CN117946018B 一种均三嗪类lsd1抑制剂及其制备方法、应用 （郑州大学）

用合物或其药学上可接受的盐：本发21.一种均三嗪类化合物，其特征在于，为式I所示的化合物或其药学上可接受的盐：1342B(OH)21作为活性成分在制备针对LSD1靶点的抑制剂中5合物在LSD1靶点蛋白抑制方面的作用，更未公开对LSD1蛋白具有高抑制活性、能够作为6中的一种；789R3为℃,或者，X为NH、R1为O-C.R2为R3为℃,或者，X为NH、R1为O-C.R2为R3为或者，X为NH、R1为-C.R2为R3为[0025]上述均三嗪类LSD1抑制剂的制备方法，采用如下合成路线①或者合成路线②制2B(OH)21进行具体限定。54.73,53.05,45.60.HR‑MS(ESI)℃,R3=H,R2＝R3=℃1.27(m,2H).13CNMR(100MHz,DMSO_d6)δ170.17,164.17,136.24,132.06,128.53,128.20,169.94,165.74,136.37,136.13,132.00,128.52,128.22,127.99,55.06,25.37,23.13.HR_xC,R2=℃R3=CNMR(100MHz,DMSO_d6)δ165.91,334.1665.CNMR(100MHz,CDCl3)δ166.51,136.45,132.347.1978.甲基1哌嗪乙胺替换为苯胺，制备得到化合物7，收率为30.2％。结构表征为：1HNMR[0080]均三嗪类化合物9，符合通式式Ⅰ,其中，X＝NH，R1＝R2=℃,R3=CNMR(100MHz,DMSOd6)δ171.01,164.58,143.57,136.46,131.32,128.47,122.34,114.24,55.59.HRMS(ESI)calcdC22H18N4O[M+H]+,8.7Hz,2H),3.66(s,2H).13CNMR(100MHz,CDCl3)δ164.95,143.03,1340.1561.[0100]均三嗪类化合物14，符合通式式Ⅰ,其中，X＝S，R1＝O-W,R2＝R3=129.86,128.77,128.51,110.61,106.92.HRMS(ESI)calcdforC21H17N5[M+H]+,340.1557；found,340.1560.NMR(100MHz,DMSO一d6)δ171.46[0112]均三嗪类化合物17，符合通式式Ⅰ,其中，X＝NH，R1＝OX.R2＝R3=136.18,132.25,128.63,128.37,128.24,128.12,122.05,112.63,40.48.HRMS(ESI)calcd[0116]均三嗪类化合物18，符合通式式Ⅰ,其中，X＝NH，R1＝O-C.R2=℃,R3=CNMR(100MHz,170.14,164.30,136.05,132.11,128.50,128.19,118.72,114.80,50.56,43.05.HRMS(ESI)410.1970.HNMR(400MHz,CDCl3)δ8.58(d,J=HNMR(400MHz,CDCl3)δ8.58(d,J=HNMR(400MHz,CDCl3)δ8.55(d,J=164.77,162.89,144.95,136.81,131.80,130.57,128.37,127.06,122.57,113.73,112.53,HNMR(400MHz,CDCl3)δ8.38(dd,J=152.52,152.26,145.15,144.91,135.83,135.70,132.34,132.25,129.39,129.26,129.04,HNMR(400MHz,CDCl3)δ8.40(d,J=C129.57,128.73,128.50,127.40,126.29,122.87,112.34,44.59,44.49,12.62.HRMS(ESI)苯硼酸替换为2异丙基苯硼酸，将步骤3)中的4甲基1哌嗪乙胺替换为N,N二乙基对苯HNMR(400MHz,CDCl3)δ8.53(d,J=CNMR(100MHz,CDCl3)δ145.11,136.66,136.55,131.96,130.21,128.42,126.58,126.18,125.58,122.67,found,438.2651.R2＝R3=CNMR(100MHz,CDCl3)δ164.83,164.22,161.79,145.12,132.09,129.92,129.84,128.45,126.53,124.47,苯硼酸替换为3乙酰基苯硼酸，将步骤3)中的4甲基1哌嗪乙胺替换为N,N二乙基对苯137.16,132.12,131.28,128.79,128.47,122.92,122.70,112.28,44.60,12.60.苯硼酸替换为3乙酰氨基苯硼酸，将步骤2)中的4甲基1哌嗪乙胺替换为N,N二乙基对R2=HNMR(400MHz,CDCl3)δ8.617.1Hz,4H),1.19(t,J＝7.0Hz164.78,164.19,145.05,136.53,132.80,131.99,130.89,128.62,128.42,126.64,122.71,115.39(J＝21.6Hz),112.36,44.60,12.61.HRMS(ESI)calcdforC25H24FN5[M+H]+,150.86,145.02,136.54,131.97,128.42,126.72,124.48,123.99,122.66,112.50,112.40,144.95,136.32,131.99,131.14,130.61,128.67,128.38,128.15,126.77,124.46,123.98,found,402.1748.。)δ9.40(s,131.95,129.46,128.43,128.04,127.77,127.51,126.82,126.24,122.67,112.42,44.62,HNMR(400MHz,CDCl3)δ8.96(s,7X.R2＝R3=CNMR(100MHz,CDCl3)δ164.37,147.71,147.64,147.11,145.05,142.22,139.83,138.57,138.48,136.23,132.12,128.89,128.62,128.45,127.60,126.65,126.19,125.15,124.64,124.49,124.01,122.77,122.64,122.48,119.12,112.41,44.63,12.64.HRMS(ESI)calcdforC27H25N5S[M+R3δ8.51(d,J128.61,128.35,126.89,122.61,112.43,47.45,44.62,15.41,12.60.HRMS(ESI)calcdforR3128.36,126.84,122.61,112.42,44.62,33.17,12.60,6.65.HRMS(ESI)calcdforC25H27N733替换为N,N二乙基对苯二胺，制备得到化合物44，收率为48.0％。结构表征为：1HNMR136.51,135.86,131.84,131.70,128.93,128.59,128.35,128.29,127.83,126.81,122.60,476.2558.[0230]1)将化合物Ⅱ(2g，10.85mmol)、4‑甲基苯基溴化镁(0.5MinTHF)(24mL，饱和食盐水(3×10mL)洗涤有机相，无水硫酸镁干燥，柱层析纯化即得到均三嗪类化合物128.60,127.07,122.53,112.54,44.64,39.22,21.59,12.59.HRMS(ESI)calcdforC24H27N7CNMR(100MHz,CDCl3)δ170.88162.81,144.90,140.56,132.28,130.43,129.13,127.12,122.54,113.71,112.54,55.44,xC.R2＝R3=161.76,145.09,140.62,139.15,132.44,129.76,126.65,124.21,122.73,118.50,115.26,418.2147.24.14,12.54.[0254]LSD1抑制活性测定：样品为实施例1～51所制备得到的均三嗪类化合物经纯化得加入LSD1底物H3K4me2并孵育，最后加入荧光染料Amplex和辣根过氧化