TW201932462A - 經取代的咪唑并吡啶醯胺類及其用途 - Google Patents
經取代的咪唑并吡啶醯胺類及其用途 Download PDFInfo
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- TW201932462A TW201932462A TW107137149A TW107137149A TW201932462A TW 201932462 A TW201932462 A TW 201932462A TW 107137149 A TW107137149 A TW 107137149A TW 107137149 A TW107137149 A TW 107137149A TW 201932462 A TW201932462 A TW 201932462A
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- Prior art keywords
- heart failure
- compound
- acid
- imidazo
- concentrated
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
本申請案係關於新穎經取代的咪唑并吡啶醯胺類、其等製備方法、其等單獨或組合之用於治療及/或預防疾病之用途及其等於製造用於治療及/或預防疾病之醫藥品，特別是用於治療及/或預防心血管、神經及中樞神經以及代謝病症之醫藥品。
Description
本申請案係關於新穎經取代的咪唑并吡啶醯胺類、其等製備方法、其等單獨或組合之用於治療及/或預防疾病之用途及其等於製造用於治療及/或預防疾病之醫藥品，特別是用於治療及/或預防心血管、神經及中樞神經以及代謝病症之醫藥品。
α-2B腎上腺素受體(ADRA2B)屬於受到天然傳遞素腎上腺素和去甲腎上腺素活化的腎上腺素受體之群，且因此其負責腎上腺素及去甲腎上腺素所媒介的作用α-2B腎上腺素受體為與抑制性Gαi信號途徑相關之G蛋白偶聯受體(GPCR)。
該受體係在腦部內中樞地且在平滑血管肌肉細胞上周邊地表現，且媒介中央地鈉滯留及周邊的血管收縮(Am J Physiol Regulatory Integrative Comp Physiol.2002；283：R287-295)。其亦高度表現於腎臟中(Clin Sci(Lond).2005；109(5)：431-7)，其中其在腎臟灌注及利尿可具有可能的角色(International Journal of Cardiology 2004；97：367-372)。
如同與許多G蛋白偶聯受體之情況一樣，對於ADRA2B，許多內源性激動劑也誘導GRK(G蛋白受體激酶)依賴性磷酸化，導致受體的去敏化和內化。在藉由激動劑使受體延長刺激的情況下，受體的這種去敏化和內化導致下游信號級聯的活化減少(G蛋白活化)，且因而導致細胞對激動劑的反應性降低。在ADRA2B的遺傳DD變異體中，在受體的第3個細胞內環中有3種穀胺酸缺失，其減少激動劑誘導的受體磷酸化和去敏化。
此造成激動劑刺激後受體及信號級聯之延長活化(Cell Commun Signal.2011；9(1)：5)。
一些研究已顯示ADRA2B DD變異體與某些病症發生有顯著的關聯性。在正常族群中，根據種族，20-30%的人攜帶該受體的DD變異體。在患有心臟病症的患者中，攜帶DD變異體的人的比例增加至幾乎50%。因此，DD變異體與人類中心肌梗塞及心臟猝死之發生顯著地相關(J Am Coll Cardiol.2003；41(2)：190-4；J Am Coll Cardiol.2001；37(6)：1516-22)。根據DD變異體延長活性之體外發現，DD變異體被認為經由延長的受體活化而導致小冠狀血管和內皮功能障礙的功能降低(Clin Sci(Lond).2002；103(5)：517-24；Clin Sci(Lond).2003；104(5)：509-20)。因此，ADRA2B的DD基因型被認為是上述疾病的遺傳風險因素。
此外，ADRA2B的DD變異體與缺血性中風的發生顯著相關。此也似乎是基於小血管的功能性紊亂(Clin Neurol Neurosurg.2013；115(1)：26-31)。這些關聯性研究(遺傳數據)指出ADRA2B受體-獨立於基因型-對於缺血性病症、特別是缺血性心臟病的病理學相關性。
與ADRA2B的DD變異體相關的還有由創傷事件的增強回憶引起的創傷後應激障礙(PTSD)的發生(Nat Neurosci.2007；10(9)：1137-9；Neurobiol Learn Mem.2014；112：75-86)。作為神經傳遞質，去甲腎上腺素係涉及情緒記憶過程之處理。ADRA2B受體的DD變異體可能是去甲腎上腺素作為對情緒事件的反應之效果增加的結果，導致杏仁核活化增強和情緒回憶增加。在患有PTSD的患者中，杏仁核活化增加與症狀的嚴重程度相關(Li et al.,Psychopharmacology 2015；Rasch et al PNAS 2009；van Stegeren,Acta Psychologica,2008)。這些作用由中樞ADRA2B受體媒介，且由此影響去甲腎上腺素能信號轉導。
另外，可能證實DD變異體與第2型糖尿病的早期發作有關(Exp Clin Endocrinol Diabetes 2006；114：424-427)。
因此，抑制ADRA2B受體代表心血管、神經和中樞神經以及代謝病症之有希望的治療選擇。
在心血管疾病領域，對新型治療方法的需求很大。即使以目前可用的
治療，心肌梗塞後的發病率和死亡率仍然很高。即使在冠狀動脈血管快速重新打開(再灌注、經皮冠狀動脈介入治療(PCI))之情況下，心肌梗塞為原因的死亡率仍然很高：7%-11%的患者由於梗塞而死亡，且在一年內，22%的患者由於心肌梗塞導致心衰竭而必須去醫院就診(Freisinger et al.,European Heart Journal(2014)35,979-988)。
心肌梗塞期間血流的破壞導致在所討論的冠狀血管供應的面積之區域中的細胞死亡。通常認為，重新打開閉塞的血管並且因此恢復血流對於挽救受影響的心臟組織是極為重要的；然而，矛盾的是，恢復的血流也會導致組織損傷，其抵消再灌注的最初優勢。梗塞的最終大小的50%可歸因於此再灌注損傷(Fröhlich et al,European Heart Journal 2013,34)。儘管在心外膜血管中重新打開原始阻塞，但小冠狀血管中的血流流動(微血管功能障礙)係導致再灌注損傷並因此導致最終梗塞大小。
需要用於減少梗塞大小和維持心臟功能的新穎治療策略以改善患者存活及預防心肌梗塞後的心衰竭。
本發明的一個目的是鑑定及提供新穎之作為ADRA2B受體的有效拮抗劑的低分子量化合物，且因此適合用於治療和/或預防心血管、神經和中樞神經以及代謝病症。
另一個目的在於鑑定用於心肌梗塞患者的ADRA2B拮抗劑，特別是用於減少再灌注損傷。
舉例而言，ADRA2B抑制劑係說明於WO 03/008387及於WO2010/033393。WO2009/47506及WO2009/47522係揭示作為酪胺酸激酶抑制劑之咪唑并吡啶羧醯胺。
EP 1277754係揭示作為磷脂酸肌醇3-激酶(Pl3K)抑制劑之咪唑并吡啶衍生物且可因而使用作為抗腫瘤劑。
WO 2008/027812係揭示可作為大麻素受體配體、例如CB2配體之咪唑并吡啶及咪唑并嘧啶衍生物。
WO 2008/134553係說明可特別用於治療疼痛之雙環化合物。
作為TNF活性調節劑之咪唑并吡啶衍生物係說明於WO 2014/009295中。
然而，先前技術並未說明本文中說明及定義之本發明之通式(I)咪唑并吡啶醯胺類。
目前已發現本發明之化合物具有達成本發明目的之令人驚訝及有利的性質。
特別地，已發現本發明化合物為ADRA2B拮抗劑。特定而言，由於其等良好的溶解性，根據本發明之化合物合適用於非經腸胃之投予形式(European Pharmacopoeia,6th Edition,initial volumes(Ph.Eur.6.0),p.1024)，因而得到可得之新穎治療選擇。因此，所提及化合物係特別適用於急性治療，例如經皮冠狀動脈介入治療期間的急性投予，以及亦適用於可能導致灌注不足和器官損傷(心臟，腎臟，腦)的其他急性情況。
本發明係提供式(I)之化合物
其中A代表下式之帶正電荷的氮雜雜芳族
其中*代表連接點，R1、R2及R3a、R3b相互獨立地為選自由下列組成的群組之基團：氫、胺基、(C1-C4)-烷基、(C1-C4)-烷氧基、單-(C1-C4)-烷基胺基、二-(C1-C4)-烷基胺基、苯氧基及六氫吡啶-1-基，
其中苯氧基及六氫吡啶-1-基可經(C1-C4)-烷基及/或氟取代，及其中在(C1-C4)-烷基、(C1-C4)-烷氧基、單-(C1-C4)-烷基胺基及二-(C1-C4)-烷基胺基中之烷基基團可各經氟至多五取代，R4代表(C1-C4)-烷基，其可經氟至多五取代，或代表式CH2CN、CH2CONH2之基團，D代表下式之雜芳族
其中**代表連接點，R5及R6相互獨立地代表氫、(C1-C4)-烷基或(C1-C4)-烷氧基，其中(C1-C4)-烷基及(C1-C4)-烷氧基可各經氟至多五取代，L代表CH2，n代表0、1、2或3之數目，及X-代表生理上可接受之陰離子，以及式(I)化合物之溶劑合物、鹽類及鹽類之溶劑合物。
本發明亦涵蓋本發明化合物之合適形式，例如代謝物、水合物、溶劑合物、前藥、鹽類，特別是醫藥上可接受的鹽類及/或共沉澱物。
根據本發明之式(I)化合物已以鹽形式存在；然而，其等可形成額外之加成鹽。本發明之化合物為式(I)化合物及其鹽類、溶劑合物及鹽類之溶劑合物，式(I)所涵蓋之化合物及以下提及的化學式之化合物，以及其鹽類、溶劑合物及鹽類之溶劑合物，及式(I)所涵蓋與如下作為實施例引用者及其鹽類、溶劑合物及鹽類之溶劑合物之化合物，若式(I)所涵蓋的化合物及以下提及的化合物並非已是鹽類、溶劑合物及鹽類之溶劑合物。
本發明內文中較佳的鹽類為本發明化合物之生理上可接受之鹽類。亦涵蓋的是本身不適合用於醫藥應用、但可用於例如分離或純化本發明的化合物之鹽類。
術語「醫藥上可接受之鹽類」係指根據本發明之無機或有機酸加成鹽。
參見例如S.M.Berge,et al.“Pharmaceutical Salts”,J.Pharm.Sci.1977,66,1-19。
本發明化合物的合適的醫藥上可接受的鹽可為，例如，本發明化合物的酸加成鹽，如與無機酸的酸加成鹽，或“礦物酸”，例如鹽酸，氫氟酸，氫溴酸，氫碘酸，硫酸，胺基磺酸，二硫酸，磷酸或硝酸，例如，或與有機酸之酸加成鹽，例如甲酸，乙酸，乙醯乙酸，丙酮酸，三氟乙酸，丙酸，丁酸，己酸，庚酸，十一烷酸，月桂酸，苯甲酸，水楊酸，2-(4-羥基苯甲醯基)苯甲酸，樟腦酸，肉桂酸，環戊烷丙酸，二葡萄糖酸，3-羥基-2-萘甲酸，菸酸，雙羥萘酸，果膠酸，3-苯基丙酸，新戊酸，2-羥基乙磺酸，衣康酸(itaconic acid)，三氟甲磺酸，十二烷基硫酸，乙磺酸，苯磺酸，對甲苯磺酸，甲磺酸，2-萘磺酸，萘二磺酸，樟腦磺酸，檸檬酸，酒石酸，硬脂酸，乳酸，草酸，丙二酸，琥珀酸，蘋果酸，己二酸，海藻酸，馬來酸，富馬酸，D-葡萄糖酸，杏仁酸、抗壞血酸、葡糖庚酸、甘油磷酸、天冬胺酸、磺基水楊酸、或硫氰酸。
本領域技術人員將進一步瞭解到，所請求的化合物之酸加成鹽可藉由化合物與適當的無機或有機酸經由許多已知方法中任一種反應來製備。本發明包括本發明化合物之所有可能的鹽，其為單一鹽類或任何比例的該鹽類之任何混合物。
本發明內文中生理上可接受之陰離子為礦物酸、羧酸及磺酸之陰離子，例如以下之鹽類：氫氯酸、氫氟酸，氫溴酸，氫碘酸，硫酸，磷酸，甲磺酸，乙磺酸，甲苯磺酸，苯磺酸，萘二磺酸，甲酸，乙酸，三氟乙酸，丙酸，乳酸，酒石酸，蘋果酸，檸檬酸，富馬酸，馬來酸和苯甲酸。較佳的是下列酸的陰離子：氫氯酸，氫溴酸，甲酸。特別較佳的是氫氯酸，氫溴酸和甲酸的陰離子。
在本發明的內文中的溶劑合物係以本發明化合物的那些形式被敘述，其藉由與溶劑分子配位形成固態或液態的複合物。水合物是溶劑合物的特定形式，其中與水配位。在本發明的內文中較佳的溶劑合物為水合物。
本發明的化合物視它們的結構而定可以不同的立體異構形式存在，即以構型異構物的形式存在，或者若合適時，以構象異構物形式存在(鏡像異構物及/或非鏡像異構物，包括在阻轉異構物(atropisomers)的情況下)。因此，本發明涵蓋鏡像異構物和非鏡像異構物，以及其等各自的混合物。立體異構的均相成分可以已知的方式從鏡像異構物及/或非鏡像異構物之這種混合物中分離出來；較佳係使用用於此目的之層析方法，特別是在非掌性或掌性相上的HPLC層析法。在羧酸作為中間物或最終產物的情況下，或者也可能藉由使用掌性胺鹼經由非鏡像液構鹽進行分離。
若本發明化合物可以互變異構形式存在，則本發明包括所有互變異構形式。
在根據本發明的式(I)化合物中，除了所示的式A之外，帶正電的氮雜雜芳族化合物還可存在於由A組成之各自有貢獻的中間(mesomeric)結構中，特別是以下有貢獻的結構：
通式(I)的化合物可採同位素變體的形式。因此，本發明包括通式(I)化合物的一種或多種同位素變體，尤其是通式(I)的含氘化合物。
化合物或試劑的術語「同位素變體」係定義為由此構成該化合物之具有一種或多種同位素的非天然部分的化合物。
術語「通式(I)化合物之同位素變體」係定義為由此形成化合物之具有一或多個同位素的非天然部分之通式(I)化合物。
「非天然部分」的表示應理解為意指高於其固有頻率的這種同位素之一部分。在這方面使用的同位素的固有頻率可以見於"Isotopic Compositions of the Elements 1997",Pure Appl.Chem.,70(1),217-235,1998。
這種同位素的例子是氫，碳，氮，氧，磷，硫，氟，氯，溴和碘的穩定和放射性同位素，例如2H(氘)，3H(氚)，11C，13C，14C，15N，17O，18O，32P，33P，33S，34S，35S，36S，18F，36Cl，82Br，123I，124I，125I，129I
及131I。
關於本文中所指定病症之治療及/或預防，通式(I)化合物之同位素變體較佳含有氘(「含氘之通式(I)化合物」)。其中已併入一或多種放射性同位素(例如3H或14C)的通式(I)化合物之同位素變體有利於例如藥物及/或受質組織分佈研究。此等同位素因為彼等之併入容易及可偵測性而為特佳的。正電子發射同位素例如18F或11C可能併入通式(I)化合物中。通式(I)化合物之此等同位素變體可適用於活體內成像應用。在臨床前研究或臨床研究內，含氘及含13C之通式(I)化合物可用於質譜分析。
通式(I)化合物之同位素變體通常可藉由熟習此項技術者已知的方法製備，如本文流程圖及/或實施例中所述之彼等方法，藉由用該試劑之同位素變體(較佳含氘試劑)取代該試劑。根據所欲氘化位點，在一些情況下，可將來自D2O之氘直接併入化合物中或併入可用於合成該等化合物之試劑中。可用於將氘併入分子中之其他試劑為氘氣。烯鍵及炔鍵之催化氘化為併入氘的直接途徑。可能使用金屬觸媒(亦即Pd、Pt及Rh)在氘氣存在下以將含官能基之烴中的氫直接交換為氘。各種氘化試劑及合成建構組元(building block)可購自各公司，例如C/D/N Isotopes,Quebec,Canada；Cambridge Isotope Laboratories Inc.,Andover,MA,USA；及CombiPhos Catalysts,Inc.,Princeton,NJ,USA。
術語「含氘之通式(I)化合物」係定義為其中一或多個氫原子經一或多個氘原子置換且其中通式(I)化合物於各氘化位置之氘的豐度高於氘之天然豐度(其為約0.015%)之通式(I)化合物。特別地，在含氘之通式(I)化合物中，通式(I)化合物於各氘化位置之氘的豐度係高於10%、20%、30%、40%、50%、60%、70%或80%，較佳高於90%、95%、96%或97%，甚至更佳地，在該(等)位置高於98%或99%。將明顯的是，各氘化位置之氘豐度與其他氘化位置之氘豐度無關。
經由選擇性併入一或多個氘原子至通式(I)化合物，可能改變該分子之物化性質(例如，酸度[C.L.Perrin,et al.,J.Am.Chem.Soc.,2007,129,4490]、鹼度[C.L.Perrin et al.,J.Am.Chem.Soc.,2005,127,9641]、親脂性[B.Testa et al.,Int.J.Pharm.,1984,19(3),271])及/或代謝特徵，且可造
成母體化合物與代謝物之比率或所形成代謝物量的改變。此類改變可造成特定治療益處，因此在一些情況下可為較佳。已有報導指出，代謝速率與代謝轉化率下降，其中代謝物比率改變(A.E.Mutlib et al.,Toxicol.Appl.Pharmacol.,2000,169,102)。暴露於母體化合物與代謝物之這些改變，對通式(I)之含氘化合物的藥效動力學、耐受性、及功效可具有重要影響。在一些情況下，氘取代作用係減少或消除不欲或有毒代謝物之形成，並增進所需代謝物之形成(例如，Nevirapine：A.M.Sharma et al.,Chem.Res.Toxicol.,2013,26,410；Efavirenz：A.E.Mutlib et al.,Toxicol.Appl.Pharmacol.,2000,169,102)。在其他情況下，氘化之主要作用為降低全身清除率。因此，化合物之生物半衰期增加。潛在之臨床益處將包括維持類似全身性暴露之能力，伴隨降低峰值(peak)濃度及增加谷值(trough)濃度。此可導致較低之副作用且增進功效，取決於特定化合物之藥物動力學/藥效動力學關係。ML-337(C.J.Wenthur et al.,J.Med.Chem.,2013,56,5208)與奧當卡替(odanacatib)(K.Kassahun et al.,WO2012/112363)為此氘作用之實例。仍有其他案例已報導，其中降低代謝率導致藥物曝露增加，而不改變全身清除率之速率(例如，Rofecoxib：F.Schneider et al.,Arzneim.Forsch./Drug.Res.,2006,56,295；Telaprevir：F.Maltais et al.,J.Med.Chem.,2009,52,7993)。顯示此作用之氘化藥物可具有減少劑量之需求(例如，更低劑量數或更低劑量以達到所需功效)及/或可產生更低代謝物負荷。
通式(I)化合物可具多個潛在代謝攻擊位點。為了最適化上述對物化性質與代謝特徵之影響，可選擇具有一特定型態之一或多個氘-氫交換的含氘之通式(I)化合物。具體而言，含氘之通式(I)化合物之氘原子係連接至碳原子及/或位於通式(I)化合物之那些位置，其係代謝酵素(如細胞色素P450)之攻擊位點。
本發明亦另外包括根據本發明之化合物的前藥。在本文中，術語「前藥」係指化合物，其本身可為具生物學活性的或無活性的、但在其於體內停留時間內係反應(例如代謝或水解)而得到本發明化合物。
在本發明的上下文中，除非另有說明，否則取代基係定義如下：
在本發明的上下文中，烷基或(C1-C4)-烷基為具有1至4個碳原子之直鏈或支鏈烷基基團。較佳實例包括：甲基、乙基、n-丙基、異丙基、正丁基、異丁基、1-甲基丙基、三級丁基。較佳的是甲基、乙基及異丙基。特別較佳的是甲基。
在本發明的上下文中，烷氧基或(C1-C4)-烷氧基為具有1至4個碳原子之直鏈或支鏈烷氧基基團。較佳實例包括：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基及三級丁氧基。較佳的是甲氧基及乙氧基。特別較佳的是甲氧基。
在本發明的上下文中，單-(C1-C4)-烷基胺基為具有具1至4個碳原子之直鏈或支鏈烷基取代基之胺基基團。較佳實例包括下列：甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、二級丁基胺基及三級丁基胺基。特別較佳的是甲基胺基。
在本發明的上下文中，二-(C1-C4)-烷基胺基為具有兩個相同或不同的具1至4個碳原子之直鏈或支鏈烷基取代基之胺基基團。較佳實例包括下列：N,N-二甲基胺基、N,N-二乙基胺基、N-乙基-N-甲基胺基、N-甲基-N-正丙基胺基、N-異丙基-N-甲基胺基、N-異丙基-N-正丙基胺基、N,N-二異丙基胺基、N-正丁基-N-甲基胺基及N-三級丁基-N-甲基胺基。特別較佳的是二甲基胺基。
當本發明化合物中的基團被取代時，基團可為單-或多取代，除非另有說明。在本發明的上下文中，出現超過一次之所有基團係彼此獨立地定義。經一或二個相同或不同的取代基之取代為較佳的。非常特別較佳的是經一個取代基取代。
在本發明的上下文中，術語「治療(treatment)」或「治療(treating)」包括抑制、延遲、緩和、減輕、限制、減少、壓抑、排斥或治癒疾病、病況、病症、損傷或健康問題，或這類狀態及/或這類狀態的症狀之發展、過程及/或進展，及/或其症狀的消退。病症、疾病、狀況或狀態的治療或預防可能是部分或完全的。術語「療法」在此理解為與術語「治療」同義。
術語「預防(prevention)」、「預防(prophylaxis)」或「排除(preclusion)」在本發明的上下文中同義使用，並且是指避免或減少如下的風險：感染，
經歷、罹患或患有疾病、病況、病症、傷害或健康問題、或這些狀態和/或這些狀態的症狀之發展或進步。
治療或預防疾病、病況、病症、損傷或健康問題可為部分或完全的。
在本發明內文中，較佳的是通式(I)之化合物，其中R1、R2及R3a、R3b相互獨立地為選自下列之基團：氫、乙基胺基、二甲基胺基、甲基胺基、胺基、甲基、乙基、三氟甲基、三級丁基、異丙基、苯氧基或六氫吡啶-1-基，R4代表甲基，R5及R6相互獨立地代表氫、甲基、乙基、異丙基或甲氧基，n代表1或2之數目，X-代表溴離子、氯離子或甲酸根，且A代表下式帶正電荷之氮雜雜芳族
其中*代表連接點，D代表下式之雜芳族
其中**代表連接點，及L代表CH2，及其溶劑合物、鹽類及鹽類之溶劑合物。
本發明內文中特別較佳的是通式(I)化合物，其中R1代表氫或甲基胺基，R2代表氫或甲基，
R3a、R3b代表氫，R4代表甲基，R5及R6相互獨立地代表甲基、甲氧基或氫，n代表1或2之數目，X-代表溴離子、氯離子或甲酸根，及A代表下式帶正電荷之氮雜雜芳族
其中*代表連接點，D代表下式之雜芳族
其中**代表連接點，及L代表CH2，及其溶劑合物、鹽類及鹽類之溶劑合物。
在本發明內文中，較佳的也為選自下列組成的群組之化合物：1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)氯化吡啶鎓鹽酸鹽
2-[({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)甲基]-1-甲基咪唑并[1,2-a]吡啶-1-鎓甲酸酯
1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)吡啶鎓甲酸酯
1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)氯化吡啶鎓
1-[2-({[3-(1,4-二甲基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)吡啶鎓甲酸酯
1-[2-({[3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)吡啶鎓甲酸酯
2-[({[3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)甲基]-1-甲基咪唑并[1,2-a]吡啶-1-鎓甲酸酯
1-[2-({[3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-3-甲基-4-(甲基胺基)吡啶鎓甲酸酯
1-[2-({[3-(4-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)溴化吡啶鎓
及其溶劑合物、鹽類及鹽類之溶劑合物。
本發明進一步提供一種用於製備根據本發明之式(I)化合物之方法，其特徵在於使式(II)化合物或其對應羧酸
其中D具有如上給予的定義，在惰性溶劑中與縮合劑例如1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽於鹼例如4-二甲基胺基吡啶之存在下與式(III)化合物反應A-(L)n-NH2 (III)其中A、L及n具有如上給予的意義。
用於方法步驟(II)+(III)→(I)之惰性溶劑為，舉例而言，鹵烴類，例如二氯甲烷、三氯乙烯、氯仿或氯苯，醚類，例如二乙醚、二烷、四氫呋喃、乙二醇二甲醚，烴類，例如苯、甲苯、二甲苯、己烷、環己烷或礦物油餾分，或其他溶劑，例如乙腈、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲亞碸、N,N'-二甲基丙烯基脲(DMPU)、N-甲基吡咯啶酮(NMP)或吡啶。同樣可以使用所述溶劑的混合物，較佳的是使用二氯甲烷、四氫呋喃或吡啶。特別較佳的是使用二氯甲烷。
適合作為用於方法步驟(II)+(III)→(I)中醯胺形成之縮合劑為，舉例而言，碳二亞胺類，例如N,N'-二乙基-、N,N'-二丙基-、N,N'-二異丙基-、
N,N'-二環己基碳二亞胺(DCC)或N-(3-二甲基胺基丙基)-N'-乙基碳二亞胺鹽酸鹽(EDC)，光氣衍生物，例如N,N'-羰基二咪唑(CDI)，1,2-唑鎓化合物，例如2-乙基-5-苯基-1,2-唑鎓3-硫酸鹽或2-三級丁基-5-甲基異唑鎓過氯酸鹽，醯基胺基化合物，例如2-乙氧基-1-乙氧基羰基-1,2-二氫喹啉或氯甲酸異丁酯，丙烷膦酸酐(T3P)、1-氯-N,N,2-三甲基丙烯-1-胺、二乙基氰基膦酸鹽、雙(2-側氧基-3-唑啶基)磷醯氯、苯并三唑-1-基氧基三(二甲基胺基)磷鎓六氟磷酸鹽、苯并三唑-1-基氧基三(吡咯啶基)磷鎓六氟磷酸鹽(PyBOP)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸鹽(TBTU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(HBTU)、2-(2-側氧基-1-(2H)-吡啶基)-1,1,3,3-四甲基脲四氟硼酸鹽脲四氟硼酸鹽(TPTU)、O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(HATU)或O-(1H-6-氯苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸鹽(TCTU)，視情況地與其他助劑例如1-羥基苯并三唑(HOBt)或N-羥基琥珀醯亞胺(HOSu)組合。較佳的是使用EDC、HATU、DCC及T3P。特別較佳的是使用EDC。
適合作為用於方法步驟(II)+(III)→(I)中醯胺形成之鹼為，舉例而言，鹼金屬碳酸鹽，例如鹼金屬碳酸鹽，例如碳酸鈉或碳酸鉀或碳酸氫鈉或碳酸氫鉀，或有機鹼，例如三烷基胺，如三乙基胺(TEA)、N-甲基嗎啉、N-甲基六氫吡啶或N,N-二異丙基乙基胺(DIPEA)或4-(二甲基胺基)吡啶(DMAP)。較佳的是使用DMAP、TEA及DIPEA。特別較佳的是使用DMAP。
縮合反應(II)+(III)→(I)通常是在-20℃至+100℃、較佳在0℃至+60℃之溫度範圍內進行。轉換作用可在標準、升高或減低的壓力(例如0.5至5巴(bar))下完成。一般而言，室溫及標準壓力被使用。
或者，式(I)羧酸鹽也可首先轉換成對應的氯化碳且受者可接著被直接轉換或於與式(III)化合物之分開的反應中被轉換成本發明之化合物。碳化氯由羧酸之形成係藉由熟習該項技術者已知的方法進行，例如藉由在合適的鹼例如於吡啶之存在下、及視情況地添加二甲基甲醯胺、視情況地在合適的惰性溶劑中以亞硫醯氯、硫醯氯或草醯氯處理(II)或對應的游離羧酸。
在(II)+(III)→(I)之縮合反應中，處理(work-up)性質決定何種相對陰離子(counteranion)。舉例而言，若粗產物藉由製備性HPLC使用包含甲酸之水性流動相而純化時，係得到甲酸鹽。在另一方面，若粗產物藉由例如於胺基-官能化的矽膠(來自Biotage,SNAP NH-Cartridge)上之管柱層析而純化時，視合成途徑而定得到氯化物或溴化物。若A1‘之烷基化係根據以下反應平衡式A1'+(IV)→(V)使用經酞醯亞胺-保護的氯乙基胺(IV)
以得到建構組元(V)
且後續去保護作用係使用氫氯酸而進行時(亦參考流程1)，係得到氯化物。
若烷基化係使用適當的溴化物進行且保護基團係以溴化氫移除時，係得到溴化物。其他生理上可接受的相對陰離子可使用離子交換劑由甲酸鹽、氯化物或溴化物而得到。
使用之化合物為商業上可購得的，其可從文獻中獲知，或可以類似於文獻之方法製備。
一般方法係藉由以下流程(流程1)以例示方式說明：流程1：
其中A1'代表
及A1代表
且*、L、n、D、R1、R2、R3a及R3b具有以上所示的意義。
另外的一般方式係藉由以下流程(流程2)作為實例方式說明：
其中A2'代表
A2代表
且*、L、n、D、R1、R2及R4具有以上所示的意義。
一替代方法變化係示於流程3中：流程3：
其中A、L、n及D具有以上所示的意義。化合物[A(L)nNH2xHCl]+Cl-係如上所述得到。
詳細的過程也可見於實驗部分的起始化合物和中間物的製備部分中。
本發明化合物具有有價值的藥理學性質，且可用於治療和/或預防人和動物的病症。
根據本發明的化合物是ADRA2B受體之強力的、化學穩定的拮抗劑，且因此適用於治療和/或預防病症和病理過程，特別是心血管、腎病、神經和中樞神經病症。
在本發明的內文中，心血管系統病症或心血管病症被理解為表是例如以下疾病：急性和慢性心衰竭，動脈性高血壓，冠心病，穩定和不穩定型心絞痛，心肌缺血，心肌梗塞，冠狀動脈微血管功能障礙，微血管阻塞，無復流現象，休克，動脈粥樣硬化，心肌肥厚，心肌纖維化，心房和心室性心律不整，短暫性和缺血性發作，中風，缺血性和出血性中風，先兆子癇，炎性心血管疾病，周邊和心血管疾病，周邊灌注障礙，周邊動脈閉塞性疾病，原發性和繼發性雷諾氏症候群(Raynaud's syndrome)，微循環受損，動脈肺動脈高壓，冠狀動脈和周邊動脈痙攣，血栓形成，血栓栓塞性疾病，水腫發展，例如肺水腫，腦水腫，腎水腫
或心衰竭相關性水腫，及例如血栓溶解治療、經皮腔內血管成形術(PTA)、經腔冠狀動脈成形術(PTCA)、心臟移植和旁路(bypass)手術後之再狹窄，及微血管和大血管損傷(血管炎)，再灌注損傷，動脈和靜脈血栓形成，微量白蛋白尿，心肌功能不全，內皮功能障礙，周邊和心臟血管疾病。
在本發明的內文中，術語「心衰竭」也包括更具體或相關類型的疾病，例如急性失代償性心衰竭，右心衰竭，左心衰竭，全球衰竭，缺血性心肌病，擴張型心肌病，先天性心臟缺陷，心臟瓣膜缺損，與心臟瓣膜缺損相關的心衰竭，二尖瓣狹窄，二尖瓣關閉不全，主動脈瓣狹窄，主動脈瓣關閉不全，三尖瓣狹窄，三尖瓣關閉不全，肺動脈瓣狹窄，肺動脈瓣膜功能不全，複合心臟瓣膜缺損，心肌炎(心肌炎)，慢性心肌炎，急性心肌炎，病毒性心肌炎，糖尿病性心衰竭，酒精性心肌病，心臟儲積病症，正常收縮分率心衰竭(HFpEF)，舒張期心衰竭，低收縮分率心衰竭(HfrEF收縮期心衰竭)。
在本發明內文中，心房和心室性心律不整亦包括更具體或相關類型的疾病，例如：心房顫動，陣發性心房顫動，間歇性心房顫動，永久性心房顫動，心房撲動，竇性心律不整，竇性心搏過速，被動異位(passive heterotopia)，活動性異位，脫逸收縮，期外收縮，衝動傳導障礙，心房腔失調症候群，過敏性頸動脈竇，心搏過速，房室結再入性心搏過速(AV node reentry tachycardia)，房室折返性心搏過速，WPW症候群(Wolff-Parkinson-White)，Mahaim心搏過速，隱性輔助傳導通路，永久性交界再入性心動過速，局灶性房性心搏過速，交界性異位性心動過速，心房折返性心動過速，心室性心搏過速，心室撲動，心室顫動，心臟性猝死。
在本發明的內文中，術語冠狀心臟病也包括更具體或相關類型的疾病，例如：缺血性心臟病，穩定型心絞痛，急性冠狀動脈症候群，不穩定型心絞痛，NSTEMI(非ST波段上升的心肌梗塞)，STEMI(ST波段上升的心肌梗塞)，缺血性心肌損傷，心律紊亂和心肌梗塞。
在本發明的內文中，中樞神經系統和神經系統之病症或中樞神經和神經病症應理解為例如以下病症：短暫性和缺血性發作，中風，缺血性和出血性中風，憂鬱症，焦慮症，創傷後壓力症，多發性神經病變，糖
尿病性多發性神經病變，壓力相關性高血壓。
根據本發明之化合物係進一步適合用於治療及/或預防多囊性腎臟疾病(PCKD)及ADH分泌異常症候群(SIADH)。
此外，根據本發明的化合物適用於治療和/或預防腎病，特別是急性和慢性腎功能不全以及急性和慢性腎衰竭。
對於本發明之目的，術語急性腎功能不全包括需要和不需要透析之腎病、腎衰竭和/或腎功能不全的急性表現，以及潛在的或相關的腎病，例如腎灌注不足，透析中的低血壓，體積不足(如脫水，失血)，休克，急性腎小球腎炎，溶血性尿毒症候群(HUS)，血管性突發(動脈或靜脈血栓形成或栓塞)，膽固醇栓塞，急性Bence-Jones腎臟發生漿細胞瘤，急性囊上或囊下流出阻塞，免疫性腎臟疾病如腎移植排斥反應，免疫複合物引發的腎臟疾病，腎小管擴張，高磷酸鹽血症和/或急性腎臟疾病，其特點是需要透析，以及在腎臟局部切除之情形，經由強迫利尿之脫水，惡性高血壓之不加控制的血壓升高，尿道阻塞及感染和類澱粉變性，以及具腎小球因素之全身性疾病，例如風濕免疫系統性疾病，如紅斑狼瘡，腎動脈血栓形成，腎靜脈血栓形成，鎮痛性腎病和腎小管酸中毒，以及X射線造影劑和藥物引發的急性間質性腎病。
在本發明的內文中，術語「慢性腎功能不全」包括有或沒有透析之腎病、腎衰竭和/或腎功能不全的慢性表現，以及潛在的或相關的腎病，例如腎低灌注，透析中低血壓，阻塞性尿路病，腎小球病，腎小球和腎小管性蛋白尿，腎水腫，血尿，原發性、繼發性和慢性腎小球腎炎，膜性和膜性增生性腎小球腎炎，Alport症候群，腎小球硬化，腎小管間質疾病，腎病性疾病，例如原發性和先天性腎病，腎臟炎症，免疫性腎臟疾病，例如腎移植排斥，免疫複合物引發的腎臟疾病，糖尿病和非糖尿病腎病，腎盂腎炎，腎囊腫，腎硬化，高血壓性腎硬化和腎病症候群，其可以藉由診斷來定特徵，例如，肌酐和/或水排泄異常減少，尿素、氮、鉀和/或肌酐的血液濃度異常升高，腎酶例如穀胺醯合成酶之活性改變，尿液滲透壓或尿量改變，升高的微量白蛋白尿，大量白蛋白尿，腎小球和小動脈病變，腎小管擴張，高磷血症和/或需要透析，以及對於腎細胞癌，在
腎部分切除後，經由強迫利尿之脫水，惡性高血壓不加控制的血壓升高，尿道阻塞及感染和類澱粉變性，以及具腎小球因素之全身性疾病，例如風濕免疫系統性疾病，如紅斑狼瘡，及腎動脈狹窄，腎動脈血栓形成，腎靜脈血栓形成，鎮痛性腎病和腎小管酸中毒，以及X射線造影劑和藥物引發的急性間質性腎病。此外，X射線造影劑和藥物引發的慢性間質性腎病，代謝症候群和血脂異常。本發明亦包括根據本發明的化合物之用途，其用於治療和/或預防腎功能不全的後遺症，例如，肺水腫，心衰竭，尿毒症，貧血，電解質紊亂(例如，高鉀血症，低鈉血症)和在骨骼和碳水化合物代謝中病症。
此外，根據本發明的化合物也適用於治療及/或預防肺動脈高血壓(PAH)和其他形式的肺高血壓(PH)，慢性阻塞性肺疾病(COPD)，急性呼吸窘迫症候群(ARDS)，急性肺損傷(ALI)，α-1-抗胰蛋白酶缺乏症(AATD)，肺纖維化，肺氣腫(例如由香煙煙霧引起的肺氣腫)，囊性纖維化(CF)，急性冠狀動脈症候群(ACS)，心肌炎症(心肌炎)和其他自體免疫性心臟病(心包炎，心內膜炎，瓣膜炎，主動脈炎，心肌病)，心源性休克，動脈瘤，敗血症(SIRS)，多器官功能衰竭(MODS，MOF)，腎臟炎症性疾病，慢性腸道疾病(IBD，克隆氏症，UC)，胰腺炎，腹膜炎，類風濕性疾病，炎性皮膚病和炎性眼病。
根據本發明的化合物也可以用於治療和/或預防具有間歇性或持續性特徵的不同嚴重程度的哮喘病症(屈光性哮喘，支氣管哮喘，過敏性哮喘，內源性哮喘，外源性哮喘，藥物或塵埃誘發的哮喘)，各種形式的支氣管炎(慢性支氣管炎，傳染性支氣管炎，嗜酸細胞性支氣管炎)，閉塞性細支氣管炎，支氣管擴張，肺炎，特發性間質性肺炎，農民的肺和相關疾病，咳嗽和感冒(慢性炎症性咳嗽，醫源性咳嗽)，鼻粘膜炎症(包括與藥物有關的鼻炎，血管舒縮性鼻炎和季節性過敏性鼻炎，例如花粉症)和息肉。
根據本發明的化合物還適用於治療和/或預防內部器官的纖維化病症，例如肺，心臟，腎，骨髓，特別是肝臟，以及皮膚病學纖維和纖維化眼部病症。在本發明的內文中，術語「纖維變性疾病」特別包括以下術語：肝纖維化，肝硬化，肺纖維化，心內膜心肌纖維化，心肌病，腎病，腎
小球腎炎，間質性腎纖維化，由糖尿病引起的纖維化損傷，骨髓纖維化和類似的纖維化疾病，硬皮病，侷限性硬皮病(morphea)，瘢痕瘤(keloids)，肥厚性瘢痕(也在外科手術後)，痣，糖尿病性視網膜病變和增殖性玻璃體視網膜病變。
此外，根據本發明的化合物還可以用於治療和/或預防血脂異常(高膽固醇血症，高甘油三酯血症，餐後血漿甘油三酯濃度升高，低α-脂蛋白血症，合併高血脂症)，代謝病症(第1型和第2型糖尿病，代謝症候群，超重，肥胖)，腎病和神經病變)，癌症(皮膚癌，腦腫瘤，乳腺癌，骨髓瘤，白血病，脂肪肉瘤，胃腸道癌，肝臟癌，胰臟癌，肺癌，腎癌，泌尿道癌，前列腺和生殖道癌，及淋巴增生系統中的惡性腫瘤，例如霍奇金和非霍奇金淋巴瘤)，胃腸道和腹部疾病(舌炎，牙齦炎，牙周炎，食道炎，嗜酸性胃腸炎，肥大細胞增多症，克隆氏症，結腸炎，直腸炎，瘙癢症，腹瀉，乳糜瀉，肝炎，慢性肝炎，肝纖維化，肝硬化，胰臟炎和膽囊炎)，皮膚病症(過敏性皮膚病，牛皮癬，痤瘡，濕疹，神經性皮炎，各種形式的皮炎，以及角膜炎，牛癬，血管炎，蜂窩組織炎，脂膜炎，紅斑性狼瘡，紅斑，淋巴瘤，皮膚癌，Sweet's症候群，Weber-Christian症候群，瘢痕，疣，寒冷)，骨骼和關節疾病，以及骨骼肌(各種形式的關節炎，各種形式的關節病，硬皮病和具炎症或免疫學成分之其他疾病)，例如伴腫瘤症候群，在器官移植後的排斥反應和傷口癒合和血管生成的情況下，特別是在慢性傷口的情況下。
根據本發明的式(I)化合物額外地適用於治療和/或預防眼科疾病，例如青光眼，血壓正常的青光眼，高眼壓及其組合，年齡相關性黃斑變性(AMD)，乾性或非滲出性AMD，潮濕或滲出性或新生血管性AMD，脈絡膜新生血管(CNV)，視網膜剝離，糖尿病性視網膜病變，視網膜色素上皮細胞(RPE)萎縮性病變，視網膜色素上皮(RPE)肥厚性病變，糖尿病性黃斑水腫，糖尿病性視網膜病變，視網膜靜脈阻塞，脈絡膜視網膜靜脈阻塞，黃斑水腫，視網膜靜脈阻塞導致的黃斑水腫，眼前部的血管生成，例如角膜血管生成，例如在角膜炎、角膜移植或角膜移植術後，由於缺氧(大量佩戴隱形眼鏡)，翼狀胬肉結膜，視網膜下水腫和視網膜內水腫引起
的角膜血管生成。
此外，根據本發明的式(I)化合物適用於治療及/或預防由外傷性前房出血、眼眶周圍水腫、術後黏彈性保留、眼內炎症、皮質類固醇的使用、瞳孔阻滯或特發性原因所引起的升高和高的眼內壓，以及小梁切除術(trabeculectomy)後和由於術前添加引起之升高的眼內壓。
由於其生物化學及藥理學性質型態，根據本發明之化合物特別適合用於治療及/或預防急性心衰竭、右心衰竭、左心衰竭、全心衰竭、糖尿病心衰竭、正常收縮分率心衰竭(HFpEF)、舒張期心衰竭、低收縮分率心衰竭(HfrEF收縮期心衰竭)、冠狀動脈心臟疾病、穩定及不穩定型心絞痛、心肌缺血、急性冠狀動脈症候群、NSTEMI(非ST波段上升的心肌梗塞)、STEMI(ST波段上升的心肌梗塞)、缺血性心臟肌肉損傷、心肌梗塞、冠狀動脈微血管功能障礙、微血管阻塞、無復流現象、短暫及缺血性發作、缺血性及出血性中風、周邊及心臟血管疾病、周邊循環受損、周邊動脈阻塞性疾病、原發性及繼發性雷諾氏症候群、微循環障礙、動脈性肺高壓、冠狀動脈及周邊動脈之痙攣、再狹窄(例如在血栓溶解治療、經皮腔內血管形成術(PTA)、腔內冠狀動脈血管形成術(PTCA)之後)、再灌注損傷、內皮功能障礙、缺血性心肌病變、腎功能不全和腎病及壓力相關高血壓。
上述充分定特徵的人類疾病也可以在其他哺乳動物中具有相當的病因而發生，且可同樣地在其中以本發明的化合物治療。
本發明進一步提供根據本發明之化合物，其用於治療及/或預防急性心衰竭、冠狀動脈心臟疾病、心肌梗塞、微血管功能障礙、周邊動脈阻塞性疾病、腎功能不全及腎病之方法中。
治療或預防疾病、病況、病症、損傷或健康問題可為部分或完全的。
本發明因而進一步提供本發明化合物之用途，其用於治療及/或預防病症，特別是上述的病症。
本發明進一步提供本發明化合物之用途，其用於製造治療及/或預防病症、特別是上述的病症之藥物。
本發明進一步提供包含至少一種本發明化合物之藥物，其用於治療及
/或預防病症，特別是上述的病症。
本發明進一步提供本發明化合物之用途，其用於治療及/或預防病症、特別是上述的病症之方法中。
本發明進一步提供治療及/或預防病症、特別是上述的病症之方法，其使用有效量之至少一種本發明化合物。
本發明化合物可單獨使用，或者，若需要時，可與一種或多種其它藥理活性物質組合使用，條件是此組合不會導致不希望的和不可接受的副作用。因此，本發明進一步提供包含至少一種本發明化合物和一種或多種其他藥物的藥物，特別是用於治療和/或預防上述病症。適用於此目的的組合活性成分的較佳實例包括：
●降血壓劑，作為實例及較佳來自下列之群組：鈣拮抗劑，血管收縮素AII拮抗劑，ACE抑制劑，NEP抑制劑，血管肽酶抑制劑及這些之組合，如沙可比曲(sacubitril)/纈沙坦(valsartan)，另外之尼可地爾(nicorandil)，內皮素拮抗劑，血栓素(thromboxan)A2拮抗劑，腎素抑制劑，α-受體阻斷劑，β-受體阻斷劑，礦皮質素受體拮抗劑，ρ-激酶抑制劑，利尿劑，以及其他血管活性化合物，例如腺苷及腺苷受體促效劑；
●抗心律不整劑，作為實例及較佳係為鈉通道阻斷劑、β受體阻斷劑、鉀通道阻斷劑、鈣拮抗劑、If通道阻斷劑、毛地黃屬(digitalis)、副交感神經阻斷藥(迷走神經阻斷劑(vagoliytics))、擬交感神經作用劑及其他抗心律不整劑，例如腺苷、腺苷受體促效劑及維那卡蘭(vernakalant)；
●正性肌力藥劑(positive-inotrop agents)，舉例而言，強心苷(毛地黃(dogoxin))、β-腎上腺素能及多巴胺能促效劑，例如異丙腎上腺素(isoprenalin)、腎上腺素、去甲腎上腺素(noradrenalin)、多巴胺或多保他命(dobutamin)及放鬆素(serelaxin)；
●血管加壓素-受體-拮抗劑，作為實例及較佳係為考尼伐坦(conivaptan)、托伐普坦(tolvaptan)、利希普坦(lixivaptan)、莫札伐普坦(mozavaptan)、沙他伐坦(satavaptan)、SR-121463、RWJ 676070或
BAY 86-8050，以及敘述於WO 2010/105770、WO2011/104322及WO 2016/071212中之化合物；
●鈉利尿劑肽類，作為實例及較佳為動脈利鈉肽(ANP)、利鈉肽B型(BNP,Nesiritid)、利鈉肽C型(CNP)或腎利尿素(urodilatin)；
●心肌肌球蛋白之活化劑，作為實例及較佳為omecamtiv mecarbil(CK-1827452)；
●鈣-增敏劑，作為實例及較佳為左西孟旦(levosimendan)；
●影響粒線體功能/ROS產生之活性化合物，舉例而言，粒線體靶向肽(Bendavia/elamipritide)；
●調節心臟能量代謝之藥劑，作為實例及較佳為乙莫克舍(etomoxir)、二氯乙酸鹽(dichloracetate)、雷諾嗪(ranolazine)或曲美他嗪(trimetazidine)，全部或部分腺苷A1受體促效劑，例如GS-9667(先前已知為CVT-3619)、卡帕諾生(capadenoson)及納雷德生(neladenoson)；
●影響心跳速率之藥劑，作為實例及較佳為伊伐布雷定(ivabradin)；
●抑制環鳥苷單磷酸(cGMP)及/或環腺苷單磷酸(cAMP)降解的化合物，例如磷酸二酯酶(PDE)1、2、3、4及/或5的抑制劑，尤其是PDE 5抑制劑如西地那非(sildenafil)，伐地那非(vardenafil)及他達拉非(tadalafil)，烏地那非(udenafil)、達生他非(desantafil)、阿伐那菲(avanafil)、米羅那非(mirodenafil)、羅地那非(lodenafil)或PF-00489791；
●抗血栓劑，作為實例及較佳來自下列之群組：血小板凝集抑制劑、抗凝血劑或促纖維蛋白分解物質；
●支氣管擴張劑，作為實例及較佳選自來自下列之群組：β-腎上腺素能受體促效劑，例如特別是沙丁胺醇(albuterol)、異丙腎上腺素(isoproterenol)、異丙喘寧(metaproterenol)、特布他林(terbutalin)、福莫特羅(formoterol)或沙美特羅(salmeterol)，或者選自抗膽鹼能藥之群組，例如特別是異丙托溴銨(ipratropium bromide)；
●抗發炎劑，作為實例及較佳係來自糖皮質類固醇之群組，例如，特別是潑尼松(prednisone)、潑尼松龍(prednisolone)、甲基潑尼松龍、
氟羥潑尼松龍(triamcinolone)、地塞米松(dexamethasone)、倍氯米松(beclomethasone)、倍他美松(betamethasone)、氟尼縮松(flunisolide)、布地縮松(budesonide)或氟地縮松(fluticasone)；以及非類固醇的抗發炎劑(NSAIDs)，例如，特別是乙醯基水楊酸(阿斯匹靈)、伊布洛芬(ibuprofen)、萘普生(naproxen)，5-胺基水楊酸衍生物，白三烯拮抗劑，TNF-α-抑制劑及化學激活素-受體拮抗劑，例如CCR1、2及/或5抑制劑；
●調節脂肪代謝之活性化合物，作為實例及較佳來自下列群組：甲狀腺受體促效劑，膽固醇合成抑制劑，例如作為實例及較佳地HMG-CoA還原酶或角鯊烯合成抑制劑，ACAT抑制劑，CETP抑制劑，MTP抑制劑，PPAR-α，PPAR-γ及/或PPAR-δ促效劑，膽固醇吸收抑制劑，脂肪酶抑制劑，聚合膽汁酸吸附劑，膽汁酸再吸收抑制劑及脂蛋白(a)拮抗劑。
●抑制訊號傳導級聯之化合物，作為實例及較佳為來自激酶抑制劑之群組，尤其是來自酪胺酸激酶抑制劑及/或絲胺酸/蘇胺酸激酶抑制劑；
●抑制細胞外基質降解與改變之化合物，作為實例及較佳為基質金屬蛋白酶(MMP)抑制劑，尤其是凝乳酶、基質裂解素(stromelysin)、膠原酶、明膠酶及蛋白聚醣酶(aggrecanases)(在此內文中特別是MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11與MMP-13)以及金屬彈性蛋白酶(MMP-12)及嗜中性球彈性蛋白酶(HNE)之抑制劑，例如西維來司他(sivelestat)或DX-890；
●阻斷血清素與其受體結合之化合物，作為實例及較佳為5-HT2b受體之拮抗劑；
●有機硝酸鹽與NO供體，作為實例及較佳為硝普鈉(sodium nitroprusside)、硝基甘油、單硝酸異山梨醇(isosorbide mononitrate)、二硝酸異山梨醇、嗎多明(molsidomine)或SIN-1，以及吸入性NO；
●NO-非依賴性、但血色素-依賴性之可溶性鳥苷酸環化酶刺激劑，例如，尤其是WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO2014/068099及2014/131760中所敘述之化合物；
●NO-非依賴性且血色素-非依賴性之可溶性鳥苷酸環化酶活化劑，例如，尤其是WO 01/19355、WO 01/19780、WO2012/139888及2014/012934中所敘述之化合物；
●增加cGMP合成之化合物，舉例而言，sGC調節劑，例如，作為實例及較佳為利希奎特(riociguat)、西那奎特(cinaciguat)或維利奎特(vericiguat)；
●前列環素類似物，作為實例及較佳為伊洛前列素(iloprost)、貝前列素(beraprost)、曲前列素(treprostinil)或依前列醇(epoprostenol)；
●抑制可溶性環氧化物水解酶(sEH)之化合物，舉例而言，N,N'-二環己基脲、12-(3-金剛烷-1-基-脲基)十二烷酸或1-金剛烷-1-基-3-{5-[2-(2-乙氧基乙氧基)乙氧基]戊基}脲；
●調節葡萄糖代謝作用之化合物，舉例而言，胰島素、雙胍、噻唑啶二酮、磺醯基脲、阿卡波糖(acarbose)、DPP4抑制劑、GLP-1類似物或SGLT-1抑制劑；
●調節神經遞質之活性化合物，舉例而言，三環類抗抑鬱藥，例如阿米替林(amitryptiline)和丙咪嗪(imipramine)，單氧化酶(MAO)抑制劑如嗎氯苯甲醯胺(moclobemid)，5-羥色胺/去甲腎上腺素再攝取抑制劑如文拉法辛(venlaflaxin)，選擇性5-羥色胺再攝取抑制劑如舍曲林(sertraline)或去甲腎上腺素/5-羥色胺選擇性之抗抑鬱藥，例如米氮平(mirtazepine)。
●抗焦慮、鎮靜和催眠作用的物質，即所謂的鎮靜劑，例如具有短期或中期作用的苯二氮呯類藥物(benzodiazepines)。
●止痛藥，例如鴉片類藥物(opiates)。
降血壓藥劑較佳被理解為表示來自下列群組之化合物：鈣拮抗劑、血管收縮素AII拮抗劑、ACE抑制劑、內皮肽拮抗劑、TXA2拮抗劑、腎素抑制劑、α-受體阻斷劑、β-受體阻斷劑、礦物皮質激素受體拮抗劑、ρ-激酶抑制劑及利尿劑。
在本發明之一個較佳具體實例中，本發明之化合物係與鈣拮抗劑組合投藥，舉例而言及較佳為硝苯地平(nifedipine)、氨氯地平(amlodipine)、維拉帕米(verapamil)或地爾硫(diltiazem)。
在本發明之一個較佳具體實例中，本發明之化合物係與血管收縮素AII拮抗劑組合投藥，舉例而言及較佳為氯沙坦(losartan)、坎地沙坦(candesartan)、纈沙坦(valsartan)、替米沙坦(telmisartan)或愛普沙坦(embursatan)、厄貝沙坦(irbesartan)、奧美沙坦(olmesartan)、伊普沙坦(eprosartan)或阿齊沙坦(azilsartan)，或與雙重血管收縮素AII拮抗劑/NEP抑制劑組合投藥，舉例而言及較佳為LCZ696(纈沙坦/沙卡布曲(sacubitril))。
在本發明之一個較佳具體實例中，根據本發明之化合物係與ACE抑制劑組合投藥，舉例而言及較佳為依那普利(enalapril)、卡托普利(captopril)、賴諾普利(lisinopril)、雷米普利(ramipril)、地拉普利(delapril)、福辛普利(fosinopril)、喹那普利(quinopril)、培哚普利(perindopril)或群多普利(trandopril)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與內皮素拮抗劑組合投藥，舉例而言及較佳為波生坦(bosentan)、達盧生坦(darusentan)、安倍生坦(ambrisentan)、avosentan、macitentan、atrasentan或司他生坦(sitaxsentan)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與血栓素拮抗劑組合投藥，舉例而言及較佳為賽曲思特(seratrodast)或KP-496。
在本發明之一個較佳具體實例中，本發明之化合物係與腎素抑制劑組合投藥，舉例而言及較佳為阿利吉崙(aliskiren)、SPP-600或SPP-800。
在本發明之一個較佳具體實例中，本發明之化合物係與α-1-受體阻斷劑組合投藥，舉例而言及較佳為哌唑嗪(prazosin)。
在本發明之一個較佳具體實例中，本發明之化合物係與β-受體阻斷劑組合投藥，舉例而言及較佳為普萘洛爾(propranolol)、阿替洛爾(atenolol)、噻嗎洛爾(timolol)、吲哚洛爾(pindolol)、心得舒(alprenolol)、心得平(oxprenolol)、噴布洛爾(penbutolol)、布拉洛爾(bupranolol)、美替洛爾(metipranolol)、納多洛爾(nadolol)、美平多爾(mepindolol)、卡瑞洛爾(carazolol)、索他洛爾(sotalol)、美托洛爾(metoprolol)、倍他洛爾(betaxolol)、塞利洛爾(celiprolol)、比索洛爾(bisoprolol)、卡替洛爾(carteolol)、艾司洛
爾(esmolol)、拉貝洛爾(labetalol)、卡維地洛(carvedilol)、阿大普爾(adaprolol)、蘭地洛爾(landiolol)、奈必洛爾(nebivolol)、依泮洛爾(epanolol)或布新洛爾(bucindolol)。
在本發明之一個較佳具體實例中，本發明之化合物係與礦物皮質激素受體拮抗劑組合投藥，舉例而言及較佳為安體舒通(spironolactone)、依普利酮(eplerenone)或芬尼酮(finerenone)。
在本發明之一個較佳具體實例中，本發明之化合物係與ρ激酶抑制劑組合投藥，舉例而言及較佳為法舒地爾(fasudil)、Y-27632、SLx-2119、BF-66851、BF-66852、BF-66853、KI-23095、SB-772077、GSK-269962A或BA-1049。
在本發明之一個較佳具體實例中，本發明之化合物係與利尿劑組合投藥，舉例而言，托拉塞米(furosemide)、呋塞米(torasemide)、布美他尼(bumetanide)及吡咯他尼(piretanide)，及與保鉀利尿劑例如阿米洛利(amiloride)及氨苯喋啶(triamterene)組合，以及與噻嗪類利尿劑組合，例如氫氯噻嗪(hydrochlorothiazide)、氯噻酮(chlorthalidone)、希伯胺(xipamide)及吲噠帕胺(indapamide)。
抗血栓劑係較佳地被理解為表示來自下列群組之化合物：血小板凝集抑制劑、抗凝血劑或促纖維蛋白分解物質。
在本發明之一個較佳具體實例中，本發明化合物係與血小板凝集抑制劑組合投藥，舉例而言及較佳為阿斯匹靈、氯吡格雷(clopidogrel)、普拉格雷(prasugrel)、噻氯匹定(ticlopidine)、百無凝(ticagrelor)、坎格雷洛(cangrelor)、依諾格雷(elinogrel)、替羅非班(tirofiban)，PAR-1拮抗劑，例如沃拉帕沙(vorapaxar)，PAR-4拮抗劑，EP3拮抗劑，例如DG041，或腺苷轉運體抑制劑，例如潘生丁(dipyridamol)。
在本發明之一個較佳具體實例中，本發明化合物係與GPIIb/IIIa拮抗劑組合投藥，舉例而言及較佳為替羅非班(tirofiban)或阿昔單抗(abciximab)。
在本發明之一個較佳具體實例中，本發明化合物係與凝血酶抑制劑組合投藥，舉例而言及較佳為達比加群(dabigatran)、希美加群(ximelagatran)、
美拉加群(melagatran)、比伐盧定(bivalirudin)或克賽(clexane)。
在本發明之一個較佳具體實例中，本發明化合物係與因子Xa抑制劑組合投藥，舉例而言及較佳為利伐沙班(rivaroxaban)、阿哌沙班(apixaban)、依杜沙班(edoxaban)(DU-176b)、達雷沙班(darexaban)、貝曲沙班(betrixaban)、奧米沙班(otamixaban)、雷塔沙班(letaxaban)、非地沙班(fidexaban)、瑞拉沙班(razaxaban)、磺達肝癸鈉(fondaparinux)、艾卓肝素(idraparinux)，及凝血酶抑制劑，例如，舉例而言及較佳為達比加群(dabigatran)，雙重凝血酶/因子Xa抑制劑，例如，舉例而言及較佳為他諾吉群(tanogitran)，或因子XIa抑制劑。
在本發明之一個較佳具體實例中，本發明化合物係與肝素或低分子量(LMW)肝素衍生物組合投藥，例如，舉例而言，亭扎肝素(tinzaparin)、舍托肝素(certoparin)、帕肝素(parnaparin)、那屈肝素(nadroparin)、阿地肝素(ardeparin)、伊諾肝素(enoxaparin)、瑞維肝素(reviparin)、達肝素(dalteparin)、達那肝素(danaparoid)、semuloparin(AVE 5026)、阿都米肝素(adomiparin)(M118)and及EP-42675/ORG42675。
在本發明之一個較佳具體實例中，本發明化合物係與維生素K拮抗劑組合投藥，舉例而言及較佳為乙苄香豆(Macumar或phenprocoumon)。
在本發明之一個較佳具體實例中，本發明化合物係與前纖維蛋白溶解化合物組合投藥，舉例而言及較佳為鏈激酶、尿激酶或纖維蛋白溶酶原活化劑。
脂肪代謝調節劑較佳被理解為表示來自下列群組之化合物：CETP抑制劑、甲狀腺受體促效劑、膽固醇合成抑制劑例如HMG-CoA-還原酶或角鯊烯合成抑制劑、ACAT抑制劑、MTP抑制劑、PPAR-α、PPAR-γ及/或PPAR-δ促效劑、膽固醇吸收抑制劑、聚合膽汁酸吸附劑、膽汁酸再吸收抑制劑、脂肪酶抑制劑及脂蛋白拮抗劑(a)拮抗劑。
在本發明之一個較佳具體實例中，本發明之化合物係與CETP抑制劑組合投藥，舉例而言及較佳為托斯賽曲匹(torcetrapib)(CP-529 414)、安那賽曲匹(anacetrapib)、JJT-705或CETP疫苗(Avant)。
在本發明之一個較佳具體實例中，本發明之化合物係與甲狀腺受體促
效劑組合投藥，舉例而言及較佳為D-甲狀腺素(thyroxine)、3,5,3'-三碘甲狀腺素(T3)、CGS 23425或阿昔替羅(axitirome)(CGS 26214)。
在本發明之一個較佳具體實例中，本發明之化合物係與來自斯他汀類的HMG-CoA-還原酶抑制劑組合投藥，舉例而言及較佳為洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)或匹伐他汀(pitavastatin)。
在本發明之一個較佳具體實例中，本發明之化合物係與角鯊烯合成抑制劑組合投藥，舉例而言及較佳為BMS-188494或TAK-475。
在本發明之一個較佳具體實例中，本發明之化合物係與ACAT抑制劑組合投藥，舉例而言及較佳為阿伐麥布(avasimibe)、油甲芐胺(melinamide)、帕替麥布(pactimibe)、依魯麥布(eflucimibe)或SMP-797。
在本發明之一個較佳具體實例中，本發明之化合物係與MTP抑制劑組合投藥，舉例而言及較佳為英普他派(implitapide)、BMS-201038、R-103757或JTT-130。
在本發明之一個較佳具體實例中，本發明之化合物係與PPAR-γ激動劑組合投藥，舉例而言及較佳為吡格列酮(pioglitazone)或羅格列酮(rosiglitazone)。
在本發明之一個較佳具體實例中，本發明之化合物係與PPAR-δ促效劑組合投藥，舉例而言及較佳為GW 501516或BAY 68-5042。
在本發明之一個較佳具體實例中，本發明之化合物係與膽固醇吸收抑制劑組合投藥，舉例而言及較佳為依澤替米貝(ezetimibe)、替奎安(tiqueside)或帕馬苷(pamaqueside)。
在本發明之一個較佳具體實例中，本發明之化合物係與脂肪酶抑制劑組合投藥，舉例而言及較佳為奧利司他(orlistat)。
在本發明之一個較佳具體實例中，本發明之化合物係與聚合膽汁酸吸附劑組合投藥，舉例而言及較佳為消膽胺(cholestyramine)、考來替泊(colestipol)、考來維倫(colesolvam)、CholestaGel或考來替蜜(colestimide)。
在本發明之一個較佳具體實例中，本發明之化合物係與膽汁酸再吸收抑制劑組合投藥，舉例而言及較佳為ASBT(=IBAT)抑制劑，例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在本發明之一個較佳具體實例中，本發明之化合物係與脂蛋白拮抗劑(a)拮抗劑組合投藥，舉例而言及較佳為吉卡濱鈣(gemcabene calcium)(CI-1027)或菸鹼酸。
抑制訊號傳導級聯之活性化合物較佳被理解為表示來自以下群組之化合物：酪胺酸激酶抑制劑及/或絲胺酸/蘇胺酸抑制劑；
在本發明之一個較佳具體實例中，本發明之化合物係與激酶抑制劑組合投藥，舉例而言及較佳為硼替佐米(bortezomib)、卡奈替尼(canertinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、伊馬替尼(imatinib)、拉帕替尼(lapatinib)、來他替尼(lestaurtinib)、洛那法尼(lonafarnib)、尼達尼布(nintedanib)、達沙替尼(dasatinib)、尼洛替尼(nilotinib)、博舒替尼(bosutinib)、阿西替尼(axitinib)、替拉替尼(telatinib)、伊馬替尼(imatinib)、布立尼布(brivanib)、帕唑帕尼(pazopanib)、培加替尼(pegaptinib)、培利替尼(pelitinib)、賽瑪西尼(semaxanib)、索拉非尼(sorafenib)、瑞格菲尼(regorafenib)、舒尼替尼(sunitinib)、坦度替尼(tandutinib)、替吡法尼(tipifarnib)、瓦他拉尼(vatalanib)、法舒地爾(fasudil)、氯尼達明(lonidamine)、來氟米特(leflunomide)、BMS-3354825或Y-27632。
在本發明之一個較佳具體實例中，本發明之化合物係與影響葡萄糖代謝之藥劑組合投藥，舉例而言及較佳為胰島素、磺醯基脲、阿卡波糖(acarbose)、DPP4抑制劑、GLP-1類似物或SGLT-1抑制劑。.
調節神經遞質之活性化合物較佳被理解為表示來自以下群組：三環類抗抑鬱藥，單氧化酶(MAO)抑制劑，5-羥色胺/去甲腎上腺素再攝取抑制劑(SNR)及去甲腎上腺素/5-羥色胺選擇性之抗抑鬱藥(NaSSa)。
在本發明之一個較佳具體實例中，本發明之化合物係與三環類抗抑鬱藥組合投藥，舉例而言及較佳為阿米替林(amitryptiline)和丙咪嗪(imipramine)。
在本發明之一個較佳具體實例中，本發明之化合物係與單氧化酶(MAO)抑制劑組合投藥，舉例而言及較佳為嗎氯苯甲醯胺(moclobemide)。
在本發明之一個較佳具體實例中，本發明之化合物係與選擇性5-羥色胺/去甲腎上腺素再攝取抑制劑(SNRI)組合投藥，舉例而言及較佳為文拉法辛(venlaflaxine)。
在本發明之一個較佳具體實例中，本發明之化合物係與選擇性5-羥色胺再攝取抑制劑例如舍曲林(sertraline)組合投藥。
在本發明之一個較佳具體實例中，本發明之化合物係與去甲腎上腺素/5-羥色胺選擇性之抗抑鬱藥(NaSSa)組合投藥，舉例而言及較佳為米氮平(mirtazepine)。
具有鎮痛、抗焦慮或鎮靜性質之活性化合物較佳被理解為表示來自鴉片類及苯二氮呯類藥物。
在本發明之一個較佳具體實例中，本發明之化合物係與鴉片類藥物組合投藥，舉例而言及較佳為嗎啡或舒芬太尼(sufentanil)或芬太尼(fentanyl)。
在本發明之一個較佳具體實例中，本發明之化合物係與苯二氮呯類藥物組合投藥，舉例而言及較佳為咪達唑侖(midazolam)或地西泮(diazepam)。
增加cGMP合成之活性化合物例如sGC調節劑較佳被理解為刺激或活化可溶性鳥苷酸環化酶之化合物。
在本發明之一個較佳具體實例中，本發明之化合物係與sGC調節劑組合投藥，舉例而言及較佳為利希奎特(riociguat)、西那奎特(cinaciguat)或維利奎特(vericiguat)。
在本發明之一個較佳具體實例中，本發明之化合物係與全部或部分腺苷A1受體促效劑組合投藥，例如GS-9667(先前已知為CVT-3619)、卡帕諾生(capadenoson)及納雷德生(neladenoson)或影響粒線體功能/ROS產生之活性化合物，例如粒線體靶向肽(Bendavia/elamipritide)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與TGFβ拮抗劑組合投藥，舉例而言及較佳為吡非尼酮(pirfenidone)或夫蘇木單抗
(fresolimumab)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與TNFα拮抗劑組合投藥，舉例而言及較佳為阿達木單抗(adalimumab)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與HIF-PH抑制劑組合投藥，舉例而言及較佳為莫立司他(molidustat)或羅沙司他(roxadustat)。
在本發明之一個較佳具體實例中，根據本發明之化合物係與5-羥色胺受體拮抗劑組合投藥，舉例而言及較佳為PRX-08066。
特別較佳者為根據本發明的化合物與一或多個其他活性化合物之組合，該一或多個其他活性化合物係選自由以下組成之群組：血小板凝集抑制劑、抗凝血劑、前纖維蛋白溶解物質、影響心臟能量代謝及粒線體功能/ROS產生之物質、降血壓藥物、礦物皮質激素受體拮抗劑、HMG CoA還原酶抑制劑、調節脂質代謝的藥物、調節葡萄糖代謝的活性化合物及用於焦慮和疼痛治療的活性化合物，例如苯二氮呯類和鴉片類藥物。
本發明進一步提供醫藥品及醫藥組成物，其包含至少一種本發明的化合物物，通常一起與一或多種惰性、無毒、醫藥上合適的賦形劑，以及其用於上述目的之用途。
根據本發明之化合物可以全身及/或局部地作用。為此目的，其等可以合適的方式投予，舉例而言，例如經由口部、非經腸胃、肺部、鼻部、舌下、舌部、頰部、直腸、陰道、皮膚、經皮、經結膜、經耳途徑或作為植入物或支架。
根據本發明之化合物可以合適這些投藥途徑之投藥形式被投予。
非經腸胃投藥可在避免吸收步驟(例如靜脈內、動脈內、心內、脊椎內或腰內(intralumbar)途徑)或包括再吸收(例如肌內、皮下、皮內、經皮、玻璃體內或腹膜內途徑)而達成。合適用於非經腸胃投藥之形式特別為呈溶液、懸浮液、乳液、冷凍乾燥物或無菌粉末形式之用於注射及輸注的製劑。
用於經口投藥之合適投藥形式係為根據先前技術作用且快速及/或以改良方式遞送、且其含有呈結晶及/或非晶形及/或溶解形式的本發明化合
物之投予形式，舉例而言，例如錠劑(未塗覆或經塗覆的錠劑，例如以腸衣塗層或不可溶或具延遲溶解的塗層，其控制根據本發明的化合物之釋放)、快速於口內崩解的錠劑、薄膜/薄片、薄膜/冷凍乾燥物、膠囊(例如硬式或軟式明膠膠囊)、經糖塗覆的錠劑、顆粒、丸劑、粉末、乳劑、懸浮劑、氣溶膠或溶液。
用於其他投藥途徑之合適投予形式為，舉例而言，用於吸入之醫藥形式(包括粉末吸入劑，噴霧器)、鼻用滴劑、溶液或噴劑；用於舌部、舌下或頰部投藥之錠劑、薄膜/薄片或膠囊、栓劑、眼部滴劑、眼部油膏、眼部洗液、眼部插入劑、耳部滴劑、噴劑、粉劑、沖洗液或棉塞、陰道用膠囊、水性懸浮液(洗液、搖溶混合物)、親脂性懸浮液、乳液、微乳液、油膏、乳霜、經皮醫療系統(例如貼布)、乳劑、糊劑、泡沫劑、灑粉劑、植入物或支架。
根據本發明之化合物可被轉換成上述之投予形式。此可以本身已知的方式藉由與醫藥上合適之賦形劑混合來達成。此等賦形劑特別包括：●填料與載劑(例如，纖維素、微晶纖維素(例如Avicel®)、乳糖、甘露糖醇、澱粉、磷酸鈣(例如Di-Cafos®))，●油膏基質(例如，凡士林、石蠟、三酸甘油酯、蠟類、羊毛蠟、羊毛蠟醇、羊毛脂、親水性油膏、聚乙二醇)，●栓劑基質(例如，聚乙二醇、可可脂、硬脂)，●溶劑(例如，水、乙醇、異丙醇、甘油、丙二醇、中鏈三酸甘油酯、脂肪油、液態聚乙二醇、石蠟)，●界面活性劑、乳化劑、分散劑或濕化劑(例如，十二烷基硫酸鈉、卵磷脂、磷脂類、脂肪醇(例如，Lanette®)、山梨糖醇酐脂肪酸酯類(例如，Span®)、聚氧乙烯山梨糖醇酐脂肪酸酯類(例如，Tween®)、聚氧乙烯脂肪酸甘油酯類(例如，Cremophor®)、聚氧乙烯脂肪酸酯類、聚氧乙烯脂肪醇醚類、甘油脂肪酸酯類、泊洛沙姆(poloxamer)(例如：Pluronic®))，●緩衝物質、及酸類與鹼類(例如磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉、碳酸銨、三羥基胺基甲烷(trometamol)、三乙醇胺)，
●等滲劑(例如，葡萄糖、氯化鈉)，●吸附劑(例如，高度分散矽石)，●黏度增加劑、凝膠形成劑、增稠劑或結合劑(例如，聚乙烯吡咯烷酮、甲基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、羧甲基纖維素-鈉、澱粉、卡波姆(carbomer)、聚丙烯酸(例如，Carbopol®)、藻酸鹽、明膠)，●崩解劑(例如，改質澱粉、羧甲基纖維素-鈉、澱粉乙醇酸鈉(例如，Explotab®)、交聯聚乙烯吡咯烷酮、交聯羧甲纖維素-鈉(例如，AcDiSol®))，●流動調節劑、潤滑劑、助滑劑及釋模劑(例如，硬脂酸鎂、硬脂酸、滑石、高度分散矽石(例如，Aerosil®))，●塗覆材料(例如，糖、蟲膠)及用於快速或以修飾方式溶解的薄膜或擴散膜之膜形成劑(例如，聚乙烯吡咯烷酮(例如，Kollidon®)、聚乙烯醇、羥基丙基甲基纖維素、羥基丙基纖維素、乙基纖維素、羥基丙基甲基纖維素酞酸酯、纖維素乙酸酯、纖維素乙酸酯酞酸酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如，Eudragit®))，●膠囊材料(例如，明膠、羥基丙基甲基纖維素)，●合成性聚合物(例如，聚丙交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如，Eudragit®)，聚乙烯吡咯烷酮(例如，Kollidon®)、聚乙烯醇、聚乙酸乙烯酯、聚環氧乙烷、聚乙二醇與其等共聚物與嵌段共聚物)，●塑化劑(例如，聚乙二醇、丙二醇、甘油、三乙酸甘油酯、三乙醯基檸檬酸酯、酞酸二丁酯)，●滲透增強劑，●安定劑(舉例而言，抗氧化劑，例如，抗壞血酸、棕櫚酸抗壞血基酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙基酯)，●防腐劑(例如，對羥基苯甲酸酯、山梨酸、硫柳汞、氯化烷基二甲基苄基銨、乙酸氯己定(chlorhexidine acetate)、苯甲酸鈉)，●染料(舉例而言，無機色素，例如，氧化鐵、二氧化鈦)，●風味劑、甜味劑、調味劑與/或味道遮蔽劑。
非經腸胃投予為較佳的。特別較佳的是靜脈內(iv)投予，特別是於生理食鹽水中。
本發明進一步提供醫藥組成物，其包含至少一種根據本發明之化合物，通常一起與一或多種醫藥上合適的賦形劑，以及其根據本發明之用途。
通常，已發現在非經腸胃投予的情況下，有利的是投予約0.001至1mg/kg體重、較佳地約0.01至0.5mg/kg體重之量，以達成有效之結果。在口服投予的情況下，劑量為約0.01至100mg/kg，較佳約0.01至20mg/kg，最佳0.1至10mg/kg體重。在肺內投予的情況下，該量通常為每次吸入約0.1至50mg。
然而，仍可在一些情況下有必要偏離所述量，且特定地為體重、投藥途徑、個人對活性化合物之反應、製劑性質及當施用發生投藥時的時間點或間隔之函數。因此，在一些情況下，以低於上述最低量管理可能已足夠，而在其他情況下，必須超過上述的上限量。若施用較大量時，建議是在一天內將這些分成數個個別劑量投藥。
以下具體實施例係說明本發明。本發明不侷限於該等實例。
除非另有說明，以下試驗與實例中的百分比為重量百分比；重量份(parts are by weight)。液體/液體溶液之溶劑比率、稀釋比率、及濃度在各情況下係以體積為主。
方法1：儀器：Waters Single Quad MS系統；儀器Waters UPLC Acquity；管
柱：Waters BEH C18 1.7μm 50 x 2.1mm；流動相A：1l水+1.0ml(25%濃度氨)/l，流動相B：1l乙腈；梯度：0.0min 92% A→0.1min 92% A→1.8min 5% A→3.5min 5% A；烘箱：50℃；流速：0.45ml/min；UV偵測：210nm(208-400nm)。
方法2：MS儀器類型：Thermo Scientific FT-MS；儀器類型UHPLC+：Thermo Scientific UltiMate 3000；管柱：Waters,HSST3,2.1 x 75mm,C18 1.8μm；流動相A：1l水+0.01%甲酸；流動相B：1l乙腈+0.01%甲酸；梯度：0.0min 10% B→2.5min 95% B→3.5min 95% B；烘箱：50℃；流速：0.90ml/min；UV偵測：210nm/最佳整合路徑210-300nm。
方法3：儀器：Waters ACQUITY SQD UPLC系統；管柱：Waters Acquity UPLC HSS T3 1.8μm 50 x 1mm；流動相A：1l水+0.25ml 99%濃度甲酸，流動相B：1l乙腈+0.25ml 99%濃度甲酸；梯度：0.0min 90% A→1.2min 5% A→2.0min 5% A；烘箱：50℃；流速：0.40ml/min；UV偵測：208-400nm。
方法4：儀器：Agilent MS Quad 6150；HPLC：Agilent 1290；管柱：Waters Acquity UPLC HSS T3 1.8μm 50 x 2.1mm；流動相A：1l水+0.25ml 99%濃度甲酸，流動相B：1l乙腈+0.25ml 99%濃度甲酸；梯度：0.0min 90% A→0.3min 90% A→1.7min 5% A→3.0min 5% A；烘箱：50℃；流速：1.20ml/min；UV偵測：205-305nm。
方法5：MS儀器類型：ThermoFisherScientific LTQ-Orbitrap-XL；HPLC儀器類型：Agilent 1200SL；管柱：Agilent,POROSHELL 120,3 x 150mm,SB-C18 2.7μm；流動相A：1l水+0.1%三氟乙酸；流動相B：1l乙腈+0.1%三氟乙酸；梯度：0.0min 2% B→0.3min 2% B→5.0min 95% B→10.0min 95% B；烘箱：40℃；流速：0.75ml/min；UV偵測：210nm。
方法6：儀器：Waters ACQUITY SQD UPLC系統；管柱：Waters Acquity UPLC HSS T3 1.8μm 50 x 1mm；流動相A：1l水+0.25ml 99%濃度甲酸，流動相B：1l乙腈+0.25ml 99%濃度甲酸；梯度：0.0min 95% A→6.0min 5% A→7.5min 5% A；烘箱：50℃；流速：0.35ml/min；UV偵測：210-400nm。
其他細節：
在藉由層析純化本發明化合物之情況下，特別是藉由管柱層析法純化，用於例如Biotage SNAP柱KP-Sil®或KP-NH®之預填充矽膠柱，係與Biotage系統(SP4®或Isolera Four®)組合，所使用之洗提液為己烷/乙酸乙酯或二氯甲烷/甲醇梯度。
在藉由製備性HPLC經由上述方法(其中洗提液含有添加劑例如三氟乙酸或甲酸)純化本發明化合物之情況下，本發明化合物可以鹽類形式得到，例如三氟乙酸鹽或甲酸鹽，若本發明化合物含有足夠的鹼性官能性時。此鹽類可藉由熟習該項技術者已知的多種方法被轉化成對應的游離鹼。
在下文說明之本發明合成中間物與實施例之情況下，任何呈對應鹼或酸的鹽形式之化合物通常為未知確實化學計量組成之鹽類，如藉由各別製備及/或純化方法所得。除非另有更詳細說明，否則外加在名稱與結構式上例如：「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x鹽酸」、「xCF3COOH」、「x Na+」應瞭解並無意代表此等鹽類之化學計量，而係僅說明本文所存在之形成鹽組份之特徵。
此點同樣適用於若合成中間物或實施例或其鹽類係藉由所述製備及/或純化方法以未知化學計量組成(若有指定型態時)之溶劑合物(例如水合物)所得到時。
此外，根據本發明之二級胺可以旋轉異構物/異構物混合物存在，特別是在NMR研究中。純度數值通常基於LC/MS色譜圖中的相應峰積分，但也可藉助於1H NMR光譜另外確定。若沒有指示純度，根據LC/MS色譜圖中的自動峰積分，純度通常為100%，或純度尚未明確確定。
若指示純度<100%，則理論%之陳述產率通常校正純度。在含溶劑或污染的批次中，正式的產率可為「>100%」；在這些情況下，產率不根據溶劑或純度進行校正。
在所有1H NMR光譜數據中，化學位移δ[ppm]=以ppm陳述。
在以下段落中報告的1H NMR光譜中質子信號的多重性代表在各情況下所觀察到的信號形式，且並未考慮任何高階信號現象。通常，所述化學位移係指所討論信號的中心。在寬多重峰的情況下，給予出間隔。被溶劑或水遮蔽的信號暫時指定或尚未被列出。顯著擴大的信號-例如由
分子部分的快速旋轉或由於交換質子引起的-同樣地被暫時分配(通常稱為寬多重峰或寬單重峰)或未列出。
若陳述時，熔點及熔點範圍係未經校正的。
所選擇的合成中間體和實施例之1H NMR數據係以1H NMR峰列表的形式陳述。對於每個信號峰值，首先列出δ[ppm]=以ppm為單位的值，然後列出圓括號中的信號強度。列出了不同信號峰值的δ[ppm]=值/信號強度數對，且彼此之間用逗號分隔。因此，實例的峰值列表採用以下形式：δ[ppm]=1(強度1),δ[ppm]=2(強度2),...,δ[ppm]=i(強度i),...,δ[ppm]=n(強度n)。
尖銳信號的強度係與印出的NMR光譜實例中的信號高度(以cm為單位)相關，且相較於其他信號顯示信號強度的真實比例。在寬信號的情況下，相較於頻譜中最強的信號，可給予幾個峰值或信號的中間及其相對強度。1H NMR峰值的列表與常規的1H NMR印出圖(printouts)類似，且因此通常含有常規NMR解釋中列出的所有峰值。此外，與常規的1H NMR印出圖一樣，其等可包含溶劑信號，同樣由本發明提供的目標化合物之立體異構物信號，及/或雜質峰。目標化合物的立體異構物峰及/或雜質峰通常平均而言具有比目標化合物的峰更低的強度(例如，純度>90%)。這種立體異構物和/或雜質可以是特定製備方法的典型。因此，它們的峰可以參考「副產物指紋」幫助識別製備過程的再現。若需要時，藉由已知方法(MestreC，ACD模擬或使用經驗確定的預期值)計算目標化合物的峰的專家可視情況地使用另外的強度過濾器分離目標化合物的峰。這種分離會與常規1H NMR解讀中的峰值挑選相似。呈波峰列表形式之NMR數據呈現之進一步詳細內容可參見公開文獻："Citation of NMR Peaklist Data within Patent Applications"(參見http：//www.researchdisclosure.com/searching-disclosures,Research Disclosure Database Number 605005,2014,1st August 2014)。在該所述Research Disclosure Database Number 605005中例行說明之波峰挑選法中，「最小高度」參數可設在1%至4%之間。視所分析化合物之化學結構類型及/或濃度而定，可建議將「最小高度」參數設定在<1%之數值。
其製備未在下文中明確說明的所有反應物或試劑係從通常可獲得的來源商業上購得。對於其製備同樣未在下文說明且不可商業上得到或從通常不可獲得的來源獲得的所有其他反應物或試劑，參考其中說明其等製備的公開文獻。
將2-溴-1,1-二甲氧基乙胺(140ml,1.2mol)首先加入於365ml水及濃縮的鹽酸鹽(8.5ml)中，並使其於85℃攪拌1小時。使混合物冷卻且小心加入固體碳酸氫鈉(104g,1.23mol)(pH=8)。將2-胺基異菸鹼酸甲酯(125g,822mmol)加入，且使懸浮液在100℃攪拌三小時。使接著出現的溶液冷卻至室溫且攪拌隔夜。將再形成的懸浮液以抽吸過濾，且以水重複洗滌殘留物。使固體(標題化合物)於真空乾燥箱中在40℃下乾燥隔夜。使用氫氧化鈉水溶液將濾液調整至pH 10且以氯化鈉使其飽和。將混合物萃取三次，每次用500ml乙酸乙酯萃取。使合併的有機相於硫酸鎂上乾燥、過濾且濃縮。將以此方式得到的殘留物(標題化合物)在高真空下乾燥，將兩種標題化合物的進料合併。此得到總共108g(75%理論值，100%純度)之標題化合物。
LC-MS(方法1)：Rt=0.95min；MS(ESIpos)：m/z=177[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：3.325(16.00),7.317(3.44),7.320(3.29),7.334(3.63),7.337(3.52),7.799(8.51),8.156(15.65),8.650(5.65),8.667(5.53).
將咪唑并[1,2-a]吡啶-7-甲酸甲酯(51.1g,290mmol)溶於2.5l乙腈中。加入1-碘吡咯啶-2,5-二酮(68.5g,304mmol)且使混合物在室溫下攪拌四天，將混合物加入3.5l水中、使用碳酸氫鈉調整至pH 8且攪拌15分鐘。將沉澱物以抽吸過濾，且以飽和碳酸氫鈉水溶液洗滌一次並以水洗滌一次。接著將固體懸浮於乙腈中且吸乾，將固體在減壓下乾燥兩天，得到總共81g(93%之理論值)標題化合物。
LC-MS(方法2)：Rt=1.30min；MS(ESIpos)：m/z=303[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：3.896(0.56),3.909(16.00),7.453(1.52),7.457(1.59),7.471(1.63),7.475(1.70),7.944(3.59),8.162(1.97),8.436(2.14),8.454(2.16).
將甲基3-碘咪唑并[1,2-a]吡啶-7-甲酸(2.80g,9.27mmol)及肆(三苯基膦)鈀(0)(536mg,463μmol)首先加入於75ml 1,2-二甲氧基乙烷中，加入(3,5-二甲基-1,2-唑-4-基)硼酸(3.27g,23.2mmol)、碳酸鉀(2.56g,18.5mmol)及37ml水。使混合物在75℃攪拌4.5小時，加入更多的(3,5-二甲基-1,2-唑-4-基)硼酸(653mg,4.64mmol)及肆(三苯基膦)鈀(0)(268mg,232μmol)，且將混合物在75℃攪拌24小時。藉由矽膠色層分析(340g Snap Cartridge Biotage®；Biotage-Isolera-One®；二氯甲烷/甲醇1：1+0.45%乙酸)
純化反應混合物。將產物餾份合併且濃縮，此得到總共1230mg(52%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.56min；MS(ESIpos)：m/z=258[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.11),0.008(1.11),1.563(0.48),1.574(0.43),2.128(15.93),2.336(16.00),3.243(0.57),3.896(0.47),7.337(1.56),7.342(1.62),7.355(1.62),7.359(1.70),7.920(4.55),8.195(2.21),8.235(2.02),8.253(1.97).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(3.85g,14.2mmol)首先加入於90ml四氫呋喃/甲醇中，加入氫氧化鈉水溶液(28ml,1.0M,28mmol)，且將混合物在室溫下攪拌30分鐘。於旋轉蒸發器上除去有機溶劑，且以4N鹽酸使殘留物酸化。將沉澱固體以抽吸濾出且於高真空下乾燥。此得到2.42g(100%純，66%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.54min；MS(ESIpos)：m/z=258[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.21),0.008(1.15),2.128(15.97),2.336(16.00),7.340(1.54),7.344(1.56),7.358(1.57),7.362(1.61),7.927(4.93),8.199(2.56),8.241(2.00),8.260(1.89),13.365(0.82).
將濾液濃縮且將殘留物以甲醇攪拌。將不可溶的鹽類濾出且丟棄。將濾液再濃縮且將殘留物以乙腈攪拌。將固體以抽吸濾出且在高真空下乾燥，此得到(100%純，37%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.57min；MS(ESIpos)：m/z=258[M+H]+
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(680mg,
2.51mmol)首先加入於16ml四氫呋喃/甲醇(3：1)中，加入氫氧化鈉水溶液(5.0ml,1.0M,5.0mmol)且使混合物在室溫下攪拌隔夜。以1N鹽酸鹽使反應混合物中和及濃縮。以甲醇攪拌殘留物且將不可溶的鹽類丟棄。將濾液濃縮且將殘留物以乙腈攪拌。將固體以抽吸濾出且在高真空下乾燥，此得到總共630mg(90%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.56min；MS(ESIpos)：m/z=258[M+2H-Na]+
將3-碘咪唑并[1,2-a]吡啶-7-甲酸甲酯(50.0g,166mmol)首先加入於2.51的N,N-二甲基甲醯胺中。加入(3,5-二甲基-1,2-唑-4-基)硼酸(46.7g,331mmol)及氟化銫(75.4g,497mmol)。在10分鐘內，使氬氣通過反應混合物。加入[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)(13.5g,16.6mmol)，使混合物加熱至90℃且攪拌三小時。將混合物加入水及少量飽和碳酸氫鈉水溶液中，且以乙酸乙酯萃取三次。以水及飽和氯化鈉水溶液洗滌合併之有機相，使其於硫酸鎂上乾燥、過濾且濃縮。藉由矽膠管柱層析(1500g管柱，Biotage-Isolera-One®；梯度乙酸乙酯於環己烷中20-100%)純化殘留物。將產物部分合併且濃縮，此得到總共32.2g(72%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=1.13min；MS(ESIpos)：m/z=272[M+H]+
將1-(咪唑并[1,2-a]吡啶-2-基)甲酸二胺鹽酸鹽水合物(1.00g,4.20mmol)首先加入於15ml四氫呋喃中，且冷卻至0℃。在此溫度，連續加入三乙胺(1.8ml,13mmol)、4-二甲基胺基吡啶(77.0mg,630μmol)及二碳酸二-三級丁酯(1.0ml,4.4mmol)。使反應混合物在室溫下攪拌隔夜，加入水且以乙酸乙酯萃取混合物。以水及飽和氯化鈉水溶液洗滌有機層，使其於硫酸鎂上乾燥、過濾級濃縮，此得到422mg(41%理論值，69%純度)之標題化合物。
LC-MS(方法1)：Rt=1.21min；MS(ESIpos)：m/z=248[M+H]+
將(咪唑并[1,2-a]吡啶-2-基甲基)胺甲酸三級丁酯(963mg,3.89mmol)首先加入於18ml四氫呋喃中，且加入碘甲烷(1.1ml,18mmol)且使混合物在室溫下攪拌隔夜。將沉澱的固體以抽吸過濾，以四氫呋喃洗滌且在高真空下乾燥。此得到1.36g(87%理論值，97%純度)之標題化合物。
LC-MS(方法3)：Rt=0.43min；MS(ESIpos)：m/z=262[M-I]+
將2-{[(三級丁氧基羰基)胺基]甲基}-1-甲基咪唑并[1,2-a]吡啶-1-鎓碘化物(1.36g,3.49mmol)首先加入於35ml二氯甲烷中，加入於二烷之4N鹽酸鹽(8.7ml,4.0M,35mmol)，且使混合物在室溫下攪拌4小時。將固體以抽吸濾出且以二氯甲烷洗滌。使固體在高真空下乾燥，此得到830mg
(73%理論值，100%純度)之標題化合物。
LC-MS(方法3)：Rt=0.14min；MS(ESIneg)：m/z=162[M-I-HCl]+
將N-甲基吡啶-4-胺(5.00g,46.2mmol)首先加入於100ml N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(11.7g,46.2mmol)，且使混合物在110℃攪拌隔夜。將沉澱的固體以抽吸濾出，以甲基三級丁基醚洗滌，且使固體在高真空下乾燥，此得到13.7g(82%理論值，100%純度)之標題化合物。
LC-MS(方法3)：Rt=0.39min；MS(ESIpos)：m/z=282[M-Br]+
將3-碘咪唑并[1,2-a]吡啶-7-甲酸甲酯(250mg,828μmol)、1,4-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H-吡唑(221mg,993μmol)及碳酸鉀(377mg,2.73mmol)首先加入於5ml的1,4-二烷中，且使混合物以氬氣脫氣10分鐘。接著加入[1,1-雙(二苯基膦基)二茂鐵二氯鈀/二氯甲烷複合物(33.8mg,41.4μmol)，且使混合物在110℃攪拌隔夜。將反應混合物濃縮且使殘留物溶於乙酸乙酯中且以水及飽和氯化鈉水溶液洗滌。使有機相於硫酸鈉上乾燥且濃縮。使殘留物施用於Isolute且以管柱層析
(50g Biotage Snap Cartridge Ultra®；Biotage-Isolera-One®；二氯甲烷/甲醇梯度2%甲醇-20%甲醇；流速：100ml/min)純化。合併產物部分且濃縮，此得到122mg(40%理論值，74%純度)之標題化合物。
LC-MS(方法3)：Rt=0.61min；MS(ESIpos)：m/z=271[M+H]+
將1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-(甲基胺基)溴化吡啶鎓(13.7g,37.8mmol)於50ml的48%濃度的溴化氫水溶液在回流下於100℃加熱兩天。使反應混合物冷卻，且將形成的固體濾出且丟棄。將濾液濃縮且使殘留物以四氫呋喃攪拌。將固體濾出、以四氫呋喃洗滌且於高真空下乾燥，此得到11.5g(97%理論值)之標題化合物。
LC-MS(方法1)：Rt=0.22min；MS(ESIpos)：m/z=152[M-HBr-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(2.31),0.008(2.34),2.524(1.28),2.911(15.94),2.923(16.00),4.348(2.67),4.363(4.93),4.378(2.67),6.893(1.82),6.900(2.48).
將3-(1,4-二甲基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(122mg,
451μmol)首先加入於7ml的四氫呋喃/水(3：1)，加入氫氧化鋰(21.6mg,903μmol)，且使混合物在室溫下攪拌二小時。將反應混合物濃縮且經由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化殘留物。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到59mg(51%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.62min；MS(ESIpos)：m/z=257[M+H]+
將N-甲基吡啶-4-胺(2.00g,18.5mmol)首先加入20ml的N,N-二甲基甲醯胺，加入2-(3-溴丙基)-1H-異吲哚-1,3(2H)-二酮(4.96g,18.5mmol)，且使混合物在110℃攪拌隔夜。將沉澱的固體以抽吸濾出且以甲基三級丁基醚洗滌。使固體於高真空下乾燥，此得到5.62g(81%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.83min；MS(ESIpos)：m/z=296[M-Br]+
將於21ml 48%濃度的溴化氫水溶液之1-[3-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)丙基]-4-(甲基胺基)溴化吡啶鎓(5.62g,14.9mmol)於回流下在100℃加熱隔夜。使反應混合物冷卻，且將形成之固體濾出且丟棄。將濾
液濃縮且將殘留物以四氫呋喃攪拌。將固體濾出、以四氫呋喃洗滌且於高真空下乾燥，此得到3.75g(77%理論值)之標題化合物。
LC-MS(方法1)：Rt=1.41min；MS(ESIpos)：m/z=166[M-HBr-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.01),2.017(0.82),2.035(2.75),2.053(3.90),2.072(2.94),2.090(0.99),2.755(0.47),2.770(1.74),2.786(2.82),2.805(2.84),2.821(1.64),2.835(0.46),2.882(0.57),2.898(16.00),2.910(15.96),4.222(3.36),4.239(6.63),4.256(3.21),6.904(1.78),6.911(3.39),6.924(6.38),6.939(3.56),6.945(1.86),7.839(2.89),8.153(2.85),8.171(2.83),8.356(2.75),8.373(2.78),8.725(1.80),8.736(1.82).
將3-碘咪唑并[1,2-a]吡啶-7-甲酸甲酯(250mg,828μmol)、1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H-吡唑(221mg,993μmol)及碳酸鉀(377mg,2.73mmol)首先加入於5ml的1,4-二烷中，且使混合物以氬氣脫氣10分鐘。接著加入[1,1-雙(二苯基膦基)二茂鐵二氯鈀/二氯甲烷複合物(33.8mg,41.4μmol)，且使混合物在110℃攪拌隔夜。將反應混合物濃縮，使殘留物溶於乙酸乙酯中且以水及飽和氯化鈉水溶液洗滌。將有機相於硫酸鈉上乾燥、過濾且濃縮。使殘留物施用於Isolute且藉由管柱層析(25g Biotage Snap Cartridge Ultra®；Biotage-Isolera-One®；二氯甲烷/甲醇梯度2%甲醇-10%甲醇)而純化。將產物部份合併且濃縮，此得到143mg(47%理論值，73%純度)之標題化合物。
LC-MS(方法2)：Rt=1.18min；MS(ESIpos)：m/z=271[M+H]+
將3-(1-乙基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(143mg,529μmol)首先加入於8ml四氫呋喃/水(3：1)中，加入氫氧化鋰(25.3mg,1.06mmol)，且使混合物在室溫下攪拌隔夜。以水稀釋反應混合物，並以1N氫氯酸使其酸化。以乙酸乙酯洗滌混合物，將水相除去、濃縮且藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到39mg(26%理論值，89%純度)之標題化合物。
LC-MS(方法3)：Rt=0.33min；MS(ESIpos)：m/z=257[M+H]+
在氬氣下，將3-溴咪唑并[1,2-a]吡啶-7-甲酸甲酯(150mg,588μmol)、(2-甲氧基吡啶-3-基)硼酸(135mg,882μmol)及肆(三苯基膦)鈀(0)(6.80mg,5.88μmol)加入6.7ml的N,N-二甲基甲醯胺。然後，加入2M碳酸鈉水溶液(1.5ml,2.0M,2.9mmol)，且使混合物在130℃振盪75分鐘。以甲酸使反應混合物酸化，並使其通過注射過濾器過濾且藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：
0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到30.5mg(18%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=1.23min；MS(ESIpos)：m/z=284[M+H]+
將3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(30.5mg,108μmol)首先加入於2.2ml四氫呋喃/水(3：1)中，且加入1M氫氧化鋰水溶液(1.1ml,1.0M,1.1mmol)。將反應混合物在室溫下攪拌1.5小時，將混合物濃縮，將少許水加入殘留物中，且使混合物酸化至pH 3-4，並接著藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到25.2mg(87%理論值，100%純度)之標題化合物。
LC-MS(方法4)：Rt=0.53min；MS(ESIpos)：m/z=270[M+H]+
將N-甲基吡啶-3-胺(1.00g,9.25mmol)首先加入於20ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(2.35g,9.25mmol)，且使混合物在110℃攪拌隔夜。將混合物濃縮且以二氯甲烷攪拌。將固體以抽吸濾出、以二氯甲烷洗滌且在高真空下乾燥，此得到1.8g(54%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.68min；MS(ESIpos)：m/z=282[M-Br]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]：2.682(7.73),2.690(7.71),4.135(2.25),4.143(3.24),4.152(2.36),4.689(2.34),4.697(3.14),4.706(2.20),7.185(1.37),7.194(1.35),7.613(1.01),7.628(1.96),7.652(1.73),7.661(1.77),7.666(1.00),7.676(0.93),7.840(0.47),7.854(16.00),7.869(0.40),8.208(2.03),8.217(1.98),8.244(2.94).
將於6.6ml 48%濃度的溴化氫水溶液之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-3-(甲基胺基)溴化吡啶鎓(1.80g,4.97mmol)在回流下於100℃加熱隔夜。使反應混合物冷卻，並將形成的固體濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到1.7g(82%理論值，75%純度)之標題化合物。
1H-NMR(500MHz,DCOOD)δ[ppm]：2.906(1.56),3.896(0.56),4.981(0.51),8.116(3.20),10.224(16.00).
將2-甲基吡啶-4-胺(1.00g,9.25mmol)首先加入於20ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(2.35g,9.25mmol)，且使混合物在110℃攪拌隔夜。使反應混合物基本上濃縮且以乙腈攪拌。將固體以抽吸濾出，且在-10℃下以乙腈洗滌，此得到970mg(28%理論值，98%純度)之標題化合物。
LC-MS(方法2)：Rt=0.66min；MS(ESIpos)：m/z=282[M-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.78),2.475(5.44),2.648(16.00),4.036(1.87),4.051(3.75),4.066(2.06),4.638(1.98),4.653(3.56),4.668(1.81),6.239(3.70),7.483(0.43),7.505(0.93),7.522(1.12),7.528(1.17),7.544(2.36),7.550(2.05),7.606(3.44),7.628(2.01),7.853(2.07),7.864(2.15),7.871(2.47),7.876(8.50),7.884(8.57),7.889(2.67),7.895(2.05),7.900(0.92),7.906(1.10),7.946(3.23),7.952(3.23).
將於3.5ml 48%濃度的溴化氫水溶液之4-胺基-1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-2-甲基溴化吡啶鎓(970mg,2.68mmol)在回流下於100℃加熱30小時。使反應混合物冷卻，並將形成的固體濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到900mg(96%理論值，89%純度)之標題化合物。
LC-MS(方法5)：Rt=0.66min；MS(ESIpos)：m/z=152[M-HBr-Br]+
將N-甲基吡啶-3-胺(1.00g,9.25mmol)首先加入於20ml的N,N-二甲基甲醯胺中，加入2-(3-溴丙基)-1H-異吲哚-1,3(2H)-二酮(2.48g,9.25mmol)，且使混合物在110℃攪拌隔夜。將沉澱的固體以抽吸濾出、以甲基三級丁基醚洗滌且在高真空下乾燥，此得到2.20g(63%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.74min；MS(ESIpos)：m/z=296[M-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.225(1.01),2.241(3.14),2.259(4.36),2.276(3.23),2.293(1.07),2.772(16.00),2.784(15.76),3.649(4.40),3.664(8.09),3.680(4.14),4.503(3.90),4.522(6.20),4.540(3.71),7.193(2.63),7.205(2.53),7.563(2.65),7.567(2.43),7.585(3.54),7.589(3.28),7.700(2.99),7.714(3.28),7.722(2.39),7.736(2.30),7.846(3.32),7.856(4.85),7.859(4.97),7.868(10.50),7.875(5.84),7.877(5.58),7.884(10.44),7.890(5.19),7.894(4.62),7.896(4.30),7.906(2.93),8.156(5.84),8.188(4.27),8.202(3.96).
將於7.7ml 48%濃度的溴化氫水溶液之1-[3-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)丙基]-3-(甲基胺基)溴化吡啶鎓(2.20g,5.85mmol)在回流下於
100℃加熱36小時。使反應混合物冷卻，並將形成的固體濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到120mg(6%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.195(1.43),2.444(0.43),2.459(0.95),2.475(1.49),2.490(0.91),2.791(14.20),3.275(1.06),3.291(1.46),3.306(1.00),4.556(1.53),4.571(2.34),4.586(1.48),7.558(0.61),7.561(0.59),7.576(1.01),7.579(1.04),7.616(0.97),7.622(0.41),7.628(1.02),7.634(0.57),7.646(0.57),7.951(2.14),7.960(2.56),8.116(16.00),10.477(13.24).
在一密閉容器中，將於2.3ml丙酮之(吡啶-3-基甲基)胺基甲酸三級丁基酯(400mg,1.92mmol)及碘甲烷(140μl,2.3mmol)在75℃振盪隔夜。將反應混合物濃縮，且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到575mg(85%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.52min；MS(ESIpos)：m/z=223[M-I]+
將3-{[(三級丁氧基羰基)胺基]甲基}-1-甲基碘化吡啶鎓(572mg,1.63
mmol)首先加入於4ml的二氯甲烷中，加入於1,4-二烷(4.1ml,4.0M,16mmol)之鹽酸，且使混合物在室溫下攪拌1.5小時。將反應溶液濃縮且溶於乙腈中，並再濃縮三次。將殘留物在高真空下乾燥，此得到415mg(89%理論值，100%純度)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.56),0.008(0.54),4.264(4.19),4.367(16.00),8.196(1.10),8.211(1.33),8.216(1.38),8.231(1.25),8.719(1.55),8.739(1.60),8.783(1.46),8.999(1.66),9.014(1.60),9.229(2.42).
將N,N-二甲基吡啶-4-胺(2.00g,16.4mmol)首先加入於20ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(4.16g,16.4mmol)，且使混合物在110℃攪拌隔夜。將沉澱的固體以抽吸濾出、以甲基三級丁基醚洗滌且在高真空下乾燥，此得到5.04g(82%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.75min；MS(ESIpos)：m/z=296[M-Br]+
將於19ml 48%濃度的溴化氫水溶液之4-(二甲基胺基)-1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]溴化吡啶鎓(5.04g,13.4mmol)在100℃
攪拌隔夜。使反應混合物冷卻，並將形成的固體濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到3.55g(81%理論值，100%純度)之標題化合物。
LC-MS(方法1)：Rt=1.32min；MS(ESIpos)：m/z=166[M-HBr-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：3.040(0.67),3.172(1.20),3.359(6.47),3.388(2.45),3.419(13.71),4.440(7.12),4.455(12.63),4.470(6.81),7.109(15.57),7.128(16.00),8.109(6.23),8.289(14.04),8.308(13.55).
將1-(4-甲基吡啶-2-基)甲胺(250mg,2.05mmol)首先加入於22ml二烷/水1/1中，且連續加入碳酸鉀(2.83g,20.5mmol)及二碳酸二-三級丁基酯(520μl,2.3mmol)。將混合物於室溫下攪拌隔夜。使相分離且以乙酸乙酯萃取水相2次。將合併的有機相於硫酸鈉上乾燥且過濾，使濾液濃縮且使殘留物於高真空下乾燥，此得到415mg(95%純，87%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.85min；MS(ESIpos)：m/z=223[M+H]+
在一密閉容器中，使於2.1ml丙酮之[(4-甲基吡啶-2-基)甲基]胺基甲酸三級丁基酯(415mg,95%純，1.77mmol)及碘甲烷(130μl,2.1mmol)在75℃振盪隔夜。將反應溶液濃縮，使殘留物以乙腈濃縮3次，且在高真
空下乾燥，此得到676mg(97%純，102%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.62min；MS(ESIpos)：m/z=237[M-I]+
將於二烷(4.6ml,4.0M,19mmol)之鹽酸加入2-{[(三級丁氧基羰基)胺基]甲基}-1,4-二甲基碘化吡啶鎓(676mg,1.86mmol)中，且使混合物在室溫下攪拌一小時。將反應溶液濃縮，且使殘留物以乙腈濃縮3次，且在高真空下乾燥，此得到428mg(100%純，77%理論值)之標題化合物。
LC-MS(方法1)：Rt=1.26min；MS(ESIpos)：m/z=137[M-I-HCl]+
在氬氣下，將N,3-二甲基吡啶-4-胺(689mg,5.64mmol)首先加入於12ml的N,N-二甲基甲醯胺中，加入2-(2-chlor乙基)-1H-異吲哚-1,3(2H)-二酮(1.18g,5.64mmol)，且使混合物在110℃攪拌48小時。將沉澱的固體以抽吸濾出，以二乙醚及乙酸乙酯洗滌，並在高真空下乾燥，此得到1.14g(100%純，61%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.74min；MS(ESIpos)：m/z=296[M-Cl]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.059(16.00),2.911(8.46),2.922(8.56),3.998(2.07),4.010(2.97),4.023(2.39),4.348(2.42),4.362(2.95),4.374(2.12),6.790(2.82),6.808(2.88),7.830(0.78),7.834(0.58),7.842
(1.63),7.852(10.91),7.857(11.45),7.866(1.61),7.874(0.54),7.879(0.74),8.047(0.97),8.253(3.63),8.300(1.93),8.318(1.86).
將於5.5ml濃縮鹽酸(於水37%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-3-甲基-4-(甲基胺基)氯化吡啶鎓(1.14g,3.44mmol)在100℃攪拌隔夜。加入額外的1.5ml濃縮鹽酸(於水37%濃度)，且使混合物再一次於100℃下攪拌隔夜。當冷卻時，固體沉澱，將後者以抽吸濾出且丟棄。使濾液濃縮且使固體由四氫呋喃/乙腈再結晶，此得到799mg(95%純，93%理論值)之標題化合物。
LC-MS(方法1)：Rt=1.30min；MS(ESIpos)：m/z=166[M-Cl-HCl]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.121(16.00),2.949(7.77),2.961(7.76),3.312(2.76),3.333(4.93),4.481(2.87),4.493(1.53),6.917(2.27),6.935(2.30),8.115(0.93),8.263(2.44),8.352(1.44),8.370(1.39),8.547(1.44).
在氬氣下，將N,2-二甲基吡啶-4-胺(895mg,7.32mmol)首先加入於15ml的N,N-二甲基甲醯胺中，加入2-(2-氯乙基)-1H-異吲哚-1,3(2H)-二酮(1.54g,7.32mmol)，且使混合物在110℃攪拌48小時。將沉澱的固體以
抽吸濾出，以二乙醚及乙酸乙酯洗滌且在高真空下乾燥。然後將固體於矽膠(流動相：二氯甲烷/甲醇/甲酸100/10/1至100/30/1)上純化。將產物部份合併且濃縮，並使殘留物於高真空下乾燥，此得到313mg(100%純，13%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.45min；MS(ESIpos)：m/z=296[M-Cl]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.605(16.00),2.828(5.30),2.840(5.41),2.862(7.91),2.874(7.81),3.943(3.52),3.957(6.36),3.971(3.94),4.370(2.38),4.384(5.06),4.398(4.49),4.412(1.58),6.652(1.30),6.672(2.25),6.685(1.17),6.691(1.14),6.751(1.69),6.841(2.93),6.847(2.78),7.845(2.28),7.856(3.86),7.868(12.91),7.877(13.37),7.888(3.90),7.899(2.22),7.976(2.93),7.994(2.85),8.205(11.61),8.228(1.84),8.712(1.16).
將於1.5ml的濃縮鹽酸(於水37%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-2-甲基-4-(甲基胺基)氯化吡啶鎓(310g,934μmol)在100℃攪拌隔夜。加入額外的1.5ml濃縮鹽酸(於水37%濃度)，且使混合物再一次於100℃下攪拌隔夜。當冷卻時，固體沉澱，將固體以抽吸濾出且丟棄。使濾液濃縮且使殘留物由四氫呋喃/乙腈/甲醇再結晶，此得到182mg(90%純，74%理論值)之標題化合物。
LC-MS(方法1)：Rt=0.82min；MS(ESIpos)：m/z=166[M-Cl-HCl]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.07),0.008(0.91),2.518(2.43),2.591(2.46),2.880(2.68),2.892(2.66),3.229(0.62),3.318(16.00),3.324(9.54),4.392(0.56),4.406(0.75),4.420(0.49),6.847(0.78).
將N-乙基吡啶-4-胺(500mg,4.09mmol)首先加入於10ml的N,N-二甲基甲醯胺中，加入2-(2-氯乙基)-1H-異吲哚-1,3(2H)-二酮(858mg,4.09mmol)，並使混合物在110℃攪拌過週末。將沉澱的固體以抽吸濾出，以甲基三級丁基醚洗滌且在高真空下乾燥，此得到849mg(100%純，62%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.77min；MS(ESIpos)：m/z=296[M-Cl]+
將於5ml濃縮鹽酸(於水37%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-(乙基胺基)氯化吡啶鎓(848mg,2.56mmol)在回流下於100℃加熱隔夜。當冷卻時，固體沉澱，將後者濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到543mg(100%純，89%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(2.58),1.172(7.58),1.190(16.00),1.208(7.59),2.328(0.56),2.670(0.58),3.283(3.50),3.301(6.90),3.332(5.53),3.351(1.33),4.407(2.71),4.420(3.54),6.891(1.65),6.898(1.67),6.909(1.74),6.958(1.93),6.976(1.97),8.130(1.86),8.145(1.52),8.300(2.65),8.317(2.71),8.859(1.14).
將3-乙基吡啶(2.00g,18.7mmol)首先加入於20ml N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(4.74g,18.7mmol)，且使混合物在110℃攪拌隔夜。在旋轉蒸發器上除去N,N-二甲基甲醯胺且將殘留物與甲基三級丁基醚攪拌。將沉澱的固體以抽吸濾出，以甲基三級丁基醚洗滌且在高真空下乾燥，此得到5.30g(100%純，79%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.70min；MS(ESIpos)：m/z=282[M-Br]+
將於20ml濃縮氫溴酸(於水48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-3-乙基溴化吡啶鎓(5.30g,14.7mmol)在回流下於100℃加熱隔夜。當冷卻時，固體沉澱，將後者濾出且丟棄。將濾液濃縮且使殘留物與四氫呋喃攪拌。將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到3.61g(79%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.274(7.42),1.293(16.00),1.312(7.71),2.820(1.89),2.839(5.59),2.858(5.48),2.877(1.77),3.383(4.56),4.861(2.70),4.875(4.27),4.890(2.55),8.127(3.08),8.143(4.28),8.147(4.58),8.162(4.07),8.545(2.44),8.565(2.23),8.924(2.40),8.939(2.31),9.056(3.59).
在一密封容器中，將於2.5ml丙酮之(吡啶-2-基甲基)胺基甲酸三級丁基酯(470μl,2.4mmol)及碘甲烷(180μl,2.9mmol)在75℃攪拌隔夜。將反應混合物濃縮且使殘留物在高真空下乾燥，此得到810mg(96%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.87),0.008(0.49),1.366(0.77),1.425(16.00),1.487(0.99),2.086(7.32),2.519(0.50),4.290(12.40),4.583(2.42),4.597(2.27),7.887(0.89),7.898(1.23),7.918(0.92),7.988(0.61),8.006(1.06),8.022(0.62),8.551(0.64),8.570(1.10),8.590(0.54),8.972(1.38),8.987(1.31).
將2-{[(三級丁氧基羰基)胺基]甲基}-1-甲基碘化吡啶鎓(810mg,2.31mmol)首先加入於24ml的二氯甲烷中，加入於二烷之鹽酸(5.8ml,4.0M,23mmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且將殘留物與二氯甲烷攪拌。將沉澱固體以抽吸濾出、以二氯甲烷洗滌且在高真空下乾燥，此得到627mg(100%純，95%理論值)之標題化合物。
LC-MS(方法1)：Rt=0.25min；MS(ESIpos)：m/z=123[M-I-HCl]+
將4-(三氟甲基)吡啶(310μl,2.7mmol)首先加入於10ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(677mg,2.66mmol)，且使混合物在110℃攪拌72小時。將反應混合物濃縮，將甲基三級丁基醚加入油狀殘留物中，且使混合物再次濃縮。將目前為固體的殘留物與甲基三級丁基醚攪拌，並將固體濾出、以甲基三級丁基醚洗滌且在高真空下乾燥，此得到390mg(100%純，36%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.45min；MS(ESIpos)：m/z=321[M-Br]+
將於5ml濃縮鹽酸(於水48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-(三氟甲基)溴化吡啶鎓(390mg,972μmol)在回流下於100℃加熱隔夜。當冷卻時，固體沉澱，將後者濾出且丟棄。將濾液濃縮，使殘留物與四氫呋喃攪拌，且將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到181mg(100%純，53%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.329(0.77),2.671(0.69),3.584(9.46),5.002(10.26),8.043(6.71),8.789(15.09),8.805(16.00),9.428(11.27),9.442(10.28).
將1-(5-甲基吡啶-2-基)甲胺(150mg,1.23mmol)首先加入於4.1ml的氫氧化鈉溶液(1N in water)中，在0℃加入二碳酸二-三級丁基酯(340μl,1.5mmol)，且使混合物在室溫下攪拌隔夜。將乙酸乙酯加入反應混合物中，且使混合物以水洗滌2次且以飽和NaCl溶液洗滌1次。將有機相於硫酸鈉上乾燥、過濾且濃縮。將殘留物藉由管柱層析(10g Biotage Snap Cartridge Ultra®；Biotage-Isolera-One®；CH/EA梯度，TLC：CH/EA 1/1)而純化。將產物部份合併且濃縮，並將殘留物於高真空下乾燥，此得到168mg(100%純，62%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.50min；MS(ESIpos)：m/z=223[M+H]+
在一密封容器中，將於1.6ml丙酮之[(5-甲基吡啶-2-基)甲基]胺基甲酸三級丁基酯(372mg,78%純，1.31mmol)及碘甲烷(98μl,1.6mmol)於75℃振盪隔夜。使反應溶液濃縮，使殘留物由乙腈中濃縮3次且在高真空下乾燥，此得到597mg(98%純，123%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.66min；MS(ESIpos)：m/z=237[M-I]+
將於二烷(4.1ml,4.0M,16mmol)之鹽酸加入2-{[(三級丁氧基羰基)
胺基]甲基}-1,5-二甲基碘化吡啶鎓(597mg,1.64mmol)中，且使混合物在室溫下攪拌一小時。將反應溶液濃縮，使殘留物由乙腈中濃縮3次且在高真空下乾燥，此得到483mg(95%純，93%理論值)之標題化合物。
LC-MS(方法1)：Rt=1.67min；MS(ESIpos)：m/z=137[M-I-HCl]+
將3-甲基吡啶(2.00g,21.5mmol)首先加入於20ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(5.46g,21.5mmol)，且使混合物在110℃攪拌隔夜。將N,N-二甲基甲醯胺於旋轉蒸發器上除去，且使殘留物與甲基三級丁基酯攪拌。將沉澱固體以抽吸濾出、以甲基三級丁基酯洗滌且在高真空下乾燥，此得到6.39g(96%純，82%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.60min；MS(ESIpos)：m/z=268[M-Br]+
將於25ml濃縮氫溴酸(於水48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-3-甲基溴化吡啶鎓(6.39g,18.4mmol)在回流下於100℃加熱隔夜。當冷卻時，固體沉澱，將後者濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將沉澱的固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到4.55g(83%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.518(16.00),3.544(1.90),4.829(1.79),4.843(3.01),4.857(1.68),8.101(2.52),8.117(3.09),8.121(3.19),8.136(2.60),8.494(1.72),8.514(1.56),8.894(1.57),8.909(1.50),9.016
(2.34).
將3-(4-甲基-1H-吡唑-1-基)丙烷-1-胺(350mg,2.51mmol)首先加入於10ml的四氫呋喃中且使其冷卻至0℃。在此溫度時，連續加入三乙基胺(1.1ml,7.5mmol)、4-二甲基胺基吡啶(46.1mg,377μmol)及二碳酸二-三級丁基酯(610μl,2.6mmol)。接著使反應混合物緩慢回溫至室溫且攪拌隔夜。將反應混合物於水及乙酸乙酯之間分配，以水及以飽和NaCl溶液洗滌有機相，使其於硫酸鈉上乾燥且過濾，將濾液濃縮且使殘留物於高真空下乾燥，此得到537mg(43%純，39%理論值)之標題化合物。
LC-MS(方法6)：Rt=2.18min；MS(ESIpos)：m/z=240[M+H]+
在一密封容器中，將於2.7ml丙酮之[3-(4-甲基-1H-吡唑-1-基)丙基]胺基甲酸三級丁基酯(537mg,2.24mmol；43% pure)及碘甲烷(170μl,2.7mmol)於75℃振盪隔夜。將反應溶液濃縮，且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將產物部分合併且濃縮，且使殘留物於高真空下乾燥，此得到403mg(70%純，33%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.41min；MS(ESIpos)：m/z=254[M-I]+
將於二烷(2.6ml,4.0M,11mmol)之鹽酸加入1-{3-[(三級丁氧基羰基)胺基]丙基}-2,4-二甲基-1H-吡唑-2-鎓甲酸酯(403mg,1.06mmol)，且使混合物在室溫下攪拌3.5小時。將反應溶液濃縮，且使殘留物由乙腈再濃縮三次且在高真空下乾燥，此得到331mg(98%純，97%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.24min；MS(ESIpos)：m/z=154[M-I-HCl]+
在氬氣下，將3-碘咪唑并[1,2-a]吡啶-7-甲酸甲酯(200mg,662μmol)、1-異丙基-1H-吡唑-5-基)硼酸(122mg,795μmol)及碳酸鉀(302mg,2.2mmol)首先加入於4ml的二烷中，且使混合物以氬氣脫氣10分鐘。接著加入[1,1-雙(二苯基膦基)二茂鐵二氯鈀/二氯甲烷複合物(27.0mg,33.1μmol)，並使反應混合物在110℃攪拌隔夜。將混合物濃縮，且使殘留物溶於乙酸乙酯中，並以水及飽和NaCl溶液洗滌。將有機相於硫酸鈉上乾燥、過濾且濃縮。將殘留物藉由管柱層析(10g Biotage Snap Cartridge Ultra®；Biotage-Isolera-One®；CH/EA梯度，12% EA-100% EA；流速：36ml/min；TLC：CH/EA 1/1)而純化。將產物部分濃縮，且使殘留物於高真空下乾燥，此得到80mg(89%純，38%理論值)之標題化合物。
LC-MS(方法2)：Rt=1.36min；MS(ESIpos)：m/z=285[M+H]+
將3-(1-異丙基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸甲酯(80.0mg,89%純，250μmol)首先加入於5ml的四氫呋喃/水3：1中，加入氫氧化鋰(12.0mg,500μmol)，且使混合物在60℃攪拌1.5小時。將反應混合物濃縮，並將殘留物溶於乙腈/水中且冷凍乾燥，此得到90mg(100%純，130%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.356(15.82),1.373(16.00),4.352(0.43),4.368(1.10),4.385(1.48),4.401(1.09),4.418(0.43),6.606(3.63),6.611(3.85),7.449(1.57),7.468(1.66),7.674(0.65),7.700(3.24),7.704(3.36),7.765(4.34),7.988(3.46),8.004(1.93).
將N-甲基吡啶-4-胺(1.00g,9.25mmol)首先加入於10ml的N,N-二甲基甲醯胺中，加入2-(2-氯乙基)-1H-異吲哚-1,3(2H)-二酮(1.94g,9.25mmol)，且將混合物在110℃攪拌隔夜。將沉澱固體以抽吸濾出、以甲基三級丁基醚洗滌且在高真空下乾燥，此得到1.99g(100%純，68%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.67min；MS(ESIpos)：m/z=282[M-Cl-]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]：2.857(16.00),2.867(15.78),3.981(3.82),3.991(4.85),4.002(3.96),4.357(4.07),4.368(4.70),4.378(3.51),6.801(2.60),6.806(2.94),6.816(2.64),6.821(2.88),6.882(3.22),6.888(2.82),6.897(3.19),6.903(2.74),7.835(2.94),7.840(2.53),7.844(4.04),7.848(5.05),7.853(12.68),7.861(12.85),7.866(5.22),7.871(3.90),7.874(2.34),7.879(2.71),8.141(3.12),8.145(3.18),8.156(3.02),8.160(3.03),8.350(2.91),8.353(2.83),8.365(2.82),8.368(2.70),9.077(2.07),9.087(2.03).
將1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-(甲基胺基)氯化吡啶鎓(16.0g,50.2mmol)在100℃於100ml濃縮鹽酸中攪拌2天。將沉澱固體以抽吸濾出且丟棄，將濾液濃縮且以四氫呋喃攪拌殘留物。使固體以抽吸濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到12g(100%純，106%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.892(15.95),2.904(16.00),3.286(3.87),3.299(3.90),4.462(4.14),4.477(7.20),4.491(3.94),6.910(2.46),6.917(3.11),6.928(2.52),6.935(3.26),6.962(2.92),6.968(2.48),6.980(2.92),6.986(2.51),8.188(3.45),8.206(3.36),8.384(3.46),8.402(3.34),8.575(3.87),9.081(1.81).
將3-碘咪唑并[1,2-a]吡啶-7-甲酸甲酯(1.00g,3.31mmol)首先加入於20ml四氫呋喃中，加入氫氧化鋰溶液(6.6ml,1.0M,6.6mmol)，且使混合物在室溫下攪拌2小時。使四氫呋喃於旋轉蒸發器上除去，且以4N鹽酸使水性殘留物酸化(pH 3)。將沉澱固體以抽吸濾出、以乙腈洗滌且在高真空下乾燥。更多固體由濾液中沉澱，將固體以抽吸濾出，以乙腈洗滌且在高真空下乾燥，此得到總共743mg(100%純，78%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.67min；MS(ESIpos)：m/z=288[M+H]+
將3-碘咪唑并[1,2-a]吡啶-7-甲酸(81.4mg,283μmol)首先加入於2ml的二氯甲烷中，加入2-(胺基甲基)-1-甲基咪唑并[1,2-a]吡啶-1-鎓碘化物鹽酸鹽(1：1：1)(92.0mg,283μmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(81.3mg,424μmol)及4-二甲基胺基吡啶(104mg,848μmol)，且使混合物在室溫下攪拌隔夜。將沉澱固體以抽吸濾出，以二氯甲烷洗滌且在高真空下乾燥，此得到121mg(100%純，99%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.71min；MS(ESIpos)：m/z=432[M-I]+
將4-三級丁基吡啶(540μl,3.7mmol)首先加入於5ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(940mg,3.70mmol)，且使混合物在110℃攪拌隔夜。將混合物於旋轉蒸發器上濃縮，將甲基三級丁基醚加入殘留物中，且使混合物再次濃縮。將殘留物於高真空下乾燥48小時，且接著與甲基三級丁基醚再次攪拌並使其濃縮。將殘留物最終與四氫呋喃攪拌，且將固體以抽吸濾出，以四氫呋喃洗滌且在高真空下乾燥，此得到1.06g(100%純，74%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.95min；MS(ESIpos)：m/z=309[M-Br]+
將於14ml濃縮氫溴酸(於水48%濃度)之4-三級丁基-1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]溴化吡啶鎓(1.06g,2.72mmol)在100℃攪拌48小時。當冷卻時，固體沉澱。將固體濾出且丟棄，並將濾液濃縮。將殘留物與四氫呋喃攪拌，且將固體以抽吸濾出，以四氫呋喃洗滌且在高真空下乾燥，此得到799mg(100%純，86%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.14min；MS(ESIpos)：m/z=179[M-H-2Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.381(16.00),3.522(0.54),4.808(0.43),4.823(0.66),4.837(0.40),8.075(0.41),8.241(1.13),8.258(1.18),8.956(0.88),8.973(0.81).
將4-異丙基吡啶(500mg,4.13mmol)首先加入於5.5ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(1.05g,4.13mmol)，且使混合物在110℃攪拌隔夜。使反應混合物於旋轉蒸發器上濃縮，且使殘留物與甲基三級丁基醚攪拌、過濾且在高真空下乾燥，此得到1.28g(93%純，77%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.83min；MS(ESIpos)：m/z=295[M-Br]+
將1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-異丙基溴化吡啶鎓(1.28g,3.41mmol)首先加入於18ml濃縮氫溴酸(於水48%濃度)，且在100℃攪拌48小時。當冷卻時，固體沉澱。將固體濾出且丟棄，並將濾液濃縮。將殘留物與四氫呋喃攪拌、過濾且以四氫呋喃洗滌且在高真空下乾燥，此得到920mg(95%純，79%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.14min；MS(ESIpos)：m/z=166[M-HBr-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.43),1.288(15.93),1.305(16.00),3.220(0.92),3.237(1.20),3.254(0.88),3.376(1.32),4.793(1.41),4.807(2.21),4.822(1.33),8.070(1.24),8.135(3.54),8.152(3.67),8.943(2.76),8.959(2.56).
將3-碘咪唑并[1,2-a]吡啶-7-甲酸(550mg,1.91mmol)and 1-(2-胺基乙基)-4-(甲基胺基)溴化吡啶鎓氫溴酸鹽(1：1：1)(657mg,2.10mmol)首先加入於30ml的二氯甲烷中，且加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(549mg,2.86mmol)及4-二甲基胺基吡啶(700mg,5.73mmol)，且使混合物在室溫下攪拌隔夜。將反應混合物施用於Isolute®且以矽膠層析(28g Snap Cartridge KP-NH Biotage®；Biotage-Isolera-One®；二氯甲烷/甲醇梯度10%甲醇至40%甲醇)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到797mg(95%純，79%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.68min；MS(ESIpos)：m/z=422[M-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：0.950(1.15),0.968(2.48),0.986(1.39),1.116(0.45),1.453(0.54),1.470(0.82),1.488(0.58),2.107(7.82),2.136(0.45),2.163(0.59),2.181(0.96),2.199(0.50),2.861(15.62),2.873(16.00),2.943(10.33),2.965(1.51),2.982(1.52),2.997(0.96),3.040(1.42),3.122(0.68),3.162(1.20),3.176(1.24),3.226(2.11),3.706(4.43),3.718(4.65),3.732(2.16),4.304(3.83),4.318(5.58),4.330(3.64),5.756(0.75),6.571(0.92),6.574(0.83),6.587(1.01),6.810(2.49),6.817(3.46),6.828(2.44),6.835(3.81),6.848(3.50),6.854(2.40),6.866(3.32),6.873(2.57),7.361(3.69),7.364(4.05),7.379(3.74),7.382(4.20),7.872(11.63),8.081(8.11),8.106(3.63),8.293(3.37),8.310(3.37),8.395(5.54),8.413(5.27),8.599(2.60),8.611(2.48),8.852(1.67),8.866(3.40),8.881(1.72).
將4-乙基吡啶(530μl,4.7mmol)首先加入於6ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(1.19g,4.67mmol)，且使混合物在110℃攪拌隔夜。將反應混合物於旋轉蒸發器上濃縮，且使殘留物與甲基三級丁基醚攪拌。將固體以抽吸濾出，以甲基三級丁基醚洗滌且在高真空下乾燥，此得到1.35g(85%純，68%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.44min；MS(ESIpos)：m/z=281[M-Br]+
將於21ml濃縮氫溴酸(於水48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-乙基溴化吡啶鎓(1.35g,3.74mmol)在100℃攪拌48小時。當冷卻時，固體沉澱。將固體濾出且使濾液於旋轉蒸發器上濃縮。將殘留物與四氫呋喃攪拌，且將固體以抽吸濾出，以四氫呋喃洗滌且在高真空下乾燥，此得到1.11g(95%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.05),0.008(1.05),1.262(7.42),1.281(16.00),1.300(7.52),2.731(7.67),2.772(0.63),2.891(9.39),2.907(1.82),2.926(5.16),2.945(5.01),2.964(1.57),3.412(0.54),3.485(1.27),3.500(2.39),3.514(2.45),3.526(1.50),3.542(0.93),3.560(0.43),3.637(0.49),3.652(0.87),3.668(0.43),3.971(1.82),4.782(2.02),4.797
(3.46),4.810(1.96),7.953(1.42),8.049(1.89),8.089(5.82),8.106(5.78),8.914(3.80),8.930(3.70).
將3-苯氧基吡啶(500mg,2.92mmol)首先加入於3.8ml的N,N-二甲基甲醯胺中，加入2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(742mg,2.92mmol)，且使混合物在110℃攪拌48小時。將反應混合物在旋轉蒸發器上濃縮，並使殘留物與甲基三級丁基醚攪拌。將甲基三級丁基醚倒出，且使殘留物於高真空下乾燥，此得到1.1g(78%純，69%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.95min；MS(ESIpos)：m/z=345[M-Br]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.106(0.80),2.328(0.49),2.670(0.44),2.731(1.84),2.766(0.46),2.778(0.44),2.891(2.16),3.853(0.74),3.866(1.03),3.880(0.59),3.932(0.49),4.153(2.44),4.165(3.19),4.177(2.57),4.311(0.54),4.325(0.93),4.338(0.55),4.819(2.60),4.831(3.18),4.843(2.32),7.064(0.70),7.083(0.80),7.107(4.54),7.126(5.46),7.129(4.33),7.197(0.44),7.258(1.22),7.276(2.98),7.295(1.95),7.395(3.84),7.416(4.99),7.434(3.42),7.450(0.48),7.831(1.77),7.848(1.63),7.857(1.39),7.863(2.38),7.866(2.64),7.878(16.00),7.903(1.24),8.115(1.83),8.129(1.93),8.136(2.26),8.151(2.24),8.165(0.97),8.313(1.99),8.318(1.92),8.335(1.56),8.340(1.62),8.371(0.60),8.382(0.74),8.992(2.61),9.008(2.49),9.215(3.17).
將於14ml濃縮氫溴酸(於水48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-3-苯氧基溴化吡啶鎓(1.10g,2.59mmol)在100℃攪拌48小時。當冷卻時，固體沉澱。將固體濾出且使濾液於旋轉蒸發器上濃縮。使殘留物與甲醇/四氫呋喃攪拌，並將固體濾出、以四氫呋喃洗滌且在高真空下乾燥，此得到593mg(78%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.150(0.75),0.146(0.60),1.760(0.99),2.328(0.99),2.367(1.04),2.670(0.97),2.710(0.91),2.773(0.63),2.864(0.52),3.531(7.25),3.601(0.99),3.634(0.60),3.650(1.14),4.855(10.05),6.971(0.78),7.098(0.97),7.226(0.80),7.265(13.82),7.285(16.00),7.338(3.84),7.356(8.82),7.375(5.30),7.527(11.00),7.547(14.84),7.567(7.68),7.876(1.08),8.048(6.30),8.169(4.92),8.184(5.20),8.191(7.94),8.206(8.17),8.257(6.68),8.281(3.99),8.829(5.54),8.842(5.33),9.055(9.73).
將4-(六氫吡啶-1-基)吡啶(500mg,3.08mmol)首先加入於4ml的N,N-二甲基甲醯胺，2-(2-溴乙基)-1H-異吲哚-1,3(2H)-二酮(783mg,3.08mmol)中，且使混合物在110℃攪拌隔夜。將沉澱固體以抽吸濾出，以甲基三級丁基醚洗滌且在高真空下乾燥，此得到692mg(100%純，54%理論值)之
標題化合物。
LC-MS(方法2)：Rt=0.96min；MS(ESIpos)：m/z=336[M-Br-]+
將於9ml水性氫溴酸(48%濃度)之1-[2-(1,3-二側氧-1,3-二氫-2H-異吲哚-2-基)乙基]-4-(六氫吡啶-1-基)溴化吡啶鎓(690mg,1.66mmol)在100℃攪拌3小時。當冷卻時，固體沉澱。將後者濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體濾出，以四氫呋喃洗滌且在高真空下乾燥，將固體再一次溶於9ml水性氫溴酸(48%濃度)中，且使混合物在110℃攪拌1.5天，然後將沉澱固體以抽吸濾出且丟棄。將濾液濃縮且以四氫呋喃攪拌殘留物。將固體以抽吸濾出，以四氫呋喃洗滌且在高真空下乾燥，此得到390mg(64%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(2.18),0.008(2.12),1.596(12.04),1.605(10.17),1.689(5.81),1.701(5.76),3.333(5.34),3.346(5.36),3.479(2.67),3.542(0.88),3.695(12.37),3.708(16.00),3.722(12.32),4.367(5.26),4.382(9.20),4.396(4.81),7.280(13.14),7.300(13.63),8.011(5.15),8.207(10.12),8.225(9.57).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及1-(2-胺基乙基)-4-(二甲基胺基)溴化吡啶鎓氫溴酸鹽(1：1：1)(63.6mg,194μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌1.5小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且由乙腈/水中冷凍乾燥隔夜。得到50mg(56%理論值，98%純度)之標題化合物。
LC-MS(方法2)：Rt=0.63min；MS(ESIpos)：m/z=405[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.114(10.41),2.323(10.60),3.155(16.00),3.748(1.56),3.760(1.60),4.405(1.64),7.005(2.22),7.023(2.22),7.304(0.94),7.321(0.91),7.860(2.03),8.207(2.56),8.339(1.60),8.508(1.17).
將1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)甲酸吡啶鎓(500mg,1.15mmol)首先加入於1.1ml的4N水性鹽酸中且攪拌5分鐘，後續將反應混合物濃縮，此操作重複四次。將殘留物溶於5ml水中且冷凍乾燥，得到507mg(96%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.60min；MS(ESIpos)：m/z=391[M-HCl-Cl]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.173(15.69),2.395(16.00),2.854(5.59),2.866(5.59),3.757(0.80),3.770(1.79),3.783(1.85),3.796(0.88),4.404(1.51),4.416(2.17),4.428(1.38),6.837(1.00),6.843(1.21),6.855(1.07),6.862(1.24),6.917(0.98),6.934(0.97),7.801(1.01),7.814(0.74),8.182(1.32),8.200(1.30),8.379(1.33),8.397(1.32),8.522(3.44),8.635(1.76),8.653(1.67),9.061(0.52),9.732(0.62).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及(2-胺基甲基)-1-甲基咪唑并[1,2-a]吡啶-1-鎓碘化物鹽酸鹽(1：1：1)(63.3mg,194μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌一小時。將反應混合物濃縮，且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且由乙腈/水冷凍乾燥隔夜。得到55mg
(62%理論值，99%純度)之標題化合物。
LC-MS(方法2)：Rt=0.60min；MS(ESIpos)：m/z=401[M-HCO2]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]：-0.007(0.47),1.563(0.49),2.116(1.11),2.124(16.00),2.146(0.71),2.325(0.96),2.333(15.60),3.495(0.42),3.898(0.49),4.073(13.30),4.856(2.06),4.866(1.99),7.442(1.17),7.445(1.18),7.457(1.15),7.460(1.13),7.522(0.76),7.535(1.49),7.549(0.80),7.884(4.49),8.007(0.79),8.025(1.04),8.040(0.88),8.206(1.72),8.225(1.36),8.262(1.61),8.277(1.50),8.352(2.28),8.427(1.67),8.546(1.75),8.899(1.07),8.912(1.03),10.079(0.51),10.089(0.91),10.100(0.48).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(865mg,3.36mmol)首先加入於10ml的二氯甲烷中，加入1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(1.16g,3.70mmol)、4-二甲基胺基吡啶(1.23g,10.1mmol)及1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(967mg,5.04mmol)，且使混合物在室溫下攪拌隔夜。將反應混合物藉由矽膠層析(110g Biotage NH-Snap Cartridge®；Biotage-Isolera-One®；二氯甲烷/甲醇梯度2%甲醇-40%甲醇；流速：100ml/min)純化。將產物部分合併且濃縮，然後將粗產物溶於10ml水/乙腈中，加入3ml甲酸且使混合物攪拌20分鐘。將混合物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50%
B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)以數個部分純化。此獲得二個含有產物的部分，將第一含有產物的部分濃縮且冷凍乾燥，得到167mg(11%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.60min；MS(ESIpos)：m/z=391[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.114(15.52),2.323(16.00),2.854(6.29),3.714(2.38),3.725(2.45),4.332(2.60),6.835(1.27),6.854(0.92),6.886(0.97),7.290(1.24),7.304(1.20),7.863(2.79),8.119(1.21),8.177(1.95),8.217(1.27),8.228(1.17),8.312(1.39),8.329(1.31),8.541(1.49).
將第二含有產物的部分濃縮，溶於10ml乙腈/水中，加入3ml甲酸且使混合物攪拌1小時。將混合物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且冷凍乾燥，得到360mg(25%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.62min；MS(ESIpos)：m/z=391[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.116(15.89),2.325(16.00),2.857(5.52),2.869(5.49),3.700(1.07),3.714(2.07),3.726(2.13),3.740(1.12),4.316(1.56),4.330(2.23),4.342(1.44),6.842(1.29),6.856(2.89),6.873(1.11),7.274(1.48),7.277(1.50),7.295(1.54),7.866(3.76),8.105(1.38),8.123(1.24),8.164(2.85),8.222(1.71),8.240(1.61),8.310(1.37),8.327(1.27),8.449(1.14),8.922(0.42),9.085(0.53).
將90ml之Amberlite IRA 410氯化物形式裝入空匣內，將500ml 1M甲酸鈉水溶液通過離子交換劑，然後加入500ml水。
將1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)氯化吡啶鎓(1.00g,2.34mmol)溶於3ml水中且通過步驟1中所述的離子交換劑。將該離子交換劑以250ml水洗滌，並將
合併的濾液濃縮且在高真空下乾燥。將殘留物分成三部份且藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將產物部份合併、濃縮且冷凍乾燥，此得到787mg(100%純，77%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.59min；MS(ESIpos)：m/z=391[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.115(15.84),2.324(16.00),2.856(4.73),2.868(4.74),3.698(0.94),3.712(1.91),3.724(1.98),3.738(0.99),4.311(1.51),4.325(2.18),4.337(1.40),6.842(1.55),6.853(2.27),6.860(1.64),7.272(1.35),7.290(1.40),7.864(3.67),8.100(1.35),8.118(1.15),8.161(2.47),8.220(1.44),8.238(1.40),8.306(1.26),8.323(1.24),8.440(1.95).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(2.97g,10.64mmol)及1-(2-銨基乙基)-4-(甲基胺基)二氯化吡啶鎓(2.38g,10.64mmol)首先加入於30ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(3.09g,16.1mmol)及4-二甲基胺基吡啶(3.90g,31.9mmol)，且使混合物在室溫下攪拌隔夜。將反應混合物施用於Isolute®且藉由管柱層析(375g Biotage Snap Cartridge KP-NH®；Biotage-Isolera-One®；二氯甲烷/甲醇梯度5%甲醇-40%甲醇；流速：150ml/min)純化。將含有產物得部分合併且藉由蒸發濃縮。將殘留物溶於水中且冷凍乾燥，此得到2.55g(100%純，56%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.60min；MS(ESIpos)：m/z=391[M-Cl-]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.118(15.72),2.327(16.00),2.861(11.94),2.943(0.44),3.323(1.28),4.336(1.43),4.349(2.05),4.361(1.30),6.845(1.22),6.864(2.11),6.887(1.07),7.290(1.49),7.293(1.39),7.307(1.50),7.311(1.44),7.868(5.44),8.119(1.20),8.137(1.24),8.190(2.69),8.223(2.08),8.241(1.97),8.319(1.35),8.337(1.24),9.027(0.44).
將3-(1,4-二甲基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸(59.0mg,230μmol)及1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(72.1mg,230μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(66.2mg,345μmol)及4-二甲基胺基吡啶(84.4mg,691μmol)，且使混合物在室溫下攪拌一小時。將反應混合物濃縮，且殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物得部分合併且藉由蒸發濃縮，得到41mg(39%理論值，96%純度)之標題化合物。
LC-MS(方法2)：Rt=0.66min；MS(ESIpos)：m/z=390[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.95),0.008(0.79),1.069(0.58),1.872(14.04),2.103(0.48),2.144(0.44),2.860(4.76),3.637(0.99),3.652(16.00),3.717(1.54),3.729(1.59),3.901(0.52),4.315(1.25),4.329(1.85),4.341(1.16),6.839(1.01),6.856(1.95),6.874(0.87),6.880(0.79),
7.316(1.27),7.334(1.33),7.508(3.86),7.980(4.00),8.046(1.62),8.064(1.52),8.112(1.07),8.129(1.06),8.205(2.13),8.312(1.17),8.330(1.09),8.557(2.73),9.144(0.41).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及1-(3-胺基丙基)-4-(甲基胺基)溴化吡啶鎓氫溴酸鹽(1：1：1)(63.6mg,194μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌1.5小時。將反應混合物濃縮，且殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到41mg(44%理論值，95%純度)之標題化合物。
LC-MS(方法2)：Rt=0.64min；MS(ESIpos)：m/z=405[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.035(0.42),2.052(1.54),2.068(2.34),2.085(1.61),2.112(3.08),2.123(15.78),2.152(0.46),2.320(2.82),2.333(16.00),2.849(6.22),2.861(6.05),3.157(0.85),3.300(0.96),3.316(2.41),3.330(2.39),3.346(0.94),4.207(1.77),4.224(3.47),4.241(1.74),6.850(1.17),6.868(1.20),6.912(1.11),6.929(1.14),7.361(1.78),7.381(1.83),7.697(0.70),7.863(4.51),8.163(1.59),8.166(1.67),8.181(1.60),
8.184(1.64),8.230(6.07),8.248(1.93),8.364(1.60),8.382(1.59),8.432(4.36),8.943(0.81),9.088(0.47).
將3-(1-乙基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸(39.0mg,152μmol)及1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(47.6mg,152μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(43.8mg,228μmol)及4-二甲基胺基吡啶(55.8mg,457μmol)，且使混合物在室溫下攪拌一小時。將反應混合物濃縮，且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且由乙腈/水冷凍乾燥隔夜，得到15mg(22%理論值，96%純度)之標題化合物。
LC-MS(方法2)：Rt=0.67min；MS(ESIneg)：m/z=388[M-HCO2-2H]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.149(0.68),-0.008(6.13),0.008(5.34),0.146(0.68),1.272(7.25),1.290(16.00),1.308(7.36),2.150(0.84),2.328(1.36),2.367(1.00),2.670(1.39),2.710(1.10),2.860(8.27),2.869(7.96),3.714(3.04),3.727(3.12),4.063(2.04),4.081(6.31),4.099(6.21),4.117(1.94),4.323(3.61),6.692(6.31),6.697(6.39),6.838(3.22),6.847(3.46),6.857(3.35),7.319(2.59),7.337(2.67),7.716(6.05),7.720(6.00),7.793(0.60),8.011(8.56),8.100(2.12),8.115(2.33),8.184(4.84),8.280
(3.43),8.298(5.18),8.316(2.15),8.559(5.39),8.792(1.28),9.022(1.36).
將3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-甲酸(47.7mg,92%純，163μmol)及1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(51.1mg,163μmol)首先加入於5.3ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(46.9mg,245μmol)及4-二甲基胺基吡啶(59.8mg,489μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到49.5mg(64%理論值，95%純度)之標題化合物。
LC-MS(方法4)：Rt=0.55min；MS(ESIpos)：m/z=403[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.43),0.008(1.23),2.154(1.28),2.857(4.86),2.869(4.85),2.942(0.51),3.715(1.61),3.728(1.56),3.901(16.00),4.315(1.18),4.330(1.65),4.342(1.07),6.837(0.68),6.843(1.17),6.858(2.39),6.874(1.18),6.880(0.69),7.181(1.40),7.193(1.51),7.199(1.44),7.212(1.43),7.263(1.20),7.267(1.20),7.281(1.17),7.285(1.27),7.865(4.02),7.908(1.55),7.913(1.67),7.927(1.59),7.931(1.56),8.110(1.11),8.128(1.21),8.137(1.89),8.156(3.68),8.307(1.14),8.325(1.01),8.340(1.53),8.345(1.56),8.353(1.51),8.358(1.39),8.488(1.48),
8.903(0.71),8.915(0.71),9.044(0.51),9.058(0.97),9.071(0.49).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及3-(胺基甲基)-1-甲基碘化吡啶鎓鹽酸鹽(1：1：1)(55.7mg,194μmol)首先加入於6ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)再純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到78mg(97%理論值，98%純度)之標題化合物。
LC-MS(方法3)：Rt=0.23min；MS(ESIpos)：m/z=362[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.124(16.00),2.334(15.98),3.431(0.50),4.365(11.33),4.688(2.67),4.702(2.69),5.755(1.65),7.388(1.43),7.392(1.47),7.406(1.46),7.410(1.51),7.891(5.48),8.094(0.88),8.109(1.09),8.114(1.14),8.129(1.01),8.274(2.00),8.292(1.92),8.318(2.71),8.391(0.79),8.537(1.28),8.557(1.17),8.890(1.33),8.905(1.29),9.022
(2.16),9.603(0.87).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(60.0mg,233μmol)及1-(2-銨基乙基)-3-(甲基胺基)二溴化吡啶鎓(73.0mg,233μmol)首先加入於3ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(67.1mg,350μmol)及4-二甲基胺基吡啶(85.5mg,700μmol)，且使混合物在室溫下攪拌72小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到43mg(42%理論值，99%純度)之標題化合物。
LC-MS(方法2)：Rt=0.61min；MS(ESIpos)：m/z=391[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.149(0.59),-0.008(4.93),0.008(4.93),0.146(0.61),2.115(15.55),2.147(0.75),2.323(16.00),2.366(0.66),2.388(1.51),2.670(0.87),2.710(0.76),2.732(6.20),2.745(6.23),3.845(1.56),3.858(1.61),4.611(1.32),4.624(1.98),4.637(1.27),7.180(0.85),7.190(0.89),7.243(1.42),7.247(1.44),7.261(1.42),7.265(1.51),7.580(0.85),7.602(1.21),7.607(1.27),7.681(1.30),7.695(1.41),7.702(0.90),7.717(0.95),7.871(4.82),8.127(3.70),8.139(1.68),8.154(1.86),8.233(2.00),8.251(1.87),8.378(0.78),8.911(0.76).
在製備1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-3-(甲基胺基)甲酸吡啶鎓上，得到17mg(17%理論值，100%純度)作為副產物之標題化合物。
LC-MS(方法2)：Rt=0.54min；MS(ESIpos)：m/z=377[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.149(0.81),-0.008(6.93),0.008(6.53),0.146(0.81),2.073(0.94),2.114(15.69),2.322(16.00),2.366(0.52),2.670(0.63),2.710(0.54),2.941(1.11),3.805(1.38),3.817(1.44),4.592(1.69),6.634(1.96),7.260(1.09),7.278(1.15),7.547(0.77),7.572(1.25),7.642(1.00),7.656(1.08),7.678(0.67),7.868(4.82),8.102(1.82),8.116(1.44),8.140(2.00),8.223(1.67),8.241(1.56),8.554(2.52).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(60.0mg,233μmol)及4-胺基-1-(2-銨基乙基)-2-甲基二溴化吡啶鎓(73.0mg,233
μmol)首先加入於3ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(67.1mg,350μmol)及4-二甲基胺基吡啶(85.5mg,700μmol)，且使混合物在室溫下攪拌72小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)再純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到36mg(34%理論值，96%純度)之標題化合物。
LC-MS(方法2)：Rt=0.61min；MS(ESIpos)：m/z=391[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.561(0.80),1.573(0.80),2.118(15.68),2.147(0.98),2.326(16.00),2.352(0.47),2.630(13.63),2.670(0.59),2.709(0.44),3.462(1.08),3.778(2.45),3.792(2.52),3.806(1.26),3.895(1.03),4.558(1.57),4.572(2.78),4.586(1.53),6.331(2.50),7.274(1.43),7.292(1.49),7.511(0.86),7.516(0.86),7.533(1.74),7.538(1.83),7.574(2.11),7.596(1.02),7.874(3.58),7.981(1.04),8.150(2.89),8.235(1.56),8.253(1.48),8.400(2.24),8.408(2.28).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(60.0mg,
233μmol)及1-(3-銨基丙基)-3-(甲基胺基)二溴化吡啶鎓(76.3mg,233μmol)首先加入於7.5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(67.1mg,350μmol)及4-二甲基胺基吡啶(85.5mg,700μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)直接純化。將含有產物的部分合併、濃縮且在高真空下乾燥，得到42mg(40%理論值，100%純度)之標題化合物。
LC-MS(方法2)：Rt=0.67min；MS(ESIneg)：m/z=403[M-2H-HCO2]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.55),0.008(1.43),2.124(15.80),2.146(1.04),2.194(1.14),2.210(1.69),2.227(1.16),2.323(1.25),2.333(16.00),2.524(0.90),2.780(5.84),2.792(5.89),3.357(5.15),3.371(5.15),4.526(1.27),4.543(2.52),4.561(1.23),7.362(1.52),7.383(1.44),7.568(0.90),7.573(0.93),7.590(1.17),7.595(1.21),7.714(1.08),7.728(1.17),7.735(0.85),7.750(0.85),7.867(4.82),8.213(1.52),8.227(1.63),8.239(5.30),8.257(2.60),8.525(2.73),8.948(0.47).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及2-(胺基甲基)-1,4-二甲基碘化吡啶鎓鹽酸鹽(1：1：1)(58.4mg,194μmol)首先加入於15ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,
583μmol)且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到35mg(98%純，42%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.63min；MS(ESIpos)：m/z=376[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.03),0.008(0.81),2.129(16.00),2.329(1.46),2.338(15.97),2.464(0.46),2.579(10.08),4.322(10.68),4.360(0.46),4.890(2.68),4.903(2.71),5.754(1.84),7.425(1.44),7.429(1.49),7.443(1.46),7.447(1.49),7.848(1.19),7.864(1.14),7.905(5.07),7.919(2.28),8.280(1.99),8.298(1.88),8.396(2.62),8.502(1.83),8.850(2.03),8.866(1.97),9.909(0.75).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(50.0mg,179μmol)及1-(2-胺基乙基)-3-甲基-4-(甲基胺基)氯化吡啶鎓鹽酸鹽(1：1：1)(46.9mg,197μmol)首先加入於2ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(51.5mg,269μmol)及4-二甲基胺基吡啶(65.6mg,537μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮，使殘留物溶於甲醇中，加入0.5ml甲酸，且在旋轉蒸發器上於50℃蒸發15分鐘期間。然後，使混合物藉由製備性HPLC(管柱：Chromatorex C18
10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 10% B；5min 10% B；19min 50% B；20min 95% B；26min 10% B；流速：100ml/min；0.1%甲酸)純化。將含有產物的部分合併且濃縮，並將殘留物溶於水/乙腈中且冷凍乾燥，此得到43.3mg(100%純，54%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.65min；MS(ESIpos)：m/z=405[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.080(10.98),2.115(16.00),2.146(0.61),2.324(15.78),2.908(5.10),2.915(4.84),3.447(1.02),3.733(1.81),3.744(1.83),4.349(2.08),6.825(1.53),6.843(1.54),7.285(1.34),7.303(1.37),7.861(2.13),8.114(0.63),8.169(2.44),8.215(1.31),8.238(2.79),8.295(1.11),8.312(1.08),8.551(0.77).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(50.0mg,179μmol)及1-(2-胺基乙基)-2-甲基-4-(甲基胺基)氯化吡啶鎓鹽酸鹽(1：1：1)(46.9mg,197μmol)首先加入於2ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(51.5mg,269μmol)及4-二甲基胺基吡啶(65.6mg,537μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮，使殘留物溶於甲醇中，加入0.5ml甲酸，且使其旋轉蒸發器上蒸發15分鐘期間。然後，將混合物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 10% B；5min 10% B；19min 50% B；20min 95% B；26min 10% B；流速：100ml/min；0.1%甲酸)純化。將含有產物的部分合併且濃縮，且使殘留物溶於水/乙腈中並冷
凍乾燥，此得到36mg(100%純，45%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.69min；MS(ESIpos)：m/z=405[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.39),0.008(0.90),2.074(0.54),2.119(16.00),2.146(0.83),2.327(15.93),2.606(6.17),2.828(2.07),2.849(3.06),2.859(2.53),3.434(1.28),3.692(2.02),3.705(2.00),4.331(1.79),4.344(1.55),6.747(1.60),6.800(1.09),7.291(1.07),7.307(1.06),7.868(1.71),8.024(0.52),8.041(0.59),8.173(1.63),8.229(1.42),8.245(1.28),8.534(0.43).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(100mg,358μmol)及1-(2-銨基乙基)-4-(乙基胺基)二氯化吡啶鎓(93.8mg,394μmol)首先加入於2ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(103mg,537μmol)及4-二甲基胺基吡啶(131mg,1.07mmol)，且使混合物在是溫下攪拌隔週末。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併且濃縮，並將殘留物溶於水/乙腈中並冷凍乾燥，此得到112mg(100%純，69%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.71min；MS(ESIpos)：m/z=405[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.05),0.008(1.00),1.136
(3.32),1.154(7.09),1.172(3.42),2.115(15.93),2.324(16.00),3.228(0.56),3.246(1.48),3.263(1.75),3.277(1.54),3.295(0.77),3.712(1.57),3.723(1.61),4.325(1.88),6.857(1.83),6.863(1.80),6.875(1.81),7.282(1.31),7.300(1.35),7.862(4.54),8.111(0.97),8.129(1.04),8.171(2.38),8.216(1.74),8.234(1.63),8.281(1.01),8.297(0.96),8.549(2.43).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及1-(2-胺基乙基)-3-乙基溴化吡啶鎓氫溴酸鹽(1：1：1)(60.7mg,194μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌三小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併且濃縮，且使殘留物溶於水/乙腈中且冷凍乾燥，此得到67mg(99%純，79%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.66min；MS(ESIpos)：m/z=390[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.125(3.30),1.144(6.98),1.162(3.39),2.108(15.98),2.317(16.00),2.728(0.97),2.747(2.86),2.766(2.79),2.785(0.89),3.434(0.61),3.899(0.76),3.913(1.75),3.926(1.78),3.939(0.79),4.817(1.94),7.271(1.24),7.289(1.28),7.853(3.00),8.019(0.97),
8.035(1.22),8.039(1.24),8.055(1.07),8.188(4.11),8.206(1.49),8.457(1.37),8.478(1.25),8.585(1.06),9.008(1.04),9.021(1.01),9.153(1.48).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(50.0mg,179μmol)及2-(胺基甲基)-1-甲基碘化吡啶鎓鹽酸鹽(1：1：1)(51.3mg,179μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(51.5mg,269μmol)及4-二甲基胺基吡啶(65.6mg,537μmol)，且使混合物在室溫下攪拌48小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到40mg(100%純，55%理論值)之標題化合物。
LC-MS(方法3)：Rt=0.26min；MS(ESIpos)：m/z=362[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.60),0.008(0.54),2.075(0.57),2.130(16.00),2.285(0.57),2.339(15.95),2.942(0.95),3.408(1.20),4.411(11.92),4.951(2.75),4.964(2.70),7.429(1.36),7.432(1.33),7.447(1.37),7.450(1.34),7.906(4.54),8.008(0.75),8.025(1.40),8.042(0.79),8.086(1.51),8.106(1.61),8.283(1.85),8.301(1.75),8.394(2.71),8.495(1.19),8.516(0.98),8.535(1.54),8.554(0.72),9.023(1.57),9.038(1.51),10.094(0.45).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(100mg,358μmol)及1-(2-銨基乙基)-4-(三氟甲基)二溴化吡啶鎓(107mg,394μmol)首先加入於2ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(103mg,537μmol)及4-二甲基胺基吡啶(131mg,1.07mmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且在高真空下乾燥，將殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)再純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到50mg(91%純，27%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.72min；MS(ESIpos)：m/z=430[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.110(15.91),2.122(2.59),2.318(16.00),2.330(2.79),2.891(0.43),3.469(1.48),3.485(1.48),3.935(1.85),3.947(1.88),4.938(2.18),7.232(1.47),7.249(1.51),7.852(0.60),7.865(4.73),8.147(2.95),8.219(2.13),8.237(2.06),8.460(3.96),8.688(2.87),8.703(2.94),9.367(0.52),9.500(2.58),9.515(2.48).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及2-(胺基甲基)-1,5-二甲基碘化吡啶鎓鹽酸鹽(1：1：1)(58.4mg,194μmol)首先加入於6ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且在高真空下乾燥，將殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)再純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到47mg(91%純，52%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.61min；MS(ESIpos)：m/z=376[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(0.42),0.008(0.40),1.398(0.59),2.075(1.24),2.115(0.69),2.122(1.83),2.130(15.87),2.154(0.61),2.323(0.73),2.330(1.75),2.339(16.00),2.431(0.42),2.469(10.38),4.360(11.57),4.899(2.66),4.912(2.67),7.399(1.33),7.403(1.39),7.417(1.38),7.421(1.45),7.908(4.87),7.976(1.90),7.997(2.08),8.288(2.11),8.306(2.01),8.345(0.78),8.364(3.69),8.388(1.21),8.950(2.35),9.758(0.62).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)及1-(2-胺基乙基)-3-甲基溴化吡啶鎓氫溴酸鹽(1：1：1)(57.9mg,194μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(71.2mg,583μmol)，且使混合物在室溫下攪拌三小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併且濃縮，並使殘留物溶於水/乙腈中且冷凍乾燥，此得到53mg(100%純，65%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.58min；MS(ESIpos)：m/z=376[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.140(16.00),2.354(15.94),2.478(11.38),3.892(0.86),3.906(1.85),3.919(1.88),3.933(0.86),4.749(1.52),4.762(2.21),4.775(1.36),7.416(1.00),7.433(1.01),8.017(1.13),8.033(1.30),8.037(1.38),8.052(1.24),8.151(1.57),8.226(2.29),8.414(1.39),8.432(1.34),8.458(1.39),8.478(1.26),8.907(1.48),8.922(1.41),9.068(2.40),9.114(0.81).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(50.0mg,179μmol)及1-(3-胺基丙基)-2,4-二甲基-1H-吡唑-2-鎓甲酸酯鹽酸鹽(1：1：1)(62.6mg,197μmol)首先加入於2ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(51.5mg,269μmol)及4-二甲基胺基吡啶(65.6mg,537μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮，並使殘留物溶於甲酸中且藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到62mg(96%純，76%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.62min；MS(ESIpos)：m/z=393[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.087(11.28),2.123(16.00),2.133(2.26),2.150(2.21),2.168(0.51),2.332(15.49),3.356(1.34),3.371(2.57),3.386(2.57),3.401(1.36),3.707(0.43),4.087(14.14),4.472(1.46),4.490(2.84),4.507(1.43),5.755(3.87),7.352(1.26),7.370(1.31),7.870(4.41),8.226(2.59),8.247(1.81),8.265(1.72),8.298(2.94),8.380(1.55),8.418(2.28),8.905(0.54).
將3-(1-異丙基-1H-吡唑-5-基)咪唑并[1,2-a]吡啶-7-甲酸鋰(90.0mg,326μmol)及1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(112mg,358μmol)首先加入於5ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞
胺鹽酸鹽(93.7mg,489μmol)及4-二甲基胺基吡啶(119mg,977μmol)，且使混合物在室溫下攪拌48小時。加入更多的1-(2-銨基乙基)-4-(甲基胺基)二溴化吡啶鎓(50.0mg,160μmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(50.0mg,260μmol)及4-二甲基胺基吡啶(50.0mg,409μmol)，且使混合物在室溫下攪拌額外48小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到58mg(97%純，38%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.73min；MS(ESIpos)：m/z=404[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.39),0.008(1.29),1.360(15.93),1.376(16.00),2.150(0.41),2.857(5.60),3.717(1.83),3.729(1.87),4.330(2.19),4.363(1.18),4.379(1.46),4.396(1.07),4.412(0.41),6.642(4.11),6.647(4.11),6.835(0.97),6.852(1.67),6.866(0.92),7.326(1.13),7.343(1.20),7.733(3.20),7.737(3.09),7.964(4.28),8.110(1.09),8.128(1.10),8.196(2.04),8.214(1.72),8.232(1.53),8.309(1.25),8.327(1.18),8.561(2.45).
將2-({[(3-碘咪唑并[1,2-a]吡啶-7-基)羰基]胺基}甲基)-1-甲基咪唑并[1,2-a]吡啶-1-鎓(120mg,278μmol)、(2-甲氧基吡啶-3-基)硼酸(84.9mg,555μmol)、碳酸鉀(115mg,833μmol)及[1,1-雙(二苯基膦基)二茂鐵二氯鈀(II)
(20.3mg,27.8μmol)首先在氬氣下加入。將3.5ml脫氣的二烷/水(4：1)加入，且使混合物在90℃攪拌一小時。以甲醇稀釋反應混合物，且加入0.2ml甲醇。將混合物過濾且使濾液藉由製備性HPLC(管柱：RP,Chromatorex C18,250 x 30mm 10μm；流速：50ml/min；mobile phase：A=water+0.1% formic acid,B=乙腈；梯度：0min 5% B,9min 5% B,24min 95% B,27min 95% B,29min 10% B；偵測：210nm)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到42mg(100%純，33%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.71min；MS(ESIpos)：m/z=413[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：3.366(2.73),3.904(16.00),4.068(12.78),4.846(2.26),4.859(2.22),7.187(1.47),7.200(1.55),7.206(1.54),7.218(1.52),7.402(1.25),7.420(1.29),7.521(0.80),7.539(1.59),7.555(0.88),7.890(1.49),7.927(1.59),7.931(1.70),7.945(1.56),7.950(1.49),8.009(0.79),8.030(1.11),8.048(0.90),8.188(1.00),8.205(2.59),8.228(1.37),8.319(1.97),8.345(1.66),8.350(1.67),8.358(1.63),8.362(1.52),8.421(2.31),8.887(1.35),8.903(1.30),9.717(0.56).
將3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-甲酸(60.0mg,80%純，178μmol)及1-(2-胺基乙基)-3-甲基-4-(甲基胺基)氯化吡啶鎓鹽酸鹽(1：1：1)(42.3mg,178μmol)首先加入於1.9ml的二氯甲烷中，加入1-(3-二甲基胺
基丙基)-3-乙基碳二亞胺鹽酸鹽(51.1mg,267μmol)及4-二甲基胺基吡啶(65.1mg,533μmol)，且使混合物在室溫下攪拌隔夜。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到17mg(100%純，21%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.72min；MS(ESIneg)：m/z=415[M-2H-HCO2]-
1H-NMR(400MHz,DMSO-d6)δ[ppm]：-0.008(1.14),0.008(0.95),2.080(9.55),2.096(0.52),2.151(1.89),2.328(0.45),2.523(1.12),2.670(0.46),2.912(5.24),2.923(5.18),2.941(0.68),3.355(1.82),3.727(1.52),3.739(1.54),3.799(1.03),3.900(16.00),4.318(1.23),4.332(1.79),4.344(1.14),6.845(1.89),6.863(1.91),7.182(1.48),7.194(1.56),7.200(1.54),7.213(1.55),7.251(1.34),7.256(1.32),7.269(1.31),7.274(1.37),7.865(5.03),7.911(1.61),7.916(1.66),7.929(1.57),7.934(1.51),7.966(0.78),7.977(0.76),8.139(4.14),8.158(1.82),8.214(2.24),8.271(1.15),8.289(1.12),8.341(1.53),8.346(1.55),8.353(1.52),8.358(1.38),8.522(1.17),9.012(0.75).
將3-(2-甲氧基吡啶-3-基)咪唑并[1,2-a]吡啶-7-甲酸(60.0mg,80%純，
178μmol)及1-(2-胺基乙基)-2-甲基-4-(甲基胺基)氯化吡啶鎓鹽酸鹽(1：1：1)(42.3mg,178μmol)首先加入於1.9ml的二氯甲烷中，並加入2ml的二甲基甲醯胺、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(51.1mg,267μmol)及4-二甲基胺基吡啶(65.1mg,533μmol)，且使混合物在室溫下攪拌隔夜。加入更多的1-(2-胺基乙基)-2-甲基-4-(甲基胺基)氯化吡啶鎓鹽酸鹽(1：1：1)(21mg,90μmol)、4-二甲基胺基吡啶(32.6mg,265μmol)及1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(26mg,135μmol)，且使混合物再次於室溫下攪拌隔夜。將反應混合物在40℃攪拌三小時。然後，將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到11.7mg(95%純，14%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.65min；MS(ESIpos)：m/z=417[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：0.925(0.41),1.919(0.57),2.154(1.41),2.611(5.38),2.834(1.98),2.846(2.36),2.854(3.19),2.867(2.99),3.395(0.62),3.689(1.71),3.703(1.76),3.903(16.00),4.325(1.67),4.339(1.47),6.715(1.14),6.724(1.17),6.764(0.42),6.815(1.07),7.183(1.47),7.195(1.58),7.201(1.58),7.214(1.52),7.265(1.21),7.284(1.24),7.872(5.12),7.912(1.63),7.917(1.74),7.931(1.55),7.935(1.59),8.011(0.95),8.029(0.92),8.153(4.06),8.171(1.79),8.206(0.67),8.225(0.55),8.343(1.69),8.347(1.75),8.355(1.68),8.360(1.51),8.446(2.83),8.631(0.64),9.078(0.90).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)首先加入於2ml的二氯甲烷中，加入1-(2-銨基乙基)-4-三級丁基二溴化吡啶鎓(66.1mg,194μmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9mg,292μmol)及4-二甲基胺基吡啶(95.0mg,777μmol)，且使混合物在室溫下攪拌48小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.50min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到58mg(100%純，59%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.85min；MS(ESIpos)：m/z=418[M-HCO2-HCO2H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.345(16.00),2.111(5.51),2.319(5.56),3.865(0.60),3.879(0.61),4.748(0.66),7.216(0.47),7.234(0.48),7.867(1.44),8.122(0.88),8.141(1.12),8.159(1.09),8.227(0.61),8.245(0.58),8.345(0.88),8.964(0.95),8.981(0.93).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)首先加入於2ml的二氯甲烷中，加入1-(2-銨基乙基)-4-異丙基二溴化吡啶鎓(63.4mg,194μmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9g,292mmol)及二甲基胺基吡啶(95.0mg,777μmol)，且使混合物在室溫下攪拌48小時。將反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到14.5mg(100%純，17%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.77min；MS(ESIpos)：m/z=404[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.248(13.24),1.265(13.42),2.111(16.00),2.319(15.81),3.172(0.84),3.189(1.11),3.206(0.85),3.224(0.42),3.339(1.20),3.871(1.63),3.883(1.67),4.755(1.77),7.238(1.16),7.256(1.19),7.861(3.52),8.031(2.65),8.047(2.78),8.149(2.11),8.212(1.43),8.230(1.38),8.555(1.67),8.998(2.03),9.012(1.66).
將1-(2-{[(3-碘咪唑并[1,2-a]吡啶-7-基)羰基]胺基}乙基)-4-(甲基胺基)溴化吡啶鎓(70.0mg,139μmol)、(4-甲氧基吡啶-3-基)硼酸(42.6mg,279μmol)、碳酸鉀(57.8mg,418μmol)及[1,1-雙(二苯基膦基)二茂鐵二氯鈀(II)(10.2mg,13.9μmol)首先在氬氣下加入。將2ml脫氣的二烷/水(4：1)加入，且使混合物在90℃攪拌三小時。以甲醇稀釋反應混合物，加入0.5ml甲酸且將混合物過濾。將濾液藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 10% B；5min 10% B；19min 50% B；20min 95% B；26min 10% B；流速：100ml/min；0.1%甲酸)純化。將含有產物得部分合併且藉由蒸發濃縮。使殘留物藉由製備性TLC(Alox neutral，流動相：二氯甲烷/甲醇10：1)再純化，此得到22.1mg(95%純，31%理論值)之標題化合物。
1H-NMR(500MHz,DMSO-d6)δ[ppm]：0.006(1.46),2.869(15.13),3.714(1.71),3.721(1.74),3.884(16.00),4.313(1.66),4.323(2.29),4.334(1.53),6.833(1.16),6.847(1.39),6.856(1.40),6.870(1.19),7.239(1.62),7.243(1.65),7.254(1.64),7.257(1.69),7.309(2.77),7.321(2.87),7.872(6.30),8.102(3.49),8.116(3.37),8.149(3.08),8.300(1.17),8.315(1.18),8.517(6.03),8.613(3.43),8.624(3.28),8.893(0.83).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸(50.0mg,194μmol)首先加入於2ml的二氯甲烷中，加入1-(2-銨基乙基)-4-乙基二溴化吡啶鎓(60.7mg,194μmol)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(55.9g,292mmol)及二甲基胺基吡啶(95.0mg,777μmol)，且使混合物在室溫下攪拌48小時。反應混合物濃縮且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到22mg(100%純，26%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.71min；MS(ESIpos)：m/z=390[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：1.221(3.25),1.239(6.82),1.258(3.45),2.111(15.76),2.146(0.47),2.319(16.00),2.864(1.06),2.882(2.98),2.901(2.92),2.920(1.02),3.015(0.47),3.868(2.24),3.880(2.29),4.747(2.38),7.240(1.51),7.257(1.54),7.862(3.91),7.991(3.24),8.007(3.27),8.148(2.56),8.210(1.73),8.228(1.64),8.507(1.84),8.978(2.58).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(100g,358μmol)及1-(2-胺基乙基)-3-苯氧基溴化吡啶鎓(117mg,394μmol)首先加入於3ml的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(103mg,537μmol)及4-二甲基胺基吡啶(131g,1.07mmol)，且使混合物在室溫下攪拌四小時。將反應混合物溶於水/乙腈中且藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且於高真空下乾燥，此得到103mg(99%純，57%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.88min；MS(ESIpos)：m/z=454[M-HCO2]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.112(15.97),2.321(16.00),3.387(0.72),3.893(1.65),3.903(1.60),4.801(1.86),7.124(3.00),7.143(3.62),7.210(0.75),7.229(1.87),7.247(1.21),7.270(1.38),7.287(1.39),7.355(2.45),7.375(3.12),7.394(1.58),7.881(5.10),8.086(0.90),8.102(0.96),8.108(1.12),8.123(1.08),8.177(2.39),8.233(1.89),8.251(2.72),8.266(0.93),8.510(5.33),8.917(1.26),8.931(1.18),9.130(1.90),9.364(0.40).
將1-(2-{[(3-碘咪唑并[1,2-a]吡啶-7-基)羰基]胺基}乙基)-4-(甲基胺基)溴化吡啶鎓(70.0mg,139μmol)、(2-甲基吡啶-3-基)硼酸(38.2mg,279μmol)、碳酸鉀(57.8mg,418μmol)及[1,1-雙(二苯基膦基)二茂鐵二氯鈀(II)(10.2mg,13.9μmol)首先在氬氣下加入，將2ml脫氣的二烷/水(1：1)加入，
且使混合物在90℃攪拌1.5小時。以甲醇稀釋反應混合物，加入0.5ml甲酸且使混合物過濾。將濾液藉由製備性HPLC(管柱：Chromatorex C18 10μm,125 x 40mm，流動相：A=水，B=乙腈；梯度：0.0min 10% B；5min 10% B；19min 50% B；20min 95% B；26min 10% B；流速：100ml/min；0.1%甲酸)純化。將含有產物的部分合併、濃縮且在高真空下乾燥，使殘留物藉由製備性TLC(Alox neutral，流動相：二氯甲烷/甲醇10：1)再純化。此得到21.3mg(90%純，32%理論值)之標題化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]：2.309(1.58),2.324(15.42),2.868(16.00),3.718(2.12),4.313(1.85),4.326(2.66),4.339(1.71),6.834(1.42),6.850(3.40),6.866(1.72),7.262(1.84),7.266(1.96),7.280(1.89),7.284(2.02),7.408(1.25),7.420(1.35),7.427(1.40),7.439(1.39),7.837(1.72),7.841(1.84),7.856(1.63),7.860(1.65),7.890(4.98),7.908(0.55),8.103(3.22),8.121(2.99),8.182(3.68),8.298(1.48),8.317(1.58),8.614(1.66),8.618(1.75),8.626(1.69),8.630(1.66),8.911(0.77).
將3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-甲酸鈉(100mg,358μmol)及1-(2-銨基乙基)-4-(六氫吡啶-1-基)二溴化吡啶鎓(145mg,394μmol)首先加入於2m的二氯甲烷中，加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(103mg,537μmol)及4-二甲基胺基吡啶(131mg,1.07mmol)，且使混合物在室溫下攪拌隔夜。然後，將反應混合物濃縮，且使殘留物藉由製備性HPLC(管柱：Chromatorex C18 10μm,250 x 30mm，
流動相：A=水，B=乙腈；梯度：0.0min 5% B；3min 5% B；20min 50% B；23min 100% B；26min 5% B；流速：50ml/min；0.1%甲酸)純化。將產物部份合併、濃縮且冷凍乾燥，此得到39.8mg(89%純，20%理論值)之標題化合物。
LC-MS(方法2)：Rt=0.92min；MS(ESIpos)：m/z=445[M-HCO2]+
1H-NMR(500MHz,DMSO-d6)δ[ppm]：1.553(2.64),1.560(2.26),1.636(0.62),1.649(1.26),1.659(1.34),2.114(16.00),2.323(14.93),3.627(2.68),3.638(3.37),3.648(2.62),3.743(1.30),3.752(1.31),4.364(1.09),4.374(1.55),7.182(2.05),7.197(2.09),7.310(1.18),7.325(1.33),7.848(1.27),7.862(0.8).
對抗α2B腎上腺素受體(ADRA2B)之拮抗性係使用重組人類α2B-Gα16受體融合蛋白CHO細胞系測試，該CHO係胞系亦另外重組地表現發光蛋白粒線體螅蛋白(obelin)。
將細胞在37℃及5% CO2下培養於具有L-穀醯胺之Dulbecco’s改良的Eagle’s培養基/NUT混合物F12(其額外含有10%(v/v)去活化的胎牛血清、1mM丙酮酸鈉、0.9mM碳酸氫鈉、50U/ml青黴素、50μg/ml鏈黴素、2.5μg/ml雙性黴素B(amphotericin B)及1mg/ml遺傳黴素(Geneticin))。將以不含酵素之Hank's-為主的細胞解離緩衝液使細胞繼代。使用之所有細胞培養試劑係來自於Invitrogen(Carlsbad,USA)。
在白色384-孔微量滴定板上進行發光測量。將2000細胞/孔以25μl體積平板培養，並在30℃及5% CO2下於具有腔腸素(coelenterazine)(α2B：5μg/ml)之細胞培養基中培養一天。將測試物質(10μl)的連續稀釋液加入細胞中，在6分鐘之後，將去甲腎上腺素加入細胞中(35μl；最終濃度：EC50-EC80)，並使用CCD(電荷耦合裝置)照相機(Hamamatsu Corporation,Shizuoka,Japan)於一不透光盒子中測量發射的光50秒。
測試物質係以至高最大濃度10μM檢測。IC50值(顯示於表1)係由適
當的劑量-反應曲線而計算。
可進行麻醉和分解的犬隻之血液動力學研究以分析物質的體內功效。
為此目的，使用戊巴比妥鈉和溴化泮庫溴銨(pancuronium bromide)誘發麻醉，並使用戊巴比妥鈉、芬太尼(fentanyl)和環境空氣/氧氣混合物維持麻醉。此外，輸注林格(Ringer)乳酸鹽溶液。
後來測定冠狀動脈血流儲量需要冠狀動脈血流量之量化。此可藉由放
置在冠狀血管周圍的流量計探針來實現。
在靜脈內或冠狀動脈內投予例如腺苷的擴張劑(通常為140μg/kg/min，輸注5分鐘)後，可使用流量計探針測量作為腺苷反應之冠狀動脈血流量的增加。
「投予腺苷期間的冠狀動脈血流」(例如腺苷輸注期間的峰值流量)與「基礎流量」(腺苷輸注前通常3分鐘的平均流量)之比較係允許關於冠狀動脈血流儲量所作的陳述，亦即，除了用於供給心肌的基礎流量之外，還可以提供在壓力下的最大血容量。冠狀動脈血流儲量(腺苷/基礎流量下的峰值流量)可從這些測量值確定。
隨後，將L-NAME(通常60μg/kg/min，以15μl/kg/min連續輸注60分鐘)輸注至犬隻，尤其是阻斷內皮NO合成酶以模擬內皮損傷。
藉由進一步連續輸注L-NAME，然後重複投予腺苷-如上所述-以確定由於L-NAME輸注(阻斷NO合成酶)導致的冠狀動脈血流儲量之減少。最後，藉由進一步連續輸注L-NAME，然後在媒劑投予和隨後投予ADRA2b拮抗劑後測定對冠狀動脈血流儲量(如上所述的腺苷輸注)的影響。媒劑和ADRA2b拮抗劑係以「團塊(bole)(50μl/kg)+輸注(輸注速率：450μl/kg/h)」靜脈內投予。
為了評估物質的體內功效，可能測定物質對大鼠中梗塞區域大小(基於風險的低灌注區域)的影響，以及心臟功能的血液動力學參數。為此目的，將以物質處理的動物與僅接受安慰劑的動物比較。原則上，大鼠中急性心肌梗塞的方法包括外科手術(在麻醉和鎮痛下)，其中冠狀動脈，較佳地LAD(左前降支動脈)以縫合線結紮，且在確定的阻塞階段30分鐘之後再次開放。在此之後，藉由移除縫線(心臟組織再灌注)重新打開血管。再次關閉動物的胸部，並使用縫合材料(Vicryl L 4-0或5-0(V990H))縫合肌肉層和表皮。在麻醉和鎮痛的最後檢查中，動物配備有器械(經由頸動脈引入Millar導管(2F)以測量心臟血液動力學)。在測量結束時，使用過量的麻醉劑(異氟烷>5%，戊巴比妥>200mg/kg)和/或在深度麻醉下放血而使動
物在沒有醒來的情況下無痛地犧牲。於死後藉由以伊文思藍(Evans Blue)(0.2%)灌注進行危險區域(非灌注區域)和心臟中的梗塞大小之測定，以確定由於閉塞而未灌注的區域(風險區域)且隨後藉由TTC染色(三苯基四唑氯化物(TTC)，(活體染色))檢測重要組織。
可以進行對大鼠的血液動力學研究以評估物質的體內功效。為此目的，用利血壓平(reserpine)(5mg/kg s.c.)預處理大鼠(WiWu株)3天。此導致動物中腎上腺素能激動劑和拮抗劑的增強作用。在以此方式預處理的大鼠中，在麻醉下侵入性地測量血壓。首先，給動物投予拮抗劑(i.v.)，然後靜脈內投予ADRA2激動劑右美托咪定(dexmedetomidine)3μg/kg/min(15分鐘)。選擇性ADRA2b拮抗劑係以劑量依賴性方式抵消激動劑誘發的血壓升高。
iv(靜脈內)研究：
為了檢測物質的藥物動力學特性，可將討論的物質作為團塊(bole)或輸液投予動物(例如大鼠，犬)。較佳地，將這些物質配製成0.9%濃度的鹽水，血漿/二甲亞碸(99/1)，聚乙二醇/乙醇/水，比例為50/10/40(其他合適的調配劑也是可能的)。
可經由導管或靜脈穿刺從動物中取出血液樣品，並收集在含有抗凝血劑(例如肝素鋰或EDTA鉀)的管中。在以下時間點，從試驗動物中取血液樣本：物質投予後0.033、0.083、0.167、0.25、0.283、0.333、0.5、0.75、1、2、3、5、7、24小時。(也可能在稍後的時間點去除較少的樣本或其他樣本。)為了獲得血漿，將血液樣本離心。取出上清液(血漿)並進一步直接處理或冷凍用於後續樣本製備。對於樣本製備，將50μl血漿與250μl乙腈(沉澱劑乙腈也含有內標準物ISTD用於後續分析測定)混合，然後使其在室溫下靜置5分鐘，接著將混合物以16000g離心3分鐘。取出上清液，加入500μl適用於流動相的緩衝液。然後藉由LC-MS/MS分析(例如使用
來自Phenomenex的Gemini 5μM C18 110A 50mm x 3mm(或150mm×3mm)柱的液相色譜法；使用API 5500或API 6500的質譜法檢查樣本；SCIEX，加拿大)以測定個別樣本中物質的濃度。
除了血漿濃度之外，還可測定所討論的物質的全血與血漿的濃度比。為此目的，將該物質在全血中以一定濃度培育20分鐘。然後，如上所述處理樣本以測定血漿中物質的濃度。濃度組除以血漿中測量的濃度係得到參數Cb/Cp。
藉由非房室模型分析(NCA)計算藥物動力學參數。用於計算參數的算法基於藥效動力學的一般教科書中公布的規則(例如Rowland and Tozer,Clinical Pharmacokinetics and Pharmacodynamics,ISBN 978-0-7817-5009-7)。
主要藥物動力學參數清除率(CL)和分佈容積(Vss)可計算如下：
本發明之化合物可如下轉換為醫藥組成物：
將根據本發明之化合物以低於飽和溶解度的濃度溶解於生理學上可耐受的溶劑(例如等滲鹽水，5%葡萄糖溶液和/或30%PEG 400溶液)中。溶液藉由過濾滅菌且用於填充無菌和無熱原的注射容器。
Claims (12)
- 一種式(I)化合物，
- 根據請求項1之式(I)化合物，其中R1、R2及R3a、R3b相互獨立地為選自下列之基團：氫、乙基胺基、二甲基胺基、甲基胺基、胺基、甲基、乙基、三氟甲基、三級丁基、異丙基、苯氧基或六氫吡啶-1-基，R4代表甲基，R5及R6相互獨立地代表氫、甲基、乙基、異丙基或甲氧基，n代表1或2之數目，X-代表溴離子、氯離子或甲酸根，且A代表下式帶正電荷之氮雜雜芳族
- 根據請求項1或2之式(I)化合物，其中R1代表氫或甲基胺基，R2代表氫或甲基，R3a、R3b代表氫，R4代表甲基，R5及R6相互獨立地代表甲基、甲氧基或氫，n代表1或2之數目，X-代表溴離子、氯離子或甲酸根，且A代表下式帶正電荷之氮雜雜芳族
- 根據請求項1、2或3之式(I)化合物，其選自下列組成之群組1-[2-({[3-(3,5-二甲基-1,2-唑-4-基)咪唑并[1,2-a]吡啶-7-基]羰基}胺基)乙基]-4-(甲基胺基)氯化吡啶鎓鹽酸鹽
- 一種製備如請求項1至4中定義的式(I)化合物之方法，其特徵在於使式(II)化合物或其對應的羧酸
- 根據請求項1至4中任一項之式(I)化合物，其用於治療及/或預防疾病。
- 根據請求項1至4中任一項之式(I)化合物，其用於治療及/或預防下列之方法中：急性心衰竭、右心衰竭、左心衰竭、全心衰竭、糖尿病心衰竭、正常收縮分率心衰竭(HFpEF)、舒張期心衰竭、低收縮分率心衰竭(HfrEF收縮期心衰竭)、不穩定型心絞痛、心肌缺血、急性冠狀動脈症候群、NSTEMI(非ST波段上升的心肌梗塞)、STEMI(ST波段上升的心肌梗塞)、缺血性心臟肌肉損傷、心肌梗塞、冠狀動脈微血管功能障礙、微血管阻塞、無復流現象、短暫及缺血性發作、缺血性及出血性中風、周邊及心臟血管疾病、周邊循環受損、周邊動脈阻塞性疾病、原發性及繼發性雷諾氏症候群(Raynaud’s syndrome)、微循環障礙、動脈性肺高壓、冠狀動脈及周邊動脈之痙攣、再狹窄(例如在血栓溶解治療、經皮腔內血管形成術(PTA)、腔內冠狀動脈血管形成術(PTCA)之後)、再灌注損傷、內皮功能障礙、缺血性心肌病變、腎功能不全、腎病及壓力相關高血壓。
- 一種如請求項1至4中任一項定義的式(I)化合物之用途，其係用於製備治療及/或預防下列之醫藥品：急性心衰竭、右心衰竭、左心衰竭、全心衰竭、糖尿病心衰竭、正常收縮分率心衰竭(HFpEF)、舒張期心衰竭、低收縮分率心衰竭(HfrEF收縮期心衰竭)、冠狀心臟疾病、穩定及不穩定型心絞痛、心肌缺血、急性冠狀動脈症候群、NSTEMI(非ST波段上升的心肌梗塞)、STEMI(ST波段上升的心肌梗塞)、缺血性心臟肌肉損傷、心肌梗塞、冠狀動脈微血管功能障礙、微血管阻塞、無復流現象、短暫及缺血性發作、缺血性及出血性中風、周邊及心臟血管疾病、周邊循環受損、周邊動脈阻塞性疾病、原發性及繼發性雷諾氏症候群、微循環障礙、動脈性肺高壓、冠狀動脈及周邊動脈之痙 攣、再狹窄(例如在血栓溶解治療、經皮腔內血管形成術(PTA)、腔內冠狀動脈血管形成術(PTCA)之後)、再灌注損傷、內皮功能障礙、缺血性心肌病變、腎功能不全、腎病及壓力相關高血壓。
- 一種醫藥品，其包含如請求項1至4中任一項定義的式(I)化合物與一或多種惰性、非毒性之醫藥上合適之賦形劑。
- 一種醫藥品，其包含如請求項1至4中任一項定義的式(I)化合物與一或多種選自下列群組之活性化合物組合：血小板凝集抑制劑、抗凝血劑、前纖維蛋白溶解物質、影響心臟能量代謝及粒線體功能/ROS產生之物質、降血壓藥物、礦物皮質激素受體拮抗劑、HMG CoA還原酶抑制劑、調節脂質代謝的藥物、調節葡萄糖代謝的活性化合物及用於焦慮和疼痛治療的活性化合物，例如苯二氮呯類和鴉片類藥物。
- 根據請求項9或10之醫藥品，其係用於治療及/或預防急性心衰竭、右心衰竭、左心衰竭、全心衰竭、糖尿病心衰竭、正常收縮分率心衰竭(HFpEF)、舒張期心衰竭、低收縮分率心衰竭(HfrEF收縮期心衰竭)、冠狀動脈心臟疾病、穩定及不穩定型心絞痛、心肌缺血、急性冠狀動脈症候群、NSTEMI(非ST波段上升的心肌梗塞)、STEMI(ST波段上升的心肌梗塞)、缺血性心臟肌肉損傷、心肌梗塞、冠狀動脈微血管功能障礙、微血管阻塞、無復流現象、短暫及缺血性發作、缺血性及出血性中風、周邊及心臟血管疾病、周邊循環受損、周邊動脈阻塞性疾病、原發性及繼發性雷諾氏症候群、微循環障礙、動脈性肺高壓、冠狀動脈及周邊動脈之痙攣、再狹窄(例如在血栓溶解治療、經皮腔內血管形成術(PTA)、腔內冠狀動脈血管形成術(PTCA)之後)、再灌注損傷、內皮功能障礙、缺血性心肌病變、腎功能不全、腎病及壓力相關高血壓。
- 一種治療及/或預防人類及動物中急性心衰竭、右心衰竭、左心衰竭、全心衰竭、糖尿病心衰竭、正常收縮分率心衰竭(HFpEF)、舒張期心衰竭、低收縮分率心衰竭(HfrEF收縮期心衰竭)、冠狀動脈心臟疾病、穩定及不穩定型心絞痛、心肌缺血、急性冠狀動脈症候群、NSTEMI(非ST波段上升的心肌梗塞)、STEMI(ST波段上升的心肌梗塞)、缺 血性心臟肌肉損傷、心肌梗塞、冠狀動脈微血管功能障礙、微血管阻塞、無復流現象、短暫及缺血性發作、缺血性及出血性中風、周邊及心臟血管疾病、周邊循環受損、周邊動脈阻塞性疾病、原發性及繼發性雷諾氏症候群、微循環障礙、動脈性肺高壓、冠狀動脈及周邊動脈之痙攣、再狹窄(例如在血栓溶解治療、經皮腔內血管形成術(PTA)、腔內冠狀動脈血管形成術(PTCA)之後)、再灌注損傷、內皮功能障礙、缺血性心肌病變、腎功能不全、腎病及壓力相關高血壓之方法，其使用包括使用有效量之至少一種如請求項1至4中任一項定義的式(I)化合物或如請求項9至11中任一項定義之醫藥品。
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| SG11202106582YA (en) | 2018-12-20 | 2021-07-29 | Incyte Corp | Imidazopyridazine and imidazopyridine compounds as inhibitors of activin receptor-like kinase-2 |
| TWI829857B (zh) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶 |
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| DE102011007272A1 (de) | 2011-04-13 | 2012-10-18 | Bayer Pharma Aktiengesellschaft | Verzweigte 3-Phenylpropionsäure-Derivate und ihre Verwendung |
| US9309243B2 (en) | 2012-07-13 | 2016-04-12 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of TNF activity |
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| US9624214B2 (en) | 2012-11-05 | 2017-04-18 | Bayer Pharma Aktiengesellschaft | Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use |
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| JOP20200073A1 (ar) | 2020-04-29 |
| EP3700903A1 (de) | 2020-09-02 |
| BR112020007967A2 (pt) | 2020-10-20 |
| ECSP20023043A (es) | 2020-06-30 |
| UY37947A (es) | 2019-05-31 |
| CN111225917A (zh) | 2020-06-02 |
| MA50440A (fr) | 2020-09-02 |
| PH12020550472A1 (en) | 2021-03-15 |
| AR113790A1 (es) | 2020-06-10 |
| SG11202003641RA (en) | 2020-05-28 |
| CL2020001075A1 (es) | 2021-01-22 |
| CO2020004968A2 (es) | 2020-05-05 |
| DOP2020000072A (es) | 2020-08-31 |
| AU2018354785A1 (en) | 2020-04-23 |
| CU20200041A7 (es) | 2021-03-11 |
| WO2019081353A1 (de) | 2019-05-02 |
| KR20200076686A (ko) | 2020-06-29 |
| PE20201280A1 (es) | 2020-11-24 |
| US20200339567A1 (en) | 2020-10-29 |
| EA202091020A1 (ru) | 2020-07-24 |
| CR20200173A (es) | 2020-06-26 |
| NI202000029A (es) | 2020-10-09 |
| IL273954A (en) | 2020-05-31 |
| CA3084422A1 (en) | 2019-05-02 |
| MX2020004190A (es) | 2020-08-03 |
| JP2021500366A (ja) | 2021-01-07 |
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