TW201803866A - Novel substituted benzimidazoles, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments - Google Patents

Novel substituted benzimidazoles, processes for their preparation, pharmaceutical preparations comprising them and their use for preparing medicaments Download PDF

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TW201803866A
TW201803866A TW106117811A TW106117811A TW201803866A TW 201803866 A TW201803866 A TW 201803866A TW 106117811 A TW106117811 A TW 106117811A TW 106117811 A TW106117811 A TW 106117811A TW 201803866 A TW201803866 A TW 201803866A
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methyl
carboxamide
benzimidazol
trifluoromethyl
pyridine
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史文 林
厄瑞屈 波斯
蘭哈德 努伯梅爾
沃夫 波默
茱蒂斯 剛瑟
尼可 史密特
朵羅西 安卓思
賀爾格 席比尼奇
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拜耳製藥公司
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present application relates to novel substituted benzimidazoles, to processes for their preparation, to their use, alone or in combinations, for the treatment and/or prophylaxis of diseases, and to their use for preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, of lymphoma, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disorders, insulin resistance, kidney disorders, neoplastic disorders and psoriasis.

Description

新穎經取代之苯并咪唑，其製備方法，包含其之醫藥製劑及其用於製備藥劑之用途Novel substituted benzimidazole, its preparation method, medicinal preparation containing it and its use for preparing medicament

本發明係關於新穎經取代之苯并咪唑，該等新穎經取代之苯并咪唑於治療及/或預防疾病之用途及其用於製備用於治療及/或預防疾病尤其增生性疾病、自體免疫性疾病、代謝及炎性疾病諸如(例如)類風濕性關節炎、脊柱關節炎(尤其牛皮癬性脊柱關節炎及別赫捷列夫氏病)、慢性阻塞性肺病(縮寫：COPD)、多發性硬化、全身性紅斑狼瘡、痛風、代謝症候群、脂肪肝肝炎、胰島素抗性、腎病、子宮內膜異位症及炎症引起或慢性疼痛及淋巴瘤之藥劑之用途。 本發明係關於通式(I)之新穎經取代之苯并咪唑，其抑制與白細胞介素-1受體相關聯之激酶4 (IRAK4)。The present invention relates to novel substituted benzimidazoles, the use of these novel substituted benzimidazoles in the treatment and / or prevention of diseases and their preparation for the treatment and / or prevention of diseases, especially proliferative diseases, autologous Immune diseases, metabolic and inflammatory diseases such as (for example) rheumatoid arthritis, spinal arthritis (especially psoriatic spinal arthritis and Bekhterev's disease), chronic obstructive pulmonary disease (abbreviation: COPD), multiple Use of medicaments for cirrhosis, systemic lupus erythematosus, gout, metabolic syndrome, fatty liver hepatitis, insulin resistance, nephropathy, endometriosis and inflammation or chronic pain and lymphoma. The present invention relates to a novel substituted benzimidazole of general formula (I) which inhibits kinase 4 (IRAK4) associated with interleukin-1 receptor.

人類IRAK4(與白細胞介素-1受體相關聯之激酶4)於免疫系統之啟動激活中起著重要關鍵作用。因此，該激酶為用於開發抑制炎症物質之發展之重要的治療靶分子。IRAK4籍由多種細胞表達表現及介導除TLR3之外之Toll樣類鐸受體(TLR)及由IL-1R(受體)、IL-18R、IL-33R及IL-36R組成之白細胞介素(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)。 無論剔除IRAK4之小鼠還是來自缺乏IRAK4之患者之人類細胞不對藉由TLR(除TLR3之外)及IL-1β家族之刺激作出反應(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配體或IL-1β家族之配體結合至各自之受體導致MyD88 [髓系分化原初反應基因(88)]之募集及結合至受體。結果，MyD88與IRAK4相互作用，導致與激酶IRAK1或IRAK2相互作用並活化該等激酶IRAK1或IRAK2之活性錯合物之形成(Kollewe、Mackensen等人，Journal of Biological Chemistry，2004；Precious等人，J. Biol. Chem.，2009)。由於此所致之，NF(核因子)-κB信號路徑及MAPK (絲裂原活化蛋白激酶)信號路徑經活化(Wang、Deng等人，Nature，2001)。NF-κB信號路徑及MAPK信號路徑二者之活化導致與不同免疫過程相關聯之過程。例如，存在諸如(例如)細胞介素、化學激活素及COX-2(環氧合酶-2)之各種炎症信號分子及酵素之表現增加及與炎症相關聯之基因(例如COX-2，IL-6(白細胞介素-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)。此外，該等過程可與特定細胞類型(例如單核細胞、巨噬細胞、數突細胞、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)。 IRAK4於各種炎性疾病之病理學中之核心作用已藉由野生型(WT)小鼠與具有激酶滅活形式之IRAK4 (IRAK4 KDKI)之遺傳改造動物之直接比較得以證實。IRAK4 KDKI動物於多發性硬化、動脈粥樣硬化、心肌梗塞及阿爾茨海默氏病(Alzheimer's disease)之動物模型中具有改善的臨床現象(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)。此外，發現動物模型中之IRAK4之缺失憑藉改善的抗病毒反應與同時減少的全身炎症保護免於病毒引起的心肌炎(Valaperti，Nishii等人，Circulation，2013)。已顯示IRAK4之表現與小柳原田(Vogt-Koyanagi-Harada)症候群之程度相關聯(Sun，Yang等人，PLoS ONE，2014)。此外，已顯示IRAK4針對藉由漿細胞樣樹突細胞產生之免疫錯合物-介導之IFNα (α干擾素)之高相關性，其為於全身性紅斑狼瘡(SLE)之發病機理中之關鍵過程(Chiang等人，The Journal of Immunology，2010)。此外，該信號路徑係與肥胖症相關聯(Ahmad，R., P. Shihab等人，Diabetology & Metabolic Syndrome，2015)。 此外IRAK4於先天性免疫中之關鍵作用，亦暗示IRAK4影響稱作Th17 T細胞(適應性免疫之組分)之分化。在缺乏IRAK4激酶活性之情況下，生成相較於WT小鼠較少的產生IL-17之T細胞(Th17 T細胞)。IRAK4之抑制使動脈粥樣硬化、1型糖尿病、類風濕性關節炎、脊柱關節炎(尤其牛皮癬性脊柱關節炎及別赫捷列夫氏病)、紅斑狼瘡、牛皮癬、白癜風、巨細胞動脈炎、慢性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)之預防及/或治療可行(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於TLR (除TLR3之外)及IL-1受體家族之MyD88介導之信號級聯中之核心作用，可利用IRAK4之抑制來預防及/或治療由上述受體介導之疾病。TLR以及IL-1受體家族之組分涉及風濕性關節炎、牛皮癬性關節炎、重症肌無力、血管炎(例如***(Behcet's disease))、具有多血管炎及巨細胞動脈炎之肉芽腫病、胰腺炎、全身性紅斑狼瘡、皮肌炎及多發性肌炎、包括(例如)胰島素抗性、高血壓、異常脂蛋白血症及肥胖症、糖尿病(1型及2型)、糖尿病性腎病、骨關節炎、乾燥症候群及敗血症之代謝症候群(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 and Koch，J Interferon Cytokine Res，2011；Akash，Shen等人，Journal of Pharmaceutical Sciences，2012；Goh and Midwood, Rheumatology，2012；Dasu, Ramirez等人，Clinical Science，2012；Ouziel，Gustot等人，Am J Patho，2012；Ramirez and 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)。諸如牛皮癬、特應性皮炎、金德勒氏(Kindler's)症候群、大皰性類天皰瘡、過敏性接觸性皮炎、斑禿、痤瘡及尋常痤瘡之皮膚病係與IRAK4-介導之TLR信號路徑或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)。 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)、結節病及肺動脈高壓之肺病亦顯示與各種TLR介導之信號路徑相關聯。肺病之發病機理可為感染介導或非感染介導之過程(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亦及IL-1R家族成員亦涉及其他諸如過敏、白塞病、痛風、紅斑狼瘡、成年發病斯提耳病(Still's disease)、心包炎及諸如潰瘍性結腸炎及克羅恩氏病(Crohn's disease)之慢性炎性腸病、移植排斥及移植物抗宿主反應之炎性疾病之發病機理及因此此處IRAK4之抑制為適宜的預防及/或治療之方法(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)。 藉由TLR及IL-1R家族介導之婦科疾病諸如子宮腺肌症、痛經、***困難及子宮內膜異位症，尤其與子宮內膜異位症相關聯之疼痛及其他諸如痛經、***困難、排尿困難及排便困難之與子宮內膜異位症相關聯之症狀可受IRAK4抑制劑之預防性及/或治療性使用之積極影響(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抑制劑之預防性及/或治療性使用亦可對動脈粥樣硬化具有積極影響(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)。 除已所提及之疾病之外，於諸如視網膜缺血、角膜炎、過敏性結膜炎、乾性角膜結膜炎、黃斑變性及葡萄膜炎之眼病之發病機理中已描述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之抑制亦為用於(例如)肝纖維化、心肌炎、原發性膽汁性肝硬化、囊性纖維化之纖維化疾病之適宜治療方法(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)。 憑藉IRAK4於藉由TLR及IL-1R家族介導之疾病中具有之關鍵地位，可利用IRAK4抑制劑以預防及/或治療方式治療(例如)脂肪肝肝炎及尤其非酒精性脂肪性肝病(NAFLD)及/或非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)之慢性肝病(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)。 此外，IRAK4抑制劑亦適用於腎功能不全及腎病諸如(例如)慢性腎病(CKD)、慢性腎衰竭、腎小球疾病、糖尿病性腎病變、狼瘡性腎炎、IgA腎炎(伯格氏病(Berger's disease))、腎硬化之治療。所提及之疾病係與TLR信號路徑及亦與IL-1受體家族之組分相關聯(Suzuki，Suzuki等人，Journal of the American Society of Nephrology，2008；Hahn，Cho等人，Pediatric Nephrology，2009；Conti，Spinelli等人，Clinical Reviews in Allergy & Immunology，2010；Bao，Na等人，Journal of Clinical Immunology，2011；Devaraj，Tobias等人，Arterioscler Thromb Vasc Biol，2011；Rosa Ramirez及Ravi Krishna Dasu，Curr Diabetes Rev，2012；Urbonaviciute，Starke等人，Arthritis & Rheumatism，2013；Batal等人，Transplantation，2014；Jialal，Major等人，J Diabetes Complications，2014；Lin及Tang，Nephrology Dialysis Transplantation，2014；Zawada，Rogacev等人，Epigenetic，2014；Elsherbiny及Al-Gayyar，Cytokine，2016；Yang等人，Mol Med Rep，2016)。 由於IRAK4於TLR介導之過程中之核心作用，IRAK4之抑制亦可治療及/或預防(例如)心肌再灌注損傷、心肌梗塞、高血壓、高血壓症之心血管及神經系統疾病 (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)，亦及阿爾茨海默氏病、中風、腦發作、顱腦創傷、肌萎縮側索硬化(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)。 由於於瘙癢症及包括急性、慢性、炎性及神經性疼痛之疼痛之情況中涉及經由TRAK4的TLR介導之信號與IL-1受體家族介導之信號，故可假設經由IRAK4之抑制於所提及之適應症中存在治療效果。疼痛之實例包括痛覺過敏、異常性疼痛、經前疼痛、與子宮內膜異位症相關聯之疼痛、手術後疼痛、間質性膀胱炎、CRPS(複雜性區域疼痛症候群)、三叉神經痛、***炎、由脊髓損傷引起之疼痛、炎症引起之疼痛、下背痛、癌症疼痛、與化療相關聯之疼痛、HIV治療引起之神經病變、燒傷引起之疼痛及慢性疼痛(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(活化之B細胞瀰漫型大細胞B細胞淋巴瘤)、套細胞淋巴瘤及瓦爾登斯特倫(Waldenström)病亦及慢性淋巴細胞白血病、黑素瘤、胰腫瘤及肝細胞癌係以MyD88中之突變或MyD88中之活性變化為特徵，該等疾病可由IRAK抑制劑治療(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於ras依賴性腫瘤中起著重要作用及因此IRAK4抑制劑亦適用於治療其等(Kfoury，A.，K. L. Corf等人，Journal of the National Cancer Institute，2013)。由於所提及之適應症與信號路徑相關聯，亦可假設經由IRAK4之抑制於乳癌、卵巢癌、結腸直腸癌、頭頸部癌、肺癌、***癌中存在治療效果 (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)。 炎症疾病諸如包括FCAS(家族性寒冷性自體炎性症候群)、MWS (穆韋二氏(Muckle-Wells)症候群)、NOMID (新生兒發病多系統炎性疾病)及CONCA(慢性嬰兒性神經性皮膚性及關節性)症候群之CAPS(與隱熱蛋白(cryopyrin)相關聯之週期性症候群)、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、成年發病斯提耳病、貝賽特氏症(Adamantiades-Behcet disease)、類風濕性關節炎、骨關節炎、乾性角膜結膜炎、PAPA症候群(化膿性關節炎、壞疽性膿皮病及痤瘡)、施尼茨勒症候群(Schnitzler's syndrome)及乾燥症候群係藉由阻斷IL-1信號路徑進行治療；因此IRAK4抑制劑亦適用於治療所提及之疾病(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之配體IL-33特定言之涉及急性腎衰竭之發病機理及因此IRAK4之抑制用於預防及/或治療之為適宜治療方法(Akcay，Nguyen等人，Journal of the American Society of Nephrology，2011)。IL-1受體家族之組分與心肌梗塞、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)相關聯及因此可預期經由IRAK4之抑制於所提及之適應症中之預防及/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)。 先前技術揭示大量IRAK4抑制劑(參見，例如，Annual Reports in Medicinal Chemistry(2014), 49, 117-133)。 WO2015091426描述吲唑諸如實例WO2015091426-64，其在2位置處經甲醯胺側鏈取代並抑制IRAK-4。然而，未描述苯并咪唑。 WO2003030902及Bioorg. Med. Chem. Lett. 16 (2006) 2842-2845描述作為IRAK4抑制劑之2-甲醯胺基苯并咪唑。 WO13042137描述作為IRAK4抑制劑的在2位置處經嗎啉取代之苯并咪唑，其中該嗎啉經由環氮連接至苯并咪唑。此外，該等苯并咪唑在1位置處未經取代。該等苯并咪唑可在5位置處經羥烷基取代，其中2-羥基丙-2-基未明確揭示於WO 13042137中。唯一明確揭示之苯并咪唑衍生物為WO 13042137-48 (6'-胺基-N-(2-嗎啉基-lH-苯并[d]咪唑-6-基)-[2,3'-聯吡啶]-6-甲醯胺)。 WO2006030031描述尤其作為mGluR2之陽性異位調節子之苯并咪唑，其中該等苯并咪唑可在1位置處經C1 -C6 烷基取代。然而，未明確揭示經甲基之取代。亦未明確揭示苯并咪唑。 WO2004072069描述作為類香草素受體(VR1)拮抗劑用於治療疼痛之苯并咪唑甲醯胺，其中該等苯并咪唑甲醯胺可在甲醯胺基團處經經取代之雜芳基取代。所提及之可能的雜芳基為吡啶基(較佳地3-吡啶基)、異噻唑基、噻唑基、噁唑基或吡唑基。此外，該等苯并咪唑甲醯胺可在1位置處經C1 至C12 烷基及在5位置處經C1 -C12 烷基取代，該等烷基可經-OH取代。僅明確揭示兩種苯并咪唑：WO2004072069-11 (N-(1H-苯并咪唑-6-基)-6-(4-氟苯基)-2-甲基菸鹼醯胺)及WO2004072069-12 (6-(4-氟苯基)-2-甲基-N-(1-甲基-1H-苯并咪唑-6-基)菸鹼醯胺)。 WO9422839描述作為多巴胺D4 受體之拮抗劑之苯并咪唑，其中該等苯并咪唑可在5位置處經烴取代。烴為可含有至多18個碳原子之直鏈、分支鏈或環狀基團(諸如，例如C1 -C6 烷基)。然而，未揭示在5位置處經羥烷基取代之苯并咪唑。 WO200157020描述作為因子Xa之抑制劑之苯并咪唑。該等苯并咪唑可在2位置處經以下基團取代： C1 -C8 烷基，然而其未經取代， C1 -C6 烷基-C3 -C8 環烷基，但並非C1 -C6 烷基-C3 -C8 雜環烷基， C1 -C8 烷基-NR10 R10 ，其中R10 可為H或C1 -C8 烷基， C1 -C8 -OR10 ，其中R10 可為H或C1 -C8 烷基。 WO 2010042785描述苯并咪唑於負趨化性之用途。所述之苯并咪唑可在5位置處經C1 -C10 烷基取代；然而，用於此部分之C1 -C10 烷基未經取代。 WO 2013186229描述調節TNF-α之苯并咪唑。然而，未揭示經1-甲基取代之苯并咪唑。 WO2007076092描述作為Raf激酶調節劑之苯并咪唑；然而，其不具有在5位置處之羥烷基取代。 亦未明確描述具有在5位置處之3-羥丁基以及1-甲基之苯并咪唑衍生物。Human IRAK4 (kinase 4 associated with interleukin-1 receptor) plays an important key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inhibitory substances. IRAK4 is composed of a variety of cells that express and mediate Toll-like receptors (TLRs) other than TLR3 and interleukins composed of IL-1R (receptors), IL-18R, IL-33R, and IL-36R (IL) Signal transduction of receptors of the 1β family (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010). Neither IRAK4-deleted mice nor human cells from patients lacking IRAK4 respond to stimulation by TLR (except TLR3) and the IL-1β family (Suzuki, Suzuki et al., Nature, 2002; Davidson, Currie et al. , The Journal of Immunology, 2006; Ku, von Bernuth et al., JEM, 2007; Kim, Staschke et al., JEM, 2007). The binding of TLR ligands or IL-1β family ligands to their respective receptors results in the recruitment and binding of MyD88 [myeloid differentiation primary response gene (88)] to the receptors. As a result, MyD88 interacts with IRAK4, resulting in the formation of active complexes that interact with kinases IRAK1 or IRAK2 and activate these kinases IRAK1 or IRAK2 (Kollewe, Mackensen et al., Journal of Biological Chemistry, 2004; Precious et al., J . Biol. Chem., 2009). As a result of this, the NF (nuclear factor) -κB signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway are activated (Wang, Deng et al., Nature, 2001). The activation of both the NF-κB signaling pathway and the MAPK signaling pathway leads to processes associated with different immune processes. For example, there are increased expression of various inflammatory signaling molecules and enzymes such as (for example) cytokines, chemosactivators, and COX-2 (cyclooxygenase-2) and genes associated with inflammation (eg, COX-2, IL -6 (Interleukin-6), IL-8) has increased mRNA stability (Holtmann, Enninga et al., Journal of Biological Chemistry, 2001; Datta, Novotny et al., The Journal of Immunology, 2004). In addition, these processes can be associated with the proliferation and differentiation of specific cell types (eg, monocytes, macrophages, numerocytes, T cells, and B cells) (Wan, Chi et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007). The core role of IRAK4 in the pathology of various inflammatory diseases has been confirmed by direct comparison of wild-type (WT) mice with genetically engineered animals that have kinase-inactivated forms of IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have improved clinical phenomena in animal models of multiple sclerosis, atherosclerosis, myocardial infarction, and Alzheimer's disease (Rekhter, Staschke et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue et al., Circulation, 2009; Staschke, Dong et al., The Journal of Immunology, 2009; Kim, Febbraio et al., The Journal of Immunology, 2011; Cameron, Tse et al., The Journal of Neuroscience, 2012). In addition, it was found that the absence of IRAK4 in animal models protects against virus-induced myocarditis with improved antiviral response and simultaneously reduced systemic inflammation (Valaperti, Nishii et al., Circulation, 2013). It has been shown that the performance of IRAK4 is correlated with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang et al., PLoS ONE, 2014). In addition, IRAK4 has been shown to be highly correlated with immune complex-mediated IFNα (interferon alpha) produced by plasmacytoid dendritic cells, which is one of the pathogenesis of systemic lupus erythematosus (SLE) The key process (Chiang et al., The Journal of Immunology, 2010). In addition, this signal pathway is associated with obesity (Ahmad, R., P. Shihab et al., Diabetology & Metabolic Syndrome, 2015). In addition, the key role of IRAK4 in innate immunity also implies that IRAK4 affects the differentiation of Th17 T cells (components of adaptive immunity). In the absence of IRAK4 kinase activity, fewer IL-17-producing T cells (Th17 T cells) are produced than WT mice. Inhibition of IRAK4 causes atherosclerosis, type 1 diabetes, rheumatoid arthritis, spinal arthritis (especially psoriatic spinal arthritis and Bekhterev's disease), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis , Prevention and / or treatment of chronic inflammatory bowel disease and viral diseases (such as HIV (human immunodeficiency virus), hepatitis virus) is feasible (Staschke et al., The Journal of Immunology, 2009; Marquez et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza et al., International Journal of Inflammation, 2014; Wang et al., Experimental and Therapeutic Medicine, 2015; Ciccia et al., Rheumatology, 2015). Due to the central role of IRAK4 in TLR (other than TLR3) and the MyD88-mediated signaling cascade of the IL-1 receptor family, IRAK4 inhibition can be used to prevent and / or treat diseases mediated by the above receptors. The components of the TLR and IL-1 receptor family are involved in rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis (e.g. Behcet's disease), those with polyangiitis and giant cell arteritis Granulomatosis, pancreatitis, systemic lupus erythematosus, dermatomyositis and polymyositis, including (for example) insulin resistance, hypertension, abnormal lipoproteinemia and obesity, diabetes (types 1 and 2), Diabetic nephropathy, osteoarthritis, Sjogren's syndrome and sepsis metabolic syndrome (Yang, Tuzun et al., J Immunol, 2005; Candia, Marquez et al., The Journal of Rheumatology, 2007; Scanzello, Plaas et al., Curr Opin Rheumatol 2008; Deng, Ma-Krupa et al., Circ Res, 2009; Roger, Froidevaux et al., PNAS, 2009; Devaraj, Tobias et al., Arterioscler Thromb Vasc Biol, 2011; Kim, Cho et al., Clin Rheumatol, 2010; Carrasco Et al., Clinical and Experimental Rheumatology, 2011; Gambuzza, Licata et al., Journal of Neuroimmunology, 2011; Fresno, Archives Of Physiology And Biochemistry, 2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez et al., Clinical Science, 2012; Ouziel, Gustot et al., Am J Patho, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012, Okiyama et al., Arthritis Rheum, 2012; Chen et al., Arthritis Research & Therapy, 2013; Holle, Windmoller et al., Rheumatology (Oxford), 2013; Li, Wang Et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof et al., Cell Mol Life Sci, 2013; Caso, Costa et al., Mediators of Inflammation, 2014; Cordiglieri, Marolda et al., J Autoimmun, 2014; Jiaalal, Major et al. , J Diabetes Complications, 2014; Kaplan, Yazgan et al, Scand J Gastroenterol, 2014; Talabot-Aye et al, Cytokine, 2014; Zong, Dorph et al, Ann Rheum Di, 2014; Ballak, Stienstra et al, Cytokine, 2015 ; Timper, Seelig et al., J Diabetes Complications, 2015). Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne and acne vulgaris and IRAK4-mediated TLR signal pathway Or the IL-1R family (Schmidt, Mittnacht et al., J Dermatol Sci, 1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad et al., Archives of Dermatology, 2004; Niebuhr, Langnickel et al., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali et al., Am J Clin Dermatol, 2010; Viguier, Guigue et al., Annals of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis, Aksentijevich et al. , Archives of Dermatology, 2012; Dispenza, Wolfert et al., J Invest Dermatol, 2012; Minkis, Aksentijevich et al., Archives of Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab et al., BMC Dermatology, 2013; Sedimbi, Hagglof et al., Cell Mol Life Sci, 2013; Wollina, Koch et al., Indi an Dermatol Online, 2013; Foster, Baliwag et al., The Journal of Immunology, 2014). Pulmonary diseases such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension have also been shown to be mediated by various TLRs The signal path is associated. The pathogenesis of lung disease can be infection-mediated or non-infection-mediated processes (Ramirez Cruz, Maldonado Bernal et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu et al., Infection and Immunity, 2005; Seki, Tasaka et al., Inflammation Research, 2010; Xiang, Fan et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo et al., The FASEB Journal, 2011; Nadigel, Prefontaine et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro et al., Mol Med, 2012; Deng, Yang et al., PLoS One, 2013; Freeman, Martinez et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013). TLR and IL-1R family members are also involved in other such as allergies, Behcet's disease, gout, lupus erythematosus, adult-onset Still's disease, pericarditis, and such as ulcerative colitis and Crohn's disease The pathogenesis of chronic inflammatory bowel disease, transplant rejection and graft-versus-host reaction inflammatory diseases and the inhibition of IRAK4 here is a suitable method of prevention and / or treatment (Liu-Bryan, Scott et al., Arthritis & Rheumatism, 2005; Piggott, Eisenbarth et al., J Clin Inves, 2005; Christensen, Shupe et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen et al., The Journal of Immunology, 2010; Rakoff -Nahoum, Hao et al, Immunity, 2006; Heimesaat, Fischer et al, PLoS ONE, 2007; Heimesaat, Nogai et al, Gut, 2010; Kobori, Yagi et al, J Gastroenterol, 2010; Schmidt, Raghavan et al, Nat Immunol, 2010; Shi, Mucsi et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin et al., Arthritis Res Ther, 20 13; Hao, Liu et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy et al., Cytokine & Growth Factor Reviews, 2013; Zhu , Jiang et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen et al., Contact Dermatitis, 2014; D'Elia, Brucato et al., Clin Exp Rheumatol, 2015; Jain, Thongprayoon et al., Am J Cardiol., 2015; Li, Zhang et al., Oncol Rep., 2015). Gynecological diseases mediated by TLR and IL-1R family such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, especially pain associated with endometriosis and other dysmenorrhea, dyspareunia 1. Symptoms associated with endometriosis due to dysuria and dysuria can be positively affected by the prophylactic and / or therapeutic use of IRAK4 inhibitors (Akoum, Lawson et al., Human Reproduction, 2007; Allhorn, Boing Et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima et al., Journal of Obstetrics and Gynaecology Research, 2013; Santulli, Borghese et al., Human Reproduction, 2013). Prophylactic and / or therapeutic use of IRAK4 inhibitors may also have a positive effect on atherosclerosis (Seneviratne, Sivagurunathan et al., Clinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi et al., International Journal of Molecular Sciences, 2013 ; Sedimbi, Hagglof et al., Cell Mol Life Sci, 2013). In addition to the diseases already mentioned, IRAK4-mediated TLR processes have been described in the pathogenesis of eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, dry keratoconjunctivitis, macular degeneration, and uveitis (Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor et al, J Leukoc Biol, 2011; Chang, McCluskey et al , Clinical & Experimental Ophthalmology, 2012; Guo, Gao et al., Immunol Cell Biol, 2012; Lee, Hattori et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao et al., Investigative Ophthalmology & Visual Science, 2014). Inhibition of IRAK4 is also a suitable treatment method for fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, and cystic fibrosis (Zhao, Zhao et al., Scand J Gastroenterol, 2011; Benias , Gopal et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu et al., Biochim Biophys Acta., 2015). With the key position of IRAK4 in diseases mediated by the TLR and IL-1R families, IRAK4 inhibitors can be used to prevent and / or treat (for example) fatty hepatitis and especially non-alcoholic fatty liver disease (NAFLD) ) And / or non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) chronic liver disease (Nozaki, Saibara et al., Alcohol Clin Exp Res, 2004; Csak, T., A. Velayudham et al., Am J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama et al., Gastroenterology, 2010; Kamari, Shaish et al., J Hepatol, 2011; Ye, Li et al., Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013; Ceccarelli, S., V. Nobili et al., World J Gastroenterol, 2014; Miura, Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic et al., World J Gastroenterol, 2014). In addition, IRAK4 inhibitors are also suitable for renal insufficiency and kidney diseases such as, for example, chronic kidney disease (CKD), chronic renal failure, glomerular disease, diabetic nephropathy, lupus nephritis, IgA nephritis (Berger's disease (Berger's disease)), treatment of renal sclerosis. The mentioned diseases are associated with the TLR signaling pathway and also with components of the IL-1 receptor family (Suzuki, Suzuki et al., Journal of the American Society of Nephrology, 2008; Hahn, Cho et al., Pediatric Nephrology, 2009; Conti, Spinelli et al., Clinical Reviews in Allergy & Immunology, 2010; Bao, Na et al., Journal of Clinical Immunology, 2011; Devaraj, Tobias et al., Arterioscler Thromb Vasc Biol, 2011; Rosa Ramirez and Ravi Krishna Dasu, Curr Diabetes Rev, 2012; Urbonaviciute, Starke et al., Arthritis & Rheumatism, 2013; Batal et al., Transplantation, 2014; Jiaal, Major et al., J Diabetes Complications, 2014; Lin and Tang, Nephrology Dialysis Transplantation, 2014; Zawada, Rogacev et al., Epigenetic, 2014; Elsherbiny and Al-Gayyar, Cytokine, 2016; Yang et al., Mol Med Rep, 2016). Due to the core role of IRAK4 in TLR-mediated processes, IRAK4 inhibition can also treat and / or prevent (for example) myocardial reperfusion injury, myocardial infarction, hypertension, and cardiovascular and neurological diseases of hypertension (Oyama, Blais et al., Circulation, 2004; Timmers, Sluijter et al., Circulation Research, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos et al., Clin Sci (Lond) , 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013; Hernanz, Martínez-Revelles et al, British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015; Bomfim, Echem et al., Life Sciences, 2015), as well as Alzheimer's disease, stroke, brain attack, craniocerebral trauma, amyotrophic lateral sclerosis (ALS) and Parkinson's disease (Brough, Tyrrell Et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, etc. , The Journal of Immunology, 2011; Lim, Kou et al., The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson et al., Disease Models & Mechanisms, 2013; Noelker, Morel et al., Sci. Rep., 2013; Wang, Wang et al., Stroke, 2013; Xiang, Chao et al., Rev Neurosci, 2015; Lee, Lee et al., J Neuroinflammation, 2015). As itching and pain including acute, chronic, inflammatory, and neuropathic pain involve TLR-mediated signaling via TRAK4 and IL-1 receptor family-mediated signaling, it can be assumed that inhibition via IRAK4 There are therapeutic effects in the indications mentioned. Examples of pain include hyperalgesia, allodynia, premenstrual pain, pain associated with endometriosis, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, Prostatitis, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, pain associated with chemotherapy, neuropathy caused by HIV treatment, pain caused by burns, and chronic pain (Wolf, Livshits et al., Brain, Behavior, and Immunity, 2008; Kim, Lee, and others, Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, and others, Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha, and others People, European Journal of Pharmacology, 2012; Kwok, Hutchinson et al., PLoS ONE, 2012; Nicotra, Loram et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake et al., Neurobiology of Disease , 2013; Han, Zhao et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes Cheung et al., Journal of Neuroinflammation, 2013; Zhao, Zhang et al., Neuroscience, 2013; Liu, Zhang et al., Cell Research, 2014; Park, Stokes et al., Cancer Chemother Pharmacol, 2014; Van der Watt, Wilkinson et al. , BMC Infect Dis, 2014; Won, KA, MJ Kim et al., J Pain, 2014; Min, Ahmad et al., Photochem Photobiol., 2015; Schrepf, Bradley et al., Brain Behav Immun, 2015; Wong, L., JD Done et al., Prostate, 2015). This also applies to some tumor diseases. Specific lymphomas such as ABC-DLBCL (activated B-cell diffuse large-cell B-cell lymphoma), mantle cell lymphoma and Waldenström disease, as well as chronic lymphocytic leukemia, melanoma, pancreatic tumor and Hepatocellular carcinoma lines are characterized by mutations in MyD88 or changes in activity in MyD88. These diseases can be treated by IRAK inhibitors (Ngo, Young et al., Nature, 2011; Puente, Pinyol et al., Nature, 2011; Ochi, Nguyen Et al., J Exp Med, 2012; Srivastava, Geng et al., Cancer Research, 2012; Treon, Xu et al., New England Journal of Medicine, 2012; Choi, Kim et al., Human Pathology, 2013; Liang, Chen et al. , Clinical Cancer Research, 2013). In addition, MyD88 plays an important role in ras-dependent tumors and therefore IRAK4 inhibitors are also suitable for the treatment of them (Kfoury, A., KL Corf et al., Journal of the National Cancer Institute, 2013). Since the mentioned indications are associated with signal pathways, it can also be assumed that inhibition by IRAK4 has therapeutic effects in breast cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer, and prostate cancer (Szczepanski, Czystowska et al. Cancer Res, 2009; Zhang, He et al., Mol Biol Rep, 2009; Wang, Qian et al., Br J Cancer Kim, 2010; Jo et al., World J Surg Oncol, 2012; Zhao, Zhang et al., Front Immunol, 2014 ; Chen, Zhao et al., Int J Clin Exp Pathol, 2015). Inflammatory diseases such as FCAS (familial cold auto-inflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal multiple system inflammatory disease) and CONCA (chronic infantile neuropathy) Skin- and arthritis syndrome CAPS (cyclic syndrome associated with cryopyrin), FMF (familial Mediterranean fever), HIDS (high-IgD syndrome), TRAPS (with tumor necrosis factor receptor 1 (Associated cyclic syndrome), juvenile idiopathic arthritis, adult-onset STI, Adamantiades-Behcet disease, rheumatoid arthritis, osteoarthritis, dry keratoconjunctivitis, PAPA syndrome (Suppurative arthritis, gangrenous pyoderma and acne), Schnitzler's syndrome and Sjogren's syndrome are treated by blocking the IL-1 signaling pathway; therefore IRAK4 inhibitors are also suitable for treatment Related diseases (Narayanan, Corrales et al., Cornea, 2008; Brenner, Ruzicka et al., British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, Europe an Journal of Immunology, 2011; Gul, Tugal-Tutkun et al., Ann Rheum Dis, 2012; Pettersson, Annals of Medicine Petterson, 2012; Ruperto, Brunner et al., New England Journal of Medicine, 2012; Nordström, Knight et al., The Journal of Rheumatology, 2012; Vijmasi, Chen et al., Mol Vis, 2013; Yamada, Arakaki et al., Opinion on Therapeutic Targets, 2013; de Koning, Clin Transl Allergy, 2014). IL-33R ligand IL-33 specifically relates to the pathogenesis of acute renal failure and therefore inhibition of IRAK4 is a suitable treatment method for prevention and / or treatment (Akcay, Nguyen et al., Journal of the American Society of Nephrology , 2011). Components of the IL-1 receptor family are associated with myocardial infarction, different lung diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS) and can therefore be expected to The inhibitory and / or therapeutic effect of IRAK4 inhibition in the mentioned indications (Kang, Homer et al., The Journal of Immunology, 2007; Imaoka, Hoshino et al., European Respiratory Journal, 2008; Couillin, Vasseur et al., The Journal of Immunology, 2009; Abbate, Kontos et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke et al., European Respiratory Journal, 2011; Haenuki, Matsushita et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell et al., The American Journal of Cardiology, 2013; Alexander-Brett et al., The Journal of Clinical Investigation, 2013; Bunting , Shadie et al., BioMed Research International, 2013; Byers, Alexander- Brett et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto et al., J Interferon Cytokine Res, 2013; Martínez-González, Roca et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi et al., PLoS ONE, 2013; Qiu, Li et al., Immunology, 2013; Li, Guabiraba et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar et al., Molecular Immunology, 2014; Lugrin, Parapanov et al., The Journal of Immunology, 2015). The prior art discloses a large number of IRAK4 inhibitors (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133). WO2015091426 describes indazoles such as example WO2015091426-64, which is substituted with a methylamide side chain at position 2 and inhibits IRAK-4. However, benzimidazole is not described. WO2003030902 and Bioorg. Med. Chem. Lett. 16 (2006) 2842-2845 describe 2-carboxamidobenzimidazole as an IRAK4 inhibitor. WO13042137 describes benzimidazole substituted with morpholine at position 2 as an IRAK4 inhibitor, wherein the morpholine is connected to benzimidazole via ring nitrogen. In addition, the benzimidazole is unsubstituted at the 1 position. These benzimidazoles may be substituted with hydroxyalkyl groups at the 5 position, of which 2-hydroxypropan-2-yl is not explicitly disclosed in WO 13042137. The only clearly disclosed benzimidazole derivative is WO 13042137-48 (6'-amino-N- (2-morpholinyl-1H-benzo [d] imidazol-6-yl)-[2,3'- Bipyridine] -6-carboxamide). WO2006030031 describes benzimidazoles which are especially positive ectopic regulators of mGluR2, where these benzimidazoles can be substituted with C 1 -C 6 alkyl groups at the 1 position. However, the substitution with methyl is not explicitly disclosed. Nor did it reveal benzimidazole. WO2004072069 describes benzimidazole methylamide as a vanilloid receptor (VR1) antagonist for the treatment of pain, wherein the benzimidazole methylamide can be substituted with a substituted heteroaryl group at the methylamide group . Possible heteroaryl groups mentioned are pyridyl (preferably 3-pyridyl), isothiazolyl, thiazolyl, oxazolyl or pyrazolyl. In addition, the benzimidazolamides may be substituted with C 1 to C 12 alkyl groups at 1 position and C 1 -C 12 alkyl groups at 5 positions, and these alkyl groups may be substituted with -OH. Only two benzimidazoles are specifically disclosed: WO2004072069-11 (N- (1H-benzimidazol-6-yl) -6- (4-fluorophenyl) -2-methylnicotinamide) and WO2004072069-12 (6- (4-fluorophenyl) -2-methyl-N- (1-methyl-1H-benzimidazol-6-yl) nicotinamide). WO9422839 describes benzimidazoles as antagonists of the dopamine D 4 receptor, where the benzimidazoles can be substituted with hydrocarbons at the 5 position. Hydrocarbons are straight chain, branched chain, or cyclic groups (such as, for example, C 1 -C 6 alkyl groups) that can contain up to 18 carbon atoms. However, benzimidazole substituted with a hydroxyalkyl group at the 5 position is not disclosed. WO200157020 describes benzimidazole as an inhibitor of factor Xa. These benzimidazoles can be substituted at the 2 position with the following groups: C 1 -C 8 alkyl, however it is unsubstituted, C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, but not C 1 -C 6 alkyl-C 3 -C 8 heterocycloalkyl, C 1 -C 8 alkyl-NR 10 R 10 , where R 10 may be H or C 1 -C 8 alkyl, C 1 -C 8 -OR 10 , wherein R 10 may be H or C 1 -C 8 alkyl. WO 2010042785 describes the use of benzimidazole for negative chemotaxis. The benzimidazole may be substituted with C 1 -C 10 alkyl at the 5 position; however, the C 1 -C 10 alkyl used in this part is unsubstituted. WO 2013186229 describes benzimidazole which regulates TNF-α. However, benzimidazole substituted with 1-methyl is not disclosed. WO2007076092 describes benzimidazole as a Raf kinase modulator; however, it does not have a hydroxyalkyl substitution at the 5 position. The benzimidazole derivatives having 3-hydroxybutyl and 1-methyl at the 5 position are also not explicitly described.

本發明所解決之問題為提供新穎化合物，其充當與白細胞介素-1受體相關聯之激酶-4 (IRAK4)之抑制劑。 本發明提供通式(I)之化合物，

Figure TW201803866AD00001
式(I) 其中： R1 表示含有1或2個相同或不同選自由O、S及N組成之群雜原子且經由環碳原子連接的之5-或6員雜芳基， 其中5員雜芳基可經C3 -C6 環烷基或可經鹵素取代之C1 -C3 烷基單取代， 且其中，於該5員雜芳基具有含義吡唑基之情況下，吡唑基在N處可經C3 -C6 環烷基或可經鹵素取代之C1 -C3 烷基單取代， 及其中6員雜芳基可經選自由鹵素、C1 -C3 烷氧基、NH2 、可經鹵素取代之C1 -C3 烷基組成之群之相同或不同取代基單或雙取代， A表示鍵或C1 -C6 烷基， 於A為C1 -C6 烷基之情況下R2 表示氫、C1 -C3 烷氧基、S(=O)2 -C1 -C3 烷基、NH(C1 -C3 烷基)、N(C1 -C3 烷基)2 或含有一或兩個相同或不同選自O、S、S(=O)2 、N、NH、N(C1 -C3 烷基)之雜原子或雜原子基團及經由環碳原子或環氮原子連接之4、5或6員雜環烷基， 或 於A為鍵之情況下，R2 表示可經–OH單取代之C1 -C6 烷基或表示含有選自N(C1 -C3 烷基)、O、S(=O)2 之群之雜原子或雜原子基團及經由雜環烷基之環碳原子連接之5或6員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。 該等新穎IRAK4抑制劑尤其適用於治療及預防以過度反應的免疫系統為特徵之增生性、代謝性及炎性疾病。此處應特別提及炎性皮膚病、心血管病、肺病、眼病、神經系統疾病、疼痛疾病及癌症疾病。 此外，該等新穎IRAK4抑制劑適用於治療及預防以下疾病： •自體免疫性及炎性疾病，尤其類風濕性關節炎、多發性硬化、全身性紅斑狼瘡、脊柱關節炎及痛風， •代謝疾病，尤其諸如脂肪肝之肝病及 •亦及腎病，尤其慢性腎病、腎病變及 •婦科疾病，尤其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與子宮內膜異位症相關聯之症狀，諸如痛經、***困難、排尿困難及排便困難。The problem solved by the present invention is to provide novel compounds that act as inhibitors of kinase-4 (IRAK4) associated with interleukin-1 receptors. The present invention provides compounds of general formula (I),
Figure TW201803866AD00001
Formula (I) where: R 1 represents a 5- or 6-membered heteroaryl group containing 1 or 2 identical or different heteroatoms selected from the group consisting of O, S and N and connected via a ring carbon atom, of which 5 members are hetero The aryl group may be mono-substituted with C 3 -C 6 cycloalkyl or C 1 -C 3 alkyl which may be substituted with halogen, and wherein, in the case where the 5-membered heteroaryl group has the meaning of pyrazolyl, pyrazolyl At N, it may be mono-substituted with C 3 -C 6 cycloalkyl or C 1 -C 3 alkyl which may be substituted with halogen, and the 6-membered heteroaryl group may be selected from halogen, C 1 -C 3 alkoxy , NH 2 , C 1 -C 3 alkyl groups which may be substituted by halogen, the same or different substituents are mono- or di-substituted, A represents a bond or C 1 -C 6 alkyl group, where A is C 1 -C 6 In the case of alkyl, R 2 represents hydrogen, C 1 -C 3 alkoxy, S (= O) 2 -C 1 -C 3 alkyl, NH (C 1 -C 3 alkyl), N (C 1- C 3 alkyl) 2 or a heteroatom or group containing one or two heteroatoms selected from O, S, S (= O) 2 , N, NH, N (C 1 -C 3 alkyl) and via the 4, 5 or 6-membered heterocycloalkyl ring carbon atom or a nitrogen atom of the ring, or in the case where the key of A, R 2 represents -OH may be mono substituted with the C 1 -C 6 alkyl, or Comprising illustrates selected N (C 1 -C 3 alkyl), O, S (= O ) 2 hetero atoms or hetero atom of the group and the heteroaryl group via the 5 or 6-membered heterocyclic groups connected to carbon atoms of Cycloalkyl, and its diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts. These novel IRAK4 inhibitors are particularly suitable for the treatment and prevention of proliferative, metabolic and inflammatory diseases characterized by an overreactive immune system. Special mention should be made here of inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, nervous system diseases, pain diseases and cancer diseases. In addition, these novel IRAK4 inhibitors are suitable for the treatment and prevention of the following diseases: • Autoimmune and inflammatory diseases, especially rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, spinal arthritis and gout, • Metabolism Diseases, especially liver diseases such as fatty liver and • also kidney disease, especially chronic kidney disease, nephropathy and • gynecological diseases, especially endometriosis and pain associated with endometriosis and other endometrium Symptoms associated with ectopic disease, such as dysmenorrhea, difficulty in intercourse, difficulty in urinating, and difficulty in defecation.

於下述本發明之合成中間體及製備實例之情況中，以對應的鹼或酸之鹽之形式指明之任何化合物一般而言為未知精確化學計量組成之鹽，如藉由各自之製備及/或純化方法獲得。除非於更多細節中指明，否則於此等鹽之情況下不應因此在化學計量意義上理解名字及結構式之添加諸如「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x HCl」、「x CF3 COOH」、「x Na+ 」，但僅具有關於存在其中之成鹽組分之描述性特徵。 若藉由所述之製備及/或純化方法以未知化學計量組成(若其等具有限定類型)之溶劑化物(例如水合物)之形式獲得合成中間體或製備實例或其鹽，則此相應地適用。 若式(I)所涵蓋及下述之化合物非為已經之鹽、溶劑化物及鹽之溶劑化物，則本發明之化合物為式(I)之化合物及其鹽、溶劑化物及鹽之溶劑化物，式(I)所涵蓋且具有下述式之化合物及其鹽、溶劑化物及鹽之溶劑化物及式(I)所涵蓋且以下引用作為製備實例之化合物及其鹽、溶劑化物及鹽之溶劑化物。 本發明之上下文中較佳之鹽為本發明之化合物之生理學上可接受的鹽。然而，本發明亦包括自身不適用於醫藥應用但可用於(例如)根據本發明之化合物之單離或純化之鹽。 本發明之化合物之生理學上可接受的鹽包括無機酸、羧酸及磺酸之酸加成鹽，例如與下列酸之鹽：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。 本發明之化合物之生理學上可接受的鹽亦包括習知鹼之鹽，舉例而言及較佳地鹼金屬鹽(例如鈉鹽及鉀鹽)、鹼土金屬鹽(例如鈣鹽及鎂鹽)及源自氨或具有1至16個碳原子之有機胺之銨鹽，舉例而言及較佳地乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲胺基乙醇、普魯卡因、二苄胺、N-甲基嗎啉、精胺酸、離胺酸、乙二胺及N-甲基哌啶。 本發明之上下文中之溶劑化物經描述為藉由與溶劑分子配位形成呈固態或液態之錯合物之本發明之化合物之其等形式。水合物為溶劑化物之特定形式，其中配位係與水達成。 根據本發明之化合物取決於其結構可以不同的立體異構形式，即以構型異構體或其他之形式存在，若適宜，則呈構象異構體(對映異構體及/或非對映異構體，包括於阻轉異構體之情況中之其等)。因此本發明涵蓋對映異構體與非對映異構體及其各自之混合物。立體異構同質成分可以已知方式自對映異構體及/或非對映異構體之此等混合物中單離；針對此目的較佳地利用層析法，尤其在非對掌性或對掌性相上之HPLC層析法。 若本發明之化合物可以互變異構形式出現，則本發明涵蓋所有互變異構形式。 本發明亦包括本發明之化合物之所有適宜的同位素變體。應瞭解此處本發明之化合物之同位素變體意指於本發明之化合物內之至少一個原子經換成相同原子序數但具有與通常或主要於自然界出現之原子質量不同之原子質量之另一原子之化合物。可併入根據本發明之化合物之同位素之實例為氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之其等，諸如2 H(氘)、3 H(氚)、13 C、14 C、15 N、17 O、18 O、32 P、33 P、33 S、34 S、35 S、36 S、18 F、36 Cl、82 Br、123 I、124 I、129 I及131 I。根據本發明之化合物之特定同位素變體諸如尤其其中併入一個或多個放射性同位素之彼等可利於(例如)作用機理或體內之活性化合物分佈之檢驗；由於可選性及可檢驗性之比較容易，特定言之，利用3 H或14 C同位素標記之化合物適用於此目的。此外，(例如)氘之同位素之併入可導致由於化合物之更大的代謝穩定性之特定治療效益，例如體內半衰期之延長或所需之活性劑量之減少。因此根據本發明之化合物之此等修飾可於一些情況下亦構成本發明之較佳實施例。根據本發明之化合物之同位素變體可藉由熟習此項技術者熟知之方法，例如藉由以下另外描述之方法及述於製備實例中之程序、藉由利用各自試劑及/或起始化合物之對應之同位素變體製備。 本發明另外提供根據本發明之化合物之所有可能的結晶及多晶形式，其中該多晶型可於所有濃度範圍內以單個多晶型或以複數個多晶型之混合物存在。 此外本發明亦涵蓋本發明之化合物之前藥。上下文中之術語「前藥」指自身可為生物活性或非活性但在體內滯留時間期間經反應(例如用代謝或用水解方法)得到本發明之化合物之化合物。 本發明之上下文中，除非另作指明，否則取代基具有以下含義： 本發明之上下文中之烷基 為具有指明之特定數目之碳原子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-甲丙基、2-甲丙基、第三丁基、正戊基、1-乙丙基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲丙基、正己基、1-甲戊基、2-甲戊基、3-甲戊基、4-甲戊基、1-乙丁基及2-乙丁基。 本發明之上下文中之環烷基 為於各者情況下具有指明數目之碳原子之單環飽和烷基。實例包括環丙基、環丁基、環戊基及環己基。 本發明之上下文中之雜環烷基 為具有共4至6個環原子之飽和雜環，其中一或兩個環碳原子可由選自N、NH、N(C1 -C3 烷基)、O、S及SO2 系列之相同或不同的雜原子或雜原子基團取代。較佳之實例包括哌啶-1-基、吡咯啶-1-基、哌嗪-1-基、4-甲基哌嗪-1-基、1,1-二氧代四氫(dioxidotetrahydro)噻吩-3-基、1-甲基吖丁啶-3-基、1,1-二氧代四氫-2H-噻喃-3-基、四氫-2H-吡喃-4-基、環氧丙烷-3-基。 本發明之上下文中之雜芳基 為具有5或6個環原子之單環芳族環體系，其包含一或兩個環雜原子及經由環碳原子連接。 該雜芳基可為諸如(例如)噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、異噁唑基、異噻唑基、噁二唑基、***基、噻二唑基或四唑基之5員雜芳基或諸如(例如)吡啶基、噠嗪基、嘧啶基、吡嗪基或三嗪基之6員雜芳基。 一般而言及除非另作指明，否則該等雜芳基或伸雜芳基包括所有可能之異構形式，例如與分子其餘部分之連接點有關之互變異構體及位置異構體。因此，作為示例性、非排他性實例，術語吡啶基包括吡啶-2-基、吡啶-3-基及吡啶-4-基；或術語噻吩基包括噻吩-2-基及噻吩-3-基。 本發明之上下文中之烷氧基 為具有指明之特定數目之碳原子之直鏈或分支鏈烷氧基。可提及之實例包括甲氧基、乙氧基、正丙氧基及異丙氧基。 本發明之上下文中之鹵素 為氟、氯及溴。較佳地為氟。 本發明之上下文中之羥基 為OH。 在鍵處之符號*表示分子中之鍵合點。 當本發明之化合物中之自由基經取代時，除非另作指明，否則該等自由基可經單或多取代。於本發明之上下文中，所有出現一次以上之自由基予以彼此獨立地定義。 R1 之另一個實施例為選自以下之基團：

Figure TW201803866AD00002
其中： R3 表示C3 -C6 環烷基或可經鹵素取代之C1 -C3 烷基， R4 表示C1 -C3 烷氧基、NH2 或可經鹵素取代之C1 -C3 烷基及 R5 表示氫或鹵素且 *表示分子中之連接點。 R1 之又一個實施例為選自以下之基團：
Figure TW201803866AD00003
其中： R3 表示C3 -C6 環烷基或可經鹵素取代之C1 -C3 烷基及 R4 表示C1 -C3 烷氧基、NH2 或可經鹵素取代之C1 -C3 烷基及 R5 表示氫或鹵素且 *表示分子中之連接點。 R1 之又一個實施例為選自以下之基團：
Figure TW201803866AD00004
其中： R3 表示可經鹵素取代之C1 -C3 烷基及 R4 表示可經鹵素取代之C1 -C3 烷基及 R5 表示氫且 *表示分子中之連接點。 R1 之又一個實施例為選自6-(三氟甲基)吡啶-2-基、2-(三氟甲基)-1,3-噻唑-4-基、2-環丙基-1,3-噁唑-4-基、4-(三氟甲基)-1,3-噻唑-2-基、6-(1,1-二氟乙基)吡啶-2-基之基團。 R3 之另一個實施例為C3 -C6 環烷基或可經氟原子單至五取代之C1 -C3 烷基。 R3 之又一個實施例為C3 -C6 環烷基或可經氟原子單至三取代之C1 -C3 烷基。 R3 之又一個實施例為環丙基或可經氟原子單至三取代之C1 -C3 烷基。 R4 之另一個實施例為C1 -C3 烷氧基、NH2 或可經氟原子單至五取代之C1 -C3 烷基。 R4 之又一個實施例為C1 -C3 烷氧基、NH2 或可經氟原子單至三取代之C1 -C3 烷基。 R4 之又一個實施例為甲氧基、NH2 或可經氟原子單至三取代之C1 -C3 烷基。 R4 之又一個實施例為可經氟原子單至三取代之C1 -C3 烷基。 R5 之另一個實施例為氫或鹵素。 R5 之又一個實施例為氫或氟。 R5 之又一個實施例為氫。 A之另一個實施例為鍵或C1 -C3 烷基。 於A表示C1 -C6 烷基或C1 -C3 烷基之情況下，R2 之另一個實施例為氫、甲氧基、S(=O)2 -CH3 、NHCH3 、N(CH3 )2 或含有1或2個選自O、S、S(=O)2 、N、NH、N(C1 -C3 -烷基)之相同或不同雜原子或雜原子基團及經由環碳原子或環氮原子連接之4、5或6員雜環烷基。 於A表示C1 -C3 烷基之情況下，R2 之又一個實施例為選自嗎啉-4-基、1-甲基吖丁啶-3-基及4-甲基哌嗪-1-基之基團。 於A為鍵之情況下，R2 之另一個實施例為C1 -C6 烷基，其中C1 -C6 烷基可經–OH單取代或含有選自NH、N(C1 -C3 烷基)、O、S(=O)2 之群之雜原子或雜原子基團及經由環碳原子連接之6員雜環烷基。 於A為鍵之情況下，R2 之又一個實施例為1,1-二氧代四氫-2H-噻喃-3-基或3-羥基-3-甲基丁基。 本發明另外提供通式(I)之化合物，其中 R1 表示選自以下之基團
Figure TW201803866AD00005
其中： R3 表示環丙基或C1 -C3 烷基，其中C1 -C3 烷基可經氟原子單至三取代， R4 表示H、甲氧基、NH2 、可經氟原子單至三取代之C1 -C3 烷基， R5 表示氫或氟及 *表示分子中之連接點， A表示鍵或C1 -C3 -烷基， 於A為C1 -C3 -烷基之情況下，R2 表示氫、甲氧基、S(=O)2 –CH3 、-N(CH3 )2 或含有一或兩個選自O、S(=O)2 、N、NH-CH3 之相同或不同雜原子或雜原子基團及經由環碳原子或環氮原子連接之4、5或6員雜環烷基， 或 於A為鍵之情況下，R2 表示3-羥基-3-甲基丁基或表示含有作為雜原子基團之S(=O)2 及經由環碳原子連接之6員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。 本發明另外提供通式(I)之化合物，其中 R1 表示選自以下之基團
Figure TW201803866AD00006
其中： R3 表示環丙基或C1 -C3 烷基，其中C1 -C3 烷基可經氟原子單至三取代， R4 表示H、可經氟原子單至三取代之C1 -C3 烷基， R5 表示氫及 *表示分子中之連接點， A表示鍵或C1 -C3 烷基， 於A為C1 -C3 烷基之情況下，R2 表示氫或含有一或兩個選自O、N、NH-CH3 之相同或不同雜原子或雜原子基團及經由環碳原子或環氮原子連接之6員雜環烷基， 或 於A為鍵之情況下，R2 表示3-羥基-3-甲基丁基或表示含有作為雜原子基團之S(=O)2 及經由環碳原子連接之6員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。 本發明另外提供通式(I)之化合物，其中 R1 表示6-(三氟甲基)吡啶-2-基、2-(三氟甲基)-1,3-噻唑-4-基、2-環丙基-1,3-噁唑-4-基、4-(三氟甲基)-1,3-噻唑-2-基、6-(1,1-二氟乙基)吡啶-2-基； A表示鍵或C1 -C3 烷基， 於A為C1 -C3 烷基之情況下，R2 表示嗎啉-4-基或4-甲基哌嗪-1-基 或 於A為鍵之情況下，R2 表示3-羥基-3-甲基丁基或表示1,1-二氧代四氫-2H-噻喃-3-基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。 本發明另外提供通式(I)之化合物，其中 R1 表示6-(三氟甲基)吡啶-2-基、2-(三氟甲基)-1,3-噻唑-4-基、6-(1,1-二氟乙基)吡啶-2-基； A表示鍵及 R2 表示3-羥基-3-甲基丁基或表示1,1-二氧代四氫-2H-噻喃-3-基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。 本發明另外提供以下化合物之列表： 本發明另外尤其提供以下化合物之列表： 根據本發明之化合物充當IRAK4激酶之抑制劑及具有驚人的有用之藥理活性譜。 因此，除上述之標的之外，本發明亦提供根據本發明之化合物用於治療及/或預防人類及動物疾病之用途。 利用根據本發明之IRAK4抑制劑治療及/或預防婦科疾病、炎性皮膚病、心血管疾病、肺病、眼病、自體免疫性疾病、疼痛疾病、代謝疾病、痛風、肝病、代謝症候群、胰島素抗性、腎病及癌症係特別佳的。 根據本發明之化合物適用於預防及/或治療各種疾病及疾病相關之狀態，尤其由TLR(除TLR3之外)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、動脈粥樣硬化、心肌梗塞、阿爾茨海默氏病、病毒引起的心肌炎、痛風、小柳原田症候群、紅斑狼瘡、牛皮癬、脊柱關節炎及關節炎。 根據本發明之化合物亦可用於預防及/或治療由MyD88及TLR(除TLR3之外)介導之疾病。其包括多發性硬化、類風濕性關節炎、脊柱關節炎(尤其牛皮癬性脊柱關節炎及別赫捷列夫氏病)、包括胰島素抗性、糖尿病、骨關節炎、乾燥症候群、巨細胞性動脈炎、敗血症、多發性肌炎及皮肌炎之代謝症候群、諸如牛皮癬、特應性皮炎、斑禿、痤瘡及尋常痤瘡之皮膚疾病、諸如肺纖維化、慢性阻塞性肺疾病(COPD)、急性呼吸窘迫症候群(ARDS)、急性肺損傷(ALI)、間質性肺病(ILD)、結節病及肺動脈高壓之肺病。 由於根據本發明之化合物之作用機理，其適用於預防及/或治療TLR介導之疾病，白塞病、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諸如痛經、***困難、排尿困難及排便困難之其他與子宮內膜異位症相關聯之症狀。此外，根據本發明之化合物適用於預防及/或治療移植排斥反應、紅斑狼瘡、成年發病斯提耳病及諸如潰瘍性結腸炎及克羅恩氏病之慢性炎性腸病之情況。 除已列出之疾病之外，根據本發明之化合物之用途亦適用於以下疾病之治療及/或預防：諸如角膜炎、過敏性結膜炎、乾性角膜結膜炎、黃斑變性及葡萄膜炎之眼病；諸如動脈粥樣硬化、心肌再灌注損傷、心肌梗塞、高血壓之心血管疾病及諸如阿爾茨海默氏病、中風及帕金森氏症之神經系統疾病。 根據本發明之化合物之作用機理亦可預防及/或治療由TLR及IL-1受體家族介導之肝病尤其NAFLD、NASH、ASH、肝纖維化及肝硬化。 此外，根據本發明之化合物適用於預防及/或治療由TLR及IL-1受體家族介導之腎病尤其慢性腎病及腎病變。 根據本發明之化合物亦提供瘙癢症及疼痛尤其急性、慢性、炎性及神經性疼痛之預防及/或治療。 由於根據本發明之化合物之作用機理，其適用於預防及/或治療諸如淋巴瘤、慢性淋巴性白血病、黑素瘤及肝細胞癌、乳癌、***癌及Ras依賴性腫瘤之腫瘤疾病。 此外，根據本發明之化合物亦適用於治療及/或預防經由IL-1受體家族介導之疾病。該等疾病包括CAPS(與隱熱蛋白相關聯之週期性症候群)，其包括FCAS(家族性寒冷性自體炎性症候群)、MWS (穆韋二氏症候群)、NOMID (新生兒發病多系統炎性疾病)及CONCA (慢性嬰兒性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、成年發病斯提耳病、貝賽特氏症、類風濕性關節炎、牛皮癬、關節炎、別赫捷列夫氏病、骨關節炎、乾性角膜結膜炎及乾燥症候群、多發性硬化、紅斑狼瘡、斑禿、1型糖尿病、2型糖尿病及心肌梗塞後遺症。諸如哮喘、COPD、特發性間質性肺炎及ARDS之肺病、諸如子宮內膜異位症及與子宮內膜異位症相關聯之疼痛之婦科疾病及諸如痛經、***困難、排尿困難及排便困難之其他與子宮內膜異位症相關聯之症狀、諸如克羅恩氏病及潰瘍性結腸炎之慢性炎性腸病係與IL-1受體家族之調節異常相關聯及適用於根據本發明之化合物之治療及/或預防用途。 根據本發明之化合物亦可用於IL1受體家族介導之諸如中風、阿爾茨海默氏病、腦發作、顱腦創傷之神經系統疾病及諸如牛皮癬、特應性皮炎、痤瘡、斑禿及過敏性接觸性皮炎之皮膚病之治療及/或預防。 此外，根據本發明之化合物適用於治療及/或預防疼痛疾病，尤其急性、慢性、炎性及神經性疼痛。較佳地包括痛覺過敏、異常性疼痛、來自關節炎(諸如骨關節炎、類風濕性關節炎、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、手術後疼痛、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***炎之疼痛、由脊髓損傷引起之疼痛、炎症引起之疼痛、下背痛、癌症疼痛、與化療相關聯之疼痛、HIV治療引起之神經病變、燒傷引起之疼痛及慢性疼痛。 本發明亦另外提供利用有效量之至少一種根據本發明之化合物來治療及/或預防疾病(尤其上述疾病)之方法。 於本發明之上下文中，術語「治療(treatment)」或「處理(treating)」包括疾病、病狀、病症、損傷或健康問題或該等狀態及/或該等狀態之症狀之發展、過程或進展之抑制、延遲、檢查、減輕、減弱、限制、減少、壓制、擊退或治癒。本文術語「治療(therapy)」應理解為與術語「治療(treatment)同義。 於本發明之上下文中，術語「預防(prevention)」、「預防(prophylaxis)」、「阻止(preclusion)」係同義地使用及指避免或降低接觸、經歷、遭受或罹患疾病、病狀、病症、損傷或健康問題之風險或該等狀態及/或該等狀態之症狀之發展或推進。 疾病、病狀、病症、損傷或健康問題之治療及/或預防可係部分或完全的。 根據本發明之化合物可經單獨使用，或若所需，與其他活性化合物組合使用。本發明另外提供包含至少一種根據本發明之化合物及一種或多種其他活性化合物之藥劑，其尤其用於治療及/或預防上述疾病。適宜組合活性化合物之較佳實例包括： 一般可提及活性化合物諸如抗菌(例如青黴素(penicillin)、萬古黴素(vancomycin)、環丙沙星(ciprofloxacin))、抗病毒(例如阿昔洛維(aciclovir)、奧塞米韋(oseltamivir))及抗黴素 (例如萘替芳(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(cyclosporin)、Methotrexat®、TNF拮抗劑(例如，Humira®、依那西普(Etanercept)、英夫利昔單抗(Infliximab))、IL-1抑制劑(例如，阿那白滯素(Anakinra)、康納單抗(Canakinumab)、利納西普(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)、巴瑞替尼(Baricitinib)、GLPG0634)、來氟米特(leflunomid)、環磷醯胺、利妥昔單抗(rituximab)、貝利單抗(belimumab)、他克莫司(tacrolimus)、雷帕黴素(rapamycin)、麥考酚酸嗎乙酯(mycophenolate mofetil)、干擾素、皮質類固醇(例如潑尼松(prednisone)、潑尼松龍(prednisolone)、甲基潑尼松龍(methylprednisolone)、氫化可的松(hydrocortisone)、倍他米松(betamethasone))、環磷醯胺、咪唑硫嘌呤及柳氮磺胺吡啶；撲熱息痛(paracetamol)、非類固醇抗炎物質(NSAIDS)(阿司匹林(aspirin)、布洛芬(ibuprofen)、萘普生(naproxen)、依託度酸(etodolac)、塞來考昔(celecoxib)、秋水仙素(colchicine))。 以下應提及用於腫瘤治療：免疫療法(例如阿地白介素(aldesleukin)、阿侖單抗(alemtuzumab)、巴厘昔單抗(basiliximab)、卡妥索單抗(catumaxomab)、西莫白介素(celmoleukin)、地尼白介素(denileukin)、地吉妥辛(diftitox)、依庫麗單抗(eculizumab)、依決洛單抗(edrecolomab)、吉姆單抗(gemtuzumab)、替伊莫單抗(ibritumomab tiuxetan)、咪喹莫特(imiquimod)、α干擾素、β干擾素、γ干擾素、普利姆瑪(ipilimumab)、來那度胺(lenalidomid)、來諾拉提(lenograstim)、米伐木肽(mifamurtid)、奧法木單抗(ofatumumab)、奧普瑞白介素(oprelvekin)、畢西巴尼(picibanil)、普樂沙福(plerixafor)、多醣-K、沙莫司亭(sargramostim)、西普魯塞-T (sipuleucel-T)、他索納明(tasonermin)、替西白介素(teceleukin)、托珠單抗(tocilizumab))；抗增生物質，例如但非排他地：安吖啶(amsacrin)、***樹膠酸(arglabin)、三氧化二砷、天門冬醯胺酶、博來黴素(bleomycin)、白消安(busulfan)、放線菌素(dactinomycin)、多西他奇(docetaxel)、表柔比星(epirubicin)、培洛黴素(peplomycin)、曲妥單抗(trastuzumab)、利妥昔單抗、奧濱尤妥單抗(obinutuzumab)、奧法木單抗、托西莫單抗(tositumomab)、芳香酶抑制劑(例如依西美坦(exemestan)、法曲唑(fadrozol)、福美坦(formestan)、來曲唑(letrozol)、阿納托司唑(anastrozol)、伏氯唑(vorozol))、抗***劑(例如氯地孕酮(chlormadinon)、氟維司群(fulvestrant)、環硫雄醇(mepitiostan)、他莫西芬(tamoxifen)、雷洛昔芬(raloxifen)、托瑞米芬(toremifen))、***(例如雌(甾)二醇、聚雌(甾)二醇磷酸酯)、促孕激素(例如，乙酸甲羥孕酮(medroxyprogesteron)、甲地孕酮(megestrol))、拓撲異構酶I抑制劑(例如依立替康(irinotecan)、托泊替康(topotecan))、拓撲異構酶II抑制劑(例如胺柔比星(amrubicin)、道諾黴素(daunorubicin)、依利醋銨(elliptinium acetate)、依託泊苷(etoposid)、去甲氧基柔紅黴素(idarubicin)、米托蒽醌(mitoxantron)、替尼泊苷(teniposid))、微管活性物質(例如卡巴他賽(cabazitaxel)、櫻草素(eribulin)、紫杉醇(paclitaxel)、長春花鹼(vinblastin)、長春花新鹼(vincristin)、長春地辛(vindesin)、長春瑞濱(vinorelbin))、端粒酶抑制劑(例如伊美司他(imetelstat))、烷基化物質及組蛋白去乙醯化酶抑制劑(例如苯達莫司汀(bendamustin)、卡莫司汀(carmustin)、氮芥(chlormethin)、達卡巴嗪(dacarbazin)、雌氮芥(estramustin)、異環磷醯胺、環己亞硝脲、二溴甘露醇、二溴衛矛醇、尼莫司汀(nimustin)、潑尼莫司汀(prednimustin)、甲基苄肼、雷莫司汀(ranimustin)、鏈脲黴素(streptozotocin)、替莫唑胺(temozolomid)、噻替派(thiotepa)、蘇消安(treosulfan)、曲磷胺(trofosfamid)、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)、胺魯米特(aminoglutethimid)、貝沙羅汀(bexaroten)、MMP抑制劑(肽擬似物、非肽擬似物及四環素，例如馬馬司他(marimastat)、BAY 12-9566、BMS-275291、氯膦酸鹽(clodronate)、普啉司他(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)、咗他莫司(zotarolimus)、抗代謝物(例如克羅拉濱(clofarabin)、去氧氟尿苷(doxifluridin)、甲胺喋呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)、克拉屈濱(cladribin)、阿糖胞苷(cytarabin)、氟達拉濱(fludarabin)、巰基嘌呤(mercaptopurin)、甲胺喋呤、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、替加氟(tegafur)、硫鳥嘌呤(tioguanin))、鉑化合物(例如卡波鉑(carboplatin)、順氯胺鉑(cisplatin)、順鉑(cisplatinum)、依他鉑(eptaplatin)、洛鉑(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、恩扎魯胺(enzalutamid)、氟他胺(flutamid)、尼魯米特(nilutamid)、比卡魯胺(bicalutamid)、乙酸環丙氯地孕酮(cyproteron)、乙酸酯環丙氯地孕酮(cyproteron acetate))、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)、促性腺素釋放素激動劑及拮抗劑(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))、甲硫胺酸胺基肽酶抑制劑(例如苯甲醯胺衍生物、TNP-470、PPI-2458)、類肝素酶抑制劑(例如SST0001、PI-88)；抗遺傳改造之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，格爾德黴素(geldamycin)衍生物，諸如17-烯丙基胺基格爾德黴素、17-去甲氧基格爾德黴素(17AAG)、17-DMAG、瑞他黴素(retaspimycin)鹽酸鹽、IPI-493、AUY922、BIIB028、STA-9090、KW-2478)、驅動蛋白紡錘體蛋白抑制劑(例如SB715992、SB743921、潘他米丁(pentamidine)/氯丙嗪)、MEK(絲裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase))抑制劑(例如曲美替尼(trametinib)、BAY 86-9766(refametinib)、AZD6244)、激酶抑制劑(例如：索拉非尼(sorafenib)、瑞格拉非尼(regorafenib)、拉帕替尼(lapatinib)、索坦(Sutent)、達沙替尼(dasatinib)、西妥昔單抗(cetuximab)、BMS-908662、GSK2118436、AMG 706、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、伊馬替尼(imatinib)、尼祿替尼(nilotinib)、帕唑帕尼(pazopanib)、(roniciclib)、舒尼替尼(sunitinib)、凡德他尼(vandetanib)、維羅非尼(vemurafenib))、刺蝟信號抑制劑(例如，環巴明(cyclopamin)、維莫德吉(vismodegib))、BTK(布魯頓(Bruton's)酪胺酸激酶)抑制劑(例如依魯替尼(ibrutinib))、JAK/泛-JAK (詹納斯激酶)抑制劑(例如SB-1578、巴瑞西替尼(baricitinib)、托法替尼、帕林替尼(pacritinib)、莫美羅替尼(momelotinib)、盧梭利替尼(ruxolitinib)、VX-509、AZD-1480、TG-101348)、PI3K抑制劑(例如BAY 1082439、BAY 80-6946(可潘利昔(copanlisib))、ATU-027、SF-1126、DS-7423、GSK-2126458、布潘利昔(buparlisib)、PF-4691502、BYL-719、XL-147、XL-765、艾代拉裡斯(idelalisib))、SYK(脾酪胺酸激酶)抑制劑(例如伏他馬替尼(fostamatinib)、Excellair、PRT-062607)、p53基因療法、雙膦酸鹽(例如伊膦酸鹽(etridonat)、氯膦酸鹽(clodronat)、替魯膦酸鹽(tiludronat)、帕米膦酸鹽(pamidronat)、阿侖棒酸(alendronic acid)、伊班膦酸鹽(ibandronat)、利塞膦酸鹽(risedronat)、唑來膦酸二鈉(zoledronat))。用於組合之活性化合物之實例包含以下：利妥昔單抗、環磷醯胺、阿黴素(doxorubicin)、阿黴素與雌(甾)酮(oestrone)之組合、長春新鹼、苯丁酸氮芥(chlorambucil)、氟達拉濱、***(dexamethasone)、克拉屈濱、潑尼松、131I-chTNT、阿比特龍(abirateron)、阿柔比星(aclarubicin)、阿利維A酸(alitretinoin)、比生群(bisantren)、甲醯四氫葉酸鈣(calcium folinate)、左亞葉酸鈣(calcium levofolinate)、卡培他濱(capecitabin)、卡莫氟(carmofur)、氯甲雙磷酸(clodronic acid)、羅米司亭(romiplostim)、克立他酶(crisantaspase)、阿法達貝泊汀(darbepoetin alfa)、地西台賓(decitabin)、狄諾塞麥(denosumab)、二溴螺氯銨(dibrospidium chloride)、艾曲波帕(eltrombopag)、內皮他丁(endostatin)、環硫雄醇(epitiostanol)、阿法依伯汀(epoetin alfa)、非格司亭(filgrastim)、福莫司汀(fotemustin)、硝酸鎵、鹽酸吉西他賓(gemcitabin)、麩胱甘肽(氧化型)二鈉鹽(glutoxim)、二鹽酸組胺、羥基尿素、英丙舒凡(improsulfan)、伊沙匹隆(ixabepilon)、蘭樂肽(lanreotid)、蘑菇多醣(lentinan)、左旋咪唑、麥角乙脲、氯尼達明(lonidamin)、馬索丙考(masoprocol)、甲基***(methyltestosterone)、甲氧沙林(methoxsalen)、甲胺基酮戊酸鹽、米特福辛(miltefosin)、(mitoguazon)、絲裂黴素(mitomycin)、米托坦(mitotan)、奈拉濱(nelarabin)、尼妥珠單抗(nimotuzumab)、根瘤菌劑(nitracrin)、奧美拉唑(omeprazol)、帕利夫明(palifermin)、帕尼單抗(panitumumab)、培門冬酶(pegaspargase)、PEG依泊丁(甲氧基-PEG依泊丁)、乙二醇化非格司亭(pegfilgrastim)、聚乙二醇干擾素α-2b、潘他唑新(pentazocin)、噴司他丁(pentostatin)、培磷醯胺(perfosfamid)、吡柔比星(pirarubicin)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、卟菲爾鈉(porfimer-sodium)、普拉曲沙(pralatrexate)、喹高利特(quinagolid)、雷佐生(razoxan)、西佐喃(sizofiran)、索布佐生(sobuzoxan)、甘胺雙唑鈉(sodium glycididazole)、他米巴羅汀(tamibaroten)、替加氟與吉美嘧啶(gimeracil)及奧替拉西(oteracil)之組合、睾酮(testosterone)、替曲膦(tetrofosmin)、薩力多胺(thalidomide)、胸腺法新(thymalfasin)、曲貝替定(trabectedin)、維生素A酸(tretinoin)、腈環氧雄烷(trilostan)、色胺酸、烏苯美司(ubenimex)、(vapreotid)、釔-90玻璃微珠、淨司他丁(zinostatin)、淨司他丁斯酯。 亦適用於腫瘤治療的為諸如化療(例如，阿紮胞苷(azacitidine)、貝洛替康(belotecan)、依諾他濱(enocitabine)、美法侖(melphalan)、戊柔比星(valrubicin)、長春氟寧(vinflunin)、佐柔比星(zorubicin))、放射療法(例如I-125接種、鈀-103接種、鐳-223氯化物)或光照療法(例如替莫泊芬(temoporfin)、他拉泊芬(talaporfin))之非藥劑治療之組合，該非藥劑治療可伴隨根據本發明之IRAK4抑制劑之藥劑治療或於諸如化療、放射療法或光照療法之非藥劑治療結束後，補充根據本發明之IRAK4抑制劑之藥劑治療。 除上述其等之外，根據本發明之TRAK4抑制劑亦可與以下活性化合物組合： 用於阿爾茨海默氏病治療之活性化合物，例如乙醯膽鹼酯酶抑制劑(例如，多奈哌齊(donepezil)、利凡斯的明(rivastigmine)、加蘭他敏(galantamin)、他克林(tacrine)、NMDA (N-甲基-D-天門冬胺酸鹽)受體拮抗劑(例如美金剛)；用於治療帕金森氏症之L-DOPA/碳度巴(L-3,4-二羥***酸)、COMT(兒茶酚-O-甲基轉移酶)抑制劑(例如恩他卡朋(entacapon))、多巴胺激動劑(例如羅平尼咯(ropinrol)、普拉克索(pramipexol)、溴隱亭(bromocriptin))、MAO-B(單胺氧化酶-B)抑制劑(例如司來吉蘭(selegilin))、抗膽鹼能劑(例如，三己芬迪(trihexyphenidyl))及NMDA拮抗劑(例如金剛胺(amantadin))；用於治療多發性硬化之β干擾素(IFN-β) (例如IFNβ-1b、IFNβ-1a、Avonex®及Betaferon®)、乙酸格拉替雷(glatiramer acetate)、免疫球蛋白、那他珠單抗(natalizumab)、芬戈莫德(fingolimod)及免疫抑制劑諸如米托蒽醌(mitoxantrone)、咪唑硫嘌呤及環磷醯胺；用於治療肺病之物質，例如β-2-擬交感神經劑(例如舒喘寧(salbutamol))、抗膽鹼能劑(例如葡萄糖吡喀(glycopyrronium))、甲基黃嘌呤(例如茶鹼(theophylline))、白細胞三烯受體拮抗劑(例如孟魯司特(montelukast))、PDE-4(磷酸二酯酶4型)抑制劑(例如羅氟司特(roflumilast))、甲胺喋呤、IgE抗體、咪唑硫嘌呤及環磷醯胺、含皮質醇製劑；用於治療骨關節炎之物質，諸如非類固醇抗炎物質(NSAID)。除提及之兩種治療之外，可提及用於諸如類風濕性關節炎、脊柱關節炎及幼年特發性關節炎之類風濕性疾病的甲胺喋呤、來氟米特、Jak/STAT抑制劑(例如，托法替尼、巴瑞替尼、GLPG0634)、TNF拮抗劑(例如，Humira®、依那西普、英夫利昔單抗)、IL-1抑制劑(例如阿那白滯素、康納單抗、利納西普)及針對B細胞及T細胞治療之生物製劑(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(單胺氧化酶)抑制劑(例如司來吉蘭)、干擾素及抗驚厥劑(例如加巴噴丁(gabapentin))；用於治療心血管疾病之活性化合物，諸如β-受體阻斷劑(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(例如氫氯苯噻噠嗪)、鈣離子通道阻斷劑(例如硝苯地平(nifedipine))、他汀(例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin))；抗糖尿病藥劑，例如甲福明(metformin)、格列奈(例如那格列奈(nateglinide))、DPP-4 (二肽基肽酶-4)抑制劑(例如利拉利汀(linagliptin)、沙克列汀(saxagliptin)、西他列汀(sitagliptin)、維格列汀(vildagliptin))、SGLT2 (鈉/葡萄糖共轉運蛋白2)抑制劑/格列淨(gliflozin) (例如達格列淨(dapagliflozin)、依帕格列淨(empagliflozin))、腸促胰島素擬似物(葡萄糖依賴性促胰島素肽(GIP)激素及類胰高血糖素肽1 (GLP-1)類似物/激動劑)(例如艾塞那肽(exenatide)、利拉魯肽(liraglutide)、利西拉來(lixisenatide))、α-葡萄糖苷酶抑制劑(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))、胰島素增敏劑(例如匹格列酮(pioglitazone))及胰島素療法(例如NPH胰島素、賴脯胰島素(insulin lispro))、用於治療低血糖之物質，其等用於治療糖尿病及代謝症候群。降脂藥劑，例如貝特(例如苯紮貝特(bezafibrate)、依託貝特(etofibrate)、非諾貝特(fenofibrate)、吉非貝琪(gemfibrozil))、菸酸衍生物(例如菸酸/拉羅皮蘭(laropiprant))、依澤替米貝(ezetimib)、他汀(例如辛伐他汀、氟伐他汀)、陰離子交換劑(例如考來烯胺(colestyramine)、考來替泊(colestipol)、考來維侖(colesevelam))。活性化合物諸如美沙拉嗪(mesalazine)、柳氮磺胺吡啶、咪唑硫嘌呤、6-巰基嘌呤或甲胺喋呤、益生菌(Mutaflor、VSL#3®、乳酸桿菌GG、胚牙乳酸桿菌、嗜酸乳酸桿菌、乾酪乳酸桿菌、嬰兒雙岐桿菌35624、屎腸球菌SF68、長雙歧桿菌、大腸桿菌Nissle 1917)、抗生素例如環丙沙星及甲硝噠唑(metronidazole)、抗腹瀉藥劑例如洛派丁胺(loperamide)或緩瀉劑(比沙可啶(bisacodyl))，其等用於治療慢性炎性腸病。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抗炎物質(NSAID)、可的松(cortisone)、氯喹(chloroquin)、環孢黴素(cyclosporine)、咪唑硫嘌呤、貝利單抗、利妥昔單抗、環磷醯胺。舉例而言但不排他地，用於器官移植物之鈣神經蛋白抑制劑(例如他克莫司及環孢素(ciclosporin))、細胞分化抑制劑(例如咪唑硫嘌呤、麥考酚酸嗎乙酯、麥考酚酸、依維莫司或西羅莫司)、雷帕黴素、巴厘昔單抗、達克珠單抗(daclizumab)、抗CD3抗體、抗T細胞血球素/抗淋巴細胞血球素。用於皮膚病之維生素D3類似物(例如)鈣泊三醇(calcipotriol)、他凱西醇(tacalcitol)或骨化三醇(calcitriol)、水楊酸、尿素、環孢素、甲胺喋呤、依法利珠單抗(efalizumab)。用於治療腎病、腎病變及腎小球疾病之糖皮質激素(例如潑尼松)、免疫抑制物質諸如咪唑硫嘌呤、環磷醯胺、麥考酚酸嗎乙酯、羥化氯喹、ACE抑制劑(例如甲巰丙脯酸、貝那普利、依那普利(enalapril)、福辛普利(fosinopril))、血管收縮素受體阻斷劑(例如氯沙坦、纈沙坦)、β-受體阻斷劑(例如美托洛爾)、鈣離子通道阻斷劑(例如硝苯地平)及免疫抑制劑諸如環孢素。 亦應提及包含至少一種根據本發明之化合物及一或多種其他活性化合物，特定言之EP4抑制劑(***素E2受體4抑制劑)、P2X3抑制劑(P2X嘌呤受體3)、PTGES抑制劑(***素E合酶抑制劑)或AKR1C3抑制劑(阿爾多酮(aldo-keto)還原酶家族1成員C3抑制劑)之藥劑，其用於治療及/或預防上述疾病。 本發明之化合物可全身及/或局部地起作用。出於此目的，其等可以例如藉由口服、非經腸、肺部、鼻部、舌下、舌部、口腔、直腸、真皮、經皮或結膜途徑之適宜方式、經由耳朵或作為移植物或支架(stent)投與。 本發明之化合物可以適用於該等投藥途徑之投藥形式投與。 用於口服投與之適宜投藥方式為彼等根據先前技術工作及迅速及/或以改性方式釋放本發明之化合物及以結晶及/或非晶型及/或溶解形式包含本發明之化合物者，例如錠劑(未包衣或包衣錠劑，例如利用抗胃液劑或溶解遲緩或不溶性塗料，其控制本發明之化合物之釋放)、於口腔內迅速崩解之錠劑或薄膜/扁圓體、薄膜/凍乾物、膠囊(例如硬或軟凝膠膠囊)、糖衣包裹之錠劑、顆粒劑、丸劑、粉劑、乳液、懸浮液、氣溶膠或溶液。 非經腸投藥可利用避免再吸收步驟(例如藉由靜脈內、動脈內、心臟內、脊柱內或腰髓內途徑)或利用包含再吸收(例如藉由肌肉內、皮下、皮內、經皮或腹膜內途徑)實現。適用於非經腸投藥之投藥形式包括以溶液、懸浮液、乳液、凍乾物或無菌粉末形式之用於注射及輸液之製劑。 用於其他投藥途徑，適宜實例為吸入藥劑(包括粉末吸入器、噴霧器)、滴鼻劑、溶液或噴霧；用於舌部、舌下或口腔投藥之錠劑、薄膜/扁圓體或膠囊、栓劑、耳或眼用製劑、***膠囊、水性懸浮液(洗液、振動混合物)、親脂性懸浮液、軟膏、乳霜、透皮治療系統(例如貼片)、乳、膏劑、泡沫、敷粉、移植物或支架。 較佳係口服及非經腸投藥，尤其口服投藥。 本發明之化合物可經轉換成提及之投藥形式。此可以本身已知之方式藉由與惰性、無毒、醫藥上適宜之賦形劑混合來實現。該等賦形劑包括載劑(例如微晶纖維素、乳糖、甘露醇)、溶劑(例如液態聚乙二醇)、乳化劑及分散或浸濕劑(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)及香味劑及/或氣味校正劑。 本發明另外提供藥劑，其包含通常與一種或多種惰性、無毒、醫藥上適宜之賦形劑一同之至少一種根據本發明之化合物及其用於上述目的之用途。 一般而言，於非經腸投藥之情況下，為達成有效效果宜投與約0.001至1 mg/kg體重，較佳地約0.01至0.5 mg/kg體重之量。於口服之情況下，劑量為約0.01至100 mg/kg體重，較佳地約0.01至20 mg/kg體重及最佳地0.1至10 mg/kg體重。 然而於一些情況下脫離指定量可係必要的，具體而言作為體重、投藥途徑、個體對活性化合物之反應、製劑性質及投藥發生之時間或間隔之函數。因此於一些情況下，可足以以少於上述最小量管理，而於其他情況下必須超過提及之上限。於較大量之投藥情況下，可可取地將藥劑分成一天中若干單個劑量。 接下來之工作實例說明本發明。本發明不限於該等實例。 除非另作指明，否則接下來於試驗及實例中之百分比為重量百分比；份數為重量份數。於各者情況中用於液體/液體溶液之溶劑比、稀釋比及濃度數據係基於體積計。 於以下合成反應圖1中說明根據本發明之式(I)之物質之製法。
Figure TW201803866AD00007
反應圖1 用於合成一些根據本發明之化合物之起始物質為羧酸R2 -A-CO2 H，其中R2 如式(I)中所定義，其為市售的或可藉由自文獻已知途徑或類似於自文獻已知途徑製備(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)。可從羧酸酯繼續，藉由水解或於正丁酯之情況下藉由與(例如)鹽酸或三氟乙酸之酸反應，製備一些羧酸R2 -A-CO2 H，其中R2 如式(I)中所定義(參見，例如Dalton Transactions, 2014, 43, 19, 7176-7190)。羧酸R2 -A-CO2 H亦可以其鹼金屬鹽之形式用於反應中。可視情況地自鹵化單元R2 -A-I、R2 -A-Br或R2 -A-Cl(其中R2 如式(I)中所定義)，藉由在一氧化碳氣氛中，視情況在加壓下，在膦配體例如1,3-雙(二苯膦基)丙烷、鈀化合物例如乙酸鈀(II)及在鹼例如三乙胺之存在下，於溶劑例如二甲亞碸中添加乙醇或甲醇反應，來製備作為用於製備羧酸R2 -A-CO2 H之起始物質之羧酸酯(製備方法參見，例如WO 2012112743、WO 2005082866、Chemical Communications(Cambridge, England) , 2003, 15, 1948-1949、WO 200661715)。起始物質R2 -A-I、R2 -A-Br、R2 -A-Cl為市售或可藉由來自文獻已知之途徑製備。於WO2012061926；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中說明例示性製備方法。 以3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)開始，藉由與適宜羧酸R2 -A-CO2 H反應製備化合物1.1，其中R2 具有於技術方案中提及之含義及R2 可另外經羧酸酯取代。出於此目的，可使用各種來自文獻已知之偶合試劑(Amino Acids, Peptides and Proteins in Organic Chemistry.第3卷-Building Blocks；Catalysis and Coupling Chemistry，Andrew B. HughesWiley，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-乙基碳二亞胺鹽酸鹽與1-羥基-1H-苯并***水合物(HOBt，WO2012107475；Bioorg. Med. Chem. Lett., 2008, 18, 2093)、四氟硼酸(1H-苯并***-1-基氧基)(二甲胺基)-N,N-二甲基甲亞銨(TBTU，CAS-RN 125700-67-6)、六氟磷酸(二甲胺基)-N,N-二甲基(3H-[1,2,3]***并[4,5-b]吡啶-3-基氧基)甲亞銨(HATU，CAS-RN 148893-10-1)、丙烷膦酸酐(呈於乙酸乙酯或DMF中之溶液中，CAS-RN 68957-94-8)或二-1H-咪唑-1-基甲酮(CDI)組合作為偶合試劑，於各者情況下添加鹼諸如三乙胺或N-乙基-N-異丙基丙-2-胺至反應混合物中。該等偶合試劑較佳地為HATU、N-[3-(二甲胺基)丙基]-N'-乙基碳二亞胺(EDC，CAS-RN 1892-57-5)與1H-苯并***-1-醇水合物(1:1)(HOBt，CAS-RN 123333-53-9)及TBTU之組合。使用之鹼較佳地為三乙胺或N-乙基-N-異丙基丙-2-胺。較佳溶劑為THF或DMF。 可自化合物1.1，藉由用酸視情況加熱下處理來製備化合物1.2。藉由處理化合物1.1，視情況於惰性溶劑中，用適宜酸在室溫或在40℃至200℃下進行該反應。適宜酸為(例如)乙酸、三氟乙酸或鹽酸。該酸亦可用作溶劑。 或者，可直接自3-胺基-4-(甲胺基)苯甲酸甲酯，藉由與羧酸在酸性脫水條件下(例如與丙烷膦酸酐)反應或藉由於惰性溶劑中在室溫或在40℃至200℃下碳醯氯反應，製備化合物1.2。 藉由化合物1.2之硝化可得到化合物1.3。用於此目的之可用方法為熟習此項技術者已知之硝化方法，例如使用硝酸與濃硫酸組合或使用濃硫酸與硝酸鉀。 以化合物1.3開始，可藉由硝基之還原製備化合物1.4。例如，可在氫氣氛圍下使用碳載鈀(WO2007/48070)，於水及乙醇中使用鐵或氯化銨(US2003/236260)或氯化錫(II) (WO2008/128009)還原該硝基。 可自化合物1.4，以類似於製備化合物1.1所述之方式，使用式R1 -COOH之適宜羧酸製備化合物「中間體」，其中R1 具有技術方案1給定之含義。 可自中間體，藉由格利雅反應，使用(例如)溴化甲基鎂製備通式(I)之化合物。可於諸如***或四氫呋喃之適宜溶劑中於-30℃至50℃溫度範圍中，但較佳地在室溫下進行該反應。 或者，可自中間體，藉由與甲基鋰在-78℃至室溫之溫度下反應，得到通式(I)之化合物。 若自由基R2 含有諸如羧酸甲酯或羧酸乙酯之羧酸酯，其可在上述用於中間體轉化成通式(I)之化合物之條件下轉化成丙-2-醇。 若於根據本發明之化合物之合成中之個別合成步驟需保護基，可藉由熟習此項技術者已知之方法引入或移除其等保護基(適宜保護基之引入及移除亦參見P. G. M. Wuts、T. W. Greene，Greene's Protective Groups in Organic Synthesis，第4版，ISBN：9780471697541)。實例化合物之合成 縮寫及說明 術語飽和鹽水 意指飽和氯化鈉水溶液。 使用ACD/LABS (批版本12.01.)軟體生成中間體及實例之化學名稱。方法 藉由LC-MS分析根據本發明之化合物及其前驅體及/或中間體。 LC-MS方法(分析型)：UPLC-MS 方法 A 儀器：Waters Acquity UPLC-MS SQD3001；管柱：Acquity UPLC BEH C18 1.7 50 x 2.1mm；流動相A：水+0.1%甲酸，流動相B：乙腈；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：2 µl；DAD掃描：210至400 nm。 UPLC-MS方法B 儀器：Waters Acquity UPLC-MS SQD3001；管柱：Acquity UPLC BEH C18 1.7 50 x 2.1mm；流動相A：水+0.2%氨水(32%)，流動相B：乙腈；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：2 µl；DAD掃描：210至400 nm；ELSD。 UPLC-MS方法C 儀器：Waters Acquity UPLC-MS ZQ4000；管柱： Acquity UPLC BEH C18 1.7 50 x 2.1mm；流動相A：水+0.05%甲酸，流動相B：乙腈+0.05%甲酸；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：2 µl；DAD掃描：210至400 nm。 UPLC-MS方法D 儀器：Waters Acquity UPLC-MS ZQ4000；管柱： Acquity UPLC BEH C18 1.7 50x2.1mm；流動相A：水+0.2%氨水(32%)，流動相B：乙腈；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：2 µl；DAD掃描：210至400 nm；ELSD。 UPLC-MS方法E 儀器：Waters Acquity UPLC-MS ZQ2000；管柱：Acquity UPLC BEH C18 1.7 50x2.1mm；流動相A：水+0.1%甲酸，流動相B：乙腈；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：1 µl；DAD掃描：210至400 nm；ELSD。 UPLC-MS方法F 儀器：Waters Acquity UPLC-MS ZQ2000；管柱： Acquity UPLC BEH C18 1.7 50x2.1mm；流動相A：水+0.2%氨水(32%)，流動相B：乙腈；梯度：0至1.6 min 1-99% B，1.6至2.0 min 99% B；流速0.8 ml/min；溫度：60℃；注射：1 µl；DAD掃描：210至400 nm；ELSD。 於一些情況下，藉由在矽膠上之管柱層析法純化物質混合物。 對於一些本發明之化合物及其前驅體及/或中間體之製備，使用來自Biotage之Isolera® 裝置在矽膠上實施管柱層析法純化(「急驟層析法」)。出於此目的，使用來自Biotage之濾筒，例如各種尺寸之濾筒「SNAP Cartridge，KP_SIL」。 以1 H NMR峰列表之形式陳述所選化合物之1 H NMR數據。此處，對於各信號峰，首先δ值(單位為ppm)及接著於圓括弧內列出信號強度。由逗號分開彼此列出數對不同信號峰之δ值-信號強度數；因此，化合物之峰列表具有以下形式：δ1(強度1)，δ2(強度2)，…，δi(強度i)，…，δn(強度n)。 於NMR光譜之印製實例中，尖信號之強度係與信號之高度(單位為cm)相關聯及顯示相較於其他信號之信號強度之正確比率。於寬信號之情況下，可顯示若干個峰或中間之信號及其相對於光譜中最強信號之相對強度。1 H NMR峰列表類似於習知1 H NMR印出及因此通常包含列於習知NMR解讀中之所有峰。此外，類似習知1 H NMR印出，其可顯示溶劑信號、談論之目標化合物之立體異構體的信號、雜質之峰、13 C伴峰及/或旋轉邊帶。目標化合物之立體異構體之峰及/或雜質之峰通常平均具有較目標化合物(例如具有＞90%之純度)之峰更低的強度。該等立體異構體及/或雜質就特定製備方法而言可係典型的。因此其等之峰可有助於參考「副產物指紋」識別製備方法之再現。由專家藉由已知方法(MestreC、ACD模擬或使用經驗評估之預期值)計算目標化合物之峰可在需要時視情況使用其他強度過濾器來單離目標化合物之峰。此單離將類似於習知1H NMR解讀中所談論之峰拾取(peak picking)。以峰列表形式提交之NMR數據之細節描述可見於出版物「Citation of NMR Peaklist Data within Patent Applications」(參見http://www.researchdisclosure.com/searching-disclosures，Research Disclosure 資料庫編號605005，2014，2014年8月1日)。於引用之研究揭示內容中描述之峰拾取常規中，參數「MinimumHeight」可經調整至在1%與4%之間之值。然而，取決於化學結構之性質及/或取決於待測化合物之濃度，調整參數「MinimumHeight」至＜1%值亦可係有利的。 中間體1-12-(3- 甲氧基 -3- 側氧基丙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00008
步驟 1 3-[(4- 甲氧基 -4- 側 氧丁醯基 ) 胺基 ]-4-( 甲胺基 ) 苯甲酸甲酯 在室溫下，在5.8 ml (41.6 mmol)三乙胺之存在下，於75 ml DMF中將5 g (27.7 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及5.5 g (41.6 mmol) 4-甲氧基-4-側氧丁酸(CAS-RN 3878-55-5)與15.8 g (41.6 mmol) HATU攪拌6小時。藉由HPLC純化，得到6.5 g (80%)標題化合物。 UPLC-MS(ESI+)：[M + H]+ =295;Rt = 0.82 min(方法E)。步驟 2 2-(3- 甲氧基 -3- 側氧基丙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸 甲酯 在40℃下，將6.5 g (22 mmol) 3-[(4-甲氧基-4-側氧基丁醯基)胺基]-4-(甲胺基)苯甲酸甲酯於52 ml乙酸中攪拌48小時。濃縮得到6.4 g無需進一步純化即可進一步使用之殘餘物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.91 - 2.97(m, 2H), 3.12 - 3.19(m, 2H), 3.62 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 7.61 - 7.65 (m, 1H), 7.83 - 7.88 (m, 1H), 8.13-8.16 (m, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 277；Rt = 0.70 min(方法E)。步驟 3 2-(3- 甲氧基 -3- 側氧基丙基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸 甲酯 將6.43 g 2-(3-甲氧基-3-側氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(23 mmol)溶解於50 ml濃硫酸中並緩慢添加2.7 ml濃硝酸與濃硫酸之混合物(1:1.4)。於添加結束後，將混合物在室溫下攪拌1小時。將反應混合物添加至500 g冰中並用飽和碳酸氫鈉溶液將pH調整至10。抽濾掉沉澱產物，將該沉澱產物溶解於300 ml乙酸乙酯、200 ml二氯甲烷及100 ml乙腈之混合物中，經硫酸鎂乾燥並濃縮。此過程得到5.8 g (78%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.91 - 3.01 (m, 2H), 3.15 - 3.27 (m, 2H), 3.62 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 7.96 (s, 1H), 8.46 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 322；Rt = 0.89 min(方法E)。步驟 4 6- 胺基 -2-(3- 甲氧基 -3- 側氧基丙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸 甲酯 於氫氣氛圍下，在室溫下，將含於77 ml甲醇及180 ml THF之混合物中之5.8 g (18 mmol) 2-(3-甲氧基-3-側氧基丙基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯與1.6 g 10%碳載鈀攪拌2小時。過濾混合物，於濃縮濾液後得到5.4 g無需進一步純化即可進一步使用之殘餘物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.83 - 2.90 (m, 2H), 3.00 - 3.07 (m, 2H), 3.58 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 6.43 (sbr, 2H), 6.64 (s, 1H), 7.91 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 292；Rt = 0.59 min(方法E)。步驟 5 2-(3- 甲氧基 -3- 側氧基丙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 在室溫下，在359 µl (2.5 mmol)三乙胺之存在下，於4.6 ml DMF中使0.5 g (1.7 mmol) 6-胺基-2-(3-甲氧基-3-側氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及492 mg (2.5 mmol)6-(三氟甲基)吡啶-2-甲酸(CAS-RN 131747-42-7)與979 mg (2.5 mmol)HATU反應1.5小時。將反應混合物添加至100 ml水中並攪拌15 min。抽濾，得到700 mg (88%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.90 - 2.97 (m, 2H), 3.14 - 3.21 (m, 2H), 3.63 (s, 3H), 3.79 (s, 3H), 3.94 (s, 3H), 8.21 - 8.26 (m, 1H), 8.28 (s, 1H), 8.39 - 8.45 (m, 1H), 8.47 - 8.51 (m, 1H), 8.95 (s, 1H), 12.98 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 465；Rt = 1.15 min(方法A)。 類似於中間體1-1步驟5之合成法，自6-胺基-2-(3-甲氧基-3-側氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-1步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00009
Figure TW201803866AD00010
Figure TW201803866AD00011
Figure TW201803866AD00012
Figure TW201803866AD00013
Figure TW201803866AD00014
Figure TW201803866AD00015
Figure TW201803866AD00016
Figure TW201803866AD00017
Figure TW201803866AD00018
Figure TW201803866AD00019
 中間體1-131- 甲基 -2-[2-( 甲磺醯基 ) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00020
步驟 1 4-( 甲胺基 )-3-{[3-( 甲磺醯基 ) 丙醯基 ] 胺基 } 苯甲酸甲酯 在室溫下，在7.9 ml (57 mmol)三乙胺之存在下，於75 ml DMF中使6.85 g (38 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及8.68 g (57 mmol)3-(甲磺醯基)丙酸(CAS-RN 645-83-0)與22 g (57 mmol) HATU反應1小時。將反應混合物添加至400 g冰中並用飽和碳酸氫鈉溶液將pH調整至10。抽濾掉沉澱產物，得到12.8 g無需進一步純化即可進一步使用之粗產物。 UPLC-MS (ESI+)：[M + H]+ = 315；Rt = 0.81 min(方法A)。步驟 2 1- 甲基 -2-[2-( 甲磺醯基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自4-(甲胺基)-3-{[3-(甲磺醯基)丙醯基]胺基}苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 297；Rt = 0.69 min(方法A)。步驟 3 1- 甲基 -2-[2-( 甲磺醯基 ) 乙基 ]-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 342；Rt = 0.78 min(方法E)。步驟 4 6- 胺基 -1- 甲基 -2-[2-( 甲磺醯基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸 甲酯 將10.3 g (30 mmol) 1-甲基-2-[2-(甲磺醯基)乙基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯溶解於310 ml乙酸中。添加1.6 g Pd/C (10 %)及使混合物於氫氣氛圍下氫化。於氫氣吸收停止後(2.5小時)，過濾該混合物並濃縮濾液至幹，得到定量產量之標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 3.08 (s, 3H), 3.22 - 3.29 (m, 2H), 3.60 (s, 3H), 3.61 - 3.68 (m, 2H), 3.80 (s, 3H), 6.46 (sbr, 2H), 6.66 (s, 1H), 7.93 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 312；Rt = 0.56 min(方法E)。步驟 5 1- 甲基 -2-[2-( 甲磺醯基 ) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸 (CAS-RN 131747-42-7)，製法類似於中間體1-1之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 3.11 (s, 3H), 3.36 - 3.40 (m, 2H), 3.69 - 3.75 (m, 2H), 3.81 (s, 3H), 3.95 (s, 3H), 8.21 - 8.25 (m, 1H), 8.30 (s, 1H), 8.39 - 8.45 (m, 1H), 8.47 - 8.51 (m, 1H), 8.96 (s, 1H), 12.97 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 485；Rt = 1.08 min(方法E)。 類似於中間體1-13步驟5之合成法，自6-胺基-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-13步驟4)及之對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00021
Figure TW201803866AD00022
Figure TW201803866AD00023
Figure TW201803866AD00024
Figure TW201803866AD00025
 中間體1-192-(2- 甲氧基乙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00026
步驟 1 3-[(3- 甲氧丙醯基 ) 胺基 ]-4-( 甲胺基 ) 苯甲酸甲酯 在室溫下，在11 ml (83 mmol)三乙胺之存在下，於150 ml THF中使10 g (55 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及8.6 g (83 mmol)3-甲氧基丙酸(CAS-RN 2544-06-1)與31 g (83 mmol) HATU反應過夜。濾掉所形成之沉澱並用二氯甲烷洗滌及濃縮濾液，得到52 g無需進一步純化即可進一步使用之粗產物。 UPLC-MS (ESI+)：[M + H]+ = 267；Rt = 0.79 min(方法A)。步驟 2 2-(2- 甲氧基乙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自3-[(3-甲氧丙醯基)胺基]-4-(甲胺基)苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 249；Rt = 0.64 min(方法E)。步驟 3 2-(2- 甲氧基乙基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸 甲酯 自2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 294；Rt = 0.86 min(方法A)。步驟 4 6- 胺基 -2-(2- 甲氧基乙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-(2-甲氧基乙基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 3.00 - 3.07 (m, 2H), 3.34 (s, 3H), 3.58 (s, 3H), 3.72 - 3.78 (m, 2H), 6.43 (sbr, 2H), 6.64 (s, 1H), 7.92 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 264；Rt = 0.56 min(方法E)。步驟 5 2-(2- 甲氧基乙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 3.19 - 3.25 (m, 2H), 3.29 (s, 3H), 3.79 - 3.85 (m, 5H), 3.98 (s, 3H), 8.22 - 8.26 (m, 1H), 8.30 (s, 1H), 8.39 - 8.45 (m, 1H), 8.47 - 8.51 (m, 1H), 8.99 (s, 1H), 12.98 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 437；Rt = 1.05 min(方法A)。 類似於中間體1-1步驟5之合成法，自6-胺基-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-19步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00027
Figure TW201803866AD00028
Figure TW201803866AD00029
Figure TW201803866AD00030
Figure TW201803866AD00031
Figure TW201803866AD00032
Figure TW201803866AD00033
Figure TW201803866AD00034
Figure TW201803866AD00035
 中間體 1-29 2-(3- 甲氧基丙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00036
步驟 1 3-[(4- 甲氧丁醯基 ) 胺基 ]-4-( 甲胺基 ) 苯甲酸甲酯 在室溫下，在9.8 ml (70 mmol)三乙胺之存在下，於126 ml THF中使8.4 g (46 mmol) 3-胺基-4-(甲胺基) 苯甲酸甲酯(CAS-RN 66315-16-0)及7.7 g (65 mmol)4-甲氧基丁酸(CAS-RN 29006-02-8)與26.6 g (70 mmol) HATU反應1小時。濃縮反應混合物並將其溶解於100 ml二氯甲烷中。用飽和碳酸氫鈉溶液、水及飽和氯化鈉溶液洗滌該二氯甲烷溶液並經硫酸鎂乾燥。濃縮，得到26 g無需進一步純化即可進一步使用之粗產物。 UPLC-MS (ESI+)：[M + H]+ = 281；Rt = 0.83 min(方法E)。步驟 2 2-(3- 甲氧基丙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸 甲酯 在80℃下，將13 g (46 mmol) 3-[(4-甲氧丁醯基)胺基]-4-(甲胺基)苯甲酸甲酯(26 g來自步驟1之粗產物)於110 ml乙酸中攪拌4小時。濃縮混合物並藉由在矽膠上之層析法純化殘餘物，得到7.76 g (63%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 263；Rt = 0.65 min(方法E)。步驟 3 2-(3- 甲氧基丙基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸 甲酯 自2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 308；Rt = 0.91 min(方法A)。步驟 4 6- 胺基 -2-(3- 甲氧基丙基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-(3-甲氧基丙基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 278；Rt = 0.61 min(方法E)。步驟 5 2-(3- 甲氧基丙基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.98 - 2.09 (m, 2H), 2.90 - 2.97 (m, 2H), 3.26 (s, 3H), 3.42 - 3.49 (m, 2H), 3.76 (s, 3H), 3.94 (s, 3H), 8.22 - 8.26 (m, 1H), 8.28 (s, 1H), 8.39 - 8.44 (m, 1H), 8.46 - 8.51 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 451；Rt = 1.23 min(方法F)。 類似於中間體1-1步驟5之合成法，自6-胺基-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-29步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00037
Figure TW201803866AD00038
Figure TW201803866AD00039
Figure TW201803866AD00040
Figure TW201803866AD00041
 中間體 1-35 1- 甲基 -2-[2-( 嗎啉 -4- 基 ) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00042
步驟 1 4-( 甲胺基 )-3-{[3-( 嗎啉 -4- 基 ) 丙醯基 ] 胺基 } 苯甲酸甲酯 自3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及3-(嗎啉-4-基)丙酸鹽酸鹽(CAS-RN 6319-95-5)，製法類似於中間體1-13之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 322；Rt = 0.82 min(方法F)。步驟 2 1- 甲基 -2-[2-( 嗎啉 -4- 基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自4-(甲胺基)-3-{[3-(嗎啉 -4-基)丙醯基]胺基}苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 304；Rt = 0.82 min(方法F)。步驟 3 6- 胺基 -1- 甲基 -2-[2-( 嗎啉 -4- 基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 將3.7 g 1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-5-甲酸甲酯(12 mmol)溶解於27 ml濃酸酸中並緩慢添加3.4 ml濃硝酸與濃硫酸之混合物(1:1.4)。於添加結束後，在室溫下攪拌混合物3小時。將反應混合物添加至300 g冰中並用飽和碳酸氫鈉溶液將pH調整至9。用500 ml乙酸乙酯萃取混合物三次。合併之有機相經硫酸鎂乾燥並濃縮之。此過程得到3.4 g (80%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 349；Rt = 0.86 min(方法F)。步驟 4 6- 胺基 -1- 甲基 -2-[2-( 嗎啉 -4- 基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 將3.14 g (9 mmol) 6-胺基-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-5-甲酸甲酯溶解於31 ml乙醇及6.3 ml水中。添加64 mg氯化銨及1.34 g (24 mmol)鐵粉並在90℃下將混合物攪拌5小時。於冷卻至室溫後，過濾該混合物及濃縮濾液至乾。此過程得到2.81 g (97%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 319；Rt = 0.74 min(方法F)。步驟 5 1- 甲基 -2-[2-( 嗎啉 -4- 基 ) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 在室溫下，在183 µl (1.32 mmol)三乙胺之存在下，於3 ml DMF中使0.4 g (0.88 mmol) 6-胺基-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-5-甲酸甲酯及252 mg (1.32 mmol) 6-(三氟甲基)吡啶-2-甲酸與500 mg (1.32 mmol) HATU反應過夜。藉由製備型HPLC純化反應混合物，得到243 mg (56%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.77 - 2.84 (m, 2H), 3.06 - 3.12 (m, 2H), 3.55 - 3.62 (m, 4H), 3.79 (s, 3H), 3.94 (s, 3H), 8.20 - 8.24 (m, 1H), 8.27 (s, 1H), 8.38 - 8.44 (m, 1H), 8.46 - 8.50 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 492；Rt = 1.15 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-35步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00043
Figure TW201803866AD00044
Figure TW201803866AD00045
Figure TW201803866AD00046
Figure TW201803866AD00047
 中間體1-411- 甲基 -2-( 嗎啉 -4- 基甲基 )-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00048
步驟 1 4-( 甲胺基 )-3-[( 嗎啉 -4- 基乙醯基 ) 胺基 ] 苯甲酸甲酯 自甲基-3-胺基-4-(甲胺基)苯甲酸酯(CAS-RN 66315-16-0)及嗎啉-4-基乙酸(CAS-RN 3235-69-6)，製法類似於中間體1-13之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 308；Rt = 0.85 min(方法F)。步驟 2 1- 甲基 -2-( 嗎啉 -4- 基甲基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自甲基-4-(甲胺基)-3-[(嗎啉-4-基乙醯基)胺基]苯甲酸酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 290；Rt = 0.88 min(方法F)。步驟 3 1- 甲基 -2-( 嗎啉 -4- 基甲基 )-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 335；Rt = 0.91 min(方法F)。步驟 4 6- 胺基 -1- 甲基 -2-( 嗎啉 -4- 基甲基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-(嗎啉-4-基甲基)-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 305；Rt = 0.78 min(方法F)。步驟 5 1- 甲基 -2-( 嗎啉 -4- 基甲基 )-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.42 - 2.49 (m, 4H), 3.54 - 3.61 (m, 4H), 3.82 (s, 2H), 3.89 (s, 3H), 3.95 (s, 3H), 8.22 - 8.26 (m, 1H), 8.32 (s, 1H), 8.39 - 8.45 (m, 1H), 8.47 - 8.51 (m, 1H), 8.98 (s, 1H), 12.99 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 478；Rt = 1.22 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-5-甲酸甲酯(中間體1-41步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00049
Figure TW201803866AD00050
Figure TW201803866AD00051
Figure TW201803866AD00052
Figure TW201803866AD00053
Figure TW201803866AD00054
Figure TW201803866AD00055
 中間體1-491- 甲基 -2-[2-(4- 甲基哌嗪 -1- 基 ) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00056
步驟 1 4-( 甲胺基 )-3-{[3-(4- 甲基哌嗪 -1- 基 ) 丙醯基 ] 胺基 } 苯甲酸甲酯 在室溫下，在4 ml (29 mmol)三乙胺之存在下，於52 ml DMF中使3.49 g (19 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及5 g (29 mmol) 3-(4-甲基哌嗪-1-基)丙酸(CAS-RN 55480-45-0)與11 g (29 mmol) HATU反應過夜。濃縮混合物並將其溶解於乙酸乙酯中，用飽和碳酸氫鈉溶液、水及飽和氯化鈉溶液洗滌，用硫酸鎂乾燥並濃縮之。此過程得到14.6 g無需進一步純化即可進一步使用之殘餘物。 UPLC-MS (ESI+)：[M + H]+ = 335；Rt = 0.81 min(方法F)。步驟 2 1- 甲基 -2-[2-(4- 甲基哌嗪 -1- 基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自4-(甲胺基)-3-{[3-(4-甲基哌嗪-1-基)丙醯基]胺基}苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 317；Rt = 0.80 min(方法F)。步驟 3 1- 甲基 -2-[2-(4- 甲基哌嗪 -1- 基 ) 乙基 ]-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 362；Rt = 0.83 min(方法F)。步驟 4 6- 胺基 -1- 甲基 -2-[2-(4- 甲基哌嗪 -1- 基 ) 乙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基 -2-[2-(4-甲基哌嗪 -1-基)乙基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 332；Rt = 0.73 min(方法F)。步驟 5 1- 甲基 -2-[2-(4- 甲基哌嗪 -1-yl) 乙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.16 (s, 3H), 2.76 - 2.82 (m, 2H), 3.02 - 3.09 (m, 2H), 3.77 (s, 3H), 3.94 (s, 3H), 8.19 - 8.24 (m, 1H), 8.26 (s, 1H), 8.37 - 8.43 (m, 1H), 8.44 - 8.50 (m, 1H), 8.92 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 505；Rt = 1.11 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-49步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00057
Figure TW201803866AD00058
Figure TW201803866AD00059
Figure TW201803866AD00060
Figure TW201803866AD00061
 中間體1-551- 甲基 -2-[3-( 嗎啉 -4- 基 ) 丙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00062
步驟 1 4-( 甲胺基 )-3-{[4-( 嗎啉 -4- 基 ) 丁醯基 ] 胺基 } 苯甲酸甲酯 在室溫下，在7.5 ml (53 mmol)三乙胺之存在下，於45 ml DMF中使2.75 g (15 mmol) 4-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及4.8 g (23 mmol)4-(嗎啉-4-基)丁酸鹽酸鹽(CAS-RN 39493-84-0)與8.7 g (23 mmol) HATU反應過夜。將反應混合物倒入水中並用乙酸乙酯萃取。用飽和碳酸氫鈉溶液、水及飽和氯化鈉溶液洗滌有機相，經硫酸鎂乾燥並濃縮之。此過程得到4.5 g (87%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 336；Rt = 0.81 min(方法F)。步驟 2 1- 甲基 -2-[3-( 嗎啉 -4- 基 ) 丙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自4-(甲胺基)-3-{[4-(嗎啉-4-基)丁醯基]胺基}苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 318；Rt = 0.85 min(方法F)。步驟 3 1- 甲基 -2-[3-( 嗎啉 -4- 基 ) 丙基 ]-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 將4.4 g (14 mmol) 1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-5-甲酸甲酯溶解於44 ml濃硫酸中並添加2.1 g (21 mmol)硝酸鉀。於30 min後，將混合物添加至冰中，添加碳酸氫鈉至飽和，用乙酸乙酯萃取混合物及萃取液經硫酸鎂乾燥並濃縮之。此過程得到3.57 g (71%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 363；Rt = 0.88 min(方法F)。步驟 4 6- 胺基 -1- 甲基 -2-[3-( 嗎啉 -4- 基 ) 丙基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 將3.5 g (9.6 mmol) 1-甲基-2-[3-(嗎啉-4-基)丙基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯溶解於35 ml乙醇及7 ml水中。添加69 mg (1.2 mmol)氯化銨及1.4 g (26 mmol)鐵粉並在70℃下攪拌混合物2小時。於冷卻至室溫後，過濾該混合物並濃縮濾液至乾。藉由層析法純化殘餘物。此過程得到0.73 g (23%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 333；Rt = 0.77 min(方法F)。步驟 5 1- 甲基 -2-[3-( 嗎啉 -4- 基 ) 丙基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.91 - 2.01 (m, 2H), 2.30 - 2.36 (m, 4H), 2.36 - 2.43 (m, 2H), 2.89 - 2.95 (m, 2H), 3.47 - 3.54 (m, 4H), 3.78 (s, 3H), 3.94 (s, 3H), 8.21 - 8.25 (m, 1H), 8.27 (s, 1H), 8.38 - 8.45 (m, 1H), 8.46 - 8.51 (m, 1H), 8.94 (s, 1H), 12.98 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 506；Rt = 1.18 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-45步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00063
Figure TW201803866AD00064
Figure TW201803866AD00065
Figure TW201803866AD00066
 中間體1-602-[3-( 二甲胺基 ) 丙基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00067
步驟 1 3-{[4-( 二甲胺基 ) 丁醯基 ] 胺基 }-4-( 甲胺基 ) 苯甲酸甲酯 自-3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及4-(二甲胺基)丁酸鹽酸鹽(CAS-RN 69954-66-1)，製法類似於中間體1-55之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 294；Rt = 0.86 min(方法F)。步驟 2 2-[3-( 二甲胺基 ) 丙基 ]-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自3-{[4-(二甲胺基)丁醯基]胺基}-4-(甲胺基)苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 276；Rt = 0.90 min(方法F)。步驟 3 2-[3-( 二甲胺基 ) 丙基 ]-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-[3-(二甲胺基)丙基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-55之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 321；Rt = 0.93 min(方法F)。步驟 4 6- 胺基 -2-[3-( 二甲胺基 ) 丙基 ]-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 將1.76 g (5.5 mmol) 2-[3-(二甲胺基)丙基]-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯溶解於18 ml甲醇中，添加7.3 g (38 mmol)氯化錫(II)並在70℃下攪拌混合物1小時。於冷卻後，添加50 ml水並用飽和碳酸氫鈉溶液將pH調整至9。過濾混合物及濃縮濾液至乾。用300 ml乙醇處理殘餘物並將其過濾掉。濃縮濾液，得到1.11 g (69%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 291；Rt = 0.81 min(方法F)。步驟 5 2-[3-( 二甲胺基 ) 丙基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-2-[3-(二甲胺基)丙基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.89 - 1.97 (m, 2H), 2.15 (s, 6H), 2.31 - 2.37 (m, 2H), 2.88 - 2.93 (m, 2H), 3.77 (s, 3H), 3.94 (s, 3H), 8.21 - 8.24 (m, 1H), 8.28 (s, 1H), 8.39 - 8.44 (m, 1H), 8.46 - 8.50 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 464；Rt = 1.22 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-2-[3-(二甲胺基)丙基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-60步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00068
Figure TW201803866AD00069
Figure TW201803866AD00070
Figure TW201803866AD00071
 中間體 1-65 (±) 2-[(1,1- 二氧代四氫噻吩 -3- 基 ) 甲基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00072
步驟 1 (±) 3-{[(1,1- 二氧代四氫噻吩 -3- 基 ) 乙醯基 ] 胺基 }-4-( 甲胺基 ) 苯甲酸甲酯 在室溫下，在3.5 ml (25 mmol)三乙胺之存在下，於43 ml DMF中使3 g (16 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及4.45 g (25 mmol) (±)(1,1-二氧代四氫噻吩-3-基)乙酸(CAS-RN 4785-66-4)與9.5 g (25 mmol) HATU反應1小時。濃縮反應混合物並將其溶解於二氯甲烷中，用飽和碳酸氫鈉溶液、水及飽和氯化鈉溶液洗滌，用硫酸鎂乾燥並濃縮之。此過程得到7.8 g無需進一步純化即可用於下個步驟之粗產物。 UPLC-MS (ESI+)：[M + H]+ = 340；Rt = 0.76 min(方法E)。步驟 2 (±) 2-[(1,1- 二氧代四氫噻吩 -3- 基 ) 甲基 ]-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 在50℃下，將5.6 g (17 mmol)(±) 3-{[(1,1-二氧代四氫噻吩-3-基)乙醯基]胺基}-4-(甲胺基)苯甲酸甲酯(7.8 g自步驟1之粗產物)於100 ml乙酸中攪拌過夜。濃縮反應混合物並藉由層析法純化殘餘物。此過程得到4.56 g (85%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 323；Rt = 0.69 min(方法E)。步驟 3 (±) 2-[(1,1- 二氧代四氫噻吩 -3- 基 ) 甲基 ]-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 將4.5 g (14 mmol)(±) 2-[(1,1-二氧代四氫噻吩-3-基)甲基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯溶解於31 ml濃硫酸中並添加2.1 g (21 mmol)硝酸鉀。將混合物攪拌過夜及倒入冰中並添加飽和碳酸氫鈉溶液至達到10之pH為止。抽濾，得到4.92 g (95%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 368；Rt = 0.81 min(方法E)。步驟 4 (±) 6- 胺基 -2-[(1,1- 二氧代四氫噻吩 -3- 基 ) 甲基 ]-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 2-[(1,1-二氧代四氫噻吩-3-基)甲基]-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 338；Rt = 0.56 min(方法E)。步驟 5 (±) 2-[(1,1- 二氧代四氫噻吩 -3- 基 ) 甲基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 6-胺基-2-[(1,1-二氧代四氫噻吩-3-基)甲基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.90 - 2.02 (m, 1H), 2.34 - 2.44 (m, 1H), 2.91 - 3.17 (m, 5H), 3.22 - 3.30 (m, 1H), 3.40 - 3.46 (m, 1H), 3.77 (s, 3H), 3.94 (s, 3H), 8.21 - 8.25 (m, 1H), 8.32 (s, 1H), 8.39 - 8.44 (m, 1H), 8.46 - 8.51 (m, 1H), 8.95 (s, 1H), 12.98 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 511；Rt = 1.09 min(方法E)。 類似於中間體1-35步驟5之合成法，自(±) 6-胺基-2-[(1,1-二氧代四氫噻吩-3-基)甲基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯 (中間體1-65步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00073
Figure TW201803866AD00074
Figure TW201803866AD00075
Figure TW201803866AD00076
 中間體1-701- 甲基 -2-[(1- 甲基吖丁啶 -3- 基 ) 甲基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00077
步驟 1 3-(2-{[5-( 甲氧羰基 )-2-( 甲胺基 ) 苯基 ] 胺基 }-2- 側氧乙基 ) 吖丁啶 -1- 甲酸第三丁酯 自3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及[1-(第三丁氧羰基)吖丁啶-3-基]乙酸(CAS-RN 183062-96-6)，製法類似於中間體1-55之步驟1。 UPLC-MS (ESI-)：[M - H]- = 376；Rt = 1.06 min(方法F)。步驟 2 2-{[1-( 第三丁氧羰基 ) 吖丁啶 -3- 基 ] 甲基 }-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自3-(2-{[5-(甲氧羰基)-2-(甲胺基)苯基]胺基}-2-側氧乙基)吖丁啶-1-甲酸第三丁酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 360；Rt = 1.11 min(方法F)。步驟 3 2-( 吖丁啶 -3- 基甲基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 將9.92 g (28 mmol) 2-(吖丁啶-3-基甲基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯溶解於200 ml二氯甲烷中並添加16 ml (207 mmol)三氟乙酸。在室溫下攪拌過夜後，將混合物倒入冰中並藉由添加飽和碳酸氫鈉溶液使pH為10。用乙酸乙酯萃取該混合物三次及乾燥有機相並濃縮之，得到5.1 g (72%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 260；Rt = 0.82 min (方法F)。步驟 4 1- 甲基 -2-[(1- 甲基吖丁啶 -3- 基 ) 甲基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 將2.5 ml甲醛溶液(12 mol/l，含於水中)添加至含在55 ml甲醇中之5.1 g (20 mmol) 2-(吖丁啶-3-基甲基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯之並將混合物攪拌15 min。將溶液冷卻至5℃並分步添加3.77 g (100 mmol)硼氫化鈉。於添加結束45分鐘後，濃縮反應混合物至乾。粗產物無需進一步純化即可用於下個步驟。 UPLC-MS (ESI+)：[M + H]+ = 274；Rt = 0.85 min(方法F)。步驟 5 1- 甲基 -2-[(1- 甲基吖丁啶 -3- 基 ) 甲基 ]-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 319；Rt = 0.87 min(方法 B)。步驟 6 6- 胺基 -1- 甲基 -2-[(1- 甲基吖丁啶 -3- 基 ) 甲基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 289；Rt = 0.85 min(方法F)。步驟 7 1- 甲基 -2-[(1- 甲基吖丁啶 -3- 基 ) 甲基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-35之步驟5。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 2.22 (s, 3H), 2.83 - 2.97 (m, 3H), 3.14 - 3.18 (m, 2H), 3.76 (s, 3H), 3.93 (s, 3H), 8.20 - 8.24 (m, 1H), 8.27 (s, 1H), 8.38 - 8.44 (m, 1H), 8.45 - 8.50 (m, 1H), 8.92 (s, 1H), 12.96 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 462；Rt = 1.19 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-70步驟6)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00078
Figure TW201803866AD00079
Figure TW201803866AD00080
Figure TW201803866AD00081
 中間體1-75(±) 2-(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00082
步驟 1 (±) 3-{[(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ) 羰基 ] 胺基 }-4-( 甲胺基 ) 苯甲酸甲酯 在0.5 ml (53.6 mmol)三乙胺之存在下，於8 ml DMF中，將0.59 g (3.3 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及0.65 g (3.6 mmol) (±)四氫-2H-噻喃-3-甲酸1,1-二氧化物(CAS-RN 167011-35-0)與1.4 g (3.6 mmol) HATU攪拌1小時。濃縮反應混合物並用50 ml水處理殘餘物，導致產物之沉澱。過濾掉沉澱，得到1.3 g粗產物。 UPLC-MS (ESI+)：[M + H]+ = 341；Rt = 0.78 min(方法E)。步驟 2 (±) 2-(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 在50℃下，將1.1 g (3.3 mmol)(±) 3-{[(1,1-二氧代四氫-2H-噻喃-3-基)羰基]胺基}-4-(甲胺基)苯甲酸甲酯 (1.3 g自步驟1之粗產物)於20 ml乙酸中攪拌過夜。濃縮反應混合物並藉由層析法純化殘餘物。此過程得到793 mg (74%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 322；Rt = 0.80 min(方法B)。步驟 3 (±) 2-(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 將1.1 g (3.4 mmol) (±) 2-(1,1-二氧代四氫-2H-噻喃-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯溶解於7 ml濃硫酸中並添加525 mg (5.2 mmol)硝酸鉀。將混合物在室溫下攪拌3小時及倒入冰中，並添加飽和碳酸氫鈉溶液至達到10之pH為止。將混合物抽濾，得到909 mg產物，將濾液用50 ml二氯甲烷萃取三次並濃縮之，得到另外148 mg標題化合物。總計得到1.05 g (86%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 368；Rt = 0.83 min(方法E)。步驟 4 (±) 6- 胺基 -2-(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 在氫氣氛圍下，在室溫下，將含於11 ml甲醇及32 ml THF之混合物中之1.05 g (2.9 mmol) (±) 2-(1,1-二氧代四氫-2H-噻喃-3-基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯與0.5 g 10%碳載鈀攪拌3小時。過濾混合物，於濃縮濾液後，得到897 mg (92%) 標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 338；Rt = 0.65 min(方法E)。步驟 5 (±) 2-(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 在室溫下，在93 µl (0.66 mmol)三乙胺之存在下，於3 ml DMF中使0.15 g (0.44 mmol)(±) 6-胺基-2-(1,1-二氧代四氫-2H-噻喃-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及127 mg (0.66 mmol)6-(三氟甲基)吡啶-2-甲酸與253 mg (0.66 mmol) HATU反應過夜。添加30 ml水並將混合物攪拌15 min。過濾掉沉澱固體，用10 ml水及10 ml己烷洗滌並乾燥之。此過程得到198 mg (87%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.73 - 1.85 (m, 1H), 2.00 - 2.20 (m, 3H), 3.09 - 3.18 (m, 1H), 3.38 - 3.45 (m, 1H), 3.50 - 3.58 (m, 1H), 3.62 - 3.72 (m, 1H), 3.83 (s, 3H), 3.95 (s, 3H), 8.21 - 8.26 (m, 1H), 8.31 (s, 1H), 8.38 - 8.45 (m, 1H), 8.47 - 8.51 (m, 1H), 8.97 (s, 1H), 12.97 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ = 511；Rt = 1.13 min(方法E)。 類似於中間體1-75步驟5之合成法，自(±) 6-胺基-2-(1,1-二氧代四氫-2H-噻喃-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-75步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00083
Figure TW201803866AD00084
Figure TW201803866AD00085
 中間體1-79(±) 1- 甲基 -2-( 四氫呋喃 -3- 基甲基 )-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ]­ 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00086
步驟 1 (±) 4-( 甲胺基 )-3-[( 四氫呋喃 -3- 基乙醯基 ) 胺基 ] 苯甲酸甲酯 自3-胺基-4-(甲胺基)­苯甲酸甲酯(CAS-RN 66315-16-0)及(±)四氫呋喃-3-基乙酸(CAS-RN 138498-97-2)，製法類似於中間體1-55之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 293；Rt = 0.89 min。(方法F)步驟 2 (±) 1- 甲基 -2-( 四氫呋喃 -3- 基甲基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 4-(甲胺基)-3-[(四氫呋喃-3-基乙醯基)胺基]苯甲酸甲酯，製法類似於中間體1-1之步驟2。 UPLC-MS (ESI+)：[M + H]+ = 275；Rt = 0.90 min。(方法F)步驟 3 (±) 1- 甲基 -6- 硝基 -2-( 四氫呋喃 -3- 基甲基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-55之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 320；Rt = 0.90 min。(方法F)步驟 4 (±) 6- 胺基 -1- 甲基 -2-( 四氫呋喃 -3- 基甲基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 1-甲基-6-硝基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-35之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 290；Rt = 0.81 min。(方法F)步驟 5 (±) 1- 甲基 -2-( 四氫呋喃 -3- 基甲基 )-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 6-胺基-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-5-甲酸甲基酯，製法類似於中間體1-35之步驟5。1 H NMR (500 MHz, DMSO-d6) δ [ppm]：2.089 (0.65), 2.515 (0.91), 2.518 (0.84), 2.522 (0.65), 2.794 (0.74), 2.979 (1.75), 2.989 (1.86), 2.994 (1.73), 3.004 (1.45), 3.433 (1.21), 3.445 (1.21), 3.449 (1.32), 3.462 (1.26), 3.674 (1.21), 3.690 (1.47), 3.705 (0.78), 3.770 (14.72), 3.782 (0.78), 3.792 (0.78), 3.798 (1.17), 3.809 (1.17), 3.877 (1.30), 3.891 (1.45), 3.894 (1.43), 3.908 (1.26), 3.937 (16.00), 8.212 (1.56), 8.214 (1.62), 8.227 (1.82), 8.229 (1.82), 8.287 (5.72), 8.393 (0.84), 8.408 (1.75), 8.424 (1.06), 8.469 (1.93), 8.485 (1.19), 8.928 (5.20), 12.966 (2.64)。 類似於中間體1-35步驟5之合成法，自(±) 6-胺基-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-5-甲酸甲酯(中間體1-79步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00087
Figure TW201803866AD00088
Figure TW201803866AD00089
Figure TW201803866AD00090
 中間體1-84(±) 2-[(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ) 甲基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00091
步驟 1 (±) 3-({[1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ] 乙醯基 } 胺基 )-4-( 甲胺基 )­ 苯甲酸甲酯 自3-胺基-4-(甲胺基)­苯甲酸甲酯(CAS-RN 66315-16-0)及(±)(1,1-二氧代四氫-2H-噻喃-3-基)乙酸，製法類似於中間體1-55之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 355；Rt = 0.77 min(方法E)。步驟 2 (±) 2-{-1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ] 甲基 }-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 在室溫下，將含於28 ml乙酸中之1.7 g (4.8 mmol) (±) 3-({[1,1-二氧代四氫-2H-噻喃-3-基]乙醯基}胺基)-4-(甲胺基)苯甲酸甲酯攪拌36小時及接著在50℃下過夜。濃縮混合物並將二氯甲烷添加至殘餘物，導致固體之沉澱。將所獲得之母液層析純化及產物溶離份與該固體合併。此過程得到1.48 g (90%)標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 337；Rt = 0.69 min(方法E)。步驟 3 (±) 2-[(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ) 甲基 ]-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 2-{-1,1-二氧代四氫-2H-噻喃-3-基]甲基}-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-55之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 381；Rt = 0.83 min(方法E)。步驟 4 (±) 6- 胺基 -2-[(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ) 甲基 ]-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體 1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 352；Rt = 0.56 min(方法A)步驟 5 (±) 2-[(1,1- 二氧代四氫 -2H- 噻喃 -3- 基 ) 甲基 ]-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 6-胺基-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H NMR (400 MHz, DMSO-d6 ) δ[ppm]：1.230 (1.15), 1.352 (1.26), 1.829 (0.79), 2.074 (2.32), 2.332 (1.12), 2.518 (6.20), 2.523 (4.26), 2.673 (1.15), 2.686 (0.71), 2.727 (2.08), 2.888 (2.43), 2.987 (2.38), 3.005 (2.05), 3.036 (1.26), 3.051 (1.20), 3.061 (1.53), 3.095 (1.20), 3.126 (0.90), 3.267 (0.93), 3.766 (0.85), 3.784 (13.27), 3.937 (0.74), 3.946 (16.00), 8.221 (1.64), 8.224 (1.67), 8.241 (1.97), 8.243 (1.91), 8.332 (5.79), 8.398 (0.82), 8.418 (1.83), 8.438 (1.12), 8.482 (1.94), 8.500 (1.09), 8.965 (4.97), 12.983 (2.70)。 UPLC-MS (ESI+)： [M + H]+ = 525；Rt = 1.10 min(方法E)。 類似於中間體1-35步驟5之合成法，自(±) 6-胺基-2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-84步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00092
Figure TW201803866AD00093
Figure TW201803866AD00094
 中間體1-882-(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00095
步驟 1 3-{[(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 ) 羰基 ] 胺基 }-4-( 甲胺基 )­ 苯甲酸甲酯 自3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及四氫-2H-噻喃-4-甲酸1,1-二氧化物(CAS-RN 64096-87-3)，製法類似於中間體1-55之步驟1。 UPLC-MS (ESI+)：[M + H]+ = 341；Rt = 0.76 min(方法E)。步驟 2 2-(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 在80℃下，將含於156 ml乙酸中之9 g (26 mmol) 3-{[(1,1-二氧代四氫-2H-噻喃-4-基)羰基]胺基}-4-(甲胺基)苯甲酸甲酯攪拌4小時。濃縮混合物並添加二氯甲烷至殘餘物，導致固體之沉澱。將所得到之固體抽濾掉。此過程得到定量產量之標題化合物。 UPLC-MS (ESI+)：[M + H]+ = 323；Rt = 0.71 min(方法E)。步驟 3 2-(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-(1,1-二氧代四氫-2H-噻喃-4-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體 1-55之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 368；Rt = 0.82 min(方法E)。步驟 4 6- 胺基 -2-(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸 甲酯 自2-(1,1-二氧代四氫-2H-噻喃-4-基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體 1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ = 338；Rt = 0.58 min(方法E)。步驟 5 2-(1,1- 二氧代四氫 -2H- 噻喃 -4- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-2-(1,1-二氧代四氫-2H-噻喃-4-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H NMR (400 MHz, DMSO-d6) δ [ppm]：1.352 (1.16), 2.264 (0.89), 2.290 (1.53), 2.300 (1.63), 2.322 (2.87), 2.326 (2.52), 2.331 (1.79), 2.518 (4.59), 2.522 (3.09), 2.664 (0.78), 2.668 (1.06), 2.673 (0.75), 2.686 (1.09), 2.727 (2.26), 2.888 (2.78), 3.256 (0.92), 3.288 (1.63), 3.321 (1.08), 3.333 (1.23), 3.359 (1.41), 3.395 (1.04), 3.509 (0.97), 3.523 (0.87), 3.534 (1.04), 3.544 (0.78), 3.836 (14.18), 3.881 (1.37), 3.949 (16.00), 4.002 (1.15), 8.222 (1.88), 8.225 (1.93), 8.242 (2.26), 8.244 (2.26), 8.332 (6.34), 8.399 (1.06), 8.418 (2.15), 8.438 (1.29), 8.480 (2.33), 8.499 (1.30), 8.983 (5.58), 12.983 (3.27)。 UPLC-MS (ESI+)：[M + H]+ = 511；Rt = 1.12 min(方法F) 類似於中間體1-35步驟5之合成法，自6-胺基-2-(1,1-二氧代四氫-2H-噻喃-4-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-88步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00096
Figure TW201803866AD00097
Figure TW201803866AD00098
Figure TW201803866AD00099
 中間體1-932-( 甲氧甲基 )-1- 甲基 -6-({[6-( 三氟甲基 l) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00100
步驟 1 3-[( 甲氧乙醯基 ) 胺基 ]-4-( 甲胺基 ) 苯甲酸甲酯 將含於2.5 ml DMF中之3 g (16.6 mmol) 3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)、1.65 g (18 mmol)甲氧基乙酸(CAS-RN 625-45-6)、2.56 ml三乙胺及7 g (18 mmol) HATU攪拌一小時。接著濃縮反應溶液及無需進一步純化即可用於下個步驟。 UPLC-MS (ESI+)：[M + H]+ =253；Rt = 0.78 min(方法E)步驟 2 2-( 甲氧甲基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸 甲酯 在80℃下，將含於100 ml乙酸中之4.2 g (16 mmol)3-[(甲氧乙醯基)胺基]-4-(甲胺基)苯甲酸甲酯攪拌過夜。濃縮混合物及將殘餘物層析純化。此過程得到定量產量之標題化合物。 UPLC-MS (ESI+)：[M + H]+ =235；Rt = 0.83 min(方法F)。步驟 3 2-( 甲氧甲基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-(甲氧甲基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ =280；Rt = 0.87 min(方法F)。步驟 4 6- 胺基 -2-( 甲氧甲基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自2-(甲氧甲基)-1-甲基-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ =250；Rt = 0.58 min(方法E)。步驟 5 2-( 甲氧甲基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H NMR (400 MHz, DMSO-d6) δ [ppm]：2.518 (1.61), 2.522 (1.04), 2.727 (1.83), 2.888 (2.31), 3.385 (16.00), 3.855 (11.86), 3.959 (12.59), 4.789 (5.95), 8.226 (1.27), 8.228 (1.34), 8.245 (1.54), 8.247 (1.56), 8.362 (4.53), 8.400 (0.69), 8.420 (1.51), 8.440 (0.95), 8.480 (1.73), 8.499 (0.95), 9.038 (4.04), 12.994 (2.17)。 UPLC-MS (ESI+)：[M + H]+ =423；Rt = 1.19 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯(中間體1-93步驟4)及對應的羧酸製備以下中間體。
Figure TW201803866AD00101
Figure TW201803866AD00102
Figure TW201803866AD00103
Figure TW201803866AD00104
 中間體1-981- 甲基 -2-[( 甲磺醯基 ) 甲基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00105
步驟 1 4-( 甲胺基 )-3-{[( 甲磺醯基 ) 乙醯基 ] 胺基 } 苯甲酸甲酯 自3-胺基-4-(甲胺基)苯甲酸甲酯(CAS-RN 66315-16-0)及(甲磺醯基)乙酸(CAS-RN 2516-97-4)，製法類似於中間體1-93之步驟1。 UPLC-MS (ESI+)：[M + H]+ =301；Rt = 0.75 min(方法E)。步驟 2 1- 甲基 -2-[( 甲磺醯基 ) 甲基 ]-1H- 苯并咪唑 -5- 甲酸 甲酯 自4-(甲胺基)-3-{[(甲磺醯基)乙醯基]胺基}苯甲酸甲酯，製法類似於中間體1-93之步驟2。 UPLC-MS (ESI+)：[M + H]+ =283；Rt = 0.78 min(方法F)步驟 3 1- 甲基 -2-[( 甲磺醯基 ) 甲基 ]-6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟3。 UPLC-MS (ESI+)：[M + H]+ = 328；Rt = 0.80 min(方法F)。步驟 4 6- 胺基 -1- 甲基 -2-[( 甲磺醯基 ) 甲基 ]-1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[(甲磺醯基)甲基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ =298；Rt = 0.65 min(方法E)。步驟 5 1- 甲基 -2-[( 甲磺醯基 ) 甲基 ]-6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯 自6-胺基-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H NMR (400 MHz, DMSO-d6 ) δ [ppm]：2.518 (4.19), 2.523 (2.97), 3.173 (12.06), 3.894 (16.00), 4.046 (13.22), 5.121 (4.86), 8.028 (3.09), 8.031 (3.18), 8.182 (3.71), 8.186 (3.52), 8.218 (1.54), 8.222 (1.66), 8.237 (1.87), 8.240 (1.98), 8.375 (0.72), 8.394 (1.86), 8.413 (1.56), 8.424 (2.07), 8.427 (2.30), 8.444 (0.85), 10.915 (2.60)。 UPLC-MS (ESI+)：[M + H]+ =471；Rt = 1.11 min(方法F)。 類似於中間體1-35步驟5之合成法，自6-胺基-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-5-甲酸甲酯(中間體1-98步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00106
Figure TW201803866AD00107
Figure TW201803866AD00108
 中間體1-102(±) 2-(1,1- 二氧代四氫噻吩 -3- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸甲酯
Figure TW201803866AD00109
步驟 1 (±) 3-{[(1,1- 二氧代四氫噻吩 -3- 基 ) 羰基 ] 胺基 }-4-( 甲胺基 ) 苯甲酸甲酯 自3-胺基-4-(甲胺基)­苯甲酸甲酯(CAS-RN 66315-16-0)及(±)四氫噻吩-3-甲酸-1,1-二氧化物 (CAS-RN 4785-67-5)，製法類似於中間體1-93之步驟1。 UPLC-MS (ESI+)：[M + H]+ =327；Rt = 0.77 min(方法E)。步驟 2 (±) 2-(1,1- 二氧代四氫噻吩 -3- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 3-{[(1,1-二氧代四氫噻吩-3-基)羰基]胺基}-4-(甲胺基)苯甲酸甲酯，製法類似於中間體1-93之步驟2。 UPLC-MS (ESI+)：[M + H]+ =309；Rt = 0.79 min(方法F)。步驟 3 (±) 2-(1,1- 二氧代四氫噻吩 -3- 基 )-1- 甲基 -6- 硝基 -1H- 苯并咪唑 -5- 甲酸甲酯 自(±) 2-(1,1-二氧代四氫噻吩-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-55之步驟3。 UPLC-MS (ESI+)：[M + H]+ =354；Rt = 0.83 min(方法F)步驟 4 (±) 6- 胺基 -2-(1,1- 二氧代四氫噻吩 -3- 基 )-1- 甲基 -1H- 苯并咪唑 -5- 甲酸甲酯 自1-甲基-2-[(甲磺醯基)甲基]-6-硝基-1H-苯并咪唑-5-甲酸甲酯，製法類似於中間體1-1之步驟4。 UPLC-MS (ESI+)：[M + H]+ =324；Rt = 0.64 min(方法E)。步驟 5 (±) 2-(1,1- 二氧代四氫噻吩 -3- 基 )-1- 甲基 -6-({[6-( 三氟甲基 ) 吡啶 -2- 基 ] 羰基 } 胺基 )-1H- 苯并咪唑 -5- 甲酸 甲酯 自(±) 6-胺基-2-(1,1-二氧代四氫噻吩-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯及6-(三氟甲基)吡啶-2-甲酸，製法類似於中間體1-1之步驟5。1 H NMR (400 MHz, DMSO-d6 ) δ [ppm]：2.326 (0.87), 2.402 (0.67), 2.422 (0.69), 2.518 (3.91), 2.522 (2.65), 2.664 (0.84), 2.668 (0.96), 2.673 (0.82), 3.247 (0.67), 3.266 (0.69), 3.271 (0.72), 3.290 (0.64), 3.385 (0.67), 3.396 (0.69), 3.404 (0.67), 3.416 (0.89), 3.447 (1.26), 3.471 (0.96), 3.481 (1.11), 3.504 (1.19), 3.662 (0.89), 3.684 (0.99), 3.696 (0.72), 3.717 (0.74), 3.836 (14.96), 3.947 (16.00), 4.181 (0.69), 4.197 (0.74), 4.203 (0.72), 8.221 (1.71), 8.224 (1.76), 8.240 (2.08), 8.243 (2.08), 8.343 (6.23), 8.398 (0.91), 8.417 (1.98), 8.437 (1.21), 8.480 (2.25), 8.498 (1.29), 8.976 (5.69), 12.973 (3.14)。 UPLC-MS (ESI+)：[M + H]+ =497；Rt = 1.14 min(方法F)。 類似於中間體1-35步驟5之合成法，自(±) 6-胺基-2-(1,1-二氧代四氫噻吩-3-基)-1-甲基-1H-苯并咪唑-5-甲酸甲酯 (中間體1-102步驟4)及對應的羧酸(行1)製備以下中間體。
Figure TW201803866AD00110
Figure TW201803866AD00111
Figure TW201803866AD00112
Figure TW201803866AD00113
 實例 一般實驗程序：格利雅反應，以中間體開始(反應圖1)，得到通式(I)之化合物(反應圖1)。 一般實驗程序1a 先將苯并咪唑-5-甲酸甲酯(中間體)溶解於THF中並冷卻至0℃。接著逐滴添加12至15當量之溴化甲基鎂溶液(市售含於甲基-THF、THF或***中之溶液)，保持反應混合物之溫度在5至10℃。接著在室溫下攪拌該混合物過夜。添加飽和氯化銨溶液及移除有機相，經硫酸鎂乾燥並濃縮。 將來自第一格利雅反應之殘餘物溶解於THF中並冷卻至0℃。接著逐滴添加12至15當量之溴化甲基鎂溶液(市售含於2-甲基四氫呋喃、THF或***中之溶液)，保持反應混合物之溫度在5至10℃。接著在0℃下攪拌該混合物1小時。添加飽和氯化銨溶液及移除有機相，經硫酸鎂乾燥並濃縮。藉由HPLC純化所得之殘餘物。 一般實驗程序1b 將苯并咪唑-5-甲酸甲酯(中間體)溶解於THF中並冷卻至0至5℃。接著逐滴添加6當量之溴化甲基鎂溶液(市售含於2-甲基四氫呋喃、THF或***中之溶液)，保持反應混合物之溫度在5至10℃。接著在室溫下攪拌該混合物過夜。添加飽和氯化銨溶液及移除有機相，經硫酸鎂乾燥並濃縮。一旦殘餘物之分析(UPLC-MS)顯示起始物質之大量轉化，則藉由HPLC純化該殘餘物。或者，若起始物質反應不完全，則該殘餘物經受如下所述之另一格利雅反應。 將來自第一格利雅反應之殘餘物溶解於THF中並冷卻至0至5℃。接著逐滴添加6當量之溴化甲基鎂溶液(市售含於2-甲基四氫呋喃、THF或***中之溶液)，保持反應混合物之溫度在5至10℃。接著在0至5℃下攪拌該混合物1小時。添加飽和氯化銨溶液及移除有機相，經硫酸鎂乾燥並濃縮。藉由HPLC純化所得之殘餘物。 實例2-1 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺
Figure TW201803866AD00114
將700 mg (1.5 mmol) 2-(3-甲氧基-3-側氧基丙基)-1-甲基-6-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-苯并咪唑-5-甲酸甲酯(中間體1-1)溶解於45 ml THF中並冷卻至0℃。接著逐滴添加含於2-甲基四氫呋喃中之5.3 ml (18 mmol)溴化甲基鎂(3.4 mol/l)溶液。接著在室溫下攪拌反應混合物過夜。添加30 ml飽和氯化銨溶液及攪拌混合物5 min。移除有機相，經硫酸鎂乾燥並濃縮。 將殘餘物溶解於45 ml THF中並冷卻至0℃。接著逐滴添加含於2-甲基四氫呋喃中之5.3 ml (18 mmol)溴化甲基鎂(3.4 mol/l)溶液。在0℃下攪拌反應混合物1小時。添加30 ml飽和氯化銨溶液及將混合物攪拌5 min。移除有機相，經硫酸鎂乾燥並濃縮。藉由HPLC純化殘餘物。此過程得到105 mg (15%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.18 (s, 6H), 1.61 (s, 6H), 1.82 - 1.89 (m, 2H), 2.87 - 2.94 (m, 2H), 3.73 (s, 3H), 4.48 (s, 1H), 5.90 (s, 1H), 7.51 (s, 1H), 8.16 - 8.20 (m, 1H), 8.36 - 8.42 (m, 1H), 8.44 - 8.49 (m, 1H), 8.55 (s, 1H), 12.49 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ =465；Rt = 0.90 min(方法A)。 根據一般實驗程序1a及類似於實例2-1之製法，自適宜中間體(中間體)製備以下實例。
Figure TW201803866AD00115
Figure TW201803866AD00116
Figure TW201803866AD00117
Figure TW201803866AD00118
Figure TW201803866AD00119
Figure TW201803866AD00120
Figure TW201803866AD00121
Figure TW201803866AD00122
Figure TW201803866AD00123
Figure TW201803866AD00124
Figure TW201803866AD00125
 實例2-13 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-6-(三氟甲基)吡啶-2-甲醯胺
Figure TW201803866AD00126
將100 mg (0.2 mmol) 1-甲基-2-[2-(甲磺醯基)乙基]-6-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-苯并咪唑-5-甲酸甲酯(中間體1-13)溶解於10 ml THF中並冷卻至0至5℃。接著逐滴添加0.36 ml (1.2 mmol)含溴化甲基鎂(3.4 mol/l)之2-甲基四氫呋喃溶液。此後，在5℃下攪拌反應混合物1小時。添加4 ml飽和氯化銨溶液及將混合物攪拌5 min。移除有機相，經硫酸鎂乾燥並濃縮。 將殘餘物溶解於10 ml THF中並冷卻至0℃。接著逐滴添加0.36 ml (1.2 mmol)含溴化甲基鎂(3.4 mol/l)之2-甲基四氫呋喃溶液。將反應混合物在0至5℃下攪拌1小時。添加4 ml飽和氯化銨溶液及將混合物攪拌5 min。移除有機相，經硫酸鎂乾燥並濃縮。藉由HPLC純化殘餘物。此過程得到31 mg (31%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.61 (s, 6H), 3.09 (s, 3H), 3.65 - 3.72 (m, 2H), 3.76 (s, 3H), 5.92 (s, 1H), 7.55 (s, 1H), 8.15 - 8.20 (m, 1H), 8.35 - 8.41 (m, 1H), 8.44 - 8.49 (m, 1H), 8.58 (s, 1H), 12.51 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ =485；Rt = 1.00 min(方法A)。 根據一般實驗程序1b及類似於實例2-13之製法，自適宜中間體(中間體)製備以下實例。
Figure TW201803866AD00127
Figure TW201803866AD00128
Figure TW201803866AD00129
Figure TW201803866AD00130
Figure TW201803866AD00131
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Figure TW201803866AD00169
Figure TW201803866AD00170
Figure TW201803866AD00171
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Figure TW201803866AD00177
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Figure TW201803866AD00179
Figure TW201803866AD00180
Figure TW201803866AD00181
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Figure TW201803866AD00183
Figure TW201803866AD00184
Figure TW201803866AD00185
Figure TW201803866AD00186
Figure TW201803866AD00187
 實例2-75 (±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺
Figure TW201803866AD00188
將150 mg (0.29 mmol)(±) 2-(1,1-二氧代四氫-2H-噻喃-3-基)-1-甲基-6-({[6-(三氟甲基)吡啶-2-基]羰基}胺基)-1H-苯并咪唑-5-甲酸甲酯(中間體1-75)溶解於9 ml THF中並冷卻至0℃。接著逐滴添加0.52 ml (1.7 mmol)含溴化甲基鎂(3.4 mol/l)之2-甲基四氫呋喃溶液。接著在室溫下攪拌反應混合物30 min。接著添加4 ml飽和氯化銨溶液及將混合物攪拌5 min。移除有機相，經硫酸鎂乾燥並濃縮。藉由HPLC純化殘餘物。此過程得到68 mg (45%)標題化合物。1 H-NMR (400MHz, DMSO-d6 )：δ [ppm] = 1.60 (s, 6H), 1.69 - 1.81 (m, 1H), 1.98 - 2.20 (m, 3H), 3.09 - 3.17 (m, 1H), 3.44 - 3.50 (m, 1H), 3.58 - 3.68 (m, 1H), 3.78 (s, 3H), 5.92 (s, 1H), 7.56 (s, 1H), 8.15 - 8.20 (m, 1H), 8.35 - 8.41 (m, 1H), 8.44 - 8.48 (m, 1H), 8.58 (s, 1H), 12.51 (s, 1H)。 UPLC-MS (ESI+)：[M + H]+ =511；Rt = 0.97 min(方法A)。 實例2-75-1 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺對映異構體A。藉由對掌性HPLC將外消旋化合物(±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺(實例2-75)分離為對映異構體。此過程得到21 mg標題化合物(對映異構體A)及24 mg (對映異構體B實例2-75-2)。 分析： 儀器： Agilent HPLC 1260；管柱：Chiralpak IB 3µ 100 x 4.6mm； 流動相A：MTBE+0.1體積%之二乙胺(99%)；流動相B：甲醇；等度：50%A+50%B； 流速1.4 ml/min；溫度：25℃；DAD 254 nm 對映異構體A Rt = 1.19 min 製備： 儀器：Labomatic HD5000，Labocord-5000；Gilson GX-241，Labcol Vario 4000， 管柱：Chiralpak IB 5µ 250 x 30mm；流動相A：MTBE+0.1體積%之二乙胺(99%)； 流動相B：甲醇；等度：50%A+50%B；流速 40.0 ml/min；UV 254 nm 對映異構體A Rt =4.0至5.1 min 實例2-75-2 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺對映異構體B。藉由對掌性HPLC將外消旋化合物(±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺 (實例 2-75)分離為對映異構體。此過程得到24 mg標題化合物(對映異構體B)及21 mg (對映異構體A實例2-75-1)。 分析： 儀器：Agilent HPLC 1260；管柱：Chiralpak IB 3µ 100 x 4.6mm； 流動相A：MTBE+0.1體積%之二乙胺(99%)；流動相B：甲醇；等度：50%A+50%B； 流速1.4 ml/min；溫度：25℃；DAD 254 nm 對映異構體B Rt = 1.61 min 製備 儀器：Labomatic HD5000，Labocord-5000；Gilson GX-241，Labcol Vario 4000， 管柱：Chiralpak IB 5µ 250 x 30mm；流動相A：MTBE+0.1體積%之二乙胺(99%)； 流動相B：甲醇；等度：50%A+50%B；流速 40.0 ml/min；UV 254 nm 對映異構體B Rt = 5.9至6.9 min。 根據一般實驗程序1b及類似於實例2-75之製法，自適宜中間體(中間體)製備以下實例。
Figure TW201803866AD00189
Figure TW201803866AD00190
Figure TW201803866AD00191
 根據一般實驗程序1b及類似於實例2-75之製法，自適宜中間體(中間體)製備以下實例。
Figure TW201803866AD00192
Figure TW201803866AD00193
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Figure TW201803866AD00219
 生理療效之評估 針對TrkA之IRAK4激酶活性及選擇性之抑制 IRAK4 激酶檢定 於下述IRAK4 TR-FRET檢定(TR-FRET=時差式螢光共振能量轉移)中量測根據本發明之物質之IRAK4抑制活性。 於桿狀病毒感染之昆蟲細胞(Hi5，BTI-TN-5B1-4，自Invitrogen購得之細胞系，目錄編號B855-02)中表現及經由親和層析法純化之來自N-端GST(麩胱甘肽S-轉移酶)與人類IRAK4(IRAK4寄存編號NP_057207.2(單向運輸編號Q9NWZ3))之重組融合蛋白用作酵素。用於激酶反應之受質為可自(例如)Biosyntan GmbH (Berlin-Buch)購得之生物素化肽生物素-Ahx-KKARFSRFAGSSPSQASFAEPG (以醯胺形式之C-端)。 對於該檢定，自受試物質含於DMSO中之2 mM溶液製備11種自20 µM至0.073 nM範圍內之不同濃度。將50 nl各自溶液吸量管移入黑色低容量384孔微量滴定板(Greiner Bio-One，弗裡肯豪森，德國)，添加2 µl含IRAK4之檢定緩衝液[50 mM HEPES pH 7.5，5 mM MgCl2 ，1.0 mM二硫蘇糖醇，30 µM活化之正釩酸鈉，0.1% (w/v)牛γ球蛋白(BGG) 0.04% (v/v) nonidet-P40 (Sigma)]及將該混合物培育15 min以允許在激酶反應之前物質與酶之預結合。接著藉由添加3 µl三磷酸腺苷 (ATP，1.67 mM=於5 µl檢定體積中之最終濃度：1 mM)及肽受質(0.83 µM=於5 µl檢定體積中之最終濃度：0.5 µM)含在檢定緩衝液之溶液開始激酶反應及將所得之混合物在22℃下培育45 min之反應時間。將IRAK4之濃度調整至酵素之各自活性及設置使得於線性範圍內實施該檢定。典型濃度為約0.2nM級數。藉由添加5 µl含TR-FRET檢測試劑[0.1 µM鏈黴抗生物素-XL665 (Cisbio Bioassays；法國，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標記之抗小鼠-IgG抗體(Perkin-Elmer，產品編號AD0077；或者，可使用來自Cisbio Bioassays之鋱穴狀化合物標記之抗小鼠-IgG抗體)之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)終止該反應。 將所得之混合物在22℃培育1小時以允許生物素化磷酸化受質與檢測試劑之錯合物之形成。接著藉由量測自銪螯合物標記之抗小鼠-IgG抗體至鏈黴抗生物素-XL665之能量共振轉移來評估磷酸化受質之含量。為此，於350 nm激發後，用(例如) Rubystar (BMG Labtechnologies，奧芬堡，德國)或Viewlux (Perkin-Elmer)之TR-FRET量測儀器量測在620 nm及665 nm處之螢光發射。採用665 nm及622 nm之發射比率作為磷酸化受質之含量之量度。將數據標準化(無受試物質之酵素反應=0%抑制；所有其他檢定組分但無酵素=100%抑制)。通常，在11種自20 µM至0.073 nM範圍內(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)之不同濃度在相同微量滴定板上測試該等受試物質。在檢定之前藉由連續稀釋製備稀釋系列(於100% DMSO中，2 mM至7.3 nM)。藉由4-參數擬合計算IC50 值。 例示性化合物顯示IRAK4激酶活性之抑制(參見表1及1A)。表 1 ： 實例化合物於IRAK4及TrkA激酶檢定中之IC50 值。表 1A ：實例化合物於IRAK4及TrkA激酶檢定中之IC50 值。 例示性化合物對 IRAK4 之結合動力學： 該實驗直接證實受試物質與IRAK4蛋白之間之相互作用。藉由量測結合動力學，可識別具有長解離速率之受試物質，其可導致更長的靶結合及因此在細胞內之靶上之活性。 對於表面電漿子共振(SPR)量測，使用重組生物素化全長IRAK4蛋白(IRAK4之胺基酸1-460，寄存編號NP_057207.2(單向運輸編號Q9NWZ3))，該蛋白質可自日本Carna Biosciences (產品編號：09-445-20N)購得。利用鏈黴抗生物素-生物素相互作用，將該生物素化IRAK4蛋白固定在SA-Biacore晶片(GE Healthcare，產品編號29104992)上。為此，於1x HBS-EP+(自10x HBS-EP+緩衝液(GE Healthcare，產品編號BR100669)製備)中將生物素化IRAK4蛋白稀釋至5 µg/ml及接著於相同緩衝液中在SA-Biacore晶片之鏈黴抗生物素表面上將其捕獲。此過程導致約1000個回應單位之信號。參考池由不飽和鏈黴抗生物素組成。於100%二甲亞碸(DMSO，Sigma-Aldrich，德國)中將受試物質稀釋至10 mM及接著於運行緩衝液(1x HBS-EP+ pH 7.4[自HBS-EP+緩衝液10x(GE Healthcare)：0.1 M HEPES、1.5 M NaCl、30 mM EDTA及0.5% v/v洗滌劑P20製備]，1% v/v DMSO)中進一步稀釋。對於動力學量測，製備受試物質之連續稀釋物(0.235 nM至0.15 µM)，接著將其注射到表面上。在25℃及100 µl/min之流速下於運行緩衝液中量測結合動力學。為此，注射受試物質持續80 s及接著記錄解離持續1000 s。所得到之感測圖(sensogram)為針對空白試驗值及參考表面之雙參考及利用Biacore T200評估軟體以軟體中貯存之公式將其擬合至1:1結合模型。 目標滯留時間為解離速率常數值之倒數值，目標滯留時間=1/解離速率常數。 例示性化合物顯示在IRAK4上之長滯留時間(參見表2)。表 2 ： 例示性化合物之結合動力學 TrkA 激酶檢定 藉由NGF(神經生長因子)之結合活化Trk (與原肌球蛋白有關之激酶)-A。其涉及(例如)腫瘤之惡性轉化、趨化性及轉移。尤其，TrkA係與成人中包括慢性疼痛及癌症疼痛之痛覺感受及神經病性疼痛相關聯(Hirose，Kuroda等人，Pain Practice，2016)。 然而，應注意，TrkA對於交感神經之發育係重要的。具有TrkA之功能喪失型突變之患者發展遺傳性感覺及之IV型自主神經病變(CIPA，對疼痛先天不敏感及無汗症)，其與顯著疼痛及溫度感覺障礙相關聯(Indo, Clinical Genetics, 2012)。此外，TrkA似乎在膽鹼能神經元的成熟過程中、於胸腺發育、早期卵巢發育中及於某些免疫細胞之發育中起作用(Tessarollo, L.，Cytokine & Growth Factor Reviews，1998；Garcı́a-Suárez，Germanà等人，Journal of Neuroimmunology，2000；Coppola，Barrick等人，Development，2004；Dissen，Garcia-Rudaz等人，Seminars in reproductive medicine，2009)。由於提及之潛在功能，確定關於TrkA之選擇性。 於下述TrkA-HTRF檢定(HTRF=均相時差式螢光 ( H omogeneousT imeR esolvedF luorescence) )中量測本發明之物質之TrkA抑制活性。 使用之激酶為自德國弗裡堡ProQinase GmbH(產品編號：0311-0000-2)購得之於桿狀病毒感染之昆蟲細胞(Sf9)中表現並藉由親和力層析法純化之由N-端His6標記之GST及人類TrkA之C-端片段(TrkA寄存編號NP_002520.2之胺基酸443-796)組成之重組融合蛋白。用於激酶反應之受質為自CisBio Bioassays (#61GT0BLA)之生物素化聚麩胺酸、酪胺酸(4:1)共聚物。 對於檢定，將50 nl受試物質含於DMSO中之100倍濃縮溶液移入黑色小容量384孔微量滴定板(Greiner Bio-One，弗裡肯豪森，德國)，添加2 µl 含於檢定緩衝液[8 mM MOPS/HCl pH 7.0，10 mM MgCl2 ，1.0 mM二硫蘇糖醇，0.2 mM EDTA，0.01%(v/v) Nonidet-P40(自Sigma)]中之IRAK4溶液及將該混合物培育15 min，以在激酶反應之前使物質與酶初步結合。接著藉由添加3 µl含於檢定緩衝液中之三磷酸腺苷溶液(ATP，1.67µM=於5 µl檢定體積中之最終濃度：10 µM)及受質(2.27 µg/ml µM =於5 µl檢定體積中之最終濃度：1.36 µg/ml)之溶液開始激酶反應及將所得之混合物在22℃下培育60 min之反應時間。使TrkA之濃度適於酵素之各自活性及經調整使得於線性範圍內(於5 µl檢定體積中之典型最終TrkA濃度在約20 pg/µl之數量級)操作該檢定。藉由添加5 µl含HTRF檢測試劑(30 nM鏈黴抗生物素-XL665 (Cisbio Bioassays；France)及1.4 nM PT66銪螯合物，一種來自Perkin Elmer之銪螯合物標記之抗磷酸酪胺酸抗體(代替PT66-銪螯合物，亦可使用來自Cisbio Bioassays之PT66 Tb穴狀化合物))之EDTA水溶液(100 mM EDTA，含0.2%[w/v]牛血清白蛋白[BSA]之50 mM HEPES/HCl溶液pH 7.0)之溶液終止該反應。將所得之混合物在22℃下培育1小時以允許生物素化磷酸化受質與檢測試劑之錯合物之形成。隨後，藉由量測自PT66-銪螯合物至鏈黴抗生物素-XL665之能量共振轉移評估磷酸化受質之含量。為此，於350 nm激發後於HTRF量測儀器(例如)Rubystar(BMG Labtechnologies，奧芬堡，德國)或Viewlux (Perkin-Elmer)中量測在620 nm及665 nm處之螢光發射。採用665 nm及622 nm之發射比率作為磷酸化受質之含量之量度。將數據標準化(無抑制劑之酵素反應=0%抑制；所有其他檢定組分但無酵素=100%抑制)。通常，在11種自20 µM至0.073 nM之範圍內(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0.072 nM)之不同濃度在相同微量滴定板上測試該等受試物質；在檢定之前，在100倍濃縮溶液(即，於100% DMSO中2 mM至7.3 nM)之水平下藉由連續稀釋製備稀釋系列，取決於用於各種濃度之雙值之移液器，精確濃度可改變，及使用4-參數擬合計算IC50 值。 例示性化合物顯示針對TrkA之高選擇性(參見表1)。 THP-1細胞中之TNF-α分泌 藉助於此測試，可測試物質抑制THP-1細胞(人類單核細胞急性白血病細胞系)中之TNF-α(腫瘤壞死因子α)之分泌之能力。TNF-α為涉及炎症過程之細胞介素。於此測試中，藉由細菌脂多醣(LPS)之培育引發TNF-α分泌。 將THP-1細胞保存於連續懸浮細胞培養物[無L-麩丙胺酸二肽(GE Healthcare，目錄號E15-039)，補充有胎牛血清(FCS) 10% (Invitrogen，目錄號10082-147)、1% L-麩胺醯胺(Sigma，目錄號G7513)、1%青黴素/鏈黴素(PAA，目錄號P11-010)及50 µM 2-巰基乙醇(Gibco，目錄號31350-010)之RPMI 1460培養基]及不應超過1 x 106 個細胞/ml之細胞濃度。於細胞培養基(補充有L-麩胺醯胺、青黴素、鏈黴素及2-巰基乙醇之RPMI 1460培養基)中實施該檢定。 將THP-1細胞以2.5x105 個細胞/孔之細胞密度播種於96孔板中。根據本發明之化合物於恆定體積之100% DMSO中經受連續稀釋及以8種自10 µM至3 nM範圍內之不同濃度用於檢定中使得最終DMSO濃度為0.4% DMSO。在實際刺激之前，將細胞接著隨其預培養30 min。為引發細胞介素分泌，利用1 µg/ml LPS (Sigma，大腸桿菌(Escherichia coli ) 0127:B8，目錄號L4516)刺激細胞6小時。作為中性對照，利用1 µg/ml LPS及0.04% DMSO處理細胞及作為抑制劑對照，僅利用0.04% DMSO處理細胞。利用CellTiter-Glo發光檢定(Promega，目錄號G7571 (G755/G756A))依照製造商之指示測定細胞成活力。利用人類促發炎9-Plex組織培養套組(MSD，目錄號K15007B)依照製造商之指示測定細胞培養上清液中之TNF-α分泌量。 以中性與抑制劑對照之間之百分比比率表示物質之活性。利用4-參數擬合計算IC50 值。 例示性化合物顯示THP-1細胞中TNF-α之分泌之抑制(參見表3)。表 3 ： 實例化合物關於THP-1細胞中TNF-α之分泌之IC50 值 IL-1β介導之炎症之活體內模型 為評估根據本發明之通式(I)之化合物於IL-1β介導之疾病中之潛在效力，向雌性Balb/c小鼠(約8週齡，Charles River實驗室，德國)腹膜腔內注射IL-1β及檢查發明化合物對IL-1β介導之細胞介素分泌之效應。各組有5隻動物。對照組利用用於溶解物質及IL-1β之媒劑處理。向物質處理組及陽性對照組各者腹膜腔內投與90 µg IL-1β /kg體重(R&D，目錄號401-ML/CF)。在投與IL-1β之前6小時，於陽性對照組中投與該物質或其媒劑。於投與IL-1β後2小時，使用小鼠促炎症反應7-Plex組織培養套組(MSD，目錄號K15012B)依照製造商之指示於最終移除血液後測定血漿中之TNF-α。活體內佐劑引發之關節炎模型 為測定本發明通式(I)之化合物的抗炎活性，於關節炎模型中檢查其用於其活體內療效。出於此目的，在第0天向雄性Lewis大鼠(約100至125 g，Charles River實驗室，德國)各者皮下投與100 µl弗氏完全佐劑(CFA)溶液(溶解於弗氏不完全佐劑[Difco Lab，目錄號-263910]中之結核分歧桿菌(M. tuberculosis ) H37Ra[Difo Lab，目錄號-231141])至尾基部。各組有n=8隻大鼠。健康對照組及疾病對照組二者均包含於該研究中。各對照組僅利用受試物質之媒劑給於口服處理。以預防性方式實施利用不同劑量之受試物質之治療，即藉由口服，自第0天開始。在第0天，根據疾病活性評分(基於分數制度之關節炎之嚴重程度評定)額外測定動物之起始狀況。於該分數制度中，根據關節發炎之程度，針對包括關節腫脹之紅斑之存在就兩後爪及加起來判定0至4分(0=無；1=輕度；2=中度；3=明顯；4=嚴重)。為測定化合物之抗炎療效，藉助自當動物首先展示關節炎之信號時第8天之疾病活性評分對動物之疾病狀態記分及隨後每週3次直至結束(第20天)。利用單因素變方分析(ANOVA)及藉助多重比較分析(鄧恩試驗)與對照組比較來實施統計分析。In the case of the following synthetic intermediates and preparation examples of the present invention, any compound specified in the form of a corresponding base or acid salt is generally a salt of unknown exact stoichiometric composition, such as by the respective preparation and / or Or purification method. Unless specified in more detail, in the case of these salts, the addition of names and structural formulas such as "hydrochloride", "trifluoroacetate", "sodium salt" or "X HCl", "x CF3 COOH "," x Na+ ", But only has descriptive characteristics regarding the presence of salt-forming components. If a synthetic intermediate or preparation example or salt thereof is obtained by the described preparation and / or purification method in the form of a solvate (e.g., hydrate) of unknown stoichiometric composition (if they have a defined type), then this accordingly Be applicable. If the compounds covered by formula (I) and the following compounds are not already salts, solvates and solvates of salts, then the compounds of the present invention are compounds of formula (I) and their salts, solvates and solvates of salts, Compounds covered by formula (I) and having the following formula and their salts, solvates and solvates of salts and compounds covered by formula (I) and cited below as preparation examples and their salts, solvates and solvates of salts . Preferred salts in the context of the present invention are the physiologically acceptable salts of the compounds of the present invention. However, the present invention also includes salts that are not suitable for pharmaceutical applications by themselves but can be used, for example, to isolate or purify compounds according to the present invention. The physiologically acceptable salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as salts with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid Acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. The physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, for example and preferably alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts) and Ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine. Solvates in the context of the present invention are described as other forms of the compounds of the present invention which form complexes in solid or liquid form by coordination with solvent molecules. Hydrates are a specific form of solvates, where the coordination is achieved with water. The compounds according to the invention may be in different stereoisomeric forms depending on their structure, ie in the form of configurational isomers or other forms, if appropriate, in conformational isomers (enantiomers and / or Enantiomers, including those in the case of atropisomers, etc.). The invention therefore covers enantiomers and diastereomers and their respective mixtures. The stereoisomeric and homogeneous components can be isolated from these mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, chromatography is preferably used, especially in non-diametric or HPLC chromatography on the palm phase. If the compounds of the present invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms. The invention also includes all suitable isotopic variations of the compounds of the invention. It should be understood that the isotopic variation of the compound of the present invention means that at least one atom in the compound of the present invention is replaced by another atom having the same atomic number but having another atomic mass different from the atomic mass that usually or mainly occurs in nature Of compounds. Examples of isotopes of compounds that can be incorporated according to the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, etc.2 H (deuterium),3 H (tritium),13 C,14 C,15 N,17 O,18 O,32 P,33 P,33 S,34 S,35 S,36 S,18 F,36 Cl,82 Br,123 I,124 I,129 I and131 I. Specific isotopic variants of the compounds according to the invention, such as among others in which one or more radioactive isotopes are incorporated, may facilitate (for example) the detection of the mechanism of action or the distribution of active compounds in the body; due to the comparison of selectivity and testability Easy, specifically, use3 H or14 Compounds labeled with C isotopes are suitable for this purpose. In addition, for example, the incorporation of isotopes of deuterium can lead to specific therapeutic benefits due to the greater metabolic stability of the compound, such as an increase in half-life in vivo or a reduction in the required active dose. Therefore, such modifications of the compounds according to the present invention may also constitute preferred embodiments of the present invention in some cases. Isotopic variants of the compounds according to the invention can be obtained by methods familiar to those skilled in the art, for example by the methods described further below and the procedures described in the preparation examples, by using the respective reagents and / or starting compounds The corresponding isotope variants are prepared. The invention additionally provides all possible crystalline and polymorphic forms of the compounds according to the invention, wherein the polymorphic form can exist as a single polymorphic form or as a mixture of multiple polymorphic forms in all concentration ranges. In addition, the present invention also covers the prodrugs of the compounds of the present invention. The term "prodrug" in this context refers to a compound that itself can be biologically active or inactive, but is reacted (eg, metabolized or hydrolyzed) during the residence time in the body to obtain the compound of the present invention. In the context of the present invention, unless otherwise specified, the substituents have the following meanings:alkyl It is a straight-chain or branched-chain alkyl group having the specified number of carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tertiary butyl, n-pentyl, 1-ethylpropyl , 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl Group, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. In the context of the present inventionCycloalkyl It is a monocyclic saturated alkyl group having the indicated number of carbon atoms in each case. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the context of the present inventionHeterocycloalkyl It is a saturated heterocyclic ring with 4 to 6 ring atoms in total, where one or two ring carbon atoms can be selected from N, NH, N (C1 -C3 Alkyl), O, S and SO2 The same or different heteroatoms or heteroatom groups of the series are substituted. Preferred examples include piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 1,1-dioxotetrahydrothiophene- 3-yl, 1-methylazetidin-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-3-yl, tetrahydro-2H-pyran-4-yl, propylene oxide -3-yl. In the context of the present inventionHeteroaryl It is a monocyclic aromatic ring system having 5 or 6 ring atoms, which contains one or two ring heteroatoms and is connected via a ring carbon atom. The heteroaryl group may be, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , Thiadiazolyl or tetrazolyl 5-membered heteroaryl or 6-membered heteroaryl such as, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl. In general and unless otherwise specified, these heteroaryl or heteroaryl groups include all possible isomeric forms, such as tautomers and positional isomers related to the points of attachment of the rest of the molecule. Thus, as an illustrative, non-exclusive example, the term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. In the context of the present inventionAlkoxy It is a straight-chain or branched-chain alkoxy group having the specified number of carbon atoms. Examples that may be mentioned include methoxy, ethoxy, n-propoxy and isopropoxy. In the context of the present inventionhalogen Fluorine, chlorine and bromine. Preferably fluorine. In the context of the present inventionHydroxyl OH. The symbol * at the bond indicates the bonding point in the molecule. When the free radicals in the compounds of the present invention are substituted, unless otherwise specified, these free radicals may be substituted by single or multiple. In the context of the present invention, all free radicals that occur more than once are defined independently of each other. R1 Another embodiment is a group selected from:
Figure TW201803866AD00002
Among them: R3 Means C3 -C6 Cycloalkyl or C which may be substituted by halogen1 -C3 Alkyl, R4 Means C1 -C3 Alkoxy, NH2 Or C which may be substituted by halogen1 -C3 Alkyl and R5 Represents hydrogen or halogen and * represents the point of attachment in the molecule. R1 Yet another embodiment is a group selected from:
Figure TW201803866AD00003
Among them: R3 Means C3 -C6 Cycloalkyl or C which may be substituted by halogen1 -C3 Alkyl and R4 Means C1 -C3 Alkoxy, NH2 Or C which may be substituted by halogen1 -C3 Alkyl and R5 Represents hydrogen or halogen and * represents the point of attachment in the molecule. R1 Yet another embodiment is a group selected from:
Figure TW201803866AD00004
Among them: R3 C that can be substituted by halogen1 -C3 Alkyl and R4 C that can be substituted by halogen1 -C3 Alkyl and R5 Represents hydrogen and * represents the connection point in the molecule. R1 Yet another embodiment is selected from 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-cyclopropyl-1,3 -Groups of oxazol-4-yl, 4- (trifluoromethyl) -1,3-thiazol-2-yl, 6- (1,1-difluoroethyl) pyridin-2-yl. R3 Another example is C3 -C6 Cycloalkyl or C which may be substituted by one to five fluorine atoms1 -C3 alkyl. R3 Yet another embodiment is C3 -C6 Cycloalkyl or C which may be substituted by one to three fluorine atoms1 -C3 alkyl. R3 Yet another embodiment is cyclopropyl or C which may be mono- to tri-substituted with fluorine atoms1 -C3 alkyl. R4 Another example is C1 -C3 Alkoxy, NH2 Or C which may be substituted by one to five fluorine atoms1 -C3 alkyl. R4 Yet another embodiment is C1 -C3 Alkoxy, NH2 Or C which may be substituted by fluorine atoms one to three1 -C3 alkyl. R4 Yet another embodiment is methoxy, NH2 Or C which may be substituted by fluorine atoms one to three1 -C3 alkyl. R4 Yet another embodiment is C which may be substituted by one to three fluorine atoms1 -C3 alkyl. R5 Another example is hydrogen or halogen. R5 Yet another embodiment is hydrogen or fluorine. R5 Yet another example is hydrogen. Another example of A is a key or C1 -C3 alkyl. Yu A means C1 -C6 Alkyl or C1 -C3 In the case of alkyl, R2 Another example is hydrogen, methoxy, S (= O)2 -CH3 , NHCH3 , N (CH3 )2 Or contains 1 or 2 selected from O, S, S (= O)2 , N, NH, N (C1 -C3 -Alkyl groups) the same or different heteroatoms or heteroatom groups and 4, 5 or 6 membered heterocycloalkyl groups connected via ring carbon atoms or ring nitrogen atoms Yu A means C1 -C3 In the case of alkyl, R2 Yet another embodiment is a group selected from morpholin-4-yl, 1-methylazetidin-3-yl and 4-methylpiperazin-1-yl. In the case where A is a bond, R2 Another example is C1 -C6 Alkyl, where C1 -C6 The alkyl group may be mono-substituted with -OH or contain a group selected from NH, N (C1 -C3 Alkyl), O, S (= O)2 Group of heteroatoms or heteroatom groups and 6-membered heterocycloalkyl groups connected via ring carbon atoms. In the case where A is a bond, R2 Yet another embodiment is 1,1-dioxotetrahydro-2H-thiopyran-3-yl or 3-hydroxy-3-methylbutyl. The invention further provides compounds of general formula (I) wherein R1 Represents a group selected from
Figure TW201803866AD00005
Among them: R3 Means cyclopropyl or C1 -C3 Alkyl, where C1 -C3 Alkyl groups can be substituted by fluorine atoms from one to three, R4 Represents H, methoxy, NH2 、 C which can be substituted by fluorine atom single to triple1 -C3 Alkyl, R5 Represents hydrogen or fluorine and * represents the connection point in the molecule, A represents a bond or C1 -C3 -Alkyl, where A is C1 -C3 -In the case of alkyl, R2 Represents hydrogen, methoxy, S (= O)2 –CH3 , -N (CH3 )2 Or contains one or two selected from O, S (= O)2 , N, NH-CH3 The same or different heteroatoms or heteroatom groups and 4, 5 or 6-membered heterocycloalkyl groups connected through a ring carbon atom or ring nitrogen atom, or in the case where A is a bond, R2 Represents 3-hydroxy-3-methylbutyl or contains S (= O) as a heteroatom group2 And 6-membered heterocycloalkyl groups connected via ring carbon atoms, and their diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts. The invention further provides compounds of general formula (I) wherein R1 Represents a group selected from
Figure TW201803866AD00006
Among them: R3 Means cyclopropyl or C1 -C3 Alkyl, where C1 -C3 Alkyl groups can be substituted by fluorine atoms from one to three, R4 Represents H, C which can be substituted by fluorine atom single to three1 -C3 Alkyl, R5 Indicates hydrogen and * indicates the connection point in the molecule, A indicates a bond or C1 -C3 Alkyl, where A is C1 -C3 In the case of alkyl, R2 Represents hydrogen or contains one or two selected from O, N, NH-CH3 The same or different heteroatoms or heteroatom groups and 6-membered heterocycloalkyl groups connected through a ring carbon atom or ring nitrogen atom, or in the case where A is a bond, R2 Represents 3-hydroxy-3-methylbutyl or contains S (= O) as a heteroatom group2 And 6-membered heterocycloalkyl groups connected via ring carbon atoms, and their diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts. The invention further provides compounds of general formula (I) wherein R1 Represents 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl , 4- (trifluoromethyl) -1,3-thiazol-2-yl, 6- (1,1-difluoroethyl) pyridin-2-yl; A represents a bond or C1 -C3 Alkyl, where A is C1 -C3 In the case of alkyl, R2 Represents morpholin-4-yl or 4-methylpiperazin-1-yl or when A is a bond, R2 Represents 3-hydroxy-3-methylbutyl or represents 1,1-dioxotetrahydro-2H-thiopyran-3-yl, and its diastereomers, enantiomers, metabolites, Salts, solvates or solvates of their salts. The invention further provides compounds of general formula (I) wherein R1 Represents 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 6- (1,1-difluoroethyl) pyridine-2- Base; A represents bond and R2 Represents 3-hydroxy-3-methylbutyl or represents 1,1-dioxotetrahydro-2H-thiopyran-3-yl, and its diastereomers, enantiomers, metabolites, Salts, solvates or solvates of their salts. The present invention additionally provides a list of the following compounds: The present invention additionally provides in particular a list of the following compounds: The compounds according to the invention act as inhibitors of IRAK4 kinase and have a surprisingly useful spectrum of pharmacological activity. Therefore, in addition to the above-mentioned targets, the present invention also provides the use of the compounds according to the present invention for the treatment and / or prevention of human and animal diseases. Treatment and / or prevention of gynecological diseases, inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, autoimmune diseases, pain diseases, metabolic diseases, gout, liver diseases, metabolic syndrome, insulin resistance using the IRAK4 inhibitor according to the present invention Sex, kidney disease and cancer are particularly good. The compounds according to the invention are suitable for the prevention and / or treatment of various diseases and disease-related states, especially diseases and / or pathologies mediated by TLR (other than TLR3) and / or IL-1 receptor family are directly mediated by IRAK4 Diseases. Diseases associated with IRAK4 include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Ogata Harada syndrome, lupus erythematosus, psoriasis, spinal arthritis, and arthritis. The compounds according to the invention can also be used to prevent and / or treat diseases mediated by MyD88 and TLR (other than TLR3). It includes multiple sclerosis, rheumatoid arthritis, spinal arthritis (especially psoriatic spinal arthritis and Bekhterev's disease), including insulin resistance, diabetes, osteoarthritis, Sjogren's syndrome, giant cell arteries Inflammation, sepsis, polymyositis and dermatomyositis metabolic syndrome, skin diseases such as psoriasis, atopic dermatitis, alopecia areata, acne and acne vulgaris, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute breathing Distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension. Due to the mechanism of action of the compound according to the invention, it is suitable for the prevention and / or treatment of TLR-mediated diseases, Behcet's disease, gout, endometriosis and pain associated with endometriosis and such as Dysmenorrhea, difficulty in intercourse, difficulty in urinating, and difficulty in defecation are other symptoms associated with endometriosis. In addition, the compounds according to the invention are suitable for the prevention and / or treatment of transplant rejection, lupus erythematosus, adult-onset Stil's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. In addition to the listed diseases, the use of the compounds according to the invention is also suitable for the treatment and / or prevention of the following diseases: eye diseases such as keratitis, allergic conjunctivitis, dry keratoconjunctivitis, macular degeneration and uveitis; Atherosclerosis, myocardial reperfusion injury, myocardial infarction, cardiovascular diseases of hypertension and neurological diseases such as Alzheimer's disease, stroke and Parkinson's disease. The mechanism of action of the compounds according to the invention can also prevent and / or treat liver diseases mediated by the TLR and IL-1 receptor family, especially NAFLD, NASH, ASH, liver fibrosis and cirrhosis. In addition, the compounds according to the present invention are suitable for the prevention and / or treatment of nephropathy mediated by TLR and IL-1 receptor family, especially chronic nephropathy and nephropathy. The compounds according to the invention also provide prevention and / or treatment of pruritus and pain, especially acute, chronic, inflammatory and neuropathic pain. Due to the mechanism of action of the compound according to the invention, it is suitable for the prevention and / or treatment of tumor diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors. In addition, the compounds according to the invention are also suitable for the treatment and / or prevention of diseases mediated by the IL-1 receptor family. These diseases include CAPS (Cyclic Syndrome Associated with Cryptothermal Protein), which includes FCAS (Family Cold Autologous Inflammatory Syndrome), MWS (Mouweier's Syndrome), NOMID (Newborn-onset multisystem inflammation Sexual disease) and CONCA (chronic infantile neurodermal and arthritis) syndrome, FMF (familial Mediterranean fever), HIDS (high IgD syndrome), TRAPS (cyclic syndrome associated with tumor necrosis factor receptor 1) , Juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, rheumatoid arthritis, psoriasis, arthritis, Bekhterev's disease, osteoarthritis, dry keratoconjunctivitis, and xerostomia , Multiple sclerosis, lupus erythematosus, alopecia areata, type 1 diabetes, type 2 diabetes and sequelae of myocardial infarction. Pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia and ARDS, gynecological diseases such as endometriosis and pain associated with endometriosis and such as dysmenorrhea, difficulty in sexual intercourse, difficulty in urination and defecation Difficult other symptoms associated with endometriosis, chronic inflammatory bowel disease such as Crohn's disease and ulcerative colitis are associated with abnormal regulation of the IL-1 receptor family and apply to Therapeutic and / or prophylactic use of the inventive compounds. The compounds according to the invention can also be used for IL1 receptor family-mediated neurological diseases such as stroke, Alzheimer's disease, brain attack, craniocerebral trauma, and such as psoriasis, atopic dermatitis, acne, alopecia areata and allergy Treatment and / or prevention of skin diseases of contact dermatitis. Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of pain diseases, especially acute, chronic, inflammatory and neuropathic pain. Preferably include hyperalgesia, allodynia, pain from arthritis (such as osteoarthritis, rheumatoid arthritis, spinal arthritis), premenstrual pain, pain associated with endometriosis, surgery Posterior pain, pain from interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain from prostatitis, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, Pain associated with chemotherapy, neuropathy caused by HIV treatment, pain caused by burns, and chronic pain. The present invention also provides a method of using an effective amount of at least one compound according to the present invention to treat and / or prevent diseases (especially the aforementioned diseases). In the context of the present invention, the term "treatment" or "treating" includes diseases, conditions, disorders, injuries or health problems or the development, process or symptoms of these conditions and / or symptoms of such conditions Inhibition, delay, inspection, mitigation, reduction, limitation, reduction, suppression, repression or cure of progress. The term "therapy" herein should be understood as synonymous with the term "treatment". In the context of the present invention, the terms "prevention", "prophylaxis" and "preclusion" are synonymous Local use and refers to avoiding or reducing the risk of contact, experience, suffering or suffering from disease, pathology, illness, injury or health problems or the development or advancement of these conditions and / or symptoms of these conditions. The treatment and / or prevention of diseases, conditions, disorders, injuries or health problems may be partial or complete. The compounds according to the invention can be used alone or, if desired, in combination with other active compounds. The invention additionally provides a medicament comprising at least one compound according to the invention and one or more other active compounds, especially for the treatment and / or prevention of the above-mentioned diseases. Preferred examples of suitable combinations of active compounds include: General mention may be made of active compounds such as antibacterial (eg penicillin, vancomycin, ciprofloxacin), antiviral (eg acyclovir ( aciclovir), oseltamivir) and antimycin (eg naftifin, nystatin) substances and γ-globulin, immunomodulatory and immunosuppressive compounds such as cyclosporin (cyclosporin), Methotrexat®, TNF antagonists (eg Humira®, Etanercept, Infliximab), IL-1 inhibitors (eg Anakinra) , Canakinumab (Rilonacept), phosphodiesterase inhibitors (eg Apremilast), Jak / STAT inhibitors (eg Tofacitinib), Baricitinib (GLPG0634), leflunomid, leflunomid, cyclophosphamide, rituximab, belimumab, tacrolimus, thunder Rapamycin, mycophenolate mofetil, interferon, cortex Sterols (e.g. prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, Imidazathioprine and sulfasalazine; paracetamol (paracetamol), non-steroidal anti-inflammatory substances (NSAIDS) (aspirin, ibuprofen), naproxen (naproxen), etodolac (etodolac), stopper Come to celecoxib, colchicine). The following should be mentioned for tumor therapy: immunotherapy (eg aldesleukin, alemtuzumab), balimiximab (basiliximab), catumaxomab (catumaxomab), celmoleukin (celmoleukin) ), Denileukin, diftitox, eculizumab, edrecolomab, edrecolomab, gemtuzumab, ibritumomab tiuxetan ), Imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab, ipilimumab, lenalidomid, lenograstim, milvalopeptide ( mifamurtid), ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, cypro Ruse-T (sipuleucel-T), tasonermin, teceleukin, tocilizumab); anti-proliferative biomass, such as but not exclusively: acridine (amsacrin) , Arabic acid (arglabin), arsenic trioxide, asparaginase, bleomycin Busulfan, dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab Anti, Obinutuzumab, ofatumumab, tositumomab, aromatase inhibitors (e.g. exemestan), fadrozol, formestane (formestan), letrozole (letrozol), anastrozol (anastrozol), vorozol (vorozol)), antiestrogen (e.g., chlormadinon, fulvestrant, cyclic Thioandrostane (mepitiostan), tamoxifen (raloxifen), raloxifen (raloxifen), toremifene (toremifen)), estrogen (e.g. estradiol, polyestrodiol) Phosphate esters), progestogens (e.g. medroxyprogesteron, megestrol), topoisomerase I inhibitors (e.g. irinotecan, topotecan )), Topoisomerase II inhibitors (e.g. amrubicin, daunorubicin), elliptinium acetate, etopo sid), idarubicin, mitoxantron, teniposid), microtubule active substances (e.g. cabazitaxel, eribulin ), Paclitaxel, vinblastin, vincristin, vindesin, vinorelbin), telomerase inhibitors (e.g. imetelstat) ), Alkylating substances and histone deacetylase inhibitors (eg bendamustin, carmustin, chlormethin, dacarbazin, estradiol Mustard (estramustin), ifosfamide, cyclohexylnitrosourea, dibromomannitol, dibromomantelol, nimustin, prednimustin, benzhydrazine, Ranimustin, streptozotocin, temozolomid, thiotepa, treosulfan, trofosfamid, vorinostat, Romidepsin (panobinostat); substances that affect the process of cell differentiation, such as abarelix ), Aminoglutethimid, bexaroten, MMP inhibitors (peptide mimetics, non-peptide mimetics and tetracyclines, such as marimastat, BAY 12-9566, BMS-275291, Clodronate, prinomastat, doxycycline, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) Temsirolimus, zotarolimus, antimetabolites (e.g. clofarabin, doxifluridin), methotrexate, 5-fluorouracil , Cladribin, cytarabin, fludarabin, mercaptopurin, methotrexate, pemetrexed, raltitrexed , Tegafur, tioguanin, platinum compounds (such as carboplatin, cisplatin, cisplatinum, eptaplatin, loplatin) (lobaplatin), miriplatin, nedaplatin, oxaliplatin); anti-angiogenic compounds (E.g. bevacizumab), anti-androgen compounds (e.g. bevacizumab, enzalutamid, flutamid, nilutamid, bicalutamide ( bicalutamid), cyproteron acetate (cyproteron), cyproteron acetate (cyproteron acetate), proteasome inhibitors (e.g. bortezomib (bortezomib), carfilzomib (carfilzomib), Opprozomib (ONYX0914), gonadotropin-releasing agonists and antagonists (eg, abarelix, buserelin, deslorelin, garni Ganirelix, goserelin, histrelin, triptorelin, degarelix, leuprorelin, methiamine Acid aminopeptidase inhibitors (such as benzamide derivatives, TNP-470, PPI-2458), heparanase inhibitors (such as SST0001, PI-88); inhibitors of genetically modified Ras protein ( For example, farnesyl transferase inhibitors such as lonafarnib, tipifarnib), HSP90 inhibitors (eg, gelda mycin) derivatives such as 17-allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17-DMAG, retaspimycin hydrochloride, IPI -493, AUY922, BIIB028, STA-9090, KW-2478), kinesin spindle protein inhibitors (e.g. SB715992, SB743921, pentamidine / chlorpromazine), MEK (mitogen-activated protein kinase Kinase (mitogen-activated protein kinase kinase) inhibitors (eg trametinib, BAY 86-9766 (refametinib), AZD6244), kinase inhibitors (eg: sorafenib), regrafenib (Regorafenib), lapatinib, satin (Sutent), dasatinib (dasatinib), cetuximab (cetuximab), BMS-908662, GSK2118436, AMG 706, erlotinib ( erlotinib), gefitinib (gefitinib), imatinib (imatinib), nilotinib (nilotinib), pazopanib (pazopanib), (roniciclib), sunitinib (sunitinib), vandetanib (vandetanib), vemurafenib (vemurafenib), hedgehog signaling inhibitors (eg, cyclopamin, vismodegib), BTK (Bruce (Bruton's) tyrosine kinase) inhibitors (e.g. ibrutinib), JAK / Pan-JAK (Janus kinase) inhibitors (e.g. SB-1578, baricitinib, barotinib) Fatinib, pacritinib, momelotinib, ruxolitinib, VX-509, AZD-1480, TG-101348), PI3K inhibitors (e.g. BAY 1082439, BAY 80-6946 (copanlisib), ATU-027, SF-1126, DS-7423, GSK-2126458, buparlisib, PF-4691502, BYL-719, XL-147, XL-765, idelalisib), SYK (splenic tyrosine kinase) inhibitors (e.g. fostamatinib, Excellair, PRT-062607), p53 gene therapy, bisphosphonates (e.g. Iridonat, clodronat, tiludronat, pamidronat, alendronic acid, ibandronat ), Risedronate, zoledronat). Examples of active compounds for combination include the following: rituximab, cyclophosphamide, doxorubicin, the combination of doxorubicin and estrone (oestrone), vincristine, phentermine Chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 131I-chTNT, abirateron, aclarubicin, alevitine (alitretinoin), bisantren, calcium folinate, calcium levofolinate, capecitabin, carmofur, chlorometaphosphate (clodronic acid), romiplostim, crisantaspase, darbepoetin alfa, decitabin, denosumab, dibromide Dibrospidium chloride, eltrombopag, endostatin, epitopiostanol, epietin alfa, filgrastim, formaldehyde Fotemustin, gallium nitrate, gemcitabine hydrochloride (gemcitabin), glutathione (oxidized) disodium salt (glutoxim), histamine dihydrochloride, hydroxyurea, improsulfan, ixabepilon, lanreotid, lentinan, levamisole, ergocarbazide, chlorine Nidamin (lonidamin), Masoprocol (masoprocol), methyltestosterone (methyltestosterone), methoxsalen (methoxsalen), methanone valerate, miltefosin (miltefosin), (mitoguazon), Mitomycin, mitotan, nelarabin, nimotuzumab, nitracrin, omeprazol, palivmin ( palifermin), panitumumab, pegaspargase, PEG-epobutin (methoxy-PEG-epobutin), PEGylated filgrastim (pegfilgrastim), polyethylene glycol interference Alpha-2b, pentazocin (pentazocin), pentostatin (pentostatin), perfosfamid (perfosfamid), pirarubicin (pirarubicin), pikamycin (plicamycin), polyglucosamine ( poliglusam), porfimer-sodium, pralatrexate, quinagolid, razoxan, sizof iran), sobuzoxan, sodium glycididazole, tamibaroten, tegafur in combination with gimeracil and oteracil, testosterone (testosterone), tetrofosmin, thalidomide, thymalfasin, trabectedin, tretinoin, trilostan, Tryptophan, ubenimex, (vapreotid), yttrium-90 glass beads, zinostatin, net statin. Also suitable for cancer treatment are such as chemotherapy (eg, azacitidine, belotecan, enocitabine, melphalan, valrubicin) , Vinflunin, zorubicin, radiotherapy (e.g. I-125 vaccination, palladium-103 vaccination, radium-223 chloride) or light therapy (e.g. temoporfin), Talaporfin (talaporfin)) is a combination of non-pharmaceutical treatment, which can be accompanied by the pharmaceutical treatment of the IRAK4 inhibitor according to the present invention or after the non-pharmaceutical treatment such as chemotherapy, radiotherapy or phototherapy, supplement Invented pharmaceutical treatment of IRAK4 inhibitors. In addition to the above, the TRAK4 inhibitors according to the present invention can also be combined with the following active compounds: Active compounds for the treatment of Alzheimer's disease, such as acetylcholinesterase inhibitors (eg, donepezil ), Rivastigmine, galantamin, tacrine, NMDA (N-methyl-D-aspartate) receptor antagonists (e.g. memantine) ; L-DOPA / Carbidopa (L-3,4-Dihydroxyamphetamine), COMT (Catechol-O-Methyltransferase) inhibitors (such as entacapone) for the treatment of Parkinson ’s disease (entacapon)), dopamine agonists (e.g. ropinrol, pramipexol, bromocriptin), MAO-B (monoamine oxidase-B) inhibitors (e.g. selegilin )), Anticholinergic agents (for example, trihexyphenidyl) and NMDA antagonists (for example, amantadin); interferon beta (IFN-beta) (for example, IFNbeta) for the treatment of multiple sclerosis -1b, IFNβ-1a, Avonex® and Betaferon®), glatiramer acetate, immunoglobulin, natalizumab, fingoli (fingolimod) and immunosuppressive agents such as mitoxantrone, azathioprine, and cyclophosphamide; substances used to treat lung diseases, such as β-2-sympathomimetics (eg, salbutamol) , Anticholinergic agents (such as glycopyrronium), methylxanthines (such as theophylline), leukotriene receptor antagonists (such as montelukast), PDE-4 (Phosphodiesterase type 4) inhibitors (such as roflumilast), methotrexate, IgE antibodies, imazathiopurine and cyclophosphamide, cortisol-containing preparations; used to treat osteoarthritis Substances, such as nonsteroidal anti-inflammatory substances (NSAID). In addition to the two treatments mentioned, mention may be made of rheumatic diseases such as rheumatoid arthritis, spinal arthritis, and juvenile idiopathic arthritis Methotrexate, leflunomide, Jak / STAT inhibitors (eg, tofacitinib, barretinib, GLPG0634), TNF antagonists (eg, Humira®, etanercept, infliximab ), IL-1 inhibitors (e.g. anakinra, conjumumab, linaccept) and treatment against B cells and T cells Biologics (eg rituximab, abatacept). Neurotrophic substances such as acetylcholinesterase inhibitors (eg, donepezil), MAO (monoamine oxidase) inhibitors (eg, selegiline) , Interferon and anticonvulsants (eg gabapentin); active compounds for the treatment of cardiovascular diseases, such as β-receptor blockers (eg metoprolol), ACE inhibitors (eg beta Benazepril), angiotensin receptor blockers (e.g. losartan, valsartan), diuretics (e.g. hydrochlorothiazide), calcium channel blockers Agents (e.g. nifedipine), statins (e.g. simvastatin, fluvastatin); anti-diabetic agents such as metformin, glinaze (e.g. nateglinide) (nateglinide)), DPP-4 (dipeptidyl peptidase-4) inhibitors (e.g. linagliptin), saxagliptin, sitagliptin, viltagliptin ( vildagliptin)), SGLT2 (sodium / glucose cotransporter 2) inhibitor / gliflozin (e.g. dagliflozin (da pagliflozin), empagliflozin), insulinotropic mimetics (glucose-dependent insulinotropic peptide (GIP) hormones and glucagon peptide 1 (GLP-1) analogs / agonists) (e.g. Exenatide, liraglutide, lixisenatide), alpha-glucosidase inhibitors (e.g. acarbose, miglitol, Voglibiose) and sulfonylurea (e.g. glibenclamide, tolbutamide), insulin sensitizers (e.g. pioglitazone) and insulin therapy ( For example, NPH insulin, insulin lispro (insulin lispro), substances used to treat hypoglycemia, etc. are used to treat diabetes and metabolic syndrome. Lipid-lowering agents, such as fibrate (eg bezafibrate, etofibrate, fenofibrate, gemfibrozil), niacin derivatives (eg nicotinic acid / Laropiprant), ezetimib, statin (e.g. simvastatin, fluvastatin), anion exchanger (e.g. colestyramine), colestipol , Colesevelam (colesevelam)). Active compounds such as mesalazine, sulfasalazine, imazathiopurine, 6-mercaptopurine or methotrexate, probiotics (Mutaflor, VSL # 3®, Lactobacillus GG, Lactobacillus germs, acidophilus Lactobacillus, Lactobacillus casei, Bifidobacterium infantis 35624, Enterococcus faecium SF68, Bifidobacterium longum, E. coli Nissle 1917), antibiotics such as ciprofloxacin and metronidazole, anti-diarrhea agents such as Lopa Loperamide or laxative (bisacodyl), which are used to treat chronic inflammatory bowel disease. Immunosuppressive agents for the treatment of lupus erythematosus, such as glucocorticoids and non-steroidal anti-inflammatory substances (NSAIDs), cortisone (cortisone), chloroquine (chloroquin), cyclosporine (cyclosporine), imidazothiopurine, Bailey MAb, rituximab, cyclophosphamide. For example, but not exclusively, calcineurin inhibitors for organ transplants (eg tacrolimus and ciclosporin), cell differentiation inhibitors (eg imazathioprine, mycophenolate mofetil) Esters, mycophenolic acid, everolimus or sirolimus), rapamycin, Baliximab, daclizumab, anti-CD3 antibodies, anti-T-cell hemoglobin / anti-lymphocytes Hemoglobin. Vitamin D3 analogues for skin diseases (for example) calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate , Efalizumab (efalizumab). Glucocorticoids (e.g. prednisone), immunosuppressive substances such as imazathiopurine, cyclophosphamide, mycophenolate mofetil, hydroxychloroquine, ACE inhibitors for the treatment of nephropathy, nephropathy and glomerular diseases Agents (e.g. captopril, benazepril, enalapril, fosinopril), angiotensin receptor blockers (e.g. losartan, valsartan), Beta-blockers (eg metoprolol), calcium channel blockers (eg nifedipine) and immunosuppressants such as cyclosporine. It should also be mentioned that it contains at least one compound according to the invention and one or more other active compounds, specifically EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purine receptor 3), PTGES inhibition Agents (prostaglandin E synthase inhibitors) or AKR1C3 inhibitors (aldo-keto reductase family 1 member C3 inhibitors), which are used to treat and / or prevent the above diseases. The compounds of the invention can act systemically and / or locally. For this purpose, etc. can be, for example, by oral, parenteral, lung, nasal, sublingual, lingual, oral, rectal, dermal, transdermal or conjunctival routes, via the ear or as a graft Or stent. The compound of the present invention can be administered in a form suitable for administration in these administration routes. Suitable administration methods for oral administration are those in which they worked according to the prior art and quickly and / or in a modified manner release the compound of the invention and include the compound of the invention in crystalline and / or amorphous and / or dissolved form , Such as lozenges (uncoated or coated lozenges, for example using anti-gastric agents or slow-dissolving or insoluble coatings, which control the release of the compound of the invention), lozenges or films / oblates that disintegrate rapidly in the oral cavity Body, film / lyophilisate, capsule (eg hard or soft gel capsule), sugar-coated lozenges, granules, pills, powder, emulsion, suspension, aerosol or solution. Parenteral administration can be used to avoid reabsorption steps (e.g. by intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or to include reabsorption (e.g. by intramuscular, subcutaneous, intradermal, transdermal) Or intraperitoneal route) to achieve. The administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. For other administration routes, suitable examples are inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays; lozenges, films / oblates or capsules for tongue, sublingual or oral administration, Suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, vibrating mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), creams, ointments, foams, powders , Grafts or stents. It is preferably oral and parenteral administration, especially oral administration. The compounds of the present invention can be converted into the mentioned administration forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such excipients include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersing or wetting agents (e.g. sodium lauryl sulfate, polyoxygen Sorbitol oleate), binders (such as polyvinylpyrrolidone), synthetic and natural polymers (such as albumin), stabilizers (such as antioxidants, such as ascorbic acid), colorants (such as inorganic pigments, such as iron Oxides) and fragrances and / or odor correctors. The invention additionally provides a medicament comprising at least one compound according to the invention and its use for the above-mentioned purposes, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients. Generally speaking, in the case of parenteral administration, an amount of about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight is preferably administered in order to achieve an effective effect. In the case of oral administration, the dose is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight and most preferably 0.1 to 10 mg / kg body weight. However, in some cases it may be necessary to deviate from the specified amount, specifically as a function of body weight, route of administration, individual response to the active compound, the nature of the formulation, and the time or interval at which the administration occurs. Therefore, in some cases, it may be sufficient to manage with less than the above minimum amount, while in other cases, the mentioned upper limit must be exceeded. In the case of larger doses, it is desirable to divide the medicament into several single doses in a day. The following working examples illustrate the invention. The invention is not limited to these examples. Unless otherwise specified, the following percentages in the tests and examples are weight percentages; parts are parts by weight. In each case, the solvent ratio, dilution ratio, and concentration data for the liquid / liquid solution are based on volume. The preparation method of the substance of formula (I) according to the present invention is illustrated in the following synthesis reaction diagram 1.
Figure TW201803866AD00007
Reaction Diagram 1 The starting material for the synthesis of some compounds according to the invention is carboxylic acid R2 -A-CO2 H, where R2 As defined in formula (I), it is commercially available or can be prepared by a route known from the literature or similar to a route known from the literature (see, for example, 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). It can be continued from the carboxylic acid ester, by hydrolysis or in the case of n-butyl ester by reacting with (for example) hydrochloric acid or trifluoroacetic acid to prepare some carboxylic acid R2 -A-CO2 H, where R2 As defined in formula (I) (see, for example, Dalton Transactions, 2014, 43, 19, 7176-7190). Carboxylic acid R2 -A-CO2 H can also be used in the reaction in the form of its alkali metal salt. Self-halogenation unit R as appropriate2 -A-I, R2 -A-Br or R2 -A-Cl (where R2 (As defined in formula (I)), by means of a phosphine ligand such as 1,3-bis (diphenylphosphino) propane, a palladium compound such as palladium (II) acetate under a pressure of carbon monoxide, optionally under pressure And in the presence of a base such as triethylamine, in a solvent such as dimethyl sulfoxide to add ethanol or methanol reaction, to prepare for the preparation of carboxylic acid R2 -A-CO2 The carboxylic acid ester of the starting material of H (see, for example, WO 2012112743, WO 2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948-1949, WO 200661715). Starting material R2 -A-I, R2 -A-Br, R2 -A-Cl is commercially available or can be prepared by methods known from the literature. In WO2012061926; 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, Exemplary preparation methods are described in 2014, 24, 16, 4039–4043; US2007185058; WO2009117421. Start with methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0), by combining with the appropriate carboxylic acid R2 -A-CO2 H reaction to prepare compound 1.1, where R2 With the meaning mentioned in the technical solution and R2 It can be additionally substituted with carboxylate. For this purpose, various coupling reagents known from the literature (Amino Acids, Peptides and Proteins in Organic Chemistry. Volume 3-Building Blocks; Catalysis and Coupling Chemistry, Andrew B. Hughes Wiley, Chapter 12-Peptide-Coupling Reagents , 407-442; Chem. Soc. Rev., 2009, 38, 606). For example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, 2093), tetrafluoroboric acid (1H-benzotriazol-1-yloxy) (dimethylamino) -N, N-dimethylformimmonium (TBTU, CAS -RN 125700-67-6), hexafluorophosphate (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridine-3- Yloxy) methyliminium (HATU, CAS-RN 148893-10-1), propanephosphonic anhydride (as a solution in ethyl acetate or DMF, CAS-RN 68957-94-8) or di-1H- Imidazol-1-yl ketone (CDI) is combined as a coupling reagent, in each case a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine is added to the reaction mixture. The coupling reagents are preferably HATU, N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide (EDC, CAS-RN 1892-57-5) and 1H-benzene The combination of benzotriazole-1-ol hydrate (1: 1) (HOBt, CAS-RN 123333-53-9) and TBTU. The base used is preferably triethylamine or N-ethyl-N-isopropylpropan-2-amine. The preferred solvent is THF or DMF. Compound 1.2 can be prepared from compound 1.1 by treatment with an acid under optional heating. By treating compound 1.1, optionally in an inert solvent, the reaction is carried out with a suitable acid at room temperature or at 40 ° C to 200 ° C. Suitable acids are, for example, acetic acid, trifluoroacetic acid or hydrochloric acid. The acid can also be used as a solvent. Alternatively, it can be directly from methyl 3-amino-4- (methylamino) benzoate, by reaction with carboxylic acid under acidic dehydration conditions (for example with propanephosphonic anhydride) or by inert solvent at room temperature or Carbonyl chloride was reacted at 40 ° C to 200 ° C to prepare compound 1.2. Compound 1.3 can be obtained by nitration of compound 1.2. Available methods for this purpose are nitrification methods known to those skilled in the art, such as using nitric acid in combination with concentrated sulfuric acid or using concentrated sulfuric acid with potassium nitrate. Starting with compound 1.3, compound 1.4 can be prepared by reduction of the nitro group. For example, palladium on carbon (WO2007 / 48070) can be used under a hydrogen atmosphere, and iron or ammonium chloride (US2003 / 236260) or tin (II) chloride (WO2008 / 128009) can be used to reduce the nitro group in water and ethanol. The formula R can be used from compound 1.4 in a manner similar to that described for the preparation of compound 1.11 -COOH's suitable carboxylic acid preparation compound "intermediate", where R1 It has the meaning given by technical solution 1. Compounds of general formula (I) can be prepared from intermediates by Grignard reaction using, for example, methylmagnesium bromide. The reaction can be carried out in a suitable solvent such as diethyl ether or tetrahydrofuran in a temperature range of -30 ° C to 50 ° C, but preferably at room temperature. Alternatively, the compound of general formula (I) can be obtained from an intermediate by reacting with methyllithium at a temperature of -78 ° C to room temperature. If free radical R2 Contains carboxylic acid esters such as methyl carboxylate or ethyl carboxylate, which can be converted to propan-2-ol under the conditions described above for the conversion of intermediates to compounds of general formula (I). If the individual synthetic steps in the synthesis of the compound according to the invention require protecting groups, other protecting groups can be introduced or removed by methods known to those skilled in the art (for the introduction and removal of suitable protecting groups also see PGM Wuts , TW Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, ISBN: 9780471697541).Example Compound Synthesis Abbreviations and descriptions the termSaturated brine Means saturated aqueous sodium chloride solution. Use ACD / LABS (Lot Version 12.01.) Software to generate chemical names of intermediates and examples.method The compounds according to the invention and their precursors and / or intermediates are analyzed by LC-MS. LC-MS method (analytical):UPLC-MS method A Instrument: Waters Acquity UPLC-MS SQD3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1mm; mobile phase A: water + 0.1% formic acid, mobile phase B: acetonitrile; gradient: 0 to 1.6 min 1-99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 2 µl; DAD scan: 210 to 400 nm. UPLC-MS Method B Instrument: Waters Acquity UPLC-MS SQD3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1mm; mobile phase A: water + 0.2% ammonia water (32%), mobile phase B: acetonitrile; gradient: 0 To 1.6 min 1-99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 2 µl; DAD scan: 210 to 400 nm; ELSD. UPLC-MS Method C Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 50 x 2.1mm; Mobile phase A: water + 0.05% formic acid, mobile phase B: acetonitrile + 0.05% formic acid; gradient: 0 To 1.6 min 1-99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 2 µl; DAD scan: 210 to 400 nm. UPLC-MS Method D Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; mobile phase A: water + 0.2% ammonia water (32%), mobile phase B: acetonitrile; gradient: 0 to 1.6 min 1-99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 2 µl; DAD scan: 210 to 400 nm; ELSD. UPLC-MS Method E Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Mobile phase A: water + 0.1% formic acid, mobile phase B: acetonitrile; gradient: 0 to 1.6 min 1- 99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 1 µl; DAD scan: 210 to 400 nm; ELSD. UPLC-MS Method F Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; mobile phase A: water + 0.2% ammonia water (32%), mobile phase B: acetonitrile; gradient: 0 to 1.6 min 1-99% B, 1.6 to 2.0 min 99% B; flow rate 0.8 ml / min; temperature: 60 ° C; injection: 1 µl; DAD scan: 210 to 400 nm; ELSD. In some cases, the substance mixture is purified by column chromatography on silica gel. For the preparation of some compounds of the invention and their precursors and / or intermediates, Isolera from Biotage is used® The device performs column chromatography purification on silica gel ("flash chromatography"). For this purpose, filter cartridges from Biotage are used, such as various sizes of filter cartridges "SNAP Cartridge, KP_SIL". To1 H NMR peak list form states the selected compound1 H NMR data. Here, for each signal peak, first the δ value (in ppm) and then the signal strength are listed in parentheses. Separate each other by a comma to list the number of delta values of different signal peaks-the number of signal intensities; therefore, the compound peak list has the following form: δ1 (intensity 1), δ2 (intensity 2), ..., δi (intensity i), ... δn (intensity n). In the printed example of NMR spectroscopy, the intensity of the sharp signal is correlated with the height of the signal (in cm) and shows the correct ratio of the signal intensity compared to other signals. In the case of wide signals, several peaks or intermediate signals and their relative intensities relative to the strongest signal in the spectrum can be displayed.1 H NMR peak list is similar to conventional knowledge1 H NMR prints out and therefore usually contains all peaks listed in conventional NMR interpretation. In addition, similar knowledge1 H NMR prints, it can display the signal of the solvent, the signal of the stereoisomer of the target compound in question, the peak of impurities,13 C with peaks and / or rotating sidebands. The peak of the stereoisomer of the target compound and / or the peak of the impurity generally have a lower intensity than the peak of the target compound (for example, with a purity of> 90%). Such stereoisomers and / or impurities may be typical in terms of specific preparation methods. Therefore, their peaks can be helpful for reproducing the preparation method by referring to the "by-product fingerprint". The peak of the target compound can be calculated by experts by known methods (MestreC, ACD simulation or expected value using empirical evaluation). If necessary, other intensity filters can be used to isolate the peak of the target compound. This separation will be similar to peak picking as discussed in the interpretation of conventional 1H NMR. A detailed description of the NMR data submitted in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see http://www.researchdisclosure.com/searching-disclosures, Research Disclosure database number 605005, 2014, (August 1, 2014). In the peak picking routine described in the cited research disclosure, the parameter "MinimumHeight" can be adjusted to a value between 1% and 4%. However, depending on the nature of the chemical structure and / or depending on the concentration of the test compound, it may also be advantageous to adjust the parameter "MinimumHeight" to a value of <1%. Intermediate 1-12- (3- Methoxy -3- Pendant propyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00008
step 1 3-[(4- Methoxy -4- side Oxybutylamide ) Amine ] -4- ( Methylamino ) Methyl benzoate At room temperature, in the presence of 5.8 ml (41.6 mmol) of triethylamine, 5 g (27.7 mmol) of methyl 3-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 5.5 g (41.6 mmol) 4-methoxy-4-oxobutanoic acid (CAS-RN 3878-55-5) were stirred with 15.8 g (41.6 mmol) HATU for 6 hours. Purification by HPLC gave 6.5 g (80%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 295; Rt = 0.82 min (Method E).step 2 2- (3- Methoxy -3- Pendant propyl )-1- methyl -1H- Benzimidazole -5- Formic acid Methyl ester At 40 ° C, 6.5 g (22 mmol) of methyl 3-[(4-methoxy-4-oxobutanoyl) amino] -4- (methylamino) benzoate was stirred in 52 ml of acetic acid 48 hours. Concentrate to give 6.4 g of residue that can be used further without further purification.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.91-2.97 (m, 2H), 3.12-3.19 (m, 2H), 3.62 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 7.61-7.65 ( m, 1H), 7.83-7.88 (m, 1H), 8.13-8.16 (m, 1H). UPLC-MS (ESI +): [M + H]+ = 277; Rt = 0.70 min (Method E).step 3 2- (3- Methoxy -3- Pendant propyl )-1- methyl -6- Nitro -1H- Benzimidazole -5- Formic acid Methyl ester Dissolve 6.43 g of methyl 2- (3-methoxy-3-oxopropyl) -1-methyl-1H-benzimidazole-5-carboxylate (23 mmol) in 50 ml of concentrated sulfuric acid and slowly Add 2.7 ml of a mixture of concentrated nitric acid and concentrated sulfuric acid (1: 1.4). After the addition was completed, the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 500 g of ice and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The precipitated product was filtered off with suction, and the precipitated product was dissolved in a mixture of 300 ml of ethyl acetate, 200 ml of dichloromethane, and 100 ml of acetonitrile, dried over magnesium sulfate, and concentrated. This process gave 5.8 g (78%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.91-3.01 (m, 2H), 3.15-3.27 (m, 2H), 3.62 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 7.96 (s, 1H), 8.46 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 322; Rt = 0.89 min (Method E).step 4 6- Amine -2- (3- Methoxy -3- Pendant propyl )-1- methyl -1H- Benzimidazole -5- Formic acid Methyl ester Under a hydrogen atmosphere, at room temperature, 5.8 g (18 mmol) of 2- (3-methoxy-3-oxopropyl) -1-containing in a mixture of 77 ml of methanol and 180 ml of THF Methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester was stirred with 1.6 g of 10% palladium on carbon for 2 hours. The mixture was filtered, and after concentration of the filtrate, 5.4 g of residue was obtained that could be used further without further purification.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.83-2.90 (m, 2H), 3.00-3.07 (m, 2H), 3.58 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 6.43 (sbr, 2H), 6.64 (s, 1H), 7.91 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 292; Rt = 0.59 min (Method E).step 5 2- (3- Methoxy -3- Pendant propyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate At room temperature, in the presence of 359 µl (2.5 mmol) of triethylamine, 0.5 g (1.7 mmol) of 6-amino-2- (3-methoxy-3- pendant) in 4.6 ml of DMF Propyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 492 mg (2.5 mmol) 6- (trifluoromethyl) pyridine-2-carboxylic acid (CAS-RN 131747-42-7) React with 979 mg (2.5 mmol) HATU for 1.5 hours. The reaction mixture was added to 100 ml of water and stirred for 15 min. Suction filtration gave 700 mg (88%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.90-2.97 (m, 2H), 3.14-3.21 (m, 2H), 3.63 (s, 3H), 3.79 (s, 3H), 3.94 (s, 3H), 8.21-8.26 ( m, 1H), 8.28 (s, 1H), 8.39-8.45 (m, 1H), 8.47-8.51 (m, 1H), 8.95 (s, 1H), 12.98 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 465; Rt = 1.15 min (Method A). Similar to the synthesis method in step 5 of intermediate 1-1, from 6-amino-2- (3-methoxy-3- pendoxypropyl) -1-methyl-1H-benzimidazole-5- Methyl formate (intermediate 1-1 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00009
Figure TW201803866AD00010
Figure TW201803866AD00011
Figure TW201803866AD00012
Figure TW201803866AD00013
Figure TW201803866AD00014
Figure TW201803866AD00015
Figure TW201803866AD00016
Figure TW201803866AD00017
Figure TW201803866AD00018
Figure TW201803866AD00019
 Intermediate 1-131- methyl -2- [2- ( Mesylate ) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00020
step 1 4- ( Methylamino ) -3-{[3- ( Mesylate ) Propionyl ] Amine } Methyl benzoate At room temperature, in the presence of 7.9 ml (57 mmol) of triethylamine, in 75 ml of DMF, 6.85 g (38 mmol) of methyl 3-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 8.68 g (57 mmol) 3- (methylsulfonyl) propionic acid (CAS-RN 645-83-0) were reacted with 22 g (57 mmol) HATU for 1 hour. The reaction mixture was added to 400 g of ice and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The precipitated product was filtered off with suction to obtain 12.8 g of crude product that could be used further without further purification. UPLC-MS (ESI +): [M + H]+ = 315; Rt = 0.81 min (Method A).step 2 1- methyl -2- [2- ( Mesylate ) Ethyl ] -1H- Benzimidazole -5- Methyl formate From methyl 4- (methylamino) -3-{[3- (methylsulfonyl) propionyl] amino] amino} benzoate, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 297; Rt = 0.69 min (Method A).step 3 1- methyl -2- [2- ( Mesylate ) Ethyl ] -6- Nitro -1H- Benzimidazole -5- Methyl formate From 1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 342; Rt = 0.78 min (Method E).step 4 6- Amine -1- methyl -2- [2- ( Mesylate ) Ethyl ] -1H- Benzimidazole -5- Formic acid Methyl ester 10.3 g (30 mmol) 1-methyl-2- [2- (methylsulfonyl) ethyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester was dissolved in 310 ml of acetic acid. 1.6 g Pd / C (10%) was added and the mixture was hydrogenated under hydrogen atmosphere. After hydrogen absorption ceased (2.5 hours), the mixture was filtered and the filtrate was concentrated to dryness to give the title compound in quantitative yield.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 3.08 (s, 3H), 3.22-3.29 (m, 2H), 3.60 (s, 3H), 3.61-3.68 (m, 2H), 3.80 (s, 3H), 6.46 (sbr, 2H), 6.66 (s, 1H), 7.93 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 312; Rt = 0.56 min (Method E).step 5 1- methyl -2- [2- ( Mesylate ) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2- Formic acid (CAS-RN 131747-42-7), the preparation method is similar to step 5 of intermediate 1-1.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 3.11 (s, 3H), 3.36-3.40 (m, 2H), 3.69-3.75 (m, 2H), 3.81 (s, 3H), 3.95 (s, 3H), 8.21-8.25 ( m, 1H), 8.30 (s, 1H), 8.39-8.45 (m, 1H), 8.47-8.51 (m, 1H), 8.96 (s, 1H), 12.97 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 485; Rt = 1.08 min (Method E). Synthetic method similar to intermediate 1-13 step 5, from 6-amino-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester (Intermediate 1-13 Step 4) and its corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00021
Figure TW201803866AD00022
Figure TW201803866AD00023
Figure TW201803866AD00024
Figure TW201803866AD00025
 Intermediate 1-192- (2- Methoxyethyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00026
step 1 3-[(3- Methoxypropionyl ) Amine ] -4- ( Methylamino ) Methyl benzoate At room temperature, in the presence of 11 ml (83 mmol) of triethylamine, 10 g (55 mmol) of methyl 3-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 8.6 g (83 mmol) 3-methoxypropionic acid (CAS-RN 2544-06-1) were reacted with 31 g (83 mmol) HATU overnight. The formed precipitate was filtered off and washed with dichloromethane and the filtrate was concentrated to obtain 52 g of crude product that could be used further without further purification. UPLC-MS (ESI +): [M + H]+ = 267; Rt = 0.79 min (Method A).step 2 2- (2- Methoxyethyl )-1- methyl -1H- Benzimidazole -5- Methyl formate From 3-[(3-methoxypropionyl) amino] -4- (methylamino) benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 249; Rt = 0.64 min (Method E).step 3 2- (2- Methoxyethyl )-1- methyl -6- Nitro -1H- Benzimidazole -5- Formic acid Methyl ester From 2- (2-methoxyethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 294; Rt = 0.86 min (Method A).step 4 6- Amine -2- (2- Methoxyethyl )-1- methyl -1H- Benzimidazole -5- Methyl formate From 2- (2-methoxyethyl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-1.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 3.00-3.07 (m, 2H), 3.34 (s, 3H), 3.58 (s, 3H), 3.72-3.78 (m, 2H), 6.43 (sbr, 2H), 6.64 (s, 1H), 7.92 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 264; Rt = 0.56 min (Method E).step 5 2- (2- Methoxyethyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-2- (2-methoxyethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2-carboxylic acid, preparation method Similar to step 5 of intermediate 1-1.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 3.19-3.25 (m, 2H), 3.29 (s, 3H), 3.79-3.85 (m, 5H), 3.98 (s, 3H), 8.22-8.26 (m, 1H), 8.30 ( s, 1H), 8.39-8.45 (m, 1H), 8.47-8.51 (m, 1H), 8.99 (s, 1H), 12.98 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 437; Rt = 1.05 min (Method A). Similar to intermediate 1-1 step 5 synthesis method, from 6-amino-2- (2-methoxyethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (intermediate 1-19 Step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00027
Figure TW201803866AD00028
Figure TW201803866AD00029
Figure TW201803866AD00030
Figure TW201803866AD00031
Figure TW201803866AD00032
Figure TW201803866AD00033
Figure TW201803866AD00034
Figure TW201803866AD00035
 Intermediate 1-29 2- (3- Methoxypropyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00036
step 1 3-[(4- Methoxybutyroyl ) Amine ] -4- ( Methylamino ) Methyl benzoate At room temperature, in the presence of 9.8 ml (70 mmol) of triethylamine, 8.4 g (46 mmol) of methyl 3-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 7.7 g (65 mmol) 4-methoxybutyric acid (CAS-RN 29006-02-8) reacted with 26.6 g (70 mmol) HATU for 1 hour. The reaction mixture was concentrated and dissolved in 100 ml of dichloromethane. The methylene chloride solution was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate. Concentrate to obtain 26 g of crude product that can be used further without further purification. UPLC-MS (ESI +): [M + H]+ = 281; Rt = 0.83 min (Method E).step 2 2- (3- Methoxypropyl )-1- methyl -1H- Benzimidazole -5- Formic acid Methyl ester At 80 ° C, 13 g (46 mmol) of 3-[(4-methoxybutyryl) amino] -4- (methylamino) benzoic acid methyl ester (26 g of crude product from step 1) in 110 ml Stir in acetic acid for 4 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel to give 7.76 g (63%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 263; Rt = 0.65 min (Method E).step 3 2- (3- Methoxypropyl )-1- methyl -6- Nitro -1H- Benzimidazole -5- Formic acid Methyl ester From 2- (3-methoxypropyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 308; Rt = 0.91 min (Method A).step 4 6- Amine -2- (3- Methoxypropyl )-1- methyl -1H- Benzimidazole -5- Methyl formate From 2- (3-methoxypropyl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 278; Rt = 0.61 min (Method E).step 5 2- (3- Methoxypropyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-2- (3-methoxypropyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2-carboxylic acid, preparation method Similar to step 5 of intermediate 1-1.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.98-2.09 (m, 2H), 2.90-2.97 (m, 2H), 3.26 (s, 3H), 3.42-3.49 (m, 2H), 3.76 (s, 3H), 3.94 ( s, 3H), 8.22-8.26 (m, 1H), 8.28 (s, 1H), 8.39-8.44 (m, 1H), 8.46-8.51 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 451; Rt = 1.23 min (Method F). Similar to intermediate 1-1 step 5 synthesis method, from 6-amino-2- (3-methoxypropyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (intermediate 1-29 Step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00037
Figure TW201803866AD00038
Figure TW201803866AD00039
Figure TW201803866AD00040
Figure TW201803866AD00041
 Intermediate 1-35 1- methyl -2- [2- ( Morpholine -4- base ) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00042
step 1 4- ( Methylamino ) -3-{[3- ( Morpholine -4- base ) Propionyl ] Amine } Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and 3- (morpholin-4-yl) propionic acid hydrochloride (CAS-RN 6319-95 -5), the preparation method is similar to step 1 of intermediate 1-13. UPLC-MS (ESI +): [M + H]+ = 322; Rt = 0.82 min (Method F).step 2 1- methyl -2- [2- ( Morpholine -4- base ) Ethyl ] -1H- Benzimidazole -5- Methyl formate From 4- (methylamino) -3-{[3- (morpholin-4-yl) propionyl] amino] amino} benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 304; Rt = 0.82 min (Method F).step 3 6- Amine -1- methyl -2- [2- ( Morpholine -4- base ) Ethyl ] -1H- Benzimidazole -5- Methyl formate Dissolve 3.7 g of 1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester (12 mmol) in 27 ml of concentrated acid and slowly Add 3.4 ml of a mixture of concentrated nitric acid and concentrated sulfuric acid (1: 1.4). After the end of the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to 300 g of ice and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted three times with 500 ml ethyl acetate. The combined organic phase was dried over magnesium sulfate and concentrated. This procedure gave 3.4 g (80%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 349; Rt = 0.86 min (Method F).step 4 6- Amine -1- methyl -2- [2- ( Morpholine -4- base ) Ethyl ] -1H- Benzimidazole -5- Methyl formate 3.14 g (9 mmol) of 6-amino-1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester was dissolved in 31 ml of ethanol And 6.3 ml water. 64 mg of ammonium chloride and 1.34 g (24 mmol) of iron powder were added and the mixture was stirred at 90 ° C for 5 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. This process yielded 2.81 g (97%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 319; Rt = 0.74 min (Method F).step 5 1- methyl -2- [2- ( Morpholine -4- base ) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate At room temperature, in the presence of 183 µl (1.32 mmol) of triethylamine, 0.4 g (0.88 mmol) of 6-amino-1-methyl-2- [2- (morpholine- 4-yl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 252 mg (1.32 mmol) 6- (trifluoromethyl) pyridine-2-carboxylic acid were reacted with 500 mg (1.32 mmol) HATU overnight. The reaction mixture was purified by preparative HPLC to obtain 243 mg (56%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.77-2.84 (m, 2H), 3.06-3.12 (m, 2H), 3.55-3.62 (m, 4H), 3.79 (s, 3H), 3.94 (s, 3H), 8.20- 8.24 (m, 1H), 8.27 (s, 1H), 8.38-8.44 (m, 1H), 8.46-8.50 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 492; Rt = 1.15 min (Method F). Synthetic method similar to intermediate 1-35 step 5, from 6-amino-1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazole-5-carboxylic acid The methyl ester (intermediate 1-35 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00043
Figure TW201803866AD00044
Figure TW201803866AD00045
Figure TW201803866AD00046
Figure TW201803866AD00047
 Intermediate 1-411- methyl -2-( Morpholine -4- Methyl ) -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00048
step 1 4- ( Methylamino ) -3-[( Morpholine -4- Acetyl acetyl ) Amine ] Methyl benzoate From methyl-3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and morpholin-4-ylacetic acid (CAS-RN 3235-69-6) Similar to step 1 of intermediate 1-13. UPLC-MS (ESI +): [M + H]+ = 308; Rt = 0.85 min (Method F).step 2 1- methyl -2-( Morpholine -4- Methyl ) -1H- Benzimidazole -5- Methyl formate From methyl-4- (methylamino) -3-[(morpholin-4-ylacetyl) amino] benzoate, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 290; Rt = 0.88 min (Method F).step 3 1- methyl -2-( Morpholine -4- Methyl ) -6- Nitro -1H- Benzimidazole -5- Methyl formate From 1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 335; Rt = 0.91 min (Method F).step 4 6- Amine -1- methyl -2-( Morpholine -4- Methyl ) -1H- Benzimidazole -5- Methyl formate From 1-methyl-2- (morpholin-4-ylmethyl) -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-35. UPLC-MS (ESI +): [M + H]+ = 305; Rt = 0.78 min (Method F).step 5 1- methyl -2-( Morpholine -4- Methyl ) -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2-carboxylic acid, The preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.42-2.49 (m, 4H), 3.54-3.61 (m, 4H), 3.82 (s, 2H), 3.89 (s, 3H), 3.95 (s, 3H), 8.22-8.26 ( m, 1H), 8.32 (s, 1H), 8.39-8.45 (m, 1H), 8.47-8.51 (m, 1H), 8.98 (s, 1H), 12.99 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 478; Rt = 1.22 min (Method F). Similar to the synthesis method in step 5 of intermediate 1-35, from 6-amino-1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester (middle The following intermediates are prepared in steps 1-41 and corresponding carboxylic acids (row 1).
Figure TW201803866AD00049
Figure TW201803866AD00050
Figure TW201803866AD00051
Figure TW201803866AD00052
Figure TW201803866AD00053
Figure TW201803866AD00054
Figure TW201803866AD00055
 Intermediate 1-491- methyl -2- [2- (4- Methylpiperazine -1- base ) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00056
step 1 4- ( Methylamino ) -3-{[3- (4- (4- Methylpiperazine -1- base ) Propionyl ] Amine } Methyl benzoate At room temperature, in the presence of 4 ml (29 mmol) triethylamine, 3.49 g (19 mmol) methyl 3-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 5 g (29 mmol) 3- (4-methylpiperazin-1-yl) propionic acid (CAS-RN 55480-45-0) reacted with 11 g (29 mmol) HATU overnight . The mixture was concentrated and dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This process yielded 14.6 g of residue that could be used further without further purification. UPLC-MS (ESI +): [M + H]+ = 335; Rt = 0.81 min (Method F).step 2 1- methyl -2- [2- (4- Methylpiperazine -1- base ) Ethyl ] -1H- Benzimidazole -5- Methyl formate From 4- (methylamino) -3-{[3- (4-methylpiperazin-1-yl) propionyl] amino] amino} benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1 . UPLC-MS (ESI +): [M + H]+ = 317; Rt = 0.80 min (Method F).step 3 1- methyl -2- [2- (4- Methylpiperazine -1- base ) Ethyl ] -6- Nitro -1H- Benzimidazole -5- Methyl formate From 1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-35 . UPLC-MS (ESI +): [M + H]+ = 362; Rt = 0.83 min (Method F).step 4 6- Amine -1- methyl -2- [2- (4- Methylpiperazine -1- base ) Ethyl ] -1H- Benzimidazole -5- Methyl formate From 1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to intermediate 1 -Step 4 of 35. UPLC-MS (ESI +): [M + H]+ = 332; Rt = 0.73 min (Method F).step 5 1- methyl -2- [2- (4- Methylpiperazine -1-yl) Ethyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl Group) pyridine-2-carboxylic acid, the preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.16 (s, 3H), 2.76-2.82 (m, 2H), 3.02-3.09 (m, 2H), 3.77 (s, 3H), 3.94 (s, 3H), 8.19-8.24 ( m, 1H), 8.26 (s, 1H), 8.37-8.43 (m, 1H), 8.44-8.50 (m, 1H), 8.92 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 505; Rt = 1.11 min (method F). Synthetic method similar to intermediate 1-35 step 5, from 6-amino-1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazole The following intermediates were prepared from methyl-5-carboxylate (Intermediate 1-49, Step 4) and the corresponding carboxylic acid (row 1).
Figure TW201803866AD00057
Figure TW201803866AD00058
Figure TW201803866AD00059
Figure TW201803866AD00060
Figure TW201803866AD00061
 Intermediate 1-551- methyl -2- [3- ( Morpholine -4- base ) Propyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00062
step 1 4- ( Methylamino ) -3-{[4- ( Morpholine -4- base ) Ding Yanji ] Amine } Methyl benzoate At room temperature, in the presence of 7.5 ml (53 mmol) triethylamine, 2.75 g (15 mmol) methyl 4-amino-4- (methylamino) benzoate (CAS- RN 66315-16-0) and 4.8 g (23 mmol) 4- (morpholin-4-yl) butyrate hydrochloride (CAS-RN 39493-84-0) were reacted with 8.7 g (23 mmol) HATU overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This procedure gave 4.5 g (87%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 336; Rt = 0.81 min (Method F).step 2 1- methyl -2- [3- ( Morpholine -4- base ) Propyl ] -1H- Benzimidazole -5- Methyl formate From 4- (methylamino) -3-{[4- (morpholin-4-yl) butyryl] amino] amino} benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 318; Rt = 0.85 min (Method F).step 3 1- methyl -2- [3- ( Morpholine -4- base ) Propyl ] -6- Nitro -1H- Benzimidazole -5- Methyl formate Dissolve 4.4 g (14 mmol) 1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazole-5-carboxylic acid methyl ester in 44 ml of concentrated sulfuric acid and add 2.1 g (21 mmol) potassium nitrate. After 30 min, the mixture was added to ice, sodium bicarbonate was added to saturation, the mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate and concentrated. This procedure gave 3.57 g (71%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 363; Rt = 0.88 min (Method F).step 4 6- Amine -1- methyl -2- [3- ( Morpholine -4- base ) Propyl ] -1H- Benzimidazole -5- Methyl formate Dissolve 3.5 g (9.6 mmol) 1-methyl-2- [3- (morpholin-4-yl) propyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester in 35 ml ethanol And 7 ml of water. 69 mg (1.2 mmol) ammonium chloride and 1.4 g (26 mmol) iron powder were added and the mixture was stirred at 70 ° C for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography. This process gave 0.73 g (23%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 333; Rt = 0.77 min (Method F).step 5 1- methyl -2- [3- ( Morpholine -4- base ) Propyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine- 2-Formic acid, the preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.91-2.01 (m, 2H), 2.30-2.36 (m, 4H), 2.36-2.43 (m, 2H), 2.89-2.95 (m, 2H), 3.47-3.54 (m, 4H) ), 3.78 (s, 3H), 3.94 (s, 3H), 8.21-8.25 (m, 1H), 8.27 (s, 1H), 8.38-8.45 (m, 1H), 8.46-8.51 (m, 1H), 8.94 (s, 1H), 12.98 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 506; Rt = 1.18 min (Method F). Synthetic method similar to intermediate 1-35 step 5, from 6-amino 1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazole-5-carboxylic acid methyl The ester (intermediate 1-45 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00063
Figure TW201803866AD00064
Figure TW201803866AD00065
Figure TW201803866AD00066
 Intermediate 1-602- [3- ( Dimethylamino ) Propyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00067
step 1 3-{[4- ( Dimethylamino ) Ding Yanji ] Amine } -4- ( Methylamino ) Methyl benzoate From methyl-3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and 4- (dimethylamino) butyric acid hydrochloride (CAS-RN 69954-66- 1), the preparation method is similar to step 1 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 294; Rt = 0.86 min (Method F).step 2 2- [3- ( Dimethylamino ) Propyl ]-1- methyl -1H- Benzimidazole -5- Methyl formate From 3-{[4- (dimethylamino) butanoyl] amino} -4- (methylamino) benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 276; Rt = 0.90 min (Method F).step 3 2- [3- ( Dimethylamino ) Propyl ]-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate From 2- [3- (dimethylamino) propyl] -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 321; Rt = 0.93 min (Method F).step 4 6- Amine -2- [3- ( Dimethylamino ) Propyl ]-1- methyl -1H- Benzimidazole -5- Methyl formate 1.76 g (5.5 mmol) of 2- [3- (dimethylamino) propyl] -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester was dissolved in 18 ml of methanol, 7.3 g (38 mmol) of tin (II) chloride was added and the mixture was stirred at 70 ° C for 1 hour. After cooling, 50 ml of water was added and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was filtered and the filtrate was concentrated to dryness. Treat the residue with 300 ml of ethanol and filter it off. The filtrate was concentrated to obtain 1.11 g (69%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 291; Rt = 0.81 min (Method F).step 5 2- [3- ( Dimethylamino ) Propyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-2- [3- (dimethylamino) propyl] -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2- Formic acid, the preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.89-1.97 (m, 2H), 2.15 (s, 6H), 2.31-2.37 (m, 2H), 2.88-2.93 (m, 2H), 3.77 (s, 3H), 3.94 ( s, 3H), 8.21-8.24 (m, 1H), 8.28 (s, 1H), 8.39-8.44 (m, 1H), 8.46-8.50 (m, 1H), 8.93 (s, 1H), 12.97 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 464; Rt = 1.22 min (Method F). Synthetic method similar to intermediate 1-35 step 5, from 6-amino-2- [3- (dimethylamino) propyl] -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (Intermediate 1-60 Step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00068
Figure TW201803866AD00069
Figure TW201803866AD00070
Figure TW201803866AD00071
 Intermediate 1-65 (±) 2-[(1,1- Dioxotetrahydrothiophene -3- base ) methyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00072
step 1 (±) 3-{[(1,1- Dioxotetrahydrothiophene -3- base ) Acetyl ] Amine } -4- ( Methylamino ) Methyl benzoate At room temperature, in the presence of 3.5 ml (25 mmol) of triethylamine, 3 g (16 mmol) of 3-amino-4- (methylamino) benzoic acid methyl ester (CAS- RN 66315-16-0) and 4.45 g (25 mmol) (±) (1,1-dioxotetrahydrothiophen-3-yl) acetic acid (CAS-RN 4785-66-4) and 9.5 g (25 mmol ) HATU reaction for 1 hour. The reaction mixture was concentrated and dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. This process yielded 7.8 g of crude product that was used in the next step without further purification. UPLC-MS (ESI +): [M + H]+ = 340; Rt = 0.76 min (Method E).step 2 (±) 2-[(1,1- Dioxotetrahydrothiophene -3- base ) methyl ]-1- methyl -1H- Benzimidazole -5- Methyl formate At 50 ° C, 5.6 g (17 mmol) (±) 3-{[(1,1-dioxotetrahydrothiophen-3-yl) ethynyl] amino} -4- (methylamino) Methyl benzoate (7.8 g of crude product from step 1) was stirred in 100 ml of acetic acid overnight. The reaction mixture was concentrated and the residue was purified by chromatography. This process yielded 4.56 g (85%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 323; Rt = 0.69 min (Method E).step 3 (±) 2-[(1,1- Dioxotetrahydrothiophene -3- base ) methyl ]-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate Dissolve 4.5 g (14 mmol) (±) 2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester Add 31 g (21 mmol) of potassium nitrate to 31 ml of concentrated sulfuric acid. The mixture was stirred overnight and poured into ice and saturated sodium bicarbonate solution was added until a pH of 10 was reached. Suction filtration gave 4.92 g (95%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 368; Rt = 0.81 min (Method E).step 4 (±) 6- Amine -2-[(1,1- Dioxotetrahydrothiophene -3- base ) methyl ]-1- methyl -1H- Benzimidazole -5- Methyl formate From (±) 2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, preparation method Similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 338; Rt = 0.56 min (Method E).step 5 (±) 2-[(1,1- Dioxotetrahydrothiophene -3- base ) methyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From (±) 6-amino-2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6 -(Trifluoromethyl) pyridine-2-carboxylic acid, the preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.90-2.02 (m, 1H), 2.34-2.44 (m, 1H), 2.91-3.17 (m, 5H), 3.22-3.30 (m, 1H), 3.40-3.46 (m, 1H) ), 3.77 (s, 3H), 3.94 (s, 3H), 8.21-8.25 (m, 1H), 8.32 (s, 1H), 8.39-8.44 (m, 1H), 8.46-8.51 (m, 1H), 8.95 (s, 1H), 12.98 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 511; Rt = 1.09 min (Method E). Similar to the synthesis method in step 5 of intermediate 1-35, from (±) 6-amino-2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -1-methyl- 1H-Benzimidazole-5-carboxylic acid methyl ester (intermediate 1-65 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00073
Figure TW201803866AD00074
Figure TW201803866AD00075
Figure TW201803866AD00076
 Intermediate 1-701- methyl -2-[(1- Methyl azetidine -3- base ) methyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00077
step 1 3- (2-{[5- ( Methoxycarbonyl )-2-( Methylamino ) Phenyl ] Amine }-2- Pendant oxyethyl ) Azetidine -1- Tert-butyl formate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and [1- (third butoxycarbonyl) azetidine-3-yl] acetic acid (CAS- RN 183062-96-6), the preparation method is similar to step 1 of intermediate 1-55. UPLC-MS (ESI-): [M-H]- = 376; Rt = 1.06 min (Method F).step 2 2-{[1- ( Third butoxycarbonyl ) Azetidine -3- base ] methyl }-1- methyl -1H- Benzimidazole -5- Methyl formate From 3- (2-{[5- (methoxycarbonyl) -2- (methylamino) phenyl] amino] -2-oxoethyl) azetidine-1-carboxylic acid tert-butyl ester, preparation method Similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 360; Rt = 1.11 min (method F).step 3 2-( Azetidine -3- Methyl )-1- methyl -1H- Benzimidazole -5- Methyl formate Dissolve 9.92 g (28 mmol) of 2- (aziridine-3-ylmethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester in 200 ml of dichloromethane and add 16 ml ( 207 mmol) trifluoroacetic acid. After stirring at room temperature overnight, the mixture was poured into ice and the pH was adjusted to 10 by adding saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate and the organic phase was dried and concentrated to give 5.1 g (72%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 260; Rt = 0.82 min (Method F).step 4 1- methyl -2-[(1- Methyl azetidine -3- base ) methyl ] -1H- Benzimidazole -5- Methyl formate 2.5 ml of formaldehyde solution (12 mol / l in water) was added to 5.1 g (20 mmol) 2- (acridin-3-ylmethyl) -1-methyl-1H in 55 ml of methanol -Methyl benzimidazole-5-carboxylate and the mixture was stirred for 15 min. The solution was cooled to 5 ° C and 3.77 g (100 mmol) sodium borohydride was added in steps. 45 minutes after the end of the addition, the reaction mixture was concentrated to dryness. The crude product was used in the next step without further purification. UPLC-MS (ESI +): [M + H]+ = 274; Rt = 0.85 min (Method F).step 5 1- methyl -2-[(1- Methyl azetidine -3- base ) methyl ] -6- Nitro -1H- Benzimidazole -5- Methyl formate From 1-methyl-2-[(1-methylazetidin-3-yl) methyl] -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-35. UPLC-MS (ESI +): [M + H]+ = 319; Rt = 0.87 min (Method B).step 6 6- Amine -1- methyl -2-[(1- Methyl azetidine -3- base ) methyl ] -1H- Benzimidazole -5- Methyl formate From 1-methyl-2-[(1-methylazetin-3-yl) methyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to intermediate 1- Step 4 of 35. UPLC-MS (ESI +): [M + H]+ = 289; Rt = 0.85 min (Method F).step 7 1- methyl -2-[(1- Methyl azetidine -3- base ) methyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2-[(1-methylazetidin-3-yl) methyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl ) Pyridine-2-carboxylic acid, the preparation method is similar to step 5 of intermediate 1-35.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 2.22 (s, 3H), 2.83-2.97 (m, 3H), 3.14-3.18 (m, 2H), 3.76 (s, 3H), 3.93 (s, 3H), 8.20-8.24 ( m, 1H), 8.27 (s, 1H), 8.38-8.44 (m, 1H), 8.45-8.50 (m, 1H), 8.92 (s, 1H), 12.96 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 462; Rt = 1.19 min (method F). Similar to the synthesis method in step 5 of intermediate 1-35, from 6-amino-1-methyl-2-[(1-methylazetidin-3-yl) methyl] -1H-benzimidazole- The following intermediates were prepared with methyl 5-formate (intermediate 1-70 step 6) and the corresponding carboxylic acid (row 1).
Figure TW201803866AD00078
Figure TW201803866AD00079
Figure TW201803866AD00080
Figure TW201803866AD00081
 Intermediate 1-75(±) 2- (1,1- Dioxotetrahydro -2H- Thiran -3- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00082
step 1 (±) 3-{[(1,1- Dioxotetrahydro -2H- Thiran -3- base ) Carbonyl ] Amine } -4- ( Methylamino ) Methyl benzoate In the presence of 0.5 ml (53.6 mmol) triethylamine, in 8 ml DMF, 0.59 g (3.3 mmol) methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16 -0) and 0.65 g (3.6 mmol) (±) tetrahydro-2H-thiopyran-3-carboxylic acid 1,1-dioxide (CAS-RN 167011-35-0) stirred with 1.4 g (3.6 mmol) HATU 1 hour. The reaction mixture was concentrated and the residue was treated with 50 ml of water, resulting in precipitation of the product. The precipitate was filtered off to obtain 1.3 g of crude product. UPLC-MS (ESI +): [M + H]+ = 341; Rt = 0.78 min (Method E).step 2 (±) 2- (1,1- Dioxotetrahydro -2H- Thiran -3- base )-1- methyl -1H- Benzimidazole -5- Methyl formate At 50 ° C, 1.1 g (3.3 mmol) (±) 3-{[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) carbonyl] amino} -4- (methylamine Methyl) benzoate (1.3 g of crude product from step 1) was stirred in 20 ml of acetic acid overnight. The reaction mixture was concentrated and the residue was purified by chromatography. This process yielded 793 mg (74%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 322; Rt = 0.80 min (Method B).step 3 (±) 2- (1,1- Dioxotetrahydro -2H- Thiran -3- base )-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate Dissolve 1.1 g (3.4 mmol) (±) 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester In 7 ml of concentrated sulfuric acid, add 525 mg (5.2 mmol) potassium nitrate. The mixture was stirred at room temperature for 3 hours and poured into ice, and saturated sodium bicarbonate solution was added until a pH of 10 was reached. The mixture was filtered with suction to obtain 909 mg of product, and the filtrate was extracted three times with 50 ml of dichloromethane and concentrated to obtain another 148 mg of the title compound. A total of 1.05 g (86%) of the title compound was obtained. UPLC-MS (ESI +): [M + H]+ = 368; Rt = 0.83 min (Method E).step 4 (±) 6- Amine -2- (1,1- Dioxotetrahydro -2H- Thiran -3- base )-1- methyl -1H- Benzimidazole -5- Methyl formate Under a hydrogen atmosphere, at room temperature, 1.05 g (2.9 mmol) (±) 2- (1,1-dioxotetrahydro-2H-thiran in a mixture of 11 ml methanol and 32 ml THF -3-yl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester was stirred with 0.5 g of 10% palladium on carbon for 3 hours. The mixture was filtered, and after the filtrate was concentrated, 897 mg (92%) of the title compound was obtained. UPLC-MS (ESI +): [M + H]+ = 338; Rt = 0.65 min (Method E).step 5 (±) 2- (1,1- Dioxotetrahydro -2H- Thiran -3- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate At room temperature, in the presence of 93 µl (0.66 mmol) triethylamine, in 0.15 g (0.44 mmol) (±) 6-amino-2- (1,1-dioxotetrazole) in 3 ml DMF Hydrogen-2H-thiopyran-3-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 127 mg (0.66 mmol) 6- (trifluoromethyl) pyridine-2-carboxylic acid mg (0.66 mmol) HATU reaction overnight. 30 ml of water was added and the mixture was stirred for 15 min. The precipitated solid was filtered off, washed with 10 ml water and 10 ml hexane and dried. This process yielded 198 mg (87%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.73-1.85 (m, 1H), 2.00-2.20 (m, 3H), 3.09-3.18 (m, 1H), 3.38-3.45 (m, 1H), 3.50-3.58 (m, 1H) ), 3.62-3.72 (m, 1H), 3.83 (s, 3H), 3.95 (s, 3H), 8.21-8.26 (m, 1H), 8.31 (s, 1H), 8.38-8.45 (m, 1H), 8.47-8.51 (m, 1H), 8.97 (s, 1H), 12.97 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 511; Rt = 1.13 min (Method E). Synthetic method similar to intermediate 1-75 step 5, from (±) 6-amino-2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -1-methyl- 1H-Benzimidazole-5-carboxylic acid methyl ester (intermediate 1-75 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00083
Figure TW201803866AD00084
Figure TW201803866AD00085
 Intermediate 1-79(±) 1- methyl -2-( Tetrahydrofuran -3- Methyl ) -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00086
step 1 (±) 4- ( Methylamino ) -3-[( Tetrahydrofuran -3- Acetyl acetyl ) Amine ] Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and (±) tetrahydrofuran-3-ylacetic acid (CAS-RN 138498-97-2), the preparation method is similar In step 1 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 293; Rt = 0.89 min. (Method F)step 2 (±) 1- methyl -2-( Tetrahydrofuran -3- Methyl ) -1H- Benzimidazole -5- Methyl formate From (±) 4- (methylamino) -3-[(tetrahydrofuran-3-ylacetyl) amino] benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 275; Rt = 0.90 min. (Method F)step 3 (±) 1- methyl -6- Nitro -2-( Tetrahydrofuran -3- Methyl ) -1H- Benzimidazole -5- Methyl formate From (±) 1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 320; Rt = 0.90 min. (Method F)step 4 (±) 6- Amine -1- methyl -2-( Tetrahydrofuran -3- Methyl ) -1H- Benzimidazole -5- Methyl formate From (±) 1-methyl-6-nitro-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-35. UPLC-MS (ESI +): [M + H]+ = 290; Rt = 0.81 min. (Method F)step 5 (±) 1- methyl -2-( Tetrahydrofuran -3- Methyl ) -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From (±) 6-amino-1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 5 of intermediate 1-35 .1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 2.089 (0.65), 2.515 (0.91), 2.518 (0.84), 2.522 (0.65), 2.794 (0.74), 2.979 (1.75), 2.989 (1.86), 2.994 (1.73), 3.004 (1.45), 3.433 (1.21), 3.445 (1.21), 3.449 (1.32), 3.462 (1.26), 3.674 (1.21), 3.690 (1.47), 3.705 (0.78), 3.770 (14.72), 3.782 (0.78), 3.792 (0.78), 3.798 (1.17), 3.809 (1.17), 3.877 (1.30), 3.891 (1.45), 3.894 (1.43), 3.908 (1.26), 3.937 (16.00), 8.212 (1.56), 8.214 (1.62), 8.227 (1.82), 8.229 (1.82), 8.287 (5.72), 8.393 (0.84), 8.408 (1.75), 8.424 (1.06), 8.469 (1.93), 8.485 (1.19), 8.928 (5.20), 12.966 (2.64). Synthetic method similar to intermediate 1-35 step 5, from (±) 6-amino-1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester (Intermediate 1-79 Step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00087
Figure TW201803866AD00088
Figure TW201803866AD00089
Figure TW201803866AD00090
 Intermediate 1-84(±) 2-[(1,1- Dioxotetrahydro -2H- Thiran -3- base ) methyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00091
step 1 (±) 3-({[1,1- Dioxotetrahydro -2H- Thiran -3- base ] Acetyl } Amine ) -4- ( Methylamino ) Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and (±) (1,1-dioxotetrahydro-2H-thiopyran-3-yl ) Acetic acid, the preparation method is similar to step 1 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 355; Rt = 0.77 min (Method E).step 2 (±) 2-{-1,1- Dioxotetrahydro -2H- Thiran -3- base ] methyl }-1- methyl -1H- Benzimidazole -5- Methyl formate At room temperature, 1.7 g (4.8 mmol) (±) 3-({[1,1-dioxotetrahydro-2H-thiopyran-3-yl] acetyl) contained in 28 ml of acetic acid Amino) -4- (methylamino) benzoic acid methyl ester was stirred for 36 hours and then overnight at 50 ° C. The mixture was concentrated and dichloromethane was added to the residue, resulting in precipitation of a solid. The obtained mother liquor was purified by chromatography and the product fraction was combined with the solid. This process yielded 1.48 g (90%) of the title compound. UPLC-MS (ESI +): [M + H]+ = 337; Rt = 0.69 min (Method E).step 3 (±) 2-[(1,1- Dioxotetrahydro -2H- Thiran -3- base ) methyl ]-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate From (±) 2-{-1,1-dioxotetrahydro-2H-thiopyran-3-yl] methyl} -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar In step 3 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 381; Rt = 0.83 min (Method E).step 4 (±) 6- Amine -2-[(1,1- Dioxotetrahydro -2H- Thiran -3- base ) methyl ]-1- methyl -1H- Benzimidazole -5- Methyl formate From (±) 2-[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) methyl] -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid Methyl ester, the preparation method is similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 352; Rt = 0.56 min (Method A)step 5 (±) 2-[(1,1- Dioxotetrahydro -2H- Thiran -3- base ) methyl ]-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From (±) 6-amino-1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2- Formic acid, the preparation method is similar to step 5 of intermediate 1-1.1 H NMR (400 MHz, DMSO-d6 ) δ [ppm]: 1.230 (1.15), 1.352 (1.26), 1.829 (0.79), 2.074 (2.32), 2.332 (1.12), 2.518 (6.20), 2.523 (4.26), 2.673 (1.15), 2.686 (0.71) , 2.727 (2.08), 2.888 (2.43), 2.987 (2.38), 3.005 (2.05), 3.036 (1.26), 3.051 (1.20), 3.061 (1.53), 3.095 (1.20), 3.126 (0.90), 3.267 (0.93) , 3.766 (0.85), 3.784 (13.27), 3.937 (0.74), 3.946 (16.00), 8.221 (1.64), 8.224 (1.67), 8.241 (1.97), 8.243 (1.91), 8.332 (5.79), 8.398 (0.82) , 8.418 (1.83), 8.438 (1.12), 8.482 (1.94), 8.500 (1.09), 8.965 (4.97), 12.983 (2.70). UPLC-MS (ESI +): [M + H]+ = 525; Rt = 1.10 min (Method E). Synthetic method similar to step 5 of intermediate 1-35, from (±) 6-amino-2-[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) methyl] -1 -Methyl-1H-benzimidazole-5-carboxylic acid methyl ester (intermediate 1-84 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00092
Figure TW201803866AD00093
Figure TW201803866AD00094
 Intermediate 1-882- (1,1- Dioxotetrahydro -2H- Thiran -4- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00095
step 1 3-{[(1,1- Dioxotetrahydro -2H- Thiran -4- base ) Carbonyl ] Amine } -4- ( Methylamino ) Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (CAS-RN 64096-87-3), the preparation method is similar to step 1 of intermediate 1-55. UPLC-MS (ESI +): [M + H]+ = 341; Rt = 0.76 min (Method E).step 2 2- (1,1- Dioxotetrahydro -2H- Thiran -4- base )-1- methyl -1H- Benzimidazole -5- Methyl formate At 80 ° C, 9 g (26 mmol) 3-{[(1,1-dioxotetrahydro-2H-thiopyran-4-yl) carbonyl] amino] -4 contained in 156 ml of acetic acid -Methyl (methylamino) benzoate was stirred for 4 hours. The mixture was concentrated and dichloromethane was added to the residue, causing precipitation of solids. The solid obtained is filtered off with suction. This process yielded the title compound in quantitative yield. UPLC-MS (ESI +): [M + H]+ = 323; Rt = 0.71 min (Method E).step 3 2- (1,1- Dioxotetrahydro -2H- Thiran -4- base )-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate From 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to that of intermediate 1-55 Step 3. UPLC-MS (ESI +): [M + H]+ = 368; Rt = 0.82 min (Method E).step 4 6- Amine -2- (1,1- Dioxotetrahydro -2H- Thiran -4- base )-1- methyl -1H- Benzimidazole -5- Formic acid Methyl ester From 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to the middle Step 4 of Body 1-1. UPLC-MS (ESI +): [M + H]+ = 338; Rt = 0.58 min (Method E).step 5 2- (1,1- Dioxotetrahydro -2H- Thiran -4- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (tri Fluoromethyl) pyridine-2-carboxylic acid, the preparation method is similar to step 5 of intermediate 1-1.1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.352 (1.16), 2.264 (0.89), 2.290 (1.53), 2.300 (1.63), 2.322 (2.87), 2.326 (2.52), 2.331 (1.79), 2.518 (4.59), 2.522 (3.09), 2.664 (0.78), 2.668 (1.06), 2.673 (0.75), 2.686 (1.09), 2.727 (2.26), 2.888 (2.78), 3.256 (0.92), 3.288 (1.63), 3.321 (1.08), 3.333 (1.23), 3.359 (1.41), 3.395 (1.04), 3.509 (0.97), 3.523 (0.87), 3.534 (1.04), 3.544 (0.78), 3.836 (14.18), 3.881 (1.37), 3.949 (16.00), 4.002 (1.15), 8.222 (1.88), 8.225 (1.93), 8.242 (2.26), 8.244 (2.26), 8.332 (6.34), 8.399 (1.06), 8.418 (2.15), 8.438 (1.29), 8.480 (2.33), 8.499 (1.30), 8.983 (5.58), 12.983 (3.27). UPLC-MS (ESI +): [M + H]+ = 511; Rt = 1.12 min (Method F) Similar to intermediate 1-35, Step 5, from 6-amino-2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1 -Methyl-1H-benzimidazole-5-carboxylic acid methyl ester (intermediate 1-88 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00096
Figure TW201803866AD00097
Figure TW201803866AD00098
Figure TW201803866AD00099
 Intermediate 1-932-( Methoxymethyl )-1- methyl -6-({[6- ( Trifluoromethyl l) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00100
step 1 3-[( Methoxyacetyl ) Amine ] -4- ( Methylamino ) Methyl benzoate 3 g (16.6 mmol) 3-amino-4- (methylamino) benzoic acid methyl ester (CAS-RN 66315-16-0), 1.65 g (18 mmol) methoxy group contained in 2.5 ml DMF Acetic acid (CAS-RN 625-45-6), 2.56 ml triethylamine and 7 g (18 mmol) HATU were stirred for one hour. The reaction solution is then concentrated and used in the next step without further purification. UPLC-MS (ESI +): [M + H]+ = 253; Rt = 0.78 min (Method E)step 2 2-( Methoxymethyl )-1- methyl -1H- Benzimidazole -5- Formic acid Methyl ester At 80 ° C, 4.2 g (16 mmol) of methyl 3-[(methoxyethoxy) amino] -4- (methylamino) benzoate in 100 ml of acetic acid was stirred overnight. The mixture was concentrated and the residue was purified by chromatography. This process yielded the title compound in quantitative yield. UPLC-MS (ESI +): [M + H]+ = 235; Rt = 0.83 min (Method F).step 3 2-( Methoxymethyl )-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate From 2- (methoxymethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 280; Rt = 0.87 min (Method F).step 4 6- Amine -2-( Methoxymethyl )-1- methyl -1H- Benzimidazole -5- Methyl formate From 2- (methoxymethyl) -1-methyl-6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 250; Rt = 0.58 min (Method E).step 5 2-( Methoxymethyl )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-2- (methoxymethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2-carboxylic acid, the preparation method is similar to the intermediate Step 5 of Body 1-1.1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (1.61), 2.522 (1.04), 2.727 (1.83), 2.888 (2.31), 3.385 (16.00), 3.855 (11.86), 3.959 (12.59), 4.789 (5.95), 8.226 (1.27), 8.228 (1.34), 8.245 (1.54), 8.247 (1.56), 8.362 (4.53), 8.400 (0.69), 8.420 (1.51), 8.440 (0.95), 8.480 (1.73), 8.499 (0.95), 9.038 (4.04), 12.994 (2.17). UPLC-MS (ESI +): [M + H]+ = 423; Rt = 1.19 min (method F). Synthetic method similar to intermediate 1-35 step 5, from methyl 6-amino-2- (methoxymethyl) -1-methyl-1H-benzimidazole-5-carboxylic acid (intermediate 1-93 Step 4) and the corresponding carboxylic acid prepare the following intermediates.
Figure TW201803866AD00101
Figure TW201803866AD00102
Figure TW201803866AD00103
Figure TW201803866AD00104
 Intermediate 1-981- methyl -2-[( Mesylate ) methyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00105
step 1 4- ( Methylamino ) -3-{[( Mesylate ) Acetyl ] Amine } Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and (methylsulfonyl) acetic acid (CAS-RN 2516-97-4), the preparation method is similar to the intermediate Step 1 of Body 1-93. UPLC-MS (ESI +): [M + H]+ = 301; Rt = 0.75 min (Method E).step 2 1- methyl -2-[( Mesylate ) methyl ] -1H- Benzimidazole -5- Formic acid Methyl ester From 4- (methylamino) -3-{[((methylsulfonyl) ethoxy] amino] amino} benzoic acid methyl ester, the preparation method is similar to step 2 of intermediate 1-93. UPLC-MS (ESI +): [M + H]+ = 283; Rt = 0.78 min (Method F)step 3 1- methyl -2-[( Mesylate ) methyl ] -6- Nitro -1H- Benzimidazole -5- Methyl formate From 1-methyl-2-[(methylsulfonyl) methyl] -1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 3 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 328; Rt = 0.80 min (Method F).step 4 6- Amine -1- methyl -2-[( Mesylate ) methyl ] -1H- Benzimidazole -5- Methyl formate From 1-methyl-2-[(methylsulfonyl) methyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 298; Rt = 0.65 min (Method E).step 5 1- methyl -2-[( Mesylate ) methyl ] -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate From 6-amino-1-methyl-2-[(methylsulfonyl) methyl] -1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoromethyl) pyridine-2-carboxylic acid, The preparation method is similar to Step 5 of Intermediate 1-1.1 H NMR (400 MHz, DMSO-d6 ) δ [ppm]: 2.518 (4.19), 2.523 (2.97), 3.173 (12.06), 3.894 (16.00), 4.046 (13.22), 5.121 (4.86), 8.028 (3.09), 8.031 (3.18), 8.182 (3.71) , 8.186 (3.52), 8.218 (1.54), 8.222 (1.66), 8.237 (1.87), 8.240 (1.98), 8.375 (0.72), 8.394 (1.86), 8.413 (1.56), 8.424 (2.07), 8.427 (2.30) , 8.444 (0.85), 10.915 (2.60). UPLC-MS (ESI +): [M + H]+ = 471; Rt = 1.11 min (method F). Similar to the synthesis method in step 5 of intermediate 1-35, from 6-amino-1-methyl-2-[(methylsulfonyl) methyl] -1H-benzimidazole-5-carboxylic acid methyl ester (middle The following intermediates are prepared in steps 4-) of body 1-98 and the corresponding carboxylic acids (row 1).
Figure TW201803866AD00106
Figure TW201803866AD00107
Figure TW201803866AD00108
 Intermediate 1-102(±) 2- (1,1- Dioxotetrahydrothiophene -3- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Methyl formate
Figure TW201803866AD00109
step 1 (±) 3-{[(1,1- Dioxotetrahydrothiophene -3- base ) Carbonyl ] Amine } -4- ( Methylamino ) Methyl benzoate From methyl 3-amino-4- (methylamino) benzoate (CAS-RN 66315-16-0) and (±) tetrahydrothiophene-3-carboxylic acid-1,1-dioxide (CAS-RN 4785-67-5), the preparation method is similar to step 1 of intermediate 1-93. UPLC-MS (ESI +): [M + H]+ = 327; Rt = 0.77 min (Method E).step 2 (±) 2- (1,1- Dioxotetrahydrothiophene -3- base )-1- methyl -1H- Benzimidazole -5- Methyl formate From (±) 3-{[(1,1-dioxotetrahydrothiophen-3-yl) carbonyl] amino} -4- (methylamino) benzoic acid methyl ester, the preparation method is similar to intermediate 1-93 Of step 2. UPLC-MS (ESI +): [M + H]+ = 309; Rt = 0.79 min (Method F).step 3 (±) 2- (1,1- Dioxotetrahydrothiophene -3- base )-1- methyl -6- Nitro -1H- Benzimidazole -5- Methyl formate From (±) 2- (1,1-dioxotetrahydrothiophen-3-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to that of intermediate 1-55 3. UPLC-MS (ESI +): [M + H]+ = 354; Rt = 0.83 min (Method F)step 4 (±) 6- Amine -2- (1,1- Dioxotetrahydrothiophene -3- base )-1- methyl -1H- Benzimidazole -5- Methyl formate From 1-methyl-2-[(methylsulfonyl) methyl] -6-nitro-1H-benzimidazole-5-carboxylic acid methyl ester, the preparation method is similar to step 4 of intermediate 1-1. UPLC-MS (ESI +): [M + H]+ = 324; Rt = 0.64 min (Method E).step 5 (±) 2- (1,1- Dioxotetrahydrothiophene -3- base )-1- methyl -6-({[6- ( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine ) -1H- Benzimidazole -5- Formic acid Methyl ester From (±) 6-amino-2- (1,1-dioxotetrahydrothiophen-3-yl) -1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester and 6- (trifluoro Methyl) pyridine-2-carboxylic acid, the preparation method is similar to step 5 of intermediate 1-1.1 H NMR (400 MHz, DMSO-d6 ) δ [ppm]: 2.326 (0.87), 2.402 (0.67), 2.422 (0.69), 2.518 (3.91), 2.522 (2.65), 2.664 (0.84), 2.668 (0.96), 2.673 (0.82), 3.247 (0.67) , 3.266 (0.69), 3.271 (0.72), 3.290 (0.64), 3.385 (0.67), 3.396 (0.69), 3.404 (0.67), 3.416 (0.89), 3.447 (1.26), 3.471 (0.96), 3.481 (1.11) , 3.504 (1.19), 3.662 (0.89), 3.684 (0.99), 3.696 (0.72), 3.717 (0.74), 3.836 (14.96), 3.947 (16.00), 4.181 (0.69), 4.197 (0.74), 4.203 (0.72) , 8.221 (1.71), 8.224 (1.76), 8.240 (2.08), 8.243 (2.08), 8.343 (6.23), 8.398 (0.91), 8.417 (1.98), 8.437 (1.21), 8.480 (2.25), 8.498 (1.29) , 8.976 (5.69), 12.973 (3.14). UPLC-MS (ESI +): [M + H]+ = 497; Rt = 1.14 min (Method F). Similar to the synthesis method in step 5 of intermediate 1-35, from (±) 6-amino-2- (1,1-dioxotetrahydrothiophen-3-yl) -1-methyl-1H-benzo Imidazole-5-carboxylic acid methyl ester (intermediate 1-102 step 4) and the corresponding carboxylic acid (row 1) prepare the following intermediates.
Figure TW201803866AD00110
Figure TW201803866AD00111
Figure TW201803866AD00112
Figure TW201803866AD00113
 Examples General experimental procedure: Grignard reaction, starting with an intermediate (reaction diagram 1) to obtain a compound of general formula (I) (reaction diagram 1). General Experimental Procedure 1a First, methyl benzimidazole-5-carboxylate (intermediate) is dissolved in THF and cooled to 0 ° C. Next, 12 to 15 equivalents of methylmagnesium bromide solution (commercially available solution in methyl-THF, THF, or ether) was added dropwise, keeping the temperature of the reaction mixture at 5 to 10 ° C. The mixture was then stirred at room temperature overnight. Saturated ammonium chloride solution was added and the organic phase was removed, dried over magnesium sulfate and concentrated. The residue from the first Grignard reaction was dissolved in THF and cooled to 0 ° C. Next, 12 to 15 equivalents of methylmagnesium bromide solution (commercially available solution in 2-methyltetrahydrofuran, THF, or diethyl ether) was added dropwise, keeping the temperature of the reaction mixture at 5 to 10 ° C. Then the mixture was stirred at 0 ° C for 1 hour. Saturated ammonium chloride solution was added and the organic phase was removed, dried over magnesium sulfate and concentrated. The resulting residue was purified by HPLC. General Experimental Procedure 1b Methyl benzimidazole-5-carboxylate (intermediate) was dissolved in THF and cooled to 0 to 5 ° C. Next, 6 equivalents of methylmagnesium bromide solution (commercially available solution in 2-methyltetrahydrofuran, THF, or ether) was added dropwise, keeping the temperature of the reaction mixture at 5 to 10 ° C. The mixture was then stirred at room temperature overnight. Saturated ammonium chloride solution was added and the organic phase was removed, dried over magnesium sulfate and concentrated. Once analysis of the residue (UPLC-MS) showed substantial conversion of the starting material, the residue was purified by HPLC. Alternatively, if the starting material reaction is not complete, the residue undergoes another Grignard reaction as described below. The residue from the first Grignard reaction was dissolved in THF and cooled to 0 to 5 ° C. Next, 6 equivalents of methylmagnesium bromide solution (commercially available solution in 2-methyltetrahydrofuran, THF, or ether) was added dropwise, keeping the temperature of the reaction mixture at 5 to 10 ° C. Then the mixture was stirred at 0 to 5 ° C for 1 hour. Saturated ammonium chloride solution was added and the organic phase was removed, dried over magnesium sulfate and concentrated. The resulting residue was purified by HPLC. Example 2-1 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
Figure TW201803866AD00114
700 mg (1.5 mmol) 2- (3-methoxy-3-oxopropyl) -1-methyl-6-({[6- (trifluoromethyl) pyridin-2-yl] carbonyl } Amino) -1H-benzimidazole-5-carboxylic acid methyl ester (Intermediate 1-1) was dissolved in 45 ml of THF and cooled to 0 ° C. Next, a solution of 5.3 ml (18 mmol) methylmagnesium bromide (3.4 mol / l) in 2-methyltetrahydrofuran was added dropwise. The reaction mixture was then stirred at room temperature overnight. Add 30 ml of saturated ammonium chloride solution and stir the mixture for 5 min. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was dissolved in 45 ml of THF and cooled to 0 ° C. Next, a solution of 5.3 ml (18 mmol) methylmagnesium bromide (3.4 mol / l) in 2-methyltetrahydrofuran was added dropwise. The reaction mixture was stirred at 0 ° C for 1 hour. 30 ml of saturated ammonium chloride solution was added and the mixture was stirred for 5 min. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was purified by HPLC. This procedure yielded 105 mg (15%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.18 (s, 6H), 1.61 (s, 6H), 1.82-1.89 (m, 2H), 2.87-2.94 (m, 2H), 3.73 (s, 3H), 4.48 (s, 1H), 5.90 (s, 1H), 7.51 (s, 1H), 8.16-8.20 (m, 1H), 8.36-8.42 (m, 1H), 8.44-8.49 (m, 1H), 8.55 (s, 1H) , 12.49 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 465; Rt = 0.90 min (Method A). The following examples were prepared from suitable intermediates (intermediates) according to general experimental procedure 1a and a method similar to Example 2-1.
Figure TW201803866AD00115
Figure TW201803866AD00116
Figure TW201803866AD00117
Figure TW201803866AD00118
Figure TW201803866AD00119
Figure TW201803866AD00120
Figure TW201803866AD00121
Figure TW201803866AD00122
Figure TW201803866AD00123
Figure TW201803866AD00124
Figure TW201803866AD00125
 Example 2-13 N- {5- (2-Hydroxyprop-2-yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} -6- (trifluoromethyl) pyridine-2-carboxamide
Figure TW201803866AD00126
100 mg (0.2 mmol) 1-methyl-2- [2- (methylsulfonyl) ethyl] -6-({[6- (trifluoromethyl) pyridin-2-yl] carbonyl) amino ) -1H-Benzimidazole-5-carboxylic acid methyl ester (Intermediate 1-13) was dissolved in 10 ml of THF and cooled to 0 to 5 ° C. Then 0.36 ml (1.2 mmol) of 2-methyltetrahydrofuran solution containing methylmagnesium bromide (3.4 mol / l) was added dropwise. Thereafter, the reaction mixture was stirred at 5 ° C for 1 hour. 4 ml of saturated ammonium chloride solution was added and the mixture was stirred for 5 min. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was dissolved in 10 ml of THF and cooled to 0 ° C. Then 0.36 ml (1.2 mmol) of 2-methyltetrahydrofuran solution containing methylmagnesium bromide (3.4 mol / l) was added dropwise. The reaction mixture was stirred at 0 to 5 ° C for 1 hour. 4 ml of saturated ammonium chloride solution was added and the mixture was stirred for 5 min. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was purified by HPLC. This procedure gave 31 mg (31%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.61 (s, 6H), 3.09 (s, 3H), 3.65-3.72 (m, 2H), 3.76 (s, 3H), 5.92 (s, 1H), 7.55 (s, 1H) , 8.15-8.20 (m, 1H), 8.35-8.41 (m, 1H), 8.44-8.49 (m, 1H), 8.58 (s, 1H), 12.51 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 485; Rt = 1.00 min (Method A). The following examples were prepared from suitable intermediates (intermediates) according to general experimental procedures 1b and methods similar to Examples 2-13.
Figure TW201803866AD00127
Figure TW201803866AD00128
Figure TW201803866AD00129
Figure TW201803866AD00130
Figure TW201803866AD00131
Figure TW201803866AD00132
Figure TW201803866AD00133
Figure TW201803866AD00134
Figure TW201803866AD00135
Figure TW201803866AD00136
Figure TW201803866AD00137
Figure TW201803866AD00138
Figure TW201803866AD00139
Figure TW201803866AD00140
Figure TW201803866AD00141
Figure TW201803866AD00142
Figure TW201803866AD00143
Figure TW201803866AD00144
Figure TW201803866AD00145
Figure TW201803866AD00146
Figure TW201803866AD00147
Figure TW201803866AD00148
Figure TW201803866AD00149
Figure TW201803866AD00150
Figure TW201803866AD00151
Figure TW201803866AD00152
Figure TW201803866AD00153
Figure TW201803866AD00154
Figure TW201803866AD00155
Figure TW201803866AD00156
Figure TW201803866AD00157
Figure TW201803866AD00158
Figure TW201803866AD00159
Figure TW201803866AD00160
Figure TW201803866AD00161
Figure TW201803866AD00162
Figure TW201803866AD00163
Figure TW201803866AD00164
Figure TW201803866AD00165
Figure TW201803866AD00166
Figure TW201803866AD00167
Figure TW201803866AD00168
Figure TW201803866AD00169
Figure TW201803866AD00170
Figure TW201803866AD00171
Figure TW201803866AD00172
Figure TW201803866AD00173
Figure TW201803866AD00174
Figure TW201803866AD00175
Figure TW201803866AD00176
Figure TW201803866AD00177
Figure TW201803866AD00178
Figure TW201803866AD00179
Figure TW201803866AD00180
Figure TW201803866AD00181
Figure TW201803866AD00182
Figure TW201803866AD00183
Figure TW201803866AD00184
Figure TW201803866AD00185
Figure TW201803866AD00186
Figure TW201803866AD00187
 Example 2-75 (±) N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl -1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
Figure TW201803866AD00188
150 mg (0.29 mmol) (±) 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -1-methyl-6-({(6- (trifluoromethyl ) Pyridin-2-yl] carbonyl} amino) -1H-benzimidazole-5-carboxylic acid methyl ester (intermediate 1-75) was dissolved in 9 ml of THF and cooled to 0 ° C. Next, 0.52 ml (1.7 mmol) of 2-methyltetrahydrofuran solution containing methylmagnesium bromide (3.4 mol / l) was added dropwise. Then the reaction mixture was stirred at room temperature for 30 min. Then 4 ml of saturated ammonium chloride solution was added and the mixture was stirred for 5 min. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was purified by HPLC. This process yielded 68 mg (45%) of the title compound.1 H-NMR (400MHz, DMSO-d6 ): Δ [ppm] = 1.60 (s, 6H), 1.69-1.81 (m, 1H), 1.98-2.20 (m, 3H), 3.09-3.17 (m, 1H), 3.44-3.50 (m, 1H), 3.58-3.68 (m, 1H), 3.78 (s, 3H), 5.92 (s, 1H), 7.56 (s, 1H), 8.15-8.20 (m, 1H), 8.35-8.41 (m, 1H), 8.44- 8.48 (m, 1H), 8.58 (s, 1H), 12.51 (s, 1H). UPLC-MS (ESI +): [M + H]+ = 511; Rt = 0.97 min (Method A). Example 2-75-1 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl- 1H-Benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide enantiomer A. The racemic compound (±) N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2- Yl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide (Example 2-75) was separated into enantiomers. This procedure gave 21 mg of the title compound (Enantiomer A) and 24 mg (Enantiomer B Example 2-75-2). Analysis: Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3µ 100 x 4.6mm; Mobile phase A: MTBE + 0.1% by volume of diethylamine (99%); Mobile phase B: methanol; Isocratic: 50% A + 50% B; flow rate 1.4 ml / min; temperature: 25 ° C; DAD 254 nm enantiomer ARt = 1.19 min Preparation: Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, Column: Chiralpak IB 5µ 250 x 30mm; Mobile phase A: MTBE + 0.1% by volume of diethylamine (99%) ; Mobile phase B: methanol; isocratic: 50% A + 50% B; flow rate 40.0 ml / min; UV 254 nm enantiomer ARt = 4.0 to 5.1 min Example 2-75-2 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxyprop-2-yl)- 1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide enantiomer B. The racemic compound (±) N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2- Yl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide (Example 2-75) was separated into enantiomers. This procedure gave 24 mg of the title compound (enantiomer B) and 21 mg (enantiomer A Example 2-75-1). Analysis: Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3µ 100 x 4.6mm; Mobile phase A: MTBE + 0.1% by volume of diethylamine (99%); Mobile phase B: methanol; Isocratic: 50% A + 50% B; flow rate 1.4 ml / min; temperature: 25 ° C; DAD 254 nm enantiomer BRt = 1.61 min Preparation instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, Column: Chiralpak IB 5µ 250 x 30mm; Mobile phase A: MTBE + 0.1% by volume of diethylamine (99%); Mobile phase B: methanol; isocratic: 50% A + 50% B; flow rate 40.0 ml / min; UV 254 nm enantiomer BRt = 5.9 to 6.9 min. The following examples were prepared from suitable intermediates (intermediates) according to general experimental procedure 1b and a preparation method similar to Examples 2-75.
Figure TW201803866AD00189
Figure TW201803866AD00190
Figure TW201803866AD00191
 The following examples were prepared from suitable intermediates (intermediates) according to general experimental procedure 1b and a preparation method similar to Examples 2-75.
Figure TW201803866AD00192
Figure TW201803866AD00193
Figure TW201803866AD00194
Figure TW201803866AD00195
Figure TW201803866AD00196
Figure TW201803866AD00197
Figure TW201803866AD00198
Figure TW201803866AD00199
Figure TW201803866AD00200
Figure TW201803866AD00201
Figure TW201803866AD00202
Figure TW201803866AD00203
Figure TW201803866AD00204
Figure TW201803866AD00205
Figure TW201803866AD00206
Figure TW201803866AD00207
Figure TW201803866AD00208
Figure TW201803866AD00209
Figure TW201803866AD00210
Figure TW201803866AD00211
Figure TW201803866AD00212
Figure TW201803866AD00213
Figure TW201803866AD00214
Figure TW201803866AD00215
Figure TW201803866AD00216
Figure TW201803866AD00217
Figure TW201803866AD00218
Figure TW201803866AD00219
 Evaluation of physiological effects Inhibition of IRAK4 kinase activity and selectivity against TrkA IRAK4 Kinase assay The IRAK4 inhibitory activity of the substance according to the present invention was measured in the following IRAK4 TR-FRET assay (TR-FRET = time difference fluorescence resonance energy transfer). N-terminal GST (bran) derived from baculovirus-infected insect cells (Hi5, BTI-TN-5B1-4, cell line purchased from Invitrogen, catalog number B855-02) and purified by affinity chromatography Recombinant fusion protein of Glutathione S-transferase) and human IRAK4 (IRAK4 deposit number NP_057207.2 (one-way transport number Q9NWZ3)) was used as an enzyme. The substrate used for the kinase reaction is the biotinylated peptide Biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in the form of amide) commercially available from, for example, Biosyntan GmbH (Berlin-Buch). For this test, eleven different concentrations ranging from 20 µM to 0.073 nM were prepared from a 2 mM solution of the test substance contained in DMSO. Pipette 50 nl of each solution into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), add 2 µl of the assay buffer containing IRAK4 [50 mM HEPES pH 7.5, 5 mM MgCl2 , 1.0 mM dithiothreitol, 30 µM activated sodium orthovanadate, 0.1% (w / v) bovine gamma globulin (BGG) 0.04% (v / v) nonidet-P40 (Sigma)] and the mixture Incubate for 15 min to allow pre-combination of substances and enzymes before the kinase reaction. Then by adding 3 µl adenosine triphosphate (ATP, 1.67 mM = final concentration in 5 µl test volume: 1 mM) and peptide substrate (0.83 µM = final concentration in 5 µl test volume: 0.5 µM) included in the test The buffer solution starts the kinase reaction and the resulting mixture is incubated at 22 ° C for 45 min reaction time. Adjust the concentration of IRAK4 to the respective activity and settings of the enzyme so that the test is performed in the linear range. Typical concentrations are in the order of 0.2 nM. By adding 5 µl TR-FRET detection reagent [0.1 µM streptavidin-XL665 (Cisbio Bioassays; France, catalog number 610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, "STK antibody" , Catalog number 35-002] and 0.6 nM LANCE EU-W1024 labeled anti-mouse-IgG antibody (Perkin-Elmer, product number AD0077; alternatively, anti-mouse-IgG labeled with a cryptate compound from Cisbio Bioassays can be used Antibody) in EDTA aqueous solution (100 mM EDTA, 0.4% [w / v] bovine serum albumin [BSA], contained in 25 mM HEPES pH 7.5) to terminate the reaction. The resulting mixture was incubated at 22 ° C for 1 hour to allow the formation of the complex of biotinylated phosphorylated substrate and detection reagent. The phosphorylated substrate content was then assessed by measuring the energy resonance transfer from the anti-mouse-IgG antibody labeled with europium chelate to streptavidin-XL665. For this purpose, after excitation at 350 nm, the fluorescence at 620 nm and 665 nm is measured using TR-FRET measuring instruments such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer) emission. The emission ratio of 665 nm and 622 nm is used as a measure of the phosphorylation substrate content. Standardize the data (enzyme reaction without test substance = 0% inhibition; all other tested components but no enzyme = 100% inhibition). Generally, in 11 different concentrations ranging from 20 µM to 0.073 nM (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 and 0.073 nM) Test the test substances on the same microtiter plate. Dilution series (2 mM to 7.3 nM in 100% DMSO) were prepared by serial dilutions before verification. Calculate IC by 4-parameter fitting50 value. Exemplary compounds show inhibition of IRAK4 kinase activity (see Tables 1 and 1A).table 1 : IC of example compounds in IRAK4 and TrkA kinase assay50 value.table 1A : IC of example compounds in IRAK4 and TrkA kinase assay50 value. Exemplary compound pairs IRAK4 The combined dynamics: This experiment directly confirmed the interaction between the test substance and IRAK4 protein. By measuring binding kinetics, a test substance with a long dissociation rate can be identified, which can result in longer target binding and therefore activity on the target within the cell. For surface plasmon resonance (SPR) measurement, recombinant biotinylated full-length IRAK4 protein (amino acid 1-460 of IRAK4, deposit number NP_057207.2 (one-way transport number Q9NWZ3)) is used, which is available from Carna of Japan Biosciences (product number: 09-445-20N) was purchased. Using the streptavidin-biotin interaction, the biotinylated IRAK4 protein was immobilized on a SA-Biacore wafer (GE Healthcare, product number 29104992). For this purpose, the biotinylated IRAK4 protein was diluted to 5 µg / ml in 1x HBS-EP + (prepared from 10x HBS-EP + buffer (GE Healthcare, product number BR100669)) and then in SA-Biacore in the same buffer It is captured on the surface of the streptavidin of the wafer. This process resulted in a signal of approximately 1000 response units. The reference pool consists of unsaturated streptavidin. The test substance was diluted to 10 mM in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, Germany) and then run in running buffer (1x HBS-EP + pH 7.4 [from HBS-EP + buffer 10x (GE Healthcare) : 0.1 M HEPES, 1.5 M NaCl, 30 mM EDTA and 0.5% v / v detergent P20], further diluted in 1% v / v DMSO). For kinetic measurements, prepare a serial dilution of the test substance (0.235 nM to 0.15 µM) and then inject it onto the surface. The binding kinetics were measured in running buffer at 25 ° C and a flow rate of 100 µl / min. For this purpose, the test substance was injected for 80 s and then the dissociation was recorded for 1000 s. The obtained sensogram is the double reference for the blank test value and the reference surface and it is fitted to the 1: 1 binding model using the formula stored in the software using Biacore T200 evaluation software. The target residence time is the reciprocal value of the dissociation rate constant, and the target residence time = 1 / dissociation rate constant. Exemplary compounds show a long residence time on IRAK4 (see Table 2).table 2 : Exemplary compound binding kinetics TrkA Kinase assay Trk (kinase associated with tropomyosin) -A is activated by the binding of NGF (nerve growth factor). It involves, for example, malignant transformation, chemotaxis, and metastasis of tumors. In particular, TrkA is associated with analgesia and neuropathic pain in adults including chronic pain and cancer pain (Hirose, Kuroda et al., Pain Practice, 2016). However, it should be noted that TrkA is important for the development of sympathetic nerves. Patients with loss-of-function mutations in TrkA develop hereditary sensation and type IV autonomic neuropathy (CIPA, congenital insensitivity to pain and no sweat), which is associated with significant pain and temperature sensory disturbance (Indo, Clinical Genetics, 2012). In addition, TrkA seems to play a role in the maturation of cholinergic neurons, thymus development, early ovarian development and the development of certain immune cells (Tessarollo, L., Cytokine & Growth Factor Reviews, 1998; Garcı ́a- Suárez, Germanà et al., Journal of Neuroimmunology, 2000; Coppola, Barrick et al., Development, 2004; Dissen, Garcia-Rudaz et al., Seminars in reproductive medicine, 2009). Due to the potential function mentioned, the selectivity regarding TrkA was determined. In the following TrkA-HTRF test (HTRF =Homogeneous time difference fluorescent ( H omogeneous T ime R esolved F luorescence) ), The TrkA inhibitory activity of the substance of the present invention is measured. The kinase used was N-terminal from N-terminal that was obtained from ProQinase GmbH (Product No. 0311-0000-2) purchased from Baculovirus-infected insect cells (Sf9) and purified by affinity chromatography. Recombinant fusion protein composed of His6-labeled GST and human TrkA C-terminal fragment (TrkA accession number NP_002520.2 amino acid 443-796). The substrate used for the kinase reaction was a biotinylated polyglutamic acid and tyrosine (4: 1) copolymer from CisBio Bioassays (# 61GT0BLA). For the assay, 50 nl of the test substance in 100-fold concentrated solution in DMSO was transferred to a black small-capacity 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), and 2 μl of the assay buffer was added [8 mM MOPS / HCl pH 7.0, 10 mM MgCl2 , 1.0 mM dithiothreitol, 0.2 mM EDTA, 0.01% (v / v) Nonidet-P40 (from Sigma)] IRAK4 solution and incubate the mixture for 15 min to allow the substance and enzyme to be preliminarily reacted before the kinase reaction Combine. Then by adding 3 µl adenosine triphosphate solution (ATP, 1.67 µM = final concentration in 5 µl test volume: 10 µM) and substrate (2.27 µg / ml µM = in 5 µl test volume) The final concentration: 1.36 µg / ml) solution starts the kinase reaction and the resulting mixture is incubated at 22 ° C for 60 min reaction time. The concentration of TrkA is adapted to the respective activity of the enzyme and is adjusted so that the assay is operated in a linear range (typical final TrkA concentration in a 5 µl assay volume is on the order of about 20 pg / µl). By adding 5 µl of HTRF detection reagent (30 nM streptavidin-XL665 (Cisbio Bioassays; France) and 1.4 nM PT66 europium chelate, an anti-phosphotyrosine labeled with europium chelate from Perkin Elmer EDTA aqueous solution (100 mM EDTA, containing 0.2% [w / v] bovine serum albumin [BSA] 50 mM of antibody (instead of PT66-europium chelate, PT66 Tb cave compound from Cisbio Bioassays)) A solution of HEPES / HCl solution pH 7.0) terminated the reaction. The resulting mixture was incubated at 22 ° C for 1 hour to allow the formation of the complex between the biotinylated phosphorylated substrate and the detection reagent. Subsequently, the content of phosphorylated substrate was evaluated by measuring the energy resonance transfer from PT66-europium chelate to streptavidin-XL665. For this purpose, the fluorescence emission at 620 nm and 665 nm is measured in an HTRF measuring instrument (for example) Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer) after excitation at 350 nm. The emission ratio of 665 nm and 622 nm is used as a measure of the phosphorylation substrate content. Standardize the data (enzyme reaction without inhibitor = 0% inhibition; all other tested components but without enzyme = 100% inhibition). Generally, there are 11 types of differences from 20 µM to 0.073 nM (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 and 0.072 nM) Concentration test the test substances on the same microtiter plate; before the verification, prepare a dilution series by serial dilution at a level of 100-fold concentrated solution (ie, 2 mM to 7.3 nM in 100% DMSO), depending on Double-value pipette for various concentrations, the precise concentration can be changed, and the IC is calculated using 4-parameter fitting50 value. Exemplary compounds show high selectivity against TrkA (see Table 1). TNF-α secretion in THP-1 cells With this test, the substance can be tested for its ability to inhibit the secretion of TNF-α (tumor necrosis factor α) in THP-1 cells (human monocyte acute leukemia cell line). TNF-α is a cytokine involved in the inflammatory process. In this test, TNF-α secretion is induced by the cultivation of bacterial lipopolysaccharide (LPS). THP-1 cells were stored in continuous suspension cell culture [without L-glutamine dipeptide (GE Healthcare, catalog number E15-039), supplemented with fetal bovine serum (FCS) 10% (Invitrogen, catalog number 10082-147 ), 1% L-glutamine (Sigma, catalog number G7513), 1% penicillin / streptomycin (PAA, catalog number P11-010), and 50 µM 2-mercaptoethanol (Gibco, catalog number 31350-010) RPMI 1460 medium] and should not exceed 1 x 106 Cell concentration per cell / ml. The test is performed in a cell culture medium (RPMI 1460 medium supplemented with L-glutamine, penicillin, streptomycin, and 2-mercaptoethanol). Change THP-1 cells to 2.5x105 The cell density per cell / well was seeded in 96-well plates. The compound according to the invention was subjected to serial dilutions in a constant volume of 100% DMSO and was used in the assay at 8 different concentrations ranging from 10 µM to 3 nM so that the final DMSO concentration was 0.4% DMSO. Before the actual stimulation, the cells were then pre-incubated with them for 30 min. To trigger cytokine secretion, use 1 µg / ml LPS (Sigma, E. coli (Escherichia coli ) 0127: B8, catalog number L4516) stimulate cells for 6 hours. As a neutral control, cells were treated with 1 µg / ml LPS and 0.04% DMSO and as an inhibitor control, cells were treated with only 0.04% DMSO. Cell viability was measured using CellTiter-Glo Luminescence Assay (Promega, catalog number G7571 (G755 / G756A)) according to the manufacturer's instructions. The amount of TNF-α secretion in the cell culture supernatant was measured using the human proinflammatory 9-Plex tissue culture kit (MSD, catalog number K15007B) according to the manufacturer's instructions. The activity of the substance is expressed as a percentage ratio between neutral and inhibitor control. Calculate IC using 4-parameter fitting50 value. Exemplary compounds show inhibition of TNF-α secretion in THP-1 cells (see Table 3).table 3 : Example compound IC for secretion of TNF-α in THP-1 cells50 value The in vivo model of IL-1β-mediated inflammation is to evaluate the potential efficacy of compounds of general formula (I) according to the present invention in IL-1β-mediated diseases. Charles River Laboratories, Germany) Intraperitoneal injection of IL-1β and examination of the effect of the inventive compounds on IL-1β-mediated cytokine secretion. There are 5 animals in each group. The control group was treated with a vehicle for dissolving substances and IL-1β. 90 µg IL-1β / kg body weight (R & D, catalog number 401-ML / CF) was administered intraperitoneally to each of the substance treatment group and the positive control group. Six hours before the administration of IL-1β, the substance or its vehicle was administered in the positive control group. Two hours after the administration of IL-1β, the mouse proinflammatory 7-Plex tissue culture kit (MSD, catalog number K15012B) was used to determine TNF-α in plasma after the final removal of blood according to the manufacturer's instructions.Arthritis model induced by in vivo adjuvant In order to determine the anti-inflammatory activity of the compound of the general formula (I) of the present invention, its efficacy in vivo was examined in an arthritis model. For this purpose, each male Lewis rat (approximately 100 to 125 g, Charles River Laboratories, Germany) was subcutaneously administered 100 µl of Freund's complete adjuvant (CFA) solution (dissolved in Freund's Mycobacterium tuberculosis in complete adjuvant [Difco Lab, catalog number -263910] (M. tuberculosis ) H37Ra [Difo Lab, catalog number -231141]) to the base of the tail. There were n = 8 rats in each group. Both the healthy control group and the disease control group were included in the study. Each control group was treated orally with vehicle of test substance only. The treatment with different doses of the test substance is carried out in a prophylactic manner, ie by oral administration, starting from day 0. On day 0, the initial condition of the animal is additionally determined based on the disease activity score (severity assessment of arthritis based on a score system). In this score system, according to the degree of joint inflammation, the two hind paws and the sum of the red spots including joint swelling are judged to be 0 to 4 points (0 = none; 1 = mild; 2 = moderate; 3 = obvious ; 4 = serious). To determine the anti-inflammatory efficacy of the compound, the disease status of the animal was scored with the aid of the disease activity score on day 8 when the animal first displayed the signal of arthritis and then 3 times a week until the end (day 20). Statistical analysis was performed using single factor variable analysis (ANOVA) and multiple comparison analysis (Dunn test) compared with the control group.

無no

Claims (16)

一種通式(I)之化合物，
Figure TW201803866AC00001
式(I) 其中： R1 表示含有1或2個相同或不同選自由O、S及N組成之群之雜原子且經由環碳原子連接之5-或6-員雜芳基， 其中5員雜芳基可經C3 -C6 環烷基或可經鹵素取代的C1 -C3 烷基單取代， 及其中，於該5-員雜芳基具有含義吡唑基之情況下，吡唑基在N處可經C3 -C6 環烷基或可經鹵素取代的C1 -C3 烷基單取代， 及其中6-員雜芳基可經相同或不同來自由鹵素、C1 -C3 烷氧基、NH2 、可經鹵素取代之C1 -C3 烷基組成之群之取代基單或二取代， A表示鍵或C1 -C6 烷基， 於A為C1 -C6 烷基之情況下，R2 表示氫、C1 -C3 -烷氧基、S(=O)2 -C1 -C3 烷基、NH(C1 -C3 烷基)、N(C1 -C3 烷基)2 或含有一或兩個相同或不同選自O、S、S(=O)2 、N、NH、N(C1 -C3 烷基)之雜原子或雜原子基團且經由環碳原子或環氮原子連接的4-、5-或6-員雜環烷基， 或 於A為鍵之情況下，R2 表示可經–OH單取代之C1 -C6 烷基或表示含有選自N(C1 -C3 烷基)、O、S(=O)2 之群之雜原子或雜原子基團且經由雜環烷基之環碳原子連接的5-或6-員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。A compound of general formula (I),
Figure TW201803866AC00001
Formula (I) where: R 1 represents a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from the group consisting of O, S and N and connected via a ring carbon atom, of which 5 members The heteroaryl group may be mono-substituted with a C 3 -C 6 cycloalkyl group or a C 1 -C 3 alkyl group which may be substituted with halogen, and, in the case where the 5-membered heteroaryl group has the meaning pyrazolyl, pyridine The azole group may be mono-substituted with a C 3 -C 6 cycloalkyl group or a C 1 -C 3 alkyl group which may be substituted with halogen at N, and the 6-membered heteroaryl group thereof may be freely selected from halogen, C 1 through the same or different -C 3 alkoxy, NH 2 , C 1 -C 3 alkyl which may be substituted with halogen, the substituents of the group are mono- or di-substituted, A represents a bond or C 1 -C 6 alkyl, where A is C 1 -C 6 alkyl, R 2 represents hydrogen, C 1 -C 3 -alkoxy, S (= O) 2 -C 1 -C 3 alkyl, NH (C 1 -C 3 alkyl), N (C 1 -C 3 alkyl) 2 or contains one or two heteroatoms selected from O, S, S (= O) 2 , N, NH, N (C 1 -C 3 alkyl) Or a heteroatom group and a 4-, 5-, or 6-membered heterocycloalkyl group connected through a ring carbon atom or a ring nitrogen atom, or in the case where A is a bond, R 2 represents C that may be monosubstituted by -OH 1 -C 6 Alkyl or means 5- containing a heteroatom or heteroatom group selected from the group of N (C 1 -C 3 alkyl), O, S (= O) 2 and connected via a ring carbon atom of a heterocycloalkyl Or 6-membered heterocycloalkyl, and its diastereomers, enantiomers, metabolites, salts, solvates or solvates of its salts. 如請求項1之通式(I)之化合物，其中： R1 表示選自以下之基團：
Figure TW201803866AC00002
其中： R3 表示環丙基或C1 -C3 烷基，其中C1 -C3 烷基可經氟原子單至三取代， R4 表示H、甲氧基、NH2 、可經氟原子單至三取代之C1 -C3 烷基， R5 表示氫或氟且 *表示該分子中之連接點， A表示鍵或C1 -C3 烷基， 於A為C1 -C3 烷基之情況下，R2 表示氫、甲氧基、S(=O)–CH3 、-N(CH3 )2 或含有一或兩個相同或不同選自O、S(=O)2 、N、NH-CH3 的雜原子或雜原子基團且經由環碳原子或環氮原子連接之4、5或6員雜環烷基， 或 於A為鍵之情況下，R2 表示3-羥基-3-甲基丁基或表示含有如雜原子基團S(=O)2 且經由環碳原子連接之6員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。A compound of general formula (I) according to claim 1, wherein: R 1 represents a group selected from:
Figure TW201803866AC00002
Wherein: R 3 represents cyclopropyl or C 1 -C 3 alkyl group, wherein C 1 -C 3 alkyl group may be mono- to tri-substituted with fluorine atom, R 4 represents H, methoxy, NH 2 , may pass fluorine atom Mono- to tri-substituted C 1 -C 3 alkyl, R 5 represents hydrogen or fluorine and * represents the point of attachment in the molecule, A represents a bond or C 1 -C 3 alkyl, where A is C 1 -C 3 alkyl In the case of radicals, R 2 represents hydrogen, methoxy, S (= O) –CH 3 , -N (CH 3 ) 2 or contains one or two identical or different from O, S (= O) 2 , A heteroatom or a heteroatom group of N, NH-CH 3 and a 4, 5 or 6 membered heterocycloalkyl group connected via a ring carbon atom or a ring nitrogen atom, or in the case where A is a bond, R 2 represents 3- Hydroxy-3-methylbutyl or represents a 6-membered heterocycloalkyl group containing a heteroatom group S (= O) 2 and connected via a ring carbon atom, and its diastereomers and enantiomers , Metabolites, salts, solvates or solvates of their salts. 如請求項2之通式(I)之化合物，其中： R1 表示選自以下之基團：
Figure TW201803866AC00003
其中： R3 表示環丙基或C1 -C3 烷基，其中C1 -C3 烷基可經氟原子單至三取代， R4 表示H、可經氟原子單至三取代之C1 -C3 烷基， R5 表示氫且 *表示於該分子中之連接點， A表示鍵或C1 -C3 烷基， 於A為C1 -C3 烷基之情況下，R2 表示氫或含有一或兩個相同或不同選自O、N、NH-CH3 之雜原子或雜原子基團且經由環碳原子或環氮原子連接之6-員雜環烷基， 或 於A為鍵之情況下，R2 表示3-羥基-3-甲基丁基或表示含有作為雜原子基團之S(=O)2 且經由環碳原子連接之6-員雜環烷基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。A compound of general formula (I) as in claim 2, wherein: R 1 represents a group selected from:
Figure TW201803866AC00003
Wherein: R 3 represents a cyclopropyl group or a C 1 -C 3 alkyl group, wherein the C 1 -C 3 alkyl group may be mono- to tri-substituted with a fluorine atom, R 4 represents H, a C 1 that may be mono- to tri-substituted with a fluorine atom -C 3 alkyl, R 5 represents hydrogen and * represents the point of attachment in the molecule, A represents a bond or C 1 -C 3 alkyl, and when A is C 1 -C 3 alkyl, R 2 represents Hydrogen or a 6-membered heterocycloalkyl group containing one or two heteroatoms or heteroatom groups selected from O, N, NH-CH 3 and connected via a ring carbon atom or ring nitrogen atom, or in A In the case of a bond, R 2 represents 3-hydroxy-3-methylbutyl or 6-membered heterocycloalkyl containing S (= O) 2 as a heteroatom group and connected via a ring carbon atom, and Its diastereomers, enantiomers, metabolites, salts, solvates or solvates of its salts. 如請求項3之通式(I)之化合物，其中： R1 表示6-(三氟甲基)吡啶-2-基、2-(三氟甲基)-1,3-噻唑-4-基、2-環丙基-1,3-噁唑-4-基、4-(三氟甲基)-1,3-噻唑-2-基、6-(1,1-二氟乙基)吡啶-2-基； A表示鍵或C1 -C3 烷基， 於A為C1 -C3 烷基之情況下，R2 表示嗎啉-4-基或4-甲基哌嗪-1-基， 或 於A為鍵之情況下，R2 為3-羥基-3-甲基丁基或表示1,1-二氧代四氫(dioxidotetrahydro)-2H-噻喃-3-基， 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。A compound of the general formula (I) according to claim 3, wherein: R 1 represents 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl , 2-cyclopropyl-1,3-oxazol-4-yl, 4- (trifluoromethyl) -1,3-thiazol-2-yl, 6- (1,1-difluoroethyl) pyridine -2-yl; A represents a bond or C 1 -C 3 alkyl, in the case where A is C 1 -C 3 alkyl, R 2 represents morpholin-4-yl or 4-methylpiperazine-1- Group, or when A is a bond, R 2 is 3-hydroxy-3-methylbutyl or 1,1-dioxotetrahydro-2H-thiopyran-3-yl, and Diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts. 如請求項4之通式(I)之化合物，其中： R1 表示6-(三氟甲基)吡啶-2-基、2-(三氟甲基)-1,3-噻唑-4-基、6-(1,1-二氟乙基)吡啶-2-基； A表示鍵， R2 表示3-羥基-3-甲基丁基或表示1,1-二氧代四氫-2H-噻喃-3-基 及其非對映異構體、對映異構體、代謝產物、鹽、溶劑化物或其鹽之溶劑化物。A compound of the general formula (I) according to claim 4, wherein: R 1 represents 6- (trifluoromethyl) pyridin-2-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl , 6- (1,1-difluoroethyl) pyridin-2-yl; A represents a bond, R 2 represents 3-hydroxy-3-methylbutyl or 1,1-dioxotetrahydro-2H- Thian-3-yl and its diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts. 如請求項2之通式(I)之化合物，其為： 2-1 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶2-甲醯胺 2-2 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-(三氟甲基)-1,3-噻唑-4-甲醯胺 2-3 6-(二氟甲基)-N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-4 2-環丙基 -N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-1,3-噁唑-4-甲醯胺 2-5 6-(1,1-二氟乙基)-N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-6 5-氟-N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-甲基吡啶-2-甲醯胺 2-7 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-4-(三氟甲基)-1,3-噻唑-2-甲醯胺 2-8 6-乙基-N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基 -1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-9 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-甲基吡啶-2-甲醯胺 2-10 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-甲氧基吡啶-2-甲醯胺 2-11 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-12 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噁唑-5-甲醯胺 2-13 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-14 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-15 2-環丙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-1,3-噁唑-4-甲醯胺 2-16 5-氟-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-6-甲基吡啶-2-甲醯胺 2-17 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-18 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(甲磺醯基)乙基]-1H-苯并咪唑-6-基}-2-甲基-1,3-噻唑-4-甲醯胺 2-19 N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-20 6-(二氟甲基)-N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-21 N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-22 2-環丙基-N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-1,3-噁唑-4-甲醯胺 2-23 1-(二氟甲基)-N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-1H-吡唑-3-甲醯胺 2-24 N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-25 5-氟-N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-6-甲基吡啶-2-甲醯胺 2-26 N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-6-甲氧基吡啶-2-甲醯胺 2-27 N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噁唑-5-甲醯胺 2-28 6-乙基-N-[5-(2-羥丙-2-基)-2-(2-甲氧基乙基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-29 N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-30 N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-31 2-環丙基-N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-1,3-噁唑-4-甲醯胺 2-32 N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-33 5-氟-N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-6-甲基吡啶-2-甲醯胺 2-34 N-[5-(2-羥丙-2-基)-2-(3-甲氧基丙基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-35 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-36 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-37 5-氟-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}-6-甲基吡啶-2-甲醯胺 2-38 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-39 6-胺基-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-40 2-環丙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(嗎啉-4-基)乙基]-1H-苯并咪唑-6-基}-1,3-噁唑-4-甲醯胺 2-41 N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-42 1-(二氟甲基)-N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-1H-吡唑-3-甲醯胺 2-43 6-(二氟甲基)-N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-44 N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-45 N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-46 5-氟-N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-6-甲基吡啶-2-甲醯胺 2-47 N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-48 2-環丙基-N-[5-(2-羥丙-2-基)-1-甲基-2-(嗎啉-4-基甲基)-1H-苯并咪唑-6-基]-1,3-噁唑-4-甲醯胺 2-49 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-50 6-胺基-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-51 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-52 N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-53 2-環丙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}-1,3-噁唑-4-甲醯胺 2-54 5-氟-N-{5-(2-羥丙-2-基)-1-甲基-2-[2-(4-甲基哌嗪-1-基)乙基]-1H-苯并咪唑-6-基}-6-甲基吡啶-2-甲醯胺 2-55 N-{5-(2-羥丙-2-基)-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-56 N-{5-(2-羥丙-2-基)-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-57 6-(1,1-二氟乙基)-N-{5-(2-羥丙-2-基)-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-58 1-乙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-6-基}-1H-吡唑-3-甲醯胺 2-59 N-{5-(2-羥丙-2-基)-1-甲基-2-[3-(嗎啉-4-基)丙基]-1H-苯并咪唑-6-基}-2-甲基-1,3-噻唑-4-甲醯胺 2-60 N-{2-[3-(二甲胺基)丙基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-61 N-{2-[3-(二甲胺基)丙基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-62 6-(1,1-二氟乙基)-N-{2-[3-(二甲胺基)丙基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-63 N-{2-[3-(二甲胺基)丙基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-1-乙基-1H-吡唑-3-甲醯胺 2-64 N-{2-[3-(二甲胺基)丙基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-2-甲基-1,3-噻唑-4-甲醯胺 2-65 (±)N-{2-[(1,1-二氧代四氫噻吩-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-66 (±)N-{2-[(1,1-二氧代四氫噻吩-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-1-乙基-1H-吡唑-3-甲醯胺 2-67 (±)N-{2-[(1,1-二氧代四氫噻吩-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-68 (±)6-(1,1-二氟乙基)-N-{2-[(1,1-二氧代四氫噻吩-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-69 (±)N-{2-[(1,1-二氧代四氫噻吩-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-2-甲基-1,3-噻唑-4-甲醯胺 2-70 N-{5-(2-羥丙-2-基)-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-71 1-乙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-6-基}-1H-吡唑-3-甲醯胺 2-72 N-{5-(2-羥丙-2-基)-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-6-基}-2-甲基-1,3-噻唑-4-甲醯胺 2-73 6-(1,1-二氟乙基)-N-{5-(2-羥丙-2-基)-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-74 N-{5-(2-羥丙-2-基)-1-甲基-2-[(1-甲基吖丁啶-3-基)甲基]-1H-苯并咪唑-6-基}-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-75 (±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-75-1 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺(對映異構體A) 2-75-2 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺(對映異構體B) 2-76 (±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-77 (±)6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-77-1 6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺(對映異構體A) 2-77-2 6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺(對映異構體B) 2-78 (±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-79 (±)N-[5-(2-羥丙-2-基)-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-80 (±)1-乙基-N-[5-(2-羥丙-2-基)-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-6-基]-1H-吡唑-3-甲醯胺 2-81 (±)N-[5-(2-羥丙-2-基)-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-82 (±)6-(1,1-二氟乙基)-N-[5-(2-羥丙-2-基)-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-83 (±)N-[5-(2-羥丙-2-基)-1-甲基-2-(四氫呋喃-3-基甲基)-1H-苯并咪唑-6-基]-2-三氟甲基)-1,3-噻唑-4-甲醯胺 2-84 (±)N-{2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-85 (±)N-{2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-1-乙基-1H-吡唑-3-甲醯胺 2-86 (±)6-(1,1-二氟乙基)-N-{2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-87 (±)N-{2-[(1,1-二氧代四氫-2H-噻喃-3-基)甲基]-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-88 N-[2-(1,1-二氧代四氫-2H-噻喃-4-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-89 N-[2-(1,1-二氧代四氫-2H-噻喃-4-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-1-乙基-1H-吡唑-3-甲醯胺 2-90 N-[2-(1,1-二氧代四氫-2H-噻喃-4-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-91 6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫-2H-噻喃-4-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-92 N-[2-(1,1-二氧代四氫-2H-噻喃-4-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-93 N-[5-(2-羥丙-2-基)-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 2-94 1-乙基-N-[5-(2-羥丙-2-基)-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-6-基]-1H-吡唑-3-甲醯胺 2-95 N-[5-(2-羥丙-2-基)-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-96 6-(1,1-二氟乙基)-N-[5-(2-羥丙-2-基)-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-97 N-[5-(2-羥丙-2-基)-2-(甲氧甲基)-1-甲基-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-98 N-{5-(2-羥丙-2-基)-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-6-基}-6-三氟甲基)吡啶-2-甲醯胺 2-99 1-乙基-N-{5-(2-羥丙-2-基)-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-6-基}-1H-吡唑-3-甲醯胺 2-100 6-(1,1-二氟乙基)-N-{5-(2-羥丙-2-基)-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-6-基}吡啶-2-甲醯胺 2-101 N-{5-(2-羥丙-2-基)-1-甲基-2-[(甲磺醯基)甲基]-1H-苯并咪唑-6-基}-4-三氟甲基)-1,3-噻唑-2-甲醯胺 2-102-1 N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 (對映異構體A) 2-102-2 N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-三氟甲基)吡啶-2-甲醯胺 (對映異構體B) 2-103 (±)N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-1-乙基-1H-吡唑-3-甲醯胺 2-104 (±)N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-甲基-1,3-噻唑-4-甲醯胺 2-105 (±)6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺 2-106 (±)N-[2-(1,1-二氧代四氫噻吩-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-4-三氟甲基)-1,3-噻唑-2-甲醯胺。The compound of general formula (I) as in claim 2, which is: 2-1 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl)- 1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine 2-carboxamide 2-2 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -2- (trifluoromethyl) -1,3-thiazole-4-carboxamide 2-3 6- (difluoromethyl) -N- (2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H- Benzimidazol-6-yl] pyridine-2-carboxamide 2-4 2-cyclopropyl-N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxypropyl- 2-yl) -1-methyl-1H-benzimidazol-6-yl] -1,3-oxazole-4-carboxamide 2-5 6- (1,1-difluoroethyl) -N -[2- (3-Hydroxy-3-methylbutyl) -5- (2-hydroxypropyl-2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-methyl Acetamide 2-6 5-fluoro-N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazole -6-yl] -6-picoline-2-carboxamide 2-7 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -4- (trifluoromethyl) -1,3-thiazole-2-carboxamide 2-8 6-ethyl-N- [2- (3-hydroxy-3-methyl Butyl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-9 N- [2- (3- Hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6-methylpyridine-2-carboxamide 2-10 N- [2- (3-Hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl]- 6-methoxypyridine-2-carboxamide 2-11 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl) -1-methyl -1H-benzimidazol-6-yl] -2-methyl-1,3-thiazole-4-carboxamide 2-12 N- [2- (3-hydroxy-3-methylbutyl) -5 -(2-Hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -2-methyl-1,3-oxazole-5-carboxamide 2-13 N- {5- (2-Hydroxyprop-2-yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6-yl} -6-trifluoromethyl Yl) pyridine-2-carboxamide 2-14 N- {5- (2-hydroxypropan-2-yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H- Benzimidazol-6-yl} -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2-15 2-cyclopropyl-N- {5- (2-hydroxypropan-2- Yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} -1,3-oxazole-4-carboxamide 2-16 5 -Fluoro-N- {5- (2-hydroxypropan-2-yl) -1-methyl-2- [ 2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} -6-picoline-2-carboxamide 2-17 N- {5- (2-hydroxypropan-2- Yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole-2- Formamide 2-18 N- {5- (2-Hydroxypropyl-2-yl) -1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6- Yl) -2-methyl-1,3-thiazole-4-carboxamide 2-19 N- [5- (2-hydroxyprop-2-yl) -2- (2-methoxyethyl)- 1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide 2-20 6- (difluoromethyl) -N- [5- (2- Hydroxypropan-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-21 N- [5- (2-hydroxypropyl-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl) -2-trifluoromethyl) -1,3 -Thiazole-4-carboxamide 2-22 2-cyclopropyl-N- [5- (2-hydroxypropyl-2-yl) -2- (2-methoxyethyl) -1-methyl- 1H-benzimidazol-6-yl] -1,3-oxazole-4-carboxamide 2-23 1- (difluoromethyl) -N- [5- (2-hydroxyprop-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl] -1H-pyrazole-3-carboxamide 2-24 N- [5- (2- Hydroxypropyl-2-yl) -2- (2-methoxyethyl) -1-methyl -1H-benzimidazol-6-yl] -2-methyl-1,3-thiazole-4-carboxamide 2-25 5-fluoro-N- [5- (2-hydroxyprop-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl] -6-methylpyridine-2-carboxamide 2-26 N- [5- (2 -Hydroxypropan-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl] -6-methoxypyridine-2-carboxamide 2 -27 N- [5- (2-Hydroxypropan-2-yl) -2- (2-methoxyethyl) -1-methyl-1H-benzimidazol-6-yl] -2-methyl -1,3-oxazole-5-carboxamide 2-28 6-ethyl-N- [5- (2-hydroxyprop-2-yl) -2- (2-methoxyethyl) -1 -Methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-29 N- [5- (2-hydroxyprop-2-yl) -2- (3-methoxypropyl ) -1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide 2-30 N- [5- (2-hydroxyprop-2-yl) -2- (3-methoxypropyl) -1-methyl-1H-benzimidazol-6-yl] -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2- 31 2-cyclopropyl-N- [5- (2-hydroxypropyl-2-yl) -2- (3-methoxypropyl) -1-methyl-1H-benzimidazol-6-yl] -1,3-oxazole-4-carboxamide 2-32 N- [5- (2-hydroxypropyl-2-yl) -2- (3-methoxypropyl) -1-methyl-1H -Benzimidazol-6-yl] -4-trifluoromethyl) -1,3-thi -2-carboxamide 2-33 5-fluoro-N- [5- (2-hydroxyprop-2-yl) -2- (3-methoxypropyl) -1-methyl-1H-benzo Imidazol-6-yl] -6-picoline-2-carboxamide 2-34 N- [5- (2-hydroxypropyl-2-yl) -2- (3-methoxypropyl) -1 -Methyl-1H-benzimidazol-6-yl] -2-methyl-1,3-thiazole-4-carboxamide 2-35 N- {5- (2-hydroxypropyl-2-yl)- 1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2-36 N- {5- (2-Hydroxyprop-2-yl) -1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazole-6-yl} -2 -Trifluoromethyl) -1,3-thiazole-4-carboxamide 2-37 5-fluoro-N- {5- (2-hydroxypropan-2-yl) -1-methyl-2- [2 -(Morpholin-4-yl) ethyl] -1H-benzimidazol-6-yl} -6-picoline-2-carboxamide 2-38 N- {5- (2-hydroxypropyl-2 -Yl) -1-methyl-2- [2- (morpholin-4-yl) ethyl] -1H-benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole -2-carboxamide 2-39 6-amino-N- {5- (2-hydroxypropyl-2-yl) -1-methyl-2- [2- (morpholin-4-yl) ethyl ] -1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-40 2-cyclopropyl-N- {5- (2-hydroxyprop-2-yl) -1-methyl-2 -[2- (morpholin-4-yl) ethyl] -1H-benzimidazol-6-yl} -1,3-oxazole-4-carboxamide Amine 2-41 N- [5- (2-Hydroxypropan-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazol-6-yl] -6 -Trifluoromethyl) pyridine-2-carboxamide 2-42 1- (difluoromethyl) -N- [5- (2-hydroxypropan-2-yl) -1-methyl-2- (? Olin-4-ylmethyl) -1H-benzimidazol-6-yl] -1H-pyrazole-3-carboxamide 2-43 6- (difluoromethyl) -N- [5- (2- Hydroxypropyl-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-44 N- [5 -(2-Hydroxypropan-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazol-6-yl] -2-trifluoromethyl) -1 , 3-thiazole-4-carboxamide 2-45 N- [5- (2-hydroxyprop-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzene Benzimidazol-6-yl] -4-trifluoromethyl) -1,3-thiazol-2-carboxamide 2-46 5-fluoro-N- [5- (2-hydroxypropan-2-yl)- 1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazol-6-yl] -6-methylpyridine-2-carboxamide 2-47 N- [5- (2 -Hydroxypropan-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzimidazol-6-yl] -2-methyl-1,3-thiazole-4 -Methamide 2-48 2-cyclopropyl-N- [5- (2-hydroxypropyl-2-yl) -1-methyl-2- (morpholin-4-ylmethyl) -1H-benzene Benzimidazol-6-yl] -1,3-oxazole-4-carboxamide 2-49 N- {5 -(2-Hydroxyprop-2-yl) -1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazole-6-yl} -6 -Trifluoromethyl) pyridine-2-carboxamide 2-50 6-amino-N- {5- (2-hydroxypropan-2-yl) -1-methyl-2- [2- (4- Methylpiperazin-1-yl) ethyl] -1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-51 N- {5- (2-hydroxypropyl-2-yl) -1 -Methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole- 2-Methamide 2-52 N- {5- (2-Hydroxypropan-2-yl) -1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl]- 1H-benzimidazol-6-yl} -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2-53 2-cyclopropyl-N- {5- (2-hydroxypropyl- 2-yl) -1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl] -1H-benzimidazol-6-yl} -1,3-oxazole-4 -Methamide 2-54 5-fluoro-N- {5- (2-hydroxyprop-2-yl) -1-methyl-2- [2- (4-methylpiperazin-1-yl) ethyl Group] -1H-benzimidazol-6-yl} -6-picoline-2-carboxamide 2-55 N- {5- (2-hydroxyprop-2-yl) -1-methyl-2 -[3- (morpholin-4-yl) propyl] -1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2-56 N- {5- ( 2-hydroxyprop-2-yl) -1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazole-6- } -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2-57 6- (1,1-difluoroethyl) -N- {5- (2-hydroxypropan-2- Yl) -1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-58 1-ethyl- N- {5- (2-Hydroxypropyl-2-yl) -1-methyl-2- [3- (morpholin-4-yl) propyl] -1H-benzimidazole-6-yl} -1H -Pyrazole-3-carboxamide 2-59 N- {5- (2-hydroxypropyl-2-yl) -1-methyl-2- [3- (morpholin-4-yl) propyl]- 1H-benzimidazol-6-yl} -2-methyl-1,3-thiazole-4-carboxamide 2-60 N- {2- [3- (dimethylamino) propyl] -5- (2-Hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2-61 N- {2- [ 3- (dimethylamino) propyl) -5- (2-hydroxypropyl-2-yl) -1-methyl-1H-benzimidazol-6-yl} -2-trifluoromethyl) -1 , 3-thiazole-4-carboxamide 2-62 6- (1,1-difluoroethyl) -N- {2- [3- (dimethylamino) propyl] -5- (2-hydroxyl Prop-2-yl) -1-methyl-1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-63 N- {2- [3- (dimethylamino) propyl]- 5- (2-Hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl} -1-ethyl-1H-pyrazole-3-carboxamide 2-64 N- { 2- [3- (dimethylamino) propyl] -5- (2-hydroxypropyl-2-yl) -1-methyl-1H-benzene Imidazol-6-yl} -2-methyl-1,3-thiazole-4-carboxamide 2-65 (±) N- {2-[(1,1-dioxotetrahydrothiophen-3-yl ) Methyl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2- 66 (±) N- {2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -5- (2-hydroxyprop-2-yl) -1-methyl-1H- Benzimidazole-6-yl} -1-ethyl-1H-pyrazole-3-carboxamide 2-67 (±) N- {2-[(1,1-dioxotetrahydrothiophene-3- Yl) methyl] -5- (2-hydroxypropyl-2-yl) -1-methyl-1H-benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole-2 -Methamide 2-68 (±) 6- (1,1-difluoroethyl) -N- {2-[(1,1-dioxotetrahydrothiophen-3-yl) methyl] -5 -(2-Hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-69 (±) N- {2-[(1,1 -Dioxotetrahydrothiophen-3-yl) methyl] -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl} -2-methyl- 1,3-thiazole-4-carboxamide 2-70 N- {5- (2-hydroxypropyl-2-yl) -1-methyl-2-[(1-methylazetidine-3-yl ) Methyl] -1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2-71 1-ethyl-N- {5- (2-hydroxypropyl-2 -Yl) -1-methyl-2-[(1-methylazetidin-3-yl) methyl ] -1H-benzimidazole-6-yl} -1H-pyrazole-3-carboxamide 2-72 N- {5- (2-hydroxyprop-2-yl) -1-methyl-2- [ (1-methylazetidin-3-yl) methyl) -1H-benzimidazol-6-yl) -2-methyl-1,3-thiazole-4-carboxamide 2-73 6- ( 1,1-difluoroethyl) -N- {5- (2-hydroxypropan-2-yl) -1-methyl-2-[(1-methylazetidin-3-yl) methyl] -1H-benzimidazol-6-yl} pyridine-2-carboxamide 2-74 N- {5- (2-hydroxypropyl-2-yl) -1-methyl-2-[(1-methyl Azetidine-3-yl) methyl) -1H-benzimidazol-6-yl} -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2-75 (±) N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropyl-2-yl) -1-methyl-1H-benzimidazole-6- Yl] -6-trifluoromethyl) pyridine-2-carboxamide 2-75-1 N- (2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-Hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide (enantiomer A) 2 -75-2 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H- Benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide (enantiomer B) 2-76 (±) N- [2- (1,1-dioxo Tetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl Yl-1H-benzimidazol-6-yl) -4-trifluoromethyl) -1,3-thiazole-2-carboxamide 2-77 (±) 6- (1,1-difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazole -6-yl] pyridine-2-carboxamide 2-77-1 6- (1,1-difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2H-thiopyran -3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide (enantiomer A) 2 -77-2 6- (1,1-difluoroethyl) -N- (2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropyl -2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide (enantiomer B) 2-78 (±) N- (2- (1, 1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -2-methyl Yl-1,3-thiazole-4-carboxamide 2-79 (±) N- [5- (2-hydroxypropan-2-yl) -1-methyl-2- (tetrahydrofuran-3-ylmethyl ) -1H-benzimidazol-6-yl) -6-trifluoromethyl) pyridine-2-carboxamide 2-80 (±) 1-ethyl-N- [5- (2-hydroxypropyl-2 -Yl) -1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazol-6-yl] -1H-pyrazole-3-carboxamide 2-81 (±) N- [5- (2-Hydroxyprop-2-yl) -1-methyl-2- (tetrahydrofuran -3-ylmethyl) -1H-benzimidazol-6-yl) -2-methyl-1,3-thiazole-4-carboxamide 2-82 (±) 6- (1,1-difluoro Ethyl) -N- [5- (2-hydroxypropan-2-yl) -1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazol-6-yl] pyridine-2 -Methamide 2-83 (±) N- [5- (2-hydroxypropan-2-yl) -1-methyl-2- (tetrahydrofuran-3-ylmethyl) -1H-benzimidazole-6 -Yl] -2-trifluoromethyl) -1,3-thiazole-4-carboxamide 2-84 (±) N- {2-[(1,1-dioxotetrahydro-2H-thiopyran -3-yl) methyl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-methyl Acetamide 2-85 (±) N- {2-[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) methyl] -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl) -1-ethyl-1H-pyrazole-3-carboxamide 2-86 (±) 6- (1,1-difluoroethyl) -N- {2-[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) methyl] -5- (2-hydroxyprop-2-yl) -1-methyl-1H -Benzimidazol-6-yl} pyridine-2-carboxamide 2-87 (±) N- {2-[(1,1-dioxotetrahydro-2H-thiopyran-3-yl) methyl ] -5- (2-Hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole-2-carboxamide 2-88 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-4- ) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide 2-89 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazole-6- Yl] -1-ethyl-1H-pyrazole-3-carboxamide 2-90 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5- ( 2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -2-methyl-1,3-thiazole-4-carboxamide 2-91 6- (1, 1-difluoroethyl) -N- (2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5- (2-hydroxyprop-2-yl) -1-methyl Yl-1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-92 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5- (2-Hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl) -4-trifluoromethyl) -1,3-thiazole-2-carboxamide 2-93 N -[5- (2-Hydroxypropan-2-yl) -2- (methoxymethyl) -1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2 -Methamide 2-94 1-ethyl-N- [5- (2-hydroxyprop-2-yl) -2- (methoxymethyl) -1-methyl-1H-benzimidazole-6- Yl] -1H-pyrazole-3-carboxamide 2-95 N- [5- (2-hydroxypropyl-2-yl) -2- (methoxymethyl) -1-methyl-1H-benzo Imidazol-6-yl] -2-methyl-1,3-thiazole-4-carboxamide 2-96 6- (1, 1-difluoroethyl) -N- [5- (2-hydroxypropyl-2-yl) -2- (methoxymethyl) -1-methyl-1H-benzimidazol-6-yl] pyridine- 2-Methamide 2-97 N- [5- (2-Hydroxypropan-2-yl) -2- (methoxymethyl) -1-methyl-1H-benzimidazol-6-yl] -4 -Trifluoromethyl) -1,3-thiazole-2-carboxamide 2-98 N- {5- (2-hydroxyprop-2-yl) -1-methyl-2-[(mesylsulfonyl ) Methyl] -1H-benzimidazol-6-yl} -6-trifluoromethyl) pyridine-2-carboxamide 2-99 1-ethyl-N- {5- (2-hydroxypropyl-2 -Yl) -1-methyl-2-[(methylsulfonyl) methyl] -1H-benzimidazol-6-yl} -1H-pyrazole-3-carboxamide 2-100 6- (1 , 1-difluoroethyl) -N- {5- (2-hydroxypropyl-2-yl) -1-methyl-2-[(methylsulfonyl) methyl] -1H-benzimidazole-6 -Yl} pyridine-2-carboxamide 2-101 N- {5- (2-hydroxypropan-2-yl) -1-methyl-2-[(methanesulfonyl) methyl] -1H-benzene Benzimidazol-6-yl} -4-trifluoromethyl) -1,3-thiazole-2-carboxamide 2-102-1 N- [2- (1,1-dioxotetrahydrothiophene-3 -Yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6-trifluoromethyl) pyridine-2-carboxamide (enantiomer Isomer A) 2-102-2 N- (2- (1,1-dioxotetrahydrothiophen-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl- 1H-benzimidazole-6-yl] -6-tri Fluoromethyl) pyridine-2-carboxamide (enantiomer B) 2-103 (±) N- (2- (1,1-dioxotetrahydrothiophen-3-yl) -5- ( 2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -1-ethyl-1H-pyrazole-3-carboxamide 2-104 (±) N- [ 2- (1,1-dioxotetrahydrothiophen-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -2- Methyl-1,3-thiazole-4-carboxamide 2-105 (±) 6- (1,1-difluoroethyl) -N- [2- (1,1-dioxotetrahydrothiophene- 3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide 2-106 (±) N- (2 -(1,1-dioxotetrahydrothiophen-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] -4-tri Fluoromethyl) -1,3-thiazole-2-carboxamide. 如請求項6之通式(I)之化合物，其為： 2-1 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺 2-2 N-[2-(3-羥基-3-甲基丁基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-2-(三氟甲基)-1,3-噻唑-4-甲醯胺 2-75 (±)N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺 2-75-1 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺(對映異構體A) 2-75-2 N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]-6-(三氟甲基)吡啶-2-甲醯胺(對映異構體B) 2-77 (±)6-(1,1-二氟乙基)-N-[2-(1,1-二氧代四氫-2H-噻喃-3-基)-5-(2-羥丙-2-基)-1-甲基-1H-苯并咪唑-6-基]吡啶-2-甲醯胺。The compound of the general formula (I) according to claim 6, which is: 2-1 N- [2- (3-hydroxy-3-methylbutyl) -5- (2-hydroxyprop-2-yl)- 1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide 2-2 N- [2- (3-hydroxy-3-methylbutyl ) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl) -2- (trifluoromethyl) -1,3-thiazole-4-carboxamide Amine 2-75 (±) N- (2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl -1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide 2-75-1 N- [2- (1,1-dioxotetrahydro-2H- Thian-3-yl) -5- (2-hydroxypropan-2-yl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-methyl Acetamide (Enantiomer A) 2-75-2 N- [2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxypropyl-2 -Yl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide (enantiomer B) 2-77 (±) 6 -(1,1-difluoroethyl) -N- (2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5- (2-hydroxyprop-2-yl) -1-methyl-1H-benzimidazol-6-yl] pyridine-2-carboxamide. 如請求項1至7中任一項所定義之通式(I)之化合物，其用於治療及/或預防疾病之方法中。The compound of general formula (I) as defined in any one of claims 1 to 7 is used in a method for treating and / or preventing diseases. 如請求項1至7中任一項所定義之通式(I)之化合物，其用於治療及/或預防腫瘤性疾病、皮膚疾病、婦科疾病、心血管疾病、肺疾病、眼病、神經系統疾病、代謝疾病、肝病、腎病、炎性疾病、自體免疫性疾病及疼痛之方法中。The compound of general formula (I) as defined in any one of claims 1 to 7 for use in the treatment and / or prevention of neoplastic diseases, skin diseases, gynecological diseases, cardiovascular diseases, lung diseases, eye diseases, nervous system Methods for diseases, metabolic diseases, liver diseases, kidney diseases, inflammatory diseases, autoimmune diseases and pain. 如請求項1至7中任一項所定義之通式(I)之化合物，其用於治療及/或預防淋巴瘤、黃斑變性、牛皮癬、紅斑狼瘡、多發性硬化、COPD、痛風、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、慢性腎病、腎病變、子宮內膜異位症及與子宮內膜異位症有關之疼痛及其他諸如痛經、***困難、排尿困難及排便困難之與子宮內膜異位症相關聯之症狀之方法中。The compound of general formula (I) as defined in any one of claims 1 to 7, which is used for the treatment and / or prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, Liver fibrosis, insulin resistance, metabolic syndrome, spondyloarthritis and rheumatoid arthritis, chronic kidney disease, nephropathy, endometriosis and pain related to endometriosis and other such as dysmenorrhea, sexual intercourse Difficulties, difficulty urinating, and difficulty defecating are among the symptoms associated with endometriosis. 如請求項1至7中任一項所定義之通式(I)之化合物，其用於治療及/或預防疼痛之方法中，該疼痛包括急性、慢性、炎性及神經性疼痛，較佳地痛覺過敏、異常性疼痛、來自關節炎(諸如骨關節炎、類風濕性關節炎、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、手術後疼痛、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***炎之疼痛、由脊髓損傷引起之疼痛、炎症引起之疼痛、下背痛、癌症疼痛、與化療相關聯之疼痛、HIV治療引起之神經病變、燒傷引起之疼痛及慢性疼痛。The compound of general formula (I) as defined in any one of claims 1 to 7, which is used in a method for treating and / or preventing pain, the pain including acute, chronic, inflammatory and neuropathic pain, preferably Hyperalgesia, allodynia, pain from arthritis (such as osteoarthritis, rheumatoid arthritis, spinal arthritis), premenstrual pain, pain associated with endometriosis, postoperative pain, Pain from interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain from prostatitis, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, chemotherapy related Joint pain, neuropathy caused by HIV treatment, pain caused by burns, and chronic pain. 一種如請求項1至7中任一項所定義之通式(I)之化合物於製備藥劑之用途。Use of a compound of general formula (I) as defined in any one of claims 1 to 7 in the preparation of a medicament. 如請求項12之用途，其中該藥劑係用於治療及/或預防腫瘤性疾病、皮膚疾病、婦科疾病、心血管疾病、肺病、眼病、神經系統疾病、代謝疾病、肝病、腎病、炎性疾病、自體免疫性疾病及疼痛。The use according to claim 12, wherein the medicament is used to treat and / or prevent neoplastic diseases, skin diseases, gynecological diseases, cardiovascular diseases, lung diseases, eye diseases, nervous system diseases, metabolic diseases, liver diseases, kidney diseases, inflammatory diseases 1. Autoimmune diseases and pain. 如請求項12或13之用途，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、COPD、痛風、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、慢性腎病、腎病、子宮內膜異位症及與子宮內膜異位症有關之疼痛及其他諸如痛經、***困難、排尿困難及排便困難之與子宮內膜異位症相關聯之症狀。The use according to claim 12 or 13 is for the treatment and / or prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome, Spondyloarthritis and rheumatoid arthritis, chronic kidney disease, nephropathy, endometriosis, and pain associated with endometriosis Symptoms associated with ectopic disease. 如請求項12或13之用途，其係用於治療及/或預防疼痛，疼痛包括急性、慢性、炎性及神經性疼痛，較佳地痛覺過敏、異常性疼痛、來自關節炎(諸如骨關節炎、類風濕性關節炎、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、手術後疼痛、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***炎之疼痛、由脊髓損傷引起之疼痛、炎症引起之疼痛、下背痛、癌症疼痛、與化療相關聯之疼痛、HIV治療引起之神經病變、燒傷引起之疼痛及慢性疼痛。The use as claimed in claim 12 or 13 is for the treatment and / or prevention of pain, including acute, chronic, inflammatory and neuropathic pain, preferably hyperalgesia, allodynia, arthritis (such as bone and joint Inflammation, rheumatoid arthritis, spinal arthritis) pain, premenstrual pain, pain associated with endometriosis, postoperative pain, pain from interstitial cystitis, CRPS (complex regional pain Syndrome), trigeminal neuralgia, pain from prostatitis, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, pain associated with chemotherapy, neuropathy caused by HIV treatment, pain caused by burns And chronic pain. 一種藥劑，其包含如請求項1至7中任一項所定義之式(I)之化合物與惰性無毒醫藥上適宜之賦形劑之組合。A medicament comprising a combination of a compound of formula (I) as defined in any one of claims 1 to 7 and an inert non-toxic pharmaceutically suitable excipient.
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