CN111051300A - 作为组蛋白脱乙酰基酶1和/或2(hdac1-2)的选择性抑制剂的新杂芳基酰胺衍生物 - Google Patents
作为组蛋白脱乙酰基酶1和/或2(hdac1-2)的选择性抑制剂的新杂芳基酰胺衍生物 Download PDFInfo
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- CN111051300A CN111051300A CN201880056722.5A CN201880056722A CN111051300A CN 111051300 A CN111051300 A CN 111051300A CN 201880056722 A CN201880056722 A CN 201880056722A CN 111051300 A CN111051300 A CN 111051300A
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Abstract
本发明涉及式(I)的新型杂芳基酰胺衍生物
Description
技术领域
本发明涉及新杂芳基酰胺衍生物,作为选自HDAC1和HDAC2的至少一种酶组蛋白脱乙酰基酶I类的选择性抑制剂。
本发明的其它目标是提供制备这些化合物的方法;包含有效量的这些化合物的药物组合物;用于治疗病理状况、障碍或疾病的化合物,该病理状况可通过抑制选自HDAC1和HDAC2的至少一种酶组蛋白脱乙酰基酶I类的活性而被改善,如癌症、神经退行性疾病、感染性疾病、炎性疾病、心力衰竭和心脏肥厚、糖尿病、多囊肾病、镰状细胞病和β-地中海贫血病。
背景技术
组蛋白脱乙酰基酶(HDACs)催化乙酰基基团从组蛋白(组织和调节核小体中染色质结构的蛋白)的去除。HDAC介导的染色质结合组蛋白的脱乙酰化作用调控整个基因组中各种基因的表达。重要的是,HDACs已与癌症以及其它健康状况关联。
存在至少18种HDAC亚型,其可被细分为三个家族的HDACs:I类(HDACs 1、2、3、和8)和II类(HDACs 4、5、6、7、9和10)。HDACs是具有保守催化核心,但尺寸、结构域结构、组织表达模式和细胞定位不同的锌依赖性酰胺水解酶(Johnstone,Ricky W.Histone-deacetylase inhibitors:novel drugs for the treatment of cancer.Nature reviewsDrug discovery,2002,vol.1,no 4,p.287-299)。另一种HDAC——HDAC11——居于这两类之间的界限。III类HDACs(Sirtuins 1-7)是NAD+依赖性的,并且序列与I和II类不相关(HOLBERT,Marc A.;MARMORSTEIN,Ronen.Structure and activity of enzymes thatremove histone modifications.Current opinion in structural biology,2005,vol.15,no 6,p.673-680)。
作为蛋白质乙酰化的常见翻译后修饰的调节剂,锌依赖性组蛋白脱乙酰基酶(I和II类HDAC)在多种细胞过程中起至关重要的作用。锌依赖性组蛋白脱乙酰基酶家族已被各种各样地涉及不同的疾病状态。锌依赖性HDACs作为抗癌药物目标已受到很多关注。这些酶的抑制剂显示诱导转化细胞的终末分化的显著能力,设想是通过影响选定的组蛋白赖氨酸残基的乙酰化状态来改变基因表达图谱(MARKS,Paul A.,et al.Histone deacetylaseinhibitors.Advances in cancer research,2004,vol.91,p.137-168)。
然而,已知HDACs与细胞内的多种调控蛋白形成多蛋白复合物。每种同工酶与特定一系列调控蛋白和转录因子相互作用,并具有特定一组底物,因此各自调控特定一系列基因和蛋白质(WITT,Olaf,et al.HDAC family:What are the cancer relevant targets?.Cancer letters,2009,vol.277,no 1,p.8-21)。
HDAC1/HDAC2和癌症
与其它I类酶相比,HDAC1和HDAC2是用于治疗癌症和其它疾病的新兴治疗目标。(HUANG,Lili.Targeting histone deacetylases for the treatment of cancer andinflammatory diseases.Journal of cellular physiology,2006,vol.209,no 3,p.611-616)。RNAi介导的HDAC1表达的敲低抑制增殖,并且重要的是,体外诱导若干肿瘤细胞系的凋亡(GLASER,Keith B.,et al.Role of class I and class II histone deacetylasesin carcinoma cells using siRNA.Biochemical and biophysical researchcommunications,2003,vol.310,no 2,p.529-536)。
同样,已显示在不存在HDAC1的情况下,细胞可停滞在细胞周期的G1期或G2/M过渡,导致有丝分裂细胞缺失、细胞生长抑制和凋亡细胞百分比增加。(SENESE,Silvia,etal.Role for histone deacetylase 1in human tumor cell proliferation.Molecularand cellular biology,2007,vol.27,no 13,p.4784-4795)。
另外,还已知在结肠癌细胞中,HDAC1和HDAC2过表达,在这种情况下,转录因子和表观遗传调节因子之间的相互作用协调所述细胞中HDAC1和HDAC2启动子活性的激活。(YANG,Hui,et al.Overexpression of histone deacetylases in cancer cells iscontrolled by interplay of transcription factors and epigeneticmodulators.The FASEB Journal,2014,vol.28,no 10,p.4265-4279)。
已证明利用化合物或RNA干扰的选择性HDAC1/HDAC2抑制在神经母细胞瘤细胞系中诱导分化并降低存活率。(FRUMM,Stacey M.,et al.Selective HDAC1/HDAC2inhibitors induce neuroblastoma differentiation.Chemistry&biology,2013,vol.20,no 5,p.713-725)。
最近,研究公开了组蛋白脱乙酰基酶2(HDAC2)的抑制或沉默恢复了胰腺导管腺癌(PDAC)细胞中的原生纤毛形成。原生纤毛的缺失在包括PDAC细胞的肿瘤细胞中经常观察到,表明这种细胞器的缺乏可通过异常信号转导和无能退出细胞周期而促进肿瘤发生。HDAC2的失活导致Aurora A表达降低,其促进原生纤毛的分解。根据这些研究,HDAC2独立于Kras(其促进Aurora表达)来控制纤毛发生,表明HDAC2是PDAC细胞中原生纤毛形成的新型调控剂。(KOBAYASHI,Tetsuo,et al.HDAC2 promotes loss of primary cilia inpancreatic ductal adenocarcinoma.EMBO reports,2016,p.e201541922)。
另一方面,已证明HDAC1/HDAC2抑制剂是B细胞急性淋巴母细胞白血病(B-ALL)的潜在治疗选择,并且该特定抑制剂可对B-ALL患者具有治疗用处。(STUBBS,Matthew C.,etal.Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Optionfor B-ALL.Clinical Cancer Research,2015,vol.21,no 10,p.2348-2358)。
关于中枢神经系统(CNS)肿瘤(具体地脑和脊髓肿瘤),已知血脑屏障(BBB)渗透是阻碍成胶质细胞瘤(GBM)的成功治疗靶向的主要问题之一,因为98%以上的药物无法跨越BBB。关于这点,已报道I类HDAC抑制剂,具体地HDAC1/HDAC2抑制剂,跨越BBB。这种抑制剂在体外对一组脑肿瘤起始细胞系(BTIC系)呈现细胞毒性,并在体内原位BTIC模型中与烷基化剂替莫唑胺(TMZ)结合延长存活期。(GRINSHTEIN,Natalie,et al.Small moleculeepigenetic screen identifies novel EZH2 and HDAC inhibitors that targetglioblastoma brain tumor-initiating cells.Oncotarget,2016,vol.7,no 37,p.59360-59376)。
其它研究已指出,选择性组蛋白脱乙酰基酶I类抑制剂克服替莫唑胺抗性并下调替莫唑胺抗性成胶质细胞瘤细胞系中NF-κB调控的促存活基因的表达。(Zong-yang Li,etal,Histone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance byBlocking NF-κB-Dependent Transcription in Glioblastoma Cell Lines,NeurochemRes,September 2016,DOI 10.1007/s11064-016-2043-5)。
有研究证明抑制HDAC1和HDAC2对降低急性髓样白血病(AML)细胞中BRCA1、CHK1、和RAD51的表达、增强阿糖胞苷或柔红霉素诱导的DNA损伤和凋亡、以及消除阿糖胞苷或柔红霉素诱导的细胞周期检查点激活是必要的(ZHAO,J.,et al.Histone deacetylases1and 2cooperate in regulating BRCA1,CHK1,and RAD51 expression in acutemyeloid leukemia cells.Oncotarget,2016)。
组蛋白脱乙酰基酶2(HDAC2)对于胚胎发育至关重要,影响与免疫响应相关的细胞因子信号传导,并且在实体肿瘤中通常显著过表达。具体地,在肺癌中,已证明HDAC2的异常表达及其失活导致肿瘤细胞生长衰退和细胞凋亡激活——通过p53和Bax激活以及Bcl2抑制。(JUNG,Kwang Hwa,et al.HDAC2 overexpression confers oncogenic potential tohuman lung cancer cells by deregulating expression of apoptosis and cellcycle proteins.Journal of cellular biochemistry,2012,vol.113,no 6,p.2167-2177)。
另一方面,研究已证明与正常子宫颈上皮相比,宫颈异型增生和宫颈癌中HDAC1/HDAC2表达升高。在所述研究中,硼替佐米(bortezomib)和HDAC抑制剂联合并显示对HPV阳性而非HPV阴性宫颈癌细胞系的协同杀伤。类似地,硼替佐米和HDAC1/HDAC2抑制剂联合治疗HeLa异种移植物显著地、比单独使用硼替佐米剂更有效地抑制肿瘤生长,表明HDAC抑制剂与硼替佐米联合治疗值得探索对宫颈癌的治疗。(LIN,Zhenhua,et al.Combination ofproteasome and HDAC inhibitors for uterine cervical cancer treatment.ClinicalCancer Research,2009,vol.15,no 2,p.570-577)。
其它研究已将HDACs 1和HDAC2在肝细胞癌(HCC)中的表达及其相关性与临床数据和患者存活率联系起来。所述研究证明,与正常组织相比,HDAC1和HDAC2在癌细胞中的表达显著更高。具体地,在低级和早期肿瘤下,高HDAC2表达与存活差相关(p<0.05),表明HDAC2表达对患者的存活具有影响。(QUINT,Karl,et al.Clinical significance of histonedeacetylases 1,2,3,and 7:HDAC2 is an independent predictor of survival inHCC.Virchows Archiv,2011,vol.459,no 2,p.129-139)。另外,已发现在肝细胞癌(HCC)患者组织中,果糖-1,6-双磷酸酶(FBP1)的低表达与高水平HDAC1和HDAC2蛋白相关。HDAC抑制剂对HCC细胞的处理或HDAC1和/或HDAC2的敲低使FBP1表达恢复并抑制HCC细胞生长。(YangJ,et al.Inhibiting histone deacetylases suppresses glucose metabolism andhepatocellular carcinoma growth by restoring FBP1 expression.Sci Rep.2017Mar6;7:43864)。
HDAC2过表达已与乳腺癌的转移、进展和多药抗性蛋白表达增加相关联,表明HDAC2可以是乳腺癌患者(具体地接受蒽环类治疗的患者)的预后因子(ZHAO,Haishan,etal.HDAC2 overexpression is a poor prognostic factor of breast cancer patientswith increased multidrug resistance-associated protein expression whoreceived anthracyclines therapy.Japanese journal of clinical oncology,2016)。
同时,HDAC1表达与肿瘤的分子亚型显著相关,其中在乳房浸润性导管癌的管腔肿瘤中观察到最高的表达(SEO,Jinwon,et al.Expression of histone deacetylasesHDAC1,HDAC2,HDAC3,and HDAC6 in invasive ductal carcinomas of thebreast.Journal of breast cancer,2014,vol.17,no 4,p.323-331)。
HDAC1和HDAC2涉及癌症的若干证据表明,对这些亚型具有选择性的抑制剂可显示与泛HDAC抑制剂相比提高的治疗指数——通过增强的临床效力和/或更好的耐受性。
HDAC1/HDAC2和神经退行性疾病
大量数据表明HDACs牵涉各种生物学过程。与此相符,研究已显示I类HDAC在神经系统发育中起重要作用。
关于上述内容,HDAC抑制剂治疗已被显示在神经退行性疾病的遗传模型中减轻认知缺陷(FISCHER,Andre,et al.Recovery of learning and memory is associated withchromatin remodeling.Nature,2007,vol.447,no 7141,p.178-182.),而且其已被用于治疗与阿尔茨海默氏病(AD)早期阶段相关的认知缺陷(KILGORE,Mark,et al.Inhibitors ofclass 1histone deacetylases reverse contextual memory deficits in a mousemodel of Alzheimer's disease.Neuropsychopharmacology,2010,vol.35,no 4,p.870-880)。这些研究表明,通过HDAC抑制来调控记忆对多种记忆和认知障碍具有相当的治疗潜力。
新近的文献现将I类HDACS(具体地HDAC1和HDAC2)定位成大脑发育的重要控制点。高度同源的HDAC1和HDAC2在中枢神经系统年龄依赖性演化过程中神经元委任(neuronalcommitment)和分化的不同阶段被检测到。这表明其对发育特异性基因表达调控和中枢神经系统CNS维持的贡献。这些过程呈现对表观遗传基因调控的破坏特别敏感,导致与智力低下以及复杂精神障碍相关的综合征等。HDAC1和HDAC2在大脑发育过程中的表达以及HDAC1和HDAC2在神经发生中的涉及已通过进行的研究得到广泛证明。(ZIEMKA-NALECZ,Malgorzata;JAWORSKA,Joanna;ZALEWSKA,Teresa.Histone deacetylases 1and 2arerequired for brain development.International Journal of DevelopmentalBiology,2015,vol.59,no 4-5-6,p.171-177;以及其中的参考文献)。
同样,其它研究已证明HDAC2的选择性药理抑制是可行的,并且对此酶的催化活性的抑制充当针对增强在多种神经和精神障碍中受到影响的学习和记忆过程的治疗方法(WAGNER,F.F.,et al.Kinetically selective inhibitors of histone deacetylase 2(HDAC2)as cognition enhancers.Chemical science,2015,vol.6,no 1,p.804-8159)。因此,已显示HDAC2调控记忆过程,并且因此是记忆影响状况(如但不限于阿尔茨海默氏病、创伤后应激障碍或药物成瘾)中用于记忆增强或消退的关注目标。(XU,Ke,et al.TargetingHDACs:a promising therapy for Alzheimer's disease.Oxidative medicine andcellular longevity,2011,vol.2011)。
除此之外,其它研究已公开HDAC1涉及包括亨廷顿氏病在内的聚谷氨酰胺障碍,以及HDAC1选择性抑制剂作为这些障碍的治疗干预的应用(THOMAS,ElizabethA.Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders:therapeutic implications for selective HDAC1/HDAC3inhibitors.Pharmaceuticals,2014,vol.7,no 6,p.634-661)。
类似地,已确定HDAC1-2同种型特异性抑制剂在体外和体内帕金森氏病(PD)模型中都具有针对MPP+/MPTP引起的神经元死亡的保护作用,表明HDAC1和2的选择性抑制可以为PD治疗的新策略铺路(CHOONG,Chi-Jing,et al.A novel histone deacetylase 1and2isoform-specific inhibitor alleviates experimental Parkinson'sdisease.Neurobiology of aging,2016,vol.37,p.103-116)。
HDAC1/HDAC2和炎性疾病
研究已显示,新证据链显示HDAC1/2介导的组蛋白低乙酰化造成的染色质结构的表观遗传调控涉及蜂毒(BV)引起的持续性自发伤害感受(persistent spontaneousnociception)(PSN)和热超敏性,并证明这些I类HDACi在预防外周炎性疼痛发生的有益作用。(YANG,F.,et al.Selective class I histone deacetylase inhibitors suppresspersistent spontaneous nociception and thermal hypersensitivity in a ratmodel of bee venom-induced inflammatory pain,Acta physiologica Sinica,2015,vol.67,no 5,p.447-454)。
另一方面,研究已证明,在心力衰竭(HF)大鼠的左心室(LVs)中较高水平的HDAC1和HDAC2的表达。此研究表明HDAC抑制可改善心脏功能并减弱心力衰竭(HF)对心脏代谢和炎症的影响(LKHAGVA,Baigalmaa,et al.Novel histone deacetylase inhibitormodulates cardiac peroxisome proliferator-activated receptors andinflammatory cytokines in心力衰竭.Pharmacology,2015,vol.96,no 3-4,p.184-191)。
蛋白质乙酰化是调控转录和炎性事件的重要机制。研究已显示,非选择性组蛋白脱乙酰基酶抑制剂可保护大鼠视网膜免受缺血性损伤。此研究已证明,抑制HDAC2表达可有效减少缺血性视网膜损伤,表明选择性HDAC2抑制剂的开发可为缺血性视网膜损伤提供有效的治疗。(FAN,Jie,et al.Inhibition of HDAC2 Protects the Retina From IschemicInjury Inhibition of HDAC2 Protects Retina From Ischemic Injury.Investigativeophthalmology&visual science,2013,vol.54,no 6,p.4072-4080)。
HDAC1/HDAC2和心力衰竭
HDAC2已被鉴定为心脏中的重要分子目标,并且结合Gsk3β被认为是调控途径的组分,提供用于心脏肥厚和心力衰竭治疗的有吸引力的治疗目标(TRIVEDI,Chinmay M.,etal.Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3βactivity.Nature medicine,2007,vol.13,no 3,p.324-331)。
响应各种肥厚性应激的Hsp70诱导以及随后的HDAC2激活引发心脏肥厚,突出HSP70/HDAC2是调控肥厚的新机制(MCKINSEY,Timothy A.Targeting inflammation inheart failure with histone deacetylase inhibitors.Molecular medicine,2011,vol.17,no 5,p.434)。
Mocetinostat对充血性心力衰竭(CHF)动物的体内治疗降低CHF心肌中HDAC1和HDAC2的CHF依赖性上调,改善心脏功能并减小疤痕尺寸和总胶原蛋白量,证明心脏成纤维细胞通过HDAC1-2抑制而得到体内调控(NURAL-GUVENER,Hikmet,et al.Anti-fibroticeffects of class I HDAC inhibitor,mocetinostat is associated with IL-6/Stat3signalling in ischemic heart failure.International journal of molecularsciences,2015,vol.16,no5,p.11482-11499)。
其它疾病中的HDAC1/HDAC2
最近的报道表明,HDAC2已被报道在糖尿病db/db小鼠的肝细胞中与IRS-1结合。这些小鼠已被常规用于筛选各种胰岛素模拟物以及胰岛素增敏剂(BAYLEY,Jeppe Seamus;PEDERSEN,Thomas Holm;NIELSEN,OleSkeletal muscle dysfunction inthedb/db mouse model of type 2diabetes.Muscle&nerve,2016,vol.54,no 3,p.460-468)。HDAC2与IRS-1的这种结合导致IRS-1的乙酰化降低和胰岛素受体介导的酪氨酸磷酸酶化降低。因此,HDAC抑制剂曲古抑菌素A(TSA)或HDAC2基因沉默增强了IRS-1的乙酰化并部分地减弱胰岛素抗性(C.Kaiser,S.R.James,Acetylation of insulin receptorsubstrate-1is permissive for tyrosine phosphorylation,BMC Biol.2(2004)23)。
另一方面,选择性组蛋白脱乙酰基酶(HDAC)抑制剂已出现作为持续性人免疫缺陷病毒1型(HIV-1)感染的潜在抗潜伏治疗。(BARTON,Kirston M.,et al.SelectiveHDACinhibition for the disruption of latent HIV-1infection.PloS one,2014,vol.9,no 8,p.e102684)。具体地,选择性抑制I类HDACs的HDAC抑制剂恩替诺特(entinostat)在潜在感染的原代CD4T细胞中诱导病毒表达,使此化合物成为未来临床试验的有吸引力的新选择。(WIGHTMAN,Fiona,et al.Entinostat is a histone deacetylaseinhibitor selective for class 1histone deacetylases and activates HIVproduction from latently infected primary T cells.AIDS(London,England),2013,vol.27,no 18,p.2853)。
其它研究已揭示HDAC1在多囊肾疾病(PKD)发病中的关键作用,并指出HDAC抑制剂是PKD治疗的候选药物。所述研究证明,通过敲低HDAC1来抑制I类HDACs抑制了由pkd2缺陷引起的肾囊肿形成和身体弯曲(body curvature)。(CAO,Ying,et al.Chemicalmodifierscreen identifies HDAC inhibitors as suppressors of PKD models.Proceedings oftheNational Academy of Sciences,2009,vol.106,no 51,p.21819-21824)。
已知HDAC1/HDAC2的化学抑制通过激活GATA2而诱导胎儿血红蛋白(HBF)。旨在重新激活胎儿血红蛋白(HbF)的治疗性干预是有希望的缓解镰状细胞病(SCD)和β-地中海贫血的方法。研究已显示组蛋白脱乙酰基酶1或2的基因敲低足以诱导HbF。(SHEARSTONE,Jeffrey R.,et al.Chemical Inhibition of Histone Deacetylases 1and2InducesFetal Hemoglobin through Activation of GATA2.PloS one,2016,vol.11,no4,p.e0153767)。
最后,已证明I类HDAC抑制剂在黑色素瘤中上调PD-L1的表达,并在较小程度上上调PD-L2的表达。HDAC抑制剂治疗导致PDL1基因的组蛋白乙酰化快速上调,造成增强和持久的基因表达。所述PD-L1上调限于I类HDAC(具体地HDAC1和HDAC2)的抑制。在小鼠B16F10模型中探索了HDAC抑制与PD-1阻断联合治疗黑色素瘤的功效。结果突显了表观遗传修饰剂增强免疫治疗的能力,提供了联合HDAC抑制剂与PD-1阻断的理论依据(WOODS,David M.,etal.HDAC inhibition upregulates PD-1ligands in melanoma andaugmentsimmunotherapy with PD-1blockade.Cancer immunology research,2015,vol.3,no 12,p.1375-1385)。
HDAC抑制剂
组蛋白脱乙酰基酶的若干种抑制剂已被开发并批准用于治疗人类疾病,具体地作为抗癌药剂,如:伏立诺他(vorinostat)(皮肤T细胞淋巴瘤和多发性骨髓瘤)、罗米地辛(外周T细胞淋巴瘤)、和贝利司他(belinostat)(外周T细胞淋巴瘤)(TAN,Jiahuai,etal.Novel histone deacetylase inhibitors in clinical trials as anti-canceragents.Journal of hematology&oncology,2010,vol.3,no 1,p.5)。即使这些抑制剂被批准用于皮肤和/或外周T细胞淋巴瘤,这些药物仍在临床试验中被研究用于其它类型的癌症,作为单一试剂或与其它药物联合,并且其它HDAC抑制剂处于各种血液学和实体肿瘤的临床试验的不同阶段。
除了有前途的对抗癌活性的作用外,HDAC抑制剂在其它疾病(如肠纤维化、自身免疫、炎性疾病、代谢障碍等)中的应用也正在增长。
然而,HDAC抑制剂也与毒性相关。HDAC抑制剂的使用所观察到的最常见的3级和4级不利事件是血小板减少症、嗜中性白细胞减少、贫血、疲劳和腹泻(MOTTAMAL,Madhusoodanan,et al.Histone deacetylase inhibitors in clinical studies astemplates for new anticancer agents.Molecules,2015,vol.20,no 3,p.3898-39419)。
已知的HDAC抑制剂不能显示突出的HDAC同工酶选择性。此事实可在临床环境(具体地在其中需要延长要物给予的疾病和状况的治疗)中引起严重的问题。因此,选择性HDAC抑制剂的设计允许仅对具体疾病或状况相关的同工酶(一种或多种)优先抑制,进而降低适得其反和/或不利作用的可能性,和最小化由对其它HDAC同工酶的不想要的和不期望的抑制导致的在患者中的细胞毒性作用。因此,期望开发新的同种型选择性HDAC抑制剂,在患者中提供更大的功效和更小的毒性。
仍需要提供HDAC抑制剂,具体地特定HDAC类别的有效和/或选择性抑制剂。
因此,本发明要解决的问题是提供新的化合物作为组蛋白脱乙酰基酶I类的抑制剂,并且更具体地,作为选自HDAC1和HDAC2的组蛋白脱乙酰基酶的选择性抑制剂。
本发明的作者已开发出新的N-(3-氨基吡啶-2-基)烟酰胺衍生物,其被方便地取代,作为HDAC1和/或HDAC2的有效和选择性抑制剂。
发明内容
在其一方面(方面1)中,本发明涉及式(I)的杂芳基酰胺衍生物:
其中:
-X1和X2独立地表示选自-CH和N的基团;
-R1表示:
a)苯基基团,其任选地被选自卤素原子、直链或支链C1-C4卤代烷基基团和直链或支链C1-C4烷氧基的一个或多个取代基取代,
b)五元或六元杂芳基环,其任选地被选自卤素原子、直链或支链C1-C4烷氧基、氰基基团、直链或支链C1-C4卤代烷基、直链或支链C1-C4烷基、C3-C6环烷基、C3-C6环烷氧基和C5-C6杂环状环(任选地被一个或多个卤素原子取代)的一个或多个取代基取代;
-R2表示选自下列的基团:
a)-N(R3)(R4)基团,其中:
1-R3和R4与其结合的氮原子一起形成五元或六元饱和环,该五元或六元饱和环任选地包含另外的选自N和O的杂原子作为环部分,该五元或六元饱和环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代,其中R5和R6与其结合的氮原子一起形成五元或六元饱和环,该五元或六元饱和环任选地包含选自N和O的另外的杂原子作为环部分,该五元或六元饱和环任选地被C1-C3烷基基团取代,或
2-R3和R4独立地表示选自氢原子、C3-C6环烷基基团和直链或支链C1-C3烷基的基团,其任选地被包含选自N和O的一个或两个杂原子作为环部分的五元或六元杂环取代,该五元或六元杂环任选地被直链或支链C1-C3烷基基团取代。
b)苯基环,其任选地被选自卤素原子和氰基基团的一种或多个取代基取代,
c)C3-C6环烷基,其任选地被选自直链或支链C1-C3烷基和羟基基团的一个或多个取代基取代,
d)C5-C6杂芳基,其任选地被选自卤素原子、直链或支链C1-C3烷基和直链或支链C1-C3烷氧基和-N(R5)(R6)基团的基团取代,其中R5和R6与其结合的氮原子一起形成五元或六元饱和环,该五元或六元饱和环任选地包含选自N和O的另外的杂原子作为环部分,该五元或六元饱和环任选地被C1-C3烷基基团取代,
e)氢原子,
及其药学上可接受的盐。
本发明的其它方面是:
方面2)制备方面1的化合物的方法。
方面3)包含有效量的方面1的化合物的药物组合物。
方面4)根据方面3的药物组合物,其进一步包含治疗有效量的一种或多种治疗剂,该治疗剂选自化学治疗剂、抗炎剂、类固醇、免疫抑制剂、治疗性抗体和腺苷拮抗剂。
方面5)方面1所限定的化合物,其用于治疗可通过抑制组蛋白脱乙酰基酶I类(具体地HDAC1和HDAC2)而改善的疾病或病理状况。
方面6)治疗疾病的方法,该疾病可通过抑制选自HDAC1和HDAC2的组蛋白脱乙酰基酶I类而改善,所述方法通过向需要所述治疗的对象给予方面1的化合物或方面3或4的药物组合物进行,其中所述疾病可选自癌症,选自结肠癌、肺癌、乳腺癌、中枢神经系统(CNS)癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和选自急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤的T细胞恶性病;神经退行性疾病,选自阿尔茨海默氏病、创伤后应激障碍、药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病(Kennedy'sdisease)、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病(Pitt Hopkins)、脊髓性和延髓性肌萎缩、感染性疾病、选自过敏、哮喘、自身免疫疾病、乳糜泻、肾小球性肾炎、肝炎、炎性肠病、再灌注损伤和移植排斥的炎性疾病、心力衰竭和心脏肥厚、糖尿病、多囊肾病、和镰状细胞病(SCD)和β-地中海贫血病。中枢神经系统(CNS)癌选自脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤(gangliogliomas)、神经鞘瘤(Schwannomas)、和颅咽管瘤。
方面7)方面1的化合物与一种或多种治疗剂的组合产物,该治疗剂选自化学治疗剂、抗炎剂、类固醇、免疫抑制剂、治疗性抗体和腺苷拮抗剂,其可与本申请的化合物组合用于治疗HDAC相关疾病、障碍或状况。所述一种或多种另外的药剂可被同时或相继地给予患者。
示例性化学治疗剂包括蛋白体抑制剂(例如,硼替佐米)、用于治疗CNS癌症的化学治疗剂(包括替莫唑胺、卡铂、卡莫司汀(BCNU)、顺铂、环磷酰胺、依托泊苷、伊立替康、洛莫司汀(CCNU)、甲氨蝶呤、丙卡巴肼、长春新碱)和其它化学治疗剂(如沙利度胺、来那度胺(revlimid)和DNA损伤剂(如美法仑、多柔比星、环磷酰胺、长春新碱、依托泊苷、卡莫司汀等)。
示例性抗炎化合物包括阿司匹林、水杨酸胆碱、塞来考昔(celecoxib)、双氯芬酸钾、双氯芬酸钠、双氯芬酸钠与米索前列醇、二氟苯水杨酸、依托度酸、非诺洛芬、氟比洛芬、布洛芬、酮洛芬、甲氯芬那酸钠、甲芬那酸、萘丁美酮、萘普生、萘普生钠、丙嗪、吡罗昔康(piroxicam)、罗非考昔(rofecoxib)、双水杨酯、水杨酸钠、舒林酸、托美丁钠、伐地考昔(valdecoxib)等。
示例性类固醇包括皮质类固醇,如可的松、地塞米松、氢化可的松、甲基泼尼松龙、泼尼松龙、泼尼松等。
示例性免疫抑制剂包括硫唑嘌呤(azathioprine)、苯丁酸氮芥、环磷酰胺、环孢菌素、达利珠单抗(daclizumab)、英夫利昔单抗(infliximab)、甲氨蝶呤、他克莫司等。
用于组合治疗的治疗性抗体的实例包括但不限于曲妥珠单抗(trastuzumab)(例如抗HER2)、兰尼单抗(ranibizumab)(例如抗VEGF-A)、贝伐单抗(bevacizumab)(例如抗VEGF)、帕尼单抗(panitumumab)(例如抗EGFR)、西妥昔单抗(cetuximab)(例如抗EGFR)、利妥昔单抗(rituxan)(抗CD20)和针对c-MET的抗体。
用于组合治疗的腺苷拮抗剂的实例包括但不限于CPI-444;PBF-509;和AZD4635(HTL-1071)。
在又一方面(方面8),本发明涉及组合产品,其包含式(I)化合物或其药学上可接受的盐以及一种或多种免疫治疗剂,该免疫治疗剂可用于治疗癌症,更优选地结肠癌、肺癌、乳腺癌、选自脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)和颅咽管瘤的中枢神经系统癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和T细胞恶性病如白血病和淋巴瘤,例如,急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤。
在优选的实施方式中,组合产品包含式(I)化合物或其药学上可接受的盐或共晶体,以及一种或多种免疫治疗剂,该免疫治疗剂选自抗CTLA4抗体(如伊匹木单抗(Ipilimumab)和曲美木单抗(Tremelimumab))、抗PD1抗体(如MDX-1106(纳武单抗(nivolumab))、MK3475(帕博利珠单抗(pembrolizumab))、CT-011(匹利珠单抗(pidilizumab))和AMP-224、和抗PDL1抗体(如MPDL3280A、MEDI4736和MDX-1105)。组合产品的组分处于相一制剂或单独制剂中。
在其它优选的实施方式中,组合产品包含式(I)化合物或其药学上可接受的盐或共晶体,以及一种或多种化学治疗剂,该化学治疗剂选自卡铂、卡莫司汀(BCNU)、顺铂、环磷酰胺、依托泊苷、伊立替康、洛莫司汀(CCNU)、甲氨蝶呤、丙卡巴肼、替莫唑胺、长春新碱。
因此,本发明的衍生物和药学上可接受的盐以及包含这种化合物和/或其盐的药物组合物可用于治疗人体病理状况或疾病的方法,所述方法包括向需要所述治疗的对象给予有效量的本发明的杂芳基酰胺衍生物或其药学上可接受的盐。
如前所述,本发明的杂芳基酰胺衍生物可用于治疗或预防已知易于通过用选自HDAC1和HDAC2的组蛋白脱乙酰基酶I类的抑制剂治疗而减轻的疾病。这种疾病包括癌症,如结肠癌、肺癌、乳腺癌、选自脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)、和颅咽管瘤的中枢神经系统(CNS)癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和T细胞恶性病如白血病和淋巴瘤——例如急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤;神经退行性疾病,选自阿尔茨海默氏病、创伤后应激障碍、药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病、脊髓性和延髓性肌萎缩;感染性疾病、选自过敏、哮喘、自身免疫疾病、乳糜泻、肾小球性肾炎、肝炎、炎性肠病、再灌注损伤和移植排斥的炎性疾病;心力衰竭和心脏肥厚;糖尿病、多囊肾病和镰状细胞病(SCD)和β-地中海贫血病。
如本文所用,术语卤素原子包括氯、氟、溴或碘原子,优选氟、氯或溴原子。术语卤代用作前缀时,具有相同的含义。
如本文所用,术语卤代烷基用于表示被一个或多个卤素原子,优选一个、两个或三个卤素原子,取代的C1-C4烷基。优选地,卤素原子选自氟或氯原子。在优选的实施方式中,卤代烷基基团是被一个、两个或三个氟或氯原子取代的C1-C4烷基。
如本文所用,术语烷基基团用于表示具有1至6个碳原子的直链或支链烃自由基(CnH2n+1)。实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、1-甲基-丁基、2-甲基-丁基、异戊基、1-乙基丙基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、2-甲基戊基和3-甲基戊自由基。在优选的实施方式中,所述烷基基团具有1至3个碳原子(C1-C3烷基)。
如本文所用,术语环烷基包括具有3至12个碳原子的烃环基团。所述环烷基基团可具有单个环状环或多个稠合环。这种环烷基基团包括例如单环结构(如环丙基、环丁基、环戊基、环己基等)或多环结构(如金刚烷基、双环[2.2.1]庚烷、1,3,3三甲基双环[2.2.1]庚-2-基、(2,3,3-三甲基双环[2.2.1]庚-2-基))。在优选的实施方式中,所述环烷基基团包括具有3至6个碳原子的烃环状基团。
如本文所用,术语C1-C4烷氧基用于表示含有连接至氧原子的直链或支链C1-C4烷基基团的自由基(CnH2n+1-O-)。优选的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、二氟甲氧基、羟基甲氧基、2-羟基乙氧基或2-羟基丙氧基。
如本文所用,术语环烷氧基用于表示含有连接至氧原子的C3-C6的环烷基自由基。
如本文所用,术语五元或六元杂芳基环和C5-C6杂芳基环无差别地用于表示含有碳、氢和选自N、O和S的一个或多个杂原子作为环部分的杂芳族环。优选的基团是任选地取代的吡啶基、嘧啶基、噻吩基。当杂芳基自由基带有2个或更多个取代基时,该取代基可以相同或不同。
如本文所用,术语C5-C6杂环状环和五元或六元饱和杂环无差别地用于表示含有碳、氢和选自N和O的一个或多个杂原子作为环部分的饱和杂环。所述基团可任选地被一个或多个取代基取代。优选的自由基是任选地取代的哌啶基、哌嗪基和吗啉基。当杂环自由基带有2个或更多个取代基时,该取代基可以相同或不同。
如本文所用,本发明的一般结构中存在的原子、自由基、链或环中的一些是“任选地取代的”。这意味着这些原子、自由基、链或环可未被取代或在任何位置被一个或多个(例如1、2、3或4个)取代基取代,借此结合至未被取代的原子、自由基、链或环的氢原子被化学上可接受的原子、自由基、链或环替换。当存在两个或更多个取代基时,各取代基可以相同或不同。
如本文所用,术语药学上可接受的盐用于表示与药学上可接受的酸或碱(形成)的盐。药学上可接受的酸包括无机酸(例如盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸和硝酸),和有机酸(例如柠檬酸、富马酸、马来酸、苹果酸、扁桃酸、抗坏血酸、草酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药学上可接受的碱包括碱金属(例如钠或钾)、碱土金属(例如钙或镁)氢氧化物、和有机碱(例如烷基胺、芳基烷基胺和杂环胺)。
根据本发明的其它优选的盐是季铵化合物,其中阴离子(X-n)的等同形式与N原子的正电荷缔合。X-n可以是各种无机酸的阴离子(如例如氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根)或有机酸的阴离子(如例如乙酸根、马来酸根、富马酸根、柠檬酸根、草酸根、琥珀酸根、酒石酸根、苹果酸根、扁桃酸根、三氟乙酸根、甲磺酸根和对甲苯磺酸根)。X-n优选为选自氯离子、溴离子、碘离子、硫酸根、硝酸根、乙酸根、马来酸根、草酸根、琥珀酸根或三氟乙酸根的阴离子。更优选地,X-为氯离子、溴离子、三氟乙酸根或甲磺酸根。
如本文所用,术语“抑制剂”指代阻断或以其它方式干扰具体生物活性的分子,如化合物、药物、酶或激素。术语“抑制剂”与术语拮抗剂同义。
术语“HDAC1/2选择性”意为该化合物与HDAC1和HDAC2的结合程度显著大于,如5X、10X、15X、20X或更多地大于,任何其它类型的HDAC酶(如HDAC3或HDAC6)。即,化合物对HDAC1和/或HDAC2相对于任何其它类型的HDAC酶具有选择性。
根据本发明的一个实施方式,X1为-CH基团。在更优选的实施方式中,X1和X2为-CH基团。
根据本发明的一个实施方式,R1表示任选地被选自卤素原子、C1-C4卤代烷基和C1-C4烷氧基的一个或多个取代基取代的苯基基团。在更优选的实施方式中,R1表示任选地被选自卤素原子的一个或多个取代基取代的苯基基团。
在本发明的另一实施方式中,R1表示任选地被选自氰基基团、卤素原子和C1-C4卤代烷基的一个或多个取代基取代的五元或六元杂芳基环。在更优选的实施方式中,R1表示吡啶基或噻吩基环。
根据本发明的一个实施方式,R2表示-N(R3)(R4)基团,其中R3和R4与其结合的氮原子一起形成任选地包含选自N和O的杂原子作为环部分的5元或6元饱和杂环,该杂环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代,其中R5和R6与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子作为环部分的五元或六元饱和环,该环任选地被C1-C3烷基基团取代。在更优选的实施方式中,R2表示任选地被C1-C3烷基基团或-N(R5)(R6)基团取代的哌嗪基、哌啶基或吗啉基环。
根据本发明的一个实施方式,R2表示-N(R3)(R4)基团,其中R3和R4独立地表示选自氢原子、C3-C6环烷基基团和直链或支链C1-C3烷基的基团,其任选地被包含一个或两个N原子作为环部分的5元或6元杂环取代,该环任选地被C1-C3烷基基团取代。在更优选的实施方式中,R2表示-N(R3)(R4)基团,其中R3表示被包含一个或两个N原子的5元或6元饱和杂环取代的直链C1-C3烷基,该杂环任选地被C1-C3烷基基团取代;并且R4为氢原子。
根据本发明的一个实施方式,R2表示任选地被选自卤素原子和氰基基团的一个或多个取代基取代的苯基环。在优选的实施方式中,苯基环被一个卤素原子或被一个氰基基团取代。
根据本发明的另一实施方式,R2表示C3-C6环烷基。在更优选的实施方式中,R2表示环丙基或环戊基环。
根据本发明的另一实施方式,R2表示任选地被选自卤素原子和氰基基团的一个或多个取代基取代的C5-C6杂芳基。在优选的实施方式中,C5-C6杂芳基被一个卤素原子或被一个氰基基团取代。在更优选的实施方式中,R2表示任选地被选自卤素原子和氰基基团的一个或多个取代基(优选地被一个卤素原子或被一个氰基基团)取代的吡啶基或嘧啶基环。
在本发明的进一步优选的实施方式中,在式(I)的化合物中,X1和X2表示-CH基团,R1表示任选地被一个或多个卤素原子取代的苯基基团,并且R2表示-N(R3)(R4)基团,其中R3和R4与其结合的氮原子一起形成任选地包含选自N和O的杂原子的6元饱和杂环,该6元饱和杂环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代,其中R5和R6与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子的五元或六元饱和环,其任选地被C1-C3烷基基团取代。在更优选的实施方式中,R2表示任选地被C1-C3烷基基团取代的哌嗪基环。
本发明的具体个体化合物包括:
N-(3-氨基-6-苯基吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-苯基吡啶-2-基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)烟酰胺
N-(3-氨基-6-苯基吡啶-2-基)-6-吗啉代烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-吗啉代烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-(4-甲氧基苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(5-氨基-[2,4'-联吡啶]-6-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-(3,4-二氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-苯基吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺
N-(3-氨基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)嘧啶-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-吗啉代嘧啶-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺
N-(3-氨基-6-苯基吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-苯基烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氟苯基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,4'-联吡啶]-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,3'-联吡啶]-5-羧酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(3-氰基苯基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环丙基烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环戊基烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(哌嗪-1-基)烟酰胺
N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(哌嗪-1-基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氨基哌啶-1-基)烟酰胺
N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(4-氨基哌啶-1-基)烟酰胺
N-(3-氨基-6-(噻吩-2-基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(4-甲基哌嗪-1-基)乙基)氨基)烟酰胺
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(吡啶-3-基)乙基)氨基)烟酰胺
在以下方案中概述了式(I)化合物的合成。
在方案1中,描述了式(IV)的中间体化合物的合成。
方案1
试剂和条件:a)NH3,EtOH,0℃-RT,3-6h;b)R1-B(OH)2,Pd2(dba)3,SPhos,K3PO4,
甲苯/H2O,回流过夜。
将商业可得的式(II)试剂与氨在乙醇中于0℃下反应,以得到式(III)的衍生物。根据方案1,利用钯催化剂如三(二亚苄基丙酮)二钯(0),在SPhos(二环己基(2',6'-二甲氧基-[1,1'-联苯基]-2-基)膦)和碱(如一水合磷酸三钾)的水溶液存在下,于110℃在12h内与硼酸或硼酸酯衍生物的Suzuki型偶联提供了式(IV)的化合物。
方案2
在方案2中,描述了式(VI)的中间体化合物的合成。
试剂和条件:c)氯甲酸乙酯,TEA,NaHMDS,THF,-35℃-室温。
关于式(VI)酰胺的制备,以混合酸酐的形式活化式(V)的羧酸。在三乙胺的存在下,使相应的酸与氯甲酸乙酯反应生成此酸酐。式(VI)酰胺的合成通过在碱(例如双(三甲基甲硅烷基)酰胺钠(NaHMDS)的存在下,在-35℃至室温之间的温度下,式(IV)的杂芳基胺与相应的混合羧酸酸酐的反应进行。
方案3
在方案3中,描述了根据本发明的式(I)化合物的合成,其中R2是苯基或杂芳基环。
试剂和条件:d)R2-B(OH)2,Pd2(dba)3,SPhos,K3PO4,甲苯/H2O,回流过夜/伯胺或仲胺,DIPEA,DMSO,110℃;e)H2,(Pd/C)。
通式(I)的化合物由式(VI)的中间体分两步制备。当R2表示任选取代的环烷基、苯基或杂芳基基团时,根据本发明,利用钯催化反应的标准方法,通过与相应硼酸或硼酸酯衍生物的Suzuki型偶联引入基团R2,以提供式(VII)的化合物。
方案4
在方案4中,描述了根据本发明的式(I)化合物的合成,其中R2为-N(R3)(R4)。
试剂和条件:f)R2-B(OH)2,Pd2(dba)3,SPhos,K3PO4,甲苯/H2O,回流过夜/-N(R3)(R4),DIPEA,DMSO,110℃;g)H2,(Pd/C)。
在R2表示-NR3R4基团的情况下,根据本发明的定义,中间体(VI)与伯胺或仲胺在N,N-二异丙基乙基胺(DIPEA)存在下在DMSO中于110℃下的反应产生式(VIIa)的化合物。
,随后在方案3所述的钯催化剂(Pd/C)存在下用氢气进行的式(VIIa)化合物的硝基还原,得到式(I)化合物,即本发明的主题。
可选地,本发明的式(I)化合物也可利用与上述相同的反应但采用方案5中所示的顺序来制备。
方案5
试剂和条件:h)R2-B(OH)2,Pd2(dba)3,SPhos,K3PO4,甲苯/H2O,回流过夜/伯胺或仲胺,DIPEA,DMSO,110℃;i)氯甲酸乙酯,TEA,NaHMDS,THF,-35℃-室温;j)H2,(Pd/C)。
药理活性
组蛋白脱乙酰基酶测定
利用生化HDAC测定法(Reaction Biology Corp.生化测定服务)确定本发明化合物的抑制活性。在HDAC 1、HDAC2、HDAC3、HDAC4、HDAC5、HDAC6、HDAC7、HDAC 8、HDAC9、HDAC10和HDAC11酶的生化测定中测试具有指定剂量的化合物。
针对11种HDACs,以单次(singlicate)10剂IC50模式,利用从10μM开始的3倍连续稀释,测试化合物。以10剂IC50,利用从10μM开始的3倍连续稀释,测试HDAC参考化合物曲古抑菌素A(TSA)和TMP269。
HDAC1、2、3、6、10的底物:来自p53残基379-382的荧光肽(RHKK(Ac)AMC)。HDAC4、5、7、9和11的底物:荧光HDAC 2a类底物(三氟乙酰赖氨酸)。HDAC 8的底物:来自p53残基379-382的荧光肽(RHK(Ac)K(Ac)AMC)。
通用反应程序:(标准IC50确定)
a.将2X酶添加至反应板的孔中,除无酶(No En)对照孔外。在无酶孔中添加缓冲液。
b.通过声学技术(Echo550;纳升范围),将在100%DMSO中待测试的化合物添加至酶混合物中。将混合物下旋(spinned down)并预培育。
c.将2X底物混合物(荧光HDAC底物和辅因子(500μΜ烟酰胺腺嘌呤二核苷酸(NAD<+>),在所有Sirt测定中)添加至所有反应孔中以启动反应。使板旋转并摇动。
d.将板在30℃下密封培育1-2hr。
e.添加具有曲古抑菌素A(或TMP269或NAD<+>)的显影剂,以终止反应并产生荧光色。
f.利用EnVision Multilabel平板读取器(Perkin Elmer)读取荧光(激励,360;发射,460)。
g.在显色达到平稳之后,采集端点读数用于分析。
数据分析:利用GraphPad Prism 4程序,基于sigmoidal剂量响应方程,计算酶活性的百分比(相对于DMSO对照)和IC50值。输入空白(DMSO)值作为浓度1.00E-12进行曲线拟合。
结果
在表1中显示HDAC活性抑制测定中本发明选定化合物的结果(IC50范围:A<0,2μM;0,2μM<B<1μM;1μM<=C<50μM m,D>=50μM)。
表1.
*空白单元格:表示没有抑制或不能拟合至IC50曲线的化合物活性
从表1中描述的结果可以看出,本发明的化合物是组蛋白脱乙酰基酶1和/或2(HDAC1和/或HDAC2)的有效抑制剂。
在一些实施方式中,从表1中描述的结果可以看出,本发明的化合物是HDAC1和HDAC2相对于其它组蛋白脱乙酰基酶亚型的有效和选择性抑制剂。
因此,本发明的衍生物及其药学上可接受的盐以及包含这种化合物和/或其盐的药物组合物可用于治疗人体障碍的方法中,该方法包括向需要这种治疗的对象给予有效量的式(I)化合物或其药学上可接受的盐。
本发明的化合物可用于治疗或预防已知易于通过抑制组蛋白脱乙酰基酶I类(具体地组蛋白脱乙酰基酶1和2(HDAC1、HDAC2))而改善的疾病。这种疾病选自癌症;神经退行性疾病;感染性疾病;炎性疾病;心力衰竭和心脏肥厚;糖尿病;多囊肾病、和镰状细胞病(SCD)和β-地中海贫血病。
本发明化合物的一种治疗用途是治疗增生性疾病或障碍,如癌症。癌症包括结肠癌、肺癌、乳腺癌、中枢神经系统(CNS)癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和T细胞恶性病,其选自急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤。中枢神经系统(CNS)癌包括脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)、和颅咽管瘤。
本发明化合物的另一治疗用途是还治疗神经退行性疾病,其选自阿尔茨海默氏病、创伤后应激障碍或药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病、脊髓性和延髓性肌萎缩。
本发明化合物的另一种治疗用途是还治疗病毒感染性疾病或障碍,如HIV。
本发明化合物的另一种治疗用途是还治疗炎性疾病,其选自过敏、哮喘、自身免疫疾病、乳糜泻、肾小球性肾炎、肝炎、炎性肠病、再灌注损伤和移植排斥。
本发明还提供药物组合物,其包含作为活性成分的至少一种式(I)杂芳基酰胺衍生物或其药学上可接受的盐结合其它治疗剂和药学上可接受的赋形剂(如载体或稀释剂)。根据制剂的性质以及在施用前是否进行进一步的稀释,活性成分可占组合物的按重量计0.001%至99%,优选按重量计0.01%至90%。优选地,组合物以适于口服、局部、鼻部、直肠、经皮或注射给予的形式构成。
与活性化合物或这种化合物的盐混合以形成本发明组合物的药学上可接受的赋形剂本身是公知的,并且所用的实际赋形剂取决于给予组合物的预期方法等。
本发明的组合物优选被设置用于注射或口服(per os)给予。在这种情况下,用于口服给予的组合物可采取片剂、阻滞片剂、舌下片剂、胶囊、吸入气溶胶、吸入溶液、干粉吸入剂或液体制剂的形式,如混合物、酏剂、糖浆或悬浮液,其全部含有本发明的化合物;这种制剂可通过本领域公知的方法来制备。
可用于制备组合物的稀释剂包括连同着色剂或调味剂(如需)与活性成分相容的那些液体或固体稀释剂。片剂或胶囊可方便地含有2和500mg之间的活性成分或其等量盐。
被设置用于口服使用的液体组合物可以是溶液或悬浮液的形式。溶液可以是活性化合物的可溶性盐或其它衍生物与例如蔗糖结合形成糖浆的水溶液。悬浮液可包含本发明的不溶性活性化合物或其药学上可接受的盐与水结合,以及悬浮剂或调味剂。
用于肠胃外注射的组合物可由可溶性盐制备,所述可溶性盐可被冷冻干燥或可以不被冷冻干燥,并且可被溶解在无热原的水性介质或其它合适的肠胃外注射流体中。
有效剂量通常在每天2-2000mg活性成分的范围内。每日剂量可以以每天一次或多次处理给予,优选1至4次处理。
通过以下实施例进一步示例了本发明。以下作为示例给出,而不以任何方式限制本发明的范围。通过以下实施例示例本发明化合物的合成,包括中间体的制备,其不一任何方式限制本发明的范围。
简称
在本申请中,使用以下简称,其具有相应的定义:
RT:室温
Pd2(dba)3:三(二亚苄基丙酮)二钯
SPhos:二环己基(2',6'-二甲氧基-[1,1'-联苯基]-2-基)膦
TEA:三乙胺
NaHMDS:双(三甲基甲硅烷基)酰胺钠
THF:四氢呋喃
DMSO:二甲基亚砜
实施例
概述.试剂、溶剂和起始产品从商业来源获得。术语“浓缩”指代利用Büchi旋转蒸发仪进行的真空蒸发。在指示时,反应产物通过“快速”色谱法在硅胶(40-63μm)上用指示的溶剂系统纯化。光谱数据在Varian Mercury 400光谱仪中测量。熔点在Büchi 535仪器中测量。HPLC-MS在配备有Gilson 321活塞泵、Gilson 864真空脱气机、Gilson 189注射模块、1/1000Gilson分流器、Gilson 307泵、Gilson 170检测器和Thermoquest Fennigan aQa检测器的Gilson仪器上进行。
方案6:实施例1的合成
步骤1:6-氯-3-硝基吡啶-2-胺(中间体2)的合成
用氨气吹扫0℃的化合物1(5g.0.026mol)的乙醇(50ml)溶液3h,然后使其在室温下搅拌过夜。用水稀释反应混合物,并将形成的沉淀物过滤并用水然后用己烷洗涤,并干燥,以获得中间体2(3.65g,81.2%产率)。
步骤2:3-硝基-6-苯基吡啶-2-胺(中间体3)的合成
将中间体2(8.62g,0.05mol)、苯基硼酸(5.05g)、二环己基(2',6'-二甲氧基-[1,1'-联苯基]-2-基)膦(0.567g)、一水合磷酸三钾(23.85g)、30mL甲苯和3mL水添加至3颈100mL圆底烧瓶中。将氮气直接鼓泡到混合物中20分钟。添加Pd2(dba)3(0.316g),并且混合物在氮气下回流过夜。用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。有机层经硫酸镁干燥,过滤并蒸发至残余物。将残余物通过柱层析法纯化,最初用20%乙酸乙酯/己烷洗脱,并添加乙酸乙酯以冲洗掉产物。用己烷洗涤产物,以得到中间体3(8.02g,75%产率)。
步骤4:6-氯-N-(3-硝基-6-苯基吡啶-2-基)烟酰胺(中间体4)的合成
添加6-氯-3-烟酸(1g)的THF(10ml)溶液、TEA(1.5ml)和氯甲酸乙酯(1.45ml),并使其在室温下搅拌1h。用水稀释反应混合物,并将形成的沉淀物过滤并干燥,以获得酸酐。在-35℃下缓慢添加中间体3(1g)的THF(50ml)溶液、NaHMDS(10ml),并使其在相同温度下搅拌1h。向此溶液立即添加在THF(5ml)中的酸酐(1.2g),并使反应混合物升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体4(0.96g,78%产率)。
步骤5:6-(4-甲基哌嗪-1-基)-N-(3-硝基-6-苯基吡啶-2-基)烟酰胺(中间体5)的合成
向N-甲基-哌嗪(226mg)的DMSO(10v)溶液添加DIPEA(437mg),并将中间体4(400mg)在密封管中于110℃加热过夜。通过TLC监测反应完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体5,为浅黄色固体(310mg,67%产率)。
步骤6:N-(3-氨基-6-苯基吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺的合成。实施例1
向中间体5(310mg)的乙醇(20ml)和乙酸乙酯(35ml)溶液添加Pd/C(10%)(46mg,15%(w/w)),并使反应在氢气下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土(celite)过滤并蒸发至残余物。通过制备型HPLC纯化残余物,以获得实施例1,为灰白色固体(20mg,10%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.25(br,s,1H),8.80(d,J=4.4Hz,1H),8.15(d,J=11.6Hz,1H),7.955(d,J=7.2Hz,2H),7.68(d,J=8.0Hz,1H),7.42(t,J=7.6Hz,2H),7.31(m,2H),6.92(d,J=9.2Hz,1H),5.14(br,s,2H),3.65(t,J=4.8Hz,4H),2.40(t,J=4.8Hz,4H),2.22(s,3H)。
HPLC-MS:Rt 11.120m/z 389.6(MH+)。
以下实施例利用方案6中描述的程序,从相应的吡啶-2-胺和烟酸衍生物开始合成。
实施例2:N-(3-氨基-6-苯基吡啶-2-基)烟酰胺
1H-NMR(400MHz,DMSO-d6):δ=10.60(s,1H),9.18(s,1H),8.77(dd,J=6.0,1.2Hz,1H),8.37(d,J=8.0Hz,1H),7.94(d,J=7.6Hz,2H),7.71(d,J=8.4Hz,1H),7.58(m,1H),7.42(t,J=7.6Hz,H),7.31(m,2H),5.29(br s,2H)。
HPLC-MS:Rt 9.891m/z 291.0(MH+)。
实施例3:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)烟酰胺
1H-NMR(400MHz,DMSO-d6)δ=10.59(s,1H),9.17(d,J=2.0Hz,1H),8.77(dd,J=6.8,1.6Hz,1H),8.37(m,1H),7.98(m,2H),7.69(d,J=8.4Hz,1H),7.58(m,1H),7.26(m,3H),5.29(br,s,2H)。
HPLC-MS:Rt 10.590m/z 309.0(MH+)。
实施例4:N-(3-氨基-6-苯基吡啶-2-基)-6-吗啉代烟酰胺
1H-NMR(400MHz,DMSO-d6)δ=10.27(br,s,1H),8.28(d,J=2.0Hz,1H),8.19(dd,J=11.0,2.0Hz,1H),7.96(d,J=7.6Hz,2H),7.68(d,J=8.4Hz,1H),7.42(t,J=7.6Hz,2H),7.31(m,2H),6.93(d,J=9.2Hz,1H),5.15(br,s,2H),3.72(m,4H),3.60(m,4H)。
HPLC-MS:Rt 9.828m/z 376.3(MH+)。
实施例5:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-吗啉代烟酰胺
1H-NMR(400MHz,DMSO-d6)δ=10.27(br,s,1H),8.81(d,J=2.4Hz,1H),8.18(dd,J=11.6,2.4Hz,1H),8.00(m,2H),7.67(d,J=8.0Hz,1H),7.26(m,3H),6.93(d,J=8.8Hz,1H),5.15(br,s,2H),3.72(m,4H),3.61(m,4H)。
HPLC-MS:Rt 10.855m/z 394.4(MH+)。
实施例6:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
1H-NMR(400MHz,DMSO-d6)δ=10.24(s,1H),8.79(br,s,1H),8.15(dd,J=11.6,2.4Hz,1H),8.00(m,2H),7.69(d,J=8.4Hz,1H),7.26(m,3H),6.92(d,J=9.2Hz,1H),5.14(br,s,2H),3.65(br,s,4H),2.55(br,s,4H),2.22(s,3H)。
HPLC-MS:Rt 11.906m/z 407.4(MH+)。
实施例7:N-(3-氨基-6-(4-甲氧基苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺
1H-NMR(400MHz,DMSO-d6)δ=10.21(s,1H),8.79(d,J=2.8Hz,1H),8.15(dd,J=11.6,2.4Hz,1H),7.89(d,J=8.8Hz,2H),7.59(d,J=8.0Hz,1H),7.25(d,J=8.4Hz,1H),6.97(m,3H),5.01(br,s,2H),3.78(s,3H),3.65(t,J=4.8Hz,4H),2.41(t,J=4.8Hz,4H),2.22(s,3H).
HPLC-MS:Rt 8.759m/z 419.2(MH+)。
实施例8:N-(5-氨基-[2,4'-联吡啶]-6-基)-6-(4-甲基哌嗪-1-基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.22(s,1H),8.79(d,J=2.4Hz,1H),8.57(dd,J=6.4,2.0Hz,2H),8.14(dd,J=11.6,2.4Hz,1H),7.90(dd,J=6.4,2.0Hz,2H),7.84(d,J=8.4Hz,1H),7.27(d,J=8.4Hz,1H),6.92(d,J=9.2Hz,1H),5.43(br,s,2H),3.65(m,4H),2.41(m,4H),2.22(s,3H)。
HPLC-MS:Rt 3.743m/z 390.2(MH+)。
实施例9:N-(3-氨基-6-(3,4-二氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.09(s,1H),8.75(br,s,1H),8.10(d,J=8.0Hz,1H),7.90(m,1H),7.75(br,s,1H),7.66(d,J=7.6Hz,1H),7.41(m,1H),7.23(d,J=7.2Hz,1H),6.87(d,J=8.8Hz,1H),5.15(br,s,2H),3.61(br,s,4H),2.38(br,s,4H),2.2(s,3H)。
HPLC-MS:Rt 10.548m/z 425.2(MH+)。
方案7:实施例10的合成
步骤3:2-氯-N-(3-硝基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺(中间体6)的合成
添加2-氯嘧啶-5-羧酸(1g)的THF(50ml)溶液、TEA(2.73g)和氯甲酸乙酯(1.7g),并使其在室温下搅拌1h。用水(50ml)稀释反应混合物,并将形成的沉淀物过滤并干燥以获得酸酐。在-35℃下,缓慢添加中间体3(1g)的THF(50ml)溶液NaHMDS(12.7ml),并使其在相同温度下搅拌1h。向此溶液立即添加THF(5ml)中的酸酐,并使其升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体6(200mg,14%产率)。
步骤7:2-(4-甲基哌嗪-1-基)-N-(3-硝基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺(中间体7)的合成
N-甲基-哌嗪(141mg)的DMF(4ml)溶液添加DIPEA(272mg),并将中间体4(250mg)在密封管中于80℃下加热过夜。通过TLC监测反应完成后,用乙酸乙酯/水稀释反应混合物。分离层,用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。用正戊烷磨碎粗产物,以得到中间体7,为浅棕色固体(200mg,69%产率)。
步骤8:N-(3-氨基-6-苯基吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺的合成。实施例10。
向中间体7(200mg)的乙醇(10ml)和乙酸乙酯(25ml)溶液添加Pd/C(10%)(30mg,15%(w/w)),并使反应在氢气下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得实施例10,为灰白色固体(70mg,18%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.33(s,1H),8.93(s,2H),7.99(m,2H),7.69(d,J=8.4Hz,1H),7.42(t,J=7.6Hz,2H),7.31(m,2H),5.20(br,s,2H),3.85(m,4H),2.39(m,4H),2.22(s,3H)。
HPLC-MS:Rt 6.673m/z 390.5(MH+)。
以下实施例利用方案7描述的程序,从相应的吡啶-2-胺和嘧啶-5-羧酸衍生物开始合成。
实施例11:N-(3-氨基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.73(s,1H),9.36(m,3H),7.93(d,J=7.6Hz,2H),7.72(d,J=8.0Hz,1H),7.42(t,J=7.2Hz,2H),7.31(m,2H),5.39(br,s,2H)。
HPLC-MS:Rt 8.382m/z 292.2(MH+)。
实施例12:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)嘧啶-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.72(s,1H),9.36(d,J=4.8Hz,1H),9.31(s,2H),7.98(dd,J=14.4,6.0Hz,2H),7.70(d,J=8.4Hz,1H),7.25(m,3H),5.39(br,s,2H)。
HPLC-MS:Rt 11.104m/z 310.3(MH+)。
实施例13:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.35(s,1H),8.96(s,2H),7.95(d,J=7.6Hz,2H),7.69(d,J=8.0Hz,1H),7.42(t,J=7.6Hz,2H),7.29(m,2H),5.21(br,s,2H),3.85(t,J=4.4Hz,4H),3.69(t,J=4.4Hz,4H)。
HPLC-MS:Rt 12.094m/z 377.3(MH+)。
实施例14:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-吗啉代嘧啶-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.34(s,1H),8.97(s,2H),7.99(m,2H),7.68(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.27(t,J=8.8Hz,2H),5.21(br,s,2H),3.85(t,J=4.4Hz,4H),3.69(t,J=4.4Hz,4H)。
HPLC-MS:Rt 12.456m/z 395.6(MH+)。
实施例15:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.32(s,1H),8.93(s,2H),7.99(m,2H),7.67(d,J=8.4Hz,1H),7.25(t,J=8.8Hz,3H),5.21(br,s,2H),3.86(m,4H),2.44(m,4H),2.24(s,3H)。
HPLC-MS:Rt 7.205m/z 408.3(MH+)。
方案8:实施例16的合成
步骤1:2-(环丙基氨基)-N-(3-硝基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺(中间体8)的合成
向环丙胺(96.5mg)的DMF(3ml)溶液添加DIPEA(327mg),并将中间体6(300mg)在密封管中于110℃下加热过夜。通过TLC监测反应完成后,用水稀释反应混合物。通过过滤收集析出的固体,以获得所需的中间体8,为浅黄色固体(300mg,93%产率)。
步骤2:N-(3-氨基-6-苯基吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺的合成。实施例16。
向中间体8(300mg)的乙醇(10ml)和乙酸乙酯(50ml)溶液添加Pd/C(10%)(60mg,15%(w/w)),并使反应在氢气下(Balloon atm)搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过制备型HPLC纯化残余物,以获得实施例16,为浅黄色固体(130mg,26%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.26(s,1H),8.89(br,s,2H),8.03(d,J=4.0Hz,1H),7.99(m,2H),7.66(d,J=8.4Hz,1H),7.42(t,J=8.4Hz,2H),7.31(m,2H),5.18(br,s,2H),2.84(m,1H),0.75(m,2H),0.55(m,2H)。
HPLC-MS:Rt 11.419m/z 347.1(MH+)。
以下实施例利用方案8描述的程序,从相应2-氯-N-(3-硝基吡啶-2-基)嘧啶-5-羧酰胺和胺衍生物开始合成。
实施例17:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺。
1H-NMR:NMR(400MHz,DMSO-d6)δ=10.26(s,1H),8.89(br,s,2H),8.03(d,J=4.0Hz,1H),7.99(m,2H),7.66(d,J=8.4Hz,1H),7.25(m,3H),5.18(br,s,2H),2.86(m,1H),0.75(m,2H),0.54(m,2H)。
HPLC-MS:Rt 12.233m/z 365.1(MH+)。
方案9:实施例18的合成
步骤1:6-苯基烟酸甲酯(中间体10)的合成
将中间体9(500mg)、苯基硼酸(499mg)、Cs2CO3(1.52g)、8ml 1,4-二烷和0.5ml水添加至3颈100mL圆底烧瓶中。将氮气直接鼓泡至混合物中20分钟。添加Pd(dppf)Cl2.CH2Cl2(238mg,0.1eq.),并使混合物在氮气下于110℃回流2h。用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,并分离出中间体10,为灰白色固体(606mg;94%产率)。
步骤2:6-苯基烟酸(中间体11)的合成
向中间体10(606mg)的甲醇(30ml)溶液添加10%NaOH溶液(2.5ml),并使反应在70℃下回流3h。通过TLC监测反应完成后,将反应混合物蒸发,并通过2N HCl使其呈酸性,以得到固体,将该固体过滤并干燥,以获得中间体11,为灰白色固体(460mg,75%产率)。
步骤3:6-(4-氟苯基)-3-硝基吡啶-2-胺(中间体12)的合成
将中间体2(700mg)、4-氟苯基硼酸(788mg)、Cs2CO3(2.1g)、50ml 1,4-二烷和3ml水添加至3颈100ml圆底烧瓶中。将氮气直接鼓泡到混合物中20分钟。添加Pd(dppf)Cl2.CH2Cl2(328mg,0.1eq.),并使混合物在氮气下于110℃回流2h。用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,并分离出中间体12,为浅黄色固体(725mg,67%产率)。
步骤4:N-(6-(4-氟苯基)-3-硝基吡啶-2-基)-6-苯基烟酰胺(中间体13)的合成
添加中间体11(250mg)的THF(30ml)溶液、TEA(380.6mg)和氯甲酸乙酯(339mg),并使其在室温下搅拌1h。用水稀释反应混合物,并将形成的沉淀物过滤并干燥以获得酸酐。在-35℃下缓慢添加中间体12(234mg)的THF(30ml)溶液、NaHMDS(1.0M,在THF中)(3.2ml),并使其在相同温度下搅拌1h。向此溶液立即添加THF(5ml)中的酸酐,并使反应混合物升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体13,为浅黄色固体(230mg,58%产率)。
步骤5:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-苯基烟酰胺的合成。实施例18。
向中间体13(230mg)的乙醇(12ml)和乙酸乙酯(30ml)溶液添加Pd/C(10%)(35mg,15%(w/w)),并使反应在氢气(Balloon atm)下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得期望的化合物,为灰白色固体(103mg,35%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.60(s,1H),9.26(s,1H),8.47(dd,J=10.8,2.9Hz,1H),8.21(d,J=8.4Hz,2H),8.16(d,J=8.4Hz,1H),7.99(m,2H),7.7(d,J=8.4Hz,1H),7.57(m,3H),7.28(m,3H),5.28(s,2H)。
HPLC-MS:Rt 16.154m/z 385.2(MH+)。
以下实施例利用方案9中描述的程序,从相应吡啶-2-胺和烟酸衍生物开始合成。
实施例19:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氟苯基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.60(s,1H),9.25(s,1H),8.47(dd,J=10.4,2.4Hz,1H),8.28(m,2H),8.16(d,J=8.4Hz,1H),7.99(m,2H),7.7(d,J=8.4Hz,1H),7.39(m,2H),7.28(m,3H),5.28(s,2H)。
HPLC-MS:Rt 15.831m/z 403.2(MH+)。
实施例20:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,4'-联吡啶]-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.66(s,1H),9.31(s,1H),8.76(d,J=4.4,2H),8.54(d,J=7.6Hz,1H),8.32(d,J=8.0Hz,1H),8.16(d,J=4.4Hz,2H),7.96(m,2H),7.7(d,J=8.4Hz,1H),7.28(m,3H),5.31(s,2H)。
HPLC-MS:Rt 11.682m/z 386.1(MH+)。
实施例21:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,3'-联吡啶]-5-羧酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.63(s,1H),9.37(d,J=1.6Hz,1H),9.29(d,J=1.6Hz,1H),8.70(dd,J=6.4,1.6Hz,1H),8.56(m,1H),8.51(dd,J=10.8,2.4Hz,1H),8.26(d,J=8.0Hz,1H),7.99(m,2H),7.70(d,J=8.4Hz,1H),7.59(m,1H),7.28(m,3H),5.30(br,s,2H)。
HPLC-MS:Rt 12.080m/z 385.8(MH+)。
实施例22:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(3-氰基苯基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.68(s,1H),9.29(br,s,1H),8.65(br,s,1H),8.57(m,2H),8.32(d,J=8.0Hz,1H),8.00(m,3H),7.79(m,2H),7.28(m,3H),5.33(br,s,2H)。
HPLC-MS:Rt 14.559m/z 410.2(MH+)。
方案10:实施例23的合成
步骤1:6-环丙基-N-(6-(4-氟苯基)-3-硝基吡啶-2-基)烟酰胺(中间体15)的合成
添加中间体14(412mg)的THF(35ml)溶液、TEA(770.5mg)和氯甲酸乙酯(686.6mg),并使其在室温下搅拌1h。用水稀释反应混合物,并将形成的沉淀物过滤并干燥,以获得酸酐。在-35℃下,缓慢添加中间体12(297mg)的THF(35ml)溶液、NaHMDS(1.0M,在THF中)(5ml),并使其在相同温度下搅拌1h。向此溶液立即添加THF(5ml)中的酸酐,并使反应混合物升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体15,为浅黄色固体(190mg,32%产率)。
步骤2:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环丙基烟酰胺(实施例23)的合成
向中间体15(190mg)的乙醇(12ml)和乙酸乙酯(30ml)溶液添加Pd/C(10%)(28.5mg,15%(w/w)),并使反应在氢气(Balloon atm)下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的化合物,为浅黄色固体(38mg,21%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.45(s,1H),9.00(d,J=2.0Hz,1H),8.22(dd,J=10.8,2.4Hz,1H),7.98(m,2H),7.67(d,J=8.0Hz,1H),7.45(d,J=8.4Hz,1H),7.26(m,3H),5.21(s,2H),2.24(m,1H),1.05(m,4H)。
HPLC-MS:Rt 13.997m/z 349.1(MH+)。
以下实施例利用方案10描述的程序,从相应吡啶-2-胺衍生物和6-环戊基烟酸开始合成。
实施例24:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环戊基烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.51(s,1H),9.09(d,J=2.0Hz,1H),8.26(dd,J=10.8,2.4Hz,1H),7.98(m,2H),7.69(d,J=8.4Hz,1H),7.44(d,J=8.0Hz,1H),7.26(m,3H),5.25(s,2H),3.3(m,1H),2.04(m,3H),1.80(m,6H)。
HPLC-MS:Rt 15.746m/z 424.2(MH+)。
方案11:实施例25的合成
步骤1:6-氯-N-(6-(4-氟苯基)-3-硝基吡啶-2-基)烟酰胺(中间体16)的合成
添加6-氯-3-烟酸(430mg)的THF(30ml)溶液、TEA(830mg)和氯甲酸乙酯(739mg),并使其在室温下搅拌1h。用水稀释反应混合物,并将形成的沉淀物过滤并干燥,以获得酸酐。在-35℃下,缓慢添加中间体12(510mg)的THF(30ml)溶液、NaHMDS(6.8ml),并使其在相同温度下搅拌1h。向此溶液立即添加THF(5ml)中的酸酐,并使反应混合物升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁稀释,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体16(665mg,78%产率)。
步骤2:N-(6-(4-氟苯基)-3-硝基吡啶-2-基)-6-(哌嗪-1-基)烟酰胺(中间体17)的合成
向哌嗪(207.5mg)的DMSO(4ml)溶液添加DIPEA(622.5mg),并将中间体16(300mg)在密封管中于110℃下加热过夜。通过TLC监测反应完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体17,为浅棕色半固体(142mg,28%产率)。
步骤3:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(哌嗪-1-基)烟酰胺(实施例25)的合成
向中间体17(142mg)的乙醇(12ml)和乙酸乙酯(24ml)溶液添加Pd/C(10%)(22.0mg,15%(w/w)),并使反应在氢气(Balloon atm)下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的化合物,为棕色固体(26mg,20%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.20(br,s,1H),8.75(d,J=2.0Hz,1H),8.1(dd,J=11.2,2.0Hz,1H),7.96(m,2H),7.63(d,J=8.4Hz,1H),7.2(m,3H),6.85(d,J=8.8Hz,1H),5.11(br,s,2H),3.54(m,4H),2.75(m,4H),1.95(s,1H)。
HPLC-MS:Rt 8.070m/z 393.2(MH+)。
以下实施例利用方案11中所描述的程序,从相应的嘧啶-2-胺和烟酸衍生物开始合成。
实施例26:N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(哌嗪-1-基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.56(s,1H),8.78(d,J=2.4Hz,1H),8.36(s,1H),8.28(m,2H),8.13(dd,J=11.2,2.4Hz,1H),7.29(m,2H),6.90(d,J=8.8Hz,1H),5.29(br,s,2H),3.60(m,4H),2.79(m,4H).(-NH丢失)。
HPLC-MS:Rt 8.120m/z 394.2(MH+)。
方案12:实施例27的合成
步骤1:(1-(5-((6-(4-氟苯基)-3-硝基吡啶-2-基)氨基甲酰基)吡啶-2-基)哌啶-4-基)氨基甲酸叔丁酯(中间体18)的合成
向哌啶-4-基氨基甲酸叔丁酯(469mg)的DMSO(5ml)溶液添加DIPEA(726.2mg),并将中间体16(350mg)在密封管中于110℃下加热过夜。通过TLC监测反应完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体18,为浅棕色半固体(400mg,64%产率)。
步骤2:6-(4-氨基哌啶-1-基)-N-(6-(4-氟苯基)-3-硝基吡啶-2-基)烟酰胺(中间体19)的合成
在0℃下向中间体18(390mg)的DCM(12ml)溶液添加TFA(3ml),并使反应在氮气中于室温下搅拌3h。通过TLC监测反应完成后,将反应混合物用碳酸氢钠碱化(PH~8),并蒸发至残余物,以获得所需的中间体19,为棕色固体(390mg,98%产率)。
步骤3:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氨基哌啶-1-基)烟酰胺(实施例27)的合成
向中间体19(319mg)的乙醇(12ml)和乙酸乙酯(25ml)溶液添加Pd/C(10%)(47.8mg,15%(w/w)),并使反应在氢气(Balloon atm)下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的化合物,为浅棕色固体(140mg,46%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.33(s,1H),8.87(d,J=2.4Hz,1H),8.24(dd,J=11.2,2.4Hz,1H),8.09(br,s,2H),8.06(m,2H),7.73(d,J=8.4Hz,1H),7.33(m,2H),7.04(d,J=9.2Hz,1H),5.21(br,s,2H),4.57(d,J=13.6Hz,2H),3.10(t,J=11.6Hz,2H),2.2(d,J=10.0Hz,2H),1.55(m,2H)。
HPLC-MS:Rt 7.974m/z 407.2(MH+)。
以下实施例利用方案12描述的程序,从相应的嘧啶-2-胺和烟酸衍生物开始合成。
实施例28:N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(4-氨基哌啶-1-基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=8.74(d,J=2.0Hz,1H),8.33(s,1H),8.25(m,2H),8.08(dd,J=11.2,2.4Hz,1H),7.26(m,2H),6.89(d,J=9.2Hz,1H),5.25(br,s,2H),4.31(d,J=13.2Hz,2H),3.03(m,2H),2.89(m,1H),1.82(m,2H),1.19(m,2H).(-NH和-NH2丢失)。
HPLC-MS:Rt 8.144m/z 408.2(MH+)。
方案13:实施例29的合成
步骤1:3-硝基-6-(噻吩-2-基)吡啶-2-胺(中间体20)的合成
将中间体2(600mg)、噻吩-2-硼酸(533mg)、Cs2CO3(1.8g)、10ml 1,4-二烷和2ml水添加至3颈100mL圆底烧瓶中。将氮气直接鼓泡至混合物中20分钟。添加Pd(dppf)Cl2.CH2Cl2(140mg),并使混合物在氮气中于110℃下回流3h。用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,并分离出中间体20,为灰白色固体(300mg,78%产率)。
步骤2:6-(4-甲基哌嗪-1-基)-N-(3-硝基-6-(噻吩-2-基)吡啶-2-基)烟酰胺(中间体22)的合成
添加中间体21(597mg)的DMF(30ml)溶液、DIPEA(435mg)和TBTU(953mg),并使其在室温下搅拌1h。用水稀释反应混合物,并将形成的沉淀物过滤并干燥以获得酸酐。在-35℃下,缓慢添加中间体20(300mg)的THF(50ml)溶液、NaHMDS(2.7ml),并使其在相同温度下搅拌1h。向此溶液立即添加THF(5ml)中的酸酐,并使反应混合物升温至室温。完成后,用乙酸乙酯/水稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并在蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体22,为黄色固体(400mg,72%产率)。
步骤3:N-(3-氨基-6-(噻吩-2-基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺的合成。实施例29。
向中间体22(200mg)的甲醇/乙醇(20/3ml)和THF/乙酸乙酯(9/9ml)溶液添加Pd/C(10%)(40mg,20%(w/w)),并使反应在氢气(Balloon atm)下搅拌过夜。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的化合物,为浅橙色固体(25mg,13%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.23(s,1H),8.79(d,J=2.4Hz,1H),8.15(dd,J=11.6,2.4Hz,1H),7.61(d,J=8.4Hz,1H),7.52(dd,J=4.8,1.2Hz,1H),7.44(dd,J=6.0,1.2Hz,1H),7.22(d,J=8.0Hz,1H),7.08(m,1H),6.92(d,J=9.2Hz,1H),5.13(br,s,2H),3.65(t,J=4.4Hz,4H),2.40(t,J=4.8Hz,4H),2.22(s,3H)。
HPLC-MS:Rt 8.778m/z 395.1(MH+)。
方案14:实施例30的合成
步骤1:N-(6-(4-氟苯基)-3-硝基吡啶-2-基)-6-((2-(4-甲基哌嗪-1-基)乙基)氨基)烟酰胺(中间体23)的合成
向中间体16(500mg)的DMSO(20ml)和DIPEA(1.44ml,6eq.)溶液添加2-(4-甲基-哌嗪-1-基)-乙基-二氮烯(400mg)中,然后使反应在110℃下加热16h。此时间之后,用水和添加的乙酸乙酯稀释反应混合物。分离层,并用乙酸乙酯萃取水层。将有机层经硫酸镁干燥,过滤并蒸发至残余物。通过柱层析法纯化残余物,以获得所需的中间体23(250mg,42%产率)。
步骤2:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(4-甲基哌嗪-1-基)乙基)氨基)烟酰胺(实施例30)的合成
向中间体23(240mg)的乙醇(7.5ml)和水(2.5ml)溶液添加Fe(112mg)和NH4Cl(215mg),使反应在90℃下加热1h。通过TLC监测反应完成后,将反应混合物通过硅藻土过滤并蒸发至残余物。通过制备型HPLC纯化残余物,以获得所需的化合物,为浅黄色固体(21mg,10%产率)。
1H-NMR(400MHz,DMSO-d6):δ=10.12(s,1H),8.71(d,J=2.4Hz,1H),8.00(m,3H),7.65(d,J=8.4Hz,1H),7.26(m,3H),7.05(br,1H),6.55(d,J=8.8Hz,1H),5.11(br,s,2H),3.45(m,2H),2.67(m,3H),2.33(m,5H),2.18(s,3H)。
HPLC-MS:Rt 8.684m/z 450.2(MH+)。
以下实施例利用方案14所描述的程序,从相应的2-氯-N-(3-硝基吡啶-2-基)嘧啶-5-羧酰胺和胺衍生物开始合成。
实施例31:N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(吡啶-3-基)乙基)氨基)烟酰胺。
1H-NMR(400MHz,DMSO-d6)δ=10.13(s,1H),8.73(d,J=2.0Hz,1H),8.47(br,s,1H),8.42(d,J=4.0Hz,1H),8.00(m,2H),7.69(m,2H),7.34(m,2H),7.26(m,2H),6.53(d,J=8.8Hz,1H),5.12(br,s,2H),3.61(m,4H),2.91(br,s,2H)。
HPLC-MS:Rt 9.725m/z 429.1(MH+)。
Claims (17)
1.式(I)的化合物:
其中:
-X1和X2独立地表示选自-CH和N的基团;
-R1表示:
a)苯基基团,所述苯基基团任选地被选自卤素原子、直链或支链C1-C4卤代烷基基团、和直链或支链烷氧基的一个或多个取代基取代,
b)五元或六元杂芳基环,所述五元或六元杂芳基环任选地被选自卤素原子、直链或支链C1-C4烷氧基、氰基基团、直链或支链C1-C4卤代烷基、直链或支链C1-C3烷基、C3-C6环烷基、C3-C6环烷氧基和任选地被一个或多个卤素原子取代的C5-C6杂环状环的一个或多个取代基取代;
-R2表示选自下列的基团:
a)-N(R3)(R4)基团,其中:
1-R3和R4与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子作为环部分的五元或六元饱和杂环,所述五元或六元饱和杂环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代,其中R5和R6与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子作为环部分的、任选地被C1-C3烷基基团取代的五元或六元饱和杂环,或
2-R3和R4独立地表示选自氢原子、C3-C6环烷基基团和直链或支链C1-C3烷基的基团,所述基团任选地被包含选自N和O的一个或两个杂原子作为环部分的五元或六元杂环取代,所述五元或六元杂环任选地被直链或支链C1-C3烷基基团取代,
b)苯基环,所述苯基环任选地被选自卤素原子和氰基基团的一个或多个取代基取代,
c)C3-C6环烷基,所述C3-C6环烷基任选地被选自直链或支链C1-C3烷基和羟基基团的一个或多个取代基取代,
d)C5-C6杂芳基,所述C5-C6杂芳基任选地被选自卤素原子、直链或支链C1-C3烷基和直链或支链C1-C4烷氧基和-N(R5)(R6)基团的基团取代,其中R5和R6与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子作为环部分的、任选地被C1-C3烷基基团取代的五元或六元饱和环,
e)氢原子,
及其药学上可接受的盐。
2.根据权利要求1所述的化合物,其中X1和X2为-CH基团。
3.根据权利要求2所述的化合物,其中R1表示任选地被一个或多个卤素原子取代的苯基基团。
4.根据权利要求3所述的化合物,其中R2表示-N(R3)(R4)基团,其中R3和R4与其结合的氮原子一起形成任选地包含选自N和O的另外的杂原子作为环部分的五元或六元饱和杂环,所述杂环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代。
5.根据权利要求4所述的化合物,其中R2表示任选地被C1-C3烷基基团或-N(R5)(R6)基团取代的哌嗪基、哌啶基或吗啉基环。
6.根据权利要求1、2、4和5中任一项所述的化合物,其中R1表示任选地被选自氰基基团、卤素原子和直链或支链C1-C4卤代烷基的一个或多个取代基取代的五元或六元杂芳基环。
7.根据权利要求1至3中任一项所述的化合物,其中R2表示-N(R3)(R4)基团,其中R3和R4独立地表示选自氢原子、C3-C6环烷基基团和直链或支链C1-C3烷基的基团,所述基团任选地被包含一个或两个N原子的5元或6元饱和杂环取代,所述杂环任选地被C1-C3烷基基团取代,具体地其中R2表示-N(R3)(R4)基团,其中R3表示被包含一个或两个N原子的5元或6元饱和杂环取代的直链C1-C3烷基,所述5元或6元饱和杂环任选地被C1-C3烷基基团取代;并且R4为氢原子。
8.根据权利要求1至3中任一项所述的化合物,其中R2表示任选地被选自卤素原子和氰基基团的一个或多个取代基取代的苯基环。
9.根据权利要求1至3中任一项所述的化合物,其中R2表示任选地被选自卤素原子和氰基基团的一个或多个取代基取代的C5-C6杂芳基。
10.根据权利要求1所述的化合物,其中X1和X2为-CH基团,R1表示任选地被一个或多个卤素原子取代的苯基基团,并且R2表示-N(R3)(R4)基团,其中R3和R4与其结合的氮原子一起形成任选地包含选自N和O的杂原子的6元杂环,所述6元杂环任选地被C1-C3烷基基团或-N(R5)(R6)基团取代。
11.根据权利要求10所述的化合物,其中R2表示任选地被C1-C3烷基基团取代的哌嗪基环。
12.根据权利要求1所述的化合物,所述化合物为下列中的一种:
N-(3-氨基-6-苯基吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-苯基吡啶-2-基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)烟酰胺、
N-(3-氨基-6-苯基吡啶-2-基)-6-吗啉代烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-吗啉代烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-(4-甲氧基苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(5-氨基-[2,4'-联吡啶]-6-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-(3,4-二氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-苯基吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺、
N-(3-氨基-6-苯基吡啶-2-基)嘧啶-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)嘧啶-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-吗啉代嘧啶-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)嘧啶-5-羧酰胺、
N-(3-氨基-6-苯基吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-2-(环丙基氨基)嘧啶-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-苯基烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氟苯基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,4'-联吡啶]-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-[2,3'-联吡啶]-5-羧酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(3-氰基苯基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环丙基烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-环戊基烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(哌嗪-1-基)烟酰胺、
N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(哌嗪-1-基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-(4-氨基哌啶-1-基)烟酰胺、
N-(5-氨基-2-(4-氟苯基)嘧啶-4-基)-6-(4-氨基哌啶-1-基)烟酰胺、
N-(3-氨基-6-(噻吩-2-基)吡啶-2-基)-6-(4-甲基哌嗪-1-基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(4-甲基哌嗪-1-基)乙基)氨基)烟酰胺、
N-(3-氨基-6-(4-氟苯基)吡啶-2-基)-6-((2-(吡啶-3-基)乙基)氨基)烟酰胺。
13.权利要求1至12中任一项所限定的化合物,用于治疗疾病或病理状况,其中疾病或病理状况选自癌症,具体地选自结肠癌、肺癌、乳腺癌、诸如脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)和颅咽管瘤的中枢神经系统癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和选自急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤的T细胞恶性病;神经退行性疾病,具体地选自阿尔茨海默氏病、创伤后应激障碍或药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病、脊髓性和延髓性肌萎缩;感染性疾病;炎性疾病;心力衰竭和心脏肥厚;糖尿病;多囊肾病、镰状细胞病和β-地中海贫血病。
14.权利要求1至12中任一项所限定的化合物用于制备治疗疾病或病理状况的药物的应用,其中疾病或病理状况选自癌症,具体地选自结肠癌、肺癌、乳腺癌、诸如脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)和颅咽管瘤的中枢神经系统癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和选自急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤的T细胞恶性病;神经退行性疾病,具体地选自阿尔茨海默氏病、创伤后应激障碍或药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病、脊髓性和延髓性肌萎缩;感染性疾病;炎性疾病;心力衰竭和心脏肥厚;糖尿病;多囊肾病、镰状细胞病和β-地中海贫血病。
15.治疗疾病或病理状况的方法,所述疾病或病理状况选自癌症,具体地选自结肠癌、肺癌、乳腺癌、诸如脑膜瘤、成神经细胞瘤、成胶质细胞瘤、成神经管细胞瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、神经节神经胶质瘤、神经鞘瘤(Schwannomas)和颅咽管瘤的中枢神经系统癌、子宫颈癌、胰腺腺癌、肝细胞癌、胃癌、组织癌和选自急性髓样白血病、急性淋巴母细胞白血病、皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、B细胞淋巴瘤和多发性骨髓瘤的T细胞恶性病;神经退行性疾病,具体地选自阿尔茨海默氏病、创伤后应激障碍或药物成瘾、帕金森氏病、亨廷顿氏病、淀粉样-β(Aβ)毒性、弗里德赖希氏共济失调、肌强直性营养不良、脊髓性肌萎缩、脆性X综合征、脊髓小脑性共济失调、肯尼迪氏病、肌萎缩性侧索硬化、尼-皮二氏病、皮特-霍普金斯病、脊髓性和延髓性肌萎缩;感染性疾病;炎性疾病;心力衰竭和心脏肥厚;糖尿病;多囊肾病、镰状细胞病和β-地中海贫血病,所述方法包括向需要其的对象给予有效量的权利要求1至12中任一项所限定的化合物。
16.药物组合物,所述药物组合物包含权利要求1至12中任一项所限定的化合物、药学上可接受的稀释剂或载体、和任选地治疗有效量的一种或多种进一步治疗剂,所述进一步治疗剂选自化学治疗剂、抗炎剂、类固醇、免疫抑制剂、和治疗抗体。
17.组合产品,所述组合产品包含根据权利要求1至12中任一项所述的化合物和至少一种治疗剂,所述治疗剂选自化学治疗剂、抗炎剂、类固醇、免疫抑制剂、免疫治疗剂、治疗抗体和腺苷拮抗剂,具体地选自下列的那些:抗CTLA4抗体,选自伊匹木单抗和曲美木单抗;抗PD1抗体,如MDX-1106(纳武单抗)、MK3475(帕博利珠单抗)、CT-011(匹利珠单抗)和AMP-224;抗PDL1抗体,选自MPDL3280A、MEDI4736和MDX-1105;卡铂、卡莫司汀(BCNU)、顺铂、环磷酰胺、依托泊苷、伊立替康、洛莫司汀(CCNU)、甲氨蝶呤、丙卡巴肼、替莫唑胺、长春新碱。
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