TWI724995B - 作為生長激素釋放肽受體激動劑之絲胺酸衍生物 - Google Patents
作為生長激素釋放肽受體激動劑之絲胺酸衍生物 Download PDFInfo
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- TWI724995B TWI724995B TW104125459A TW104125459A TWI724995B TW I724995 B TWI724995 B TW I724995B TW 104125459 A TW104125459 A TW 104125459A TW 104125459 A TW104125459 A TW 104125459A TW I724995 B TWI724995 B TW I724995B
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- oxo
- amino
- methyl
- pyridine
- tetrahydro
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- HDOZVRUNCMBHFH-UHFFFAOYSA-N zotepine Chemical compound CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12 HDOZVRUNCMBHFH-UHFFFAOYSA-N 0.000 description 1
- 229960004496 zotepine Drugs 0.000 description 1
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Abstract
本發明係關於化學式(I)的新型化合物或其藥學上可接受的鹽或溶劑化物、該等的製備製程、含有該等之藥物組成物及該等在治療中之用途,例如作為生長激素促分泌素受體(亦被稱為生長激素釋放肽受體或GHSR1a受體)的調節劑和/或用於治療和/或預防由生長激素釋放肽受體介導之紊亂。
Description
本發明係關於新型絲胺酸衍生物、該等的製備製程、可使用於該等的製程之中間體及含有該化合物之藥物組成物。本發明還係有關於絲胺酸衍生物在治療中之用途,例如作為生長激素促分泌素受體(亦被稱為生長激素釋放肽受體或GHSRla受體)的調節劑和/或用於治療和/或預防癌症厭食症/惡病質;由抗癌藥物引起之惡病質及厭食症;由抗癌藥物引起之痛覺過敏;COPD(chronic obstructive pulmonary disease:慢性阻塞性肺病)/COPD惡病質;肌少症;飲食失調症及神經性飲食失調症;體重降低抑制;癌症患者術後早期恢復;慢性呼吸道感染;炎症;IBD(inflammatory bowel disease:炎症性腸病);FD(functional-dyspepsia:功能性消化不良);便秘;糖尿病性胃輕癱及胃輕癱;心臟衰竭;心肌梗塞;糖尿病神經病變;帕金森氏症;多發性硬化症;生長激素缺乏症的診斷及治療;老年人QOL(quality of life:生活質量)改善;脊髓損傷患者的腸道運動障礙;術後腸阻塞;及由嗎啡誘導之腸阻塞。
生長激素釋放肽係用於生長激素(GH)促分泌素受體之內源性配體。生長激素釋放肽最初从胃裡被純化,係位置3的絲胺酸被n-辛醯化的28胺基酸肽類激素。生長激素釋放肽具有較強的GH释放活性,因此被認為在维持GH释放及能量平衡方面發揮重要的作用(非專利文獻
1)。尤其,認為具有較強的食慾刺激活性。此外,已知生長激素釋放肽激動劑對癌症厭食症/惡病質(非專利文獻2、3及4);由抗癌藥物引起之惡病質及厭食症(非專利文獻4及5);由抗癌藥物引起之痛覺過敏(非專利文獻5);COPD/COPD惡病質(非專利文獻6及7);肌少症(非專利文獻8);飲食失調症及神經性飲食失調症(非專利文獻9);體重降低抑制(非專利文獻10);癌症患者術後早期恢復(非專利文獻11);慢性呼吸道感染(非專利文獻7);炎症(非專利文獻12);IBD(非專利文獻12);FD(非專利文獻4);便秘(非專利文獻9);糖尿病性胃輕癱及胃輕癱(非專利文獻4及13);心臟衰竭(非專利文獻14、15及16);心肌梗塞(非專利文獻14、15及16);糖尿病神經病變(非專利文獻17);帕金森氏症(非專利文獻18);多發性硬化症(非專利文獻19);生長激素缺乏症的診斷及治療(非專利文獻20);老年人QOL的改善(非專利文獻20);脊髓損傷患者的腸道運動障礙(非專利文獻21);術後腸阻塞(非專利文獻4及22);及由嗎啡誘導之腸阻塞(非專利文獻22)的治療和/或預防有用。
(先前技術文獻)
(非專利文獻)
{非專利文獻1}Scientifica 2013, Article ID 518909(http://dx.doi.org/10.1155/2013/518909), 25 pages, 2013
{非專利文獻2}The Oncologist 12, 594-600, 2007.
{非專利文獻3}Support Care Cancer 21, 2409-2415, 2013
{非專利文獻4}Neurogastroenterol Motil 20, 177-184, 2008
{非專利文獻5}Endocrinology 149, 455-460, 2008
{非專利文獻6}BMC Pulmonary Medicine 13, 37-46, 2013
{非專利文獻7}Methods in Enzymology 514, 399-407, 2012
{非專利文獻8}Arch Med Sci 9, 166-171, 2013
{非專利文獻9}Frontiers in Endocrinology 4, 1-27, 2013
{非專利文獻10}Ann intern Med 149, 601-611, 2008
{非專利文獻11}Gastric Cancer 17, 200-205, 2014
{非專利文獻12}Mol Nutr Food Res 52, 855-866, 2008
{非專利文獻13}Neurogastroenterol Motil 25, e140-e150, 2013
{非專利文獻14}Journal of Cardiology 59, 8-13, 2012
{非專利文獻15}Curr Opin Clin Nutr Metab Care 16, 619-624, 2013
{非專利文獻16}Endocrinology 153, 2436-2443, 2012
{非專利文獻17}Biochemical and Biophysical Research Communications 389, 405-408, 2009
{非專利文獻18}Stereotact Funct Neurosurg 90, 104-112, 2012
{非專利文獻19}Ir J neurol 12, 60-65, 2013
{非專利文獻20}Drug Discovery Today 4, 497-506, 1999
{非專利文獻21}Neurogastroenterol Motil 21, 71-77, 2009
{非專利文獻22}Peptides 26, 1598-1601, 2005
因此,希望找到調節生長激素釋放肽受體活性之新化合物。
其中:A為芳基;較佳的芳基為苯基、萘基或吡啶基;更為佳的芳基為苯基或吡啶基;最為佳的A為苯基、2-吡啶基或3-吡啶基;X為CH或N;R1獨立地選自由(1)氫、(2)鹵素、(3)C1-6烷基,其中,該烷基未被取代或被一個以上的獨立地選自鹵素、羥基、-O-C1-6烷基、氨基、C1-6烷基氨基及(C1-6烷基)(C1-6烷基)N-中之取代基取代、(4)-O-C1-6烷基,其中,該烷基未被取代或被一個以上的獨立地選自鹵素、羥基、-O-C1-6烷基、氨基、C1-6烷基氨基及(C1-6烷基)(C1-6烷基)N-中之取代基取代、(5)-CN及(6)-SO2C1-6烷基所構成之群組;較佳的R1獨立地選自由以下所構成之群組;(1)氫、(2)鹵素、(3)三氟甲基、(4)三氟甲氧基及(5)-CN;更為佳的R1獨立地選自由以下所構成之群組:(1)氫、(2)-F、(3)-Cl、(4)三氟甲基、(5)三氟甲氧基及(6)-CN;R2為氫或C1-6烷基,其中,該烷基未被取代或被一個以上的獨立地選自鹵素、羥基、-O-C1-6烷基、氨基、C1-6烷基氨基及(C1-6烷基)(C1-6烷基)N-中之取代基取代;較佳的R2為C1-6烷基,其中,該烷基未被取代或被1至3個獨立地選自鹵素中之取代基取代;更為佳的R2為甲基或二氟乙基;最為佳的R2為甲基或2,2-二氟乙基;p為1、2、3,或4;當p為2以上時,R1可相同或不同;較佳的p為1
或2。
[2]本發明提供[1]所述之上述化學式(I)所表示之化合物或其藥學上可接受的鹽,其中:A為苯基、萘基或吡啶基。
[3]本發明提供[1]或[2]所述之上述化學式(I)所表示之化合物或其藥學上可接受的鹽,其中:A為苯基、萘基或吡啶基;R2為氫或C1-C6烷基,其中,該烷基未被取代或被1至3個獨立地選自鹵素中之取代基取代。
[4]本發明提供[1]至[3]中任一項所述之上述化學式(I)所表示之化合物或其藥學上可接受的鹽,其中:A為苯基、萘基或吡啶基;R1獨立地選自由以下所構成之群組;(1)氫、(2)鹵素、(3)三氟甲基、(4)三氟甲氧基、(5)-CN及(6)-SO2C1-6烷基;R2為C1-6烷基,其中,該烷基未被取代或被1至3個獨立地選自鹵素中之取代基取代。
[5]本發明提供[1]至[4]中任一項所述之上述化學式(I)所表示之化合物或其藥學上可接受的鹽,其中:A為苯基、萘基或吡啶基;R1獨立地選自由以下所構成之群組;(1)氫、(2)-F,(3)-Cl(4)三氟甲基、(5)三氟甲氧基、(6)-CN及(7)-SO2CH3;R2為甲基或二氟乙基。
[6]本發明提供[1]至[5]中任一項所述之上述化學式(I)所表示之化合物或其藥學上可接受的鹽,其中:A為苯基、2-吡啶基或3-吡啶基;R1獨立地選自由以下所構成之群組;(1)氫、(2)-F、(3)-Cl、
(4)三氟甲基、(5)三氟甲氧基及(6)-CN;R2為甲基或2,2-二氟乙基。
[7]本發明的合適的個別化合物如下:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-
基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫
-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;
2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;及2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;或其藥學上可接受的鹽。
[8]本發明的更合適的個別化合物如下:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;及2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;或其藥學上可接受的鹽。
[9]本發明提供一種藥物組成物,其包含[1]至[8]中任一項所述之
化合物或其藥學上可接受的鹽及藥學上可接受的載體。
[10]本發明提供[9]所述之藥物組成物,其還包含另一藥理活性劑。
[11]本發明提供治療患有由生長激素釋放肽受體介導之病症或紊亂之包括人在內之動物之方法,其包含將有效量的[1]至[8]中任一項所述之化學式(I)的化合物或藥學上可接受的鹽給藥於前述受治者。
[12]本發明提供[11]所述之方法,其中,前述病症或紊亂選自由以下所構成之群組:癌症厭食症/惡病質;由抗癌藥物引起之惡病質及厭食症;由抗癌藥物引起之痛覺過敏;COPD/COPD惡病質;肌少症;飲食失調症及神經性飲食失調症;體重降低抑制;癌症患者術後早期恢復;慢性呼吸道感染;炎症;IBD;FD;便秘;糖尿病性胃輕癱及胃輕癱;心臟衰竭;心肌梗塞;糖尿病神經病變;帕金森氏症;多發性硬化症;生長激素缺乏症的診斷及治療;老年人QOL的改善;脊髓損傷患者的腸道運動障礙;術後腸阻塞;及由嗎啡誘導之腸阻塞;以及其組合。
[13]本發明提供[1]至[8]中任一項所述之化合物或藥學上可接受的鹽或其組成物在製造用於治療由生長激素釋放肽受體介導之病症或紊亂之藥物中之用途。
[14]本發明提供[13]所述之用途,其中,前述病症或紊亂選自由以下所構成之群組:癌症厭食症/惡病質;由抗癌藥物引起之惡病質及厭食症;由抗癌藥物引起之痛覺過敏;COPD/COPD惡病質;肌少症;飲食失調症及神經性飲食失調症;體重降低抑制;癌症患者術後早期恢復;慢性呼吸道感染;炎症;IBD;FD;便秘;糖尿病性胃輕癱及胃輕癱;心臟衰竭;心肌梗塞;糖尿病神經病變;帕金森氏症;多發性硬化症;生長激素缺乏症的診斷及治療;老年人QOL的改善;脊髓損傷患者的腸道運動障礙;術後腸阻塞;及由嗎啡誘導之腸阻塞;以及其組合。
[15]本發明提供[1]至[8]中任一項所述之化合物或其藥學上可接受的鹽,其用於治療由生長激素釋放肽受體介導之病症或紊亂。
[16]本發明提供一種藥物組成物的製備製程,其包含將[1]至[8]中任一項所述之化合物或其藥學上可接受的鹽與藥學上可接受的載體、稀釋劑或賦形劑進行混合。
[17]本發明提供一種在有意識的禁食小鼠中生長激素(GH)反應的測定過程,其包含將測試化合物口服給藥於BALB/c小鼠。
[18]本發明提供一種在大鼠中順鉑-誘導之惡病質/厭食症的測定過程,其包含在傍晚將測試化合物及順鉑給藥於處理得當的大鼠。
[19]本發明提供一種在承載有AH-130細胞之大鼠中惡病質(體重降低及肌肉萎縮)的測定過程,其包含將測試化合物口服給藥於腹膜內注射了大於1×108的AH-130腹水肝癌細胞之未成熟之雄性大鼠。
本發明的絲胺酸衍生物係生長激素釋放肽受體激動劑,並且具有多種治療應用,特別是用於治療癌症厭食症/惡病質;由抗癌藥物引起之惡病質及厭食症;由抗癌藥物引起之痛覺過敏;COPD/COPD惡病質;肌少症;飲食失調症及神經性飲食失調症;體重降低抑制;癌症患者術後早期恢復;慢性呼吸道感染;炎症;IBD;FD;便秘;糖尿病性胃輕癱及胃輕癱;心臟衰竭;心肌梗塞;糖尿病神經病變;帕金森氏症;多發性硬化症;生長激素缺乏症的診斷及治療;老年人QOL的改善;脊髓損傷患者的腸道運動障礙;術後腸阻塞;及由嗎啡誘導之腸阻塞。
如下述方案I所說明,本發明由位於絲胺酸衍生物的中央之一部分絲胺酸表徵。Pfizer Inc.於WO97/24369中揭示了生長激素釋放肽受體激動劑,其被視為結構上接近先前技術。最接近的化合物被認為係WO97/24369中的實施例183的化合物,其係方案II中所說明之高絲胺酸
衍生物。與高絲胺酸的例子相比,本發明的絲胺酸衍生物對生長激素釋放肽受體顯現出更好的活性。如本說明書的實驗中的表7所示,從高絲胺酸衍生物去除一個碳會使該活性急劇增加。
相對於本領域中公開之其他化合物,本發明的化合物可顯示出更少的毒性、良好的吸收與分佈、良好的溶解度、更少的血漿蛋白質結合、更少的藥物-藥物相互作用、良好的代謝穩定性、HERG通道中的減少的抑制活性和/或減少的QT延長。
如同本領域技術人員領會到的那樣,本申請中所使用之術語“鹵素”或“鹵代”意在包括氟代、氯代、溴代及碘代。類似地,如在C1-6中所示,1-6定義為被認定具有序號1、2、3、4、5或6。基於上述定義,如在C1-6烷基中所示,C1-6定義為被認定烷基具有1、2、3、4、5或6個碳原子之基團。被指定為用取代基獨立地取代之基團可獨立地被多個
那樣的取代基取代。
本申請中所使用之術語“烷基”係指直鏈飽和一價烴基或分支的飽和一價烴基,例如指甲基、乙基、丙基、2-丙基、丁基(包括所有異構形態)、戊基(包括所有異構形態)等。
本申請中所使用之術語“芳基”係指可含有選自O、N及S中之0至4個雜原子之單碳環或雙碳環或者單雜環或雙雜環,但並不限定於苯基、萘基、苯並呋喃基、苯並呋吖基、苯並咪唑啉酮基、苯並咪唑基、苯並異噻唑基、苯並異噁唑基、苯並噻二唑基、苯並噻唑基、苯並噁二唑基、苯並噁唑啉基、苯並噁唑基、苯並噻吩基、苯並三唑基、咔唑基、咔啉基、色滿基、噌啉基、2,3-二氧代吲哚基、呋喃基、呋吖基、呋喃並吡啶基、呋喃並吡咯基、咪唑基、咪唑並吡嗪基、咪唑並吡啶基、咪唑並嘧啶基、咪唑並噻唑基、吲唑基、吲哚嗪基、吲哚啉基、吲哚基、異苯並呋喃基、異色滿基、異吲哚基、異喹啉基、異噁唑並吡啶基、異噁唑啉基、異噁唑基、異噻唑基、萘啶基、噁唑啉基、噁二唑基、噁唑基、氧雜環丁烷基、2-氧代吲哚基、酞嗪基、吡唑並吡啶基、吡唑並嘧啶基、吡唑基、吡嗪基、吡啶基、嘧啶基、哒嗪基、吡啶並嘧啶基、吡咯並吡啶基、吡咯基、喹唑啉基、喹啉基、喹噁啉基、四唑並吡啶基、四唑基、噻二唑基(thiadiazolyl)、噻唑基、噻吩基、噻吩並吡嗪基、噻吩並吡唑基、噻吩並吡啶基、噻吩並吡咯基、三唑並嘧啶基、三唑基、4-氧代-1,4-二氫喹啉基、2-氧代-1,2-二氫吡啶基、4-氧代-1,4-二氫嘧啶基、2-氧代-1,2-二氫喹啉基、4-氧代-4H-吡啶並[1,2-a]嘧啶基、4-氧代-1,4-二氫-1,8-萘啶基及該等的N-氧化物。
本申請中所使用之術語“治療”係指出緩解指定的病症、消除或減輕病症的病狀、延遲或消除病症的進展、以及預防或遲緩有病史之患者或受治者中該病症之復發。
本申請中所使用之術語“傍晚”係指約16:00至24:00,約17:00
至20:00為較佳。
如果沒有特別提及,本申請中所使用之冠詞“a”或“an”係指其冠詞所提及之對象的單數形和複數形這兩者。
本申請中所使用之術語“動物”包括哺乳動物對象或非哺乳動物對象。合適的哺乳動物對象的例子可包括但並不限定於人、齧齒類、伴侶動物、家畜及靈長類。合適的齧齒類可包括但並不限定於小鼠、大鼠、地鼠、沙鼠及豚鼠。合適的伴侶動物可包括但並不限定於貓、狗、兔及雪貂。合適的家畜可包括但並不限定於馬、山羊,羊、豬、牛、美洲鴕及羊駝。合適的靈長類可包括但並不限定於黑猩猩、狐猴、猕猴、狨猴、蜘蛛猴、松鼠猴及長尾猴。合適的非哺乳動物對象的例子可包括但並不限定於鳥類、爬蟲類、兩棲類及魚類。鳥類的非限制性例子包括雞、火雞、鴨及鵝。較佳的哺乳動物對象為人。
本發明的化合物的鹽亦包含於本發明的範疇內。由於該等的藥學上的使用潛力,化學式(I)的化合物的鹽為藥學上可接受為較佳。合適的藥學上可接受的鹽可包括酸加成鹽。藥學上可接受的酸加成鹽可藉由化學式(I)的化合物與合適的無機酸或有機酸(諸如氫溴酸、鹽酸、氫碘酸、硫酸、硝酸、磷酸、對甲苯磺酸、甲磺酸或萘磺酸)任意地在諸如有機溶劑之類的合適的溶劑中反應形成,以獲得通常藉由例如結晶及過濾而分離之鹽。化學式(I)的化合物的藥學上可接受的酸加成鹽的例子包括HCI、HBr、HI、硫酸鹽或硫酸氫鹽、硝酸鹽、磷酸鹽或磷酸氫鹽、乙酸鹽、苯甲酸鹽、琥珀酸鹽、糖酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、乳酸鹽、檸檬酸鹽、酒石酸鹽、葡糖酸鹽、樟腦磺酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及雙羥萘酸鹽。關於合適的藥學鹽,請查看文獻[Berge et al,J.Pharm,Sci,66,1-19,1977;P L Gould,International Journal of Pharmaceutics,33(1986),201-217];及[Bighley et al,Encyclopedia of Pharmaceutical
Technology,Marcel Dekker Inc,New York 1996,Volume 13,page 453-497]。例如三氟乙酸鹽等藥學上不可接受的其他鹽可對本發明的化合物的製備有用,該等構成本發明的另一方面。本發明在其範疇內包括化學式(I)的化合物的鹽的所有可能的化學計量及非化學計量形態。
有機化學領域的技術人員將理解很多有機化合物能夠與溶劑形成錯合物,該等有機化合物在溶劑內反應或從溶劑中沉澱或結晶化。該等錯合物被稱為“溶劑化物”。例如,含水之錯合物被稱為“水合物”。本發明的化合物的溶劑化物在本發明範疇內。
具有非藥學上可接受的抗衡離子或相關溶劑的鹽及溶劑化物包括在本發明的範圍內,例如在製備化學式(I)的其他化合物及其藥學上可接受的鹽時用作中間體。
化學式(I)的化合物可以以晶體形態具備多形體,其包括在本發明的範疇內。
另外,化學式(I)的化合物的所謂的“前體藥物”亦包括在本發明的範疇內。因此,其本身可能幾乎或完全不具有藥理活性之化學式(I)的化合物的特定衍生物當給藥於體內或體表時,例如可藉由水解或水解性斷裂而轉化為具有目標活性之化學式(I)的化合物。該種衍生物以“前體藥物”提及。關於前體藥物用途的詳細資訊可查看下述文獻:Pro-drugs as Novel Delivery Systems,Vol.14,ACS Symposium Series(T Higuchi and W Stella)and Bioreversible Carriers in Drug Design,Pergamon Press,1987(ed.E B Roche,American Pharmaceutical Association)。
依本發明的前體藥物係可藉由例如將化學式(I)的化合物中存在之合適的官能基作為例如文獻:Design of Prodrugs by H.Bundgaard(Elsevier,1985)中所記載之“前體部分(pro-moiety)”,由本領域
技術人員周知之特定部分取代而進行製備。依本發明的前體藥物的一部分例子包括以下:(i)當化學式(I)的化合物中含有醇官能基(-OH)時,羥基被在體內可轉化為羥基之部分取代之化合物。前述在體內可轉化為羥基之部分係指,例如藉由水解和/或酶例如酯酶在體內可變换為羥基之部分。前述部分的例子包括但並不限定於在體內可容易水解之酯基及醚基。用醯氧基烷基、1-(烷氧基羰氧基)烷基、酞基及醯氧基烷氧基羰基(例如新戊醯氧基甲氧基羰基)取代羥基的氫之部分為較佳;及(ii)當化學式(I)的化合物中含有氨基時,將藉由與合適的酸性鹵化物或合適的酸酐的反應而製備之吡咯並吡啶酮衍生物作為前體藥物來舉例說明。作為前體藥物,吡咯並吡啶酮衍生物為-NHCO(CH2)2OCH3、-NHCOCH(NH2)CH3等最為佳。
依前述實施例及其他前體藥物類型的實施例之替換基團的進一步的實施例可查看上述參考文獻。
此外,化學式(I)的化合物能够以前體藥物來給藥。本申請中所使用之術語亦即化學式(I)的化合物的“前體藥物”係給藥於患者時最終在體內釋放化學式(I)的化合物之化合物功能性衍生物。當以前體藥物給藥化學式(I)的化合物時,本領域技術人員可實施下列中的一種以上:(a)變更前述化合物的體內起效時間;(b)變更前述化合物的體內作用持續時間;(c)變更前述化合物的體內輸送或分佈;(d)變更前述化合物的體內溶解度;以及(e)克服前述化合物所面臨之副作用或其他難點。用於製備前體藥物之典型的功能性衍生物包括在體內以化學形態或酶的形態裂解之化合物的修飾。包括磷酸鹽、醯胺、酯、硫代酯、碳酸鹽及氨基甲酸鹽的製備之該等修飾對本領域技術人員而言係周知的。
特定的化學式(I)的化合物可存在一個以上的手性碳原子。在該情況下,化學式(I)的化合物作為立體異構物存在。本發明擴展至包括對映異構物、非對映異構物及其混合物例如外消旋體在內之諸如化學式(I)的化合物的立體異構物形態之類的所有光學異構物。不同之立體異構物形態可藉由常規方法相互分離或分解,或者任意給定之異構物可藉由常規的立體選擇性或非對稱合成來得到。
本申請中,特定化合物可以以多種互變異構物形態存在,且應該理解為本發明包括所有該種互變異構物形態。
本發明還包括本發明的化合物的所有合適的同位素變體(isotopic variation)。本發明的同位素變體被定義為至少一個原子被具有相同的原子數但原子質量與自然界中常見之原子的原子質量不同之原子替代。可摻入於本發明的化合物中之同位素的例子分別包括諸如2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F及36CI之類的氫、碳、氮、氧、磷、硫、氟及氯的同位素。本發明的特定同位素變體,例如摻入了諸如3H或14C之類之放射性同位素對藥物和/或基質組織分佈研究有用。從製備之容易性及可檢測性之觀點考慮,氚(亦即3H)及碳-14(亦即14C)的同位素尤為佳。並且,由諸如重氫(亦即2H)之類的同位素進行之取代可提供更大代謝穩定性的特定治療方面的優勢,例如增加體內半衰期或減少劑量需要,因此根據情況這可以是較佳的。本發明的化合物的同位素變體一般能夠藉由諸如解說性方法之類的常規程序來進行製備,或者能夠藉由在後述之化合物中所記載之使用適當的同位素變體之合適的製劑來進行製備。
本發明的另一實施形態還提供化學式(I)的化合物及其藥學上可接受的鹽或溶劑化物,其用於醫學療法,尤其用於治療由生長激素釋放肽受體介導之紊亂。
本發明的另一實施形態係有關用於預防和/或治療由生長激素釋
放肽受體介導之紊亂之生長激素釋放肽受體活性的調節方法。
本發明的另一實施形態提供治療患有由生長激素釋放肽受體介導之紊亂之包括人在內之動物之方法,其包括將有效量的化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物給藥於前述受治者。該種治療包含給藥治療有效量的包括其藥學上可接受的鹽或溶劑化物之化學式(I)的化合物之步驟。該種治療亦可包含給藥治療有效量的含有包括其藥學上可接受的鹽或溶劑化物之化學式(I)的化合物之藥物組成物之步驟。
本發明的另一實施形態提供化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物在製備用於治療由生長激素釋放肽受體介導之紊亂之藥物中之用途。
在生長激素釋放肽受體中,內源性配體的生長激素釋放肽的作用顯示為有效的生長激素釋放活性、食慾刺激、胃運動的促進及酸分泌、積極的心血管功效及對骨形成之直接作用。因此,生長激素釋放肽受體調節劑在生長激素不足、飲食失調症、胃腸道疾病、心血管疾病、骨質疏鬆症、老化及分解代謝狀態或慢性消耗性綜合症的治療中可獲得有益的效果(Kojima and Kangawa,Nature Clinical Practice,Feb 2006,VoI.2,No.2,80-88)。生長激素釋放肽受體調節劑在睡眼障礙的治療中亦可獲得有益的效果(Brain Research,1088(2006)131-140)。
與生長激素釋放肽受體有關、因此可由生長激素釋放肽受體介導之、生長激素釋放肽受體調節劑可獲得有益的效果之特定紊亂包括肥胖症及肥胖症相關風險因素。並且,肥胖症相關風險因素包括糖尿病、糖尿病相關併發症、代謝綜合症、心血管疾病(包括動脈粥樣硬化及異常血脂症),但並不限定於此。
在由生長激素釋放肽受體介導之其他疾病和/或病症中,生長激素釋放肽包括以下:生長激素不足狀態的治療、肌肉質量的增加、骨密
度的增加、男性及女性治療性性功能障礙的治療、促進體重增加、促進體重維持、促進食慾增加(例如促進體重增加、體重維持或食慾增加對具有伴有體重降低之紊亂之患者或治療中的患者有用)。伴有體重降低之疾病或紊亂的例子包括厭食症、暴食症、癌症惡病質、AIDS、消耗症、惡病質及虛弱老年人的消耗症。伴有體重降低的治療的例子包括化療法、放射線療法、臨時或永久性固定化及透析。
疾病或病症進一步包括睡眼障礙、充血性心臟衰竭、代謝障礙、記憶功能改善、乳腺癌、甲狀腺癌、改善缺血性神經或肌肉損傷。
本發明的化合物藉由調節生長激素釋放肽受體的活性來發揮功能。該等可藉由作為激動劑、部分激動劑、反向激動劑、拮抗劑或部分拮抗劑發揮作用而使受體活化/非活化。
飲食失調症包括:神經性厭食症(307.1),包括亞型限制型(Restricting Type)及暴食/清除型(Binge-Eating/Purging Type);神經性暴食症(307.51),包括亞型清除型及非清除型;肥胖症;強迫性飲食失調症;暴食症;及另行指定之飲食失調症(307.50)[上述所列疾病後面的括號內的數字係指Diagnostic and Statistical Manual of Mental Disorders,第4版,由American Psychiatric Association(DSM-IV)出版和/或the International Classification of Diseases,第10版(ICD-10)中之分類代碼]。
本發明的另一實施形態提供化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物在製備用於治療飲食失調症之藥物中之用途。
本發明的另一實施形態提供治療患有飲食失調症之包括人在內之動物之方法,其包括將有效量的化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物給藥於前述受治者。
胃腸道疾病包括胃腸阻塞、胃潰瘍及諸如克羅恩氏病及潰瘍性結腸炎之類的炎症性腸病。本發明的化合物亦有可能對與胃食管反流和/
或消化不良有關的症狀的緩解、有或沒有食慾-/代謝相關的惡病質的治療有用,並且在麻痺性腸阻塞或假梗阻及諸如便秘型大腸急躁症之類的與便秘有關的病症的治療中有用。
心血管疾病包括心臟衰竭及擴張型心肌病。
分解代謝狀態或慢性消耗性綜合症可在術後患者中出現,並且包括AIDS-相關消耗性綜合症及諸如癌症惡病質之類的癌症相關消耗性綜合症。
雖然可以在治療中使用治療有效量的化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物作為化學原料而給藥,但可將活性成分作為藥物組成物。因此,本發明的另一實施形態中提供在一種以上的藥學上可接受的載體、稀釋劑或賦形劑的混合物中含有化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物之藥物組成物。載體、稀釋劑或賦形劑必須與製劑的其他成分相容,且對其接受者無害。本發明的另一實施形態還提供包含將化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物與一種以上的藥學上可接受的載體、稀釋劑或賦形劑進行混合之藥物組成物的製備製程。
本發明的藥物組成物可被配製成用於任何適當的途徑例如口服(包括口腔或舌下)、直腸、鼻腔、局部(包括口腔、舌下或經皮)、陰道或非口服(包括皮下、肌肉內、靜脈內或皮內)途徑給藥。因此,本發明的藥物組成物可被配製為例如片劑、膠囊、粉末、顆粒、錠劑、霜劑或液體製劑,諸如口服或無菌非口服溶液或懸浮液。這樣的藥學製劑可藉由藥學領域中周知之任何方法進行製備,例如可藉由與活性成分與載體或賦形劑結合來進行製備。
用於口服給藥片劑及膠囊之可以成為單位劑量型,且可含有:諸如結合劑,例如糖漿、阿拉伯膠、明膠、山梨糖醇、黃蓍膠、或聚乙烯吡咯烷酮;填充劑,例如乳糖、糖、玉米澱粉、磷酸鈣、山梨糖醇
或甘胺酸;壓片潤滑劑,例如硬脂酸鎂、滑石、聚乙二醇或二氧化矽;崩解劑,例如馬鈴薯澱粉;或可接受的潤濕劑,諸如十二烷基硫酸鈉之類的常規賦形劑。片劑可按照藥學實踐中周知之方法進行包衣。口服液體製劑可以是例如水性或油性懸浮液、溶液、乳液、糖漿或酏劑的形態,或者可在使用前用於與水或其他合適的媒介物進行重構(reconstitution)之乾燥產物。該種液體製劑可含有常規添加劑:諸如懸浮劑,例如山梨糖醇、甲基纖維素、葡萄糖漿、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁凝膠或氫化食用脂肪;乳化劑,例如卵磷脂、脫水山梨醇單油酸酯或阿拉伯膠;非水性媒介物(可包括食用油),例如杏仁油、諸如甘油、丙二醇或乙醇之類的油脂;防腐劑,例如甲基或丙基對羥基苯甲酸或山梨酸;及根據需要可含有常規的調味劑或著色劑。
本發明的局部製劑可呈現軟膏、霜劑或乳液、眼膏及眼或耳滴劑、浸漬敷料(impregnated dressing)及氣溶膠,且可含有諸如防腐劑、幫助藥物浸透之溶劑、軟膏及霜劑形態的潤膚劑之類的適當的常規添加劑。製劑亦可含有諸如霜劑或軟膏基質及乳液用乙醇或油醇之類的相溶的常規載體。該種載體可以在製劑中以約1%至高達約98%的含有量存在。更通常地,該等會形成高達約80%的製劑。
適合於非口服給藥之藥學製劑包括:水性及非水性無菌注射液,其可包含抗氧化劑、緩衝劑、抑菌劑及使給藥對象的血液與製劑具有等張性之溶質等;及水性或非水性無菌懸浮液,其可包含懸浮劑及增稠劑。製劑可以以例如密封安瓿及小瓶等單位劑量或多劑量容器提供,並且可以以在使用前僅需要立即添加例如注射用水等無菌液體載體之冷凍乾燥(凍乾)狀態儲存。臨時注射液和懸浮液可由無菌粉末、顆粒及片劑進行製備。
用於直腸給藥之藥學製劑可以以栓劑或灌腸劑提供。
載體為固體之適合於鼻腔給藥之藥學製劑可包含具有例如20至500微米範圍的粒子尺寸之較粗的粉末,該粉末採取以在鼻子靠近容器之狀態下例如藉由通過鼻道之迅速吸入之鼻煙之方式給藥。載體為液體之合適的製劑以包含活性成分的水性或油性溶液鼻噴霧劑或鼻滴劑給藥。
適合於吸入給藥之藥學製劑包括微細顆粒的粉塵或氣霧,其可藉由例如劑量加壓氣溶膠、噴霧器或吸入器等各種計量裝置來生成。
適合於陰道給藥之藥學製劑可以以子宮托、衛生棉條(tampons)、霜劑、凝膠、糊劑、泡沫或噴霧製劑提供。
應當理解,除了上述提及之成分以外,該製劑還可包含與製劑類型有關的習知技術中的其他的習知製劑。
化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物的治療有效量取決於包括例如人或其他動物的年齡及體重、需要治療之準確病症及其嚴重狀態、製劑的性質、以及給藥途徑等在內之許多因素,並且最終由護理醫師或獸醫的判斷。但是,用於治療治療由生長激素釋放肽受體介導之紊亂之化學式(I)的化合物的有效量一般是一天0.1至100mg/kg範圍(對象(動物)的體重),更通常地是一天1至10mg/kg(體重)。因此,在70kg的成年動物的情況下,一天的實際用量通常是70至700mg,並且,該用量可以以一天單一劑量或者更通常地以一天的總用量相同之方式一天多次的劑量(例如兩次、三次、四次、五次或六次)提供。藥學上可接受的鹽或其溶劑化物的有效量可按照化學式(I)的化合物其本身的有效量的比例來確定。
用於在本發明中使用的之化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物可以與一種以上的其他治療劑組合使用。因此,在另一實施形態中,本發明提供化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物與另外的治療劑(抗肥胖劑可成為一例)之組合。在又
一實施形態中,本發明還提供包含化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物與另一治療劑之組合在治療由生長激素釋放肽受體介導之紊亂中之用途。
當化學式(I)的化合物或其藥學上可接受的鹽或溶劑化物與一種以上的其他治療劑組合使用時,該化合物可以依次或同時藉由任何方便的途徑給藥。
上面提及之組合為了進行使用,可以方便地以藥學製劑的形式提供,因此包含如上所定義之組合之藥學製劑最佳地與藥學上可接受的載體或賦形劑藥學製劑配合,這構成本發明的另一形態。該種組成物的各構成要素可以以分開的或結合的藥物製劑依次或同時給藥。
當在結合於同一製劑中時,可以理解該兩種化合物必須是穩定的且彼此以及與製劑中的其他組分相容,並且可以被配製用於給藥。當分開配製時,可以以任何方便的製劑提供,為方便起見,可以以該化合物在該領域周知之方式提供。
當一種化合物與針對相同疾病有效的第二治療活性劑組合使用時,各化合物的劑量可能與單獨使用化合物時的劑量不同。本領域技術人員可容易掌握適當的劑量。
本發明的化合物特別在炎性痛和泌尿系統疾病或紊亂的治療中可以有效地與另一藥理活性化合物或者兩種以上的又一藥理活性化合物結合。例如,生長激素釋放肽受體激動劑、尤其是化學式(I)的化合物或其前體藥物或其藥學上可接受的鹽或溶劑化物可以與選自以下中之一種以上的藥劑組合而同時、依次或分開給藥:-阿片鎮痛劑,例如嗎啡、海洛因、氫嗎啡酮、氧嗎啡酮、左啡諾、左洛啡烷、美沙酮、哌替啶、芬太奴、可卡因、可待因、雙氫可待因、氧可酮、氫可酮、丙氧芬、納美芬、納洛芬、納洛酮、納曲酮、丁丙諾啡、布托啡諾、納布啡或噴他佐辛;
-非甾體類抗炎藥(NSAID),例如阿司匹林、雙氯芬酸、二氟尼柳、依托度酸、芬布芬、非諾洛芬、氟苯柳、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、甲氯芬那酸、甲滅酸、美洛昔康、萘丁美酮、萘普生、尼美舒利、硝基氟吡洛芬、奧沙拉秦、奧沙普秦、保泰松、吡羅昔康、柳氮磺吡啶、舒林酸、托美汀或佐美酸;-巴比妥酸鹽類鎮定劑,例如異戊巴比妥、阿普比妥、仲丁比妥、布他比妥、普羅米那、美沙比妥、美索比妥、戊巴比妥、苯巴比妥、司可巴比妥、他布比妥、硫戊巴比妥或戊硫代巴比妥;具有鎮定作用之苯二氮卓,例如氯氮唑、氯卓酸鹽(clorazepate)、地西泮、氟西泮、勞拉西泮、奧沙西泮、替馬西泮或三唑侖;-具有鎮定作用的H1拮抗劑,例如苯海拉明、吡拉明、異丙嗪、撲爾敏或氯環嗪;-鎮定劑,例如苯乙派啶酮、甲丙氨酯、甲喹酮或氯醛比林;-骨骼肌緩和劑,例如巴氯芬、卡立普多、氯唑沙宗、環苯扎林、美索巴莫或奧芬那君;- NMDA受體拮抗劑,例如右美沙芬((+)-3-羥基-N-甲基嗎啡喃)或其代謝產物右啡烷((+)-3-羥基-N-甲基嗎啡喃)、氯胺酮、美金剛、吡咯喹啉醌、順式-4-(膦醯甲基)-2-呱啶甲酸、布地品、EN-3231(MorphiDex(商標)、嗎啡與右美沙芬的組合製劑)、托吡酯、奈拉美生(neramexane)或包含NR2B拮抗劑之培净福太(perzinfotel),例如艾芬地爾、曲索羅地(traxoprodil)或(-)-(R)-6-{2-[4-(3-氟苯基)-4-羥基-1-呱啶基]-1-羥基乙基-3,4-二氫-2(1H)-喹啉酮;- α-腎上腺素能作用藥,例如多沙唑嗪、坦洛新、可樂定、胍法辛、右美托咪定、莫達非尼或4-氨基-6,7-二甲氧基-2-(5-甲烷-磺醯胺基-1,2,3,4-四氫異喹啉-2-基)-5-(2-吡啶)喹唑啉;-三環抗抑鬱藥,例如地昔帕明、丙米嗪、阿米替林或去甲替林;
-抗驚厥藥,例如卡馬西平、拉莫三嗪、托吡酯或丙戊酸;-速激肽(NK)拮抗劑,尤其是NK-3、NK-2或NK-1拮抗劑,例如(αR,9R)-7-[3,5-雙(三氟甲基)苄基]-8,9,10,11-四氫-9-甲基-5-(4-甲苯基)-7H-[1,4]二氮雜芳辛並[2,1-g][1,7]-萘啶-6,13-二酮(TAK-637)、5-[[(2R,3S)-2-[(1R)-1-[3,5-雙(三氟甲基)苯基]乙氧基-3-(4-氟苯基)-4-嗎啉]-甲基]-1,2-二氫-3H-1,2,4-三唑-3-酮(MK-869)、阿瑞匹坦、拉奈匹坦、達匹坦或3-[[2-甲氧基-5-(三氟甲氧基)苯基]-甲基氨基]-2-苯基呱啶(2S,3S);-毒蕈鹼樣拮抗劑,例如奧昔布甯、托特羅定、丙哌維林、曲司氯銨、達非那新、索非那新、替米維林及異丙托溴銨;- COX-2選擇性抑制劑,例如塞來考昔、羅非考昔、帕瑞考昔、伐地考昔、地拉考昔、依托考昔或蘆米考昔;-煤焦油鎮痛劑、尤其是撲熱息痛;-神經安定劑,例如氟哌利多、氯丙嗪、氟呱啶醇、奮乃靜、硫利達嗪、美索達嗪、三氟拉嗪、氟奮乃靜、氯氮平、奧氮平、利司哌酮、齊拉西酮、喹硫平、舍吲哚、阿立哌唑、索奈哌唑、布南色林、伊洛哌酮、哌羅匹隆、雷氯必利、佐替平、聯苯蘆諾、阿塞那平、魯拉西酮、胺磺必利、帕利哌酮(balaperidone)、帕潘立酮(palindore)、依利色林、奧沙奈坦、利莫納班、美克林坦(meclinertant)、Miraxion(商標)或沙立佐坦(sarizotan);-辣椒素(vanilloid)受體激動劑(例如樹脂毒素)或拮抗劑(例如辣椒平);-瞬時受體電位陽離子通道亞型(V1、V2、V3、V4、M8、M2、A1)激動劑或拮抗劑;- β-腎上腺素能作用藥,例如普萘洛爾;-局部麻醉劑,例如美西律;
-皮質類固醇,例如地塞米松;- 5-HT受體激動劑或拮抗劑、尤其是5-HT1B/1D激動劑,例如依來曲坦、舒馬普坦、那拉曲坦、佐米曲坦或利扎曲坦;- 5-HT2A受體拮抗劑,例如R(+)-α-(2,3-二甲氧基-苯基)-1-[2-(4-氟苯基乙基)]-4-呱啶甲醇(MDL-100907);-膽鹼能(煙鹼性)鎮痛劑,例如伊普尼可林(TC-1734)、(E)-N-甲基-4-(3-吡啶基)-3-丁烯-1-胺(RJR-2403)、(R)-5-(2-吖丁啶基甲氧基)-2-氯吡啶(ABT-594)或煙鹼;- Tramadol(商標);- PDEV抑制劑,例如5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺醯基)苯基]-1-甲基-3-正丙基-1,6-二氫-7H-吡唑並[4,3-d]嘧啶-7-酮(西地那非)、(6R,12aR)-2,3,6,7,12,12a-六氫-2-甲基-6-(3,4-亞甲二氧基苯基)-吡嗪並[2’,1’:6,1]-吡啶並[3,4-b]吲哚-1,4-二酮(IC-351或他達拉非)、2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑並[5,1-f][1,2,4]三嗪-4-酮(伐地那非)、5-(5-乙醯基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-吖丁啶基)-2,6-二氫-7H-吡唑並[4,3-d]嘧啶-7-酮、5-(5-乙醯基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-異丙基-3-吖丁啶基)-2,6-二氫-7H-吡唑並[4,3-d]嘧啶-7-酮、5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺醯基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氫-7H-吡唑並[4,3-d]嘧啶-7-酮、4-[(3-氯-4-甲氧基苄基)氨基]-2-[(2S)-2-(羥甲基)吡咯烷-1-基]-N-(嘧啶-2-基甲基)嘧啶-5-羧醯胺、3-(1-甲基-7-氧代-3-丙基-6,7-二氫-1H-吡唑並[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基苯磺醯胺;- α-2-δ配體,例如加巴噴丁、普瑞巴林、3-甲基加巴噴丁、(3-(氨
基甲基)雙環[3.2.0]庚-3-基)乙酸、(3S,5R)-3-(氨基甲基)-5-甲基庚酸、(3S,5R)-3-氨基-5-甲基庚酸、(3S,5R)-3-氨基-5-甲基辛酸、(2S,4S)-4-(3-氯苯氧基)脯胺酸、(2S,4S)-4-(3-氟苄基)脯胺酸、[(1R,5R,6S)-6-(氨基甲基)雙環[3.2.0]庚-6-基]乙酸、3-((1-(氨基甲基)環己基)甲基)-4H-[1,2,4]噁二唑-5-酮、C-[1-((1H-四唑-5-基)甲基)環庚基]甲胺、(3S,4S)-(1-(氨基甲基)-3,4-二甲基環戊基)乙酸、(3S,5R)-3-(氨基甲基)-5-甲基辛酸、(3S,5R)-3-氨基-5-甲基壬酸、(3S,5R)-3-氨基-5-甲基辛酸、(3R,4R,5R)-3-氨基-4,5-二甲基庚酸及(3R,4R,5R)-3-氨基-4,5-二甲基辛酸;-大麻素;-代謝型谷胺酸亞型1受體(mGluR1)拮抗劑;-血清素再吸收抑制劑,例如舍曲林、舍曲林代謝產物去甲基舍曲林、氟西汀、去甲氟西汀(氟西汀去甲基代謝產物)、氟伏沙明、帕羅西汀、西酞普蘭、西酞普蘭代謝產物去甲基西酞普蘭、草酸依地普侖、d,l-芬氟拉明、非莫西汀、伊福西汀、氰基度琉平(cyanodothiepin)、利托西汀、達泊西汀、奈法唑酮、西文氯胺及曲唑酮;-去甲腎上腺素(norepinephrine)再吸收抑制劑,例如馬普替林、洛非帕明、米氮平、羥丙替林、非唑拉明、托莫西汀、米安色林、安非他酮、安非他酮代謝產物羥基安非他酮、諾米芬辛及維洛沙秦(Vivalan(商標))、尤其是選擇性去甲腎上腺素再吸收抑制劑,例如瑞波西汀、尤其是(S,S)-瑞波西汀;-雙重血清素-去甲腎上腺素再吸收抑制劑,例如文拉法辛、文拉法辛代謝產物O-去甲文拉法辛、氯米帕明、氯米帕明代謝產物去甲氯米帕明、度洛西汀、米那普侖及丙米嗪;-誘導型一氧化氮合成酶(iNOS)抑制劑,例如S-[2-[(1-亞氨基乙基)氨基]乙基]-L-同型半胱胺酸、
S-[2-[(1-亞氨基乙基)-氨基]乙基]-4,4-二氧代-L-半胱胺酸、S-[2-[(1-亞氨基乙基)氨基]乙基]-2-甲基-L-半胱胺酸、(2S,5Z)-2-氨基-2-甲基-7-[(1-亞氨基乙基)氨基]-5-庚酸、2-[[(1R,3S)-3-氨基-4-羥基-1-(5-噻唑基)-丁基]硫基]-5-氯-3-吡啶甲腈;2-[[(1R,3S)-3-氨基-4-羥基-1-(5-噻唑基)丁基]硫基]-4-氯苯腈、(2S,4R)-2-氨基-4-[[2-氯-5-(三氟甲基)苯基]硫基]-5-噻唑丁醇、2-[[(1R,3S)-3-氨基-4-羥基-1-(5-噻唑基)丁基]硫基]-6-(三氟甲基)-3-吡啶甲腈、2-[[(1R,3S)-3-氨基-4-羥基-1-(5-噻唑基)丁基]硫基]-5-氯苯腈、或N-[4-[2-(3-氯苄基氨基)乙基]苯基]噻吩-2-甲脒或胍乙基二硫化物;-乙醯膽鹼酯酶抑制劑,例如多奈哌齊;-前列腺素E2 4亞型(EP4)拮抗劑,例如N-[({2-[4-(2-乙基-4,6-二甲基-1H-咪唑並[4,5-c]吡啶-1-基)苯基]乙基}氨基)-羰基]-4-甲基苯磺醯胺、或4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]苯甲酸;-白三烯B4拮抗劑;例如1-(3-聯苯基-4-基甲基-4-羥基-苯並二氫呋喃-7-基)-環戊羧酸(CP-105696)、5-[2-(2-羧乙基)-3-[6-(4-甲氧基苯基)-5E-己烯基]氧基苯氧基]-戊酸(ONO-4057)或DPC-11870;- 5-脂肪氧合酶抑制劑,例如齊留通、6-[(3-氟-5-[4-甲氧基-3,4,5,6-四氫-2H-吡喃-4-基])苯氧基甲基]-1-甲基-2-喹諾酮(ZD-2138)或2,3,5-三甲基-6-(3-吡啶基甲基)-1,4-苯醌(CV-6504);-鈉通道阻斷劑,例如利多卡因;-鈣通道阻斷劑,例如齊考諾肽、唑尼沙胺、米貝拉地爾;
- 5-HT3拮抗劑,例如昂丹司瓊;-降鈣素基因相關肽(CGRP)拮抗劑;-緩激肽(BK1及BK2)拮抗劑;-電壓門控鈉依賴性通道阻斷劑(Nav1.3、Nav1.7、Nav1.8);-電壓依賴性鈣通道阻斷劑(N-型、T-型);- P2X(離子通道型ATP受體)拮抗劑;-酸-敏感離子通道(ASIC1a、ASIC3)拮抗劑;-血管收縮素AT2拮抗劑;-趨化素CCR2B受體拮抗劑;-組織蛋白酶(B,S,K)抑制劑;- σ1受體激動劑或拮抗劑;及其藥學上可接受的鹽及溶劑化物。
尤其,本發明的治療劑或預防劑能夠與化療劑、免疫治療劑、利尿劑等組合使用為較佳。
化療劑的例子包括:諸如環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司汀、雷莫司汀、替莫唑胺等烷基化劑;諸如胺甲喋呤、氟尿嘧啶、替加氟、卡莫氟、去氧氟尿苷、卡培他濱、阿糖胞苷、安西他濱、依諾他濱、阿糖胞苷十八烷基磷酸鹽(cytarabine ocfosfate)、吉西他濱、巰嘌呤、氟達拉濱等核酸代謝物;諸如多柔比星、道諾黴素(daunorubicin)、吡柔比星、表阿黴素(epirubicin)、伊達比星、米托蒽醌、絲裂黴素C、博來黴素、培洛黴素等抗腫瘤抗生素;諸如長春新鹼、長春鹼、長春地辛、長春瑞濱、紫杉醇、多烯紫衫醇等微管抑制劑;諸如順鉑、卡鉑、奈達鉑等鉑類藥物;諸如伊立替康、拓撲替康(nogitecan)、依託泊苷等拓樸異構酶抑制劑;諸如曲妥珠單抗、利妥昔單抗、伊馬替尼(imanitib)等分子靶向治療劑;等等。
免疫治療劑的例子包括胞壁醯二肽衍生物、香菇多糖、西佐糖
(sizofiran)、烏苯美司、溶鏈菌(picibanil)、云芝多糖(krestin)、干擾素、白細胞介素、粒細胞集落刺激因子、紅細胞生成素等。
利尿劑的例子包括:諸如可可鹼水楊酸鈉之類的黃嘌呤衍生物藥劑;諸如乙噻嗪(ethiazide)、環戊甲噻嗪、三氯甲噻嗪、氫氯噻嗪、氫氟甲噻嗪、苄氫氯噻嗪、戊氟噻嗪、泊利噻嗪(polythiazide)、甲氯噻嗪等利尿藥;諸如螺甾內酯、三胺喋呤等抗醛固酮藥;諸如乙醯唑胺等碳酸酐酶抑制劑;諸如氯噻酮、美夫西特、吲達帕胺、呋塞米、阿佐醯胺等氯苯磺醯胺藥物;異山梨醇、依他尼酸、吡咯他尼、布美他尼等。
該種組合提供包括治療中的協同活性在內之顯著的優勢。
所有出版物、包括但並不限定於該說明書中引用的於專利和專利申請在本說明書中作為參考而併入本文中,如同每個單獨的出版物在這裡被充分闡述那樣,具體地且單獨地指定藉由引用而被併入本文中。
一般合成
在整個本申請中,以下述含義使用下述略語:DCM 二氯甲烷
DMA N,N-二甲基乙醯胺
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲醯胺
DMSO 二甲基亞碸
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽
EtOAc 醋酸乙酯
EtOH 乙醇
ESI 電噴灑游離
HOBT 1-羥基苯並三唑
HBTU 苯並三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯
HPLC 高壓液相層析
LC 液相層析
LG 離去基
MeCN 乙腈
MeOH 甲醇
MHz 兆赫茲
MS 質譜分析
NMR 核磁共振
PG 保護基
T3P 2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷(trioxatriphosphinane)2,4,6-三氧化物
TBME 甲基叔丁醚
TFA 三氟乙酸
THF 四氫呋喃
TLC 薄層層析
tR 滯留時間
UV 紫外線
術語“鹼”對所使用之鹼的種類同樣沒有特別限制,在此可同等地使用在該種類型的反應中通常使用之任意鹼。該種鹼的例子包括以下:鹼金屬氫氧化物,例如氫氧化鋰、氫氧化鈉、氫氧化鉀、磷酸鉀及氫氧化鋇;鹼金屬氫化物,例如氫化鋰、氫化鈉及氫化鉀;鹼金屬醇鹽,例如甲醇鈉、乙醇鈉及叔丁醇鉀;鹼金屬碳酸鹽,例如碳酸鋰、碳酸鈉、碳酸鉀及碳酸銫;鹼金屬碳酸氫鹽,例如碳酸氫鋰、碳酸氫鈉及碳酸氫鉀;胺,例如N-甲基嗎啉、三乙胺、三丙胺、三丁胺、二異丙基乙胺、N-甲基呱啶、吡啶、4-吡咯烷吡啶、皮考啉,2,6-二(叔丁基)-4-甲基吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二氮雜
雙環[4.3.0]壬-5-烯(DBN)、1,4-二氮雜雙環[2.2.2]辛烷(DABCO)、1,8-二氮雜雙環[5.4.0]十一碳-7-烯(DBU)、盧剔啶及可力丁;鹼金屬氨基化物,例如氨基鋰、氨基鈉、氨基鉀、二異丙氨基鋰、二異丙氨基鉀、二異丙氨基鈉、雙(三甲矽基)氨基鋰及雙(三甲矽基)氨基鉀。其中,三乙胺、二異丙基乙胺、DBU、DBN、DABCO、吡啶、盧剔啶、可力丁、碳酸鈉、碳酸氫鈉、氫氧化鈉、碳酸鉀、碳酸氫鉀、氫氧化鉀、磷酸鉀、氫氧化鋇及碳酸銫為較佳。
前述反應一般且較佳地在惰性溶劑的存在下進行。只要不對反應或試劑帶來壞影響、且溶劑可以將試劑溶解至至少某種程度,則所使用之溶劑種類並沒有特別限制。適當的溶劑的例子非限定性地包括以下:鹵代烴,例如二氯甲烷、氯仿、四氯化碳及二氯乙烷;醚,例如二乙醚、二異丙醚、THF及二噁烷;芳香族烴,例如苯、甲苯及硝基苯;醯胺,例如DMF、N,N-二甲基乙醯胺(DMA)及六甲基磷醯三胺;胺,例如N-甲基嗎啉、三乙胺、三丙胺、三丁胺、二異丙基乙胺、N-甲基呱啶、吡啶、4-吡咯烷吡啶、N,N-二甲基苯胺及N,N-二乙基苯胺;醇,例如甲醇、乙醇、丙醇、異丙醇及丁醇;腈,例如乙腈及苄腈;亞碸,例如二甲基亞碸(DMSO)及環丁碸;酮,例如丙酮及二乙酮。在該等溶劑中,包含DMF、DMA、DMSO、THF、二乙醚、二異丙醚、乙二醇二甲醚、乙腈、二氯甲烷、二氯乙烷及氯仿為較佳,但並不限定於此。
實施例
用下述非限定性實施例對本發明進行說明,如沒有特別提及,所有試劑均係市售品,所有操作均在室溫至環境溫度亦即約18-25℃範圍內進行;使用旋轉蒸發器在減壓下並在到達約60℃的浴溫度下進行溶劑的蒸發;用薄層層析(TLC)或LC-MS(低分辨質譜)監控反應,僅以說明的目的給出反應時間;用以下述技術中的至少一種來確認所
有分離化合物的結構和純度:TLC(Merck矽膠60 F254預塗TLC板或Merck NH2 F254預塗HPTLC板)、質譜分析或NMR。僅以說明的目的給出收率。使用Wakogel(登錄商標)C-300HGT或Fuji Silysia Chromatorex(登錄商標)DM2035(氨基型,30-50微米)或Biotage silica(32-63mm,KP-Sil)或Biotage氨基結合矽(35-73mm,KP-NH)來進行快速管柱層析。藉由下述裝置獲得低分辨質譜資料(ESI)。
裝置;带有UV2487檢測器及ZQ2000質譜儀之Waters Alliance 2695 HPLC系統
利用下述裝置及條件,使用HPLC(製備型LC-MS)執行化合物的提純。
裝置;Waters MS-trigger Auto-purification系統
管柱;Waters XBridge C18,19×50mm,5微米粒子尺寸
條件A:甲醇或乙腈/0.05%(v/v)氨水溶液
條件B:甲醇或乙腈/0.05%(v/v)甲酸水溶液
HPLC滯留時間的確定條件:
方法:QC1
裝置:帶有TUV檢測器及ZQ2000質譜儀之Waters ACQUITY Ultra Performance LC
管柱:Waters ACQUITY C18,2.1×100mm,1.7微米粒子尺寸
管柱溫度:60℃
流速:0.7mL/min
運行時間:3min
UV檢測:210nm
MS檢測:ESI正/負模式
流動相:
A1:10mM乙酸銨
B1:乙腈
方法:QC2
裝置:帶2996PDA檢測器及ZQ2000質譜儀之Waters Alliance2795 HPLC系統
管柱:XBridge C18,4.6×50mm,3.5微米粒子尺寸
管柱溫度:45℃
流速:1.2mL/min
運行時間:4.5min
UV檢測:210-400nm(掃描範圍)
MS檢測:ESI正/負模式
流動相:
A:水
B:乙腈
C:1%甲酸水溶液
D:1%氨水溶液
利用下述裝置及條件執行光學純度評估:
裝置:帶有2996PDA detector之Waters Alliance2695 HPLC系統
管柱:DAICEL CHIRALCEL OD-H,4.6×250mm,5微米粒子尺寸
管柱溫度:25℃(室溫)
流動相:正己烷/2-丙醇/二乙胺=90/10/0.1(v/v/v)
流速:1mL/min
運行時間:30min
自動取樣器溫度:5℃
UV檢測:259nm
對於四甲基矽烷(TMS)以百万分之一(parts per million)(ppm)作為內部標準,沒有特別提及就可以使用氘代氯仿(99.8% D)或二甲基亞碸(99.9% D)來作為溶劑,並以270MHz(JEOL JNM-LA 270分光儀)或300MHz(JEOL JNM-LA300)確定NMR資料;所使用之常規略語如下:s=單線、d=雙重線、t=三重線、q=四重線、m=多重線、br=廣域等。化學記號具有該等通常的含義;M(摩爾/升)、L(升)、mL(毫升)、g(克)、mg(毫克)、mol(摩爾)、mmol(毫摩爾)。
每個製備化合物一般由ChemBioDraw(Ultra,version 12.0,
CambridgeSoft)命名。
化學式(I)的所有絲胺酸衍生物可藉由以下示出之一般方法中所記載之程序進行製備,或者可藉由實施例部分及製備部分中所記載之具體方法或在該等方法施加通常變更來進行製備。本發明不僅包括化學式(I)的絲胺酸衍生物的該等製備製程的任意一種以上,而且還包括使用於其中之任意的新型中間體。
在下述一般方法中,除非另有說明,關於化學式(I)的絲胺酸衍生物的描述如前面所定義。
在步驟A-a中,化學式(III)的化合物可藉由去保護、接著藉由對應的鹽的動態動力學離析,由化學式(II)的化合物進行製備。去保護可藉由本領域技術人員所周知之常規方法來實施(由T.W.Greene et al.编辑之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。此外,去保護之化合物係可使用合適的溶劑,藉由使用諸如D-酒石酸之類(但
並不限定於此)的光學纯酸之動態動力學離析轉換為光學純鹽。合適的溶劑的例子包括諸如DCM(二氯甲烷)、丙酮、EtOAc、THF及水。動態動力學離析可在溫度約0至150℃、更佳地在約20至100℃下進行。動態動力學離析可進行一段時間,一般情況下進行約1hr至48hr。
在步驟A-b中,化學式(IV)的化合物係可使用諸如T3P、HBTU及EDC-HOBT之類(但並不限定於此)的合適的縮合劑,藉由與化學式(VII-a)的化合物之醯胺化,由化學式(III)的化合物進行製備。縮合可較佳地在諸如三乙胺及N,N-二異丙基乙胺之類的鹼的存在下,在諸如EtOAc、THF、DMF、DMA及DCM之類的合適的溶劑中,於約-70至60℃的溫度下進行約1-24小時。
在步驟A-c中,化學式(V)的化合物係可藉由去保護,由化學式(IV)的化合物進行製備。去保護係可藉由本領域技術人員所周知之常規方法來實施(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。
在步驟A-d中,化學式(VI)的化合物係可使用諸如T3P、HBTU及EDC-HOBT之類(但並不限定於此)的合適的縮合劑,藉由與2-((叔丁氧基羰基)氨基)-2-甲基丙酸之醯胺化,由化學式(V)的化合物進行製備。縮合係可在諸如三乙胺及N,N-二異丙基乙胺之類的鹼的存在下,在諸如EtOAc、THF、DMF、DMA及DCM之類的合適的溶劑中,於約0至60℃的溫度下進行約1-24小時為較佳。
在步驟A-e中,化學式(I)的化合物係可藉由去保護,由化學式(VI)的化合物進行製備。去保護可藉由本領域技術人員所周知之常規方法來實施(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。
在步驟A-f中,化學式(VI)的化合物係可使用諸如T3P、HBTU及EDC-HOBT之類(但並不限定於此)的合適的縮合劑,藉由與化學式(VII-b)的化合物之醯胺化,由化學式(III)的化合物進行製備。縮合係可在諸如三乙胺及N,N-二異丙基乙胺之類的鹼的存在下,在諸如EtOAc、THF、DMF、DMA及DCM之類的合適的溶劑中,於約-40至60℃的溫度下進行約1-24小時為較佳。
在步驟B-a中,化學式(IX)的化合物係可藉由與化學式(XIV)的化合物之Mitsunobu反應,由化學式(VIII)的化合物進行製備。Mitsunobu反應係可在作為偶聯劑之偶氮-二羧酸酯(包括但並不限定於諸如偶氮二羧酸二乙酯、偶氮二羧酸二異丙酯、偶氮二羧酸二叔丁酯及雙(2-甲氧基乙基)偶氮二羧酸酯)的存在下,在有機溶劑中進行,並且,可在諸如三苯基膦之類的合適的還原劑(但並不限定於此)的存在下,於惰性有機溶劑中進行。合適的惰性有機溶劑的例子包括諸如THF、1,4-二噁烷、MeCN、TBME及甲苯。反應可在約-20至150℃
的溫度下進行,在約0至60℃下進行為較佳。在一般情況下,反應時間為約30分鐘至48小時,約30分鐘至24小時為較佳。
在步驟B-b中,化學式(X)的化合物係可藉由去保護,由化學式(IX)的化合物進行製備。去保護可藉由本領域技術人員所周知之常規方法來實施(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。
在步驟B-c中,化學式(XI)的化合物可係藉由氨基部分的保護,由化學式(X)的化合物進行製備。保護可藉由本領域技術人員所周知之常規方法來進行(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。
在步驟B-d中,化學式(VII-a)的化合物係可藉由化學式(XI)的酯化合物的水解進行製備。水解可藉由常規程序進行。在典型的程序中,水解在鹼性條件下例如在氫氧化鈉、氫氧化鉀或氫氧化鋰的存在下進行。合適的溶劑包括水、甲醇、乙醇、丙醇、丁醇、2-甲氧基乙醇、乙二醇、THF、DME、1,4-二噁烷、DMF、及DMA,但並不限定於此。反應可在約20至100℃的溫度下進行約10min至24hr。
在步驟B-e中,化學式(XII)的化合物係可藉由酸性條件下的處理來進行製備。在典型的程序中,反應可在酸性條件下例如在氫氯酸、氫溴酸的存在下進行。合適的溶劑包括水、1,4-二噁烷、THF、MeCN,但並不限定於此。反應可在約50至120℃的溫度下進行約1hr至24hr。
在步驟B-f中,化學式(VII-a)的化合物係可藉由氨基部分的保護,由化學式(XII)的化合物進行製備。保護可藉由本領域技術人員所周知之常規方法來進行(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)
中所記載之典型的氨基保護基)。
在步驟B-g中,化學式(XIII)的化合物係可藉由氨基部分的保護,由化學式(X)的化合物進行製備。保護可藉由本領域技術人員所周知之常規方法來進行(由T.W.Greene et al.編輯之“Protective Groups in Organic Synthesis Forth Edition”(John Wiley & Sons,2007)中所記載之典型的氨基保護基)。
在步驟B-h中,化學式(VII-b)的化合物係可藉由化學式(XIII)的酯化合物的水解進行製備。水解可藉由常規程序進行。在典型的程序中,水解在鹼性條件下例如在氫氧化鈉、氫氧化鉀或氫氧化鋰的存在下進行。合適的溶劑包括水、甲醇、乙醇、丙醇、丁醇、2-甲氧基乙醇、乙二醇、THF、DME、1,4-二噁烷、DMF及DMA,但並不限定於此。反應可在約20至100℃的溫度下進行約10min至24hr。
在步驟C-a中,化學式(II)的化合物係可藉由與化學式(XVI)的化合物原位形成腙,接著進行閉環,由化學式(XV)的化合物進行製備。反應可在金屬乙酸鹽(包括但並不限定於諸如乙酸鈉、乙酸鉀及乙酸鋰)的存在下進行。合適的溶劑包括甲醇、乙醇、丙醇、丁醇、2-甲氧基乙醇、乙二醇、THF、DME及1,4-二噁烷,但並不限定於此。反應可在約50至150℃的溫度下進行約1hr至48hr。
下述合成中之所有起始原料能夠商購、或者能夠藉由中間體合成部分中另行提及之本領域技術人員所周知之常規方法來得到。
核合成部分
如下製備核化合物。將核化合物的名稱及結構示於表3。
核1:3a-苄基-2-(2,2-二氟乙基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮2,2,2-三氟乙酸酯
步驟1:3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-羧酸叔丁酯
在回流溫度下,將1-叔丁基3-甲基3-苄基-4-氧代哌啶-1,3-二羧酸酯(2.4g,7.0mmol)、(2,2-二氟乙基)肼鹽酸鹽(930mg,7.0mmol)與乙酸鈉(2.3g,28mmol)的EtOH(40mL)混合物攪拌24hr。冷卻至室溫之後,在真空中濃縮混合物。用EtOAc(80mL)稀釋殘留物。用水清洗稀釋之混合物,並經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用25% EtOAc的己烷進行洗脫)提純殘留物而獲得作為白色固體之標題化合物(1.8g,65%的收率)。
MS(ESI)m/z:394(M+H)+
步驟2:3a-苄基-2-(2,2-二氟乙基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮2,2,2-三氟乙酸酯
在0℃下,在3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-羧酸叔丁酯(100mg,0.25mmol)的DCM(3mL)溶液中添加三氟乙酸(2mL),並在相同溫度下,將混合物攪拌1hr。在真空中濃縮混合物而獲得作為淺黃色膠狀物之標題化合物(104mg,>99%的收率)。
MS(ESI)m/z:294(M+H)+,292(M-H)-
核2:(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯
步驟1:2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-羧酸叔丁酯
以與核1的步驟1類似的方式,以87%的收率(3600mg,淺紫色膠狀物)由1-叔丁基3-甲基4-氧代-3-(吡啶-2-基甲基)哌啶-1,3-二羧酸酯(3700mg,11mmol)製備標題化合物。
1H-NMR(270MHz,CDCl3)delta 8.38(1H,d,J=3.9Hz),7.58-7.50(1H,m),7.13-7.05(2H,m),5.94-5.30(1H,m),4.75-4.40(2H,br),4.10-3.76(2H,m),3.42-3.26(2H,m),2.93-2.50(4H,m),1.53(9H,s)。
MS(ESI)m/z:395(M+H)+。
步驟2:(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
將2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-羧酸叔丁酯(4.9g,13mmol,外消旋)的DCM(50mL)溶液冷卻至0℃,並緩慢添加三氟乙酸(4.1mL)。在室溫下將混合物攪拌1.5hr,接著冷卻至0℃。在相同溫度下,在生成之懸浮液中添加三乙胺(9.6mL,69mmol)。用DCM(50mL)稀釋所生成之黃色的透明溶液,並用鹽水(30mL×3)清洗,經Na2SO4乾燥,過濾,並在真空中濃縮而獲得作為褐色油性之標題化合物(3.8g,>100%的收率)。
MS(ESI)m/z:295(M+H)+。
1H-NMR(270MHz,CDCl3)delta 8.41(1H,d,J=5.9Hz),7.58-7.51(1H,m),7.14-7.06(2H,m),5.76(1H,tt,J=55.7Hz,4.6Hz),4.16-3.72(2H,m),3.53-3.32(4H,m),2.74-2.52(4H,m)。未觀察到NH。
MS(ESI)m/z:295(M+H)+。
步驟3:(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯
將(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(ca.12.5mmol)溶液溶解於DCM
(6mL)和丙酮(20mL)中。在室溫下,在混合物中添加D-酒石酸(2.07g,13.8mmol)的丙酮-水(7:3,10mL)溶液。混合物立即變為白色漿液。再次添加丙酮(10mL),使混合物更容易攪拌。在室溫下徹夜攪拌之後,過濾混合物,用冷丙酮(10mL)清洗固體,並在減壓下以40℃乾燥3小時而得到作為白色固體之標題化合物(4.68g,84%)。
1H NMR(DMSO-d6,270MHz)delta 8.33(1H,d,J=5.9Hz),7.66-7.60(1H,m),7.19-7.08(2H,m),5.96(1H,tt,J=55.3Hz,4.0Hz),4.28(2H,s),4.03-3.74(2H,m),3.62(1H,d,J=14.1Hz),3.41-3.18(4H,m),3.14(1H,d,J=14.1Hz),2.50-2.33(2H,m)。
MS(ESI)m/z:295(M+H)+。
中間體合成部分
如下製備中間體化合物。將中間體化合物的名稱及結構示於表4。
中間體1:(R)-2-((叔丁氧基羰基)氨基)-3-(2,4-二氟苯氧基)丙酸
步驟1:(R)-甲基3-(2,4-二氟苯氧基)-2-(三苯甲基氨基)丙酸酯
在0℃下,在(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(800mg,
2.2mmol)、2,4-二氟苯酚(370mg,2.9mmol)及三苯基膦(760mg,2.9mmol)的THF(15mL)攪拌溶液中滴加雙(2-甲氧基乙基)偶氮二羧酸酯(670mg,2.9mmol)的THF(2mL)溶液。在室溫下將混合物攪拌2hr。濃縮混合物,並用EtOAc(50mL)稀釋殘留物。用飽和的NaHCO3水溶液、接著用鹽水清洗稀釋之混合物,並經Na2SO4乾燥。進行過濾之後,濃縮濾液。藉由管柱層析(矽膠,用3%至13%EtOAc的己烷進行洗脫)提純殘留物而獲得作為無色膠狀物的標題化合物(771mg,74%的收率)。
1H NMR(300MHz,CDCl3)delta 7.52(6H,d,J=7.3Hz),7.30-7.16(9H,m),6.99-6.72(3H,m),4.29(1H,d,J=9.5,5.2Hz),4.02(1H,dd,J=9.5,6.9Hz),3.78-3.71(1H,m),3.24(3H,s),2.88(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2,4-二氟苯氧基)丙酸酯
在室溫下,在(R)-甲基3-(2,4-二氟苯氧基)-2-(三苯甲基氨基)丙酸酯(760mg,1.6mmol)的DCM(10mL)攪拌溶液中添加三氟乙酸(3.7mL),並在相同溫度下,將混合物攪拌2hr。在混合物中添加MeOH(25mL),並將生成之混合物攪拌5min,接著在真空中濃縮。將殘留物溶解於DCM(20mL)中,接著,在室溫下,將三乙胺(0.67mL,4.8mmol)及二碳酸二叔丁酯(530mg,2.4mmol)依次添加到混合物中。在室溫下攪拌2hr之後,在真空中濃縮混合物。藉由管柱層析(矽膠,用5%至14%EtOAc的己烷進行洗脫)提純殘留物而獲得作為無色油之標題化合物(470mg,88%的收率)。
1H NMR(300MHz,CDCl3)delta 6.96-6.75(3H,m),5.53(1H,d,J=8.8Hz),4.66-4.63(1H,m),4.42(1H,dd,J=8.8,2.9Hz),4.25
(1H,dd,J=9.2,3.3Hz),3.79(3H,s),1.46(9H,s)。
MS(ESI)m/z:232(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(2,4-二氟苯氧基)丙酸
在(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2,4-二氟苯氧基)丙酸酯(470mg,1.4mmol)的THF(10mL)攪拌溶液中添加LiOH一水合物(65mg,1.6mmol),接著,將水(2mL)添加到混合物中。在室溫下,將混合物攪拌30min。在混合物中添加0.5N氫氯酸(hydrochloric acid)(2mL),並用EtOAc(50mL×2)萃取混合物。將萃取物經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用9%MeOH的DCM進行洗脫)提純殘留物而獲得作為無色膠狀物之標題化合物(200mg,45%的收率)。
MS(ESI)m/z:318(M+H)+,316(M-H)-。
中間體2:(R)-2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸
步驟1:(R)-甲基3-苯氧基-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以23%的收率(390mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1.4g,3.9mmol)和苯酚(0.73g,7.8mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.54-7.49(6H,m),7.30-7.16(11H,m),6.96(1H,t,J=7.3Hz),6.88(2H,d,J=8.0Hz)4.26(1H,dd,J=9.2,4.8Hz),4.03-4.00(1H,m),3.76-3.72(1H,m),3.22(3H,s),2.88(1H,br s)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸酯
以與中間體1的步驟2類似的方式,以87%的收率(230mg,無色膠狀物)由(R)-甲基3-苯氧基-2-(三苯甲基氨基)丙酸酯(390mg,
0.89mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.28(2H,t,J=7.7Hz),6.98(1H,t,J=7.3Hz),6.88(2H,d,J=8.1Hz),5.52(1H,d,J=8.0Hz),4.67(1H,dt,J=8.8,2.6Hz),4.40(1H,dd,J=9.2,2.7Hz),4.20(1H,dd,J=9.5,2.9Hz),3.77(3H,s),1.49(9H,s)。
MS(ESI)m/z:232(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸
以與中間體1的步驟3類似的方式,以73%的收率(150mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸酯(220mg,0.75mmol)製備標題化合物。
MS(ESI)m/z:282(M+H)+,280(M-H)-。
中間體3:(R)-2-((叔丁氧基羰基)氨基)-3-(4-氯苯氧基)丙酸
步驟1:(R)-甲基3-(4-氯苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以56%的收率(730mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1.0g,2.8mmol)和4-氯苯酚(0.46g,3.6mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.53-7.49(6H,m),7.28-7.16(11H,m),6.82-6.77(2H,m),4.20(1H,dd,J=9.2,4.8Hz),4.00-3.95(1H,m),3.80-3.67(1H,m),3.23(3H,s),2.87(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(4-氯苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以95%的收率(480mg,無色膠狀物)由(R)-甲基3-(4-氯苯氧基)-2-(三苯甲基氨基)丙酸酯(720mg,1.5mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.23(2H,d,J=8.8Hz),6.81(2H,d,J=9.5Hz),5.49(1H,d,J=8.1Hz),4.74-4.61(1H,m),4.37(1H,dd,J=9.2,2.7Hz),4.18(1H,dd,J=9.5,2.9Hz),3.72(3H,s),1.46(9H,s)。
MS(ESI)m/z:230(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(4-氯苯氧基)丙酸
以與中間體1的步驟3類似的方式,以58%的收率(260mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(4-氯苯氧基)丙酸酯(480mg,1.4mmol)製備標題化合物。
MS(ESI)m/z:316(M+H)+,314(M-H)-。
中間體4:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸
步驟1:(R)-甲基3-(3-氯苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以76%的收率(890mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(900mg,2.5mmol)和3-氯苯酚(420mg,3.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.53-7.13(16H,m),6.95-6.70(3H,m),4.23(1H,dd,J=9.2,4.7Hz),3.99(1H,dd,J=9.5,6.6Hz),3.77-3.68(1H,m),3.23(3H,s),2.88(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以73%的收率(450mg,無色油)由(R)-甲基3-(3-氯苯氧基)-2-(三苯甲基氨基)丙酸酯(880mg,1.8mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.20(1H,t,J=8.1Hz),6.96
(1H,d,J=8.0Hz),6.89(1H,t,J=2.2Hz),6.77(1H,dd,J=8.4,2.6Hz),5.49(1H,d,J=4.4Hz),4.69-4.65(1H,m),4.38(1H,dd,J=9.2,2.6Hz),4.20(1H,dd,J=8.8,2.9Hz),3.78(3H,s),1.46(9H,s)。
MS(ESI)m/z:230(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸
以與中間體1的步驟3類似的方式,以57%的收率(240mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸酯(440mg,1.3mmol)製備標題化合物。
MS(ESI)m/z:316(M+H)+,314(M-H)-。
中間體5:(R)-2-((叔丁氧基羰基)氨基)-3-(3,5-二氯苯氧基)丙酸
步驟1:(R)-甲基3-(3,5-二氯苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以42%的收率(530mg,無色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(900mg,2.5mmol)和3,5-二氯苯酚(530mg,3.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.51(6H,d,J=7.3Hz),7.35-7.17(9H,m),6.98-6.95(1H,br s),6.78(2H,d,J=1.5Hz),4.21(1H,dd,J=9.2,4.8Hz),3.97(1H,dd,J=8.8,6.6Hz),3.74-3.67(1H,m),3.25(3H,s),2.88(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3,5-二氯苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以85%的收率(320mg,無色膠狀物)由(R)-甲基3-(3,5-二氯苯氧基)-2-(三苯甲基氨基)丙
酸酯(520mg,1.0mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 6.98(1H,d,J=1.5Hz),6.79(2H,d,J=1.5Hz),5.45(1H,d,J=8.8Hz),4.68-4.65(1H,m),4.37(1H,dd,J=8.8,1.5Hz),4.20(1H,dd,J=9.2,2.6Hz),3.79(3H,s),1.46(9H,s)。
MS(ESI)m/z:264(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3,5-二氯苯氧基)丙酸
以與中間體1的步驟3類似的方式,以48%的收率(140mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3,5-二氯苯氧基)丙酸酯(310mg,0.85mmol)製備標題化合物。
MS(ESI)m/z:250(M-Boc+H)+,348(M-H)-。
中間體6:(R)-2-((叔丁氧基羰基)氨基)-3-(2-(三氟甲基)苯氧基)丙酸
步驟1:(R)-甲基3-(2-(三氟甲基)苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以55%的收率(690mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(900mg,2.5mmol)和2-(三氟甲基)苯酚(530mg,3.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.56-7.46(7H,m),7.30-7.17(10H,m),7.04-6.96(2H,m),4.36(1H,dd,J=8.8,3.6Hz),4.07-4.02(1H,m),3.82-3.74(1H,m),3.22(3H,s),2.92(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-(三氟甲基)苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以86%的收率(420mg,無色油)由(R)-甲基3-(2-(三氟甲基)苯氧基)-2-(三苯甲基氨基)丙酸酯(680mg,1.3mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.56(1H,d,J=8.1Hz),7.49(1H,t,J=8.1Hz),7305(1H,t,J=7.3Hz),6.96(1H,d,J=8.1Hz),5.51(1H,d,J=8.8Hz),4.72(1H,dt,J=8.8,2.6Hz),4.48(1H,dd,J=8.8,2.2Hz),4.30(1H,dd,J=9.2,2.6Hz),3.78(3H,s),1.46(9H,s)。
MS(ESI)m/z:364(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(2-(三氟甲基)苯氧基)丙酸
以與中間體1的步驟3類似的方式,以55%的收率(220mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-(三氟甲基)苯氧基)丙酸酯(410mg,1.1mmol)製備標題化合物。
MS(ESI)m/z:250(M-Boc+H)+,348(M-H)-。
中間體7:(R)-2-((叔丁氧基羰基)氨基)-3-(3,4-二氟苯氧基)丙酸
步驟1:(R)-甲基3-(3,4-二氟苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以56%的收率(660mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(900mg,2.5mmol)和3,4-二氟苯酚(420mg,3.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.52-7.49(6H,m),7.30-7.17(9H,m),7.05(1H,q,J=9.3Hz),6.73-6.65(1H,m),6.59-6.53(1H,m),4.17(1H,dd,J=9.5,5.1Hz),3.94(1H,dd,J=9.5,6.6Hz),3.73-3.66(1H,m),3.24(3H,s),2.87(1H,d,J=10.3Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3,4-二氟苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以81%的收率(370mg,無色油)由(R)-甲基3-(3,4-二氟苯氧基)-2-(三苯甲基氨基)丙酸酯(650mg,1.4mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.06(1H,q,J=9.3Hz),6.75-6.67(1H,m),6.61-6.55(1H,m),5.46(1H,d,J=8.0Hz),4.70-4.61(1H,m),4.34(1H,dd,J=8.8,2.9Hz),4.16(1H,dd,J=9.5,2.9Hz),3.78(3H,s),1.46(9H,s)。
MS(ESI)m/z:332(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3,4-二氟苯氧基)丙酸
以與中間體1的步驟3類似的方式,以57%的收率(200mg,淺褐色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3,4-二氟苯氧基)丙酸酯(360mg,1.1mmol)製備標題化合物。
MS(ESI)m/z:318(M-Boc+H)+,316(M-H)-。
中間體8:(R)-2-((叔丁氧基羰基)氨基)-3-(2-氯苯氧基)丙酸
步驟1:(R)-甲基3-(2-氯苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以68%的收率(880mg,無色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1000mg,2.8mmol)和2-氯苯酚(460mg,3.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.53(6H,d,J=7.3Hz),7.36-6.92(11H,m),6.93-6.88(2H,m),4.35(1H,dd,J=8.8,5.1Hz),4.05-3.99(1H,m),3.85-3.78(1H,m),3.24(3H,s),2.91(1H,d,J=10.3Hz)。
MS(ESI)m/z:494(M+Na+H)+。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-氯苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以90%的收率(550mg,無色油)由(R)-甲基3-(2-氯苯氧基)-2-(三苯甲基氨基)丙酸酯(870mg,1.8mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.35(1H,dd,J=8.1,1.5Hz),7.21(1H,td,J=7.7,1.5Hz),6.96-6.90(2H,m),5.60(1H,d,J=8.8Hz),4.76-4.66(1H,m),4.45(1H,dd,J=9.2,2.6Hz),4.27(1H,dd,J=9.5,2.9Hz),3.80(3H,s),1.46(9H,s)。
MS(ESI)m/z:330(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(2-氯苯氧基)丙酸
以與中間體1的步驟3類似的方式,以51%的收率(260mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-氯苯氧基)丙酸酯(540mg,1.6mmol)製備標題化合物。
MS(ESI)m/z:216(M-Boc+H)+,314(M-H)-。
中間體9:(R)-3-(3,5-雙(三氟甲基)苯氧基)-2-((叔丁氧基羰基)氨基)丙酸
步驟1:(R)-甲基3-(3,5-雙(三氟甲基)苯氧基)-2-(三苯甲基氨基)丙酸酯
與中間體1的步驟1類似的方式,以35%的收率(550mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1000mg,2.8mmol)和3,5-雙(三氟甲基)苯酚(830mg,3.6mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.52(6H,d,J=7.3Hz),7.34-7.18(12H,m),4.28(1H,dd,J=9.5,4.4Hz),4.03(1H,dd,J=9.5,6.6Hz),
3.81-3.70(1H,m),3.28(3H,s),2.93(1H,d,J=9.5Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基3-(3,5-雙(三氟甲基)苯氧基)-2-((叔丁氧基羰基)氨基)丙酸酯
以與中間體1的步驟2類似的方式,以96%的收率(390mg,無色油)由(R)-甲基3-(3,5-雙(三氟甲基)苯氧基)-2-(三苯甲基氨基)丙酸酯(540mg,0.94mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.50(1H,s),7.31(2H,s),5.50(1H,d,J=8.0Hz),4.79-4.69(1H,m),4.49(1H,dd,J=9.1,2.6Hz),4.33(1H,8.8,2.9Hz),3.81(3H,s),1.46(9H,s)。
MS(ESI)m/z:432(M+H)+。
步驟3:(R)-3-(3,5-雙(三氟甲基)苯氧基)-2-((叔丁氧基羰基)氨基)丙酸
以與中間體1的步驟3類似的方式,以30%的收率(110mg,無色膠狀物)由(R)-甲基3-(3,5-雙(三氟甲基)苯氧基)-2-((叔丁氧基羰基)氨基)丙酸酯(380mg,0.88mmol)製備標題化合物。
MS(ESI)m/z:418(M+H)+,416(M-H)-。
中間體10:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸
步驟1:(R)-甲基3-(3-氟苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以74%的收率(1400mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1500mg,4.2mmol)和3-氟苯酚(610mg,5.4mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.60-7.48(6H,m),7.31-7.15(10H,m),6.70-6.55(3H,m),4.22(1H,dd,J=9.9,5.3Hz),3.99(1H,dd,J=9.2,6.6Hz),3.76-3.68(1H,m),3.23(3H,s),2.88(1H,d,
J=10.5Hz)。
MS(ESI)m/z:478(M+Na)+。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以77%的收率(290mg,無色油)由(R)-甲基3-(3-氟苯氧基)-2-(三苯甲基氨基)丙酸酯(550mg,1.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.26-7.18(1H,m),6.72-6.57(3H,m),5.48(1H,d,J=7.9Hz),4.72-4.62(1H,m),4.38(1H,dd,J=9.2,2.6Hz),4.20(1H,dd,J=9.2,3.3Hz),3.78(3H,s),1.46(9H,s)。
MS(ESI)m/z:314(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸
以與中間體1的步驟3類似的方式,以29%的收率(80mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸酯(290mg,0.93mmol)製備標題化合物。
MS(ESI)m/z:300(M+H)+,298(M-H)-。
中間體11:(R)-2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸
步驟1:(R)-甲基3-(3-甲氧基苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以43%的收率(830mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1500mg,4.2mmol)和3-甲氧基苯酚(670mg,5.4mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.60-7.50(6H,m),7.30-7.13(10H,m),6.54-6.40(3H,m),4.24(1H,dd,J=9.2,5.3Hz),4.01(1H,
dd,J=9.2,6.6Hz),3.82(3H,s),3.80-3.70(1H,m),3.23(3H,s),2.88(1H,d,J=10.5Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以93%的收率(530mg,淺褐色油)由(R)-甲基3-(3-甲氧基苯氧基)-2-(三苯甲基氨基)丙酸酯(820mg,1.8mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.17(1H,t,J=8.2Hz),6.55-6.44(3H,m),5.49(1H,d,J=7.9Hz),4.68-4.62(1H,m),4.38(1H,dd,J=9.6,2.3Hz),4.18(1H,dd,J=9.2,2.6Hz),3.78(3H,s),3.77(3H,s),1.46(9H,s)。
MS(ESI)m/z:326(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸
以與中間體1的步驟3類似的方式,以43%的收率(220mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸酯(530mg,1.6mmol)製備標題化合物。
MS(ESI)m/z:312(M+H)+,310(M-H)-。
中間體12:(R)-2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸
步驟1:(R)-甲基3-(2-氟苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以71%的收率(890mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1000mg,2.8mmol)和2-氟苯酚(400mg,3.6mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.52(6H,d,J=7.2Hz),7.28-7.15
(9H,m),6397-6.87(4H,m),4.32(1H,dd,J=9.2,5.3Hz),4.06(1H,dd,J=9.9,6.6Hz),3.78(1H,br s),3.23(3H,s),2.89(1H,br s)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以89%的收率(550mg,無色油)由(R)-甲基3-(2-氟苯氧基)-2-(三苯甲基氨基)丙酸酯(890mg,2.0mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.10-7.02(2H,m),6.98-6.90(2H,m),5.54(1H,d,J=7.9Hz),4.71-4.61(1H,m),4.46(1H,dd,J=9.2,2.6Hz),4.27(1H,dd,J=9.6,3.0Hz),3.78(3H,s),1.46(9H,s)。
MS(ESI)m/z:314(M+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸
以與中間體1的步驟3類似的方式,以50%的收率(260mg,無色糖漿)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸酯(550mg,1.7mmol)製備標題化合物。
MS(ESI)m/z:300(M+H)+,298(M-H)-。
中間體13:(R)-2-(2-((叔丁氧基羰基)氨基)-2-甲基丙醯胺基)-3-(4-氰基苯氧基)丙酸
步驟1:(R)-甲基3-(4-氰基苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以49%的收率(630mg,白色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1000mg,2.8mmol)和4-羥基苯甲腈(660mg,5.5mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.58(2H,d,J=8.6Hz),7.56-7.48(6H,m),7.30-7.15(9H,m),6.91(2H,d,J=8.6Hz),4.25(1H,dd,J=9.2,4.6Hz),4.03(1H,dd,J=9.2,5.9Hz),3.74(1H,m),3.25(3H,s),2.90(1H,d,J=9.9Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-(2-((叔丁氧基羰基)氨基)-2-甲基丙醯胺基)-3-(4-氰基苯氧基)丙酸酯
在室溫下,在(R)-甲基3-(4-氰基苯氧基)-2-(三苯甲基氨基)丙酸酯(630mg,1.4mmol)的DCM(8mL)攪拌溶液中緩慢添加三氟乙酸(3mL),並在相同溫度下將混合物攪拌2hr。在混合物中添加MeOH(1mL)。將生成之混合物攪拌5min,接著在真空中濃縮。將殘留物溶解於DCM(5mL)中,接著,在室溫下將2-((叔丁氧基羰基)氨基)-2-甲基丙酸(280mg,1.4mmol)、1-乙基-3-(3-二甲基氨基丙基)碳二亞胺鹽酸鹽(WSC,390mg,2.0mmol)、1H-苯並[d][1,2,3]三唑-1-醇(HOBt,210mg,1.4mmol)及三乙胺(0.94mL,6.8mmol)依次添加到溶液中。徹夜攪拌之後,將飽和的NaHCO3水溶液添加到混合物中,並用DCM(30mL×2)萃取混合物。將萃取物經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用25%至50%EtOAc的己烷進行洗脫)提純殘留物而獲得作為白色固體之標題化合物(220mg,40%的收率)。
1H NMR(300MHz,CDCl3)delta 7.57(2H,d,J=8.6Hz),7.33(1H,m),6.93(2H,d,J=8.6Hz),4.97(1H,m),4.84(1H,m),4.43(1H,dd,J=9.2,3.3Hz),4.29(1H,dd,J=9.2,2.6Hz),3.78(3H,s),1.49(3H,s),1.47(3H,s),1.33(9H,s)。
MS(ESI)m/z:406(M+H)+,404(M-H)-。
步驟3:(R)-2-(2-((叔丁氧基羰基)氨基)-2-甲基丙醯胺基)
-3-(4-氰基苯氧基)丙酸
以與中間體1的步驟3類似的方式,以24%的收率(51mg,無色油)由(R)-甲基2-(2-((叔丁氧基羰基)氨基)-2-甲基丙醯胺基)-3-(4-氰基苯氧基)丙酸酯(220mg,0.54mmol)製備標題化合物。
MS(ESI)m/z:392(M+H)+。
中間體14:(R)-2-((叔丁氧基羰基)氨基)-3-(萘-2-基氧基)丙酸
步驟1:(R)-甲基3-(萘-2-基氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以32%的收率(430mg,白色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1000mg,2.8mmol)和萘-2-醇(520mg,3.6mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.77-7.70(3H,m),7.56-7.40(7H,m),7.40-7.10(12H,m),4.39(1H,dd,J=9.2,4.6Hz),4.17-4.08(1H,m),3.82-3.77(1H,m),3.24(3H,s),2.94(1H,d,J=10.6Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(萘-2-基氧基)丙酸酯
以與中間體1的步驟2類似的方式,以95%的收率(290mg,無色油)由(R)-甲基3-(萘-2-基氧基)-2-(三苯甲基氨基)丙酸酯(430mg,0.88mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.78-7.64(3H,m),7.47-7.32(2H,m),7.15-7.09(2H,m),5.55(1H,d,J=8.6Hz),4.75-4.68(1H,m),4.52(1H,dd,J=9.2,2.6Hz),4.33(1H,dd,J=9.2,3.3Hz),3.78(3H,s),1.47(9H,s)。
MS(ESI)m/z:246(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(萘-2-基氧基)
丙酸
以與中間體1的步驟3類似的方式,以46%的收率(130mg,無色糖漿)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(萘-2-基氧基)丙酸酯(290mg,0.84mmol)製備標題化合物。
MS(ESI)m/z:332(M+H)+,330(M-H)-。
中間體15:(R)-2-((叔丁氧基羰基)氨基)-3-(萘-1-基氧基)丙酸
步驟1:(R)-甲基3-(萘-1-基氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以46%的收率(920mg,白色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1500mg,4.2mmol)和萘-1-醇(780mg,5.4mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 8.16(1H,d,J=8.6Hz),7.78(1H,d,J=7.9Hz),7.56(6H,d,J=7.9Hz),7.50-7.33(4H,m),7.30-7.17(9H,m),6.81(1H,d,J=7.9Hz),4.46(1H,dd,J=8.9,4.9Hz),4.26-4.20(1H,m),3.93-3.85(1H,m),3.25(3H,s),3.01(1H,d,J=10.5Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(萘-1-基氧基)丙酸酯
以與中間體1的步驟2類似的方式,以>99%的收率(650mg,無色油)由(R)-甲基3-(萘-1-基氧基)-2-(三苯甲基氨基)丙酸酯(910mg,1.9mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 8.15-8.12(1H,m),7.81-7.78(1H,m),7.52-7.44(3H,m),7.36(1H,t,J=7.9Hz),6.78(1H,d,J=7.9Hz),5.63(1H,d,J=8.6Hz),4.87-4.77(1H,m),4.52(1H,dd,J=9.2,2.7Hz),4.42(1H,dd,J=8.9,2.3Hz),3.79(3H,s),1.46
(9H,s)。
MS(ESI)m/z:246(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(萘-1-基氧基)丙酸
以與中間體1的步驟3類似的方式,以69%的收率(420mg,無色糖漿)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(萘-1-基氧基)丙酸酯(640mg,1.9mmol)製備標題化合物。
MS(ESI)m/z:332(M+H)+,330(M-H)-。
中間體16:(R)-2-((叔丁氧基羰基)氨基)-3-((5-氯吡啶-3-基)氧基)丙酸
步驟1:(R)-甲基3-((5-氯吡啶-3-基)氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以37%的收率(720mg,白色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1500mg,4.2mmol)和5-氯吡啶-3-醇(700mg,5.4mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 8.20(1H,d,J=1.3Hz),8.16(1H,d,J=2.0Hz),7.53-7.45(6H,m),7.34-7.15(10H,m),4.25(1H,dd,J=9.2,4.6Hz),4.02(1H,dd,J=9.2,6.6Hz),3.77-3.69(1H,m),3.27(3H,s),2.95(1H,d,J=9.9Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-2-((叔丁氧基羰基)氨基)-3-((5-氯吡啶-3-基)氧基)丙酸
在室溫下,在(R)-甲基3-((5-氯吡啶-3-基)氧基)-2-(三苯甲基氨基)丙酸酯(600mg,1.3mmol)的二噁烷(10mL)溶液中添加6N氫氯酸(3mL)。在回流溫度下,將混合物攪拌4hr。冷卻至室溫之後,在真空中濃縮混合物而獲得白色固體。將白色固體懸浮於二
噁烷(5mL)中,並將飽和的NaHCO3水溶液(1mL)和二-叔丁基二碳酸酯(550mg,2.5mmol)依次添加到混合物中。在室溫下,將混合物攪拌5hr,並用水(40mL)進行稀釋。用DCM(10mL×2)清洗混合物,並藉由添加2N氫氯酸(~pH5)而使水層酸化。用EtOAc(40mL×2)萃取水層,並將萃取物經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液而獲得作為無色膠狀物之標題化合物(390mg,97%的收率)。
1H NMR(300MHz,CDCl3)delta 8.24(1H,s),8.18(1H,s),7.32-7.27(1H,m),5.59(1H,d,J=7.2Hz),4.75-4.66(1H,m),4.53-4.45(1H,m),4.40-4.33(1H,m),1.47(9H,s)。未觀察到COOH。
MS(ESI)m/z:317(M+H)+,315(M-H)-。
中間體17:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氰基苯氧基)丙酸
步驟1:(R)-甲基3-(3-氰基苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以23%的收率(580mg,無色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(2000mg,5.5mmol)和3-羥基苯甲腈(1000mg,8.3mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.52(6H,d,J=7.3Hz),7.50-7.16(11H,m),7.11-7.08(2H,m),4.26-4.21(1H,m),4.03-3.97(1H,m),3.77-3.69(1H,m),3.25(3H,s),2.90(1H,d,J=9.9Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氰基苯氧基)丙酸酯
以與中間體1的步驟2類似的方式,以93%收率(370mg,淺黃色油)由(R)-甲基3-(3-氰基苯氧基)-2-(三苯甲基氨基)丙酸酯(570mg,1.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.41-7.36(1H,m),7.28(1H,d,J=6.6Hz),7.14-7.10(2H,m),5.48(1H,d,J=7.9Hz),4.69(1H,d,J=7.9Hz),4.41(1H,dd,J=9.2,2.6Hz),4.25(1H,dd,J=9.2,3.3Hz),3.79(3H,s),1.46,1.49(9H,s)。
MS(ESI)m/z:221(M-Boc+H)+。
步驟3:(R)-2-((叔丁氧基羰基)氨基)-3-(3-氰基苯氧基)丙酸
以與中間體1的步驟3類似的方式,以45%的收率(150mg,無色膠狀物)由(R)-甲基2-((叔丁氧基羰基)氨基)-3-(3-氰基苯氧基)丙酸酯(360mg,1.1mmol)製備標題化合物。
MS(ESI)m/z:307(M+H)+。
中間體18:(R)-2-((叔丁氧基羰基)氨基)-3-(吡啶-2-基氧基)丙酸
步驟1:(R)-甲基3-(吡啶-2-基氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,分別使用代替雙(2-甲氧基乙基)偶氮二羧酸酯和三苯基膦之(E)-二氮烯-1,2-二基雙(哌啶-1-基甲酮)(ADDP,7000mg,28mmol)和三丁基膦(5600mg,28mmol),以15%的收率(887mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(5000mg,14mmol)和吡啶-2-醇(2000mg,21mmol)製備標題化合物。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-2-((叔丁氧基羰基)氨基)-3-(吡啶-2-基氧基)丙酸
以與中間體16的步驟2類似的方式,以38%的收率(210mg,無色膠狀物)由(R)-甲基3-(吡啶-2-基氧基)-2-(三苯甲基氨基)丙
酸酯(860mg,2.0mmol)製備標題化合物。
MS(ESI)m/z:283(M+H)+,281(M-H)-。
中間體19:(R)-2-((叔丁氧基羰基)氨基)-3-((5-氟吡啶-3-基)氧基)丙酸
步驟1:(R)-甲基3-((5-氟吡啶-3-基)氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以40%的收率(760mg,白色固體)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(1500mg,4.2mmol)和5-氟吡啶-3-醇(560mg,5.0mmol)製備標題化合物。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-2-((叔丁氧基羰基)氨基)-3-((5-氟吡啶-3-基)氧基)丙酸
以與中間體16的步驟2類似的方式,以46%的收率(230mg,無色膠狀物)由(R)-甲基3-((5-氟吡啶-3-基)氧基)-2-(三苯甲基氨基)丙酸酯(760mg,1.7mmol)製備標題化合物。
MS(ESI)m/z:301(M+H)+,299(M-H)-。
中間體20:(R)-2-((叔丁氧基羰基)氨基)-3-((6-(三氟甲基)吡啶-2-基)氧基)丙酸
步驟1:(R)-甲基3-((6-(三氟甲基)吡啶-2-基)氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以81%的收率(2300mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(2000mg,5.5mmol)和6-(三氟甲基)吡啶-2-醇(900mg,5.5mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.68(1H,t,J=7.9Hz),7.51(6H,d,J=7.9Hz),7.28-7.14(10H,m),6.88(1H,d,J=8.6Hz),
4.78(1H,dd,J=10.9,4.9Hz),4.47(1H,dd,J=10.9,6.9Hz),3.77(1H,quint,J=5.6Hz),3.16(3H,s),2.86(1H,d,J=10.5Hz)。
MS(ESI)m/z:觀察到243(正離子)的片段信號。
步驟2:(R)-2-((叔丁氧基羰基)氨基)-3-((6-(三氟甲基)吡啶-2-基)氧基)丙酸
以與中間體16的步驟2類似的方式,以70%的收率(580mg,無色固體)由(R)-甲基3-((6-(三氟甲基)吡啶-2-基)氧基)-2-(三苯甲基氨基)丙酸酯(1200mg,2.4mmol)製備標題化合物。
MS(ESI)m/z:251(M-Boc+H)+,349(M-H)-。
中間體21:(R)-2-((叔丁氧基羰基)氨基)-3-(4-氟苯氧基)丙酸
步驟1:(R)-甲基3-(4-氟苯氧基)-2-(三苯甲基氨基)丙酸酯
以與中間體1的步驟1類似的方式,以15%的收率(95mg,無色膠狀物)由(R)-甲基3-羥基-2-(三苯甲基氨基)丙酸酯(0.50g,1.4mmol)和4-氟苯酚(0.20g,1.8mmol)製備標題化合物。
MS(ESI)m/z:478(M+Na)+,且觀察到243(正離子)的片段信號。
步驟2:(R)-2-((叔丁氧基羰基)氨基)-3-(4-氟苯氧基)丙酸
以與中間體16的步驟2類似的方式,以72%的收率(45mg,無色油)由(R)-甲基3-(4-氟苯氧基)-2-(三苯甲基氨基)丙酸酯(95mg,0.21mmol)製備標題化合物。
1H NMR(270MHz,CDCl3):delta 7.00-6.93(2H,m),6.86-6.80(2H,m),5.49(1H,d,J=7.9Hz),4.68(1H,d,J=8.6Hz),4.40(1H,dd,J=9.2,2.6Hz),4.19(1H,dd,J=9.2,3.3Hz)。
MS(ESI)m/z:300(M+H)+,298(M-H)-。
實施例1:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧
代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
在氮氣氛下,將(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(100mg,0.25mmol)的EtOAc(3mL)懸浮液冷卻至-5℃,並在相同溫度下,將三乙胺(0.18mL,1.3mmol)滴加到懸浮液中。攪拌20min之後,在相同溫度下,將(R)-2-((叔丁氧基羰基)氨基)-3-(2,4-二氟苯氧基)丙酸(113mg,0.36mmol,中間體1的步驟3)的EtOAc(2mL)溶液和2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷2,4,6-三氧化物(0.30mL,0.51mmol;在EtOAc中的1.7M溶液)依次添加到混合物中。在-5℃下攪拌1hr之後,藉由添加飽和的NaHCO3水溶液(5mL)而使混合物淬滅。用水稀釋混合物,並用EtOAc(20mL×3)進行萃取。用鹽水清洗合併之有機層,並經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用50%EtOAc的己烷進行洗脫)提純殘留物而獲得作為無色固體之標題化合物(72mg,52%的收率)。
MS(ESI)m/z:543(M+H)+
步驟2:(R)-5-((R)-2-氨基-3-(2,4-二氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
在0℃下,在((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(70mg,0.13mmol)的DCM(1mL)攪拌溶液中一次性添加三氟乙酸(1mL),並在相同溫度下持續攪拌1hr。在真空中濃縮混合物,並用DCM(5mL)稀釋殘留物。用飽和的NaHCO3水溶液、接著用鹽水清洗萃取之溶液,並經Na2SO4乾燥。進行過濾之
後,在真空中濃縮濾液而獲得作為無色膠狀物之標題化合物(66mg,>99%的收率)。
MS(ESI)m/z:443(M+H)+
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
在室溫下,在(R)-5-((R)-2-氨基-3-(2,4-二氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(66mg,0.15mmol)、2-((叔丁氧基羰基)氨基)-2-甲基丙酸(38mg,0.19mmol)及三乙胺(0.083mL,0.60mmol)的DCM(1mL)溶液中添加苯並三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU,68mg,0.18mmol)。攪拌1hr之後,在真空中濃縮混合物。使殘留物通過短管柱層析(氨基-凝膠,用EtOAc進行洗脫)而獲得作為無色膠狀物之標題化合物(60mg,87%的收率)。
MS(ESI)m/z:628(M+H)+,626(M-H)-
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
在0℃下,在(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(81mg,0.13mmol)的DCM(1mL)攪拌溶液中添加三氟乙酸(1mL)的一部分,並在相同溫度下持續攪拌2hr。在真空中濃縮混合物,並用DCM(5mL)稀釋殘留物。用飽和的NaHCO3水溶液、接著用鹽水清洗,並經Na2SO4乾燥。進行過濾之後,去除溶劑和揮發物。藉由製備型LC-MS提純殘留物而獲得11mg(16%的收率)標題化合物。
將製備型LC-MS和品質檢驗(QC)方法的條件示於表5。
實施例2:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以50%的收率(510mg,白色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(800mg,2.0mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸(630mg,2.2mmol,中間體2的步驟3)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.31-7.15(5H,m),7.10-6.90(3H,m),6.87(2H,d,J=7.9Hz),5.52-5.42(1H,m),5.23-5.05(2H,m),4.61-4.50(1H,m),4.26-4.08(2H,m),3.23(1H,d,J=13.2Hz),3.09(3H,s),3.08-2.90(2H,m),2.66-2.50(2H,m),1.45(9H,s)。未觀察到NHBoc。
MS(ESI)m/z:507(M+H)+,505(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-苯氧基丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以95%的收率(390mg,白色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯(800mg,2.0mmol)製備標題化合物。
MS(ESI)m/z:407(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-
四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以99%的收率(560mg,白色固體)由(R)-5-((R)-2-氨基-3-苯氧基丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(390mg,0.96mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(230mg,1.2mmol)製備標題化合物。
1H NMR(300MHz,CDCl3)delta 7.35-7.12(5H,m),7.10-7.04(2H,m),7.00-6.84(3H,m),5.52-5.42(1H,m),5.07(1H,d,J=12.5Hz),4.85(1H,br s),4.64-4.52(1H,m),4.30-4.22(1H,m),4.16-4.10(1H,m),3.19(1H,d,J=13.8Hz),3.07(3H,s),3.05-2.85(2H,m),2.64-2.50(2H,m),1.51(3H,s),1.49(3H,s),1.38(9H,s)未觀察到CONH和NHBoc。
MS(ESI)m/z:592(M+H)+,590(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以86%的收率(395mg,白色固體)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(550mg,0.93mmol)製備標題化合物。在該情況下,藉由管柱層析(NH-凝膠,用0%至80%EtOAc的己烷進行洗脫)提純標題化合物。
1H-NMR(300MHz,CDCl3)delta 8.45(1H,d,J=7.3Hz),7.30-7.15(5H,m),7.12-6.85(5H,m),5.45-5.35(1H,m),5.09(1H,d,J=12.5Hz),4.61(1H,d,J=10.6Hz),4.24(2H,d,J=6.6Hz),3.22(1H,
d,J=13.1Hz),3.08(3H,s),3.10-2.85(3H,m),2.65-2.48(2H,m),1.40(3H,s),1.35(3H,s)。未觀察到NH2。
MS(ESI)m/z:492(M+H)+,490(M-H)-。
產物的一部分藉由製備型LC-MS進行進一步提純而獲得標題化合物。
實施例3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以53%的收率(73mg,白色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(100mg,0.25mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(4-氯苯氧基)丙酸(110mg,0.36mmol,中間體3的步驟3)製備標題化合物。
MS(ESI)m/z:541(M+H)+。
步驟2:(R)-5-((R)-2-氨基-3-(4-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以>99%的收率(61mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(70mg,0.13mmol)製備標題化合物。
MS(ESI)m/z:441(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙
烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以94%的收率(81mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(4-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(61mg,0.14mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(35mg,0.17mmol)製備標題化合物。
1H-NMR(300MHz,CDCl3)delta 7.31-7.18(5H,m),7.09-7.08(2H,m),6.82(2H,d,J=8.8Hz),5.46(1H,q,J=7.1Hz),5.08(1H,d,J=12.5Hz),4.86(1H,s),4.62-4.51(1H,m),4.31-4.20(1H,m),4.16-4.03(1H,m),3.19(1H,d,J=13.9Hz),3.08-2.86(7H,m),2.65-2.53(2H,m),1.50(3H,s),1.49(3H,s),1.37(9H,s)。
MS(ESI)m/z:626(M+H)+,624(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以16%的收率(11mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(81mg,0.13mmol)製備標題化合物。
實施例4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以61%收率(105mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(100mg,0.25mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸(120mg,0.38mmol,中間體4的步驟3)製備標題化合物。
MS(ESI)m/z:541(M+H)+。
步驟2:(R)-5-((R)-2-氨基-3-(3-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以>99%的收率(79mg,無色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(95mg,0.18mmol)製備標題化合物。
MS(ESI)m/z:441(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以>99%的收率(100mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(3-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(68mg,0.15mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(39mg,0.19mmol)製備標題化合物。
MS(ESI)m/z:626(M+H)+,624(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以14%的收率(11mg)由(1-
(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(92mg,0.15mmol)製備標題化合物。
實施例5:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以47%的收率(86mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(130mg,0.32mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3,5-二氯苯氧基)丙酸(130mg,0.38mmol,中間體5的步驟3)製備標題化合物。
MS(ESI)m/z:575(M+H)+。
步驟2:(R)-5-((R)-2-氨基-3-(3,5-二氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以>99%的收率(70mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(76mg,0.13mmol)製備標題化合物。
MS(ESI)m/z:475(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以>99%的收率(89mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(3,5-二氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(61mg,0.13mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(33mg,0.16mmol)製備標題化合物。
MS(ESI)m/z:660(M+H)+,658(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以18%的收率(12mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(81mg,0.12mmol)製備標題化合物。
實施例6:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以66%的收率(77mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(130mg,0.32mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(2-(三氟甲基)苯氧基)丙酸(85mg,0.24mmol,中間體6的步驟3)製備標題化合物。
MS(ESI)m/z:575(M+H)+,573(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(2-(三氟甲基)苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以86%的收率(45mg)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)氨基甲酸叔丁酯(64mg,0.11mmol)製備標題化合物。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以>99%的收率(79mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(2-(三氟甲基)苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(45mg,0.095mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(23mg,0.11mmol)製備標題化合物。
MS(ESI)m/z:660(M+H)+,658(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以22%的收率(14mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(75mg,0.11mmol)製備標題化合物。
實施例7:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以66%的收率(73mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(130mg,0.32mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3,4-二氟苯氧基)丙酸(77mg,0.24mmol,中間體7的步驟3)製備標題化合物。
MS(ESI)m/z:543(M+H)+,541(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(3,4-二氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以92%的收率(54mg)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(72mg,0.13mmol)製備標題化合物。
MS(ESI)m/z:443(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以>99%的收率(91mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(3,4-二氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(54mg,0.12mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(23mg,0.11mmol)製備標題化合物。
MS(ESI)m/z:628(M+H)+,626(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-
四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以15%的收率(12mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(91mg,0.15mmol)製備標題化合物。
實施例8:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以60%的收率(66mg,無色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(80mg,0.20mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(2-氯苯氧基)丙酸(77mg,0.24mmol,中間體8的步驟3)製備標題化合物。
MS(ESI)m/z:541(M+H)+,539(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(2-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以>99%的收率(58mg)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(61mg,0.11mmol)製備標題化合物。
MS(ESI)m/z:441(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以96%的收率(79mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(2-氯苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(58mg,0.13mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(32mg,0.16mmol)製備標題化合物。
MS(ESI)m/z:626(M+H)+,624(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以22%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(69mg,0.11mmol)製備標題化合物。
實施例9:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以43%的收率(54mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(80mg,0.20mmol)和(R)
-3-(3,5-雙(三氟甲基)苯氧基)-2-((叔丁氧基羰基)氨基)丙酸(100mg,0.24mmol,中間體9的步驟3)製備標題化合物。
MS(ESI)m/z:643(M+H)+,641(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(3,5-雙(三氟甲基)苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以91%的收率(40mg)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(52mg,0.081mmol)製備標題化合物。
MS(ESI)m/z:543(M+H)+。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以>99%的收率(55mg,無色膠狀物)由(R)-5-((R)-2-氨基-3-(3,5-雙(三氟甲基)苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(40mg,0.074mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(32mg,0.16mmol)製備標題化合物。
MS(ESI)m/z:728(M+H)+,726(M-H)-。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以32%的收率(14mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙
烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(50mg,0.069mmol)製備標題化合物。
實施例10:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以45%的收率(48mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(80mg,0.20mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸(79mg,0.26mmol,中間體10的步驟3)製備標題化合物。
MS(ESI)m/z:525(M+H)+,523(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
在0℃下,在((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(30mg,0.057mmol)的DCM(2mL)攪拌溶液中一次性添加三氟乙酸(2mL),並在相同溫度下持續攪拌2hr。在真空中濃縮混合物而獲得黃色糖漿。將殘留物溶解於DCM(4mL)中。在室溫下,將混合物添加到三乙胺(0.017mL,0.23mmol)和苯並三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU,27mg,0.072mmol)中。攪拌1hr之後,在真空中濃縮混合物。使殘留物通過短管柱層析(氨基-凝膠,用EtOAc進行洗脫)而獲得作為白色固體之標題化合物
(51mg,>99%的收率)。
MS(ESI)m/z:610(M+H)+,608(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以32%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(48mg,0.079mmol)製備標題化合物。
實施例11:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以62%的收率(85mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(80mg,0.20mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸(103mg,0.33mmol,中間體11的步驟3)製備標題化合物。
MS(ESI)m/z:537(M+H)+,535(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以96%的收率(78mg,白色
固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(70mg,0.13mmol)製備標題化合物。
MS(ESI)m/z:622(M+H)+,620(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以18%的收率(9mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(60mg,0.097mmol)製備標題化合物。
實施例12:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以57%的收率(76mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(100mg,0.25mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸(114mg,0.38mmol,中間體12的步驟3)製備標題化合物。
MS(ESI)m/z:525(M+H)+,523(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙
烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以>99%的收率(74mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(60mg,0.11mmol)製備標題化合物。
MS(ESI)m/z:610(M+H)+,608(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以22%的收率(11mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(60mg,0.098mmol)製備標題化合物。
實施例13:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以45%的收率(90mg,白色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(140mg,0.36mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(萘-2-基氧基)丙酸(130mg,0.39mmol,中間體14的步驟3)製備標題化合物。
MS(ESI)m/z:557(M+H)+,555(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以>99%的收率(100mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(87mg,0.15mmol)製備標題化合物。
MS(ESI)m/z:642(M+H)+,640(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以14%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(100mg,0.16mmol)製備標題化合物。
實施例14:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以67%的收率(140mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(150mg,0.38mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(萘-1-基氧基)丙酸(150mg,0.46mmol,
中間體15的步驟3)製備標題化合物。
MS(ESI)m/z:557(M+H)+,555(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以82%的收率(120mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(130mg,0.23mmol)製備標題化合物。
MS(ESI)m/z:642(M+H)+,640(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以14%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(110mg,0.17mmol)製備標題化合物。
實施例15:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以53%的收率(170mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3
(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(250mg,0.64mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-((5-氯吡啶-3-基)氧基)丙酸(180mg,0.58mmol,中間體16的步驟2)製備標題化合物。
MS(ESI)m/z:542(M+H)+,540(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟1類似的方式,以86%的收率(170mg,白色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(160mg,0.30mmol)製備標題化合物。
MS(ESI)m/z:627(M+H)+,625(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以11%的收率(16mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(170mg,0.27mmol)製備標題化合物。
實施例16:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以42%的收率(110mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(190mg,0.48mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-氰基苯氧基)丙酸(150mg,0.48mmol,中間體17的步驟3)製備標題化合物。
MS(ESI)m/z:532(M+H)+,530(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以>99%的收率(113mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(86mg,0.16mmol)製備標題化合物。
MS(ESI)m/z:617(M+H)+,615(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以14%的收率(12mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(100mg,0.17mmol,實施例X的步驟X)製備標題化合物。
實施例17:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫
-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以68%的收率(140mg,無色膠狀物)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(160mg,0.41mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(吡啶-2-基氧基)丙酸(140mg,0.49mmol,中間體18的步驟2)製備標題化合物。
MS(ESI)m/z:508(M+H)+,506(M-H)-。
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以86%的收率(130mg,無色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)氨基甲酸叔丁酯(130mg,0.25mmol)製備標題化合物。
MS(ESI)m/z:593(M+H)+,591(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以12%的收率(12mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(120mg,0.20mmol)製備標題化合物。
實施例18:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-
基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以58%的收率(120mg,無色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(150mg,0.38mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-((5-氟吡啶-3-基)氧基)丙酸(130mg,0.42mmol,中間體19的步驟2)製備標題化合物。
MS(ESI)m/z:526(M+H)+,524(M-H)-
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以95%的收率(120mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(110mg,0.20mmol)製備標題化合物。
MS(ESI)m/z:611(M+H)+,609(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以15%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(110mg,0.17mmol)製備標題化合物。
實施例19:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以78%的收率(170mg,無色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(150mg,0.38mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-((6-(三氟甲基)吡啶-2-基)氧基)丙酸(150mg,0.42mmol,中間體20的步驟2)製備標題化合物。
MS(ESI)m/z:576(M+H)+,574(M-H)-
步驟2:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例10的步驟2類似的方式,以98%的收率(180mg,無色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)氨基甲酸叔丁酯(160mg,0.28mmol)製備標題化合物。
MS(ESI)m/z:661(M+H)+,659(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以8%的收率(12mg)由(1-
(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(170mg,0.26mmol)製備標題化合物。
實施例20:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以36%的收率(29mg,白色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(51mg,0.13mmol)和(R)-2-(2-((叔丁氧基羰基)氨基)-2-甲基丙醯胺基)-3-(4-氰基苯氧基)丙酸(51mg,0.13mmol,中間體13的步驟3)製備標題化合物。
MS(ESI)m/z:617(M+H)+,617(M-H)-
步驟2:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以54%的收率(13mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(29mg,0.047mmol)製備標題化合物。
實施例21:2-氨基-N-((R)-1-((R)-3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代
-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
步驟1:((2R)-1-(3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯(非對映異構物混合物)
以與實施例1的步驟1類似的方式,以84%的收率(120mg,無色膠狀物)由3a-苄基-2-(2,2-二氟乙基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮2,2,2-三氟乙酸酯(100mg,0.26mmol,核1的步驟2)和(R)-2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸(86mg,0.31mmol,中間體2的步驟3)製備標題化合物。
MS(ESI)m/z:557(M+H)+,555(M-H)-
步驟2:(1-(((2R)-1-(3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(非對映異構物混合物)
以與實施例10的步驟2類似的方式,以>99%的收率(200mg,白色固體)由((2R)-1-(3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯(120mg,0.22mmol)製備標題化合物。
MS(ESI)m/z:642(M+H)+,640(M-H)-。
步驟3:2-氨基-N-((R)-1-((R)-3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以6%的收率(10mg)由(1-(((2R)-1-(3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(200mg,0.31mmol)製備
標題化合物。
在該情況下,在製備型LC-MS條件下,收集所希望之非對映異構物作為極性更強的非對映異構物。
實施例22:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以40%的收率(50mg,無色膠狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)氨基)-3-苯氧基丙酸(76mg,0.27mmol,中間體2的步驟3)製備標題化合物。
MS(ESI)m/z:558(M+H)+,556(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-苯氧基丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
在室溫下,在((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)氨基甲酸叔丁酯(50mg,0.090mmol)的DCM(1mL)攪拌溶液中添加三氟乙酸(5mL),並在相同溫度下將混合物攪拌30min。在真空中濃縮混合物。藉由強陽離子交換柱(Isolute(登錄商標)SCX,1g/6mL,Biotage)提純殘留物而獲得作為透明無色膠狀物之標題化合物(35mg,84%的收率)。
MS(ESI)m/z:458(M+H)+。
步驟3:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺
將(R)-5-((R)-2-氨基-3-苯氧基丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(34mg,0.074mmol)的溶液和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(18mg,0.089mmol)的EtOAc(2mL)冷卻至0℃。在混合物中依次添加三乙胺(0.031mL,0.22mmol)和2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷2,4,6-三氧化物(0.087mL,0.15mmol;1.7M溶液的EtOAc),並在相同溫度下,將生成之混合物攪拌1hr。在真空中濃縮混合物。接著,將三氟乙酸(2mL)添加到殘留物中,並在室溫下將混合物攪拌30min。在真空中濃縮混合物。藉由強陽離子交換柱(BondElute(登錄商標)SCX,1g/6mL,Varian Inc.)提純殘留物,接著藉由製備型LC-MS進一步提純而獲得10mg(25%的收率)標題化合物。
實施例23:2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以30%的收率(40mg,無色膠狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)
氨基)-3-(2-氯苯氧基)丙酸(85mg,0.27mmol,中間體8的步驟3)製備標題化合物。
MS(ESI)m/z:592(M+H)+,590(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(2-氯苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例22的步驟2類似的方式,以89%的收率(33mg,無色油)由((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(40mg,0.068mmol)製備標題化合物。
MS(ESI)m/z:492(M+H)+。
步驟3:2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例22的步驟3類似的方式,以28%的收率(10mg)由(R)-5-((R)-2-氨基-3-(2-氯苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(30mg,0.060mmol)製備標題化合物。
實施例24:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以31%的收率(41mg,無色膠
狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)氨基)-3-(2-氟苯氧基)丙酸(81mg,0.27mmol,中間體12的步驟3)製備標題化合物。
MS(ESI)m/z:576(M+H)+,574(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(2-氟苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例22的步驟2類似的方式,以92%的收率(31mg,無色油)由((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(41mg,0.071mmol)製備標題化合物。
MS(ESI)m/z:476(M+H)+。
步驟3:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例22的步驟3類似的方式,以30%的收率(11mg)由(R)-5-((R)-2-氨基-3-(2-氟苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(31mg,0.065mmol)製備標題化合物。
實施例25:2-氨基-N-((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)
-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以37%的收率(49mg,無色膠狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-氯苯氧基)丙酸(85mg,0.27mmol,中間體4的步驟3)製備標題化合物。
MS(ESI)m/z:592(M+H)+,590(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(3-氯苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例22的步驟2類似的方式,以87%的收率(36mg,無色油)由((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(49mg,0.083mmol)製備標題化合物。
MS(ESI)m/z:492(M+H)+。
步驟3:2-氨基-N-((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例22的步驟3類似的方式,以22%的收率(9mg)由(R)-5-((R)-2-氨基-3-(3-氯苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(36mg,0.072mmol,實施例22的步驟3)製備標題化合物。
實施例26:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-
氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以48%的收率(64mg,無色膠狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-甲氧基苯氧基)丙酸(84mg,0.27mmol,中間體11的步驟3)製備標題化合物。
MS(ESI)m/z:588(M+H)+,586(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(3-甲氧基苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例22的步驟2類似的方式,以82%的收率(43mg,無色油)由((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(64mg,0.11mmol)製備標題化合物。
MS(ESI)m/z:488(M+H)+。
步驟3:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例22的步驟3類似的方式,以24%的收率(12mg)由(R)-5-((R)-2-氨基-3-(3-甲氧基苯氧基)丙醯基)-2-(2,2-二氟乙基)
-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(43mg,0.089mmol)製備標題化合物。
實施例27:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以36%的收率(47mg,無色膠狀物)由(R)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2S,3S)-2,3-二羥基琥珀酸酯(100mg,0.23mmol,核2的步驟3)和(R)-2-((叔丁氧基羰基)氨基)-3-(3-氟苯氧基)丙酸(100mg,0.34mmol,中間體10的步驟3)製備標題化合物。
MS(ESI)m/z:576(M+H)+,574(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(3-氟苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例22的步驟2類似的方式,以91%的收率(35mg,無色油)由((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(47mg,0.082mmol)製備標題化合物。
MS(ESI)m/z:476(M+H)+。
步驟3:2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-
基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例22的步驟3類似的方式,以36%的收率(15mg)由(R)-5-((R)-2-氨基-3-(3-氟苯氧基)丙醯基)-2-(2,2-二氟乙基)-3a-(吡啶-2-基甲基)-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(35mg,0.074mmol)製備標題化合物。
實施例28:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟1類似的方式,以56%的收率(45mg,白色固體)由(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(60mg,0.15mmol)和(R)-2-((叔丁氧基羰基)氨基)-3-(4-氟苯氧基)丙酸(45mg,0.15mmol,中間體16的步驟2)製備標題化合物。
MS(ESI)m/z:525(M+H)+,523(M-H)-。
步驟2:(R)-5-((R)-2-氨基-3-(4-氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟2類似的方式,以定量收率(37mg,無色油)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(45mg,0.086mmol)製備標題化合物。
步驟3:(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟3類似的方式,以96%的收率(50mg,無色油)由(R)-5-((R)-2-氨基-3-(4-氟苯氧基)丙醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(37mg,0.86mmol)和2-((叔丁氧基羰基)氨基)-2-甲基丙酸(26mg,1.3mmol)製備標題化合物。
MS(ESI)m/z:610(M+H)+。
步驟4:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟4類似的方式,以22%的收率(11mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(45mg,0.074mmol)製備標題化合物。
將製備型LC-MS和品質檢驗(QC)方法的條件示於表5。
比較例1:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)-2-甲基丙醯胺
步驟1:((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯
在氮氣氛下,將(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯(1500mg,3.81mmol)的EtOAc(30mL)懸浮液冷卻至-50℃,並在相同溫度下滴加三乙胺(1.06mL,7.62mmol)來實現(R)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(2R,3R)-2,3-二羥基琥珀酸酯的游離鹼化(freebasing)及三乙基酒石酸銨(triethylammonium tartrate)的鹽形成。將混合物攪拌15min之後,將補加量的三乙胺(1.59mL,11.4mmol)滴加到混合物中,並在-50℃下將混合物攪拌10min。在混合物中添加溶解於EtOAc(20mL)中之三乙基銨(R)-2-((叔丁氧基羰基)氨基)-4-羥基丁酸酯(triethylammonium(R)-2-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate)15min,並添加2,4,6-三丙基-1,3,5,2,4,6-三氧雜三磷雜環己烷2,4,6-三氧化物(4.49mL,7.63mmol,EtOAc中的1.7M溶液)10min。在-50℃下,將混合物另行攪拌2hr,並在相同溫度下,藉由添加飽和的NaHCO3水溶液(50mL)使反應淬滅。將混合物加熱至室溫,用水(50mL)稀釋,並用EtOAc(50mL×3)萃取。用鹽水清洗合併之有機層,並經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用5%MeOH的EtOAc進行洗脫)提純殘留物而獲得作為無色固體之標題化合物(1170mg,69%的收率)。
MS(ESI)m/z:445(M+H)+。
步驟2:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)氨基甲酸叔丁酯
在0℃下,在((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(200mg,0.45mmol)、苯酚(64mg,0.68mmol)及三苯基膦(236mg,0.90mmol)的THF(8mL)溶液中逐滴添加雙(2-甲氧基乙基)偶氮二羧酸酯(211mg,0.90mmol)的THF(1mL)溶液。在室溫下徹夜攪拌之後,用水稀釋混合物,並用EtOAc萃取。用飽和的NaHCO3水溶液和鹽水清洗萃取物,並經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,15%至50%EtOAc的己烷)提純殘留物而獲得作為白色固體之標題化合物(194mg,83%的收率)。
MS(ESI)m/z:521(M+H)+。
步驟3:
(R)-5-((R)-2-氨基-4-苯氧基丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
在0℃下,在((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)氨基甲酸叔丁酯(194mg,0.37mmol)的DCM(5mL)溶液中添加三氟乙酸(2mL),並在相同溫度下將混合物攪拌30min。接著,在真空中濃縮混合物,用DCM稀釋殘留物,用飽和的NaHCO3水溶液、接著用鹽水清洗混合物,並經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,用10%至50%EtOAc的己烷進行洗脫)提純殘留物而獲得作為無色膠狀物之標題化合物(104mg,67%的收率)。
MS(ESI)m/z:421(M+H)+。
步驟4:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
在室溫下,在(R)-5-((R)-2-氨基-4-苯氧基丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(100mg,0.24mmol)、2-((叔丁氧基羰基)氨基)-2-甲基丙酸(73mg,0.36mmol)及三乙胺(0.13mL,0.95mmol)的DCM(6mL)懸浮液中添加苯並三氮唑-N,N,N’,N’-四甲基脲六氟磷酸酯(HBTU,48mg,0.36mmol)。在相同溫度下徹夜攪拌之後,在真空中濃縮混合物。使殘留物通過短管柱層析(矽-膠,用2%至20%EtOAc的己烷進行洗脫)而獲得作為無色固體之標題化合物(131mg,91%的收率)。
MS(ESI)m/z:506(M-Boc+H)+。
步驟5:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)-2-甲基丙醯胺
在0℃下,在(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-4-苯氧基丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(130mg,0.22mmol)的DCM(4mL)溶液中添加三氟乙酸(2mL)。在相同溫度下攪拌2hr之後,在真空中濃縮混合物。用DCM稀釋殘留物,用飽和的NaHCO3水溶液和鹽水清洗混合物,並經Na2SO4乾燥。進行過濾之後,去除過濾之溶劑和揮發物。藉由製備型LC-MS提純殘留物而獲得9.4mg(9%的收率)作為淺褐色固體之標題化合物。
將製備型LC-MS和品質檢驗(QC)方法的條件示於表6。
比較例2:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
步驟1:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟2類似的方式,以>99%的收率(187mg,油)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(150mg,0.34mmol)和3,4-二氟苯酚(132mg,1.0mmol)製備標題化合物。
MS(ESI)m/z:557(M+H)+,555(M-H)-。
步驟2:
(R)-5-((R)-2-氨基-4-(3,4-二氟苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟3類似的方式,以41%的收率(62mg,黃色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(187mg,0.34mmol)製備標題化合物。
MS(ESI)m/z:457(M+H)+。
步驟3:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟4類似的方式,以>99%的收率(84mg,無色
固體)由(R)-5-((R)-2-氨基-4-(3,4-二氟苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(60mg,0.13mmol)製備標題化合物。
MS(ESI)m/z:542(M-Boc+H)+。
步驟4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟5類似的方式,以12%的收率(9.3mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,4-二氟苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(84mg,0.13mmol)製備標題化合物。
比較例3:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
步驟1:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟2類似的方式,以45%的收率(213mg,白色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(130mg,0.29mmol)和3,5-雙(三氟甲基)苯酚(202mg,0.88mmol)製備標題化合物。
MS(ESI)m/z:601(M-tBu+H)+。
步驟2:
(R)-5-((R)-2-氨基-4-(3,5-雙(三氟甲基)苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟3類似的方式,以62%的收率(50mg,褐色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(213mg,0.15mmol)製備標題化合物。
MS(ESI)m/z:557(M+H)+。
步驟3:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟4類似的方式,以>99%的收率(67mg,白色固體)由(R)-5-((R)-2-氨基-4-(3,5-雙(三氟甲基)苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(50mg,0.090mmol)製備標題化合物。
MS(ESI)m/z:742(M+H)+。
步驟4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟5類似的方式,以23%的收率(12mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3,5-雙(三氟甲基)苯氧基)-1-氧代丁
烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(59mg,0.080mmol)製備標題化合物。
比較例4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
步驟1:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟2類似的方式,以45%的收率(213mg,白色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(60mg,0.14mmol)和4-氟苯酚(30mg,0.27mmol)製備標題化合物。
MS(ESI)m/z:601(M-tBu+H)+。
步驟2:
(R)-5-((R)-2-氨基-4-(4-氟苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟3類似的方式,以13%的收率(24mg,褐色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(191mg,0.43mmol)製備標題化合物。
MS(ESI)m/z:439(M+H)+。
步驟3:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-
吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟4類似的方式,以82%的收率(28mg,無色膠狀物)由(R)-5-((R)-2-氨基-4-(4-氟苯氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(24mg,0.055mmol)製備標題化合物。
MS(ESI)m/z:624(M+H)+,622(M-H)-。
步驟4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟5類似的方式,以42%的收率(9.8mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(4-氟苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(28mg,0.045mmol)製備標題化合物。
比較例5:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
步驟1:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟2類似的方式,以>99%的收率(182mg,淺褐色膠狀物)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-
四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(150mg,0.34mmol)和5-氟吡啶-3-醇(57mg,0.51mmol)製備標題化合物。
MS(ESI)m/z:540(M+H)+。
步驟2:
(R)-5-((R)-2-氨基-4-((5-氟吡啶-3-基)氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮
以與實施例1的步驟3類似的方式,以21%的收率(32mg,淺褐色固體)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(182mg,0.34mmol)製備標題化合物。
MS(ESI)m/z:440(M+H)+。
步驟3:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟4類似的方式,以89%的收率(38mg,淺褐色固體)由(R)-5-((R)-2-氨基-4-((5-氟吡啶-3-基)氧基)丁醯基)-3a-苄基-2-甲基-4,5,6,7-四氫-2H-吡唑並[4,3-c]吡啶-3(3aH)-酮(30mg,0.068mmol)製備標題化合物。
MS(ESI)m/z:625(M+H)+,623(M-H)-。
步驟4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟5類似的方式,以32%的收率(9.7mg)由(1-
(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-((5-氟吡啶-3-基)氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(38mg,0.061mmol)製備標題化合物。
比較例6:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
步驟1:
((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯
在0℃下,在((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-羥基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(150mg,0.34mmol)、3-羥基苯甲腈(60mg,0.51mmol)及三丁基膦(0.17mL,0.38mmol)的THF(2mL)溶液中逐滴添加1,1’-(偶氮羰基)-二哌啶(170mg,0.65mmol)的THF(4mL)溶液。在室溫下攪拌3天之後,將混合物用飽和的NaHCO3水溶液和EtOAc稀釋來進行分離。將有機層經Na2SO4乾燥。進行過濾之後,在真空中濃縮濾液。藉由管柱層析(矽膠,50%至75%的EtOAc的己烷)提純殘留物而獲得作為無色膠狀物之標題化合物(105mg,57%的收率)。
MS(ESI)m/z:546(M+H)+,544(M-H)-。
步驟2:
3-((R)-3-氨基-4-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-氧代丁氧基)苯甲腈
以與實施例1的步驟3類似的方式,以>99%的收率(74mg,淺褐
色油)由((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(91mg,0.17mmol)製備標題化合物。
MS(ESI)m/z:446(M+H)+。
步驟3:
(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯
以與實施例1的步驟4類似的方式,以>99%的收率(105mg,黃色膠狀物)由3-((R)-3-氨基-4-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-氧代丁氧基)苯甲腈(74mg,0.17mmol)製備標題化合物。
MS(ESI)m/z:631(M+H)+,629(M-H)-。
步驟4:
2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)-2-甲基丙醯胺
以與實施例1的步驟5類似的方式,以19%的收率(17mg)由(1-(((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-4-(3-氰基苯氧基)-1-氧代丁烷-2-基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁酯(105mg,0.17mmol)製備標題化合物。
體外藥理學測定
在穩定表達人生長激素釋放肽受體之HEK293細胞中由生長激素釋放肽受體激動活性誘導之Ca2+內流的測量
在37℃下,將穩定表達人生長激素釋放肽受體之HEK293細胞在5%CO2的加濕培養箱中保持於補充有10%胎牛血清、100單位/ml青黴素、100microg/ml鏈黴素及500microg/ml G418之達爾博克氏改良伊格
爾培養基(Dulbecco’s modified Eagle medium)(高葡萄糖),並使其生長至60-80%細胞匯合度(confluence)。在測定前一天,將細胞以10,000細胞/孔的密度接種於多聚-D-賴胺酸塗覆之384-孔板(BD FALCON),並在培養箱中徹夜培養。
在測定當天,用分析緩衝液(20mM HEPES,pH7.4的Hanks’平衡鹽溶液)將細胞清洗三次,並在室溫下培養1小時,從而加載0.5microM Fluo-4 AM試劑(Invitrogen)。
去除Fluo-4,並用分析緩衝液清洗之後,在細胞中添加各種化合物的濃縮液。用熒光成像讀板儀(fluorescence imaging plate reader)FDSS6000(Hamamatsu Photonics)監控細胞內鈣濃度的變化。
由11-點劑量-反應研究確定本發明的化合物的EC50值。使用各資料點的複孔(duplicate well)平均值來生成曲線。最後,使用藉由XL擬合(ID Business Solutions Ltd)確定之最佳擬合劑量曲線來計算出EC50值。
所有被測化合物在上述測定中顯示出小於約500nanoM的EC50。較佳的化合物在上述測定中顯示出小於約50nanoM的EC50。
更為佳的化合物在上述測定中顯示出小於約10nanoM的EC50。
較佳的化合物如下:
實施例1-8、10-14、16及21-27。
更為佳的化合物如下:
實施例9、17、18及20。
表7.絲胺酸衍生物與高絲胺酸衍生物之間的人生長激素釋放肽EC50的比例
體內藥理學測定
在有意識的小鼠中生長激素(GH)反應
從Charles River Japan購入雌性BALB/c小鼠(7週齡),並在每一
個籠子容納四隻或五隻動物。徹夜禁食之後,口服給藥測試化合物。在給藥後的5、10、30分鐘,採集血液樣品。在每個時間點使用兩隻或三隻動物。使用EIA kit(Rat Growth Hormone EIA KIT,SPI-Bio,France)測定小鼠GH的血漿濃度。
本發明的化合物在上述測定中顯示出大於等於15ng/ml的小鼠GH的血漿濃度。
麻醉大鼠一般用於研究生長激素釋放肽化合物(常規方法參閱以下:Endocrinol Japan 31(1984)539-547,Journal of Endocrinology 171(2001)481-489,Gastroenterology 123(2002)1120-1128,Peptides 32(2011)1001-1007)。在常規測定中,需要靜脈內給藥測試化合物,因此該等不適合於口服藥物的探索性調研中。但是,上述測定可在禁食狀態下口服給藥,其在藥物探索中對測試化合物的生長激素釋放的評估有用。這是用於評估生長激素釋放的、在有意識的禁食小鼠中生長激素(GH)反應的測定過程的第一個實例。
在大鼠中對順鉑-誘導之惡病質/厭食症之影響
從Japan SLC,Inc購入雄性Wistar大鼠(7-8週齡),在12-h光照、12-小時黑暗的循環(早上8點開燈)下,分別單獨地容納於溫度和濕度經控制之腔室中。使大鼠適應實驗環境至少5天,並處理兩次。隨意供給食物和水。大鼠被分類為所謂的假手術對照組和順鉑處理組這兩組。從第0天至第2天,在光照週期的末期腹膜內給藥順鉑(0.6mg/kg/day,Wako Pure Chemical)。對於假手術大鼠僅提供生理鹽水。在即將給藥順鉑之前,將測試化合物口服給藥3天(從第0天至第2天)。為了預防順鉑-誘導之中毒性腎損害,在給藥鹽或順鉑之後,立即皮下給藥2-3mL的生理鹽水。從第0天至第4天,每天測定體重及食物消耗量。
在用順鉑處理之大鼠中觀察到統計上體重及食物消耗量顯著地
減少。化合物的口服給藥使得用順鉑處理的大鼠的體重及食物消耗量顯著增加。
有生長激素釋放肽在短期內顯示出減少食物消耗量的部分報道(常規方法參閱以下:Endocrinology 149(2008)455-460,Endocrinology 151(2010)3773-3782,Neurogastroenterol Motil 25(2013)373-e292,Peptides 46(2013)13-19,Vitamins and Hormones 92(2013)301-317)。沒有報導在5天的研究中,生長激素釋放肽激動劑顯示出抑制持續的體重降低且抑制食物攝取量減少。當適用5天常規測定時,該等研究因大鼠中之順鉑-誘導之中毒性腎損害而未能獲得成功。為了解決該問題作出了巨大努力。最後,驚奇地發現如下改變條件會帶來成功的結果:1)在傍晚給藥;2)使用適應實驗環境至少5天且至少兩次處理得當的大鼠;及3)加載鹽,其對惡病質/厭食症的評估有用。這是大鼠中順鉑-誘導之惡病質/厭食症的測定過程的首例。
承載有(bearing)AH-130細胞的大鼠中對惡病質的影響
從Japan SLC,Inc購入雄性Wistar大鼠(4週齡),在12-h光照、12-小時黑暗的循環(早上8點開燈)下,分別單獨地容納於溫度和濕度經控制之腔室中。使大鼠適應實驗環境至少5天,並處理兩次。隨意供給食物和水。大鼠被分類為所謂的假手術對照組和腫瘤承載(tumor bearer)組。在第0天,後者腹膜內注射大於1×108的AH-130腹水肝癌細胞(Tohoku University,Sendai,Japan)。對於假手術大鼠僅提供PBS。腫瘤承載組進一步分類為處理組和未處理組,前者在光照週期的末期口服給藥測試化合物9天(第0天至第8天)。一周測定兩次體重。在實驗結束時,用CO2處死大鼠,解剖胸大肌並進行稱重。
在接種AH-130腹水肝癌細胞後的5天,與假手術組相比,體重明顯減少。在給藥本發明的化合物之大鼠中,與對照組相比,第9天的體重及胸大肌重量顯著增加。
沒有生長激素釋放肽激動劑抑制持續的體重降低之報導。為了解決該問題作出了巨大努力。最後,驚奇地發現如下改變條件會帶來成功的結果:1)利用未成熟之大鼠來代替成熟大鼠;2)增加細胞數(大於1×108的AH-130腹水肝癌細胞);及3)在傍晚給藥。上述測定過程對藥物探索中的惡病質的評估有用。這是在承載有AH-130細胞之大鼠中惡病質(體重降低及肌肉萎縮)的測定過程的第一個成功的實例。
Claims (13)
- 如請求項1之化合物或其藥學上可接受的鹽,其中:R2為氫或C1-C6烷基,其中,該烷基未被取代或被1至3個獨立地選自鹵素中之取代基取代。
- 如請求項1之化合物或其藥學上可接受的鹽,其中:R1獨立地選自由以下所構成之群組:(1)氫、(2)鹵素、(3)三氟甲基、(4)三氟甲氧基、及(5)-CN;R2為C1-6烷基,其中,該烷基未被取代或被1至3個獨立地選自鹵素中之取代基取代。
- 如請求項1之化合物或其藥學上可接受的鹽,其中:R1獨立地選自由以下所構成之群組;(1)氫、(2)-F、(3)-Cl、(4)三氟甲基、(5)三氟甲氧基及(6)-CN;R2為甲基或二氟乙基。
- 如請求項1之化合物或其藥學上可接受的鹽,其中:A為苯基、2-吡啶基或3-吡啶基;R1獨立地選自由以下所構成之群組;(1)氫、(2)-F、(3)-Cl、(4)三氟甲基、(5)三氟甲氧基及(6)-CN;R2為甲基或2,2-二氟乙基。
- 如請求項1之化合物或其藥學上可接受的鹽,其中,該化合物選自由以下所構成之群組:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-二氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺; 2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(2-(三氟甲基)苯氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氯苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,5-雙(三氟甲基)苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-2-基氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(萘-1-基氧基)-1- 氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氯吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-(吡啶-2-基氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-((5-氟吡啶-3-基)氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-((6-(三氟甲基)吡啶-2-基)氧基)丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-(2,2-二氟乙基)-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟 乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(3-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;及2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺。
- 如請求項1之化合物或其藥學上可接受的鹽,其中,該化合物選自由以下所構成之群組:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7- 四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-3-(2-氯苯氧基)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(2-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-甲氧基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺; 2-氨基-N-((R)-1-((R)-2-(2,2-二氟乙基)-3-氧代-3a-(吡啶-2-基甲基)-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;及2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺。
- 如請求項1之化合物或其藥學上可接受的鹽,其中,該化合物選自由以下所構成之群組:2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-1-氧代-3-苯氧基丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3,4-二氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(3-氰基苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺;及2-氨基-N-((R)-1-((R)-3a-苄基-2-甲基-3-氧代-3a,4,6,7-四氫-2H-吡唑並[4,3-c]吡啶-5(3H)-基)-3-(4-氟苯氧基)-1-氧代丙烷-2-基)-2-甲基丙醯胺。
- 一種藥物組成物,其包含請求項1至8中任一項之化合物或其藥學上可接受的鹽及藥學上可接受的載體。
- 一種藥物組成物的製備方法,其包含將請求項1至8中任一項之化合物或其藥學上可接受的鹽與藥學上可接受的載體、稀釋劑或賦形劑進行混合。
- 一種如請求項1之化合物之篩選方法,其係包含將該化合物口服 給藥於有意識的禁食BALB/c小鼠,及測定該小鼠生長激素(GH)的血漿濃度,以評估該化合物之GH反應。
- 一種如請求項1之化合物在製造用於緩解順鉑-誘導之惡病質/厭食症之醫藥組合物之用途。
- 一種如請求項1之化合物在製造用於緩解腹水肝癌所導致之惡病質之醫藥組合物之用途。
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CN106459147B (zh) | 2021-08-06 |
JP6051392B1 (ja) | 2016-12-27 |
TW201613921A (en) | 2016-04-16 |
EP3131916A4 (en) | 2017-03-15 |
EP3131916B1 (en) | 2018-11-14 |
CN106459147A (zh) | 2017-02-22 |
MX2017001408A (es) | 2017-05-10 |
CA2951619C (en) | 2023-01-10 |
KR101980180B1 (ko) | 2019-05-20 |
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