CN116903559A - Fxr调节剂及其应用 - Google Patents
Fxr调节剂及其应用 Download PDFInfo
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- CN116903559A CN116903559A CN202310418323.1A CN202310418323A CN116903559A CN 116903559 A CN116903559 A CN 116903559A CN 202310418323 A CN202310418323 A CN 202310418323A CN 116903559 A CN116903559 A CN 116903559A
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- CN
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- Prior art keywords
- alkyl
- hydrogen
- phenyl
- group
- chloro
- Prior art date
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- 239000012453 solvate Substances 0.000 claims abstract description 32
- 229940002612 prodrug Drugs 0.000 claims abstract description 31
- 239000000651 prodrug Substances 0.000 claims abstract description 31
- 239000013078 crystal Substances 0.000 claims abstract description 8
- -1 nitro, methyl Chemical group 0.000 claims description 633
- 239000001257 hydrogen Substances 0.000 claims description 333
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 320
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 190
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 159
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 81
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 72
- 125000002541 furyl group Chemical group 0.000 claims description 63
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- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 claims description 8
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
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- 206010008635 Cholestasis Diseases 0.000 claims description 5
- 231100000359 cholestasis Toxicity 0.000 claims description 5
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
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- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
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- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 206010067125 Liver injury Diseases 0.000 claims description 4
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- 206010060862 Prostate cancer Diseases 0.000 claims description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
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Classifications
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Abstract
本发明涉及FXR调节剂及其应用,具体提供了式I所示化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯。
Description
技术领域
本发明涉及医药领域,具体涉及FXR调节剂及其应用。
背景技术
法尼醇X受体(FXR)属于核受体(nuclear receptors,NRs)超家族的一员。核受体超家族由48个配体依赖的转录因子组成,控制特定基因的表达,调节哺乳动物的代谢、发育和繁殖等生理过程,并与多种人类疾病有关,包括炎症、癌症、生殖障碍、代谢综合征、心血管疾病等。NRs超家族的活性可通过结合亲脂性小分子配体来调节,后者进入脂质双分子层调控细胞内外的生理活动。根据配体选择性,NRs超家族通常分为三类:I类、II类和III类。I类为经典的内分泌核受体,由内分泌腺合成的类固醇激素作为它们的配体,包括雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)、雄激素受体(androgen receptor,AR)、糖皮质激素受体(glucocorticoid receptor,GR)和矿物皮质激素受体(mineralocorticoid receptor,MR),这些NRs以同源二聚体的方式与它们的靶DNA序列结合。第II类是尚未发现相应配体的孤儿NRs,它们通常以单体或同源二聚体的形式与DNA结合,如维甲酸相关孤儿受体(retinoid-related orphan receptors,RORs)和神经生长因子IB(nerve growth factor IB,Nurr77)等。第III类为领养的孤儿NRs,即近期发现配体的II类孤儿核受体,包括法尼醇X受体(farnesoid X receptor,FXR)、过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)、肝脏X受体(liverX receptor,LXR)和维甲酸X受体(retinoid X receptor,RXR)等。
1995年,Seol等利用双杂交酵母系统,鉴定出一种可以与RXRα相互作用的新蛋白,并命名为RXR相互作用蛋白14(RXR-interacting protein 14,RIP14)。同年,Forman等从大鼠肝脏cDNA文库中克隆出小鼠RIP14的同源基因,并发现甲戊酸途径的中间体法尼醇(farnesol)能够在超生理浓度下激活大鼠RIP14,因此将RIP14重新命名为FXR。已知FXR有两个基因,分别为FXRα(NR1H4)和FXRβ(NR1H5)。已有的研究表明,FXRα在多种代谢稳态和疾病调节中发挥重要作用。与FXRα不同的是,FXRβ是人类和灵长类的一种假基因,在啮齿动物、兔子和狗中表达,其功能和作用尚不清楚。FXR在肝脏,肠道,肾脏,肾上腺中高度表达,在脂肪组织和心脏中表达较少。四种FXRα亚型均以组织特异性的方式表达,FXRα1和FXRα2主要在人肝脏中表达,FXRα3和FXRα4主要在人肾脏和结肠中表达,而在人小肠中四种亚型均有表达。
FXR的蛋白结构由486个氨基酸组成,全长晶体结构至今尚未被解析,但有多个FXR-LBD(氨基酸序列248-472)与配体结合的共晶结构被解析,为FXR配体的发现和理性药物设计提供了基础。FXR在多种代谢稳态和疾病调节中发挥重要作用,特别是在糖代谢、胆固醇代谢、脂质代谢和胆汁酸代谢中,均有着重要的调控功能。FXR发挥生理功能的机制一部分是由FXR/RXR异二聚体与靶基因启动子中FXR反应元件(FXR-RE)的结合直接介导,其他的则是通过下游信号因子的调节,例如通过核受体SHP、纤维母细胞生长因子15/19(fibroblast growth factor 15/19,FGF15/19)的作用抑制CYP7A1的活性,从而抑制胆汁酸的合成。目前,针对FXR靶点的药物研究集中在代谢性疾病方面。主要包括高脂血症、胆汁淤积症、非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)、糖尿病、心血管疾病和肥胖。除了上述与代谢相关疾病外,FXR对肠病、炎症以及癌症的治疗作用也有相关研究报道。
FXR调控剂包括激动剂和抑制剂(或拮抗剂),其中,激动剂的类型如甾体类(例如初级BAs(CA和CDCA),以及次级BAs(DCA和LCA),INT-767,MFA-1,NIHS1600,TC-100等)和非甾体类(异噁唑衍生物-GW4064,氮杂[4,5-b]吲哚衍生物-WAY-362450,苯并咪唑衍生物,Fexaramine类衍生物,以及邻氨基苯甲酸衍生物等);拮抗剂的类型包括天然产物类FXR拮抗剂(如甾体衍生物、萜类衍生物、Tuberatolide衍生物、白术内酯衍生物、穿心莲内酯衍生物、查尔酮类衍生物、苯酚类衍生物等)和合成类FXR拮抗剂(如异噁唑衍生物,1,3,4-三取代吡唑酮衍生物,2,3,4-三取代吡唑类化合物,吡唑-4-甲酰胺衍生物、苯烷基醚衍生物、3-叔丁基苯甲酸酯/酰胺衍生物、苯并咪唑衍生物、叔丁基苯衍生物、恶二唑衍生物等)。
不过,本领域技术人员仍然渴望一种新型结构的FXR调节剂,用于代谢相关疾病、心血管疾病、肝脏疾病、癌症、肠病、炎症等疾病的研究和治疗。
发明内容
本申请发明人通过深入的研究和创造性的发现,得到了一种新型结构的FXR调节剂,可用于预防和/或治疗代谢相关疾病、心血管疾病、肝脏疾病、癌症、肠病、炎症等疾病。
为此,在本发明的第一方面,提供了式I所示化合物,或该化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
L选自其中,X与苯环相连,Y与R4相连;
X选自
Y选自
R5选自氢、C1-C6烷基;
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn、C3-C10环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环,可选地所述4-7元含氮杂环中的任意一个-CH2-被-O-取代;
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
Rs、Rt各自独立地选自C1-C6烷基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
2)X1选自/>Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
3)X2选自/>Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、
其中,X为且Y为/>时,式I所示的化合物不为以下化合物:
本发明一些实施方式提供了式I所示化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
L选自其中,X与苯环相连,Y与R4相连;
X选自
Y选自
R5选自氢、C1-C6烷基;
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环;
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
Rs、Rt各自独立地选自C1-C6烷基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
2)
X1选自
Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
3)X2选自/>Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、其中,X为/>且Y为/>时,式I所示的化合物不为以下化合物:
/>
在一些实施方案中,L为其中,X与苯环相连,Y与R4相连。
在一些实施方案中,X为/>
在一些实施方案中,Y选自
在一些实施方案中,Y为
在一些实施方案中,R5选自氢、甲基、乙基、正丙基。
在一些实施方案中,R1a选自氢、卤素、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、
在一些实施方案中,R1b选自氢、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成5元杂环,优选地,所述5元杂环含有1-2个(优选2个)杂原子,优选地,所述杂原子选自O、S。
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成或
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Ra、Rb各自独立地选自甲基、乙基、正丙基,或者,Ra、Rb和与它们共同连接的氮原子一起形成
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基、苯基、C1-C6烷基,任选地,所述5元杂芳基、苯基各自独立地被Rc所取代。
在一些实施方案中,R6选自呋喃基、噻吩基、苯基、C1-C6烷基、吡咯基,任选地,所述呋喃基、噻吩基、吡咯基各自独立地被Rc所取代。
在一些实施方案中,R6选自呋喃基、噻吩基、苯基、C1-C6烷基,任选地,所述呋喃基、噻吩基各自独立地被Rc所取代。
在一些实施方案中,R6选自任选地,各自独立地被Rc所取代。
在一些实施方案中,R6选自任选地,/> 各自独立地被Rc所取代。
在一些实施方案中,R6选自
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,Rc选自卤素、硝基、氰基、C1-C6烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基、C1-C6卤代烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基、三氟甲基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基。
在一些实施方案中,Rc选自溴、氯、甲基。
在一些实施方案中,R2选自/>
在一些实施方案中,R2为
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C4烷氧基、C2-C6烯基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>-NRmRn、环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、-O-C(CH3)3,任选地,所述/>各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>-NRmRn,任选地,所述/>各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自/>
环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、/>-O-C(CH3)3。
在一些实施方案中,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、甲基、/> -(CH2)3CH3、-CH=CH2,-C=CH2CH3、-O-C(CH3)3。
在一些实施方案中,R3选自甲基、/>
在一些实施方案中,R3选自
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成5-6元含氮杂环,可选地所述5-6元含氮杂环中的任意一个-CH2-被-O-取代。
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成6元含氮饱和杂环,可选地所述6元含氮杂环中的任意一个-CH2-被-O-取代,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Rm、Rn均为甲基或乙基,或者,Rm、Rn和与它们共同连接的氮原子一起形成
在一些实施方案中,Rm、Rn均为乙基,或者,Rm、Rn和与它们共同连接的氮原子一起形成
在一些实施方案中,Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、三氟甲基、溴。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、三氟甲基。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、
在一些实施方案中,Rx选自氯、溴。
在一些实施方案中,Rs、Rt均为甲基。
在一些实施方案中,R8、R9各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R8选自氢、C1-C6烷基、卤素(优选氯)、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、 />
R8选自氢、甲基、氯、/>且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、
R7、R8、R10、R11为氢。在一些实施方案中,Ru选自氢、C1-C6烷基。
在一些实施方案中,Ru选自氢、甲基、三氟甲基。
在一些实施方案中,Ru选自氢、甲基。
在一些实施方案中,Ry选自氢、C1-C6烷基。
在一些实施方案中,Ry选自氢、三氟甲基。
在一些实施方案中,Ry为氢。
在一些实施方案中,Rv、Rw各自独立地选自氢、C1-C6烷基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基、三氟甲基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基。
在一些实施方案中,作为整体,选自以下:/>
在一些实施方案中,作为整体,选自以下:
在一些实施方案中,X1为
在一些实施方案中,Rz选自甲基、乙酰基。
在一些实施方案中,R12、R13、R14、R15均为氢。
在一些实施方案中,作为整体,选自/>
在一些实施方案中,X2为
在一些实施方案中,X2为
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6卤代烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素。
在一些实施方案中,R16选自氢、卤素、C1-C6卤代烷基,R17、R18为氢。
在一些实施方案中,R16选自氢、卤素,R17、R18为氢。
在一些实施方案中,R16选自氢、氯、三氟甲基,R17、R18为氢。
在一些实施方案中,R16选自氢、氯,R17、R18为氢。
在一些实施方案中,R19选自氢、卤素、C1-C6烷基。
在一些实施方案中,R19选自氢、氯、甲基、三氟甲基。
在一些实施方案中,R19选自氢、氯、甲基。
在一些实施方案中,R20选自羧基、在一些实施方案中,/>作为整体,选自/>/>
在一些实施方案中,作为整体,选自/>
在一些实施方案中,作为整体,选自/>/>
在本发明的第二方面,本发明提供了式I-1所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
X选自
Y选自
R5选自氢、C1-C6烷基;
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环;
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
Rs、Rt各自独立地选自C1-C6烷基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
2)X1选自/>Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
3)X2选自/>Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、且,X为/>且Y为时,式I-1所示的化合物不为以下化合物:/>
/>
/>
/>
在一些实施方案中,L为其中,X与苯环相连,Y与R4相连。
在一些实施方案中,X为
在一些实施方案中,Y选自
在一些实施方案中,Y为
在一些实施方案中,R5选自氢、甲基、乙基、正丙基。
在一些实施方案中,R1a选自氢、卤素、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、
在一些实施方案中,R1b选自氢、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成5元杂环,优选地,所述5元杂环含有1-2个(优选2个)杂原子,优选地,所述杂原子选自O、S。
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成或
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Ra、Rb各自独立地选自甲基、乙基、正丙基,或者,Ra、Rb和与它们共同连接的氮原子一起形成
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基、苯基、C1-C6烷基,任选地,所述5元杂芳基、苯基各自独立地被Rc所取代。
在一些实施方案中,R6选自呋喃基、噻吩基、苯基、C1-C6烷基,任选地,所述呋喃基、噻吩基各自独立地被Rc所取代。
在一些实施方案中,R6选自任选地,/> 各自独立地被Rc所取代。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,Rc选自卤素、硝基、氰基、C1-C6烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基、C1-C6卤代烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基、三氟甲基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基。
在一些实施方案中,R2选自 />
在一些实施方案中,R2为
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>-NRmRn,任选地,所述/>各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>
在一些实施方案中,R3选自
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Rm、Rn均为乙基,或者,Rm、Rn和与它们共同连接的氮原子一起形成
在一些实施方案中,Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、三氟甲基。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、
在一些实施方案中,Rs、Rt均为甲基。
在一些实施方案中,R8、R9各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R8选自氢、C1-C6烷基、卤素(优选氯)、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、
R8选自氢、甲基、氯、/>且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、 />
R7、R8、R10、R11为氢。
在一些实施方案中,Ru选自氢、C1-C6烷基。
在一些实施方案中,Ru选自氢、甲基、三氟甲基。
在一些实施方案中,Ru选自氢、甲基。
在一些实施方案中,Ry选自氢、C1-C6烷基。
在一些实施方案中,Ry选自氢、三氟甲基。
在一些实施方案中,Ry为氢。
在一些实施方案中,Rv、Rw各自独立地选自氢、C1-C6烷基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基、三氟甲基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基。
在一些实施方案中,作为整体,选自以下:
在一些实施方案中,作为整体,选自以下:/>
在一些实施方案中,X1为
在一些实施方案中,Rz选自甲基、乙酰基。
在一些实施方案中,R12、R13、R14、R15均为氢。
在一些实施方案中,作为整体,选自/>
在一些实施方案中,X2为
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6卤代烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素。
在一些实施方案中,R16选自氢、卤素、C1-C6卤代烷基,R17、R18为氢。
在一些实施方案中,R16选自氢、卤素,R17、R18为氢。
在一些实施方案中,R16选自氢、氯、三氟甲基,R17、R18为氢。
在一些实施方案中,R16选自氢、氯,R17、R18为氢。
在一些实施方案中,R19选自氢、卤素、C1-C6烷基。
在一些实施方案中,R19选自氢、氯、甲基、三氟甲基。
在一些实施方案中,R19选自氢、氯、甲基。
在一些实施方案中,R20选自羧基、/>
在一些实施方案中,作为整体,选自/>
在一些实施方案中,作为整体,选自/> />
在本发明的第三方面,本发明提供了式I-1-1所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn、C3-C10环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环;
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
Rs、Rt各自独立地选自C1-C6烷基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
2)
X1选自
Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
3)
X2选自
Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、
R5选自氢、C1-C6烷基。
在本发明一些实施方式提供了式I-1-1所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环;
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
Rs、Rt各自独立地选自C1-C6烷基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
2)
X1选自Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
3)X2选自/>Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、R5选自氢、C1-C6烷基。/>
在一些实施方案中,R1a选自氢、卤素、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、-NRaRb。
在一些实施方案中,R1a选自氢、氯、甲氧基、
在一些实施方案中,R1b选自氢、C1-C6烷氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、-NRaRb。
在一些实施方案中,R1b选自氢、甲氧基、
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成5元杂环,优选地,所述5元杂环含有1-2个(优选2个)杂原子,优选地,所述杂原子选自O、S。
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成
在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Ra、Rb各自独立地选自甲基、乙基、正丙基,或者,Ra、Rb和与它们共同连接的氮原子一起形成
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基、苯基、C1-C6烷基,任选地,所述5元杂芳基、苯基各自独立地被Rc所取代。
在一些实施方案中,R6选自呋喃基、噻吩基、苯基、C1-C6烷基,任选地,所述呋喃基、噻吩基各自独立地被Rc所取代。
在一些实施方案中,R6选自任选地,/> 各自独立地被Rc所取代。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,Rc选自卤素、硝基、氰基、C1-C6烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基、C1-C6卤代烷基。
在一些实施方案中,Rc选自卤素、硝基、C1-C6烷基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基、三氟甲基。
在一些实施方案中,Rc选自溴、氯、硝基、甲基。
在一些实施方案中,R2选自
在一些实施方案中,R2为
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C4烷氧基、C2-C6烯基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>-NRmRn、环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、-O-C(CH3)3,任选地,所述/>各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>-NRmRn,任选地,所述/>各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代。
在一些实施方案中,R3选自甲基、/>
环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3、-CH=CH2、-C=CH2CH3、/>-O-C(CH3)3。
在一些实施方案中,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、/>-O-C(CH3)3。
在一些实施方案中,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、甲基、/> -(CH2)3CH3、-CH=CH2,-C=CH2CH3、-O-C(CH3)3。/>
在一些实施方案中,R3选自甲基、/>
在一些实施方案中,R3选自
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成5-6元含氮杂环。
在一些实施方案中,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子。
在一些实施方案中,Rm、Rn均为乙基,或者,Rm、Rn和与它们共同连接的氮原子一起形成
在一些实施方案中,Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、三氟甲基。
在一些实施方案中,Rx选自氟、氯、甲基、甲氧基、硝基、
在一些实施方案中,Rs、Rt均为甲基。
在一些实施方案中,R8、R9各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,R8选自氢、C1-C6烷基、卤素(优选氯)、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-,且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9选自氢、羧基、
R8选自氢、甲基、氯、/>且R8、R9不同时为氢,R7、R10、R11为氢。
在一些实施方案中,R9选自羧基、
R7、R8、R10、R11为氢。
在一些实施方案中,作为整体,选自以下:
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在一些实施方案中,作为整体,选自以下:
在一些实施方案中,Ru选自氢、C1-C6烷基。
在一些实施方案中,Ru选自氢、甲基、三氟甲基。
在一些实施方案中,Ru选自氢、甲基。
在一些实施方案中,Ry选自氢、C1-C6烷基。
在一些实施方案中,Ry选自氢、三氟甲基。
在一些实施方案中,Ry为氢。
在一些实施方案中,Rv、Rw各自独立地选自氢、C1-C6烷基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基、三氟甲基。
在一些实施方案中,Rv、Rw各自独立地选自氢、甲基、乙基。
在一些实施方案中,X1为
在一些实施方案中,Rz选自甲基、乙酰基。
在一些实施方案中,R12、R13、R14、R15均为氢。
在一些实施方案中,作为整体,选自/>
在一些实施方案中,X2为
在一些实施方案中,X2为
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素、C1-C6卤代烷基。
在一些实施方案中,R16、R17、R18各自独立地选自氢、卤素。
在一些实施方案中,R16选自氢、卤素、C1-C6卤代烷基,R17、R18为氢。
在一些实施方案中,R16选自氢、卤素,R17、R18为氢。
在一些实施方案中,R16选自氢、氯、三氟甲基,R17、R18为氢。
在一些实施方案中,R16选自氢、氯,R17、R18为氢。
在一些实施方案中,R19选自氢、卤素、C1-C6烷基。
在一些实施方案中,R19选自氢、氯、甲基、三氟甲基。
在一些实施方案中,R19选自氢、氯、甲基。
在一些实施方案中,R20选自羧基、
在一些实施方案中,作为整体,选自/>/>
在一些实施方案中,作为整体,选自/>
在一些实施方案中,作为整体,选自/>/>
在一些实施方案中,R5选自氢、甲基、乙基、正丙基。
在一些实施方案中,R5选自甲基、乙基。
在本发明的第四方面,本发明提供了式I-1-2所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a选自氢、卤素;
R1b选自氢、卤素;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基;
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基;
且,式I-1-2所示的化合物不为以下化合物:
在一些实施方案中,R1a选自氢、氯。
在一些实施方案中,R1b为氢。
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基。
在一些实施方案中,R6选自呋喃基、噻吩基。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,R2为
在一些实施方案中,Rx选自氟、氯。
在一些实施方案中,R3选自
在一些实施方案中,R9选自C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9选自R7、R8、R10、R11为氢。
在一些实施方案中,Ru为氢。
在一些实施方案中,R4选自/>
在本发明的第五方面,本发明提供了式I-1-3所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a选自氢、卤素;
R1b选自氢、卤素;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基;
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基;
R5选自氢、C1-C6烷基。
在一些实施方案中,R1a选自卤素。
在一些实施方案中,R1a为氯。
在一些实施方案中,R1b为氢。
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基。
在一些实施方案中,R6选自呋喃基、噻吩基。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,R2为
在一些实施方案中,R3为苯基,所述苯基任选被1个选自Rx的基团所取代。
在一些实施方案中,R3为
在一些实施方案中,Rx为氯。
在一些实施方案中,R8和R9中,任意一个选自C1-C6烷基-C(=O)-N(Ru)-,另一个为氢,R7、R10、R11为氢。
在一些实施方案中,R8和R9中,任意一个为另一个为氢,R7、R10、R11为氢。
在一些实施方案中,Ru为氢。
在一些实施方案中,R4选自
在一些实施方案中,R5选自氢、甲基、乙基。
在本发明的第六方面,本发明提供了式I-1-4所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a选自氢、卤素;
R1b选自氢、卤素;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基;
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基;
R5选自氢、C1-C6烷基。
在一些实施方案中,R1a选自卤素。
在一些实施方案中,R1a为氯。
在一些实施方案中,R1b为氢。
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基。
在一些实施方案中,R6选自呋喃基、噻吩基。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,R2为
在一些实施方案中,R3为苯基,所述苯基任选被1个选自Rx的基团所取代。
在一些实施方案中,R3为
在一些实施方案中,Rx为氯。
在一些实施方案中,R9选自C1-C6烷基-C(=O)-N(Ru)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9为R7、R8、R10、R11为氢。
在一些实施方案中,Ru为氢。
在一些实施方案中,R4为
在一些实施方案中,R5选自氢、乙基。
在本发明的第七方面,本发明提供了式I-2所示的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
R1a选自氢、C1-C6烷氧基;
R1b选自氢、C1-C6烷氧基;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
R6选自5-6元杂芳基;
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
Ru选自氢、C1-C6烷基;
且,式I-2所示的化合物不为以下化合物:
在一些实施方案中,R1a为氢。
在一些实施方案中,R1b选自C1-C6烷氧基。
在一些实施方案中,R1b为甲氧基。
在一些实施方案中,n选自1、2、3。
在一些实施方案中,n选自1、2。
在一些实施方案中,n为1。
在一些实施方案中,R6选自5元杂芳基。
在一些实施方案中,R6选自呋喃基、噻吩基。
在一些实施方案中,R6选自
在一些实施方案中,R6为
在一些实施方案中,R2为
在一些实施方案中,Rx为氯。
在一些实施方案中,R3选自
在一些实施方案中,R9选自C1-C6烷基-C(=O)-N(Ru)-,R7、R8、R10、R11为氢。
在一些实施方案中,R9选自R7、R8、R10、R11为氢。在一些实施方案中,Ru为氢。/>
在一些实施方案中,R4选自在一些实施方案中,前述的化合物选自以下:
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在本发明的第八方面,本发明提供了药物组合物,其包含前述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,以及任选的药学上可以接受的辅料。
本发明的化合物可作为FXR调节剂,用于预防或治疗与FXR相关的疾病。在一些实施方案中,FXR调节剂为激动剂。在一些实施方案中,FXR调节剂为抑制剂(或拮抗剂)。
由此,在本发明的第九方面,本发明提供了前述的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯在制备药物中的用途,或者前述的药物组合物在制备药物中的用途,或者以下式II所示的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯在制备药物中的用途,所述药物用于治疗和/或预防与FXR受体有关的疾病;
其中:
R1’选自氢、卤素、C1-C6烷氧基、-NRa’Rb’;
Ra’、Rb’各自独立地选自氢、C1-C6烷基;
R2’选自-(CH2)n’-R5’;
n'选自0、1、2、3、4、5、6;
R5’选自5-6元杂芳基、苯基、5-6元饱和杂环、C3-C6环烷基、C1-C6烷基、C1-C6烷氧基-C1-C6烷基,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟)的基团所取代;
R3’选自苯基、5-6元杂芳基、C1-C6烷基、-NRc’Rd’,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟、氯)的基团所取代;
Rc’、Rd’各自独立地选自氢、C1-C6烷基、苯基,所述苯基任选地被1个选自C1-C6烷氧基(优选甲氧基)的基团所取代;
R4’选自C1-C6烷基。
在一些实施方案中,R1’选自氢、氯、甲氧基、
在一些实施方案中,Ra’、Rb’各自独立地选自C1-C6烷基。
在一些实施方案中,Ra’、Rb’为乙基。
在一些实施方案中,n'选自0、1、2、3。
在一些实施方案中,n'选自0、1、2。
在一些实施方案中,n'选自0、1。
在一些实施方案中,R5’选自呋喃基、苯基、四氢呋喃基、C3-C6环烷基、C1-C6烷基、C1-C6烷氧基-C1-C6烷基,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟)的基团所取代。
在一些实施方案中,R5’选自
在一些实施方案中,R2’选自
在一些实施方案中,R3’选自苯基、呋喃基、噻吩基、C1-C6烷基、-NRc’Rd’,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟、氯)的基团所取代。
在一些实施方案中,Rc’、Rd’中,任意一个为氢,另一个选自C1-C6烷基、苯基,所述苯基任选地被1个选自C1-C6烷氧基(优选甲氧基)的基团所取代。
在一些实施方案中,Rc’、Rd’中,任意一个为氢,另一个选自
在一些实施方案中,R3’选自
在一些实施方案中,R4’为甲基。
在一些实施方案中,式II所示的化合物选自式II-1、II-2、II-3:
其中,R1’、R2’、R3’、R4’的定义如前所述。
在一些实施方案中,式II所示的化合物选自以下:
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在一些实施方案中,所述与FXR受体有关的疾病选自代谢相关疾病、心血管疾病、肝脏疾病、癌症、肾病、肠病、炎症或其任意组合。
在一些实施方案中,所述代谢相关疾病选自糖脂代谢疾病、胆固醇代谢疾病、脂质代谢疾病、胆汁酸代谢疾病或其任意组合。
在一些实施方案中,所述糖脂代谢疾病选自肥胖症、糖尿病(如2型糖尿病)、血脂异常、高脂血症、高胆固醇、胆汁淤积症、非酒精性脂肪肝、非酒精性脂肪性肝炎或其任意组合。
在一些实施方案中,所述心血管疾病选自动脉粥样硬化、心肌缺血再灌注损伤或其组合。
在一些实施方案中,所述肝脏疾病选自肝切除、肝损伤或其组合。
在一些实施方案中,所述癌症选自乳腺癌、食管癌、肺癌、胰腺癌、肾癌、肝癌、前列腺癌或其任意组合。
在一些实施方案中,所述肾病选自肾炎、肾病综合征、动脉粥样栓塞性肾脏疾病或其任意组合。
在本发明的第十方面,本发明提供了前述的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,或者前述的药物组合物,或者前述第九方面所述的式II所示的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其用于治疗和/或预防与FXR受体有关的疾病。
在一些实施方案中,所述与FXR受体有关的疾病选自代谢相关疾病、心血管疾病、肝脏疾病、癌症、肾病、肠病、炎症或其任意组合。
在一些实施方案中,所述代谢相关疾病选自糖脂代谢疾病、胆固醇代谢疾病、脂质代谢疾病、胆汁酸代谢疾病或其任意组合。
在一些实施方案中,所述糖脂代谢疾病选自肥胖症、糖尿病(如2型糖尿病)、血脂异常、高脂血症、高胆固醇、胆汁淤积症、非酒精性脂肪肝、非酒精性脂肪性肝炎或其任意组合。
在一些实施方案中,所述心血管疾病选自动脉粥样硬化、心肌缺血再灌注损伤或其组合。
在一些实施方案中,所述肝脏疾病选自肝切除、肝损伤或其组合。
在一些实施方案中,所述癌症选自乳腺癌、食管癌、肺癌、胰腺癌、肝癌、肾癌、前列腺癌或其任意组合。
在一些实施方案中,所述肾病选自肾炎、肾病综合征、动脉粥样栓塞性肾脏疾病或其任意组合。
在本发明的第十一方面,本发明提供了治疗和/或预防与FXR受体有关的疾病的方法,其包括:给与受试者有效量的前述的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,或者前述的药物组合物,或者前述第九方面所述的式II所示的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯。
在一些实施方案中,所述与FXR受体有关的疾病选自代谢相关疾病、心血管疾病、肝脏疾病、癌症、肾病、肠病、炎症或其任意组合。
在一些实施方案中,所述代谢相关疾病选自糖脂代谢疾病、胆固醇代谢疾病、脂质代谢疾病、胆汁酸代谢疾病或其任意组合。
在一些实施方案中,所述糖脂代谢疾病选自肥胖症、糖尿病(如2型糖尿病)、血脂异常、高脂血症、高胆固醇、胆汁淤积症、非酒精性脂肪肝、非酒精性脂肪性肝炎或其任意组合。
在一些实施方案中,所述心血管疾病选自动脉粥样硬化、心肌缺血再灌注损伤或其组合。
在一些实施方案中,所述肝脏疾病选自肝切除、肝损伤或其组合。
在一些实施方案中,所述癌症选自乳腺癌、食管癌、肺癌、胰腺癌、肾癌、肝癌、前列腺癌或其任意组合。
在一些实施方案中,所述肾病选自肾炎、肾病综合征、动脉粥样栓塞性肾脏疾病或其任意组合。
具体实施方式
应该理解,此处采用的术语目的在于描述具体的实施方案,并非意在限制。此外,尽管类似或者等价于此处描述的任何方法、装置和材料均可用于实施或者测试本发明,但是现在描述的是优选的方法、装置和材料。
本发明中,除非以其他方式明确指出,在本文中通篇采用的描述方式“…各自独立地选自”既可以是指在不同基团中,相同或不同的符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同或不同的符号之间所表达的具体选项之间互相不影响。
本发明化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
术语“烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如,“C1-C6烷基”是指C1、C2、C3、C4、C5和C6。另外,例如“C1-C6烷基”是指具有1至6个碳原子的烷基,优选“C1-C4烷基”,更优选“C1-C3烷基”。烷基的实例包括但不限于甲基、乙基、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基、叔丁基)、戊基(例如正戊基、异戊基、新戊基)等。
术语“烷氧基”指的是任意上述烷基(例如C1-C6烷基、C1-C4烷基、C1-C3烷基等)通过氧原子(-O-)连接到分子的其余部分。
术语“C1-C6卤代烷基”指的是任意上述烷基(例如C1-C6烷基、C1-C4烷基、C1-C3烷基等)中的一个或多个氢原子被卤素(优选氟、氯)替代得到的基团,例如,单氟甲基、二氟乙基、三氟甲基、等。
术语“C3-C6环烷基”指的是
杂原子指的是N、O或S。
卤素指的是氟、氯、溴或碘。
术语“杂芳基”是指在至少一个环中具有至少一个杂原子(N、O或S)的被取代的和未被取代的芳香族5-元或6-元单环基团、8-元、9-元或10-元二环基团和11-元至14-元三环基团,该含杂原子环任选还具有1个、2个或3个选自N、O或S的杂原子。其中,在至少一个环中具有至少一个杂原子(N、O或S)的被取代的和未被取代的芳香族8-元、9-元或10-元二环基团和11-元至14-元三环基团即为“稠杂芳基”。为二环或三环的杂芳基,需要二环或三环整体结构形成芳香体系。杂芳基可在任一环的任一可用氮或碳原子上连接。且本领域技术人员可以理解,稠环中每两个环之间共用两个相邻的原子(优选碳原子)。
示例性单环杂芳基包括但不限于:吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、恶二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、三氮唑基等。
示例性二环杂芳基包括但不限于:吲哚基、5-氮杂吲哚基、吡咯并[2,3-d]嘧啶基、5,6-二氮杂吲哚基、6-氮杂吲哚基、7-氮杂吲哚基、吡唑并[3,4-b]吡啶基、吡咯并[2,3-c]哒嗪基、噻吩并[2,3-d]咪唑基、噻吩并[2,3-d]咪唑基、吡唑并[3,4-c]吡啶基、苯并噻唑基、苯并咪唑基、苯并噁唑基、苯并噻吩基、喹啉基、异喹啉基、苯并呋喃基、吲嗪基、喹喔啉基、吲唑基、吡咯并嘧啶基、呋喃并吡啶基、异吲哚基等。
术语“杂环”、“杂环的”或“杂环基”可互换使用并且是指被取代的和未被取代的3-元至7-元(优选4-7元、更优选5-6元)单环基团、7-元至11-元二环基团和10-元至15-元三环基团,其中可以包含一个或多个双键,但不构成芳香环;其中至少一个环具有至少一个杂原子(N、O或S)。完成二环和三环基团的稠环可仅含有碳原子且可为饱和或部分饱和,不构成芳香环。杂环基团可在任何可用氮或碳原子上连接。
示例性单环杂环基包括氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂环庚三烯基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、1,3-二氧杂环戊烷基等,优选如
其中,“饱和杂环”指的是上述定义的杂环中不含有不饱和键,如不含有双键,例如,“含氮饱和杂环”可以是
术语“被取代的”是指指定原子或基团上的任一或多个氢被指定基团的选择替代,条件为不超过指定原子的正常价态。
本发明中,“R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代”,其指的是,所述苯基或5-6元杂芳基可以被取代,也可以不被取代。其中,“所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代”,其指的是,所述苯基、5-6元杂芳基各自独立地被1个选自Rx的基团所取代,或者,所述苯基、5-6元杂芳基各自独立地被2个选自Rx的基团所取代。“所述苯基、5-6元杂芳基各自独立地被2个选自Rx的基团所取代”,其中,所述苯基和所述5-6元杂芳基的2个取代基团可以相同,也可以不同,同时,选自Rx的2个基团可以相同,也可以不同。例如,所述苯基、5-6元杂芳基各自独立地被2个选自Rx的基团所取代,且Rx选自氟、氯、甲基、甲氧基、硝基时,所述苯基可以被氟、氯所取代,或者,所述苯基可以被2个氯所取代;所述5-6元杂芳基可以被氟、氯所取代,或者,所述5-6元杂芳基可以被2个氯所取代,或者,所述5-6元杂芳基可以被甲基、甲氧基所取代,或者,所述5-6元杂芳基可以被2个甲基所取代。其余类似的定义可以参照前述内容进行理解。
从所有上述描述中,对本领域技术人员显而易见的是,其名称是复合名称的任意基团,例如“C1-C6烷基-O-C(=O)-C1-C6烷基”或“C1-C6烷氧基-C1-C6烷基”,应该指的是常规地从左向右从其衍生的部分例如从被“C1-C6烷基-O-C(=O)-”取代的“C1-C6烷基”或者从被“C1-C6烷氧基”取代的“C1-C6烷基”来构建,其中“C1-C6烷基”如上文所定义。具体地,“C1-C6烷基-O-C(=O)-C1-C6烷基”例如可以为或者,“C1-C6烷氧基-C1-C6烷基”例如可以为/>其余类似的复合基团可以参照前述内容进行理解。
本发明中,式I所示的结构式可以为/>
本发明中,对于式I所示的结构式如果在一些实施方案中,R1a、R1b和与它们分别相连的碳原子一起,形成/>其指的是,所述杂环/>通过所述虚线双键与式I所示的结构式的母核中的苯环相稠合,即稠合后式I所示的结构式变为/>/>
本发明中,R4选自时,/>表示该氧代基存在或不存在,也就是说,可以为/>
本发明中,“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状,可以是预防性的;和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状;(b)抑制疾病的症状,即阻止其发展;或(c)缓解疾病的症状,即,导致疾病或症状退化。
本发明中,“受试者”指脊椎动物。在某些实施方案中,脊椎动物指哺乳动物。哺乳动物包括,但不限于,牲畜(诸如牛)、宠物(诸如猫、犬、和马)、灵长类动物、小鼠和大鼠。在某些实施方案中,哺乳动物指人。
本发明中,“有效量”指在必需的剂量和时间上有效实现期望的治疗或预防效果的量。本发明的物质/分子的“治疗有效量”可根据诸如个体的疾病状态、年龄、性别和体重及该物质/分子在个体中引发期望应答的能力等因素而变化。治疗有效量还涵盖该物质/分子的治疗有益效果胜过任何有毒或有害后果的量。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然,由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的,因此预防有效量会低于治疗有效量。在癌症的情况中,药物的治疗有效量可减少癌细胞数;缩小肿瘤体积;抑制(即一定程度的减缓,优选停止)癌细胞浸润到周围器官中;抑制(即一定程度的减缓,优选停止)肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻与癌症有关的一种或多种症状。
本发明涉及的药物组合物可以包含药学上可接受的辅料,辅料包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂等等。
本发明所述药物组合物可以根据不同给药途径而制备成各种形式。例如,所述的药物组合物可以以下面的任意方式施用:口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服或静脉内用药方式。
本发明所述的化合物任选地还可与其它一种或多种活性成分联合使用,其各自用量和比例可由本领域技术人员根据具体病症和患者具体情况以及临床需要等而进行调整。
如本文所使用,除非另外说明,术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物,或者它们在它们不反应的形式中不具有或仅具有较低活性。通常可以使用公知的方法制备前药,例如Burger'sMedicinal Chemistry and DrugDiscovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
本文所述的化合物中的立体异构体,当以化学名称特别指定为(R)-或(S)-异构体时,应分别理解为主要构型为(R)-异构体或(S)-异构体。任何不对称碳原子可以存在于(R)-、(S)-或(R、S)-构型中,优选以(R)-或(S)-构型存在。
“溶剂化物”或“溶剂合物”可以互换使用,指的是以与某种溶剂分子的组合存在的化合物。该组合可以包括化学计量的量的某种溶剂,例如一水合物或二水合物,或者可以包括任意量的水;又如,甲醇或乙醇可以形成“醇化物”,其也可以为化学计量的或非化学计量的。在本文中使用的术语“溶剂合物”指的是固体形式,即,在溶剂的溶液中的化合物虽然其可以为溶剂化的,但是它不是如本文中使用的术语的溶剂合物。
如本文中所使用的,术语“药学上可接受的盐”是指,(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐,并且包括但不限于,碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等;无机碱盐,如铵盐;有机碱盐,如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及,(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH2)与适当的无机或者有机阴离子(酸)形成的盐,并且包括但不限于,氢卤酸盐,如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等;无机酸盐,如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对苯磺酸盐等;有机酸盐,如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等;氨基酸盐,如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
如本文中所使用的,术语“药学上可接受的酯”是指,本发明所提供的化合物中存在的-COOH与适当的醇形成的酯,或者本发明所提供的化合物中存在的-OH与适当的酸(例如,羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于,甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下,可以发生水解反应生成相应的酸或醇。
如本文中所使用的,术语“晶型”是指物质的晶体结构。物质在结晶时由于受各种因素影响,使分子内或分子间键合方式发生改变,致使分子或原子在晶格空间排列不同,形成不同的晶体结构。本发明化合物可以一种晶体结构存在,也可以多种晶体结构存在,即具有“多晶型”。本发明化合物可以不同的晶型存在。
下面结合具体实施例对本发明进行进一步的解释说明。如无特殊说明,以下实施例所使用的原料均可以市购获得。
化合物F44-S1~F44-S5、F44-S35~F44-S39、F44-S43~F44-S59和F44-S111~F44-S117的合成路线见方案1.1。首先,邻硝基苯甲醛或取代的邻硝基苯甲醛和取代的胺在甲醇中还原胺化生成中间体M1。中间体M1在二氯甲烷中与取代的酰氯缩合反应生成中间体M2后,硝基还原生成中间体M3。中间体M3与碘甲烷或碘乙烷反应生成中间体M4、M5。中间体M3与取代的酰氯或取代的磺酰氯反应得到化合物F44-S1~F44-S5。中间体M4、M5与取代的酰氯或取代的磺酰氯反应得到化合物M6,F44-S9~F44-S34。中间体M6在强碱体系下水解得到化合物F44-S35~F44-S39、F44-S43~F44-S59和F44-S111~F44-S117。
方案1.1化合物F44-S1~F44-S5、F44-S9~F44-S34、F44-S35~F44-S39、F44-S43~F27-S59和F44-S111~F44-S117。试剂和反应条件:(a)取代的胺,硼氢化钠,甲醇,反应12h,收率:47%;(b)取代的酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:49%;(c)水合肼,10%钯碳,甲醇,反应12h,收率:98%;(d)碘甲烷或碘乙烷或取代的酰氯或取代的磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:12-94%;(e)取代的酰氯或取代的磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:14-94%;(f)氢氧化锂,水/乙醇,升温至回流反应1h,收率:40-94%。
上述R1与前文R1a或R1b表示的基团相同,且步骤e得到产物中的R4为酯基,步骤f得到的产物中的R4为羧酸基。
化合物F44-S6的合成路线见方案1.2。化合物F44-S1在强碱条件下与溴丙烷反应得到化合物F44-S6。
方案1.2化合物F44-S6。试剂和反应条件:(a)氢化钠,N,N-二甲基甲酰胺,溴丙烷,反应12h,收率:38%。
化合物F44-S7、F44-S8的合成路线见方案1.3。中间体M3与N-(4-甲酰基苯基)乙酰胺在甲醇中脱水缩合得到化合物F44-S7。化合物F44-S7在甲醇中还原得到化合物F44-S8。
方案1.3化合物F44-S7、F44-S8。试剂和反应条件:(a)N-(4-甲酰基苯基)乙酰胺,甲醇,回流反应36h,收率:74%;(b)硼氢化钠,甲醇,反应12h,收率:77%。
化合物F44-S40的合成路线见方案1.4。中间体M5与4-硝基苯磺酰氯在无水二氯甲烷中缩合生成中间体M20。中间体M20在甲醇中还原生成中间体M21。
中间体M21与2,2,6-三甲基-4H-1,3-二英-4-酮在四氢呋喃中得到化合物F44-S40。
方案1.4化合物F44-S40。试剂和反应条件:(a)4-乙酰氨基苯磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:33%;(b)硼氢化钠,甲醇,反应12h,收率:76%;(c)2,2,6-三甲基-4H-1,3-二英-4-酮,甲醇钠,四氢呋喃,回流反应48h,收率:21%。
化合物F44-S41、F44-S42的合成路线见方案1.5。化合物F44-S35与N,N'-羰基二咪唑和氨水在四氢呋喃中反应得到化合物F44-S41。化合物F44-S41与4-二甲氨基吡啶、吡啶和乙酰氯在无水二氯甲烷中反应得到化合物F44-S42。
方案1.5化合物F44-S41、F44-S42。试剂和反应条件:(a)N,N'-羰基二咪唑,氨水,四氢呋喃,反应36h,收率:96%;(b)4-二甲氨基吡啶,吡啶,乙酰氯,无水二氯甲烷,反应12h,收率:36%。
化合物F44-S60~F44-S68的合成路线见方案2.1。取代的邻/间羟基苯甲醛与呋喃甲胺在甲醛中还原胺化生成中间体M8。中间体M8与取代的苯甲酰氯在无水二氯甲烷中反应生成中间体M9。中间体M9与取代的苯磺酰氯在无水二氯甲烷中反应得到F44-S60~F44-S68。
方案2.1化合物F44-S60~F44-S68。试剂和反应条件:(a)呋喃甲胺,硼氢化钠,甲醇,反应12h,收率:61%;(b)取代的苯甲酰氯,吡啶,三乙胺,无水二氯甲烷,反应3h,收率:29%;(c)取代的苯磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:41-92%。
化合物F44-S69’~F44-S110’的合成路线见方案3.1。2-氨基-5-氯苯腈在无水四氢呋喃中还原生成中间体M10。中间体M10与二碳酸二叔丁酯在无水二氯甲烷中反应生成中间体M11。中间体M11与碘乙烷在乙腈中反应生成中间体M12。中间体M12与5-(氯磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯在二氯甲烷中缩合生成中间体M13后,与三氟乙酸在二氯甲烷中生成中间体M14。中间体M14与取代的醛在甲醇中还原胺化生成中间体M15后,与与取代的酰氯或磺酰氯和碳酸钾在无水二氯甲烷中反应生成中间体M6。中间体M6在强碱体系下水解得到化合物F44-S69’~F44-S99’、F44-S100~F44-S110。
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方案3.1化合物F44-S69’~F44-S99’、F44-S100~F44-S110。试剂和反应条件:(a)四氢铝锂,无水四氢呋喃,升温至回流反应4h,收率:81%;(b)二碳酸二叔丁酯,三乙胺,无水二氯甲烷,反应12h,收率:90%;(c)碘乙烷,碳酸钾,乙腈,70℃反应12h,收率:44%;(d)5-(氯磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,碳酸钾,无水二氯甲烷,反应12h,收率:76%;(e)三氟乙酸,二氯甲烷,反应12h,收率:99%;(f)取代的醛,硼氢化钠,甲醇,反应12h,收率:14-70%;(g)取代的酰氯或磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:35-99%;(h)氢氧化锂,水/乙醇,升温至回流反应1h,收率:40-94%。
化合物F44-S118~F44-S124的合成路线见方案4.1。中间体M1与环丙基甲酰氯在二氯甲烷中生成中间体M17后,在甲醇中还原反应生成中间体M18。中间体M18与碘乙烷在乙腈中反应生成中间体M19。中间体M19与取代的磺酰氯在无水二氯甲烷中缩合生成中间体M6。中间体M6在强碱体系下水解得到化合物F44-S118~F44-S124。
方案4.1化合物F44-S118~F44-S124。试剂和反应条件:(a)环丙基甲酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:95%;(b)水合肼,10%钯碳,甲醇,反应12h,收率:88%;(c)碘乙烷,碳酸钾,无水二氯甲烷,反应12h,收率:79%;(d)取代的磺酰氯,碳酸钾,无水二氯甲烷,反应12h,收率:16-51%;(f)氢氧化锂,水/乙醇,升温至回流反应1h,收率:78-94%。
步骤f得到产物中的R4为酯基,步骤g得到的产物中的R4为羧酸基。
实施例1
N-(5-氯-2-硝基苄基)-1-(呋喃-2-基)甲胺(M1)
将5-氯-2-硝基苯甲醛(1.86g,10mmol),2-呋喃甲胺(1.16g,12mmol),加入甲醇(20mL)中室温搅拌4h,在冰浴条件下缓慢加入硼氢化钠(0.57g,15mmol)室温反应过夜,TLC检测反应完毕后,加水猝灭反应,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=9/1~6/1)得淡黄色液体2.50g,收率47%。1H NMR(400MHz,Chloroform-d)δ7.92(d,J=8.7Hz,1H),7.69(d,J=2.2Hz,1H),7.39–7.32(m,2H),6.30(dd,J=3.2,1.9Hz,1H),6.18(d,J=3.2Hz,1H),4.05(s,2H),3.81(s,2H).13C NMR(101MHz,Chloroform-d)δ153.2,147.2,142.2,139.9,137.9,131.0,128.1,126.4,110.3,107.5,49.5,45.8.
实施例2
2-氯-N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M2)
将N-(5-氯-2-硝基苄基)-1-(呋喃-2-基)甲胺(2.54g,9.5mmol),碳酸钾(1.57g,11.4mmol)加入无水二氯甲烷(20mL)中,冰浴条件下缓慢滴加邻氯苯甲酰氯(1.66g,9.5mmol),室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=15/1~3/1)得淡黄色液体1.88g,收率49%。1H NMR(400MHz,Chloroform-d)δ8.28–6.77(m,8H),6.48–5.76(m,2H),5.62–3.86(m,4H).13C NMR(101MHz,Chloroform-d)δ169.1,148.3,146.4,143.1,142.6,140.4,134.9,134.6,130.7,130.3,130.0,129.8,128.9,128.5,128.4,128.0,127.3,127.1,126.8,126.5,110.5,109.7,49.0,46.0,45.8,41.7.
实施例3
N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(M3)
将2-氯-N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)苯甲酰胺(1.62g,4mmol),水合肼(0.40g,8mmol),10%钯碳(0.10g,0.4mmol)加入甲醇(20mL)中加热至50℃反应过夜,在冰浴条件下缓慢滴加邻氯苯甲酰氯(1.66g,9.5mmol),室温反应过夜,TLC检测反应完毕后,用硅藻土过滤后减压蒸馏除去滤液,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/1)得淡黄色固体1.47g,收率98%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=8.7Hz,1H),7.67(d,J=1.6Hz,1H),7.54–7.43(m,2H),7.43–7.31(m,4H),7.31–7.14(m,2H),6.26–6.14(m,1H),6.05(d,J=3.1Hz,1H),5.40(d,J=17.3Hz,1H),4.83(d,J=17.5Hz,1H),4.44(d,J=15.9Hz,1H),4.24(d,J=15.9Hz,1H).13C NMR(101MHz,Chloroform-d)δ169.0,149.1,148.3,146.3,143.0,142.6,140.4,140.3,134.9,134.6,134.6,130.7,130.6,130.3,130.2,129.9,129.7,128.8,128.5,128.5,128.3,128.0,127.3,127.2,127.0,126.8,126.5,110.6,110.4,109.7,49.0,46.0,45.7,41.6.
实施例4
N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)
将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(188mg,0.5mmol),4-乙酰氨基苯磺酰氯(117mg,0.5mmol),碳酸钾(138mg,1mmol)加入无水二氯甲烷(2mL)中室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=1/2)得淡黄色固体34mg,收率12%。1H NMR(400MHz,Chloroform-d)δ9.43(s,1H),8.05(s,1H),7.62(d,J=8.5Hz,2H),7.46(dd,J=29.5,8.6Hz,3H),7.29(d,J=15.2Hz,5H),7.20(s,1H),7.04–6.96(m,1H),6.26(s,1H),6.14–6.02(m,1H),4.50(d,J=14.5Hz,1H),4.30–4.11(m,2H),3.93(d,J=14.9Hz,1H),2.05(s,3H).13C NMR(101MHz,Chloroform-d)δ171.4,170.3,148.1,143.5,142.5,135.2,134.3,131.6,131.1,130.6,130.1,129.9,129.8,129.0,128.4,128.0,127.4,124.9,119.3,110.8,110.1,60.6,44.7,44.3,29.8,29.4,24.7,21.2,14.3.HRMS(ESI)[M+H]+calcd for C27H24Cl2N3O5S:572.0814;found:572.0823.
实施例5
N-(2-(4-乙酰氨基苯甲酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S2)
将4-乙酰氨基苯磺酰氯(198mg,1.1mmol),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(209mg,1.1mmol),1-羟基苯并三唑(149mg,1.1mmol),4-二甲氨基吡啶(6mg,0.05mmol)加入无水二氯甲烷(1mL)中室温搅拌2h,滴加N,N-二异丙基乙胺(210mg,1.5mmol),然后加入N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(187mg,0.5mmol)的二氯甲烷(1mL)溶液,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=1/2)得淡黄色固体172mg,收率64%。1H NMR(400MHz,Chloroform-d)δ10.84–10.04(m,1H),8.72(d,J=20.6Hz,1H),8.29–7.83(m,3H),7.61–7.23(m,8H),7.21–7.08(m,1H),6.49–6.09(m,2H),5.23–4.18(m,4H),1.97(dd,J=11.3,3.9Hz,3H).13C NMR(101MHz,CDCl3)δ169.5,169.4,169.2,166.6,166.4,148.5,148.3,143.3,143.2,141.9,141.7,137.1,135.8,134.6,134.5,131.3,130.9,130.8,130.4,129.8,129.7,129.7,129.5,1293,129.1,128.9,128.8,128.6,128.6,128.5,127.9,127.3,127.2,126.6,126.1,124.8,124.6,119.0,110.7,110.6,110.0,109.8,45.0,44.6,44.2,44.1,24.3.HRMS(ESI)[M+H]+calcd forC28H24Cl2N3O4:536.1144;found:536.1148.
实施例6
N-(2-((4-乙酰氨基苯基)磺酰胺基)苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺(F44-S3)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为N-(2-氨基苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得无色液体48mg,收率22%。1H NMR(400MHz,Chloroform-d)δ9.63(d,J=8.8Hz,1H),8.46(d,J=7.1Hz,1H),7.74–7.62(m,2H),7.55(dt,J=17.0,8.9Hz,3H),7.38(s,3H),7.31–7.24(m,1H),7.23–7.02(m,4H),6.42–6.06(m,2H),4.47–4.16(m,4H),2.10(s,3H).13C NMR(101MHz,CDCl3)δ169.5,168.6,158.3(d,J=247.2Hz,1C),148.3,143.3,142.6,136.5,134.2,132.0(d,J=9.2Hz,1C),131.1,129.8,128.9,128.7(d,J=2.5Hz,1C),128.3,126.7,124.8(d,J=4.3Hz,1C),123.0(d,J=17.4Hz,1C),122.8,119.3,116.2(d,J=20.9Hz,1C),110.7,109.9,44.8,44.7,24.6.19F NMR(376MHz,CDCl3)δ-114.4,-114.5.HRMS(ESI)[M+H]+calcdfor C27H25N3O5FS:522.1499;found:522.1501.
实施例7
N-(2-((4-丁酰氨基苯基)磺酰氨基)苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺(F44-S4)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为N-(2-氨基苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得无色液体60mg,收率27%。1H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.22(s,1H),7.68(d,J=8.7Hz,2H),7.59(d,J=8.7Hz,2H),7.53(d,J=8.3Hz,1H),7.38(s,3H),7.31–7.24(m,1H),7.19(t,J=7.5Hz,1H),7.16–6.99(m,3H),6.45–6.26(m,1H),6.18(d,J=2.9Hz,1H),4.32(d,J=29.0Hz,4H),2.30(t,J=7.4Hz,2H),1.67(q,J=7.4Hz,2H),0.91(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.4,168.6,158.3(d,J=247.1Hz,1C),148.4,143.3,142.6,136.5,134.2,132.0(d,J=5.6Hz,1C),129.8,128.7(d,J=2.5Hz,1C),128.3,126.7,124.7,123.0(d,J=17.4Hz,1C),122.7,119.3,116.2(d,J=20.8Hz,1C),110.7,109.9,44.8,44.7,39.5,18.9,13.8.19F NMR(376MHz,CDCl3)δ-114.4,-114.5.HRMS(ESI)[M+H]+calcd for C29H29N3O5FS:550.1812;found:550.1816.
实施例8
N-(2-((4-丁酰氨基苯基)磺酰氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S5)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体37mg,收率26%。1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),7.93(s,1H),7.65–7.49(m,4H),7.41(d,J=8.7Hz,1H),7.34–7.22(m,5H),7.18(d,J=10.1Hz,1H),7.00(d,J=2.3Hz,1H),6.25(dd,J=3.2,1.9Hz,1H),6.09(d,J=3.2Hz,1H),4.51(d,J=14.7Hz,1H),4.28–4.07(m,2H),3.94(d,J=14.8Hz,1H),2.22(t,J=7.4Hz,2H),1.61(h,J=7.4Hz,2H),0.86(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.2,170.2,148.1,143.5,142.6,135.2,134.3,134.2,131.6,131.1,130.6,130.1,129.9,129.7,129.0,128.4,128.0,127.4,124.9,119.4,110.8,110.1,44.7,44.3,39.6,18.9,13.8.HRMS(ESI)[M+H]+calcd for C29H28Cl2N3O5S:600.1133;found:600.1127.
实施例9
N-(2-((4-乙酰氨基-N-丙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S6)
将N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)(114mg,0.2mmol),氢化钠(10mg,0.2mmol)在冰浴条件下加入N,N-二甲基甲酰胺(2mL)中,0℃搅拌1h,加入溴丙烷(37mg,0.3mmol)室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/2)得淡黄色固体69mg,收率38%。1H NMR(400MHz,Chloroform-d)δ9.77(d,J=9.3Hz,1H),7.91(d,J=8.3Hz,2H),7.55(d,J=8.7Hz,1H),7.43–7.28(m,7H),7.24(s,1H),7.09(d,J=2.1Hz,1H),6.38–6.31(m,1H),6.18(d,J=3.0Hz,1H),4.57(d,J=14.6Hz,1H),4.34–4.14(m,2H),3.91(d,J=14.6Hz,1H),3.68–3.60(m,2H),1.81(s,3H),1.48(dt,J=14.9,7.4Hz,2H),0.85(d,J=7.4Hz,3H).13C NMR(101MHz,Chloroform-d)δ170.1,169.5,148.0,147.1,143.4,135.1,134.1,131.5,131.0,130.5,130.0,129.8,129.8,128.7,128.6,128.6,127.9,127.3,124.6,110.7,110.0,50.8,44.6,44.0,35.9,31.9,29.7,29.3,27.2,25.5,22.9,22.7,21.1,14.1,11.2.HRMS(ESI)[M+H]+calcd for C30H30N3O5SCl2:614.1283;found:614.1274.
实施例10
(E)-N-(2-((4-乙酰氨基亚苄基)氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S7)
将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(187mg,0.5mmol),N-(4-甲酰基苯基)乙酰胺(82mg,0.5mmol)加入甲醇(1.5mL)中回流反应36h,TLC检测反应完毕后,冷却至室温析出白色固体,抽滤,滤渣用甲醇洗三次,干燥后得白色固体193mg,收率74%。1H NMR(400MHz,Chloroform-d)δ9.17(d,J=23.6Hz,1H),8.19(d,J=38.1Hz,1H),7.87–7.39(m,6H),7.38–7.00(m,5H),6.88(dd,J=36.2,8.5Hz,1H),6.50–5.84(m,2H),5.08(dd,J=73.3,15.3Hz,1H),4.89–3.97(m,3H),2.05(d,J=11.7Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.5,169.4,169.3,159.9,159.6,150.0,149.1,148.8,148.7,142.8,142.3,142.1,141.9,135.4,135.3,132.3,131.8,131.5,131.3,131.2,131.1,130.7,130.5,130.4,130.4,129.9,129.8,128.9,128.4,128.3,128.2,128.0,127.8,127.2,127.1,119.5,119.3,118.9,110.5,110.4,109.4,109.0,47.6,45.5,43.7,41.5,24.4.HRMS(ESI)[M+H]+calcd for C28H24N3O3Cl2:520.1195;found:520.1190.
实施例11
N-(2-((4-乙酰氨基苄基)氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S8)
将(E)-N-(2-((4-乙酰氨基亚苄基)氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(156mg,0.3mmol)加入甲醇(1.5mL)中,冰浴条件下缓慢加入硼氢化钠(15mg,0.4mmol),室温反应过夜,TLC检测反应完毕后,加水猝灭反应,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/1~1/1)得白色固体121mg,收率77%。1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),7.39(tt,J=20.0,12.4Hz,7H),7.20(d,J=7.7Hz,2H),7.09(d,J=5.7Hz,2H),6.47(d,J=8.6Hz,1H),6.33(s,1H),6.13(s,1H),5.91(s,1H),5.13(d,J=14.6Hz,1H),4.44–4.07(m,5H),2.00(d,J=25.4Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.3,169.0,148.7,145.7,143.1,137.4,135.0,134.4,131.6,130.7,130.4,129.8,129.5,128.1,127.6,127.2,120.1,119.9,111.9,110.6,109.7,47.5,44.3,43.6,24.2.HRMS(ESI)[M+H]+calcd for C28H26N3O3Cl2:522.1351;found:522.1345.
实施例12
2-氯-N-(5-氯-2-(甲基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M4)
将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(374mg,1mmol),多聚甲醛(150mg,5mmol),甲醇钠(270mg,5mmol)加入甲醇(2mL)中升温至回流搅拌4h,降温至室温,在冰浴条件下缓慢加入硼氢化钠(190mg,5mmol)升温至回流反应1h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=6/1)得白色固体2.50g,收率78%。1HNMR(400MHz,Chloroform-d)δ7.29(ddt,J=9.4,6.5,3.6Hz,3H),7.22(dd,J=5.9,3.5Hz,2H),7.09(dd,J=8.7,2.5Hz,1H),6.93(d,J=2.4Hz,1H),6.42(d,J=8.7Hz,1H),6.23(dd,J=3.0,1.9Hz,1H),6.02(d,J=3.3Hz,1H),5.35(s,1H),5.08(d,J=14.7Hz,1H),4.02(t,J=13.4Hz,2H),3.94(d,J=14.7Hz,1H),2.74(s,3H).13CNMR(101MHz,Chloroform-d)δ169.1,148.9,146.9,143.0,135.2,131.5,130.5,130.4,129.7,129.5,128.1,127.1,119.6,119.4,110.5,110.4,109.5,44.0,43.4,30.4.
实施例13
N-(2-((4-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S9)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-氯-2-(甲基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体255mg,收率88%。1H NMR(400MHz,Chloroform-d)δ9.48–8.78(m,1H),7.66(dd,J=30.0,8.3Hz,2H),7.49(d,J=13.3Hz,3H),7.44–7.31(m,4H),7.24(d,J=39.2Hz,1H),7.04(d,J=8.0Hz,1H),6.44–6.04(m,3H),5.61–4.12(m,4H),3.04(s,3H),2.09–1.95(m,3H).13C NMR(101MHz,Chloroform-d)δ169.8,169.7,169.6,149.8,148.6,148.5,143.4,143.2,143.0,142.6,138.8,138.8,138.4,135.2,134.6,134.5,130.9,130.3,129.9,129.7,129.3,129.2,128.5,128.4,128.3,128.0,127.8,127.5,127.3,119.3,119.1,110.7,110.6,110.0,109.8,109.4,46.4,45.5,45.1,44.5,39.0,29.7,24.5,24.4,24.2.HRMS(ESI)[M+H]+calcd for C28H26Cl2N3O5S:586.0970;found:586.0979.
实施例14
N-(2-((3-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S10)
按照N-(2-((4-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S9)所用方法,将4-乙酰氨基苯磺酰氯替换为3-乙酰氨基苯磺酰氯,其余条件均一致。得白色固体260mg,收率89%。1H NMR(400MHz,Chloroform-d)δ9.02(d,J=13.2Hz,1H),8.03–7.63(m,2H),7.59–6.96(m,9H),6.74–5.89(m,3H),5.57–4.00(m,4H),3.10(s,3H),2.03(d,J=12.3Hz,3H).13CNMR(101MHz,Chloroform-d)δ169.5,149.7,148.7,143.0,142.9,142.5,139.5,139.4,139.3,139.1,138.4,138.1,136.2,135.1,134.6,130.7,130.6,130.4,130.3,129.9,129.8,129.5,129.4,128.6,128.4,127.9,127.6,127.4,127.3,124.4,124.3,123.1,123.0,119.0,110.6,110.5,109.8,109.6,109.4,46.2,45.5,44.7,44.3,39.3,39.1,29.7,29.3,29.3,29.1,27.2,24.2,24.2.HRMS(ESI)[M+H]+calcd for C28H26N3O5SCl2:586.0970;found:586.0969.
实施例15
N-(2-(4-乙酰氨基-N-甲基苯甲酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S11)
按照N-(2-((4-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S9)所用方法,将4-乙酰氨基苯磺酰氯替换为4-乙酰氨基苯甲酰氯,其余条件均一致。得淡黄色固体142mg,收率52%。1H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.79–6.69(m,12H),6.40–5.80(m,2H),5.44–4.71(m,1H),4.23(dt,J=84.5,15.5Hz,3H),3.55–2.80(m,3H),2.11–1.79(m,3H).13CNMR(101MHz,CDCl3)δ170.2,169.3,148.4,143.2,143.1,140.7,134.8,133.9,130.8,130.7,130.2,130.0,129.9,129.4,128.9,128.7,128.2,127.9,127.3,118.3,110.7,110.6,109.7,109.5,45.4,43.6,38.1,24.3,24.2.HRMS(ESI)[M+H]+calcd for C29H26Cl2N3O4:550.1300;found:550.1298.
实施例16
N-(2-(3-乙酰氨基-N-甲基苯甲酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S12)
按照N-(2-((4-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S9)所用方法,将4-乙酰氨基苯磺酰氯替换为3-乙酰氨基苯甲酰氯,其余条件均一致。得淡黄色固体158mg,收率58%。1H NMR(400MHz,Chloroform-d)δ9.08–8.51(m,1H),8.19–7.64(m,1H),7.62–6.89(m,10H),6.90–6.53(m,1H),6.49–5.93(m,2H),5.51–4.75(m,1H),4.62(td,J=20.6,18.3,12.1Hz,1H),4.53–4.15(m,2H),3.27(d,J=19.7Hz,3H),2.13–1.73(m,3H).13C NMR(101MHz,Chloroform-d)δ171.4,169.2,169.0,148.5,143.4,141.5,138.6,134.8,134.6,133.7,131.0,130.3,130.0,129.1,128.8,128.3,128.2,128.1,128.1,127.3,126.8,123.1,120.7,119.2,110.7,109.9,109.7,109.5,47.5,47.3,46.1,45.7,37.4,37.1,24.1.HRMS(ESI)[M+H]+calcd for C29H26Cl2N3O4:550.1300;found:550.1306.
实施例17
N-(2-((4-乙酰氨基-N-甲基苯基)磺酰胺)-5-氯苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺(F44-S13)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为N-(5-氯-2-(甲基氨基)苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体129mg,收率57%。1H NMR(400MHz,Chloroform-d)δ9.33–8.82(m,1H),7.58(dd,J=23.5,8.5Hz,2H),7.50–7.32(m,3H),7.32–7.15(m,4H),7.10(t,J=8.7Hz,1H),7.00–6.91(m,1H),6.49–5.99(m,3H),5.42–4.12(m,4H),3.04–2.62(m,3H),1.96(d,J=17.6Hz,3H).13C NMR(101MHz,CDCl3)δ169.8,169.6,168.1,168.0,158.2(d,J=245.9Hz,1C),150.0,149.8,148.9,148.6,143.4,143.1,142.6,139.2,139.1,138.6,138.4,134.6,131.8(d,J=8.1Hz,1C),130.0,129.3,129.2,128.8(d,J=3.0Hz,1C),128.4,128.4,128.3,128.2,127.9,127.5,124.9(d,J=3.1Hz,1C),124.6(d,J=3.0Hz,1C),123.8(d,J=17.5Hz,1C),119.2,119.1,116.1(d,J=20.8Hz,1C),110.6,110.5,109.8,109.5,109.2,108.9,48.6,46.2,44.9,41.9,39.1,39.0,38.9,24.4,24.3.19F NMR(376MHz,CDCl3)δ-114.4,-114.5,-115.1.HRMS(ESI)[M-H]-calcd for C28H24N3O5FSCl:568.1109;found:568.1120.
实施例18
N-(2-((4-丁酰胺基-N-甲基苯基)磺酰胺基)-5-氯苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺(F44-S14)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为N-(5-氯-2-(甲基氨基)苄基)-2-氟-N-(呋喃-2-基甲基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得淡黄色液体125mg,收率52%。1HNMR(400MHz,Chloroform-d)δ9.24–8.64(m,1H),7.82–7.62(m,2H),7.60–7.41(m,3H),7.41–7.24(m,4H),7.23–7.17(m,1H),7.09–7.00(m,1H),6.60–5.99(m,3H),5.64–4.20(m,4H),3.13–2.77(m,3H),2.24(dt,J=23.1,7.3Hz,2H),1.65(dp,J=13.9,6.8Hz,2H),0.89(dt,J=20.4,7.4Hz,3H).13C NMR(101MHz,CDCl3)δ172.7,172.5,168.0,167.9,158.2(d,J=245.8Hz,1C),149.8,148.9,148.6,143.4,143.3,143.1,143.0,142.9,142.5,142.4,140.2,139.2,139.0,138.6,138.4,134.6,134.5,131.7(d,J=7.8Hz,1C),129.9,129.3,129.2,128.8,128.8,128.6,128.4,128.2,127.9,127.5,127.4,124.9(d,J=2.9Hz,1C),123.9(d,J=17.7Hz,1C),119.2,119.0,116.1(d,J=20.8Hz,1C),110.6,110.5,109.7,109.5,109.2,108.8,48.6,46.1,44.9,41.9,39.2,39.0,18.8,13.7,13.6.19F NMR(376MHz,CDCl3)δ-114.4,-115.0.HRMS(ESI)[M-H]-calcd for C30H28N3O5FSCl:596.1422;found:596.1431.
实施例19
N-(2-((4-丁酰氨基-N-甲基苯基)磺酰氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S15)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S9)所用方法,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体169mg,收率92%。1H NMR(400MHz,Chloroform-d)δ9.48–8.57(m,1H),7.70(dd,J=34.8,8.4Hz,2H),7.55–7.17(m,8H),7.05(d,J=8.2Hz,1H),6.53–6.00(m,3H),5.68–4.04(m,4H),3.04(s,3H),2.35–2.08(m,2H),1.71–1.54(m,2H),0.95–0.76(m,3H).13C NMR(101MHz,CDCl3)δ172.9,172.5,169.6,169.6,149.8,148.5,143.5,143.4,143.2,143.0,142.6,139.3,138.8,138.4,135.2,134.6,134.5,130.9,130.6,130.3,130.2,129.9,129.6,129.3,129.2,128.4,128.3,128.2,128.0,127.8,127.5,127.3,119.3,119.1,110.7,110.6,110.0,109.8,109.4,46.4,45.5,45.1,44.5,39.4,39.3,39.0,18.9,18.8,13.8,13.7.HRMS(ESI)[M+H]+calcd for C30H30Cl2N3O5S:614.1283;found:614.1287.
实施例20
2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M5)
将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(374mg,1mmol),碘乙烷(156mg,5mmol),碳酸钾(690mg,5mmol)加入乙腈(2mL)中升温至回流反应过夜,TLC检测反应完毕后,降温至室温,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=8/1)得淡黄色固体380mg,收率94%。1H NMR(400MHz,Chloroform-d)δ7.49–7.37(m,3H),7.37–7.18(m,3H),7.17–7.02(m,1H),6.62(dd,J=43.9,8.3Hz,1H),6.42–6.31(m,1H),6.15(d,J=3.2Hz,1H),5.58–5.31(m,1H),5.19(dd,J=18.2,14.6Hz,1H),4.30–4.09(m,3H),3.34–3.08(m,2H),1.37(q,J=7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.0,168.9,149.3,149.0,147.6,146.2,143.0,142.9,135.6,135.4,132.4,131.7,130.5,130.5,130.4,130.4,129.9,129.8,129.7,129.5,128.2,128.1,127.2,127.1,119.6,119.3,118.1,115.1,110.9,110.5,110.5,109.8,109.5,109.3,44.5,44.0,43.4,43.2,38.4,38.2,14.5,14.3.
实施例21
N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,温度升温至回流,其余条件均一致。得淡黄色固体149mg,收率50%。1H NMR(400MHz,Chloroform-d)δ9.67–9.22(m,1H),7.77–7.61(m,2H),7.58–7.32(m,7H),7.30–6.99(m,2H),6.66–5.96(m,3H),5.78–4.03(m,4H),3.86(dt,J=14.4,7.2Hz,1H),3.30–2.73(m,1H),2.08–1.89(m,3H),1.09–0.54(m,3H).13C NMR(101MHz,CDCl3)δ169.9,169.8,169.7,149.5,148.6,148.5,143.4,143.4,143.1,142.8,142.5,140.5,140.1,136.2,136.0,135.0,134.8,134.7,134.6,131.2,130.9,130.8,130.6,130.5,130.2,130.2,130.1,129.8,129.0,129.0,128.6,128.5,128.4,128.1,128.1,127.8,127.7,127.6,127.4,127.3,127.3,127.1,119.2,119.2,119.0,110.6,110.5,110.0,109.4,46.7,46.4,46.2,45.6,45.3,45.1,24.3,24.2,24.1,13.5,13.4,12.8.HRMS(ESI)[M+H]+calcd for C29H28N3O5SCl2:600.1127;found:600.1121.
实施例22
N-(2-(4-乙酰氨基-N-乙基苯甲酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S17)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-乙酰氨基苯甲酰氯,其余条件均一致。得淡黄色固体65mg,收率15%。1H NMR(400MHz,Chloroform-d)δ8.39(d,J=55.7Hz,1H),7.66–6.97(m,12H),6.48–5.81(m,2H),5.42–4.74(m,1H),4.51–3.72(m,4H),3.70–3.39(m,1H),2.14–1.91(m,3H),1.26(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ171.3,169.4,169.2,149.3,148.6,143.2,140.2,134.2,134.0,130.9,130.7,130.3,129.9,129.5,128.4,128.3,127.5,127.3,118.3,110.7,110.6,109.4,60.5,45.6,44.2,24.4,21.1,14.3,12.8.HRMS(ESI)[M+H]+calcd for C30H28Cl2N3O4:564.1457;found:564.1458.
实施例23
N-(2-((4-乙酰氨基苄基)(乙基)氨基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S18)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为N-(4-溴甲基苯基)乙酰胺,其余条件均一致。得白色固体129mg,收率47%。1H NMR(400MHz,Chloroform-d)δ8.85(d,J=7.9Hz,1H),7.58–7.25(m,7H),7.23–7.11(m,2H),7.10–6.84(m,3H),6.62–5.79(m,2H),5.42–4.49(m,2H),4.48–4.01(m,2H),3.79(dd,J=92.5,8.3Hz,2H),2.75(dq,J=73.3,6.1,5.0Hz,2H),2.02(s,3H),0.81(dt,J=79.2,7.0Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.5,169.4,169.2,169.2,149.8,149.0,148.2,147.8,142.9,142.4,137.7,137.6,135.3,135.2,135.1,134.2,133.4,132.9,130.6,130.4,130.3,130.3,129.9,129.8,129.7,129.6,129.0,128.9,128.3,127.8,127.5,127.5,127.4,127.2,127.0,126.7,124.9,124.1,119.8,119.6,110.6,110.4,109.2,109.0,58.4,58.2,47.6,47.4,46.8,45.0,42.9,41.5,29.6,24.2,11.9,11.8.HRMS(ESI)[M+H]+calcd forC30H30N3O3Cl2:550.1664;found:550.1661.
实施例24
N-(2-((3-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S19)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为3-乙酰氨基苯磺酰氯,其余条件均一致。得白色固体101mg,收率56%。1H NMR(400MHz,Chloroform-d)δ9.45–8.81(m,1H),8.14–7.49(m,3H),7.49–7.29(m,5H),7.25–6.98(m,3H),6.62–5.88(m,3H),5.66–4.04(m,4H),3.99–3.45(m,1H),3.34–2.58(m,1H),2.10–1.73(m,3H),1.16–0.62(m,3H).13CNMR(101MHz,Chloroform-d)δ169.6,169.6,149.9,149.6,148.9,148.8,142.9,142.8,142.4,139.5,139.5,135.8,135.2,134.8,130.6,130.2,129.9,129.8,129.7,129.4,129.4,129.2,128.8,128.7,127.8,127.4,127.3,127.2,124.3,124.2,123.1,122.9,122.8,118.8,118.8,110.6,110.5,110.5,110.5,109.9,109.3,47.1,46.9,46.7,46.0,45.7,45.0,29.7,29.3,24.2,24.1,13.5,12.8.HRMS(ESI)[M+H]+calcd for C29H28N3O5SCl2:600.1127;found:600.1125.
实施例25
2-氯-N-(5-氯-2-((N-乙基-4-(N-甲基乙酰氨基)苯基)磺酰胺)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S20)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(N-甲基乙酰氨基)苯磺酰氯,其余条件均一致。得白色固体45mg,收率25%。1H NMR(400MHz,Chloroform-d)δ7.79–7.55(m,2H),7.47(dd,J=10.6,5.5Hz,2H),7.42–7.29(m,5H),7.29–6.98(m,2H),6.64–5.97(m,3H),5.54–4.08(m,4H),4.04–3.58(m,1H),3.51–2.83(m,4H),1.94(d,J=48.8Hz,3H),1.18–0.68(m,3H).13C NMR(101MHz,Chloroform-d)δ170.0,169.9,169.3,169.2,149.8,149.1,148.5,142.7,142.5,142.4,141.0,135.6,135.4,135.3,135.1,135.0,130.5,130.4,130.3,129.9,129.7,129.5,128.8,128.5,128.4,128.3,128.1,127.9,127.7,127.6,127.5,127.2,127.1,127.0,110.6,110.5,109.7,109.3,109.1,48.7,47.0,46.8,46.6,45.9,45.7,44.8,44.7,37.9,37.4,29.7,29.3,27.2,25.5,22.7,22.6,14.1,13.6,12.8.HRMS(ESI)[M+H]+calcd for C30H30N3O5SCl2:614.1283;found:614.1288.
实施例26
2-氯-N-(5-氯-2-((N-乙基-4-(2-氧代丙基)苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S21)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(2-氧代丙基)苯磺酰氯,其余条件均一致。得白色固体164mg,收率55%。1H NMR(400MHz,Chloroform-d)δ7.73–7.27(m,9H),7.25–7.01(m,2H),6.66–5.85(m,3H),5.57–4.02(m,4H),4.01–3.44(m,3H),3.38–2.68(m,1H),2.18(d,J=6.8Hz,3H),1.15–0.51(m,3H).13C NMR(101MHz,Chloroform-d)δ204.6,204.5,169.3,169.2,149.8,149.2,142.7,142.4,141.0,140.0,139.8,136.5,136.0,135.8,135.5,135.5,135.4,135.1,134.8,134.8,134.7,130.5,130.4,130.2,130.2,129.9,129.8,129.6,128.8,128.6,128.4,128.2,128.2,128.0,127.7,127.6,127.5,127.3,127.2,127.1,127.0,110.6,110.5,109.7,109.4,109.3,109.3,109.0,50.0,50.0,46.9,46.7,46.5,45.8,45.6,44.7,29.9,13.6,13.5,12.8.HRMS(ESI)[M+H]+calcdfor C30H29N2O5SCl2:599.1174;found:599.1171.
实施例27
N-(2-((4-乙酰氨基-N-乙基-3-甲基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S22)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-乙酰氨基-3-甲基苯磺酰氯,其余条件均一致。得白色固体72mg,收率39%。1H NMR(400MHz,Chloroform-d)δ8.28–7.81(m,2H),7.75–7.23(m,7H),7.21–6.99(m,2H),6.78–5.90(m,3H),5.60–3.99(m,4H),3.98–3.49(m,1H),3.41–2.63(m,1H),2.28–1.98(m,6H),1.37–0.90(m,3H).13C NMR(101MHz,Chloroform-d)δ169.5,169.2,149.7,148.9,142.8,142.8,142.4,140.8,140.8,140.7,136.6,136.6,135.9,135.9,135.2,134.7,134.7,130.7,130.6,130.5,130.2,130.0,129.9,129.9,129.7,129.7,128.8,128.7,128.6,128.5,128.3,128.0,127.9,127.4,127.2,127.1,127.0,126.5,124.5,123.5,122.5,110.6,110.5,109.8,109.2,46.6,46.4,45.9,45.6,44.9,44.8,24.2,23.8,18.1,18.0,17.9,17.8,13.5,13.4,12.8.HRMS(ESI)[M+H]+calcd for C30H30N3O5SCl2:614.1283;found:614.1294.
实施例28
N-(2-((4-乙酰氨基-3-氯-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S23)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-乙酰氨基-3-氯苯磺酰氯,其余条件均一致。得白色固体69mg,收率36%。1H NMR(400MHz,Chloroform-d)δ8.76–8.41(m,1H),7.95(d,J=8.3Hz,1H),7.76–7.20(m,8H),7.19–7.02(m,1H),6.65–5.99(m,3H),5.51–4.16(m,4H),4.00–3.50(m,1H),3.36–2.78(m,1H),2.29(d,J=5.3Hz,3H),1.29–0.99(m,3H).13C NMR(101MHz,Chloroform-d)δ169.3,168.7,149.7,149.1,142.7,142.4,141.0,138.9,138.8,135.5,135.4,135.3,135.1,135.1,130.5,130.4,129.9,129.7,128.8,128.8,128.7,128.5,128.4,128.2,128.1,128.0,127.7,127.6,127.5,127.1,127.1,122.4,120.9,120.9,110.6,110.5,109.7,109.3,109.1,47.0,46.6,45.9,45.8,44.9,44.7,25.0,13.6,13.5,12.8.HRMS(ESI)[M+H]+calcd for C29H27N3O5SCl3:634.0737;found:634.0735.
实施例29
2-氯-N-(5-氯-2-((4-(3,3-二甲基脲基)-N-乙基苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S24)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(3,3-二甲基脲基)苯磺酰氯,其余条件均一致。得白色固体71mg,收率37%。1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.61–7.40(m,5H),7.40–7.13(m,5H),7.05(d,J=7.3Hz,1H),6.61–5.86(m,3H),5.76–3.94(m,4H),3.93–3.43(m,1H),3.04(ddd,J=20.2,13.3,6.5Hz,1H),2.90(d,J=18.1Hz,6H),1.27–0.89(m,3H).13CNMR(101MHz,Chloroform-d)δ169.5,155.5,155.3,155.3,149.7,148.9,148.8,144.9,144.8,144.8,142.9,142.7,142.4,140.7,140.4,136.2,136.1,135.2,134.6,130.7,130.6,130.5,130.2,129.8,129.7,129.2,129.0,128.9,128.7,128.5,128.4,128.3,128.1,128.0,127.7,127.5,127.4,127.2,127.1,127.0,118.9,118.8,118.7,110.6,110.5,109.8,109.2,46.7,46.4,46.3,45.9,45.5,45.0,44.8,36.5,36.4,13.4,13.3,12.8.HRMS(ESI)[M+H]+calcd for C30H31N4O5SCl2:629.1392;found:629.1390.
实施例30
2-氯-N-(5-氯-2-((N-乙基-4-(3-乙基脲基)苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S25)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(3-乙基脲基)苯磺酰氯,其余条件均一致。得白色固体151mg,收率80%。1H NMR(400MHz,Chloroform-d)δ8.41(d,J=11.4Hz,1H),7.87–6.98(m,11H),6.58–5.59(m,4H),5.23–4.12(m,3H),3.77(d,J=68.8Hz,1H),3.37–1.93(m,3H),1.40–0.44(m,6H).13C NMR(101MHz,Chloroform-d)δ170.3,170.0,155.5,155.4,155.4,155.4,149.4,148.4,148.2,145.0,143.1,143.0,142.8,142.5,140.3,139.9,136.4,136.2,134.9,134.8,134.5,131.1,130.9,130.3,130.1,129.9,129.1,129.1,129.0,128.5,128.3,128.1,127.8,127.5,127.4,127.4,127.3,127.2,117.4,110.6,110.5,110.0,109.5,46.6,46.3,46.2,46.2,45.6,45.4,45.4,45.1,34.7,34.6,15.2,15.1,14.9,13.4,13.4,12.8.HRMS(ESI)[M+H]+calcd for C30H31N4O5SCl2:629.1392;found:629.1390.
实施例31
4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(氯磺酰基)苯甲酸乙酯,其余条件均一致。得白色固体309mg,收率50%。1H NMR(400MHz,Chloroform-d)δ8.15(dd,J=22.3,8.1Hz,2H),7.86–7.41(m,4H),7.41–6.99(m,5H),6.61–5.92(m,3H),5.52–4.14(m,6H),4.02–3.56(m,1H),3.45–2.81(m,1H),1.40(q,J=6.8Hz,3H),1.17–0.45(m,3H).13C NMR(101MHz,Chloroform-d)δ169.1,165.0,164.9,149.8,149.1,142.7,142.3,141.7,141.0,140.7,135.4,135.3,135.1,135.0,134.8,134.6,134.5,130.5,130.4,130.2,130.1,130.0,129.8,129.6,128.8,128.6,128.5,128.3,128.0,128.0,127.7,127.6,127.5,127.1,127.1,127.0,110.6,110.5,109.7,109.3,109.1,61.7,47.1,46.9,46.7,45.9,45.7,44.8,44.7,14.3,13.6,13.5,12.9.HRMS(ESI)[M+H]+calcd forC30H29N2O6SCl2:615.1123;found:615.1124.
实施例32
2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)乙酸乙酯(F44-S27)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为2-(4-(氯磺酰基)苯基)乙酸乙酯,其余条件均一致。得白色固体273mg,收率44%。1H NMR(400MHz,Chloroform-d)δ7.80–7.55(m,2H),7.54–7.38(m,4H),7.38–7.29(m,3H),7.28–6.97(m,2H),6.91–5.95(m,3H),5.69–3.79(m,7H),3.68(d,J=12.0Hz,2H),3.34–2.74(m,1H),1.24(q,J=6.9Hz,3H),1.12–0.47(m,3H).13C NMR(101MHz,Chloroform-d)δ170.4,170.3,169.2,149.8,149.1,142.7,142.3,141.0,139.9,139.8,136.6,135.8,135.6,135.4,135.1,134.7,134.7,134.6,130.5,130.4,130.3,130.2,130.0,130.0,129.8,129.6,128.8,128.6,128.4,128.4,128.2,128.1,127.9,127.8,127.6,127.6,127.5,127.3,127.1,127.1,127.0,110.5,110.5,109.7,109.3,109.1,61.1,46.9,46.6,46.4,45.8,45.6,44.8,44.7,40.9,40.9,14.1,13.5,12.8.HRMS(ESI)[M+H]+calcd for C31H31N2O6SCl2:629.1280;found:629.1280.
实施例33
2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯基)-2-甲基丙酸乙酯(F44-S28)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为2-(4-(氯磺酰基)苯基)-2-甲基丙酸乙酯,其余条件均一致。得白色固体302mg,收率46%。1HNMR(400MHz,Chloroform-d)δ7.75–7.56(m,2H),7.54–7.40(m,4H),7.39–7.01(m,5H),6.65–5.98(m,3H),5.61–4.19(m,4H),4.13(p,J=6.9Hz,2H),4.03–3.56(m,1H),3.38–2.77(m,1H),1.59(d,J=11.2Hz,6H),1.38–0.81(m,6H).13CNMR(101MHz,Chloroform-d)δ175.6,175.5,169.1,150.5,150.4,149.8,149.1,142.6,142.3,141.0,136.2,135.9,135.7,135.6,135.4,135.2,134.7,134.7,130.4,130.3,130.2,129.8,129.6,128.8,128.6,128.4,128.1,127.8,127.5,127.5,127.3,127.1,127.1,127.0,126.5,126.5,110.5,110.5,110.4,109.7,109.3,109.0,61.1,46.9,46.8,46.6,46.5,46.4,45.8,45.7,44.7,44.7,26.4,26.3,26.3,14.0,13.5,12.8.HRMS(ESI)[M+H]+calcd for C33H35N2O6SCl2:657.1593;found:657.1587.
实施例34
乙基3-((4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)氨基)-3-氧代丙酸酯(F44-S29)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为3-((4-(氯磺酰基)苯基)氨基)-3-氧代丙酸乙酯,其余条件均一致。得白色固体69mg,收率21%。1H NMR(400MHz,Chloroform-d)δ9.99–9.57(m,1H),8.04–7.43(m,6H),7.42–6.99(m,5H),6.72–5.95(m,3H),5.67–4.07(m,6H),3.97–3.61(m,1H),3.40(d,J=28.8Hz,2H),3.21–2.77(m,1H),1.27(d,J=6.1Hz,3H),1.10–0.66(m,3H).13CNMR(101MHz,Chloroform-d)δ169.6,169.6,169.1,169.0,168.7,164.3,164.1,164.0,149.7,148.9,148.8,142.9,142.8,142.4,142.4,142.3,142.2,140.7,140.5,136.0,135.9,135.6,135.2,134.8,134.6,132.4,131.7,131.6,130.7,130.6,130.5,130.3,130.2,129.9,129.9,129.8,129.8,129.2,128.7,128.7,128.5,128.4,128.1,128.0,127.7,127.6,127.5,127.4,127.3,127.1,127.0,119.5,119.4,110.6,110.5,109.8,109.3,62.0,61.9,61.8,61.8,46.8,46.5,46.4,46.0,45.7,45.0,44.9,42.4,42.2,42.1,35.9,31.9,29.8,29.7,29.6,29.5,29.5,29.3,29.3,29.2,27.2,25.6,22.7,14.1,13.5,13.4,12.8.HRMS(ESI)[M+H]+calcd for C32H32N3O7SCl2:672.1338;found:672.1342.
实施例35
N-(2-((4-(3-乙酰脲基)-N-乙基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S30)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(3-乙酰脲基)苯磺酰氯,其余条件均一致。得白色固体46mg,收率24%。1H NMR(400MHz,Chloroform-d)δ9.54–8.64(m,1H),7.79–7.11(m,10H),7.06(t,J=8.8Hz,1H),6.75–5.86(m,3H),5.78–4.09(m,4H),3.97–3.54(m,1H),3.03(ddt,J=26.0,13.1,6.7Hz,1H),2.25–1.85(m,3H),1.07–0.78(m,3H).13C NMR(101MHz,Chloroform-d)δ169.8,169.8,169.7,169.5,169.5,149.7,148.8,148.6,143.3,143.1,143.0,142.8,142.5,140.6,140.1,136.2,136.0,135.2,135.2,134.7,134.6,134.6,130.9,130.8,130.7,130.7,130.5,130.3,130.2,129.9,129.9,129.8,129.3,129.1,129.0,128.6,128.4,128.4,128.0,127.8,127.7,127.5,127.4,127.2,127.0,119.3,119.2,119.0,110.6,110.5,109.8,109.3,46.7,46.4,46.4,46.1,45.5,45.2,45.1,31.9,29.8,29.7,29.6,29.6,29.5,29.5,29.3,29.3,29.2,27.2,25.6,24.4,24.2,24.1,22.7,14.1,13.5,13.3,12.8.HRMS(ESI)[M+H]+calcd for C30H29N4O6SCl2:643.1185;found:643.1201.
实施例36
N-(2-((4-(2-乙酰胺基-2-氧乙基)-N-乙基苯基)磺胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S31)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-(2-乙酰氨基-2-氧乙基)苯磺酰氯,其余条件均一致。得白色固体72mg,收率23%。1H NMR(400MHz,Chloroform-d)δ9.55(d,J=7.7Hz,1H),7.72–7.28(m,9H),7.06(t,J=8.8Hz,2H),6.65–5.90(m,3H),5.50–4.06(m,4H),4.01–2.62(m,4H),2.27(s,3H),1.13–0.61(m,3H).13C NMR(101MHz,Chloroform-d)δ172.1,170.7,169.5,149.7,149.0,142.8,142.7,142.4,140.9,139.4,139.3,135.8,135.5,135.3,134.8,130.6,130.5,130.4,130.3,129.9,129.7,128.8,128.6,128.5,128.4,128.2,128.0,127.9,127.7,127.6,127.5,127.4,127.2,127.1,127.0,110.6,110.5,109.8,109.2,48.8,48.7,46.9,46.7,46.5,45.9,45.7,44.9,43.4,43.4,31.9,29.7,29.5,29.3,29.3,29.2,27.2,25.1,25.1,22.7,14.1,13.5,13.5,12.8.HRMS(ESI)[M+H]+calcd for C31H30N3O6SCl2:642.1232;found:642.1243.
实施例37
2-氯-N-(5-氯-2-((N-乙基-1-甲基-2-氧代吲哚)-5-磺胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S32)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为1-甲基-2-氧代二氢吲哚-5-磺酰氯,其余条件均一致。得白色固体26mg,收率14%。1H NMR(400MHz,Chloroform-d)δ7.86–7.28(m,7H),7.11(dt,J=18.9,8.3Hz,2H),6.95–6.74(m,1H),6.69–5.97(m,3H),5.61–4.11(m,4H),4.08–3.66(m,1H),3.65–3.37(m,2H),3.24(d,J=8.8Hz,4H),1.13–0.79(m,3H).13C NMR(101MHz,Chloroform-d)δ174.7,174.6,174.5,169.3,150.1,149.8,149.6,149.4,149.4,149.2,142.7,142.5,142.3,137.5,135.9,134.8,131.0,130.6,130.4,130.3,129.9,129.9,129.7,129.4,128.9,128.7,128.5,128.3,128.2,127.8,127.5,127.2,127.0,125.0,124.8,124.1,124.1,124.0,123.9,110.6,110.5,110.5,110.4,109.7,109.3,109.0,107.8,107.7,107.6,46.9,46.6,46.4,45.8,44.7,35.3,35.3,31.9,29.8,29.7,29.6,29.5,29.5,29.5,29.3,29.3,29.2,27.2,26.5,25.5,22.7,14.1,13.6,12.8.HRMS(ESI)[M+H]+calcd for C30H28N3O5SCl2:612.1127;found:612.1121.
实施例38
N-(2-((1-乙酰基-N-乙基二氢吲哚)-5-磺胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S33)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为1-乙酰二氢吲哚-5-磺酰氯,其余条件均一致。得白色固体46mg,收率25%。1H NMR(400MHz,Chloroform-d)δ8.25(dd,J=19.6,8.0Hz,1H),7.78–6.99(m,10H),6.79–5.86(m,3H),5.58–4.19(m,4H),4.13(q,J=8.9Hz,2H),3.95–3.55(m,1H),3.43–2.71(m,3H),2.50–2.07(m,3H),1.18–0.69(m,3H).13C NMR(101MHz,Chloroform-d)δ169.5,169.3,150.1,149.8,149.5,149.2,147.0,142.7,142.5,142.4,142.2,141.0,138.8,137.5,136.0,134.7,132.1,131.0,130.4,130.3,129.9,129.7,128.6,128.4,127.8,127.7,127.6,127.5,127.4,127.2,127.1,124.4,116.4,110.6,110.5,110.5,110.4,109.7,109.0,49.1,46.9,46.6,46.4,45.8,45.7,44.8,44.6,44.5,29.8,29.7,29.6,29.6,29.5,29.5,29.5,29.3,29.3,29.2,27.5,27.2,24.3,14.1,13.5,12.8.HRMS(ESI)[M+H]+calcd for C31H30N3O5SCl2:626.1283;found:626.1280.
实施例39
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为5-(氯磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体328mg,收率49%。1H NMR(400MHz,Chloroform-d)δ8.13–7.83(m,1H),7.82–7.43(m,4H),7.42–6.96(m,5H),6.66–5.91(m,3H),5.54–4.15(m,6H),4.06–3.64(m,1H),3.41–2.85(m,1H),2.57(d,J=14.5Hz,3H),1.45(td,J=7.0,3.6Hz,3H),1.17–0.51(m,3H).13C NMR(101MHz,Chloroform-d)δ169.2,159.7,159.6,155.9,149.8,149.1,143.1,143.0,142.7,142.3,141.1,135.8,135.5,135.4,134.8,134.7,133.3,132.7,132.3,130.4,130.3,130.2,129.8,129.6,129.3,128.8,128.6,128.5,128.4,128.3,128.1,127.8,127.5,127.0,125.4,125.3,122.4,122.2,112.8,112.7,110.5,110.4,109.6,109.3,109.0,61.5,61.5,47.0,46.7,46.5,45.9,45.7,44.8,44.7,14.3,13.6,13.5,12.8,9.3,9.3.HRMS(ESI)[M+H]+calcd for C33H31N2O7SCl2:669.1229;found:669.1221.
实施例40
4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)
将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(185mg,0.3mmol),氢氧化锂(15mg,0.6mmol)溶于乙醇(8mL)和水(2mL)组成的混合溶液中,100℃搅拌1h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(10mL)溶解,用1M稀盐酸调节PH值为3.0,静止5h后,减压抽滤、干燥得白色固体165mg,收率94%。1HNMR(400MHz,Chloroform-d)δ11.27(s,1H),8.37–7.58(m,4H),7.57–6.85(m,7H),6.67–5.91(m,3H),5.54–4.11(m,4H),3.84(d,J=75.4Hz,1H),3.14(d,J=92.6Hz,1H),1.25–0.35(m,3H).13C NMR(101MHz,Chloroform-d)δ169.7,169.5,169.3,149.6,148.9,142.9,142.6,142.6,142.5,141.5,140.9,140.8,135.3,135.2,135.1,133.8,133.8,133.6,130.8,130.7,130.6,129.9,129.7,128.9,128.7,128.5,128.5,128.1,127.9,127.7,127.2,127.1,110.6,110.5,109.8,109.6,109.3,47.2,47.1,46.8,46.0,45.1,44.8,13.6.HRMS(ESI)[M+H]+calcd for C28H25N2O6SCl2:587.0810;found:587.0814.
实施例41
2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)乙酸(F44-S36)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)乙酸乙酯,其余条件均一致。得白色固体195mg,收率81%。1H NMR(400MHz,Chloroform-d)δ9.89(s,1H),7.75–7.53(m,2H),7.52–7.40(m,3H),7.39–7.29(m,4H),7.07(t,J=10.5Hz,2H),6.49–6.03(m,3H),5.50–4.27(m,4H),4.23–3.80(m,1H),3.68(d,J=11.7Hz,2H),3.28–2.81(m,1H),1.11–0.51(m,3H).13C NMR(101MHz,Chloroform-d)δ175.0,169.6,149.6,149.0,142.7,142.4,140.8,139.3,139.1,136.8,135.8,135.8,135.7,135.5,135.1,134.9,134.8,130.5,130.4,130.3,130.1,130.0,129.9,129.7,128.9,128.6,128.4,128.4,128.3,128.2,128.0,127.7,127.6,127.5,127.4,127.1,127.0,127.0,110.6,110.5,109.8,109.1,46.9,46.7,46.5,45.9,45.8,45.0,44.8,40.8,13.5,12.8.HRMS(ESI)[M+H]+calcd forC29H27N2O6SCl2:601.0967;found:601.0967.
实施例42
2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)-2-甲基丙酸(F44-S37)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为2-(4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯基)-2-甲基丙酸乙酯,其余条件均一致。得白色固体150mg,收率80%。1H NMR(400MHz,Chloroform-d)δ10.75(s,1H),7.91–7.29(m,9H),7.23–6.88(m,2H),6.62–6.38(m,1H),6.37–5.98(m,2H),5.42–4.10(m,4H),4.01–3.52(m,1H),3.42–2.65(m,1H),1.60(d,J=10.8Hz,6H),1.13–0.44(m,3H).13CNMR(101MHz,Chloroform-d)δ181.0,180.9,169.7,169.6,149.7,149.5,149.0,142.7,142.4,140.9,135.8,135.5,135.2,134.9,134.8,130.5,130.4,129.7,128.9,128.6,128.5,128.3,128.2,128.0,127.7,127.7,127.5,127.2,127.1,127.0,126.7,126.7,126.5,110.6,110.5,109.8,109.2,46.9,46.7,46.5,45.9,45.8,44.9,44.8,26.3,26.2,13.6,12.8.HRMS(ESI)[M+H]+calcd for C31H31N2O6SCl2:629.1280;found:629.1288.
实施例43
3-((4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)氨基)-3-氧代丙酸(F44-S38)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基3-((4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯基)氨基)-3-氧代丙酸酯,其余条件均一致。得白色固体134mg,收率53%。1H NMR(400MHz,DMSO-d6)δ12.72–12.32(m,1H),7.77(dd,J=23.7,8.4Hz,2H),7.67–7.13(m,9H),6.69–6.17(m,3H),5.41–4.16(m,4H),3.81(s,1H),3.26–2.85(m,3H),1.04–0.31(m,3H).13C NMR(101MHz,DMSO-d6)δ170.8,169.3,169.1,168.2,149.8,149.0,144.0,143.7,143.2,142.8,135.6,135.1,135.0,133.4,133.1,130.9,130.7,129.6,129.4,129.3,128.9,128.3,128.1,127.6,126.8,118.6,110.6,109.2,108.9,46.1,45.9,45.1,44.9,44.2,29.0,24.1,13.2,12.6.HRMS(ESI)[M-H]-calcd for C30H26N3O7SCl2:642.0869;found:642.0873.
实施例44
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S39)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体225mg,收率88%。1H NMR(400MHz,Chloroform-d)δ8.13–7.31(m,8H),7.12(d,J=40.6Hz,2H),6.63–5.99(m,3H),5.50–4.34(m,4H),4.28–2.86(m,2H),2.59(d,J=13.7Hz,3H),1.18–0.43(m,3H).13C NMR(101MHz,Chloroform-d)δ169.8,163.6,163.4,156.3,149.6,149.0,148.9,142.8,142.7,142.6,142.4,140.9,135.7,135.4,135.1,134.9,133.5,132.9,132.5,130.6,130.5,130.3,129.9,129.7,129.3,128.9,128.6,128.5,128.4,128.2,127.9,127.6,127.5,127.4,127.2,127.1,122.6,122.5,113.0,113.0,110.6,110.5,109.8,109.2,47.1,46.8,46.6,46.0,45.9,45.1,44.9,13.6,13.5,12.9,9.5,9.5.HRMS(ESI)[M+H]+calcd for C31H27N2O7SCl2:641.0916;found:641.0922.
实施例45
2-氯-N-(5-氯-2-((N-乙基-4-硝基苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M20)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为4-硝基苯磺酰氯,其余条件均一致。得白色固体310mg,收率33%。
实施例46
N-(2-((4-氨基-N-乙基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(M21)
按照N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(M3)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-氯-2-((N-乙基-4-硝基苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体142mg,收率76%。
实施例47
2-氯-N-(5-氯-2-((N-乙基-4-(3-氧代丁酰胺基)苯基)磺酰胺基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(F44-S40)
将N-(2-((4-氨基-N-乙基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(79mg,0.14mmol),甲醇钠(12mg,0.14mmol),2,2,6-三甲基-4H-1,3-二英-4-酮(24mg,0.17mmol)加入四氢呋喃(0.5mL)中,回流反应48h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/2~1/2)得白色固体19mg,收率21%。1H NMR(400MHz,Chloroform-d)δ7.99–6.91(m,11H),6.56–6.00(m,3H),5.60–3.45(m,7H),3.30–2.85(m,1H),2.42–1.70(m,3H),1.17–0.85(m,3H).13C NMR(101MHz,Chloroform-d)δ202.3,169.5,165.2,148.7,142.1,141.2,134.2,134.3,133.3,131.1,129.8,129.4,128.5,128.6,126.6,122.5,122.6,119.7,114.7,110.6,110.4,32.0,29.9,29.8,29.4,27.3,14.2.HRMS(ESI)[M+H]+calcd for C31H30N3O6SCl2:642.1232;found:642.1232.
实施例48
N-(2-((4-氨基甲酰基-N-乙基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S41)
将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(788mg,1.3mmol),N,N'-羰基二咪唑(260mg,1.6mmol)加入四氢呋喃(25mL)中,40℃搅拌过夜,加入氨水(2mL)反应36h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=1/2)得白色固体757mg,收率96%。1H NMR(400MHz,Chloroform-d)δ8.1–7.8(m,2H),7.7–6.9(m,10H),6.6–5.9(m,4H),5.6–4.1(m,4H),3.9(dq,J=14.5,7.3Hz,1H),3.3–2.8(m,1H),1.2–0.4(m,3H).13C NMR(101MHz,Chloroform-d)δ169.5,167.9,149.7,148.8,143.0,142.8,142.5,140.7,140.5,139.6,137.9,135.4,135.1,135.1,130.8,130.2,129.8,128.7,128.3,128.3,128.1,127.9,127.5,127.3,127.2,110.6,110.5,109.8,109.3,46.7,46.0,45.7,44.9,13.6.HRMS(ESI)[M+H]+calcdfor C28H26Cl2N3O5S:586.0970;found:586.0966.
实施例49
N-(2-((4-(乙酰氨基甲酰基)-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S42)
将N-(2-((4-氨基甲酰基-N-乙基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(58mg,0.1mmol),4-二甲氨基吡啶(1mg,0.01mmol),吡啶(16mg,0.2mmol),乙酰氯(8mg,0.1mmol)加入无水二氯甲烷(0.5mL)中,回流反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=1/2)得白色固体23mg,收率36%。1H NMR(400MHz,Chloroform-d)δ9.59–9.35(m,1H),8.01(q,J=8.3Hz,2H),7.84–7.04(m,9H),6.54–5.99(m,3H),5.38–4.10(m,4H),4.01–3.62(m,1H),3.26(dt,J=14.0,7.0Hz,1H),2.57(d,J=14.3Hz,3H),1.18–0.71(m,3H).13C NMR(101MHz,Chloroform-d)δ173.5,169.5,164.8,164.7,149.9,149.2,142.9,142.5,142.3,141.2,141.0,137.0,135.4,130.7,130.4,130.0,129.8,128.8,128.7,128.6,128.5,128.2,127.9,127.6,127.2,110.7,110.6,109.8,109.3,47.3,46.8,46.1,44.9,29.9,29.7,29.4,27.3,25.8,22.8,13.7.HRMS(ESI)[M+H]+calcd for C30H29Cl2N3O6S:628.1076;found:628.1068.
实施例50
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-43)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-4-甲氧基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体188mg,收率76%。1H NMR(400MHz,Chloroform-d)δ8.16–7.87(m,1H),7.87–7.05(m,8H),7.04–6.81(m,1H),6.55–6.09(m,2H),6.08–5.74(m,1H),5.47–4.92(m,1H),4.92–4.15(m,5H),4.02–3.67(m,1H),3.56(d,J=10.6Hz,3H),3.31–2.83(m,1H),2.58(d,J=18.3Hz,3H),1.45(td,J=7.1,3.0Hz,3H),1.17–0.51(m,3H).13C NMR(101MHz,CDCl3)δ169.2,159.8,159.7,158.9,158.7,155.9,155.9,150.2,149.6,142.9,142.4,142.1,138.1,137.8,135.7,135.3,133.6,132.6,130.7,130.2,130.1,129.7,129.4,129.3,129.2,128.9,128.3,128.1,127.6,127.3,127.3,127.0,126.8,125.5,125.4,122.5,122.4,114.3,113.9,113.4,113.1,112.7,112.5,110.5,110.4,109.4,108.5,61.6,61.5,55.2,55.2,47.0,46.6,46.5,45.2,44.0,43.7,14.3,13.5,12.9,9.2.
实施例51
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S43)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体150mg,收率79%。1H NMR(400MHz,Chloroform-d)δ11.69(s,1H),8.15–7.88(m,1H),7.87–7.51(m,3H),7.51–7.12(m,5H),6.92(d,J=7.1Hz,1H),6.57–5.76(m,3H),5.52–4.96(m,1H),4.96–4.12(m,3H),4.07–3.68(m,1H),3.56(s,3H),3.10(d,J=82.0Hz,1H),2.83–2.38(m,3H),1.46–0.96(m,2H),0.74(d,J=91.3Hz,1H).13CNMR(101MHz,CDCl3)δ170.1,170.0,163.4,163.3,159.0,158.9,156.2,149.9,149.4,143.0,142.6,142.2,138.2,138.0,135.3,133.8,132.7,130.5,130.2,129.5,129.3,129.1,128.3,127.8,127.6,127.1,127.0,126.9,126.7,122.8,122.6,114.3,114.0,113.7,113.3,112.7,110.6,110.5,109.6,108.8,55.3,55.3,47.1,46.6,45.5,44.0,13.5,13.0,9.4.HRMS(ESI)[M-H]-calcd for C32H28ClN2O8S:635.1255;found:635.1255.
实施例52
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4,5-二甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-44)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-4,5-二甲氧基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体220mg,收率86%。1H NMR(400MHz,Chloroform-d)δ8.20–7.89(m,1H),7.89–7.55(m,2H),7.54–6.68(m,6H),6.49–6.33(m,1H),6.33–6.02(m,1H),5.86(d,J=34.3Hz,1H),5.56–4.15(m,6H),4.06–3.68(m,4H),3.39(d,J=18.5Hz,3H),3.28–2.95(m,1H),2.69–2.47(m,3H),1.46(td,J=7.1,2.9Hz,3H),1.06(dt,J=21.2,7.1Hz,2H),0.81(d,J=34.5Hz,1H).13C NMR(101MHz,CDCl3)δ169.5,169.2,169.1,159.7,159.6,155.8,155.8,150.2,149.5,149.2,149.1,147.7,143.0,142.3,141.9,135.6,135.2,133.9,131.7,131.6,130.3,130.0,129.8,129.5,129.3,129.2,129.1,129.0,128.7,128.3,127.7,127.3,127.1,126.9,125.3,125.2,122.5,122.4,122.3,112.6,112.4,110.7,110.5,110.4,109.7,109.5,108.8,108.4,61.6,56.0,55.6,55.5,47.0,46.5,46.4,45.2,44.1,43.8,41.4,14.3,13.5,13.0,9.3,9.2.
实施例53
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4,5-二甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S44)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4,5-二甲氧基苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体171mg,收率86%。1H NMR(400MHz,Chloroform-d)δ11.40(s,1H),8.34–6.64(m,9H),6.63–5.70(m,3H),5.68–4.09(m,4H),3.93(s,4H),3.40(d,J=14.6Hz,3H),3.10(d,J=51.9Hz,1H),2.70–2.39(m,3H),1.19–0.92(m,2H),0.83(d,J=40.9Hz,1H).13C NMR(101MHz,CDCl3)δ170.3,170.0,163.1,163.0,156.2,150.0,149.3,147.9,147.8,143.0,142.5,142.1,135.2,134.8,134.0,133.1,131.5,130.6,130.1,130.0,129.6,129.4,129.2,129.0,128.5,127.6,127.2,127.0,126.7,126.6,122.7,122.6,112.8,112.6,110.9,110.6,110.5,109.8,109.1,108.7,56.1,55.7,55.7,47.1,46.6,45.4,44.4,44.1,41.7,13.5,13.1,9.4.HRMS(ESI)[M-H]-calcd for C33H30ClN2O9S:665.1361;found:665.1364.
实施例54
乙基5-(N-(6-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯并[d][1,3]二氧戊环-5-基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-45)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-((6-(乙氨基)苯并[d][1,3]二氧戊环-5-基)甲基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体210mg,收率84%。1H NMR(400MHz,Chloroform-d)δ8.21–7.88(m,1H),7.86–7.54(m,2H),7.52–7.32(m,4H),7.32–6.73(m,2H),6.50–6.07(m,2H),6.07–5.70(m,3H),5.40–4.16(m,6H),4.00–3.57(m,1H),3.32–2.77(m,1H),2.59(d,J=17.4Hz,3H),1.45(td,J=7.1,2.6Hz,3H),1.35–0.95(m,2H),0.75(d,J=85.8Hz,1H).13C NMR(101MHz,CDCl3)δ169.5,169.3,159.8,159.7,155.9,155.9,150.0,149.4,148.1,146.7,142.9,142.5,142.1,135.5,133.7,133.1,132.8,130.3,130.1,130.0,129.8,129.5,129.3,128.9,128.3,127.6,127.1,127.0,125.5,125.4,122.4,122.2,112.8,112.7,110.5,110.4,109.4,108.7,107.9,107.5,107.3,106.7,102.0,101.8,61.5,46.9,46.4,45.4,44.7,44.4,14.3,13.4,12.8,9.3,9.3.
实施例55
乙基5-(N-(6-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯并[d][1,3]二氧戊环-5-基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S45)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(6-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯并[d][1,3]二氧戊环-5-基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体173mg,收率89%。1H NMR(400MHz,Chloroform-d)δ11.49(s,1H),8.40–7.89(m,1H),7.88–7.55(m,2H),7.55–6.74(m,6H),6.63–5.57(m,5H),5.52–4.10(m,4H),3.81(d,J=73.2Hz,1H),3.05(d,J=82.2Hz,1H),2.59(d,J=16.7Hz,3H),1.19–0.48(m,3H).13C NMR(101MHz,CDCl3)δ170.1,169.9,163.6,156.2,149.8,149.3,148.2,147.0,146.9,143.0,142.6,142.2,135.2,133.8,133.0,130.5,130.2,130.1,129.8,129.6,129.4,129.1,128.5,127.7,127.5,127.1,122.7,112.9,110.6,110.5,109.7,108.9,108.1,107.6,107.4,106.9,102.1,101.9,47.0,46.5,45.5,44.6,13.5,9.5.HRMS(ESI)[M-H]-calcd for C32H26ClN2O9S:649.1048;found:649.1046.
实施例56
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-46)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(4-(二甲基氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体68mg,收率91%。1H NMR(400MHz,Chloroform-d)δ8.16–7.91(m,1H),7.90–7.09(m,8H),6.75(ddd,J=28.9,8.7,2.3Hz,1H),6.59–5.95(m,2H),5.94–5.49(m,1H),5.43–4.16(m,6H),3.83(ddq,J=72.8,14.4,7.4Hz,1H),3.36–2.90(m,1H),2.87–2.31(m,9H),1.46(td,J=7.1,2.2Hz,3H),1.14–0.57(m,3H).13C NMR(101MHz,CDCl3)δ169.3,160.0,159.9,156.0,155.9,150.5,149.9,149.9,143.0,142.4,142.1,136.0,130.2,129.7,129.5,129.2,128.2,127.8,127.6,127.0,126.9,125.6,125.5,122.6,112.9,112.7,112.5,111.4,110.5,110.5,61.7,61.7,46.7,40.5,40.3,14.4,13.6,9.4.
实施例57
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S46)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体38mg,收率59%。1H NMR(400MHz,Chloroform-d)δ9.11(s,1H),8.19–7.90(m,1H),7.90–7.13(m,8H),6.92(d,J=75.1Hz,1H),6.61–5.67(m,3H),5.30(t,J=15.7Hz,1H),4.92–4.08(m,3H),3.84(ddq,J=75.8,14.4,7.5Hz,1H),3.36–2.98(m,1H),2.88–2.47(m,8H),1.40–0.58(m,4H).13C NMR(101MHz,CDCl3)δ169.8,163.0,156.3,156.3,150.3,149.6,143.0,142.9,142.6,142.2,135.6,133.3,130.5,129.8,129.3,128.4,127.8,127.2,127.0,126.8,122.8,112.7,110.7,110.6,109.7,46.8,45.5,41.0,29.8,13.8,13.2,9.5.HRMS(ESI)[M-H]-calcd for C33H31ClN3O7S:648.1571;found:648.1566.
实施例58
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-47)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(4-(乙基(甲基)氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体158mg,收率98%。1H NMR(400MHz,Chloroform-d)δ8.31–7.02(m,9H),6.85–6.59(m,1H),6.53–6.04(m,2H),5.84–5.47(m,1H),5.46–4.16(m,6H),3.84(ddq,J=73.6,14.3,7.1Hz,1H),3.36–2.89(m,3H),2.69–2.45(m,6H),1.46(td,J=7.1,2.6Hz,3H),1.19–0.56(m,6H).13C NMR(101MHz,CDCl3)δ169.2,159.9,159.8,155.8,155.8,150.5,149.9,148.6,142.9,142.3,142.0,138.1,137.8,136.0,135.6,130.1,130.1,129.6,129.4,129.1,128.2,127.7,127.3,126.9,126.9,125.6,125.5,122.6,113.1,112.6,112.4,111.1,110.5,110.4,109.3,61.6,46.6,46.6,46.5,37.1,37.1,14.3,13.6,11.1,9.3.
实施例59
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S47)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体106mg,收率69%。1H NMR(400MHz,Chloroform-d)δ11.09(s,1H),8.21–7.07(m,10H),7.04–5.78(m,3H),5.64–4.11(m,4H),3.87(d,J=80.8Hz,1H),3.25(d,J=39.9Hz,3H),2.82(d,J=57.7Hz,3H),2.51(d,J=9.8Hz,3H),1.29–0.89(m,5H),0.75(d,J=75.8Hz,1H).13C NMR(101MHz,CDCl3)δ169.7,162.4,156.1,156.0,150.0,149.1,143.8,142.7,142.2,138.8,135.2,130.6,130.4,130.2,129.7,129.5,128.9,127.7,127.2,127.0,125.3,122.4,113.2,112.8,110.6,110.5,109.7,109.1,46.7,45.7,13.7,13.1,10.8,10.6,9.4,9.4.HRMS(ESI)[M-H]-calcdfor C34H33ClN3O7S:662.1728;found:662.1735.
实施例60
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二乙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-48)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(4-(二乙氨基)-2-(乙氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体252mg,收率99%。1H NMR(400MHz,Chloroform-d)δ8.25–7.03(m,9H),6.78–6.54(m,1H),6.50–6.02(m,2H),5.67(dd,J=34.6,23.2Hz,1H),5.44–4.16(m,6H),3.85(ddq,J=74.5,14.3,7.3Hz,1H),3.44–2.83(m,5H),2.56(d,J=20.3Hz,3H),1.45(td,J=7.1,2.4Hz,3H),1.18–0.65(m,9H).13CNMR(101MHz,CDCl3)δ169.1,159.8,159.7,155.7,155.7,150.4,149.9,147.4,142.8,142.2,141.8,138.1,137.8,135.9,135.5,134.6,133.6,130.0,130.0,129.5,129.4,129.1,128.3,127.7,127.1,127.0,126.8,126.8,125.5,125.4,124.2,122.4,112.5,112.1,110.6,110.4,110.3,109.1,108.2,61.5,47.2,46.6,44.9,44.0,44.0,43.3,14.3,13.6,13.1,12.3,12.3,9.2.
实施例61
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二乙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S48)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二乙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体166mg,收率66%。1H NMR(400MHz,Chloroform-d)δ11.96(s,1H),8.27–7.06(m,10H),7.03–6.04(m,3H),5.57–4.16(m,4H),3.92(d,J=87.5Hz,1H),3.74–2.80(m,5H),2.49(s,3H),1.32–0.57(m,9H).HRMS(ESI)[M-H]-calcdfor C34H33ClN3O7S:662.1728;found:662.1735.13C NMR(101MHz,CDCl3)δ169.6,162.3,156.0,150.0,149.2,144.5,142.6,142.2,138.8,135.3,135.1,130.6,129.8,129.6,128.5,127.7,127.2,126.9,126.7,124.6,124.3,122.2,113.0,112.7,110.6,110.5,109.7,109.1,47.1,46.9,46.7,45.8,13.6,13.1,11.5,11.0,9.4,9.4.HRMS(ESI)[M-H]-calcd for C35H35ClN3O7S:676.1884;found:676.1891.
实施例62
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-49)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(4-(乙基(丙基)氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体180mg,收率96%。1H NMR(400MHz,Chloroform-d)δ8.19–7.87(m,1H),7.87–7.08(m,8H),6.77–6.53(m,1H),6.52–6.03(m,2H),5.60(dd,J=32.6,22.4Hz,1H),5.40–4.17(m,6H),3.86(ddq,J=73.0,14.3,7.4Hz,1H),3.37–2.97(m,3H),2.97–2.72(m,2H),2.55(d,J=20.2Hz,3H),1.45(td,J=7.2,2.3Hz,3H),1.17(ddt,J=70.1,14.5,7.9Hz,4H),0.90(d,J=7.4Hz,4H),0.65(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ169.1,159.8,159.7,155.7,155.7,150.5,149.9,147.6,142.8,142.2,141.8,138.1,137.8,135.9,135.6,133.6,130.0,130.0,129.6,129.4,129.1,129.0,128.3,127.7,127.1,127.0,126.8,125.5,125.4,122.4,112.5,111.9,110.5,110.4,110.3,109.1,108.5,61.5,51.8,51.8,46.7,44.9,44.6,20.4,20.4,14.3,13.6,13.1,12.0,12.0,11.0,11.0,9.3,9.2.
实施例63
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S49)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体110mg,收率64%。1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),8.46–7.10(m,10H),7.10–5.62(m,4H),5.49–4.16(m,4H),3.87(d,J=77.1Hz,1H),3.54–2.26(m,9H),1.00(q,J=92.2,78.6Hz,8H).13C NMR(101MHz,CDCl3)δ169.8,162.9,162.7,156.1,150.2,149.5,142.5,142.1,138.5,138.1,135.5,135.2,133.2,130.4,129.6,127.9,127.3,127.1,127.0,122.6,112.6,110.5,46.7,45.4,29.7,13.7,13.2,11.1,9.4.HRMS(ESI)[M-H]-calcd for C36H37ClN3O7S:690.2041;found:690.2028.
实施例64
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-50)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S364)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(4-(二丙基氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体318mg,收率96%。1HNMR(400MHz,Chloroform-d)δ8.15–7.68(m,2H),7.57(ddd,J=35.7,20.3,9.0Hz,2H),7.45–7.11(m,5H),6.76–6.51(m,1H),6.51–6.01(m,2H),5.71–5.41(m,1H),5.38–4.16(m,6H),3.87(ddq,J=71.0,14.3,7.2Hz,1H),3.48–3.06(m,1H),2.90(ddd,J=19.5,9.3,5.7Hz,4H),2.66–2.47(m,3H),1.45(td,J=7.2,2.0Hz,3H),1.29(dt,J=15.3,7.5Hz,4H),1.16–0.74(m,3H),0.66(t,J=7.4Hz,6H).13C NMR(101MHz,CDCl3)δ169.1,159.8,159.7,155.8,150.5,149.9,147.8,142.8,142.2,141.9,137.8,136.0,135.6,133.6,130.0,129.6,129.4,129.1,128.2,127.8,127.1,126.8,125.5,125.4,122.3,112.5,111.9,110.3,108.5,61.5,52.5,52.5,46.8,45.0,20.2,20.1,14.3,13.6,13.1,11.0,11.0,9.3,9.2.
实施例65
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S50)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体93mg,收率40%。1H NMR(400MHz,Chloroform-d)δ11.46(s,1H),8.22–7.10(m,10H),7.07–6.02(m,3H),5.48–4.16(m,4H),3.90(d,J=70.1Hz,1H),3.18(d,J=143.4Hz,5H),2.53(d,J=11.0Hz,3H),1.93–0.98(m,6H),0.76(d,J=45.2Hz,7H).13C NMR(101MHz,CDCl3)δ173.0,169.6,162.8,155.9,150.0,149.2,144.0,142.5,142.0,138.4,138.0,135.2,133.0,130.4,129.6,128.4,126.8,125.0,122.3,112.7,110.4,109.5,108.8,46.8,29.6,19.6,13.6,13.1,10.9,10.9,9.3.HRMS(ESI)[M-H]-calcd for C37H39ClN3O7S:704.2197;found:704.2195.
实施例66
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-51)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-4-(吡咯烷-1-基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体180mg,收率81%。1HNMR(400MHz,Chloroform-d)δ8.17–7.04(m,9H),6.66–6.45(m,1H),6.33(t,J=25.5Hz,2H),5.52(dd,J=40.2,27.3Hz,1H),5.34–4.86(m,1H),4.86–4.13(m,5H),3.99–3.58(m,1H),3.35–2.92(m,3H),2.92–2.68(m,2H),2.54(d,J=21.0Hz,3H),1.85(s,4H),1.43(td,J=7.1,2.4Hz,3H),1.13–0.56(m,3H).13C NMR(101MHz,CDCl3)δ169.2,159.8,159.8,155.9,155.9,150.5,150.0,147.4,142.9,142.3,142.0,137.8,136.0,135.6,133.3,130.1,129.6,129.0,128.2,127.7,127.6,126.9,126.8,125.5,125.5,122.6,112.5,112.3,112.1,110.4,110.4,108.6,61.6,47.4,46.5,25.3,14.4,13.5,9.3.
实施例67
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S51)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体153mg,收率87%。1H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04(m,4H),3.82(d,J=65.1Hz,1H),2.93(d,J=67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H).13C NMR(101MHz,Chloroform-d)δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127.8,126.9,126.6,126.4,122.8,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[M-H]-calcd for C35H33ClN3O7S:674.1728;found:674.1735.
实施例68
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-52)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-4-(哌啶-1-基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体91mg,收率75%。1H NMR(400MHz,Chloroform-d)δ8.12–7.77(m,1H),7.65(ddd,J=37.4,15.8,8.1Hz,2H),7.52–7.08(m,6H),6.90(dt,J=8.9,4.8Hz,1H),6.35(t,J=23.9Hz,2H),6.02–5.62(m,1H),5.42–4.15(m,6H),3.84(ddd,J=75.2,13.1,7.1Hz,1H),3.35–2.93(m,1H),2.93–2.65(m,4H),2.64–2.47(m,3H),1.61–1.37(m,9H),1.35–1.16(m,1H),0.95–0.42(m,2H).13C NMR(101MHz,CDCl3)δ172.5,169.3,159.9,159.9,156.0,156.0,151.6,150.4,149.9,143.0,142.4,142.1,136.0,133.2,130.2,130.1,129.7,129.3,129.2,128.3,128.0,127.7,127.4,127.3,127.0,126.9,125.5,122.7,117.0,116.4,115.1,115.1,112.6,110.5,110.5,110.5,108.8,61.7,50.1,50.0,46.6,45.2,25.5,25.5,24.1,24.1,24.1,14.4,13.6,9.4,9.4.
实施例69
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S52)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-5-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体65mg,收率73%。1HNMR(400MHz,Chloroform-d)δ10.28(s,1H),8.17–6.95(m,10H),6.93–5.76(m,3H),5.23–3.89(m,4H),3.55(d,J=197.4Hz,1H),2.95(s,4H),2.53(d,J=7.3Hz,3H),1.93–0.47(m,10H).13C NMR(101MHz,CDCl3)δ173.1,169.7,162.7,156.1,150.2,149.5,144.0,142.6,132.8,130.5,129.6,127.3,127.1,127.0,122.7,112.6,110.6,46.6,29.8,25.0,24.7,13.7,9.5.HRMS(ESI)[M-H]-calcd for C37H39ClN3O7S:688.1884;found:688.1890.
实施例70
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-53)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-(二甲基氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体436mg,收率48%。1HNMR(400MHz,Chloroform-d)δ8.13–7.86(m,1H),7.86–7.52(m,2H),7.51–7.14(m,5H),7.03–6.52(m,1H),6.51–6.00(m,4H),5.63–4.71(m,2H),4.47(qd,J=7.2,2.7Hz,4H),3.82(ddq,J=70.8,13.9,7.0Hz,1H),2.98(s,7H),2.58(d,J=18.9Hz,3H),1.45(td,J=7.1,2.7Hz,3H),1.15–0.59(m,3H).13C NMR(101MHz,Chloroform-d)δ169.4,159.9,159.8,155.9,155.8,150.5,150.4,150.2,149.7,142.8,142.3,142.0,139.0,136.0,135.4,130.2,130.2,130.0,129.8,129.5,129.3,129.1,128.5,128.0,127.8,127.3,127.3,127.1,126.8,125.7,125.6,125.3,124.7,122.4,122.3,112.6,112.4,111.0,110.8,110.5,110.4,109.4,108.8,108.5,61.5,61.5,47.1,46.5,45.4,44.6,40.5,40.3,14.4,13.6,13.5,13.0,9.3.
实施例71
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S53)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二甲氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体249mg,收率75%。1H NMR(400MHz,Chloroform-d)δ9.42(s,1H),8.37–5.96(m,13H),5.66–5.06(m,1H),5.05–4.60(m,2H),4.50(dd,J=33.6,14.1Hz,1H),3.84(d,J=74.2Hz,1H),3.04(s,7H),2.56(d,J=14.7Hz,3H),1.49–0.49(m,3H).13C NMR(101MHz,Chloroform-d)δ170.0,162.3,156.0,149.9,149.2,143.0,142.5,142.1,135.1,134.8,133.8,133.0,130.5,130.4,129.2,128.2,127.7,127.2,126.9,126.3,126.2,122.5,112.5,110.5,109.7,108.9,46.5,45.6,44.9,41.8,40.9,13.5,12.9,9.3.HRMS(ESI)[M-H]-calcd for C33H31ClN3O7S:648.1571;found:648.1581.
实施例72
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-54)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-(乙基(甲基)氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体480mg,收率62%。1H NMR(400MHz,Chloroform-d)δ8.13–7.86(m,1H),7.86–7.51(m,2H),7.51–7.14(m,5H),7.02–6.50(m,1H),6.49–6.03(m,4H),5.57–4.15(m,6H),3.81(dtd,J=70.1,14.3,13.6,7.2Hz,1H),3.40(q,J=7.2,6.4Hz,2H),2.93(s,4H),2.57(d,J=20.1Hz,3H),1.45(td,J=7.1,2.6Hz,3H),1.21–0.54(m,6H).13C NMR(101MHz,Chloroform-d)δ169.4,169.3,159.8,159.8,155.8,155.8,150.3,149.7,149.1,149.0,148.8,142.8,142.4,142.2,142.0,139.0,136.0,135.4,134.3,133.3,130.5,130.2,129.9,129.7,129.5,129.3,129.1,128.4,128.0,127.7,127.2,127.0,126.8,125.6,125.5,124.8,124.3,122.5,122.4,122.2,112.5,112.4,110.7,110.5,110.4,109.4,108.7,108.5,61.5,61.4,47.0,46.6,46.5,45.3,44.5,37.5,37.4,14.3,13.6,13.4,13.0,11.5,11.4,9.3.
实施例73
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S54)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(甲基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体352mg,收率98%。1H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.54–6.90(m,9H),6.43(td,J=95.0,87.8,53.1Hz,4H),5.63–4.20(m,4H),3.84(d,J=65.0Hz,1H),3.44(s,2H),3.09(d,J=87.7Hz,4H),2.57(s,3H),1.09(d,J=52.3Hz,6H).13C NMR(101MHz,Chloroform-d)δ169.8,162.3,155.8,149.9,149.1,148.3,147.8,143.3,142.4,142.0,135.1,134.7,133.7,133.0,130.4,129.6,129.2,128.2,127.6,127.0,125.7,122.3,112.4,110.4,109.5,108.8,47.8,47.0,46.4,44.8,41.4,38.4,37.8,13.4,12.9,11.2,9.2.HRMS(ESI)[M-H]-calcd for C34H33ClN3O7S:662.1728;found:648.1741.
实施例74
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二乙氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-55)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-(二乙氨基)-2-(乙氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体538mg,收率75%。1H NMR(400MHz,Chloroform-d)δ8.13–7.51(m,3H),7.50–7.14(m,5H),7.00–6.50(m,1H),6.50–6.24(m,3H),6.24–6.03(m,1H),5.61–4.22(m,6H),4.03–3.62(m,1H),3.37(d,J=7.5Hz,4H),3.27–2.92(m,1H),2.57(d,J=20.9Hz,3H),1.45(td,J=7.1,2.5Hz,3H),1.18(q,J=7.0Hz,6H),1.12–0.64(m,3H).13C NMR(101MHz,Chloroform-d)δ169.2,159.8,159.7,155.8,155.7,150.3,149.6,147.9,147.6,142.7,142.3,142.2,141.9,139.0,135.9,135.4,130.1,129.7,129.5,129.2,129.0,128.3,128.1,128.0,127.7,127.1,126.9,126.8,125.6,125.5,124.2,123.7,122.4,122.2,112.4,112.3,110.4,110.3,110.0,109.3,108.5,61.4,61.4,46.4,44.5,44.3,44.1,14.3,13.5,13.4,13.0,12.6,12.5,9.2.
实施例75
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二乙氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S55)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二乙氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体243mg,收率72%。1H NMR(400MHz,Chloroform-d)δ8.71–7.86(m,2H),7.85–5.95(m,12H),5.65–4.10(m,4H),4.05–3.78(m,1H),3.78–3.27(m,4H),3.28–2.91(m,1H),2.71–2.43(m,3H),1.45–0.57(m,9H).13C NMR(101MHz,Chloroform-d)δ163.1,156.2,156.1,150.3,149.5,142.6,142.2,135.6,135.2,130.6,130.5,129.9,129.5,129.3,128.5,127.4,127.3,127.0,126.5,122.7,112.6,110.6,110.6,109.8,108.9,68.0,47.2,46.6,45.7,45.1,25.7,13.7,13.6,13.2,12.5,12.2,9.5.HRMS(ESI)[M-H]-calcd for C35H35ClN3O7S:676.1884;found:676.1895.
实施例76
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-56)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-(乙基(丙基)氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体140mg,收率81%。1H NMR(400MHz,Chloroform-d)δ8.12–7.51(m,3H),7.34(tdd,J=28.6,22.9,7.9Hz,5H),6.97–6.49(m,1H),6.49–5.95(m,4H),5.51–4.14(m,6H),3.79(ddq,J=62.3,14.4,7.1Hz,1H),3.58–3.31(m,2H),3.22(s,3H),2.69–2.46(m,3H),1.62(ddt,J=11.3,7.4,3.7Hz,2H),1.45(td,J=7.1,2.1Hz,3H),1.17(q,J=6.8Hz,3H),1.11–0.75(m,6H).13C NMR(101MHz,CDCl3)δ169.3,159.9,159.9,155.9,155.9,150.4,149.8,148.0,142.8,142.3,142.0,139.0,136.1,135.5,130.2,129.8,129.4,129.1,128.4,128.2,127.8,127.3,127.0,126.9,125.7,125.6,124.3,123.8,122.6,122.4,112.4,110.5,110.4,110.1,109.8,109.3,108.6,61.5,52.1,52.0,46.6,45.3,45.0,44.9,44.6,41.2,20.8,14.4,13.6,13.1,12.4,12.4,11.5,9.3.
实施例77
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S56)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(乙基(丙基)氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体108mg,收率78%。1H NMR(400MHz,Chloroform-d)δ10.57(s,1H),8.54–6.91(m,10H),6.59–6.18(m,3H),5.53–4.22(m,4H),4.07–2.94(m,6H),2.75–2.42(m,3H),1.63(s,2H),1.30–0.54(m,10H).13C NMR(101MHz,CDCl3)δ170.0,169.8,162.8,156.3,156.1,150.1,149.3,143.1,142.7,142.2,135.1,130.5,129.9,129.5,129.3,129.2,128.6,127.8,127.3,127.0,126.3,122.6,112.6,110.6,109.9,109.0,47.1,46.8,46.6,45.8,45.2,13.7,13.1,11.4,11.3,9.4.HRMS(ESI)[M-H]-calcd for C36H37ClN3O7S:690.2041;found:690.2048.
实施例78
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-57)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-(二丙基氨基)-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体70mg,收率60%。1H NMR(400MHz,Chloroform-d)δ8.10–7.51(m,3H),7.50–7.11(m,5H),6.96–6.48(m,1H),6.47–5.99(m,4H),5.42–4.17(m,6H),3.79(ddq,J=64.0,14.5,7.2Hz,1H),3.39–2.93(m,5H),2.68–2.50(m,3H),1.62(q,J=7.4Hz,4H),1.45(td,J=7.1,2.4Hz,3H),0.95(dt,J=12.2,7.3Hz,8H),0.74(s,1H).13CNMR(101MHz,CDCl3)δ169.3,160.0,160.0,156.0,155.9,150.5,149.9,148.2,142.9,142.0,139.1,136.1,135.6,130.3,129.8,129.2,128.4,128.1,127.9,127.3,126.9,125.8,125.7,124.4,123.8,122.6,122.4,112.5,110.6,110.5,110.2,108.7,61.6,61.6,52.9,52.7,46.6,45.4,41.2,20.5,14.4,13.7,13.2,11.5,11.5,9.4.
实施例79
5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S57)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(二丙基氨基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体54mg,收率77%。1H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.10–6.09(m,13H),5.46–4.15(m,4H),4.11–3.63(m,1H),3.16(d,J=97.4Hz,5H),2.72–2.38(m,3H),1.96–0.81(m,13H).13C NMR(101MHz,CDCl3)δ169.8,163.1,156.3,150.3,142.7,142.2,135.2,130.7,129.9,129.6,128.6,127.9,127.4,127.0,122.7,110.7,46.7,13.7,13.2,11.5,11.3,9.5.HRMS(ESI)[M-H]-calcd for C37H39ClN3O7S:704.2197;found:704.2208.
实施例80
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-58)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-5-(吡咯烷-1-基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体87mg,收率93%。1HNMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04(m,4H),3.82(d,J=65.1Hz,1H),2.93(d,J=67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H).13CNMR(101MHz,CDCl3)δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127.8,126.9,126.6,126.4,122.8,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[M-H]-calcd for C35H33ClN3O7S:674.1728;found:674.1735.
实施例81
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S58)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(吡咯烷-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体15mg,收率56%。1HNMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04(m,4H),3.82(d,J=65.1Hz,1H),2.93(d,J=67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H).13C NMR(101MHz,CDCl3)δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127.8,126.9,126.6,126.4,122.8,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[M-H]-calcd for C35H33ClN3O7S:674.1728;found:674.1735.
实施例82
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-59)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(2-(乙基氨基)-5-(哌啶-1-基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得淡黄色固体87mg,收率93%。1H NMR(400MHz,Chloroform-d)δ8.11–7.51(m,3H),7.51–6.79(m,6H),6.67–6.48(m,1H),6.48–5.96(m,3H),5.57–4.13(m,6H),3.97–3.59(m,1H),3.19(t,J=5.4Hz,5H),2.71–2.48(m,3H),1.66(dt,J=33.5,5.1Hz,6H),1.45(td,J=7.1,2.7Hz,3H),1.13–0.59(m,3H).13C NMR(101MHz,CDCl3)δ169.5,160.0,159.9,156.0,155.9,152.1,151.8,150.4,149.7,142.9,142.4,142.1,139.5,139.1,136.0,135.4,134.3,130.3,129.9,129.6,129.4,129.2,128.5,128.0,127.7,127.4,127.3,127.1,126.9,125.7,125.6,122.5,122.4,114.9,114.5,114.2,112.7,112.5,110.6,110.5,109.6,108.9,108.5,61.6,61.6,49.9,49.7,47.1,46.6,45.4,44.5,25.8,25.7,24.3,24.2,14.4,13.7,13.5,13.0,9.5,9.4.
实施例83
乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S59)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯替换为乙基5-(N-(2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-4-(哌啶-1-基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得白色固体62mg,收率75%。1HNMR(400MHz,Chloroform-d)δ10.18(s,1H),8.23–7.09(m,10H),6.66–5.95(m,3H),5.65–4.15(m,4H),4.08–2.86(m,6H),2.72–2.44(m,3H),2.03–1.19(m,6H),1.12–0.57(m,3H).13C NMR(101MHz,CDCl3)δ162.9,156.2,150.2,149.3,143.5,142.7,142.3,135.4,130.7,130.0,129.5,129.4,129.3,127.4,127.0,126.0,122.6,112.7,110.6,110.0,47.2,46.6,45.8,25.3,13.7,13.1,9.5.HRMS(ESI)[M-H]-calcd for C36H35ClN3O7S:688.1884;found:688.1895.
实施例84
4-氯-2-(((呋喃-2-基甲基)氨基)甲基)苯酚(M8)
按照N-(5-氯-2-硝基苄基)-1-(呋喃-2-基)甲胺(M1)所用方法,将5-氯-2-硝基苯甲醛替换为5-氯-2-羟基苯甲醛,其余条件均一致。得黄色固体1.44g,收率61%。1H NMR(400MHz,Chloroform-d)δ7.39(d,J=1.9Hz,1H),7.11(dd,J=8.6,2.7Hz,1H),6.93(d,J=2.6Hz,1H),6.77(d,J=8.7Hz,1H),6.34(dd,J=3.2,1.8Hz,1H),6.21(d,J=3.2Hz,1H),3.89(s,2H),3.79(s,2H).13C NMR(101MHz,Chloroform-d)δ156.9,151.6,142.5,128.6,128.3,123.6,123.5,117.8,110.4,108.3,50.7,44.2.
实施例85
2-氯-N-(5-氯-2-羟基苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M9)
将4-氯-2-(((呋喃-2-基甲基)氨基)甲基)苯酚(948mg,4mmol),三乙胺(606mg,6mmol)加入无水二氯甲烷(15mL)中,冰浴条件下缓慢滴加邻氯苯甲酰氯(700mg,4mmol),室温反应3h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=6/1)得白色固体439mg,收率29%。1H NMR(400MHz,Chloroform-d)δ9.25(s,1H),7.37(dtd,J=20.3,7.0,2.0Hz,5H),7.17(dd,J=8.7,2.6Hz,1H),7.00(d,J=2.6Hz,1H),6.90(d,J=8.7Hz,1H),6.38–6.30(m,1H),6.24(d,J=3.3Hz,1H),4.82(d,J=14.8Hz,1H),4.44–4.22(m,3H).13C NMR(101MHz,Chloroform-d)δ170.7,155.0,148.1,143.3,134.1,131.0,131.0,130.7,130.1,129.9,128.0,127.2,123.8,122.8,119.0,110.7,110.1,45.2,44.5.
实施例86
4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基4-乙酰氨基苯磺酸盐(F44-S60)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-氯-2-羟基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体137mg,收率48%。1H NMR(400MHz,Chloroform-d)δ9.32(d,J=13.2Hz,1H),7.76–7.52(m,4H),7.50–7.31(m,5H),7.31–7.04(m,2H),6.82(d,J=8.7Hz,1H),6.39–6.05(m,2H),4.96(d,J=16.0Hz,1H),4.45(t,J=20.6Hz,1H),4.35(d,J=16.0Hz,1H),4.27–4.08(m,1H),2.07–1.95(m,3H).13CNMR(101MHz,Chloroform-d)δ169.8,169.5,149.2,148.1,146.0,145.8,144.8,143.2,142.6,134.7,134.6,133.1,132.1,131.6,130.9,130.8,130.3,130.2,130.0,129.9,129.6,129.5,129.1,129.1,128.7,128.6,128.3,128.2,127.6,127.4,124.0,123.7,119.2,119.1,110.5,110.0,109.5,46.5,45.6,42.7,41.6,24.3,14.2.HRMS(ESI)[M+H]+calcd for C27H23N2O6SCl2:573.0654;found:573.0660.
实施例87
2-((3-氟-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基4-乙酰苯磺酸盐(F44-S61)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为3-氟-N-(呋喃-2-基甲基)-N-(2-羟基苄基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-乙酰苯磺酰氯,其余条件均一致。得白色固体104mg,收率80%。1H NMR(400MHz,Chloroform-d)δ8.21–7.82(m,4H),7.49–7.04(m,9H),6.26(d,J=50.5Hz,2H),4.39(d,J=90.9Hz,4H),2.66(d,J=2.6Hz,3H).13C NMR(101MHz,CDCl3)δ169.5,168.6,158.3(d,J=247.2Hz,1C),148.3,143.3,142.6,136.5,134.2,132.0(d,J=9.2Hz,1C),131.1,129.8,128.9,128.7(d,J=2.5Hz,1C),128.3,126.7,124.8(d,J=4.3Hz,1C),123.0(d,J=17.4Hz,1C),122.8,119.3,116.2(d,J=20.9Hz,1C),110.7,109.9,44.8,44.7,26.6.19FNMR(376MHz,CDCl3)δ-114.4,-114.5.
实施例88
4-氯-2-((2,6-二氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基4-乙酰氨基苯磺酸盐(F44-S62)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2,6-二氯-N-(5-氯-2-羟基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,其余条件均一致。得白色固体223mg,收率74%。1H NMR(400MHz,Chloroform-d)δ8.91(d,J=22.2Hz,1H),7.75–7.53(m,4H),7.53–7.06(m,6H),6.82(dd,J=43.7,8.8Hz,1H),6.47–5.97(m,2H),4.73(d,J=17.9Hz,2H),4.24(d,J=32.1Hz,2H),2.05(d,J=22.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.6,169.4,166.5,166.4,149.0,147.5,145.8,145.7,144.6,144.5,143.2,142.5,134.0,133.8,133.1,133.0,132.1,132.0,131.9,131.1,131.0,131.0,129.6,129.5,129.3,129.1,128.4,124.1,123.5,119.2,119.1,110.6,110.3,109.8,46.0,45.5,43.4,41.7,24.4,24.4.HRMS(ESI)[M+H]+calcd for C27H22N2O6SCl3:607.0264;found:607.0264.
实施例89
4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基4-丁酰氨基苯磺酸盐(F44-S63)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(5-氯-2-羟基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体141mg,收率47%。1H NMR(400MHz,Chloroform-d)δ9.18(d,J=24.6Hz,1H),7.71(dd,J=26.0,8.6Hz,2H),7.63(d,J=8.5Hz,2H),7.51–7.31(m,5H),7.31–7.05(m,2H),6.79(dd,J=24.2,8.7Hz,1H),6.46–5.92(m,2H),5.01(d,J=16.0Hz,1H),4.46(d,J=16.1Hz,1H),4.36(d,J=15.9Hz,1H),4.19(q,J=19.6,15.4Hz,1H),2.29–2.11(m,2H),1.61(dp,J=14.4,7.1Hz,2H),0.86(dt,J=14.7,7.3Hz,3H).13CNMR(101MHz,Chloroform-d)δ172.8,172.7,169.5,169.4,149.2,148.1,146.0,145.8,144.9,143.1,142.6,134.8,134.6,133.1,132.2,131.6,130.9,130.8,130.3,130.3,130.0,129.9,129.6,129.5,129.1,129.0,128.7,128.5,128.3,128.1,128.0,127.6,127.4,127.3,124.0,123.6,119.3,119.2,110.5,110.0,109.5,46.5,45.7,42.7,41.6,39.1,18.6,13.6.HRMS(ESI)[M+H]+calcd for C29H27N2O6SCl2:601.0967;found:601.0963.
实施例90
4-氯-2-((2,6-二氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基4-丁酰氨基苯磺酸盐(F44-S64)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2,6-二氯-N-(5-氯-2-羟基苄基)-N-(呋喃-2-基甲基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体131mg,收率41%。1H NMR(400MHz,Chloroform-d)δ9.04(d,J=12.7Hz,1H),7.85–7.46(m,5H),7.45–7.21(m,4H),7.20–7.07(m,1H),6.79(dd,J=56.8,8.6Hz,1H),6.50–5.98(m,2H),4.77(d,J=33.5Hz,2H),4.27(d,J=24.8Hz,2H),2.23(dt,J=14.7,7.5Hz,2H),1.64(tt,J=14.7,7.4Hz,2H),0.89(dt,J=14.8,7.4Hz,3H).13CNMR(101MHz,Chloroform-d)δ172.7,172.6,166.5,166.4,148.9,147.5,145.8,144.8,143.2,142.6,134.1,133.8,133.1,132.9,132.1,132.1,131.8,131.2,131.0,129.6,129.5,129.5,129.3,129.1,128.4,128.2,124.1,123.5,119.3,119.1,110.6,110.3,109.8,46.0,45.6,43.5,41.7,39.2,18.7,13.7,13.7.HRMS(ESI)[M+H]+calcd for C29H26N2O6SCl3:635.0577;found:635.0565.
实施例91
5-((2,6-二氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-2-甲氧基苯基4-乙酰氨基苯磺酸盐(F44-S66)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2,6-二氯-N-(呋喃-2-基甲基)-N-(3-羟基-4-甲氧基苄基)苯甲酰胺,其余条件均一致。得白色固体230mg,收率83%。1H NMR(400MHz,Chloroform-d)δ9.07(d,J=20.1Hz,1H),7.78–7.63(m,4H),7.41–7.22(m,5H),7.08(d,J=8.6Hz,1H),6.80(t,J=8.7Hz,1H),6.39–6.05(m,2H),4.66(d,J=40.0Hz,2H),4.21(d,J=6.3Hz,2H),3.53(d,J=16.2Hz,3H),2.10(d,J=2.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ169.7,169.6,166.0,165.8,151.7,151.2,149.2,148.1,144.2,144.0,143.1,142.5,138.3,138.1,134.3,134.3,132.1,131.8,131.0,130.9,129.7,129.6,129.5,128.4,128.4,128.3,127.1,124.5,124.3,118.8,118.8,113.0,112.7,110.6,110.5,110.0,109.6,55.8,55.7,50.7,46.6,44.0,39.4,24.5.HRMS(ESI)[M+H]+calcd for C28H25N2O7SCl2:603.0760;found:603.0758.
实施例92
5-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-2-甲氧基苯基4-丁酰氨基苯磺酸盐(F44-S67)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(呋喃-2-基甲基)-N-(3-羟基-4-甲氧基苄基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体263mg,收率88%。1H NMR(400MHz,Chloroform-d)δ8.85(d,J=16.1Hz,1H),7.71(d,J=4.1Hz,4H),7.49–6.75(m,8H),6.54–5.93(m,2H),5.05(dd,J=108.5,15.0Hz,1H),4.43–4.03(m,3H),3.53(d,J=8.4Hz,3H),2.26(td,J=7.5,2.5Hz,2H),1.66(h,J=7.4Hz,2H),0.90(t,J=7.3Hz,3H).13CNMR(101MHz,Chloroform-d)δ172.6,172.5,168.9,168.8,151.5,151.2,149.5,148.7,144.2,144.1,143.1,142.6,138.4,138.2,135.3,135.2,130.7,130.6,130.4,130.3,129.9,129.8,129.7,129.7,129.5,129.4,128.7,128.2,128.0,127.9,127.8,127.5,127.4,127.3,124.2,123.5,118.9,118.8,113.0,112.9,110.5,110.5,109.6,109.3,55.8,55.7,50.6,46.1,44.2,39.7,39.2,18.7,13.7.HRMS(ESI)[M+H]+calcd for C30H30N2O7SCl:597.1462;found:597.1456.
实施例93
5-((2,6-二氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-2-甲氧基苯基4-丁酰氨基苯磺酸盐(F44-S68)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2,6-二氯-N-(呋喃-2-基甲基)-N-(3-羟基-4-甲氧基苄基)苯甲酰胺,将4-乙酰氨基苯磺酰氯替换为4-丁酰胺基苯磺酰氯,其余条件均一致。得白色固体291mg,收率92%。1HNMR(400MHz,Chloroform-d)δ9.00(d,J=19.6Hz,1H),7.79–7.66(m,4H),7.43–7.05(m,6H),6.81(t,J=8.2Hz,1H),6.38–6.02(m,2H),4.68(d,J=37.6Hz,2H),4.21(d,J=8.4Hz,2H),3.53(d,J=13.6Hz,3H),2.29(td,J=7.6,1.8Hz,2H),1.67(hd,J=7.4,1.7Hz,2H),0.91(t,J=7.4Hz,3H).13CNMR(101MHz,Chloroform-d)δ172.7,172.6,165.9,165.8,151.6,151.2,149.2,148.1,144.3,144.1,143.1,142.5,138.3,138.0,134.4,134.3,132.1,131.8,131.0,130.9,129.7,129.6,129.4,129.3,128.4,128.4,128.3,127.0,124.5,124.3,118.8,118.8,113.0,112.7,110.6,110.5,110.0,109.6,55.7,55.6,50.7,46.6,44.0,39.4,39.2,18.7,13.7.HRMS(ESI)[M+H]+calcd for C30H29N2O7SCl2:631.1073;found:631.1072.
实施例94
5-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-2-甲氧基苯基4-乙酰氨基苯磺酸盐(F44-B19)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(呋喃-2-基甲基)-N-(3-羟基-4-甲氧基苄基)苯甲酰胺,其余条件均一致。得白色固体230mg,收率83%。
实施例95
5-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)-2-甲氧基苯基4-乙酰氨基苯磺酸盐(F44-S65)
按照N-(2-((4-乙酰氨基苯基)磺酰胺基)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S1)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺替换为2-氯-N-(呋喃-2-基甲基)-N-(3-羟基-4-甲氧基苄基)苯甲酰胺,其余条件均一致。得白色固体230mg,收率83%。1H NMR(400MHz,Chloroform-d)δ9.21(d,J=18.1Hz,1H),7.70(d,J=10.6Hz,4H),7.48–6.73(m,8H),6.51–5.98(m,2H),5.04(dd,J=106.7,15.1Hz,1H),4.43–4.06(m,3H),3.51(d,J=4.7Hz,3H),2.07(s,3H).13C NMR(101MHz,Chloroform-d)δ169.7,169.7,169.0,168.9,151.5,151.2,149.5,148.6,144.2,144.1,143.1,142.6,138.3,138.1,135.2,130.7,130.7,130.3,130.3,129.9,129.8,129.7,129.5,129.4,128.7,128.2,128.1,127.8,127.8,127.5,127.4,127.3,124.2,123.5,118.8,118.8,113.0,112.9,110.6,110.5,109.6,109.3,55.8,55.7,50.6,46.2,44.3,39.8,24.4.HRMS(ESI)[M+H]+calcd for C28H26N2O7SCl:569.1149;found:569.1145.
实施例96
2-(氨基甲基)-4-氯苯胺(M10)
将四氢铝锂(3.80g,100mmol)加入反应瓶中,氩气保护后,加入无水四氢呋喃(50mL),再缓慢滴加2-氨基-5-氯苯腈(7.65g,50mmol)的无水四氢呋喃(50mL)溶液,升温至回流后反应4h,TLC检测反应完毕后,缓慢加水猝灭反应,过滤后取溶液,减压蒸馏除去溶剂,加水(50mL)溶解,乙酸乙酯(50mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(DCM/CH3OH=10/1~5/1)得白色固体6.34g,收率81%。
实施例97
(2-氨基-5-氯苯甲酰基)氨基甲酸叔丁酯(M11)
将2-(氨基甲基)-4-氯苯胺(M10)(6.34g,40mmol),三乙胺(4.44g,44mmol)加入无水二氯甲烷(100mL)中,冰浴条件下缓慢滴加二碳酸二叔丁酯(8.72g,40mmol),室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(50mL)溶解,乙酸乙酯(50mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=10/1~3/1)得淡黄色固体9.29g,收率90%。
实施例98
叔丁基(5-氯-2-(乙基氨基)苄基)氨基甲酸酯(M12)
将(2-氨基-5-氯苯甲酰基)氨基甲酸叔丁酯(M11)(4.65g,18mmol),碘乙烷(14.0g,90mmol),碳酸钾(12.4g,90mmol)加入乙腈(100mL)中,70℃反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(50mL)溶解,乙酸乙酯(50mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=20/1)得淡黄色固体2.23g,收率44%。
实施例99
5-(N-(2-(((叔丁氧基羰基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M13)
按照5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(F44-S34)所用方法,将2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺替换为叔丁基(5-氯-2-(乙基氨基)苄基)氨基甲酸酯(M12),其余条件均一致。得淡黄色固体3.28g,收率76%。
实施例100
5-(N-(2-((氨基甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M14)
将5-(N-(2-(((叔丁氧基羰基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M13)(3.28g,6mmol),三氟乙酸(5mL)加入二氯甲烷(25mL)中,室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(DCM/CH3OH=10/1)得淡黄色固体2.70g,收率99%。
实施例101
5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)
将5-(N-(2-((氨基甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M14)(225mg,0.5mmol),特戊醛(52mg,0.6mmol),加入甲醇(10mL)中室温搅拌4h,在冰浴条件下缓慢加入硼氢化钠(30mg,0.8mmol)室温反应过夜,TLC检测反应完毕后,加水猝灭反应,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/1)得淡黄色固体166mg,收率64%。
实施例102
5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)
将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)(166mg,0.32mmol),碳酸钾(66mg,0.48mmol)加入无水二氯甲烷(10mL)中,冰浴条件下缓慢滴加邻氯苯甲酰氯(67mg,0.38mmol),室温反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(20mL)溶解,乙酸乙酯(20mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=3/1)得白色固体192mg,收率91%。1H NMR(400MHz,Chloroform-d)δ8.05–7.83(m,1H),7.83–7.56(m,2H),7.55–7.10(m,4H),7.03(dd,J=19.2,6.9Hz,2H),6.42–6.13(m,1H),5.47–4.54(m,2H),4.47(q,J=7.1Hz,1H),4.34–3.93(m,3H),3.77(ddd,J=46.2,13.0,7.5Hz,1H),3.64–2.92(m,1H),2.83(dd,J=12.6,6.3Hz,1H),2.59(d,J=12.0Hz,3H),1.35(dt,J=79.7,7.1Hz,3H),1.15(d,J=11.3Hz,8H),0.96–0.61(m,2H),0.34(t,J=6.8Hz,1H).13C NMR(101MHz,CDCl3)δ170.1,160.0,159.7,156.0,143.1,142.8,142.3,141.7,136.3,135.2,135.0,134.8,132.4,130.0,129.8,129.5,129.4,129.3,128.3,127.8,127.7,127.6,127.1,126.8,125.6,125.3,122.3,112.8,61.6,60.3,57.2,52.3,51.4,46.5,35.0,28.8,28.6,14.3,14.2,12.4,9.3,9.2.
实施例103
5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S69’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69),其余条件均一致。得白色固体140mg,收率76%。1H NMR(400MHz,Chloroform-d)δ7.89(d,J=18.4Hz,1H),7.61(d,J=22.4Hz,2H),7.43–6.89(m,6H),6.43–6.06(m,1H),5.08(dd,J=78.9,17.0Hz,1H),4.73(dd,J=96.5,17.4Hz,1H),4.48–3.51(m,2H),3.50–2.75(m,2H),2.58(s,3H),1.17(s,9H),0.81(d,J=74.6Hz,2H),0.34(s,1H).13C NMR(101MHz,CDCl3)δ171.3,170.8,163.4,156.2,143.4,142.1,141.4,135.8,135.3,135.1,135.0,132.4,132.3,130.5,130.3,129.9,129.5,128.4,127.8,127.2,126.9,126.3,122.5,57.6,51.6,46.6,35.1,28.7,28.5,13.0,12.5,9.5.HRMS(ESI)[M-H]-calcd forC31H31Cl2N2O6S:629.1280;found:629.1278.
实施例104
5-(N-(4-氯-2-((((5-甲基呋喃-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-70)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为5-甲基呋喃醛,其余条件均一致。得白色固体190mg,收率70%。
实施例105
5-(N-(4-氯-2-((((5-甲基呋喃-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-70)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((5-甲基呋喃-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-70),其余条件均一致。得白色固体180mg,收率75%。1H NMR(400MHz,Chloroform-d)δ8.07–7.86(m,1H),7.86–7.61(m,2H),7.61–7.29(m,5H),7.10–6.97(m,1H),6.51–5.72(m,3H),5.44–4.78(m,2H),4.76–4.09(m,4H),3.88(d,J=75.3Hz,1H),3.40–2.81(m,1H),2.68–2.50(m,3H),2.27(s,3H),1.45(td,J=7.0,3.4Hz,3H),1.10(dt,J=14.8,6.8Hz,2H),0.69(d,J=98.9Hz,1H).13C NMR(101MHz,CDCl3)δ169.2,159.8,159.7,156.0,152.4,147.7,147.1,143.0,141.3,141.2,135.7,135.5,135.4,134.9,134.8,134.7,133.3,132.8,132.7,132.4,131.8,131.0,130.4,129.8,129.6,129.3,128.9,128.5,128.3,127.6,127.5,127.4,127.3,127.0,126.9,126.5,125.5,125.4,122.4,122.3,112.8,110.6,110.0,106.5,106.3,61.6,47.0,46.8,46.5,46.1,45.0,44.8,14.3,13.5,9.3,9.3.
实施例106
5-(N-(4-氯-2-((((5-甲基呋喃-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S70’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((((5-甲基呋喃-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-70),其余条件均一致。得白色固体140mg,收率76%。1HNMR(400MHz,DMSO-d6)δ8.20–7.80(m,2H),7.78–7.13(m,7H),6.81–5.76(m,3H),5.48–4.12(m,4H),4.05–2.95(m,2H),2.59(d,J=15.6Hz,3H),2.23(d,J=12.0Hz,3H),1.12–0.41(m,3H).13C NMR(101MHz,DMSO)δ168.1,160.9,155.4,151.9,147.9,147.0,143.9,140.7,135.9,135.4,135.3,135.1,133.5,133.2,132.4,132.0,131.7,130.8,129.6,129.4,129.3,128.6,128.3,127.9,127.5,126.9,126.8,124.3,122.2,113.0,110.1,106.6,106.4,13.3,13.1,9.0.HRMS(ESI)[M-H]-calcd for C32H27Cl2N2O7S:653.0916;found:653.0912.
实施例107
5-(N-(2-((((5-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-71)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为5-溴-2-呋喃甲醛,其余条件均一致。得白色固体42mg,收率14%。
实施例108
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(2-((((5-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-71),其余条件均一致。得白色固体45mg,收率86%。1H NMR(400MHz,Chloroform-d)δ8.09–7.84(m,1H),7.74(q,J=11.5,10.2Hz,1H),7.70–7.44(m,3H),7.44–7.27(m,3H),7.12–7.02(m,1H),6.53–6.00(m,3H),5.39–4.00(m,7H),3.31–2.87(m,1H),2.63–2.51(m,3H),1.46(td,J=7.1,3.5Hz,1H),1.30–0.48(m,5H).13C NMR(101MHz,CDCl3)δ169.5,160.3,156.2,152.1,151.2,143.0,141.1,135.9,135.3,135.1,130.7,130.4,129.7,129.5,129.4,129.3,128.8,128.6,128.3,127.7,127.6,127.3,127.2,126.0,125.9,122.6,113.0,112.9,112.8,112.5,112.3,61.8,52.5,47.2,46.8,45.6,44.5,14.5,13.7,9.5,0.1.
实施例109
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S72)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71),其余条件均一致。得白色固体28mg,收率65%。1H NMR(400MHz,DMSO-d6)δ8.17–7.79(m,2H),7.74–7.07(m,7H),6.75–6.14(m,3H),5.42–4.28(m,4H),4.05–2.82(m,3H),2.64–2.42(m,4H),1.23(s,1H).13C NMR(101MHz,DMSO)δ160.8,155.3,152.2,143.9,135.0,134.8,133.2,131.6,131.0,130.8,129.7,129.3,128.0,127.6,126.8,124.2,122.2,121.3,113.0,112.9,112.5,112.4,112.0,13.3,9.0.HRMS(ESI)[M-H]-calcd for C31H24BrCl2N2O7S:716.9859;found:716.9862.
实施例110
5-(N-(2-((((3-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-72)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为3-溴-2-呋喃甲醛,其余条件均一致。得白色固体68mg,收率22%。
实施例111
5-(N-(2-((N-((3-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-72)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(2-((((3-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-72),其余条件均一致。得白色固体86mg,收率99%。1H NMR(400MHz,Chloroform-d)δ8.07–7.70(m,2H),7.69–7.29(m,7H),7.14–6.16(m,3H),5.47–4.80(m,2H),4.79–3.52(m,5H),3.37–2.84(m,1H),2.58(d,J=10.7Hz,3H),1.46(td,J=7.1,2.5Hz,3H),1.12(dt,J=33.6,6.4Hz,2H),0.69(d,J=85.1Hz,1H).13C NMR(101MHz,CDCl3)δ169.4,159.9,159.8,156.1,147.1,146.6,143.2,143.1,135.7,135.5,135.0,134.9,134.4,133.2,132.4,132.3,131.4,130.6,130.5,130.4,129.8,129.4,129.0,128.9,128.6,128.4,128.1,127.9,127.6,127.4,127.2,127.1,127.0,126.7,125.6,125.5,122.4,114.1,112.9,112.8,100.1,61.7,61.7,46.7,14.4,13.8,9.5,9.4.
实施例112
5-(N-(2-((N-((3-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S71)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((3-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-72),其余条件均一致。得白色固体28mg,收率65%。1H NMR(400MHz,DMSO-d6)δ8.23–6.30(m,12H),5.67–4.08(m,4H),4.01–3.59(m,1H),3.36–2.93(m,1H),2.62–2.51(m,3H),1.10–0.40(m,3H).13C NMR(101MHz,DMSO)δ168.2,166.8,160.9,155.3,147.0,144.3,144.0,135.5,134.9,134.9,133.5,131.6,131.0,130.8,129.7,129.3,129.3,128.0,127.6,126.6,123.9,122.0,113.8,112.9,112.8,99.3,98.9,46.3,13.4,9.0,9.0.HRMS(ESI)[M-H]-calcd for C31H24BrCl2N2O7S:716.9865;found:716.9862.
实施例113
5-(N-(4-氯-2-(((噻吩-2-基甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-73)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为2-噻吩甲醛,其余条件均一致。得白色固体152mg,收率56%。
实施例114
5-(N-(4-氯-2-((2-氯-N-(噻吩-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-73)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-(((噻吩-2-基甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-73),其余条件均一致。得白色固体182mg,收率95%。1HNMR(400MHz,Chloroform-d)δ7.95(d,J=54.4Hz,1H),7.82–7.18(m,8H),7.13–6.74(m,3H),6.55–6.17(m,1H),5.62–5.06(m,1H),5.03–4.44(m,4H),4.00(d,J=2.8Hz,1H),3.97–3.65(m,1H),3.34–2.83(m,1H),2.58(d,J=11.2Hz,3H),1.52–0.92(m,5H),0.63(d,J=61.6Hz,1H).13C NMR(101MHz,CDCl3)δ171.0,169.0,160.1,160.0,159.7,159.7,156.0,143.1,143.0,142.8,142.8,140.9,138.5,138.4,135.8,135.5,135.0,132.4,132.3,130.6,130.3,129.7,129.4,129.3,128.8,128.5,128.3,127.9,127.6,127.4,127.2,127.2,127.0,126.9,126.9,126.6,126.0,125.8,125.7,125.5,125.4,122.3,112.8,61.6,61.6,60.3,52.3,46.5,21.0,14.3,14.2,9.3,9.3,9.3.
实施例115
5-(N-(4-氯-2-((2-氯-N-(噻吩-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S77)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-(噻吩-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-73),其余条件均一致。得白色固体136mg,收率77%。1H NMR(400MHz,DMSO-d6)δ8.45–6.73(m,12H),6.56(d,J=43.1Hz,1H),5.60–4.28(m,4H),3.77(d,J=75.6Hz,1H),3.37–2.83(m,1H),2.55(d,J=10.9Hz,3H),1.09–0.26(m,3H).13C NMR(101MHz,DMSO)δ168.6,161.4,155.8,144.9,139.2,136.1,135.5,135.4,134.1,133.7,132.1,131.5,131.3,130.2,129.8,129.7,129.6,128.6,128.0,127.5,127.1,127.0,126.8,124.2,124.1,122.5,113.4,113.3,46.5,9.5.HRMS(ESI)[M-H]-calcd for C31H25Cl2N2O6S2:655.0531;found:655.0530.
实施例116
5-(N-(4-氯-2-((((5-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-74)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为5-甲基-2-噻吩甲醛,其余条件均一致。得白色固体87mg,收率31%。
实施例117
5-(N-(4-氯-2-((2-氯-N-((5-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-74)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((5-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-74),其余条件均一致。得棕色固体68mg,收率61%。1H NMR(400MHz,Chloroform-d)δ8.05–7.86(m,1H),7.77–7.43(m,4H),7.41–7.31(m,2H),7.26–6.96(m,2H),6.94–6.47(m,2H),6.47–6.20(m,1H),5.47–4.26(m,4H),4.08–3.59(m,4H),3.32–2.83(m,1H),2.58(d,J=11.8Hz,3H),2.47(d,J=13.0Hz,3H),2.12–0.42(m,5H).13C NMR(101MHz,CDCl3)δ169.1,160.3,160.2,156.1,143.0,142.9,141.1,140.8,136.0,135.8,135.5,135.1,134.5,133.2,132.6,132.3,131.4,130.7,130.6,130.4,129.8,129.4,129.1,128.8,128.5,128.4,127.9,127.8,127.6,127.3,127.0,126.7,126.0,125.8,125.0,124.7,122.6,122.5,112.9,52.5,52.5,48.3,46.6,15.5,15.5,13.7,9.4,9.4.
实施例118
5-(N-(4-氯-2-((2-氯-N-((5-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S78)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((5-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-74),其余条件均一致。得淡黄色固体53mg,收率79%。1H NMR(400MHz,DMSO-d6)δ8.06(d,J=35.0Hz,1H),7.85(dd,J=23.3,8.1Hz,1H),7.76–7.04(m,7H),6.97–6.36(m,3H),5.50–4.20(m,4H),4.06–2.30(m,9H),0.95(d,J=63.2Hz,2H).13CNMR(101MHz,DMSO)δ160.8,155.4,143.8,140.0,139.8,136.3,135.5,135.0,133.3,131.7,131.1,130.8,129.7,129.2,129.1,127.5,127.2,127.0,126.8,125.1,124.6,124.4,124.3,113.0,112.9,15.0,9.0.HRMS(ESI)[M-H]-calcd for C32H27Cl2N2O6S2:669.0688;found:669.0684.
实施例119
5-(N-(4-氯-2-((((4-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-75)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为4-甲基-2-噻吩甲醛,其余条件均一致。得白色固体126mg,收率45%。
实施例120
5-(N-(4-氯-2-((2-氯-N-((4-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-75)
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按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((4-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-75),其余条件均一致。得紫色固体173mg,收率99%。1H NMR(400MHz,Chloroform-d)δ8.09–7.86(m,1H),7.81–7.41(m,4H),7.41–7.13(m,4H),7.10–6.77(m,2H),6.49–6.16(m,1H),5.58–4.20(m,6H),3.83(ddd,J=69.7,13.2,7.0Hz,1H),3.35–2.77(m,1H),2.58(d,J=12.4Hz,3H),2.28–1.96(m,4H),1.46(td,J=7.1,3.0Hz,3H),1.04(dt,J=50.2,7.1Hz,2H).13C NMR(101MHz,CDCl3)δ169.1,159.8,159.8,156.0,143.1,143.1,141.0,138.2,138.1,137.2,135.8,135.5,135.0,134.2,133.0,132.4,132.1,131.2,130.6,130.4,130.1,129.7,129.4,129.3,128.9,128.5,128.4,127.9,127.7,127.5,127.2,127.1,126.9,126.6,125.5,125.4,122.5,122.4,121.2,120.8,112.8,61.7,61.6,46.5,15.7,15.6,14.4,13.5,9.4,9.4.
实施例121
5-(N-(4-氯-2-((2-氯-N-((4-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S79)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((4-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-75),其余条件均一致。得淡粉色固体114mg,收率77%。1H NMR(400MHz,DMSO-d6)δ8.23–7.94(m,1H),7.85(dd,J=23.2,8.2Hz,1H),7.76–6.34(m,10H),5.66–4.90(m,1H),4.88–4.23(m,3H),3.82(d,J=73.7Hz,1H),3.41–2.83(m,1H),2.57(d,J=13.3Hz,3H),2.15(d,J=22.3Hz,3H),1.12–0.31(m,3H).13C NMR(101MHz,DMSO)δ160.7,160.7,155.4,143.7,138.5,136.9,136.4,135.6,135.0,134.9,133.6,133.3,131.7,131.0,130.8,129.8,129.7,129.2,129.2,128.1,127.7,127.5,127.1,126.8,124.5,124.4,122.3,121.5,121.2,113.0,112.9,46.0,15.3,15.3,9.0,9.0.HRMS(ESI)[M-H]-calcd for C32H27Cl2N2O6S2:669.0688;found:669.0693.
实施例122
5-(N-(4-氯-2-((((3-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-76)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为3-甲基-2-噻吩甲醛,其余条件均一致。得白色固体151mg,收率54%。
实施例123
5-(N-(4-氯-2-((2-氯-N-((3-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-76)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((3-甲基噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-76),其余条件均一致。得紫色固体173mg,收率96%。1H NMR(400MHz,Chloroform-d)δ8.04–7.86(m,1H),7.78–7.55(m,3H),7.47–7.17(m,5H),7.17–6.69(m,2H),6.57–6.19(m,1H),5.56–5.04(m,1H),5.02–3.44(m,6H),3.38–2.81(m,1H),2.58(d,J=8.9Hz,3H),2.38–1.53(m,3H),1.46(t,J=7.1Hz,3H),1.23–0.33(m,3H).13C NMR(101MHz,CDCl3)δ166.9,159.8,159.7,156.0,156.0,143.1,143.1,143.0,142.5,136.3,135.6,135.4,135.1,135.0,135.0,132.9,132.7,132.3,132.0,131.9,131.2,131.1,130.9,130.9,130.5,130.2,130.1,129.8,129.7,129.4,129.3,128.5,128.3,128.3,127.8,127.5,127.1,127.0,126.9,126.6,125.4,125.4,124.2,122.3,112.9,112.8,61.6,61.6,47.0,46.5,39.1,14.4,13.8,13.6,13.3,9.4,9.3.
实施例124
5-(N-(4-氯-2-((2-氯-N-((3-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S80)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((3-甲基噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-76),其余条件均一致。得淡粉色固体99mg,收率55%。1H NMR(400MHz,DMSO-d6)δ8.38–6.34(m,12H),5.53–2.47(m,9H),2.27–0.15(m,6H).13C NMR(101MHz,DMSO)δ166.8,160.8,160.7,155.4,143.7,142.9,136.7,135.5,135.5,135.1,133.2,132.6,132.2,131.6,130.9,129.8,129.7,129.4,129.3,129.2,128.9,127.7,127.5,127.2,126.8,124.5,124.4,124.2,122.2,113.0,112.9,48.0,46.3,46.0,13.4,13.4,12.9,9.0,9.0.HRMS(ESI)[M-H]-calcd for C32H27Cl2N2O6S2:669.0688;found:669.0695.
实施例125
5-(N-(4-氯-2-((((5-溴噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-77)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为5-溴噻吩-2-甲醛,其余条件均一致。得白色固体74mg,收率24%。
实施例126
5-(N-(4-氯-2-((2-氯-N-((5-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-77)
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按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((5-溴噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-77),其余条件均一致。得白色固体68mg,收率74%。1H NMR(400MHz,Chloroform-d)δ8.10–7.29(m,8H),7.26–7.02(m,2H),6.96–6.51(m,2H),6.50–6.15(m,1H),5.46–4.44(m,4H),4.06–3.73(m,3H),3.32–2.83(m,1H),2.59(d,J=11.6Hz,3H),1.52–1.16(m,2H),1.10(t,J=6.9Hz,1H),1.04–0.79(m,1H),0.64(d,J=55.9Hz,2H).13C NMR(101MHz,CDCl3)δ169.6,169.2,160.3,160.2,156.2,143.0,140.9,140.3,135.9,135.6,135.2,133.4,132.5,132.4,131.5,130.8,130.6,129.9,129.8,129.5,129.3,129.0,128.6,128.4,128.1,127.6,127.5,127.3,127.2,127.1,126.8,125.8,122.5,113.0,61.8,52.5,48.5,47.9,46.7,44.6,14.5,13.7,13.0,9.5,9.4.
实施例127
5-(N-(4-氯-2-((2-氯-N-((5-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S83)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((5-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-77),其余条件均一致。得白色固体41mg,收率62%。1H NMR(400MHz,DMSO-d6)δ8.27–6.20(m,12H),5.46–4.26(m,4H),4.03–2.35(m,6H),1.24(s,1H).13C NMR(101MHz,DMSO)δ161.0,155.3,141.0,135.6,134.6,133.6,131.6,130.9,130.2,129.7,129.5,129.4,128.5,128.2,127.6,127.0,126.6,122.1,112.9,111.7,47.8,46.0,9.0.HRMS(ESI)[M-H]-calcd for C31H24BrCl2N2O6S2:732.9648;found:732.9642.
实施例128
5-(N-(4-氯-2-((((4-溴噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-78)
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按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为4-溴噻吩-2-甲醛,其余条件均一致。得白色固体108mg,收率35%。
实施例129
5-(N-(4-氯-2-((2-氯-N-((4-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-78)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((4-溴噻吩-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-78),其余条件均一致。得白色固体80mg,收率62%。1H NMR(400MHz,Chloroform-d)δ8.08–7.86(m,1H),7.80–7.29(m,6H),7.27–7.04(m,3H),7.03–6.54(m,1H),6.53–6.13(m,1H),5.55–4.32(m,4H),4.08–3.70(m,4H),3.32–2.84(m,1H),2.59(d,J=9.8Hz,3H),2.11–0.39(m,5H).13CNMR(101MHz,CDCl3)δ169.3,160.3,160.2,156.1,143.0,135.9,135.7,135.1,132.5,132.2,131.4,130.9,130.6,130.3,130.0,129.4,128.7,128.6,128.1,127.6,127.4,127.3,127.1,126.7,125.8,123.6,122.6,122.5,112.9,109.1,52.5,52.5,46.7,13.6,9.4,9.4.
实施例130
5-(N-(4-氯-2-((2-氯-N-((4-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S78’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((4-溴噻吩-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-78),其余条件均一致。得白色固体52mg,收率71%。1H NMR(400MHz,DMSO-d6)δ8.35–7.15(m,10H),6.98(d,J=47.8Hz,1H),6.77–6.33(m,1H),5.63–4.23(m,4H),4.16–2.22(m,6H),1.29–0.78(m,2H).13C NMR(101MHz,DMSO)δ160.7,155.4,143.7,140.9,135.6,134.8,134.6,133.6,133.3,131.7,131.2,130.9,129.8,129.5,129.2,129.1,128.2,127.6,126.8,124.4,123.9,122.3,113.0,112.9,108.2,107.7,46.0,9.0.HRMS(ESI)[M-H]-calcd for C31H24BrCl2N2O6S2:732.9636;found:732.9634.
实施例131
5-(N-(4-氯-2-((((1-甲基-1H-吡咯-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-79)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为N-甲基-2-吡咯甲醛,其余条件均一致。得白色固体137mg,收率50%。
实施例132
5-(N-(4-氯-2-((2-氯-N-((1-甲基-1H-吡咯-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-79)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((((1-甲基-1H-吡咯-2-基)甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-79),其余条件均一致。得白色固体172mg,收率99%。1H NMR(400MHz,Chloroform-d)δ8.13–6.93(m,10H),6.71–6.44(m,1H),6.30–5.93(m,2H),5.52–5.11(m,1H),5.10–4.65(m,1H),4.48(qd,J=7.1,2.1Hz,3H),4.15–3.57(m,3H),3.29(s,1H),3.22–2.75(m,1H),2.58(d,J=9.1Hz,3H),1.46(td,J=7.1,2.2Hz,3H),1.34–0.33(m,4H).13CNMR(101MHz,CDCl3)δ169.4,166.8,159.8,156.0,143.2,143.1,143.1,142.6,141.3,135.6,135.3,135.2,135.0,134.9,132.4,131.2,131.0,130.9,130.5,130.3,130.2,129.8,129.5,129.4,128.4,128.3,128.1,127.6,127.4,127.2,127.1,127.0,126.9,125.5,125.4,123.7,122.3,113.0,112.8,107.2,61.6,61.6,60.4,47.0,46.5,39.1,34.4,33.7,21.1,14.4,14.2,13.6,13.4,9.4,9.4,9.4.
实施例133
5-(N-(4-氯-2-((2-氯-N-((1-甲基-1H-吡咯-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S79’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-((1-甲基-1H-吡咯-2-基)甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-79),其余条件均一致。得粉色固体107mg,收率65%。1H NMR(400MHz,Chloroform-d)δ10.44(s,1H),8.07–7.80(m,1H),7.79–6.95(m,9H),6.58(d,J=67.0Hz,1H),6.30–5.93(m,2H),5.53–5.17(m,1H),5.12–3.97(m,3H),3.71(d,J=49.5Hz,2H),3.34–2.75(m,2H),2.58(d,J=7.3Hz,3H),1.37–0.81(m,2H),0.56(d,J=128.5Hz,2H).13C NMR(101MHz,CDCl3)δ169.9,167.4,163.7,156.2,143.4,142.2,141.0,135.7,135.3,135.1,135.0,134.8,132.6,132.4,131.5,131.0,130.7,130.3,130.2,129.9,129.6,129.5,128.6,128.3,128.2,127.7,127.1,127.0,126.4,123.8,123.1,122.4,112.9,111.7,108.3,107.3,47.0,46.5,44.9,39.3,34.5,33.7,13.6,13.5,13.2,12.6,9.5,0.1.HRMS(ESI)[M-H]-calcd for C32H28Cl2N3O6S:652.1076;found:652.1074.
实施例134
5-(N-(2-((苄氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-80)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为苯甲醛,其余条件均一致。得白色固体260mg,收率38%。
实施例135
5-(N-(2-((N-苄基-2-氯代氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-80)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(2-((苄氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-80),其余条件均一致。得白色固体156mg,收率87%。1H NMR(400MHz,Chloroform-d)δ8.05–7.79(m,1H),7.79–7.61(m,1H),7.56(s,1H),7.48–7.00(m,11H),6.38(dd,J=75.4,11.9Hz,1H),5.64–4.61(m,2H),4.53(s,1H),4.51–4.30(m,3H),3.96–3.54(m,1H),3.33–2.82(m,1H),2.55(d,J=8.1Hz,3H),1.44(td,J=7.1,2.4Hz,3H),0.92(d,J=122.9Hz,2H),0.52(d,J=69.7Hz,1H).13CNMR(101MHz,CDCl3)δ169.6,159.8,159.7,156.0,143.1,143.0,141.0,136.3,135.6,135.5,135.0,134.9,132.4,130.4,129.8,129.4,129.3,128.7,127.8,127.6,127.4,127.1,127.0,125.5,125.4,122.4,112.8,112.8,63.6,61.6,61.6,60.6,46.4,41.7,34.1,14.5,14.4,14.1,9.3,9.3.
实施例136
5-(N-(2-((N-苄基-2-氯代氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S80’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-苄基-2-氯代氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-80),其余条件均一致。得白色固体116mg,收率78%。1H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.09–7.81(m,1H),7.80–6.99(m,13H),6.63–6.20(m,1H),5.69–5.09(m,1H),5.02–4.11(m,3H),3.96–3.52(m,1H),3.32–2.78(m,1H),2.57(d,J=8.4Hz,3H),1.17–0.34(m,3H).13CNMR(101MHz,CDCl3)δ170.2,163.6,163.4,156.3,143.0,142.9,140.8,136.0,135.8,135.5,135.2,135.0,132.5,130.6,130.5,129.9,129.4,129.4,128.8,128.0,127.7,127.5,127.4,127.2,127.0,122.7,113.0,46.5,9.5,9.5.HRMS(ESI)[M-H]-calcd forC33H27Cl2N2O6S:649.0967;found:649.0967.
实施例137
5-(N-(4-氯-2-((苯乙氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-81)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为苯乙醛,其余条件均一致。得白色固体520mg,收率44%。
实施例138
5-(N-(4-氯-2-((2-氯-N-苯乙基苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-81)
按照5-(N-(4-氯-2-((2-氯-N-新戊基苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-69)所用方法,将5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)替换为5-(N-(4-氯-2-((苯乙氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-81),其余条件均一致。得白色固体348mg,收率87%。1H NMR(400MHz,Chloroform-d)δ8.14–7.83(m,1H),7.80–7.72(m,1H),7.70–7.22(m,6H),7.22–6.76(m,6H),6.35(d,J=8.5Hz,1H),5.63–4.37(m,4H),4.33–3.28(m,3H),3.28–2.68(m,3H),2.56(d,J=16.3Hz,3H),1.51–1.34(m,3H),1.14(t,J=6.2Hz,2H),0.64(d,J=78.5Hz,1H).13C NMR(101MHz,CDCl3)δ169.4,159.7,159.7,156.0,156.0,143.1,141.5,138.6,137.8,136.0,135.8,135.5,135.0,133.3,132.5,130.3,130.0,129.7,129.5,129.4,129.0,128.9,128.6,128.0,127.9,127.7,127.2,127.0,126.5,125.5,125.4,122.4,112.9,61.6,50.5,49.0,47.2,46.6,44.0,41.7,34.8,33.3,14.4,13.8,9.4.
实施例139
5-(N-(4-氯-2-((2-氯-N-苯乙基苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S81’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-苯乙基苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-81),其余条件均一致。得淡黄色固体218mg,收率66%。1HNMR(400MHz,Chloroform-d)δ9.77(s,1H),8.20–6.79(m,14H),6.31(dd,J=52.0,7.3Hz,1H),5.77–4.43(m,2H),4.17(d,J=84.8Hz,1H),3.89–3.27(m,2H),3.26–2.72(m,3H),2.58(d,J=16.6Hz,3H),1.16(s,2H),0.67(d,J=84.3Hz,1H).13C NMR(101MHz,CDCl3)δ170.1,162.8,162.6,156.2,143.0,143.0,141.1,138.4,137.6,135.9,135.5,135.1,133.1,132.3,130.5,130.0,129.7,129.4,129.0,128.8,128.5,128.0,127.7,127.3,127.1,126.6,126.5,122.5,113.0,50.6,49.1,47.1,46.6,44.2,34.7,33.2,13.7,12.9,9.4,9.4.HRMS(ESI)[M-H]-calcd forC34H29Cl2N2O6S:663.1123;found:663.1127.
实施例140
5-(N-(2-((((5-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S82’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((((5-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-71),其余条件均一致。得白色固体220mg,收率76%。
实施例141
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)乙酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-83)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为乙酰氯,其余条件均一致。得白色固体237mg,收率73%。1H NMR(400MHz,Chloroform-d)δ7.99(dd,J=14.3,2.0Hz,1H),7.77–7.62(m,2H),7.21–7.01(m,2H),6.45–6.18(m,3H),5.12(dd,J=47.2,17.4Hz,1H),4.85–4.26(m,4H),4.02(s,3H),3.16(ddq,J=19.7,13.6,6.9Hz,1H),2.52(d,J=62.9Hz,5H),2.11(d,J=56.7Hz,2H),1.54–1.43(m,1H),1.07(dt,J=15.5,7.1Hz,3H).13C NMR(101MHz,CDCl3)δ171.4,171.3,160.0,159.6,156.6,156.0,155.9,152.7,152.0,142.9,142.8,141.7,141.1,135.7,135.6,135.1,134.8,133.1,132.3,129.4,129.3,129.3,128.4,128.3,128.1,127.8,127.5,127.1,127.1,127.0,126.7,125.7,125.6,122.4,122.3,121.8,121.0,112.8,112.2,112.1,111.8,111.8,61.5,52.3,48.9,46.9,46.7,45.4,44.9,41.8,21.7,21.4,14.3,13.5,13.5,9.3,9.2.
实施例142
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)乙酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S83’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)乙酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-83),其余条件均一致。得白色固体143mg,收率46%。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.88(t,J=9.8Hz,1H),7.78–7.63(m,1H),7.26(dd,J=18.6,7.8Hz,1H),7.05(d,J=26.7Hz,1H),6.69–6.55(m,1H),6.45(td,J=25.5,24.9,2.9Hz,2H),5.04–4.43(m,4H),3.95(dp,J=14.2,6.9Hz,1H),3.22(dt,J=15.6,8.0Hz,1H),2.58(d,J=16.8Hz,3H),2.30(d,J=37.4Hz,2H),2.07(s,1H),1.00(q,J=6.7Hz,3H).13C NMR(101MHz,DMSO)δ170.8,170.5,160.7,155.5,155.4,153.1,152.9,143.6,141.6,141.2,135.8,135.7,133.7,133.3,132.4,131.9,129.3,129.2,127.9,127.4,127.0,126.8,126.7,126.0,124.6,122.4,122.2,121.1,120.6,113.0,112.4,112.3,111.9,111.5,48.5,46.3,46.2,45.3,45.2,41.7,21.5,21.2,13.3,13.1,9.0.HRMS(ESI)[M-H]-calcd forC26H23BrClN2O7S:621.0098;found:621.0098.
实施例143
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)新戊酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-84)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为特戊酰氯,其余条件均一致。得白色固体293mg,收率84%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.0Hz,1H),7.78–7.57(m,2H),7.17(s,1H),7.07(dd,J=8.3,2.4Hz,1H),6.37–6.22(m,3H),5.49–4.43(m,4H),4.07–3.76(m,4H),3.13(dq,J=13.6,6.9Hz,1H),2.60(s,3H),1.57–1.28(m,9H),1.23(d,J=3.8Hz,2H),1.09(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ178.7,160.3,156.2,143.0,141.8,135.9,135.2,129.5,128.5,127.7,127.4,125.9,122.4,113.0,112.5,112.1,111.6,110.6,57.4,52.5,47.0,39.4,28.5,14.5,13.7,9.5.
实施例144
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)新戊酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S84’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)新戊酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-84),其余条件均一致。得淡黄色固体30mg,收率9%。
实施例145
5-(N-(2-((1-((5-溴呋喃-2-基)甲基)-3,3-二甲基脲基))甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-85)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为二甲氨基甲酰氯,其余条件均一致。得白色固体203mg,收率60%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.0Hz,1H),7.72(dd,J=8.8,1.5Hz,1H),7.65(d,J=8.8Hz,1H),7.49(d,J=2.1Hz,1H),7.12–7.03(m,1H),6.39(dd,J=8.4,2.9Hz,1H),6.35(d,J=3.2Hz,1H),6.24(d,J=3.2Hz,1H),4.79(d,J=18.1Hz,1H),4.63(d,J=18.0Hz,1H),4.55–4.08(m,3H),4.07–3.68(m,4H),3.17(dq,J=13.7,6.8Hz,1H),2.92(s,6H),2.60(s,3H),1.47(t,J=7.1Hz,1H),1.06(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ164.5,160.1,159.7,156.0,153.8,143.1,142.8,142.4,135.8,135.0,133.0,132.9,129.4,129.3,128.5,127.7,127.4,127.2,127.1,125.7,125.4,122.3,120.6,112.8,112.3,111.9,61.6,52.3,49.2,46.8,45.1,38.6,14.3,13.5,9.3,9.3.
实施例146
5-(N-(2-((1-((5-溴呋喃-2-基)甲基)-3,3-二甲基脲基))甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S85’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((1-((5-溴呋喃-2-基)甲基)-3,3-二甲基脲基))甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-85),其余条件均一致。得白色固体162mg,收率50%。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.88(d,J=8.7Hz,1H),7.68(d,J=8.7Hz,1H),7.39(s,1H),7.25(d,J=8.3Hz,1H),6.62(d,J=8.5Hz,1H),6.48(d,J=2.8Hz,1H),6.45–6.25(m,1H),4.56(q,J=17.6Hz,2H),4.31(dd,J=75.6,16.1Hz,2H),3.89(dd,J=13.2,7.0Hz,1H),3.22(dd,J=13.1,6.7Hz,1H),2.86(s,6H),2.59(s,3H),0.96(t,J=6.9Hz,3H).13C NMR(101MHz,DMSO)δ163.6,160.7,155.4,153.8,143.4,142.4,135.8,133.4,132.4,129.4,129.2,127.4,126.9,124.7,122.2,120.4,113.0,112.4,111.6,56.1,48.1,46.2,45.6,18.6,13.3,9.0.HRMS(ESI)[M-H]-calcd for C27H26BrClN3O7S:650.0363;found:650.0364.
实施例147
5-N(-(2-((N-((5-溴呋喃-2-基)甲基)哌啶-1-甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-86)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为1-哌啶酰氯,其余条件均一致。得白色固体214mg,收率59%。1HNMR(400MHz,Chloroform-d)δ7.98(s,1H),7.75–7.40(m,3H),7.12–7.02(m,1H),6.45–6.21(m,3H),4.80–4.11(m,3H),4.10–3.66(m,6H),3.56–3.10(m,4H),2.88–1.89(m,5H),1.61(s,4H),1.46(t,J=7.1Hz,1H),1.28(dt,J=17.7,7.2Hz,1H),1.04(dt,J=13.7,7.1Hz,3H).13CNMR(101MHz,CDCl3)δ164.3,160.1,155.9,155.9,155.8,153.8,143.9,142.8,142.4,135.8,135.6,134.9,134.6,133.0,130.2,129.2,129.2,128.6,127.7,127.5,127.4,127.2,127.0,125.7,122.3,122.2,120.6,120.5,112.8,112.8,112.2,111.8,111.6,109.9,61.5,52.3,49.0,47.9,46.8,46.7,46.0,45.0,41.7,25.6,24.6,14.3,13.5,13.5,9.3.
实施例148
5-N(-(2-((N-((5-溴呋喃-2-基)甲基)哌啶-1-甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S86’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-N(-(2-((N-((5-溴呋喃-2-基)甲基)哌啶-1-甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-86),其余条件均一致。得淡黄色固体158mg,收率46%。1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.94–7.55(m,3H),7.22(s,1H),6.66–6.28(m,3H),4.72–3.69(m,6H),3.21(s,4H),2.55(s,4H),1.22(d,J=235.9Hz,8H).13C NMR(101MHz,DMSO)δ163.8,161.8,155.7,154.1,153.1,145.6,142.8,141.1,136.4,136.3,133.8,133.7,132.6,129.9,129.4,128.5,127.8,127.2,126.8,123.4,122.3,121.5,120.9,113.2,113.0,112.8,111.9,48.4,47.8,46.6,46.3,46.1,44.3,25.7,24.6,13.7,9.5.HRMS(ESI)[M-H]-calcd for C30H30BrClN3O7S:690.0676;found:690.0682.
实施例149
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)吗啉-4-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-87)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为4-吗啉碳酰氯,其余条件均一致。得白色固体240mg,收率66%。1H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.74–7.62(m,2H),7.40(d,J=2.1Hz,1H),7.11(dd,J=8.4,2.0Hz,1H),6.43–6.29(m,2H),6.25(d,J=3.2Hz,1H),4.87(d,J=18.0Hz,1H),4.69(d,J=18.0Hz,1H),4.58–4.08(m,3H),4.08–3.60(m,8H),3.34(s,4H),3.15(dq,J=13.7,6.8Hz,1H),2.60(s,3H),1.47(t,J=7.1Hz,1H),1.07(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ164.0,160.0,159.6,155.9,153.3,143.0,142.8,141.8,135.9,134.9,132.7,132.6,129.3,129.2,128.4,127.5,127.4,127.1,127.0,125.6,125.3,122.2,120.7,112.7,112.3,111.9,66.4,61.5,52.3,49.1,47.3,46.7,44.5,14.3,13.4,9.3,9.2.
实施例150
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)吗啉-4-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S87’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)吗啉-4-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-87),其余条件均一致。得白色固体189mg,收率54%。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.85(d,J=8.6Hz,1H),7.63(d,J=8.6Hz,1H),7.35(s,1H),7.27(d,J=8.3Hz,1H),6.61(d,J=8.4Hz,1H),6.55–6.46(m,1H),6.42(s,1H),4.85–4.53(m,2H),4.38(dd,J=84.7,16.1Hz,2H),3.90(dd,J=12.8,6.8Hz,1H),3.66(s,4H),3.45–3.06(m,5H),2.58(d,J=13.7Hz,3H),0.96(t,J=6.6Hz,3H).13C NMR(101MHz,DMSO)δ163.3,161.7,155.1,153.4,146.5,142.0,136.0,133.4,131.8,129.8,129.4,127.6,126.8,126.1,121.8,120.6,112.7,112.5,111.8,65.9,48.0,47.1,46.2,45.3,13.3,9.1.HRMS(ESI)[M-H]-calcd for C29H28BrClN3O8S:692.0469;found:692.0467.
实施例151
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)呋喃-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-88)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为呋喃甲酰氯,其余条件均一致。得白色固体261mg,收率74%。1HNMR(400MHz,Chloroform-d)δ8.09–7.94(m,1H),7.77–7.61(m,2H),7.59–7.00(m,4H),6.74–6.14(m,4H),5.72–4.08(m,5H),4.06–3.89(m,3H),3.19(s,1H),2.69–1.97(m,4H),1.47(td,J=7.1,2.4Hz,1H),1.33–1.08(m,3H).13C NMR(101MHz,CDCl3)δ160.5,160.0,159.7,156.0,152.4,144.5,143.1,142.8,141.4,135.7,134.9,129.4,129.3,128.3,127.7,127.2,127.1,125.7,125.4,122.4,117.3,113.0,112.8,112.3,111.5,61.5,52.3,46.8,41.6,14.3,14.1,13.5,9.3,9.3.
实施例152
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)呋喃-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S88’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)呋喃-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-88),其余条件均一致。得白色固体91mg,收率27%。1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.95–7.75(m,2H),7.66(d,J=8.4Hz,1H),7.34–7.01(m,3H),6.77–6.56(m,2H),6.47(d,J=18.9Hz,2H),4.88(s,4H),3.94(dd,J=12.6,6.8Hz,1H),3.23(dd,J=12.2,6.3Hz,1H),2.57(d,J=18.5Hz,3H),1.01(t,J=6.2Hz,3H).13C NMR(101MHz,DMSO)δ161.4,159.8,155.2,152.6,146.5,145.7,145.6,141.1,135.8,133.3,131.8,129.6,129.3,127.7,126.3,122.4,121.9,116.8,112.8,112.5,111.7,46.3,13.3,9.0.HRMS(ESI)[M-H]-calcd for C29H23BrClN2O8S:673.0047;found:673.0052.
实施例153
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)噻吩-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-89)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)-2-氯代苯甲酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-71)所用方法,将邻氯苯甲酰氯替换为噻吩甲酰氯,其余条件均一致。得白色固体300mg,收率83%。1HNMR(400MHz,Chloroform-d)δ8.00(s,1H),7.75–7.44(m,3H),7.34(s,1H),7.27–6.88(m,2H),6.54–6.13(m,3H),5.77–4.08(m,5H),4.01(s,3H),3.16(dq,J=13.3,6.2Hz,1H),2.60(s,4H),1.47(td,J=6.9,3.1Hz,1H),1.17(dt,J=70.3,7.2Hz,3H).13C NMR(101MHz,CDCl3)δ165.0,160.0,159.6,156.5,155.9,142.8,141.1,136.8,135.8,135.0,130.1,129.3,129.3,129.2,128.5,127.9,127.3,127.2,127.1,125.7,125.4,122.3,121.3,112.8,112.3,112.3,111.9,110.2,67.9,61.5,57.0,52.3,46.7,14.3,13.5,9.3,9.3.
实施例154
5-(N-(2-((N-((5-溴呋喃-2-基)甲基)噻吩-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S89’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((N-((5-溴呋喃-2-基)甲基)噻吩-2-甲酰胺)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-89),其余条件均一致。得淡黄色固体213mg,收率62%。1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.01–7.53(m,4H),7.36–7.13(m,3H),6.66(d,J=7.4Hz,1H),6.49(d,J=9.7Hz,2H),5.50–4.65(m,4H),4.10–3.77(m,1H),3.23(dd,J=13.1,6.9Hz,1H),2.62(s,3H),1.00(s,3H).13CNMR(101MHz,DMSO)δ164.1,161.3,155.3,152.4,145.2,140.9,137.0,135.8,133.5,131.8,130.8,129.6,129.4,129.2,127.9,127.6,126.5,126.4,123.1,122.1,121.0,112.8,112.5,112.3,46.3,13.3,9.1.HRMS(ESI)[M-H]-calcd forC29H23BrClN2O7S2:688.9819;found:688.9825.
实施例155
5-(N-(4-氯-2-(((呋喃-2-基甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M16)
按照5-(N-(4-氯-2-((新戊基氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-69)所用方法,将特戊醛替换为糠醛,其余条件均一致。得白色固体2.46g,收率74%。
实施例156
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)
按照5-(N-(2-((N-((5-溴呋喃-2-基)甲基)乙酰氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-83)所用方法,将5-(N-(2-((((5-溴呋喃-2-基)甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M15-71)替换为5-(N-(4-氯-2-(((呋喃-2-基甲基)氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M16),其余条件均一致。得白色固体230mg,收率80%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=14.2Hz,1H),7.77–7.62(m,2H),7.37(d,J=38.2Hz,1H),7.20–6.99(m,2H),6.45–6.21(m,3H),5.09(dd,J=52.4,17.5Hz,1H),4.88–4.39(m,5H),3.98(ddd,J=25.4,12.7,7.7Hz,1H),3.16(ddq,J=32.3,13.5,6.8Hz,1H),2.60(s,3H),2.30(d,J=104.4Hz,3H),1.46(t,J=7.1Hz,3H),1.05(t,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ171.4,171.3,159.6,159.5,155.9,155.8,150.4,149.9,143.0,142.9,142.5,142.1,141.8,141.2,135.6,135.5,135.1,134.7,133.0,132.1,129.3,129.2,128.3,128.2,127.9,127.7,127.3,127.0,126.9,126.6,125.3,125.2,122.2,122.2,112.7,112.7,110.3,110.3,108.9,108.7,61.5,61.4,48.6,46.7,46.5,45.6,45.1,41.7,21.6,21.4,14.2,13.4,13.3,9.2.
实施例157
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S90’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90),其余条件均一致。得白色固体206mg,收率95%。1HNMR(400MHz,DMSO-d6)δ8.11(s,1H),7.88(d,J=9.0Hz,1H),7.63(d,J=39.0Hz,2H),7.28(dd,J=18.9,8.5Hz,1H),7.11(d,J=29.6Hz,1H),6.62(d,J=8.1Hz,1H),6.40(t,J=21.3Hz,2H),5.06–4.45(m,4H),3.96(s,1H),3.24(s,1H),2.61(s,3H),2.38(s,2H),2.08(s,1H),1.00(s,3H).13C NMR(101MHz,DMSO)δ171.0,170.6,161.3,155.3,150.7,150.5,145.1,143.1,142.6,141.8,141.3,135.9,135.8,133.8,133.4,132.3,131.7,129.6,129.3,128.0,127.5,126.9,126.5,126.1,123.2,122.2,122.0,112.9,110.6,108.8,108.5,48.4,46.4,45.3,45.1,41.6,21.6,21.3,13.3,13.2,9.1.HRMS(ESI)[M-H]-calcd for C26H24ClN2O7S:543.0993;found:543.0995.
实施例158
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)新戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-91)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为特戊酰氯,其余条件均一致。得白色固体190mg,收率62%。1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.74–7.59(m,2H),7.34(s,1H),7.19(s,1H),7.07(d,J=8.2Hz,1H),6.45–6.29(m,2H),6.26(s,1H),5.57–3.85(m,7H),3.14(dq,J=13.4,6.7Hz,1H),2.60(s,3H),1.46(t,J=7.1Hz,3H),1.38(s,8H),1.26(s,1H),1.05(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.7,156.0,143.1,142.1,141.8,135.7,135.0,129.4,128.4,127.4,127.1,125.4,122.2,112.8,110.4,108.5,61.6,46.8,39.2,28.4,14.3,13.4,9.3.
实施例159
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)新戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S91’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)新戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-91),其余条件均一致。得白色固体158mg,收率90%。1HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.85(d,J=8.4Hz,1H),7.62(d,J=11.5Hz,2H),7.26(d,J=7.4Hz,1H),7.06(s,1H),6.62(d,J=8.2Hz,1H),6.41(s,1H),6.29(s,1H),5.18–4.80(m,2H),4.73–4.28(m,2H),3.90(dd,J=13.4,7.0Hz,1H),3.20(dd,J=13.6,7.0Hz,1H),2.59(s,3H),1.32(s,9H),0.94(s,3H).13C NMR(101MHz,DMSO)δ177.1,161.6,155.2,150.6,146.2,142.7,141.6,135.9,133.4,131.9,129.8,129.4,127.5,126.2,122.0,121.8,112.8,110.6,108.5,47.3,46.3,38.7,28.2,13.3,9.1.HRMS(ESI)[M-H]-calcd for C29H30ClN2O7S:585.1462;found:585.1465.
实施例160
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-92)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为正戊酰氯,其余条件均一致。得白色固体160mg,收率93%。1H NMR(400MHz,Chloroform-d)δ7.99(d,J=12.7Hz,1H),7.78–7.60(m,2H),7.44–7.29(m,1H),7.14(s,1H),7.06(dd,J=24.9,8.4Hz,1H),6.43–6.22(m,3H),5.11(dd,J=48.1,17.6Hz,1H),4.89–4.36(m,4H),4.04–3.88(m,2H),3.16(ddq,J=33.5,13.5,6.9Hz,1H),2.70(td,J=7.4,3.3Hz,1H),2.60(s,3H),2.35(hept,J=7.6Hz,1H),2.19–1.24(m,7H),1.06(t,J=6.2Hz,3H),0.94(dt,J=31.5,7.3Hz,3H).13C NMR(101MHz,CDCl3)δ174.0,174.0,160.0,159.7,159.6,156.0,155.9,150.7,150.1,143.1,143.0,142.9,142.5,142.1,142.1,141.6,135.7,135.6,135.1,134.8,133.2,132.3,129.4,129.3,129.2,128.5,128.3,127.9,127.7,127.3,127.2,127.1,127.0,126.8,125.6,125.4,125.3,122.3,122.3,112.8,112.8,110.4,110.4,108.8,108.7,61.5,61.5,52.3,47.8,46.9,46.6,45.4,45.0,42.0,32.7,27.3,27.3,22.5,22.3,14.3,13.8,13.8,13.5,13.3,9.3,9.2.
实施例161
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S92’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)戊酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-92),其余条件均一致。得白色固体141mg,收率92%。1HNMR(400MHz,Chloroform-d)δ7.95(d,J=6.7Hz,1H),7.64(d,J=15.6Hz,2H),7.35(d,J=38.7Hz,1H),7.19–6.95(m,2H),6.42–6.02(m,3H),5.25–4.38(m,6H),3.12(ddd,J=28.0,12.9,6.7Hz,1H),2.84–2.68(m,1H),2.60(d,J=7.4Hz,3H),2.39(p,J=7.6Hz,1H),1.73(dp,J=30.0,7.5Hz,2H),1.40(ddq,J=40.3,14.5,7.2Hz,2H),1.04(t,J=6.9Hz,2H),0.92(dt,J=32.3,7.3Hz,3H).13CNMR(101MHz,CDCl3)δ175.1,156.1,156.0,150.4,149.7,144.4,142.8,142.4,141.7,141.3,135.8,135.7,135.3,134.9,132.9,132.1,129.8,129.7,128.3,127.9,127.6,126.9,125.3,122.4,112.9,110.5,109.2,109.0,48.2,46.9,46.7,45.7,45.1,42.4,32.9,27.6,27.5,22.6,22.4,13.9,13.9,13.5,13.5,9.4.HRMS(ESI)[M-H]+calcd forC29H30ClN2O7S:585.1462;found:585.1465.
实施例162
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-93)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为丙烯酰氯,其余条件均一致。得白色固体101mg,收率91%。1H NMR(400MHz,Chloroform-d)δ7.99(d,J=12.7Hz,1H),7.73(dd,J=14.4,9.2Hz,1H),7.65(d,J=8.9Hz,1H),7.37(d,J=36.0Hz,1H),7.16(s,1H),7.12–7.02(m,1H),7.02–6.29(m,5H),5.90–5.67(m,1H),5.20(dd,J=57.4,17.6Hz,1H),4.91–4.45(m,3H),4.02(s,4H),3.16(ddq,J=33.3,13.5,6.8Hz,1H),2.60(s,3H),1.26(s,1H),1.07(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ167.3,167.1,160.1,156.1,150.4,149.9,143.0,142.8,142.4,141.8,141.5,135.8,135.5,135.3,135.0,133.3,132.4,129.9,129.4,129.2,128.5,128.2,128.1,127.9,127.6,127.3,127.0,125.7,122.5,112.9,110.5,109.2,108.9,52.4,47.9,47.0,46.7,46.0,45.0,42.5,29.7,13.5,13.4,9.3.
实施例163
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S93’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-93),其余条件均一致。得白色固体66mg,收率69%。1HNMR(400MHz,DMSO-d6)δ8.08(s,1H),7.86(d,J=8.7Hz,1H),7.77–7.49(m,2H),7.31–7.19(m,1H),7.09(d,J=18.9Hz,1H),6.58(t,J=8.4Hz,1H),6.36(t,J=28.0Hz,2H),5.03–4.50(m,4H),3.90(dd,J=12.9,6.9Hz,1H),3.71(t,J=5.9Hz,1H),3.49(q,J=6.9Hz,1H),3.20(tt,J=11.9,6.8Hz,1H),2.89(t,J=6.0Hz,1H),2.57(s,3H),0.96(t,J=6.9Hz,3H).13C NMR(101MHz,DMSO)δ171.6,171.1,161.0,155.3,150.6,150.5,144.5,143.1,142.6,141.6,141.2,135.9,135.6,133.6,133.3,132.3,129.4,129.3,127.5,126.7,126.6,123.7,122.2,122.1,112.9,110.5,108.7,108.4,66.4,66.0,65.6,65.4,47.3,46.3,45.1,44.4,41.7,32.9,15.1,15.1,13.3,13.1,9.0.HRMS(ESI)[M-H]+calcd for C27H24ClN2O7S:555.0993;found:555.0989.
实施例164
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-94)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为甲基丙烯酰氯,其余条件均一致。得白色固体107mg,收率94%。1H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.70(s,1H),7.64(d,J=8.7Hz,1H),7.38(s,1H),7.29–6.93(m,2H),6.44–6.23(m,3H),5.42–4.30(m,6H),4.02(s,3H),3.93(dd,J=12.9,7.1Hz,1H),3.16(s,1H),2.59(s,3H),2.31–0.78(m,8H).13C NMR(101MHz,CDCl3)δ173.5,160.2,156.1,142.9,141.8,135.7,129.4,128.6,127.3,125.8,122.5,112.9,110.5,109.2,52.4,46.9,20.8,13.4,9.4.
实施例165
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S94’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基丙烯酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-94),其余条件均一致。得白色固体73mg,收率72%。1H NMR(400MHz,DMSO-d6)δ8.15–8.02(m,1H),7.85(d,J=8.6Hz,1H),7.73–6.88(m,4H),6.71–6.19(m,3H),5.57–4.28(m,6H),3.88(dq,J=14.3,7.3Hz,1H),3.30–3.07(m,1H),2.57(d,J=3.1Hz,3H),2.51(s,1H),2.00(s,2H),1.04–0.90(m,3H).13C NMR(101MHz,DMSO)δ177.8,172.3,161.1,155.2,150.0,145.0,141.3,139.9,135.8,129.5,129.3,127.9,126.4,126.3,123.1,122.0,112.8,110.6,108.9,78.2,51.4,46.2,20.3,13.2,9.0.HRMS(ESI)[M-H]+calcd forC28H26ClN2O7S:569.1149;found:569.1151.
实施例166
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2,2-二甲基丙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-95)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为氯代特戊酰氯,其余条件均一致。得白色固体168mg,收率92%。1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.66(q,J=8.9Hz,2H),7.31(d,J=30.3Hz,2H),7.09(d,J=8.1Hz,1H),6.41–6.24(m,3H),5.81–4.28(m,5H),4.27–3.89(m,3H),3.86(d,J=11.0Hz,1H),3.75(d,J=11.0Hz,1H),3.13(dq,J=13.6,6.8Hz,1H),2.60(s,3H),1.47(d,J=6.6Hz,8H),1.05(t,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ175.4,160.1,159.7,156.0,150.3,143.1,142.9,142.2,141.2,135.7,135.1,129.4,129.3,128.3,127.6,127.3,127.2,127.1,125.7,125.4,122.3,122.2,112.8,110.5,108.9,61.6,54.0,52.3,48.0,46.8,44.5,24.1,23.6,14.3,13.4,9.3,9.3.
实施例167
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2,2-二甲基丙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S95’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2,2-二甲基丙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-95),其余条件均一致。得白色固体149mg,收率93%。1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.63(s,2H),7.37–7.19(m,2H),7.07(d,J=6.8Hz,1H),6.32(dd,J=19.6,5.5Hz,3H),5.39(s,1H),5.20–4.53(m,4H),3.81(dd,J=39.0,10.6Hz,2H),3.09(s,1H),2.58(s,3H),1.48(s,6H),1.02(s,3H).13C NMR(101MHz,CDCl3)δ175.9,164.5,156.0,150.1,144.6,142.4,141.0,135.8,135.1,132.2,129.7,128.4,127.8,127.3,126.9,125.2,122.2,112.9,110.6,109.1,54.0,48.1,46.8,44.7,24.2,23.8,13.4,9.4.HRMS(ESI)[M-H]+calcd for C29H29Cl2N2O7S:619.1073;found:619.1075.
实施例168
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-96)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为环丙基甲酰氯,其余条件均一致。得白色固体162mg,收率97%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=12.3Hz,1H),7.80–7.60(m,2H),7.36(d,J=40.0Hz,1H),7.28–7.00(m,2H),6.46–6.18(m,3H),5.23(dd,J=147.6,17.6Hz,1H),4.80(ddd,J=22.4,17.4,8.0Hz,2H),4.46(dd,J=15.2,8.9Hz,2H),4.06–3.88(m,2H),3.16(ddq,J=33.5,13.7,6.8Hz,1H),2.59(s,3H),1.46(t,J=7.1Hz,2H),1.34–0.98(m,7H),0.90(s,1H),0.79(d,J=7.0Hz,1H).13C NMR(101MHz,CDCl3)δ174.5,174.4,160.0,159.7,156.0,156.0,150.7,150.4,143.1,143.1,142.5,142.2,142.1,141.8,135.7,135.5,135.1,134.8,133.2,132.4,129.4,129.3,128.5,128.1,127.9,127.7,127.4,127.3,127.1,127.0,125.6,125.3,122.3,112.8,110.4,110.4,108.9,108.5,61.6,52.3,48.0,46.9,46.6,46.0,44.9,42.6,31.8,29.6,29.6,22.6,14.3,13.5,13.4,11.5,11.4,9.3,9.2,8.4,8.2,7.9.
实施例169
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S96’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-96),其余条件均一致。得白色固体122mg,收率79%。1H NMR(400MHz,Chloroform-d)δ7.81(d,J=8.5Hz,1H),7.70–7.42(m,2H),7.40–7.13(m,2H),7.07–6.94(m,1H),6.31(d,J=9.8Hz,2H),6.25(s,1H),5.48–4.37(m,5H),3.06(s,1H),2.46(d,J=20.4Hz,3H),1.26(s,2H),1.11(s,1H),1.05–0.95(m,3H),0.90(s,1H),0.84–0.65(m,1H).13C NMR(101MHz,CDCl3)δ175.1,155.8,155.6,150.6,150.0,142.8,142.4,141.6,135.8,135.7,135.2,134.9,132.1,129.9,127.8,127.3,126.6,112.9,110.6,110.5,109.2,108.7,48.2,46.8,46.3,45.1,42.9,32.0,29.8,29.4,22.8,14.2,13.5,11.7,11.6,9.3,8.5.HRMS(ESI)[M-H]+calcd for C28H26ClN2O7S:569.1149;found:569.1153.
实施例170
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丁烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-97)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为环丁基甲酰氯,其余条件均一致。得白色固体162mg,收率94%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=6.6Hz,1H),7.76–7.68(m,1H),7.68–7.61(m,1H),7.35(d,J=35.9Hz,1H),7.15–6.98(m,2H),6.43–6.16(m,3H),5.04(dd,J=26.4,17.6Hz,1H),4.94–4.25(m,4H),4.03–3.89(m,2H),3.79–3.03(m,2H),2.60(d,J=4.9Hz,3H),2.57–1.78(m,7H),1.46(t,J=7.1Hz,2H),1.06(q,J=6.6Hz,3H).13C NMR(101MHz,CDCl3)δ175.5,175.3,160.0,159.7,159.6,156.0,155.9,150.7,150.0,143.1,143.0,142.9,142.5,142.1,142.1,141.6,135.6,135.6,135.1,134.8,133.2,132.3,129.4,129.3,129.2,128.5,128.2,127.6,127.6,127.2,127.1,127.0,126.9,125.7,125.6,125.4,125.3,122.3,112.8,112.8,110.4,110.3,108.7,61.6,61.5,52.3,47.2,46.9,46.6,45.4,44.5,41.8,37.1,36.9,25.6,25.5,24.8,24.7,18.0,17.8,14.3,13.5,13.3,9.3.
实施例171
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丁烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S97’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丁烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-97),其余条件均一致。得白色固体151mg,收率98%。1H NMR(400MHz,Chloroform-d)δ7.90(d,J=6.1Hz,1H),7.63(d,J=12.4Hz,2H),7.33(d,J=33.2Hz,1H),7.14–6.94(m,2H),6.60–6.20(m,3H),5.12–4.24(m,6H),3.51(dp,J=171.5,9.1,8.6Hz,1H),3.23–2.95(m,1H),2.51(dd,J=32.4,13.4Hz,4H),2.41–2.15(m,2H),2.04(dd,J=18.6,8.8Hz,1H),1.93(dt,J=17.5,9.5Hz,1H),1.17–0.81(m,3H).13C NMR(101MHz,CDCl3)δ176.2,176.1,156.0,155.8,150.5,149.6,145.1,142.8,142.3,141.7,141.4,135.7,135.2,134.9,132.7,132.1,129.8,129.7,128.3,127.8,127.5,126.9,124.7,122.2,112.9,110.6,110.5,109.0,108.9,47.4,46.7,45.6,44.6,42.1,37.3,37.0,25.7,25.2,24.9,18.1,17.9,13.5,13.4,9.4.HRMS(ESI)[M-H]+calcd for C29H28ClN2O7S:583.1306;found:583.1318.
实施例172
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环戊烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-98)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为环戊基甲酰氯,其余条件均一致。得白色固体158mg,收率90%。1H NMR(400MHz,Chloroform-d)δ7.98(d,J=9.7Hz,1H),7.77–7.60(m,2H),7.36(d,J=37.1Hz,1H),7.19–6.98(m,2H),6.45–6.19(m,3H),5.15(dd,J=81.2,17.6Hz,1H),4.93–4.31(m,4H),4.03–3.87(m,2H),3.41–2.78(m,2H),2.60(d,J=3.4Hz,3H),2.13–1.50(m,9H),1.46(t,J=7.1Hz,2H),1.05(q,J=6.6Hz,3H).13C NMR(101MHz,CDCl3)δ177.4,177.3,160.1,159.7,159.7,156.0,156.0,150.8,150.2,143.2,143.1,142.9,142.6,142.1,141.9,135.7,135.6,135.1,134.8,133.4,133.3,132.5,132.4,129.4,129.4,129.3,128.6,128.2,127.7,127.3,127.1,127.0,125.7,125.4,125.4,122.4,122.3,112.8,112.8,110.5,110.4,108.7,108.6,61.6,61.5,52.3,47.7,46.9,46.7,45.6,44.9,42.2,41.2,41.0,31.1,30.9,30.5,30.4,26.3,26.2,26.1,14.3,13.5,13.3,9.3.
实施例173
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环戊烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S98’)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环戊烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-98),其余条件均一致。得白色固体145mg,收率96%。1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.65(s,2H),7.34(d,J=38.0Hz,1H),7.20–6.94(m,2H),6.41–6.29(m,2H),6.27(s,1H),5.36–4.66(m,5H),4.58(s,1H),3.46–2.67(m,2H),2.66–1.49(m,10H),1.03(t,J=6.3Hz,3H).13C NMR(101MHz,CDCl3)δ178.2,178.1,164.2,156.0,155.9,150.6,149.8,144.8,142.8,142.3,141.8,141.7,135.8,135.7,135.2,134.9,132.8,132.1,129.8,129.7,128.3,127.9,127.5,127.0,125.0,122.3,112.9,110.6,110.5,109.0,108.9,47.9,46.9,46.7,45.8,45.1,42.5,41.4,41.2,31.1,30.9,30.6,26.3,26.2,13.5,13.4,9.4.HRMS(ESI)[M-H]+calcd for C30H30ClN2O7S:597.1462;found:597.1469.
实施例174
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环己烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-99)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为环己基甲酰氯,其余条件均一致。得白色固体132mg,收率99%。1H NMR(400MHz,Chloroform-d)δ7.99(dd,J=7.3,1.8Hz,1H),7.72(ddd,J=17.2,8.8,1.9Hz,1H),7.65(dd,J=8.8,5.9Hz,1H),7.43–7.29(m,1H),7.17–6.97(m,2H),6.43–6.18(m,3H),5.13(dd,J=64.0,17.6Hz,1H),4.90–4.32(m,3H),4.02(s,4H),3.15(ddq,J=36.1,13.6,6.9Hz,1H),3.00–2.37(m,4H),2.02–1.16(m,11H),1.06(td,J=7.1,3.5Hz,3H).13C NMR(101MHz,CDCl3)δ177.2,160.2,160.1,156.1,156.0,150.8,150.2,142.9,142.8,142.7,142.2,142.1,135.7,135.6,135.2,134.9,133.4,132.4,129.4,129.3,128.6,128.2,127.8,127.7,127.3,127.2,126.9,125.8,125.7,122.4,112.9,110.5,110.4,108.7,108.7,52.4,47.6,47.0,46.7,45.3,44.9,42.1,40.8,40.6,30.0,29.8,29.4,29.3,26.0,25.8,25.7,25.6,13.6,13.4,9.3.
实施例175
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环己烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S99’)
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按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环己烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-99),其余条件均一致。得白色固体99mg,收率85%。1H NMR(400MHz,DMSO-d6)δ8.08(d,J=5.3Hz,1H),7.86(d,J=8.7Hz,1H),7.77–7.39(m,2H),7.23(td,J=10.5,8.5,5.4Hz,1H),6.96(s,1H),6.57(t,J=8.2Hz,1H),6.49–6.16(m,2H),5.11–4.44(m,4H),3.92(ddq,J=20.6,14.4,7.3,6.8Hz,1H),3.43–3.11(m,1H),2.95(t,J=10.3Hz,1H),2.57(s,3H),1.90–1.52(m,5H),1.41(tt,J=26.1,12.1Hz,3H),1.28–1.03(m,2H),0.96(q,J=7.2Hz,3H).13CNMR(101MHz,DMSO)δ176.2,175.7,161.1,155.3,155.2,150.7,150.6,144.8,143.1,142.6,141.8,135.8,135.6,133.5,133.2,132.3,131.5,129.5,129.4,129.3,127.8,127.3,126.6,126.4,126.0,123.3,122.1,122.0,112.9,110.5,110.5,108.6,108.3,47.4,46.2,45.2,44.5,41.8,29.4,29.4,29.3,29.1,25.5,25.4,25.1,13.3,13.1,9.0.HRMS(ESI)[M-H]+calcd for C31H32ClN2O7S:611.1619;found:611.1624.
实施例176
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-3,3-二甲基脲基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-100)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为二甲氨基甲酰氯,其余条件均一致。得白色固体175mg,收率58%。1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.76–7.67(m,1H),7.64(d,J=8.7Hz,1H),7.50–7.43(m,1H),7.34(s,1H),7.11–7.01(m,1H),6.39(d,J=8.4Hz,1H),6.34–6.22(m,2H),4.77–4.61(m,2H),4.60–4.39(m,3H),4.18(d,J=15.7Hz,1H),3.90(dq,J=14.4,7.2Hz,1H),3.18(dq,J=13.7,6.8Hz,1H),2.93(s,6H),2.59(s,3H),1.46(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ164.6,159.7,155.9,151.3,143.0,142.6,142.0,135.6,134.8,133.0,129.3,128.6,127.8,127.2,127.0,125.4,122.2,112.7,110.4,108.7,61.5,48.8,46.7,45.4,38.6,14.3,13.3,9.3.
实施例177
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-3,3-二甲基脲基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S100)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-3,3-二甲基脲基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-100),其余条件均一致。得白色固体138mg,收率83%。1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.80(d,J=8.6Hz,1H),7.59(s,2H),7.35(s,1H),7.24(d,J=7.9Hz,1H),6.59(d,J=8.4Hz,1H),6.40(s,1H),6.30(s,1H),4.51(s,2H),4.44(d,J=16.0Hz,1H),4.20(d,J=15.9Hz,1H),3.84(dq,J=14.7,7.5Hz,1H),3.20(dq,J=13.7,6.8Hz,1H),2.86(s,6H),2.57(s,3H),0.92(s,3H).13C NMR(101MHz,DMSO)δ163.7,162.4,154.9,151.2,148.2,142.6,142.6,135.9,133.2,131.7,130.0,129.5,127.3,126.9,125.5,121.4,120.0,112.5,110.5,108.5,47.8,46.1,45.7,38.2,13.2,9.0.HRMS(ESI)[M-H]-calcd forC27H27ClN3O7S:572.1258;found:572.1263.
实施例178
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)哌啶-1-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-101)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为1-哌啶酰氯,其余条件均一致。得白色固体195mg,收率61%。1H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.67(d,J=10.1Hz,1H),7.60(t,J=6.4Hz,1H),7.36(d,J=8.9Hz,1H),7.29(d,J=8.5Hz,1H),7.02(d,J=8.3Hz,1H),6.36(d,J=8.4Hz,1H),6.28(d,J=10.2Hz,1H),6.23(d,J=9.5Hz,1H),4.84–4.49(m,2H),4.45(q,J=7.0Hz,2H),4.18–3.79(m,4H),3.29(s,3H),3.16(dd,J=13.5,6.3Hz,2H),2.56(s,3H),1.68–1.38(m,8H),0.99(q,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ164.5,160.1,159.8,156.0,153.5,151.4,144.0,143.0,142.8,142.7,142.0,141.9,135.7,135.6,134.8,134.7,133.2,130.4,129.3,129.3,128.7,127.9,127.5,127.2,127.1,127.0,125.8,125.5,122.3,112.8,112.8,110.4,110.2,108.5,107.2,61.6,52.3,48.6,48.0,48.0,47.9,46.9,46.7,46.1,45.6,25.8,25.6,24.8,24.7,14.3,13.6,13.4,9.3.
实施例179
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)哌啶-1-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S101)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)哌啶-1-甲酰胺基)甲基)苯基)-N-甲基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-101),其余条件均一致。得淡黄色固体159mg,收率86%。1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(d,J=8.7Hz,1H),7.62(d,J=13.8Hz,2H),7.32(s,1H),7.25(d,J=7.7Hz,1H),6.61(d,J=8.1Hz,1H),6.41(s,1H),6.29(s,1H),4.48(d,J=38.9Hz,3H),4.21(d,J=15.9Hz,1H),3.94–3.78(m,1H),3.27(s,5H),2.58(s,3H),1.55(s,6H),0.94(s,3H).13C NMR(101MHz,DMSO)δ163.5,161.7,155.1,151.2,146.5,142.7,142.7,135.9,133.3,132.1,129.7,129.6,127.3,126.8,126.0,121.7,112.7,110.5,108.4,47.5,47.4,46.2,46.0,25.3,24.2,13.3,9.1.HRMS(ESI)[M-H]-calcd for C30H31ClN3O7S:612.1571;found:612.1573.
实施例180
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吗啉-4-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-102)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为4-吗啉碳酰氯,其余条件均一致。得白色固体234mg,收率73%。1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.73–7.61(m,2H),7.41–7.33(m,2H),7.13–7.04(m,1H),6.38(d,J=8.5Hz,1H),6.30(dd,J=9.0,2.4Hz,2H),4.87–4.65(m,2H),4.59(d,J=15.7Hz,1H),4.48(q,J=7.0Hz,2H),4.18(d,J=15.7Hz,1H),3.92(dq,J=14.5,7.2Hz,1H),3.74(dq,J=17.2,6.4Hz,4H),3.36(t,J=8.3Hz,4H),3.15(dq,J=13.6,6.8Hz,1H),2.59(s,3H),1.46(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)δ164.1,159.6,155.9,150.9,143.0,142.1,142.1,135.8,134.8,132.7,129.3,128.4,127.6,127.3,127.0,125.3,122.2,112.7,110.4,108.9,66.4,61.5,48.6,47.4,46.6,45.0,14.2,13.3,9.2.
实施例181
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吗啉-4-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S102)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吗啉-4-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-102),其余条件均一致。得白色固体145mg,收率65%。1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.94–7.77(m,1H),7.61(s,2H),7.29(d,J=26.6Hz,2H),6.62(s,1H),6.37(d,J=33.1Hz,2H),4.89–4.07(m,4H),3.87(s,1H),3.65(s,4H),3.30(s,5H),2.59(s,3H),0.93(s,3H).13C NMR(101MHz,DMSO)δ163.4,161.3,155.2,150.9,145.1,142.7,142.2,135.9,133.3,132.1,129.5,127.4,126.8,126.4,123.1,121.9,112.8,110.5,108.7,65.9,47.5,47.1,46.2,45.6,13.2,9.0.HRMS(ESI)[M-H]-calcd for C29H29ClN3O8S:614.1364;found:614.1371.
实施例182
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-103)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为呋喃甲酰氯,其余条件均一致。得白色固体270mg,收率87%。1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.73(d,J=8.7Hz,1H),7.65(d,J=8.7Hz,1H),7.52–6.99(m,5H),6.57–6.23(m,4H),5.63–4.44(m,6H),3.98(dd,J=14.6,8.9Hz,1H),3.18(s,1H),2.60(s,3H),1.46(t,J=7.1Hz,3H),1.08(t,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ160.5,159.6,156.4,155.8,150.1,147.0,144.4,142.9,142.3,141.5,135.6,134.8,129.3,129.2,128.3,127.5,127.0,125.3,122.2,117.1,112.8,112.7,111.3,110.4,110.2,61.4,46.6,14.2,13.3,9.2,9.1.
实施例183
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S103)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-103),其余条件均一致。得淡黄色固体225mg,收率88%。1H NMR(400MHz,DMSO-d6)δ8.06–7.79(m,3H),7.64(d,J=8.0Hz,2H),7.43–7.05(m,3H),6.83–6.54(m,2H),6.41(d,J=16.7Hz,2H),4.86(s,4H),3.93(dd,J=13.7,7.3Hz,1H),3.23(dd,J=13.8,7.4Hz,1H),2.58(d,J=15.4Hz,3H),1.00(s,3H).13C NMR(101MHz,DMSO)δ162.3,160.0,155.0,150.2,148.3,146.7,145.6,143.0,141.3,136.0,133.5,131.5,130.1,129.4,127.8,126.5,125.7,121.6,120.1,116.7,112.6,111.7,110.7,109.0,46.3,13.3,9.1.HRMS(ESI)[M-H]-calcd for C29H24ClN2O8S:595.0942;found:595.0945.
实施例184
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-104)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为噻吩甲酰氯,其余条件均一致。得白色固体112mg,收率35%。1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.71(d,J=8.7Hz,1H),7.64(d,J=8.7Hz,1H),7.55–7.20(m,4H),7.17–7.06(m,1H),7.02(s,1H),6.49–6.24(m,3H),4.97(dd,J=48.4,13.8Hz,2H),4.48(q,J=7.1Hz,2H),3.94(dq,J=14.5,7.2Hz,1H),3.16(s,1H),2.60(s,3H),2.35(s,2H),1.46(t,J=7.1Hz,3H),1.04(t,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ171.2,170.7,164.9,159.6,155.9,149.9,143.0,142.4,141.3,137.1,135.8,135.0,129.8,129.3,129.2,128.5,127.7,127.4,127.1,125.3,122.3,112.8,110.5,109.4,63.5,61.5,60.5,60.4,46.6,41.6,34.0,14.4,14.3,14.1,13.3,9.3.
实施例185
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S104)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-104),其余条件均一致。得白色固体164mg,收率99%。1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.01–7.37(m,5H),7.36–7.01(m,3H),6.66(s,1H),6.42(s,2H),4.84(d,J=52.3Hz,4H),3.93(s,1H),3.23(s,1H),2.62(s,3H),0.98(s,3H).13C NMR(101MHz,DMSO)δ164.1,161.2,155.3,149.9,145.0,143.1,141.0,137.1,135.9,133.5,131.9,130.7,129.5,129.4,129.2,127.5,126.5,123.3,122.1,112.9,110.6,109.2,46.3,13.2,9.1.HRMS(ESI)[M-H]-calcd for C29H24ClN2O7S2:611.0713;found:611.0721.
实施例186
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吡啶甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-105)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为2-吡啶甲酰氯,其余条件均一致。得白色固体174mg,收率55%。1H NMR(400MHz,Chloroform-d)δ8.55(dd,J=78.9,4.5Hz,1H),7.97(d,J=29.0Hz,1H),7.89–7.33(m,7H),7.06(ddd,J=8.3,5.5,2.5Hz,1H),6.45–6.37(m,1H),6.34(d,J=8.5Hz,1H),6.26–6.15(m,1H),5.21(dd,J=30.3,17.1Hz,1H),5.10–4.84(m,2H),4.61–4.44(m,3H),3.91(ddd,J=47.2,13.0,7.3Hz,1H),3.17(ddq,J=60.5,13.6,6.8Hz,1H),2.59(d,J=6.0Hz,3H),1.46(t,J=7.0Hz,3H),1.02(dt,J=76.3,7.1Hz,3H).13C NMR(101MHz,CDCl3)δ169.6,169.3,159.8,159.8,156.0,154.1,153.4,150.3,148.1,148.1,143.1,142.4,142.2,141.8,141.6,137.0,136.9,135.7,135.5,135.0,134.8,133.2,132.7,129.4,128.6,128.0,127.6,127.5,127.2,127.1,125.5,125.4,124.8,124.7,124.2,124.1,122.4,122.3,112.8,112.8,110.5,110.4,109.2,108.8,61.6,49.2,46.9,46.6,46.2,46.0,42.5,14.4,13.5,13.2,9.4.
实施例187
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吡啶甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S105)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)吡啶甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-105),其余条件均一致。得白色固体116mg,收率91%。1H NMR(400MHz,DMSO-d6)δ8.63(dd,J=82.7,4.9Hz,1H),8.22–7.19(m,9H),6.61(dd,J=32.9,8.4Hz,1H),6.50–6.05(m,2H),5.23–4.33(m,4H),3.89(ddq,J=63.6,14.6,7.4Hz,1H),3.19(ddq,J=58.0,13.8,6.9Hz,1H),2.66–2.52(m,3H),1.34–0.65(m,3H).13C NMR(101MHz,DMSO)δ169.1,168.8,160.9,155.4,153.7,153.5,150.1,150.0,148.4,148.3,144.0,143.0,142.7,141.2,141.0,137.6,137.5,135.9,135.6,133.4,132.2,131.9,129.3,129.0,127.8,127.6,127.2,126.7,126.5,125.0,124.9,124.2,123.6,123.2,122.2,113.0,110.5,108.8,108.7,48.4,46.3,46.1,45.7,45.3,41.8,13.3,12.9,9.0.HRMS(ESI)[M-H]-calcd forC30H25ClN3O7S:606.1102;found:606.1098.
实施例188
5-(N-(2-((5-溴-N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-106)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为5-溴呋喃-2-羰酰氯,其余条件均一致。得白色固体194mg,收率98%。1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.73(d,J=8.7Hz,1H),7.65(d,J=8.7Hz,1H),7.41–6.99(m,4H),6.39(d,J=8.1Hz,3H),6.33(s,1H),5.74–3.88(m,8H),3.19(s,1H),2.60(s,3H),1.46(t,J=7.1Hz,2H),1.09(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,159.6,156.0,149.9,148.7,143.0,142.8,142.5,141.3,135.7,134.9,129.3,129.2,128.4,127.6,127.2,127.0,125.7,125.3,125.0,122.4,122.3,119.4,113.5,112.8,110.5,109.4,61.5,52.3,46.8,14.3,13.5,9.3,9.2.
实施例189
5-(N-(2-((5-溴-N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S106)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-((5-溴-N-(呋喃-2-基甲基)呋喃-2-甲酰胺基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-106),其余条件均一致。得白色固体164mg,收率88%。1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.72(d,J=8.9Hz,1H),7.65(d,J=8.8Hz,1H),7.23(d,J=105.1Hz,4H),6.56–6.36(m,3H),6.32(s,1H),5.57–4.52(m,4H),3.97(dd,J=13.0,7.0Hz,1H),3.17(s,1H),2.62(s,3H),1.09(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ163.6,156.2,149.7,148.4,143.7,142.6,141.1,135.8,135.1,129.6,128.5,127.8,127.2,126.2,125.6,122.5,120.2,113.8,112.9,110.6,109.9,49.2,46.8,13.5,9.5.HRMS(ESI)[M-H]+calcd for C29H23Cl2BrN2O8S:673.0047;found:673.0044.
实施例190
5-(N-(4-氯-2-((5-氯-N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-107)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为5-氯噻吩-2-甲酰氯,其余条件均一致。得白色固体174mg,收率92%。1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.71(d,J=8.8Hz,1H),7.65(d,J=8.8Hz,1H),7.55–6.96(m,4H),6.84(s,1H),6.49–6.36(m,2H),6.34(s,1H),6.04–3.78(m,8H),3.15(dq,J=13.5,6.8Hz,1H),2.61(s,3H),1.46(t,J=7.1Hz,2H),1.05(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ163.7,160.1,159.7,156.0,149.7,143.1,142.9,142.6,141.0,136.3,135.9,135.3,135.1,129.4,129.3,129.1,128.5,127.9,127.3,127.2,127.1,126.6,125.7,125.4,122.4,122.3,112.9,110.6,109.6,61.6,52.4,46.7,14.3,13.4,9.3,9.3.
实施例191
5-(N-(4-氯-2-((5-氯-N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S107)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((5-氯-N-(呋喃-2-基甲基)噻吩-2-甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-107),其余条件均一致。得白色固体149mg,收率89%。1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.61(s,2H),7.43–7.03(m,4H),6.81(s,1H),6.36(dd,J=25.6,9.5Hz,3H),5.00–4.38(m,4H),3.89(s,1H),3.08(s,1H),2.54(s,3H),1.01(s,3H).13CNMR(101MHz,CDCl3)δ164.9,164.1,155.8,149.4,145.2,142.8,140.8,136.0,135.6,135.2,132.2,129.8,129.5,128.6,128.1,127.3,126.7,124.5,122.2,112.9,110.7,109.8,46.7,29.7,13.4,9.4.HRMS(ESI)[M-H]+calcd for C29H23Cl2N2O7S2:645.0324;found:645.0322.
实施例192
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2-苯基乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-108)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为苯乙酰氯,其余条件均一致。得白色固体176mg,收率97%。1H NMR(400MHz,Chloroform-d)δ7.96(d,J=8.6Hz,1H),7.74–7.59(m,2H),7.44–7.18(m,6H),7.03(dd,J=17.0,9.2Hz,2H),6.33(d,J=6.5Hz,2H),6.26(d,J=6.9Hz,1H),5.15(dd,J=77.5,17.6Hz,1H),4.87–4.74(m,1H),4.73–4.51(m,1H),4.51–3.79(m,6H),3.77(s,1H),3.13(ddq,J=33.5,13.4,6.7Hz,1H),2.58(d,J=5.0Hz,3H),1.45(t,J=7.2Hz,2H),1.02(dt,J=14.1,7.1Hz,3H).13C NMR(101MHz,CDCl3)δ171.9,171.9,160.0,159.7,159.6,156.0,155.9,150.4,149.8,143.1,143.0,142.9,142.7,142.1,141.8,141.0,135.6,135.5,135.0,134.9,134.8,134.5,133.2,133.1,132.2,129.4,129.3,129.0,128.9,128.8,128.4,128.2,127.8,127.7,127.3,127.1,127.0,126.9,126.8,125.7,125.6,125.4,125.3,122.4,122.3,112.8,112.8,110.5,110.4,108.9,108.9,61.5,61.5,52.3,48.2,46.8,46.6,45.3,45.0,42.0,40.9,40.4,14.3,13.5,13.3,9.2,9.2.
实施例193
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2-苯基乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S108)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)-2-苯基乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-108),其余条件均一致。得白色固体160mg,收率95%。1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.59(s,2H),7.28(ddt,J=39.3,26.7,8.0Hz,6H),6.99(q,J=10.6,8.8Hz,2H),6.55–6.01(m,3H),5.27–4.31(m,6H),4.09(q,J=15.1Hz,1H),3.07(d,J=22.8Hz,1H),2.51(d,J=12.3Hz,3H),1.09–0.70(m,3H).13C NMR(101MHz,CDCl3)δ172.8,155.9,155.7,150.1,149.4,145.3,142.9,142.3,141.4,140.7,135.8,135.7,135.1,134.9,134.6,134.2,132.6,131.9,129.8,129.8,129.1,128.8,128.6,127.6,127.2,127.0,126.7,124.3,122.2,112.8,110.6,110.5,109.2,109.2,48.4,46.8,45.5,45.0,42.2,41.0,40.6,13.5,13.4,9.3.HRMS(ESI)[M-H]+calcd for C32H28ClN2O7S:619.1306;found:619.1306.
实施例194
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基磺酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-109)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为甲磺酰氯,其余条件均一致。得白色固体100mg,收率86%。1H NMR(400MHz,Chloroform-d)δ7.95(d,J=1.4Hz,1H),7.72(d,J=1.7Hz,2H),7.65(d,J=8.7Hz,1H),7.54–7.40(m,1H),7.07(dd,J=8.5,2.4Hz,1H),6.42(d,J=3.1Hz,1H),6.39–6.34(m,1H),6.30(d,J=8.5Hz,1H),4.88(d,J=17.2Hz,1H),4.71(d,J=17.2Hz,1H),4.56(d,J=16.3Hz,1H),4.31(d,J=16.3Hz,1H),4.02(s,4H),3.15(dq,J=13.8,6.9Hz,1H),2.84(s,3H),2.59(s,3H),1.06(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.2,156.1,149.3,143.1,142.9,141.1,135.6,135.2,132.5,129.4,128.9,128.0,127.3,125.8,122.6,112.9,110.7,110.5,52.4,47.1,46.8,43.9,39.0,13.5,9.3.
实施例195
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基磺酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S109)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)甲基磺酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-109),其余条件均一致。得白色固体71mg,收率75%。1H NMR(400MHz,DMSO-d6)δ8.00(d,J=1.9Hz,1H),7.83(d,J=8.7Hz,1H),7.64(s,1H),7.60(dd,J=8.7,2.0Hz,1H),7.42(d,J=2.3Hz,1H),7.23(dd,J=8.5,2.4Hz,1H),6.52(d,J=8.6Hz,1H),6.39(d,J=2.0Hz,2H),4.69(d,J=17.7Hz,1H),4.58(d,J=17.6Hz,1H),4.48(d,J=16.0Hz,1H),4.39(d,J=16.0Hz,1H),3.90(dq,J=14.6,7.3Hz,1H),3.18(dq,J=13.7,6.8Hz,1H),3.02(s,3H),2.55(s,3H),0.95(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO)δ161.6,155.1,149.3,146.8,143.4,141.4,135.5,133.2,131.5,129.8,128.9,127.7,127.5,126.0,121.7,121.3,112.7,110.6,110.1,47.2,46.2,44.4,13.2,9.0.HRMS(ESI)[M-H]+calcd forC25H24ClN2O8S2:579.0663;found:579.0667.
实施例196
5-(N-(2-(((叔丁氧基羰基)(呋喃-2-基甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M6-110)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)乙酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-90)所用方法,将乙酰氯替换为二碳酸二叔丁酯,其余条件均一致。得白色固体105mg,收率90%。1H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.71(s,1H),7.63(d,J=8.8Hz,1H),7.35(s,1H),7.21(s,1H),7.08–6.99(m,1H),6.36(s,1H),6.28(d,J=11.1Hz,2H),4.97–4.61(m,2H),4.45(q,J=18.2,15.2Hz,2H),4.01(s,3H),3.92(dq,J=14.3,7.2Hz,1H),3.17(s,1H),2.59(s,3H),1.49(d,J=36.7Hz,9H),1.04(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ160.2,156.1,142.9,134.8,129.3,127.3,125.9,122.4,112.8,110.3,80.6,52.4,46.8,28.4,13.5,9.3.
实施例197
5-(N-(2-(((叔丁氧基羰基)(呋喃-2-基甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S110)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(2-(((叔丁氧基羰基)(呋喃-2-基甲基)氨基)甲基)-4-氯苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M6-110),其余条件均一致。得白色固体81mg,收率80%。1H NMR(400MHz,DMSO-d6)δ8.10(d,J=1.6Hz,1H),7.88(d,J=8.8Hz,1H),7.65(d,J=7.4Hz,1H),7.61–7.51(m,1H),7.23(dd,J=8.5,2.4Hz,1H),7.06(s,1H),6.57(d,J=8.4Hz,1H),6.39(s,1H),6.27(s,1H),4.58(td,J=45.7,41.8,15.1Hz,4H),3.88(dd,J=12.7,6.7Hz,1H),3.20(dq,J=13.2,6.3Hz,1H),2.57(s,3H),1.40(d,J=53.8Hz,9H),0.95(s,3H).13C NMR(101MHz,DMSO)δ160.7,155.4,143.6,142.6,142.1,133.1,132.2,129.3,129.2,127.4,126.8,126.6,124.5,122.2,113.0,110.4,79.7,46.2,27.9,13.2,9.0.HRMS(ESI)[M-H]+calcd forC29H30ClN2O8S:601.1411;found:601.1417.
实施例198
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-甲酸乙酯(M6-111)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为5-(氯磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸乙酯,其余条件均一致。得白色固体160mg,收率23%。1H NMR(400MHz,Chloroform-d)δ8.08–7.86(m,1H),7.77–7.47(m,2H),7.46–7.32(m,5H),7.19(d,J=33.8Hz,1H),7.03(q,J=8.5,7.3Hz,1H),6.53–6.03(m,3H),5.47–4.17(m,6H),4.07–3.68(m,4H),3.23–2.81(m,1H),2.64–2.45(m,3H),1.44(td,J=7.1,3.4Hz,3H),1.05(dt,J=22.4,6.8Hz,2H),0.64(d,J=75.2Hz,1H).13C NMR(101MHz,CDCl3)δ169.3,162.3,162.3,149.8,149.2,142.6,142.3,141.1,139.9,136.2,135.9,135.4,134.6,134.5,130.4,129.8,129.6,128.9,128.7,128.6,128.5,128.2,127.8,127.6,127.5,127.4,127.3,127.0,126.3,123.8,123.8,122.5,122.4,121.7,121.6,110.5,110.4,110.4,109.7,109.0,60.9,60.9,46.8,46.5,46.3,45.8,44.7,32.5,14.3,13.5,12.8,10.8,10.7.
实施例199
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸(F44-S111)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-甲酸乙酯(M6-111),其余条件均一致。得白色固体137mg,收率85%。1H NMR(400MHz,Chloroform-d)δ8.19–7.84(m,1H),7.81–6.94(m,9H),6.66–5.93(m,3H),5.57–4.55(m,3H),4.44(s,1H),4.27–3.73(m,4H),2.88(d,J=218.7Hz,4H),1.15–0.44(m,3H).13C NMR(101MHz,CDCl3)δ166.9,166.8,149.2,142.8,141.1,140.5,136.3,130.6,129.7,129.1,128.6,127.5,127.2,126.7,126.5,124.5,122.9,110.6,46.5,46.0,44.9,32.8,13.6,11.0.HRMS(ESI)[M-H]-calcd for C32H28N3O6SCl2:652.1076;found:652.1077.
实施例200
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-112)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为5-(氯磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得淡黄色固体78mg,收率28%。1HNMR(400MHz,Chloroform-d)δ8.21–7.86(m,1H),7.85–7.57(m,3H),7.56–7.33(m,5H),7.26–6.99(m,2H),6.58–5.99(m,3H),5.48–4.15(m,6H),4.04–3.66(m,1H),3.36–2.83(m,1H),1.44(td,J=7.1,3.6Hz,3H),1.17–0.49(m,3H).13C NMR(101MHz,CDCl3)δ158.9,158.9,157.3,150.1,149.9,149.6,149.2,148.0,147.9,142.8,142.6,137.3,135.7,135.4,135.0,133.5,133.1,130.5,130.4,129.7,128.9,128.5,128.3,127.8,127.6,127.1,127.0,127.0,126.9,124.1,113.7,113.7,113.6,113.6,113.1,112.9,110.6,110.6,110.5,110.5,109.7,62.1,47.1,46.7,46.0,45.7,44.7,14.4,13.7.
实施例201
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-羧酸(F44-S112)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-112),其余条件均一致。得白色固体63mg,收率84%。1HNMR(400MHz,Chloroform-d)δ8.14–7.86(m,1H),7.82–7.57(m,3H),7.41(d,J=37.0Hz,5H),7.26–6.97(m,2H),6.59–5.98(m,3H),5.54–4.11(m,4H),4.02–3.70(m,1H),3.29–2.88(m,1H),1.14–0.52(m,3H).13CNMR(101MHz,CDCl3)δ170.0,157.4,149.8,149.6,149.2,148.9,142.9,142.7,140.9,138.6,135.7,135.1,133.4,130.7,129.8,129.0,127.7,127.2,124.2,114.6,113.2,110.6,110.0,46.7,29.8,13.6.HRMS(ESI)[M-H]-calcd for C30H23N2O7SCl2:625.0603;found:625.0607.
实施例202
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-113)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为6-(氯磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得淡黄色固体148mg,收率15%。1H NMR(400MHz,Chloroform-d)δ7.93–7.52(m,3H),7.51–7.32(m,5H),7.25(s,1H),7.05(dd,J=15.0,7.7Hz,1H),6.54–6.05(m,3H),5.42–4.17(m,6H),4.04–3.67(m,1H),3.38–2.87(m,1H),2.61(d,J=9.1Hz,3H),1.54–1.38(m,3H),1.06(dt,J=22.6,6.8Hz,2H),0.65(d,J=73.3Hz,1H).13C NMR(101MHz,CDCl3)δ169.3,159.8,159.8,159.7,153.0,152.9,150.1,149.8,149.5,149.1,144.0,142.7,142.5,142.2,141.0,136.4,136.0,135.6,135.0,134.9,133.1,133.0,132.8,130.4,130.3,129.9,129.6,128.8,128.5,128.3,128.0,127.9,127.5,127.1,127.0,124.9,122.6,121.7,121.6,112.6,110.6,110.5,110.5,110.4,109.7,109.4,109.1,61.7,47.1,46.7,45.9,45.6,44.7,14.3,13.6,12.9,9.3,9.3.
实施例203
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S113)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-113),其余条件均一致。得白色固体118mg,收率86%。1H NMR(400MHz,Chloroform-d)δ7.94–7.32(m,8H),7.27–6.97(m,2H),6.66–5.93(m,3H),5.50–4.16(m,4H),4.05–3.66(m,1H),3.39–2.82(m,1H),2.62(d,J=8.6Hz,3H),1.14–0.49(m,3H).13CNMR(101MHz,CDCl3)δ169.9,163.3,163.2,163.0,153.3,153.2,149.8,149.5,149.2,148.9,143.9,143.7,142.8,142.6,142.5,140.8,138.5,136.6,136.2,135.0,133.0,132.9,130.7,129.7,128.9,128.6,128.3,128.1,127.5,127.1,126.2,126.0,122.6,122.0,112.7,110.6,110.5,109.9,109.6,109.3,47.1,46.9,46.7,46.0,44.9,13.6,12.9,9.5.HRMS(ESI)[M-H]-calcd for C31H25N2O7SCl2:639.0760;found:639.0764.
实施例204
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-114)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为6-(氯磺酰基)苯并呋喃-2-甲酸乙酯,其余条件均一致。得淡黄色固体181mg,收率35%。1HNMR(400MHz,Chloroform-d)δ7.99–7.73(m,2H),7.73–7.55(m,2H),7.51–7.32(m,5H),7.28–6.98(m,2H),6.62–6.01(m,3H),5.41–4.16(m,6H),3.99–3.52(m,1H),3.34–2.90(m,1H),1.48–1.41(m,3H),1.07(dt,J=22.4,6.9Hz,2H),0.66(d,J=71.1Hz,1H).13C NMR(101MHz,CDCl3)δ158.9,158.8,154.4,154.3,150.1,149.5,149.2,149.0,142.8,142.5,136.0,135.0,131.0,130.8,130.5,130.3,129.7,128.9,127.9,127.6,127.2,127.1,123.4,123.3,123.3,113.1,112.9,110.6,110.5,110.5,109.7,62.1,46.7,45.9,45.6,14.3,13.6,13.0.
实施例205
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-羧酸(F44-S114)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-114),其余条件均一致。得白色固体57mg,收率33%。1HNMR(400MHz,Chloroform-d)δ8.00–7.29(m,9H),7.25–6.98(m,2H),6.58–5.98(m,3H),5.49–4.16(m,4H),4.00–3.66(m,1H),3.31–2.90(m,1H),1.13–0.51(m,3H).13C NMR(101MHz,CDCl3)δ170.0,154.5,149.2,148.9,142.9,142.7,140.8,136.5,135.2,131.0,130.7,129.8,129.0,127.2,123.2,113.9,113.0,110.6,110.0,46.8,29.8,13.6.HRMS(ESI)[M-H]-calcd for C30H23N2O7SCl2:625.0603;found:625.0609.
实施例206
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-115)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为5-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯,其余条件均一致。得淡黄色固体70mg,收率10%。1HNMR(400MHz,Chloroform-d)δ8.29–8.02(m,2H),8.01–7.89(m,1H),7.77–7.63(m,1H),7.62–7.42(m,2H),7.41–7.32(m,3H),7.26–6.99(m,2H),6.55–6.03(m,3H),5.48–4.17(m,6H),4.03–3.69(m,1H),3.35–2.88(m,1H),1.47–1.40(m,3H),1.14–0.96(m,2H),0.66(d,J=71.8Hz,1H).13C NMR(101MHz,CDCl3)δ162.1,162.1,150.2,149.6,149.2,146.1,146.0,145.8,142.8,142.6,138.3,138.2,137.3,137.0,136.8,135.7,135.4,135.0,134.5,134.1,130.5,130.4,130.3,130.2,130.2,129.7,128.9,128.0,127.8,127.6,127.3,127.1,125.9,125.8,125.2,125.1,125.1,125.0,123.5,123.4,110.6,110.5,110.5,109.8,62.2,62.1,60.4,47.1,46.7,45.9,45.6,29.7,21.1,14.4,14.3,13.7.
实施例207
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-羧酸(F44-S115)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-115),其余条件均一致。得白色固体50mg,收率78%。1H NMR(400MHz,Chloroform-d)δ8.31–7.79(m,3H),7.69(d,J=15.1Hz,1H),7.59–7.31(m,5H),7.07(dd,J=17.7,9.1Hz,2H),6.59–5.96(m,3H),5.50–4.16(m,4H),4.06–3.70(m,1H),3.12(d,J=90.0Hz,1H),1.18–0.47(m,3H).13C NMR(101MHz,CDCl3)δ170.0,166.1,149.9,149.3,149.0,146.5,142.9,142.7,138.7,138.4,135.1,131.3,130.6,129.8,129.0,128.6,127.2,126.0,110.6,47.2,46.7,13.7.HRMS(ESI)[M-H]-calcd for C30H23N2O6SCl2:641.0375;found:641.0378.
实施例208
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-S203)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯,其余条件均一致。得淡黄色固体83mg,收率12%。1HNMR(400MHz,Chloroform-d)δ8.26–8.04(m,2H),8.02–7.91(m,1H),7.75–7.60(m,1H),7.59–7.43(m,2H),7.39–7.31(m,3H),7.26–6.97(m,2H),6.53–6.05(m,3H),5.45–4.17(m,6H),4.04–3.71(m,1H),3.31–2.99(m,1H),1.42(dd,J=7.0,3.6Hz,3H),1.09(tt,J=17.4,6.9Hz,2H),0.66(d,J=71.9Hz,1H).13C NMR(101MHz,CDCl3)δ169.4,162.0,162.0,161.9,150.1,149.8,149.5,149.2,142.8,142.6,141.6,141.5,138.6,138.5,138.4,137.2,135.6,135.5,135.1,130.5,130.3,129.7,129.6,129.5,129.5,128.9,128.5,128.0,127.8,127.6,127.4,127.3,127.1,126.0,125.8,123.9,123.8,123.7,123.5,123.5,110.6,110.5,110.5,109.8,109.5,62.2,62.1,60.4,47.2,46.7,45.9,45.6,44.7,29.7,21.1,14.3,14.3,13.7.
实施例209
6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-羧酸(F44-S203)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-116),其余条件均一致。得白色固体58mg,收率75%。1H NMR(400MHz,Chloroform-d)δ8.28–7.89(m,3H),7.86–7.29(m,7H),7.13–6.97(m,1H),6.72–5.86(m,3H),5.48–4.16(m,4H),3.89(d,J=70.0Hz,1H),3.14(d,J=85.9Hz,1H),1.24–0.44(m,3H).13C NMR(101MHz,CDCl3)δ170.0,165.8,149.3,149.0,142.9,142.7,142.1,141.8,141.7,140.9,138.7,138.6,135.7,135.2,130.5,129.8,129.0,128.6,127.7,127.2,126.2,123.8,123.6,110.6,46.8,29.8,13.7.HRMS(ESI)[M-H]-calcd for C30H23N2O6SCl2:641.0375;found:641.0371.
实施例210
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯(M6-S201)
按照N-(2-((4-乙酰氨基-N-乙基苯基)磺酰胺)-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(F44-S16)所用方法,将4-乙酰氨基苯磺酰氯替换为5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯,其余条件均一致。得淡黄色固体46mg,收率13.4%。1H NMR(400MHz,Chloroform-d)δ8.18–7.97(m,1H),7.97–7.83(m,1H),7.83–7.29(m,7H),7.06(dt,J=18.6,8.7Hz,1H),6.65–5.99(m,3H),5.51–4.49(m,3H),4.46–4.17(m,3H),4.01–3.69(m,1H),3.28–2.88(m,1H),2.84–2.69(m,3H),1.43(td,J=7.1,3.6Hz,3H),1.08(dq,J=19.1,6.9Hz,2H),0.65(d,J=67.8Hz,1H).13C NMR(101MHz,CDCl3)δ162.9,149.9,149.3,144.5,144.3,142.8,142.6,141.0,140.0,130.5,130.4,130.0,129.8,128.9,128.6,127.6,127.1,125.5,125.3,125.3,124.2,123.4,110.6,109.8,61.8,47.1,46.6,44.8,29.8,14.4,13.7,13.3.
实施例211
5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸(F44-S201)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯(M6-117),其余条件均一致。得白色固体20mg,收率43%。1H NMR(400MHz,Chloroform-d)δ8.24–7.29(m,8H),7.15(d,J=67.4Hz,2H),6.67–5.90(m,3H),5.42–4.14(m,4H),4.05–3.68(m,1H),3.09(d,J=89.6Hz,1H),2.74(dd,J=15.1,7.9Hz,3H),1.07(dt,J=15.1,7.0Hz,2H),0.67(d,J=74.4Hz,1H).13C NMR(101MHz,CDCl3)δ167.7,149.9,149.2,144.9,144.8,142.9,141.2,140.1,135.2,130.6,128.6,127.7,127.2,125.5,124.4,123.5,110.6,47.2,46.7,29.8,13.7,13.4.HRMS(ESI)[M-H]-calcd forC31H25N2O6S2Cl2:655.0531;found:655.0532.
实施例212
N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M17)
按照2-氯-N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M2)所用方法,将邻氯苯甲酰氯替换为环丙基甲酰氯,其余条件均一致。得淡黄色固体15.8g,收率95%。
实施例213
N-(2-氨基-5-氯苯基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M18)
按照N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(M3)所用方法,将2-氯-N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M2)替换为N-(5-氯-2-硝基苄基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M17),其余条件均一致。得淡黄色固体12.7g,收率88%。
实施例214
N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M19)
按照2-氯-N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)苯甲酰胺(M5)所用方法,将N-(2-氨基-5-氯苄基)-2-氯-N-(呋喃-2-基甲基)苯甲酰胺(M3)替换为N-(2-氨基-5-氯苯基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M18),其余条件均一致。得淡黄色固体11.0g,收率79%。
实施例215
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)
将N-(5-氯-2-(乙基氨基)苄基)-N-(呋喃-2-基甲基)环丙烷甲酰胺(M19)(332mg,1.0mmol),5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯(383mg,1.2mmol),碳酸钾(207mg,2.0mmol)加入无水二氯甲烷(2mL)中,升温至回流反应过夜,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(5mL)溶解,乙酸乙酯(5mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=4/1)得淡黄色固体138mg,收率20%。1HNMR(400MHz,Chloroform-d)δ8.16–8.03(m,1H),7.94(dd,J=8.4,3.7Hz,1H),7.77–7.60(m,1H),7.45–7.23(m,2H),7.18–7.05(m,1H),6.48–6.21(m,3H),5.25(dd,J=140.1,17.7Hz,1H),4.95–4.71(m,2H),4.69–4.37(m,3H),4.07–3.87(m,1H),3.15(ddt,J=28.9,12.9,6.9Hz,1H),2.83–2.71(m,3H),1.94(ddt,J=191.0,8.0,3.5Hz,1H),1.44(t,J=7.1Hz,3H),1.09(dt,J=26.1,5.8Hz,5H),0.92–0.76(m,2H).13C NMR(101MHz,CDCl3)δ174.6,174.5,162.7,162.6,151.1,150.7,150.4,144.5,144.4,142.6,142.2,142.2,142.1,141.8,140.8,140.8,139.9,137.1,135.7,135.5,135.2,134.9,134.3,133.5,130.0,129.9,129.0,128.5,128.1,127.9,127.7,127.5,127.4,127.3,127.0,125.3,125.2,124.1,124.0,123.4,123.2,110.5,110.4,108.9,108.7,108.6,61.7,61.7,48.0,46.9,46.6,46.0,44.9,42.6,42.4,14.3,13.5,13.4,13.2,11.6,11.4,8.5,8.2,8.0.
实施例216
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸(F44-S118)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118),其余条件均一致。得淡黄色固体121mg,收率94%。1H NMR(400MHz,Chloroform-d)δ8.24–7.29(m,8H),7.15(d,J=67.4Hz,2H),6.67–5.90(m,3H),5.42–4.14(m,4H),4.05–3.68(m,1H),3.09(d,J=89.6Hz,1H),2.74(dd,J=15.1,7.9Hz,3H),1.07(dt,J=15.1,7.0Hz,2H),0.67(d,J=74.4Hz,1H).13C NMR(101MHz,CDCl3)δ167.7,149.9,149.2,144.9,144.8,142.9,141.2,140.1,135.2,130.6,128.6,127.7,127.2,125.5,124.4,123.5,110.6,47.2,46.7,29.8,13.7,13.4.HRMS(ESI)[M-H]-calcd forC31H25N2O6S2Cl2:655.0531;found:655.0532.
实施例217
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-甲酸乙酯(M6-119)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为5-(氯磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸乙酯,其余条件均一致。得淡黄色固体270mg,收率40%。1H NMR(400MHz,Chloroform-d)δ7.98(dd,J=12.6,1.8Hz,1H),7.53(ddd,J=16.1,8.8,1.8Hz,1H),7.43–7.31(m,2H),7.19(dd,J=43.5,2.1Hz,1H),7.03(ddd,J=26.4,8.4,2.3Hz,1H),6.47–6.22(m,3H),5.25(dd,J=143.4,17.7Hz,1H),4.96–4.39(m,5H),4.06–3.90(m,4H),3.10(ddd,J=23.7,12.9,6.8Hz,1H),2.54(d,J=5.7Hz,3H),2.25–1.67(m,1H),1.45(t,J=7.1Hz,3H),1.16–0.97(m,5H),0.92–0.75(m,2H).13CNMR(101MHz,CDCl3)δ174.4,174.3,162.1,162.1,150.6,150.4,142.3,142.1,142.0,141.6,139.8,139.7,136.0,135.8,134.6,134.3,128.5,128.2,127.6,127.6,127.4,127.2,127.1,126.8,126.2,123.7,122.3,121.4,110.3,110.2,108.7,108.4,60.8,47.9,46.6,46.3,45.8,44.7,42.4,32.4,14.2,13.3,13.2,11.4,11.2,10.6,8.3,8.1,7.8.
实施例218
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸(F44-S119)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-甲酸乙酯(M6-119),其余条件均一致。得淡黄色固体224mg,收率87%。1H NMR(400MHz,Chloroform-d)δ8.02(d,J=7.1Hz,1H),7.47(dd,J=49.0,8.1Hz,2H),7.34(d,J=31.1Hz,1H),7.25–6.96(m,2H),6.51–6.18(m,3H),5.24(dd,J=154.3,17.4Hz,1H),4.90–4.40(m,3H),4.19–3.75(m,4H),3.10(ddd,J=19.3,12.6,6.7Hz,1H),2.62(d,J=9.3Hz,3H),1.95(d,J=186.1Hz,1H),1.21–0.75(m,7H).13C NMR(101MHz,CDCl3)δ175.2,150.7,150.4,142.7,142.4,141.8,140.4,136.1,135.0,134.8,128.4,128.1,127.7,127.2,126.6,124.3,122.9,110.6,110.5,109.1,108.8,48.3,46.9,46.6,42.9,32.8,13.5,11.8,11.6,11.0,8.8,8.5,8.3.HRMS(ESI)[M-H]-calcd for C29H29N3O6SCl:582.1466;found:582.1475.
实施例219
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-120)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为5-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯,其余条件均一致。得淡黄色固体249mg,收率37%。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=13.6Hz,1H),8.11(d,J=6.1Hz,1H),8.00(dd,J=8.5,5.3Hz,1H),7.67(dd,J=13.7,9.3Hz,1H),7.50–7.18(m,2H),7.18–7.05(m,1H),6.49–6.22(m,3H),5.25(dd,J=150.2,17.7Hz,1H),4.81(td,J=21.3,20.2,6.0Hz,2H),4.71–4.38(m,3H),4.09–3.86(m,1H),3.18(ddp,J=26.6,13.6,6.9,5.7Hz,1H),1.94(dtt,J=193.5,8.1,4.6Hz,1H),1.43(t,J=7.1Hz,3H),1.17–1.00(m,5H),0.94–0.75(m,2H).13C NMR(101MHz,CDCl3)δ174.4,174.3,161.8,161.7,150.6,150.3,145.9,145.7,142.4,142.1,142.0,141.6,138.1,138.0,136.9,136.7,135.5,135.3,135.0,134.8,134.7,133.9,130.0,130.0,128.4,128.0,127.7,127.4,127.1,125.6,125.6,124.8,123.5,110.4,110.3,108.8,108.4,62.0,47.9,46.8,46.6,45.8,44.8,42.4,14.2,13.4,13.3,11.4,11.2,8.4,8.1,7.8.
实施例220
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸(F44-S120)
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按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-120),其余条件均一致。得淡黄色固体184mg,收率78%。1H NMR(400MHz,Chloroform-d)δ8.21–7.32(m,4H),7.22–6.87(m,2H),6.60–5.97(m,3H),5.11(dd,J=236.0,16.8Hz,2H),4.76–4.40(m,2H),3.92(d,J=31.2Hz,1H),3.10(s,1H),1.91(d,J=189.6Hz,1H),0.95(q,J=57.2,55.5Hz,7H).13CNMR(101MHz,CDCl3)δ175.2,150.6,142.8,142.4,141.6,138.8,135.2,110.6,109.3,108.8,48.3,46.9,42.9,13.6,11.6,8.6.HRMS(ESI)[M-H]-calcd for C27H24N2O6S2Cl:571.0764;found:571.0768.
实施例221
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-121)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯,其余条件均一致。得淡黄色固体340mg,收率51%。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=10.6Hz,1H),8.12(s,1H),8.01(dd,J=8.4,4.5Hz,1H),7.72–7.54(m,1H),7.43–7.00(m,3H),6.50–6.20(m,3H),5.24(dd,J=154.3,17.7Hz,1H),4.81(ddd,J=23.9,18.0,7.5Hz,2H),4.71–4.35(m,3H),4.14–3.85(m,1H),3.19(ddt,J=26.7,12.9,5.7Hz,1H),1.95(dtt,J=192.7,8.1,4.6Hz,1H),1.43(t,J=7.1Hz,3H),1.18–0.99(m,5H),0.93–0.75(m,2H).13C NMR(101MHz,CDCl3)δ174.3,174.2,161.6,161.6,150.5,150.3,142.4,142.1,141.9,141.5,141.4,138.5,138.3,135.7,135.4,135.2,134.9,134.8,134.7,129.3,128.4,128.1,127.6,127.3,127.0,125.9,123.5,123.2,123.2,110.3,110.2,108.8,108.4,61.9,61.9,47.8,46.8,46.6,45.8,44.7,42.4,14.1,13.3,13.2,11.4,11.2,8.3,8.1,7.8.
实施例222
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-1,3-二甲基-1H-吲哚-2-羧酸(F44-S121)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并[b]噻吩-2-甲酸乙酯(M6-121),其余条件均一致。得淡黄色固体275mg,收率84%。1H NMR(400MHz,Chloroform-d)δ8.20–7.30(m,4H),7.23–6.84(m,2H),6.27(dd,J=19.8,9.9Hz,3H),5.47–4.37(m,4H),3.93(d,J=31.0Hz,1H),3.11(s,1H),1.90(d,J=188.2Hz,1H),1.25–0.48(m,7H).13C NMR(101MHz,CDCl3)δ175.2,150.6,142.8,142.4,141.6,135.3,123.5,110.6,109.3,48.3,46.9,42.9,13.6,11.8,8.7.HRMS(ESI)[M-H]-calcd for C27H24N2O6S2Cl:571.0764;found:571.0770.
实施例223
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-122)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为5-(氯磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得淡黄色固体210mg,收率28%。1H NMR(400MHz,Chloroform-d)δ8.19–8.00(m,1H),7.82–7.67(m,2H),7.61(d,J=4.4Hz,1H),7.45–7.19(m,2H),7.16–7.06(m,1H),6.50–6.19(m,3H),5.24(dd,J=150.8,17.7Hz,1H),4.93–4.41(m,5H),4.09–3.85(m,1H),3.16(ddt,J=26.8,11.9,6.9Hz,1H),1.93(dtt,J=193.2,8.1,4.1Hz,1H),1.45(t,J=7.1Hz,3H),1.16–1.00(m,5H),0.93–0.75(m,2H).13C NMR(101MHz,CDCl3)δ174.4,174.4,158.7,158.6,157.2,157.1,150.6,150.3,147.9,147.8,142.5,142.1,142.0,141.7,135.6,135.4,135.0,134.7,133.7,132.9,128.4,128.0,127.8,127.7,127.4,127.2,127.1,126.8,123.9,123.8,113.5,113.5,113.0,113.0,110.4,110.3,108.9,108.5,62.0,61.9,47.9,46.8,46.6,45.9,44.8,42.5,14.2,13.4,13.3,11.4,11.3,8.4,8.2,8.1,7.9.
实施例224
5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-羧酸(F44-S122)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-122),其余条件均一致。得淡黄色固体169mg,收率84%。1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.77–7.28(m,4H),7.25–6.94(m,2H),6.63–5.95(m,3H),5.47–4.42(m,4H),3.94(ddd,J=36.5,12.0,6.7Hz,1H),3.12(dq,J=19.2,6.2Hz,1H),1.93(d,J=190.9Hz,1H),1.22–0.75(m,7H).13CNMR(101MHz,CDCl3)δ175.4,157.4,150.5,150.1,142.8,142.4,141.6,135.8,135.6,135.3,135.0,132.9,128.0,127.6,124.1,113.2,110.6,109.3,108.9,48.3,46.8,45.1,43.0,13.6,13.5,11.8,11.7,8.6.HRMS(ESI)[M-H]-calcd for C27H24N2O7SCl:555.0993;found:555.1000.
实施例225
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-123)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为6-(氯磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得淡黄色固体222mg,收率29%。1H NMR(400MHz,Chloroform-d)δ7.85(d,J=15.6Hz,1H),7.78(dd,J=8.3,4.4Hz,1H),7.66–7.54(m,1H),7.44–7.21(m,2H),7.17–7.06(m,1H),6.59–6.11(m,3H),5.24(dd,J=144.0,17.6Hz,1H),4.96–4.71(m,2H),4.70–4.33(m,3H),4.08–3.85(m,1H),3.32–3.04(m,1H),2.63(s,3H),2.24–1.66(m,1H),1.46(t,J=7.1Hz,3H),1.16–0.99(m,5H),0.94–0.76(m,2H).13C NMR(101MHz,CDCl3)δ174.5,174.5,174.4,159.7,159.6,152.8,150.9,150.6,150.3,144.0,143.9,142.4,142.3,142.2,142.0,141.9,141.6,139.2,136.8,135.8,135.5,135.2,135.0,134.7,133.1,132.9,128.9,128.3,128.0,127.8,127.8,127.7,127.5,127.1,126.8,126.8,124.7,122.5,122.4,121.7,121.6,112.5,112.4,110.4,110.3,110.3,108.9,108.6,108.5,61.6,61.5,47.9,46.9,46.7,45.9,44.8,42.5,42.4,14.2,13.4,13.3,11.4,11.3,11.2,9.2,8.4,8.3,8.2,8.1,7.9.
实施例226
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(F44-S123)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯(M6-123),其余条件均一致。得淡黄色固体177mg,收率84%。1H NMR(400MHz,Chloroform-d)δ7.87(d,J=9.9Hz,1H),7.76(d,J=8.0Hz,1H),7.58(dd,J=15.4,8.1Hz,1H),7.35(d,J=44.5Hz,1H),7.25–6.97(m,2H),6.53–6.12(m,3H),5.25(dd,J=148.3,17.5Hz,1H),4.95–4.35(m,3H),3.95(ddt,J=34.0,13.2,6.9Hz,1H),3.15(ddq,J=26.1,12.9,6.8,6.3Hz,1H),2.65(s,3H),2.24–1.66(m,1H),1.21–0.78(m,7H).13C NMR(101MHz,CDCl3)δ175.5,175.4,153.3,150.8,150.6,142.8,142.4,142.3,141.6,135.5,135.4,133.4,127.4,122.7,121.9,112.9,110.7,110.6,109.3,108.9,48.3,47.1,46.9,45.1,43.0,13.5,11.8,11.7,9.5,8.6.HRMS(ESI)[M-H]-calcd for C28H26N2O7SCl:569.1149;found:569.1153.
实施例227
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-124)
按照5-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-甲酸乙酯(M6-118)所用方法,将5-(氯磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯替换为6-(氯磺酰基)甲基苯并呋喃-2-甲酸乙酯,其余条件均一致。得淡黄色固体55mg,收率16%。1H NMR(400MHz,Chloroform-d)δ7.92(d,J=16.8Hz,1H),7.83(dd,J=8.3,4.4Hz,1H),7.67–7.56(m,2H),7.36–7.23(m,2H),7.10(tt,J=8.5,5.0Hz,1H),6.47–6.22(m,3H),5.25(dd,J=134.4,17.6Hz,1H),4.93–4.30(m,5H),4.07–3.85(m,1H),3.29–3.06(m,1H),2.21–1.63(m,1H),1.45(t,J=7.1Hz,3H),1.16–1.01(m,5H),0.84(dd,J=38.0,7.0Hz,2H).13C NMR(101MHz,CDCl3)δ174.8,174.7,158.9,158.8,154.4,151.1,150.8,150.5,149.1,149.0,142.6,142.4,142.3,142.2,142.1,141.8,139.5,136.9,136.5,136.0,135.6,135.4,135.3,135.0,131.2,131.0,129.1,128.5,128.1,128.0,127.8,127.7,127.5,127.4,127.0,127.0,123.5,123.3,123.2,113.1,113.1,113.0,112.9,110.6,110.5,110.4,109.0,108.8,108.7,108.5,62.2,62.2,48.0,47.1,46.8,46.1,45.0,42.7,42.5,29.8,14.4,13.6,13.5,13.5,11.6,11.5,11.4,8.6,8.5,8.3,8.2,8.0.
实施例228
6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)甲基苯并呋喃-2-羧酸(F44-S124)
按照4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰氨基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸(F44-S35)所用方法,将4-(N-(4-氯-2-((2-氯-N-(呋喃-2-基甲基)苯甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯甲酸乙酯(F44-S26)替换为6-(N-(4-氯-2-((N-(呋喃-2-基甲基)环丙烷甲酰胺基)甲基)苯基)-N-乙基氨磺酰基)苯并呋喃-2-甲酸乙酯(M6-124),其余条件均一致。得淡黄色固体39mg,收率78%。1HNMR(400MHz,Chloroform-d)δ7.91(d,J=7.8Hz,1H),7.86–7.72(m,1H),7.72–7.45(m,2H),7.41–7.29(m,1H),7.25–6.95(m,2H),6.58–6.09(m,3H),5.23(dd,J=160.6,17.1Hz,1H),4.97–4.34(m,3H),3.95(ddt,J=35.5,14.3,7.1Hz,1H),3.15(ddd,J=20.9,13.1,7.1Hz,1H),2.25–1.64(m,1H),1.22–0.76(m,7H).13CNMR(101MHz,CDCl3)δ175.7,175.5,154.5,150.8,150.5,142.5,142.3,141.5,139.1,135.5,131.3,123.6,113.6,113.1,110.7,110.6,110.6,109.3,109.1,48.3,46.9,42.9,29.8,13.6,11.9,11.7,8.6.HRMS(ESI)[M-H]-calcd for C27H24N2O7SCl:555.0993;found:555.0991.
另外,以下化合物可以参照上述的合成方法制备得到。
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另外,本申请发明人还参照上述的合成方法制备得到了以下化合物。
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生物活性部分
1.1FXR活性评价
FXR活性通过时间分辨荧光共振能量转移(time-resolved fluorescenceresonance energy transfer,TR-FRET)实验评价,使用LanthaScreenTM TR-FRET FXR共激活实验试剂盒(ThermoFisher,Cat.PV4833)。激动剂筛选,取384孔黑板(Coring),每孔依次加入10μL含相应浓度待测化合物的Complete Coregulator buffer G,5μL 20nM FXR-LBDComplete Coregulator buffer G,5μL2.0μM Fluorescein-SRC2-2/20nM Tb-anti-GSTantibody Complete Coregulator buffer G,室温孵育1h后,酶标仪检测520nm和495nm处的荧光值,所测数值用520nm/495nm表示。每个化合物三个复孔,以CDCA作为阳性化合物,DMSO作为溶剂对照。拮抗剂筛选,取384孔黑板(Coring),每孔依次加入5μL含相应浓度待测化合物的Complete Coregulator buffer G,5μL 20nM FXR-LBD Complete Coregulatorbuffer G,5μL 200μM CDCA FXR-LBD Complete Coregulator buffer G,5μL 2.0μMFluorescein-SRC2-2/20nM Tb-anti-GST antibody Complete Coregulator buffer G,室温孵育10h,余同激动剂筛选。
上述实验中EC50数值较低的化合物,具有较好的FXR拮抗活性。
1.2细胞培养与传代
人胚胎肾细胞系HEK293A传代培养,培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10% FBS的MEM培养基,置于95%空气和5%二氧化碳的湿润气氛下37℃恒温培养。当细胞融合至90%时,弃去旧培养基,用2mL PBS洗涤细胞2次,弃去PBS后加入2mL 0.25%胰蛋白酶-0.25% EDTA混合消化液,置显微镜下观察,当细胞变圆后迅速加入2mL完全培养基终止消化,轻轻吹打,收集细胞。800rpm,4℃,离心5min,弃去上清,用完全培养基重悬细胞,分瓶培养,隔天换液。
人肝癌细胞系HepG2传代培养,培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10% FBS的DMEM培养基,余同HEK293A传代培养相同。
1.3细胞增殖抑制实验
通过MTT法检测化合物的细胞增殖抑制能力。HepG2和HEK293细胞以30%的密度接种于96孔板,孵育18h使细胞贴壁后,移除原有培养基,每孔加入给定浓度的待测化合物,对照组加入等量的DMSO。每个化合物设置三个复孔。给药48h后,MTT法检测细胞活力,空白组为不加入细胞的孔,随后用酶标仪在490nm处读取其OD值。细胞活力的计算公式为:细胞活力(%)=(OD待测-OD空白)/(OD对照-OD空白)×100。
上述实验中对HEK293细胞活力高、CC50数值较高的化合物,具有较好的安全性。对HepG2细胞抑制率较高、EC50数值较低的化合物,可以较好地抑制肿瘤细胞的增殖。
1.4细胞TC/TG检测
细胞TC/TG用南京建成TG测试盒、TC测试盒检测。HepG2细胞用0.5mmol/L FFA(油酸与棕榈酸酯按照2:1混合)和溶剂或不同浓度(20μM、40μM、80μM)的化合物孵育24h。吸弃培养液,用0.01M,pH 7.4PBS清洗一遍细胞。用细胞刮板刮下细胞,加入2-5mL,0.01M,pH7.4PBS,收集细胞悬液后,1000×g,4℃,离心10min收集细胞,按照106个细胞加入300-500μL匀浆介质的比例加入异丙醇,进行机械匀浆,充分破碎至无明显的细胞沉淀。10000×g,4℃,离心10min,取上清置于冰上待测。取2.5μL蒸馏水、标准品或样品分别与250μL蒸馏水混匀,37℃孵育10分钟,酶标仪510nm测定各孔吸光度值。TC/TG浓度计算公式:样品浓度(mmol/g protein)=(OD样品-OD空白)/(OD标准-OD空白)×标准品浓度(mmol/L)/蛋白浓度(gprotein/L)。
BCA法蛋白定量
蛋白标准品的准备:a.取1.2mL蛋白标准配制液加入到一管蛋白标准(30mg BSA))中,充分溶解后配制成25mg/mL的蛋白标准溶液。b.取适量25mg/mL蛋白标准,稀释至终浓度为0.5mg/mL。BCA工作液配制:根据样品数量,按50体积BCA试剂A加1体积BCA试剂B(50:1)配制适量BCA工作液,充分混匀。蛋白浓度测定:a.将标准品按0、1、2、4、8、12、16、20μL加到96孔板的标准品孔中,加标准品稀释液补足到20μL,相当于标准品浓度分别为0、0.025、0.05、0.1、0.2、0.3、0.4、0.5mg/mL。b.加适当体积样品到96孔板的样品孔中。如果样品不足20μL,需加标准品稀释液补足到20μL。c.各孔加入200μL BCA工作液,37℃放置20-30分钟。d.用酶标仪测定A562 nm波长处的吸光度。e.根据标准曲线和使用的样品体积计算出样品的蛋白浓度。
上述实验中TC/TG降低率较高、EC50数值较低的化合物,可以较好地降低血液和/或肝脏中的脂肪含量。
1.5急性高脂血症动物实验
雄性C57BL/6小鼠随机分为8组,Control组、Model组、SIPI-7623组(10mg/kg、30mg/kg和100mg/kg)和受试物组(3个剂量)。Model组、SIPI-7623组和受试物组腹腔注射600mg/kg的Triton WR-1339,Control组注射同等体积生理盐水。在注射诱导剂前1个小时和注射诱导剂后23h灌胃给与化合物处理,1h后,收集血液样品和组织样品。
1.6高脂饮食动物实验
雄性C57BL/6小鼠随机分为6组,Control组、HFD组、SIPI-7623组(40mg/kg)和受试物组(3个剂量)。Control组给予正常饮食,HFD组、SIPI-7623组和受试物组给予高脂饮食。Control组和HFD组灌胃给与溶剂,其他组给予相应剂量化合物处理。每天记录小鼠体重。化合物灌胃处理8周后,收集血液样品和组织样品。高脂饮食成分见表1.1。
表1.1小鼠正常饲料(Standard chow)和高脂饲料(High fat diet)配方组成
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1.7饮食诱导肥胖动物实验
雄性C57BL/6小鼠分为2组,Control组正常饮食、HFD组给予高脂饮食。高脂饮食12周后,HFD组随机分为9组:HFD组、受试物组(3个剂量)、SIPI-7623(40mg/kg)、Atorvastatin(10mg/kg)和受试物(10mg/kg)+Atorvastatin(10mg/kg)。Control组和HFD组灌胃给与溶剂,其他组给予相应剂量化合物处理。每周记录小鼠体重。化合物灌胃处理8周后,收集血液样品和组织样品。高脂饮食成分见表1.1。
1.8db/db鼠动物实验
雄性db/db小鼠随机分为5组,实验分组为db/db组、受试物组(3个剂量)和吡格列酮(7mg/kg)。db/db组给予溶剂灌胃处理,其他组给予对应化合物灌胃处理4周。每周记录小鼠体重,并检测空腹血糖。化合物灌胃4周后,收集血液样品和组织样品进行后续实验。
1.9小鼠血糖测定
1、罗氏血糖仪包括:血糖仪、采血笔、血糖试纸。
2、用酒精棉球擦拭小鼠尾尖,打开采血笔上的采样针,扎破小鼠尾尖;用血糖试纸蘸取尾尖血液,血液必须完全覆盖试纸测试区;打开血糖仪,将血糖试纸插入血糖仪,读取并记录血糖值。每只小鼠测定血糖前都应该更换采样针和血糖试纸。
2.0葡萄糖耐量试验(Glucose tolerance test,GTT)
葡萄糖耐量试验在受试物灌胃给药后第5周(实验第17周)进行。小鼠禁食16h后,腹腔注射葡萄糖(1.5g/kg),在注射葡萄糖后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。
2.1胰岛素耐量试验(Insulin tolerance test,ITT)
胰岛素耐量试验在受试物灌胃给药后第6周(实验第18周)进行。小鼠禁食4h后,腹腔注射胰岛素(1U/kg),在注射胰岛素后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。
2.2动物取材
1、小鼠称重后,使用戊巴比妥钠腹腔注射麻醉。
2、内眦取血,取20μL全血,用全血稀释液进行稀释,进行血常规检测;剩余全血常温静置2h,3000rpm,4℃,离心10min,取上层血清,进行血生化检测。
3、小鼠取完血后,打开胸腔和腹腔,分别取出肝、肠、白色脂肪和褐色脂肪组织。
4、肝脏分出一部分4%甲醛固定,用于石蜡切片和冰冻切片,剩余组织-80℃冻存。
5、肠道组织用PBS冲洗后,刮取肠道上皮细胞-80℃冻存。
6、对白色脂肪和褐色脂肪组织进行称重。
2.3肝脏中胆固醇和甘油三酯检测
1、取适量肝脏组织,加入研磨珠以PBS为buffer进行组织匀浆。
2、将匀浆液等分为两部分,一部分加入氯仿甲醇抽提,测定胆固醇和甘油三酯。向其中一管加入4倍体积氯仿甲醇抽提液(氯仿:甲醇=2:1),涡旋使其充分混匀,静置至分层,2000rpm,4℃,离心30min,吸出下层液体于新离心管,在真空浓缩仪中挥发干净溶剂,加入适量3% Triton X-100,恒温水浴摇床50-60℃溶解。用TC和TG试剂盒测定浓度。
5、取另一管匀浆液,12000rpm,4℃,离心15min,取上清,用BCA试剂盒测定蛋白浓度。
6、脂质含量=脂质浓度/蛋白浓度
2.4肝脏油红O染色
1、取相同部位相同大小的新鲜肝脏组织放置于4%中性甲醛中固定,送至检测公司制备切片并进行油红O染色。
2、取回已经制备好的切片用扫描仪扫描切片并拍照。
2.5组织HE染色
1、取相同部位相同大小的新鲜肝脏组织放置于4%中性甲醛中固定,送至检测公司制备切片并进行HE染色。
2、取回已经制备好的切片用扫描仪扫描切片并拍照。
结果与讨论
FXR拮抗活性结果与讨论
A:0.1μM<IC50<10μM
B:10μM<IC50<50μM
C:50μM<IC50<100μM
表1.2本发明化合物的FXR拮抗活性
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表1.3本发明化合物的FXR拮抗活性
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a数据以至少两个独立运行的几何平均值来表示.b Z-GS,SIPI-7623和Centatin为阳性对照。SIPI-7623处于I期临床研究,Centatin处于III期临床研究。
实验结果表明,本发明化合物具有以下一个或多个方面的效果:
(1)具有良好的FXR拮抗活性;
(2)具有良好的安全性;
(3)可以提高葡萄糖耐量;
(4)可以改善胰岛素抵抗;
(5)可以降低血糖水平;
(6)可以降低血脂水平;
(7)可以降低肝脏中的脂肪含量;
(8)可以抑制肿瘤细胞的增殖。
综上,本发明的化合物可作为FXR调节剂,用于预防和/或治疗与FXR相关的疾病,例如肿瘤或代谢性疾病。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解:根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (12)
1.式I所示化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,
其中:
L选自其中,X与苯环相连,Y与R4相连;
优选地,L为其中,X与苯环相连,Y与R4相连;
X选自
优选地,X为
Y选自
优选地,Y选自
更优选地,Y为
R5选自氢、C1-C6烷基;
优选地,R5选自氢、甲基、乙基、正丙基;
R1a、R1b各自独立地选自氢、卤素、C1-C6烷氧基、-NRaRb;或者,R1a、R1b和与它们分别相连的碳原子一起,形成5-6元杂环;
优选地,R1a选自氢、卤素、C1-C6烷氧基、-NRaRb;
更优选地,R1a选自氢、氯、甲氧基、-NRaRb;
最优选地,R1a选自氢、氯、甲氧基、
优选地,R1b选自氢、C1-C6烷氧基、-NRaRb;
更优选地,R1b选自氢、甲氧基、-NRaRb;
最优选地,R1b选自氢、甲氧基、
优选地,R1a、R1b和与它们分别相连的碳原子一起,形成5元杂环,优选地,所述5元杂环含有1-2个(优选2个)杂原子,优选地,所述杂原子选自O、S;
更优选地,R1a、R1b和与它们分别相连的碳原子一起,形成
最优选地,R1a、R1b和与它们分别相连的碳原子一起,形成
Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成4-7元含氮杂环;
优选地,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮杂环;
更优选地,Ra、Rb各自独立地选自C1-C6烷基,或者,Ra、Rb和与它们共同连接的氮原子一起形成5-6元含氮饱和杂环,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子;
最优选地,Ra、Rb各自独立地选自甲基、乙基、正丙基,或者,Ra、Rb和与它们共同连接的氮原子一起形成
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
优选地,n选自1、2、3;
更优选地,n选自1、2;
最优选地,n为1;
R6选自5-6元杂芳基、苯基、C1-C6烷基,任选地,所述5-6元杂芳基、苯基各自独立地被Rc所取代;
优选地,R6选自5元杂芳基、苯基、C1-C6烷基,任选地,所述5元杂芳基、苯基各自独立地被Rc所取代;
更优选地,R6选自呋喃基、噻吩基、苯基、C1-C6烷基、吡咯基,任选地,所述呋喃基、噻吩基、吡咯基各自独立地被Rc所取代;
进一步优选地,R6选自任选地,/> 各自独立地被Rc所取代;
更进一步优选地,R6选自
最优选地,R6为
Rc选自卤素、硝基、氰基、C1-C6烷基、C1-C6卤代烷基;
优选地,Rc选自卤素、硝基、C1-C6烷基、C1-C6卤代烷基;
更优选地,Rc选自溴、氯、硝基、甲基、三氟甲基;
更优选地,Rc选自溴、氯、甲基;
优选地,R2选自
更优选地,R2为
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn、C3-C10环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
优选地,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代;
或者优选地,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代;
更优选地,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C4烷氧基、C2-C6烯基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代;
或者更优选地,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代;
进一步优选地,R3选自甲基、/>-NRmRn、环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、-O-C(CH3)3,任选地,所述各自独立地被1-2个选自Rx的基团所取代;
或者进一步优选地,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代;
最优选地,R3选自甲基、/> 环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3、-CH=CH2、-C=CH2CH3、/>-O-C(CH3)3;
或者最优选地,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、/>-O-C(CH3)3;
或者最优选地,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、甲基、/>-(CH2)3CH3、-CH=CH2,-C=CH2CH3、-O-C(CH3)3;
Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成4-7元含氮杂环,可选地所述4-7元含氮杂环中的任意一个-CH2-被-O-取代;
优选地,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成5-6元含氮杂环,可选地所述5-6元含氮杂环中的任意一个-CH2-被-O-取代;
更优选地,Rm、Rn各自独立地选自C1-C6烷基,或者,Rm、Rn和与它们共同连接的氮原子一起形成6元含氮饱和杂环,可选地所述6元含氮杂环中的任意一个-CH2-被-O-取代,优选地,所述含氮饱和杂环包含1-3个(如1个)杂原子,优选地,所述杂原子为氮原子;
最优选地,Rm、Rn均为甲基或乙基,或者,Rm、Rn和与它们共同连接的氮原子一起形成
Rx选自卤素、硝基、C1-C6烷基、C1-C6烷氧基、-NRsRt、C1-C6卤代烷基;
优选地,Rx选自氟、氯、甲基、甲氧基、硝基、三氟甲基、溴;
优选地,Rx选自氯、溴;
Rs、Rt各自独立地选自C1-C6烷基;
优选地,Rs、Rt均为甲基;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R8、R9各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,且R8、R9不同时为氢,R7、R10、R11为氢;
更优选地,R9选自氢、羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R8选自氢、C1-C6烷基、卤素(优选氯)、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-,且R8、R9不同时为氢,R7、R10、R11为氢;
或者更优选地,R9选自羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-、C1-C6烷基-C(=O)-,R7、R8、R10、R11为氢;
最优选地,R9选自氢、羧基、
R8选自氢、甲基、氯、/>且R8、R9不同时为氢,R7、R10、R11为氢;
或者最优选地,R9选自羧基、
R7、R8、R10、R11为氢;Ru选自氢、C1-C6烷基、C1-C6卤代烷基;
优选地,Ru选自氢、甲基、三氟甲基;
Ry选自氢、C1-C6烷基、C1-C6卤代烷基;
优选地,Ry选自氢、三氟甲基;
Rv、Rw各自独立地选自氢、C1-C6烷基、C1-C6卤代烷基;
优选地,Rv、Rw各自独立地选自氢、甲基、乙基、三氟甲基;
最优选地,作为整体,选自以下:
或者,选自以下:
2)
X1选自
优选地,X1为
Rz选自C1-C6烷基、C1-C6烷基-C(=O)-;
优选地,Rz选自甲基、乙酰基;
R12、R13、R14、R15各自独立地选自氢、C1-C6烷基;
优选地,R12、R13、R14、R15均为氢;
最优选地,作为整体,选自/>3)/>
X2选自
优选地,X2为
Rq选自C1-C6烷基;
R16、R17、R18各自独立地选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;优选地,R16、R17、R18各自独立地选自氢、卤素、C1-C6卤代烷基;
更优选地,R16选自氢、卤素、C1-C6卤代烷基,R17、R18为氢;
最优选地,R16选自氢、氯、三氟甲基,R17、R18为氢;
R19选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;
优选地,R19选自氢、氯、甲基、三氟甲基;
R20选自羧基、C1-C6烷基-O-C(=O)-、HO-C1-C6烷基、
优选地,R20选自羧基、
最优选地,作为整体,选自/>
最优选地,作为整体,选自/>
最优选地,作为整体,选自/>
其中,X为且Y为/>时,式I所示的化合物不为以下化合物:
/>
/>
2.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-1所示结构:
其中:
X、Y、R1a、R1b、R2、R3、R4的定义如权利要求1所限定,且,X为且Y为/>时,式I-1所示的化合物不为以下化合物:/>
/>
/>
3.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-1-1所示结构:
其中:
R1a、R1b、R2、R5的定义如权利要求1所限定;
R3选自苯基、5-6元杂芳基、C1-C6烷基、-NRmRn、C3-C10环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、5-6元杂芳基各自独立地被1-2个选自Rx的基团所取代;
优选地,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C6烷氧基、C2-C6烯基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代;
或者优选地,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、吡啶基、呋喃基、噻吩基各自独立地被1-2个选自Rx的基团所取代;
更优选地,R3选自苯基、吡啶基、呋喃基、噻吩基、C1-C6烷基、-NRmRn、C3-C6环烷基、C1-C4烷氧基、C2-C6烯基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代;
或者更优选地,R3选自苯基、吡啶基、呋喃基、噻吩基,任选地,所述苯基、呋喃基各自独立地被1-2个选自Rx的基团所取代;
进一步优选地,R3选自甲基、/>-NRmRn、环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、-O-C(CH3)3,任选地,所述各自独立地被1-2个选自Rx的基团所取代;
或者进一步优选地,R3选自任选地,所述/> 各自独立地被1-2个选自Rx的基团所取代;
最优选地,R3选自甲基、/> 环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3、-CH=CH2、-C=CH2CH3、/>-O-C(CH3)3;
或者最优选地,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、-(CH2)3CH3,-CH=CH2,-C=CH2CH3、/>-O-C(CH3)3;
或者最优选地,R3选自 环丙烷基、环丁烷基、环戊烷基、环己烷基、甲基、/>-(CH2)3CH3、-CH=CH2,-C=CH2CH3、-O-C(CH3)3;
Rm、Rn、Rx的定义如权利要求1所限定;
R4选自:
1)
R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R8、R9各自独立地选自氢、C1-C6烷基、卤素、羧基、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,且R8、R9不同时为氢,R7、R10、R11为氢;
更优选地,R9选自氢、羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,R8选自氢、C1-C6烷基、卤素(优选氯)、C1-C6卤代烷基、C1-C6烷基-C(=O)-N(Ru)-,且R8、R9不同时为氢,R7、R10、R11为氢;
或者更优选地,R9选自羧基、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-C1-C6烷基、RvRwN-C(=O)-N(Ry)-、C1-C6烷基-O-C(=O)-、C1-C6烷基-O-C(=O)-C1-C6烷基、HO-C(=O)-C1-C6烷基、C1-C6烷基-O-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、HO-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-N(Ry)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-C1-C6烷基、C1-C6烷基-C(=O)-C1-C6烷基-C(=O)-N(Ry)-、RvRwN-C(=O)-、C1-C6烷基-C(=O)-N(Ry)-C(=O)-,R7、R8、R10、R11为氢;
最优选地,R9选自氢、羧基、 R8选自氢、甲基、氯、/>且R8、R9不同时为氢,R7、R10、R11为氢;/>
或者最优选地,R9选自羧基、 R7、R8、R10、R11为氢;
最优选地,作为整体,选自以下:
或者,选自以下:
Ru、Rv、Rw、Ry的定义如权利要求1所限定;
2)
X1、R12、R13、R14、R15的定义如权利要求1所限定;
3)
X2、R16、R17、R18、R20的定义如权利要求1所限定。
4.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-1-2所示结构:
其中:
R1a选自氢、卤素;
优选地,R1a选自氢、氯;
R1b选自氢、卤素;
优选地,R1b为氢;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
优选地,n选自1、2、3;
更优选地,n选自1、2;
最优选地,n为1;
R6选自5-6元杂芳基;
优选地,R6选自5元杂芳基;
更优选地,R6选自呋喃基、噻吩基;
进一步优选地,R6选自
最优选地,R6为
优选地,R2为
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
优选地,Rx选自氟、氯;
优选地,R3选自
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R9选自C1-C6烷基-C(=O)-N(Ru)-、C1-C6烷基-C(=O)-,R7、R8、R10、R11为氢;
更优选地,R9选自R7、R8、R10、R11为氢;
Ru选自氢、C1-C6烷基;
优选地,Ru为氢;
优选地,R4选自
且,式I-1-2所示的化合物不为以下化合物:
5.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-1-3所示结构:
其中:
R1a选自氢、卤素;
优选地,R1a选自卤素;
更优选地,R1a为氯;
R1b选自氢、卤素;
优选地,R1b为氢;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
优选地,n选自1、2、3;
更优选地,n选自1、2;
最优选地,n为1;
R6选自5-6元杂芳基;
优选地,R6选自5元杂芳基;
更优选地,R6选自呋喃基、噻吩基;
进一步优选地,R6选自
最优选地,R6为
优选地,R2为
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
优选地,R3为苯基,所述苯基任选被1个选自Rx的基团所取代;
更优选地,R3为
Rx选自卤素;
优选地,Rx为氯;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R8和R9中,任意一个选自C1-C6烷基-C(=O)-N(Ru)-,另一个为氢,R7、R10、R11为氢;
更优选地,R8和R9中,任意一个为另一个为氢,R7、R10、R11为氢;
Ru选自氢、C1-C6烷基;
优选地,Ru为氢;
优选地,R4选自
R5选自氢、C1-C6烷基;
优选地,R5选自氢、甲基、乙基。
6.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-1-4所示结构:
/>
其中:
R1a选自氢、卤素;
优选地,R1a选自卤素;
更优选地,R1a为氯;
R1b选自氢、卤素;
优选地,R1b为氢;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
优选地,n选自1、2、3;
更优选地,n选自1、2;
最优选地,n为1;
R6选自5-6元杂芳基;
优选地,R6选自5元杂芳基;
更优选地,R6选自呋喃基、噻吩基;
进一步优选地,R6选自
最优选地,R6为
优选地,R2为
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
优选地,R3为苯基,所述苯基任选被1个选自Rx的基团所取代;更优选地,R3为
Rx选自卤素;
优选地,Rx为氯;
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R9选自C1-C6烷基-C(=O)-N(Ru)-,R7、R8、R10、R11为氢;
更优选地,R9为R7、R8、R10、R11为氢;
Ru选自氢、C1-C6烷基;
优选地,Ru为氢;
优选地,R4为
R5选自氢、C1-C6烷基;
优选地,R5选自氢、乙基。
7.根据权利要求1所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物具有式I-2所示结构:
其中:
R1a选自氢、C1-C6烷氧基;
优选地,R1a为氢;
R1b选自氢、C1-C6烷氧基;
优选地,R1b选自C1-C6烷氧基;
更优选地,R1b为甲氧基;
R2选自-(CH2)n-R6;
n选自1、2、3、4、5、6;
优选地,n选自1、2、3;
更优选地,n选自1、2;
最优选地,n为1;
R6选自5-6元杂芳基;
优选地,R6选自5元杂芳基;
更优选地,R6选自呋喃基、噻吩基;
进一步优选地,R6选自
最优选地,R6为
优选地,R2为
R3为苯基,所述苯基任选被1-2个选自Rx的基团所取代;
Rx选自卤素;
优选地,Rx为氯;
优选地,R3选自/>
R4为
其中,R7、R8、R9、R10、R11各自独立地选自氢、C1-C6烷基-C(=O)-N(Ru)-,且R7、R8、R9、R10、R11不同时为氢;
优选地,R9选自C1-C6烷基-C(=O)-N(Ru)-,R7、R8、R10、R11为氢;
更优选地,R9选自R7、R8、R10、R11为氢;
Ru选自氢、C1-C6烷基;
优选地,Ru为氢;
优选地,R4选自
且,式I-2所示的化合物不为以下化合物:
8.根据权利要求1-7任一项所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,其中,所述化合物选自以下:
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9.药物组合物,其包含权利要求1-8任一项所述的化合物,或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯,以及任选的药学上可以接受的辅料。
10.权利要求1-8任一项所述的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯在制备药物中的用途,或者权利要求9所述的药物组合物在制备药物中的用途,或者以下式II所示的化合物或所述化合物的立体异构体、前药、晶型、药学上可接受的盐、药学上可接受的溶剂合物或药学上可接受的酯在制备药物中的用途,所述药物用于治疗和/或预防与FXR受体有关的疾病;
优选地,所述与FXR受体有关的疾病选自代谢相关疾病、心血管疾病、肝脏疾病、癌症、肾病、肠病、炎症或其任意组合;
优选地,所述代谢相关疾病选自糖脂代谢疾病、胆固醇代谢疾病、脂质代谢疾病、胆汁酸代谢疾病或其任意组合;
优选地,所述糖脂代谢疾病选自肥胖症、糖尿病(如2型糖尿病)、血脂异常、高脂血症、高胆固醇、胆汁淤积症、非酒精性脂肪肝、非酒精性脂肪性肝炎或其任意组合;
优选地,所述心血管疾病选自动脉粥样硬化、心肌缺血再灌注损伤或其组合;
优选地,所述肝脏疾病选自肝切除、肝损伤或其组合;
优选地,所述癌症选自乳腺癌、食管癌、肺癌、胰腺癌、肾癌、肝癌、前列腺癌或其任意组合;
优选地,所述肾病选自肾炎、肾病综合征、动脉粥样栓塞性肾脏疾病或其任意组合;
其中:
R1’选自氢、卤素、C1-C6烷氧基、-NRa’Rb’;
优选地,R1’选自氢、氯、甲氧基、
Ra’、Rb’各自独立地选自氢、C1-C6烷基;
优选地,Ra’、Rb’各自独立地选自C1-C6烷基;
更优选地,Ra’、Rb’为乙基;
R2’选自-(CH2)n’-R5’;
n′选自0、1、2、3、4、5、6;
优选地,n′选自0、1、2、3;
更优选地,n′选自0、1、2;
最优选地,n′选自0、1;
R5’选自5-6元杂芳基、苯基、5-6元饱和杂环、C3-C6环烷基、C1-C6烷基、C1-C6烷氧基-C1-C6烷基,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟)的基团所取代;
优选地,R5’选自呋喃基、苯基、四氢呋喃基、C3-C6环烷基、C1-C6烷基、C1-C6烷氧基-C1-C6烷基,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟)的基团所取代;
更优选地,R5’选自
优选地,R2’选自
R3’选自苯基、5-6元杂芳基、C1-C6烷基、-NRc’Rd’,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟、氯)的基团所取代;
优选地,R3’选自苯基、呋喃基、噻吩基、C1-C6烷基、-NRc’Rd’,任选地,所述苯基被1个选自氟、氯、溴、碘(优选氟、氯)的基团所取代;
Rc’、Rd’各自独立地选自氢、C1-C6烷基、苯基,所述苯基任选地被1个选自C1-C6烷氧基(优选甲氧基)的基团所取代;
优选地,Rc’、Rd’中,任意一个为氢,另一个选自C1-C6烷基、苯基,所述苯基任选地被1个选自C1-C6烷氧基(优选甲氧基)的基团所取代;
更优选地,Rc’、Rd’中,任意一个为氢,另一个选自
更优选地,R3’选自
R4’选自C1-C6烷基;
优选地,R4’为甲基。
11.根据权利要求10所述的用途,其中,式II所示的化合物选自式II-1、II-2、II-3:
其中,R1’、R2’、R3’、R4’的定义如权利要求10所限定。
12.根据权利要求10-11任一项所述的用途,其中,式II所示的化合物选自以下:
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