TW201531459A - 新穎雜環化合物 - Google Patents

新穎雜環化合物 Download PDF

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Publication number
TW201531459A
TW201531459A TW103138358A TW103138358A TW201531459A TW 201531459 A TW201531459 A TW 201531459A TW 103138358 A TW103138358 A TW 103138358A TW 103138358 A TW103138358 A TW 103138358A TW 201531459 A TW201531459 A TW 201531459A
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Taiwan
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methyl
benzyl
phenyl
oxy
hex
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TW103138358A
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English (en)
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Ranjit C Desai
Brijeshkumar Srivastava
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Cadila Healthcare Ltd
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Publication of TW201531459A publication Critical patent/TW201531459A/zh

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract

本發明係關於通式(I)之新穎GPR 40激動劑、其互變異構型式、其立體異構物、其藥學上可接受之鹽、含彼之藥學組成物、彼等之製備方法、這些化合物於醫藥之用途及涉及彼等之製備的中間體。 □

Description

新穎雜環化合物
本發明係關於通式(I)之新穎GPR 40激動劑、其互變異構型式、其立體異構物、其藥學上可接受之鹽、含彼之藥學組成物、彼等之製備方法、這些化合物於醫藥之用途及涉及彼等之製備的中間體。
本發明係關於G蛋白偶合受體(GPCR)激動劑，其可用於治療肥胖症、糖尿病及相關之代謝失調。
通式(I)化合物可降低血糖、調節周圍飽足感、降低或調節三酸甘油酯濃度及/或膽固醇濃度及/或低密度脂蛋白(LDL)及增加高密度脂蛋白(HDL)血漿濃度，因此可用於對抗當此降低(及增加)為有利時之不同醫學病症。故其可用於治療及/或預防肥胖症、高血脂症、高膽固醇血症、高血壓、動脈粥狀硬化疾病事件、血管再狹窄、糖尿病及許多其他相關病症。
通式(I)化合物可用於預防或降低發展成動脈粥狀硬化而導致疾病及病症諸如動脈粥狀硬化性心血管疾病、中風、冠狀動脈心臟病、腦血管疾病、周邊血管疾病及相關失調的危險性。
這些通式(I)化合物可用於治療及/或預防鬆散地定義為X症候群之代謝性失調。X症候群之特徵包括起始之胰島素抗性，隨後為高胰島素血症、異常血脂症及葡萄糖耐受不良。葡萄糖不耐受性可導致非胰島素依賴性糖尿病(NIDDM，第二型糖尿病)，其特徵為高血糖症，其如果不控制可導致糖尿病併發症或由胰島素抗性所致之代謝性失調。糖尿病不再被視為僅僅與葡萄糖代謝有關，其亦影響解剖學及生理學參數，其強度依糖尿病狀態之階段/持續時間及嚴重度而變化。本發明化合物亦可用於預防、終止或減緩上述失調連同所生成之續發疾病之進展或降低其危險性，該續發疾病諸如為心血管疾病，如動脈硬化、動脈粥狀硬化；糖尿病性視網膜病變、糖尿病性神經病變及腎病包括糖尿病性腎病變、腎小球腎炎、腎小球硬化、腎病症候群、高血壓性腎硬化及末期腎病，如微蛋白蛋尿及白蛋白尿，其可為高血糖症或高胰島素血症之結果。
糖尿病為全世界超過一億人口罹患的嚴重疾病。在美國，有起過一千兩百萬的糖尿病病患，且每年診斷出600,000個新病例。
糖尿病為用於失調群組的診斷術語，其特徵在於葡萄糖穩態異常導致血糖升高。糖尿病有許多型，但最常見的兩型為第I型(亦稱為胰島素依賴性糖尿病或IDDM)及第II型(亦稱為非胰島素依賴性糖尿病或NIDDM)。
不同型糖尿病的病因並不相同；然而，每個糖尿病患有兩件事是共同的：肝臟過度製造葡萄糖且當其變為身體主要燃料時，極少或沒有能力將葡萄糖從血液移至細胞內。
沒有糖尿病的人依賴胰島素(於胰臟中所製的激素)以將葡萄糖由血液移至身體細胞內。然而，有糖尿病的人不能製造胰島素或者不能有效地使用彼等所製造的胰島素；因此，彼等不能將葡萄糖移至彼等之細胞內。葡萄糖累積於血液中產生稱之為高血糖症的病症，且隨著時間可導致嚴重的健康問題。
糖尿病為代謝性、血管性及神經病變性組成互相有關的症候群。代謝性症候群(通常特徵為高血糖症)包含因為不存在或顯著減少的胰島素分泌及/或無效的胰島素作用所致之醣類、脂肪及蛋白質代謝的改變。血管症候群由血管的異常導致心血管、視網膜及腎併發症所組成。周邊及自律神經系統的異常亦為糖尿病症候群的一部分。
約5%至10%的糖尿病患為IDDM。這些個體不會製造胰島素，因此必需注射胰島素以保持彼等血糖濃度之正常。IDDM之特徵為因為製造胰島素之胰臟β細胞的破壞導致內生性胰島素之製造濃度低或者無法偵測到，該特徵 最輕易地將IDDM與NIDDM區分。IDDM(曾稱之為幼發型糖尿病)一樣地衝擊年輕及較年長成年人。
約90至95%的糖尿病患為第II型(或NIDDM)。NIDDM對象可製造胰島素，但其體內的細胞為胰島素抗性：細胞不對激素適當地反應，故葡萄糖累積於其血液中。NIDDM之特徵在於內生性胰島素製造與胰島素需求之間的相對差異，導致血液葡萄糖濃度升高。與IDDM形成對比，NIDDM總能製造一些內生性胰島素；許多NIDDM病患具有正常或者甚至升高的血液胰島素濃度，然而其他NIDDM病患之胰島素製造不足(Rotwein,R.et al.N.Engl.J.Med.308,65-71(1983))。大多數經診斷為NIDDM的人年齡為30歲或30歲以上，且所有新病例中有一半為55歲及55歲以上。與白種人及亞洲人相比，NIDDM更常見於美洲原住民、非裔美國人、拉丁美洲人、及拉丁裔美國人。此外，此發作可為隱伏的或者甚至臨床上不明顯的，造成診斷的困難。
NIDDM之主要致病病灶仍難以理解。許多人認為，周邊組織的主要胰島素抗性為起始事件。遺傳流行病學研究已支持此觀點。同樣地，胰島素分泌異常已被主張為NIDDM的主要缺陷。這兩種現象似乎均為促成疾病過程的主要因素(Rimoin,D.L.,et.al.Emery and Rimoin's Principles and Practice of Medical Genetics 3rd Ed.1：1401-1402(1996))。
許多NIDDM病人有久坐不動的生活方式且肥胖；他 們的體重約20%地超過依其身高和體型所建議之體重。此外，肥胖症之特徵為高胰島素血症及胰島素抗性，此為NIDDM、高血壓及動脈粥狀硬化共享之特性。
G蛋白偶合受體GPR 40之功能為作為體內長鏈游離脂肪酸(FFAs)受體，且因而涉及體內許多代謝狀況。例如，GPR 40激動劑據稱可促進胰島素分泌，而GPR 40拮抗劑可抑制胰島素分泌，故依情況而定，激動劑及拮抗劑可用於作為一些胰島素相關病症諸如第2型糖尿病、肥胖症、胰島素耐受不良、胰島素抗性、神經退化性疾病等等之醫療劑。
越來越多的證據顯示，脂肪亦可作為供特定類別受體用之細胞外配體，故充作“營養感測體”(Nolan CJ et al.J.Clinic.Invest.,2006,116,1802-1812)。游離脂肪酸可調節細胞功能。游離脂肪酸已證實為用於孤兒G蛋白偶合受體(GPCR)之配體且已經提出在生理學葡萄糖穩態中發揮重要的作用。
以GPR40、GPR120、GPR41及GPR43例示越來越多之已顯示可藉游離脂肪酸而活化之孤兒G蛋白偶合受體(GPCR)。GPR40及GPR120藉中至長鏈游離脂肪酸活化，而GPR 41及GPR 43藉短鏈脂肪酸活化(Brown AJ et al,2003)。
GPR 40於胰臟β細胞上高度表現，且增強葡萄糖刺激性胰島素分泌(Nature,2003,422,173-176,J.Bio.Chem.2003,278,11303-11311,Biochem.Biophys.Res.Commun. 2003,301,406-410)。
報告指出游離脂肪酸可從胰臟β細胞經由GPR40而調節胰島素的分泌(Lett.to Nature 2003,422,173-176)。
美國葛蘭素史克研究發展(GlaxoSmithKline Research and Development,US)於Bioorg.Med.Chem.Lett.2006,16,1840-1845中公開標題為Synthesis and activity of small molecule GPR40 agonists.(Does this describe GW9508？)的論文。另一標題為Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40：Identification of agonist and antagonist small molecules的論文由美國葛蘭素史克(GlaxoSmithKline,USA)報告於Br.J.Pharmacol.2006,148,619-928(Doesthis describe GW9508？)中。
GPR 40受體之小分子激動劑的固相合成及SAR乃由美國葛蘭素史克研究發展(Glaxo SmithKline Res.& Dev.USA)公開於Bioorg.Med.Chem.Lett.2007,16,1840-1845中，包括具有下列結構者。
美國強生藥學研究發展(Johnson & Johnson Pharmaceutical Research and development)公開“Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoic acid as a Novel Series of G-protein -coupled receptor 40 agonists(J.Med.Chem.2007,16,2807-2817)。
馬里蘭州貝塞斯達國立衛生研究院(National Institutes of Health,Bethesda,Maryland)公開“Bidirectional Iterative Approach to the Structural Delineation of the Functional Chemo print in GPR 40 for agonist Recognition(J.Med.Chem.2007,50,2981-2990)。
作為新類別GPR40(FFAR1)激動劑之下式二醯基間苯三酚類的發現
已由皮拉馬爾生命科學有限公司(Piramal Life Sciences Ltd)於Bioorg.Med.Chem.Lett.2008,18,6357-6361中公開。
下式之作為新穎G蛋白偶合受體40(GPR40)拮抗劑的1,2,3,4-四氫異喹啉-1-酮之合成及SAR已由Pfizer公開於Bioorg.Med.Chem.Lett.2009,19,2400-2403中。
皮拉馬爾生命科學有限公司(Piramal Life Sciences Ltd)於Exp.Opin.Therapeutic Patents 2009,19(2),237-264中公開“Progress in the discovery and development of small molecule modulators of G-protein coupled receptor 40(GPR40/FFA1/FFAR1),an emerging target for type 2 diabetes”。
有報告由廣州中山大學公開於Zhongguo Bingli Shengli Zazhi 2009,25(7),1376-1380中，其提及GPR 40對脂性凋亡的角色。
一種新類別之游離脂肪酸受體GPR 40拮抗劑公開於Biochem.Biophy.Res.Commun.2009,390,557-563中。
默克研究實驗室(Merck Res.Laboratories)於Bioorg.Med.Chem.Lett.2010,20,1298-1301中公開具有下式之“Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists”。
TAK-875(一種有效、選擇性、及口服生物可利用性GPR 40激動劑)由武田製藥有限公司(Takeda Pharmaceutical Ltd)報告於ACS Med.Chem.Lett.2010,1(6),290-294中。
另一個來自南丹麥大學(University of Southern Denmark)的報告”Structure -Activity of Dihydrocinnamic acids and discovery of potent FFA1(GPR40)agonist TUG-469”乃報告於ACS Med.Chem.Lett.2010,1(7),345-349中。
游離脂肪酸1受體(FFAR1或GPR40)，其於胰臟β細胞上高度表現且擴大葡萄糖刺激性胰島素分泌，已成為具有吸引力之用於治療第2型糖尿病的標的(ACS Med.Chem.Lett.2010,1(6),290-294)。
G蛋白偶合受體(GPR40)之表現及其於人類胰臟小島中之調節：第2型糖尿病及脂肪酸之角色乃報告於Nutrition Metabolism & Cardiovascular diseases 2010,20(1),22-25中。
蘭伯西(Ranbaxy)於Phytother Res.2010,24,1260-63中報告“Identification of Berberine as a novel agonist of fatty acid receptor GPR40”。
下列作為GPR40激動劑之經取3-(4-芳氧基芳基)-丙酸乃由默克研究實驗室(Merck Res.Laboratories)報告於 Bioorg.Med.Chem.Lett.2011,21,3390-3394中。
CoMSIA對經取代芳基烷酸類似物作為GPR 40激動劑的研究乃報告於Chem.Bio.Drug.Des.2011,77,361-372中。
武田(Takeda)於J.Med.Chem.2011,54(5),1365-1378進一步公開“Design,Synthesis and biological activity of potential and orally available G-protein coupled receptor 40 agonists”。
安進(Amgen)於Bioorg.Med.Chem.Lett.2012,22,1267-1270中揭示一種有效之口服生物可利用性GPR 40激動劑AMG-837
作為有效且口服生物可利用性G蛋白偶合受體40激動劑以用於治療第2型糖尿病之含有極性官能基之苯基丙酸衍生物的發現乃報告由武田(Takeda)報告於J.Med. Chem.2012,55,3756-3776中。
AM-1638之發現：一種有效及口服生物可利用性GPR40/FFA1完全激動劑乃報告於ACS Med.Chem.Lett.2012,3(9),726-730中。
(2,3-二氫-1-苯並呋喃-3-基)乙酸之最理想化：非游離酸樣，高度生物可利用性G蛋白偶合受體40/游離酸受體1激動劑作為葡萄糖依賴性促胰島素劑的發現乃由武田(Takeda)報告於J.Med.Chem.2012,55,3960-3974中。
拜耳(Bayer)揭示具有下式之茚滿、二氫苯並呋喃、及四氫萘羧酸衍生物及其作為抗糖尿病劑的用途於專利申請案案號WO 2004011446中：
武田(Takeda)揭示具有下列通式之3-(4-苄氧基苯基)丙酸衍生物於專利WO 2005063729中：
WO 2005086661 A1(2005年9月22日，安進(Amgen)公司)揭示具有下式之用於治療代謝失調之化合物、藥學組成物、及方法： Q-L1-P-L2-M-X-L3-A
Akerman等人之US 2006/0004012揭示用於治療代謝失調之某些化合物、藥學組成物及方法，該化合物為GPR 40激動劑。
WO 06/038738 A1(2006年4月13日，日本武田製藥有限公司)揭示具有下列一般結構之某些受體功能調節劑：
默克藥廠(Merck & Co.)於WO2006083781中揭示抗糖尿病性雙環化合物。其中揭示作為G蛋白偶合受體40(GPR40)激動劑之雙環化合物，包括其藥學上可接受之鹽及前藥，該雙環化合物含有稠合至環烷基或雜環之苯基或吡啶基環，有5節雜環連接，彼等可用於作為醫療用化合物，尤其用於治療第2型糖尿病及通常與包括肥胖症及脂肪失調之疾病有關之病症，諸如混合型或糖尿病性異常血脂症、高血脂症、高膽固醇血症、及高三酸甘油酯血症。
默克藥廠(Merck & Co.)於另一專利申請案WO 2006083612中揭示作為G蛋白偶合受體40(GPR40)激動劑之抗糖尿病性雙環化合物，包括其藥學上可接受之鹽及前藥，其中，該雙環化合物含有稠合吡啶環，彼等可用於作為醫療用化合物，尤其用於治療第2型糖尿病及通常與包括肥胖症及脂肪失調之疾病有關之病症，諸如混合型或 糖尿病性異常血脂症、高血脂症、高膽固醇血症、及高三酸甘油酯血症。該專利申請案中所揭示之化合物具有下列之一般結構：
其中Z選自由以下所組成之群組：CR3R4CO2R5、-OCR3R4CO2R5、N(R6)(CR3R4CO2R5)、-SCR3R4CO2R5、四唑及雜環II。
稠環化合物已由Yasum等人揭示於專利US 7820837中。提述於US 7517910中之下式申請具有GPR 40受體功能調節作用之化合物的專利，該化合物可用於作為用於預防或治療糖尿病等等之胰島素促分泌劑。
新穎之螺哌啶化合物已由禮來公司(Eli Lilly & Company)提述於WO 2011066183中。
禮來公司(Eli Lilly)亦於專利申請案案號US20110092531中揭示螺哌啶。
可用於治療糖尿病之新穎1,2,3,4-四氫喹啉衍生物已由禮來公司(Eli Lilly & Company)述於專利申請案案號WO 2013025424中。
標題為“Preparation of β- substituted carboxylic acid derivatives for the treatment of diabetes”之專利申請案WO 2013147443已由第一三共(Daichi Sankyo)公開。
皮拉馬爾企業有限公司(Piramal Enterprises Limited)已於專利申請案案號WO 2013/128378公開具有下列結構之作為GPR激動劑的苯基烷酸衍生物。
百靈佳英格翰(Boehringer Ingelheim)已公開專利申請案案號WO 2013/144097及WO 2013/144098具有以下定義之結構的標題為“New indanyloxy dihydrobenzofuranyl acetic acid derivatives and their use as GPR receptor agonists”者。
用於治療癌症之新穎醫療標的及相關療法及方法乃由兒童醫學中心公司(Children’s Medical Center Corporation)揭示於專利申請案案號WO 2014145817中。
WO 2014146604揭示具有GPR40受體功能調節作用之某些稠環化合物。
三環化合物及其用途已由SK化學有限公司(SK Chemicals Co.,Ltd.)公開於專利申請案案號WO2014133361中。
某些抗糖尿病性雙環化合物已揭示於專利申請案案號WO2014130608中。
百靈佳英格翰國際公司(Boehringer Ingelheim International)於專利申請案案號WO2013164292、WO2014122067、WO2014086712、及WO2014082918以及US20140148462、US20140221349及US20140163025中揭示某些其他茚滿氧基二氫苯並呋喃基乙酸。
武田製藥有限公司(Takeda Pharmaceutical Company Limited)已於專利申請案案號EP2743268中揭示作為GPR40受體調節劑之稠合環狀化合物。
必治妥施寶貴公司(Bristol-Myers Squibb)已於專利申請案案號WO2014078611、WO2014078610、WO2014078609及WO2014078608中揭示二氫吡唑GPR40調節劑。
LG生命科學有限公司(LG Life Sciences Limited)已於專利WO2014073904中揭示某些GPR40受體激動劑。Hancke Orozco等人已於專利申請案案號US20140128333中揭示用於降低腸部葡萄糖吸收及誘使腸促胰液素釋出之化合物、組成物、及方法。默沙東藥廠(Merck Sharp & Dohme Corp)於專利申請案案號US20140045746、WO2014022528中揭示抗糖尿病性三環化合物且另一申請案於專利US 20140038970中揭示某些橋連及稠合抗糖尿病性化合物。
可調節G蛋白偶合受體GPR40之新穎經氟取代之化合物已揭示於專利申請案案號US20140058125中。
持田製藥公司(Mochida Pharmaceutical Co)已於專利US20140057871中揭示環狀醯胺衍生物。Negoro等人已於專利申請案案號US20120035196中揭示某些羧酸化合物。數個其他專利申請案已揭示各種數目之作為GPR40調節劑的化合物。一些代表性文獻乃提供於下：Chandra Sekhar Gudla等人已於IJCPS,2014,Vol.2(5),852-861中揭示一些新穎3-取代3-(芳氧基芳基)-丙酸。
WO 2005095338、WO 2006038738、WO 2006083612、WO 2006083781、WO 2007013679、WO 2007136572、WO 2007136573、WO 2007049050、WO 20070123225、WO 2008002931、WO 2008054674、WO 2008054675、WO 200830520、WO 2008130514、WO 2008139987、WO 2009058237、WO 2009048527、WO 2009054423、US 7968552、WO 2009038204、WO 2010045258、WO 2010012650、WO 2010085522、WO 2010085525、WO 2010085528、WO 2010091176、WO 2011044073、WO 2011052756、WO 2011078371、WO 2011069958、WO 2011083752、WO 2012111849、WO 2012108478、WO 2012074126、WO 2012020738、WO 2012004261、WO 2012010413、WO 2012010413、WO 2012011125等等。
描準與胰島素依賴性第I型糖尿病及非胰島素依賴性第II型糖尿病有關之病理生理學的藥物具有許多潛在副作用且並不足以解決高比例病患之異常血脂症及高三酸甘油酯血症。治療通常聚焦在需要使用飲食、運動、降三酸甘油酯劑及胰島素之個別病患，尤其是可較佳地耐受較少副作用者。
同樣地，代謝症候群(X症候群，其特徵為高血壓及其相關病理學包括動脈粥狀硬化、血脂症、高血脂症及高膽固醇血症)與胰島素敏感性之降低有關，當受到挑戰時，其可導致異常的血糖濃度。心肌缺血及微血管疾病為已確立之與代謝症候群未治療或控制不良有關之病態。
持續地需要新穎之抗肥胖及抗糖尿病劑，尤其是可充分耐受少許副作用者。
本發明係關於可用於治療糖尿病之GPR40激動劑。人類之GPR 40於胰臟中素現。如上所討論，數種GPR 40激動劑已經發展且持續地發展。然而，這些化合物治療疾 病的醫療潛能未尚被證實，故仍需要發展更新穎的醫藥，其具有比當前之治療方案更佳或可相比之效力，具有較少之副作用且需要更低之劑量方案。
吾人於本案中揭示可作為抗糖尿病、抗肥胖症、降血脂、降脂蛋白血、及降高血糖劑之新穎式(I)化合物，其於治療及/或預防因高血脂症所致的疾病、分類在X症候群下的疾病及動脈粥狀硬化可具有有利效應，亦揭示彼等之製備方法。
本發明之主要目的係提供以通式(I)表示之新穎GPR 40激動劑、其互變異構型式、其立體異構物、其藥學上可接受之鹽、及含彼之藥學組成物或其混合物。
本發明之一實施例係提供用於製備以通式(I)表示之化合物、其互變異構型式、其立體異構物、其藥學上可接受之鹽的方法。
本發明之另一實施例係提供藥學組成物，其含有通式(I)化合物、其互變異構型式、其立體異構物、其藥學上可接受之鹽、或其混合物，與常用於製備此組成物之適當載體、溶劑、稀釋劑及其他介質組合。
本發明之又另一實施例提供藥學組成物，其包含式(I) 化合物及用於治療糖尿病、肥胖症及其他相關失調的第二種適當醫療劑。
因此，本發明關於通式(I)化合物
其互變異構型式、其立體異構物、其藥學上可接受之鹽、及含彼之藥學組成物，其中R1、R2、R3、R4、R5、R6於每次出現時各自獨立地表示H、鹵素、羥基、CN、NO2、CHO、COOH、CO、隨意經取代之選自以下的基團：烷基、烷氧基、巰基、亞碸、碸、醯基、NH2或隨意經取代之NHCO-直鏈或支鏈(C1-C6)烷基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基或OR、C(O)OR、C(O)R及SO2R基，其中‘R’於每次出現時獨立地表示隨意經取代之選自以下之基團：H、直鏈或支鏈(C1-C6)烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基；另外之實施例中，R3及R4可一起形成側氧基；‘A’選自3-7員部分飽和、不飽和或飽和環，其可另具有一個或一個以上之選自O、S、或N的雜原子；‘E’及‘D’可各自獨立地為氮或碳；‘F’可選自C、N或 O；‘G’可存在或不存在且當存在時，表示鍵或選自O、S、NRa，其中‘Ra’表示直鏈或支鏈(C1-C6)烷基；m=1-3；‘n’、‘r’、‘p’及‘s’各自獨立地表示0至6的整數；q=0-4；‘X’可存在或不存在且當存在時，選自CH2、O、S、及NRa、SO2NH；其中Ra為如稍早所定義者；‘T’選自氧、-NH、S、SO、SO2或NRa，其中Ra為如稍早所定義者；R7及R8可各自獨立地為選出之(C2-C4)炔、腈、或環烷基；另外，R7及R8可與彼所連接之碳原子組合形成3-7員環，該環可隨意地另具有一個或一個以上之選自S、N、或O的雜原子；R9及R10可選自氫、烷基、烷氧基、及鹵素基。
本發明之較佳實施例係關於通式(I’)化合物
其互變異構型式、其立體異構物、其藥學上可接受之鹽、及含彼之藥學組成物，其中R1、R2、R3及R4於每次出現時各自獨立地表示H、鹵素、羥基、CN、NO2、CHO、COOH、CO、隨意經取代之選自以下的基團：烷基、烷氧基、巰基、亞碸、碸、醯基、NH2或隨意經取代之NHCO-直鏈或支鏈(C1-C6)烷基、芳烷基、環烷基、環 烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基或OR、C(O)OR、C(O)R及SO2R基，其中‘R’於每次出現時獨立地表示隨意經取代之選自以下之基團：H、直鏈或支鏈(C1-C6)烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基；另外之實施例中，R3及R4可一起形成側氧基；‘A’選自3-7員部分飽和、不飽和或飽和環，其另具有一個或一個以上之選自O、S、或N的雜原子；‘E’及‘D’可各自獨立地為氮或碳；‘F’可選自C、N或O；‘n’、‘r’及‘s’各自獨立地表示0至6的整數；R5及R6可各自獨立為選出之(C2-C4)炔、腈、或環烷基；另外R5及R6可與彼所形成之碳原子組合形成3-7員環，該環可隨意地另具有一個或一個以上之選自S、N、或O的雜原子。
代表下式
之較佳雜環可選自下列之雙環
取代基-COOH在任何可能處可隨意地經生物電子等排替代物諸如：
等等所替代；當R1至R10之任一基團係經一或許多基團取代時，該等取代基可獨立地選自包含以下之基團：羥基、側氧基、鹵基、硫基、硝基、胺基、氰基、甲醯基、或經取代 或未經取代之選自以下之基團：脒基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、環烯基、雙環烷基、雙環烯基、烷氧基、烯氧基、環烷氧基、芳基、芳氧基、芳烷基、芳烷氧基、雜環基、雜芳基、雜環基烷基、雜芳烷基、雜芳氧基、雜芳烷氧基、雜環基氧基、雜環基烷氧基、雜環基烷氧基醯基、醯基、醯氧基、醯胺基、單取代或二取代之胺基、芳胺基、芳烷胺基、羧酸及其衍生物諸如酯類及醯胺類、羰胺基、羥烷基、胺烷基、烷氧基烷基、芳氧基烷基、芳烷氧基烷基、烷硫基、硫烷基、芳硫基、烷磺醯胺基、烷磺醯氧基、烷氧羰胺基、芳氧羰胺基、芳烷氧羰胺基、胺羰基胺基、烷胺羰基胺基、烷氧基胺基、羥基胺基、次磺醯基衍生物、磺醯基衍生物、磺酸及其衍生物。
芳基可為含有一、二或三個環之芳族系統，其中此些環可以依賴方式連接一起或者可稠合；較佳實施例中，此芳基可選自苯基、萘基、四氫萘基、茚滿、聯苯基；雜芳基表示5至8員芳族基團，其可為含有一或多個選自O、N或S之雜原子的單一或稠合環；較佳實施例中，此基團可選自吡啶基、噻吩基、呋喃基、吡咯基、唑基、噻唑基、異噻唑基、咪唑基、異唑基、二唑基、噻二唑基、三唑基、四唑基、苯並吡喃基、苯並吡喃酮基、苯並呋喃基、苯並噻吩基、吲哚啉基、吲哚基、氮雜吲哚基、氮雜吲哚啉基、苯並二氫呋喃基、苯並二氫噻吩基、吡唑並嘧啶基、吡唑並嘧啶酮基、氮雜喹唑啉基、 氮雜喹唑啉基羰基、吡啶並呋喃基、吡啶並噻吩基、噻吩並嘧啶基、噻吩並嘧啶酮基、喹啉基、嘧啶基、吡唑基、喹唑啉基、喹唑啉酮基、嘧啶酮基、嗒基、三基、苯並基、苯並酮基、苯並噻基、苯並噻酮基、苯並唑基、苯並噻唑基、苯並咪唑基、苯並三唑基、呔基、啶基、嘌呤基、咔唑基、啡噻基、啡基；術語"雜環基"表示飽和、部分飽和或不飽和之環形基團，雜原子選自氮、硫或氧；較佳實施例中，此基團可選自氮雜環丙烷基、氮雜環丁烷基、吡咯啶基、咪唑啶基、哌啶基、哌基、2-側氧基哌啶基、4-側氧基哌啶基、2-側氧基哌基、3-側氧基哌基、嗎啉基、硫代嗎啉基、2-側氧基嗎啉基、氮雜環庚三烯基、二氮雜環庚三烯基、氧雜環庚三烯基、硫氮雜環庚三烯基、唑啶基、噻唑啶基等等；部分飽和雜環基之實例包括二氫噻吩、二氫吡喃、二氫呋喃、二氫噻唑基。
-“烷基”係單獨地或與其他基團組合使用，意指含有一至六個碳之直鏈或支鏈基團，選自甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、戊基、三級戊基、正戊基、正己基等等；
-“烯基”係單獨地或與其他基團組合使用，選自含有二至六個碳原子之基團，更佳地為選自以下之基團：乙烯基、烯丙基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基等等；”烯基”包括直鏈及支鏈之二烯及三烯；
-“炔基”係單獨地或與其他基團組合使用，選自含有二至六個碳原子之直鏈或支鏈基團，更佳地為噻吩基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基等等。術語”炔基”包括二及三炔；
-“環烷基”、或“脂環基”係單獨地或與其他基團組合使用，選自含有三至六個碳原子之環狀基團，更佳地為環丙基、環丁基、環戊基、環己基等等；術語”雙環烷基”意指一個以上之環烷基稠合一起；
-“環烯基”係單獨地或與其他基團組合使用，較佳地選自環丙烯基、1-環丁烯基、2-環丁烯基、1-環戊烯基、2-環戊烯基、3-環戊烯基、1-環己烯基、2-環己烯基、3-環己烯基等等；
-“烷氧基”係單獨地或與其他基團組合使用，選自含有如上所定義之烷基且該烷基直接連接至氧原子的基團，更佳地為選自以下之基團：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、三級丁氧基、異丁氧基、戊氧基、己氧基等等；
-“環烷氧基”係單獨地或與其他基團組合使用，選自含有如上所定義之環烷基且該環烷基直接連接至氧原子的基團，更佳地為選自以下之基團：環丙氧基、環丁氧基、環戊氧基、環己氧基、環庚氧基等等；
-“芳氧基”係單獨地或與其他基團組合使用，選自含有如上所定義之芳基且該芳基直接連接至氧原子的基團， 更佳地為選自以下之基團：苯氧基、萘氧基、四氫萘氧基、聯苯氧基等等；
-“芳烷基”係單獨地或與其他基團組合使用，選自含有如上所定義之芳基且該芳基直接連接至如上所定義之烷基的基團，更佳地為選自以下之基團：苄基、苯乙基等等；
-“芳烷氧基”係單獨地或與其他基團組合使用，選自含有如上所定義之芳烷基且該芳烷基直接連接至氧原子的基團，更佳地為選自以下之基團：苄氧基、苯乙氧基等等；
-“雜芳烷基”係單獨地或與其他基團組合使用，選自含有如上所定義之雜芳基且該雜芳基直接連接至如上所定義之烷基的基團，更佳地為選自以下之基團：吡啶烷基、噻吩烷基、喹啉烷基等等；
-“烯氧基”係單獨地或與其他基團組合使用，選自含有如上所定義之烯基且該烯基連接至氧原子的基團，更佳地選自乙烯氧基、烯丙氧基、丁烯氧基、戊烯氧基、己烯氧基等等；
-“鹵烷基”選自如上所定義之烷基，且經一或多個鹵素適當地取代；諸如全鹵烷基，更佳地為全氟(C1-C6)烷基，諸如氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基、單或多鹵取代之甲基、乙基、丙基、丁基、戊基或己基；
-“鹵烷氧基”選自如上所定義之適當鹵烷基，該鹵烷 基直接連接至氧原子，更佳地為選自以下之基團：氟甲氧基、氯甲氧基、氟乙氧基、氯乙氧基等等；
-“全鹵烷氧基”選自如上所定義之適當全鹵烷基，該全鹵烷基直接連接至氧原子，更佳地為選自以下之基團：三氟甲氧基、三氟乙氧基等等；
-“雜芳氧基”、“雜芳烷氧基”、“雜環基氧基”、“雜環基烷氧基”分別選自如上所定義之適當雜芳基、雜芳基烷基、雜環基、雜環基烷基，且連接至氧原子；
-“醯基”係單獨地或與其他基團組合使用，選自含有一至八個碳原子之基團，更佳地選自甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、己醯基、庚醯基、苯甲醯基等等，彼等可經取代；
-“醯氧基”係單獨地或與其他基團組合使用，選自如上所定義之適當醯基，該醯基直接連接至氧原子，更佳地此基團選自乙醯氧基、丙醯氧基、丁醯氧基、異丁醯氧基、苯甲醯氧基等等；
-“醯胺基”係單獨地或與其他基團組合使用，選自如上所定義之適當醯基，該醯基連接至胺基，更佳地此基團選自CH3CONH、C2H5CONH、C3H7CONH、C4H9CONH、C6H5CONH等等，彼等可經取代；
-“單取代之胺基”係單獨地或與其他基團組合使用，表示經一個選自如稍早所定義之(C1-C6)烷基、經取代烷基、芳基、經取代芳基或芳烷基取代之胺基，更佳地此基團選自甲胺、乙胺、正丙胺、正丁胺、正戊胺等等；
-“二取代之胺基”係單獨地或與其他基團組合使用，表示經兩個可相同或不同之選自如稍早所定義之(C1-C6)烷基、經取代烷基、芳基、經取代芳基、或芳烷基取代之胺基，更佳地此基團選自二甲胺基、甲基乙胺基、二乙胺基、苯基甲胺基等等；
-“芳胺基”係單獨地或與其他基團組合使用，表示如上所定義之芳基，經由具有自由價鍵之胺基從氮原子鍵結，更佳地此基團選自苯胺基、萘胺基、N-甲基苯胺基等等；
-“側氧基”或”羰基”係單獨地(-C=O-)或與其他基團諸如上述烷基組合使用，例如”烷羰基”意指經上述烷基取代之羰基(-C=O-)，諸如醯基或烷醯基；
-“羧酸”基係單獨地或與其他基團組合使用，意指-COOH基，且包括羧酸之衍生物諸如酯類及醯胺類；
-“酯”基係單獨地或與其他基團組合使用，意指-COO基，且包括羧酸衍生物，更佳地該酯部分選自烷氧羰基，諸如甲氧羰基、乙氧羰基等等，其可隨意地經取代；芳氧羰基諸如苯氧羰基、萘氧羰基等等，其可隨意地經取代；芳烷氧羰基諸如苄氧羰基、苯乙氧羰基、萘基甲氧羰基等等，其可隨意地經取代；雜芳氧羰基、雜芳烷氧羰基，其中雜芳基為如上所定義者，其可隨意地經取代；雜環氧羰基，其中雜環基為如上所定義者，其可隨意地經取代；
-“醯胺”基係單獨地或與其他基團組合使用，表示胺羰基(H2N-C=O)，其中胺基為單或二取代或未經取代，更 佳地此基團選自甲基醯胺、二甲基醯胺、乙基醯胺等等；
-“胺羰基”係單獨地或與其他基團組合使用，可選自‘胺羰基’、‘胺羰基烷基”、“n-烷胺羰基”、“N-芳胺羰基”、“N,N-二烷胺羰基”、“N-烷基-N-芳胺羰基”、“N-烷基-N-羥基胺羰基”、及“N-烷基-N-羥基胺羰基烷基”，彼等各自隨意地經取代。術語“N-烷胺羰基”及“N,N-二烷胺羰基”意指如上所定義之胺羰基，其已分別地經一個烷基及經兩個烷基取代。較佳地為“低級烷胺羰基”，其具有如上所述之低級烷基且該低級烷基連接至胺羰基。術語“N-芳胺羰基”及“N-烷基-N-芳胺羰基”意指分別地經一個芳基、或一個烷基及一個芳基取代之胺羰基。術語”胺羰基烷基”包括經胺羰基取代之烷基；
-“羥烷基”係單獨地或與其他基團組合使用，選自如上所定義之烷基，且經一或多個羥基取代，更佳地此基團選自羥甲基、羥乙基、羥丙基、羥丁基、羥戊基、羥己基等等；
-“胺烷基”係單獨地或與其他基團組合使用，意指如上所定義之連接至烷基的胺基(-NH2)部分，其可經取代，諸如單及二取代之胺烷基。本案所用之術語“烷胺基”，單獨地或與其他基團組合使用，意指如上所定義之烷基，該烷基連接至胺基，其可經取代，諸如單及二取代之烷胺基；
-“烷氧基烷基”係單獨地或與其他基團組合使用，意指如上所定義之烷氧基，該烷氧基連接至如上所定義之烷 基，更佳地此基團可選自甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基等等；
-“烷硫基”係單獨地或與其他基團組合使用，意指包含如上所定義之烷基的直鏈或支鏈或環狀單價取代基，經由具有自由價鍵之二價硫原子從硫原子鍵結，更佳地此基團可選自甲硫基、乙硫基、丙硫基、丁硫基、戊硫基等等或選自環丙硫基、環丁硫基、環戊硫基、環己硫基等等之環狀烷硫基，其可隨意地經取代；
-“硫烷基”係單獨地或與其他基團組合使用，意指如上所定義之烷基，該烷基連接至式-SR’基，其中R’表示氫、烷基或芳基，例如硫甲基、甲硫基甲基、苯硫基甲基等等，其可隨意地經取代。
-“烷氧羰胺基”係單獨地或與其他基團組合使用，選自如上所定義之適當烷氧羰基，該烷氧羰基連接至胺基，更佳地為甲氧羰胺基、乙氧羰胺基等等；
-“胺羰基胺基、“烷胺羰基胺基”、“二烷胺羰基胺基”係單獨地或與其他基團組合使用，為羰基胺基(-CONH2)，該羰基胺基分別地連接至胺基(NH2)、烷胺基或二烷胺基，其中烷基為如上所定義者；
-“脒基”係單獨地或與其他基團組合使用，表示-C(=NH)-NH2基；“烷脒基”表示如上所述之烷基，該烷基連接至脒基；
-“烷氧基胺基”係單獨地或與其他基團組合使用，表示如上所定義之適當烷氧基，該烷氧基連接至胺基；
-“羥胺基”係單獨地或與其他基團組合使用，表示-NHOH部分，且可隨意地經選自上述之基團取代；
-“次磺醯基”或“次磺醯基衍生物”係單獨地或與其他基團組合使用，表示二價基，-SO-或RxSO，其中Rx為隨意經取代之選自上述之烷基、芳基、雜芳基、雜環基；
-“磺醯基”或“磺醯基衍生物”係單獨地或與其他基團組合以其他術語諸如烷磺醯基使用，表示二價基-SO2-、或RxSO2-，其中Rx為如上所定義者。更佳地，此基團可選自”烷磺醯基”，其中適當烷基(選自如上所定義者)係連接至磺醯基，諸如甲基磺醯基、乙基磺醯基、丙基磺醯基等等，“芳磺醯基”，其中芳基(如上所定義)係連接至磺醯基，諸如苯磺醯基等等。
-“磺醯氧基”係單獨地或與其他基團組合以其他術語諸如烷磺醯氧基使用，表示二價基-SO3-、或RxSO3-，其中Rx為如上所定義者。更佳地，此基團可選自”烷磺醯基”，其中適當烷基(選自如上所定義者)係連接至磺醯氧基，諸如甲磺醯氧基、乙磺醯氧基、丙磺醯氧基等等，“芳磺醯基”，其中芳基(如上所定義)係連接至磺醯基，諸如苯磺醯氧基等等。
適當基團及基團上的取代基可選自專利說明書之任一處所述者。
特別有用之化合物可選自：(S)-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸(1)； 3-(4-((3-((4H-呋喃並[3,4-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)-3-氰基丙酸鋰；3-氰基-3-(4-((3-((4-側氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸；3-氰基-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)丙酸鋰；3-氰基-3-(4-((3-((2,2-二氧化-1H-噻吩並[3,4-c]吡咯-5(3H,4H,6H)-基)甲基)苄基)氧基)苯基)丙酸；3-氰基-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((1-(三級丁氧羰基)-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(異吲哚啉-2-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((3,4-二氫喹啉-1(2H)-基)甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-(二氟甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((1-甲基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-(6-氧雜-3-氮雜雙環[3.1.1]庚烷-3-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吲哚啉-1-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((5-苄基六氫吡咯並[3,4-c]吡咯-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-((4H-噻吩並[2,3-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；甲酸6-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-6,7-二氫-5H-吡咯並[3,4-d]嘧啶-6-鎓；甲酸1-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-7-甲氧基-1,2,3,4-四氫喹啉-1-鎓；(S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-溴-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(羥甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-5-(3-((4-(1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-4,5,6,7-四氫噻吩並[3,2-c]吡啶-2-羧酸；3-環丙基-3-(3-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸；(S)-3-(4-((3-((1-甲基-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((2-胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氯-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-胺基甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-異丙基吡咯並[3,4-c]吡唑-5(2H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(甲氧羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氰基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；S)-3-(4-((3-((2-甲基-6,7-二氫吡唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(二甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((2-甲基-5-(4-(甲基磺醯基)苯基)吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(甲基磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((2-甲氧基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((2-苯基吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吡咯啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-(哌啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-((1-異丙基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(R)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(R)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((6,7-二氫-[1,2,3]三唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-(環丙基胺基甲醯基)-6,7-二氫噻吩並 [3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(吡咯啶-1-羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-硝基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(二甲胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((2-胺基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((7,8-二氫-1,6-啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-環丙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((2-乙基-6,7-二氫噻吩並[3,2-c]吡啶- 5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-乙醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-((甲胺基)甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；下列化合物可遵循類似於實例1所述之步驟再加上熟知技藝者詳知且被視為包含在本發明範圍內之適當修飾而合成。
3-(4-((3-((4H-呋喃並[3,4-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)-3-氰基丙酸
3-氰基-3-(4-((3-((4-側氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸
3-氰基-3-(4-((3-((2,2-二氧化-1H-噻吩並[3,4-c]吡咯-5(3H,4H,6H)-基)甲基)苄基)氧基)苯基)丙酸
3-氰基-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸
(S)-3-(4-((3-((2-甲氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-乙醯氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-(甲基磺醯基)-5H-吡咯並[3,4-d]嘧啶-6(7H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((6,7-二氫呋喃並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-(2,2,2-三氟乙基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-異丙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-(二甲胺基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-(三級丁基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-側氧基-1,2,6,7-四氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(S)-3-(4-((3-((2-氰基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(3S)-3-(4-((3-((4-苯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
(3S)-3-(4-((3-((4-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
本發明之新穎化合物可使用下節文章中所述之反應及技術連同(只要時機適合)熟知技藝者已知之其他適當方法製得。反應係於適於所用試劑及材料之溶劑中進行且適用於待達成之變換。熟知技藝者理解，所呈現之合成步驟的特性及順序可加以變化以達到使本發明化合物之形成最理想化的目的，又某些步驟可予修飾、改變、添加或刪除明顯的步驟以求最理想化以及為製備本發明化合物之所需。此明顯之變化亦應視為本發明之一部分。
反應圖1：通式(I)化合物可根據下述反應圖製得
式(I)化合物可根據反應圖1所描述之反應製得。
第一步驟包含將經取代羧酸(中間體1a)與適當經取代雜環(中間體2a)於肽鍵形成條件下反應以得中間體3a。中間體3a之酯可使用適當還原劑諸如二異丁基氫化鋁、氫化鋰鋁或氫硼化鈉等等還原以得中間體4a。中間體4a可進一步與式II化合物於光延(Mitsunobu)條件下反應以得中間體5a。光延(Mitsunobu)條件包含將醇中間體4a與親核劑諸如酚(式II)，使用適當膦諸如三丁膦、三苯膦、或三乙膦及偶氮二羰基諸如ADDP或偶氮二羧酸酯(DEAD)反應。
另外，中間體4a可使用適當反應物及條件組套諸如甲磺醯氯及三乙胺而轉化成具有適當離基之化合物諸如甲 磺酸酯衍生物(中間體6a)。
中間體6a可與式II化合物使用二異丙基乙胺或碳酸銫反應以得中間體5a。
中間體5a可使用鹼諸如氫氧化鋰、氫氧化鈉或氫氧化鉀而水解得式(I)之羧酸衍生物。
隨意步驟中，式(I)化合物之藥學上可接受之鹽可藉將適當式(I)化合物與藥學上可接受之鹼或與酸於適當溶劑中、於標準條件下反應而形成。隨意地，此鹽之形成可於酯中間體之水解後同時發生。
此鹽類之形成已於技藝中詳知及了解。
本發明化合物可單獨地或與一或多種選自以下之醫療劑組合使用：胰島素、胰島素衍生物及模擬劑、胰島素分泌促進劑、胰島素增敏劑、雙胍劑、α-葡萄糖苷酶抑制劑、促胰島素磺醯脲受體配體、美格替耐(meglitinides)、GLP-1、GLP-1類似物、DPP-IV抑制劑、GPR-119活化劑、鈉依賴性葡萄糖共同輸送體(SGLT2)抑制劑、PPAR調節劑、非-格列酮(non-glitazone)型PPARδ激動劑、HMG-CoA還原酶抑制劑、降膽固醇藥、凝乳酶抑制劑、抗血栓及抗血小板劑及其他抗肥胖劑或其藥學上可接受之鹽。此使用將依待治療病患之病症而定且充分在熟練操作者之範圍內。
遵循上述之一般方法，包括熟知技藝者範圍內之適當修飾及添加，下列之式(1)化合物係製備如下：實例中提供之1H NMR光譜數據(見下文)係使用400 MHz光譜儀(Bruker AVANCE-400)記錄且以δ標尺發報告。直到另有指定，否則用於NMR之溶劑為CDCl 3 。
實例1 (S)-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)基)甲基)苄基)氧基)苯基)己-4-炔酸(1)
步驟： i.3-(4,5,6,7-四氫噻吩並[3,2-c]吡啶-5-羰基)苯甲酸甲酯(中間體3)
將亞硫醯氯(16.21毫升，222毫莫耳)分成小份地於25℃加至3-(甲氧羰基)苯甲酸中間體1(10克，55.5毫莫耳)中，其後將一滴二甲基甲醯胺加入。將反應混合物於 迴流下攪拌3小時。將過量之亞硫醯氯於減壓下、於100℃蒸發。將4,5,6,7-四氫噻吩並[3,2-c]吡啶氫氯酸鹽中間體2(12.19克，69.4毫莫耳)溶於100毫升水中，將氫氧化鈉(4.44克，111毫莫耳)之25毫升水溶液加入。將4,5,6,7-四氫噻吩並[3,2-c]吡啶之游離鹼於二氯甲烷(75毫升)中萃取，於無水碳酸鉀上乾燥。將醯基氯溶於無水二氯甲烷(75毫升)中，再冷卻至0℃。
將三乙胺(15.47毫升，111毫莫耳)逐滴加至反應混合物中，其後將4,5,6,7-四氫噻吩並[3,2-c]吡啶之二氯甲烷(75毫升)溶液於0℃逐滴加入。將反應混合物加溫至25℃，再攪拌3小時。反應之進展藉TLC監測。將反應混合物倒至冰水(125毫升)中，以10%氫氯酸調整至pH約4，再以二氯甲烷(3×100毫升)萃取。將結合之有機部分以5%氫氧化鈉(100毫升)其後鹽水(100毫升)清洗，於無水硫酸鈉上乾燥，再於旋轉蒸發器上、於減壓下蒸發，以得粗製醯胺中間體3。
將粗製產物藉急驟柱式層析，使用230-400篩目矽膠作為靜置相及10-50%乙酸乙酯-己烷作為流動相予以純化，即得純3-(4,5,6,7-四氫噻吩並[3,2-c]吡啶-5-羰基)苯甲酸甲酯(12克，39.8毫莫耳，71.7%產率)。
ii.(3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基l)苯基)甲醇(中間體4)
將氫化鋰鋁(LiAlH4，3.02克，80毫莫耳)分成小份地 於25℃加至3-(4,5,6,7-四氫噻吩並[3,2-c]吡啶-5-羰基)苯甲酸甲酯中間體3(12克，39.8毫莫耳)之無水四氫呋喃(100毫升)溶液中。將反應混合物於迴流下攪拌3小時。反應之進展藉TLC藉使用流動相30%乙酸乙酯之己烷液監測。將水性硫酸鈉懸浮液逐滴加至反應混合物中以使過量之氫化鋰鋁(LiAlH4)反應中止。將乙酸乙酯(150毫升)加至反應混合物中，再迴流30分鐘，再傾析乙酸乙酯，此過程乃重覆三次以確保硫酸鋰及氫氧化鋁之白色塊中無產物。將結合之有機部分於無水硫酸鈉上乾燥，再於旋轉蒸發器上、於減壓下蒸發以得淺黃色黏塊狀之粗製產物中間體4。
將粗製醇中間體4藉急驟柱式層析，使用230-400篩目矽膠作為靜置相及10-50%乙酸乙酯-己烷作為流動相予以純化，即得純(3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苯基)甲醇中間體4(5.41克，20.86毫莫耳，52.4%產率)。
iii.(S)-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸(1)
將三乙胺(0.258毫升，1.851毫莫耳)其後將甲磺醯氯(141毫克，1.234毫莫耳)於0℃加至(3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苯基)甲醇中間體4(0.16克，0.617毫莫耳)之5毫升無水四氫呋喃溶液中。將反應混合物於25℃攪拌1小時。反應之進展藉TLC監測。將反應混合物倒至冰水(25毫升)中，再以二氯甲烷(3×25毫升) 萃取。將結合之有機部分於無水硫酸鈉上乾燥，再於旋轉蒸發器上、於減壓下蒸發以得淺黃色黏塊狀之甲磺酸3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄酯中間體(5)。
將碳酸銫(603毫克，1.851毫莫耳)其後將甲磺酸3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄酯5之2毫升乙腈溶液於25℃加至3-(4-羥苯基)己-4-炔酸(S)-甲酯中間體6(162毫克，0.740毫莫耳)之乙腈(5.00毫升)溶液中。將反應混合物於75℃攪拌3小時。反應之進展藉TLC監測。反應完全後，將揮發物於減壓下蒸發出。將反應混合物倒至冰水(25毫升)中，再將產物以二氯甲烷(3×25毫升)萃取。將結合之有機部分於無水硫酸鈉上乾燥，再於旋轉蒸發器上、於減壓下蒸發以得淺黃色黏塊狀之粗製產物。將醚性氫氯酸鹽溶液加至粗製產物中，將醚蒸發出，再將殘留物以乙酸乙酯研磨以得65毫克3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸(S)-甲酯氫氯酸鹽中間體(7)。將醚氫氯酸鹽中間體7(60毫克，0.121毫莫耳)使用四氫呋喃(2毫升)與甲醇(1毫升)之混合液水解，將氫氧化鈉(24.19毫克，0.605毫莫耳)之水(1毫升)液於25℃加入。將反應混合物於25℃攪拌12小時。反應之進展藉TLC監測。反應完全後，將揮發物蒸發出，將殘留物以冰水(5毫升)處理，調整pH至約4(1N氫氯酸)，以二氯甲烷(3×25毫升)萃取，再於無水硫酸鈉上乾燥。將溶劑於旋轉蒸發器上、於 減壓下蒸發以得粗製產物。將粗製酸藉製備TLC予以純化，即得(S)-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸1(42毫克，0.094毫莫耳，78%產率)
1H NMR(DMSO-d 6,400MHz)δ：7.42(s,1H),7.37-7.34(m,6H),6.94(d,J=8.4Hz,2H),6.75(d,J=5.2Hz,1H),5.07(s,2H),3.94(m,1H),3.68(s,2H),3.43(s,2H),2.78-2.72(m,4H),2.57-2.55(m,2H),1.77(d,J=1.6Hz,3H)；ESIMS：446.2(M+H)+。
下列化合物可藉遵循一般反應圖1及上述實例1中所述之方法，包括充分在熟知技藝者範圍內之適當修飾而製得。
實例2 3-(4-((3-((4H-呋喃並[3,4-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)-3-氰基丙酸鋰
1H NMR(DMSO-d 6 ,400MHz)δ：7.44(s,1H),7.35-7.28(m,7H),6.98(d,J=8.8Hz,2H),6.09(s,2H),4.27(dd,J=6.4,8.4Hz,1H),3.86(s,2H),3.57(s,4H),2.53-2.41(m,1H),2.33-2.32(m,1H)
實例3 3-氰基-3-(4-((3-((4-側氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸
1H NMR：(CDCl3,400MHz)：-7.47(d,J=5.2Hz,1H),7.37-7.23(m,6H),7.11(d,J=5.2Hz,1H),6.92(d,J=8.8Hz,2H),5.06(s,2H),4.77-4.68(m,2H),4.19(t,J=7.6Hz,1H),3.55(t,J=6.8Hz,2H),3.06-2.98(m,3H),2.88-2.82(m,1H)
實例4 3-氰基-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)丙酸鋰
1H NMR(CD3OD,400MHz)δ：7.48(s,1H),7.39-7.36(m,3H),7.31(dd,=2,6.8Hz,2H),6.98(dd,J=2.4,6.8Hz,2H),5.10(s,2H),4.30-4.26(m,1H),4.18(t,J=5.2Hz,2H),3.89(s,2H),3.83(s,2H),2.97(t,J=5.6Hz,2H),2.74(dd,J=8.8,15.6Hz,1H),2.58(dd,J=8.8,15.6Hz,1H).
實例5 3-氰基-3-(4-((3-((2,2-二氧化-1H-噻吩並[3,4-c]吡咯-5(3H,4H,6H)-基)甲基)苄基)氧基)苯基)丙酸
1H NMR(CD3OD,400MHz)δ：7.66(d,1H),7.60-7.51(m,3H),7.35(dd,J=2,6.8Hz,2H),7.03(dd,J=2,6.4Hz,2H),5.17(s,2H),4.60(s,2H),4.35-4.31(m,1H),4.28(s,4H),3..94(s,4H),2.99(dd,J=8.4,16.8Hz,1H),2.85(dd,J=6.4,16.4Hz,1H).
實例6 3-氰基-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸
1H NMR(CDCl3,400MHz)δ：7.58(s,1H),7.37-7.32(m,2H),7.22-7.16(m,4H),6.88(dd,J=2,6.8Hz,2H),6.71(d,J=5.2Hz,1H),5.00(s,2H),4.18-4.14(m,1H),3.99(s,2H),3.88(s,2H),3.19-3.16(m,2H),3.03-3.00(m,2H),2.87-2.81(m,1H),2.70-2.64(m,1H).
實例7 (S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.38-7.25(m,6H),6.88(d,J=5.2Hz,2H),6.33(s,1H),5.04-4.98(m,2H),4.05-4.00(m,1H),3.80-3.71(m,2H),3.64-3.55(m,2H),2.92-2.61(m,6H),2.39(s,3H),1.82(d,J=2.4Hz,3H).
實例8 (S)-3-(4-((3-((1-(三級丁氧羰基)-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.47-7.38(m,4H),7.27(d,J=8.8Hz,2H),7.18(d,J=3.2Hz,1H),6.86(d,J=8.8Hz,2H),5.94(d,J=3.2Hz,2H),5.05(s,2H),4.08(s,2H),4.05-4.01(m,1H),3.85(s(br),2H),3.30-3.15(m,4H),2.78(dd,J=8.8,15.2Hz,1H),2.65(dd,J=8,15.2Hz,1H),1.80(d,J=2.4Hz,3H),1.59(s,9H).
實例9 (S)-3-(4-((3-((6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.51(s,1H),7.42-7.33(m,4H),7.25(d,J=8.9Hz,2H),6.81(d,J=9Hz,2H),6.63(t,J=2.4Hz,1H),5.89(t,J=2.4Hz,1H),5.06(s,2H),4.07-3.99(m,3H),3.87(s,2H),3.08(s(br),2H),2.80-2.74(m,3H),2.61(m,1H),1.80(d,J=2.4Hz,3H)
實例10 (S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.41-7.38(m,4H),7.27(d,J=8.4Hz,2H),6.85(d,J=8.4Hz,2H),5.19-5.08(m,2H),4.04-3.91(m,1H),3.75(s(br),4H),2.87-2.69(m,4H),2.66(s,3H),2.58-2.41(m,2H),1.80(d,J=2.4Hz,3H)
實例11 (S)-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.40-7.26(m,6H),6.86(d,J=8.8Hz,2H),5.12(dd,J=12.8,18.4Hz,2H),4.15-4.12(m,2H),4.04-3.99(m,1H),3.86-3.69(m,4H),3.00-2.85(m,2H),2.82(dd,J=6.8,15.2Hz,1H),2.65(dd,J=6.8,15.2Hz,1H),1.82(J=2Hz,3H).
實例12 (S)-3-(4-((3-(異吲哚啉-2-基甲基)苄基)氧基)苯基)己-4-炔酸三氟乙酸
1H NMR(CDCl3,400MHz)δ：7.52-7.44(m,2H),7.42-7.34(m,4H),7.31-7.26(m,4H),6.85(d,J=8.4Hz,2H),5.09(s,2H),4.70(s,2H),4.34-4.29(m,2H),4.04-4.00(m,1H),3.32(s,2H),2.85-2.78(m,1H),2.70-2.63(m,1H),1.80(d,J=2.4Hz,3H).
實例13 (S)-3-(4-((3-((3,4-二氫喹啉-1(2H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.32-7.22(m,6H),6.99-6.90(m,4H),6.60-6.57(m,1H),6.50(d,J=8.4Hz,2H),5.02(s,2H),4.49(s,2H),4.06(s(br),1H),3.36(s(br),2H),3.02-2.78(m,4H),2.02-2.00(m,2H),1.80(s,3H).
實例14 (S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.42-7.36(m,3H),7.32-7.25(m,3H),6.90(d,J=8.4Hz,2H),6.66(s,1H),5.05(s,2H),4.06-4.02(m,1H),3.94-3.92(m,2H),3.68(s(br),2H),3.01(s(br),2H),2.88-2.85(m,2H),2.80-2.74(m,1H),2.69-2.63(m,1H),1.83(d,J=2.4Hz,3H).
實例15 (S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.47(s,1H),7.42-7.27(m,5H),7.22-7.15(m,3H),7.05-7.02(m,1H),6.93(d,J=8.8Hz,2H),5.10-5.03(m,2H),4.10-4.06(m,1H),2.02-2.00(m,2H),1.80(s,3H).,3.87-3.80(m,4H),2.96-2.86(m,4H),2.86-2.80(m,1H),2.78-2.74(m,1H),1.86(d,J=2.4Hz,3H).
實例16 (S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣(S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(DMSO-d 6 ,400MHz)δ：7.40(s,1H),7.35-7.23(m,5H),6.88(d,J=8.4Hz,2H),6.41(s,1H),5.04 (s,2H),4.00(s(br),1H),3.64(s,2H),3.32(s,2H),2.68(s,4H),2.40-2.37(m,1H),2.33(s,3H),2.27-2.21(m,1H),1.74(d,J=2Hz,3H).
實例17 (S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣(S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(DMSO-d 6 ,400MHz)δ：7.41(s,1H),7.34-7.23(m,5H),6.89(d,J=8.8Hz,2H),5.01(s,2H),4.05-3.99(m,1H),3.68(s,2H),3.56(s,2H),2.76-2.74(m,2H),2.68(s(br),2H),2.56(s,3H),2.40-2.36(m,1H),2.26-2.22(m,1H),1.73(d,J=2.4Hz,3H).
實例18 (S)-3-(4-((3-((2-(二氟甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.39-7.26(m,6H),6.91-6.59(m,4H),5.03(s,2H),4.12-4.10(m,1H),3.73(s,2H),3.55(s,2H),2.88-2.64(m,6H),1.82(d,J=2.4Hz,3H).
實例19 (S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣
1H NMR(DMSO-d 6 ,400MHz)δ：7.41(s,1H),7.37-7.24(m,5H),6.93-6.89(m,3H),5.06(s,2H),3.96-3.94(m,1H),3.66(s,2H),3.38(s,2H),2.71(s,4H),2.49-2.32(m,2H),1.76(d,J=2.4Hz,3H).
實例20 (S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣
1H NMR(DMSO-d 6 ,400MHz)δ：7.37(s,1H),7.35-7.23(m,5H),7.11-7.07(m,3H),6.98-6.97(m,1H),6.89(d,J=8.8Hz,2H),5.05(s,2H),3.99-3.97(m,1H),3.64(s,2H),3.52(s,2H),2.79-2.77(m,2H),2.65-2.64(m,2H),2.42-2.36(m,1H),2.28-2.22(m,1H),1.74(d,J=2.4Hz,3H).
實例21 (S)-3-(4-((3-((7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.94(s,1H),8.30(s,1H),7.45(s,1H),7.38-7.25(m,5H),6.86(dd,J=2,6.8Hz,2H),5.15-5.09(m,2H),4.06-4.03(m,1H),3.78-3.62(m,4H),2.89-2.73(m,6H),1.82(d,J=2.4Hz,3H).
實例22 (S)-3-(4-((3-((1-甲基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.43-7.24(m,6H),7.17(s,1H),6.88(td,J=5.2,8.4Hz,2H),5.03(s,2H),4.07(s,2H),4.02-3.97(m,5H),3.75(s,3H),2.78-2.72(m,1H),2.66-2.60(m,1H),1.80(d,J=2.4Hz,3H).
實例23 (3S)-3-(4-((3-(6-氧雜-3-氮雜雙環[3.1.1]庚烷-3-基甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.53-7.25(m,6H),6.89(d,J=8.4Hz,2H),5.09(s,2H),4.54-4.52(m,2H),4.05-3.93(m,3H),3.24-2.94(m,4H),2.81-2.75(m,1H),2.69-2.63(m,1H),2.42(d,J=8.8Hz,2H),1.83(d,J=2.4Hz,3H).
實例24 (S)-3-(4-((3-(吲哚啉-1-基甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.41(s,1H),7.37-7.25(m,5H),7.10-7.05(m,2H),6.93-6.89(m,2H),6.70-6.66(m,1H),6.51(d,J=7.6Hz,1H),5.03(s,2H),4.26(s,2H),4.07-4.02(m,1H),3.30(t,J=8.4Hz,2H),2.96(t,J=8.4Hz,2H),2.83-2.76(m,1H),2.73-2.67(m,1H),1.83(d,J=2.4Hz,3H).
實例25 (S)-3-(4-((3-((5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：8.50(s,1H),7.49(s,1H),7.40-7.35(m,3H),7.28(d,J=6.8Hz,2H),6.93(d,J=6.8Hz,2H),5.01(s,2H),4.15-4.11(m,2H),4.00-3.97(m,1H),3.87-3.83(m,4H),2.97-2.94(m,2H),2.66-2.62(m,2H),1.81(d,J=2.4Hz,3H).
實例26 (S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.52-7.20(m,6H),6.81(d,J=8.8Hz,2H),5.21-5.12(m,2H),4.00-3.95(m,1H),3.78-3.67(m,2H),3.23-2.59(m,8H),2.04-1.97(m,1H),1.81(d,J=2.4Hz,3H),1.00-0.96(m,4H).
實例27 (3S)-3-(4-((3-((5-苄基六氫吡咯並[3,4-c]吡咯-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸
1H NMR(CDCl3,400MHz)δ：8.45(s(br),0.78H,HCOOH),7.52-7.15(m,9H),7.16(d,J=7.2Hz,1H),6.78(dd,J=2.8,11.6Hz,2H),5.12(s,2H),4.05-4.00(m,1H),3.93-3.68(m,4H),3.04-3.01(m,2H),2.83-2.78(m,3H),2.68-2.64(m,1H),2.58-2.40(m,6H),1.77(d,J=2.4Hz,3H).
實例28 (S)-3-(4-((3-((4H-噻吩並[2,3-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.43(s,1H),7.39-7.24(m,6H),6.86(d,J=8.4Hz,2H),6.80(d,J=5.2Hz,1H),5.06-4.99(m,2H),4.17-4.00(m,7H),2.77-2.71(m,1H),2.65-2.59(m,1H),1.80(d,J=2.4Hz,3H).
實例29 甲酸6-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-6,7-二氫-5H-吡咯並[3,4-d]嘧啶-6-鎓
1HNMR(CDCl3,400MHz)δ：8.98(s,1H),8.63(s,1H),8.37(s,1H),7.45(s,1H),7.37-7.31(m,3H),7.25(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),5.08(s,2H),3.95-3.90(m,7H),2.55-2.52(m,1H),2.12(s,3H).
實例30 甲酸1-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)- 7-甲氧基-1,2,3,4-四氫喹啉-1-鎓
1HNMR(CDCl3,400MHz)δ 8.21(s),0.28(formate),7.33-7.28(m,3H),7.25(d,J=8.8Hz,2H),7.19(d,J=7.2Hz,1H),6.91(d,J=8.4Hz,2H),6.55(d,J=2.8Hz,1H),6.51-6.48(dd,J=8.8Hz & 2.8Hz,1H),6.39(d,J=8.8Hz,1H),5.0(s,2H),4.39(s,2H),3.95-3.90(m,3H),3.60(m,4H),3.24(t,3H),2.70(m,2H),2.58(d,2H),2.06(t,2H),1.07-1.08(s,3H).
實例31 (S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.41-7.30(m,3H),7.35-7.27(m,3H),6.90(d,J=8.4Hz,2H),5.07(s,1H),4.07-4.02(m,1H),3.82(s,2H),3.72(s,2H),2.98-2.95(m,2H),2.86-2.68(m,5H),1.83(d,J=2.4Hz,3H).
實例32 (S)-3-(4-((3-((2-溴-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.39-7.35(m,3H),7.29-7.26(m,3H),6.90(d,J=8.4Hz,2H),5.05(s,2H),4.06-4.01(m,1H),3.79(s,2H),3.70(s,2H),2.92-2.66(m,6H),1.82(d,J=2.4Hz,3H).
實例33 (S)-3-(4-((3-(吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基甲基)苄基)氧基)苯基)己-4-炔酸
1H-NMR(CDCl3,400MHz)：-δ 7.32-7.53(m,3H),7.19-7.29(m,4H),6.82-6.84(m,2H),5.16(s,2H),3.90-4.06(m,5H),3.57(s,2H),2.80-2.85(m,1H),1.81(s,3H)；
實例34 (S)-3-(4-((3-((2-(羥甲基)-6,7-二氫噻吩並[3,2-c]吡啶- 5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H-NMR(DMSO,400MHz)：-δ 7.38(s,1H),7.23-7.33(m,5H),6.92(d,J=8.8Hz,2H),6.56(s,1H),5.35(s,2H),3.91-3.94(m,1H),3.72-3.84(m,4H),3.40-3.50(m,2H(合併),2.86-2.94(m,2H),2.73-2.76(m,2H),2.50-2.58(m,2H),1.76(s,3H)；
實例35 (S)-5-(3-((4-(1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-4,5,6,7-四氫噻吩並[3,2-c]吡啶-2-羧酸
1H NMR：(DMSO-d 6,400MHz)：-7.42(s,1H),7.34-7.31(m,2H),7.27-7.26(m,1H),7.22(d,J=8.8Hz,2H),6.99(s,1H),6.90(d,J=8.8Hz,2H),5.09(s,2H),3.95-3.91(m,1H),3.65(s,2H),3.29(s,2H),2.74-2.71(m,4H),2.63-2.52(m,2H),1.76(s,3H).
實例36 3-環丙基-3-(3-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸
1H NMR：(DMSO-d 6,400MHz)：-7.46(s,1H),7.37-7.31(m,3H),7.14(t,J=8Hz,2H),6.81-6.79(m,2H),6.44(s,1H),5.05(s,2H),3.78(s,2H),3.32(s,2H),2.82-2.74(m,4H),2.49-2.44(m,2H),2.36-2.34(m,4H),1.30-1.28(m,1H),0.49-0.47(m,1H),0.27-0.24(m,2H),0.004-0.002(m,1H).
實例37 (S)-3-(4-((3-((1-甲基-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)：δ 7.53(s,1H),7.47-7.32(d,3H),7.24-7.12(m,2H),6.85(d,2H),6.51(d,1H),5.58(d,1H),5.0-4.95(d,2H),3.9-4.1(m,1H),3.87(d,1H),3.80(d,1H),3.48(s,3H),2.9-3.1(m,3H),1.08(m,3H).
實例38 (S)-3-(4-((3-((2-胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(DMSO-d6,400MHz)：δ 8.23(s,1H),7.40(s,1H),7.35(d,2H),7.32-7.24(m,3H),6.93(d,J=8.4Hz,2H),6.68(s,2H),5.06(s,2H),3.9-4.0(m,1H),3.35(s,3H),2.70-2.66(m,2H),2.58(d,2H),2.44(d,3H).
實例39 (S)-3-(4-((3-((2-氯-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣
1H NMR(CDCl3,400MHz)δ：7.39(s,1H),7.36-7.23(m,5H),6.88(d,J=8.8Hz,2H),6.78(s,1H),5.04(s,2H),3.99(s(br),1H),3.65(s,2H),3.34(s,2H),2.70(s(br),4H),2.37-2.31(m,1H),2.25-2.19(m,1H),1.73(d,J=2.4Hz,3H).
實例40 (S)-3-(4-((3-((2-胺基甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-12.22(br s,1H),7.76(br s,1H),7.42(s,1H),7.37-7.25(m,7H),6.94(d,J=8.8Hz,2H),5.07(s,2H),3.95-3.91(m,1H),3.68(s,2H),3.43(s,2H),2.78-2.76(m,2H),2.72-2.70(m,2H),2.60-2.57(m,2H),1.77(s,3H).
實例41 (S)-3-(4-((3-((2-異丙基吡咯並[3,4-c]吡唑-5(2H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H-NMR(DMSO,400MHz)：δ 12.25(m,2H),7.48-7.51(m,2H),7.39(s,3H),7.27(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),5.09(s,2H),4.40-4.47(m,1H),4.10-4.20(m, 2H),3.70-3.90(m,4H),2.66-2.66(m,2H),1.77(s,3H),1.36-1.38(m,6H)；
實例42 (S)-3-(4-((3-((2-(甲氧羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-12.22(br s,1H),7.50(s,1H),7.41(s,1H),7.37-7.24(m,5H),6.92(d,J=8.4Hz,2H),5.07(s,2H),3.95-3.91(m,1H),3.77(s,3H),3.68(s,2H),3.46(s,2H),2.84-2.81(m,2H),2.74-2.70(m,2H),2.58-2.53(m,2H),1.90(s,3H).
實例43 (S)-3-(4-((3-((2-氰基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H-NMR(DMSO,400MHz)：δ 8.83(s,1H),7.24-7.41(m,6H),6.92-6.94(m,2H),5.09(s,2H),3.91-3.94(m,1H),3.73(s,2H),3.45(s,2H),2.86-2.94(m,2H),2.73-2.76(m,2H),2.50-2.58(m,2H),1.76(s,3H)；
實例44 (S)-3-(4-((3-((2-甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-9.79(s,1H),7.70(s,1H),7.42(s,1H),7.36-7.31(m,3H),7.26-7.24(d,J=8Hz,2H),6.94-6.92(d,J=8Hz,2H),5.07(s,2H),3.93(br s,1H),3.70(s,2H),3.50(s,2H),2.89(s,2H),2.74(s,2H),1.76(s,3H),1.23(s,2H).
實例45 S)-3-(4-((3-((2-甲基-6,7-二氫吡唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(DMSO-d6,400MHz)：δ 7.41(s,1H),7.35(d,J=6.4Hz,2H),7.30(m,1H),7.25(d,J=8.8Hz,2H),6.93(d,J=8.4Hz,2H),5.73(s,1H),5.07(s,2H),3.96-3.92(m,3H),3.68(s,2H),3.52(s,2H),2.84(t,2H),2.66(t,2H),2.08(s,3H),1.77(s,3H)
實例46 (S)-3-(4-((3-((2-(甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-7.42(s,1H),7.35-7.24(m,6H),7.1-6.93-6.91(m,2H),5.07(s,2H),3.9(m,1H),3.68(s,2H),3.41(s,2H),2.71-2.70(m,2H),2.67-2.66(m,6H),1.76(s,3H).
實例47 (S)-3-(4-((3-((2-(二甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-7.53(s,1H),7.40- 7.22(m,4H),7.1-6.68(m,3H),5.08(s,2H),4.12-4.03(m,1H),3.78-3.71(m,2H),3.50(s,2H),3.17(s,6H),2.95-2.88(m,2H),2.83-2.63(m,2H),1.83(s,3H).
實例48 (3S)-3-(4-((3-((2-甲基-5-(4-(甲基磺醯基)苯基)吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.93-7.90(m,2H),7.82-7.76(m,2H),7.53-7.16(m,7H),6.92-6.86(m,3H),5.11-5.01(m,3H),4.45-4.30(m,1H),4.07-3.98(m,3H),3.30-3.20(m,1H),3.097-3.090(m,3H),3.03(s,1H),2.87-2.68(m,4H),2.33-1.98(m,8H),1.84-1.82(m,5H),1.62-1.60(m,4H)
實例49 (S)-3-(4-((3-((2-(甲基磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.48(s,1H),7.43-7.27(m,6H),6.91(dd,J=8.8,2Hz,2H),5.07(s,2H),4.07-4.03(m,1H),3.80(s,2H),3.72(s,2H),3.32(s,3H),3.15-3.09(m,2H),2.92-2.89(m,2H),2.84-2.78(m,1H),2.74-2.68(m,1H),1.83(d,J=2.4Hz,3H)
實例50 (S)-3-(4-((3-((2-甲氧基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.09(s,1H),7.53-7.26(m,6H),6.87(dd,J=6.8,2Hz,2H),5.17-5.08(m,2H),4.07-4.02(m,1H),3.98(s,3H),3.75(s(br),2H),3.58(s(br),2H),2.88-2.63(m,6H),1.82(d,J=2.4Hz,3H)
實例51 (3S)-3-(4-((3-((2-苯基吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H-NMR(CDCl3,400MHz)：δ 7.43-7.45(m,2H),7.21-7.35(m,9H),6.89-6.91(d,J=8Hz,2H),5.0(s,2H),4.03(m,1H),3.81-3.85(m,1H),3.37-3.41(m,1H),3.11-3.17(m,3H),2.74-2.80(m,1H),2.64-2.69(m,1H),3.37-2.14-2.51(m,2H),1.85-1.92(m,1H),1.81(s,3H),1.71-1.75(m,2H)；
實例52 (S)-3-(4-((3-(吡咯啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸
1H NMR(CD3OD,400MHz)δ：8.51(s,1H,HCOOH),7.60(s,1H),7.55-7.45(m,3H),7.28(d,J=8.4Hz,2H),6.91(d,J=8.8Hz,2H),5.14(s,2H),4.34(s,2H),4.02-3.98(m,1H),3.27-3.24(m,4H),2.62-2.50(m,2H),2.08-2.04(m,4H),1.80(d,J=2.4Hz,3H)
實例53 (S)-3-(4-((3-(哌啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸
1H NMR(CD3OD,400MHz)δ：8.50(s,1H,HCOOH),7.58-7.43(m,4H),7.29(d,J=8.8,Hz,2H),6.91(d,J=8.8Hz,2H),5.15(s,2H),4.23(s,2H),4.09-4.03(m,1H),3.12-3.08(m,4H),2.63-2.49(m,2H),1.83-1.79(m,7H),1.64-1.61(m,2H)
實例54 (S)-3-(4-((3-((1-異丙基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸
1H NMR(CD3OD,400MHz)δ：8.41(s,1H,HCOOH),7.54(s,1H),7.43-7.40(m,3H),7.29(dd,J=7.2,2Hz,2H),7.21(s,1H),6.93(dd,J=6.8,2Hz,2H),5.11(s,2H),4.45-4.41(m,1H),4.14(s,2H),4.07(s,2H),4.02-3.95(m,1H),3.88(s,2H),2.63-2.59(m,2H),1.80(d,J= 2.4Hz,3H),1.42(d,J=6.8Hz,6H).
實例55 (R)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.31(s,0.36 H，殘餘HCOOH),7.47-7.25(m,6H),6.86(td,J=9.6,2.8Hz,2H),6.34(s,1H),5.04(s,2H),4.07-4.01(m,3H),3.8(s(br),2H),3.20-3.12(m,2H),2.97-2.95(m,2H),2.78-2.73(m,1H),2.66-2.61(m,1H),2.41(s,3H),1.80(d,J=2.4Hz,3H).
實例56 (R)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：8.15(s,0.3H，殘餘HCOOH),7.41-7.27(m,6H),6.88(d,J=8.4Hz,2H), 5.15-5.07(m,2H),4.06-4.02(m,1H),3.90-3.82(m,4H),2.96-2.92(m,2H),2.88-2.64(m,7H),1.82(d,J=2.4Hz,3H)
實例57 (S)-3-(4-((3-((6,7-二氫-[1,2,3]三唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：7.59-7.58(m,2H),7.58-7.43(m,3H),7.29(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),5.14(s,2H),4.58-4.55(m,2H),4.19(s,2H),4.15(s,2H),4.01-3.97(m,1H),3.44-3.41(m,2H),2.70-2.58(m,2H),1.81(d,J=2.4Hz,3H).
實例58 3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CDCl3,400MHz)δ：7.42-4.27(m,5H),6.87 (dd,J=11.2,3Hz,2H),6.34(s,1H),5.05(s,2H),4.06-4.02(m,2H),3.98(s,2H),3.74(s,2H),3.10-3.04(m,2H),2.92-2.89(m,2H),2.79-2.73(m,1H),2.67-2.61(m,1H),2.41(s,3H),1.81(d,J=2.4Hz,3H).
實例59 3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸：
1H NMR(CDCl3,400MHz)δ：7.42-7.35(m,4H),7.29-7.27(m,2H),6.88(d,J=8.8Hz,2H),5.14-5.07(m,2H),4.06-4.03(m,1H),3.93-3.85(m,4H),2.99-2.97(m,2H),2.86-2.64(m,7H),1.82(d,J=2.4Hz,3H
實例60 (S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣
1H NMR(DMSO-d 6 ,400MHz)δ：7.39(s,1H),7.36- 7.23(M,5H),6.88(d,J=8.8Hz,2H),5.03(s,2H),4.02-3.99(m,1H),3.69(s,2H),3.39(s,2H),2.80-2.77(m,2H),2.72-2.69(m,2H),2.41-2.36(m,1H),2.27-2.21(m,1H),1.73(d,J=2.4Hz,3H).
實例61 (S)-3-(4-((3-((2-(環丙基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-8.34(br s,1H),7.41(s,1H),7.36-7.29(m,3H),7.27-7.24(m,3H),6.67(d,J=8.4Hz,2H),5.07(s,2H),3.95-3.91(m,1H),3.67(s,2H),3.42(s,2H),2.77-2.66(m,5H),2.57-2.51(m,2H),1.76(s,3H),0.67-0.62(m,2H),0.53-0.49(m,2H
實例62 (S)-3-(4-((3-((2-(吡咯啶-1-羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR：(DMSO-d 6,400MHz)：-7.42(s,1H),7.37-7.26(m,3H),7.25-7.13(m,3H),6.93(d,J=8.8Hz,2H),5.07(s,2H),3.94-3.87(m,1H),3.68(br s,4H),3.43(br s,4H),2.80-2.73(m,4H),2.59-2.50(m,2H),2.91-1.81(m,4H),1.76(s,3H)
實例63 (S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：7.56(s,1H),7.50-7.41(m,3H),7.28(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),6.35(s,1H),5.12(s,2H),4.15(s,2H),4.01-3.97(m,1H),3.84(s,2H),3.25-3.22(m,2H),2.96-2.93(m,2H),2.66-2.53(m,2H),2.10(s,3H),1.79(d,J=2.4Hz,3H).
實例64 (S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣
1H NMR(DMSO-d 6 ,400MHz)δ：7.38(s,1H),7.34-7.24(m,5H),6.88(d,J=8Hz,2H),5.02(s,2H),4.02-4.01(m,1H),3.66(s,2H),3.26(s,2H),2.73-2.71(m,2H),2.58(s,2H),2.41-2.37(m,1H),2.27-2.24(m,1H),2.03-2.00(m,1H),1.72(s,3H),0.98-.093(m,2H),0.86-0.82(m,2H).
實例65 (S)-3-(4-((3-((2-硝基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：7.80(s,1H),7.69(s,1H),7.61-7.52(m,3H),7.30(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),5.17(s,2H),4.54(s,2H),4.30(s,2H),4.01-3.99(m,1H),3.66(s(br),2H),3.31-3.27(m,2H),2.69-2.58(m,2H),1.80(d,J=2.4Hz,3H)
實例66 (S)-3-(4-((3-((2-(二甲胺基)-7,8-二氫吡啶並[4,3-d]嘧啶- 6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸
1H NMR(CD3OD,400MHz)δ：8.00(s,1H),7.54(s,1H),7.45-7.42(m,3H),7.28(d,J=8.4Hz,2H),6.93(d,J=8.4Hz,2H),5.13(s,2H),4.01-3.99(m,3H),3.74(s,2H),3.14(s,6H),3.10-3.07(m,2H),2.90-2.87(m,2H),2.64-2.60(m,2H),1.80(d,J=2.4Hz,3H).
實例67 (S)-3-(4-((3-((2-胺基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸
1H NMR(CD3OD,400MHz)δ：8.10(s,1H),7.67(s,1H),7.62-7.54(m,3H),7.30(dd,J=6.8,1.6Hz,2H),6.96(d,J=6.8,1.6Hz,2H),5.17(s,2H),4.52(s,2H),4.25(s,2H),4.01-3.99(m,1H),3.63(s,2H),3.09-3.05(m,2H),2.70-2.58(m,2H),1.80(d,J=2.4Hz,3H)
實例68 (S)-3-(4-((3-((7,8-二氫-1,6-啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：8.59(d,J=4Hz,1H),7.87(d,J=8Hz,1H),7.72(s,1H),7.62-7.51(m,4H),7.30(dd,J=8.8,2Hz,2H),6.96(d,J=8.8,2Hz,2H),5.17(s,2H),4.57(s,2H),4.49(s,2H),4.01-3.97(m,1H),3.75-3.72(m,2H),3.41-3.38(m,2H),2.69-2.58(m,2H),1.80(d,J=2.4Hz,3H).
實例69 (S)-3-(4-((3-((2-環丙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸
1H NMR(CD3OD,400MHz)δ：7.66(s,1H),7.60-7.52(m,2H),7.30(dd,J=6.8,2Hz,2H),6.90(dd,J=6.8,2 Hz,2H),6.50(s,1H),5.17(s,2H),4.51(s,2H),4.18(s,2H),4.01-3.97(m,1H),3.12-3.09(m,2H),2.67-2.60(m,2H),1.80(d,J=2.4Hz,3H),1.00-0.97(m,2H),0.66-0.64(m,2H)
實例70 (S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸
1H NMR(CD3OD,400MHz)δ：7.68(s,1H),7.62-7.54(m,3H),7.30(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),5.17(s,2H),4.56(s,2H),4.40(s,2H),4.01-3.97(m,1H),3.67(s(br),2H),3.07-3.04(m,2H),2.69-2.58(m,2H),2.20(s,3H),1.80(d,J=2.4Hz,3H).
實例71 (S)-3-(4-((3-((2-乙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：7.66(s,1H),7.62-7.53(m,3H),7.30(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),6.53(s,1H),5.17(s,2H),4.51(s,2H),4.20(s,2H),4.01-3.97(m,1H),3.57(s(br),2H),2.81-2.78(m,2H),2.75(q,J=7.6Hz,2H),2.69-2.57(m,2H),1.80(d,J=2.4Hz,3H),1.26(t,J=7.2Hz,3H).
實例72 (S)-3-(4-((3-((2-乙醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸
1H NMR(CD3OD,400MHz)δ：7.56-7.55(m,2H),7.49-7.42(m,3H),7.28(dd,J=6.8,2Hz,2H),6.93(dd,J=6.8,2Hz,2H),5.12(s,2H),4.09(s,2H),4.01-3.97(m,1H),3.88(s,2H),3.18-3.14(m,2H),3.07-3.04(m,2H),2.66-2.56(m,2H),2.50(s,3H),1.79(d,J=2.4Hz,3H)
實例73 (S)-3-(4-((3-((2-((甲胺基)甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸
1H NMR(CD3OD,400MHz)δ：7.67(s,1H),7.62-7.60(m,1H),7.55-7.53(m,2H),7.30(dd,J=6.8,2Hz,2H),7.03(s,1H),6.96(dd,J=6.8,2Hz,2H),5.17(s,2H),4.52(s,2H),4.36(s,2H),4.27(s,2H),4.01-3.98(m,1H),3.62(s(br),2H),3.24-3.21(m,2H),2.71(s,3H),2.69-2.62(m,2H),1.81(d,J=2.4Hz,3H).
本發明之新穎化合物可藉詳知之技術及方法及濃度藉與適當賦形劑組合而調配成適當之藥學上可接受之組成物。
式(1)化合物或含彼之藥學組成物可作為適用於人類及其他溫血動物之GPR40受體的配體，且可藉經口、局部或非經腸部投服法投服。
活性組份亦即根據本發明之式(I)化合物於藥學組成物及其單位劑型中的量可依數種因素諸如特定施用法、特定化合物之效能及期望之濃度而廣泛地變化或調整。
生物學活性：
本發明化合物之生物學活性係以此處所提述之下列體外及體內模型進行測試。
體外篩選擬案之概要
欲使用螢光分析法(FLIPR)測量化合物對細胞內Ca2+通量的ED50。
將表現GPR40之安定細胞以每孔25,000的數目接種。將50微升/孔之分析緩衝液(20mM HEPES+ 1X HBSS)加至細胞中，再將細胞於37℃培養20分鐘。將細胞裝載50微升/孔之Calcium 5染料，再於37℃培養45分鐘。
將細胞以本化合物、以1000nM之最高濃度(1：3逐步向下稀釋-10個點)挑戰。細胞內之鈣通量藉使用Screen Works 3.1工具評估且統計分析係使用Graph Pad Prism 4進行。
當使用螢光(FLIPR)分析法測量時，許多本發明化合物證實對細胞內Ca2+通量具有奈莫耳效能及顯著之刺激%。
本化合物顯現奈莫耳範圍內的效能(表1)。
測量GPR40活化作用之啟動子螢光素酶分析法
GPR40活化作用係於以GPR40 cDNA(得自Millipore,US之ChemiBrite細胞系)安定轉染之HEK293細胞中測量。將細胞以具有5XSRE序列之pGL2(Promega公司)質體短暫轉染，選殖螢光素酶基因之5’連同以β-半乳糖苷酶作為正規化對照組。簡言之，將35000個細胞/孔接種於96孔盤中。於37℃培育過夜後，將細胞以PBS清洗，再以5X-SRE-螢光素酶質體及β-半乳糖苷酶質體轉染。轉染後6小時，將培養基移出，再以含不同濃度藥物之新鮮培養基替換，並培育再16小時。然後將細胞於50微升Glo-Lysis緩衝液(Promega)中於室溫溶解30分鐘。然後將細胞離心，再收集溶解產物。螢光素酶之活性係藉將100微升螢光素酶基質(Promega)加於20微升溶解產物中，再於冷光儀中測量冷光而測得。β-半乳糖苷酶活性亦藉將20微升溶解產物加上20微升β-半乳糖苷酶緩衝液(Promega)，再於415nm監測吸光度而測得。將螢光素酶的值除以β-半乳糖苷酶的值以將轉染效率正規化(表2)。
將大多數本發明化合物對CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6及CYP3A4進行評估，結果彼等無顯著的CYP抑制效應。化合物於10μM並未顯現顯著之hERG結合力。
體外效力研究： GRP40激動劑測試化合物於n-STZ大鼠模型中之初步篩選擬案
將1-2天大的Wistar大鼠經由腹膜內路徑注射120 毫克/公斤劑量之鏈佐黴素(Streptozotocin，STZ)。令所有大鼠正常生長，再於12-14個星期大之年齡時，藉斷尾法使用血糖儀進行口服葡萄糖耐受性試驗以篩選彼等之葡萄糖不耐受性。選出顯現葡萄糖不耐受性的動物以進行測試化合物的評估。三至七天的休息期，令動物保持過夜禁食。隔天早上使用血糖儀測量血糖值，且將動物分群使得彼等之處理前的葡萄糖值在群組之間無顯著差異。將動物投服以測試化合物，然後於化合物投服之15-60分鐘後，測量“O”分之血葡萄糖值，再立即經口投服2克/公斤之葡萄糖負荷。於葡萄糖負荷後之30、60及120分鐘使用斷尾法使用血糖儀測量血葡萄糖值。亦收集葡萄糖負荷後之10分鐘的血液以測量胰島素濃度。葡萄糖之曲線下面積(AUC)係使用Graph Pad Prism軟體計算，再計算相對於經載劑處理之對照組的AUC-葡萄糖降低%(表3)。
於n-STZ大鼠OGTT模型中，化合物16、60及64之ED50業已發現分別為0.05毫克/公斤、0.04毫克/公斤及0.09毫克/公斤。
很少數化合物於大鼠中已顯現顯著藥物動力學參數(表4)
式(I)化合物或含彼之藥學組成物適用於人類及其他溫血動物，且可藉經口、局部或非經腸部投服法投服以用於治療與異常血脂症、肥胖症等等有關之各種疾病病症。
藥學組成物係藉使用慣用技術提供。較佳地，組成物為含有有效量活性組份亦即根據本發明式(I)化合物之單位劑型。
活性組份亦即根據本發明之式(I)化合物於藥學組成物及其單位劑型中的量可依特定施用法、特定化合物之效能及期望之濃度而廣泛地變化或調整。通常，活性組份之量在組成物的0.5重量%至90重量%之範圍間。

Claims (11)

  1. 一種通式(I’)化合物 其互變異構型式、其立體異構物、其藥學上可接受之鹽、及含彼之藥學組成物，其中R1、R2、R3及R4於每次出現時各自獨立地表示H、鹵素、羥基、CN、NO2、CHO、COOH、CO、隨意經取代之選自以下的基團：烷基、烷氧基、巰基、亞碸、碸、醯基、NH2或隨意經取代之NHCO-直鏈或支鏈(C1-C6)烷基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基或OR、C(O)OR、C(O)R及SO2R基，其中‘R’於每次出現時獨立地表示隨意經取代之選自以下之基團：H、直鏈或支鏈(C1-C6)烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳烷基；‘A’選自3-7員部分飽和、不飽和或飽和環，其另具有一個或一個以上之選自O、S、或N的雜原子；‘E’及‘D’各自獨立地為氮或碳；‘F’選自C、N或O；‘n’、‘r’及‘s’各自獨立地表示0至6的整數；R5及R6為各獨立選出之(C2-C4)炔、腈、或環烷基；或者R5及R6與彼所連接之碳原子組合形成3-7員環，該 環隨意地另具有一個或一個以上之選自S、N、或O的雜原子。
  2. 如申請專利範圍第1項之化合物，其中該代表下式 之雜環選自下列之雙環：
  3. 如申請專利範圍第1項之化合物，其中該COOH在任何可能處係被選自以下之生物電子等排替代物所替代：
  4. 如申請專利範圍第1項之化合物，其中R1至R6之任一基團係經一或多個基團取代，該等取代基獨立地選目包含以下之基團：羥基、側氧基、鹵基、硫基(thio)、硝基、胺基、氰基、甲醯基、或經取代或未經取代之選自以下之基團：脒基、烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、環烯基、雙環烷基、雙環烯基、烷氧基、烯氧基、環烷氧基、芳基、芳氧基、芳烷基、芳烷氧基、雜環基、雜芳基、雜環基烷基、雜芳烷基、雜芳氧基、雜芳烷氧基、雜環基氧基、雜環基烷氧基、雜環基烷氧基醯基、醯基、醯氧基、醯胺基、單取代或二取代之胺基、芳胺基、芳烷胺基、羧酸及其選自酯類及醯胺類的衍生物、羰胺基、羥烷基、胺烷基、烷氧基烷基、芳氧基烷基、芳烷氧基烷基、烷硫基(alkylthio)、硫烷基(thioalkyl)、芳硫基、烷磺醯胺基、烷磺醯氧基、烷氧羰胺基、芳氧羰胺基、芳烷氧羰胺基、胺羰基胺基、烷胺羰基胺基、烷氧基胺基、羥基胺基、次磺醯基(sulfenyl)衍生物、磺醯基衍生物、磺酸及其衍生物。
  5. 如申請專利範圍第1項之化合物，其中該雜芳基選自吡啶基、噻吩基、呋喃基、吡咯基、唑基、噻唑基、異噻唑基、咪唑基、異唑基、二唑基、噻二唑基、三唑基、四唑基、苯並吡喃基、苯並吡喃酮基、苯並呋喃基、苯並噻吩基、吲哚啉基、吲哚基、氮雜吲哚基、氮雜吲哚啉基、苯並二氫呋喃基、苯並二氫噻吩基、吡唑並嘧啶基、吡唑並嘧啶酮基、氮雜喹唑啉基、氮雜喹唑啉基羰基(azaquinazolinoyl)、吡啶並呋喃基、吡啶並噻吩基、噻吩並嘧啶基、噻吩並嘧啶酮基、喹啉基、嘧啶基、吡唑基、喹唑啉基、喹唑啉酮基、嘧啶酮基、嗒基、三基、苯並基、苯並酮基、苯並噻基、苯並噻酮基、苯並唑基、苯並噻唑基、苯並咪唑基、苯並三唑基、呔基(phthalazynil)、啶基(naphthylidinyl)、嘌呤基、咔唑基、啡噻基、啡基。
  6. 如申請專利範圍第1項之化合物，其中該雜環基選自氮雜環丙烷基、氮雜環丁烷基、吡咯啶基、咪唑啶基、哌啶基、哌基、2-側氧基哌啶基、4-側氧基哌啶基、2-側氧基哌基、3-側氧基哌基、嗎啉基、硫代嗎啉基、2-側氧基嗎啉基、氮雜環庚三烯基、二氮雜環庚三烯基、氧雜環庚三烯基(oxapinyl)、硫氮雜環庚三烯基、唑啶基、噻唑啶基等等；部分飽和雜環基之實例包括二氫噻吩、二氫吡喃、二氫呋喃、二氫噻唑基。
  7. 如申請專利範圍第1項之化合物，其選自由以下所組成之群組： (S)-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；3-(4-((3-((4H-呋喃並[3,4-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)-3-氰基丙酸鋰；3-氰基-3-(4-((3-((4-側氧基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸；3-氰基-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)丙酸鋰；3-氰基-3-(4-((3-((2,2-二氧化-1H-噻吩並[3,4-c]吡咯-5(3H,4H,6H)-基)甲基)苄基)氧基)苯基)丙酸；3-氰基-3-(4-((3-((6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((1-(三級丁氧羰基)-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((3-(三氟甲基)-5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(異吲哚啉-2-基甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((3,4-二氫喹啉-1(2H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-(二氟甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-溴-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((3,4-二氫異喹啉-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((1-甲基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-(6-氧雜-3-氮雜雙環[3.1.1]庚烷-3-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吲哚啉-1-基甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((5,6-二氫-[1,2,4]三唑並[4,3-a]吡-7(8H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((5-苄基六氫吡咯並[3,4-c]吡咯-2(1H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-((4H-噻吩並[2,3-c]吡咯-5(6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；甲酸6-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-6,7-二氫-5H-吡咯並[3,4-d]嘧啶-6-鎓；甲酸1-(3-((4-((S)-1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-7-甲氧基-1,2,3,4-四氫喹啉-1-鎓；(S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-溴-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(羥甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-5-(3-((4-(1-羧基戊-3-炔-2-基)苯氧基)甲基)苄基)-4,5,6,7-四氫噻吩並[3,2-c]吡啶-2-羧酸；3-環丙基-3-(3-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)丙酸； (S)-3-(4-((3-((1-甲基-6,7-二氫-1H-吡咯並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氯-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-胺基甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-異丙基吡咯並[3,4-c]吡唑-5(2H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(甲氧羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氰基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；S)-3-(4-((3-((2-甲基-6,7-二氫吡唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(二甲基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((2-甲基-5-(4-(甲基磺醯基)苯基)吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸； (S)-3-(4-((3-((2-(甲基磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-甲氧基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(3S)-3-(4-((3-((2-苯基吡咯啶-1-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-(吡咯啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-(哌啶-1-基甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(S)-3-(4-((3-((1-異丙基吡咯並[3,4-c]吡唑-5(1H,4H,6H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同甲酸；(R)-3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(R)-3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((6,7-二氫-[1,2,3]三唑並[1,5-a]吡-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；3-(4-((3-((2-甲基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；3-(4-((3-((2-甲基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-氯-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)- 基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-(環丙基胺基甲醯基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(吡咯啶-1-羰基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-環丙基-6,7-二氫唑並[4,5-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸鈣；(S)-3-(4-((3-((2-硝基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-(二甲胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((2-胺基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((7,8-二氫-1,6-啶-6(5H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-環丙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸；(S)-3-(4-((3-((2-乙醯胺基-6,7-二氫噻唑並[5,4-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同 2,2,2-三氟乙酸；(S)-3-(4-((3-((2-乙基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-乙醯基-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸；(S)-3-(4-((3-((2-((甲胺基)甲基)-6,7-二氫噻吩並[3,2-c]吡啶-5(4H)-基)甲基)苄基)氧基)苯基)己-4-炔酸化合物連同2,2,2-三氟乙酸。
  8. 一種藥學組成物，其包含醫療有效量之如申請專利範圍第1至7項中任一項之式(I’)化合物及隨意地一或多種藥學上可接受之載體、稀釋劑或賦形劑。
  9. 如申請專利範圍第8項之藥學組成物，係用於治療由GPR40受體所媒介之疾病。
  10. 一種藥學組成物，其包含如申請專利範圍第1至7項中任一項之式(I’)化合物連同適當之賦形劑，該藥學組成物適於治療各種與異常血脂症、肥胖症等等有關的疾病病症。
  11. 一種如申請專利範圍第1至7項中任一項之化合物於製備醫藥之用途，該醫藥用於預防或治療哺乳動物之與GPR40受體功能有關的病症。
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US20160257701A1 (en) 2016-09-08
AP2016009176A0 (en) 2016-04-30
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CA2928097A1 (en) 2015-07-02
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MX2016006337A (es) 2016-09-06
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MA38999A1 (fr) 2018-01-31
US10246470B2 (en) 2019-04-02

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