CN114456171A - 一类用于镇静催眠的苯并二氮䓬类药物、其制备方法及应用 - Google Patents
一类用于镇静催眠的苯并二氮䓬类药物、其制备方法及应用 Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
Description
技术领域
背景技术
当今社会,随着人们生活方式加快和竞争加剧,睡眠障碍/睡眠亚健康已经成为一种现代都市病,广泛存在并严重影响人们的健康和生活质量,成为一个不可忽视的社会问题。随着社会经济发展,人们的生存压力逐渐增大,失眠人群越来越多,镇静、催眠和抗焦虑药物的市场需求量也逐年增加,而镇静催眠药在治疗失眠的同时,导致意外中毒的情况也随之增多。因此,寻找安全高效易代谢的镇静、催眠和抗焦虑药物对缓解睡眠障碍和焦虑情绪、提高工作效率和生活质量具有重要意义和广阔应用前景。
苯并二氮类衍生物(benzodiazepines)是GABA受体(又称作γ-氨基丁酸A型受体)激活剂。GABAA受体是氯离子通道的门控受体,由两个α和两个β亚单位(α2β2)构成氯离子通道。β亚单位上有GABA受点,当GABA与之结合时,氯离子通道开放,使得氯离子内流,从而使神经细胞超极化,产生抑制效应。在α亚单位上则有苯并二氮受体,当苯并二氮与之结合时,能够通过促进GABA与GABAA受体的结合而使氯离子通道开放的频率增加(而不是使氯离子通道开放时间延长或使氯离子流增大),从而使更多的氯离子内流。这使得苯并二氮类衍生物能够增强GABA神经传递功能和突触抑制效应,从而在临床上产生镇静催眠、抗焦虑、抗惊厥、肌肉松弛等作用,帮助患者提高睡眠质量以及改善其他不适症状,成为临床上最常用的镇静催眠药物。
苯并二氮类药物兴起于20世纪60年代初期,属于第二代镇静催眠药,相较于第一代巴比妥类药物其镇静催眠作用更强,治疗指数更高,是当前临床上的首选镇静催眠、抗焦虑药物。第一个苯二氮卓药物氯氮(利眠宁)于1960年面市。此后,不断有新型苯二氮卓类药物涌现:包括短效(***仑/咪达***)、中效(劳拉西泮/艾司***)和长效(***)等。临床常用的苯并二氮类衍生物有20余种,尽管结构相似,但不同衍生物的临床适应症各不相同。原因在于,GABA与GABA受体的结合部位和作用呈现不均一性,不同神经的GABA门控氯通道是由不同种类的亚单位构成,不同的亚单位的组成可导致这些通道和别构调节剂的相互作用发生细微变化,产生不同的镇静催眠效应。但研究发现,当苯并二氮类药物服用剂量超过机体代谢时会引起脑内β-内啡肽释放增加,作用于中枢神经、心血管***的***受体,降低神经的兴奋性,引起中枢神经和呼吸抑制、血压降低、心率减慢等严重副作用。此外,苯并二氮类***物使用时常伴随依赖性成瘾性,且其中大多药物代谢产物仍具有一定药效从而无法使患者迅速恢复常态,长期使用易导致药物蓄积作用,阻碍了其进一步发展。因此开发临睡前用药后起效快,持续作用时间充分,次晨没有残存效应的苯并二氮类药物是亟待解决的问题。
发明内容
其中:
R1选自氢、Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,优选地,R1选自氢或Cl-6烷基,更优选地,R1选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基;
R2处于苯环的任意位置,且为单取代或多取代,优选地选自第6、7、8、9位取代,更优选地选自第7位取代;
R2选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,优选地,R2选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基,更优选地,R2选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基;R2进一步优选自氢、氯、溴、氟、硝基、三氟甲基;
X选自C或N,当X为C时,R3选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,优选地,R3选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基,更优选地,R3选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基;当X为N时,R3取代基则不存在;
R4处于苯环或吡啶环的任意位置,且为单取代或多取代,优选地选自第3’、4’、5’位取代,更优选地选自第4’位取代;
R4选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,优选地,R4选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基,更优选地,R4选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基;
R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代;优选地,R5选自氢、Cl-10烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基;更优选地,R5选自氢、甲基、乙基、正丙基、2-羟乙基、吗啉乙基、二甲胺基乙基、二乙胺基乙基、二甲胺基丙基、二乙胺基丙基、(4-苯基哌嗪-1-基)甲基、(4-苯基哌嗪-1-基)乙基、磷酰氧基甲基,
R6、R7选自氢、Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代;优选地,R6、R7选自Cl-6烷基;更优选地,R6、R7选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基;
n选自1到20,优选n选1到10,更优选地1到6;
W选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代;优选地,W选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基;更优选地,W选自氢、羟基、氯、溴、氟、硝基、氰基、R6R7N-(CH2)1-6-、三氟甲基;
其中,上述氢和上述基团中所含的氢选自氕、氘和氚。
其中,X为C;R2和R3为卤素;R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代;R5选自氢、Cl-10烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基;更优选地,R5选自氢、甲基、乙基、正丙基、2-羟乙基、吗啉乙基、二甲胺基乙基、二乙胺基乙基、二甲胺基丙基、二乙胺基丙基、(4-苯基哌嗪-1-基)甲基、(4-苯基哌嗪-1-基)乙基、磷酰氧基甲基。
其中,X为N;R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个(例如1个、2个、3个或4个)独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代;R5选自氢、Cl-10烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基;更优选地,R5选自氢、甲基、乙基、正丙基、2-羟乙基、吗啉乙基、二甲胺基乙基、二乙胺基乙基、二甲胺基丙基、二乙胺基丙基、(4-苯基哌嗪-1-基)甲基、(4-苯基哌嗪-1-基)乙基、磷酰氧基甲基。
进一步的,其中所述化合物选自:
(S)-3-(8-氯-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物66)、
(S)-3-(8-溴-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物67)、
(S)-3-(8-硝基-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物68)、
(S)-3-(8-氯-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物96)、
(S)-3-(8-溴-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物97)、
(S)-3-(8-硝基-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物98)、
部分化合物的结构为:
进一步的,本发明的化合物在药物组合物中的含量或用量可以是40mg至12000mg,适合地是100-12000mg,优选240-10800mg,更优选240-6000mg,特别优选240-4000mg,例如240mg、320mg、400mg、600mg、800mg、1200mg或2000mg。
所述药学上可接受的载体选自水、油及其他注射性溶剂,
所用药物附加剂选自淀粉、葡萄糖、乳糖、黑糖、明胶、麦芽糖、自主、硅胶、硬脂酸纳、单硬脂酸甘油醋、滑石、氧化纳、脱脂奶粉、甘油、丙二醇、乙醇、卵磷脂、甘氨酸、甘露醇、吐温80、聚山梨酯、羧甲基纤维素钠、明胶、果胶、白蛋白、海藻糖、右旋糖酐;
进一步的,其药学上可接受的盐,选自乙酸盐、己二酸盐、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、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氧化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、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、双氢萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐、铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钠盐、钾盐、铵盐、氨丁三醇盐及锌盐。
进一步的,所述化合物的制备方法,所述方法按照反应路线如下:
其中R1、R2、R3、R4、R5、W如技术方案1和3中任一项所定义,
所述方法包括以下步骤:
(1)、使所述A与N2保护的手性氨基酸或其衍生物发生缩合反应,得到中间体C,
所述反应优选在碱和缩合剂的存在下进行;所述碱例如但不限于DIPEA、N-甲基吗啉或TEA;所述缩合剂例如但不限于HATU、DCC、EDCI、PyBOP、BOP-Cl或T3P,所述反应优选在适当的溶剂中进行;所述适当的溶剂例如但不限于THF、DMF或DCM,所述反应优选在冰浴条件下或者在室温下或者在溶剂回流条件下进行,所述于性氨基酸或其衍生物例如但不限于L-谷氨酸-5-甲酯或L-谷氨酸-5-乙酯;
所述反应优选在酸性条件下进行;所述酸性条件例如但不限于三氟乙酸或盐酸,
所述反应优选在适当的溶剂中进行;所述适当的溶剂例如但不限于甲苯或THF,
(4)、使所述活性中间体E与水合肼发生取代反应,得到中间体F,
所述反应优选在适当的溶剂中进行;所述适当的溶剂例如但不限于甲苯或THF,所述反应优选在冰浴条件下或者在室温下或者在溶剂回流条件下进行,
(5)、使所述中间体F通过与硫光气反应,闭环得到目标产物G,
所述反应优选在适当的溶剂中进行;所述适当的溶剂例如但不限于DCM、DMF或THF;所述反应优选在冰浴条件下或者在室温下或者在溶剂回流条件下进行,所述反应优选在碱性条件下进行,所述碱性条件例如但不限于三乙胺、DIPEA或者K2CO3,
(6)、使所述中间体G通过与钠盐在无水溶液中反应得到目标产物H,
所述反应优选在适当的溶剂中进行,所述适当的溶剂例如但不限于DCM、CH3OH、CH3CH2OH、CH3CH(OH)CH3或THF,所述反应优选在冰浴条件下或者在室温下或者在溶剂回流条件下进行,所述反应优选在碱性条件下进行;所述碱性条件例如但不限于异丙醇钠、叔丁醇钠、甲醇钠或乙醇钠,
(7)、使所述中间体H发生取代反应,从而得到目标产物I。
所述反应优选在适当的溶剂中进行;所述适当的溶剂例如但不限于DCM、DMF或THF,所述反应优选在冰浴条件下或者在室温下或者在溶剂回流条件下进行。
进一步的,所述化合物或组合物在制备镇静催眠、抗焦虑药物中的应用,包括用于因大脑的兴奋与抑制机能失调所致的早醒型失眠的镇静、催眠、抗焦虑和遗忘等。
进一步的,一种镇静催眠方法,包括口服途径给药有效量的权利要求1-7任一项的化合物或权利要求8的药物组合物。
进一步的,一种药物制剂,该制剂包含作为活性剂的通式(I)化合物或其药用盐和药学上可接受的载体。药学上可接受的载体是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂、助剂等,它们不逆向与活性化合物或病人发生作用。
进一步的,所述剂型可以是片剂、胶囊剂、悬剂、乳剂等药剂学上常用的剂型。
进一步的,可调整给药方案以提供最佳所需响应。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。要进一步理解,对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
进一步的,所给药的本发明的化合物的量会取决于所治疗的个体、给药的频率、化合物的处置及处方医师的判断。一般而言,有效剂量为每日每kg体重约0.0004至约200mg,例如约0.04至约40mg/kg/日(单次或分次给药)。对70kg的人而言,这会合计为约0.028mg/日至约14000mg/日,例如约2.8mg/日至约2800mg/日。在一些情况下,低于前述范围的下限的剂量水平可以是足够的,而在其它情况下,仍可在不引起任何有害副作用的情况下采用较大剂量,条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的目的在于提供药物组合物,其包含有效量的本发明的化合物以及一种或多种药学上可接受的载体。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体,例如水、油及其他注射性溶剂,包括那些石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等;当所述药物组合物通过静脉内给药时,水是示例性载体;还可以使用生理盐水、葡萄糖、甘油水溶液、乙醇、丙二醇、聚乙二醇、甘油作为液体载体,特别是用于注射液或乳剂。适合的药物附加剂包括淀粉、葡萄糖、乳糖、黑糖、明胶、麦芽糖、自主、硅胶、硬脂酸纳、单硬脂酸甘油醋、滑石、氧化纳、脱脂奶粉、甘油、丙二醇、乙醇、卵磷脂、甘氨酸、甘露醇、吐温80、聚山梨酯、羧甲基纤维素钠、明胶、果胶、白蛋白、海藻糖、右旋糖酐等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。
本发明的有益效果是:本发明涉及结构新颖的苯并二氮类化合物,其具有镇静催眠和抗焦虑活性,且具有起效快速、作用时间长、无蓄积等特点。在对小鼠诱导镇静催眠实验中,本发明的苯二氮类衍生物起效时间和***仑相当,且部分化合物作用持续时间与***仑相比显著缩短,另一部分化合物作用持续时间与***相当;所涉及化合物在体内均易代谢成无活性产物且无蓄积、不会伴随嗜睡、成瘾等不良症状。因此所述通式(I)中化合物及其药用盐既能改善入睡困难又能缓解易醒早醒的睡眠障碍问题,具有潜在的镇静催眠、抗焦虑作用。本发明所述的苯二氮类衍生物不但保持对GABAA受体的高亲和力和选择性,而且通过对苯并二氮的结构修饰和羧酸酯基团的调整而具有以下优点:修饰改造后的短效和中效化合物可分别针对入睡困难和易醒早醒的睡眠障碍患者达到镇静催眠抗焦虑作用效果,起效迅速,作用时长充分,容易代谢且代谢产物无活性,从而改善因蓄积导致的长期使用耐受和依赖性,以及减少给病人神经***造成的副作用,包括嗜睡、头晕、神志错乱等。
具体实施方式
为了使本发明的目的和技术方案更加清楚,以下结合具体实施例进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。并且,下列实施例中未提及的具体实验方法,均按照常规实验方法进行。本文中的缩写具有以下含义:
化合物的结构通过核磁共振波谱(1H NMR、13C NMR)、质谱(MS)来确证;反应的监测采用薄层色谱法(TLC)或LCMS,使用的展开剂体系有:二氯甲炕和甲醇体系、正己炕和乙酸乙酯体系、石油醚和乙酸乙酯体系。
柱色谱法一般使用200~300目硅胶为固定相;洗脱剂的体系包括:二氯甲炕和甲醇体系,正己炕和乙酸乙醋体系,溶剂的体积比根据化合物的极性不同而进行调节。
在以下实施例中,如无特殊说明,反应的温度为室温(20℃~30℃)。
第一步:(S)-5-((2-氟-苯甲酰基-4-氯苯基)氨基)-4-((叔丁氧羰基)氨基)-5-氧代戊酸甲酯(化合物1c)的制备
将2-氨基-5-氯-2’-氟二苯甲酮(化合物1a,11.48g,0.046mol)和化合物N-叔丁氧羰基-L-谷氨酸-5-甲酯(化合物1b,10g,0.038mol)溶于DCM(300mL)。将混合物冷却到0℃,加入DCC(9.49g,0.046mmol),并搅拌24小时。LCMS显示反应结束。抽滤取滤液并减压蒸除反应溶剂,残留产物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得到白色固体(S)-5-((2-氟-苯甲酰基-4-氯苯基)氨基)-4-((叔丁氧羰基)氨基)-5-氧代戊酸甲酯(化合物1c,10.56g,产率:56.4%)
第二步:(S)-4-氨基-5-((2-氟苯甲酰基-4-氯苯基)氨基)-5-氧代戊酸甲酯(化合物1d)的制备
将(S)-5-((2-氟-苯甲酰基-4-氯苯基)氨基)-4-((叔丁氧羰基)氨基)-5-氧代戊酸甲酯(化合物1c,10.56g)溶于DCM(50mL)。加入TFA(50mL),搅拌20分钟直至LCMS显示反应结束。将反应液浓缩,所得残余物为粗品(S)-4-氨基-5-((2-氟苯甲酰基-4-氯苯基)氨基)-5-氧代戊酸甲酯(化合物1d,8.4g),将其直接用于下一步反应。
(S)-4-氨基-5-((2-氟苯甲酰基-4-氯苯基)氨基)-5-氧代戊酸甲酯(化合物1d,8.4g)的溶于MeOH(100mL),加入NaHCO3调节pH至约10,并搅拌24小时。LCMS显示反应结束。将反应液过滤,将滤液倾入冰水中,用乙酸乙醋萃取,将有机相用水洗3次,干燥并浓缩后,残留产物经柱层析(石油醚/乙酸乙酯,2:1,v/v)纯化得到白色(S)-3-(7-氯-2-氧代-5-(2-氟苯基)-2,3-二氢-lH-苯并[e][l,4]二氮杂-3-基)丙酸甲酯(化合物1e,7.5g)
将(S)-3-(7-氯-2-氧代-5-(2-氟苯基)-2,3-二氢-lH-苯并[e][l,4]二氮杂-3-基)丙酸甲酯(化合物1e,7.5g)溶于甲苯(200mL),加入劳森试剂(4.86g,0.012mol),将化合物加热到100℃,搅拌1.5小时,直至LCMS显示反应结束。加入饱和碳酸氢钠溶液除去过量的劳森试剂,乙酸乙酯(20ml×3)萃取,合并有机层,有机层用无水硫酸钠干燥,减压蒸除反应溶剂,残留产物经柱层析(石油醚/乙酸乙酯,7:1,v/v)纯化得淡黄色固体(S)-3-(7-氯-5-(2-氟苯基)-2-硫代-2-3,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)丙酸甲酯(化合物1f,4.07g,产率:52.1%)
将(S)-3-(7-氯-5-(2-氟苯基)-2-硫代-2-3,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)丙酸甲酯(化合物1f,4.07g)溶于50ml THF,将混合物冷却至0℃,加入80%水合肼(1.56g,0.031mol),并搅拌30分钟直至LCMS显示反应结束,用饱和NaCl除去多余的水合肼,用DCM萃取合并有机相,干燥并浓缩,得到粗品(S)-3-(7-氯-5-(2-氟苯基)-2-肼基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)丙酸甲酯(化合物1g,3.1g),将其直接用于下一步反应。
将(S)-3-(7-氯-5-(2-氟苯基)-2-肼基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)丙酸甲酯(化合物1g,3.1g)溶于80ml THF中,加TEA(1.77g,0.018mol),将混合物冷却至0℃,加硫光气(1.0g,0.009mol),并搅拌2h直至LCMS显示反应结束,抽滤取滤液并减压蒸除反应溶剂,残留产物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得到白色固体(S)-3-(8-溴-6-(吡啶-2-基)-1-硫代-2-2,4-二氢-1H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物1互变异构体,1.46g,产率:42.5%)
1H NMR(300MHz,DMSO-d6)δ:14.17(s,1H),8.46(d,J=8.7Hz,1H),7.90-7.28(m,6H),4.26(t,J=6.1Hz,1H),3.62(s,3H),2.70-2.45(m,4H);13C NMR(75MHz,DMSO-d6)δ:173.58,166.94,164.32,161.78,158.47,153.86,133.56,132.55,132.23,131.91,131.18,129.03,127.87,127.02,125.27,116.78,55.15,51.85,30.19,26.26;LC-MS(ESI)m/z:430.5[M+H]+。
实施例2-7均按照上述实施例中的相应方法合成,具体核磁、质谱碳谱表征数据如下:
1H NMR(300MHz,DMSO-d6)δ:14.15(s,1H),8.46(d,J=8.8Hz,1H),7.87(d,J=7.4Hz,1H),7.66-7.50(m,4H),7.16(s,1H),4.34(t,J=5.8Hz,1H),3.62(s,3H),2.70-2.45(m,4H);13C NMR(75MHz,DMSO-d6)δ:173.54,167.16,167.00,153.68,138.23,132.42,132.28,132.12,131.94,131.73,131.64,131.07,130.21,128.52,127.99,127.96,55.30,51.85,30.22,26.16;LC-MS(ESI)m/z:447.2[M+H]+。
1H NMR(300MHz,DMSO-d6)δ:14.17(s,1H),8.59(d,J=4.3Hz,1H),8.37(d,J=8.8Hz,1H),8.13(d,J=7.9Hz,1H),8.03-7.98(m,2H),7.60-7.54(m,2H),4.34(t,J=5.8Hz,1H),3.65(s,3H),2.70-2.45(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.70,167.81,166.51,157.68,155.34,149.03,136.91,134.69,134.01,132.24,130.18,126.91,125.28,124.90,123.99,55.09,51.71,30.17,26.18;LC-MS(ESI)m/z:457.8[M+H]+。
1H NMR(300MHz,DMSO-d6)δ:11.14(s,1H),8.38(d,J=9.1Hz,1H),7.97(d,J=8.9Hz,1H),7.66-7.54(m,2H),7.43(s,1H),7.36(t,J=7.5Hz,1H),7.24(t,J=9.8Hz,1H),4.27(t,J=6.7Hz,1H),3.60(s,3H),2.70-2.45(m,4H);13C NMR(75MHz,DMSO-d6)δ:173.60,166.91,164.26,161.78,158.48,153.87,134.09,133.46,132.45,131.93,131.60,128.02,127.05,125.28,120.85,116.80,55.14,51.87,30.20,26.27;LC-MS(ESI)m/z:475.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:14.06(s,1H),8.43(d,J=8.0Hz,1H),7.80(t,J=7.3Hz,1H),7.60-7.40(m,7H),4.17(t,J=5.7Hz,1H),3.62(s,3H),2.70-2.40(m,4H);13CNMR(75MHz,CDCl3-d1)δ:173.89,169.62,167.15,154.17,138.77,133.17,131.38,131.10,131.00,129.80(2C),129.57,128.35(2C),127.88,125.67,54.78,51.87,30.25,26.21;LC-MS(ESI)m/z:379.5[M+H]+。
1H NMR(400MHz,DMSO-d6)δ:14.06(s,1H),8.43(d,J=8.3Hz,1H),7.81(t,J=8.8Hz,1H),7.60-7.55(m,3H),7.43(d,J=9.0Hz,1H),7.28(t,J=7.7Hz,2H),4.17(t,J=7.6Hz,1H),3.62(s,3H),2.70-2.40(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.84,168.39,167.18,166.24,162.90,154.14,134.90,133.16,131.98,131.18,129.31,127.98,125.80,115.58,115.29,54.77,51.88,30.22,26.17;LC-MS(ESI)m/z:397.3[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:11.34(s,1H),8.57(d,J=8.8Hz,1H),7.71-7.41(m,7H),4.17(t,J=5.8Hz,1H),3.73(s,3H),2.81-2.60(m,4H);13C NMR(75MHz,DMSO-d6)δ:173.62,167.25,166.82,154.07,138.40,132.31,132.24,131.44,131.20,130.96,130.45,129.54,128.91,127.86,55.36,51.84,30.23,26.34;LC-MS(ESI)m/z:412.7[M+H]+。
将(S)-3-(8-氯-6-(2-氟苯基)-1-巯基-4H-苯并[f][1,2,4]***并[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物1,0.1g)溶于8ml THF中,冰浴冷却,滴加20%异丙醇钠的四氢呋喃溶液,滴加完成后室温搅拌30分钟,旋蒸除去溶剂后得到相应钠盐,加碘甲烷(0.049g,0.35mM),68℃加热回流反应8h后,减压浓缩柱层析(PE:EA=1:1)得白色固体(S)3-(8-氯-6-(2-氟苯基)-1-(甲硫基-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物8,0.075g,产率:72.8%)
1H NMR(300MHz,CDCl3-d1)δ:7.78-7.61(m,3H),7.48(q,J=6.1Hz,1H),7.34-7.24(m,2H),7.05(t,J=9.6Hz,1H),4.23(t,J=5.7Hz,1H),3.68(s,3H),2.90-2.72(m,7H);13CNMR(75MHz,CDCl3-d1)δ173.88,163.67,161.96,158.65,157.58,151.07,133.73,132.71,132.60,131.62,131.27,130.35,129.78,127.05,124.63,116.46,55.06,51.63,30.18,26.55,15.28;LC-MS(ESI)m/z:445.3[M+H]+。
实施例9-113(化合物9-113)均按照上述实施例中的相应方法合成,具体核磁、质谱碳谱表征数据如下:
1H NMR(300MHz,CDCl3-d1)δ7.67(dd,J=7.3,2.2Hz,1H),7.59(d,J=2.0Hz,1H),7.55-7.31(m,5H),7.22(dd,J=7.2,2.2Hz,1H),5.22(s,1H),3.68(s,3H),2.53(d,J=28.9Hz,4H),2.45-2.26(m,2H),2.25(d,J=12.4Hz,1H);13C NMR(75MHz,CDCl3-d1)δ173.78,160.03,150.29,147.02,140.17,138.02,131.75,129.62,129.44,129.40,125.51,125.40,122.44,118.85,117.15,115.82,54.38,51.46,32.25,27.63,14.05;LC-MS(ESI)m/z:490.3[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.30(dd,J=7.5,2.0Hz,1H),8.15(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J=7.2,2.3Hz,1H),7.50–7.31(m,2H),7.27(dd,J=7.2,2.4Hz,1H),5.15(s,1H),3.68(s,3H),2.56(s,3H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.68,160.03,150.29,148.47,146.96,143.52,141.28,129.83,129.75,128.39,124.87,124.15,123.29,122.44,120.52,115.88,57.87,51.40,32.25,27.60,14.05;LC-MS(ESI)m/z:456.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.78-7.61(m,5H),7.48(q,J=5.4Hz,1H),7.34-7.24(m,2H),7.05(t,J=9.4Hz,1H),4.23(t,J=5.7Hz,1H),3.68(s,3H),3.25(q,J=7.2Hz,2H),2.90-2.72(m,4H),1.39(t,J=7.2Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.88,163.70,162.02,158.68,157.41,150.20,133.69,132.71,131.51,131.26,130.40,129.65,127.06,125.08,124.56,116.45,55.10,51.63,30.20,27.81,26.54,14.66;LC-MS(ESI)m/z:458.9[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.67(dd,J=7.1,2.4Hz,1H),7.59(d,J=2.0Hz,1H),7.55-7.29(m,4H),7.22(dd,J=7.0,2.5Hz,1H),5.22(s,1H),3.68(s,3H),3.18(s,2H),2.50(d,J=12.4Hz,1H),2.39(d,J=12.4Hz,1H),2.37-2.19(m,2H),1.39(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.78,160.03,147.02,144.40,140.17,138.02,131.75,129.69,129.44,129.40,127.05,124.20,122.44,119.90,116.44,115.82,54.38,51.46,32.25,28.40,27.60,14.23;LC-MS(ESI)m/z:504.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.30(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.66-7.56(m,1H),7.47–7.31(m,2H),7.32-7.22(m,1H),5.15(s,1H),3.68(s,3H),3.18(s,2H),2.53(d,J=12.4Hz,1H),2.45-2.33(m,2H),2.23(d,J=12.4Hz,1H),1.40(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.90,160.03,148.47,146.96,144.00,143.52,141.28,129.50,129.44,128.71,124.87,124.15,122.86,122.44,120.52,115.88,54.38,51.43,32.25,28.40,27.60,14.23;LC-MS(ESI)m/z:470.5[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.78-7.61(m,3H),7.48(q,J=8.3Hz,1H),7.34-7.24(m,2H),7.05(t,J=9.0Hz,1H),4.23(t,J=6.2Hz,1H),3.68(s,3H),3.22(t,J=7.0Hz,2H),2.90-2.72(m,4H),1.77(q,J=7.1Hz,2H),1.01(t,J=7.2Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.89,163.69,162.02,158.68,157.40,150.42,133.67,132.70,131.50,131.27,130.42,129.65,127.06,125.11,124.57,116.45,55.11,51.63,35.33,30.21,26.54,22.68,13.17;LC-MS(ESI)m/z:473.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.67(dd,J=7.0,2.4Hz,1H),7.62-7.29(m,6H),7.21(dd,J=6.9,2.5Hz,1H),5.17(s,1H),3.68(s,3H),3.24(s,2H),2.50(d,J=12.4Hz,1H),2.452.19(m,3H),1.80(d,J=0.4Hz,3H),1.01(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.78,160.03,147.02,145.70,140.80,138.02,131.75,129.84,129.69,129.44,127.05,124.20,122.44,121.80,116.44,115.82,54.38,51.45,32.86,32.25,27.67,27.60,14.10;LC-MS(ESI)m/z:518.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.28(dd,J=7.5,2.0Hz,1H),8.17(d,J=1.9Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.28(dd,J=5.6,3.9Hz,1H),5.15(s,1H),3.68(s,3H),3.28(s,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H),1.79(s,2H),1.03(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.90,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,124.15,122.86,122.44,120.52,115.82,54.33,51.46,33.02,32.86,27.67,27.60,14.09;LC-MS(ESI)m/z:484.5[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.78-7.61(m,3H),7.48(q,J=7.3Hz,1H),7.34-7.24(m,2H),7.05(t,J=10.0Hz,1H),4.25-4.13(m,2H),3.99(q,J=5.6Hz,2H),3.68(s,3H),3.49-3.35(m,2H),2.90-2.72(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.81,163.79,162.01,158.67,157.51,150.84,133.95,132.78,131.69,131.27,130.17,129.77,126.92,125.06,124.58,116.50,61.90,54.99,51.66,36.08,30.13,26.46;LC-MS(ESI)m/z:475.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.67(dd,J=7.0,2.4Hz,1H),7.62–7.46(m,2H),7.47-7.29(m,2H),7.21(dd,J=6.9,2.5Hz,1H),7.11(d,J=7.5Hz,1H),5.15(s,1H),4.58(t,J=5.5Hz,1H),3.71-3.49(m,6H),3.43(d,J=12.4Hz,1H),2.50(d,J=12.4Hz,1H),2.39(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.78,160.03,147.02,145.12,140.80,138.02,131.75,129.84,129.65,129.44,127.05,124.20,122.44,121.80,116.44,115.82,61.40,54.38,51.45,34.93,32.03,27.60;LC-MS(ESI)m/z:520.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.28(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.41-7.23(m,1H),5.15(s,1H),4.27(t,J=5.5Hz,1H),3.71-3.54(m,6H),3.51(d,J=12.4Hz,1H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.90,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,124.15,122.86,122.44,121.02,115.82,61.63,54.33,51.46,35.01,33.02,27.60;LC-MS(ESI)m/z:486.5[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.78-7.61(m,3H),7.48(q,J=5.4Hz,1H),7.34-7.24(m,2H),7.05(t,J=9.0Hz,1H),4.38-4.21(m,3H),3.68(s,3H),3.46-3.22(m,4H),2.90-2.72(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.84,163.79,162.00,158.65,157.61,150.05,133.93,132.74,131.74,131.24,130.09,129.69,126.95,125.11,124.56,116.48,54.98,51.65,40.72,31.58,30.15,26.45;LC-MS(ESI)m/z:474.0[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.67(dd,J=7.0,2.5Hz,1H),7.62-7.46(m,2H),7.47-7.29(m,2H),7.21(dd,J=6.9,2.5Hz,1H),7.04(d,J=7.5Hz,1H),5.15(s,1H),4.49(d,J=0.7Hz,1H),4.37(d,J=0.7Hz,1H),3.71-3.51(m,5H),2.95(s,2H),2.50(d,J=12.4Hz,1H),2.39(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.78,160.03,147.02,145.12,140.80,138.02,131.75,129.84,129.69,129.44,127.05,124.20,122.44,121.80,116.44,115.82,54.38,51.45,39.99,34.13,32.03,27.60;LC-MS(ESI)m/z:519.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.29(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.41-7.23(m,1H),5.15(s,1H),4.49(d,J=0.7Hz,1H),4.37(d,J=0.7Hz,1H),3.65(d,J=17.9Hz,5H),3.00-2.82(m,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.90,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,124.15,122.86,122.44,120.52,115.82,54.33,51.46,39.99,34.37,33.02,27.60;LC-MS(ESI)m/z:485.5[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.74(d,J=8.6Hz,1H),7.64-7.54(m,2H),7.43-7.33(m,3H),7.19(s,1H),4.28(t,J=6.4Hz,1H),3.68(s,3H),2.90-2.76(m,7H);13C NMR(75MHz,CDCl3-d1)δ:173.83,166.45,157.49,151.12,138.02,133.68,132.84,131.57,131.35,131.30,131.00,130.94,130.25,129.49,127.19,124.62,55.10,51.63,30.18,26.50,15.25;LC-MS(ESI)m/z:461.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.66(dd,J=7.4,1.9Hz,1H),7.62-7.44(m,3H),7.51-7.27(m,3H),7.34-7.24(m,1H),5.32(s,1H),3.68(s,3H),2.53(d,J=28.9Hz,4H),2.45-2.26(m,2H),2.25(d,J=12.4Hz,1H);13C NMR(75MHz,CDCl3-d1)δ173.78,150.29,149.26,147.02,140.80,133.13,132.57,131.75,130.86,129.62,128.97,128.62,125.51,124.07,118.85,118.19,54.38,51.46,32.25,27.63,14.05;LC-MS(ESI)m/z:506.8[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.33(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.1Hz,1H),7.68-7.54(m,2H),7.54-7.31(m,3H),5.22(s,1H),3.68(s,3H),2.56(s,3H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.35-2.17(m,2H);13C NMR(75MHz,CDCl3-d1)δ173.78,150.96,150.29,148.47,143.37,141.28,134.20,130.98,130.35,129.35,128.71,128.62,124.17,123.83,122.86,121.02,54.38,51.43,32.25,27.60,14.05;LC-MS(ESI)m/z:472.9[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.74(d,J=8.5Hz,1H),7.64-7.54(m,2H),7.43-7.33(m,3H),7.19(s,1H),4.28(t,J=6.2Hz,1H),3.68(s,3H),3.34(q,J=7.6Hz,2H),2.90-2.72(m,4H),1.42(t,J=7.1Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.83,166.46,157.23,150.27,138.05,133.63,132.82,131.46,131.32,131.30,130.98,130.95,130.21,129.36,127.19,125.04,55.14,51.63,30.20,27.68,26.49,14.77;LC-MS(ESI)m/z:475.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.71-7.61(m,1H),7.60(d,J=2.0Hz,1H),7.57-7.25(m,6H),5.32(s,1H),3.68(s,3H),3.18(s,2H),2.50(d,J=12.4Hz,1H),2.45-2.26(m,2H),2.25(d,J=12.4Hz,1H),1.39(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.78,149.26,147.02,144.40,140.17,133.47,132.57,131.75,130.98,129.65,128.97,128.62,127.05,124.07,122.26,116.44,54.38,51.48,32.03,29.80,28.40,14.23;LC-MS(ESI)m/z:520.8[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.30(dd,J=7.5,2.0Hz,1H),8.19(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.61(dd,J=7.4,2.0Hz,1H),7.54-7.31(m,3H),5.22(s,1H),3.68(s,3H),3.18(s,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H),1.40(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.90,150.96,147.02,144.00,143.37,141.28,133.92,130.98,130.35,129.31,128.71,128.54,124.07,123.83,122.86,121.02,54.38,51.46,32.25,28.40,27.60,14.23;LC-MS(ESI)m/z:486.9[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.76-7.19(m,7H),4.28(t,J=5.7Hz,1H),3.68(s,3H),3.30(t,J=13.8Hz,2H),2.90-2.72(m,4H),1.81(q,J=6.7Hz,2H),1.04(t,J=6.9Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.85,166.46,157.22,150.50,138.06,133.61,132.84,131.47,131.35,131.29,130.99,130.95,130.22,129.35,127.18,125.09,55.19,51.64,35.17,30.23,26.52,22.73,13.23;LC-MS(ESI)m/z:488.9[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.99-7.88(m,2H),7.79(dd,J=8.4,2.5Hz,1H),7.59-7.49(m,1H),7.51-7.39(m,2H),7.41-7.27(m,1H),6.06-5.90(m,1H),3.62(s,2H),3.32(dt,J=14.5,6.4Hz,1H),3.17(dt,J=14.5,6.4Hz,1H),2.79-2.62(m,1H),2.58-2.40(m,2H),2.44-2.24(m,1H),1.93-1.58(m,2H),1.02(t,J=7.6Hz,3H);13C NMR(75MHz,CDCl3-d1)δ173.45,162.53,154.57,153.88,138.65,136.35,134.47,133.31,132.86,130.41,129.64,129.59,128.37,126.63,122.44,119.72,55.11,51.90,34.69,29.81,29.59,22.63,13.16;LC-MS(ESI)m/z:532.03[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.46(dd,J=8.5,2.1Hz,1H),8.36(d,J=2.1Hz,1H),8.25(d,J=8.5Hz,1H),7.57(dd,J=7.8,1.5Hz,1H),7.54-7.36(m,2H),7.35(td,J=7.6,1.5Hz,1H),5.12-4.94(m,1H),3.61(s,2H),3.38-3.13(m,2H),2.70-2.46(m,3H),2.35-2.17(m,1H),1.92-1.58(m,2H),1.03(t,J=7.6Hz,3H);13C NMR(75MHz,CDCl3-d1)δ173.50,162.06,154.57,153.88,146.01,138.70,137.82,134.63,130.41,129.65,128.42,128.36,128.20,126.67,125.98,123.39,55.11,51.90,34.69,29.70,29.62,22.63,13.16;LC-MS(ESI)m/z:499.11[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.75(d,J=8.6Hz,1H),7.64-7.55(m,2H),7.45-7.33(m,3H),7.19(s,1H),4.28(t,J=5.3Hz,1H),4.11-3.96(m,3H),3.68(s,3H),3.51-3.42(m,2H),2.90-2.72(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.79,166.57,157.42,150.92,137.91,133.98,132.83,131.65,131.39,131.29,130.98,130.71,130.27,129.48,127.22,125.07,62.20,55.08,51.68,36.05,30.15,26.42;LC-MS(ESI)m/z:491.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.99-7.88(m,2H),7.81(dd,J=8.4,2.5Hz,1H),7.59-7.48(m,1H),7.51-7.39(m,2H),7.39-7.27(m,1H),6.07-5.90(m,1H),4.40(t,J=7.2Hz,1H),3.75(q,J=7.0Hz,2H),3.62(s,3H),3.67–3.51(m,1H),3.39(dt,J=15.0,6.8Hz,1H),2.78-2.60(m,1H),2.60-2.38(m,2H),2.41-2.22(m,1H);13C NMR(75MHz,CDCl3-d1)δ173.42,162.52,154.54,153.87,138.65,136.35,134.89,133.44,132.85,130.33,129.69,129.62,128.28,126.66,122.43,119.94,60.25,55.10,51.89,35.35,29.70,29.59;LC-MS(ESI)m/z:534.01[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.49-8.35(m,2H),8.26(d,J=8.4Hz,1H),7.57(dd,J=7.8,1.4Hz,1H),7.54-7.38(m,2H),7.34(td,J=7.5,1.5Hz,1H),5.09-4.93(m,1H),4.40(t,J=7.2Hz,1H),3.82-3.63(m,2H),3.61(s,3H),3.68-3.40(m,2H),2.77-2.60(m,1H),2.61-2.42(m,2H),2.35-2.16(m,1H);13C NMR(75MHz,CDCl3-d1)δ173.40,162.06,154.59,153.87,146.02,138.70,137.80,134.47,130.33,129.69,128.29,128.18,127.85,126.71,125.90,123.39,60.27,55.10,51.90,35.34,29.65,29.60;LC-MS(ESI)m/z:501.09[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.79(d,J=8.7Hz,1H),7.62-7.51(m,2H),7.41-7.31(m,3H),7.15(s,1H),6.46(s,2H),4.24(t,J=7.8Hz,1H),3.77-3.52(m,7H),2.82-2.73(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.80,166.72,157.62,150.17,137.84,134.11,132.82,131.95,131.37,131.23,130.93,130.39,130.27,129.39,127.18,125.15,54.93,51.71,40.16,31.60,30.15,26.31;LC-MS(ESI)m/z:490.2[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.98-7.88(m,2H),7.81(dd,J=8.3,2.5Hz,1H),7.59-7.49(m,1H),7.51-7.39(m,2H),7.39-7.27(m,1H),6.06-5.89(m,1H),3.74(t,J=6.1Hz,2H),3.62(s,2H),3.48(dt,J=15.6,5.8Hz,1H),3.34(dt,J=15.6,5.9Hz,1H),3.18-2.88(m,2H),2.79-2.61(m,1H),2.59-2.37(m,2H),2.41-2.22(m,1H);13C NMR(75MHz,CDCl3-d1)δ173.42,162.53,154.45,153.86,138.65,136.35,134.80,133.38,132.85,130.33,129.69,129.62,128.28,126.66,122.43,119.94,55.10,51.89,40.95,35.18,29.70,29.59;LC-MS(ESI)m/z:533.03[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.47(dd,J=8.5,2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.27(d,J=8.4Hz,1H),7.56(dd,J=7.7,1.5Hz,1H),7.56-7.38(m,2H),7.34(td,J=7.5,1.5Hz,1H),5.08-4.90(m,1H),3.74(t,J=6.1Hz,2H),3.64-3.33(m,4H),3.14(dp,J=14.6,6.0Hz,1H),2.98(dp,J=14.6,5.9Hz,1H),2.74-2.57(m,1H),2.62-2.42(m,2H),2.26(dtd,J=11.0,8.4,7.7Hz,1H);13C NMR(75MHz,CDCl3-d1)δ173.39,162.06,154.50,153.88,146.02,138.70,137.80,134.48,130.33,129.69,128.29,128.17,127.79,126.71,125.90,123.39,55.10,51.90,40.95,35.19,29.65,29.60;LC-MS(ESI)m/z:500.10[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.49(d,J=8.8Hz,1H),7.64(d,J=9.5Hz,1H),7.51-7.39(m,4H),7.15(d,J=3.2Hz,1H),4.28(t,J=5.8Hz,1H),3.68(s,3H),2.80-2.62(m,4H),2.30(s,3H);13C NMR(75MHz,CDCl3-d1)δ:173.46,168.18,167.82,166.20,151.61,141.72,137.59,134.00,133.16,132.08,131.51,131.07,130.85,130.49,129.00,127.37,127.07,54.77,51.81,29.81,25.73,20.63;LC-MS(ESI)m/z:489.4[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.10(d,J=8.3Hz,1H),7.96(d,J=2.5Hz,1H),7.79(dd,J=8.4,2.5Hz,1H),7.57-7.27(m,4H),6.06-5.93(m,1H),3.62(s,3H),2.71-2.44(m,3H),2.45-2.22(m,4H);13C NMR(75MHz,CDCl3-d1)δ185.25,173.42,162.53,154.37,148.67,138.65,136.35,134.79,133.71,132.84,130.33,129.63,129.62,128.28,126.66,122.42,119.94,55.10,51.89,30.14,29.65,29.59;LC-MS(ESI)m/z:532.00[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.54-8.36(m,2H),8.34(d,J=2.0Hz,1H),7.55(ddd,J=7.7,6.0,1.8Hz,2H),7.53-7.32(m,2H),5.99(ddd,J=8.2,7.4,0.8Hz,1H),3.61(s,2H),2.71-2.40(m,3H),2.42(s,3H),2.44-2.25(m,1H);13C NMR(75MHz,CDCl3-d1)δ185.25,173.39,162.06,154.37,148.19,146.02,138.70,138.07,134.47,130.33,129.69,128.29,128.21,128.17,126.71,125.90,123.40,55.10,51.90,30.14,29.65,29.60;LC-MS(ESI)m/z:499.07[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:12.39(s,1H),8.52(d,J=8.7Hz,1H),7.62(d,J=8.6Hz,1H),7.64-7.38(m,4H),7.14(s,1H),4.28(t,J=6.3Hz,1H),4.14(q,J=7.0Hz,2H),2.76-2.57(m,4H),1.23(t,J=7.1Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.32,168.00,167.13,153.25,137.67,133.88,133.07,131.81,131.39,131.17,130.91,130.82,130.40,129.14,127.01,60.70,54.92,30.18,25.84,14.19;LC-MS(ESI)m/z:461.0[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.75(d,J=8.5Hz,1H),7.64-7.56(m,2H),7.43-7.31(m,3H),7.19(s,1H),4.28(t,J=5.6Hz,1H),4.14(q,J=7.0Hz,2H),2.90-2.76(m,7H)1.24(t,J=6.6Hz,3H);13C NMR(75MHz,CDCl3-d1)δ:173.44,166.45,157.55,151.14,138.05,133.70,132.88,131.60,131.38,131.02,130.28,129.51,127.22,124.63,60.43,55.14,30.46,26.54,15.27,14.24;LC-MS(ESI)m/z:475.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.99-7.87(m,2H),7.80(dd,J=8.4,2.5Hz,1H),7.53(dd,J=8.0,1.6Hz,1H),7.51-7.39(m,2H),7.39-7.27(m,1H),5.02(ddd,J=8.3,7.6,0.7Hz,1H),4.21-3.97(m,2H),2.64(s,3H),2.73–2.26(m,4H),1.18(t,J=6.9Hz,3H);13CNMR(75MHz,CDCl3-d1)δ172.72,162.53,154.47,153.45,138.65,136.35,134.56,133.15,132.85,130.33,129.69,129.62,128.28,126.67,122.44,119.73,60.67,55.10,30.27,29.68,16.53,14.18;LC-MS(ESI)m/z:518.02[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.52-8.35(m,2H),8.25(d,J=8.4Hz,1H),7.56(dd,J=7.7,1.5Hz,1H),7.53-7.39(m,2H),7.33(td,J=7.5,1.5Hz,1H),5.02-4.87(m,1H),4.21-3.97(m,2H),2.75-2.58(m,1H),2.64(s,3H),2.61-2.39(m,2H),2.33-2.15(m,1H),1.18(t,J=6.9Hz,3H);13C NMR(75MHz,CDCl3-d1)δ172.77,161.98,154.47,153.47,146.09,138.70,137.56,134.51,130.33,129.67,128.29,128.17,127.79,126.66,125.92,123.39,60.68,55.10,30.29,29.68,16.53,14.17;LC-MS(ESI)m/z:485.09[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.90(s,2H),7.62(dt,J=25.3,7.0Hz,2H),7.37(d,J=14.2Hz,2H),7.22(t,J=9.6Hz,1H),4.28(t,J=6.4Hz,1H),3.62(s,3H),3.07(d,J=7.2Hz,2H),2.77-2.57(m,4H),1.05(s,1H),0.45(d,J=7.9Hz,2H),0.24-0.12(m,2H);13CNMR(75MHz,CDCl3-d1)δ:173.57,163.45,161.94,161.87,161.44,156.52,153.90,134.08,133.03,132.44,132.38,131.36,130.59,130.53,129.90,127.85,127.79,127.77,127.69,124.73,124.71,122.90,116.37,116.21,55.18,51.94,38.04,29.44,29.28,11.77,6.27;LC-MS(ESI)m/z:486.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.97-7.83(m,2H),7.80(dd,J=8.4,2.5Hz,1H),7.53(dddd,J=15.6,7.6,5.0,1.6Hz,2H),7.28(dtd,J=16.5,7.7,1.4Hz,2H),4.70-4.53(m,1H),3.61(s,2H),3.36-3.21(m,1H),3.09-2.96(m,1H),2.71-2.53(m,1H),2.58-2.42(m,2H),2.36(dtd,J=10.9,8.4,7.6Hz,1H),1.40-1.20(m,5H);13C NMR(75MHz,CDCl3-d1)δ173.43,163.16,162.00,161.89,159.80,154.35,153.86,136.35,133.54,132.91,131.57,131.46,130.46,130.36,128.86,128.82,126.92,126.66,124.26,124.22,122.43,119.98,115.98,115.71,55.26,51.89,37.41,29.65,29.60,13.37,6.76;LC-MS(ESI)m/z:528.06[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.46(dd,J=8.5,2.1Hz,1H),8.35–8.19(m,2H),7.63-7.44(m,2H),7.30(dtd,J=13.2,7.7,1.4Hz,2H),4.93(t,J=8.1Hz,1H),3.61(s,2H),3.42-3.29(m,1H),3.05-2.91(m,1H),2.71-2.50(m,2H),2.55-2.27(m,2H),1.39-1.20(m,5H);13C NMR(75MHz,CDCl3-d1)δ173.39,163.12,161.47,161.36,159.76,154.35,153.88,146.14,137.98,131.60,131.49,130.48,130.37,128.16,127.31,127.25,127.07,126.81,126.00,124.32,124.28,123.39,115.95,115.68,55.26,51.90,37.41,29.65,29.61,13.37,6.76;LC-MS(ESI)m/z:495.14[M+H]+。
1H NMR(400MHz,CDCl3-d1)δ:7.95-7.85(m,2H),7.68-7.53(m,2H),7.42-7.30(m,2H),7.28-7.18(m,1H),4.30(dd,J=8.0,5.5Hz,1H),3.98(qd,J=16.4,2.6Hz,2H),3.62(s,3H),3.17(t,J=2.6Hz,1H),2.80-2.54(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.35,163.77,161.57,161.23,161.14,156.64,153.26,134.21,133.16,132.95,132.63,131.36,130.71,130.55,129.34,127.76,127.65,127.58,127.39,124.83,124.53,123.25,116.64,116.33,79.82,72.44,55.37,51.62,29.43,29.30,20.68;LC-MS(ESI)m/z:469.2[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.91(d,J=8.4Hz,1H),7.88-7.74(m,2H),7.63-7.44(m,2H),7.37-7.19(m,2H),4.90(t,J=8.0Hz,1H),4.07(dd,J=12.4,3.0Hz,1H),3.85(dd,J=12.4,3.0Hz,1H),3.62(s,2H),2.71-2.27(m,5H);13C NMR(75MHz,CDCl3-d1)δ173.39,163.17,162.00,161.89,159.80,154.01,153.86,136.35,133.51,132.85,131.57,131.46,130.43,130.33,128.86,128.82,126.93,126.66,124.29,124.25,122.43,119.81,115.98,115.71,79.08,72.66,55.26,51.89,29.65,29.59,20.39;LC-MS(ESI)m/z:512.03[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.48(dd,J=8.5,2.1Hz,1H),8.33(d,J=2.1Hz,1H),8.22(d,J=8.5Hz,1H),7.63-7.45(m,2H),7.29(dtd,J=16.4,7.7,1.4Hz,2H),4.90(t,J=8.1Hz,1H),4.08(dd,J=12.3,3.0Hz,1H),3.87(dd,J=12.3,3.0Hz,1H),3.61(s,2H),2.73-2.26(m,5H);13C NMR(75MHz,CDCl3-d1)δ173.41,163.13,161.47,161.36,159.77,154.02,153.88,146.14,137.89,131.58,131.46,130.43,130.33,128.17,127.36,127.32,127.07,126.81,126.05,124.33,124.29,123.39,115.98,115.71,79.07,72.67,55.26,51.90,29.65,29.61,20.39;LC-MS(ESI)m/z:479.11[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.93(s,2H),7.75-7.52(m,2H),7.45-7.31(m,2H),7.30-7.18(m,1H),4.31(d,J=5.9Hz,1H),3.63(s,3H),3.55-3.45(m,4H),3.35(d,J=6.7Hz,2H),2.86-2.55(m,6H),2.36(s,4H);13C NMR(75MHz,CDCl3-d1)δ:173.54,163.45,161.75,161.42,161.17,156.34,153.67,134.62,133.22,132.15,132.07,131.46,130.36,130.22,129.77,127.83,127.72,127.68,127.61,124.84,124.71,122.83,116.41,116.33,66.57,55.24,53.94,53.56,51.78,30.26,29.56,29.35;LC-MS(ESI)m/z:547.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.06(dd,J=8.7,2.2Hz,1H),7.85(d,J=8.7Hz,1H),7.74-7.47(m,3H),7.37(t,J=7.5Hz,1H),7.25(dd,J=10.6,8.6Hz,1H),4.30(t,J=6.6Hz,1H),3.64(s,3H),3.53-3.46(m,4H),3.35(d,J=6.8Hz,2H),2.89-2.56(m,6H),2.36(s,4H);13C NMR(75MHz,CDCl3-d1)δ173.40,163.21,162.00,161.89,159.85,154.56,153.86,136.19,133.51,132.95,131.61,131.50,130.38,130.28,128.98,128.94,126.92,126.66,124.32,124.28,122.44,119.83,115.98,115.71,65.42,55.26,53.50,52.67,51.93,30.41,29.65,29.61;LC-MS(ESI)m/z:591.90[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.52(dd,J=8.5,2.1Hz,1H),8.38(d,J=2.1Hz,1H),8.22(d,J=8.4Hz,1H),7.64-7.46(m,2H),7.37-7.20(m,2H),6.05-5.91(m,1H),3.66-3.50(m,7H),3.37(dt,J=14.3,5.2Hz,1H),2.81(dt,J=12.0,5.2Hz,1H),2.71–2.40(m,6H),2.42-2.22(m,3H).13C NMR(75MHz,CDCl3-d1)δ173.37,163.30,161.48,161.38,159.94,154.57,153.88,146.17,137.95,131.60,131.49,130.54,130.43,128.17,127.60,127.56,127.08,126.81,125.94,124.26,124.22,123.35,115.98,115.71,65.46,55.26,53.55,52.62,51.89,30.41,29.67,29.61;LC-MS(ESI)m/z:555.60[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.90(d,J=1.8Hz,2H),7.69-7.53(m,2H),7.41-7.31(m,2H),7.29-7.17(m,1H),4.27(dd,J=7.7,5.5Hz,1H),3.61(s,3H),3.30-3.22(m,2H),2.80-2.68(m,3H),2.68-2.52(m,4H),2.45(q,J=7.1Hz,6H),0.90(t,J=7.1Hz,6H);13CNMR(75MHz,CDCl3-d1)δ:173.49,163.48,161.84,161.77,161.52,156.36,153.37,134.73,133.25,132.58,132.39,131.41,130.67,130.46,129.73,127.74,127.62,127.58,127.39,124.68,124.51,122.76,116.45,116.26,55.22,51.83,51.53,47.82,30.37,29.51,29.33,11.51;LC-MS(ESI)m/z:531.6[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.96-7.84(m,2H),7.79(dd,J=8.4,2.5Hz,1H),7.53(dddd,J=16.9,7.6,5.0,1.6Hz,2H),7.28(dtd,J=16.4,7.7,1.4Hz,2H),6.05-5.89(m,1H),3.62(s,2H),3.51(dt,J=14.1,5.2Hz,1H),3.35(dt,J=14.1,5.2Hz,1H),2.84(dt,J=12.2,5.2Hz,1H),2.77-2.60(m,2H),2.66-2.47(m,4H),2.53-2.40(m,2H),2.43-2.24(m,1H),1.01(t,J=7.2Hz,6H);13C NMR(75MHz,CDCl3-d1)δ173.41,163.21,162.00,161.89,159.85,154.56,153.86,136.19,133.43,132.95,131.62,131.52,130.53,130.42,128.86,128.82,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,55.26,51.93,50.88,47.11,30.42,29.65,29.61,11.17;LC-MS(ESI)m/z:575.51[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.49(dd,J=8.5,2.1Hz,1H),8.32(d,J=2.1Hz,1H),8.21(d,J=8.5Hz,1H),7.54(dddd,J=20.4,7.6,5.0,1.7Hz,2H),7.37-7.20(m,2H),4.89(ddd,J=8.2,7.5,0.6Hz,1H),3.62(s,2H),3.47(dt,J=14.1,5.2Hz,1H),3.33(dt,J=14.1,5.2Hz,1H),2.87(dt,J=12.1,5.2Hz,1H),2.79-2.26(m,9H),1.01(t,J=7.2Hz,6H);13C NMR(75MHz,DMSO-d6)δ173.42,163.09,161.48,161.38,159.73,154.51,153.88,146.17,137.95,131.60,131.49,130.49,130.38,128.17,127.60,127.56,127.08,126.81,126.00,124.26,124.22,123.37,115.98,115.71,55.26,51.91,50.88,47.11,30.42,29.67,29.61,11.17;LC-MS(ESI)m/z:541.61[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.92-7.84(m,2H),7.65(td,J=7.6,1.8Hz,1H),7.58(tdd,J=7.5,5.2,1.8Hz,1H),7.42-7.31(m,2H),7.22(dd,J=10.9,8.3Hz,1H),4.28(dd,J=7.7,5.5Hz,1H),3.61(s,3H),3.24-3.06(m,2H),2.78-2.52(m,4H),2.39(tt,J=6.9,4.3Hz,2H),2.18(s,6H),1.79(q,J=7.1Hz,2H);13C NMR(75MHz,CDCl3-d1)δ:173.72,163.68,161.90,161.82,161.54,156.38,153.73,134.21,133.12,132.51,132.36,131.73,130.66,130.48,129.41,127.88,127.60,127.47,127.39,124.63,124.49,122.88,116.47,116.28,58.73,55.48,51.63,45.28,31.91,29.53,29.33,26.74;LC-MS(ESI)m/z:517.14[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.97-7.83(m,2H),7.79(dd,J=8.4,2.5Hz,1H),7.53(dddd,J=16.9,7.6,4.9,1.6Hz,2H),7.28(dtd,J=13.1,7.7,1.4Hz,2H),6.06-5.91(m,1H),3.62(s,3H),3.37-3.12(m,2H),2.70-2.53(m,2H),2.58-2.40(m,2H),2.45-2.24(m,2H),2.21(s,5H),1.94(ddq,J=21.9,13.0,6.5Hz,2H),13C NMR(75MHz,CDCl3-d1)δ173.41,163.21,162.00,161.89,159.85,154.56,153.86,136.19,133.43,132.95,131.57,131.46,130.53,130.42,128.86,128.82,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.72,57.69,55.26,51.89,44.74,30.52,29.65,29.61,27.44;LC-MS(ESI)m/z:560.49[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.48(dd,J=8.5,2.1Hz,1H),8.31(d,J=2.1Hz,1H),8.22(d,J=8.5Hz,1H),7.63-7.45(m,2H),7.37-7.20(m,2H),4.95(t,J=8.1Hz,1H),3.62(s,3H),3.30(dt,J=14.4,6.4Hz,1H),3.15(dt,J=14.4,6.4Hz,1H),2.71-2.26(m,6H),2.21(s,5H),1.91(ddq,J=20.6,13.0,6.5Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.43,163.12,161.48,161.38,159.76,154.59,153.88,146.17,137.96,131.60,131.49,130.51,130.41,128.17,127.29,127.25,127.08,126.81,126.00,124.26,124.22,123.37,115.95,115.68,57.69,55.26,51.91,44.74,30.52,29.65,29.61,27.43;LC-MS(ESI)m/z:527.59[M+H]+。
实施例60:(S)-3-(8-氯-6-(2-氟苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物60)
1H NMR(300MHz,CDCl3-d1)δ:7.96-7.83(m,3H),7.71-7.55(m,3H),7.43-7.32(m,3H),7.23(dd,J=11.0,8.3Hz,2H),4.28(dd,J=7.7,5.5Hz,2H),3.62(s,3H),2.78-2.56(m,11H);13C NMR(75MHz,CDCl3-d1)δ:173.69,163.57,161.84,161.73,161.56,156.48,153.38,134.67,133.55,132.47,132.34,131.73,130.35,130.13,129.57,127.65,127.58,127.37,127.29,124.67,124.61,122.48,116.37,116.24,55.32,53.46,52.78,52.55,51.78,45.84,30.26,29.74,29.36;LC-MS(ESI)m/z:557.18[M+H]+。
实施例61:(S)-3-(8-溴-6-(2-氟苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物61)
1H NMR(300MHz,CDCl3-d1)δ7.96-7.84(m,2H),7.80(dd,J=8.3,2.4Hz,1H),7.54(dddd,J=15.2,7.6,5.0,1.6Hz,2H),7.28(dtd,J=17.6,7.7,1.4Hz,2H),6.06-5.90(m,1H),3.66–3.50(m,4H),3.31(dt,J=14.1,5.2Hz,1H),2.93(dt,J=12.1,5.2Hz,1H),2.72-2.60(m,2H),2.65-2.49(m,4H),2.55-2.40(m,2H),2.43-2.21(m,7H).13C NMR(75MHz,CDCl3-d1)δ173.36,163.19,162.00,161.89,159.83,154.56,153.86,136.38,133.51,132.95,131.61,131.50,130.38,130.28,128.98,128.94,126.92,126.66,124.32,124.28,122.44,119.83,115.98,115.71,55.26,53.62,52.88,52.57,51.93,45.16,30.41,29.67,29.59;LC-MS(ESI)m/z:602.54[M+H]+。
实施例62:(S)-3-(8-硝基-6-(2-氟苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物62)
1H NMR(300MHz,CDCl3-d1)δ8.52(dd,J=8.4,2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.20(d,J=8.5Hz,1H),7.64-7.46(m,2H),7.28(dtd,J=18.3,7.7,1.4Hz,2H),5.98(ddd,J=8.2,7.5,0.6Hz,1H),3.66-3.49(m,4H),3.29(dt,J=14.1,5.2Hz,1H),2.84(dt,J=12.1,5.2Hz,1H),2.80-2.45(m,8H),2.52-2.29(m,5H),2.25(s,3H);13C NMR(75MHz,CDCl3-d1)δ173.36,163.30,161.48,161.38,159.94,154.51,153.88,146.17,138.11,131.60,131.49,130.54,130.43,128.17,127.60,127.56,127.08,126.81,125.94,124.26,124.22,123.35,115.98,115.71,55.26,53.62,52.88,52.57,51.93,45.16,30.41,29.67,29.61;LC-MS(ESI)m/z:568.64[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.94-7.71(m,3H),7.62(tdd,J=7.6,5.3,1.9Hz,1H),7.50-7.25(m,3H),2.63(dt,J=17.0,8.0Hz,2H),2.15-2.09(m,3H),1.94(d,J=15.2Hz,6H),1.86-1.74(m,1H),1.61-1.42(m,2H),1.26(p,J=4.6,3.6Hz,2H);13C NMR(75MHz,CDCl3-d1)δ:173.62,163.43,161.72,161.63,161.53,154.68,153.31,133.68,133.10,132.42,132.23,131.41,130.63,130.48,129.88,127.82,127.79,127.73,127.45,124.68,124.56,123.36,116.38,116.23,55.16,53.81,51.92,45.91,39.48,31.55,29.39,29.25;LC-MS(ESI)m/z:528.63[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.95-7.85(m,2H),7.80(dd,J=8.4,1.9Hz,1H),7.64-7.45(m,2H),7.28(dtd,J=16.4,7.7,1.3Hz,2H),6.05-5.91(m,1H),3.62(s,2H),3.27(p,J=5.8Hz,1H),2.74(ddd,J=12.2,7.8,5.9Hz,2H),2.68-2.51(m,1H),2.58-2.42(m,3H),2.48-2.32(m,2H),2.37-2.29(m,0H),2.29(s,3H),2.04-1.79(m,4H).13C NMR(75MHz,CDCl3-d1)δ173.41,163.21,162.00,161.89,159.85,153.44,153.01,136.19,133.07,132.95,131.60,131.49,130.53,130.42,128.86,128.82,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,55.26,54.28,51.93,45.68,34.94,31.76,29.65,29.61;LC-MS(ESI)m/z:573.50[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.51(dd,J=8.4,1.9Hz,1H),8.40(d,J=1.9Hz,1H),8.22(d,J=8.5Hz,1H),7.55(dddd,J=17.0,7.6,5.0,1.7Hz,2H),7.29(dtd,J=14.3,7.7,1.4Hz,2H),6.06-5.90(m,1H),3.62(s,2H),3.28(p,J=5.8Hz,1H),2.77(ddd,J=12.2,7.8,5.8Hz,2H),2.71-2.24(m,6H),2.29(s,3H),2.06-1.80(m,4H).13C NMR(75MHz,CDCl3-d1)δ173.37,163.09,161.48,161.38,159.73,153.42,153.03,146.17,137.52,131.60,131.49,130.51,130.41,128.17,127.60,127.56,127.08,126.81,126.05,124.26,124.22,123.35,115.98,115.71,55.26,54.28,51.91,45.68,34.92,31.67,29.67,29.61;LC-MS(ESI)m/z:539.60[M+H]+。
实施例66:(S)-3-(8-氯-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物66)
1H NMR(300MHz,CDCl3-d1)δ:7.89(s,2H),7.70-7.53(m,2H),7.42-7.31(m,2H),7.22(dd,J=10.9,8.3Hz,1H),4.35(s,1H),4.27(dd,J=7.8,5.5Hz,1H),3.45(q,J=6.0Hz,2H),3.33(s,4H),3.21-3.03(m,2H),2.80-2.57(m,4H),2.41-2.21(m,10H),1.74(q,J=6.9Hz,2H);13C NMR(75MHz,CDCl3-d1)δ:173.51,163.39,161.74,161.67,161.24,156.51,153.86,134.09,133.33,132.18,132.28,131.50,130.54,130.47,129.88,127.75,127.58,127.72,127.61,124.72,124.66,122.55,116.36,116.02,59.79,57.51,55.23,55.12,52.68,52.08,51.89,31.15,29.43,29.18,27.65;LC-MS(ESI)m/z:602.3[M+H]+。
实施例67:(S)-3-(8-溴-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物67)
1H NMR(300MHz,CDCl3-d1)δ7.94-7.77(m,3H),7.54(dddd,J=8.5,7.5,5.0,1.4Hz,2H),7.37-7.18(m,2H),6.07-5.90(m,1H),4.26(t,J=7.3Hz,1H),3.66–3.45(m,4H),3.36-3.12(m,2H),2.87(t,J=5.3Hz,3H),2.72-2.53(m,7H),2.54(dt,J=3.6,1.8Hz,1H),2.56-2.42(m,2H),2.49-2.31(m,1H),2.36-2.22(m,1H),1.88(pd,J=6.5,4.1Hz,2H).13C NMR(75MHz,CDCl3-d1)δ173.40,163.37,162.00,161.89,160.00,154.56,153.86,136.38,133.59,132.95,131.61,131.50,130.39,130.28,128.98,128.94,126.93,126.66,124.21,124.17,122.44,119.76,115.91,115.64,59.24,58.71,55.29,55.11,52.38,52.36,51.93,30.47,29.67,29.59,27.31;LC-MS(ESI)m/z:645.59[M+H]+。
实施例68:(S)-3-(8-硝基-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物68)
1H NMR(300MHz,CDCl3-d1)δ8.52(dd,J=8.4,1.9Hz,1H),8.41(d,J=1.8Hz,1H),8.22(d,J=8.3Hz,1H),7.63-7.48(m,2H),7.28(dtd,J=21.6,7.7,1.4Hz,2H),6.04-5.89(m,1H),4.27(t,J=7.3Hz,1H),3.66-3.49(m,4H),3.35(dt,J=14.4,6.4Hz,1H),3.19(dt,J=14.4,6.4Hz,1H),2.87(t,J=5.3Hz,3H),2.72-2.58(m,4H),2.64-2.44(m,6H),2.47-2.23(m,2H),1.85(ddq,J=29.5,13.0,6.5Hz,2H).13C NMR(75MHz,CDCl3-d1)δ173.36,163.30,161.56,161.45,159.94,154.60,153.88,146.16,138.12,131.61,131.50,130.46,130.35,128.16,127.78,127.74,127.08,126.81,125.94,124.35,124.31,123.35,115.91,115.64,59.24,58.71,55.26,55.11,52.44,52.41,51.94,30.45,29.67,29.59,27.31;LC-MS(ESI)m/z:612.69[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.47(d,J=8.9Hz,1H),7.87(dd,J=8.9,2.5Hz,1H),7.69-7.42(m,3H),7.41-7.31(m,2H),7.25(dd,J=10.8,8.3Hz,1H),5.19(d,J=13.4Hz,1H),5.03(d,J=13.4Hz,1H),4.33(dd,J=8.7,5.1Hz,1H),3.32(s,1H),2.88-2.54(m,7H),2.49-2.39(m,1H),1.24(s,1H);13C NMR(75MHz,CDCl3-d1)δ:173.44,163.43,161.90,161.83,161.34,153.79,153.74,134.22,133.01,132.43,132.37,131.35,130.53,130.46,129.92,127.75,127.65,127.51,127.49,124.71,124.61,123.02,116.42,116.01,66.71,58.33,55.58,51.74,43.81,29.41,29.17;LC-MS(ESI)m/z:531.2[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.97-7.83(m,2H),7.81(dd,J=8.4,2.5Hz,1H),7.53(dddd,J=16.9,7.6,5.0,1.6Hz,2H),7.36-7.19(m,2H),6.04-5.90(m,1H),4.24(d,J=13.4Hz,1H),3.99(d,J=13.4Hz,1H),3.75-3.56(m,7H),2.93(ddd,J=12.7,6.5,5.5Hz,2H),2.80-2.40(m,5H),2.41-2.23(m,1H).13C NMR(75MHz,CDCl3-d1)δ173.41,163.21,162.00,161.89,159.85,153.86,149.17,136.19,133.62,132.95,131.62,131.52,130.53,130.42,128.86,128.82,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,66.31,58.28,55.26,52.38,51.93,29.65,29.61;LC-MS(ESI)m/z:575.47[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.50(dd,J=8.4,2.1Hz,1H),8.33(d,J=2.1Hz,1H),8.23(d,J=8.5Hz,1H),7.65-7.46(m,2H),7.29(dtd,J=14.4,7.7,1.4Hz,2H),4.75(t,J=8.2Hz,1H),4.20(d,J=13.4Hz,1H),4.06(d,J=13.4Hz,1H),3.74-3.54(m,7H),2.93(ddd,J=12.7,6.8,5.3Hz,2H),2.73(ddd,J=12.7,6.9,5.2Hz,2H),2.72–2.48(m,2H),2.53-2.27(m,2H).13C NMR(75MHz,CDCl3-d1)δ173.37,163.09,161.48,161.38,159.73,153.86,149.17,146.17,137.95,131.60,131.49,130.51,130.41,128.17,127.65,127.61,127.08,126.81,126.05,124.26,124.22,123.35,115.98,115.71,66.32,58.28,55.26,52.43,51.91,29.67,29.61;LC-MS(ESI)m/z:541.57[M+H]+。
实施例72:(S)-3-(8-氯-6-(2-氟苯基)-1-((((4-苯基哌嗪-1-基)甲基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物72)
1H NMR(300MHz,CDCl3-d1)δ:8.47(d,J=8.9Hz,1H),7.92-7.83(m,1H),7.68-7.51(m,2H),7.40-7.30(m,2H),7.29-7.14(m,3H),6.93(t,J=9.3Hz,2H),6.76(t,J=7.2Hz,1H),5.28(d,J=13.4Hz,1H),5.10(d,J=13.4Hz,1H),4.37-4.23(m,1H),3.33(s,2H),3.13(t,J=4.9Hz,3H),3.02-2.85(m,4H),2.82-2.56(m,4H),2.45(dd,J=10.1,6.7Hz,1H);13CNMR(75MHz,CDCl3-d1)δ:173.46,163.40,161.84,161.81,161.33,153.79,153.34,150.64,134.18,133.22,132.16,132.12,131.39,130.49,130.33,129.94,129.11,127.75,127.63,127.53,127.49,124.63,124.45,123.18,118.61,116.59,116.44,116.31,58.36,55.28,51.91,51.72,48.41,29.39,29.19;LC-MS(ESI)m/z:605.22[M+H]+。
实施例73:(S)-3-(8-溴-6-(2-氟苯基)-1-((((4-苯基哌嗪-1-基)甲基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物73)
1H NMR(300MHz,CDCl3-d1)δ:7.87(d,J=2.4Hz,1H),7.80-7.62(m,2H),7.57(dddd,J=7.6,6.7,3.9,1.4Hz,2H),7.29(td,J=7.5,1.4Hz,1H),7.23-7.11(m,3H),6.90-6.81(m,3H),6.02-5.87(m,1H),4.34-4.09(m,2H),3.76(s,2H),3.34(ddd,J=11.8,6.4,4.2Hz,2H),3.22(ddd,J=11.8,6.5,4.2Hz,2H),2.76(ddd,J=11.7,6.4,4.2Hz,2H),2.61-2.52(m,1H),2.60-2.32(m,4H),2.41-2.15(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.34,163.22,162.45,161.76,160.45,153.56,151.31,149.21,136.45,133.70,132.32,131.37,131.67,130.78,130.43,129.23,128.68,128.45,126.57,126.34,124.23,124.12,122.45,119.56,118.50,116.12,115.91,115.64,58.79,55.33,51.53,51.74,48.44,29.32,29.52;LC-MS(ESI)m/z:649.58[M+H]+。
实施例74:(S)-3-(8-硝基-6-(2-氟苯基)-1-((((4-苯基哌嗪-1-基)甲基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物74)
1H NMR(300MHz,CDCl3-d1)δ:8.48-8.37(m,2H),8.00(d,J=8.2Hz,1H),7.56-7.38(m,2H),7.23(td,J=7.6,1.3Hz,1H),7.14-7.01(m,3H),6.88-6.73(m,3H),4.56(ddd,J=8.2,7.2,0.7Hz,1H),4.13(d,J=13.4Hz,1H),4.01(d,J=13.3Hz,1H),3.43(s,2H),3.21(ddd,J=11.8,6.3,4.2Hz,2H),3.01(ddd,J=11.8,6.5,4.2Hz,2H),2.74(ddd,J=11.8,6.4,4.2Hz,2H),2.65-2.54(m,1H),2.60-2.47(m,2H),2.53-2.42(m,1H),2.48-2.33(m,1H),2.34-2.16(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.34,163.54,161.56,161.36,160.78,153.98,151.45,149.54,146.16,137.22,131.51,131.65,130.54,130.76,129.17,128.20,127.55,127.12,127.01,126.71,126.02,124.43,124.23,123.45,118.08,116.11,115.87,115.45,58.56,55.68,51.45,51.67,48.44,29.78,29.68;LC-MS(ESI)m/z:615.68[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.93-7.81(m,2H),7.66(dd,J=6.0,3.3Hz,1H),7.53(dq,J=6.1,4.0,3.4Hz,2H),7.51-7.42(m,1H),7.19(d,J=2.3Hz,1H),4.31(dd,J=7.9,5.5Hz,1H),3.26-3.07(m,2H),2.79-2.57(m,3H),1.11(ddt,J=10.7,7.5,3.7Hz,1H),0.58-0.45(m,2H),0.34-0.21(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.43,162.78,156.44,153.88,137.85,134.75,133.44,133.26,131.45,131.39,129.69,129.45,128.57,128.38,127.21,122.56,54.73,51.82,38.13,29.58,29.14,11.63,6.31;LC-MS(ESI)m/z:503.0[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.81(d,J=2.4Hz,1H),7.74(d,J=8.4Hz,1H),7.70-7.55(m,2H),7.53-7.41(m,2H),7.32(ddd,J=7.8,5.1,3.8Hz,1H),4.79-4.50(m,1H),3.70(s,2H),3.43(dd,J=13.5,4.8Hz,1H),3.13(dd,J=13.6,4.8Hz,1H),2.71-2.43(m,3H),2.53-2.28(m,1H),1.50-1.33(m,1H),1.42-1.14(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.45,162.31,154.35,153.57,138.87,136.17,134.12,133.45,132.28,130.98,129.34,129.47,128.38,126.68,122.44,119.76,55.43,51.67,37.43,29.81,29.62,13.54,6.60;LC-MS(ESI)m/z:545.88[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.49(d,J=2.1Hz,1H),8.37(dd,J=8.5,2.1Hz,1H),8.02(d,J=8.5Hz,1H),7.67-7.48(m,3H),7.30(ddd,J=8.0,6.9,1.7Hz,1H),4.67-4.43(m,1H),3.34(s,2H),3.10-3.01(m,1H),2.90-2.85(m,1H),2.59-2.33(m,2H),2.39-2.23(m,1H),2.20-2.05(m,1H),1.46-1.21(m,5H);13C NMR(75MHz,CDCl3-d1)δ:173.50,162.65,154.76,153.55,146.81,138.09,137.32,134.46,130.71,129.98,128.12,128.23,128.46,126.87,125.67,123.75,55.43,51.56,37.56,29.65,29.23,13.45,6.76;LC-MS(ESI)m/z:511.98[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.94-7.80(m,2H),7.69-7.60(m,1H),7.58-7.48(m,2H),7.45(qd,J=5.5,2.5Hz,1H),7.20(d,J=2.4Hz,1H),4.33(dd,J=7.9,5.4Hz,1H),4.15-3.96(m,2H),3.60(s,3H),3.21(t,J=2.5Hz,1H),2.78-2.54(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.25,162.95,156.03,153.88,137.76,134.79,133.90,133.06,131.54,131.29,129.88,129.65,128.82,128.67,127.31,123.03,79.13,72.19,54.94 51.94,29.57,29.24,20.22;LC-MS(ESI)m/z:485.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.97(d,J=2.5Hz,1H),7.76(d,J=8.4Hz,1H),7.55(dd,J=8.5,2.4Hz,1H),7.48-7.31(m,3H),7.18(ddd,J=7.8,5.7,3.2Hz,1H),4.67-4.52(m,1H),4.01(dd,J=12.3,3.0Hz,1H),3.89(dd,J=12.4,3.0Hz,1H),3.71(s,2H),2.65-2.32(m,3H),2.29-2.05(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.12,162.65,154.30,153.09,138.23,136.76,134.09,133.19,132.65,130.65,129.45,129.76,128.78,126.13,122.56,119.73,79.01,72.66,55.11,51.70,29.57,29.76,20.41;LC-MS(ESI)m/z:529.87[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.49-8.34(m,2H),8.09(d,J=8.4Hz,1H),7.55-7.40(m,3H),7.30(ddd,J=7.7,7.2,1.7Hz,1H),4.89(t,J=8.0Hz,1H),4.12(dd,J=12.4,3.0Hz,1H),3.89(dd,J=12.4,3.0Hz,1H),3.60(s,2H),2.87-2.63(m,2H),2.49-2.33(m,1H),2.37-2.29(m,1H),2.21(t,J=3.0Hz,1H);13C NMR(75MHz,CDCl3-d1)δ:173.50,162.06,154.02,153.88,146.01,138.70,137.82,134.63,130.41,129.65,128.39,128.36,128.20,126.67,125.98,123.39,79.06,72.67,55.11,51.90,29.70,29.62,20.40;LC-MS(ESI)m/z:495.97[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.92(d,J=1.8Hz,2H),7.72-7.64(m,1H),7.58-7.46(m,3H),7.27-7.16(m,1H),4.34(t,J=6.6Hz,1H),3.62(s,3H),3.55(t,J=4.5Hz,4H),3.43(s,2H),2.81-2.67(m,2H),2.63(t,J=6.6Hz,4H),2.40(s,4H);13C NMR(75MHz,CDCl3-d1)δ:173.34,162.85,156.47,153.39,137.34,134.56,133.33,133.10,131.49,131.36,129.24,129.11,128.87,128.59,127.39,122.55,66.23,54.88,53.99,53.54,51.78,30.35,29.88,29.68;LC-MS(ESI)m/z:564.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.04(dd,J=8.7,2.3Hz,1H),7.83(d,J=8.7Hz,1H),7.68(dd,J=6.0,3.3Hz,1H),7.60-7.45(m,3H),7.33(d,J=2.2Hz,1H),4.33(t,J=6.6Hz,1H),3.62(s,3H),3.56-3.51(m,4H),3.39(d,J=6.2Hz,2H),2.82-2.66(m,2H),2.62(t,J=6.7Hz,4H),2.45-2.32(m,4H);13C NMR(75MHz,CDCl3-d1)δ:173.54,162.56,154.86,153.45,138.96,136.11,134.57,133.69,132.98,130.01,129.24,129.30,128.45,126.35,122.57,119.97,65.12,55.45,53.55,52.57,51.98,30.65,29.80,29.89;LC-MS(ESI)m/z:606.7[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.56-8.43(m,2H),8.13(d,J=8.3Hz,1H),7.59-7.47(m,1H),7.52-7.38(m,2H),7.37-7.25(m,1H),5.11-4.96(m,1H),3.54-3.33(m,8H),3.19(dt,J=14.1,5.2Hz,1H),2.89-2.65(m,3H),2.57-2.32(m,6H),2.20-2.11(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.11,162.45,154.44,153.90,146.22,138.67,137.48,135.92,130.33,129.68,128.45,128.85,128.68,126.15,125.68,123.42,65.82,55.15,53.47,52.98,51.75,30.09,29.61,29.01;LC-MS(ESI)m/z:571.05[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.06-7.74(m,2H),7.66(s,1H),7.49(d,J=27.1Hz,3H),7.19(s,1H),3.60(s,3H),3.32(s,2H),2.69(s,5H),0.93(s,6H);13C NMR(75MHz,CDCl3-d1)δ:173.45,162.23,156.68,153.44,137.88,134.21,133.45,133.88,131.73,131.46,129.96,129.78,128.75,128.53,127.38,122.45,54.59,51.83,51.67,47.65,30.57,29.99,29.43,11.87;LC-MS(ESI)m/z:548.1[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.95(d,J=2.4Hz,1H),7.79-7.61(m,2H),7.55-7.40(m,3H),7.28(ddd,J=7.7,6.4,2.4Hz,1H),4.76-4.62(m,1H),3.68-3.51(m,3H),3.43(dt,J=14.2,5.2Hz,1H),2.87(dt,J=12.1,5.2Hz,1H),2.79-2.56(m,3H),2.63-2.46(m,4H),2.52-2.39(m,1H),2.43-2.24(m,1H),1.03(t,J=7.2Hz,6H);13C NMR(75MHz,CDCl3-d1)δ:173.47,162.55,154.56,153.88,138.65,136.19,134.57,133.30,132.51,130.41,129.80,129.31,128.32,126.70,122.48,119.74,55.12,51.92,50.90,47.11,30.42,29.81,29.62,11.17;LC-MS(ESI)m/z:590.97[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.54(dd,J=8.5,2.1Hz,1H),8.41(d,J=2.1Hz,1H),8.29(d,J=8.3Hz,1H),7.60(dd,J=7.7,1.5Hz,1H),7.56-7.39(m,2H),7.31(td,J=7.5,1.4Hz,1H),5.98(ddd,J=8.2,7.3,0.7Hz,1H),3.76-3.56(m,4H),3.33(dt,J=14.3,5.2Hz,1H),2.81(dt,J=12.1,5.2Hz,1H),2.63-2.49(m,8H),2.32-2.14(m,1H),1.01(t,J=7.3Hz,6H);13C NMR(75MHz,CDCl3-d1)δ:173.23,162.11,154.63,153.23,146.87,138.86,137.98,134.58,130.23,129.96,128.42,128.18,128.49,126.26,125.86,123.14,55.75,51.87,50.97,47.31,30.65,29.43,29.61,11.32;LC-MS(ESI)m/z:557.07[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.93-7.80(m,2H),7.66(dd,J=5.9,3.4Hz,1H),7.53(dq,J=6.1,3.9,3.5Hz,2H),7.50-7.42(m,1H),7.19(d,J=2.3Hz,1H),4.31(dd,J=7.9,5.5Hz,1H),3.60(s,3H),3.31-3.23(m,1H),3.16(dt,J=13.4,7.2Hz,1H),2.78-2.57(m,4H),2.36(s,2H),2.17(s,6H),1.86-1.73(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.98,162.36,156.78,153.43,137.67,134.84,133.56,133.42,131.86,131.46,129.86,129.08,128.68,128.49,127.17,122.98,58.03,54.10,51.27,45.55,31.36,29.71,29.59,26.59;LC-MS(ESI)m/z:534.07[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.99(d,J=8.4Hz,1H),7.87-7.70(m,2H),7.67(dd,J=7.6,1.8Hz,1H),7.56(dd,J=7.6,1.6Hz,1H),7.39(dtd,J=23.1,7.4,1.7Hz,2H),6.01-5.91(m,1H),3.65(s,3H),3.38(dt,J=14.4,6.4Hz,1H),3.10(dt,J=14.4,6.5Hz,1H),2.67-2.34(m,6H),2.22(s,5H),2.01(dp,J=12.9,6.4Hz,1H),1.88(dp,J=12.8,6.4Hz,1H);13C NMR(75MHz,CDCl3-d1)δ:173.14,162.23,154.50,153.43,138.22,136.18,134.79,133.26,132.96,130.16,129.09,129.34,128.98,126.12,122.43,119.21,57.64,55.86,51.43,44.53,30.15,29.70,29.34,27.78;LC-MS(ESI)m/z:576.92[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.58(dd,J=8.5,2.1Hz,1H),8.43(d,J=2.1Hz,1H),8.34(d,J=8.5Hz,1H),7.55(dd,J=7.7,1.4Hz,1H),7.50–7.38(m,2H),7.32(td,J=7.5,1.5Hz,1H),4.99(t,J=8.1Hz,1H),3.61(s,3H),3.26–3.04(m,2H),2.83–2.37(m,6H),2.31(s,5H),1.95(ddt,J=17.5,12.8,6.3Hz,2H);13C NMR(75MHz,CDCl3-d1)δ:173.14,162.40,154.60,153.77,146.41,138.33,137.69,134.87,130.44,129.82,128.58,128.69,127.77,126.86,125.93,123.39,57.73,55.26,51.98,44.99,30.58,29.88,29.09,27.54;LC-MS(ESI)m/z:543.09[M+H]+。
实施例90:(S)-3-(8-氯-6-(2-氯苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物90)
1H NMR(300MHz,CDCl3-d1)δ:7.91(dd,J=8.7,2.4Hz,1H),7.84(d,J=8.7Hz,1H),7.71-7.63(m,1H),7.59-7.50(m,2H),7.50-7.41(m,1H),7.21(d,J=2.4Hz,1H),4.32(dd,J=7.9,5.5Hz,1H),3.60(s,3H),2.92-2.56(m,10H);13C NMR(75MHz,CDCl3-d1)δ:173.76,162.91,156.09,153.49,137.91,134.24,133.76,133.42,131.90,131.11,129.46,129.36,128.87,128.71,127.90,122.23,54.29,53.70,52.40,52.22,51.53,45.66,30.98,29.56,29.29;LC-MS(ESI)m/z:573.19[M+H]+。
实施例91:(S)-3-(8-溴-6-(2-氯苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物91)
1H NMR(300MHz,CDCl3-d1)δ:8.03-7.87(m,2H),7.86(dd,J=8.3,2.4Hz,1H),7.60(ddd,J=7.7,5.3,1.6Hz,2H),7.42(td,J=7.5,1.7Hz,1H),7.32(td,J=7.6,1.5Hz,1H),6.10-5.98(m,1H),3.69-3.56(m,4H),3.33(dt,J=14.2,5.2Hz,1H),2.90(dt,J=12.1,5.2Hz,1H),2.78-2.33(m,13H),2.36-2.26(s,3H);13C NMR(75MHz,CDCl3-d1)δ:173.23,162.76,154.34,153.67,138.98,136.34,134.59,133.16,132.90,130.46,129.51,129.33,128.40,126.10,122.21,119.70,55.37,53.48,52.69,52.16,51.95,45.17,30.34,29.11,29.60;LC-MS(ESI)m/z:617.99[M+H]+。
实施例92:(S)-3-(8-硝基-6-(2-氯苯基)-1-((2-(4-甲基哌嗪-1-基)乙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物92)
1H NMR(300MHz,CDCl3-d1)δ:8.56(dd,J=7.2,1.5Hz,1H),8.33(d,J=1.5Hz,1H),7.87(d,J=7.7Hz,1H),7.69-7.59(m,1H),7.56-7.33(m,3H),5.95-5.83(m,1H),3.56(s,3H),3.50-3.28(m,2H),2.88-2.60(m,2H),2.67-2.49(m,7H),2.55-2.45(m,4H),2.50-2.42(m,1H),2.42-2.29(m,0H),2.30(s,3H);13C NMR(75MHz,CDCl3-d1)δ:173.36,162.07,154.51,153.88,146.14,138.72,137.95,134.98,130.33,129.65,128.27,128.25,128.17,126.71,125.83,123.35,55.10,53.62,52.88,52.57,51.93,45.16,30.41,29.67,29.61;LC-MS(ESI)m/z:584.19[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.92-7.78(m,2H),7.70-7.60(m,1H),7.58-7.41(m,3H),7.18(d,J=2.4Hz,1H),4.31(dd,J=7.8,5.5Hz,1H),3.36(d,J=18.0Hz,4H),2.79-2.54(m,5H),2.13(s,3H),2.10-1.92(m,3H),1.90-1.79(m,1H),1.66(dtd,J=13.2,10.2,9.7,3.5Hz,1H),1.51(dtd,J=13.8,10.3,3.8Hz,1H),1.24(s,1H),1.19-0.97(m,1H);13CNMR(75MHz,CDCl3-d1)δ:173.56,162.78,154.34,153.98,137.09,134.34,133.39,133.14,131.98,131.01,129.84,129.37,128.81,128.58,127.23,123.67,54.45,53.76,51.43,45.98,39.09,31.34,29.71,29.01;LC-MS(ESI)m/z:544.17[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.02-7.93(m,1H),7.87-7.74(m,2H),7.68-7.57(m,1H),7.53-7.37(m,3H),5.75(t,J=8.3Hz,1H),3.74(p,J=4.3Hz,1H),2.95(ddd,J=12.6,7.7,5.0Hz,2H),2.81-2.69(m,2H),2.72-2.64(m,1H),2.67-2.52(m,1H),2.38-2.22(m,2H),2.25(s,2H),2.11-1.94(m,2H),1.76-1.60(m,2H);13C NMR(75MHz,CDCl3-d1)δ173.44,162.92,154.83,153.07,136.68,136.32,134.54,132.69,130.92,129.67,129.29,128.62,126.95,122.39,118.51,55.15,52.59,51.85,45.28,39.32,30.13,29.31,29.03;LC-MS(ESI)m/z:589.07[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.65(dd,J=8.9,2.0Hz,1H),8.44(d,J=2.0Hz,1H),8.20(d,J=8.9Hz,1H),7.68-7.52(m,1H),7.53-7.35(m,3H),5.75(t,J=8.3Hz,1H),3.76(p,J=4.3Hz,1H),2.92(ddd,J=12.6,7.7,5.0Hz,2H),2.82-2.63(m,2H),2.73-2.64(m,1H),2.67-2.52(m,1H),2.41-2.32(m,2H),2.24(s,2H),2.11-1.95(m,2H),1.76-1.60(m,2H).13C NMR(75MHz,CDCl3-d1)δ173.44,162.54,154.39,153.21,145.72,137.91,137.16,134.54,130.92,129.44,129.27,128.61,128.47,126.86,125.17,123.04,55.05,52.59,51.85,45.22,39.42,30.26,29.38,29.04;LC-MS(ESI)m/z:556.15[M+H]+。
实施例96:(S)-3-(8-氯-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物96)
1H NMR(300MHz,CDCl3-d1)δ:7.93-7.84(m,2H),7.74-7.65(m,1H),7.58-7.50(m,2H),7.50-7.47(m,1H),7.15(d,J=2.3Hz,1H),4.33-4.26(m,2H),3.47(q,J=5.9Hz,2H),3.43-3.35(m,0H),3.31(s,2H),3.26(dt,J=13.8,7.0Hz,1H),3.12(dt,J=13.4,7.2Hz,1H),2.78-2.57(m,3H),2.32(s,10H),1.90-1.71(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.23,162.34,156.65,153.22,137.74,134.46,133.56,133.06,131.88,131.72,129.74,129.36,128.80,128.55,127.38,122.21,59.43,57.76,55.63,54.52,52.37,52.27,51.28,31.15,29.36,29.27,27.46;LC-MS(ESI)m/z:617.23[M+H]+。
实施例97:(S)-3-(8-溴-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物97)
1H NMR(300MHz,CDCl3-d1)δ8.02-7.92(m,1H),7.87-7.73(m,2H),7.68-7.57(m,1H),7.53-7.37(m,3H),5.75(t,J=8.3Hz,1H),4.11(t,J=6.3Hz,1H),3.62(s,2H),3.60-3.45(m,2H),3.24(td,J=6.9,1.9Hz,2H),2.78-2.54(m,2H),2.60-2.52(m,1H),2.56-2.43(m,2H),2.52-2.45(m,1H),2.29-2.35(m,6H),2.40-2.21(m,2H),1.85(tt,J=6.9,5.8Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.41,162.97,156.25,153.66,136.68,136.32,134.34,134.42,132.59,130.92,129.67,129.26,128.51,126.45,122.37,118.53,59.43,57.28,55.15,54.51,52.52,51.92,51.75,30.28,29.37,29.07,27.65;LC-MS(ESI)m/z:662.13[M+H]+。
实施例98:(S)-3-(8-硝基-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物98)
1H NMR(300MHz,CDCl3-d1)δ8.65(dd,J=8.9,2.0Hz,1H),8.46(d,J=2.0Hz,1H),8.20(d,J=8.9Hz,1H),7.67-7.66(m,1H),7.53-7.34(m,3H),5.75(t,J=8.3Hz,1H),4.11(t,J=6.3Hz,1H),3.65(s,2H),3.63–3.55(m,2H),3.24(td,J=6.9,1.9Hz,2H),2.78-2.56(m,2H),2.60-2.51(m,1H),2.56-2.42(m,3H),2.49-2.34(m,7H),2.44-2.35(m,1H),2.39-2.18(m,2H),1.81(tt,J=6.9,5.8Hz,2H);13C NMR(75MHz,CDCl3-d1)δ173.44,162.54,156.32,153.82,145.72,138.32,137.06,134.54,130.92,129.41,129.27,128.61,128.42,126.96,125.17,123.04,59.43,57.27,55.05,54.51,52.52,51.92,51.85,30.28,29.37,29.07,27.55;LC-MS(ESI)m/z:629.20[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.42(d,J=8.8Hz,1H),7.86(dd,J=8.8,2.5Hz,1H),7.70-7.60(m,1H),7.58-7.51(m,2H),7.51-7.42(m,1H),7.16(d,J=2.4Hz,1H),5.21-5.08(m,2H),4.38(dd,J=8.6,5.2Hz,1H),3.60(s,3H),3.32(s,1H),2.88-2.54(m,7H),2.48-2.38(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.36,162.28,153.47,153.28,137.19,134.03,133.47,133.19,131.63,131.57,129.72,129.56,128.86,128.55,127.05,123.53,66.32,58.17,54.59,51.73,43.82,29.47,29.18;LC-MS(ESI)m/z:547.34[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.93(dd,J=1.9,0.7Hz,1H),7.87-7.74(m,2H),7.64-7.51(m,1H),7.53-7.37(m,3H),5.75(t,J=8.3Hz,1H),4.08(d,J=3.6Hz,2H),3.53(s,3H),3.69-3.52(m,4H),2.68-2.52(m,2H),2.48-2.46(m,4H),2.38-2.29(m,1H),2.33-2.21(m,1H).13C NMR(75MHz,CDCl3-d1)δ173.44,162.92,153.77,153.55,137.68,136.38,134.61,134.54,132.69,130.92,129.73,129.21,128.61,126.95,122.30,118.53,66.63,56.98,55.05,51.65,46.16,29.48,29.27;LC-MS(ESI)m/z:591.01[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.65(dd,J=9.0,2.1Hz,1H),8.46(d,J=2.2Hz,1H),8.20(d,J=8.9Hz,1H),7.67-7.56(m,1H),7.53-7.37(m,3H),5.72(t,J=8.3Hz,1H),4.08(d,J=3.6Hz,2H),3.63(s,3H),3.69-3.54(m,4H),2.72-2.57(m,2H),2.58-2.42(m,4H),2.38-2.25(m,1H),2.33-2.18(m,1H);13C NMR(75MHz,CDCl3-d1)δ173.44,162.54,153.83,153.78,145.72,138.23,137.06,134.57,130.82,129.44,129.37,128.64,128.47,126.96,125.17,123.04,66.63,56.91,55.05,51.82,46.16,29.38,29.06;LC-MS(ESI)m/z:558.13[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.97-7.83(m,2H),7.57-7.40(m,6H),4.23(dd,J=7.6,5.5Hz,1H),3.63(s,3H),2.82-2.53(m,7H);13C NMR(75MHz,CDCl3-d1)δ:173.47,166.48,153.48,153.37,139.58,133.75,133.42,132.62,130.46,130.27,128.69,128.43,128.12,122.65,55.63,51.73,29.83,29.07,16.74;LC-MS(ESI)m/z:427.06[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.82-7.70(m,2H),7.66-7.54(m,2H),7.53(d,J=8.1Hz,1H),7.52–7.43(m,2H),7.48–7.39(m,1H),5.64(t,J=8.3Hz,1H),2.72(s,3H),2.74-2.51(m,2H),2.38-2.24(m,1H),2.33-2.18(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.44,166.20,153.33,152.80,138.56,136.32,133.69,133.29,129.80,129.08,128.49,128.41,122.38,118.45,55.26,51.82,29.38,29.06,16.60;LC-MS(ESI)m/z:472.04[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.61(dd,J=8.9,2.1Hz,1H),8.59(d,J=2.2Hz,1H),8.12(d,J=9.0Hz,1H),7.69-7.66(m,2H),7.55-7.43(m,2H),7.48-7.34(m,1H),5.64(t,J=8.3Hz,1H),2.72(s,3H),2.78-2.52(m,2H),2.38-2.23(m,1H),2.33-2.18(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.44,166.07,153.35,153.07,145.66,138.78,137.34,129.81,128.93,128.42,128.42,128.42,125.72,123.07,55.32,51.81,29.34,29.16,16.62;LC-MS(ESI)m/z:438.12[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.92(d,J=2.5Hz,2H),7.52-7.42(m,6H),4.23(t,J=6.4Hz,1H),3.63(s,3H),3.43(t,J=4.6Hz,4H),2.75-2.53(m,6H),2.33-2.27(m,3H),2.09(s,1H);13C NMR(75MHz,CDCl3-d1)δ:172.36,166.71,156.82,153.23,139.62,133.81,133.53,132.55,130.71,130.52,128.64,128.37,128.10,122.51,66.73,55.87,53.44,53.31,51.34,30.36,29.52,29.37;LC-MS(ESI)m/z:526.19[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:8.09(d,J=10.9Hz,1H),7.87(d,J=8.7Hz,1H),7.61-7.48(m,6H),4.25(t,J=6.5Hz,1H),3.65(s,3H),3.56-3.39(m,6H),2.81-2.58(m,6H),2.34(s,4H);13C NMR(75MHz,CDCl3-d1)δ173.34,165.99,155.26,153.74,138.36,136.51,134.19,133.09,129.84,129.04,128.59,128.40,122.38,118.45,66.51,55.23,54.17,52.82,51.81,30.47,29.32,29.08;LC-MS(ESI)m/z:572.00[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.61(dd,J=8.9,2.1Hz,1H),8.49(d,J=2.2Hz,1H),8.12(d,J=9.0Hz,1H),7.69-7.56(m,2H),7.55-7.43(m,2H),7.48-7.39(m,1H),5.61(t,J=8.3Hz,1H),3.64-3.43(m,7H),3.35(td,J=6.3,0.8Hz,2H),2.73-2.76(m,3H),2.61-2.41(m,4H),2.41-2.14(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.44,166.04,155.51,153.77,145.66,138.78,137.67,129.60,128.98,128.49,128.46,128.42,125.71,123.07,66.23,55.42,54.12,52.79,51.85,30.47,29.35,29.07;LC-MS(ESI)m/z:537.19[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.97-7.85(m,2H),7.57-7.40(m,6H),4.23(dd,J=7.6,5.5Hz,1H),3.61(s,2H),3.11(td,J=7.2,2.7Hz,2H),2.82-2.54(m,4H),2.24-2.16(m,2H),2.02(s,6H),1.69(dq,J=14.5,7.1Hz,2H),1.27-1.11(m,1H);13C NMR(75MHz,CDCl3-d1)δ:173.57,166.82,156.35,153.86,139.08,133.50,133.02,132.63,130.71,130.21,128.66,128.68,128.42,122.91,58.46,55.26,51.91,45.36,31.13,29.46,29.28,26.47;LC-MS(ESI)m/z:499.56[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.82-7.70(m,2H),7.66-7.39(m,7H),5.64(t,J=8.3Hz,1H),3.62(s,3H),3.23(d,J=12.4Hz,1H),2.78–2.61(m,1H),2.67-2.57(m,1H),2.57(t,J=5.7Hz,2H),2.38-2.29(m,1H),2.33-2.14(m,1H),1.92-1.74(m,2H);13C NMR(75MHz,CDCl3-d1)δ173.44,165.99,156.25,153.75,138.56,136.31,134.08,133.09,129.80,129.05,128.49,128.40,122.32,118.45,58.21,55.26,51.85,44.82,30.04,29.35,29.08,26.61;LC-MS(ESI)m/z:543.11[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.63(dd,J=8.9,2.1Hz,1H),8.49(d,J=2.2Hz,1H),8.11(d,J=9.0Hz,1H),7.69-7.56(m,2H),7.55-7.39(m,3H),5.64(t,J=8.3Hz,1H),3.63(s,3H),3.23(d,J=12.4Hz,1H),2.78-2.64(m,1H),2.67-2.55(m,1H),2.57(t,J=5.7Hz,2H),2.38-2.23(m,1H),2.33-2.28(m,1H),1.92-1.74(m,2H);13C NMR(75MHz,CDCl3-d1)δ173.44,166.04,156.33,153.75,145.66,138.78,137.81,129.81,128.98,128.49,128.43,128.42,125.61,123.07,58.21,55.42,51.85,44.72,30.08,29.33,29.07,26.61;LC-MS(ESI)m/z:509.19[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ:7.82(d,J=8.2Hz,1H),7.87(s,2H),7.67-7.60(m,2H),7.51-7.40(m,4H),5.83(d,J=8.5Hz,2H),5.75(t,J=8.3Hz,1H),2.74-2.56(m,2H),2.39-2.23(m,2H);13C NMR(75MHz,CDCl3-d1)δ:173.42,161.14,157.56,157.13,154.10,137.57,134.72,134.19,132.66,131.29,131.26,129.70,129.62,128.68,128.46,127.31,123.05,66.32,66.28,58.25,51.94,29.93,29.01;LC-MS(ESI)m/z:557.34[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ7.99(dd,J=1.9,0.7Hz,1H),7.87(s,2H),7.84-7.64(m,2H),7.67-7.53(m,1H),7.53-7.35(m,3H),5.83(d,J=8.4Hz,2H),5.75(t,J=8.3Hz,1H),2.78-2.51(m,2H),2.38-2.29(m,1H),2.33-2.21(m,1H);13C NMR(75MHz,CDCl3-d1)δ173.30,161.23,157.01,156.93,153.98,136.52,136.24,135.16,133.90,132.76,130.92,129.32,128.64,128.61,126.95,122.23,118.29,66.01,65.93,58.26,51.55,29.53,29.22;LC-MS(ESI)m/z:601.96[M+H]+。
1H NMR(300MHz,CDCl3-d1)δ8.65(dd,J=9.0,2.1Hz,1H),8.41(d,J=2.2Hz,1H),8.29(d,J=8.9Hz,1H),7.87(s,2H),7.67-7.57(m,1H),7.53–7.37(m,3H),5.81(d,J=8.4Hz,2H),5.75(t,J=8.3Hz,1H),2.77-2.52(m,2H),2.38-2.18(m,2H).13C NMR(75MHz,CDCl3-d1)δ:173.30,160.78,157.01,157.04,154.03,145.72,137.80,136.97,133.90,130.72,129.30,128.61,128.46,128.44,126.75,124.61,123.23,66.11,65.82,58.24,51.72,29.53,29.52;LC-MS(ESI)m/z:567.04[M+H]+。
药理活性实验:
镇静催眠实验中,潜伏期一般是指从给药开始到受试对象意识消失之间的时间;潜伏期越短越好,表示用药后能够快速发挥作用。持续期一般是指受试对象从意识消失到意识恢复的持续时间;不同的动物模型或动物种属药物的持续期会有所不同;持续期过长,可能会对心血管和呼吸***产生不良抑制反应等问题。
实施例114、药物诱导小鼠翻正反射消失的试验:
本实验选取小鼠睡眠时间、小鼠睡眠潜伏期作为催眠作用的代表指标;将ICR小鼠(雌性,18-25g)随机分组,经灌胃给药后,记录小鼠翻正反射消失的潜伏期和持续期。实验结果见下表1。
表1.药物诱导小鼠翻正反射消失的试验
如表1显示,在小鼠实验中,本发明的化合物具有快速起效和作用时间持久的催眠效果。
实施例115、药物诱导大鼠翻正反射消失的试验:
将SD大鼠(雄性,200-280g)随机分组,经灌胃给药后,记录大鼠翻正反射的潜伏期和持续期。
表2.药物诱导大鼠翻正反射消失的试验
上表2显示,在大鼠实验中,本发明的化合物具有快速起效和作用时间持久的催眠效果。
实施例116、细胞膜片钳检测药物对细胞GABA激活电流的影响:
将待测化合物按不同浓度溶解于外液(NaCl 140mM、KCl 4.7mM、HEPES 10mM、CaCl22mM、葡萄糖10mM、MgCl2 1mM、pH 7.4)中;将HEK 293T细胞接种于盖玻片上,于DMEM培养基中于37℃和5%CO2条件下培养24h;GABACl-电流采用HEKAEPC l0USB膜片钳放大器进行全细胞记录;2μM GABA用于激发Cl-电流,膜电位钳制在-60mV。将待测化合物与2μM GABA同时处理细胞,记录对同一细胞Cl-电流的诱导效果及Emax。
表3.对细胞GABA激活电流的影响
对2μM GABA电流最大增强百分比Emax及其对应的浓度(μM):正常人为100%。百分比越大,对应浓度越低,则催眠深度越强。
表4.对细胞GABA激活电流的影响
2μM GABA所诱导电流的正向增强EC50(μM):达到一定睡眠深度所需药品的浓度,其值越低越好。
上表3和4显示,本发明的化合物具有合适的催眠深度,表明本发明的化合物具有优异的催眠作用。
实施例117、药物通过体外血脑屏障的速率
在24孔细胞培养孔中放入Transwell装置(孔径5.0μm),然后将1×105个/ml的hCMEC/D3细胞传至Transwell上层微孔中,150μL/孔,下层微孔中加入细胞培养液;待细胞铺满单层,然后将孔中培养液换为含1%FBS的EBM-2完全培养液,在CO2培养箱中继续培养10天,长为完全致密的单层。当细胞为致密的单层后,在下层培养液中加入0.1mg/ml的化合物,5分钟后检测上层培养液中化合物浓度,计算透过率:
P化合物%=C上层化合物/C下层化合物×100%
表5.药物透过血脑屏障速率的试验
上表5显示,本化合物具有快速突破血脑屏障的作用。
实施例118、药物体外血浆半衰期测试:
血浆的制备:SD大鼠禁食不禁水饲养12小时后,通过眼眶静脉丛取血;将新鲜采集的血液装至含肝素钠的离心管中,4℃条件下,5000rpm离心10min,缓慢吸取上清液,并对其进行分装。最后将收集好的SD大鼠血浆密封标记好置于-20℃保存备用。
准备目标化合物样品:分析天平精密称取目标化合物,配置成浓度为2mg/mL(溶剂为V丙酮:V吐温80:V生理盐水=1:1:3)的母液,备用。
目标化合物样品体外半衰期测定:取待测化合物母液和大鼠血浆分别为20μL和80μL,混匀,分别取9个平行ep管,标记为0,1,2,3,5,10,15,20,30min的对应测试管,分别置于37℃水浴中孵育0,1,2,3,5,10,15,20,30min,每个时间点从对应的ep管中取出50μL混合液,加入100mL乙腈沉淀蛋白,使用混匀仪涡旋10min后,12000rpm离心15min,取上清液再次12000rpm离心10min,利用UPLC-MS/MS中的Intellistat软件确定目标化合物MRM模式的最适检测方法,对相应的质谱峰面积进行积分,计算其血浆半衰期。
表6.药物体外血浆半衰期测试结果
上表6显示,本化合物具有快速突破血脑屏障的作用。
以上药理学数据显示,本发明通式(I)化合物具有快速起效、作用时间久的作用特点,并且优选化合物几乎无蓄积。
口服固体制剂:
实施例119、含活性剂化合物1的片剂:
应理解,在阅读了本发明的上述讲授内容后,本领域技术人员可以对本发明作各种修改或改动,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (12)
其中:
R1选自氢、Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,
R2处于苯环的任意位置,且为单取代或多取代,
R2选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,
X选自C或N,当X为C时,R3选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个独立地选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基取代,当X为N时,R3取代基则不存在,
R4处于苯环或吡啶环的任意位置,且为单取代或多取代,
R4选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基被选自卤素、羟基、氰基、胺基、硝基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代,
R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基被选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代,
所述R6、R7选自氢、Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基各自任选地被一个或多个独立地选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代,
n选自1到20;
W选自氢、卤素、羟基、氰基、R6R7N-(CH2)n-、三氟甲基、硝基、胺基、Cl-20烷基、C2-20烯基、C2-20炔基,3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
所述Cl-20烷基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基被选自卤素、C1-10亚烷基-卤素、羟基、C1-10亚烷基-羟基、R6R7N-(CH2)n-、氰基、C1-10亚烷基-氰基、硝基、C1-10亚烷基-硝基、胺基、Cl-20烷基、Cl-20烷氧基、C2-20烯基、C2-20炔基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基的取代基取代,
其中,上述氢和上述基团中所含的氢选自氕、氘和氚。
R1选自氢或Cl-6烷基,
R2选自第6、7、8、9位取代,
R2选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基,
R3选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基,
R4选自第3’、4’、5’位取代,
R4选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、胺基、C1-6烷基、、Cl-6烷氧基、C2-6烯基、、C2-6炔基,
R5选自氢、Cl-10烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基,
R6、R7选自Cl-6烷基,
n选自1-10,
W选自氢、卤素、羟基、R6R7N-(CH2)1-10-、三氟甲基、硝基、氰基、C1-6烷基、Cl-6烷氧基、C2-6烯基、C2-6炔基。
R1选自氢、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基,
R2选自第7位取代,
R2选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基,
R3选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基,
R4选自第4’位取代,
R4选自氢、氯、溴、氟、硝基、氰基、胺基、R6R7N-(CH2)1-6-、三氟甲基,
R5选自氢、甲基、乙基、正丙基、2-羟乙基、吗啉乙基、二甲胺基乙基、二乙胺基乙基、二甲胺基丙基、二乙胺基丙基、(4-苯基哌嗪-1-基)甲基、(4-苯基哌嗪-1-基)乙基、磷酰氧基甲基,
R6、R7选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基;
n选自1-6,
W选自氢、羟基、氯、溴、氟、硝基、氰基、R6R7N-(CH2)1-6-、三氟甲基。
X为C,R2和R3为卤素,R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基,
X为N,R5选自氢、Cl-20烷基、C1-20酰基、C2-20烯基、C2-20炔基、C1-10亚烷基-磷酸基、3-10元环烷基或C1-10亚烷基-3-10元环烷基、R6R7N-(CH2)n-、3-10元杂环基或C1-10亚烷基-3-10元杂环基、6-14元芳基或C1-10亚烷基-6-14元芳基、5-14元杂芳基或C1-10亚烷基-5-14元杂芳基。
(S)-3-(8-氯-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物66)、
(S)-3-(8-溴-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物67)、
(S)-3-(8-硝基-6-(2-氟苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物68)、
(S)-3-(8-氯-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物96)、
(S)-3-(8-溴-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物97)、
(S)-3-(8-硝基-6-(2-氯苯基)-1-((3-(4-(2-羟乙基)哌嗪-1-基)丙基)硫基)-4H-苯并[f][1,2,4]***[4,3-a][1,4]二氮杂-4-基)丙酸甲酯(化合物98)、
部分化合物的结构为:
8.一种药物组合物,其包含有效量的权利要求1-7中任一项的化合物以及一种或多种药学上可接受的载体,其中所述有效量为40mg至12000mg。
9.权利要求1-7任一项的化合物或权利要求8的药物组合物,其药学上可接受的盐,选自乙酸盐、己二酸盐、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、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氧化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、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、双氢萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐、铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钠盐、钾盐、铵盐、氨丁三醇盐及锌盐。
10.制备权利要求1-7中任一项的化合物的方法,所述方法按照反应路线如下:
其中R1、R2、R3、R4、R5、W如权利要求1和3中任一项所定义,
所述方法包括以下步骤:
(1)、使所述A与N2保护的手性氨基酸或其衍生物发生缩合反应,得到中间体C,
(4)、使所述活性中间体E与水合肼在冰浴条件下或者在室温下或者在溶剂回流条件下发生取代反应,得到中间体F,
(5)、使所述中间体F通过与硫光气在碱性条件下反应,闭环得到目标产物G,
(6)、使所述中间体G通过与钠盐在无水溶液中、碱性条件下反应得到目标产物H,
(7)、使所述中间体H发生取代反应,从而得到目标产物I。
11.权利要求1-7中任一项的化合物或权利要求8的组合物在制备镇静催眠及抗焦虑药物中的应用。
12.一种镇静催眠方法,包括口服给药有效量的权利要求1-7任一项的化合物或权利要求8的药物组合物。
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CN101501019A (zh) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | 短效苯并二氮杂盐及其多晶型 |
WO2011054845A1 (en) * | 2009-11-05 | 2011-05-12 | Glaxosmithkline Llc | Benzodiazepine bromodomain inhibitor |
CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
WO2018196662A1 (zh) * | 2017-04-28 | 2018-11-01 | 四川科伦博泰生物医药股份有限公司 | 包含苯并二氮䓬类化合物的注射用组合物及其制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN101501019A (zh) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | 短效苯并二氮杂盐及其多晶型 |
WO2011054845A1 (en) * | 2009-11-05 | 2011-05-12 | Glaxosmithkline Llc | Benzodiazepine bromodomain inhibitor |
CN106892924A (zh) * | 2015-12-17 | 2017-06-27 | 四川科伦博泰生物医药股份有限公司 | 短效苯并二氮*衍生物、其制备方法及其用途 |
WO2018196662A1 (zh) * | 2017-04-28 | 2018-11-01 | 四川科伦博泰生物医药股份有限公司 | 包含苯并二氮䓬类化合物的注射用组合物及其制备方法 |
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