TW201927312A - [beta]-D-2'-deoxy-2'-[alpha]-fluoro-2'-[beta]-C-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis C virus - Google Patents

[beta]-D-2'-deoxy-2'-[alpha]-fluoro-2'-[beta]-C-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis C virus Download PDF

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TW201927312A
TW201927312A TW106144895A TW106144895A TW201927312A TW 201927312 A TW201927312 A TW 201927312A TW 106144895 A TW106144895 A TW 106144895A TW 106144895 A TW106144895 A TW 106144895A TW 201927312 A TW201927312 A TW 201927312A
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alkyl
compound
formula
hydrogen
optionally substituted
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TW106144895A
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珍-皮爾 索馬多希
艾戴爾 摩薩
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美商亞堤製藥公司
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Abstract

Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX and Formula X that are highly active against the HCV virus when administered in an effective amount to a host in need thereof. The host can be a human or any animal that carries the viral infection. Methods of treating a subject suffering from a condition related to viral infections are also provided.

Description

用於治療C型肝炎病毒之β-D-2'-脫氧-2'-α-氟-2'-β-C-取代-4'-氟-N6-取代-6-胺基-2-取代嘌呤核苷酸β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N6-substituted-6-amino-2-substituted for the treatment of hepatitis C virus Purine nucleotide

本發明大體上係關於治療罹患由病毒感染(包括C型肝炎病毒(Hepatitis C virus，「HCV」))引起之病況之患者的核苷酸化合物、其用途及其組合物。The present invention is generally directed to nucleotide compounds, uses thereof, and compositions thereof for treating a patient suffering from a condition caused by a viral infection, including Hepatitis C virus ("HCV").

C型肝炎(HCV)為RNA單股病毒，且是丙型肝炎病毒屬(Hepacivirus genus)的成員。據估計，肝病的所有案例中75%係由HCV引起的。HCV感染可導致肝硬化及肝癌，且若任其發展，則會導致可能需要肝臟移植的肝臟衰竭。全世界有大約1700-2000萬人經感染，估計美國有3-4百萬感染。 RNA聚合酶在靶向RNA單股病毒中為關鍵組分。HCV非結構蛋白NS5B RNA依賴性RNA聚合酶為造成初始化及催化病毒RNA合成的關鍵酶。因此，HCV NS5B為用於當前藥物發現及研發抗HCV試劑的有吸引力的標靶。存在兩個主要亞類的NS5B抑制劑：核苷類似物，其經同化為其活性三磷酸酯-其充當用於聚合酶之替代基質-及非核苷抑制劑(non-nucleoside inhibitor，NNI)，其與蛋白上之別位區結合。核苷或核苷酸抑制劑模擬天然聚合酶基質且充當鏈終止劑。其抑制RNA轉錄之開始及初生RNA鏈之伸長。 除靶向RNA聚合酶之外，亦可在組合療法中靶向其他RNA病毒蛋白。舉例而言，為用於治療方法之額外標靶的HCV蛋白係NS3/4A (絲胺酸蛋白酶)及NS5A (非結構蛋白，其為HCV複製酶之必要組分且對細胞路徑發揮一系列影響)。 在2013年12月，第一核苷NS5B聚合酶抑制劑索非布韋(sofosbuvir，Sovaldi®，Gilead Sciences)審批通過。Sovaldi®為尿苷胺基磷酸酯前藥，其由肝細胞吸收且進行胞內活化以得到活性代謝物；2'-去氧-2'-α-氟-β-C-甲基尿苷-5'-三磷酸酯參見以下結構：2'-去氧-2'-α-氟-β-C-甲基尿苷-5'-三磷酸酯 Sovaldi®為第一藥物，其已展現治療某些類型之HCV感染之安全性及功效而無需共同投與干擾素。Sovaldi®為具有得到FDA批准之突破療法指定之第三藥物。 在2014年，美國FDA審批通過治療慢性C型肝炎病毒基因型1感染之Harvoni® (雷迪帕韋(ledispasvir)，NS5A抑制劑及索非布韋)。Harvoni®為審批通過以治療慢性HCV基因型1感染之第一組合丸劑。其亦為不需要投與干擾素或利巴韋林(ribavirin)之第一審批通過的方案。另外，FDA審批通過與索非布韋(Sovaldi®)組合之西咪匹韋(simeprevir，OlysioTM)作為患有基因型1 HCV感染之成人的每日一次、全部口服、無干擾素及利巴韋林之治療劑。 美國FDA在2014年亦審批通過AbbVie之VIEKIRA PakTM，一種含有達薩布韋(dasabuvir，非核苷NS5B聚合酶抑制劑)、奧匹替韋(ombitasvir，NS5A抑制劑)、帕瑞普韋和(paritaprevir，NS3/4A抑制劑)及利托那韋(ritonavir)之多丸劑封裝可在有或無利巴韋林之情況下使用VIEKIRA PakTM以治療基因型1 HCV經感染之患者，包括患有代償性肝硬化(compensated cirrhosis)之患者。VIEKIRA PakTM不需要干擾素協同療法。 在2015年7月，美國FDA審批通過TechnivieTM及DaklinzaTM以分別治療HCV基因型4及HCV基因型3。TechnivieTM (奧匹替韋/帕瑞普韋和/利托那韋)審批通過用於與利巴韋林組合使用，以治療患者之HCV基因型4而無疤痕及肝硬化，且為不需要共同投與干擾素之經HCV-4感染的患者之第一選擇。審批通過DaklinzaTM以與Sovaldi®一起使用來治療HCV基因型3感染。DaklinzaTM為第一藥物，其在治療HCV基因型3中已展現安全性及功效而無需共同投與干擾素或利巴韋林。 在2015年10月，美國FDA警告HCV治療劑Viekira Pak及Technivie會在患有潛在晚期肝病之患者中造成主要地嚴重肝臟損傷，且需要在標籤上加入關於安全性之額外資訊。 用於HCV之其他當前審批通過之治療劑包括干擾素α-2b或聚乙二醇化干擾素α-2b (Pegintron®)，其可與以下一起投與：利巴韋林(Rebetol®)、NS3/4A特拉匹韋(telaprevir，Incivek®，Vertex及Johnson & Johnson)、波普瑞韋(boceprevir，VictrelisTM，Merck)、西咪匹韋(OlysioTM，Johnson & Johnson)、帕瑞普韋和(AbbVie)、奧匹替韋(AbbVie)、(NNI)達薩布韋(ABT-333)及Merck之ZepatierTM (兩種藥物格佐匹韋(grazoprevir)及艾爾巴韋(elbasvir)的單錠劑組合)。 額外NS5B聚合酶抑制劑當前處於研發中。Merck正在研發尿苷核苷酸前藥MK-3682 (以前為Idenix IDX21437)。藥物當前處於階段II組合試驗。描述用於治療包括HCV之黃病毒(Flaviviridae)之核苷聚合酶抑制劑的美國專利及WO申請案包括以下申請的彼等：Idenix Pharmaceuticals (6,812,219；6,914,054；7,105,493；7,138,376；7,148,206；7,157,441；7,163,929；7,169,766；7,192,936；7,365,057；7,384,924；7,456,155；7,547,704；7,582,618；7,608,597；7,608,600；7,625,875；7,635,689；7,662,798；7,824,851；7,902,202；7,932,240；7,951,789；8,193,372；8,299,038；8,343,937；8,362,068；8,507,460；8,637,475；8,674,085；8,680,071；8,691,788、8,742,101、8,951,985；9,109,001；9,243,025；US2016/0002281；US2013/0064794；WO/2015/095305；WO/2015/081133；WO/2015/061683；WO/2013/177219；WO/2013/039920；WO/2014/137930；WO/2014/052638；WO/2012/154321)；Merck (6,777,395；7,105,499；7,125,855；7,202,224；7,323,449；7,339,054；7,534,767；7,632,821；7,879,815；8,071,568；8,148,349；8,470,834；8,481,712；8,541,434；8,697,694；8,715,638、9,061,041；9,156,872及WO/2013/009737)；埃默里大學(Emory University) (6,348,587；6,911,424；7,307,065；7,495,006；7,662,938；7,772,208；8,114,994；8,168,583；8,609,627；US 2014/0212382；及WO2014/1244430)；Gilead Sciences/ Pharmasset Inc. (7,842,672；7,973,013；8,008,264；8,012,941；8,012,942；8,318,682；8,324,179；8,415,308；8,455,451；8,563,530；8,841,275；8,853,171；8,871,785；8,877,733；8,889,159；8,906,880；8,912,321；8,957,045；8,957,046；9,045,520；9,085,573；9,090,642；及9,139,604)及(6,908,924；6,949,522；7,094,770；7,211,570；7,429,572；7,601,820；7,638,502；7,718,790；7,772,208；RE42,015；7,919,247；7,964,580；8,093,380；8,114,997；8,173,621；8,334,270；8,415,322；8,481,713；8,492,539；8,551,973；8,580,765；8,618,076；8,629,263；8,633,309；8,642,756；8,716,262；8,716,263；8,735,345；8,735,372；8,735,569；8,759,510及8,765,710)；Hoffman La-Roche (6,660,721)、Roche (6,784,166；7,608,599、7,608,601及8,071,567)；Alios BioPharma Inc. (8,895,723；8,877,731；8,871,737、8,846,896、8,772,474；8,980,865；9,012,427；US 2015/0105341；US 2015/0011497；US 2010/0249068；US2012/0070411；WO 2015/054465；WO 2014/209979；WO 2014/100505；WO 2014/100498；WO 2013/142159；WO 2013/142157；WO 2013/096680；WO 2013/088155；WO 2010/108135)、Enanta Pharmaceuticals (US 8,575,119；8,846,638；9,085,599；WO 2013/044030；WO 2012/125900)、Biota (7,268,119；7,285,658；7,713,941；8,119,607；8,415,309；8,501,699及8,802,840)、Biocryst Pharmaceuticals (7,388,002；7,429,571；7,514,410；7,560,434；7,994,139；8,133,870； 8,163,703； 8,242,085及8,440,813)、Alla Chem, LLC (8,889,701及WO 2015/053662)、Inhibitex (8,759,318及WO/2012/092484)、Janssen Products (8,399,429；8,431,588、8,481,510、8,552,021、8,933,052；9,006,29及9,012,428)、喬治亞大學基金會(the University of Georgia Foundation) (6,348,587；7,307,065；7,662,938；8,168,583；8,673,926、8,816,074；8,921,384及8,946,244)、RFS Pharma, LLC (8,895,531；8,859,595；8,815,829；8,609,627；7,560,550；US 2014/0066395；US 2014/0235566；US 2010/0279969；WO/2010/091386及WO 2012/158811)、University College Cardiff Consultants Limited (WO/2014/076490、WO 2010/081082；WO/2008/062206)、Achillion Pharmaceuticals, Inc. (WO/2014/169278及WO 2014/169280)、Cocrystal Pharma, Inc. (US 9,173,893)、Katholieke Universiteit Leuven (WO 2015/158913)、Catabasis (WO 2013/090420)及明尼蘇達大學董事會(the Regents of the University of Minnesota) (WO 2006/004637)。 在1976年，Moffatt等人報導關於核苷抗生素核殺菌素之合成；參見以下結構：核殺菌素 核殺菌素結構獨特，此係因為其為含有氟碳水化合物或未經取代之胺磺醯基的第一天然產物。另外，在4'位含官能性取代基之呋喃醣似乎為第一實例，參見「4'-Substituted Nucleosides. 2. Synthesis of the Nucleoside Antibiotic Nucleocidin」，Moffatt, J.G.等人, J. Am. Chem. Soc., 98(11)3346-3357, 1976。Moffatt等人亦報導關於4'-氟尿苷衍生物之合成，參見「4'-Substituted Nucleosides. 3. Synthesis of Some 4'-Fluorouridine Derivatives」，Owens, G.R.,等人, J. Org. Chem., 41(18)3010-3017, 1976。 在2010年，Verdine等人揭示4'-氟核苷之簡潔合成。在一個合成途徑中，Verdine等人用N-溴丁二醯亞胺在日光燈(275 W)下處理1-O-乙醯基-2,3,5-三-O-苯甲醯基-β-D-核糖以得到經歷氟化之溴化產物與四氟硼酸銀之混合物，從而以30%的產率得到4-氟-β-D-呋喃核糖連同幾乎等量的4-氟-α-L-呋喃來蘇糖(lyxofuranose)。使用4-氟-β-D-呋喃核糖、Verdine合成4'-氟腺苷、4'-氟肌苷及4'-氟胞苷。另外，Verdine揭示核苷2',3',5'-三苯甲酸酯5-氟尿苷之直接溴化:氟化以得到尿苷、5-氟-4'-C-氟、2',3',5'-三苯甲酸酯。參見「A Concise Synthesis of 4'-Fluoro Nucleosides」，Lee, S.等人, Org. Lett., 9(24)5007-5009, 2007。 在2010年，Alexandrova, L.A.等人揭示4'氟尿苷5'-O-三磷酸酯為HCV RNA依賴性RNA聚合酶之有效抑制劑，參見「Synthesis and Biological Properties of Pyrimidine 4'-Fluoronucleosides and 4'-Fluorouridine 5'-Triphosphate」, Ivanov, M.A.等人, Russian J. Bioorg. Chem., 36(4)488-496, 2010。 Pharmasset, Inc.申請之標題為「Modified Fluorinated Nucleoside Analogues」的US 7,429,572描述許多廣泛屬之核苷化合物，包括廣泛式：其中鹼基指代天然存在或經改質之嘌呤或嘧啶鹼；R1 可為醫藥學上可接受之脫離基，其在活體內投與時能夠提供化合物，其中R1 為H或磷酸酯；R2 可為H、C1-4 烷基、C1-4 烯基、C1-4 炔基、乙烯基、N3 、CN、Cl、Br、F、I、NO2 、C(O)O(C1-4 烷基)、C(O)O(C1-4 炔基)、C(O)O(C1-4 烯基)、O(C1-4 醯基)、O(C1-4 烷基)、O(C1-4 烯基)、S(C1-4 醯基)、S(C1-4 烷基)、S(C1-4 炔基)、S(C1-4 烯基)、SO(C1-4 醯基)、SO(C1-4 烷基)、SO(C1-4 炔基)、SO(C1-4 烯基)、SO2 (C1-4 醯基)、SO2 (C1-4 烷基)、SO2 (C1-4 炔基)、SO2 (C1-4 烯基)、O3 S(C1-4 醯基)等；且R6 可為視情況經取代之烷基(包括低碳數烷基)、氰基(CN)、CH3 、OCH3 、OCH2 CH3 、羥甲基(CH2 OH)、氟甲基(CH2 F)、疊氮基(N3 )、CHCN、CH2 N3 、CH2 NH2 、CH2 NHCH3 、CH2 N(CH3 )2 、炔(視情況經取代)或氟。關於在R6 為氟時，無屬於此極廣泛屬內所揭示之物種。 Idenix Ltd.申請之標題為「Purine Nucleoside Analogues for Treating Flaviviridae Including Hepatitis C」的WO 2005/009148描述式I之化合物，參見以下結構，其具有廣泛定義之變化。舉例而言，X為CH2 、CHOH、CH-烷基、CH-烯基、CH-炔基、C-二烷基、CH-O-烷基、CH-O-烯基、CH-O-炔基、CH-S-烷基、CH-S-烯基、CH-S-炔基、CH-鹵素或C-(鹵素)2 。可變R1' 獨立地為H、OH、視情況經取代之烷基(包括低碳數烷基)、疊氮基、氰基、視情況經取代之烯基或炔基、-C(O)O-(烷基)、-C(O)O(低碳數烷基)、-C(O)O-(烯基)、-C(O)O-(炔基)、-O(醯基)、-O(低碳數醯基)、-O(烷基)、-O(低碳數烷基)、-O(烯基)、-O(炔基)、鹵素、鹵化烷基、-NO2 、-NH2 、-NH(低碳數烷基)、-N(低碳數烷基)2 、-NH(醯基)、-N(醯基)2 、-C(O)NH2 、-C(O)NH(烷基)、-C(O)N(烷基)2 、S(O)N-烷基、S(O)N-烯基、S(O)N-炔基或SCH-鹵素，其中烷基、烯基、及/或炔基可視情況經取代。(I) Idenix申請案揭示4'-氟核苷不為任何屬。揭示4'-核苷的其他Idenix專利申請案及專利包括WO 2005/020884；美國專利第7,138,376號及美國專利第9,211,300號。 Pharmasset, Inc.申請之標題為「Nucleoside Phosphoramidate Prodrugs」的WO 2008/121634描述許多廣泛屬之核苷化合物，包括廣泛式I-5：其中：R5 為H、低碳數烷基、CN、乙烯基、O-(低碳數烷基)、羥基低碳數烷基(即-(CH2 )pOH，其中p為1-6)，其包括羥甲基(CH2 OH)、CH2 F、N3 、CH2 CN、CH2 NH2 、CH2 NHCH3 、CH2 N(CH3 )2 、炔(視情況經取代)或鹵素，鹵素包括F、Cl、Br或I，其限制條件為當X為OH時，鹼為胞嘧啶且R6 為H，R5 不能為N3 且當X為OH時，R6 為CH3 或CH2 F且B為嘌呤鹼，R5 不能為H；R6 為H、CH3 、CH2 F、CHF2 、CF3 、F或CN；X為H、OH、F、OMe、鹵素、NH2 或N3 。關於當R5 為F時，R6 為CH3 且X為F，無屬於此極廣泛屬內所揭示之物種，且關於如何製備或如何選擇放置額外取代基的位置無指導。Pharmasset的額外專利申請案及專利包括WO 2009/152095；美國專利：第號7,964,580號；第8,173,621號；第8,334,270號；第8,580,765號；第8,735,372號；第8,759,510號；第8,906,880號；第8,957,046號；及第9,085,573號。 RFS Pharma, LLC申請之標題為「Purine Nucleoside Monophosphate Prodrugs for Treatment of Cancer and Viral Infections」的WO 2010/091386揭示式I之化合物(I) 其中糖為核糖或通式(II)之經改質之核糖：。 本申請案不揭示任何物種，其中R7' 為氟，R5 為C1 -C6 烷基且 R5' 為氟。 Gilead Sciences, Inc.申請之標題為「Methods for the Preparation of Diastereomerically Pure Phosphoramidate Prodrugs」的WO 2012/012465描述許多廣泛屬之核苷化合物，其包括廣泛式Ia及Ib：其中各R1 、R2 、R7 、R22 、R23 或R24 獨立地為H、OR11 、NR11 R12 、C(O)NR11 R12 、-OC(O)NR11 R12 、C(O)OR11 、OC(O)OR11 、S(O)n Ra 、S(O)2 NR11 R12 、N3 、CN、鹵素、(C1- C8 )烷基、(C3 -C8 )碳環基、(C4 -C8 )碳環基烷基、(C2 -C8 )烯基、(C2 -C8 )炔基或芳基(C1 -C8 )烷基。關於當R24 為F時，R1 為CH3 且R2 為F；無屬於此極廣泛屬內所揭示之物種，且關於如何製備或如何選擇放置取代基的位置無指導。 MBC Pharma, Inc.申請之標題為「Vitamin B6 Derivatives of Nucleotides, Acyclonucleotides and Acyclonucleoside Phosphonates」的WO 2013/019874揭示5'-核苷之廣泛定義，參見以下：(5'-核苷) 其中E為O、C、N或S；R4 、R5 、R6 、R7 、R8 及R9 獨立地為H、OH、F、NH2 、N3 、烷基、烯基或炔基。本申請案揭示無4'-氟呋喃醣化合物及核苷化合物用維生素B6在5'位衍生。 F. Hoffmann-La Roche AG申請之標題為「2',4'-Difluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication」的WO 2013/092481揭示具有抗HCV活性之式I之嘧啶化合物，參見以下結構：Alios Biopharma, Inc.申請之標題為「Substituted Nucleosides, Nucleotides and Analogs Thereof」的WO 2014/100505揭示亞屬式：其中R3 可為羥基且R4 可為氫或。所揭示之唯一物種為以下說明之鳥嘌呤化合物：。 因為感染有HCV之人的治療選項有限，醫療上仍強烈需要研發安全、有效及良好耐受的抗HCV治療劑。需要藉由期望抗藥性可能出現(如抗HIV及抗HCV治療劑中所見)來增強，且可需要新組合藥物治療劑以治療HCV病毒。更有效的直接作用抗病毒劑可顯著縮短治療持續時間且提高感染有HCV之患者之順應性及SVR比率。因此，本發明之目標為提供治療及/或預防感染HCV的化合物、醫藥組合物及方法及用途。Hepatitis C (HCV) is a single RNA virus and is a member of the Hepacivirus genus. It is estimated that 75% of all cases of liver disease are caused by HCV. HCV infection can lead to cirrhosis and liver cancer, and if left unchecked, it can lead to liver failure that may require liver transplantation. Approximately 17 to 20 million people worldwide are infected, and an estimated 3-4 million infections in the United States. RNA polymerase is a key component in targeting RNA single-stranded viruses. The HCV non-structural protein NS5B RNA-dependent RNA polymerase is a key enzyme responsible for initializing and catalyzing the synthesis of viral RNA. Therefore, HCV NS5B is an attractive target for current drug discovery and development of anti-HCV agents. There are two major subclasses of NS5B inhibitors: nucleoside analogs that are assimilated into their active triphosphates - which serve as a surrogate matrix for polymerases - and non-nucleoside inhibitors (NNI), It binds to the other regions on the protein. A nucleoside or nucleotide inhibitor mimics a native polymerase matrix and acts as a chain terminator. It inhibits the initiation of RNA transcription and the elongation of the nascent RNA strand. In addition to targeting RNA polymerase, other RNA viral proteins can also be targeted in combination therapy. For example, the HCV protein lines NS3/4A (serine protease) and NS5A (non-structural proteins, which are essential components of HCV replicase) and are a major component of the cell pathway, are additional targets for therapeutic approaches. ). In December 2013, the first nucleoside NS5B polymerase inhibitor sofosbuvir (Sovaldi®, Gilead Sciences) was approved. Sovaldi® is a uridine amino phosphate prodrug that is taken up by hepatocytes and undergoes intracellular activation to obtain an active metabolite; 2'-deoxy-2'-α-fluoro-β-C-methyluridine- 5'-triphosphate see the following structure: 2'-Deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate Sovaldi® is the first drug that has demonstrated the safety and efficacy of treating certain types of HCV infections. There is no need to co-administer interferon. Sovaldi® is the third drug specified for FDA-approved breakthrough therapy. In 2014, the US FDA approved Harvoni® (ledispasvir, NS5A inhibitors and sofosbuvir) for the treatment of chronic hepatitis C virus genotype 1 infection. Harvoni® is the first combination pill approved for the treatment of chronic HCV genotype 1 infection. It is also the first approved approval for the administration of interferon or ribavirin. In addition, the FDA approves the use of simeprevir (OlysioTM) in combination with Sovaldi® as a daily, total oral, interferon-free and ribavivir in adults with genotype 1 HCV infection. Lin's therapeutic agent. The US FDA also approved ABBVie's VIEKIRA PakTM in 2014, a drug containing dasabuvir (a non-nucleoside NS5B polymerase inhibitor), opitavir (ombitasvir, NS5A inhibitor), parecvir and (paritaprevir). , NS3/4A inhibitors) and ritonavir multi-pill encapsulation can be used to treat genotype 1 HCV infected patients, including compensatory, with VIEKIRA PakTM with or without ribavirin Patients with cirrhosis (compensated cirrhosis). VIEKIRA PakTM does not require interferon synergistic therapy. In July 2015, the US FDA approved TechnivieTM and DaklinzaTM to treat HCV genotype 4 and HCV genotype 3, respectively. TechnivieTM (opidibiv/paripvir and/ritonavir) approved for use in combination with ribavirin to treat patients with HCV genotype 4 without scarring and cirrhosis, and without the need for common The first choice for patients with HCV-4 infection who are administered interferon. Approved by DaklinzaTM for use with Sovaldi® to treat HCV genotype 3 infection. DaklinzaTM is the first drug that has demonstrated safety and efficacy in the treatment of HCV genotype 3 without the need to co-administer interferon or ribavirin. In October 2015, the US FDA warned that HCV therapeutics Viekira Pak and Technivie would cause major liver damage in patients with potentially advanced liver disease, and additional information on safety would need to be added to the label. Other currently approved therapeutic agents for HCV include interferon alpha-2b or pegylated interferon alpha-2b (Pegintron®), which can be administered with ribavirin (Rebetol®), NS3 /4A telaprevir (Celaprevir, Incivek®, Vertex and Johnson & Johnson), boceprevir (VictrelisTM, Merck), cimetipide (OlysioTM, Johnson & Johnson), parepwe and (AbbVie) ), AbbVie, (NNI) Dasabwe (ABT-333) and Merck's ZepatierTM (single drug combination of two drugs, gazoprevir and elbasvir) ). Additional NS5B polymerase inhibitors are currently under development. Merck is developing the uridine nucleotide prodrug MK-3682 (formerly Idenix IDX21437). The drug is currently in Phase II combination trials. US Patent and WO applications describing nucleoside polymerase inhibitors for the treatment of flaviviruses including HCV (Flaviviridae) include those of the following applications: Idenix Pharmaceuticals (6,812,219; 6,914,054; 7,105,493; 7,138,376; 7,148,206; 7,157,441; 7,163,929; 7,169,766; 7,192,936; 7,365,057; 7,384,924; 7,456,155; 7,547,704; 7,582,618; 7,608,597; 7,608,600; 7,625,875; 7,635,689; 7,662,798; 7,824,851; 7,902,202; 7,932,240; 7,951,789; 8,193,372;8,299,038;8,343,937;8,362,068;8,507,460;8,637,475;8,674,085;8,680,071;8,691,788, 8,742,101,8,951,985;9,109,001; 9,243,025; US2016/0002281; US2013/0064794; WO/2015/095305; WO/2015/081133; WO/2015/061683; WO/2013/177219; WO/2013/039920; WO/2014/ 137930; WO/2014/052638; WO/2012/154321); Merck (6,777,395; 7,105,499; 7,125,855; 7,202,224; 7,323,449; 7,339,054; 7,534,767; 7,632,821; 7,879,815; 8,071,568;8,148,349;8,470,834;8,481,712;8,541,434;8,697,694;8,715,638,9,061,041 ;9,156,872 and WO/2013/009 737); Emory University (6,348,587; 6,911,424; 7,307,065; 7,495,006; 7,662,938; 7,772,208; 8,114,994; 8,168,583; 8,609,627; US 2014/0212382; and WO2014/1244430); Gilead Sciences/ Pharmasset Inc. (7,842,672; 7,973,013;8,008,264; 8,012,941; 8,012,942; 8,318,682; 8,324,179; 8,415,308; 8,455,451; 8,563,530; 8,841,275; 8,853,171; 8,871,785; 8,877,733; 8,889,159; 8,906,880; 8,912,321; 8,957,045; 8,957,046; 9,045,520; 9,085,573; 9,090,642; and 9,139,604) and (6,908,924; 6,949,522 7,094,770; 7,211,570; 7,429,572; 7,601,820; 7,638,502; 7,718,790; 7,772,208; RE42,015; 7,919,247; 7,964,580; 8,093,380; 8,114,997; 8,173,621; 8,334,270; 8,415,322;8,481,713;8,492,539;8,551,973;8,580,765;8,618,076;8,629,263;8,633,309;8,642,756;8,716,262 ; 8,716,263; 8,735,345; 8,735,372; 8,735,569; 8,759,510 and 8,765,710); Hoffman La-Roche (6,660,721), Roche (6,784,166; 7,608,599, 7,608,601 and 8,071,567); Alios BioPharma Inc. (8,8) 95,723; 8,877,731; 8,871,737, 8,846,896, 8,772,474; 8,980,865; 9,012,427; US 2015/0105341; US 2015/0011497; US 2010/0249068; US2012/0070411; WO 2015/054465; WO 2014/209979; WO 2014/100505; /100498; WO 2013/142159; WO 2013/142157; WO 2013/096680; WO 2013/088155; WO 2010/108135), Enanta Pharmaceuticals (US 8,575,119; 8,846,638; 9,085,599; WO 2013/044030; WO 2012/125900), Biota (7,268,119; 7,285,658; 7,713,941; 8,119,607; 8,415,309; 8,501,699 and 8,802,840), Biocryst Pharmaceuticals (7,388,002; 7,429,571; 7,514,410; 7,560,434; 7,994,139; 8,133,870; 8,163,703; 8,242,085 and 8,440,813), Alla Chem, LLC (8,889,701 and WO 2015/053662) ), Inhibitex (8,759,318 and WO/2012/092484), Janssen Products (8,399,429; 8,431,588, 8,481,510, 8,552,021, 8,933,052; 9,006,29 and 9,012,428), the University of Georgia Foundation (6,348,587; 7,307,065; 7,662,938) ; 8,168,583; 8,673,926, 8,816,074; 8,921,384 and 8,946,244), RFS Pharma, LLC ( 8,895,531; 8,859,595; 8,815,829; 8,609,627; 7,560,550; US 2014/0066395; US 2014/0235566; US 2010/0279969; WO/2010/091386 and WO 2012/158811), University College Cardiff Consultants Limited (WO/2014/076490, WO 2010/081082; WO/2008/062206), Achillion Pharmaceuticals, Inc. (WO/2014/169278 and WO 2014/169280), Cocrystal Pharma, Inc. (US 9,173,893), Katholieke Universiteit Leuven (WO 2015/158913), Catabasis (WO 2013/090420) and the Regents of the University of Minnesota (WO 2006/004637). In 1976, Moffatt et al. reported on the synthesis of nucleoside antibiotics such as nucleosides; see the following structure: The nucleostatin has a unique structure because it is the first natural product containing a fluorocarbohydrate or an unsubstituted sulfonamide. In addition, the furanose containing a functional substituent at the 4' position appears to be the first example, see "4'-Substituted Nucleosides. 2. Synthesis of the Nucleoside Antibiotic Nucleocidin", Moffatt, JG et al., J. Am. Chem. Soc., 98(11) 3346-3357, 1976. Moffatt et al. also reported the synthesis of 4'-fluorouridine derivatives, see "4'-Substituted Nucleosides. 3. Synthesis of Some 4'-Fluorouridine Derivatives", Owens, GR, et al., J. Org. Chem. 41 (18) 3010-3017, 1976. In 2010, Verdine et al. revealed a concise synthesis of 4'-fluoronucleosides. In a synthetic route, Verdine et al. treated 1-O-acetamido-2,3,5-tri-O-benzimidyl-β with N-bromobutaneimine under fluorescent lamps (275 W). -D-ribose to obtain a mixture of fluorinated bromination product and silver tetrafluoroborate to obtain 4-fluoro-β-D-ribofuranose in 30% yield together with almost equal amount of 4-fluoro-α- L-furantanose (lyxofuranose). 4'-fluoroadenosine, 4'-fluoroinosine and 4'-fluorocytidine were synthesized using 4-fluoro-β-D-ribofuranosylose and Verdine. In addition, Verdine reveals direct bromination of the nucleoside 2',3',5'-tribenzoate 5-fluorouridine: fluorination to give uridine, 5-fluoro-4'-C-fluoro, 2' , 3', 5'-tribenzoate. See "A Concise Synthesis of 4'-Fluoro Nucleosides", Lee, S. et al., Org. Lett., 9(24) 5007-5009, 2007. In 2010, Alexandrova, LA et al. revealed that 4'-fluorouridine 5'-O-triphosphate is a potent inhibitor of HCV RNA-dependent RNA polymerase, see "Synthesis and Biological Properties of Pyrimidine 4'-Fluoronucleosides and 4 '-Fluorouridine 5'-Triphosphate", Ivanov, MA et al, Russian J. Bioorg. Chem., 36(4) 488-496, 2010. US 7,429,572 to Pharmasset, Inc., entitled "Modified Fluorinated Nucleoside Analogues", describes a wide variety of nucleoside compounds, including a wide range: Wherein the base refers to a naturally occurring or modified purine or pyrimidine base; R 1 may be a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R 1 is H or a phosphate; R 2 may be H, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, vinyl, N 3 , CN, Cl, Br, F, I, NO 2 , C(O) O(C 1-4 alkyl), C(O)O(C 1-4 alkynyl), C(O)O(C 1-4 alkenyl), O(C 1-4 fluorenyl), O ( C 1-4 alkyl), O(C 1-4 alkenyl), S(C 1-4 fluorenyl), S(C 1-4 alkyl), S(C 1-4 alkynyl), S ( C 1-4 alkenyl), SO(C 1-4 fluorenyl), SO(C 1-4 alkyl), SO(C 1-4 alkynyl), SO(C 1-4 alkenyl), SO 2 (C 1-4 fluorenyl), SO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkynyl), SO 2 (C 1-4 alkenyl), O 3 S (C 1-4 And R 6 may be optionally substituted alkyl (including lower alkyl), cyano (CN), CH 3 , OCH 3 , OCH 2 CH 3 , hydroxymethyl (CH 2 OH) ), fluoromethyl (CH 2 F), azide (N 3 ), CHCN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , alkyne (as appropriate) Replace) or fluorine. Regarding when R 6 is fluorine, there are no species disclosed in this extremely broad genus. WO 2005/009148, entitled "Purine Nucleoside Analogues for Treating Flaviviridae Including Hepatitis C" by Idenix Ltd., describes compounds of formula I, see the structure below, which has broadly defined variations. For example, X is CH 2 , CHOH, CH-alkyl, CH-alkenyl, CH-alkynyl, C-dialkyl, CH-O-alkyl, CH-O-alkenyl, CH-O- Alkynyl, CH-S-alkyl, CH-S-alkenyl, CH-S-alkynyl, CH-halogen or C-(halogen) 2 . The variable R 1 'is independently H, OH, optionally substituted alkyl (including lower alkyl), azido, cyano, optionally substituted alkenyl or alkynyl, -C(O O-(alkyl), -C(O)O(lower alkyl), -C(O)O-(alkenyl), -C(O)O-(alkynyl), -O(醯) (), -O (lower fluorenyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), halogen, alkyl halide, -NO 2 , -NH 2 , -NH (lower alkyl), -N (lower alkyl) 2 , -NH(indenyl), -N(indenyl) 2 , -C(O)NH 2 , -C(O)NH(alkyl), -C(O)N(alkyl) 2 , S(O)N-alkyl, S(O)N-alkenyl, S(O)N-yne Or a SCH-halogen wherein the alkyl, alkenyl, and/or alkynyl groups are optionally substituted. (I) The Idenix application discloses that 4'-fluoronucleosides are not of any genus. Other Idenix patent applications and patents which disclose 4'-nucleosides include WO 2005/020884; U.S. Patent No. 7,138,376 and U.S. Patent No. 9,211,300. WO 2008/121634, entitled "Nucleoside Phosphoramidate Prodrugs" by Pharmasset, Inc., describes a number of nucleoside compounds of a wide variety, including broad formula I-5: Wherein: R 5 is H, lower alkyl, CN, vinyl, O-(lower alkyl), hydroxy lower alkyl (ie -(CH 2 )pOH, wherein p is 1-6) , which includes hydroxymethyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , alkyne (optionally substituted) or Halogen, halogen includes F, Cl, Br or I, with the proviso that when X is OH, the base is cytosine and R 6 is H, R 5 cannot be N 3 and when X is OH, R 6 is CH 3 Or CH 2 F and B is a purine base, R 5 cannot be H; R 6 is H, CH 3 , CH 2 F, CHF 2 , CF 3 , F or CN; X is H, OH, F, OMe, halogen, NH 2 or N 3 . With respect to when R 5 is F, R 6 is CH 3 and X is F, and there are no species disclosed in this extremely broad genus, and there is no guidance as to how to prepare or how to choose where to place additional substituents. Additional patent applications and patents of Pharmasset include WO 2009/152095; U.S. Patent Nos. 7,964,580; 8,093,621; 8,334,270; 8,580,765; 8,735,372; 8,759,510; 8,906,880; 8,957,046; And No. 9,085,573. WO 2010/091386 to RFS Pharma, LLC, entitled "Purine Nucleoside Monophosphate Prodrugs for Treatment of Cancer and Viral Infections", discloses a compound of formula I (I) wherein the sugar is ribose or the modified ribose of formula (II): . This application does not disclose any species in which R 7 ' is fluoro, R 5 is C 1 -C 6 alkyl and R 5 ' is fluoro. WO 2012/012465, entitled "Methods for the Preparation of Diastereomerically Pure Phosphoramidate Prodrugs" by Gilead Sciences, Inc., describes a number of widely nucleoside compounds, including the broad formulas Ia and Ib: Wherein each of R 1 , R 2 , R 7 , R 22 , R 23 or R 24 is independently H, OR 11 , NR 11 R 12 , C(O)NR 11 R 12 , -OC(O)NR 11 R 12 , C(O)OR 11 , OC(O)OR 11 , S(O) n R a , S(O) 2 NR 11 R 12 , N 3 , CN, halogen, (C 1- C 8 )alkyl, (C 3 -C 8 ) carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl (C 1 - C 8 ) alkyl. With respect to when R 24 is F, R 1 is CH 3 and R 2 is F; there are no species disclosed in this extremely broad genus, and there is no guidance as to how to prepare or how to select the position at which the substituent is placed. WO 2013/019874, entitled "Vitamin B6 Derivatives of Nucleotides, Acyclonucleotides and Acyclonucleoside Phosphonates" by MBC Pharma, Inc., discloses a broad definition of 5'-nucleosides, see below: (5'-nucleoside) wherein E is O, C, N or S; R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently H, OH, F, NH 2 , N 3 , Alkyl, alkenyl or alkynyl. This application discloses that no 4'-fluorofuranose compounds and nucleoside compounds are derived from the 5' position with vitamin B6. WO 2013/092481 to F. Hoffmann-La Roche AG, entitled "2', 4'-Difluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication", discloses pyrimidine compounds of formula I having anti-HCV activity. , see the following structure: WO 2014/100505, entitled "Substituted Nucleosides, Nucleotides and Analogs Thereof", filed by Alios Biopharma, Inc., discloses subgenus: Wherein R 3 may be a hydroxyl group and R 4 may be hydrogen or . The only species revealed are the guanine compounds described below: . Because of the limited treatment options available to people with HCV, there is a strong medical need to develop safe, effective, and well tolerated anti-HCV therapeutics. It needs to be enhanced by the expectation that resistance may occur (as seen in anti-HIV and anti-HCV therapeutics), and new combination drug therapeutics may be needed to treat HCV virus. More effective direct-acting antiviral agents can significantly reduce treatment duration and increase compliance and SVR rates in patients infected with HCV. Accordingly, it is an object of the present invention to provide compounds, pharmaceutical compositions and methods and uses for the treatment and/or prevention of HCV infection.

在以有效量向對其有需要之寄主投與時提供對HCV病毒具有高活性的式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX及式X之化合物。寄主可為攜帶病毒感染的人類或任何動物。 在一個實施例中，治療有效量之一或多種式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX及式X之化合物或其醫藥學上可接受之鹽可用於治療HCV感染。在一個實施例中，治療有效量之一或多種式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX及式X之化合物或其醫藥學上可接受之鹽可用於抑制HCV聚合酶複合物。 因此，在一個實施例中，本發明包括：及式I 式II 其中： R1 為C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)或-(C0 -C2 烷基)(C3 -C6 環烷基)； R2 為氫、C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)、CHF2 、CH2 F、CF3 、-(C0 -C2 烷基)(C3 -C6 環烷基)、-C(O)R3C 、-(C0 -C2 烷基)(芳基)、-(C0 -C2 烷基)(雜環)、-(C0 -C2 烷基)(雜芳基)；或 R1 及R2 連同其等所鍵結之氮可形成雜環； R3 為氫、、二磷酸酯、三磷酸酯、視情況經取代之羰基鍵聯之胺基酸或-C(O)R3C ； R3A 可選自O- 、OH、視情況經-O-取代之芳基、視情況經-O-取代之雜芳基或視情況經取代之雜環基； R3B 可選自O- 、OH、視情況經取代之N鍵聯之胺基酸或視情況經取代的N鍵聯之胺基酸酯； R3C 為烷基、烯基、炔基、-(C0 -C2 )(環烷基)、-(C0 -C2 )(雜環)、-(C0 -C2 )(芳基)、-(C0 -C2 )(雜芳基)、-O-烷基、-O-烯基、-O-炔基、-O-(C0 -C2 )(環烷基)、-O-(C0 -C2 )(雜環)、-O-(C0 -C2 )(芳基)、-O-(C0 -C2 )(雜芳基)、-S-烷基、-S-烯基、-S-炔基、-S-(C0 -C2 )(環烷基)、-S-(C0 -C2 )(雜環)、-S-(C0 -C2 )(芳基)或-S-(C0 -C2 )(雜芳基)，其各者可視情況經取代； R4 為單磷酸酯、二磷酸酯、三磷酸酯或經穩定化的磷酸酯前藥，包括但不限於胺基磷酸酯、硫代胺基磷酸酯或在寄主人類或動物活體內代謝為單磷酸酯、二磷酸酯或三磷酸酯的任何其他部分；或 R3 及R4 連同其等所鍵結之氧可形成3',5'-環狀前藥； R5 為氫、C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)或-(C0 -C2 烷基)(C3 -C6 環烷基)； R6 為C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)、-(C0 -C2 烷基)(C3 -C6 環烷基)、-(C0-6 烷基)(芳基)、-(C0-6 烷基)(雜芳基)、-(C0-6 烷基)(雜環)或-C(O)R3C ； R12 為CH3 、CH2 F、CHF2 、CF3 或乙炔基。 在一個實施例中，-C(O)R3C 可為-C(S)R3C 。 詳言之，已發現，如下文所述之β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷酸之5'-經穩定化的磷酸酯前藥或衍生物以及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -二甲基-2,6-二胺基嘌呤核苷酸及其他β-D-2'-去氧-2'-α-氟-2'-β-C-甲基-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸以及β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-6-胺基-2-取代嘌呤核苷酸對HCV具有高活性。 引起關注地，將β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷代謝為胺基磷酸酯涉及生產5'-單磷酸酯且後續同化N6 -甲基-2,6-二胺基嘌呤鹼以產生β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-鳥嘌呤核苷作為5'-單磷酸酯。隨後將單磷酸酯進一步同化為活性物種；5'-三磷酸酯。 2'-去氧-2'-α-氟-2'-β-C-取代-4-氟-N6 -取代-2,6-二胺基嘌呤核苷酸可藉由烷基化或醯基化在N2 位進一步經取代，其可增強核苷酸對肝臟的親脂性、藥物動力學或靶向。 不管抗病毒核苷文獻及專利申請之卷，尚未具體揭示2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷、2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -二甲基-2,6-二胺基嘌呤核苷之5'-經穩定化的磷酸酯衍生物及其他2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷衍生物。 除非另外規定，否則以β-D-組態提供本文所述之化合物。在一替代性實施例中，可以β-L-組態提供化合物。同樣，呈現對掌性之任何取代基可以外消旋、對映異構、非對映異構性形式或其任何混合物來提供。在胺基磷酸酯、硫代胺基磷酸酯或其中磷呈現對掌性的其他經穩定化的磷前藥用作R4 經穩定化的磷酸酯前藥時，其可提供為R或S對掌性磷衍生物或其混合物，包括外消旋混合物。胺基磷酸酯或硫代胺基磷酸酯之胺基酸可呈D-組態或L-組態或其混合物，包括外消旋混合物。胺基磷酸酯或硫代胺基磷酸酯之胺基酸亦可為脫氫胺基酸。所有此等立體組態之組合包括於本文所述之本發明中。 因此，如本文中所描述，本發明包括式I-X之化合物或醫藥學上可接受之組合物、鹽或其前藥：式I 在一個特定實施例中，母體核苷(parent nucleoside) (亦即，其中R4 為氫且5'位因此具有羥基的核苷)大體上不藉由腺苷脫胺酶在模擬活體內環境條件(例如，環境溫度及水性生理pH)下進行脫胺7分鐘、10分鐘、30分鐘、60分鐘或120分鐘。除非另外說明，否則時間段為30分鐘。在此實施例中，術語「大體上不脫胺」意謂母體化合物不轉換為足以提供活體內治療效果的量的對應鳥嘌呤衍生物或6-含氧衍生物。已報導N6 -二甲基-2,6-二胺基嘌呤大體上不藉由腺苷脫胺酶在長時間段(120分鐘)內脫胺，且出於該原因，已將其視為作為藥物衍生之不當化合物(參見例如，WO 2010/091386第86頁)。但是已發現，此特性有利於治療寄主中之HCV感染，因為本發明之化合物經同化為5-單磷酸酯且隨後接著在6位經同化以產生活性鳥嘌呤三磷酸酯化合物。 提供化合物、方法及組合物以藉由投與有效量的式I-VIII之化合物或其醫藥學上可接受之鹽來治療感染有HCV病毒的寄主。 化合物及組合物亦可用於治療相關病況，諸如抗HCV抗體陽性及抗原陽性病況、基於病毒之慢性肝炎、由晚期C型肝炎、肝硬化、慢性或急性C型肝炎、爆發性C型肝炎、慢性持續性C型肝炎及基於抗HCV之疲勞產生的肝癌。亦可防治性使用化合物或包括化合物之調配物以預防或限制為抗HCV抗體或抗原陽性的或已暴露於C型肝炎病毒的個體中之臨床疾病之發展。 在另一實施例中，揭示式Ia之化合物：式Ia 其中： R1 、R2 、R3 及R4 如上文所定義。 在式Ia之一個實施例中，R3 為氫。 在式Ia之一個實施例中，R1 為甲基且R2 為氫。 在式Ia之一個實施例中，R1 及R2 兩者皆為甲基。 在式Ia之一個實施例中，R1 為甲基且R2 為環丙基。 在另一實施例中，揭示式Ib之化合物：式Ib 其中： R1 、R2 、R3 及R4 如上文所定義。 在式Ib之一個實施例中，R3 為氫。 在式Ib之一個實施例中，R1 為甲基且R2 為氫。 在式Ib之一個實施例中，R1 及R2 兩者皆為甲基。 在式Ib之一個實施例中，R1 為甲基且R2 為環丙基。 在一個實施例中，揭示式II之化合物：式II 其中： R5 為氫、C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)或-(C0 -C2 烷基)(C3 -C6 環烷基)； R6 為C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)、-(C0 -C2 烷基)(C3 -C6 環烷基)、-(C0-6 烷基)(芳基)、-(C0-6 烷基)(雜芳基)、-(C0-6 烷基)(雜環)或-C(O)R3C ； R1 、R2 、R3 、R4 及R12 如上文所定義。 在另一實施例中，揭示式IIa之化合物：式IIa 其中： R1 、R2 、R3 、R4 、R5 及R6 如上文所定義。 在另一實施例中，揭示式IIb之化合物：式IIb 其中： R1 、R2 、R3 、R4 、R5 及R6 如上文所定義。 在一個實施例中，揭示式III之化合物：式III 其中本文描述變量R1 、R2 、R3 、R7 、R8 、R9a 、R9b 、R10 及R12 。 在一個實施例中，揭示式IV之化合物：式IV 其中本文描述變量R1 、R2 、R3 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式V之化合物：式V 其中本文描述變量R1 、R2 、R3 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，化合物根據式VI：式VI 其中： R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 、R10 及R12 如上文所定義。 在一個實施例中，揭示式VII之化合物：式VII 其中本文描述變量R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式VIII之化合物：式VIII 其中本文描述變量R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式IX之化合物：式IX 其中本文描述變量R1 、R2 、R3 、R4 且R' 5 為Cl、Br、F、N3 、-NHOCH3、-ONHC(=O)OCH3、CN、CONH2 、SO2 NH2 及CF3 ， 或其醫藥學上可接受之鹽。 在一個實施例中，揭示式X之化合物：式X 其中本文描述變量R1 、R2 、R3 、R4 且R' 5 為Cl、Br、F、N3 、-NHOCH3、-ONHC(=O)OCH3、CN、CONH2 、SO2 NH2 及CF3 ， 或其醫藥學上可接受之鹽。 在以上任何式中之磷可為對掌性的且因此可呈R或S對映異構體或其混合物(包括外消旋混合物)來提供。 在一個實施例中，提供化合物、方法及組合物以治療感染有或暴露於本文所述之C型肝炎病毒之寄主。本發明之化合物可以有效量單獨或與另一種抗HCV藥物組合投與以治療經感染之寄主。在某些實施例中，其可用於投與調節相同或不同路徑或抑制病毒中之不同標靶之藥物的組合。由於所揭示之β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸及其他所描述之類似物為NS5B聚合酶抑制劑，所以其可用於與蛋白酶抑制劑(諸如NS3/4A蛋白酶抑制劑(例如，特拉匹韋(Incivek®)、波普瑞韋(VictrelisTM )、西咪匹韋(OlysioTM )或帕瑞普韋和)或NS5A抑制劑(例如，奧匹替韋))組合向寄主投與化合物。本發明之化合物亦可與結構上不同之NS5B聚合酶抑制劑(諸如本文或下文所述之另一種化合物，包括Gilead's Sovaldi® )組合投與。本發明之化合物亦可與干擾素α-2a (其可經聚乙二醇化或以其他方式經改質)及/或利巴韋林組合投與。 本發明之β-D-2'-去氧-2'-α-氟-2-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸及β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N2 ,N6 -二取代-2,6-二胺基嘌呤核苷酸及β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-2-取代-N6 -取代-胺基嘌呤核苷酸通常例如以丸劑或錠劑形式經口投與，但可藉由另一種主治醫師認為適當的途徑(包括藉由靜脈內、經皮、皮下、局部、非經腸或其他適合之途徑)投與。Providing Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX and Formulae having high activity against HCV virus when administered in an effective amount to a host in need thereof Compound of X. The host may be a human or any animal carrying a viral infection. In one embodiment, a therapeutically effective amount of one or more compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X, or a pharmaceutically acceptable compound thereof The accepted salt can be used to treat HCV infection. In one embodiment, a therapeutically effective amount of one or more compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X, or a pharmaceutically acceptable compound thereof The accepted salt can be used to inhibit the HCV polymerase complex. Thus, in one embodiment, the invention includes: and Formula I Formula II wherein: R 1 is C 1 -C 5 alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl and Pentyl) or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 2 is hydrogen, C 1 -C 5 alkyl (including methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, t-butyl, tert-butyl and pentyl), CHF 2 , CH 2 F, CF 3 , -(C 0 -C 2 alkyl) (C 3 -C 6 cycloalkyl), -C(O)R 3C , -(C 0 -C 2 alkyl)(aryl), -(C 0 -C 2 alkyl)(heterocyclic), -(C 0 -C 2 alkyl)(heteroaryl); or R 1 and R 2 together with the nitrogen to which they are bonded may form a heterocyclic ring; R 3 is hydrogen, , a diphosphate, a triphosphate, optionally substituted carbonyl-linked amino acid or -C(O)R 3C ; R 3A may be selected from O - , OH, optionally -O-substituted aryl - O-substituted heteroaryl or optionally substituted heterocyclic group; R 3B may be selected from O - , OH, optionally substituted N-linked amino acids or optionally substituted N-linked amino acid ester; R 3C is alkyl, alkenyl, alkynyl, -(C 0 -C 2 )(cycloalkyl), -(C 0 -C 2 )(heterocyclic), -( C 0 -C 2 )(aryl), -(C 0 -C 2 )(heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C 0 - C 2 ) (cycloalkyl), -O-(C 0 -C 2 ) (heterocyclic), -O-(C 0 -C 2 )(aryl), -O-(C 0 -C 2 )( Heteroaryl), -S-alkyl, -S-alkenyl, -S-alkynyl, -S-(C 0 -C 2 )(cycloalkyl), -S-(C 0 -C 2 )( a heterocyclic ring, -S-(C 0 -C 2 )(aryl) or -S-(C 0 -C 2 )(heteroaryl), each of which may be optionally substituted; R 4 is a monophosphate, Diphosphate, triphosphate or stabilized phosphate prodrugs, including but not limited to amino phosphates, thioamino phosphates or metabolized to monophosphates, diphosphates in host humans or animals Or any other part of the triphosphate; or R 3 and R 4 are bonded together with oxygen and the like which may be formed of 3 ', 5'-cyclic prodrug; R 5 is hydrogen, C 1 -C 5 alkyl (including Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl and pentyl) or -(C 0 -C 2 alkyl) (C 3 - C 6 cycloalkyl); R 6 is C 1 -C 5 alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl) And pentyl), -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl), -(C 0-6 alkyl)(aryl), -(C 0-6 alkyl)( Heteroaryl), -(C 0-6 alkyl)(heterocyclic) or -C(O)R 3C ; R 12 is CH 3 , CH 2 F, CHF 2 , CF 3 or ethynyl. In one embodiment, -C(O)R 3C can be -C(S)R 3C . In particular, it has been found that β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N 6 -methyl-2, as described below, 5'-stabilized phosphate prodrug or derivative of 6-diaminopurine nucleotide and β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl- 4'-fluoro-N 6 -dimethyl-2,6-diaminopurine nucleotide and other β-D-2'-deoxy-2'-α-fluoro-2'-β-C- -4'-fluoro-N 6 -substituted-2,6-diaminopurine nucleotides and β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted- The 4'-fluoro-N 6 -substituted-6-amino-2-substituted purine nucleotide has high activity against HCV. Interestingly, β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N 6 -methyl-2,6-diaminopurine nucleus The metabolism of glycosides to aminophosphates involves the production of 5'-monophosphates and subsequent assimilation of N 6 -methyl-2,6-diaminopurine to produce β-D-2'-deoxy-2'-α- Fluor-2'-β-methyl-4'-fluoro-guanosine is used as the 5'-monophosphate. The monophosphate is then further assimilated into the active species; 5'-triphosphate. 2'-Deoxy-2'-α-fluoro-2'-β-C-substituted-4-fluoro-N 6 -substituted-2,6-diaminopurine nucleotides can be alkylated or oxime The grouping is further substituted at the N 2 position, which enhances the lipophilicity, pharmacokinetics or targeting of the nucleotide to the liver. Regardless of the antiviral nucleoside literature and the patent application, 2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N 6 -methyl-2,6 has not been specifically disclosed. -diaminopurine nucleoside, 2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N 6 -dimethyl-2,6-diaminopurine nucleus 5'-stabilized phosphate derivatives of glycosides and other 2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N 6 -substituted-2,6 a diaminopurine nucleoside derivative. The compounds described herein are provided in a β-D-configuration unless otherwise specified. In an alternative embodiment, the compound can be provided in a β-L-configuration. Likewise, any substituent present to palmity can be provided in racemic, enantiomeric, diastereomeric forms, or any mixture thereof. The amine phosphates, thio or amine phosphate wherein the phosphorous when presented to other stabilized before pharmaceutically acceptable chiral phosphorus as R 4 a stabilized phosphate prodrug, which may be provided as the R or S Palmitic phosphorus derivatives or mixtures thereof, including racemic mixtures. The amino acid of the amino phosphate or thioamino phosphate may be in a D-configuration or an L-configuration or a mixture thereof, including a racemic mixture. The amino acid of the amino phosphate or thioamino phosphate may also be a dehydroamino acid. Combinations of all such stereo configurations are included in the invention described herein. Thus, as described herein, the invention includes a compound of Formula IX or a pharmaceutically acceptable composition, salt or prodrug thereof: Formula I In one particular embodiment, the parent nucleoside (parent nucleoside) (i.e., wherein R 4 is hydrogen and the 5 'position of the nucleoside thus having a hydroxyl group) is not substantially by adenosine deaminase in a simulated in vivo Deamination is carried out for 7 minutes, 10 minutes, 30 minutes, 60 minutes or 120 minutes under ambient conditions (for example, ambient temperature and aqueous physiological pH). The time period is 30 minutes unless otherwise stated. In this embodiment, the term "substantially non-deaminating" means that the parent compound is not converted to an amount corresponding to a guanine derivative or a 6-oxygen derivative sufficient to provide a therapeutic effect in vivo. N 6 -dimethyl-2,6-diaminopurine has been reported to be substantially free of deamination by adenosine deaminase over a long period of time (120 minutes) and for this reason it has been considered An inappropriate compound derived as a drug (see, for example, WO 2010/091386, page 86). However, it has been found that this property facilitates the treatment of HCV infection in the host since the compound of the invention is assimilated to 5-monophosphate and then subsequently assimilated at position 6 to produce an active guanine triphosphate compound. The compounds, methods, and compositions are provided to treat a host infected with an HCV virus by administering an effective amount of a compound of Formulas I-VIII, or a pharmaceutically acceptable salt thereof. The compounds and compositions are also useful in the treatment of related conditions, such as anti-HCV antibody positive and antigen positive conditions, viral-based chronic hepatitis, advanced hepatitis C, cirrhosis, chronic or acute hepatitis C, fulminant hepatitis C, chronic Persistent hepatitis C and liver cancer based on fatigue caused by anti-HCV. Compounds or formulations comprising the compounds may also be used prophylactically to prevent or limit the development of clinical disease in an individual who is anti-HCV antibody or antigen positive or has been exposed to hepatitis C virus. In another embodiment, the compound of Formula Ia is disclosed: Formula Ia wherein: R 1 , R 2 , R 3 and R 4 are as defined above. In one embodiment of Formula Ia, R 3 is hydrogen. In one embodiment of Formula Ia, R 1 is methyl and R 2 is hydrogen. In one embodiment of Formula Ia, both R 1 and R 2 are methyl. In one embodiment of Formula Ia, R 1 is methyl and R 2 is cyclopropyl. In another embodiment, the compound of Formula Ib is disclosed: Formula Ib wherein: R 1 , R 2 , R 3 and R 4 are as defined above. In one embodiment of Formula Ib, R 3 is hydrogen. In one embodiment of Formula Ib, R 1 is methyl and R 2 is hydrogen. In one embodiment of Formula Ib, both R 1 and R 2 are methyl. In one embodiment of Formula Ib, R 1 is methyl and R 2 is cyclopropyl. In one embodiment, the compound of Formula II is disclosed: Wherein: R 5 is hydrogen, C 1 -C 5 alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl and Pentyl) or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 6 is C 1 -C 5 alkyl (including methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, t-butyl, tert-butyl and pentyl), -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl), -(C 0-6 Alkyl)(aryl), -(C 0-6 alkyl)(heteroaryl), -(C 0-6 alkyl)(heterocyclic) or -C(O)R 3C ; R 1 , R 2 And R 3 , R 4 and R 12 are as defined above. In another embodiment, the compound of Formula IIa is disclosed: Formula IIa wherein: R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above. In another embodiment, the compound of Formula IIb is disclosed: Formula IIb wherein: R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above. In one embodiment, the compound of Formula III is disclosed: Formula III wherein the variables R 1 , R 2 , R 3 , R 7 , R 8 , R 9a , R 9b , R 10 and R 12 are described herein. In one embodiment, the compound of Formula IV is disclosed: Formula IV wherein the variables R 1 , R 2 , R 3 , R 7 , R 8 , R 9a , R 9b and R 10 are described herein. In one embodiment, a compound of Formula V is disclosed: Formula V wherein the variables R 1 , R 2 , R 3 , R 7 , R 8 , R 9a , R 9b and R 10 are described herein. In one embodiment, the compound is according to Formula VI: Wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b , R 10 and R 12 are as defined above. In one embodiment, the compound of formula VII is disclosed: Formula VII wherein the variables R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b and R 10 are described herein. In one embodiment, the compound of formula VIII is disclosed: Formula VIII wherein the variables R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9a , R 9b and R 10 are described herein. In one embodiment, a compound of Formula IX is disclosed: Formula IX where the variables R 1 , R 2 , R 3 , R 4 and R ' 5 are described as Cl, Br, F, N 3 , -NHOCH3, -ONHC(=O)OCH3, CN, CONH 2 , SO 2 NH 2 and CF 3 , or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula X is disclosed: Formula X wherein the variables R 1 , R 2 , R 3 , R 4 and R ' 5 are described as Cl, Br, F, N 3 , -NHOCH3, -ONHC(=O)OCH3, CN, CONH 2 , SO 2 NH 2 and CF 3 , or a pharmaceutically acceptable salt thereof. Phosphorus in any of the above formulas can be provided as palmitic and thus can be in the R or S enantiomer or mixtures thereof, including racemic mixtures. In one embodiment, compounds, methods, and compositions are provided to treat a host infected or exposed to a hepatitis C virus as described herein. The compounds of the invention may be administered in an effective amount, either alone or in combination with another anti-HCV drug, to treat the infected host. In certain embodiments, it can be used to administer a combination of drugs that modulate the same or different pathways or inhibit different targets in the virus. Due to the disclosed β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N 6 -substituted-2,6-diaminopurine nucleoside Acids and other described analogs are NS5B polymerase inhibitors, so they can be used with protease inhibitors (such as NS3/4A protease inhibitors (eg, Intravek (Incivek®), Poprevir (VictrelisTM ) ), West microphone telaprevir (Olysio TM) and or Paruipuwei) or NS5A inhibitors (e.g., Austria Wei for horses)) in combination with the compound administered to the host. The compounds of this invention can also structurally different and NS5B polymerase inhibitor (such as the herein described below or another compound, comprising Gilead's Sovaldi ®) administered in combination. The compounds of the invention may also be administered in combination with interferon alpha-2a (which may be PEGylated or otherwise modified) and/or ribavirin. β-D-2′-deoxy-2′-α-fluoro-2-β-C-substituted-4′-fluoro-N 6 -substituted-2,6-diaminopurine nucleotide of the present invention β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N 2 ,N 6 -disubstituted-2,6-diaminopurine nucleoside Acid and β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-2-substituted-N 6 -substituted-aminopurine nucleotides are usually for example It is administered orally in the form of a pill or lozenge, but may be administered by another route deemed appropriate by the attending physician, including by intravenous, transdermal, subcutaneous, topical, parenteral or other suitable route.

本發明包括用於治療人類及其他寄主動物中之或暴露於人類及其他寄主動物之HCV感染的化合物、方法及組合物，其包括視情況以醫藥學上可接受之載劑投與有效量之如本文所述的式I-X之化合物或其醫藥學上可接受之鹽或前藥。本發明之化合物具有抗病毒活性或代謝為呈現該活性之化合物。 化合物及組合物亦可用於治療與HCV病毒暴露相關或由於HCV病毒暴露而出現之病況。舉例而言，活性化合物可用於治療HCV抗體陽性及HCV抗原陽性病況、基於病毒之慢性肝炎、因晚期C型肝炎、肝硬化、急性C型肝炎、爆發性C型肝炎、慢性持續性C型肝炎及基於抗HCV之疲勞產生之肝癌。在一個實施例中，亦可防治性使用化合物或包括化合物之調配物，以預防或減緩為HCV抗體或HCV抗原陽性的或已暴露於C型肝炎病毒的個體中之臨床疾病的發展。 詳言之，已發現，如下文所述之β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷酸之5'-經穩定化的磷酸酯前藥或衍生物以及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -二甲基-2,6-二胺基嘌呤核苷酸及其他β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸、β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N2 ,N6 -二取代-2,6-二胺基嘌呤核苷酸及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-2-取代-N6 -取代-胺基嘌呤核苷酸對HCV具有高活性。 不管抗病毒核苷文獻及專利申請之數量，均尚未具體揭示β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷酸之5'-經穩定化的磷酸酯衍生物以及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -二甲基-2,6-二胺基嘌呤核苷酸及其他β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-2-取代-N6 -取代-胺基嘌呤核苷酸。 除非另外規定，否則本發明所述之化合物係以β-D-組態提供。在一替代性實施例中，可以β-L-組態提供化合物。同樣，呈現對掌性之任何取代基可以外消旋、對映異構、非對映異構性形式或其任何混合物來提供。在胺基磷酸酯、硫代胺基磷酸酯或其中磷呈現對掌性的其他經穩定化的磷前藥用作R4 經穩定化的磷酸酯前藥時，其可提供為R或S對掌性磷衍生物或其混合物，包括外消旋混合物。胺基磷酸酯或硫代胺基磷酸酯之胺基酸可呈D-組態或L-組態或其混合物，包括外消旋混合物。所有此等立體組態之組合包括於本文所述之本發明中。 本發明包括以下特徵： (a)如本文所述之式I-X之化合物及其醫藥學上可接受之鹽及前藥； (b)用於治療或防治C型肝炎病毒感染之如本文所述之式I-X及其醫藥學上可接受的鹽及前藥； (c)式I-X及其醫藥學上可接受之鹽及前藥在製造用於治療C型肝炎病毒感染之藥劑中之用途； (d)一種用於製造期望用於治療C型肝炎病毒感染之治療用途之藥劑的方法，其特徵在於如本文所述之式I-X之化合物用於該製造； (e)包含有效寄主治療量之式I-X之化合物或其醫藥學上可接受的鹽或前藥連同醫藥學上可接受之載劑或稀釋劑之醫藥調配物； (f)本文所述的式I-X大體上係在不存在 所述化合物之立體異構體 下或大體上與其他化學實體隔離；及 (g)用於製備含有有效量之如本文所述之式I-X的化合物之治療產物之方法。I. 本發明之 β -D-2'- 去氧 -2'- α - 氟 -2'- β -C- 取代 -4'- 氟 -N6 - 取代 -2,6- 二胺基嘌呤核苷酸、 β -D-2'- 去氧 -2'- α - 氟 -2'- β -C- 取代 -4'- 氟 -N2 ,N6 - 二取代 -2,6- 二胺基嘌呤核苷酸 及β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-2-取代-N6 -取代-胺基嘌呤核苷酸 本發明之活性化合物為描繪於例如式I中之彼等，其可以醫藥學上可接受之組合物、鹽或其前藥提供：式I 其中： R1 為C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)或-(C0 -C2 烷基)(C3 -C6 環烷基)； R2 為氫、C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)、CHF2 、CH2 F、CF3 、-(C0 -C2 烷基)(C3 -C6 環烷基)、-C(O)R3C 、-(C0 -C2 烷基)(芳基)、-(C0 -C2 烷基)(雜環)、-(C0 -C2 烷基)(雜芳基)；或 R1 及R2 連同其等所鍵結之氮可形成雜環； R3 為氫、、二磷酸酯、三磷酸酯、視情況經取代之羰基鍵聯之胺基酸或-C(O)R3C ； R3A 可選自O- 、OH、視情況經-O-取代之芳基、視情況經-O-取代之雜芳基或視情況經取代之雜環基； R3B 可選自O- 、OH、視情況經取代之N鍵聯之胺基酸或視情況經取代的N鍵聯之胺基酸酯； R3C 為烷基、烯基、炔基、-(C0 -C2 )(環烷基)、-(C0 -C2 )(雜環)、-(C0 -C2 )(芳基)、-(C0 -C2 )(雜芳基)、-O-烷基、-O-烯基、-O-炔基、-O-(C0 -C2 )(環烷基)、-O-(C0 -C2 )(雜環)、-O-(C0 -C2 )(芳基)、-O-(C0 -C2 )(雜芳基)、-S-烷基、-S-烯基、-S-炔基、-S-(C0 -C2 )(環烷基)、-S-(C0 -C2 )(雜環)、-S-(C0 -C2 )(芳基)或-S-(C0 -C2 )(雜芳基)，其各者可視情況經取代； R4 為單磷酸酯、二磷酸酯、三磷酸酯或經穩定化的磷酸酯前藥，包括但不限於胺基磷酸酯、硫代胺基磷酸酯或在寄主人類或動物活體內代謝為單磷酸酯、二磷酸酯或三磷酸酯的任何其他部分；或 R3 及R4 連同其等所鍵結之氧可形成3',5'-環狀前藥； R12 為CH3 、CH2 F、CHF2 、CF3 或乙炔基。 經穩定化的磷酸酯前藥為可遞送單磷酸酯、二磷酸酯或三磷酸酯之任何部分。 在另一實施例中，揭示式Ia之化合物：式Ia 其中： R1 、R2 、R3 及R4 如上文所定義。 在另一實施例中，揭示式Ib之化合物：式Ib 其中： R1 、R2 、R3 及R4 如上文所定義。 在一個實施例中，揭示式II之化合物：式II 其中： R5 為氫、C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)或-(C0 -C2 烷基)(C3 -C6 環烷基)； R6 為C1 -C5 烷基(包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基及戊基)、-(C0 -C2 烷基)(C3 -C6 環烷基)、-(C0-6 烷基)(芳基)、-(C0-6 烷基)(雜芳基)、-(C0-6 烷基)(雜環)或-C(O)R3C ； R1 、R2 、R3 、R4 及R12 如上文所定義。 在另一實施例中，揭示式IIa之化合物：式IIa 其中： R1 、R2 、R3 、R4 、R5 及R6 如上文所定義。 在另一實施例中，揭示式IIb之化合物：式IIb 其中： R1 、R2 、R3 、R4 、R5 及R6 如上文所定義。 在一典型實施例中，化合物為關於對應核苷(亦即，以天然存在之組態)之β-D異構體。在替代性組態中，以β-L異構體提供化合物。化合物通常有至少90%不含相反對映異構體，且可至少有98%、99%或甚至100%不含相反對映異構體。除非另外描述，否則化合物至少有90%不含相反對映異構體。 在另一實施例中，化合物根據式III：式III 其中： R7 為氫、C1-6 烷基；C3-7 環烷基；雜芳基、雜環或包括但不限於苯基或萘基之芳基，其中苯基或萘基視情況經以下取代：C1-6 烷基、C2-6 烯基、C2-6 炔基、C1-6 烷氧基、F、Cl、Br、I、硝基、氰基、C1-6 鹵烷基、-N(R7' )2 、C1-6 醯胺基、NHSO2 C1-6 烷基、-SO2 N(R7' )2 、COR7" 及-SO2 C1-6 烷基；(R7' 獨立地為氫或C1-6 烷基；R7" 為-OR11 或-N(R7 )2 )； R8 為氫、C1-6 烷基，或R9a 或R9b 及R8 共同為(CH2 )n ，從而形成包括鄰接N原子及C原子之環狀環；其中n為2至4；R9a 及R9b (i)獨立地選自氫、C1-6 烷基、環烷基、-(CH2 )c (NR9' )2 、C1-6 羥烷基、-CH2 SH、-(CH2 )2 S(O)(Me)、-(CH2 )3 NHC(=NH)NH2 、(lH-吲哚-3-基)甲基、(lH-咪唑-4-基)甲基、-(CH2 )c COR9" 、芳基及芳基(C1-3 烷基)-，芳基可視情況經選自以下之基團取代：羥基、C1-6 烷基、C1-6 烷氧基、鹵素、硝基及氰基；(ii) R9a 及R9b 兩者皆為C1-6 烷基；(iii) R9a 及R9b 共同為(CH2 )r ，從而形成螺環；(iv) R9a 為氫且R9b 及R8 共同為(CH2 )n ，從而形成包括鄰接N原子及C原子之環狀環；(v) R9b 為氫且R9a 及R8 共同為(CH2 )n ，從而形成包括鄰接N原子及C原子之環狀環，其中c為1至6，n為2至4，r為2至5且其中R9' 獨立地為氫或C1-6 烷基且R9" 為-OR11 或-N(R11' )2 ；(vi) R9a 為氫且R9b 為氫、CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基；或(vii) R9a 為CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基，且R9b 為氫； R10 為氫、視情況經烷氧基、二(低碳數烷基)-胺基或鹵素取代之C1-6 烷基；C1-6 鹵烷基、(C0 -C2 )(C3-7 環烷基)、(C0 -C2 )(雜環烷基)、胺基醯基、(C0 -C2 )(芳基)，諸如(C0 -C2 )(苯基)、(C0 -C2 )(雜芳基)，諸如(C0 -C2 )(吡啶基)、經取代之(C0 -C2 )(芳基)或經取代之(C0 -C2 )(雜芳基)； R11 為視情況經取代之C1-6 烷基、視情況經取代之環烷基；視情況經取代之C2-6 炔基、視情況經取代之C2-6 烯基或視情況經取代之醯基，其包括但不限於C(O)(C1-6 烷基)；且 R1 、R2 、R3 及R12 如上文所定義。 在一個實施例中，揭示式IV之化合物：式IV 其中本文描述變量R1 、R2 、R3 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式V之化合物：式V 其中本文描述變量R1 、R2 、R3 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，化合物根據式VI：式VI 其中： R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 、R10 及R12 如上文所定義。 在一個實施例中，揭示式VII之化合物：式VII 其中本文描述變量R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式VIII之化合物：式VIII 其中本文描述變量R1 、R2 、R3 、R5 、R6 、R7 、R8 、R9a 、R9b 及R10 。 在一個實施例中，揭示式IX之化合物：式IX 其中本文描述變量R1 、R2 、R3 、R4 且R' 5 為Cl、Br、F、N3 、-NHOCH3、-ONHC(=O)OCH3、CN、CONH2 、SO2 NH2 及CF3 ， 或其醫藥學上可接受之鹽。 在一個實施例中，揭示式X之化合物：其中本文描述變量R1 、R2 、R3 、R4 且R' 5 為Cl、Br、F、N3 、-NHOCH3、-ONHC(=O)OCH3、CN、CONH2 、SO2 NH2 及CF3 ， 或其醫藥學上可接受之鹽。 在一替代性實施例中，提供化合物、方法及組合物以治療感染有或暴露於C型肝炎病毒之寄主。β-D-2 ' - 去氧 -2 ' -α- 氟 -2 ' -β-C- 取代 -4 ' - 氟 -N6 - 取代 -2,6- 二胺基嘌呤核苷酸之代謝 β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷胺基磷酸酯之代謝涉及生產5'-單磷酸酯且後續同化N6 -甲基-2,6-二胺基嘌呤鹼以產生β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-鳥嘌呤核苷作為5'-單磷酸酯。隨後將單磷酸酯進一步同化為活性物種；5'-三磷酸酯。β-D-2'-去氧-2'-α-氟-2'-β-甲基-4'-氟-N6 -甲基-2,6-二胺基嘌呤核苷胺基磷酸酯之代謝路徑在以下流程1中加以說明。流程1經穩定化的磷酸酯前藥 經穩定化的磷酸酯前藥為可在活體內遞送單磷酸酯、二磷酸酯或三磷酸酯之部分。舉例而言，McGuigan已在以下美國專利中揭示胺基磷酸酯：8,933,053；8,759,318；8,658,616；8,263,575；8,119,779；7,951,787及7,115,590。Alios已在US 8,895,723及8,871,737中揭示硫代胺基磷酸酯。Alios亦已在US 8,772,474中揭示環狀核苷酸。Idenix已在WO 2013/177219中揭示環狀胺基磷酸酯及胺基磷酸酯/SATE衍生物。Idenix亦已在WO 2013/039920中揭示經取代之羰氧基甲基胺基磷酸酯化合物。Hostetler已揭示脂質磷酸酯前藥，參見例如US 7,517,858。Hostetler亦已揭示膦酸酯前藥之脂質共軛物，參見例如US 8,889,658；8,846,643；8,710,030；8,309,565；8,008,308；及7,790,703。埃默里大學已在WO 2014/124430中揭示核苷酸鞘胺基醇及脂質衍生物。RFS Pharma已在WO 2010/091386中揭示嘌呤核苷單磷酸酯前藥。HepDirectTM 技術揭示於文章「Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver」, (J. Am. Chem. Soc. 126, 5154-5163 (2004)中。額外磷酸酯前藥包括但不限於磷酸酯、包括CycloSAL之3',5'-環狀磷酸酯、SATE衍生物(S-醯基-2硫酯)、及DTE (二硫代二乙基)前藥。對於揭示非限制性實例之文獻綜述參見：A. Ray及K. Hostetler, 「Application of kinase bypass strategies to nucleoside antivirals」, Antiviral Research (2011) 277-291；M. Sofia, 「Nucleotide prodrugs for HCV therapy」, Antiviral Chemistry and Chemotherapy 2011；22-23-49；及S. Peyrottes等人, 「SATE Pronucleotide Approaches: An Overview」, Mini Reviews in Medicinal Chemistry 2004, 4, 395。在一個實施例中，任何此等專利申請或文獻中所描述之5'-前藥可用於存在之化合物的R4 位置。實施例 在特定實施例中： (i) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (ii) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (iii) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (iv) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (v) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (vi) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (vii) 在式Ia中，R1 為甲基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (viii) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (ix) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (x) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為胺基磷酸酯； (xi) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為硫代胺基磷酸酯； (xii) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為單磷酸酯； (xiii) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為二磷酸酯； (xiv) 在式Ia中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為三磷酸酯； (xv) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xvi) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xvii) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為胺基磷酸酯； (xviii) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為硫代胺基磷酸酯； (xix) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為單磷酸酯； (xx) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為甲基，且R4 為二磷酸酯； (xxi) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為三磷酸酯； (xxii) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xxiii) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xxiv) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (xxv) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (xxvi) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (xxvii) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (xxviii) 在式Ia中，R1 為乙基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (xxix) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xxx) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xxxi) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (xxxii) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (xxxiii) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (xxxiv) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (xxxv) 在式Ia中，R1 為丙基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (xxxvi) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xxxvii) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xxxviii) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (xxxix) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (xl) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (xli) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (xlii) 在式Ia中，R1 為異丙基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (xliii) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xliv) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xlv) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為胺基磷酸酯； (xlvi) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為硫代胺基磷酸酯； (xlvii) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為單磷酸酯； (xlviii) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為二磷酸酯； (xlix) 在式Ia中，R1 為乙基，R2 為乙基，R3 為氫，且R4 為三磷酸酯； (l) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (li) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lii) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為胺基磷酸酯； (liii) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為硫代胺基磷酸酯； (liv) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為單磷酸酯； (lv) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為二磷酸酯； (lvi) 在式Ia中，R1 為甲基，R2 為丙基，R3 為氫，且R4 為三磷酸酯； (lvii) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，R4 為經穩定化的磷酸酯前藥； (lviii) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lix) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為胺基磷酸酯； (lx) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為硫代胺基磷酸酯； (lxi) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為單磷酸酯； (lxii) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為二磷酸酯； (lxiii) 在式Ia中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為三磷酸酯； (lxiv) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (lxv) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lxvi) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (lxvii) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (lxviii) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (lxix) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (lxx) 在式Ia中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (lxxi) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (lxxii) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lxxiii) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為胺基磷酸酯； (lxxiv) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為硫代胺基磷酸酯； (lxxv) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為單磷酸酯； (lxxvi) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為二磷酸酯； (lxxvii) 在式Ia中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為三磷酸酯； (lxxviii) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (lxxix) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lxxx) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為胺基磷酸酯； (lxxxi) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為硫代胺基磷酸酯； (lxxxii) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為單磷酸酯； (lxxxiii) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為二磷酸酯； (lxxxiv) 在式Ia中，R1 為甲基，R2 為乙基，R3 為氫，且R4 為三磷酸酯； (lxxxv) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為經穩定化的磷酸酯前藥； (lxxxvi) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (lxxxvii) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (lxxxviii) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (lxxxix) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (xc) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (xci) 在式Ia中，R1 為環丁基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (xcii) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (xciii) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (xciv) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為胺基磷酸酯； (xcv) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為硫代胺基磷酸酯； (xcvi) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為單磷酸酯； (xcvii) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為二磷酸酯； (xcviii) 在式Ib中，R1 為甲基，R2 為甲基，R3 為氫，且R4 為三磷酸酯； (xcix) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (c) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (ci) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (cii) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (ciii) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (civ) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (cv) 在式Ib中，R1 為甲基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (cvi) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，R4 為經穩定化的磷酸酯前藥； (cvii) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (cviii) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為胺基磷酸酯； (cix) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為硫代胺基磷酸酯； (cx) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為單磷酸酯； (cxi) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為二磷酸酯； (cxii) 在式Ib中，R1 為環戊基，R2 為氫，R3 為氫，且R4 為三磷酸酯； (cxiii) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為經穩定化的磷酸酯前藥； (cxiv) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (cxv) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為胺基磷酸酯； (cxvi) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為硫代胺基磷酸酯； (cxvii) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為單磷酸酯； (cxviii) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為二磷酸酯； (cxix) 在式Ib中，R1 及R2 連同其等所鍵結之氮以形成5員雜環，R3 為氫，且R4 為三磷酸酯； (cxx) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (cxxi) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (cxxii) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為胺基磷酸酯； (cxxiii) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為硫代胺基磷酸酯； (cxxiv) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為單磷酸酯； (cxxv) 在式Ib中，R1 為甲基，R2 為環丙基，R3 為甲基，且R4 為二磷酸酯； (cxxvi) 在式Ia中，R1 為甲基，R2 為環丙基，R3 為氫，且R4 為三磷酸酯； (cxxvii) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，R4 為經穩定化的磷酸酯前藥； (cxxviii) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為經穩定化的硫代磷酸酯前藥； (cxxix) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為胺基磷酸酯； (cxxx) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為硫代胺基磷酸酯； (cxxxi) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為單磷酸酯； (cxxxii) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為二磷酸酯； (cxxxiii) 在式Ib中，R1 為環丙基，R2 為環丙基，R3 為氫，且R4 為三磷酸酯； 在化合物(i)至(cxxxiii)之替代性實施例中，L-核苷用於式I-X。 在一替代性實施例中，式I R12 變量為CH2 F。 在一替代性實施例中，式I R12 變量為CHF2 。 在一替代性實施例中，式I R12 變量為CF3 。 在一替代性實施例中，式II R12 變量為CH2 F。 在一替代性實施例中，式II R12 變量為CHF2 。 在一替代性實施例中，式II R12 變量為CF3 。 在一個實施例中，提供式Ia之化合物。式Ia之化合物之非限制性實例包括： 。 在一個實施例中，提供式Ia之硫代胺基磷酸酯。式Ia之硫代胺基磷酸酯之非限制性實例包括但不限於： 。 在一個實施例中，提供式Ia之經穩定化的磷酸酯前藥。式Ia之經穩定化的磷酸酯前藥之非限制性實例在下文加以說明： 。 在另一實施例中，提供式Ia之化合物。式Ia之化合物之非限制性實例包括： 。 在一個實施例中，提供式Ia之硫代胺基磷酸酯。式Ia之硫代胺基磷酸酯之非限制性實例包括但不限於： 。 在一個實施例中，提供式Ia之經穩定化的磷酸酯前藥。式Ia之經穩定化的磷酸酯前藥之非限制性實例在下文加以說明： 。 在一個實施例中，提供式II之化合物。式II之化合物之非限制性實例包括： 。 在一個實施例中，提供式I之化合物。式I之化合物之非限制性實例包括： 。 在一個實施例中，提供式II之化合物。式II之化合物之非限制性實例包括： 。 在一個實施例中，提供式IX之化合物。式IX之化合物之非限制性實例包括： 在一個實施例中，提供式IX之化合物。式X之化合物之非限制性實例包括： 在一個實施例中，R3 為氫及在一個實施例中，R3 為氫且R4 為。 在一個實施例中，R3 為氫且R4 為。 在一個實施例中，R3 為氫且R4 為。 在一個實施例中，R3 為氫且R4 為。II. 定義 以下術語用於描述本發明。當術語不在本文中具體定義的情況下，該術語由一般技術者在將該術語應用於描述本發明中之其用途的語境下給出此項技術中公認的含義。 術語「醫藥學上可接受之鹽」或「前藥」在整個說明書中用於描述在向患者投與後提供所需活性化合物之2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸或2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N2 ,N6 -二取代-2,6-二胺基嘌呤核苷酸之任何醫藥學上可接受的形式。醫藥學上可接受之鹽之實例係由酸形成之有機酸加成鹽，其形成生理可接受的陰離子，例如，甲苯磺酸根、甲磺酸根、乙酸根、檸檬酸根、丙二酸根、酒石酸根、丁二酸根、苯甲酸根、抗壞血酸根、α-酮戊二酸根及α-甘油磷酸根。亦可形成適合之無機鹽，包括硫酸鹽、硝酸鹽、碳酸氫鹽及碳酸鹽。醫藥學上可接受之鹽可使用本領域中熟知之標準程序獲得，例如藉由使足夠鹼性化合物(諸如胺)與適合之酸(提供生理學上可接受的陰離子)反應。亦可製備羧酸之鹼金屬(例如，鈉、鉀或鋰)或鹼土金屬(例如鈣)鹽。 「醫藥學上可接受之前藥」指代在寄主中經代謝(例如水解或氧化)可以形成本發明化合物的化合物。前藥之典型實例包括在活性化合物之官能性部分上具有生物不穩定保護基的化合物。前藥包括包括可氧化、還原、胺化、脫胺、羥基化、脫羥基化、水解、脫水解、烷基化、脫烷基化、醯基化、去醯基化、磷酸化、去磷酸化、硫代胺基磷酸化、去硫代胺基磷酸化、胺基磷酸化或去胺基磷酸化以產生活性化合物的化合物。本發明之化合物具有針對HCV之抗病毒活性或代謝為呈現該活性的化合物。亦可以5'-含磷醚脂質(phosphoether lipid)、雙胺基磷酸酯、3',5'-環狀胺基磷酸酯、3',5'-環狀硫代胺基磷酸酯、DTE共軛物、混合胺基磷酸酯-SATE衍生物或「SATE」衍生物投與β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷。 術語「取代」或「視情況經取代」表明該部分可具有至少一個額外取代基，包括但不限於胺基、鹵素(F、Cl、Br、I)、OH、苯基、苯甲基、N3 、CN、烷基，包括甲基；烯基、炔基、烷氧基、鹵烷基；包括CHF2 、CH2 F及CF3 ；等。 術語「烷基」應意謂在其上下文內，可視情況經(例如，鹵素，包括F)取代之直鏈或支鏈完全飽和烴基或烷基。舉例而言，烷基可具有1、2、3、4、5、6、7或8個碳原子(亦即，C1 -C8 烷基)，1、2、3、4、5或6個碳原子(亦即，C1 -C6 烷基)或1至4個碳原子(亦即，C1 -C4 烷基)。適合之烷基之實例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、第三戊基、新戊基、己基、2-甲基戊基、3-甲基戊基、2,2-二甲基丁基及2,3-二甲基丁基。 術語「烯基」指代非芳族烴基，其含有相鄰碳原子之間的至少一個雙鍵及如本文另外所描述之與烷基類似的結構。舉例而言，烯基可具有2至8個碳原子(亦即，C2 -C8 烯基)，或2至4個碳原子(亦即，C2 -C4 烯基)。適合之烯基之實例包括但不限於乙烯基或乙烯基(-CH=CH2 )、烯丙基(-CH2 CH=CH2 )、1-丁烯基(-C=CH-CH2 CH3 )及2-丁烯基(-CH2 CH=CHCH2 )。烯基可如本文所述視情況經取代。 術語「炔基」指代含有至少一個相鄰碳原子之間的三鍵及如本文另外所描述之與烷基類似的結構的非芳族烴基。舉例而言，炔基可具有2至8個碳原子(亦即，C2 -C8 炔)或2至4個碳原子(亦即，C2 -C4 炔基)。炔基之實例包括但不限於炔屬或乙炔基及炔丙基。炔基可如本文所述視情況經取代。 術語「芳基」或「芳族」在上下文中指代經取代(如本文另外所描述)或未經取代之具有單個環(例如，苯基或苯甲基)或縮合環(例如，萘基、蒽基、菲基等)的單價芳基，且可在環上任何可用的穩定位置或如所存在之化學結構中另外指示結合至根據本發明之化合物。芳基可如本文所描述視情況經取代。 「環烷基」、「碳環」或「碳環基」指代具有3至7個碳原子作為之飽和(亦即，環烷基)或部分不飽和(例如，環烯基、環烷二烯基等)環。單環碳環具有3至7個環原子，更通常具有5或6個環原子。環烷基之非限制性實例包括環丙基、環丁基、環戊基、l-環戊-1-烯基、l-環戊-2-烯基、l-環戊-3-烯基、環己基、l-環己-1-烯基、l-環己-2-烯基及l-環己-3-烯基。 雜芳基環體系為環(單環)中具有一或多個氮、氧或硫原子的飽和或不飽和環，包括但不限於咪唑、呋喃基(furyl)、吡咯、呋喃基(furanyl)、噻吩、噻唑、吡啶、嘧啶、嘌呤、吡嗪、三唑、噁唑或稠環體系，諸如吲哚、喹啉等外加其他，其可如上文所描述視情況經取代。雜芳基包括含氮雜芳基，諸如吡咯、吡啶、吡啶酮、噠嗪、嘧啶、吡嗪、吡唑、咪唑、三唑、三嗪、四唑、吲哚、異吲哚、吲哚嗪、嘌呤、吲唑、喹啉、異喹啉、喹嗪、酞嗪、萘啶、喹喏啉、喹唑啉、噌啉、喋啶、咪唑吡啶、咪唑三嗪、吡嗪并-噠嗪、吖啶、啡啶、咔唑、咔唑啉、呸啶、啡啉、菲烯(phenacene)、噁二唑、苯并咪唑、吡咯并吡啶、吡咯并嘧啶及吡啶并嘧啶；含硫芳族雜環，諸如噻吩及苯并噻吩；含氧芳族雜環，諸如呋喃、哌喃、環戊哌喃、苯并呋喃及異苯并呋喃；及包含兩個或更多個選自氮、硫及氧中之雜原子的芳族雜環，諸如噻唑、噻二唑、異噻唑、苯并噁唑、苯并噻唑、苯并噻二唑、啡噻嗪、異噁唑、呋呫、啡噁嗪、吡唑并噁唑、咪唑并噻唑、噻吩并呋喃、呋喃并吡咯、吡啶并噁嗪、呋喃并吡啶、呋喃并嘧啶、噻吩并嘧啶及噁唑外加其他，以上所有可視情況經取代。 術語「雜環」指代含有至少一個雜原子(亦即，O、N或S)之環基，且可為芳族(雜芳基)或非芳族的。用於本發明之示例性非芳族雜環基包括例如吡咯啶基、哌啶基、哌嗪基、N-甲基哌嗪基、二氫咪唑基、吡唑啶基、咪唑啶基、嗎啉基、四氫哌喃基、氮雜環丁烷基、環氧丙烷基、氧硫雜環戊烷基、吡啶酮、2-吡咯啶酮、乙烯脲、1,3-二氧戊環、1,3-二噁烷、1,4-二噁烷、鄰苯二甲醯亞胺及丁二醯亞胺外加其他，以上所有可視情況經取代。 在一個實施例中，術語嘌呤或嘧啶鹼基包括但不限於腺嘌呤、N6 -烷基嘌呤、N6 -醯基嘌呤(其中醯基為-C(O)烷基、-C(O)(芳基)C0 -C4 烷基或-C(O)(C0 -C4 烷基)芳基)、N6 -苯甲基嘌呤、N6 -鹵基嘌呤、N6 -乙烯基嘌呤、N6 -炔屬嘌呤、N6 -醯基嘌呤、N6 -羥烷基嘌呤、N6 -硫烷基嘌呤、N2 -烷基嘌呤、N2 -烷基-6-巰基嘌呤、胸嘧啶、胞嘧啶、5-氟胞嘧啶、5-甲基胞嘧啶、6-氮雜嘧啶，包括6-氮雜胞嘧啶、2-及/或4-巰基嘧啶、尿嘧啶、5-鹵基尿嘧啶，包括5-氟尿嘧啶、C5 -烷基嘧啶、C5 -苯甲基嘧啶、C5 -鹵基嘧啶、C5 -乙烯基嘧啶、C5 -炔屬嘧啶、C5 -醯基嘧啶、C5 -羥烷基嘌呤、C5 -醯胺基嘧啶、C5 -氰基嘧啶、C5 -硝基嘧啶、C5 -胺基嘧啶、N2 -烷基嘌呤、N2 -烷基-6-巰基嘌呤、5-氮雜胞嘧啶核苷基、5-氮雜尿嘧啶、三唑并吡啶基、咪唑并吡啶基、吡咯并嘧啶基及吡唑并-嘧啶基。嘌呤鹼基包括但不限於鳥嘌呤、腺嘌呤、次黃嘌呤、視情況經取代之2,6-二胺基嘌呤及6-氯嘌呤。鹼基上之官能性氧及氮基團可視需要或視情況受保護。適合之保護基已為熟習此項技術者所熟知，且包括苯甲基、三甲基矽烷基、二甲基己基矽烷基、第三丁基二甲基矽烷基、第三丁基二苯基矽烷基、三苯甲基、烷基及醯基，諸如乙醯基及丙醯基；甲磺醯基及對甲苯磺醯基。或者，嘌呤或嘧啶鹼基可視情況經取代以使得其形成可行的前藥，其可在活體內裂解。適當的取代基之實例包括醯基部分。 術語「醯基」指代一部分，其中羰基部分，例如，-C(O)烷基，選自烷基、環烷基、低碳數烷基(亦即，C1 -C4 )；烷氧基烷基，包括甲氧基甲基；芳烷基-包括苯甲基、芳氧基烷基-諸如苯氧基甲基；芳基，包括視情況經鹵素、C1 -C4 烷基或C1 -C4 烷氧基取代之苯基。在一個實施例中，術語「醯基」指代單磷酸酯、二磷酸酯或三磷酸酯。 術語「低碳數醯基」指代其中羰基部分為低碳數烷基(亦即，C1 -C4 )之醯基。 由式R14 S(O)2 OR15 表示之術語磺酸酯，包含R14 ，其中R14 為烷基、鹵烷基、芳烷基或芳基。R15 為烷基、芳基或芳烷基。 術語「胺基酸」或「胺基酸殘基」指代D-或L-天然或非天然存在之胺基酸。代表性胺基酸包括但不限於丙胺酸、β-丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、苯丙胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、脯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸外加其他。 如本文中所用之術語「氮保護基」指代共價連接至氮且可移除且適當時通常經氫置換的部分。舉例而言，氮保護基可為向寄主投與後活體內、藉由細胞活體外移除之基團，或其可在製造過程期間經移除。適用於本發明之適合之氮保護基由Greene及Wuts在Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc中加以描述。 如本文中所用之術語「氧保護基」指代共價連接至氧且可移除且適當時通常經氫置換之部分。舉例而言，氧保護基可為向寄主投與後活體內、藉由細胞活體外移除之基團，或其可在製造過程期間經移除。適用於本發明之適合之氧保護基由Greene及Wuts在Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc中加以描述。 除非另外指示，否則磷酸酯指代單磷酸酯、二磷酸酯及三磷酸酯。 術語「磷醯胺」、「胺基磷酸酯」或「磷醯胺酸」為具有結合至三個氧基團及胺(其可視情況經取代)之磷之部分。適用於本發明之適合之胺基磷酸酯由Madela, Karolina及McGuigan在2012年, 「Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs」,Future Medicinal Chemistry 4(5), 第625-650頁 10:1021/jm300074y及Dominique, McGuigan及Balzarini在2004年, 「Aryloxy Phosphoramidate Triesters as Pro-Tides」,Mini Reviews in Medicinal Chemistry 4(4), 第371-381頁進行描述。適用於本發明之額外胺基磷酸酯描述於以下中：美國專利第5,233,031號、第7,115,590號、第7,547,704號、第7,879,815號、第7,888,330號、第7,902,202號、第7,951,789號、第7,964,580號、第8,071,568號；第8,148,349號、第8,263,575號、第8,324,179號、第8,334,270號、第8,552,021號、第8,563,530號、第8,580,765號、第8,735,372號、第8,759,318號；EP 2120565；EP 1143995；6,455,513；及8,334,270。其他胺基磷酸酯描述於背景技術中所描述之核苷專利中。 用於本發明之胺基磷酸酯基團包括以下結構之彼等： 。 用於本發明之其他胺基磷酸酯包括以下結構之彼等：其中： RP1 為視情況經取代之直鏈、支鏈或環烷基，或視情況經取代之芳基、雜芳基或雜環基或其鍵聯的組合；且 RP2 為-NRN1 RN2 基團或B'基團； 其中： RN1 及RN2 各自獨立地為H、C1-8 烷基、(C3 -C7 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-或(雜芳基)C0 -C4 烷基-；其可視情況經取代； RN1 及RN2 以及其所連接之氮原子連接而形成3至7員雜環； B'為基團； 其中： R16 為氫、(C1 -C8 )烷基、(C2 -C8 )烯基、(C2 -C8 )炔基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-或胺基酸之側鏈，例如通常選自由以下組成之群之胺基酸的側鏈(如本文另外所描述)：丙胺酸、β-丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、苯丙胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、脯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸(通常R16 為氫、甲基、異丙基或異丁基)； R17 為氫、(C1 -C8 )烷基、(C2 -C8 )烯基、(C2 -C8 )炔基、(C3 -C8 環胺基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-或胺基酸之側鏈，例如通常選自由以下組成之群之胺基酸的側鏈(如本文另外所描述)：丙胺酸、β-丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、苯丙胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、脯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸(通常R17 為氫、甲基、異丙基或異丁基)； R18 為氫或C1 -C3 烷基；或 R16 及R17 可形成(C3 -C7 )環烷基或(C3 -C7 )雜環基；或 R18 及R16 或R17 可形成(C3 -C6 )雜環基；且 R19 為氫、(C1 -C6 )烷基、(C3 -C6 )烯基、(C3 -C6 )炔基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-；或 B'為基團； 其中： R20 為氫、(C1 -C3 )烷基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-或(雜芳基)C0 -C4 烷基-； R21 為氫、(C1 -C3 )烷基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-或(雜芳基)C0 -C4 烷基-；且 R18 及R19 如上文所定義。 優選的RP1 基團包括視情況經取代之苯基、萘基及單環雜芳基，尤其在患者之細胞中增強化合物之生物可用性且呈現降低的毒性、提高的治療指數及提高的藥物動力學(化合物經更緩慢地代謝及排泄)之彼等基團(尤其親油性基團)。 術語胺基磷酸酯在整個說明書中用於描述在核苷化合物之呋喃醣環之5'位或3'位處發現且形成核苷化合物之前藥形式的基團。在一個實施例中，胺基磷酸酯可發現於核苷化合物之呋喃醣環之5'位及3'位處且形成核苷化合物之前藥形式。在另一實施例中，發現於核苷之呋喃醣環之5'位處之胺基磷酸酯可藉由在核苷化合物的呋喃醣環之3'位處形成3'羥基取代基之鍵而形成環狀胺基磷酸酯化合物且形成核苷化合物之前藥形式。 術語「硫代磷醯胺」、「硫代胺基磷酸酯」或「硫代磷醯胺酸」為具有結合至硫(P=S)、兩個氧基團及胺(其可視情況經取代)之磷的部分。適用於本發明之硫代胺基磷酸酯描述於美國專利第8,772,474號及WO 2012/040124中。 用於本發明之硫代胺基磷酸酯基團包括以下結構之彼等： 。 其他硫代胺基磷酸酯包括以下結構之彼等：其中： RP1 為視情況經取代之直鏈、支鏈或環烷基，或視情況經取代之芳基、雜芳基或雜環基或其鍵聯的組合；且 RP2 為-NRN1 RN2 基團或B'基團； 其中： RN1 及RN2 各自獨立地為H、C1-8 烷基、(C3 -C7 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-或(雜芳基)C0 -C4 烷基-；或 RN1 及RN2 以及其所連接之氮原子連接而形成3至7員雜環； B'為基團； 其中： R16 為氫、(C1 -C8 )烷基、(C2 -C8 )烯基、(C2 -C8 )炔基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-或胺基酸之側鏈，例如通常選自由以下組成之群之胺基酸的側鏈(如本文另外所描述)： 丙胺酸、β-丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、苯丙胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、脯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸(通常R16 為氫、甲基、異丙基或異丁基)； R17 為氫、(C1 -C8 )烷基、(C2 -C8 )烯基、(C2 -C8 )炔基、(C3 -C8 環胺基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-或胺基酸之側鏈，例如通常選自由以下組成之群之胺基酸的側鏈(如本文另外所描述)：丙胺酸、β-丙胺酸、精胺酸、天冬醯胺、天冬胺酸、半胱胺酸、胱胺酸、麩胺酸、麩醯胺酸、甘胺酸、苯丙胺酸、組胺酸、異白胺酸、離胺酸、白胺酸、甲硫胺酸、脯胺酸、絲胺酸、蘇胺酸、纈胺酸、色胺酸或酪胺酸(通常R17 為氫、甲基、異丙基或異丁基)； R18 為氫或C1 -C3 烷基；或 R16 及R17 可形成(C3 -C7 )環烷基或(C3 -C7 )雜環基；或 R18 及R16 或R17 可形成(C3 -C6 )雜環基；且 R19 為氫、(C1 -C6 )烷基、(C3 -C6 )烯基、(C3 -C6 )炔基、(C3 -C8 環烷基)C0 -C4 烷基-、(芳基)C0 -C4 烷基-、(C3 -C6 雜環)C0 -C4 烷基-、(雜芳基)C0 -C4 烷基-；或 B'為基團；且 R18 、R19 、R20 及R21 如上文所定義。 優選的RP1 基團包括視情況經取代之苯基、萘基及單環雜芳基，尤其向患者之細胞中增強化合物之生物可用性且呈現降低的毒性、提高的治療指數及提高的藥物動力學(化合物經更緩慢地代謝及排泄)之彼等基團(尤其親油性基團)。 硫代胺基磷酸酯可在核苷化合物之呋喃醣環之5'位或3'位處以形成核苷化合物之前藥形式。在一個實施例中，硫代胺基磷酸酯可發現於核苷化合物之呋喃醣環之5'位及3'位處且形成核苷化合物之前藥形式。在另一實施例中，發現於核苷之呋喃醣環之5'位處之硫代胺基磷酸酯可藉由在核苷化合物的呋喃醣環之3'位處形成3'羥基取代基之鍵而形成環狀硫代胺基磷酸酯化合物且形成核苷化合物之前藥形式。 如在本發明之上下文中所用之術語「D-組態」指代原理組態，其相對於非天然存在之核苷或「L」組態模擬糖部分之天然組態。關於核苷類似物，使用術語「β」或「β變旋異構物」，其中核苷鹼基在核苷類似物中之呋喃醣部分之平面上方經組態(安置)。 術語「共投與(coadminister/coadministration)」或組合療法用於描述根據本發明之至少一種2'-去氧-2'-α-氟-2'-β-C-核苷-4'-氟化合物與至少一種其他活性劑(例如適當時至少一種額外抗HCV試劑，包括其他2'-去氧-2'-α-氟-2'-β-C-甲基-4'-氟核苷試劑，其為本文所揭示)組合之投與。共投與之時序最佳由治療患者之醫療專家確定。有時，試劑較佳同時投與。或者，為組合療法而選擇之藥物可在不同時間向患者投與。當然，在超過一種病毒或其他感染或其他病況存在時，本發明化合物可與其他試劑組合以視需要治療該其他感染或病況。 如本文所用，術語寄主指代HCV病毒可在其中複製之單細胞或多細胞生物，包括細胞株及動物，且通常為人類。術語寄主具體指代經感染細胞、經所有或一部分HCV基因組轉染細胞及動物，詳言之，靈長類(包括黑猩猩)及人類。在本發明之大多數動物應用中，寄主為人類患者。然而，在某些病症中，本發明清楚地預見在家畜方面的應用。寄主可為例如牛、馬、鳥、犬、貓等。 同位素取代 本發明包括以高於天然豐度之同位素之量(亦即增濃)具有原子之所需同位素取代之化合物及化合物的用途。同位素為具有相同原子數、但具有不同質量數(亦即質子數目相同，但中子數目不同)的原子。藉助於一般實例且非限制性地，可在所描述之結構中之任何位置使用氫之同位素，例如，氘(2 H)及氚(3 H)。或者或另外，可使用碳之同位素，例如13 C及14 C。較佳同位素取代為在分子上一或多個位置處之氫之氘以改良藥物之性能。氘可在代謝期間在鍵斷裂之位置結合(α-氘動力學同位素作用)或緊靠或靠近鍵斷裂位點處結合(β-氘動力學同位素作用)。Achillion Pharmaceuticals, Inc. (WO/2014/169278及WO/2014/169280)描述核苷酸之氘化以改良其藥物動力學或藥物效應動力學，包括在分子之5位處。 用諸如氘之同位素取代可得到某些由更大代謝穩定性產生之治療優勢，諸如增加之活體內半衰期或降低之劑量需求。在代謝分解之位點處用氘取代氫可在該鍵處降低代謝速率或消除代謝。氫原子可存在於化合物之任何位置，氫原子可為氫之任何同位素，包括氕(1 H)、氘(2 H)及氚(3 H)。由此，除非上下文另外明確指示，否則本文中提及之化合物涵蓋所有可能的同位素形式。 術語「經同位素標記之」類似物指代為「氘化類似物」、「13 C標記之類似物」或「氘化/13 C標記之類似物」的類似物。術語「氘化類似物」意謂本文所述之化合物，其中H同位素(亦即氫/氕(1 H))經H同位素(亦即，氘(2 H))取代。氘取代可為部分的或全部的。部分氘取代意謂至少一個氫經至少一個氘取代。在某些實施例中，對於所關注之任何位置的同位素而言，該同位素增濃90%、95%或99%或更多。在一些實施例中，在所需位置氘增濃90%、95%或99%。除非有相反指示，否則氘化在所選擇之位置處為至少80%。核苷之氘化可出現在提供所需結果之任何可替換氫處。III. 治療或防治方法 如本文所用，治療指代向感染有C型肝炎病毒之寄主投與活性化合物。 術語「防治性」或預防性在使用時指代投與活性化合物以預防或降低病毒病症出現之可能性。本發明包括治療及防治性或預防性療法。在一個實施例中，向已暴露於由C型肝炎病毒感染之感染且因此處於由C型肝炎病毒感染之感染風險下的寄主投與活性化合物。 本發明係針對一種治療或防治C型肝炎病毒之方法，其包括HCV及相關疾病狀態、病況或HCV感染之併發症之耐藥性及多重耐藥性形式，所述併發症包括諸如無力、食慾不振、體重減輕、乳房增大(尤其在男性中)、皮疹(尤其在手掌上)、凝血困難、皮膚上蜘蛛狀血管、意識模糊、昏迷(腦病)、腹腔流體積聚(腹水)、食道靜脈曲張、門靜脈高血壓、腎衰竭、增大之脾、血細胞減少、貧血、血小板減少、黃疸及肝細胞癌症外加其他。該方法包含視情況與至少一種額外生物活性試劑(例如，額外抗HCV試劑)組合、進一步與醫藥學上可接受之載劑添加劑及/或賦形劑組合向對其有需要之寄主投與有效量之至少一種如本文所描述之β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸。 在又一態樣中，本發明為一種用於預防或防治HCV感染或疾病狀態或相關或後續疾病狀態、病況或HCV感染之併發症的方法，所述併發症包括諸如無力、食慾不振、體重減輕、乳房增大(尤其在男性中)、皮疹(尤其在手掌上)、凝血困難、皮膚上蜘蛛狀血管、意識模糊、昏迷(腦病)、腹腔流體積聚(腹水)、食道靜脈曲張、門靜脈高血壓、腎衰竭、增大之脾、血細胞減少、貧血、血小板減少、黃疸及肝細胞癌症外加其他，該方法包含與醫藥學上可接受之載劑、添加劑或賦形劑組合、視情況與另一種抗HCV試劑組合向處於風險下的患者投與有效量之至少一種如上文所描述之根據本發明的化合物。 必要時可投與5'-穩定β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸作為向受體投與後能夠直接地或間接地提供母體化合物或呈現自身活性之任何鹽或前藥。非限制性實例為醫藥學上可接受之鹽及化合物，其在官能基(諸如羥基或胺官能基)處已經改質以利用化合物之所需投與途徑改變活性5'-三磷酸酯之生物活性、藥物動力學、半衰期、受控遞送、親脂性、吸收動力學、易於磷酸化或遞送有效性。改變活性化合物特性以達成目標特性之方法對熟習此項技術者為已知的，或可由標準方法(例如，醯基化、磷酸化、硫代胺基磷酸胺基化、胺基磷酸胺基化、磷酸化、烷基化或聚乙二醇化)易於評估。IV. 醫藥組合物 在本發明之一態樣中，根據本發明之醫藥組合物包含抗HCV有效量之至少一種本文所述之5'-穩定β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代二胺基嘌呤核苷酸化合物，視情況與醫藥學上可接受之載劑、添加劑或賦形劑組合，進一步視情況與至少一種其他活性化合物組合或交替。 在本發明之一態樣中，根據本發明之醫藥組合物包含抗HCV有效量之至少一種本文所述之活性β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸化合物，視情況與醫藥學上可接受之載劑、添加劑或賦形劑組合，進一步視情況與至少一種其他抗病毒劑組合，諸如抗HCV試劑。 本發明包括醫藥組合物，其以醫藥學上可接受之載劑或賦形劑形式包括治療C型肝炎病毒感染之有效量之本發明的β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸化合物中之一者或其鹽或前藥。在一替代性實施例中，本發明包括醫藥組合物，其以醫藥學上可接受之載劑或賦形劑形式包括預防C型肝炎病毒感染之有效量之本發明的β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸化合物中之一者或其鹽或前藥。 一般熟習此項技術者將認識到治療有效量將隨待治療之感染或病況、其嚴重性、待採用之治療方案、所用試劑之藥物動力學以及待治療之患者或個體(動物或人類)而變化，且該治療量可由主治醫師或專家確定。 可在與醫藥學上可接受之載劑之摻合物中調配根據本發明之5'-穩定β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸化合物。一般而言，較佳以可經口投與之形式投與醫藥組合物，但某些調配物可藉由非經腸、靜脈內、肌肉內、局部、經皮、經頰、皮下、栓劑或其他途徑(包括鼻內噴霧)投與。靜脈內及肌肉內調配物通常以無菌生理鹽水投與。一般熟習此項技術者可改質調配物以使其更可溶於水或其他媒劑，例如，此可藉由技藝中一般眾所皆知的較小改質(鹽調配物、酯化等)就可輕易地實現。例行操作者技能中亦可很好地改變特定化合物之投與途徑及給藥方案以為患者中之最大有益效果而處理本發明化合物之藥物動力學。 在某些醫藥劑型中，化合物之前藥形式(尤其包括醯基化(乙醯基化或其他))及醚(烷基及相關)衍生物、磷酸酯、硫代胺基磷酸酯、胺基磷酸酯及本發明化合物之各種鹽形式為較佳的。一般熟習此項技術者將認識到如何容易地將本發明化合物改質為有助於在宿主生物體或患者內將活性化合物遞送至目標位點之前藥形式。例行操作者亦在適用時將本發明化合物遞送至宿主生物體或患者中之目標位點中利用前藥形式之良好的藥物動力學參數以最大化化合物之預期效果。 包括在本發明之治療活性調配物內之化合物的量為治療HCV感染、減少HCV感染可能性或抑制、減少及/或消除HCV或其副作用(包括疾病狀態、病況及/或由HCV所致而出現之併發症)之有效量。一般而言，視所有化合物、所治療之病況或感染及投與途徑而定，治療有效量之呈醫藥劑型的本發明化合物通常在每天約0.001 mg/kg至約100 mg/kg或更多、更通常略微低於患者之每天約0.1 mg/kg至超過約25 mg/kg或顯著更多的範圍內。視患者中試劑之藥物動力學而定，根據本發明之活性核苷化合物通常以在患者之每天約0.1 mg/kg至約15 mg/kg範圍內之量投與。此劑量範圍一般產生活性化合物之有效血液含量濃度，其可在患者中血液之約0.001至約100、約0.05至約100 微克/cc範圍內。 通常，為治療、預防或延緩此等感染之發作及/或降低HCV病毒感染或二級疾病狀態、病況或HCV之併發症的可能性，組合物將以在至少一日一次約250微克多至約500 mg或更多、例如至多一日四次至少25、50、100、150、250或500毫克範圍內之量以口服劑型投與。本發明化合物通常經口投與，但可非經腸、局部或以栓劑形式以及經鼻內(如經鼻噴霧)或如本文另外所描述進行投與。 在與另一種如本文另外所描述之抗HCV化合物組合共同投與本發明化合物之情況下，視待共同投與的第二試劑及其針對病毒之效能、患者病況及待治療之疾病或感染的嚴重性及投與途徑而定，待投與之根據本發明之化合物的量在患者之約0.01 mg/kg至患者之約500 mg/kg或更多、或顯著更多的範圍內。另一種抗HCV試劑可例如以在約0.01 mg/kg至約500 mg/kg範圍內之量投與。在某些較佳實施例中，一般視患者中兩種試劑之藥物動力學而定，此等化合物可通常以在約0.5 mg/kg至約50 mg/kg或更多(通常至多約100 mg/kg)的範圍內之量投與。此等劑量範圍一般產生患者中活性化合物之有效血液含量濃度。 出於本發明之目的，防治性或預防性有效量之根據本發明的組合物在如上文針對治療有效量所闡述之相同濃度範圍內，且通常與治療有效量相同。 活性化合物的投與可在每天連續(靜脈內滴注)至若干次口服或鼻內投與(例如Q.I.D.)或經皮投與之範圍內，且可包括口服、局部、非經腸、肌肉內、靜脈內、皮下、經皮(其可包括滲透增強劑)、經頰及栓劑以及其他投與途徑投與。包覆腸溶包衣口服錠劑亦可用以增強用於投與之口服途徑之化合物的生物可用性。最有效的劑型將視所選特定試劑之生物可用性/藥物動力學以及患者之疾病嚴重性而定。因為易於投與及前瞻性良好的患者順應性，所以口服劑型尤其較佳。 為製備根據本發明之醫藥組合物，治療有效量之一或多種根據本發明之化合物通常根據習知醫藥混配技術與醫藥學上可接受之載劑緊密混合以產生劑量。視所需製備形式而定，載劑可呈現各種形式以用於投與，例如口服或非經腸。在以口服劑型製備醫藥組合物中，可使用任一種常用醫藥介質。因此，對於液體口服製劑(諸如懸浮液、酏劑及溶液)而言，可使用適合載劑及添加劑，包括水、二醇、油、醇、調味劑、防腐劑、著色劑及其類似物。對於固體口服製劑(諸如粉劑、錠劑、膠囊)而言，且對於固體製劑(諸如栓劑)而言，可使用適合載劑及添加劑，包括澱粉、糖載劑(諸如右旋糖、甘露醇、乳糖及相關載劑)、稀釋劑、成粒劑、潤滑劑、黏合劑、崩解劑及其類似物。必要時，錠劑或膠囊可包覆腸溶包衣或藉由標準技術持續釋放。此等劑型之用途可顯著增強患者中化合物之生物可用性。 對於非經腸調配物而言，載劑通常會包含無菌水或氯化鈉水溶液，但亦可包括其他成分，包括有助於分散的彼等物。當然，在使用無菌水且維持無菌時，組合物及載劑亦必須經滅菌。亦可製備可注射懸浮液，在此情況下，可採用適當液體載劑、懸浮劑及其類似物。 脂質體懸浮液(包括靶向病毒抗原之脂質體)亦可藉由習知方法製備以產生醫藥學上可接受之載劑。此可適於遞送根據本發明之核苷化合物之自由核苷、醯基/烷基核苷或磷酸酯前藥形式。 在根據本發明之典型實施例中，化合物及組合物用於治療、預防或延緩HCV感染或二級疾病狀態、病況或HCV之併發症。V. 組合及交替療法 充分認識到病毒之抗藥性變異體可在用抗病毒劑長期處理後出現。抗藥性大多通常由編碼用於病毒複製之酶之基因的突變發生。針對HCV感染之藥物之功效可藉由與另一種、且甚至可能兩種或三中其他抗病毒化合物組合或交替投與化合物而延長、強化或恢復，該抗病毒化合物由該原理藥物引發不同突變或藉由不同路徑起作用。或者，藥物之藥物動力學、生物分佈、半衰期或其他參數可藉由該等組合療法(在視為一致時，其可包括交替療法)變化。由於所揭示之β-D-2'-去氧-2'-α-氟-2'-β-C-取代-4'-氟-N6 -取代-2,6-二胺基嘌呤核苷酸及其他所描述之聚合酶抑制劑，其可用於與例如以下之組合向寄主投與化合物： (1) 蛋白酶抑制劑，諸如NS3/4A蛋白酶抑制劑； (2) NS5A抑制劑； (3) 另一種NS5B聚合酶抑制劑； (4) NS5B無基質抑制劑； (5) 干擾素α-2a，其可經聚乙二醇化或以其他方式經改質，及/或利巴韋林； (6) 基於無基質之抑制劑； (7) 解螺旋酶抑制劑； (8) 反義寡脫氧核苷酸(S-ODN)； (9) 適體； (10) 核酸酶抗性核糖核酸酶； (11) iRNA，包括微RNA及SiRNA； (12) 病毒之抗體、部分抗體或域抗體(domain antibody)，或 (13) 引發寄主抗體反應之病毒抗原或部分抗原。 可與本發明之β-D-2'-D-2'-α-氟-2'-β-C-取代-2-改質-N6 -取代嘌呤核苷酸組合投與之抗HCV試劑的非限制性實例為： (i) 蛋白酶抑制劑，諸如特拉匹韋(Incivek® )、波普瑞韋(VictrelisTM )、西咪匹韋(OlysioTM )、帕瑞普韋和(ABT-450)、ACH-2684；AZD-7295；BMS-791325；丹諾普韋(danoprevir)；非利布韋(Filibuvir)；GS-9256；GS-9451；MK-5172；司屈布韋(Setrobuvir)；沙普瑞韋(Sovaprevir)；特哥布韋(Tegobuvir)；VX-135；VX-222及ALS-220； (ii) NS5A抑制劑，諸如ACH-2928、ACH-3102、IDX-719、達拉他韋(daclatasvir)、雷迪帕韋及奧匹替韋(ABT-267)； (iii) NS5B抑制劑，諸如ACH-3422；AZD-7295；克立咪唑(Clemizole)；ITX-5061；PPI-461；PPI-688、Sovaldi® 、MK-3682及梅利他濱(mericitabine)； (iv) NS5B抑制劑，諸如ABT-333、MBX-700；及， (v) 抗體，諸如GS-6624。 若投與β-D-2'-D-2'-α-氟-2'-β-C-取代-2-改質-N6 -取代嘌呤核苷酸以治療導致肝癌或肝硬化之晚期C型肝炎病毒，則在一個實施例中，化合物可與另一種通常用於治療肝細胞癌(HCC)之藥物組合或交替投與，例如，如Andrew Zhu在「New Agents on the Horizon in Hepatocellular Carcinoma」 Therapeutic Advances in Medical Oncology, V 5(1), 2013年1月, 41-50中所描述。用於其中寄主患有HCC或處於HCC風險下之組合療法之適合化合物的實例包括抗血管生成劑、舒尼替尼(sunitinib)、布立尼布(brivanib)、立尼法尼(linifanib)、雷莫蘆單抗(ramucirumab)、貝伐單抗(bevacizumab)、西地尼布(cediranib)、帕佐泮尼(pazopanib)、TSU-68、樂伐替尼(lenvatinib)、針對EGFR之抗體、mTor抑制劑、MEK抑制劑及組蛋白脫乙醯酶抑制劑。V. 本發明之 β-D-2'- 去氧 -2'-α- 氟 -2'-β-C- 取代 -4'- 氟 -N6 - 取代 6- 胺基 2- 取代嘌呤核苷酸之製備方法 用於提供本發明之化合物之一般方法為此項技術中已知的或在本文中描述。 在合成流程中使用以下縮寫。 CBr4 ：四溴化碳 DBU：1,8-二氮雜雙環[5.4.0]十一-7-烯 DCM：二氯甲烷 THF：四氫呋喃(THF)，無水 EtOAc：乙酸乙酯 EtOH：乙醇 Li(OtBu)3 AlH：三第三丁氧基氫化鋁鋰 Na2 SO4 ：硫酸鈉(無水) MeCN：乙腈 MeNH2 ：甲胺 MeOH：甲醇 Na2 SO4 ：硫酸鈉 NaHCO3 ：碳酸氫鈉 NH4 Cl：氯化銨 NH4 OH：氫氧化銨 PE：石油醚 Ph3 P：三苯膦 矽膠(230至400目，吸附劑) t-BuMgCl：第三丁基氯化鎂 t-BuOK：第三丁醇鈉 t-BuOH：第三丁醇實例 一般方法 在300 MHz傅立葉變換Brücker光譜儀上記錄1 H、19 F及31 P NMR光譜。光譜自在CDCl3 、CD3 OD或DMSO-d6 中在5 mm直徑管中製備之樣品獲得。旋轉多峰性由符號s (單峰)、d (二重峰)、t (三重峰)、m (多重峰)及br (寬峰)指示。以Hz為單位報告偶合常數(J )。MS光譜使用Agilent Technologies 6120四極MS設備上之電噴霧電離(ESI)獲得。反應一般在乾燥氮氣氛圍下使用Sigma-Aldrich無水溶劑進行。所有常見化學品購自商業來源。針對以下實例化學物質之範本 ： i) Me2 NH.HCl，DBU，MeOH，85℃；ii) l2 ，PPh3 ，咪唑，THF；iii) MeONa，MeOH，60℃；iv) TMSCI，吡啶，0℃隨後異丁醯氯；v) Et3 N.3HF，NIS，MeCN，-20℃；vi) BzONa，DMSO，100℃；vii) MeNH2 ，EtOH，75℃；viii) CbzCI，DMAP，DCM，0℃；ix)異丙基((R,S)-(五氟苯氧基)-苯氧基-磷醯基)-L-丙胺酸酯，DBU，THF；x) H2 ，Pd-C，EtOH(2R,3R,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (2) 。 向化合物1 (3.0 g，5.7 mmol)於MeOH (50 mL)中之溶液中添加二甲胺鹽酸鹽(4.7 g，57.6 mmol)及1,8-二氮雜雙環[5.4.0]十一-7-烯(8.6 mL，57.6 mmol)。將反應混合物於密封容器中在85℃下加熱6 h，冷卻至室溫(RT)且濃縮。藉由管柱層析(矽膠，DCM/MeOH 100:0至85:15)純化殘餘物。獲得呈白色固體狀之產物2 (1.6 g，86%)。(2R,3R,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 碘甲基 )-4- 甲基四氫呋喃 -3- 醇 (3) 。 向化合物2 (1.67 g，5.1 mmol)於無水THF (30 mL)中之溶液中添加三苯膦(1.60 g，6.1 mmol)及咪唑(420 mg，6.1 mmol)。隨後，逐滴添加碘(1.42 g，5.6 mmol)於無水THF (10 mL)中之溶液。在RT下攪拌混合物3 h。溶液隨後經矽藻土過濾，且濃縮。含有3 之深色殘餘物按原樣用於下一步驟。(3R,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -4- 甲基 -2- 亞甲基四氫呋喃 -3- 醇 (4) 。 向3 於MeOH (40 mL)中之溶液中添加MeONa (1.38 g，25.5 mmol)。將反應混合物在60℃下加熱15 h，且隨後冷卻至RT且濃縮。添加EtOAc (100 mL)且用NH4 Cl飽和水溶液(80 mL)及鹽水(80 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物4 (0.87 g，經2個步驟產率55%)。 N -(6-( 二甲胺基 )-9-((2R,3R,4R)-3- 氟 -4- 羥基 -3- 甲基 -5- 亞甲基四氫呋喃 -2- 基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (5) 。 在0℃下向4 (500 mg，1.6 mmol)於無水吡啶(8 mL)中之溶液中逐滴添加氯三甲基矽烷(410 µL，3.2 mmol)。在0℃下攪拌反應混合物10分鐘，且隨後逐滴添加異丁醯氯(250 µL，2.4 mmol)。在RT下攪拌橙色溶液4 h。在冷卻至0℃後，藉由添加H2 O (2 mL)及30% NH4 OH (3 mL)淬滅反應。隨後在0℃下攪拌混合物1 h。添加EtOAc (50 mL)且用NH4 Cl飽和水溶液(40 mL)及鹽水(40 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。使殘餘物與甲苯(2 × 50 mL)一起共蒸發且藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化。獲得呈無色油狀之產物5 (460 mg，產率75%)。 N -(9-((2R,3R,4S,5R)-3,5- 二氟 -4- 羥基 -5-( 碘甲基 )-3- 甲基四氫呋喃 -2- 基 )-6-( 二甲胺基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (6) 。 向5 (176 mg，0.47 mmol)於無水MeCN (8 mL)中之溶液中添加Et3 N.3HF (90 µL，0.56 mmol)。在-20℃下經45分鐘逐滴添加N -碘丁二醯亞胺(146 mg，0.65 mmol)於無水MeCN (8 mL)中之溶液。在0℃下攪拌所得橙色溶液2 h，且在RT下攪拌1 h。反應隨後用EtOAc (50 mL)稀釋且藉由添加(1:1) NaHCO3 /Na2 S2 O3 飽和水溶液(30 mL)淬滅。分離各相且將有機層用鹽水(40 mL)洗滌、經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物6 (129 mg，產率53%)。苯甲酸 ((2S,3S,4R,5R)-5-(6-( 二甲胺基 )-2- 異丁醯胺 -9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲酯 (7) 。 向6 (548 mg，1.05 mmol)於無水DMSO (40 mL)中之溶液中添加苯甲酸鈉(1.51 g，10.5 mmol)。在100℃下攪拌所得乳白色懸浮液3天。隨後將混合物冷卻，使其分配於H2 O (30 mL)與EtOAc (50 mL)之間，且分離各相。用EtOAc (3 × 30 mL)反萃取水層。用NH4 Cl飽和水溶液(2 × 50 mL)及鹽水(50 mL)洗滌經合併之有機物。有機溶液經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物7 (410 mg，產率75%)。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (8) 。 在75℃下將密封容器中之7 (330 mg，0.64 mmol)於甲胺(33%於EtOH中) (25 mL)中之溶液攪拌2天。隨後使混合物冷卻且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈白色固體狀之產物8 (180 mg，產率82%)。1 H NMR (300 MHz, CD3 OD)δ 7.93 (s, 1H), 6.43 (d,J = 22.4 Hz, 1H), 4.62 (d,J = 20.7 Hz, 1H), 3.86-3.84 (m, 2H), 3.41 (m, 6H), 1.20 (d,J = 22.2 Hz, 3H)。C13 H19 F2 N6 O3 [M+H]+ 之MS (ESI)m /z 計算值345.1；實驗值345.2。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 基苯甲基碳酸酯 (9) 。 在0℃下向8 (93 mg，0.27 mmol)及DMAP (37 mg，0.30 mmol)於無水DCM (5 mL)中之溶液中逐滴添加氯甲酸苯甲酯(43 µL，0.30 mmol)。在RT下將反應混合物攪拌45分鐘，且用DCM (5 mL)稀釋。溶液用H2 O (5 mL)、鹽水(5 mL)洗滌，經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物9 (70 mg，產率55%)。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-3-((( 苯甲氧基 ) 羰基 ) 氧基 )-2,4- 二氟 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (10) 。 在0℃下向化合物9 (51 mg，0.11 mmol)及((R ,S )-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯(73 mg，0.16 mmol)於無水THF (3 mL)中之溶液中逐滴添加DBU (33 µL，0.22 mmol)。在RT下攪拌反應混合物18 h。隨後用EtOAc (10 mL)及NH4 Cl飽和水溶液(8 mL)稀釋溶液。分離各相且用EtOAc (3 × 5 mL)反萃取水層。經合併之有機物用鹽水(15 mL)洗滌，經Na2 SO4 乾燥且濃縮。藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物10 (50 mg，63%)。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (11) 。 向化合物10 (50 mg，0.07 mmol)於EtOH (3 mL)中之溶液中添加鈀(10%/木炭) (8 mg)。用氫氣沖洗燒瓶，且在RT下於氫氣氛圍下攪拌懸浮液3 h。混合物隨後經矽藻土過濾，且濃縮。藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物11 (33 mg，77%)。1 H NMR (300 MHz, CD3 OD)δ 7.80 (s, 0.5H), 7.79 (s, 0.5H), 7.35-7.16 (m, 5H), 6.42 (d,J = 17.6 Hz, 0.5 H), 6.40 (d,J = 17.6 Hz, 0.5 H), 4.96-4.86 (與H2 O重疊, m, 1H), 4.62-4.38 (m, 2H), 3.92-3.88 (m, 1H), 3.39 (m, 6H), 1.30-1.18 (m, 12H)。31 P NMR (121 MHz, CD3 OD)δ 4.01 (s), 3.89 (s)。C25 H35 F2 N7 O7 P [M+H]+ 之MS (ESI)m /z 計算值614.2；實驗值614.2。i) MeNH2 ，EtOH，100℃；ii) l2 ，PPh3 ，咪唑，THF；iii) MeONa，MeOH，60℃ ；iv) TMSCI，吡啶，0℃隨後異丁醯氯；v) Et3 N.3HF，NIS，MeCN，-20℃；vi) BzONa，DMSO，100℃；vii) MeNH2 ，EtOH，75℃；viii) CbzCI，DMAP，DCM，0℃；ix) ((R.S)-(五氟苯氧基)-苯氧基-磷醯基)-L-丙胺酸異丙酯，DBU，THF；x) H2 ，Pd-C，EtOH(2R,3R,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (12) 。 在100℃下將密封容器中之化合物1 (2.3 g，4.4 mmol)於甲胺(33%於EtOH中) (50 mL)中之溶液攪拌3 h。隨後將混合物冷卻至RT且濃縮。藉由管柱層析(矽膠，DCM/MeOH 100:0至75:25)純化殘餘物。獲得呈灰白色固體狀之產物12 (1.4 g，100%)。(2R,3R,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 碘甲基 )-4- 甲基四氫呋喃 -3- 醇 (13) 。 向化合物12 (1.36 g，4.40 mmol)於無水THF (30 mL)中之溶液中添加三苯膦(1.38 g，5.28 mmol)及咪唑(360 mg，5.28 mmol)。隨後，逐滴添加碘(1.23 g，4.84 mmol)於無水THF (10 mL)中之溶液。在RT下攪拌混合物15 h。溶液隨後經矽藻土過濾，且濃縮。含有13 之深色殘餘物按原樣用於下一步驟。(3R,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -4- 甲基 -2- 亞甲基四氫呋喃 -3- 醇 (14) 。 向13 於MeOH (40 mL)中之溶液中添加MeONa (1.19 g，22.0 mmol)。將反應混合物在60℃下加熱15 h，且隨後冷卻至RT且濃縮。添加EtOAc (100 mL)且用NH4 Cl飽和水溶液(80 mL)及鹽水(80 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物14 (0.58 g，經2個步驟產率45%)。N -(6-(甲胺基 )-9-((2R,3R,4R)-3-氟 -4-羥基 -3-甲基 -5-亞甲基四氫呋喃 -2-基 )-9H-嘌呤 -2-基 )異丁醯胺 (15)。在0℃下向14 (300 mg，1.02 mmol)於無水吡啶(5 mL)中之溶液中逐滴添加氯三甲基矽烷(320 µL，2.54 mmol)。在0℃下攪拌反應混合物10分鐘，且隨後逐滴添加異丁醯氯(160 µL，1.54 mmol)。在RT下攪拌橙色溶液4 h。在冷卻至0℃後，藉由添加H2 O (2 mL)及30% NH4 OH (3 mL)淬滅反應。隨後在0℃下攪拌混合物1 h。添加EtOAc (50 mL)且用NH4 Cl飽和水溶液(40 mL)及鹽水(40 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。使殘餘物與甲苯(2 × 50 mL)一起共蒸發且藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化。獲得呈無色油狀之產物15 (240 mg，產率65%)。 N -(9-((2R,3R,4S,5R)-3,5- 二氟 -4- 羥基 -5-( 碘甲基 )-3- 甲基四氫呋喃 -2- 基 )-6-( 甲胺基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (16) 。 向15 (120 mg，0.33 mmol)於無水MeCN (6 mL)中之溶液中添加Et3 N.3HF (65 µL，0.40 mmol)。在-20℃下經30分鐘逐滴添加N -碘丁二醯亞胺(103 mg，0.46 mmol)於無水MeCN (6 mL)中之溶液。在0℃下攪拌所得橙色溶液2 h，且在RT下攪拌1 h。反應隨後用EtOAc (40 mL)稀釋且藉由添加(1:1) NaHCO3 /Na2 S2 O3 飽和水溶液(25 mL)淬滅。分離各相且將有機層用鹽水(30 mL)洗滌、經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物16 (85 mg，產率50%)。苯甲酸 ((2S,3S,4R,5R)-5-(6-( 甲胺基 )-2- 異丁醯胺 -9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲酯 (17) 。 向16 (85 mg，0.17 mmol)於無水DMSO (5 mL)中之溶液中添加苯甲酸鈉(245 mg，1.70 mmol)。在100℃下攪拌所得乳白色懸浮液5天。隨後將混合物冷卻，使其分配於H2 O (15 mL)與EtOAc (25 mL)之間，且分離各相。用EtOAc (3 × 10 mL)反萃取水層。用NH4 Cl飽和水溶液(2 × 20 mL)及鹽水(20 mL)洗滌經合併之有機物。有機溶液經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物17 (60 mg，產率70%)。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (18) 。 在75℃下將密封容器中之17 (60 mg，0.12 mmol)於甲胺(33%於EtOH中) (6 mL)中之溶液攪拌3天。隨後使混合物冷卻且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈白色固體狀之產物18 (29 mg，產率72%)。1 H NMR (300 MHz, CD3 OD)δ 7.94 (s, 1H), 6.42 (d,J = 16.9 Hz, 1H), 4.76-4.59 (m, 1H), 3.91-3.81 (m, 2H), 3.04 (s, 3H), 1.22 (d,J = 22.3 Hz, 3H)。C12 H17 F2 N6 O3 [M+H]+ 之MS (ESI)m/z 計算值331.1；實驗值331.2。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 基苯甲基碳酸酯 (19) 。 在0℃下向18 (27 mg，0.08 mmol)及DMAP (11 mg，0.08 mmol)於無水DCM (1 mL)中之溶液中添加氯甲酸苯甲酯(7 µL，0.08 mmol)。將反應混合物在RT下攪拌1.5 h且用DCM (4 mL)稀釋。將溶液用H2 O (3 mL)、鹽水(3 mL)洗滌，經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得產物19 以及呈無色固體狀之二保護之物種(比率：7:3；總計20 mg)，且按原樣用於下一步驟。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9-- 基 )-3-((( 苯甲氧基 ) 羰基 ) 氧基 )-2,4- 二氟 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (20) 。 在0℃下向含有化合物19 (20 mg)及((R ,S )-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯(22 mg，0.05 mmol)於無水THF (1 mL)中之溶液中添加DBU (9 µL，0.06 mmol)。將反應混合物在RT下攪拌4 h。隨後用EtOAc (5 mL)及NH4 Cl飽和水溶液(3 mL)稀釋溶液。分離各相且用EtOAc (3 × 3 mL)反萃取水層。經合併之有機物用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且濃縮。含有產物20 之殘餘物按原樣用於下一步驟。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (21) 。 向含有化合物20 之混合物於EtOH (1 mL)中之溶液中添加鈀(10%/木炭) (3 mg)。用氫氣沖洗燒瓶，且在RT下於氫氣氛圍下攪拌懸浮液3 h。混合物隨後經矽藻土過濾，且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)且隨後藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物21 (5 mg，經3個步驟10%)。1 H NMR (300 MHz, CD3 OD)δ 7.78, 7.76 (s+s, 1H), 7.35-7.16 (m, 5H), 6.41 (d,J = 17.4 Hz)及6.39 (d,J = 17.5 Hz, 1H), 4.98-4.90 (與H2 O重疊, m, 1H), 4.69-4.53 (m, 1H), 447-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.03 (s, 3H), 1.31-1.17 (m, 12H)。31 P NMR (121 MHz, CD3 OD)δ 2.63 (s), 2.50 (s)。C24 H33 F2 N7 O7 P [M+H]+ 之MS (ESI)m/z 計算值600.2；實驗值600.2。i) N-甲基-乙胺，EtOH，100℃；ii) l2 ，PPh3 ，咪唑，THF；iii) MeONa，MeOH，60℃；iv) TMSCI，吡啶，0℃隨後異丁醯氯；v) Et3 N.3HF，NIS，MeCN，-20℃；vi) BzONa，DMSO，100℃；vii) MeNH2 ，EtOH，75℃；viii) CbzCI，DMAP，DCM，0℃；ix) ((R.S)-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯，DBU，THF；x) H2 ，Pd-C，EtOH(2R,3R,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (22) 。 向化合物1 (2.9 g，5.5 mmol)於EtOH (60 mL)中之溶液中添加N -甲基-乙胺(1.4 mL，16.5 mmol)。將反應混合物在100℃下於密封容器中加熱15 h，冷卻至RT且添加30% NH4 OH (20 mL)。將反應混合物在100℃下於密封容器中加熱4 h，且冷卻至RT。藉由管柱層析(矽膠，DCM/MeOH 100:0至90:10)純化殘餘物。獲得呈白色固體狀之產物22 (1.7 g，90%)。(2R,3R,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 碘甲基 )-4- 甲基四氫呋喃 -3- 醇 (23) 。 向化合物22 (1.56 g，4.6 mmol)於無水THF (30 mL)中之溶液中添加三苯膦(2.90 g，11.0 mmol)及咪唑(750 mg，11.1 mmol)。隨後，逐滴添加碘(2.57 g，10.1 mmol)於無水THF (15 mL)中之溶液。在RT下攪拌混合物3 h。溶液隨後經矽藻土過濾，且濃縮。含有23 之深色殘餘物按原樣用於下一步驟。(3R,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -4- 甲基 -2- 亞甲基四氫呋喃 -3- 醇 (24) 。 向23 於MeOH (50 mL)中之溶液中添加MeONa (3.73 g，69.0 mmol)。將反應混合物在60℃下加熱15 h，且隨後冷卻至RT且濃縮。添加EtOAc (100 mL)且用NH4 Cl飽和水溶液(80 mL)及鹽水(80 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物24 (0.82 g，經2個步驟產率55%)。 N -(6-( 乙基 ( 甲基 ) 胺基 )-9-((2R,3R,4R)-3- 氟 -4- 羥基 -3- 甲基 -5- 亞甲基四氫呋喃 -2- 基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (25) 。 在0℃下向24 (500 mg，1.55 mmol)於無水吡啶(8 mL)中之溶液中逐滴添加氯三甲基矽烷(400 µL，3.1 mmol)。在0℃下攪拌反應混合物10分鐘，且隨後逐滴添加異丁醯氯(240 µL，2.3 mmol)。在RT下攪拌橙色溶液4 h。在冷卻至0℃後，藉由添加H2 O (2 mL)及30% NH4 OH (3 mL)淬滅反應。隨後在0℃下攪拌混合物1 h。添加EtOAc (50 mL)且用NH4 Cl飽和水溶液(40 mL)及鹽水(40 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。使殘餘物與甲苯(2 × 50 mL)一起共蒸發且藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化。獲得呈白色固體狀之產物25 (440 mg，產率72%)。N -(9-((2R,3R,4S,5R)-3,5-二氟 -4-羥基 -5-(碘甲基 )-3-甲基四氫呋喃 -2-基 )-6-(乙基 (甲基 )胺基 )-9H-嘌呤 -2-基 )異丁醯胺 (26)。向25 (275 mg，0.70 mmol)於無水MeCN (15 mL)中之溶液中添加Et3 N.3HF (140 µL，0.84 mmol)。在-20℃下經45分鐘逐滴添加N -碘丁二醯亞胺(220 mg，0.98 mmol)於無水MeCN (12 mL)中之溶液。在0℃下攪拌所得橙色溶液2 h，且在RT下攪拌1 h。反應隨後用EtOAc (50 mL)稀釋且藉由添加(1:1) NaHCO3 /Na2 S2 O3 飽和水溶液(30 mL)淬滅。分離各相且將有機層用鹽水(40 mL)洗滌、經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物26 (245 mg，產率65%)。苯甲酸 ((2S,3S,4R,5R)-5-(6-( 乙基 ( 甲基 ) 胺基 )-2- 異丁醯胺 -9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲酯 (27) 。 向26 (245 mg，0.46 mmol)於無水DMSO (15 mL)中之溶液中添加苯甲酸鈉(787 mg，6.9 mmol)。在100℃下攪拌所得乳白色懸浮液5天。隨後將混合物冷卻，使其分配於H2 O (40 mL)與EtOAc (50 mL)之間，且分離各相。用EtOAc (3 × 30 mL)反萃取水層。用NH4 Cl飽和水溶液(2 × 50 mL)及鹽水(50 mL)洗滌經合併之有機物。有機溶液經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈灰白色固體狀之產物27 (206 mg，產率84%)。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (28) 。 在80℃下將密封容器中之27 (205 mg，0.38 mmol)於甲胺(33%於EtOH中) (20 mL)中之溶液攪拌2天。隨後使混合物冷卻且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈白色固體狀之產物28 (110 mg，產率80%)。1 H NMR (300 MHz, CD3 OD)δ 7.93 (s, 1H), 6.43 (d,J = 16.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.04-3.94 (m, 2H), 3.90-3.80 (m, 2H), 3.34 (s, 3H), 1.26-1.17 (m, 6H)。C14 H21 F2 N6 O3 [M+H]+ 之MS (ESI)m/z 計算值359.2；實驗值359.2。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 基苯甲基碳酸酯 (29) 。 在0℃下向28 (30 mg，0.08 mmol)及DMAP (12 mg，0.10 mmol)於無水DCM (2 mL)中之溶液中添加氯甲酸苯甲酯(17 µL，0.12 mmol)。將反應混合物在RT下攪拌2 h且用DCM (5 mL)稀釋。溶液用H2 O (5 mL)、鹽水(5 mL)洗滌，經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物29 (25 mg，產率60%)。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-3-((( 苯甲氧基 ) 羰基 ) 氧基 )-2,4- 二氟 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (30) 。 在0℃下向化合物29 (25 mg，0.05 mmol)及((R ,S )-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯(36 mg，0.08 mmol)於無水THF (2 mL)中之溶液中添加DBU (16 µL，0.11 mmol)。在RT下攪拌反應混合物18 h。隨後用EtOAc (5 mL)及NH4 Cl飽和水溶液(4 mL)稀釋溶液。分離各相且用EtOAc (3 × 3 mL)反萃取水層。經合併之有機物用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且濃縮。含有產物30 之殘餘物按原樣用於下一步驟。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 乙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (31) 。 向含有化合物30 之混合物於EtOH (2 mL)中之溶液中添加鈀(10%/木炭) (4 mg)。用氫氣沖洗燒瓶，且在RT下於氫氣氛圍下攪拌懸浮液3 h。混合物隨後經矽藻土過濾，且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)且隨後藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物31 (14 mg，經2個步驟44%)。1 H NMR (300 MHz, CD3 OD)δ 7.75, 7.72 (s+s, 1H), 7.34-7.13 (m, 5H), 6.42 (d,J = 17.6 Hz)及6.40 (d,J = 17.7 Hz, 1H), 4.98-4.90 (與H2 O重疊, m, 1H), 4.66-4.51 (m, 1H), 4.47-4.35 (m, 1H), 4.05-3.86 (m, 3H), 3.35-3.32 (與MeOH重疊, m, 4H), 1.31-1.17 (m, 15H)。31 P NMR (121 MHz, CD3 OD)δ 4.10 (s), 4.00 (s)。C26 H37 F2 N7 O7 P [M+H]+ 之MS (ESI)m /z 計算值628.2；實驗值628.4。i) 吡咯啶，EtOH，100℃；ii) l2 ，PPh3 咪唑，THF；iii) MeONa，MeOH，60℃；iv) TMSCI，吡啶，0℃隨後異丁醯氯；v) Et3 N.3HF，NIS，MeCN，-20℃；vi) BzONa，DMSO，100℃；vii) MeNH2 ，EtOH，75℃；viii) CbzCI，DMAP，DCM，0℃；ix) ((R.S)-(五氟苯氧基)-苯氧基-磷醯基)-L-丙胺酸異丙酯，DBU，THF；x) H2 ，Pd-C，EtOH(2R,3R,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (32) 。 向化合物1 (3.0 g，5.7 mmol)於EtOH (60 mL)中之溶液中添加吡咯啶(1.45 mL，17.0 mmol)。將反應混合物在100℃下於密封容器中加熱3 h，冷卻至RT且添加30% NH4 OH (25 mL)。將反應混合物在80℃下於密封容器中加熱15 h，且冷卻至RT。藉由管柱層析(矽膠，DCM/MeOH 100:0至90:10)純化殘餘物。獲得呈白色固體狀之產物32 (1.9 g，95%)。(2R,3R,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 碘甲基 )-4- 甲基四氫呋喃 -3- 醇 (33) 。 向化合物32 (1.90 g，5.5 mmol)於無水THF (30 mL)中之溶液中添加三苯膦(3.60 g，13.7 mmol)及咪唑(930 mg，13.7 mmol)。隨後，逐滴添加碘(3.18 g，12.5 mmol)於無水THF (30 mL)中之溶液。在RT下攪拌混合物4 h。溶液隨後經矽藻土過濾，且濃縮。含有33 之深色殘餘物按原樣用於下一步驟。(3R,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-4- 氟 -4- 甲基 -2- 亞甲基四氫呋喃 -3- 醇 (34) 。 向33 於MeOH (60 mL)中之溶液中添加MeONa (4.60 g，85.3 mmol)。將反應混合物在60℃下加熱15 h，且隨後冷卻至RT且濃縮。添加EtOAc (150 mL)且用NH4 Cl飽和水溶液(100 mL)及鹽水(100 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物34 (0.94 g，經2個步驟產率52%)。 N -(6-( 吡咯啶 -1- 基 )-9-((2R,3R,4R)-3- 氟 -4- 羥基 -3- 甲基 -5- 亞甲基四氫呋喃 -2- 基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (35) 。 在0℃下向34 (900 mg，2.69 mmol)於無水吡啶(15 mL)中之溶液中逐滴添加氯三甲基矽烷(700 µL，5.40 mmol)。在0℃下攪拌反應混合物10分鐘，且隨後逐滴添加異丁醯氯(420 µL，4.03 mmol)。在RT下攪拌橙色溶液4 h。在冷卻至0℃後，藉由添加H2 O (4 mL)及30% NH4 OH (5 mL)淬滅反應。隨後在0℃下攪拌混合物1 h。添加EtOAc (100 mL)且用NH4 Cl飽和水溶液(80 mL)及鹽水(80 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。使殘餘物與甲苯(2 × 100 mL)一起共蒸發且藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化。獲得呈白色固體狀之產物35 (705 mg，產率65%)。 N -(9-((2R,3R,4S,5R)-3,5- 二氟 -4- 羥基 -5-( 碘甲基 )-3- 甲基四氫呋喃 -2- 基 )-6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (36) 。 向35 (446 mg，1.10 mmol)於無水MeCN (18 mL)中之溶液中添加Et3 N.3HF (220 µL，1.32 mmol)。在-20℃下經45分鐘逐滴添加N -碘丁二醯亞胺(346 mg，1.54 mmol)於無水MeCN (18 mL)中之溶液。在0℃下攪拌所得橙色溶液2 h，且在RT下攪拌1 h。反應隨後用EtOAc (60 mL)稀釋且藉由添加(1:1) NaHCO3 /Na2 S2 O3 飽和水溶液(40 mL)淬滅。分離各相且將有機層用鹽水(40 mL)洗滌、經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物36 (340 mg，產率56%)。苯甲酸 ((2S,3S,4R,5R)-5-(6-( 吡咯啶 -1- 基 )-2- 異丁醯胺 -9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲酯 (37) 。 向36 (290 mg，0.53 mmol)於無水DMSO (18 mL)中之溶液中添加苯甲酸鈉(1.14 g，7.9 mmol)。在100℃下攪拌所得乳白色懸浮液5天。隨後將混合物冷卻，使其分配於H2 O (50 mL)與EtOAc (60 mL)之間，且分離各相。用EtOAc (3 × 30 mL)反萃取水層。用NH4 Cl飽和水溶液(2 × 60 mL)及鹽水(60 mL)洗滌經合併之有機物。有機溶液經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈灰白色固體狀之產物37 (190 mg，產率66%)。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (38) 。 在80℃下將密封容器中之37 (190 mg，0.35 mmol)於甲胺(33%於EtOH中) (20 mL)中之溶液攪拌2天。隨後使混合物冷卻且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈白色固體狀之產物38 (90 mg，產率70%)。1 H NMR (300 MHz, CD3 OD)δ 7.96 (s, 1H), 6.43 (d,J = 22.8 Hz, 1H), 4.71-4.61 (m, 1H), 3.85 (lm, 6H), 2.00 (large, 4H), 1.20 (d,J = 29.6Hz, 3H)。C15 H21 F2 N6 O3 [M+H]+ 之MS (ESI)m/z 計算值371.2；實驗值371.2。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 基苯甲基碳酸酯 (39) 。 在0℃下向38 (30 mg，0.08 mmol)及DMAP (12 mg，0.10 mmol)於無水DCM (2 mL)中之溶液中添加氯甲酸苯甲酯(17 µL，0.12 mmol)。將反應混合物在RT下攪拌2 h且用DCM (5 mL)稀釋。溶液用H2 O (5 mL)、鹽水(5 mL)洗滌，經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物39 (25 mg，產率62%)。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-3-((( 苯甲氧基 ) 羰基 ) 氧基 )-2,4- 二氟 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (40) 。 在0℃下向化合物39 (25 mg，0.05 mmol)及((R ,S )-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯(36 mg，0.08 mmol)於無水THF (2 mL)中之溶液中添加DBU (16 µL，0.11 mmol)。將反應混合物在RT下攪拌5 h。隨後用EtOAc (5 mL)及NH4 Cl飽和水溶液(4 mL)稀釋溶液。分離各相且用EtOAc (3 × 3 mL)反萃取水層。經合併之有機物用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)粗略地純化殘餘物。彙集含產物之溶離份且40 按原樣用於下一步驟。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 吡咯啶 -1- 基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (41) 。 向含有化合物40 之混合物於EtOH (2 mL)中之溶液中添加鈀(10%/木炭) (4 mg)。用氫氣沖洗燒瓶，且在RT下於氫氣氛圍下攪拌懸浮液3 h。混合物隨後經矽藻土過濾，且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)且隨後藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物41 (7 mg，經2個步驟22%)。1 H NMR (300 MHz, CD3 OD)δ 7.79(s, 0.7H), 7.77 (s, 0.3H), 7.36-7.17 (m, 5H), 6.43 (d,J = 23.6 Hz, 0.3 H), 6.41 (d,J = 23.6 Hz, 0.7 H), 4.99-4.92 (與H2 O重疊, m, 1H), 4.60.4.40 (m, 2H), 4.93 (lm, 6H), 2.00 (m, 2H), 1.32-1.19 (m, 12H)。31 P NMR (121 MHz, CD3 OD)δ 4.15 (s), 4.01 (s)。C27 H37 F2 N7 O7 P [M+H]+ 之MS (ESI)m /z 計算值640.2；實驗值640.2。i) N-甲基-環丙胺• HCl，Et3 N，EtOH，100℃；ii) I2 ，PPh3 ，咪唑，THF；iii) MeONa，MeOH，60℃ ；iv) TMSCI，吡啶，0℃隨後異丁醯氯；v) Et3 N.3HF，NIS，MeCN，-20℃；vi) BzONa，DMSO，100℃；vii) MeNH2 ，EtOH，75℃；viii) CbzCI，DMAP，DCM，0℃；ix) ((R.S)-(五氟苯氧基)-苯氧基-磷醯基)-L-丙胺酸異丙酯，DBU，THF；x) H2 ，Pd-C，EtOH(2R,3R,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (42) 。 向化合物1 (3.0 g，5.7 mmol)於EtOH (60 mL)中之溶液中添加N -甲基-環丙胺鹽酸鹽(1.2 g，11.4 mmol)。將反應混合物在100℃下於密封容器中加熱3 h，冷卻至RT且添加30% NH4 OH (30 mL)。將反應混合物在80℃下於密封容器中加熱15 h，且冷卻至RT。藉由管柱層析(矽膠，DCM/MeOH 100:0至90:10)純化殘餘物。獲得呈白色固體狀之產物42 (1.9 g，94%)。(2R,3R,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -2-( 碘甲基 )-4- 甲基四氫呋喃 -3- 醇 (43) 。 向化合物42 (1.86 g，5.28 mmol)於無水THF (35 mL)中之溶液中添加三苯膦(3.32 g，12.68 mmol)及咪唑(862 mg，12.68 mmol)。隨後，逐滴添加碘(2.57 g，10.1 mmol)於無水THF (15 mL)中之溶液。在RT下攪拌混合物3 h。溶液隨後經矽藻土過濾，且濃縮。含有43 之深色殘餘物按原樣用於下一步驟。(3R,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-4- 氟 -4- 甲基 -2- 亞甲基四氫呋喃 -3- 醇 (44) 。 向43 於MeOH (50 mL)中之溶液中添加MeONa (2.85 g，52.8 mmol)。將反應混合物在60℃下加熱15 h，且隨後冷卻至RT且濃縮。添加EtOAc (100 mL)且用NH4 Cl飽和水溶液(80 mL)及鹽水(80 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈黃色固體狀之產物44 (0.57 g，經2個步驟產率32%)。 N -(6-( 環丙基 ( 甲基 ) 胺基 )-9-((2R,3R,4R)-3- 氟 -4- 羥基 -3- 甲基 -5- 亞甲基四氫呋喃 -2- 基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (45) 。 在0℃下向44 (560 mg，1.67 mmol)於無水吡啶(10 mL)中之溶液中逐滴添加氯三甲基矽烷(530 µL，4.19 mmol)。在0℃下攪拌反應混合物10分鐘，且隨後逐滴添加異丁醯氯(350 µL，3.35 mmol)。在RT下攪拌橙色溶液3 h。在冷卻至0℃後，藉由添加H2 O (2 mL)及30% NH4 OH (3 mL)淬滅反應。隨後在0℃下攪拌混合物1 h。添加EtOAc (50 mL)且用NH4 Cl飽和水溶液(40 mL)及鹽水(40 mL)洗滌溶液。有機物經無水Na2 SO4 乾燥且濃縮。使殘餘物與甲苯(2 × 50 mL)一起共蒸發且藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化。獲得呈白色固體狀之產物45 (505 mg，產率75%)。 N -(9-((2R,3R,4S,5R)-3,5- 二氟 -4- 羥基 -5-( 碘甲基 )-3- 甲基四氫呋喃 -2- 基 )-6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -2- 基 ) 異丁醯胺 (46) 。 向45 (359 mg，0.89 mmol)於無水MeCN (15 mL)中之溶液中添加Et3 N.3HF (175 µL，1.07 mmol)。在-20℃下經45分鐘逐滴添加N -碘丁二醯亞胺(280 mg，1.24 mmol)於無水MeCN (15 mL)中之溶液。在0℃下攪拌所得橙色溶液2 h，且在RT下攪拌1 h。反應隨後用EtOAc (50 mL)稀釋且藉由添加(1:1) NaHCO3 /Na2 S2 O3 飽和水溶液(30 mL)淬滅。分離各相且將有機層用鹽水(40 mL)洗滌、經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物46 (278 mg，產率57%)。苯甲酸 ((2S,3S,4R,5R)-5-(6-( 環丙基 ( 甲基 ) 胺基 )-2- 異丁醯胺 -9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲酯 (47) 。 . 向46 (278 mg，0.51 mmol)於無水DMSO (25 mL)中之溶液中添加苯甲酸鈉(1.09 g，7.65 mmol)。在100℃下攪拌所得乳白色懸浮液3天。隨後將混合物冷卻，使其分配於H2 O (460 mL)與EtOAc (80 mL)之間，且分離各相。用EtOAc (3 × 50 mL)反萃取水層。用NH4 Cl飽和水溶液(2 × 80 mL)及鹽水(80 mL)洗滌經合併之有機物。有機溶液經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈灰白色固體狀之產物47 (222 mg，產率80%)。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (48) 。 在80℃下將密封容器中之47 (220 mg，0.40 mmol)於甲胺(33%於EtOH中) (20 mL)中之溶液攪拌20 h。隨後使混合物冷卻且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈白色固體狀之產物48 (118 mg，產率79%)。1 H NMR (300 MHz, CD3 OD)δ 8.00 (s, 1H), 6.45 (d,J = 12.6 Hz, 1H), 4.66 (m, 1H), 3.86 (m, 2H), 3.32 (與MeOH重疊, m, 3H), 3.15 (m, 1H), 1.22 (d,J = 16.8 Hz, 3H), 0.92 (m, 2H), 0.72 (m, 2H)。C15 H21 F2 N6 O3 [M+H]+ 之MS (ESI)m/z 計算值371.2；實驗值371.2。(2S,3S,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 基苯甲基碳酸酯 (49) 。 在0℃下向48 (38 mg，0.10 mmol)及DMAP (13 mg，0.11 mmol)於無水DCM (2 mL)中之溶液中添加氯甲酸苯甲酯(17 µL，0.12 mmol)。將反應混合物在RT下攪拌3 h且用DCM (5 mL)稀釋。溶液用H2 O (5 mL)、鹽水(5 mL)洗滌，經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，PE/EtOAc 0至100%)純化殘餘物。獲得呈白色固體狀之產物49 (35 mg，產率68%)。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-3-((( 苯甲氧基 ) 羰基 ) 氧基 )-2,4- 二氟 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (50) 。 在0℃下向化合物49 (35 mg，0.07 mmol)及((R ,S )-(五氟苯氧基)-苯氧基-磷醯基)-L -丙胺酸異丙酯(50 mg，0.11 mmol)於無水THF (3 mL)中之溶液中逐滴添加DBU (21 µL，0.14 mmol)。在RT下攪拌反應混合物16 h。隨後用EtOAc (6 mL)及NH4 Cl飽和水溶液(4 mL)稀釋溶液。分離各相且用EtOAc (3 × 3 mL)反萃取水層。經合併之有機物用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且濃縮。含有產物50 之殘餘物按原樣用於下一步驟。(2S)-2-(((((2S,3S,4R,5R)-5-(2- 胺基 -6-( 環丙基 ( 甲基 ) 胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -3- 羥基 -4- 甲基四氫呋喃 -2- 基 ) 甲氧基 )( 苯氧基 ) 磷醯基 ) 胺基 ) 丙酸異丙酯 (51) 。 向含有化合物50 之混合物於EtOH (3 mL)中之溶液中添加鈀(10%/木炭) (6 mg)。用氫氣沖洗燒瓶，且在RT下於氫氣氛圍下攪拌懸浮液3 h。混合物隨後經矽藻土過濾，且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)且隨後藉由逆相管柱層析(C-18矽膠，H2 O/MeOH 100:0至0:100)純化殘餘物。獲得呈白色固體狀之產物51 (13 mg，經2個步驟29%)。1 H NMR (300 MHz, CD3 OD)δ 7.79 (m, 1H), 7.34-7.14 (m, 5H), 6.43 (d,J = 17.4 Hz)及6.41 (d,J = 18.0 Hz, 1H), 4.95-4.86 (與H2 O重疊, m, 1H), 4.63-4.52 (m, 1H), 4.47-4.34 (m, 1H), 3.96-3.85 (m, 1H), 3.32-3.30 (與MeOH重疊, m, 4H), 3.16-3.07 (m, 1H), 1.32-1.18 (m, 12H), 0.92 (m, 2H), 0.71 (m, 2H)。31 P NMR (121 MHz, CD3 OD)δ 4.16 (s), 4.05 (s)。C27 H37 F2 N7 O7 P [M+H]+ 之MS (ESI)m /z 計算值640.2；實驗值640.4。i) tBuONO，吡啶• HF，吡啶，-15℃(2S,3S,4R,5R)-5-(2- 氟 -6-( 二甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (52) 。 將8 (80 mg，0.23 mmol)於無水吡啶(500 µL)中之溶液冷卻至-15℃，添加氫氟化吡啶(300 µL)。隨後，經5 min逐滴添加亞硝酸第三丁酯(61 µL，0.46 mmol)。將混合物在10℃下攪拌4 h且藉由添加CaCO3 (800 mg)於H2 O (2 mL)中之懸浮液淬滅。將所得懸浮液在RT下攪拌15 min且用EtOAc (5 × 5 mL)萃取。經合併之有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈灰白色固體狀之產物52 (52 mg，產率65%)。1 H NMR (300 MHz, CD3 OD)δ 8.25 (s, 1H), 6.48 (d,J = 16.4 Hz, 1H), 4.59 (dd,J = 24.8, 20.0 Hz, 1H), 3.90-3.82 (m, 2H), 3.74 (br s, 3H), 3.27 (br s, 3H), 1.20 (d,J = 22.4 Hz, 3H)。C13 H17 F3 N5 O3 [M+H]+ 之MS (ESI)m /z 計算值348.1；實驗值348.2。i) tBuONO，吡啶• HF，吡啶，-15℃(2S,3S,4R,5R)-5-(2- 氟 -6-( 甲胺基 )-9H- 嘌呤 -9- 基 )-2,4- 二氟 -2-( 羥甲基 )-4- 甲基四氫呋喃 -3- 醇 (53) 。 將18 (70 mg，0.21 mmol)於無水吡啶(500 µL)中之溶液冷卻至-15℃，添加氫氟化吡啶(280 µL)。隨後，經5 min逐滴添加亞硝酸第三丁酯(57 µL，0.42 mmol)。將混合物在10℃下攪拌4 h且藉由添加CaCO3 (800 mg)於H2 O (2 mL)中之懸浮液淬滅。將所得懸浮液在RT下攪拌15 min且用EtOAc (5 × 5 mL)萃取。經合併之有機物經無水Na2 SO4 乾燥且濃縮。藉由管柱層析(矽膠，DCM/MeOH 0至10%)純化殘餘物。獲得呈灰白色固體狀之產物53 (43 mg，產率62%)。1 H NMR (300 MHz, CD3 OD)δ 8.26 (s, 1H), 6.45 (d,J = 16.5 Hz, 1H), 4.61 (m, 1H), 3.86 (m, 2H), 3.06 (s, 3H), 1.21 (d,J = 22.2 Hz, 3H)。C12 H15 F3 N5 O3 [M+H]+ 之MS (ESI)m /z 計算值 334.1；實驗值334.2。中間物 1 之合成 流程 在-20℃下向1a (111 g，300 mmol)於甲苯(200 mL)中之懸浮液中添加NaAlH2 (OCH2 CH2 OCH3 )2 (81 mL，300 mmol)，且攪拌混合物20分鐘。TLC分析指示起始材料耗盡。將反應混合物傾入經冷卻之HCl水溶液(1M，330 mL)中。經分離之有機層用水、鹽水洗滌且濃縮。藉由管柱層析(EtOAc:PE，1:8至1:4)純化粗產物以得到呈油狀物之粗1b (80 g)。將粗1b 溶解於MeOH (300 mL)及H2 O (1 mL)中，且在產物沈澱時攪拌溶液1 h。過濾後，乾燥濾餅，得到呈灰白色固體狀之1a 。向1b (75 g，185 mmol)於MeCN (20 mL)中之溶液中添加PPh3 (120 g，455 mmol)。將CBr4 (120 g，361 mmol)逐份添加至混合物中(溫度保持在-20℃以下)。在RT下攪拌1 h後，TLC指示起始材料耗盡。添加水(20 mL)，且攪拌混合物5分鐘。過濾後，用MeOH濕磨濾餅，得到1c (66 g，75%)。向2-胺基-6-氯嘌呤(69 g，414 mmol)於t -BuOH (600 mL)中之懸浮液中添加t -BuOK (46 g)。隨後在50℃下添加MeCN及T384-0 (65 g，138 mmol)。在60-65℃下攪拌20 h後，TLC指示起始材料耗盡。將混合物冷卻至RT且過濾後，使用濃HCl溶液將濾液調節至pH=7。過濾且濃縮混合物。藉由管柱層析(CH2 Cl2 )純化殘餘物，得到1 (35 g)。附錄 生物資料 實例 X. 檢定方法及生物資料 將含兩個非順反子(discistronic) HCV基因型1b螢光素酶報導複製子之Huh-7 luc/neo ET細胞接種在7.5 × 103 個細胞/毫升兩個重複96孔板上以用於平行測定抗病毒劑功效(EC50 )及細胞毒性(TC50 )。在添加化合物之前培養板24小時。將測試物品(100.0 μM之高測試濃度或1.0 μM之高測試濃度)及人類干擾素-α2b(高測試10.0 U/ml)之六個系列半對數連續稀釋液在細胞培養基中製備，且添加至用於各稀釋液之三個重複孔中的經培養之細胞中。測試板中之六個孔僅接受介質作為未經處理之對照組。在化合物存在下培養72小時後，板中之一者藉由用XTT染色用於測定細胞毒性，且另一者藉由測定螢光素酶報導活性而用於抗病毒劑功效。收集細胞毒性及功效資料且導入定製Excel工作手冊以測定TC50 及EC50 值。表XXX. 所測試之化合物之複製子檢定結果。 如本文所用，術語約及大約應解釋為包括在所述值之5%內之任何值。此外，關於值範圍引述術語約及大約應解釋為包括所述範圍之上限及下限。如本文所用，術語第一、第二、第三及其類似物應解釋為唯一地識別要素且不暗示或限制要素或步驟之任何特定排序。 濃度、量及其他數值資料可在本文中以範圍格式(例如，約5%至約20%)存在。應理解，該範圍格式僅係出於便利及簡潔目的而使用，且因此應以靈活方式解釋為不僅包括如該範圍之界限所明確引述之數值，且亦包括該範圍內所涵蓋之所有個別數值或子範圍，除非另外指示，否則如同各數值及子範圍經明確引述一樣。舉例而言，約5%至約20%之範圍應解釋為包括數值，諸如但不限於5%、5.5%、9.7%、10.3%、15%等，及子範圍，諸如但不限於5%至10%、10%至15%、8.9%至18.9%等。 雖然已僅以本發明之形式中的一些來展示或描述本發明，但熟習此項技術者將清楚本發明並不因此受到限制而是在不背離本發明之精神及範疇的情況下容許各種改變。此外，應瞭解，本發明所展示及描述之形式應視為目前之較佳實施例。可對各處理步驟及每一處理步驟做出如將對受益於本發明之熟習此項技術者顯而易見的各種改變及變化。期望將以下申請專利範圍解釋為涵蓋所有該等改變及變化，且因此應認為本說明書具有說明性而非限制性意義。此外，期望將隨附申請專利範圍視為包括替代性實施例。The present invention includes compounds, methods, and compositions for treating HCV infection in humans and other host animals or exposed to humans and other host animals, including administering an effective amount of a pharmaceutically acceptable carrier, as appropriate A compound of formula IX, or a pharmaceutically acceptable salt or prodrug thereof, as described herein. The compounds of the invention have antiviral activity or are metabolized to exhibit the activity of the compound. The compounds and compositions are also useful in the treatment of conditions associated with HCV viral exposure or due to HCV viral exposure. For example, active compounds can be used to treat HCV antibody-positive and HCV antigen-positive conditions, viral-based chronic hepatitis, advanced hepatitis C, cirrhosis, acute hepatitis C, fulminant hepatitis C, chronic persistent hepatitis C And liver cancer based on fatigue caused by anti-HCV. In one embodiment, the compound or a formulation comprising the compound may also be used prophylactically to prevent or slow the progression of clinical disease in an individual who is HCV antibody or HCV antigen positive or has been exposed to the hepatitis C virus. In particular, it has been found that β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N as described below6 - 5'-stabilized phosphate prodrug or derivative of methyl-2,6-diaminopurine nucleotide and β-D-2'-deoxy-2'-α-fluoro-2' -β-methyl-4'-fluoro-N6 - dimethyl-2,6-diaminopurine nucleotides and other β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N6 -Substituted-2,6-diaminopurine nucleotide, β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N2 ,N6 -disubstituted-2,6-diaminopurine nucleotides and β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-2-substituted- N6 The -substituted-aminopurine nucleotide has high activity against HCV. Regardless of the number of antiviral nucleoside literature and patent applications, β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N has not been specifically disclosed.6 5'-stabilized phosphate derivative of methyl-2,6-diaminopurine nucleotide and β-D-2'-deoxy-2'-α-fluoro-2'-β- Methyl-4'-fluoro-N6 - dimethyl-2,6-diaminopurine nucleotides and other β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N6 -Substituted-2,6-diaminopurine nucleotides and β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-2-substituted-N6 - Substituted-aminopurine nucleotides. Unless otherwise specified, the compounds described herein are provided in a β-D-configuration. In an alternative embodiment, the compound can be provided in a β-L-configuration. Likewise, any substituent present to palmity can be provided in racemic, enantiomeric, diastereomeric forms, or any mixture thereof. Used as an R in amino phosphates, thioamino phosphates or other stabilized phosphorus prodrugs in which phosphorus exhibits palmarity4 In the case of a stabilized phosphate prodrug, it can be provided as a R or S-p-Phosphorus derivative or a mixture thereof, including a racemic mixture. The amino acid of the amino phosphate or thioamino phosphate may be in a D-configuration or an L-configuration or a mixture thereof, including a racemic mixture. Combinations of all such stereo configurations are included in the invention described herein. The invention includes the following features: (a) a compound of formula IX as described herein, and pharmaceutically acceptable salts and prodrugs thereof; (b) for use in the treatment or prevention of hepatitis C virus infection as described herein Formula IX and pharmaceutically acceptable salts and prodrugs thereof; (c) Use of Formula IX and pharmaceutically acceptable salts and prodrugs thereof for the manufacture of a medicament for the treatment of hepatitis C virus infection; A method for the manufacture of a medicament for the therapeutic use of a hepatitis C virus infection, characterized in that a compound of formula IX as described herein is used in the manufacture; (e) Formula IX comprising a therapeutically effective amount of host a pharmaceutical formulation of a compound or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent; (f) Formula IX as described herein is substantiallydoes not exist The compoundStereoisomer And under substantially isolation from other chemical entities; and (g) a method for preparing a therapeutic product comprising an effective amount of a compound of Formulas I-X as described herein.I. The invention β -D-2'- Deoxygenation -2'- α - fluorine -2'- β -C- Replace -4'- fluorine -N 6 - Replace -2,6- Diamine fluorene nucleotides, β -D-2'- Deoxygenation -2'- α - fluorine -2'- β -C- Replace -4'- fluorine -N 2 ,N 6 - Disubstituted -2,6- Diamine fluorene nucleotide And β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-2-substituted-N6 -Substituted-Aminopurine nucleotides The active compounds of the invention are depicted, for example, in Formula I, which may be provided in a pharmaceutically acceptable composition, salt or prodrug thereof:Formula I where: R1 For C1 -C5 Alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl and pentyl) or -(C)0 -C2 Alkyl) (C3 -C6 Cycloalkyl); R2 For hydrogen, C1 -C5 Alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl and pentyl), CHF2 , CH2 F, CF3 ,-(C0 -C2 Alkyl) (C3 -C6 Cycloalkyl), -C(O)R3C ,-(C0 -C2 Alkyl)(aryl), -(C0 -C2 Alkyl) (heterocyclic), -(C0 -C2 Alkyl)(heteroaryl); or R1 And R2 A heterocyclic ring can be formed along with the nitrogen bonded thereto; R3 For hydrogen,, diphosphate, triphosphate, optionally substituted carbonyl bonded amino acid or -C(O)R3C ; R3A Can be selected from O- , OH, optionally an -O-substituted aryl group, optionally an -O-substituted heteroaryl group or an optionally substituted heterocyclic group;3B Can be selected from O- , OH, optionally substituted N-linked amino acid or optionally substituted N-linked amino acid ester; R3C Is alkyl, alkenyl, alkynyl, -(C0 -C2 )(cycloalkyl), -(C0 -C2 ) (heterocyclic), - (C0 -C2 )(aryl), -(C0 -C2 (heteroaryl), -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(C0 -C2 )(cycloalkyl), -O-(C0 -C2 ) (heterocyclic), -O-(C0 -C2 )(aryl), -O-(C0 -C2 (heteroaryl), -S-alkyl, -S-alkenyl, -S-alkynyl, -S-(C0 -C2 )(cycloalkyl), -S-(C0 -C2 ) (heterocyclic), -S-(C0 -C2 ) (aryl) or -S-(C0 -C2 (heteroaryl), each of which may be substituted as appropriate; R4 Is a monophosphate, diphosphate, triphosphate or stabilized phosphate prodrug, including but not limited to amino phosphate, thioamino phosphate or metabolite to monophosphate in a host human or animal , any other part of the diphosphate or triphosphate; or R3 And R4 Together with its oxygen bonded to form a 3',5'-cyclic prodrug; R12 For CH3 , CH2 F, CHF2 , CF3 Or ethynyl. The stabilized phosphate prodrug is any moiety that can deliver a monophosphate, diphosphate or triphosphate. In another embodiment, the compound of Formula Ia is disclosed:Formula Ia where: R1 , R2 , R3 And R4 As defined above. In another embodiment, the compound of Formula Ib is disclosed:Formula Ib where: R1 , R2 , R3 And R4 As defined above. In one embodiment, the compound of Formula II is disclosed:Formula II where: R5 For hydrogen, C1 -C5 Alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl and pentyl) or -(C)0 -C2 Alkyl) (C3 -C6 Cycloalkyl); R6 For C1 -C5 Alkyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl and pentyl), -(C0 -C2 Alkyl) (C3 -C6 Cycloalkyl), -(C0-6 Alkyl)(aryl), -(C0-6 Alkyl)(heteroaryl), -(C0-6 Alkyl) (heterocyclic) or -C(O)R3C ; R1 , R2 , R3 , R4 And R12 As defined above. In another embodiment, the compound of Formula IIa is disclosed:Formula IIa where: R1 , R2 , R3 , R4 , R5 And R6 As defined above. In another embodiment, the compound of Formula IIb is disclosed:Formula IIb where: R1 , R2 , R3 , R4 , R5 And R6 As defined above. In a typical embodiment, the compound is a beta-D isomer of the corresponding nucleoside (i.e., in a naturally occurring configuration). In an alternative configuration, the compound is provided as a beta-L isomer. The compound typically has at least 90% free of the opposite enantiomer and may be at least 98%, 99% or even 100% free of the opposite enantiomer. Unless otherwise stated, at least 90% of the compounds are free of the opposite enantiomer. In another embodiment, the compound is according to Formula III:Formula III where: R7 For hydrogen, C1-6 Alkyl; C3-7 Cycloalkyl; heteroaryl, heterocyclic or aryl including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl is optionally substituted as follows: C1-6 Alkyl, C2-6 Alkenyl, C2-6 Alkynyl, C1-6 Alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 Haloalkyl, -N(R7' )2 , C1-6 Amidoxime, NHSO2 C1-6 Alkyl, -SO2 N(R7' )2 , COR7" And -SO2 C1-6 Alkyl; (R7' Independently hydrogen or C1-6 Alkyl; R7" For -OR11 Or -N(R7 )2 ); R8 For hydrogen, C1-6 Alkyl, or R9a Or R9b And R8 Common for (CH2 )n , thereby forming a cyclic ring including adjacent N atoms and C atoms; wherein n is 2 to 4; R9a And R9b (i) independently selected from hydrogen, C1-6 Alkyl, cycloalkyl, -(CH2 )c (NR9' )2 , C1-6 Hydroxyalkyl, -CH2 SH, -(CH2 )2 S(O)(Me), -(CH2 )3 NHC(=NH)NH2 , (lH-indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2 )c COR9" , aryl and aryl (C1-3 The alkyl)-, aryl group may optionally be substituted with a group selected from the group consisting of hydroxyl, C1-6 Alkyl, C1-6 Alkoxy, halogen, nitro and cyano; (ii) R9a And R9b Both are C1-6 Alkyl; (iii) R9a And R9b Common for (CH2 )r To form a spiral ring; (iv) R9a Is hydrogen and R9b And R8 Common for (CH2 )n , thereby forming a cyclic ring including adjacent N atoms and C atoms; (v) R9b Is hydrogen and R9a And R8 Common for (CH2 )n , thereby forming a cyclic ring including adjacent N atoms and C atoms, wherein c is 1 to 6, n is 2 to 4, and r is 2 to 5 and wherein R9' Independently hydrogen or C1-6 Alkyl and R9" For -OR11 Or -N(R11' )2 ;(vi) R9a Is hydrogen and R9b For hydrogen, CH3 , CH2 CH3 , CH (CH3 )2 , CH2 CH(CH3 )2 , CH (CH3 )CH2 CH3 , CH2 Ph, CH2 -吲哚-3-yl, -CH2 CH2 SCH3 , CH2 CO2 H, CH2 C(O)NH2 , CH2 CH2 COOH, CH2 CH2 C(O)NH2 , CH2 CH2 CH2 CH2 NH2 , -CH2 CH2 CH2 NHC(NH)NH2 , CH2 -imidazol-4-yl, CH2 OH, CH(OH)CH3 , CH2 ((4'-OH)-Ph), CH2 SH or a lower carbon cycloalkyl group; or (vii) R9a For CH3 , CH2 CH3 , CH (CH3 )2 , CH2 CH(CH3 )2 , CH (CH3 )CH2 CH3 , CH2 Ph, CH2 -吲哚-3-yl, -CH2 CH2 SCH3 , CH2 CO2 H, CH2 C(O)NH2 , CH2 CH2 COOH, CH2 CH2 C(O)NH2 , CH2 CH2 CH2 CH2 NH2 , -CH2 CH2 CH2 NHC(NH)NH2 , CH2 -imidazol-4-yl, CH2 OH, CH(OH)CH3 , CH2 ((4'-OH)-Ph), CH2 SH or low carbon cycloalkyl, and R9b For hydrogen; R10 C for hydrogen, optionally substituted with alkoxy, di(lower alkyl)-amine or halogen1-6 Alkyl; C1-6 Haloalkyl, (C0 -C2 ) (C3-7 Cycloalkyl), (C0 -C2 (heterocycloalkyl), amino fluorenyl, (C0 -C2 ) (aryl), such as (C0 -C2 ) (phenyl), (C0 -C2 ) (heteroaryl), such as (C0 -C2 ) (pyridyl), substituted (C0 -C2 ) (aryl) or substituted (C0 -C2 )(heteroaryl); R11 Replaced by C as appropriate1-6 Alkyl, optionally substituted cycloalkyl; optionally substituted C2-6 Alkynyl, as appropriate, substituted C2-6 Alkenyl or optionally substituted thiol including, but not limited to, C(O)(C)1-6 Alkyl); and R1 , R2 , R3 And R12 As defined above. In one embodiment, the compound of Formula IV is disclosed:Formula IV where the variable R is described1 , R2 , R3 , R7 , R8 , R9a , R9b And R10 . In one embodiment, a compound of Formula V is disclosed:Formula V where the variable R is described1 , R2 , R3 , R7 , R8 , R9a , R9b And R10 . In one embodiment, the compound is according to Formula VI:Formula VI where: R1 , R2 , R3 , R5 , R6 , R7 , R8 , R9a , R9b , R10 And R12 As defined above. In one embodiment, the compound of formula VII is disclosed:Formula VII where the variable R is described1 , R2 , R3 , R5 , R6 , R7 , R8 , R9a , R9b And R10 . In one embodiment, the compound of formula VIII is disclosed:Formula VIII where the variable R is described1 , R2 , R3 , R5 , R6 , R7 , R8 , R9a , R9b And R10 . In one embodiment, a compound of Formula IX is disclosed:Formula IX where the variable R is described1 , R2 , R3 , R4 And R' 5 For Cl, Br, F, N3 , -NHOCH3, -ONHC(=O)OCH3, CN, CONH2 , SO2 NH2 And CF3 , or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Formula X is disclosed:The variable R is described in this paper.1 , R2 , R3 , R4 And R' 5 For Cl, Br, F, N3 , -NHOCH3, -ONHC(=O)OCH3, CN, CONH2 , SO2 NH2 And CF3 , or a pharmaceutically acceptable salt thereof. In an alternative embodiment, compounds, methods, and compositions are provided to treat a host infected or exposed to hepatitis C virus.β-D-2 ' - Deoxygenation -2 ' -α- fluorine -2 ' -β-C- Replace -4 ' - fluorine -N 6 - Replace -2,6- Metabolism of diamine-based purine nucleotides β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N6 - Metabolism of methyl-2,6-diaminopurine nucleoside phosphates involves the production of 5'-monophosphates and subsequent assimilation of N6 -Methyl-2,6-diaminopurine to produce β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-guanosine 5'-monophosphate. The monophosphate is then further assimilated into the active species; 5'-triphosphate. β-D-2'-deoxy-2'-α-fluoro-2'-β-methyl-4'-fluoro-N6 The metabolic pathway of methyl-2,6-diaminopurine nucleoside phosphate is illustrated in Scheme 1 below.Process 1Stabilized phosphate prodrug The stabilized phosphate prodrug is part of a monophosphate, diphosphate or triphosphate that can be delivered in vivo. For example, McGuigan has disclosed amine phosphates in the following U.S. patents: 8,933,053; 8,759,318; 8,658,616; 8,263,575; 8,119,779; 7,951,787 and 7,115,590. Thioamino phosphates are disclosed in U.S. Patent Nos. 8,895,723 and 8,871,737. Cyclic nucleotides are also disclosed in U.S. Patent No. 8,772,474. Cyclic amino phosphates and amino phosphate/SATE derivatives are disclosed in WO 2013/177219 by Idenix. The substituted carbonyloxymethylamino phosphate compounds are also disclosed in WO 2013/039920 by Idenix. Hostetler has disclosed lipid phosphate prodrugs, see for example US 7,517,858. Hostetler has also disclosed lipid conjugates of phosphonate prodrugs, see, for example, US 8,889,658; 8,846,643; 8,710,030; 8,309,565; 8,008,308; and 7,790,703. The sphingosine amino alcohol and lipid derivatives are disclosed in WO 2014/124430 by Emory University. The purine nucleoside monophosphate prodrug has been disclosed by RFS Pharma in WO 2010/091386. HepDirectTM The technique is disclosed in the article "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver", (J. Am. Chem Soc. 126, 5154-5163 (2004). Additional phosphate prodrugs include, but are not limited to, phosphates, including 3', 5'-cyclic phosphates of CycloSAL, SATE derivatives (S-mercapto-2 sulfur Ester), and DTE (dithiodiethyl) prodrugs. For a literature review revealing non-limiting examples, see: A. Ray and K. Hostetler, "Application of kinase bypass strategies to nucleoside antivirals", Antiviral Research (2011 277-291; M. Sofia, "Nucleotide prodrugs for HCV therapy", Antiviral Chemistry and Chemotherapy 2011; 22-23-49; and S. Peyrottes et al., "SATE Pronucleotide Approaches: An Overview", Mini Reviews in Medicinal Chemistry 2004, 4, 395. In one embodiment, the 5'-prodrugs described in any of these patent applications or documents can be used for the R of the compound present.4 position.Example In a particular embodiment: (i) in Formula Ia, R1 Is methyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (ii) in Formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (iii) in formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (iv) in formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (v) in formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (vi) in formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (vii) in formula Ia, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (viii) in formula Ia, R1 Is methyl, R2 Is methyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (ix) in Formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (x) in formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is an amino phosphate; (xi) in formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xii) in formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a monophosphate; (xiii) in formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a diphosphate; (xiv) in formula Ia, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a triphosphate; (xv) in formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (xvi) in formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xvii) in Formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is an amino phosphate; (xviii) in formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xix) in Formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a monophosphate; (xx) in Formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is methyl, and R4 Is a diphosphate; (xxi) in Formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a triphosphate; (xxii) in formula Ia, R1 Is ethyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (xxiii) in Formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xxiv) in Formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (xxv) in formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xxvi) in formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (xxvii) in Formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (xxviii) in formula Ia, R1 Is ethyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (xxix) in Formula Ia, R1 Is propyl, R2 For hydrogen, R3 For hydrogen, R4 Is a stabilized phosphate prodrug; (xxx) in formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xxxi) in Formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (xxxii) in formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xxxiii) in formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (xxxiv) in Formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (xxxv) in formula Ia, R1 Is propyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (xxxvi) in formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (xxxvii) in Formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xxxviii) in Formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (xxxix) in formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xl) in formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (xli) in formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (xlii) in formula Ia, R1 Is isopropyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (xliii) in formula Ia, R1 Is ethyl, R2 Is ethyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (xliv) in Formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xlv) in Formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is an amino phosphate; (xlvi) in formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xlvii) in formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a monophosphate; (xlviii) in formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a diphosphate; (xlix) in Formula Ia, R1 Is ethyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a triphosphate; (l) in formula Ia, R1 Is methyl, R2 Is propyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (li) in formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (lii) in Formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 Is an amino phosphate; (liii) in formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (liv) in formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 Is a monophosphate; (lv) in formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 Is a diphosphate; (lvi) in formula Ia, R1 Is methyl, R2 Is propyl, R3 Is hydrogen, and R4 Is a triphosphate; (lvii) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 For hydrogen, R4 a stabilized phosphate prodrug; (lviii) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (lix) in Formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is an amino phosphate; (lx) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a thioamino phosphate; (lxi) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a monophosphate; (lxii) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a diphosphate; (lxiii) in formula Ia, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a triphosphate; (lxiv) in formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (lxv) in Formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (lxvi) in Formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (lxvii) in formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (lxviii) in formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (lxix) in Formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (lxx) in formula Ia, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (lxxi) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (lxxii) in Formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (lxxiii) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is an amino phosphate; (lxxiv) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (lxxv) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a monophosphate; (lxxvi) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a diphosphate; (lxxvii) in formula Ia, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a triphosphate; (lxxviii) in formula Ia, R1 Is methyl, R2 Is ethyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (lxxix) in Formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a stabilized phosphorothioate prodrug; (lxxx) in Formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is an amino phosphate; (lxxxi) in formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (lxxxii) in formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a monophosphate; (lxxxiii) in formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a diphosphate; (lxxxiv) in formula Ia, R1 Is methyl, R2 Is ethyl, R3 Is hydrogen, and R4 Is a triphosphate; (lxxxv) in formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a stabilized phosphate prodrug; (lxxxvi) in formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (lxxxvii) in Formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (lxxxviii) in formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (lxxxix) in Formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (xc) in formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (xci) in formula Ia, R1 Is cyclobutyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (xcii) in formula Ib, R1 Is methyl, R2 Is methyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (xciii) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (xciv) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is an amino phosphate; (xcv) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (xcvi) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a monophosphate; (xcvii) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a diphosphate; (xcviii) in formula Ib, R1 Is methyl, R2 Is methyl, R3 Is hydrogen, and R4 Is a triphosphate; (xcix) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (c) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (ci) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (cii) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (ciii) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (civ) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (cv) in formula Ib, R1 Is methyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (cvi) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 For hydrogen, R4 a stabilized phosphate prodrug; (cvii) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (cviii) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is an amino phosphate; (cix) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a thioamino phosphate; (cx) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a monophosphate; (cxi) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a diphosphate; (cxii) in formula Ib, R1 Is cyclopentyl, R2 For hydrogen, R3 Is hydrogen, and R4 Is a triphosphate; (cxiii) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 a stabilized phosphate prodrug; (cxiv) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (cxv) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is an amino phosphate; (cxvi) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a thioamino phosphate; (cxvii) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a monophosphate; (cxviii) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a diphosphate; (cxix) in formula Ib, R1 And R2 Together with the nitrogen bonded thereto to form a 5-membered heterocyclic ring, R3 Is hydrogen, and R4 Is a triphosphate; (cxx) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (cxxi) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (cxxii) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is an amino phosphate; (cxxiii) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (cxxiv) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a monophosphate; (cxxv) in formula Ib, R1 Is methyl, R2 Is cyclopropyl, R3 Is methyl, and R4 Is a diphosphate; (cxxvi) in formula Ia, R1 Is methyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a triphosphate; (cxxvii) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 For hydrogen, R4 a stabilized phosphate prodrug; (cxxviii) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 a stabilized phosphorothioate prodrug; (cxxix) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is an amino phosphate; (cxxx) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a thioamino phosphate; (cxxxi) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a monophosphate; (cxxxii) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a diphosphate; (cxxxiii) in formula Ib, R1 Is cyclopropyl, R2 Is cyclopropyl, R3 Is hydrogen, and R4 Is a triphosphate; in an alternative embodiment of compounds (i) to (cxxxiii), L-nucleosides are used in formula I-X. In an alternative embodiment, Formula I R12 The variable is CH2 F. In an alternative embodiment, Formula I R12 The variable is CHF2 . In an alternative embodiment, Formula I R12 The variable is CF3 . In an alternative embodiment, Formula II R12 The variable is CH2 F. In an alternative embodiment, Formula II R12 The variable is CHF2 . In an alternative embodiment, Formula II R12 The variable is CF3 . In one embodiment, a compound of Formula Ia is provided. Non-limiting examples of compounds of Formula Ia include: . In one embodiment, a thioamino phosphate of Formula Ia is provided. Non-limiting examples of thioamino phosphates of Formula Ia include, but are not limited to: . In one embodiment, a stabilized phosphate prodrug of Formula Ia is provided. Non-limiting examples of stabilized phosphate prodrugs of Formula Ia are described below: . In another embodiment, a compound of Formula Ia is provided. Non-limiting examples of compounds of Formula Ia include: . In one embodiment, a thioamino phosphate of Formula Ia is provided. Non-limiting examples of thioamino phosphates of Formula Ia include, but are not limited to: . In one embodiment, a stabilized phosphate prodrug of Formula Ia is provided. Non-limiting examples of stabilized phosphate prodrugs of Formula Ia are described below: . In one embodiment, a compound of formula II is provided. Non-limiting examples of compounds of Formula II include: . In one embodiment, a compound of formula I is provided. Non-limiting examples of compounds of Formula I include: . In one embodiment, a compound of formula II is provided. Non-limiting examples of compounds of Formula II include: . In one embodiment, a compound of formula IX is provided. Non-limiting examples of compounds of formula IX include: In one embodiment, a compound of formula IX is provided. Non-limiting examples of compounds of formula X include: In one embodiment, R3 For hydrogen andIn one embodiment, R3 Is hydrogen and R4 for. In one embodiment, R3 Is hydrogen and R4 for. In one embodiment, R3 Is hydrogen and R4 for. In one embodiment, R3 Is hydrogen and R4 for.II. definition The following terms are used to describe the invention. Where a term is not specifically defined herein, the term is given by a person of ordinary skill in the context of the application of the term to describe its use in the present invention. The term "pharmaceutically acceptable salts" or "prodrugs" is used throughout the specification to describe 2'-deoxy-2'-alpha-fluoro-2'- which provides the desired active compound after administration to a patient. β-C-substituted-4'-fluoro-N6 - Substituted-2,6-diaminopurine nucleotide or 2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N2 ,N6 - any pharmaceutically acceptable form of a disubstituted-2,6-diaminopurine nucleotide. Examples of pharmaceutically acceptable salts are organic acid addition salts formed from acids which form physiologically acceptable anions such as tosylate, mesylate, acetate, citrate, malonate, tartrate , succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts can also be formed, including sulfates, nitrates, bicarbonates, and carbonates. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid which provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared. "Pharmaceutically acceptable prodrug" refers to a compound that is metabolized (eg, hydrolyzed or oxidized) in a host to form a compound of the invention. Typical examples of prodrugs include compounds having a biolabile protecting group on a functional moiety of the active compound. Prodrugs include oxidative, reductive, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, thiolation, dethiolation, phosphorylation, dephosphorylation Compounds that produce, activate, thioaminyl phosphorylation, dethiocarbamate phosphorylation, amine phosphorylation or deamination phosphorylation to produce the active compound. The compounds of the invention have antiviral activity or metabolism to HCV to exhibit such activity. It can also be 5'-phosphoether lipid, bis-amino phosphate, 3', 5'-cyclic amino phosphate, 3', 5'-cyclic thioamino phosphate, DTE Yoke, mixed amino phosphate-SATE derivative or "SATE" derivative is administered to β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro -N6 - Substituted-2,6-diaminopurine nucleoside. The term "substituted" or "optionally substituted" indicates that the moiety may have at least one additional substituent including, but not limited to, an amine group, a halogen (F, Cl, Br, I), OH, phenyl, benzyl, N.3 , CN, alkyl, including methyl; alkenyl, alkynyl, alkoxy, haloalkyl; including CHF2 , CH2 F and CF3 ;Wait. The term "alkyl" shall mean a straight or branched chain fully saturated hydrocarbon group or alkyl group, as it is, optionally substituted by (for example, halogen, including F). For example, an alkyl group can have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (ie, C1 -C8 Alkyl) 1, 2, 3, 4, 5 or 6 carbon atoms (ie, C1 -C6 Alkyl) or 1 to 4 carbon atoms (ie, C1 -C4 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl, isopentyl, Tripentyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term "alkenyl" refers to a non-aromatic hydrocarbon group containing at least one double bond between adjacent carbon atoms and a structure similar to an alkyl group as otherwise described herein. For example, an alkenyl group can have from 2 to 8 carbon atoms (ie, C2 -C8 Alkenyl), or 2 to 4 carbon atoms (ie, C2 -C4 Alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl or vinyl (-CH=CH)2 ), allyl (-CH)2 CH=CH2 ), 1-butenyl (-C=CH-CH)2 CH3 And 2-butenyl (-CH)2 CH=CHCH2 ). Alkenyl groups can be optionally substituted as described herein. The term "alkynyl" refers to a non-aromatic hydrocarbon group containing a triple bond between at least one adjacent carbon atom and a structure similar to an alkyl group as otherwise described herein. For example, an alkynyl group can have from 2 to 8 carbon atoms (ie, C2 -C8 Alkyne) or 2 to 4 carbon atoms (ie, C2 -C4 Alkynyl). Examples of alkynyl groups include, but are not limited to, acetylenic or ethynyl groups and propargyl groups. An alkynyl group can be optionally substituted as described herein. The term "aryl" or "aromatic" refers in the context to a substituted (as otherwise described herein) or unsubstituted single ring (eg, phenyl or benzyl) or condensed ring (eg, naphthyl, Monovalent aryl groups of indenyl, phenanthryl, etc., and may additionally indicate binding to a compound according to the invention at any available stable position on the ring or as in the chemical structure present. The aryl group can be optionally substituted as described herein. "Cycloalkyl", "carbocyclic" or "carbocyclyl" refers to a saturated (ie, cycloalkyl) or partially unsaturated (eg, cycloalkenyl, cycloalkaned) having from 3 to 7 carbon atoms. Alkenyl, etc.) ring. Monocyclic carbocycles have from 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl , cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl. A heteroaryl ring system is a saturated or unsaturated ring having one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic), including but not limited to imidazole, furyl, pyrrole, furanyl, Thiophene, thiazole, pyridine, pyrimidine, indole, pyrazine, triazole, oxazole or fused ring system, such as hydrazine, quinoline, and the like, which may be optionally substituted as described above. Heteroaryl includes nitrogen-containing heteroaryl such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, anthracene, isoindole, pyridazine , hydrazine, carbazole, quinoline, isoquinoline, quinolizine, pyridazine, naphthyridine, quinoxaline, quinazoline, porphyrin, acridine, imidazopyridine, imidazotriazine, pyrazine-pyridazine, Acridine, phenazin, oxazole, oxazoline, acridine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic a ring such as thiophene and benzothiophene; an oxyaromatic heterocyclic ring such as furan, piperane, cyclopentamidine, benzofuran and isobenzofuran; and two or more selected from the group consisting of nitrogen, sulfur and An aromatic heterocyclic ring of a hetero atom in oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine , pyrazoloxazole, imidazothiazole, thienofuran, furopyrrol, pyridooxazine, furopyridine, furanpyrimidine, thienopyrimidine and oxazole Others, all of the above optionally substituted. The term "heterocycle" refers to a cyclic group containing at least one hetero atom (ie, O, N or S) and may be aromatic (heteroaryl) or non-aromatic. Exemplary non-aromatic heterocyclic groups for use in the present invention include, for example, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, dihydroimidazolyl, pyrazolyl, imidazolidinyl, Polinyl, tetrahydropyranyl, azetidinyl, propylene oxide, oxathiolan, pyridone, 2-pyrrolidone, ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide, and succinimide, and all of the above may be substituted as appropriate. In one embodiment, the term purine or pyrimidine base includes, but is not limited to, adenine, N6 -alkyl hydrazine, N6 - mercapto (wherein the fluorenyl group is -C(O)alkyl, -C(O)(aryl)C0 -C4 Alkyl or -C(O)(C0 -C4 Alkyl)aryl), N6 -Benzyl hydrazine, N6 -halogen hydrazine, N6 - Vinyl 嘌呤, N6 - acetylene 嘌呤, N6 -醯基嘌呤, N6 -Hydroxyalkyl hydrazine, N6 -thioalkyl hydrazine, N2 -alkyl hydrazine, N2 -alkyl-6-mercaptopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercapto Pyrimidine, uracil, 5-halouracil, including 5-fluorouracil, C5 -alkylpyrimidine, C5 -benzylpyrimidine, C5 -halopyrimidine, C5 -vinylpyrimidine, C5 -Alkyne pyrimidine, C5 - mercaptopyrimidine, C5 -Hydroxyalkyl hydrazine, C5 -Aminopyrimidine, C5 -cyanopyrimidine, C5 -Nitropyrimidine, C5 -aminopyrimidine, N2 -alkyl hydrazine, N2 -alkyl-6-mercaptopurine, 5-azacytidine nucleoside, 5-azauracil, triazolopyridyl, imidazopyridyl, pyrrolopyrimidinyl and pyrazolo-pyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, optionally substituted 2,6-diaminopurine and 6-chloropurine. The functional oxygen and nitrogen groups on the base may be protected as needed or as appropriate. Suitable protecting groups are well known to those skilled in the art and include benzyl, trimethyldecyl, dimethylhexyldecyl, tert-butyldimethylalkyl, tert-butyldiphenyl. a decyl group, a trityl group, an alkyl group and a fluorenyl group, such as an ethyl fluorenyl group and a propyl fluorenyl group; a methanesulfonyl group and a p-toluenesulfonyl group. Alternatively, the purine or pyrimidine base may be optionally substituted such that it forms a viable prodrug that can be cleaved in vivo. Examples of suitable substituents include a thiol moiety. The term "mercapto" refers to a moiety wherein a carbonyl moiety, for example, -C(O)alkyl, is selected from alkyl, cycloalkyl, lower alkyl (ie, C).1 -C4 Alkoxyalkyl, including methoxymethyl; aralkyl-including benzyl, aryloxyalkyl- such as phenoxymethyl; aryl, including optionally halogen, C1 -C4 Alkyl or C1 -C4 Alkoxy substituted phenyl. In one embodiment, the term "mercapto" refers to a monophosphate, diphosphate or triphosphate. The term "low carbon number thiol" refers to a moiety wherein the carbonyl moiety is a lower alkyl group (ie, C)1 -C4 ) 醯 base. Formula R14 S(O)2 OR15 The term sulfonate, including R14 , where R14 It is an alkyl group, a haloalkyl group, an aralkyl group or an aryl group. R15 It is an alkyl group, an aryl group or an aralkyl group. The term "amino acid" or "amino acid residue" refers to D- or L-a natural or non-naturally occurring amino acid. Representative amino acids include, but are not limited to, alanine, beta-alanine, arginine, aspartame, aspartic acid, cysteine, cystine, glutamic acid, glutamic acid, glycine Aminic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, valine, serine, threonine, valine, tryptophan or tyramine Acid plus others. The term "nitrogen protecting group" as used herein refers to a moiety that is covalently attached to nitrogen and that is removable and, where appropriate, typically replaced with hydrogen. For example, the nitrogen protecting group can be a group that is removed from the cell by in vivo administration to the host, or it can be removed during the manufacturing process. Suitable nitrogen protecting groups for use in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc. The term "oxygen protecting group" as used herein refers to a moiety that is covalently attached to oxygen and that is removable and, where appropriate, typically replaced with hydrogen. For example, the oxygen protecting group can be a group that is removed from the cell by in vivo administration to the host, or it can be removed during the manufacturing process. Suitable oxygen protecting groups for use in the present invention are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc. Phosphates refer to monophosphates, diphosphates, and triphosphates unless otherwise indicated. The term "phospholamine", "aminophosphate" or "phosphoric acid" is a moiety having a phosphorus bonded to three oxygen groups and an amine which may optionally be substituted. Suitable amine phosphates suitable for use in the present invention by Madela, Karolina and McGuigan in 2012, "Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs",Future Medicinal Chemistry 4(5), pp. 625-650 10:1021/jm300074y and Dominique, McGuigan and Balzarini in 2004, "Aryloxy Phosphoramidate Triesters as Pro-Tides",Mini Reviews in Medicinal Chemistry 4(4), pages 371-381 are described. Additional amine phosphates suitable for use in the present invention are described in U.S. Patent Nos. 5,233,031, 7,115,590, 7,547,704, 7,879,815, 7,888,330, 7,902,202, 7,951,789, 7,964,580, No. 8, 071, 568, No. 8, 148, 349, No. 8, 263, 575, No. 8, 324, 179, No. 8, 334, 270, No. 8, 552, 021, No. 8, 563, 530, No. 8, 580, 765, No. 8,735, 372, No. 8, 759, 318; EP 2,120, 565; EP 1 143 995; 6, 455, 513; Other amino phosphates are described in the nucleoside patents described in the Background. The aminophosphate groups used in the present invention include the following structures: . Other amino phosphates useful in the present invention include the following structures:Where: RP1 a linear, branched or cyclic alkyl group substituted as appropriate, or an optionally substituted aryl, heteroaryl or heterocyclic group or a combination thereof; and RP2 For -NRN1 RN2 a group or a B' group; wherein: RN1 And RN2 Each is independently H, C1-8 Alkyl, (C3 -C7 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl- or (heteroaryl)C0 -C4 Alkyl-; which may be substituted as appropriate; RN1 And RN2 And the nitrogen atom to which they are attached is joined to form a 3 to 7 membered heterocyclic ring; B' isGroup; where: R16 For hydrogen, (C1 -C8 )alkyl, (C2 -C8 Alkenyl, (C2 -C8 Alkynyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 A side chain of an alkyl- or amino acid, such as a side chain typically selected from the group consisting of amino acids (as otherwise described herein): alanine, beta-alanine, arginine, aspartame , aspartic acid, cysteine, cystine, glutamic acid, glutamic acid, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methyl sulfide Aminic acid, valine, serine, threonine, valine, tryptophan or tyrosine (usually R16 Is hydrogen, methyl, isopropyl or isobutyl); R17 For hydrogen, (C1 -C8 )alkyl, (C2 -C8 Alkenyl, (C2 -C8 Alkynyl, (C3 -C8 Cycloamino)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 A side chain of an alkyl- or amino acid, such as a side chain typically selected from the group consisting of amino acids (as otherwise described herein): alanine, beta-alanine, arginine, aspartame , aspartic acid, cysteine, cystine, glutamic acid, glutamic acid, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methyl sulfide Aminic acid, valine, serine, threonine, valine, tryptophan or tyrosine (usually R17 Is hydrogen, methyl, isopropyl or isobutyl); R18 For hydrogen or C1 -C3 Alkyl; or R16 And R17 Can form (C3 -C7 ) cycloalkyl or (C3 -C7 a heterocyclic group; or R18 And R16 Or R17 Can form (C3 -C6 a heterocyclic group; and R19 For hydrogen, (C1 -C6 )alkyl, (C3 -C6 Alkenyl, (C3 -C6 Alkynyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 Alkyl-; or B' isGroup; where: R20 For hydrogen, (C1 -C3 )alkyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl- or (heteroaryl)C0 -C4 Alkyl-; Rtwenty one For hydrogen, (C1 -C3 )alkyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl- or (heteroaryl)C0 -C4 Alkyl-; and R18 And R19 As defined above. Preferred RP1 The group includes optionally substituted phenyl, naphthyl and monocyclic heteroaryl groups, particularly enhancing the bioavailability of the compound in the cells of the patient and exhibiting reduced toxicity, increased therapeutic index and improved pharmacokinetics (compounds) These groups (especially lipophilic groups) are metabolized and excreted more slowly. The term amino phosphate is used throughout the specification to describe a group of the drug form that is found at the 5' or 3' position of the furanose ring of the nucleoside compound and forms a nucleoside compound. In one embodiment, the amino phosphate can be found at the 5' and 3' positions of the furanose ring of the nucleoside compound and form the prodrug form of the nucleoside compound. In another embodiment, the amino phosphate found at the 5' position of the furanose ring of the nucleoside can be formed by forming a 3' hydroxyl substituent at the 3' position of the furanose ring of the nucleoside compound. A cyclic amino phosphate compound is formed and forms a nucleoside compound prior to the drug form. The term "thiophosphonamide", "thioamino phosphate" or "thiophosphoric acid" has the binding to sulfur (P=S), two oxygen groups and an amine (which may be substituted as appropriate) ) the part of the phosphorus. The thioamino phosphates suitable for use in the present invention are described in U.S. Patent No. 8,772,474 and WO 2012/040124. The thioamino phosphate groups useful in the present invention include the following structures: . Other thioamino phosphates include the following structures:Where: RP1 a linear, branched or cyclic alkyl group substituted as appropriate, or an optionally substituted aryl, heteroaryl or heterocyclic group or a combination thereof; and RP2 For -NRN1 RN2 a group or a B' group; wherein: RN1 And RN2 Each is independently H, C1-8 Alkyl, (C3 -C7 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl- or (heteroaryl)C0 -C4 Alkyl-; or RN1 And RN2 And the nitrogen atom to which they are attached is joined to form a 3 to 7 membered heterocyclic ring; B' isGroup; where: R16 For hydrogen, (C1 -C8 )alkyl, (C2 -C8 Alkenyl, (C2 -C8 Alkynyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 A side chain of an alkyl- or amino acid, such as a side chain typically selected from the group consisting of amino acids (as otherwise described herein): alanine, beta-alanine, arginine, aspartame , aspartic acid, cysteine, cystine, glutamic acid, glutamic acid, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methyl sulfide Aminic acid, valine, serine, threonine, valine, tryptophan or tyrosine (usually R16 Is hydrogen, methyl, isopropyl or isobutyl); R17 For hydrogen, (C1 -C8 )alkyl, (C2 -C8 Alkenyl, (C2 -C8 Alkynyl, (C3 -C8 Cycloamino)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 A side chain of an alkyl- or amino acid, such as a side chain typically selected from the group consisting of amino acids (as otherwise described herein): alanine, beta-alanine, arginine, aspartame , aspartic acid, cysteine, cystine, glutamic acid, glutamic acid, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methyl sulfide Aminic acid, valine, serine, threonine, valine, tryptophan or tyrosine (usually R17 Is hydrogen, methyl, isopropyl or isobutyl); R18 For hydrogen or C1 -C3 Alkyl; or R16 And R17 Can form (C3 -C7 ) cycloalkyl or (C3 -C7 a heterocyclic group; or R18 And R16 Or R17 Can form (C3 -C6 a heterocyclic group; and R19 For hydrogen, (C1 -C6 )alkyl, (C3 -C6 Alkenyl, (C3 -C6 Alkynyl, (C3 -C8 Cycloalkyl)C0 -C4 Alkyl-, (aryl) C0 -C4 Alkyl-, (C3 -C6 Heterocyclic)C0 -C4 Alkyl-, (heteroaryl) C0 -C4 Alkyl-; or B' isGroup; and R18 , R19 , R20 And Rtwenty one As defined above. Preferred RP1 The group includes optionally substituted phenyl, naphthyl and monocyclic heteroaryl groups, particularly enhancing the bioavailability of the compound in the cells of the patient and exhibiting reduced toxicity, increased therapeutic index and improved pharmacokinetics (compounds) These groups (especially lipophilic groups) are metabolized and excreted more slowly. The thioamino phosphate may be in the form of a prodrug compound at the 5' or 3' position of the furanose ring of the nucleoside compound. In one embodiment, the thioamino phosphate can be found at the 5' and 3' positions of the furanose ring of the nucleoside compound and form the prodrug form of the nucleoside compound. In another embodiment, the thioamino phosphate found at the 5' position of the furanose ring of the nucleoside can form a 3' hydroxy substituent at the 3' position of the furanose ring of the nucleoside compound. The bond forms a cyclic thioamino phosphate compound and forms a nucleoside compound prior to the drug form. The term "D-configuration" as used in the context of the present invention refers to a principle configuration that is a natural configuration of a simulated sugar moiety relative to a non-naturally occurring nucleoside or "L" configuration. With regard to nucleoside analogs, the term "β" or "β-spin isomer" is used, wherein the nucleobase is configured (placed) above the plane of the furanose moiety in the nucleoside analog. The term "coadminister/coadministration" or combination therapy is used to describe at least one 2'-deoxy-2'-α-fluoro-2'-β-C-nucleoside-4'-fluoro according to the invention. a compound and at least one other active agent (eg, at least one additional anti-HCV agent, including other 2'-deoxy-2'-α-fluoro-2'-β-C-methyl-4'-fluoronucleoside reagents, as appropriate) , which is the disclosure of the combination disclosed herein. The timing of co-injection is best determined by the medical specialist who treats the patient. Sometimes, the reagents are preferably administered at the same time. Alternatively, the drug selected for the combination therapy can be administered to the patient at different times. Of course, in the presence of more than one virus or other infection or other condition, the compounds of the invention may be combined with other agents to treat the other infection or condition as needed. As used herein, the term host refers to a single or multicellular organism in which the HCV virus can replicate, including cell strains and animals, and is typically human. The term host specifically refers to infected cells, transfected cells and animals via all or a portion of the HCV genome, in particular, primates (including chimpanzees) and humans. In most animal applications of the invention, the host is a human patient. However, in certain conditions, the present invention clearly foresees the use in livestock. The host may be, for example, a cow, a horse, a bird, a dog, a cat, or the like. Isotopic Substitution The present invention encompasses the use of compounds and compounds substituted with the desired isotopes of the atom in amounts (i.e., enriched) above the natural abundance. Isotopes are atoms that have the same number of atoms but have different mass numbers (ie, the number of protons are the same, but the number of neutrons is different). By way of a general example and without limitation, isotopes of hydrogen may be used at any position in the described structure, for example,2 H) and 氚 (3 H). Alternatively or additionally, carbon isotopes may be used, for example13 C and14 C. Preferred isotopes are substituted with hydrogen at one or more positions on the molecule to improve the performance of the drug. The ruthenium may bind at the position of the bond cleavage during metabolism (α-氘 kinetic isotope action) or bind immediately or close to the bond cleavage site (β-氘 kinetic isotope action). Achillion Pharmaceuticals, Inc. (WO/2014/169278 and WO/2014/169280) describe the deuteration of nucleotides to improve their pharmacokinetic or pharmacodynamics, including at the 5 position of the molecule. Substitution with isotopes such as guanidine may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Substitution of hydrogen with hydrazine at the site of metabolic breakdown reduces the rate of metabolism or eliminates metabolism at the bond. A hydrogen atom may be present at any position of the compound, and the hydrogen atom may be any isotopes of hydrogen, including helium (1 H), 氘 (2 H) and 氚 (3 H). Thus, the compounds referred to herein encompass all possible isotopic forms, unless the context clearly indicates otherwise. The term "isotopically labeled" analog refers to "an antimony analog",13 C-labeled analogues" or "deuterated/13 An analog of the C-labeled analog. The term "deuterated analog" means a compound as described herein, wherein the H isotope (ie hydrogen/helium (1 H)) via H isotope (ie, 氘 (2 H)) replaced.氘 substitutions may be partial or total. Partial oxime substitution means that at least one hydrogen is substituted with at least one hydrazine. In certain embodiments, the isotope is enriched by 90%, 95%, or 99% or more for an isotope at any position of interest. In some embodiments, the concentration is increased by 90%, 95%, or 99% at the desired location. Unless otherwise indicated, the deuteration is at least 80% at the selected location. Deuteration of the nucleoside can occur at any alternative hydrogen that provides the desired result.III. Treatment or prevention method As used herein, treatment refers to the administration of an active compound to a host infected with a hepatitis C virus. The term "controlling" or prophylactic, when used, refers to the administration of an active compound to prevent or reduce the likelihood of the appearance of a viral condition. The invention includes both therapeutic and prophylactic or prophylactic therapies. In one embodiment, the active compound is administered to a host that has been exposed to an infection that is infected by the hepatitis C virus and is therefore at risk of infection by the hepatitis C virus. The present invention is directed to a method of treating or preventing hepatitis C virus comprising a drug resistance and a multi-drug resistant form of HCV and related disease states, conditions or complications of HCV infection, such as weakness, appetite Loss, weight loss, breast enlargement (especially in men), rash (especially on the palm of your hand), difficulty in coagulation, spider blood vessels on the skin, confusion, coma (encephalopathy), peritoneal flow (ascites), esophageal varices Portal hypertension, renal failure, enlarged spleen, cytopenia, anemia, thrombocytopenia, jaundice and hepatocellular carcinoma plus others. The method comprises, if appropriate, in combination with at least one additional biologically active agent (eg, an additional anti-HCV agent), further in combination with a pharmaceutically acceptable carrier additive and/or excipient, effective for administering to a host in need thereof At least one of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N as described herein6 - Substituting -2,6-diaminopurine nucleotides. In still another aspect, the invention is a method for preventing or preventing a HCV infection or a disease state or a related or subsequent disease state, a condition, or a complication of an HCV infection, such as weakness, loss of appetite, weight Reduced, breast enlargement (especially in men), rash (especially on the palm of your hand), difficulty in coagulation, spider-like blood vessels on the skin, confusion, coma (encephalopathy), peritoneal flow accumulation (ascites), esophageal varices, high portal vein Blood pressure, renal failure, enlarged spleen, cytopenia, anemia, thrombocytopenia, jaundice and hepatocellular carcinoma plus others, the method comprising combining with a pharmaceutically acceptable carrier, additive or excipient, as appropriate An anti-HCV agent combination administers an effective amount of at least one compound according to the invention as described above to a patient at risk. If necessary, 5'-stabilized β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N can be administered.6 - Substituted-2,6-diaminopurine nucleotides are any salts or prodrugs which, upon administration to a recipient, are capable of providing the parent compound directly or indirectly or exhibiting self-activity. Non-limiting examples are pharmaceutically acceptable salts and compounds which have been modified at a functional group (such as a hydroxyl or amine functional group) to modify the active 5'-triphosphate organism using the desired route of administration of the compound. Activity, pharmacokinetics, half-life, controlled delivery, lipophilicity, absorption kinetics, ease of phosphorylation or delivery effectiveness. Methods for altering the properties of an active compound to achieve a desired property are known to those skilled in the art or can be by standard methods (e.g., thiolation, phosphorylation, thioguanosylphosphorylation, aminyl phosphorylation) , phosphorylation, alkylation or PEGylation) is easy to assess.IV. Pharmaceutical composition In one aspect of the invention, the pharmaceutical composition according to the invention comprises an anti-HCV effective amount of at least one of the 5'-stable β-D-2'-deoxy-2'-α-fluoro-2 described herein. '-β-C-substituted-4'-fluoro-N6 Substituted diaminoguanidine nucleotide compounds, optionally in combination with pharmaceutically acceptable carriers, additives or excipients, further optionally combined or alternating with at least one other active compound. In one aspect of the invention, the pharmaceutical composition according to the invention comprises an anti-HCV effective amount of at least one of the active β-D-2'-deoxy-2'-α-fluoro-2'-β described herein. -C-substituted-4'-fluoro-N6 a substituted-2,6-diaminopurine nucleotide compound, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient, further optionally combined with at least one other antiviral agent, such as anti-HCV Reagents. The present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient comprising an effective amount of a β-D-2'-deoxy-2'-α of the present invention for treating hepatitis C virus infection. -fluoro-2'-β-C-substituted-4'-fluoro-N6 - Substituting one of the-2,6-diaminopurine nucleotide compounds or a salt or prodrug thereof. In an alternative embodiment, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient comprising an effective amount of a beta-D-2' of the invention for preventing hepatitis C virus infection. -deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N6 - Substituting one of the-2,6-diaminopurine nucleotide compounds or a salt or prodrug thereof. Those of ordinary skill in the art will recognize that a therapeutically effective amount will be a function of the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the reagents employed, and the patient or individual (animal or human) to be treated. The change is, and the amount of treatment can be determined by the attending physician or expert. The 5'-stabilized β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substitution according to the present invention may be formulated in a blend with a pharmaceutically acceptable carrier. -4'-fluoro-N6 - Substituted-2,6-diaminopurine nucleotide compound. In general, it is preferred to administer the pharmaceutical composition in an orally administrable form, but certain formulations may be administered parenterally, intravenously, intramuscularly, topically, transdermally, buccally, subcutaneously, suppository or Other routes (including intranasal spray) are administered. Intravenous and intramuscular formulations are usually administered in sterile saline. Those skilled in the art will be able to modify the formulation to render it more soluble in water or other vehicles, for example, by minor modifications commonly known in the art (salt formulation, esterification, etc.) ) can be easily implemented. The pharmacokinetics of the compounds of the invention can also be well modified in routine operator skill by altering the route of administration of the particular compound and the dosage regimen to maximize the beneficial effects in the patient. In some pharmaceutical dosage forms, the prodrug form of the compound (especially including thiolated (acetylated or otherwise)) and ether (alkyl and related) derivatives, phosphates, thioamino phosphates, aminophosphoric acid Esters and various salt forms of the compounds of the invention are preferred. Those of ordinary skill in the art will recognize how to readily modify a compound of the invention to a form of the drug that facilitates delivery of the active compound to the target site within the host organism or patient. Routine operators also utilize the good pharmacokinetic parameters of the prodrug form in the target site in the host organism or patient where appropriate to maximize the desired effect of the compound. The amount of the compound included in the therapeutically active formulation of the invention is for treating HCV infection, reducing the likelihood of HCV infection, or inhibiting, reducing and/or eliminating HCV or its side effects (including disease states, conditions and/or by HCV) The effective amount of complications that occur. In general, a therapeutically effective amount of a compound of the invention in a pharmaceutical dosage form will generally be from about 0.001 mg/kg to about 100 mg/kg or more per day, depending on the compound, the condition being treated, or the route of infection and administration. More typically less than about 0.1 mg/kg to more than about 25 mg/kg or significantly more per day of the patient. Depending on the pharmacokinetics of the agent in the patient, the active nucleoside compound according to the present invention is typically administered in an amount ranging from about 0.1 mg/kg to about 15 mg/kg per day of the patient. This dosage range will generally result in an effective blood level concentration of the active compound which will range from about 0.001 to about 100, from about 0.05 to about 100 micrograms per cc of blood in the patient. Generally, to treat, prevent or delay the onset of such infections and/or reduce the likelihood of HCV viral infection or secondary disease state, condition or complications of HCV, the composition will be at least about 250 micrograms at least once a day. Amounts in the range of about 500 mg or more, for example up to four times at least 25, 50, 100, 150, 250 or 500 mg, are administered in an oral dosage form. The compounds of the invention are usually administered orally, but can be administered parenterally, topically or in the form of a suppository, and intranasally (e.g., by nasal spray) or as otherwise described herein. In the case of administration of a compound of the invention in combination with another anti-HCV compound as otherwise described herein, the second agent to be co-administered and its efficacy against the virus, the condition of the patient, and the disease or infection to be treated Depending on the severity and route of administration, the amount of the compound to be administered according to the invention will range from about 0.01 mg/kg of the patient to about 500 mg/kg or more, or significantly more, of the patient. Another anti-HCV agent can be administered, for example, in an amount ranging from about 0.01 mg/kg to about 500 mg/kg. In certain preferred embodiments, generally depending on the pharmacokinetics of the two agents in the patient, such compounds may generally range from about 0.5 mg/kg to about 50 mg/kg or more (typically up to about 100 mg). The amount within the range of /kg) is administered. These dosage ranges generally produce an effective blood level concentration of the active compound in the patient. For the purposes of the present invention, a prophylactically or prophylactically effective amount of a composition according to the invention is within the same range of concentrations as set forth above for a therapeutically effective amount, and is generally the same as a therapeutically effective amount. Administration of the active compound may be in the range of continuous (intravenous drip) to several oral or intranasal administration (eg, QID) or transdermal administration, and may include oral, topical, parenteral, intramuscular Intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal and suppository, and other routes of administration. Coating enteric coated oral lozenges can also be used to enhance the bioavailability of the compounds used in the oral route of administration. The most effective dosage form will depend on the bioavailability/pharmacokinetics of the particular agent selected and the severity of the disease in the patient. Oral dosage forms are especially preferred because of their ease of administration and promising patient compliance. To prepare a pharmaceutical composition according to the present invention, one or more therapeutically effective amounts of a compound according to the present invention are typically intimately mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dosage. Depending on the desired form of preparation, the carrier can take a variety of forms for administration, such as oral or parenteral. In the preparation of a pharmaceutical composition in an oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives, including water, glycols, oils, alcohols, flavors, preservatives, colorants and the like, may be employed. For solid oral preparations (such as powders, lozenges, capsules), and for solid preparations (such as suppositories), suitable carriers and additives can be used, including starch, sugar carriers (such as dextrose, mannitol, Lactose and related carriers), diluents, granulating agents, lubricants, binders, disintegrating agents and the like. If desired, the lozenge or capsule may be coated with an enteric coating or sustained release by standard techniques. The use of such dosage forms can significantly enhance the bioavailability of the compounds in the patient. For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride, but may also include other ingredients, including those which facilitate dispersion. Of course, the compositions and carriers must also be sterilized when sterile water is used and maintained sterile. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspensions, and the like may be employed. Liposomal suspensions (including liposomes that target viral antigens) can also be prepared by conventional methods to produce a pharmaceutically acceptable carrier. This may be suitable for delivery of a free nucleoside, sulfhydryl/alkyl nucleoside or phosphate prodrug form of a nucleoside compound according to the invention. In an exemplary embodiment according to the invention, the compounds and compositions are useful for treating, preventing or delaying HCV infection or secondary disease states, conditions or complications of HCV.V. Combination and alternation therapy It is well recognized that drug resistant variants of the virus can occur after prolonged treatment with antiviral agents. Most of the resistance is usually caused by a mutation in a gene encoding an enzyme for viral replication. The efficacy of a drug against HCV infection can be prolonged, strengthened or restored by administering a compound in combination with or alternately with another, and possibly even two or three other antiviral compounds, the antiviral compound eliciting different mutations by the principle drug Or by different paths. Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameters of the drug may be varied by such combination therapy (which may include alternation therapy when deemed to be consistent). Due to the disclosed β-D-2'-deoxy-2'-α-fluoro-2'-β-C-substituted-4'-fluoro-N6 - Substituted-2,6-diaminopurine nucleotides and other described polymerase inhibitors which can be used to administer compounds to a host, for example, in combination with: (1) protease inhibitors, such as NS3/4A protease Inhibitor; (2) NS5A inhibitor; (3) another NS5B polymerase inhibitor; (4) NS5B no matrix inhibitor; (5) interferon alpha-2a, which may be PEGylated or otherwise Modified, and / or ribavirin; (6) based on matrix-free inhibitors; (7) helicase inhibitors; (8) antisense oligodeoxynucleotides (S-ODN); (9) Aptamers; (10) nuclease-resistant ribonuclease; (11) iRNA, including microRNAs and siRNA; (12) antibodies to antibodies, partial antibodies or domain antibodies, or (13) initiation of host antibody responses Viral antigen or partial antigen. It can be combined with the β-D-2'-D-2'-α-fluoro-2'-β-C-substituted-2-modified-N of the present invention.6 Non-limiting examples of anti-HCV agents administered by a combination of substituted purine nucleotides are: (i) protease inhibitors such as telaprevir (Incivek)® ), Poprevir (Victrelis)TM ), cimetime (Olysio)TM ), Parecvir and (ABT-450), ACH-2684; AZD-7295; BMS-791325; danoprevir; Filibuvir; GS-9256; GS-9451; MK -5172; Setrobuvir; Sovaprevir; Tegobuvir; VX-135; VX-222 and ALS-220; (ii) NS5A inhibitors such as ACH-2928 , ACH-3102, IDX-719, daclatasvir, radivirvir and opittivir (ABT-267); (iii) NS5B inhibitors, such as ACH-3422; AZD-7295; Imidazole (Clemizole); ITX-5061; PPI-461; PPI-688, Sovaldi® , MK-3682 and melitabine; (iv) NS5B inhibitors, such as ABT-333, MBX-700; and, (v) antibodies, such as GS-6624. If administered with β-D-2'-D-2'-α-fluoro-2'-β-C-substituted-2-modified-N6 Substituting a purine nucleotide to treat an advanced hepatitis C virus that causes liver cancer or cirrhosis, in one embodiment, the compound may be administered in combination or alternately with another drug commonly used to treat hepatocellular carcinoma (HCC), For example, as described by Andrew Zhu in "New Agents on the Horizon in Hepatocellular Carcinoma" Therapeutic Advances in Medical Oncology, V 5(1), January 2013, 41-50. Examples of suitable compounds for combination therapies in which the host has HCC or are at risk of HCC include anti-angiogenic agents, sunitinib, brinirib, linifanib, Ramucirumab, bevacizumab, cediranib, pazopanib, TSU-68, lenvatinib, antibodies against EGFR, mTor inhibitor, MEK inhibitor and histone deacetylase inhibitor.V. The invention β-D-2'- Deoxygenation -2'-α- fluorine -2'-β-C- Replace -4'- fluorine -N 6 - Replace 6- Amine 2- Method for preparing substituted guanidine nucleotide General methods for providing the compounds of the invention are known in the art or are described herein. The following abbreviations are used in the synthesis process. CBr4 : carbon tetrabromide DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane THF: tetrahydrofuran (THF), anhydrous EtOAc: ethyl acetate EtOH: ethanol Li (OtBu) )3 AlH: lithium tris-butoxy aluminum hydride2 SO4 : sodium sulfate (anhydrous) MeCN: acetonitrile MeNH2 :Methylamine MeOH:Methanol Na2 SO4 :Sodium sulfate NaHCO3 : sodium bicarbonate NH4 Cl: ammonium chloride NH4 OH: Ammonium hydroxide PE: petroleum ether Ph3 P: triphenylphosphine tannin (230 to 400 mesh, adsorbent) t-BuMgCl: third butyl magnesium chloride t-BuOK: sodium third butoxide t-BuOH: third butanolInstance General method Recorded on a 300 MHz Fourier transform Brücker spectrometer1 H,19 F and31 P NMR spectrum. Spectral free CDCl3 CD3 OD or DMSO-d6 Samples prepared in a 5 mm diameter tube were obtained. The rotational multimodality is indicated by the symbols s (single peak), d (doublet), t (triplet), m (multiple peak), and br (wide peak). Report coupling constants in Hz (J ). MS spectra were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole MS apparatus. The reaction is generally carried out under a dry nitrogen atmosphere using a Sigma-Aldrich anhydrous solvent. All common chemicals are purchased from commercial sources.For the following examples of chemical substances : i) Me2 NH.HCl, DBU, MeOH, 85 ° C; ii) l2 , PPh3 , imidazole, THF; iii) MeONa, MeOH, 60 ° C; iv) TMSCI, pyridine, 0 ° C followed by isobutylphosphonium chloride; v) Et3 N.3HF, NIS, MeCN, -20 ° C; vi) BzONa, DMSO, 100 ° C; vii) MeNH2 , EtOH, 75 ° C; viii) CbzCI, DMAP, DCM, 0 ° C; ix) isopropyl ((R,S)-(pentafluorophenoxy)-phenoxy-phosphonium)-L-alanine Ester, DBU, THF; x) H2 , Pd-C, EtOH(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-4- fluorine -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (2) . Compound1 (3.0 g, 5.7 mmol) dimethylamine hydrochloride (4.7 g, 57.6 mmol) and 1,8-diazabicyclo[5.4.0] eleven-7- in MeOH (50 mL) Alkene (8.6 mL, 57.6 mmol). The reaction mixture was heated in a sealed vessel at 85 °C for 6 h, cooled to room temperature (RT) and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc:EtOAc:EtOAc Obtaining a product as a white solid2 (1.6 g, 86%).(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-4- fluorine -2-( Iodomethyl )-4- Methyltetrahydrofuran -3- alcohol (3) . Compound2 (1.67 g, 5.1 mmol) Triphenylphosphine (1.60 g, 6.1 mmol) and imidazole (420 mg, 6.1 mmol) were added to a solution of anhydrous THF (30 mL). Subsequently, a solution of iodine (1.42 g, 5.6 mmol) in dry THF (10 mL) was added dropwise. The mixture was stirred at RT for 3 h. The solution was then filtered through celite and concentrated. contain3 The dark residue was used as such in the next step.(3R, 4R, 5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-4- fluorine -4- methyl -2- Methylenetetrahydrofuran -3- alcohol (4) . to3 MeONa (1.38 g, 25.5 mmol) was added to a solution in MeOH (40 mL). The reaction mixture was heated at 60 &lt;0&gt;C for 15 h and then cooled to RT and concentrated. Add EtOAc (100 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (80 mL) and brine (80 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid4 (0.87 g, 55% yield by 2 steps). N -(6-( Dimethylamino )-9-((2R,3R,4R)-3- fluorine -4- Hydroxyl -3- methyl -5- Methylenetetrahydrofuran -2- base )-9H- 嘌呤 -2- base ) Ibuprofen (5) . At 0 ° C4 (500 mg, 1.6 mmol) chlorotrimethyl decane (410 μL, 3.2 mmol) was added dropwise to a solution of anhydrous pyridine (8 mL). The reaction mixture was stirred at 0 °C for 10 min and then isobutylphosphonium chloride (250 uL, 2.4 mmol) was then added dropwise. The orange solution was stirred at RT for 4 h. After cooling to 0 ° C, by adding H2 O (2 mL) and 30% NH4 The reaction was quenched with OH (3 mL). The mixture was then stirred at 0 ° C for 1 h. Add EtOAc (50 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (40 mL) and brine (40 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was co-evaporated with toluene (2 x 50 mL) and purified by column chromatography (EtOAc,EtOAcEtOAc Obtain a product in the form of a colorless oil5 (460 mg, yield 75%). N -(9-((2R,3R,4S,5R)-3,5- Difluoro -4- Hydroxyl -5-( Iodomethyl )-3- Methyltetrahydrofuran -2- base )-6-( Dimethylamino )-9H- 嘌呤 -2- base ) Ibuprofen (6) . to5 (176 mg, 0.47 mmol) Add Et in a solution of anhydrous MeCN (8 mL)3 N.3HF (90 μL, 0.56 mmol). Add dropwise at -20 ° C for 45 minutesN a solution of iodobutaneimine (146 mg, 0.65 mmol) in anhydrous MeCN (8 mL). The resulting orange solution was stirred at 0 °C for 2 h and stirred at RT for 1 h. The reaction was then diluted with EtOAc (50 mL) and added (1:1) NaHCO3 /Na2 S2 O3 The aqueous solution (30 mL) was quenched. The phases were separated and the organic layer was washed with brine (40 mL)2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid6 (129 mg, yield 53%).benzoic acid ((2S, 3S, 4R, 5R)-5-(6-( Dimethylamino )-2- Ibuprofen -9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methyl ester (7) . to6 (548 mg, 1.05 mmol) sodium benzoate (1.51 g, 10.5 mmol) was added to a solution in anhydrous DMSO (40 mL). The resulting milky white suspension was stirred at 100 ° C for 3 days. The mixture is then cooled and distributed to H2 O (30 mL) was taken between EtOAc (50 mL) and phases were separated. The aqueous layer was back extracted with EtOAc (3 x 30 mL). With NH4 The combined organics were washed with a saturated aqueous solution of Cl (2 x 50 mL) and brine (50 mL). Organic solution via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid7 (410 mg, yield 75%).(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (8) . Will be in a sealed container at 75 ° C7 A solution of (330 mg, 0.64 mmol) in methylamine (33% in EtOH) (25 mL) was stirred for 2d. The mixture was then allowed to cool and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining a product as a white solid8 (180 mg, yield 82%).1 H NMR (300 MHz, CD3 OD)δ 7.93 (s, 1H), 6.43 (d,J = 22.4 Hz, 1H), 4.62 (d,J = 20.7 Hz, 1H), 3.86-3.84 (m, 2H), 3.41 (m, 6H), 1.20 (d,J = 22.2 Hz, 3H). C13 H19 F2 N6 O3 [M+H]+ MS (ESI)m /z Calculated value 345.1; experimental value 345.2.(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- Phenylmethyl carbonate (9) . At 0 ° C8 (93 mg, 0.27 mmol) and a solution of DMAP (37 mg, 0.30 mmol The reaction mixture was stirred at RT for 45 min and diluted with DCM (5 mL). Solution with H2 Washed with O (5 mL) and brine (5 mL) over anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid9 (70 mg, yield 55%).(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-3-((( Benzyloxy ) Carbonyl ) Oxyl )-2,4- Difluoro -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (10) . To compound 9 (51 mg, 0.11 mmol) and (( at 0 °C)R ,S )-(pentafluorophenoxy)-phenoxy-phosphonium)-L DBU (33 μL, 0.22 mmol) was added dropwise to a solution of isopropyl propyl acetate (73 mg, 0.16 mmol) in dry THF (3 mL). The reaction mixture was stirred at RT for 18 h. Then with EtOAc (10 mL) and NH4 The solution was diluted with a saturated aqueous solution of Cl (8 mL). The phases were separated and the aqueous extracted with EtOAc (3 &lt The combined organics were washed with brine (15 mL) over Na2 SO4 Dry and concentrate. Reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solid10 (50 mg, 63%).(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (11) . Compound10 (50 mg, 0.07 mmol) palladium (10% / charcoal) (8 mg) was added to a solution in EtOH (3 mL). The flask was flushed with hydrogen and the suspension was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through celite and concentrated. Reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solid11 (33 mg, 77%).1 H NMR (300 MHz, CD3 OD)δ 7.80 (s, 0.5H), 7.79 (s, 0.5H), 7.35-7.16 (m, 5H), 6.42 (d,J = 17.6 Hz, 0.5 H), 6.40 (d,J = 17.6 Hz, 0.5 H), 4.96-4.86 (with H2 O overlap, m, 1H), 4.62-4.38 (m, 2H), 3.92-3.88 (m, 1H), 3.39 (m, 6H), 1.30-1.18 (m, 12H).31 P NMR (121 MHz, CD3 OD)δ 4.01 (s), 3.89 (s). C25 H35 F2 N7 O7 P [M+H]+ MS (ESI)m /z Calculated value 614.2; experimental value 614.2.i) MeNH2 , EtOH, 100 ° C; ii) l2 , PPh3 , imidazole, THF; iii) MeONa, MeOH, 60 ° C; iv) TMSCI, pyridine, 0 ° C followed by isobutylphosphonium chloride; v) Et3 N.3HF, NIS, MeCN, -20 ° C; vi) BzONa, DMSO, 100 ° C; vii) MeNH2 , EtOH, 75 ° C; viii) CbzCI, DMAP, DCM, 0 ° C; ix) ((RS)-(pentafluorophenoxy)-phenoxy-phosphonium)-L-alanine isopropyl ester, DBU ,THF;x) H2 , Pd-C, EtOH(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-4- fluorine -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (12) . Sealing the compound in the container at 100 ° C1 (2.3 g, 4.4 mmol) in a solution of methylamine (33% in EtOH) (50 mL). The mixture was then cooled to RT and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc:EtOAc:EtOAc Obtaining the product as an off-white solid12 (1.4 g, 100%).(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-4- fluorine -2-( Iodomethyl )-4- Methyltetrahydrofuran -3- alcohol (13) . Compound12 (1.36 g, 4.40 mmol) Triphenylphosphine (1.38 g, 5.28 mmol) and imidazole (360 mg, 5.28 mmol) were added to a solution in anhydrous THF (30 mL). Subsequently, a solution of iodine (1.23 g, 4.84 mmol) in dry THF (10 mL) was added dropwise. The mixture was stirred at RT for 15 h. The solution was then filtered through celite and concentrated. contain13 The dark residue was used as such in the next step.(3R, 4R, 5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-4- fluorine -4- methyl -2- Methylenetetrahydrofuran -3- alcohol (14) . to13 MeONa (1.19 g, 22.0 mmol) was added to a solution in MeOH (40 mL). The reaction mixture was heated at 60 &lt;0&gt;C for 15 h and then cooled to RT and concentrated. Add EtOAc (100 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (80 mL) and brine (80 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid14 (0.58 g, 45% yield by 2 steps).N -(6-(Methylamino )-9-((2R,3R,4R)-3-fluorine -4-Hydroxyl -3-methyl -5-Methylenetetrahydrofuran -2-base )-9H-嘌呤 -2-base )Ibuprofen (15). At 0 ° C14 (300 mg, 1.02 mmol) chlorotrimethylnonane (320 μL, 2.54 mmol) was added dropwise to aq. The reaction mixture was stirred at 0 °C for 10 min, and then isobutylphosphonium chloride (160 μL, 1.54 mmol) was then added dropwise. The orange solution was stirred at RT for 4 h. After cooling to 0 ° C, by adding H2 O (2 mL) and 30% NH4 The reaction was quenched with OH (3 mL). The mixture was then stirred at 0 ° C for 1 h. Add EtOAc (50 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (40 mL) and brine (40 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was co-evaporated with toluene (2 x 50 mL) and purified by column chromatography (EtOAc,EtOAcEtOAc Obtain a product in the form of a colorless oil15 (240 mg, yield 65%). N -(9-((2R,3R,4S,5R)-3,5- Difluoro -4- Hydroxyl -5-( Iodomethyl )-3- Methyltetrahydrofuran -2- base )-6-( Methylamino )-9H- 嘌呤 -2- base ) Ibuprofen (16) . to15 (120 mg, 0.33 mmol) Add Et in a solution of anhydrous MeCN (6 mL)3 N.3HF (65 μL, 0.40 mmol). Add dropwise at -20 ° C for 30 minutesN A solution of iodobutaneimine (103 mg, 0.46 mmol) in anhydrous MeCN (6 mL). The resulting orange solution was stirred at 0 °C for 2 h and stirred at RT for 1 h. The reaction was then diluted with EtOAc (40 mL) and added (1:1) NaHCO3 /Na2 S2 O3 The aqueous solution (25 mL) was quenched. The phases were separated and the organic layer was washed with brine (30 mL)2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid16 (85 mg, yield 50%).benzoic acid ((2S, 3S, 4R, 5R)-5-(6-( Methylamino )-2- Ibuprofen -9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methyl ester (17) . to16 (85 mg, 0.17 mmol) sodium benzoate (245 mg, 1.70 mmol) was added to a solution in anhydrous DMSO (5 mL). The resulting milky white suspension was stirred at 100 ° C for 5 days. The mixture is then cooled and distributed to H2 O (15 mL) was taken between EtOAc (25 mL) and phases were separated. The aqueous layer was back extracted with EtOAc (3×10 mL). With NH4 The combined organics were washed with a saturated aqueous solution of Cl (2 x 20 mL) and brine (20 mL). Organic solution via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid17 (60 mg, yield 70%).(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (18) . Will be in a sealed container at 75 ° C17 (60 mg, 0.12 mmol) in a solution of methylamine (33% in EtOH) (6 mL). The mixture was then allowed to cool and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining a product as a white solid18 (29 mg, yield 72%).1 H NMR (300 MHz, CD3 OD)δ 7.94 (s, 1H), 6.42 (d,J = 16.9 Hz, 1H), 4.76-4.59 (m, 1H), 3.91-3.81 (m, 2H), 3.04 (s, 3H), 1.22 (d,J = 22.3 Hz, 3H). C12 H17 F2 N6 O3 [M+H]+ MS (ESI)m/z Calculated 331.1; experimental value 331.2.(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- Phenylmethyl carbonate (19) . At 0 ° C18 (27 mg, 0.08 mmol) and a solution of DMAP (11 mg, 0.08 mmol) in anhydrous DCM (1 mL). The reaction mixture was stirred at rt EtOAc (EtOAc) Use solution with H2 O (3 mL), brine (3 mL), washed with anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtain product19 And the two protected species in a colorless solid (ratio: 7:3; total 20 mg) and used as such in the next step.(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9-- base )-3-((( Benzyloxy ) Carbonyl ) Oxyl )-2,4- Difluoro -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (20) . Containing compounds at 0 ° C19 (20 mg) and ((R ,S )-(pentafluorophenoxy)-phenoxy-phosphonium)-L DBU (9 μL, 0.06 mmol) was added to a solution of isopropyl propyl acetate (22 mg, 0.05 mmol) in dry THF (1 mL). The reaction mixture was stirred at RT for 4 h. Then with EtOAc (5 mL) and NH4 The solution was diluted with a saturated aqueous solution of Cl (3 mL). The phases were separated and the aqueous extracted with EtOAc (3 &lt The combined organics were washed with brine (10 mL) over Na2 SO4 Dry and concentrate. Containing product20 The residue was used as such in the next step.(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Methylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (twenty one) . Containing compounds20 Palladium (10% / charcoal) (3 mg) was added to a solution of the mixture in EtOH (1 mL). The flask was flushed with hydrogen and the suspension was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through celite and concentrated. By column chromatography (tank, DCM/MeOH 0 to 10%) and then by reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solidtwenty one (5 mg, 10% in 3 steps).1 H NMR (300 MHz, CD3 OD)δ 7.78, 7.76 (s+s, 1H), 7.35-7.16 (m, 5H), 6.41 (d,J = 17.4 Hz) and 6.39 (d,J = 17.5 Hz, 1H), 4.98-4.90 (with H2 O overlap, m, 1H), 4.69-4.53 (m, 1H), 447-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.03 (s, 3H), 1.31-1.17 (m, 12H) .31 P NMR (121 MHz, CD3 OD)δ 2.63 (s), 2.50 (s). Ctwenty four H33 F2 N7 O7 P [M+H]+ MS (ESI)m/z Calculated value 600.2; experimental value 600.2.i) N-methyl-ethylamine, EtOH, 100 ° C; ii) l2 , PPh3 , imidazole, THF; iii) MeONa, MeOH, 60 ° C; iv) TMSCI, pyridine, 0 ° C followed by isobutylphosphonium chloride; v) Et3 N.3HF, NIS, MeCN, -20 ° C; vi) BzONa, DMSO, 100 ° C; vii) MeNH2 , EtOH, 75 ° C; viii) CbzCI, DMAP, DCM, 0 ° C; ix) ((R.S)-(pentafluorophenoxy)-phenoxy-phosphonium)-L -isopropyl propylamine, DBU, THF; x) H2 , Pd-C, EtOH(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (twenty two) . Compound1 (2.9 g, 5.5 mmol) added to a solution in EtOH (60 mL)N -Methyl-ethylamine (1.4 mL, 16.5 mmol). The reaction mixture was heated in a sealed vessel at 100 ° C for 15 h, cooled to RT and added with 30% NH4 OH (20 mL). The reaction mixture was heated in a sealed vessel at 100 °C for 4 h and cooled to RT. The residue was purified by column chromatography (EtOAc, EtOAc:EtOAc:EtOAc Obtaining a product as a white solidtwenty two (1.7 g, 90%).(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -2-( Iodomethyl )-4- Methyltetrahydrofuran -3- alcohol (twenty three) . Compoundtwenty two (1.56 g, 4.6 mmol) <RTIgt; </RTI> <RTIgt; Subsequently, a solution of iodine (2.57 g, 10.1 mmol) in dry THF (15 mL) was added dropwise. The mixture was stirred at RT for 3 h. The solution was then filtered through celite and concentrated. containtwenty three The dark residue was used as such in the next step.(3R, 4R, 5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -4- methyl -2- Methylenetetrahydrofuran -3- alcohol (twenty four) . totwenty three MeONa (3.73 g, 69.0 mmol) was added to a solution in MeOH (50 mL). The reaction mixture was heated at 60 &lt;0&gt;C for 15 h and then cooled to RT and concentrated. Add EtOAc (100 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (80 mL) and brine (80 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solidtwenty four (0.82 g, 55% yield by 2 steps). N -(6-( Ethyl ( methyl ) Amine )-9-((2R,3R,4R)-3- fluorine -4- Hydroxyl -3- methyl -5- Methylenetetrahydrofuran -2- base )-9H- 嘌呤 -2- base ) Ibuprofen (25) . At 0 ° Ctwenty four (500 mg, 1.55 mmol) chlorotrimethyl decane (400 μL, 3.1 mmol) was added dropwise to aq. The reaction mixture was stirred at 0 °C for 10 min, and then isobutylphosphonium chloride (240 μL, 2.3 mmol) was added dropwise. The orange solution was stirred at RT for 4 h. After cooling to 0 ° C, by adding H2 O (2 mL) and 30% NH4 The reaction was quenched with OH (3 mL). The mixture was then stirred at 0 ° C for 1 h. Add EtOAc (50 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (40 mL) and brine (40 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was co-evaporated with toluene (2 x 50 mL) and purified by column chromatography (EtOAc,EtOAcEtOAc Obtaining a product as a white solid25 (440 mg, yield 72%).N -(9-((2R,3R,4S,5R)-3,5-Difluoro -4-Hydroxyl -5-(Iodomethyl )-3-Methyltetrahydrofuran -2-base )-6-(Ethyl (methyl )Amine )-9H-嘌呤 -2-base )Ibuprofen (26). to25 (275 mg, 0.70 mmol) Add Et in a solution of anhydrous MeCN (15 mL)3 N.3HF (140 μL, 0.84 mmol). Add dropwise at -20 ° C for 45 minutesN a solution of iodobutaneimine (220 mg, 0.98 mmol) in anhydrous MeCN (12 mL). The resulting orange solution was stirred at 0 °C for 2 h and stirred at RT for 1 h. The reaction was then diluted with EtOAc (50 mL) and added (1:1) NaHCO3 /Na2 S2 O3 The aqueous solution (30 mL) was quenched. The phases were separated and the organic layer was washed with brine (40 mL)2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid26 (245 mg, yield 65%).benzoic acid ((2S, 3S, 4R, 5R)-5-(6-( Ethyl ( methyl ) Amine )-2- Ibuprofen -9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methyl ester (27) . to26 (245 mg, 0.46 mmol) sodium benzoate (787 mg, 6.9 mmol) was added to a solution in anhydrous DMSO (15 mL). The resulting milky white suspension was stirred at 100 ° C for 5 days. The mixture is then cooled and distributed to H2 O (40 mL) was taken between EtOAc (50 mL) and phases were separated. The aqueous layer was back extracted with EtOAc (3 x 30 mL). With NH4 The combined organics were washed with a saturated aqueous solution of Cl (2 x 50 mL) and brine (50 mL). Organic solution via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining the product as an off-white solid27 (206 mg, yield 84%).(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (28) . Will be sealed in a container at 80 ° C27 (205 mg, 0.38 mmol) in a solution of methylamine (33% in EtOH) (20 mL). The mixture was then allowed to cool and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining a product as a white solid28 (110 mg, yield 80%).1 H NMR (300 MHz, CD3 OD)δ 7.93 (s, 1H), 6.43 (d,J = 16.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.04-3.94 (m, 2H), 3.90-3.80 (m, 2H), 3.34 (s, 3H), 1.26-1.17 (m, 6H). C14 Htwenty one F2 N6 O3 [M+H]+ MS (ESI)m/z Calculated 359.2; found 359.2.(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- Phenylmethyl carbonate (29) . At 0 ° C28 Benzyl chloroformate (17 μL, 0.12 mmol) was added to a solution of (30 mg, 0.08 mmol) and DMAP (12 mg, 0.10 mmol) in anhydrous DCM (2 mL). The reaction mixture was stirred at rt for 2 h and diluted with DCM (5 mL). Solution with H2 Washed with O (5 mL) and brine (5 mL) over anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid29 (25 mg, yield 60%).(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-3-((( Benzyloxy ) Carbonyl ) Oxyl )-2,4- Difluoro -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (30) . Compound at 0 ° C29 (25 mg, 0.05 mmol) and ((R ,S )-(pentafluorophenoxy)-phenoxy-phosphonium)-L Add DBU (16 μL, 0.11 mmol) to a solution of isopropyl propyl acetate (36 mg, 0.08 mmol) in dry THF (2 mL). The reaction mixture was stirred at RT for 18 h. Then with EtOAc (5 mL) and NH4 The solution was diluted with a saturated aqueous solution of Cl (4 mL). The phases were separated and the aqueous extracted with EtOAc (3 &lt The combined organics were washed with brine (10 mL) over Na2 SO4 Dry and concentrate. Containing product30 The residue was used as such in the next step.(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Ethyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (31) . Containing compounds30 Palladium (10% / charcoal) (4 mg) was added to a solution of the mixture in EtOH (2 mL). The flask was flushed with hydrogen and the suspension was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through celite and concentrated. By column chromatography (tank, DCM/MeOH 0 to 10%) and then by reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solid31 (14 mg, 44% in 2 steps).1 H NMR (300 MHz, CD3 OD)δ 7.75, 7.72 (s+s, 1H), 7.34-7.13 (m, 5H), 6.42 (d,J = 17.6 Hz) and 6.40 (d,J = 17.7 Hz, 1H), 4.98-4.90 (with H2 O overlap, m, 1H), 4.66-4.51 (m, 1H), 4.47-4.35 (m, 1H), 4.05-3.86 (m, 3H), 3.35-3.32 (overlap with MeOH, m, 4H), 1.31- 1.17 (m, 15H).31 P NMR (121 MHz, CD3 OD)δ 4.10 (s), 4.00 (s). C26 H37 F2 N7 O7 P [M+H]+ MS (ESI)m /z Calculated value 628.2; experimental value 628.4.i) pyrrolidine, EtOH, 100 ° C; ii) l2 , PPh3 Imidazole, THF; iii) MeONa, MeOH, 60 ° C; iv) TMSCI, pyridine, 0 ° C followed by isobutylphosphonium chloride; v) Et3 N.3HF, NIS, MeCN, -20 ° C; vi) BzONa, DMSO, 100 ° C; vii) MeNH2 , EtOH, 75 ° C; viii) CbzCI, DMAP, DCM, 0 ° C; ix) ((RS)-(pentafluorophenoxy)-phenoxy-phosphonium)-L-alanine isopropyl ester, DBU ,THF;x) H2 , Pd-C, EtOH(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-4- fluorine -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (32) . Compound1 (3.0 g, 5.7 mmol) Pyrrolidine (1.45 mL, 17.0 mmol) was added to a solution in EtOH (60 mL). The reaction mixture was heated in a sealed vessel at 100 ° C for 3 h, cooled to RT and added with 30% NH4 OH (25 mL). The reaction mixture was heated in a sealed vessel at 80 °C for 15 h and cooled to RT. The residue was purified by column chromatography (EtOAc, EtOAc:EtOAc:EtOAc Obtaining a product as a white solid32 (1.9 g, 95%).(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-4- fluorine -2-( Iodomethyl )-4- Methyltetrahydrofuran -3- alcohol (33) . Compound32 (1.90 g, 5.5 mmol) Triphenylphosphine (3.60 g, 13.7 mmol) and imidazole (930 mg, 13.7 mmol). Subsequently, a solution of iodine (3.18 g, 12.5 mmol) in dry THF (30 mL) was added dropwise. The mixture was stirred at RT for 4 h. The solution was then filtered through celite and concentrated. contain33 The dark residue was used as such in the next step.(3R, 4R, 5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-4- fluorine -4- methyl -2- Methylenetetrahydrofuran -3- alcohol (34) . to33 MeONa (4.60 g, 85.3 mmol) was added to a solution in MeOH (60 mL). The reaction mixture was heated at 60 &lt;0&gt;C for 15 h and then cooled to RT and concentrated. Add EtOAc (150 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (100 mL) and brine (100 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid34 (0.94 g, 52% yield by 2 steps). N -(6-( Pyrrolidine -1- base )-9-((2R,3R,4R)-3- fluorine -4- Hydroxyl -3- methyl -5- Methylenetetrahydrofuran -2- base )-9H- 嘌呤 -2- base ) Ibuprofen (35) . At 0 ° C34 (900 mg, 2.69 mmol) chlorotrimethyl decane (700 μL, 5.40 mmol) was added dropwise to a solution of anhydrous pyridine (15 mL). The reaction mixture was stirred at 0 °C for 10 min and then isobutylphosphonium chloride (420 uL, 4.03 mmol) was then added dropwise. The orange solution was stirred at RT for 4 h. After cooling to 0 ° C, by adding H2 O (4 mL) and 30% NH4 The reaction was quenched with OH (5 mL). The mixture was then stirred at 0 ° C for 1 h. Add EtOAc (100 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (80 mL) and brine (80 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was co-evaporated with toluene (2 x 100 mL) and purified by column chromatography (EtOAc,EtOAcEtOAc Obtaining a product as a white solid35 (705 mg, yield 65%). N -(9-((2R,3R,4S,5R)-3,5- Difluoro -4- Hydroxyl -5-( Iodomethyl )-3- Methyltetrahydrofuran -2- base )-6-( Pyrrolidine -1- base )-9H- 嘌呤 -2- base ) Ibuprofen (36) . to35 (446 mg, 1.10 mmol) Add Et in a solution of anhydrous MeCN (18 mL)3 N.3HF (220 μL, 1.32 mmol). Add dropwise at -20 ° C for 45 minutesN a solution of iodobutaneimine (346 mg, 1.54 mmol) in anhydrous MeCN (18 mL). The resulting orange solution was stirred at 0 °C for 2 h and stirred at RT for 1 h. The reaction was then diluted with EtOAc (60 mL) and added (1:1) NaHCO3 /Na2 S2 O3 The aqueous solution (40 mL) was quenched. The phases were separated and the organic layer was washed with brine (40 mL)2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid36 (340 mg, yield 56%).benzoic acid ((2S, 3S, 4R, 5R)-5-(6-( Pyrrolidine -1- base )-2- Ibuprofen -9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methyl ester (37) . to36 Sodium benzoate (1.14 g, 7.9 mmol) was added to a solution (290 mg, 0.53 mmol). The resulting milky white suspension was stirred at 100 ° C for 5 days. The mixture is then cooled and distributed to H2 Between O (50 mL) and EtOAc (60 mL). The aqueous layer was back extracted with EtOAc (3 x 30 mL). With NH4 The combined organics were washed with a saturated aqueous solution of Cl (2 x 60 mL) and brine (60 mL). Organic solution via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining the product as an off-white solid37 (190 mg, yield 66%).(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (38) . Will be sealed in a container at 80 ° C37 (190 mg, 0.35 mmol) in a solution of methylamine (33% in EtOH) (20 mL). The mixture was then allowed to cool and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining a product as a white solid38 (90 mg, yield 70%).1 H NMR (300 MHz, CD3 OD)δ 7.96 (s, 1H), 6.43 (d,J = 22.8 Hz, 1H), 4.71-4.61 (m, 1H), 3.85 (lm, 6H), 2.00 (large, 4H), 1.20 (d,J = 29.6Hz, 3H). C15 Htwenty one F2 N6 O3 [M+H]+ MS (ESI)m/z Calculated 371.2; experimental value 371.2.(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- Phenylmethyl carbonate (39) . At 0 ° C38 Benzyl chloroformate (17 μL, 0.12 mmol) was added to a solution of (30 mg, 0.08 mmol) and DMAP (12 mg, 0.10 mmol) in anhydrous DCM (2 mL). The reaction mixture was stirred at rt for 2 h and diluted with DCM (5 mL). Solution with H2 Washed with O (5 mL) and brine (5 mL) over anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid39 (25 mg, yield 62%).(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-3-((( Benzyloxy ) Carbonyl ) Oxyl )-2,4- Difluoro -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (40) . Compound at 0 ° C39 (25 mg, 0.05 mmol) and ((R ,S )-(pentafluorophenoxy)-phenoxy-phosphonium)-L Add DBU (16 μL, 0.11 mmol) to a solution of isopropyl propyl acetate (36 mg, 0.08 mmol) in dry THF (2 mL). The reaction mixture was stirred at RT for 5 h. Then with EtOAc (5 mL) and NH4 The solution was diluted with a saturated aqueous solution of Cl (4 mL). The phases were separated and the aqueous extracted with EtOAc (3 &lt The combined organics were washed with brine (10 mL) over Na2 SO4 Dry and concentrate. The residue was roughly purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Pooling the fractions containing the product and40 Use it as is for the next step.(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Pyrrolidine -1- base )-9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (41) . Containing compounds40 Palladium (10% / charcoal) (4 mg) was added to a solution of the mixture in EtOH (2 mL). The flask was flushed with hydrogen and the suspension was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through celite and concentrated. By column chromatography (tank, DCM/MeOH 0 to 10%) and then by reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solid41 (7 mg, 22% in 2 steps).1 H NMR (300 MHz, CD3 OD)δ 7.79(s, 0.7H), 7.77 (s, 0.3H), 7.36-7.17 (m, 5H), 6.43 (d,J = 23.6 Hz, 0.3 H), 6.41 (d,J = 23.6 Hz, 0.7 H), 4.99-4.92 (with H2 O overlap, m, 1H), 4.60.4.40 (m, 2H), 4.93 (lm, 6H), 2.00 (m, 2H), 1.32-1.19 (m, 12H).31 P NMR (121 MHz, CD3 OD)δ 4.15 (s), 4.01 (s). C27 H37 F2 N7 O7 P [M+H]+ MS (ESI)m /z Calculated value 640.2; experimental value 640.2.i) N-methyl-cyclopropylamine • HCl, Et3 N, EtOH, 100 ° C; ii) I2 , PPh3 , imidazole, THF; iii) MeONa, MeOH, 60 ° C; iv) TMSCI, pyridine, 0 ° C followed by isobutylphosphonium chloride; v) Et3 N.3HF, NIS, MeCN, -20 ° C; vi) BzONa, DMSO, 100 ° C; vii) MeNH2 , EtOH, 75 ° C; viii) CbzCI, DMAP, DCM, 0 ° C; ix) ((RS)-(pentafluorophenoxy)-phenoxy-phosphonium)-L-alanine isopropyl ester, DBU ,THF;x) H2 , Pd-C, EtOH(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (42) . Compound1 (3.0 g, 5.7 mmol) added to a solution in EtOH (60 mL)N -Methyl-cyclopropylamine hydrochloride (1.2 g, 11.4 mmol). The reaction mixture was heated in a sealed vessel at 100 ° C for 3 h, cooled to RT and added with 30% NH4 OH (30 mL). The reaction mixture was heated in a sealed vessel at 80 °C for 15 h and cooled to RT. The residue was purified by column chromatography (EtOAc, EtOAc:EtOAc:EtOAc Obtaining a product as a white solid42 (1.9 g, 94%).(2R, 3R, 4R, 5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -2-( Iodomethyl )-4- Methyltetrahydrofuran -3- alcohol (43) . Compound42 (1.86 g, 5.28 mmol), EtOAc (3. Subsequently, a solution of iodine (2.57 g, 10.1 mmol) in dry THF (15 mL) was added dropwise. The mixture was stirred at RT for 3 h. The solution was then filtered through celite and concentrated. contain43 The dark residue was used as such in the next step.(3R, 4R, 5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-4- fluorine -4- methyl -2- Methylenetetrahydrofuran -3- alcohol (44) . to43 MeONa (2.85 g, 52.8 mmol) was added to a solution in MeOH (50 mL). The reaction mixture was heated at 60 &lt;0&gt;C for 15 h and then cooled to RT and concentrated. Add EtOAc (100 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (80 mL) and brine (80 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product in the form of a yellow solid44 (0.57 g, 32% yield in 2 steps). N -(6-( Cyclopropyl ( methyl ) Amine )-9-((2R,3R,4R)-3- fluorine -4- Hydroxyl -3- methyl -5- Methylenetetrahydrofuran -2- base )-9H- 嘌呤 -2- base ) Ibuprofen (45) . At 0 ° C44 (560 mg, 1.67 mmol) chlorotrimethylnonane (530 μL, 4.19 mmol) was added dropwise to aq. The reaction mixture was stirred at 0 °C for 10 min, and then isobutylphosphonium chloride (350 μL, 3.35 mmol) was added dropwise. The orange solution was stirred at RT for 3 h. After cooling to 0 ° C, by adding H2 O (2 mL) and 30% NH4 The reaction was quenched with OH (3 mL). The mixture was then stirred at 0 ° C for 1 h. Add EtOAc (50 mL) with NH4 The solution was washed with a saturated aqueous solution of Cl (40 mL) and brine (40 mL). Organic matter via anhydrous Na2 SO4 Dry and concentrate. The residue was co-evaporated with toluene (2 x 50 mL) and purified by column chromatography (EtOAc,EtOAcEtOAc Obtaining a product as a white solid45 (505 mg, yield 75%). N -(9-((2R,3R,4S,5R)-3,5- Difluoro -4- Hydroxyl -5-( Iodomethyl )-3- Methyltetrahydrofuran -2- base )-6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -2- base ) Ibuprofen (46) . to45 (359 mg, 0.89 mmol) Add Et in a solution of anhydrous MeCN (15 mL)3 N.3HF (175 μL, 1.07 mmol). Add dropwise at -20 ° C for 45 minutesN A solution of iodobutaneimine (280 mg, 1.24 mmol) in anhydrous MeCN (15 mL). The resulting orange solution was stirred at 0 °C for 2 h and stirred at RT for 1 h. The reaction was then diluted with EtOAc (50 mL) and added (1:1) NaHCO3 /Na2 S2 O3 The aqueous solution (30 mL) was quenched. The phases were separated and the organic layer was washed with brine (40 mL)2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid46 (278 mg, yield 57%).benzoic acid ((2S, 3S, 4R, 5R)-5-(6-( Cyclopropyl ( methyl ) Amine )-2- Ibuprofen -9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methyl ester (47) . . to46 (278 mg, 0.51 mmol) sodium benzoate (1.09 g, 7.65 mmol) was added to aq. The resulting milky white suspension was stirred at 100 ° C for 3 days. The mixture is then cooled and distributed to H2 Between O (460 mL) and EtOAc (80 mL) and separate phases. The aqueous layer was back extracted with EtOAc (3 x 50 mL). With NH4 The combined organics were washed with a saturated aqueous solution of Cl (2 x 80 mL) and brine (80 mL). Organic solution via anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining the product as an off-white solid47 (222 mg, yield 80%).(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (48) . Will be sealed in a container at 80 ° C47 (220 mg, 0.40 mmol) in EtOAc (3%EtOAc) The mixture was then allowed to cool and concentrated. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining a product as a white solid48 (118 mg, yield 79%).1 H NMR (300 MHz, CD3 OD)δ 8.00 (s, 1H), 6.45 (d,J = 12.6 Hz, 1H), 4.66 (m, 1H), 3.86 (m, 2H), 3.32 (overlap with MeOH, m, 3H), 3.15 (m, 1H), 1.22 (d,J = 16.8 Hz, 3H), 0.92 (m, 2H), 0.72 (m, 2H). C15 Htwenty one F2 N6 O3 [M+H]+ MS (ESI)m/z Calculated 371.2; experimental value 371.2.(2S, 3S, 4R, 5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- Phenylmethyl carbonate (49) . At 0 ° C48 (38 mg, 0.10 mmol) and a solution of DMAP (13 mg, 0.11 mmol The reaction mixture was stirred at rt for 3 h and diluted with DCM Solution with H2 Washed with O (5 mL) and brine (5 mL) over anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAcEtOAc Obtaining a product as a white solid49 (35 mg, yield 68%).(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-3-((( Benzyloxy ) Carbonyl ) Oxyl )-2,4- Difluoro -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (50) . Compound at 0 ° C49 (35 mg, 0.07 mmol) and ((R ,S )-(pentafluorophenoxy)-phenoxy-phosphonium)-L DBU (21 μL, 0.14 mmol) was added dropwise to a solution of isopropyl propylamine (50 mg, 0.11 mmol) in anhydrous THF (3 mL). The reaction mixture was stirred at RT for 16 h. Then with EtOAc (6 mL) and NH4 The solution was diluted with a saturated aqueous solution of Cl (4 mL). The phases were separated and the aqueous extracted with EtOAc (3 &lt The combined organics were washed with brine (10 mL) over Na2 SO4 Dry and concentrate. Containing product50 The residue was used as such in the next step.(2S)-2-(((((S(2S,3S,4R,5R)-5-(2- Amine -6-( Cyclopropyl ( methyl ) Amine )-9H- 嘌呤 -9- base )-2,4- Difluoro -3- Hydroxyl -4- Methyltetrahydrofuran -2- base ) Methoxy ) Phenoxy ) Phosphonium ) Amine ) Isopropyl propionate (51) . Containing compounds50 Palladium (10% / charcoal) (6 mg) was added to a solution of the mixture in EtOH (3 mL). The flask was flushed with hydrogen and the suspension was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through celite and concentrated. By column chromatography (tank, DCM/MeOH 0 to 10%) and then by reverse phase column chromatography (C-18 tannin, H2 O/MeOH 100:0 to 0:100) purified residue. Obtaining a product as a white solid51 (13 mg, 29% in 2 steps).1 H NMR (300 MHz, CD3 OD)δ 7.79 (m, 1H), 7.34-7.14 (m, 5H), 6.43 (d,J = 17.4 Hz) and 6.41 (d,J = 18.0 Hz, 1H), 4.95-4.86 (with H2 O overlap, m, 1H), 4.63-4.52 (m, 1H), 4.47-4.34 (m, 1H), 3.96-3.85 (m, 1H), 3.32-3.30 (overlap with MeOH, m, 4H), 3.16- 3.07 (m, 1H), 1.32-1.18 (m, 12H), 0.92 (m, 2H), 0.71 (m, 2H).31 P NMR (121 MHz, CD3 OD)δ 4.16 (s), 4.05 (s). C27 H37 F2 N7 O7 P [M+H]+ MS (ESI)m /z Calculated value 640.2; experimental value 640.4.i) tBuONO, pyridine • HF, pyridine, -15 ° C(2S, 3S, 4R, 5R)-5-(2- fluorine -6-( Dimethylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (52) . will8 (80 mg, 0.23 mmol) in a solution of anhydrous pyridine (500 μL) was cooled to -15 ° C, and hydrofluorinated pyridine (300 μL) was added. Subsequently, tert-butyl nitrite (61 μL, 0.46 mmol) was added dropwise over 5 min. The mixture was stirred at 10 ° C for 4 h with the addition of CaCO3 (800 mg) in H2 The suspension in O (2 mL) was quenched. The resulting suspension was stirred at rt for 15 min and EtOAc (EtOAc &lt The combined organics are anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining the product as an off-white solid52 (52 mg, yield 65%).1 H NMR (300 MHz, CD3 OD)δ 8.25 (s, 1H), 6.48 (d,J = 16.4 Hz, 1H), 4.59 (dd,J = 24.8, 20.0 Hz, 1H), 3.90-3.82 (m, 2H), 3.74 (br s, 3H), 3.27 (br s, 3H), 1.20 (d,J = 22.4 Hz, 3H). C13 H17 F3 N5 O3 [M+H]+ MS (ESI)m /z Calculated 348.1; experimental value 348.2.i) tBuONO, pyridine • HF, pyridine, -15 ° C(2S, 3S, 4R, 5R)-5-(2- fluorine -6-( Methylamino )-9H- 嘌呤 -9- base )-2,4- Difluoro -2-( Hydroxymethyl )-4- Methyltetrahydrofuran -3- alcohol (53) . will18 (70 mg, 0.21 mmol) in a solution of anhydrous pyridine (500 μL) was cooled to -15 ° C, and hydrofluorinated pyridine (280 μL) was added. Subsequently, tert-butyl nitrite (57 μL, 0.42 mmol) was added dropwise over 5 min. The mixture was stirred at 10 ° C for 4 h with the addition of CaCO3 (800 mg) in H2 The suspension in O (2 mL) was quenched. The resulting suspension was stirred at rt for 15 min and EtOAc (EtOAc &lt The combined organics are anhydrous Na2 SO4 Dry and concentrate. The residue was purified by column chromatography (EtOAc, EtOAc (EtOAc) Obtaining the product as an off-white solid53 (43 mg, yield 62%).1 H NMR (300 MHz, CD3 OD)δ 8.26 (s, 1H), 6.45 (d,J = 16.5 Hz, 1H), 4.61 (m, 1H), 3.86 (m, 2H), 3.06 (s, 3H), 1.21 (d,J = 22.2 Hz, 3H). C12 H15 F3 N5 O3 [M+H]+ MS (ESI)m /z Calculated value 334.1; experimental value 334.2.Intermediate 1 Synthesis Process At -20 ° C1a Addition of NaAlH to a suspension of (111 g, 300 mmol) in toluene (200 mL)2 (OCH2 CH2 OCH3 )2 (81 mL, 300 mmol) and the mixture was stirred for 20 min. TLC analysis indicated the starting material was depleted. The reaction mixture was poured into a cooled aqueous HCl solution (1M, 330 mL). The separated organic layer was washed with water, brine and concentrated. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc1b (80 g). Will be rough1b Dissolved in MeOH (300 mL) and H2 In O (1 mL), the solution was stirred for 1 h while the product was being precipitated. After filtration, the filter cake was dried to give an off-white solid.1a .to1b (75 g, 185 mmol) Add PPh to a solution in MeCN (20 mL)3 (120 g, 455 mmol). CBr4 (120 g, 361 mmol) was added portionwise to the mixture (temperature was kept below -20 °C). After stirring for 1 h at RT, TLC indicated the starting material was consumed. Water (20 mL) was added and the mixture was stirred for 5 min. After filtration, the filter cake was wet-milled with MeOH to give1c (66 g, 75%).To 2-amino-6-chloropurine (69 g, 414 mmol)t Add to the suspension in -BuOH (600 mL)t -BuOK (46 g). Then add MeCN at 50 ° C andT384-0 (65 g, 138 mmol). After stirring at 60-65 ° C for 20 h, TLC indicated the starting material was consumed. After the mixture was cooled to RT and filtered, the filtrate was adjusted to pH = 7 using concentrated HCl solution. Filter and concentrate the mixture. By column chromatography (CH2 Cl2 Purify the residue to obtain1 (35 g).appendix Biological data Instance X. Verification method and biological data Inoculate Huh-7 luc/neo ET cells containing two non-cistronic HCV genotype 1b luciferase reporter replicons at 7.5 × 103 Cells/ml two replicate 96-well plates for parallel determination of antiviral efficacy (EC)50 And cytotoxicity (TC50 ). Plates were incubated for 24 hours prior to compound addition. Six series of semi-log serial dilutions of test articles (high test concentration of 100.0 μM or high test concentration of 1.0 μM) and human interferon-α2b (high test 10.0 U/ml) were prepared in cell culture medium and added to Used in cultured cells in three replicate wells of each dilution. The six wells in the test plate received only the medium as an untreated control. After 72 hours of incubation in the presence of the compound, one of the plates was used to determine cytotoxicity by staining with XTT, and the other was used for antiviral efficacy by measuring luciferase reporter activity. Collect cytotoxicity and efficacy data and import custom Excel workbooks to determine TC50 And EC50 value. Table XXX. Replicon test results for the compounds tested. As used herein, the terms about and should be construed as including any value within 5% of the stated value. In addition, reference to a range of values is to be construed as including the upper and lower limits of the range. As used herein, the terms first, second, third, and the like are to be interpreted as the sole meaning of the elements and do not imply or limit any particular ordering of the elements or steps. Concentrations, amounts, and other numerical data may be present herein in a range format (eg, from about 5% to about 20%). It is to be understood that the scope of the present invention is to be construed as being limited to the purpose of the present invention. Or sub-ranges, as the values and sub-ranges are explicitly recited, unless otherwise indicated. For example, a range of from about 5% to about 20% should be construed as including numerical values such as, but not limited to, 5%, 5.5%, 9.7%, 10.3%, 15%, etc., and sub-ranges such as, but not limited to, 5% to 10%, 10% to 15%, 8.9% to 18.9%, and the like. Although the present invention has been shown and described with respect to some aspects of the present invention, it will be understood by those skilled in the art that the invention is not limited thereto, but may be varied without departing from the spirit and scope of the invention. . In addition, it is to be understood that the forms shown and described herein are considered as the preferred embodiments. Various changes and modifications can be made to the various processing steps and each processing step as would be apparent to those skilled in the art. The scope of the following claims is to be construed as covering all such modifications and changes, and Further, it is intended that the scope of the appended claims be construed as including the alternative embodiments.

Claims (32)

一種具有式I或式II之化合物，及式I 式II 其中： R1 為C1 -C5 烷基或-(C0 -C2 烷基)(C3 -C6 環烷基)； R2 為氫、C1 -C5 烷基、CHF2 、CH2 F、CF3 、-(C0 -C2 烷基)、(C3 -C6 環烷基)、-C(O)R3C 、-C(S)R3C 、-(C0 -C2 烷基)(芳基)、-(C0 -C2 烷基)(雜環)或-(C0 -C2 烷基)(雜芳基)；或 R1 及R2 連同其等所鍵結之氮可形成雜環； R3 為氫、、二磷酸酯、三磷酸酯、視情況經取代之羰基鍵聯之胺基酸、-C(S)R3C 、-C(S)R3C 或-C(O)R3C ； R3A 為O- 、OH、視情況經-O-取代之芳基、視情況經-O-取代之雜芳基或視情況經取代之雜環基； R3B 為O- 、OH、視情況經取代之N鍵聯之胺基酸或視情況經取代之N鍵聯之胺基酸酯； R3C 為視情況經取代之烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之-(C0 -C2 )(環烷基)、視情況經取代之-(C0 -C2 )(雜環)、視情況經取代之-(C0 -C2 )(芳基)、視情況經取代之-(C0 -C2 )(雜芳基)、視情況經取代之-O-烷基、視情況經取代之-O-烯基、視情況經取代之-O-炔基、視情況經取代之-O-(C0 -C2 )(環烷基)、視情況經取代之-O-(C0 -C2 )(雜環)、視情況經取代之-O-(C0 -C2 )(芳基)、視情況經取代之-O-(C0 -C2 )(雜芳基)、視情況經取代之-S-烷基、視情況經取代之-S-烯基、視情況經取代之-S-炔基、視情況經取代之-S-(C0 -C2 )(環烷基)、視情況經取代之-S-(C0 -C2 )(雜環)、視情況經取代之-S-(C0 -C2 )(芳基)或視情況經取代之-S-(C0 -C2 )(雜芳基)； R4 為單磷酸酯、二磷酸酯、三磷酸酯或在寄主動物中可代謝為單磷酸酯、二磷酸酯或三磷酸酯之部分；或 R3 及R4 連同其等所鍵結之氧可形成3',5'-環狀前藥； R5 為氫、C1 -C5 烷基或-(C0 -C2 烷基)(C3 -C6 環烷基)； R6 為C1 -C5 烷基、-(C0 -C2 烷基)(C3 -C6 環烷基)、-(C0-6 烷基)(芳基)、-(C0-6 烷基)(雜芳基)、-(C0-6 烷基)(雜環)、-C(S)R3C 或-C(O)R3C ； R12 為CH3 、CH2 F、CHF2 、CF3 或乙炔基；或 其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物(analog)或醫藥學上可接受之鹽。a compound of formula I or formula II, and Formula I Formula II wherein: R 1 is C 1 -C 5 alkyl or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 2 is hydrogen, C 1 -C 5 alkyl , CHF 2 , CH 2 F, CF 3 , -(C 0 -C 2 alkyl), (C 3 -C 6 cycloalkyl), -C(O)R 3C , -C(S)R 3C ,- (C 0 -C 2 alkyl)(aryl), -(C 0 -C 2 alkyl)(heterocyclic) or -(C 0 -C 2 alkyl)(heteroaryl); or R 1 and R 2 together with its nitrogen bonded to form a heterocyclic ring; R 3 is hydrogen, , a diphosphate, a triphosphate, an optionally substituted carbonyl-bonded amino acid, -C(S)R 3C , -C(S)R 3C or -C(O)R 3C ; R 3A is O - , OH, optionally -O-substituted aryl, optionally -O-substituted heteroaryl or optionally substituted heterocyclic; R 3B is O - , OH, optionally substituted N a linked amino acid or an optionally substituted N-linked amino acid ester; R 3C is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally Substituted -(C 0 -C 2 )(cycloalkyl), optionally substituted -(C 0 -C 2 )(heterocyclic), optionally substituted -(C 0 -C 2 )(aryl) Substituting - (C 0 -C 2 ) (heteroaryl), optionally substituted -O-alkyl, optionally substituted -O-alkenyl, as appropriate - O-alkynyl, optionally substituted -O-(C 0 -C 2 )(cycloalkyl), optionally substituted -O-(C 0 -C 2 )(heterocyclic), optionally substituted -O-(C 0 -C 2 )(aryl), optionally substituted -O-(C 0 -C 2 )(heteroaryl), optionally substituted -S-alkyl, as appropriate Substituted -S-alkenyl, as appropriate And -S-alkynyl, optionally substituted -S-(C 0 -C 2 )(cycloalkyl), optionally substituted -S-(C 0 -C 2 )(heterocyclic), Substituting -S-(C 0 -C 2 )(aryl) or optionally substituted -S-(C 0 -C 2 )(heteroaryl); R 4 is monophosphate, diphosphate , a triphosphate or a moiety that can be metabolized to a monophosphate, diphosphate or triphosphate in a host; or R 3 and R 4 together with an oxygen bonded thereto can form a 3', 5'-ring Prodrug; R 5 is hydrogen, C 1 -C 5 alkyl or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 6 is C 1 -C 5 alkyl, -( C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl), -(C 0-6 alkyl)(aryl), -(C 0-6 alkyl)(heteroaryl), -( C 0-6 alkyl)(heterocyclic), -C(S)R 3C or -C(O)R 3C ; R 12 is CH 3 , CH 2 F, CHF 2 , CF 3 or ethynyl; Racemates, enantiomers, diastereomers, isotopically labeled analogs or pharmaceutically acceptable salts. 如請求項1之化合物，其中R4 為經穩定化的磷酸酯前藥、胺基磷酸酯或硫代胺基磷酸酯。The compound of claim 1, wherein R 4 is a stabilized phosphate prodrug, an amino phosphate or a thioamino phosphate. 如請求項1之化合物，其中該化合物為式Ia之化合物：式Ia； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物、或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is a compound of formula Ia: Formula Ia; or a racemate, enantiomer, diastereomer, isotopically labeled analog thereof, or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中該化合物為： ；或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 2, wherein the compound is: Or its racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt. 如請求項1之化合物，其中該化合物為式Ib之化合物：式Ib； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is a compound of formula Ib: Formula Ib; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R3 為氫。The compound of claim 1, wherein R 3 is hydrogen. 如請求項1之化合物，其中R1 為甲基且R2 為氫。The compound of claim 1, wherein R 1 is methyl and R 2 is hydrogen. 如請求項1之化合物，其中R1 及R2 兩者皆為甲基。The compound of claim 1, wherein both R 1 and R 2 are methyl. 如請求項1之化合物，其中R1 為甲基且R2 為環丙基。The compound of claim 1, wherein R 1 is methyl and R 2 is cyclopropyl. 如請求項1之化合物，其中該化合物為 ； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is Or its racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt. 如請求項1之化合物，其中該化合物為式II之化合物：式II 其中： R5 為氫、C1 -C5 烷基或-(C0 -C2 烷基)(C3 -C6 環烷基)； R6 為C1 -C5 烷基、-(C0 -C2 烷基)(C3 -C6 環烷基)、-(C0-6 烷基)(芳基)、-(C0-6 烷基)(雜芳基)、-(C0-6 烷基)(雜環)或-C(O)R3C ； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is a compound of formula II: Wherein R 5 is hydrogen, C 1 -C 5 alkyl or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 6 is C 1 -C 5 alkyl, - (C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl), -(C 0-6 alkyl)(aryl), -(C 0-6 alkyl)(heteroaryl), - (C 0-6 alkyl)(heterocyclic) or -C(O)R 3C ; or a racemate, enantiomer, diastereomer, isotopically labeled analog or medicinal Acceptable salt. 如請求項11之化合物，其中該化合物為 ； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 11, wherein the compound is Or its racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt. 如請求項11之方法，其中該化合物為式IIa之化合物：式IIa； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The method of claim 11, wherein the compound is a compound of formula IIa: Formula IIa; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項11之化合物，其中該化合物為式IIb之化合物：式IIb； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 11, wherein the compound is a compound of formula IIb: Formula IIb; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中該化合物為式III之化合物：式III， 其中R7 為氫、C1-6 烷基；C3-7 環烷基；雜芳基、雜環或包括但不限於苯基或萘基之芳基，其中苯基或萘基視情況經以下取代：C1-6 烷基、C2-6 烯基、C2-6 炔基、C1-6 烷氧基、F、Cl、Br、I、硝基、氰基、C1-6 鹵烷基、-N(R7' )2 、C1-6 醯胺基、NHSO2 C1-6 烷基、-SO2 N(R7' )2 、COR7" 及-SO2 C1-6 烷基；(R7' 獨立地為氫或C1-6 烷基；R7" 為-OR11 或-N(R7 )2 )； R8 為氫、C1-6 烷基，或R9a 或R9b 及R8 共同為(CH2 )n ，從而形成包括鄰接N原子及C原子之環狀環；其中n為2至4；R9a 及R9b (i)獨立地選自氫、C1-6 烷基、環烷基、-(CH2 )c (NR9' )2 、C1-6 羥烷基、-CH2 SH、-(CH2 )2 S(O)(Me)、-(CH2 )3 NHC(=NH)NH2 、(lH-吲哚-3-基)甲基、(lH-咪唑-4-基)甲基、-(CH2 )c COR9" 、芳基及芳基(C1-3 烷基)-，該等芳基視情況經選自以下之基團取代：羥基、C1-6 烷基、C1-6 烷氧基、鹵素、硝基及氰基；(ii) R9a 及R9b 兩者皆為C1-6 烷基；(iii) R9a 及R9b 共同為(CH2 )r ，從而形成螺環；(iv) R9a 為氫且R9b 及R8 共同為(CH2 )n ，從而形成包括該等鄰接N原子及C原子之環狀環；(v) R9b 為氫且R9a 及R8 共同為(CH2 )n ，從而形成包括該等鄰接N原子及C原子之環狀環，其中c為1至6，n為2至4，r為2至5且其中R9' 獨立地為氫或C1-6 烷基且R9" 為-OR11 或-N(R11' )2 ；(vi) R9a 為氫且R9b 為氫、CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基；或(vii) R9a 為CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基，且R9b 為氫； R10 為氫、視情況經烷氧基、二(低碳數烷基)-胺基或鹵素取代之C1-6 烷基；C1-6 鹵烷基、(C0 -C2 )(C3-7 環烷基)、(C0 -C2 )(雜環烷基)、胺基醯基、(C0 -C2 )(芳基)，諸如(C0 -C2 )(苯基)、(C0 -C2 )(雜芳基)，諸如(C0 -C2 )(吡啶基)、經取代之(C0 -C2 )(芳基)或經取代之(C0 -C2 )(雜芳基)； R11 為視情況經取代之C1-6 烷基、視情況經取代之環烷基；視情況經取代之C2-6 炔基、視情況經取代之C2-6 烯基或視情況經取代之醯基，其包括但不限於C(O)(C1-6 烷基)； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is a compound of formula III: Formula III, wherein R 7 is hydrogen, C 1-6 alkyl; C 3-7 cycloalkyl; heteroaryl, heterocyclic or aryl including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl Substituted as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C 1-6 haloalkyl, -N(R 7' ) 2 , C 1-6 fluorenylamine, NHSO 2 C 1-6 alkyl, -SO 2 N(R 7' ) 2 , COR 7" and -SO 2 C 1-6 alkyl; (R 7 'is independently hydrogen or C 1-6 alkyl; R 7" is -OR 11 or -N(R 7 ) 2 ); R 8 is hydrogen, C 1-6 An alkyl group, or R 9a or R 9b and R 8 together are (CH 2 ) n , thereby forming a cyclic ring including adjacent N atoms and C atoms; wherein n is 2 to 4; R 9a and R 9b (i) are independent Selected from hydrogen, C 1-6 alkyl, cycloalkyl, -(CH 2 ) c (NR 9' ) 2 , C 1-6 hydroxyalkyl, -CH 2 SH, -(CH 2 ) 2 S ( O) (Me), -(CH 2 ) 3 NHC(=NH)NH 2 , (lH-indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH 2 ) c COR 9" , aryl and aryl (C 1-3 alkyl)-, which are optionally substituted with a group selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy Base, halogen, nitro and cyano; (ii) R 9a and R 9b is both C 1-6 alkyl; (iii) R 9a and R 9b are together (CH 2 ) r to form a spiro ring; (iv) R 9a is hydrogen and R 9b and R 8 are together ( CH 2 ) n , thereby forming a cyclic ring including the adjacent N atoms and C atoms; (v) R 9b is hydrogen and R 9a and R 8 are together (CH 2 ) n , thereby forming the adjacent N atom And a cyclic ring of a C atom, wherein c is 1 to 6, n is 2 to 4, r is 2 to 5 and wherein R 9 'is independently hydrogen or C 1-6 alkyl and R 9" is -OR 11 Or -N(R 11 ' ) 2 ; (vi) R 9a is hydrogen and R 9b is hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 ) CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH (OH)CH 3 , CH 2 ((4'-OH)-Ph), CH 2 SH or a lower number of cycloalkyl groups; or (vii) R 9a is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH , CH(OH)CH 3 , CH 2 ((4'-OH)-Ph), CH 2 SH or a lower number of cycloalkyl groups, and R 9b is hydrogen; R 10 is hydrogen, optionally alkoxy, Di(lower alkyl)-amino or halogen substituted C 1-6 alkyl; C 1-6 haloalkyl, (C 0 -C 2 )(C 3-7 cycloalkyl), (C 0 -C 2 )(heterocycloalkyl), amino fluorenyl, (C 0 -C 2 )(aryl), such as (C 0 -C 2 )(phenyl), (C 0 -C 2 )(hetero) Aryl), such as (C 0 -C 2 )(pyridyl), substituted (C 0 -C 2 )(aryl) or substituted (C 0 -C 2 )(heteroaryl); R 11 Optionally substituted C 1-6 alkyl, optionally substituted cycloalkyl; optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl or, as appropriate, substituted a thiol group, including but not limited to C(O)(C 1-6 alkyl); or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutical thereof A salt that is acceptable for learning. 如請求項15之化合物，其中該化合物為式IV之化合物：式IV； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 15 wherein the compound is a compound of formula IV: Formula IV; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項15之化合物，其中該化合物為式V之化合物：式V； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 15 wherein the compound is a compound of formula V: Formula V; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中該化合物為式VI之化合物：式VI， 其中R7 為氫、C1-6 烷基；C3-7 環烷基；雜芳基、雜環或包括但不限於苯基或萘基之芳基，其中苯基或萘基視情況經以下取代：C1-6 烷基、C2-6 烯基、C2-6 炔基、C1-6 烷氧基、F、Cl、Br、I、硝基、氰基、C1-6 鹵烷基、-N(R7' )2 、C1-6 醯胺基、NHSO2 C1-6 烷基、-SO2 N(R7' )2 、COR7" 及-SO2 C1-6 烷基；(R7' 獨立地為氫或C1-6 烷基；R7" 為-OR11 或-N(R7 )2 )； R8 為氫、C1-6 烷基，或R9a 或R9b 及R8 共同為(CH2 )n ，從而形成包括該等鄰接N原子及C原子之環狀環；其中n為2至4；R9a 及R9b (i)獨立地選自氫、C1-6 烷基、環烷基、-(CH2 )c (NR9' )2 、C1-6 羥烷基、-CH2 SH、-(CH2 )2 S(O)(Me)、-(CH2 )3 NHC(=NH)NH2 、(lH-吲哚-3-基)甲基、(lH-咪唑-4-基)甲基、-(CH2 )c COR9" 、芳基及芳基(C1-3 烷基)-，該等芳基視情況經選自以下之基團取代：羥基、C1-6 烷基、C1-6 烷氧基、鹵素、硝基及氰基；(ii) R9a 及R9b 兩者皆為C1-6 烷基；(iii) R9a 及R9b 共同為(CH2 )r 從而形成螺環；(iv) R9a 為氫且R9b 及R8 共同為(CH2 )n ，從而形成包括該等鄰接N原子及C原子之環狀環；(v) R9b 為氫且R9a 及R8 共同為(CH2 )n ，從而形成包括該等鄰接N原子及C原子之環狀環，其中c為1至6，n為2至4，r為2至5且其中R9' 獨立地為氫或C1-6 烷基且R9" 為-OR11 或-N(R11' )2 ；(vi) R9a 為氫且R9b 為氫、CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基；或(vii) R9a 為CH3 、CH2 CH3 、CH(CH3 )2 、CH2 CH(CH3 )2 、CH(CH3 )CH2 CH3 、CH2 Ph、CH2 -吲哚-3-基、-CH2 CH2 SCH3 、CH2 CO2 H、CH2 C(O)NH2 、CH2 CH2 COOH、CH2 CH2 C(O)NH2 、CH2 CH2 CH2 CH2 NH2 、-CH2 CH2 CH2 NHC(NH)NH2 、CH2 -咪唑-4-基、CH2 OH、CH(OH)CH3 、CH2 ((4'-OH)-Ph)、CH2 SH或低碳數環烷基，且R9b 為氫； R10 為氫、視情況經烷氧基、二(低碳數烷基)-胺基或鹵素取代之C1-6 烷基；C1-6 鹵烷基、(C0 -C2 )(C3-7 環烷基)、(C0 -C2 )(雜環烷基)、胺基醯基、(C0 -C2 )(芳基)，諸如(C0 -C2 )(苯基)、(C0 -C2 )(雜芳基)，諸如(C0 -C2 )(吡啶基)、經取代之(C0 -C2 )(芳基)或經取代之(C0 -C2 )(雜芳基)； R11 為視情況經取代之C1-6 烷基、視情況經取代之環烷基；視情況經取代之C2-6 炔基、視情況經取代之C2-6 烯基或視情況經取代之醯基，其包括但不限於C(O)(C1-6 烷基)； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is a compound of formula VI: Formula VI, wherein R 7 is hydrogen, C 1-6 alkyl; C 3-7 cycloalkyl; heteroaryl, heterocyclic or aryl including but not limited to phenyl or naphthyl, wherein phenyl or naphthyl Substituted as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C 1-6 haloalkyl, -N(R 7' ) 2 , C 1-6 fluorenylamine, NHSO 2 C 1-6 alkyl, -SO 2 N(R 7' ) 2 , COR 7" and -SO 2 C 1-6 alkyl; (R 7 'is independently hydrogen or C 1-6 alkyl; R 7" is -OR 11 or -N(R 7 ) 2 ); R 8 is hydrogen, C 1-6 An alkyl group, or R 9a or R 9b and R 8 together are (CH 2 ) n , thereby forming a cyclic ring including the adjacent N atoms and C atoms; wherein n is 2 to 4; R 9a and R 9b (i ) independently selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, -(CH 2 ) c (NR 9' ) 2 , C 1-6 hydroxyalkyl, -CH 2 SH, -(CH 2 ) 2 S(O)(Me), -(CH 2 ) 3 NHC(=NH)NH 2 , (lH-indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH 2 ) c COR 9" , aryl and aryl (C 1-3 alkyl)-, which are optionally substituted with a group selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 Alkoxy, halogen, nitro and cyano; (ii) R 9a and R 9b are both C 1-6 alkyl; (iii) R 9a and R 9b are together (CH 2 ) r to form a spiro ring; (iv) R 9a is hydrogen and R 9b and R 8 are (CH 2 ) n , thereby forming a cyclic ring including the adjacent N atoms and C atoms; (v) R 9b is hydrogen and R 9a and R 8 are together (CH 2 ) n , thereby forming the adjacent N a cyclic ring of an atom and a C atom, wherein c is 1 to 6, n is 2 to 4, r is 2 to 5 and wherein R 9 'is independently hydrogen or C 1-6 alkyl and R 9" is -OR 11 or -N(R 11 ' ) 2 ; (vi) R 9a is hydrogen and R 9b is hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH ( CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH , CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4'-OH)-Ph), CH 2 SH or a lower number of cycloalkyl groups; or (vii) R 9a is CH 3 , CH 2 CH 3 , CH (CH 3 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH , CH(OH)CH 3 , CH 2 ((4'-OH)-Ph), CH 2 SH or a lower number of cycloalkyl groups, and R 9b is hydrogen; R 10 is hydrogen, optionally alkoxy, Di(lower alkyl)-amino or halogen substituted C 1-6 alkyl; C 1-6 haloalkyl, (C 0 -C 2 )(C 3-7 cycloalkyl), (C 0 -C 2 )(heterocycloalkyl), amino fluorenyl, (C 0 -C 2 )(aryl), such as (C 0 -C 2 )(phenyl), (C 0 -C 2 )(hetero) Aryl), such as (C 0 -C 2 )(pyridyl), substituted (C 0 -C 2 )(aryl) or substituted (C 0 -C 2 )(heteroaryl); R 11 Optionally substituted C 1-6 alkyl, optionally substituted cycloalkyl; optionally substituted C 2-6 alkynyl, optionally substituted C 2-6 alkenyl or, as appropriate, substituted a thiol group, including but not limited to C(O)(C 1-6 alkyl); or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutical thereof A salt that is acceptable for learning. 如請求項18之化合物，其中該化合物為式VII之化合物：式VII； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 18, wherein the compound is a compound of formula VII: Formula VII; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項18之化合物，其中該化合物為式VIII之化合物：式VIII； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 18, wherein the compound is a compound of formula VIII: Formula VIII; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 一種具有式IX之化合物：式IX 其中： R1 為C1 -C5 烷基或-(C0 -C2 烷基)(C3 -C6 環烷基)； R2 為氫、C1 -C5 烷基、CHF2 、CH2 F、CF3 、-(C0 -C2 烷基)、(C3 -C6 環烷基)、-C(O)R3C 、-C(S)R3C 、-(C0 -C2 烷基)(芳基)、-(C0 -C2 烷基)(雜環)、-(C0 -C2 烷基)(雜芳基)；或 R1 及R2 連同其等所鍵結之氮可形成雜環； R3 為氫、二磷酸酯、三磷酸酯、視情況經取代之羰基鍵聯之胺基酸、-C(S)R3C 、-C(S)R3C 或-C(O)R3C ； R3A 選自O- 、OH、視情況經-O-取代之芳基、視情況經-O-取代之雜芳基或視情況經取代之雜環基； R3B 選自O- 、OH、視情況經取代之N鍵聯之胺基酸或視情況經取的N鍵聯之胺基酸酯； R3C 為視情況經取代之烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之-(C0 -C2 )(環烷基)、視情況經取代之-(C0 -C2 )(雜環)、視情況經取代之-(C0 -C2 )(芳基)、視情況經取代之-(C0 -C2 )(雜芳基)、視情況經取代之-O-烷基、視情況經取代之-O-烯基、視情況經取代之-O-炔基、視情況經取代之-O-(C0 -C2 )(環烷基)、視情況經取代之-O-(C0 -C2 )(雜環)、視情況經取代之-O-(C0 -C2 )(芳基)、視情況經取代之-O-(C0 -C2 )(雜芳基)、視情況經取代之-S-烷基、視情況經取代之-S-烯基、視情況經取代之-S-炔基、視情況經取代之-S-(C0 -C2 )(環烷基)、視情況經取代之-S-(C0 -C2 )(雜環)、視情況經取代之-S-(C0 -C2 )(芳基)或視情況經取代之-S-(C0 -C2 )(雜芳基)； R4 為單磷酸酯、二磷酸酯、三磷酸酯或在寄主動物中可代謝為單磷酸酯、二磷酸酯或三磷酸酯之部分；或 R3 及R4 連同其等所鍵結之氧可形成3',5'-環狀前藥； R' 5 為Cl、Br、F、N3 、-NHOCH3、-ONHC(=O)OCH3、CN、CONH2 、SO2 NH2 及CF3 ；或 其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。A compound of formula IX: Wherein: R 1 is C 1 -C 5 alkyl or -(C 0 -C 2 alkyl)(C 3 -C 6 cycloalkyl); R 2 is hydrogen, C 1 -C 5 alkyl, CHF 2 , CH 2 F, CF 3 , -(C 0 -C 2 alkyl), (C 3 -C 6 cycloalkyl), -C(O)R 3C , -C(S)R 3C , -(C 0- C 2 alkyl)(aryl), -(C 0 -C 2 alkyl)(heterocyclic), -(C 0 -C 2 alkyl)(heteroaryl); or R 1 and R 2 together The nitrogen bonded thereto may form a heterocyclic ring; R 3 is hydrogen, a diphosphate, a triphosphate, an optionally substituted carbonyl-linked amino acid, -C(S)R 3C , -C(S)R 3C or -C(O)R 3C ; R 3A is selected from O - , OH, optionally -O-substituted aryl, optionally -O-substituted heteroaryl or optionally substituted heterocyclic; R 3B is selected from O - , OH, optionally substituted N-linked amino acid or N-linked amino acid ester as appropriate; R 3C is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, Substituting -(C 0 -C 2 )(cycloalkyl), optionally substituted -(C 0 -C 2 )(heterocyclic), optionally substituted -(C 0 -C 2 )( Aryl), optionally substituted -(C 0 -C 2 )(heteroaryl), optionally substituted -O-alkyl, optionally substituted -O-alkenyl, optionally substituted -O-alkynyl, optionally substituted -O-(C 0 -C 2 )(cycloalkyl), optionally substituted -O-(C 0 -C 2 )(heterocyclic), optionally Substituted -O-(C 0 -C 2 )(aryl), optionally substituted -O-(C 0 -C 2 )(heteroaryl), optionally substituted -S-alkyl, The situation is replaced by -S-alkenyl, as appropriate And -S-alkynyl, optionally substituted -S-(C 0 -C 2 )(cycloalkyl), optionally substituted -S-(C 0 -C 2 )(heterocyclic), Substituting -S-(C 0 -C 2 )(aryl) or optionally substituted -S-(C 0 -C 2 )(heteroaryl); R 4 is monophosphate, diphosphate , a triphosphate or a moiety that can be metabolized to a monophosphate, diphosphate or triphosphate in a host; or R 3 and R 4 together with an oxygen bonded thereto can form a 3', 5'-ring Prodrug; R ' 5 is Cl, Br, F, N 3 , -NHOCH3, -ONHC(=O)OCH3, CN, CONH 2 , SO 2 NH 2 and CF 3 ; or its racemate, enantiomer A conformation, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt. 如請求項21之化合物，其中R4 為經穩定化的磷酸酯前藥、胺基磷酸酯或硫代胺基磷酸酯。The compound of claim 21, wherein R 4 is a stabilized phosphate prodrug, an amino phosphate or a thioamino phosphate. 如請求項21之化合物，其中該化合物為式X之化合物：式X； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 21, wherein the compound is a compound of formula X: Formula X; or a racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt thereof. 如請求項21之化合物，其中R3 為氫且R4 為 ； 或其外消旋體、對映異構體、非對映異構體、經同位素標記之類似物或醫藥學上可接受之鹽。The compound of claim 21, wherein R 3 is hydrogen and R 4 is Or its racemate, enantiomer, diastereomer, isotopically labeled analog or pharmaceutically acceptable salt. 如請求項21之化合物，其中該化合物為。The compound of claim 21, wherein the compound is . 一種治療有其需要之患者之方法，該方法包含投與治療有效量的如請求項1之化合物。A method of treating a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of claim 1. 如請求項26之方法，其中該患者遭受抗HCV抗體陽性病況、抗原陽性病況、基於病毒之慢性肝炎、因晚期C型肝炎、肝硬化、慢性或急性C型肝炎、爆發性C型肝炎、慢性持續性C型肝炎或基於抗HCV之疲勞所產生的肝癌。The method of claim 26, wherein the patient is subjected to an anti-HCV antibody-positive condition, an antigen-positive condition, a virus-based chronic hepatitis, a late-stage hepatitis C, cirrhosis, chronic or acute hepatitis C, an explosive hepatitis C, and a chronic Persistent hepatitis C or liver cancer based on fatigue caused by anti-HCV. 一種醫藥學上可接受之組合物，該組合物包含如請求項1之化合物及醫藥學上可接受的載劑。A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 一種治療有其需要之患者之方法，該方法包含投與如請求項21之化合物。A method of treating a patient in need thereof, the method comprising administering a compound as claimed in claim 21. 一種醫藥學上可接受之組合物，該組合物包含如請求項21之化合物及醫藥學上可接受之載劑。A pharmaceutically acceptable composition comprising a compound of claim 21 and a pharmaceutically acceptable carrier. 如請求項1之化合物，其中該化合物包含烷基化或醯基化之核苷酸基團。The compound of claim 1, wherein the compound comprises an alkylated or thiolated nucleotide group. 如請求項21之化合物，其中該化合物包含烷基化或醯基化之核苷酸基團。The compound of claim 21, wherein the compound comprises an alkylated or thiolated nucleotide group.
TW106144895A 2017-12-20 2017-12-20 [beta]-D-2'-deoxy-2'-[alpha]-fluoro-2'-[beta]-C-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis C virus TW201927312A (en)

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