CN114957182B - 一类含有黄酮骨架结构的usp8抑制剂及其应用 - Google Patents
一类含有黄酮骨架结构的usp8抑制剂及其应用 Download PDFInfo
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- CN114957182B CN114957182B CN202210332892.XA CN202210332892A CN114957182B CN 114957182 B CN114957182 B CN 114957182B CN 202210332892 A CN202210332892 A CN 202210332892A CN 114957182 B CN114957182 B CN 114957182B
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Abstract
本发明公开了一类含有黄酮骨架结构的化合物及其应用，属于医药技术领域。本发明通过筛选化合物库以及结构改造，得到一系列含有黄酮骨架的新型USP8小分子抑制剂，丰富了USP8抑制剂的结构类型。
Description
技术领域
本发明属于医药技术领域，具体涉及一类含有黄酮骨架结构的化合物及其在制备泛素特异性蛋白酶USP8的抑制剂中的应用。
背景技术
泛素-蛋白酶体系统介导的蛋白降解是调节细胞内蛋白水平的重要机制。该途径通过活化泛素并使其与底物蛋白连接，再由蛋白酶体系统识别并降解泛素化标记的蛋白，实现对细胞信号传导、细胞凋亡、损伤修复等多种生理过程的调节(Md Tariqul Islam etal.Arch Biochem Biophys.2021,701:108811)。泛素化的逆过程依赖于去泛素化酶，该类酶通过去除底物蛋白中的泛素，保护其不被降解。泛素特异性蛋白酶8(USP8)是去泛素化酶家族的成员之一，其基因突变及功能异常与多种肿瘤、内分泌系统疾病等的发生密切相关。研究表明，当USP8的14-3-3蛋白结合位点发生突变，其去泛素化活性大大升高，导致其底物EGFR降解减少并在细胞膜上过度积累，使得促肾上腺皮质细胞过量分泌ACTH，诱导了库欣病的发生(Martin Reincke et.al.Nat.Genet.2015,47:31–38)。目前USP8抑制剂已被证实可以用于垂体瘤、非小细胞肺癌等疾病的治疗，而且在克服肿瘤细胞耐药方面也表现出了良好的效果。例如采用替尼类受体酪氨酸激酶抑制剂治疗的非小细胞肺癌患者，约有70％会出现耐药，该现象由EGFR二次突变或Met基因异常扩增导致。USP8抑制剂能够有效阻滞EGFR信号通路的激活，对吉非替尼耐药肿瘤细胞具有较强的杀伤作用(Sanguine B etal.Clinical Cancer Research,2013,19:3894-3904)。因此，通过开发抑制剂调节USP8异常的去泛素化活性，可影响其底物蛋白水平，进而发挥多种治疗作用，为抗肿瘤领域提供新的思路。
黄酮类物质广泛存在于绿色植物中，具有多样的生物活性。申请人所在课题组此前已设计合成了大量黄酮骨架化合物，通过筛选该化合物库，并对部分化合物进行结构优化，获得了一类具有USP8抑制活性的新型黄酮骨架化合物，丰富了USP8小分子抑制剂的结构类型。
发明内容
本发明通过筛选化合物库以及结构改造，得到了一系列结构新颖、活性较强的黄酮类新型USP8小分子抑制剂。
为了实现上述发明目的，本发明采用以下技术方案：
通式(Ⅰ)的化合物或其药学上可接受的盐，
X独立为于C、N或O；当X为C时，R1-X为但不局限于 等取代或非取代的N-甲基吡咯胺或N-甲基哌啶胺；当X为N时，R1-X为其中m为1、2或3，Z1为C、N或O，R3为H原子、1-3个C原子的烷基或吗啉基团；当X为O时，R1可为于1-6个原子长度的烷基、取代或未取代的芳香环、芳香杂环或其中取代基团包括单取代或多取代的烷基、烷氧基、氨基、硝基、卤素、三氟甲基、羰基、磺胺或亚磺酰亚胺基团，芳香环及芳香杂环包括呋喃、吡唑、吡啶等五元或六元环，芳香环或芳香杂环与黄酮母环之间可以含或不含苄基取代，对于/>m1为0、1、2或3，m2为2、3或4，R4为H原子、1-3个C原子的烷基或吗啉基团，Z2、Z3各自独立为C、N或O。
Y为C、N或O；当Y为C时，n为0或1，R2为H原子或吗啉基团；当Y为N时，n为1或2，R2为H原子、C原子数为1-6的烷基或羟烷基、取代或非取代的酰胺或磺酰胺、亚磺酰亚胺、取代或非取代的芳香环或芳香杂环，其中取代基团包括单取代或多取代的烷基、烷氧基、氨基、硝基、卤素、三氟甲基、羰基、磺胺或亚磺酰亚胺基团，芳香环及芳香杂环包括呋喃、吡唑、吡啶等五元或六元环，芳香环或芳香杂环与Y原子之间可以含或不含苄基取代；当Y为O时，n为1，R2不存在。
所述化合物为以下化合物式中的任意一个：
本发明所述的通式(Ⅰ)的化合物的药学上可接受的盐，是指通式(Ⅰ)的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成碱加成盐，所述酸包括：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；所述碱加成盐包括：钠盐、钾盐、铵盐、钙盐、铝盐、镁盐或其他金属盐，乙二胺、乙醇胺或其他常见碱加成盐。
通式(Ⅰ)的化合物可通过以下路线合成。
当X为O时，
当X为N时，
当X为C时，
由化合物I-1制备化合物I-2的过程，通过间苯三酚与乙腈发生Hoesch反应，催化剂选用氯化锌，溶剂优先采用乙醚；由化合物I-2制备化合物I-3的过程，通过硫酸二甲酯与酚羟基发生甲基化反应，选用碱为碳酸钾，溶剂为丙酮；由化合物I-3制备化合物I-4的过程，为碱性条件的羟醛缩合反应，碱为氢氧化钾，溶剂选用乙醇；由化合物I-4制备化合物I-5的过程，是I2催化的环合反应，溶剂为二甲基亚砜；由化合物I-5制备化合物I-6的过程，是氢溴酸中的脱甲基反应；由化合物I-6制备化合物I-7的过程，通过氢氧化四甲铵存在下过硫酸钾的氧化反应得到，溶剂为水；由化合物I-7制备化合物I-8的过程，为苄基化反应，选用碱为碳酸钾，溶剂为N,N-二甲基甲酰胺；由化合物I-8制备化合物I-9的过程，为酸性条件的水解反应，选用酸为盐酸；由化合物I-9制备化合物I-10的过程，通过卤代烃取代反应得到，选用碱为碳酸钾，溶剂为N,N-二甲基甲酰胺；由化合物I-10制备化合物I-11的过程，为碱性条件的亲核取代反应，选用碱为N,N-二异丙基乙胺，溶剂优先选用二甲基亚砜；由化合物I-11制备化合物I-12的过程，通过氢化反应脱苄基，催化剂选用Pd/C，溶剂为四氢呋喃和甲醇。
由化合物I-5制备化合物I-13的过程，通过N-溴代琥珀酰亚胺的取代反应得到，溶剂优先采用N,N-二甲基甲酰胺；由化合物I-13制备化合物I-14的过程，通过胺类的Buchwald–Hartwig偶联反应得到，选用碱为碳酸铯，催化剂优选Pd2(dba)3，配体优先选用rac-BINAP；由化合物I-14制备化合物I-15的过程，为熔融盐酸吡啶的脱甲基反应；由化合物I-15制备化合物I-16的过程，是碱性条件的亲核取代反应，选用碱为N,N-二异丙基乙胺，溶剂为二甲基亚砜。
由化合物I-17制备化合物I-18的过程，通过亲电取代反应并脱去一分子水得到，选用酸为盐酸与乙酸；由化合物I-18制备化合物I-19的过程，为乙酸酐的酰基化反应，溶剂选用三氟化硼乙醚和二氯甲烷的混合溶剂；由化合物I-19制备化合物I-20的过程，通过氟苯甲酰氯的酯化反应得到，溶剂选用吡啶；由化合物I-20制备化合物I-21的过程，是碱性条件的重排反应，选用碱为氢氧化钾，溶剂优选吡啶；由化合物I-21制备化合物I-22的过程，为酸性条件的环合反应，催化剂选用浓硫酸，溶剂为乙酸；由化合物I-22制备化合物I-23的过程，为熔融盐酸吡啶的脱甲基反应；由化合物I-23制备化合物I-24的过程，是碱性条件的亲核取代反应，选用碱为N,N-二异丙基乙胺，溶剂为二甲基亚砜。
所述通式(Ⅰ)化合物的药学上可接受的盐可通过与等化学当量或过量酸(无机酸或有机酸)在合适的溶剂或溶剂组合物中反应制得。所述酸包括但不限于氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。所述溶剂包括但不限于甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯或四氢呋喃，或任意几种混合溶剂。
本发明提供了一种药物组合物，其包括药物有效量的活性组分和药学上可接受的辅料；所述活性组分包括通式(Ⅰ)化合物和药学上可接受的盐中的一种或多种。所述药物组合物中，所述辅料包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、颗粒剂、胶囊和针剂(溶液或悬浮液)等，优选片剂、胶囊、液体、悬浮液和针剂(溶液或悬浮液)。
本发明所述化合物在临床上的给药方式可采用口服、注射等方式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1-1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
本发明还提供了所示通式(Ⅰ)的化合物在制备USP8抑制剂中的应用。
本发明还提供通式(Ⅰ)所示化合物在用于治疗USP8介导的免疫抑制相关疾病中的应用。
本发明所述的USP8介导的免疫抑制相关疾病包括癌症、神经变性疾病、血液系统疾病、内分泌系统疾病。其中癌症优选但不局限于非小细胞肺癌、肝癌、胃癌、胆管癌、乳腺癌、胰腺癌、宫颈癌、垂体瘤、多发性骨髓瘤、白血病、黑色素瘤、胶质瘤；神经系统变性疾病优选但不局限于帕金森症、阿尔兹海默症；血液系统疾病优选但不局限于范可尼贫血；内分泌系统疾病优选但不局限于库欣病。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
术语“芳香环”指含有1-12个碳原子的单环或稠合多环或联苯基团，具有完全的共轭π电子系统。芳香环的非限制性实例有苯基、萘基和联苯，芳香环可以是取代的或未取代的。
术语“芳杂环”指含有1-6个原子的单环体系，体系含有一个、两个、三个或四个为N、O或S的环杂原子，其余环原子是C，并具有完全的共轭π电子系统。未取代的芳杂环非限制性实例包括吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、噻二唑、吡唑、吡啶、嘧啶、四唑和三嗪。芳杂环可以是取代的或未取代的。
术语“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个。
术语“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
术语“三氟甲基”表示-CF3基团。
术语“硝基”表示-NO2基团。
术语“氨基”表示-NH2基团。
术语“氰基”表示-CN基团。
术语“羧基”表示-COOH基团。
术语“羟基”表示-OH基团。
术语“酯基”表示-COOCH3等甲酸酯基团。
术语“卤素”表示氟、氯、溴或碘。优选为氟、氯、溴。
附图说明
图1为LRY-18的体内抗肿瘤活性，A为肿瘤体积，B为体重，C为肿瘤照片，D瘤重统计结果；E为免疫组化结果；
图2为磷酸化EGFR(A)、ErbB2(B)、ERbB3(C)和ERα(D)统计结果；
图3为小鼠的心脏、肝脏、脾脏、肺和肾组织进行HE染色结果
图4天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)和部分血常规指标的检测结果。
具体实施方式
为了进一步阐释本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
2，4，6-三羟基苯乙酮(I-2)
在室温下将间苯三酚I-1(300g，2.38mol)溶解在无水乙醚(2L)中，依次加入无水氯化锌(63.7g，0.48mol)和无水乙腈(238g，6.00mol)，搅拌0.5h。0℃下通入干燥的氯化氢气体反应40h，TLC监测反应。反应结束后待反应液温度升至室温，抽滤，滤饼烘干至恒重后溶于水(200mL)中，加热回流6h，析出大量固体，冷却至室温，抽滤，烘干，得白色固体248g，收率62％。1H NMR(300MHz,DMSO-d6):δ＝12.27(s,2H,2,6-OH),10.41(s,1H,4-OH),5.83(s,2H,Ar-H),2.57(s,3H,CH3)ppm.HRMS(ESI)，[M+H]+calculated for C8H8O4 169.0495,found169.0502.
2-羟基-4，6-二甲氧基苯乙酮(I-3)
在三颈瓶中加入中间体I-2(42g，0.25mol)和无水丙酮(420mL)，室温搅拌溶解，再加入碳酸钾(79.5g，0.58mol)，室温条件下滴加硫酸二甲酯(66.2g，0.53mol)，1h左右滴加完毕，45℃继续反应4h。TLC监测反应完全后，静止冷却至室温，抽滤，滤液倒入5倍体积的水中，用1mol/L盐酸调pH＝3-4，析出大量固体。抽滤，干燥得白色固体37.7g，收率77％。1HNMR(300MHz,DMSO-d6):δ＝13.83(s,1H,OH),6.12(dd,2H,J1＝9.00Hz,J2＝6.00Hz,Ar-H),3.89(s,3H,6-OCH3),3.84(s,3H,4-OCH3),2.57(s,3H,CH3)ppm.HRMS(ESI)，[M+H]+calculated for C10H12O4197.0808,found 197.0808.
1-(2-羟基-4，6-二甲氧基苯基)-(E)-3-(4-氟苯基)丙基-2-烯-1-酮(I-4)
在三颈瓶中加入中间体I-3(10g，50mmol)和乙醇(100mL)，室温搅拌溶解，再加入对氟苯甲醛(6.8g，60mmol)，冰浴条件下滴加7％氢氧化钾水溶液(100mL)，滴加过程中保持温度低于5℃。1h左右滴加完毕，40℃继续反应10h，TLC监测反应。反应完毕后静止冷却至室温，反应液倒入10倍体积的水中，用6mol/L盐酸调pH＝3-4，析出大量固体。抽滤，烘干，得黄色固体13.6g，收率88％。1H NMR(300MHz,DMSO-d6):δ＝13.40(s,1H,OH),7.84(m,2H,Ar-H),7.71(m,2H,CH＝CH),7.32(t,2H,J＝9.00Hz,Ar-H),6.18(m,2H,Ar-H),3.92(s,3H,6-OCH3),3.85(s,3H,4-OCH3)ppm.
5，7-二甲氧基-2-(4-氟苯基)-4H-色烯-4-酮(I-5)
在三颈瓶中加入中间体I-4(2.2g，7.28mmol)和无水二甲亚砜(6mL)，升温至60℃，搅拌溶解，再分批加入I2(50mg，0.18mmol)，升温至130℃继续反应5h，TLC监测反应完全，反应液趁热倒入10倍体积的饱和硫代硫酸钠水溶液中，析出大量固体。抽滤，烘干，得淡黄色固体2.1g，收率95％。1H NMR(300MHz,DMSO-d6):δ＝8.15(m,2H,Ar-H),7.42(t,2H,J＝9.00Hz,Ar-H),6.90(d,1H,J＝3.00Hz,Ar-H),6.81(s,1H,CHCO),6.54(s,1H,J＝3.00Hz,Ar-H),3.92(s,3H,5-OCH3),3.86(s,3H,7-OCH3)ppm.HRMS(ESI)，[M+H]+calculated forC17H13FO4301.0871,found 301.0936.
5，7-二羟基-2-(4-氟苯基)-4H-色烯-4-酮(I-6)
在茄形瓶中加入中间体I-5(2.1g，6.99mmol)和48％的氢溴酸(25mL)，回流反应16h，TLC监测反应完全，静止冷却至室温，反应液倒入10倍体积的冰水中，析出大量固体。抽滤，滤饼用水多次洗涤至pH呈中性，得淡黄色固体1.6g，收率84％。1H NMR(300MHz,DMSO-d6):δ＝12.85(s,1H,5-OH),10.97(s,1H,7-OH),8.20(m,2H,Ar-H),7.46(t,2H,J＝9.00Hz,Ar-H),7.02(s,1H,Ar-H),6.57(s,1H,CHCO),6.26(s,1H,Ar-H)ppm.
5，7-二羟基-4-氧代-2-(4-氟苯基)-4H-色烯-8-磺酸四甲基铵盐(I-7)
在茄形瓶中加入中间体I-6(1.6g，5.88mmol)、氢氧化四甲铵(6.4g，70.21mmol)和水(32mL)，室温搅拌溶解，再分批加入过硫酸钾(3.2g，11.84mmol)，加入过程中保持温度低于30℃，室温继续反应3h，TLC监测反应完全，抽滤，滤液用磷酸二氢钾调pH＝6-7，析出固体，再每隔5min分3次加入氯化钠(4.0g)，室温搅拌3h。抽滤，滤饼用甲醇洗涤，烘干，得棕色固体1.8g，收率68％。
5，8-二羟基-7-苄氧基-2-(4-氟苯基)-4H-色烯-4-酮(I-9)
向三颈瓶中添加中间体I-7(1.8g，4.08mmol)、碳酸钾(1.1g，7.96mmol)和N，N-二甲基甲酰胺(15mL)。逐滴添加苄基溴(0.9g，5.24mmol)，然后将混合物加热至60℃反应4h。通过TLC监测反应，直到产生大量中间体I-8。然后在反应溶液冷却至室温后，将反应溶液倒入6mol/L盐酸(45mL)，并搅拌过夜以沉淀中间体I-9粗产物。通过过滤收集沉淀物，并通过四氢呋喃/甲醇重结晶以获得中间体I-9(0.56g，36％)。1H NMR(300MHz,DMSO-d6):δ＝12.30(s,1H,OH),8.26(m,2H,Ar-H),7.45(m,7H,Ar-H),7.01(s,1H,Ar-H),6.66(s,1H,CHCO),5.32(s,2H,CH2)ppm.
5-羟基-8-甲氧基-7-苄氧基-2-(4-氟苯基)-4H-色烯-4-酮(I-10)
向三颈瓶中加入中间体I-9(720mg，1.9mmol)、碳酸钾(660mg，4.8mmol)和N，N-二甲基甲酰胺(10mL)。逐滴添加硫酸二甲酯(240mg，2.1mmol)，反应回流4.5h。将反应溶液冷却至室温并过滤。减压蒸发滤液以去除溶剂。粗产物用正己烷和二氯甲烷重结晶，得到黄色固体I-10(685mg，92％)。1H NMR(300MHz,DMSO-d6):δ＝12.70(s,1H,5-OH),7.93(d,2H,J＝9.00Hz,Ar-H),7.46(m,5H,Ar-H),7.10(d,2H,J＝9.00Hz,Ar-H),6.94(s,1H,CHCO),6.80(s,1H,CHCO),5.33(s,2H,OCH2),3.85(s,3H,OCH3)ppm.
5-羟基-8-甲氧基-7-苄氧基-2-(4-(吡咯烷-1-基)苯基)-4H-色烯-4-酮(I-11)
在三颈瓶中加入中间体I-10(190mg,0.48mmol)和无水二甲亚砜(10mL)，升温至60℃，搅拌溶解，再在氮气保护下依次加入吡咯烷(344.4mg,4.8mmol)和N，N-二异丙基乙胺(124.1mg,0.96mmol)，90℃反应10h，TLC监测反应至完全，反应液趁热倒入饱和食盐水中，静止3h，抽滤，滤饼用水洗涤，烘干，得粗品200mg，硅胶柱层析得黄色固体168mg，收率78.9％。1H NMR(300MHz,DMSO-d6):δ＝12.79(s,1H,5-OH),7.86(d,2H,J＝9.00Hz,Ar-H),7.44(m,5H,Ar-H),6.97(d,2H,J＝9.00Hz,Ar-H),6.55(s,1H,CHCO),6.46(s,1H,Ar-H),5.23(s,2H,OCH2-Ar),4.00(s,3H,ArOCH3),3.42(s,4H,N(CH2CH2)2),1.70(s,4H,N(CH2CH2)2)ppm.
5，7-二羟基-8-甲氧基-2-(4-(吡咯烷-1-基)苯基)-4H-色烯-4-酮(LRY-1)
在茄形瓶中依次加入I-11(168mg,0.38mmol)、Pd/C(40mg)、四氢呋喃(10mL)和甲醇(10mL)，密闭体系通入氢气，35℃反应7h，TLC监测反应。反应完毕后静止冷却至室温，抽滤，滤液减压蒸除溶剂，硅胶柱层析得黄色固体100mg，收率74.7％。1HNMR(300MHz,DMSO-d6):δ＝12.77(s,1H,5-OH),7.86(d,2H,J＝9.00Hz,Ar-H),6.97(d,2H,J＝9.00Hz,Ar-H),6.55(s,1H,CHCO),6.46(s,1H,Ar-H),4.00(s,3H,ArOCH3),3.42(s,4H,N(CH2CH2)2),1.70(s,4H,N(CH2CH2)2)ppm.HRMS(ESI)，[M+H]+calculated for C20H19NO5353.1263,found353.1274.
实施例2
5，7-二羟基-8-环戊氧基-2-(4-(1，4-高哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-5)
用溴代环戊烷(59mg,0.4mmol)代替硫酸二甲酯、用高哌嗪(60mg,0.6mmol)代替吡咯烷之外，以与化合物LRY-1相同的方法合成得到黄色固体50mg，收率32.5％。1HNMR(300MHz,DMSO-d6):δ＝12.80(s,1H,5-OH),7.85(d,2H,J＝9.00Hz,Ar-H),6.85(d,2H,J＝9.00Hz,Ar-H),6.67(s,1H,CHCO),6.26(s,1H,Ar-H),4.81(m,1H,CH(CH2)4),3.61(s,4H,Ar-N(CH2)2),2.89(s,2H,NHCH2),2.67(s,2H,NHCH2),1.90(m,2H,NCH2CH2CH2NH),1.68(m,8H,CH(CH2)4)ppm.HRMS(ESI)，[M+H]+calculated for C25H28N2O5436.1998,found 436.2082.
实施例3
5，7-二羟基-8-(呋喃-2-基甲氧基)-2-(4-(1，4-高哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-9)
用2-氯甲基呋喃(120mg,1.03mmol)代替硫酸二甲酯、用高哌嗪(650mg,6.5mmol)代替吡咯烷之外，以与化合物LRY-1相同的方法合成得到黄色固体130mg，收率45.5％。1HNMR(300MHz,DMSO-d6):δ＝12.78(s,1H,5-OH),7.81(d,2H,J＝9.00Hz,Ar-H),7.34(s,1H,Ar-H),6.72(d,2H,J＝9.00Hz,Ar-H),6.64(s,1H,CHCO),6.38(s,1H,Ar-H),6.26(m,2H,Ar-H),4.98(s,2H,OCH2-Ar),3.66(s,4H,Ar-N(CH2)2),3.07(s,2H,NHCH2),2.86(s,2H,NHCH2),1.95(m,2H,NCH2CH2CH2NH)ppm.HRMS(ESI)，[M+H]+calculated for C25H24N2O6449.1707,found 449.1702.
实施例4
3-((5-羟基-7-苄氧基-2-(4-氟苯基)-4-氧代-4H-色烯-8-基)氧基)吡咯烷-1-甲酸苄酯(I-12)
在三颈瓶中加入中间体I-9(0.32g，0.85mmol)和N，N-二甲基甲酰胺(10mL)，室温搅拌溶解，再在氮气保护下加入碳酸钾(0.29g,2.15mmol)和中间体3-((甲基磺酰基)氧基)吡咯烷-1-羧酸苄酯(0.28g,1.02mmol)，80℃反应10h，TLC检测反应完全，反应液趁热倒入10倍体积的冰水中，用1mol/L盐酸调pH＝4-5，析出固体，静止2h，抽滤，烘干得粗品0.41g，聚酰胺柱层析得黄色固体0.3mg，收率56.8％。1H NMR(300MHz,DMSO-d6):δ＝12.91(s,1H,5-OH),7.78(d,2H,J＝9.00Hz,Ar-H),7.50(m,5H,Ar-H),7.35(m,5H,Ar-H),7.26(d,2H,J＝9.00Hz,Ar-H),6.94(s,1H,CHCO),6.77(s,1H,Ar-H),5.30(s,2H,OCH2-Ar),5.22(s,2H,OCH2-Ar),5.09(m,1H,OCH(CH2)2),3.78(m,2H,CHCH2N),3.56(m,2H,CHCH2CH2N),2.05(m,2H,CHCH2CH2N)ppm.
3-((5-羟基-7-苄氧基-2-(4-(哌嗪-1-基)苯基)-4-氧代-4H-色烯-8-基)氧基)吡咯烷-1-甲酸苄酯(I-13)
用哌嗪(220mg,2.5mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体230mg，收率68.9％。1HNMR(300MHz,DMSO-d6):δ＝12.91(s,1H,5-OH),7.78(d,2H,J＝9.00Hz,Ar-H),7.50(m,5H,Ar-H),7.35(m,5H,Ar-H),7.26(d,2H,J＝9.00Hz,Ar-H),6.94(s,1H,CHCO),6.77(s,1H,Ar-H),5.30(s,2H,OCH2-Ar),5.22(s,2H,OCH2-Ar),4.00(m,1H,OCH(CH2)2),3.78(m,2H,CHCH2N),3.56(m,2H,CHCH2CH2N),3.19(s,4H,N(CH2CH2)2NH),2.90(s,4H,N(CH2CH2)2NH),2.05(m,2H,CHCH2CH2N)ppm.
5，7-二羟基-8-(吡咯烷-3-基氧基)-2-(4-(哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-11)
以与化合物LRY-1相同的方法合成得到黄色固体95mg，收率49％。1H NMR(300MHz,DMSO-d6):δ＝12.75(s,1H,5-OH),7.92(d,2H,J＝9.00Hz,Ar-H),7.07(d,2H,J＝9.00Hz,Ar-H),6.76(s,1H,CHCO),6.30(s,1H,Ar-H),4.87(m,1H,OCH(CH2)2),3.42(m,4H,CHCH2N&CHCH2CH2N),3.20(s,4H,N(CH2CH2)2NH),3.07(s,4H,N(CH2CH2)2NH),2.10(m,2H,CHCH2CH2N)ppm.
实施例5
7-苄氧基-4-氧代-2-(4-氟苯基)-4H-色烯-5-基-对甲基苯磺酸-8-磺酸四甲基铵盐(I-14)
在三颈瓶中加入中间体I-7(6g,13.6mmol)和N，N-二甲基甲酰胺(50mL)，室温搅拌溶解，再加入碳酸钾(3.75g,27.2mmol)，室温条件下滴加溴化苄(2.45g,14.3mmol)，5min左右滴加完毕，55℃继续反应2h，TLC监测反应。反应完毕后静止冷却至室温，抽滤滤液无需纯化直接进行下一步反应。
8-羟基-7-苄氧基-2-(4-氟苯基)-4-氧代-4H-色烯-5-基-对甲基苯磺酸酯(I-15)
向滤液中加入碳酸铯(13.3g,40.8mmol)和对甲基苯磺酰氯(2.8g,15.7mmol)，升温至50℃继续反应2h，TLC监测反应完全，抽滤，滤饼用甲醇(50mL)洗涤，滤液用6mol/L盐酸调pH＝1-2，室温搅拌过夜，析出固体。抽滤，滤饼用甲醇(10mL)洗涤，烘干，得黄色固体1.9g，收率26.2％。1H NMR(300MHz,DMSO-d6):δ＝9.99(s,1H,8-OH),8.17(d,2H,J＝9.00Hz,Ar-H),7.65(d,2H,J＝9.00Hz,Ar-H),7.40(m,9H,Ar-H),6.79(s,1H,CHCO),6.78(s,1H,Ar-H),5.19(s,2H,OCH2-Ar),2.38(s,3H,Ar-CH3)ppm.
7-苄氧基-8-((1-甲基哌啶-4-基)氧基)-2-(4-氟苯基)-4-氧代-4H-色烯-5-基-对甲基苯磺酸酯(I-16)
在三颈瓶中加入中间体I-15(400mg,0.75mmol)、4-甲基哌啶醇(129mg,1.12mmol)、三苯基膦(493mg,1.88mmol)和无水四氢呋喃(100mL)，室温搅拌10min，再在氮气保护和低温条件下缓慢滴加偶氮二甲酸二乙酯(327mg,1.88mmol)，滴加完毕后升至室温反应1h，TLC监测反应完全，反应液减压蒸除溶剂，硅胶柱层析得白色固体360mg，收率75％。1HNMR(300MHz,DMSO-d6):δ＝8.08(d,2H,J＝9.00Hz,Ar-H),7.76(d,2H,J＝9.00Hz,Ar-H),7.45(m,9H,Ar-H),6.89(s,1H,CHCO),6.83(s,1H,Ar-H),5.16(s,2H,OCH2-Ar),4.25(m,1H,Ar-OCH),2.65(t,2H,J＝6.00Hz,CH2NCH3),2.39(s,3H,CH2NCH3),2.10(s,3H,Ar-CH3),1.96(t,2H,J＝6.00Hz,CH2NCH3),1.83(t,2H,J＝6.00Hz,OCH(CH2)2),1.74(t,2H,J＝6.00Hz,OCH(CH2)2)ppm.
5-羟基-7-苄氧基-8-((1-甲基哌啶-4-基)氧基)-2-(4-氟苯基)-4H-色烯-4-酮(I-17)
在三颈瓶中加入中间体I-16(200mg,0.31mmol)、氢氧化钾(35mg,0.62mmol)和甲醇(20mL)，回流反应1.5h，TLC检测反应完全，反应液中加入水(20mL)稀释，用1mol/L盐酸调pH＝7，析出固体，抽滤，滤饼烘干得粗品180mg，粗品用乙醇和乙醚混合溶剂重结晶得黄色固体140mg，收率90％。1H NMR(300MHz,DMSO-d6):δ＝12.63(s,1H,5-OH),8.12(d,2H,J＝9.00Hz,Ar-H),7.76(d,2H,J＝9.00Hz,Ar-H),7.45(m,5H,Ar-H),7.02(s,1H,CHCO),6.72(s,1H,Ar-H),5.25(s,2H,OCH2-Ar),4.04(m,1H,Ar-OCH),2.63(t,2H,J＝6.00Hz,CH2NCH3),2.08(s,3H,CH2NCH3),1.96(t,2H,J＝6.00Hz,CH2NCH3),1.72(m,4H,OCH(CH2)2)ppm.
5-羟基-7-苄氧基-8-((1-甲基哌啶-4-基)氧基)-2-(4-(甲基哌嗪-1-基)苯基)-4H-色烯-4-酮(I-18)
用N-甲基哌嗪(420mg,4.2mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体180mg，收率77％。1HNMR(300MHz,DMSO-d6):δ＝12.86(s,1H,5-OH),7.84(d,2H,J＝9.00Hz,Ar-H),7.47(m,5H,Ar-H),7.08(d,2H,J＝9.00Hz,Ar-H),6.68(s,1H,CHCO),6.65(s,1H,Ar-H),5.20(s,2H,OCH2-Ar),4.06(m,1H,Ar-OCH),3.38(s,4H,Ar-N(CH2CH2)2N),2.86(s,4H,Ar-N(CH2CH2)2N),2.64(t,2H,J＝6.00Hz,CH2NCH3),2.37(s,3H,NCH3),2.09(s,3H,CH2NCH3),1.97(t,2H,J＝6.00Hz,CH2NCH3),1.76(m,4H,OCH(CH2)2)ppm.
5，7-二羟基-8-((1-甲基哌啶-4-基)氧基)-2-(4-(甲基哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-13)
以与化合物LRY-1相同的方法合成得到黄色固体54mg，收率64.4％。1HNMR(300MHz,DMSO-d6):δ＝12.70(s,1H,5-OH),7.77(d,2H,J＝9.00Hz,Ar-H),3.96(d,2H,J＝9.00Hz,Ar-H),6.52(s,1H,CHCO),6.28(s,1H,Ar-H),4.29(m,1H,Ar-OCH),3.38(s,4H,Ar-N(CH2CH2)2N),2.97(s,4H,Ar-N(CH2CH2)2N),2.59(t,2H,J＝6.00Hz,CH2NCH3),2.37(s,3H,NCH3),2.09(s,3H,CH2NCH3),2.60(t,2H,J＝6.00Hz,CH2NCH3),1.76(m,4H,OCH(CH2)2)ppm.HRMS(ESI)，[M+H]+calculated for C26H32N3O5466.2338,found 466.2335.
实施例6
3-((5-羟基-7-苄氧基-2-(4-氟苯基)-4-氧代-4H-色烯-8-基)氧基)戊烷-2，4-二酮(I-19)
在三颈瓶中加入中间体I-9(550mg，1.45mmol)和丙酮(55mL)，室温搅拌溶解，再加入碳酸钾(300.9mg,2.18mmol)和3-氯-2，4-戊二酮(296.4mg,2.18mmol)，回流反应3h，MS检测反应完全，趁热抽滤，液减压蒸除溶剂，硅胶柱层析得黄色固体350mg，收率51.3％。1HNMR(300MHz,CDCl3):δ＝14.31(s,1H,5-OH),8.02(d,2H,J＝9.00Hz,Ar-H),7.87(m,5H,Ar-H),7.23(d,2H,J＝9.00Hz,Ar-H),6.62(s,1H,CHCO),6.51(s,1H,Ar-H),5.11(s,2H,OCH2-Ar),4.94(s,1H,OCH(COCH3)2),2.19(s,6H,OCH(COCH3)2)ppm.
5-羟基-7-苄氧基-8-((3，5-二甲基-1H-吡唑-4-基)氧基)-2-(4-氟苯基)-4H-色烯-4-酮(I-20)
在茄形瓶中加入中间体I-19(300mg，0.63mmol)和乙醇(30mL)，低温条件下(<5℃)加入醋酸(41.56mg,0.64mmol)和水合肼(34.63mg,0.64mmol)，升至室温反应3.5h，TLC监测反应完全，反应液加水(60mL)稀释，析出大量固体，抽滤，烘干，得白色固体270mg，收率90％。1H NMR(300MHz,DMSO-d6):δ＝12.64(s,1H,5-OH),11.85(s,1H,-NH-N＝),7.96(m,2H,Ar-H),7.42(m,5H,Ar-H),7.35(m,2H,Ar-H),7.07(s,1H,CHCO),6.75(s,1H,Ar-H),5.25(s,2H,OCH2-Ar),1.85(s,6H,Ar-CH3)ppm.
5-羟基-7-苄氧基-8-((3，5-二甲基-1H-吡唑-4-基)氧基)-2-(4-(1，4-高哌嗪-1-基)苯基)-4H-色烯-4-酮(I-21)
用高哌嗪(254mg,2.54mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体180mg，收率64.9％。1H NMR(300MHz,DMSO-d6):δ＝12.89(s,1H,5-OH),11.96(s,1H,-NH-N＝),7.96(m,2H,Ar-H),7.42(m,5H,Ar-H),7.35(m,2H,Ar-H),6.71(s,1H,CHCO),6.28(s,1H,Ar-H),5.21(s,2H,OCH2-Ar),3.60(s,4H,Ar-N(CH2)2),2.94(s,2H,NHCH2),2.74(s,2H,NHCH2),1.99(s,6H,Ar-CH3),1.84(m,2H,NCH2CH2CH2NH)ppm.
5，7-二羟基-8-((3，5-二甲基-1H-吡唑-4-基)氧基)-2-(4-(1，4-高哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-15)
以与化合物LRY-1相同的方法合成得到黄色固体20mg，收率29.5％。1HNMR(300MHz,DMSO-d6):δ＝12.89(s,1H,5-OH),11.96(s,1H,-NH-N＝),7.62(d,2H,J＝9.00Hz,Ar-H),6.81(d,2H,J＝9.00Hz,Ar-H),6.71(s,1H,CHCO),6.28(s,1H,Ar-H),3.60(s,4H,Ar-N(CH2)2),2.94(s,2H,NHCH2),2.74(s,2H,NHCH2),1.99(s,6H,Ar-CH3),1.84(m,2H,NCH2CH2CH2NH)ppm.HRMS(ESI)，[M+H]+calculated for C25H26N4O5463.1937,found463.1962.
实施例7
5，7-二羟基-8-((3，5-二甲基-1H-吡唑-4-基)氧基)-2-(4-(4-(呋喃-2-甲酰基)哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-17)
用呋喃-2-基(哌嗪-1-基)甲酮(756mg,4.2mmol)代替高哌嗪之外，以与化合物LRY-15相同的方法合成得到黄色固体85mg，收率44.4％。1H NMR(300MHz,DMSO-d6):δ＝12.79(s,1H,5-OH),11.92(s,1H,-NH-N＝),10.96(s,1H,7-OH),7.88(s,1H,Ar-H),7.65(d,2H,J＝9.00Hz,Ar-H),7.04(m,3H,Ar-H),6.80(s,1H,CHCO),6.66(m,1H,Ar-H),6.31(s,1H,Ar-H),3.82(s,4H,Ar-N(CH2CH2)2N),3.47(s,4H,Ar-N(CH2CH2)2N),1.98(s,6H,Ar-CH3)ppm.HRMS(ESI)，[M+H]+calculated for C29H26N4O7543.1835,found 543.1861.
实施例8
2-((7-(苄氧基)-2-(4-氟苯基)-5-羟基-4-氧代-4H-苯并吡喃-8-基)氧基)乙酸乙酯(I-22)
用氯乙酸乙酯(243mg,2.0mmol)代替3-氯-2，4-戊二酮之外，以与中间体I-19相同的方法合成得到黄色固体450mg，收率61.2％。1HNMR(300MHz,CDCl3):δ＝12.15(s,1H,5-OH),8.15(m,2H,Ar-H),7.41(m,7H,Ar-H),6.81(s,1H,CHCO),6.34(s,1H,Ar-H),5.21(s,2H,Ar-OCH2Ph),4.65(s,2H,Ar-OCH2CO),4.10(q,2H,J＝6.00Hz,OCH2CH3),1.15(t,3H,J＝6.00Hz,OCH2CH3)ppm.
(E)-2-((5-羟基-7-苄氧基-2-(4-氟苯基)-4-氧代-4H-苯并吡喃-8-基)氧基)-3-羟基丙烯酸乙酯(I-23)
在三颈瓶中加入中间体I-22(55mg，0.12mmol)和四氢呋喃(10mL)，室温搅拌溶解，再加入甲酸乙酯(10.5mg,0.2mmol)和氢化钠(4mg,0.2mmol)，40℃反应过夜，TLC检测反应完全，加入甲醇(10mL)搅拌10min，液减压蒸除溶剂，加入二氯甲烷(20mL)，再分别用水(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸除溶剂得黄色固体42mg，无需纯化直接进行下一步反应。
4-((5-羟基-7-苄氧基-2-(4-氟苯基)-4-氧代-4H-色烯-8-基)氧基)-1，2-二氢-3H-吡唑-3-酮(I-24)
在茄形瓶中加入中间体I-23(250mg，0.5mmol)和甲醇(20mL)，加入水合肼(38.3mg,0.76mmol)，室温反应4h，TLC检测反应完全，反应液减压蒸除溶剂，硅胶柱层析得黄色固体180mg，收率42％。1H NMR(300MHz,DMSO-d6):δ＝12.64(s,1H,5-OH),9.34(s,1H,-NH-CO-),8.26(m,2H,Ar-H),7.47(m,7H,Ar-H),7.06(s,1H,CHCO),6.72(s,1H,Ar-H),5.31(s,2H,OCH2-Ar),4.50(s,1H,NH-NH-CO-)ppm.
4-((5-羟基-7-苄氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-4-氧代-4H-色烯-8-基)氧基)-1，2-二氢-3H-吡唑-3-酮(I-25)
用N-甲基哌嗪(200mg,2mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体88mg，收率70％。1H NMR(300MHz,DMSO-d6):δ＝12.70(s,1H,5-OH),9.44(s,1H,-NH-CO-),8.19(m,2H,Ar-H),7.47(m,7H,Ar-H),6.99(s,1H,CHCO),6.72(s,1H,Ar-H),5.21(s,2H,OCH2-Ar),4.50(s,1H,NH-NH-CO-),3.40(s,4H,Ar-N(CH2CH2)2N),2.44(s,4H,Ar-N(CH2CH2)2N),2.23(s,3H,NCH3)ppm.
4-(5，7-二羟基-2-(4-(4-甲基哌嗪-1-基)苯基)-4-氧代-4H-色烯-8-基)氧基-1，2-二氢-3H-吡唑-3-酮(LRY-19)
以与化合物LRY-1相同的方法合成得到黄色固体30mg，收率43.7％。1HNMR(300MHz,DMSO-d6):δ＝12.70(s,1H,5-OH),10.97(s,1H,7-OH),7.88(d,2H,J＝9.00Hz,Ar-H),7.07(d,2H,J＝9.00Hz,Ar-H),6.64(s,1H,CHCO),6.51(s,1H,Ar-H),5.94(s,1H,-NH-CH＝C),4.52(s,1H,-NH-CH＝C),3.33(s,4H,Ar-N(CH2CH2)2N),2.44(s,4H,Ar-N(CH2CH2)2N),2.22(s,3H,NCH3)ppm.
实施例9
5，7-二羟基-8-((2-氨基噻唑-5-基)氧基)-2-(4-(甲基哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-21)
用2-氨基-5-溴噻唑单氢溴酸盐(310mg,1.2mmol)代替3-((甲基磺酰基)氧基)吡咯烷-1-羧酸苄酯之外，以与化合物LRY-11相同的方法合成得到黄色固体20mg，收率20％。1H NMR(300MHz,DMSO-d6):δ＝12.99(s,1H,5-OH),10.70(s,1H,7-OH),7.93(d,2H,J＝9.00Hz,Ar-H),7.12(d,2H,J＝9.00Hz,Ar-H),6.93(s,1H,CHCO),6.74(s,1H,Ar-H),6.61(m,3H,Ar-H&NH2),3.44(s,4H,Ar-N(CH2CH2)2N),2.59(s,4H,Ar-N(CH2CH2)2N),2.32(s,3H,NCH3)ppm.HRMS(ESI)，[M+H]+calculated for C23H22N4O5S 467.1344,found467.1362.
实施例10
8-溴-5，7-二甲氧基-2-(4-氟苯基)-4H-色烯-4-酮(I-26)
向三颈瓶中加入中间体I-5(15g,50mmol)和无水N，N-二甲基甲酰胺(75mL)，冰浴降温至0℃，搅拌溶解，再加入N-溴代琥珀酰亚胺(8.93g,50mmol)，缓慢升温至室温继续反应2h，TLC监测至反应完全，抽滤，滤饼用甲醇(10mL)洗涤。取出滤饼用甲醇(20mL)打浆，抽滤，滤饼干燥至恒重得白色固体15.36g，收率80％。
8-(吡咯烷-1-基)-5，7-二甲氧基-2-(4-氟苯基)-4H-色烯-4-酮(I-27)
将中间体I-26(2g,4.26mmol)、吡咯烷(0.62g,8.72mmol)、碳酸铯(2.84g,8.72mmol)、(Pd)2(dba)3(120mg,0.13mmol)和rac-BINAP(244mg,0.39mmol)加入甲苯(50mL)中，在氮气保护下回流反应36h。TLC监测至反应完全，缓慢冷却至室温，减压蒸除溶剂得到深棕色粘稠固体。固体用二氯甲烷(20mL)分散，用甲磺酸水溶液调至pH＝4-5，静置，分液得水层。水层用碳酸氢钠水溶液调至pH＝8-9，用二氯甲烷(20mL)萃取，二氯甲烷层用无水硫酸钠干燥，抽滤，减压蒸除溶剂得到黄棕色固体，干燥至恒重得黄棕色固体200mg，收率10.2％。
2-(4-氟苯基)-5-羟基-7-甲氧基-8-(吡咯烷-1-基)-4H-色烯-4-酮(I-28)
将中间体I-27(3.69g,10mmol)溶于二氯甲烷(80mL)中，溶液呈红褐色，冰浴滴加三溴化硼(4.7mL)。滴加结束后，升温至室温反应1h，TLC监测至原料消失。冰浴降温至0～5℃，滴加甲醇(80mL)淬灭三三溴化硼，减压蒸除甲醇和二氯甲烷，加入碳酸钠水溶液调节pH值至弱碱性，抽滤得黄褐色固体，干燥，柱层析得到淡黄色固体174mg，收率90.4％。
2-(4-氟苯基)-5，7-二羟基-8-(吡咯烷-1-基)-4H-色烯-4-酮(I-29)
将中间体I-28加入10当量熔融的盐酸吡啶之中，反应2h后，将反应液趁热倒入冰水浴中，以二氯甲烷萃取即得淡黄色固体163mg，收率76.5％。
5，7-二羟基-2-(4-(4-甲基哌嗪-1-基)苯基)-8-(吡咯烷-1-基)-4H-色烯-4-酮(LRY-23)
用N-甲基哌嗪(420mg,4.2mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体165mg，收率82.0％。1H NMR(300MHz,DMSO-d6):δ＝13.10(d,1H,Ar-OH),10.75(s,1H,Ar-OH),7.91(q,J＝6.00Hz,2H,Ar-H),7.08(t,J＝9.00Hz,2H,Ar-H),6.80(t,J＝12.00Hz,1H,Ar-H),6.44(d,J＝42.00Hz,1H,Ar-H),3.35(m,8H,-N-CH2-),3.21(s,2H,-CH2-),2.50(d,4H,-CH2-),2.25(s,3H,-CH3),1.97(s,2H,-CH2-).HRMS(ESI)，[M+H]+calculated for C24H27N3O4422.2136,found 422.2143.
实施例11
5，7-二羟基-2-(4-(4-(5-甲基噻吩-2-羰基)哌嗪-1-基)苯基)-8-(吡咯烷-1-基)-4H-色烯-4-酮(LRY-24)
用(5-甲基噻吩-2-基)(哌嗪-1-基)甲酮(1.26g,6.0mmol)代替吡咯烷之外，以与化合物LRY-23相同的方法合成得到黄色固体152mg，收率35.1％。1H NMR(300MHz,CDCl3):δ＝14.13(s,1H,Ar-OH),10.15(s,1H,Ar-OH),8.23(d,1H,J＝6.00Hz,CH＝C(CO)-S),7.24(d,J＝9.00Hz,2H,Ar-H),6.98(d,1H,J＝6.00Hz,CH-CH＝C(CO)-S),6.80(d,J＝9.00Hz,2H,Ar-H),6.65(s,1H,CHCO),5.84(s,1H,Ar-H),3.53(t,4H,N(CH2CH2)2),3.36(s,4H,Ar-N(CH2CH2)2N),3.19(s,4H,Ar-N(CH2CH2)2N),2.44(s,3H,-CH3),1.87(m,4H,N(CH2CH2)2)ppm.HRMS(ESI)，[M+H]+calculated for C29H29N3O5S 532.1995,found 532.1954.
实施例12
5，7-二羟基-2-(4-(4-甲基哌嗪-1-基)苯基)-8-吗啉基-4H-色烯-4-酮(LRY-25)
用吗啉(565mg,6.5mmol)代替吡咯烷之外，以与化合物LRY-23相同的方法合成得到黄色固体165mg，收率40.4％。1H NMR(300MHz,CDCl3):δ＝13.02(s,1H,Ar-OH),10.69(s,1H,Ar-OH),7.93(d,J＝6.00Hz,2H,Ar-H),7.03(d,J＝9.00Hz,2H,Ar-H),6.58(s,1H,Ar-H),6.40(s,1H,Ar-H),3.89(t,J＝3.00Hz,4H,-O-CH2-),3.50(t,J＝6.00Hz,4H,-N-CH2-),3.20(t,J＝9.00Hz,4H,-N-CH2-),2.70(t,J＝6.00Hz,4H,-N-CH2-),2.47(s,3H,-CH3)ppm.HRMS(ESI)，[M+H]+calculated for C24H27N3O5438.2085,found 438.2096.
实施例13
1-甲基-4-(2，4，6-三甲氧基苯基)-1，2，3，6-四氢吡啶(I-31)
向三颈瓶中加入1，3，5-三甲氧基苯(8.8g,0.052mol)和乙酸(20mL)，冰盐浴降温至-5℃，滴加N-甲基-4-哌啶酮(7.1g,62.8mol)，控制温度低于10℃。加毕，继续滴加浓盐酸(8mL)，反应液呈黄褐色。反应10h，向反应液中加入等体积冰水，用饱和碳酸钠调至碱性，抽滤，固体干燥，得粗品10.26g，收率65％。
2-羟基-4，6-二甲氧基-3-(1-甲基-1，2，3，6-四氢吡啶-4-基)苯乙酮(I-32)
向三颈瓶中加入中间体I-31(5g,19mmol)和二氯甲烷(80mL)，搅拌至完全溶解，在氮气保护下，降温至0℃，滴加乙酸酐(25mL)，微放热。控制温度低于5℃，滴加三氟化硼乙醚(20mL)。滴加结束后，升温至室温反应10h，TLC监测至反应完全，用饱和碳酸钠水溶液调至pH＝8，析出淡黄色固体，抽滤，干燥，甲基叔丁基醚打浆，得粗品5.4g，收率80％。
2-乙酰基-3，5-二甲氧基-6-(1-甲基-1，2，3，6-四氢吡啶-4-基)苯基4-氟苯甲酸酯(I-33)
将中间体I-32(5.1g,17.5mmol)溶于吡啶(80mL)中，溶液呈红褐色，降温至0℃，缓慢滴加对氟苯甲酰氯(6mL)，滴加结束后升温至40℃反应12h，TLC监测反应至原料消失。停止反应，冰浴降温至0℃，滴加等体积饱和碳酸钠水溶液，二氯甲烷萃取三次，合并二氯甲烷层，用食盐水洗涤3次，无水硫酸钠干燥，65℃减压蒸除吡啶，得油状红褐色化合物5.0g，收率70％。
1-(4-氟苯基)-3-(2-羟基-4，6-二甲氧基-3-(1-甲基-1，2，3，6-四氢吡啶-4-基)苯基)丙烷-1，3-二酮(I-34)
将油状物I-33溶于无水吡啶(60mL)中，升温至45℃，通氮气保护。另将氢氧化钾(1.3g,23.2mmol)研成粉末状，分批加入反应体系中，1h后，TLC监测至反应完全。停止反应，滴加饱和碳酸钠水溶液至pH＝7-8，有大量橙色固体析出，抽滤得4.9g粗品，收率65％。
3-(4-氟苯基)-5，7-二甲氧基-8-(1-甲基-1，2，3，6-四氢吡啶-4-基)-4H-色烯-4-酮(I-35)
将中间体I-34(4.1g,10mmol)溶于乙酸(80mL)中，升温至110℃，加入浓硫酸(1.4mL)。反应45min，TLC监测至反应完全，冰盐浴降温至0℃，析出大量黄色固体。抽滤，减压蒸除大部分乙酸，将剩余物与之前抽滤的固体合并，再用饱和碳酸钠水溶液调至弱碱性，析出灰白色固体3.8g，收率70％。
3-(4-氟苯基)-5-羟基-7-甲氧基-8-(1-甲基-1，2，3，6-四氢吡啶-4-基)-4H-色烯-4-酮(I-36)
以与中间体I-28相同的方法合成得到1.8g黄褐色固体，收率38％。1H NMR(300MHz,CDCl3):δ＝12.92(s,1H,5-OH),7.90(m,2H,Ar-H),7.24(d,2H,Ar-H),6.63(s,1H,COCH＝C),6.43(s,1H,Ar-H),5.75(s,1H,C＝CH),3.89(s,3H,OCH3),3.26(s,2H,NCH2CH＝C),2.80(t,2H,NCH2),2.53(s,3H,NCH3),1.27(s,2H,NCH2CH2)ppm.HRMS(ESI)，[M+H]+calculated for C22H20FNO4382.1449,found 382.1455.
2-(4-氟苯基)-5，7-二羟基-8-(1-甲基-1，2，3，6-四氢吡啶-4-基)-4H-色烯-4-酮(I-37)
以与中间体I-29相同的方法合成得到黄色固体1.1g，收率65％。1HNMR(300MHz,CD4O):δ＝7.25(m,2H,Ar-H),6.54(t,2H,Ar-H),5.92(s,1H,COCH＝C),5.46(s,1H,Ar-H),4.99(s,1H,C＝CH),2.56(t,2H,NCH2CH＝C),2.13(t,2H,NCH2),1.76(s,2H,NCH2CH2)ppm.HRMS(ESI)，[M+H]+calculated for C21H18FNO4368.1293,found 368.1289.
5，7-二羟基-8-(1-甲基-1，2，3，6-四氢吡啶-4-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-4H-色烯-4-酮(LRY-30)
将中间体I-37(150mg,0.41mol)、N，N-二异丙基乙胺(0.6mL)、二甲亚砜(2mL)依次加入单颈瓶中。氮气保护，升温至120℃，加入甲基哌嗪(0.37g,3.7mmol)，反应2h，停止反应，降温至室温，加入水(4mL)，析出橙色固体150mg，收率60％。1H NMR(300MHz,CDCl3):δ＝12.94(s,2H,OH),7.74(d,2H,Ar-H),7.00(d,2H,Ar-H),6.56(s,1H,COCH＝C),6.34(s,1H,Ar-H),5.90(s,1H,C＝CH),3.41(t,4H,ArN(CH2)2),3.35(s,2H,NCH2CH＝C),3.24(s,2H,NCH2),3.05(t,2H,CH3NCH2CH2),2.98(s,2H,CH3NCH2CH2),2.90(m,2H,CH3NCH2CH2),2.40(s,3H,NCH3)ppm.HRMS(ESI)，[M+H]+calculated for C26H29N3O4448.2231,found 448.2221.
实施例14
1-甲基-4-(2，4，6-三甲氧基苯基哌啶)-3-醇(I-38)
在三颈瓶中将中间体I-31(60g,0.23mol)和硼氢化钠(17.22g,0.46mol)溶解在无水四氢呋喃(450mL)中，在氮气保护下滴加三氟化硼乙醚(60mL,0.48mol)，并保持温度在0℃以下。将反应液升温至50-60℃，反应1.5h。将反应液降温至10℃以下，缓慢滴加水(30mL)，再滴加浓盐酸(150mL)。将反应液升温至50-60℃反应2h。用50％氢氧化钠(180-190mL)调节pH约至9，再滴加双氧水(120mL)，并控制双氧水的滴加时间在半小时以上，反应液温度在50-60℃。分离出上层有机层，并用乙酸乙酯萃取水层三次(3*200mL)。合并有机层，旋转蒸发浓缩，得油状物，用少量冰水稀释，再用2mol/L盐酸调pH至1，搅拌30min后用乙酸乙酯萃取3次(3*100mL)，将水层降温至0℃，使用10％氢氧化钠调节pH至9，再用乙酸乙酸萃取3次(3*250mL)，合并有机层，用无水硫酸钠干燥，过滤，滤液旋转蒸发浓缩，得约35g淡黄色透明油状物，收率54％。
(1-甲基-3-(2，4，6-三甲氧基苯基)吡咯烷-2-基)乙酸甲酯(I-39)
在三颈瓶中加入中间体I-38(12g,0.042mol)，三乙胺(8.63g,0.085mol)和二氯甲烷(120mL)，降温至0℃，搅拌溶解，在氮气保护下缓慢滴加甲磺酰氯(7.32g，0.064mol)，控制温度在0℃以下，反应约1h。待TLC检测反应完全，将反应液抽滤，滤饼用适量二氯甲烷洗涤，保留滤液并控温在0℃以下。
在500mL三颈瓶中加入乙酸钠(17.49g,0.213mol)和异丙醇(120mL)，搅拌升温至回流。待回流后，滴加上述滤液。反应2h，待TLC检测反应完全，停止加热，冷却，抽滤，滤液旋转蒸发浓缩得黄色油状物10.2g，收率75％。
(1-甲基-3-(2，4，6-三甲氧基苯基)吡咯烷-2-基)甲醇(I-40)
在单颈瓶中用甲醇(50mL)溶解中间体I-39(10.2g,32mmol)，然后加入水(60mL)。再在搅拌下缓慢加入50％氢氧化钠(13mL)，室温下反应约2h。待TLC检测反应完全，滤液旋转蒸发浓缩，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，抽滤，旋干，得黄色油状物7.1g，收率80％。
((2R，3S)-1-甲基-3-(2，4，6-三甲氧基苯基)吡咯烷-2-基)甲醇(I-41)
在三颈瓶中用二氯甲烷(180mL)溶解中间体I-40(9g,32mmol)，搅拌下加入L-二苯甲酰酒石酸(12.67g,33mmol)，反应液先逐渐变澄清，后又白色固体析出。室温下搅拌约2h。抽滤，滤饼用适量二氯甲烷洗涤。用水(50mL)溶解滤饼，加入适量稀盐酸促溶并调节pH约至3以下，用乙酸乙酯萃取三次。将水相用饱和碳酸钠水溶液调节pH至8左右，再用乙酸乙酯萃取三次，合并有机层，无水硫酸钠干燥，过滤，选装蒸发浓缩得淡黄色固体2.8g，收率31％。αD25＝-14。(c＝1，MeOH)HPLC检测显示手性纯度为95％。方法为：流动相：5％乙醇：95％环己烷，流速：1ml/min，等度洗脱。
((2R，3S)-3-(3-乙酰基-2，4，6-三甲氧基苯基)-1-甲基吡咯烷-2-基)乙酸甲酯(I-42)
在三颈瓶中用二氯甲烷(20mL)溶解中间体I-41(1.8g,6.4mmol)，降温至0℃以下。在氮气保护下，边搅拌边缓慢滴加三氟化硼乙醚(8.2g,57.6mmol)并保持温度在0℃以下。滴加完毕后，同样条件下滴加乙酸酐(6.5g,64mmol)。滴加完毕后，室温下反应约6h，待TLC检测原料无剩余时，停止反应。滤液旋蒸发浓缩，然后降温至0℃以下，缓慢加入适量冰水，用饱和碳酸钠水溶液调节pH至10。用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干得黄色固体1.9g，收率76％。
2-((2S，3R)-2-(乙酰氧基甲基)-1-甲基吡咯烷-3-基)-6-乙酰基-3，5-二甲氧基苯基4-氟苯甲酸酯(I-43)
在三颈瓶中用吡啶(25mL)溶解中间体I-42(2.6g,7.3mmol)，降温至0℃以下，搅拌下缓慢滴加4-氟苯甲酰氯(3.5g,22.1mmol)，保持温度在0℃以下。滴加完毕后，升温至40℃反应约4h。待TLC检测反应完全，停止反应，降温至室温，将反应液缓慢加入饱和碳酸钠水溶液(40mL)中。用二氯甲烷萃取三次，合并有机相，用水萃取一次，用饱和氯化钠水溶液萃取两次，有机相中加入无水硫酸钠干燥，抽滤，旋干，得得黄色固体2.1g，收率82％。
(2S，3R)-3-(3-(3-(4-氟苯基)-3-氧代丙酰基)-2-羟基-4，6-二甲氧基苯基)-1-甲基吡咯烷-2-基)乙酸甲酯(I-44)
以与中间体I-34相同的方法合成得到棕色油状物2.7g，收率90％。无须纯化，可直接进行下一步反应。
(2S，3R)-3-(2-(4-氟苯基)-5，7-二甲氧基-4-氧代-4H-苯并吡喃-8-基)-1-甲基吡咯烷-2-基)乙酸甲酯(I-45)
以与中间体I-35相同的方法合成得到黄色固体1.4g，收率87％。
2-(4-氟苯基)-8-((2S，3R)-2-(羟甲基)-1-甲基吡咯烷-3-基)-5，7-二甲氧基-4H-色烯-4-酮(I-46)
在单颈瓶中，加入甲醇(7.5mL)，水(8.75mL)和中间体I-45(2.5g,5.48mmol)，在搅拌下缓慢加入50％氢氧化钠(10mL)。室温下反应约3h，待TLC检测反应完全，停止反应，抽滤，滤饼用适量水洗涤，烘干得黄色固体1.1g，收率86％。
2-(4-氟苯基)-5-羟基-8-((2S，3R)-2-(羟甲基)-1-甲基吡咯烷-3-基)-7-甲氧基-4H-色烯-4-酮(I-47)
以与中间体I-36相同的方法合成得到黄色固体0.6g，收率60％。
5，7-二羟基-8-((2S，3R)-2-(羟甲基)-1-甲基吡咯烷-3-基)-2-(4-(4-哌啶吗啉-1-基)苯基)-4H-苯并吡喃-4-酮(LRY-34)
用4-(哌啶-4-基)吗啉(850mg,5.0mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体约23mg，收率17％。1H NMR(300MHz,CDCl3):δ＝13.25(s,1H,5-OH),10.88(s,1H,7-OH),7.93(d,2H,J＝9.00Hz,Ar-H),6.99(d,2H,J＝9.00Hz,Ar-H),6.55(s,1H,CHCO),6.43(s,1H,Ar-H),4.36(m,1H,CHCH2-OH),3.77(m,4H,N(CH2CH2)2O),3.71(m,1H,CHCH2-OH),3.45(m,1H,CHCH2-OH),3.32(m,1H,Ar-CH(CH2)-CH(CH2)-N),2.95(m,2H,Ar-N(CH2CH2)2CH-N),2.87(m,2H,Ar-N(CH2CH2)2CH-N),2.82(m,1H,Ar-CH(CH2)-CH(CH2)-N),2.61(t,4H,J＝4.50Hz,N(CH2CH2)2O),2.49(s,3H,Ar-CH(CH2)-CH(CH2)-N-CH3),2.45(m,1H,Ar-N(CH2CH2)2CH-N),2.40(t,2H,J＝3Hz,Ar-CHCH2CH2-N-CH3),2.19(m,2H,Ar-CHCH2CH2-N-CH3),1.99(m,2H,Ar-N(CH2CH2)2CH-N),1.69(m,2H,Ar-N(CH2CH2)2CH-N)ppm.HRMS(ESI)，(M+H)+calculated for C30H37N3O6 536.2712,found 536.2751.
实施例15
1-甲基-4-(2，4，6-三甲氧基苯基)哌啶-3-酮(I-48)
在三颈瓶中，用无水二氯甲烷(100mL)溶解草酰氯(26.2g,0.21mol)，降温至-78℃。将二甲亚砜(32.6g)稀释在二氯甲烷(50mL)中，并在氮气保护下，逐渐滴加到反应瓶中，温度控制在-65℃以下。滴加完毕后，将中间体I-38(34.2g,0.12mol)溶解在二氯甲烷(200mL)中，并缓慢滴加到反应瓶中，控制温度在-65℃以下。滴加完毕后，保持反应温度在-70℃以下反应2h。待TLC检测原料反应完全，缓慢滴加三乙胺(61.5g,0.61mol)，控制温度在-65℃以下。滴加完毕后，继续反应约30min，升至室温。用饱和碳酸钠水溶液调节pH至8左右，用二氯甲烷萃取三遍，合并有机相，用饱和氯化钠洗涤三遍有机相，加入无水硫酸钠干燥，过滤，滤液旋转蒸发浓缩，得红褐色固体23.5g，收率70％。
(S)-1-甲基-4-(2，4，6-三甲氧基苯基)哌啶-3-酮(I-49)
在单颈瓶中加入中间体I-48(23g,80mmol)及D-二苯甲酰酒石酸(29.5g,80mmol)，然后加入甲醇(140mL)，升温至回流。当反应液呈透明状时，停止加热，移至室温搅拌析晶约12h，抽滤，滤饼用甲醇洗涤三遍，烘干，得约16.8g白色固体。滤液浓缩后加入约甲醇(70mL)，重复上述操作，二次析晶后得白色固体约5.3g。向上述所得成盐物加入水(100mL)，使用2mol/L盐酸调节pH至1，搅拌约30min，然后用乙酸乙酯萃取三遍。水相用饱和碳酸钠水溶液调节pH至10，然后用乙酸乙酯萃取三遍，合并有机相，无水硫酸钠干燥，过滤，旋转蒸发浓缩，得9.8g白色固体，收率43％。
(4S)-1-甲基-4-(2，4，6-三甲氧基苯基)哌啶-3-醇(I-50)
在三颈瓶中用无水甲苯(100mL)溶解中间体I-49(9.8g,35mmol)，氮气保护，降温至-78℃，然后缓慢滴加二异丁基氢化铝甲苯溶液(70mL，1.5mol/L)，控温在-65℃以下。滴加完毕后，反应3-4h。待TLC检测反应完全，滴加甲醇(50mL)，并控温在-65℃以下。滴加完毕后，缓慢升温至室温，使用10％氢氧化钠调节pH至碱性，搅拌半小时，抽滤，滤饼用少量二氯甲烷洗涤三遍，分离出有机相，水相用二氯甲烷萃取三遍，合并有机相，用饱和氯化钠洗涤三遍。有机相用无水硫酸钠干燥，过滤，滤液旋转蒸发浓缩，得淡黄色油状物7.5g，收率76％。
(3S，4S)-1-甲基-4-(2，4，6-三甲氧基苯基)哌啶-3-醇(I-51)
在单颈瓶中，加入中间体I-50(7.5g,27mmol)，D-二苯甲酰酒石酸(9.56g,27mmol)以及甲醇(45mL)，搅拌下加热至回流溶解。将反应液冷却至室温搅拌，冷却析晶。抽滤后，滤饼再次按照上述操作进行重结晶四次，终得白色固体约4.5g。将其加入到水(50mL)中，用2mol/L盐酸调节pH至3以下，然后用乙酸乙酯萃取三次。水相用饱和碳酸钠水溶液调节pH至9，再用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液旋转蒸发浓缩，得2g白色固体，收率26％。比旋度测定为，αD25＝-49。(c＝1，MeOH)HPLC检测显示手性纯度为98％。方法为：流动相：15％乙醇：85％环己烷，流速：1ml/min，等度洗脱。
(3S，4S)-4-(3-乙酰基-2-羟基-4，6-二甲氧基苯基)-1-甲基哌啶-3-基乙酸酯(I-52)
以与中间体I-42相同的方法合成得到黄色固体1.8g，收率80％。
(3S，4S)-4-(3-(3-(4-氟苯基)-3-氧代丙酰基)-2-羟基-4，6-二甲氧基苯基)-1-甲基哌啶-3-基乙酸酯(I-53)
以与中间体I-43相同的方法合成得到棕色油状物3g，收率86％。
(3S，4S)-4-(3-(3-(4-氟苯基)-3-氧代丙酰基)-2-羟基-4，6-二甲氧基苯基)-1-甲基哌啶-3-基乙酸酯(I-54)
以与中间体I-44相同的方法合成得到棕色油状物2.7g，收率90％。
(3S，4S)-4-(2-(4-氟苯基)-5，7-二甲氧基-4-氧代-4H-苯并吡喃-8-基)-1-甲基哌啶-3-基乙酸酯(I-55)
以与中间体I-45相同的方法合成得到黄色固体2.3g，收率88％。
2-(4-氟苯基)-8-((3S，4S)-3-羟基-1-甲基哌啶-4-基)-5，7-二甲氧基-4H-色烯-4-酮(I-56)
以与中间体I-46相同的方法合成得到黄色固体1.4g，收率60％。
2-(4-氟苯基)-5-羟基-8-((3S，4S)-3-羟基-1-甲基哌啶-4-基)-7-甲氧基-4H-色烯-4-酮(I-57)
以与中间体I-47相同的方法合成得到黄色固体1.2g，收率88％。
2-(4-(1，4-二氮杂环庚-1-基)苯基)-5，7-二羟基-8-((3S，4S)-3-羟基-1-甲基哌啶-4-基)-4H-苯并吡喃-4-酮(LRY-36)
用高哌嗪(500mg,5.0mmol)代替吡咯烷之外，以与化合物I-11相同的方法合成得到黄色固体17mg，收率14％。1H NMR(300MHz,DMSO-d6):δ＝13.63(s,1H,5-OH),10.97(s,1H,7-OH),8.06(d,2H,J＝9.00Hz,Ar-H),7.07(d,2H,J＝9.00Hz,Ar-H),6.79(s,1H,CHCO),6.56(s,1H,Ar-H),5.59(s,1H,CHOH),3.99(s,1H,CHOH),3.88(s,3H,ArOCH3),3.65(s,2H,Ar-N-CH2-CH2-CH2-N),3.64(s,2H,Ar-N-CH2-CH2-N),3.36(m,3H,Ar-CH,Ar-N-CH2-CH2-N),3.18(m,6H,Ar-CH-CH(OH)-CH2-N(CH3)-CH2,Ar-N-CH2-CH2-CH2-N),2.81(s,3H,CH3-NCH2CHOH),2.21(m,2H,Ar-N-CH2-CH2-CH2-N),2.01(m,1H,Ar-CH-CH2CH2N),1.82(m,1H,Ar-CH-CH2CH2N)ppm.HRMS(ESI)，(M+H)+calculated for C26H31N3O5 466.2393,found466.2399.
实施例16
USP8小分子抑制剂酶抑制活性测试
本实施例利用底物Ubiquitin-Rho-110建立了靶向USP8的高通量筛选体系。使用DMSO将底物粉末溶解到浓度2.1mM。配制筛选所用实验缓冲液，成分包括50mM Tris-HCl pH7.5，1mM EDTA，100mM NaCl和0.05％(w/v)CHAPs。将USP8蛋白用实验缓冲液稀释到1nM，取5μL加入到384孔板中。接着加入5μL化合物稀释缓冲液，室温孵育0.5h。然后加入10μL 2.1mM底物，室温孵育。设置Molecular Devices多功能酶标仪激发波长为485nM、发射波长为535nM，分别在室温孵育15、30、40分钟后读取反应产物荧光强度，利用GraphPad Prism 8.0软件拟合求得IC50值。结果如表1所示。
表1本发明部分化合物对USP8的酶抑制活性IC50
注：“++++”表示IC50＜5μM，“+++”表示IC50＜20μM，“++”表示IC50＜50μM，“+”表示IC50＞50μM。
实施例17
细胞存活实验测定化合物对肿瘤细胞株的增殖抑制作用。
本实施例选择人乳腺癌细胞MCF7、非小细胞肺癌细胞A549及结肠癌细胞HCT116等肿瘤细胞株，选用MTT法检测化合物的细胞增殖抑制效果。细胞均以2^104mL-1的密度培养于96孔透明板中，用化合物或相同体积的DMSO处理细胞。72h后加入5mg/ml MTT，4h后吸弃培养基，用DMSO溶解蓝紫色结晶，用Thermo酶标仪测定各个孔的OD490，反映存活细胞数量。半增殖抑制浓度GI50值经GraphPad Prism 8.0软件拟合求得。结果如表2所示。
表2本发明部分化合物对肿瘤细胞株的增殖抑制活性GI50
由上表可知，本发明的化合物对多种肿瘤细胞株表现出了较好的增殖抑制效果。
实施例18USP8小分子抑制剂体内药效学研究
本实施例构建了人乳腺癌细胞MCF7的异种移植瘤小鼠模型，以验证代表性化合物LRY-18的体内抗肿瘤活性。当肿瘤生长到80-100mm3时，每隔一天通过口服灌胃给随机分组后的小鼠进行LRY-18(5mg/kg和20mg/kg)或他莫昔芬(20mg/kg)的给药，持续14天。结果显示LRY-18(20mg/kg)能够显著抑制肿瘤生长，并显示出比他莫昔芬(20mg/kg)更强的抗肿瘤活性(图1A、1C和1D)。此外，与溶媒对照组相比，LRY-18给药组没有显著的体重减轻(图1B)。为了进一步阐明LRY-18在体内发挥药效的作用机制，通过免疫组织化学检测了磷酸化EGFR、ErbB2、ERbB3和ERα(图1E和图2A-C)在给药组异种移植肿瘤中的表达情况。与对照组相比，LRY-18给药组中四种蛋白水平均显著下调。收集小鼠的心脏、肝脏、脾脏、肺和肾组织进行HE染色，未观察到明显的形态或结构变化(图3)。此外，还对(图4A-D)。与对照组相比，LRY-18给药组的所有检测指标均无显著变化。
Claims (5)
1.一种化合物或其药学上可接受的盐，其特征在于：所述化合物为以下化合物式中的任意一个：
2.根据权利要求1所述化合物或其药学上可接受的盐，其特征在于：所述药学上可接受的盐是指所述的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成的碱加成盐，所述酸为氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；所述碱加成盐为钠盐、钾盐、铵盐、钙盐、铝盐、镁盐、乙二胺盐或乙醇胺盐。
3.一种药物组合物，包括药物有效量的活性组分和药学上可接受的辅料，其特征在于：所述活性组分包括权利要求1或2所述的的化合物或其药学上可接受的盐中的一种或多种。
4.权利要求1或2所述的化合物或其药学上可接受的盐及权利要求3所述的药物组合物在制备USP8抑制剂中的应用。
5.权利要求1或2所述的化合物或其药学上可接受的盐及权利要求3所述的组合物制备治疗癌症药物中的应用；所述的癌症为非小细胞肺癌、胃癌、乳腺癌、胶质瘤或结肠癌。
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