CN108503645A - 含氨甲基的哌嗪酮类化合物及其制备方法和应用 - Google Patents
含氨甲基的哌嗪酮类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种含氨甲基的哌嗪酮类化合物及其制备方法和应用。该类化合物具有如通式(I)所示的结构。本发明还提供该化合物的制备方法及应用。本发明的化合物具有一定的抑制AKT1激酶的活性和对PC‑3肿瘤细胞的生长抑制活性,用于制备抗肿瘤药物。
Description
技术领域
本发明涉及有机化合物合成及医药应用领域,尤其涉及一种含氨甲基的哌嗪酮类化合物及其制备方法和应用。
背景技术
AKT是一种丝氨酸/苏氨酸蛋白激酶,又被称为PKB,由约480个氨基酸组成,其分子量大约为60kDa。AKT存在三种高度同源的亚型,分别是AKT1(PKBα)、AKT2(PKBβ) 和AKT3(PKBγ),这三种亚型由位于14q32、19q13与1q44不同染色体上的不同基因所表达。(参见:Cheng,G.Z.;Park,S.;Shu,S.;He,L.;Kong,W.;Zhang,W.;Yuan,Z.;Wang,L.H.; Cheng,J.Q.Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery.Curr Cancer Drug Targets 2008,8,2-6.)AKT三种亚型在总体氨基酸序列上同源性超过80%,它们具有相似的结构:(1)一个氨基末端PH(pleckstrinhomology,普列克底物蛋白同源)域;(2)一个高度保守的中心激酶催化域;(3)一个羧基末端调节域。AKT的三种亚型,在氨基末端PH域、中心激酶催化域、羧基末端调节域的同源性分别为78-85%、 87-91%、69-77%。(参见:Kumar,C.C.;Madison,V.AKT crystal structureand AKT-specific inhibitors.Oncogene 2005,24,7493-7501.)
PI3K/AKT/mTOR信号通路是肿瘤细胞突变最为频繁的信号通路之一,在细胞信号传导以及促进细胞增殖、生存、分化和凋亡等过程中发挥着重要作用。该通路分子的突变和异常活化与肿瘤的发生、发展以及肿瘤治疗的耐药性密切相关。(参见:De,L.A.;Maiello,M. R.;D'Alessio,A.;Pergameno,M.;Normanno,N.The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways:role in cancer pathogenesis and implications fortherapeutic approaches. Expert Opin Ther Targets 2012,16Suppl 2:S17.)AKT是该信号通路的关键性节点,异常活化或者过表达的AKT已经在许多肿瘤中如***癌、淋巴瘤、急慢性白血病、骨髓瘤、乳腺癌、结肠癌、胰腺癌、黑色素瘤等被发现。活化的AKT通过磷酸化一系列下游底物如 GSK3β、Bad、Caspase 9、FOXO、ASK1、p21Cip1、p27Kip1等调节细胞信号传导、促进细胞生长、增殖、分化、存活、抑制细胞凋亡。近年来以AKT为靶点的抗肿瘤药物研究已经成为研究的热点。
发明内容
本发明的目的在于提供一种具有AKT抑制活性的含氨甲基的哌嗪酮类化合物,该类化合物具有良好的细胞生长抑制活性和对AKT1的抑制活性;本发明的另一目的在于提供该含氨甲基的哌嗪酮类化合物的制备方法及其制药用途。
为实现上述目的,本发明采用下述技术方案:
一、含氨甲基的哌嗪酮类化合物或其药用盐
一种含氨甲基的哌嗪酮类化合物或其药用盐,其结构如通式I所示:
通式I中,
R1是氢,卤素,多取代卤素,硝基,氨基,取代氨基,氰基,C1~6直链或支链烷氧基,C1~6直链或支链烷基;
R3是C1~6直链或支链烷基,C1~6直链或支链烷氧基,多元杂环;
Z是:
其中,R2是氢,卤素,C1~6烷基,氨基,取代氨基;
优选的,R1是氢,氟,溴,氯或2,4-二氯取代;R2是氢,溴,氯;R3是甲基异丙氨基,乙基氨基;
进一步优选的,所述含氨甲基的哌嗪酮类化合物或其药用盐选自下列化合物之一:
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM1)、
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM2)、
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基) 丙-1-酮(AM3)、
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)2-(4-溴苯基)-3-(异丙基氨基)丙-1- 酮(AM4)、
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3- (异丙基氨基)丙-1-酮(AM5)、
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM6)、
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM7)、
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM8)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基)丙-1- 酮(AM9)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基) 丙-1-酮(AM10)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基) 丙-1-酮(AM11)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基)丙-1- 酮(AM12)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基) 丙-1-酮(AM13)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基) 丙-1-酮(AM14)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1- 酮(AM15)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM16)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM17)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基) 丙-1-酮(AM18)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM19)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM20)、
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM21)、
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM22)、
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM23)、
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM24)、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1- 酮(AM25)、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基) 丙-1-酮(AM26)、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM27)、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM28)、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM29)、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM30)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基)丙 -1-酮(AM31)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基) 丙-1-酮(AM32)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基) 丙-1-酮(AM33)。
上述优选的33个化合物名称后的括号中为其相应的代号,为叙述方便和表达简洁,上述括号中的代号在本说明书以下内容中将被直接应用。
二、含氨甲基的哌嗪酮类化合物或其药用盐的制备方法
本发明含氨甲基的哌嗪酮类化合物或其药用盐的制备方法,包括步骤:
(1)起始原料A-1、B-1、C-1、D-1、E-1、1a-1d和4a-4c与Boc-哌嗪,在DMF或者 NMP溶液中,加入或者微波条件下反应分别得中间体A-2、中间体B-2、中间体C-2、中间体D-2、中间体E-2、中间体2a-2d、中间体5a-5c;
(2)中间体A-2、B-2、C-2在甲胺醇溶液中,加热反应分别得中间体A-3、中间体B-3、中间体C-3;
(3)中间体A-3、中间体B-3、中间体C-3、中间体D-2、中间体E-2、中间体2a-2d、中间体5a-5c,在乙酸乙酯/浓盐酸溶液或三氟乙酸/二氯甲烷或盐酸二氧六环溶液中脱去叔丁氧羰基,分别得中间体A-4、中间体B-4、中间体C-4、中间体D-3、中间体E-3、中间体3a-3d、中间体6a-6c;
(4)将中间体酸X-1用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体胺(A-4,B-4,C-4,D-3,E-3,3a或6a-6c),室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA,反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得目标化合物AM1-AM20,洗脱***为体积比50:1~10:1的DCM/MeOH;
(5)将中间体酸X-1用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3b-3d室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM21-AM30,此过程中洗脱溶剂为体积比1:2~1:4的乙酸乙酯:石油醚;
(6)将中间体酸X-2用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3a-3c室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM31-AM33;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,N,N-二甲基甲酰胺(DMF)或2-甲基吡咯烷酮(NMP),N,N- 二异丙基乙胺(DIEA);b.质量比27%~70%甲胺醇溶液,100℃;c.乙酸乙酯/浓盐酸溶液或三氟乙酸(TFA)/二氯甲烷(DCM),室温;d.盐酸二氧六环溶液,甲醇,室温;e.(i)中间体酸X,HBTU,DIEA,DMF,(ii)TFA,DCM或(ii)HCl·二氧六环,甲醇,室温。
根据本发明优选的,化合物AM1-AM6的制备方法,具体步骤如下:
(i)将起始原料A-1、B-1、C-1,用DMF溶解,依次将DIEA,1-Boc哌嗪加入反应瓶中,90℃反应4h,TLC检测反应完全,将反应液倒入10倍量冰水中,析出大量白色固体,过滤,用水洗滤饼,干燥,得中间体A-2、B-2、C-2;
(ii)中间体A-2、B-2、C-2加入茄型瓶中,加入20-30mL甲胺醇溶液,100℃密封反应6h,反应完毕后,冷却至室温析出白色晶体,将反应瓶放入-20℃冷却2h,析出更多白色晶体,过滤,干燥得中间体A-3、B-3、C-3;
(iii)将中间体A-3、B-3、C-3,用二氯甲烷溶解,室温下加入三氟乙酸(TFA),室温搅拌过夜,反应完毕,减压蒸干溶剂得油状物,用饱和碳酸钠水溶液调pH至10,析出淡黄色固体,过滤,干燥得粗品,柱层析纯化得中间体A-4、B-4、C-4,洗脱***为二氯甲烷/ 甲醇(50:1),此过程中,DCM与TFA的体积比为1:2~1:4;
(iv)将中间体酸X-1用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体A-4、B-4、C-4,室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA(DCM 与TFA的体积比为1:2~1:4),反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9-10,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得AM1-AM6,洗脱***为体积比50:1~10:1DCM/MeOH;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,90℃,DMF,DIEA;b.甲胺醇溶液,100℃;c.TFA,DCM,室温;e.(i)中间体酸X-1,HBTU,DIEA,DMF(ii)TFA,DCM。
根据本发明优选的,化合物AM7-AM30的制备方法,具体步骤如下:
(i)将起始原料D-1、E-1、1a-1d和4a-4c,用NMP溶解,依次加入1-Boc哌嗪和DIEA,150℃微波反应20min,将反应液倒入10倍量冰水中,析出白色沉淀,用乙酸乙酯萃取,合并有机相,依次用氯化铵,食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得中间体D-2、E-2、2a-2d和5a-5c,洗脱***为体积比9:1~12:1的石油醚/ 乙酸乙酯;
(ii)中间体D-2、E-2、2a-2d和5a-5c,用乙酸乙酯溶解,室温下,加入浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得中间体D-3、E-3、3a-3d和6a-6c;
(iii)将中间体酸X-1,用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体D-3、E-3、3a和6a-6c,室温反应过夜,TLC检测反应完全后,将反应液用10 倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA, DCM与TFA的体积比为1:2~1:4,反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9-10,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得AM7-AM20,洗脱***为体积比50:1~10:1的DCM/MeOH;
(iv)将中间体酸X-1用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3b-3d室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM21-AM30,此过程中洗脱溶剂为体积比1:2~1:4的乙酸乙酯:石油醚;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,150℃,NMP,DIEA;d.TFA,DCM,室温或盐酸二氧六环溶液,甲醇,室温e.(i)中间体酸X-1,HBTU,DIEA,DMF(ii)TFA,DCM或者(ii) 盐酸二氧六环溶液。
根据本发明优选的,化合物AM31-AM33的制备方法,具体步骤如下:
(i)将起始原料1a-1c用NMP溶解,依次加入1-Boc哌嗪和DIEA,150℃微波反应20min,将反应液倒入10倍量冰水中,析出白色沉淀,用乙酸乙酯萃取,合并有机相,依次用氯化铵,食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得中间体2a-2c,洗脱***为体积比9:1~12:1的石油醚/乙酸乙酯;
(ii)中间体2a-2c,用乙酸乙酯溶解,室温下,加入浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得中间体3a-3c;
(iii)将中间体酸X-2用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3a-3c室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM31-AM33,此过程中洗脱溶剂为体积比1:2~1:4乙酸乙酯:石油醚;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,150℃,NMP,DIEA;d.盐酸二氧六环溶液,甲醇,室温e.(i)中间体酸X-2,HBTU,DIEA,DMF(ii)盐酸二氧六环溶液。
本发明的室温为25℃。
三、含氨甲基的哌嗪酮类化合物或其药用盐的应用
实验数据表明,在浓度为1μM下,化合物AM9-AM21和AM25,AM27-AM33对Akt1 的抑制活性都较强,在浓度为10nM下,化合物AM10,AM13,AM16-AM17,AM28,AM30, AM33对Akt1的抑制活性也较强;而化合物AM1-AM2,AM6,AM27-AM30对PC-3肿瘤细胞的生长抑制活性也较强。因此,本发明还提供含氨甲基的哌嗪酮类化合物或其药用盐在制备抗肿瘤药物中的应用,所述的肿瘤为套细胞淋巴瘤和***癌。
以下实验例仅用于说明本发明的技术效果,但所述的实验例不用于限制本发明。
实验例.化合物对Akt1抑制活性测试及对PC-3细胞的生长抑制测定实验
1)化合物对AKT1激酶抑制活性实验:
实验材料和仪器:
HTRF试剂盒(德国Cisbio公司)、生物级DMSO(美国Sigma-Aldrich公司)、电子分析天平ER-182A型(日本A&D公司)、AKT1激酶200ng/μL(日本Carna Biosciences 公司)、384微孔板(美国Perkin Elmer公司)、酶标仪(Perkin Elmer Inspire多功能酶标仪)、台式离心机(美国Thermo Scientific公司)。
实验步骤:
冰浴条件下,将4μL化合物(用激酶缓冲液稀释),2μL底物KinEASE STK S3(AKT1底物)和2μL AKT1激酶依次加入到384孔板上,混匀,离心,加入2μL ATP混匀离心, 37℃下孵育40分钟。加入10μL anti-Eu(K)STK抗体溶液和treptavidin-XL665缓冲液等体积的混合液(含有的EDTA可终止酶反应),室温孵育2h,采用BioTek多功能酶标仪 Synnergy 2TM检测发射波长620nm和665nm的荧光值。
实验中,分别设有空白对照(P),背景对照(N)和化合物组(C),化合物组是将不同浓度待测化合物溶液(4μL)加入到384孔板中,阳性对照组则是加入相同体积的1×激酶缓冲液,其余与合物组相同,阴性对照组不加待测化合物,也不加AKT1激酶溶液,用1×激酶缓冲液代替,其他与化合物组相同。
抑制率的计算公式为:
其中c为测试组,n为背景组,p为空白组。
目标化合物对AKT1激酶抑制活性测定实验结果见表1。
2)化合物对肿瘤细胞的生长抑制活性实验:
实验材料与仪器:
人***癌细胞株PC-3(上海中科院细胞典藏中心),人套细胞淋巴瘤细胞株Mino, Rec-1,Jeko-1,Maver-1,Z138,Granta-519,JVM-2,JVM-13(美国典型培养物保藏中心 -American Type Culture Collection,ATCC),F-12培养基、RPMI-1640培养基(美国Sigma 公司)、胎牛血清(美国Sigma公司)、HEPES缓冲液(美国CORNING公司)、青霉素纳(10000units/mL)-硫酸链霉素(10mg/mL)(美国Sigma公司)、台盼蓝试剂-Trypan bluesolution(美国Sigma公司)、倒置光学显微镜(美国Fisher Scientific公司)、细胞培养箱(美国NUAIER公司)、超净工作台(美国NUAIER公司)、细胞计数器-TC20TM Automated CellCounter)(美国Bio-Rad公司)、电热恒温水浴锅(美国Fisher Scientific公司)、台式离心机(美国Thermo Scientific公司)、酶标仪(BioTek Synergy HTX多功能检测仪)、超低温冰箱(美国Thermo Scientific公司)。
化合物对前列癌细胞(PC-3)生长抑制活性实验
实验方法:
化合物对PC-3细胞生长抑制活性测定,采用MTT法。取对数生长期的PC-3细胞 (5×103个),接种于96孔板中,每孔加入10%(体积分数)胎牛血清(FBS)F-12 培养基,将铺好的96孔板置于37℃、5%(v/v)的CO2恒温培养箱内孵育12h,依次加入100μL培养基,1μL不同浓度的化合物(DMSO的终浓度不高于0.5%),再将96孔板置于37℃、5%(v/v)CO2恒温培养箱孵育72h;将10μL MTT溶液加入 96孔板中(每孔),再次将96孔板与37℃孵育4h。孵育完毕,离心20min(2500r·min-1)。去掉上清液,将200μL DMSO加入每孔中,振荡,充分溶解。用酶联免疫检测仪 (Bio-Rad 680)检测570nm处测吸光度(OD值)。
化合物抑制率由公式:抑制率(IR%)=(空白组OD值-给药组OD值)/空白组OD 值×100%,计算,再根据抑制率浓度曲线得IC50值。
化合物对PC-3细胞生长抑制活性测定结果见表1。
表1.目标化合物的活性测定数据
表1实验数据表明,在浓度为1μM下,化合物AM9-AM21和AM25,AM27-AM33对 Akt1的抑制活性都较强,在浓度为10nM下,化合物AM10,AM13,AM16-AM17,AM28, AM30,AM33对Akt1的抑制活性也较强;而化合物AM1-AM2,AM6,AM27-AM30对PC-3 肿瘤细胞的生长抑制活性也较强。
具体实施方式
结合实施例对本发明作进一步的说明,应该说明的是,下述说明仅是为了解释本发明,并不对其内容进行限定。实施例中采用的条件可以根据现有的设备条件做进一步调整,未注明的实施条件通常为常规实验中的条件。
实施例:
1)中间体A-2的制备
称取2,4-二氯吡咯并嘧啶(2.55g,13.56mmol),用DMF(15mL)溶解,室温下依次加入DIEA(27.12mmol)、1-Boc哌嗪(2.65g),室温搅拌反应过夜,反应完毕,析出白色固体,将反应液倒入150ml冰水中,析出大量白色固体,过滤,用30mL水洗滤饼,干燥得粗品4.34g(A-2),不经纯化直接进行下一步反应。白色固体,产率95%。1H NMR(400MHz, DMSO)δ11.94(s,1H),7.19(d,J=3.5Hz,1H),6.67(d,J=3.5Hz,1H),3.91–3.78(m,4H), 3.47(s,4H),1.41(s,9H).
2)中间体B-2的制备
称取2,4-二氯噻吩并[3,2-d]嘧啶(2.8g,13.65mmol),用DMF(10mL)溶解,依次将DIEA(7.0g,54.62mmol),1-Boc哌嗪(3.0g,16.39mmol)加入反应瓶中,90℃反应4h, TLC检测反应完全,将反应液倒入10倍量冰水中,析出大量白色固体,过滤,用水(20mL×3) 洗滤饼,干燥,得白色固体B-2(4.32g)B-2:白色固体,产率89%,1H NMR(400MHz,DMSO) δ8.32(d,J=5.5Hz,1H),7.41(d,J=5.5Hz,1H),4.03–3.88(m,4H),3.53(s,4H),1.43(s,9H). 3)中间体C-2的制备
称取2,4-二氯嘧啶(2.0g,13.43mmol),用DMF(15mL)溶解,依次加入三乙胺(TEA)(2.72g,26.85mmol),1-Boc哌嗪(2.75g,14.77mmol),室温搅拌过夜,反应液中有白色固体析出,TLC检测反应完毕,将反应液到200mL冰水中,大量白色固体析出,过滤,干燥得白色固体C-2(3.8g,13.43mmol)
C-2:白色固体,产率95%,1H NMR(400MHz,DMSO)δ8.10(d,J=6.2Hz,1H),6.84(d,J=6.2 Hz,1H),3.62(s,4H),3.47–3.37(m,4H),1.42(s,9H).
4)中间体2a-2d的制备
称取4-氯-5-取代-7H-吡咯并[2,3-d]嘧啶(13.56mmol),用DMF(15mL)溶解,室温下依次加入DIEA(15.42mmol)、1-Boc哌嗪(14.23mmol),150℃室温搅拌反应过夜,反应完毕,析出白色固体,将反应液倒入150ml冰水中,析出大量白色固体,过滤,用30mL水洗滤饼,干燥得中间体2a-2d(13.56mmol),不经纯化直接进行下一步反应。
4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2a)
灰白色固体,产率93%,MS(ESI)m/z:318.4[M+H]+
4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2b)
灰白色固体,产率60%,1H NMR(600MHz,DMSO)δ11.73(s,1H),8.15(s,1H),7.20(d,J=0.6 Hz,1H),6.64(d,J=1.8Hz,1H),3.86(s,4H),3.48(s,4H),1.43(s,9H)MS(ESI)m/z:304[M+H]+
4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2c)
灰白色固体,产率50%,1H NMR(400MHz,DMSO)δ12.23(s,1H),8.29(s,1H),7.52(d,J= 2.8Hz,1H),3.52(s,8H),1.43(s,9H)。
4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(2d)
浅黄色固体,产率47%,1H NMR(400MHz,DMSO)δ12.21(s,1H),8.37(s,1H),7.52(d,J=2.6 Hz,1H),3.52(s,8H),1.42(s,9H)。
5)中间体5a-5c的制备
称取4-氯-3-取代-1H-吡唑并[3,4-d]嘧啶(4a-4c)(12.85mmol),用DMF(8mL)溶解,室温下依次加入DIEA(15.42mmol)、1-Boc哌嗪(13.49mmol),150℃,微波反应20min,反应完毕,将反应液倒入150mL冰水中,析出大量固体,过滤,用30mL水洗滤饼,干燥得中间体5a-5c不经纯化直接进行下一步反应。
4-(1H-吡唑并[3,4-d]嘧啶)-哌嗪-1-甲酸叔丁基酯(5a)
白色固体,产率89%,1H NMR(400MHz,DMSO)δ8.94(s,1H),8.60(s,1H),1.39(s,9H) 4-(3-氯-1H-吡唑并[3,4-d]嘧啶)-哌嗪-1-甲酸叔丁基酯(5b)
淡黄色固体,产率86%,1H NMR(400MHz,DMSO)δ8.36(s,1H),1.40(s,9H)
4-(3-溴-1H-吡唑并[3,4-d]嘧啶)-哌嗪-1-甲酸叔丁基酯(5c)
白色固体,产率88%,1H NMR(400MHz,DMSO)δ8.38(s,1H),1.41(s,9H)
6)中间体D-2的制备
称取6-氯-9H-嘌呤(2.0g,12.94mmol),用2-甲基吡咯烷酮(NMP)(10mL)溶解,依次加入1-Boc哌嗪(2.65g,14.2mmol)和N,N-二异丙基乙胺(DIEA)(2.51g,19.41mmol), 150℃微波反应25min,将反应液倒入120mL冰水中,析出白色沉淀,用乙酸乙酯(25mL×3) 萃取,合并有机相,依次用氯化铵(20mL×3),食盐水(20mL×3)洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得白色中间体D-2(3.6g,12.94mmol),洗脱***为石油醚/乙酸乙酯(9:1)。类白色固体,产率:91%,1H NMR(400MHz,DMSO)δ13.09 (s,1H),8.23(s,1H),8.15(s,1H),4.21(br,4H),3.44(br,4H),1.43(s,9H).
7)中间体E-2的制备
称取4-氯喹唑啉(2.5g,15.2mmol),用NMP(10mL)溶解,依次加入1-叔丁氧羰基哌嗪(3.1g,16.7mmol)和DIEA(3.95,30.4mmol),120℃微波反应25min,将反应液倒入120mL冰水中,析出白色沉淀,用乙酸乙酯(20mL×3)萃取,合并有机相,依次用氯化铵(15mL×3),食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得中间体E-2(4.3g),洗脱***为石油醚/乙酸乙酯(9:1)。类白色固体,产率88%,1H NMR(400MHz,DMSO)δ8.88(s,1H),8.24(d,J=8.4Hz,1H),8.09–7.93(m,2H),7.72(t, J=7.7Hz,1H),7.49–7.15(m,1H),4.26–4.14(m,4H),3.62(s,4H),1.44(s,9H).
8)中间体A-3的制备
称取A-2(2.5g,7.4mmol)放入35mL封管中,加入20mL甲醇胺,110℃回流24h,TLC检测反应完全,将反应液冷却至室温,有白色固体析出,将反应液放入-20℃冰箱冷却2h,析出大量白色固体,过滤,干燥得2.12g(A-3),白色固体,产率86%。1H NMR(400MHz,DMSO) δ10.93(s,1H),6.73(dd,J=13.5,10.4Hz,1H),6.38(d,J=1.5Hz,1H),5.96(d,J=4.8Hz,1H), 3.80–3.71(m,4H),3.43(s,4H),2.75(d,J=4.8Hz,3H),1.42(s,9H).
9)中间体B-3的制备
称取B-2(2.0g,5.64mmol)加入35mL封管中,加入20mL甲胺醇溶液,100℃密封反应6h,反应完毕后,冷却至室温析出白色晶体,将反应瓶放入-20℃冷却2h,析出更多白色晶体,过滤,干燥得白色针状固体B-3(1.5g),白色针状固体,产率76%。1H NMR(400MHz,DMSO)δ7.96(d,J=5.5Hz,1H),7.10(d,J=5.2Hz,1H),6.43(d,J=4.7Hz,1H),3.82(s,4H),3.51(br,4H),2.79(d,J=4.7Hz,3H),1.43(s,9H).
10)中间体C-3的制备
称取C-2(2.2g,7.36mmol)放入35mL封管中,加入20mL甲胺醇溶液,110℃回流48h,TLC检测反应完全,将反应液冷却至室温,有白色固体析出,将反应液放入-20℃冰箱冷却2h,析出大量白色固体,过滤,干燥得白色固体C-3(1.82g,7.36mmol)白色固体,产率 84%,1H NMR(400MHz,DMSO)δ7.81(d,J=5.6Hz,1H),6.47(s,1H),6.01(d,J=5.6Hz,1H), 3.52(br,4H),3.36(d,J=4.0Hz,3H),2.73(d,J=4.8Hz,3H),1.42(s,9H).
11)中间体A-4的制备
称取A-3(0.9g,2.71mmol),用二氯甲烷(4mL)溶解,室温下加入(1mL)三氟乙酸(TFA)室温搅拌4h,反应完毕,减压蒸干溶剂得油状物,用饱和碳酸钠水溶液调pH至10,用二氯甲烷(30mL×3)萃取,合并有机相,用饱和食盐水(20mL×3)洗有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得0.54g(A-4),洗脱***为二氯甲烷/甲醇(20:1)。淡绿色固体,产率78%,1H NMR(400MHz,DMSO)δ11.90(s,1H),7.21(d,J=1.6 Hz,1H),6.65(d,J=2.9Hz,1H),5.02(br,1H),3.94–3.73(m,4H),2.98–2.73(m,4H).
12)中间体B-4的制备
称取B-3(1.2g,3.43mmol),用二氯甲烷(6mL)溶解,室温下加入(2mL)三氟乙酸(TFA),室温搅拌过夜,反应完毕,减压蒸干溶剂得油状物,用饱和碳酸钠水溶液调pH至 10,析出淡黄色固体,过滤,干燥,柱层析纯化得B-4(0.65g)洗脱***为二氯甲烷/甲醇 (50:1~20:1)。白色固体,产率76%,1H NMR(400MHz,DMSO)δ7.98(s,1H),7.11(s,1H), 6.50(s,1H),3.91(s,4H),3.07(s,4H),2.79(s,3H).
13)中间体C-4的制备
称取C-3(1.5g,5.11mmol),用二氯甲烷(6mL)溶解,室温下加入(2mL)三氟乙酸(TFA) 室温搅拌过夜,反应完毕,减压蒸干溶剂得油状物,用饱和碳酸钠水溶液调pH至10,析出白色固体,过滤,干燥得粗品,柱层析纯化得白色固体C-4(0.76g,5.11mmol),洗脱***为二氯甲烷/甲醇(30:1)。白色固体,产率56%,1H NMR(400MHz,DMSO)δ8.31(s,1H),7.97(d,J=6.6Hz,1H),6.55(d,J=7.0Hz,1H),4.04(s,4H),3.18(s,4H),2.89(s,3H).
14)中间体D-3的制备
称取中间体D-2(3.0g,9.86mmol),用(6mL)乙酸乙酯溶解,室温下,加入(2mL)浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得灰白色中间体D-3(2.4g,9.86mmol),灰白色固体,产率88%,1H NMR(400MHz,DMSO)δ9.71(br,2H),8.45(s,1H),8.39(s,1H), 4.52(s,4H),3.28(s,4H).
15)中间体E-3的制备
称取中间体E-2(3.0g,9.54mmol),用乙酸乙酯(6mL)溶解,室温下,加入(2mL)浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得灰白色中间体E-3(2.3g),灰白色固体,产率84%,1H NMR(400MHz,DMSO)δ10.02(s,2H),8.95(s,1H),8.25(d,J=8.4Hz,1H), 8.10–8.02(m,2H),7.74(ddd,J=8.4,5.6,2.7Hz,1H),4.37(s,4H),3.34(s,4H).
中间体3a-3d和中间体6a-6c的制备与中间体D-3和E-3的制备类似
5-甲基-4-(哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶二盐酸盐(3a)
灰白色固体,产率83%,MS(ESI)m/z:218.3[M+H]+
4-(哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶二盐酸盐(3b)
白色固体,产率90%,1H NMR(400MHz,D2O)δ8.33(s,1H),7.36(d,J=3.7Hz,1H),6.83(d, J=3.7Hz,1H),4.30–4.25(m,4H),3.50–3.44(m,4H)MS(ESI)m/z:204[M+H]+
5-氯-4-(哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶二盐酸盐(3c)
白色固体,产率91%,1H NMR(400MHz,D2O)δ8.32(s,1H),7.45(s,1H),4.09–4.02(m, 4H),3.51–3.46(m,4H)MS(ESI)m/z:238[M+H]+
5-溴-4-(哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶二盐酸盐(3d)
浅黄色固体,产率90%,1H NMR(400MHz,D2O)δ8.32(s,1H),7.52(d,J=2.4Hz,1H),4.05 –3.98(m,4H),3.54–3.47(m,4H)MS(ESI)m/z:282[M+H]+
4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(6a)
类白色固体,产率84%,1H NMR(400MHz,DMSO)δ9.99(s,2H)8.97(s,1H),8.63(s,1H), 4.32(s,4H),3.35(s,4H).
3-氯-4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(6b)
灰白色固体,产率68%,1H NMR(400MHz,DMSO)δ8.36(d,J=5.7Hz,1H),3.93–3.79(m,4H),3.12–3.00(m,4H).
3-溴-4-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶二盐酸盐(6c)
类白色固体,产率88%,1H NMR(400MHz,DMSO)δ8.38(s,1H),3.96–3.74(m,4H),3.20–3.07(m,4H).
16)化合物AM1-AM20的制备
将中间体酸X-1(0.5mmol)用DMF(6mL)溶剂溶解,依次加入HBTU(0.53mmol), DIEA(3.0mmol),室温搅拌15min,加入中间体胺(A-4,B-4,C-4,D-3,E-3,3a或6a-6c)(0.5mmol),室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷(3×30mL)萃取,合并有机相,依次用氯化铵(20mL×3),食盐水 (20mL×3),无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷(4mL) 溶解,室温下加入1mL TFA,反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9,用二氯甲烷(20mL×3)萃取,合并有机相,用食盐水(20mL×3)洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得目标化合物,洗脱***为DCM/MeOH (50:1~10:1)。
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM1)
类白色油状物,产率67%,1H NMR(400MHz,DMSO)δ7.96(d,J=4.9Hz,1H),7.68(s,1H), 7.38(dd,J=34.9,8.0Hz,2H),7.09(s,1H),6.45(br,1H),4.45(br,1H),3.87(d,J=2.7Hz,2H), 3.84–3.55(m,4H),3.47–3.33(m,4H),3.15(br,1H),2.77(br,4H),1.00(s,6H).13C NMR(101 MHz,DMSO)δ170.04,164.09,161.22,158.34,135.28,133.95,133.09(d,J=4.1Hz),130.90, 129.40,128.40,123.94,104.73,49.38,48.78,45.30(2C),44.89,44.62,41.91,28.55,22.69,22.54.
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM2)类白色油状物,产率66%,1H NMR(400MHz,DMSO)δ7.95(d,J=5.5 Hz,1H),7.54(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.09(d,J=5.3Hz,1H),6.45(d,J=4.8 Hz,1H),4.28–4.18(m,1H),3.88–3.59(m,6H),3.52–3.41(m,2H),3.20–3.11(m,1H),2.77 (s,3H),2.68(dd,J=11.5,5.2Hz,1H),2.58(dd,J=13.8,6.8Hz,2H),0.98(s,6H).13C NMR(101 MHz,DMSO)δ170.60,164.18,161.25,158.34,138.48,133.05,132.06(2C),130.63(2C),124.00, 120.65,104.61,51.19,48.69,47.55,46.14,45.59,45.31,44.94,41.79,28.56,22.77.
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基) 丙-1-酮(AM3)白色固体,产率71%,mp:169-171℃,1H NMR(400MHz,DMSO)δ7.74(d, J=46.0Hz,2H),7.38(d,J=36.4Hz,2H),6.47(s,1H),5.99(s,1H),4.43(s,1H),3.62-3.50(m, 5H),3.31(br,1H),3.11-3.02(m,2H),2.71(br,6H),0.98(s,6H).13C NMR(101MHz,DMSO)δ 169.88,162.78,162.43,157.26,135.46,133.89,133.00,130.92,129.32,128.40,99.99,49.53, 48.72,46.07,44.95,44.68,43.36,41.77,28.16,22.88,22.67.
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)2-(4-溴苯基)-3-(异丙基氨基)丙-1- 酮(AM4)白色固体,产率68%,mp:186-189℃,1H NMR(400MHz,DMSO)δ7.79(d,J=5.7Hz,1H),7.53(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),6.46(s,1H),5.97(d,J=5.6Hz,1H), 4.20(dd,J=8.2,5.4Hz,1H),3.64–3.45(m,5H),3.40-3.35(m,2H),3.17–3.08(m,1H),2.99 (br,1H),2.79–2.63(m,5H),2.56-2.54(m,1H),0.98–0.94(m,6H).13C NMR(101MHz,DMSO) δ170.51,162.78,162.43,157.25,138.64,132.04,131.57,130.60,120.58,51.32,48.61,47.70, 44.95,43.45,42.74,41.60,28.20,23.02,22.88.
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3- (异丙基氨基)丙-1-酮(AM5)棕色固体,产率43%,mp:170-172℃,1H NMR(400MHz,DMSO)δ11.00(s,1H),7.71(s,1H),7.39(dd,J=44.8,7.1Hz,2H),6.74(s,1H),6.35(s,1H),6.00(s,1H),4.47(s,1H),3.87(br,2H),3.74(br,1H),3.57(br,4H),3.25-3.13(m,2H),2.85-2.74 (m,7H),1.03(s,6H).13C NMR(101MHz,DMSO)δ169.64,159.33,157.26,155.25,134.97, 134.13,133.12,130.96,129.63,128.42,118.05,101.18,96.26,49.21,48.87,46.14,45.07,44.67, 44.37,42.08,28.73,22.05,21.84.
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM6)棕色固体,产率49%,mp189-192℃,1H NMR(400MHz,DMSO) δ10.99(s,1H),7.57(d,J=8.4Hz,2H),7.30(d,J=8.5Hz,2H),6.74(dd,J=3.4,2.2Hz,1H),6.32(dd,J=3.4,1.6Hz,1H),5.99(q,J=4.7Hz,1H),4.28(dd,J=8.0,5.0Hz,1H),3.89–3.74 (m,2H),3.76-3.67(m,1H),3.61-3.57(m,3H),3.27-3.21(m,2H),2.95(br,1H),2.79(br,3H), 2.73(d,J=4.8Hz,3H),1.06(d,J=4.3Hz,6H).13C NMR(101MHz,DMSO)δ169.91,159.45, 157.28,155.31,137.63,132.25,130.63,120.88,119.27,118.06,116.31,101.29,96.18,49.75, 49.07,49.06(m),46.48,45.09,41.98,28.67,21.63,21.28.
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM7)类白色固体,产率54%,mp:152-155℃,1H NMR(400MHz,DMSO)δ8.25(s,1H),7.62(d,J=8.3Hz,2H),7.32(d,J=8.4Hz,2H),7.13(s,1H),4.56(br,1H),3.81(br, 1H),3.67(s,2H),3.65–3.56(m,2H),3.53(br,2H),3.43(br,2H),3.01(d,J=10.5Hz,1H),2.86 (d,J=11.2Hz,1H),2.30(s,3H),1.23(dd,J=6.2,2.8Hz,6H).13C NMR(101MHz,DMSO)δ 168.65,160.48,151.85,150.18,136.12,132.63(2C),130.66(2C),126.45,121.68,107.89,106.70, 51.07,49.67,49.16,45.26,45.02,42.15,31.07,19.13,18.69,13.38.
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM8)类白色固体,产率51%,mp:165-168℃,1H NMR(400MHz,DMSO)δ8.25(s,1H),7.73(s,1H),7.47(d,J=8.1Hz,1H),7.32(d,J=8.4Hz,1H),7.13(s,1H),4.59(s, 1H),3.81(s,1H),3.74–3.42(m,8H),2.87(br,2H),2.31(s,3H),1.11(br,6H).13CNMR(101 MHz,DMSO)δ169.16,160.46,151.87,150.16,133.99,133.51(2C),130.92,129.67,128.60, 126.42,107.92,106.71,49.85,49.11,45.17,43.67(2C),42.17,31.06,21.23,20.88,13.39.
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氟苯基)-3-(异丙氨基)丙烷-1- 酮(AM9)浅黄色固体,产率71%,1H-NMR(400MHz,D2O)δ8.15(s,1H),7.28(dd,J=7.5, 4.5Hz,3H),7.06(t,J=8.7Hz,2H),6.67(d,J=3.6Hz,1H),4.36(dd,J=8.3,5.0Hz,1H),4.11– 3.82(m,4H),3.80–3.61(m,3H),3.61–3.44(m,4H),3.39(dt,J1=13.2Hz,J2=6.6Hz,1H), 3.29–3.20(m,1H),1.23(dd,J=6.5,3.9Hz,6H).13C NMR(100MHz,D2O)δ170.99,163.68, 161.24,152.00,142.13,129.88,124.26,116.72,116.50,103.95,102.04,66.55,51.68,47.01, 45.15(2C),43.20,40.77,17.93(2C).
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氟苯基)-3-(异丙氨基) 丙烷-1-酮(AM10)浅黄色固体,产率73%,1H NMR(400MHz,D2O)δ8.14(s,1H),7.34(s,1H),7.29(dd,J=8.6,5.2Hz,2H),7.09(t,J=8.8Hz,2H),4.39(dd,J=8.2,5.1Hz,1H),4.05– 3.72(m,3H),3.71–3.48(m,5H),3.40(dt,J=13.1,6.6Hz,1H),3.26(dd,J=12.7,5.0Hz,1H), 3.14–3.04(m,1H),1.24(dd,J=6.5,4.1Hz,6H).13C-NMR(100MHz,D2O)δ170.64,163.71, 161.27,153.58,145.83,142.94,130.22,129.93,123.68,116.77,116.56,105.17,101.36,51.68, 49.18,48.42,47.04,45.08,44.34,41.52,17.98,17.89.
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氟苯基)-3-(异丙氨基) 丙烷-1-酮(AM11)浅黄色固体,产率70%,1H-NMR(400MHz,D2O)δ8.14(s,1H),7.40(s,1H), 7.29(dd,J=8.6,5.2Hz,2H),7.09(t,J=8.8Hz,2H),4.39(dd,J=8.2,5.1Hz,1H),4.00(dt,J= 12.8,6.7Hz,1H),3.87(dd,J=10.0,6.3Hz,1H),3.74(dd,J=8.7,4.5Hz,1H),3.69–3.50(m, 5H),3.39(dt,J=13.2,6.6Hz,1H),3.25(dd,J=12.7,5.0Hz,1H),3.06-2.97(m,1H),1.23(dd,J =6.4,4.2Hz,6H).13C-NMR(100MHz,D2O)δ170.55,163.71,161.26,154.16,146.92,130.26, 129.93(2C),126.62,116.79(2C),103.10,89.02,51.67,49.88,48.93,47.05,45.05,44.55,41.63, 17.98(2C).
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氯苯基)-3-(异丙氨基)丙烷-1- 酮(AM12)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.14(s,1H),7.29(s,1H),7.26 (d,J=5.3Hz,2H),7.20(d,J=8.5Hz,2H),6.64(d,J=3.6Hz,1H),4.34(dd,J=8.3,4.9Hz, 1H),4.03(br,J=9.8Hz,2H),3.90(br,J=7.7Hz,2H),3.79–3.69(m,1H),3.68–3.45(m,5H), 3.38(dt,J=13.1,6.5Hz,1H),3.27–3.17(m,1H),1.22(dd,J=6.4,3.8Hz,6H).13C-NMR(100 MHz,D2O)δ170.81,142.13,134.15,132.70,129.74(2C),129.41(2C),124.28,103.87,101.98, 66.55,51.70,46.85,45.29,45.22,44.85,43.18,40.56,17.98(2C).
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氯苯基)-3-(异丙氨基) 丙烷-1-酮(AM13)浅黄色固体,产率72%,1H-NMR(400MHz,D2O)δ8.15(dd,J=8.6,3.2Hz,1H),7.35(dd,J=8.7,4.3Hz,3H),7.24(d,J=8.5Hz,2H),4.38(dd,J=8.1,5.0Hz,1H),4.03(dd,J=14.2,7.1Hz,1H),3.96–3.85(m,1H),3.76(dd,J=8.2,4.1Hz,1H),3.72–3.50(m, 8H),3.40(dt,J=13.2,6.6Hz,1H),3.24(dd,J=12.6,4.8Hz,1H),3.16–3.03(m,1H),1.24(dd, J=6.4,4.1Hz,6H).13C-NMR(100MHz,D2O)δ170.42,153.55,142.89,134.22,132.98, 129.84(2C),129.48(2C),123.71,90.46,66.55,62.52,51.72,49.12,48.28,46.91,45.24,44.25, 41.49,17.89(2C).
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-氯苯基)-3-(异丙氨基) 丙烷-1-酮(AM14)浅黄色固体,产率74%,1H-NMR(400MHz,D2O)δ8.15(dd,J=8.6,3.2Hz,1H),7.35(dd,J=8.7,4.3Hz,3H),7.24(d,J=8.5Hz,2H),4.38(dd,J=8.1,5.0Hz,1H),4.03(dd,J=14.2,7.1Hz,1H),3.96–3.85(m,1H),3.76(dd,J=8.2,4.1Hz,1H),3.72–3.50(m, 8H),3.40(dt,J=13.2,6.6Hz,1H),3.24(dd,J=12.6,4.8Hz,1H),3.16–3.03(m,1H),1.24(dd, J=6.4,4.1Hz,6H).13C-NMR(100MHz,D2O)δ170.42,153.55,142.89,134.22,132.98, 129.84(2C),129.48(2C),123.71,90.46,66.55,62.52,51.72,49.12,48.28,46.91,45.24,44.25, 41.49,17.89(2C).
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-溴苯基)-3-(异丙氨基)丙烷-1- 酮(AM15)浅黄色固体,产率69%,1H-NMR(400MHz,D2O)δ8.14(s,1H),7.42(d,J=8.4Hz, 2H),7.25(s,1H),7.15(d,J=8.4Hz,2H),6.62(s,1H),4.34(dd,J=7.6,4.8Hz,1H),4.03(d,J= 10.7Hz,2H),3.89(dd,J=16.2,7.5Hz,2H),3.72–3.71(m,J=11.6,6.7Hz,1H),3.60–3.44(m, 4H),3.39(dt,J=13.1,6.5Hz,1H),3.22(dd,J=12.7,4.6Hz,1H),1.23(dd,J=6.4,3.6Hz, 6H).13C-NMR(100MHz,D2O)δ170.72,152.05,142.10,133.27,132.73(2C),129.71(2C), 124.31,122.30,103.87,101.93,66.55,51.74,46.81,45.38,45.23,44.83,43.20,40.56,17.89(2C).
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-溴苯基)-3-(异丙氨基) 丙烷-1-酮(AM16)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.13(s,1H),7.47(d,J=8.4Hz,2H),7.33(s,1H),7.17(d,J=8.4Hz,2H),4.36(dd,J=8.5,4.9Hz,1H),4.04–3.97 (m,1H),3.92–3.85(m,1H),3.75(dd,J=8.9,4.5Hz,1H),3.68–3.50(m,6H),3.38(dt,J=13.1, 6.5Hz,1H),3.23(dd,J=12.7,4.8Hz,1H),3.11–3.03(m,1H),1.23(dd,J=6.5,4.1Hz, 6H).13C-NMR(100MHz,D2O)δ170.34,153.56,145.61,142.89,133.48,132.82(2C),129.75(2 C),123.72,122.37,105.11,101.22,51.72,49.10,48.24,46.83,45.32,44.25,41.48,17.88(2C).
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(4-溴苯基)-3-(异丙氨基) 丙烷-1-酮(AM17)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.14(d,J=6.0Hz,1H), 7.51–7.44(m,1H),7.43–7.37(m,1H),7.22–7.12(m,2H),4.42–4.30(m,1H),4.02(dd,J= 12.3,5.1Hz,1H),3.94–3.80(m,2H),3.79–3.68(m,1H),3.65(s,2H),3.56(s,4H),3.39(td,J= 12.6,6.4Hz,1H),3.28–3.18(m,1H),1.24(dt,J=6.5,3.4Hz,6H).13C-NMR(100MHz,D2O)δ 170.70,170.23,142.09,133.27,132.85,129.81,124.30,122.40,122.31,103.86,66.55,51.75, 49.99,48.68,46.85,45.33,44.51,41.66,17.91,17.89.
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(异丙氨基)丙烷-1-酮(AM18)浅黄色固体,产率68%,1H-NMR(400MHz,D2O)δ8.16(s,1H),7.51(s,1H), 7.28(d,J=3.5Hz,1H),7.14(dd,J=8.4,1.8Hz,1H),7.07(d,J=8.4Hz,1H),6.65(d,J=3.4 Hz,1H),4.65(dd,J=9.3,3.6Hz,1H),4.12–4.00(m,2H),3.92(d,J=5.5Hz,2H),3.74–3.67 (m,2H),3.63–3.56(m,1H),3.52(dd,J=12.7,9.5Hz,1H),3.42(dt,J=13.6,6.8Hz,1H),3.35 (dd,J=8.8,4.3Hz,1H),3.16(dd,J=12.7,3.2Hz,1H),1.26(dd,J=6.4,3.8Hz,6H).13C-NMR (100MHz,D2O)δ170.41,152.12,142.19,135.06,133.91,130.39,130.17,129.40,128.40,124.35, 103.76,101.94,66.56,51.85,45.31,45.14,44.63,43.06,42.61,40.48,18.06,17.88.
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(异丙氨基) 丙烷-1-酮(AM19)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.19(d,J=2.3Hz,1H), 7.56(s,1H),7.39(d,J=4.3Hz,1H),7.25(dd,J=8.4,1.0Hz,1H),7.13(d,J=8.4Hz,1H),4.10 –4.00(m,1H),3.93(s,1H),3.86–3.71(m,2H),3.65(d,J=5.7Hz,2H),3.60(dd,J=8.4,4.7 Hz,1H),3.55–3.50(m,1H),3.40(ddd,J=23.9,15.0,9.1Hz,2H),3.18(dd,J=12.7,3.4Hz, 2H),1.26(dd,J=6.0,4.6Hz,6H).13C-NMR(100MHz,D2O)δ170.08,135.21,133.83(2C), 130.55,130.24,129.67,128.56(2C),123.83,62.51,51.83(2C),48.95,48.22,45.17,44.05, 42.63(2C),41.50,18.04,17.88.
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(异丙氨基)丙烷-1-酮(AM20)浅黄色固体,产率71%,1H-NMR(400MHz,D2O)δ8.18–8.15(m,1H),7.51(t,J=2.2Hz,1H),7.28(t,J=2.9Hz,1H),7.16–7.11(m,1H),4.64(dd,J=9.6,4.0Hz, 1H),4.12–3.99(m,1H),3.98–3.87(m,1H),3.77–3.67(m,1H),3.62–3.47(m,1H),3.47– 3.30(m,1H),3.23–3.11(m,1H),1.26(td,J=6.3,3.2Hz,1H).13C-NMR(100MHz,D2O)δ170.40,142.13,135.06,133.91,130.37,130.17,129.40,128.40,124.36,103.78,101.93,66.55, 51.84(2C),45.31,45.13,44.65,43.05,42.60,40.48,17.88(2C).
17)化合物AM21-AM30的制备
将中间体酸X-1(0.5mmol)用DMF(6mL)溶解,依次加入HBTU(0.53mmol),DIEA(3.0mmol),室温活化15min后,分别加入中间体3b-3d(0.5mmol),室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM21-AM30,此过程中洗脱溶剂为体积比1:2~1:4的乙酸乙酯:石油醚
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM21)类白色固体,产率:58%,mp:138~140℃,1H NMR(400MHz,DMSO)δ8.21(s,1H),8.14(s,1H), 7.60(d,J=7.2Hz,2H),7.33(d,J=8.1Hz,2H),4.51(br,1H),4.31(br,2H),3.95(s,1H),3.72(s, 1H),3.60(br,3H),3.43(br,3H),3.15(s,1H),2.92(d,J=9.6Hz,1H),1.15(s,6H).13C NMR(101 MHz,DMSO)δ169.26,153.46,152.18,151.99,138.99,136.86,132.46,130.68,121.37,119.30, 50.33,49.06,48.65,45.73,45.08(2C),42.16,20.21,19.93.
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM22) 类白色固体,产率:66%,mp:113-116℃,1H NMR(400MHz,DMSO)δ8.19(d,J=29.3Hz, 2H),7.71(s,1H),7.45(d,J=7.5Hz,1H),7.36(d,J=8.3Hz,1H),4.58(s,1H),4.34(s,2H),3.98 (s,1H),3.87–3.47(m,5H),3.30–3.13(m,2H),2.94(s,1H),2.80(d,J=8.6Hz,1H),1.06(s, 6H).13C NMR(101MHz,DMSO)δ169.55,153.45,152.09,152.01,139.02,134.86,133.94, 133.30,130.94,129.55,128.53,119.31,49.37,48.64,46.05–44.38(m),44.47,44.47,44.11,42.19, 21.86,21.66.
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM23)淡黄色固体,产率:56%,mp:160-162℃,1H NMR(400MHz,DMSO)δ8.62(s,1H),7.99(d,J =8.3Hz,1H),7.81(s,2H),7.56(d,J=8.2Hz,3H),7.30(d,J=8.4Hz,2H),4.29(br,1H),3.82– 3.62(m,5H),3.58-3.48(m,1H),3.53–3.45(m,1H),3.28-3.25(m,2H),3.00–2.87(m,1H),2.84 –2.74(m,2H),1.07–1.02(m,6H).13C NMR(101MHz,DMSO)δ170.02,164.12,153.98, 151.71,137.70,133.30,132.26(2C),130.61(2C),128.50,126.24,125.76,121.00,116.32,49.36 (3C),46.83,46.13,44.93,41.83,21.71(2C).
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM24) 淡黄色固体,产率:53%,mp:155~157℃,1H NMR(400MHz,DMSO)δ8.63(s,1H),8.01(d, J=8.2Hz,1H),7.82(s,2H),7.67(s,1H),7.54(s,1H),7.43(d,J=8.3Hz,1H),7.34(d,J=8.4 Hz,1H),4.46(s,1H),3.85–3.66(m,5H),3.61(br,1H),3.49–3.42(m,1H),3.20–3.08(m,1H), 2.91-2.64(m,3H),0.99(d,J=5.8Hz,6H).13C NMR(101MHz,DMSO)δ169.99,164.11,153.97, 151.71,135.36,133.96,133.29,133.04,130.87,129.44,128.49,128.39,126.25,125.81,116.33, 49.29,49.22,48.79,48.730,44.93,44.71,41.87(s),22.80(2C).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1- 酮(AM25)白色固体,产率42%,mp:185-187℃,1H NMR(400MHz,DMSO)δ13.59(s,1H),8.23(s,2H),7.54(d,J=8.0Hz,2H),7.30(d,J=8.1Hz,2H),4.22(s,1H),3.95(br,2H), 3.87–3.62(m,4H),3.59-3.41(m,2H),3.28-3.21(m,1H),3.23–3.11(m,1H),2.81-2.75(s,1H), 2.69-2.58(m,1H),0.97(s,6H).13C NMR(101MHz,DMSO)δ170.74,156.92,155.94,155.08, 138.45,134.00,132.06(2C),130.63(2C),120.73,100.02,63.48,51.28,48.68,47.78,46.15,44.60, 41.86,41.40,22.89(2C).
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基) 丙-1-酮(AM26)白色固体,产率32%,mp:167-169℃,1H NMR(400MHz,DMSO)δ13.59(s,1H),8.26(s,2H),8.24(s,1H),7.72(s,1H),7.44(dd,J=8.5,2.1Hz,1H),7.33(d,J=8.5Hz, 1H),4.56(br,1H),4.03-3.95(m,2H),3.91–3.49(m,6H),3.31–3.21(m,2H),2.93-2.84(m,1H), 2.84–2.75(m,1H),1.07(s,6H).13C NMR(101MHz,DMSO)δ169.79,157.08,155.97,154.82, 133.95(2C),133.11,130.95(2C),129.81,128.06,100.39,63.49,49.43,45.85,44.46,43.99,42.05, 41.64,23.60,23.09.
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM27)类白色固体,产率36%,mp:172-175℃,1H NMR(400MHz,DMSO)δ 8.32(s,1H),7.67(s,1H),7.42(dd,J=8.5,2.2Hz,1H),7.35(d,J=8.5Hz,1H),4.50-4.79(m, 1H),3.87-3.82(m,2H),3.76-3.70(m,4H),3.49–3.40(m,2H),3.20-3.08(m,1H),2.83-2.76(m, 1H),0.99(d,J=6.2Hz,6H).13C NMR(101MHz,DMSO)δ170.11,158.26,156.79,155.44, 135.35,134.26,132.87,130.68,129.37,128.35,98.89,49.58,48.77,48.07,45.93,44.91,44.50, 41.78,22.66,22.45.
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM28)类白色固体,产率37%,mp:187-190℃,1H NMR(400MHz,DMSO)δ8.31 (s,1H),7.54(d,J=8.3Hz,2H),7.30(d,J=8.3Hz,2H),4.28(s,1H),3.84–3.65(m,6H),3.55– 3.43(m,2H),3.18(t,J=14.5Hz,2H),2.82(br,1H),1.00(d,J=5.0Hz,6H).13CNMR(101MHz, DMSO)δ170.62,158.55,157.29,155.75,138.17,132.19(2C),131.37,130.21(2C),99.12,50.85, 48.88,48.44,47.27,46.07,45.08,41.78,22.47,22.39.HRMS(ESI):m/z for C21H25Br2N7O [M+H]+,calculated 552.0467,found 552.0556.
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM29)白色固体,产率46%,mp:173-176℃,1H NMR(400MHz,DMSO)δ8.34 (s,1H),7.68(s,1H),7.43(d,J=8.0Hz,1H),7.34(d,J=8.2Hz,1H),4.49(s,1H),3.84–3.64(m, 6H),3.48-3.35(m,1H),3.26-2.24(m,1H),3.20–3.10(m,1H),2.86-2.57(m,2H),0.99(s, 6H).13C NMR(101MHz,DMSO)δ170.03,158.98,157.06,157.06,154.95,133.93,133.08, 130.95,129.30,128.45,119.14,52.63,49.04,48.93,46.06,44.96,44.46,41.93,22.53,22.41.
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基) 丙-1-酮(AM30)类白色固体,产率38%,mp:175-178℃,1H NMR(400MHz,DMSO)δ8.33 (s,1H),7.53(d,J=8.2Hz,2H),7.30(d,J=8.3Hz,2H),4.29–4.19(m,1H),3.82–3.59(m,6H), 3.54-3.49(m,1H),3.19–3.10(m,1H),3.10-3.04(m,1H),2.76(dt,J=12.2,6.1Hz,1H),2.67(dd, J=11.5,5.2Hz,1H),0.97(d,J=6.2Hz,6H).13C NMR(101MHz,DMSO)δ170.70,158.85, 157.12,155.03,138.56,131.83(2C),130.25(2C),120.67,118.97,101.53,51.27,49.22,49.12, 48.59,46.13,45.07,41.79,23.01,22.87.HRMS(ESI):m/zfor C21H25BrClN7O[M+H]+,calculated 508.0972,found 508.1061.
17)化合物AM31-AM33的制备
将中间体酸X-2(1.0mmol)用DMF(8mL)溶解,室温的条件下搅拌20min,冰浴冷却至0℃,加入HBTU(1.10mmol,418mg)和DIEA(3mmol,116mg),继续冰浴搅拌10min,然后加入中间体3a-3c(1.00mmol),在冰浴的条件下,继续搅拌48h,待反应至完全后,停止反应;向反应液中加入10倍DMF体积的冷蒸馏水,待沉淀慢慢析出至完全,将沉淀过滤,水洗,真空干燥后,柱层析分离纯化(洗脱剂为石油醚:乙酸乙酯=2:1)得到油状液体,然后将所得物置于于5ml甲醇溶液中,搅拌10min后加入4M的HCl-二氧六环溶液15ml,室温下搅拌48h,减压蒸除有机溶剂,蒸除后析出固体,过滤,用乙酸乙酯洗涤滤饼,真空干燥,得到目标化合物AM31-AM33。
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(乙氨基)丙-1- 酮(AM31)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.17(s,1H),7.53(d,J=1.8 Hz,1H),7.29(d,J=3.6Hz,1H),7.15(dd,J=8.4,1.8Hz,1H),7.08(d,J=8.4Hz,1H),6.66(d, J=3.6Hz,1H),4.13–4.00(m,2H),4.00–3.87(m,2H),3.71–3.62(m,4H),3.52(dd,J=12.8, 8.6Hz,1H),3.41–3.31(m,1H),3.21(dd,J=12.8,4.2Hz,1H),3.07(q,J=7.2Hz,2H),1.21(t, J=7.2Hz,3H).13C-NMR(100MHz,D2O)δ170.50,142.24,135.13,133.95,130.22,129.44, 128.43,124.34,103.74,101.97,66.55,47.48,45.29,44.62,43.67,43.07,42.36,40.45,10.12(2C).
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(乙氨基) 丙-1-酮(AM32)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.14(s,1H),7.53(d,J =2.1Hz,1H),7.34(s,1H),7.24(dd,J=8.4,2.1Hz,1H),7.14(d,J=8.4Hz,1H),4.07–3.97(m, 2H),3.94–3.85(m,1H),3.80–3.72(m,1H),3.72–3.66(m,1H),3.62(ddd,J=10.6,6.4,2.4Hz, 2H),3.52(dd,J=8.2,3.9Hz,1H),3.33(dt,J=9.5,7.8Hz,1H),3.22(dd,J=12.9,4.3Hz,1H), 3.14(ddd,J=14.7,6.9,3.1Hz,1H),3.08(q,J=7.3Hz,2H),1.21(t,J=7.3Hz,3H).13C-NMR (100MHz,D2O)δ170.09,145.67,143.12,135.23,133.89,130.49,130.25,129.77,128.62,123.68, 105.02,101.27,61.70,48.97,48.18,47.55,44.11,43.70,42.41,41.52,20.50.
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)-哌嗪-1-基)-2-(2.4-二氯苯基)-3-(乙氨基) 丙-1-酮(AM33)浅黄色固体,产率75%,1H-NMR(400MHz,D2O)δ8.14(s,1H),7.53(d,J =2.1Hz,1H),7.34(s,1H),7.24(dd,J=8.4,2.1Hz,1H),7.14(d,J=8.4Hz,1H),4.07–3.97(m, 2H),3.94–3.85(m,1H),3.80–3.72(m,1H),3.72–3.66(m,1H),3.62(ddd,J=10.6,6.4,2.4Hz, 2H),3.52(dd,J=8.2,3.9Hz,1H),3.33(dt,J=9.5,7.8Hz,1H),3.22(dd,J=12.9,4.3Hz,1H), 3.14(ddd,J=14.7,6.9,3.1Hz,1H),3.08(q,J=7.3Hz,2H),1.21(t,J=7.3Hz,3H).13C-NMR (100MHz,D2O)δ170.09,145.67,143.12,135.23,133.89,130.49,130.25,129.77,128.62,123.68, 105.02,101.27,61.70,48.97,48.18,47.55,44.11,43.70,42.41,41.52,20.50。
Claims (9)
1.一种含氨甲基的哌嗪酮类化合物或其药用盐,其特征在于,其结构如通式I所示:
通式I中,
R1是氢,卤素,多取代卤素,硝基,氨基,取代氨基,氰基,C1~6直链或支链烷氧基,C1~6直链或支链烷基;
R3是C1~6直链或支链烷基,C1~6直链或支链烷氧基,多元杂环;
Z是:
其中,R2是氢,卤素,C1~6烷基,氨基,取代氨基。
2.如权利要求1所述的含氨甲基的哌嗪酮类化合物,其特征在于,R1是氢,氟,溴,氯或2,4-二氯取代;R2是氢,溴,氯;R3是甲基异丙氨基,乙基氨基。
3.如权利要求1或2所述的含氨甲基的哌嗪酮类化合物,其特征在于,选自下列化合物之一:
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM1)、
1-(4-(2-(甲基氨基)噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM2)、
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM3)、
1-(4-(2-(甲基氨基)嘧啶-4-基)哌嗪-1-基)2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM4)、
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM5)、
1-(4-(2-(甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM6)、
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM7)、
1-(4-(5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM8)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基)丙-1-酮(AM9)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基)丙-1-酮(AM10)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氟苯基)-3-(异丙基氨基)丙-1-酮(AM11)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基)丙-1-酮(AM12)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基)丙-1-酮(AM13)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-氯苯基)-3-(异丙基氨基)丙-1-酮(AM14)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM15)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM16)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM17)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM18)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM19)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM20)、
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM21)、
1-(4-(9H-嘌呤-6-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM22)、
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM23)、
1-(4-(喹唑啉-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM24)、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM25)、
1-(4-(1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM26)、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM27)、
1-(4-(3-氯-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM28)、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(异丙基氨基)丙-1-酮(AM29)、
1-(4-(3-溴-1H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-基)-2-(4-溴苯基)-3-(异丙基氨基)丙-1-酮(AM30)、
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基)丙-1-酮(AM31)、
1-(4-(5-氯-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基)丙-1-酮(AM32)、
1-(4-(5-溴-7H-吡咯并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-(2,4-二氯苯基)-3-(乙基氨基)丙-1-酮(AM33)。
4.如权利要求1所述的含氨甲基的哌嗪酮类化合物的制备方法,包括步骤:
(1)起始原料A-1、B-1、C-1、D-1、E-1、1a-1d和4a-4c与Boc-哌嗪,在DMF或者NMP溶液中,加入或者微波条件下反应分别得中间体A-2、中间体B-2、中间体C-2、中间体D-2、中间体E-2、中间体2a-2d、中间体5a-5c;
(2)中间体A-2、B-2、C-2在甲胺醇溶液中,加热反应分别得中间体A-3、中间体B-3、中间体C-3;
(3)中间体A-3、中间体B-3、中间体C-3、中间体D-2、中间体E-2、中间体2a-2d、中间体5a-5c,在乙酸乙酯/浓盐酸溶液或三氟乙酸/二氯甲烷或盐酸二氧六环溶液中脱去叔丁氧羰基,分别得中间体A-4、中间体B-4、中间体C-4、中间体D-3、中间体E-3、中间体3a-3d、中间体6a-6c;
(4)将中间体酸X-1用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体胺(A-4,B-4,C-4,D-3,E-3,3a或6a-6c),室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA,反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得目标化合物AM1-AM20,洗脱***为体积比50:1~10:1的DCM/MeOH;
(5)将中间体酸X-1用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3b-3d室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM21-AM30,此过程中洗脱溶剂为体积比1:2~1:4的乙酸乙酯:石油醚;
(6)将中间体酸X-2用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3a-3c室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM31-AM33;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,N,N-二甲基甲酰胺(DMF)或2-甲基吡咯烷酮(NMP),N,N-二异丙基乙胺(DIEA);b.质量比27%~70%甲胺醇溶液,100℃;c.乙酸乙酯/浓盐酸溶液或三氟乙酸(TFA)/二氯甲烷(DCM),室温;d.盐酸二氧六环溶液,甲醇,室温;e.(i)中间体酸X,HBTU,DIEA,DMF,(ii)TFA,DCM或(ii)HCl·二氧六环,甲醇,室温。
5.如权利要求3所述的含氨甲基的哌嗪酮类化合物AM1-AM6的制备方法,包括步骤:
(i)将起始原料A-1、B-1、C-1,用DMF溶解,依次将DIEA,1-Boc哌嗪加入反应瓶中,90℃反应4h,TLC检测反应完全,将反应液倒入10倍量冰水中,析出大量白色固体,过滤,用水洗滤饼,干燥,得中间体A-2、B-2、C-2;
(ii)中间体A-2、B-2、C-2加入茄型瓶中,加入20-30mL甲胺醇溶液,100℃密封反应6h,反应完毕后,冷却至室温析出白色晶体,将反应瓶放入-20℃冷却2h,析出更多白色晶体,过滤,干燥得中间体A-3、B-3、C-3;
(iii)将中间体A-3、B-3、C-3,用二氯甲烷溶解,室温下加入三氟乙酸(TFA),室温搅拌过夜,反应完毕,减压蒸干溶剂得油状物,用饱和碳酸钠水溶液调pH至10,析出淡黄色固体,过滤,干燥得粗品,柱层析纯化得中间体A-4、B-4、C-4,洗脱***为二氯甲烷/甲醇(50:1),此过程中,DCM与TFA的体积比为1:2~1:4;
(iv)将中间体酸X-1用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体A-4、B-4、C-4,室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA(DCM与TFA的体积比为1:2~1:4),反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9-10,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得AM1-AM6,洗脱***为体积比50:1~10:1DCM/MeOH;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,90℃,DMF,DIEA;b.甲胺醇溶液,100℃;c.TFA,DCM,室温;e.(i)中间体酸X-1,HBTU,DIEA,DMF(ii)TFA,DCM。
6.如权利要求3所述的含氨甲基的哌嗪酮类化合物AM7-AM30的制备方法,包括步骤:
(i)将起始原料D-1、E-1、1a-1d和4a-4c,用NMP溶解,依次加入1-Boc哌嗪和DIEA,150℃微波反应20min,将反应液倒入10倍量冰水中,析出白色沉淀,用乙酸乙酯萃取,合并有机相,依次用氯化铵,食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得中间体D-2、E-2、2a-2d和5a-5c,洗脱***为体积比9:1~12:1的石油醚/乙酸乙酯;
(ii)中间体D-2、E-2、2a-2d和5a-5c,用乙酸乙酯溶解,室温下,加入浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得中间体D-3、E-3、3a-3d和6a-6c;
(iii)将中间体酸X-1,用DMF溶剂溶解,依次加入HBTU,DIEA,室温搅拌15min,加入中间体D-3、E-3、3a和6a-6c,室温反应过夜,TLC检测反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,用二氯甲烷萃取,合并有机相,依次用氯化铵,食盐水,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,将粗品用二氯甲烷溶解,室温下加入TFA,DCM与TFA的体积比为1:2~1:4,反应4h,减压蒸除反应液,用饱和碳酸钠调pH至9-10,用二氯甲烷萃取,合并有机相,用食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除二氯甲烷得粗品,柱层析分离纯化得AM7-AM20,洗脱***为体积比50:1~10:1的DCM/MeOH;
(iv)将中间体酸X-1用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3b-3d室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM21-AM30,此过程中洗脱溶剂为体积比1:2~1:4的乙酸乙酯:石油醚;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,150℃,NMP,DIEA;d.TFA,DCM,室温或盐酸二氧六环溶液,甲醇,室温e.(i)中间体酸X-1,HBTU,DIEA,DMF(ii)TFA,DCM或者(ii)盐酸二氧六环溶液。
7.如权利要求3所述的含氨甲基的哌嗪酮类化合物AM31-AM33的制备方法,包括步骤:
(i)将起始原料1a-1c用NMP溶解,依次加入1-Boc哌嗪和DIEA,150℃微波反应20min,将反应液倒入10倍量冰水中,析出白色沉淀,用乙酸乙酯萃取,合并有机相,依次用氯化铵,食盐水洗涤有机相,无水硫酸钠干燥,过滤,减压蒸除溶剂得粗品,柱层析纯化得中间体2a-2c,洗脱***为体积比9:1~12:1的石油醚/乙酸乙酯;
(ii)中间体2a-2c,用乙酸乙酯溶解,室温下,加入浓盐酸,室温搅拌6h,析出灰白色固体,过滤,干燥,得中间体3a-3c;
(iii)将中间体酸X-2用DMF溶解,依次加入HBTU,DIEA,室温活化15min后,分别加入中间体3a-3c室温反应过夜,反应完全后,将反应液用10倍量冰水淬灭,析出白色沉淀,过滤干燥得固体,柱层析纯化得粗品,将其用甲醇溶解,在盐酸二氧六环溶液中脱除叔丁氧羰基得化合物AM31-AM33,此过程中洗脱溶剂为体积比1:2~1:4乙酸乙酯:石油醚;
合成路线如下:
试剂及条件:a.1-Boc-哌嗪,150℃,NMP,DIEA;d.盐酸二氧六环溶液,甲醇,室温e.(i)中间体酸X-2,HBTU,DIEA,DMF(ii)盐酸二氧六环溶液。
8.一种如权利要求1-3任一项所述含氨甲基的哌嗪酮类化合物在制备抗肿瘤药物中的应用。
9.一种药物组合物,包含权利要求1-3任一项所述含氨甲基的哌嗪酮类化合物和一种或多种药学上可接受载体或赋形剂。
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