CN115551855A - 半乳凝素-3的小分子抑制剂 - Google Patents
半乳凝素-3的小分子抑制剂 Download PDFInfo
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- CN115551855A CN115551855A CN202180033194.3A CN202180033194A CN115551855A CN 115551855 A CN115551855 A CN 115551855A CN 202180033194 A CN202180033194 A CN 202180033194A CN 115551855 A CN115551855 A CN 115551855A
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- fluorophenyl
- triazol
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P37/00—Drugs for immunological or allergic disorders
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
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Abstract
本公开内容涉及抑制Gal‑3的式(I)或式(II)化合物,并且包括可药用盐、包含这类化合物的组合物以及使用和制备这类化合物和组合物的方法。
Description
相关申请的交叉参考
本申请要求于2020年5月5日提交的美国临时申请No.63/020,041的优先权权益;该临时申请的内容通过引用整体并入本文。
发明背景
半乳凝素-3(Gal-3)是一种约30KDa的β-半乳糖苷结合凝集素(Cell 76:597-598),其参与调节炎性和纤维化过程。(Immunological Reviews 230:160-171)。在不受控的炎症和促纤维化情况中,Gal-3促进成纤维细胞增殖和转化并介导胶原蛋白的产生(Circulation 110:3121-3128)。
Gal-3定位于多种细胞部位,例如细胞质、细胞核和细胞表面。Gal-3也由各种细胞类型、主要是巨噬细胞和单核细胞分泌进入血流(J Pharmacol Exp Ther351:336–343)。文献中有多条证据支持Gal-3参与多个器官的纤维化过程的发展,例如肺(AmJ.Respir.Crit.Care Med.185:537-546)、肝脏(PNAS 103:5060-5065)和肾脏(Am.J.Pathol.172:288-298)。Gal-3还已经被确定为心力衰竭的生物标志物,表明Gal-3的调节在治疗心力衰竭方面具有潜在用途(Curr.Heart Fail.Rep.7:1-8)。Gal-3的调节可用于治疗癌症,因为Gal-3参与在血管生成、细胞凋亡和转移途径中起关键作用的细胞生长和分化(Galectin-3C:Human Lectin for Treatment of Cancer.ACS Symposium Series,Vol.1115.第12章,195–23)。最近,Gal-3抑制剂已经被证明在联合免疫疗法中使用时具有积极作用(Galectin Therapeutics.Press Release,2017年2月7日)。
一些公开和专利申请记载了Gal-3的合成抑制剂,它们被探索用作抗纤维化剂。这些途径的最近实例有WO2005113568、WO2005113569、WO2014067986、WO2017080973、WO2016120403、US20140099319和WO2018209255。
发明描述
本公开内容涉及抑制Gal-3的本发明的化合物,并且包括可药用盐、包含这类化合物的组合物以及使用和制备这类化合物和组合物的方法。
在第一方面,本发明特别提供了式(I)或式(II)化合物:
或其可药用盐,其中:
X独立地选自-C(O)-、-CH2-和-CH2C(O)-;
Ar1独立地是苯基或萘基;和其中各个环部分被1至5个选自如下的取代基取代:氰基、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C1-4卤代烷氧基;
R1独立地选自H、C1-4烷基、C1-4卤代烷基和-CH2C(O)OH;
R2独立地选自H、被0-1个OH取代的C1-4烷基、C1-4卤代烷基、-(CH2)0-2-C3-6环烷基、和-(CH2)0-2-被0-3个卤素取代的苯基;
R3独立地是C3-6环烷基,或包括4至7个环原子的杂环烷基,其中1-2个环原子各自独立地选自N(,N(RB)和O和S;其中所述环部分被0-1个R5和1个R5A取代;
R5独立地是OH、氰基、卤素、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、和被0-1个OH取代的C1-4烷基;
R5C独立地选自:氰基、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C1-4卤代烷氧基;
R5E独立地选自:H、C1-4烷基、Bn、-C(O)(C1-4烷基)、-C(O)O(C1-4烷基)和
R5F独立地是-NH-苯基,其中所述苯基被0-2个选自氰基、卤素、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基的取代基取代。
在第二方面,在第一方面的范围内,其中:
X是-C(O)-;和Ar1是被1-3个卤素取代的苯基。
在另一方面,在第一或第二方面的范围内,其中:
Ar1是被1-3个F取代的苯基。
在另一方面,在第一或第二方面的范围内,其中所述化合物具有式(I)。
在另一方面,在第一或第二方面的范围内,其中所述化合物具有式(II)。
在第三方面,在第一或第二方面的范围内,其中:
R3独立地是C5-6环烷基,或包括4至6个环原子的杂环烷基,其中1至2个环原子各自独立地选自N(RB)、N(RE)和O;其中所述环部分各自被0-1个R5和1个R5A取代。
在第四方面,在第一至第三方面的范围内,其中:
在第五方面,在第一至第四方面的范围内,其中:
在第六方面,在第一至第四方面的范围内,其中:
在另一方面,在第一至第四方面的范围内,其中:
在第七方面,在第一至第四方面的范围内,其中:
R1独立地是H或C1-4烷基;和
R2独立地选自H、被0-1个OH取代的C1-4烷基、C1-4卤代烷基、-(CH2)0-1-环丙基、和-CH2-(被0-2个卤素取代的苯基)。
在第八方面,在第一至第五方面的范围内,其中:
R1独立地是H或CH3;和
R2独立地选自:H、CH3、-CH2CH3、-CH2CH2OH、-CH2CHF2、环丙基和环丙基甲基。
在另一方面,在第一至第六方面任一者的范围内,其中R1是H。
在另一方面,在第一至第六方面任一者的范围内,其中R1是CH3。
在另一方面,本发明提供了选自所示例的实施例的化合物或其可药用盐。
在另一方面,本发明提供了选自所示例的实施例的化合物或其可药用盐。
除非另有指出,否者这些术语具有如下含义。“烷基”指由1至6个碳组成的直链或支链烷基基团。“环烷基”指由3至7个碳组成的单环环系。具有烃部分的术语(例如烷氧基)包括由1至6个碳组成的对该烃部分而言的直链或支链异构体。“卤素”包括氟、氯、溴和碘。“卤代烷基”和“卤代烷氧基”包括从单卤代到全卤代的所有卤素化异构体。“芳基”指具有5至12个碳原子的单环或双环芳香族环系,其中一个或两个环是芳香性的。芳基的代表性实例包括但不限于茚满基、茚基、萘基、苯基和四氢萘基。“杂芳基”指具有1-5个独立地选自氮、氧和硫的杂原子的5至7元单环或8至11元双环芳香族环系。当未指明键合链接位置时,键合可以链接在任意适当的位置,如本领域实践人员所理解的那样。取代基和键合方式的组合仅仅是产生稳定化合物的那些,如本领域实践人员所理解的那样。附加说明和多个附加说明的术语意欲向本领域技术人员澄清键合关系。例如,诸如((R)烷基)的术语指进一步被取代基R取代的烷基取代基。
本发明包括化合物的所有可药用盐形式。可药用盐是其中抗衡离子对化合物的生理活性或毒性没有显著贡献并且照此发挥药理学等效物作用的那些盐。这些盐可以根据普通有机技术、使用市售试剂来制备。一些阴离子盐形式包括乙酸盐、醋硬脂酸盐(acistrate)、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡糖醛酸盐(glucouronate)、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和昔萘酸盐(xinofoate)。一些阳离子盐形式包括铵、铝、苄星盐(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环己胺、哌嗪、钾、钠、氨丁三醇和锌。
一些本发明的化合物以立体异构形式存在。本发明包括化合物的所有立体异构形式,包括对映异构体和非对映体。制备和分离立体异构体的方法是本领域已知的。本发明包括化合物的所有互变异构形式。本发明包括阻转异构体和旋转异构体。
本发明旨在包括在本发明化合物中出现的原子的所有同位素。同位素包括原子序数相同但质量数不同的原子。作为一般示例而非限制,氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述那些类似的方法、使用适当的同位素标记的试剂代替其它使用的未标记的试剂来制备。这类化合物可具有多种潜在用途,例如作为测定生物活性的标准品和试剂。在稳定的同位素的情况下,这类化合物可具有有利地改变生物学、药理学或药代动力学性质的潜力。
生物学方法
Gal 3HTRF分析
分析缓冲液组合物:25mM HEPES,100mM NaCl,0.005%吐温20,0.05%BSA,在无菌水中制备(所有试剂来自Sigma)。
对照:
阳性对照:100%DMSO(1μL)+His-标记的hGal-3(20μL)+B-ASF(20μL)+抗-His铽抗体(5μL)+Strep d2抗体(5μL)。
阴性对照:100%DMSO(1μL)+His-标记的hGal-3(20μL)+抗-His铽抗体(5μL)+Strep d2抗体(5μL)。
贮备液制备:
方案:在384白色Opti板中于室温一式三份进行Gal-3分析,以250-300rpm轻微振摇。由初始储备液制备了2.525X工作储备液浓度的His-标记的重组人Gal-3(hGal-3)和2.525X工作储备液浓度的B-ASF。由工作储备液,将20μLhGal-3(15nM)和20μL B-ASF(15nM)加入板中。在阴性对照中仅加入hGal-3。对于在100%DMSO中的化合物,制备了50x工作储备液的浓度范围。将1μL化合物等分式样加至各孔,每孔与20μL hGal-3预孵育30分钟。然后加入20μLB-ASF,另外孵育1小时。为了检测信号,加入5μL(终浓度1.0nM)铽标记的抗-His抗体,孵育30分钟,然后加入5μL(终浓度20nM)链霉抗生物素d2,另外孵育1小时。采用HTRF筛选方案(激发波长=340nm,发射波长=615nm/665nm)在Envision 2104Multilabel Reader上检测分析信号。采用Toolset和Curve Master分析数据。结果在试验部分中报告(IC50,μM)。所有报告的IC50用HTRF分析产生,另有具体说明除外。
Gal-3 ELISA分析
材料:
1.包涂缓冲液:磷酸盐缓冲盐水(1x)-PBS
通过将从Sigma Aldrich获得的1袋PBS包(目录号:P3813-5x10Pak)溶解在1升Milli-Q水中,制备了溶液。
2.来自胎牛血清的Asialofetuin,II-型.Sigma Aldrich(目录号:A1908-50MG)。
3.胎牛血清.Invitrogen(目录号:26400-044-500mL)。
4.吐温-20.Sigma Aldrich(目录号:P1379-250mL)。
5.BD OptEIA酶试剂链霉抗生物素-HRP(目录号:554066)。
6.硫酸.Sigma Aldrich(目录号:25,810-5)。
7.低聚甲醛.Sigma Aldrich(目录号:P6148-500G)。
8.TMB底物.BD Biosciences(目录号:555214)。
9.生物素标记的h半乳凝素-3–将通过蛋白质组学小组内部合成的生物素标记的hGal-3的0.82mg/mL贮备液(28.6kDa,28.6713uM)用于滴定。
10.TD-139(EXT-001109-01-001):内部合成的小分子,在h半乳凝素-3中和结合分析中用作内标用于小分子筛选。
A.方案
a.板的包涂:在1x PBS中制备15nM浓度的ASF,根据板地图铺在96孔平底nunc板(Nunc immuno plate,Maxisorp,目录号:439454)中,用顶密封盖密封板后于4℃孵育过夜。
b.板的固定和封闭:在分析当天,倒出包涂溶液,通过加入100μL 2%低聚甲醛溶液并于37℃孵育30分钟使板固定,用300μL洗涤缓冲液(含0.05%吐温-20的PBS)洗涤3次,自旋干燥,用于封闭。
稍后将板用10%FBS封闭,于室温孵育1小时。稍后将板用300μL洗涤缓冲液(含0.05%吐温-20的PBS)洗涤3次。
B.孵育:将来自上述洗涤的板自旋干燥后,根据板地图在板上加入在板地图中指明的各种浓度的100μL测试化合物(与15nM浓度的h半乳凝素-3或m半乳凝素-3于室温-RT预孵育1小时)。板一式两份进行,用于数据重复和可重现性。
将这些板于RT孵育1小时,用洗涤缓冲液洗涤5次,自旋干燥,加入100μL链霉抗生物素HRP(1:1000稀释),于室温孵育1小时,用洗涤缓冲液洗涤7次。
C.检测:将来自前述洗涤的板自旋干燥后,向各孔加入100μL TMB底物,于室温孵育15分钟。稍后用2N硫酸终止反应,将板在spectramax中于450nm读数。
结果:在用平均对照标准化后,将所得读数(OD)相对于对照孔作图,分析程序化合物的Log半数抑制浓度(Log IC50)值。
总结:在报告中给出了程序化合物的IC50值(以来自Curve master compilation的Excel模式附上)。板对照TD-139对于人和鼠半乳凝素-3分别具有10.3nM和108.12nM的IC50值。同样在半-log图中进行了描绘。
药物组合物和使用方法
本发明的化合物抑制Gal-3。因此,本发明的另一方面是包含治疗有效量的本发明的化合物或其可药用盐和可药用载体的药物组合物。
本发明的另一方面是用本发明的化合物治疗罹患选自如下的疾病或病症的患者的方法:器官(包括肝脏、肾脏、肺、心脏和皮肤)纤维化、肝脏疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流疾病)、细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞白细胞(CLL))和癌细胞侵袭性转移)、炎性疾病和病症(包括银屑病、肾病和肺炎)、胃肠道疾病和病症(包括肠易激惹综合征(IBS)、炎性肠病(IBD)和胰腺分泌异常)、肾脏疾病和病症、泌尿道相关性疾病和病症(包括良性前列腺增生症或与神经性膀胱疾病、脊髓肿瘤、椎间盘突出、脊椎管狭窄相关的症状和衍生自糖尿病的症状)、下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和尿频)、胰腺疾病和病症、异常血管发生相关性疾病和病症(包括动脉阻塞)、硬皮病、脑相关疾病和病症(包括脑梗死和脑出血)、神经性疼痛和周围神经病、眼部疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增殖性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过术瘢痕)。
本发明的另一方面是用于治疗肾纤维化、肺纤维化、肝纤维化、动脉纤维化和系统性硬化病的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗器官(包括肝脏、肾脏、肺、心脏和皮肤)纤维化的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗肝脏疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流疾病)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞白细胞(CLL))和癌细胞侵袭性转移)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗炎性疾病和病症(包括银屑病、肾病和肺炎)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗胃肠道疾病和病症(包括肠易激惹综合征(IBS)、炎性肠病(IBD)和胰腺分泌异常)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗肾脏疾病和病症的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗泌尿道相关性疾病和病症(包括良性前列腺增生症或与神经性膀胱疾病、脊髓肿瘤、椎间盘突出、脊椎管狭窄相关的症状和衍生自糖尿病的症状)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和尿频)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗胰腺疾病和病症的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗异常血管发生相关性疾病和病症(包括动脉阻塞)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗脑相关疾病和病症(包括脑梗死和脑出血)的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗神经性疼痛和周围神经病的方法,该方法包括给患者施用本发明的化合物。
本发明的另一方面是用于治疗眼部疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增殖性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过术瘢痕)的方法,该方法包括给患者施用本发明的化合物。
本发明的化合物可用于治疗和/或预防Gal-3在其中起作用的病症。
本发明的化合物可用于制备药剂,所述药剂用于治疗和/或预防其中抑制Gal-3的生理活性是有用的病症,例如其中Gal-3受体参与、牵涉在疾病的病因学或病理学中或者与疾病的至少一种症状相关的疾病。
本发明的化合物可以单独使用,与其它本发明的化合物组合使用,或者与一种或多种、优选一种至两种其它活性剂组合使用。
“治疗有效”指提供有意义的患者益处所需的活性剂的量,如病患领域的实践人员所理解的那样。
“患者”指遭受痛苦和适于疗法的人,如本领域实践人员所理解的那样。
“治疗”、“疗法”、“方案”和相关术语如本领域实践人员所理解的那样进行使用。
本发明的化合物通常作为包含治疗有效量的本发明的化合物或其可药用盐和可药用载体的药物组合物给出,其可以含有常规的赋形剂。治疗有效量是提供有意义的患者益处所需的量。可药用载体是常规已知的具有可接受的安全性的那些。组合物涵盖所有常规的固体和液体形式,包括胶囊、片剂、锭剂(losenges)和粉末以及液体混悬剂、糖浆剂、酏剂(elixers)和溶液剂。组合物采用常规配制技术制备,通常使用用于组合物的常规赋形剂(例如粘合剂和湿润剂)和载体(例如水和醇)。参见例如Remington’s PharmaceuticalSciences,第17版,Mack出版公司,伊斯顿,PA(1985)。
固体组合物通常以剂量单位配制,优选每个剂量提供约1至1000mg活性成分的组合物。剂量的一些实例有1mg、10mg、100mg、250mg、500mg和1000mg。通常,其它抗逆转录病毒药物将存在于与临床使用的该类药物相似的单位范围内。通常,这是0.25-1000mg/单位。
液体组合物经常是剂量单位范围。通常,液体组合物的单位剂量范围为1-100mg/mL。剂量的一些实例有1mg/mL、10mg/mL、25mg/mL、50mg/mL和100mg/mL。
本发明涵盖所有常规施用方式;优选口服和胃肠外方法。通常,给药方案与临床使用的其它药物相似。通常,每日剂量为每天1-100mg/kg体重。通常,更多的化合物是需要口服,较少是胃肠外。然而,具体的给药方案将由医生根据合理的医学判断来确定。
化学方法
对本领域技术人员来说显而易见的是,本公开不限于上述说明性实(施)例,并且可以以其它具体形式体现而不背离其基本属性。因此,实(施)例应在所有方面考虑为说明性和非限制性的,对所附权利要求、而不是前述实(施)例进行参考,因此所有在权利要求的含义和范围内的变化旨在被包含在内。
A部分
LCMS分析在偶联有Waters TUV和SQ质量检测器的Waters Acquity UPLC系统上进行(柱:BEH C18 2.1x50mm;流动相A:含0.05%TFA的水;流动相B:含0.05%TFA的乙腈;梯度:2-98%B,历经1.6分钟;流速:0.8mL/min);HPLC分析在偶联有SPD-10AV UV检测器的Shimadzu LC10-AT HPLC系统上进行(柱YMC S5 Combiscreen ODS 4.6x50mm;流动相A:5:95乙腈:水,含0.1%TFA;流动相B:95:5乙腈:水,含0.1%TFA;梯度:历经40分钟0-100%B,然后1分钟保持在100%B;流速:1mL/min);制备型HPLC纯化在偶联有SPD 20UV检测器的Shimadzu LC-8制备型HPLC系统上进行。详细条件在实验操作中记载。
制备方法
对各个实施例和中间体报道的分析型LC-MS/HPLC保留时间使用以下通用分析型LC-MS/HPLC条件之一:
LCMS条件:
方法A:柱:Ascentis Express C18(50x2.1mm),2.7μm;流动相A:5:95乙腈:水,含10mM NH4OAc;流动相B:95:5乙腈:水,含10mM NH4OAc;温度:50℃;梯度:历经3分钟0-100%B。
方法B:柱:Ascentis Express C18(50x2.1mm),2.7μm;流动相A:5:95乙腈:水,含0.1%TFA;流动相B:95:5乙腈:水,含0.1%TFA;温度:50℃;梯度:历经3分钟0-100%B;流速:1.1ml/min。
方法C:柱-KINETEX-XB-C18(75X3mm-2.6μm);流动相A:10mM NH4COOH的水溶液:ACN(98:02);流动相B:10mM NH4COOH的水溶液:ACN(02:98);梯度=历经4分钟20-100%B;流速:1.1mL/min;检测:UV 254nm。
方法D:柱:Waters Acquity UPLC BEH C18(2.1x50mm),1.7μ;流动相A:0.1%TFA的水溶液;流动相B:0.1%TFA的ACN溶液;梯度=历经1.1分钟20-90%B,然后0.6分钟保持在90%B;温度:50℃;流速:0.7mL/min;检测:UV 220nm。
方法E:柱:Waters Acquity UPLC BEH C18(2.1x50mm)1.7μ,流动相A:5mMNH4OAc,乙腈(95:5);流动相B:5mM NH4OAc:ACN(5:95),梯度=历经1.1分钟20-90%B,然后0.6分钟保持在90%B;温度:50℃;流速:0.7mL/min;检测:UV 220nm。
方法F:柱-ZORBAX SB-C18(50X4.6mm-5.0μm);流动相A:10mM NH4COOH的水溶液:ACN(98:02);流动相B:10mM NH4COOH的水溶液:ACN(02:98);梯度=历经4分钟30-100%B;流速:1.5mL/min;检测:UV 254nm。制备型HPLC条件:
方法A:柱:Waters XBridge C18,19x150mm,5-μm粒子;流动相A:10-mM NH4OAc;流动相B:乙腈;梯度:历经20分钟15-50%B,然后5分钟保持在100%B;流速:15mL/min。
方法B:柱:Inertsil ODS(250*19)mm-5μm粒子;流动相A:10-mM NH4OAc-pH 4.5;流动相B:ACN;梯度:历经27分钟30-50%B,然后5分钟保持在100%B;流速:17mL/min。
方法C:柱Symmetry C8(300mm x 19mm)-7μm粒子;流动相A:10-mM NH4OAc-pH4.5;流动相B:ACN;梯度:历经24分钟50-70%B,然后5分钟保持在100%B;流速:17mL/min。
方法D:柱:Inertsil ODS(250*19)mm-5μm粒子;流动相A:10-mM NH4OAc-pH 4.5;流动相B:ACN;梯度:历经20分钟25-60%B,然后5分钟保持在100%B;流速:30mL/min。
方法E:柱:Lux-cellulose C4(250X21.2)mm,5μm粒子;流动相A:0.1%DEA的MeOH溶液;梯度:历经20分钟100%A,然后5分钟保持在100%B;流速:19mL/min。
方法F:柱:Lux-cellulose C2(250X21.2)mm,5μm粒子;流动相A:10mM甲酸铵;流动相B:ACN:MeOH(1:1);梯度:历经20分钟80%B,然后5分钟保持在100%B;流速:19mL/min。
羧酸中间体的合成:
步骤1:合成(2R,3R,4S,5R,6R)-3,4,5-三羟基-6-(羟基甲基)四氢-2H-吡喃-2-甲酸甲基酯:由β-D-半乳糖五乙酸酯按照文献方法合成(参考:Synthesis,2007,6,845-852和其中引用的文献)。
步骤2:合成(2S,4aR,6R,7R,8R,8aR)-7,8-二羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:于室温在Ar氛围下将对甲苯磺酸一水合物(1.199g,6.30mmol)加至(2R,3R,4S,5R,6R)-3,4,5-三羟基-6-(羟基甲基)四氢-2H-吡喃-2-甲酸甲基酯(29g,90mmol)和苯甲醛二甲基缩醛(33.8mL,225mmol)在乙腈(563mL)中的搅拌混悬液中。混合物用Ar脱气三次,超声2分钟。然后,将反应混合物于室温搅拌4小时,用TEA(5.77mL,41.4mmol)淬灭,搅拌10分钟。混合物过滤,滤液在减压下浓缩,得到粗产物,将其经硅胶色谱法纯化(EtOAc在正己烷中的50-100%溶液),得到标题化合物(16.3g,52.5mmol,58%),为白色固体。1H NMR(400MHz,氯仿-d):δ7.53-7.49(m,2H),7.40-7.36(m,3H),5.57(s,1H),4.39(dd,J=12.5,1.5Hz,1H),4.28(dd,J=4.0,1.0Hz,1H),4.15-4.05(m,2H),3.87-3.84(m,4H),3.73(td,J=9.0,4.0Hz,1H),3.56(q,J=1.5Hz,1H),3.24(d,J=2.5Hz,1H),2.63(d,J=8.5Hz,1H)。
步骤3:合成(2S,4aR,6R,7S,8S,8aS)-7-乙酰氧基-2-苯基-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:于-15℃向(2S,4aR,6R,7R,8R,8aR)-7,8-二羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(17.3g,55.8mmol)在DCM(180mL)中的溶液中加入吡啶(18.04mL,223mmol),混合物搅拌10分钟。在氩气下历经15分钟滴加三氟甲磺酸酐(8.48mL,50.2mmol),混合物于-15℃搅拌1小时。使反应混合物历经2小时达到室温。于0℃加入乙酰氯(4.76mL,66.9mmol),混合物温热至室温,搅拌10小时。加入DCM(300mL),溶液用0.7N HCl(150mL)、饱和碳酸氢钠(2x100mL)和盐水溶液洗涤。分离有机层,经硫酸钠干燥.。在减压下除去溶剂,经硅胶色谱法纯化(EtOAc在正己烷中的30-80%溶液),得到标题化合物(14g,28.9mmol,52%),为白色固体。1H NMR(400MHz,氯仿-d):δ7.53(dd,J=7.4,2.1Hz,2H),7.44-7.36(m,3H),5.64(d,J=9.9Hz,1H),5.60(s,1H),5.00(dd,J=9.9,3.6Hz,1H),4.53(d,J=3.6Hz,1H),4.42(dd,J=12.8,1.5Hz,1H),4.08(dd,J=12.8,1.5Hz,1H),4.03(d,J=9.9Hz,1H),3.77(s,3H),3.59(d,J=1.0Hz,1H),2.10(s,3H)。
步骤4:合成(2S,4aR,6R,7R,8R,8aR)-7-乙酰氧基-8-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(2S,4aR,6R,7S,8S,8aS)-7-乙酰氧基-2-苯基-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(32g,66.1mmol)在DMF(320mL)中的溶液中加入四丁基硝酸铵(50.3g,165mmol),用氩气脱气两次,混合物于50℃加热6小时。然后,将反应混合物用EtOAc(500mL)稀释,用水洗涤(4x200mL),经硫酸钠干燥,在减压下浓缩。残余物经硅胶色谱法纯化(EtOAc在正己烷中的60-100%溶液),得到标题化合物(15g,42.6mmol,64%),为黄色固体。1H NMR(400MHz,氯仿-d):δ7.55-7.51(m,2H),7.42-7.36(m,3H),5.55(s,1H),5.39(dd,J=10.3,2.8Hz,1H),4.45(d,J=10.3Hz,1H),4.37(dd,J=12.8,1.5Hz,1H),4.23(t,J=3.1Hz,1H),4.16-4.13(m,1H),4.05(dd,J=12.8,2.0Hz,1H),3.79(d,J=1.5Hz,1H),3.75(s,3H),2.10(s,3H)。
步骤5:合成(2S,4aR,6R,7S,8R,8aS)-7-乙酰氧基-2-苯基-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(2S,4aR,6R,7R,8R,8aR)-7-乙酰氧基-8-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(2.3g,6.53mmol)在DCM(20mL)中的溶液中加入吡啶(2.112mL,26.1mmol),混合物冷却至-15℃,然后在氩气下滴加三氟甲磺酸酐(1.654mL,9.79mmol),于-15℃搅拌1小时。使反应混合物温热至室温,搅拌2小时。然后,反应混合物用DCM(200mL)稀释,用0.7N HCl水溶液(50mL)、NaHCO3水溶液(2x50mL)、盐水溶液洗涤,经硫酸钠干燥。在减压下除去溶剂,残余物经硅胶色谱法纯化(EtOAc在正己烷中的30-80%溶液),得到标题化合物(1.2g,2.477mmol,38%),为固体。1H NMR(400MHz,氯仿-d):δ7.54-7.49(m,2H),7.43-7.38(m,3H),5.60(s,1H),5.54(dd,J=10.5,3.0Hz,1H),5.28(t,J=3.3Hz,1H),4.43-4.37(m,2H),4.30(dd,J=3.5,1.0Hz,1H),4.11(dd,J=12.8,1.5Hz,1H),3.80(s,3H),3.78(d,J=1.5Hz,1H),2.10(s,3H)。
步骤6:合成(2S,4aR,6R,7R,8S,8aR)-7-乙酰氧基-8-叠氮基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(2S,4aR,6R,7S,8R,8aS)-7-乙酰氧基-2-苯基-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(1.8g,41.3mmol)在DMF(18mL)中的溶液中一次性加入四丁基叠氮化铵(3.17g,11.15mmol)。混合物用Ar脱气,于50℃加热5小时。反应混合物用EtOAc(200mL)稀释,用水洗涤(3x100mL),经硫酸钠干燥和浓缩。残余物经硅胶色谱法纯化(EtOAc在正己烷中的50-90%溶液),得到标题化合物(1.2g,3.18mmol,86%),为灰白色固体。LC-MS,[M+18]+=395.2,{方法C:tR=2.37min}。1H NMR(300MHz,氯仿-d):δ7.53(dd,J=7.2,2.3Hz,2H),7.42-7.33(m,3H),5.60(s,1H),5.58-5.51(m,1H),4.40-4.33(m,2H),4.06(dd,J=12.7,1.7Hz,1H),3.99(d,J=9.8Hz,1H),3.76(s,3H),3.50(s,1H),3.41(dd,J=10.4,3.2Hz,1H),2.11(s,3H)。
步骤7:合成(4aR,6R,7R,8S,8aR)-7-乙酰氧基-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(4aR,6R,7R,8S,8aR)-7-乙酰氧基-8-叠氮基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(1.2g,3.18mmol)在DMF(50mL)和水(10.00mL)中的溶液中依次加入1-乙炔基-3-氟苯(1.146g,9.54mmol)、抗坏血酸钠(0.693g,3.50mmol)和硫酸铜(II)五水合物(0.715g,2.86mmol)。反应混合物用氮气脱气10分钟,加热至80℃达1小时。反应混合物冷却至室温,用水(60mL)和DCM(50mL)稀释,搅拌1小时。反应混合物经硅藻土垫过滤,用DCM(100mL)洗涤,滤液用于进一步后处理。分离出有机层,水层用DCM(2x100mL)反萃取,将合并的有机层用水(400mL)、盐水(100mL)洗涤,有机层经硫酸钠干燥,在减压下浓缩。向粗残余物中加入二乙醚,经布氏漏斗过滤出固体,干燥1小时,得到标题化合物(1.1g,2.211mmol,69.5%产率),为白色固体。LC-MS,[M+H]+=498.2,{方法C:tR=2.71min}。1H NMR(400MHz,CDCl3):δppm 8.07(s,1H),7.54-7.50(m,2H),7.48-7.35(m,6H),7.05-6.99(m,1H),5.90(dd,J=11.1,9.6Hz,1H),5.52(s,1H),5.21(dd,J=11.1,3.4Hz,1H),4.51-4.47(m,2H),4.23(d,J=9.5Hz,1H),4.12(dd,J=12.8,1.8Hz,1H),3.81(s,3H),3.80-3.78(m,1H),1.87(s,3H)。
步骤-8:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸:向(4aR,6R,7R,8S,8aR)-7-乙酰氧基-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(2g,4.02mmol)在四氢呋喃(20mL)和水(10mL)中的搅拌溶液中加入氢氧化锂(0.48g,20.10mmol),混合物于室温搅拌2小时。用LCMS确认反应完全后,在减压下除去四氢呋喃。残余物用水(100mL)稀释,用1.5N HCl溶液调节pH至约2-3。将沉淀的固体过滤,用水洗涤,在减压下干燥,得到标题化合物(1.8g,定量)。LC-MS,[M+H]+=442.2,{方法C:tR=3.31min}。1H NMR(400MHz,MEOH-d4)δppm 8.46(s,1H),7.56(dt,J=10.2,2.2Hz,2H),7.49-7.40(m,3H),7.37-7.30(m,3H),7.09(td,J=8.4,2.3Hz,1H),5.56(s,1H),5.12(dd,J=10.5,3.5Hz,1H),4.62(t,J=10.0Hz,1H),4.54(d,J=3.5Hz,1H),4.37(d,J=12.5Hz,1H),4.18(dd,J=12.5,1.5Hz,1H),4.06(d,J=9.5Hz,1H),3.89(s,1H)。
C2-甲氧基羧酸中间体的合成:
步骤-1:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(1.55g,3.51mmol)在DMF(10mL)中的搅拌溶液中加入K2CO3(4.85g,35.1mmol),然后加入MeI(1.976mL,31.6mmol),于室温搅拌16小时。通过LCMS确认反应完全后,将反应物质在冰水(100mL)中淬灭,搅拌10分钟。过滤固体,用水洗涤,在减压下干燥,得到标题化合物,为灰白色固体(1.45g,91%).LC-MS,[M+H]+=456.2,{方法F:tR=1.95min}。1H NMR(400MHz,MEOH-d4)δppm 8.41(s,1H),7.58(d,J=8.0Hz,1H),7.55-7.50(m,1H),7.47-7.40(m,3H),7.37-7.32(m,3H),7.07(td,J=8.3,2.5Hz,1H),5.56(s,1H),5.11(dd,J=11.0,3.5Hz,1H),4.68-4.61(m,1H),4.53(d,J=2.5Hz,1H),4.32-4.26(m,1H),4.20-4.13(m,2H),3.89(s,1H),3.82(s,3H)。
步骤-2:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(1.45g,3.18mmol)在DMF(20mL)中的搅拌溶液中加入4A MS(1g),于室温搅拌10分钟。然后,依次加入氧化银(3.69g,15.92mmol)和MeI(0.1mL,15.92mmol),于室温搅拌16小时。经硅藻土垫过滤反应物质,用过量DCM(20mL)洗涤,滤液在减压下浓缩,得到(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯,为灰白色固体(1.3g,87%),将其未经进一步纯化原样用于下一步骤。LC-MS,[M+H]+=470.2,{方法F:tR=2.15min}。1HNMR(400MHz,MEOH-d4)δppm 8.59(s,1H),7.62-7.58(m,1H),7.55(dt,J=10.0,2.0Hz,1H),7.50-7.42(m,3H),7.40-7.35(m,3H),7.08(td,J=8.4,2.3Hz,1H),5.58(s,1H),5.19(dd,J=10.5,3.5Hz,1H),4.50(d,J=2.5Hz,1H),4.47-4.43(m,1H),4.29(dd,J=12.8,1.8Hz,1H),4.19-4.13(m,2H),3.87(s,1H),3.84(s,3H),3.12(s,3H)。
步骤-3:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸:向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(1.3g,2.8mmol)在四氢呋喃(50mL)和水(50mL)中的搅拌溶液中加入氢氧化锂(0.33g,13.85mmol),于室温搅拌1小时。用LCMS确认反应完全后,在减压下除去溶剂。然后,残余物用水(100mL)稀释,用1.5N HCl水溶液调节pH至约2-3。将沉淀的固体过滤,用水洗涤,在减压下干燥,得到标题化合物,为灰白色固体(1.1g,85%)。LC-MS,[M+H]+=456.2,{方法F:tR=0.64min}。1HNMR(400MHz,MEOH-d4)δppm 8.58(s,1H),7.61(d,J=6.5Hz,1H),7.55(dd,J=10.0,2.5Hz,1H),7.50-7.41(m,3H),7.36(d,J=3.5Hz,3H),7.11-7.04(m,1H),5.58(s,1H),5.16(dd,J=11.0,3.5Hz,1H),4.50(d,J=3.0Hz,1H),4.42-4.35(m,1H),4.34-4.29(m,1H),4.16(dd,J=12.8,1.8Hz,1H),4.06(d,J=9.0Hz,1H),3.84(s,1H),3.18(s,3H)。
C2-脱氧羧酸中间体(例如(4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸)的合成:
步骤-1:合成(4aR,6R,7R,8S,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-((甲基磺酰基)氧基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:于0℃向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(300mg,0.66mmol)在吡啶(4mL)中的搅拌溶液中加入甲磺酰氯(0.13mL,1.71mmol),反应混合物搅拌6小时。反应混合物用冰水淬灭,搅拌5分钟。所得固体过滤,用过量水洗涤,干燥,得到标题化合物,为灰白色固体(0.26g,72%)。LC-MS,[M+H]+=534.2,{方法C:tR=1.990min}。
步骤-2:合成(4aR,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基-4,4a,8,8a-四氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:于室温向(4aR,6R,7R,8S,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-((甲基磺酰基)氧基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(260mg,0.487mmol)在2,6-二甲基吡啶(25mL)中的溶液中加入氧化铝(碱式)(2.5g,24.37mmol),反应混合物于50℃加热16小时。在减压下除去溶剂,粗残余物经硅胶色谱法纯化(MeOH在DCM中的2-3%溶液),得到标题化合物(0.19g,83%),为浅黄色固体。LC-MS,[M+1]+=438.2,{方法C:tR=1.966min}。1H NMR(400MHz,氯仿-d)δppm 7.93(s,1H),7.50-7.56(m,2H),7.28-7.41(m,6H),7.00-7.05(m,1H),6.00-6.04(m,1H),5.96-5.99(m,1H),5.57(s,1H),4.64(dd,J=12.8,1.8Hz,1H),4.50-4.54(m,1H),4.29-4.34(m,1H),4.12-4.20(m,1H),3.85(s,3H)。
步骤-3:合成(4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯:向(4aR,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基-4,4a,8,8a四氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(0.22g,0.503mmol)在EtOAc(8mL)中的脱气溶液中加入披钯碳(10%w/w,50%湿)(54mg,0.05mmol),混合物于室温在氢气压力(~1atm)下搅拌12小时。反应混合物经硅藻土垫过滤,用过量EtOAc/MeOH(1:1,30mL)洗涤,滤液在减压下浓缩,得到标题化合物(0.2g,90%),为灰白色固体。LC/MS[M+H]+=440.2,{方法B:tR=1.25min}。1H NMR(400MHz,氯仿-d)δppm7.94(s,1H),7.48-7.56(m,2H),7.34-7.44(m,6H),6.96-7.11(m,1H),5.54(s,1H),5.13-5.26(m,1H),4.50(dd,J=12.5,1.5Hz,1H),4.27-4.42(m,2H),4.03-4.20(m,1H),3.82(s,3H),3.70(d,J=1.5Hz,1H),2.58-2.69(m,1H),2.34-2.42(m,1H)。
步骤-4:合成(4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸:于室温向(4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸甲基酯(0.2g,0.455mmol)在THF(8mL)、水(2.0mL)中的搅拌溶液中加入LiOH(0.044g,1.821mmol),继续搅拌2小时。用LCMS确认反应完全后,在减压下除去四氢呋喃。残余物用水(100mL)稀释,用1.5N HCl溶液调节pH至约2-3。将沉淀的固体过滤,用水洗涤,在减压下干燥,得到标题化合物(0.17g,88%),为灰白色固体。LC/MS[M+H]+=426.2,{方法A:tR=0.79min}。
实施例1a和1b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体1和异构体2)。
步骤-1:合成3-叠氮基环己烷-1-烯:于室温向3-溴环己烷-1-烯(7.1mL,62.1mmol)在CCl4(100mL)/水(100mL)混合物中的搅拌溶液中加入叠氮化钠(14.1g,217mmol),搅拌48小时。分离水层,用DCM(2X50mL)萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥和浓缩,得到3-叠氮基环己烷-1-烯(6.6g,86%),为浅黄色液体。1H NMR(400MHz,氯仿-d)δppm 5.94-6.07(m,1H),5.66-5.75(m,1H),3.83-3.92(m,1H),1.96-2.17(m,2H),1.84-1.94(m,1H),1.69-1.80(m,2H),1.57-1.68(m,1H)。
步骤-2:合成(1R,2R,6S)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(外消旋物):于0℃向3-叠氮基环己烷-1-烯(5.5g,44.7mmol)在二氯甲烷(200mL)中的溶液中加入mCPBA(15.4g,67.0mmol)(溶于20mL DCM)。使反应混合物达到室温,搅拌16小时。反应混合物冷却至0℃,将沉淀的固体过滤,用DCM(50mL)洗涤。滤液用饱和Na2SO3溶液、10%NaHCO3水溶液、盐水溶液洗涤,经硫酸钠干燥,浓缩,得到粗产物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的0-2%溶液),得到(1R,2R,6S)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(1.9g,30%,顺式异构体)和(1S,2R,6R)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(2.9g,46%,反式异构体)。
顺式异构体:1H NMR(400MHz,氯仿-d)δppm 3.50-3.66(m,1H),3.32(dd,J=4.0,2.0Hz,1H),3.25-3.28(m,1H),1.77-1.97(m,2H),1.58-1.74(m,3H),1.19-1.38(m,1H)。
反式异构体:1H NMR(400MHz,氯仿-d)δppm 3.83(t,J=6.8Hz,1H),3.19-3.28(m,1H),3.09(d,J=3.5Hz,1H),1.97-2.08(m,1H),1.76-1.93(m,2H),1.45-1.53(m,1H),1.28-1.40(m,2H)。
步骤-3:合成1-((1S,2R,6R)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(外消旋物):于室温向(1S,2R,6R)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(0.5g,3.59mmol)在DMF(5mL)和水(1.5mL)中的溶液中加入抗坏血酸钠(0.71g,3.59mmol)、硫酸铜(II)五水合物(0.81g,3.23mmol)和3-氟苯基乙炔(1.7mL,14.37mmol)。反应混合物于85℃加热30分钟。反应混合物冷却至室温,用1:1DCM(50mL)和水(50mL)稀释,于室温搅拌15分钟。反应混合物经硅藻土垫过滤,用DCM(20mL)洗涤。从滤液中分离出有机层,水层用DCM(2x20mL)反萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥,浓缩,得到粗残余物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的40-50%溶液),得到1-((1S,2R,6R)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(0.53g,57%),为浅黄色固体。LC/MS[M+H]+=260.2,tR=2.266min(方法C)。
步骤-4:合成(1R,2R,6S)-2-叠氮基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(外消旋物):于室温向1-((1R,2S,6S)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(200mg,0.771mmol)在MeOH(16mL)和水(4.00mL)中的溶液中加入氯化铵(103mg,1.928mmol)和叠氮化钠(251mg,3.86mmol)。反应混合物于75℃加热16小时。反应混合物冷却至室温,在减压下除去MeOH,用EtOAc(3X25mL)萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥、在减压下浓缩,得到粗残余物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的20-25%溶液),得到(1R,2R,6S)-2-叠氮基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(0.22g,98%),为灰白色固体。LC/MS[M+H]+=303.2,tR=1.699min(方法F)。
步骤-5:合成(1S,2R,6S)-2-氨基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(外消旋物):向(1R,2R,6S)-2-叠氮基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(210mg,0.695mmol)在MeOH(20mL)中的脱气溶液中加入披钯碳(10%w/w,50%湿)(74mg,0.069mmol),混合物于室温在氢气压力(~1atm)搅拌2小时。反应混合物经硅藻土垫过滤,用过量MeOH(10mL)洗涤,滤液在减压下浓缩,得到(1S,2R,6S)-2-氨基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(170mg,71%)。LC/MS[M+H]+=277.0,tR=1.255min(方法F)。
步骤-6:合成((2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺:于室温向(2S,4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)(50mg,0.110mmol)在DMF(2mL)中的溶液中加入DIPEA(0.06mL,0.329mmol)和HATU(62.6mg,0.165mmol),搅拌15分钟。然后加入(1S,2R,6S)-2-氨基-6-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(36.4mg,0.132mmol),于室温搅拌混合物1小时。反应混合物用冰冷的水(10mL)淬灭,搅拌15分钟。所得固体过滤,用过量水洗涤,残余物干燥,得到粗残余物的非对映体混合物。粗残余物进一步通过制备型-HPLC纯化[方法F],得到两种异构体:异构体1:20mg,21%产率;LC/MS[M+H]+=714.2,tR=2.897min(方法C).异构体2:15mg,19%产率;LC/MS[M+H]+=714.2,tR=2.878min(方法C)。
步骤-7:将((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(20mg,0.028mmol,异构体1)在70%乙酸水溶液(5mL)中的溶液于70℃搅拌过夜。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗产物通过制备型LCMS(方法A)纯化,得到实施例1a,为白色固体(4.5mg,25%产率).LC-MS,[M+H]+=626.2,[tR=1.688min,方法A]和&[tR=1.710min,方法B]。1H NMR(400MHz,MEOH-d4)δppm 8.59(s,1H),8.39(s,1H),7.66(dd,J=7.8,4.2Hz,2H),7.62-7.56(m,2H),7.49-7.41(m,2H),7.08(m,2H),4.91(dd,J=10.8,2.7Hz,1H),4.57-4.44(m,1H),4.28-4.21(m,1H),4.11(d,J=2.7Hz,1H),4.03-3.89(m,3H),3.82-3.77(m,2H),3.75-3.69(m,1H),3.19-3.12(m,3H),2.24-2.12(m,2H),2.05(d,J=11.7Hz,1H),1.95(d,J=13.2Hz,1H),1.68-1.54(m,2H)。hGal3 IC50(ELISA)=0.7μM;hGal3 IC50(HTRF)=0.29μM。
实施例1b:将((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(15mg,0.021mmol,异构体2)在70%乙酸水溶液(5mL)中的溶液于70℃搅拌过夜。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗产物通过制备型LCMS(方法A)纯化,得到实施例1b,为白色固体(1.1mg,8%产率).LC-MS,[M+H]+=626.2,[tR=1.690min,方法A]和&[tR=1.688min,方法B]。1H NMR(400MHz,MEOH-d4)δppm 8.63(s,1H),8.40(s,1H),7.72-7.57(m,4H),7.51-7.42(m,2H),7.13-7.05(m,2H),4.93(dd,J=10.8,2.7Hz,1H),4.58-4.45(m,1H),4.27(t,J=9.9Hz,1H),4.12(d,J=2.4Hz,1H),4.02-3.89(m,3H),3.85-3.79(m,2H),3.77-3.71(m,1H),3.20(s,3H),2.26-2.14(m,2H),2.12(br.s.,1H),1.98(d,J=11.5Hz,1H),1.71-1.59(m,2H)。hGal3 IC50(ELISA)=16μM。
以与实施例1a和1b类似的方式,在合成序列中用适当的乙炔替换1-氟-3-乙炔基苯,制备了表1中的实施例。
表1
实施例6a和6b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体1和异构体2)
步骤-1:合成1-((1R,2S,6S)-7-氧杂双环[4.1.0]庚烷-2-基)-5-(3-氟苯基)-1H-1,2,3-三唑(外消旋物):向(1R,2S,6S)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(100mg,0.719mmol)和3-氟苯基乙炔(0.34mL,2.87mmol)在甲苯(3mL)中的搅拌溶液中加入氯(1,5-环辛二烯)(五甲基环戊二烯)钌(8.19mg,0.022mmol)。反应混合物于85℃加热4小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的40-50%溶液),得到标题化合物(175mg,92%),为灰白色固体。LC/MS[M+H]+=260.2,tR=2.12min(方法C)。
步骤-2:合成(1R,2R,6S)-2-叠氮基-6-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(外消旋物):于室温向1-((1R,2S,6S)-7-氧杂双环[4.1.0]庚烷-2-基)-5-(3-氟苯基)-1H-1,2,3-三唑(170mg,0.656mmol)在MeOH(8mL)和水(2mL)中的溶液中加入氯化铵(88mg,1.639mmol)和叠氮化钠(213mg,3.28mmol)。反应混合物于75℃加热16小时。反应混合物冷却至室温,在减压下除去MeOH,用EtOAc(3X25mL)萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥,在减压下浓缩,得到粗残余物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的20-25%溶液),得到标题化合物(0.15g,72%),为棕色固体。LC/MS[M+H]+=303.5,tR=1.10min(方法E)。
步骤-3:合成(1S,2R,6S)-2-氨基-6-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(外消旋物):向(1R,2R,6S)-2-叠氮基-6-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(150mg,0.496mmol)在MeOH(10mL)中的脱气溶液中加入披钯碳(10%w/w,50%湿)(53mg,0.050mmol),反应混合物于室温在氢气压力(~1atm)搅拌2小时。反应混合物经硅藻土垫过滤,用过量MeOH(10mL)洗涤,滤液在减压下浓缩,得到标题化合物(68mg,40%)。LC/MS[M+H]+=277.2,tR=1.18min(方法F)。
步骤-4:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:于室温向((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)在DMF(2mL)中的溶液中加入DIPEA(0.06mL,0.329mmol)和HATU(62.6mg,0.165mmol),搅拌15分钟。然后,加入(1S,2R,6S)-2-氨基-6-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)环己醇(36.4mg,0.132mmol),混合物于室温搅拌1小时。反应混合物用冰冷的水(10mL)淬灭,搅拌15分钟。所得固体过滤,用过量水洗涤,残余物干燥,得到粗残余物的非对映体混合物。粗残余物进一步通过制备型HPLC纯化[方法E],得到异构体1和异构体2。
异构体1:10mg,13%产率;LC/MS[M+H]+=714.2,tR=2.461min(方法F)。
异构体2:15mg,17%产率;LC/MS[M+H]+=714.2,tR=2.457min(方法F)。
步骤-5:将((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体1)(10mg,0.014mmol)混悬于70%乙酸水溶液(3mL,52.4mmol)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到实施例6a(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体1(2.9mg,33%)。LC/MS[M+H]+=626.1,tR=1.667min(方法A);1H NMR(400MHz,MEOH-d4)δppm8.63(s,1H),7.80(s,1H),7.70(d,J=7.8Hz,1H),7.66-7.54(m,2H),7.51-7.38(m,3H),7.29(td,J=8.6,2.4Hz,1H),7.10(td,J=8.6,2.4Hz,1H),4.93(dd,J=10.6,2.8Hz,1H),4.38-4.30(m,1H),4.29-4.16(m,2H),4.12(d,J=2.7Hz,1H),3.94(d,J=9.3Hz,1H),3.92-3.79(m,3H),3.77-3.69(m,1H),3.19(s,3H),2.28-2.16(m,1H),2.06(d,J=10.8Hz,2H),1.89(d,J=13.4Hz,1H),1.67-1.44(m,2H)。hGal3IC50=27μM。
实施例6b:将(2S,4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体2)(15mg,0.021mmol)混悬于70%乙酸水溶液(5mL,87mmol)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(5-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体2(5.5mg,42%)。LC/MS[M+H]+=626.1,tR=1.683min(方法A);1H NMR(400MHz,MEOH-d4)δppm8.61(s,1H),7.81(s,1H),7.68(d,J=8.1Hz,1H),7.65-7.55(m,2H),7.51-7.40(m,3H),7.32-7.26(m,1H),7.14-7.07(m,1H),4.92(dd,J=10.9,3.1Hz,1H),4.39-4.31(m,1H),4.29-4.16(m,2H),4.12(d,J=2.7Hz,1H),3.94(d,J=9.3Hz,1H),3.90(br.s.,1H),3.85-3.79(m,2H),3.77-3.72(m,1H),3.17(s,3H),2.28-2.16(m,1H),2.11-1.98(m,2H),1.88(d,J=13.7Hz,1H),1.63-1.47(m,2H).hGal3 IC50=0.90μM。
步骤-1:合成(1R,2R,6S)-2-叠氮基-6-(4-氟-1H-吲唑-1-基)环己醇和(1R,2R,6S)-2-叠氮基-6-(4-氟-2H-吲唑-2-基)环己醇(外消旋物):于室温向(1S,2R,6R)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(300mg,2.156mmol)和4-氟-1H-吲唑(308mg,2.264mmol)在DMSO(3mL)中的溶液中加入DBU(0.975mL,6.47mmol)。反应混合物于100℃加热16小时。反应混合物冷却至室温,用EtOAc(3x30mL)萃取,用水、盐水洗涤,经硫酸钠干燥,在减压下浓缩,得到粗产物。粗残余物通过制备型HPLC纯化(方法B),得到N1-区域异构体(1R,2R,6S)-2-叠氮基-6-(4-氟-1H-吲唑-1-基)环己醇(120mg,20%)和N2-区域异构体(1R,2R,6S)-2-叠氮基-6-(4-氟-2H-吲唑-2-基)环己醇(150mg,20%)。
N1-区域异构体:1H NMR(400MHz,氯仿-d)δppm 8.12(d,J=0.8Hz,1H),7.16-7.39(m,2H),6.76-6.83(m,1H),4.29-4.38(m,1H),4.15-4.23(m,1H),3.48-3.57(m,1H),2.39(d,J=3.5Hz,1H),2.13-2.20(m,1H),2.04-2.11(m,1H),1.94-2.00(m,1H),1.43-1.68(m,3H)。LC/MS[M+H]+=276.2,tR=1.98min(方法F)。
N2-区域异构体:1H NMR(400MHz,氯仿-d)δppm 8.06(d,J=0.8Hz,1H),7.43(s,1H),7.11-7.25(m,1H),6.66-6.73(m,1H),4.19-4.36(m,1H),4.06(t,J=9.6Hz,1H),3.46-3.57(m,1H),2.20-2.26(m,1H),2.09-2.17(m,2H),1.96-2.02(m,1H),1.50-1.59(m,2H)。LC/MS[M+H]+=276.2,tR=2.12min(方法C)。
步骤-2:合成(1S,2R,6S)-2-氨基-6-(4-氟-1H-吲唑-1-基)环己醇(外消旋物):向(1R,2R,6S)-2-叠氮基-6-(4-氟-1H-吲唑-1-基)环己醇(100mg,0.363mmol)在MeOH(5mL)中的脱气溶液中加入披钯碳(10%w/w)(39mg,0.036mmol),于室温在氢气压力(~1atm)下搅拌反应混合物2小时。反应混合物经硅藻土垫过滤,用过量MeOH(10mL)洗涤,滤液在减压下浓缩,得到(1S,2R,6S)-2-氨基-6-(4-氟-1H-吲唑-1-基)环己醇(65mg,62%)。LC/MS[M+H]+=250.0,tR=1.26min(方法F)。
步骤-3:合成(4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)在DMF(5mL)中的溶液中加入DIPEA(0.19mL,1.098mmol)和HATU(83mg,0.220mmol),搅拌15分钟。然后加入(1S,2R,6S)-2-氨基-6-(4-氟-1H-吲唑-1-基)环己醇(外消旋物)(28mg,0.110mmol),混合物于室温搅拌1小时。反应混合物用冰冷的水(10mL)淬灭,搅拌15分钟。所得固体过滤,用过量水洗涤,残余物干燥,得到粗残余物的非对映体混合物。粗残余物通过制备型HPLC纯化[方法E],得到异构体1和异构体2。
异构体1:21mg,27%产率;LC/MS[M+H]+=687.2,tR=2.54min(方法F)。
异构体2:20mg,26%产率;LC/MS[M+H]+=6872,tR=2.55min(方法F)。
步骤-4:合成(2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体1和2):将(4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体-1)(20mg,0.029mmol)混悬于70%乙酸水溶液(5mL)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到实施例7a,(2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体1(7.8mg,45%)。LC/MS[M+H]+=599.1,tR=1.77min(方法A);1H NMR(400MHz,MEOH-d4)δ=8.60(s,1H),8.14(s,1H),7.68(d,J=8.1Hz,1H),7.62(d,J=10.3Hz,1H),7.49-7.43(m,2H),7.39-7.34(m,1H),7.12-7.07(m,1H),6.83-6.81(m,1H),4.93(dd,J=10.9,2.8Hz,1H),4.57(br.s,1H),4.27-4.12(m,1H),4.13-4.05(m,3H),4.03(d,J=9.3Hz,1H),3.93-3.73(m,3H),3.16(s,3H),2.16-1.92(m,4H),1.71-1.52(m,2H)。hGal3 IC50=0.64μM。
实施例7b:以与实施例7a,异构体1所述类似的方式,采用(4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体2)(20mg,0.029mmol)制得。粗残余物通过制备型HPLC纯化[方法A],得到(2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-氟-1H-吲唑-1-基)-2-羟基环己基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体2(8.1mg,46%)。LC/MS[M+H]+=599.1,tR=1.747min(方法A);1H NMR(400MHz,MEOH-d4)δppm 8.63(s,1H),8.13(s,1H),7.70(d,J=7.8Hz,1H),7.64(d,J=10.3Hz,1H),7.50-7.43(m,2H),7.38-7.33(m,1H),7.12-7.07(m,1H),6.82-6.80(m,1H),4.93(dd,J=10.6,2.8Hz,1H),4.60-4.47(m,1H),4.28(t,J=10.0Hz,1H),4.15-3.98(m,3H),3.94(d,J=9.3Hz,1H),3.87-3.76(m,2H),3.76-3.67(m,1H),3.18(s,3H),2.22-1.89(m,4H),1.77-1.56(m,2H).hGal3 IC50=23μM。
实施例8:合成(2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-氟-2H-吲唑-2-基)-2-羟基环己基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺
步骤1:合成(1S,2R,6S)-2-氨基-6-(4-氟-2H-吲唑-2-基)环己醇(外消旋物):向(1R,2R,6S)-2-叠氮基-6-(4-氟-2H-吲唑-2-基)环己醇(150mg,0.545mmol))在MeOH(10mL)中的脱气溶液中加入披钯碳(10%w/w)(58mg,0.054mmol),反应混合物于室温在氢气压力(~1atm)下搅拌2小时。反应混合物经硅藻土垫过滤,用过量MeOH(10mL)洗涤,滤液在减压下浓缩,得到标题化合物(80mg,45%),为灰白色固体。LC/MS[M+H]+=250.2,tR=0.74min(方法C)。
步骤-2:合成(4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-氟-2H-吲唑-2-基)-2-羟基环己基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)在DMF(5mL)中的溶液中加入DIPEA(0.19mL,1.098mmol)和HATU(83mg,0.220mmol),搅拌15分钟。然后于室温加入(1S,2R,6S)-2-氨基-6-(4-氟-2H-吲唑-2-基)环己醇(外消旋物)(27.4mg,0.110mmol),搅拌1小时。反应混合物用冰冷的水(10mL)淬灭,搅拌15分钟。所得固体过滤,用过量水洗涤,残余物干燥,得到粗残余物的非对映体混合物。粗残余物进一步通过制备型HPLC纯化[方法E],得到异构体1和异构体2。
异构体1:10mg,13%产率;LC/MS[M+H]+=687.0,tR=2.318min(方法F)。
异构体2:12mg,15%产率;LC/MS[M+H]+=687.2,tR=2.328min(方法F)。
步骤-3:将(4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-氟-2H-吲唑-2-基)-2-羟基环己基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体1)(10mg,0.015mmol)混悬于70%乙酸水溶液(5mL)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到实施例8(2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-氟-2H-吲唑-2-基)-2-羟基环己基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(1.6mg,18%)。LC/MS[M+H]+=599.1,tR=1.685min(方法A);1H NMR(400MHz,MEOH-d4)δ=8.60(s,1H),8.37(s,1H),7.67(d,J=7.6Hz,1H),7.61(d,J=10.0Hz,1H),7.50-7.41(m,2H),7.29-7.21(m,1H),7.09(t,J=8.4Hz,1H),6.72(dd,J=10.5,7.6Hz,1H),4.92(dd,J=10.8,2.4Hz,1H),4.46(br.s.,1H),4.25(t,J=9.9Hz,1H),4.12(d,J=2.2Hz,1H),4.07-3.91(m,3H),3.86-3.67(m,3H),3.17(s,3H),2.31-2.13(m,2H),2.10-1.90(m,2H),1.72-1.55(m,2H)。hGal3 IC50=0.57μM。
实施例9a和9b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体1和2
步骤-1:合成(1R,2R,6S)-2-叠氮基-6-(3-溴-1H-1,2,4-三唑-1-基)环己醇(外消旋物):向(1S,2R,6R)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(200mg,1.437mmol)和3-溴-1H-1,2,4-三唑(213mg,1.437mmol)在DMSO(2mL)中的溶液中加入DBU(0.650mL,4.31mmol),于100℃加热16小时。通过LCMS确认反应完全后,反应物质用EtOAc(20mL)和水(20mL)稀释。分离有机层,水层用EtAOc(2x10mL)反萃取。合并的有机萃取物用盐水(20mL)洗涤,经Na2SO4干燥。在减压下除去溶剂,粗物质经快速色谱法纯化(60-120目硅胶柱,乙酸乙酯在石油醚中的50-60%溶液)。纯化后浓缩,产生(1R,2R,6S)-2-叠氮基-6-(3-溴-1H-1,2,4-三唑-1-基)环己醇(143mg,0.5mmol,35%),为灰白色固体。LC-MS,[M+2]+=289.0,{方法F,tR:1.030min,ELSD检测器}。
步骤-2:合成(1R,2R,6S)-2-叠氮基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇(外消旋物):向(1R,2R,6S)-2-叠氮基-6-(3-溴-1H-1,2,4-三唑-1-基)环己醇(110mg,0.383mmol)、(3-氟苯基)硼酸(64.3mg,0.460mmol)在1,4-二噁烷(3mL)和水(0.450mL)中的溶液中加入K2CO3(116mg,0.843mmol)。反应混合物用N2脱气,在N2下加入Pd(Ph3P)4(22.14mg,0.019mmol)。将小瓶密封,于95℃加热16小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物,将其经快速色谱法纯化(60-120硅胶,乙酸乙酯在石油醚中的80-90%溶液),得到(1R,2R,6S)-2-叠氮基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇(58mg,47%),为灰白色固体。LC-MS,[M+H]+=303.2,tR:2.256min{方法C}。
步骤-3:合成(1S,2R,6S)-2-氨基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇(外消旋物):以类似于实施例1a,步骤-5中所述的方式,使用(1R,2R,6S)-2-叠氮基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇制备,得到(1S,2R,6S)-2-氨基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇(0.048g,87%产率),为灰白色固体。LC-MS,[M+H]+=277.2{tR:0.730min,方法E}。
步骤-4:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:以类似于实施例1a,步骤-6中所述的方式,使用(1S,2R,6S)-2-氨基-6-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)环己醇(33.4mg,0.121mmol)和(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(0.05g,0.110mmol)制备。粗物质经快速色谱法纯化(60-120硅胶,6-10%MeOH的CHCl3溶液),得到(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体1)(0.020g,24%产率)和(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体2)(0.024g,22%产率).LC-MS,[M+H]+=714.2{方法F,tR:2.375-异构体-1/2.350异构体-2}。
步骤-5:向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体1)(20mg,0.028mmol)在二氯甲烷(1mL)中的搅拌溶液中加入三氟乙酸(0.15mL,1.947mmol),反应混合物于室温搅拌2h。然后在减压下除去溶剂,粗物质经制备型HPLC纯化{方法A}。将预期的级分在减压下浓缩,得到实施例9a:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体1)(4.8mg,27.4%产率),为灰白色固体。LC-MS,[M+H]+=626.1,[tR=1.682min,方法A]和&[tR=1.691min,方法B]。1H NMR(400MHz,MEOH-d4)δppm8.61(s,1H),8.50(s,1H),7.88(d,J=7.8Hz,1H),7.76(d,J=10.3Hz,1H),7.67(d,J=7.8Hz,1H),7.62(d,J=10.0Hz,1H),7.53-7.42(m,2H),7.17(td,J=8.4,2.3Hz,1H),7.13-7.06(m,1H),4.92(dd,J=10.8,2.9Hz,1H),4.36-4.22(m,2H),4.12(d,J=2.9Hz,1H),4.02-3.88(m,3H),3.85-3.78(m,2H),3.76-3.70(m,1H),3.18(s,3H),2.22-2.12(m,2H),2.08-2.02(m,1H),1.98-1.92(m,1H),1.68-1.52(m,2H)。hGal3IC50=0.5μM。
实施例9b:以类似于实施例9a中所述的方式,在步骤5中使用(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1R,2S,3S)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体2)(0.024g,0.034mmol)制备。粗物质经制备型HPLC纯化{方法A}。将预期的级分在减压下浓缩,得到(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(3-(3-氟苯基)-1H-1,2,4-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体2)(1.01mg,4.5%产率),为灰白色固体。LC-MS,[M+H]+=626.1,[tR=1.661min,方法A]和&[tR=1.668min,方法B]。1H NMR(400MHz,MEOH-d4)δppm 8.63(s,1H),8.49(s,1H),7.87(d,J=7.6Hz,1H),7.75(d,J=10.3Hz,1H),7.70(d,J=7.3Hz,1H),7.63(d,J=11.0Hz,1H),7.51-7.44(m,2H),7.20-7.07(m,2H),4.94-4.90(m,1H),4.35-4.24(m,2H),4.12(d,J=3.4Hz,1H),3.97-3.86(m,3H),3.84-3.79(m,2H),3.76-3.70(m,1H),3.20(s,3H),2.22-2.06(m,4H),1.94(br.s.,1H),1.65-1.57(m,1H)。hGal3 IC50=>100μM。
环己基_N_甲基_类似物:
步骤-1:合成1-((1S,2R,6R)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(外消旋物):于室温向(1S,2R,6R)-2-叠氮基-7-氧杂双环[4.1.0]庚烷(0.5g,3.59mmol)在DMF(5mL)和水(1.5mL)中的溶液中加入抗坏血酸钠(0.71g,3.59mmol)、硫酸铜(II)五水合物(0.81g,3.23mmol)和3-氟苯基乙炔(1.7mL,14.37mmol)。反应混合物于85℃加热30分钟。反应混合物冷却至室温,用1:1DCM(50mL)和水(50mL)稀释,于室温搅拌15分钟。反应混合物经硅藻土垫过滤,用DCM(20mL)洗涤。从滤液中分离出有机层,水层用DCM(2x20mL)反萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥和浓缩,得到粗残余物。粗残余物经快速色谱法纯化(EtOAc在正己烷中的40-50%溶液),得到1-((1S,2R,6R)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(0.53g,57%),为浅黄色固体。LC/MS[M+H]+=260.2,tR=2.266min(方法C)。
步骤-2:合成(1R,2R,6S)-2-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(甲基氨基)环己醇(外消旋物):在密闭试管中,将1-((1S,2R,6R)-7-氧杂双环[4.1.0]庚烷-2-基)-4-(3-氟苯基)-1H-1,2,3-三唑(110mg,0.424mmol)和甲胺(在乙醇中的33%溶液)(5mL,0.424mmol)加热至65℃达16小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物用正戊烷研磨,干燥,得到(1R,2R,6S)-2-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(甲基氨基)环己醇(109mg,88%)。LC/MS[M+H]+=291.0,tR=1.372min(方法F)。
步骤-3:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:于室温向((2S,4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.11mmol)在DMF(2mL)中的溶液中加入DIPEA(0.06mL,0.33mmol)和HATU(63mg,0.16mmol),搅拌15分钟。然后加入(1R,2R,6S)-2-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(甲基氨基)环己醇(35.1mg,0.121mmol),混合物于室温搅拌1小时。反应混合物用冰冷的水(10mL)淬灭,搅拌15分钟。所得固体过滤,用过量水洗涤,残余物干燥,得到粗残余物的非对映体混合物。粗残余物进一步通过制备型SFC纯化,得到异构体1和异构体2。
制备型SFC条件
柱/尺寸:Chiralcel OD-H(250X21)mm,5u
%CO2:60%
%共溶剂:40%的在MEOH中的0.2%DEA
总流速:80.0g/min
背压:100巴
温度:25℃
UV:242nm
异构体1:35mg,37%产率;LC/MS[M+H]+=728.2,tR=3.178min(方法C)。
异构体2:25mg,31%产率;LC/MS[M+H]+=728.0,tR=2.635min(方法F)。
实施例10a:将(2S,4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体1)(35mg,0.048mmol)混悬于70%乙酸水溶液(5mL)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到((2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺异构体1(9.3mg,30%),为灰白色固体。LC/MS[M+H]+=640.2,tR=1.788min(方法A);1H NMR(400MHz,MEOH-d4)δppm 8.71,8.70(两个单峰,1H),8.53,8.42(两个单峰,1H),7.76-7.57(m,4H),7.53-7.42(m,2H),7.15-7.05(m,2H),5.03-4.96(m,1H),4.76-4.66(m,1H),4.58(m,1H),4.55-4.35(m,3H),4.34-4.04(m,4H),3.21,3.00(两个单峰,3H),3.13,3.11(两个单峰,3H),2.27-2.09(m,2H),2.04-1.90(m,2H),1.85(m,2H){外消旋混合物}。hGal3 IC50=5.5μM。
实施例10b:将((2S,4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(异构体2)(25mg,0.034mmol)混悬于70%乙酸水溶液(5mL,87mmol)中,于70℃加热16小时。反应混合物冷却至室温,在减压下浓缩,得到粗残余物。粗残余物通过制备型HPLC纯化[方法A],得到((2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((1S,2R,3R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-羟基环己基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺异构体2(2.2mg,10%)。LC/MS[M+H]+=640.2,tR=1.78min(方法A);1H NMR(400MHz,MEOH-d4)δppm 8.72,8.71(两个单峰,1H),8.47,8.45(两个单峰,1H),7.75-7.57(m,4H),7.53-7.43(m,2H),7.10(t,J=8.4Hz,2H),5.03-4.95(m,1H),4.65-4.49(m,3H),4.47-4.40(m,1H),4.21-4.00(m,2H),3.94-3.84(m,1H),3.83-3.64(m,2H),3.21,2.98(两个单峰,3H),3.14,3.11(两个单峰,3H),2.28-2.11(m,2H),2.10-1.95(m,2H),1.94-1.64(m,2H).[外消旋混合物];hGal3 IC50=0.091μM。
以与实施例10a和10b类似的方式,在合成序列中用适当的烷基胺代替甲基胺,制备了表2中的实施例。
表2
实施例16a和16b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺(异构体1和2)
步骤-1:合成(1S,5R,6R)-5-羟基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(外消旋物):于0℃在N2下向N-Boc-3-羟基-1,2,3,6-四氢吡啶(500mg,2.51mmol)在DCM(25mL)中的溶液中加入碳酸氢钠(211mg,2.51mmol),然后加入在DCM(3mL)中的mCPBA(928mg,3.76mmol)。使反应混合物温热至室温,搅拌24小时。反应混合物用DCM(100mL)稀释,经硅藻土垫过滤,滤液用饱和Na2SO3(2x50mL)、饱和NaHCO3(2x50mL)和饱和NaCl(25mL)洗涤。有机层经Na2SO4干燥,过滤,浓缩,粗残余物通过硅胶色谱法纯化(40%→50%乙酸乙酯的己烷溶液),得到标题化合物(430mg,80%产率),为白色固体。1H NMR(400MHz,氯仿-d)δ4.01(br.s,1H),3.92-3.44(m,5H),3.10(dd,J=12.8,7.2Hz,1H),1.29(s,9H)(外消旋混合物)。
步骤-2:合成(1S,5S,6R)-5-叠氮基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(外消旋物):向(1S,5R,6R)-5-羟基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(325mg,1.510mmol)在THF(50mL)中的搅拌溶液中加入三苯膦(792mg,3.02mmol)。反应混合物冷却至0℃。在N2下依次加入DEAD(0.478mL,3.02mmol)和DPPA(0.651mL,3.02mmol)。使反应混合物温热至室温,搅拌16小时。在减压下除去溶剂,粗残余物通过硅胶色谱法纯化(10%→15%乙酸乙酯的己烷溶液),得到标题化合物(230mg,64%产率),为浅黄色油。1HNMR(400MHz,DMSO-d6)δ4.09-3.82(m,2H),3.62-3.38(m,4H),3.17(dd,J=13.1,3.3Hz,1H),1.40(s,9H)(外消旋混合物)。
步骤-3:合成(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(外消旋物):于室温向(1R,5R,6S)-5-叠氮基-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(1.6g,6.66mmol)在DMF(30mL)和水(7.50mL)中的溶液中依次加入抗坏血酸钠(1.319g,6.66mmol)、硫酸铜(II)五水合物(1.496g,5.99mmol)和3-氟苯基乙炔(3.08mL,26.6mmol)。将反应混合物用N2脱气5分钟,加热至85℃达30分钟。混合物冷却至室温,用冰冷的水(100mL)稀释,搅拌15分钟,得到固体。将固体过滤,混悬于DCM(100mL)中,经硅藻土垫过滤,用过量DCM洗涤。滤液经硫酸钠干燥和浓缩。残余物通过硅胶纯化(40%→80%乙酸乙酯的己烷溶液),得到标题化合物(1.1g,46%产率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.83(br.s,1H),7.59-7.55(m,2H),7.42-7.38(m,1H),7.10-7.07(m,1H),5.18-5.06(m,1H),4.34-4.29(m,1H),3.93-3.45(m,5H),1.47-1.11(m,9H)(外消旋混合物);LC/MS,[M+H]+=361.0,tR=2.01min(方法E).
步骤-4:合成(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-5-(甲基氨基)哌啶-1-甲酸叔丁基酯(外消旋物):将在甲胺(在乙醇中的33%溶液)中的(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(100mg,0.277mmol)(5mL,0.277mmol)在密闭试管中于65℃加热16小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物用戊烷研磨,在减压下干燥,得到(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-5-(甲基氨基)哌啶-1-甲酸叔丁基酯(105mg,94%)。LC-MS,[M+H]+=392.2,{方法C:tR=1.855min}。
步骤-5:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)在DMF(2mL)中的搅拌溶液中依次加入DIPEA(0.058mL,0.329mmol)和HATU(62.6mg,0.165mmol),搅拌15分钟。然后加入(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-5-(甲基氨基)哌啶-1-甲酸叔丁基酯(47.3mg,0.121mmol),反应混合物于室温搅拌1小时。反应混合物用冰水淬灭,搅拌15分钟。所得固体过滤,干燥,得到粗残余物。粗残余物通过硅胶纯化(5-10%MeOH的氯仿溶液),得到(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯,为非对映体混合物,将其进一步通过手性SFC纯化,得到两种异构体:
制备型SFC方法信息:
柱/尺寸:Chiralcel OJ-H(250X21)mm,5u
%CO2:70%
%共溶剂:30%的IPA+ACN
总流速:70.0g/min
背压:100巴
温度:25℃
UV:244nm
分析型手性SFC条件:
分析柱:ChiralCel OJH(250X4.6)mm,5u
BPR压力:100巴
温度:22.3℃
流速:2.8g/min
流动相:CO2/IPA+ACN(70/30)
检测波长:UV 200-400nm
异构体1:(30mg,31%产率);手性SFC tR=1.8min;LC-MS,[M+H]+=829.0,{方法F:tR=2.855min};
异构体2:(28mg,31%产率);手性SFC tR=5.15min;LC-MS,[M+H]+=829.0,{方法F:tR=3.0min};
步骤-6:向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯异构体1(30mg,0.036mmol)在二氯甲烷(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),混合物于室温搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型HPLC方法A纯化,得到实施例16a:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺异构体1(10.6mg,47%产率),为灰白色固体。LC-MS,[M+H]+=641.3,{方法A:tR=1.520}。1H NMR(400MHz,MEOH-d4)δppm 8.72,8.68(两个单峰,1H),8.45(m,1H),7.74-7.55(m,4H),7.51-7.41(m,2H),7.14-7.04(m,2H),4.97(dd,J=10.6,2.8Hz,1H),4.67-4.49(m,2H),4.48-4.24(m,3H),4.10(dd,J=7.9,2.6Hz,1H),3.95(dd,J=8.4,3.8Hz,1H),3.89-3.76(m,2H),3.74-3.68(m,1H),3.43-3.35(m,1H),3.23,3.00(两个单峰,3H),3.22-3.16(m,1H),3.14-3.10(m,3H),3.09-3.01(m,1H)[*外消旋混合物];hGal3 IC50=3.5μM。
实施例16b:于室温向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯异构体2(28mg,0.034mmol)在二氯甲烷(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型LC/MS方法A纯化,得到(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺异构体2(12.4mg,0.019mmol,57%),为灰白色固体。LC-MS,[M+H]+=641.1,{方法A:tR=1.517}。1H NMR(400MHz,MEOH-d4)δppm 8.71,8.68(两个单峰,,1H),8.53,8.51(两个单峰,1H),7.73-7.57(m,4H),7.51-7.42(m,2H),7.14-7.05(m,2H),4.97(dt,J=10.3,3.4Hz,1H),4.57-4.37(m,2H),4.30-4.21(m,1H),4.08(dd,J=7.5,2.3Hz,1H),4.01-3.96(m,1H),3.90-3.67(m,5H),3.50-3.41(m,2H),3.27,3.00(两个单峰,3H),3.13-3.10(m,3H),3.04(m,1H){外消旋混合物}。hGal3 IC50=0.044μM。
实施例17a和17b:合成(2R,4R,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺(异构体1和2)
步骤-1:合成(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯:于室温向(4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.118mmol)在DMF(2mL)中的搅拌溶液中依次加入DIPEA(0.062mL,0.353mmol)和HATU(67.0mg,0.176mmol),搅拌15分钟。然后加入(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-5-(甲基氨基)哌啶-1-甲酸叔丁基酯(50.6mg,0.129mmol),反应混合物于室温搅拌1小时。反应混合物用冰水淬灭,搅拌15分钟。所得固体过滤,干燥,得到粗残余物。粗残余物通过硅胶纯化(5-10%MeOH的氯仿溶液),得到(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯,为非对映体混合物,将其进一步通过纯化手性SFC,得到两种异构体:
制备型SFC方法信息:
柱/尺寸:Chiralcel OJ-H(250X21)mm,5u
%CO2:80%
%共溶剂:20%的IPA+ACN
总流速:70.0g/min
背压:100巴
温度:25℃
UV:244nm
分析型手性SFC条件:
分析柱:ChiralCel OJH(250X4.6)mm,5u
BPR压力:100巴
温度:22.3℃
流速:3g/min
流动相:CO2/IPA+ACN(75/25)
检测波长:UV 200-400nm
异构体1:(28mg,0.035mmol,30%);手性SFC tR=3.74min;LC-MS,[M+H]+=799.1,{方法F:tR=3.888min};
异构体2:(29mg,0.034mmol,29%);手性SFC tR=5.91min;LC-MS,[M+H]+=799.2,{方法F:tR=3.505min};
步骤-2:于室温向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯(异构体1)(28mg,0.035mmol)在DCM(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型HPLC方法A纯化,得到实施例17a:(2R,4R,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺异构体1(10.9mg,50%),为灰白色固体。LC-MS,[M+H]+=611.3,{方法A:tR=1.257}。1H NMR(400MHz,MEOH-d4)δppm 8.53-8.46(m,2H),7.71-7.59(m,4H),7.52-7.42(m,2H),7.15-7.06(m,2H),5.13(d,J=12.5Hz,1H),4.81-4.74(m,1H),4.68(dd,J=9.2,6.5Hz,1H),4.56-4.35(m,2H),4.14(s,1H),4.01-3.56(m,5H),3.48-3.36(m,1H),3.25,3.00(两个单峰,3H),3.06(q,J=7.3Hz,1H),2.91-2.79(m,1H),2.25-2.14(m,1H){外消旋混合物};hGal3 IC50=5.2μM。
实施例17b:于室温向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯异构体2(29mg,0.036mmol)在DCM(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型LC/MS方法A纯化,得到((2R,4R,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-5-羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺异构体2(6.7mg,0.011mmol,30%),为灰白色固体。LC-MS,[M+H]+=611.3,{方法A:tR=1.255}。1H NMR(400MHz,MEOH-d4)δppm 8.54-8.46(m,2H),7.70-7.57(m,4H),7.51-7.41(m,2H),7.14-7.05(m,2H),5.15-5.06(m,1H),4.95-4.86(m,1H),4.74-4.61(m,1H),4.48-4.41(m,1H),4.32(td,J=10.9,4.3Hz,1H),4.10(s,1H),4.01-3.70(m,5H),3.57-3.43(m,1H),3.24,2.99(两个单峰,3H),3.05(q,J=7.4Hz,1H),2.85-2.69(m,1H),2.32-2.15(m,1H){外消旋混合物}。hGal3 IC50=0.13μM。
实施例18a和18b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-3,5-二羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺(异构体1和2)
步骤-1:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.113mmol)在DMF(2mL)中的搅拌溶液中依次加入DIPEA(0.059mL,0.340mmol)和HATU(64.6mg,0.170mmol),搅拌15分钟。然后加入(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-5-(甲基氨基)哌啶-1-甲酸叔丁基酯(48.8mg,0.125mmol),反应混合物于室温搅拌1小时。反应混合物用冰水淬灭,搅拌15分钟。所得固体过滤,干燥,得到粗残余物。粗残余物通过硅胶纯化(5-10%MeOH的氯仿溶液),得到(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯,为非对映体混合物,将其进一步通过制备型HPLC方法C纯化,得到两种异构体:
分析型HPLC条件:
分析柱:Symmetry C9(250X4.6)mm,5u
流动相A:0.1%TFA的水溶液
流动相B:ACN
流速:1mL/min
梯度:历经20分钟20-100%B,然后10分钟保持在100%B
检测波长:UV 200-400nm
异构体1:(25mg,0.030mmol,27%);HPLC tR=16.083min;LC-MS,[M+H]+=815.0,{方法F:tR=2.683min}。
异构体2:(21mg,0.025mmol,22%);HPLC tR=16.700min;LC-MS,[M+H]+=815.2,{方法F:tR=3.98min}。
步骤-2:于室温向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯异构体1(25mg,0.031mmol)在DCM(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型HPLC方法D纯化,得到实施例18a:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-3,5-二羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺异构体1(8mg,41%产率),为灰白色固体。LC-MS,[M+H]+=627.2,{方法C:tR=1.500}。1H NMR(400MHz,MEOH-d4)δppm 8.44,8.43(两个单峰,1H),8.36,8.34(两个单峰,1H),7.70-7.56(m,4H),7.50-7.41(m,2H),7.13-7.04(m,2H),4.98-4.90(m,1H),4.80-4.75(m,1H),4.65-4.50(m,2H),4.44(d,J=9.0Hz,1H),4.37-4.28(m,1H),4.23(td,J=10.7,4.8Hz,1H),4.14(d,J=2.5Hz,1H),4.01(dd,J=8.3,3.8Hz,1H),3.93-3.77(m,2H),3.75-3.69(m,2H),3.43-3.34(m,1H),3.24(s,1H),3.22-3.12(m,2H)[*外消旋混合物];hGal3 IC50=1.8μM。
实施例18b:于室温向(3S,4S,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-羟基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰氨基)-4-羟基哌啶-1-甲酸叔丁基酯异构体2(16mg,0.020mmol)在DCM(1mL)中的溶液中加入三氟乙酸(0.15mL,1.947mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型LC/MS方法A纯化,得到(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)-3,5-二羟基-6-(羟基甲基)-N-甲基四氢-2H-吡喃-2-甲酰胺异构体2(2.8mg,22%),为灰白色固体。LC-MS,[M+H]+=627.1,{方法A:tR=1.517}。1H NMR(400MHz,MEOH-d4)δppm 8.55(d,J=2.9Hz,1H),8.53(d,J=2.4Hz,1H),7.72-7.66(m,2H),7.64(d,J=7.6Hz,2H),7.53-7.44(m,2H),7.16-7.07(m,2H),4.97(dd,J=10.6,2.8Hz,1H),4.80-4.73(m,1H),4.48-4.39(m,2H),4.16(d,J=3.4Hz,1H),4.05(d,J=5.4Hz,1H),3.94-3.70(m,6H),3.55-3.46(m,1H),3.29,3.02(两个单峰,3H),3.06(d,J=7.8Hz,1H),{外消旋混合物}。hGal3 IC50=0.05μM。
实施例19.合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-1-甲基哌啶-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺
步骤-1:合成(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷(纯手性):于室温向(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁基酯(100mg,0.277mmol)在二氯甲烷(5mL)中的搅拌溶液中依次加入100mg 4A分子筛和BF3.OEt2(0.105mL,0.832mmol),搅拌30分钟。反应混合物经硅藻土垫过滤,用过量DCM(20mL)洗涤,滤液在减压下浓缩,得到(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷(70mg,83%产率),为浅黄色油;LC-MS,[M+H]+=261.4,{方法E:tR=0.90min}。
步骤-2:合成(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-3-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷:向(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂双环[4.1.0]庚烷(70mg,0.269mmol)在MeOH(5mL)中的搅拌溶液中加入低聚甲醛(40.4mg,1.345mmol)和0.1mL AcOH,于室温搅拌10min。然后加入氰基硼氢化钠(16.90mg,0.269mmol),于室温搅拌16小时。在减压下除去MeOH,粗残余物用10%MeOH的DCM溶液(2X30mL)萃取,用水、盐水洗涤,经硫酸钠干燥和浓缩。残余物经硅胶色谱法纯化(EtOAc在正己烷中的20-50%溶液),得到(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-3-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷(70mg,92%产率),为灰白色固体。LC-MS,[M+H]+=275.2,{方法C:tR=1.828min}.
步骤-3:合成(3R,4R,5S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-1-甲基-5-(甲基氨基)哌啶-4-醇:将在甲胺(33%乙醇溶液)中的(1R,5R,6S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-3-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷(70mg,0.255mmol)(5mL,0.255mmol)在密闭试管中于65℃加热16小时。反应混合物冷却至室温,在减压下除去溶剂,得到标题化合物(65mg,81%产率),为棕色固体。LC-MS,[M+H]+=306.2,{方法C:tR=0.833min}.
步骤-4:合成(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-1-甲基哌啶-3-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(30mg,0.066mmol)在DMF(2mL)中的搅拌溶液中依次加入DIPEA(0.035mL,0.198mmol)和HATU(37.6mg,0.099mmol),搅拌15分钟。然后加入(3R,4R,5S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-1-甲基-5-(甲基氨基)哌啶-4-醇(24.14mg,0.079mmol),反应混合物于室温搅拌1小时。反应混合物用冰水淬灭,搅拌15分钟。所得固体过滤,干燥,得到标题化合物(35mg,55%产率),为棕色固体。LC-MS,[M+H]+=743.2,{方法C:tR=2.88min}。
步骤-5:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-1-甲基哌啶-3-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(30mg,0.040mmol)在二氯甲烷(3mL)中的溶液中加入三氟乙酸(0.5mL,6.49mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物。将粗物质经制备型HPLC方法D纯化,得到实施例19:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基-1-甲基哌啶-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺(18.7mg,0.029mmol,71%),为灰白色固体。LC-MS,[M+H]+=655.1,{方法A:tR=1.685min}。1H NMR(400MHz,MEOH-d4)δppm 8.62,8.59(两个单峰,1H),8.41,8.38(两个单峰,1H),7.63-7.48(m,4H),7.42-7.33(m,2H),7.05-6.96(m,2H),4.88(dd,J=10.1,3.1Hz,1H),4.54-4.47(m,1H),4.41-4.23(m,3H),4.01(d,J=2.9Hz,1H),3.89(d,J=3.2Hz,1H),3.81-3.74(m,2H),3.71-3.59(m,4H),3.17-3.15(m,3H),3.05-2.86(m,6H),2.75(s,1H){外消旋混合物}。hGal3 IC50=0.02μM。
实施例20a和20b:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺(异构体1和2)
步骤-1:合成3-叠氮基-3,6-二氢-2H-吡喃:于0℃在N2下向3,6-二氢-2H-吡喃-3-醇(1g,9.99mmol)在DCM(50mL)中的搅拌溶液中依次加入三乙胺(2.78mL,19.98mmol)和甲磺酰氯(0.934mL,11.99mmol),搅拌30分钟。然后,反应混合物用DCM(100mL)萃取,用水、盐水洗涤,经硫酸钠干燥和浓缩。将粗甲磺酸酯溶于DMSO(10mL)中,加入叠氮化钠(2.74g,42.1mmol),于室温搅拌16小时。反应混合物用EtOAc(3x50mL)萃取,用水、盐水洗涤,经硫酸钠干燥。在减压下除去溶剂,得到粗残余物,将其经快速色谱法纯化(EtOAc在正己烷中的15-20%溶液),得到3-叠氮基-3,6-二氢-2H-吡喃(0.75g,5.95mmol,71%)。1H NMR(400MHz,氯仿-d)δppm 6.07-6.22(m,1H),5.84-5.97(m,1H),4.18-4.25(m,1H),4.07-4.15(m,1H),3.96(ddd,J=12.0,3.0,1.0Hz,1H),3.81-3.86(m,1H),3.55(br.s,1H)。
步骤-2:合成1-(3,6-二氢-2H-吡喃-3-基)-4-(3-氟苯基)-1H-1,2,3-三唑:向3-叠氮基-3,6-二氢-2H-吡喃(0.74g,5.91mmol)在DMF(10mL)和水(3mL)中的溶液中加入抗坏血酸钠(1.172g,5.91mmol)、硫酸铜(II)五水合物(1.329g,5.32mmol)和3-氟苯基乙炔(2.73mL,23.66mmol)。反应混合物用N2脱气10min,于85℃加热15分钟。然后,反应混合物冷却至室温,用DCM(50mL)/水(50mL)稀释,搅拌30分钟。分离有机层,水层用DCM(2x30mL)反萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥和浓缩。粗残余物经快速色谱法纯化(EtOAc在正己烷中的35-50%溶液),得到标题化合物(1.36g,5.45mmol,92%),为浅黄色固体。LC-MS,[M+H]+=246.2,{方法C:tR=2.006min}。
步骤-3:合成(3S,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4-二醇(外消旋物):于室温向1-(3,6-二氢-2H-吡喃-3-基)-4-(3-氟苯基)-1H-1,2,3-三唑(0.4g,1.631mmol)在丙酮(4mL)和水(1mL)中的搅拌溶液中加入4-甲基吗啉-N-氧化物(0.287g,2.446mmol)和四氧化锇(2.048mL,0.163mmol,2.5%w/v,在叔丁醇中),搅拌14小时。反应混合物用饱和Na2SO3溶液淬灭,在减压下除去丙酮,得到粗残余物。粗残余物用EtOAc(2X100mL)萃取,用水、盐水洗涤,经硫酸钠干燥和浓缩。粗残余物经快速色谱法纯化(EtOAc在正己烷中的80-100%溶液),得到标题化合物(0.25g,0.895mmol,55%)。LC-MS,[M+H]+=280.2,{方法C:tR=1.025min}。
步骤-4:合成(3aS,7S,7aR)-7-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃2,2-二氧化物(外消旋物):于室温向(3S,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3,4-二醇(0.25g,0.895mmol)在DCM(10mL)中的搅拌溶液中加入TEA(0.250mL,1.790mmol),搅拌5分钟。然后,将反应混合物冷却至0℃,在N2下加入SOCl2(0.131mL,1.790mmol)。使反应混合物达到室温,于室温搅拌1小时。在减压下除去溶剂,粗物质用EtOAc(2X50mL)萃取,用水、盐水洗涤,经硫酸钠干燥。在减压下除去溶剂,粗残余物经快速色谱法纯化(EtOAc在正己烷中的60-95%溶液),得到标题化合物(0.23g,0.707mmol,79%).LC-MS,[M+H]+=326.4,{方法E:tR=1.08min}。
步骤-5:合成(3aS,7S,7aR)-7-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃2,2-二氧化物(外消旋物):于室温向(3aS,7S,7aR)-7-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃2-氧化物(0.2g,0.615mmol)在乙腈(3mL)和水(1mL)中的搅拌溶液中加入高碘酸钠(0.263g,1.230mmol)和三氯化钌(III)水合物(0.014g,0.061mmol),搅拌12小时。在减压下除去溶剂,粗物质用EtOAc(2X50mL)萃取,用水、盐水洗涤,经硫酸钠干燥。在减压下除去溶剂,粗残余物经快速色谱法纯化(EtOAc在正己烷中的80-100%溶液),得到标题化合物(160mg,0.469mmol,76%)。LC-MS,[M+H]+=342.2,{方法F:tR=2.028min}。
步骤-6:合成(3R,4R,5S)-3-叠氮基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇(外消旋物):于室温向(3aS,7S,7aR)-7-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃2,2-二氧化物(160mg,0.469mmol)在DMF(4mL)中的搅拌溶液中加入叠氮化钠(122mg,1.875mmol)。然后将反应混合物于60℃加热3小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物溶于THF(2mL)中,于0℃加入1mL储备溶液[1mL H2SO4+0.4mL水+8.6mL THF],搅拌30分钟。反应混合物用NaHCO3碱化,经硅藻土垫过滤,用过量EtOAc洗涤。滤液在减压下浓缩,得到粗残余物,将其经快速色谱法纯化(EtOAc在正己烷中的60-95%溶液),得到标题化合物(90mg,0.296mmol,63%)。LC-MS,[M+H]+=305.2,{方法C:tR=1.94min}。
步骤-7:合成(3R,4S,5S)-3-氨基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇(外消旋物):向(3R,4R,5S)-3-叠氮基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇(90mg,0.296mmol)在MeOH(4mL)中的搅拌溶液中加入10%Pd/C(6.30mg,0.030mmol),于室温在氢气氛围下搅拌16小时。反应混合物经硅藻土过滤,用过量MeOH洗涤,滤液浓缩,得到标题化合物(60mg,0.216mmol,73%)。LC-MS,[M+H]+=279.5,{方法E:tR=0.72min}
步骤-8:于室温向(3R,4S,5S)-3-氨基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇(45.8mg,0.165mmol)在DMF(2mL)中的搅拌溶液中加入DIPEA(0.192mL,1.098mmol)。5分钟后,加入(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(50mg,0.110mmol)和HATU(104mg,0.274mmol),反应混合物于室温搅拌12小时。然后,反应混合物用冰冷的水稀释,搅拌10分钟。将所得固体过滤,干燥,得到含有(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺的粗残余物,为非对映异构混合物。粗残余物通过制备型HPLC纯化,分离出两种非对映体。
制备型HPLC方法信息:柱:Lux-cellulose C4(250X21.2)mm,5微米;流动相A:-流动相B:0.1%DEA在MeOH中;流速:19mL/min;时间(min)/%B:0/100,20/100;异构体1:(20mg,0.028mmol,25.5%产率)LC-MS,[M+H]+=716.0,{方法F:tR=2.287min}
异构体2:(18mg,0.025mmol,22.91%产率)。LC-MS,[M+H]+=716.0,{方法F:tR=2.30min}
步骤-9:将(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺异构体1(20mg,0.028mmol)混悬于80%AcOH水溶液(1mL)中,于70℃加热14小时。然后,反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗物质经制备型HPLC纯化[方法A],得到实施例20a:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体1(5mg,7.89μmol 28%)。LC-MS,[M+H]+=628.1,{方法A:tR=1.618min};1H NMR(400MHz,MEOH-d4)δ=8.63(s,1H),8.48(s,1H),7.70(dd,J=7.7,3.1Hz,2H),7.66-7.61(m,2H),7.53-7.46(m,2H),7.13(td,J=8.1,4.0Hz,2H),4.95(dd,J=10.6,2.8Hz,1H),4.67(d,J=4.4Hz,1H),4.35-4.25(m,3H),4.21(dd,J=10.3,4.9Hz,1H),4.15(d,J=2.7Hz,1H),4.11-4.05(m,1H),4.03-3.94(m,2H),3.87-3.81(m,2H),3.79-3.73(m,1H),3.47(t,J=10.9Hz,1H),3.20(s,3H).hGal3 IC50=36μM。
实施例20b:按照对实施例20a步骤9中所用相同的操作,但是用(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺异构体2作为起始原料,制备了(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺异构体2(5.5mg,8.76μmol,34.8%产率)。LC-MS,[M+H]+=628.1,{方法A:tR=1.610min}。1H NMR(400MHz,MEOH-d4)δ=8.63(s,1H),8.48(s,1H),7.70(dd,J=7.7,3.1Hz,2H),7.66-7.61(m,2H),7.53-7.46(m,2H),7.13(td,J=8.1,4.0Hz,2H),4.95(dd,J=10.6,2.8Hz,1H),4.67(d,J=4.4Hz,1H),4.35-4.25(m,3H),4.21(dd,J=10.3,4.9Hz,1H),4.15(d,J=2.7Hz,1H),4.11-4.05(m,1H),4.03-3.94(m,2H),3.87-3.81(m,2H),3.79-3.73(m,1H),3.47(t,J=10.9Hz,1H),3.20(s,3H)。hGal3 IC50=0.09μM。
实施例21:合成(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3R,4S,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-甲酰胺
步骤-1:合成N-(3,6-二氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(外消旋物):于0℃向3,6-二氢-2H-吡喃-3-醇(1.667g,16.65mmol)、N-甲基-4-硝基苯磺酰胺(3.0g,13.88mmol)在THF(30mL)中的搅拌溶液中加入三苯膦(7.28g,27.8mmol)和DIAD(5.40mL,27.8mmol)。使混合物温热至室温,搅拌18小时。反应混合物用EtOAc(3X50mL)萃取,用水、盐水洗涤,经硫酸钠干燥和浓缩。粗残余物经快速色谱法纯化(EtOAc在正己烷中的0-30%溶液),得到标题化合物(4g,13.41mmol,97%),为灰白色固体。1H NMR(400MHz,氯仿-d)δppm8.34-8.41(m,2H),7.97-8.08(m,2H),6.02-6.09(m,1H),5.36-5.42(m,1H),4.37-4.43(m,1H),4.08-4.15(m,1H),3.96-4.04(m,1H),3.76(d,J=4.0Hz,2H),2.92(s,3H)。
步骤-2:合成N-((3S,4R,5S)-4,5-二羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(外消旋物):于室温向N-(3,6-二氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(4.0g,13.41mmol)在丙酮(50mL)和水(13.33mL)中的搅拌溶液中加入4-甲基吗啉-N-氧化物(2.356g,20.11mmol)和四氧化锇(5.05mL,0.402mmol,2.5%w/v,在叔丁醇中),搅拌16小时。反应混合物用饱和Na2SO3溶液淬灭,在减压下除去丙酮,得到粗残余物。粗物质用EtOAc(2x100mL)萃取,用水、盐水洗涤,经硫酸钠干燥和浓缩。残余物经快速色谱法纯化(EtOAc在正己烷中的80-100%溶液),得到标题化合物(3.5g,10.53mmol,79%),为灰白色固体。1HNMR(300MHz,DMSO-d6)δppm 8.36(d,J=8.7Hz,2H),8.06(d,J=8.7Hz,2H),4.75(d,J=4.2Hz,1H),4.53(d,J=6.4Hz,1H),3.98(br td,J=10.6,4.9Hz,1H),3.50-3.70(m,4H),3.24-3.37(m,2H,与水峰合并),2.79(s,3H).
步骤-3:合成N-((3aS,7S,7aR)-2,2-二氧化四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃-7-基)-N-甲基-4-硝基苯磺酰胺(外消旋物):于0℃向N-((3S,4R,5S)-4,5-二羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(3.5g,10.53mmol)在DCM(30mL)中的搅拌溶液中依次加入TEA(2.94mL,21.06mmol)和亚硫酰氯(1.537mL,21.06mmol),搅拌1小时。然后,反应混合物用DCM(2x75mL)萃取,用水、盐水洗涤,经硫酸钠干燥。在减压下除去溶剂,得到残余物,将其未经进一步纯化用于下一步骤。于0℃向N-甲基-4-硝基-N-((3aS,7S,7aR)-2-氧化四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃-7-基)苯磺酰胺(3.8g,10.04mmol)在乙腈(100mL)/水(66.7mL)中的搅拌溶液中依次加入高碘酸钠(4.30g,20.09mmol)和三氯化钌(III)水合物(0.163g,0.036mmol)。然后使反应混合物达到室温,搅拌12小时。在减压下除去溶剂,得到粗残余物,粗物质用EtOAc(150mL)萃取,用水(100mL)、饱和NaHSO4溶液(3x50mL)洗涤,经Na2SO4干燥。在减压下除去溶剂,得到粗残余物,将其经快速色谱法纯化(EtOAc在正己烷中的70-100%溶液),得到N-((3aS,7S,7aR)-2,2-二氧化四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃-7-基)-N-甲基-4-硝基苯磺酰胺(3.5g,8.87mmol,88%),为灰白色固体。1H NMR(400MHz,DMSO-d6)δppm 8.42(d,J=9.0Hz,2H),8.06-8.10(m,2H),5.55-5.61(m,1H),5.38-5.42(m,1H),4.23-4.32(m,2H),3.76(dd,J=14.8,1.8Hz,1H),3.62-3.68(m,1H),3.48-3.55(m,1H),2.89(s,3H)。
步骤-4:合成N-((3S,4S,5R)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(外消旋物):于室温向N-((3aS,7S,7aR)-2,2-二氧化四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃-7-基)-N-甲基-4-硝基苯磺酰胺(0.7g,1.775mmol)在DMF(15mL)中的搅拌溶液中加入叠氮化钠(0.462g,7.10mmol)。然后,反应混合物于60℃加热2小时。反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物溶于THF(8.6mL)中,于0℃加入0.4mL水和1mL H2SO4,搅拌30分钟。反应混合物用固体NaHCO3碱化,经硅藻土垫过滤,用过量EtOAc洗涤。滤液在减压下浓缩,得到粗残余物,将其经快速色谱法纯化(EtOAc在正己烷中的30-50%溶液),得到标题化合物(0.5g,1.352mmol,76%)。LC-MS,[M+18]+=375.2,{方法C:tR=1.917min}。
步骤-5:合成N-((3S,4S,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(外消旋物):于室温向N-((3S,4S,5R)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(2.2g,6.16mmol)在DMF(20mL)和水(5.00mL)中的溶液中加入抗坏血酸钠(1.220g,6.16mmol)、硫酸铜(II)五水合物(1.383g,5.54mmol)和1-乙炔基-3-氟苯(2.85mL,24.63mmol)。反应混合物用N2脱气10分钟,于80℃加热30分钟。然后,反应混合物冷却至室温,用DCM(100mL)/水(100mL)稀释,搅拌30分钟。分离有机层,水层用DCM(2x50mL)反萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥和浓缩。粗残余物经快速色谱法纯化(0-15%MeOH的DCM溶液),得到N-((3S,4S,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(2.1g,4.40mmol,71%),为灰白色固体。LC-MS,[M+H]+=478.2,{方法C:tR=2.453min}。
步骤-6:合成(3R,4R,5S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(甲基氨基)四氢-2H-吡喃-4-醇:于室温向N-((3S,4S,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺(1g,2.094mmol)在丙酮(10mL)中的溶液中依次加入碳酸钾(0.868g,6.28mmol)和苯硫酚(0.346g,3.14mmol),搅拌16小时。然后在减压下除去溶剂,得到粗残余物,将其经快速色谱法纯化(0-20%MeOH(10%氨)/DCM),得到(3R,4R,5S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(甲基氨基)四氢-2H-吡喃-4-醇,为外消旋混合物。将外消旋混合物进一步通过SFC纯化,分离出对映异构体。
制备型手性HPLC条件:
制备柱:Chiralpak IA(250X30)mm,5um
BPR压力:100巴
温度:25℃
流速:60g/min
流动相:CO2/0.2%DEA的MeOH溶液(70/30)
检测波长:245nm
样品制备:10mg/1mL MeOH:
分析型手性HPLC条件:
分析柱:Chiralpak IA(250X30)mm,5um
BPR压力:100巴
温度:30℃
流速:3g/min
流动相:CO2/0.2%DEA的MeOH溶液(70/30)
检测波长:UV 200-400nm
对映体1(非预期):0.15g:手性HPLC tR=3.63min;LC-MS,[M+H]+=293.2,{方法C:tR=0.934min};
对映体2(预期):0.18g:手性HPLC tR=5.77min;LC-MS,[M+H]+=293.1,{方法C:tR=0.941min}。
步骤-7:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(200mg,0.439mmol)在DMF(5mL)中的搅拌溶液中依次加入HATU(334mg,0.878mmol)、DIPEA(0.767mL,4.39mmol)和(3R,4R,5S)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(甲基氨基)四氢-2H-吡喃-4-醇对映体2(128mg,0.439mmol),搅拌16小时。反应混合物倒入冰冷的水(100mL)中,搅拌10分钟。将所得固体过滤,干燥,得到粗残余物,将其进一步经快速色谱法纯化(0-10%MeOH的DCM溶液),得到(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(0.195g,0.259mmol,59%),为灰白色固体。LC-MS,[M+H]+=730.2,{方法C:tR=3.051min};
步骤-8:将(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(195mg,0.267mmol)混悬于70%AcOH水溶液(10mL)中,于70℃加热16小时。然后,反应混合物冷却至室温,在减压下除去溶剂,得到粗残余物。粗残余物通过制备型HPLC方法B纯化,得到实施例21:(2R,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-N-((3S,4R,5R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺(0.095g,0.148mmol,55%),为灰白色固体。LC-MS,[M+H]+=642.2,{方法C:tR=1.95}。1H NMR(400MHz,MEOH-d4)δppm 8.70(d,J=8.5Hz,1H),8.49(d,J=8.0Hz,1H),7.57-7.71(m,4H),7.43-7.49(m,2H),7.06-7.12(m,2H),4.98(br d,J=8.0Hz,1H),4.62-4.78(m,1H),4.41-4.60(m,3H),4.06-4.26(m,3H),3.65-4.01(m,6H),2.99-3.26(m,6H)[*外消旋混合物];hGal3 IC50=0.03μM。
实施例22:合成(2R,3R,4S,5R,6R)-N-((3S,4R,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺(异构体1和2)
步骤-1:于室温向5-氟-1H-吡唑并[3,4-b]吡啶(67.8mg,0.494mmol)在THF(3mL)中的搅拌溶液中加入18-冠醚-6(171mg,0.647mmol)和NaH(25.9mg,0.647mmol,60%w/w),于80℃回流10分钟。然后,历经5分钟滴加N-((3aS,7S,7aR)-2,2-二氧化四氢-3aH-[1,3,2]二氧杂硫杂环戊烷并[4,5-c]吡喃-7-基)-N-甲基-4-硝基苯磺酰胺(150mg,0.380mmol)在THF(3mL)中的溶液,于80℃回流16小时。反应混合物冷却至0℃,用浓HCl(约pH=1)酸化,进一步于80℃回流2小时。反应混合物冷却至室温,用10%NaHCO3水溶液中和,用EtOAc(2X25mL)萃取。合并的有机萃取物用水、盐水洗涤,经硫酸钠干燥和浓缩。粗残余物经快速色谱法纯化(EtOAc在正己烷中的60-80%溶液),得到N-((3S,4S,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺,为外消旋物。外消旋物进一步通过手性SFC纯化,得到纯的对映异构体-1和对映异构体-2。
制备型手性HPLC条件:
制备柱:Chiralpak ADH(250X30)mm,5um
BPR压力:100巴
温度:25℃
流速:60g/min
流动相:CO2/0.4%DEA的EtOH溶液(60/40)
检测波长:245nm
样品制备:10mg/1mL MeOH:
分析型手性HPLC条件:
分析柱:Chiralpak ADH(250X4.6)mm,5um
BPR压力:100巴
温度:25℃
流速:3g/min
流动相:CO2/0.4%DEA的EtOH溶液(60/40)
检测波长:UV 200-400nm
对映体1:(50mg,0.111mmol,29.1%产率);手性HPLC tR=5.59min;LC-MS,[M+H]+=452.2,{方法C:tR=2.352min};
对映体2:(50mg,0.111mmol,29.1%产率);手性HPLC tR=8.23min;LC-MS,[M+H]+=452.2,{方法C:tR=2.353min}。
步骤-2:于室温向N-((3S,4S,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-N-甲基-4-硝基苯磺酰胺对映体1(50mg,0.111mmol)在丙酮(2mL)中的搅拌溶液中加入K2CO3(45.9mg,0.332mmol),然后加入苯硫酚(0.031mL,0.299mmol),搅拌2小时。然后在减压下除去溶剂,得到粗残余物,粗物质经快速色谱法纯化(5-15%MeOH(5%NH3水溶液),在CHCl3中),得到(3R,4R,5S)-3-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-5-(甲基氨基)四氢-2H-吡喃-4-醇(20mg,0.075mmol,68%)。LC-MS,[M+H]+=267.2,{方法D:tR=0.57min}。
步骤-3:于室温向(4aR,6R,7R,8R,8aR)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酸(25mg,0.055mmol)和(3R,4R,5S)-3-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-5-(甲基氨基)四氢-2H-吡喃-4-醇(14.62mg,0.055mmol)在DMF(0.6mL)中的搅拌溶液中依次加入DIPEA(0.048mL,0.274mmol)和HATU(31.3mg,0.082mmol),搅拌16小时。然后,反应混合物用20mL冰冷的水稀释,搅拌10分钟。将所得固体过滤,干燥,得到(4aR,6R,7R,8R,8aR)-N-((3S,4R,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(25mg,0.036mmol,65%)。LC-MS,[M+H]+=704.4,{方法D:tR=1.28min}。
步骤-4:将(4aR,6R,7R,8R,8aR)-N-((3S,4R,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-8-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-甲氧基-N-甲基-2-苯基六氢吡喃并[3,2-d][1,3]二噁烯-6-甲酰胺(30mg,0.043mmol)混悬于70%AcOH水溶液(10mL)中,于75℃加热16小时。反应混合物冷却至室温,通过制备型HPLC方法A纯化,得到实施例22a:(2R,3R,4S,5R,6R)-N-((3S,4R,5R)-5-(5-氟-1H-吡唑并[3,4-b]吡啶-1-基)-4-羟基四氢-2H-吡喃-3-基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基-N-甲基四氢-2H-吡喃-2-甲酰胺异构体1(13.4mg,0.022mmol,51%)。LC-MS,[M+H]+=616.1,{方法A:tR=1.54min}。1H NMR(400MHz,MEOH-d4)δ=8.71(d,J=7.0Hz,1H),8.52(dt,J=6.5,2.0Hz,1H),8.15(d,J=3.0Hz,1H),7.97(dt,J=8.4,3.1Hz,1H),7.70(d,J=8.0Hz,1H),7.67-7.60(m,1H),7.47(td,J=7.9,5.8Hz,1H),7.09(td,J=8.5,2.5Hz,1H),5.16-4.95(m,2H),4.79-4.65(m,1H),4.58-4.51(m,1H),4.46-4.41(m,1H),4.25-4.13(m,2H),4.09-3.88(m,3H),3.88-3.65(m,4H),3.26(s,1H),3.12(s,2H),3.09(s,2H),3.01(s,1H).hGal3 IC50=>10μM.
实施例22b:以类似于对实施例22a所述的方式,通过在步骤-2中采用对映体2作为起始原料制得。LC-MS,[M+H]+=616.1,{方法A:tR=1.54min}。1HNMR(400MHz,MEOH-d4)δppm8.67-8.75(m,1H),8.39-8.53(m,1H),8.13-8.22(m,1H),7.98(d,J=2.5Hz,1H),7.38-7.80(m,3H),7.02-7.17(m,1H),5.18-5.32(m,1H),4.92-5.12(m,2H),4.71-4.82(m,2H),4.38-4.49(m,1H),3.66-4.15(m,8H),3.27(s,1H),3.09-3.12(m,3H),3.04(s,2H)(外消旋混合物)。hGal3 IC50=0.04。
Claims (13)
1.式(I)或式(II)化合物:
或其可药用盐,其中:
X独立地选自-C(O)-、-CH2-和-CH2C(O)-;
Ar1独立地是苯基或萘基;和其中各个环部分被1至5个选自如下的取代基取代:
氰基、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C1-4卤代烷氧基;
R1独立地选自H、C1-4烷基、C1-4卤代烷基和-CH2C(O)OH;
R2独立地选自H、被0-1个OH取代的C1-4烷基、C1-4卤代烷基、-(CH2)0-2-C3-6环烷基、和-(CH2)0-2-被0-3个卤素取代的苯基;
R3独立地是C3-6环烷基,或包括4-7个环原子的杂环烷基,其中1-2个环原子各自独立地选自N(,N(RB)和O和S;其中所述环部分被0-1个R5和1个R5A取代;
R5独立地是OH、氰基、卤素、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、和被0-1个OH取代的C1-4烷基;
R5C独立地选自:氰基、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基和C1-4卤代烷氧基;
R5F独立地是-NH-苯基,其中所述苯基被0-2个选自氰基、卤素、卤素、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基的取代基取代。
2.权利要求1的化合物,其中:
X是-C(O)-;和Ar1是被1-3个卤素取代的苯基。
3.权利要求1或权利要求2的化合物,其中:
R3独立地是C5-6环烷基,或包括4至6个环原子的杂环烷基,其中1至2个环原子各自独立地选自N(RB)、N(RE)和O;其中所述环部分各自被0-1个R5和1个R5A取代。
7.权利要求1至4任一项的化合物,其中:
R1独立地是H或C1-4烷基;和
R2独立地选自H、被0-1个OH取代的C1-4烷基、C1-4卤代烷基、-(CH2)0-1-环丙基、和-CH2-(被0-2个卤素取代的苯基)。
8.权利要求1至5任一项的化合物,其中:
R1独立地是H或CH3;和
R2独立地选自:H、CH3、-CH2CH3、-CH2CH2OH、-CH2CHF2、环丙基和环丙基甲基。
9.权利要求1的化合物,其中所述化合物选自所示例的实施例,或其可药用盐。
10.组合物,包含治疗有效量的权利要求1至9任一项的化合物或其可药用盐以及一种或多种可药用载体。
11.权利要求1至9任一项的化合物或其可药用盐或者权利要求10的组合物,用作药剂。
12.用于治疗器官(包括肝、肾脏、肺、心脏和皮肤)纤维化、肝脏疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流疾病)、细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞白细胞(CLL))和癌细胞侵袭性转移)、炎性疾病和病症(包括银屑病、肾病和肺炎)、胃肠道疾病和病症(包括肠易激惹综合征(IBS)、炎性肠病(IBD)和胰腺分泌异常)、肾脏疾病和病症、泌尿道相关性疾病和病症(包括良性前列腺增生症或与神经性膀胱疾病、脊髓肿瘤、椎间盘突出、脊椎管狭窄相关的症状和衍生自糖尿病的症状)、下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和尿频)、胰腺疾病和病症、异常血管发生相关性疾病和病症(包括动脉阻塞)、硬皮病、脑相关疾病和病症(包括脑梗死和脑出血)、神经性疼痛和周围神经病、眼部疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增殖性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过术瘢痕)的用途,包括给患者施用治疗有效量的权利要求1至9任一项的化合物或其可药用盐。
13.权利要求12的用途,其中所述疾病或病症是肾纤维化、肺纤维化、肝纤维化、动脉纤维化或系统性硬化病。
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