CN116410207A - 一类泛素化特异性蛋白酶抑制剂及其制备方法与应用 - Google Patents
一类泛素化特异性蛋白酶抑制剂及其制备方法与应用 Download PDFInfo
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- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Abstract
本发明涉及一种式I所示化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药,以及包含其的药物组合物,其制备方法,及其医药用途,所述化合物具有抑制USP28和/或USP25的活性,所述式I结构如下:
Description
本申请是申请日为2019年5月9日,申请号为201910385956.0,发明名称为“一类泛素化特异性蛋白酶抑制剂及其制备方法与应用”的发明专利申请的分案申请。
技术领域
本发明涉及药物领域,具体地,本发明涉及一类新的泛素化特异性蛋白酶抑制剂及其制备方法和用途。
背景技术
细胞功能的正常发挥依赖于胞内蛋白质稳态,而维持此稳态则依赖于蛋白质合成和降解的动态平衡。细胞主要通过蛋白酶体降解途径来去除不再需要的蛋白,例如受到损伤或已完成使命的蛋白。通过蛋白酶体途径降解的蛋白质通常被通过48号位赖氨酸相连的多聚泛素链标记。蛋白质的多聚泛素标记是一系列酶作用的结果,主要包括E1、E2、E3。E1通过在其自身半胱氨酸残基和由76个氨基酸组成的泛素的C-末端羧基之间形成高能硫酯键来激活泛素;被激活的泛素被转移到E2的半胱氨酸残基上(哺乳动物中大约有50种E2偶联酶);继而,在E3连接酶的作用下(哺乳动物细胞中大约有500种E3),E2偶联酶将泛素转移到一个靶蛋白的赖氨酸残基。本质上,E3连接酶只是将E2偶联酶和底物聚集在一起,使得泛素从E2上被转移到靶蛋白上(Annu.Rev.Biochem.2009,78,477&2018,87,697;J.Am.Soc.Nephrol.2006,17,1807)。在细胞的一系列活动中,泛素介导的、通过蛋白酶体的蛋白降解是必需的一种调控手段,例如细胞周期、细胞凋亡(Front Cell.Dev.Biol.2018,6,11;Cell Death Differ.1999,6,303;J.Cell.Mol.Med.2002,6,25)、DNA损伤检查点控制(DNA Repair 2010,9,1229;Biochim.Biophys.Acta 2014,1843,150;Cell DeathDiffer.2010,17,78;ISRN Mol.Biol.2012,146748),等等。
相对于泛素化,细胞也拥有去泛素化的能力,以便更精确的调控蛋白稳态。去泛素化是由去泛素化酶(DUBs)催化的。DUBs是一类特异的蛋白水解酶(Physiol.Rev.2013,93,1289;Oncogene 2012,31,2373;Biochem.J.2015,465,1;BMC Biochem.2008,9Suppl 1,S3;Protein Sci.2014,23,344)。在哺乳动物中,已知大约有100多种DUBs,它们被分成了几个家族,包括泛素特异性蛋白酶(USP)家族,泛素C-末端水解酶(UCH)家族,卵巢肿瘤蛋白酶(OTU)家族和Machado-Josephin结构域(MJD)家族。
我们知道蛋白酶体介导的蛋白降解***的失调与多种人类疾病密切相关,包括肿瘤、免疫和神经***的一些疾病(Front Mol.Neurosci.2014,7,70;Cardiovasc.Res.2010,85,251;Essays Biochem.2005,41,187;Front Biosci.2014,19,886;CancerBiol.Ther.2002,1,337;IUBMB Life 2015,67,544;Acta Neuropathol.2009,118,329;Int.J.Biochem.Cell.Biol.2018,101,80;J.Clin.Oncol.2013,31,1231;CancerMetastasis Rev.2017,36,635;Circ.Res.2013,112,1046;Drug Resist.Updat.2015,23,1;Biochim.Biophys.Acta 2014,1843,13;Cancer Metastasis Rev.2017,36,683;CancerSci.2009,100,24)。
USP28是一种泛素特异性蛋白酶,在维持c-MYC(Nat.Cell.Biol.2007,9,765)、LSD1(Cell Rep.2013,5,224)、HIF1alpha(Blood 2012,119,1292)、Notch1(J.Clin.Invest.2014,124,3407)、53BP1(Mol.Cell.Biol.2014,34,2062)和CLASPIN(Cell2006,126,529)等蛋白水平中起重要的作用,防止它们仍在发挥功能时被降解。几乎所有这些底物,尤其是c-MYC,在肿瘤发生和发展中起重要作用。也有证据表明USP28在肿瘤中是过表达的且表达水平高的病人预后较差(Tumor Biol.2014,35,4017;BBA-Mol.Basis.Dis.2019,1865,599;Biochem.Pharmacol.2018,150,280;Oncotarget,2017,8,39627;Transl.Oncol.2017,10,80;J.Cell.Mol.Med.2015,19,799)。这使USP28成为一个有吸引力的肿瘤治疗靶点。
c-MYC作为一个转录因子,它激活了细胞生长和增殖相关基因的表达(Biochim.Biophys.Acta,2015,1849,506;Annu.Rev.Cell Dev.Biol.2000,16,653;TrendsBiochem.Sci.1997,22,177;Adv.Cancer Res.1996,70,95;Lung Cancer 2001,34Suppl 2,S43)。几乎所有的生长调节信号通路最终都需要c-MYC来发挥作用,这使c-MYC在肿瘤治疗中成为一个最具潜力的靶点(Cancer Lett.2003,197,125;Expert Opin.Ther.Targets2003,7,623;Cell 2004,117,153-156;Semin.Cancer Biol.2006,16,318)。然而,过去几十年的研究经验表明直接调控c-MYC活性的小分子化合物几乎不可能被找到(Biochim.Biophys.Acta 2015,1849,525)。退而求其次,目前人们在努力寻找间接抑制c-MYC功能的方法。其中一种方法是利用c-MYC蛋白不稳定的特性。FBW7是c-MYC的主要E3连接酶,促进其泛素化和降解(Curr.Biol.2004,14,1852;EMBO J.2004,23,2116),而USP28在此过程中起到相反的作用(Nat.Cell Biol.2007,9,765)。因此,抑制USP28能够潜在地降低c-MYC的稳定性从而减慢或者阻止肿瘤细胞的增殖。
LSD1是一个在基因表达的表观遗传调控中起到重要作用的组蛋白去甲基化酶(Curr.Opin.Chem.Biol.2007,11,561;Epigenomics 2016,8,1103)。已经在大量的恶性肿瘤中发现LSD1是过表达的,并且LSD1被认为对肿瘤干细胞的维持起着非常重要的作用(Hum.Pathol.2012,43,1300;Fertil.Steril.2014,101,740;Int.J.Cancer,2011,128,574;J.Ovarian Res.2013,6,75;Int.J.Gynecol.Cancer,2015,25,1453;PLoS One,2015,10,e0118002;Tumor Biol.2013,34,173;World J.Gastroenterol.2012,18,6651)。在乳腺癌细胞中,LSD1缺失造成了干细胞群的丢失,也降低了细胞的增殖潜力(Cell Rep.2013,5,224)。另外,在肿瘤免疫中,LSD1也被确定为一个关键的调节因子(Cell 2018,174,549)。因此,抑制USP28可以使LSD1和c-MYC这两个异常重要的癌蛋白不稳定,降低它们的胞内水平,从而达到阻止肿瘤细胞增殖的目的。
敲除了USP28的小鼠胚胎发育正常且出生后生长正常,成年小鼠未发现有明显的不健康状况,生育能力也未有减弱,表明USP28在小鼠里是非必需的(J.Clin.Invest.2014,124,3407;Mol.Cell.Biol.2014,34,2062)。然而,USP28缺失小鼠对APC突变诱导的结肠癌却表现出抵抗力(J.Clin.Invest.2014.124,3407),提示至少在结肠癌中USP28是一个有价值的治疗靶点。
近年来的研究使人们不断地认识到细胞衰老在个体衰老中的重要作用(Nat.Rev.Mol.Cell.Biol.2007,8,729;Exp.Gerontol.2001,36,1619;Nat.Med.2015,21,1424;J.Physiol.Anthropol.2007,26,365;Mol.Biol.Cell,2015,26,4524;Curr.Opin.Cell.Biol.1991,3,230;Adv.Exp.Med.Biol.2017,1002,189;Mech.AgeingDev.2008,129,460;J.Cell.Biochem.2007,101,1355;Nat.Rev.Nephrol.2017,13,77;Nature 2014.509,439)。更重要的是,清除衰老细胞可以提升老年动物的健康状况(Nature2011,479,232;J.Clin.Invest.2018,128,1217;Nat.Med.2017.23,775-781;Clin.Pharmacol.Ther.2013,93,105)。衰老相关的分泌表型(SASP)是指衰老细胞能分泌大量细胞因子,其中许多细胞因子可引发炎症反应的现象(J.Clin.Invest.2013,123,966)。现有研究表明在细胞衰老过程中需要USP28的参与(Genes Dev.2017,31,1933),因此抑制USP28可能在老年人中产生有益健康的效果。
USP25是一个与USP28非常接近的同源基因,并且与USP28缺陷小鼠相似,缺乏USP25的小鼠也未表现出任何非健康的性状(Nat.Immunol.2012,13,1110)。然而,这两个去泛素化酶定位于细胞不同区域(USP28在胞核中而USP25在细胞质中),并且其底物谱也不相同。Tankyrase是USP25的底物之一(Cell Rep.2017.31,1024)。它是一个多聚-ADP-核糖基转移酶,参与多种生物过程,例如Wnt信号通路、端粒长度维持和囊泡运输。阻止USP25的功能可导致Wnt信号的减弱(Genes Dev.2017,31,1024)。考虑到已知Wnt信号在癌症中的作用,可以预测抑制USP25也将对肿瘤治疗产生有益的效果。基于USP28和USP25的同源性,可以预见,任何靶向USP28的小分子也会靶向USP25,但这反而有可能增加它们在***中的价值。
据报道,USP25能通过去泛素化TRAF5和TRAF6两个蛋白来负调控IL17介导的免疫反应(Nat.Immunol.2012,13,1110)。进一步的研究表明USP25也可以去泛素化TRAF3蛋白从而调控依赖TLR4的固有免疫反应(PLoS One 2013,8,e80976)。因此,抑制USP25有可能有益于机体针对肿瘤和感染的免疫反应。
发明内容
为改善现有技术存在的问题,提供新颖的具有USP28/USP25抑制活性的结构,本发明提供下式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药:
其中:
X为C-R5或N;
m为0、1、2、3、4、5或6;
n为1或2;
Z为氮氢(NH),氧(O)、硫(S)或亚甲基(CH2);虚线键表示可以为键或不存在;
p和q相同或不同,彼此独立地选自0、1、2或3;
R1、R2、R5相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基,所述无取代的(C1-C12)脂肪烃基为1~12碳原子和相应的氢原子组成的脂肪烃基,所述取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基;
R3为无取代或取代的(C1-C12)脂肪烃基,所述无取代的(C1-C12)脂肪烃基为由1~12碳原子和相应的氢原子组成的脂肪烃基,取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基;
每一个R4、R6和R8相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基,所述无取代的(C1-C12)脂肪烃基为由1~12碳原子和相应的氢原子组成的脂肪烃基,取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基;
R7选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基,所述无取代的(C1-C12)脂肪烃基为由1~12碳原子和相应的氢原子组成的脂肪烃基,取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基,条件是,当R6为H时,R7不为H;
或R7选自无取代或任选地被一个、两个或更多个R9所取代的3-20元杂环基或5-20元杂芳基;
R9选自氢、卤素、羟基、氨基以及任选地无取代或取代的(C1-C12)脂肪烃基,所述无取代的(C1-C12)脂肪烃基为由1~12碳原子和相应的氢原子组成的脂肪烃基,取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基。
根据本发明的实施方案,所述“无取代的(C1-C12)脂肪烃基为由1~12碳原子和相应的氢原子组成的脂肪烃基,取代的(C1-C12)脂肪烃基为包含一个、两个或更多个卤素和/或氧、硫、氮、磷原子的(C1-C12)脂肪烃基”,其中卤素、例如氧、硫、氮、磷可以在(C1-C12)脂肪烃基的直链或支链上,还可以在直链或支链的任何一个位置上,所述的(C1-C12)脂肪烃基优选可以为(C1-C10)脂肪烃基(C1-C8)脂肪烃基(C1-C6)脂肪烃基;例如可选自以下基团:(C1-C6)脂肪烃基,(C1-C6)脂肪烃基氧基、N-(C1-C6)脂肪烃基胺基、N,N-二-(C1-C3)脂肪烃基胺基、(C1-C6)脂肪烃基巯基,卤代(C1-C6)脂肪烃基,卤代(C1-C6)脂肪烃基氧基、(单或二-N取代)卤代(C1-C6)脂肪烃基胺基、卤代(C1-C6)脂肪烃基巯基、(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪烃基巯基(C1-C6)脂肪烃基、N-(C1-C6)脂肪烃基氨基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基氨基(C1-C6)脂肪烃基,例如可以为甲基、乙基、丙基、异丙基、环丙基,甲氧基甲基、乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基,N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基;根据本发明的实施方案,R3可选自甲基、乙基、丙基、丁基、甲氧基甲基,乙氧基甲基,丙氧基甲基,甲氧基乙基,乙氧基乙基,丙氧基乙基,甲氧基丙基,乙氧基丙基,丙氧基丙基,N-甲基胺甲基,N-甲基胺乙基,N-乙基胺乙基,N,N-二甲基胺甲基,N,N-二甲基胺乙基,N,N-二乙基胺乙基;
根据本发明的实施方案,Y可选自根据本发明的实施方案,所述R7可选自无取代或任选地被一个、两个或更多个R9所取代的,含有一个、两个或更多个N的3-20元杂环基或5-20元杂芳基,进一步的,优选为仅含有一个或两个N作为杂原子的3-10元杂环基。
根据本发明的实施方案,R7可选自无取代或任选地被一个、两个或更多个R9所取代的以下基团:
根据本发明的实施方案,所述式I结构进一步选自如下式II结构:
所述式II中,R1、R2、R3、R4、X和Y定义如式I中所定义。
根据本发明的实施方案,优选如下化合物(I-1至I-85)或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药:
本发明进一步提供了通式I所示化合物的制备方法,包括以下步骤:
中间体羧酸A和中间体胺B在碱性条件下经肽偶联试剂作用形成酰胺,再脱去保护基三氟乙酰基(Tfac)和叔丁氧羰基(Boc)得到目标化合物I:
(其中,R’4和Y’分别为式I的R4和Y,或者羟基、氨基等活泼基团用Boc保护的R4和Y)
试剂与反应条件:a)酰胺偶联反应:偶联试剂选自EDCI-HOBt、BOP、HATU,碱选自DEA、TEA、EDCI或DMAP;溶剂选自DCM或DMF;b)脱Tfac反应:碱选自K2CO3或NaOMe,溶剂选自MeOH;c)脱Boc反应:稀盐酸-甲醇。
根据本发明的实施方案,上述中间体A可经以下步骤制备得到(原料可由商业途径获得):
试剂与反应条件:a)DMF;b)NaOMe/DMF;c)(Tfac)2O/NaHCO3/CHCl3;d)NaH/DMF,R3-I;e)TFA/DCM。
根据本发明的实施方案,部分中间体B-I(例如B-Ia或B-Ib)可由商业途径或者经典的合成方法获得:
R'4、R’6、R’7和R’8分别为通式I的R4、R6、R7和R8或者羟基和氨基被Boc保护的R4、R6、R7和R8(当R4、R6、R7和R8含有羟基或氨基等活泼基团时)
根据本发明的实施方案,另一部分中间体B-II可经以下步骤制备得到:
R'4和R’6分别为通式I的R4和R6或者羟基或氨基被Boc保护的R4和R6(当R4和R6含有羟基或氨基等活泼基团时)
试剂与反应条件:a)BnCl,KI,K2CO3/MeCN;b)H-R7-Boc,Pd(OAc)2,X-phos,Cs(CO3)2,toluene;c)HCO2NH4,Pd(OH)2/C,MeOH.
除非另有定义,上述X,R1,R2,R3,R4,R6,R7,R8,m,n,p,q定义同式I。
根据本发明的实施方案,所述通式I所涵盖的式II均可由上述通用制备方法合成得到,根据式II结构可以明确其所采用的相应原料结构。
本发明还提供了一种药物组合物,其包含式(I)的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药作为活性成分。
根据本发明的实施方案,所述的药物组合物进一步包含治疗有效量的所述式I化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药和药学上可接受的载体。
所述药物组合物中的载体为“可接受的”,其可与组合物的活性成分相容(并且优选地,能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。
本发明进一步提供所述式(I)的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药或所述药物组合物在制备用于治疗与抑制USP28相关的疾病或障碍的药物中的用途。
本发明进一步提供所述式(I)的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药或所述药物组合物在制备用于治疗与抑制USP25相关的疾病或障碍的药物中的用途。
本发明进一步提供所述式(I)的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药或所述药物组合物在制备用于治疗与抑制USP25和USP28相关的疾病或障碍的药物中的用途。
本发明还提供一种治疗或预防与USP28和/或USP25的调节相关的疾病或障碍的方法,所述方法包括向患有所述疾病或障碍中的至少一种的患者给予式(I)的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药。
根据本发明的实施方案,所述USP25和/或USP28相关的疾病或障碍包括癌症、炎症、自身免疫疾病、病毒感染和细菌感染。
根据本发明的实施方案,所述药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物,此类组合物可含有一种或多种选自以下的成分:甜味剂、矫味剂、着色剂和防腐剂,以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂,造粒剂、崩解剂,粘合剂,和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收,因而在较长时间内提供缓释作用的已知技术将其包衣。
根据本发明的实施方案,所述药物组合物中,活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂;水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂,分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂;油混悬液可通过使活性成分悬浮于植物油,或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂,以提供可口的制剂。可通过加入抗氧化剂保存这些组合物;通过加入水可使适用于制备水混悬的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
根据本发明的实施方案,所述药物组合物也可以是水包油乳剂的形式。油相可以是植物油,或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂,乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
根据本发明的实施方案,所述药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射,将注射液或微乳注入患者的血流中。或者,最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
根据本发明的实施方案,所述药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用任何调和固定油。此外,脂肪酸也可以制备注射剂。
根据本发明的实施方案,可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合等;另外,最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。本发明的有益效果:
本发明提供了一类结构新颖的泛素化特异性蛋白酶抑制剂,经实验验证,本发明的化合物对于USP28和/或USP25有良好的抑制活性,相较于现有技术抑制剂的活性可高于15倍以上。
术语解释:
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。“更多个”表示三个或三个以上。
术语“卤素”指F、Cl、Br和I。换言之,F、Cl、Br和I在本说明书中可描述为“卤素”。
术语“脂肪烃基”包括饱和或不饱和,直链或支链的链状或环状烃基,所述脂肪烃基的类型可选自烷基、烯基、炔基等,所述脂肪烃基的碳原子数优选为1~12,还可以为1~10,进一步的优选范围为1~6,具体可包括但不限于如下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,1-甲基-2-丙炔基,3-丁炔基,1-戊炔基、1-己炔基、环丙基、环丁基、环戊基和环己基;所述脂肪烃基可任选包括一个或多个其它适宜的取代基。上述取代基的实例可以包括羟基、卤素、氰基和氨基等基团,例如所述脂肪烃基可以包含一个、两个或更多个卤素,即意味着脂肪烃基的一个、两个或更多个氢原子可以被同等数量的卤素所取代。如果所述烃基含有超过一个碳,那么那些碳不必必须彼此连接。例如,其中至少两个碳可以经适宜的元素或者基团进行连接。也就是说,所述脂肪烃基基团可以任选地包含一个、两个或更多个杂原子(或解释为任选地杂原子***至脂肪烃基中任选地C-C键和C-H键)。适宜的杂原子对于本领域熟练技术人员而言是显而易见的,并且包括例如硫、氮、氧、磷和硅。所述包含杂原子的脂肪烃基基团可选自以下基团:(C1-C6)脂肪烃基氧基、(C1-C6)脂肪烃基巯基,卤代(C1-C6)脂肪烃基,卤代(C1-C6)脂肪烃基氧基、卤代(C1-C6)脂肪烃基硫基、(C1-C6)脂肪烃基氧基(C1-C6)脂肪烃基、(C1-C6)脂肪烃基巯基(C1-C6)脂肪烃基、N-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基、N,N-二-(C1-C3)脂肪烃基胺基(C1-C6)脂肪烃基,例如可以为甲氧基甲基,乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基;其他基团中所含“脂肪烃基”部分同上述解释。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个独立选自N、O和S的杂原子,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。所述3-20元杂环基可以进一步选自如下基团:
除非另有说明,杂环基或杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
在任何用于制备本发明化合物的方法中,可能必需和/或期望保护任何有关分子上的敏感或反应性基团。这可通过常规的保护基来实现,如本领域教科书或工具书描述的保护基。可使用本领域已知的方法在方便的后续阶段移除保护基团。本领域技术人员将认识到,取决于具体的保护基团,可将其他试剂用于该去保护步骤,包括但不限于Pd/C、Pd(OH)2、PdCl2、Pd(OAc)2/Et3SiH、雷尼镍、适当选择的酸、适当选择的碱、氟化物等等。
可以根据已知的方法,例如通过萃取、过滤、柱层析、FCC或制备型HPLC来分离目标化合物。
根据其分子结构,本发明的化合物可以是手性的,因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物,或者以此形式用于合成。在外消旋的胺的情况中,通过与光学活性的拆分试剂反应,从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸,例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物),也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物,例如,己烷/异丙醇/乙腈。
本领域技术人员将理解,由于氮需要具有可用的孤对电子用于被氧化为氧化物,因此并非所有的含氮杂环都可以形成N-氧化物;本领域技术人员将识别能够形成N-氧化物的含氮杂环。本领域技术人员还将认识到叔胺能够形成N-氧化物。制备杂环和叔胺的N-氧化物的合成方法对于本领域技术人员而言是熟知的,所述合成方法包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基氢过氧化物如叔丁基氢过氧化物、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷氧化杂环和叔胺。这些制备N-氧化物的方法已在文献中广泛地描述和综述。
药学上可接受的盐可以是例如在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐,例如与如下无机酸形成的酸加成盐:例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸,或硫酸氢盐、或者与如下有机酸形成的酸加成盐:例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
另外,具有足够酸性的本发明的化合物的另一种适合的药学上可接受的盐是碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、铵盐,或与提供生理学可接受的阳离子的有机碱形成的盐,例如与如下物质形成的盐:钠离子、钾离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。作为实例,所述药学上可接受的盐包括基团-COOH与如下物质形成的盐:钠离子、钾离子、钙离子、镁离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
另外,碱性含氮基团可用如下试剂季铵化:低级烷基卤化物,例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;硫酸二烷基酯,例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯;长链卤化物,例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基溴化物等。作为实例,药学上可接受的盐包括盐酸盐、硫酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐等。
由于本发明的化合物可存在多个成盐位点,所述“药学上可接受的盐”不仅包括本发明化合物其中1个成盐位点上形成的盐,而且还包括其中2、3或全部成盐位点上形成的盐。为此,所述“药学上可接受的盐”中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化,例如可以是4:1~1:4,如3:1、2:1、1:1、1:2、1:3等。
根据本发明,药学上可接受的阴离子包括选自由无机酸或有机酸电离生成的阴离子。所述“无机酸”包括但不限于盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸。所述“有机酸”包括但不限于甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
根据不同取代基的位置和性质,本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在,仅有一个不对称中心时,产生外消旋混合物,含有多个不对称中心时,得到非对映异构体混合物。在某些情况下,由于围绕特定键的旋转受阻还可能存在不对称性,例如该中心键连接特定化合物的两个被取代的芳族环。并且,取代基还可以顺式或反式异构的形式存在。
本发明化合物还包括其各自所有可能的立体异构体,其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体,或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法,特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本发明中,所涉及的化合物亦包括经同位素标记的化合物,所述经同位素标记的化合物与式I中所示的那些相同,但是其中一或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的原子替代。可掺入本发明的化合物的同位素的实例包括H、C、N、O、S、F及Cl的同位素,分别诸如2H、3H、13C、11C、14C、15N、18O、17O、32P、35S、18F及36Cl。含有上述同位素和/或其他原子的其他同位素的本发明的化合物、其前药、或者所述化合物或所述前药的药学上可接受的盐在本发明的范围内。本发明的某些经同位素标记的化合物,例如掺入放射性同位素(诸如3H和14C)的化合物可用于药物和/或底物组织分布测定。氚(即3H)和碳14(即14C)同位素因易于制备和可检测性而成为特别优选的。再者,以较重的同位素(诸如氘,即2H)替代可提供源自更高的代谢稳定性的某些治疗优势(例如增加的体内半衰期或减少的剂量需求),并因此可在某些情况下是优选的。如权利要求所请求保护的本发明化合物可特别地限定以氘或氚替代。此外,取代基中出现的氢未单独列明术语氘或氚并不表示排除氘或氚,而是同样也可以包含氘或氚。
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变:预期应用(体外或者体内),或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等,其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变:所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送***。
术语“辅料”是指可药用惰性成分。赋形剂种类的实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性,即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的药学上可接受的载体的实例为:糖类,例如乳糖、蔗糖、甘露醇和山梨醇;淀粉类,例如玉米淀粉、木薯淀粉和土豆淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素和甲基纤维素;磷酸钙类,例如磷酸二钙和磷酸三钙;硫酸钠;硫酸钙;聚乙烯吡咯烷酮;聚乙烯醇;硬脂酸;硬脂酸碱土金属盐,例如硬脂酸镁和硬脂酸钙;硬脂酸;植物油类,例如花生油、棉籽油、芝麻油、橄榄油和玉米油;非离子、阳离子和负离子表面活性剂;乙二醇聚合物;脂肪醇类;和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
术语“溶剂化物”是本发明的化合物的那些形式,其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式,其中配位作用是与水进行。在本发明中,优选的溶剂化物是水合物。进一步的,本发明通式I化合物的药学上可接受的溶剂化物(水合物)是指化合物I与化学计量学的一个或多个分子的水或其他溶剂形成的共晶和包合物。可用于溶剂化物的溶剂包括但不限于:水、甲醇、乙醇、乙二醇和醋酸。
术语“前药”或称为“药物前体”,代表化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前药可以是酯,在本发明中酯可以作为前药的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基/羧基,即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
本发明所述“癌症”包括但不限于:膀胱癌、乳腺癌(如导管癌)、***(如鳞状细胞癌)、结肠直肠癌(如腺癌)、食道癌(如鳞状细胞癌)、胃癌(如腺癌、成神经管细胞瘤、结肠癌、绒毛膜癌、鳞状细胞癌),头部和颈部癌症,血液癌症(如急性淋巴细胞性贫血、急性骨髓性白血病、急性淋巴细胞白血病B细胞、间变性大细胞淋巴瘤、B细胞淋巴瘤、伯基特淋巴瘤、慢性淋巴细胞白血病、慢性嗜酸粒细胞白血病/高嗜酸性粒细胞综合征、慢性粒细胞白血病、何杰金氏淋巴瘤、套细胞淋巴瘤、多发性骨髓瘤、T细胞急性淋巴细胞白血病)、肺癌(如支气管肺泡腺癌、间皮瘤、粘液表皮样癌、小细胞肺癌、非小细胞肺癌、腺癌、鳞状细胞癌)、肝癌(如肝细胞癌)、淋巴瘤、神经***癌症(如胶质母细胞瘤、神经母细胞瘤、神经胶质瘤)、卵巢癌(如腺癌)、胰腺癌(如导管癌)、***癌(如腺癌)、肾癌(如肾细胞癌、肾透明细胞癌)、肉瘤(如软骨肉瘤,尤因肉瘤、纤维肉瘤、多源肉瘤、骨肉瘤、横纹肌肉瘤、滑膜肉瘤)、皮肤癌(如黑色素瘤、表皮样癌、鳞状细胞癌)、甲状腺癌(如髓样癌)和子宫癌,等。
本发明所述“自身免疫疾病”或“自身免疫障碍”是指由于对自身组织的攻击而免疫介导的病症,但也可能涉及对微生物的免疫应答。自身免疫疾病的例子包括但不限于:多发性硬化症、牛皮癣、肠道炎症性疾病、溃疡性结肠炎、克罗恩病、风湿性关节炎、多发性关节炎、本地和***性硬皮病、***性红斑狼疮、盘状红斑狼疮、皮肤红斑、皮肤红斑狼疮(包括冻疮红斑狼疮、狼疮肾炎、盘状红斑狼疮、亚急性皮肤红斑狼疮、皮肌炎、多肌炎、特发性水肿、慢性甲状腺炎、格林-巴利综合征、格雷夫斯病、重症肌无力、干燥综合征、结节性全动脉炎、自身免疫性肠病、葡萄膜炎、自身免疫性***、慢性免疫性血小板减少性紫癜、结肠炎、糖尿病、牛皮癣、寻常天疱疮、增生性肾小球肾炎、威斯科特-奥尔德里奇综合征、自身免疫性淋巴组织增生综合症、慢性关节炎、炎症慢性鼻窦炎、结肠炎、腹腔疾病、炎症性肠病、巴洛氏食道癌、炎症性胃炎、自身免疫性肾炎、自身免疫性血管炎、自身免疫性肝炎、自身免疫性心脏炎、自身免疫性脑炎和自身免疫介导的血液疾病),等。
具体实施方式
下面结合具体实施例对本发明作进一步描述。本发明包括但不限于以下实施例。
以下所述实施例中的实验方法,如无特别说明,均为常规方法;所得化合物以Varian Mercury-plus 400核磁共振仪和Waters Q-TOF-Ultima质谱仪测定其1H NMR谱和质谱;所述试剂和生物材料,如无特别说明,均可从商业途径获得。
在以下实施例和本文别处使用的简写说明:
实施例1.
制备中间体A-1(3-(N-甲基-N-三氟乙酰基胺基)-噻吩[2,3-b]吡啶-2-羧酸):
试剂和反应条件:
a)向反应瓶(500mL)中加入硫代乙酸钾(57.11g,0.50mol)和无水DMF(250mL),r.t.搅拌下滴加溴代乙酸叔丁酯1a-1(97.53g,0.50mol),滴加完r.t.继续反应30min。反应液80℃减压浓缩除去溶剂,冷却后加水(150mL)溶解,氯仿(150mL)萃取2次,氯仿层用饱和NaCl溶液(100mL)洗涤2次,无水Na2SO4干燥,过滤,减压浓缩,得橙红色液体1a-2(95.01g,收率99.9%)。
b)向反应瓶(250mL)中加入2-乙酰硫基乙酸叔丁酯1a-2(10.46g,55mmol)、2-氯-3-氰基吡啶1a-3(6.93g,50mmol)和无水DMF(100mL),冷却至0-5℃,分批加入NaOMe(3.24g,60mmol)。升温至r.t.继续反应1h。搅拌下反应液倾入水(1.2L)中,大量浅黄色固体析出,抽滤,水洗,乙醇-水重结晶,得3-氨基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(1a-4,10.26g,收率82%)。
c)向反应瓶(250mL)中加入1a-4(10.01g,40mmol)、NaHCO3(6.72g,80mmol)和无水氯仿(80mL),r.t.搅拌下滴加(Tfac)2O 6.8mL(48mmol),滴加完,r.t.继续反应30min。反应液加水(40mL),r.t.搅拌至无气体产生,分出氯仿层,水层用氯仿(40mL)萃取2次。合并氯仿层,饱和NaCl溶液(80mL)洗涤2次,无水Na2SO4干燥,抽滤,得3-N-三氟乙酰基氨基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(1a-5,13.85g,收率100%)。
d)向反应瓶(250mL)中加入1a-5(13.85g,40mmol)和无水DMF(70mL),冷却至0-5℃,加NaH(1.92g,48mmol,含量60%),至无气体放出后,滴加MeI(3.24mL,52mmol)/DMF(10ml)。滴加完,升温至r.t.反应2h。反应液用醋酸调pH至7,加水(50mL),氯仿(50mL)萃取3次,合并氯仿层,饱和NaCl溶液(50mL)洗涤2次,无水Na2SO4干燥,减压浓缩,浓缩物经CHCl3-PE重结晶,得N-甲基-N-三氟乙酰基-3-氨基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯(1a-6,12.84g,收率89%)。
e)向反应瓶(50mL)中加入1a-6(2.88g,8mmol)、干燥DCM(20mL)和TFA(10mL),40℃过夜反应。减压浓缩除去DCM和TFA,得黄色胶状物。过硅胶柱,CHCl3:MeOH=50:1,7:3梯度洗脱,得N-甲基-N-三氟乙酰基-3-氨基噻吩并[2,3-b]吡啶-2-甲酸(A-1,2.38g,收率98%)。A-1:LC-MS(+ESI):m/z 305([M+H]+);1H NMR(400MHz,DMSO-d6)δ8.70(dd,J=4.6,1.3Hz,1H),8.26(d,J=8.1Hz,1H),7.53(dd,J=8.1,4.6Hz,1H),3.28(s,3H).
使用适当的合成前体,根据上文针对实施例1(中间体A-1)试剂和反应条件合成下表1中的实施例中间体A-2~A-26。
表1:
实施例2.
制备中间体A-27(3-N-乙基胺基-6-甲基噻吩[2,3-b]吡啶-2-羧酸):
试剂和反应条件:
a)向反应瓶(250mL)中加入2-乙酰硫基乙酸叔丁酯1a-2(10.46g,55mmol)、2-氯-3-氰基-6-甲基吡啶2a-1(7.63g,50mmol)和无水DMF(100mL),冷却至0-5℃,分批加入NaOMe(3.24g,60mmol)。升温至r.t.继续反应1h。搅拌下反应液倾入水(1.2L)中,大量浅黄色固体析出,抽滤,水洗,乙醇-水重结晶,得3-氨基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯2a-2(10.57g,80%)。
b)向反应瓶(250mL)中加入2a-2(10.57g,40mmol)、乙醛(2.81mL,50mmol)和乙腈(80mL),Et3SiH(19.14mL,120nmol);r.t.搅拌下滴加(Tfac)2O(16.90mL,120mmol),滴加完,r.t.继续反应18h。反应液减压浓缩除去溶剂和残留试剂,硅胶柱层析纯化(PE-EA梯度洗脱),得3-N-乙基胺基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯2a-3(10.64g,91%)。
c)向反应瓶(50mL)中加入2a-3(5.85g,20mmol)、干燥二氯甲烷(20mL)和三氟乙酸(20mL),40℃过夜反应。减压浓缩除去溶剂和残留试剂,硅胶柱层析纯化(CHCl3-MeOH梯度洗脱),得3-N-乙基胺基-6-甲基噻吩并[2,3-b]吡啶-2-甲酸A-27(4.49g,95%),(+)-ESI-MS:m/z 237([M+H]+);1H NMR(400MHz,CDCl3)δ8.31(d,J=8.5Hz,1H),7.14(d,J=8.5Hz,1H),3.45(m,2H),2.67(s,3H),1.33(t,J=7.2Hz,3H)。
使用适当的合成前体,根据上文针对实施例2(中间体A-27)概述的程序合成在下表2中的实施例中间体A-28~A-29。
表2:
实施例3.
制备中间体A-30(3-(N-甲基-N-三氟乙酰基胺基-6-羟基甲基噻吩[2,3-b]吡啶-2-羧酸):
反应试剂和条件:
a)向反应瓶(250mL)中加入2-乙酰硫基乙酸叔丁酯1a-2(10.64g,56mmol)、2-氯-3-氰基-6-乙酰氧甲基吡啶3a-1(10.53g,50mmol)和无水DMF(100mL),冷却至0-5℃,分批加入NaOMe(3.24g,60mmol)。升温至r.t.继续反应1h。搅拌下反应液倾入水(1.2L)中,大量浅黄色固体析出,抽滤,水洗,乙醇-水重结晶,得3-氨基-6-乙酰氧甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯3a-2(13.54g,84%)。
b)向反应瓶(250mL)中加入3a-2(13.54g,42mmol)、NaHCO3(6.72g,80mmol)和无水氯仿(80mL),r.t.搅拌下滴加(Tfac)2O(6.8mL,48mmol),滴加完,r.t.继续反应30min。反应液加水(40mL),r.t.搅拌至无气体产生,分出氯仿层,水层用氯仿(40mL)萃取2次。合并氯仿层,饱和NaCl溶液(80mL)洗涤2次,无水Na2SO4干燥,抽滤,得3-N-三氟乙酰基胺基-6-乙酰氧甲基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯3a-3(17.22g,98%)。
c)向反应瓶(250mL)中加入3a-3(16.73g,40mmol)和无水DMF(70mL),冷却至0-5℃,加NaH(1.92g,48mmol,含量60%),至无气体放出后,滴加MeI(3.24mL,52mmol)/DMF(10ml)。滴加完,升温至r.t.反应2h。反应液用醋酸调pH至7,加水(50mL),氯仿(50mL)萃取3次,合并氯仿层,饱和NaCl溶液(50mL)洗涤2次,无水Na2SO4干燥,减压浓缩,浓缩物经CHCl3-PE重结晶,得N-甲基-N-三氟乙酰基-3-氨基噻吩并[2,3-b]吡啶-2-甲酸叔丁酯3a-4(12.84g,89%)。
d)向反应瓶(50mL)中加入3a-4(3.35g,8mmol)、干燥二氯甲烷(20mL)和三氟乙酸(10mL),40℃过夜反应。减压浓缩除去二氯甲烷和残留三氟乙酸,过硅胶柱纯化,CHCl3-MeOH 20:1→3:1梯度洗脱,得3-N-甲基-N-三氟乙酰基胺基-6-羟基甲基噻吩并[2,3-b]吡啶-2-甲酸A-30(2.54g,95%),(+)-ESI-MS:m/z 335([M+H]+);1H NMR(400MHz,DMSO-d6)δ8.50(d,J=8.1Hz,1H),7.34(d,J=8.1Hz,1H),4.91(s,2H),3.28(s,3H)。
实施例4.
制备中间体B-1(3-(4-(2-氨基乙基)苯基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯):
反应试剂和条件:
a)向反应瓶(250mL)中加入对溴苯乙胺1b-1(10.00g,50mmol)、KI(0.41g,2.5mmol)、K2CO3(16.58g,120mmol)和乙腈(100mL),升温至回流,滴加BnCl(20.89g,165mmol)。滴加完,回流反应2h。反应液滤除无机盐,滤液减压浓缩浓缩除去乙腈,浓缩物加氯仿(200mL),用饱和NaCl溶液(100mL×2)洗涤,无水Na2SO4干燥,减压浓缩得粗品。粗品减压浓缩除去过量BnCl和副产物苄醇,得1b-2(浅黄色液体18.39g,97%)。
b)向反应瓶(250mL)中加入1b-3(4.25g,20mmol)、1b-2(9.13g,24mmol)、Pd(OAc)2(449mg,2mmol)、X-phos(953mg,2mmol)、Cs2CO3(13.03g,40mmol)和甲苯(80mL),抽真空置换N2,升温至100℃,反应18h。反应液滤除不溶物,滤液减压浓缩,浓缩物过硅胶柱,PE:EA=19:1,9:1梯度洗脱,得1b-4(8.59g,84%)。
c)向反应瓶(250mL)中加入1b-4(8.15g,15.9mmol)、HCO2NH4(20.09g,318.5mmol)、Pd(OH)2/C(2.26g,含15%Pd)和MeOH(65mL),抽真空置换N2,升温至60℃,过夜反应。反应液滤除不溶物,滤液减压浓缩除甲醇,浓缩物加氯仿(200mL),用饱和NaCl溶液(50mL×3)洗,无水Na2SO4干燥,减压浓缩得粗品。粗品过硅胶柱,CHCl3-MeOH 20:1→8:2梯度洗脱,得B-1(5.15g,93%),(+)-ESI-MS:m/z 332([M+H]+);1H NMR(400MHz,CDCl3)δ7.08(d,J=8.5Hz,2H),6.77(d,J=8.5Hz,2H),4.33(m,2H),3.37(d,J=10.0Hz,2H),2.95(br s,2H),2.92(t,J=6.8Hz,2H),2.67(t,J=6.8Hz,2H),1.92(m,4H),1.84(m,2H),1.46(s,9H)。
使用适当的合成前体,根据上文针对实施例4(中间体B-1)试剂和反应条件合成在下表3中的实施例中间体B-2~B-26。
表3:
实施例5:
制备中间体B-21(4-(4-氨基乙基苯基)哌啶-1-羧酸叔丁酯):
试剂与反应条件
a)向50mL微波管中添加1b-2(l.66g,4.35mmol)、4-(四甲基-1,3,2-二氧杂环戊硼烷2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(2.69g,8.70mmol)、Pd(dppf)Cl2(0.32g,0.44mmol)、碳酸钾(1.20g,8.68mmol)、乙醇(10mL)和水(2mL)。将混合物在130℃下在微波辐射下加热1h。滤除残留固体,将滤液减压浓缩。将所得粗产物通过硅胶柱层析纯化,用EA-PE梯度洗脱,得到黄色固体2b-1(419mg,20%)。
b)向反应瓶(25mL)中加入2b-1(400mg,0.83mmol)、HCO2NH4(1.05g,16.65mmol)、Pd(OH)2/C(115mg,含15%Pd)和MeOH(5mL),抽真空置换N2,升温至60℃,过夜反应。反应液滤除不溶物,滤液减压浓缩除甲醇,浓缩物加氯仿(10mL),用饱和NaCl溶液(10mL)洗涤3次,无水Na2SO4干燥,减压浓缩得粗品。粗品过硅胶柱,CHCl3-MeOH 20:1→5:1梯度洗脱,得B-21(227mg,90%),(+)-ESI-MS:m/z 305([M+H]+).
使用适当的合成前体,根据上文针对实施例5(中间体B-21)概述的程序合成在下表4中的实施例中间体B-22~B-24。
表4:
实施例6
制备中间体B-25(3-(4-(1-氨基-异丙基)苯基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯):
试剂与反应条件
a)向100mL圆底烧瓶中添加对溴苯乙酮3b-1(3.38g,17.0mmol)、3,8-二氮杂二环[3.2.1]辛烷-8-甲酸叔丁酯(3.00g,14.1mmol)、碳酸钾(5.86g,42.4mmol)、和HMPA(30mL)。将所得溶液在70℃下在油浴中搅拌过夜,然后冷却至r.t.并用水(30mL)淬灭。将所得溶液用EA(30mL)萃取三次,合并有机层,减压浓缩后用硅胶柱层析纯化(EA-PE 1:5洗脱),得到棕色油状物3b-2(1.68g,30%),ESI-MS(m/z):331[M+H]+。
b)向100mL圆底烧瓶中添加3b-2(1.65g,5mmol)、叔丁醇钾(1.13g,13.0mmol)、TosMIC(1.46g,7.5mmol)、叔丁醇(20mL)和DME(20mL)。将所得溶液在90℃下在油浴中搅拌过夜,反应完冷却,加水(20mL)淬灭。反应溶液用EA(20mL)萃取3次,合并有机层用无水Na2SO4干燥,过滤,减压浓缩后,用硅胶柱层析纯化(EA-PE 1:5洗脱),得到棕色油状物3b-3(1.13g,66%),ESI-MS(m/z):342[M+H]+。
c)向保持氮气吹扫的100mL圆底烧瓶中添加3b-3(0.96g,2.8mmol)、NH3/MeOH(7M,20mL)、和雷尼镍(500mg)。将反应混合物持续通氢气,r.t.搅拌2h。过滤反应液滤除固体,滤液减压浓缩后,用硅胶柱层析纯化(二氯甲烷-甲醇10:1洗脱),得到黄色油状物B-25(790mg,82%),ESI-MS(m/z):346[M+H]+。
实施例7
制备中间体B-26((S)-1-(4-溴苯基)-2-氨基-3-甲氧基丙烷):
试剂与反应条件
a)向100mL圆底烧瓶中添加4b-1(12.25g,50mmol)和无水酒精(30mL),冷却至0℃,搅拌,缓慢滴入SOCl2(5.45mL,75mmol),滴完后升至r.t.,搅拌过夜。反应完减压浓缩除去溶剂,加水(30mL),用EA(30mL)萃取三次,合并有机层,减压浓缩得到4b-2(11.70g,86%)。
b)向100mL圆底烧瓶中添加4b-2(9.52g,35mmol)、BnCl(11.5mL,100mmol),KI(8.3g,50mmol),K2CO3(6.91g,50mmol)和MeCN(30mL),在60℃搅拌反应4h。反应完冷却,加水(30mL)淬灭,用EA(30mL)萃取3次,合并有机层,减压浓缩后,用硅胶柱层析纯化(EA-PE 1:5洗脱),得到4b-3(14.25,90%),ESI-MS(m/z):452[M+H]+。
c)向保持氮气吹扫的100mL圆底烧瓶中添加4b-3(13.57g,30mmol)、NaBH4(2.27g,60mmol)和THF(30mL),r.t.搅拌2h。过滤反应液滤除固体,滤液加入饱和的碳酸钾溶液20mL,分出有机层减压浓缩后,用硅胶柱层析纯化(二氯甲烷-甲醇20:1洗脱),得到4b-4(9.85g,80%),ESI-MS(m/z):410[M+H]+。
d)向反应瓶(25mL)中加入4b-4(0.92g,4mmol)、无水THF(5mL)和NaH(0.192g,4.8mmol,含量60%),r.t.搅拌30min后,滴加MeI(0.33mL,5.2mmol)/DMF(1ml)。滴加完后反应2h。反应液用醋酸调pH至7,加水(5mL),氯仿(5mL)萃取3次,合并氯仿层,饱和NaCl溶液(5mL)洗涤2次,无水Na2SO4干燥,减压浓缩,浓缩物经CHCl3-PE重结晶,得B-26(859mg,收率88%),ESI-MS(m/z):244[M+H]+。
实施例8
制备中间体B-27(3-(4-(2-氨基-3-乙氧基丙基)苯基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯):
试剂与反应条件
反应a和b同实例7的a和b。
c)向反应瓶(250mL)中加入1b-3(4.25g,20mmol)、4b-3(9.04g,20mmol)、Pd(OAc)2(449mg,2mmol)、X-phos(953mg,2mmol)、Cs2CO3(13.03g,40mmol)和甲苯(80mL),抽真空置换N2,升温至100℃,反应18h。反应液滤除不溶物,滤液减压浓缩,浓缩物过硅胶柱,PE:EA=19:1→9:1梯度洗脱,得5b-1(9.34g,82%)。
d)向反应瓶(250mL)中加入5b-1(8.15g,15.9mmol)、HCO2NH4(20.09g,318.5mmol)、Pd(OH)2/C(2.26g,含15%Pd)和MeOH(65mL),抽真空置换N2,升温至60℃,过夜反应。反应液滤除不溶物,滤液减压浓缩除甲醇,浓缩物加氯仿(200mL),用饱和NaCl溶液(50mL×3)洗,无水Na2SO4干燥,减压浓缩得粗品。粗品过硅胶柱,CHCl3-MeOH 20:1→8:2梯度洗脱,得B-27(4.57g,91%)。(+)-ESI-MS:m/z 390([M+H]+)。
使用适当的合成前体,根据上文针对实施例7和8(中间体B-26和B-27)概述的程序合成在下表5中的实施例中间体B-28~B-30。
表5:
实施例9
制备化合物I-1(N-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)苯乙基-6-甲基-3-甲基氨基噻吩[2,3-b]吡啶-2-甲酰胺)及其盐酸盐
a)向反应瓶(10mL)中加入A-2(382mg,1.2mmol)、B-1(398mg,1.2mmol)、EDCI(276mg,1.44mmol)、HOBt(178mg,1.32mmol)和干燥DMF(4mL),加入DIEA(611uL,3.6mmol),升温至60℃反应2h。反应液80℃减压浓缩,浓缩物过硅胶柱,PE:EA=7:3→6:4梯度洗脱,得酰胺624mg(收率82%)。
b)向反应瓶(10mL)中加入酰胺(604mg,0.96mmol)和二氯甲烷(4mL),加三氟乙酸(745uL,10mmol),升温至40℃过夜反应。反应完后,减压除去二氯甲烷和三氟乙酸,得脱Boc产物。
c)脱Boc产物中加入MeOH(4mL)和K2CO3(553mg,4mmol),r.t.搅拌30min。反应液加水(10mL)和氯仿(10mL×3)萃取,合并氯仿层,饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,减压浓缩,得脱Tfac产物I-1(238mg,57%),(+)-ESI-MS:m/z 436;1H NMR(400MHz,CDCl3)δ8.30(d,J=8.5Hz,1H),8.10(q,J=5.7Hz,1H),7.15(d,J=8.6Hz,2H),7.12(d,J=8.5Hz,1H),6.80(d,J=8.6Hz,2H),5.59(t,J=5.6Hz,1H),3.78(br s,2H),3.60(td,J=6.9,5.6Hz,2H),3.47(dd,J=11.4,2.3Hz,2H),3.32(d,J=5.7Hz,3H),3.02(dd,J=11.3,1.5Hz,2H),2.83(t,J=6.9Hz,2H),2.67(s,3H),1.94(br s,4H)。
d)I-1(237mg)用MeOH(8mL)溶解,r.t.搅拌下加36%盐酸(120uL),大量橙黄色固体析出。抽滤,少量MeOH洗涤除去游离HCl,得I-1盐酸盐(253mg,100%),(+)-ESI-MS:m/z436;1H NMR(400MHz,DMSO-d6)δ9.50-9.46(m,2H),8.49(d,J=8.5Hz,1H),7.87(t,J=4.9Hz,1H),7.30(d,J=8.5Hz,1H),7.09(d,J=8.6Hz,2H),6.84(d,J=8.6Hz,2H),6.53(brs,3H),4.09(br s,2H),3.55(dd,J=11.2,1.6Hz,2H),3.36(tt,J=7.8,4.8Hz,2H),3.17(s,3H),3.08(d,J=12.8Hz,2H),2.72(t,J=7.8Hz,2H),2.59(s,3H),1.97(m,2H),1.91(m,2H).13C NMR(125MHz,DMSO-d6)δ164.7,158.2,157.6,148.3,146.8,133.5,130.1,129.2,124.4,119.5,114.6,53.7,50.6,41.0,34.4,32.9,25.4,23.7.
使用适当的合成前体,根据上文针对实施例9(化合物I-1)试剂和反应条件合成下表6中的实施例化合物I-2~I-82。
表6:
实施例10
制备化合物I-83(N-4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)苯乙基-6-氨基-3-甲基氨基噻吩[2,3-b]吡啶-2-甲酰胺)
试剂和反应条件:
a)向25mL烧瓶中加入I-82a(111mg,0.2mmol)、氨基甲酸叔丁酯(117mg,1.0mmol)、Cs2CO3(326mg,1.0mmol)和1,4-二噁烷(1ml),搅匀,加入X-Phos Pd(II)(39.5mg,0.05mmol)。使氮气通过反应混合物冒泡2分钟,并然后将反应加热至90℃过夜。反应完成后,冷却至r.t.,滤除固体,滤液减压除去溶剂,用硅胶柱层析纯化(EA-PE 1:5→2:3梯度洗脱),得到浅黄色固体的氨基化产物I-83a(42mg,33%),(+)-ESI-MS:m/z 637。
b)向反应瓶(5mL)中加入I-83a(21.2mg,0.033mmol)和DCM(1mL),加TFA(100uL,1.535mmol),升温至40℃过夜反应。反应完后,减压除去DCM和TFA,得I-83(7.92mg,55%),(+)-ESI-MS:m/z 437;1H NMR(400MHz,DMSO-d6)δ7.91(d,J=8.4Hz,1H),7.87(t,J=5.0Hz,1H),7.10(d,J=8.6Hz,2H),6.84(d,J=8.6Hz,2H),6.55(br s,2H),6.52(br s,1H),6.45(d,J=8.6Hz,1H),4.10(br s,2H),3.56(br d,J=11.2Hz,2H),3.37(td,J=7.2,5.0Hz,2H),3.18(s,3H),3.09(br d,J=11.5Hz,2H),2.73(t,J=7.2Hz,2H),2.60(s,3H),1.90-2.00(m,4H)。
使用适当的合成前体,根据上文针对实施例10(化合物I-83)试剂和反应条件合成下表7中的实施例化合物I-84~I-85。
表7:
实施例11.
采用泛素-罗丹明110法测定USP28活性。
纯化的USP28以及用于测定DUBs活性的底物泛素-罗丹明110(Ubiquitin-Rhodamine110)均来自R&D Systems。测试化合物首先溶解于DMSO制备成10mM的母液,然后用缓冲溶液[含20mM Tris-HCl(pH 8.0),2mM CaCl2,3mM的BME,0.01% Prionex,0.01%Triton X-100]稀释成所需浓度(其中DMSO含量≤0.5%),预先与USP28(终浓度4nM)在96孔板混匀并在室温孵育30分钟,然后加入底物(泛素-罗丹明110)至125nM。整个反应最终体积为20μL。加入底物后立即开始在酶标仪上检测释放出来的荧光(激发波长485nm,发射波长535nm)。按以下公式计算测试化合物对USP25的抑制率:
抑制%=1-[(测试化合物+底物的荧光值-测试化合物(无底物)的荧光值)/DMSO对照组的平均荧光值-测试化合物(无底物)的荧光值]
根据不同浓度下测试化合物对USP28的抑制率,计算出其IC50值
实施例12.
采用泛素-罗丹明110法测定USP25活性。
纯化的USP25以及用于测定DUBs活性的底物泛素-罗丹明110(Ubiquitin-Rhodamine110)均来自R&D Systems。测试化合物首先溶解于DMSO制备成10mM的母液,然后用缓冲溶液[含20mM Tris-HCl(pH 8.0),2mM CaCl2,3mM的BME,0.01% Prionex,0.01%Triton X-100]稀释成所需浓度(其中DMSO含量≤0.5%),预先与USP25(终浓度15nM)在96孔板混匀并在室温孵育30分钟,然后加入底物(泛素-罗丹明110)至125nM。整个反应最终体积为20μL。加入底物后立即开始在酶标仪上检测释放出来的荧光(激发波长485nm,发射波长535nm),按以下公式计算测试化合物对USP25的抑制率:
抑制%=1-[(测试化合物+底物的荧光值-测试化合物(无底物)的荧光值)/DMSO对照组的平均荧光值-测试化合物(无底物)的荧光值]
同实施例11,根据不同浓度下测试化合物对USP25的抑制率,计算出其IC50值
表8本发明实施例化合物对USP28和USP25的抑制活性(IC50)
上述表8中的符号对应代表的IC50范围如下:
实施例13
参照实施例11和实施例12针对本发明代表性化合物以及如下对比化合物结构进行USP28和USP25的抑制活性(IC50)的测试,结果参见下表9
表9:本发明化合物与现有技术化合物对USP28和USP25的抑制活性(IC50,nM)对比
上述实验结果表明,本发明的实例化合物对比结构优化前的现有技术化合物在USP28和/或USP25的抑制活性上均有非常显著的改进,如表9所示,改进化合物对于USP28和USP25的抑制活性均是现有技术化合物的15倍以上,说明本发明通式I的3-NH2的单烃基(或取代烃基)化是该类型化合物USP28和USP25抑制活性的一个关键位点。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (10)
1.一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药:
其中:
X为C-R5或N;
n为1或2;
Z为氮氢(NH),氧(O)、硫(S)或亚甲基(CH2);虚线键表示可以为键或不存在;
p和q相同或不同,彼此独立地选自0、1、2或3;R3为(C1-C6)烷基;
m为0、1、2、3、4、5或6;
R1、R2、R5相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及任选地无取代或取代的如下基团:(C1-C6)烷基,(C1-C6)烷基氧基,卤代(C1-C6)烷基,卤代(C1-C6)烷基氧基;
每一个R4和R8相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及(C1-C6)烷基,(C1-C6)烷基氧基,卤代(C1-C6)烷基,卤代(C1-C6)烷基氧基;
m为1、2、3、4、5或6;
R1、R2、R5相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及(C1-C6)烷基;
每一个R4相同或不同,选自氢、卤素、羟基、氨基以及(C1-C6)烷基;
每一个R6相同或不同,彼此独立地选自(C1-C6)烷基氧基,环丙基、环丁基、环戊基和环己基;
R7选自如下基团:
2.根据权利要求1所述的式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药,其特征在于:R4和R8选自氢。
3.根据权利要求1或2所述的式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药,其特征在于:R1、R2、R5相同或不同,彼此独立地选自氢、卤素、羟基、氨基以及(C1-C6)烷基。
4.根据权利要求1-3任一项所述的式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药,其特征在于:R1、R2、R5相同或不同,彼此独立地选自氢或(C1-C6)烷基。
7.根据权利要求6所述的制备方法,其特征在于:
所述步骤中的试剂与反应条件包括:a)酰胺偶联反应:偶联试剂选自EDCI-HOBt、BOP、HATU,碱选自DEA、TEA、EDCI或DMAP;溶剂选自DCM或DMF;b)脱Tfac反应:碱选自K2CO3或NaOMe,溶剂选自MeOH;c)脱Boc反应:稀盐酸-甲醇;
优选的,所述中间体羧酸A可经以下步骤制备得到:
该步骤中,试剂与反应条件可以为:a)DMF;b)NaOMe/DMF;c)(Tfac)2O/NaHCO3/CHCl3;d)NaH/DMF,R3-I;e)TFA/DCM;
优选的,部分中间体B-I可由商业途径或者经典的合成方法获得:
R'4、R’6、R’7和R’8分别为通式I的R4、R6、R7和R8或者羟基和氨基被Boc保护的R4、R6、R7和R8(当R4、R6、R7和R8含有羟基或氨基等活泼基团时);
优选的,部分中间体B-II可经以下步骤制备得到:
其中,R'4和R’6分别为通式I的R4和R6或者羟基或氨基被Boc保护的R4和R6(当R4和R6含有羟基或氨基等活泼基团时),
该步骤中,试剂与反应条件可以为:a)BnCl,KI,K2CO3/MeCN;b)H-R7-Boc,Pd(OAc)2,X-phos,Cs(CO3)2,toluene;c)HCO2NH4,Pd(OH)2/C,MeOH;
所述X,R1,R2,R3,R4,R6,R7,R8,m,n,p,q定义同式I。
8.一种药物组合物,其特征在于,所述药物组合物包含权利要求1-5任一项所述的式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药。
9.权利要求1-5任一项所述的式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、药学上可接受的盐或前药或权利要求8所述的药物组合物在制备用于治疗与抑制USP28和/或USP25相关的疾病或障碍的药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述USP28和/或USP25相关的疾病或障碍包括癌症、炎症、自身免疫疾病、病毒感染和细菌感染。
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WO2023241640A1 (zh) * | 2022-06-15 | 2023-12-21 | 深圳湾实验室 | 一类靶向去泛素化酶usp25和usp28的小分子抑制剂 |
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