CN110869352A - 化学化合物 - Google Patents
化学化合物 Download PDFInfo
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- CN110869352A CN110869352A CN201880031403.9A CN201880031403A CN110869352A CN 110869352 A CN110869352 A CN 110869352A CN 201880031403 A CN201880031403 A CN 201880031403A CN 110869352 A CN110869352 A CN 110869352A
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- amino
- alkyl
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- ring system
- nitrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
本公开涉及式(I)的化合物及其药学上可接受的盐,药物组合物,使用方法及其制备方法。本文公开的化合物通过抑制炎性体来抑制IL‑1家族的细胞因子的成熟,并且可以用于治疗其中涉及炎性体活性的病症,例如尤其是自身炎性疾病和自身免疫疾病和癌症。
Description
本公开涉及特定的新颖化合物及其直接相关的前药或药学上可接受的盐,其具有炎性体抑制活性,因此可用于治疗人或动物体的方法。本公开还涉及制备这些化合物的方法,涉及包含它们的药物组合物,以及它们在治疗涉及炎性体活性的病症例如自身炎性疾病和自身免疫疾病中的用途。
背景
自身免疫疾病与促炎因子的过度产生有关。其中之一是白细胞介素-1(IL-1),由激活的巨噬细胞、单核细胞、成纤维细胞和先天免疫系统的其他组分(如树突状细胞)产生。它参与多种细胞活动,包括细胞增殖、分化和凋亡(Seth L.al.Rev.Immunol.2009.27:621-68)。
IL-1家族的细胞因子是高度活跃的,并且作为炎症的重要介体,主要与急性和慢性炎症相关(Sims J.et al.Nature Reviews Immunology 10,89-102(2010年2月))。IL-1的过度产生被认为是某些自身免疫和自身炎性疾病的介体。自身炎性疾病的特征是在没有自身抗体、感染或抗原特异性T淋巴细胞的情况下反复发作和无缘无故的炎症。
IL-1超家族的促炎细胞因子包括IL-1α、IL-1β、IL-18和IL-36α、β、γ,并且作为宿主先天免疫应答的一部分响应病原体和其他细胞应激物而产生。与通过由内质网和高尔基体组成的标准细胞分泌部加工和释放的许多其他分泌的细胞因子不同,IL-1家族成员缺乏内质网进入所需的前导序列,因此在翻译后保留在细胞内。此外,IL-1β、IL-18和IL-36α、β、λ合成为前细胞因子,该前细胞因子需要蛋白水解激活以成为最佳配体用于与靶细胞上的其同源受体结合。
在IL-1α、IL-1β和IL-18的情况下,现在认识到,称为炎性体的多聚体蛋白复合物负责激活IL-1β和IL-18的前体形式(proform)并负责这些细胞因子的细胞外释放。炎性体复合物通常由以下组成:传感器分子,例如NLR(核苷酸-寡聚化结构域(NOD)样受体),衔接分子ASC(与凋亡相关的斑点样蛋白质,含有CARD(半胱氨酸天冬氨酸蛋白酶募集结构域))和半胱氨酸天冬氨酸蛋白酶前体-1。响应多种“危险信号”,包括病原体相关分子模式(PAMP)和危险相关分子模式(DAMP),炎性体的亚单位在细胞内寡聚形成超分子结构。PAMP包括诸如肽聚糖、病毒DNA或RNA和细菌DNA或RNA的分子。另一方面,DAMP由多种内源性无菌触发物组成,所述触发物包括尿酸单钠晶体,二氧化硅,明矾,石棉,脂肪酸,神经酰胺,胆固醇晶体和β-淀粉样肽的聚集体。炎性体平台的组装促进半胱氨酸天冬氨酸蛋白酶前体-1的自催化,产生负责激活和释放proIL-1β和pro-IL-18的高活性半胱氨酸蛋白酶。因此,仅在响应检测到并响应特定分子危险信号的炎性体传感器时实现这些高度炎性细胞因子的释放。
在人类中,将22种NLR蛋白根据其N末端结构域分为四个NLR亚家族。NLRA包含CARD-AT结构域,NLRB(NAIP)包含BIR结构域,NLRC(包括NOD1和NOD2)包含CARD结构域,NLRP包含热蛋白(pyrin)结构域。多个NLR家族成员与炎性体形成有关,包括NLRP1、NLRP3、NLRP6、NLRP7、NLRP12和NLRC4(IPAF)。
包含PYHIN结构域的其他两种结构上不同的炎性体结构(含有热蛋白和HIN结构域的蛋白质)(即缺失黑色素瘤2(AIM2)和IFNλ-诱导蛋白16(IFI16))(Latz et al.,Nat RevImmunol 2013 13(6)397-311)用作细胞内DNA传感器。
要求炎性体平台组装以实现来自单核细胞和巨噬细胞的IL-1和IL-18的激活和释放,确保了它们的产生是通过两步过程仔细配合的。首先,细胞必须遇到引起NLRP3、pro-IL-1β和pro-IL-18的NFκB依赖性转录的引发配体(例如TLR4受体配体LPS或炎性细胞因子例如TNFα)。新翻译的前细胞因子仍保持在细胞内且无活性,除非产生细胞遇到第二信号导致炎性体支架激活和半胱氨酸天冬氨酸蛋白酶前体-1成熟。
除了pro-IL-1β和pro-IL-18的蛋白水解激活之外,活性半胱氨酸天冬氨酸蛋白酶-1还通过裂解消皮素-D触发称为细胞焦亡的炎性细胞死亡形式。细胞焦亡使成熟形式的IL-1β和IL-18外在化,同时释放出警报素分子(促进炎症并激活先天和适应性免疫的化合物),例如高迁移率族蛋白B1(HMGB1)、IL-33和IL-1α。
尽管炎性体激活显得已成为宿主对病原体免疫的重要组成部分,但NLRP3炎性体在其响应内源性无菌危险信号时被激活的能力方面是独特的。已经阐明了许多这样的无菌信号,并且它们的形成与特定的疾病状态有关。例如,在痛风患者中发现的尿酸晶体是NLRP3激活的有效触发因素。类似地,在动脉粥样硬化患者中发现的胆固醇晶体也可以促进NLRP3激活。认识到无菌危险信号作为NLRP3激活剂的作用导致IL-1和IL-18涉及多种病理生理指征,包括代谢、生理学、炎性、血液学和免疫学病症。
与人类疾病的联系通过以下发现得到最好的例证:导致功能获得的NLRP3基因的突变导致一系列自身炎性病况,统称为冷吡啉相关周期性综合征(CAPS),包括家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)和新生儿发作的多系统炎性疾病(NOMID)(Hoffman et al.,Nat Genet.29(3)(2001)301-305)。同样,无菌介体诱导的NLRP3激活也涉及多种病症,包括关节变性(痛风、类风湿关节炎、骨关节炎)、心脏代谢(2型糖尿病、动脉粥样硬化、高血压)、中枢神经系统(阿尔茨海默氏病、帕金森氏病、多发性硬化症)、胃肠道(克罗恩氏病)、肺部(慢性阻塞性肺疾病)和纤维化(非酒精性脂肪肝病、非酒精性肝脂肪变性、特发性肺纤维化)。
涉及IL-1作为致病因素的疾病的当前治疗选择包括IL-1受体拮抗剂阿那白滞素,1型IL-1受体的含Fc可溶性融合构建体,IL-1受体辅助蛋白利纳西普和抗IL-1β单克隆抗体康纳单抗。例如,康纳单抗被许可用于CAPS,肿瘤坏死因子受体相关周期性综合征(TRAPS),高免疫球蛋白D综合征(HIDS)/甲羟戊酸激酶缺乏症(MKD),家族性地中海热(FMF)和痛风。
据报道一些小分子抑制NLRP3炎性体的功能。例如,格列本脲是NLRP3激活的特异性抑制剂,尽管是在体内不可能达到的微摩尔浓度下。非特异性药物,如小白菊内酯、Bay11-7082和3,4-亚甲二氧基-β-硝基苯乙烯据报道会减少NLRP3激活,但预期具有有限的治疗用途,这是由于它们共享由吸电子基团取代激活的烯烃组成的共同结构特征;这会导致不希望地形成与带有巯基的蛋白质的共价加合物。还报道了许多天然产物,例如β-羟基丁酸酯、萝卜硫素、槲皮苷和丹酚酸抑制NLRP3激活。同样,其他分子靶标的许多效应子/调节剂据报道减少NLRP3的激活,包括G蛋白偶联受体TGR5的激动剂,钠-葡萄糖共转运抑制剂epigliflozin,多巴胺受体拮抗剂A-68930、5-羟色胺再摄取抑制剂氟西汀,芬那酸酯非甾体类抗炎药和β-肾上腺素受体阻滞剂奈比洛尔。这些分子作为长期治疗NLRP3依赖性炎性病症的治疗剂的用途仍有待确立。先前已将一系列含磺酰脲的分子鉴定为pro-IL-1β的翻译后加工的有效和选择性抑制剂(Perregaux et al.,J Pharmacol.Exp.Ther.299,187-197,2001)。来自这项工作的示例分子CP-456,773最近被表征为NLRP3激活的特异性抑制剂(Coll et al.,Nat Med 21.3(2015):248-255.)。
本公开源自需要提供进一步的化合物以特异性调节NLRP3依赖性细胞过程。特别地,期望相对于现有化合物具有改善的物理化学,药理学和药学性质的化合物。
概述
根据第一方面,本公开涉及式(I)的化合物或其前药或药学上可接受的盐:
其中:
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1或2个独立地选自氧,氮和硫的杂原子,其中所述杂环R7环系统任选地被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
或其中R7选自5或6元单环芳基或非芳基环系统,其任选包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,任选包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元饱和或部分不饱和的碳环系统,且其中所述R7环系统被1个或多个取代基取代,所述取代基独立选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
其中R8为任选地N-连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;且
R4为H,烷基,单环烷基或单环芳基。
在一些实施方案中,R1为选自以下的12、13、14、15或16元三环部分不饱和碳环系统:
其中#表示与式(I)氮原子的键;其中n和na是独立地选自0、1、2和3的整数;其中R9选自氢,(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
或选自以下的12、13、14、15或16元三环部分不饱和碳环系统
其中#表示与式(I)氮原子的键;其中n和na是独立地选自0、1、2和3的整数;其中R9选自氢,(1-6C)烷基,卤素,CF3和OCF3;或
其中#表示与式(I)氮原子的键;其中R9选自氢,(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;或
其中#表示与式(I)氮原子的键;其中R9选自氢,(1-6C)烷基,卤素,CF3和OCF3;或
未取代的六氢引达省环:
其中#表示与式(I)氮原子的键。
根据另一方面,本公开涉及式(II)的化合物或其前药或药学上可接受的盐:
其中:
R2是H
R3是烷基(C1-4)-R7,其中R7是
5或6元单环芳基或非芳基环系统,其包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1或2个独立地选自氧,氮和硫的杂原子,其中所述杂环R7环系统任选地被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
或
5或6元单环芳基或非芳基环系统,任选地包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,任选包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元饱和或部分不饱和的碳环系统,且其中所述R7环系统被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
其中R8是任选地N-连接的5或6元单环杂芳基环,其包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,其包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;和
R4为H,烷基,单环烷基或单环芳基。
申请人发现,本公开的化合物用作NLRP3炎性体激活的有效抑制剂,因此预期可用于治疗其中涉及炎性体活性的疾病。
在一些实施方案中,R3为甲基或乙基-R7。
优选地,R7是任选具有至少一个羟基取代的单环芳基。
优选地,R7是具有氰基取代的单环芳基。
优选地,R7是包含1、2或3个独立地选自氧,氮和硫的杂原子的5或6元单环芳基环。
在一些实施方案中,R4为甲基或乙基。
根据另一方面,提供了式(I)的化合物,或其前药或药学上可接受的盐:
其中:
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1或2个独立地选自氧,氮和硫的杂原子,其中所述环系统任选地被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基,任选地N连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,或任选地N连接的3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;和
R4为H,烷基,单环烷基或单环芳基。
在另一方面,本公开涉及式(I)的化合物或其前药或药学上可接受的盐:
其中:
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其任选包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,任选包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元饱和或部分不饱和的碳环系统,且所述环系统被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基,任选地N连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,和任选地N连接的3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;和
R4为H,烷基,单环烷基或单环芳基。
根据本公开的另一方面,提供了药物组合物,其包含与药学上可接受的稀释剂或载体混合的本文定义的化合物或其药学上可接受的盐。
根据本公开的另一方面,提供了在体外或体内抑制炎性体(例如NLRP3炎性体)活性的方法,所述方法包括使细胞与有效量的如本文所定义的式(I)或(II)的化合物或其药学上可接受的盐接触。
根据本公开的另一方面,提供了治疗需要这种治疗的患者的其中涉及炎性体活性的疾病或病症的方法,所述方法包括向所述患者施用治疗有效量的如本文所定义的式(I)或(II)的化合物或其药学上可接受的盐或本文定义的药物组合物。
根据本公开的另一方面,提供了治疗需要这种治疗的患者的自身炎性病症,自身免疫病症,神经退行性疾病或癌症的方法,所述方法包括向所述患者施用治疗有效量的如本文所定义的式(I)或(II)的化合物或其药学上可接受的盐或本文定义的药物组合物。
根据本公开的另一个方面,提供了治疗需要这种治疗的患者的自身炎性病症和/或自身免疫病症的方法,所述自身炎性病症和/或自身免疫病症选自冷吡啉相关自身炎性综合征(CAPS),包括家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征、新生儿发作的多系统炎性疾病(NOMID)、家族性地中海热和非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、痛风、类风湿性关节炎、骨关节炎、克罗恩氏病、COPD、纤维化、肥胖症、2型糖尿病、多发性硬化症和发生在蛋白质错误折叠疾病(例如朊病毒疾病)中的神经炎症,所述方法包括向所述患者施用治疗有效量的如本文所定义的式(I)或(II)的化合物或其药学上可接受的盐或本文定义的药物组合物。
根据本公开的另一方面,提供了治疗需要这种治疗的患者的神经退行性疾病例如帕金森氏病或阿尔茨海默氏病的方法,所述方法包括向所述患者施用治疗有效量的如本文所定义的式(I)或(II)的化合物或其药学上可接受的盐或本文定义的药物组合物。
根据本公开的另一方面,提供了用于治疗的如本文所定义的式(I)、(II)的化合物或其药学上可接受的盐或药物组合物。
根据本公开的另一方面,提供了如本文所定义的式(I)、(II)的化合物或其药学上可接受的盐或如本文所定义的药物组合物,用于治疗其中涉及炎性体活性的病症。
在一个实施方案中,该组合物用于治疗癌症。在特别优选的实施方案中,癌症选自转移性癌,胃肠癌,皮肤癌,非小细胞肺癌和结直肠腺癌。
根据本公开的另一方面,提供了本文定义的式(I)、(II)的化合物或其药学上可接受的盐、水合物或溶剂化物,或药物组合物,用于治疗自身炎性病症,自身免疫病症,神经退行性疾病或癌症。在特定的实施方案中,所述自身炎性或自身免疫病症是冷吡啉相关自身炎性综合征(CAPS),例如家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征、新生儿发作的多系统炎性疾病(NOMID)、家族性地中海热和非酒精性脂肪肝疾病(NAFLD)、痛风、类风湿性关节炎、克罗恩氏病、COPD、纤维化、肥胖症、2型糖尿病、多发性硬化症或发生在蛋白质错误折叠疾病(例如朊病毒疾病)中的神经炎症。在另一个实施方案中,神经退行性疾病是帕金森氏病或阿尔茨海默氏病,NASH和骨关节炎。
根据本公开的另一方面,提供了如本文所定义的式(I)、(II)的化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗自身炎性病症、自身免疫病症、神经退行性疾病或癌症。适当地,自身炎性或自身免疫病症是冷吡啉相关自身炎性综合征(CAPS),例如家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征、新生儿发作的多系统炎性疾病(NOMID)、家族性地中海热和非酒精性脂肪肝疾病(NAFLD)、NASH、骨关节炎、痛风、类风湿性关节炎、克罗恩氏病、COPD、纤维化、肥胖症、2型糖尿病或发生在蛋白质错误折叠疾病(例如朊病毒疾病)中的神经炎症。适当地,神经退行性疾病是帕金森氏病或阿尔茨海默氏病或多发性硬化症。
根据本公开的另一方面,提供了制备如本文所定义的式(I)、(II)的化合物或其药学上可接受的盐的方法。
根据本公开的另一方面,提供了可通过本文所定义的制备化合物的方法获得的,或通过本文所定义的制备化合物的方法获得的,或通过本文所定义的制备化合物的方法直接获得的式(I)、(II)的化合物或其药学上可接受的盐。
根据本公开的另一方面,提供了本文所定义的新颖的中间体,其适用于本文所述的任何一种合成方法。
除非另有定义,否则本文中使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解的相同含义。尽管类似于或等同于本文描述的那些的方法和材料可以用于本公开的实践或测试中,下面描述了合适的方法和材料。本文提及的所有出版物、专利申请、专利和其他参考文献通过引用整体并入本文。在发生冲突的情况下,以本说明书包括定义为准。另外,材料、方法和实施例仅是说明性的,并不意图是限制性的。
根据以下详细说明和权利要求,本公开的其他特征和优点将显而易见。
详细说明
与人类疾病的联系通过以下发现得到最好的例证:导致功能获得的NLRP3基因的突变导致一系列自身炎性病况,统称为冷吡啉相关周期性综合征(CAPS),包括家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)和新生儿发作的多系统炎性疾病(NOMID)(Hoffman et al.,Nat Genet.29(3)(2001)301-305)。同样,无菌介体诱导的NLRP3激活也涉及多种病症,包括关节变性(痛风、类风湿关节炎、骨关节炎)、心脏代谢(2型糖尿病、动脉粥样硬化、高血压)、中枢神经系统(阿尔茨海默氏病、帕金森氏病、多发性硬化症)、胃肠道(克罗恩氏病)、肺部(慢性阻塞性肺疾病)和纤维化(非酒精性脂肪肝病、非酒精性肝脂肪变性、特发性肺纤维化)。
定义
除非另有说明,否则说明书和权利要求书中使用的下列术语具有以下含义,如以下所述。
应当理解,对“治疗(treating)”或“治疗(treatment)”的提及包括减轻病况的已确定的症状。因此,对状态、病症或病况的“治疗(treating)”或“治疗(treatment)”包括:(1)预防或延迟可能患有或易于患有所述状态、病症或病况但尚未经历或表现出所述状态、病症或病况的临床或亚临床症状的人中出现的所述状态、病症或病况的临床症状的表现,(2)抑制该状态、病症或病况,即阻止、减少或延迟该疾病或其复发(在维持治疗的情况下)或其至少一种临床或亚临床症状的出现,或(3)缓解或减轻疾病,即引起该状态、病症或病况或其至少一种临床或亚临床症状的消退。
“治疗有效量”是指当施用于哺乳动物以治疗疾病时足以对疾病实现这种治疗的化合物的量。“治疗有效量”将根据化合物,疾病及其严重程度,以及待治疗的哺乳动物的年龄、体重等而变化。
在本说明书中,术语“烷基”包括直链和支链烷基,例如丙基、异丙基和叔丁基。然而,对单独的烷基如“丙基”的提及仅特定于直链形式,而对单独的支链烷基如“异丙基”的提及仅特定于支链形式。例如,“(1-6C)烷基”包括(1-4C)烷基,(1-3C)烷基,丙基,异丙基和叔丁基。
“亚烷基”,“亚烯基”或“亚炔基”是位于两个其他化学基团之间并用于连接两个其他化学基团的烷基,烯基或炔基。因此,“(1-6C)亚烷基”是指1-6个碳原子的直链饱和二价烃基或3-6个碳原子的支链饱和二价烃,例如,亚甲基、亚乙基、亚丙基、2-甲基亚丙基、亚戊基等。
“(2-6C)亚烯基”是指二个至六个碳原子的直链二价烃基或三个至六个碳原子的支链二价烃基,其含有至少一个双键,例如在亚乙烯基、2,4-亚戊二烯基等中。
“(2-6C)亚炔基”是指二个至六个碳原子的直链二价烃基或三个至六个碳原子的支链二价烃基,其含有至少一个三键,例如在亚乙炔基,亚丙炔基和亚丁炔基等中。
“(3-8C)环烷基”是指含有3至8个碳原子的烃环,例如环丙基,环丁基,环戊基,环己基,环庚基或双环庚基。
术语“卤代”是指氟代、氯代、溴代和碘代。
术语“(1-6C)烷氧基”的合适值包括甲氧基,乙氧基,丙氧基,异丙氧基和丁氧基。
术语“(1-3C)烷基氨基”的合适值包括甲基氨基,乙基氨基,丙基氨基和异丙基氨基。
术语“二-[(1-3C)烷基]-氨基”的合适值包括二甲基氨基,二乙基氨基,N-乙基-N-甲基氨基和二异丙基氨基。
术语“芳基”是指具有5至12个碳原子的环状或多环芳环。术语芳基包括一价种类和二价种类。芳基的实例包括但不限于苯基,联苯基,萘基等。方便地,芳基是苯基。
术语“5元单环杂芳基环系统”当用于定义环系统时,其中该环系统任选地包含1、2或3个独立地选自氧,氮和硫的杂原子。合适的实例包括呋喃基,噻吩基,吡咯基,异噁唑基,噻唑基,异噻唑基,吡唑基,咪唑基,噁二唑基,噻二唑基,三唑基和四唑基。
术语“8、9或10元双环杂芳基环系统”当用于定义形成的环系统时,任选地包含1、2或3个独立地选自氧,氮和硫的杂原子。合适的实例包括吲哚基,异吲哚基,吲唑基,苯并咪唑基,苯并噁噻唑基,苯并噁二唑基,苯并噻二唑基,喹啉基,异喹啉基,嘌呤基,1,8-萘啶基,蝶啶基,1H-吡咯并[3,2-b]吡啶基,1H-吡咯并[2,3-c]吡啶基,吡啶并[3,2-d]嘧啶基和吡啶并咪唑基。术语“8、9或10元双环杂芳基环系统”还涵盖部分芳族双环系统,其中第一环为芳族而另一个第二环为非芳族、饱和或部分饱和的。部分芳族双环系统的合适实例包括例如4,5,6,7-四氢吲哚基,4,5,6,7-四氢异吲哚基和2H,4H,5H,6H-环戊二烯并[c]吡咯基。
术语“5或6元单环杂芳基环系统”是指包含1、2或3个独立地选自氧,氮和硫的杂原子的5或6元芳族环系统。合适的实例包括呋喃基,噻吩基,吡咯基,异噁唑基,噻唑基,异噻唑基,吡唑基,咪唑基,噁二唑基,噻二唑基,三唑基,四唑基,吡啶基,嘧啶基,吡嗪基和哒嗪基。
术语“3、4、5或6元单环杂环基环系统”是指3、4、5或6元非芳族饱和或部分饱和的杂环系统,其中该环系统任选地包含1或2个独立地选自氧,氮和硫的杂原子,其中环硫原子任选地被氧化以形成S-氧化物。合适的例子包括环氧乙烷基,氮杂环丙烷基,氮杂环丁烷基,氧杂环丁烷基,吡咯啉基,吡咯烷基,咪唑啉基,咪唑烷基,吡唑啉基,吡唑烷基,吗啉基,硫代吗啉基,哌啶基,高哌啶基,哌嗪基,高哌嗪基,四氢呋喃基,四氢吡喃和四氢-1,4-噻嗪基。
术语“12、13、14、15或16元三环部分不饱和杂环系统”当用于定义环系统时,是指12、13、14、15或16部分不饱和杂环系统,其包含1或2个独立地选自氧,氮和硫的杂原子,其中环硫原子任选地被氧化以形成S-氧化物。合适的实例包括环,例如2-氮杂三环[7.3.0.03,]十二烷-1,3(7),8-三烯基,1,2,3,4,5,6,7,8-八氢吖啶基,7-氮杂三环[7.3.0.02,]十二烷-1,6,8-三烯基,1,2,3,4,7,8,9,10-八氢菲啶基,1H,2H,3H,6H,7H,8H,9H-环戊二烯并[c]异喹啉基,1H,2H,3H,6H,7H,8H,9H-环戊二烯并[c]喹诺酮基,1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]喹诺酮基,1H,2H,3H,5H,6H,7H-环戊二烯并[b]吡呤基,1H,2H,3H,5H,6H,7H,8H-环己二烯并[b]吡呤基,1H,2H,3H,5H,6H,7H-环戊二烯并[b]吡呤基和1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]吲嗪基。
术语“12、13、14、15或16元三环部分不饱和碳环系统”仅包含碳原子。合适的例子包括环,例如1,2,3,5,6,7-六氢-对称-引达省基,1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘基,1,2,3,6,7,8-六氢不对称-引达省基,1,2,3,4,5,6,7,8-八氢蒽基,1,2,3,4,5,6,7,8-八氢菲基和1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘基。
术语“3、4、5或6元饱和或部分不饱和的碳环系统”是指仅包含碳原子的单环系统。合适的例子包括环丙烷基,环戊烷基,环己烷基和环己烯基。
短语“本公开的化合物”是指一般和具体地在本文中公开的那些化合物。
本公开的化合物
为了避免疑问,应当理解,当在本说明书中基团被限定为“在此之前定义的”或“本文之前定义的”,该基团包括最先出现和最广泛的定义以及该基团每一个和所有的特定定义。
本公开内容的特定化合物包括例如式(I)或(II)的化合物或其药学上可接受的盐,其中,除非另有说明,R1,R2,R3,R4和任何相关的取代基的每一个具有本文之前定义的任何含义。
通常选择组成式(I)或(II)的化合物的各种官能团和取代基,以使化合物的分子量不超过1000道尔顿。更通常地,化合物的分子量将小于900,例如小于800,或小于750,或小于700,或小于650道尔顿。更方便地,分子量小于600,例如为550道尔顿或更小。
本公开化合物的合适的药学上可接受的盐是,例如,足够碱性的本公开化合物的酸加成盐,例如,与例如无机酸或有机酸的酸加成盐,所述无机酸或有机酸例如盐酸,氢溴酸,硫酸,磷酸,三氟乙酸,甲酸,柠檬酸甲磺酸盐或马来酸。另外,足够酸性的本公开化合物的合适的药学上可接受的盐是碱金属盐,例如钠或钾盐,碱土金属盐,例如钙或镁盐,铵盐或与提供药学上可接受的阳离子的有机碱的盐,例如与甲胺,二甲胺,三甲胺,哌啶,吗啉或三-(2-羟乙基)胺形成的盐。
应当理解,式(I)、(II)的化合物及其任何药学上可接受的盐包括所述化合物的所有异构形式的立体异构体,立体异构体的混合物,多晶型物。
具有相同分子式但其原子的键合性质或顺序或其原子在空间中的排列不同的化合物称为“异构体”。其原子空间排列不同的异构体称为“立体异构体”。彼此不是镜像的立体异构体被称为“非对映异构体”,彼此是不可重叠的镜像的立体异构体被称为“对映异构体”。当化合物具有不对称中心,例如,它键合到四个不同的基团,则可能有一对对映异构体。对映异构体可以通过其不对称中心的绝对构型表征,并由Cahn和Prelog的R定序和S定序规则描述,或者可以通过分子旋转偏振光平面的方式表征,并称为右旋或左旋(即分别为(+)或(-)-异构体)。手性化合物可以单独的对映异构体或其混合物形式存在。包含等比例对映异构体的混合物称为“外消旋混合物”。
本公开的化合物可具有一个或多个不对称中心;因此,此类化合物可以作为单独的(R)-或(S)-立体异构体或其混合物产生。除非另有说明,否则说明书和权利要求书中特定化合物的描述或命名旨在包括单个对映异构体及其混合物,外消旋物或其他形式。确定立体化学和分离立体异构体的方法是本领域众所周知的(参见“Advanced OrganicChemistry(高级有机化学)”,第4版J.March,John Wiley and Sons,New York,2001第4章的讨论),例如通过由旋光起始原料合成或通过拆分外消旋形式。本公开内容的一些化合物可具有几何异构中心(E-和Z-异构体)。应当理解,本公开涵盖具有炎性体抑制活性的所有光学,非对映异构体和几何异构体及其混合物。
本公开还涵盖包含一个或多个同位素取代的本文定义的本公开的化合物。
还应理解,某些式(I)或(II)的化合物可以以溶剂化物以及非溶剂化物形式例如水合物形式存在。合适的药学上可接受的溶剂化物是例如水合物,例如半水合物,一水合物,二水合物或三水合物。应当理解,本公开涵盖了具有炎性体抑制活性的所有此类溶剂化物形式。
还应理解,某些式(I)或(II)的化合物可表现出多态性,并且本公开内容涵盖具有炎性体抑制活性的所有此类形式或其混合物。众所周知,可以使用常规技术来分析结晶材料,该技术例如X射线粉末衍射分析,差示扫描量热法,热重分析,漫反射红外傅里叶变换(DRIFT)光谱,近红外(NIR)光谱,溶液和/或固态核磁共振光谱。这种结晶材料的水含量可以通过Karl Fischer分析法确定。
式(I)或(II)的化合物可以多种不同的互变异构形式存在,并且提及式I的化合物包括所有这些形式。为了避免疑问,当化合物可以几种互变异构形式之一存在,并且仅具体描述或显示一种时,所有其他形式仍被式(I)所涵盖。互变异构形式的实例包括酮-,烯醇-和烯醇化物形式,例如,见于以下互变异构对中:酮/烯醇(如下所示),亚胺/烯胺,酰胺/亚氨基醇,脒/脒,亚硝基/肟,硫酮/烯硫醇和硝基/酸硝基。
含有胺官能团的式(I)或(II)化合物也可以形成N-氧化物。本文中提及的含有胺官能团的式I化合物也包括N-氧化物。当化合物含有多个胺官能团时,一个或多于一个氮原子可被氧化形成N-氧化物。N-氧化物的具体实例是叔胺或含氮杂环的氮原子的N-氧化物。可以通过用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺来形成N-氧化物,例如参见Advanced Organic Chemistry,by Jerry March,4th Edition,WileyInterscience,pages(高级有机化学,by Jerry March,第4版,Wiley Interscience,页码)。更具体地,可以通过L.W.Deady(Syn.Comm.1977,7,509-514)的程序制备N-氧化物,其中使胺化合物与间氯过氧苯甲酸(mCPBA)例如在惰性溶剂如二氯甲烷中反应。
式(I)或(II)的化合物可以以前药的形式给药,所述前药在人或动物体内分解以释放本公开的化合物。前药可用于改变本公开化合物的物理性质和/或药代动力学性质。当本公开的化合物包含可以连接改性基团的合适的基团或取代基时,可以形成前药。前药的实例包括可以在式(I)或(II)的化合物的羧基或羟基形成的体内可裂解的酯衍生物,以及可以在式(I)或(II)的化合物的羧基或氨基形成的体内可裂解的酰胺衍生物。
因此,本公开内容包括当通过有机合成可获得时以及当通过其前药的裂解而在人或动物体内可获得时,如上文所定义的式(I)或(II)的那些化合物。因此,本公开包括通过有机合成方式产生的那些式(I)或(II)的化合物,以及通过前体化合物的代谢在人体或动物体内产生的这类化合物,即式(I)或(II)的化合物可以是合成产生的化合物或代谢产生的化合物。
式(I)或(II)的化合物的合适的药学上可接受的前药是基于合理的医学判断而适用于对人或动物体给药而没有不希望的药理活性并且没有过度的毒性的前药。已经描述了各种形式的前药,例如描述在以下文件中:
a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985);
b)Design of Prodrugs,edited by H.Bundgaard,(Elsevier,1985);
c)A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5“Design and Application of Prodrugs”,byH.Bundgaard p.113-191(1991);
d)H.Bundgaard,Advanced Drug Delivery RevieWs,8,1-38(1992);
e)H.Bundgaard,et al.,Journal of Pharmaceutical Sciences,77,285(1988);
f)N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984);
g)T.Higuchi and V.Stella,“ProDrugs as Novel Delivery Systems”,A.C.S.Symposium Series,Volume 14;和
h)E.Roche(editor),“Bioreversible Carriers in Drug Design”,PergamonPress.1987。
具有羧基的式(I)或(II)的化合物的合适的药学上可接受的前药是例如其体内可裂解的酯。含有羧基的式(I)或(II)的化合物的体内可裂解的酯为例如在人或动物体内裂解以产生母体酸的药学上可接受的酯。适用于羧基的合适的药学上可接受的酯包括:C1-6烷基酯,例如甲基,乙基和叔丁基酯;C1-6烷氧基甲基酯,例如甲氧基甲基酯;C1-6烷酰氧基甲基酯,例如新戊酰氧基甲基酯,3-酞基酯;C3-8环烷基羰基氧基-C1-6烷基酯,例如环戊基羰基氧基甲基酯和1-环己基羰基氧基乙基酯;2-氧代-1,3-二氧杂环戊烯基甲基酯,例如5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基甲基酯和C1-6烷氧基羰基氧基-C1-6烷基酯,例如甲氧基羰基氧基甲基和1-甲氧基羰基氧基乙基酯。
具有羟基的式(I)或(II)的化合物的合适的药学上可接受的前药是例如其体内可裂解的酯或醚。含有羟基的式(I)或(II)的化合物的体内可裂解的酯或醚是例如在人或动物体内裂解以产生母体羟基化合物的药学上可接受的酯或醚。用于羟基的合适的药学上可接受的酯形成基团包括无机酯,例如磷酸酯(包括磷酰胺环状酯)。用于羟基的其他合适的药学上可接受的酯形成基团包括(1-10C)烷酰基,例如乙酰基,苯甲酰基,苯乙酰基和取代的苯甲酰基和苯乙酰基,(1-10C)烷氧基羰基,例如乙氧基羰基,N,N-(C1-6)2氨基甲酰基,2-二烷基氨基乙酰基和2-羧基乙酰基。苯乙酰基和苯甲酰基上的环取代基的实例包括氨基甲基,N-烷基氨基甲基,N,N-二烷基氨基甲基,吗啉代甲基,哌嗪-1-基甲基和4-(C1-4烷基)哌嗪-1-基甲基。羟基的合适的药学上可接受的醚形成基团包括α-酰氧基烷基,例如乙酰氧基甲基和新戊酰氧基甲基。
具有羧基的式(I)或(II)化合物的合适的药学上可接受的前药是例如其体内可裂解的酰胺,例如与胺例如氨,C1-4烷基胺如甲胺,(C1-4烷基)2胺如二甲胺,N-乙基-N-甲胺或二乙胺,C1-4烷氧基-C2-4烷基胺如2-甲氧基乙胺,苯基-C1-4烷基胺如苄胺,和氨基酸如甘氨酸或其酯形成的酰胺。
具有氨基的式(I)或(II)的化合物的合适的药学上可接受的前药是例如其体内可裂解的酰胺衍生物。来自氨基的合适的药学上可接受的酰胺包括,例如与C1-1 0烷酰基如乙酰基,苯甲酰基,苯乙酰基和取代的苯甲酰基和苯乙酰基形成的酰胺。苯乙酰基和苯甲酰基上的环取代基的实例包括氨基甲基,N-烷基氨基甲基,N,N-二烷基氨基甲基,吗啉代甲基,哌嗪-1-基甲基和4-(C1-4烷基)哌嗪-1-基甲基。
式(I)或(II)的化合物的体内作用可以部分地由在施用式(I)或(II)的化合物后在人或动物体内形成的一种或多种代谢物发挥。如上所述,式(I)或(II)的化合物的体内作用也可以通过前体化合物(前药)的代谢来发挥。
尽管本公开可以涉及通过任选的,优选的或合适的特征或以其他方式以特定实施方案在本文定义的任何化合物或特定组的化合物,本公开内容还可以涉及具体排除所述任选的,优选的或合适的特征或特定实施方案的任何化合物或特定组的化合物。本公开的特征涉及R1处的特定结构基团,其与如本文所定义的权利要求的范围有关。在某些情况下,特定的基团定义与本发明无关,因此可以放弃的结构。当R1对应于被至少2个基团直接取代的苯基时,可以放弃这种结构,所述基团包括:1个卤素基团和1个甲基基团;2个或更多个卤素基团;或2个甲基基团。
适当地,本公开排除不具有本文定义的生物学活性的任何单独的化合物。
一般制备方法
本公开的化合物可以通过本领域已知的任何合适的技术来制备。在所附的实施例中进一步描述了制备这些化合物的特定方法。
在本文描述的合成方法的描述中以及用于制备起始原料的任何参考合成方法中,应理解所有提议的反应条件,包括溶剂的选择,反应气氛,反应温度,实验持续时间和后处理程序可以由本领域技术人员选择。
有机合成领域的技术人员应理解,存在于分子各个部分上的官能团必须与所使用的试剂和反应条件相容。
将理解的是,在本文定义的方法中合成本公开的化合物期间,或在某些起始原料的合成期间,可能期望保护某些取代基以防止其不希望的反应。化学领域技术人员将理解何时需要这种保护,以及如何可将这样的保护基放置到位,然后再除去。有关保护基的例子,请参见有关该主题的许多一般教科书之一,例如Theodora Green的‘ProtectiveGroups in Organic Synthesis(有机合成中的保护基)’(出版商:John Wiley&Sons)。可以通过文献中描述的或化学领域技术人员已知的适合于除去所讨论的保护基团的任何方便的方法除去保护基团,选择这样的方法以便实现保护基团的除去且对分子中的其他位置基团的干扰最小。因此,如果反应物例如包括例如氨基、羧基或羟基的基团,则可能需要在本文所述的某些反应中保护该基团。
举例来说,用于氨基或烷基氨基的合适的保护基是,例如,酰基,例如烷酰基如乙酰基,烷氧基羰基,例如甲氧基羰基,乙氧基羰基或叔丁氧基羰基,芳基甲氧基羰基,例如苄氧基羰基,或芳酰基,例如苯甲酰基。上述保护基的脱保护条件必然随保护基的选择而变化。因此,例如,可以通过例如用合适的碱,例如碱金属氢氧化物,例如氢氧化锂或氢氧化钠水解,除去酰基如烷酰基或烷氧基羰基或芳酰基。或者,可以例如通过用合适的酸(例如盐酸,硫酸或磷酸或三氟乙酸)处理来去除酰基,例如叔丁氧基羰基;并且可以去除例如苄氧基羰基的芳基甲氧基羰基,例如,通过经催化剂例如钯/碳氢化,或通过用路易斯酸例如三(三氟乙酸)硼处理。伯氨基的合适的供选保护基是例如邻苯二甲酰基,其可以通过用烷基胺例如二甲基氨基丙胺或用肼处理而除去。
合适的用于羟基的保护基是,例如,酰基,例如烷酰基,例如乙酰基,芳酰基,例如苯甲酰基,或芳基甲基,例如苄基。上述保护基的脱保护条件将必然随保护基的选择而变化。因此,例如,可以例如通过用合适的碱例如碱金属氢氧化物,例如氢氧化锂,氢氧化钠或氨水解,除去诸如烷酰基或芳酰基的酰基。或者,可以例如通过经催化剂如钯/碳氢化来除去芳基甲基如苄基。
羧基的合适保护基为例如酯化基团,例如甲基或乙基,其可以例如通过用碱如氢氧化钠水解而除去,或例如叔丁基,其可以例如通过用酸例如有机酸如三氟乙酸处理而除去,或例如苄基,其可以例如通过经催化剂如钯/碳氢化而除去。
一旦通过本文定义的任何一种方法合成了式(I)或(II)的化合物后,该方法然后可进一步包括以下附加步骤:
(i)除去存在的任何保护基;
(ii)将式(I)或(II)的化合物转化为另一种式(I)或(II)的化合物;
(iii)形成其药学上可接受的盐,水合物或溶剂化物;和/或
(iv)形成其前药。
可以使用本领域熟知的技术分离和纯化所得的式(I)或(II)的化合物。
方便地,化合物的反应在合适的溶剂存在下进行,该溶剂优选在各自的反应条件下是惰性的。合适的溶剂的实例包括但不限于烃,例如己烷,石油醚,苯,甲苯或二甲苯;氯代烃,例如三氯乙烯,1,2-二氯乙烷,四氯甲烷,氯仿或二氯甲烷;醇,例如甲醇,乙醇,异丙醇,正丙醇,正丁醇或叔丁醇;醚,例如乙醚,二异丙醚,四氢呋喃(THF),2-甲基四氢呋喃,环戊基甲基醚(CPME),甲基叔丁基醚(MTBE)或二噁烷;二醇醚,例如乙二醇单甲基或单乙基醚或乙二醇二甲醚(二甘醇二甲醚);酮,例如丙酮,甲基异丁基酮(MIBK)或丁酮;酰胺,例如乙酰胺,二甲基乙酰胺,二甲基甲酰胺(DMF)或N-甲基吡咯烷酮(NMP);腈,例如乙腈;亚砜,例如二甲基亚砜(DMSO);硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯或乙酸甲酯,或所述溶剂的混合物或与水的混合物。
根据反应步骤和所用条件,反应温度合适地在约-100℃至300℃之间。
反应时间通常在一分钟的若干分之几到几天之间的范围内,这取决于各个化合物的反应性和各个反应条件。合适的反应时间可以通过本领域已知的方法,例如反应监测容易地确定。基于上面给出的反应温度,合适的反应时间通常在10分钟至48小时之间的范围内。
而且,通过利用本文所述的程序,结合本领域普通技术,可以容易地制备本公开的其他化合物。本领域技术人员将容易理解,可以使用以下制备程序的条件和方法的已知变化来制备这些化合物。
如有机合成领域的技术人员将理解的,本公开的化合物可容易地通过各种合成途径获得,其中一些在所附的实施例中举例说明。技术人员将容易地认识到将使用哪种类型的试剂和反应条件以及在任何特定情况下如何应用和调整它们(必要或有用的任何情况),以获得本公开的化合物。此外,本公开的一些化合物可以通过使本公开的其他化合物在合适的条件下反应而容易地合成,例如,通过将存在于本公开的化合物或其合适的前体分子中的一种特定的官能团转化为另一种,所述转化是通过应用标准的合成方法,例如还原,氧化,加成或取代反应;那些方法是技术人员众所周知的。同样,技术人员将在必要或有用的任何时候应用合成保护(或保护)基团;合适的保护基团以及引入和除去它们的方法对于化学合成领域的技术人员是众所周知的,并且在例如P.G.M.Wuts,T.W.Greene,“Greene’sProtective Groups in Organic Synthesis”,4th edition(2006)(John Wiley&Sons)中更详细地描述。
药物组合物
根据本公开的另一方面,提供了药物组合物,其包含如上文所定义的本公开的化合物或其药学上可接受的盐,水合物或溶剂化物,以及药学上可接受的稀释剂或载体。
本公开的组合物可以是适合口服使用(例如,片剂,锭剂,硬或软胶囊,水性或油性悬浮液,乳剂,可分散的粉剂或颗粒剂,糖浆剂或酏剂),局部使用(例如乳剂,软膏剂,凝胶剂或水性或油性溶液或悬浮液),吸入给药(例如,作为细碎粉末或液体气雾剂),吹入给药(例如,作为细碎粉末)或肠胃外给药(例如作为用于静脉内,皮下,肌内,腹膜内或肌内给药的无菌水性或油性溶液或作为用于直肠给药的栓剂)的形式。
本公开的组合物可以使用本领域众所周知的常规药物赋形剂通过常规程序获得。因此,旨在用于口服使用的组合物可包含例如一种或多种着色剂,甜味剂,调味剂和/或防腐剂。
用于治疗的本公开化合物的有效量是足以治疗或预防本文所指的与炎性体相关的病况,减慢其进展和/或减少与该病况相关的症状的量。
与一种或多种赋形剂结合以产生单一剂型的活性成分的量必须根据所治疗的个体和特定的给药途径而变化。例如,意图对人口服给药的制剂通常含有例如0.5mg至0.5g的活性剂(更合适地0.5至100mg,例如1至30mg),并与可以占总组合物重量的约5%-约98%的适当和方便的量的赋形剂混合。
根据众所周知的医药原理,式I化合物用于治疗或预防目的的剂量大小自然将根据病况的性质和严重程度,动物或患者的年龄和性别以及给药途径而变化。
在将本公开的化合物用于治疗或预防目的时,通常将其给药以使得接受的每日剂量为例如0.1mg/kg至75mg/kg体重范围,如果需要,则以分剂量给予。通常,当采用肠胃外途径时,将给予较低的剂量。因此,例如,对于静脉内或腹膜内给药,通常将使用例如0.1mg/kg至30mg/kg体重范围的剂量。类似地,对于吸入给药,将使用例如0.05mg/kg至25mg/kg体重范围的剂量。口服给药也可能是合适的,特别是片剂形式。通常,单位剂型将包含约0.5mg至0.5g的本公开的化合物。
治疗用途和应用
本公开提供了充当炎性体活性的抑制剂的化合物。因此,本公开提供了体外或体内抑制炎性体活性的方法,所述方法包括使细胞与有效量的本文定义的化合物或其药学上可接受的盐接触。
本公开的化合物的有效性可以通过工业上接受的测定法/疾病模型根据本领域中描述的和在当前常识中发现的阐明它们的标准实践来确定。
本公开还提供了治疗需要这种治疗的患者中涉及炎性体活性的疾病或病症的方法,所述方法包括向所述患者给予治疗有效量的本文定义的化合物或其药学上可接受的盐,或药物组合物。
一般而言,抑制IL-1家族细胞因子成熟的本公开化合物在属于IL-1家族细胞因子的细胞因子活性形式水平升高介导或相关的所有治疗适应症中均有效(Sims J.etal.Nature Reviews Immunology 10,89-102(February 2010)。
示例性疾病和相应的参考文献将在以下给出:自身炎性疾病和自身免疫疾病如CAPS(Dinarello CA.Immunity.2004Mar;20(3):243-4;Hoffman HM.al.Reumatología2005;21(3)),痛风,类风湿性关节炎(Gabay C et al.Arthritis Research&Therapy2009,11:230;Schett G.et al.Nat Rev Rheumatol.2016Jan;12(1):14-24.),克罗恩氏病(Jung Mogg Kim Korean J Gastroenterol Vol.58No.6,300-310),COPD(Mortaz E.etal.Tanaffos.2011;10(2):9-14.),纤维化(Gasse P.et al.Am J Respir Crit CareMed.2009May 15;179(10):903-13),肥胖症,2型糖尿病((Dinarello CA.et al.Curr OpinEndocrinol Diabetes Obes.2010 Aug;17(4):314-21)),多发性硬化症(见EAE-modelinColl RC.et al.Nat Med.2015Mar;21(3):248-55)和许多其他疾病(Martinon F.etal.Immunol.2009.27:229-65)如帕金森氏病或阿尔茨海默氏病(Michael T.et al.Nature493,674-678(31January 2013);Halle A.et al.,Nat Immunol.2008Aug;9(8):857-65;Saresella M.et al.Mol Neurodegener.2016Mar 3;11:23)甚至某些肿瘤病症。
合适地,根据本公开的化合物可以用于治疗选自以下的疾病:自身炎性疾病,自身免疫疾病,神经退行性疾病和癌症。所述自身炎性和自身免疫疾病合适地选自NASH,骨关节炎癌症,冷吡啉相关周期性综合征(CAPS)(例如家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征/新生儿发作的多系统炎性疾病CNOMID)),家族性地中海热和非酒精性脂肪肝疾病(NAFLD),痛风,类风湿性关节炎,克罗恩氏病,COPD,纤维化,肥胖症,2型糖尿病,多发性硬化症和发生在蛋白质错误折叠疾病(例如朊病毒疾病)中的神经炎症。所述神经退行性疾病合适地选自帕金森氏病和阿尔茨海默氏病。
因此,本公开的化合物可用于治疗选自以下的疾病:冷吡啉相关周期性综合征(CAPS),例如家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征、新生儿发作的多系统炎性疾病(NOMID)、家族性地中海热和非酒精性脂肪肝疾病(NAFLD)、痛风、类风湿性关节炎、克罗恩氏病、COPD、纤维化、肥胖症、2型糖尿病、多发性硬化症、发生在蛋白质错误折叠疾病(例如朊病毒疾病)中的神经炎症、帕金森氏病和阿尔茨海默氏病。
癌症治疗;与炎性体联系
慢性炎症反应长期以来被观察到与各种类型的癌症有关。在恶性转化或癌症治疗期间,炎性体可能会响应危险信号而被激活,这种激活可能在癌症中既有益又有害。
IL-1表达在多种癌症(包括乳腺癌,前列腺癌,结肠癌,肺癌,头颈癌和黑色素瘤)中升高,并且具有IL-1生成肿瘤的患者预后通常较差(Lewis,Anne M.,et al.″Interleukin-1and cancer progression:the emerging role of interleukin-1receptor antagonist as a novel therapeutic agent in cancer treatment.″Journal of translational medicine 4.1(2006):48)。
源于上皮细胞(癌)或腺上皮(腺癌)的癌症是异类的;由许多不同的细胞类型组成。这可能包括成纤维细胞,免疫细胞,脂肪细胞,内皮细胞和周细胞等,所有这些可能是分泌细胞因子/趋化因子的(Grivennikov,SergeiI.,Florian R.Greten,and MichaelKarin.″Immunity,inflammation,and cancer.″Cell 140.6(2010):883-899)。这可以通过免疫细胞浸润导致与癌症相关的炎症。肿瘤中存在白细胞是已知的,但是直到最近才显然的是,炎性微环境是所有肿瘤的重要组成部分。大多数肿瘤(>90%)是体细胞突变或环境因素而非种系突变的结果,癌症的许多环境原因与慢性炎症有关(20%的癌症与慢性感染有关,30%与吸烟/吸入污染物有关,35%与饮食因素有关(所有癌症中20%与肥胖症有关)(Aggarwal,Bharat B.,R.V.Vijayalekshmi,and Bokyung Sung.″Targetinginflammatory pathways for prevention and therapy of cancer:short-term friend,long-term fbe.″Clinical Cancer Research 15.2(2009):425-430)。
GI癌症
胃肠(GI)道癌症通常与慢性炎症相关。例如,幽门螺杆菌感染与胃癌有关(Amieva,Manuel,and Richard M.Peek.″Pathobiology of Helicobacter pylori-Induced Gastric Cancer.″Gastroenterology 150.1(2016):64-78)。结肠直肠癌与炎性肠病有关(Bernstein,Charles N.,et al.″Cancer risk in patients withinflammatory bowel disease.″Cancer 91.4(2001):854-862)。胃中的慢性炎症导致IL-1和其他细胞因子的上调(Basso D,et al.,(1996)Helicobacter pylori infectionenhances mucosal interleukin-1beta,interleukin-6,and the soluble receptor ofinterleukin-2.Int J Clin Lab Res 26:207-210),IL-1基因的多态性会增加胃癌的风险(WangP,et al.,(2007)Association of interleukin-1gene polymorphisms withgastric cancer:a meta-analysis.Int J Cancer 120:552-562)。
在19%的胃癌病例中,半胱氨酸天冬氨酸蛋白酶-1表达降低,这与分期、淋巴结转移和存活率相关(Jee et al.,2005)。猪鼻支原体与胃癌的发展有关,其NLRP3炎性体的激活可能与其促进胃癌转移有关(Xu et al.,2013)。
皮肤癌
紫外线辐射是造成皮肤癌的最大环境风险,通过引起DNA损伤,免疫抑制和炎症促进皮肤癌。最恶性的皮肤癌,黑色素瘤,其特征在于炎性细胞因子的上调,所有这些因子均可被IL-1调节(Lázár-Molnár,Eszter,et al.″Autocrine and paracrine regulation bycytokines and growth factors in melanoma.″Cytokine 12.6(2000):547-554)。全身性炎症通过体内IL-1依赖性机制诱导黑色素瘤细胞转移和生长的增强。在B16F10小鼠黑色素瘤模型中使用百里醌抑制转移被显示依赖于NLRP3炎性体的抑制(Ahmad,Israr,et al.″Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3inflammasome.″Toxicology and applied pharmacology 270.1(2013):70-76)。
成胶质细胞瘤
NLRP3有助于神经胶质瘤的放射治疗抵抗。电离辐射可诱导NLRP3表达,而NLRP3抑制在放射治疗后降低肿瘤的生长并延长小鼠存活时间。因此,NLRP3炎性体的抑制可为放射抵抗的神经胶质瘤提供治疗策略(Li,Lianling,and Yuguang Liu.″Aging-related genesignature regulated by Nlrp3 predicts glioma progression.″American journal ofcancer research 5.1(2015):442)。
转移
更广泛地,申请人认为NLRP3参与了转移的促进,因此NLRP3的调节应该可能阻止转移。IL-1参与肿瘤的发生,肿瘤的侵袭,转移,肿瘤宿主的相互作用(Apte,Ron N.,etal.″The involvement of IL-1 in tumorigenesis,tumor invasiveness,metastasisand tumor-host interactions.″Cancer and Metastasis Reviews 25.3(2006):387-408)和血管生成(Voronov,Elena,et al.″IL-1is required for tumor invasivenessand angiogenesis.″Proceedings of the National Academy of Sciences 100.5(2003):2645-2650)。
IL-1基因经常在几种类型的人类癌症患者的转移灶中表达。例如,IL-1mRNA在所有测试的转移性人类肿瘤样本(具体包括非小细胞肺癌,结直肠腺癌和黑色素瘤样品)的超过一半中都高度表达(Elaraj,Dina M.,et al.″The role of interleukin 1in growthand metastasis of human cancer xenografts.″Clinical Cancer Research 12.4(2006):1088-1096),并且IL-1RA抑制产生IL-1的肿瘤中异种移植物的生长,但在体外没有抗增殖作用。
此外,IL-1信号传导是预测乳腺癌患者发生骨转移风险增加的生物标志物。在小鼠模型中,IL-1及其受体在转移到骨的乳腺癌细胞中比未转移的细胞上调。在小鼠模型中,IL-1受体拮抗剂阿那白滞素减少了增殖和血管生成,也对肿瘤环境产生了显著影响,减少了骨转换标志物IL-1和TNF α(Holen,Ingunn,et al.″IL-1 drives breast cancergrowth and bone metastasis in vivo.″Oncotarget(2016)。
IL-18诱导了人白血病细胞系HL-60中MMP-9的产生,因此有利于细胞外基质的降解以及癌细胞的迁移和侵袭(Zhang,Bin,et al.″IL-18increases invasiveness of HL-60myeloid leukemia cells:up-regulation of matrix metalloproteinases-9(MMP-9)expression.″Leukemia research 28.1(2004):91-95)。另外,IL-18可以通过诱导肝窦状隙内皮上VCAM-1的表达来支持肝脏中肿瘤转移的发展(Carrascal,Maria Teresa,et al.″Interleukin-18binding protein reduces b16melanoma hepatic metastasis byneutralizing adhesiveness and growth factors of sinusoidal endothelium.″Cancer Research 63.2(2003):491-497)。
CD36
脂肪酸清除剂受体CD36在准备启动pro-IL-1的基因转录和诱导NLRP3炎性体复合物的组装中起双重作用。CD36和TLR4-TLR6异质二聚体识别oxLDL,启动导致NLRP3和pro-IL-1的转录上调的信号传导途径(信号1)。CD36还介导oxLDL内在化进入溶酶体区室,在那里形成晶体,诱导溶酶体破裂和NLRP3炎性体的激活(信号2)(Kagan,J.and Horng T.,″NLRP3 inflammasome activation:CD36serves double duty.″Nature immunology 14.8(2013):772-774)。
人口腔癌细胞的亚群表达高水平的脂肪酸清除剂受体CD36,并且在其启动转移的能力方面是独特的。棕榈酸或高脂饮食增强CD36+细胞的转移潜力。中和抗CD36抗体阻断人类口腔癌原位小鼠模型中的转移。CD36+转移启动细胞的存在与多种类型癌症的预后不良有关。提出了饮食脂质可能促进转移(Pasqual,G,Avgustinova,A.,Mejetta,S,Martin,M,Castellanos,A,Attolini,CS-O,Berenguer,A.,Prats,N,Toll,A,Hueto,JA,Bescos,C,DiCroce,L,and Benitah,SA.2017“Targeting metastasis-initiating cells through thefatty acid receptor CD36”Nature 541:41-45)。
在肝细胞癌中,外源性棕榈酸激活上皮-间叶细胞转化(EMT)样程序,并诱导迁移,该迁移被CD36抑制剂磺基-N-琥珀酰亚胺基油酸酯减少(Nath,Aritro,et al.″Elevatedfree fatty acid uptake via CD36promotes epithelial-mesenchymal transition inhepatocellular carcinoma.″Scientific reports 5,2015)。体重指数与EMT的程度无关,突出表明实际上CD36和游离脂肪酸是重要的。
癌症干细胞(CSC)使用CD36促进其维持。氧化的磷脂(CD36的配体)存在于成胶质细胞瘤中,并且CSC而不是非CSC的增殖随着暴露于氧化的LDL而增加。CD36也与患者的预后相关。
化疗抵抗
除直接的细胞毒性作用外,化学治疗剂还利用宿主免疫系统,其有助于抗肿瘤活性。然而,吉西他滨和5-FU显示在骨髓来源的抑制性细胞中激活NLRP3,导致产生IL-1,其降低了抗肿瘤功效。从机理上讲,这些药剂使溶酶体不稳定,释放出组织蛋白酶B以激活NLRP3。IL-1驱动了IL-17由CD4+T细胞产生,进而削弱了化疗的功效。当在NLRP3-/-或Caps1-/-小鼠或用IL-1RA处理的WT小鼠中建立肿瘤时,观察到了吉西他滨和5-FU的更高的抗肿瘤作用。因此,骨髓来源的抑制性细胞NLRP3激活限制了吉西他滨和5-FU的抗肿瘤功效(Bruchard,Mélanie,et al.″Chemotherapy-triggered cathepsin B release inmyeloid-derived suppressor cells activates the Nlrp3inflammasome and promotestumour growth.″Nature medicine 19.1(2013):57-64.)。因此,本公开的化合物可用于化学疗法以治疗多种癌症。
本公开的化合物或其药学上可接受的盐可以作为单独的疗法单独给予,或者可以与一种或多种其他物质和/或治疗一起给予。这种联合治疗可以通过同时,顺序或分开给予治疗的各个组分来实现。
例如,可通过施用佐剂来增强治疗效果(即,佐剂本身可能仅具有极小的治疗益处,但是与另一种治疗剂组合,对个体的总体治疗益处被增强)。可替代地,仅作为示例,可以通过将式(I)或(II)的化合物与也具有治疗益处的另一种治疗剂(也包括治疗方案)一起施用来增加个体所经历的益处。
在本公开的化合物与其他治疗剂组合施用的情况下,本公开的化合物可能不需要通过与其他治疗剂相同的途径施用,并且由于不同的物理和化学特性,可能通过不同途径施用。例如,本公开的化合物可以口服施用以产生并维持其良好的血液水平,而其他治疗剂可以静脉内施用。可以根据本领域已知的确定的方案进行初始给药,然后,基于观察到的效果,有技能的临床医生可以改变剂量,给药方式和给药时间。
其他治疗剂的具体选择将取决于主治医师的诊断以及他们对个体状况以及适当的治疗方案的判断。根据本公开的该方面,提供了用于治疗涉及炎性体活性的疾病的组合,其包含上文定义的本公开的化合物或其药学上可接受的盐和另一种合适的药剂。
根据本公开的另一方面,提供了药物组合物,其包含本公开的化合物或其药学上可接受的盐,以及合适的且药学上可接受的稀释剂或载体。
式(I)或(II)的化合物及其药学上可接受的盐除了其在治疗药物中的用途,还可以用作药理学工具,用于开发和标准化体外和体内测试系统,以评估炎性体的抑制剂在实验动物(如狗,兔,猴,大鼠和小鼠)中的作用,作为寻找新治疗剂的一部分。
在本公开的任何上述药物组合物,过程,方法,用途,药物和制造特征中,本文所述的本公开的大分子的任何替代实施方案也适用。
给药途径
本公开的化合物或包含这些化合物的药物组合物可以通过任何方便的给药途径向受试者给药,无论是全身地/外周地还是局部地(即,在所需作用部位)。
给药途径包括但不限于口服(例如通过摄食);含服;舌下;透皮(包括例如通过贴剂,膏剂等);透粘膜(包括例如通过贴剂,膏剂等);鼻内(例如通过鼻喷雾);眼部(例如通过滴眼液);肺部(例如通过吸入或吹入疗法,使用例如通过气雾剂,例如通过口或鼻进行);直肠(例如通过栓剂或灌肠剂);阴道(例如通过阴道栓剂);肠胃外,例如通过注射,包括皮下,皮内,肌内,静脉内,动脉内,心内,鞘内,脊柱内,囊内,囊下,眶内,腹膜内,气管内,表皮下,关节内,蛛网膜下和胸骨内;通过例如皮下或肌内植入贮库或储库。
已经描述了本公开,通过示例而非限制的方式提供以下实施例。
具体实施例
现在将参考以下示例性实施例来描述本公开。
本节中可能出现的一些缩写定义如下:
ACN 乙腈
Boc 叔丁氧基羰基
TFA 三氟乙酸
MeOH 甲醇
HCl 盐酸
DCM 二氯甲烷
TLC 薄层色谱
DMSO 二甲亚砜
HPLC 高效液相色谱
EtOAc 乙酸乙酯
FCC 快速柱色谱
THF 四氢呋喃
NaOH 氢氧化钠
UPLC 超高效液相色谱
Ar 氩气
SM 起始原料
LC-MS 液相色谱-质谱
Et3N 三乙胺
RM 反应混合物
eq. 当量
rt 室温/环境温度
h 小时
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Me4tBuXPhos 甲磺酸根合(2-二叔丁基膦基-3,4,5,6四甲基-2′,4′,6′-三异丙基-1,1-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)
HPLC 高效液相色谱
本公开的化合物可以根据以下方案和实施例的程序使用合适的材料制备,并且通过以下具体实施例进一步举例说明。显示了根据以下实施例制备的化合物的分析数据。除非另有说明,否则所有起始原料均得自商业供应商,未进一步纯化即使用。除非另有说明,否则所有温度均以℃表示,并且所有反应均在室温下进行。通常通过二氧化硅色谱法,制备型薄层色谱法或制备型HPLC来纯化化合物。
1H NMR在400MHz光谱仪上记录。相对于残余溶剂信号(对于DMSO-d6中的1H NMR,δ=2.5ppm)以ppm为单位报告化学位移(δ)。1H NMR数据报道如下:化学位移(多重性,偶合常数和氢数)。多重性缩写如下:s(单峰),d(双重峰),t(三重峰)和m(多重峰)。
LC-MS分析
UPLC-MS:
设备:Shimadzu LC-MS 2020柱:Waters Acquity UPLC HSS C18,50mm x 2.1mm x1.8μm
洗脱液:
(A)ACN中的0.1%甲酸
(B)水中0.1%甲酸
自动取样器:注入体积:1μl
泵:
时间[min] | 流速[mL/min] | %B |
0.00 | 0.5 | 95 |
0.00 | 0.5 | 95 |
4.00 | 0.5 | 5 |
5.00 | 0.5 | 5 |
5.20 | 0.5 | 95 |
6.00 | 0.5 | 95 |
柱室:柱温:25℃,分析时间:6分钟
检测器:波长:200-300nm(254,230,270,280nm)
HPLC-MS:
设备:MS Bruker Amazon SL;LC Dionex Ultimate 3000;HPLC,具有UV-Vis或DAD检测器
柱:Kinetex XB C184.6x50mm 2.6μm
洗脱液:
(A)0.1%甲酸-水溶液
(B)0.1%甲酸-ACN溶液
自动取样器:注入体积:1μl
泵:流速:0.5ml/min
柱室:柱温:25℃,分析时间:12分钟
检测器:波长200-300nm(220,254,280nm)
一般程序:
一般程序A
向搅拌的氨基酯(或具有1当量的Et3N的氨基酯盐酸盐)在ACN中的溶液中滴加中间体A在ACN中的溶液。将RM搅拌过夜,然后过滤。所得沉淀物用ACN洗涤,并减压干燥,得到所需产物。
一般程序B:
向0℃的冷却的甲醇溶液中滴加亚硫酰氯(20当量),并将RM在0℃下搅拌30分钟。添加氨基酸,并将RM在环境温度下搅拌过夜。减压蒸发RM,得到所需产物。
一般程序C:
向Boc保护的起始原料的MeOH溶液中滴加4M HCl/.二噁烷(20当量)。搅拌反应混合物直至在TLC上不再可见起始原料,然后蒸发以得到所需产物。
中间体:
以下中间体如下制备:
中间体A
4-异氰酸基-1,2,3,5,6,7-六氢-对称引达省(中间体A)
步骤13-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮
在剧烈搅拌下,将氯化铝(12.4g,0.093mol)在DCM(50ml)中的悬浮液在氩气气氛下冷却至-10℃。在0.5小时内向其中滴加3-氯丙酰氯(11g,0.093mol)和茚满(10g,0.085mol)在DCM(15ml)中的溶液,温度保持在-15℃至-5℃之间。使反应升温至室温,并搅拌过夜。在30分钟内将反应混合物滴加到冷的(0℃)2M HCl中,温度保持在0℃至10℃之间。分离各层,水相用DCM(3×30ml)洗涤。依次用水,饱和碳酸氢钠和盐水洗涤合并的有机层。有机相经Na2SO4干燥,过滤并减压蒸发至约30ml。加入己烷(50ml)并继续蒸发,重复该程序两次。进一步加入己烷(50ml)后,过滤浆液并干燥,得到3-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮,为棕褐色固体。
Y=81%
MS ES+:未电离
1H NMR(400MHz,DMSO-d6)δ7.84(d,1H),7.78-7.76(m,1H),7.37(d,J=8Hz,1H),3.92(t,J=6Hz,2H),3.51(t,J=6Hz,2H),2.92(t,J=8Hz,4H),2.09-2.01(m,2H).
步骤28-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮、4-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮和5-硝基-1,2,3,6,7,8-六氢不对称引达省-3-酮的混合物
将3-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮(82g,0.39mol)分批加入到浓硫酸(71ml,1.34mol)中。将所得混合物加热至60℃达2天。将RM冷却至0℃,并逐滴加入硝酸(26ml,0.59mol)和硫酸(26ml,0.49mol)的混合物。将RM在0℃至5℃之间的温度搅拌1小时。将RM在冰浴冷却下缓慢加入到水和DCM的混合物中。分离各层,水层用DCM萃取。依次用盐水和饱和碳酸氢钠洗涤合并的有机层。有机层经Na2SO4干燥并过滤。粗混合物通过FCC(己烷/乙酸乙酯)纯化。通过从MeOH中结晶进一步纯化产物,得到所需产物。
8-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮:
Y=36%
MS ES+:218
1H NMR(400MHz,DMSO-d6)δ7.67(s,1H),3.15-3.08(m,2H),3.04(t,J=8Hz,2H),2.90(t,J=8Hz,2H),2.77-2.71(m,2H),2.17-2.10(m,2H)
4-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮:
Y=5%
MS ES+:218
1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),3.41-3.36(m,2H),3.34-3.29(m,3H),3.02(t,J=8Hz,2H),2.77-2.69(m,2H),2.17-2.10(m,2H).
5-硝基-1,2,3,6,7,8-六氢不对称引达省-3-酮:
Y=4%
MS ES+:218
1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),3.39(t,J=8Hz,2H),3.14-3.09(m,2H),3.01(t,J=8Hz,2H),2.81-2.73(m,2H),2.23-2.15(m,2H).
步骤3
1,2,3,5,6,7-六氢-对称引达省-4-胺
将8-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮和4-硝基-1,2,3,5,6,7-六氢-对称引达省-1-酮(7.00g,0.032mol)的混合物悬浮在MeOH(70ml)中。将其用20%氢氧化钯/碳(50%水湿润1.72g,0.012mol)处理,然后用甲磺酸(3.41g,0.035mol)处理。将混合物在35psi下氢化5小时。催化剂通过过滤除去,并用MeOH洗涤。滤液用水(350ml)稀释,然后用2NNaOH将pH调节至11。过滤得到的浆液,并将粗固体从MeOH/水(9∶1)中重结晶,得到1,2,3,5,6,7-六氢-对称引达省-4-胺,为无色晶体针状。
Y=73%
MS ES+:174.1
1H NMR(400MHz,DMSO-d6)δ6.35(s,1H),4.52(s,2H),2.72(t,J=7Hz,4H),2.59(t,J=7Hz,4H),2.00-1.93(m,4H).
步骤4
4-异氰酸基-1,2,3,5,6,7-六氢-对称引达省(中间体A)
向1,2,3,5,6,7-六氢-对称引达省-4-胺(1.1g,6.35mmol)和Et3N(0.973ml,6.98mmol)在THF(20ml)中的搅拌的溶液中一次性加入三光气(0.64g,2.16mmol)。将混合物加热至回流4小时,然后冷却至室温。蒸发THF,并将残余物吸收在戊烷中,并通过硅胶塞过滤。真空蒸发溶剂,得到白色固体状的4-异氰酸基-1,2,3,5,6,7-六氢-对称引达省。
Y=71%
MS ES+:未电离
1H NMR(400MHz,氯仿-d)δ6.96(s,1H),2.94-2.89(m,8H),2.22-2.03(m,4H).
中间体B
乙基1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-5-胺(中间体B)
步骤1
3-氯-1-(5,6,7,8-四氢萘-2-基)丙-1-酮
将氯化铝(5.58g,0.042mol)在DCM(30ml)中的悬浮液在氩气氛下在剧烈搅拌下冷却至-10℃。在0.5小时内向其中滴加3-氯丙酰氯(3.6ml,0.038mol)和萘满(5g,0.038mol)在DCM(10ml)中的溶液,将温度保持在-15℃至-5℃之间。使反应升温至室温,并搅拌过夜。在30分钟内将反应混合物滴加到冷的(0℃)2M HCl中,温度保持在0℃至10℃之间。分离各层,水相用DCM(3×20ml)洗涤。依次用水,饱和碳酸氢钠和盐水洗涤合并的有机层。有机相经Na2SO4干燥,过滤并在减压下蒸发,以提供黄色固体状的3-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮。
Y=91%
MS ES+:未电离
1H NMR(400MHz,DMSO-d6)δ7.84(d,1H),7.69-7.66(m,2H),7.20(d,J=8Hz,1H),3.91(t,J=6Hz,2H),3.49(t,J=6Hz,2H),2.78(d,J=4Hz,4H),1.77-1.72(m,4H).
步骤2
9-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮,4-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮和5-硝基-1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-3-酮的混合物
将3-氯-1-(5,6,7,8-四氢萘-2-基)丙-1-酮(7.52g,34mmol)分批加入到浓硫酸(36ml)中。将所得混合物加热至60℃达2天。将RM冷却至0℃,并逐滴加入硝酸(2.4ml,52mmol)和硫酸(2.4ml)的混合物。将RM在0℃至5℃之间的温度搅拌1小时。将RM在冰浴冷却下缓慢加入到水和DCM的混合物中。分离各层,水层用DCM萃取。依次用盐水和饱和碳酸氢钠洗涤合并的有机层。有机层经Na2SO4干燥并过滤。粗混合物通过FCC(己烷/乙酸乙酯)纯化,得到9-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮,4-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮和5-硝基-1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-3-酮的混合物,为黄色半固体。
Y=13%
MS ES+:232
步骤3
1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-5-胺(中间体B)
将9-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮,4-硝基-1H,2H,3H,5H,6H,7H,8H-环戊二烯并[b]萘-1-酮和5-硝基-1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-3-酮的混合物(0.992g,2.3mmol)悬浮在MeOH(40ml)中。将其用20%氢氧化钯/碳(50%水湿润0.389g,0.21mmol)处理,然后用甲磺酸(0.32ml,4.8mmol)处理。将混合物在35psi下氢化过夜。催化剂通过过滤除去,并用MeOH洗涤。滤液用水(50ml)稀释,然后用2M NaOH将pH调节至11。过滤得到的浆液,并将粗固体通过FCC(己烷/乙酸乙酯)纯化,得到1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-5-胺,为棕色油。
Y=19%
MS ES+:188.4
1H NMR(400MHz,DMSO-d6)δ6.35(s,1H),4.42(s,2H),2.69(t,J=8Hz,2H),2.58(t,J=7Hz,2H),2.48(t,J=6Hz,2H),2.32(t,J=6Hz,2H),1.95-1.88(m,2H),1.76-1.60(m,4H).
本文中定义的某些中间体可以是新颖的,并且可以将这些作为本公开的进一步特征来提供。
另外的起始原料
用于制备本公开的化合物的起始原料可以通过实施例中所述的方法或本身已知的方法,如合成有机化学的文献中所述以及为技术人员已知的方法来制备,或者可以商购获得。如果需要,用于该方法的起始原料还可以通过不将它们从反应混合物中分离出来,而是立即将它们进一步转化为本公开的化合物或中间体化合物,从而原位形成。另一方面,通常可以逐步进行反应。
以下另外的起始原料用于制备本公开的化合物,其制备方法包括如下:
2-氨基-3-(2-羟基苯基)丙酸甲酯盐酸盐
SM:2-氨基-3-(2-羟基苯基)丙酸
一般程序B
产物未经进一步纯化即用于下一步。
MS ES+:196
1-[3-(溴甲基)苯基]乙烷-1-酮
将间甲苯基乙酮(5g,37mmol),N-溴琥珀酰亚胺(leq,6.6g,37mmol)和苯甲酸过氧酸酐(0.2eq,1.8g,7.5mmol)的乙腈溶液在氩气下于85℃搅拌过夜。减压除去溶剂。残余物通过FCC(EtOAc/己烷0-5%)纯化,得到所需的产物,为黄色油。
Y=58%
MS ES+:未电离
1H NMR(400MHz,氯仿-d)δ8.00(t,J=2Hz,1H),7.94-7.88(m,1H),7.65-7.59(m,1H),7.48(t,J=8Hz,1H),4.56(s,2H),2.64(s,3H).
2-[(3-乙酰基苯基)甲基]-2-乙酰胺基丙二酸1,3-二乙酯
将1-[(3-溴甲基)苯基]乙烷-1-酮(2.5g,11.7mmol)、乙酰胺基丙二酸二乙酯(1eq,2.55g,11.7mmol)、K2CO3(1.2eq,1.95g,14.1mmol)、碘化钾(0.25eq,487mg,2.9mmol)和Cs2CO3(1.2eq,4.59g,14.1mmol)在乙腈(100ml)中的悬浮液加热至回流并搅拌过夜。将反应混合物冷却至室温,通过硅藻土垫过滤并真空浓缩。通过FCC(EtOAc/己烷0-50%)纯化,得到所需产物,为白色固体。
Y=67%
MS ES+:350.0
3-(3-乙酰基苯基)-2-氨基丙酸盐酸盐
将2-[(3-乙酰基苯基)甲基]-2-乙酰胺基丙二酸1,3-二乙酯(2.74g,7.84mmol)在6M HCl(80ml)中的悬浮液加热至回流16小时。使反应混合物冷却至室温。蒸发溶剂,并将固体过滤,用乙醚洗涤三次,并真空干燥,得到相应的产物,为白色固体。
Y=98%
MS ES-:207.0
3-(3-乙酰基苯基)-2-氨基丙酸甲酯
SM:3-(3-乙酰基苯基)-2-氨基丙酸盐酸盐
一般程序B
产物进一步通过FCC(0-7%MeOH/DCM)纯化,得到所需的产物,为白色固体。
Y=8%
MS ES+:222.0
(2R)-2-氨基-3-(4-氰基苯基)丙酸甲酯
SM:(2R)-2-氨基-3-(4-氰基苯基)丙酸
一般程序B
将产物另外在pH=8-9的水和EtOAc中分配,分离,并将有机物干燥(Na2SO4)并浓缩。通过FCC(DCM/MeOH)进一步纯化,得到所需产物。
Y=63%
MS ES+:205
(2R)-2-氨基-3-(3-氰基苯基)丙酸甲酯盐酸盐
SM:(2R)-2-氨基-3-(3-氰基苯基)丙酸
一般程序B
Y=67%
MS ES+:205
2-氨基-3-(3-溴苯基)丙酸甲酯
SM:2-氨基-3-(3-溴苯基)丙酸
一般程序B
将产物另外在pH=8-9的水和EtOAc中分配,分离,将有机物干燥(Na2SO4),浓缩,得到所需产物。
Y=57%
MS ES+:257.9;259.9
3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:2-氨基-3-(3-溴苯基)丙酸甲酯
一般程序A
Y=74%
MS ES+:457;459
1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.47-7.42(m,1H),7.42-7.38(m,1H),7.27(t,J=8Hz,1H),7.23-7.18(m,1H),6.87(s,1H),6.40(d,J=8Hz,1H),4.53-4.48(m,1H),3.66(s,3H),3.11-3.07(m,1H),2.99-2.93(m,1H),2.79(t,J=7Hz,4H),2.63(t,J=7Hz,4H),1.98-1.91(m,4H).
(2R)-2-氨基-3-(吡啶-3-基)丙酸甲酯盐酸盐
SM:3-(3-吡啶基)-D-丙氨酸
一般程序B
Y=63%
MS ES+:181.0
3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸甲酯
将2-氨基-3-(3-溴苯基)丙酸甲酯盐酸盐(550mg,1.867mmol)和Et3N(0.520ml,1.2eq.,3.734mmol)溶解在二噁烷(25ml)中。向其中滴加二碳酸二叔丁酯(489mg,2eq.,2.240mmol)在二噁烷(25ml)中的溶液。将RM在室温下搅拌直至不再在TLC上观察到起始原料。粗产物通过FCC(己烷/EtOAc)纯化,得到所需产物。
Y=60%
MS ES+:未电离
2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯
将3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸甲酯(100mg,0.28mmol),(1H-吡唑-3-基)硼酸(47mg,1.5eq.,0.42mmol),[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(12mg,0.05eq.,0.014mmol)和Na2CO3(89mg,3eq.,0.837mmol)溶于ACN(2ml)及一滴水。将RM在微波反应器中于90℃辐射1小时。将粗反应混合物通过硅藻土过滤,用MeOH洗涤,并在减压下浓缩。将粗产物通过FCC(DCM/MeOH)纯化,得到所需产物。
Y=26%
MS ES+:346
2-氨基-3-[3-(1H-吡唑-5-基)苯基]丙酸甲酯盐酸盐
SM:2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯
一般程序C
粗产物未经进一步纯化即用于下一步。
(2R)-2-氨基-3-(3-羟基苯基)丙酸甲酯盐酸盐
SM:(2R)-2-氨基-3-(3-羟基苯基)丙酸
一般程序B
Y=74%
MS ES+:195.9
(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸酯
将(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸(2.5g,7.26mmol)和K2CO3(1.2g,1.2eq.,8.72mmol)悬浮在DMF(30ml)中并在室温下搅拌30分钟,然后将反应混合物冷却至0℃。滴加MeI(3.1g,3eq.,21.8mmol),在通过TLC显示完成反应后,添加水(150ml),并将混合物用Et2O萃取。蒸发有机相,得到所需产物。
Y=88%
MS ES+:未电离
1H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.43-7.40(m,1H),7.33(d,J=8Hz,1H),7.28-7.22(m,2H),4.23-4.17(m,1H),3.63(s,3H),3.05-3.00(m,1H),2.87-2.81(m,1H),1.33(s,9H).
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯
将(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸甲酯(300mg,0.84mmol),(1H-吡唑-3-基)硼酸(141mg,1.5eq.,1.26mmol),双(二苯基膦基)二茂铁]二氯钯(II)(34mg,0.05eq.,0.042mmol)和Na2CO3(266mg,3eq.,2.51mmol)悬浮在ACN(10ml)和水(1ml)中。将RM在微波反应器中于90℃辐射1小时。RM通过硅藻土过滤,用MeOH洗涤并在减压下浓缩以得到所需产物,其未经纯化即用于下一步。
Y=76%
MS ES+:246
(2R)-2-氨基-3-[3-(1H-吡唑-5-基)苯基]丙酸甲酯盐酸盐
SM:(2R)-2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯
一般程序C
粗产物未经纯化即用于下一步。
(2R)-2-氨基-3-(3-溴苯基)丙酸甲酯盐酸盐
SM:(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸甲酯
一般程序C
粗产物不经纯化即用于下一步
Y=97%
MS ES+:258;260
(2R)-3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸酯
SM:(2R)-2-氨基-3-(3-溴苯基)丙酸甲酯盐酸盐
一般程序A
Y=89%
MS ES+:457;459
(2R)-3-{[(叔丁氧基)羰基]氨基}-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸酯
SM:(2R)-2-氨基-3-{[(叔丁氧基)羰基]氨基}丙酸甲酯盐酸盐
一般程序A
Y=92%
MS ES+:418
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),6.98(t,J=6Hz,1H),6.88(s,1H),6.38(d,J=8Hz,1H),4.30-4.25(m,1H),3.63(s,3H),3.27(t,J=6Hz,2H),2.79(t,J=7Hz,4H),2.74-2.64(m,4H),1.99-1.92(m,4H),1.38(s,9H).
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(3-乙酰胺基苯基)丙酸甲酯
在微波小瓶中装入(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸酯(50mg,0.14mmol)、K3PO4(62mg,0.29mmol,2.1eq.)、Pd2(dba)3(6mg,0.007mmol,0.05eq.)和Me4tBuXPhos(17mg,0.035mmol,0.25eq.)。将管密封,抽真空并用氩气回填(三次)。将乙酰胺(17mg,2当量,0.28mmol)在叔丁醇(5ml)中的溶液添加到管中。将RM在110℃下搅拌24小时。反应混合物通过硅藻土过滤,用MeOH洗涤并在减压下浓缩。粗产物通过FCC纯化,得到所需产物。
Y=27%
MS ES+:337
(2R)-2-氨基-3-(3-乙酰胺基苯基)丙酸甲酯盐酸盐
SM:(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(3-乙酰胺基苯基)丙酸甲酯
一般程序C
粗产物未经纯化即用于下一步。
氨基-3-(1-甲基-1H-吡唑-4-基)丙酸甲酯二盐酸盐
SM:2-氨基-3-(1-甲基-1H-吡唑-4-基)丙酸
一般程序B
该产物未经纯化即用于下一步。
Y=94%
MS ES+:184
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-[3-(2-氧代吡咯烷-1-基)苯基]丙酸甲酯
在微波小瓶中装入(2R)-3-(3-溴苯基)-2-{[(叔丁氧基)羰基]氨基}丙酸酯(50mg,0.14mmol),K3PO4(62mg,0.293mmol,2.1eq.),Pd2(dba)3(6mg,0.007mmol,0.05eq.)和Me4tBuXPhos(17mg,0.035mmol,0.25eq.)。将管密封,抽真空并用氩气回填(三次)。向其中加入吡咯烷酮(23mg,0.28mmol,2eq.)在叔丁醇(5ml)中的溶液。将RM在110℃下搅拌24小时。RM通过硅藻土过滤,用MeOH洗涤并在减压下浓缩以得到所需产物,其未经纯化即用于下一步。
Y=59%
MS ES+:363
(2R)-2-氨基-3-{3-[(2-氧代环戊基)氨基]苯基}丙酸甲酯
SM:(2R)-2-{[(叔丁氧基)羰基]氨基}-3-[3-(2-氧代吡咯烷-1-基)苯基]丙酸甲酯
一般程序C
粗产物未经纯化即用于下一步。
3-(1,2,3,5,6,7-六氢-对称引达省-4-基)-5-({3-[(1H-吡唑-3-基)氨基]苯基}甲基)咪唑烷-2,4-二酮
在密封管中装入(2R)-3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯(75mg,0.139mmol),3-氨基吡唑(14mg,0.164mmol),tBuONa(33mg,0.293mmol,2.1eq.),2-二-叔丁基膦基-2′,4′,6′-三异丙基联苯,tBuXPhos配体(4mg,0.008mmol,0.05eq.)和氯[2-(二-叔丁基膦基)-2′,4′,6′-三异丙基-1,1′-联苯基][2-(2-氨基乙基)苯基)]钯(II)tBuXPhos 1G预催化剂(6mg,0.008mmol,0.05eq.)。将管密封,抽真空并回填氩气(3次),然后加入叔丁醇(2ml)。将RM在110℃下搅拌24小时。RM通过硅藻土过滤,用MeOH洗涤并在减压下浓缩。粗产物通过FCC纯化,得到所需产物。
Y=85%
MS ES+:427
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-{3-[(1H-吡唑-3-基)氨基]苯基}丙酸
将3-(1,2,3,5,6,7-六氢-对称引达省-4-基)-5-({3-[(1H-吡唑-3-基)氨基]苯基}甲基)咪唑烷-2,4-二酮(60mg,0.141mmol)悬浮在5M NaOH(2ml)中,并在室温下搅拌过夜。蒸发RM,得到所需产物,其未经纯化即用于下一步。
Y=80%
MS ES+:446.4
(2R)-2-氨基-3-[3-(1H-吡唑-3-基)苯基]丙酸二盐酸盐
将(2R)-2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯(203mg,0.60mmol)和6M HCl(10ml)的混合物加热回流过夜。将RM冷却至室温,用水(50ml)稀释,并用乙醚(50ml)洗涤。然后在减压下蒸发水相,得到所需的产物,为黄色固体。
Y=100%
MS ES+:232.1
1H NMR(400MHz,DMSO-d6)δ8.59-8.43(m,3H),7.80(d,J=2Hz,1H),7.79-7.77(m,1H),7.76-7.72(m,1H),7.39(t,J=8Hz,1H),7.27-7.21(m,1H),6.75(d,J=2Hz,1H),4.25-4.17(m,1H),3.22-3.17(m,2H).
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸
将2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸甲酯(140mg,0.5mmol)悬浮在MeOH(1ml)中。加入1M NaOH(5ml),并将反应混合物在室温搅拌过夜,然后真空浓缩。将残余物用2M HCl酸化至pH2,并将所得沉淀过滤并用水洗涤,得到所需产物,为白色固体。
Y=73%
MS ES+:275.0
1H NMR(400MHz,DMSO)δ12.47(s,1H),7.90(s,1H),6.88(s,1H),6.26(t,J=6Hz,1H),3.76(d,J=6Hz,2H),2.80(t,J=7Hz,4H),2.70(t,J=7Hz,4H),2.01-1.91(m,4H).
(2R)-2-氨基-3-甲氧基丙酸甲酯盐酸盐
SM:(2R)-2-氨基-3-甲氧基丙酸
一般程序B
产物未经进一步纯化即用于下一步。
MS ES+:175[M+ACN]
2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸
在微波小瓶中装入(2R)-2-[(叔丁氧基)羰基氨基]-3-(3-溴苯基)丙酸(1.6g,4.66mmol,1eq.),1H-吡唑-3-硼酸(1.3g,3.6mmol,2.5eq.),Na2CO3(618mg,5.83mmol,4eq.),和MeCN:H2O(10∶1,22mL)。用氩气吹扫反应混合物,并添加Pd(dppf)Cl2(341mg,0.46mmol,0.1eq.)。将反应混合物在微波辐射下于90℃加热1h。然后将其通过硅藻土垫过滤,用MeOH洗涤,并将滤液真空浓缩,得到标题化合物,为棕色固体。
Y=51%
MS ES+:332.2
(2R)-2-氨基-3-[3-(1H-吡唑-3-基)苯基]丙酸乙酯盐酸盐
将2-{[(叔丁氧基)羰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸(250mg,1mmol,1eq.)溶解在EtOH中,并将反应混合物冷却至0℃。加入亚硫酰氯(0.029mL,0.83mmol,1.1eq.),并将反应混合物在70℃下搅拌过夜。冷却至室温后,将其真空浓缩。加入Et2O,滤出所得棕色固体。将固体溶解在MeOH中,并通过SCX滤筒过滤,用MeOH洗涤,并用1M NH3的MeOH溶液洗脱产物。蒸发滤液,得到标题化合物,为浅棕色固体。
Y=37%
MS ES+:260.2
(2R)-2-氨基-3-(吡啶-3-基)丙酸2-甲氧基乙酯盐酸盐
向(2R)-2-氨基-3-(吡啶-3-基)丙酸(150mg,0.536mmol,1eq.)在2-甲氧基乙醇(2ml)中的溶液中在0℃下逐滴添加亚硫酰氯(21μl,1.1eq.)。将RM在氩气下于60℃加热2小时。然后将RM冷却至室温,倒入饱和NaHCO3水溶液中,并将混合物用DCM萃取两次。合并的有机物经Na2SO4干燥,过滤并真空浓缩,得到标题化合物,为白色固体。
Y=71%
MS ES+:225.3
1H NMR(400MHz,DMSO-d6)δ8.42(d,J=2Hz,1H),8.41(d,J=2Hz,1H),7.68-7.58(m,1H),7.33-7.27(m,1H),4.15-4.11(m,1H),3.63-3.59(m,1H),3.53-3.44(m,3H),3.40-3.28(m,2H),3.25(s,3H),2.92-2.85(m,1H),2.84-2.76(m,1H).
(2R)-2-氨基-3-(吡啶-3-基)丙酸环丁酯
将(2R)-2-氨基-3-(吡啶-3-基)丙酸(100mg,0.60mmol,1eq.)和环丁醇(860mg,12.03mmol,20eq.)悬浮在甲苯中。加入对甲苯磺酸一水合物(343mg,1.80mmol,3eq.),并将混合物加热至回流2小时。减压浓缩反应混合物,并将残余物溶于DCM/水(1∶1)。混合物用饱和NaHCO3水溶液中和,水层用DCM萃取两次。合并的有机物用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到标题化合物,为棕色油。
Y=46%
MS ES+:222.3
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸
将(2R)-2-氨基-3-(吡啶-3-基)丙酸(1.5g,9mmol,1eq.)溶于二噁烷(30ml)和水(30ml)中,然后将得到的溶液用碳酸氢钠(3g,36.1mmol,4eq.)处理。将所得混合物冷却至0℃,并滴加Boc酸酐(2.36g,11mmol,1.2eq.)的二噁烷(10ml)溶液。将反应混合物在0℃下搅拌1h,并使其温热至室温过夜。减压蒸发二噁烷,所得水溶液用乙酸乙酯洗涤两次。用10%硫酸氢钾水溶液中和水层,并用正丁醇萃取溶液3次。合并的有机层经硫酸钠干燥,过滤并真空蒸发,得到标题化合物,为浅黄色油。
Y=51%
MS ES+:267.2
1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.46-8.43(m,1H),8.43-8.39(m,1H),7.67(d,J=8Hz,1H),7.35-7.28(m,1H),7.17(d,J=8Hz,1H),4.16-4.08(m,1H),3.10-3.02(m,1H),2.87-2.78(m,1H),1.31(s,9H).
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸环丙基甲酯
将(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸(300mg,1.12mmol,1eq.)和DMAP(14mg,0.113mmol,0.1eq.)溶解在无水的DCM(12ml)中。将反应混合物冷却至0℃,并加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(281mg,1.46mmol,1.3eq.),然后加入环丙基甲醇(119μl,1.46mmol,1.3eq.)。将反应混合物在室温在氩气下搅拌18小时。加入乙酸乙酯,并滤出不溶物。真空浓缩滤液,得到标题化合物,为油。
Y=56%
MS ES+:321.3
(2R)-2-氨基-3-(吡啶-3-基)丙酸环丙基甲酯
将(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸环丙基甲酯(200mg,0.52mmol)溶解于DCM(1ml)和TFA(2ml)中。将反应混合物在室温搅拌过夜。然后将其用DCM稀释并用饱和NaHCO3水溶液中和。将水层用DCM萃取两次,并将合并的有机物经Na2SO4干燥,过滤并真空浓缩,得到标题化合物,为黄色油。
Y=59%
MS ES+:221.3
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸环戊酯
向(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸(150mg,0.56mmol,1eq.)在DMF(4ml)中的溶液中在0℃下,加入环戊醇(256μl,2.81mmol,5eq.),1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(140mg,0.73mmol,1.3eq.)和DMAP(7mg,0.056mmol,0.1eq.)。将反应混合物在室温搅拌过夜,然后用乙酸乙酯稀释。将混合物过滤并将滤液在减压下浓缩。粗产物通过FCC(NH2改性的硅胶)用己烷∶EtOAc(4∶1)纯化,得到标题产物,为无色油。
Y=31%
MS ES+:335.3
1H NMR(400MHz,DMSO-d6)δ8.45-8.40(m,2H),7.67(d,J=8Hz,1H),7.37-7.29(m,2H),5.10-5.02(m,1H),4.17-4.08(m,1H),3.03-2.96(m,1H),2.93-2.86(m,1H),1.85-1.70(m,2H),1.65-1.55(m,3H),1.53-1.40(m,3H),1.33(s,9H).
(2R)-2-氨基-3-(吡啶-3-基)丙酸环戊酯二-TFA盐
将(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡啶-3-基)丙酸环戊酯(100mg,0.26mmol,1eq.)溶于DCM(1ml)中,加入TFA(2ml)。将反应混合物在室温搅拌过夜,并减压浓缩,得到标题化合物,为棕色油。
Y=78%
MS ES+:235.3
(2R)-2-氨基-3-(吡啶-3-基)丙酸盐酸盐
在压力容器中,将(2R)-2-氨基-3-(吡啶-3-基)丙酸(2g,12.0mmol,1eq.)悬浮在无水EtOH(30ml)中。将混合物在冰浴上冷却至0℃,并在氩气下加入浓硫酸(0.5ml)。密封容器,并将混合物在85℃下搅拌18小时。冷却至室温后,将反应混合物蒸发至其体积的四分之一,倒入饱和碳酸氢钠中。混合物用CHCl3萃取四次,合并的有机层经硫酸钠干燥并过滤。向滤液中加入4M HCl/二噁烷(12ml)。蒸发所得溶液,得到无色油,将其溶于EtOH(10ml)中。将溶液加入到快速搅拌的Et2O(100ml)中并继续搅拌1h,直到所得油固化成白色固体。滤出固体,用Et2O洗涤,真空干燥,得到标题化合物,为白色粉末。
Y=61%
MS ES+:195.3
1H NMR(400MHz,DMSO-d6)δ9.11-8.91(m,4H),8.86(d,J=6Hz,1H),8.56(d,J=8Hz,1H),8.08-8.00(m,1H),4.55-4.45(m,1H),4.27-4.10(m,2H),3.47(d,J=7Hz,2H),1.17(t,J=7Hz,2H).
2-氨基-3-(4-甲基-1H-吡唑-1-基)丙酸甲酯盐酸盐
将2-氨基-3-(4-甲基-1H-吡唑-1-基)丙酸酯(70mg,0.34mmol)在3M盐酸/甲醇(5ml)中的溶液在室温搅拌16h。真空除去溶剂,得到所需产物。
Y=92%
MS ES+:184
2-氨基-3-(嘧啶-2-基)丙酸乙酯二盐酸盐
在小瓶中将2-氨基-3-(嘧啶-2-基)丙酸二盐酸盐(0.10g,0.417mmol)悬浮在EtOH(1ml)中并冷却至0℃。加入浓H2SO4(0.1ml),将小瓶密封并在80℃加热18h。RM倒入饱和碳酸氢钠,用CHCl3萃取四次。合并的有机物经Na2SO4干燥并过滤。在搅拌下向滤液中加入4MHCl/二噁烷(2ml)。蒸发该溶液,得到无色油,然后将其溶于最小量的EtOH(约2ml)中。将该溶液加入快速搅拌的MeCN(10ml)中以使产物结晶。将固体过滤并真空干燥,得到所需产物,为灰白色固体。
Y=66%
MS ES+:196.3
(2R)-2-氨基-3-(5-甲氧基吡啶-3-基)丙酸甲酯二盐酸盐
将(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(5-甲氧基吡啶-3-基)丙酸甲酯(0.26g,0.8mmol)溶于4M HCl/二噁烷(5ml)中,在室温下搅拌4小时。蒸发溶剂,并将固体溶解在水中,并用EtOAc洗涤。将水相冷冻干燥,得到所需产物,为棕色固体。
Y=37%
MS ES+:211.2
2-[(二苯基亚甲基)氨基]乙酸乙酯
将甘氨酸乙酯盐酸盐(1.00g,7.16mmol)溶于无水DCM(40ml)。逐滴加入苯甲酮亚胺(1.20ml,7.16mmol)。将RM在室温搅拌18小时。将RM通过硅藻土过滤,用DCM洗涤,并将滤液真空浓缩。将所得油与己烷一起研磨,得到所需产物,为白色固体。
Y=97%
MS ES+:268
2-[(二苯基亚甲基)氨基]-3-(3-甲基-1,2,4-噁二唑-5-基)丙酸乙酯
在干燥烧瓶中,将2M LDA/THF(0.59ml,1.18mmol)在氮气下冷却至-78℃。加入2-[(二苯基亚甲基)氨基]乙酸乙酯的THF(12ml)溶液,并将RM在-78℃下搅拌30分钟。逐滴加入5-(氯甲基)-3-甲基-1,2,4-噁二唑(0.12ml,1.18mmol),并将RM在-78℃下搅拌1h,然后在室温下搅拌18h。RM用饱和NH4Cl猝灭,用水稀释并用EtOAc萃取。有机物经Na2SO4干燥,过滤并蒸发。粗产物通过FCC(二氧化硅,20%EtOAc/己烷)纯化,得到所需产物。
Y=20%
MS ES+:364
2-氨基-3-(3-甲基-1,2,4-噁二唑-5-基)丙酸乙酯盐酸盐
将2-[(二苯基亚甲基)氨基]-3-(3-甲基-1,2,4-噁二唑-5-基)丙酸乙酯(80mg,0.23mmol)溶解在乙醚(2ml)中并冷却至0℃。逐滴加入1M HCl水溶液(1.1ml,1.1mmol),并使反应温热至室温。将RM搅拌72小时,然后浓缩以除去有机溶剂。将水相用1M HCl稀释并用Et2O洗涤。将水相真空浓缩并冷冻干燥,得到所需产物,为黄色固体。
Y=80%
MS ES+:200
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(哒嗪-3-基)丙酸甲酯
将锌粉(0.12g,1.8mmol)添加到用氮气吹扫的干燥烧瓶中。加入无水的DMF(1.0ml),然后加入碘(43mg,0.2mmol)。溶液由无色变为黄色,然后又变为无色。加入(2S)-2-{[(叔丁氧基)羰基]氨基}-3-碘丙酸甲酯(0.20g,0.60mmol),然后加入碘(43mg,0.2mmol)。将溶液在环境温度下搅拌,观察到放热。向该溶液中添加Pd2(dba)3(28mg,0.04mmol),SPhos(25mg,0.12mmol)和3-溴哒嗪(0.25g,1.6mmol)。将RM在室温下在氮气下搅拌18小时。将RM过滤两次,并通过FCC(二氧化硅,EtOAc/己烷)纯化,得到所需产物。
Y=43%
MS ES+:282
(2R)-2-氨基-3-(哒嗪-3-基)丙酸甲酯盐酸盐
一般程序C
Y=97%
MS ES+:182
2-[(二苯基亚甲基)氨基]-3-(1,2-噁唑-4-基)丙酸乙酯
在干燥烧瓶中装入2M LDA/THF/己烷/甲苯(0.59ml,1.18mmol),并在氮气下冷却至-78℃。逐滴加入2-[(二苯基亚甲基)氨基]乙酸乙酯(0.30g,1.12mmol)的无水THF(16ml)溶液。将RM在-78℃下搅拌30分钟,然后加入4-(溴甲基)-1,2-噁唑(0.19g,1.18mmol),并在-78℃下继续搅拌1h。让RM温热至室温并搅拌16小时。RM经冰水冷却,并用饱和NH4Cl猝灭。有机物用EtOAc萃取,经硫酸钠干燥,过滤并浓缩。获得所需产物,未经进一步纯化即直接使用。
Y=51%
MS ES+:349.1
2-氨基-3-(1,2-噁唑-4-基)丙酸乙酯盐酸盐
将2-[(二苯基亚甲基)氨基]-3-(1,2-噁唑-4-基)丙酸乙酯(0.30g,0.86mmol)溶解在乙醚(4ml)中并冷却至0℃。将1M盐酸(2.0ml,1.0mmol)逐滴加入,让RM温热至室温并搅拌16小时。用水稀释RM,并用乙醚洗涤。将水相真空干燥,得到所需产物,直接使用。
Y=94%
MS ES+:185.2
2-[(二苯基亚甲基)氨基]-3-(1,2-噁唑-3-基)丙酸乙酯
在干燥烧瓶中装入2M LDA/THF/己烷/甲苯(0.78ml,1.56mmol),并在氮气下冷却至-78℃。逐滴加入2-[(二苯基亚甲基)氨基]乙酸乙酯(0.40g,1.49mmol)的无水THF(14ml)溶液。将RM在-78℃下搅拌30分钟,然后加入3-(溴甲基)异噁唑(0.148ml,1.56mmol),并在-78℃下继续搅拌1h。让RM温热至室温并搅拌16小时。将RM经冰水冷却,并用饱和NH4Cl猝灭。用EtOAc萃取有机物,经硫酸钠干燥,过滤并浓缩。得到所需产物,为黄色油,未经进一步纯化即直接使用。
Y=25%
MS ES+:349.1
2-氨基-3-(1,2-噁唑-3-基)丙酸乙酯盐酸盐
将2-[(二苯基亚甲基)氨基]-3-(1,2-噁唑-3-基)丙酸乙酯(0.13g,0.39mmol)溶于乙醚(2ml)中并冷却至0℃。将1M盐酸(1.9ml,1.9mmol)逐滴加入;让RM温热至室温并搅拌16小时。RM用1M盐酸稀释,并用乙醚洗涤。将水相真空干燥,得到所需产物,为黄色固体,直接使用。
Y=81%
MS ES+:185
6-(丙-1-烯-2-基)-2,3-二氢-1H-茚-5-胺
将6-溴-2,3-二氢-1H-茚-5-胺(1.50g,7.1mmol)和K3PO4(3.75g,17.7mmol)置于管中。加入甲苯(12ml)和水(6ml)。然后加入乙酸钯(0.16g,0.7mmol),三环己基膦(0.20g,0.7mmol)和异丙烯基硼酸频哪醇酯(1.78g,10.6mmol),将管密封,在105℃加热16小时。将RM通过硅藻土过滤,将有机溶剂蒸发,并将得到的悬浮液在EtOAc和盐水之间分配。浓缩有机相,并通过FCC(二氧化硅,4:1己烷/EtOAc)纯化,得到所需产物。
Y=5%
MS ES+:174.3
6-(丙-2-基)-2,3-二氢-1H-茚-5-胺
将6-(丙-1-烯-2-基)-2,3-二氢-1H-茚-5-胺(0.267g,1.54mmol)溶解在MeOH(5ml)中。添加10%重量Pd/C(16mg),并用氩气吹扫RM。使用Parr氢化装置将RM氢化6小时。RM通过硅藻土过滤,浓缩,得到所需产物,未经进一步纯化即使用。
Y=82%
MS ES+:176.3
5-异氰酸基-6-(丙-2-基)-2,3-二氢-1H-茚
将6-(丙-2-基)-2,3-二氢-1H-茚-5-胺(222mg,1.27mmol)溶解在THF(10ml)中,并加入三乙胺(0.19ml,0.14mmol)。然后将RM用三光气(128mg,0.4mmol)处理,将RM加热回流4小时并冷却至RT。真空除去溶剂,将残余物溶于戊烷中,并通过二氧化硅过滤。蒸发滤液,得到所需产物。
Y=26%
MS ES+,在MeOH中:234.3(氨基甲酸酯)
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(嘧啶-5-基)丙酸甲酯
将锌粉(0.12g,1.8mmol)添加到用氮气吹扫的干燥烧瓶中。加入无水的DMF(1.0ml),然后加入碘(43mg,0.2mmol)。溶液由无色变为黄色,然后又变为无色。加入(2S)-2-{[(叔丁氧基)羰基]氨基}-3-碘丙酸甲酯(0.20g,0.60mmol),然后加入碘(43mg,0.2mmol)。将溶液在环境温度下搅拌,观察到放热。向该溶液中添加Pd2(dba)3(28mg,0.04mmol),SPhos(24mg,0.12mmol)和5-碘嘧啶(0.33g,1.6mmol)。将RM在室温下在氮气下搅拌18小时。将RM过滤两次,然后通过FCC(二氧化硅,EtOAc/己烷)纯化,得到所需产物。
Y=80%
MS ES+:282
(2R)-2-氨基-3-(嘧啶-5-基)丙酸甲酯盐酸盐
一般程序C
Y=94%
MS ES+:182.2
(2R)-2-{[(叔丁氧基)羰基]氨基}-3-(吡嗪-2-基)丙酸甲酯
将锌粉(0.24g,3.6mmol)加入用氮气吹扫的干燥烧瓶中。加入无水的DMF(2ml),然后加入碘(86mg,0.4mmol)。溶液由无色变为黄色,然后又变为无色。加入(2S)-2-{[(叔丁氧基)羰基]氨基}-3-碘丙酸甲酯(0.40g,1.2mmol),然后加入碘(86mg,0.4mmol)。将溶液在环境温度下搅拌,观察到放热。向该溶液中添加Pd2(dba)3(28mg,0.04mmol),SPhos(24mg,0.12mmol)和2-碘吡嗪(0.32g,1.5mmol)。将RM在室温下在氮气下搅拌18小时。将RM过滤两次,然后通过FCC(二氧化硅,EtOAc/己烷)纯化,得到所需产物。
Y=90%
MS ES+:282
(2R)-2-氨基-3-(吡嗪-2-基)丙酸甲酯盐酸盐
一般程序C
Y=66%
MS ES+:182.1
2-[(二苯基亚甲基)氨基]-3-(哒嗪-4-基)丙酸乙酯
在干燥烧瓶中装入2M LDA/THF/己烷/甲苯(1.2ml,4.86mmol),并在氮气下冷却至-78℃。逐滴加入2-[(二苯基亚甲基)氨基]乙酸乙酯(0.65g,2.43mmol)的无水THF(25ml)溶液。将RM在-78℃下搅拌30分钟,然后加入4-(溴甲基)哒嗪氢溴酸盐(0.65g,2.55mmol)和三乙胺(0.356ml,2.55mmol),并在-78℃下继续搅拌1h。让RM温热至室温并搅拌16小时。RM经冰水冷却,并用饱和NH4Cl猝灭。有机物用EtOAc萃取,经硫酸钠干燥,过滤并浓缩。粗产物通过FCC(二氧化硅,20%(EtOAc+1%Et3N)/己烷纯化,得到所需产物。
Y=13%
MS ES+:360.1
2-氨基-3-(哒嗪-4-基)丙酸乙酯盐酸盐
将2-[(二苯基亚甲基)氨基]-3-(哒嗪-4-基)丙酸乙酯(0.14g,0.38mmol)溶解在乙醚(2.5ml)中。加入1M盐酸(1.0ml,1.0mmol),并将RM搅拌16小时。RM用1M盐酸稀释,并用乙醚洗涤。将水相真空干燥,得到所需的产物,为棕色油,直接使用。
Y=83%
MS ES+:196
甲磺酸(嘧啶-4-基)甲酯
将(嘧啶-4-基)甲醇(0.20g,1.82mmol)在DCM(4ml)中的溶液冷却至0℃,并用三乙胺(0.506ml,3.63mmol)和甲磺酸(0.281ml,3.63mmol)处理。让RM温热至室温并搅拌4小时。RM用DCM稀释,依次用水和盐水洗涤,经硫酸钠干燥并浓缩,得到所需产物,直接使用。
Y=91%
MS ES+:188.9
2-[(二苯基亚甲基)氨基]-3-(嘧啶-4-基)丙酸乙酯
在干燥烧瓶中装入2M LDA/THF/己烷/甲苯(2.25ml,4.50mmol),并在氮气下冷却至-78℃。逐滴加入2-[(二苯基亚甲基)氨基]乙酸乙酯(0.60g,2.24mmol)在无水THF(20ml)中的溶液。将RM在-78℃下搅拌30分钟,然后加入甲磺酸(嘧啶-4-基)甲酯(0.44g,2.36mmol),并在-78℃下继续搅拌1h。让RM温热至室温并搅拌16小时。将RM经冰水冷却,并用饱和NH4Cl猝灭。有机物用EtOAc萃取,经硫酸钠干燥,过滤并浓缩,得到所需产物,将其直接用于下一步。
Y=14%
MS ES+:360.1
2-氨基-3-(嘧啶-4-基)丙酸乙酯盐酸盐
将2-[(二苯基亚甲基)氨基]-3-(嘧啶-4-基)丙酸乙酯(0.46g,1.71mmol)溶解在乙醚(3ml)中。加入1M盐酸(3ml,3mmol),并将RM搅拌16小时。RM用1M盐酸稀释,并用乙醚洗涤。将水相真空干燥,得到所需产物,直接使用。
Y=25%
MS ES+:196
本公开的实施例化合物
本公开的以下化合物如下制备,所需的必要步骤和起始原料如前所述:
2A
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(3-羟基苯基)丙酸甲酯
SM:2-氨基-3-(3-羟基苯基)丙酸甲酯盐酸盐
一般程序A
Y=8%
MS ES+:395.2
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.88(s,1H),7.08(t,J=8Hz,1H),6.87(s,1H),6.67-6.61(m,1H),6.61-6.55(m,2H),6.29(d,J=8Hz,1H),4.48-4.43(m,1H),3.64(s,3H),2.99-2.83(m,2H),2.79(t,J=7Hz,4H),2.65(t,J=8Hz,4H),1.98-1.91(m,4H).
2B
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(2-羟基苯基)丙酸甲酯
SM:2-氨基-3-(2-羟基苯基)丙酸甲酯盐酸盐
一般程序A
Y=16%
MS ES+:395
1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.81(s,1H),7.09-7.00(m,2H),6.86(s,1H),6.79(d,J=7Hz,1H),6.73-6.70(m,1H),6.27(d,J=8Hz,1H),4.50-4.45(m,1H),3.60(s,3H),3.04-2.82(m,2H),2.78(t,J=7Hz,4H),2.67-2.55(m,4H),1.97-1.90(m,4H).
2C
3-(3-乙酰基苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:3-(3-乙酰基苯基)-2-氨基丙酸甲酯
一般程序A
Y=71%
MS ES+:421.3
1H NMR(400MHz,CDCl3)δ7.82(d,J=8Hz,1H),7.66(s,1H),7.35(t,J=8Hz,1H),7.26(s,1H),7.03(s,1H),5.88(s,1H),4.91-4.82(m,2H),3.75(s,3H),3.27-3.20(m,1H),3.11-3.04(m,1H),2.88(t,J=7Hz,4H),2.81-2.72(m,2H),2.71-2.61(m,2H),2.57(s,3H),2.08-1.97(m,4H).
2D
(2R)-3-(4-氰基苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:(2R)-2-氨基-3-(4-氰基苯基)丙酸甲酯
一般程序A
Y=15%
MS ES+:404.2
1H NMR(400MHz,DMSO-d6)δ7.83-7.74(m,3H),7.42(d,J=8Hz,2H),6.87(s,1H),6.42(d,J=8Hz,1H),4.59-4.53(m,1H),3.66(s,3H),3.19-3.15(m,1H),3.07-3.01(m,1H),2.78(t,J=7Hz,4H),2.61-2.54(m,4H),1.94(五重峰,J=7Hz,4H).
2E
(2R)-3-(3-氰基苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:(2R)-2-氨基-3-(3-氰基苯基)丙酸甲酯盐酸盐
一般程序A
通过从MeOH中结晶进一步纯化产物,得到标题化合物,为白色固体。
Y=5%
MS ES+:404.2
1H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.72(d,J=7Hz,1H),7.66(s,1H),7.58-7.50(m 2H),6.87(s,1H),6.42(d,J=8Hz,1H),4.58-4.52(m,1H),3.67(s,3H),3.17-3.14(m,1H),3.04-2.99(m,1H),2.78(t,J=7Hz,4H),2.60(t,J=7Hz,4H),1.98-1.90(m,4H).
2F
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-2-基)丙酸甲酯
SM:(2R)-2-氨基-3-(吡啶-2-基)丙酸甲酯盐酸盐
一般程序A
Y=23%
MS ES+:380
1H NMR(400MHz,DMSO-d6)δ8.48-8.46(m,1H),7.89(s,1H),7.73-7.71(m,1H),7.30-7.22(m,2H),6.87(s,1H),6.45(d,J=8Hz,1H),4.69-4.62(m,1H),3.33(s,3H),3.21-3.13(m,2H),2.78(t,J=7Hz,4H),2.66-2.56(m,4H),1.97-1.89(m,4H).
2G
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(羟基甲基)苯基]丙酸甲酯
在密封的管中,将(三丁基甲锡烷基)甲醇(52mg,0.164mmol,1.5eq.),四(三苯基膦)钯(0)(6.3mg,0.005mmol,0.05eq.)和3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯(50mg,0.109mmol)在室温和氩气气氛下溶于无水二噁烷中。将反应混合物在80℃下搅拌18h。冷却至室温后,将反应混合物浓缩并通过快速柱色谱法(DCM/MeOH)纯化,得到所需的产物,为黄色固体。
Y=45%
MS ES+:409.2
1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.26(t,J=8Hz,1H),7.19(d,J=8Hz,1H),7.13(s,1H),7.05(d,J=7Hz,1H),6.87(s,1H),6.33(d,J=8Hz,1H),5.16(t,J=5Hz,1H),4.52-4.43(m,3H),3.64(s,3H),3.06-3.02(m,1H),2.98-2.92(m,1H),2.79(t,J=7Hz,4H),2.64(t,J=7Hz,4H),2.00-1.89(m,4H).
2H
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸甲酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸甲酯盐酸盐
一般程序A
产物通过制备型HPLC进一步纯化。
Y=6%
MS ES+:380.3
1H NMR(400MHz,DMSO-d6)δ8.46-8.44(m,1H),8.41(d,J=2Hz,1H),7.85(s,1H),7.63-7.61(m,1H),7.35-7.32(m,1H),6.87(s,1H),6.45(d,J=8Hz,1H),4.55-4.49(m,1H),3.66(s,3H),3.13-3.08(m,1H),3.01-2.95(m,1H),2.78(t,J=7Hz,4H),2.61(t,J=7Hz,4H),1.98-1.90(m,4H).
2I
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(1-甲基-1H-咪唑-5-基)苯基]丙酸甲酯
在密封管中,将1-甲基-5-(三丁基甲锡烷基)咪唑(61mg,0.164mmol,1.5eq.),四(三苯基膦)钯(0)(6.3mg,0.005mmol,0.05eq.)和3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯(50mg,0.109mmol)在室温下和氩气气氛下溶解于无水二噁烷中。将反应混合物在80℃下搅拌18h。冷却至室温后,将反应混合物浓缩并通过制备型HPLC纯化,得到所需的产物,为黄色胶状物。
Y=10%
MS ES+:459.4
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.84-7.73(m,2H),7.52-7.45(m,3H),7.41-7.34(m,1H),6.87(s,1H),6.46(d,J=8Hz,1H),4.61-4.54(m,1H),3.83(s,3H),3.67(s,3H),3.19-3.14(m,1H),3.07-3.01(m,1H),2.77(t,J=7Hz,4H),2.60-2.55(m,4H),1.98-1.89(m,4H).
2J
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(1H-吡唑-5-基)苯基]丙酸甲酯
SM:2-氨基-3-[3-(1H-吡唑-5-基)苯基]丙酸甲酯盐酸盐
一般程序A
Y=18%
MS ES+:445.3
1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),7.85(s,1H),7.78(s,1H),7.73-7.58(m,2H),7.33(t,J=7Hz,1H),7.19-7.06(m,1H),6.85(s,1H),6.67(s,1H),6.37(d,J=8Hz,1H),4.58-4.49(m,1H),3.66(s,3H),3.13-3.08(m,1H),3.03-2.97(m,1H),2.77(t,J=7Hz,4H),2.61(t,J=7Hz,4H),1.96-1.86(m,4H).
2K
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(3-羟基苯基)丙酸甲酯
SM:(2R)-2-氨基-3-(3-羟基苯基)丙酸甲酯盐酸盐
一般程序A
Y=50%
MS ES+:395.1
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),7.89(s,1H),7.08(t,J=8Hz,1H),6.87(s,1H),6.66-6.61(m,1H),6.61-6.56(m,2H),6.30(d,J=8Hz,1H),4.48-4.43(m,1H),3.64(s,3H),2.97-2.93(m,1H),2.90-2.85(m,1H),2.79(t,J=7Hz,4H),2.68-2.60(m,4H),1.98-191(m,4H).
2L
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸甲酯
SM:(2R)-2-氨基-3-[3-(1H-吡唑-5-基)苯基]丙酸甲酯盐酸盐
一般程序A
产物通过快速柱色谱进一步纯化,得到标题化合物。
Y=32%
MS ES+:445
1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),7.88-7.50(m,4H),7.41-7.28(m,1H),7.19-7.06(m,1H),6.85(s,1H),6.67(s,1H),6.37(d,J=8Hz,1H),4.61-4.47(m,1H),3.66(s,3H),3.13-3.09(m,1H),3.03-2.98(m,1H),2.77(t,J=7Hz,4H),2.61(t,J=7Hz,4H),1.95-1.87(m,4H).
2M
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(羟基甲基)苯基]丙酸甲酯
在密封管中,将(三丁基甲锡烷基)甲醇(153mg,0.44mmol,1eq.),四(三苯基膦)钯(0)(25.2mg,0.005mmol)和(2R)-3-(3-溴苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯(200mg,0.44mmol)在室温下,在氩气气氛下,溶解在无水二噁烷中。将反应混合物在80℃下搅拌18h。冷却至室温后,将反应混合物浓缩并通过快速柱色谱法(DCM/MeOH)纯化,得到标题化合物,为黄色固体。
Y=10%
MS ES+:409
1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.26(t,J=8Hz,1H),7.19(d,J=8Hz,1H),7.13(s,1H),7.05(d,J=8Hz,1H),6.87(s,1H),6.34(d,J=8Hz,1H),5.16(t,J=6Hz,1H),4.52-4.43(m,3H),3.64(s,3H),3.06-3.02(m,1H),2.98-2.93(m,1H),2.79(t,J=7Hz,4H),2.64(t,J=7Hz,4H),1.98-1.91(m,4H).
2N
(2R)-3-氨基-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:(2R)-3-{[(叔丁氧基)羰基]氨基}-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
一般程序C
Y=82%
MS ES+:318.2
1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.14(s,3H),6.90(s,1H),6.83(d,J=8Hz,1H),4.54-4.49(m,1H),3.70(s,3H),3.253.21(m,1H),3.16-3.03(m,1H),2.80(t,J=7Hz,4H),2.72(t,J=7Hz,4H),2.00-1.93(m,4H).
2O
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-4-(甲基硫烷基)丁酸甲酯
SM:D-蛋氨酸甲酯盐酸盐
一般程序A
Y=72%
MS ES+:363.2
1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),6.88(s,1H),6.52(d,J=8Hz,1H),4.35-4.30(m,1H),3.66(s,3H),2.79(t,J=7Hz,4H),2.68(t,J=7Hz,4H),2.06(s,3H),2.00-1.85(m,6H).
2P
(2R)-3-(3-乙酰胺基苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯
SM:(2R)-2-氨基-3-(3-乙酰胺基苯基)丙酸甲酯盐酸盐
一般程序A
最终化合物通过FCC进一步纯化,得到标题化合物,为白色固体。
Y=11%
MS ES+:436.4
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),6.93(t,J=8Hz,1H),6.87(s,1H),6.47-6.40(m,1H),6.40-6.35(m,1H),6.32-6.24(m,2H),5.00(s,1H),4.46-4.34(m,1H),3.64(s,2H),2.91-2.75(m,6H),2.67-2.63(m,4H),1.98-1.91(m,4H).
2Q
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(1-甲基-1H-吡唑-4-基)丙酸甲酯
SM:2-氨基-3-(1-甲基-1H-吡唑-4-基)丙酸甲酯二盐酸盐
一般程序A
最终化合物通过FCC进一步纯化,得到标题化合物,为白色固体。
产率=5%
MS ES+:383.3
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.45(s,1H),7.22(d,J=1Hz,1H),6.88(s,1H),6.30(d,J=8Hz,1H),4.45-4.35(m,1H),3.79(s,3H),3.66(s,3H),2.91-2.82(m,2H),2.79(t,J=7Hz,4H),2.67(t,J=7Hz,4H),1.99-1.92(m,4H).
2R
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(2-氧代吡咯烷-1-基)苯基]丙酸甲酯
SM:(2R)-2-氨基-3-{3-[(2-氧代环戊基)氨基]苯基}丙酸甲酯
一般程序A
最终化合物通过FCC进一步纯化,得到标题化合物,为白色固体。
Y=38%
MS ES+:462.8
1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),7.62-7.54(m,1H),7.46(s,1H),7.30(t,J=8Hz,lH),6.95(d,J=8Hz,1H),6.87(s,1H),6.33(d,J=8Hz,1H),4.53-4.48(m,1H),3.89-3.76(m,2H),3.66(s,3H),3.10-2.90(m,2H),2.78(t,J=7Hz,4H),2.62(t,J=7Hz,4H),2.10-2.02(m,2H),1.97-1.90(m,4H).
2S
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}戊二酸1,5-二甲酯
SM:(2R)-2-氨基戊二酸1,5-二甲酯盐酸盐
一般程序A
Y=34%
MS ES+:375.2
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),6.88(s,1H),6.49(d,J=8Hz,1H),4.28-4.22(m,1H),3.65(s,3H),3.60(s,3H),2.80(t,J=7Hz,4H),2.68(t,J=7Hz,4H),2.45-2.35(m,2H),2.05-1.92(m,5H),1.91-1.80(m,1H).
2T
2-[({1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-5-基}氨基甲酰基)氨基]乙酸乙酯
将1H,2H,3H,6H,7H,8H,9H-环戊二烯并[a]萘-5-胺(20mg,0.107mmol)溶于ACN(1ml)中。向其中加入2-异氰酸基乙酸乙酯(17mg,1.2eq.,0.128mmol)在ACN(1ml)中的溶液,并将反应混合物在室温搅拌过夜。将得到的沉淀物过滤,用ACN洗涤,并在减压下干燥,得到标题化合物,为白色固体。
Y=97%
MS ES+:317
1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.34(s,1H),6.68(t,J=6Hz,1H),4.14-4.08(m,2H),3.84(d,J=6Hz,2H),2.78(t,J=8Hz,2H),2.67(t,J=7Hz,2H),2.55(t,J=5Hz,2H),2.52-2.46(m,6H),2.01-1.94(m,2H),1.76-1.66(m,4H),1.21(t,J=7Hz,3H).
2U
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-{3-[(1H-吡唑-3-基)氨基]苯基}丙酸甲酯
SM:(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-{3-[(1H-吡唑-3-基)氨基]苯基}丙酸
一般程序B
产物通过制备型HPLC进一步纯化,得到所需的产物,为白色固体。
Y=38%
MS ES+:460
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.90(s,1H),7.57(d,J=2Hz,1H),7.18-7.13(m,2H),7.12-7.07(m,1H),6.86(s,1H),6.53(d,J=7Hz,1H),6.26(d,J=8Hz,1H),5.86(d,J=2Hz,1H),4.47(m,1H),3.65(s,3H),2.97-2.86(m,2H),2.78(t,J=7Hz,4H),2.66-2.62(m,4H),1.97-1.90(m,4H).
2V
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(1H-吡唑-3-基)苯基]丙酸
将(2R)-2-氨基-3-[3-(1H-吡唑-3-基)苯基]丙酸二盐酸盐(180mg,0.59mmol)溶于1M NaOH(0.7ml,1.20mmol),并冷却至0℃。然后将所得溶液用中间体A(120mg,0.60mmol)的丙酮(1.4ml)溶液逐滴处理。在室温下搅拌24小时后,加入另一部分的中间体A(120mg,0.60mmol)/丙酮(1.4ml)。将RM在室温下再搅拌24小时。将RM过滤,并将收集的固体用丙酮研磨。将其通过制备型HPLC进一步纯化,得到标题化合物,为白色粉末。
Y=7%
MS ES+431.1
1H NMR(400MHz,DMSO-d6)δ12.92(s,2H),7.87(s,1H),7.70(s,1H),7.67-7.61(m,2H),7.32(t,J=8Hz,1H),7.14(d,J=8Hz,1H),6.84(s,1H),6.64(d,J=2Hz,1H),6.25(d,J=8Hz,1H),4.46-4.41(m,1H),3.17-3.12(m,1H),3.01-2.96(m,1H),2.77(t,J=7Hz,4H),2.62(t,J=7Hz,4H),1.94-1.87(m,4H).
2W
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丁二酸1,4-二甲酯
SM:(2R)-2-氨基丁二酸1,4-二甲酯盐酸盐
一般程序A
Y=46.7%
MS ES+:361.0
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),6.88(s,1H),6.57(d,J=8.5Hz,1H),4.64-4.54(m,1H),3.65(s,3H),3.63(s,3H),2.87-2.74(m,6H),2.67(t,J=7.3Hz,4H),2.02-1.88(m,4H).
2X
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸乙酯
将2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸(80mg,0.3mmol)悬浮在二噁烷(1ml)中,然后用1,1’-羰基二咪唑(61mg,0.37mmol)处理。在室温搅拌15分钟后,加入乙醇(2ml,33.5mmol),并将RM回流4小时。将RM蒸发,用水研磨,过滤并从沸腾的乙醇中重结晶,得到标题化合物,为白色粉末。
Y=22%
MS ES+:303.1
1H NMR(400MHz,DMSO)δ7.92(s,1H),6.89(s,1H),6.33(t,J=6Hz,1H),4.13-4.07(m,2H),3.81(d,J=6Hz,2H),2.80(t,J=7Hz,4H),2.70(t,J=7Hz,4H),2.09-1.84(m,4H),1.21(t,J=7Hz,3H).
2Y
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸甲酯
SM:(2R)-2-氨基-3-苯基丙酸甲酯盐酸盐
一般程序A
Y=44%
MS ES+:379.1
1H NMR(400MHz,DMSO)δ7.85(s,1H),7.49-7.05(m,5H),6.87(s,1H),6.33(d,J=8Hz,1H),4.53-4.44(m,1H),3.64(s,3H),3.11-3.01(m,1H),3.0-2.92(m,1H),2.79(t,J=7Hz,4H),2.63(t,J=7Hz,4H),2.03-1.87(m,4H).
2Z
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(4-羟基苯基)丙酸甲酯
SM:(2R)-2-氨基-3-(4-羟基苯基)丙酸甲酯盐酸盐
一般程序A
Y=33%
MS ES+:395.3
1H NMR(400MHz,DMSO)δ9.25(s,1H),7.86(s,1H),6.96(d,J=8Hz,2H),6.87(s,1H),6.68(d,J=8Hz,2H),6.24(d,J=8Hz,1H),4.44-4.37(m,1H),2.96-2.83(m,2H),2.79(t,J=7Hz,4H),2.64(t,J=7Hz,4H),2.0-1.90(m,4H).
2AA
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸丙-2-基酯
SM:2-氨基乙酸丙-2-基酯盐酸盐
一般程序A
Y=58%
MS ES+:317.2
1H NMR(400MHz,DMSO)δ7.91(s,1H),6.89(s,1H),6.32(t,J=6Hz,1H),4.97-4.88(m,1H),3.78(d,J=6Hz,2H),2.80(t,J=7Hz,4H),2.71(t,J=7Hz,4H),2.0-1.92(m,4H),1.22(d,J=6Hz,6H).
2BB
(2R)-3-氨基甲酰基-2-{[(1,2,3,5,6,7-六氢-对称引达省-4基)氨基甲酰基]氨基}丙酸甲酯
SM:(2R)-2-氨基-3-氨基甲酰基丙酸甲酯盐酸盐
一般程序A
Y=50%
MS ES+:346.1
1H NMR(400MHz,DMSO)δ8.07(s,1H),7.46(s,1H),6.96(s,1H),6.87(s,1H),6.44(d,J=8Hz,1H),4.50(s,1H),3.62(s,3H),2.79(t,J=7Hz,4H),2.74-2.64(m,5H),2.56(d,J=4Hz,1H),2.04-1.89(m,4H).
2CC
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(噻吩-2-基)丙酸甲酯
SM:(2R)-2-氨基-3-(噻吩-2-基)丙酸甲酯盐酸盐
一般程序A
Y=81%
MS ES+:385.1
1H NMR(400MHz,DMSO)δ7.99(s,1H),7.41-7.38(m,1H),7.0-6.97(m,1H),6.88(s,2H),6.43(d,J=8Hz,1H),4.55-4.48(m,1H),3.67(s,3H),3.31-3.20(m,2H),2.80(t,J=7Hz,4H),2.68(t,J=7Hz,4H),2.00-1.92(m,4H).
2DD
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(1H-咪唑-1-基)丙酸甲酯
SM:2-氨基-3-(1H-咪唑-1-基)丙酸甲酯盐酸盐
一般程序A
Y=64%
MS ES+:369.2
1H NMR(400MHz,DMSO)δ7.97(s,1H),7.53(s,1H),7.07(s,1H),6.90(d,J=4Hz,2H),6.51(d,J=8Hz,1H),4.65-4.55(m,1H),4.46-4.27(m,2H),3.69(s,3H),2.80(t,J=7Hz,4H),2.67(t,J=7Hz,4H),2.00-1.93(m,4H).
2EE
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}乙酸甲酯
SM:中间体A和2-氨基乙酸甲酯盐酸盐
一般程序A
Y=68%
MS ES+:289.0
1H NMR(400MHz,DMSO)δ7.92(s,1H),6.89(s,1H),6.34(t,J=6Hz,1H),3.84(d,J=6Hz,2H),3.64(s,3H),2.80(t,J=7Hz,4H),2.70(t,J=7Hz,4H),2.09-1.84(m,4H)..
2FF
(2S)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸
SM:(2S)-2-氨基-3-苯基丙酸
一般程序A
Y=62%
MS ES+:365.1;
1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),7.88(s,1H),7.36-7.26(m,J=7Hz,2H),7.27-7.17(m,3H),6.86(s,1H),6.23(d,J=8Hz,1H),4.49-4.39(m,1H),3.13-3.05(m,1H),2.98-2.90(m,1H),2.79(t,J=7Hz,4H),2.65(t,J=7Hz,4H),2.00-1.90(m,4H).
2GG
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸甲酯
以下混合物:(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸甲酯和(2S)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸甲酯
2HH
(2R)-3-(3-氨基苯基)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4基)氨基甲酰基]氨基}丙酸甲酯
SM:中间体A和(2R)-2-氨基-3-(3-乙酰胺基苯基)丙酸甲酯
一般程序A
Y=10%
MS ES+:394.7
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),6.93(t,J=8Hz,1H),6.87(s,1H),6.47-6.40(m,1H),6.40-6.35(m,1H),6.34-6.23(m,2H),5.00(s,1H),4.46-4.34(m,1H),3.64(s,2H),2.91-2.75(m,6H),2.65(t,J=7.8Hz,4H),2.01-1.89(m,4H).
2II
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-甲氧基丙酸甲酯
SM:(2R)-2-氨基-3-甲氧基丙酸甲酯盐酸盐
一般程序A
Y=75%
MS ES+:333.1
1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),6.87(s,1H),6.51(d,J=9Hz,1H),4.45-4.37(m,1H),3.77-3.70(m,1H),3.66(s,3H),3.61-3.52(m,1H),3.28(s,3H),2.79(t,J=7Hz,4H),2.68(t,J=7Hz,4H),2.03-1.89(m,4H).
2JJ
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-羟基丙酸甲酯
SM:(2R)-2-氨基-3-羟基丙酸甲酯盐酸盐
一般程序A
通过在最小量的DMSO中研磨进一步纯化化合物。将得到的固体过滤,依次用ACN和Et2O洗涤,并在真空下干燥,得到标题化合物,为白色粉末。
Y=68%
MS ES+:319.1
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),6.88(s,1H),6.46(d,J=8Hz,1H),5.17(t,J=4Hz,2H),4.36-4.19(m,1H),3.90-3.73(m,1H),3.66(s,3H),2.80(t,J=6Hz,4H),2.75-2.63(m,4H),2.05-1.88(m,4H).
2KK
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-[3-(1H-吡唑-4-基)苯基]丙酸乙酯
SM:(2R)-2-氨基-3-[3-(1H-吡唑-3-基)苯基]丙酸乙酯盐酸盐
一般程序A
将化合物通过制备TLC(己烷:乙酸乙酯4:1)进一步纯化,得到标题化合物,为黄色固体。
Y=1%
MS ES+:459.2
1H NMR(400MHz,DMSO-d6)δ12.93(宽s,1H),8.24(宽s,1H),7.76-7.59(m,3H),7.33(t,J=8Hz,1H),7.14(d,J=8Hz,1H),6.84(s,1H),6.80(宽s,1H),6.67(d,J=2Hz,1H),4.52-4.41(m,1H),4.14-4.03(m,2H),3.12-2.96(m,2H),2.77(t,J=7Hz,4H),2.62(t,J=7Hz,4H),1.98-1.90(m,4H),1.16(t,J=7Hz,3H).
2LL
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸
向(2R)-2-氨基-3-(吡啶-3-基)丙酸(200mg,1.2mmol,1eq.)在丙酮/H2O(1∶1,8ml)中的悬浮液中添加Et3N(252μl,1.8mmol,1.5eq.),并将混合物搅拌5分钟。加入中间体A(264mg,1.3mmol,1.1eq.)的THF(2mL)溶液,并将反应混合物在室温搅拌过夜。将混合物的体积在真空下减少至一半,并且滤出所得白色沉淀,依次用水,ACN和Et2O洗涤,并在真空下干燥,得到标题化合物,为白色粉末。
Y=68%
MS ES+:366.3
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.44(d,J=4Hz,1H),8.41(s,1H),7.86(s,1H),7.61(d,J=7Hz,1H),7.37-7.29(m,1H),6.86(s,1H),6.32(d,J=8Hz,1H),4.50-4.38(m,1H),3.18-3.06(m,1H),3.01-2.91(m,1H),2.78(t,J=7Hz,4H),2.63(t,J=7Hz,4H),1.98-1.90(m,4H).
2MM
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸2-甲氧基乙酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸2-甲氧基乙酯盐酸盐
一般程序A
Y=28%
MS ES+:424.5
1H NMR(400MHz,DMSO-d6)δ8.47-8.44(m,1H),8.42(d,J=2Hz,1H),7.92(s,1H),7.68-7.59(m,1H),7.38-7.30(m,1H),6.87(s,1H),6.50(d,J=8Hz,1H),4.58-4.49(m,1H),4.26-4.14(m,2H),3.59-3.48(m,2H),3.28(s,3H),3.14-3.06(m,1H),3.05-2.96(m,1H),2.79(t,J=7Hz,4H),2.62(t,J=7Hz,4H),1.98-1.90(m,4H).
2NN
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸环丁酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸环丁酯
一般程序A
粗产物通过制备型HPLC(HCOOH缓冲液)进一步纯化,得到标题化合物,为白色固体。
Y=2%
MS ES+:420.4
1H NMR(400MHz,DMSO-d6)δ8.51-8.35(m,2H),7.91(s,1H),7.68-7.59(m,1H),7.38-7.29(m,1H),6.87(s,1H),6.49(d,J=8Hz,1H),4.96-4.85(m,1H),4.50-4.39(m,1H),3.12-3.04(m,1H),3.04-2.95(m,1H),2.78(t,J=7Hz,4H),2.63(t,J=7Hz,4H),2.30-2.20(m,2H),1.99-1.89(m,4H),1.80-1.68(m,1H),1.67-1.52(m,1H).
2OO
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸环丙基甲酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸环丙基甲酯
一般程序A
产物通过制备型HPLC(HCOOH缓冲液)纯化,得到标题化合物,为白色固体。
Y=8%
MS ES+:420.4
1H NMR(400MHz,DMSO-d6)δ8.48-8.40(m,2H),7.93(s,1H),7.64(d,J=8Hz,1H),7.38-7.29(m,1H),6.87(s,1H),6.51(d,J=8Hz,1H),4.56-4.47(m,1H),3.91(d,J=7Hz,2H),3.13-3.05(m,1H),3.05-2.97(m,1H),2.78(t,J=7Hz,4H),2.63(t,J=7Hz,4H),2.02-1.85(m,4H),1.13-0.99(m,1H),0.56-0.47(m,2H),0.34-0.21(m,2H).
2PP
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸环戊酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸环戊酯二三氟甲烷磺酸盐
一般程序A
粗产物通过制备型HPLC(HCOOH缓冲液)纯化,得到标题化合物,为白色固体。
Y=9%
MS ES+:434.5
1H NMR(400MHz,DMSO-d6)δ8.45(d,J=5Hz,1H),8.43-8.38(m,1H),7.85(s,1H),7.63(d,J=8Hz,1H),7.40-7.29(m,1H),6.88(s,1H),6.42(d,J=8Hz,1H),5.12-5.03(m,1H),4.47-4.37(m,1H),3.11-2.94(m,2H),2.79(t,J=7Hz,4H),2.63(d,J=7Hz,4H),1.952.02-1.88(m,4H),1.87-1.72(m,2H),1.67-1.46(m,6H).
2QQ
(2R)-3-氰基-2-{[(1,2,3,5,6,7-六氢-对称引达省-4基)氨基甲酰基]氨基}丙酸甲酯
将(2R)-3-氨基甲酰基-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}丙酸甲酯(实施例2BB)(103mg,0.3mmol,1eq.)悬浮在无水DCM(3ml)中。加入对甲苯磺酰氯(239mg,1.2mmol,4.2eq.),随后加入吡啶(240μl,3mmol,10eq.),并将RM在室温下在氩气下搅拌72h。蒸发RM,并将所得固体依次用DCM,H2O和Et2O洗涤。粗产物通过制备型HPLC(甲酸缓冲液)纯化,得到标题化合物。
Y=13%
MS ES+:350.3[M+Na]+
1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),6.90(s,1H),6.82(d,J=8Hz,1H),4.61-4.53(m,1H),3.69(s,3H),3.11-2.95(m,2H),2.80(t,J=7Hz,4H),2.70(t,J=7Hz,4H),2.91-1.93(m,J=7Hz,4H).
2RR
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡啶-3-基)丙酸乙酯
SM:(2R)-2-氨基-3-(吡啶-3-基)丙酸盐酸盐
一般程序A
Y=69%
MS ES+:394.5
1H NMR(400MHz,DMSO-d6)δ8.45(d,J=3Hz,2H),8.42(s,1H),7.88(s,1H),7.63(d,J=7Hz,1H),7.37-7.28(m,1H),6.87(s,1H),6.46(d,J=8Hz,1H),4.54-4.41(m,1H),4.15-4.07(m,1H),3.14-2.94(m,2H),2.79(t,J=7Hz,4H),2.62(t,J=7Hz,4H),1.98-1.90(m,J=7Hz,4H),1.17(t,J=7Hz,3H).
2SS
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸
将(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-苯基丙酸甲酯[中间体2Y](31mg,0.08mmol)溶于MeOH(2ml)和水(2ml)中,然后用LiOH.H2O(6mg,0.14mmol)处理。将RM在室温搅拌18小时。
2TT
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(4-甲基-1H-吡唑-1-基)丙酸甲酯
SM:2-氨基-3-(4-甲基-1H-吡唑-1-基)丙酸甲酯盐酸盐
一般程序A
Y=13%
MS ES+:383.3
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.38(t,J=1Hz,1H),7.26(t,J=1Hz,1H),6.89(s,1H),6.36(d,J=8Hz,1H),4.67-4.58(m,1H),4.50-4.35(m,2H),3.66(s,3H),2.80(t,J=7Hz,4H),2.66(t,J=7Hz,4H),2.03-1.89(m,7H)
2UU
(2R)-2-({[2,6-双(丙-2-基)苯基]氨基甲酰基}氨基)-3-(吡啶-3-基)丙酸乙酯
在小瓶中装入(2R)-2-氨基-3-(3-氰基苯基)丙酸甲酯盐酸盐(50mg,0.217mol),4-N,N-二甲基氨基吡啶(约2mg)和MeCN(1ml)。加入2,6-二异丙基苯基异氰酸酯(43mg,0.217mmol)的MeCN(1ml)溶液,然后加入三乙胺(0.076ml,0.54mmol)。将小瓶密封并在室温搅拌18小时。所得溶液用DCM稀释,用水洗涤,经Na2SO4干燥并蒸发。粗产物通过FCC(二氧化硅,0-100%EtOAc/己烷)纯化,得到所需的产物,为白色固体。
Y=48%
MS ES+:398.3
1H NMR(400MHz,DMSO-d6)δ8.45(d,J=5Hz,2H),7.64(d,J=7Hz,1H),7.57(s,1H),7.40-7.30(m,1H),7.19(t,J=8Hz,1H),7.10(s,1H),7.08(s,1H),6.55(d,J=7Hz,1H),4.55-4.45(m,1H),4.09(q,J=7Hz,2H),3.19-3.05(m,2H),3.05-2.95(m,2H),1.17(t,J=7Hz,3H),1.09(d,J=6Hz,12H).
2VV
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(嘧啶-2-基)丙酸乙酯
SM:2-氨基-3-(嘧啶-2-基)丙酸乙酯二盐酸盐
一般程序A
Y=43%
MS ES+:395.5
1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),8.74(d,J=5Hz,2H),7.94(s,1H),7.39(t,J=5Hz,1H),6.87(s,1H),6.51(d,J=9Hz,1H),4.83-4.72(m,1H),4.10-4.00(m,3H),3.13-3.02(m,6H),2.78(t,J=7Hz,4H),2.66-2.58(m,4H),2.00-1.86(m,4H),1.19(t,J=7Hz,9H),1.10(t,J=7Hz,3H).与三乙胺盐酸盐复合。
2WW
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(5-甲氧基吡啶-3-基)丙酸甲酯
SM:(2R)-2-氨基-3-(5-甲氧基吡啶-3-基)丙酸甲酯二盐酸盐
一般程序A
产物通过酸性制备型HPLC纯化,然后通过制备型TLC(二氧化硅,9∶1DCM/MeOH等度洗脱)进一步纯化。
Y=15%
MS ES+:410.5
1H NMR(300MHz,CDCl3)δ8.19(s,1H),7.91(s,1H),7.05(s,1H),6.96(s,1H),5.85(s,1H),4.92-4.82(m,2H),3.82(s,3H),3.75(s,3H),3.23-3.15(m,1H),3.05-2.97(m,1H),2.89(t,J=8Hz,4H),2.77-2.67(m,4H),2.10-2.00(m,4H)
2XX
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(3-甲基-1,2,4-噁二唑-5-基)丙酸乙酯
SM:2-氨基-3-(3-甲基-1,2,4-噁二唑-5-基)丙酸乙酯盐酸盐
一般程序A
粗产物通过酸性制备型HPLC纯化,得到所需产物。
Y=23%
MS ES+:399.5
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),6.89(s,1H),6.61(d,J=8Hz,1H),4.75-4.67(m,1H),4.16-4.07(m,2H),3.46-3.35(m,2H),2.79(t,J=7Hz,4H),2.65(t,J=7Hz,4H),2.32(s,3H),2.01-1.90(m,4H),1.17(t,J=7Hz,3H)
2YY
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(哒嗪-3-基)丙酸甲酯
SM:(2R)-2-氨基-3-(哒嗪-3-基)丙酸甲酯盐酸盐
一般程序A
粗产物通过酸性制备型HPLC纯化,得到所需的产物,为白色固体。
Y=23%
MS ES+:381.4
1H NMR(400MHz,DMSO-d6)δ9.12(dd,J=5,2Hz,1H),7.90(s,1H),7.66-7.58(m,2H),6.86(s,1H),6.53(d,J=8Hz,1H),4.76-4.71(m,1H),3.63(s,3H),3.44-3.32(m,2H),2.79-2.75(m,4H),2.60-2.56(m,4H),1.96-1.89(m,4H)
2ZZ
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(1,2-噁唑-4-基)丙酸乙酯
SM:2-氨基-3-(1,2-噁唑-4-基)丙酸乙酯盐酸盐
一般程序A
粗产物通过酸性制备型HPLC纯化,得到所需的产物,为白色固体。
Y=16%
MS ES+:384.8
1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.47(s,1H),7.88(s,1H),6.88(s,1H),6.49(d,J=8Hz,1H),4.49-4.40(m,1H),4.11(q,J=8Hz,2H),2.97-2.84(m,2H),2.81-2.78(m,4H),2.68-2.64(m,4H),1.99-1.92(m,4H),1.19(t,J=8Hz,3H)
2AB
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(1,2-噁唑-3-基)丙酸乙酯
SM:2-氨基-3-(1,2-噁唑-3-基)丙酸乙酯盐酸盐
一般程序A
Y=66%
MS ES+:384
1H NMR(400MHz,DMSO-d6)δ8.85(d,J=2Hz,1H),7.95(s,1H),6.88(s,1H),6.51-6.48(m,2H),4.62-4.53(m,1H),4.17-4.06(m,2H),3.19-3.06(m,2H),2.81-2.78(m,4H),2.68-2.64(m,4H),2.00-1.89(m,4H),1.18(t,J=7Hz,3H)
2AC
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(1,3-噁唑-2-基)丙酸乙酯
SM:2-氨基-3-(1,3-噁唑-2-基)丙酸乙酯盐酸盐
一般程序A
Y=21%
MS ES+:384.4
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),8.03(s,1H),7.15(s,1H),6.88(s,1H),6.53(d,J=8Hz,1H),4.69-4.63(m,1H),4.14-4.04(m,2H),3.23(d,J=6Hz,2H),2.82-2.76(m,4H),2.68-2.63(m,4H),1.99-1.90(m,4H),1.16(t,J=7Hz,3H)
2AD
(2R)-2-({[6-(丙-2-基)-2,3-二氢-1H-茚-5-基]氨基甲酰基}氨基)-3-(吡啶-3-基)丙酸乙酯
将5-异氰酸基-6-(丙-2-基)-2,3-二氢-1H-茚(30mg,0.15mmol),(2R)-2-氨基-3-(吡啶-3-基)丙酸乙酯盐酸盐(34mg,0.15mmol)和DMAP(小刮铲末端)在乙腈(3ml)中的溶液用三乙胺(52μl,0.37mmol)处理。将RM在室温搅拌16小时。浓缩RM,用1M HCl稀释并用DCM萃取。有机相经硫酸钠干燥并蒸发。将得到的固体悬浮在己烷中,过滤并用Et2O洗涤。粗产物通过制备TLC(二氧化硅,EtOAc/己烷)进一步纯化,得到所需产物。
Y=22%
MS ES+:396.2
1H NMR(400MHz,DMSO-d6)δ8.52-8.48(m,2H),7.77-7.72(m,2H),7.46-7.40(m,1H),7.25(s,1H),7.07(s,1H),6.72(d,J=9Hz,1H),4.58-4.49(m,1H),4.15-4.06(m,2H),3.15-2.96(m,3H),2.82-2.71(m,4H),2.01-1.91(m,2H),1.20-1.09(m,9H)
2AE
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(嘧啶-5-基)丙酸甲酯
SM:(2R)-2-氨基-3-(嘧啶-5-基)丙酸甲酯盐酸盐
一般程序A
粗产物通过酸性制备型HPLC纯化,得到所需的产物,为白色固体。
Y=85%
MS ES+:381.5
1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.66(s,2H),7.84(s,1H),6.87(s,1H),6.53(d,J=8Hz,1H),4.60-4.53(m,1H),3.68(s,3H),3.15(dd,J=14,5Hz,1H),3.01-2.95(m,1H),2.80-2.76(m,4H),2.61-2.57(m,4H),1.98-1.90(m,4H).
2AF
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(吡嗪-2-基)丙酸甲酯
SM:(2R)-2-氨基-3-(吡嗪-2-基)丙酸甲酯盐酸盐
一般程序A
粗产物通过酸性制备型HPLC纯化,得到所需的产物,为白色固体。
Y=3%
MS ES+:381.5
1H NMR(400MHz,DMSO-d6)δ8.60-8.55(m,2H),8.52(d,J=3Hz,1H),7.88(s,1H),6.87(s,1H),6.51(d,J=8Hz,1H),4.73-4.65(m,1H),3.64(s,3H),3.30-3.16(m,2H),2.80-2.76(m,4H),2.61-2.57(m,4H),1.96-1.90(m,4H).
2AG
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(哒嗪-4-基)丙酸乙酯
SM:2-氨基-3-(哒嗪-4-基)丙酸乙酯盐酸盐
一般程序A
通过酸性制备型HPLC纯化粗产物,得到所需的产物,为白色固体。
Y=21%
MS ES+:395.4
1H NMR(400MHz,DMSO-d6)δ9.14(d,J=5Hz,1H),9.11(s,1H),7.83(s,1H),7.56-7.54(m,1H),6.88(s,1H),6.51(d,J=8Hz,1H),4.61-4.53(m,1H),4.12(q,J=7Hz,2H),3.15(dd,J=14,5Hz,1H),3.06-3.0(m,1H),2.80-2.76(m,4H),2.62-2.58(m,4H),1.98-1.90(m,4H),1.19(t,J=7Hz,3H).
2AH
(2R)-2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(嘧啶-2-基)丙酸乙酯
SM:2-氨基-3-(嘧啶-2-基)丙酸乙酯二盐酸盐
根据实施例2VV详述的程序合成外消旋化合物。通过手性HPLC分离外消旋物,得到所需产物,为白色固体。
Y=14%
MS ES+:395
1H NMR(400MHz,DMSO-d6)δ8.74(d,J=5Hz,2H),7.92(s,1H),7.40(t,J=5Hz,1H),6.87(s,1H),6.49(d,J=9Hz,1H),4.85-4.69(m,1H),4.05(q,J=7Hz,2H),3.32-3.29(m,2H),2.78(t,J=7Hz,4H),2.71-2.56(m,4H),2.04-1.83(m,4H),1.10(t,J=7Hz,3H).
2AI
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(嘧啶-4-基)丙酸乙酯
SM:2-氨基-3-(嘧啶-4-基)丙酸乙酯盐酸盐
一般程序A
通过酸性制备型HPLC纯化粗产物,得到所需的产物,为白色固体。
Y=10%
MS ES+:395.4
1H NMR(400MHz,DMSO-d6)δ9.09(d,J=1Hz,1H),8.72(d,J=5Hz,1H),7.92(s,1H),7.49-7.42(m,1H),6.87(s,1H),6.53(d,J=8Hz,1H),4.73-4.66(m,1H),4.09(q,J=7Hz,2H),3.23-3.16(m,1H),3.06-3.0(m,1H),2.81-2.76(m,4H),2.64-2.58(m,4H),1.98-1.88(m,4H),1.15(t,J=7Hz,3H).
2AJ
2-{[(1,2,3,5,6,7-六氢-对称引达省-4-基)氨基甲酰基]氨基}-3-(嘧啶-2-基)丙酸
SM:2-氨基-3-(嘧啶-2-基)丙酸二盐酸盐
一般程序A
Y=26%
MS ES+:367.1
1H NMR(300MHz,DMSO-d6)δ12.58(br.s,1H),8.73(d,J=5Hz,2H),7.89(s,1H),7.38(t,J=5Hz,1H),6.86(s,1H),6.39(d,J=9Hz,1H),4.77-4.68(m,1H),2.80-2.75(m,4H),2.64-2.58(m,4H),1.98-1.88(m,4H).2个质子被水或DMSO峰遮盖。
公开的结构的概述-表
活性
体外抑制活性测定
利用下文描述的试验测定了本公开的化合物的生物活性。
PBMC IC50测定试验
测试了本公开的化合物在外周血单核细胞(PBMC)中NLRP3激活后,其对IL1-β释放的抑制活性。
通过在Histopaque-1077(Sigma,cat no.10771)上的密度梯度离心将PBMC与血沉棕黄层分离。分离的细胞接种到96孔板的孔中,并与脂多糖(LPS)一起培养3小时。培养基交换后,加入本公开的化合物(每孔一种化合物),并将细胞培养30分钟。接下来,将细胞用ATP(5mM)或尼日利亚菌素(10μM)刺激1h,并收集来自孔的细胞培养基用于进一步分析。
通过使用IL-1β酶联免疫吸附测定法(ELISA)Ready-SET-Go!,eBiosciencecat.No.88-7261-88对培养基中的IL-1β进行定量检测来测定IL-1β向培养基中的释放。简而言之,在第一步中,将高亲和力结合板(Corning,Costar 9018或NUNC Maxisorp CatNo.44-2404)在4℃下用试剂盒中包含的特异性捕获抗体(抗人IL-1βref.14-7018-68)涂覆过夜。随后,将板在室温(rt)下用封闭缓冲液封闭1小时,并且在用缓冲液(含0.05%Tween-20的PBS)洗涤后与蛋白质标准品和培养基一起培养。在室温培养2小时后,洗涤板并与试剂盒中包括的生物素化的检测抗体(抗人IL-1β生物素ref.33-7110-68)在室温培养1小时。洗涤板,并与HRP--抗生蛋白链菌素在室温下一起培养30分钟,并再次洗涤。加入3,39,5,59-四甲基联苯胺-过氧化物酶(TMB)后,产生信号,直到出现颜色,用2M H2SO4终止反应。用微板分光光度计(BioTek)检测450nm的信号。IL-1βELISA的检测范围是2-150ng/ml。
使用Graph Pad Prism软件进行IC50值的测定,并且本公开化合物的测量的IC50值显示在下表1中。
表1
这些结果表明,本公开的化合物能够抑制炎性体激活后的IL-1β释放。
等同物
本公开的一个或多个实施方案的细节在以上所附的描述中阐明。尽管类似于或等同于本文描述的那些方法和材料的任何方法和材料都可以用于本公开的实践或测试中,现在描述优选的方法和材料。根据说明书和权利要求书,本公开的其他特征,目的和优点将是显而易见的。在说明书和所附权利要求书中,单数形式包括复数对象,除非上下文另外明确指出。除非另有定义,否则本文中使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解的相同含义。本说明书中引用的所有专利和出版物均通过引用并入本文。
前面的描述仅出于说明的目的给出,并且不旨在将本公开限制为所公开的精确形式,而是由其所附的权利要求书来限定。
Claims (19)
1.式(I)的化合物或其药学上可接受的盐:
其中:
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统是未取代的六氢引达省环
其中#表示与式(I)氮原子的键,或所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1或2个独立地选自氧,氮和硫的杂原子,其中所述杂环R7环系统任选地被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
或
其中R7选自5或6元单环芳基或非芳基环系统,其任选包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,任选包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元饱和或部分不饱和的碳环系统,且所述R7环系统被1个或多个取代基取代,所述取代基独立选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基和R8,
其中R8为任选地N-连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;且
R4为H,烷基,单环烷基或单环芳基。
2.权利要求1的化合物,其中R3是甲基-R7或乙基-R7。
3.权利要求1或权利要求2的化合物,其中R7是任选被至少一个羟基取代的单环芳基。
4.权利要求1或权利要求2的化合物,其中R7是具有氰基取代的单环芳基。
5.权利要求1或权利要求2的化合物,其中R7为包含1、2或3个独立地选自氧、氮和硫的杂原子的5或6元单环芳基环。
6.前述权利要求中任一项的化合物,其中R4是烷基(C1-C4)或环烷基(C3-C6)。
7.前述权利要求中任一项的化合物,其中R1为:
选自以下的12、13、14、15或16元三环部分不饱和碳环系统:
其中#表示与式(I)氮原子的键;其中n和na是独立地选自0、1、2和3的整数;其中R9选自氢,(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;或
选自以下的12、13、14、15或16元三环部分不饱和碳环系统
其中#表示与式(I)氮原子的键;其中n和na是独立地选自0、1、2和3的整数;其中R9选自氢,(1-6C)烷基,卤素,CF3和OCF3;或
其中#表示与式(I)氮原子的键;其中R9选自氢,(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;或
其中#表示与式(I)氮原子的键;其中R9选自氢,(1-6C)烷基,卤素,CF3和OCF3;或
未取代的六氢引达省环:
其中#表示与式(I)氮原子的键。
9.式(I)的化合物或其前药或药学上可接受的盐:
其中:
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,包含1或2个独立地选自氧,氮和硫的杂原子,其中所述R7环系统任选地被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基,任选地N连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,或任选地N连接的3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;和
R4为H,烷基,单环烷基或单环芳基。
10.式(I)的化合物或其前药或药学上可接受的盐:
其中
R1是5或6元烷基或芳基单环,具有至少一个包含(2-8C)烷基的基团取代基,或9或10元双环部分不饱和碳环系统,其中所述双环系统任选被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3,或12、13、14、15或16元三环部分不饱和碳环系统,其中所述三环系统任选地被1、2、3或4个取代基取代,所述取代基独立地选自(1-6C)烷基,(2-6C)亚烯基,(2-6C)亚炔基,(3-8C)环烷基,(1-3C)烷氧基,卤素,氧代,羟基,氰基,氨基,(1-3C)烷基氨基,二-[(1-3C)烷基]-氨基,CF3,OCF3,S(O)2CH3,S(O)CH3,S(O)2NH2,S(O)2NHCH3,S(O)2N(CH3)2,NHS(O)2CH3和N(CH3)S(O)2CH3;
R2为H;
R3为烷基(C1-4)-R7,
其中R7选自5或6元单环芳基或非芳基环系统,其任选包含1、2或3个独立地选自氧,氮和硫的杂原子,或3、4、5或6元单环杂环基环系统,任选包含1或2个独立地选自氧,氮和硫的杂原子,或3、4、5或6元饱和或部分不饱和的碳环系统,且所述R7环系统被1个或多个取代基取代,所述取代基独立地选自(1-6C)烷基,烷基羟基,硝基,OH,COCH3,卤素,氨基,氰基,任选地N连接的5或6元单环杂芳基环,包含1或2个独立地选自氧,氮和硫的杂原子,和任选地N连接的3、4、5或6元单环杂环基环系统,包含1个独立地选自氧,氮和硫的杂原子,所述环任选地被烷基,氧代,卤素或氨基取代;和
R4为H,烷基,单环烷基或单环芳基。
11.药物组合物,其包含与药学上可接受的稀释剂或载体混合的前述权利要求中任一项所定义的化合物或其药学上可接受的盐。
12.在体外或体内抑制NLRP3炎性体活性的方法,所述方法包括使细胞与有效量的根据前述权利要求中任一项的化合物或其药学上可接受的盐接触。
13.治疗需要这种治疗的患者的其中涉及炎性体活性的疾病或病症的方法,所述方法包括向所述患者施用治疗有效量的根据前述权利要求中任一项的化合物或其药学上可接受的盐或组合物。
14.治疗需要这种治疗的患者的自身炎性病症,自身免疫病症,神经退行性疾病或癌症的方法,所述方法包括向所述患者施用治疗有效量的根据前述权利要求中任一项的化合物。
15.根据前述权利要求1-11中任一项的化合物,包括其前药或药学上可接受的盐或组合物,或药物组合物,其用于治疗。
16.根据前述权利要求1-11中任一项的化合物,该化合物用于治疗其中涉及炎性体活性的病症。
17.根据权利要求1-11中任一项的化合物,该化合物用于治疗病症,其中所述病症是癌症,所述癌症选自胃肠道癌,皮肤癌,非小细胞肺癌和结直肠腺癌。
18.根据权利要求17所述的化合物,该化合物用于治疗病症,其中所述病症选自自身炎性病症,自身免疫病症,神经退行性疾病或癌症的治疗。
19.根据权利要求18任一项的化合物,其中所述病症选自冷吡啉相关自身炎性综合征(CAPS),包括家族性冷性自身炎性综合征(FCAS)、Muckle-Wells综合征(MWS)、慢性婴儿神经性皮肤和关节(CINCA)综合征、新生儿发作的多系统炎性疾病(NOMID)、家族性地中海热、非酒精性脂肪肝疾病(NAFLD)、痛风、类风湿性关节炎、克罗恩氏病、COPD、纤维化、肥胖症、2型糖尿病、多发性硬化症、发生在蛋白质错误折叠疾病中的神经炎症、帕金森氏病、骨关节炎、非酒精性脂肪性肝炎(NASH)和阿尔茨海默氏病。
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