-2(83mg,产率:100%),直接用于下一步反应。MS m/z:452[M+1]+.
步骤3,化合物14的制备
向中间体14-2(83mg,0.18mmol)的DCM(10mL)澄清溶液中,搅拌下依次加入4-甲基-1,2,3-恶二唑-3-羧酸(26mg,0.2mmol),DIPEA(48mg,0.37mmol)和HBTU(84mg,0.22mmol),氮气保护,于室温下反应过夜。LCMS显示反应完成,向反应液中加水(20mL)洗,分出DCM层,干燥后旋干,残余物用Pre.HPLC分离纯化,得化合物14(57mg,0.1mmol,收率55%)。MS m/z:562[M+1]+。
实施例15
室温下,向中间体15-2(55mg,262.85umol,可参考中间体Z-1制备方法由相应的氨基酸得到)的2毫升四氢呋喃溶液中加入原料15-1(125.84mg,341.71umol)和硼酸三甲酯(136.68mg,1.31mmol),随后升温至80℃于封管中反应8小时,冷却,减压浓缩除去溶剂,经MPLC分离纯化即可得到中间体15-3(75mg,156.71umol,59.62%yield)。
参考实施例14步骤2中间体14-2和化合物14的制备方法,中间体15-3脱苄氧羰基(Cbz)保护即可得到中间体15-4,再与1-甲基-1H-吡唑-5-羧酸即可得到中间体15-5,15-5经碱水解得羧酸15-6,最后15-6与(S)-2-氨基丁烷缩合即可得到化合物15,MS(ESI)m/z=480[M+1]+,1H NMR(400MHz,DMSO-d6)δ8.45(d,J=2.2Hz,1H),8.25(s,1H),7.93(d,J=2.2Hz,1H),7.49(d,J=2.1Hz,1H),6.97(d,J=2.1Hz,1H),5.05(d,J=8.9Hz,1H),4.00(s,3H),3.79–3.66(m,1H),2.00(d,J=10.2Hz,1H),1.86(d,J=12.5Hz,1H),1.72(d,J=12.3Hz,1H),1.68–1.57(m,2H),1.54(s,6H),1.46(d,J=12.3Hz,1H),1.42–1.27(m,2H),1.28–1.02(m,5H),0.99(d,J=6.7Hz,3H),0.75(t,J=7.4Hz,3H).
实施例16
类似地,中间体15-6与(R)-2-氨基-1-丁醇缩合即可得到化合物16,MS(ESI)m/z=496[M+1]+,1H NMR(400MHz,DMSO-d6)δ8.51(d,J=2.2Hz,1H),8.28(s,1H),7.96(d,J=2.2Hz,1H),7.49(d,J=2.1Hz,1H),6.97(d,J=2.1Hz,1H),5.05(d,J=8.8Hz,1H),4.00(s,3H),3.76–3.64(m,1H),3.35–3.22(m,2H),2.71(m,0.5H),2.40–2.34(m,0.5H),2.07–1.91(m,1H),1.86(d,J=12.5Hz,1H),1.72(d,J=11.6Hz,1H),1.61(d,J=12.4Hz,2H),1.55(d,J=3.0Hz,6H),1.51–1.41(m,2H),1.34–0.91(m,6H),0.76(t,J=7.4Hz,3H).
实施例17
中间体17-1与4-甲基呋咱-3-羧酸缩合即可得到化合物17,MS(ESI)m/z=603[M+1]+,1H NMR(400MHz,Methanol-d4)δ8.58–8.50(m,1H),8.33–8.26(m,1H),8.07–7.95(m,1H),5.63(dd,J=6.2,1.7Hz,1H),4.71(q,J=7.6Hz,1H),4.60–4.26(m,1H),3.94–3.75(m,1H),3.71–3.40(m,2H),3.01–2.79(m,1H),2.58(dt,J=13.4,7.2Hz,1H),2.53(s,3H),2.09(dd,J=31.4,3.7Hz,3H),1.31–1.20(m,3H),1.05–0.94(m,1H),0.79(qt,J=8.6,5.0Hz,2H),0.51(q,J=7.5Hz,2H),0.37(dq,J=8.6,4.8Hz,2H),0.30(dq,J=9.7,5.0Hz,2H),0.23–0.13(m,1H),0.08(dt,J=10.0,5.3Hz,1H).
实施例18
中间体17-1与4-乙基呋咱-3-羧酸缩合即可得到化合物18,MS(ESI)m/z=617[M+1]+,1H NMR(400MHz,Methanol-d4)δ8.51–8.46(m,1H),8.26(d,J=4.5Hz,1H),7.99(t,J=2.3Hz,1H),5.63(dd,J=6.1,1.6Hz,1H),4.71(d,J=8.2Hz,1H),4.58–4.25(m,1H),3.95–3.74(m,1H),3.69–3.42(m,2H),2.98(qd,J=7.6,1.9Hz,2H),2.88(dt,J=42.5,6.9Hz,1H),2.53(ddt,J=20.4,14.3,8.2Hz,1H),2.09(dd,J=31.0,3.7Hz,3H),1.31(t,J=7.5Hz,3H),1.28–1.20(m,3H),1.03–0.94(m,1H),0.84–0.71(m,2H),0.50(dt,J=9.6,4.6Hz,2H),0.36(q,J=6.7Hz,2H),0.33–0.23(m,2H),0.16(d,J=2.3Hz,1H),0.12–0.02(m,1H).
实施例19
中间体19-1与4-乙基呋咱-3-羧酸缩合即可得到化合物19,MS(ESI)m/z=617[M+1]+,1H NMR(400MHz,MeOD)δ8.82(d,J=21.7Hz,1H),8.53–8.29(m,1H),7.46(d,J=2.1Hz,1H),6.85(s,1H),6.66(s,1H),5.40–5.21(m,1H),5.16(t,J=9.5Hz,1H),4.55(d,J=10.3Hz,1H),4.29(s,1H),3.84(t,J=9.9Hz,1H),3.74–3.56(m,1H),3.49(dd,J=21.0,11.1Hz,1H),1.99(dd,J=25.7,8.7Hz,3H),1.87–1.68(m,3H),1.64(d,J=7.1Hz,3H),1.52(s,1H),1.24–1.01(m,4H).
实施例20
将中间体20-1(310mg,711.80umol)溶于5毫升甲苯中,室温下加入TEA(93.63mg,925.34umol,129.06uL),叠氮磷酸二苯酯(207mg,854umol),混合物氮气保护下于80℃下搅拌反应2小时,冷却至室温后,用1N稀盐酸淬灭反应,并加热至60℃搅拌反应10小时,反应液减压浓缩至干,经反相MPLC纯化(乙腈/水,0.05%碳酸氢铵)即可得到中间体20-2,(183mg,450.16umol,63.24%产率),MS(ESI)m/z=407(M+1)+。
将中间体20-2(186mg,457.54umol)溶于1毫升甲醇中,室温下加入2-([(苄氧基)羰基]氨基)-3,3,3-三氟-丙酸(478.03mg,1.83mmol),混合物室温搅拌20分钟后,加入氰基硼氢化钠(172.95mg,2.75mmol),随后反应混合物于微波70℃反应1.5小时,反应液减压浓缩至干,经反相MPLC纯化(乙腈/水,0.05%碳酸氢铵)即可得到中间体20-3,(105mg,161.11umol,35.21%产率),MS(ESI)m/z=652(M+1)+。
将中间体20-3(105mg,161.11umol)溶于2.5毫升二氯甲烷中,冰浴搅拌下加入33%氢溴酸0.3毫升,恢复室温搅拌反应3小时,反应液减压浓缩至干,经反相MPLC纯化(乙腈/水,0.05%碳酸氢铵)即可得到中间体20-4,(15mg,28.98umol,17.99%产率),MS(ESI)m/z=518(M+1)+。
室温氮气保护下,向中间体20-4(15mg,28.98umol)的1毫升无水DMF溶液中加入CDI(25.03mg,173.88umol),室温搅拌15分钟后,升温至65℃搅拌反应5小时,反应液冷却至室温后,经反相MPLC纯化(乙腈/水,0.05%碳酸氢铵)即可得到化合物20,(12mg,21.79umol,75.18%产率,98.7%purity),MS(ESI)m/z=544(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.61–7.54(m,1H),7.51(d,J=2.2Hz,2H),7.32(dd,J=8.6,1.8Hz,1H),6.95(d,J=2.2Hz,1H),5.55(d,J=6.7Hz,1H),4.58(s,1H),4.27–4.17(m,1H),4.09(s,3H),3.82(t,J=10.1Hz,1H),3.55(dd,J=10.3,4.3Hz,1H),1.79(s,3H),1.74(s,3H),0.98–0.90(m,1H),0.85–0.72(m,2H),0.53–0.43(m,2H),0.42–0.33(m,1H),0.31–0.20(m,3H),0.18–0.10(m,1H),-0.04–-0.13(m,1H).
为了说明本发明的有益效果,本发明提供以下试验例。
试验例1IL-17A酶联免疫吸附测定(ELISA)实验
通过竞争性ELISA对IL-17A抑制剂对受体-配体结合的抑制情况进行了定量检测。将0.2μg/ml IL-17A(Sino Biological lnc.Cat#12047-H07B)以100μl每孔在96孔板中37度孵育30分钟。用PBST(PBS,0.05%Tween-20)洗板4次,每次200μl每孔,加入200μl 5%脱脂牛奶于25度摇床上孵育30分钟。准备100X浓度待测化合物,浓度从0.003μM到30μM。用PBST(PBS,0.05%Tween-20)洗板4次后加入89μl PBST和1μl 100X浓度待测化合物混匀后于25度预孵育10分钟。加入10μl 16nM IL-17R于25度摇床上孵育30分钟。洗板4次后,加入100μl抗Fc标签HRP偶联抗体于25度摇床上孵育30分钟。洗板4次后,加入100μl TMB底物溶液25度避光孵育。加入20%HCl后,采用酶标仪于450nm波长检测光吸收值。
按照上述方法对实施例制备的化合物进行IL-17A抑制活性检测。
按照上述方法对实施例制备的化合物进行去IL-17A抑制活性检测,试验结果见表1,其中测定各化合物的IC50按照说明分类,表1中:
“+”表示IC50测定值小于100μM大于1μM;
“++”表示IC50测定值小于1μM大于100nM;
“+++”表示IC50测定值小于100nM;
表1、化合物对IL-17A的抑制活性
实施例 | IC<sub>50</sub> | 实施例 | IC<sub>50</sub> | 实施例 | IC<sub>50</sub> |
1 | +++ | 8 | ++ | 15 | ++ |
2 | +++ | 9 | +++ | 16 | ++ |
3 | ++ | 10 | ++ | 17 | ++ |
4 | +++ | 11 | ++ | 18 | +++ |
5 | +++ | 12 | ++ | 19 | ++ |
6 | ++ | 13 | ++ | 20 | +++ |
7 | +++ | 14 | +++ |
试验表明,本发明实施例的化合物具有良好的IL-17A抑制活性,可以有效用于与IL-17A活性异常疾病的治疗。
综上所述,本发明公开的式I所示的新化合物,表现出了良好的IL-17A抑制活性,为临床治疗与IL-17A活性异常相关的疾病提供了一种新的药用可能。
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