TWI772386B - 雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用 - Google Patents
雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用 Download PDFInfo
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- TWI772386B TWI772386B TW107109077A TW107109077A TWI772386B TW I772386 B TWI772386 B TW I772386B TW 107109077 A TW107109077 A TW 107109077A TW 107109077 A TW107109077 A TW 107109077A TW I772386 B TWI772386 B TW I772386B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 125000001072 heteroaryl group Chemical group 0.000 title abstract description 33
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical class NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 title abstract description 18
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- 238000000034 method Methods 0.000 claims description 33
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- 125000003118 aryl group Chemical group 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 30
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Abstract
本發明涉及雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用。具體而言,本發明涉及一種通式(I)所示的雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及含有該衍生物的醫藥組成物以及其作為治療劑,特別是作為A2a受體拮抗劑的用途和在製備用於治療藉由對A2a受體的抑制而改善的病況或病症的藥物中的用途,其中通式(I)的各取代基與說明書中的定義相同。
Description
本發明屬於醫藥領域,涉及一種通式(I)所示的雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及含有該衍生物的醫藥組成物以及其作為治療劑,特別是作為A2a受體拮抗劑的用途和在製備用於治療藉由對A2a受體的抑制而改善的病況或病症的藥物中的用途。
腺苷是天然存在的嘌呤核苷,是許多生理功能的內源性調節劑。在心血管系統、中樞神經、呼吸系統、腎臟、脂肪和血小板的功能調節中發揮重要作用。
腺苷的作用由G蛋白偶聯受體家族介導,目前已知至少有四種亞型的腺苷受體,分類為A1、A2a、A2b和A3。其中A1和A3受體抑制酶腺苷酸環化酶的活性,而A2a和A2b受體刺激該酶的活性,由此調節細胞中環AMP水準,藉由這些受體,腺苷調節廣泛的生理功能。
A2a受體(A2aR)在機體分佈較為廣泛,在中樞神經系統 主要表現於紋狀體,在外周、心、肝、肺、腎等組織也均有表現。數個臨床前研究表明,腺苷A2a受體拮抗劑對於治療神經變性疾病,主要是帕金森病、亨廷頓病或阿茲海默症具有驚人療效(Trends in Neurosci.2006,29(11),647-654;Expert Opinion on Therapeutic Patents,2007,17,979-991等)。而且也可以用於治療其他中樞神經系統(CNS)相關的疾病例如抑鬱、過動症候群、睡眠障礙和焦慮症(Clin.Neuropharmacol.2010,33,55-60;J.Neurosci.2010,30(48),16284-16292;Parkinsonisn Relat.Disord.2010,16(6),423-426;及其中的參考獻:Mov.Disorders,2010,25(2),S305)。此外,腺苷A2a受體拮抗劑還具有作為神經保護劑的治療潛力(參見Jenner P.J Neuro 1.2000;24 7Suppl2:1143-50)。
近來研究表明,在缺血低氧、炎症、創傷、移植等諸多病理過程中,腺苷A2a受體的啟動可以發揮重要的免疫調節作用,這可能與A2a受體在T細胞、B細胞、單核巨噬細胞、嗜中性球等多種免疫細胞上表現水準較高有關。此外,A2a受體的活化可以促使機體產生免疫耐受,密切參與了腫瘤細胞“免疫逃逸”或“免疫抑制”的形成,為腫瘤的發生發展創造了有利條件。Lokshin及其同事(Cancer Res.2006 Augl;66(15):7758-65)證實自然殺傷細胞上的A2a受體活化可以藉由升高cAMP,啟動PKA抑制自然殺傷細胞對腫瘤細胞的殺傷。還有研究表明,啟動A2a受體的活化可以促進黑色素瘤A375細胞、成纖維瘤NIH3T3細胞及嗜 鉻細胞瘤PC12細胞等腫瘤細胞的增殖,其可能與T細胞上A2a受體的活化可以抑制T細胞活化、增殖、與腫瘤細胞的黏附及對腫瘤細胞產生細胞毒性作用相關;而A2a受體基因敲除的小鼠則可以加強CD8+T細胞抗腫瘤的免疫作用,顯著抑制腫瘤的增殖。因此,A2a受體拮抗劑也可用於腫瘤的治療。
儘管對多種腺苷受體亞型具有顯著生物學活性的化合物可具有治療作用,但它們可導致不想要的副作用。例如腺苷A1受體在組織缺血/缺氧時,在中樞、循環、消化系統和骨骼肌中,細胞在處於缺氧和低氧的壓力環境時,胞外聚集的腺苷藉由啟動胞膜上的A1受體啟動相應的保護機制,從而增加細胞對缺氧低氧的耐受。位於免疫細胞上的A1受體在低氧環境中能促進細胞免疫反應。另外,A1受體還能降低游離脂肪酸和三酸甘油酯,參與調節血糖。因此,A1受體的持續阻斷可能會引起有機體組織中各種不良反應的發生(Chinese Pharmacological Bulletin,2008,24(5),573-576)。如有文獻報導,在動物模型上,阻斷A1受體將會產生焦慮、覺醒等不良反應(Basic & Clinical Pharmacology & Toxicology,2011,109(3),203-7)。腺苷受體A3(如Gessi S等人,Pharmacol.Ther.117(1),2008,123-140所述)在心肌缺血期間釋放的腺苷在心臟中發揮強力的保護作用,A3受體的持續阻斷可能增加由任何預先存在的或正在發展的缺血性心臟病引起的併發症的可能性,所述缺血性心臟病諸如心絞痛或心衰竭。
目前,雖然已有許多化合物經開發為A2a受體的拮抗劑用於治療很多疾病,如WO2007116106、WO2009080197、WO2011159302、WO2011095625、WO2014101373、WO2015031221中所述。但仍有低溶解性、光敏性、低活性、低選擇性和生物利用率較低等問題存在。
本發明提供一種新型雜芳基并[4,3-c]嘧啶-5-胺類結構的腺苷A2a受體拮抗劑,并發現具有此類結構的化合物具有強抑制活性和高選擇性,并且此類結構的化合物在腦中的游離藥物濃度低,透過血腦屏障能力弱,對藥物進腦後可能產生的副作用低。
本發明的目的在於提供一種通式(I)所示的化合物:
或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中:G為N或CR4;環A選自環烷基、芳基和雜芳基; R1相同或不同,各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基;R2選自烷氧基、羥基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基;其中所述的烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要經選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氧代基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基、C(O)OR5和Rb中的一個或多個取代基所取代;R3選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基;R4選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基;R5選自氫原子、烷基、胺基、鹵烷基、環烷基、雜環基、芳基和雜芳基;Rb為雜環基烷基,其中所述的雜環基烷基中的雜環基視需要經選自烷氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、環烷基氧基、雜環基、芳基、雜芳基和C(O)OR5中的一個或多個取代基所取代;且n為1、2、3或4。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物,其中所述的R2選自氰基、環烷基、雜環基、芳 基和雜芳基;其中所述的環烷基、雜環基、芳基和雜芳基各自獨立地視需要經選自鹵素、烷基、鹵烷基、烷氧基、氧代基、環烷基、雜環基和Rb中的一個或多個取代基所取代;Rb為雜環基烷基,其中所述的雜環基烷基中的雜環基視需要經一個或多個烷基所取代。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物為通式(II)所示的化合物:
或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中:環B選自環烷基、雜環基、芳基和雜芳基;R6相同或不同,各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氧代基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基、C(O)OR5和Rb;s為0、1、2、3或4;且環A、G、R1、R3、R5、Rb和n如通式(I)中所定義。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物為通式(III)所示的化合物:
或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中:R6相同或不同,各自獨立地選自鹵素、烷基、鹵烷基、烷氧基、氧代基、環烷基、雜環基和Rb;Rb為雜環基烷基,其中所述的雜環基烷基中的雜環基視需要經一個或多個烷基所取代;環A、環B、R1、R3、n和s如通式(II)中所定義。
在本發明一個較佳的實施方案中,所述的通式(II)所示的化合物,其中所述環B選自苯基、5至6員雜環基或5至10員雜芳基;較佳係苯基、吡啶基、吡唑基、吡啶-2-酮基、咪唑基、吡咯基、呋喃基、噻吩基、哌啶基、1,2,3,6-四氫吡啶基、異喹啉基、喹啉基、喹啉基、吲哚基、吲唑基、苯并呋喃基或苯并噻吩基。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物為通式(III’)所示的化合物: 或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中:R6相同或不同,各自獨立地選自氫原子、鹵素、烷基、鹵烷基、烷氧基、氧代基、環烷基、雜環基和Rb;Rb為雜環基烷基,其中所述的雜環基烷基中的雜環基視需要經一個或多個烷基所取代;s為0、1、2、3或4;環A、R1、R3和n如通式(I)中所定義。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物,其中所述的環A為芳基或雜芳基,較佳為苯基或呋喃基。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物,其中所述的R1選自氫原子、鹵素或烷基。
在本發明一個較佳的實施方案中,所述的通式(I)所示的化合物,其中所述的R3選自氫原子、鹵素或烷基。
或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽。
本發明的另一方面涉及一種通式(IV)所示的化合物:
或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中:X為鹵素;環A、G、R1、R3和n如通式(I)中所定義。
本發明的另一方面涉及一種醫藥組成物,所述醫藥組成物含有治療有效量的本發明通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,以及一種或多種醫藥上可接受的載體、稀釋劑或賦形劑。
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物在製備用於抑制A2a受體的藥物中的用途。
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物在製備用於治療藉由對A2a受體抑制而改善的病況或病症的藥物中的用途。
在本發明中,藉由對A2a受體抑制而改善的病況或病症選自腫瘤、抑鬱症、認知功能病症、神經退行性病症(帕金森氏病、亨廷頓氏病、阿茲海默症或肌萎縮性側索硬化等)、注意力相關病症、錐體外症候群、異常運動障礙、肝硬化、肝纖維化、脂肪肝、皮膚纖維化、睡眠障礙、中風、腦損傷、神經炎症和成癮行為;較佳為腫瘤。
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物在製備治療腫瘤、抑鬱症、認知功能病症、神經退行性病症(帕金森氏病、亨廷頓氏病、阿茲海默症或肌萎縮性側索硬化等)、注意力相關病症、錐體外症候群、異常運動障礙、肝硬化、肝纖維化、脂肪肝、皮膚纖維化、睡眠障礙、中風、腦損傷、神經炎症和成癮行為,較佳腫瘤的藥物中的用途。
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物在製備治療腫瘤的藥物中的用途。
本發明還涉及一種抑制A2a受體的方法,其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物。
本發明還涉及一種治療藉由對A2a受體抑制而改善的病況或病症的方法,其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物。
本發明涉及一種治療腫瘤、抑鬱症、認知功能病症、神經退行性病症(帕金森氏病、亨廷頓氏病、阿茲海默症或肌萎縮性側索硬化等)、注意力相關病症、錐體外症候群、異常運動障礙、肝硬化、肝纖維化、脂肪肝、皮膚纖維化、睡眠障礙、中風、腦損傷、神經炎症和成癮行為,較佳腫瘤的方法,其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物。
本發明進一步涉及一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其醫藥上可接受之鹽或包含其醫藥組成物,其用作藥物。
本發明還涉及通式(I)所示的化合物或其互變異構 體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物,其用作A2a受體拮抗劑。
本發明還涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物,其治療藉由對A2a受體抑制而改善的病況或病症。
本發明還涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物,其用於治療腫瘤、抑鬱症、認知功能病症、神經退行性病症(帕金森氏病、亨廷頓氏病、阿茲海默症或肌萎縮性側索硬化等)、注意力相關病症、錐體外症候群、異常運動障礙、肝硬化、肝纖維化、脂肪肝、皮膚纖維化、睡眠障礙、中風、腦損傷、神經炎症和成癮行為,較佳腫瘤。
本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式,或其醫藥上可接受之鹽,或包含其醫藥組成物,其用於治療腫瘤。
本發明中所述的腫瘤選自黑色素瘤、腦瘤、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌、肺癌、腎癌、乳腺癌、卵巢癌、前列腺癌、皮膚癌、神經母細胞瘤、肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸腫瘤、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多 症、白血病、甲狀腺腫瘤、輸尿管腫瘤、膀胱癌、膽囊癌、膽管癌、絨毛膜上皮癌和兒科腫瘤;較佳為肺癌。
含活性成分的醫藥組成物可以是適用於口服的形式,例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊,或糖漿劑或酏劑。可按照本領域任何已知製備藥用組成物的方法製備口服組成物,此類組成物可含有一種或多種選自以下的成分:甜味劑、矯味劑、著色劑和防腐劑,以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑,造粒劑、崩解劑,粘合劑,和潤滑劑。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收,因而在較長時間內提供緩釋作用的已知技術將其包衣。
也可用其中活性成分與惰性固體稀釋劑或其中活性成分與水溶性載體或油溶媒混合的軟明膠膠囊提供口服製劑。
水懸浮液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑,分散劑或濕潤劑。水混懸液也可以含有一種或多種防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。
油混懸液可藉由使活性成分懸浮於植物油,或礦物油配製而成。油懸浮液可含有增稠劑。可加入上述的甜味劑和矯味劑,以提供可口的製劑。可藉由加入抗氧化劑保存這些組成物。
藉由加入水可使適用于製備水混懸的可分散粉末和顆粒提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑。適宜的分散劑或濕潤劑和懸浮劑可說明上述的例子。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組成物。
本發明的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油,或礦物油或其混合物。適宜的乳化劑可以是天然產生的磷脂,乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。
本發明的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒或溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳可藉由局部大量注射,將注射液或微乳注入患者的血流中。或者,最好按可保持本發明化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恆定濃度,可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。
本發明的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術,用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可接受的無毒稀釋劑或溶劑中製備的無菌注射溶液或混懸液。此外,可方便地用無菌固定油 作為溶劑或懸浮介質。為此目的,可使用任何調和固定油。此外,脂肪酸也可以製備注射劑。
可按用於直腸給藥的栓劑形式給予本發明化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體,因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。
如本領域技術人員所熟知的,藥物的給藥劑量依賴於多種因素,包括但並非限定於以下因素:所用具體化合物的活性、患者的年齡、患者的體重、患者的健康狀況、患者的行為、患者的飲食、給藥時間、給藥方式、排泄的速率、藥物的組合等;另外,最佳的治療方式如治療的模式、通式化合物(I)的日用量或醫藥上可接受之鹽的種類可以如傳統的治療方案來驗證。
除非有相反陳述,在說明書和申請專利範圍中使用的術語具有下述含義。
術語“烷基”指飽和脂肪族烴基團,其為包含1至20個碳原子的直鏈或支鏈基團,較佳含有1至12個碳原子的烷基,更佳含有1至6個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲 基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基,非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,當經取代時,取代基可以在任何可使用的連接點上經取代,所述取代基較佳獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基),其 中烷基的定義如上所述。烷氧基的非限制性實例包括:甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取代的或非取代的,當經取代時,取代基較佳為一個或多個以下基團,其獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基,環烷基環包含3至20個碳原子,較佳包含3至12個碳原子,較佳包含3至10個碳原子,更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等;多環環烷基包括螺環、稠環和橋環的環烷基。環烷基可以是取代的或非取代的,當經取代時,取代基可以在任何可使用的連接點上經取代,所述取代基較佳獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基,其包含3至20個環原子,其中一個或多個環原子為選自氮、氧或S(O)m(其中m是整數0至2)的雜原子,但不包括-O-O-、-O-S-或-S-S-的環部分,其餘環原子為碳。較佳包含3至12個環原子,其中1~4個是雜原子;更佳 包含3至10個環原子,其中1-4是雜原子;更佳包含5至6個環原子;其中1-3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、四氫吡喃基、1,2.3.6-四氫吡啶基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基等。多環雜環基包括螺環、稠環和橋環的雜環基。
雜環基可以是取代的或非取代的,當經取代時,取代基可以在任何可使用的連接點上經取代,所述取代基較佳獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“芳基”指6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團,其為具有共軛的π電子體系的多環(即其帶有相鄰對碳原子的環)基團,較佳為6至10員,例如苯基和萘基。所述芳基環可以稠合於雜芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為芳基環,其非限制性實例包括:
芳基可以是取代的或非取代的,當經取代時,取代基可以在任何可使用的連接點上經取代,所述取代基較佳獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系,其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員,更佳為5員或6員,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、四唑基等。所述雜芳基環可以稠合於芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為雜芳基環,其非限制性實例包括:
雜芳基可以是取代的或非取代的,當經取代時,取代基可以在任何可使用的連接點上經取代,所述取代基較佳獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基和-C(O)OR5中的一個或多個取代基所取代。
術語“氧代基”指=O。
術語“環烷基氧基”指環烷基-O-。
術語“雜環基烷基”指烷基經一個或多個雜環基取代,其中烷基和雜環基如上所定義。術語“鹵烷基”指烷基經一個或多個鹵素取代,其中烷基如上所定義。
術語“羥基”指-OH。
術語“羥烷基”指經羥基取代的烷基,其中烷基如上所定義。
術語“鹵素”指氟、氯、溴或碘。
術語“胺基”指-NH2。
術語“氰基”指-CN。
術語“硝基”指-NO2。
“視需要”或“視需要地”意味著隨後所描述的事件或環境可以但不必發生,該說明包括該事件或環境發生或不發生地場合。例如,“視需要經烷基取代的雜環基團”意味著烷基可以但不必須存在,該說明包括雜環基團經烷基取代的情形和雜環基團不經烷基取代的情形。
“取代的”指基團中的一個或多個氫原子,較佳為最多5個,更佳為1~3個氫原子彼此獨立地經相應數目的取代基取代。不言而喻,取代基僅處在它們的可能的化學位置,本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如,具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。
“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/醫藥上可接受之鹽或前體藥物與其他化學組分的混合物,以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥,利於活性成分的吸收進而發揮生物活性。
“醫藥上可接受之鹽”是指本發明化合物的鹽,這類鹽用於哺乳動物體內時具有安全性和有效性,且具有應有的生物活性。
其中:R5如通式(I)中所定義。
為了完成本發明的目的,本發明採用如下技術方案:
通式(IV)的化合物和通式(V)的化合物反應在鹼性條件下,在催化劑存在下發生suzuki偶聯反應得到通式(II)的化合物,其中:提供鹼性條件的試劑包括有機鹼和無機鹼類,所述的有機鹼類包括,但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、乙酸鉀、第三丁醇鈉、第三丁醇鉀和正丁醇鈉,所述的無機鹼類包括,但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰;所述的催化劑包括,但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、雙(二亞芐基丙酮)鈀、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1'-雙(二苄基磷)二氯二戊鐵鈀或三(二亞苄基丙酮)二鈀,較佳為[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀;上述反應較佳在溶劑中進行,所用溶劑包括,但不限於:醋酸、甲醇、乙醇、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二 氧六環、乙二醇二甲醚、水或N,N-二甲基甲醯胺及其混合物;其中:X為鹵素;W為或環A、環B、G、R1、R3、R6、n和s如通式(II)中所定義。
第一步,通式(III-1)的化合物和水合肼反應得到通式(III-2)的化合物;第二步,通式(III-2)的化合物和通式(III-3)的化合物反應得到通式(IIIA)的化合物;第三步,通式(IIIA)的化合物和通式(V)的化合物反應在鹼性條件下,在催化劑存在下發生suzuki偶聯反應得到 通式(III)的化合物,其中:提供鹼性條件的試劑包括有機鹼和無機鹼類,所述的有機鹼類包括,但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、乙酸鉀、第三丁醇鈉、第三丁醇鉀和正丁醇鈉,所述的無機鹼類包括,但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰;所述的催化劑包括,但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、雙(二亞芐基丙酮)鈀、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1'-雙(二苄基磷)二氯二戊鐵鈀或三(二亞苄基丙酮)二鈀,較佳為[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀;上述反應較佳在溶劑中進行,所用溶劑包括,但不限於:醋酸、甲醇、乙醇、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二氧六環、乙二醇二甲醚、水或N,N-二甲基甲醯胺及其混合物;其中:X為鹵素;W為或 環A、環B、R1、R3、R6、n和s如通式(III)中所定義。
第一步,通式(III-1)的化合物和水合肼反應得到通式(III-2)的化合物;第二步,通式(III-2)的化合物和通式(V)的化合物反應在鹼性條件下,在催化劑存在下發生suzuki偶聯反應得到通式(IIIB)的化合物;第三步,通式(IIIB)的化合物和通式(III-3)的化合物反應得到通式(III)的化合物;其中:提供鹼性條件的試劑包括有機鹼和無機鹼類,所述的有機鹼類包括,但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、乙酸鉀、第三丁醇鈉、第三丁醇鉀和正丁醇鈉,所述的無機鹼類包括,但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰; 所述的催化劑包括,但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、雙(二亞芐基丙酮)鈀、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1'-雙(二苄基磷)二氯二戊鐵鈀或三(二亞苄基丙酮)二鈀,較佳為[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀;上述反應較佳在溶劑中進行,所用溶劑包括,但不限於:醋酸、甲醇、乙醇、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二氧六環、乙二醇二甲醚、水或N,N-二甲基甲醯胺及其混合物;其中:X為鹵素;W為或環A、環B、R1、R3、R6、n和s如通式(III)中所定義。
第一步,通式(III-1)的化合物和水合肼反應得到通式(III-2)的化合物;第二步,通式(III-2)的化合物和通式(III’a)的化合物反應在鹼性條件下,在催化劑存在下發生suzuki偶聯反應得到通式(III’b)的化合物;第三步,通式(III’b)的化合物和通式(III-3)的化合物反應得到通式(III’)的化合物;其中:提供鹼性條件的試劑包括有機鹼和無機鹼類,所述的有機鹼類包括,但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、乙酸鉀、第三丁醇鈉、第三丁醇鉀和正丁醇鈉,所述的無機鹼類包括,但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、醋酸鉀、碳酸銫、氫氧化鈉和氫氧化鋰;所述的催化劑包括,但不限於鈀/碳、雷尼鎳、四-三苯基膦鈀、二氯化鈀、醋酸鈀、雙(二亞芐基丙酮)鈀、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、1,1'-雙(二苄基磷)二氯二戊鐵鈀或三(二亞苄基丙酮)二鈀,較佳為[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀; 上述反應較佳在溶劑中進行,所用溶劑包括,但不限於:醋酸、甲醇、乙醇、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二氧六環、乙二醇二甲醚、水或N,N-二甲基甲醯胺及其混合物;其中:X為鹵素;W為或環A、R1、R3、R6、n和s如通式(III)中所定義。
以下結合實施例用於進一步描述本發明,但這些實施例並非限制著本發明的範圍。
化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀,測定溶劑為氘代二甲基亞碸(DMSO-d 6 ),氘代氯仿(CDCl3),氘代甲醇(CD3OD),內標為四甲基矽烷(TMS)。
MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商:Thermo,型號:Finnigan LCQ advantage MAX)。
HPLC的測定使用安捷倫1200DAD高壓液相層析儀(Sunfire C18 150×4.6mm層析柱)和Waters 2695-2996高壓液相層析儀(Gimini C18 150×4.6mm層析柱)。
手性HPLC分析測定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)。
薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板,薄層層析法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm,薄層層析分離純化產品採用的規格是0.4mm~0.5mm。
柱層析一般使用煙臺黃海矽膠200至300目矽膠為載體。
手性製備柱層析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)。
CombiFlash快速製備儀使用Combiflash Rf200(TELEDYNE ISCO)。
激酶平均抑制率及IC50值的測定用NovoStar酶標儀(德國BMG公司)。
本發明的已知的起始原料可以採用或按照本領域已知的方法來合成,或可購買自ABCR GmbH & Co.KG,Acros Organics,Aldrich Chemical Company,韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。
實施例中無特殊說明,反應能夠均在氬氣氛或氮氣氛下進行。
氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。
氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。
加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。
氫化反應通常抽真空,充入氫氣,反復操作3次。
微波反應使用CEM Discover-S 908860型微波反應器。
實施例中無特殊說明,溶液是指水溶液。
實施例中無特殊說明,反應的溫度為室溫,為20℃~30℃。
實施例中的反應進程的監測採用薄層層析法(TLC),反應所使用的展開劑,純化化合物採用的柱層析的沖提劑的體系和薄層層析法的展開劑體系包括:A:二氯甲烷/甲醇體系,B:正己烷/乙酸乙酯體系,C:石油醚/乙酸乙酯體系,D:丙酮,E:二氯甲烷/丙酮體系,F:乙酸乙酯/二氯甲烷體系,G:乙酸乙酯/二氯甲烷/正己烷,H:乙酸乙酯/二氯甲烷/丙酮,溶劑的體積比如化合物的極性不同而進行調節,也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。
將4-氯-6-苯基嘧啶-2-胺1a(2g,9.75mmol,採用習知的方法“Bioorganic & Medicinal Chemistry Letters,2011,21(8),2497-2501”製備而得)和N-碘代丁二醯亞胺(2.6g,11.7mmol)溶於30mL乙酸中,加畢,反應16小時。反應液中加入200mL飽和碳酸氫鈉,用乙酸乙酯萃取(100mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌(100mL),無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,殘餘物用矽膠層析法以沖提劑體系B純化,得標題化合物1b(2.88g,產率:89%)。
MS m/z(ESI):332.2[M+1]
在氮氣氛下,依次加入化合物1b(2.88g,8.7mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-6-(三氟甲基)吡啶1c(2.7g,9.17mmol,採用習知的方法 “Journal of Medicinal Chemistry,2012,55(5),1898-1903”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(0.64g,0.87mmol)和碳酸鉀(3.6g,26.1mmol)溶解於66mL 1,4-二氧六環和水(V/V=10:1)的混合溶液中,加熱至83℃,攪拌3小時。停止反應,冷卻至室溫,過濾,濾液中加入200mL乙酸乙酯,再用飽和氯化鈉溶液洗滌(100mL),無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,殘餘物用矽膠層析法以沖提劑體系B純化,得標題化合物1d(2.4g,產率:76%)。
MS m/z(ESI):365.4[M+1]
依次加入化合物1d(100mg,0.275mmol)和85%水合肼(62mg,2.747mmol)溶於10mL乙醇中,回流條件下,攪拌反應17小時。停止反應,冷卻至室溫,反應液中加入30mL水,用乙酸乙酯萃取(30mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌(50mL×2),無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,得粗製品標題化合物1e(85mg),其不經純化直接用於下一步反應。
MS m/z(ESI):361.4[M+1]
依次將粗製品1e(85mg,0.275mmol)加入2mL原甲酸(三)乙酯,140℃條件下,攪拌反應0.5小時。停止反應,冷卻至室溫,反應液減壓濃縮,所得殘餘物用高效液相層析法純化,得標題化合物1(6mg,產率:6.9%)。
MS m/z(ESI):371.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.38(s,1H),8.42(brs,2H),7.59(s,1H),7.42(s,1H),7.35-7.31(m,5H),2.48(s,3H)。
將化合物1a(500mg,2.431mmol)和N-溴代丁二醯亞胺(519mg,2.918mmol)溶於16mL N,N-二甲基甲醯胺中,加畢,反應1小時。反應液中加入50mL水,用乙酸乙酯萃取(50mL×3),合併有機相,有機相依次用水(100mL×3)和飽和氯化鈉溶液(200mL)洗滌,無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,得粗製品標題化合物2a(698 mg),其不經純化直接用於下一步反應。
MS m/z(ESI):284.2[M+1]
依次將粗製品2a(692mg,2.432mmol)和85%水合肼(1.432mg,24.32mmol)溶於20mL乙醇中,回流條件下,攪拌反應1小時。反應液冷卻至室溫,攪拌反應0.5小時。過濾,濾餅依次用乙醇(3mL×2)和乙醚(3mL×2)洗滌,收集濾餅,濾餅乾燥,得粗製品標題化合物2b(480mg),其不經純化直接用於下一步反應。
MS m/z(ESI):280.3[M+1]
將粗製品2b(480mg,1.713mmol)加入5mL的原甲酸(三)乙酯中,140℃條件下,攪拌反應15分鐘。停止反應,冷卻至室溫,過濾,濾餅依次用乙醇(3mL×3)和乙醚(5mL×3)洗滌,收集濾餅,濾餅乾燥,得標題化合物2c(348mg,產率:62.4%)。
MS m/z(ESI):290.3[M+1]
在氬氣氛下,依次將化合物2c(120mg,0.414mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1H-吡唑2d(120mg,0.620mmol,採用習知的方法“Journal of the American Chemical Society,2014,136(11),4287-4299”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(30mg,0.041mmol)和碳酸鉀(171mg,1.241mmol)溶解於6mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×3),有機相減壓濃縮,殘餘物高效液相層析法純化,得標題化合物2(33mg,產率:28.7%)。
MS m/z(ESI):278.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 12.79(brs,1H),9.32(s,1H),7.98(brs,2H),7.41-7.37(m,7H)。
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)喹啉3a(106mg,0.414mmol,採用習知的方法“Journal of the American Chemical Society,2013,135(50),18730-18733”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於6mL 1,4-二 氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌2小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(50mL×3),有機相減壓濃縮,殘餘物用矽膠層析法以沖提劑體系A純化,得標題化合物3(49mg,產率:41.9%)。
MS m/z(ESI):339.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.38(s,1H),8.88-8.87(m,1H),8.29-8.27(m,1H),8.20(brs,2H),8.05-8.04(m,1H),7.88-7.85(m,1H),7.54-7.50(m,2H),7.37-7.34(m,2H),7.24-7.20(m,3H)。
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶4a(105mg,0.414mmol,採用習知的方法“Organic Syntheses,2005,82,126-133”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於10mL 1,4-二氧六環和水(V/V=4:1) 的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×4),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物4(20.7mg,產率:17.8%)。
MS m/z(ESI):337.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.36(s,1H),8.38(brs,2H),7.36-7.32(m,5H),7.19-7.14(m,2H),2.35(s,3H)。
在氬氣氛下依次加入6-溴-8-甲基喹啉5b(444mg,2.00mmol,採用習知的方法“Journal of Organic Chemistry,2014,79(11),5379-5385”製備而得)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧雜環戊硼烷)5a(508mg,2.00 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(292mg,0.40mmol)和乙酸鉀(588mg,6.00mmol)溶解於10mL乙二醇二甲醚溶液中,加熱至80℃,攪拌12小時。停止反應,冷卻至室溫,過濾,濾液加入20mL乙酸乙酯,依次用水(10mL)洗滌,飽和氯化鈉溶液(10mL)洗滌,用無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用薄層層析法以展開劑體系B純化,得到標題化合物5c(320mg,產率:59.5%)。
MS m/z(ESI):270.1[M+1]
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、5c(130mg,0.482mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於5mL 1,4-二氧六環和水(V/V=4:1)的混合溶液中,加熱至90℃,攪拌2小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×3),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物5(32mg,產率:26.4%)。
MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 19.37(s,1H),8.90-8.89(m,1H),8.21-8.19(m,3H),7.78(s,1H),7.51-7.49(m,2H),7.37-7.36(m,2H),7.22-7.20(m,3H),2.60(s,3H)。
在氬氣氛下依次加入5-溴-7-氟-1H-吲唑6a(1.27g,5.90mmol,採用專利申請“WO2012037410”公開的方法製備而得)、化合物5a(2.25g,8.86mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(432mg,0.56mmol)和乙酸鉀(1.74g,17.7mmol)溶解於40mL乙二醇二甲醚溶液中,加熱至80℃,攪拌12小時。停止反應,冷卻至室溫,加入10mL乙酸乙酯,過濾,濾液減壓蒸餾,殘餘物用矽膠層析法以沖提劑體系B純化,得到標題化合物6b(1.178g,產率:76.0%)。
MS m/z(ESI):263.2[M+1]
在氬氣氛下,依次將化合物2c(117mg,0.348mmol)、6b(100mg,0.382mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.035mmol)和碳酸鉀(192mg,1.387mmol)溶解於10mL 1,4-二氧六環和水(V/V=4:1)的混合溶液中,加熱至90℃,攪拌2小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×3),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物6(13mg,產率:10.8%)。
MS m/z(ESI):346.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 13.65(brs,1H),9.34(s,1H),8.13-8.11(m,3H),7.55(s,1H),7.35-7.33(m,2H),7.23-7.22(m,3H),7.05-7.02(m,1H)。
在氬氣氛下依次加入6-溴-8-氟喹啉7a(226mg,1.00 mmol,採用習知方法“Journal of Medicinal Chemistry,2010,53(10),4066-4084”製備而得)、化合物5a(305mg,1.20mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(146mg,0.20mmol)和乙酸鉀(294mg,3.00mmol)溶解於10mL乙二醇二甲醚溶液中,加熱至80℃,攪拌12小時。停止反應,冷卻至室溫,過濾,濾液減壓蒸餾,殘餘物用CombiFlash快速製備儀以沖提劑體系B純化,得到標題化合物7b(220mg,產率:80.1%)。
MS m/z(ESI):274.1[M+1]
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、7b(100mg,0.414mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於6mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(40mL×4),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物7(20mg,產率:16.3%)。
MS m/z(ESI):357.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.38(s,1H),8.94-8.93(m,1H),8.35-8.33(m,1H),8.26(brs,2H),7.86(s,1H),7.62-7.59(m,1H),7.40-7.36(m,3H),7.26-7.24(m,3H)。
在氬氣氛下依次加入5-溴-4,6-二氯嘧啶-2-胺8a(5g,20.585mmol,採用專利申請“US20100331294”公開的方法製備而得)、4,4,5,5-四甲基-2-(5-甲基呋喃-2-基)-1,3,2-二氧雜戊硼烷8b(4.283g,20.585mmol,採用習知的方法“Organometallics,2015,34(7),1307-1320”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(1.506g,2.058mmol)和碳酸鉀(8.535g,61.756mmol)溶解於150mL 1,4-二氧六環和水(V/V=4:1)的混合溶液中,攪拌2小時。停止反應,反應液中加入200mL水,乙酸乙酯萃取(200mL×3),有機相加入100-200目二氧化矽,減壓濃縮,殘餘物用CombiFlash快速製備儀以沖提劑體系B純化,得標題化合物8c(2.0g,產率:33.7%)。
MS m/z(ESI):288.2[M+1]
依次將化合物8c(1.88g,6.516mmol)和15mL 85%水合肼溶於120mL乙醇中,攪拌反應17小時。停止反應,過濾,乾燥濾餅,得粗製品標題化合物8d(1.5g),其不經純化直接用於下一步反應。
MS m/z(ESI):284.3[M+1]
依次將粗製品8d(1.5g,5.279mmol)加入20mL的原甲酸(三)乙酯中,140℃條件下,攪拌反應15分鐘。停止反應,冷卻至室溫,過濾,濾餅用正己烷洗滌(20mL×2),乾燥,得粗製品標題化合物8e(1.13g,產率:72.8%)。
MS m/z(ESI):294.3[M+1]
在氬氣氛下,依次將粗製品8e(140mg,0.476mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-6-(三氟甲基)吡啶8f(205mg,0.714mmol,採用習知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(35mg,0.048mmol)和碳酸鉀(197mg,1.428mmol)溶解於6mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90 ℃,攪拌2.5小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(50mL×3),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物8(80mg,產率:44.9%)。
MS m/z(ESI):375.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.30(s,1H),8.26(brs,2H),7.68(s,1H),7.64(s,1H),6.70-6.69(m,1H),6.20-6.19(m,1H),2.60(s,3H),2.03(s,3H)。
在氬氣氛下依次加入5-溴-7-(三氟甲基)-1H-吲唑9a(0.5g,1.88mmol,採用專利申請“WO2012056372”公開的方法製備而得)、化合物5a(575mg,2.26mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(275mg,0.38mmol)和乙 酸鉀(554mg,5.66mmol)溶解於10mL乙二醇二甲醚溶液中,加熱至80℃,攪拌2小時。停止反應,冷卻至室溫,過濾,濾液減壓蒸餾,殘餘物用CombiFlash快速製備儀以沖提劑體系C純化,得到標題化合物9b(270mg,產率:45.9%)。
MS m/z(ESI):313.2[M+1]
在氬氣氛下,依次將化合物2c(117mg,0.348mmol)、9b(35mg,0.11mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.035mmol)和碳酸鉀(192mg,1.387mmol)溶解於5mL 1,4-二氧六環和水(V/V=4:1)的混合溶液中,加熱至90℃,攪拌2小時。停止反應,反應液中加入10mL水,二氯甲烷和甲醇(V/V=8:1)混合溶液萃取(20mL×3),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物6(10mg,產率:22%)。
MS m/z(ESI):396.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 13.66(s,1H),9.36(s,1H),8.25-8.09(m,4H),7.53(s,1H),7.33-7.31(m,2H),7.25-7.23(m,3H)。
在氬氣氛下,依次將化合物2c(140mg,0.482mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1H-吲唑10a(141mg,0.579mmol,採用習知方法“Journal of Medicinal Chemistry,2014,57(9),3856-3873”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(35mg,0.048mmol)和碳酸鉀(200mg,1.448mmol)溶解於12mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,二氯甲烷和水(V/V=8:1)混合溶液萃取(30mL×3),有機相減壓濃縮,殘餘物用高效液相層析法純化,得標題化合物10(8.6mg,產率:5.4%)。
MS m/z(ESI):328.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 13.05(brs,1H),9.33(s,1H),8.05-8.01(m,3H),7.75(s,1H),7.53-7.41(m,1H),7.35-7.33(m,2H),7.20-7.07(m,4H)。
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶11a(91mg,0.414mmol,採用習知的方法“Organic Letters,2009,11(16),3586-3589”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於6mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×3),有機相減壓濃縮,殘餘物高效液相層析法純化,得標題化合物11(27mg,產率:24.8%)。
MS m/z(ESI):317.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.25(brs,2H),7.32-7.30(m,5H),6.97(s,2H),2.32(s,6H)。
在氬氣氛下,依次將化合物2c(100mg,0.345mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶12a(91mg,0.414mmol,採用習知的方法“Journal of the American Chemical Society,2014,136(11),4133-4136”製備而得)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(25mg,0.034mmol)和碳酸鉀(143mg,1.034mmol)溶解於6mL 1,4-二氧六環和水(V/V=5:1)的混合溶液中,加熱至90℃,攪拌3小時。停止反應,反應液中加入50mL水,乙酸乙酯萃取(30mL×3),有機相減壓濃縮,殘餘物高效液相層析法純化,得標題化合物12(6.8mg,產率:6.5%)。
MS m/z(ESI):303.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.29-8.26(m,3H),7.32-7.25(m,6H),6.99(s,1H),2.39(s,3H)。
氬氣氛下將化合物2c(1.0g,3.45mmol)、氰化鋅(484mg,4.13mmol)、鋅(22mg,0.34mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(124mg,0.17mmol)和三(二亞苄基丙酮)二鈀(156mg,0.17mmol)溶於30mL N,N-二甲基甲醯胺,60℃條件下,反應12小時。反應結束,矽藻土過濾,濾餅用甲醇洗滌,濾液中加入30mL水,二氯甲烷和甲醇(V/V=8:1)混合溶液萃取(30mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用矽膠柱層析法以沖提劑A體系純化,得標題化合物13(650mg,產率:80.0%)。
MS m/z(ESI):237.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.24(brs,1H),8.83(brs,1H),8.64(s,1H),7.92-7.89(m,2H),7.59-7.57(m,3H)。
將4-氯-6-(4-氯苯基)嘧啶-2-胺14a(11g,38.03mmol,採用專利申請“DE102006008880A1”公開的方法製備而得)和N-溴代丁二醯亞胺(7.11g,39.93mmol)溶於300mL N,N-二甲基甲醯胺中,加畢,攪拌反應2小時。反應液中加入1L水,用乙酸乙酯萃取(300mL×4),合併有機相,有機相依次用水(100mL×3)和飽和氯化鈉溶液(200mL×2)洗滌,無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,得粗製品標題化合物14b(12g),產物不經純化直接用於下一步反應。
MS m/z(ESI):318.2[M+1]
依次將粗製品化合物14b(12g,37.62mmol)和40mL 85%水合肼溶於400mL乙醇中,攪拌反應17小時。反應液過濾,濾餅依次用乙醇(50mL)和正己烷(100mL×2)洗滌,收集濾餅,濾餅乾燥,得粗製品標題化合物14c(10.28g),產物不經純化直接用於下一步反應。
MS m/z(ESI):314.3[M+1]
將粗製品化合物14c(2g,6.36mmol)和1.16mL的原甲酸(三)乙酯(1.04g,6.99mmol)加入50mL乙醇中,回流條件下,攪拌反應4小時。反應液冷卻至室溫,減壓濃縮,殘餘物中加入51mL乙醇和正己烷(V/V=1:50)混合溶液攪拌,過濾,收集濾餅,得標題化合物14d(2g,產率:96.9%)。
MS m/z(ESI):324.3[M+1]
氬氣氛下,依次將化合物14d(250mg,770.27μmol)、化合物1c(265.36mg,924.32μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(56.36mg,77.03μmol)、碳酸鉀(319.36mg,2.31mmol)加入10mL 1,4-二氧六環和水(V/V=4:1)的混合溶劑中,加熱至90℃,攪拌2小時。反應液冷卻至室溫,減壓濃縮,殘餘物用CombiFlash快速製備儀以沖提劑體系B純化,所得粗製品用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物14(64.4mg,產率:20.7%)。
MS m/z(ESI):405.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.39(s,1H),8.46(brs,2H),7.58(s,1H),7.49(s,1H),7.43-7.35(m,4H),2.50(s, 3H)。
在氬氣氛下,依次將4,6-二氯嘧啶-2-胺15a(10g,60.98mmol,阿達馬斯試劑有限公司)、(4-氟苯基)硼酸15b(8.53g,60.98mmol,韶遠科技上海有限公司)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(4.46g,6.10mmol)和碳酸鉀(16.83g,121.96mmol)加入250mL 1,4-二氧六環和水(V/V=4:1)的混合溶劑中,加熱至60℃,攪拌3小時。反 應液冷卻至室溫,加入300mL水,用乙酸乙酯(150mL×3)萃取,合併有機相,有機相減壓濃縮,殘餘物用矽膠層析法以沖提劑體系B純化,得到標題化合物15c(11.0g,產率:76.0%)。
MS m/z(ESI):224.3[M+1]
將化合物15c(11.0g,49.19mmol)溶於100mL N,N-二甲基甲醯胺中,分批加入N-溴代丁二醯亞胺(8.75g,49.19mmol),攪拌1小時。反應液中加入400mL水,用乙酸乙酯萃取(100mL×3),合併有機相,有機相依次用水(100mL×3)和飽和氯化鈉溶液(200mL)洗滌,無水硫酸鈉乾燥,過濾,收集濾液,濾液減壓濃縮,得粗製品標題化合物15d(6.0g),產品不經純化直接用於下一步反應。
MS m/z(ESI):301.9[M+1]
依次將粗製品化合物15d(5.5g,18.18mmol)和10mL 85%水合肼溶於20mL乙醇中,回流條件下,攪拌反應1小時。反應液冷卻至室溫,攪拌反應0.5小時。過濾,濾餅依次用乙醇(3mL×2)和乙醚(3mL×2)洗滌,收集濾餅,真空乾燥,得粗製品標題化合物15e(4.4g),產品不經純化直接用於下一步反應。
MS m/z(ESI):298.1[M+1]
依次將粗製品化合物15e(500mg,1.68mmol)和原甲酸(三)乙酯(497mg,3.35mmol)加入20mL乙醇中,回流3小時。反應液冷卻至室溫,過濾,濾餅2mL乙醇洗滌一次,收集濾餅,得粗製品標題化合物15f(460mg),產物不經純化直接下一步反應。
MS m/z(ESI):307.9[M+1]
氬氣氛下,將粗製品化合物15f(120mg,389.47μmol)、化合物4a(138.24mg,545.26μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(28.50mg,38.95μmol)、碳酸鉀(161.48mg,1.17mmol)加入6.0mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至90℃,攪拌2小時。反應液冷卻至室溫,加入50mL水,用乙酸乙酯萃取(30mL×3),合併有機相,有機相減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物15(22mg,產率:15.9%)。
MS m/z(ESI):355.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.38(brs,2H),7.40-7.37(m,2H),7.20-7.18(m,4H),2.37(s,3H)。
氬氣氛下,依次將化合物15f(100mg,324.56μmol)、化合物1c(111.81mg,389.47μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(23.73mg,32.46μmol)、碳酸鉀(89.71mg,649.12μmol)加入6.0mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至90合,攪拌2小時。反應液冷卻至室溫,加入20mL水,用乙酸乙酯萃取(10mL×3),合併有機相,有機相減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物16(34mg,產率:26.9%)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.40(brs,2H),7.56(s,1H),7.43(s,1H),7.34-7.37(m,2H),7.13-7.17(m,2H),2.49(s,3H)。
依次將2-(甲硫基)-6-苯基嘧啶-4-胺17a(1.2g,5.5mmol,採用習知的方法“Chemical & Pharmaceutical Bulletin,1981,29(4),948-54”)和N-溴代丁二醯亞胺(1.1g,6.1mmol)加入20mL N,N-二甲基甲醯胺中,攪拌反應1小時。加入水,用乙酸乙酯萃取3次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得粗製品標題化合物17b(550mg),產物不經純化直接用於下一步反應。
MS m/z(ESI):296.0[M+1]
將粗製品化合物17b(250mg,0.84mmol)溶於10mL 1,4-二氧六環,滴加氯乙醛(249mg,1.27mmol),90℃條 件下,攪拌36小時。反應液冷卻至室溫,加入飽和碳酸氫鈉溶液,用乙酸乙酯萃取3次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用薄層層析法以展開劑體系A純化,得標題化合物17c(195mg,產率:72%)。
MS m/z(ESI):320.1[M+1]
將化合物17c(195mg,0.61mmol)溶於10mL二氯甲烷中,分批加入間氯過氧苯甲酸(316mg,1.83mmol),攪拌反應3小時。反應液中加入飽和碳酸氫鈉溶液,用乙酸乙酯萃取3次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得粗製品標題化合物17d(210mg),產物不經純化直接用於下一步反應。
MS m/z(ESI):352.1[M+1]
將粗製品化合物17d(210mg,0.59mmol)溶於10mL 1,4-二氧六環,滴加1mL 30%胺水,攪拌反應1小時。反應液中加入水,用二氯甲烷和甲醇(V/V=10:1)混合溶液萃取3次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用薄層層析法以展開劑體系A純化,得標題化合物17e(172mg,產 率:46%)。
MS m/z(ESI):289.1[M+1]
氬氣氛下,依次將化合物17e(80mg,0.28mmol)、化合物1c(95mg,0.332mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(20mg,28μmol)、碳酸鉀(87mg,0.56mmol)加入10mL 1,4-二氧六環和水(V/V=4:1)的混合溶劑中,加熱至90℃,攪拌3小時。反應液冷卻至室溫,加入水,用二氯甲烷和甲醇(V/V=8:1)混合溶液萃取3次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用薄層層析法以展開劑體系A純化,得標題化合物17(15mg,產率:14%)。
MS m/z(ESI):370.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 8.02(s,1H),7.99(brs,2H),7.57(s,1H),7.55(s,1H),7.43(s,1H),7.30(brs,5H),2.45(s,3H)。
在氬氣氛下,依次將化合物15a(11g,63.72mmol)、(2,4-二氟苯基)硼酸18a(10.06g,63.72mmol,上海書亞科技有限公司)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(4.66g,6.37mmol)和碳酸鉀(26.42g,191.17mmol)加入500mL 1,4-二氧六環和水(V/V=4:1)的混合溶劑中,90℃條件下,攪拌反應2小時。反應液過濾,濾液分液,水相用乙酸乙酯萃取(200mL×2),合併有機相,減壓濃縮,殘餘物用矽膠層析法以沖提劑體系B純化,得標題化合物18b(14.04g,產率:91.2%)。
MS m/z(ESI):242.3[M+1]
將化合物18b(14.04g,58.11mmol)溶於300mL的N,N-二甲基甲醯胺中,加入N-溴代丁二醯亞胺(11.38g, 63.92mmol),攪拌反應1小時。反應液倒入1L水中,攪拌30分鐘,過濾,收集濾餅,真空乾燥,得粗製品標題化合物18c(16g),產品不經純化直接進行下一步反應。
MS m/z(ESI):320.0[M+1]
將粗製品化合物18c(16g,49.92mmol)溶於250mL乙醇中,加入50mL 85%水合肼,攪拌反應17小時。反應液過濾,濾餅依次用乙醇(20mL×2)、正己烷(20mL×2)洗滌,乾燥濾餅,得標題化合物18d(12g,產率:76.1%)。
MS m/z(ESI):316.0[M+1]
將化合物18d(4g,12.65mmol)和原甲酸(三)乙酯(2.25g,15.18mmol)溶解於50mL乙醇中,回流條件下,攪拌反應2小時。停止反應,冷卻至室溫,反應液減壓濃縮,所得殘餘物用5mL乙醇打漿0.5小時,過濾,濾餅用無水乙醚(10mL×2)洗滌,乾燥濾餅,得標題化合物18e(3.85g,產率:93.4%)。
MS m/z(ESI):326.2[M+1]
氬氣氛下,依次將化合物18e(110mg,337.32μmol)、 化合物1c(145.26mg,505.98μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(24.7mg,33.73μmol)、碳酸鉀(93.1mg,674.64μmol)加入12mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至90℃,攪拌3小時。反應冷卻至室溫,加入水,用乙酸乙酯萃取(20mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物18(31mg,產率:22.6%)。
MS m/z(ESI):407.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.41(s,1H),8.50(brs,2H),7.55(brs,2H),7.44(s,1H),7.20-7.18(m,2H),2.49(s,3H)。
將4-氯-6-(2-氟苯基)嘧啶-2-胺19a(1.5g,6.71mmol,採用專利申請的公開的方法“WO 2014162039A1”製備而得)溶於20mL的N,N-二甲基甲醯胺中,加入N-溴代丁二醯亞胺(1.31g,7.38mmol),攪拌反應1小時。反應液中加入120mL水,攪拌,過濾,收集濾餅,真空乾燥,得粗製品標題化合物19b(1.9g),產品不經純化直接進行下一步反應。
MS m/z(ESI):301.9[M+1]
將粗製品化合物19b(1.9g,6.28mmol)溶於30mL乙醇中,加入85%水合肼(125.61mmol,7.18mL),60℃條件下,攪拌1小時。反應液過濾,濾餅用乙醇(20mL×2)洗滌,乾燥濾餅,得標題化合物19c(1.7g,產率:90.8%)。
MS m/z(ESI):297.8[M+1]
將化合物19c(1.7g,5.70mmol)加入10mL原甲酸(三)乙酯中,130℃條件下,攪拌0.5小時。反應液冷卻至室溫,過濾,濾餅中加入乙酸乙酯,攪拌,過濾,乾燥濾餅,得標題化合物19d(1.1g,產率:62.6%)。
MS m/z(ESI):307.9[M+1]
氬氣氛下,依次將化合物19d(200mg,649.12μmol)、化合物11a(151.32mg,649.12μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(47.45mg,64.91μmol)、碳酸鉀(179.16mg,1.30mmol)加入12mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至80℃,攪拌3小時。反應液冷卻至室溫,加入水,用乙酸乙酯萃取(20mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物19(26mg,產率:12%)。
MS m/z(ESI):335.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.38(s,1H),8.30(s,2H),7.41(brs,2H),7.19-7.22(m,1H),7.09-7.13(m,1H),6.91(s,2H),2.29(s,6H)。
氬氣氛下,依次將2-(二氟甲基)-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶20a(247.56mg,919.96μmol,採用專利申請“WO2011095625A1”公開的方法製備而得)、化合物18e(200mg,613.31μmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(44.88mg,61.33μmol)、碳酸鉀(254.29mg,1.84mmol)加入12mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至90℃,攪拌2小時。反應液冷卻至室溫,減壓濃縮,殘餘物用CombiFlash快速製備儀以沖提劑體系B純化,所得粗製品用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物20(26mg,產率:12%)。
MS m/z(ESI):389.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.40(s,1H),8.44(brs,2H),7.54(s,1H),7.40-7.18(m,4H),6.96-6.69(m,1H),2.44(s,3H)。
將4-氯-2-甲硫基-6-苯基-嘧啶21a(1.5g,6.34mmol,採用習知的方法“Tetrahedron,1994,50(34),10299-308”製備而得)溶於40mL乙腈中,加入2-胺基丙-1-醇(713.91mg,9.50mmol)和N,N-二異丙基乙胺(1.64g,12.67mmol),75℃條件下,反應72小時。反應液減壓濃縮,殘餘物用矽膠柱層析法以沖提劑體系A純化,得標題化合物21b(1.5g,產率:86%)。
MS m/z(ESI):276.2[M+1]
將化合物21b(1.5g,5.45mmol)溶於30mL N,N-二甲 基甲醯胺中,分批加入N-溴代丁二醯亞胺(969.50mg,5.45mmol),攪拌反應1小時。加入150mL水,用二氯甲烷和甲醇混合溶液(V/V=8:1)萃取3次,合併有機相,依次用水、飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用矽膠柱層析法以沖提劑體系A純化,得標題化合物21c(1.2g,產率:62.2%)。
MS m/z(ESI):354.1[M+1]
將化合物21c(2.3g,6.49mmol)溶於40mL二氯甲烷中,加入三乙胺(983.59mg,9.74mmol),滴加甲磺醯氯(892.44mg,7.79mmol),攪拌過夜。加入飽和碳酸氫鈉溶液,二氯甲烷萃取三次(30mL×3),合併有機相,飽和氯化鈉洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用矽膠柱層析法以沖提劑體系A純化,得標題化合物21d(1.2g,產率:55%)。
MS m/z(ESI):336.0[M+1]
將化合物21d(1.2g,3.57mmol)加入1,4二氧六環中,加入二氧化錳(3.14g,35.69mmol),90℃條件下,反應36小時。反應液冷卻至室溫,墊矽藻土過濾,濾餅用甲醇洗滌,濾液減壓濃縮,殘餘物用矽膠柱層析法以沖提 劑體系A純化,得標題化合物21e(750mg,產率:62.9%)。
MS m/z(ESI):334.1[M-1]
將化合物21e(320mg,957.41μmmol)溶於5mL三氟乙酸,滴加過氧化氫(0.5mL 957.41μmmol),攪拌1小時。反應液用飽和碳酸鈉溶液中和,二氯甲烷萃取(30mL×3),合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,得到粗製品化合物21f(350mg),產物不經純化直接用於下一步反應。
將粗製品化合物21f(350mg,955.68μmmol)溶於10mL 1,4-二氧六環,加入一水合胺(1.0mL,955.68μmmol,),40℃條件下,反應1小時。反應液減壓濃縮,加入水,二氯甲烷和甲醇混合溶液(V/V=8:1)萃取三次,合併有機相,有機相用飽和氯化鈉溶液洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用薄層層析法以展開劑體系A純化,得標題化合物21g(215mg,產率:74.2%)。
氬氣氛下,依次將化合物21g(215mg,709.20μmmol)、化合物11a(247.99mg,1.06mmol)、[1,1'-雙(二 苯基膦基)二茂鐵]二氯化鈀(51.84mg,70.92μmmol)、碳酸氫鈉(131.06mg,1.56mmol)加入12mL 1,4-二氧六環和水(V/V=5:1)的混合溶劑中,加熱至80℃,攪拌2小時。反應液冷卻至室溫,加入水,乙酸乙酯萃取(20mL×3),合併有機相,飽和氯化鈉溶液洗滌,硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物21(45mg,產率:19.3%)。
MS m/z(ESI):330.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 7.68(s,1H),7.65(s,2H),7.28(s,2H),7.24(s,3H),6.89(s,2H),2.31(s,6H),2.27(s,3H)。
將2-(氯甲基)-6-甲基吡啶22b(1g,7.06mmol)和碳酸鉀(1.46g,10.59mmol)溶於40mL乙腈,加入1-甲基哌嗪22a(848.57mg,8.47mmol,939.72uL),80℃條件下,反應17小時。反應液用矽膠柱層析法以沖提劑體系A純化,得標題化合物22c(1g,產率:69%)。
MS m/z(ESI):206.4[M+1]
氬氣氛下,將化合物22c(1g,4.87mmol)、化合物5a(146.13μmmol)、甲氧基(環辛二烯)銥(I)二聚體(78.44mg,292.26μmmol)溶於40mL正己烷。80℃條件下,反應17小時。反應液減壓濃縮,反應液用矽膠柱層析法以沖提劑體系B純化,得標題化合物22d(217mg,產率:13.5%)。
採用實施例5合成途徑,將第一步原料5b替換為22d,製得標題化合物22(27.6mg)。
MS m/z(ESI):415.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.26(brs,2H),7.32-7.28(m,6H),6.85(s,1H),3.38(s,2H),2.54(s,3H),2.43(s,3H),2.19-2.09(m,8H)。
採用實施例4合成途徑,將第一步原料化合物4a替換為2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-6-(三氟甲基)吡啶23a(採用習知的方法“Research on Chemical Intermediates,2013,39(4),1917-1926”製備而得),製得標題化合物23(11.8mg)。
MS m/z(ESI):391.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.40(s,1H),8.58(brs,2H),7.82(s,1H),7.65(s,1H),7.40-7.36(m,5H)。
採用實施例17合成途徑,將第五步原料化合物1c替換為化合物4a,製得標題化合物24(32mg)。
MS m/z(ESI):336.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 8.00(s,1H),7.93(s,2H),7.55(s,1H),7.31(s,5H),7.14(d,2H),2.33(s,3H)。
採用實施例4合成途徑,將第一步原料化合物4a替換為2-甲氧基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶25a(採用習知的方法“Chemistry-A European Journal,2017,23(24),5663-5667”製備而得),製得標題化合物25(11.8mg)。
MS m/z(ESI):333.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.33(s,1H),8.24(brs,2H),7.36-7.29(m,5H),6.76(s,1H),6.48(s,1H),3.77(s,3H),2.29(s,3H)。
在氬氣氛下,依次加入2-乙基-6-甲基吡啶26a(1g,8.25mmol,韶遠科技上海有限公司)、化合物5a(2.31g,9.08mmol)、(1Z,5Z)-cycloocta-1,5-diene;iridium;methyloxonium(164.10mg,247.57μmmol)和4-第三丁基-2-(4-第三丁基-2-吡啶基)吡啶(588mg,6.00mmol)於40mL正己烷溶液中,加熱至80℃,攪拌17小時。反應液減壓濃縮,殘餘物用矽膠柱層析法以沖提劑體系B純化,得到2-乙基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶26b(809mg,產率:39.7%)。
MS m/z(ESI):248.2[M+1]
採用實施例4合成途徑,將第一步原料化合物4a替換為26b,製得標題化合物26(136.6mg)。
MS m/z(ESI):331.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.25(brs,2H),7.32-7.28(m,5H),7.12(s,1H),6.80(s,1H),2.57-2.55(m,2H),2.37(s,3H),1.03-1.00(m,3H)。
採用實施例19合成途徑,將第四步原料化合物11a替換為化合物4a,製得標題產物27(73mg)。
MS m/z(ESI):355.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 8.39(s,1H),8.44(s,2H),7.49-7.45(m,2H),7.28-7.24(m,1H),7.17-7.14(m,2H),7.11(s,1H),2.33(s,3H)。
採用實施例15合成途徑,將第五步原料化合物4a替換為化合物11a,製得標題產物28(38mg)。
MS m/z(ESI):335.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.24(brs,2H),7.39-7.35(m,2H),7.16-7.11(m,2H),6.95(s,2H),2.33(s,6H)。
採用實施例15合成途徑將第一步原料化合物15b替換為(3-氟苯基)硼酸29a,得到化合物8-溴-7-(3-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺29b; 將實施例15的第五步原料化合物4a替換為化合物1c,製得標題化合物29(28mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.39(s,1H),8.46(brs,2H),7.60(s,1H),7.48(s,1H),7.36-7.34(m,1H),7.23-7.19(m,2H),7.10-7.08(m,1H),2.49(s,3H)。
採用實施例11合成途徑,將第一步原料化合物11a替換為2-環丙基-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶30a(採用專利申請“WO2011070131A1”公開的方法製備而得),製得標題化合物30(43mg)。
MS m/z(ESI):343.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.23(brs,2H),7.47-7.31(m,5H),6.92-6.87(m,2H),2.28(s,3H),1.98-1.90(m,1H),0.84-0.72(m,4H)。
採用實施例17合成途徑,將第五步原料化合物1c替換為化合物11a,值得標題化合物31(40mg)。
MS m/z(ESI):316.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 8.00(s,1H),7.99(s,2H),7.51(d,1H),7.31-7.29(m,2H),7.26-7.25(m,3H),6.91(s, 2H),2.30(s,6H)。
氬氣氛下,將6-氯-2-(甲硫基)嘧啶-4-胺32a(2.0g,11.39mmol,上海畢得科技有限公司)和(4-氟苯基)硼酸(2.39g,17.08mmol)溶於50mL甲苯中,依次加入四(三苯基膦)鈀(657.60mg,569.35μmmol)和碳酸鈉(2.41g,22.77mmol)和10mL水。90℃,攪拌3小時。加入水,乙酸乙酯萃取三次(50mL×3),合併有機相,飽和氯化鈉洗滌,無水硫酸鈉乾燥,過濾,濾液減壓濃縮,殘餘物中加入甲醇攪拌,過濾,收集濾餅,得6-(4-氟苯基)-2-(甲硫基)嘧啶-4-胺32b(1.3g,產率:48.5%)。
採用實施例17合成途徑,第一步原料化合物17a替換為化合物32b,製得8-溴-7-(4-氟苯基)咪唑并[1,2-c]嘧啶-5-胺32c; 將實施例17的第五步原料化合物1c替換為化合物11a,製得標題化合物32(70mg)。
MS m/z(ESI):334.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 7.98(d,1H),7.82(s,2H),7.52(d,1H),7.35-7.32(m,2H),7.28-7.08(m,2H),6.92(s,2H),2.32(s,6H)。
採用實施例19的合成途徑,將第四步原料化合物11a替換為化合物1c,製得標題化合物33(25mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.43(s,1H),8.48(brs,2H),7.55(s,1H),7.50-7.44(m,2H),7.42(s,1H),7.28-7.26(m,1H),7.15-7.12(m,1H),2.46(s,3H)。
採用實施例18合成途徑,將第五步原料化合物1c替換為化合物4a,製得標題化合物34(30.4mg)。
MS m/z(ESI):373.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.39(s,1H),8.46(brs,2H),7.55-7.54(m,1H),7.25-7.14(m,4H),2.36(s,3H)。
採用實施例15合成途徑,將第一步原料化合物15b替換為對甲苯基硼酸35a(上海達瑞化學有限公司),製得8-溴-7-(p-甲苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺35b;將實施例15第五步原料化合物15f替換為化合物 35b,製得標題化合物35(21.3mg)。
MS m/z(ESI):351.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.33(brs,2H),7.26-7.13(m,6H),2.36(s,3H),2.30(s,3H)。
採用實施例14合成途徑,將第四步原料化合物1c替換為化合物4a,製得標題化合物36(45.9mg)。
MS m/z(ESI):371.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.36(s,1H),8.40(brs,2H),7.43-7.35(m,4H),7.20-7.18(m,2H),2.38(s,3H)。
採用實施例2合成途徑,將第四步原料化合物2d替 換為4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶37a(上海畢得醫藥科技有限公司),製得標題化合物37(20mg)。
MS m/z(ESI):289.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.35(s,1H),8.47-8.46(m,2H),8.29(brs,2H),7.33-7.29(m,7H)。
採用實施例2合成途徑,將第四步原料化合物2d替換為2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶38a(阿達馬斯試劑有限公司),製得標題化合物38(20mg)。
MS m/z(ESI):323.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.36(s,1H),8.40(brs,2H),8.28-8.27(m,1H),7.47(s,1H),7.38-7.31(m,5H),7.23-7.22(m,1H)。
採用實施例18合成途徑,將第五步原料1c替換為2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-6-(三氟甲基)吡啶(採用習知的方法“Research on Chemical Intermediates,2013,39(4),1917-1926”製備而得),製得標題化合物39(19.8mg)。
MS m/z(ESI):427.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.66(s,1H),8.80(brs,2H),7.80(s,1H),7.70(s,1H),7.65-7.59(m,1H),7.29-7.22(m,2H)。
採用實施例18合成途徑,將第五步原料1c替換為化合物11a,製得標題化合物40(40mg)。
MS m/z(ESI):353.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.54(s,1H),8.43(brs, 2H),7.51-7.45(m,1H),7.21-7.10(m,2H),6.92(s,2H),2.31(s,6H)。
採用實施例18合成途徑,將第五步原料1c替換為化合物25a,製得標題化合物41(10.6mg)。
MS m/z(ESI):369.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.37(s,1H),8.33(brs,2H),7.50-7.48(m,1H),7.22-7.13(m,2H),6.76(s,1H),6.45(s,1H),3.76(s,3H),2.30(s,3H)。
採用實施例1合成途徑,將第四步原料原甲酸(三)乙酯替換為原乙酸三乙酯,製得標題化合物42(52mg)。
MS m/z(ESI):385.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 7.69(brs,2H),7.55(s,1H),7.41(s,1H),7.35-7.31(m,5H),2.96(s,3H),2.46(s,3H)。
採用實施例4合成途徑,將第一步原料化合物4a替換為1-異丙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶-2(1H)-酮43a(採用專利申請公開的方法“WO2011143426A1”製備而得),製得標題化合物43(31mg)。
MS m/z(ESI):347.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.33(s,1H),8.13(brs,2H),7.47-7.33(m,7H),6.38-6.35(m,1H),4.97-4.90(m,1H),0.99-0.97(m,6H)。
採用實施例18合成途徑,將第五步原料1c替換為化合物30a,製得標題化合物44(79.4mg)。
MS m/z(ESI):379.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.38(s,1H),8.33(brs,2H),7.52-7.46(m,1H),7.21-7.11(m,2H),6.90-6.85(m,2H),2.28(s,3H),1.95-1.85(m,1H),0.85-0.83(m,2H),0.72-0.70(m,2H)。
採用實施例18合成途徑,將第五步原料1c替換為化合物12a,製得標題化合物45(79.4mg)。
MS m/z(ESI):339.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.46(s,1H),8.40(brs,2H),8.31-8.30(m,1H),7.53-7.47(m,1H),7.22-7.11(m,3H),6.98-6.97(m,1H),2.39(s,3H)。
採用實施例15合成途徑,將第一步原料化合物15b替換為(2-氯-4-氟苯基)硼酸(韶遠科技上海有限公司),製得8-溴-7-(2-氯-4-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺46a;將實施例15的第五步原料化合物4a替換為化合物1c,製得標題化合物46(32mg)。
MS m/z(ESI):423.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.43(s,1H),8.54(brs,2H),7.54(s,1H),7.53-7.49(m,2H),7.47(s,1H),7.40-7.28(m,1H),2.47(s,3H)。
採用實施例22合成途徑,將原料化合物22c替換為4-((6-氯吡啶-2-基)甲基)嗎啉(採用專利申請“US20150361100A1”公開的方法製備而得),製得標題化合物47(34.8%)。
MS m/z(ESI):422.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.37(s,1H),7.58(s,1H),7.48-7.33(m,5H),7.05(s,1H),3.35-3.28(m,6H),2.11(s,2H),1.90-1.87(m,4H)。
採用實施例43合成途徑,將第一步原料化合物43a替換為嗎啉48a,製得標題化合物48(30.8mg)。
MS m/z(ESI):402.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.23(brs,2H),7.35-7.28(m,6H),6.85(s,1H),3.42-3.35(m,6H), 2.44(s,3H),2.13-2.05(m,4H)。
採用實施例15合成途徑,將第一步原料化合物15b替換為(4-氯-2-氟苯基)硼酸(韶遠科技上海有限公司),製得8-溴-7-(4-氯-2-氟苯基)-[1,2,4]三唑并[4,3-c]嘧啶-5-胺49a;將實施例15的第五步原料化合物4a替換為化合物1c,製得標題化合物49(20mg)。
MS m/z(ESI):422.7[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.43(s,1H),8.54(brs,2H),7.56-7.52(m,2H),7.45(s,1H),7.42-7.38(m,2H),2.48(s,3H)。
採用實施例15合成途徑,將第一步原料化合物15b替換為(4-氯-2-氟苯基)硼酸(韶遠科技上海有限公司),製得標題化合物50(30mg)。
MS m/z(ESI):389.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.41(s,1H),8.47(brs,2H),7.54-7.50(m,1H),7.44-7.39(m,2H),7.18(s,1H),7.14(s,1H),2.36(s,3H)。
氬氣氛下,依次將化合物15f(1.00g,3.25mmol)、化合物20a(1.05g,3.90mmol)、[1,1'-雙(二苯基膦基)二 茂鐵]二氯化鈀(238mg,324.6μmol)、碳酸氫鈉(682mg,8.11mmol)加入55mL 1,4-二氧六環和水(V/V=9:2)的混合溶劑中,加熱至95℃,攪拌17小時。反應液冷卻至室溫,過濾,濾液減壓濃縮,殘餘物用高效液相色製備(Waters 2767-SQ Detecor2,沖提體系:碳酸氫銨,水,乙腈)純化,得標題化合物51(50mg)。
MS m/z(ESI):371.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.37(s,1H),8.38(brs,2H),7.44(s,1H),7.39-7.36(m,2H),7.32(s,1H),7.19-7.14(m,2H),6.98-6.70(m,1H),2.46(s,3H)。
採用實施例14合成途徑,將原料化合物1c替換為化合物20a,製得標題化合物52(32mg)。
MS m/z(ESI):387.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.37(s,1H),8.39(brs,2H),7.40-7.43(m,2H),7.33-7.38(m,4H),6.84(t,1H),2.46(s,3H)。
採用實施例14合成途徑,將原料化合物1c替換為化合物2-(氟甲基)-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶53a(採用專利申請“WO201195625A1”公開的方法製備而得),製得標題化合物53(4mg)。
MS m/z(ESI):369.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.36(s,1H),8.36(brs,2H),7.42-7.32(m,3H),7.19(s,1H),5.42-5.30(m,2H),7.19-7.14(m,2H),2.40(s,3H)。
採用實施例14合成途徑,將原料化合物1c替換為化合物11a,製得標題化合物54(47.5mg)。
MS m/z(ESI):351.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.34(s,1H),8.27(brs,2H),7.39-7.33(m,4H),6.96(s,2H),2.34(s,6H)。
採用實施例15合成途徑,將原料化合物4a替換為化台物53a,製得標題化合物55(20mg)。
MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.36(s,1H),8.31(brs,2H),7.40-7.36(m,2H),7.20-7.13(m,4H),5.42-5.31(m,2H),2.41(s,3H)。
採用實施例19合成途徑,將原料化合物11a替換為化合物20a,製得標題化合物56(105.6mg)。
MS m/z(ESI):371.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.53(s,1H),8.50(brs,2H),7.47-7.42(m,2H),7.37(s,1H),7.31(s,1H),7.26-7.24(m,1H),7.13-7.11(m,1H),6.94-6.66(m,1H),2.41(s,3H)。
採用實施例19合成途徑,將原料化合物11a替換為化合物53a,製得標題化合物57(58mg)。
MS m/z(ESI):353.2[M+1]
1H NMR(400MHz,METHANOL-d 4)δ 9.29(s,1H),7.51-7.48(m,1H),7.43-7.41(m,1H),7.26-7.21(m,3H),7.04-6.99(m,1H),5.37-5.25(m,2H),2.45(s,3H)。
採用實施例18合成途徑,將原料化合物1c替換為化合物53a,製得標題化合物58(30mg)。
MS m/z(ESI):371.1[M+1]
1H NMR(400MHz,CD3OD)δ 9.29(s,1H),7.59-7.55(m,1H),7.27-7.25(m,2H),7.06-7.02(m,1H),6.91-6.86(m,1H),5.40-5.28(m,2H),2.48(s,3H)。
採用實施例49合成途徑,將原料化合物1c替換為化合物20a,製得標題化合物59(49.1mg)。
MS m/z(ESI):405.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ 9.42(s,1H),7.54-7.50(m, 1H),7.40-7.30(m,4H),6.97-6.69(m,1H),3.43(brs,2H),2.44(s,3H)。
測試例:生物學評價
測試例1、本發明化合物對腺苷A2a受體(adenosine A2a receptor,A2aR)cAMP訊息傳遞路徑,腺苷A2b受體(adenosine A2b receptor,A2bR)cAMP訊息傳遞路徑,腺苷A1受體(adenosine A1 receptor,A1R)cAMP訊息傳遞路徑和腺苷A3受體(adenosine A3 receptor,A3R)cAMP訊息傳遞路徑抑制活性的測定。
以下方法用來測定本發明化合物對腺苷A2a受體cAMP訊息傳遞路徑,腺苷A2b受體cAMP訊息傳遞路徑,腺苷A1受體cAMP訊息傳遞路徑和腺苷A3受體cAMP訊息傳遞路徑的抑制活性。實驗方法簡述如下:
一、實驗材料及儀器
1.CHO-K1/A2aR細胞(NM_000675.5)或CHO-K1/A2bR細胞(NM_000676.2)或CHO-K1/A1R細胞(NM_000674.2)或CHO-K1/A3R細胞(NM_000677.3)
2.胎牛血清(Gibco,10099-141)
3.博來黴素(Thermo,R25001)或G418(ENZO,ALX-380-013-G005)或嘌呤黴素(Thermo,10687-010)
4.DMEM/F12培養基(GE,SH30023.01)
5.細胞分離緩衝液(Thermo Fisher,13151014)
6.HEPES(Gibco,42360-099)
7.牛血清白蛋白(MP Biomedicals,219989725)
8.咯利普蘭(sigma,R6520-10MG)
9.腺苷脫胺酶(sigma,10102105001)
10.毛喉素(sigma,F6886)
11.2Cl-IB-MECA(Tocrics,1104/10)
12.N6-環戊基腺苷(Tocris,1702/50)
13.平衡鹽緩衝液(Thermo,14025-092)
14.cAMP動態2試劑盒(cAMP dynamic 2 kit)(Cisbio,62AM4PEB)
15.384孔板(Corning,4514)或(Nunc,267462#)
16.乙基咔唑(Torcis,1691/10)
17.PHERAstar多功能酶標儀(Cisbio,62AM4PEB)
二、實驗步驟
2.1腺苷A2a受體
CHO-K1/A2aR細胞用含有10%胎牛血清和800μg/ml博來黴素的DMEM/F12培養基進行培養。實驗時使用細胞分離緩衝液消化細胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡鹽緩衝液重懸細胞並計數,將細胞密度調整為106個/ml。在384孔板中每孔加入5μl細胞懸液,2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的受試化合物,室溫培養30分鐘。每孔再加入2.5μl用含有 20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的乙基咔唑,室溫培養30分鐘。化合物終濃度是:10000,2000,400,80,16,3.2,0.64,0.128,0.0256,0.00512,0.001024nM,乙基咔唑終濃度是20nM。細胞內cAMP濃度使用cAMP動態2試劑盒檢測。用cAMP裂解緩衝液按1:4的比例分別稀釋cAMP-d2和抗cAMP-Eu-穴狀化合物(Anti-cAMP-Eu-Cryptate)。每孔加入5μl稀釋後的cAMP-d2,再加入5μl稀釋後的抗cAMP-Eu-穴狀化合物,室溫避光培養1小時。採用PHERAstar多功能酶標儀讀取HTRF訊號值。用Graphpad Prism軟體計算化合物抑制活性的IC50值,見表1。
2.2腺苷A1受體
CHO-K1/A1R用含有10%胎牛血清和1mg/mlG418的DMEM/F12培養基進行培養。實驗時使用細胞分離緩衝液消化細胞,然後用含有20mM HEPES和0.1%牛血清白蛋白的平衡鹽緩衝液重懸細胞並計數,將細胞密度調整為5×105個/ml。在384孔板中每孔加入12.5μl細胞懸液,6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的受試化合物,室溫培養30分鐘。每孔再加入6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的毛喉素和N6-環戊基腺苷,室溫培養30分鐘。化合物終濃 度是:100000,10000,1000,100,10,1,0.1和0nM,毛喉素的終濃度是10μM,CPA的終濃度是10nM。細胞內cAMP濃度使用cAMP動態2試劑盒檢測。用cAMP裂解緩衝液按照1:4的比例分別稀釋cAMP-d2和抗cAMP-Eu-穴狀化合物。每孔加入12.5μl稀釋後的cAMP-d2,再加入12.5μl稀釋後的抗cAMP-Eu-穴狀化合物,室溫避光培養1小時。採用PHERAstar多功能酶標儀讀取HTRF訊號值。用Graphpad Prism軟體計算化合物抑制活性的IC50值,見表2。
2.3腺苷A3受體
CHO-K1/A3R用含有10%胎牛血清和10μg/ml嘌呤黴素的DMEM/F12培養基進行培養。實驗時使用細胞分離緩衝液消化細胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡鹽緩衝液重懸細胞並計數,將細胞密度調整為5×105/ml。在384孔板中每孔加入12.5μl細胞懸液,6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的受試化合物,室溫培養30分鐘。每孔再加入6.25μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的毛喉素和2Cl-IB-MECA,室溫培養30分鐘。化合物終濃度是:100000,10000,1000,100,10,1,0.1和0nM,毛喉素的終濃度是10μM,2Cl-IB-MECA的終濃度是5nM。細胞內cAMP濃度使用cAMP動態2試劑盒檢測。用cAMP裂 解緩衝液按照1:4的比例分別稀釋cAMP-d2和抗cAMP-Eu-穴狀化合物。每孔加入12.5μl稀釋後的cAMP-d2,再加入12.5μl稀釋後的抗cAMP-Eu-穴狀化合物,室溫避光培養1小時。採用PHERAstar多功能酶標儀讀取HTRF訊號值。用Graphpad Prism軟體計算化合物抑制活性的IC50值,見表2。
2.4腺苷A2b受體(adenosine A2b receptor,A2bR)
CHO-K1/A2bR用含有10%胎牛血清和1mg/ml G418的DMEM/F12培養基進行培養。實驗時使用細胞分離緩衝液消化細胞,用含有20mM HEPES和0.1%牛血清白蛋白的平衡鹽緩衝液重懸細胞並計數,將細胞密度調整為106個/ml。在384孔板中每孔加入5μl細胞懸液,2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的受試化合物,室溫培養30分鐘。每孔再加入2.5μl用含有20mM HEPES,0.1%牛血清白蛋白,54μM咯利普蘭和2.7U/ml腺苷脫胺酶的平衡鹽緩衝液配製的4×濃度的乙基咔唑(Torcis,1691/10),室溫培養30分鐘。化合物終濃度是:100000,10000,1000,100,10,1,0.1和0nM,乙基咔唑終濃度是1μM。細胞內cAMP濃度使用cAMP動態2試劑盒檢測。用cAMP裂解緩衝液按1:4的比例分別稀釋cAMP-d2和抗cAMP-Eu-穴狀化合物。每孔加入5μl稀釋後的cAMP-d2,再加入5μl稀釋後的抗cAMP-Eu-穴狀化合物,室溫避光培養1小時。採用PHERAstar多功能酶標儀 讀取HTRF訊號值。用Graphpad Prism軟體計算化合物抑制活性的IC50值。見表3。
結論:本發明化合物對腺苷A2a受體cAMP訊息傳遞路徑具有明顯的抑制活性。
結論:本發明化合物對腺苷A1受體和A3受體抑制活性作用較弱,說明本發明化合物對A2a受體具有高選擇性。
結論:本發明化合物對腺苷A2b受體抑制活性作用較 弱,說明本發明化合物對A2a受體具有高選擇性。
測試例2、本發明化合物小鼠腦通透性的測定
本發明化合物小鼠腦通透性採用如下實驗方法測定:
一.實驗材料與儀器
1.RED裝置(Device Inserts)(Thermo Scientific,QL21291110)
2.API 4000 Q-trap線性離子阱質譜儀(Applied Biosystems)
3.LC-30A超高壓液相層析系統(島津)
4.pH7.4 PBS(100mM,4℃冰箱保存)
5.C57小鼠,由傑思捷實驗動物有限公司提供,動物生產許可證號SCXK(滬)2013-0006。
二.實驗動物操作
C57小鼠4隻,雌性,12/12小時光/暗調節,溫度24±3℃恆溫,濕度50-60%,自由進食飲水。禁食一夜後分別灌胃給藥。給藥劑量20mg/kg,給藥組於給藥後0.5h採血後處死(採血量0.5ml),血樣置於肝素化試管中,3500rpm離心10min分離血漿,記為血漿1,於80℃保存;處死後的動物心臟灌流生理鹽水,去除腦組織中多餘血液,取腦組織,濾紙吸幹殘留的血液,記為腦組織1,80℃保存。另取3隻動物取空白血漿和腦組織2,處理方法同給藥組。
三.血漿蛋白結合平衡透析過程
3.1樣品製備
用DMSO溶解藥物化合物至20mM,得到儲備液I;移取適量儲備液I,用甲醇稀釋得到200μM稀釋儲備液II;移取10μl儲備液II于1.5ml Eppendorf管中,加入990μl空白血漿,混勻得到2μM血漿樣品2(DMSO含量0.2%),用於該濃度血漿蛋白結合率的測定。移取上述配好的50μl血漿樣品,記為T0,置於-4℃冰箱保存待測。
3.2實驗過程
取RED裝置將平衡透析管插至於96孔的底板中。取上述配製好的含待測物血漿樣品2及相應空白血漿樣品300μl,置於紅色標記的孔中(plasma chamber)。取500μl pH 7.4磷酸緩衝鹽溶液,置於並排紅色標記的另一孔中(buffer chamber)。按上述步驟處理方法,每個化合物每一個濃度為2個樣本。完畢用封條(sealing tape)覆蓋96孔板,並將整塊底板放至熱混儀中,以400rpm轉速,於37℃平衡4h。培養結束後,從熱混儀中取出96孔底板裝置,完成平衡透析。取25μl平衡後的血漿樣品或透析液樣品,加入25μl相對應的未平衡的不含藥的空白磷酸鹽緩衝液或不含藥的空白血漿,加入內標(乙腈配製)200μl,渦旋混合5min,離心10min(4000rpm),取上清液進行LC/MS/MS分析。T0樣品不經培養,直接採用上述建立的LC/MS/MS法分別測定總藥物(plasma chamber)及游離藥物(buffer chamber)與內標物層析峰面積比,計算游離百分率(fu plasma%)。
四.腦組織蛋白結合平衡透析過程
腦組織蛋白結合平衡透析過程:空白腦組織2按照稀釋因數=11的比例用pH7.4 PBS將腦組織製成空白腦勻漿,加入化合物配製成2μM腦勻漿,其餘與血漿蛋白結合的操作相同,採用建立的LC/MS/MS法分別測定總藥物(brain homo chamber)及游離藥物(buffer chamber)與內標物層析峰面積比,計算游離百分率(fu brain hom%)。
五.腦通透試驗數據計算方法
5.1採用建立的LC/MS/MS法分別測定小鼠給藥後0.5h的血漿1和腦組織1中的藥物濃度,此為總濃度(Ctotal,p和Ctotal,b);
5.2採用RED Device Inserts裝置,用平衡透析法分別測定化合物在小鼠血漿和腦組織中的蛋白結合率,從而計算出游離百分率(fu plasma%,fu brain%);血漿游離百分率(fu plasma%)Cbuffer/Cplasma×100%;腦勻漿游離百分率(fu brain hom%)=Cbuffer/Cbrain hom×100%;腦組織游離百分率(fu brain%)=fu brain hom/(Df-(Df-1)×fu brain hom)×100%;此處Df=11
5.3採用以下公式計算血腦通透指數Kp-unbound。
六.試驗結果與討論
結論:本發明化合物在腦中的游離藥物濃度低,透過血腦屏障能力弱,較少藥物進腦,可能產生的副作用低。
Claims (15)
- 一種通式(I)所示之化合物、或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,
- 如申請專利範圍第1項所述(I)之化合物、或其互變異 構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其為通式(III)所示的化合物:
- 如申請專利範圍第2或3項所述(I)之化合物、或其互變異構體、內消旋體、外消旋體、對映異構體、非對 映異構體、或其混合物形式或其醫藥上可接受之鹽,其中,該環B選自:苯基、吡啶基、吡唑基、吡啶-2-酮基、咪唑基、吡咯基、呋喃基、噻吩基、哌啶基、四氫吡啶基、異喹啉基、喹啉基、喹喔啉基、吲哚基、吲唑基、苯并呋喃基和苯并噻吩基。
- 如申請專利範圍第1至3項中任一項所述(I)之化合物、或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其為通式(III’)所示的化合物:
- 如申請專利範圍第1至3項中任一項所述(I)之化合物、或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,其中,該環A為苯基或呋喃基。
- 一種醫藥組成物,該醫藥組成物含有治療有效量的如申請專利範圍第1至7項中任一項所述之化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其醫藥上可接受之鹽,以及一種或多種醫藥上可接受的載體、稀釋劑或賦形劑。
- 一種用途,其係如申請專利範圍第1至7項中任一項所述之化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其 醫藥上可接受之鹽或如申請專利範圍第11項所述之醫藥組成物在製備用於抑制A2a受體的藥物中的用途。
- 一種用途,其係如申請專利範圍第1至7項中任一項所述之化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其醫藥上可接受之鹽或如申請專利範圍第11項所述的醫藥組成物在製備用於治療藉由對A2a受體的抑制而改善的病況或病症的藥物中的用途。
- 如申請專利範圍第13項所述的用途,其中,該藉由對A2a受體的抑制而改善的病況或病症係選自腫瘤、抑鬱症、認知功能病症、神經退行性病症、注意力相關病症、錐體外症候群、異常運動障礙、肝硬化、肝纖維化、脂肪肝、皮膚纖維化、睡眠障礙、中風、腦損傷、神經炎症和成癮行為。
- 如申請專利範圍第14項所述的用途,其中,該藉由對A2a受體的抑制而改善的病況或病症為腫瘤。
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EP3575301A4 (en) | 2020-08-05 |
KR20190129851A (ko) | 2019-11-20 |
JP2020510012A (ja) | 2020-04-02 |
JP7111733B2 (ja) | 2022-08-02 |
RU2764655C2 (ru) | 2022-01-19 |
RU2019131111A3 (zh) | 2021-04-16 |
US20210032224A1 (en) | 2021-02-04 |
AU2018233367B2 (en) | 2021-08-12 |
UA125592C2 (uk) | 2022-04-27 |
CN109963854B (zh) | 2022-04-12 |
CA3054976A1 (en) | 2018-09-20 |
AU2018233367A1 (en) | 2019-08-29 |
US11312705B2 (en) | 2022-04-26 |
EP3575301A1 (en) | 2019-12-04 |
WO2018166493A1 (zh) | 2018-09-20 |
TW201835083A (zh) | 2018-10-01 |
BR112019017108A2 (pt) | 2020-04-07 |
CN109963854A (zh) | 2019-07-02 |
MX2019010354A (es) | 2019-10-22 |
RU2019131111A (ru) | 2021-04-16 |
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