CN116514779B 2,4-二取代-5-氟嘧啶衍生物及其制备方法和应用 （长沙晶易医药科技股份有限公司）

区麓天路28号金瑞麓谷科技园A-3栋8activationinhibitors.BioorgaMedicinalChemistryLetters.20152,4-二取代-5-氟嘧啶衍生物及其制备方法R本发明还公开了所述化合物的制备方法和它们21为2为3R4为Z和R2另一为：34为N241(5氟4((4(4异戊基哌嗪1基)苯基)氨基)嘧啶2基)1H苯并[d]咪唑2N6N6N6N6N6N6胺基)吡啶2基)哌嗪1羧酸酯；胺基)吡啶3基)哌嗪1羧酸酯；N6N6N6N61(4(4((2((2(二甲基胺基)1H苯并[d]咪唑6基)胺基)5氟嘧啶4基)胺N62(4(4((2((2(二甲基胺基)1H苯并[d]咪唑6基)胺基)5氟嘧啶4基)胺5N6(5氟4((4(4异戊基哌嗪1基)苯基)胺基)嘧啶2基)N2，N2二甲基1H苯N6(4((4(4苄基哌嗪1基)苯基)胺基)5氟嘧啶2基)N2，N2二甲基1H苯并1(4(4((2((2(二甲基胺基)1H苯并[d]咪唑6基)胺基)5氟嘧啶4基)胺N6(5氟2((4(吡咯1基)苯基)胺基)嘧啶4基)N2，N2二甲基1H苯并[d]咪N6(5氟2((4(哌嗪1基)苯基)胺基)嘧啶4基)N2，N2二甲基1H苯并[d]咪N6(5氟2((6(哌嗪1基)吡啶3基)胺基)嘧啶4基)N2，N2二甲基1H苯并N6(2((4(二甲基胺基)苯基)胺基)5氟嘧啶4基)N2，N2二甲基1H苯N6(5氟2((5(哌嗪1基)吡啶2基)胺基)嘧啶4基)N2，N2二甲基1H苯并1(4(4((4((2(二甲基胺基)1H苯并[d]咪唑6基)胺基)5氟嘧啶2基)胺N6(5氟2((4(4异戊基哌嗪1基)苯基)胺基)嘧啶4基)N2，N2二甲基1H苯N666啶类衍生物或其药学上可用的盐以及药学上72,4_二取代_5_氟嘧啶衍生物及其制备方法和没有成功的药物上市(NatRevDrugDiscov,2016,15(8):568；AmJKidneyDis.2022,对这些下游靶标寻找高效的肾间质纤维化治疗药物并不化合物均是通过脱靶效应研究发现的，如TAE_226(NatMed.2012,18(4):580)、CTx_(phosphateniclosamide)(KidneyInternational.2017,92:612)可以通过干扰Smad3与[0005]发明专利201911152583.9和PCT/CN2020/129308公开了一种含脲基苯并咪唑类衍8[0007]发明专利CN106565673公开了一种具有Wnt信号通路抑制活性的5_氟嘧啶杂环化[0009]发明专利CN105017159公开了一种5_氟_2,4_二取代氨基嘧啶衍生物及其制备方和R2可分别独立选自：9[0022]优选的，R1和R2任一为：R4为Z为氢，R1和R2另一不为：C5烷基酰[0042]叔丁基4(4((2((1H苯并[d]咪唑2基)氨基)5氟嘧啶4基)氨基)苯基)[0044]叔丁基4(4((5氟2(((四氢呋喃2基)甲基)氨基)嘧啶4基)氨基)苯基)[0059]甲基4((5氟4((4(4异戊基哌嗪1基)苯基)氨基)嘧啶2基)氨基)苯甲[0060]叔丁基4(5(2(2氨基1H苯并[d]咪唑1基)[0062]1(5氟4(6(4异戊基哌嗪1基)吡啶3基)嘧啶2基)1H苯并[d]咪唑[0068]叔丁基4(4((2(([0070]叔丁基4(5((2(([0071]叔丁基4(5((2(([0087]N6(2((4(二甲基胺基)苯基)胺基)5氟嘧啶4基)N2，N2二甲基1H苯并[0090]N6(5氟2((4(4异戊基哌嗪1基)苯基)胺基)嘧啶4基)N2，N2二甲基N6氟嘧啶与硼酸酯反应生成的中间体继续与2氨基苯并咪唑反应得到可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学[0103]另一方面，本发明所述化合物包括使用各种同位素标记的本发明所定义的化合2CO3,Xantphos,Pd2(dba)3,1,4_dioxane,N2protection,sealed2CO3条件和试剂:a.Correspondingamines,DMSO,K2CO3,90℃,5hordiethylamine,DMSO,唑片段16，在通过氢气还原的方法将硝基还原成氨基合成得到含氨基的苯并咪唑片段17。然后以18a_c作为起始原料，亲核取代反应接入对应脂肪氨基达到对位为硝基的芳香环联做溶剂的条件下发生Buchwald–Hartwig偶联反应得到目标化合物23a_i。其中23f_h脱BocK2CO3,65℃,16h；for25d,2_bromoethan_1_ol,ACN,Et3N,r.t.,16h；for25e,ethanesulfonylchloride,ACN,Etfor25h,3,3_dimethylbutanoylchloride,ACN,Et3N,_10℃,10min；for25i,2_isocyanato_2_methylpropane,AC条件和试剂:a.17,MeOH,H2O,60℃,12h；b.(Boc)2O,DMAP,Et3N,DCM,r.t.,24h；[0128]首先化合物17和原料12在甲醇做溶剂不需要任何碱性试剂的条件下发生亲核取[0132]将化合物5(2.03g，5mmoδ9.87(s,1H),[0134]叔丁基4(4((2((1H苯并[d]咪唑2基)氨基)5氟嘧啶4基)氨基)苯基)130.78,124.32,116.68,79.49,49.06,28.55.HRMS151.45,149.20,148.07,140.71,140.55,137.94,131.10,130.69,128124.77,124.56,116.71,104.44,79.48,49.25,28.55.HRMS(ESI)m/zcalcdfor473.2723.147.03,136.92,132.18,122.17,120.86,116.62,79.41,49.47,47.22,28.53.HRMS(ESI)m/CNMR(125MHz,DMSOd6)δ166.49,155.37,155.35,154.30,150.74,148.12,146.12,140.49,140.38,140.23,131.18,130.42,124.18,121.34,117.59,116.70,79.44,52.06,49.41,28.52.HRMS(ESI)m/z[0143]叔丁基4(5(2(2氨基1H苯并[d]咪唑1基)HNMR(500MHz,DMSOd6)δ8.838.77(m,2H),8.13(q,J＝4.9,4.0Hz,CNMR147.12,146.86,143.53,137.90,137.83,131.92,123.63,119.79,117.23,117.17,115.70,114.22,107.10,79.61,44.32,28.53.HRMS(ESI)m/zcalcdfor[C25H27FN8O2+H]+:151.45,150.81,149.18,142.20,140.73,140.57,140.23,137.95,130.73,128.05,126.28,125.05,124.82,124.77,116.08,104.43,49.06,45.86.HRMS(ESI)m/zcalcdfor[C23H22FN7131.73,122.17,120.94,116.04,49.62,47.25,45.48.HRMS(ESI)m/zcalcdfor[C20H22FN7+13CNMR(101MHz,DMSOd6)δ166.51,155.4150.78,150.67,148.88,146.14,140.34,140.15,130.49,130.42,124.24,121.34,117.59,423.1968.[0156]1(5氟4(6(哌嗪1基)吡啶3基)嘧啶2基)1H苯并[d]咪唑2胺的制HNMR(400MHz,DMSOd6)δ8.80(dd,J＝15.8,3.0Hz,2H),8.198.07(m,146.57,143.50,137.58,131.89,123.56,119.73,116.60,115.65,114.25,106.72,45.76,Et3N＝20HNMR(500MHz,DMSOd6)δ9.87(s,1H),143.36,139.77,139.60,131.91,128.89,125.63,123.19,119.20,115.98,115.23,56.55,found:475.2762.[0160]5氟N4(4(4异戊基哌嗪1基)苯基)N2异喹啉3基)嘧啶2,4二胺的制备HNMR(500MHz,DMSOd6)δ9.47(s,1H),9.32(s,1H),9.06(s,1H),8.33(s,CNMR(125MHz,DMSOd6异戊基哌嗪1基)苯基)N249.44,35.62,29.69,29.43,26.72,23.35,22.73.HRMS(ESI)m/zcalcdfor[C25H32FN7+H]+:[0165]甲基4((5氟4((4(4异戊基哌嗪1基)苯基)氨基)嘧啶2基)氨基)苯甲Chloroformd)δ166.96,148.81,144.36,139.73,139.58,130.76,129.25,123.30,122.84,[0167]1(5氟4(6(4异戊基哌嗪1基)吡啶3基)嘧啶2基)1H苯并[d]咪唑HNMR(400MHz,Chloroformd)δ9.08(d,J＝2.5Hz,1H),8.52(d,J=13CNMR(101MHz,Chloroformd)δ159.84,153.77,153.07,150.49,150.35,150.25,145.50,145.23,142.52,137.64,131.93,123.73,120.49,116.14,114.49,106.10,57.01,53.05,44.68,35.85,26.67,22.76.HRMS(ESI)m/z[0169]实施例4：1(5氟4((4(4甲基哌141.66,139.81,139.61,131.91,128.95,125.66,123.19,119.20,116.07,115.25,115.21,CNMR(101MHz,DMSOd6)δ154.50,149.35,143.36,139.80,139.60,131.90,128.95,125.66,123.20,119.20,116.03,115.23,151.10,149.60,148.62,142.59,140.62,129.79,115.89,52.93,52.14,48.66,12.46.HRMS=8.4Hz,1H),3.18(s,6H).HRM=6.7Hz,4H),2.04–1.94(m,4H).HRMS(ESI)m/zcalcdfor[C10H12N2O2+H]+:193.0972；[0195]将4吗啉硝基苯(6.24g，30mmol)，铁粉(8.40g，150mmol)，氯化铵(7.95g，固体析出，抽滤得灰白色固体，用甲醇重结晶得灰白色固体5.0g，收率81％。1HNMRHNMR(500MHz,DMSOd6)δ9.70(s,1H),8.18(d,JHNMR(500MHz,DMSOd6)δ2H),6.75(d,J＝9.1Hz,2H),2.89(s,6H).HRMS(ESI)m/zcalcdfor[C12H12ClFN4+H]+:[0215]将化合物22a(2.53g，8mmol)，化合物9(1,4g，8mmol)，Pd2(d[0218]N6(4((4(二乙基氨基)苯基)氨基)5氟嘧啶2基)N2，N2二甲基1H苯并150.44,142.19,140.25,139.46,137.34,131.32,125.66,123.88,114.96,112.27,111.05,[0220]N6(4((4(二丙基氨基)苯基)氨基)5氟嘧啶2基)N2，N2二甲基1H苯并141.72,141.70,139.84,139.74,139.57,139.41,134.78,133.25,130.23,127.78,123.41,114.35,113.79,112.06,111.79,108.15,[0224]叔丁基4(4((2((156.79,156.74,150.10,150.01,147.29,141.73,140.29,139.78,134.16,132.04,122.60,[0226]叔丁基4(5((2((156.60,156.58,155.74,154.41,150.27,150.18,141.81,141.16,140.43,140.28,139.85,136.89,135.94,132.38,127.51,112.95,107.44,79.47,55.39,45.51,38.57,28.55.HRMS[0228]叔丁基4(6((2((149.34,149.23,145.16,143.69,141.64,141.42,141.23,139.19,136.46,116.05,113.38,111.56,104.59,79.51,52.45,49.08,38.60,28.52.HRMS(ESI)m/zcalcd[0230]N6(4((4(二甲基氨基)苯基)氨基)5氟嘧啶2基)N2，N2二甲基1H苯并150.20,147.40,141.78,140.05,139.90,139.83,134.12,129.1413CNMR140.19,139.73,133.88,131.43,122.63,115.94,113.41,50.25,45.98,38.55.HRMS(ESI)149.33,149.23,144.56,144.37,141.58,141.40,141.32,141.22,139.13,6一步分离纯化(DCM:MeOH:Et3N＝80:1:1)得白色固体0.20g，收率44％。1HNMR(500MHz,CNMR(125MHz,DMSOd6)δ152.45,150.29,146.31,142.05,140.15,136.73,132.48,132.15,123.07,116.67,114.80,111.20,102.78,52.82,46.67,42.75,39.15.HRMS(ESI)m/zcalcdfor[C24H28FN9+H]+:462.2524found:150.08,150.00,147.20,141.72,140.38,140.25,139.77,134.32,131.99,122.61,116.71,113.26,49.44,46.01,38.61,21.67.HRMS(ESI)m/zcalcdfor[C25H28FN9O+H]+:6147.41,141.71,140.35,140.31,140.18,139.75,134.11,131.47,122.66,116.05,113.10,54.39,49.34,48.54,38.57,18.53.HRMS(ESI)m/zcalcdfor[C26H32FN9+H]+:156.57,150.10,147.38,141.71,140.33,140.17,139.79,134.26,131.48,122.71,116.05,[0247]使用上述实施例13的方法，以化合物24a，乙烷磺酰氯为原料，制备得到化合物156.74,156.69,150.02,149.63,146.87,146.54,141.78,140.37,140.17,139.41,133.82,[0248]N6(5氟4((4(4异戊基哌嗪1基)苯基)氨基)嘧啶2基)N2，N2二甲基49.22,38.56,35.76,26.31,23.09.HRMS(ESI)m/zcalcdfor[C28H36FN9+H]+:518.3150found:518.3155[M[0250]N6(4((4(4苄基哌嗪1基)苯基)氨基)5氟嘧啶2基)N2，N2二甲基1H140.31,140.18,139.73,138.54,133.97,131.45,129.39,128.67,127.45,122.62,116.07,546.3100found:546.3106[0258]叔丁基6((叔丁氧基碳酸酯)(2氯5氟嘧啶4基)氨基)2(二甲基氨基)[0259]将N6(2氯5氟嘧啶4基)N2，N2二甲基1H苯并[d]咪唑2,6二胺剂，得橙红色油状物，放置于油泵中抽干2h，得橙红色固体4.72g，收率93％。1HNMR[0261]将6((叔丁氧基羰基)(2氯5氟嘧啶4基)氨基)2(二甲基氨基)1H苯并滤，旋干有机溶剂，得黑色油状物，用硅胶柱层析对其150.68,146.73,141.75,140.35,140.34,140.21,140.19,139.80,133.81,120.17,116.31,114.35,50.92,46.19,38.51.HRMS(ESI)m/zcalcdfor[C23H26FN9+H]+:448.2368found:[0268]N6(2((4(二甲基氨基)苯基)氨基)5氟嘧啶4基)N2，N2二甲基1H苯并156.53,150.67,150.59,146.15,141.69,140.35,140.19,139.74,131115.36,113.48,111.16,107.34,41.28,38.58.HRMS(ESI)m/zcalcdfor[C156.53,150.67,150.59,146.15,141.69,140.35,140.19,139.74,131.8115.36,113.48,111.16,107.34,41.28,38.58.HRMS(ESI)m/zcalcdfor[C2449.2320found:449.23N6CNMR132.38,130.94,130.77,128.38,127.52,119.24,117.67,111.44,111.20,107.04,105.32,13CNMR[0276]N6(5氟4((4(4异戊基哌嗪1基)苯基)氨基)嘧啶2基)N2，N2二甲基141.83,140.49,140.34,139.88,134.61,132.41,120.26,116.81,116.05,111.24,106.91,55.09,51.77,47.54,38.79,33[0290](2)试剂与仪器：96孔板(Corn96孔板中间60孔中每孔加入100μL细胞悬液(每孔3_5×103个细胞)，四周36孔中每孔加入板置于培养箱中培养48h；弃去含化合物的培养基以及PBS，96孔板每孔加入100μL含10%