CN107365302B - 螺三元环、螺五元环类肽脱甲酰基酶抑制剂 - Google Patents
螺三元环、螺五元环类肽脱甲酰基酶抑制剂 Download PDFInfo
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- CN107365302B CN107365302B CN201610310999.9A CN201610310999A CN107365302B CN 107365302 B CN107365302 B CN 107365302B CN 201610310999 A CN201610310999 A CN 201610310999A CN 107365302 B CN107365302 B CN 107365302B
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- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
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- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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- 229960003165 vancomycin Drugs 0.000 description 1
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- 150000003952 β-lactams Chemical class 0.000 description 1
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Abstract
本发明公开了一类新型的含螺三元环、螺五元环类肽脱甲酰基酶抑制剂的抗菌活性和抗肿瘤活性。本发明的含螺三元环、螺五元环类螺环类肽脱甲酰基酶抑制剂可作为一类新型的抗菌剂,通过抑制细菌蛋白质合成中所需肽脱甲酰基酶的活性对多种抗生素耐药的革兰氏阳性菌菌株都有效,且不影响人体的蛋白质合成过程,从而选择性杀死细菌;本发明的含螺三元环、螺五元环类螺环类肽脱甲酰基酶抑制剂还可作为一类新型的抗癌药物,通过抑制癌症细胞线粒体中的肽脱甲酰基酶,可以影响细胞的能量平衡:从而使得线粒体膜去极化,ATP耗竭和促使细胞凋亡,在较低浓度下对多种癌细胞菌株如结直肠癌、肺癌、胃癌和肝癌具有较好的抑制活性。
Description
技术领域
本发明属于抗菌和抗癌药物技术研究领域,涉及一类肽脱甲酰基酶抑制剂,具 体涉及新型螺三元环、螺五元环类肽脱甲酰基酶抑制剂。
背景技术
抗生素(antibiotics)是指一系列能在一定浓度下对病原体有抑制和杀灭作用的化 学物质,其包括由微生物、动植物产生的代谢物,也包括用化学方法合成或半合成 的化合物。抗生素不仅指抗菌物质,抗肿瘤、抗病毒、抗寄生虫等物质亦属抗生素 范畴。抗生素是使我们能够延长寿命、更健康地生活和受益于现代医学的重要支柱。
随着抗生素的大量出现和广泛使用,抗生素耐药性问题日益凸显,产生耐药性 的速度越来越快,时间之快,耐药谱之广,令人乍舌。
全球超过95%金黄色葡萄球菌几乎对所有的盘尼西林都耐药,对90%的甲氧西林耐药;超过80%的大肠杆菌已对三分之一的第三代头孢菌素不敏感,对90%的氟喹諾 酮耐药。不仅如此,很多细菌开始产生了多重耐药。在临床中,甲氧西林耐药的金 黄色葡萄球菌对阿莫西林、左氧氟沙星、利福平、甚至是万古霉素都产生了耐药; 大肠杆菌和克雷伯氏肺炎菌形成了新的耐药机制,产生新德里金属-β-内酰胺酶 1(New Delhi metallo-β-lactamase 1,NDM-1),几乎对所有的β-内酰胺类药物都耐药。
化疗是目前临床上治疗恶性肿瘤的最重要手段之一,然而由于肿瘤细胞常常会对化疗药物产生耐药而导致患者对治疗不再敏感,最终导致化疗失败。尽管表皮生 长因子受体(EGFR)抑制剂易瑞沙和特罗凯等在治疗非小细胞肺癌中取得了很大的 成功,但其耐药问题日益突出,耐药一半源自EGFR T790M突变。肝细胞癌是世界上 最常见的恶性癌症之一,对化疗药物也通常表现出高度耐受性。近一半的乳腺癌从 一开始治疗就对赫赛汀产生了耐药。
鉴于抗生素耐药情况日益严峻,开发新的作用机制的抗生素迫在眉睫,而肽脱 甲酰基酶抑制剂则是近年来研究比较热的新作用靶点之一。肽脱甲酰基酶(peptidedeformylase,PDF)是一种金属蛋白酶,不仅广泛存在于细菌体内,也存在于恶性疟 原虫和人体中。在细菌合成蛋白的过程中,PDF可以脱除甲硫氨酸上的甲酰基,从 而使细菌能够合成出功能化的蛋白质。脱除甲酰基的过程是细菌合成蛋白的必须过 程。而人体细胞合成蛋白过程却不依赖甲酰基脱除的过程,细菌与人体合成蛋白过 程的这种差异使PDF有可能成为抗菌药物作用的新靶点。PDF抑制剂通过与PDF 酶的螯合,使细菌在合成蛋白过程中脱甲酰基步骤受阻,从而起到选择性抑制细菌 生长的目的。与正常人体细胞比,多种癌症细胞如:结直肠癌、肺癌、前列腺癌等 细胞的PDF是过度表达的,通过抑制癌细胞线粒体中的肽脱甲酰基酶,可以影响细 胞的能量平衡:从而使得癌细胞线粒体膜去极化,ATP耗竭和促使细胞凋亡。PDF 抑制剂可发展成为具有较好抗菌活性的广谱抗菌剂和抗癌活性的抗癌药物。
PDF抑制剂所包含的结构:金属鳌合基团(Metal Binding Group,MBG)和含P1、P2、P3结构部分的拟肽或非肽类骨架(式(a)PDF抑制剂一般结构)。
尽管有诸多PDF抑制剂被开发出来,用于临床前的研究,甚至有些化合物进入 了临床(如式(b)~(d)),但是由于化合物本身性质的原因导致活性不佳,或表现 出临床毒性,最终都未能成功上市。比如:放线菌素Actinonin是第一个被发现的 PDF抑制剂,其表现了良好的抗革兰氏阳性菌和阴性菌的活性,但是由于体内代谢 的不稳定,最终导致无体内的活性。LBM415,进入抗菌活性的一期临床(Phase I) 试验,具广谱活性,但是发现高剂量时会引起高铁血红蛋白症(Clin.Pharmacol. Ther.2011,90,256);GSK1322322,也被FDA终止抗菌活性的一期临床的研究,原 因类似,出现代谢活性化合物,造成对机体的毒性(临床研究终止原因见 ClinicalTrials.gov中的项目编号NCT01818011)。
发明内容
本发明提供了一类结构新颖、活性较佳、毒性小的螺三元环类、螺五元环类肽 脱甲酰基酶抑制剂,用于抑制对现有抗生素耐药的细菌,包括革兰氏阳性菌,如金 黄色葡萄球菌、表皮葡萄球菌、粪肠球菌、屎肠球菌、肺炎链球菌,和严重影响人 类健康的革兰氏阴性菌,如卡他莫拉菌等;本发明还报道了所述螺三元环类、螺五 元环类肽脱甲酰基酶抑制剂选择性抑制癌细胞如结直肠癌、肺癌、胃癌和肝癌等增 殖的作用。
本发明的螺三元环类、螺五元环类肽脱甲酰基酶抑制剂,属于抗生素,含以下 式(1)~(4)四类结构:
第一类:
式(1)中,n=2-4;R1为正丁基,环戊甲基;R2为芳香环,芳香杂环,杂环,烷基; R3为氢或烷基。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化 物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H- 吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、 2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、 3-甲酸甲酯-2-噻吩基;R3为氢。
进一步优选地,所述螺三元环类、螺五元环类肽脱甲酰基酶抑制剂为实施例1-9、14-23、25-41中的化合物。
第二类:
式(2)中,n=2-4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为芳香杂环。
进一步优选地,n=2和4;R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧二恶唑、1,2,4-氧二恶唑、1,3,4-三氮唑。
进一步优选地,所述螺三元环类、螺五元环类肽脱甲酰基酶抑制剂为实施例10-13、 24、42中的化合物。
第三类:
式(3)中,n=2-4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环,杂环,烷基; R3为氢或烷基。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为芳香杂环;R3为氢。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化 物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H- 吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、 2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、 3-甲酸甲酯-2-噻吩基;R3为氢。
进一步优选地,所述螺三元环类、螺五元环类肽脱甲酰基酶抑制剂为43-57、61-74、 77-80中的化合物。
第四类:
式(4)中,n=2-4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为芳香杂环。
进一步优选地,n=2和4;R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧二恶唑、1,2,4-氧二恶唑、1,3,4-三氮唑。
进一步优选地,所述螺三元环类、螺五元环类肽脱甲酰基酶抑制剂为58-60、75、76中的化合物。
本发明的式(1)~(4)螺三元环类、螺五元环类肽脱甲酰基酶抑制剂的分子量 介于300-600;可溶于二氯甲烷、丙酮、乙腈、甲醇、乙醇、N,N‐二甲基甲酰胺、二 甲基亚砜等溶剂;微溶于乙醚、水等,不溶于石油醚;通常为无色或微黄色粉末或 泡沫。
本发明还提出了将所述式(1)~(4)所示螺三元环类、螺五元环类肽脱甲酰基 酶抑制剂在抑制细菌肽脱甲酰基酶中的应用。
其中,所述细菌包括金黄色葡萄球菌,表皮葡萄球菌、粪肠球菌、屎肠球菌、 肺炎链球菌、卡他莫拉菌。
本发明采用左氧氟沙星和LBM415作为对照化合物,对所合成的80个新化合物 进行了四十六株临床分离菌株(菌株见表1)的体外抗菌活性筛选(80个化合物一 览表见表2)。
本发明还提出了将所述式(1)~(4)所示螺三元环类、螺五元环类肽脱甲酰基 酶抑制剂在制备抗肿瘤药物中的应用。
其中,所述肿瘤是指结直肠癌、肺癌、胃癌和肝癌。
本发明采用cck-8法测定了化合物对结直肠癌细胞、肺癌细胞、胃癌细胞、肝 癌细胞等四种肿瘤细胞的增殖抑制效果。
本发明新型的含螺三元环、螺五元环类肽脱甲酰基酶抑制剂具有抗菌活性和抗肿瘤活性。本发明的螺环类肽脱甲酰基酶抑制剂的作用机制是:通过抑制细菌蛋白 质合成中所需肽脱甲酰基酶的活性,且不影响人体的蛋白质合成过程,从而选择性 杀死细菌;通过抑制癌症细胞线粒体中的肽脱甲酰基酶,可以影响细胞的能量平衡: 从而使得线粒体膜去极化,ATP耗竭和促使细胞凋亡。本发明的抑制剂由于新颖的 作用机制,使得其不易产生如市售抗生素的耐药性。该类肽脱甲酰基酶抑制剂不仅 可作为一类新型的抗菌剂,对多种抗生素耐药的革兰氏阳性菌菌株都有效,如金黄 色葡萄球菌,表皮葡萄球菌、粪肠球菌、屎肠球菌、肺炎链球菌;并对革兰氏阴性 菌如卡他莫拉菌等有效。还可作为一类新型的抗癌药物,对多种癌细胞菌株如结直 肠癌、肺癌、胃癌和肝癌具有低微摩尔的抑制活性。
与现有技术化合物相比,本发明具有明显的技术优势:
(1)本发明的螺三元环类、螺五元环类肽脱甲酰基酶抑制剂通过分子对接研究 和实验抗菌活性筛选等方法发现的(80个化合物抗菌活性见表3所示)。通过分子 对接研究,发现了用于活性提高的配体与靶蛋白间的额外的疏水作用力,即抑制剂 的螺三元环可以和蛋白上的精氨酸残基形成较强的作用力,这一结论得到实验的支 持,如实施例2中的化合物对耐甲氧西林葡萄球菌(MRSA)的最低抑菌浓度MIC达 到0.125-0.25μg/mL,而LBM415的MIC=0.5-1μg/mL,本发明实施例2中的化合物 提高了四倍,有了显著的提高(见对照实验一中表6);通过实验发现,螺五元环的 引入对螺五元环类抑制剂活性的提高也起到了显著影响,如实施例77、实施例78、 实施例79等等;
(2)本发明采用芳香酰胺修饰的策略,使得改造后一些化合物(如实施例3、 实施例4、实施例5、实施例6、实施例7、实施例8、实施例15、实施例16、实施 例19、实施例21、实施例22、实施例23、实施例25、实施例26、实施例27、实 施例28、实施例29、实施例30、实施例33、实施例38等等)对受试菌株的活性有 了实质性的提高,如对耐甲氧西林葡萄球菌(MRSA)的最低抑菌浓度MIC达到 <0.008-0.06μg/mL,远远优于先导化合物LBM415(MIC=0.5-1μg/mL)和已上市抗 生素药物左氧沙星(MIC=16>128μg/mL);以唑类化合物为酰胺生物电子等排体的 策略的应用,不仅使化合物活性得到了保持,大部分化合物MIC=0.5-2μg/mL,如: 实施例10、实施例11、实施例12、实施例13、实施例75等;关键是本发明增加了 化合物的稳定性,也降低了化合物的代谢毒性(见对照实验二表7);
(3)本发明的螺三元环类、螺五元环类肽脱甲酰基酶抑制剂体外抗菌实验表明,其不仅 对革兰氏阳性菌如金黄色葡萄球菌、表皮葡萄球菌、耐药金黄色葡萄球菌、耐药的表皮葡萄 球菌、粪肠球菌、屎肠球菌、肺炎链球菌有效,最低抑制浓度仅有<0.008μg/mL,其活性比 先导化合物LBM415高60倍,如实施例3、实施例4、实施例6、实施例33、实施例38、实 施例64、实施例72、实施例73等;而且对严重影响人类健康的革兰氏阴性菌卡他莫拉菌等 表现出很好的活性,最低抑菌浓度低至0.06μg/mL,如实施例22、实施例33等(见对照实 验三表8)。
(4)本发明的螺三元环类、螺五元环类肽脱甲酰基酶抑制剂在30μM的浓度条件下可 以很有效地抑制多种癌细胞增殖如:结直肠癌、肺癌、胃癌和肝癌等的增殖,突出表现出对 消化道癌细胞的选择性抑制(见表4和5)。
具体实施方法
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验 方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别 限制内容。
实验方法
1.本发明采用美国临床和实验室标准协会(Clinical and LaboratoryStandards Institute, CLSI)抗菌药物敏感性试验操作规程推荐的琼脂二倍稀释法测定受试样品对所试菌株的最低 抑菌浓度(Minimal Inhibitory Concentration,MIC),通过与对照药LBM415、左氧沙星的体外 抗菌活性比较,考察了全部合成化合物对近三年临床分离的四十六株革兰阳性致病菌和革兰 阴性致病菌的体外抗菌活性。
表1.体外抗菌活性筛选的受试临床分离菌株
菌株名称 | 株数 |
甲氧西林耐药金黄色葡萄球菌(Staphylococcus aureus)MRSA | 4 |
甲氧西林敏感金黄色葡萄球菌(Staphylococcus aureus)MSSA | 4 |
2.本发明采用CCK-8法测定了实施例1-80中所述螺三元环类、螺五元环类肽 脱甲酰基酶抑制剂对结直肠癌细胞、肺癌细胞、胃癌细胞、肝癌细胞等四种肿瘤细 胞的增殖抑制效果。首先测定了80个化合物抗结直肠癌细胞增殖的活性,然后优选 30个抗结直肠癌细胞增殖活性好的化合物,考察了其对结直肠癌细胞、肺癌细胞、 胃癌细胞、肝癌细胞等四种肿瘤细胞的抑制活性。
(1)将HCT-116结直肠癌细胞株、A549肺癌细胞株、MGC-803胃癌细胞株、 BEL-7402肝癌细胞株制成单细胞悬液,180μL接种于96孔培养板中,CO2培养箱 (37℃,5%CO2,95%空气)过夜培养;
(2)各螺三元环类、螺五元环类肽脱甲酰基酶抑制剂用DMSO溶解,用相应 的细胞培养基配制成终浓度为30μM的药物溶液,分别加入到上述细胞(20μL/孔) 中,对照组加入1‰DMSO,CO2培养箱中培养72小时;
(3)培养72h后倾去培养液,加入100μL 1:10稀释的CCK-8溶液,37℃孵育 2小时后,使用酶标仪SpectraMax M5测450nm处吸光度A,参考波长620nm,计 算对肿瘤细胞生长的抑制率。
其中,步骤(1)中,所述单细胞悬液的浓度为2000细胞/孔;
其中,步骤(2)中,HCT-116结直肠癌细胞采用McCoy’s 5A培养基(10%含新生牛血清、1%双抗),A549肺癌细胞采用F12培养基(10%含新生牛血清、1%双抗), MGC-803胃癌细胞采用培1640培养基(10%含新生牛血清、1%双抗),BEL-7402肝 癌细胞采用1640培养基(10%含新生牛血清、1%双抗);
步骤(2)中所述抑制率的计算方法为1-(A药物处理组-A空白对照)/(A无药物处理组-A空白对照),A为吸光度。
化合物的制备方法
氨基化合物的合成通式(X1)
步骤1:在酸中加入DMF溶解后,冰浴下加入2.1个当量N-甲基咪唑,然后缓慢滴 加1个当量MsCl,搅拌15min后加入1个当量Boc保护的胺,反应用TLC检测, 反应完毕,EA稀释,用10%的柠檬酸洗涤,水相用50mLEA萃取2次,合并有机 相后依次用饱和碳酸氢钠、饱和食盐水洗涤,有机相浓缩得产物。
步骤2:向上步所得产物中加入HCl/MeOH溶液,待反应完毕后,得产物。
最终化合物的合成通式(X2)
异羟肟酸系列:
式中n=2或4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环,杂环,烷基。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化 物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H- 吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、 2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、 3-甲酸甲酯-2-噻吩基。
式中n=2或4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧二恶唑、 1,2,4-氧二恶唑、1,3,4-三氮唑。
步骤3:首先将酸溶解在DMF中,冰浴下依次加入5倍当量的DIPEA,缩合剂HATU(1.05个当量),搅拌15分钟后加入所合成的胺(1.0个当量),反应完毕,反应 液用乙酸乙酯稀释后,加10%的柠檬酸水溶液洗涤2次,水相用乙酸乙酯萃取2次, 合并有机相,用饱和碳酸氢钠溶液,饱和氯化钠洗涤,经无水硫酸钠干燥,过滤, 浓缩后得粗品,直接用于下一步。
步骤4:将粗品溶于二氯甲烷(2mL),滴加三氟醋酸(1mL)。在室温搅拌反应2 小时后,加饱和碳酸钠水溶液中和,分得有机相。水相用二氯甲烷萃取一次,合并 有机相,无水硫酸钠干燥、旋干得粗品。
羟肟酸系列:
式中n=2或4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环,杂环,烷基。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化 物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H- 吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、 2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、 3-甲酸甲酯-2-噻吩基。
式中n=2或4,R1为正丁基,环戊甲基;R2为芳香环或芳香杂环。
优选地,n=2和4;R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧二恶唑、 1,2,4-氧二恶唑、1,3,4-三氮唑。
步骤3:如同异羟肟酸系列的操作步骤3。
步骤4:如同异羟肟酸系列的操作步骤4。
步骤5:取上一步所得酸溶于DMF中,冰浴下依次加入5倍当量的DIPEA,缩合剂HATU(1.05个当量),搅拌15分钟后加入3倍盐酸羟胺,反应完毕,制备型HPLC 纯化得最终产物。
表2.合成最终化合物一览表
表3.化合物抗菌活性一览表
表4.化合物在30μM的浓度条件下抗结直肠癌细胞增殖抑制率活性
结果表明:实施例6、22、29、36、38、40、46、51、57、62、63、64、65、 66、70、72、73、75、76、78、79中有21个化合物在30μM的浓度下对结直肠癌 细胞HCT116的增殖抑制率超过了50%,其中实施例29化合物的增殖抑制率最高, 为94%。说明所合成的化合物在30μM的浓度下具有明显的抑制结直肠癌细胞 HCT116增殖的作用。
表5.优选化合物在30选化的浓度条件下抗结直肠癌细胞、肺癌细胞、胃癌细胞、肝癌细胞等增殖抑制率活性
选择实施例6、22、25、29、32、33、34、36、38、40、46、51、55、57、61、 62、63、64、65、66、67、70、71、72、73、75、76、77、78、79中,结直肠癌细 胞HCT116增殖抑制效果好(抑制率≥30%)的30个化合物,考察它们对其它癌症 细胞如:肺癌细胞、胃癌细胞、肝癌细胞等增殖抑制率活性。结果表明:实施例46、 57、62、63、64、65、66、70、72、73、76、78、79中13个化合物在30μM的浓 度下对肺癌细胞A549的增殖抑制率超过了50%,其中实施例76化合物的增殖抑制 率最高,为94%;实施例6、29、38、40、62、63、64、65、66、72、73、75、76、 79中14个化合物在30μM的浓度下对胃癌细胞MGC-803的增殖抑制率超过了50%, 其中实施例29化合物的增殖抑制率最高,为78%;实施例6、22、25、29、33、34、 36、38、40、46、51、55、57、62、63、64、65、66、67、70、72、73、75、76、 77、78、79中27个化合物在30μM的浓度下对肝癌细胞BEL-7402的增殖抑制率超 过了50%,其中实施例64、65、73化合物的增殖抑制率最高,为81%。
比较来看,化合物对消化道类的癌症细胞如:结直肠癌细胞、胃癌细胞和肝癌 细胞的增殖抑制作用更为明显。
实施例1
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己酰胺基)-N-(1H-吡唑-3-基)-5-氮杂螺[2.4]庚烷-6- 酰胺的合成
步骤1:在60mL二氧六环中加入3-氨基吡唑(1.50g,18.0mmol),三甲胺(4.5g,20.6mmol),4-(二甲氨基)吡啶(0.15g,1.2mmol),搅拌溶解后加入Boc2O,加热回流8h, 反应完毕,旋出溶剂,然后用EA稀释并萃取,依次用10%的柠檬酸、饱和食盐水 洗涤,有机相浓缩后得油状物,过柱(PE/DCM=2/1)得白色固体状产物(1.6g,产率 48%)。
步骤2:操作如合成通式(X1)中的步骤1。在酸(2.05g,8.5mmol)中加入20mLDMF 溶解后,冰浴下加入N-甲基咪唑(1.54g,18.7mmol),然后缓慢滴加MsCl(1.07g,9.4 mmol),搅拌15min后加入Boc保护的胺(1.56g,8.5mmol),反应用TLC检测,反 应完毕,EA稀释,用10%的柠檬酸洗涤,水相用50mL EA萃取2次,合并有机相 后依次用饱和碳酸氢钠、饱和食盐水洗涤,有机相浓缩得油状产物。
步骤3:向油状物中加入20mL和10mL的5M的HCl/MeOH溶液,室温下反应过夜, 反应完毕,旋干得油状物(2.0g,两步产率100%)。
1H NMR(400MHz,DMSO)δ11.53(s,1H),10.66(d,J=4.0Hz,1H),8.94(s,1H),7.79(s,1H),6.52(s,1H),4.70-4.51(m,1H),3.31-3.24(m,1H),3.21-3.15(m,1H),2.43-2.27(m,1H),2.01(dd,J=12.7,7.5Hz,1H),0.80-0.57(m,4H).
13C NMR(101MHz,DMSO)δ165.97,144.77,96.15,55.94,51.54,37.61,18.42,10.22, 9.83.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。两步收率为18%。
LC-MS(ESI):[M+1]+=378.15,tR=1.88min.
1H NMR(400MHz,CDCl3)δ8.36-7.98(m,1H),7.80-7.75(m,1H),6.00-5.84(m,1H),5.67-5.41(m,1H),5.15(s,1H),4.40-3.87(m,2H),3.86-3.31(m,2H),3.26-2.72(m,1H),2.44-2.36(m,1H),2.07-1.83(m,1H),1.84-1.65(m,1H),1.67-1.21(m,5H),0.97-0.82 (m,3H),0.76-0.42(m,4H).
13C NMR(101MHz,CDCl3)δ172.19,167.99,158.69,157.56,129.84,101.83,58.87,54.75,51.31,40.60,37.93,29.81,28.93,22.74,20.77,13.96,12.89,8.80.
HRMS(ESI):calculated for C18H27N5O4Na[M+Na]+=400.1961;found 400.1949.
实施例2
5-氟-2-((S)-5-((R)-2-((N-羟基甲酰胺基)甲基)己羰基)-5-氮杂螺[2.4]庚烷-6-酰胺基)吡 啶N-氮氧化合物的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2(2.1g,白色固体,两步收率68%)。
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:所得油状物(242mg,0.46mmol)溶于乙酸乙酯(3mL),加入过氧化氢 尿素复合物(133mg,1.40mmol)和邻苯二甲酸酐(207mg,1.40mmol)。混合物 在室温搅拌2小时。反应结束后,用硫代硫酸钠淬灭反应,用乙酸乙酯萃取。干燥 浓缩有机相得到粗品。
步骤5:操作如合成通式(X2)中的步骤4。三步收率为45%。
LC-MS(ESI):[M+1]+=423.02,tR=1.80min.
1H NMR(400MHz,CDCl3)δ10.55(s,1H),8.49(dd,J=9.4,6.6Hz,1H),8.21-8.18(m,1H),7.79(s,1H),7.19-7.09(m,1H),4.97(dd,J=8.5,3.6Hz,1H),4.00-3.78(m,2H),3.50-3.26(m,2H),3.17-2.80(m,1H),2.40-2.25(m,1H),2.11-1.92(m,1H),1.80-1.46(m,2H),1.44-1.26(m,4H),0.89(t,J=6.8Hz,3H),0.76-0.61(m,4H).
13C NMR(101MHz,CDCl3)δ173.35,170.54,157.91,154.73(d,J=248.1Hz),141.69, 127.21(d,J=36.5Hz),115.69(d,J=20.1Hz),114.77(d,J=7.8Hz),61.81,54.81, 51.31,40.55,36.87,29.81,28.96,22.67,21.25,13.87,12.94,8.46.
HRMS(ESI):calculated for C20H27N4O5NaF[M+Na]+=445.1863;found 445.1845.
实施例3
(S)-N-(5-(特丁基)异恶唑-3-基)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基) -5-氮杂螺[2.4]庚烷-6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2(1.4g,白色固体,两步收率47%)。
1H NMR(400MHz,D2O)δ6.14(s,1H),4.44-4.41(m,1H),3.12-2.93(m,2H),2.19(dd,J=13.4,8.9Hz,1H),1.86(dd,J=13.4,6.1Hz,1H),0.52-0.29(m,4H).
13C NMR(101MHz,D2O)δ183.22,167.90,157.06,93.24,60.23,52.67,37.13,32.51, 27.67,20.09,9.86,8.49.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率28%。
LC-MS(ESI):[M+1]+=435.24,tR=2.25min.
1H NMR(400MHz,CDCl3)δ9.94(s,1H),7.81(s,1H),6.69(s,1H),4.84(dd,J=8.2,4.2Hz,1H),4.07-3.68(m,2H),3.68-3.30(m,2H),3.20-2.80(m,1H),2.36-1.95(m,2H),1.74-1.43(m,2H),1.39-1.23(m,13H),0.91-0.82(m,3H),0.76-0.60(m,4H).
13C NMR(101MHz,CDCl3)δ181.38,173.47,169.95,157.67,157.62,93.55,61.29,55.06,51.36,40.77,36.21,32.98,29.85,28.92,28.64,22.70,21.28,13.85,12.41,9.18.
HRMS(ESI):calculated for C22H34N4O5Na[M+Na]+=457.2427;found 457.2426.
实施例4
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨 基)苯基)-5-氮杂螺[2.4]庚烷-6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2(3.1g,黄色固体,两步收率66%)。
1H NMR(400MHz,D2O)δ9.39(s,1H),9.10(d,J=8.1Hz,1H),8.87(d,J=5.5Hz,1H),8.39(d,J=6.1Hz,1H),8.16-8.11(m,1H),7.63(s,1H),7.55(d,J=6.2Hz,1H), 7.25(d,J=8.2Hz,1H),7.16(d,J=7.9Hz,1H),4.66-4.60(m,1H),3.27(d,J=3.3Hz, 2H),2.39(dd,J=13.1,8.9Hz,1H),2.12(s,3H),2.10-2.00(m,1H),0.73-0.57(m,4H).
13C NMR(101MHz,D2O)δ167.92,164.58,155.40,151.87,145.43,143.57,141.24,135.16,134.34,133.74,131.92,131.34,127.79,120.66,118.45,108.22,60.22,52.71,37.45,20.18,16.50,9.61,8.85.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得淡黄色固体,两步收率38%。
LC-MS(ESI):[M+1]+=572.27,tR=2.11min.
1H NMR(400MHz,CDCl3)δ9.38(s,1H),9.24(s,1H),8.67(d,J=4.0Hz,1H), 8.51-8.25(m,3H),7.87(s,1H),7.49-7.39(m,1H),7.38-7.05(m,4H),5.06-4.61(m,1H), 4.13-3.61(m,2H),3.57-3.22(m,2H),3.19-2.84(m,1H),2.32-2.24(m,3H),2.21-2.09(m, 2H),1.85-1.38(m,2H),1.36-1.12(m,4H),0.94-0.69(m,3H),0.71-0.54(m,4H).
13C NMR(101MHz,CDCl3)δ173.98,168.95,162.54,160.62,159.01,157.23,151.09, 148.33,137.43,136.89,135.19,132.84,130.57,124.48,123.84,115.34,113.32,108.02, 61.63,55.45,51.49,41.14,35.16,30.12,28.89,22.66,21.11,18.40,17.66,13.70,8.32.
HRMS(ESI):calculated for C31H38N7O4[M+H]+=572.2985;found 572.2980.
实施例5
(S)-N-(3-氟吡啶-2-基)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-5-氮杂螺[2.4]庚烷-6-酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2(1.7g,白色固体,两步收率45%)。
1H NMR(400MHz,D2O)δ8.20(d,J=5.5Hz,1H),8.06(t,J=9.0Hz,1H),7.56-7.50(m,1H),4.90-4.79(m,1H),3.31(s,2H),2.61-2.39(m,1H),2.15(dd,J=13.4,6.1Hz, 1H),0.76-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.94,150.12(d,J=255.5Hz),138.18,137.92(d,J=13.4Hz),130.12(d,J=16.9Hz),123.10(d,J=5.8Hz),60.39,52.83,37.21,20.06,9.96,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到淡黄色固体, 两步收率37%。
LC-MS(ESI):[M+1]+=406.70,tR=2.35min.
1H NMR(400MHz,CDCl3)δ8.40-8.15(m,1H),8.01-7.79(m,1H),7.65-7.35(m,1H),7.33-7.00(m,1H),5.05-4.66(m,1H),4.30-3.64(m,2H),3.62-3.21(m,2H),3.05(m,1H),2.78-1.90(m,2H),1.84-1.40(m,2H),1.41-1.14(m,4H),1.00-0.51(m,7H).
13C NMR(101MHz,CDCl3)δ173.98,168.98,157.19,150.39(d,J=258.5Hz),143.63(d,J=5.6Hz),140.45(d,J=12.1Hz),123.73(d,J=17.4Hz),121.04,61.31,55.35,51.28,40.97,35.11,30.08,28.90,22.67,21.10,13.85,13.71,8.13.
HRMS(ESI):calculated for C20H28FN4O4[M+H]+=407.2110;found 407.2126.
实施例6
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(5-甲基噻唑-2-基)-5-氮杂螺[2.4]庚烷-6- 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2(680mg,白色固体,两步收率100%)。
1H NMR(400MHz,D2O)δ7.24(s,1H),4.77(dd,J=8.9,6.5Hz,1H),3.24(s,2H),2.38(dd,J=13.4,9.1Hz,1H),2.28(s,3H),2.05(dd,J=13.4,6.3Hz,1H),0.72-0.45(m, 4H).
13C NMR(101MHz,D2O)δ168.01,159.21,129.86,124.06,60.16,52.75,36.68,20.02, 11.03,9.78,8.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到类白色固体, 两步收率42%。
LC-MS(ESI):[M+1]+=408.72,tR=2.67min.
1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.64(s,1H),4.68(d,J=7.6Hz,1H),4.24(t,J=10.5Hz,1H),3.93(d,J=11.5Hz,1H),3.41(d,J=12.5Hz,1H),3.02(d,J=11.5 Hz,1H),2.62(s,1H),2.40(dd,J=12.2,8.0Hz,1H),2.30(s,3H),2.13(d,J=12.3Hz, 1H),1.73-1.41(m,2H),1.39-1.16(m,4H),0.88(t,J=6.6Hz,3H),0.72-0.50(m,2H), 0.30-0.05(m,2H).
13C NMR(101MHz,CDCl3)δ174.04,171.12,158.73,153.63,135.01,126.02,61.53,53.99,53.60,43.50,39.25,31.29,29.17,22.90,19.23,13.84,13.26,11.72,5.98.
HRMS(ESI):calculated for C19H29N4O4S[M+H]+=409.1910;found 409.1922.
实施例7
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(3-(吡啶-3-基)苯基)-5-5-氮杂螺[2.4]庚 烷-6-酰胺的合成
步骤1:在混合物3-溴吡啶(2.37g,15mmol)、3-氨基苯硼酸单水合物(2.32g,15mmol)和Pd(PPh3)4(520mg,0.45mmol)中加入乙二醇二甲醚(30mL)和水(15 mL),体系用氮气置换三次,加热回流12小时。反应结束后,冷却,除去溶剂,剩 余物经过柱分离(DCM/EA:5/1到2/1)得到黄色半固体产物(680mg,27%收率)。 1H NMR(400MHz,CDCl3)δ8.81(d,J=2.0Hz,1H),8.57(,J=4.7Hz,1H),7.84(d,J =7.9Hz,1H),7.34(dd,J=7.9,4.8Hz,1H),7.26(dd,J=8.8,6.8Hz,1H),6.96(d,J= 7.6Hz,1H),6.88(s,1H),6.73(dd,J=8.0,2.1Hz,1H),3.83(brs,2H).
13C NMR(101MHz,CDCl3)δ148.31,148.21,147.06,138.96,136.88,134.41,130.05, 123.52,117.48,114.82,113.63.
步骤2:操作如合成通式(X1)中的步骤1。将(S)-5-(叔丁基)-5-氮杂螺[2.4]庚烷-6-羧酸 (950mg,3.94mmol)溶于DMF(5mL)中,然后加入NMI(0.7mL,8.67mmol)。 冷至0℃,滴加MsCl(451mg,3.94mmol),搅拌15分钟。然后加入3-(吡啶-3- 基)苯胺(670mg,3.94mmol)。TLC监控反应进程。待反应结束后,反应液用乙 酸乙酯稀释,10%柠檬酸水溶液洗涤,水相用乙酸乙酯萃取(2x20mL)。有机相 合并后先用饱和碳酸钠水溶液洗,然后用饱和食盐水洗。于旋蒸下减压浓缩后得粗 产物。
步骤3:将粗品溶于10mL乙醚中,加入5mL HCl/MeOH溶液(5M),室温搅拌 过夜。收集并干燥沉淀得棕色固体(900mg,两步69%收率)。
1H NMR(400MHz,D2O)δ8.54(s,1H),8.35(d,J=5.7Hz,1H),8.31(d,J=8.2Hz,1H),7.69(dd,J=7.8,6.2Hz,1H),7.38(s,1H),7.15-7.05(m,2H),4.44-4.38(m,1H), 3.08(d,J=11.4Hz,1H),3.03(d,J=11.4Hz,1H),2.16(dd,J=13.2,8.8Hz,1H),1.80 (dd,J=13.3,6.6Hz,1H),0.54-0.29(m,4H).
13C NMR(101MHz,D2O)δ167.95,144.27,139.57,138.97,138.77,137.47,133.84,130.50,127.45,124.14,122.41,119.26,60.25,52.75,37.49,20.24,9.55,9.03.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到类白色固体, 两步收率19%。
LC-MS(ESI):[M+1]+=464.85,tR=2.33min.
1H NMR(400MHz,CDCl3)δ9.68(s,1H),8.65(d,J=1.6Hz,1H),8.43(d,J=3.8Hz,1H),7.84-7.71(m,2H),7.66(s,1H),7.39(d,J=7.6Hz,1H),7.23(dd,J=7.8,4.7Hz, 1H),7.16(t,J=7.9Hz,1H),7.05(d,J=7.6Hz,1H),4.81(t,5.2Hz),3.92-3.58(m,2H), 3.56-3.32(m,2H),3.15-3.02(m,1H),2.14-1.98(m,1H),1.72-1.34(m,2H),1.36-1.11(m, 4H),0.80-0.64(m,3H),0.63-0.48(s,4H).
13C NMR(101MHz,CDCl3)δ173.77,169.72,157.20,147.90,147.76,139.28,137.91, 136.55,134.85,129.36,123.65,122.19,119.26,118.10,61.64,55.59,51.68,50.53,41.17, 36.00,30.12,28.87,22.66,21.12,13.73,9.05.
HRMS(ESI):calculated for C26H32N4O4Na[M+Na]+=487.2321;found 487.2318.
实施例8
(S)-5-((R)-2-((N-羟酰胺基)甲基)己羰基)-N-(3-(2-吡啶氨基)苯基)-5-氮杂螺[2.4]庚烷 -6-酰胺的合成
步骤1:在反应瓶中加入xantphos(347mg,3mol%)、Pd2(dba)3(366mg,2mol%)2-氨基嘧啶(1.92g,20mmol)和叔丁醇钠(1.92g,20mmol)。将体系用氮气置换三 次。3-溴-1-硝基苯(4.04g,20mmol)的甲苯溶液(20mL)加入到反应中。加热至 95℃,反应18小时。冷却后,硅藻土过滤(滤饼先用200mL甲苯洗以除去杂质, 而后用10%MeOH的乙酸乙酯混合液(500mL)洗脱得粗品,经乙酸乙酯打浆得黄 色固体纯品(2.6g,60%收率)。
LC-MS(ESI):[M+1]+=217.00,tR=2.45min.
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.51(d,J=4.7Hz,2H),7.90-7.83(m,2H),7.70(s,1H),7.47(t,J=8.1Hz,1H),6.85(t,J=4.7Hz,1H).
13C NMR(101MHz,CDCl3)δ159.57,158.12,148.86,140.74,129.51,124.47,116.94, 113.74,113.61.
步骤2:将含10%Pd/C(50mg),N-(3-硝基苯基)嘧啶基-2-胺(1.3g,6.0mmol)80%水合肼(1mL)的三氟乙醇(20mL)溶液,加热到80℃反应5小时。反应结束后, 过滤掉催化剂,所得滤液浓缩可得产物(1.1g,100%收率)。
LC-MS(ESI):[M+1]+=186.76,tR=1.17min.
1H NMR(400MHz,CDCl3)δ8.39(d,J=4.8Hz,2H),7.86(brs,1H),7.16(t,J=1.9Hz,1H),7.09(t,J=8.0Hz,1H),6.94-6.83(m,1H),6.66(t,J=4.8Hz,1H),6.37(dd,J=7.9,2.0Hz,1H),3.67(brs,2H).
13C NMR(101MHz,CDCl3)δ160.29,157.96,147.26,140.52,129.71,112.29,109.95, 109.75,106.28.
步骤3:操作如合成通式(X1)中的步骤1。(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧 酸(965mg,4.0mmol)溶于DMF(8mL),加入NMI(722mg,8.8mmol)冷至0℃, 滴加MsCl(460mg,4.0mmol),搅拌15分钟。而后加入N-(2-嘧啶基)苯-1,3-二胺 (745mg,4.0mmol)。反应结束后,用乙酸乙酯稀释,10%柠檬酸水溶液洗涤,有 机相用乙酸乙酯萃取(2x50mL)。合并的有机相用饱和碳酸钠和食盐水洗涤。减压 浓缩得黄色固体。
步骤4:固体溶于2:1DCM/TFA(8mL/4mL)溶液中,在室温下反应1小时。反应完 毕后加入几滴水,用固体碳酸钠固体中和。经无水Na2SO4干燥,滤除不溶固体后浓 缩滤液得游离碱(500mg,两步收率50%)。
1H NMR(400MHz,CDCl3)δ9.81(brs,1H),8.34(m,2H),8.00-7.90(m,1H),7.72-7.50(m,1H),7.46-7.25(m,1H),7.26-7.09(m,1H),6.71-6.47(m,1H),4.19-3.76(m,1H), 3.16-2.85(m,1H),2.91-2.52(m,1H),2.28-2.05(m,1H),2.00-1.77(m,1H),0.82-0.21(m, 4H).
13C NMR(101MHz,CDCl3)δ172.97,160.08,157.97,140.14,138.46,129.36,115.19, 113.66,112.55,110.39,61.41,54.68,39.12,22.40,10.88,9.55.
步骤5:操作如合成通式(X2)中的步骤3。
步骤6:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到类白色固体, 两步收率37%。
1H NMR(400MHz,CDCl3)δ9.81(brs,1H),8.34(m,2H),8.00-7.90(m,1H),7.72-7.50(m,1H),7.46-7.25(m,1H),7.26-7.09(m,1H),6.71-6.47(m,1H),4.19-3.76(m,1H), 3.16-2.85(m,1H),2.91-2.52(m,1H),2.28-2.05(m,1H),2.00-1.77(m,1H),0.82-0.21(m, 4H).
13C NMR(101MHz,CDCl3)δ172.97,160.08,157.97,140.14,138.46,129.36,115.19, 113.66,112.55,110.39,61.41,54.68,39.12,22.40,10.88,9.55.
LC-MS(ESI):[M+1]+=481.36,tR=2.35min.
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.37(d,J=4.7Hz,2H),8.12(s,1H),7.87(s,1H),7.77(s,1H),7.47(d,J=7.5Hz,1H),7.24-7.07(m,2H),6.66(t,J=4.8Hz,1H), 5.06-4.47(m,1H),4.08-3.56(m,2H),3.55-3.30(m,2H),3.23-2.76(m,1H),2.29-1.88(m, 2H),1.75-1.41(m,2H),1.40-1.19(m,4H),1.05-0.70(m,3H),0.74-0.45(m,4H).
13C NMR(101MHz,CDCl3)δ173.78,169.36,159.92,157.93,157.38,139.95,138.86, 129.19,115.26,114.12,112.26,110.94,61.66,55.48,51.60,41.14,35.63,30.14,28.92, 22.68,21.13,13.78,12.95,8.90.
HRMS(ESI):calculated for C25H33N6O4[M+1]+=481.2563;found 481.2566.
实施例9
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(4-(3-吡啶基)嘧啶-2-基)-5-氮杂螺[2.4] 庚烷-6-酰胺的合成
步骤1:将3-二甲氨基-1-(3-吡啶基)-2-丙烯基-1-酮(1.76g,10.0mmol)悬于正丁醇(20 mL),依次加入盐酸胍(1.15g,12.0mmol)和NaOH(480mg,12.0mmol)。混合 物加热到120℃,反应过夜。收集析出的固体,用水(50mL)洗涤后,真空干燥得 淡黄色晶体(1.51g,88%收率)。
1H NMR(400MHz,DMSO)δ9.23(d,J=2.0Hz,1H),8.67(dd,J=4.7,1.3Hz,1H),8.38(dt,J=8.0,1.8Hz,1H),8.36(d,J=5.1Hz,1H),7.52(dd,J=8.0,4.8Hz,1H), 7.20(d,J=5.1Hz,1H),6.81(s,2H).
13C NMR(101MHz,DMSO)δ163.78,161.53,159.36,151.11,147.93,134.11,132.44,123.72,105.99.
步骤2:将(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(2.0g,8.5mmo)溶于DMF (20mL),加入NMI(2.1g,25.5mmol),冷至0℃,滴加MsCl(978mg,8.5mmol), 搅拌15分钟。然后加入4-(3-吡啶基)嘧啶-2-胺(980mg,5.7mmol)和氯化锂(721 mg,17.0mmol)。室温搅拌反应48小时后,反应液用乙酸乙酯稀释,用10%柠檬 酸水溶液洗涤,水相用乙酸乙酯萃取(2x50mL)。有机相用饱和碳酸钠和食盐水洗。 减压浓缩后,粗品用硅胶柱纯化(DCM/MeOH=100/1-30/1)得纯品(1.0g,44%收 率)。
1H NMR(400MHz,CDCl3)(two rotomers were observed)δ9.98(brs,0.5H),9.28(d,J= 2.0Hz,1H),9.06(brs,0.5H),8.83-8.70(m,2H),8.42(d,J=8.0Hz,1H),7.56-7.40(m, 2H),4.96-4.60(m,1H),3.65-3.50(m,1H),3.45-3.10m,1H),2.50-2.25(m,1H), 2.20-2.05(m,1H),1.51(s,9H),0.78-0.54(s,4H).
步骤3:分离所得的产物溶于10mL乙醚中,加入5mL HCl/MeOH溶液(5M), 室温搅拌反应过夜。收集沉淀,干燥后得白色固体(584mg,63%收率)。
1H NMR(400MHz,D2O)δ9.09(s,1H),8.65(d,J=5.4Hz,1H),8.62(d,J=3.9Hz,1H),8.47(d,J=8.1Hz,1H),7.68(d,J=5.3Hz,1H),7.61(dd,J=8.0,5.2Hz,1H), 4.79-4.76(m,1H),3.42-3.27(m,2H),2.50(dd,J=13.4,9.0Hz,1H),2.15(dd,J=13.2, 6.1Hz,1H),0.94-0.60(m,4H).
13C NMR(101MHz,D2O)δ162.87,159.54,149.77,146.43,138.16,137.44,134.43,132.17,124.98,114.33,60.83,52.79,37.24,26.35,20.10,18.44,9.85,8.57.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到类白色固体, 两步收率19%。
LC-MS(ESI):[M+1]+=466.74,tR=2.20min.
1H NMR(400MHz,CDCl3)δ9.91(s,1H),9.37-9.08(m,1H),8.85-8.53(m,1H),8.37(s, 2H),7.87(s,1H),7.65-7.12(m,2H),5.55-5.00(m,1H),4.14-3.64(m,2H),3.55-3.10(m, 2H),3.02-2.58(m,1H),2.45-2.10(m,2H),2.05-1.46(m,2H),1.45-1.10(m,4H),1.00-0.30(m,7H).
13C NMR(101MHz,CDCl3)δ180.38,173.69,162.72,159.32,157.91,157.76,151.70, 148.31,134.89,131.89,123.83,111.79,61.70,55.39,51.35,42.84,41.02,35.71,30.09, 28.87,22.71,21.02,13.75,8.41.
HRMS(ESI):calculated for C24H31N6O4[M+1]+=467.2407;found 467.2399.
实施例10
N-((R)-2-((S)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-羰基)己基)-N-羟甲酰胺的合 成
步骤1:将(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-甲酸(2.4g,10mmol)放在烧瓶中, 加入N,N-二甲基甲酰胺DMF(25mL)使之溶解,冰浴下加入N-甲基咪唑NMI(1.8 mL,22mmol),然后滴加甲磺酰氯(0.78mL,10mmol),0℃下搅拌15分钟。然 后加入邻苯二胺(2.8g,20mmol)。反应体系于室温下搅拌6小时。待反应结束, 反应液用乙酸乙酯稀释,有机相用10%柠檬酸水溶液洗涤三次除去过量的邻苯二胺。 最后有机相经干燥、浓缩后得粉红色粗品,为泡沫状固体。
步骤2:将所得固体溶解于20mL甲基叔丁基醚中,加入4mL醋酸。将该溶液加热 回流3小时,反应结束后用饱和Na2CO3溶液中和至中性。分离得到有机层,浓缩 得到关环产物。
步骤3:将油状关环产物溶解在20mL乙醚中,加入5M的HCl/MeOH溶液(10mL), 搅拌过夜。收集析出的白色固体并真空干燥之,得1.3g产品,三步总收率45%。
1H NMR(400MHz,D2O)δ7.67-7.58(m,2H),7.49-7.39(m,2H),5.41(t,J=8.6Hz,1H),3.55-3.46(m,1H),3.25-3.15(m,1H),2.68-2.57(m,1H),2.39-2.28(m,1H), 0.85-0.60(m,4H).
13C NMR(101MHz,D2O)δ144.90,130.95,127.05,114.21,36.52,20.20,11.92,7.25.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到半固体,两步收率为32%。
LC-MS(ESI):[M+1]+=385.06,tR=1.51min.
1H NMR(400MHz,CDCl3)δ12.10(s,1H),8.30-7.79(m,1H),7.74-7.34(m,2H),7.29-7.16(m,2H),5.58-5.42(m,1H),4.21-4.01(m,1H),3.97-3.87(m,1H),3.84-3.68(m,1H),3.55-3.40(m,1H),3.31-3.11(m,1H),2.76-2.57(m,1H),2.40-2.07(m,1H), 1.70-1.45(m,2H),1.39-1.22(m,4H),0.94-0.83(m,3H),0.73-0.49(m,2H),0.32-0.15(m, 2H).
13C NMR(101MHz,CDCl3)δ174.59,161.90,154.44,123.20,122.92,56.75,53.81,48.09,43.15,41.24,29.69,29.11,22.86,19.00,14.11,13.86,5.90.
HRMS(ESI):calculated for C21H28N4O3[M+1]+=385.2060;found 385.2013.
实施例11
N-羟基-N-((R)-2-((S)-6-(3-(吡啶-3-基)-1,2,4-恶二唑-5-基)-5-氮杂螺[2.4]庚烷-5-羰基) 己基)甲酰胺的合成
步骤1:将3-氰基吡啶(5.2g,50mmol)溶于50mL乙醇中,然后加入羟胺盐酸盐(4.2g,60mmol),NaHCO3(5.0g,60mmol)和水(3mL)。混合物加热回流12小时。加 入无水Na2SO4,过滤后用乙醚(50mL)稀释后析出白色晶体(6.6g,96%收率)。 1H NMR(400MHz,DMSO)δ9.87(s,1H),8.87(d,J=2.1Hz,1H),8.57(dd,J=4.8, 1.5Hz,1H),8.03(dt,J=8.0,1.9Hz,1H),7.41(dd,J=8.0,4.8Hz,1H),6.01(s,2H).
13C NMR(101MHz,DMSO)δ149.72,148.92,146.56,132.82,129.01,123.22.
步骤2:将(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(2.49g,10.3mmol)溶于DMF (25mL)中,然后加入N,N'-羰基二咪唑(CDI,1.75g,10.3mmol)。混合物室温搅 拌8小时后,加入N-羟基-(3-吡啶基)甲脒(1.41g,10.3mmol),然后再加入另一当 量的CDI(1.75g,10.3mmol)。于氮氛下,将反应加热到90℃,反应12小时。冷 却后,用乙酸乙酯(50mL)稀释,经10%柠檬酸水溶液洗涤,乙酸乙酯(50mL) 萃取。收集的有机相依次用10%柠檬酸水溶液,饱和碳酸氢钠水溶液和食盐水洗涤, 浓缩后得粗品(3.2g,84%收率)。
LC-MS(ESI):[M+1]+=343.19,tR=2.32min.
1H NMR(400MHz,CDCl3)(two rotomers were observed)δ9.35-9.29(m,1H),8.79-8.73(m,1H),8.56-8.27(m,1H),7.55-7.37(m,1H),5.38-5.20(m,1H),3.58-3.38 (m,2H),2.64-2.41(m,1H),1.47(s,4H),1.32(s,5H),0.81-0.47(m,4H).
步骤3:油状物(2.1g,5.67mmol)溶于10mL乙醚,加入10mL HCl/MeOH溶液(5 M),反应搅拌过夜。反应液加少量水,加碳酸钠固体中和酸,待气泡消失后,滤 除固体,滤液浓缩干后即得游离碱(1.2g,80%收率)。
LC-MS(ESI):[M+1]+=243.89,tR=1.13min.
1H NMR(400MHz,CDCl3)δ9.33(d,J=1.7Hz,1H),8.74(dd,J=4.8,1.4Hz,1H),8.37(dt,J=7.9,1.7Hz,1H),7.43(dd,J=7.9,4.9Hz,1H),4.76(dd,J=7.7,6.1Hz, 1H),3.14(d,J=10.0Hz,1H),3.01(d,J=10.0Hz,1H),2.30(dd,J=12.6,7.8Hz,1H), 2.19(dd,J=12.6,5.9Hz,1H),0.65(s,4H).
13C NMR(101MHz,CDCl3)δ182.26,166.29,151.99,148.70,134.72,123.59,123.11, 55.07,54.87,40.42,22.22,11.54,11.38.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到无色油状物, 两步收率33%。
LC-MS(ESI):[M+1]+=413.69,tR=2.33min.
1H NMR(400MHz,CDCl3)δ9.20(d,J=1.2Hz,1H),8.79-8.57(dd,J=3.6Hz,1H),8.28(dd,J=6.2,1.6Hz,1H),7.73(s,1H),7.35(dd,J=7.9,4.9Hz,1H),5.51(dd,J= 8.1,4.0Hz,1H),3.94-3.67(m,2H),3.66-3.47(m,1H),3.42-3.26(m,1H),3.16-2.82(m, 1H),2.40(dd,J=12.9,8.2Hz,1H),2.03-1.78(m,1H),1.64-1.39(m,2H),1.37-1.16(m, 4H),0.84(t,J=7.0Hz,3H),0.74-0.42(m,4H).
13C NMR(101MHz,CDCl3)δ180.16,172.50,166.33,157.43,151.85,148.55,134.84, 123.63,123.28,54.52,54.10,51.66,40.86,38.86,29.99,28.76,22.77,21.17,13.87, 12.48,8.58.
HRMS(ESI):calculated for C21H28N5O4[M+1]+=414.2141;found 414.2146.
实施例12
N-羟基-N-((R)-2-((S)-6-(5-(吡啶-2-基)-1,3,4-恶二唑-2-基)-5-氮杂螺[2.4]庚烷-5-羰基) 己基)甲酰胺的合成
步骤1:(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(1.0g,4.14mmol)溶于DMF (10mL)中,加入NMI(1.8mL,22mmol),在0℃下,滴加MsCl(475mg,4.14 mmol),搅拌15分钟。然后加入2-吡啶甲酰肼(569mg,4.14mmo)。反应6小时 后,用乙酸乙酯稀释,10%柠檬酸水溶液洗涤,水相用乙酸乙酯萃取(2x50mL)。 合并的有机相依次用饱和碳酸氢钠和食盐水洗涤,浓缩后即得无色油状产物(1.5g, 100%收率)。
LC-MS(ESI):[M+1]+=361.09,tR=2.10min.
步骤2:油状物(1.5g,4.14mmol)溶于THF(20mmol)中,然后分批加入Burgess 试剂(2.9g,10.35mmol),混合物在室温下搅拌3小时。待反应完成后,反应液用 乙醚稀释,然后加入水。分离得到的有机相经饱和食盐水洗涤两次,无水Na2SO4干燥,过滤,浓缩后得粗产物(1.4g,100%收率)。
LC-MS(ESI):[M+1]+=343.13,tR=2.53min.
步骤3:油状物(1.4g,4.13mmol)溶于2:1DCM/TFA(6mL/3mL)中,混合物室温 搅拌反应1小时。反应结束后,反应液中加入几滴水,然后用碳酸钠固体中和。经 无水硫酸钠干燥,滤去不溶物。滤液浓缩至干得游离碱(1.0g,100%收率)。
LC-MS(ESI):[M+1]+=243.08,tR=1.34min.
1H NMR(400MHz,CDCl3)δ8.78(d,J=4.6Hz,1H),8.25(d,J=7.9Hz,1H),7.89(td,J=7.8,1.6Hz,1H),7.46(ddd,J=7.6,4.9,0.9Hz,1H),4.78(dd,J=7.4,6.4Hz,1H), 3.14(d,J=10.0Hz,1H),2.98(d,J=10.0Hz,1H),2.37-2.15(m,2H),0.74-0.52(m, 4H).
13C NMR(101MHz,CDCl3)δ169.54,164.25,150.23,143.57,137.21,125.79,123.10, 54.79,54.16,39.87,22.21,11.59,11.32.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到无色油状物, 两步收率25%。
LC-MS(ESI):[M+1]+=413.76,tR=2.47min.
1H NMR(400MHz,CDCl3)δ8.45(d,J=4.0Hz,1H),8.19-7.85(m,1H),7.75-7.25(m,2H),7.22-7.00(m,1H),5.50-4.92(m,1H),4.04-3.44(m,2H),3.42-2.96(m,2H), 2.98-2.60(m,1H),2.58-2.07(m,1H),2.06-1.57(m,1H),1.45-1.17(m,2H),1.16-0.92(m, 4H),0.72-0.53(m,3H),0.47-0.16(m,4H).
13C NMR(101MHz,CDCl3)δ175.27,172.56,167.63,166.49,164.20,163.74,161.76, 157.54,150.29,150.15,143.56,141.99,138.38,137.11,126.75,125.69,123.48,123.00, 54.59,53.87,53.56,53.09,51.04,47.66,41.11,40.99,38.69,38.64,30.74,30.04,29.13, 28.77,22.91,22.74,21.02,19.07,15.71,13.86,13.78,12.41,8.83,8.68,6.36.
HRMS(ESI):calculated for C21H28N5O4[M+1]+=414.2141;found 414.2157.
实施例13
N-((R)-2-((S)-6-([1,2,4]三氮唑[4,3-a]吡啶-3-基)-5-氮杂螺[2.4]庚烷-5-羰基)己基)-N-羟 基酰胺的合成
步骤1:将(S)-5-(叔丁氧羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(2.4g,10mmol)溶于DMF (25mL),加入NMI(1.8mL,22mmol)。冷却至0℃,滴加MsCl(0.78mL,10mmol), 搅拌15分钟。然后2-吡啶肼(1.1g,10mmol)加入到溶液中。反应6小时,用乙酸 乙酯稀释,加入水(100mL),乙酸乙酯萃取(2x50mL)。有机相用饱和食盐水 洗涤。旋蒸浓缩得粗品,乙醚打浆后得类白色固体(2.35g,71%收率)。
LC-MS(ESI):[M+1]+=332.86,tR=1.74min.
步骤2:将固体(2.35g,7.1mmol)溶于二氯乙烷DCE(30mL),加入Lawesson 试剂(2.9g,7.1mmol)。于氮氛条件下,反应液加热到80℃,反应3小时。结束 后,依次用饱和碳酸钠溶液、10%柠檬酸水溶液和饱和食盐水洗涤。浓缩反应液用 硅胶柱纯化(洗脱剂:DCM/MeOH=50/1到30/1)得无色油状物(2.0g,90%收率)。 LC-MS(ESI):[M+1]+=315.22,tR=2.19min.
步骤3:油状物(2.0g,6.36mmol)溶于20mL乙醚,加入10mLHCl/MeOH溶液(5 M),室温下搅拌过夜。收集得到的沉淀干燥后得白色固体(820mg,45%收率)。 LC-MS(ESI):[M+1]+=214.79,tR=1.17min.
1H NMR(400MHz,D2O)δ8.68(d,J=11.1Hz,1H),8.10-7.95(m,2H),7.55(d,J=3.7Hz,1H),5.76(dd,J=6.8Hz,1H),3.61(d,J=11.4Hz,1H),3.48(d,J=11.4Hz,1H), 2.70-2.53(m,2H),0.95-0.71(m,4H).
13C NMR(101MHz,D2O)δ145.96,143.31,137.51,124.76,118.88,111.94,52.75,52.36,36.80,19.88,10.36,9.63.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。柱层析(DCM:MeOH=10:1)得到无色油状物, 两步收率23%。
LC-MS(ESI):[M+1]+=386.03,tR=2.00min.
1H NMR(400MHz,CDCl3)δ8.49-8.35(m,1H),7.85(s,1H),7.77-7.71(m,1H), 7.28-7.21(m,1H),7.03-6.76(m,1H),5.79-5.39(m,1H),4.04-3.77(m,2H),3.78-3.37(m, 2H),3.24-2.90(m,1H),2.87-2.59(m,1H),2.40-2.16(m,1H),1.62-1.30(m,2H),1.22 -0.99(m,4H),0.93-0.47(m,7H).
13C NMR(101MHz,CDCl3)δ172.93,157.21,149.67,147.19,127.20,123.46,116.01, 113.42,54.93,51.40,48.34,41.16,39.13,29.91,28.77,22.45,21.39,13.72,11.62,10.36. HRMS(ESI):calculated for C20H27N5O3Na[M+Na]+=408.2012;found408.2029.
实施例14
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(4-吗啉苯基)-5-氮杂螺[2.4]庚烷-6-酰胺 的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=302.05,tR=1.06min.
1H NMR(400MHz,DMSO)δ10.82(s,1H),7.52(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),4.55(t,J=7.9Hz,1H),3.78-3.67(m,4H),3.19(dd,J=37.9,11.2Hz,2H), 3.08-3.02(m,4H),2.33(dd,J=12.9,8.2Hz,1H),2.01(dd,J=12.9,7.6Hz,1H), 0.78-0.53(m,4H).
13C NMR(101MHz,DMSO)δ165.87,147.72,130.32,120.50,115.35,66.04,59.59,51.66,48.71,37.81,20.35,10.34,9.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率30%。
LC-MS(ESI):[M+1]+=473.29,tR=1.79min.
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.40(d,J=7.4Hz,2H),6.82(d,J=6.8Hz,2H),4.83(s,1H),4.17-3.64(m,7H),3.53-3.27(m,2H),3.08(s,5H),2.16(s,2H),1.28 (d,J=20.0Hz,6H),0.84(s,3H),0.80-0.50(m,4H).
实施例15
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(吡嗪-2-基)-5-氮杂螺[2.4]庚烷-6-酰胺的 合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.57min.
1H NMR(400MHz,D2O)δ8.98(d,J=96.9Hz,1H),8.31(t,J=81.8Hz,2H), 4.66-4.49(m,1H),3.26-2.81(m,2H),2.29-1.62(m,2H),0.63-0.09(m,4H).
13C NMR(101MHz,D2O)δ148.55,144.82,137.12,133.80,60.43,52.76,37.11,20.13, 9.77,8.95,8.64.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率26%。
LC-MS(ESI):[M+1]+=390.19,tR=1.56min.
1H NMR(400MHz,CDCl3)δ8.48-8.12(m,3H),7.82(s,1H),5.31(s,1H),4.96(s1H), 3.89(d,J=9.2Hz,1H),3.76-2.54(m,4H),2.30-2.20(m,1H),1.77-1.28(m,7H),0.86(s, 3H),0.81-0.58(m,4H).
实施例16
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己酰基)-N-(嘧啶-4-基)-5-螺[2.4]庚烷-6-甲酰胺的 合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.43min.
1H NMR(400MHz,D2O)δ9.08(s,1H),8.78(d,J=6.8Hz,1H),8.42(t,J=31.2Hz,1H),4.82(dd,J=8.7,6.4Hz,1H),3.50-3.15(m,2H),2.57-2.00(m,2H),0.88-0.58(m,4H).
13C NMR(101MHz,D2O)δ169.77,152.74,150.17,111.15,60.98,52.82,36.76,20.08, 9.91,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率28%。
LC-MS(ESI):[M+1]+=390.19,tR=1.76min.
1H NMR(400MHz,CDCl3)δ9.84(d,J=23.5Hz,2H),9.05-6.75(m,4H),4.97(t,J=36.3Hz,1H),4.27-2.60(m,5H),1.58-0.98(m,8H),0.97-0.30(m,7H).
实施例17
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(异恶唑-5-基)-5-氮杂螺[2.4]庚烷-6-酰胺 的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.11,tR=0.57min.
1H NMR(400MHz,DMSO)δ10.66(s,1H),9.01(s,1H),8.51(d,J=1.6Hz,1H),6.29(d,J=1.6Hz,1H),4.98-4.32(m,1H),3.29-2.98(m,2H),2.45-1.87(m,2H),0.85-0.47 (m,4H).
13C NMR(101MHz,DMSO)δ165.75,160.13,152.15,88.25,59.47,51.64,37.35,20.12, 10.27,9.78
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率27%。
LC-MS(ESI):[M+1]+=379.17,tR=1.88min.
1H NMR(400MHz,CDCl3)δ8.14(s,1H),7.78(d,J=23.1Hz,1H),6.38(d,J=41.7Hz,1H),5.03-4.72(m,1H),3.97-3.79(m,2H),3.54-2.85(m,3H),2.11(d,J=12.2Hz, 1H),1.74-1.17(m,7H),0.88(s,3H),0.78-0.60(m,4H).
实施例18
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)己酰基)-N-环丙基-5-氮杂螺[2.4]庚烷-6- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=182.98,=0.55min
1H NMR(400MHz,CDCl3)δ7.82(s,1H),3.93(dd,J=8.7,5.2Hz,1H),3.00-2.95(m,1H),2.89(s,1H),2.77-2.71(m,2H),2.24-1.78(m,2H),0.97-0.25(m,8H).
13C NMR(101MHz,CDCl3)δ175.92,60.94,54.70,39.27,22.37,22.09,11.00,9.48,6.30,6.27.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率28%。
LC-MS(ESI):[M+1]+=352.14,tR=1.46min
1H NMR(400MHz,CDCl3)δ8.35(d,J=16.0Hz,1H),8.02-7.48(m,1H),7.10-6.43(m, 1H),4.84-4.32(m,1H),4.02-3.80(m,1H),3.77-3.41(m,2H),3.18-3.02(m,1H),3.01-2.38(m,2H),2.27-1.90(m,2H),1.45-1.05(m,6H),0.99-0.78(m,4H),0.76-0.35(m,7H).
实施例19
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己酰基)-N-(4-甲基噻唑-2-基)-5-螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=237.60,tR=0.66min.
1H NMR(400MHz,DMSO)δ9.09(d,J=4.8Hz,1H),6.89(d,J=0.9Hz,1H), 4.92-4.46(m,1H),3.42-2.98(m,2H),2.48-1.85(m,5H),0.88-0.41(m,4H).
13C NMR(101MHz,DMSO)δ167.14,157.01,146.07,108.59,59.22,51.52,37.47,20.13,16.53,10.22,9.90.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率28%。
LC-MS(ESI):[M+1]+=409.53,tR=1.90min.
1H NMR(400MHz,CDCl3)δ11.53(s,1H),7.84(S,1H),6.86(s,1H),5.31(s,1H),5.13-2.78(m,5H),2.68-1.89(m,4H),1.42(dd,J=104.6,66.9Hz,7H),1.11-0.17(m, 7H).
实施例20
(S)-5-((R)-3-环丙基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(恶唑-2-基)-5-氮杂螺[2.4]庚烷 -6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.32,tR=0.36min.
1H NMR(400MHz,DMSO)δ10.77(s,1H),7.95(s,1H),7.19(s,1H),4.64(s,1H),3.19(dd,J=12.2,6.2Hz,2H),2.38(dd,J=12.9,8.5Hz,1H),2.01(dd,J=12.8,6.7Hz,1H),0.67(d,J=9.3Hz,4H).
13C NMR(101MHz,DMSO)δ167.30,152.62,136.22,125.77,59.63,51.56,37.35,20.08,10.36,9.71.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率22%。
LC-MS(ESI):[M+1]+=379.52,tR=1.83min.
1H NMR(400MHz,CDCl3)δ7.57-7.39(m,1H),7.02(d,J=15.1Hz,1H),5.32(d,J=17.8Hz,1H),3.77(d,J=9.5Hz,2H),3.48(d,J=9.6Hz,1H),3.12-2.89(m,2H), 2.83-2.63(m,2H),1.75-1.13(m,11H),0.96-0.60(m,4H).
实施例21
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己酰基)-N-(5-甲基异恶唑-3基)-5-螺[2.4]庚烷-6-甲 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=221.79,tR=0.93min.
1H NMR(400MHz,DMSO)δ10.71(s,1H),6.62(s,1H),4.56(s,1H),3.17(d,J=11.9Hz,2H),2.39(s,2H),2.33(dd,J=12.8,8.5Hz,1H),1.98(dd,J=12.9,7.0Hz,1H), 0.65(d,J=14.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.05,167.12,157.36,96.21,59.47,51.57,37.49,20.16, 12.10,10.16,9.88.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率32%。
LC-MS(ESI):[M+1]+=393.22,tR=1.69min.
1H NMR(400MHz,DMSO)δ11.00(d,J=65.0Hz,1H),8.45-7.49(m,1H),6.61(s,1H),4.66(d,J=79.9Hz,1H),3.73-3.15(m,5H),2.43(d,J=56.1Hz,5H),2.20-1.69(m,2H),1.66-1.02(m,6H),0.86(s,3H),0.58(d,J=30.4Hz,4H).
实施例22
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己羰基)-N-(噻唑-2-基)-5-氮杂螺[2.4]庚烷-6-酰胺的 合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.38,tR=0.92min.
1H NMR(400MHz,DMSO)δ10.84(s,1H),7.53(d,J=3.1Hz,1H),7.34(d,J=3.2Hz,1H),4.79-4.59(m,1H),3.21(ddd,J=15.7,10.7,5.6Hz,2H),2.37(dd,J=12.9,8.4Hz,1H),2.03(dd,J=13.0,6.9Hz,1H),0.77-0.57(m,4H).
13C NMR(101MHz,DMSO)δ167.07,157.46,137.44,114.41,59.19,51.59,37.46,20.16,10.22,9.94.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率26%。
LC-MS(ESI):[M+1]+=395.04,tR=1.69min.
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.83(s,1H),7.49-6.90(m,1H),5.38(d,J=29.3Hz,1H),4.10(dd,J=25.4,13.2Hz,1H),4.01(d,J=8.4Hz,1H),3.41(dd,J=33.5,11.2Hz,2H),3.14(s,1H),2.49-2.25(m,1H),1.76(d,J=5.9Hz,1H),1.39-1.26(m,6H),1.02-0.80(m,3H),0.69-0.53(m,4H).
实施例23
(S)-5-((R)-2-((N-羟甲酰胺基)甲基)己酰基)-N-(1,3,4-噻二唑-2-基)-5-氮杂螺[2.4]庚烷 ‐6‐甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.87,tR=0.63min.
1H NMR(400MHz,DMSO)δ10.85(dd,J=52.8,47.6Hz,1H),9.13(t,J=28.8Hz,1H),4.96-4.50(m,1H),3.47-2.92(m,2H),2.46-1.89(m,2H),1.15-0.23(m,4H).
13C NMR(101MHz,DMSO)δ167.60,158.24,149.57,59.31,51.59,37.35,20.10,10.31, 9.77.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率32%。
LC-MS(ESI):[M+1]+=396.18,tR=1.53min.
1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.57(s,1H),5.39-4.77(s,1H),4.76-4.21(m, 1H),4.20-3.63(m,1H),3.61-3.44(m,2H),3.43-3.28(m,2H),3.27-2.74(m,1H),2.70-2.31(m,1H),1.52-1.17(m,2H),1.12-0.88(m,4H),0.87-0.54(m,3H),0.52-0.03(m,4H).
实施例24
N-((R)-2-((S)-6-(1-(2-(N,N-二甲基)乙基)-1H-苯并[d]咪唑-2-基)-5-氮杂螺[2.4]庚烷-5- 羰基)己酰基)-N-羟基甲酰胺的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
步骤4:取步骤3中产物加入THF溶解,然后加入2.5倍当量的NaH,30分钟后加 入1.5倍当量二甲氨基氯乙烷,50℃下回流反应,反应完毕,加入水,EA,萃取, 无水硫酸钠干燥后浓缩过柱得产物。
LC-MS(ESI):[M+1]+=285.17,tR=0.57min.
1H NMR(400MHz,D2O)δ7.80-7.61(m,2H),7.58-7.39(m,2H),5.50(dd,J=9.1,7.8Hz,1H),4.93-4.76(m,2H),3.69-3.22(m,4H),2.96(s,6H),2.67-2.22(m,2H),0.88-0.63(m,4H).
13C NMR(101MHz,D2O)δ147.40,135.78,132.90,126.31,126.04,117.18,111.46,54.06,52.87,52.72,43.42,39.33,38.01,20.39,11.70,7.58.
步骤5:操作如合成通式(X2)中的步骤3。
步骤6:操作如合成通式(X2)中的步骤4,制备冻干得白色固体,两步收率27%。
LC-MS(ESI):[M+1]+=456.35,tR=1.56min.
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.90-7.72(m,2H),7.40-7.31(m,2H),5.89-5.44(m,1H),5.45-5.21(m,1H),4.67-4.47(m,1H),4.31-3.97(m,3H),3.85-3.72(m,1H),3.55-3.50(m 1H),3.46-3.30(m,1H),2.92-2.66(m,8H),2.16-1.89(m,1H), 1.87-1.62(m,1H),1.46-1.34(m,2H),1.32-1.19(m,5H),0.84-0.71(m,3H),0.69-049(m, 4H).
实施例25
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(4-吗啉苯基)-5-螺[2.4]庚烷-6- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=302.05,tR=1.06min.
1H NMR(400MHz,DMSO)δ10.82(s,1H),7.52(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),4.55(t,J=7.9Hz,1H),3.78-3.67(m,4H),3.19(dd,J=37.9,11.2Hz,2H), 3.08-3.02(m,4H),2.33(dd,J=12.9,8.2Hz,1H),2.01(dd,J=12.9,7.6Hz,1H), 0.78-0.53(m,4H).
13C NMR(101MHz,DMSO)δ165.87,147.72,130.32,120.50,115.35,66.04,59.59,51.66,48.71,37.81,20.35,10.34,9.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率35%。
LC-MS(ESI):[M+1]+=499.31,tR=1.76min.
1H NMR(400MHz,CDCl3)δ7.84(d,J=17.4Hz,1H),7.54-7.32(m,2H),6.87(dd,J=13.7,10.3Hz,2H),5.05-4.71(m,1H),4.22-3.80(m,8H),3.23-3.00(m,5H),2.06(d,J=8.2Hz,4H),1.90-1.37(m,10H),0.75-0.40(m,3H).
实施例26
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙羰基)-N-(吡嗪-2-基)-5-氮杂螺[2.4]庚烷 -6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.57min.
1H NMR(400MHz,D2O)δ8.98(d,J=96.9Hz,1H),8.31(t,J=81.8Hz,2H), 4.66-4.49(m,1H),3.26-2.81(m,2H),2.29-1.62(m,2H),0.63-0.09(m,4H).
13C NMR(101MHz,D2O)δ148.55,144.82,137.12,133.80,60.43,52.76,37.11,20.13, 9.77,8.95,8.64.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率32%。
LC-MS(ESI):[M+1]+=416.21,tR=1.65min.
1H NMR(400MHz,CDCl3)δ9.48(s,1H),8.42-8.25(m,1H),8.22(d,J=10.1Hz,1H),7.76(d,J=46.4Hz,1H),4.93(s,1H),4.03-3.50(m,3H),3.36(m,1H),3.19(d,J=6.3 Hz,1H),2.23(d,J=12.1Hz,1H),2.02-1.19(m,12H),0.83-0.59(m,4H).
实施例27
(S)-5-((R)-3-环戊基‐2‐((N‐羟甲酰胺基)甲基)丙酰基)‐N‐(嘧啶‐4‐基)‐5‐螺[2.4]庚烷‐6‐甲 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.43min.
1H NMR(400MHz,D2O)δ9.08(s,1H),8.78(d,J=6.8Hz,1H),8.42(t,J=31.2Hz,1H),4.82(dd,J=8.7,6.4Hz,1H),3.50-3.15(m,2H),2.57-2.00(m,2H),0.88-0.58(m,4H).
13C NMR(101MHz,D2O)δ169.77,152.74,150.17,111.15,60.98,52.82,36.76,20.08, 9.91,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率28%。
LC-MS(ESI):[M+1]+=416.21,tR=1.26min.
1H NMR(400MHz,CDCl3)δ11.25-9.16(m,2H),9.12-8.46(m,2H),8.42-7.54(m,2H),5.30(s,1H),4.15-3.60(m,2H),3.23(ddt,J=86.3,30.4,19.1Hz,3H),2.36-1.19(m,13H),0.80-0.24(m,4H).
实施例28
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(5-氟吡啶-2-基)-5-氮杂螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=236.09,tR=1.00min.
1H NMR(400MHz,D2O)δ8.25(s,1H),7.98-7.87(m,1H),7.64(dd,J=9.2,3.9Hz,1H),4.75-4.73(m,1H),3.48-3.21(m,2H),2.44(dd,J=13.3,9.0Hz,1H),2.13(dd,J=13.3,6.4Hz,1H),0.79-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.10,156.72(d,1JC-F=250.3Hz),144.96,131.48(d,2JC-F=30.9Hz),131.10(d,2JC-F=18.7Hz),118.14(d,3JC-F=6.2Hz).
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率36%。
LC-MS(ESI):[M+1]+=434.22,tR=1.95min.
1H NMR(400MHz,CDCl3)δ10.33(s,1H),8.64-7.75(m,2H),7.61-6.95(m,1H),4.71(s,1H),4.11-3.74(m,1H),3.71-3.49(m,1H),3.46-2.87(m,2H),2.86-2.50(m,1H), 2.47-2.07(m,1H),1.72(m,6H),1.53-1.17(m,4H),1.16-0.76(m,2H),0.73-0.21(m,3H).
实施例29
(S)-5-((R)-3-环戊甲基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(5-甲基噻唑-2-基)-5-螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=238.45,tR=1.09min.
1H NMR(400MHz,D2O)δ7.24(s,1H),4.77(dd,J=8.9,6.5Hz,1H),3.24(s,2H),2.38(dd,J=13.4,9.1Hz,1H),2.28(s,3H),2.05(dd,J=13.4,6.3Hz,1H),0.72-0.45(m, 4H).
13C NMR(101MHz,D2O)δ168.01,159.21,129.86,124.06,60.16,52.75,36.68,20.02, 11.03,9.78,8.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率35%。
LC-MS(ESI):[M+1]+=435.24,tR=1.93min.
1H NMR(400MHz,CDCl3)δ13.75(d,J=200.5Hz,1H),10.54(s,1H),7.67(dd,J=86.8,36.9Hz,1H),7.15(d,J=89.5Hz,1H),5.67-4.98(m,1H),4.85-2.78(m,5H), 2.58-1.06(m,17H),0.96-0.31(m,4H).
实施例30
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(3-氟吡啶-2-基)-5-螺[2.4]庚烷 -6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=235.90,tR=0.60min.
1H NMR(400MHz,D2O)δ8.20(d,J=5.5Hz,1H),8.06(t,J=9.0Hz,1H),7.56-7.50(m,1H),4.90-4.79(m,1H),3.31(s,2H),2.61-2.39(m,1H),2.15(dd,J=13.4,6.1Hz, 1H),0.76-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.94,150.12(d,J=255.5Hz),138.18,137.92(d,J=13.4Hz),130.12(d,J=16.9Hz),123.10(d,J=5.8Hz),60.39,52.83,37.21,20.06,9.96,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率38%。
LC-MS(ESI):[M+1]+=433.22,tR=1.65min.
1H NMR(400MHz,CDCl3)δ9.40(d,J=352.7Hz,1H),8.24(dd,J=55.9,22.9Hz,1H),7.88(d,J=28.7Hz,1H),7.65-7.41(m,1H),7.39-7.03(m,1H),5.24-4.45(m,1H),4.24-3.99(m,1H),3.97-3.58(m,2H),2.88(dddd,J=100.0,91.1,60.9,42.5Hz,2H),2.44-1.37(m,11H),1.18-0.98(m,2H),0.93-0.50(m,4H).
实施例31
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(1H-吡唑-3-基)-5-氮杂螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
1H NMR(400MHz,DMSO)δ11.53(s,1H),10.66(d,J=4.0Hz,1H),8.94(s,1H),7.79(s,1H),6.52(s,1H),4.70-4.51(m,1H),3.31-3.24(m,1H),3.21-3.15(m,1H),2.43-2.27(m,1H),2.01(dd,J=12.7,7.5Hz,1H),0.80-0.57(m,4H).
13C NMR(101MHz,DMSO)δ165.97,144.77,96.15,55.94,51.54,37.61,18.42,10.22, 9.83.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率31%。
LC-MS(ESI):[M+1]+=404.56,tR=1.16min.
1H NMR(400MHz,CDCl3)δ11.40(s,1H),11.18(s,1H),7.92-7.62(m,1H),7.58-7.36(m,1H),6.92(d,J=66.8Hz,1H),5.51-5.21(m,1H),4.60(t,J=8.8Hz,1H),4.36-3.96 (m,2H),3.81-3.66(m,2H),2.81-2.44(m,2H),2.36-1.62(m,11H),0.76-0.19(m,4H).
实施例32
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-环丙基-5-氮杂螺[2.4]庚烷-6- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=182.98,tR=0.550min
1H NMR(400MHz,CDCl3)δ7.82(s,1H),3.93(dd,J=8.7,5.2Hz,1H),3.00-2.95(m,1H),2.89(s,1H),2.77-2.71(m,2H),2.24-1.78(m,2H),0.97-0.25(m,8H).
13C NMR(101MHz,CDCl3)δ175.92,60.94,54.70,39.27,22.37,22.09,11.00,9.48,6.30,6.27.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率27%。
LC-MS(ESI):[M+1]+=378.16,tR=1.60min
1H NMR(400MHz,CDCl3)δ8.67-7.74(m,1H),7.27(s,1H),7.05-6.31(m,1H), 4.89-4.33(dt,J=14.5,10.4Hz,1H),4.04-3.79(m,1H),3.79-3.64(m,1H),3.61-3.13(m, 2H),3.13-2.84(m,1H),2.84-2.57(m,1H),2.29-2.05(m,1H),1.88-1.54(m,6H), 1.53-1.04(m,4H),1.03-0.18(m,7H).
实施例33
(S)-5-((R)-3-环戊甲基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(4-甲基噻唑-2-基)-5-螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=237.60,tR=0.66min.
1H NMR(400MHz,DMSO)δ9.09(d,J=4.8Hz,1H),6.89(d,J=0.9Hz,1H), 4.92-4.46(m,1H),3.42-2.98(m,2H),2.48-1.85(m,5H),0.88-0.41(m,4H).
13C NMR(101MHz,DMSO)δ167.14,157.01,146.07,108.59,59.22,51.52,37.47,20.13,16.53,10.22,9.90.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率29%。
LC-MS(ESI):[M+1]+=435.24,tR=1.91min.
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.27(s,1H),6.75-6.30(m,1H),4.93(s,1H), 4.26-3.35(m,6H),2.22-1.36(m,16H),0.83-0.48(m,4H).
实施例34
3-((S)-5-((R)-3‐环戊基‐2‐((N‐羟胺基)甲基)丙酰基)‐5‐螺[2.4]庚烷‐6‐甲酰)噻吩‐2‐羧酸 甲酯的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=281.76,tR=1.85min.
1H NMR(400MHz,DMSO)δ11.86(s,1H),8.11(d,J=5.4Hz,1H),7.89(d,J=5.4Hz,1H),3.92(dt,J=16.2,8.1Hz,1H),3.84(s,3H),2.98(d,J=10.0Hz,1H),2.71(d,J=10.0Hz,1H),2.11(dd,J=12.4,9.0Hz,1H),1.80(dd,J=12.4,4.4Hz,1H),0.63-0.33 (m,4H).
13C NMR(101MHz,DMSO)δ173.46,163.00,143.39,133.02,121.38,109.96,61.15,54.16,51.94,39.11,22.40,11.14,9.04.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率37%。
LC-MS(ESI):[M+1]+=478.45,tR=2.19min.
1H NMR(400MHz,CDCl3)δ11.29-10.18(m,1H),8.61-7.01(m,3H),4.73(ddd,J=34.4,10.2,5.4Hz,1H),4.17-3.27(m,6H),2.14-1.00(m,14H),0.94-0.37(m,4H).
实施例35
N-((R)-2-(环戊甲基)-3-((S)-6-(1,1-二氧化硫代吗啉-4-羰基)-5-氮杂螺[2.4]庚烷-5- 基)-3-丙羰基)-N-羟甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=259.00,tR=0.37min.
1H NMR(400MHz,DMSO)δ9.94(t,J=76.9Hz,1H),8.16(t,J=56.7Hz,1H), 4.42-3.90(m,1H),3.64-3.25(m,2H),3.21-2.53(m,8H),2.53-2.01(m,2H),2.01-0.66(m, 4H).
13C NMR(101MHz,DMSO)δ167.37,57.55,51.79,50.64,50.55,43.26,40.80,36.27,33.89,20.33,10.13,9.41.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率27%。
LC-MS(ESI):[M+1]+=456.16,tR=1.63min.
1H NMR(400MHz,CDCl3)δ7.88(s,1H),4.99(s,1H),4.66(d,J=13.7Hz,1H),4.26(d,J=13.2Hz,1H),3.98(s,2H),3.93-3.66(m,3H),3.61-2.94(m,7H),2.09-1.94(m, 2H),1.92-1.20(m,10H),0.80-0.50(m,4H).
实施例36
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙羰基)-N-(恶唑-2-基)-5-氮杂螺[2.4]庚烷 -6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.32,tR=0.36min.
1H NMR(400MHz,DMSO)δ10.77(s,1H),7.95(s,1H),7.19(s,1H),4.64(s,1H),3.19(dd,J=12.2,6.2Hz,2H),2.38(dd,J=12.9,8.5Hz,1H),2.01(dd,J=12.8,6.7Hz,1H),0.67(d,J=9.3Hz,4H).
13C NMR(101MHz,DMSO)δ167.30,152.62,136.22,125.77,59.63,51.56,37.35,20.08,10.36,9.71.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率24%。
LC-MS(ESI):[M+1]+=405.06,tR=1.58min.
1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.59(s,1H),7.14(s,1H),5.36(s,1H),4.18(s,1H),3.65(s,1H),3.42-2.94(m,3H),2.20(s,1H),1.93-0.72(m,12H),0.42-0.13(m,4H).
实施例37
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(异恶唑-5-基)-5-氮杂螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.11,tR=0.57min.
1H NMR(400MHz,DMSO)δ10.66(s,1H),9.01(s,1H),8.51(d,J=1.6Hz,1H),6.29(d,J=1.6Hz,1H),4.98-4.32(m,1H),3.29-2.98(m,2H),2.45-1.87(m,2H),0.85-0.47 (m,4H).
13C NMR(101MHz,DMSO)δ165.75,160.13,152.15,88.25,59.47,51.64,37.35,20.12, 10.27,9.78
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率32%。
LC-MS(ESI):[M+1]+=405.53,tR=1.32min.
1H NMR(400MHz,CDCl3)δ10.59(d,J=42.7Hz,1H),8.26-8.04(m,1H),7.81(s,1H),6.44-6.16(m,1H),4.98-4.70(m,1H),3.94-3.69(m,2H),3.56-3.28(m,2H),2.31-2.06(m,2H),1.85-1.08(m,11H),0.84-0.54(m,4H).
实施例38
(S)-N-(5-(叔丁基)异恶唑-3-基)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)‐5-氮 杂螺[2.4]庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=265.07,tR=1.44min.
1H NMR(400MHz,D2O)δ6.14(s,1H),4.44-4.41(m,1H),3.12-2.93(m,2H),2.19(dd,J=13.4,8.9Hz,1H),1.86(dd,J=13.4,6.1Hz,1H),0.52-0.29(m,4H).
13C NMR(101MHz,D2O)δ183.22,167.90,157.06,93.24,60.23,52.67,37.13,32.51, 27.67,20.09,9.86,8.49.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率31%。
LC-MS(ESI):[M+1]+=461.66,tR=1.46min.
1H NMR(400MHz,CDCl3)δ11.25(s,1H),9.77(s,1H),8.36(s,1H),8.02-7.46(m,1H), 6.68(d,J=28.5Hz,1H),4.92-4.53(m,1H),4.09-3.73(m,2H),3.63-3.41(m,2H),3.31-2.71(m,2H),1.76-1.25(m,20H),0.80-0.49(m,4H).
实施例39
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙羰基)-N-(5-甲基异恶唑-3-基)-5-氮杂螺 [2.4]庚烷-6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=221.79,tR=0.93min.
1H NMR(400MHz,DMSO)δ10.71(s,1H),6.62(s,1H),4.56(s,1H),3.17(d,J=11.9Hz,2H),2.39(s,2H),2.33(dd,J=12.8,8.5Hz,1H),1.98(dd,J=12.9,7.0Hz,1H), 0.65(d,J=14.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.05,167.12,157.36,96.21,59.47,51.57,37.49,20.16, 12.10,10.16,9.88.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率16%。
LC-MS(ESI):[M+1]+=419.11,tR=1.84min.
1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.18(s,1H),4.73(d,J=74.6Hz,1H),3.73(d,J=67.7Hz,2H),3.25(m,3H),2.38(s,3H),2.05(m,2H),1.66-1.16(m,11H),0.57 (m,4H).
实施例40
(S)-5-((S)-3-环戊基-2-((N-羟甲酰胺)甲基)丙酰基)-N-(噻唑-2-基)-5-螺[2.4]庚烷-6-甲 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.38,tR=0.92min.
1H NMR(400MHz,DMSO)δ10.84(s,1H),7.53(d,J=3.1Hz,1H),7.34(d,J=3.2Hz,1H),4.79-4.59(m,1H),3.21(ddd,J=15.7,10.7,5.6Hz,2H),2.37(dd,J=12.9,8.4Hz,1H),2.03(dd,J=13.0,6.9Hz,1H),0.77-0.57(m,4H).
13C NMR(101MHz,DMSO)δ167.07,157.46,137.44,114.41,59.19,51.59,37.46,20.1 6,10.22,9.94.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,色谱制备(DCM:MeOH=10:1)得白色固体,两步收率42%。
LC-MS(ESI):[M+1]+=421.00,tR=1.84min.
1H NMR(400MHz,CDCl3)δ11.84(s,1H),10.46(s,1H),8.51-7.68(m,1H),7.34(d,J=60.6Hz,1H),7.04-6.56(m,1H),5.26-4.62(m,1H),4.43-2.80(m,5H),2.34-1.68(m,6H),1.44-0.98(m,7H),0.72(ddt,J=59.3,52.3,23.7Hz,4H).
实施例41
(S)-5-((R)-3-环戊基-2-((N-羟甲酰胺基)甲基)丙酰基)-N-(1,3,4-噻二唑-2-基)-5-氮杂螺 [2.4]庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.87,tR=0.63min.
1H NMR(400MHz,DMSO)δ10.85(dd,J=52.8,47.6Hz,1H),9.13(t,J=28.8Hz,1H),4.96-4.50(m,1H),3.47-2.92(m,2H),2.46-1.89(m,2H),1.15-0.23(m,4H).
13C NMR(101MHz,DMSO)δ167.60,158.24,149.57,59.31,51.59,37.35,20.10,10.31, 9.77.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率33%。
LC-MS(ESI):[M+1]+=422.14,tR=1.65min.
1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.27(s,1H),6.06-5.12(m,1H),5.15-4.62(m, 1H),4.29-3.82(m,1H),3.79-3.02(m,3H),2.99-2.34(m,1H),2.31-2.15(m,1H),2.10-1.50(m,7H),1.48-1.26(m,5H),1.17-0.95(m,2H),0.86-0.69(m,2H).
实施例42
N-((R)-3-((S)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-基)-2-(环戊甲基)-3-丙羰基)- N-羟甲酰胺基的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
LC-MS(ESI):[M+1]+=214.16,tR=0.94min.
1H NMR(400MHz,D2O)δ7.67-7.58(m,2H),7.49-7.39(m,2H),5.41(t,J=8.6Hz,1H),3.55-3.46(m,1H),3.25-3.15(m,1H),2.68-2.57(m,1H),2.39-2.28(m,1H), 0.85-0.60(m,4H).
13C NMR(101MHz,D2O)δ144.90,130.95,127.05,114.21,36.52,20.20,11.92,7.25.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4,柱层析(DCM:MeOH=10:1)得白色固体,两步收率33%。
LC-MS(ESI):[M+1]+=412.18,tR=1.60min.
1H NMR(400MHz,CDCl3)δ8.44-7.11(m,5H),5.58(s,1H),4.04(s,1H),3.89-2.64(m, 4H),2.51-2.02(m,2H),1.95-0.94(m,11H),0.89-0.29(m,4H).
实施例43
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(4-吗啉苯基)-5-螺[2.4]庚烷-6-甲酰胺 的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=302.05,tR=1.06min.
1H NMR(400MHz,DMSO)δ10.82(s,1H),7.52(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),4.55(t,J=7.9Hz,1H),3.78-3.67(m,4H),3.19(dd,J=37.9,11.2Hz,2H), 3.08-3.02(m,4H),2.33(dd,J=12.9,8.2Hz,1H),2.01(dd,J=12.9,7.6Hz,1H), 0.78-0.53(m,4H).
13C NMR(101MHz,DMSO)δ165.87,147.72,130.32,120.50,115.35,66.04,59.59,51.66,48.71,37.81,20.35,10.34,9.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=514.83,tR=1.56min.
1H NMR(400MHz,CDCl3)δ7.34(s,1H),6.90(s,1H),5.06(s,1H),4.46(s,1H),3.71(d,J=18.0Hz,3H),3.17(d,J=17.6Hz,3H),2.82(d,J=28.7Hz,1H),2.36(s,1H), 1.97(s,1H),1.67-1.08(m,3H),0.89-0.52(m,4H).
实施例44
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(吡嗪-2-基)-5-螺[2.4]庚烷-6-甲酰胺的 合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.57min.
1H NMR(400MHz,D2O)δ8.98(d,J=96.9Hz,1H),8.31(t,J=81.8Hz,2H), 4.66-4.49(m,1H),3.26-2.81(m,2H),2.29-1.62(m,2H),0.63-0.09(m,4H).
13C NMR(101MHz,D2O)δ148.55,144.82,137.12,133.80,60.43,52.76,37.11,20.13, 9.77,8.95,8.64.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=390.52,tR=1.36min.
1H NMR(400MHz,DMSO)δ12.86-11.39(m,1H),10.31(d,J=98.3Hz,1H), 7.83-6.53(m,3H),5.52-4.73(m,1H),4.11(dd,J=44.5,40.2Hz,1H),3.94-3.35(m,2H), 3.03-0.74(m,13H),0.71-0.24(m,4H).
实施例45
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(嘧啶-4-基)-5-螺[2.4]庚烷-6-甲酰胺的 合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.43min.
1H NMR(400MHz,D2O)δ9.08(s,1H),8.78(d,J=6.8Hz,1H),8.42(t,J=31.2Hz,1H),4.82(dd,J=8.7,6.4Hz,1H),3.50-3.15(m,2H),2.57-2.00(m,2H),0.88-0.58(m,4H).
13C NMR(101MHz,D2O)δ169.77,152.74,150.17,111.15,60.98,52.82,36.76,20.08, 9.91,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=390.52,tR=1.38min.
1H NMR(400MHz,CDCl3)δ8.97(s,1H),8.78(s,1H),7.67(s,1H),4.94(s,1H),3.52-2.98(m,3H),2.89-2.34(m,3H),1.92-1.09(m,7H),0.89(s,3H),0.68-0.42(m,4H).
实施例46
(S)-N-(5-氟吡啶-2-基)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-5-螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=236.09,tR=1.00min.
1H NMR(400MHz,D2O)δ8.25(s,1H),8.11-7.80(m,1H),7.65(dd,J=9.1,3.7Hz,1H),4.74(d,J=7.9Hz,1H),3.44-3.15(m,2H),2.59-1.94(m,2H),0.84-0.47(m,4H).
13C NMR(101MHz,D2O)δ169.09,157.99,155.50,144.99,118.16,118.10,60.33,52.77,37.08,20.12,9.73,8.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率36%。
LC-MS(ESI):[M+1]+=407.52,tR=1.93min.
1H NMR(400MHz,CDCl3)δ10.41(d,J=191.4Hz,1H),9.42(d,J=136.3Hz,1H),8.11(dt,J=70.7,24.8Hz,2H),7.65-7.17(m,1H),5.20-4.40(m,1H),4.16-1.83(m,7H),1.79-0.97(m,9H),0.97-0.21(m,6H).
实施例47
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(5-甲基噻唑-2-基)-5-氮杂螺[2.4]庚烷 -6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=238.45,tR=1.09min.
1H NMR(400MHz,D2O)δ7.24(s,1H),4.77(dd,J=8.9,6.5Hz,1H),3.24(s,2H),2.38(dd,J=13.4,9.1Hz,1H),2.28(s,3H),2.05(dd,J=13.4,6.3Hz,1H),0.72-0.45(m, 4H).
13C NMR(101MHz,D2O)δ168.01,159.21,129.86,124.06,60.16,52.75,36.68,20.02, 11.03,9.78,8.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率25%。
LC-MS(ESI):[M+1]+=409.53,tR=1.38min.
1H NMR(400MHz,DMSO)δ12.02(d,J=79.3Hz,1H),10.37(s,1H),9.07-8.35(m,1H),7.38-6.92(m,1H),5.51-4.35(m,1H),3.83-3.38(m,2H),3.34(s,2H),2.97-2.61(m,1H),2.54-2.43(m,2H),2.40-2.28(m,2H),2.28-1.67(m,4H),1.56-1.06(m,6H), 0.99-0.81(m,2H),0.78-0.19(m,4H).
实施例48
(S)-5-((R)-2-(2-(羟氨基)-2-氧代乙基)己酰基)-N-(哒嗪-3-基)-5-氮杂螺[2.4]庚烷-6-酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.55min.
1H NMR(400MHz,D2O)δ9.19(d,J=5.0Hz,1H),8.78(d,J=9.2Hz,1H),8.29(dd,J=9.2,5.2Hz,1H),4.92-4.78(m,1H),3.47-3.15(m,2H),2.50(dd,J=13.4,9.1Hz,1H),2.20(dd,J=13.4,6.3Hz,1H),0.85-0.59(m,4H).
13C NMR(101MHz,D2O)δ169.33,155.57,145.59,134.68,128.12,60.68,52.82,36.96, 20.13,9.84,8.65.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=390.26,tR=1.68min.
1H NMR(400MHz,CDCl3)δ10.42(s,1H),8.88(s,1H),8.44(t,J=36.8Hz,1H),7.50(s,1H),5.17-4.79(m,1H),3.83-3.65(m,1H),3.58(dd,J=19.5,9.4Hz,1H),3.18(d,J=7.0Hz,1H),2.41-2.16(m,2H),2.04(t,J=18.5Hz,1H),1.62(d,J=4.2Hz,1H), 1.50-1.36(m,6H),0.84(s,3H),0.75-0.48(m,4H).
实施例49
(S)-N-(3-氟吡啶-2-基)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-5-氮杂螺[2.4]庚烷-6- 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=235.90,tR=0.60min.
1H NMR(400MHz,D2O)δ8.20(d,J=5.5Hz,1H),8.06(t,J=9.0Hz,1H),7.56-7.50(m,1H),4.90-4.79(m,1H),3.31(s,2H),2.61-2.39(m,1H),2.15(dd,J=13.4,6.1Hz, 1H),0.76-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.94,150.12(d,J=255.5Hz),138.18,137.92(d,J=13.4Hz),130.12(d,J=16.9Hz),123.10(d,J=5.8Hz),60.39,52.83,37.21,20.06,9.96,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率22%。
LC-MS(ESI):[M+1]+=407.33,tR=1.63min.
1H NMR(400MHz,DMSO)δ10.57-10.32(m,1H),10.30-10.06(m,1H),9.11-8.61(m,1H),8.59-7.77(m,2H),7.82-7.13(m,1H),5.25-4.52(m,1H),3.75-3.52(m,2H),3.34(s,2H),3.22-3.01(m,2H),2.95-2.57(m,1H),2.36-1.70(m,2H),1.55-1.25(m,7H), 1.11-0.35(m,4H).
实施例50
(S)-N-环丙基-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-5-氮杂螺[2.4]庚烷-6-甲酰胺 的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=182.98,tR=0.550min
1H NMR(400MHz,CDCl3)δ7.82(s,1H),3.93(dd,J=8.7,5.2Hz,1H),3.00-2.95(m,1H),2.89(s,1H),2.77-2.71(m,2H),2.24-1.78(m,2H),0.97-0.25(m,8H).
13C NMR(101MHz,CDCl3)δ175.92,60.94,54.70,39.27,22.37,22.09,11.00,9.48,6.30,6.27.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率25%。
LC-MS(ESI):[M+1]+=352.33,tR=1.47min
1H NMR(400MHz,CDCl3)δ6.13-5.33(m,1H),3.72(d,J=6.1Hz,2H),3.33-2.98(m,2H),2.64-1.84(m,1H),1.70-1.62(m,1H),1.52-1.41(m,12H),1.39-1.21(m,4H), 1.19-0.52(m,3H).
实施例51
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(4-甲基噻唑-2-基)-5-螺[2.4]庚烷-6-甲 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.43min.
1H NMR(400MHz,DMSO)δ9.09(d,J=4.8Hz,1H),6.89(d,J=0.9Hz,1H), 4.92-4.46(m,1H),3.42-2.98(m,2H),2.48-1.85(m,5H),0.88-0.41(m,4H).
13C NMR(101MHz,DMSO)δ167.14,157.01,146.07,108.59,59.22,51.52,37.47,20.13,16.53,10.22,9.90.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率29%。
LC-MS(ESI):[M+1]+=409.34,tR=1.84min.
1H NMR(400MHz,DMSO)δ12.02(d,J=79.3Hz,1H),10.37(s,1H),9.07-8.35(m,1H),7.38-6.92(m,1H),5.51-4.35(m,1H),3.83-3.38(m,2H),3.34(s,2H),2.97-2.61(m,1H),2.54-2.43(m,2H),2.40-2.28(m,2H),2.28-1.67(m,4H),1.56-1.06(m,6H), 0.99-0.81(m,2H),0.78-0.19(m,4H).
实施例52
(S)-N-(1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰 基)-5-螺[2.4]庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=278.38,tR=1.10min.
1H NMR(400MHz,D2O)δ8.01-7.76(m,1H),7.59(d,J=22.1Hz,1H),4.53-4.38(m,2H),3.69-3.39(m,3H),2.86-2.73(m,6H),2.41-2.27(m,1H),2.11-1.94(m,1H), 1.32-0.90(m,2H),0.74-0.53(m,4H).
13C NMR(101MHz,D2O)δ167.17,133.04,123.88,119.97,56.50,52.60,48.83,46.22, 43.03,37.19,20.12,9.59,8.76.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=449.35,tR=1.13min.
1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.18(s,1H),5.30(d,J=161.0Hz,3H),3.75(d,J=12.0Hz,3H),3.28-2.38(m,10H),2.27-0.72(m,11H),0.37(d,J=91.8Hz,4H).
实施例53
(S)-5-((R)-2-(2-(羟氨基)-2-氧代乙基)己酰基)-N-(恶唑-2-基)-5-氮杂螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.32,tR=0.36min.
1H NMR(400MHz,DMSO)δ10.77(s,1H),7.95(s,1H),7.19(s,1H),4.64(s,1H),3.19(dd,J=12.2,6.2Hz,2H),2.38(dd,J=12.9,8.5Hz,1H),2.01(dd,J=12.8,6.7Hz,1H),0.67(d,J=9.3Hz,4H).
13C NMR(101MHz,DMSO)δ167.30,152.62,136.22,125.77,59.63,51.56,37.35,20.08,10.36,9.71.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率23%。
LC-MS(ESI):[M+1]+=379.23,tR=1.49min.
1H NMR(400MHz,DMSO)δ11.57-10.73(m,1H),10.59-9.67(m,1H),9.10-8.40(m,1H),7.86(d,J=7.9Hz,1H),7.17-6.58(m,1H),3.71-3.47(m,1H),3.34(s,1H), 3.03-2.77(m,1H),2.70(d,J=8.0Hz,4H),2.55-2.41(m,2H),2.29-1.79(m,2H), 1.63-0.89(m,7H),0.85(t,J=6.5Hz,2H),0.63-0.14(m,2H).
实施例54
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(异恶唑-5-基)-5-螺[2.4]庚烷-6-甲酰胺 的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.11,tR=0.57min.
1H NMR(400MHz,DMSO)δ10.66(s,1H),9.01(s,1H),8.51(d,J=1.6Hz,1H),6.29(d,J=1.6Hz,1H),4.98-4.32(m,1H),3.29-2.98(m,2H),2.45-1.87(m,2H),0.85-0.47 (m,4H).
13C NMR(101MHz,DMSO)δ165.75,160.13,152.15,88.25,59.47,51.64,37.35,20.12, 10.27,9.78
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=379.23,tR=1.53min.
1H NMR(400MHz,CDCl3)δ10.99(t,J=150.4Hz,1H),9.89(s,1H),8.45-7.95(m,1H),7.27(s,1H),6.63-6.16(m,1H),5.05-4.48(m,1H),3.98-3.33(m,2H),3.11-1.04(m,12H),1.01-0.28(m,6H).
实施例55
(S)-N-(5-(叔丁基)异恶唑-3-基)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-5-氮杂螺 [2.4]庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=265.07,tR=1.44min.
1H NMR(400MHz,D2O)δ6.14(s,1H),4.44-4.41(m,1H),3.12-2.93(m,2H),2.19(dd,J=13.4,8.9Hz,1H),1.86(dd,J=13.4,6.1Hz,1H),0.52-0.29(m,4H).
13C NMR(101MHz,D2O)δ183.22,167.90,157.06,93.24,60.23,52.67,37.13,32.51, 27.67,20.09,9.86,8.49.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率23%。
LC-MS(ESI):[M+1]+=435.30,tR=2.02min.
1H NMR(400MHz,CDCl3)δ11.01(d,J=134.6Hz,1H),10.47-9.87(m,1H),6.74-6.29 (m,1H),5.65(s,1H),5.05-4.42(m,1H),3.96-3.16(m,2H),3.05-2.71(m,2H),2.51-1.95 (m,2H),1.36-1.13(m,18H),0.90-0.50(m,4H).
实施例56
(S)-5-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(5-甲基异恶唑-3-基)-5-螺[2.4]庚烷 -6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=221.79,tR=0.93min.
1H NMR(400MHz,DMSO)δ10.71(s,1H),6.62(s,1H),4.56(s,1H),3.17(d,J=11.9Hz,2H),2.39(s,2H),2.33(dd,J=12.8,8.5Hz,1H),1.98(dd,J=12.9,7.0Hz,1H), 0.65(d,J=14.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.05,167.12,157.36,96.21,59.47,51.57,37.49,20.16, 12.10,10.16,9.88.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率29%。
LC-MS(ESI):[M+1]+=393.42,tR=1.79min.
1H NMR(500MHz,CDCl3)δ6.59(s,1H),4.98(s,1H),4.06(d,J=161.2Hz,2H),3.46-2.23(m,7H),1.96(s,1H),1.72-1.14(m,6H),1.03-0.28(m,7H).
实施例57
(S)-5-((R)-2‐(2‐(羟胺基)‐2‐氧代乙基)己酰基)‐N‐(5‐(三氟甲基)噻唑‐2‐基)‐5‐螺[2.4]庚烷 ‐6‐甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=292.22,tR=1.28min
1H NMR(400MHz,DMSO)δ10.46(s,1H),8.09(d,J=0.9Hz,1H),4.67(dd,J=8.1,7.0Hz,1H),3.26-3.17(m,2H),2.36(dd,J=13.2,8.5Hz,1H),2.06(dd,J=13.2,6.6Hz,1H),0.76-0.61(m,4H).
13C NMR(101MHz,DMSO)δ167.88,159.26,121.96,119.23,117.58,59.25,51.77,37.12,20.13,10.32,9.60.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率32%。
LC-MS(ESI):[M+1]+=463.08,tR=2.00min.
1H NMR(400MHz,CDCl3)δ12.92-11.05(m,1H),10.14(s,1H),8.07-6.63(m,1H),5.60-4.50(m,1H),3.71(ddd,J=49.1,46.6,9.5Hz,2H),3.46-2.27(m,2H),2.08(ddd,J =54.9,36.3,19.1Hz,2H),1.80-1.12(m,6H),1.10-0.31(m,7H).
实施例58
(R)-3-((S)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-甲酰基)-N-羟庚酰胺的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
LC-MS(ESI):[M+1]+=214.16,tR=0.94min.
1H NMR(400MHz,D2O)δ7.67-7.58(m,2H),7.49-7.39(m,2H),5.41(t,J=8.6Hz,1H),3.55-3.46(m,1H),3.25-3.15(m,1H),2.68-2.57(m,1H),2.39-2.28(m,1H), 0.85-0.60(m,4H).
13C NMR(101MHz,D2O)δ144.90,130.95,127.05,114.21,36.52,20.20,11.92,7.25.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。
步骤6:操作如合成通式(X2)中的步骤5,三步收率17%。
LC-MS(ESI):[M+1]+=385.49,tR=1.65min.
1H NMR(400MHz,DMSO)δ7.48(s,2H),7.15(t,J=21.2Hz,2H),5.48-5.07(m,1H),3.88-3.53(m,2H),3.41(dd,J=23.6,16.5Hz,2H),2.81(d,J=51.3Hz,1H),2.40-2.11 (m,2H),1.84-1.00(m,9H),0.79-0.30(m,4H).
实施例59
(R)-3-((R)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-羰基)-N-羟庚酰胺基的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
LC-MS(ESI):[M+1]+=385.49,tR=1.65min.
1H NMR(400MHz,CDCl3)δ7.57(s,2H),7.22(s,2H),5.43(dd,J=36.1,29.6Hz,1H),3.93-3.79(m,1H),3.48-3.31(m,1H),3.09-2.28(m,5H),2.07-1.90(m,1H),1.24(dd,J=26.4,11.2Hz,5H),0.78-0.61(m,7H).
实施例60
(R)-3-((S)-6-(1-(2-(二甲氨基)乙基)-1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-羰基)-N- 羟庚基酰胺的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
LC-MS(ESI):[M+1]+=285.17,tR=0.57min.
1H NMR(400MHz,D2O)δ7.80-7.61(m,2H),7.58-7.39(m,2H),5.50(dd,J=9.1,7.8Hz,1H),4.93-4.76(m,2H),3.69-3.22(m,4H),2.96(s,6H),2.67-2.22(m,2H),0.88-0.63(m,4H).
13C NMR(101MHz,D2O)δ147.40,135.78,132.90,126.31,126.04,117.18,111.46,54.06,52.87,52.72,43.42,39.33,38.01,20.39,11.70,7.58.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。
步骤6:操作如合成通式(X2)中的步骤5,三步收率17%。
LC-MS(ESI):[M+1]+=456.34tR=1.23min.
1H NMR(400MHz,DMSO)δ10.34(d,J=47.3Hz,1H),9.91(d,J=51.5Hz,1H), 8.00-7.62(m,2H),7.57-7.26(m,2H),5.40(dd,J=26.3,18.9Hz,1H),5.03-4.68(m,2H), 4.02(d,J=9.4Hz,1H),3.76-3.66(m,1H),3.64-3.50(m,2H),3.04-2.76(m,6H),2.50(s, 2H),2.48-1.85(m,4H),1.46-1.17(m,7H),1.20-0.99(m,2H),0.86-0.58(m,6H).
实施例61
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(4-吗啉苯基)-5-氮杂螺[2.4]庚烷-6- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=302.05,tR=1.06min.
1H NMR(400MHz,DMSO)δ10.82(s,1H),7.52(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),4.55(t,J=7.9Hz,1H),3.78-3.67(m,4H),3.19(dd,J=37.9,11.2Hz,2H), 3.08-3.02(m,4H),2.33(dd,J=12.9,8.2Hz,1H),2.01(dd,J=12.9,7.6Hz,1H), 0.78-0.53(m,4H).
13C NMR(101MHz,DMSO)δ165.87,147.72,130.32,120.50,115.35,66.04,59.59,51.66,48.71,37.81,20.35,10.34,9.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率23%。
LC-MS(ESI):[M+1]+=499.68,tR=1.68min.
1H NMR(400MHz,DMSO)δ10.38(s,1H),9.96-9.56(m,1H),8.70(s,1H),7.43(t,J=8.7Hz,2H),6.81(t,J=44.5Hz,2H),4.63-4.33(m,1H),3.72(s,2H),3.60(dd,J=31.0,9.4Hz,1H),3.22(d,J=11.5Hz,2H),3.03(d,J=3.8Hz,2H),2.50(s,8H),2.25-0.45 (m,15H).
实施例62
(S)-5-((R)-2-(环戊甲基)-4-(羟胺)-4-氧代丁基)-N-(吡嗪-2-基)-5-氮杂螺[2.4]庚烷-6-酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.57min.
1H NMR(400MHz,D2O)δ8.98(d,J=96.9Hz,1H),8.31(t,J=81.8Hz,2H), 4.66-4.49(m,1H),3.26-2.81(m,2H),2.29-1.62(m,2H),0.63-0.09(m,4H).
13C NMR(101MHz,D2O)δ148.55,144.82,137.12,133.80,60.43,52.76,37.11,20.13, 9.77,8.95,8.64.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率27%。
LC-MS(ESI):[M+1]+=416.59,tR=1.59min.
1H NMR(400MHz,CDCl3)δ10.15(s,1H),8.46-7.88(m,3H),4.78(s,1H),3.88(dd,J=28.6,9.4Hz,1H),3.64-3.39(m,1H),3.24-2.54(m,3H),2.08-1.91(m,1H),1.87-1.17(m,12H),0.81-0.46(m,4H).
实施例63
(S)-5-((R)-2-(环戊甲基)-4-(羟氨基)-4-氧代丁基)-N-(嘧啶-4-基)-5-氮杂螺[2.4]庚烷-6- 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.43min.
1H NMR(400MHz,D2O)δ9.08(s,1H),8.78(d,J=6.8Hz,1H),8.42(t,J=31.2Hz,1H),4.82(dd,J=8.7,6.4Hz,1H),3.50-3.15(m,2H),2.57-2.00(m,2H),0.88-0.58(m,4H).
13C NMR(101MHz,D2O)δ169.77,152.74,150.17,111.15,60.98,52.82,36.76,20.08, 9.91,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率24%。
LC-MS(ESI):[M+1]+=416.57,tR=1.54min.
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.85(s,1H),8.58(t,J=5.0Hz,1H),8.13(s, 1H),4.83(s,1H),3.84(d,J=9.8Hz,1H),3.73-2.64(m,4H),2.13(d,J=5.8Hz,1H),1.96-1.20(m,12H),0.72-0.45(m,4H).
实施例64
(S)-5-((R)-2-(环戊甲基)-4-(羟氨基)-4-氧代丁基)-N-(5-氟吡啶-2-基)-5-氮杂螺[2.4] 庚烷-6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=236.09,tR=1.00min.
1H NMR(400MHz,D2O)δ8.25(s,1H),7.98-7.87(m,1H),7.64(dd,J=9.2,3.9Hz,1H),4.75-4.73(m,1H),3.48-3.21(m,2H),2.44(dd,J=13.3,9.0Hz,1H),2.13(dd,J=13.3,6.4Hz,1H),0.79-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.10,156.72(d,1JC-F=250.3Hz),144.96,131.48(d,2JC-F=30.9Hz),131.10(d,2JC-F=18.7Hz),118.14(d,3JC-F=6.2Hz).
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率18%。
LC-MS(ESI):[M+1]+=433.56,tR=1.56min.
1H NMR(400MHz,CDCl3)δ9.60(s,1H),8.36-7.72(m,2H),7.43-7.12(m,1H),4.82(d, J=63.6Hz,1H),3.88(dd,J=25.2,9.4Hz,1H),3.27-2.40(m,4H),2.01-1.86(m,1H),1.85-1.18(m,12H),0.72-0.50(m,4H).
实施例65
(S)-5-((R)-2-(环戊甲基)-4-(羟氨基)-4-氧代丁基)-N-(5-甲基噻唑-2-基)-5-氮杂螺[2.4]庚 烷-6-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=238.45,tR=1.09min.
1H NMR(400MHz,D2O)δ7.24(s,1H),4.77(dd,J=8.9,6.5Hz,1H),3.24(s,2H),2.38(dd,J=13.4,9.1Hz,1H),2.28(s,3H),2.05(dd,J=13.4,6.3Hz,1H),0.72-0.45(m, 4H).
13C NMR(101MHz,D2O)δ168.01,159.21,129.86,124.06,60.16,52.75,36.68,20.02, 11.03,9.78,8.73.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率19%。
LC-MS(ESI):[M+1]+=435.59,tR=1.35min.
1H NMR(400MHz,CDCl3)δ10.34(s,1H),7.00(s,1H),5.01-4.58(m,1H),3.95-3.64(m,1H),3.54(d,J=10.0Hz,1H),3.10-2.82(m,1H),2.58-2.11(m,5H),1.87-0.91(m,12H),0.72-0.58(m,4H).
实施例66
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(哒嗪-3-基)-5-螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=219.14,tR=0.55min.
1H NMR(400MHz,D2O)δ9.19(d,J=5.0Hz,1H),8.78(d,J=9.2Hz,1H),8.29(dd,J=9.2,5.2Hz,1H),4.92-4.78(m,1H),3.47-3.15(m,2H),2.50(dd,J=13.4,9.1Hz,1H),2.20(dd,J=13.4,6.3Hz,1H),0.85-0.59(m,4H).
13C NMR(101MHz,D2O)δ169.33,155.57,145.59,134.68,128.12,60.68,52.82,36.96, 20.13,9.84,8.65.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=416.59,tR=1.48min.
1H NMR(400MHz,CDCl3)δ11.83-9.51(m,2H),9.12-8.70(m,1H),8.46(dd,J=30.4,8.8Hz,1H),7.69-7.34(m,1H),5.44-4.71(m,1H),4.31-0.87(m,18H),0.83-0.17(m, 4H).
实施例67
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(3-氟吡啶-2-基)-5-螺[2.4]庚烷-6- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=235.90,tR=0.60min.
1H NMR(400MHz,D2O)δ8.20(d,J=5.5Hz,1H),8.06(t,J=9.0Hz,1H),7.56-7.50(m,1H),4.90-4.79(m,1H),3.31(s,2H),2.61-2.39(m,1H),2.15(dd,J=13.4,6.1Hz, 1H),0.76-0.54(m,4H).
13C NMR(101MHz,D2O)δ169.94,150.12(d,J=255.5Hz),138.18,137.92(d,J=13.4Hz),130.12(d,J=16.9Hz),123.10(d,J=5.8Hz),60.39,52.83,37.21,20.06,9.96,8.50.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=433.56,tR=1.49min.
1H NMR(400MHz,CDCl3)δ10.25(d,J=63.9Hz,1H),9.75(s,1H),8.23(dd,J=59.2,44.9Hz,1H),7.45(tq,J=16.9,8.5Hz,1H),7.09(dd,J=26.9,23.5Hz,1H),4.82(d,J =52.3Hz,1H),4.04-3.29(m,2H),3.02-0.93(m,16H),0.92-0.31(m,4H).
实施例68
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-环丙基-5-氮杂螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=182.98,tR=0.550min
1H NMR(400MHz,CDCl3)δ7.82(s,1H),3.93(dd,J=8.7,5.2Hz,1H),3.00-2.95(m,1H),2.89(s,1H),2.77-2.71(m,2H),2.24-1.78(m,2H),0.97-0.25(m,8H).
13C NMR(101MHz,CDCl3)δ175.92,60.94,54.70,39.27,22.37,22.09,11.00,9.48,6.30,6.27.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率25%。
LC-MS(ESI):[M+1]+=378.59,tR=1.49min.
1H NMR(400MHz,DMSO)δ10.37(d,J=8.2Hz,1H),8.88-8.46(m,1H),7.89-7.36(m,1H),4.55-4.09(m,1H),3.69-3.37(m,2H),3.38-3.26(m,2H),3.25-2.89(m,1H), 2.87-2.55(m,2H),2.42-2.12(m,1H),2.08-1.81(m,2H),1.80-1.24(m,9H),1.00-0.24(m, 8H).
实施例69
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(恶唑-2-基)-5-螺[2.4]庚烷-6-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.32,tR=0.36min.
1H NMR(400MHz,DMSO)δ10.77(s,1H),7.95(s,1H),7.19(s,1H),4.64(s,1H),3.19(dd,J=12.2,6.2Hz,2H),2.38(dd,J=12.9,8.5Hz,1H),2.01(dd,J=12.8,6.7Hz,1H),0.67(d,J=9.3Hz,4H).
13C NMR(101MHz,DMSO)δ167.30,152.62,136.22,125.77,59.63,51.56,37.35,20.08,10.36,9.71.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率25%。
LC-MS(ESI):[M+1]+=405.49,tR=1.48min.
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.15(s,1H),5.07(s,1H),3.63-3.00(m,3H), 2.89-2.39(m,3H),1.93-1.19(m,12H),0.62-0.48(m,4H).
实施例70
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(异恶唑-5-基)-5-螺[2.4]庚烷-6-甲 酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=208.32,tR=0.36min.
1H NMR(400MHz,DMSO)δ10.77(s,1H),7.95(s,1H),7.19(s,1H),4.64(s,1H),3.19(dd,J=12.2,6.2Hz,2H),2.38(dd,J=12.9,8.5Hz,1H),2.01(dd,J=12.8,6.7Hz,1H),0.67(d,J=9.3Hz,4H).
13C NMR(101MHz,DMSO)δ167.30,152.62,136.22,125.77,59.63,51.56,37.35,20.08,10.36,9.71.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=405.46,tR=1.53min.
1H NMR(400MHz,CDCl3)δ11.40-9.93(m,1H),8.54-7.96(m,1H),6.56-6.17(m,1H),4.92-4.22(m,1H),4.11-3.12(m,2H),3.10-0.92(m,15H),0.91-0.22(m,4H).
实施例71
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(5-甲基异恶唑-3-基)-5-螺[2.4]庚烷 -6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=221.79,tR=0.93min.
1H NMR(400MHz,DMSO)δ10.71(s,1H),6.62(s,1H),4.56(s,1H),3.17(d,J=11.9Hz,2H),2.39(s,2H),2.33(dd,J=12.8,8.5Hz,1H),1.98(dd,J=12.9,7.0Hz,1H), 0.65(d,J=14.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.05,167.12,157.36,96.21,59.47,51.57,37.49,20.16, 12.10,10.16,9.88.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率45%。
LC-MS(ESI):[M+1]+=419.59,tR=1.32min.
1H NMR(400MHz,CDCl3)δ10.80-9.61(m,2H),7.27(s,1H),6.83-6.31(m,1H),5.32(d,J=16.2Hz,1H),4.76(d,J=35.4Hz,1H),4.32-1.82(m,12H),1.79-1.10(m,6H), 1.06-0.20(m,6H).
实施例72
(S)-5-((R)-2-(环戊甲基)-4-(羟氨基)-4-氧代丁酰基)-N-(噻唑-2-基)-5-氮杂螺[2.4]庚烷 -6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.38,tR=0.92min.
1H NMR(400MHz,DMSO)δ10.84(s,1H),7.53(d,J=3.1Hz,1H),7.34(d,J=3.2Hz,1H),4.79-4.59(m,1H),3.21(ddd,J=15.7,10.7,5.6Hz,2H),2.37(dd,J=12.9,8.4Hz,1H),2.03(dd,J=13.0,6.9Hz,1H),0.77-0.57(m,4H).
13C NMR(101MHz,DMSO)δ167.07,157.46,137.44,114.41,59.19,51.59,37.46,20.16,10.22,9.94.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率21%。
LC-MS(ESI):[M+1]+=421.46,tR=1.46min.
1H NMR(400MHz,DMSO)δ12.13(s,1H),10.35(d,J=21.1Hz,1H),8.87-8.56(m,1H),7.46(d,J=3.2Hz,1H),7.20(d,J=3.2Hz,1H),4.65(t,J=7.0Hz,1H),3.80-3.41 (m,2H),2.99-2.75(m,1H),2.23(dd,J=14.7,8.7Hz,1H),2.11-1.95(m,2H),1.92-1.63 (m,4H),1.50(ddd,J=27.3,13.9,6.3Hz,5H),1.21(dd,J=13.7,7.3Hz,2H),1.04(ddd, J=19.6,11.1,7.4Hz,2H),0.76-0.59(m,3H),0.58-0.45(m,2H).
实施例73
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(5-(三氟甲基)噻唑-2-基)-5-螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=292.22,tR=1.28min
1H NMR(400MHz,DMSO)δ10.46(s,1H),8.09(d,J=0.9Hz,1H),4.67(dd,J=8.1,7.0Hz,1H),3.26-3.17(m,2H),2.36(dd,J=13.2,8.5Hz,1H),2.06(dd,J=13.2,6.6Hz,1H),0.76-0.61(m,4H).
13C NMR(101MHz,DMSO)δ167.88,159.26,121.96,119.23,117.58,59.25,51.77,37.12,20.13,10.32,9.60.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=489.17,tR=2.12min.
1H NMR(400MHz,CDCl3)δ13.14-11.09(m,1H),10.14(d,J=58.3Hz,1H),7.44(dd,J=111.4,81.1Hz,2H),5.29-4.55(m,1H),4.17-3.27(m,2H),3.24-2.51(m,2H), 2.48-0.84(m,14H),0.82-0.28(m,3H).
实施例74
(S)-5-((R)-2-(环戊甲基)-4-(羟胺基)-4-氧代丁基)-N-(1,3,4-噻二唑-2-基)-5-氮杂螺[2.4] 庚烷-6-甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=224.87,tR=0.63min.
1H NMR(400MHz,DMSO)δ10.85(dd,J=52.8,47.6Hz,1H),9.13(t,J=28.8Hz,1H),4.96-4.50(m,1H),3.47-2.92(m,2H),2.46-1.89(m,2H),1.15-0.23(m,4H).
13C NMR(101MHz,DMSO)δ167.60,158.24,149.57,59.31,51.59,37.35,20.10,10.31, 9.77.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率23%。
LC-MS(ESI):[M+1]+=422.14,tR=1.58min.
1H NMR(400MHz,DMSO)δ12.64(s,1H),10.35(d,J=21.9Hz,1H),9.36-9.02(m,1H),8.96-8.41(m,1H),4.89-4.51(m,1H),2.25-1.98(m,2H),1.95-0.95(m,12H), 0.94-0.24(m,4H).
实施例75
(R)-4-((S)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-基)-3-(环戊甲基)-N-羟基-4-氧代 丁酰胺的合成
步骤1:操作如实施例1中步骤1。
步骤2:操作如实施例1中步骤2。
步骤3:操作如实施例1中步骤3。
LC-MS(ESI):[M+1]+=214.16,tR=0.94min.
1H NMR(400MHz,D2O)δ7.67-7.58(m,2H),7.49-7.39(m,2H),5.41(t,J=8.6Hz,1H),3.55-3.46(m,1H),3.25-3.15(m,1H),2.68-2.57(m,1H),2.39-2.28(m,1H), 0.85-0.60(m,4H).
13C NMR(101MHz,D2O)δ144.90,130.95,127.05,114.21,36.52,20.20,11.92,7.25.
步骤4:操作如合成通式(X2)中的步骤3。
步骤5:操作如合成通式(X2)中的步骤4。
步骤6:操作如合成通式(X2)中的步骤5,三步收率16%。
LC-MS(ESI):[M+1]+=411.53,tR=1.34min.
1H NMR(400MHz,CDCl3)δ7.97-7.47(m,2H),7.49-7.28(m,1H),7.21(dd,J=15.3,12.4Hz,2H),5.66-5.29(m,1H),3.93-3.26(m,2H),3.18-2.90(m,2H),2.87-2.58(m, 1H),2.55-2.10(m,2H),1.94-0.99(m,11H),0.81-0.25(m,4H).
实施例76
(R)-4-((R)-6-(1H-苯并咪唑-2-基)-5-氮杂螺[2.4]庚烷-5-基)-3-(环戊甲基)-N-羟基-4-氧 代丁酰胺的合成
制备分离所得旋转异构体
LC-MS(ESI):[M+1]+=411.53,tR=1.32min.
1H NMR(400MHz,CDCl3)δ12.46(s,1H),7.53(s,2H),7.16(s,2H),5.25(s,1H),3.84(s,1H),2.98(d,J=42.9Hz,2H),2.74-2.31(m,3H),2.08(s,1H),1.88-1.06(m, 11H),0.69-0.52(m,4H).
实施例77
(S)-2-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(吡嗪-2-基)-2-氮杂螺[4.4]壬烷-3-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=246.92,tR=1.02min.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率23%。
LC-MS(ESI):[M+1]+=418.5,tR=1.38min.
1H NMR(400MHz,DMSO)δ11.17-10.66(m,1H),10.24(d,J=95.0Hz,1H),9.30(s,1H),8.38(d,J=17.7Hz,2H),4.69-4.37(m,1H),3.95-3.06(m,2H),3.02-2.64(m,1H),2.42-1.76(m,4H),1.74-0.43(m,17H).
实施例78
(S)-N-(5-氟吡啶-2-基)-2-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-2-螺[4.4]壬烷-3-甲酰 胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=263.93,tR=1.28min.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率20%。
LC-MS(ESI):[M+1]+=435.18,tR=2.03min.
1H NMR(400MHz,CDCl3)δ9.77(d,J=529.3Hz,2H),7.82-6.38(m,2H),4.73(s,1H),3.96-2.84(m,3H),2.63-1.91(m,6H),1.89-0.45(m,17H).
实施例79
(S)-2-((R)-2-(2-(羟氨基)-2-氧代乙基)己酰基)-N-(5-甲基噻唑-2-基)-2-氮杂螺[4.4]壬 烷-3-酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=268.09,tR=1.21min.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率21%。
LC-MS(ESI):[M+1]+=437.39,tR=2.02min.
1H NMR(400MHz,CDCl3)δ7.18(s,1H),5.25(s,1H),3.36-3.28(m,2H),3.13-3.08(m, 1H),2.63(dd,J=24.7,10.3Hz,1H),2.51-2.31(m,4H),1.87-1.13(m,16H),0.89(s,3H).
实施例80
(S)-2-((R)-2-(2-(羟胺基)-2-氧代乙基)己酰基)-N-(5-甲基异恶唑-3-基)-2-螺[4.4]壬烷-3- 甲酰胺的合成
步骤1:操作如合成通式(X1)中的步骤1。
步骤2:操作如合成通式(X1)中的步骤2。
LC-MS(ESI):[M+1]+=249.23,tR=0.98min.
1H NMR(400MHz,DMSO)δ10.71(s,1H),6.62(s,1H),4.56(s,1H),3.17(d,J=11.9Hz,2H),2.39(s,2H),2.33(dd,J=12.8,8.5Hz,1H),1.98(dd,J=12.9,7.0Hz,1H), 0.65(d,J=14.3Hz,4H).
13C NMR(101MHz,DMSO)δ170.05,167.12,157.36,96.21,59.47,51.57,37.49,20.16, 12.10,10.16,9.88.
步骤3:操作如合成通式(X2)中的步骤3。
步骤4:操作如合成通式(X2)中的步骤4。
步骤5:操作如合成通式(X2)中的步骤5,三步收率30%。
LC-MS(ESI):[M+1]+=421.31,tR=1.49min.
1H NMR(400MHz,DMSO)δ10.88(s,1H),6.62(d,J=31.4Hz,1H),4.48-4.05(m,1H),3.33(s,8H),2.50(dt,J=3.5,1.7Hz,9H),1.87-0.99(m,8H),0.96-0.73(m,2H).
对照实验一
B、C化合物来源于专利CN101584694A和CN101869563A。
表6.三元环引入对活性的影响
Sybyl打分是利用Sybyl X2软件的打分函数给出的,分数越高,说明预测的最 低抑菌浓度越低。结合实验所测得的最低抑菌浓度,不难发现三元环的引入对活性 提高的作用是明显的。
对照实验二
由于LBM415、GSK1322322等PDF抑制剂在代谢过程中会产生芳香羟胺、芳 香肼类活性物种,进而造成人体高铁血红蛋白症的产生。为此本专利采用了连续波 长法方法,扫描了血样在紫外可见光分光光度计500至700nm波长范围内的吸收谱, 然后计算三个健康志愿者血样经所合成的化合物作用后高铁血红蛋白的含量。
实验材料:烟酰胺腺嘌呤二核苷酸磷酸(NADPH)还原体系,包括葡萄糖-6- 磷酸二钠、烟酰胺腺嘌呤二核苷磷酸和葡萄糖-6-磷酸脱氢酶(购自上海源叶生物技 术公司)加到1mL磷酸缓冲溶液(PBS,pH 7.4)中于37℃摇床型水浴中摇晃10min, 冷至0℃。混合人员肝细胞组分S9购自Xenotech公司(20mg S9蛋白/1mL悬浮 介质)。化合物用配成50mM浓度的储备液,-20℃保存待用。Dapsone用作阳性对 照实验试剂,购自Sigma Aldrich。1%w/vtriton X-100自配。血样用含EDTA抗凝 剂的Vacutainer管收集(BD,Franklin Lakes,美国),来自三个健康志愿者,采集后 立即使用。
血样与药物孵育体系配制:250μL孵育体系由220μL全血、25μL S9(终浓度: 2mgS9蛋白/mL孵化液),2.5μL NADPH形成体系(终浓度:10mM G-6-P,1mM NADP,7.5units/mL)和2.5μL化合物储备液(终浓度500μM)组成。取2mL孵育 体系放于Eppendorf管中,于37℃水浴下摇晃孵化5小时。
高铁血红蛋白的含量测定:取60μL孵化后的样品,用3.0mL 1%Triton X-100 裂解后,用紫外-可见光分光光度计测定高铁血红蛋白(MetHb)的含量。Triton X-100 溶液做空白对照。样品放置于比色皿后1分钟,记录待测样光谱,波长从500nm到 700nm;加入铁氰化钾2mg后,静止2分钟,使样品血中亚铁完全氧化后,铁氰化 钾饱和的高铁血红蛋白的标准谱。高铁血红蛋白形成百分含量(MetHb%)通过630 nm处吸光度值比来获得。MetHb%=(A'-AB')/AM'其中,A'为630nm处样品的总吸 光度,AB'为630nm处样品中还原型血的基值吸光度,AM'为630nm处铁氰化钾 饱和的氧化型血的吸光度。
表7.化合物体外高铁血红蛋白毒性的评价
体外毒性实验结果表明,与对照药LBM415、GSK1322322相比,合成的螺三元 环化合物2、3、6、7、8和9对血液的高铁血红蛋白形成概率较低;酰胺生物电子 等排体唑类化合物的毒性非常小。
对照实验三
表8.实施例化合物和对照化合物对革兰氏阴性菌卡他莫拉菌的MIC对比
相较于对照化合物,所合成的化合物对革兰氏阴性菌卡他莫拉菌的抗菌活性有很明 显地提高。
Claims (5)
1.一种螺三元环、螺五元环类肽脱甲酰基酶抑制剂,其特征在于,所述抑制剂结构如式(1)所示:
式(1)中,n=2-4,R1为正丁基、环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H-吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、3-甲酸甲酯-2-噻吩基;R3为氢。
2.一种螺三元环、螺五元环类肽脱甲酰基酶抑制剂,其特征在于,所述抑制剂结构如式(2)所示:
式(2)中,n=2-4,R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧杂二恶唑、1,2,4-氧杂二恶唑、1,3,4-三氮唑。
3.一种螺三元环、螺五元环类肽脱甲酰基酶抑制剂,其特征在于,所述抑制剂结构如式(3)所示:
式(3)中,n=2-4,R1为正丁基,环戊甲基;R2为1H-吡唑-3-基、5-氟吡啶1-氧化物-2-基、5-(叔丁基)异恶唑-3-基、6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1-氨基-3-基、3-氟吡啶-2-基、5-甲基噻唑-2-基、3-(吡啶-3-基)苯基、N-(嘧啶-2-基)苯-1-氨基-3-基、4-(吡啶-3-基)嘧啶-2-基、4-吗啡啉苯基、2-吡嗪基、3-哒嗪基、4-嘧啶基、1-甲基-1H-吡唑-4-基、5-异恶唑基、环丙基、4-甲基噻唑-2-基、2-恶唑基、5-甲基异恶唑-3-基、2-噻唑基、1,3,4-硫二唑-2-基、5-(三氟甲基)噻唑-2-基、双乙基砜基、苯并噻唑-2-基、3-甲酸甲酯-2-噻吩基;R3为氢。
4.一种螺三元环、螺五元环类肽脱甲酰基酶抑制剂,其特征在于,所述抑制剂结构如式(4)所示:
式中n=2-4,R1为正丁基,环戊甲基;R2为2-苯并咪唑基、1,3,4-氧二恶唑、1,2,4-氧二恶唑、1,3,4-三氮唑。
5.一种螺三元环、螺五元环类肽脱甲酰基酶抑制剂,其特征在于,所述抑制剂选自:
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1784380A (zh) * | 2003-05-08 | 2006-06-07 | 诺瓦蒂什股份公司 | 新的放线酰胺素生物电子等排体 |
CN101584694A (zh) * | 2009-06-15 | 2009-11-25 | 华东师范大学 | 含2,5-二氢吡咯的肽脱甲酰基酶抑制剂及合成方法 |
CN101869563A (zh) * | 2010-07-02 | 2010-10-27 | 华东师范大学 | 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂 |
CN102452958A (zh) * | 2010-10-20 | 2012-05-16 | 天津药物研究院 | N-甲酰羟胺类化合物及其制备方法和用途 |
-
2016
- 2016-05-11 CN CN201610310999.9A patent/CN107365302B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1784380A (zh) * | 2003-05-08 | 2006-06-07 | 诺瓦蒂什股份公司 | 新的放线酰胺素生物电子等排体 |
CN101584694A (zh) * | 2009-06-15 | 2009-11-25 | 华东师范大学 | 含2,5-二氢吡咯的肽脱甲酰基酶抑制剂及合成方法 |
CN101869563A (zh) * | 2010-07-02 | 2010-10-27 | 华东师范大学 | 含4-亚甲基吡咯烷的肽脱甲酰基酶抑制剂 |
CN102452958A (zh) * | 2010-10-20 | 2012-05-16 | 天津药物研究院 | N-甲酰羟胺类化合物及其制备方法和用途 |
Non-Patent Citations (4)
Title |
---|
Actinonin与肽脱甲酰基酶作用模式的分子动力学模拟研究;高剑 等;《中国医药导报》;20160130;第13卷(第3期);797-801 * |
New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment;Lv, Fengping等;《Bioorganic & Medicinal Chemistry Letters》;20160527;第26卷(第15期);3714-3718 * |
新型肽脱甲酰基酶(PDF)抑制剂的研究——含丁二酰异羟肟酸衍生物的设计与合成;汤立达 等;《中国新药杂志》;20061030;第15卷(第10期);21-27 * |
肽脱甲酰基酶及其抑制剂的研究进展;宋林晨,等;《中国抗生素杂志》;20090130;第34卷(第1期);1-6 * |
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