CN105026398B - 用于治疗疾病诸如癌症的三唑并[4,5-d]嘧啶衍生物 - Google Patents
用于治疗疾病诸如癌症的三唑并[4,5-d]嘧啶衍生物 Download PDFInfo
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- CN105026398B CN105026398B CN201480012252.4A CN201480012252A CN105026398B CN 105026398 B CN105026398 B CN 105026398B CN 201480012252 A CN201480012252 A CN 201480012252A CN 105026398 B CN105026398 B CN 105026398B
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Abstract
式I的化合物,其中R1和R2具有在权利要求1中指出的含义,是GCN2的抑制剂,且尤其可以用于治疗癌症。
Description
背景技术
本发明的目的是发现新的具有有价值特性的化合物,特别是可以用于制备药物的那些化合物。
本发明涉及化合物和化合物在抑制、调控和/或调节由蛋白激酶(特别是免疫调节或应激反应激酶)引起的信号转导中的用途,此外,还涉及包含这些化合物的药物组合物和所述化合物用于治疗激酶诱导的疾病的用途。
因为蛋白激酶调节几乎每种细胞过程,包括代谢、细胞增殖、细胞分化和细胞存活,所以它们是各种疾病状态的治疗干预的有吸引力的靶标。例如,蛋白激酶在其中发挥关键作用的细胞周期控制、免疫调节、应激反应和血管生成是与许多疾病状况相关的细胞过程,所述疾病状况诸如但不限于:癌症,炎性疾病,神经变性疾病,慢性感染,异常血管生成和与其相关的疾病,动脉粥样硬化,黄斑变性,糖尿病,肥胖症和疼痛。
式I的化合物抑制被称为一般性调控阻遏蛋白激酶2(general controlnonderepressible 2) (GCN2)的应激反应eIF2激酶EIF2AK4。
实体瘤癌症治疗的许多策略集中在尽可能手术去除肿瘤块和随后通过放射疗法和用更特异性地靶向癌细胞途径的细胞毒素剂或抑制剂的化学疗法根除任何残留的肿瘤细胞。但是,这样的方法的成功受到限制,经常不持续。这主要是因为这样的细胞毒素剂的狭窄的治疗窗(特异性和副作用)和癌细胞适应通过细胞毒素剂或其它抑制剂施加的选择压力的能力。获得对初次治疗抵抗的少量肿瘤(干)细胞的存活可足以引发(seed)肿瘤的再生长。在大多数情况下,这些复发与起始肿瘤相比更难以治疗。因此,更成功的肿瘤细胞靶向可能需要平行靶向肿瘤细胞的多个存活和逃脱机制(Muller和Prendegast 2007)。
恶性肿瘤的发展伴有细胞生理学的较多参与。该过程期间,癌细胞获得数个特性,其是无限增殖化或对生长抑制信号不敏感的基础。此外,肿瘤细胞亦改变与微环境和微环境外的相互作用。后者区域包括肿瘤细胞从免疫监视逃脱的策略(Muller和Prendegast2007)。免疫监视限制恶性肿瘤生长,而且提供选择压力,其触发逃避免疫反应的机制的产生,如[Dunn等2004]综述。基本上已经常观察到除去T细胞免疫性足以增加肿瘤发生率[Shankaran等2001],并且认为免疫逃脱影响肿瘤相对于进展的休眠,促进侵袭和转移,并负面影响治疗反应。
数种机制研究发现,免疫逃脱与肿瘤微环境内的代谢改变具有重要关联。此处,在介导对抗原的免疫耐受性中的重要作用与必需氨基酸色氨酸和精氨酸的分解代谢相关,所述分解代谢分别通过酶吲哚胺2,3-双加氧酶(IDO)和精氨酸酶I (ARG)进行(Bronte和Zanovello, 2005; Muller等, 2005b; Muller和Prendergast, 2007; Munn和Mellor,2007; Popovic等, 2007)。
IDO是催化色氨酸降解成犬尿氨酸的单链氧化还原酶。IDO不负责将过量膳食色氨酸分解代谢,而是负责调节局部环境中色氨酸的水平。癌症患者中色氨酸分解代谢的升高表现为明显改变的色氨酸或分解代谢产物的血清浓度,并且这与通常在肿瘤和引流淋巴结中升高的IDO相关。按照数个出版物,IDO过表达与癌症的预后不良有关[Okamoto等2005;Brandacher等, 2006]。
T细胞显得优先对IDO活化敏感,使得当色氨酸饥饿时它们不能分裂,因此不能被呈递给它们的抗原激活。Munn和Mellor及其同事揭示,IDO通过阻抑T细胞活化和通过产生对肿瘤抗原的外周耐受性来调节免疫性(Mellor和Munn, 2004)。这些机制包括破坏通过肿瘤细胞募集到其邻近微环境或肿瘤-引流淋巴结的免疫细胞。此处,通过抗原呈递细胞清除的肿瘤抗原被交叉呈递到适应性免疫系统。除了直接具有耐受原性(toleragenic)之外,成熟的DC还具有扩增调节性T细胞(Treg)的能力[Moser 2003]。
除了色氨酸分解代谢外,精氨酸的转化在肿瘤调节的微环境中增加,并且大量报告表明精氨酸酶活化在肿瘤生长和发展期间的作用。在肿瘤侵润的髓系细胞中,通过精氨酸酶I (ARG1)、精氨酸酶II (ARG2)将精氨酸转化成脲和鸟氨酸,并通过一氧化氮合酶的可诱导形式(NOS2)将其氧化成瓜氨酸和一氧化氮(NO)。
经常在具有结肠癌、乳腺癌、肺癌和前列腺癌的患者中观察到增加的ARG活性[Cederbaum 2004],其与前列腺癌中发现的ARG和NOS的过表达有关[Keskinege等2001,Aaltoma等2001, Wang等2003]。表明ARG在侵润巨噬细胞中的活性损害抗原特异性的T细胞反应和CD3受体的表达。此外,ARG和NOS在肿瘤相关髓系细胞中的累积活性可产生对抗原特异性T淋巴细胞的抑制信号,其最终导致细胞凋亡[Bronte 2003 a; 2003b]。
IDO相关机制和ARG相关机制两者在感知各自氨基酸浓度的耗尽浓度的点合并。在氨基酸剥夺期间,称为一般性调控阻遏蛋白激酶2 (GCN2)的eIF2激酶EIF2AK4与细胞内聚集的脱酰tRNA相互作用。因此假定GCN2从自抑制型改变为活性构象,并进一步通过自磷酸化作用而活化。然后已知的唯一底物蛋白质eIF2a被磷酸化,因此翻译起始复合物受到抑制[Harding等2000]。这减少了一般性的Cap依赖性翻译起始,并且由此减少相应蛋白质的产生。另一方面,这主要通过cap依赖性起始经由活化转录因子4 (ATF4)而诱导应激相关靶基因的特异性表达。通过表达各自的应激反应蛋白,例如氨基酸代谢中的酶,细胞试图补偿具体的细胞应激[Wek等.2006]。如果应激持续,则所述途径将转换成经由促凋亡转录因子CCAAT/增强子结合蛋白同源蛋白(CHOP)的转录而促进细胞死亡[Oyadomari 2004]。显示色氨酸饥饿触发GCN2依赖性应激信号转导途径。在T细胞中,改变eIF2a磷酸化和翻译起始引起细胞生长停滞(Munn等2005)。Sharma等[2007]公开了成熟Treg的直接IDO诱导和GCN2依赖性的活化。类似地,Fallarino等[2006]发现GCN2依赖性转变CD4+CD25-细胞为产生IL-10和TGFβ的CD25+FoxP3+ Treg。Rodriguez等[2007]确定经由色氨酸或精氨酸耗尽与TCR信号转导联合的GCN2途径的活化导致CD3ζ链下调、细胞周期停滞和无反应性。
重要地是,GCN2途径不仅对肿瘤的免疫逃脱重要,而且在直接调节肿瘤存活中起到积极的作用。Ye等[2010]发现前述转录因子ATF4在人类实体瘤中过表达,表明在肿瘤进展中的重要作用。氨基酸和葡萄糖剥夺是实体瘤中存在的典型应激,并活化GCN2途径以上调氨基酸合成和转运中涉及的ATF4靶基因。与正常组织相比,在人类和小鼠肿瘤中观察到GCN2活化/过表达和磷酸-eIF2a增加,并且ATF4或GCN2表达的废除显著抑制体内肿瘤生长。结论是GCN2-eIF2a-ATF4途径对维持肿瘤细胞中的代谢稳态是关键的。
总体上,现有生物学通过适应性机制干扰对阻止肿瘤免疫逃脱有吸引力的ARG/IDO途径。此处,GCN2功能的干扰特别引人关注,因为它是两种途径(IDO和ARG)的合并点,以及它为直接阻碍肿瘤代谢提供另外的机会。
数种途径抑制剂已被考虑作为免疫调节剂。这些抑制剂主要靶向IDO或ARG蛋白质的酶功能(Muller和Scherle, 2006)。精氨酸酶抑制剂N-羟基-nor-L-Arg的施用阻止小鼠中s.c.3LL肺癌的生长[Rodriguez 2004]。已报道供给NO的阿司匹林类例如NCX 4016 (2-(乙酰基氧基)-苯甲酸3-(硝基氧基甲基)苯基酯)干扰髓系细胞的抑制性酶活性。口服施用NO阿司匹林将荷瘤宿主的免疫状态正常化,增加肿瘤-抗原-特异性T淋巴细胞的数量和功能,并且提高通过癌症疫苗接种引发的抗肿瘤免疫的预防和治疗有效性(DeSanto 2005)。
底物类似物1甲基-色氨酸(1MT)和相关分子在癌症背景和其它环境下已广泛用于靶向IDO。Friberg等(2002)和Uyttenhove等(2003)研究证实,1MT可限制过表达IDO的肿瘤生长。但是,在数个肿瘤模型中1MT不能引起肿瘤消退,表明当IDO抑制作为单一疗法应用时仅有适度的抗肿瘤功效。与此相反,1MT和各种细胞毒素化学治疗剂的组合治疗引起已建立的MMTV-neu/HER2肿瘤消退,所述肿瘤对任何单一药剂疗法反应差[Muller等2005a]。治疗前小鼠的CD4+或CD8+ T细胞的免疫耗竭废除了该模型中观察到的组合功效,证实了1MT间接通过T细胞介导的抗肿瘤免疫活化而起作用的预期。IDO靶向对1MT作用是必需的重要证据通过以下论证来提供:在IDO遗传缺陷的小鼠中1MT缺少抗肿瘤活性[Hou等, 2007]。
GCN2的抑制使得能够合并氨基酸饥饿诱导的免疫编辑的两条途径分支,并减少肿瘤防止任一分支的抑制的选择。此外,如上文详述,GCN2抑制提供干扰肿瘤代谢的机会,其同时可增强单一疗法或与其它抗癌方法的组合疗法的功效。
如上文所述,eIF2激酶GCN2通过与脱酰tRNA相互作用而活化,所述脱酰tRNA直接因为营养剥夺应激而累积。其它细胞应激因素例如UV辐照、氧化还原应激或蛋白酶体抑制可间接诱导GCN2活化[Wek等2006]。在所有已知的情况下,eIF2a被磷酸化,这主要通过cap非依赖性起始经由活化转录因子4 (ATF4)诱导应激相关靶基因的特异性表达。
Mitsuda等(2007)表明,早老因子-1通过活化转录因子4 (ATF4)(其受GCN2调节)而被诱导。大脑皮层中由γ-分泌酶自淀粉样蛋白前体蛋白产生的淀粉样蛋白-β(Aβ)的积聚是阿尔茨海默氏病中的常见和关键事件。特别是,早老因子是γ-分泌酶活性所必需的。Ohata等(2010)描述GCN2-eIF2α-ATF4信号转导在调节γ-分泌酶在自噬受损细胞中的活性中的作用:因为自噬作用是维持氨基酸水平所必需的,所以自噬-溶酶体系统的受损可引起细胞中氨基酸失调。自噬-溶酶体系统被论述为通过GCN2的γ-分泌酶活性的重要调节剂,在自噬退化中引起Aβ积聚,其可以是减少Aβ产生的可能治疗靶标。γ-分泌酶在阿尔茨海默氏病(AD)的发生中起重要作用。γ-分泌酶活性富集在自噬泡中,并且其增加淀粉样蛋白-β(Aβ)合成。
老年斑主要由源自于淀粉样蛋白前体蛋白(APP)的β-淀粉样蛋白肽(Aβ)组成,所述APP已经过通过β-分泌酶(BACE-1)和γ-分泌酶的蛋白水解加工。O'Connor等(2008)发现,BACE-1水平在翻译上通过eIF2α的磷酸化而增加。
在促进γ-分泌酶活化或BACE-1诱导而造成脑中Aβ积聚和斑形成的这样的疾病条件下,GCN2的抑制将提供有价值的途径以调节或甚至终止神经变性疾病的进展。
描述了持续而非急性的寄生虫或病毒感染与甚至对感染生物体或颗粒有免疫活性的宿主的免疫赦免的状况的建立有关。这与局部诱导IDO表达有关。Makala等(J InfectDis. 2011年3月1日;203(5):715-25)表明,皮肤硕大利什曼原虫感染刺激免疫调节酶吲哚胺2,3双加氧酶(IDO)在局部淋巴结中的表达。诱导的IDO减弱树突细胞的T细胞刺激功能,并阻抑对外源和名义的(nominal)寄生虫抗原的局部T细胞反应。IDO的除去减少了局部炎症和寄生虫负荷,这如同在建立的感染的小鼠中IDO的药理学抑制。de Souza Sales (Clin Exp Immunol. 2011年8月;165(2):251-63)确证吲哚胺2,3-双加氧酶在瘤型麻风免疫抑制中的作用。Boasso等(Blood.2007年4月15日;109(8):3351-9)发现HIV通过在浆细胞样树突细胞中诱导吲哚胺2,3-双加氧酶抑制CD4+ T细胞增殖,并且IDO的体外抑制导致在HIV感染的患者的PBMC中CD4(+) T细胞增殖反应增加。
IDO/GCN2途径的抑制药物可用于增强宿主对慢性和持续性感染的免疫。
文献:
1.Aaltoma, S.H., P.K.Lipponen和V.M.Kosma.2001.Inducible nitric oxidesynthase (iNOS) expression and its prognostic value in prostate cancer.Anticancer Res.21:3101-3106.
2.Brandacher, G.; Perathoner, A.; Ladurner, R.; Schneeberger, S.;Obrist, P.; Winkler, C.; Werner, E.R.; Werner-Felmayer, G.; Weiss, H.G.;Gobel, G.; Margreiter, R.; Konigsrainer, A.; Fuchs, D.; Amberger,A.Prognostic value of indoleamine 2,3- dioxygenase expression in colorectalcancer: effect on tumorinfiltrating T cells .Clin.Cancer Res.2006, 12, 1144-1151.
3.Bronte V, Zanovello P.(2005).Regulation of immune responses by L-arginine metabolism .Nat Rev Immunol 5: 641-654.
4.Bronte, V., P.Serafini, C.De Santo, I.Marigo, V.Tosello, A.Mazzoni,D.M.Segal, C.Staib, M.Lowel, G.Sutter等2003a.IL-4- induced arginase 1suppresses alloreactive T cells in tumor-bearing mice .J.Immunol.170:270-278.
5.Bronte, V., P.Serafini, A.Mazzoni, D.M.Segal和P.Zanovello.2003b.L-arginine metabolism in myeloid cells controls T-lymphocyte functions .TrendsImmunol.24:302-306
6.Carmela De Santo, Paolo Serafini, Ilaria Marigo, Luigi Dolcetti,Manlio Bolla,§Piero Del Soldato, Cecilia Melani, Cristiana Guiducci, MarioP.Colombo, Manuela Iezzi, Piero Musiani, Paola Zanovello和VincenzoBronte.Nitroaspirin corrects immune dysfunction in tumor-bearing hosts andpromotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U SA.2005年3月15日; 102(11): 4185-4190
7.Cederbaum, S.D., H.Yu, W.W.Grody, R.M.Kern, P.Yoo和R.K.Iyer.2004.Arginases I and II: do their functions overlap?Mol.Genet.Metab.81:S38-44.
8.T.O'Connor, K.R.Sadleir, E.Maus, R.A.Velliquette, J.Zhao, S.L.Cole,W.A.Eimer, B.Hitt, L.A.Bembinster, S.Lammich, S.F.Lichtenthaler, S.S.Hebert,S.B.De, C.Haass, D.A.Bennett, R.Vassar, Phosphorylation of the translationinitiation factor eIF2alpha increases BACE1 levels and promotesamyloidogenesis .Neuron, 60 (2008), 第988-1009页
9.Dey, M., Cao, C., Sicheri, F.和T.E.Dever.Conserved IntermolecularSalt Bridge Required for Activation of Protein Kinases PKR, GCN2, and PERK.JBC 282(9): 6653, 2007.
10.Dunn, G.P.; Old, L.J.; Schreiber, R.D.The immunobiology of cancerimmunosurveillance and immunoediting .Immunity 2004, 21, 137-148.
11.Fallarino, F.U.Grohmann, S.You, B.C.等The combined effects fotryptophan starvation and tryptophan catabolites down-regulate T cellreceptor zeta-chain and induce a regulatory phenotype in naïve T cells.J.Immunol.176:6752, 2006.
12.Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A,Extermann M等(2002).Indoleamine 2,3-dioxygenase contributes to tumor cellevasion of T cell-mediated rejection .Int.J Cancer 101: 151-155
13.Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, RonD.Regulated translation initiation controls stress-induced gene expression inmammalian cells. Mol Cell.2000年11月;6(5):1099-108.
14.Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M等(2007).Inhibition of indoleamine 2,3-dioxygenase in dendritic cells bystereoisomers of 1-methyl-tryptophan correlates with antitumor responses.Cancer Res 67: 792-801.
15.Keskinege, A., S.Elgun和E.Yilmaz.2001.Possible implications ofarginase and diamine oxidase in prostatic carcinoma. Cancer Detect.Prev.25:76-79.
16.Mellor AL, Munn DH.(2004).IDO expression by dendritic cells:tolerance and tryptophan catabolism .Nat Rev Immunol 4: 762-774.
17.Mitsuda T, Hayakawa Y, Itoh M, Ohta K, Nakagawa T.ATF4 regulatesgamma-secretase activity during amino acid imbalance , Biochem Biophys ResCommun.2007 Jan 19;352(3):722-7.
18.Moser, M. Dendritic cells in immunity and tolerance-do theydisplay opposite functions? Immunity 2003, 19, 5-8.
19.Muller, A.J.和P.A.Scherle. Targeting the mechanisms of tumoralimmune tolerance with small-molecule inhibitors. Nat.Rev.Cancer.6:613, 2006.
20.Muller AJ, Prendergast GC.(2007).Indoleamine 2,3-dioxygenase inimmune suppression and cancer. Curr Cancer Drug Targets 7: 31-40.
21.Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, PrendergastGC.(2005a).Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatorytarget of the tumor suppressor gene Bin1, potentiates cancer chemotherapy.Nature Med 11: 312-319.
22.Muller AJ, Malachowski WP, Prendergast GC.(2005b).Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors .Expert Opin Ther Targets 9: 831-849.
23.Munn, D.H., M.D.Sharma, B.Baban, H.P.Harding, Y.Zhang, D.Ron,A.L.Mellor.GCN2 kinase in T cells mediates proliferative arrest and anergyinduction in response to indoleamine 2,3-dioxygenase .Immunity.22:633, 2005
24.Ohta K, Mizuno A, Ueda M, Li S, Suzuki Y, Hida Y, Hayakawa-Yano Y,Itoh M, Ohta E, Kobori M, Nakagawa T.Autophagy impairment stimulates PS1expression and gamma-secretase activity .Autophagy.2010 ;6(3):345-52
25.Okamoto, A.; Nikaido, T.; Ochiai, K.; Takakura, S.; Saito, M.;Aoki, Y.; Ishii, N.; Yanaihara, N.; Yamada, K.; Takikawa, O.; Kawaguchi, R.;Isonishi, S.; Tanaka, T.; Urashima, M.Indoleamine 2,3-dioxygenase serves as amarker of poor prognosis in gene expression profiles of serous ovarian cancercells .Clin.Cancer Res.2005, 11, 6030-6039.
26.Oyadomari S, Mori M.Roles of CHOP/GADD153 in endoplasmic reticulumstress. Cell Death Differ.2004年4月;11(4):381-9.
27.GC Prendergast, Immune escape as a fundamental trait of cancer:focus on IDO .Oncogene (2008) 27, 3889-3900
28.Popovic PJ, Zeh III HJ, Ochoa JB.(2007).Arginine and immunity .JNutr 137: 1681S-1686 S.
29.Rodriguez, P.C., D.G.Quiceno, J.Zabaleta, B.Ortiz, A.H.Zea,M.B.Piazuelo,A.Delgado, P.Correa, J.Brayer, E.M.Sotomayor, S.Antonia,J.B.Ochoa和A.C.Ochoa.Arginase I Production in the Tumor Microenvironment byMature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-SpecificT-Cell Responses. Canc.Res.64:5839, 2004
30.Rodriguez, P.C., D.G.Quiceno和A.C.Ochoa.L-arginine availabilityregulates T-lymphocyte cell-cycle progression .Blood.109:1568, 2007.
31.Shankaran, V.; Ikeda, H.; Bruce, A.T.; White, J.M.; Swanson, P.E.;Old, L.J.; Schreiber, R.D.IFNgamma and lymphocytes prevent primary tumourdevelopment and shape tumour immunogenicity .Nature 2001, 410, 1107-1111.
32.Sharma, M.D., B.Baban, P.Chandler, D-Y.Hou, N.Singh, H.Yagita,M.Azuma, B.R.Blazar, A.L.Mellor和D.H.Munn.Plasmacytoid dendritic cells frommouse tumor-draining lymph nodes directly activate mature Tregs viaindoleamine 2,3-dioxygenase .J.Clin.Invest.117:2570, 2007.
33.Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D,Parmentier N等(2003).Evidence for a tumoral immune resistance mechanism basedon tryptophan degradation by indoleamine 2,3- dioxygenase .Nat Med 9: 1269-1274
34.Wang, J., M.Torbenson, Q.Wang, J.Y.Ro和M.Becich.2003.Expression ofinducible nitric oxide synthase in paired neoplastic and non-neoplasticprimary prostate cell cultures and prostatectomy specimen.Urol.Oncol.21:117-122.
35.Wek RC, Jiang HY, Anthony TG.Coping with stress: eIF2 kinases andtranslational control.Biochem Soc Trans.2006年2月;34 (Pt 1):7-11.
36.Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN,Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C.The GCN2-ATF4 pathway iscritical for tumour cell survival and proliferation in response to nutrientdeprivation.EMBO J.2010年6月16日;29(12):2082-96。
具体而言,本发明涉及化合物并涉及化合物的用途,其中通过GCN2的信号转导的抑制、调控和/或调节起作用。
因此,通过免疫调节或应激反应激酶(特别是GCN2)特异性地抑制、调控和/或调节信号转导的小化合物的合成是合乎需要的,并且是本发明的目的。
此外,本发明的目的是合成用于预防和治疗恶性肿瘤、神经变性疾病和慢性感染的新化合物,所述肿瘤包括、但不限于实体瘤癌症、淋巴或血液系统的癌症。
已发现,本发明的化合物和其盐具有非常有价值的药理学性质,同时被良好地耐受。
此外,式I的化合物可用于分离和研究GCN2的活性或表达。此外,它们特别适合用于与GCN2活性失调或干扰相关的疾病的诊断方法。
优选除了对GCN2的抑制活性之外,式I的化合物还可抑制酪氨酸激酶FMS(CSF1R)、GSK3α、GSK3β、FLT3或FLT4或这些激酶的组合。
Fms样酪氨酸激酶3 (FLT3),其亦称为FLK-2 (胎儿肝激酶2)和STK-I (干细胞激酶1),在造血干细胞的增殖和分化中起重要作用。在超过80%的骨髓性患者的细胞中和急性成淋巴细胞性白血病细胞的部分细胞中FLT3受体激酶以极高水平表达。此外,所述酶还可存在于处于淋巴原始细胞危象的患慢性髓性白血病的患者的细胞上。已报道,FLT3激酶在30%的急性髓样白血病(AML)中以及在急性成淋巴细胞性白血病(ALL)的亚组中发生突变(Gilliland等, Blood 100, 1532-1542 (2002); Stirewalt等, Nat.Rev.Cancer, 3,650-665 (2003)。FLT3突变的活化突变与预后差有关(Malempati等, Blood, 104, 11(2004)。FLT3抑制剂正在开发中,并且一些已显示对AML有前景的临床效果(Levis等Int.J.Hematol, 52, 100- 107 (2005)。
已报道小分子FLT3抑制剂中的一些有效诱导具有FLT3-活化突变的细胞系的细胞凋亡,并延长在其骨髓细胞中表达突变型FLT3的小鼠的存活(Levis等, Blood, 99, 3885-3891 (2002); Kelly等, Cancer Cell, 1, 421-432 (2002); Weisberg等, CancerCell, 1, 433-443 (2002); Yee等, Blood, 100, 2941-2949 (2002)。
美国专利申请20090054358描述了用于免疫抑制和特别用于治疗免疫相关病症的Flt3抑制剂,所述病症例如器官排斥、骨髓移植排斥、非骨髓根除性骨髓移植排斥、强直性脊椎炎、关节炎、再生障碍性贫血、贝切特氏病、1型糖尿病、移植物抗宿主病、格雷夫斯氏病、自身免疫性溶血性贫血、韦格纳氏肉芽肿病、高IgE综合征、特发性血小板减少性紫癜、类风湿性关节炎、克罗恩病、多发性硬化、重症肌无力、银屑病和狼疮(除了其它自身免疫疾病之外)。Flt3抑制剂还可用于治疗神经学病症例如神经变性疾病,例如由轴突变性引起的疾病。神经变性疾病包括例如多发性硬化;脱髓鞘核病症(demyelinating core disorder)例如多发性硬化、急性横贯性脊髓炎,但不限于此。
Scott等(Bioorg.Med Chem Let.(2008) 18 (17)第4794页)描述了用于治疗癌症的CSF-1R抑制剂。CSF-1R是III类受体酪氨酸激酶的成员。集落刺激因子1 (CSF-1),亦称为巨噬细胞/单核细胞集落刺激因子(M-CSF),与CSF-1R结合,导致二聚作用、自磷酸化作用和信号转导的活化。CSF-1/CSF-1R信号转导是正常单核细胞发育所必需的。在癌症中,已鉴定出促肿瘤发生巨噬细胞,并且其与乳腺癌、卵巢癌和前列腺癌中预后差有关。已报道在数种肿瘤类型中CSF-1和CSF-1R水平升高,所述肿瘤类型包括乳腺癌、卵巢癌和子宫内膜癌,并且所述升高还与侵袭和转移有关。因此,CSF-1R活性的抑制可通过降低肿瘤相关巨噬细胞(TAM)的水平而对肿瘤具有多重作用,并且可对肿瘤自身具有直接作用(C.E.Lewis,J.W.Pollard, Cancer Res., 66 (2006), 第605页; I.Bingle, N.等, J.Pathol., 196(2002), 第254页; B.M.Kacinski, Ann.Med., 27 (1995), 第79页; E.Garwood等J ClinOncol 26: 2008)。
Su JL等(Cancer Cell.2006年3月;9(3):209-23)报道VEGF-C/Flt-4轴(axis)促进癌细胞的侵袭和转移。Flt-4,一种VEGF受体,经其特异性配体VEGF-C活化。所产生的信号转导途径促进血管产生和/或淋巴管产生。VEGF-C/Flt-4轴提高癌细胞移动性和侵袭性,并有助于促进癌细胞转移。各种类型癌症的肿瘤组织检查揭示了与临床转移和患者存活率紧密相关的高水平Flt-4和VEGF-C表达。Flt-4激酶的抑制可降低在不同类型癌症中的侵袭能力。
组合对GCN2的抑制特异性和对FMS (CSF1R)、FLT3或FLT4或这些激酶的组合的抑制特异性,可具有治疗不同疾病阶段的恶性肿瘤的特别优势。它可以组合刺激对癌/肿瘤细胞的免疫反应的作用,以降低肿瘤相关巨噬细胞的水平,以及癌症对转移形成的侵袭能力。在又一方面,对GCN2的抑制活性特别与FLT3的抑制的组合可有利于治疗神经变性病症,因为它可通过调节脑中蛋白沉积的产生而对炎性过程具有协同抑制作用。在另一方面,对GCN2的抑制活性特别与FLT3的抑制的组合可提供调节免疫反应以治疗免疫相关病症和炎性或自身免疫疾病的优势。
在另一个实施方案中,本发明特别涉及抑制、调控和/或调节通过GCN2、FMS(CSF1R)、GSK3α、GSK3β、FLT3或FLT4或这些激酶的组合的信号转导的式I的化合物,涉及包含这些化合物的组合物,并且涉及其用于治疗受GCN2、FMS (CSF1R)、GSK3α、GSK3β、FLT3或FLT4或这些激酶的组合诱导或调节的疾病和病患的方法。
本发明的另一目的是合成用于预防和治疗恶性肿瘤(包括、但不限于实体瘤癌症、淋巴或血液系统的癌症)、神经变性疾病、免疫相关病症(例如关节炎、银屑病、狼疮、多发性硬化或其它自身免疫疾病)以及慢性感染的新化合物。
式I的化合物可进一步用于分离和研究GCN2、FMS (CSF1R)、GSK3α、GSK3β、FLT3或FLT4的活性或表达。此外,它们特别适合用于与GCN2、FMS (CSF1R)、GSK3α、GSK3β、FLT3或FLT4活性失调或干扰相关的疾病的诊断方法。宿主或患者可属于任何哺乳动物物种,例如灵长类物种,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、牛、狗、猫等。动物模型具有实验研究的益处,提供用于治疗人类疾病的模型。
可通过体外测试来测定具体细胞对用本发明化合物治疗的易感性。通常将细胞培养物与各种浓度的本发明化合物混合一段时间,所述时间足以允许活性剂例如抗IgM诱导细胞反应例如表面标记物的表达,通常在约1小时和1周之间。可使用来自血液或来自活组织检查样本的培养细胞进行体外测试。所表达的表面标记物的量通过流式细胞术使用识别所述标记物的特异性抗体来评价。
剂量根据所用的具体化合物、具体疾病、患者状态等而改变。治疗剂量通常足以显著减少靶组织中不需要的细胞群,同时患者的生存力得以维持。治疗通常持续直至出现显著减少,例如细胞负荷减少至少约50%,并且治疗可持续直至体内基本不再检测出不需要的细胞。
为鉴定信号转导途径和检测各种信号转导途径间的相互作用,许多科学家已开发了合适的模型或模型系统,例如细胞培养模型(例如Khwaja等, EMBO, 1997, 16, 2783-93)和转基因动物模型(例如White等, Oncogene, 2001, 20, 7064-7072)。为了测定信号转导级联中的某些阶段,可利用相互作用化合物以调节信号(例如Stephens等,Biochemical J., 2000, 351, 95-105)。本发明化合物还可用作用于在动物和/或细胞培养模型中或在本申请提及的临床疾病中测试激酶依赖性信号转导途径的试剂。
激酶活性的测量是本领域技术人员熟知的技术。使用底物例如组蛋白(例如Alessi等, FEBS Lett. 1996, 399, 3, 第333-338页)或碱性髓鞘蛋白测定激酶活性的通用测试系统描述于文献中(例如Campos-González, R.和Glenney, Jr., J.R. 1992, J.Biol. Chem. 267, 第14535页)。
为鉴定激酶抑制剂,可利用各种测定系统。在闪烁迫近测定(Sorg等,J.of.Biomolecular Screening, 2002, 7, 11-19)和闪烁板测定中,测量作为底物的蛋白或肽经γATP的放射性磷酸化。在存在抑制性化合物的情况下,可检测出放射性信号降低或根本没有放射性信号。此外,均相时间分辨荧光共振能量转移(HTR-FRET)和荧光偏振(FP)技术适于作为测定方法(Sills等, J.of Biomolecular Screening, 2002, 191-214)。
其它非放射性ELISA测定法使用特异性磷酸-抗体(磷酸-AB)。磷酸-AB只结合磷酸化的底物。该结合可通过化学发光使用第二过氧化物酶缀合的抗绵羊抗体检测(Ross等,2002, Biochem.J.)。
此外,式I的化合物会抑制GSK3α和GSK3β(糖原合酶激酶-3α和β)。
GSK3抑制剂会抑制乳腺癌细胞生长并从而为对基于激素的疗法具有抗性的乳腺癌提供创新方案(H.M. Kim等, PLoS One, 2013; 8(4):e60383)。
C. Fionda等, J. Immunol. 2013年6月15日; 190(12):6662-72)报道了GSK3抑制剂的抗骨髓瘤活性。
E. Grissilli等, Clin. Cancer Res. 2013年7月15日; 19(14):3820-31报道了GSK3抑制剂的抗结肠癌活性。
S.V. Madhunapantula等, Pigment Cell Melanoma Res. 2013年8月19日doi:10.1111/pcmr.12156报道了GSK3α和GSK3β抑制剂的抗骨髓瘤活性。
GSK3已经涉入不同的疾病诸如糖尿病、炎症、癌症、阿尔茨海默氏病和双相型障碍。GSK3负调节胰岛素介导的糖原合成和葡萄糖体内稳态,并且已经在II型糖尿病和肥胖动物模型中报道了增加的GSK3的表达和活性(Geetha Vani Rayasam等, British Journalof Pharmacology (2009), 156, 885-898)。
现有技术
在WO 2005/012307 A1和WO 2006/075023 A2中将三唑并嘧啶衍生物描述为用于治疗疾病如阿尔茨海默氏病或糖尿病的GSK3抑制剂。
发明内容
本发明涉及式I的化合物及其可药用的衍生物、溶剂合物、盐、互变异构体和立体异构体,包括它们的所有比例的混合物
其中
R1表示Ar或Het,
R2表示具有1-7个C-原子的直链或支链烷基,其中2个邻近碳原子可以形成双键或三键,且其可以被Hal单-、二-、三-、四-或五-取代,和/或其可以被OR3、N(R3)2、Het1、CN、COOR3、OCOOR3、CONH2、CONHA、CONA2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet1、O[C(R3)2]mN(R3)2、O[C(R3)2]pHet1、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet1、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet1、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet1和/或COA单取代或二取代,
或者
表示具有3-7个C-原子的环烷基或环戊烯基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、O[C(R3)2]pN(R3)2、[C(R3)2]pAr、[C(R3)2]pHet1、O[C(R3)2]pHet1、CN、[C(R3)2]pCOOR3、O[C(R3)2]pCOOR3、CONH2、CONHA、CONA2、[C(R3)2]pNR3COA、CONR3SO2A、NR3SO2A、SO2N(R3)2、S(O)nA、COHet1、O[C(R3)2]mN(R3)2、[C(R3)2]pNR3COOA、[C(R3)2]pNR3COOCH2Ph、NR3CON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet1、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet1、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet1、CONH(CH2)pHet2、CONR3NR3COA、CONR3N(R3)2、CONHCyc、COA、=S、=NR3和/或=O单取代或二取代,
或者
表示哌啶基、四氢吡喃基、吡咯烷基、氮杂环丁基、硫杂环戊烷基、氧杂环丁基、3-氮杂-二环[3.1.0]己基、四氢噻吩基、四氢噻喃基、4,5,6,7-四氢-1H-吲唑-5-基、4,5,6,7-四氢-1H-吲唑-6-基、四氢吡唑基、四氢呋喃基或六氢哒嗪基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pAr、[C(R3)2]pHet1、[C(R3)2]pHet3、CN、[C(R3)2]pCOOR3、CO[C(R3)2]pN(R3)2、CO[C(R3)2]pHet1、CO[C(R3)2]pHet3、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet1、O[C(R3)2]mN(R3)2、O[C(R3)2]pHet1、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet1、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet1、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet1、C(O)R3、=S、=NR3和/或=O单取代或二取代,
R3表示H或具有1-6个C-原子的直链或支链烷基,
Ar表示苯基或萘基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、O[C(R3)2]pN(R3)2、[C(R3)2]pHet1、[C(R3)2]pHet3、NO2、CN、[C(R3)2]pCOOR3、O[C(R3)2]pCOOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet1、O[C(R3)2]pHet1、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet1、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet1、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet1、S(O)nHet1、CHO和/或COA单-、二-或三-取代,
或表示薁基(azulenyl),
Het表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基、吲嗪基、噌啉基、喹啉基、异喹啉基、苯并噁唑基、1,3-苯并间二氧杂环戊烯基、苯并噻吩基、苯并呋喃基、咪唑并吡啶基、二氢吲哚基、喹喔啉基、咪唑并[1,2-a]吡啶基、苯并[1,2,5]噻二唑基、萘啶基、2,3-二氢-苯并[1,4]二氧杂环己烯基、喹唑啉基、苯并噻唑基或呋喃并[3,2-b]吡啶基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、O[C(R3)2]pN(R3)2、[C(R3)2]pHet1、NO2、CN、[C(R3)2]pCOOR3、O[C(R3)2]pCOOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet1、O[C(R3)2]pHet1、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet1、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet1、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet1、S(O)nHet1、CHO、COA、=S和/或=O单取代或二取代,
Het1表示吡唑基、哒嗪基、吡啶基、噁唑基、异噁唑基、噁二唑基、吡嗪基、吲哚基、二氢吡咯基、吡咯烷基、氮杂环丁基、氧杂环丁基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢呋喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、四氢吡喃基或哌嗪基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pHet2、NO2、[C(R3)2]pCN、[C(R3)2]pCOOR3、O[C(R3)2]pCOOR3、[C(R3)2]pCON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet2、O[C(R3)2]mN(R3)2、O[C(R3)2]pHet2、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet2、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet2、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet2、S(O)nHet2、CHO、COA、=S和/或=O单取代或二取代,
Het2表示吡唑基、噁二唑基、吡啶基、三唑基、四唑基、哒嗪基、吡咯烷基、氮杂环丁基、氮杂氧杂环丁基、四氢咪唑基、四氢吡唑基、四氢呋喃基、哌啶基、吗啉基、四氢吡喃基或哌嗪基,其中的每一个是未被取代的或被Hal、A、OA、CN、COOA、CONH2、S(O)nA、S(O)nAr、COA和/或=O单取代或二取代,
Het3表示吡唑基、吡啶基、嘧啶基或吡嗪基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pHet2、NO2、CN、[C(R3)2]pCOOR3、O[C(R3)2]pCOOR3、CON(R3)2、NR3COA、NR3SO2A、SO2N(R3)2、S(O)nA、COHet2、O[C(R3)2]mN(R3)2、O[C(R3)2]pHet2、NHCOOA、NHCON(R3)2、NHCOO[C(R3)2]mN(R3)2、NHCOO[C(R3)2]pHet2、NHCONH[C(R3)2]mN(R3)2、NHCONH[C(R3)2]pHet2、OCONH[C(R3)2]mN(R3)2、OCONH[C(R3)2]pHet2、S(O)nHet2、CHO、COA、=S和/或=O单取代或二取代,
Ph表示苯基,
Cyc表示具有3-7个C-原子的环烷基,其可以被OH单取代或二取代,
A表示具有1-10个C-原子的直链或支链烷基,其中1、2或3个不相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子替换,且其中1-7个H-原子可以被OH、F和/或Cl替换,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4。
本发明还涉及这些化合物的光学活性形式(立体异构体)、对映异构体、外消旋体、非对映异构体以及水合物和溶剂合物。
本发明还涉及式I的化合物的盐的溶剂合物,例如盐酸盐的一水合物或二水合物。
此外,本发明涉及式I的化合物的药学上可接受的衍生物。
术语化合物的溶剂合物用于指惰性溶剂分子加合至化合物上,其因它们互相的吸引力而形成。溶剂合物为例如一水合物或二水合物或醇化物。
术语药学上可接受的衍生物用于指例如本发明化合物的盐以及所谓的前药化合物。
如本文所用并除非另有说明,术语“前药”意指式I的化合物的衍生物,其可在生物条件(体外或体内)下水解、氧化或以其它方式反应,以提供活性化合物、特别是式I的化合物。前药的例子包括、但不限于式I的化合物的衍生物和代谢产物,包括生物可水解的基团例如生物可水解的酰胺、生物可水解的酯、生物可水解的氨基甲酸酯、生物可水解的碳酸酯、生物可水解的酰脲和生物可水解的磷酸酯类似物。在某些实施方案中,带有羧基官能团的化合物的前药是羧酸的低级烷基酯。羧酸酯通过使分子上存在的任何羧酸基团酯化而方便地形成。可通常使用熟知的方法制备前药,所述方法例如描述于Burger的MedicinalChemistry and Drug Discovery第六版(Donald J.Abraham主编, 2001, Wiley)和Designand Application of Prodrugs (H.Bundgaard主编, 1985, Harwood AcademicPublishers Gmfh)的那些。
表述“有效量”表示药物或药学上的活性成分的量,其在组织、系统、动物或人类中引起例如研究者或医师所寻找或需要的生物学或医学反应。
此外,表述“治疗上的有效量”表示与没有接受该量的相应对象相比,具有下列结果的量:
改善治疗、治愈、预防或消除疾病、综合症、状况、病患、病症或副作用,以及减少疾病、病患或病症的发展。
表述“治疗有效量”还包括有效增加正常生理功能的量。
本发明还涉及式I的化合物的混合物、例如两种非对映异构体的混合物、例如比例为1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的两种非对映异构体的混合物的用途。
这些特别优选是立体异构体化合物的混合物。
“互变异构体”是指彼此处于平衡的化合物异构形式。异构形式的浓度取决于化合物存在的环境,并且可以根据例如化合物是固体还是在有机或水溶液中而不同。
本发明涉及式I的化合物及其盐,并且涉及式I的化合物及其可药用的盐、溶剂合物、互变异构体和立体异构体的制备方法,其特征在于,
使式II的化合物
其中R1具有在权利要求1中指出的含义,
与式III的化合物反应
R2-NH2 III
其中R2具有在权利要求1中指出的含义
和/或
将式I的碱或酸转化成它的盐之一。
在上文和下文中,基团R1和R2具有关于式I指出的含义,除非明确地另外说明。
对于所有出现超过一次的基团,它们的含义彼此独立。
A表示烷基,其是直链的(线性的)或支链的,且具有1、2、3、4、5、6、7、8、9或10个C原子。A优选地表示甲基,此外表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外也表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,进一步更优选地表示例如三氟甲基。
A非常特别优选地表示具有1、2、3、4、5或6个C原子的烷基,优选地表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
此外,A表示例如CH2OCH3、CH2CH2OH、OCH2CH2NH2、CH2NHCH2或NHCH2CH3。
具有3-7个C-原子的环烷基优选地表示环丙基、环丁基、环戊基、环己基或环庚基。
R1特别优选地表示4-甲氧基苯基、4-乙氧基苯基、4-[1-(2-羟基乙基)吡唑-4-基]苯基、4-[1-(2-甲氧基乙基)吡唑-4-基]苯基、2-甲基-喹啉-6-基、4-(2-甲氧基-乙氧基)苯基、4-(2-甲氧基-1-甲氧基甲基-乙氧基)苯基、4-(四氢-吡喃-4-基氧基)苯基或4-(3-羟基-3-甲基-丁氧基)苯基。
R2优选地表示具有1-7个C-原子的直链或支链烷基,其中2个邻近碳原子可以形成双键或三键,且其可以被Hal单-、二-、三-、四-或五-取代,和/或其可以被CN、CONH2、CONHA、CONA2和/或O[C(R3)2]mN(R3)2单取代或二取代,
或者
优选地表示具有3-7个C-原子的环烷基或环戊烯基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pAr、[C(R3)2]pHet1、[C(R3)2]pCOOR3、[C(R3)2]pNR3COOA、S(O)nA、CN、CONR3SO2A、SO2N(R3)2、CONH2、CONHA、CONA2、CONH(CH2)pHet2、[C(R3)2]pHet1、COHet1、CONR3NR3COA、CONR3N(R3)2、CONHCyc和/或[C(R3)2]pNR3COOCH2Ph单取代或二取代,
或者
优选地表示哌啶基、四氢吡喃基、吡咯烷基、氮杂环丁基、硫杂环戊烷基、氧杂环丁基、3-氮杂-二环[3.1.0]己基、四氢噻吩基、四氢噻喃基、4,5,6,7-四氢-1H-吲唑-5-基、4,5,6,7-四氢-1H-吲唑-6-基、四氢吡唑基、四氢呋喃基或六氢哒嗪基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pHet1、[C(R3)2]pHet3、SO2N(R3)2、S(O)nA、[C(R3)2]pCOOR3、CO[C(R3)2]pN(R3)2、CO[C(R3)2]pHet1、CO[C(R3)2]pHet3、C(O)R3和/或=O单取代或二取代。
R2特别优选地表示环丙基、环丁基、环戊基、环己基、4-羟基-环己基、4-氨基-环己基、4-氨基-环丁基、4-羟基-环丁基、3-羟基-环戊基、3-氨基-环戊基、3-氨基羰基-环丁基、3-氨基羰基-环戊基、3-氨基羰基-环己基、四氢呋喃基或3-[(3-羟基-3-甲基-丁基)氨基羰基]环戊基。
R3优选地表示H或具有1、2、3或4个C原子的烷基,特别优选地表示H或甲基。
Ar表示,例如,邻-、间-或对-甲苯基,邻-、间-或对-乙基苯基,邻-、间-或对-丙基苯基,邻-、间-或对-异丙基苯基,邻-、间-或对-叔丁基苯基,邻-、间-或对-羟基苯基,邻-、间-或对-硝基苯基,邻-、间-或对-氨基苯基,邻-、间-或对-(N-甲基氨基)苯基,邻-、间-或对-(N-甲基氨基羰基)苯基,邻-、间-或对-甲氧基苯基,邻-、间-或对-乙氧基苯基,邻-、间-或对-乙氧基羰基苯基,邻-、间-或对-(N,N-二甲基氨基)苯基,邻-、间-或对-(N,N-二甲基氨基羰基)苯基,邻-、间-或对-(N-乙基氨基)苯基,邻-、间-或对-(N,N-二乙基氨基)苯基,邻-、间-或对-氟苯基,邻-、间-或对-溴苯基,邻-、间-或对-氯苯基,邻-、间-或对-(甲基磺酰氨基)苯基,邻-、间-或对-(甲基磺酰基)苯基,邻-、间-或对-氰基苯基,邻-、间-或对-羧基苯基,邻-、间-或对-甲氧基羰基苯基,邻-、间-或对-甲酰基苯基,邻-、间-或对-乙酰基苯基,邻-、间-或对-氨基磺酰基苯基,邻-、间-或对-[2-(吗啉-4-基)乙氧基]苯基,邻-、间-或对-[3-(N,N-二乙基氨基)丙氧基]苯基,进一步更优选地表示2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基,2,4-或2,5-二硝基苯基,2,5-或3,4-二甲氧基苯基,3-硝基-4-氯苯基,3-氨基-4-氯-、2-氨基-3-氯-、2-氨基-4-氯-、2-氨基-5-氯-或2-氨基-6-氯苯基,2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨基苯基,2,3-二氨基苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基,2,4,6-三甲氧基苯基,2-羟基-3,5-二氯苯基,对-碘苯基,3,6-二氯-4-氨基苯基,4-氟-3-氯苯基,2-氟-4-溴苯基,2,5-二氟-4-溴苯基,3-溴-6-甲氧基苯基,3-氯-6-甲氧基苯基,3-氯-4-乙酰氨基苯基,3-氟-4-甲氧基苯基,3-氨基-6-甲基苯基,3-氯-4-乙酰氨基苯基或2,5-二甲基-4-氯苯基。
Ar进一步更优选地表示苯基或萘基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pCOOR3、S(O)nA、[C(R3)2]pHet1、O[C(R3)2]pHet1和/或[C(R3)2]pHet3单-、二-或三-取代。
此外,Ar表示薁基。
Het优选地表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基、吲嗪基、噌啉基、喹啉基、异喹啉基、苯并噁唑基、1,3-苯并间二氧杂环戊烯基、苯并噻吩基、苯并呋喃基、咪唑并吡啶基、二氢吲哚基、喹喔啉基、咪唑并[1,2-a]吡啶基、苯并[1,2,5]噻二唑基、萘啶基、2,3-二氢-苯并[1,4]二氧杂环己烯基、喹唑啉基、苯并噻唑基或呋喃并[3,2-b]吡啶基,其中的每一个是未被取代的或被A、Hal、[C(R3)2]pHet1、=O和/或[C(R3)2]pOR3单取代或二取代。
Het1优选地表示吡唑基、哒嗪基、噁唑基、异噁唑基、噁二唑基、四氢-吡喃基、二氢吡咯基、吡咯烷基、氮杂环丁基、氧杂环丁基、四氢咪唑基、哌啶基、吗啉基或哌嗪基,其中的每一个是未被取代的或被A、[C(R3)2]pHet2、[C(R3)2]pCN、[C(R3)2]pN(R3)2、[C(R3)2]pCON(R3)2、[C(R3)2]pOR3和/或=O单取代或二取代。
Het2优选地表示吡唑基、噁二唑基、吡啶基、四唑基、哒嗪基、吡咯烷基、氮杂环丁基、氮杂氧杂环丁基、四氢咪唑基、四氢吡唑基、四氢呋喃基、哌啶基、吗啉基、四氢吡喃基或哌嗪基,其中的每一个是未被取代的或被A和/或=O单取代。
Hal优选地表示F、Cl或Br,但是也表示I,特别优选地表示F或Cl。
贯穿本发明,出现超过1次的所有基团可以是相同或不同的,即彼此独立。
式I的化合物可具有1个或多个手性中心,并且因此可以多种立体异构形式存在。式I包括所有这些形式。
因此具体而言,本发明涉及式I的化合物,其中所述基团中的至少1个具有上述优选含义之一。一些优选组的化合物可通过下述子式Ia至Id及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体(包括它们的所有比例的混合物)表达,其与式I一致并且其中未更详细指定的基团具有关于式I指出的含义,但其中
在Ia中,R2表示具有1-7个C-原子的直链或支链烷基,其中2个邻近碳原子可以形成双键或三键,且其可以被Hal单-、二-、三-、四-或五-取代,和/或其可以被CN、CONH2、CONHA、CONA2和/或O[C(R3)2]mN(R3)2单取代或二取代,
或者
表示具有3-7个C-原子的环烷基或环戊烯基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pAr、[C(R3)2]pHet1、[C(R3)2]pCOOR3、[C(R3)2]pNR3COOA、S(O)nA、[C(R3)2]pHet1、COHet1、CN、CONR3SO2A、SO2N(R3)2、CONH2、CONHA、CONA2、CONH(CH2)pHet2、CONR3NR3COA、CONR3N(R3)2、CONHCyc和/或[C(R3)2]pNR3COOCH2Ph单取代或二取代,
或者
表示哌啶基、四氢吡喃基、吡咯烷基、氮杂环丁基、硫杂环戊烷基、氧杂环丁基、3-氮杂-二环[3.1.0]己基、四氢噻吩基、四氢噻喃基、4,5,6,7-四氢-1H-吲唑-5-基、4,5,6,7-四氢-1H-吲唑-6-基、四氢吡唑基、四氢呋喃基或六氢哒嗪基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pHet1、[C(R3)2]pHet3、SO2N(R3)2、S(O)nA、[C(R3)2]pCOOR3、CO[C(R3)2]pN(R3)2、CO[C(R3)2]pHet1、CO[C(R3)2]pHet3、C(O)R3和/或=O单取代或二取代;
在Ib中,Ar表示苯基或萘基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pCOOR3、S(O)nA、[C(R3)2]Het1、O[C(R3)2]pHet1和/或[C(R3)2]pHet3单-、二-或三-取代,
或表示薁基;
在Ic中,Het1表示吡唑基、哒嗪基、噁唑基、异噁唑基、噁二唑基、四氢-吡喃基、四氢呋喃基、二氢吡咯基、吡咯烷基、氮杂环丁基、氧杂环丁基、四氢咪唑基、哌啶基、吗啉基或哌嗪基,其中的每一个是未被取代的或被A、[C(R3)2]pHet2、[C(R3)2]pCN、[C(R3)2]pN(R3)2、[C(R3)2]pCON(R3)2、[C(R3)2]pOR3和/或=O单取代或二取代;
在Id中,R1表示Ar或Het,
R2表示具有1-7个C-原子的直链或支链烷基,其中2个邻近碳原子可以形成双键或三键,且其可以被Hal单-、二-、三-、四-或五-取代,和/或其可以被CN、CONH2、CONHA、CONA2和/或O[C(R3)2]mN(R3)2单取代或二取代,
或者
表示具有3-7个C-原子的环烷基或环戊烯基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pOR3、[C(R3)2]pN(R3)2、[C(R3)2]pAr、[C(R3)2]pHet1、[C(R3)2]pCOOR3、[C(R3)2]pNR3COOA、S(O)nA、CN、CONR3SO2A、SO2N(R3)2、CONH2、CONHA、CONA2、CONH(CH2)pHet2、[C(R3)2]pHet1、COHet1、CONR3NR3COA、CONR3N(R3)2、CONHCyc和/或[C(R3)2]pNR3COOCH2Ph单取代或二取代,
或者
表示哌啶基、四氢吡喃基、吡咯烷基、氮杂环丁基、硫杂环戊烷基、氧杂环丁基、3-氮杂-二环[3.1.0]己基、四氢噻吩基、四氢噻喃基、4,5,6,7-四氢-1H-吲唑-5-基、4,5,6,7-四氢-1H-吲唑-6-基、四氢吡唑基、四氢呋喃基或六氢哒嗪基,其中的每一个可以被A和/或Hal单-、二-、三-、四-或五-取代,和/或其可以被[C(R3)2]pHet1、SO2N(R3)2、S(O)nA、[C(R3)2]pHet3、[C(R3)2]pCOOR3、CO[C(R3)2]pN(R3)2、CO[C(R3)2]pHet1、CO[C(R3)2]pHet3、C(O)R3和/或=O单取代或二取代,
R3表示H或具有1-6个C-原子的直链或支链烷基,
Ar表示苯基或萘基,其中的每一个是未被取代的或被Hal、A、[C(R3)2]pOR3、O[C(R3)2]pCOOR3、S(O)nA、[C(R3)2]pHet1、O[C(R3)2]pHet1和/或[C(R3)2]pHet3单-、二-或三-取代,
或表示薁基,
Het表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基、吲嗪基、噌啉基、喹啉基、异喹啉基、苯并噁唑基、1,3-苯并间二氧杂环戊烯基、苯并噻吩基、苯并呋喃基、咪唑并吡啶基、二氢吲哚基、喹喔啉基、咪唑并[1,2-a]吡啶基、苯并[1,2,5]噻二唑基、萘啶基、2,3-二氢-苯并[1,4]二氧杂环己烯基、喹唑啉基、苯并噻唑基或呋喃并[3,2-b]吡啶基,其中的每一个是未被取代的或被A、Hal、[C(R3)2]pHet1、=O和/或[C(R3)2]pOR3单取代或二取代,
Het1表示吡唑基、哒嗪基、噁唑基、异噁唑基、噁二唑基、四氢-吡喃基、四氢呋喃基、二氢吡咯基、吡咯烷基、氮杂环丁基、氧杂环丁基、四氢咪唑基、哌啶基、吗啉基或哌嗪基,其中的每一个是未被取代的或被A、[C(R3)2]pHet2、[C(R3)2]pCN、[C(R3)2]pN(R3)2、[C(R3)2]pCON(R3)2、[C(R3)2]pOR3和/或=O单取代或二取代,
Het2表示表示吡唑基、噁二唑基、吡啶基、三唑基、四唑基、哒嗪基、吡咯烷基、氮杂环丁基、氮杂氧杂环丁基、四氢咪唑基、四氢吡唑基、四氢呋喃基、哌啶基、吗啉基、四氢吡喃基或哌嗪基,其中的每一个是未被取代的或被A和/或=O单取代,
Het3表示吡唑基、吡啶基、嘧啶基或吡嗪基,其中的每一个是未被取代的或被A、[C(R3)2]pHet2和/或[C(R3)2]pOR3单取代或二取代,
Ph表示苯基,
Cyc表示具有3-7个C-原子的环烷基,其可以被OH单取代或二取代,
A表示具有1-10个C-原子的直链或支链烷基,其中1、2或3个不相邻的CH-和/或CH2-基团可以被N-、O-和/或S-原子替换,且其中1-7个H-原子可以被OH、F和/或Cl替换,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4。
特别优选的是选自“A212”、“A140”、“A187”、“A218”、“A150”、“A135”、“A167”、“A168”、“A253”、“A293”的化合物,及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物。
此外,式I的化合物及其制备的起始原料通过本身已知的方法制备,如在文献(例如在标准著作中,例如更准确而言Houben-Weyl, Methoden der organischen Chemie [有机化学的方法], Georg-Thieme-Verlag, Stuttgart)中所述。在此也可以使用在此未更详细提及的本身已知的变通形式。
式II和III的起始化合物通常是已知的。但是如果它们是新的,它们可通过本身已知的方法制备。
可优选通过将式II的化合物与式III的化合物反应获得式I的化合物。
反应通常在技术人员已知的条件下进行,并且该条件对于所述反应来说是已知和适宜的,所述反应属于在杂芳族环系上的亲核取代。
根据所用的条件,反应时间是在几分钟和14天之间,反应温度是在约0°和140°之间,通常在20°和120°之间,特别是在约60°和约110°之间。
合适的惰性溶剂的例子为烃,例如己烷、石油醚、苯、甲苯或二甲苯;氯化烃,例如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;二醇醚,例如乙二醇单甲醚或乙二醇单乙醚、乙二醇二甲醚(diglyme);酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯,或所述溶剂的混合物。
特别优选的是2-甲氧基乙醇。
此外,游离的氨基可以以常规方式使用酰基氯或酸酐酰化,或使用未取代或取代的卤代烷,有利地在惰性溶剂例如二氯甲烷或THF中和/或在碱例如三乙胺或吡啶的存在下在-60和+30°之间的温度下烷基化。
药用盐和其它形式
本发明所述的化合物可以以其最终的非盐形式使用。另一方面,本发明还包括这些化合物的药学上可接受的盐形式的使用,所述药学上可接受的盐可以通过本领域已知的操作由各种有机和无机酸和碱衍生得到。式I的化合物的药学上可接受的盐形式大部分通过常规方法制备。如果式I的化合物含有羧基,则其适宜的盐之一可通过使该化合物与适宜的碱反应从而产生相应的碱加成盐来形成。这类碱有例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,如哌啶、二乙醇胺和N-甲基-谷氨酰胺。也包括式I的化合物的铝盐。就某些式I的化合物而言,可以通过用药学上可接受的有机和无机酸处理这些化合物来形成酸加成盐,所述酸例如卤化氢,如氯化氢、溴化氢或碘化氢;其它无机酸及其相应的盐,如硫酸盐、硝酸盐或磷酸盐等;和烷基-和单芳基-磺酸盐,如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸及其相应的盐,如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I的化合物的药学上可接受的酸加成盐包括以下盐:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯基磺酸盐)、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、半乳糖二酸盐(得自粘酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、palmoate、果胶酸盐、过硫酸盐,苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不代表限于此。
此外,本发明的化合物的碱盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、铁(II)盐、锂盐、镁盐、锰(III)盐、锰(II)盐、钾盐、钠盐和锌盐,但这不代表限于此。在上述盐中,优选铵盐;碱金属盐钠盐和钾盐,以及碱土金属盐钙盐和镁盐。衍生自药学上可接受的有机无毒碱的式I的化合物的盐包括以下物质的盐:伯、仲和叔胺、被取代的胺,还包括天然存在的被取代的胺、环状胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N′-二苄基乙二胺(benzathine)、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡糖、组氨酸、哈胺(hydrabamine)、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤类、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟基甲基)甲基胺(氨基丁三醇),但这不代表限于此。
可以用诸如以下试剂将含有碱性含氮基团的本发明的化合物季铵化:(C1-C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;硫酸二(C1-C4)烷基酯,例如硫酸二甲酯、硫酸二乙酯和硫酸二戊酯;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂酰的氯化物、溴化物和碘化物;以及芳基(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。可以用该类盐来制备水溶性和油溶性的本发明的化合物。
优选的上述药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨基丁三醇,但这不代表限于此。
特别优选的是,盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
如下制备碱性式I的化合物的酸加成盐:通过将游离碱形式与足够量所需的酸接触,从而以常规方式形成盐。可以通过将盐形式与碱接触并以常规方式分离出游离碱而再生游离碱。就某些物理性质而言,游离碱形式在某些方面与其相应的盐形式不同,例如在极性溶剂中的溶解度方面;然而,对于本发明的目的而言,盐在其它方面与其各自的游离碱形式相当。
如上所述,式I的化合物的药学上可接受的碱加成盐是用金属或胺如碱金属和碱土金属或有机胺形成的。优选的金属有钠、钾、镁和钙。优选的有机胺有N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡萄糖胺和普鲁卡因。
如下制备本发明的酸性化合物的碱加成盐:通过将游离酸形式与足够量所需的碱进行接触,从而以常规方式形成盐。可以通过将盐形式与酸接触并以常规方式分离出游离酸而再生游离酸。就某些物理性质而言,游离酸形式在某些方面与其相应的盐形式不同,例如在极性溶剂中的溶解度方面;然而,对于本发明的目的而言,盐在其它方面与其各自的游离酸形式相当。
如果本发明的化合物含有一个以上能形成这类药学上可接受的盐的基团,则本发明还包括多重盐。典型的多重盐形式包括例如酒石酸氢盐、二乙酸盐、二富马酸盐、二葡甲胺、二磷酸盐、二钠盐和三盐酸盐,但这不代表限于此。
关于上文所述,可见在本文前后关系中的表述“药学上可接受的盐”用于指包含呈其盐之一形式的式I的化合物的活性成分,特别是如果与游离形式的活性成分或较早使用的活性成分的任何其它盐形式相比,该盐形式赋予活性成分改进的药代动力学性质的话。活性成分的药学上可接受的盐形式还可首次为该活性成分提供合乎需要的药代动力学性质(其较早并没有所述药代动力学性质),并且关于其在机体内的治疗功效甚至可能对该活性成分的药效学具有积极影响。
同位素
此外,式I的化合物意图包括其同位素标记的形式。除了以下事实以外,式I的化合物的同位素标记的形式与所述化合物是等同的:所述化合物的一个或多个原子被原子质量或质量数与自然界中常见的所述原子的原子质量或质量数不同的一个或多个原子替换。易于商业购得且可以通过众所周知的方法引入式I的化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。含有一个或多个上述同位素和/或其它原子的其它同位素的式I的化合物、其前药、或其任一种的药学上可接受的盐意图成为本发明的一部分。同位素标记的式I的化合物可以以多种有利的方式使用。例如,同位素标记的式I的化合物(其中例如已经掺入放射性同位素如3H或14C)适合用于药物和/或底物组织分布测定。由于易于制备和优良的可检测性,特别优选这些放射性同位素,即氚(3H)和碳-14 (14C)。在式I的化合物中引入较重的同位素如氘(2H)具有治疗优点,这归因于该同位素标记的化合物的较高代谢稳定性。较高代谢稳定性直接导致增加的体内半衰期或更低的剂量,其在大多数情况下将代表本发明的优选实施方案。通常,通过进行在合成方案及有关描述中、在实施例部分中和在本文的制备部分中公开的操作,用易得的同位素标记的反应物替换非同位素标记的反应物,可以制备同位素标记的式I的化合物。
为了通过初级动力学同位素效应控制所述化合物的氧化代谢的目的,还可以将氘(2H)引入式I的化合物中。所述初级动力学同位素效应是由同位素核的交换而引起的化学反应速率的变化,所述变化又由在该同位素交换后共价键形成所需的基态能的变化引起。较重同位素的交换经常导致化学键的基态能的降低,因此使限速键断裂的速率降低。如果键断裂发生在沿多产物反应的坐标的鞍点区或其附近,则可以明显改变产物分布比率。例如:当氘与不可交换位点处的碳原子键合时,kM/kD = 2-7的速率差异是典型的。如果将该速率差异成功地应用于易于氧化的式I的化合物,则可显著地改变所述化合物的体内性质,并导致改善的药代动力学性质。
在发现和开发治疗剂时,本领域技术人员试图优化药代动力学参数,并同时保持合乎需要的体外性质。有理由推测,许多具有差药代动力学性质的化合物易于氧化代谢。目前可得到的体外肝微粒体测定会提供关于这类氧化代谢的过程的有价值的信息,所述信息又允许合理地设计通过对抗这类氧化代谢而具有提高的稳定性的氘化的式I的化合物。由此得到式I的化合物的药代动力学性质的显著改善,并且可以以下述方式定量地表示:体内半衰期(t/2)、最大治疗效果时的浓度(Cmax)、剂量响应曲线下面积(AUC)以及F的增加;以及降低的清除率、剂量及材料成本。
以下内容意图解释上述内容:将具有氧化代谢的多个潜在攻击位点(例如苄基上的氢原子和与氮原子键合的氢原子)的式I的化合物制备为一系列类似物,其中氢原子的不同组合被氘原子替代,以致于这些氢原子中的一些、大部分或全部被氘原子替代。半衰期确定能够有利地并精确地确定已经改善的氧化代谢抗性的改善的程度。以此方式确定了作为这类氘-氢交换的结果,母体化合物的半衰期可以延长最多达100%。
式I的化合物中的氘-氢交换也可以用于实现有利地改变起始化合物的代谢物谱,以便减少或消除不希望的有毒代谢物。例如,如果有毒代谢物通过氧化性的碳-氢(C-H)键裂解而产生,那么可以合理地假定,氘化的类似物将极大地减少或消除不希望的代谢物的产生,即使在特定的氧化不是定速步骤的情况下。关于氘-氢交换的现有技术的其它信息,可以参见例如,Hanzlik等人, J. Org. Chem. 55, 3992-3997, 1990, Reider等人, J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette等人, Biochemistry 33(10) 2927-2937, 1994, 和Jarman等人.Carcinogenesis 16(4), 683-688, 1993。
此外,本发明涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂合物、互变异构体和立体异构体(包括它们的所有比例的混合物)和任选的赋形剂和/或辅剂。
药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式施用。这样的单位可包含例如0.5 mg-1 g、优选1 mg-700 mg、尤其优选5 mg-100 mg的根据本发明的化合物,这取决于所治疗的病症、施用方法以及患者的年龄、体重和状况,或者药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式施用。优选的剂量单位制剂是包含活性成分的如上指出的每日剂量或部分剂量或者其相当部分的那些制剂。此外,这类药物制剂可以用药学领域通常已知的方法来制备。
药物制剂可适用于经由任何所需的适宜方法施用,例如口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或透皮)、阴道或肠胃外(包括皮下、肌内、静脉内或真皮内)方法。这样的制剂可使用药学领域已知的所有方法制备,例如通过将活性成分与赋形剂或辅剂混合。
适于口服施用的药物制剂可以作为独立单位进行施用,所述的独立单位例如有胶囊或片剂;粉末或颗粒;在水性或非水性液体中的溶液或混悬液;可食用的泡沫或泡沫食物;或水包油型液体乳剂或油包水型液体乳剂。
因此,例如,就以片剂或胶囊形式口服施用而言,可以将活性成分组分与口服无毒的和药学上可接受的惰性赋形剂如乙醇、甘油、水等合并。粉末通过将化合物粉碎至适当细的大小并将其与以相似方式粉碎的药用赋形剂如可食用的碳水化合物如淀粉或甘露醇混合来制备。也可以存在矫味剂、防腐剂、分散剂和染料。
通过如上所述制备粉末混合物并填充到成型的明胶壳中,制备胶囊。在进行填充操作前,可以向粉末混合物中加入助流剂和润滑剂,如高度分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇。也可以加入崩解剂或增溶剂如琼脂、碳酸钙或碳酸钠以提高胶囊被服用后的药物利用度。
此外,如果需要或必要,也可以向混合物中掺入适宜的粘合剂、润滑剂和崩解剂以及染料。适宜的粘合剂包括淀粉、明胶、天然糖类如葡萄糖或β-乳糖、由玉米制得的甜味剂、天然和合成橡胶如阿拉伯胶、西黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂非限制性地包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。如下制备片剂:例如制备粉末混合物,将该混合物制粒或干压,加入润滑剂和崩解剂并将整个混合物压成片剂。通过将以适当方式粉碎的化合物与上述稀释剂或基质混合,并任选地与粘合剂如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮、溶出阻滞剂如石蜡、吸收促进剂如季盐和/或吸收剂如膨润土、高岭土或磷酸二钙混合,制备粉末混合物。可以通过用粘合剂如糖浆、淀粉糊、acadia胶浆或者纤维素或聚合物材料的溶液润湿并将其过筛而将粉末混合物制粒。作为制粒的一种替代选择,可以使粉末混合物通过压片机,得到形状不均匀的块状物,将其破碎从而形成颗粒。通过加入硬脂酸、硬脂酸盐、滑石或矿物油可对颗粒进行润滑以防止粘附在片剂铸模上。然后,将被润滑的混合物压成片剂。也可以将本发明的化合物与自由流动的惰性赋形剂合并,然后在不进行制粒或干压步骤的情况下直接压成片剂。可以存在由虫胶隔离层、糖或聚合物物质层和蜡的光泽层组成的透明或不透明的保护层。可以向这些包衣中加入染料以便能区别不同的剂量单位。
口服液体如溶液、糖浆和酏剂可以被制备成剂量单位形式以便给定量包含预定量的化合物。糖浆可以通过将化合物溶解于具有适宜矫味剂的水性溶液中来制备,而酏剂是用无毒的醇性媒介物制备。混悬液可以通过将化合物分散于无毒媒介物中来制备。也可以加入增溶剂和乳化剂如乙氧基化的异硬脂醇和聚氧乙烯山梨醇醚类、防腐剂、矫味添加剂如薄荷油或天然甜味剂或糖精或其它人工甜味剂等。
如果需要,可以将用于口服施用的剂量单位制剂包封于微囊中。也可以以释放被延长或延迟的方式来制备制剂,例如通过将微粒材料用聚合物、蜡等进行包衣或者将其包埋于聚合物、蜡等中来制备制剂。
式I的化合物及其盐、溶剂合物、互变异构体和立体异构体也可以以脂质体递送系统如小单层囊泡、大单层囊泡和多层囊泡的形式进行施用。可以从各种磷脂如胆固醇、硬脂胺或磷脂酰胆碱形成脂质体。
式I的化合物及其盐、溶剂合物、互变异构体和立体异构体也可以用单克隆抗体作为独立载体而被递送,其中所述化合物分子与所述单克隆抗体偶联。也可以将化合物偶联到作为靶向药物载体的可溶性聚合物上。该类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬酰氨基苯酚或聚氧化乙烯聚赖氨酸(被棕榈酰基取代)。还可以将化合物偶联到一类适于实现药物控释的生物可降解聚合物上,例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯类、聚缩醛类、聚二羟基吡喃类、聚氰基丙烯酸酯类和水凝胶的交联或两亲性嵌段共聚物。
适合经皮施用的药物制剂可以作为与接受者的表皮长期紧密接触的独立硬膏剂施用。因此,例如,可以用离子电渗疗法使活性成分从硬膏剂中递送,如PharmaceuticalResearch, 3(6), 318 (1986)中的通用术语所述。
适合局部施用的药用化合物可以被配制成软膏剂、乳膏剂、混悬剂、洗剂、粉末、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油。
对于眼或其它外部组织例如口和皮肤的治疗,制剂优选地以局部用软膏剂或乳膏剂的形式被应用。在配制软膏剂的情况中,可以将活性成分与石蜡的或水可混溶的乳膏基质一起应用。可替换地,可以用水包油型乳膏基质或油包水型基质将活性成分配制成乳膏剂。
适合局部应用于眼的药物制剂包括滴眼剂,其中将活性成分溶解或混悬于适宜的载体、特别是水性溶剂中。
适合在口中局部应用的药物制剂包括锭剂、软锭剂和漱口剂。
适合直肠施用的药物制剂可以以栓剂或灌肠剂的形式施用。
其中载体物质是固体的适合鼻施用的药物制剂包含具有例如在20-500微米范围内的粒度的粗粉末,其以从鼻中吸入的方式施用,即经由鼻道从靠近鼻的含粉末容器迅速吸入。以液体作为载体物质、作为鼻喷雾剂或滴鼻剂施用的适宜制剂包括活性成分在水或油中的溶液。
适合通过吸入施用的药物制剂包括细微粒粉或雾,所述细微粒粉或雾可通过各种类型的含气雾剂的加压分配器、喷雾器或吹入器来产生。
适合阴道施用的药物制剂可以作为子宫托、卫生栓、乳膏剂、凝胶剂、糊剂、泡沫或喷雾制剂来施用。
适合肠胃外施用的药物制剂包括:水性的和非水性的无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,借此使得制剂与要治疗的接受者的血液等张;以及水性的和非水性的无菌混悬液,其可以包含混悬介质和增稠剂。制剂可以在单剂量或多剂量容器、例如密封的安瓿和小瓶中施用,并以冷冻干燥(低压冻干)状态储存,使得仅需在临用前加入无菌载体液体例如注射用水。按照处方制备的注射溶液和混悬液可以从无菌粉末、颗粒和片剂制备。
不言而喻,除了上面特别提及的组分外,制剂还可以包含就该特定类型制剂而言在本领域中常用的其它试剂;因此,例如,适合口服施用的制剂可以包含矫味剂。
式I的化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的准确病症及其严重程度、制剂的性质和施用方法,并最终由主治医生或兽医来决定。但是,根据本发明的化合物的有效量通常是在0.1-100 mg/kg接受者(哺乳动物)体重/天的范围内,特别是通常在1-10 mg/kg体重/天的范围内。因此,对于体重为70kg的成年哺乳动物而言,每天的实际量通常在70-700mg之间,其中该量可以作为每天的单次剂量施用,或者通常在每天的一系列分份剂量(例如,2、3、4、5或6份)中施用,使得总日剂量相同。可以将其盐、溶剂合物、互变异构体和立体异构体的有效量确定为本发明的化合物本身的有效量的分数。可以假定,相似剂量适用于治疗上述的其它病症。
公开的式I的化合物可与其它已知治疗剂组合施用,所述治疗剂包括用于治疗RA(类风湿性关节炎)的药剂。如本文所用,术语“用于治疗RA的药剂”涉及为了治疗RA的目的而施用给患有RA患者的任何药剂。
优选(但不排他)下文的药物与式I的化合物组合:
1.NSAID (非类固醇抗炎药物)和镇痛药
2.糖皮质激素(低口服剂量)
3.常规的缓解疾病的抗风湿性药物(DMARD)
- 甲氨蝶呤
- 来氟米特
- 柳氮磺吡啶
- 羟氯喹
- 硫唑嘌呤
- 环孢素
- 米诺环素
- 金
4.生物反应调节剂(BRM) --> 炎性过程所涉及的靶标分子/免疫细胞,包括以下药剂:
- TNF抑制剂
- 依那西普(Enbrel)
- 英夫利昔单抗(Remicade)
- 阿达木单抗(Humira)
- B细胞定向疗法
- 利妥昔单抗(Rituxan)
- T细胞/B细胞共活化信号抑制剂
- 阿巴西普(Orencia)
- IL-1受体拮抗剂
- 阿那白滞素(Kineret)
作用机制 | |
戈利木单抗 | 针对TNF的全人化单克隆抗体 |
培化舍珠单抗 | 仅具有与聚乙二醇连接的Fab部分的抗TNF药剂 |
托珠单抗 | 结合可溶且膜表达的IL-6受体的人化单克隆抗IL-6抗体 |
奥瑞珠单抗 | 消耗B细胞的人化第二代抗CD20抗体 |
奥法木单抗 | 人单克隆抗CD20 IgG1抗体 |
地舒单抗 | 结合并抑制核因子-kB配体的受体活化剂的全人化单克隆抗体 |
TRU-015 | 新类型的针对CD20的蛋白疗法 |
口服小分子(JAK, Syk, MAP激酶抑制剂) | 胞质靶标 |
耐受原(dnaJP1) | 基于T细胞耐受化的免疫疗法 |
该类型的组合治疗可借助于同时、连续或分别分配该治疗的各组分来实现。该类型的组合产品使用根据本发明的化合物。
此外,本发明涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂合物、互变异构体和立体异构体(包括它们的所有比例的混合物)以及至少一种另外的药物活性成分。
本发明还涉及由如下的单独包组成的套盒(试剂盒):
(a) 有效量的式I的化合物和/或其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物,
和
(b) 有效量的另外的药物活性成分。
该套盒包含适宜的容器,如盒、单个瓶、袋或安瓿。该套盒可以包含例如单独的安瓿,每个安瓿各自包含有效量的式I的化合物和/或其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物,
和有效量的呈溶解或冻干形式的另外的药物活性成分。
本文所用的“治疗”意指整体或部分上缓解与病症或疾病相关的症状,或者减慢或停止那些症状的进一步进展或恶化,或者防止或预防具有发展疾病或病症风险的对象的疾病或病症。
与式(I)化合物有关的术语”有效量”可意指这样的量,其能够整体或部分缓解与病症或疾病相关的症状,或者减慢或停止那些症状的进一步进展或恶化,或者防止或预防患有本文所公开的疾病或具有发展所述疾病的风险的对象的疾病或病症,所述疾病或病症例如炎性病症、免疫病症、癌症、代谢病症、神经变性病症、慢性感染或通过抑制激酶或激酶途径(在一个实施方案中为GCN2途径)可治疗或可预防的病症。在另一个实施方案中,这涉及通过抑制选自GCN2、FMS (CSF1R)、FLT3或FLT4或它们的组合的激酶或激酶途径可治疗或可预防的病症。在一个实施方案中,式(I)化合物的有效量是例如在体外或体内抑制细胞内的激酶的量。在某些实施方案中,与未处理细胞中的激酶活性相比,有效量的式(I)化合物抑制细胞内的激酶达10%、20%、30%、40%、50%、60%、70%、80%、90%或99%。式(I)化合物的有效量(例如在药物组合物中)可以为产生所需效果的水平;例如,对于口服和胃肠外施用两者而言,在单位剂量中约0.005 mg/kg对象体重至约10 mg/kg对象体重。
用途
本发明化合物适于在治疗免疫调节和应激反应激酶诱导的疾病中作为药物活性成分用于哺乳动物,尤其是人。这些疾病包括恶性肿瘤,其包括、但不限于实体瘤癌症、淋巴或血液系统的癌症、肿瘤细胞的增殖、促进实体瘤生长的病理性新血管形成(或血管发生);神经变性疾病(阿尔茨海默氏病、脱髓鞘性核病症、多发性硬化等);免疫相关病症如关节炎、银屑病、狼疮或其它自身免疫疾病以及慢性感染。
本发明包括式I的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防癌症的药物中的用途。该治疗的优选癌源自于脑癌、泌尿生殖道癌、淋巴系统癌、胃癌、喉癌和肺癌。另一组优选形式的癌为单核细胞性白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、黑素瘤和乳腺癌。另一组优选形式的癌症包括、但不限于宫颈癌、成神经细胞瘤、睾丸癌、巨球蛋白血症和肉瘤。
还包括本发明权利要求1的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防神经学病症、特别是神经变性疾病、例如通过轴突变性或通过蛋白斑沉积引起的疾病的药物中的用途。神经变性疾病包括例如脱髓鞘性核病症,例如多发性硬化、急性横贯性脊髓炎、肌萎缩性侧索硬化、克雅病或阿尔茨海默氏病。
还包括本发明权利要求1的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗慢性感染的药物中的用途。这样的慢性感染可涉及寄生虫例如利什曼原虫、麻风病或HIV病毒感染等。
还包括本发明权利要求1的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防其中涉及血管发生的疾病的药物中的用途。
其中涉及血管发生的所述疾病为眼疾病,例如视网膜血管生成、糖尿病性视网膜病、年龄诱导的黄斑变性等。
本发明包括式I的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防免疫相关病症的药物中的用途,所述免疫相关病症如(除了其它自身免疫疾病外)强直性脊椎炎、关节炎、再生障碍性贫血、贝切特氏病、1型糖尿病、移植物抗宿主病、格雷夫斯氏病、自身免疫性溶血性贫血、韦格纳氏肉芽肿病、高IgE综合征、特发性血小板减少性紫癜、类风湿性关节炎、克罗恩病、多发性硬化、重症肌无力、银屑病和狼疮。其还可用于治疗器官排斥、骨髓移植排斥、非骨髓根除性骨髓移植排斥,增强非骨髓根除性条件方案后的骨髓移植物移入,以及它们的组合。
还包括式I的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防哺乳动物中免疫调节或应激反应激酶诱导的疾病或免疫调节或应激反应激酶诱导的病症的药物中的用途,其中对于该方法,将治疗有效量的本发明化合物施用给需要这种治疗的患病哺乳动物。治疗量根据具体疾病而改变,可由本领域技术人员决定而无需过度工作。
本发明还包括式I的化合物和/或其生理学上可接受的盐和溶剂合物在制备用于治疗或预防视网膜血管生成的药物中的用途。
表述“免疫调节或应激反应激酶诱导的疾病或病症”是指取决于一种或多种免疫调节或应激反应激酶的活性的病理状况。免疫调节或应激反应激酶直接或间接参与各种细胞活动的信号转导途径,所述细胞活动包括增殖、粘连和迁移以及分化。与免疫调节或应激反应激酶活性相关的疾病包括恶性肿瘤(实体瘤癌症、淋巴或血液系统的癌症等)、神经变性疾病、免疫相关病症如关节炎、银屑病、狼疮、多发性硬化或其它自身免疫疾病以及慢性感染。
本发明特别涉及用于治疗其中GCN2的抑制、调控和/或调节抑制起作用的疾病的式I的化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物。
本发明特别涉及用于抑制GCN2的式I的化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物。
本发明特别涉及用于治疗恶性肿瘤(实体瘤癌症、淋巴或血液系统的癌症等)、神经变性疾病、免疫相关病症如关节炎、银屑病、狼疮、多发性硬化或其它自身免疫疾病以及慢性感染的式I的化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物。
特别优选的是用于治疗其中疾病是恶性肿瘤的疾病的用途。
恶性肿瘤优选选自肺、鳞状上皮、膀胱、胃、肾、头和颈、食道、宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃和/或喉的肿瘤。
恶性肿瘤进一步优选选自肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、结肠癌和乳腺癌。
进一步优选治疗血液和免疫系统的恶性肿瘤的用途,优选治疗选自急性髓样白血病、慢性髓样白血病、急性淋巴性白血病和/或慢性淋巴性白血病的肿瘤的用途。
本发明特别涉及用于治疗或预防炎性病症、免疫学病症、自身免疫病症、变应性病症、风湿性病症、血栓性病症、癌症、感染、神经变性疾病、神经炎性疾病、心血管疾病或代谢病症的方法,所述方法包括:给有此需要的对象施用有效量的式I的化合物或其药学上可接受的盐、互变异构体、立体异构体或溶剂合物。
在另一方面,本文提供在表达激酶的细胞中抑制所述激酶的方法,包括使所述细胞与有效量的式I的化合物或其药学上可接受的盐、互变异构体、立体异构体或溶剂合物接触。在一个实施方案中,所述激酶为GCN2或其突变体或亚型、或者它们中的2种或更多种的组合。
式I的化合物可用于治疗或预防的代表性免疫学病症包括、但不限于贝赫切特综合征、非变应性肥大细胞疾病(例如,肥大细胞增多症和过敏反应的治疗)、强直性脊椎炎、骨关节炎、类风湿性关节炎(RA)、多发性硬化、狼疮、炎性肠病、溃疡性结肠炎、克罗恩病、重症肌无力、格雷夫斯氏病、移植排斥、体液移植排斥、非体液移植排斥、细胞移植排斥、免疫性血小板减少性紫癜(ITP)、特发性血小板减少性紫癜、糖尿病、对细菌、寄生虫、蠕虫感染或病毒感染的免疫反应、湿疹、皮炎、移植物抗宿主病、Goodpasture病、新生儿溶血病、自身免疫性溶血性贫血、抗磷脂综合征、ANCA相关的血管炎、Churg-Strauss综合征、韦格纳氏肉芽肿病、寻常型天疱疮、血清病、混合性冷沉球蛋白血症、与IgM抗体有关的外周神经病、显微镜下多血管炎、桥本甲状腺炎、舍格伦综合征、纤维化病症(例如依赖于先天性或适应性免疫系统或局部间充质细胞的那些)或原发性胆汁性肝硬化。
式I的化合物可用于治疗或预防的代表性自身免疫病症包括、但不限于自身免疫性溶血性贫血(A1HA)、贝赫切特综合征、克罗恩病、I型糖尿病、Goodpasture病、格雷夫斯氏病、桥本甲状腺炎、特发性血小板减少性紫癜、狼疮、多发性硬化、肌萎缩性侧索硬化、重症肌无力、寻常型天疱疮、原发性胆汁性肝硬化、类风湿性关节炎、硬皮病、舍格伦综合征、溃疡性结肠炎或韦格纳氏肉芽肿病。
式I的化合物可用于治疗或预防的代表性变应性病症包括、但不限于过敏反应、枯草热、变应性结膜炎、变应性鼻炎、变应性哮喘、特应性皮炎、湿疹、荨麻疹、粘膜病症、组织病症和某些胃肠病症。
式I的化合物可用于治疗或预防的代表性风湿性病症包括、但不限于类风湿性关节炎、痛风、强直性脊椎炎或骨关节炎。
式I的化合物可用于治疗或预防的代表性炎性病症包括、但不限于非ANCA (抗嗜中性粒细胞胞质自身抗体)血管炎(例如,其中GCN2功能与嗜中性粒细胞粘连、血细胞渗出和/或激活有关)、银屑病、哮喘、变应性鼻炎、变应性结膜炎、慢性荨麻疹、荨麻疹、过敏反应、支气管炎、慢性阻塞性肺病、囊性纤维化、炎性肠病、肠易激综合征、痛风、克罗恩病、粘液性结肠炎、溃疡性结肠炎、对肠内抗原过敏(例如麸质肠病)、糖尿病(例如I型糖尿病和II型糖尿病)和肥胖。在某些实施方案中,炎性病症为皮肤病学病症,例如银屑病、风疹(urticaria)、荨麻疹(hives)、湿疹、硬皮病或皮炎。在其它实施方案中,炎性病症为炎性肺病,例如哮喘、支气管炎、慢性阻塞性肺病(COPD)或成人/急性呼吸窘迫综合症(ARDS)。在其它实施方案中,炎性病症为胃肠病症,例如炎性肠病、溃疡性结肠炎、克罗恩病、特发性炎性肠病、肠易激综合症或痉挛性结肠。
式I的化合物可用于治疗或预防的代表性感染包括、但不限于细菌、寄生虫、朊病毒、病毒感染或蠕虫侵袭。
式I的化合物可用于治疗或预防的代表性癌症包括、但不限于头、颈、眼、口、咽喉、食管、支气管、喉、咽、胸、骨、肺、结肠、直肠、胃、前列腺、膀胱、子宫、子宫颈、乳房、卵巢、睾丸或其它生殖器官、皮肤、甲状腺、血液、淋巴结、肾、肝、胰腺、脑、中枢神经系统的癌症、实体瘤和血液传播的肿瘤。
式I的化合物可用于治疗或预防的代表性心血管疾病包括、但不限于再狭窄、动脉粥样硬化和其后果,例如中风、心肌梗死、对心、肺、肠、肾、肝、胰腺、脾或脑的局部缺血损伤。
式I的化合物可用于治疗或预防的代表性代谢病症包括、但不限于肥胖和糖尿病(例如I型和II型糖尿病)。在一个特别的实施方案中,本文提供用于治疗或预防胰岛素抵抗的方法。在某些实施方案中,本文提供用于治疗或预防导致糖尿病(例如II型糖尿病)的胰岛素抵抗的方法。在另一个实施方案中,本文提供用于治疗或预防X综合征或代谢综合征的方法。在另一个实施方案中,本文提供用于治疗或预防II型糖尿病、I型糖尿病、缓慢发作型I型糖尿病、尿崩症(例如神经原性尿崩症、肾原性尿崩症、致渴性尿崩症或促孕性尿崩症)、糖尿病、妊娠糖尿病、多囊性卵巢综合征、青春发生型糖尿病、青少年糖尿病、胰岛素依赖性糖尿病、非胰岛素依赖性糖尿病、营养不良相关的糖尿病、趋酮症性糖尿病、前驱糖尿病(例如葡萄糖代谢受损)、囊性纤维化相关的糖尿病、血色素沉着病和抗酮症性糖尿病的方法。
式I的化合物可用于治疗或预防的代表性神经变性和神经炎性疾病包括、但不限于亨廷顿病、阿尔茨海默氏病、病毒(例如HIV)或细菌相关的脑炎和损伤。
在另一个实施方案中,本文提供用于治疗或预防纤维化的疾病和病症的方法。在一个特定的实施方案中,本文提供用于治疗或预防特发性肺部纤维化、骨髓纤维化、肝纤维化、脂肪纤维化和脂肪性肝炎的方法。
在另一个实施方案中,本文提供用于治疗或预防与血栓形成事件相关的疾病的方法,所述疾病例如但不限于动脉粥样硬化、心肌梗死和缺血性中风。
本发明特别涉及用于治疗和/或预防炎性病症、免疫学病症、自身免疫病症、变应性病症、风湿性病症、血栓性病症、癌症、感染、神经变性疾病、神经炎性疾病、心血管疾病和代谢病症的式I的化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物,所述方法包括给有此需要的对象施用有效量的权利要求1的化合物。
此外,本发明特别涉及用于治疗和/或预防癌症的化合物,其中待治疗的癌症是实体瘤或血液和免疫系统的肿瘤。
此外,本发明特别涉及用于治疗和/或预防癌症的化合物,其中肿瘤源自于急性髓样白血病、慢性髓样白血病、急性淋巴性白血病和/或慢性淋巴性白血病。
此外,本发明特别涉及用于治疗和/或预防癌症的化合物,其中实体瘤源自于上皮、膀胱、胃、肾、头和颈、食道、宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉、骨(包括软骨肉瘤和尤因肉瘤)、生殖细胞(包括胚胎组织肿瘤)和/或肺的肿瘤,源自于单核细胞性白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、神经纤维瘤、血管肉瘤、乳腺癌和/或恶性黑素瘤。
此外,本发明特别涉及用于治疗和/或预防选自以下的疾病的用途:类风湿性关节炎、系统性狼疮、哮喘、多发性硬化、骨关节炎、缺血性损伤、巨细胞动脉炎、炎性肠病、糖尿病、囊性纤维化、银屑病、舍格伦综合征和移植器官排斥。
此外,本发明特别涉及用于治疗和/或预防选自以下的疾病的化合物:阿尔茨海默氏病、唐氏综合征、伴有Dutch型淀粉样变性的遗传性脑出血、脑淀粉样蛋白血管病、克雅病、额颞叶痴呆、亨廷顿病、帕金森病。
此外,本发明特别涉及用于治疗和/或预防选自以下的疾病的化合物:利什曼原虫、分枝杆菌(包括麻风分枝杆菌(M.leprae)、结核分枝杆菌(M.tuberculosis)和/或鸟分枝杆菌(M.avium))、利什曼原虫、疟原虫、人免疫缺陷病毒、爱泼斯坦-巴尔病毒、单纯疱疹病毒、丙型肝炎病毒。
此外,本发明特别涉及用于抑制GSK3的式I的化合物及其药学上可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们的所有比例的混合物。
所公开的式I的化合物可与其它已知的治疗剂组合施用,所述治疗剂包括抗癌药。此处所用的术语“抗癌药”涉及为治疗癌症目的而施用给患有癌症的患者的任何药剂。
本文定义的抗癌治疗可作为单一疗法施用,或者除了本发明化合物之外还可包括常规手术或放射疗法或化学疗法。所述化学疗法可包括一种或多种以下类型的抗肿瘤药:
(i)医学肿瘤学中使用的抗增殖/抗肿瘤/DNA损伤剂和其组合,例如烷化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安和亚硝脲)、抗代谢物(例如抗叶酸剂,例如氟嘧啶,如5-氟尿嘧啶和替加氟、雷替曲塞、氨甲喋呤、胞嘧啶阿拉伯糖苷、羟基脲和吉西他滨)、抗肿瘤抗生素(例如蒽环类,如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素和光神霉素)、抗有丝分裂剂(例如长春花生物碱类,如长春新碱、长春碱、长春地辛和长春瑞滨;和紫杉烷类,如紫杉醇和泰索帝)、拓扑异构酶抑制剂(例如表鬼臼毒素类,如依托泊苷和替尼泊苷、安吖啶、托泊替康、依立替康和喜树碱)和细胞分化剂(例如全-反式-维甲酸、13-顺式-维甲酸和芬维A胺);
(ii)细胞生长抑制剂,例如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、雌激素受体下调剂(例如氟维司群)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕酮(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿纳托唑、来曲唑、vorazole和依西美坦)和5α-还原酶的抑制剂例如非那司提;
(iii)抑制癌细胞侵袭的药剂(例如金属蛋白酶抑制剂如马立马司他,和尿激酶纤溶酶原激活物受体功能的抑制剂);
(iv)生长因子功能的抑制剂,例如所述抑制剂包括生长因子抗体、生长因子受体抗体(例如抗erbb2抗体曲妥单抗[赫赛汀TM]和抗erbbl抗体西妥昔单抗[C225])、法尼基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼, AZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼, OSI-774)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033)),例如血小板来源的生长因子家族的抑制剂和例如肝细胞生长因子家族的抑制剂;
(v)抗血管生成药,例如抑制血管内皮生长因子作用的那些(例如抗血管内皮细胞生长因子抗体贝伐单抗[阿瓦斯汀TM]、化合物例如在公布的国际专利申请WO 97/22596、WO97/30035、WO 97/32856和WO 98/13354中公开的那些)和通过其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂和血管他丁);
(vi)血管损伤剂,例如考布他汀A4和在国际专利申请WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)反义疗法,例如针对上文所列靶标的那些,例如ISIS 2503,一种抗Ras反义;
(viii)基因治疗方法,包括例如用于置换异常基因(例如异常p53或异常BRCA1或BRCA2)的方法、GDEPT (基因定向的酶前药疗法)方法(例如使用胞嘧啶脱氨酶、胸腺嘧啶激酶或细菌硝基还原酶的那些)和用于提高患者对化学疗法或放射疗法耐受性的方法(例如多重耐药性基因疗法);和
(ix)免疫治疗方法,包括例如用于增加患者肿瘤细胞的免疫原性的离体和体内方法例如用细胞因子(例如白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子)转染、用于降低T细胞无反应性的方法、使用转染的免疫细胞(例如细胞因子转染的树突细胞)的方法、使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
优选(但不排他)来自下表1的药物与式I的化合物组合。
公开的式I的化合物可与其它已知治疗剂组合施用,所述治疗剂包括抗癌剂。如本文所用,术语“抗癌剂”涉及为了治疗癌症的目的而施用给癌症患者的任何药剂。
上面定义的抗癌治疗可作为单一疗法施用,或者除了本文中公开的式I的化合物之外还可包括常规手术或放射疗法或药物治疗。这样的药物治疗(例如化学疗法或靶向治疗)可以包括一种或多种、但是优选一种下述抗肿瘤剂:
烷化剂
诸如六甲蜜胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡、托西酸盐、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、塞替派、曲奥舒凡、mechloretamine、卡波醌;
阿帕齐醌、福莫司汀、葡膦酰胺、帕磷酰胺、哌泊溴烷、曲磷胺、尿嘧啶氮芥、TH-3024、VAL-0834;
铂化合物
诸如卡铂、顺铂、依他铂、miriplatine水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;
洛铂、奈达铂、吡铂、沙铂;
DNA改变剂
诸如氨柔比星、比生群、地西他滨、米托蒽醌、丙卡巴肼、曲贝替定、氯法拉滨;
安吖啶、溴他利星、匹克生琼、拉罗莫司汀1,3;
拓扑异构酶抑制剂
诸如依托泊苷、伊立替康、雷佐生、索布佐生、替尼泊苷、托泊替康;
氨萘非特、贝洛替康、依利醋铵、伏利拉辛;
微管修饰剂
诸如卡巴他赛、多西他赛、艾立布林、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;
福他布林、替司他赛;
抗代谢物
诸如天门冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;
去氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟2,3、三甲曲沙;
抗癌抗生素
诸如博来霉素、更生霉素、多柔比星、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地新、链佐星、戊柔比星、净司他丁、佐柔比星、柔红霉素(daunurobicin)、普卡霉素;
阿柔比星、培洛霉素、吡柔比星;
激素/拮抗剂
诸如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡普睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙氟甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚;
阿考比芬、达那唑、地洛瑞林、环硫雄醇、orteronel、enzalutamide1,3;
芳香酶抑制剂
诸如氨鲁米特、阿那曲唑、依西美坦、法倔唑、来曲唑、睾内酪;
福美坦;
小分子激酶抑制剂
诸如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞戈非尼、鲁索替尼、索拉非尼、舒尼替尼、凡他尼布、威罗菲尼、波舒替尼、吉非替尼、阿昔替尼;
阿法替尼、alisertib、达拉菲尼、dacomitinib、dinaciclib、度维替尼、恩扎妥林、nintedanib、lenvatinib、linifanib、linsitinib、马赛替尼、米哚妥林、莫替沙尼、奈拉替尼、orantinib、哌立福新、泊那替尼、radotinib、rigosertib、替匹法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、apatinib4、cabozantinibS-malate 1,3、ibrutinib1,3、icotinib4、buparlisib2、cipatinib4、cobimetinib1,3、idelalisib1,3、fedratinib1、XL-6474;
光敏剂
诸如甲氧沙林3;
卟吩姆钠、他拉泊芬、替莫泊芬;
抗体
诸如阿仑珠单抗、贝索单抗、Brentuximab vedotin、西妥昔单抗、地舒单抗、伊匹木单抗、奥法木单抗、帕木单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、贝伐珠单抗、培妥珠单抗2,3;
卡妥索单抗、依洛珠单抗、依帕珠单抗、法利珠单抗、mogamulizumab、奈昔木单抗、尼妥珠单抗、阿托珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎芦木单抗、扎木单抗、马妥珠单抗、dalotuzumab1,2,3、onartuzumab1,3、雷妥莫单抗1、tabalumab1,3、EMD-5257974、nivolumab1,3;
细胞因子
诸如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3;
西莫白介素、他索那敏、替西白介素、奥普瑞白介素1,3、重组干扰素β-1a4;
药物缀合物
诸如地尼白介素2、替伊莫单抗、碘苄胍I123、泼尼莫司汀、曲妥单抗-emtansine、雌莫司汀、吉妥珠单抗、奥加米星、阿柏西普;
贝辛白介素、依度曲肽、伊珠单抗奥加米星、他那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗1,3,
vintafolide1,3;
疫苗
诸如sipuleucel3;vitespen3、emepepimut-S3、oncoVAX4、rindopepimut3、troVax4、MGN-16014、MGN-17034;
其它
阿利维A酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、香菇多糖、甲酪氨酸、米法莫肽、帕米磷酸、培门冬酶、喷司他丁、sipuleucel3、西佐喃、他米巴罗汀、坦罗莫司、沙利度胺、维A酸、vismodegib、唑来膦酸、伏林司他;
塞来考昔、西仑吉肽、恩替司他、依他硝唑、ganetespib、伊屈诺昔、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培维A酸、普利肽新、泊马度胺、procodazol、地磷莫司、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、曲贝德生、乌苯美司、伐司朴达、今又生4、溶血性链球菌制剂4、reolysin4、盐酸瑞螺旋霉素1,3、trebananib2,3、维鲁利秦4、卡非佐米1,3、内皮他丁4、immucothel4、贝林司他3、MGN-17034;
1 Prop. INN (提议的国际非专有名称)
2 Rec. INN (推荐的国际非专有名称)
3 USAN (美国采用的名称)
4无INN。
下列缩写分别指下文的定义:
aq(水性的)、h (小时)、g(克)、L (升)、mg (毫克)、MHz(兆赫)、min.(分钟)、mm(毫米)、mmol (毫摩尔)、mM(毫摩尔的)、m.p.(熔点)、eq (当量)、ml (毫升)、 μl (微升)、ACN (乙腈)、AcOH (乙酸)、CDCl3 (氘化氯仿)、CD3OD (氘化甲醇)、CH3CN (乙腈)、c-hex(环己烷)、DCC (二环己基碳二亚胺)、DCM (二氯甲烷)、DIC (二异丙基碳二亚胺)、DIEA(二异丙基乙胺)、DMF (二甲基甲酰胺)、DMSO (二甲亚砜)、DMSO-d6 (氘化二甲亚砜)、EDC(1-(3-二甲基-氨基-丙基)-3-乙基碳二亚胺)、ESI (电喷射离子化)、EtOAc (乙酸乙酯)、Et2O (乙醚)、EtOH (乙醇)、HATU (二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-铵六氟磷酸盐)、HPLC (高效液相色谱法)、i-PrOH (2-丙醇)、K2CO3 (碳酸钾)、LC(液相色谱法)、MeOH (甲醇)、MgSO4 (硫酸镁)、MS (质谱法)、MTBE (甲基叔丁醚)、NaHCO3 (碳酸氢钠)、NaBH4 (硼氢化钠)、NMM (N-甲基吗啉)、NMR (核磁共振)、PyBOP (苯并三唑-1-基-氧基-三吡咯烷子基-鏻六氟磷酸盐)、RT (室温)、Rt(保留时间)、SPE (固相萃取)、TBTU (2-(1-H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐)、TEA (三乙胺)、TFA (三氟乙酸)、THF (四氢呋喃)、TLC (薄层色谱法)、UV (紫外线)。
体外测定法的描述
GCN2:测定法原理和条件
该测定法可量化丝氨酸激酶GCN2 (一般性调控阻遏蛋白激酶2)的活性。
该激酶涉及细胞的应激代谢。在饥饿(氨基酸耗尽)时其被活化。其天然底物是eIF2a (真核起始因子2α亚单位),一种转录因子,在细胞中氨基酸瓶颈的情况下其被GCN2激活(磷酸化)。这进而导致蛋白质合成停止。GCN2的抑制造成终止该机制。在“饥饿”应激时细胞不能终止蛋白产生。
按两步骤进行测定:酶反应和检测步骤。在第一步骤中,将GCN2与10µM ATP和80nM GFP标记的底物eIF2α一起在室温下温育。
酶反应通过添加EDTA来终止。磷酸化的eIF2α的量通过TR-FRET (Lanthascreen)来测定:形成由抗体和GFP标记的磷酸-eIF2a组成的复合物,其在340 nm激发时允许FRET。
GCN2活性与发射波长520 nm处(磷酸肽敏感波长=GFP的发射)的荧光单位和495nm处(参考波长=铽螯合物的发射)的荧光单位的比率成正比。
酶反应中的终浓度
Hepes, pH 7.0 50 mM
MgCl2 10 mM
MnCl2 5 mM
BSA 0.1%
DMSO 1%
ATP 10 uM
DTT 2 mM
GFP-eIF2a 80 nM (底物)
GCN2 30 nM (酶)
测定程序
4 uL 酶溶液(在测定缓冲液中)
1.5 uL 化合物(在化合物稀释缓冲液/6.3%DMSO中)
温育 在室温20 min
4 uL 底物/ATP混合物(在测定缓冲液中)
温育 在室温90 min
10 uL 停止/检测混合物(在抗体稀释缓冲液中)
温育 在室温60 min
读出 Lanthascreen 340/495/520。
用于确定化合物活性的细胞测定法
将人U2OS细胞(2000个细胞/孔)接种到384-孔平板中并温育20小时。
第二天,用试验化合物处理细胞,并温育2小时。然后给细胞添加终浓度为600µM的色氨醇(tryptophanol),然后将它们温育30分钟。
通过免疫细胞化学进行细胞GCN2活性的分析。简言之,用甲醛将细胞固定在孔表面上,并用Triton X-100透化。将第一抗体(抗-磷酸-eIF2α(Ser51, Cell SignallingTechnology, #3398)在所处理的细胞上温育20小时,然后用第二抗体(抗-兔-IgG-Alexa488; Molecular Probes # 11008)温育60分钟。
通过在Acumen Explorer系统(TTPLabtech)中扫描平板,进行磷酸化的GCN2的分析和定量。将得到的数据相对于未处理的对照孔(仅DMSO)标准化,并表示为%效果值。使用Graph Pad Prism软件进行IC50值的确定。
GSK3α
将GSK3α(h)与8 mM MOPS pH 7.0、0.2 mM EDTA、20µM YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (磷酸GS2肽)、10 mM乙酸镁和[γ-33P-ATP] (比活性大约500 cpm/Pmol,所需要的浓度)一起温育。通过加入MgATP,开始反应。在室温温育40分钟以后,通过加入3%磷酸溶液来停止反应。然后将10µL反应物印迹在P30 filtermat上并在50 mM磷酸中洗涤3次(历时5分钟)和在甲醇中洗涤1次,然后干燥和闪烁计数。在10µM ATP或Km ATP进行测定。用于KmATP方案的ATP浓度是10µM ATP,而用于GSK3a(h)的实际KM ATP是10µM。
GSK3β
将GSK3β(h)与8 mM MOPS pH 7.0、0.2 mM EDTA、20µM YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (磷酸GS2肽)、10 mM乙酸镁和[γ-33P-ATP] (比活性大约500 cpm/Pmol,所需要的浓度)一起温育。通过加入MgATP,开始反应。在室温温育40分钟以后,通过加入3%磷酸溶液来停止反应。然后将10µL反应物印迹在P30 filtermat上并在50 mM磷酸中洗涤3次(历时5分钟)和在甲醇中洗涤1次,然后干燥和闪烁计数。在10µM ATP或Km ATP进行测定。用于KmATP方案的ATP浓度是10µM ATP,而用于GSK3a(h)的实际KM ATP是10µM。
1H NMR:
Bruker 400-或500 MHz
HPLC/MS条件A
柱:Chromolith Performance ROD RP-18e, 50 x 4.6 mm2
梯度: 在2.8 min中A:B = 96:4至0:100
流速:2.40 ml/min
洗脱液A:水+ 0.05%甲酸
洗脱液B:乙腈+ 0.04%甲酸
波长:220 nm
质谱法:正模式
HPLC/MS条件B
柱:Chromolith Performance ROD RP-18e, 100 x 3 mm2
梯度: 在1.8 min中A:B = 99:1至0:100
流速:2.0 ml/min
洗脱液A:水+ 0.05%甲酸
洗脱液B:乙腈+ 0.04%甲酸
波长:220 nm
质谱法:正模式
HPLC/MS条件C
柱:Chromolith Performance ROD RP-18e, 100 x 3 mm2
梯度:在3.5 min中A:B = 99:1至0:100
流速:2.0 ml/min
洗脱液A:水+ 0.05%甲酸
洗脱液B:乙腈+ 0.04%甲酸
波长:220 nm
质谱法:正模式。
上文和下文中,所有温度以℃表示。在下列实施例中,“常规后处理(work-up)”是指:如果必要的话添加水,如果必要的话将pH值调至2-10之间的值(这取决于终产物的构成),将混合物用乙酸乙酯或二氯甲烷萃取,分离各相,有机相经硫酸钠干燥并蒸发,并将残余物通过硅胶上的色谱法纯化和/或通过结晶纯化。硅胶上的Rf值;洗脱液:乙酸乙酯/甲醇9:1。
实施例
中间体的制备
5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶的合成
在用冰外部冷却下向2,4-二氯-5-硝基-嘧啶(5.82 g, 30 mmol)在二氧杂环己烷(90 ml)中的溶液中缓慢地加入N-乙基二异丙胺(5.61 ml, 33 mmol)。然后,仍然在冷却下,缓慢地加入对茴香胺(4.06 g, 33 mmol)在二氧杂环己烷(12 ml)中的溶液。将反应混合物在室温搅拌3小时。将溶剂蒸发,并将残余物溶解于水(100 ml)中。将固体滤出,用水洗涤并在真空下干燥,得到作为橙色晶体的(2-氯-5-硝基-嘧啶-4-基)-(4-甲氧基-苯基)-胺;HPLC/MS 1.94 min (B), [M+H] 281; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.35(s, 1H), 9.11 (s, 1H), 7.46 - 7.39 (m, 2H), 7.03 - 6.96 (m, 2H), 3.79 (s,3H)。
用海绵体镍作为催化剂(2.0 g)在室温和在常压下氢化(2-氯-5-硝基-嘧啶-4-基)-(4-甲氧基-苯基)-胺(8.13 g, 29.0 mmol)在THF (90 ml)中的溶液。将催化剂滤出,并将滤液蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为红棕色固体的2-氯-N4-(4-甲氧基-苯基)-嘧啶-4,5-二胺;HPLC/MS 1.68 min (B), [M+H] 251; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.51 (s, 1H), 7.57 - 7.49 (m, 2H),7.60 (s, 1H), 7.58 - 7.49 (m, 2H), 6.99 - 6.91 (m, 2H), 5.19 (s, 2H), 3.76(s, 3H)。
向2-氯-N4-(4-甲氧基-苯基)-嘧啶-4,5-二胺(2.59 g, 10.3 mmol)在乙腈(22ml)中的溶液中加入亚硝酸丁酯(1.81 ml, 15.5 mmol),并将反应混合物在80℃搅拌1小时。将反应混合物冷却至室温并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为灰白色晶体的5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 2.23 min (A), [M+H] 262; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.82(s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H)。
类似地制备以下化合物:
5-氯-3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;灰色粉末;HPLC/MS2.87 min (C), [M+H] 276;
5-氯-3-(4-吗啉-4-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;黄色固体;
HPLC/MS 1.87 min (B), [M+H] 317; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.80 (s, 1H), 7.88 - 7.80 (m, 2H), 7.26 - 7.19 (m, 2H), 3.82 - 3.75 (m, 4H),3.29 - 3.22 (m, 4H);
(R)-1-[4-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-苯基]-吡咯烷-3-醇, 黄色固体;HPLC/MS 1.76 min (B), [M+H] 317; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.78(s, 1H), 7.73 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 5.00 (d, J = 3.8Hz, 1H), 4.45 (m, 1H), 3.50 (dd, J = 10.3, 4.8 Hz, 1H), 3.47 - 3.34 (m, 2H),3.21 - 3.14 (m, 1H), 2.09 (dtd, J = 13.2, 8.5, 4.8 Hz, 1H), 2.01 - 1.90 (m,1H)。
6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-喹啉盐酸盐的合成
在用冰外部冷却下向6-氨基喹啉(401 mg, 2.78 mmol)在二氧杂环己烷(15 ml)中的溶液中缓慢地加入2,4-二氯-5-硝基-嘧啶(491 mg, 2.53 mmol)。然后,仍然在冷却下,缓慢地加入N-乙基二异丙胺(0.47 ml, 2.78 mmol)。将反应混合物在室温搅拌3小时。将溶剂蒸发,并将残余物溶解于水中。将固体滤出,用水洗涤并在真空下干燥,得到作为橙色晶体的(2-氯-5-硝基-嘧啶-4-基)-喹啉-6-基-胺;HPLC/MS 1.67 min (A), [M+H] 302。
用海绵体镍作为催化剂(1.0 g)在室温和在常压下氢化(2-氯-5-硝基-嘧啶-4-基)-喹啉-6-基-胺(793 mg, 2.63 mmol)在THF (20 ml)中的溶液。20小时以后,将催化剂滤出,并将滤液蒸发,得到作为棕红色晶体的2-氯-N4-喹啉-6-基-嘧啶-4,5-二胺;HPLC/MS1.27 min (A), [M+H] 272。
向2-氯-N4-喹啉-6-基-嘧啶-4,5-二胺(562 mg, 2.07 mmol)在37%盐酸水溶液(9ml)中的浆中加入亚硝酸钠(286 mg, 4.14 mmol),并将反应混合物在室温搅拌2小时。将反应混合物蒸发。将残余物与庚烷一起研磨,得到粗制的6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-喹啉盐酸盐,将其原样用于以后的反应;HPLC/MS 1.91 min (A), [M+H] 283。
类似地制备以下化合物:
5-氯-3-(6-甲氧基-吡啶-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;浅棕色晶体;HPLC/MS 2.50 min (C), [M+H] 263;
1-[4-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-苯基]-吡咯烷-2-酮;HPLC/MS1.73 min (B), [M+H] 315;
5-氯-3-(4-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 2.25 min (A),[M+H] 250; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.85 (s, 1H), 8.11 (dd, J = 9.0,4.8 Hz, 2H), 7.59 (t, J = 8.7 Hz, 2H)。
5-氯-3-(4-氯-3-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶的合成
在用冰外部冷却下向2,4-二氯-5-硝基-嘧啶(1.04 g, 5.36 mmol)在THF (20ml)中的溶液中缓慢地加入4-氯-3-氟-苯基胺(678 mg, 4.66 mmol)。然后,仍然在冷却下,缓慢地加入三乙胺(0.65 ml, 4.66 mmol)在THF (5 ml)中的溶液。将反应混合物在室温搅拌1小时。将固体滤出,并用THF洗涤。将滤液蒸发,并从甲醇结晶,得到作为黄色晶体的(4-氯-3-氟-苯基)-(2-氯-5-硝基-嘧啶-4-基)-胺;HPLC/MS 2.98 min (C), [M+H] 303。
向(4-氯-3-氟-苯基)-(2-氯-5-硝基-嘧啶-4-基)-胺(1.28 g, 4.23 mmol)在乙酸乙酯(17 ml)和乙醇(12 ml)的混合物中的溶液中加入氯化锡(II) (4.01 g, 21.2mmol),并将反应混合物在70℃搅拌2小时。将反应混合物用饱和碳酸钠溶液碱化,经硅藻土垫过滤,并将残余物用乙酸乙酯洗涤。将滤液的有机相分离,经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为棕色晶体的2-氯-N4-(4-氯-3-氟-苯基)-嘧啶-4,5-二胺;HPLC/MS 2.60 min (C), [M+H] 273。
向2-氯-N4-(4-氯-3-氟-苯基)-嘧啶-4,5-二胺(617 mg, 2.26 mmol)在37%盐酸水溶液(10 ml)中的浆中加入亚硝酸钠(312 mg, 4.53 mmol),并将反应混合物在室温搅拌2小时。将冰加入反应混合物中。将得到的沉淀物滤出,用水洗涤和在真空下干燥,得到作为棕色粉末的5-氯-3-(4-氯-3-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 3.03min (C), [M+H] 284。
类似地制备以下化合物:
6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-3,3-二甲基-1,3-二氢-吲哚-2-酮;米色粉末;HPLC/MS 2.00 min (A), [M+H] 315;
5-氯-3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶;米色粉末;HPLC/MS 2.15 min (A), [M+H] 306;
6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-喹喔啉;黄色粉末;HPLC/MS 1.93min (A), [M+H] 284;
3-[4-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-苯氧基]-丙酸的合成
在用冰外部冷却下向2,4-二氯-5-硝基-嘧啶(1.02 g, 5.25 mmol)在THF (20ml)中的溶液中缓慢地加入3-(4-氨基-苯氧基)-丙酸甲酯(1.02 g, 5.25 mmol)。然后,仍然在冷却下,缓慢地加入二异丙基乙胺(1.07 ml, 6.30 mmol)。将反应混合物在室温搅拌1小时。将固体滤出,并用THF洗涤。将滤液蒸发,并将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为暗红色晶体的3-[4-(2-氯-5-硝基-嘧啶-4-基氨基)-苯氧基]-丙酸甲酯;HPLC/MS 2.73 min (C), [M+H] 353。
向3-[4-(2-氯-5-硝基-嘧啶-4-基氨基)-苯氧基]-丙酸甲酯(1.54 g, 4.37mmol)在乙酸乙酯(20 ml)和乙醇(5 ml)的混合物中的溶液中加入氯化锡(II) (2.49 g,13.1 mmol),并将反应混合物在70℃搅拌1小时。将反应混合物用饱和碳酸钠溶液碱化,经硅藻土垫过滤,并将残余物用乙酸乙酯洗涤。将滤液的有机相分离,经硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为棕色油的3-[4-(5-氨基-2-氯-嘧啶-4-基氨基)-苯氧基]-丙酸甲酯,其在静置后结晶;HPLC/MS 2.24min (C), [M+H] 323。
向3-[4-(5-氨基-2-氯-嘧啶-4-基氨基)-苯氧基]-丙酸甲酯(1.39 g, 4.30mmol)在37%盐酸水溶液(13 ml)中的浆中加入亚硝酸钠(594 mg, 8.61 mmol),并将反应混合物在室温搅拌3小时。将冰加入反应混合物中。将得到的沉淀物滤出,用水洗涤并在真空下干燥,得到作为浅黄色粉末的3-[4-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-苯氧基]-丙酸;HPLC/MS 2.33 min (C), [M+H] 320。
3-(4-溴-苯基)-5-氯-3H-[1,2,3]三唑并[4,5-d]嘧啶的合成
在用冰外部冷却下向4-溴苯胺(3.78 g, 22.0 mmol)在二氧杂环己烷(100 ml)中的溶液中缓慢地加入2,4-二氯-5-硝基-嘧啶(3.88 g, 20 mmol)。然后,仍然在冷却下,缓慢地加入二异丙基乙胺(3.74 ml, 22.0 mmol)。将反应混合物在室温搅拌1小时。将固体滤出,并用THF洗涤。将滤液溶解于水中,将固体滤出,用水洗涤并在真空下干燥,得到(4-溴-苯基)-(2-氯-5-硝基-嘧啶-4-基)-胺;HPLC/MS 2.08 min (B), [M+H] 331。
向(4-溴-苯基)-(2-氯-5-硝基-嘧啶-4-基)-胺(5.97 g, 18.13 mmol)在乙酸乙酯(100 ml)和乙醇(50 ml)的混合物中的溶液中加入氯化锡(II) (10.3 g, 54.4 mmol),并将反应混合物在70℃搅拌1小时。将反应混合物冷却至室温,用饱和碳酸钠溶液碱化,经硅藻土垫过滤,并将残余物用乙酸乙酯洗涤。将滤液的有机相分离,经硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为浅棕色粉末的N4-(4-溴-苯基)-2-氯-嘧啶-4,5-二胺;HPLC/MS 1.86 min (B), [M+H] 301。
向N4-(4-溴-苯基)-2-氯-嘧啶-4,5-二胺(3.33 g, 11.1 mmol)在乙腈(50 ml)中的溶液中加入亚硝酸丁酯(1.72 g, 16.7 mmol),并将反应混合物在70℃搅拌1小时。将反应混合物冷却至室温并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为棕色粉末的3-(4-溴-苯基)-5-氯-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 2.09 min (B), [M+H] 312。
类似地合成以下化合物:
5-氯-3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;
HPLC/MS 3.10 min (C), [M+H] 358。
实施例1
(1-甲基-1H-吡唑-4-基甲基)-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-胺(“B1”)的合成
将粗制的6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-喹啉盐酸盐(85 mg, 约0.15 mmol)和(1-甲基吡唑-4-基)甲胺(18.4 mg, 0.17 mmol)在2-甲氧基乙醇(5 ml)中的溶液加热至100℃,并在该温度搅拌2小时。将反应混合物蒸发,并将残余物在硅胶柱上用乙酸乙酯/甲醇作为洗脱液进行色谱分离,得到作为黄色粉末的(1-甲基-1H-吡唑-4-基甲基)-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-胺;HPLC/MS 1.99 min (C),[M+H] 358; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.30 (s, 1H), 9.00 (dd, J = 4.2,1.7 Hz, 1H), 8.83 (s, 1H), 8.65 (d, J = 9.2 Hz, 1H), 8.58 - 8.50 (m, 2H),8.30 (d, J = 9.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.44 (s, 1H), 4.47 (d, J = 5.3Hz, 2H), 3.75 (s, 3H)。
类似地制备以下化合物:
[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-丙-2-炔基-胺(“A1”)
HPLC/MS 2.71 min (C), [M+H] 295; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.30 (s, 1H), 8.45 (s, 1H), 8.07 (s, 2H), 7.21 - 7.14 (m, 2H), 4.19 - 4.09(m, 4H), 3.06 (s, 1H), 1.38 (t, J=7.0, 3H);
3,3-二甲基-6-{5-[(5-甲基-吡嗪-2-基甲基)-氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-1,3-二氢-吲哚-2-酮(“B2”)
HPLC/MS 1.83 min (A), [M+H] 402; 1H NMR (500 MHz, DMSO-d6) δ [ppm]10.61 (s, 1H), 9.29 (s, 1H), 8.84 - 8.71 (m, 1H), 8.59 (s, 1H), 8.52 - 8.44(m, 1H), 7.73 - 7.60 (m, 2H), 7.55 - 7.45 (m, 1H), 4.77 - 4.67 (m, 2H), 2.45(s, 3H), 1.32 (s, 6H);
{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-(5-甲基-吡嗪-2-基甲基)-胺(“B3”)
HPLC/MS 1.90 min (A), [M+H] 393; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.28 (s, 1H), 8.76 - 8.69 (m, 1H), 8.56 - 8.43 (m, 2H), 7.99 - 7.82 (m, 2H),7.23 - 7.10 (m, 2H), 4.76 - 4.62 (m, 2H), 4.21 - 4.17 (m, 2H), 3.72 - 3.69(m, 2H), 3.34 (s, 3H), 2.45 (s, 3H);
[3-(4-氯-3-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1-甲基-1H-吡唑-4-基甲基)-胺(“B4”)
HPLC/MS 2.70 min (C), [M+H] 359; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.27 (s, 1H), 8.60 (t, J = 5.1 Hz, 1H), 8.31 (dd, J = 10.6, 2.4 Hz, 1H), 8.16(d, J = 8.9 Hz, 1H), 7.91 (t, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.40 (s, 1H),4.41 (d, J = 5.8 Hz, 2H), 3.76 (s, 3H);
(5-甲基-吡嗪-2-基甲基)-(3-喹喔啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-胺(“B5”)
HPLC/MS 1.79 min (A), [M+H] 371; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.38 (s, 1H), 9.08 (d, J = 1.9 Hz, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.94 (t, J= 5.4 Hz, 1H), 8.86 (s, 1H), 8.64 (s, 2H), 8.53 (s, 1H), 8.34 (d, J = 9.1 Hz,1H), 4.75 (d, J = 5.9 Hz, 2H), 2.44 (s, 3H);
{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-(1-甲基-1H-吡唑-4-基甲基)-胺(“B6”)
HPLC/MS 1.91 min (A), [M+H] 381; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.38 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.38 (s,1H), 7.22 (m, 2H), 4.38 (s, 2H), 4.19 (t, J = 4.5 Hz, 2H), 3.75 (s, 3H), 3.73- 3.67 (m, 2H), 3.33 (s, 3H);
异丙基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A2”)
HPLC/MS 1.98 min (B), [M+H] 285; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.26 - 9.19 (m, 1H), 8.08 - 7.93 (m, 3H), 7.19 (d, J=8.9, 2H), 4.28 - 4.06(m, 1H), 3.85 (s, 3H), 1.24 - 1.18 (m, 6H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(四氢-吡喃-4-基)-胺(“A3”)
HPLC/MS 1.80 min (B), [M+H] 327; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.33 - 9.21 (m, 1H), 8.18 - 7.88 (m, 3H), 7.23 - 7.11 (m, 2H), 4.16 - 3.94(m, 1H), 3.92 - 3.87 (m, 2H), 3.85 (s, 3H), 3.47 - 3.37 (m, 2H), 1.95 - 1.79(m, 2H), 1.63 - 1.51 (m, 2H);
环丙基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A4”)
HPLC/MS 1.89 min (B), [M+H] 283; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.31 - 8.02 (m, 3H), 7.18 (d, J=8.7, 2H), 3.85 (s, 3H), 2.84(s, 1H), 0.78 - 0.71 (m, 2H), 0.59 - 0.54 (m, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-氧杂环丁烷-3-基-胺(“A5”)
HPLC/MS 1.29 min (B), [M+H] 299;
[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[2-(1-甲基-1H-吡唑-4-基)-乙基]-胺(“B7”)
HPLC/MS 1.85 min (B), [M+H] 365; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.20 - 8.14 (m, 1H), 8.05 - 7.99 (m, 2H), 7.50 (s, 1H), 7.27(s, 1H), 7.20 - 7.14 (m, 2H), 4.13 (q, J=7.0, 2H), 3.76 (s, 3H), 3.51 - 3.44(m, 2H), 2.76 - 2.69 (m, 2H), 1.37 (t, J=7.0, 3H);
2-(3,4-二氟-苯基)-2-[3-(6-甲氧基-吡啶-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-乙醇(“B8”)
HPLC/MS 2.62 min (C), [M+H] 400; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.30 (s, 1H), 8.76 (s, 1H), 8.54 (d, J = 7.4 Hz, 1H), 8.32 (s, 1H), 8.26 (dd,J = 8.8, 2.9 Hz, 1H), 7.46 (ddd, J = 11.8, 7.9, 2.1 Hz, 1H), 7.41 - 7.32 (m,1H), 7.25 (ddd, J = 9.8, 4.7, 2.6 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 5.24 (s,1H), 4.98 (q, J = 7.1 Hz, 1H), 3.97 (s, 3H), 3.74 (dd, J = 10.9, 7.5 Hz, 1H),3.67 (dd, J = 11.0, 5.7 Hz, 1H);
[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[2-(1H-吡唑-4-基)-乙基]-胺(“B9”)
HPLC/MS 1.77 min (B), [M+H] 351; 1H NMR (400 MHz, DMSO-d6) δ [ppm]12.54 (s, 1H), 9.23 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.56 (s,1H), 7.37 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.54 -3.44 (m, 2H), 2.77 (t, J = 7.5 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H);
反式-4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷醇(“A6”)
HPLC/MS 1.70 min (B), [M+H] 341; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.21 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.20 (d, J= 8.8 Hz, 3H), 4.63 (d, J = 4.3 Hz, 1H), 3.86 (s, 3H), 3.71 (m, 1H), 3.4 (m,1H), 1.91 (m, 4H), 1.43 - 1.21 (m, 4H);
叔丁基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A7”)
HPLC/MS 2.09 min (B), [M+H] 299; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.72 (s, 1H), 7.23 - 7.16 (m, 2H),3.85 (s, 3H), 1.44 (s, 9H);
N-(1,1-二氧代硫杂环戊烷-3-基)-3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-胺(“A8”)
HPLC/MS 1.71 min (B), [M+H] 361; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.34 (s, 1H), 8.55 (s, 1H), 8.01 (bs, 2H), 7.19 (d, J = 9.0 Hz, 2H), 4.66 (s,1H), 3.85 (s, 3H), 3.57 (dd, J = 13.5, 7.6 Hz, 1H), 3.45 - 3.33 (m, 1H), 3.29- 3.12 (m, 2H), 2.27 (m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1-丙基-环丙基)-胺(“A9”)
HPLC/MS 2.16 min (B), [M+H] 325; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.21 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8.6, 2H), 7.20 (d, J=8.7, 2H), 3.85(s, 3H), 1.70 - 1.59 (m, 2H), 1.45 - 1.34 (m, 2H), 0.87 (t, J=7.4, 3H), 0.80- 0.63 (m, 4H);
反式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A10”)
外消旋混合物;HPLC/MS 1.69 min (B), [M+H] 327; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.21 (s, 1H), 8.14 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H),7.20 (m, J = 8.3 Hz, 2H), 4.51 (m, 1H), 4.37 (m, 1H), 4.23 (m, 1H), 3.85 (s,3H), 2.15 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H), 1.52 (m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-苯乙基-胺(“B10”)
HPLC/MS 2.13 min (B), [M+H] 347; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.21 (s, 1H), 8.04 (d, J=8.7, 2H), 7.33 - 7.24 (m, 4H), 7.23 -7.15 (m, 3H), 3.86 (s, 3H), 3.62 - 3.50 (m, 2H), 2.95 - 2.87 (m, 2H);
苄基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“B11”)
HPLC/MS 2.05 min (B), [M+H] 333; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.25 (s, 1H), 8.75 - 8.64 (m, 1H), 7.98 - 7.92 (m, 2H), 7.44 - 7.27 (m, 4H),7.22 (t, J=7.3, 1H), 7.19 - 7.12 (m, 2H), 4.54 (d, J=5.7, 2H), 3.85 (s, 3H);
{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基}-甲醇(“A11”)
HPLC/MS 1.87 min (B), [M+H] 355; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.50 (s, 1H), 8.09 - 8.02 (m, 2H), 7.23 - 7.14 (m, 2H), 4.22 - 4.15 (m,1H), 3.89 (s, 3H), 3.44 (d, J = 5.9 Hz, 2H), 1.89 (m, 2H), 1.77 - 1.59 (m,5H), 1.51 (m, 2H);
环戊基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A12”)
HPLC/MS 2.12 min (B), [M+H] 311; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.25 (s, 1H), 8.75 - 8.64 (m, 1H), 7.98 - 7.92 (m, 2H), 7.44 - 7.27 (m, 4H),7.22 (t, J=7.3, 1H), 7.19 - 7.12 (m, 2H), 4.54 (d, J=5.7, 2H), 3.85 (s, 3H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[3-(4-甲基-哌嗪-1-基)-丙基]-胺(“A13”)
HPLC/MS 1.44 min (A), [M+H] 383; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.28 (s, 1H), 8.07 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 3.89 (s, 3H),3.82 - 3.25 (m, 12H), 2.96 (s, 3H), 2.15 - 2.08 (m, 2H);
反式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-1-三氟甲基-环戊烷醇(“A67”)
HPLC/MS 1.95 min (B), [M+H] 395;
反式-2-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基}-乙醇(“A72”)
HPLC/MS 2.65 min (C), [M+H] 369; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.25 (s, 1H), 8.03 (m, 2H), 7.19 (d, J = 7.6 Hz, 2H), 3.87 (s, 3H),3.76 (m, 1H), 3.47 (t, J = 6.4 Hz, 2H), 2.01 (m, 2H), 1.83 - 1.76 (m, 2H),1.44 - 1.29 (m, 5H), 1.10 - 0.99 (m, 2H);
顺式-2-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基}-乙醇(“A73”)
HPLC/MS 2.67min (C), [M+H] 369; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.27(s, 1H), 8.06 - 8.01 (m, 2H), 7.23 - 7.15 (m, 2H), 4.02 - 3.98 (m, 1H), 3.86(s, 3H), 3.45 (t, J = 6.8 Hz, 2H), 1.78 (m, 2H), 1.63 - 1.41 (m, 8H), 1.40 -1.33 (m, 1H);
[2-(2-氨基-乙氧基)-乙基]-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺甲酸盐(“A74”)
HPLC/MS 1.41 min (B), [M+H] 330; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.25 (s, 1H), 8.18 - 7.89 (m, 3H), 7.19 (d, J=8.8, 2H), 3.85 (s, 3H),3.66 - 3.49 (m, 6H), 2.85 (t, J=5.4, 2H);
[3-(3-氨基-丙氧基)-丙基]-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺甲酸盐(“A76”)
HPLC/MS 1.43 min (B), [M+H] 358; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.34 - 9.19 (m, 1H), 8.18 - 7.90 (m, 3H), 7.19 (d, J=8.7, 2H), 3.85 (s,3H), 3.51 - 3.37 (m, 6H), 2.79 - 2.71 (m, 2H), 1.91 - 1.77 (m, 2H), 1.71 (p,J=6.5, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(3,4,5,6-四氢-2H-[1,4']联吡啶-4-基)-胺(“A82”)
HPLC/MS 1.96 min (C), [M+H] 403; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.21 (d, J = 7.7 Hz, 2H), 8.08 (m, 1H), 7.22 (d, J = 7.8Hz, 1H), 7.18 (d, J = 9.1 Hz, 1H), 4.23 (m, 3H), 3.88 (s, 3H), 3.48 (m, 2H),2.18 (m, 2H) 1.73 (m, 2H);
(顺式)-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-N',N'-二甲基-环戊烷-1,3-二胺(“A108”)
HPLC/MS 1.45 min (B), [M+H] 354。
实施例2
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-甲基-胺(“A14”)的合成
在密闭反应瓶中将5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(131 mg, 0.50 mmol)在甲基胺水溶液(40重量%, 2 ml)中的浆加热至80℃,并在该温度搅拌30分钟。将混合物冷却至室温,并加入过量的水。将固体滤出,用水洗涤并在真空下干燥,得到作为灰白色晶体的[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-甲基-胺;HPLC/MS 2.42 min (C), [M+H] 257; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.22(s, 1H), 8.05 (, 3H), 7.19 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H), 2.90 (m, 3H)。
类似地制备以下化合物:
乙基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A16”)
HPLC/MS 2.64 min (C), [M+H] 271; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.36 (s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 7.23 - 7.14 (m, 2H), 4.32 (p, J = 6.5Hz, 1H), 3.88 (s, 3H), 2.05 (m, 2H), 1.76 (m, 2H), 1.72 - 1.59 (m, 2H)。
实施例3
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1,2,2,6,6-五甲基-哌啶-4-基)-胺(“A15”)的合成
将5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(131 mg, 0.50mmol)和4-氨基-1,2,2,6,6-五甲基哌啶(104 mg, 0.60 mmol)在2-甲氧基乙醇(1 ml)中的溶液加热至100℃,并在该温度搅拌1小时。将反应混合物冷却至室温,并在二氯甲烷和2 NNaOH之间分配。将有机相蒸发,并将残余物在硅胶柱上用甲醇/二氯甲烷作为洗脱液进行色谱分离,得到作为浅黄色晶体的[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1,2,2,6,6-五甲基-哌啶-4-基)-胺;HPLC/MS 1.87 min (C), [M+H] 396; 1H NMR(400 MHz, DMSO-d6) δ [ppm] 8.21 - 8.08 (m, 2H), 8.05 (d, J = 7.2 Hz, 1H),7.14 - 7.07 (m, 2H), 4.21 - 4.03 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H), 1.97 -1.82 (m, 2H), 1.41 (d, J = 12.1 Hz, 2H), 1.11 (s, 12H)。
类似地制备以下化合物:
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(2,2,6,6-四甲基-哌啶-4-基)-胺(“A17”)
HPLC/MS 1.89 min (C), [M+H] 382; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.17 - 8.10 (m, 2H), 8.06 (d, J = 7.2 Hz, 1H), 7.14 - 7.07 (m,2H), 4.23 (dtd, J = 11.6, 7.9, 3.6 Hz, 1H), 3.83 (s, 3H), 1.88 (dd, J = 12.2,3.5 Hz, 2H), 1.26 - 1.02 (m, 15H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1-甲基-哌啶-4-基)-胺(“A18”)
HPLC/MS 1.72 min (C), [M+H] 340;
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(3-甲基-3-氮杂-二环[3.1.0]己-6-基)-胺(“A19”)
HPLC/MS 1.33 min (B), [M+H] 338; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.7 Hz,2H), 3.86 (s, 3H), 3.06 (d, J = 8.8 Hz, 2H), 2.88 (s, 1H), 2.35 (d, J = 7.7Hz, 2H), 2.25 (s, 3H), 1.62 (s, 2H)。
实施例4
4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-1-甲基-吡咯烷-2-酮(“A20”)的合成
向5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(97 mg, 0.37mmol)和4-氨基-1-甲基-吡咯烷-2-酮盐酸盐(65 mg, 0.37 mmol)在2-甲氧基乙醇(3 ml)中的溶液中加入N-乙基二异丙胺(0.13 ml, 0.75 mmol)。将混合物加热至100℃,并在该温度搅拌1小时。将反应混合物蒸发,并将残余物在硅胶柱上用甲醇/二氯甲烷作为洗脱液进行色谱分离,得到作为灰白色粉末的4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-1-甲基-吡咯烷-2-酮;HPLC/MS 1.62 min (B), [M+H] 34; 1H NMR (500MHz, DMSO-d6) δ [ppm] 9.29 (s, 1H), 8.50 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H),7.20 (d, J = 8.6 Hz, 3H), 4.53 - 4.47 (m, 1H), 3.85 (s, 3H), 3.74 (dd, J =10.2, 7.3 Hz, 1H), 3.36 (m, 1H), 2.74 (s, 3H), 2.72 - 2.65 (m, 1H), 2.46 -2.38 (m, 1H)。
类似地制备以下化合物:
环丁基-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A21”)
HPLC/MS 2.02 min (B), [M+H] 297; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.41 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.21 (d, J= 8.8 Hz, 2H), 4.35 (dd, J = 16.4, 8.4 Hz, 1H), 3.85 (s, 3H), 2.30 (m, 2H),2.11 - 2.01 (m, 2H), 1.72 (m, 2H);
[2-(4-氯-苯基)-环丙基]-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A22”)
HPLC/MS 2.24 min (B), [M+H] 393; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.27 (s, 1H), 8.69 - 8.59 (m, 1H), 7.90 - 7.85 (m, 2H), 7.36 (d, J=8.1, 2H),7.22 (d, J=8.3, 2H), 6.82 - 6.75 (m, 2H), 3.82 (s, 3H), 2.95 - 2.85 (m, 1H),2.03 - 1.96 (m, 1H), 1.50 - 1.44 (m, 1H), 1.33 - 1.25 (m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(4,5,6,7-四氢-1H-吲唑-5-基)-胺(“A23”)
HPLC/MS 1.70 min (B), [M+H] 363; 1H NMR (500 MHz, DMSO-d6) δ [ppm]12.33 (s, 1H), 9.25 (s, 1H), 8.17 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 8.5 Hz,2H), 7.18 (d, J = 9.0 Hz, 2H), 4.16 - 4.10 (m, 1H), 3.83 (s, 3H), 2.94 - 2.87(m, 1H), 2.84 - 2.75 (m, 1H), 2.73 - 2.62 (m, 1H), 2.61 - 2.51 (m, 1H), 2.21- 2.13 (m, 1H), 1.79 (m, 1H);
反式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁醇(“A24”)
HPLC/MS 1.66 min (B), [M+H] 313; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.20 (d, J= 8.5 Hz, 2H), 5.03 (d, J = 4.4 Hz, 1H), 4.37 - 4.29 (m, 2H), 3.86 (s, 3H),2.35 - 2.26 (m, 2H), 2.25 - 2.17 (m, 2H);
顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁醇(“A25”)
HPLC/MS 1.68 min (B), [M+H] 313; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.20 (d, J= 8.8 Hz, 2H), 5.06 (d, J = 5.9 Hz, 1H), 3.91 (m, 1H), 3.85 (s, 3H), 3.84 -3.76 (m, 1H), 2.70 - 2.57 (m, 2H), 1.94 - 1.85 (m, 2H);
顺式-4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷醇(“A26”)
HPLC/MS 1.77 min (B), [M+H] 341; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.18 - 7.79 (m, 3H), 7.18 (d, J = 8.3 Hz, 2H), 4.40 (m, 1H),3.85 (s, 3H), 3.75 (m, J = 4.4 Hz, 1H), 3.4 (m, 1H), 1.78 (m, 2H), 1.73 -1.61 (m, 4H), 1.57 - 1.47 (m, 2H);
顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A27”)
HPLC/MS 1.81 min (B), [M+H] 327; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.39 (s, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.23 - 7.14 (m, 2H), 4.40 (tt, J =7.7, 5.3 Hz, 1H), 4.27 (tt, J = 5.4, 3.7 Hz, 1H), 3.88 (s, 3H), 2.23 (ddd, J= 13.5, 7.8, 5.7 Hz, 1H), 2.14 - 2.01 (m, 1H), 1.78 (m, 4H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(S)-四氢-呋喃-3-基-胺(“A28”)
HPLC/MS 1.79 min (B), [M+H] 313; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.27 (s, 1H), 8.37 (m, 1H), 8.03 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 4.41 (m,1H), 3.95 (m, 1H), 3.85 (s, 3H), 3.74 (q, J = 7.9 Hz, 1H), 3.65 (m, 1H), 3.28(m, 1H), 2.19 (m, 1H), 1.98 (m, 1H);
反式-3-[3-(4-溴-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A29”)
HPLC/MS 1.86 min (B), [M+H] 375/378; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.85 (d, J= 8.5 Hz, 2H), 4.50 (m, 1H), 4.39 (q, J = 6.9 Hz, 1H), 4.24 (m, 1H), 2.16 (m,1H), 1.99 - 1.85 (m, 2H), 1.76 (m, 1H), 1.63 - 1.50 (m, 2H);
{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-(3-吡啶-2-基-丙基)-胺(“A68”)
HPLC/MS 1.87 min (C), [M+H] 406; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.27 (s, 1H), 8.75 (d, J = 5.8 Hz, 1H), 8.47 (t, J = 7.8 Hz, 1H), 8.02(m, 3H), 7.86 (t, J = 6.9 Hz, 1H), 7.23 - 7.14 (m, 2H), 4.26 - 4.19 (m, 2H),3.79 - 3.71 (m, 2H), 3.56 (t, J = 6.4 Hz, 2H), 3.38 (s, 3H), 3.17 (t, J = 7.7Hz, 2H), 2.17 (p, J = 6.8 Hz, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[1-(2-吗啉-4-基-乙基)-哌啶-4-基]-胺(“A78”)
HPLC/MS 1.33 min (B), [M+H] 439;
(1S,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(“A79”)
HPLC/MS 1.80 min (B), [M+H] 355; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.26 (s, 1H), 8.04 (m, 2H), 7.23 - 7.16 (m, 2H), 4.27 (m, 1H), 3.87 (s,3H), 2.81 (p, J = 8.5 Hz, 1H), 2.39 - 2.26 (m, 1H), 2.07 - 1.81 (m, 4H), 1.70(m, 1H);
(1R,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(“A81”)
HPLC/MS 1.81 min (B), [M+H] 355;
[2-(5-氟-1H-吲哚-3-基)-乙基]-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-胺(“A84”)
HPLC/MS 2.91 min (C), [M+H] 448; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.32 (s, 1H), 8.07 - 8.02 (m, 2H), 7.36 (dd, J = 8.8, 4.5 Hz, 1H), 7.32(dd, J = 9.9, 2.5 Hz, 1H), 7.28 (s, 1H), 7.22 - 7.15 (m, 2H), 6.90 (td, J =9.2, 2.5 Hz, 1H), 4.25 - 4.19 (m, 2H), 3.79 - 3.69 (m, 4H), 3.38 (s, 3H),3.08 (t, J = 7.4 Hz, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[1-(2-吡咯烷-1-基-乙基)-哌啶-4-基]-胺(“A86”)
HPLC/MS 1.26 min (B), [M+H] 423;
4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-2-酮(“A87”)
HPLC/MS 1.59 min (B), [M+H] 340; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.14 - 7.93 (m, 2H), 7.19 (d, J = 9.1 Hz, 2H), 4.35 (m,1H), 3.88 (s, 3H), 3.41 (m, 1H), 3.33 (ddd, J = 13.1, 8.9, 4.7 Hz, 1H), 2.82(dd, J = 17.4, 6.1 Hz, 1H), 2.56 - 2.48 (m, 1H), 2.28 - 2.03 (m, 1H), 1.90(m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-((S)-1-吡啶-4-基-吡咯烷-3-基)-胺(“A88”)
HPLC/MS 1.99 min (C), [M+H] 389; 1H NMR (400 MHz, DMSO-d6) δ [ppm]13.7(s, 1H), 9.31 (s, 1H), 8.55 (s, 1H), 8.21 (d, J = 6.8 Hz, 2H), 8.06 (m, 2H),7.19 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 6.9 Hz, 3H), 4.67 (m, 1H), 3.85 (m,4H), 3.72 (m, 2H), 3.61 (m, 2H), 2.37 (dq, J = 13.7, 7.3 Hz, 1H), 2.24 (m,1H);
{(1R,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-氨基甲酸苄酯(“A89”)
HPLC/MS 2.08 min (B), [M+H] 460; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.26 (s, 1H), 8.06 (m, 2H), 7.42 - 7.34 (m, 4H), 7.34 - 7.28 (m, 1H),7.19 (d, J = 8.6 Hz, 2H), 5.04 (s, 2H), 4.29 (m, 1H), 3.95 (p, J = 7.2 Hz,1H), 3.87 (s, 3H), 2.45 - 2.35 (m, 1H), 2.01 (dq, J = 13.8, 7.3 Hz, 1H), 1.91(dq, J = 13.5, 7.4, 7.0 Hz, 1H), 1.81 - 1.70 (m, 1H), 1.70 - 1.61 (m, 1H),1.60 - 1.51 (m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(R)-四氢-呋喃-3-基-胺(“A98”)
HPLC/MS 1.81 min (B), [M+H] 313; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.24 - 7.16 (m, 2H), 4.51 (m,1H), 4.02 - 3.85 (m, 5H), 3.77 (td, J = 8.1, 5.7 Hz, 1H), 3.72 (m, 1H), 2.25(dq, J = 12.6, 7.6 Hz, 1H), 2.10 - 1.97 (m, 1H);
(反式)-3-[3-(5-甲氧基-吡啶-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A99”)
HPLC/MS 1.96 min (C), [M+H] 328; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.26 (s, 1H), 8.39 (d, J = 3.0 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.75(dd, J = 9.0, 3.1 Hz, 1H), 4.45 (m, 1H), 4.24 (tt, J = 5.9, 3.2 Hz, 1H), 3.96(s, 3H), 2.14 (m, 1H), 1.94 (m, 2H), 1.75 (dt, J = 13.3, 6.7 Hz, 1H), 1.60 -1.44 (m, 2H)。
(1S,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(“A101”)
HPLC/MS 2.02 min (B), [M+H] 451; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.27 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 8.05 - 7.91 (m, 2H), 4.35 (m,1H), 2.85 (p, J = 8.5 Hz, 1H), 2.37 (dt, J = 14.6, 7.7 Hz, 1H), 1.99 (m, 4H),1.76 (m, 1H);
(反式)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A102”)
HPLC/MS 1.52 min (B), [M+H] 348; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.43 (dd, J = 5.2, 1.4 Hz, 1H), 9.34 - 9.26 (m, 3H), 9.09 (d, J = 10.3Hz, 1H), 8.56 (d, J = 9.3 Hz, 1H), 8.21 (dd, J = 8.4, 5.2 Hz, 1H), 4.56 (m,1H), 4.30 (m, 1H), 2.28 - 2.20 (m, 1H), 2.09 (m, 1H), 2.00 (ddt, J = 12.8,8.4, 6.0 Hz, 1H), 1.80 (m, 1H), 1.63 (m, 2H);
(S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-甲酸叔丁酯(“A103”)
HPLC/MS 2.15 min (B), [M+H] 426;
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(1-甲基-哌啶-3-基)-胺甲酸盐(“A104”)
HPLC/MS 1.39 min (B), [M+H] 340;
(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-甲酸叔丁酯(“A105”)
HPLC/MS 2.15 min (B), [M+H] 426;
反式-1-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基}-哌啶-4-醇甲酸盐(“A106”)
HPLC/MS 1.43 min (B), [M+H] 424; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (m, 1H), 8.13 (s, 1H), 8.11 - 7.92 (m, 2H), 7.19 (d, J = 8.7 Hz,2H), 3.97 (m, 1H), 3.87 (s, 3H), 3.7 (m, 1H), 3.44 (d, J = 11.4 Hz, 1H), 3.32- 3.18 (m, 3H), 3.05 (t, J = 12.5 Hz, 1H), 2.23 - 2.09 (m, 4H), 2.05 - 1.97(m, 1H), 1.97 - 1.86 (m, 1H), 1.85 - 1.78 (m, 1H), 1.73 - 1.57 (m, 3H), 1.50- 1.37 (m, 2H);
顺式-1-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基}-哌啶-4-醇甲酸盐(“A107”)
HPLC/MS 1.48 min (B), [M+H] 424; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.30 (s, 1H), 8.13 (s, 1H), 8.04 (m, 2H), 7.19 (d, J = 8.9 Hz, 2H), 4.18 (m,1H), 3.87 (s, 3H), 3.74 - 3.63 (m, 1H), 3.44 - 3.37 (m, 1H), 3.32 - 3.21 (m,3H), 3.11 - 3.02 (m, 1H), 2.18 - 1.77 (m, 6H), 1.75 - 1.58 (m, 3H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-((R)-1-吡啶-4-基-吡咯烷-3-基)-胺(“A109”)
“A109”盐酸盐: HPLC/MS 2.00 min (C), [M+H] 389;
(1S,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸甲酯(“A110”)
HPLC/MS 1.97 min (B), [M+H] 369;
{(1S,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-甲醇(“A111”)
HPLC/MS 1.80 min (B), [M+H] 341;
{(1S,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-甲醇(“A112”)
HPLC/MS 1.79 min (B), [M+H] 341;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸甲酯(“A113”)
HPLC/MS 1.89 min (B), [M+H] 369;
{(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-甲醇(“A114”)
HPLC/MS 1.77 min (B), [M+H] 341;
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[(R)-1-(1-甲基-1H-吡唑-4-基)-吡咯烷-3-基]-胺(“A115”)
HPLC/MS 1.72 min (B), [M+H] 392。
实施例5
{顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁基}-氨基甲酸叔丁酯(“A30”)和顺式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环丁烷-1,3-二胺盐酸盐(“A31”)的合成
将5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(144 mg, 0.55mmol)和顺式-(3-氨基-环丁基)-氨基甲酸叔丁酯(113 mg, 0.61 mmol)在2-甲氧基乙醇(3ml)中的溶液加热至80℃,并在该温度搅拌18小时。将反应混合物蒸发,并将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为浅粉红色粉末的顺式-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁基}-氨基甲酸叔丁酯;HPLC/MS 2.02 min (B), [M+H] 412; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.24 (s,1H), 8.42 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.6 Hz,2H), 7.19 - 7.15 (m, 1H), 3.92 - 3.87 (m, 1H), 3.85 (s, 3H), 3.74 (m, 1H),2.64 (m, 2H), 1.98 - 1.88 (m, 2H), 1.38 (s, 9H)。
类似地制备以下化合物:
{反式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁基}-氨基甲酸叔丁酯(“A32”)
HPLC/MS 1.99 min (B), [M+H] 412; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.24 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.25 (m,1H), 7.23 - 7.10 (m, 2H), 4.28 (m, 1H), 4.09 (m, 1H), 3.85 (s, 3H), 2.30 (m,4H), 1.39 (s, 9H);
{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己基甲基}-氨基甲酸叔丁酯(“A33”)
HPLC/MS 2.13 min (B), [M+H] 454;
4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-甲酸叔丁酯(“A34”)
HPLC/MS 2.14 min (B), [M+H] 426; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.24 (s, 1H), 8.02 (m, 3H), 7.19 (d, J = 8.6 Hz, 2H), 3.95 (m, 2H), 3.92 (s,3H), 3.23 - 3.10 (m, 1H), 2.92 (m, 1H), 2.78 (m, 1H), 1.92 - 1.83 (m, 2H),1.40 (m, 11H);
{反式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-氨基甲酸叔丁酯(“A35”)
外消旋体, HPLC/MS 2.07 min (B), [M+H] 426; 1H NMR (500 MHz, DMSO-d6/TFA-d1) δ [ppm] 9.30 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 9.1 Hz,2H), 4.42 (m, 1H), 4.03 (p, J = 7.0 Hz, 1H), 3.88 (s, 3H), 2.23 - 2.14 (m,1H), 2.05 (m, 1H), 1.98 - 1.91 (m, 2H), 1.64 (m, 1H), 1.57 - 1.49 (m, 1H),1.42 (s, 9H);
3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-氮杂环丁烷-1-甲酸叔丁酯(“A36”)
HPLC/MS 2.05 min (B), [M+H] 398;
(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-甲酸叔丁酯(“A65”)
HPLC/MS 2.04 min (B), [M+H] 412;
(S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-甲酸叔丁酯(“A66”)
HPLC/MS 2.04 min (B), [M+H] 412。
向{顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁基}-氨基甲酸叔丁酯(49.4 mg, 0.12 mmol)在二氧杂环己烷(1 ml)和甲醇(1 ml)的混合物中的溶液中加入4 N的HCl在二氧杂环己烷中的溶液(2 ml)。将反应混合物在室温搅拌2小时。将已经形成的沉淀物滤出,用二氧杂环己烷洗涤并在真空下干燥,得到作为奶油色粉末的顺式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环丁烷-1,3-二胺盐酸盐(“A31”);HPLC/MS 1.41 min (B), [M+H] 312; 1H NMR (400 MHz, DMSO-d6) δ[ppm] 9.29 (s, 1H), 8.53 (s, 1H), 8.27 (s, 3H), 8.04 (d, J = 8.4 Hz, 2H),7.25 - 7.16 (m, 3H), 4.09 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 2.70 (m, 2H),2.19 (m, 2H)。
类似地制备以下化合物:
(3-氮杂-二环[3.1.0]己-6-基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺盐酸盐(“A37”)
HPLC/MS 1.32 min (B), [M+H] 324; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.65 - 9.56 (m, 2H), 9.30 (m, 2H), 8.45 - 8.41 (m, 1H), 8.20 (d, J = 8.6 Hz,2H), 7.24 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H), 3.40 (m, 3H), 2.98 - 2.92 (m,1H), 2.00 (m, 2H);
反式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环丁烷-1,3-二胺盐酸盐(“A38”)
HPLC/MS 1.33 min (B), [M+H] 312; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.28 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 9.1 Hz, 2H), 4.67(m, 1H), 3.89 (m, 4H), 2.58 (m, 4H);
(4-氨基甲基-环己基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺盐酸盐(“A39”)
HPLC/MS 1.44 min (B), [M+H] 354; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.23 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.97 (m, 4H), 7.19 (d, J = 8.2 Hz,2H), 3.85 (m, 4H), 2.72 - 2.65 (m, 2H), 2.07 - 2.01 (m, 1H), 1.95 (m, 1H),1.88 - 1.81 (m, 2H), 1.63 - 1.55 (m, 1H), 1.31 (m, 2H), 1.16 - 1.04 (m, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-哌啶-4-基-胺盐酸盐(“A40”)
HPLC/MS 1.39 min (B), [M+H] 326; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.29 (s, 1H), 8.05 (m, 2H), 7.23 - 7.14 (m, 2H), 4.18 (m, 1H), 3.88 (s,3H), 3.41 (m, 2H), 3.12 (m, 1H), 3.04 (td, J = 12.7, 2.9 Hz, 1H), 2.16 (m,2H), 1.84 (m, 2H);
反式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺盐酸盐(“A41”)
HPLC/MS 1.39 min (B), [M+H] 326; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.29 (s, 1H), 8.07 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 4.53(m, 1H), 3.88 (s, 3H), 3.77 (p, J = 7.0 Hz, 1H), 2.37 - 2.19 (m, 2H), 2.18 -2.06 (m, 2H), 1.81 - 1.64 (m, 2H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(R)-吡咯烷-3-基-胺盐酸盐(“A69”)
HPLC/MS 1.41 min (B), [M+H] 312; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.05 (m, 2H), 7.18 (d, J = 9.0 Hz, 1H), 4.66 (m, 1H),3.88 (s, 3H), 3.57 (m, 1H), 3.52 - 3.42 (m, 1H), 3.37 (m, 2H), 2.33 (m, 1H),2.20 (m, 1H);
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(S)-吡咯烷-3-基-胺盐酸盐(“A77”)
HPLC/MS 1.37 min (B), [M+H] 312;
{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-(R)-吡咯烷-3-基-胺(“A116”)
“A116”盐酸盐HPLC/MS 1.36 min (B), [M+H] 362;
{(顺式)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基甲基}-氨基甲酸叔丁酯(“A117”)
HPLC/MS 2.12 min (B), [M+H] 440;
(1S,3R)-N3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-环戊烷-1,3-二胺(“A118”)
HPLC/MS 1.43 min (B), [M+H] 376;
(1S,3R)-N3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环戊烷-1,3-二胺(“A119”)
HPLC/MS 1.33 min (B), [M+H] 347;
(1R,3R)-N3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺(“A120”)
“A120”盐酸盐HPLC/MS 1.42 min (B), [M+H] 326;
(1S,3R)-N3-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环戊烷-1,3-二胺(“A121”)
HPLC/MS 1.42 min (B), [M+H] 420;
((1R,3S)-3-氨基甲基-环戊基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A122”)
HPLC/MS 1.46 min (B), [M+H] 340;
(1R,3R)-N-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环戊烷-1,3-二胺(“A123”)
HPLC/MS 1.44 min (B), [M+H] 420;
(1R,3R)-N-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺(“A124”)
HPLC/MS 1.57 min (C), [M+H] 361;
(1R,3R)-N-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环戊烷-1,3-二胺(“A125”)
HPLC/MS 1.49 min (C), [M+H] 434;
[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(R)-吡咯烷-3-基-胺(“A126”)
HPLC/MS 1.25 min (C), [M+H] 390。
实施例6
1-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-乙酮(“A42”)和[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-哌啶-3-基-胺盐酸盐(“A43”)的合成
向5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(118 mg, 0.45mmol)和1-(3-氨基-哌啶-1-基)-乙酮盐酸盐(88.4 mg, 0.50 mmol)在2-甲氧基乙醇(3ml)中的溶液中加入N-乙基二异丙胺(0.15 ml, 0.90 mmol)。将混合物加热至80℃,并在该温度搅拌1小时。将反应混合物蒸发,并将残余物在硅胶柱上用乙酸乙酯/甲醇作为洗脱液进行色谱分离,得到作为浅粉红色粉末的1-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-乙酮;HPLC/MS 1.71 min (B), [M+H] 368。
向1-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-乙酮(73 mg, 0.20 mmol)在水(1 ml)中的混悬液中加入37%盐酸水溶液(134µl)。将混合物加热至90℃,并在该温度搅拌44小时。将反应混合物蒸发,并低压冻干,得到作为橙色粉末的[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-哌啶-3-基-胺盐酸盐;HPLC/MS 1.38 min (B), [M+H] 326。
实施例7
反式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A44”)的合成
将5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(81 mg, 0.31mmol)和反式-环己烷-1,4-二胺(72 mg, 0.63 mmol)在2-甲氧基乙醇(3 ml)中的溶液加热至80℃,并在该温度搅拌18小时。将反应混合物蒸发,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为浅粉红色粉末的反式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺;HPLC/MS 1.39 min (B), [M+H]340; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.25 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H),8.03 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.37 (bs, 2H), 3.86 (s,3H), 3.70 (m, 1H), 2.87 (m, 1H), 1.99 (m, 4H), 1.37 (m, 4H)。
类似地制备以下化合物
顺式-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A45”)
HPLC/MS 1.43 min (B), [M+H] 340; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.29 (s, 1H), 8.02 (m, 2H), 7.88 (m, 3H), 7.20 (d, J = 9.1 Hz, 2H), 3.93 (m,1H), 3.86 (s, 3H), 3.13 (m, 1H), 1.99 (m, 2H), 1.74 (m, 6H);
N-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A53”)
HPLC/MS 1.98 min (C), [M+H] 436; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.27 (s, 1H), 8.02 (m, 4H), 3.81 (m, 1H), 3.10 m, 1H), 2.15 - 2.03 (m,4H), 1.48 (m, 4H);
N-[3-(4-吗啉-4-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A64”)
HPLC/MS 1.38 min (B), [M+H] 395; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.10 (d, J = 9.1 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 3.95- 3.84 (m, 5H), 3.40 (m, 4H), 3.09 (m, 1H), 2.08 (m, 4H), 1.61 - 1.40 (m,4H);
N-[3-(4-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(反式)-环己烷-1,4-二胺(“A75”)
HPLC/MS 1.84 min (C), [M+H] 328; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.21 (dd, J = 8.9, 4.8 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H),3.85 (m, 1H), 3.12 - 3.06 (m, 1H), 2.17 - 2.04 (m, 4H), 1.61 - 1.44 (m, 4H);
反式-N-[3-(5-吗啉-4-基-吡啶-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A96”)
HPLC/MS 1.31 min (B), [M+H] 396; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.43 - 8.36 (m, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.65 (dd,J = 9.0, 3.1 Hz, 1H), 3.93 - 3.63 (m, 5H), 3.34 (m, 14H), 3.06 (m, 1H), 2.06(m, 4H), 1.47 (m, 4H);
N-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环己烷-1,4-二胺(“A100”)
HPLC/MS 1.33 min (B), [M+H] 361; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.46 (dd, J = 5.3, 1.5 Hz, 1H), 9.41 - 9.29 (m, 3H), 9.10 (dd, J = 9.3,2.3 Hz, 1H), 8.59 (d, J = 9.3 Hz, 1H), 8.24 (dd, J = 8.5, 5.3 Hz, 1H), 4.00 -3.94 (m, 1H), 3.12 (m, 1H), 2.14 (m, 4H), 1.69 - 1.41 (m, 4H);
N-{3-[4-(四氢-吡喃-4-基氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-反式-环己烷-1,4-二胺(“A127”)
HPLC/MS 1.47 min (B), [M+H] 410;
(S)-1-{4-[5-(4-氨基-环己基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡咯烷-3-醇(“A128”)
HPLC/MS 1.37 min (B), [M+H] 395;
N-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-反式-环己烷-1,4-二胺(“A129”)
HPLC/MS 1.43 min (B), [M+H] 390。
实施例8
3-(4-{5-[3-(4-硝基-吡唑-1-基)-丙基氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-苯氧基)-丙酸(“A46”)和3-(4-{5-[3-(4-氨基-吡唑-1-基)-丙基氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-苯氧基)-丙酸(“A47”)的合成
向3-(4-硝基-吡唑-1-基)-丙胺二盐酸盐(340 mg, 1.40 mmol)在2-甲氧基乙醇(20 ml)中的溶液中加入3-[4-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-苯氧基]-丙酸(447 mg, 1.40 mmol)和三乙胺(581µl, 4.19 mmol)。将混合物加热至100℃,并在该温度搅拌90分钟。将反应混合物蒸发,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为灰色粉末的3-(4-{5-[3-(4-硝基-吡唑-1-基)-丙基氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-苯氧基)-丙酸;HPLC/MS 2.33 min (C), [M+H] 454; 1H NMR(500 MHz, DMSO-d6) δ [ppm] 12.4 (bs, 1H), 9.24 (s, 1H), 8.88 (s, 1H), 8.25(s, 1H), 8.18 (t, J = 5.8 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.6Hz, 2H), 4.27 (m, 4H), 3.37 (m, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.16 (m, 2H)。
用炭载钯作为催化剂(0.1 g)在室温和在常压下氢化3-(4-{5-[3-(4-硝基-吡唑-1-基)-丙基氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-苯氧基)-丙酸(63 mg, 0.14 mmol)在THF (20 ml)中的溶液。20小时以后,将催化剂滤出,并将滤液蒸发。通过制备型HPLC纯化残余物,得到作为白色无定形固体的3-(4-{5-[3-(4-氨基-吡唑-1-基)-丙基氨基]-[1,2,3]三唑并[4,5-d]嘧啶-3-基}-苯氧基)-丙酸;HPLC/MS 1.73 min (C), [M+H] 424; 1HNMR (500 MHz, DMSO-d6) δ [ppm] 9.75 (bs, 3H), 9.27 (s, 1H), 8.22 (s, 1H),8.04 (d, J = 8.3 Hz, 2H), 7.95 (s, 1H), 7.55 (s, 1H), 7.21 (d, J = 8.9 Hz,2H), 4.29 (t, J = 6.0 Hz, 2H), 4.24 (m, 2H), 3,4 (m, 2H), 2.77 (t, J = 6.0Hz, 3H), 2.12 (m, 2H)。
实施例9
2-二甲基氨基-1-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-乙酮(“A48”)的合成
向[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-哌啶-4-基-胺盐酸盐(163 mg, 0.45 mmol)和N,N-二甲基甘氨酸(51.6 mg, 0.50 mmol)在DMF (3 ml)中的溶液中加入O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU) (209 mg,0.65 mmol)、1-羟基苯并三唑水合物(HOBt) (20. 3 mg, 0.13 mmol)和4-甲基吗啉(NMM)(0.16 ml, 1.50 mmol),并将反应混合物在室温搅拌1小时。将反应混合物在水和乙酸乙酯之间分配。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用甲醇/二氯甲烷作为洗脱液进行色谱分离,得到作为白色粉末的2-二甲基氨基-1-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-乙酮;HPLC/MS 1.43 min (B), [M+H]411; 1H NMR (500 MHz, DMSO-d6/TFA-d1) δ [ppm] 9.24 (s, 1H), 8.02 (m, 2H), 7.14(d, J = 9.0 Hz, 2H), 4.35 (d, J = 16.2 Hz, 1H), 4.28 (m, 1H), 4.24 (d, J =16.1 Hz, 1H), 4.07 (m, 1H), 3.82 (s, 3H), 3.64 (dq, J = 13.8, 3.2 Hz, 1H),3.20 (t, J = 12.4 Hz, 1H), 3.02 (m, 1H), 2.82 (s, 3H), 2.81 (s, 3H), 2.00 (m,2H), 1.58 (m, 1H), 1.48 (m, 1H)。
类似地制备以下化合物:
3-二甲基氨基-1-{4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-哌啶-1-基}-丙烷-1-酮(“A49”)
HPLC/MS 1.42 min (B), [M+H] 425; 1H NMR (500 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.28 (s, 2H), 8.05 (m, 2H), 7.19 (d, J = 8.6 Hz, 2H), 4.32 (m, 1H),4.06 (m, 1H), 3.92 - 3.87 (m, 1H), 3.86 (s, 3H), 3.32 (t, J = 6.8 Hz, 2H),3.24 (m, 1H), 2.98 - 2.83 (m, 3H), 2.82 (s, 6H), 2.01 (m, 2H), 1.56 (m, 1H),1.46 (m, 1H)。
2-二甲基氨基-1-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-氮杂环丁烷-1-基}-乙酮(“A62”)
HPLC/MS 1.38 min (B), [M+H] 383;
3-二甲基氨基-1-{3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-氮杂环丁烷-1-基}-丙烷-1-酮(“A63”)
HPLC/MS 1.38 min (B), [M+H] 397;
2-二甲基氨基-1-{(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-乙酮甲酸盐(“A83”)
HPLC/MS 1.40 min (B), [M+H] 397; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.19 (s, 3H), 8.00 (m, 3H), 7.09 (m, 2H), 4.52 (m, 1H), 4.08 (m, 2H),3.79 (s, 3H), 3.68 (dt, J = 11.1, 6.0 Hz, 1H), 3.64 - 3.33 (m, 3H), 2.85 -2.76 (m, 6H), 2.30 - 2.02 (m, 2H);
3-二甲基氨基-1-{(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-丙烷-1-酮甲酸盐(“A85”)
HPLC/MS 1.39 min (B), [M+H] 411;
1-{(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-2-吡唑-1-基-乙酮(“A90”)
HPLC/MS 1.73 min (B), [M+H] 420; 1H NMR (500 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.29 (s, 1H), 8.09 (m, 2H), 7.79 (m, 1H), 7.74 - 7.56 (m, 1H), 7.20 (m,2H), 6.36 (m, 1H), 5.27 - 5.03 (m, 2H), 4.55 (m, 1H), 3.88 (s, 3H), 3.84 -3.57 (m, 3H), 3.57 - 3.32 (m, 1H), 2.40 - 1.99 (m, 2H);
2-二甲基氨基-1-{(S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-乙酮甲酸盐(“A91”)
HPLC/MS 1.43 min (B), [M+H] 397;
3-二甲基氨基-1-{(S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-丙烷-1-酮甲酸盐(“A92”)
HPLC/MS 1.47 min (B), [M+H] 411; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.30 (s, 1H), 8.13 (s, 1H), 8.11 - 7.98 (m, 2H), 7.20 (m, 2H), 4.56 (m, 0H),3.87 (s, 3H), 3.83 (dd, J = 10.7, 6.1 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.64 -3.41 (m, 2H), 3.37 - 3.26 (m, 2H), 2.81 (m, 7H), 2.38 - 1.98 (m, 2H);
1-{(S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-2-吡唑-1-基-乙酮(“A93”)
HPLC/MS 1.69 min (B), [M+H] 420;
3-二甲基氨基-1-((R)-3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-吡咯烷-1-基)-丙烷-1-酮(“A130”)
“A130”甲酸盐HPLC/MS 1.43 min (B), [M+H] 461;
3-(4-甲基-哌嗪-1-基)-1-((R)-3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-吡咯烷-1-基)-丙烷-1-酮(“A131”)
HPLC/MS 1.39 min (B), [M+H] 516;
1-{(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-3-(4-甲基-哌嗪-1-基)-丙烷-1-酮(“A132”)
“A132”甲酸盐HPLC/MS 1.43 min (B), [M+H] 466;
3-(4-甲基-哌嗪-1-基)-1-[(R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-吡咯烷-1-基]-丙烷-1-酮(“A133”)
“A133”甲酸盐HPLC/MS 1.35 min (B), [M+H] 487;
3-(4-甲基-哌嗪-1-基)-1-{(R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-基}-丙烷-1-酮(“A134”)
HPLC/MS 1.31 min (B), [M+H] 501。
实施例10
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[2-(4-甲基-哌嗪-1-基)-乙基]-胺(“A50”)的合成
向5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(200 mg, 0.76mmol)在THF (4 ml)中的溶液中加入三乙胺(107µl, 0.76 mmol)。将反应混合物在室温搅拌1小时。将反应混合物在二氯甲烷和水之间分配。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇进行色谱分离,得到作为灰白色粉末的[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[2-(4-甲基-哌嗪-1-基)-乙基]-胺;HPLC/MS1.47 min (A), [M+H] 369; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 9.22 (s, 1H), 8.03(d, J = 8.2 Hz, 2H), 7.92 (m, 1H), 7.17 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H),3.49 - 3.41 (m, 2H), 3.30 (m, 2H), 2.53 (m, 2H), 2.45 (m, 2H), 2.30 (m, 4H),2.14 (s, 3H)。
类似地制备以下化合物:
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-(3-吡咯烷-1-基-丙基)-胺(“A61”)
HPLC/MS 1.59 min (A), [M+H] 354; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.08 - 8.03 (m, 2H), 7.20 (d, J = 8.9 Hz, 2H), 3.88 (s,3H), 3.62 - 3.47 (m, 4H), 3.31 - 3.23 (m, 2H), 3.08 - 2.98 (m, 2H), 2.07 -1.97 (m, 4H), 1.89 (m, 2H);
(R)-1-{4-[5-((反式)-4-氨基-环己基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡咯烷-3-醇(“A70”)
HPLC/MS 1.36min (B), [M+H] 395; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.25 (s, 1H), 7.87 (m, 2H), 6.74 (d, J = 9.0 Hz, 2H), 4.48 (tt, J =4.9, 2.6 Hz, 1H), 3.75 (m, 1H), 3.51 (dd, J = 10.2, 4.8 Hz, 1H), 3.45 (td, J= 9.0, 7.0 Hz, 1H), 3.39 (td, J = 8.7, 3.5 Hz, 1H), 3.24 - 3.17 (m, 1H), 3.10- 3.01 (m, 1H), 2.17 - 1.94 (m, 6H), 1.54 - 1.37 (m, 4H);
1-{4-[5-((反式)-4-氨基-环己基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡咯烷-2-酮(“A71”)
HPLC/MS 1.36min (B), [M+H] 393; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.21 (d, J = 8.5 Hz, 2H), 7.98 - 7.91 (m, 2H), 3.95 (t, J= 7.0 Hz, 2H), 3.88 (m, 1H), 3.10 (m, 1H), 2.57 (m, 2H), 2.23 - 2.07 (m, 6H),1.51 (m, 4H);
{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-[3-(4-甲氧基-苯基)-丙基]-胺(“A80”)
HPLC/MS 3.05 min (C), [M+H] 435。
实施例11
反式-3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A51”)的合成
将(反式)-3-[3-(4-溴-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(146 mg, 0.39 mmol)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(106 mg, 0.51 mmol)和碳酸钾(163 mg, 1.17 mmol)在二氧杂环己烷(1 ml)和水(0.1 ml)的混合物中的混悬液用氮气冲洗,并在搅拌下加热至80℃。加入二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加成化合物(32 mg, 0.04 mmol),并将反应物在密闭反应瓶中在80℃在氮气下搅拌18小时。使反应混合物达到室温。将已经形成的沉淀物滤出,用水洗涤并在真空下干燥,得到作为灰色粉末的(反式)-3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇;HPLC/MS 1.66 min(B), [M+H] 377; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.23 (s, 1H), 8.24 (s, 1H),8.17 (d, J = 8.1 Hz, 2H), 8.08 (m, 1H), 7.96 (s, 1H), 7.83 (d, J = 8.3 Hz,2H), 4.55 (s, 1H), 4.42 (m, 1H), 4.25 (m, 1H), 3.89 (s, 3H), 3.57 (s, 3H),2.18 (m, 1H), 2.00 - 1.86 (m, 2H), 1.82 - 1.74 (m, 1H), 1.54 (m, 2H)。
类似地制备以下化合物:
N-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环己烷-1,4-二胺(“A52”)
原料为N-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环己烷-1,4-二胺(“A53”,实施例7)和1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑;
HPLC/MS 1.89 min (C), [M+H] 434; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.29 (s, 1H), 8.24 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H),7.88 - 7.80 (m, 2H), 4.37 (t, J = 5.2 Hz, 2H), 3.87 (m, 1H), 3.79 (t, J = 5.2Hz, 2H), 3.31 (s, 3H), 3.10 (m, 1H), 2.12 (m, 4H), 1.52 (m, 4H);
N-{3-[4-(1-乙基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-(反式)-环己烷-1,4-二胺三氟乙酸盐(“A54”)
原料为“A53”和1-乙基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑;
HPLC/MS 1.95 min (C), [M+H] 404; 1H NMR (400 MHz, DMSO-d6/TFA-d1) δ[ppm] 9.28 (s, 1H), 8.27 (d, J = 0.8 Hz, 1H), 8.17 (d, J = 8.3 Hz, 2H), 8.01(s, 1H), 7.92 - 7.70 (m, 2H), 4.24 (q, J = 7.3 Hz, 2H), 3.84 (m, 1H), 3.09(m, 1H), 2.28 - 1.99 (m, 4H), 1.68 - 1.27 (m, 7H)。
实施例12
将“A10”手性分离成“A55”和“A56”
将(反式)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A10”)在Chiralpak AD柱上用庚烷/乙醇作为洗脱液进行色谱分离,得到2种对映异构体:
首先洗脱的对映异构体: “A55”, 浅黄色粉末;HPLC/MS 1.69 min (B), [M+H]327 (任意分配的绝对构型)
第二洗脱的对映异构体“A56”, 浅黄色粉末;HPLC/MS 1.72 min (B), [M+H] 327(任意分配的绝对构型)。
实施例13
反式-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A57”)的合成
将(反式)-3-[3-(4-溴-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(195 mg, 0.52 mmol)、1-[2-(四氢-吡喃-2-基氧基)-乙基]-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(219 mg, 0.68 mmol)和碳酸钾(216 mg, 1.57mmol)在二氧杂环己烷(2 ml)和水(0.2 ml)的混合物中的混悬液用氮气冲洗,并在搅拌下加热至80℃。加入二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加成化合物(43 mg,0.05 mmol),并将反应物在氮气下在密闭反应瓶中在80℃搅拌18小时。将反应混合物蒸发,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为黄色粉末的(反式)-3-[3-(4-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇;HPLC/MS 1.82 min (B), [M+H] 491。
向(反式)-3-[3-(4-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(72 mg, 0.35 mmol)在二氯甲烷(6 ml)中的溶液中加入盐酸在二氧杂环己烷中的溶液(4 M, 410µl),并将反应混合物在室温搅拌1小时。将固体滤出,用二氯甲烷洗涤和在真空下干燥,得到作为浅棕色固体的(反式)-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇盐酸盐;HPLC/MS 1.55 min (B), [M+H] 407 1H NMR (500 MHz,DMSO-d6, TFA-d1) δ [ppm] 8.29 (s, 1H), 8.18 (m, 2H), 8.03 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 4.47 (m, 1H), 4.27 (m, 1H), 4.22 (t, J = 5.6 Hz, 2H), 3.81 (t,J = 5.6 Hz, 2H), 2.19 (m, 1H), 2.04 - 1.89 (m, 2H), 1.80 (m, 1H), 1.56 (m2H)。
实施例14
(1S,3R)-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺(“A58”) [第一对映异构体]和(1R,3S)-N-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺(“A59”) [第二对映异构体]的合成
向5-氯-3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(525 mg, 2.01mmol)和顺式-3-氨基-环戊基)-氨基甲酸叔丁酯盐酸盐(521 mg, 2.20 mmol)在2-甲氧基乙醇(15 ml)中的溶液中加入N-乙基二异丙胺(0.75 ml, 4.41 mmol)。将混合物加热至80℃,并在该温度搅拌3小时。将反应混合物冷却至室温。将固体滤出,用甲醇洗涤并在真空下干燥,得到作为米色粉末的{顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-氨基甲酸叔丁酯;HPLC/MS 2.06 min (B), [M+H] 426。
将{顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-氨基甲酸叔丁酯在Chiralpak AD-H柱上用超临界二氧化碳/甲醇(含有0.5%二乙胺)80: 20作为洗脱液进行色谱分离,得到两种对映异构体:
首先洗脱的对映异构体: N-[(1S,3R)-3-[[3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊基]氨基甲酸叔丁酯, 白色固体。
第二洗脱的对映异构体: N-[(1R,3S)-3-[[3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊基]氨基甲酸叔丁酯;淡米色固体
将N-[(1S,3R)-3-[[3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊基]氨基甲酸叔丁酯(136 mg, 0.32 mmol)在氯化氢于二氧杂环己烷中的溶液(4 M溶液, 1.1ml)中制浆,并加入甲醇(0.5 ml)。将反应混合物在室温搅拌3小时。将固体滤出,用二氯甲烷洗涤并在真空下干燥,得到作为白色固体的(1S,3R)-N3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺盐酸盐;HPLC/MS 1.47 min (B), [M+H]326; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.28 (s, 1H), 8.10 - 8.04 (m,2H), 7.23 - 7.16 (m, 2H), 4.30 (m, 1H), 3.87 (s, 3H), 3.60 (q, J = 7.5 Hz,1H), 2.11 - 1.99 (m, 2H), 1.89 - 1.73 (m, 2H), 1.67 (dt, J = 14.3, 7.5 Hz,1H)。
类似地处理N-[(1R,3S)-3-[[3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊基]氨基甲酸叔丁酯,得到作为白色固体的(1R,3S)-N3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-环戊烷-1,3-二胺盐酸盐;HPLC/MS 1.44 min (B), [M+H]326。
实施例15
{(1R,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-(4-甲基-哌嗪-1-基)-甲酮(“A60”)的合成
向(1R,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(142 mg, 0.40 mmol)在DMF (2 ml)中的溶液中加入N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(153 mg, 0.80 mmol)、1-羟基苯并三唑水合物(122 mg, 0.80mmol)和1-甲基哌嗪(47.7 mg, 0.48 mmol),并将反应混合物在室温搅拌3小时。将反应混合物在水和乙酸乙酯之间分配。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为白色粉末的{(1R,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-(4-甲基-哌嗪-1-基)-甲酮;HPLC/MS 1.49 min (B), [M+H] 437; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm]9.27 (s, 1H), 8.06 (m, 2H), 7.24 - 7.15 (m, 2H), 4.56 (m, 1H), 4.37 (m, 1H),4.21 (m, 1H), 3.88 (s, 3H), 3.45 (m, 3H), 3.24 (m, 1H), 3.01 (m, 3H), 2.86(s, 3H), 2.25 (dt, J = 14.4, 7.4 Hz, 1H), 2.11 - 1.60 (m, 5H)。
类似地制备以下化合物:
{(1S,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-(4-甲基-哌嗪-1-基)-甲酮(“A97”)
HPLC/MS 1.49 min (B), [M+H] 437; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.25 (s, 1H), 8.05 (m, 2H), 7.23 - 7.16 (m, 2H), 4.52 (m, 1H), 4.30 (s,1H), 4.21 (m, 1H), 3.87 (s, 3H), 3.56 - 3.43 (m, 2H), 3.38 (t, J = 13.5 Hz,1H), 3.22 (m, 1H), 3.12 - 3.00 (m, 1H), 3.00 - 2.90 (m, 2H), 2.84 (s, 3H),2.23 (m, 1H), 2.05 - 1.98 (m, 1H), 1.97 - 1.89 (m, 2H), 1.88 - 1.82 (m, 1H),1.75 (m, 1H)。
实施例16
反式-3-{3-[5-(1-甲基-1H-吡唑-4-基)-吡啶-2-基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A94”)的合成
HPLC/MS 1.50 min (B), [M+H] 378; 1H NMR (400 MHz, DMSO-d6) ppm [ppm]9.35 - 9.21 (m, 1H), 8.96 - 8.86 (m, 1H), 8.40 - 8.24 (m, 2H), 8.24 - 7.99(m, 3H), 4.65 - 4.34 (m, 2H), 4.29 - 4.18 (m, 1H), 3.91 (s, 3H), 2.23 - 2.03(m, 1H), 2.03 - 1.84 (m, 2H), 1.84 - 1.62 (m, 1H), 1.62 - 1.41 (m, 2H)。
实施例17
反式-N-{3-[4-(2-吗啉-4-基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基}-环己烷-1,4-二胺(“A95”)的合成
HPLC/MS 1.41 min (C), [M+H] 439; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.26 (s, 1H), 8.13 (s, 1H), 8.12 - 8.02 (m, 2H), 7.32 - 7.24 (m, 2H),4.50 (t, J = 4.8 Hz, 2H), 4.07 - 3.99 (m, 2H), 3.85 - 3.71 (m, 3H), 3.67 (t,J = 4.9 Hz, 2H), 3.60 (d, J = 12.5 Hz, 2H), 3.29 m, 2H), 3.07 (m, 1H), 2.13 -2.01 (m, 4H), 1.54 - 1.38 (m, 4H)。
实施例18
(1R,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A135”)的合成
在反应烧瓶中,将2,4-二氯-5-硝基-嘧啶(41.7 g, 215 mmol)溶解在THF (250ml)中,并将溶液在冰浴中冷却。在搅拌和外部冷却(3-5℃)下,逐滴加入4-(2-甲氧基-乙氧基)-苯基胺(35.9 g, 215 mmol)在THF (250 ml)中的溶液。形成橙色沉淀物。然后,仍然在冷却(2-5℃)下,缓慢地加入三乙胺(29.8 ml, 215 mmol)。使反应混合物达到室温并搅拌30分钟。将反应混合物抽滤,并将残余物用THF充分洗涤。将滤液蒸发,并将残余物与叔丁基甲基醚一起研磨,得到作为橙红色晶体的(2-氯-5-硝基-嘧啶-4-基)-[4-(2-甲氧基-乙氧基)-苯基]-胺;HPLC/MS 1.93 min (B), [M+H] 325;
1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.12 (s, 1H), 7.41 (d, J =9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz, 1H), 4.38 - 3.96 (m, 2H), 3.87 - 3.56 (m,2H), 3.32 (s, 3H)。
向(2-氯-5-硝基-嘧啶-4-基)-[4-(2-甲氧基-乙氧基)-苯基]-胺(68.9 g, 212mmol)在THF (710 ml)中的溶液中加入海绵体镍-催化剂(pH-中性, THF-润湿),并将混合物在常压和室温氢化40小时。将反应混合物抽滤。将滤液蒸发,并在真空下干燥,得到作为棕色固体的2-氯-N4-[4-(2-甲氧基-乙氧基)-苯基]-嘧啶-4,5-二胺;HPLC/MS 1.63 min(B), [M+H] 295;
1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.59 (s, 1H), 7.53 (d, J =9.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 5.17 (s, 2H), 4.20 - 3.97 (m, 2H),3.80 - 3.50 (m, 2H), 3.31 (s, 3H)。
向2-氯-N4-[4-(2-甲氧基-乙氧基)-苯基]-嘧啶-4,5-二胺(57.0 g, 193 mmol)在乙腈(600 ml)中的溶液中加入亚硝酸丁酯(30.8 g, 34.9 ml, 290 mmol)。将溶液加热至70℃,并在该温度搅拌3小时。将反应混合物冷却至室温,并在减压下浓缩。将残余物在硅胶柱(1 kg硅胶60)上用叔丁基甲基醚作为洗脱液进行色谱分离。将含有产物的级分合并,并在减压下浓缩,直到沉淀物形成。将固体滤出,用庚烷洗涤并在真空下干燥,得到作为浅黄色晶体的5-氯-3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 2.63 min (C), [M+H] 306;
1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.94 (d, J = 9.1 Hz, 2H),7.28 (d, J = 9.0 Hz, 2H), 4.42 - 4.06 (m, 3H), 3.90 - 3.66 (m, 2H), 3.35 (s,3H)。
向5-氯-3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶(3.36g, 11.0 mmol)在2-甲氧基乙醇(50 ml)中的溶液中加入(1R,3R)-3-氨基-环戊烷甲酸盐酸盐(1.82 g, 11.0 mmol)和N-乙基二异丙胺(3.75 ml, 22.1 mmol)。将混合物加热至80℃,并在该温度搅拌90分钟。将反应混合物冷却至室温并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为米色无定形固体的(1R,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸;HPLC/MS1.77 min (B), [M+H] 399;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.23 (s, 1H), 8.05 (bs, 2H), 7.17(d, J = 8.8 Hz, 2H), 4.31 (bs, 1H), 4.24 - 4.06 (m, 2H), 3.79 - 3.62 (m, 2H),3.32 (s, 3H), 3.00 - 2.81 (m, 1H), 2.21 (bs, 1H), 2.10 - 1.94 (m, 2H), 1.84(ddd, J = 13.2, 8.9, 5.8 Hz, 1H), 1.76 (m, 1H), 1.68 (m, 1H)。
在反应烧瓶中,将(1R,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸(1.55 g, 3.87 mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(1.50 g, 7.82 mmol)和1-羟基苯并三唑水合物(525 mg, 3.89mmol)溶解在0.5M的氨在二氧杂环己烷中的溶液(40 ml, 20.0 mmol氨)中。将反应混合物在60℃搅拌16小时。然后将它蒸发,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为浅黄色固体的(1R,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺;HPLC/MS 1.65 min (B), [M+H]398;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.28 (s, 1H), 8.09 (bs, 2H), 7.32- 6.93 (m, 2H), 4.37 (bs, 1H), 4.32 - 4.08 (m, 2H), 3.79 - 3.68 (m, 2H), 3.36(s, 3H), 2.87 (p, J = 8.0 Hz, 1H), 2.23 - 2.05 (m, 2H), 2.06 - 1.96 (m, 1H),1.87 (m, 1H), 1.74 (m, 2H)。
类似地制备以下化合物
(1S,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A136”)
HPLC/MS 1.73 min (B), [M+H] 354;
(1S,3S)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A137”)
HPLC/MS 1.70 min (B), [M+H] 354;
(1S,3R)-3-[3-(4-吡咯烷-1-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A138”)
HPLC/MS 1.91 min (B), [M+H] 393;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(“A139”)
HPLC/MS 1.79 min (B), [M+H] 355;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A140”)
HPLC/MS 1.68 min (B), [M+H] 354;
(1S,3R)-3-[3-(2-甲基-苯并噁唑-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A141”)
HPLC/MS 2.20 min (C), [M+H] 379;
4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-丁酰胺(“A142”)
HPLC/MS 1.61 min (B), [M+H] 328;
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.22 (s, 1H), 8.19 - 7.89 (m, 3H),7.29 - 7.14 (m, 3H), 6.72 (s, 1H), 3.85 (s, 3H), 3.44 - 3.27 (m, 2H), 2.19 -2.09 (m, 2H), 1.88 - 1.73 (m, 2H);
4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷甲酸酰胺(“A143”)
HPLC/MS 1.71 min (B), [M+H] 368;
3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-丁酰胺(“A144”)
HPLC/MS 2.22 min (C), [M+H] 328;
(反式)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环丁烷甲酸酰胺(“A145”)
HPLC/MS 1.62 min (B), [M+H] 340;
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.24 (s, 1H), 8.45 (d, J=6.5, 1H),8.00 (d, J=8.6, 2H), 7.28 - 7.13 (m, 3H), 6.75 (s, 1H), 4.46 - 4.35 (m, 1H),3.86 (s, 3H), 3.02 - 2.89 (m, 1H), 2.53 - 2.37 (m, 2H), 2.34 - 2.14 (m, 2H);
(1R,3R)-3-[3-(4-吡咯烷-1-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A146”)
HPLC/MS 1.86 min (B), [M+H] 393;
(1R,3R)-3-[3-(2-甲基-苯并噻唑-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A147”)
HPLC/MS 1.66 min (B), [M+H] 395;
(反式)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷甲酸酰胺(“A148”)
HPLC/MS 2.36 min (C), [M+H] 368;
(1S,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A149”)
HPLC/MS 1.82 min (B), [M+H] 368;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.24 (s, 1H), 7.98 (d, J =8.8 Hz, 2H), 7.11 (d, J = 9.1 Hz, 2H), 4.40 - 4.25 (m, 1H), 4.08 (q, J = 6.9Hz, 2H), 2.77 (p, J = 7.8 Hz, 1H), 2.17 (ddd, J = 12.9, 8.5, 6.7 Hz, 1H),1.98 - 1.67 (m, 5H), 1.34 (t, J = 7.0 Hz, 3H);
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A150”)
HPLC/MS 1.75 min (B), [M+H] 368;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.34 (s, 1H), 8.08 (d, J =8.5 Hz, 1H), 7.36 - 7.03 (m, 2H), 4.59 - 4.37 (m, 1H), 4.15 (q, J = 7.0 Hz,2H), 2.98 (p, J = 8.0 Hz, 1H), 2.25 (dt, J = 13.7, 7.4 Hz, 1H), 2.22 - 2.14(m, 1H), 2.09 (dtd, J = 11.7, 7.7, 4.3 Hz, 1H), 1.95 (ddd, J = 13.5, 8.7, 5.2Hz, 1H), 1.87 - 1.68 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H);
(1R,3R)-3-{3-[4-((S)-3,3,3-三氟-2-羟基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A151”)
HPLC/MS 1.71 min (B), [M+H] 352;
(1R,3R)-3-[3-(3-氟-4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A152”)
HPLC/MS 2.33 min (C), [M+H] 372;
(1R,3R)-3-{3-[4-(2-羟基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A153”)
HPLC/MS 1.53 min (B), [M+H] 384;
(1R,3R)-3-{3-[3-氟-4-(3-氧代-吗啉-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A154”)
HPLC/MS 1.54 min (B), [M+H] 441;
(1R,3R)-3-{3-[4-((R)-3,3,3-三氟-2-羟基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A155”)
HPLC/MS 1.70 min (B), [M+H] 452;
(1R,3R)-3-[3-(2,3-二氢-苯并[1,4]二氧杂环己烯-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A156”)
HPLC/MS 2.26 min (C), [M+H] 382;
(1R,3R)-3-[3-(4-乙氧基-3-氟-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A157”)
HPLC/MS 1.79 min (B), [M+H] 386;
(1R,3R)-3-[3-(3-氟-4-吗啉-4-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A158”)
HPLC/MS 1.73 min (B), [M+H] 427;
(1R,3R)-3-{3-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A159”)
HPLC/MS 1.92 min (C), [M+H] 372;
(1R,3R)-3-{3-[4-(2-吡唑-1-基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A160”)
HPLC/MS 1.65 min (B), [M+H] 434;
(1R,3R)-3-{3-[4-(3,3,3-三氟-2-羟基-2-三氟甲基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A161”)
HPLC/MS 1.88 min (B), [M+H] 520;
(1R,3R)-3-[3-(4-甲氧基-3-甲基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A162”)
HPLC/MS 1.75 min (B), [M+H] 368;
(1R,3R)-3-[3-(3,5-二氟-4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A163”)
HPLC/MS 1.79 min (B), [M+H] 390;
(1R,3R)-3-[3-(4-异丙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A164”)
HPLC/MS 1.80 min (B), [M+H] 382;
(反式)-3-{3-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环己烷甲酸酰胺(“A165”)
HPLC/MS 1.54 min (B), [M+H] 386;
(1S,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A166”)
HPLC/MS 1.72 min (B), [M+H] 398;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.28 (s, 1H), 8.05 (d, J =8.5 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 4.33 (bs, 1H), 4.26 - 4.17 (m, 2H),3.86 - 3.68 (m, 2H), 3.36 (s, 3H), 2.78 (p, J = 8.1 Hz, 1H), 2.26 - 2.15 (m,1H), 1.96 (ddt, J = 15.5, 8.1, 4.4 Hz, 1H), 1.91 - 1.83 (m, 2H), 1.78 (td, J= 14.4, 7.3 Hz, 2H);
(1R,3R)-3-{3-[4-(2-甲氧基-1-甲氧基甲基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A167”)
HPLC/MS 1.68 min (B), [M+H] 442;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.25 (s, 1H), 7.97 (d, J =8.7 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H), 4.61 (p, J = 5.1 Hz, 1H), 4.35 (p, J =6.2 Hz, 1H), 3.52 (d, J = 5.0 Hz, 4H), 3.24 (s, 6H), 2.89 (p, J = 8.0 Hz,1H), 2.22 - 2.02 (m, 2H), 1.98 (td, J = 8.5, 4.3 Hz, 1H), 1.85 (ddd, J =13.3, 8.6, 5.1 Hz, 1H), 1.78 - 1.59 (m, 2H);
(1R,3R)-3-{3-[4-(四氢-吡喃-4-基氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A168”)
HPLC/MS 1.72 min (B), [M+H] 424;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.28 (s, 1H), 8.08 (bs, 2H),7.25 (d, J = 8.8 Hz, 2H), 4.70 (tt, J = 8.5, 4.0 Hz, 1H), 4.37 (bs, 1H), 3.91(dt, J = 11.6, 4.4 Hz, 2H), 3.54 (ddd, J = 11.9, 9.4, 2.8 Hz, 2H), 2.87 (p, J= 8.0 Hz, 1H), 2.25 - 1.95 (m, 5H), 1.88 (m, 1H), 1.81 - 1.59 (m, 4H);
(1R,3R)-3-{3-[4-(2-乙氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A169”)
HPLC/MS 1.66 min (B), [M+H] 412;
(1R,3R)-3-[(3-薁-2-基三唑并[4,5-d]嘧啶-5-基)氨基]环戊烷甲酰胺(“A169a”)
(1R,3R)-3-[[3-(6-氟-2-萘基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A169b”)
(1R,3R)-3-[[3-(4-叔-丁氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A169c”)
(1R,3R)-3-[[3-[4-(2-羟基-1,1-二甲基-乙氧基)苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A169d”)
(1R,3R)-3-[[3-[4-[(3R)-四氢呋喃-3-基]氧基苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A169e”)
(1R,3R)-3-[[3-[4-[(3S)-四氢呋喃-3-基]氧基苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A169f”)
。
实施例19
(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A170”)的合成
在反应烧瓶中,将2,4-二氯-5-硝基-嘧啶(7.76 g, 40.0 mmol)溶解在THF (40ml)中,并将溶液在冰浴中冷却。在搅拌和外部冷却(3-5℃)下,逐滴加入4-碘-苯基胺(8.76g, 40.0 mmol)在THF (20 ml)中的溶液。然后,仍然在冷却(2-5℃)下,缓慢地加入三乙胺(5.54 ml, 40.0 mmol)在THF (20 ml)中的溶液。将反应混合物在冰冷却下搅拌30分钟,然后使其达到室温。将反应混合物抽滤,并将残余物用THF充分洗涤。将滤液蒸发,并将残余物用水处理。将固体滤出,用水洗涤并在真空下干燥,得到作为黄色粉末的(2-氯-5-硝基-嘧啶-4-基)-(4-碘-苯基)-胺;HPLC/MS 2.13 min (B), [M+H] 377。
向(2-氯-5-硝基-嘧啶-4-基)-(4-碘-苯基)-胺(11.4 g, 30.3 mmol)在乙酸乙酯(120 ml)和乙醇(60 ml)的混合物中的溶液中加入氯化锡(II) (17.2 g, 90.8 mmol),并将反应混合物在70℃搅拌60分钟。将反应混合物冷却至室温,用饱和碳酸钠溶液碱化,经硅藻土垫过滤,并将残余物用乙酸乙酯洗涤。将滤液的有机相分离,经硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱分离,得到作为棕色固体的2-氯-N4-(4-碘-苯基)-嘧啶-4,5-二胺;HPLC/MS 2.72 min (C), [M+H] 347。
向2-氯-N4-(4-碘-苯基)-嘧啶-4,5-二胺(8.50 g, 24.5 mmol)在乙腈(110 ml)中的溶液中加入亚硝酸丁酯(4.30 ml, 36.8 mmol)。将溶液加热至70℃,并在该温度搅拌90分钟。将反应混合物冷却至室温。将固体滤出,用乙腈和2-丙醇洗涤并在真空下干燥,得到作为棕色粉末的5-氯-3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶;HPLC/MS 3.14min (C), [M+H] 358。
向5-氯-3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(1.79 g, 5.0 mmol)在2-甲氧基乙醇(12.5 ml)中的溶液中加入(1R,3R)-3-氨基-环戊烷甲酸盐酸盐(910 mg,5.50 mmol)和N-乙基二异丙胺(1.87 ml, 11.0 mmol)。将混合物加热至80℃,并在该温度搅拌3小时。将反应混合物冷却至室温并加入水。将得到的沉淀物滤出,用水洗涤并在真空下干燥,得到作为米色固体的(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸;HPLC/MS 2.82 min (C), [M+H] 451。
向(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2.26 g, 5.02 mmol)在THF (12 ml)中的混悬液中加入N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(1.93 g, 10.1 mmol)、1-羟基苯并三唑水合物(678 mg, 5.02mmol)和0.5M的氨在二氧杂环己烷中的溶液(50.2 ml, 25.1 mmol氨)。将反应混合物在室温搅拌3天。然后将它在二氯甲烷和饱和的碳酸氢钠溶液之间分配。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为灰白色晶体的(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺;HPLC/MS 2.61 min (C), [M+H] 450;
1H NMR (300 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.27 (s, 1H), 8.12 (d, J =8.4 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 4.41 (bs, 1H), 2.91 (p, J = 7.9 Hz,1H), 2.43 - 1.97 (m, 3H), 1.96 - 1.59 (m, 3H)。
类似地制备以下化合物:
(1S,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A171”)
HPLC/MS 1.94 min (B), [M+H] 450;
(1S,3R)-3-(3-苯并[1,2,5]噻二唑-5-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A172”)
HPLC/MS 2.43 min (C), [M+H] 382;
(1R,3R)-3-[3-(6-甲氧基-吡啶-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A173”)
HPLC/MS 1.64 min (B), [M+H] 355;
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.25 (s, 1H), 8.92 (s, 1H), 8.44 -8.36 (m, 1H), 8.31 - 8.23 (m, 1H), 7.23 (s, 1H), 7.11 (d, J=9.0, 1H), 6.70(s, 1H), 4.34 - 4.22 (m, 1H), 3.95 (s, 3H), 2.78 (p, J=7.9, 1H), 2.12 - 2.00(m, 2H), 1.98 - 1.77 (m, 2H), 1.73 - 1.56 (m, 2H);
(1R,3R)-3-(3-苯并[1,2,5]噻二唑-5-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A174”)
HPLC/MS 2.34 min (C), [M+H] 382;
(1R,3R)-3-[3-(5-甲氧基-吡啶-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A175”)
HPLC/MS 1.50 min (B), [M+H] 355;
(1R,3R)-3-[3-(3-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A176”)
HPLC/MS 1.84 min (B), [M+H] 450; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.77 (bs, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 8.0Hz, 0H), 7.42 (t, J = 8.1 Hz, 1H), 4.42 (bs, 1H), 2.96 (p, J = 8.0 Hz, 1H),2.22 (m, 2H), 2.15 - 1.91 (m, 2H), 1.90 - 1.65 (m, 2H);
(1R,3R)-3-[3-(5-碘-吡啶-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A177”)
HPLC/MS 2.19 min (C), [M+H] 451;
(1R,3R)-3-[3-(5-乙氧基-吡啶-2-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A178”)
HPLC/MS 2.06 min (C), [M+H] 369;
(1R,3R)-3-[3-(6-乙氧基-吡啶-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A179”)
HPLC/MS 2.29 min (C), [M+H] 369;
(1R,3R)-3-[3-(2-甲基-苯并呋喃-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A180”)
HPLC/MS 2.51 min (C), [M+H] 378;
(1R,3R)-3-[3-(2-甲氧基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A181”)
HPLC/MS 2.50 min (C), [M+H] 405;
(1R,3R)-3-{3-[2-(2-乙氧基-乙氧基)-喹啉-6-基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A182”)
HPLC/MS 2.55 min (C), [M+H] 463;
(1R,3R)-3-[3-(1,2-二甲基-1H-苯并咪唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A183”)
HPLC/MS 1.63 min (C), [M+H] 392;
(1R,3R)-3-[3-(2-甲基-喹唑啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A184”)
HPLC/MS 1.37 min (B), [M+H] 390; 1H NMR (500 MHz, DMSO-d6) δ [ppm] =9.76 (s, 1H), 9.30 (s, 1H), 9.09 - 9.04 (m, 1H), 8.92 - 8.83 (m, 1H), 8.41(d, J=6.6, 1H), 8.18 (d, J=9.1, 1H), 7.34 - 7.25 (m, 1H), 6.83 - 6.73 (m,1H), 4.46 - 4.37 (m, 1H), 2.88 - 2.77 (m, 4H), 2.35 - 2.27 (m, 1H), 2.16 -1.91 (m, 2H), 1.84 - 1.57 (m, 3H);
(1R,3R)-3-[3-(2-甲基-2H-吲唑-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A185”)
HPLC/MS 1.56 min (B), [M+H] 378; 1H NMR (400 MHz, DMSO-d6) δ [ppm] =9.31 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 7.97 (2H), 4.45 (s, 1H), 4.28 (s,3H), 2.93 (p, J = 8.0 Hz, 1H), 2.25 - 2.10 (m, 2H), 2.10 - 1.91 (m, 2H), 1.86- 1.70 (m, 2H);
(1R,3R)-3-[3-(2-甲基-2H-吲唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A186”)
HPLC/MS 1.56 min (B), [M+H] 378; 1H NMR (500 MHz, DMSO-d6) δ [ppm] =9.29 (s, 1H), 8.60 (m, 2H), 8.07 (bs, 1H), 7.87 (d, J = 9.2 Hz, 1H), 4.59 -4.30 (m, 1H), 4.26 (s, 3H), 2.87 (p, J = 7.9 Hz, 1H), 2.30 - 2.15 (m, 1H),2.10 (tt, J = 11.8, 5.0 Hz, 1H), 2.01 (dq, J = 11.0, 8.1 Hz, 1H), 1.84 (ddd,J = 13.6, 8.8, 5.6 Hz, 1H), 1.75 (dtd, J = 18.3, 12.8, 7.0 Hz, 2H);
(1R,3R)-3-[(3-噌啉-6-基三唑并[4,5-d]嘧啶-5-基)氨基]环戊烷甲酰胺(“A186a”)
(1R,3R)-3-[[3-(7-甲氧基-3-喹啉基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186b”)
(1R,3R)-3-[[3-(2-甲基吲嗪-7-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186c”)
(1R,3R)-3-[[3-(2-甲基吲嗪-6-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186d”)
(1R,3R)-3-[[3-(2-甲基咪唑并[1,2-a]吡啶-6-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186e”)
(1R,3R)-3-[[3-(2-甲基-1H-吲哚-5-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186f”)
(1R,3R)-3-[[3-(2-甲基异吲哚-5-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186g”)
(1R,3R)-3-[[3-(7-甲基吲嗪-2-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186h”)
(1R,3R)-3-[[3-(1H-吲唑-5-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186i”)
(1R,3R)-3-[[3-(2-甲基-3H-苯并咪唑-5-基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A186j”)
。
实施例20
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A187”)的合成
将2,4-二氯-5-硝基-嘧啶(11.5 g,59.3 mmol)在THF (25 ml)中的溶液冷却至0℃。在搅拌下向该溶液中逐滴加入6-氨基-2-甲基喹啉(10.4 g, 65.9 mmol)在THF (95ml)中的溶液。使反应混合物达到室温。将已经形成的沉淀物滤出,用水洗涤并在真空下干燥,得到作为黄色晶体的(2-氯-5-硝基-嘧啶-4-基)-(2-甲基-喹啉-6-基)-胺盐酸盐;HPLC/MS 1.42 min (A), [M+H] 316; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.84 (s,1H), 9.24 (s, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.49 - 8.34 (m, 2H), 8.22 (dd, J= 9.1, 2.4 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 2.96 (s, 3H)。
向(2-氯-5-硝基-嘧啶-4-基)-(2-甲基-喹啉-6-基)-胺盐酸盐(10.27 g, 29.2mmol)在水(80 ml)中的混悬液中加入氯化铵(935 mg, 17.5 mmol)和乙醇(80 ml)。将混合物在搅拌下加热至55℃,然后逐份加入颗粒尺寸为10µm的铁(8.15 g, 146 mmol)。将反应混合物在55℃搅拌18小时。将反应混合物经硅藻土过滤,并用乙醇洗涤。将滤液蒸发,并在真空下干燥,得到作为黄色固体的2-氯-N4-(2-甲基-喹啉-6-基)-嘧啶-4,5-二胺,将其原样用在下一步中;HPLC/MS 1.26 min (B), [M+H] 286。
向粗制的2-氯-N4-(2-甲基-喹啉-6-基)-嘧啶-4,5-二胺(12.9 g, 大约28 mmol)在乙腈(100 ml)中的溶液中加入亚硝酸丁酯(8.64 ml, 70.2 mmol)。将溶液加热至80℃,并在该温度搅拌2小时。将反应混合物冷却至室温,并在减压下浓缩。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为浅黄色固体的6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2-甲基-喹啉;HPLC/MS 1.61 min (B), [M+H] 297;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.93 (s, 1H), 9.34 (d, J =8.6 Hz, 1H), 9.12 (d, J = 2.3 Hz, 1H), 8.90 (dd, J = 9.2, 2.3 Hz, 1H), 8.59(d, J = 9.2 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 3.04 (s, 3H)。
向6-(5-氯-[1,2,3]三唑并[4,5-d]嘧啶-3-基)-2-甲基-喹啉(1.16 g, 4.0mmol)在2-甲氧基乙醇(18 ml)中的溶液中加入(1R,3R)-3-氨基-环戊烷甲酸盐酸盐(729mg, 4.4 mmol)和N-乙基二异丙胺(1.36 ml, 8.0 mmol)。将混合物加热至80℃,并在该温度搅拌3天。将反应混合物冷却至室温并浓缩。将残余物在硅胶柱上用甲醇/二氯甲烷作为洗脱液进行色谱分离,得到作为浅橙色固体的(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸;HPLC/MS 1.52 min (B), [M+H] 390。
在反应烧瓶中,向(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(845 mg, 2.17 mmol)中加入N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(832 mg, 4.34 mmol)、1-羟基苯并三唑水合物(295 mg, 2.18 mmol)和0.5M的氨在二氧杂环己烷中的溶液(22 ml, 11 mmol氨)。将得到的混悬液在室温搅拌18小时。将反应混合物浓缩,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为浅橙色无定形固体的(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺;HPLC/MS 1.41 min (B), [M+H] 389;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.34 (m, 3H), 9.19 - 9.04(m, 1H), 8.51 (d, J = 9.3 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 4.56 (m, 1H),2.95 (p, J = 8.0 Hz, 1H), 2.40 (m, 1H), 2.13 (m, 2H), 1.91 - 1.67 (m, 3H)。
类似地制备以下化合物:
(1S,3R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸(“A188”)
HPLC/MS 1.64 min (B), [M+H] 376;
(1S,3R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A189”)
HPLC/MS 1.55 min (B), [M+H] 375;
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.29 (s, 1H), 9.00 (dd, J=4.2,1.7, 1H), 8.86 (d, J=2.4, 1H), 8.67 - 8.60 (m, 1H), 8.58 - 8.52 (m, 1H), 8.38(d, J=6.9, 1H), 8.29 (d, J=9.1, 1H), 7.71 - 7.63 (m, 1H), 7.39 - 7.30 (m,1H), 6.87 - 6.76 (m, 1H), 4.39 - 4.28 (m, 1H), 2.79 - 2.71 (m, 1H), 2.29 -2.19 (m, 1H), 2.06 - 1.96 (m, 1H), 1.90 - 1.73 (m, 4H);
(1R,3R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A190”)
HPLC/MS 1.55 min (B), [M+H] 375;
1H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.30 (s, 1H), 9.03 - 8.93 (m, 2H),8.68 (dd, J=9.2, 2.5, 1H), 8.60 (d, J=8.3, 1H), 8.36 (d, J=6.5, 1H), 8.28 (d,J=9.3, 1H), 7.70 - 7.62 (m, 1H), 7.34 - 7.21 (m, 1H), 6.80 - 6.66 (m, 1H),4.47 - 4.33 (m, 1H), 2.89 - 2.77 (m, 1H), 2.32 - 1.53 (m, 6H);
(1S,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A191”)
HPLC/MS 1.47 min (B), [M+H] 389;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] = 9.32 (s, 1H), 9.26 (m,2H), 9.08 (d, J = 9.4 Hz, 1H), 8.51 (d, J = 9.3 Hz, 1H), 8.11 (d, J = 8.7 Hz,1H), 4.48 (bs, 1H), 3.04 (s, 3H), 2.87 (p, J = 7.5 Hz, 1H), 2.28 (dt, J =13.3, 6.4 Hz, 1H), 1.91 (m, 5H);
(反式)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷甲酸酰胺(“A192”)
HPLC/MS 1.95 min (C), [M+H] 403;
(1S,3S)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A193”)
HPLC/MS 1.44 min (B), [M+H] 389;
(1R,3R)-3-(3-[1,5]萘啶-2-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A194”)
HPLC/MS 1.91 min (C), [M+H] 376;
(1R,3R)-3-[3-(1-甲基-1H-吲唑-5-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A195”)
HPLC/MS 1.52 min (B), [M+H] 378;
(1R,3R)-3-[[3-(7-甲基-3-喹啉基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A195a”)
(1R,3R)-3-[[3-(2-甲基-1-氧代-6-异喹啉基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A195b”)
。
实施例21
(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A196”)和(1S,3S)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A197”)的合成
向5-氯-3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶(2.36 g, 6.6 mmol)在2-甲氧基乙醇(30 ml)中的溶液中加入反式-3-氨基环戊烷醇盐酸盐(外消旋混合物; 1.0g, 7.3 mmol)和N-乙基二异丙胺(2.47 ml, 14.5 mmol)。将混合物加热至80℃,并在该温度搅拌90分钟。将反应混合物冷却至室温并加入水。将得到的沉淀物滤出,用水洗涤并在真空下干燥,得到作为米色固体的(反式)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(外消旋混合物);HPLC/MS 1.94 min (B), [M+H] 423;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.26 (s, 1H), 8.16 - 8.05(m, 2H), 8.06 - 7.96 (m, 2H), 4.51 (bs, 1H), 4.32 (tt, J = 6.0, 3.2 Hz, 1H),2.24 (dt, J = 12.6, 7.6 Hz, 1H), 2.11 - 1.93 (m, 2H), 1.81 (dt, J = 13.3, 6.6Hz, 1H), 1.61 (ddt, J = 12.2, 8.1, 5.0 Hz, 2H)。
用Lux-Amylose-2作为固定相和用庚烷/乙醇8: 2作为流动相,将(反式)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇通过手性色谱法在手性柱上分离,得到两种对映异构体。两种对映异构体都是米色固体。LC/MS数据和NMR数据与外消旋混合物的那些数据相同。
类似地制备以下化合物:
(反式)-3-[3-(4-吡咯烷-1-基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A198”)
HPLC/MS 1.91 min (B), [M+H] 366;
(反式)-3-[3-(2-甲基-苯并噁唑-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A199”)
HPLC/MS 2.17 min (C), [M+H] 352;
(反式)-3-(3-苯并[1,2,5]噻二唑-5-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A200”)
HPLC/MS 2.40 min (C), [M+H] 355;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环己烷醇(“A201”)
HPLC/MS 1.79 min (C), [M+H] 341; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.33 (s, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.24 - 7.16 (m, 2H), 4.31 (bs,1H), 4.05 (bs, 1H), 3.88 (s, 3H), 1.92 (m, 1H), 1.85 - 1.19 (m, 7H);
(反式)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A202”)
HPLC/MS 1.48 min (B), [M+H] 362;
(1R,3R)-3-{3-[4-(2-羟基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A203”)
HPLC/MS 1.53 min (B), [M+H] 357;
(1R,3R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A204”)
HPLC/MS 1.54 min (B), [M+H] 348;
(反式)-3-{3-[4-((S)-3,3,3-三氟-2-羟基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A205”)
HPLC/MS 1.73 min (B), [M+H] 425;
(反式)-3-[3-(6-乙氧基-吡啶-3-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A206”)
HPLC/MS 1.76 min (B), [M+H] 342; 1H NMR (400 MHz, DMSO-d6) δ ppm =9.36 - 9.20 (m, 1H), 8.93 - 8.76 (m, 1H), 8.41 - 8.25 (m, 1H), 8.25 - 7.93(m, 1H), 7.08 (d, J=8.9, 1H), 4.55 - 4.46 (m, 1H), 4.46 - 4.32 (m, 3H), 4.28- 4.17 (m, 1H), 2.22 - 2.02 (m, 1H), 2.02 - 1.83 (m, 2H), 1.83 - 1.62 (m,1H), 1.60 - 1.43 (m, 2H), 1.37 (t, J=7.0, 3H);
(反式)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A207”)
HPLC/MS 2.52 min (C), [M+H] 341; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 4.50(bs, 1H), 4.30 (tt, J = 6.0, 3.2 Hz, 1H), 4.15 (q, J = 6.9 Hz, 2H), 2.30 -2.13 (m, 1H), 1.99 (m, 2H), 1.80 (dt, J = 13.4, 6.7 Hz, 1H), 1.69 - 1.50 (m,2H), 1.40 (t, J = 7.0 Hz, 3H);
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A208”)
HPLC/MS 1.48 min (B), [M+H] 362;
(反式)-3-[3-(2-甲基-喹唑啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A209”)
HPLC/MS 1.33 min (B), [M+H] 363; 1H NMR (400 MHz, DMSO-d6) δ ppm =9.67 - 9.64 (m, 1H), 9.28 (s, 1H), 9.04 - 8.97 (m, 1H), 8.89 - 8.81 (m, 1H),8.37 - 8.29 (m, 1H), 8.18 (d, J=9.1, 1H), 4.68 - 4.54 (m, 1H), 4.53 - 4.44(m, 1H), 4.31 - 4.21 (m, 1H), 2.83 (s, 3H), 2.25 - 2.02 (m, 2H), 2.01 - 1.88(m, 1H), 1.82 - 1.69 (m, 1H), 1.67 - 1.45 (m, 2H);
(反式)-3-[3-(4-异丙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A210”)
HPLC/MS 1.87 min (B), [M+H] 355。
实施例22
(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A211”)的合成
向(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(314 mg, 0.70 mmol)和1-(2-乙氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(242 mg, 0.91 mmol)在二氧杂环己烷(2 ml)中的溶液中加入水(0.2 ml)和碳酸钾(290 mg, 2.10 mmol)。将混合物用氮气冲洗,并加热至80℃。加入二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加成化合物(57 mg, 0.07 mmol),并将混合物在密闭反应瓶中在80℃搅拌18小时。使反应混合物达到室温并用水处理。将得到的沉淀物滤出,用水洗涤并在真空下干燥。将它在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为米色固体的(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺;HPLC/MS 2.33min (C), [M+H] 462; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.30 (s, 1H),8.26 (m, 3H), 8.06 (s, 1H), 7.90 - 7.84 (m, 2H), 4.50 - 4.42 (m, 1H), 4.36(t, J = 5.4 Hz, 2H), 3.82 (t, J = 5.4 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 2.94(p, J = 8.0 Hz, 1H), 2.28 - 2.12 (m, 1H), 2.06 (dtd, J = 11.2, 7.4, 6.8, 4.1Hz, 1H), 1.95 (ddd, J = 13.3, 8.7, 4.2 Hz, 1H), 1.79 (m, 2H), 1.12 (t, J =7.0 Hz, 3H)。
类似地制备以下化合物:
(1R,3R)-3-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A212”)
HPLC/MS 1.67 min (B), [M+H] 421;
(1R,3R)-3-(3-{4-[1-(2-吡咯烷-1-基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A213”)
HPLC/MS 1.40 min (B), [M+H] 460;
3-(4-{4-[5-(反式-3-羟基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡唑-1-基)-丙腈(“A214”)
HPLC/MS 1.65 min (B), [M+H] 416;
N-(3-{4-[1-(2-吡唑-1-基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-环己烷-1,4-二胺(“A215”)
HPLC/MS 1.44 min (B), [M+H] 470;
(1S,3R)-3-(3-{4-[1-(2-吡咯烷-1-基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A216”)
HPLC/MS 1.81 min (C), [M+H] 487;
(1R,3R)-3-(3-{4-[1-(2-氰基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A217”)
HPLC/MS 2.20 min (C), [M+H] 443;
(1R,3R)-3-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A218”)
HPLC/MS 2.23 min (C), [M+H] 448;
(1R,3R)-3-(3-{5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-吡啶-2-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A219”)
HPLC/MS 1.96 min (C), [M+H] 449;
(1R,3R)-3-[3-(4-{1-[2-(5-甲基-[1,2,4]噁二唑-3-基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A220”)
HPLC/MS 1.65 min (B), [M+H] 500;
(1R,3R)-3-(3-{3-氟-4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A221”)
HPLC/MS 2.35 min (C), [M+H] 466;
(1R,3R)-3-(3-{3-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A222”)
HPLC/MS 1.66 min (B), [M+H] 448;
(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-3-氟-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A223”)
HPLC/MS 2.46 min (C), [M+H] 480;
(1R,3R)-3-(3-{6-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-吡啶-3-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A224”)
HPLC/MS 2.07 min (C), [M+H] 449;
(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸(2-甲氧基-乙基)-酰胺(“A225”)
HPLC/MS 2.45 min (C), [M+H] 520; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.31 (s, 1H), 8.27 (m, 3H), 8.06 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H),4.46 (bs, 1H), 4.37 (t, J = 5.3 Hz, 2H), 3.82 (t, J = 5.3 Hz, 2H), 3.49 (q, J= 7.0 Hz, 2H), 3.39 (t, J = 5.6 Hz, 2H), 3.30 (t, J = 5.6 Hz, 2H), 3.27 (s,3H), 2.93 (p, J = 8.0 Hz, 1H), 2.19 (m, 2H), 2.04 (dt, J = 11.8, 7.9 Hz, 1H),1.93 (ddd, J = 13.5, 8.3, 4.9 Hz, 1H), 1.84 - 1.67 (m, 2H), 1.13 (t, J = 7.0Hz, 3H);
(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸(2-羟基-乙基)-酰胺(“A226”)
HPLC/MS 1.69 min (B), [M+H] 506;
(1R,3R)-3-(3-{4-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A227”)
HPLC/MS 1.73 min (B), [M+H] 435; 1H NMR (400 MHz, DMSO-d6) δ [ppm] =9.36 - 9.19 (m, 1H), 8.27 (s, 1H), 8.24 - 8.14 (m, 2H), 8.14 - 8.04 (m, 1H),8.00 (s, 1H), 7.89 - 7.77 (m, 2H), 4.64 - 4.49 (m, 1H), 4.48 - 4.36 (m, 1H),4.34 - 4.18 (m, 3H), 3.78 (t, J=5.4, 2H), 3.45 (q, J=7.0, 2H), 2.25 - 2.06(m, 1H), 2.02 - 1.86 (m, 2H), 1.85 - 1.66 (m, 1H), 1.63 - 1.44 (m, 2H), 1.08(t, J=7.0, 3H);
(1R,3R)-3-(3-{3-氟-4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A228”)
HPLC/MS 1.75 min (B), [M+H] 439;
(1R,3R)-3-(3-{6-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-吡啶-3-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A229”)
HPLC/MS 2.18 min (C), [M+H] 463;
(1R,3R)-3-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-3-甲基-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A230”)
HPLC/MS 1.70 min (B), [M+H] 462;
(1R,3R)-3-{3-[4-(1-吡啶-3-基甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A231”)
HPLC/MS 1.50 min (B), [M+H] 454;
(1R,3R)-3-(3-{4-[1-(2-羟基-2-甲基-丙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A232”)
HPLC/MS 1.86 min (A), [M+H] 435; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.28 (d, J = 0.8 Hz, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.10(d, J = 0.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 2H), 4.54 (bs, 1H), 4.33 (tt, J =5.8, 3.1 Hz, 1H), 4.15 (s, 2H), 2.25 (q, J = 7.0, 6.6 Hz, 1H), 2.13 - 1.92(m, 2H), 1.83 (dt, J = 13.4, 6.6 Hz, 1H), 1.70 - 1.53 (m, 2H), 1.17 (s, 6H);
(1R,3R)-3-(3-{4-[1-(2-羟基-2-甲基-丙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A233”)
HPLC/MS 2.17 min (C), [M+H] 462;
(反式)-3-(3-{6-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-吡啶-3-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A234”)
HPLC/MS 1.62 min (B), [M+H] 422;
(1R,3R)-3-(3-{4-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸(1-甲基-哌啶-4-基甲基)-酰胺(“A235”)
“A235”甲酸盐: HPLC/MS 1.49 min (B), [M+H] 559; 1H NMR (500 MHz, DMSO-d6) δ [ppm] = 9.25 (s, 1H), 8.30 - 8.18 (m, 3H), 8.16 (s, 1H), 7.99 (s, 1H),7.88 - 7.75 (m, 3H), 4.52 - 4.32 (m, 1H), 4.30 (t, J=5.3, 2H), 3.74 (t, J=5.3, 2H), 3.26 (s, 3H), 2.94 (t, J=6.3, 2H), 2.90 - 2.77 (m, 3H), 2.29 - 2.18(m, 3H), 2.14 - 1.90 (m, 5H), 1.90 - 1.82 (m, 1H), 1.73 - 1.64 (m, 2H), 1.64- 1.56 (m, 2H), 1.44 - 1.33 (m, 1H), 1.21 - 1.09 (m, 2H);
2-[2-(4-{4-[5-((1R,3R)-3-羟基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡唑-1-基)-乙基]-2H-哒嗪-3-酮(“A236”)
HPLC/MS 1.61 min (B), [M+H] 485;
(1R,3R)-3-[3-(4-{1-[2-(6-氧代-6H-哒嗪-1-基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A237”)
HPLC/MS 1.60 min (B), [M+H] 512; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.23 (m, 3H), 7.99 (s, 1H), 7.87 - 7.77 (m, 3H), 7.38(dd, J = 9.4, 3.8 Hz, 1H), 6.95 (dd, J = 9.5, 1.6 Hz, 1H), 4.65 - 4.58 (m,2H), 4.58 - 4.51 (m, 2H), 4.41 (bs, 1H), 2.90 (p, J = 8.0 Hz, 1H), 2.16 (m,2H), 2.03 (dtd, J = 10.7, 7.2, 6.3, 4.0 Hz, 1H), 1.92 (m, 1H), 1.78 (m, 2H);
(1R,3R)-3-(3-{5-[1-(2-乙氧基-乙基)-1H-吡唑-4-基]-吡啶-2-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A238”)
HPLC/MS 1.50 min (B), [M+H] 463;
(1R,3R)-3-(3-{5-[1-(2-氰基-乙基)-1H-吡唑-4-基]-吡啶-2-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A239”)
HPLC/MS 1.42 min (B), [M+H] 444;
(1R,3R)-3-[[3-(4-嘧啶-5-基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A239a”)
(1R,3R)-3-[[3-[4-(6-甲基-3-吡啶基)苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A239b”)
(1R,3R)-3-[[3-[4-[1-[2-甲氧基-1-(甲氧基甲基)乙基]吡唑-4-基]苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A239c”)
(1R,3R)-3-[[3-[4-(5-甲基嘧啶-2-基)苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A239d”)
(1R,3R)-3-[[3-[5-[1-(2-吡唑-1-基乙基)吡唑-4-基]-2-吡啶基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A239e”)
。
实施例23
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(3-羟基-3-甲基-丁基)-酰胺(“A240”)的合成
向(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(184 mg, 0.50 mmol)在THF (2 ml)中的溶液中加入4-氨基-2-甲基-丁-2-醇(103 mg, 1.00 mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(144 mg, 0.75mmol)和1-羟基苯并三唑水合物(76.5 mg, 0.50 mmol)。将反应混合物在室温搅拌4小时。将反应混合物过滤。将滤液浓缩,并将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为浅黄色固体的(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(3-羟基-3-甲基-丁基)-酰胺;HPLC/MS 1.80 min (B),[M+H] 454;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.27 (s, 1H), 8.08 (bs, 2H),7.28 - 7.03 (m, 2H), 4.37 (bs, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.24 - 3.08 (m,2H), 2.82 (p, J = 8.0 Hz, 1H), 2.10 (m, 2H), 2.03 - 1.91 (m, 1H), 1.91 - 1.80(m, 1H), 1.78 - 1.62 (m, 2H), 1.60 - 1.52 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H),1.12 (s, 6H)。
类似地制备以下化合物:
{(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-(4-甲基-哌嗪-1-基)-甲酮(“A241”)
“A241”甲酸盐HPLC/MS 1.47 min (B), [M+H] 437;
(1S,3R)-3-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸[2-(4-甲基-哌嗪-1-基)-乙基]-酰胺(“A242”)
HPLC/MS 1.37 min (B), [M+H] 501;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸二甲基酰胺(“A243”)
HPLC/MS 1.81 min (B), [M+H] 382;
(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸[2-(4-甲基-哌嗪-1-基)-乙基]-酰胺(“A244”)
HPLC/MS 1.46 min (B), [M+H] 480;
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2-羟基-乙基)-酰胺(“A245”)
HPLC/MS 1.40 min (B), [M+H] 433; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.43 (d, J = 8.7 Hz, 1H), 9.36 (s, 1H), 9.29 (s, 1H), 9.05 (d, J = 9.0Hz, 1H), 8.46 (d, J = 9.3 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 4.53 (p, J = 7.0Hz, 1H), 3.42 (t, J = 6.0 Hz, 2H), 3.19 (t, J = 6.1 Hz, 2H), 3.00 (s, 3H),2.89 (m 1H), 2.35 (m, 1H), 2.18 - 1.96 (m, 2H), 1.86 - 1.59 (m, 3H);
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2-甲氧基-乙基)-酰胺(“A246”)
HPLC/MS 1.50 min (B), [M+H] 447;
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2-羟基-乙基)-酰胺(“A247”)
HPLC/MS 1.73 min (B), [M+H] 412;
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2-甲氧基-乙基)-酰胺(“A248”)
HPLC/MS 1.85 min (B), [M+H] 426;
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(1-甲基-哌啶-4-基甲基)-酰胺(“A249”)
“A249”甲酸盐:
HPLC/MS 2.02 min (C), [M+H] 479; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.12 (s, 1H), 8.08 (bs, 2H), 7.18 (d, J = 9.0 Hz, 2H),4.42 (bs, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.52 - 3.41 (m, 2H), 3.21 (m, 1H),3.10 - 2.99 (m, 2H), 2.91 (m, 3H), 2.77 (s, 3H), 2.15 (m, 2H), 2.03 (m, 1H),1.96 - 1.81 (m, 3H), 1.81 - 1.62 (m, 4H), 1.41 (t, J = 7.0 Hz, 3H);
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸[2-(4-甲基-哌嗪-1-基)-乙基]-酰胺(“A250”)
“A250”甲酸盐HPLC/MS 1.40 min (B), [M+H] 516;
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(2-羟基-2-甲基-丙基)-甲基-酰胺(“A251”)
HPLC/MS 2.63 min (C), [M+H] 454;
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(1-甲基-哌啶-4-基甲基)-酰胺(“A252”)
“A252”甲酸盐HPLC/MS 1.34 min (B), [M+H] 500;
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸(3-羟基-3-甲基-丁基)-酰胺(“A253”)
HPLC/MS 1.55 min (B), [M+H] 475;
(1R,3R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸((反式)-3-羟基-环戊基)-酰胺(“A254”)
HPLC/MS 1.41 min (B), [M+H] 473;
(1R,3R)-3-[[3-(2-甲基-6-喹啉基)三唑并[4,5-d]嘧啶-5-基]氨基]-N-(2-吗啉代乙基)环戊烷甲酰胺(“A254a”)
。
实施例24
(1R,3R)-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A255”)的合成
向(1R,3R)-3-[3-(4-碘-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(179 mg, 0.40 mmol)和1-[2-(四氢-吡喃-2-基氧基)-乙基]-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(168 mg, 0.52 mmol)在二氧杂环己烷(2ml)中的溶液中加入水(0.2 ml)和碳酸钾(1660 mg, 1.2 mmol)。将混合物用氮气冲洗,并加热至80℃。加入二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加成化合物(33 mg,0.04 mmol),并将混合物在密闭反应瓶中在80℃搅拌16小时。使反应混合物达到室温并在水和二氯甲烷之间分配。将有机相经硫酸钠干燥并蒸发。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为米色固体的(1R,3R)-3-[3-(4-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺;HPLC/MS 2.44 min (C), [M+H] 518。
向(1R,3R)-3-[3-(4-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(77.6 mg, 0.15 mmol)在二氯甲烷(1.5 ml)中的溶液中加入甲醇(0.8 ml)和4 N的盐酸在二氧杂环己烷中的溶液(275µl),并将反应混合物在50℃搅拌60分钟。将溶剂蒸发,并将残余物用饱和的碳酸氢钠溶液处理。将固体滤出,用水洗涤和在真空下干燥。将残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱分离,得到作为白色晶体的(1R,3R)-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺;HPLC/MS2.03 min (C), [M+H] 434;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ [ppm] 9.29 (s, 1H), 8.32 (s, 1H),8.25 (d, J = 8.3 Hz, 2H), 8.08 (s, 1H), 7.88 (d, J = 8.6 Hz, 2H), 4.42 (bs,1H), 4.26 (t, J = 5.5 Hz, 2H), 3.85 (t, J = 5.5 Hz, 2H), 2.90 (p, J = 7.9 Hz,1H), 2.18 (m, 2H), 2.09 - 1.98 (m, 1H), 1.92 (m, 1H), 1.86 - 1.64 (m, 2H)。
类似地制备以下化合物:
2-(4-{4-[5-(反式-4-氨基-环己基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡唑-1-基)-乙醇(“A256”)
HPLC/MS 1.35 min (B), [M+H] 420;
2-(4-{4-[5-((1R,3S)-3-氨基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡唑-1-基)-乙醇(“A257”)
HPLC/MS 1.41 min (B), [M+H] 406;
(1S,3R)-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A258”)
HPLC/MS 1.55 min (B), [M+H] 434;
(1R,3R)-3-(3-{4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷醇(“A259”)
HPLC/MS 1.55 min (B), [M+H] 407;
(1R,3R)-3-(3-{3-氟-4-[1-(2-羟基-乙基)-1H-吡唑-4-基]-苯基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A260”)
HPLC/MS 1.60 min (B), [M+H] 452;
(1R,3R)-3-(3-{5-[1-(2-羟基-乙基)-1H-吡唑-4-基]-吡啶-2-基}-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基)-环戊烷甲酸酰胺(“A261”)
HPLC/MS 1.82 min (C), [M+H] 435。
实施例25
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-((反式)-3-甲基硫烷基-环戊基)-胺(“A262”)、((反式)-3-甲磺酰基-环戊基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A263”)和((顺式)-3-甲磺酰基-环戊基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A264”)的合成
“A262”: HPLC/MS 2.11 min (B), [M+H] 356;反式-异构体: 1H NMR (500 MHz,DMSO-d6, TFA-d1) δ [ppm] 9.27 (s, 1H), 8.06 (d, J = 9.6 Hz, 2H), 7.19 (d, J =9.1 Hz, 1H), 4.31 (bs, 1H), 3.87 (s, 3H), 3.18 - 2.96 (m, 1H), 2.51 - 1.51(多重峰, 6), 顺式-异构体的信号: δ 7.19 (d, J = 9.3 Hz, 2H), 4.43 (bs, 1H),3.29 (p, J = 6.9 Hz, 1H);
“A263”(反式-异构体): HPLC/MS 1.77 min (B), [M+H] 389; 1H NMR (500MHz, DMSO-d6, TFA-d1) δ [ppm] 9.26 (s, 1H), 8.05 (bs, 2H), 7.20 (d, J = 8.7Hz, 2H), 4.33 (bs, 1H), 3.87 (s, 3H), 3.81 - 3.59 (m, 1H), 2.95 (s, 3H), 2.47(m, 1H), 2.06 (m, 4H), 1.79 (m, 1H);
“A264”(顺式-异构体): HPLC/MS 1.79 min (B), [M+H] 389; 1H NMR (500MHz, DMSO-d6, TFA-d1) δ [ppm] 9.22 (s, 1H), 8.30 - 7.78 (m, 2H), 7.14 (d, J =8.9 Hz, 2H), 4.38 (bs, 1H), 3.82 (s, 3H), 3.77 (td, J = 9.1, 4.6 Hz, 1H),2.91 (s, 3H), 2.47 - 2.32 (m, 1H), 2.24 - 2.12 (m, 1H), 2.11 - 2.04 (m, 1H),2.04 - 1.91 (m, 2H), 1.79 (m, 1H)。
实施例26
(1R,3R)-3-[3-(4-{1-[2-(1H-四唑-5-基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A265”)的合成
TMSN3 = 叠氮基三甲基硅烷
“A265”: 深紫色固体;HPLC/MS 1.77 min (C), [M+H] 486; 1H NMR (400 MHz,DMSO-d6, TFA-d1) δ [ppm] 9.30 (s, 1H), 8.31 - 8.17 (m, 3H), 8.00 (s, 1H), 7.82(d, J = 8.4 Hz, 2H), 4.67 (t, J = 6.8 Hz, 2H), 4.46 (bs, 1H), 3.56 (t, J =6.8 Hz, 2H), 2.95 (p, J = 7.9 Hz, 1H), 2.21 (m, 2H), 2.06 (m, 1H), 1.96 (m,1H), 1.89 - 1.68 (m, 2H)。
反式-3-[3-(4-{1-[2-(1H-四唑-5-基)-乙基]-1H-吡唑-4-基}-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷醇(“A266”)
类似地进行制备:HPLC/MS 1.77 min (B), [M+H] 459。
实施例27
[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[(1R,3S)-3-(5-甲基-噁唑-2-基)-环戊基]-胺(“A267”)的合成
HPLC/MS 2.89 min (C), [M+H] 392; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.08 (bs, 2H), 7.28 - 7.03 (m, 3H), 4.47 (bs, 1H), 3.88(s, 3H), 3.55 (p, J = 8.4 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.36 (d, J = 1.3 Hz,3H), 2.31 - 2.00 (m, 4H), 1.92 (d, J = 8.6 Hz, 1H)。
实施例28
3-(4-{4-[5-(反式-3-羟基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯基}-吡唑-1-基)-丙酰胺(“A268”)的合成
HPLC/MS 1.55 min (B), [M+H] 434; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 8.09 (m, 3H), 7.94 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 4.45 (p, J = 6.9Hz, 1H), 4.39 (t, J = 6.5 Hz, 2H), 4.26 (tt, J = 5.8, 3.1 Hz, 1H), 2.73 (t, J= 6.5 Hz, 2H), 2.18 (m, 1H), 2.01 (ddd, J = 12.9, 7.4, 3.0 Hz, 1H), 1.97 -1.87 (m, 1H), 1.74 (ddd, J = 13.4, 7.4, 5.9 Hz, 1H), 1.61 - 1.47 (m, 2H)。
实施例29
((R)-1-甲磺酰基-吡咯烷-3-基)-(3-喹啉-6-基-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基)-胺(“A269”)的合成
HPLC/MS 1.63 min (B), [M+H] 411; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.47 (dd, J = 5.4, 1.5 Hz, 1H), 9.44 (d, J = 8.5 Hz, 1H), 9.36 (s, 1H),9.32 (s, 1H), 9.16 (d, J = 9.6 Hz, 1H), 8.61 (d, J = 9.3 Hz, 1H), 8.25 (dd, J= 8.5, 5.3 Hz, 1H), 4.69 (bs, 1H), 3.83 (m, 1H), 3.58 (dt, J = 9.9, 7.3 Hz,1H), 3.53 - 3.36 (m, 2H), 2.94 (s, 3H), 2.37 (m, 1H), 2.20 (m, 1H)。
((R)-1-甲磺酰基-吡咯烷-3-基)-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A269a”)
类似地进行制备:
实施例30
(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-磺酸酰胺(“A270”)的合成
HPLC/MS 1.71 min (B), [M+H] 391; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.22 (s, 1H), 8.04 (bs, 2H), 7.14 (d, J = 8.7 Hz, 2H), 4.45 (bs, 1H), 3.81(s, 3H), 3.52 (dd, J = 10.4, 6.5 Hz, 1H), 3.34 (dt, J = 9.8, 7.2 Hz, 1H),3.21 (dt, J = 9.8, 7.6 Hz, 1H), 3.16 (m, 1H), 2.22 (dq, J = 13.9, 7.1 Hz,1H), 2.02 (m, 1H)。
实施例31
1-((R)-3-{3-[4-(1-甲基-1H-吡唑-4-基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-吡咯烷-1-基)-4-哌嗪-1-基-丁-1-酮(“A271”)的合成
“A271”二盐酸盐: HPLC/MS 1.34 min (B), [M+H] 516; 1H NMR (400 MHz,DMSO-d6, d-TFA) δ 9.27 (s, 1H), 8.20 (s, 1H), 8.20 - 8.05 (m, 2H), 7.96 (s,1H), 7.80 (d, J = 8.0 Hz, 2H), 4.51 (d, J = 29.6 Hz, 2H), 3.55 (m, 13H), 2.40(dt, J = 13.9, 6.9 Hz, 2H), 2.27 (m, 1H), 2.13 m, 2H), 2.01 - 1.86 (m, 2H)。
实施例32
(1R,4S)-4-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊-2-烯甲酸酰胺(“A272”)和(1S,4S)-4-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊-2-烯甲酸酰胺(“A273”)的合成
“A272”: HPLC/MS 2.35 min (C), [M+H] 352; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.31 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 9.0 Hz,2H), 5.97 (m, 2H), 5.11 (bs, 1H), 3.88 (s, 3H), 3.49 (m, 1H), 2.56 - 2.48 (m,1H), 1.97 (dt, J = 13.3, 5.2 Hz, 1H)。
“A273”: HPLC/MS 2.24 min (C), [M+H] 352;1H NMR (500 MHz, DMSO-、TFA-d1)δ [ppm] 9.28 (s, 1H), 8.20 - 7.85 (m, 2H), 7.21 (d, J = 9.0 Hz, 2H), 5.94 (m,2H), 5.16 (bs, 1H), 3.87 (s, 3H), 3.66 (ddd, J = 8.6, 4.3, 2.2 Hz, 1H), 2.58-2.51 (m, 1H), 1.99 (ddd, J = 13.2, 8.7, 4.6 Hz, 1H)。
实施例33
(1R,3R)-3-{3-[4-(2-甲氧基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲腈(“A274”)的合成
HPLC/MS 1.88 min (B), [M+H] 380; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.08 (bs, 2H), 7.48 - 7.00 (m, 2H), 4.46 (bs, 1H), 4.33 -4.09 (m, 2H), 3.87 - 3.63 (m, 2H), 3.37 (s, 3H), 3.20 (p, J = 7.7 Hz, 1H),2.36 - 1.99 (m, 4H), 1.99 - 1.69 (m, 2H)。
顺式-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲腈(“A275”)
类似地进行制备;HPLC/MS 1.90 min (B), [M+H] 336; 1H NMR (500 MHz,DMSO-d6, TFA-d1) δ [ppm] 9.31 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.18 (d, J =9.0 Hz, 2H), 4.38 (bs, 1H), 3.88 (s, 3H), 3.02 (p, J = 8.1 Hz, 1H), 2.56 (dt,J = 13.1, 7.8 Hz, 1H), 2.19 - 2.05 (m, 3H), 2.05 - 1.96 (m, 1H), 1.91 (m,1H)。
实施例34
(1R,3R)-3-[3-(4-羟基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A276”)、(1R,3R)-3-{3-[4-(2-吗啉-4-基-乙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A277”)、(1R,3R)-3-{3-[4-(3-羟基-1,1-二甲基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A278”)和(1R,3R)-3-{3-[4-(哌啶-4-基甲氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A279”)的合成
“A276”: HPLC/MS 1.98 min (C), [M+H] 340; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.41 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.9 Hz,2H), 4.46 (p, J = 6.2 Hz, 1H), 3.00 (p, J = 8.0 Hz, 1H), 2.33 - 2.15 (m, 2H),2.10 (dtd, J = 11.2, 7.4, 6.8, 4.1 Hz, 1H), 1.97 (ddd, J = 13.7, 8.8, 5.1 Hz,1H), 1.90 - 1.69 (m, 2H);
“A277”: HPLC/MS 1.66 min (C), [M+H] 453; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.29 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 9.0 Hz,2H), 4.55 - 4.51 (m, 2H), 4.39 (bs, 1H), 4.12 - 3.98 (m, 2H), 3.87 - 3.75 (m,2H), 3.70 (t, J = 4.9 Hz, 2H), 3.63 (d, J = 12.6 Hz, 2H), 3.31 (td, J = 12.3,3.7 Hz, 2H), 2.92 (p, J = 8.0 Hz, 1H), 2.26 - 2.09 (m, 2H), 2.09 - 1.99 (m,1H), 1.92 (m, 1H), 1.84 - 1.66 (m, 2H);
“A278”: HPLC/MS 2.20 min (C), [M+H] 426; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.30 (s, 1H), 8.21 - 8.05 (m, 2H), 7.25 (d, J = 8.9 Hz, 2H),4.44 (bs, 1H), 3.73 (t, J = 7.3 Hz, 2H), 2.93 (p, J = 8.0 Hz, 1H), 2.33 -2.11 (m, 2H), 2.06 (qd, J = 8.1, 4.5 Hz, 1H), 1.95 (t, J = 7.3 Hz, 2H), 1.94- 1.89 (m, 1H), 1.77 (m, 2H), 1.36 (s, 6H);
“A279”: HPLC/MS 1.78 min (C), [M+H] 437; 1H NMR (500 MHz, DMSO-d6) δ[ppm] 9.30 (s, 1H), 8.11 (d, J = 9.5 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 4.41(bs, 1H), 4.01 (d, J = 6.2 Hz, 2H), 3.40 (d, J = 12.7 Hz, 2H), 3.04 - 2.89(m, 3H), 2.18 (m, 3H), 2.11 - 1.97 (m, 3H), 1.92 (ddd, J = 13.4, 9.3, 5.6 Hz,1H), 1.76 (m, 2H), 1.68 - 1.50 (m, 2H)。
实施例35
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸N'-乙酰基-酰肼(“A280”)和[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-[(1R,3R)-3-(5-甲基-[1,3,4]噁二唑-2-基)-环戊基]-胺(“A281”)的合成
“A280”: HPLC/MS 2.29 min (C), [M+H] 425; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.29 (s, 1H), 8.27 - 7.95 (m, 2H), 7.19 (d, J = 8.3 Hz, 2H),4.43 (bs, 1H), 4.15 (q, J = 7.0 Hz, 2H), 2.97 (p, J = 7.9 Hz, 1H), 2.17 (m,2H), 2.10 - 2.01 (m, 1H), 1.99 - 1.92 (m, 1H), 1.91 (s, 3H), 1.85 - 1.68 (m,2H), 1.41 (t, J = 7.0 Hz, 3H);
“A281”: HPLC/MS 2.73 min (C), [M+H] 407; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.21 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.0 Hz,2H), 4.45 (bs, 1H), 4.07 (q, J = 6.9 Hz, 2H), 3.53 (p, J = 7.8 Hz, 1H), 2.39(s, 3H), 2.38 - 2.26 (m, 1H), 2.27 - 2.01 (m, 3H), 1.98 - 1.71 (m, 2H), 1.34(t, J = 7.0 Hz, 3H)。
实施例36
(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰肼(“A282”)和[(1R,3R)-3-(5-氨基-[1,3,4]噁二唑-2-基)-环戊基]-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基]-胺(“A283”)的合成
“A282”: HPLC/MS 2.27 min (C), [M+H] 383; 1H NMR (400 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.20 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 9.0 Hz,2H), 4.40 (bs, 1H), 4.05 (q, J = 6.9 Hz, 2H), 2.95 (p, J = 7.8 Hz, 1H), 2.09(m, 3H), 1.90 (ddt, J = 13.5, 9.0, 5.2 Hz, 1H), 1.73 (m, 2H), 1.32 (t, J =7.0 Hz, 3H);
“A283”: HPLC/MS 1.75 min (B), [M+H] 408; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.29 (s, 1H), 8.07 (bs, 2H), 7.17 (d, J = 9.1 Hz, 2H), 4.50(bs, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.57 (p, J = 8.0 Hz, 1H), 2.36 (dt, J =14.3, 7.4 Hz, 1H), 2.32 - 2.25 (m, 1H), 2.23 (m, 2H), 1.97 (dq, J = 12.0, 7.5Hz, 1H), 1.89 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H)。
实施例37
(R)-3-[3-(2-甲基-喹啉-6-基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-甲酸酰胺(“A284”)的合成
HPLC/MS 1.38 min (B), [M+H] 390; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.54 - 8.90 (m, 4H), 8.51 (d, J = 9.3 Hz, 1H), 8.11 (d, J = 8.6 Hz,1H), 4.73 (bs, 1H), 3.88 (dd, J = 11.3, 6.0 Hz, 1H), 3.68 (m, 1H), 3.65 -3.49 (m, 2H), 3.05 (s, 3H), 2.42 - 2.29 (m, 1H), 2.29 - 2.17 (m, 1H)。
(R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-吡咯烷-1-甲酸酰胺(“A285”)
类似地进行制备;HPLC/MS 1.62 min (B), [M+H] 355。
实施例38
N-{(1R,3R)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷羰基}-甲磺酰胺(“A286”)的合成
HPLC/MS 2.64 min (C), [M+H] 446; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.30 (s, 1H), 8.10 (bs, 2H), 7.19 (d, J = 9.0 Hz, 2H), 4.40 (bs, 1H),4.15 (q, J = 7.0 Hz, 2H), 3.26 (s, 3H), 3.11 - 3.01 (m, 1H), 2.28 (m, 1H),2.12 (m, 2H), 2.02 - 1.90 (m, 1H), 1.90 - 1.70 (m, 2H), 1.41 (t, J = 7.0 Hz,3H)。
实施例39
2-{(反式)-3-[3-(4-乙氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-2H-哒嗪-3-酮(“A287”)的合成
HPLC/MS 1.91 min (B), [M+H] 419; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.26 (s, 1H), 8.36 (d, J = 6.0 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 8.01 (dd, J= 3.8, 1.7 Hz, 1H), 7.42 (dd, J = 9.4, 3.8 Hz, 1H), 7.16 (d, J = 9.0 Hz, 2H),6.92 (d, J = 9.1 Hz, 1H), 5.60 - 5.48 (m, 1H), 4.51 (m, 1H), 4.13 (q, J = 6.9Hz, 2H), 2.35 - 2.14 (m, 3H), 2.12 - 1.97 (m, 1H), 1.83 (m, 2H), 1.38 (t, J =7.0 Hz, 3H)。
实施例40
(反式)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷磺酸酰胺(“A288”)的合成
HPLC/MS 2.35 min (C), [M+H] 390; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.28 (s, 1H), 8.12 (bs, 2H), 7.20 (d, J = 8.7 Hz, 2H), 4.45 (bs, 1H),3.88 (s, 3H), 3.68 (tt, J = 9.0, 6.6 Hz, 1H), 2.38 (dt, J = 13.7, 6.8 Hz,1H), 2.27 - 1.97 (m, 4H), 1.89 - 1.68 (m, 1H)。
实施例41
(1R,3R)-3-{3-[4-(1-羟基-1-甲基-乙基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A289”)的合成
HPLC/MS 1.60 min (B), [M+H] 382; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ[ppm] 9.29 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 4.44(bs, 1H), 2.93 (p, J = 8.0 Hz, 1H), 2.18 (m, 2H), 2.10 - 2.00 (m, 1H), 1.93(ddd, J = 13.3, 8.7, 5.2 Hz, 1H), 1.77 (m, 2H), 1.54 (s, 6H)。
(反式)-3-{3-[4-(1-羟基-1-甲基-乙基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷醇(“A290”)
类似地进行制备:HPLC/MS 1.63 min (B), [M+H] 355。
实施例42
1-{(1R,3R)-3-[3-(4-甲氧基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊基}-吡咯烷-2-酮(“A291”)的合成
HPLC/MS 1.80 min (B), [M+H] 394; 1H NMR (400 MHz, DMSO-d6) δ [ppm]9.29 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 4.67 (p, J= 8.2 Hz, 1H), 4.45 (bs, 1H), 3.88 (s, 3H), 3.43 (t, J = 7.0 Hz, 2H), 2.32(dd, J = 8.7, 7.4 Hz, 2H), 2.26 - 2.16 (m, 1H), 2.09 (dt, J = 14.9, 7.9 Hz,1H), 2.03 - 1.94 (m, 3H), 1.88 (ddd, J = 13.5, 8.4, 5.0 Hz, 1H), 1.82 - 1.60(m, 2H)。
实施例43
3-{4-[5-((1R,3R)-3-氨甲酰基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯氧基}-丙酸甲酯(“A292”)和(1R,3R)-3-{3-[4-(3-羟基-3-甲基-丁氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A293”)的合成
“A292”: HPLC/MS 1.75 min (B), [M+H] 426;
“A293”: HPLC/MS 1.62 min (B), [M+H] 426; 1H NMR (500 MHz, DMSO-d6,TFA-d1) δ [ppm] 9.30 (s, 1H), 8.09 (bs, 2H), 7.20 (d, J = 9.0 Hz, 2H), 4.41(bs, 1H), 4.23 (t, J = 7.1 Hz, 2H), 2.91 (p, J = 8.0 Hz, 1H), 2.16 (m, 1H),2.09 - 1.99 (m, 2H), 1.95 (t, J = 7.1 Hz, 2H), 1.92 - 1.86 (m, 1H), 1.78 (m,2H), 1.24 (s, 6H)。
类似地制备以下化合物:
{4-[5-((1R,3R)-3-氨甲酰基-环戊基氨基)-[1,2,3]三唑并[4,5-d]嘧啶-3-基]-苯氧基}-乙酸甲酯(“A294”)
HPLC/MS 1.60 min (B), [M+H] 412;
(1R,3R)-3-{3-[4-(2-羟基-2-甲基-丙氧基)-苯基]-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基}-环戊烷甲酸酰胺(“A295”)
HPLC/MS 1.55 min (B), [M+H] 412。
实施例44
(1R,3R)-3-[3-(4-甲磺酰基-苯基)-3H-[1,2,3]三唑并[4,5-d]嘧啶-5-基氨基]-环戊烷甲酸酰胺(“A296”)的合成
HPLC/MS 1.50 min (B), [M+H] 402; 1H NMR (500 MHz, DMSO-d6) δ [ppm]9.29 (s, 1H), 8.66 (bs, 2H), 8.24 (d, J = 8.8 Hz, 2H), 4.45 (bs, 1H), 3.29(s, 3H), 2.93 (p, J = 8.0 Hz, 1H), 2.28 (m, 1H), 2.16 (m, 1H), 2.07 (m, 1H),1.90 (ddd, J = 13.5, 8.7, 5.3 Hz, 1H), 1.81 (m, 2H)。
实施例45
3-[(1S,3R)-3-[[3-(4-甲氧基苯基)三唑并[4,5-d]嘧啶-5-基]氨基]环戊基]-4H-1,2,4-噁二唑-5-酮(“A297”)和3-(4-甲氧基苯基)-N-[(1R,3S)-3-(5-甲基-1,2,4-噁二唑-3-基)环戊基]三唑并[4,5-d]嘧啶-5-胺(“A298”)的合成
实施例46
(1R,3R)-3-[[3-[4-(4-哌啶基氧基)苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A299”)和(1R,3R)-3-[[3-[4-[(1-甲基-4-哌啶基)氧基]苯基]三唑并[4,5-d]嘧啶-5-基]氨基]环戊烷甲酰胺(“A300”)的合成
药理学数据
表2 一些代表性的式I化合物的GCN2抑制
。
表3 一些式I化合物的GSK3α和GSK3β抑制
。
下述实施例涉及药物:
实施例A:注射瓶
将100 g式I的活性成分和5 g磷酸氢二钠在3 l重蒸馏水中的溶液使用2 N盐酸调至pH 6.5,无菌过滤,转移进注射瓶中,在无菌条件下低压冻干,并在无菌条件下密封。每个注射瓶含有5 mg活性成分。
实施例B:栓剂
将20 g式I的活性成分和100 g大豆卵磷脂及1400 g可可脂的混合物熔化,倒入模型中并使之冷却。每个栓剂含有20 mg活性成分。
实施例C: 溶液
从1 g式I的活性成分、9.38 g NaH2PO4∙2 H2O、28.48 g Na2HPO4∙12 H2O和0.1 g苯扎氯铵在940 ml重蒸馏水中制备溶液。将pH调至6.8,将溶液补足至1 l,并通过辐射灭菌。该溶液可以以滴眼剂的形式使用。
实施例D: 软膏剂
在无菌条件下将500 mg式I的活性成分与99.5 g凡士林混合。
实施例E: 片剂
以常规方式压制1 kg式I的活性成分、4 kg乳糖、1.2 kg马铃薯淀粉、0.2 kg滑石和0.1 kg硬脂酸镁的混合物,使得以每片含有10 mg活性成分的方式得到片剂。
实施例F: 糖衣片
类似于实施例E压制片剂,并随后以常规方式用蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料的包衣包覆。
实施例G: 胶囊剂
以使得每个胶囊含有20 mg活性成分的方式,将2 kg式I的活性成分以常规方式引入硬明胶胶囊中。
实施例H: 安瓿
将1 kg式I的活性成分在60 l重蒸馏水中的溶液无菌过滤,转移进安瓿中,在无菌条件下低压冻干,并在无菌条件下密封。每个安瓿含有10 mg活性成分。
Claims (15)
1.化合物,其选自
及其药学上可接受的盐。
2.药物,其包含至少一种权利要求1的化合物和/或其药学上可接受的盐,和任选的药学上可接受的载体、赋形剂或媒介物。
3.权利要求1的化合物及其药学上可接受的盐在制备用于治疗和/或预防炎性病症、免疫学病症、变应性病症、风湿性病症、血栓性病症、癌症、感染、神经变性疾病、心血管疾病和代谢病症的药物中的用途。
4.根据权利要求3所述的用途,其中所述炎性病症是神经炎性疾病。
5.根据权利要求3所述的用途,其中所述免疫学病症是自身免疫病症。
6.根据权利要求3所述的用途,其中所述癌症是实体瘤或血液和免疫系统的肿瘤。
7.根据权利要求6所述的用途,其中所述实体瘤源自于上皮,膀胱,胃,肾,头和颈,食道,宫颈,甲状腺,肠,肝,脑,前列腺,泌尿生殖道,淋巴系统,喉,骨,生殖细胞,和/或肺的肿瘤,源自于单核细胞性白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、神经纤维瘤、血管肉瘤、乳腺癌和/或恶性黑素瘤。
8.根据权利要求7所述的用途,其中所述骨的肿瘤选自软骨肉瘤和尤因肉瘤。
9.根据权利要求7所述的用途,其中所述生殖细胞肿瘤选自胚胎组织肿瘤。
10.根据权利要求3所述的用途,其中所述病症选自类风湿性关节炎、系统性狼疮、哮喘、多发性硬化、骨关节炎、缺血性损伤、巨细胞动脉炎、炎性肠病、糖尿病、囊性纤维化、银屑病、舍格伦综合征和移植器官排斥。
11.根据权利要求3所述的用途,其中所述病症选自阿尔茨海默氏病、唐氏综合征、伴有Dutch型淀粉样变性的遗传性脑出血、脑淀粉样蛋白血管病、克雅病、额颞叶痴呆、亨廷顿病、帕金森病。
12.根据权利要求3所述的用途,其中所述病症选自利什曼原虫,分枝杆菌,疟原虫,人免疫缺陷病毒,爱泼斯坦-巴尔病毒,单纯疱疹病毒,丙型肝炎病毒。
13.药物,其包含至少一种权利要求1的化合物和/或其药学上可接受的盐,和至少一种另外的药物活性成分。
14.由如下的单独包组成的套盒:
(a)有效量的权利要求1的化合物和/或其药学上可接受的盐,
和
(b)有效量的另外的药物活性成分。
15.化合物,其选自
及其药学上可接受的盐。
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6888006B2 (ja) * | 2015-10-29 | 2021-06-16 | イーフェクター セラピューティクス, インコーポレイテッド | Mnk1およびmnk2を阻害するピロロ−、ピラゾロ−、イミダゾ−ピリミジンおよびピリジン化合物 |
EP3848035A1 (en) | 2015-12-10 | 2021-07-14 | PTC Therapeutics, Inc. | 1,4-disubstituted pyridazine compounds for treating huntington's disease |
TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
CA3033461A1 (en) | 2016-08-10 | 2018-02-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compounds as inhibitors of gcn2 |
ES2970715T3 (es) | 2016-12-22 | 2024-05-30 | Prec Pharmaceuticals Inc | Composiciones y métodos para inhibir la actividad de la arginasa |
SG11201911615WA (en) | 2017-06-05 | 2020-01-30 | Ptc Therapeutics Inc | Compounds for treating huntington's disease |
CA3067592A1 (en) | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | Methods for treating huntington's disease |
CA3067591A1 (en) | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | Methods for treating huntington's disease |
WO2019152809A1 (en) * | 2018-02-02 | 2019-08-08 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
WO2019191092A1 (en) | 2018-03-27 | 2019-10-03 | Ptc Therapeutics, Inc. | Compounds for treating huntington's disease |
JP2021527051A (ja) * | 2018-06-05 | 2021-10-11 | ラプト・セラピューティクス・インコーポレイテッド | ピラゾロ−ピリミジン−アミノ−シクロアルキル化合物及びその治療的使用 |
JP7421507B2 (ja) | 2018-06-27 | 2024-01-24 | ピーティーシー セラピューティクス, インコーポレイテッド | ハンチントン病を処置するためのヘテロ環式およびヘテロアリール化合物 |
WO2020005882A1 (en) | 2018-06-27 | 2020-01-02 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
US20210299233A1 (en) * | 2018-07-12 | 2021-09-30 | The Children's Medical Center Corporation | Method for treating cancer |
KR102328423B1 (ko) * | 2018-09-11 | 2021-11-18 | 재단법인 대구경북첨단의료산업진흥재단 | 신규 트리아졸로-피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
GB202008749D0 (en) | 2020-06-09 | 2020-07-22 | Ip2Ipo Innovations Ltd | Novel compounds |
US20230279006A1 (en) * | 2020-07-08 | 2023-09-07 | Klotho Therapeutics, Inc. | Novel compounds and methods for increasing klotho gene expression |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1823068A (zh) * | 2003-07-16 | 2006-08-23 | 詹森药业有限公司 | 作为糖原合酶激酶3抑制剂的三唑并嘧啶衍生物 |
WO2006091737A1 (en) * | 2005-02-24 | 2006-08-31 | Kemia, Inc. | Modulators of gsk-3 activity |
CN101119988A (zh) * | 2005-02-16 | 2008-02-06 | 阿斯利康(瑞典)有限公司 | 化学化合物 |
WO2012025186A1 (en) * | 2010-08-27 | 2012-03-01 | Merck Patent Gmbh | Triazolopyrazine derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5962594A (ja) * | 1982-09-30 | 1984-04-10 | Ss Pharmaceut Co Ltd | 3,5―ジ置換―トリアゾロピリミジン誘導体 |
PT1853588E (pt) * | 2005-02-16 | 2008-08-25 | Astrazeneca Ab | Compostos químicos |
-
2014
- 2014-02-10 CN CN201480012252.4A patent/CN105026398B/zh not_active Expired - Fee Related
- 2014-02-10 WO PCT/EP2014/000361 patent/WO2014135244A1/en active Application Filing
- 2014-02-10 US US14/772,865 patent/US9855268B2/en active Active
- 2014-02-10 AU AU2014224975A patent/AU2014224975B2/en not_active Ceased
- 2014-02-10 ES ES14704286T patent/ES2636936T3/es active Active
- 2014-02-10 JP JP2015560571A patent/JP6427115B2/ja active Active
- 2014-02-10 EP EP14704286.5A patent/EP2964649B1/en not_active Not-in-force
- 2014-02-10 CA CA2903903A patent/CA2903903C/en active Active
- 2014-03-05 AR ARP140100697A patent/AR094982A1/es unknown
-
2015
- 2015-08-27 IL IL240877A patent/IL240877A0/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1823068A (zh) * | 2003-07-16 | 2006-08-23 | 詹森药业有限公司 | 作为糖原合酶激酶3抑制剂的三唑并嘧啶衍生物 |
CN101119988A (zh) * | 2005-02-16 | 2008-02-06 | 阿斯利康(瑞典)有限公司 | 化学化合物 |
WO2006091737A1 (en) * | 2005-02-24 | 2006-08-31 | Kemia, Inc. | Modulators of gsk-3 activity |
WO2012025186A1 (en) * | 2010-08-27 | 2012-03-01 | Merck Patent Gmbh | Triazolopyrazine derivatives |
Non-Patent Citations (3)
Title |
---|
2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3);Christopher Lum,等;《Bioorganic & Medicinal Chemistry Letters》;20080506;第18卷(第12期);第3580页表4 * |
Synthesis of Novel N,3-Substituted 3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-amines;HANSEN, F. K.,等;《Synthesis》;20100201;第2010卷(第4期);第689页图1、第690页表3 * |
Triazolo[4,5-d]pyrimidines. IX. Reactions of 5-chloro- and 5-(methylsulfonyl)-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidines with C-nucleophiles;KI Tanji,等;《Chemical & Pharmaceutical Bulletin》;19891231;第37卷(第7期);第1731页图1 * |
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