TWI717061B - 新穎經取代吲唑、其製法、包含其之醫藥製劑及其製備藥劑之用途 - Google Patents
新穎經取代吲唑、其製法、包含其之醫藥製劑及其製備藥劑之用途 Download PDFInfo
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- TWI717061B TWI717061B TW108137338A TW108137338A TWI717061B TW I717061 B TWI717061 B TW I717061B TW 108137338 A TW108137338 A TW 108137338A TW 108137338 A TW108137338 A TW 108137338A TW I717061 B TWI717061 B TW I717061B
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Abstract
本申請案係關於新穎經取代吲唑、其製法、其單獨或以組合方式於治療及/或預防疾病之用途及其於製備用於治療及/或預防疾病，尤其用於治療及/或預防子宮內膜異位症及與子宮內膜異位症相關聯之疼痛及其他的與子宮內膜異位症相關聯之症狀(諸如痛經、性交困難、排尿困難及排便困難)、淋巴瘤、類風濕性關節炎、脊柱關節炎(尤其係牛皮癬性脊柱關節炎及別赫捷列夫氏病(Bekhterev's disease))、紅斑狼瘡、多發性硬化症、黃斑變性、COPD、痛風、脂肪肝病、胰島素抗性、腫瘤性疾病及牛皮癬之藥劑之用途。
Description
本申請案係關於新穎經取代吲唑、其製法、用於製備該等新穎化合物之中間物、該等新穎經取代吲唑於治療及/或預防疾病之用途及其製備用於治療及/或預防疾病，尤其增生疾病、自體免疫疾病、代謝及發炎性疾病，例如類風濕性關節炎、脊柱關節炎(特別是牛皮癬性脊柱關節炎及別赫捷列夫氏病(Bekhterev's disease))、慢性阻塞性肺病(縮寫：COPD)、多發性硬化症、全身性紅斑狼瘡、痛風、代謝症候群、脂肪肝肝炎、胰島素抗性、子宮內膜異位症及發炎誘發之疼痛或慢性疼痛及淋巴瘤之藥劑之用途。
本發明係關於抑制介白素-1受體相關激酶4(IRAK4)之通式(I)之新穎經取代吲唑。
人類IRAK4(介白素-1受體相關激酶4)在活化免疫系統中扮演重要角色。因此，此激酶為用於發展發炎抑制物質之重要治療性標靶分子。IRAK4係由許多細胞表現且介導Toll樣受體(TLR)(除了TLR3之外)及由IL-1R(受體)、IL-18R、IL-33R及IL-36R組成之介白素(IL)-1β家族之受體之信號轉導(Janeway及Medzhitov, Annu. Rev. Immunol., 2002；Dinarello, Annu. Rev. Immunol., 2009；Flannery及Bowie, Biochemical Pharmacology, 2010)。
IRAK4基因敲除小鼠及缺少IRAK4之患者之人類細胞均對TLR(除了TLR3之外)及IL-1β家族之刺激不起反應(Suzuki, Suzuki等人, Nature, 2002; Davidson, Currie等人, The Journal of Immunology, 2006；Ku, von Bernuth等人, JEM, 2007；Kim, Staschke等人, JEM, 2007)。
TLR配位體或IL-1β家族之配位體與各自受體之結合導致募集MyD88[髓樣分化初級反應基因(88)]及其與受體之結合。結果，MyD88與IRAK4相互作用，導致形成與激酶IRAK1或IRAK2相互作用並將其活化之活性複合物(Kollewe, Mackensen等人, Journal of Biological Chemistry, 2004；Precious等人, J. Biol. Chem., 2009)。由此所致，NF(核因子)-κB信號傳遞通路及MAPK(絲裂原活化蛋白激酶)信號通路得以活化(Wang, Deng等人, Nature, 2001)。NF-κB信號通路及MAPK信號通路二者之活化導致與不同免疫過程相關聯之過程。例如，各種發炎信號分子及酵素諸如細胞介素、趨化介素及COX-2(環氧化酶-2)之表現增加，且發炎相關基因例如COX-2、IL-6(介白素-6)、IL-8之mRNA穩定性增加(Holtmann, Enninga等人, Journal of Biological Chemistry, 2001；Datta, Novotny等人, The Journal of Immunology, 2004)。另外，此等過程可能與特定細胞類型例如單核細胞、巨噬細胞、樹突細胞、T細胞及B細胞之增殖及分化相關聯(Wan, Chi等人, Nat Immunol, 2006; McGettrick及J. O'Neill, British Journal of Haematology, 2007)。
早已藉由直接比較野生型(WT)小鼠與具有IRAK4之激酶非活化形式(IRAK4 KDKI)之基因改造動物顯示IRAK4在各種發炎疾病之病理中之重要作用。IRAK4 KDKI動物在多發性硬化症、動脈粥樣硬化、心肌梗塞及阿茲海默氏症(Alzheimer's disease)之動物模型中具有改善之臨床表現(Rekhter, Staschke等人, Biochemical and Biophysical Research Communication, 2008；Maekawa, Mizue等人, Circulation, 2009；Staschke, Dong等人, The Journal of Immunology, 2009；Kim, Febbraio等人, The Journal of Immunology, 2011；Cameron, Tse等人, The Journal of Neuroscience, 2012)。另外，已發現動物模型中IRAK4之缺失以增進之抗病毒反應及同時減輕之全身性發炎形式防止病毒誘發之心肌炎(Valaperti, Nishii等人, Circulation, 2013)。亦已顯示IRAK4之表現與伏格特-小柳-原田症候群(Vogt-Koyanagi-Harada syndrome)之疾病活性相關聯(Sun, Yang等人, PLoS ONE, 2014)。此外，已顯示IRAK4於全身性紅斑狼瘡(SLE)之發病機理中之關鍵過程-漿細胞樣樹突細胞之免疫複合物介導之IFNα(干擾素-α)產生之高度相關性(Chiang等人, The Journal of Immunology, 2010)。另外，信號傳遞通路與肥胖相關聯(Ahmad, R., P. Shihab等人, Diabetology & Metabolic Syndrome, 2015)。
與IRAK4在先天性免疫中之至關重要作用一樣，亦顯示IRAK4會影響Th17 T細胞(適應性免疫之成分)之分化。在不存在IRAK4激酶活性下，與WT小鼠比較，產生更少的產生IL-17之T細胞(Th17 T細胞)。IRAK4之抑制可預防及/或治療動脈粥樣硬化、1型糖尿病、類風濕性關節炎、脊柱關節炎(特別是牛皮癬性脊柱關節炎及別赫捷列夫氏病)、紅斑狼瘡、牛皮癬、白斑病、巨細胞動脈炎、慢性發炎性腸病及病毒性疾病(例如HIV(人類免疫缺陷病毒)、肝炎病毒)(Staschke等人, The Journal of Immunology, 2009；Marquez等人, Ann Rheum Dis, 2014；Zambrano-Zaragoza等人, International Journal of Inflammation, 2014；Wang等人, Experimental and Therapeutic Medicine, 2015; Ciccia等人, Rheumatology, 2015)。
由於IRAK4在TLR(除了TLR3之外)及IL-1受體家族之MyD88介導之信號級聯中具有重要作用，因此IRAK4之抑制可用於預防及/或治療由所述受體介導之疾病。TLR亦及IL-1受體家族之成分涉及類風濕性關節炎、牛皮癬、關節炎、重度肌無力症、血管炎(例如貝西氏病(Behçet's disease)、肉芽腫病併發多血管炎及巨細胞動脈炎)、胰臟炎、全身性紅斑狼瘡、皮肌炎及多發性肌炎、代謝症候群(包括(例如)胰島素抗性、高血壓、異常脂蛋白血症(dyslipoproteinaemia)及肥胖)、糖尿病(1型及2型)、糖尿病性腎病、骨關節炎、修格連氏症候群(Sjögren syndrome)及敗血症之發病機理(Yang, Tuzun等人, J Immunol, 2005；Candia, Marquez等人, The Journal of Rheumatology, 2007；Scanzello, Plaas等人. Curr Opin Rheumatol, 2008；Deng, Ma-Krupa等人, Circ Res, 2009；Roger, Froidevaux等人, PNAS, 2009；Devaraj, Tobias等人, Arterioscler Thromb Vasc Biol, 2011；Kim, Cho等人, Clin Rheumatol, 2010；Carrasco等人, Clinical and Experimental Rheumatology, 2011；Gambuzza, Licata等人, Journal of Neuroimmunology, 2011；Fresno, Archives Of Physiology And Biochemistry, 2011；Volin及Koch, J Interferon Cytokine Res, 2011；Akash, Shen等人, Journal of Pharmaceutical Sciences, 2012；Goh及Midwood, Rheumatology, 2012；Dasu, Ramirez等人, Clinical Science, 2012；Ouziel, Gustot等人, Am J Patho, 2012；Ramirez及Dasu, Curr Diabetes Rev, 2012, Okiyama等人, Arthritis Rheum, 2012；Chen等人, Arthritis Research & Therapy, 2013；Holle, Windmoller等人, Rheumatology (Oxford), 2013；Li, Wang等人, Pharmacology & Therapeutics, 2013；Sedimbi, Hagglof等人, Cell Mol Life Sci, 2013；Caso, Costa等人, Mediators of Inflammation, 2014；Cordiglieri, Marolda等人, J Autoimmun, 2014；Jialal, Major等人, J Diabetes Complications, 2014；Kaplan, Yazgan等人, Scand J Gastroenterol, 2014；Talabot-Aye等人, Cytokine, 2014；Zong, Dorph等人, Ann Rheum Di, 2014；Ballak, Stienstra等人, Cytokine, 2015；Timper, Seelig等人, J Diabetes Complications, 2015)。皮膚疾病諸如牛皮癬、異位性皮膚炎、金德勒氏症候群(Kindler's syndrome)、大皰性類天疱瘡、過敏性接觸性皮膚炎、斑禿、反常型痤瘡(acne inversa)及尋常型痤瘡(acne vulgaris)係與IRAK4介導之TLR信號傳遞通路以及IL-1R家族相關聯(Schmidt, Mittnacht等人, J Dermatol Sci, 1996；Hoffmann, J Investig Dermatol Symp Proc, 1999；Gilliet, Conrad等人, Archives of Dermatology, 2004；Niebuhr, Langnickel等人, Allergy, 2008；Miller, Adv Dermatol, 2008；Terhorst, Kalali等人, Am J Clin Dermatol, 2010；Viguier, Guigue等人, Annals of Internal Medicine, 2010；Cevikbas, Steinhoff, J Invest Dermatol, 2012；Minkis, Aksentijevich等人, Archives of Dermatology, 2012；Dispenza, Wolpert等人, J Invest Dermatol, 2012；Minkis, Aksentijevich等人, Archives of Dermatology, 2012；Gresnigt及van de Veerdonk, Seminars in Immunology, 2013；Selway, Kurczab等人, BMC Dermatology, 2013；Sedimbi, Hagglof等人, Cell Mol Life Sci, 2013；Wollina, Koch等人. Indian Dermatol Online, 2013；Foster, Baliwag等人, The Journal of Immunology, 2014)。
肺病諸如肺纖維化、阻塞性肺病(COPD)、急性呼吸窘迫症候群(ARDS)、急性肺損傷(ALI)、間質性肺病(ILD)、類肉瘤病及肺動脈高壓症亦顯示與各種TLR介導之信號通路相關聯。肺病之發病機理可受到感染性或非感染性過程影響(Ramirez Cruz, Maldonado Bernal等人, Rev Alerg Mex, 2004；Jeyaseelan, Chu等人, Infection and Immunity, 2005；Seki, Tasaka等人, Inflammation Research, 2010；Xiang, Fan等人, Mediators of Inflammation, 2010；Margaritopoulos, Antoniou等人, Fibrogenesis & Tissue Repair, 2010；Hilberath, Carlo等人, The FASEB Journal, 2011；Nadigel, Prefontaine等人, Respiratory Research, 2011；Kovach及Standiford, International Immunopharmacology, 2011；Bauer, Shapiro等人, Mol Med, 2012；Deng, Yang等人, PLoS One, 2013；Freeman, Martinez等人, Respiratory Research, 2013；Dubaniewicz, A., Human Immunology, 2013)。TLR及IL-1R家族成員亦涉及其他發炎性疾病諸如過敏、貝西氏病、痛風、紅斑狼瘡、成人斯蒂爾病(adult-onset Still's disease)、心包炎及慢性發炎性腸病(諸如潰瘍性結腸炎及克羅恩氏病(Crohn's disease))、移植排斥及移植物抗宿主反應之發病機理，及因此此處IRAK4之抑制係適宜之預防及/或治療方法(Liu-Bryan, Scott等人, Arthritis & Rheumatism, 2005；Piggott, Eisenbarth等人, J Clin Inves, 2005；Christensen, Shupe等人, Immunity, 2006；Cario, Inflammatory Bowel Diseases, 2010；Nickerson, Christensen等人, The Journal of Immunology, 2010；Rakoff-Nahoum, Hao等人, Immunity, 2006；Heimesaat, Fischer等人, PLoS ONE, 2007；Heimesaat, Nogai等人, Gut, 2010；Kobori, Yagi等人, J Gastroenterol, 2010；Schmidt, Raghavan等人, Nat Immunol, 2010；Shi, Mucsi等人, Immunological Reviews, 2010；Leventhal及Schroppel, Kidney Int, 2012；Chen, Lin等人, Arthritis Res Ther, 2013；Hao, Liu等人, Curr Opin Gastroenterol, 2013；Kreisel及Goldstein, Transplant International, 2013；Li, Wang等人, Pharmacology & Therapeutics, 2013；Walsh, Carthy等人, Cytokine & Growth Factor Reviews, 2013；Zhu, Jiang等人, Autoimmunity, 2013；Yap及Lai, Nephrology, 2013；Vennegaard, Dyring-Andersen等人, Contact Dermatitis, 2014；D'Elia, Brucato等人, Clin Exp Rheumatol, 2015；Jain, Thongprayoon等人, Am J Cardiol., 2015；Li, Zhang等人, Oncol Rep., 2015)。
由TLR及IL-1R家族介導之婦科疾病，諸如子宮肌腺症、痛經、性交困難及子宮內膜異位症(特別是與子宮內膜異位症相關聯之疼痛及其他的與子宮內膜異位症相關聯之症狀(諸如痛經、性交疼痛、排尿困難及排便困難))可受到IRAK4抑制劑之預防及/或治療用途正面影響(Akoum, Lawson等人, Human Reproduction, 2007；Allhorn, Boing等人, Reproductive Biology and Endocrinology, 2008；Lawson, Bourcier等人, Journal of Reproductive Immunology, 2008；Sikora, Mielczarek-Palacz等人, American Journal of Reproductive Immunology, 2012；Khan, Kitajima等人, Journal of Obstetrics and Gynaecology Research, 2013；Santulli, Borghese等人, Human Reproduction, 2013)。IRAK4抑制劑之預防及/或治療用途亦可對動脈粥樣硬化具有正面影響(Seneviratne, Sivagurunathan等人, Clinica Chimica Acta, 2012；Falck-Hansen, Kassiteridi等人, International Journal of Molecular Sciences, 2013；Sedimbi, Hagglof等人, Cell Mol Life Sci, 2013)。
除了已提及的疾病外，已在眼病諸如視網膜缺血(retinal ischaemia)、角膜炎、過敏性結膜炎、乾燥性角膜結膜炎、黃斑變性及葡萄膜炎之發病機理中描述IRAK4介導之TLR過程(Kaarniranta及Salminen, J Mol Med (Berl), 2009；Sun及Pearlman, Investigative Ophthalmology & Visual Science, 2009；Redfern及McDermott, Experimental Eye Research, 2010；Kezic, Taylor等人, J Leukoc Biol, 2011；Chang, McCluskey等人, Clinical & Experimental Ophthalmology, 2012；Guo, Gao等人, Immunol Cell Biol, 2012；Lee, Hattori等人, Investigative Ophthalmology & Visual Science, 2012；Qi, Zhao等人, Investigative Ophthalmology & Visual Science, 2014)。
IRAK4之抑制亦係針對於纖維變性疾病，例如肝纖維化、心肌炎、原發性膽汁性肝硬化、囊性纖維化之適宜治療方法(Zhao, Zhao等人, Scand J Gastroenterol, 2011；Benias, Gopal等人, Clin Res Hepatol Gastroenterol, 2012；Yang, L.及E. Seki, Front Physiol, 2012；Liu, Hu等人, Biochim Biophys Acta., 2015)。
根據IRAK4在TLR-及IL-1R家族介導之疾病中具有的重要位置，可以使用IRAK4抑制劑之預防及/或治療方式治療慢性肝病，例如脂肪肝肝炎(且尤其非酒精性脂肪肝病(NAFLD)及/或非酒精性脂肪肝炎(NASH))、酒精性脂肪肝炎(ASH)(Nozaki, Saibara等人, Alcohol Clin Exp Res, 2004；Csak, T., A. Velayudham等人, Am J Physiol Gastrointest Liver Physiol, 2011；Miura, Kodama等人, Gastroenterology, 2010；Kamari, Shaish等人, J Hepatol, 2011；Ye, Li等人, Gut, 2012；Roh, Seki, J Gastroenterol Hepatol, 2013；Ceccarelli, S., V. Nobili等人, World J Gastroenterol, 2014；Miura, Ohnishi, World J Gastroenterol, 2014；Stojsavljevic, Palcic等人, World J Gastroenterol, 2014)。
由於IRAK4在TLR介導之過程中之重要角色，IRAK4之抑制亦可治療及/或預防心血管及神經疾病，例如心肌再灌注損傷、心肌梗塞、高血壓(Oyama, Blais等人, Circulation, 2004；Timmers, Sluijter等人, Circulation Research, 2008；Fang及Hu, Med Sci Monit, 2011；Bijani, International Reviews of Immunology, 2012；Bomfim, Dos Santos等人, Clin Sci (Lond), 2012；Christia及Frangogiannis, European Journal of Clinical Investigation, 2013；Thompson及Webb, Clin Sci (Lond), 2013；Hernanz, Martínez-Revelles等人, British Journal of Pharmacology, 2015；Frangogiannis, Curr Opin Cardiol, 2015；Bomfim, Echem等人, Life Sciences, 2015)、亦及阿茲海默氏症、中風、顱腦創傷、肌萎縮性側索硬化症(ALS)及帕金森氏症(Parkinson's)(Brough, Tyrrell等人, Trends in Pharmacological Sciences, 2011；Carty及Bowie, Biochemical Pharmacology, 2011；Denes, Kitazawa, Cheng等人, The Journal of Immunology, 2011；Lim, Kou等人, The American Journal of Pathology, 2011；Béraud及Maguire-Zeiss, Parkinsonism & Related Disorders, 2012；Denes, Wilkinson等人, Disease Models & Mechanisms, 2013；Noelker, Morel等人, Sci.Rep., 2013；Wang, Wang等人, Stroke, 2013；Xiang, Chao等人, Rev Neurosci, 2015；Lee, Lee等人, J Neuroinflammation, 2015)。
由於在瘙癢及疼痛(包括急性、慢性、發炎性及神經性疼痛)中涉及經由IRAK4之TLR介導之信號及IL-1受體家族介導之信號，故可認為通過IRAK4之抑制在所述適應症中具有治療效應。疼痛的實例包括痛覺過敏、痛覺異常、經前疼痛、與子宮內膜異位症相關聯之疼痛、術後疼痛、間質性膀胱炎、CRPS(複雜性區域疼痛症候群)、三叉神經痛、前列腺炎、由脊髓損傷誘發之疼痛、發炎誘發之疼痛、下背疼痛、癌症疼痛、與化學療法相關聯之疼痛、HIV治療誘發之神經病變、燒傷誘發之疼痛及慢性疼痛(Wolf, Livshits等人, Brain, Behavior, and Immunity, 2008；Kim, Lee等人, Toll-like Receptors:Roles in Infection and Neuropathology, 2009；del Rey, Apkarian等人, Annals of the New York Academy of Sciences, 2012；Guerrero, Cunha等人, European Journal of Pharmacology, 2012；Kwok, Hutchinson等人, PLoS ONE, 2012；Nicotra, Loram等人, Experimental Neurology, 2012；Chopra及Cooper, J Neuroimmune Pharmacol, 2013；David, Ratnayake等人, Neurobiology of Disease, 2013；Han, Zhao等人, Neuroscience, 2013；Liu及Ji, Pflugers Arch., 2013；Stokes, Cheung等人, Journal of Neuroinflammation, 2013；Zhao, Zhang等人, Neuroscience, 2013；Liu, Zhang等人, Cell Research, 2014；Park, Stokes等人, Cancer Chemother Pharmacol, 2014；Van der Watt, Wilkinson等人, BMC Infect Dis, 2014；Won, K. A., M. J. Kim等人, J Pain, 2014；Min, Ahmad等人, Photochem Photobiol., 2015；Schrepf, Bradley等人, Brain Behav Immun, 2015；Wong, L., J. D. Done等人, Prostate, 2015)。
此亦適用於一些腫瘤疾病。特定淋巴瘤(例如ABC-DLBCL(活化B細胞瀰漫性大細胞B細胞淋巴瘤)、套細胞淋巴瘤及華氏病(Waldenström's disease))亦及慢性淋巴白血病、黑色素瘤、胰臟腫瘤及肝細胞癌之特徵在於MyD88之突變或MyD88活性之改變，其可藉由IRAK4抑制劑來治療(Ngo, Young等人, Nature, 2011；Puente, Pinyol等人, Nature, 2011；Ochi, Nguyen等人, J Exp Med, 2012；Srivastava, Geng等人, Cancer Research, 2012；Treon, Xu等人, New England Journal of Medicine, 2012；Choi, Kim等人, Human Pathology, 2013；(Liang, Chen等人, Clinical Cancer Research, 2013)。此外，MyD88在ras依賴性腫瘤中發揮重要作用，及因此IRAK4抑制劑亦適用於其治療(Kfoury, A., K. L. Corf等人, Journal of the National Cancer Institute, 2013)。亦可認為通過IRAK4之抑制在乳癌、卵巢癌、結腸直腸癌、頭頸癌、肺癌、前列腺癌中具有治療效應，此乃因所述適應症與信號傳遞通路相關聯(Szczepanski, Czystowska等人, Cancer Res, 2009；Zhang, He等人, Mol Biol Rep, 2009；Wang, Qian等人, Br J Cancer Kim, 2010；Jo等人, World J Surg Oncol, 2012；Zhao, Zhang等人, Front Immunol, 2014；Chen, Zhao等人, Int J Clin Exp Pathol, 2015)。
發炎性疾病，諸如CAPS(與隱熱蛋白(cryopyrin)相關聯之週期性症候群)，包括FCAS(家族性冷因性自體發炎症候群)、MWS(穆克爾-韋二氏症候群(Muckle-Wells syndrome))、NOMID(新生兒多系統發炎性疾病)及CONCA(慢性嬰兒型、神經性、皮膚性及關節性)症候群；FMF(家族性地中海熱)、HIDS(高IgD症候群)、TRAPS(與腫瘤壞死因子受體1相關聯之週期性症候群)、幼年特發性關節炎、成人斯蒂爾病、貝塞特氏病(Adamantiades-Behçet's disease)、類風濕性關節炎、骨關節炎、乾燥性角膜結膜炎、PAPA症候群(化膿型關節炎、壞疽性膿皮病及痤瘡)、薛尼茲勒氏症候群(Schnitzler's syndrome)及修格連氏症候群係藉由阻斷IL-1信號通路得以治療；因此此處IRAK4抑制劑亦適用於治療所述疾病(Narayanan, Corrales等人, Cornea, 2008；Brenner, Ruzicka等人, British Journal of Dermatology, 2009；Henderson及Goldbach-Mansky, Clinical Immunology, 2010；Dinarello, European Journal of Immunology, 2011；Gul, Tugal-Tutkun等人, Ann Rheum Dis, 2012；Pettersson, Annals of MedicinePetterson, 2012；Ruperto, Brunner等人, New England Journal of Medicine, 2012；Nordström, Knight等人, The Journal of Rheumatology, 2012；Vijmasi, Chen等人, Mol Vis, 2013；Yamada, Arakaki等人, Opinion on Therapeutic Targets, 2013；de Koning, Clin Transl Allergy, 2014)。IL-33R之配位體IL-33特別涉及急性腎衰竭之發病機理，及因此IRAK4之抑制對於預防及/或治療而言係適宜治療方法(Akcay, Nguyen等人, Journal of the American Society of Nephrology, 2011)。IL-1受體家族之成員與心肌梗塞、不同肺病(諸如哮喘、COPD、特發性間質性肺炎、過敏性鼻炎、肺纖維化及急性呼吸窘迫症候群(ARDS))相關聯，及因此通過IRAK4之抑制預期在所述適應症中具有預防及/或治療作用(Kang, Homer等人, The Journal of Immunology, 2007；Imaoka, Hoshino等人, European Respiratory Journal, 2008；Couillin, Vasseur等人, The Journal of Immunology, 2009；Abbate, Kontos等人, The American Journal of Cardiology, 2010；Lloyd, Current Opinion in Immunology, 2010；Pauwels, Bracke等人, European Respiratory Journal, 2011；Haenuki, Matsushita等人, Journal of Allergy and Clinical Immunology, 2012；Yin, Li等人, Clinical & Experimental Immunology, 2012；Abbate, Van Tassell等人, The American Journal of Cardiology, 2013；Alexander-Brett等人, The Journal of Clinical Investigation, 2013；Bunting, Shadie等人, BioMed Research International, 2013；Byers, Alexander-Brett等人, The Journal of Clinical Investigation, 2013；Kawayama, Okamoto等人, J Interferon Cytokine Res, 2013；Martínez-González, Roca等人, American Journal of Respiratory Cell and Molecular Biology, 2013；Nakanishi, Yamaguchi等人, PLoS ONE, 2013；Qiu, Li等人, Immunology, 2013；Li, Guabiraba等人, Journal of Allergy and Clinical Immunology, 2014；Saluja, Ketelaar等人, Molecular Immunology, 2014；Lugrin, Parapanov等人, The Journal of Immunology, 2015)。
先前技術揭示許多IRAK4抑制劑(參見，例如，Annual Reports in Medicinal Chemistry (2014), 49, 117 – 133)。
US8293923及US20130274241揭示具有3-經取代吲唑結構之IRAK4抑制劑。未描述2-經取代吲唑。
WO2013106254及WO2011153588揭示2,3-經二取代吲唑衍生物。
WO2007091107描述用於治療裘馨型肌肉萎縮(Duchenne muscular dystrophy)之2-經取代吲唑衍生物。所揭示之化合物不具有6-羥基烷基取代。
WO2015091426描述在2位置經甲醯胺側鏈取代之吲唑，諸如實例64。
WO2015104662揭示以下通式之2-經取代吲唑：
其中R2
為烷基或環烷基。明確描述在2位置具有甲基、2-甲氧基乙基及環戊基之2-經取代吲唑(實例1、4及76)。亦藉由實例117描述在1位置具有羥乙基取代基之吲唑衍生物。然而，未描述在1位置或2位置具有3-羥基-3-甲基丁基取代基之吲唑衍生物。
在2位置具有經羥基取代之烷基之吲唑一般涵蓋於該通式中，但未明確揭示於WO2015104662中。
在2位置(於該位置，烷基另外經甲基磺醯基取代)具有烷基之吲唑未涵蓋於WO2015104662中之該通式及R2
取代基之定義中。
除了吲唑上1及2位置之上述取代模式外，WO2015104662描述在6位置具有取代之吲唑，其中R1
定義為以下：烷基、氰基、-NRa
Rb
或選自環烷基、芳基或雜環基之視需要經取代之基團，其中該等取代基獨立地為烷基、烷氧基、鹵素、羥基、羥烷基、胺基、胺基烷基、硝基、氰基、鹵烷基、鹵烷氧基、-OCOCH2
-O-烷基、-OP(O)(O-烷基)2
或-CH2
-OP(O)(O-烷基)2
。對於R1
為烷基之咪唑化合物，有效申請日為2015年1月7日(WO2015104662之國際申請日)。優先權被主張的印度申請案146/CHE/2014及3018/CHE/2014未揭示R1
為烷基之任何吲唑化合物。
因此，以下通式之吲唑化合物：
其中R1
為視需要經取代之烷基，首次在2015年1月7日及因此在本申請案之優先權申請日之後描述。
WO2015104662中針對R1
所述之6位置之取代基之實例為環丙基、環己基、氰基、3-氟苯基及飽和雜環取代基。在位置6具有經羥基取代之烷基之吲唑未明確述於WO2015104662中。
本發明所解決的問題係提供作為介白素-1受體相關激酶-4(IRAK4)之抑制劑之新穎化合物之問題。
該等新穎的IRAK4抑制劑尤其適用於治療及預防特徵為反應過度免疫系統之增生、代謝及發炎性疾病。此處應特別提及發炎性皮膚病、心血管疾病、肺病、眼病、神經疾病、疼痛病症及癌症。
此外，該等新穎的IRAK4抑制劑適用於治療及預防以下疾病：
● 自體免疫及發炎性疾病，尤其是類風濕性關節炎、多發性硬化症、全身性紅斑狼瘡、脊柱關節炎及痛風，
● 代謝疾病，尤其是肝病，諸如脂肪肝，及
● 婦科疾病，尤其是子宮內膜異位症及與子宮內膜異位症相關聯之疼痛及其他的與子宮內膜異位症相關聯之症狀(諸如痛經、性交疼痛、排尿困難及排便困難)。
本發明提供通式(I)之化合物
其中：
R1
為C1
-C6
烷基，於此情況中，該C1
-C6
烷基係未經取代或相同或不同地經
鹵素、羥基、未經取代或經單-或多鹵素取代之C3
-C6
環烷基、或R6
、R7
SO2
、R7
SO或R8
O基單-或多取代；
或選自以下之基團：
其中*表示該基團鍵結至該分子其餘部分之鍵結位點；
R2
及R3
始終具有相同定義且同時為氫或C1
-C6
烷基；
R4
為鹵素、氰基、未經取代或相同或不同地經單或多取代之C1
-C6
烷基或未經取代或相同或不同地經單或多取代之C3
-C6
環烷基，且該等取代基係選自鹵素及羥基之群；
R5
為氫、鹵素或未經取代或經單-或多鹵素取代之C1
-C6
烷基；
R6
為具有4至6個環原子之未經取代或經單-或二甲基取代之單環飽和雜環，其含有選自O、S、SO及SO2
之群之雜原子或雜基；
R7
為C1
-C6
烷基，於此情況中，該C1
-C6
烷基係未經取代或相同或不同地經鹵素、羥基或C3
-C6
環烷基單-或多取代，
或R7
為C3
-C6
環烷基；
R8
為C1
-C6
烷基，於此情況中，該C1
-C6
烷基係未經取代或相同或不同地經鹵素單-或多取代；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
就本發明之述於後文之合成中間物及工作實例而言，指定的呈對應鹼或酸之鹽形式之任何化合物一般為未知的確切化學計量組成之鹽，如藉由各別製法及/或純化製程獲得。除非更詳細地指明，否則除名稱及結構式以外者，諸如「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x HCl」、「x CF3
COOH」、「x Na+
」因此不應在此等鹽之化學計量意義上理解，但僅具有關於其中提出的鹽形成組分之描述性字元。
此相應地適用，若合成中間物或工作實例或其鹽藉由所述製備及/或純化製程呈未知化學計量組成之溶劑合物例如水合物(若其係所定義的類型)形式獲得。
本發明化合物為式(I)之化合物及其鹽、溶劑合物及鹽之溶劑合物、式(I)所涵蓋且具有如下文所述式之化合物及其鹽、溶劑合物及鹽之溶劑合物及式(I)所涵蓋且下文描述作實施例之化合物及其鹽、溶劑合物及鹽之溶劑合物，若該等式(I)所涵蓋且在下文述及之化合物不係鹽、溶劑合物及鹽之溶劑合物。
本發明背景內容中之較佳鹽為本發明化合物之生理上可接受之鹽。然而，本發明亦涵蓋本身不適於醫藥應用但可例如用於單離或純化本發明化合物之鹽。
本發明化合物之生理上可接受之鹽包括礦酸、羧酸及磺酸之酸加成鹽，例如，下列酸之鹽：鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、蘋果酸、檸檬酸、富馬酸、馬來酸及苯甲酸。
本發明化合物之生理上可接受之鹽亦包括習知鹼之鹽，例如且較佳者係鹼金屬鹽(例如鈉鹽及鉀鹽)、鹼土金屬鹽(例如鈣鹽及鎂鹽)及衍生自氨或具有1至16個碳原子之有機胺(例如且較佳者係乙胺、二乙胺、三乙胺、乙基二異丙基胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲基胺基乙醇、普魯卡因、二苄基胺、N-甲基嗎啉、精胺酸、離胺酸、乙二胺及N-甲基哌啶)之銨鹽。
本發明背景內容中之溶劑合物描述作本發明化合物與溶劑分子配位形成固態或液態複合物之彼等形式。水合物為溶劑合物與水配位之特定形式。
本發明化合物可根據其結構呈不同立體異構形式，亦即，呈構形異構體抑或若適宜則呈構象異構體(對映體及/或非鏡像異構體，包括阻轉異構體情況之彼等)形式存在。本發明因此涵蓋對映體及非鏡像異構體及其各自混合物。可以已知方法自對映體及/或非鏡像異構體之此等混合物單離該等立體異構均質成分；為此目的，較佳使用層析法，尤其係於非對掌性或對掌性相上之HPLC層析法。
若本發明化合物可呈互變異構形式存在，則本發明涵蓋所有互變異構形式。
本發明亦涵蓋本發明化合物之所有適宜同位素變體。本發明化合物之同位素變體在此處應理解為意指本發明化合物中之至少一個原子經過相同原子序數但原子質量與通常或主要在自然中存在之原子質量不同之另一原子交換之化合物。可併入本發明化合物中之同位素之實例為氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之彼等，諸如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I及131I。本發明化合物之特定同位素變體，諸如，特定言之，彼等已併入一或多個放射性同位素者可有益於例如作用機制或體內活性成分分佈之檢查；由於相對的製備容易度及可偵測性，特定言之，經3H或14C同位素標記之化合物適用於此目的。此外，同位素例如氘之併入可導致由於化合物之較大代謝穩定性，例如體內半衰期之延長或所需活性劑量之減少所致之特定治療益處；本發明化合物之此等修飾因此可在一些情況中亦構成本發明之較佳實施例。可由熟悉此項技術者已知的製程，例如，由進一步述於下文之方法及述於工作實例中之程序，藉由使用各別試劑及/或起始化合物之對應同位素修飾來製備本發明化合物之同位素變體。
本發明進一步提供本發明化合物之所有可能的結晶及多晶形式，其中該等多晶型物可呈在所有濃度範圍內之單一多晶型物或複數種多晶型物之混合物形式存在。
本發明另外亦涵蓋本發明化合物之前藥。術語「前藥」在該情況中係指可本身為生物活性或非活性但在其體內停留時間期(例如經過代謝或經過水解)轉化為本發明化合物之化合物。
在本發明之背景內容中，除非另作指明，否則取代基具有以下含義：烷基
在本發明之背景內容中表示具有指定的特定碳原子數之直鏈或分支鏈烷基。實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、1-甲基丙基、2-甲基丙基、第三丁基、正戊基、1-乙基丙基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基及2-乙基丁基。較佳者係甲基、乙基、正丙基、正丁基、2-甲基丁基、3-甲基丁基及2,2-二甲基丙基。環烷基
在本發明之背景內容中為具有各情況中指定的碳原子數之單環飽和烷基。較佳的實例包括環丙基、環丁基、環戊基及環己基。 烷氧基
在本發明之背景內容中表示具有指定的特定碳原子數之直鏈或分支鏈烷氧基。1至6個碳原子為較佳。實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、1-甲基丙氧基、正丁氧基、異丁氧基、第三丁氧基、正戊氧基、異戊氧基、1-乙基丙氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基及正己氧基。尤佳者為具有1至4個碳原子之直鏈或分支鏈烷氧基。可描述作較佳者之實例為甲氧基、乙氧基、正丙氧基、1-甲基丙氧基、正丁氧基及異丁氧基。鹵素
在本發明之背景內容中為氟、氯及溴。較佳者為氟。羥基
在本發明之背景內容中為OH。單化飽和雜環
為具有4至6個環原子且含有選自O、S、SO及SO2
之群之雜原子或雜基之單環飽和雜環。具有選自O、SO及SO2
之群之雜原子或雜基之雜環為較佳。實例包括：氧雜環丁烷、四氫呋喃、四氫-2H-吡喃-4-基、1,1-二氧代四氫-2H-硫基吡喃-3-基、1,1-二氧代四氫-2H-硫基吡喃-2-基、1,1-二氧代四氫-2H-硫基吡喃-4-基、1,1-二氧代四氫噻吩-3-基、1,1-二氧代四氫噻吩-2-基、1,1-二氧代硫雜環丁-2-基或1,1-二氧代硫雜環丁-3-基。其中尤佳者為氧雜環丁烷及四氫呋喃。極佳者為氧雜環丁-3-基。
鍵結處之符號*表示分子中之鍵結位點。
當本發明化合物中之基團經取代時，除非另作指明，否則該等基團可係經單-或多取代。在本發明之背景內容中，所有多於一次出現的基團係彼此獨立地定義。經一個、兩個或三個相同或不同取代基取代為較佳。
R1
之一較佳實施例為經1個、2個或3個氟原子取代之C2
-C6
烷基。尤佳者為2,2,2-三氟乙基、3,3,3-三氟丙基及4,4,4-三氟丁基。極佳者為4,4,4-三氟丁基。
R1
之另一較佳實施例為經一或兩個羥基或一個C1
-C3
烷氧基或經三氟取代之C1
-C3
烷氧基取代之C2
-C6
烷基。尤佳者為經羥基或C1
-C3
烷氧基或三氟甲氧基或2,2,2-三氟乙氧基取代之C2
-C5
烷基。極佳者為3-羥基-3-甲基丁基、3-甲氧基丙基、3-羥丙基、3-三氟甲氧基丙基、2-甲氧基乙基或2-羥乙基。尤佳者為3-羥基-3-甲基丁基。
更佳地，R1
為經C1
-C6
-烷基-SO2
基取代之C2
-C6
烷基。經甲基-SO2
-取代之C2
-C4
烷基為特別佳。尤佳的R1
為2-(甲基磺醯基)乙基或3-(甲基磺醯基)丙基。就後一基團而言，2-(甲基磺醯基)乙基為特別佳。
又較佳地，R1
為經以下基團取代之C1
-C3
烷基：氧雜環丁基、四氫呋喃基、四氫-2H-吡喃-4-基、1,1-二氧代四氫-2H-硫基吡喃-3-基、1,1-二氧代四氫-2H-硫基吡喃-2-基、1,1-二氧代四氫-2H-硫基吡喃-4-基、1,1-二氧代四氫噻吩-3-基、1,1-二氧代四氫噻吩-2-基、1,1-二氧代硫雜環丁-2-基或1,1-二氧代硫雜環丁-3-基。尤佳者為經氧雜環丁基取代之C1
-C3
烷基。尤佳之R1
為氧雜環丁-3-基甲基。
對於始終具有相同定義之R2
及R3
，氫或甲基為較佳。甲基為特佳。
就R4
而言，較佳者為未經取代或經單-或多鹵素取代之C1
-C3
烷基或經一個羥基取代之C1
-C3
烷基或經一個羥基及三個氟原子取代之C1
-C3
烷基。
對於R4
，尤佳者為以下基團：甲基、乙基、三氟-C1
-C3
烷基、二氟-C1
-C3
烷基、羥甲基、1-羥乙基、2-羥丙-2-基及2,2,2-三氟-1-羥乙基。對於R4
，尤佳者為甲基、三氟甲基及二氟甲基。此處尤佳者為三氟甲基。
R5
之一較佳實施例為氫、氟、氯或C1
-C3
烷基。更佳地，R5
為氫、氟或甲基。最佳地，R5
為氫或氟。
尤佳者亦為其中R4
為甲基或三氟甲基及R5
為氟之化合物。極佳者為其中R4
為甲基及R5
為氟之化合物，其中R5
係在R4
之鄰位。
對於R6
，較佳的實施例包括氧雜環丁基、四氫呋喃基、四氫-2H-吡喃-4-基、1,1-二氧代四氫-2H-硫基吡喃-3-基、1,1-二氧代四氫-2H-硫基吡喃-2-基、1,1-二氧代四氫-2H-硫基吡喃-4-基、1,1-二氧代四氫噻吩-3-基、1,1-二氧代四氫噻吩-2-基、1,1-二氧代硫雜環丁-2-基或1,1-二氧代硫雜環丁-3-基。其中尤佳為氧雜環丁基。極佳為氧雜環丁-3-基。
R7
僅連接至官能基-SO2
-及-SO-，亦即，為經R7
取代之-SO2
-或SO基。在該連接中，R7
較佳為C1
-C4
烷基，其中該C1
-C4
烷基係未經取代或經羥基或經環丙基單取代或經三個氟原子取代。又較佳的R7
為環丙基。尤佳的R7
為甲基、乙基或羥乙基。極佳的R7
為甲基。
此意指，就經R7
SO2
-或R7
SO-取代之C1
-C6
烷基而言，在R1
之背景內容中，較佳者為經C1
-C6
-烷基-SO2
或C1
-C6
-烷基-SO取代之C1
-C6
烷基。對於R1
，此處較佳者尤其為甲基磺醯基乙基及甲基磺醯基丙基。其中極佳者為甲基磺醯基乙基。
對於R8
，較佳者為未經取代之C1
-C4
烷基或經三氟取代之C1
-C4
烷基。尤佳者為甲基、乙基、三氟甲基或2,2,2-三氟乙基。極佳者為甲基、三氟甲基或2,2,2-三氟乙基。
較佳者為式(I)之化合物，其中
R1
為C1
-C6
烷基，於此情況中，該C1
-C6
烷基係未經取代或相同或不同地經氟、羥基或R6
、R7
SO2
、R7
SO或R8
O基單-或多取代；
R2
及R3
始終具有相同定義且同時為氫或C1
-C3
烷基；
R4
為鹵素、氰基或C1
-C3
烷基，於此情況中，該C1
-C3
烷基係未經取代或相同或不同地經鹵素或羥基單-或多取代；
R5
為氫、氟、氯或C1
-C3
烷基；
R6
為氧雜環丁基或四氫呋喃基；
R7
為C1
-C4
烷基，於此情況中，該C1
-C4
烷基係未經取代或經羥基或經環丙基單取代或經三個氟原子取代；
R8
為未經取代之C1
-C4
烷基或經三氟取代之C1
-C4
烷基；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
較佳者另外為式(I)之化合物，其中
R1
為C2
-C6
烷基，於此情況中，C2
-C6
烷基係未經取代，或
C2
-C6
烷基係經單-、二-或三氟取代或
C2
-C6
烷基係經羥基、R6
、R7
SO2
或R8
O單取代，
或其中R1
為經氧雜環丁基取代之C1
-C3
烷基；
R2
及R3
始終具有相同定義且同時為氫或甲基；
R4
為未經取代或經單-或多鹵素取代之C1
-C3
烷基或經一個羥基取代之C1
-C3
烷基或經一個羥基及三個氟原子取代之C1
-C3
烷基；
R5
為氫、氟或C1
-C3
烷基；
R7
為C1
-C3
烷基；
R8
為C1
-C4
烷基，於此情況中，該C1
-C4
烷基係未經取代或經單-、二-或三氟取代；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
尤佳者亦為通式(I)之化合物，其中
R1
為經羥基或C1
-C3
烷氧基或三氟甲氧基或2,2,2-三氟乙氧基或三氟甲基取代之C2
-C5
烷基或
為經甲基-SO2
取代之C2
-C4
烷基或
為經氧雜環丁-3-基取代之C1
-C2
烷基；
R2
及R3
始終具有相同定義且同時為氫或甲基；
R4
為甲基、乙基、三氟-C1
-C3
烷基、二氟-C1
-C3
烷基、羥甲基、1-羥乙基、2-羥丙-2-基及2,2,2-三氟-1-羥乙基及
R5
為氫、氟或甲基；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
極佳者為化合物，其中
R1
為4,4,4-三氟丁基、3-羥基-3-甲基丁基、3-羥丁基、3-甲氧基丙基、3-羥丙基、3-羥基-2-甲基丙基、3-羥基-2,2-二甲基丙基、3-三氟甲氧基丙基、2-甲氧基乙基、2-羥乙基、2-(甲基磺醯基)乙基或3-(甲基磺醯基)丙基；
R2
及R3
同時為甲基或氫及
R4
為二氟甲基、三氟甲基或甲基及
R5
為氫或氟；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
極佳者亦為化合物，其中
R1
為3-羥基-3-甲基丁基、3-羥丁基、3-羥基-2-甲基丙基、
3-羥基-2,2-二甲基丙基、3-(甲基磺醯基)丙基或2-(甲基磺醯基)乙基；
R2
及R3
同時為甲基；
R4
為二氟甲基或三氟甲基；及
R5
為氫；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
尤佳者亦另外為化合物，其中
R1
為3-羥基-3-甲基丁基、3-羥丁基、3-羥基-2-甲基丙基、
3-羥基-2,2-二甲基丙基、3-(甲基磺醯基)丙基或2-(甲基磺醯基)乙基；
R2
及R3
同時為甲基；
R4
為甲基及
R5
為氟，於此情況中，R5
係在R4
的鄰位；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
本發明尤其提供以下化合物：
1) N-[6-(2-羥丙-2-基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
2) N-[6-(羥甲基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
3) N-[6-(2-羥丙-2-基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
4) N-[6-(羥甲基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
5) N-[2-(2-羥乙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
6) N-[6-(2-羥丙-2-基)-2-(3-羥丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
7) N-[2-(2-羥乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
8) N-[6-(2-羥丙-2-基)-2-(氧雜環丁-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
9) N-[6-(羥甲基)-2-(氧雜環丁-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
10) N-{6-(2-羥丙-2-基)-2-[3-(甲基磺醯基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺
11) N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
12) N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺
13) 6-(二氟甲基)-N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]吡啶-2-甲醯胺
14) 6-(二氟甲基)-N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}吡啶-2-甲醯胺
15) 6-(二氟甲基)-N-[6-(2-羥丙-2-基)-2-(3-羥丙基)-2H-吲唑-5-基]吡啶-2-甲醯胺
16) N-[6-(2-羥丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
17) N-{6-(2-羥丙-2-基)-2-[3-(三氟甲氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺
18) N-{6-(2-羥丙-2-基)-2-[3-(2,2,2-三氟乙氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺
19) 5-氟-N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲醯胺
20) N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲醯胺
21) 6-(2-羥丙-2-基)-N-[6-(2-羥丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]吡啶-2-甲醯胺
22) N-{2-[2-(1-羥基環丙基)乙基]-6-(2-羥丙-2-基)-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺。
本發明進一步提供一種自通式(II)之化合物製備通式(III)之化合物之方法，
其中
R1
為4,4,4-三氟丁基、3-羥基-3-甲基丁基、3-甲氧基丙基、3-羥丙基、3-羥基-2-甲基丙基、3-羥基-2,2-二甲基丙基、3-三氟甲氧基丙基、2-甲氧基乙基、2-羥乙基、2-(甲基磺醯基)乙基、3-(甲基磺醯基)丙基或2-(1-羥基環丙基)乙基；
R4
為二氟甲基、三氟甲基或甲基；及
R5
為氫或氟；
該方法係藉由使(II)與經適當取代之烷基鹵化物或4-甲基苯磺酸烷酯在碳酸鉀之存在下反應。
本發明進一步提供通式(III)之化合物
其中
R1
為4,4,4-三氟丁基、3-羥基-3-甲基丁基、3-甲氧基丙基、3-羥丙基、3-羥丁基、3-羥基-2-甲基丙基、3-羥基-2,2-二甲基丙基、3-三氟甲氧基丙基、2-甲氧基乙基、2-羥乙基、2-(甲基磺醯基)乙基、3-(甲基磺醯基)丙基或2-(1-羥基環丙基)乙基；
R4
為二氟甲基、三氟甲基或甲基；及
R5
為氫或氟；
及其非鏡像異構體、對映體、代謝物、鹽、溶劑合物或鹽之溶劑合物。
較佳者尤其為通式(III)之以下化合物：
5-{[(5-氟-6-甲基吡啶-2-基)羰基]胺基}-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯及
2-(3-羥基-3-甲基丁基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯。
通式(III)之化合物適用於製備一部分的通式(I)之化合物。
另外，通式(III)之化合物為介白素-1受體相關激酶-4(IRAK4)之抑制劑。
本發明進一步提供一種自式(III)之化合物藉由與溴化甲基鎂之格林納反應(Grignard reaction)來製備通式(I)之本發明化合物之方法
其中
R1
為4,4,4-三氟丁基、3-羥基-3-甲基丁基、3-羥丁基、3-甲氧基丙基、3-羥丙基、3-羥基-2-甲基丙基、3-羥基-2,2-二甲基丙基、3-三氟甲氧基丙基、2-甲氧基乙基、2-羥乙基、3-(甲基磺醯基)丙基2-(1-羥基環丙基)乙基；
R2
及R3
為甲基；
R4
為二氟甲基、三氟甲基或甲基；及
R5
為氫或氟。
本發明化合物作為IRAK4激酶之抑制劑且具有不可預見的有效藥理學活性譜。
因此，除了上述標的外，本發明亦提供一種以本發明化合物於治療及/或預防人及動物中疾病之用途。
用本發明IRAK4抑制劑治療及/或預防婦科疾病、發炎性皮膚病、心血管疾病、肺病、眼病、自體免疫疾病、疼痛病症、代謝疾病、痛風、肝病、代謝症候群、胰島素抗性及癌症特別佳。
本發明化合物適用於預防及/或治療各種疾病及疾病相關狀態，尤其是由TLR(除了TLR3外)及/或IL-1受體家族介導之疾病及/或病理由IRAK4直接介導之疾病。與IRAK4相關聯之疾病包括多發性硬化症、動脈粥樣硬化、心肌梗塞、阿茲海默氏症、病毒誘發之心肌炎、痛風、伏格特-小柳-原田症候群、紅斑狼瘡、牛皮癬、脊柱關節炎及關節炎。
本發明化合物亦可用於預防及/或治療由MyD88及TLR(除了TLR3外)介導之疾病。此包括多發性硬化症、類風濕性關節炎、脊柱關節炎(特別是牛皮癬性脊柱關節炎及別赫捷列夫氏病)、代謝症候群(胰島素抗性、糖尿病、骨關節炎、修格連氏症候群、巨細胞動脈炎、敗血症、多發性皮肌炎及皮肌炎)、皮膚病(諸如牛皮癬、異位性皮膚炎、斑禿、反常型痤瘡及尋常型痤瘡)、肺病(諸如肺纖維化、慢性阻塞性肺病(COPD)、急性呼吸窘迫症候群(ARDS)、急性肺損傷(ALI)、間質性肺病(ILD)、類肉瘤病及肺動脈高壓症)。
由於本發明化合物之作用機制，因此其等適用於預防及/或治療TLR介導之疾病：貝西氏病、痛風、子宮內膜異位症及與子宮內膜異位症相關聯之疼痛及其他的與子宮內膜異位症相關聯之症狀(諸如痛經、性交疼痛、排尿困難及排便困難)。此外，本發明化合物適用於預防及/或治療移植排斥、紅斑狼瘡、成人斯蒂爾病及慢性發炎性腸病(諸如潰瘍性結腸炎及克羅恩氏病)之病例。
除了已經列出的疾病外，本發明化合物之用途亦適用於治療及/或預防以下疾病：眼病，諸如角膜炎、過敏性結膜炎、乾燥性角膜結膜炎、黃斑變性及葡萄膜炎；心血管疾病，諸如動脈粥樣硬化、心肌再灌注損傷、心肌梗塞、高血壓；及神經疾病(諸如阿茲海默氏症、中風及帕金森氏症)。
本發明化合物之作用機制亦可預防及/或治療由TLR及IL-1受體家族介導之肝病，特別是NAFLD、NASH、ASH、肝纖維化及肝硬化。
本發明化合物亦可預防及/或治療瘙癢及疼痛，尤其是急性、慢性、發炎性及神經性疼痛。
由於本發明化合物之作用機制，因此其等適用於預防及/或治療腫瘤疾病，諸如淋巴瘤、慢性淋巴性白血病、黑色素瘤及肝細胞癌、乳癌、前列腺癌及Ras依賴性腫瘤。
除此之外，本發明化合物適用於治療及/或預防經由IL-1受體家族介導之疾病。此等疾病包括CAPS(與隱熱蛋白相關聯之週期性症候群)，包括FCAS(家族性冷因性自體發炎症候群)、MWS(穆克爾-韋二氏症候群)、NOMID(新生兒多系統發炎性疾病)及CONCA(慢性嬰兒型、神經性、皮膚性及關節性)症候群、FMF(家族性地中海熱)、HIDS(高IgD症候群)、TRAPS(與腫瘤壞死因子受體1相關聯之週期性症候群)、幼年特發性關節炎、成人斯蒂爾病、貝塞特氏病、類風濕性關節炎、牛皮癬、關節炎、別赫捷列夫氏病、骨關節炎、乾燥性角膜結膜炎及修格連氏症候群、多發性硬化症、紅斑狼瘡、斑禿、1型糖尿病、2型糖尿病及心肌梗塞後遺症。肺病(諸如哮喘、COPD、特發性間質性肺炎及ARDS)、婦科疾病(諸如子宮內膜異位症及與子宮內膜異位症相關聯之疼痛及其他的與子宮內膜異位症相關聯之症狀(諸如痛經、性交困難、排尿困難及排便困難))、慢性發炎性腸病(諸如克羅恩氏病及潰瘍性結腸炎)係與IL-1受體家族之失調相關聯且適於本發明化合物之治療及/或預防用途。
本發明化合物亦可用於治療及/或預防IL-1受體家族介導之神經疾病(諸如中風、阿茲海默氏症、顱腦創傷)及皮膚疾病(諸如牛皮癬、異位性皮膚炎、反常型痤瘡、斑禿及過敏性接觸性皮膚炎)。
此外，本發明化合物適用於治療及/或預防疼痛病症，尤其是急性、慢性、發炎性及神經性疼痛。此較佳包括痛覺過敏、痛覺異常、來自關節炎(諸如骨關節炎、類風濕性關節炎及脊柱關節炎)之疼痛、經前疼痛、與子宮內膜異位症相關聯之疼痛、術後疼痛、來自間質性膀胱炎之疼痛、CRPS(複雜性區域疼痛症候群)、三叉神經痛、來自前列腺炎之疼痛、由脊髓損傷誘發之疼痛、發炎誘發之疼痛、下背疼痛、癌症疼痛、與化學療法相關聯之疼痛、HIV治療誘發之神經病變、燒傷誘發之疼痛及慢性疼痛。
本發明亦進一步提供一種使用有效量之至少一種本發明化合物治療及/或預防疾病(尤其是上述疾病)之方法。
在本發明之背景內容中，術語「治療」包括抑制、延遲、檢查、緩解、減緩、限制、減輕、制止、抵制或治癒疾病、病症、病狀、損傷或健康問題、或此等狀態及/或此等狀態之症狀之發展、病程或進程。術語「療法」在此處應理解為與術語「治療」同義。
術語「防止」、「預防」及「阻止」在本發明之背景內容中係同義使用且係指避免或降低感染、經歷、遭受或罹患疾病、病症、病狀、損傷或健康問題之風險、或此等狀態及/或此等狀態之症狀之發展或進展之風險。
疾病、病症、病狀、損傷或健康問題之治療或預防可係部分或完全的。
本發明化合物可單獨或若需要則與其他活性成分組合使用。本發明進一步提供含有至少一種本發明化合物及一或多種其他活性成分(尤其用於治療及/或預防上述疾病之活性成分)之藥劑。適於組合之活性成分之較佳實例包括：
一般可提及諸如以下活性成分：抗細菌劑(例如青黴素、萬古黴素(vancomycin)、環丙沙星(ciprofloxacin))、抗病毒劑(例如阿昔洛韋(aciclovir)、奧司他韋(oseltamivir))及抗黴劑(例如萘替芬(naftifin)、制黴菌素(nystatin))物質及γ球蛋白、免疫調節及免疫抑制化合物(諸如環孢菌素、Methotrexat®)、TNF拮抗劑(例如Humira®、伊那西普(Etanercept)、英夫利昔單抗(Infliximab))、IL-1抑制劑(例如阿那白滯素(Anakinra)、卡那單抗(Canakinumab)、利洛納塞(Rilonacept))、磷酸二酯酶抑制劑(例如阿普斯特(Apremilast))、Jak/STAT抑制劑(例如托法替尼(Tofacitinib)、巴瑞西替尼(Baricitinib)、GLPG0634)、來氟米特(leflunomid)、環磷醯胺、利妥昔單抗(rituximab)、貝利木單抗(belimumab)、他克莫司(tacrolimus)、雷帕黴素(rapamycin)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、干擾素、皮質類固醇(例如強的松(prednisone)、脫氫皮質醇(prednisolone)、甲潑尼龍(methylprednisolone)、氫化可的松(hydrocortisone)、倍他米松(betamethasone))、環磷醯胺、硫唑嘌呤(azathioprine)及柳氮磺胺吡啶(sulfasalazine)；對乙醯胺基酚(paracetamol)、非類固醇消炎藥(NSAIDS)(阿斯匹靈(aspirin)、布洛芬(ibuprofen)、奈普生(naproxen)、依托度酸(etodolac)、塞來考昔(celecoxib)、秋水仙素(colchicine))。
腫瘤療法提及下列：免疫療法(例如阿地白介素(aldesleukin)、阿來組單抗(alemtuzumab)、巴利昔單抗(basiliximab)、凱妥昔單抗(catumaxomab)、西莫白介素(celmoleukin)、地尼白介素(denileukin diftitox)、艾庫組單抗(eculizumab)、依決洛單抗(edrecolomab)、吉妥珠單抗(gemtuzumab)、替伊莫單抗(ibritumomab tiuxetan)、咪喹莫特(imiquimod)、干擾素α、干擾素β、干擾素γ、易普利單抗(ipilimumab)、來那度胺(lenalidomide)、雷諾格拉斯蒂姆(lenograstim)、米伐木肽(mifamurtide)、奧法妥木單抗(ofatumumab)、奧普瑞白介素(oprelvekin)、畢西巴尼(picibanil)、普樂沙福(plerixafor)、多醣-K、沙格司亭(sargramostim)、西普魯塞-T(sipuleucel-T)、他索納明(tasonermin)、替西白介素(teceleukin)、托珠單抗(tocilizumab))、抗增生劑(例如(但非排他地)安吖啶(amsacrine)、阿格拉賓(arglabin)、三氧化二砷、天冬醯胺酸酶、博來黴素(bleomycin)、白消安(busulfan)、放線菌素D(dactinomycin)、多西他賽(docetaxel)、表柔比星(epirubicin)、培洛黴素(peplomycin)、曲妥珠單抗(trastuzumab)、利妥昔單抗、奧比妥珠單抗(obinutuzumab)、奧法妥木單抗(ofatumumab)、托西奠單抗(tositumomab))、芳香酶抑制劑(例如依西美坦(exemestane)、法屈唑(fadrozole)、福美斯坦(formestane)、來曲唑(letrozole)、阿那曲唑(anastrozole)、伏氯唑(vorozole))、抗雌激素藥(例如氯地孕酮(chlormadinone)、氟維司群(fulvestrant)、美雄烷(mepitiostane)、他莫昔芬(tamoxifen)、托瑞米芬 (toremifen))、雌激素藥(例如雌二醇、聚磷酸雌二醇、雷洛昔芬(raloxifen))、促孕激素(例如甲羥孕酮、甲地孕酮)、拓撲異構酶I抑制劑(例如伊立替康(irinotecan)、拓撲替康(topotecan))、拓撲異構酶II抑制劑(例如氨柔比星(amrubicin)、柔紅黴素(daunorubicin)、依利醋銨(elliptiniumacetate)、依託泊苷(etoposide)、伊達比星(idarubicin)、米托蒽醌(mitoxantrone)、替尼泊苷(teniposide))、微管活性物質(例如卡巴他賽(cabazitaxel)、艾日布林(eribulin)、太平洋紫衫醇(paclitaxel)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春瑞濱(vinorelbine))、端粒酶(telomerase)抑制劑(例如伊美司他(imetelstat))、烷基化物質及組蛋白脫乙醯酶抑制劑(例如苯達莫司汀(bendamustine)、卡莫司汀(carmustine)、氮芥(chlormethine)、達卡巴嗪(dacarbazine)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、洛莫司汀(lomustine)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、潑尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、雷莫司汀(ranimustine)、鏈佐黴素(streptozotocin)、替莫唑胺(temozolomide)、噻替哌(thiotepa)、曲奧蘇凡(treosulfan)、曲磷胺(trofosfamide)、伏立諾他(vorinostat)、羅咪酯肽(romidepsin)、帕比司他(panobinostat))；影響細胞分化過程之物質(諸如阿巴瑞克(abarelix)、胺基穀硫胺(aminoglutethimide)、貝沙羅汀(bexarotene))、MMP抑制劑(肽模擬物、非肽模擬物及四環素，例如馬立馬司他(marimastat)、BAY 12-9566、BMS-275291、氯膦酸鹽(clodronate)、普馬司他(prinomastat)、多西環素(doxycycline))、mTOR抑制劑(例如西羅莫司(sirolimus)、依維莫司(everolimus)、替西羅莫司(temsirolimus)、唑他莫司(zotarolimus))、抗代謝物(例如克羅拉濱(clofarabine)、去氧氟尿苷(doxifluridine)、甲胺喋呤(methotrexate)、5-氟尿嘧啶、克拉屈濱(cladribine)、阿糖胞苷(cytarabine)、氟達拉濱(fludarabine)、巰基嘌呤、甲胺喋呤、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、替加氟(tegafur)、硫鳥嘌呤(tioguanine))、鉑化合物(例如卡鉑、順鉑(cisplatin)、順鉑(cisplatinum)、依鉑(eptaplatin)、樂鉑(lobaplatin)、米鉑(miriplatin)、奈達鉑(nedaplatin)、奧沙利鉑(oxaliplatin))；抗血管生成化合物(例如貝伐單抗(bevacizumab))、抗雄激素化合物(例如貝伐單抗、恩雜魯胺(enzalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、環丙孕酮(cyproterone)、乙酸環丙孕酮)、蛋白酶體抑制劑(例如硼替佐米(bortezomib)、卡非佐米(carfilzomib)、奧普佐米(oprozomib)、ONYX0914)、促性腺素釋放素促效劑及拮抗劑(例如阿巴瑞克(abarelix)、布舍瑞林(buserelin)、地洛瑞林(deslorelin)、加尼瑞克(ganirelix)、戈舍瑞林(goserelin)、組胺瑞林(histrelin)、曲普瑞林(triptorelin)、地加瑞克(degarelix)、亮丙瑞林(leuprorelin))、甲硫胺酸胺肽酶抑制劑(例如苯甲醯胺衍生物、TNP-470、PPI-2458)、肝素酶抑制劑(例如SST0001、PI-88)；抗基因改造Ras蛋白之抑制劑(例如法尼基轉移酶抑制劑，諸如洛那法尼(lonafarnib)、替吡法尼(tipifarnib))、HSP90抑制劑(例如膠達那黴素(geldamycin)衍生物，諸如17-烯丙基胺基膠達那黴素、17-去甲氧基膠達那黴素(17AAG)、17-DMAG、鹽酸瑞他黴素(retaspimycin hydrochloride)、IPI-493、AUY922、BIIB028、STA-9090、KW-2478)、紡錘體驅動蛋白(kinesin spindle protein)抑制劑(例如SB715992、SB743921、噴他脒(pentamidine)/氯丙嗪(chlorpromazine))、MEK(絲裂原活化蛋白激酶激酶)抑制劑(例如曲美替尼(trametinib)、BAY 86-9766(瑞法替尼(refametinib))、AZD6244)、激酶抑制劑(例如：索拉非尼(sorafenib)、瑞格菲尼(regorafenib)、拉帕替尼(lapatinib)、Sutent®、達沙替尼(dasatinib)、西妥昔單抗(cetuximab)、BMS-908662、GSK2118436、AMG 706、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、伊馬替尼(imatinib)、尼勒替尼(nilotinib)、帕唑帕尼(pazopanib)、羅尼克尼(roniciclib)、蘇尼替尼(sunitinib)、凡德他尼(vandetanib)、維羅非尼(vemurafenib))、刺猬信號傳遞抑制劑(例如環巴胺(cyclopamine)、維莫德吉(vismodegib))、BTK(Bruton酪胺酸激酶)抑制劑(例如依布魯替尼(ibrutinib))、JAK/pan-JAK(janus激酶)抑制劑(例如SB-1578、巴瑞西替尼(baricitinib)、托法替尼(tofacitinib)、帕林替尼(pacritinib)、莫美替尼(momelotinib)、魯索利替尼(ruxolitinib)、VX-509、AZD-1480、TG-101348)、PI3K抑制劑(例如BAY 1082439、BAY 80-6946(庫潘尼西(copanlisib))、ATU-027、SF-1126、DS-7423、GSK-2126458、布帕尼西(buparlisib)、PF-4691502、BYL-719、XL-147、XL-765、艾代尼西(idelalisib))、SYK(脾臟酪胺酸激酶)抑制劑(例如福他替尼(fostamatinib)、Excellair、PRT-062607)、p53基因療法、雙膦酸鹽(例如依替膦酸鹽(etidronate)、氯膦酸鹽、替魯膦酸鹽(tiludronate)、帕米膦酸鹽(pamidronate)、阿侖膦酸(alendronic acid)、伊班膦酸鹽(ibandronate)、利塞磷酸鹽(risedronate)、唑來瞵酸鹽(zoledronate))。為比較，亦應以下活性成分，例如(但非排他地)：利妥昔單抗、環磷醯胺、多柔比星、多柔比星組合雌酮、長春新鹼、苯丁酸氮芥、氟達拉濱(fludarabin)、地塞米松(dexamethasone)、克拉屈濱(cladribin)、強的松、131I-chTNT、阿比特龍(abiraterone)、阿柔比星(aclarubicin)、阿曲諾英(alitretinoin)、比生群(bisantrene)、亞葉酸鈣、左亞葉酸鈣、卡培他濱(capecitabin)、卡莫氟(carmofur)、氯膦酸、羅米司亭(romiplostim)、克立他酶(crisantaspase)、促紅細胞生成素α(darbepoetin alfa)、地西他濱(decitabine)、德奴單抗(denosumab)、二溴螺氯銨(dibrospidium chloride)、艾曲波帕(eltrombopag)、內皮細胞抑制素、環硫雄醇(epitiostanol)、α依泊汀(epoetin alfa)、惠爾血(filgrastim)、福莫司汀(fotemustin)、硝酸鎵、吉西他濱(gemcitabine)、氧化型谷胱甘肽(glutoxim)、組胺二鹽酸鹽、羥基脲、英丙舒凡(improsulfan)、伊沙匹隆(ixabepilone)、蘭瑞肽(lanreotide)、蘑菇多糖(lentinan)、左美索(levamisole)、麥角乙脲(lisuride)、氯尼达明(lonidamine)、馬索羅酚(masoprocol)、甲基睪酮、甲氧沙林(methoxsalen)、胺基戊酮酸甲酯、米替福新(miltefosine)、米托胍腙(mitoguazone)、絲裂黴素、米托坦(mitotane)、奈拉濱(nelarabine)、尼托珠單抗(nimotuzumab)、氯啶(nitracrin)、奧美拉唑(omeprazole)、帕利夫明(palifermin)、盤尼圖單抗(panitumumab)、培門冬酶(pegaspargase)、PEG β依泊汀(甲氧基-PEG β依泊汀)、乙二醇化非格司亭(pegfilgrastim)、乙二醇化干擾素α-2b、潘他唑新(pentazocine)、噴托他丁(pentostatin)、培磷醯胺(perfosfamide)、吡柔比星(pirarubicin)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、喹高利特(quinagolide)、雷佐生(razoxane)、西佐喃(sizofirane)、索布佐生(sobuzoxan)、甘胺雙唑鈉(sodium glycididazole)、他米巴羅汀(tamibarotene)、替加氟與吉美拉西(gimeracil)之組合及奧特拉西(oteracil)、睪固酮(testosterone)、曲膦明(tetrofosmin)、撒利多胺(thalidomide)、胸腺法新(thymalfasin)、曲貝替定(trabectedin)、維甲酸(tretinoin)、曲洛司坦(trilostane)、色胺酸(tryptophan)、烏苯美司(ubenimex)、伐普肽(vapreotide)、釔-90玻璃微球、淨司他丁(zinostatin)、淨司他丁斯酯(zinostatin stimalamer)。
亦適用於腫瘤療法者為非藥物療法諸如化學療法(例如阿札胞苷(azacitidine)、貝洛替康(belotecan)、依諾他濱(enocitabine)、美法侖(melphalan)、伐蘆比星(valrubicin)、長春氟寧(vinflunin)、佐柔比星(zorubicin))、放射療法(例如I-125種子、鈀-103種子、氯化鐳-223)或光線療法(例如替莫泊芬(temoporfin)、他拉泊芬(talaporfin))之組合，其係藉由使用本發明IRAK4抑制劑之藥物治療達成或其在非藥物腫瘤療法諸如化學療法、放射療法或光線療法已結束後藉由使用本發明IRAK4抑制劑之藥物治療補充。
除了彼等上述者之外，本發明IRAK4抑制劑亦可與以下活性成分進行組合：
用於阿茲海默氏症療法之活性成分，例如乙醯膽鹼酯酶抑制劑(例如多奈哌齊(donepezil)、雷斯替明(rivastigmine)、加蘭他敏(galantamine)、塔克林(tacrine))、NMDA(N-甲基-D-天冬胺酸)受體拮抗劑(例如美金剛胺(memantine))；用於治療帕金森氏症之L-DOPA/碳度巴(carbidopa)(L-3,4-二羥基苯基丙胺酸)、COMT(兒茶酚-O-甲基轉移酶)抑制劑(例如恩他卡朋(entacapone))、多巴胺促效劑(例如羅匹尼羅(ropinirole)、普拉克索(pramipexole)、溴隱亭(bromocriptine))、MAO-B(單胺基氧化酶-B)抑制劑(例如司來吉蘭(selegiline))、抗膽鹼藥(例如苯海索(trihexyphenidyl))及NMDA拮抗劑(例如金剛胺(amantadine))；用於治療多發性硬化症之β干擾素(IFN-β)(例如IFN β-1b、IFN β-1a Avonex®及Betaferon®)、乙酸格拉替雷(glatiramer acetate)、免疫球蛋白、那他株單抗(natalizumab)、芬格莫德(fingolimod)及免疫抑制劑(諸如米托蒽醌、硫唑嘌呤及環磷醯胺)；用於治療肺病之物質，例如β-2-擬交感神經藥(例如沙丁胺醇(salbutamol))、抗膽鹼藥(例如格隆銨(glycopyrronium))、甲基黃嘌呤(例如茶鹼(theophylline))、白三烯素受體拮抗劑(例如孟魯司特(montelukast))、PDE-4(4型磷酸二酯酶)抑制劑(例如羅氟司特(roflumilast))、甲胺喋呤、IgE抗體、硫唑嘌呤及環磷醯胺、含皮質固醇製劑；用於治療骨關節炎之物質，諸如非類固醇消炎藥(NSAID)。除了提及的這兩種療法外，類風濕性疾病例如類風濕性關節炎、脊柱關節炎及幼年特發性關節炎應提及甲胺喋呤及用於B細胞及T細胞療法之生物製劑(例如利妥昔單抗、阿巴西普(abatacept))。神經營養性物質，諸如乙醯膽鹼酯酶抑制劑(例如多奈哌齊)、MAO(單胺基氧化酶)抑制劑(例如司來吉蘭)、干擾素及抗驚厥藥(例如加巴噴丁(gabapentin))；用於治療心血管疾病之活性成分，諸如β-阻斷劑(例如美托洛爾(metoprolol))、ACE抑制劑(例如貝那普利(benazepril))、血管收縮素受體阻斷劑(例如氯沙坦(losartan)、纈沙坦(valsartan))、利尿劑(例如氫氯噻嗪)、鈣通道阻斷劑(例如硝苯地平(nifedipine))、斯他汀類(statins)(例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin))；抗糖尿病藥，例如二甲雙胍(metformin)、格列奈類(glinides)(例如那格列奈(nateglinide))、DPP-4(二肽基肽酶-4)抑制劑(例如利格列汀(linagliptin)、沙西列汀(saxagliptin)、西他列汀(sitagliptin)、維格列汀(vildagliptin))、SGLT2(鈉/葡萄糖共轉運體2)抑制劑/格列凈(gliflozin)(例如達格列凈(dapagliflozin)、艾帕格列淨(empagliflozin))、腸促胰島素擬似物(激素葡萄糖依賴性促胰島素肽(GIP)及升糖素樣肽1(GLP-1)類似物/促效劑)(例如艾塞那肽(exenatide)、利拉魯肽(liraglutide)、利西拉肽(lixisenatide))、α-葡糖苷酶抑制劑(例如阿卡波糖(acarbose)、米格列醇(miglitol)、伏格列波糖(voglibiose))及磺醯脲(例如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide))、胰島素敏化劑(例如吡格列酮(pioglitazone))及胰島素療法(例如NPH胰島素、賴脯胰島素(insulin lispro))、用於治療低血糖症之物質、用於治療糖尿病及代謝症候群之物質。降血脂藥，例如纖維酸酯(例如苯扎貝特(bezafibrate)、依託貝特(etofibrate)、非諾貝特(fenofibrate)、吉非羅齊(gemfibrozil))、菸鹼酸衍生物(例如菸鹼酸/拉羅匹侖(laropiprant))、愛西提米(ezetimib)、斯他汀類(statins)(例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin))、陰離子交換劑(例如考來烯胺(colestyramine)、考來替(colestipol)、考來維侖(colesevelam))。活性成分，諸如美沙拉嗪(mesalazine)、柳氮磺胺吡啶(sulfasalazine)、硫唑嘌呤(azathioprine)、6-巰基嘌呤或甲胺喋呤、益生菌(Mutaflor、VSL#3®、鼠李餹乳桿菌GG(Lactobacillus GG)、胚芽乳桿菌(Lactobacillus plantarum)、嗜酸乳酸菌(L. acidophilus)、凱喜菌(L. casei)、嬰兒雙歧桿菌35624(Bifidobacterium infantis 35624)、糞腸球菌SF68(Enterococcus fecium SF68)、長雙歧桿菌(Bifidobacterium longum)、尼氏大腸桿菌1917(Escherichia coli Nissle 1917))、抗生素(例如環丙沙星(ciprofloxacin)及甲硝噠唑(metronidazole))、抗腹瀉藥(例如洛哌丁胺(loperamide)或用於治療慢性發炎性腸病之緩瀉劑(吡沙可啶(bisacodyl)))。用於治療紅斑狼瘡之免疫抑制劑，諸如糖皮質激素及非類固醇消炎藥(NSAID)、皮質酮、氯奎寧(chloroquine)、環孢黴素、硫唑嘌呤、貝利木單抗、利妥昔單抗、環磷醯胺。例如(但非排他地)，用於器官移植之鈣依賴磷酸酶抑制劑(例如他克莫司及環孢素(ciclosporin))、細胞分裂抑制劑(例如硫唑嘌呤、黴酚酸嗎啉乙酯、黴酚酸、依維莫司或西羅莫司)、雷帕黴素、巴利昔單抗、達利珠單抗(daclizumab)、抗CD3抗體、抗T淋巴細胞球蛋白/抗淋巴細胞球蛋白。用於皮膚疾病之維生素D3類似物，例如鈣泊三醇(calcipotriol)、他卡西醇(tacalcitol)或骨化三醇(calcitriol)、水楊酸、脲、環孢素、甲胺喋呤、依法利株單抗。
亦應提及包含至少一種本發明化合物及一或多種其他的用於治療及/或預防前述疾病之活性成分(尤其是EP4抑制劑(前列腺素E2受體4抑制劑)、P2X3抑制劑(P2X嘌呤受體3)、PTGES抑制劑(前列腺素E合成酶抑制劑)或AKR1C3抑制劑(醛酮還原酶家族1成員C3抑制劑))之藥劑。
本發明化合物可全身性及/或局部地起作用。為此目的，其等可以適宜方式，例如藉由經口、非經腸、肺、鼻、舌下、舌、頰內、直腸、真皮、經皮或結膜途徑、經由耳或呈植入物或支架形式加以投與。
本發明化合物可以適於此等投藥途徑之投藥形式投與。
經口投與之適宜投藥形式為彼等根據先前技術有效且快速及/或以改良方式釋放本發明化合物且包含呈晶型及/或非晶型及/或溶解形式之本發明化合物者，例如錠劑(未經塗覆或經塗覆之錠劑，例如塗覆控制本發明化合物之釋放之抗胃液或延遲溶解或不溶性塗層)、在口腔中快速崩解之錠劑或膜/扁圓片(oblate)、膜/凍乾製劑、膠囊(例如硬或軟明膠膠囊)、糖塗覆錠劑、顆粒、丸劑、粉末、乳液、懸浮液、氣霧劑或溶液。
非經腸投與可無需吸收步驟(例如，藉由靜脈內、動脈內、心臟內、脊柱內或腰內途徑)或在包括吸收下(例如，藉由肌肉內、皮下、皮內、經皮或腹膜內途徑)達成。適於非經腸投與之投與形式包括適於注射及輸注之呈溶液、懸浮液、乳液、凍乾製劑或無菌粉末形式之製劑。
對於其他投藥途徑，適宜的實例為可吸入式藥劑形式(包括粉末吸入器、噴霧器)、滴鼻劑、溶液或噴霧劑、錠劑、適於舌、舌下或頰內投藥之膜/扁圓片或膠囊、栓劑、耳或眼製劑、陰道膠囊、水性懸浮液(洗劑、振盪混合劑)、親脂性懸浮液、軟膏、霜劑、經皮治療系統(例如貼劑)、乳劑、糊劑、泡沫劑、灑粉、植入物或支架。
較佳係經口或非經腸投與，尤其是經口投與。
本發明化合物可轉化成所述投藥形式。此可以本身已知的方式藉由與惰性、非毒性、醫藥上適宜之賦形劑混合來達成。此等賦形劑包括載劑(例如微晶纖維素、乳糖、甘露糖)、溶劑(例如液態聚乙二醇)、乳化劑及分散或潤濕劑(例如十二烷基硫酸鈉、聚氧山梨糖醇油酸酯)、黏合劑(例如聚乙烯吡咯啶酮)、合成及天然聚合物(例如白蛋白)、穩定劑(例如抗氧化劑，例如抗壞血酸)、著色劑(例如無機顏料，例如鐵氧化物)及香味及/或氣味矯正劑。
本發明進一步提供包含至少一種本發明化合物及通常連同一或多種毒性、非毒性、醫藥上適宜之賦形劑之藥劑及其於前述目的之用途。
一般而言，已發現就非經腸投與而言投與約0.001至1 mg/kg，較佳約0.01至0.5 mg/kg體重之量有利於達成有效結果。就口服而言，劑量為約0.01至100 mg/kg，較佳約0.01至20 mg/kg且最佳0.1至10 mg/kg體重。
然而，在一些情況中劑量可能需要衍生自規定量，具體而言，隨體重、投藥途徑、個體對活性成分反應、製劑性質及進行投與之時間或時間間隔而改變。因此，在一些情況中，可足夠地控制在小於上述的下限，而在其他情況中，必須超出所述的上限。就投與更大量而言，可將該等更大量分為一天中之若干個別劑量。
隨後的工作實例說明本發明。本發明並不受限於該等實例。
除非有相反規定，否則隨後的測試及實例中之百分比為重量百分比；份數為重量份。在各情況中，液體/液體溶液之溶劑比、稀釋比及濃度數據係以體積計。本發明化合物之製法
由隨後的合成反應圖說明本發明化合物之製法。
用於合成本發明化合物之起始物質為羧酸(中間物V3)，其等可自市面購得或可依文獻已知的途徑或類似於文獻已知的途徑製備(參見，例如，European Journal of Organic Chemistry 2003, 8, 1559 – 1568, Chemical and Pharmaceutical Bulletin, 1990, 38, 9, 2446 – 2458, Synthetic Communications 2012, 42, 658 – 666, Tetrahedron, 2004, 60, 51, 11869 - 11874)(參見，例如，合成反應圖1)。一些羧酸V3可自羧酸酯(中間物V2)開始藉由水解(請參閱，例如，使6-(羥甲基)吡啶-2-羧酸乙酯與含在甲醇中之氫氧化鈉水溶液反應，WO200411328)或-就第三丁酯而言-藉由與酸，例如氯化氫或三氟乙酸反應(請參閱，例如，Dalton Transactions, 2014, 43, 19, 7176 – 7190)製得。羧酸V3亦可呈其鹼金屬鹽形式使用。中間物V2亦可視需要自具有氯、溴或碘作為取代基X1
之中間物V1藉由在一氧化碳氛圍中，視需要在提高的壓力下，於膦配位體例如1,3-雙(二苯基膦基)丙烷、鈀化合物例如乙酸鈀(II)及鹼例如三乙胺之存在下，且添加含在溶劑例如二甲亞碸中之乙醇或甲醇反應製得(關於製法，參見，例如，WO2012112743、WO 2005082866、Chemical Communications (Cambridge, England), 2003, 15, 1948 – 1949、WO200661715)。中間物V1可自市面購得或可藉由文獻已知的途徑製備。例示性製法詳細述於WO 2012061926、European Journal of Organic Chemistry, 2002, 2, 327 – 330, Synthesis, 2004, 10, 1619 – 1624、Journal of the American Chemical Society, 2013, 135, 32, 12122 – 12134、Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039 – 4043、US2007185058、WO2009117421中。
X1
為氯、溴或碘。
Rd
為甲基、乙基、苄基或第三丁基。
R4
、R5
各如通式(I)中所定義。
5-胺基-1H-吲唑-6-羧酸甲酯(中間物2)可自1H-吲唑-6-羧酸甲酯(中間物0)開始依合成反應圖2藉由類似於WO 2008/001883在木炭載鈀之存在下硝化並以氫還原中間物1之硝基獲得。對於自中間物2開始製備中間物3，可使用文獻已知的各種偶聯試劑(Amino Acids, Peptides and Proteins in Organic Chemistry, 第3卷– Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, 第12章 - Peptide-Coupling Reagents, 407-442; Chem.Soc.Rev., 2009, 38, 606)。例如，可使用1-(3-二甲胺基丙基)-3-乙基碳化二亞胺鹽酸鹽與作為偶聯試劑之1-羥基-1H-苯并三唑水合物(HOBt，WO2012107475；Bioorg.Med.Chem.Lett., 2008, 18, 2093)、四氟硼酸(1H-苯并三唑-1-基氧基)(二甲胺基)-N,N-二甲基甲亞銨(TBTU，CAS 125700-67-6)、六氟磷酸(二甲胺基)-N,N-二甲基(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基氧基)甲銨(HATU，CAS 148893-10-1)、丙基磷酸酐(呈含在乙酸乙酯或DMF中之溶液，CAS68957-94-8)或二-1H-咪唑-1-基甲酮(CDI)之組合，且在各情況中添加鹼諸如三乙胺或N-乙基-N-異丙基丙-2-胺至該反應混合物。較佳者係使用含在THF中之TBTU及N-乙基-N-異丙基丙-2-胺。
取代基R4
、R5
各如通式(I)中所定義。
自中間物3開始，可製備2-經取代吲唑衍生物(中間物4)(參見合成反應圖3)。針對於此目的之適用反應包括彼等與視需要經取代之烷基氯化物、烷基溴化物、烷基碘化物或4-甲基苯磺酸烷酯之反應。所使用的烷基鹵化物或4-甲基苯磺酸烷酯可自市面購得或可類似於文獻已知的途徑製得(對於4-甲基苯磺酸烷酯之製法，一個實例為適宜之醇與4-甲基苯磺醯氯在三乙胺或吡啶之存在下反應；參見，例如，Bioorganic and Medicinal Chemistry, 2006, 14, 12 4277 – 4294)。視需要，就使用烷基氯化物或烷基溴化物而言，亦可添加添加鹼金屬碘化物，諸如碘化鉀或碘化鈉。所使用的鹼可為例如碳酸鉀、碳酸銫或氫化鈉。就反應性烷基鹵化物而言，在一些情況中，亦可使用N-環己基-N-甲基環己胺。適用的溶劑包括(例如)1-甲基吡啶-2-酮、DMF、DMSO或THF。視需要，所使用的烷基鹵化物或4-甲基苯磺酸烷酯可具有已視需要事先經保護基保護之官能基(亦參見P. G. M. Wuts, T. W. Greene,Greene’s Protective Groups in Organic Synthesis
, 第四版, ISBN:9780471697541)。若使用(例如)具有一或多個羥基之烷基鹵化物或4-甲基苯磺酸烷酯，則此等羥基可視需要經熟悉此項技術者悉知的第三丁基(二甲基)甲矽烷基或類似的含矽保護基保護。或者，羥基亦可經四氫-2H-吡喃(THP)基或經乙醯基或苯甲醯基保護。所使用的保護基可接著在合成中間物4後抑或在合成(I)後脫去。若例如使用第三丁基(二甲基甲矽烷基)作為保護基，則其可使用(例如)含在溶劑諸如THF中之氟化四丁基銨脫去。THP保護基可例如使用4-甲基苯磺酸(視需要呈單水合物形式)脫去。乙醯基或苯甲醯基可藉由用氫氧化鈉水溶液處理脫去。
視需要，所使用的烷基鹵化物或4-甲基苯磺酸烷酯可含有可藉由熟悉此項技術者已知的氧化或還原反應轉化之官能基(參見，例如，Science of Synthesis
, Georg Thieme Verlag)。若例如官能基為硫醚基，則此可藉由文獻已知的方法氧化為亞碸基或碸基。在亞碸基之情況下，其可同樣被氧化為碸基。對於此等氧化步驟，可使用例如3-氯過苯甲酸(CAS 937-14-4)(於此點上，亦參見，例如，US201094000，係關於2-(甲基硫烷基)乙基-1H-吡唑衍生物氧化為2-(甲基亞磺醯基)乙基-1H-吡唑衍生物及另一2-(甲基硫烷基)乙基-1H-吡唑衍生物氧化為2-(甲基磺醯基)乙基-1H-吡唑衍生物)。若所使用的烷基鹵化物或甲苯磺酸酯含有酮基，則此可藉由熟悉此項技術者已知的還原方法還原為醇基(參見，例如，Chemische Berichte, 1980, 113, 1907 – 1920，係關於硼氫化鈉之使用)。此等氧化或還原步驟可在合成中間物4後抑或在合成通式(I)之本發明化合物後實現。或者，中間物4可經由中間物3與視需要經取代之烷醇之光延(Mitsunobu)反應(參見，例如，K. C. K. Swamy等人. Chem. Rev. 2009, 109, 2551 – 2651)製得。可使用各種膦(諸如三苯基膦、三丁基膦或1,2-二苯基膦基乙烷)與偶氮二羧酸二異丙酯(CAS 2446-83-5)或其他的文獻提及的二氮烯衍生物之組合(K. C. K. Swamy等人. Chem. Rev. 2009, 109, 2551 – 2651)。較佳者係使用三苯基膦及偶氮二羧酸二異丙酯。若烷醇具有官能基，則可像上述的與烷基鹵化物之反應一樣進行已知保護基策略(其他指示可參見P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Organic Synthesis, 第四版, ISBN:9780471697541)及可像上述的與烷基鹵化物之反應一樣對應於合成中間物4抑或在合成通式(I)之本發明化合物後實現氧化或還原步驟。自中間物4開始，通式(I)(其中R2
及R3
係如C1
-C6
烷基所定義(其中R2
及R3
具有相同定義))之本發明化合物可藉由格林納反應(請參閱，例如，EP 2489663中1H-吲唑-6-羧酸甲酯衍生物與溴化甲基鎂之反應)獲得。對於格林納反應，可使用鹵化烷基鎂。尤佳者為含在THF或乙醚中抑或含在THF及乙醚之混合物中之氯化甲基鎂或溴化甲基鎂。或者，自中間物4開始，通式(I)(其中R2
及R3
係如C1
-C6
-烷基(其中R2
及R3
具有相同定義)所定義)之本發明化合物可藉由與烷基鋰試劑反應(請參閱，例如，WO2006116412中2-胺基-4-氯-1-甲基-1H-苯并咪唑-7-羧酸甲酯衍生物與異丙基鋰或第三丁基鋰之反應)獲得。自中間物4開始，可藉由用含在THF中之氫化鋁鋰、含在THF中之硼氫化鋰或含在THF中之硼氫化鈉(視需要添加甲醇、或硼氫化鋰及硼氫化鈉之混合物)還原製得通式(I)(其中R2
及R3
係如H所定義)之本發明化合物。
取代基R1
、R2
、R3
、R4
、R5
各如通式(I)中所定義。
自中間物3開始，可藉由格林納反應(請參閱，例如，合成反應圖4)獲得中間物5，其中R2
及R3
係如C1
-C6
烷基(其中R2
及R3
具有相同定義)所定義。為此目的，可使用適宜之鹵化烷基鎂，例如，含在THF中或含在乙醚中抑或含在THF及二乙醚之混合物中之氯化甲基鎂或溴化甲基鎂。
自中間物5開始，接著可製備本發明化合物(I)之部分(I-a)，其中R2
及R3
係如C1
-C6
烷基(其中R2
及R3
具有相同定義)所定義。為此目的，類似於合成反應圖3(製備中間物3)，適用的反應為彼等中間物5與視需要經取代之烷基氯化物、烷基溴化物、烷基碘化物或4-甲基苯磺酸烷酯之反應者。可使用與合成反應圖3中所述類似之彼等保護基策略。
或者，為製備本發明化合物(I)之部分(I-a)，其中R2
及R3
係如C1
-C6
烷基(其中R2
及R3
具有相同定義)所定義，可使用中間物5與視需要經取代之烷醇之光延反應(類似於合成反應圖3)。
若式(I-a)化合物中之R1
包括適宜之官能基，則可隨後視需要類似於合成反應圖3地使用氧化或還原反應以製備其他本發明化合物。
取代基R1
、R4
、R5
各如通式(I)中所定義。R2
及R3
始終具有相同定義且同時為C1
-C6
烷基。
自中間物1開始，可以另一方法(參見合成反應圖5)製備中間物4。首先，藉由如合成反應圖3(自中間物3製備中間物4)中之方法將中間物1轉化成中間物6。
可接著藉由還原硝基將中間物6轉化成中間物7。例如，可用碳載鈀於氫氣氛圍下(請參閱，例如，WO2013174744，係關於將6-異丙氧基-5-硝基-1H-吲唑還原為6-異丙氧基-1H-吲唑-5-胺)或藉由使用含在水及乙醇中之鐵及氯化銨(亦參見，例如，Journal of the Chemical Society, 1955, 2412-2419)或藉由使用氯化錫(II)(CAS 7772-99-8)還原硝基。較佳使用含在水及乙醇中之鐵及氯化銨。可類似於合成反應圖2(自中間物2製備中間物3)地實現自中間物7製備中間物4。
如針對合成反應圖3所述，可視需要如在合成反應圖5之情況中般使用保護基策略。視需要，另外可自中間物6或中間物7開始，如針對合成反應圖3所述般，進行熟悉此項技術者已知的氧化或還原反應(請參閱，例如Science of Synthesis
, Georg Thieme Verlag)。
該等取代基R1
、R4
、R5
各如通式(I)中所定義。實例化合物之合成 縮寫及說明 
術語氯化鈉溶液始終意指飽和氯化鈉水溶液。
使用ACD/LABS(Batch 12.01版)軟體產生中間物及實例之化學名稱。方法
在一些情況中，藉由LC-MS分析本發明化合物及其前驅物及/或中間物。
方法A1：UPLC(MeCN-HCOOH)：
儀器：Waters Acquity UPLC-MS SQD 3001；管柱：Acquity UPLC BEH C18 1.7 50×2.1 mm；洗脫劑A：水+0.1體積%甲酸(99%)，洗脫劑B：乙腈；梯度：0-1.6 min 1-99% B，1.6-2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射體積：2 µl；DAD掃描：210-400 nm；MS ESI+, ESI-，掃描範圍160-1000 m/z；ELSD。
方法A2：UPLC(MeCN-NH3
)：
儀器：Waters Acquity UPLC-MS SQD 3001；管柱：Acquity UPLC BEH C18 1.7 50×2.1 mm；洗脫劑A：水+0.2體積%氨(32%)，洗脫劑B：乙腈；梯度：0-1.6 min 1-99% B，1.6-2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射體積：2 µl；DAD掃描：210-400 nm；MS ESI+, ESI-，掃描範圍160-1000 m/z；ELSD。
方法A3：(LC-MS)
儀器：Agilent 1290 Infinity LC；管柱：Acquity UPLC BEH C18 1.7 50×2.1 mm；洗脫劑A：水+0.05體積%甲酸，洗脫劑B：乙腈+0.05體積%甲酸；梯度：0-1.7 min 2-90% B，1.7-2.0 min 90% B；流速1.2 ml/min；溫度：60℃；注射體積：2 µl；DAD掃描：190-390 nm；MS：Agilent TOF 6230。
方法A4：(LC-MS)
儀器：Waters Acquity；管柱：Kinetex(Phenomenex)，50×2 mm；洗脫劑A：水+0.05體積%甲酸，洗脫劑B：乙腈+0.05體積%甲酸；梯度：0-1.9 min 1-99% B，1.9-2.1 min 99% B；流速1.5 ml/min；溫度：60℃；注射體積：0.5 µl；DAD掃描：200-400 nm。
在一些情況中，本發明化合物及其前驅物及/或中間物係藉由以下例示性製備型HPLC方法純化：
方法P1：系統：Waters自動純化系統：泵2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD；管柱：XBridge C18 5 µm 100×30 mm；洗脫劑A：水+0.1體積%甲酸，洗脫劑B：乙腈；梯度：0-8 min 10-100% B，8-10 min 100% B；流速：50 ml/min；溫度：室溫；溶液：max. 250 mg / max. 2.5 ml DMSO或DMF；注射體積：1×2.5 ml；偵測：DAD掃描範圍210–400 nm；MS ESI+, ESI-，掃描範圍160-1000 m/z。
方法P2：系統：Waters自動純化系統：泵254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100；管柱：XBridge C18 5 µm 10×30 mm；洗脫劑A：水+0.2體積%氨(32%)，洗脫劑B：甲醇；梯度：0-8 min 30-70% B；流速：50 ml/min；溫度：室溫；偵測：DAD掃描範圍210-400 nm；MS ESI+, ESI-，掃描範圍160-1000 m/z；ELSD。
方法P3：系統：Labomatic，泵：HD-5000，餾份收集器：LABOCOL Vario-4000，UV偵測器：Knauer UVD 2.1S；管柱：XBridge C18 5 µm 100×30 mm；洗脫劑A：水+0.2體積%氨(25%)，洗脫劑B：乙腈；梯度：0-1 min 15% B，1-6.3 min 15-55% B，6.3-6.4 min 55-100% B，6.4-7.4 min 100% B；流速：60 ml/min；溫度：室溫；溶液：max. 250 mg / 2 ml DMSO；注射體積：2×2 ml；偵測：UV 218 nm；軟體：SCPA PrepCon5。
方法P4：系統：Labomatic，泵：HD-5000，餾份收集器：LABOCOL Vario-4000，UV偵測器：Knauer UVD 2.1S；管柱：Chromatorex RP C18 10 µm 125×30 mm；洗脫劑A：水+0.1體積%甲酸，洗脫劑B：乙腈；梯度：0-15 min 65-100% B；流速：60 ml/min；溫度：室溫；溶液max. 250 mg / 2 ml DMSO；注射體積：2×2 ml；偵測：UV 254 nm；軟體：SCPA PrepCon5。
方法P5：系統：Sepiatec:Prep SFC100，管柱：Chiralpak IA 5 µm 250×20 mm；洗脫劑A：二氧化碳，洗脫劑B：乙醇；梯度：等濃度20% B；流速：80 ml/min；溫度：40℃；溶液：max. 250 mg/2 ml DMSO；注射體積：5×0.4 mL；偵測：UV 254 nm。
方法P6：系統：Agilent:Prep 1200, 2×製備型泵, DLA, MWD, Gilson:Liquid Handler 215；管柱：Chiralcel OJ-H 5 µm 250×20 mm；洗脫劑A：己烷，洗脫劑B：乙醇；梯度：等濃度30% B；流速：25 ml/min；溫度：25℃；溶液：187 mg/8 ml乙醇/甲醇；注射體積：8×1.0 ml；偵測：UV 280 nm。
方法P7：系統：Labomatic，泵：HD-5000，餾份收集器：LABOCOL Vario-4000，UV偵測器：Knauer UVD 2.1S；管柱：XBridge C18 5 µm 100×30 mm；洗脫劑A：水+0.1體積%甲酸，洗脫劑B：乙腈；梯度：0-3 min:65% B等濃度，3-13 min:65-100% B；流速：60 ml/min；溫度：室溫；溶液：max. 250 mg/2 ml DMSO；注射體積：2×2 ml；偵測：UV 254 nm。
方法P8：系統：Agilent:Prep 1200, 2×製備型泵, DLA, MWD, Gilson:Liquid Handler 215；管柱：Chiralpak IF 5 µm 250×20 mm；洗脫劑A：乙醇，洗脫劑B：甲醇；梯度：等濃度50% B；流速：25 ml/min；溫度：25℃；溶液：600 mg/7 ml N,N-二甲基甲醯胺；注射體積：10×0.7 ml；偵測：UV 254 nm。
在一些情況中，藉由在矽膠上進行之管柱層析純化物質混合物。
為製備一些本發明化合物及其前驅物及/或中間物，於矽膠上使用Biotage之Isolera®
裝置進行管柱層析純化(「急驟層析」)。使用Biotage之管柱，例如不同尺寸之「SNAP Cartridge, KP_SIL」及Interchim之不同尺寸之「Interchim Puriflash Silica HP 15UM flash column」管柱進行該管柱層析純化。起始物質 中間物 V2-1 6-(2- 羥丙 -2- 基 ) 吡啶 -2- 羧酸甲酯 
將2.00 g (9.26 mmol) 2-(6-溴吡啶-2-基)丙-2-醇(CAS 638218-78-7)溶解於20 ml甲醇及20 ml DMSO中。隨後，添加250 mg 1,3-雙(二苯基膦基)丙烷、130 mg乙酸鈀(II)及3 ml三乙胺。用一氧化碳在室溫下淨化反應混合物三次且於13巴一氧化碳氛圍下攪拌30 min。藉由施用真空移除一氧化碳氛圍且於於14巴一氧化碳氛圍下在100℃下攪拌該混合物24 h。使高壓釜減壓，添加水至該反應混合物，且用乙酸乙酯萃取該反應混合物三次，用飽和碳酸氫鈉水溶液及氯化鈉溶液洗滌，通過疏水性過濾器過濾並濃縮。此提供1.60 g粗產物。
UPLC-MS(方法A1)：Rt
=0.76 min(UV偵測器：TIC)，質量實測值195.00。中間物 V3-1 6-(2- 羥丙 -2- 基 ) 吡啶 -2- 羧酸鉀 
首先將中間物0至1之1.60 g粗產物加入15 ml甲醇中，添加0.74 g氫氧化鉀且在50℃下攪拌混合物16.5 h。在濃縮後，此提供2.1 g無需進一步純化即可使用的殘餘物。
UPLC-MS(方法A1)：Rt
=0.47 min(UV偵測器：TIC)，質量實測值181.00。中間物 1-1 5- 硝基 -1H- 吲唑 -6- 羧酸甲酯 
在具有CPG攪拌器、滴液漏斗及內部溫度計之三頸燒瓶中將4.60 g (26.1 mmol) 1H-吲唑-6-羧酸甲酯(CAS號：170487-40-8)溶解於120 ml硫酸(96%)中並冷卻至-15℃。在15 min期間，將已製得並事先冷卻的硝化酸(10 ml 96%硫酸含於5 ml 65%硝酸中)滴加至該溶液。滴加結束後，再攪拌該混合物1 h(內部溫度在-13℃)。將該反應混合物添加至冰，及藉由吸力過濾出沉澱，用水洗滌且在乾燥箱中於50℃在減壓下乾燥。獲得5.49 g標題化合物。
UPLC-MS(方法A2)：Rt
=0.75 min
MS(ESIpos): m/z = 222 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.87 (s, 3 H), 7.96 (s, 1 H), 8.44 (s, 1 H), 8.70 (s, 1 H), 13.98 (br. s., 1 H)。中間物 2-1 5- 胺基 -1H- 吲唑 -6- 羧酸甲酯 
將4.40 g (19.8 mmol) 5-硝基-1H-吲唑-6-羧酸甲酯(中間物1-1)溶解於236 ml甲醇中並用1.06 g (0.99 mmol)活性碳載鈀在標準氫氣壓力於25℃下氫化3 h。使該反應混合物濾過矽藻土，用甲醇洗滌過濾器，及濃縮濾液。獲得3.53 g標題化合物。1
H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.85 (s, 3 H) 6.01 (s, 2 H) 6.98 (s, 1 H) 7.79 - 7.91 (m, 1 H) 7.99 (s, 1 H) 12.84 (br. s., 1 H)。中間物 3-1 5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 吲唑 -6- 羧酸甲酯 
首先將4.95 g (25.9 mmol) 6-(三氟甲基)吡啶-2-羧酸加入45 ml THF中。添加9.07 g (28.2 mmol)四氫硼酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓及4.92 ml (28.2 mmol) N-乙基-N-異丙基丙-2-胺及在25℃下攪拌該混合物30 min。隨後，添加4.50 g (23.5 mmol) 5-胺基-1H-吲唑-6-羧酸甲酯(中間物2-1)且在25℃下攪拌24 h。藉由吸力使反應混合物濾過膜過濾器及用THF繼而用水洗滌固體，及在乾燥箱中乾燥過夜。獲得7.60 g標題化合物。
UPLC-MS(方法A2)：Rt
=1.16 min
MS(ESIpos): m/z = 365 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (s, 1 H)。中間物 3-2 5-({[6-( 二氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 吲唑 -6- 羧酸甲酯 
首先將2.85 g (23.5 mmol) 6-(二氟甲基)吡啶-2-羧酸加入30 ml THF中。添加6.05 g (18.8 mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓及3.3 ml N-乙基-N-異丙基丙-2-胺及在室溫下攪拌該混合物10分鐘。隨後，添加3.00 g (15.7 mmol) 5-胺基-1H-吲唑-6-羧酸甲酯且在室溫下攪拌該混合物過夜。將該反應混合物與水混合，及藉由吸力過濾出沉澱且用水及二氯甲烷重複洗滌。此提供1.53 g (理論量之27%)標題化合物。分離濾液相，濃縮有機相，與少量二氯甲烷混合並懸浮於超音波浴中，且藉由吸力過濾出沉澱。此提供另一份1.03 g的標題化合物。
1H-NMR(第一產物部分，300MHz, DMSO-d6): δ [ppm]= 3.99 (s, 3H), 7.09 (t, 1H), 8.00 (d, 1H), 8.21 - 8.40 (m, 4H), 9.14 (s, 1H), 12.53 (s, 1H), 13.44 (s, 1H)。中間物 3-3 5-({[6-(2- 羥丙 -2- 基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 吲唑 -6- 羧酸甲酯 
首先將2.10 g 6-(2-羥丙-2-基)吡啶-2-羧酸鉀(中間物V3-1)加入15 ml THF中。添加3.69 g (11.5 mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓及2.00 ml N-乙基-N-異丙基丙-2-胺且在室溫下攪拌該混合物15 min。隨後，添加1.83 g (9.58 mmol) 5-胺基-1H-吲唑-6-羧酸甲酯(中間物2-1)且在室溫下攪拌該混合物19 h。將該混合物與水及乙酸乙酯混合，過濾出未溶解的固體，分離濾液相，及用乙酸乙酯萃取水相兩次，用氯化鈉溶液洗滌，通過疏水性過濾器過濾，濃縮並藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)進行純化。移除溶劑後，獲得1.56 g呈黃色泡沫之標題化合物。
UPLC-MS(方法A1)：Rt
=1.00 min(UV偵測器：TIC Smooth)，質量實測值354.00。
1H-NMR (500MHz,DMSO-d6): δ [ppm] = 1.63 (s, 6H), 3.97 (s, 3H), 5.37(s ,1H), 7.90 - 7.95 (m, 1H), 8.03-8.07 (m, 2H), 8.23(s, 1H),8.29 (s, 1H), 9.19 (s, 1H), 12.79 (s, 1H), 13.41 (br.s., 1H)。中間物 4-1 2-( 氧雜環丁 -3- 基甲基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
將1.00 g (2.66 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)溶解於10 ml DMF中且在添加1.10 g (7.99 mmol)碳酸鉀及221 mg (1.33 mmol)碘化鉀後，在25℃下攪拌該混合物30 min。添加603 mg (3.99 mmol) 3-溴甲基氧雜環丁烷，且在25℃下攪拌該混合物24 h。將該反應混合物分配在水與乙酸乙酯之間。用乙酸乙酯萃取該混合物兩次，且通過疏水性過濾器過濾合併的有機相並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得260 mg標題化合物。
UPLC-MS(方法A2)：Rt
=1.24 min
MS(ESIpos): m/z = 435 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.49 - 3.64 (m, 1 H), 3.95 (s, 3 H), 4.49 (t, 2 H), 4.68 (dd, 2 H), 4.81 (d, 2 H), 8.20 (dd, 1 H), 8.35 - 8.41 (m, 1 H), 8.43 - 8.49 (m, 2 H), 8.55 - 8.58 (m, 1 H), 9.06 (s, 1 H), 12.53 (s, 1 H)。中間物 4-2 2-(2- 甲氧基乙基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
將1.00 g (2.75 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)溶解於5 ml DMF中，且在攪拌的同時添加387 µl (4.12 mmol) 2-溴乙基甲基醚、1.14 g (8.23 mmol)碳酸鉀及228 mg (1.37 mmol)碘化鉀。在25℃下攪拌該反應混合物24 h，用水稀釋及用乙酸乙酯萃取兩次。通過疏水性過濾器過濾合併的有機相並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得12 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.24 min
MS(ESIpos): m/z = 423 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.24 (s, 3 H), 3.86 (t, 2 H), 3.96 (s, 3 H), 4.65 (t, 2 H), 8.21 (dd, 1 H), 8.35 - 8.42 (m, 1 H), 8.43 - 8.51 (m, 2 H), 8.52 (d, 1 H), 9.06 (s, 1 H), 12.53 (s, 1 H)。中間物 4-3 2-(3- 甲氧基丙基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
將1.00 g (2.75 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)溶解於5 ml DMF中，且在攪拌的同時添加460 µl (4.12 mmol) 1-溴-3-甲氧基丙烷、1.14 g (8.23 mmol)碳酸鉀及228 mg (1.37 mmol)碘化鉀。在25℃下攪拌該反應混合物72 h，用水稀釋及用乙酸乙酯萃取兩次。通過疏水性過濾器過濾合併的有機相並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得28 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.29 min
MS (ESIpos): m/z = 437 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 2.17 (五重峰, 2 H), 3.24 (s, 3 H), 3.33 - 3.36 (m, 2 H), 3.96 (s, 3 H), 4.53 (t, 2 H), 8.21 (dd, 1 H), 8.35 - 8.42 (m, 1 H), 8.45 - 8.49 (m, 2 H), 8.54 (d, 1 H), 9.06 (s, 1 H), 12.54 (s, 1 H)。中間物 4-4 2-(3- 羥基 -3- 甲基丁基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 製法 1 
首先將930 mg (2.55 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)、1.06 g碳酸鉀及212 mg碘化鉀加入9 ml DMF中且攪拌該混合物15 min。接著，添加0.62 ml 4-溴-2-甲基丁-2-醇且在60℃下攪拌該混合物16 h。將該混合物與水混合及用乙酸乙酯萃取兩次，且用飽和氯化鈉溶液洗滌萃取物三次，過濾及濃縮。於矽膠上進行之管柱層析純化(己烷/乙酸乙酯)提供424 mg標題化合物。
UPLC-MS(方法A2)：Rt
=1.21 min(UV偵測器：TIC)，質量實測值450.00。1
H-NMR (400 MHz, DMSO-d6
): δ [ppm]= 1.16 (s, 6 H) 2.02 - 2.11 (m, 2 H) 3.96 (s, 3 H) 4.51 - 4.60 (m, 3 H) 8.20 (dd,J
=7.83, 1.01 Hz, 1 H) 8.39 (s, 1 H) 8.45 (s, 2 H) 8.55 (d,J
=0.76 Hz, 1 H) 9.05 (s, 1 H) 12.52 (s, 1 H)製法 2
首先將1.95 g (7.03 mmol) 5-胺基-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物7-1)加入30 ml THF中。添加1.48 g (7.73 mmol) 6-(三氟甲基)吡啶-2-羧酸、2.71 g (8.44 mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓及1.47 ml (8.44 mmol) N-乙基-N-異丙基丙-2-胺且在25℃下攪拌該混合物20.5 h。添加水，用乙酸乙酯萃取該混合物三次及用氯化鈉溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯梯度)分離殘餘物。獲得2.79 g標題化合物。
UPLC-MS(方法A1)：Rt
=1.23 min(UV偵測器：TIC)，質量實測值450.00。中間物 4-5 2-(2-{[ 第三丁基 ( 二甲基 ) 甲矽烷基 ] 氧基 } 乙基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
首先將1.00 g (2.66 mmol，97%) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)加入50 ml DMF中，在攪拌的同時添加1.10 g (7.99 mmol)碳酸鉀及221 mg (1.33 mmol)碘化鉀，且在25℃下攪拌該混合物30 min。隨後，添加857 µl (3.99 mmol) (2-溴乙氧基)(第三丁基)二甲基矽烷且在25℃下攪拌該混合物24 h。用水稀釋該反應混合物及用乙酸乙酯萃取。通過疏水性過濾器過濾合併的有機相並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得400 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.58 min
MS (ESIpos): m/z = 523(M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.18 - -0.13 (m, 6 H), 0.74 (s, 9 H), 3.96 (s, 3 H), 4.08 (t, 2 H), 4.57 (t, 2 H), 8.15 - 8.25 (m, 1 H), 8.32 - 8.43 (m, 1 H), 8.43 - 8.52 (m, 3 H), 9.07 (s, 1 H), 12.53 (s, 1 H)。中間物 4-6 2-(3-{[ 第三丁基 ( 二甲基 ) 甲矽烷基 ] 氧基 } 丙基 )-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
類似於中間物4-5，將1.00 g (2.75 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)溶解於10 ml DMF中，在攪拌的同時添加1.14 g (8.24 mmol)碳酸鉀及228 mg (1.37 mmol)碘化鉀，且在25℃下攪拌該混合物30 min。隨後，添加1.04 g (4.12 mmol) (3-溴丙氧基)(第三丁基)二甲基矽烷且在25℃下攪拌該混合物24 h。過濾該反應混合物及用乙酸乙酯洗滌濾餅。將該反應混合物分配在水與乙酸乙酯之間及用乙酸乙酯萃取水相兩次。通過疏水性過濾器過濾合併的有機相並濃縮。製備型HPLC純化殘餘物提供428 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.63 min
MS (ESIpos): m/z = 537(M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = -0.02 - 0.06 (m, 6 H), 0.87 (s, 9 H), 2.14 (五重峰, 2 H), 3.62 (t, 2 H), 3.96 (s, 3 H), 4.54 (t, 2 H), 8.20 (d, 1 H), 8.35 - 8.42 (m, 1 H), 8.43 - 8.48 (m, 3 H), 8.49 - 8.53 (m, 1 H), 9.06 (s, 1 H)。中間物 4-7 5-({[6-(2- 羥丙 -2- 基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2-(4,4,4- 三氟丁基 )-2H- 吲唑 -6- 羧酸甲酯 
首先將300 mg (0.80 mmol) 5-({[6-(2-羥丙-2-基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-3)加入4.5 ml DMF中。添加287 mg (1.21 mmol) 1,1,1-三氟-4-碘丁烷及333 mg碳酸鉀且在100℃下攪拌該混合物23 h。添加水，及用乙酸乙酯萃取該混合物三次。濃縮該混合物及藉由製備型HPLC純化產物。此提供72 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.26 min(UV偵測器：TIC)，質量實測值464.17。中間物 4-8 5-{[(5- 氟 -6- 甲基吡啶 -2- 基 ) 羰基 ] 胺基 }-2-(3- 羥基 -3- 甲基丁基 )-2H- 吲唑 -6- 羧酸甲酯 
類似於中間物4-4 (製法2)，使195 mg (0.46 mmol) 5-胺基-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物7-1)與78 mg (0.50 mmol) 5-氟-6-甲基吡啶-2-羧酸在19.5 h內反應。於類似的水性處理後獲得228 mg粗產物。
UPLC-MS(方法A1)：Rt
=1.20 min(UV偵測器：TIC)，質量實測值414.00。中間物 4-9 2-(3- 羥基 -3- 甲基丁基 )-5-{[(6- 甲基吡啶 -2- 基 ) 羰基 ] 胺基 }-2H- 吲唑 -6- 羧酸甲酯 
類似於中間物4-4之製法(製法2)，使195 mg (0.45 mmol) 5-胺基-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物7-1)與70 mg (0.50 mmol) 6-甲基吡啶-2-羧酸在19.5 h內反應。於類似的水性處理後獲得278 mg呈粗產物之標題化合物。
UPLC-MS(方法A1)：Rt
=1.14 min(UV偵測器：TIC)，質量實測值396.00。中間物 4-10 2-[3-(2,2,2- 三氟乙氧基 ) 丙基 ]-5-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2H- 吲唑 -6- 羧酸甲酯 
在100℃下攪拌250 mg (0.58 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)、193 mg (0.88 mmol) 3-溴丙基2,2,2-三氟乙醚、242 mg碳酸鉀及145 mg碘化鉀含在3 ml DMF中之混合物20 h。添加水，用乙酸乙酯萃取該混合物及用氯化鈉溶液洗滌萃取物並濃縮。藉由製備型HPLC純化提供52 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.39 min(UV偵測器：TIC)，質量實測值504.12。中間物 4-11 5-({[6-( 二氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-2-(3- 羥基 -3- 甲基丁基 )-2H- 吲唑 -6- 羧酸甲酯 
首先將2.00 g 5-胺基-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物7-1)加入40 ml THF中。添加1.50 g 6-(二氟甲基)吡啶-2-羧酸、2.78 g四氟硼酸O
-(苯并三唑-1-基)-N
,N
,N
',N
'-四甲基脲鎓(TBTU, CAS號125700-67-6)及1.5 ml N-乙基-N-異丙基丙-2-胺且在RT下攪拌該混合物24 h。添加水，用乙酸乙酯萃取該混合物三次，及用氯化鈉溶液洗滌合併的有機相然後通過疏水性過濾器過濾。濃縮該混合物及藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。此提供3.05 g呈黃色固體之標題化合物。
UPLC-MS(方法A1)：Rt=1.15 min(UV偵測器TIC)，質量實測值432.00。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.17 (s, 6H), 2.04 - 2.11 (m, 2H), 3.99 (s, 3H), 4.52 - 4.60 (m, 3H), 7.10 (t, 1H), 8.00 (dd, 1H), 8.28 - 8.38 (m, 2H), 8.44 – 8.47 (m, 1H), 8.56 (d, 1H), 9.05 (s, 1H), 12.49 (s, 1H)。中間物 5-1 N-[6-(2- 羥丙 -2- 基 )-1H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
小心地將6.9 ml (5當量)含在乙醚中之3M溴化甲基鎂溶液添加至經在冰-水冷卻浴中冷卻的1.50 g (4.12 mmol) 5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-1)含在20 ml THF中之溶液。攪拌該混合物同時用冰浴冷卻1 h繼而在室溫下冷卻19.5 h。添加另一份2當量的溴化甲基鎂溶液且在室溫下再攪拌該混合物24 h。添加飽和氯化銨水溶液及攪拌該混合物且用乙酸乙酯萃取三次。用氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得763 mg標題化合物。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.63 (s, 6H), 5.99 (s, 1H), 7.49 (s, 1H), 8.06 (s, 1H), 8.14 - 8.19 (m, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.32 (s, 1H), 12.97 (s, 1H)。中間物 5-2 6-( 二氟甲基 )-N-[6-(2- 羥丙 -2- 基 )-1H- 吲唑 -5- 基 ] 吡啶 -2- 甲醯胺 
類似於中間物5-1之製法，使含在10 ml THF中之2.40 g (6.93 mmol) 5-({[6-(二氟甲基)吡啶-2-基]羰基}胺基)-1H-吲唑-6-羧酸甲酯(中間物3-2)與三份含在乙醚(6.9 ml，然後在室溫下攪拌45 min；11.6 ml，然後在室溫下攪拌2 h；6.9 ml，然後在室溫下攪拌2 h)中之3M溴化甲基鎂溶液反應。於針對於中間物5-1進行處理後，獲得2.39 g粗產物，該粗產物無需進一步純化即可進一步使用。中間物 6-1 2-(3- 羥基 -3- 甲基丁基 )-5- 硝基 -2H- 吲唑 -6- 羧酸甲酯 
首先將5.00 g (22.6 mmol) 5-硝基-1H-吲唑-6-羧酸甲酯(中間物1-1)加入40 ml DMF中。添加5.65 g (33.9 mmol) 4-溴-2-甲基丁-2-醇、9.37 g (67.8 mmol)碳酸鉀及5.63 g (33.9 mmol)碘化鉀且在100℃下攪拌該混合物20 h。添加水，用乙酸乙酯萃取該混合物三次及用氯化鈉溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)純化殘餘物。將獲得的固體與乙醚攪拌，藉由吸力過濾出，用二乙醚洗滌及乾燥。獲得2.49 g標題化合物。
UPLC-MS(方法A1)：Rt
=0.93 min(UV偵測器：TIC)，質量實測值307.00。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.15 (s, 6H), 2.02 - 2.11 (m, 2H), 3.84 (s, 3H), 4.54 (s, 1H), 4.58 - 4.65 (m, 2H), 8.05 (s, 1H), 8.69 (s, 1H), 8.86 (s, 1H)。中間物 7-1 5- 胺基 -2-(3- 羥基 -3- 甲基丁基 )-2H- 吲唑 -6- 羧酸甲酯 
將4.53 g鐵及217 mg氯化銨添加至含在30 ml乙醇及10 ml水中之2.49 g (8.10 mmol) 2-(3-羥基-3-甲基丁基)-5-硝基-2H-吲唑-6-羧酸甲酯(中間物6-1)，且在90℃下攪拌該混合物21.5 h。使該混合物濾過矽藻土且用乙醇洗滌三次，及濃縮濾液並將殘餘物與水混合。用乙酸乙酯實施萃取三次(為改良相分離，添加氯化鈉溶液)。用氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。此提供1.95 g(理論量之85%)標題化合物。
UPLC-MS(方法A1)：Rt
=0.67 min(UV偵測器：TIC)，質量實測值277.00。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.14 (s, 6H), 1.96 - 2.08 (m, 2H), 3.85 (s, 3H), 4.39 - 4.51 (m, 3H), 5.81 (s, 2H), 6.80 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H)。工作實例 實例 1 N-[6-(2- 羥丙 -2- 基 )-2-(2- 甲氧基乙基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將75 mg (0.18 mmol) 2-(2-甲氧基乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-2)溶解於500 µl THF中且與887 µl (0.89 mmol)含在THF中之1 M溴化甲基鎂溶液混合。在25℃下攪拌該反應混合物60 min。隨後，小心地添加1 ml飽和氯化銨水溶液及過濾該混合物。用乙酸乙酯萃取水相兩次，及合併有機相，通過疏水性過濾器過濾並濃縮。將殘餘物溶解於3 ml DMSO中及藉由製備型HPLC純化。冷凍乾燥含產物部分。獲得20 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.08 min
MS (ESIpos): m/z = 423 (M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 3.22 (s, 3 H), 3.82 (t, 2 H), 4.55 (t, 2 H), 5.96 (s, 1 H), 7.57 (s, 1 H), 8.16 (d1 H), 8.29 - 8.42 (m, 2 H), 8.42 - 8.50 (m, 1 H), 8.71 (s, 1 H), 12.36 (s, 1 H)實例 2 N-[6-( 羥甲基 )-2-(2- 甲氧基乙基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將13 mg (0.36 mmol)氫化鋁鋰懸浮於1 ml THF中及使該混合物冷卻至0℃。滴加溶解在500 µl THF中之75 mg (0.17 mmol) 2-(2-甲氧基乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-2)且在25℃下攪拌該混合物60 min。用水稀釋該混合物且用乙酸乙酯萃取兩次，及用氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾，濃縮並於減壓下乾燥。此提供13 mg標題化合物。
UPLC-MS(方法A2)：Rt
=0.99 min
MS (ESIpos): m/z = 394 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.23 (s, 3 H), 3.83 (t, 2 H), 4.56 (t, 2 H), 4.69 (d, 2 H), 5.77 (t, 1 H), 7.57 (s, 1 H), 8.19 (d, 1 H), 8.33 - 8.41 (m, 2 H), 8.43 - 8.47 (m, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H)實例 3 N-[6-(2- 羥丙 -2- 基 )-2-(3- 甲氧基丙基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將75 mg (0.17 mmol) 2-(3-甲氧基丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-3)溶解於500 µl THF中且與859 µl (0.86 mmol)含在THF中之1 M甲基溴化鎂溶液混合。在25℃下攪拌該反應混合物60 min。隨後，小心地添加1 ml飽和氯化銨溶液且過濾該混合物。用乙酸乙酯萃取水相兩次，及合併有機相，通過疏水性過濾器過濾並濃縮。將殘餘物溶解於3 ml DMSO中且藉由製備型HPLC純化。冷凍乾燥含產物部分。獲得25 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.13 min
MS (ESIpos): m/z = 437 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 2.14 (五重峰, 2 H), 3.23 (s, 3 H), 3.26 - 3.32 (m, 2 H), 4.44 (t, 2 H), 5.95 (s, 1 H), 7.58 (s, 1 H), 8.16 (d, 1 H), 8.31 - 8.40 (m, 2 H), 8.43 - 8.48 (m, 1 H), 8.72 (s, 1 H), 12.36 (s, 1 H)。實例 4 N-[6-( 羥甲基 )-2-(3- 甲氧基丙基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將13 mg氫化鋁鋰懸浮於THF中且使該混合物冷卻至0℃。滴加75 mg (0.17 mmol)含在THF中之2-(3-甲氧基丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-3)且使該混合物在30 min內冷卻至室溫。用水稀釋該混合物並過濾，用乙酸乙酯洗滌殘餘物及用乙酸乙酯萃取濾液。用氯化鈉溶液洗滌合併的乙酸乙酯相，通過疏水性過濾器過濾並濃縮。藉由製備型HPLC純化殘餘物。1
H NMR (300 MHz, DMSO-d 6
): δ [ppm] = 2.14 (五重峰, 2 H), 3.23 (s, 3 H), 3.29 (t, 2 H), 4.45 (t, 2 H), 4.68 (d, 2 H), 5.77 (t, 1 H), 7.58 (s, 1 H), 8.18 (d, 1 H), 8.32 - 8.48 (m, 3 H), 8.51 (s, 1 H), 11.21 (s, 1 H)。實例 5 N-[2-(2- 羥乙基 )-6-(2- 羥丙 -2- 基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 步驟 A ：
N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺之製法
將100 mg (0.19 mmol) 2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-5)溶解於1 ml THF中且與669 µl (0.67 mmol)含在THF中之1 M甲基溴化鎂溶液混合。在25℃下攪拌該反應混合物60 min。添加另一份287 µl (0.29 mmol)的含在THF中之1 M溴化甲基鎂溶液且在25℃下攪拌該混合物3 h。隨後，小心地添加20 ml飽和氯化銨及過濾該混合物。用乙酸乙酯萃取水相兩次，及合併有機相，於硫酸鎂上乾燥，過濾，濃縮並於減壓下乾燥。此提供50 mg N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺。
UPLC-MS(方法A2)：Rt
=1.51 min
MS (ESIpos): m/z = 523(M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.17 - -0.09 (m, 6 H), 0.78 (s, 9 H), 1.62 (s, 6 H), 4.04 (t, 2 H), 4.47 (t, 2 H), 5.98 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.29 (s, 1 H), 8.37 (t, 1 H), 8.45 (d, 1 H), 8.73 (s, 1 H), 12.38 (s, 1 H)。步驟 B ： 
將50 mg (96 µmol) N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺溶解於1.0 ml THF中且與144 µl (0.14 mmol)之氟化四丁基銨含在THF中之1 M溶液混合。在室溫下攪拌該反應混合物1 h。用水稀釋該混合物且用乙酸乙酯萃取兩次，及用飽和氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。此提供36 mg N-[2-(2-羥乙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(實例5)。1
H-NMR (400MHz, DMSO-d6
): d [ppm] = 1.62 (s, 6H), 3.86 (q, 2H), 4.43 (t, 2H), 4.95 (t, 1H), 5.94 (s, 1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.30 (s, 1H), 8.37 (t, 1H), 8.45 (d, 1H), 8.72 (s, 1H), 12.36 (s, 1H)。
UPLC-MS(方法A2)：Rt
=0.97 min(UV偵測器：TIC)，質量實測值408.00。實例 6 N-[6-(2- 羥丙 -2- 基 )-2-(3- 羥丙基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺
步驟A：
N-[2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺之製法
將50 mg (0.09 mmol) 2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-6)溶解於500 µl THF中且與326 µl (0.33 mmol)含在THF中之1 M溴化甲基鎂溶液混合。在25℃下攪拌反應混合物60 min。隨後，小心地添加20 ml飽和氯化銨溶液且用乙酸乙酯萃取該混合物兩次。通過疏水性過濾器過濾合併的有機相，濃縮並於減壓下乾燥。藉由製備型HPLC純化殘餘物。獲得40 mg N-[2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺。
UPLC-MS(方法A1)：Rt
=1.58 min
MS (ESIpos): m/z = 537(M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = 0.02 - 0.05 (m, 6 H), 0.84 - 0.91 (m, 9 H), 1.62 (s, 6 H), 2.02 - 2.18 (m, 2 H), 3.55 - 3.62 (m, 2 H), 4.45 (t, 2 H), 5.96 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.31 (s, 1 H), 8.33 - 8.42 (m, 1 H), 8.45 (d, 1 H), 8.72 (s, 1 H), 12.37 (s, 1 H)。步驟 B ： 
將37 mg (0.07 mmol) N-[2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺溶解於500 µl THF中且與207 µl (0.21 mmol)含在THF中之1 M氟化四丁基銨溶液混合。在25℃下攪拌反應混合物2 h。用水稀釋該混合物及用乙酸乙酯萃取兩次，且用飽和氯化鈉溶液洗滌合併的有機相，過濾並濃縮。藉由製備型HPLC純化後，獲得10 mg N-[6-(2-羥丙-2-基)-2-(3-羥丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(實例6，含有次要組分)。
UPLC-MS(方法A2)：Rt
=1.00 min
MS (ESIpos): m/z = 423 (M+H)+ 1
H NMR 所選信號 (400 MHz, DMSO-d6): δ [ppm] = 1.61 (s), 2.00 - 2.12 (m), 3.38 (t, 2 H), 4.44 (t, 2 H), 4.62 (br. s., 1 H), 5.93 (br. s., 1 H), 7.55 (s, 1 H), 8.13 (d, 1 H), 8.27 - 8.38 (m, 2 H), 8.43 (d, 1 H), 8.71 (s, 1 H), 12.30 (br. s., 1 H)。實例 7 N-[2-(2- 羥乙基 )-6-( 羥甲基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 步驟 A ：
N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
將100 mg (0.19 mmol) 2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-5)溶解於1 ml THF中且與191 µl (0.38 mmol) 2 M硼氫化鋰溶液混合。讓該混合物在25℃下攪拌24 h。添加14 mg (0.38 mmol)硼氫化鈉及500 µl甲醇，且在25℃下攪拌該混合物4 h。添加另一份14 mg (0.38 mmol)的硼氫化鈉，且在25℃下攪拌該混合物24 h。小心地將水添加至該反應混合物且移除有機殘餘物。接著用乙酸乙酯萃取該混合物兩次，且用飽和氯化鈉溶液洗滌合併的有機相兩次，通過疏水性過濾器過濾並濃縮。將殘餘物溶解於2 ml DMSO中且藉由製備型HPLC純化。此可提供30 mg N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺。
UPLC-MS(方法A2)：Rt
=1.44 min
MS (ESIpos): m/z = 495(M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = -0.16 - -0.12 (m, 6 H), 0.75 - 0.79 (m, 9 H), 4.05 (t, 2 H), 4.48 (t, 2 H), 4.69 (d, 2 H), 5.75 - 5.77 (m, 1 H), 7.57 (s, 1 H), 8.18 (dd, 1 H), 8.30 - 8.33 (m, 1 H), 8.38 (t, 1 H), 8.45 (d, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H)。步驟 B ： 
將33 mg (0.07 mmol) N-[2-(2-{[第三丁基(二甲基)甲矽烷基]氧基}乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺溶解於1 ml THF中且與100 µl (0.10 mmol)含在THF中之1 M四丁基氟化鋰溶液。在25℃下攪拌反應混合物1 h。用水稀釋該混合物且用乙酸乙酯萃取兩次，及用飽和氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾，濃縮並於減壓下乾燥。獲得25 mg N-[2-(2-羥乙基)-6-(羥甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(實例7)。
UPLC-MS(方法A2)：Rt
=0.87 min
MS (ESIpos): m/z = 381 (M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.87 (q, 2 H), 4.44 (t, 2 H), 4.69 (d, 2 H), 4.98 (t, 1 H), 5.70 - 5.81 (m, 1 H), 7.57 (s, 1 H), 8.11 - 8.23 (m, 1 H), 8.31 - 8.42 (m, 2 H), 8.43 - 8.49 (m, 1 H), 8.51 (s, 1 H), 11.20 (s, 1 H)。實例 8 N-[6-(2- 羥丙 -2- 基 )-2-( 氧雜環丁 -3- 基甲基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將50 mg (0.12 mmol) 2-(氧雜環丁-3-基甲基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-1)溶解於500 µl THF中且與576 µl(0.58 mmol)含在THF中之1 M溴化甲基鎂溶液混合。在25℃下攪拌反應混合物60 min。隨後，小心地添加20 ml飽和氯化銨水溶液且濃縮該混合物。用乙酸乙酯萃取水相兩次，且合併有機相，於硫酸鎂上乾燥，過濾並濃縮。將殘餘物溶解於2.0 ml DMSO且藉由製備型HPLC純化。冷凍乾燥含產物部分。獲得30 mg標題化合物。
UPLC-MS(方法A2)：Rt
=1.03 min
MS (ESIpos): m/z = 435 (M+H)+ 1
H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.62 (s, 6 H), 3.45 - 3.61 (m, 1 H), 4.48 (t, 2 H), 4.66 (dd, 2 H), 4.72 (d, 2 H), 5.94 (s, 1 H), 7.57 (s, 1 H), 8.16 (d, 1 H), 8.33 - 8.42 (m, 2 H), 8.42 - 8.47 (m, 1 H), 8.72 (s, 1 H), 12.36 (s, 1 H)。實例 9 N-[6-( 羥甲基 )-2-( 氧雜環丁 -3- 基甲基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將75 mg (0.17 mmol) 2-(氧雜環丁-3-基甲基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-1)溶解於1 ml THF/甲醇(1:1)混合物中，且添加8 mg (0.21 mmol)氫氧化鈉。讓該混合物在25℃下攪拌60 min。濃縮反應混合物，且將殘餘物與水混合。劇烈攪拌該懸浮液15 min，及藉由吸力過濾出固體，用水洗滌兩次且用二乙醚洗滌兩次，然後於減壓下乾燥。獲得48 mg標題化合物。
UPLC-MS(方法A2)：Rt
=0.94 min
MS (ESIpos): m/z = 407 (M+H)+ 1
H NMR (300 MHz, DMSO-d6): δ [ppm] = 3.55 (s, 1 H), 4.48 (t, 2 H), 4.61 - 4.77 (m, 6 H), 7.57 (s, 1 H), 8.18 (dd, 1 H), 8.33 - 8.49 (m, 3 H), 8.51 (s, 1 H), 11.21 (s, 1 H)。實例 10 N-{6-(2- 羥丙 -2- 基 )-2-[3-( 甲基磺醯基 ) 丙基 ]-2H- 吲唑 -5- 基 }-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
在室溫攪拌500 mg (1.32 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)、569 mg碳酸鉀及114 mg碘化鉀含在5.0 ml DMF中之混合物15 min。添加414 mg 1-溴-3-(甲基磺醯基)丙烷且在室溫下攪拌該混合物過夜。添加水，用乙酸乙酯萃取該混合物兩次且用氯化鈉溶液洗滌萃取物並濃縮。藉由管柱層析(二氯甲烷/甲醇梯度)純化殘餘物。將產物部分與乙醚攪拌，過濾然後乾燥。獲得59 mg標題化合物。
UPLC-MS(方法A2)：Rt
=1.02 min
MS (ESIpos): m/z = 485 (M+H)+1
H-NMR (300MHz, DMSO-d6
): δ [ppm]= 1.63 (s, 6H), 2.26 - 2.42 (m, 2H), 2.99 (s, 3H), 3.06 - 3.16 (m, 2H), 4.55 (t, 2H), 5.96 (s, 1H), 7.60 (s, 1H), 8.16 (d, 1H), 8.33 - 8.48 (m, 3H), 8.73 (s, 1H), 12.37 (s, 1H)。實例 11
N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺
製法1
首先將705 mg (1.57 mmol) 2-(3-羥基-3-甲基丁基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-4)加入10 ml THF中且在冰-水冷卻浴中冷卻。添加2.6 ml (5.0當量) 3M溴化甲基鎂溶液(含於乙醚中)及讓該混合物攪拌同時用冰浴冷卻1 h繼而在室溫下冷卻4.5 h。添加另一份1當量的溴化甲基鎂溶液且讓該混合物在室溫下攪拌20.5 h。再添加另一份1當量的溴化甲基鎂溶液且讓該混合物在室溫下攪拌22 h。將反應混合物與飽和氯化銨水溶液混合，攪拌且用乙酸乙酯萃取三次。用氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。此提供790 mg殘餘物，其藉助於製備型HPLC純化。此提供234 mg標題化合物及164 mg產物部分，將該產物部分與乙醚攪拌。藉由吸力過濾接著乾燥之後，獲得另一份146 mg的標題化合物。
UPLC-MS(方法A1)：Rt
=1.10 min(UV偵測器：TIC)，質量實測值450.00。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.14 (s, 6H), 1.61 (s, 6H), 1.99 - 2.08 (m, 2H), 4.42 - 4.55 (m, 3H), 5.93 (s, 1H), 7.56 (s, 1H), 8.15 (dd, 1H), 8.32 - 8.39 (m, 2H), 8.41 - 8.47 (m, 1H), 8.70 (s, 1H), 12.34 (s, 1H)。
製法2
在室溫下攪拌500 mg (1.37 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)、569 mg碳酸鉀及114 mg碘化鉀含在5 ml DMF中之混合物15 min。添加344 mg (1.5當量) 4-溴-2-甲基丁-2-醇且將該混合物加熱至100℃維持2 h。添加另一份0.5當量的4-溴-2-甲基丁-2-醇且在室溫下攪拌該混合物16 h。將該混合物與水混合且用乙酸乙酯萃取兩次，及用飽和氯化鈉溶液洗滌合併的有機相且通過疏水性過濾器過濾並濃縮。藉由於矽膠上進行之管柱層析純化(己烷/乙酸乙酯)來純化殘餘物。此提供100 mg產物部分，將該產物部分與乙醚攪拌。過濾固體並乾燥。獲得60 mg標題化合物。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.14 (s, 6 H), 1.61 (s, 6H), 1.99 - 2.07 (m, 2 H), 4.43 - 4.52 (m, 3 H) 5.94 (s, 1 H) 7.57 (s, 1 H) 8.15 (dd, 1H) 8.33 - 8.40 (m, 2 H), 8.42 - 8.48 (m, 1 H), 8.71 (s, 1 H), 12.35 (s, 1 H)實例 12
N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺
使160 mg (0.44 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)連同182 mg碳酸鉀及36 mg碘化鉀懸浮於1.0 ml DMF中，且在室溫下攪拌該混合物15 min。接著添加123 mg 2-溴乙基甲基碸(0.66 mmol)且在室溫下攪拌該混合物過夜。添加水，用乙酸乙酯萃取該混合物兩次且用飽和氯化鈉水溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由製備型HPLC純化殘餘物提供20 mg標題化合物。
UPLC(方法A2)：Rt
=1.01 min；
MS (ESIpos): m/z = 471 (M+H)+1
H NMR (400 MHz, DMSO-d 6
): δ [ppm]= 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4.86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.13 - 8.19 (m, 1 H), 8.37 (s, 1 H), 8.41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H)。實例 13
6-(二氟甲基)-N-[2-(3-羥基-3-甲基丁基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]吡啶-2-甲醯胺
製法1
在室溫下攪拌250 mg 6-(二氟甲基)-N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]吡啶-2-甲醯胺(中間物5-2之粗產物)、144 mg碘化鉀及239 mg碳酸鉀含在2.5 ml DMF中之混合物15 min。添加145 mg (0.87 mmol) 4-溴-2-甲基丁-2-醇，在110℃下攪拌該混合物3 h，添加另一份96 mg的4-溴-2-甲基丁-2-醇且在110℃下攪拌該混合物4 h。添加水，用乙酸乙酯萃取該混合物兩次且用半飽和氯化鈉水溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由於矽膠上進行之管柱層析(己烷/乙酸乙酯)進行純化。獲得61 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.00 min(UV偵測器：TIC)，質量實測值432.00。1
H-NMR (300MHz, DMSO-d6
): δ [ppm]= 1.14 (s, 6H), 1.63 (s, 6H), 1.97 - 2.08 (m, 2H), 4.41 - 4.55 (m, 3H), 5.99 (s, 1H), 7.03 (t, 1H), 7.56 (s, 1H), 7.94 – 8.00 (m, 1H), 8.24 - 8.38 (m, 3H), 8.71 (s, 1H), 12.49 (s, 1H)。
製法2
類似於實例11之製法(製法1)，使3.00 g 5-({[6-(二氟甲基)吡啶-2-基]羰基}胺基)-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物4-11)與3M甲基溴化鎂溶液(含於乙醚中)反應。於粗產物藉由與乙醚攪拌過濾接著藉由製備型HPLC之純化後，獲得1.37 g標題化合物。實例 14
6-(二氟甲基)-N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}吡啶-2-甲醯胺
在室溫下攪拌250 mg 6-(二氟甲基)-N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]吡啶-2-甲醯胺(中間物5-2之粗產物)、144 mg碘化鉀及239 mg碳酸鉀含在2.5 ml DMF中之混合物15 min。添加162 mg 2-溴乙基甲基碸(0.87 mmol)且在110℃下攪拌該混合物3 h。添加水，用乙酸乙酯萃取該混合物兩次且用半飽和氯化鈉水溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由製備型HPLC純化殘餘物且產物部分藉由於矽膠上進行之管柱層析純化(己烷/乙酸乙酯)來另外純化。獲得40 mg標題化合物。1
H-NMR (400MHz, DMSO-d6
):δ [ppm]= 1.65 (s, 6H), 2.90 (s, 3H), 3.85 (t, 2H), 4.85 (t, 2H), 6.03 (s, 1H), 7.04 (t, 1H), 7.59 (s, 1H), 7.98 (d, 1H), 8.25 - 8.36 (m, 2H), 8.43 (s, 1H), 8.75 (s, 1H), 12.52 (s, 1H)。實例 15 6-( 二氟甲基 )-N-[6-(2- 羥丙 -2- 基 )-2-(3- 羥丙基 )-2H- 吲唑 -5- 基 ] 吡啶 -2- 甲醯胺 步驟 A ：
N-[2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(二氟甲基)吡啶-2-甲醯胺之製法
在室溫下攪拌250 mg 6-(二氟甲基)-N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]吡啶-2-甲醯胺(中間物5-2)、48 mg碘化鉀及239 mg碳酸鉀含在2.5 ml DMF中之混合物15 min。添加219 mg (0.87 mmol，1.5當量) (3-溴丙氧基)(第三丁基)二甲基矽烷且在110℃下攪拌該混合物3 h。添加另一份1當量的(3-溴丙氧基)(第三丁基)二甲基矽烷且在100℃下攪拌該混合物4 h。添加水，用乙酸乙酯萃取該混合物且用氯化鈉水溶液洗滌萃取物，通過疏水性過濾器過濾並濃縮。藉由管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得92 mg標題化合物。步驟 B ： 
類似於實例6步驟B之製法，使92 mg N-[2-(3-{[第三丁基(二甲基)甲矽烷基]氧基}丙基)-6-(2-羥丙-2-基)-2H-吲唑-5-基]-6-(二氟甲基)吡啶-2-甲醯胺與0.53 ml含在THF中之1 M氟化四丁基銨溶液在1 h內反應。進行如實例6中之水性處理且藉由製備型HPLC純化，提供46 mg標題化合物。
UPLC-MS(方法A1)：Rt
=0.92 min(UV偵測器：TIC)，質量實測值404.00。1
H-NMR (400MHz, DMSO-d6
):δ [ppm]= 1.64 (s, 6H), 2.05 (五重峰, 2H), 3.35 - 3.46 (m, 2H), 4.45 (t, 2H), 4.64 (t, 1H), 5.99 (s, 1H), 7.04 (t, 1H), 7.57 (s, 1H), 7.95 – 7.99 (m, 1H), 8.25 - 8.36 (m, 3H), 8.73 (s, 1H), 12.50 (s, 1H)。實例 16 N-[6-(2- 羥丙 -2- 基 )-2-(4,4,4- 三氟丁基 )-2H- 吲唑 -5- 基 ]-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
將210 mg (0.58 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)含在3 ml DMF中之混合物與0.11 ml (0.87 mmol) 1,1,1-三氟-4-碘丁烷及239 mg碳酸鉀混合，且在80℃下攪拌該混合物6 h。添加水後，用乙酸乙酯萃取該混合物三次，且用飽和氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。藉由製備型HPLC純化粗產物。獲得19 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.27 min(UV偵測器：TIC)，質量實測值474.15。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.62 (s, 6H), 2.10 - 2.33 (m), 4.49 (t, 2H), 5.94 (s, 1H), 7.59 (s, 1H), 8.13 - 8.18 (m, 1H), 8.32 - 8.41 (m, 2H), 8.41 - 8.47 (m, 1H), 8.72 (s, 1H), 12.35 (s, 1H)。實例 17 N-{6-(2- 羥丙 -2- 基 )-2-[3-( 三氟甲氧基 ) 丙基 ]-2H- 吲唑 -5- 基 }-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
首先將150 mg (0.33 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)加入2 ml THF中。添加58 mg (0.40 mmol) 3-(三氟甲氧基)丙-1-醇、131 mg三苯基膦及71 µl偶氮二羧酸二異丙酯(DIAD，CAS 2446-83-5)且在室溫下攪拌該混合物19 h。添加 0.83 ml氫氧化鈉溶液(2M)且在40℃下攪拌該混合物5 h。用水稀釋該混合物且用乙酸乙酯萃取三次，及濃縮合併的有機相且藉由製備型HPLC純化。獲得16 mg呈粗產物之標題化合物。
UPLC-MS(方法A2)：Rt
=1.26 min(UV偵測器：TIC)，質量實測值490.14。1
H-NMR (400MHz, DMSO-d6
, 所選信號): δ [ppm]= 1.61 (s, 6H), 1.84 (d, 1H), 2.32 (五重峰, 2H), 4.08 (t, 2H), 4.51 (t, 2H), 7.58 (s, 1H), 8.15 (d, 1H), 8.31 – 8.39 (m, 2H), 8.44 (d, 1H), 8.72 (s, 1H), 12.35 (s, 1H)。實例 18 N-{6-(2- 羥丙 -2- 基 )-2-[3-(2,2,2- 三氟乙氧基 ) 丙基 ]-2H- 吲唑 -5- 基 }-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
類似於實例11之製法(製法1)，使52 mg (0.10 mmol)含在3 ml THF中之2-[3-(2,2,2-三氟乙氧基)丙基]-5-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-2H-吲唑-6-羧酸甲酯(中間物4-10)與2×171 µl含在乙醚中之3M溴化鎂溶液反應。藉由製備型HPLC純化提供12 mg標題化合物。
UPLC-MS(方法A1)：Rt
=1.25 min(UV偵測器：TIC)，質量實測值504.16。1
H-NMR (500 MHz, DMSO-d6
): δ [ppm] = 1.63 (s, 6H), 2.20(五重峰, 2H), 3.58(t, 2H),4.05(q, 2H), 4.47(t, 2H),5.94(s, 1H), 7.58 (s, 1H), 8.15 (dd, 1H), 8.32 (s, 1H), 8.36 (t, 1H), 8.45(d, 1H), 8.73 (s, 1H), 12.36 (s,1H)。實例 19 5- 氟 -N-[2-(3- 羥基 -3- 甲基丁基 )-6-(2- 羥丙 -2- 基 )-2H- 吲唑 -5- 基 ]-6- 甲基吡啶 -2- 甲醯胺 
首先將228 mg (0.31 mmol) 5-{[(5-氟-6-甲基吡啶-2-基)羰基]胺基}-2-(3-羥基-3-甲基丁基)-2H-吲唑-6-羧酸甲酯(中間物4-8)加入4.5 ml THF中且用冰冷卻浴冷卻。添加0.63 ml 3M溴化甲基鎂溶液(含於乙醚中)且讓該混合物攪拌同時用冰浴冷卻2 h繼而在室溫下冷卻21 h。將該反應混合物與飽和氯化銨水溶液混合且用乙酸乙酯萃取三次。濃縮合併的有機相。藉由製備型HPLC純化殘餘物。獲得82 mg標題化合物。
UPLC-MS(方法A2)：Rt
=1.03 min(UV偵測器：TIC)，質量實測值414.21。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.13 (s, 6H), 1.63 (s, 6H), 1.99 - 2.05 (m, 2H), 2.55 - 2.59 (m, 3H), 4.42 - 4.50 (m, 3H), 5.95 (s, 1H), 7.54 (s, 1H), 7.83 (t, 1H), 8.05 (dd, 1H), 8.31 (s, 1H), 8.68 (s, 1H), 12.33 (s, 1H)。實例 20 N-[2-(3- 羥基 -3- 甲基丁基 )-6-(2- 羥丙 -2- 基 )-2H- 吲唑 -5- 基 ]-6- 甲基吡啶 -2- 甲醯胺 
首先將278 mg (0.48 mmol) 2-(3-羥基-3-甲基丁基)-5-{[(6-甲基吡啶-2-基)羰基]胺基}-2H-吲唑-6-羧酸甲酯(中間物4-9)加入5.0 ml THF中且用冰冷卻浴冷卻。添加0.97 ml 3M溴化甲基鎂溶液(含於乙醚中)且讓該混合物攪拌同時用冰浴冷卻2 h繼而在室溫下冷卻20.5 h。添加另一份0.48 ml的3M溴化甲基鎂溶液且讓該混合物在室溫下攪拌67 h。將該混合物與飽和氯化銨水溶液混合且用乙酸乙酯萃取三次，及用氯化鈉溶液洗滌萃取物，通過疏水過濾器過濾並濃縮。藉由製備型HPLC純化殘餘物。獲得111 mg標題化合物。
UPLC-MS(方法A2)：Rt
=0.97 min(UV偵測器：TIC)，質量實測值396.22。1
H-NMR (400MHz, DMSO-d6
): δ [ppm]= 1.15 (s, 6H), 1.64 (s, 6H), 2.00 - 2.08 (m, 2H), 2.61 (s, 3H), 4.41 - 4.59 (m, 3H), 5.92 (s, 1H), 7.50 (dd, 1H), 7.56 (s, 1H), 7.90 - 7.99 (m, 2H), 8.33 (s, 1H), 8.70 (s, 1H), 12.39 (s, 1H)。實例 21 6-(2- 羥丙 -2- 基 )-N-[6-(2- 羥丙 -2- 基 )-2-(4,4,4- 三氟丁基 )-2H- 吲唑 -5- 基 ] 吡啶 -2- 甲醯胺 
在冰/水冷卻浴中冷卻72 mg (0.16 mmol) 5-({[6-(2-羥丙-2-基)吡啶-2-yl]羰基}胺基)-2-(4,4,4-三氟丁基)-2H-吲唑-6-羧酸甲酯(中間物4-7)含在10 ml THF中之溶液。添加0.26 ml含在乙醚中之3M溴化甲基鎂溶液並攪拌該混合物2 h且接著在室溫下攪拌20 h。添加另一份1當量的3M溴化甲基鎂溶液且在室溫下攪拌該混合物24 h。添加飽和氯化銨水溶液，用乙酸乙酯萃取該混合物三次且用氯化鈉溶液洗滌萃取物並濃縮。製備型HPLC提供22 mg (理論量的31%)標題化合物。
UPLC-MS(方法A2)：Rt
=1.15 min(UV偵測器：TIC)，質量實測值464.20。1
H-NMR (400MHz, DMSO-d6
):δ [ppm]= 1.56 (s, 6H), 1.64 (s, 6H), 2.07 - 2.34 (m, 4H), 4.49 (t, 2H), 5.32 (s, 1H), 6.05 (s, 1H), 7.60 (s, 1H), 7.87 (dd, 1H), 7.99 - 8.05 (m, 2H), 8.35 (s, 1H), 8.79 (s, 1H), 12.45 (s, 1H)。實例 22 N-{2-[2-(1- 羥基環丙基 ) 乙基 ]-6-(2- 羥丙 -2- 基 )-2H- 吲唑 -5- 基 }-6-( 三氟甲基 ) 吡啶 -2- 甲醯胺 
首先將250 mg (0.69 mmol) N-[6-(2-羥丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲醯胺(中間物5-1)加入5 ml DMSO中。添加159 mg (0.96 mmol) 1-(2-溴乙基)環丙醇、285 mg碳酸鉀及171 mg碘化鉀且在100℃下攪拌該混合物5 h。添加水且用乙酸乙酯萃取該混合物三次。用氯化鈉溶液洗滌合併的有機相，通過疏水性過濾器過濾並濃縮。藉由製備型HPLC(管柱：Waters XBridge C18 5 µ 100×30 mm，洗脫劑A：水+0.1重量%甲酸(99%)，洗脫劑B：乙腈)純化殘餘物。冷凍乾燥提供45 mg標題化合物。1
H-NMR (500MHz, DMSO-d6
): δ [ppm]= 0.18 - 0.22 (m, 2H), 0.48 - 0.52 (m, 2H), 1.62 (s, 6H), 2.08 (t, 2H), 4.54 - 4.60 (m, 2H), 5.36 (s, 1H), 5.96 (s, 1H), 7.57 (s, 1H), 8.16 (dd, 1H), 8.34 - 8.39 (m, 2H), 8.45 (d, 1H), 8.72 (s, 1H), 12.36 (s, 1H)。生理效力之評定 IRAK4 激酶檢定
在後文所述的IRAK4 TR-FRET檢定(TR-FRET=時差式螢光共振能量轉移)中測量本發明物質之IRAK4-抑制活性。
使用表現於經桿狀病毒感染之昆蟲細胞(Hi5(BTI-TN-5B1-4)細胞株，購自Invitrogen，目錄號B855-02)中且通過親和層析純化之來自N端GST(麩光甘肽S-轉移酶)及人類IRAK4之重組型融合蛋白作為酵素。用於激酶反應之受質為生物素化肽生物素-Ahx-KKARFSRFAGSSPSQASFAEPG(C端呈醯胺形式)，其可例如購自Biosyntan GmbH (Berlin-Buch)。
對於該檢定，自測試物質之2 mM DMSO溶液製備在20 µM至0.073 nM範圍內的11種不同濃度。吸移50 nl各自溶液於黑色低容量384孔微量滴定盤(Greiner Bio-One，Frickenhausen，Germany)中，添加IRAK4含在檢定緩衝液[50 mM HEPES pH 7.5、5 mM MgCl2、1.0 mM二硫蘇糖醇、30 µM活化原釩酸鈉、0.1%(w/v)牛γ-球蛋白(BGG)、0.04%(v/v) nonidet-P40(Sigma)]中之溶液2 µl且培養該混合物15 min以使該等物質在激酶反應之前預先結合至該酵素。接著藉由添加腺苷三磷酸(ATP，1.67 mM=含於5 µl檢定體積中之最終濃度：1 mM)及肽受質(0.83 µM=含於5 µl檢定體積中之最終濃度：0.5 µM)含在檢定緩衝液中之溶液3 µl開始激酶反應，且在22℃下培養所得混合物45 min反應時間。將IRAK4之濃度調整至酵素之各自活性並設置使得該檢定在線性範圍內進行。典型濃度為約0.2 nM級別。藉由添加TR-FRET偵測試劑[0.1 µM鰱黴親和素-XL665(Cisbio Bioassays；France，目錄號610SAXLG)]及1.5 nM抗磷酸絲胺酸抗體[Merck Millipore，STK抗體」，目錄號35-002]及0.6 nM LANCE EU-W1024標記抗小鼠-IgG抗體(Perkin-Elmer，產品代號AD0077；或者，可使用鋱穴狀化合物標記抗小鼠-IgG抗體，Cisbio Bioassays)含在EDTA水溶液(100 mM EDTA、0.4 %[w/v]牛血清白蛋白[BSA]含於25 mM HEPES pH 7.5中)中之溶液5 µl來終止反應。
在22℃下培養所得混合物1 h以形成生物素化磷酸化受質與偵測試劑之複合物。接著藉由測量自銪螯合物標記抗小鼠-IgG抗體轉移至鏈黴親和素-XL665之共振能量來評估磷酸化受質的量。對此，在TR-FRET測量儀器，例如Rubystar(BMG Labtechnologies，Offenburg，Germany)或Viewlux(Perkin-Elmer)中於350 nm下激發後測量在620 nm及665 nm下之螢光發射。使用在665 nm及622 nm下之發射之比率作為磷酸化受質的量之量度。將該數據標準化(無測試物質之酵素反應=0%抑制作用；存在所有其他檢定組分但無酵素=100%抑制作用)。典型地，於相同微量滴定盤上以在20 µM至0.073 nM範圍內的11種不同濃度(20 µM、5.7 µM、1.6 µM、0.47 µM、0.13 µM、38 nM、11 nM、3.1 nM、0.89 nM、0.25 nM及0.073 nM)測試該等測試物質。在檢定(2 mM至7.3 nM，含於100% DMSO中)之前藉由連續稀釋製備稀釋系列。藉由4-參數擬合計算IC50
值。表 1
：IRAK4激酶檢定中實例化合物之IC50
值 
亦在上述IRAK4 TR-FRET檢定中測量通式(III)之本發明物質對IRAK4之抑制活性。例如，提及下述：具有IC50
=21.7 nM之化合物中間物4-2、具有IC50
=13.0 nM之中間物4-3及具有IC50
=6.2 nM之中間物4-4。THP-1 細胞中之 TNF- α 分泌
此測試適於測試物質抑制THP-1細胞(人類單核細胞急性白血病細胞株)中TNF-α(腫瘤壞死因子α)之分泌之能力。TNF-α為涉及發炎過程之細胞介素。在此測試中，藉由用細菌脂多糖(LPS)培養觸發TNF-α分泌。
將THP-1細胞保存於連續懸浮細胞培養基[具有L-Glutamax (Gibco，目錄號61870-044)之補充胎牛血清(FCS) 10%(Invitrogen，目錄號10082-147)、1%青黴素/鏈黴素(Gibco BRL，目錄號15140-114)之RPMI 1460培養基]中且不應超過1×106
個細胞/ml之細胞濃度。該檢定係在細胞培養基(具有L-Glutamax之補充FCS 10%之RPMI 1460培養基)中進行。
在各情況中，以每孔2至2.5 µl細胞懸浮液(相當於4000個細胞)分散至384孔測試板(Greiner，目錄號784076)中，在該測試板的各孔中，40至50 nl物質已溶解於100% DMSO中。此係使用各物質在20 µM至0.073 nM範圍內的10種不同濃度來完成。在室溫下培養該等細胞15 min。接著將2至2.5 µl溶解於細胞培養基中之0.1 µg/ml LPS(Sigma，大腸桿菌055:B5，目錄號L5418) (最終濃度0.05 µg/ml)分散至各孔中。作為中性對照，用0.05 µg/ml LPS及1% DMSO處理細胞，及作為抑制對照，僅用1% DMSO處理細胞。
以80 g離心該等板30 s且在37℃、5% CO2
及95%大氣濕度下培養17 h。使用TNF-α HTRF偵測套組(Cisbio，目錄號62TNFPEB/C)測定TNF-α的量。對此，各情況中添加2 µl的由依製造商說明書溶解於複水緩衝液中之抗-TNF-α-XL665結合物及抗-TNF-α-穴狀化合物結合物組成之偵測溶液以用於HTRF(均相时间解析螢光)測試。添加後，在室溫下培養該混合物3 h或在4℃下培養過夜。接著在620/665 nm下使用可HTRF操作之測量儀器諸如BMG PheraStar來讀取信號。
該等物質之活性表示為中性及抑制對照之間的比率，單位為百分比。使用4參數擬合計算IC50
值。表 2
：實例化合物相對於THP-1細胞中TNF-α之分泌之IC50
值 
人類 PBMC( 周邊血液單核細胞 ) 中活體外 LPS( 脂多糖 ) 誘發之細胞介素產生
檢驗通式(I)之本發明化合物對人類PBMC中誘發之細胞介素產生之效應。細胞介素產生係在此處藉由LPS(TLR4配位體)誘發，此導致活化IRAK4介導之信號通路。
人類PBMC係從抗凝固人全血獲得。對此目的，首先吸移15 ml Ficoll-Paque(Biochrom，目錄號L6115)於Leucosep管中且添加20 ml人血。在室溫下以800 g離心血液15 min後，移去含有血小板之血漿並丟棄。將PBMC轉移至離心管中且藉由PBS(磷酸鹽緩衝鹽水)(Gibco，目錄號14190)處理。在室溫下以250 g離心細胞懸浮液10 min並丟棄上清液。將PBMC再懸浮於完全培養基(RPMI 1640，無L-麩醯胺酸(PAA，目錄號E15-039)、10% FCS；50 U/ml青黴素、50 µg/ml鏈黴素(PAA，目錄號P11-010)及1% L-麩醯胺酸(Sigma，目錄號G7513))中。
該檢定係亦在完全培養基中進行。PBMC係以2.5×105
個細胞/孔之細胞密度接種於96孔板中。在恆定體積的100% DMSO中連續稀釋本發明化合物且以在10 µM至3 nM範圍內的8種不同濃度用於該檢定使得最終DMSO濃度為0.4% DMSO。於實際刺激之前，接著由其預培養細胞30 min。為誘發細胞介素分泌，用0.1 µg/ml LPS(Sigma，大腸桿菌0128:B12，目錄號L2887)刺激細胞24小時。使用CellTiter-Glo發光檢定(Promega，目錄號G7571(G755/G756A))依製造商說明書測定細胞存活率。使用Human ProInflammatory 9-Plex Tissue Culture套組(MSD，目錄號K15007B)依製造商說明書測定細胞培養上清液中所分泌的TNF-α量。舉例來說，實例化合物11及實例化合物12具有≤1 µM的活性。人類樹突細胞 (DC) 之活體外 TLR-4/TLR-7 誘發之介白素 (IL)-23 分泌
在人類DC中檢驗通式(I)之本發明化合物對誘發產生促發炎性細胞介素IL-23(其對於產生TH-17細胞起重要作用)之效應。據述TH-17細胞在疾病諸如類風濕性關節炎、牛皮癬性關節炎、別赫捷列夫氏病(僵直性脊椎炎)抑或多發性硬化症之發病機理中扮演重要角色(Lubberts, Nat. Rev. Rheumatol., 2015；Marinoni等人, Auto. Immun. Highlights, 2014；Isailovic等人, J. Autoimmun., 2015；Staschke等人, J Immunol., 2009)。為偵測本發明化合物對IL-23產生之效應，使人類初級單核細胞(從人類PBMC使用磁力分離[Miltenyi Biotech，單核細胞分離套組，目錄號130-091-153]且藉由添加含在完全培養基(VLE(極低含量的內毒素) RPMI 1640[Biochrom AG，目錄號FG1415]、10%胎牛血清(FBS)[Gibco，目錄號10493-106]；50 µM β-巰基乙醇[Gibco，目錄號31350]、50 U/ml青黴素及鏈黴素[Gibco，目錄號15140-114])中之生長因子(重組型人類GM-CSF[PeproTech，目錄號300-03]及IL-4[PeproTech，目錄號200-04])單離得)在培養基中於6天內分化為DC。在已收穫DC後，將其再懸浮於完全培養基且以2×105
個細胞/孔之細胞密度接種於96孔板(Costar，目錄號3599)中。在恆定體積的100% DMSO中連續稀釋本發明化合物且以在10 µM至1 nM範圍內的9種不同濃度用於該檢定。此處應確保所使用9種濃度之各者之DMSO濃度百分比始終為0.1% DMSO。用本發明化合物對DC進行30分鐘預培養。此後，藉由添加10 ng/ml LPS(Sigma，大腸桿菌(Escherichia coli
)血清型0127:B8，目錄號L3129)(TLR4配位體)及2.5 µg/ml TLR-7/8配位體R848(Invivogen，目錄號tlrl-r848-5)在培養箱(37℃、95%rH、5% CO2
)中刺激DC 24小時以產生IL-23，LPS及TLR-7/8配位體R848均活化IRAK4介導之信號傳遞通路。在此24小時的培養時間後，收穫上清液且使用市售hIL-23 ELISA(eBiosciences，目錄號88-7237-88)分析，此依製造商說明書進行。舉例來說，例如就實例化合物12而言，人類DC中IL-23之抑制之結果顯示於圖1中。人類漿細胞樣樹突細胞 (pDC) 之活體內 TLR-7/8- 或 TLR-9 誘發之 IFN α 產生
藉助於此測試，可研究通式(I)之本發明化合物對人類pDC中IFNα(干擾素-α)(為全身性紅斑狼瘡之發病機理中之重要細胞介素(Mathian等人, Arthritis Rheum, 2009；Crow M.K., Rheum Dis Clin N Am, 2010))之產生之效應。針對此目的，如上所述自全血分離人類PBMC及自其使用市售細胞分離套組(Miltenyi Biotech，漿細胞樣樹突細胞分離套組II，目錄號130-097-415)單離漿細胞樣DC(pDC)。將獲得的pDC再懸浮於完全培養基(補充10% FBS[Gibco，目錄號10493-106]及50 U青黴素/鏈黴素[Gibco，目錄號15140-114]之RPMI 1640+GlutaMax[Gibco
，目錄號61870-010])中且以5×104
個細胞/孔之細胞密度接種於96孔微量滴定板(Costar，目錄號3599)中。在恆定體積的100% DMSO中連續稀釋本發明化合物且以在10 µM至1 nM範圍內的9種不同濃度用於該檢定。確保9種測試濃度之各者之DMSO濃度百分比始終為0.1% DMSO。用本發明化合物對pDC進行30分鐘預培養。用TLR7/8配位體(咪喹莫特(R837)，Invivogen，目錄號tlrl-imq)或用TLR-9配位體(CPG-A(ODN2216)，Invivogen，目錄號tlrl-2216-1)刺激pDC且此導致活化IRAK4介導之信號傳遞通路。在培養24小時後，移去細胞培養上清液且使用市售人類IFNα ELISA(IFNalpha多亞型ELISA套組，pbl Assay Science，目錄號41105-1)分析。舉例來說，例如就實例化合物12而言，人類漿細胞樣DC中IFNα之抑制之結果顯示於圖2中。TLR 介導之發炎之活體內模型
檢驗通式(I)之本發明化合物在活體內TLR介導之發炎模型中之活體內效力。此機理模型尤其顯示本發明化合物於TLR4介導之疾病中之潛在效應，因為使用LPS介導之發炎模型。此模型中，將雌性Balb/c小鼠(約8週大；Charles River Laboratories，Germany)分成各5隻動物的組。用已溶解物質的媒劑(物質媒劑)亦及用已溶解LPS的媒劑處理對照組。物質處理組以及陽性對照組經腹膜內(i.p.)接受0.2 mg LPS/kg體重(Sigma，目錄號L4391)(脂多糖，來自大腸桿菌0111:B4)。此外，用上述物質媒劑處理陽性對照組。在藉由投與LPS誘發發炎16小時前經口投與該物質。為檢驗本發明化合物於發炎中之效應，1.5小時後從該等動物採集血樣。使用小鼠促發炎性7-Plex組織培養套組(MSD，目錄號K15012B)依製造商說明書測定血漿中特定細胞介素之濃度。IRAK4抑制劑在TLR介導之發炎模型中有效。圖3顯示血漿中TNF-α的量，其藉由投與實例化合物11比LPS誘發之濃度以劑量依賴性方式減少。IL-1β 介導之發炎之活體內模型
為評估通式(I)之本發明化合物在IL-1β介導之疾病中之潛在效力，向雌性Balb/c小鼠(約8週大，Charles River Laboratories，Germany)i.p.投與IL-1β且檢驗本發明化合物於IL-1β介導之細胞介素分泌之效應。每組有5隻動物。以用於溶解物質及IL-1β之媒劑處理對照組。物質處理組及陽性對照組各i.p.投與90 µg IL-1β /kg體重(R&D，目錄號401-ML/CF)。陽性對照組中之物質或其媒劑係在投與IL-1β 6小時前投與。投與IL-1β 2小時後，使用小鼠促發炎性7-Plex組織培養套組(MSD，目錄號K15012B)依製造商說明書測定自血液分離得的血樣中之TNF-α。IL-1β之投與導致增加的TNF-α血漿濃度，其藉由實例化合物11及12處理得到抑制。由圖4說明此點。活體內佐劑誘發之關節炎模型
為測定通式(I)之本發明化合物之抗發炎活性，檢驗其在關節炎模型中之活體內效力。針對此目的，在第0天，對各雄性路易士(Lewis)大鼠(約100至125 g，Charles River Laboratories，Germany)在尾基部中皮下投與100 µl完全弗氏佐劑(complete Freund's adjuvant)(CFA)溶液(結核分枝桿菌H37Ra(M. tuberculosis
H37Ra)[Difo Lab，目錄號231141]溶解於不完全弗氏佐劑(Incomplete Freund's adjuvant) [Difco Lab，目錄號263910]中)。每組有n=8隻大鼠。該研究中既包括健康對照組又包括患病對照組。對各對照組提供僅用測試物質之媒劑之p.o.處理。以預防方式，亦即，從第0天開始，藉由經口投與，進行測試物質之不同劑量之處理。在第0天，另外根據疾病活性評分(基於分數系統評定關節炎嚴重度等級)確定動物之起始條件。此處，根據兩隻後爪出現紅斑包括關節腫脹之關節發炎程度判定該等分數0至4(0=無；1=輕度；2=中度；3=顯著；4=重度)並加總。為確定該等化合物之抗發炎效力，藉助於疾病活性評分從第8天(動物最先出現關節炎征兆時)開始評分動物之疾病活性，且隨後每週3次，直到結束(第20天)。使用單因子變異數分析(ANOVA)且藉由藉助於多重比較分析(鄧恩試驗法(Dunnett's test))與對照組比較進行統計分析。
大鼠中s.c.投與CFA導致大鼠中具有顯著關節發炎之急性關節炎。藉由用實例化合物11之處理抑制該誘發之關節炎。由圖5說明此點。小鼠中活體內膠原蛋白抗體誘發之關節炎模型
檢驗通式(I)之本發明化合物在另一鼠科關節炎模型中之抗發炎效應。針對此目的，對各雌性Balb/c小鼠(約9週大，Charles River Laboratories，Kingston，Canada)於第0天在尾靜脈中經靜脈內注射200 µl膠原蛋白抗體混合物(10 mg/ml；ArthritoMab，MD Bioproducts)(除了該研究中包括的健康對照組之外)。第6天，此等小鼠接著各接受進一步腹膜內注射200 µl LPS。每組有n=10隻小鼠。該研究中包括健康對照組及患病對照組。對各對照組提供僅測試物質之媒劑之p.o.處理。以預防方式，亦即，從第0天開始，藉由經口投與，進行測試物質之不同劑量之處理。在實驗過程中，基於所有四隻爪的疾病活性評分之分數判定系統基礎，評分疾病程度。在此分數判定中，判定健康爪無分數，而在從趾引起通過蹠骨關節到踝關節之關節發炎之特定程度之各情況中判定從1[例如趾之輕度發炎]至4[延伸於整隻爪之重度發炎]之分數，說明如下：
● 0=正常
● 1=紅斑及局限於跗骨或踝或趾之輕度腫脹
● 2=紅斑及從踝延伸至蹠骨之輕度腫脹(2階段)
● 3=紅斑及從踝延伸遠至蹠骨關節之中度腫脹
● 4=紅斑及涵蓋蹠骨、腳及趾之重度腫脹
針對此參數，事先在開始實驗前提前一天(第-1天)確定起始條件且隨後從第8天開始每週三次評分此疾病活性評分。使用單因子變異數分析(ANOVA)且藉由藉助於多重比較分析(鄧恩試驗法)與對照組比較進行統計分析。
小鼠中i.v.投與膠原蛋白抗體混合物(包括於隨後i.p.投與LPS)導致具有顯著關節發炎之急性關節炎。藉由用實例化合物12之處理抑制此誘發之關節炎。由圖6說明此點。活體內 NASH 小鼠模型
為實驗上誘發NASH，對45隻雄性2天大的C57BL/6小鼠各皮下注射200 µg鏈佐黴素(STZ；Sigma-Aldrich，USA)。從4週大開始，對此等動物隨意餵養高脂飲食(HFD；57 kcal%脂肪，#HFD32，來自CLEA，Japan)。6週大時，將該等動物隨機分成3個組(每組15隻動物)。雖然該等組中一個組不接受任何處理，但其他2個組4週每天以媒劑或測試物質經口處理。於4週的處理後，於麻醉下以無痛方式殺死所有動物，及移去肝臟並在布安氏溶液(Bouin's solution)中固定以用於組織學研究(H. Denk, 「Fixierung histologischer Präparate」[Fixing of Histological Preparations]：P. Böck(編輯): 「Romeis Mikroskopische Technik」 [Romei's Microscopy Techniques], Urban & Schwarzenberg, Munich-Vienna-Baltimore 1989, 第17版, 第97頁, ISBN 3-541-11227-1)。此後，將肝臟樣本浸泡於石蠟中且製備5 µm厚的石蠟切片。染色各肝臟之組織學切片，a)用蘇木精-伊紅(haematoxylin-eosin)(HC)染色，以確定NAFLD活性分數(NAS)，及b)用苦味酸-天狼星紅(Picro-Sirius red)(Waldeck，Germany)染色，以確定肝纖維化。基於D.E. Kleiner等人, Hepatology 41 (2005), 1313-1321(表1)所推薦的標準，在蘇木精-伊紅切片中判定NAFLD活性分數。對於纖維變性區域之組織學定量，在200倍顯微鏡放大率下對各切片拍攝5張數位照片(DFC280；Leica，Germany)及使用ImageJ軟體(National Institute of Health，USA)判定纖維變性之百分率。活體內 db/db 小鼠模型
使用30隻雄性8週大的db/db小鼠。此模型為肥胖、胰島素抗性及2型糖尿病之較好接受的模型(Aileen JF King；The use of animal models in diabetes research; British Journal of Pharmacology 166 (2012), 877–894)。實驗期間，該等動物隨意接受標準飲食(RM1(E) 801492, SDS)及自來水。將該等動物隨機分成3個組(每組10隻動物)且以測試物質經口處理6週。研究期間，在不同時間點(開始處理前、開始處理後3週及處理結束前2天)自動物採集血液以測定胰島素敏感度參數(例如HbA1c、葡萄糖含量、胰島素含量)。此外，在開始處理前1天及結束處理後2天進行OGTT(口服葡萄糖耐受測試)作為用於判定胰島素敏感度之參數。此外，計算HOMA-IR指數(空腹胰島素濃度(mU/l) * 空腹葡萄糖濃度(mmol/l) / 22.5)。與活體內 B 細胞淋巴瘤相關聯之異種移植模型
在鼠科異種移植模型中研究通式(I)之本發明化合物之抗腫瘤活性。針對此目的，對雌性C.B-17 SCID小鼠皮下植入人類B細胞淋巴細胞株(例如TMD-8)。在平均腫瘤尺寸20至30 mm2
時，以本發明化合物開始口服單藥治療性處理或藉由投與本發明化合物與標準療法之組合，各係經口投與。然而，事先隨機分組該等動物。一旦未經處理之對照組具有大腫瘤，則即刻結束處理。每週三次測量腫瘤尺寸及體重。體重減輕為處理相關毒性之量度(＞10%=臨界，停止處理直到恢復，＞20%=毒性，終止)。藉由電子測徑規偵測腫瘤面積[長度(mm)×寬度(mm)]。研究結束時，亦測定腫瘤重量。抗腫瘤效力定義處理組之腫瘤重量對對照組之腫瘤重量之比率(T/C)[處理組第x天之腫瘤重量/對照組第x天之腫瘤重量]或處理組之腫瘤面積對對照組之腫瘤面積之比率[處理組第x天之腫瘤面積/對照組第x天之腫瘤面積]。T/C大於0.5之化合物定義為活性(有效)。使用單因子ANOVA且藉由藉助於成對比較分析(鄧恩試驗法)與對照組比較進行統計分析。
圖 1
：實例化合物12對人類單核細胞產生之DC中IL-23之抑制。數據顯示為平均值及標準偏差。圖 2
：實例化合物12對(A)咪喹莫特(R837)-或(B)CpG-A-刺激之人類漿細胞樣DC中INF-α之抑制。數據顯示為平均值及標準偏差。圖 3
：用實例化合物11處理LPS誘發之發炎導致所分泌TNF-α的量減少。數據顯示為平均值及標準偏差。圖 4
：用實例化合物11(左側)及12(右側)處理IL-1β誘發之發炎導致所分泌TNF-α的量之劑量依賴性減少。數據顯示為平均值及標準偏差。圖 5
：實例化合物11在類風濕性關節炎之動物模型(佐劑誘發之大鼠模型)中之抗發炎效應。基於疾病活性分數測得之類風濕性關節發炎之顯著且劑量依賴性抑制。數據對應於平均值+標準偏差。單因子ANOVA變異數分析及隨後藉助於鄧恩試驗法進行與CFA對照組之多重比較分析；*p＜0.05；**p＜0.01；***p＜0.001；****p＜0.0001。圖 6
：實例化合物12在類風濕性關節炎之動物模型(膠原蛋白抗體誘發之小鼠模型)中之抗發炎效應。基於疾病活性分數測得之類風濕性關節發炎之顯著且劑量依賴性抑制。數據對應於平均值+標準偏差。藉助於單因子ANOVA變異數分析及隨後之多重比較分析(鄧恩試驗法)計算得膠原蛋白抗體(AK)對照組與處理組之間之統計顯著性(*p＜0.05；**p＜0.01；***p＜ 0.001；****p＜0.0001)。
Claims (29)
- 一種通式(I)之化合物或其非鏡像異構體、對映體或鹽，
- 如請求項1之化合物或其非鏡像異構體、對映體或鹽，其中R1為C1-C6烷基，其中該C1-C6烷基係經R7SO2基或R7SO基單取代，或其中該C1-C6烷基係經R7SO2基或R7SO基之至少一者及一個或多個另一選自由以下所組成之群的取代基多取代：氟、羥基、R6基或R8O基；R2及R3始終具有相同定義且同時為氫或C1-C3烷基；R4為鹵素、氰基或C1-C3烷基，於此情況中，該C1-C3烷基係未經取代或相同或不同地經鹵素或羥基單-或多取代；R5為氫、氟、氯或C1-C3烷基；R6為氧雜環丁基或四氫呋喃基；R7為C1-C4烷基，於此情況中，該C1-C4烷基係未經取代或係經羥基或經環丙基單取代或經三個氟原子取代；R8為未經取代之C1-C4烷基或經三氟取代之C1-C4烷基。
- 如請求項1或2之化合物或其非鏡像異構體、對映體或鹽，其中R4為二氟甲基、三氟甲基或甲基。
- 如請求項1或2之化合物或其非鏡像異構體、對映體或鹽，其中R5為氫或氟。
- 如請求項1或2之化合物或其非鏡像異構體、對映體或鹽，其中R2及 R3同時為氫或甲基。
- 如請求項2之化合物或其非鏡像異構體、對映體或鹽，其中R1為C2-C6烷基，於此情況中，該C2-C6烷基係經R7SO2基單取代；R2及R3始終具有相同定義且同時為氫或甲基；R4為未經取代或經單-或多鹵素取代之C1-C3烷基或經一個羥基取代之C1-C3烷基或經一個羥基及三個氟原子取代之C1-C3烷基；R5為氫、氟或C1-C3烷基；R7為C1-C3烷基。
- 如請求項6之化合物或其非鏡像異構體、對映體或鹽，其中R1為經甲基-SO2-取代之C2-C4烷基；R2及R3始終具有相同定義且同時為氫或甲基；R4係選自由以下所組成之群：甲基、乙基、三氟-C1-C3烷基、二氟-C1-C3烷基、羥甲基、1-羥乙基、2-羥丙-2-基及2,2,2-三氟-1-羥乙基；R5為氫、氟或甲基。
- 如請求項7之化合物或其非鏡像異構體、對映體或鹽，其中R1為2-(甲基磺醯基)乙基或3-(甲基磺醯基)丙基；R2及R3同時為甲基或氫；R4為二氟甲基、三氟甲基或甲基； R5為氫或氟。
- 如請求項8之化合物或其非鏡像異構體、對映體或鹽，其中R1為3-(甲基磺醯基)丙基或2-(甲基磺醯基)乙基；R2及R3同時為甲基；R4為二氟甲基或三氟甲基；R5為氫。
- 如請求項8之化合物或其非鏡像異構體、對映體或鹽，其中R1為3-(甲基磺醯基)丙基或2-(甲基磺醯基)乙基；R2及R3同時為甲基；R4為甲基；R5為氟，於此情況中，R5係在R4的鄰位。
- 如請求項1或2之化合物或其非鏡像異構體、對映體或鹽，其中該化合物係如下：1)N-{6-(2-羥丙-2-基)-2-[3-(甲基磺醯基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺；2)N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲醯胺；或3)6-(二氟甲基)-N-{6-(2-羥丙-2-基)-2-[2-(甲基磺醯基)乙基]-2H-吲唑-5-基}吡啶-2-甲醯胺。
- 如請求項1或2所定義之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其係用於治療及/或預防疾病。
- 如請求項1或2所定義之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其係用於治療及/或預防腫瘤性疾病、皮膚疾病、婦科疾病、心血管疾病、肺病、眼科疾病、神經疾病、代謝疾病、肝病、發炎疾病、自體免疫疾病及疼痛之方法中。
- 如請求項1或2所定義之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其係用於治療及/或預防淋巴瘤、黃斑變性、牛皮癬、紅斑狼瘡、多發性硬化症、慢性阻塞性肺病(COPD)、痛風、非酒精性脂肪肝炎(NASH)、肝纖維化、胰島素抗性、代謝症候群、脊柱關節炎及類風濕性關節炎、及子宮內膜異位症之方法中。
- 如請求項1或2所定義之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其係用於治療及/或預防子宮內膜異位症相關疼痛及其他的與子宮內膜異位症相關聯之症狀之方法中。
- 如請求項15之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其中該與子宮內膜異位症相關聯之症狀係痛經、性交困難、排尿困難及排便困難。
- 如請求項1或2所定義之通式(I)之化合物或其非鏡像異構體、對映體 或鹽，其係用於治療及/或預防急性、慢性、發炎性及神經性疼痛之方法中。
- 如請求項17之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其係用於治療及/或預防痛覺過敏、痛覺異常、來自關節炎之疼痛、經前疼痛、與子宮內膜異位症相關聯之疼痛、術後疼痛、來自間質性膀胱炎之疼痛、CRPS(複雜性區域疼痛症候群)、三叉神經痛、來自前列腺炎之疼痛、由脊髓損傷誘發之疼痛、發炎誘發之疼痛、下背疼痛、癌症疼痛、與化學療法相關聯之疼痛、HIV治療誘發之神經病變、燒傷誘發之疼痛及慢性疼痛之方法中。
- 如請求項18之通式(I)之化合物或其非鏡像異構體、對映體或鹽，其中該關節炎係骨關節炎、類風濕性關節炎及脊柱關節炎。
- 一種如請求項1至11中任一項所定義之通式(I)之化合物或其非鏡像異構體、對映體或鹽之用途，其係用於製造治療及/或預防腫瘤性疾病、皮膚疾病、婦科疾病、心血管疾病、肺病、眼科疾病、神經疾病、代謝疾病、肝病、發炎性疾病、自體免疫疾病及疼痛之藥劑。
- 如請求項20之用途，其係針對於治療及/或預防淋巴瘤、黃斑變性、牛皮癬、紅斑狼瘡、多發性硬化症、慢性阻塞性肺病(COPD)、痛風、非酒精性脂肪肝炎(NASH)、肝纖維化、胰島素抗性、代謝症候群、脊柱關節炎及類風濕性關節炎、及子宮內膜異位症。
- 如請求項20之用途，其係針對於治療及/或預防子宮內膜異位症相關疼痛及其他的與子宮內膜異位症相關聯之症狀。
- 如請求項22之用途，其中該與子宮內膜異位症相關聯之症狀係痛經、性交困難、排尿困難及排便困難。
- 如請求項20之用途，其係針對於治療及/或預防急性、慢性、發炎性及神經性疼痛。
- 如請求項24之用途，其係針對於治療及/或預防痛覺過敏、痛覺異常、來自關節炎之疼痛、經前疼痛、與子宮內膜異位症相關聯之疼痛、術後疼痛、來自間質性膀胱炎之疼痛、CRPS(複雜性區域疼痛症候群)、三叉神經痛、來自前列腺炎之疼痛、由脊髓損傷誘發之疼痛、發炎誘發之疼痛、下背疼痛、癌症疼痛、與化學療法相關聯之疼痛、HIV治療誘發之神經病變、燒傷誘發之疼痛及慢性疼痛。
- 如請求項25之用途，其中該關節炎係骨關節炎、類風濕性關節炎及脊柱關節炎。
- 一種藥劑，其包含如請求項1至11中任一項所定義之式(I)之化合物或其非鏡像異構體、對映體或鹽與惰性、非毒性、醫藥上適宜之賦形劑之組合。
- 一種自通式(II)之化合物製備通式(III)之化合物之方法，
- 一種通式(III)之化合物或其非鏡像異構體、對映體或鹽，
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| TWI784954B (zh) * | 2016-06-01 | 2022-12-01 | 德商拜耳製藥公司 | 2－取代之吲唑於治療及預防自體免疫病症之用途 |
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