TW200418452A - Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases - Google Patents
Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases Download PDFInfo
- Publication number
- TW200418452A TW200418452A TW92130711A TW92130711A TW200418452A TW 200418452 A TW200418452 A TW 200418452A TW 92130711 A TW92130711 A TW 92130711A TW 92130711 A TW92130711 A TW 92130711A TW 200418452 A TW200418452 A TW 200418452A
- Authority
- TW
- Taiwan
- Prior art keywords
- phenyl
- fluoro
- benzofuran
- carboxylic acid
- formamidine
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
Description
200418452 玫、發明說明: 【發明所屬之技術領域】 本發明係有關新穎之苯并呋喃衍生物與類似物,以及包 含相同成分之組合物,及有關治療或預防與此相關之病毒 感染與疾病之用途,特別是那些由肝炎C病毒造成之病毒感 染及與相關疾病。 【先前技術】 C型肝炎是常見的會造成慢性肝炎、肝硬化、肝臟衰竭與 肝癌之感染。肝炎C病毒(HCV)感染的案例,至少85%會造 成慢性肝炎。在美國,其為造成肝臟移植之主要原因,且 每年至少引發10,000個死亡病例(Hepatology,1997, 26 (增補 版 1),2S-10S)。 在美國,醫師使用干擾素與干擾素合併ribavirin (雷巴威 林)以治療HCV引起之肝癌。這些治療使某些病人體内之血 清酶反應改善。其餘的人則對治療無反應。對有反應者而 言,僅在極少百分比之病人可見持續之臨床改善;大部分 病人在停止後即回復。因此,慢性C型肝炎之治療的有效性 變化很大,且治癒率仍低。甚且,治療通常伴隨相當之副 作用。 很清楚地,我們需要對肝炎C病毒(HCV)造成之感染與疾 病之新的治療與預防方法。 肝炎C病毒是黃病毒科(Flaviviridae)之一員。HCV之基因 體為正向股之單股直線RNA (Hepatology,1997, 26 (增補版 1),11S-14S)。HCV展現廣泛之遺傳異質性,目前至少已確 88828.doc 200418452 認6種基因型與超過50種亞型。 經HCV感染後,病毒RNA會轉譯成多蛋白。此一約3,000 個殘基之多蛋白,後續會受宿主之肽酶與病毒編碼之蛋白 酶切成個別蛋白。HCV基因體編碼結構性蛋白(病毒組合所 需)與非結構性蛋白(複製所需)。某些非結構性蛋白包括: NS2、NS3、NS4A、NS4B、NS5A與 NS5B (J. General Virology, 2000,81,163 1-1648)。NS5B為病毒複製所須之RNA依賴型 RNA聚合酶。在諸如HCV之正向股RNA病毒,RNA為唯一 之遺傳材料。由於哺乳類宿主細胞一般缺乏RNA依賴型 RNA聚合酶活性,該正向股之RNA病毒編碼其自身之病毒 粒子子代生產所必須之複製性聚合酶(在HCV之情形為 NS5B)。因而,NS5B活性之抑制提供HCV藥物設計之吸引 性目標。 【發明内容】 根據一方面,本發明提供治療與預防病毒感染,以及與 活的宿主之病毒感染相關之疾病之化合物與組合物。本發 明化合物具下列通式:200418452 Description of the invention: [Technical field to which the invention belongs] The present invention relates to novel benzofuran derivatives and analogs, and compositions containing the same ingredients, and to the treatment or prevention of related viral infections and diseases Uses, especially those caused by hepatitis C virus and related diseases. [Prior art] Hepatitis C is a common infection that causes chronic hepatitis, cirrhosis, liver failure, and liver cancer. At least 85% of cases of hepatitis C virus (HCV) infection cause chronic hepatitis. It is the leading cause of liver transplantation in the United States and causes at least 10,000 deaths each year (Hepatology, 1997, 26 (Supplementary 1), 2S-10S). In the United States, physicians use interferon and interferon combined with ribavirin to treat liver cancer caused by HCV. These treatments have improved the serum enzyme response in some patients. The rest did not respond to treatment. For those who responded, sustained clinical improvement was seen in only a very small percentage of patients; most patients recovered after stopping. Therefore, the effectiveness of treatment for chronic hepatitis C varies widely, and the cure rate remains low. Moreover, treatment is often accompanied by considerable side effects. Clearly, we need new treatments and preventions for infections and diseases caused by hepatitis C virus (HCV). Hepatitis C virus is a member of the Flaviviridae family. The HCV genome is a single-stranded linear RNA with a forward strand (Hepatology, 1997, 26 (Supplementary Edition 1), 11S-14S). HCV exhibits a wide range of genetic heterogeneity, and at least 88828.doc 200418452 has identified 6 genotypes and more than 50 subtypes. After HCV infection, viral RNA is translated into polyproteins. This polyprotein of about 3,000 residues is subsequently digested into individual proteins by the host's peptidase and virus-encoded protein. The HCV genome encodes structural proteins (required for viral combinations) and non-structural proteins (required for replication). Some non-structural proteins include: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 163 1-1648). NS5B is an RNA-dependent RNA polymerase required for viral replication. In forward-strand RNA viruses such as HCV, RNA is the only genetic material. Since mammalian host cells generally lack RNA-dependent RNA polymerase activity, this forward-stranded RNA virus encodes a replicative polymerase (in the case of HCV, NS5B) necessary for the production of its own viral particle progeny. Thus, inhibition of NS5B activity provides an attractive target for HCV drug design. SUMMARY OF THE INVENTION According to one aspect, the present invention provides compounds and compositions for the treatment and prevention of viral infections and diseases related to viral infections in living hosts. The compounds of the invention have the following general formula:
其中:among them:
Ri代表選自氫、烷基、i素與氰基所組成之群組之基, R2代表選自氫、經取代或未經取代之烷基、經取代或未 88828.doc 200418452 經取代之烷氧基、羥基、環烷基、環烷氧基、多氟烷基、 多氟燒氧基、iS素、胺基、單燒胺基、二燒胺基、氰基、 經取代或未經取代之芊氧基與經取代或未經取代之雜環基 所組成之群組之基, R3代表選自氫、經取代或未經取代之烷基、經取代或未 經取代之烷氧基、烯基、鹵素、羥基、多氟烷基、多氟烷 氧基、甲醯基、羧基、烷羰基、烷氧羰基、羥烷羰基、胺 基、經取代或未經取代之單烷胺基、二烷胺基、氰基、醯 胺基、烷氧醯胺基、經取代或未經取代之雜芳胺基、乙醯 基績酸基胺基、脲基、瘦酿胺、績胺、經取代之績胺、經 取代或未經取代之雜環磺醯基、烷硫基、烷亞硫醯基、烷 磺醯基、烷基磺酸與經取代或未經取代之雜環基與 -o(ch2)-c(=o)-r7所組成之群組之基, R4代表選自氫、烷基、鹵素與烷氧基所組成之群組之基, R5代表選自烷(Ci-CO基與環烷基所組成之群組之基, R6代表選自經取代或未經取代之芳基與經取代或未經取 代之雜芳基所組成之群組之基, R7代表選自二烷胺基、經取代或未經取代之芳胺基、經 取代或未經取代之雜芳胺基與經取代或未經取代之芳基所 組成之群組之基, 該單烷胺基取代基係一或多種獨立選自環烷基、羥基、 烷氧基與經取代或未經取代之雜環基所組成之群組之基, 該芳胺基取代基與該雜芳胺基取代基係一或多種獨立選 自烷基與燒氧羧基所組成之群組之基, 88828.doc -10- 200418452 該磺胺取代基係一或多種獨立選自烯基、環烷基、烷氧 基、羥基、ii素、多氟烷基、多氟烷氧基、羧基、烷羰基 、燒氧羧基、複醯胺、經取代或未經取代之芳基與經取代 或未經取代之雜環基所組成之群組之基, 該雜環磺醯基取代基係一或多種獨立選自烷氧基與羥基 所組成之群組之基, 該烷基取代基與該烷氧基取代基係一或多種獨立選自晞 基、胺基、單烷胺基、二烷胺基、烷氧基、環烷基、羥基 、叛基、鹵素、氰基、多氟燒基、多氟燒氧基、續驢胺、 叛醯胺、燒續酸基、燒羰基、燒氧羰基、鏡基、苯并[1,3 ] 二噚畊基、經取代或未經取代之芳基與經取代或未經取代 之雜環基所組成之群組之基, 該雜環基取代基係一或多種獨立選自烷基、胺基、醯胺 基、單烷胺基、環烷基-烷胺基、二烷胺基、烷氧基、烷氧烷 基、羥基、羥烷基、環烷基、羧基、羧醯胺、iS素、i烷基 、氰基、多氟烷基、多氟烷氧基、烷磺醯基、烷羰基、環烷 羰基、烷氧羰基、巯基、氧基、經取代或未經取代之芳基、 芳烷基與經取代或未經取代之雜芳基所組成之群組之基, 該雜芳基取代基係一或多種獨立選自烷基、胺基、烷氧 基、烷氧烷基、羥基、羥烷基、環烷基、羧基、羧醯胺、 鹵素、多氟烷基、多氟烷氧基、烷磺醯基、巯基與氧基所 組成之群組之基, 該苄氧基取代基係一或多種獨立選自烷基、烷氧基、多 氟烷基、多氟烷氧基、羥基、羧基、烷氧羰基、i素、氰 88828.doc -11 - 200418452 基、烷磺醯基與苯基所組成之群組之基, 該芳基取代基係一或多種獨立選自烷基、烷氧基、羥基 、鹵素、多氟烷基、多氟烷氧基、氰基、胺基、單烷胺基 、-一燒胺基、胺燒基、虎氧挺氧基、酸胺基、驢胺燒基、 叛基、垸橫驢基、燒羧基、垸氧窥基、魏基與雜環基所組 成之群組之基,及其醫藥上可接受之鹽; 其限制條件為’該式並不包括選自下列所組成之群組之 化合物· 5 -甲氧基-2-苯基-苯并吱喃-3-幾酸甲酸胺與經基 -2-苯基-苯并呋喃-3-羧酸甲醯胺。 本發明亦係有關包含式I之抗病毒化合物之醫藥組人物 ,與治療與預防肝癌C病毒造成的感染之對應使用方法,以 及製備本文所述之抗病毒化合物之中間體化合物與相關方 法。 【實施方式】 在一方面,本發明提供式I化合物: 88828.docRi represents a group selected from the group consisting of hydrogen, an alkyl group, a prime element, and a cyano group, and R2 represents a group selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted 88828.doc 200418452 Oxy, hydroxy, cycloalkyl, cycloalkoxy, polyfluoroalkyl, polyfluoroalkoxy, iS element, amine, monoamine, diamine, cyano, substituted or unsubstituted A alkoxy group and a substituted or unsubstituted heterocyclic group, R3 represents a group selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, Alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formamyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, substituted or unsubstituted monoalkylamino, Dialkylamino, cyano, amido, alkoxyamido, substituted or unsubstituted heteroarylamino, ethylamino, amino, urea, lean amine, amino, Substituted amines, substituted or unsubstituted heterocyclic sulfosulfanyl, alkylthio, alkylthiosulfanyl, alkylsulfinyl, alkylsulfonic acid, and substituted or unsubstituted A group consisting of a cyclic group and -o (ch2) -c (= o) -r7, R4 represents a group selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy, and R5 represents a group selected from Alkane (Ci-CO group and cycloalkyl group group, R6 represents a group selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, R7 represents a group selected from the group consisting of a dialkylamino group, a substituted or unsubstituted arylamine group, a substituted or unsubstituted heteroarylamine group, and a substituted or unsubstituted aryl group, the Monoalkylamino substituents are one or more groups independently selected from the group consisting of cycloalkyl, hydroxyl, alkoxy, and substituted or unsubstituted heterocyclic groups. The arylamino substituent and the hetero The arylamine substituent is one or more groups independently selected from the group consisting of an alkyl group and an alkyloxy carboxyl group. 88828.doc -10- 200418452 The sulfonamide substituent is one or more groups independently selected from an alkenyl group and a cycloalkyl group. , Alkoxy, hydroxy, fluorene, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, oxocarboxyl, fluorenamine, substituted or unsubstituted aryl groups, and A group of a group consisting of a substituted or unsubstituted heterocyclic group, the heterocyclic sulfonyl substituent is one or more groups independently selected from the group consisting of an alkoxy group and a hydroxyl group, and the alkyl group is substituted And the alkoxy substituent are independently selected from one or more of fluorenyl, amine, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, alkyl, halogen, cyano, poly Fluorenyl, polyfluorinyloxy, ammonium, benzylamine, ammonium acid, carbonyl, oxocarbonyl, mirror group, benzo [1,3] dioxenyl, substituted or unsubstituted A group consisting of a substituted aryl group and a substituted or unsubstituted heterocyclic group, the heterocyclic group substituent being one or more independently selected from alkyl, amine, amido, and monoalkylamino , Cycloalkyl-alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, cycloalkyl, carboxyl, carboxamidine, iS element, ialkyl, cyano, polyalkyl Fluoroalkyl, polyfluoroalkoxy, alkanesulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, mercapto, oxy, substituted or unsubstituted aryl, aralkyl and substituted or unsubstituted A group of groups consisting of substituted heteroaryl groups, the heteroaryl substituents being one or more independently selected from alkyl, amine, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, cycloalkyl , A carboxyl group, a carboxylic acid amine, a halogen, a polyfluoroalkyl group, a polyfluoroalkoxy group, an alkanesulfonyl group, a mercapto group, and an oxy group; the benzyloxy substituent is independently selected from one or more groups Alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, i-prime, cyano 88828.doc -11-200418452, alkylsulfonyl and phenyl groups Group, the aryl substituent is one or more independently selected from the group consisting of alkyl, alkoxy, hydroxyl, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amine, monoalkylamino,- A group consisting of monoamine, amine, oxobutoxy, acid amine, donkey amine, renyl, hydrazone, carboxyl, oxonyl, weyl and heterocyclic groups And its pharmaceutically acceptable salts; the limitation is that the formula does not include compounds selected from the group consisting of: 5-methoxy-2-phenyl-benzo Acid-carboxylic acid and amine -3- several warp-2-phenyl - benzofuran-3-carboxylic acid A Amides. The present invention also relates to a person in the pharmaceutical group including an antiviral compound of formula I, a corresponding use method for treating and preventing infection caused by C virus of liver cancer, and an intermediate compound and a related method for preparing the antiviral compound described herein. [Embodiment] In one aspect, the invention provides a compound of formula I: 88828.doc
其中Ri、R2、R3、R4、115與尺6係如上述之定義。 在第二方面,本發明提供下式之化合物:Ri, R2, R3, R4, 115 and ruler 6 are as defined above. In a second aspect, the invention provides a compound of the formula:
200418452 其中:200418452 of which:
Ri代表選自氫、基、鹵素與氰基所組成之群組之基, R2代表選自氫、經取代或未經取代之烷基、經取代或未 經取代之烷氧基、羥基、環烷基、環烷氧基、多氟烷基、 多氟烷氧基、鹵素、胺基、單烷胺基、二烷胺基、氰基、 經取代或未經取代之苄氧基與經取代或未經取代之雜環基 所組成之群組之基,Ri represents a group selected from the group consisting of hydrogen, radical, halogen and cyano, and R2 represents a group selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, hydroxyl, cyclic Alkyl, cycloalkoxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amine, monoalkylamino, dialkylamino, cyano, substituted or unsubstituted benzyloxy and substituted Or a group of unsubstituted heterocyclic groups,
Rh代表選自經取代或未經取代之燒基、經取代或未經取 代之烷氧基、晞基、鹵素、羥基、多氟烷基、多氟烷氧基 、甲龜基、叛基、院黢基、燒氧羰基、護燒^談基、胺基、 經取代或未經取代之單烷胺基、二烷胺基、氰基、醯胺基 、烷氧醯胺基、經取代或未經取代之雜芳胺基、乙醯基磺 醯基胺基、脲基、羧醯胺、磺胺、經取代之磺胺、經取代 或未經取代之雜環磺醯基、烷硫基、烷亞硫醯基、烷磺醯 基、烷基磺酸與經取代或未經取代之雜環基與-〇(CH2)-C( = 0)-R7所組成之群組之基, JU代表選自氫、烷基、鹵素與烷氧基所組成之群組之基, R5代表選自燒(C1 - C 6)基與環奴基所組成之群組之基, R6代表選自經取代或未經取代之芳基與經取代或未經取 代之雜芳基所組成之群組之基, R?代表選自二燒胺基、經取代或未經取代之芳胺基、經 取代或未經取代之雜芳胺基與經取代或未經取代之芳基所 組成之群組之基, 該單烷胺基取代基係一或多種獨立選自環烷基、羥基、 B8828.doc -13- 200418452 烷氧基與經取代或未經取代之雜環基所組成之群組之基, 該芳胺基取代基與該雜芳胺基取代基係一或多種獨立選 自烷基與烷氧談基所組成之群組之基, 該續胺取代基係一或多種獨立選自烯基、環燒基、燒氧 基、羥基、鹵素、多氟烷基、多氟烷氧基、羧基、烷羰基 、燒氧談基、叛醯胺、經取代或未經取代之芳基與經取代 或未經取代之雜環基所組成之群組之基, 該雜環磺醯基取代基係一或多種獨立選自烷氧基與羥基 所組成之群組之基, 該烷基取代基與該烷氧基取代基係一或多種獨立選自烯 基、胺基、單烷胺基、二烷胺基、烷氧基、環烷基、經基 、羧基、S素、氰基、多氟烷基、多氟烷氧基、磺醯胺、 羧醯胺、烷磺醯基、烷羰基、烷氧羰基、巯基、苯并[1,3] 二吟畊基、經取代或未經取代之芳基與經取代或未經取代 之雜環基所組成之群組之基, 該雜環基取代基係一或多種獨立選自烷基、胺基、醯胺 基、單烷胺基、環烷基-烷胺基、二烷胺基、烷氧基、烷氧 烷基、羥基、羥烷基、環烷基、羧基、羧醯胺、鹵素、鹵 烷基、氰基、多氟烷基、多氟烷氧基、烷磺醯基、烷羰基、 環烷羰基、烷氧羰基、銃基、氧基、經取代或未經取代之 芳基、芳烷基與經取代或未經取代之雜芳基所組成之群組 之基, 該雜芳基取代基係一或多種獨立選自烷基、胺基、烷氧 基、烷氧烷基、羥基、羥烷基、環烷基、羧基、羧醯胺、 88828.doc -14- 200418452 鹵素、多氟燒基、多氟燒氧基、燒續酿基、疏基與氧基所 組成之群組之基, 該芊氧基取代基係一或多種獨立選自烷基、烷氧基、多 氟烷基、多氟烷氧基、羥基、羧基、烷氧羰基、函素、氰 基、燒續醯基與苯基所組成之群組之基, 該芳基取代基係一或多種獨立選自烷基、烷氧基、羥基 、鹵素、多氟燒基、多氟燒氧基、氰基、胺基、單院胺基 、二燒胺基、胺燒基、燒氧燒氧基、st胺基、si胺燒基、 羧基、烷磺醯基、烷羰基、烷氧羰基、疏基與雜環基所組 成之群組之基,及其醫藥上可接受之鹽。 在第三方面,本發明提供下式化合物:Rh represents a group selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a fluorenyl group, a halogen, a hydroxy group, a polyfluoroalkyl group, a polyfluoroalkoxy group, a methylketyl group, a thiol group, Ranyl, oxocarbonyl, oxoalkyl, amine, substituted or unsubstituted monoalkylamino, dialkylamino, cyano, ethylamino, alkoxyamino, substituted or Unsubstituted heteroarylamino, ethylsulfonamido, ureido, carboxyamido, sulfa, substituted sulfa, substituted or unsubstituted heterocyclic sulfoamido, alkylthio, alkyl A group consisting of thionyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic group, and -0 (CH2) -C (= 0) -R7, JU stands for election A group selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy, R5 represents a group selected from the group consisting of alkyl (C1-C 6) and cyclonyl, and R6 represents a group selected from substituted or R? Represents a group selected from the group consisting of an unsubstituted aryl group and a substituted or unsubstituted heteroaryl group, and R? Represents a group selected from a diamine group, a substituted or unsubstituted arylamine group, a substituted or unsubstituted Superseded A group consisting of an amine group and a substituted or unsubstituted aryl group, the monoalkylamino substituent is one or more independently selected from cycloalkyl, hydroxyl, B8828.doc -13- 200418452 alkoxy A group consisting of a substituted or unsubstituted heterocyclic group, the arylamino substituent and the heteroarylamino substituent are one or more independently selected from the group consisting of an alkyl group and an alkoxy group A group of groups, the continuous amine substituent is one or more independently selected from alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, and oxygen A radical of the group consisting of a phenyl group, a benzylamine, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic group, the heterocyclic sulfonyl substituent is independently selected from one or more A group of alkoxy and hydroxy groups, the alkyl substituent and the alkoxy substituent are one or more independently selected from alkenyl, amine, monoalkylamino, dialkylamino, alkoxy Radical, cycloalkyl, mesityl, carboxyl, sulfonium, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxysulfonamide, alkylsulfonyl Alkylcarbonyl, alkoxycarbonyl, sulfhydryl, benzo [1,3] dihydrocarbyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, Heterocyclyl substituents are one or more independently selected from alkyl, amino, amido, monoalkylamino, cycloalkyl-alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxyl , Hydroxyalkyl, cycloalkyl, carboxyl, carboxamido, halogen, haloalkyl, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkanesulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl , Fluorenyl, oxy, substituted or unsubstituted aryl, aralkyl and substituted or unsubstituted heteroaryl group, the heteroaryl substituent is one or more independent Selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxyl, hydroxyalkyl, cycloalkyl, carboxyl, carboxyamido, 88828.doc -14- 200418452 halogen, polyfluoroalkyl, polyfluorocarbon A group consisting of an oxy group, a succinyl group, a thiol group, and an oxy group, and the alkoxy substituent is one or more kinds independently selected from alkyl, alkoxy, polyfluoroalkyl, poly Alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, functional group, cyano, fluorenyl, and phenyl groups; the aryl substituent is one or more independently selected from alkyl, alkoxy Base, hydroxyl, halogen, polyfluorenyl, polyfluorinated oxy, cyano, amine, monoamine, diamine, amine, oxyalkyl, st, si Base, carboxyl, alkanesulfonyl, alkylcarbonyl, alkoxycarbonyl, sulfo and heterocyclic groups, and pharmaceutically acceptable salts thereof. In a third aspect, the invention provides a compound of the formula:
其中: K代表選自氫、烷基、鹵素與氰基所組成之群組之基, R2代表選自氫、經取代或未經取代之院基、經取代或未 經取代之烷氧基、羥基、環烷基、環烷氧基、多氟烷基、 多氟燒氧基、iS素、胺基、單烷胺基、二燒胺基、氰基、 經取代或未經取代之苄氧基與經取代或未經取代之雜環基 所組成之群組之基, R3代表選自氫、經取代或未經取代之烷基、經取代或未 經取代之烷氧基、烯基、li素、羥基、多氟烷基、多氟烷 88828.doc -15 - 200418452 氧基、甲醯基、羧基、烷羰基、烷氧羰基、羥嫁羰基、胺 基、經取代或未經取代之單燒胺基、二:fe胺基、戴基、酉监 胺基、烷氧醯胺基、經取代或未經取代之雜芳胺基、乙驢 基續驢基胺基、腸基、幾驢胺、績胺、經取代之〜胺 Ί 取代或未經取代之雜環績驢基、燒硫基、貌亞硫酸基、燒 磺醯基、烷基磺酸與經取代或未經取代之雜環基與 -0(CH2)-C(=0)-R7所組成之群組之基, FU代表選自氫、烷基、鹵素與烷氧基所組成之群組之基, R5代表選自烷(CrCd基與環烷基所組成之群組之基, R6a代表選自經取代之芳基與經取代或未經取代之雜芳 基所組成之群組之基, R7代表選自二烷胺基、經取代或未經取代之芳胺基、經 取代或未經取代之雜芳胺基與經取代或未經取代之芳基所 組成之群組之基, 該單烷胺基取代基係一或多種獨立選自環烷基、羥基、 烷氧基與經取代或未經取代之雜環基所組成之群組之基, 該芳胺基取代基與該雜芳胺基取代基係一或多種獨立選 自烷基與烷氧羰基所組成之群組之基, 該磺胺取代基係一或多種獨立選自烯基、環烷基、燒氧 基、羥基、函素、多氟烷基、多氟烷氧基、羧基、烷羰基 、烷氧羰基、羧醯胺、經取代或未經取代之芳基與經取代 或未經取代之雜環基所組成之群組之基, 該雜環績醯基取代基係一或多種獨立選自燒氧基與經基 所組成之群組之基, 88828.doc -16 - 200418452 該烷基取代基與該烷氧基取代基係一或多種獨立選自烯 基、胺基、單烷胺基、二烷胺基、烷氧基、環烷基、輕基 、瘦基、ii素、氰基、多氟燒基、多氟燒氧基、續ίΐ胺、 羧醯胺、烷磺醯基、烷羰基、烷氧羰基、銃基、苯并[1,3] 二崎畊基、經取代或未經取代之芳基與經取代或未經取代 之雜環基所組成之群組之基, 該雜環基取代基係一或多種獨立選自燒基、胺基、醯胺 基、單燒胺基、環燒基-燒胺基、二燒胺基、燒氧基、燒氧 燒基、輕基、羥燒基、環燒基、獲基、叛驢胺、齒素、鹵 烷基、氰基、多氟烷基、多氟烷氧基、烷磺醯基、烷羰基、 環燒談基、燒氧黢基、酸基、氧基、經取代或未經取代之 芳基、芳烷基與經取代或未經取代之雜芳基所組成之群組 之基, 該雜芳基取代基係一或多種獨立選自烷基、胺基、烷氧 基、坑氧燒基、喪基、技基、環燒基、叛基、叛醒胺、 鹵素、多氟烷基、多氟烷氧基、烷磺醯基、鲩基與氧基所 組成之群组之基, 該苄氧基取代基係一或多種獨立選自烷基、烷氧基、多 氟烷基、多氟烷氧基、羥基、羧基、烷氧羰基、卣素、氰 基、燒續醯基與苯基所組成之群組之基, 該芳基取代基係一或多種獨立選自烷基、烷氧基、羥基 、鹵素、多氟烷基、多氟烷氧基、氰基、胺基、單烷胺基 、二烷胺基、胺烷基、烷氧烷氧基、醯胺基、醯胺烷基、 羧基、烷磺醯基、烷羰基、烷氧羰基、巯基與雜環基所組 88828.doc -17- 200418452 成之群組之基,及其醫藥上可接受之鹽。 在第四方面,本發明提供下式化合物:Wherein: K represents a group selected from the group consisting of hydrogen, alkyl, halogen and cyano, and R2 represents a group selected from hydrogen, substituted or unsubstituted academic group, substituted or unsubstituted alkoxy group, Hydroxyl, cycloalkyl, cycloalkoxy, polyfluoroalkyl, polyfluoroalkoxy, iS element, amino, monoalkylamino, dialkylamino, cyano, substituted or unsubstituted benzyloxy A group consisting of a group and a substituted or unsubstituted heterocyclic group, R3 represents a group selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkenyl, Li, hydroxyl, polyfluoroalkyl, polyfluoroalkane 88828.doc -15-200418452 oxy, formamyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxycarbonylcarbonyl, amino, substituted or unsubstituted Monoamine amine, di: fe amine, diyl, amine, alkoxy amine, substituted or unsubstituted heteroaryl amine, ethylammonium, ammonium, intestine, Donkey amines, amines, substituted ~ amine hydrazones, substituted or unsubstituted heterocyclic groups, thiol, thiosulfite, sulfamoyl, alkylsulfonic acid and substituted or An unsubstituted heterocyclic group and a group consisting of -0 (CH2) -C (= 0) -R7. FU represents a group selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy. R5 represents a group selected from the group consisting of alkane (CrCd group and cycloalkyl group), R6a represents a group selected from the group consisting of substituted aryl group and substituted or unsubstituted heteroaryl group, R7 Represents a group selected from the group consisting of a dialkylamino group, a substituted or unsubstituted arylamine group, a substituted or unsubstituted heteroarylamine group, and a substituted or unsubstituted aryl group, the monomer Alkylamino substituents are one or more groups independently selected from the group consisting of cycloalkyl, hydroxyl, alkoxy and substituted or unsubstituted heterocyclic groups, the arylamino substituent and the heteroaryl The amine substituent is one or more groups independently selected from the group consisting of an alkyl group and an alkoxycarbonyl group, and the sulfonamide substituent is one or more groups independently selected from an alkenyl group, a cycloalkyl group, an alkyloxy group, a hydroxyl group, a functional group Element, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamido, substituted or unsubstituted aryl, and substituted or unselected A group of a heterocyclic group consisting of one or more substituents independently selected from the group consisting of an alkoxy group and an alkyl group, 88828.doc -16-200418452 the alkane group And one or more alkoxy substituents are independently selected from the group consisting of alkenyl, amine, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, light, leptyl, ii, Cyano, polyfluorenyl, polyfluorinyloxy, fluorenamide, carboxamido, alkanesulfonyl, alkylcarbonyl, alkoxycarbonyl, fluorenyl, benzo [1,3] erakizaki, A group of a group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group, wherein the heterocyclic group substituent is one or more independently selected from an alkyl group, an amine group, an amine group, Monoamine, cycloalkyl-cycloalkyl, dialkylamine, oxyalkyl, oxyalkyl, light, hydroxyalkyl, cycloalkyl, alkyl, ammonium, halogen, haloalkane Cyano, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkanesulfonyl, alkylcarbonyl, cycloalkyl, alkoxymethyl, acid, oxy, substituted or unsubstituted aryl, Aralkyl and substituted A group of groups consisting of an unsubstituted heteroaryl group, the heteroaryl substituent is one or more independently selected from the group consisting of alkyl, amine, alkoxy, oxyalkyl, benzyl, technical, and cyclic Alkyl, alkyl, amine, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkanesulfonyl, fluorenyl, and oxy; the benzyloxy substituent is one or A plurality of groups independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxyl, carboxyl, alkoxycarbonyl, halogen, cyano, fluorenyl and phenyl The aryl substituent is one or more independently selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amine, monoalkylamino, and dialkylamino. , Aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkanesulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto and heterocyclic groups 88828.doc -17- 200418452 Group basis, and its pharmaceutically acceptable salts. In a fourth aspect, the invention provides a compound of the formula:
其中: 心代表選自氫、甲基與氯基所組成之群組之基, R2代表選自氫、甲基、乙基、異丙基、正丁基、環丙基 、羥基、羥甲基、甲氧甲基、甲氧基、三氟甲氧基、二氟 甲氧基、環丙甲氧基、羧甲氧基、氰甲氧基、氰甲基甲氧 基、1-羥f基-環丙基甲氧基、胺甲醯甲氧基、甲基胺甲醯 甲氧基、二乙基胺甲醯甲氧基、(4_乙氧基羰基_苯基胺甲醯 基)-甲氧基、第三-丁氧羰基甲氧基、乙氧基、2_甲氧乙氧 基、2_氯基-乙氧基、2-羧乙氧基、2,2,2-三氟乙氧基、丨兴‘ 氟基_苯基)-乙氧基、2-(4-氟基-苯基)-2-氧基-乙氧基、2-(4-甲氧基-苯基)-2-氧基-乙氧基、丙氧基、異丙氧基、氧基_ 丙氧基、2-¾基-丙氧基、3-#呈基-丙氧基、2-幾基-2-甲基_ 丙氧基、3-溴基-丙氧基、3-乙氧基_丙氧基、丁氧基、2_羥 基-2-甲基-丁氧基、環戊氧基、晞丙氧基、氰基、氯基、氟 基、甲烷磺酸、苄氧基、2-苯基芊氧基、2-二氟甲氧基_芊 氧基、3-甲氧基-芊氧基、3_甲氧羰基_苄氧基、3_羧基-芊氧 基、3-氰基-苄氧基、4_甲氧基_芊氧基、‘氟基_苄氧基、4_ 氰基-爷氧基、4-甲氧羰基-苄氧基、4-羧基-苄氧基、4-羧基 88828.doc -18- 200418452 -3-羥基-苄氧基、‘甲烷磺醯基-芊氧基、3,4_二氟基_苄氧基 、3,5-一甲氧基-苄氧基、2,2-二甲基-4-氧基-4H-苯并[ι,3] 二,畊-5-基甲氧基、2,2-二甲基-4-氧基-4H-苯并[1,3]二噚 畊-7-基甲氧基、2,2-二甲基-4-氧基-4H-苯并[1,3]二噚畊 基甲氧基、3-氯甲基_[1,2,4]噻二唑-5-基氧基、5-氯基-[1,2,4] P塞一'哇-3'"基甲氧基、5-氯基-[1,2,3]喧二吐-4-基甲氧基、5-對-曱苯基-[1,3,4]嘮二唑-2-基甲氧基、5-(3,5-二甲基-異噚 唆-4-基)-[1,2,4]噚二唑-3-基甲氧基、5_(環丙甲基-胺基) -[1,2,4]噻二唑-3-基甲氧基、5-第三-丁基-[1,2,4]噚二唑-3-基甲氧基、5-(4-甲氧基-苯基)_[1,2,4]吟二峻-3-基甲氧基、 5-二乙基胺基-[1,2,4]噻二唑-3-基甲氧基、[1,3,4]噻二唑-2-基胺甲醯基甲氧基、3,5-二甲基-異噚唑—4-基、異噚唑-3-基 甲氧基、3,5-二甲基-異巧唑基甲氧基、5 -甲基-異崎唑-3-基甲氧基、嘧唑-2-基甲氧基、噻唑4-基甲氧基、2-甲基-嘧唑-4-基甲氧基、1-嘧唑_2_基-乙氧基、嘧唑基胺甲醯 基甲氧基、(4,5-二甲基-嘧唑—2-基胺甲醯基)-甲氧基、4-氯 基-1-甲基-1H-吡唑-3-基甲氧基、2-吡唑-1-基-乙氧基、 2-(3,5-二甲基-吡唑-1-基乙氧基、心乙氧基羰基^塞唑 基甲氧基、4-羧基-嘧唑-2-基甲氧基、5-胺基-4H-[1,2,4]三 口坐-3-基甲氧基、噻吩-2-基、呋喃-2-基、2-嗎福啉-4-基-乙 氧基、3-六氫吡啶-1-基-丙氧基、四氫-呋喃基、1-甲基-1H-四吐-5-基甲氧基、1-甲基-1H-咪唑_2-基甲氧基、丨_苄基—1H_ 味峻-2-基甲氧基、3H -味峻-4-基甲氧基、叶(:咬-4-基-甲氧基 、6-溴甲基4啶-2-基甲氧基與2-(4-氰基-六氫吡啶-1-基)- 88828.doc -19- 200418452 乙氧基所組成之群組之基, R3代表選自氣、甲基、甲氧基、經基、經甲基、;μ藉基_ 乙基、1-羥基-2-甲基-丙基、丨_羥基_丨_甲基-乙基、甲醯基 、脲基、乙烯基、溴基、氯基、氰基、乙醯基、2-羥基.乙 醯基、羧基、三亞甲五胺基、羧酸醯胺、胺基、甲基胺 基、二甲基胺基、乙基胺基、二乙基胺基、異丙基胺基、 第三丁基胺基、乙基-甲基_胺基、2-甲氧基-乙基胺基、環 丙基甲基-胺基、2,3-二羥基-丙基胺基、丨_甲基胺基-乙基、 二甲基胺甲基、1-胺基-1-甲基_乙基、2-胺基-1-羥基-1-甲基 -乙基、乙醯基胺基、1-乙醯基胺基-丨_甲基-乙基、(2-甲氧 基-乙基)-甲基-胺基、乙基_(2_甲氧基_乙醯基)_胺基、3_氯 基-丙烷-1-磺醯基胺基、甲烷磺醯基胺基、乙基-甲烷磺醯 基-胺基、異丙基-甲烷磺醯基-胺基、異丁基-甲烷磺醯基_ 胺基、環丁基-甲烷磺醯基-胺基、環戊基-甲烷磺醯基_胺基 、環丙基甲基-甲烷磺醯基-胺基、(2_羥基-乙基)-甲烷磺醯 基_胺基、(2-羥基-丙基)-甲烷磺醯基-胺基、(2-氟基-乙基)_ 甲烷磺醯基-胺基、2-(4-氟基-苯基)-2-羥基-乙基]-甲烷磺醯 基-胺基、(1-羥甲基-環丙甲基)-甲烷磺醯基-胺基、(4_羧基_ 苄基)-甲烷磺醯基-胺基、烯丙基-甲烷磺醯基-胺基、乙醯 基-甲燒續S篮基-胺基、苄基-甲燒磺醯基-胺基、羧甲基-甲 烷績醯基-胺基、甲烷續醯基胺基-甲基、1 -甲烷續醯基胺基 -1 -甲基-乙基、甲烷磺醯基-甲基-胺基、1_(甲烷磺醯基-甲 基-胺基)-乙基、甲燒續醯基-丙基-胺基、甲垸績_基_(2_甲 氧基-乙基)-胺基、甲烷磺醯基_(2,2,2_三氟基-乙基胺基、 88828.doc -20- 200418452 甲烷磺醒基-(2-氧基-丙基)_胺基、甲烷磺醯基_(2_三氟甲氧 基-乙基)-胺基、甲坑續酿基-(4-甲氧基-爷基)_胺基、甲燒磺 酉盈基-(4-甲氧羰基-苄基)_胺基、甲烷磺醯基-甲氧甲基-胺基 、甲烷磺醯基-甲基胺甲醯基甲基-胺基、(甲烷磺醯基-甲基 -胺基)-甲基、胺績醯基、甲基胺續醯基、二甲基胺磺醯基 、乙基胺磺醯基、環丙基胺磺醯基、環丁基胺磺醯基、3-甲fe % S篮基·冬基、4-甲燒續_基·苯基、爷氧基、1 H- P比口坐 -4-基、2H-p比峻-3-基、1-甲基-iH-p比峻-3-基、2-甲基-2H-吡唑-3-基、5-甲基-1H-吡唑-4-基、5-甲基-2H-吡唑-3-基、 1,5-二甲基-1H-吡唑-3-基、2,5-二甲基-2H-吡唑-3-基、2,5-二甲基-2H-峨唆-3-基胺基、3,5-二甲基-1H-P比峻-4-基、1,3,5-三甲基-lH-p比嗤-4-基、異崎嗤-3-基、5-甲基-異4吐-3-基、 3-環丙基-異呤唑-5-基、5-環丙基-異噚唑-3-基、3,5-二甲基 -異吟唑-4-基、3,5-二甲基-異呤唑-4-基胺基、5-甲氧基甲基 -異噚唑-3-基、5-乙氧基甲基·異吟唑-3-基、5-異丙氧基甲 基-異哼唑-3-基、5-羥甲基-異噚唑-3-基、4-(2-羥基-乙基)-異呤唑-3-基、3-甲氧基甲基-5-甲基-異嘮唑-4-基、5-甲氧基 甲基-3-甲基-異号峻-4-基、5-環丙基-3-甲氧基甲基-異p号峻 -4-基、3-環丙基-5-甲氧基甲基-異崎嗤-4-基、(3,5-二甲基-異噚唑-4-基甲基)-甲烷磺醯基-胺基、3-甲氧基甲基-異嘮唑 -5-基、3-甲基-異嘮唑-5-基、甲烷磺醯基-(5-甲基-異哼唑-3-基甲基)-胺基、噻唑-2-基、噻唑-5-基、甲烷磺醯基-噻唑-2-基甲基-胺基、甲烷磺醯基-噻唑-4-基甲基-胺基、甲烷磺醯 基-(2-甲基-噻唑-4-基甲基)-胺基、(4-羧基-噻唑-2-基甲基)- 88828.doc -21 - 200418452 甲醯基-胺基、(4_乙氧羰基^塞唑_2_基甲基)_甲烷磺醯 基-胺基、吡啶-3-基、吡啶-‘基、吡啶-4_基胺基、6_氟基_ 吡啶-3-基、甲烷磺醯基_吡啶_4_基甲基_胺基、(6_溴甲基_ 吡啶-2-基甲基)_甲烷磺醯基_胺基、吡咯啶_1_基、吡咯啶 基、吡咯哫磺醯基、3-羥基-吡咯啶-1-基、3-羥基-吡咯 啶-1-磺醯基、5_氧基_吡咯啶_3-基、^乙醯基_吡咯啶_2-基 、1-乙醯基-吡咯啶-3-基、丨―胺甲醯基_吡咯啶_2_基、丨_甲基 胺甲醯基-吡咯啶_2_基、各甲基胺甲醯基氧基-吡咯啶 基、1-環丙烷羰基-吡咯啶-2-基、1-甲烷磺醯基_吡咯啶 基 1甲彡元卞δΜ基-峨嘻淀-3 -基、3 -胺基-u比哈淀_ 1 •爲、 甲燒磺醯基-吡咯啶-1-基、1Η_吡咯_2_基、m_吡嘻_3_爲 3-氰基-4-羥基-2-氧基-2,5-二氫-吡咯-1-基甲基、呋喃爲 咬喃-3-基、(吱喃-3-基甲基)-胺基、四氫-吱喃基、( 氫-咬喃-2-基甲基)-胺基、[1,3,4]口号二口坐-2-基、[1,2,4], 唑-3-基、5_甲基-[U〆]噚二唑_3-基、5_甲基-啰〜〜 -2-基、5-三氟甲基-[1,2,4]$二峻-3_基、嗎福淋-4-基、 ___ 世 2,6、 一甲基-嗎福淋-4 -基、2 -嗎福淋-4 -基-乙基胺基、嗎福株 續S!基、甲烷磺醯基-(2-嗎福啉_4_基-乙基)-胺基、硬$、 琳-4_基、硫嗎福琳_4_磺醯基、1_氧基_硫嗎福淋、、、、 ^ 土、1,1、 一氧基-1λ6-異p墓口坐淀-2-基、2-氧基·崎峻淀-5-基、5-审甘 ^ τ 基、2、 氧基-吟唑啶_5_基、哼唑-5-基、1Η-咪唑-4-基、n味文 基、2,5-二氧基-咪唑啶-4-基、4-甲基-2,5-二氧基-咪咭、厶 尤%、4、 基、嘧啶-5-基、2,5-二甲基-2Η-[1,2,4]三唑-3-基、9 、 -2Η-[1,2,4]三唑-3-基、4Η_[1,2,4]三唑-3-基、5-甲基 甲4 2H. 88828.doc -22- 200418452 [1,2,4]三唑-3-基、1H-四唑-5-基、1-甲基-1H-四唑-5-基甲氧 基、甲烷磺醯基-(1-甲基-1H-四唑-5-基甲基)-胺基、六氫吡 咬-1-基、4-氟基-六氫p比淀-1-基、4,4-二氟基-六氫峨淀-1-基、3-經基-六氫u比淀_1_基、4 -輕基·六氫?比淀-1-基、4-¾基 -六氫吡啶-1-續醯基、4-胺甲醯基-六氫吡畊-1-基、4-甲基-六氫吡畊-1-基與5-氯基-[1,2,4]嘧二唑-3-基甲基, R4代表選自氫與甲基所組成之群組之基,Where: Heart represents a group selected from the group consisting of hydrogen, methyl, and chloro, and R2 represents a group selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, hydroxyl, and methylol. , Methoxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropylmethoxy, carboxymethoxy, cyanomethoxy, cyanomethylmethoxy, 1-hydroxyf -Cyclopropylmethoxy, amine formamyl methoxy, methylamine formamyl methoxy, diethylamine formamyl methoxy, (4-ethoxycarbonyl_phenylamine formamyl)- Methoxy, tert-butoxycarbonylmethoxy, ethoxy, 2-methoxyethoxy, 2-chloro-ethoxy, 2-carboxyethoxy, 2,2,2-trifluoro Ethoxy, Fluoro-phenyl) -ethoxy, 2- (4-fluoro-phenyl) -2-oxy-ethoxy, 2- (4-methoxy-phenyl) ) -2-oxy-ethoxy, propoxy, isopropoxy, oxy-propoxy, 2-¾yl-propoxy, 3- # imyl-propoxy, 2-quinyl 2-methyl_propoxy, 3-bromo-propoxy, 3-ethoxy_propoxy, butoxy, 2-hydroxy-2-methyl-butoxy, cyclopentyloxy , Fluorenyl propoxy, cyano, chloro, fluoro, methanesulfonate , Benzyloxy, 2-phenylfluorenyloxy, 2-difluoromethoxy-fluorenyloxy, 3-methoxy-fluorenyloxy, 3-methoxycarbonyl-benzyloxy, 3-carboxy-fluorenyl Oxy, 3-cyano-benzyloxy, 4-methoxy-fluorenyloxy, 'fluoro-benzyloxy, 4-cyano-benzyloxy, 4-methoxycarbonyl-benzyloxy, 4- Carboxy-benzyloxy, 4-carboxy 88828.doc -18- 200418452 -3-hydroxy-benzyloxy, 'methanesulfonyl-fluorenyloxy, 3,4-difluorobenzyloxy, 3,5 -Monomethoxy-benzyloxy, 2,2-dimethyl-4-oxy-4H-benzo [ι, 3] di, phen-5-ylmethoxy, 2,2-dimethyl -4-oxy-4H-benzo [1,3] difluorene-7-ylmethoxy, 2,2-dimethyl-4-oxy-4H-benzo [1,3] difluorene Cultylmethoxy, 3-chloromethyl_ [1,2,4] thiadiazol-5-yloxy, 5-chloro- [1,2,4] PSer 'Wow-3' " Ylmethoxy, 5-chloro- [1,2,3] xanthiene-4-ylmethoxy, 5-p-fluorenyl- [1,3,4] fluorenediazole-2- Methoxy, 5- (3,5-dimethyl-isofluoren-4-yl)-[1,2,4] fluoradiazol-3-ylmethoxy, 5- (cyclopropylmethyl- Amine)-[1,2,4] thiadiazol-3-ylmethoxy, 5-third-butyl- [1,2,4] pyridazol-3-ylmethoxy , 5- (4-methoxy-phenyl) _ [1,2,4] indion-3-ylmethoxy, 5-diethylamino- [1,2,4] thiadiazole -3-ylmethoxy, [1,3,4] thiadiazol-2-ylaminomethylmethylmethoxy, 3,5-dimethyl-isoxazol-4-yl, isoxazole- 3-ylmethoxy, 3,5-dimethyl-isoxazolylmethoxy, 5-methyl-isoazazol-3-ylmethoxy, pyrazol-2-ylmethoxy, thiazole 4-ylmethoxy, 2-methyl-pyrazol-4-ylmethoxy, 1-pyrazol_2-yl-ethoxy, pyrazolylaminomethylmethylmethoxy, (4,5 -Dimethyl-pyrazol-2-ylaminomethylmethyl) -methoxy, 4-chloro-1-methyl-1H-pyrazol-3-ylmethoxy, 2-pyrazole-1- Ethoxy-ethoxy, 2- (3,5-dimethyl-pyrazol-1-ylethoxy, ethoxyethoxycarbonyl, thiazolylmethoxy, 4-carboxy-pyrazol-2-yl Methoxy, 5-amino-4H- [1,2,4] tris (3-methylmethoxy), thien-2-yl, furan-2-yl, 2-morpholin-4-yl- Ethoxy, 3-hexahydropyridin-1-yl-propoxy, tetrahydro-furyl, 1-methyl-1H-tetrat-5-ylmethoxy, 1-methyl-1H-imidazole_ 2-ylmethoxy, 丨 _benzyl-1H_ Weijun-2-ylmethoxy, 3H-Weijun-4-ylmethoxy, leaf (: Bent-4-yl-methoxy, 6-bromomethyl4pyridin-2-ylmethoxy and 2- (4-cyano-hexahydropyridin-1-yl)-88828.doc -19- 200418452 a group of groups consisting of ethoxy groups, R3 represents a group selected from the group consisting of gas, methyl, methoxy, mesityl, mesityl; μ borrowed group_ethyl, 1-hydroxy-2-methyl-propyl Methyl group, methyl group, methyl group, methyl group, methyl group, urea group, vinyl group, bromo group, chloro group, cyano group, ethyl group, 2-hydroxy group. Amine, carboxylic acid amine, amine, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, tertiary butylamino, ethyl-methyl Amino-amino, 2-methoxy-ethylamino, cyclopropylmethyl-amino, 2,3-dihydroxy-propylamino, methylamino-ethyl, dimethyl Aminomethyl, 1-amino-1-methyl_ethyl, 2-amino-1-hydroxy-1-methyl-ethyl, ethylamino, 1-ethylamino- 丨 _ Methyl-ethyl, (2-methoxy-ethyl) -methyl-amino, ethyl_ (2-methoxy_ethylfluorenyl) _amino, 3-chloro-propane-1- Sulfonylamino, methanesulfonylamino, ethyl-methanesulfonylamino Group, isopropyl-methanesulfonyl-amino group, isobutyl-methanesulfonyl-amino group, cyclobutyl-methanesulfonyl-amino group, cyclopentyl-methanesulfonyl-amino group, Cyclopropylmethyl-methanesulfonyl-amino group, (2-hydroxy-ethyl) -methanesulfonyl-amino group, (2-hydroxy-propyl) -methanesulfonyl-amino group, (2 -Fluoro-ethyl) _methanesulfonyl-amino, 2- (4-fluoro-phenyl) -2-hydroxy-ethyl] -methanesulfonyl-amino, (1-hydroxymethyl -Cyclopropylmethyl) -methanesulfonyl-amino group, (4-carboxy_benzyl) -methanesulfonyl-amino group, allyl-methanesulfonyl-amino group, ethenyl-methane Continued S-basic-amino, benzyl-methylsulfanyl-amino, carboxymethyl-methanesulfanyl-amino, methane-sulfanylamino-methyl, 1-methanesulfanylamino -1 -methyl-ethyl, methanesulfonyl-methyl-amino, 1- (methanesulfonyl-methyl-amino) -ethyl, methylsulfanyl-propyl-amino, methyl Achievement group_ (2_methoxy-ethyl) -amino group, methanesulfonyl group ((2,2,2_trifluoro-ethylamino group), 88828.doc -20- 200418452 -(2-oxy-propyl) _amino, methane Fluorenyl_ (2_trifluoromethoxy-ethyl) -amino group, methyl pentyl group- (4-methoxy-methyl group) _amino group, methylsulfonyl sulfonyl group- (4-methyl Oxycarbonyl-benzyl) _amino, methanesulfonyl-methoxymethyl-amine, methanesulfonyl-methylaminomethylmethyl-amino, (methanesulfonyl-methyl-amine ) -Methyl, amine sulfonyl, methylamine sulfonyl, dimethylamine sulfonyl, ethylamine sulfonyl, cyclopropylaminesulfonyl, cyclobutylaminesulfonyl, 3 -Methylfe% S-base-based, winter-based, 4-methylsulfonyl-phenyl, unyloxy, 1H-P than p--4-yl, 2H-p than p--3-yl, 1- Methyl-iH-p than Jun-3-yl, 2-methyl-2H-pyrazol-3-yl, 5-methyl-1H-pyrazol-4-yl, 5-methyl-2H-pyrazole -3-yl, 1,5-dimethyl-1H-pyrazol-3-yl, 2,5-dimethyl-2H-pyrazol-3-yl, 2,5-dimethyl-2H-methyl Fluoren-3-ylamino, 3,5-dimethyl-1H-P than jun-4-yl, 1,3,5-trimethyl-1H-p than fluoren-4-yl, isocrazy- 3-yl, 5-methyl-isotetra-3-yl, 3-cyclopropyl-isoxazol-5-yl, 5-cyclopropyl-isoxazol-3-yl, 3,5-di Methyl-isonizol-4-yl, 3,5-dimethyl-isopurazol-4-ylamino, 5-methoxymethyl -Isoxazol-3-yl, 5-ethoxymethyl-isisonazol-3-yl, 5-isopropoxymethyl-isoxazol-3-yl, 5-hydroxymethyl-isoamidine Azol-3-yl, 4- (2-hydroxy-ethyl) -isopurazol-3-yl, 3-methoxymethyl-5-methyl-isoxazol-4-yl, 5-methoxy Methylmethyl-3-methyl-isopropyl-4-yl, 5-cyclopropyl-3-methoxymethyl-isopropyl-4-yl, 3-cyclopropyl-5-methoxy Methylmethyl-isocrazy-4-yl, (3,5-dimethyl-isoxazol-4-ylmethyl) -methanesulfonyl-amino, 3-methoxymethyl-isofluorenyl Azol-5-yl, 3-methyl-isoxazol-5-yl, methanesulfonyl- (5-methyl-isoxazol-3-ylmethyl) -amino, thiazol-2-yl, Thiazol-5-yl, methanesulfonyl-thiazol-2-ylmethyl-amine, methanesulfonyl-thiazol-4-ylmethyl-amine, methanesulfonyl- (2-methyl-thiazole) 4-ylmethyl) -amino group, (4-carboxy-thiazol-2-ylmethyl)-88828.doc -21-200418452 formamyl-amino group, (4-ethoxycarbonyl ^ selazole_2 _Ylmethyl) _methanesulfonyl-amino, pyridin-3-yl, pyridin-'yl, pyridin-4-ylamino, 6_fluoroyl_pyridin-3-yl, methanesulfonyl_pyridine _4_methylmethyl_amino, (6_bromo Methyl_pyridin-2-ylmethyl) _methanesulfonyl_amino, pyrrolidin_1_yl, pyrrolidinyl, pyrrolidinsulfonyl, 3-hydroxy-pyrrolidin-1-yl, 3- Hydroxy-pyrrolidin-1-sulfonyl, 5-oxy_pyrrolidin_3-yl, ^ ethylsulfonyl_pyrrolidin-2-yl, 1-ethynyl-pyrrolidin-3-yl, 丨 ― Carbaminyl_pyrrolidine_2_yl, 丨 Methylcarbaminyl-pyrrolidine_2_yl, each methylaminomethaneoxy-pyrrolidyl group, 1-cyclopropanecarbonyl-pyrrolidine -2-yl, 1-methanesulfonyl_pyrrolidinyl, 1-methylsulfonium δM-yl-ehikolide-3 -yl, 3-amino-u-bihalidone_ 1 -Pyrrolidin-1-yl, 1Η_pyrrole_2_yl, m_pyridine_3_ are 3-cyano-4-hydroxy-2-oxy-2,5-dihydro-pyrrole-1-yl Methyl and furan are sulfan-3-yl, (cran-3-ylmethyl) -amino, tetrahydro-cranyl, (hydro-sulfan-2-ylmethyl) -amine, [ 1,3,4] slogans two-mouthed 2-yl, [1, 2, 4], azole-3-yl, 5-methyl- [U〆] pyridazol-3-yl, 5-methyl -啰 ~~ -2-yl, 5-trifluoromethyl- [1,2,4] $ dijun-3_yl, morpholin-4-yl, ___ world 2,6, monomethyl-? Fu Lin -4 -Base, 2-Morpho Phenyl-4 -yl-ethylamino, morphone S! Yl, methanesulfonyl- (2-morpholine_4-yl-ethyl) -amino, hardyl, lin-4_yl , Thiomorpholin_4_sulfonyl, 1_oxy_thiomorpholin ,,,, ^ earth, 1,1, monooxy-1λ6-isop graveyard sitting 2-yl, 2 -Oxyzaki-yodo-5-yl, 5-triazol ^ τ, 2, oxy-indazol-5-yl, humidaz-5-yl, 1-imidazol-4-yl, n Wenji, 2,5-dioxy-imidazolidin-4-yl, 4-methyl-2,5-dioxy-imidazolium, stilbene%, 4, yl, pyrimidin-5-yl, 2, 5-dimethyl-2Η- [1,2,4] triazol-3-yl, 9, -2Η- [1,2,4] triazol-3-yl, 4Η_ [1,2,4] tris Azol-3-yl, 5-methylformyl 4 2H. 88828.doc -22- 200418452 [1,2,4] triazol-3-yl, 1H-tetrazol-5-yl, 1-methyl-1H -Tetrazol-5-ylmethoxy, methanesulfonyl- (1-methyl-1H-tetrazol-5-ylmethyl) -amino, hexahydropyridin-1-yl, 4-fluoro -Hexahydrop-pyridian-1-yl, 4,4-difluoro-hexahydroeodo-1-yl, 3-pyridyl-hexahydrou-pyridine_1-yl, 4-light-based ? Biyodo-1-yl, 4-¾yl-hexahydropyridine-1-continyl, 4-aminomethylpyridyl-hexahydropyridine-1-yl, 4-methyl-hexahydropyridine-1- And 5-chloro- [1,2,4] pyrimidazol-3-ylmethyl, R4 represents a group selected from the group consisting of hydrogen and methyl,
Rs代表選自甲基、乙基、異丙基、與環丙基所組成之群 組之基,與 R6代表選自苯基、4-甲基-苯基、4-乙基-苯基、4-甲氧基-苯基、4-羥基-苯基、4-溴基-苯基、2-氯基-苯基、2-氟基-苯基、4-氟基-苯基、2,4-二氟基-苯基、3,4-二氟基-苯基、 4-溴基-3-氟基-苯基、3-氯基-4-氟基-苯基、4-氯基-3-氟基-苯基、2,4,5-三氟基-苯基、3-氟基-4_曱基-苯基、4-氟基-3-甲基-苯基、4-氟基-3-羥基-苯基、2-乙氧基-4-氟基-苯基、3-三氟甲基-苯基、4-三氟甲基-苯基、4-氰基-苯基、4_胺基_ 私基、4-(乙驢基胺基-甲基)_苯基、4_嗎福琳冬基-苯基、4_ 吡咯啶-1-基-苯基、呋喃-2-基、呋喃_3_基、3-甲基-呋喃_2_ 基、噻吩-2-基、5-氯基-嘧吩-2-基、吡啶_4_基與吡啶_3-基, 其限制條件為該式不包括選自下列所組成之群組之化合物 5甲氧基-2-苯基-苯并呋喃-3-羧酸甲醯胺與5-羥基苯基 -苯并呋喃_3_羧酸甲醯胺。 式I之較佳化合物包括其中1為_0(^3或_〇(CH)(CH3)2、 -CHWH3與之化合物。 88828.doc -23- 200418452 其他之較佳之式i化合物包括其中為甲基之化合物。 本發明之較佳方面包括其中R6所代表之芳基為經取代之 苯基之式I化合物,該苯基取代基為一或多種獨立選自氟基 、氯基、漠基、甲氧基與氰基所組成之群組之基。 本發明之另一較佳方面包括式Ic化合物:Rs represents a group selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl, and R6 represents a group selected from phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-methoxy-phenyl, 4-hydroxy-phenyl, 4-bromo-phenyl, 2-chloro-phenyl, 2-fluoro-phenyl, 4-fluoro-phenyl, 2, 4-difluoro-phenyl, 3,4-difluoro-phenyl, 4-bromo-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro 3-fluoro-phenyl, 2,4,5-trifluoro-phenyl, 3-fluoro-4-fluorenyl-phenyl, 4-fluoro-3-methyl-phenyl, 4- Fluoro-3-hydroxy-phenyl, 2-ethoxy-4-fluoro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-cyano-benzene Group, 4-amino group, private group, 4- (ethosylamino-methyl) _phenyl group, 4-morpholinol-phenyl group, 4-pyrrolidin-1-yl-phenyl group, furan- 2-yl, furan_3-yl, 3-methyl-furan_2_yl, thien-2-yl, 5-chloro-pyrimin-2-yl, pyridin-4-yl and pyridin-3-yl, The limitation is that the formula does not include compounds selected from the group consisting of 5methoxy-2-phenyl-benzofuran-3-carboxylic acid formamide and 5-hydroxyphenyl-benzofuran. Formamidine carboxylate . Preferred compounds of formula I include compounds in which 1 is _0 (^ 3 or _〇 (CH) (CH3) 2, -CHWH3 and 88.doc.-23- 200418452. Other preferred compounds of formula i include wherein Preferred aspects of the invention include compounds of formula I in which the aryl group represented by R6 is a substituted phenyl group, the phenyl substituent being one or more independently selected from the group consisting of fluoro, chloro, molyl, A group of methoxy and cyano groups. Another preferred aspect of the invention includes compounds of formula Ic:
其中Aik為纟元基而R!、R3與R4係如上述式I之參考資料所定義 ,及其醫藥上可接受之鹽。 本發明之較佳化合物包括2_(4_氟基_苯基甲氧基_6_嗎 福啉基-苯并呋喃羧酸甲醯胺、2-(4-氟基-苯基)-5_異丙 氧基-6-嗎福啉-4-基-苯并呋喃-3-叛酸甲醯胺、2-(4-氟基-笨 基)-5-異丙氧基甲烷磺醯基胺基-苯并呋喃_3_羧酸甲醯 胺、2-(4•氟基-苯基)-5-異丙氧基-6-[(2-甲氧基-乙基)_甲基_ 胺基]-苯并呋喃-3-羧酸甲醯胺、5_芊氧基(‘氟基_苯基) -6-嗎福琳-4-基-苯并呋喃-3_羧酸甲醯胺與2-(4-氟基-苯基) -6-[(吱喃-3-基甲基)-胺基]異丙氧基-苯并呋喃羧酸甲 醯胺、6-(3,5-二甲基-異嘮唑-4-基)-2-(4-氟基-苯基)-5_甲氧 基-苯并呋喃-3-羧酸甲醯胺、5-環丙基-2-(4-氟基-苯基) -6-[(2-羥基·乙基)_甲烷磺醯基-胺基]_苯并呋喃_3_羧酸甲酸 胺、6_(3,5-二甲基-異嘮唑|基)_2-(4_氟基·苯基)_5-(3名基-丙氧基)_苯并呋喃-3-羧酸甲醯胺,及其醫藥上可接受之鹽。 88828.doc -24- 200418452 "酸—方面,本發明提供包括一或多種式i化合物,合 " 可接又之載體媒介之醫藥組合物。較佳醫藥組合 物包括一或多種下表1所列之化合物,及其醫藥上可接受之 鹽,合併醫藥上可接受之載體媒介。 、根據再另方面,本發明提供活的宿主,例如包括人類 <甫礼頦 < 預防或治療與肝炎C感染與和此類感染有關之 疾病之方法,包括施予易受感染或罹患此感染之宿主,治 療有效量之式I化合物。 本焱明之另一方面,提供對於例如包括人類之哺乳類之 活的僧主,預防或治療與肝炎C感染與和此類感染有關之疾 病疋万法。此方法包括施予易受感染或罹患此感染之宿主 ,治療有效量之選自5_甲氧基-2_苯基_苯并呋喃_3_羧酸甲醯 胺與5-羥基-2-苯基-苯并呋喃羧酸甲醯胺所組成之群組 之化合物。 上述式I化合物,其異構物與醫藥上可接受之鹽展現抗病 母活性。本發明化合物對抗肝炎C病毒特別有效,而且可用 於預防與或治療宿主之與此病毒相關之感染與疾病。 已進行之活體外研究(細胞為基礎與生化的)顯示本文所 述化合物做為抗病毒藥劑之用途。例如,於包含HCV複製 子之人類肝臟衍生之細胞株評估代表性化合物之抗病毒活 性。而且,抗病毒活性係以RNA合成之酶分析測定化合物 對病毒RdRp之抑制活性。 當使用於本文時,“本發明化合物”之用語意指集合的式I 化合物,其醫藥上可接受之鹽及其混合物。本發明化合物 88828.doc -25 - 200418452 在本文係藉其化學結構與/或化學名稱認定。在提及 =化學結構與化學名稱,而且t化學名稱與化學結構衝突 時’以化學結構決定其身分。 當,用於本文時,“燒基,,之用語針對直鏈或支鏈之可達 10個碳原子之脂防族烴基’較佳者可達6個碳原子,更佳者 為"個碳原子。類似地,“垸基,,或其任何變化之合併型式 之㈣係用以命名取代基’諸如燒氧基(4燒基)、環燒^ 、方基(-燒基-芳基)、單垸胺基(_NH_燒基)、胺燒基卜燒 f-NH2)、烷硫基(_s_烷基)、烷亞硫醯基(_s(=〇)_烷基)、烷 續臨基(-SWW基)、燒基績酸(_〇_s(〇)2_燒基),或其類似 物’亦針對直鏈或支鏈之可達1()個碳原子之脂芳族烴基, 較佳者為1_6個碳原子,以個碳原子更佳。還有在本文結 構式之“alk”表示貌基,若顯示其二價性時,則“仙,,表示^ 應之伸燒基。此外,“垸基(w之用語表示具^個碳原 子之烷基。 當使用於本文時,“缔基,,之用語針對包含至少一個雙鍵 之直鍵或支鍵之2_7個礙原子之脂肪族烴基。Λ類缔基部分 可此存在Ε或Ζ組態,本發明化合物包括兩種組態。“块基” 之用語當使用於本文時,針對包含至少—個三鍵之直鍵或 支鏈之2-7個碳原子之脂肪族烴基。Among them, Aik is a unitary radical and R !, R3, and R4 are as defined in the reference of Formula I above, and a pharmaceutically acceptable salt thereof. Preferred compounds of the present invention include 2- (4-fluoro-phenylmethoxy-6-morpholinol-benzofurancarboxylic acid formamidine, 2- (4-fluoro-phenyl) -5_ Isopropoxy-6-morpholin-4-yl-benzofuran-3-methanoic acid formamidine, 2- (4-fluoroyl-benzyl) -5-isopropoxymethanesulfonylamine -Benzofuran_3_carboxylic acid formamide, 2- (4 • fluoro-phenyl) -5-isopropoxy-6-[(2-methoxy-ethyl) _methyl_ Amine] -benzofuran-3-carboxylic acid formamidine, 5-methoxy ('fluoro group_phenyl) -6-morpholin-4-yl-benzofuran-3_carboxylic acid formamidine Amine and 2- (4-fluoro-phenyl) -6-[(crean-3-ylmethyl) -amino] isopropoxy-benzofurancarboxylic acid formamide, 6- (3, 5-dimethyl-isoxazol-4-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine, 5-cyclopropyl -2- (4-fluoro-phenyl) -6-[(2-hydroxy · ethyl) _methanesulfonyl-amino] _benzofuran_3_carboxylic acid carboxylic acid amine, 6_ (3,5 -Dimethyl-isoxazol | yl) _2- (4-fluoro group · phenyl) _5- (3 group-propoxy) _benzofuran-3-carboxylic acid formamidine, and its pharmacy Acceptable salt 88828.doc -24- 200418452 " acid The present invention provides a pharmaceutical composition comprising one or more compounds of formula i, which are " accessible carrier vehicles. Preferred pharmaceutical compositions include one or more of the compounds listed in Table 1 below, and pharmaceutically acceptable salts thereof. Incorporate a pharmaceutically acceptable carrier medium. According to yet another aspect, the present invention provides a live host, for example, a method of preventing or treating human < Fulet < " >, preventing or treating hepatitis C infection and diseases associated with such infection. , Including administering to a host susceptible to or suffering from the infection, a therapeutically effective amount of a compound of formula I. Another aspect of the present invention provides for the prevention or treatment of hepatitis C infection and the treatment of living monks, including human mammals, for example. Diseases related to such infections. This method includes administering to a host susceptible to or suffering from the infection, a therapeutically effective amount selected from 5-methoxy-2_phenyl_benzofuran_3_carboxy Compounds of the group consisting of formamidine acid and formamidine 5-hydroxy-2-phenyl-benzofurancarboxylate. The compounds of the above formula I, their isomers and pharmaceutically acceptable salts exhibit disease resistance. Activity. The present invention It is particularly effective against hepatitis C virus and can be used to prevent and / or treat host-associated infections and diseases with this virus. In vitro studies (cell-based and biochemical) performed have shown the compounds described herein as antiviral agents For example, human liver-derived cell lines containing HCV replicons are used to evaluate the antiviral activity of representative compounds. Furthermore, the antiviral activity is determined by RNA synthesis enzyme assays for the inhibitory activity of the compounds against viral RdRp. As used herein, the term "compounds of the invention" means a collection of compounds of formula I, their pharmaceutically acceptable salts and mixtures thereof. The compounds of the present invention 88828.doc -25-200418452 are identified herein by their chemical structure and / or chemical name. When referring to = chemical structure and chemical name, and t chemical name conflicts with chemical structure ', its chemical structure determines its identity. When used in this text, the term "carbon radical" refers to a linear or branched aliphatic aliphatic hydrocarbon group of up to 10 carbon atoms. The preferred is up to 6 carbon atoms, and the more preferred is " Carbon atom. Similarly, "fluorenyl, or a combination of any variation thereof, is used to name substituents such as alkoxy (4-alkyl), cycloalkyl, and square (-alkyl-aryl) ), Monofluorenylamino group (_NH_alkyl), amine alkyl group (f-NH2), alkylthio (_s_alkyl), alkylthiothio (_s (= 〇) _alkyl), alkyl Sequential group (-SWW group), alkanoic acid (_〇_s (〇) 2- alkynyl), or the like 'is also aimed at straight or branched chain lipids up to 1 () carbon atoms The aromatic hydrocarbon group is preferably 1 to 6 carbon atoms, and more preferably 1 carbon atom. In addition, in the structural formula of this article, "alk" represents a radical group, and if its bivalence is displayed, "xian" means ^ Ying Zhiyan group. In addition, "fluorene group (the term" w "has ^ carbon atoms Alkyl group. As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing 2 to 7 atomic hindering atoms containing at least one straight or branched double bond. The Λ-type alkenyl moiety may exist as E or Z Configurations, the compounds of the present invention include two configurations. The term "block group" as used herein refers to an aliphatic hydrocarbon group containing at least one straight or branched two to three carbon bond of 2-7 carbon atoms.
“苯基”之用語當使用於本文時,針對s基。“經取代 <苯基”之用語,針對經指示之取代基所取代之苯基。 當使用於本文時,“芳基,,之用語,當如此使用或,或為 88828.doc -26- 200418452 合併型式例如“芳烷基,,使用時,針對具有6-10個碳原子之包 括但不限於’苯基與莕基之芳香族碳環基。 4芳基’’之用語,當使用於本文時,意指環上至少具有 個反原子與一或多個氧、氮或硫原子之5-或6-環芳香環基 著如例如咬喃基、p塞吩基、p比淀基、峨p各基、$嗤基、 噻唑基、咪唑基、吡唑基、異吟唑基、異噻唑基、呤 一坐基、1,2,4-呤二唑基、ι,2,3-三唑基、ι,2,4·三唑基、1-3- 草醯硫酸基、噻二唑基、四唑基及其類似物。 當使用於本文時,“環烷基,,之用語針對3_7個碳原子之非 芳香族碳環基,諸如例如環丙基、環丁基、環戊基、環己 基,及類似物。 當使用於本文時,“環烷氧基,,之用語針對式_〇_環烷基之 基或取代基,其中該環烷基係如上數之定義。 产當使用於本文時,“多氟烷基,,之用語針對具有一或多個 氟基取代基之基或取代基,並包括全氟燒基。實例包括三 既甲基與三氟乙基。當使用於本文時,,,多氟垸氧基,,之用 語針對具有-或多個氟基取代基之垸氧基,並包括全氣燒 氧基。實例包括三氟甲氧基與三氟乙氧基。 當使用於本文時,“雜環基,,之用語針對其環上至少具有 -個碳原子與1_4個獨立選自氧、氮或硫原子之雜原子之芳 香族或非芳香族環基。雜環基之附接點,得經由碳原子或 經由雜原子。雜環基較佳者為3]〇個碳原丨,而更佳者為4 、5或6環。雜環基之實例包括三亞甲五胺基、吱❹、四 氫吱喃基”塞吩基”《基喻各基、㈣料、^各淀 88828.doc -27- 200418452 基、六氫ρ比淀基、六氫峨p井基、喊鍵基、号峻基、吟吐淀 基、遠α坐基、咪吐基、咪咬p定基、说。坐基、2 - P比吐淋基、 異哼唑基、異嘧唑基、嗎福啉基、硫嗎福啉基、1,2,3-哼二 唑基、1,3,4-噚二唑基、1,2,4-嘮二唑基、1,2,3-三唑基、1,2,4-三α坐基、1 - 3 -草驗硫酸基、ρ塞二吐基、四吐基及其類似物。 當使用於本文時,“醯胺基”之用語針對式NR’fC( = 0)Rf’^ 基或取代基,其中R”與Rm獨立地代表氫、烷基或環烷基。 類似地,“醯胺烷基”之用語當使用於本文時,針對式-烷基 -NR’’C(=0)Rm基或取代基,其中R”與Rf”係如先前之定義。 “烷氧醯胺基”之用語,當使用於本文時,針對式 -NR’fC( = 0)-烷基-烷氧基之基或取代基,其中R”、烷基與烷 氧基係如先前之定義。 “羧醯胺”之用語,當使用於本文時,針對式C(=0)-NR’’R’n 之基或取代基,其中Rn與R’”係如先前之定義。 “脲基”之用語,當使用於本文時,針對式-NR’C(=0)-NRnRm之基或取代基,其中11’’與11’”係如先前之定義,而Rf 代表氫或烷基。 “磺胺”之用語,當使用於本文時,針對式-S02NRnR’"或 NRn-S02Rm之基或取代基,其中Rn與R’n係如先前之定義。 經取代之磺胺之用語,當使用於本文時,針對式-N(烷基) -S02(烷基)之基或取代基,其中至少有一個烷基係進一步經 指示之取代基取代。 “乙醯磺醯基胺基”之用語,當使用於本文時,針對式 -N(S02-R"HC(=0)CH3),其中R”係如先前之定義。 88828.doc -28- 200418452 “雜環磺醯基”之用語,當使用於本文時,針對式-so2-het 之基或取代基,其中HET係如上述之雜環基。較佳之雜環 績驢基包括吨p各淀績驢基、六氫p比淀續Si基、嗎福琳基績 酉藍基與硫嗎福淋基續酸基。 “芳胺基”之用語,當使用於本文時,針對式-N(Rf’)-芳基 之基或取代基,其中R’’與芳基係如先前之定義。經取代之 芳胺基,當使用於本文時,針對其中該芳基進一步經指示 之取代基取代之芳胺基或芳胺取代基。 “雜芳胺基”之用語,當使用於本文時,針對式-N(R")-雜 芳基之基或取代基,其中R’’與雜芳基係如先前之定義。經 取代之雜芳胺基,當使用於本文時,針對其中該雜芳基進 一步經指示之取代基取代之雜芳胺基或雜芳胺取代基。 經取代之單烷胺基,當使用於本文時,針對如上述定義 之單烷胺基之基或取代基,其中該烷基進一步經指示之取 代基所取代。類此,“環烷基-烷胺基”之用語,當使用於本 文時,針對如上述定義之單烷胺之基或取代基,其中該烷 基進一步經上述之環烷基取代。 “羧基”之用語,當使用於本文時,針對式-C( = 0)0H之基 或取代基。 “羰基”之用語,不論單獨或與其他用語一同使用,諸如“烷 氧羰基”時,表示-C(=0)-。 “烷羰基”之用語,當使用於本文時,針對式-C(=0)烷基 之基或取代基;並包括例如甲基羰基、乙基羰基、丙基羰 基、丁基羰基與戊基羰基。類此,“環烷羰基”之用語,當 88828.doc -29- 200418452 使用於本文時,針對式-c(=o)-環烷基之基或取代基。 “經燒羧基”之用語,當使用於本文時,針對式-C(=0)-院 基-OH之化合物。 “烷氧羰基”之用語,當使用於本文時,針對式-C(=0)-0-烷基之基或取代基;並包括例如甲氧羰基、乙氧羰基、丙 氧羰基、丁氧羰基與戊氧羰基。 “甲醯基”之用語,當使用於本文時,針對式-C(=0)-H之 基或取代基。 “疏基”之用語,當使用於本文時,針對式-SH之基或取代 基。 “苄氧基”之用語,當使用於本文時,針對式-OCH2-苯基 之基或取代基。經取代之苄氧基為其中該苯基進一步經指 示之取代基取代之苄氧基。 經取代之單烷基胺,當使用於本文時,針對式-NH-烷基 之基或取代基;其中該燒基進一步經指示之取代基取代。 “己烷”之用語,當使用於本文時,針對直鏈與支鏈之己 燒烴溶劑混合物,其中該溶劑混合物大部分包含正己虎與 少量支鏈己烷。 “鹵素”之用語,當使用於本文時,針對選自氯、溴、碘 與氟所組成之群組之基或取代基。 “鹵烷基”之用語,當使用於本文時,針對如上述定義之 進一步經如上述定義之i素所取代之烷基。 “psig”之用語,針對錶壓磅/平方英吋。 “HPLC”之用語,當使用於本文時,針對高效液相色層分 88828.doc -30- 200418452 析法。 “TLC”之用語’當使用於本文時 “互轡显捃仏, 卞尽巴臂+析法。 構物型式,,之用語,當使用於本文時 氣原子移動所形士、-士夕# 針對因為 斤y成<一或多種異構物型式。 胺基”之用語’當使用於本文時,針對.2_基。 “苯并叫二^井基”之用語,當使用於本文時,釺對式The term "phenyl" as used herein refers to the s group. The term "substituted < phenyl" refers to a phenyl substituted with the indicated substituent. As used herein, the term "aryl," when used as such, or, is 88828.doc -26- 200418452 combined forms such as "aralkyl," when used, for inclusions having 6-10 carbon atoms But not limited to the aromatic carbocyclyl group of 'phenyl and fluorenyl. The term `` 4aryl '', as used herein, means a 5- or 6-ring aromatic ring having at least one counter atom and one or more oxygen, nitrogen or sulfur atoms on the ring, such as e.g. p-secenyl, p-pyridyl, e-pyridyl, fluorenyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, 1,2,4-pyridine Diazolyl, ι, 2,3-triazolyl, ι, 2,4 · triazolyl, 1-3-oxadiasulfate, thiadiazolyl, tetrazolyl, and the like. As used herein, the term "cycloalkyl," refers to non-aromatic carbocyclic groups of 3-7 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When used As used herein, the term "cycloalkoxy" refers to a group or substituent of the formula -cycloalkyl, wherein the cycloalkyl is as defined above. As used herein, the term "polyfluoroalkyl," refers to a group or substituent having one or more fluoro substituents, and includes perfluoroalkyl. Examples include trimethyl and trifluoroethyl As used herein, the term "polyfluoroalkoxy" refers to fluorenyloxy having-or more fluoro substituents, and includes all gas alkoxy. Examples include trifluoromethoxy and trifluoromethoxy. Fluoroethoxy. As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic group having at least one carbon atom and one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur atoms on its ring. Family ring base. The attachment point of the heterocyclic group can be via a carbon atom or via a heteroatom. Heterocyclyl is preferably 3 carbon atoms, and more preferably 4, 5, or 6 rings. Examples of heterocyclic groups include trimethylenepentaminyl, stilbene, tetrahydrosuccinyl, "sedenyl", "synthetic radicals, materials, genomics 88828.doc -27- 200418452, hexahydrogen ratio Dianji, hexahydropyridine, yoke bond, No. Junji, Yintu Dianji, far α sitting group, mitoyl, mibiting pding group, said. Sorryl, 2-P-pyridyl, isoxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, 1,2,3-humdiazolyl, 1,3,4-fluorene Diazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-tri-alpha phenyl, 1-3 -oxosulfate, ρ-dithiol , Tetrayl and its analogs. As used herein, the term "amido" refers to a group or substituent of the formula NR'fC (= 0) where R "and Rm independently represent hydrogen, alkyl, or cycloalkyl. Similarly, The term "amidoalkyl" as used herein refers to the formula -alkyl-NR "C (= 0) Rm group or substituent, where R" and Rf "are as previously defined." Alkoxy " The term "amino", as used herein, refers to a group or substituent of the formula -NR'fC (= 0) -alkyl-alkoxy, wherein R ", alkyl and alkoxy are as previously defined . The term "carboxamide", as used herein, refers to a group or substituent of the formula C (= 0) -NR "R'n, where Rn and R '" are as previously defined. "Ureido" The term, when used herein, refers to a group or substituent of the formula -NR'C (= 0) -NRnRm, where 11 "and 11 '" are as previously defined, and Rf represents hydrogen or alkyl. The term "sulfonamide", as used herein, refers to a group or substituent of the formula -S02NRnR '" or NRn-S02Rm, where Rn and R'n are as previously defined. The term substituted sulfonamide, as used herein, refers to a group or substituent of the formula -N (alkyl) -S02 (alkyl) in which at least one alkyl group is further substituted with the indicated substituent. The term "acetamidinesulfonylamino", as used herein, is directed to the formula -N (S02-R " HC (= 0) CH3), where R "is as previously defined. 88828.doc -28- 200418452 The term "heterocyclic sulfonyl", as used herein, refers to a group or substituent of the formula -so2-het, in which HET is a heterocyclic group as described above. Preferred heterocyclic groups include t Dydonyl, hexahydrop-doped Si, morpholinyl, stilbene blue, and thiomorphoyl sulfonic acid. When used herein, the term "arylamino" refers to formula -N (Rf ')-an aryl group or substituent, wherein R "and aryl are as previously defined. A substituted arylamine group, as used herein, is directed to a substituent in which the aryl group is further indicated. Substituted arylamino or arylamine substituents. The term "heteroarylamino", as used herein, refers to a group or substituent of the formula -N (R ")-heteroaryl, where R '' and hetero Aryl is as previously defined. A substituted heteroarylamino group, when used herein, is directed to a heteroarylamino group in which the heteroaryl group is further substituted with a indicated substituent or Aromatic amine substituents. A substituted monoalkylamino group, as used herein, is directed to a monoalkylamino group or substituent as defined above, wherein the alkyl group is further substituted with the indicated substituent. Similarly, The term "cycloalkyl-alkylamino", as used herein, refers to a monoalkylamine group or substituent as defined above, wherein the alkyl group is further substituted with a cycloalkyl group as described above. When used herein, it refers to a group or substituent of the formula -C (= 0) OH. The term "carbonyl", whether used alone or in conjunction with other terms, such as "alkoxycarbonyl", means -C (= 0)-. The term "alkylcarbonyl", as used herein, refers to a group or substituent of an alkyl group of the formula -C (= 0); and includes, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butyl Carbonyl and pentylcarbonyl. Similarly, the term "cycloalkylcarbonyl", when 88828.doc -29-200418452 is used herein, refers to a group or substituent of the formula -c (= o) -cycloalkyl. The term "burning carboxyl", as used herein, refers to a compound of formula -C (= 0) -Cyno-OH. "Alkane The term "carbonyl," as used herein, refers to a group or substituent of the formula -C (= 0) -0-alkyl; and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and pentyl. Oxycarbonyl. The term "formamyl", when used herein, refers to a group or substituent of the formula -C (= 0) -H. The term "thio", when used herein, refers to the formula -SH. Group or substituent. The term "benzyloxy", as used herein, refers to a group or substituent of the formula -OCH2-phenyl. A substituted benzyloxy is a substituent in which the phenyl is further indicated. Substituted benzyloxy. A substituted monoalkylamine, as used herein, is directed to a group or substituent of the formula -NH-alkyl; wherein the alkyl group is further substituted with the indicated substituent. The term "hexane", as used herein, is directed to a mixture of linear and branched hexane hydrocarbon solvents, where the solvent mixture mostly contains n-Hexanol and a small amount of branched hexane. The term "halogen", as used herein, refers to a group or substituent selected from the group consisting of chlorine, bromine, iodine and fluorine. The term "haloalkyl", as used herein, refers to an alkyl group, as defined above, further substituted with a prime as defined above. The term "psig" refers to gauge pressure in pounds per square inch. The term "HPLC", as used herein, refers to the HPLC chromatography 88828.doc -30- 200418452 analysis. The term "TLC" when used in this article "exhibits each other clearly, and makes use of the arm + analysis method. The structure type, the term, when used in this article, the shape of the atomic movement,-士 夕 # For the reason that y becomes one or more isomers. The term "amino group" when used herein is directed to the .2-group. The term "benzo" is called "two-well-based".
X 之基或取代基。 =的宿主,’之用語,當使用於本文時,針對活的且能夠 又π晴火C病毒《病毒感染之生物,例如哺乳類,包括 類0 本發明化合物與其異構物型式及其醫藥上可接受之鹽, f可用於治療與預防病毒感染,特別係肝炎c病毒,與^的 、、之疾病,^合併彼此,或其他具生物活性之物質使用 時;包括但是不限於選自下列所組成之群組者:干擾素、 聚乙缔二醇化之干擾素、雷巴威林、蛋白酶抑制劑、聚合 酶抑制劑、小的干擾性RNA化合物、反義化合物、核嘗酸 類似物、核苷類似物、免疫球蛋白、免疫調節劑、保肝劑 、消炎藥劑、抗生素、抗病毒劑與抗感染化合物。此類合 併療法亦包括同時或依序提供本發明化合物與其他醫藥劑 或增^劑,諸如阿塞克洛維(aCycl〇vir)、費米塞克洛維 (famicyclovir)、發岡塞克洛維(vaigancyci〇vir)與相關化合物 ’雷巴威林與相關化合物,金剛烷胺與相關化合物,不同 88828.doc •31 - 200418452 干擾素諸如例如千俱本 干擾素_α、干擾素_β、干擾素 物,以及干擾夸夕扶也&丄 τ及其方員似 。此外,例如兩ρ在从k 哔化〈干擾素 两巴威林與干擾素之合併,可 發明之化合物,做為另冰、夕 、 土乂一種本 為另外 < 夕重合併療法之組合施用。 =合併絲可為依序,亦即以—種藥劑之治療先, 為弟二種藥劑(例如,個別治療包括本發明之不同一 或/、中#冶療包括本發明之化合物,而其他-種包括一 或义種生物活性樂劑),或其可為以兩種藥劑相同時間治療 (同:地)<衣序療法可在完成第一種治療後,開始第二種療 法可之合理時間内。以兩種藥劑相同時間之治4,可為相 同之日劑量或為分開之劑量。以兩種之同時或依序之合併 療法之劑量,將視合併療法成分之吸收、分布、代謝:與 排泄速率’以及其他熟諳此藝者已知之因素而定。劑量值 亦視欲減輕之病症之嚴重性而定。應進一步了解的是,對 任何特別病患而言,特定之劑量療法、與進度可根據病患 (需求與施予或監督合併療法者之職業判斷而隨時調整。 在^ 步之具體貫施例,本發明化合物可與其他hcv聚 合酶之抑制劑用在治療人類HCV之合併療法型式中。Radical or substituent of X. = Host, the term ', when used herein, is directed against living and capable of π sunny fire C virus "virus-infected organisms, such as mammals, including class 0 compounds of the present invention and their isoforms and their pharmaceutically acceptable Accepted salts, f can be used for the treatment and prevention of viral infections, especially hepatitis C virus, when combined with or other diseases, or other biologically active substances; including but not limited to the composition selected from the following Group of people: interferon, polyethylene glycol interferon, rabavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, antisense compounds, nucleotide analogs, nucleosides Analogs, immunoglobulins, immunomodulators, hepatoprotective agents, anti-inflammatory agents, antibiotics, antivirals and anti-infective compounds. Such combination therapies also include the simultaneous or sequential provision of a compound of the invention with other pharmaceutical agents or extenders, such as aCyclvir, famicyclovir, Fagancyclovir Vaigancycivir and related compounds' rebavirin and related compounds, amantadine and related compounds, different 88828.doc • 31-200418452 interferons such as, for example, Trichomon interferon_α, interferon_β, Interferon substances, as well as interfering with Kuai Fu & 丄 τ and its members. In addition, for example, when two rhodium is combined from interferon and two interferon and interferon, a compound can be invented as a combination of another ice, evening, and earthworm, which is a combination of another < evening sun combined therapy . = The combined silk can be sequential, that is, the treatment of one agent first, the two agents (for example, the individual treatment includes a different one of the invention or /, the Chinese medicine treatment includes the compound of the invention, and the other- (Including one or a kind of biologically active muscarinic agent), or it can be treated with two agents at the same time (same: ground) < clothes order therapy may be reasonable after the first treatment is completed and the second therapy may be started in time. Treatment with two agents at the same time4 can be the same daily dose or separate doses. The dosage of two concurrent or sequential combination therapies will depend on the absorption, distribution, metabolism: and excretion rate of the components of the combination therapy, and other factors known to those skilled in the art. The dose value also depends on the severity of the condition to be reduced. It should be further understood that, for any particular patient, the specific dose therapy, and progress can be adjusted at any time according to the patient (needs and professional judgment of the person who administers or supervises the combined therapy. Specific implementation examples in step ^ The compounds of the present invention can be used in combination therapy with other hcv polymerase inhibitors in the treatment of human HCV.
在更進一步之具體實施例’本發明化合物可與其他HCV 生命週期之抑制劑用在治療人類HCV之合併療法型式,後In a further specific embodiment, the compound of the present invention can be used in combination with other HCV life cycle inhibitors in a combination therapy mode for treating human HCV.
者之例諸如例如HCV細胞附接或病毒進入、HCV轉譯、HCV RNA轉錄或複製、HCV成熟、組合或病毒釋出等之抑制劑 ’或HCV酶活性之抑制劑,諸如HCV核苷酸轉移酶、螺旋 酶、蛋白酶或聚合酶。 88828.doc -32- 200418452 只要該合併不會消減本發明之群的化合物之抗病毒活性 ,或其醫藥組合物之抗病毒活性,則本發明之合併療法打 算包括任何本發明之群的化合物與本發明之群之其他化合 物之化學相容的組合。 “干擾素-α”之用語,當使用於本文時,意指抑制病毒複 製與細胞增生並調節免疫反應之高度均質性之物種專一性 之蛋白質家族。典型適當之干擾素包括,但不限於重組之 干擾素 a-2b諸如購自 Schering Corporation,Kenilworth,NJ 之INTRON-A INTERFERON;重組之干擾素a-2a,諸如購 自11(^111&11-1^尺〇〇1^,>1111:16丫,1^之11(^61>〇11干擾素;重組之干 擾素 a-2c,諸如購自 Boehringer Ingelheim Pharmaceutical, Inc·,Ridgefield,Conn·之 BEROFOR ALPHA 2 INTERFERON ;干擾素α-nl,諸如 SUMIFERON之購自 Sumitomo, Japan之 純化的天然α干擾素之混合物;或為購自Glaxo-Wellcome Ltd·,London,Great Britain 之Wellferon干擾素 a-nl(INS); 或諸如美國專利號碼4,897,471與4,695,623所述之共識性“ 干擾素(其内容全文並列於本文供參考,特別是其實例7、8 或 9);與購自 Amgen,Inc·,Newbury Park,Calif·,之特定產物 ,或干擾素α-η3,Interferon Sciences所製造並購自Purdue Frederick Co.,Norwalk,Conn.,之商標為 ALFERON之天然干 擾素混合物。使用干擾素或a-2b較佳。因為,干擾素 a -2b在所有干擾素之間,為全世界所有的治療慢性肝炎C 感染之干擾素中獲得最大認可者。在美國專利4,503,901中 有干擾素a-2b之製造說明。 88828.doc -33 - 200418452 ‘‘聚乙烯二醇化之干擾素,,之用語,當使用於本文時,意 指經聚乙一醇修飾 < 干擾素之共軛體,以干擾素與干 擾素a-2b較佳。較佳之聚乙二醇_干擾素a_2b之共軛體為 PEG.sub.12000.-f ^ a-2b〇 uPEG.sub. 12000-IFN aji] 1η 當使用於本文時,意指共軛體之經諸如根據國際申請號碼 W〇95/13G9G之方法製備,並包含干擾素α·2由_2b胺基間 之脲醋連結,而且聚乙二醇之平均分子量為12卿。 本文所述之化合物亦可料㈣或解決細胞、組織或器 官培養與其他活體外應用時之病毒感染。例如,若包括本 發明化合物做為細胞或組織培養之生長培養液之補充物, 以及細胞或組織培養之成公,, 、、、 成刀了預防先I不受病毒感染者 之病毒感染或培養之;亏染。締、衾 、 、、工通备治療期之經熟練之技術 人員決定之任何次數之治療條件後,上述化合物亦可用以 消減培養物或其他受病毒咸汰 、 心、末或万朱之生物材料(例如血 液)所含之病毒。 本發明化合物可與諸如氫氯 L乳馼及魬、乙酸、乳酸或並 類似物之無機與有機酸; /、 ^ /、渚如虱虱化鈉或鉀、六氳吡 哫、氫氧化銨,或其類似物之無 _ 飞匕 鹽。式I化合物之醫藥可接典、〆、”,形成有用之 之方法係根據熟諳此藝者熟悉 物於乙醇,並添加約U當量 天J化口 ah制丄 虱虱化鈉或風氧化鉀,允許形 “。醫藥可接受之鹽之實例列於下表3。 本發明化合物之異構物型 之雜環取#其、 括不党限制之可能出現 〈碓%取代基又不同異構物。 令又所畫又化學結構與因此 88828.doc -34- 200418452 之本發明化合物,亦涵蓋所有這些對應之可能之互變異構 型式。此類互變異構物在某些實例可能藉由熟諳此藝者已 知之方法解析成個別化合物。 本發明化合物可用以治療活的宿主,例如包括人類之哺 乳類之HCV。當施於活的宿主時,該化合物可單獨使用, 或做為醫藥組合物之用。 包括本發明化合物,不論單獨或合併彼此之醫藥組合物 ,以提供對抗肝炎C感染之治療。本發明之抗病毒醫藥組合 物,包括做為活性成分之一或多種上述之式I化合物,合併 醫藥可接受之載體媒介或輔助藥劑。 該組合物可製成包括錠劑、膜衣錠、藥丸或糖衣藥丸之 不同施用型式,或為可充填入諸如膠囊之適當容器,或是 若為懸浮液之情形,可充填入瓶中。當使用於本文時,“醫 藥可接受之載體媒介”只要適合所需之特定劑型,可包括任 何與全部之溶劑、稀釋劑、或其他液體載劑、分散液或懸 浮液幫助劑、界面活性劑、等張劑、濃稠或乳化劑、防腐 劑、固體接著劑、潤滑劑及其類似物。Remington’s Pharmaceutical Sciences,第 20版,A. R. Gennaro (William & Wilkins,Baltimore,MD,2000)揭示調配醫藥組合物所用之 不同載體,與其已知之製備技術。迄今,所有傳統載體媒 介除了諸如藉生產任何不必要之生物效應,或是以破壞性 方式與醫藥組合物之任何其他成分作用之任何與本發明之 抗病毒化合物不相容者外,其使用皆為本發明範疇所涵蓋。 在本發明之醫藥組合物中,根據組合物總重量,該活性 88828.doc -35 - 200418452 藥劑存在之量係以重量計,可能為至少0.5%,而且通常不 逾9 0 %,包括任何之載體媒介與/或輔助藥劑。較佳者,活 性藥劑之比例隨組合物之重量而改變,其變化介於組合物 之5至50%。 可使用適於經腸或非經腸施用之有機或無機固體或液體 載體媒介,製成本組合物。明膠、乳糖、澱粉、硬脂酸鎂 、滑石、蔬菜與動物脂肪與油、膠、聚二醇、或其他已知 之醫藥成分,可能皆適合做為載體培養基或賦形劑之用。 施用本發明化合物時可採任何能有效減弱病毒感染性之 量與路徑。因此,當使用於本文時,“可有效減弱病毒感染 性之量”之表示法,係針對無毒但足量之抗病毒,以提供所 需之對病毒感染之預防與/或治療。所需之正確量視不同病 患之物種、年齡與病患之一般情況、感染嚴重性、特定之 抗病毒藥劑、施用模式,及類似者而定。 該抗病毒化合物較佳者係調配成劑量單位型式,以便易 於施用並維持劑量一致性。當使用於本文時,“劑量單位型 式”針對適用於接受治療之病患之物理各別量之抗病毒藥 劑。每一劑量應包含經計算以產生所需治療效果之活性物 質之量,或聯合任何之選用的醫藥載體與或補充性活性藥 劑。典型地,施用本發明之抗病毒化合物時之單位劑量包 含組合物重量由約2毫克至約7000毫克之抗病毒藥劑,以由 約10毫克至約2 0 0 0毫克之範圍較佳。 施用該化合物時,考慮欲治療之感染之特性與嚴重性, 可經口服,直腸,諸如藉肌内注射、皮下注射、靜脈内浸 88828.doc -36- 200418452 潤或類似者之非經腸方式,腦池内、陰道内、腹膜内、局 4等路徑,並可採諸如粉末、油膏、或滴劑或類似物型式 ;或藉諸如氣溶膠或類似者之吸入方式。視施用路徑而定 ,本發明化合物之施用劑量每天約〇 〇5至約1〇〇毫克/公斤病 患體重,每天一或多次,以達所需療果。 本發明化合物典型地每天可施用由1至4次以傳送上述之 曰劑:r °然而,本文所述之化合物與組合物之正確之施用 万法須視接受治療之個別宿主或病患之需求、施用之治療 型怨以及參與之醫護專家之判斷而定。 敛於本發.明化合物產生之抑制病毒RNA合成之效果,我 們預期這些化合物不僅可用於治療病毒感染,亦包括病毒 感染之預防。不論治療或預防病毒感染,該劑量實質上可 能相同。 下列貫例係提供以進一步詳細說明本發明。這些實例說 明本發明之代表性化合物之適當合成方法。然而,合成方 法係欲說明而非僅限制於下列範例。製備本發明化合物之 起始材料若非市售即是根據下述實例之一或是利用已知化 學方法即可很方便製成。 2-味喃-3-基-5-甲氧基-苯并呋喃-羧酸甲醯胺之製備 l(aK2-^喃-3-基-5-羥基-苯并呋喃羧酸 乙酯)。Examples include, for example, inhibitors of HCV cell attachment or viral entry, HCV translation, HCV RNA transcription or replication, HCV maturation, combination or virus release, or inhibitors of HCV enzyme activity, such as HCV nucleotide transferase , Helicase, protease or polymerase. 88828.doc -32- 200418452 As long as the combination does not diminish the antiviral activity of a compound of the group of the invention, or the antiviral activity of a pharmaceutical composition thereof, the combination therapy of the invention is intended to include any compound of the group of the invention and Chemically compatible combination of other compounds of the group of the invention. The term "interferon-α", as used herein, means a family of highly specific species-specific proteins that inhibit virus replication and cell proliferation and regulate the immune response. Typical suitable interferons include, but are not limited to, recombinant interferon a-2b such as INTRON-A INTERFERON purchased from Schering Corporation, Kenilworth, NJ; recombinant interferon a-2a such as purchased from 11 (^ 111 & 11- 1 ^ foot 〇〇1 ^, > 1111: 16 ah, 1 ^ of 11 (^ 61 > 〇11 interferon; recombinant interferon a-2c, such as purchased from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn. BEROFOR ALPHA 2 INTERFERON; interferon alpha-nl, such as a mixture of purified natural alpha interferon purchased from Sumitomo, Japan by SUMIFERON; or Wellferon interferon a- purchased from Glaxo-Wellcome Ltd., London, Great Britain nl (INS); or a consensus "interferon such as described in U.S. Patent Nos. 4,897,471 and 4,695,623 (the contents of which are incorporated herein by reference in their entirety, and in particular Examples 7, 8 or 9); and purchased from Amgen, Inc., Newbury Park, Calif., A specific product, or interferon α-η3, manufactured by Interferon Sciences and purchased from Purdue Frederick Co., Norwalk, Conn., A natural interferon mixture with the trademark ALFERON. Use interferon or a-2b Better. Because interferon a-2b is among all the interferons and is the world's largest accredited interferon for the treatment of chronic hepatitis C infection. There are instructions for the manufacture of interferon a-2b in US Patent 4,503,901. 88828. doc -33-200418452 '' Polyglycolized interferon, the term, when used herein, means a polyethylene glycol-modified conjugate of interferon, interferon and interferon a-2b Better. The preferred conjugate of polyethylene glycol_interferon a_2b is PEG.sub.12000.-f ^ a-2b〇uPEG.sub. 12000-IFN aji] 1η When used herein, it means co- The conjugate is prepared, for example, according to the method of international application number WO95 / 13G9G, and contains interferon α · 2 linked by urea and vinegar between _2b amine groups, and the average molecular weight of polyethylene glycol is 12 Å. The compounds described can also infect or resolve viral infections in cell, tissue or organ culture and other in vitro applications. For example, if the compounds of the present invention are included as supplements for growth culture fluids of cells or tissue cultures, and cells or tissues Cultivation becomes public, and ... I is not the first anti-virus infection by the virus or culture of; loss of dye. The above-mentioned compounds can also be used to reduce cultures or other biological materials that are affected by viruses, bacteria, heart, or blood, after any number of treatment conditions determined by skilled technicians during the treatment period. (Eg blood). The compound of the present invention can be used with inorganic and organic acids such as hydrochloro-L lactate and hydrazone, acetic acid, lactic acid or the like; /, ^ /, such as sodium or potassium lice, hexapyridine, ammonium hydroxide, Or its analogs without _ flying dagger salt. The medicine of the compound of formula I can be used as a formula, to form a useful method, according to the person familiar with the art in ethanol, and to add about U equivalent days to make lice lice sodium or wind potassium, Allow shape ". Examples of pharmaceutically acceptable salts are listed in Table 3 below. The isomers of the compounds of the present invention are heterocyclic, which may include <%% substituents and different isomers. Let us also draw the chemical structure and therefore the compounds of the present invention 88828.doc -34- 200418452, also covering all these corresponding possible tautomeric forms. Such tautomers may, in some instances, be resolved into individual compounds by methods known to those skilled in the art. The compounds of the present invention can be used to treat living hosts, such as human mammalian HCV. When administered to a living host, the compound can be used alone or as a pharmaceutical composition. A pharmaceutical composition comprising a compound of the present invention, whether alone or in combination with each other, to provide a treatment against hepatitis C infection. The antiviral pharmaceutical composition of the present invention comprises, as an active ingredient, one or more compounds of the above formula I, combined with a pharmaceutically acceptable carrier vehicle or auxiliary agent. The composition can be prepared in different administration forms including lozenges, film-coated tablets, pills, or sugar-coated pills, or can be filled into a suitable container such as a capsule, or in the case of a suspension, filled into a bottle. As used herein, a "pharmaceutically acceptable carrier medium" may include any and all solvents, diluents, or other liquid carriers, dispersions or suspension aids, and surfactants, as long as they are suitable for the particular dosage form required. , Isotonic agents, thickening or emulsifying agents, preservatives, solid adhesives, lubricants and the like. Remington's Pharmaceutical Sciences, 20th edition, A. R. Gennaro (William & Wilkins, Baltimore, MD, 2000) discloses different carriers for formulating pharmaceutical compositions and their known preparation techniques. To date, all traditional carrier media have been used except for the production of any unnecessary biological effects, or any incompatible with the antiviral compounds of the present invention in a destructive manner with any other component of the pharmaceutical composition Covered by the scope of the present invention. In the pharmaceutical composition of the present invention, based on the total weight of the composition, the active 88828.doc -35-200418452 is present in an amount by weight that may be at least 0.5%, and usually not more than 90%, including any Carrier vehicle and / or adjuvant. Preferably, the proportion of the active agent varies with the weight of the composition, and it varies from 5 to 50% of the composition. The composition can be formulated using organic or inorganic solid or liquid carrier vehicles suitable for parenteral or parenteral administration. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyglycols, or other known pharmaceutical ingredients may be suitable for use as carrier media or excipients. The compounds of the present invention can be administered in any amount and route effective to reduce viral infectivity. Therefore, when used herein, the expression "amount effective to reduce viral infectivity" refers to a non-toxic but sufficient amount of anti-virus to provide the necessary prevention and / or treatment of viral infection. The exact amount required will depend on the species of the individual patient, the age and general condition of the patient, the severity of the infection, the specific antiviral agent, the mode of administration, and the like. The antiviral compound is preferably formulated in a dosage unit form to facilitate administration and maintain dosage consistency. As used herein, a "dosage unit type" refers to a physically separate amount of an antiviral agent suitable for the patient being treated. Each dose should contain the amount of active substance calculated to produce the desired therapeutic effect, or a combination of any selected pharmaceutical carrier and or supplementary active agent. Typically, the unit dose of an antiviral compound of the present invention comprises an antiviral agent having a composition weight of from about 2 mg to about 7000 mg, preferably in a range from about 10 mg to about 2000 mg. When administering this compound, taking into account the nature and severity of the infection to be treated, it can be administered orally, rectally, such as by intramuscular injection, subcutaneous injection, intravenous immersion 88828.doc -36- 200418452 or similar parenteral Intracranial, intravaginal, intraperitoneal, bureau 4 and other paths, and can be used such as powder, ointment, or drops or the like; or by inhalation such as aerosol or similar. Depending on the route of administration, the compound of the present invention is administered at a dose of about 0.05 to about 100 mg / kg of the patient's body weight one or more times a day to achieve the desired therapeutic effect. The compounds of the invention can typically be administered from 1 to 4 times per day to deliver the aforementioned agents: r ° However, the proper administration of the compounds and compositions described herein will depend on the needs of the individual host or patient being treated , The therapeutic grievance administered and the judgment of the participating healthcare professionals. Concentrating on the effect of inhibiting viral RNA synthesis produced by this compound, we expect that these compounds can be used not only to treat viral infections, but also to prevent viral infections. Whether treating or preventing a viral infection, the dose may be substantially the same. The following examples are provided to further illustrate the invention. These examples illustrate suitable synthetic methods for representative compounds of the present invention. However, the synthetic method is intended to be illustrative, and not limited to the following examples. The starting materials for preparing the compounds of the present invention can be conveniently prepared, if not commercially available, according to one of the following examples or by using known chemical methods. Preparation of 2-amidan-3-yl-5-methoxy-benzofuran-carboxylic acid formamide (aK2- ^ an-3-yl-5-hydroxy-benzofurancarboxylic acid ethyl ester).
88828.doc -37- 200418452 在一經烤箱乾燥之氬氣壓下之25毫升三頸燒瓶中溶β-氧 基呋喃丙酸乙酯(2·22公克、12.2毫莫耳)於絕對乙醇(4毫 升)同時瓷棒攪拌。添加氯化鋅(無水,1.66公克、12.2毫 莫耳)並以磁棒攪拌反應直至呈均質(2〇分鐘)。將固體1,‘ 苯亂(1.32公克、12·2毫莫耳)放入反應燒瓶上之以指狀物加 盍《玻璃棉絕緣的支臂添加漏斗(使用棉化塞)。令反應於油 >合中溫和迴流加熱,藉熱乙醇緩慢溶解並經18小時時間將 Μ-苯酿滴入壺中。將反應冷卻至室溫並以水處理(約1⑻毫 升)。經乙酸乙酯(3Χ75毫升)萃取後,合併有機層,經 脫水並蒸發。藉由HPLC (矽膠,乙酸乙酯/己烷)純化生成之 油,提供1.42克(43%)淡黃色結晶之產物。 物l(b)(2-吱喃-3-基-5-甲氧基-苯并呋喃-3-羧 酸乙酯)。88828.doc -37- 200418452 In a 25 ml three-necked flask under oven-dried argon pressure, ethyl β-oxyfuranpropionate (2.22 g, 12.2 mmol) was dissolved in absolute ethanol (4 ml). At the same time the porcelain sticks are stirred. Zinc chloride (anhydrous, 1.66 g, 12.2 mmol) was added and the reaction was stirred with a magnetic bar until homogeneous (20 minutes). Put solid 1, benzene (1.32 grams, 12.2 millimoles) in the reaction flask and add 指 "glass wool insulated arm addition funnel (using cotton plug). The reaction in oil was heated under mild reflux, slowly dissolved with hot ethanol, and M-benzene was dropped into the pot over 18 hours. The reaction was cooled to room temperature and treated with water (about 1 ⑻mL). After extraction with ethyl acetate (3 × 75 ml), the organic layers were combined, dehydrated and evaporated. The resulting oil was purified by HPLC (silica gel, ethyl acetate / hexane) to provide 1.42 g (43%) of the product as pale yellow crystals. Compound l (b) (2-crean-3-yl-5-methoxy-benzofuran-3-carboxylic acid ethyl ester).
在經烤箱乾燥之氬氣壓下之50毫升燒瓶中合併化合物 l(a)( 1.42公克、5.21毫莫耳)、碳酸鉀(磨碎的,2.16公克、 15.6毫莫耳)與無水乙腈(20毫升)。將破化卸燒(3.25毫升、 52·2毫莫耳)加入此混合物,並將反應迴流加熱18小時。將反 應冷卻至室溫,並於蒸發溶劑前濾過CeliteTM 503 (秒藻土) 片。藉由HPLC (矽膠,乙酸乙酯/己烷)純化生成之固體,提 供1.37克(92%)淡黃色結晶之所需產物。 c.製備化合物l(c_l(2-吱喃-3-基-5 -甲氧基-苯并呋喃-3―致 88828.doc -38 - 200418452Combine oven 1 (a) (1.42 g, 5.21 mmol), potassium carbonate (ground, 2.16 g, 15.6 mmol) and anhydrous acetonitrile (20 mL) in a 50 mL flask under oven-dried argon ). Decombustion (3.25 ml, 52.2 mmol) was added to this mixture, and the reaction was heated at reflux for 18 hours. The reaction was cooled to room temperature and filtered through a CeliteTM 503 (Secondary Celite) sheet before the solvent was evaporated. The resulting solid was purified by HPLC (silica gel, ethyl acetate / hexane) to provide 1.37 g (92%) of the desired product as pale yellow crystals. c. Preparation of compound l (c-1 (2-crean-3-yl-5 -methoxy-benzofuran-3) to 88828.doc -38-200418452
於5〇毫升燒瓶中,將化合物l(b)(1.37公克、4.78毫莫耳) 與氯氧化4甲粒(〇·4公克、713毫莫耳)合併於5〇%乙醇水溶液 (3 5 4升)。令該混合物迴流隔夜並冷卻至室溫。蒸發—半溶 劑’並以3莫耳濃度HC1酸化,過濾產生之白色沈澱、水洗 ’並於60。〇真空乾燥,提供1.21克(97%)所需產物。 d· 基-5-甲氣基-笨并咕喃-楼酸甲酸胺之〇 將化合物l(c)(〇〇5公克、〇19毫莫耳)溶於經烤箱乾燥之 氯氣壓下之10毫升燒瓶中之無水四氫呋喃(THF)(3毫升)。於 磁棒攪拌下添加l5l,_羰基二咪唑(〇〇5公克、〇·31毫莫耳), 並令生成之混合物溫和加熱至約50〇c達3〇分鐘以驅除c〇2 。添加過量甲胺(2·〇莫耳濃度之THF溶液、2毫升),並持續 加;^ 4小時。爿十反應冷卻至室溫,並蒸發溶劑產生油,其藉 HPLC (反相C18,乙赌/水)純化。冷凍乾燥後,分離〇〇21 克(39%)白色固體之所需產物。 實例2 蒸基-5_三氟甲氡基-笨并咕响_3_兔^^釀胺之製備 a.Ul化合物2(a)_(5-幾基-2-苯基-苯并呋喃_3-羧酸乙酯)。In a 50 ml flask, compound 1 (b) (1.37 g, 4.78 mmol) was combined with 4-methyl oxychloride (0.4 g, 713 mmol) in a 50% ethanol aqueous solution (3 5 4 Rise). The mixture was refluxed overnight and cooled to room temperature. Evaporation-semi-solvent 'and acidified at 3 moles HC1, the white precipitate produced by filtration, washed with water' and mixed at 60 ° C. O Vacuum drying provided 1.21 g (97%) of the desired product. d. 5-Methanyl-benzyl-pyrano-uranyl formate amine. Compound l (c) (0.05 g, 019 mmol) was dissolved in an oven-dried chloroform at 10 Anhydrous tetrahydrofuran (THF) (3 ml) in a ml flask. 15 l, -carbonyldiimidazole (0.05 g, 0.31 mmol) was added with stirring by a magnetic bar, and the resulting mixture was gently heated to about 50 ° C for 30 minutes to drive off C02. An excess of methylamine (a 2.0 mol THF solution, 2 ml) was added, and the addition was continued for 4 hours. The reaction was cooled to room temperature and the solvent was evaporated to give an oil, which was purified by HPLC (reverse phase C18, ethyl acetate / water). After lyophilization, 021 g (39%) of the desired product was isolated as a white solid. Example 2 Preparation of Dimethyl-5_trifluoromethylfluorenyl-benzylpyridine_3_rabbitamine amine a.Ul Compound 2 (a) _ (5-Epi-2-phenyl-benzofuran _3-carboxylic acid ethyl ester).
2(a) 88828.doc -39- 200418452 中間體化合物實質上是根據上述實例1、步騾a之一般方 法製成,然而使用芊醯基乙酸乙酯取代β-氧基-3-呋喃丙酸 乙酯。 b.製備化合物2(b)(5-硫甲基硫羰氧基-2-苯基-苯并呋喃 -3-羧酸乙酯)。2 (a) 88828.doc -39- 200418452 The intermediate compound is essentially prepared according to the general method of Example 1 and step 骡 a above, but β-oxy-3-furanpropionic acid is replaced with ethyl ethyl fluorenyl Ethyl ester. b. Preparation of compound 2 (b) (5-thiomethylthiocarbonyloxy-2-phenyl-benzofuran-3-carboxylic acid ethyl ester).
在開口於大氣壓之25毫升燒瓶中,將硫酸氫四丁基銨 (0·06公克、0.177毫莫耳)加入12莫耳濃度氫氧化鈉(5毫升) 與二硫化碳(5毫升),同時磁力攪拌。添加化合物2(a)(0.5 公克、1.77毫莫耳)與碘化鉀烷(0.12毫升、1.93毫莫耳),並 令該混合物於室溫下劇烈攪拌1小時。將反應混合物倒入分 液漏斗,收取有機層,並以二硫化碳(3X10毫升)洗水層。 合併有機層,經硫酸鈉脫水’並蒸發溶劑,產生撥色油, 令其經HPLC (矽膠,乙酸乙酯/己烷)純化,提供0.42克(63%) 澄清油之所需產物。 c.製備化合物苯基-5-三氟甲氧基-苯并呋喃-3_幾 酸乙酯)。In a 25 ml flask opened at atmospheric pressure, add tetrabutylammonium hydrogen sulfate (0.06 g, 0.177 mmol) to 12 mole sodium hydroxide (5 ml) and carbon disulfide (5 ml), while magnetically stirring . Compound 2 (a) (0.5 g, 1.77 mmol) and potassium iodide (0.12 ml, 1.93 mmol) were added, and the mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was poured into a separatory funnel, the organic layer was collected, and the aqueous layer was washed with carbon disulfide (3 × 10 ml). The organic layers were combined, dehydrated over sodium sulfate, and the solvent was evaporated to produce a color-shifting oil, which was purified by HPLC (silica gel, ethyl acetate / hexane) to provide 0.42 g (63%) of the desired product as a clear oil. c. Preparation of the compound phenyl-5-trifluoromethoxy-benzofuran-3-ethylacetate).
在一個氬氣壓下之25毫升燒瓶中,將HF/吡啶(70%、2.56 88828.doc -40- 200418452 毫升)加入-781:之1,3-二溴-5,5-二甲基内醯脲(0.96克、3.36 毫莫耳)與化合物2(b)(0.42克、M3毫莫耳)之二氯甲烷(1〇 毫升)懸浮液。一旦添加完成(20分鐘),將反應轉移至冰浴 ,並於〇°C磁力攪拌1小時。然後,將反應混合物倒入5〇 : 50之飽和NaHCCVNaHSCMIOO毫升)水溶液,並以乙醚萃取 (3 X 40毫升)。令有機層經硫酸鈉脫水,並蒸發溶劑。令粗 產物經HPLC(反相C18,乙腈/水)純化,提供0.12克(30%)黃 色油之所需產物。 d.2^_苯基-5-三氟甲氧基-苯并呋喃-3-#酸甲醯胺之攀碑。 標題化合物實質上係根據上述之實例1、步騾^與^製成; 然而,在步騾c使用化合物2(c)而非化合物1(b)。 實例3 二氟基-萎基)—5_甲氧基·苯并呋喃_3_淼酸甲醯胺之 製備 a•製備化合物H(3_(3,4-二氟基-苯基)-3-氧基-丙酸乙酯)。In a 25 ml flask under argon pressure, HF / pyridine (70%, 2.56 88828.doc -40-200418452 ml) was added to -781: 1,3-dibromo-5,5-dimethylinner A suspension of urea (0.96 g, 3.36 mmol) and compound 2 (b) (0.42 g, M3 mmol) in dichloromethane (10 ml). Once the addition was complete (20 minutes), the reaction was transferred to an ice bath and magnetically stirred at 0 ° C for 1 hour. The reaction mixture was then poured into a 50:50 saturated aqueous solution of NaHCCVNaHSCMIO (100 ml) and extracted with ether (3 x 40 ml). The organic layer was dehydrated over sodium sulfate and the solvent was evaporated. The crude product was purified by HPLC (reverse phase C18, acetonitrile / water) to provide 0.12 g (30%) of the desired product as a yellow oil. d. 2 ^ _phenyl-5-trifluoromethoxy-benzofuran-3- # acid formamide monument. The title compound was essentially prepared according to Example 1 above, steps 骡 ^ and ^; however, compound 2 (c) was used instead of compound 1 (b) in step 骡 c. Example 3 Preparation of Difluoro-Arytyl) -5_methoxy · benzofuran_3_methanesulfonic acid formamidine a • Preparation of compound H (3_ (3,4-difluoroyl-phenyl) -3 -Oxy-ethyl propionate).
令丙二酸乙酿4甲鹽(7.46克、43.8毫莫耳mMgCl2 (314克 、33.0毫莫耳)於無水THF(36毫升)混合,並迴流々小時。於 刀開之3,4 一氟下酸(5·22克、33〇毫莫耳)之無水毫 升)溶液中一次添加u,-羰基二咪唑(6 29克、38 8毫莫耳) ,並另該混合物加熱30分鐘。然後,於室溫將第二種溶液 加入MgCh溶液。令反應混合物於室溫攪拌隔夜(16小時)。 -41 - 88828.doc 200418452 2反應燒瓶於冰浴冷卻,並添加HC1溶液(1〇毫升濃HO與2〇 耄升化〇)。令生成之混合物於室溫攪拌i小時。添加乙酸乙 酷以萃取產物,並以鹽液與水洗合併之有機層,經Na2s〇4 脫水,並濃縮以生成油殘渣。令粗產物經短的即驟管柱(矽 膠,10: 90乙酸乙酉旨/己垸)純化,提供7〇克(93%)灰白色油 之所需產物。 比1^^^(2_(3,4_二氟基_苯基)_5_羥基_苯并呋喃 -3-叛酸乙酯)。,Let methyl malonate 4 methyl salt (7.46 g, 43.8 mmol mMgCl2 (314 g, 33.0 mmol)) be mixed in anhydrous THF (36 ml) and refluxed for 々 hours. 3,4 monofluoro To a solution of acetic acid (5.22 g, 33 mmol) in anhydrous ml) was added u, -carbonyldiimidazole (629 g, 38.8 mmol) in one portion, and the mixture was heated for another 30 minutes. Then, the second solution was added to the MgCh solution at room temperature. The reaction mixture was allowed to stir at room temperature overnight (16 hours). -41-88828.doc 200418452 2 The reaction flask was cooled in an ice bath, and a solution of HC1 (10 ml of concentrated HO and 20 mL) was added. The resulting mixture was allowed to stir at room temperature for i hours. Ethyl acetate was added to extract the product, and the combined organic layers were washed with saline and water, dehydrated over Na 2 SO 4, and concentrated to form an oil residue. The crude product was purified on a short flash column (silica gel, 10:90 ethyl acetate / hexane) to provide 70 g (93%) of the desired product as an off-white oil. Than 1 ^^^ (2_ (3,4_difluoroyl_phenyl) _5_hydroxy_benzofuran-3-ethyl ethyl acetate). ,
將絕對乙醇(10毫升)加入含無水ZnC12 (2·98克、21.9毫莫 耳,於烤箱中預乾燥1小時)之經烤箱乾燥之氬氣下之燒瓶 。然後,將化合物3(a)(5.0克、21.9毫莫耳)加入上述之澄清 溶液。將1,4-苯醌(2·37克、21·9毫莫耳)放入具支臂之添加 燒开瓦(燒瓶底層有一片玻璃棉),並於添加燒瓶上裝置冷凝器 々燒瓶中之反應混合物於油浴中加熱至1 。〇。令乙醇緩 I*又迴泥過添加燒瓶之支臂(包覆玻璃棉與鋁络);然後,經隔 畏(18小時)緩慢洗去1,4-苯醌。另該反應混合物冷卻至室溫 ,以乙酸乙酯稀釋,經鹽液與水洗,並經Na2S〇4脫水。濃 縮後,令殘渣經急驟管柱層析(矽膠,弘1〇%乙酸乙酯之己 烷溶液)純化,提供3.60克(52%)淡黃色油之所需產物。 c·製合物3(公(2-(3,4-二氟基-苯基)_5_甲氧基-苯并呋 喃_3 -叛酸乙酉旨)。 88828.doc -42-Absolute ethanol (10 ml) was added to an oven-dried argon flask containing anhydrous ZnC12 (2.98 g, 21.9 mmol, pre-dried in the oven for 1 hour). Then, compound 3 (a) (5.0 g, 21.9 mmol) was added to the above-mentioned clear solution. Put 1,4-benzoquinone (2.37 g, 21.9 mmol) into an added boiled tile (with a piece of glass wool on the bottom of the flask) with arms, and install a condenser on the addition flask into the flask The reaction mixture was heated to 1 in an oil bath. 〇. Let the ethanol slowly I * return to the sludge and pass through the arms of the addition flask (covered with glass wool and aluminum mesh); then, slowly wash away the 1,4-benzoquinone through the barrier (18 hours). The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine and water, and dehydrated with Na 2 SO 4. After concentration, the residue was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to provide 3.60 g (52%) of the desired product as a pale yellow oil. c. Preparation 3 (common (2- (3,4-difluoro-phenyl) _5_methoxy-benzofuran_3 -acetic acid ethyl acetate). 88828.doc -42-
200418452 將碳酸钾(276毫克、2.0毫莫耳)加入化合物3(b)(255毫克 、〇·8毫莫耳)之乙腈(5毫升)溶液。令混合物迴流加熱30分 鐘,然後,冷卻至室溫。添加碘化甲烷(249微升、4·0毫莫 耳)’並令反應混合物攪:拌隔夜。令混合物經水稀釋,並萃 取入乙酸乙酯。以鹽液洗有機層並脫水。令粗產物經管柱 層析(矽膠,5 : 95乙酸乙酯/己烷)純化,提供235毫克(88%) 白色固體之所需產物。 d.复JlL·化合物3(dl(2-(3,4-二氟基-苯基)-5-甲氧基-苯并呋 喃-3-叛酸)。200418452 Potassium carbonate (276 mg, 2.0 mmol) was added to a solution of compound 3 (b) (255 mg, 0.8 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for 30 minutes, and then cooled to room temperature. Methane iodide (249 µl, 4.0 mmol) was added 'and the reaction mixture was stirred: stir overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saline solution and dehydrated. The crude product was purified by column chromatography (silica gel, 5:95 ethyl acetate / hexane) to provide 235 mg (88%) of the desired product as a white solid. d. Compound JlL · Compound 3 (dl (2- (3,4-difluoro-phenyl) -5-methoxy-benzofuran-3-metanoic acid).
3(d) 私氫氧化納(10當里丨辰度、0·5晕升)加入化合物3(c)(23〇 毫克、0.69毫莫耳)之絕對乙醇(8毫升)之熱溶液。令反應混 合物加熱至90°C並攪拌2小時。經冷卻至室溫後,以1〇% HCl 將該混合物酸化至pH 2。令生成之懸浮液經乙酸乙酯萃取 ,NadCU脫水,並濃縮以提供定量產率之白色固體(21〇毫 克)。該產物不經進一步純化即直接進行下一步驟。 e.2-(3,4-二氣基-苯基^酸甲醯胺 之製備。 88828.doc -43- 200418452 將甲胺(0.45毫升、2.0莫耳濃度之thF溶液)加入化合物 3(d)(91*克、〇·30*莫耳)之無水N,N-二甲基甲醯胺(DMF)(5 笔升)溶液,隨之添加苯并三唑基氧基參吡咯啶基銹六氟 石外酸鹽(PyBOP)(156*克、〇·3〇毫莫耳)。令生成之反應混合 物於室溫攪拌2小時,以水稀釋,經乙酸乙酯萃取,脫水並 ;辰縮。令粗產物經層析純化(石夕膠、1 〇 ·· 9〇乙酸乙酯/己燒) ’提供72毫克(76%)白色固體之產物。 實例4 醯基胺基-甲基)-苯基異丙氧甚-笨并咭喃-3_羧 疲_甲醯胺之備 a•复備化合物4(a) (3-(4-溴基-苯基)-3-氧基·丙酸乙酯)。3 (d) Sodium hydroxide (10 ° C, 0.5 ° L) was added to a hot solution of compound 3 (c) (23 mg, 0.69 mmol) in absolute ethanol (8 ml). The reaction mixture was heated to 90 ° C and stirred for 2 hours. After cooling to room temperature, the mixture was acidified to pH 2 with 10% HCl. The resulting suspension was extracted with ethyl acetate, NadCU was dehydrated, and concentrated to provide a quantitative white solid (20 mg). The product was carried on to the next step without further purification. e. Preparation of 2- (3,4-dioxo-phenylammonium methanoate. 88828.doc -43- 200418452) Methylamine (0.45 ml, 2.0 mole concentration thF solution) was added to compound 3 ) (91 * g, 0.30 * mol) in anhydrous N, N-dimethylformamide (DMF) (5 pens) solution, followed by addition of benzotriazolyloxypyrrolidinyl rust Hexafluorolite (PyBOP) (156 * grams, 0.30 millimoles). The resulting reaction mixture was stirred at room temperature for 2 hours, diluted with water, extracted with ethyl acetate, dehydrated and dried. The crude product was purified by chromatography (Shijiao gum, 1 ·· 90 ethyl acetate / hexane). 72 mg (76%) of the product was provided as a white solid. Example 4 (Amidinoamino-methyl)- Phenylisopropoxyl-benzylpyran-3_carboxamidine_formamidine Preparation a • Compound 4 (a) (3- (4-Bromo-phenyl) -3-oxy · propane Acid ethyl ester).
令丙二酸乙酯鉀鹽(5.63克、33.08毫莫耳)與氯化鎂(2.37 克、24.87毫莫耳)於氬氣壓下之THF (60毫升)迴流4小時。 於第二個反應容器中,將1,1 羰基二咪唑(4.76克、29.35毫 莫耳)添加至氬氣下之4-溴芊酸(5.0克、24.87毫莫耳)之THF (30毫升)溶液,並令該溶液溫和迴流3〇分鐘。將二者之反應 皆冷卻至室溫,並將第二種溶液逐滴加入丙二酸乙酯/氯化 鎂混合物。令反應混合物於室溫攪拌16小時。令濃鹽酸(10 毫升)與水(20毫升)於添加漏斗中混合,並以15分鐘時間逐 滴添加至反應混合物。藉旋轉蒸發去除有機溶劑,並以乙 酸乙酯萃取產物數次。合併有機層,經鹽液洗並濃縮。令 88828.doc -44- 200418452 產物經急驟/ & 曰析(石夕膠,乙酸乙酯/己烷梯度)純化,提供6 〇7 克灣橙色油之所需產物。 · 溴基_苯基)_5_羥基_苯并呋喃_3_ 羧酸乙酯)。Ethyl malonate potassium salt (5.63 g, 33.08 mmol) and magnesium chloride (2.37 g, 24.87 mmol) were refluxed under argon pressure in THF (60 ml) for 4 hours. In a second reaction vessel, 1,1 carbonyldiimidazole (4.76 g, 29.35 mmol) was added to 4-bromoarsinic acid (5.0 g, 24.87 mmol) in THF (30 ml) under argon. Solution, and gently reflux the solution for 30 minutes. Both reactions were cooled to room temperature, and the second solution was added dropwise to the ethyl malonate / magnesium chloride mixture. The reaction mixture was allowed to stir at room temperature for 16 hours. Concentrated hydrochloric acid (10 ml) and water (20 ml) were mixed in an addition funnel and added dropwise to the reaction mixture over a period of 15 minutes. The organic solvent was removed by rotary evaporation, and the product was extracted several times with ethyl acetate. The organic layers were combined, washed with brine and concentrated. The product 88828.doc -44- 200418452 was purified by flash analysis (stone gum, ethyl acetate / hexane gradient) to provide 6.07 g of the desired product as an orange oil. · Bromo_phenyl) _5_hydroxy_benzofuran_3_carboxylic acid ethyl ester).
將添加漏斗、燒瓶、攪拌棒與氯化鋅(3.02克、22.13毫莫 耳)於烤相中乾燥1小時,並於氬氣下冷卻。將化合物4(a)(6 〇 克、22.13毫莫耳)溶於乙醇⑴毫升),並加入含氯化辞之燒 瓶。經添加漏斗(包覆玻璃棉與鋁箔並利用棉花塞)添加I〆— 苯醌(2.39公克、22·13毫莫耳)。令反應於油浴中加熱至1〇5;^ ,同時調整冷凝入添加漏斗之乙醇量,以促進丨,4•苯醌之“ 小時添加。當i,4-苯酿消耗完後將反應冷卻至室溫,添加乙 酸乙酯,並以鹽液洗粗產物。以乙酸乙酯洗水層數次,合 併有機層並濃縮。令產物經急驟層析(矽膠, 梯度)純化,並觸之乙酸乙醋之己燒液中超音波= 提供2.24克(28%)橙色固體之所需產物。 溴基-苯基)_5_異丙氧基-苯并呋喃 -3-羧酸乙酯)。The addition funnel, flask, stir bar and zinc chloride (3.02 g, 22.13 mmol) were dried in the baking phase for 1 hour and cooled under argon. Compound 4 (a) (60 g, 22.13 mmol) was dissolved in ethanol (ml) and added to a flask containing chloride. I 添加 —benzoquinone (2.39 g, 22 · 13 mmol) was added through an addition funnel (covering glass wool and aluminum foil and using a cotton plug). The reaction was heated in an oil bath to 105; ^, and the amount of ethanol condensed into the addition funnel was adjusted to promote the "hourly" addition of benzoquinone. When the i, 4-benzene was consumed, the reaction was cooled At room temperature, ethyl acetate was added, and the crude product was washed with brine. The aqueous layer was washed several times with ethyl acetate, and the organic layers were combined and concentrated. The product was purified by flash chromatography (silica gel, gradient) and contacted with acetic acid. Ultrasonic in ethyl acetate's hexane solution = 2.24 g (28%) of the desired product as an orange solid. Bromo-phenyl) -5_isopropoxy-benzofuran-3-carboxylic acid ethyl ester).
將化合物4(b)(l〇.59克、29.32毫莫耳)與乙猜⑽毫升)加 88828.doc -45- 200418452 入含無水碳酸鉀(1〇·13克、73.30毫莫耳)之經烤箱乾燥之燒 瓶。令混合物迴流加熱1小時,然後,冷卻至室溫。添加2-破化丙烷(8.78毫升、87.96毫莫耳),並令反應混合物迴流加 熱16小時。令反應混合物冷卻至室溫,濃縮、溶於乙酸乙 酯並過濾。真空下濃縮濾液,並將粗產物再結晶(乙酸乙酯 與己虎),提供9.38克(79%)褐色固體之所需產物。 d ·製備化合物4(d) (2-(4 ->臭基-冬基)-5 -異丙氧基-苯并咬喃 -3 -幾酸)。Compound 4 (b) (10.59 grams, 29.32 millimoles) and ethidium chloride (ml) were added 88828.doc -45- 200418452 to a solution containing anhydrous potassium carbonate (10.3 grams, 73.30 millimoles). Oven-dried flask. The mixture was heated at reflux for 1 hour and then cooled to room temperature. 2-Decomposed propane (8.78 ml, 87.96 mmol) was added and the reaction mixture was heated at reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, concentrated, dissolved in ethyl acetate and filtered. The filtrate was concentrated in vacuo, and the crude product was recrystallized (ethyl acetate and hexane) to provide 9.38 g (79%) of the desired product as a brown solid. d-Preparation of compound 4 (d) (2- (4--> Styrolyl- winteryl) -5 -isopropoxy-benzoanan-3 -chitoic acid).
將氫氧化鉀粒(1.0克、17.82毫莫耳)加入化合物4(c)(2.02 克、5.01毫莫耳)之ι:1乙醇/水(25毫升/25毫升)之懸浮液。令 反應混合物迴流加熱2小時。將反應混合物冷卻至室溫,並 真空濃縮。將粗產物萃取至乙酸乙酯而不經酸化。濃縮有 機層’並將固體再結晶(乙酸乙酯與己烷),提供^“克(99%) 橙色固體之所需產物。 溴基-苯基)-5-異丙氧基-苯并呋喃 -3-羧酸甲醯胺)。Potassium hydroxide particles (1.0 g, 17.82 mmol) were added to a suspension of compound 4 (c) (2.02 g, 5.01 mmol) in 1: 1 ethanol / water (25 ml / 25 ml). The reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was extracted into ethyl acetate without acidification. The organic layer was concentrated and the solid was recrystallized (ethyl acetate and hexane) to provide ^ "g (99%) of the desired product as an orange solid. Bromo-phenyl) -5-isopropoxy-benzofuran -3-carboxylic acid formamidine).
4(e) 將1-(3·二甲基胺基丙基)-3-乙基羰二亞胺(1.40克、7.32 宅莫耳)、1-#呈基苯并三唑(〇 99克、7.32毫莫耳)與甲胺(4.88 88828.doc -46- 200418452 笔升、2.0莫耳濃度之THF溶液、9·75毫莫耳)加入化合物4(d) (1·83克、4.88毫莫耳)之二氯甲烷(35毫升)溶液。令反應混 合物於室溫攪拌16小時,然後濃縮、溶於乙酸乙酯並水洗 。將有機層真空濃縮,並令粗產物經急驟層析(矽膠,乙酸 乙酯/己烷梯度)純化,提供L24克(66%)黃色固體之所需產 物。 f.惠」I化合物4(f)(2-(4-氰基-苯基)-5-異丙氧基-苯并吱喃 -3-羧酸甲醯胺)。4 (e) 1- (3-Dimethylaminopropyl) -3-ethylcarbonyldiimide (1.40 g, 7.32 mol), 1- # is benzotriazole (0 99 g , 7.32 millimoles) and methylamine (4.88 88828.doc -46- 200418452 pen liters, 2.0 Molar concentration of THF solution, 9.75 millimoles) was added to compound 4 (d) (1.83 grams, 4.88 millimoles). Mol) in dichloromethane (35 ml). The reaction mixture was allowed to stir at room temperature for 16 hours, then concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 24 g (66%) of the desired product as a yellow solid. f. "Hui" compound 4 (f) (2- (4-cyano-phenyl) -5-isopropoxy-benzoanan-3-carboxylic acid formamidine).
將氰化銅(1.95克、21.81毫莫耳)加入化合物4(e)(121克、 3·12毫莫耳)之1-甲基·2_吡咯啶酮…⑽)^毫升)溶液。令反 應混合物於油浴加熱至17〇°C。將反應冷卻至室溫,以水與 乙酸乙酯稀釋,並濾過CeliteTM塞,經乙酸乙酯與水潤濕。 令各層分離,並真空濃縮有機層。經急驟層析(矽膠,乙酸 乙酯/己燒梯度)純化粗產物,提供〇·68克(65%)所需產物。 化合物4(g)(2-(4-胺甲基-苯基)-5-異丙氧基_苯并吱 喃-3-羧酸甲醯胺、HC1鹽)。Copper cyanide (1.95 g, 21.81 mmol) was added to a solution of compound 4 (e) (121 g, 3.12 mmol) in 1-methyl · 2-pyrrolidone ... (ii) (ml). The reaction mixture was heated to 170 ° C in an oil bath. The reaction was cooled to room temperature, diluted with water and ethyl acetate, and filtered through a CeliteTM plug, and wet with ethyl acetate and water. The layers were separated and the organic layer was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate / hexanes gradient) to provide 0.68 g (65%) of the desired product. Compound 4 (g) (2- (4-aminomethyl-phenyl) -5-isopropoxy-benzo-anthran-3-carboxylic acid formamidine, HC1 salt).
令10% Pd/C (0.10克)混合以水與濃鹽酸(0·5毫升),並加 入含化合物4(f)(0.68克、2.03毫莫耳)甲醇(15毫升)溶液之反 88828.doc -47- 200418452 應燒瓶。令反應燒瓶於55 psig氫氣下之Parr振盪器振盪16 小時。令反應混合物滤過CeliteTM,經乙醇潤濕。真空濃縮 濾液,並將粗產物再結晶(乙酸乙酯),提供0 65克(86%)深 黃色固體之所需產物。 h.ijf化会构4(h)(2-[4-(乙醯基胺基-甲基)-苯基]異丙 氧基-苯并咬喃-3 -叛酸甲g盔胺)。10% Pd / C (0.10 g) was mixed with water and concentrated hydrochloric acid (0.5 ml), and the solution containing compound 4 (f) (0.68 g, 2.03 mmol) in methanol (15 ml) was added 88828. doc -47- 200418452 should be flask. The reaction flask was shaken on a Parr shaker under 55 psig of hydrogen for 16 hours. The reaction mixture was filtered through CeliteTM and wet with ethanol. The filtrate was concentrated in vacuo and the crude product was recrystallized (ethyl acetate) to provide 0 65 g (86%) of the desired product as a dark yellow solid. h.ijf. 4 (h) (2- [4- (Ethylamido-methyl) -phenyl] isopropoxy-benzo-anan-3 -metamate).
4⑻ 將三乙胺(0.037毫升、0.267毫莫耳)加入含化合物4(g)(5〇 毫克、0.133毫莫耳)之二氯甲烷(1〇毫升)溶液。將乙酸酐 (0·015φ升、0.160¾莫耳)加入該溶液,並令反應於室溫攪 拌。16小時後,將二氣甲烷(1〇毫升)與水(15毫升)加入混合 物’令各層分離。真空濃縮有機層,並令粗產物經急騾層 析(矽膠、乙醇/乙酸乙酯)純化,提供5〇毫克(96%)灰白色 固體之所需產物。 實例5 輕基-苯基異丙氣盖-苯并呋喃-3-#酸甲醯胺之製備 a·製僮j匕合物氧基-苯基)-3-氧基-丙酸乙酯)。4) Triethylamine (0.037 ml, 0.267 mmol) was added to a dichloromethane (10 ml) solution containing compound 4 (g) (50 mg, 0.133 mmol). Acetic anhydride (0.015? Liter, 0.160 ¾ mole) was added to the solution, and the reaction was stirred at room temperature. After 16 hours, digas methane (10 ml) and water (15 ml) were added to the mixture 'to separate the layers. The organic layer was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, ethanol / ethyl acetate) to provide 50 mg (96%) of the desired product as an off-white solid. Example 5 Preparation of light-phenyl-isopropyl gas cap-benzofuran-3- # formamidine .
-48- 88828.doc 200418452 令丙二酸乙酯鉀鹽(9.92公克、58.27毫莫耳)與氯化鎂 (4·17克、43.81毫莫耳)於氬氣下之THF (100毫升)迴流4小時 。於第二個反應容器中,將!,!,_羰基二咪唑(〇1)1)(8.38克、 51·7〇毫莫耳)加入氬氣下之4-爷氧基爷酸(10克、43.81毫莫 耳)之THF (60毫升)溶液。令該溶液溫和迴流3〇分鐘。將二 者之反應皆冷卻至室溫,並將第二種溶液逐滴加入丙二酸 乙酿/氯化鎂混合物。令反應混合物於室溫攪拌隔夜。16小 時後’將鹽酸溶液(20毫升濃HC1與40毫升水)加至反應混合 物。真空下去除有機溶劑,並以乙酸乙酯萃取產物數次。 合併有機層,經鹽液洗並濃縮。令產物經急騾層析(矽膠, 乙酸乙酯/己烷梯度)純化,提供1〇克(77%)淡黃色固體之所 需產物。 物5(b)(2-(4_爷氧基-苯基)-5-羥基-苯并呋喃 -3-羧酸乙酯)。-48- 88828.doc 200418452 reflux ethyl potassium malonate (9.92 g, 58.27 mmol) and magnesium chloride (4.17 g, 43.81 mmol) in THF (100 ml) for 4 hours under argon . In the second reaction vessel, will! ,! Carbonyl diimidazole (〇1) 1) (8.38 g, 51.7 mmol) was added with THF (10 ml, 43.81 mmol) in THF (60 ml) under argon. Solution. The solution was allowed to reflux gently for 30 minutes. Both reactions were cooled to room temperature, and the second solution was added dropwise to the ethyl malonate / magnesium chloride mixture. The reaction mixture was allowed to stir at room temperature overnight. After 16 hours', a hydrochloric acid solution (20 ml of concentrated HC1 and 40 ml of water) was added to the reaction mixture. The organic solvent was removed under vacuum and the product was extracted several times with ethyl acetate. The organic layers were combined, washed with brine and concentrated. The product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 10 g (77%) of the desired product as a pale yellow solid. 5 (b) (2- (4-Ethoxy-phenyl) -5-hydroxy-benzofuran-3-carboxylic acid ethyl ester).
將化合物5(a)(10.0克、33·52毫莫耳)溶於乙醇(15毫升), 並加入含氯化鋅(烤箱乾燥,4·57克、33·52毫莫耳)之烤箱乾 燥之燒瓶。將克、33.52毫莫耳)放人添加漏斗 (包覆玻璃棉與銘羯並利用棉花塞)。令反應於油洛加熱至 i〇〇°c,同時調整冷凝入添加漏斗之乙醇量,以促進1,肛^ 醌之18小時添加。當1,4 —苯醌消耗完後,將混合物冷卻至^Compound 5 (a) (10.0 g, 33.52 mmol) was dissolved in ethanol (15 ml), and oven dried with zinc chloride (oven dried, 4.57 g, 33.52 mmol) was added. Flask. Put grams, 33.52 millimoles) into the addition funnel (cover the glass wool with Ming Ming and use a cotton plug). The reaction was heated in Yolo to 100 ° C, and the amount of ethanol condensed into the addition funnel was adjusted to promote the addition of 1, anthraquinone for 18 hours. When 1,4-benzoquinone is consumed, cool the mixture to ^
HO 88828.doc -49- 200418452 溫,添加乙酸乙酯,並以鹽液洗粗產物。以乙酸乙酯洗水 層數次,合併有機層並真空濃縮。令產物經急驟層析(矽膠 ’乙酸乙酯/己燒梯度)純化,並於15%之乙酸乙酯之己燒溶 液中超首波振盪以提供4.08克(31%)固體之所需產物。 c ·兔備化_合物5 (,g}_( 2-(4 -卞乳基-苯基)-5 -異丙氧基-苯并口夫 喃_3_叛酸乙酯)。HO 88828.doc -49- 200418452 warm, add ethyl acetate, and wash the crude product with saline. The aqueous layer was washed several times with ethyl acetate, and the organic layers were combined and concentrated in vacuo. The product was purified by flash chromatography (silica gel's ethyl acetate / hexanes gradient) and super-first-waved in a 15% ethyl acetate-fired solution to provide 4.08 g (31%) of the desired product as a solid. c. Rabbit preparation_complex 5 (, g) _ (2- (4 -fluorenyl-phenyl) -5 -isopropoxy-benzohuffan-3-ethyl behenate).
將化合物5(b)(4.07克、10.48毫莫耳)與乙腈(60毫升)加入 含碳酸鉀(烤箱乾燥,3.62克、26.20毫莫耳)之烤箱乾燥之燒 瓶。令混合物迴流加熱1小時,然後,冷卻至室溫。添加 碘化丙烷(3.14毫升、31.43毫莫耳),並令反應混合物再次迴 流加熱。16小時後,令反應混合物冷卻至室溫,濃縮、、、办 於乙酸乙酯並水洗。真空濃縮有機層,並經急.驟層析(石夕$ ,乙酸乙酯/己烷梯度)純化,提供4.07克(90%)黃色固體之 鲁 產物。Compound 5 (b) (4.07 g, 10.48 mmol) and acetonitrile (60 ml) were added to an oven-dried flask containing potassium carbonate (oven dried, 3.62 g, 26.20 mmol). The mixture was heated at reflux for 1 hour and then cooled to room temperature. Propane iodide (3.14 ml, 31.43 mmol) was added and the reaction mixture was heated under reflux again. After 16 hours, the reaction mixture was cooled to room temperature, concentrated, and washed with ethyl acetate. The organic layer was concentrated in vacuo and purified by flash chromatography (Shi Xi $, ethyl acetate / hexane gradient) to provide 4.07 g (90%) of the product as a yellow solid.
喃-3 -幾酸)。Ran-3-a few acids).
88828.doc -50- 200418452 將氫氧化鉀粒(〇·5克、891毫莫耳)加入化合物5(c)(i 克、2.32«莫耳)之1:1乙醇/水(2〇毫升/2〇毫升)懸浮液。令反 應混合物迴流加熱2小時,然後冷卻至室溫。添加丨莫耳濃 度鹽酸’氯出沉澱物並乾燥以提供〇 92克(99%)白色固體之 產物。 苄氧基_苯基)_5-異丙氧基_苯并味 喃-3-羧酸甲醯胺)’。88828.doc -50- 200418452 Add potassium hydroxide particles (0.5 g, 891 mmol) to compound 5 (c) (i g, 2.32 «mol) in 1: 1 ethanol / water (20 ml / 20 ml) suspension. The reaction mixture was heated at reflux for 2 hours and then cooled to room temperature. Mortar-concentrated hydrochloric acid 'was added to remove the precipitate and dried to provide 0.92 g (99%) of the product as a white solid. Benzyloxy_phenyl) _5-isopropoxy_benzobenzopyran-3-carboxylic acid formamidine) '.
將化合物5(d)(0.92克、2.48毫莫耳)與苯并三唑_1_基_氧基 -參-咐哈呢基-鱗六氟磷酸鹽(129克、2.48毫莫耳)於氬氣下 混合’並經甲胺(2〇毫升、2.0莫耳濃度之THF溶液)處理。將 落液於室溫攪拌3小時。濃縮反應混合物、溶於乙酸乙酯並 水洗。濃縮有機層,並經急驟層析(矽膠,乙酸乙酯/己烷梯 度)純化,提供0.78克(76%)白色固體之所需產物。 f.ULl匕合物5(ϋ(2-(4-羥基-苯基)-5-異丙氧基-苯并吱喃 -3-羧酸甲醯胺)。Compound 5 (d) (0.92 grams, 2.48 millimoles) and benzotriazole_1_yl_oxy-shen-saw-Hanayl-phosphonium hexafluorophosphate (129 grams, 2.48 millimoles) Mix under argon and treat with methylamine (20 ml, 2.0 Molar THF solution). The falling liquid was stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 0.78 g (76%) of the desired product as a white solid. f. UL1 dagger compound 5 (fluorene (2- (4-hydroxy-phenyl) -5-isopropoxy-benzoanan-3-carboxylic acid formamidine).
5(f) 將10% Pd/C (0·1〇克)之水混合物加入含化合物5(θ(〇 78 克、1.88¾莫耳)之乙醇/乙酸乙醋(20毫升/1〇毫升)溶液。令 88828.doc -51 - 200418452 反應混合物於55 psig氫氣之Parr振盪器振盪6小時。令反應 混合物滤過CeliteTM,經乙酸乙酯與乙醇潤濕。濃縮濾液, 並令粗產物再結晶(乙酸乙酯與己燒),提供0.57克(93%)灰 白色固體之所需產物。 實例6 2-(4-氟基-苯基)-5-異丙氧基-6-说^7各淀-1-基-笨并咬喃-3-瘦 酸甲縫胺之製備 a.製__備化合物6(aV3-(;4-氟基-苯基)-3-氧基-丙酸乙酯)。5 (f) A 10% Pd / C (0.10 g) water mixture was added to ethanol / ethyl acetate (20 ml / 10 ml) containing compound 5 (θ (0 78 g, 1.88 ¾ mole)). Solution. Let 88828.doc -51-200418452 shake the reaction mixture on a Parr shaker at 55 psig of hydrogen for 6 hours. Filter the reaction mixture through CeliteTM, wet with ethyl acetate and ethanol. Concentrate the filtrate and recrystallize the crude product ( Ethyl acetate and hexane) to provide 0.57 g (93%) of the desired product as an off-white solid. Example 6 2- (4-Fluoro-phenyl) -5-isopropoxy-6-say Preparation of 1-yl-benzyl-3-alanine methaneamine a. Preparation of compound 6 (aV3-(; 4-fluoro-phenyl) -3-oxy-propionic acid ethyl ester ).
以1小時將4-氟苄酸(275克、1.96莫耳)之THF (1升)加入 1,1’-羰基二咪唑(CDI)(381克、2.36莫耳)之THF (1升)溶液。 於30°C攪拌反應混合物1小時,然後為室溫隔夜。以5分鐘 時間將氯化鎂:(186克、1.96莫耳)加入丙二酸乙醋钾鹽(435 克、2.56莫耳)之THF (2升)之第二種混合物。令生成之混合 物於密閉裝置攪拌隔夜。以11/2小時時間,將第一種混合物 加入丙二酸混合物。令該反應混合物於室溫擾拌數小時, 然後加溫至3 0°C經數小時。令反應混合物經4當量濃度HC1 (1.0升)處理,並令各層分離。以水(1升)稀釋水層,經Hci (250毫升)|^化至約pjj 1,並經乙酸乙酉旨(1升)洗。濃縮有機 層以提供65克粗產物。濃縮原始有機層以去除thf,經乙酸 乙酯(1升)稀釋,並以水(1升)潤濕。合併有機層與65克粗產 物,並濃縮成油。令該油經乙酸乙酯(1升)稀釋,並經5〇/〇 88828.doc -52- 200418452 真空蒸餾粗產物,提供THF (1 liter) of 4-fluorobenzoic acid (275 g, 1.96 mol) was added to a solution of 1,1'-carbonyldiimidazole (CDI) (381 g, 2.36 mol) in THF (1 liter) over 1 hour. . The reaction mixture was stirred at 30 ° C. for 1 hour and then at room temperature overnight. Magnesium chloride: (186 g, 1.96 moles) was added over 5 minutes to a second mixture of potassium ethyl malonate (435 g, 2.56 moles) in THF (2 liters). The resulting mixture was allowed to stir overnight in a closed device. The first mixture was added to the malonic acid mixture over a period of 11/2 hours. The reaction mixture was allowed to stir at room temperature for several hours, and then warmed to 30 ° C for several hours. The reaction mixture was treated with 4 equivalents of HC1 (1.0 liter) and the layers were separated. The aqueous layer was diluted with water (1 liter), reduced to about pjj 1 with Hci (250 ml), and washed with ethyl acetate (1 liter). The organic layer was concentrated to provide 65 g of crude product. The original organic layer was concentrated to remove thf, diluted with ethyl acetate (1 liter), and wet with water (1 liter). The organic layers were combined with 65 g of crude product and concentrated to an oil. The oil was diluted with ethyl acetate (1 liter) and the crude product was vacuum distilled over 50 / 〇 88828.doc -52- 200418452 to provide
NaHC03 (1升)潤濕。濃縮有機層 322克(78%)所需產物。 b.製備化合物 幾酸乙酯)。 基_笨基)-5-羥基-苯并呋喃-3-NaHC03 (1 liter) wets. The organic layer was concentrated 322 g (78%) of the desired product. b. Preparation of compound Ethyl Acetate). -Benzyl) -5-hydroxy-benzofuran-3-
將化合物6(a)(157克、0.75莫耳)加入含氯化辞(1〇〇克、〇74 莫耳)與乙醇(250毫升)之燒瓶,並以另外之乙醇(約5〇毫升) 洗入。混合Μ-苯酿(8〇公克、0.74莫耳)與CeliteTM(4(^),龙 放入輕塞以玻璃棉之添加漏斗。令反應混合物加熱至95τ ,並以約4毫升/分鐘之速率添加丨,4_苯醌。當丨,‘苯醌消耗 几後,將混合物冷卻至室溫,添加乙酸乙酯(2升),並以水 (1升)與鹽液洗粗產物。過濾去除不溶之不純物,濃縮濾液。 令生成之固體於二氯甲烷(500毫升)中攪拌,並冷卻至_20τ 過/慮去除另外之不純物。濃縮遽液,混合二氯甲燒(4〇〇 毫升)與粗產物,冷卻至-20°C並過滤。令分離之固體經二氯 甲烷潤濕並風乾,提供71.8克(32.3%)之所需產物。 化合物6(c_i( 2-(4 -氟基-苯基)-5-異丙氧基-苯并咬喃 -3-羧酸乙酯)。Compound 6 (a) (157 g, 0.75 mol) was added to a flask containing chloride (100 g, 074 mol) and ethanol (250 ml), and another ethanol (about 50 ml) was added. Wash in. Mix M-Benzene (80 g, 0.74 mol) with CeliteTM (4 (^), put the light stopper into the glass funnel to add the funnel. Heat the reaction mixture to 95τ, and at a rate of about 4 ml / min Add 4-benzoquinone. When the benzoquinone is consumed, cool the mixture to room temperature, add ethyl acetate (2 liters), and wash the crude product with water (1 liter) and brine. Remove The insoluble impurities are concentrated. The filtrate is concentrated. The resulting solid is stirred in dichloromethane (500 ml) and cooled to _20τ. The other impurities are removed. The mash is concentrated and mixed with dichloromethane (400 ml). The crude product was cooled to -20 ° C and filtered. The separated solid was wetted with dichloromethane and air-dried to provide 71.8 g (32.3%) of the desired product. Compound 6 (c_i (2- (4-fluoro -Phenyl) -5-isopropoxy-benzoanan-3-carboxylic acid ethyl ester).
88828.doc -53 - 200418452 將碳酸铯(111·6克、343毫莫耳)加入化合物6(b)(73.5克、 245毫莫耳)之1-甲基_2_吡咯啶酮(250毫升)。令反應混合物 於油浴中加熱至5(TC達16小時,然後冷卻至室溫。過濾去 除固體 < 不純物,並以鹽液與第三丁基甲基醚稀釋漉液。 令各層分離,並以第三丁基甲基醚潤濕水層數次。合併有 機層並濃縮。過濾分離彼經隔夜形成之固體並經己烷潤濕 ,提供約28克所需產物。經管柱層析(矽膠,乙酸乙酯/己烷 梯度)純化濾液,提供另外之47.2克之所需產物。 d.ij廣化合物6(d)(6-溴基-2-(4-氟基-苯基)_5_異丙氧基_ 苯并呋喃-3·羧酸乙酯)。88828.doc -53-200418452 Cesium carbonate (111.6 g, 343 mmol) was added to 1-methyl-2-pyrrolidone (250 ml) of compound 6 (b) (73.5 g, 245 mmol) ). The reaction mixture was heated in an oil bath to 5 ° C. for 16 hours, and then cooled to room temperature. The solids were removed by filtration, and the mash was diluted with a salt solution and a third butyl methyl ether. Tributyl methyl ether wets the water layer several times. The organic layers are combined and concentrated. The solid formed overnight is filtered and wetted with hexane to provide about 28 g of the desired product. Column chromatography (silica gel, ethyl acetate) / Hexane gradient) to purify the filtrate to provide an additional 47.2 g of the desired product. D.ij compound 6 (d) (6-bromo-2- (4-fluoro-phenyl) _5_isopropoxy_ Benzofuran-3 · ethyl carboxylate).
將溴(0.75毫升、0.014莫耳)之無水二噚烷(2〇毫升)溶液經 1小時加入可經由前述步驟製成之無水二噚烷(5〇毫升)之化 合物6(〇(4.59克、0.014毫莫耳)之溶液。令反應混合物於3〇〇 watt-燈之室溫氬氣下攪拌i小時。加另外3滴的溴,並令反 應攪拌隔夜。令反應混合物濃縮至1/2體積,以水稀釋、經乙 酸乙酉日萃取’紅MgS04脫水並濃縮。令粗產物經Ηριχ (反相 ,乙腈/水梯度)純化,提供白色固體之所需產物。 e.im物6(红(2-(4-氟基-苯基)-5-異丙氧基-6-吡咯啶 -1-基-苯并咬喃-3-叛酸乙酉旨)。 88828.doc -54- 200418452A solution of bromine (0.75 ml, 0.014 mol) in anhydrous dioxane (20 ml) was added over 1 hour to an anhydrous dioxane (50 ml) compound 6 (0 (4.59 g, 0.014 mmol). The reaction mixture was stirred at 300 watt-lamp under room temperature argon for 1 hour. Add another 3 drops of bromine and stir the reaction overnight. The reaction mixture was concentrated to 1/2 volume Diluted with water, extracted with red acetate MgS04 after dehydration with ethyl acetate and dehydrated and concentrated. The crude product was purified by Ηρχ (reverse phase, acetonitrile / water gradient) to provide the desired product as a white solid. E.im 6 (red (2 -(4-fluoro-phenyl) -5-isopropoxy-6-pyrrolidin-1-yl-benzoanan-3-acetic acid). 88828.doc -54- 200418452
將含碳酸铯(乾燥,0.217克)之烤箱乾燥之燒瓶放入氬氣 壓下之乾的袋中,並添加化合物6(幻(〇25〇克、〇 594毫莫耳) 、參(二苯亞甲基丙酮)二鈀(0)(0·0163克、〇〇178毫莫耳)與 rac-2,2-雙(二苯基膦基)_u,_二莕基(消旋混合物,〇〇ιι克 、0.0177¾莫耳)。將燒瓶自乾的袋中取出,清洗,並充填 鲁 氬氣使之成真空(3x)。於燒瓶中添加無水甲苯(1〇毫升),隨 之為吡咯啶(0.059毫升)。於油浴中將反應混合物加熱至95它 隔夜,然後冷卻至室溫,經乙醚稀釋,濾過CeHteTM片並經 乙醚洗。蒸發溶劑,並藉急驟層析(矽膠,乙酸乙酯/己烷) 純化粗產物,以提供〇·117克(49%)黃色油之所需產物。 合物6(Γ)·(2-(4-氟基-苯基)_5_異丙氧基-6-吡咯啶 -1-基-苯并呋喃-3-羧酸)。An oven-dried flask containing cesium carbonate (dry, 0.217 g) was placed in a dry bag under argon pressure, and compound 6 (magnesium (0,250 g, 0594 mmol), ginseng (diphenylene) was added. Methylacetone) dipalladium (0) (0.016 g, 0.00178 mmol) and rac-2,2-bis (diphenylphosphino) _u, _diamidino (racemic mixture, 〇〇 ιg, 0.0177¾ mole). Remove the flask from the dry bag, wash it, and fill it with argon to make it vacuum (3x). Add anhydrous toluene (10 ml) to the flask, followed by pyrrolidine (0.059 ml). The reaction mixture was heated to 95 overnight in an oil bath, then cooled to room temperature, diluted with ether, filtered through CeHteTM tablets and washed with ether. The solvents were evaporated and flash chromatography (silica gel, ethyl acetate) / Hexane) The crude product was purified to provide 0.117 g (49%) of the desired product as a yellow oil. Compound 6 (Γ) · (2- (4-fluoro-phenyl) _5_isopropoxy -6-pyrrolidin-1-yl-benzofuran-3-carboxylic acid).
知氫氧化鉀(一粒)加入化合物6(e)(〇 n4克、〇·277毫莫耳) <2:1乙醇/水(2·〇毫升/1〇毫升)溶液。令反應混合物迴流加 熱超過2小時,然後於室溫攪拌隔夜。藉蒸發自混合物中去 除乙醇。將剩餘之油溶於水中並以3當量濃度之鹽酸稀釋至 88828.doc '55- 200418452 固體形成(約pH 7.5)。過濾黃色固體以提供〇 〇9克(85%)所需 產物。 g·製備化—合物6(g)(2-(4_氟基-苯基)_5_異丙氧基吡咯啶 -1-基-苯并呋喃-3-羧酸甲醯胺)。It is known that potassium hydroxide (one grain) was added with a compound 6 (e) (On4 g, 0.277 mmol) < 2: 1 ethanol / water (2.0 ml / 10 ml) solution. The reaction mixture was heated at reflux for more than 2 hours and then stirred at room temperature overnight. The ethanol was removed from the mixture by evaporation. The remaining oil was dissolved in water and diluted with 3 equivalents of hydrochloric acid to 88828.doc '55-200418452. A solid formed (about pH 7.5). The yellow solid was filtered to provide 0.9 g (85%) of the desired product. g · Preparation of compound 6 (g) (2- (4-fluoro-phenyl) -5-isopropoxypyrrolidin-1-yl-benzofuran-3-carboxylic acid formamidine).
將木并二唆-1-基-氧基-參-峨洛淀基-鱗六氟鱗酸鹽(1 克、0.183毫莫耳)加入化合物6(f) SBE-0628-198 (79.0毫克、 0.206毫莫耳)之甲胺(3.0毫升、2.0莫耳濃度之THF溶液)溶液 之直氣下之烤箱乾燥之燒瓶。令反應混合物於室溫攪拌6小 時,然後真空濃縮。經急騾層析(矽膠,乙酸乙酯/己烷)純 化生成之油,提供0.045克(63%)黃色固體之產物。 實例7 —一氣甲氧基-2-(4 -氟基-笨基)-笨并咬喃-3-巍酸甲酿胺之 製備 合物二氣甲氧基-2-(4-氟基-苯基)_苯并呋 喃-3-叛酸乙酯)。Xylidene-1-yl-oxy-shen-erodolide-squadenahexafluoroscale salt (1 g, 0.183 mmol) was added to compound 6 (f) SBE-0628-198 (79.0 mg, 0.206 mmol) of methylamine (3.0 ml, 2.0 mol THF solution) in an oven-dried flask under direct air. The reaction mixture was allowed to stir at room temperature for 6 hours and then concentrated in vacuo. Purification of the resulting oil by flash chromatography (silica gel, ethyl acetate / hexane) provided 0.045 g (63%) of the product as a yellow solid. Example 7 — Preparation of a mono-gas methoxy-2- (4-fluoro-benzyl) -benzyl-3-anthamic acid methylamino amine digas methoxy-2- (4-fluoro- Phenyl) _benzofuran-3-ethyl acetate).
和琪化钾(28毫克、0.167毫莫耳)與碳酸钾(0.69克、5.00 88828.doc -56- 二:)、入可根據貝例6製成之化合物6(b) (0.50克、1.67 2 — A )、2 丁酮溶液。令反應混合物於室溫攪拌10分鐘。 :=氯二氟乙酸乙醋(0.32毫升、2·5〇毫莫耳),並令該反應 : ]時。令反應冷卻至室並真空濃縮。溶粗產物於乙 2乙私並經水與1莫耳濃度氫氯酸洗。濃縮產物,並藉急 辱Τ層析(矽膠,乙酸乙酯/己烷梯度)純化,提供毫克(22%) 白色固體之所需產物。 二氟甲氧基_2_(4_氟基_苯基)_苯并呋 喃-3-羧酸)。 ^ 7(b) 將氫氧化鉀顆粒(0·50克,891毫莫耳)加入化合物7(幻 (0·13克、0.371毫莫耳)之1:1乙醇/水(7毫升/7毫升)懸浮液。令 反應混合物迴流加熱Κ5小時。將反應混合物冷卻至室溫並 真S ;辰縮。添加1莫耳濃度氫氣酸至溶液變酸,形成沉澱。過 濾固體並乾燥’提供120毫克(1〇〇〇/0)白色固體之所需產物。 会物7(红(5_二氟甲氧基-2-(4-氟基-苯基)-笨并呋 喃-3-羧酸甲醯胺)。And potassium potassium (28 mg, 0.167 mmol) and potassium carbonate (0.69 g, 5.00 88828.doc -56- di :), compound 6 (b) (0.50 g, 1.67) which can be prepared according to Example 6 2 — A), 2 methyl ethyl ketone solution. The reaction mixture was allowed to stir at room temperature for 10 minutes. : = Ethyl chlorodifluoroacetate (0.32 ml, 2.50 mmol), and the reaction was allowed to take place:] hr. The reaction was allowed to cool to the chamber and concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with water and 1 molar hydrochloric acid. The product was concentrated and purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide mg (22%) of the desired product as a white solid. Difluoromethoxy_2_ (4-fluoroyl_phenyl) _benzofuran-3-carboxylic acid). ^ 7 (b) potassium hydroxide particles (0.50 g, 891 mmol) were added to compound 7 (magic (0.13 g, 0.371 mmol)) in 1: 1 ethanol / water (7 ml / 7 ml ) Suspension. The reaction mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and cooled down. Add 1 molar hydrogen acid until the solution became acidic, forming a precipitate. Filter the solid and dry to provide 120 mg ( 100/0) The desired product as a white solid. Meeting 7 (Red (5-difluoromethoxy-2- (4-fluoro-phenyl) -benzylfuran-3-carboxylic acid formamidine amine).
將1-(3-二甲基胺基丙基)-3 -乙基談二亞胺鹽酸鹽(〇.η克 88828.doc -57- 200418452 0.558毫莫耳)與甲 0.745毫莫耳)加入 、0.558¾莫耳)、1-輕苯并三唾(乃毫克、 胺(2.0莫耳濃度之THF溶液,〇·37毫升、 化合物7⑻(0.12克、〇.372毫莫耳)之二氯甲垸⑽毫升)溶液 。令反應混合物於室溫攪拌16小時、然後濃縮,溶於乙酸 乙酯並以水洗。濃縮有機層,並經急驟層析(矽膠,乙酸乙 酯/己烷梯度)純化粗產物,提供87毫克(7〇%)白色固體之所 需產物。 a Μ4-氟基-苯基 V5_ 吴 生Aildl酸甲醯脖夕寧備 標題化合物(0.038克、黃色固體)實質上是根據上述實例6 所逑之一般方法製成,然而,在步騾e不使用乾的袋子並以 2-甲氧基乙胺取代吡咯啶。而且,標題化合物係經反相HpLc 、利用60%至90%之乙腈的水溶液梯度加以純化。 實例9 基苯某-蓋^呋喃-3_勒酸甲醯胺之掣備 a·复盘化合物9X^(3-甲氧基-6-甲基-2_苯基flavyiium氯化 物)。Add 1- (3-Dimethylaminopropyl) -3 -ethyl-diimide hydrochloride (0.08 g 88828.doc -57- 200418452 0.558 mmol) and methyl 0.745 mmol) Add, 0.558¾ mole), 1-light benzotrisalyl (i.e. mg, amine (2.0 Molar concentration in THF solution, 0.37 ml, compound 7⑻ (0.12 g, 0.372 mmol) dichloro) Formaldehyde solution). The reaction mixture was stirred at room temperature for 16 hours, then concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by flash chromatography (silica gel, ethyl acetate / hexane gradient). The crude product provided 87 mg (70%) of the desired product as a white solid. A M4-Fluoro-phenyl V5_Wusheng Aildl Acid Formamidine The title compound (0.038 g, yellow solid) was essentially based on It was prepared by the general method described in Example 6 above, however, in step 骡 e, a dry bag was not used and pyrrolidine was replaced with 2-methoxyethylamine. Moreover, the title compound was subjected to reversed phase HpLc using 60% to 90 % Of acetonitrile in water was purified by gradient. Was 9X ^ (3- methoxy-6-methyl-phenyl flavyiium -2_ chloride).
將無水HC1通氣經過0°c之2-羥基_5-甲基苄醛(2 〇克、 14.69¾莫耳)與2-甲氧基苯乙酮(2毫升、1451毫莫耳)之乙 酉父乙酯(28¾升)與乙醇(7毫升)溶液丨小時。然後,將反應加 88828.doc -58- 200418452 過濾分離固體 蓋並放入冰箱56小時。加乙醚至沉掇形成 提供3·73克(88%)所需之鹽。 -苯并呋喃-3-羧酸甲酯)。 b.复化合物甲基-2-苯基Anhydrous HC1 was ventilated through 0 ° C of 2-hydroxy-5-methylbenzaldehyde (20 g, 14.69¾ mole) and 2-methoxyacetophenone (2 ml, 1451 mmol). A solution of ethyl acetate (28 ¾ liters) and ethanol (7 ml) was allowed to stand for 1 hour. The reaction was then 88828.doc -58- 200418452 filtered to separate the solid lid and placed in the refrigerator for 56 hours. Add ether to settle to provide 3.73 g (88%) of the desired salt. -Methyl benzofuran-3-carboxylic acid). b. Complex compound methyl-2-phenyl
將過氧化氫(7.5毫升、72·8毫莫耳)加入化合物9⑷(3.5克 。〇毛莫耳)之50%甲醇水落液(72毫升)。令反應混合物 籲 玛泥加熱隔夜,冷卻至室溫並經乙醚稀釋。令各層分離, 並以乙醚卒取水層(2χ)。合併有機層,以鹽液洗,脫水 (MgS04)並蒸發。藉珍膠之管柱層析純化,利社丄己燒/乙 酸乙酿為溶離液,提供736毫克(22 6%)白色固體之所需化合 物。 甲基|苯基-苯并咬喃叛酸)。Hydrogen peroxide (7.5 ml, 72.8 millimoles) was added to compound 9⑷ (3.5 g. Molole) in 50% methanol in water (72 ml). The reaction mixture was allowed to warm overnight, cooled to room temperature and diluted with ether. The layers were separated and the aqueous layer was taken with ether (2x). The organic layers were combined, washed with saline, dehydrated (MgS04) and evaporated. Purified by gel column chromatography, Lishe hexane / acetic acid was used as the eluent to provide 736 mg (22 6%) of the desired compound as a white solid. Methyl | phenyl-benzoanuronic acid).
將氫氧化鉀水溶液(4當量濃度、12毫升)加入化合物9(b) (6^笔克、2.46毫莫耳)之甲醇(15毫升)懸浮液。令反應於高 ^見拌攸。令混合物冷卻至室溫,並以i當量濃度氫氯酸 酸化至pH 2。抽氣過濾收集沉澱物,水洗並乾燥,生成471 毫克(76%)所需之羧酸。 88828.doc -59- 200418452An aqueous potassium hydroxide solution (4 equivalents, 12 ml) was added to a methanol (15 ml) suspension of compound 9 (b) (6 pen grams, 2.46 mmol). Make the response high. The mixture was allowed to cool to room temperature and acidified to pH 2 with i-equivalent hydrochloric acid. The precipitate was collected by suction filtration, washed with water and dried to yield 471 mg (76%) of the desired carboxylic acid. 88828.doc -59- 200418452
分別將甲胺(0.495毫升之2莫耳濃度THF溶液、〇·99毫莫耳) 、1-[3-(二甲基胺基)丙基]_3_乙基羰二亞胺鹽酸鹽(142毫克 、0.742毫莫耳)與羥苯并三唑(1〇〇毫克、〇·742毫莫耳)加入 化合物9(c)(125cs克、0.495¾莫耳)之無水二氯甲烷(2毫升) 溶液。令反應於室溫之氬氣下攪拌隔夜,加丨當量濃度氫氯 酸止熱並經二氯甲烷萃取。以鹽液洗有機層,脫水(MgS〇4) 並蒸發。藉矽膠之管柱層析純化,利用二氯甲烷為溶離液 ’提供49毫克(37%)白色固體之標題產物。 實例10 甲基_2_(4:氟基-苯基苯赶—咬喃_3·淼醢甲崦胺乏擎借 a·-製..備...化合物9(a)( 1-(心氟基-苯基)·2_甲氧基-乙酮)。Methylamine (0.495 ml of a 2 molar solution in THF, 0.99 mmol), 1- [3- (dimethylamino) propyl] -3_ethylcarbonyldiimine hydrochloride ( 142 mg, 0.742 mmol) and hydroxybenzotriazole (100 mg, 0.742 mmol) were added to compound 9 (c) (125cs g, 0.495¾ Mol) in anhydrous dichloromethane (2 mL ) Solution. The reaction was allowed to stir overnight at room temperature under argon, the equivalent concentration of hydrochloric acid was added to stop the heat and extracted with dichloromethane. The organic layer was washed with saline, dehydrated (MgS04) and evaporated. Purified by column chromatography on silica gel using dichloromethane as the eluent ' to provide 49 mg (37%) of the title product as a white solid. Example 10 Methyl_2_ (4: fluoro-phenylbenzene sulfonate-bitan_3. Miao succinimidine depletion by a ... Preparation ... Compound 9 (a) (1- ( Fluoro-phenyl) · 2-methoxy-ethanone).
將4-氟苄醯氣(25.6克、161毫莫耳)之乙腈(60毫升)溶液逐 滴加入0°C、氬氣下之三甲基矽烷重氮甲烷(96毫升之2莫耳 濃度溶液、193.2毫莫耳)與三乙胺(27毫升、193.2毫莫耳) 之無水乙腈(250毫升)溶液。令反應於〇°C攪拌2小時,然後 ’加蓋並於冰箱放置隔夜。經旋轉蒸發去除溶劑,並溶殘 渣於飽和碳酸氫鈉溶液,經乙酸乙酯萃取。以水與鹽液洗 有機物,脫水(MgS〇4)並蒸發以生成25.16克黃色固體。溶 固體於無水甲醇(200¾升)’並添加三乳化硼化物(19.4毫 升、161毫莫耳)。令反應於室溫攪拌2小時,經旋轉蒸發去 88828.doc -60- 200418452 除落劑。溶殘渣於乙醚,並以水與鹽液洗,脫水(MgS〇4) 並备發。利用5:1之己烷/乙酸乙酯之矽膠管柱層析純化,提 供18.77克(69%)橙色固體之所需產物。 氟基-苯基吱喃淼醢甲醯胺之製 標題化合物實質上是根據實例9、步騾a-b製成,然而, 在步驟a以2-甲氧基-4’ -氟基苯乙g同取代2_甲氧基苯乙酮並 以化合物10(a)取代2-甲氧基苯乙酮。A solution of 4-fluorobenzylhydrazone gas (25.6 g, 161 mmol) in acetonitrile (60 ml) was added dropwise to 0 ° C trimethylsilane diazomethane (96 ml of a 2 molar solution) , 193.2 mmoles) and triethylamine (27 ml, 193.2 mmoles) in anhydrous acetonitrile (250 ml). The reaction was allowed to stir at 0 ° C for 2 hours, then was capped and left in the refrigerator overnight. The solvent was removed by rotary evaporation, and the residue was dissolved in a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organics were washed with water and saline, dehydrated (MgS04) and evaporated to yield 25.16 g of a yellow solid. The solid was dissolved in anhydrous methanol (200¾ liters) 'and tri-emulsified boride (19.4 ml, 161 mmol) was added. The reaction was allowed to stir at room temperature for 2 hours, and 88828.doc -60-200418452 scavenger was removed by rotary evaporation. The residue was dissolved in diethyl ether, washed with water and saline, dehydrated (MgS04) and prepared. Purification using 5: 1 hexane / ethyl acetate silica gel column chromatography provided 18.77 g (69%) of the desired product as an orange solid. The title compound made from fluoro-phenylammoniummidine is essentially prepared according to Example 9, Step 骡 ab, however, in step a, 2-methoxy-4'-fluorophenylethyl g is the same as Substitute 2-methoxyacetophenone and replace 2-methoxyacetophenone with compound 10 (a).
實例U 基-5_(2,2,2-三氟基并咭喃_3_勒_甲醯胺之 製備— a.H化合物11⑷(5_羥基_2_苯基苯并呋喃_3_羧酸)。 88828.docExample Preparation of U-based-5_ (2,2,2-trifluoropyrano-3_le_formamidine — aH compound 11⑷ (5_hydroxy_2_phenylbenzofuran_3_carboxylic acid) 88828.doc
化合物11 (a)貫質上是根據上述實例3、步騾d之一般方法 製成,然而,以化合物2(a)取代化合物3(c)。 b.製備樹脂11(b)。Compound 11 (a) was prepared according to the general method of Example 3 and Step d in the above. However, Compound 2 (a) was used instead of Compound 3 (c). b. Preparation of resin 11 (b).
令經4-甲醯基-3-甲氧基苯氧基甲基功能化之苯乙烯 脂 -61- 200418452 乙烯基苯共聚物(2克,Aidrich、〇·9毫莫耳/克)於乙酸之 一鼠甲k (2〇耄升)中膨脹’然後歷乾。添加1 %乙酸之二氯 甲烷(20毫升)隨之為甲胺(2莫耳濃度thf,4毫升),並令該 混合物超音波震盪2〇分鐘。然後,令樹脂混合物於室溫靜 置16小時。然後添加經超音波震盪之乙氧基硼氫化鈉(422 笔克、2¾莫耳)之1%乙酸之二氯乙烷(5毫升)懸浮液,隨之 在室溫溫和攪拌16小時。添加甲醇(5毫升)並瀝乾溶劑。然 後以甲醇與一氯甲虎徹底洗樹脂。重複反應確保完全消耗 結合於樹脂之醛。不必定特徵直接令乾燥之樹脂進行下一 步驟。 c.ldlL#子脂 lUc、。Let 4-methylmethyl-3-methoxyphenoxymethyl functionalized styrene grease-61- 200418452 vinylbenzene copolymer (2 g, Aidrich, 0.9 mmol / g) in acetic acid One of them was swollen in K (20 μl) and then dried. Add 1% dichloromethane in acetic acid (20 ml) followed by methylamine (2 mole concentration thf, 4 ml) and allow the mixture to sonicate for 20 minutes. Then, the resin mixture was allowed to stand at room temperature for 16 hours. A 1% suspension of 1% acetic acid in dichloroethane (5 ml) of sodium ethoxyborohydride (422 pens, 2¾ mol), which was sonicated, was added, followed by gentle stirring at room temperature for 16 hours. Methanol (5 ml) was added and the solvent was drained. Then wash the resin thoroughly with methanol and chloroform. Repeated reactions ensure complete consumption of the aldehyde bound to the resin. It is not necessary to specify the characteristics and let the dried resin go to the next step. c.ldlL # 子 脂 lUc.
令樹脂11(b)於DMF (6毫升)中膨脹,然後添加化合物 ll(a)(325毫克,1.5毫莫耳),隨之添加苯并三唑-;1_基-氧基_ 參-吡咯啶-鱗六氟磷酸鹽(78〇毫克、15毫莫耳,Resin 11 (b) was swelled in DMF (6 ml), then compound 11 (a) (325 mg, 1.5 mmol) was added, followed by benzotriazole-; 1-yl-oxy_- Pyrrolidine-squarehexafluorophosphate (78 mg, 15 mmol,
NovaBiochem)、二異丙基乙胺(0.523毫升、3毫莫耳)與DMF (4毫升)。令反應混合物於氮氣下溫和攪拌4小時,然後瀝乾 。在DMF (6X10*升)、甲醇(6X10毫升)與二氣甲烷(6χ1〇 *升)中徹底洗樹脂,並真空乾燥。令乾燥之樹脂繼續至步 驟d。 88828.doc 62- 200418452 令少量樣本經25%三氟乙酸(TFA)之二氯甲烷(CH2C12)處 理,以定性評估樹脂之負載。30分鐘後,濾除TFA-CH2C12 混合物,並將濾液蒸乾。藉LC-MS與NMR定性來自TFA處理 之乾燥產物之特徵,顯示樹脂負載成功。 d·製備2-笨基-542.2,2-三氟某-乙氣基苯并哇喃-3-藉_ 甲驢胺〇 將碳酸铯(325毫克、1毫莫耳)混合DMF (2毫升)並加熱至 75°C 10分鐘。添加樹脂ll(c)(150毫克,約0.135毫莫耳)做為 固體,隨之添加將2,2,2-三氟乙基破化物(2 10毫克、1毫莫耳) 與DMF (2毫升)。令反應混合物於氮氣下75°C加熱18小時。 然後,令樹脂冷卻至室溫,並經DMF (6X10毫升)、甲醇(6 X10毫升)與二氯甲烷(CH2C12)(6X10毫升)徹底洗過,並真 空乾燥。令乾燥之樹脂經25% TFA之CH2C12處理60分鐘。濾 除tfa-chW2混合物’並將濾液蒸乾。然後藉反相HPLC於 Gilson HPLC-MS半製備系統(經〇·ι〇/0乙酸之乙腈/水溶離)純 化’提供12.7¾克(27°/〇)所需產物。 實例12 m狀基:苯基)-5- ^^_苯并咭喃_3_勒酸甲醯胺之制借 a.l備化合物12(&1〇}^化合物12iaVin (2气4-氟基-苯基) -5-羥基-苯并呋喃-3-羧酸甲酯與2_(4_氟基_苯基卜5_羥基_苯 并呋喃-3-羧酸乙酯)。NovaBiochem), diisopropylethylamine (0.523 ml, 3 mmol) and DMF (4 ml). The reaction mixture was stirred gently under nitrogen for 4 hours and then drained. The resin was thoroughly washed in DMF (6X10 * L), methanol (6X10ml) and digas methane (6x10 * L), and dried under vacuum. Let the dried resin continue to step d. 88828.doc 62- 200418452 A small sample was treated with 25% trifluoroacetic acid (TFA) in dichloromethane (CH2C12) to qualitatively evaluate the resin load. After 30 minutes, the TFA-CH2C12 mixture was filtered off, and the filtrate was evaporated to dryness. Characterization of the dried product from TFA treatment by LC-MS and NMR showed successful resin loading. d · Preparation of 2-benzyl-542.2,2-trifluoro-ethanylbenzovanan-3-boron_methyldonamine. Mix cesium carbonate (325 mg, 1 mmol) with DMF (2 ml) And heated to 75 ° C for 10 minutes. Resin ll (c) (150 mg, about 0.135 mmol) was added as a solid, followed by the addition of 2,2,2-trifluoroethyl ester (2 10 mg, 1 mmol) and DMF (2 Ml). The reaction mixture was heated under nitrogen at 75 ° C for 18 hours. Then, the resin was allowed to cool to room temperature, washed thoroughly with DMF (6 × 10 ml), methanol (6 × 10 ml), and dichloromethane (CH2C12) (6 × 10 ml), and dried under vacuum. The dried resin was treated with 25% TFA in CH2C12 for 60 minutes. The tfa-chW2 mixture 'was filtered off and the filtrate was evaporated to dryness. It was then purified by reverse-phase HPLC on a Gilson HPLC-MS semi-preparative system (acetonitrile / water dissociation with 0. 0/0 acetic acid) to provide 12.7¾ (27 ° / 0) of the desired product. Example 12 Preparation of m-like group: phenyl) -5-^^ _ benzopyran_3_methanoic acid melanidine Preparation of compound 12 (& 1〇) ^ Compound 12iaVin (2-gas 4-fluoro group -Phenyl) -5-hydroxy-benzofuran-3-carboxylic acid methyl ester and 2- (4-fluoro-phenylphenyl 5-hydroxy-benzofuran-3-carboxylic acid ethyl ester).
88828.doc -63- 200418452 在虱氣壓下之經烤箱乾燥之燒瓶中放入4_氟基芊醯乙酸 f酯(4.0克、20·4毫莫耳)、氯化鋅(無水,2·73克、2〇4毫莫 耳)與、纟巴對乙醇(8耄升)同時磁棒攪拌。將固體之丨,4-苯醌 (2.21克、20.4毫莫耳)放入反應燒瓶上之添加漏斗。令反應 於油浴中溫和迴流加熱,經熱乙醇緩慢溶解並經18小時將 1,4-苯醌滴入壺中。將反應冷卻至室溫,然後經乙酸乙酯(4〇 毫升)與水稀釋。經乙酸乙酯(2χ)萃取後,合併有機層,經 NaJCU脫水,濾過矽膠並蒸乾。過濾生成之殘渣,然後藉 HPLC (石夕膠,40%乙酸乙醋/己烷)純化,並藉結晶由熱乙酸 乙酯/己烷進一步純化粗產物,提供2〇9克(36%)化合物 12(a)⑴與化合物i2(a)(ii)之混合物。 12(b)〇l遵^合物 12fbVin (2-(4_ 氟基-苯基) -5-甲氧基-苯并呋喃_3_羧酸甲酯與2_(4_氟基-苯基)_5_甲氧 基-苯并呋喃-3-羧酸乙酯)。88828.doc -63- 200418452 Put 4-fluorofluoroacetic acid f-ester (4.0 g, 20.4 mmol), zinc chloride (anhydrous, 2.73 Grams, 204 millimoles), and babar on ethanol (8 liters) while magnetic stirring. The solid, 4-benzoquinone (2.21 g, 20.4 mmol) was placed in an addition funnel on the reaction flask. The reaction was heated under gentle reflux in an oil bath, slowly dissolved in hot ethanol and 1,4-benzoquinone was dropped into the pot over 18 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (40 mL) and water. After extraction with ethyl acetate (2x), the organic layers were combined, dehydrated over NaJCU, filtered through silica gel and evaporated to dryness. The resulting residue was filtered, and then purified by HPLC (Shi Xijiao, 40% ethyl acetate / hexane), and the crude product was further purified from hot ethyl acetate / hexane by crystallization to provide 209 g (36%) of the compound. A mixture of 12 (a) fluorene and compound i2 (a) (ii). 12 (b) 〇l compliance compound 12fbVin (2- (4-fluoro-phenyl) -5-methoxy-benzofuran 3-carboxylic acid methyl ester and 2- (4-fluoro-phenyl) _5_methoxy-benzofuran-3-carboxylic acid ethyl ester).
12(b)(1) 12(b)(ii) 將碘化甲烷(0.43毫升、6·99毫莫耳)加入氬氣下之化合物 12(a)⑴與化合物I2(a)(ii)(h00克、3·49毫莫耳)、碳酸鉀(磨 碎,1.21克、8·73毫莫耳)、與無水乙腈(15毫升)。令反應混合 物於氬氣下迴流加熱18小時,然後,冷卻至室溫並攪拌24 小時。以乙腈(10毫升)稀釋該混合物並過濾,隨之蒸乾溶劑 。以60:40乙酸乙酯/己烷稀釋粗固體,再過濾並藉HpLc (石夕 88828.doc -64- 200418452 膠,乙酸乙酯/己烷)純化,提供〇·85克(78%)所需產物。 合物12(cK2-(4-氟基-苯基V5-甲氧基-苯并味喃 -3-羧酸)。12 (b) (1) 12 (b) (ii) Methane iodide (0.43 ml, 6.99 mmol) was added to compound 12 (a) ⑴ and compound I2 (a) (ii) ( h00 g, 3.49 mmoles), potassium carbonate (milled, 1.21 g, 8.73 mmoles), and anhydrous acetonitrile (15 ml). The reaction mixture was heated at reflux under argon for 18 hours, then, cooled to room temperature and stirred for 24 hours. The mixture was diluted with acetonitrile (10 ml) and filtered, and the solvent was evaporated to dryness. The crude solid was diluted with 60:40 ethyl acetate / hexane, filtered, and purified by HpLc (Shi Xi 88828.doc -64- 200418452 gum, ethyl acetate / hexane) to provide 0.85 g (78%) of Desired product. Compound 12 (cK2- (4-fluoro-phenyl V5-methoxy-benzosulfan-3-carboxylic acid).
將化合物混合物12(b)(0.85克,2.70毫莫耳)與氫氧化卸粒 (〇·23克、4.06毫莫耳)於乙醇(24毫升)與水(4毫升)中合併。 令混合物溫和迴流隔夜,並冷卻至室溫。旋轉蒸發去除溶 劑,並溶剩餘固體於水。經3莫耳濃度HC1酸化並沉澱出固 體,過滤之,經水與己燒洗過,並於真空部分乾燥,提供 0.84克所需產物。 d·也含物l2(d)之掣備(2-(4-氟基-苯基)-5-甲氧基-苯并呋 喃-3-羧酸甲醯胺)。Compound mixture 12 (b) (0.85 g, 2.70 mmol) was combined with hydrated pellets (0.23 g, 4.06 mmol) in ethanol (24 mL) and water (4 mL). The mixture was allowed to reflux gently overnight and cooled to room temperature. Rotary evaporation removes the solvent and dissolves the remaining solids in water. The solid was acidified by HC1 at a concentration of 3 moles, and the solid was precipitated, filtered, washed with water and burned, and partially dried under vacuum to provide 0.84 g of the desired product. d. Preparation of the substance 12 (d) (2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine).
將1,1’-羰基二咪唑(42毫克、0.262毫莫耳)加入氬氣下之 化合物12(c)(50毫克,約〇·175毫莫耳)之無水THF(3毫升)溶 液。令反應混合物溫和加熱3〇分鐘以驅除c〇2,其後,添加 過I乙胺(40重f %水溶液、i毫升)。令反應混合物於室溫 技拌隔夜。瘵乾洛劑,藉HPLC(反相C18,1毫升二甲颯之 乙腈/水,2x)純化粗產物。藉旋轉蒸發去除乙腈,並過濾分 88828.doc -65- 200418452 離固體,以水與己烷洗,提供14·3毫克(28%)所需產物。 實例13 氟基-苯基)-5-甲氧基二^羧酸甲醯胺^ 製備 a.复i待—化合物13(a)(6-溴-2-(4-氟基-苯基)_5_甲氧基-苯并 咬喃-3 -叛酸乙酯)。1,1'-carbonyldiimidazole (42 mg, 0.262 mmol) was added to a solution of compound 12 (c) (50 mg, ca. 175 mmol) in anhydrous THF (3 ml) under argon. The reaction mixture was heated gently for 30 minutes to drive off C02, after which 1 ethylamine (40 wt. F% aqueous solution, 1 ml) was added. The reaction mixture was allowed to stir overnight at room temperature. The dried product was purified by HPLC (reverse phase C18, 1 ml of dimethylacetone in acetonitrile / water, 2x). The acetonitrile was removed by rotary evaporation, and 88828.doc -65- 200418452 was isolated by filtration. The solid was washed with water and hexane to provide 14.3 mg (28%) of the desired product. Example 13 Fluoro-phenyl) -5-methoxydi ^ carboxylic acid formamidine ^ Preparation a. Compound i- Compound 13 (a) (6-bromo-2- (4-fluoro-phenyl) _5_methoxy-benzoanan-3 -ethyl metaboate).
將溴(127毫克、〇·795毫莫耳)之無水二噚烷(1毫升)溶液經 20分鐘逐滴加入實質上經由實例12步驟b製備之化合物 12(b)(ii)(250毫克、〇·795毫莫耳)之無水二呤烷(3毫升)溶液 。令反應於300-watt燈泡、室溫之氬氣下攪拌3小時。令反 應混合物經水稀釋,濾出固體,以水與己烷洗,並於真空 烤相乾燥。令粗產物經HPLC (反相,乙腈/水梯度)純化,提 供47毫克(15〇/0)白色固體之所需產物。 b·^二氧基-苯并呋喃 I之製傭。 皿 標題化合物實質上是根據實例1、步騾c與d所述之通常方 法製成,然而,在步驟c以化合物13(&)取代化合物i(b)。 f例14 并呋喃-3-羧酸甲醯胺<^^ 14(a)(ii)(5^1 基-6_ 甲基 _2_ 88828.doc 200418452 苯基苯并呋喃羧酸乙酯與5-羥基-7-甲基-2-苯基-苯并呋 喃-3-叛酸乙酯)。A solution of bromine (127 mg, 0.795 mmol) in anhydrous dioxane (1 ml) was added dropwise over 20 minutes to compound 12 (b) (ii) (250 mg, 0. 795 mmol) in anhydrous diuridine (3 ml). The reaction was allowed to stir in a 300-watt bulb under room temperature argon for 3 hours. The reaction mixture was diluted with water, the solid was filtered off, washed with water and hexane, and dried in a vacuum baking phase. The crude product was purified by HPLC (reverse phase, acetonitrile / water gradient) to provide 47 mg (15/0) of the desired product as a white solid. b. ^ Dioxy-benzofuran I system. The title compound was essentially prepared according to the usual method described in Example 1, Steps 骡 c and d, however, in step c, Compound 13 (&) was substituted for Compound i (b). f Example 14 Benzofuran-3-carboxylic acid formamide < ^^ 14 (a) (ii) (5 ^ 1 group-6_methyl_2_ 88828.doc 200418452 phenylbenzofurancarboxylic acid ethyl ester with 5 -Hydroxy-7-methyl-2-phenyl-benzofuran-3-acetic acid ethyl ester).
十、、巴對乙醇(30¾升)與苄醯基乙酸乙酯(9.9毫升、57.3毫 莫耳)加入氬氣下之含無水ZnCh (7_8克、57.3毫莫耳,烤箱中 預乾燥1小時)之烤箱乾燥之燒瓶中。將甲基_丨,4_苯醌〇克 、57·3*莫耳)放入有支臂之添加漏斗(漏斗底部有玻璃棉片) 中並在添加漏斗上配置冷凝器。令燒瓶中之反應混合物 於油浴中緩慢加熱。乙醇迴流過添加漏斗之支臂(包覆玻璃 棉與鋁箔),然後經隔夜緩慢洗落甲基4 +苯醌〇8小時)。令 反應混合物冷卻至室溫,經乙酸乙酯(約2〇〇毫升)稀釋,經 水(2 X 300毫升)洗並經ΝαΑ〇4脫水。濃縮後,令殘渣經管柱 層析(無水負載於矽膠,乙酸乙酯/己烷溶劑梯度)純化,並藉 為乙fe乙酉旨/己fe以2批結晶’產生化合物i4(a)(i)與化人物 14(a)(ii)之混合物,其不經進一步純化即進行至下一步驟 b·製備化会1進14(bKO與化合物14ibVn\ri甲為〜甲芙 -2-苯基-苯并呋喃-3-羧酸乙酯與5-甲氧基_7-甲基_2苯其 苯并呋喃-3-羧酸乙酯)。X. Bar-to-ethanol (30 ¾ liters) and ethyl benzylacetate (9.9 ml, 57.3 mmol) were added to anhydrous ZnCh under argon (7-8 g, 57.3 mmol, pre-dried in the oven for 1 hour). Oven-dried flask. Put methyl_, 4-benzoquinone (0 g, 57.3 * mol) into an addition funnel (with a glass wool sheet at the bottom of the funnel) with an arm and configure a condenser on the addition funnel. The reaction mixture in the flask was slowly heated in an oil bath. The ethanol was refluxed through the arm of the addition funnel (covered with glass wool and aluminum foil), and then methyl 4 + benzoquinone was slowly washed off overnight (8 hours). The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (about 200 ml), washed with water (2 x 300 ml) and dehydrated with NαΑ04. After concentration, the residue was purified by column chromatography (anhydrous loading on silica gel, ethyl acetate / hexane solvent gradient), and crystallized in 2 batches to produce compound i4 (a) (i). The mixture with chemical characters 14 (a) (ii), which proceeded to the next step without further purification. B. Preparation of chemical compounds 1 into 14 (bKO and compound 14ibVn \ ri A is ~ methyl-2-phenyl- Ethyl benzofuran-3-carboxylic acid and 5-methoxy-7-methyl-2-benzo-2-benzofuran-3-carboxylic acid ethyl ester).
14(b)(i)14 (b) (i)
14(b)(ii) 88828.doc -67- 200418452 將化合物混合物14(a)(l.〇〇克、3·37毫莫耳)、碳酸鉀(磨 碎,1.16克、8.42毫莫耳)與無水乙腈(20毫升)在氬氣下之烤 箱乾燥之50毫升燒瓶中合併。將碘化甲烷(0.42毫升、6.75 毫莫耳)加入此混合物,並令該反應於氬氣下迴流加熱3小 時。然後,將反應混合物冷卻至室溫,並旋轉蒸發去除溶 劍。以乙酸乙酯稀釋殘渣並過濾,隨之蒸發溶劑。經己烷 稀釋生成之油,並過滤分離固體。令粗產物經HPLc (矽膠 ’乙酸乙酯/己烷)純化,提供〇·135克化合物14⑼⑴與〇.432 克化合物14(b)(ii)。 基-2二苯并咭喃_3_羚酸甲醯胺之製 備° 栝過化合物實質上是根據上述實例12、步驟〇與d所述之 通吊万法製成,然而,在步騾c以化合物14(1})(1)取代化合物 12(b) 〇 實例15 二苯基)_5-異兩氧某-2,3- 基-笨某)-5-異而 甲醯胺之製借_14 (b) (ii) 88828.doc -67- 200418452 Compound mixture 14 (a) (1.0 g, 3.37 mmol), potassium carbonate (milled, 1.16 g, 8.42 mmol) Combine with anhydrous acetonitrile (20 ml) in an oven-dried 50 ml flask under argon. Methyl iodide (0.42 ml, 6.75 mmol) was added to the mixture and the reaction was heated under reflux for 3 hours under argon. Then, the reaction mixture was cooled to room temperature, and the rotary sword was removed by rotary evaporation. The residue was diluted with ethyl acetate and filtered, followed by evaporation of the solvent. The resulting oil was diluted with hexane and the solid was isolated by filtration. The crude product was purified by HPLc (silica gel 'ethyl acetate / hexane) to provide 0.135 g of compound 14⑼⑴ and 0.432 g of compound 14 (b) (ii). The preparation of methy-2dibenzopyran_3_methanepyrene acetic acid is essentially made according to the method described in Example 12, Steps 0 and d above, however, in step 骡 c Substitute compound 14 (1)) (1) for compound 12 (b). Example 15 Diphenyl) -5-isodioxo-2,3-yl-benzyl) -5-isobutyramide _
-丁氧幾基胺基-p比咯症-1 -基)-Butoxychitylamino-p-pyrrozoosis-1 -yl)
88828.doc 200418452 將無水碳酸铯(270毫克、0.830毫莫耳)、雙(二苯亞甲基 丙酮)二鈀(0)(11毫克、〇·〇119毫莫耳)、rac-2,2-雙(二苯基膦 基二萘基(11毫克、〇·0178毫莫耳)、3-(第三)-丁氧羰 胺基)吡咯啶(0.132克、0.712毫莫耳)與根據實例6製成之化 合物6(d)(250毫克、0.593毫莫耳)放入經氬氣脫氣與清洗數 次之烤箱乾燥之二頸燒瓶。將無水甲苯(2毫升)注射入反應 混合物,並令反應燒瓶經氬氣清洗。令反應於8crc、氬氣 下攪拌18小時,然後冷卻至室溫,經乙醚(8毫升)稀釋,並 滤過矽膠片。蒸發溶劑,並令生成之油經HPLC (反相,乙 腈/水梯度)純化,提供所需產物。 b.HJL舍物15(b)(6-(3-胺基-吡咯啶-1_基)-2-(4-氟基_苯 基)-5-異丙氧基-苯并呋喃_3_幾酸)。88828.doc 200418452 Anhydrous cesium carbonate (270 mg, 0.830 mmol), bis (diphenylmethyleneacetone) dipalladium (0) (11 mg, 0.00119 mmol), rac-2,2 -Bis (diphenylphosphino dinaphthyl) (11 mg, 0.00178 mmol), 3- (third) -butoxycarbonylamino) pyrrolidine (0.132 g, 0.712 mmol) and according to examples Compound 6 (d) (250 mg, 0.593 mmol) prepared in 6 was placed in an oven-dried two-necked flask that was degassed and washed several times with argon. Anhydrous toluene (2 ml) was injected into the reaction mixture, and the reaction flask was purged with argon. The reaction was allowed to stir at 8 crc under argon for 18 hours, then cooled to room temperature, diluted with ether (8 ml), and filtered through a silicone sheet. The solvent was evaporated and the resulting oil was purified by HPLC (reverse phase, acetonitrile / water gradient) to provide the desired product. b.HJL house 15 (b) (6- (3-Amino-pyrrolidin-1_yl) -2- (4-fluoro_phenyl) -5-isopropoxy-benzofuran_3 _ A few sour).
知化合物15(a)與3個氫氧化鉀顆粒(約〇.4克)於乙醇(3〇毫Known compound 15 (a) and 3 potassium hydroxide particles (about 0.4 g) in ethanol (30 mmol)
反應經6莫耳濃度乙酸酸化至約pH 液處理至形成沉澱。濾出固體,餐 燥提供86毫克所需產物。 胺基-吡 並咯文基-策某異丙氫某 製備。 氟磷酸鹽(PyBOP) 知苯并一唑-1-基氧基參吡咯啶鱗六氟磷酸鹽 〇 88828.doc 200418452 (123毫克、0.216毫莫耳)加入氬氣下之甲胺(10毫升、2〇莫 耳濃度之THF溶液)與化合物I5(b)(86毫克、0.216毫莫耳)之 典水DMF混合物。令生成之反應混合物於室溫擺掉3 〇分鐘 ’並於旋轉蒸發皿濃縮。令粗固體經超音波震盪並溶於乙 酸乙醋。以水洗溶液,脫水並濃縮。令粗產物經製備hPLC (反相C18,乙/水,加上4滴二甲颯以安定產物)純化,提供 20毫克標題化合物。 實例16 苯基)-5-異丙氣基-笨并咭喃-3-淼建^甲酉f 胺之製備 氟基-苯基)-5-異丙氧基-苯并吱 喃-3-羧酸)。The reaction was treated with 6 mol of acetic acid to about pH until a precipitate formed. The solid was filtered off and the meal provided 86 mg of the desired product. Amino-pyrrolovenyl-Ceisopropylhydrogen Preparation. Fluorophosphate (PyBOP) Benzotriazol-1-yloxy ginsyl pyrrolidine hexafluorophosphate 08888.doc 200418452 (123 mg, 0.216 mmol) methylamine (10 ml, A 20% molar solution of THF) and a typical water DMF mixture of compound I5 (b) (86 mg, 0.216 mmol). The resulting reaction mixture was allowed to shake at room temperature for 30 minutes' and concentrated on a rotary evaporator. The crude solid was sonicated and dissolved in ethyl acetate. The solution was washed with water, dehydrated and concentrated. The crude product was purified by preparative hPLC (reverse phase C18, B / water, plus 4 drops of dimethylformamide to stabilize the product) to provide 20 mg of the title compound. Example 16 Preparation of phenyl) -5-isopropenyl-benzylpyran-3-methane ^ formamidine amine Preparation of fluoro-phenyl) -5-isopropoxy-benzocran-3- carboxylic acid).
將根據實例6製成之化合物6(c)(18.5克、5·4莫耳)加入氫 氧化鉀(9.1克、〇·612莫耳)之1:1乙醇/水(2〇〇毫升)之攪拌溶 液。經迴流溫度攪拌12小時後,去除溶劑並溶剩餘泥漿於 水,並經第二丁基甲基醚萃取。棄置有機層,並以3當量濃 度鹽酸酸化水層。過漉分離固體,經水與己烷潤濕,並於 60C真2烤箱乾燥,提供15〇克(88%)所需產物。 氟基_苯基)_5_異丙氧基硝基_ 苯并吱喃-3-叛酸)。 88828.doc -70-Compound 6 (c) (18.5 g, 5.4 moles) prepared according to Example 6 was added to potassium hydroxide (9.1 g, 0.612 moles) in 1: 1 ethanol / water (200 ml). Stir the solution. After stirring at reflux temperature for 12 hours, the solvent was removed and the remaining slurry was dissolved in water and extracted with second butyl methyl ether. The organic layer was discarded, and the aqueous layer was acidified with 3 equivalents of hydrochloric acid. The solid was isolated by centrifugation, wet with water and hexane, and dried in a 60 ° C oven to provide 150 g (88%) of the desired product. Fluoro_phenyl) _5_isopropoxynitro_benzocran-3-acid acid). 88828.doc -70-
16(b) 200418452 將(4:1)之濃(70%)硝酸(2〇〇毫升)與冰醋酸(5〇毫升)混合 物倒入裝配溫度計、機械攪拌棒與固體加成漏斗之5〇〇毫升 一頌燒砥。以乙醇/乾冰浴將該溶液冷卻至_1〇艺。經。分鐘 ,舲根據前述步騾製成之化合物16(a)(1〇 〇克、318莫耳)分 批加入。令反應於-l〇°C攪拌1小時,然後允許再經另外4小 時回溫至l〇°C。將懸浮液小心倒入冰冷的水中,並過濾收 集沉澱,以水充分洗過,然後風乾。該黃色粉末為‘與6_ 硝基異構物之16:84的混合物。令該異構物經再結晶(15〇毫 升乙酸乙酯加上2毫升己烷逐滴添加直至呈雲狀)分離,以 提供8.2克(72%)黃色粉末之所需產物。 c·篁AiL金物16(cK2_(4-氟基-苯基V5-異丙氧基-6-硝基-苯并呋喃-3-羧酸甲醯胺)。16 (b) 200418452 Pour a mixture of (4: 1) concentrated (70%) nitric acid (200 ml) and glacial acetic acid (50 ml) into an assembly thermometer, mechanical stir bar and solid addition funnel. One milliliter of chanterelles. The solution was cooled to 10 ° C in an ethanol / dry ice bath. through. Minutes, compound 16 (a) (100 g, 318 moles) prepared according to the previous step was added in portions. The reaction was allowed to stir at -10 ° C for 1 hour and then allowed to warm to 10 ° C over another 4 hours. The suspension was carefully poured into ice-cold water, and the precipitate was collected by filtration, washed thoroughly with water, and then air-dried. The yellow powder was a mixture of 16:84 with the 6-nitro isomer. The isomer was separated by recrystallization (150 ml of ethyl acetate plus 2 ml of hexane dropwise until clouded) to provide 8.2 g (72%) of the desired product as a yellow powder. c. 篁 AiL gold 16 (cK2- (4-fluoro-phenyl V5-isopropoxy-6-nitro-benzofuran-3-carboxylic acid formamide)).
將1-輕基苯并三唑(純度98%,2·82克、20.9毫莫荨)、隨 之為無水二氯甲烷(70毫升)加入乾氬氣下之100毫升乾燒瓶 中之化合物16(b)(5克、13·9莫耳)。然後導入1-(3-二甲基胺 基丙基)-3-乙基羰二亞胺鹽酸鹽(4克、20·9毫莫耳)。最後, 88828.doc -71 - 200418452 將甲胺溶液(2莫耳濃度之THF溶液,13.9毫升、27·8莫耳)加 入該泥漿,並劇烈攪拌。令反應混合物於室溫攪拌隔夜。 以二氯甲烷(120毫升)稀釋反應混合物,然後經水(3χ)與鹽 液(3χ)洗。分離有機層,經硫酸鎂脫水,並濾過矽膠片,經 乙酸乙酯潤濕。濃縮有機層,提供5·01克(97%)所需產物。 d.製偷化合物16idV6-胺基-2-(4-氟基-苯基)-5-異丙氧基_ 苯并呋喃-3-羧酸甲醯胺)。Add 1-light benzotriazole (98% purity, 2.82 g, 20.9 mmol) followed by anhydrous dichloromethane (70 mL) to compound 16 in a 100 mL dry flask under dry argon (b) (5 grams, 13.9 mol). Then, 1- (3-dimethylaminopropyl) -3-ethylcarbonyldiimide hydrochloride (4 g, 20.9 mmol) was introduced. Finally, 88828.doc -71-200418452 methylamine solution (a THF solution with a concentration of 2 moles, 13.9 ml, 27.8 moles) was added to the slurry and stirred vigorously. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane (120 ml) and washed with water (3x) and saline (3x). The organic layer was separated, dehydrated over magnesium sulfate, and filtered through a silicone pad, and wet with ethyl acetate. The organic layer was concentrated to provide 5.01 g (97%) of the desired product. d. Preparation of stealing compound 16idV6-amino-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine).
將活化之10% Pd/c (200毫克、10%重量)加入根據上述步 驟c製成之化合物16(c)(2.0克、10.7毫莫耳)之乙酸乙醋(125 毫升)之經超音波震盪之懸浮液。令該混合物於5〇 psig氫氣 壓之Pair震盪器攪拌隔夜。然後,令反應濾過CeliteTM片, 經9:1之乙酸乙酯/甲醇混合物潤濕。濃縮濾液,提供178克 (97%)之純的預期產物。 春 實例17 _6-胺基- 2-(4-氟基-笨某)-5 -甲氧基-笨并峡味-3-卷酸甲硫胺 之製備 a.製備化会_物17j^(2-(4-氟基-苯基)-5-甲氧基-6-硝基-苯 并呋喃-3-羧酸)。Ultrasonically add activated 10% Pd / c (200 mg, 10% by weight) to ethyl acetate (125 ml) of compound 16 (c) (2.0 g, 10.7 mmol) prepared according to step c above. Shaking suspension. The mixture was allowed to stir overnight in a Pair shaker at 50 psig hydrogen pressure. The reaction was then filtered through a CeliteTM tablet and wet with a 9: 1 ethyl acetate / methanol mixture. The filtrate was concentrated to provide 178 g (97%) of the pure expected product. Spring Example 17 Preparation of 6-Amino- 2- (4-fluoro-benzum) -5 -methoxy-benzylamine-flavor-3-methylsulfanilate a. Preparation of Chemical Society_ 物 17j ^ ( 2- (4-fluoro-phenyl) -5-methoxy-6-nitro-benzofuran-3-carboxylic acid).
88828.doc -72- 200418452 中間體化合物實質上是根據上述之實例16、步騾b之一般 方法製成’然而’以化合物12(c)取代化合物I6(a)。 氟基-苯基)-5-甲氧基硝基-苯 并吱喃-3-叛酸甲醯胺)。88828.doc -72- 200418452 Intermediate compounds are essentially prepared according to the general method of Example 16, Step 骡 b, described above, 'but' instead of compound I6 (a) with compound 12 (c). Fluoro-phenyl) -5-methoxynitro-benzyl-3-benzylformamide).
分別於化合物17(a)(2.0克、6·04毫莫耳)之無水二氯甲烷 (50¾升)懸浮液中加入甲胺(6¾升、2莫耳濃度之thF溶液) 、1-[3-(—甲基胺基)丙基]-3 -乙基談二亞胺鹽酸鹽(edci) (1.74克、9.06¾莫耳)與卷基苯并三峻(1 22克、9·〇6毫莫耳) 。令該混合物攪拌隔夜。加水(100毫升)將反應止熱,並經 一氯甲fe (50¾升)稀釋。令各層分離,並以二氯甲燒(3χ)萃 取水層。令合併之有機層經水與鹽液洗,經硫酸鎂脫水, 並;辰縮。令油經己健/乙酸(3:1)研製,提供黃色固體,將之 過濾並風乾。此反應產生2.0克(97%)之預期化合物。 匕^基'2-(41基-苯基)-5-甲—哺_3_羧酸甲 醯胺之製備。 琢標題化合物實質上是根據上述之實例16、步驟d之一般 方法製成,然而,以化合物17(b)取代化合物16(c)。 實例18 氟基-苯基)-5二喃_3_藉酸 甲醯胺之 88828.doc -73- 200418452 將二異丙基乙胺(83 ·2微升、477微莫耳)、隨之為乙酸肝 (239微莫耳)加入根據實例17製成之6-胺基-2-(4-氟基-苯基) -5-甲氧基-苯并呋喃-3-羧酸甲醯胺(75毫克、239微莫耳)之 無水三氯甲烷(3毫升)溶液。1小時後,以水(3毫升)將反應 止熱。濃縮乾後,令粗油經HPLC(反相,C18,乙腈/水加上 0.1%乙酸)純化,提供73毫克(87%)標題化合物。 實例19 1-(4-氟基-茉基)-5-異丙氧基-6-甲基胺基-苽#岵略 甲醯胺之製備 將根據實例16製成之6-胺基-2-(4-氟基-苯基異丙氧基 -苯并呋喃-3-羧酸甲醯胺(55毫克、161微莫耳)溶於無水乙酸 (2毫升)。將三乙胺(25微升、193微莫耳)加入反應混合物, 隨之緩慢添加硫酸二甲酯(17微升、177微莫耳)。2小時後, 加水(1毫升)。將反應濃縮乾,並經HPLC (反相)純化粗產物 ’提供32毫克(56%)之純產物。 實例20 氟基-苯基異丙氳篡-苯吃扶喃_3-勒 酸甲醯胺之絮借 該標題化合物(35毫克、59%)實質上是根據實例19之一般 万法製成,然而,三乙胺與硫酸二甲酯之當量加倍。 實例21 異丙氧基-6-甲ij菱醯基胺基二苯并咭喃 -3-羧酸甲醯胺之 將根據實例16製成之6-胺基-2-(4-氟基-苯基)_5_異丙氧基 88828.doc 200418452 -冬并呋喃-3-羧酸甲醯胺(1〇〇毫克、292微莫耳)溶於氬氣下 之無水二氯甲烷(3毫升)。令反應於冰浴中冷卻至〇Q(:。於氬 氣下混合吡啶(16.83微升、321微莫耳)與甲烷磺醯氯(22·61 微升、292微莫耳),然後逐滴加入第一種苯胺溶液中。令 反應混合物回溫至室溫達丨小時。以水(2〇毫升)稀釋反應混 合物,並以二氯甲烷(3 Χ10毫升)萃取。令合併之有機層經i 當量濃度HC1、水、飽和碳酸氫鈉水溶液與鹽液洗過,並真 空濃縮。令粗產物經管柱層析(矽膠,2〇〜5〇%乙酸乙酯/己 烷梯度)純化,提供68毫克(56%)之產物。 2-(4-氟基-苯基)-5-異丙氧基_6-甲烷磺醯基胺基-苯并呋 喃-3-羧酸甲醯胺之替代製備方法如下: a·製座·化合物2l(a>l(3-(4-氟基_苯基)_3_氧基·丙酸乙酯)。To a suspension of compound 17 (a) (2.0 g, 6.04 mmol) in anhydrous dichloromethane (50¾ liter) was added methylamine (6¾ liter, 2 mol concentration thF solution), 1- [3 -(-Methylamino) propyl] -3 -ethyl dianimine hydrochloride (edci) (1.74 g, 9.06 ¾ mole) and rollylbenzotrimethylene (1 22 g, 9 · 〇 6 millimoles). The mixture was allowed to stir overnight. The reaction was quenched by the addition of water (100 ml) and diluted with monochloromethane (50¾ liters). The layers were separated and the aqueous layer was extracted with dichloromethane (3x). The combined organic layers were washed with water and saline, dehydrated with magnesium sulfate, and dried. The oil was triturated with Jijian / acetic acid (3: 1) to provide a yellow solid, which was filtered and air-dried. This reaction yielded 2.0 g (97%) of the expected compound. Preparation of D'yl (2- (41-yl-phenyl) -5-methyl-methyl-3-methylcarboxylate). The title compound is substantially prepared according to the general method of Example 16 and Step d described above, however, Compound 16 (c) is replaced by Compound 17 (b). Example 18 Fluoro-phenyl) -5diran_3_ borrowed from formamidine 88828.doc -73- 200418452 Diisopropylethylamine (83 · 2 μl, 477 μmol) was followed by To liver acetate (239 μmol) was added 6-amino-2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine prepared according to Example 17 (75 mg, 239 μmol) in anhydrous chloroform (3 ml). After 1 hour, the reaction was quenched with water (3 ml). After concentrating to dryness, the crude oil was purified by HPLC (reverse phase, C18, acetonitrile / water plus 0.1% acetic acid) to provide 73 mg (87%) of the title compound. Example 19 Preparation of 1- (4-Fluoro-Mosyl) -5-isopropoxy-6-methylamino-fluorene ## Succinimidine A 6-amino-2 to be prepared according to Example 16 -(4-Fluoro-phenylisopropoxy-benzofuran-3-carboxylic acid formamide (55 mg, 161 μmol) was dissolved in anhydrous acetic acid (2 mL). Triethylamine (25 μ Liters, 193 micromoles) was added to the reaction mixture, followed by the slow addition of dimethyl sulfate (17 microliters, 177 micromoles). After 2 hours, water (1 mL) was added. The reaction was concentrated to dryness and subjected to HPLC (reaction). Phase) Purified crude product 'provided 32 mg (56%) of the pure product. Example 20 A fluoro-phenylisopropylammonium-benzofuran-3 methanomethoxamine was borrowed from the title compound (35 mg , 59%) was essentially prepared according to the general method of Example 19, however, the equivalents of triethylamine and dimethyl sulfate were doubled. Example 21 Isopropoxy-6-methylij Lingolinaminodibenzo 6-Amino-2- (4-fluoro-phenyl) _5_isopropoxy88828.doc 200418452-Dongfuran-3 -Formamidine carboxylate (100 mg, 292 μmol) Anhydrous dihydrate dissolved in argon Methyl chloride (3 ml). Allow the reaction to cool to 0 ° C in an ice bath (: .pyridine (16.83 μl, 321 μmol) and sulfonyl chloride (22.61 μl, 292 μl under argon). Mol), and then added dropwise to the first aniline solution. The reaction mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with i-equivalent concentration HC1, water, saturated sodium bicarbonate aqueous solution and saline solution, and concentrated in vacuo. The crude product was subjected to column chromatography (silica gel, 20-50% ethyl acetate / hexane). Gradient) purification provided 68 mg (56%) of the product. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid The alternative preparation method of formamidine is as follows: a. Preparation. Compound 2l (a> l (3- (4-fluoro group_phenyl) _3_oxy. Ethyl propionate).
々丙一敗乙酉曰之卸鹽(U8公斤、9.28莫耳)之thf (8.〇升) 之泥漿經氯化鎂(0.68公斤、7.14莫耳)一次處理。令該放熱 反應於65〜70°C攪拌6小時,然後為室溫隔夜。同時,將氟 芊酸(1.00公斤、7.14莫耳)之THF (3.7升)溶液緩慢加入u,_ 羰基二咪唑(1.39公斤、8.56莫耳)之THF(37#)混合物,並 於3(TC攪拌2小時。令該溶液經} 1/4小時加入丙二酸乙酯之 2 0〜3 0 C混合物’並於3 0 °C攪拌隔夜。 令混合物冷卻至20°C,並經稀HC1 (4當量濃度、7 〇升)中 和,並去除水層。濃縮溶液,並藉高真空蒸餾收集產物。 88828.doc -75 - 200418452 溶生成之溶液於乙酸乙§旨,並經5%錢氫㈣濕。濃縮有 機層,蒸餘收集產物’提虹36公斤無色油之所需產物。 化合物21(a)亦可根據下列方法製成: 將甲苯(7.20公;η加入氮氣壓下之含第三丁氧化绅⑽ 公斤、23.17莫耳)之燒瓶。攪動混合物,然後經20分鐘時間 添加碳酸二乙醋(6.61公斤、55.96莫耳)。令反應加熱至>7yc 逾!小時。令反應冷卻至赃,並經i小時時間添加心氣苯 乙酮(2.00公斤、14.91莫耳),經甲苯(〇3公斤)潤濕。令反應The thf (8.0 liters) of the unsalted salt (U8 kg, 9.28 mol) of the sulphuric acid was treated with magnesium chloride (0.68 kg, 7.14 mol) in a single treatment. The exothermic reaction was allowed to stir at 65 to 70 ° C for 6 hours and then overnight at room temperature. At the same time, a THF (3.7 liter) solution of fluoxamic acid (1.00 kg, 7.14 moles) was slowly added to a THF (37 #) mixture of carbonyldiimidazole (1.39 kg, 8.56 moles), and the mixture was added at 3 (TC Stir for 2 hours. Let the solution be mixed with 20 to 30 ° C of ethyl malonate over 1/4 hour and stir overnight at 30 ° C. Allow the mixture to cool to 20 ° C and dilute HC1 ( 4 equivalent concentration, 70 liters) and neutralized, and the water layer was removed. The solution was concentrated, and the product was collected by high vacuum distillation. 88828.doc -75-200418452 The resulting solution was dissolved in ethyl acetate and subjected to 5% hydrogen hydrogen Wet. Concentrate the organic layer and collect the desired product of 36 kg of colorless oil by distillation. Compound 21 (a) can also be prepared according to the following method: Toluene (7.20 g; Tributyl oxide (kg, 23.17 moles) flask. Stir the mixture, then add diethyl carbonate (6.61 kg, 55.96 moles) over 20 minutes. Let the reaction heat to> 7yc for more than! Hours. Let the reaction cool To the stolen, and add qi acetophenone (2.00 kg, 14.91 mole) over i hours Benzene (03 kg) wets. Makes the reaction
於約7〇〜饥再攪拌1小時。將反應冷卻至室溫並再擾拌隔 夜。添加氫氯酸與水之溶液(3.3升濃硫酸之87公斤水溶液)Stir at about 70 ~~ for another hour. The reaction was cooled to room temperature and stirred overnight. Add solution of hydrochloric acid and water (3.3 liters of 87 kg of concentrated sulfuric acid in water)
,並令反應混合10分鐘。令各層分離,並以水(2〇升)盘W 碳酸氫鈉⑹公打潤濕水層。藉真空蒸餘分離產物,提供 2.44公斤(80%)之所需產物。 b·麗氟基_苯基)_5_幾基-苯并呋喃_3_ 羧酸乙酯)。And let the reaction mix for 10 minutes. The layers were separated and the aqueous layer was wetted with water (20 liters) pan W sodium bicarbonate. The product was isolated by vacuum evaporation to provide 2.44 kg (80%) of the desired product. b. fluorofluoro_phenyl) _5_isopropyl-benzofuran_3_carboxylic acid ethyl ester).
/經6小時時間將對-苯酉昆(617克、5·7ι莫耳)之 (3·6升) /合液加入105C之含氯化鋅(778〜81〇克、約5·7莫耳)與化合 物21(a)(1200克、5·71莫耳)之乙醇升)溶液,蒸館掉thf 4持此溫度。1小時後’以水/乙酸乙酯(6升/8升)將反應 止熱。過爐去除不溶材料,並以水(3升)洗有機層,以及濃 縮乾。令固體於二氯甲燒(2升)巾成泥漿並過滤。將分離之 88828.doc -76- 200418452/ P-phenylbenzidine (617 g, 5.7 mol) (3.6 liters) over a period of 6 hours / The mixture is added with 105C zinc chloride (778 ~ 81 g, about 5.7 mol) Ear) and compound 21 (a) (1200 g, 5.71 mol) in ethanol liters) solution, steaming thf 4 to maintain this temperature. After 1 hour 'the reaction was quenched with water / ethyl acetate (6 L / 8 L). Remove insoluble materials in an oven and wash the organic layer with water (3 liters) and concentrate to dryness. The solids were slurried in dichloromethane (2 liters) and filtered. 88828.doc -76- 200418452
,取得1012克白色固體之所需產物。 lR NMR m CDC13 (300 MHz): 8.02 (m5 2H); 7.51 (d5 iH J=2.90 Hz); 7.38 (d,1H); 7·16 (m,2H); 6.88 (dd,1H,J=8/7〇’ 2.79); 5.09 (s? IH); 4.40 (q? 2H5 J=7.2 Hz); 1.40 (t? 3H? J.7>2〇 Hz) 0 Mass Spec: (M+l)=301。 c·製盤..化合物21(c).(2-(4_氟基-苯基)_5-異丙氧基_苯并咬 喃-3-羧酸乙酯)。1012 g of the desired product were obtained as a white solid. lR NMR m CDC13 (300 MHz): 8.02 (m5 2H); 7.51 (d5 iH J = 2.90 Hz); 7.38 (d, 1H); 7.16 (m, 2H); 6.88 (dd, 1H, J = 8 / 7〇 '2.79); 5.09 (s? IH); 4.40 (q? 2H5 J = 7.2 Hz); 1.40 (t? 3H? J.7 > 2〇Hz) 0 Mass Spec: (M + l) = 301 . c. Disk making: Compound 21 (c). (2- (4-fluoro-phenyl) _5-isopropoxy_benzo-3-anthanoic acid ethyl ester).
令化合物21(b)(2.35公斤、7.83莫耳)之1 —甲基-2-吡咯啶酮 (8.3升)溶液經碳酸铯(5.1〇公斤、15·65莫耳)處理1〇分鐘。添 加2-溴化^丙烷(2.98公斤、24.26莫耳),並令反應混合物於5〇^ 加熱隔夜。將反應加入稀氫氧化銨(18升)並攪動3〇分鐘。 令混合物經水(11.8升)稀釋,並經庚烷(14·7升)萃取。令各 層分離,並以水潤濕有機層。藉旋轉蒸發濃縮,提供會固 化並生成定量產率之產物。 NMR in CDCI3 (300 MHz): 8.02 (m? 2H); 7.56 (d5 1H? J=2.34 Hz); 7.40 (d? 1H? J=8.79 Hz); 7.16 (t? 2H5 J=8.79 Hz); 6.95 (dd5 1H, J=8.79 Hz); 4.59 (m? 1H); 4.41 (q? 2H? J=7.03) 與 1.39 (m,9H)。Mass Spec: (M+l)=343。 d·复it化合物21(d)(2-(4•氟基-苯基)-5-異丙氧基-6-硝基-苯并呋喃-3-羧酸乙酯)。A solution of compound 21 (b) (2.35 kg, 7.83 moles) in 1-methyl-2-pyrrolidone (8.3 liters) was treated with cesium carbonate (5.10 kg, 15.65 moles) for 10 minutes. Add 2-bromopropane (2.98 kg, 24.26 moles) and allow the reaction mixture to heat at 50 ^ overnight. The reaction was added with dilute ammonium hydroxide (18 liters) and stirred for 30 minutes. The mixture was diluted with water (11.8 liters) and extracted with heptane (14.7 liters). The layers were separated and the organic layer was wetted with water. Concentration by rotary evaporation provided a product that would solidify and produce quantitative yields. NMR in CDCI3 (300 MHz): 8.02 (m? 2H); 7.56 (d5 1H? J = 2.34 Hz); 7.40 (d? 1H? J = 8.79 Hz); 7.16 (t? 2H5 J = 8.79 Hz); 6.95 (dd5 1H, J = 8.79 Hz); 4.59 (m? 1H); 4.41 (q? 2H? J = 7.03) and 1.39 (m, 9H). Mass Spec: (M + l) = 343. d. Compound 21 (d) (2- (4 • fluoro-phenyl) -5-isopropoxy-6-nitro-benzofuran-3-carboxylic acid ethyl ester).
88828.doc -77- 200418452 於約20°C,將化合物21(c)(2.68公斤、7.83莫耳)之氯仿溶 液緩慢加入冷的氯仿(13.4公斤)與70%硝酸(6.7公斤)之混人 物。1小時後,令反應混合物冷卻至室溫,並經水(8·6升) 稀釋。令有機層分離,洗之並濃縮成固體。令粗產物與$ 三丁基甲基醚混合,並攪動1小時。過濾收集固體,經庚燒 潤濕,並乾燥以提供2.43克(80%)之所需產物。 lR NMR in CDC13 (300 MHz): 8.05 (m5 2H); 8.00 (s? 1H)·88828.doc -77- 200418452 At approximately 20 ° C, slowly add a solution of compound 21 (c) (2.68 kg, 7.83 moles) in chloroform to a mixture of cold chloroform (13.4 kg) and 70% nitric acid (6.7 kg). . After 1 hour, the reaction mixture was cooled to room temperature and diluted with water (8.6 liters). The organic layer was separated, washed and concentrated to a solid. The crude product was mixed with tributyl methyl ether and stirred for 1 hour. The solid was collected by filtration, wetted with heptane, and dried to provide 2.43 g (80%) of the desired product. lR NMR in CDC13 (300 MHz): 8.05 (m5 2H); 8.00 (s? 1H)
7.76 (s,1H); 7.20 (m,2H); 4.71 (septuplet,1H,J=6.00 Hz); 4.42 (q,2H,J=7.20 Hz); 1.45 (d,6H,J=6.00 Hz); 1.41 (t,3H J=7.20 Hz) 0 Mass Spec: (M+l) = 388 0 e.製備化合物21(ei(6-胺基-2-(4-氟基-茉某豈丙氧基_ 苯并呋喃-3-羧酸乙酯)。7.76 (s, 1H); 7.20 (m, 2H); 4.71 (septuplet, 1H, J = 6.00 Hz); 4.42 (q, 2H, J = 7.20 Hz); 1.45 (d, 6H, J = 6.00 Hz); 1.41 (t, 3H J = 7.20 Hz) 0 Mass Spec: (M + l) = 388 0 e. Preparation of compound 21 (ei (6-amino-2- (4-fluoro-molyboxypropyl) _ Benzofuran-3-carboxylic acid ethyl ester).
將化合物21(d)(285.10克、0.736莫耳)與乙酸異丙酯(1升) 於厚壁Parr管中合併。令10% Pd/C (16.51克)經乙酸異丙酯 (1200毫升)小心濕潤,並洗入Parr管。令反應混合物經0〜50 psig氫氣壓之Parr震盪器中氫化,直至氫吸收停止。令該混 合物濾過CeliteTM,並經乙酸異丙酯(1升)濕潤。藉旋轉蒸發 濃縮濾液,並分離剩餘濕固體。 利用287.52克(0.74莫耳)之化合物21(d)、16.67克之10% Pd/C與1200毫升乙酸異丙酯重覆上述反應,合併產物,並 88828.doc -78- 200418452 直接用於下一步騾。 f·製備化合物2_l.(f)(2-(4-氟基-苯基-異丙氧基-6-甲烷磺 醯基胺基-苯并呋喃-3-羧酸乙醋)。Compound 21 (d) (285.10 g, 0.736 mol) was combined with isopropyl acetate (1 liter) in a thick-walled Parr tube. 10% Pd / C (16.51 g) was carefully moistened with isopropyl acetate (1200 ml) and washed into a Parr tube. The reaction mixture was hydrogenated in a Parr shaker with 0-50 psig hydrogen pressure until hydrogen absorption ceased. The mixture was filtered through CeliteTM and moistened with isopropyl acetate (1 liter). The filtrate was concentrated by rotary evaporation and the remaining wet solids were separated. The above reaction was repeated using 287.52 g (0.74 mole) of compound 21 (d), 16.67 g of 10% Pd / C and 1200 ml of isopropyl acetate. The products were combined and used directly in the next step 88828.doc -78- 200418452. Alas. f. Preparation of compound 2-1. (f) (2- (4-fluoro-phenyl-isopropoxy-6-methanesulfonamido-benzofuran-3-carboxylic acid ethyl acetate).
將化合物21 (e)(約1 ·48莫耳)溶於二氯甲燒(5 ·6升),並於冰 /乙醇浴冷卻。一次添加甲烷磺醯氯(186·27克、1.63莫耳) ’隨之經25分鐘逐滴添加二異丙基乙胺(21〇16克、1.63莫 耳)。允终反應回溫至室溫,並於氮氣下攪拌約3 6小時。令 反應於水(2升)間進行區分,令各層分離,並令有機層經水 (3 X 2升)潤濕。令合併之水層經二氯甲烷(5〇〇毫升)逆萃取 ,並合併有機層。藉旋轉蒸發濃縮有機層。於濃縮期間, 於產物開始形成沉澱後,緩慢添加乙醇。去除二氯甲烷後 ’以第三丁基甲基醚(5 〇〇毫升)稀釋混合物。過濾分離產物 ,並風乾以提供603.1克產物(90,8%)與二取代之胺(8.9%)之 混合物。 !H NMR in DMSO (300 MHz): 9.00 (s, 1H); 8.05 (m? 3H); 7.60 (s? 1H); 7.53 (s? 1H); 7.39 (dd? J=8.8 & 8.8 Hz? 2H); 4.73 (septet,J=5.9 Hz,1H); 4.32 (q,j=7 〇 hz,2H); 3.00 (s,3H); 1.37 (d,J=5.9 Hz,6H); 1·32 (t,J=7.〇 Hz,3H)。 g.製備化合物2irgV2-r4-i[莘-y壬)5 $丙氧基-6-甲烷 續感基胺基-苯并吱喃-3-叛酸)。 88828.doc -79- 200418452Compound 21 (e) (about 1.48 moles) was dissolved in dichloromethane (5.6 liters) and cooled in an ice / ethanol bath. Methanesulfonyl chloride (186 · 27 g, 1.63 moles) was added in one portion 'followed by diisopropylethylamine (2,016 g, 1.63 moles) dropwise over 25 minutes. The final reaction was allowed to warm to room temperature and was stirred under nitrogen for about 36 hours. The reaction was distinguished between water (2 liters), the layers were separated, and the organic layer was wetted with water (3 X 2 liters). The combined aqueous layers were back-extracted with dichloromethane (500 ml), and the organic layers were combined. The organic layer was concentrated by rotary evaporation. During the concentration period, after the product started to form a precipitate, ethanol was slowly added. After the dichloromethane was removed, the mixture was diluted with tert-butyl methyl ether (500 ml). The product was isolated by filtration and air-dried to provide a mixture of 603.1 g of product (90,8%) and disubstituted amine (8.9%). ! H NMR in DMSO (300 MHz): 9.00 (s, 1H); 8.05 (m? 3H); 7.60 (s? 1H); 7.53 (s? 1H); 7.39 (dd? J = 8.8 & 8.8 Hz? 2H); 4.73 (septet, J = 5.9 Hz, 1H); 4.32 (q, j = 7 〇hz, 2H); 3.00 (s, 3H); 1.37 (d, J = 5.9 Hz, 6H); 1.32 (t, J = 7.0 Hz, 3H). g. Preparation of compound 2irgV2-r4-i [fluorene-ynon) 5 $ propoxy-6-methane (continuous amino-benzo-benzoan-3-acid). 88828.doc -79- 200418452
私化合物21(f)(570克)加入乙醇(6升)與i當量濃度仏〇1^ (6升)之溶液。將該溶液緩慢加熱至乃艺達數小時。然後移 除熱源,並當混合物達約5〇°C時,加6當量濃度]^^直至約 pH 2。令該混合物攪拌約15分鐘,並藉過濾快速分離固體 ,並經50/50之乙醇/水(5〇〇毫升),然後為水(5〇〇毫升)潤濕 · 。令固體於真空烤箱中乾燥,提供513克之所需產物。 H NMR m DMSO (300 MHz)化合物21(g),實質如上述製 式:8.97 (s,1H); 8.05 (m,2H); 7.58 (s,1H); 7.54 (s,1H); 7·38 (dd,J=8.8 & 8.8 Hz,2H); 4·69 (septet,J=5.9 Hz,1H); 2.99 (s, 3H); 1.35 (d,J=5.9 Hz,6H)。 h.l_備化_合物21(M(2_(4-氟基-苯基)_5_異丙氧基-6-甲烷 磺醯基胺基-苯并呋喃—3-叛酸甲醯胺)。 應Compound 21 (f) (570 g) was added with a solution of ethanol (6 liters) and i-equivalent concentration of 0.001 (6 liters). This solution was slowly heated to Naida for several hours. The heat source was then removed and when the mixture reached approximately 50 ° C, a 6 equivalent concentration was added] to approximately pH 2. The mixture was allowed to stir for about 15 minutes, and the solid was quickly separated by filtration, and wetted with 50/50 ethanol / water (500 mL), then water (500 mL). The solid was dried in a vacuum oven to provide 513 grams of the desired product. H NMR m DMSO (300 MHz) Compound 21 (g), substantially as described above: 8.97 (s, 1H); 8.05 (m, 2H); 7.58 (s, 1H); 7.54 (s, 1H); 7. · 38 (dd, J = 8.8 & 8.8 Hz, 2H); 4.69 (septet, J = 5.9 Hz, 1H); 2.99 (s, 3H); 1.35 (d, J = 5.9 Hz, 6H). h.l_ 备 化 _ Compound 21 (M (2_ (4-fluoro-phenyl) _5_isopropoxy-6-methanesulfonylamino-benzofuran-3-3-methanomethamine ). Should
21(h) 將化合物21(g)(440.7克、1·〇82莫耳)與二氯甲烷(4.4升)混 合’並於氬氣下攪拌。一次添加羰基二咪唑(236 8克、 1 ·46莫耳)°允許混合物攪拌2小時,然後,於冰/乙醇浴冷 卻。以15分鐘,將在冰/乙醇浴預冷卻之甲胺莫耳濃度之 88828.doc -80 - THF;各液,705.2克、1·6莫耳)加入反應。允許反應於室溫攪 拌隔仗。藉冰(500克)與水(2升)將反應止熱。其次,添加HC1 直至pH 2。令各層分離,並水(2χ2升)洗有機層。合併水層 以一氯甲烷萃取。合併有機層,並蒸發去除揮發物。開 始形成固體後添加乙醇(1升)。當結晶開始時,添加5%之水 的乙%(1升)液。將混合物冷卻至室溫,並攪拌隔夜。過攄 分離固體,以2〇%之水的乙醇(1升)液潤濕,並乾燥以提供 380.75克之所需產物。 實例22處會例23 6-乙基胺基-2-(4-氟基-苯基)_5-異丙氧基_苯并呋喃羧酸 甲醯胺與6-一乙基胺基-2-(4-氟基-苯基)-5-異丙氧基-苯并 呋喃-3-羧酸甲醯胺之製備 私一芳丙基乙胺(407微升、2.34毫莫耳)與琪化乙燒(187 极升、2.34¾莫耳)加入根據實例μ製成之卜胺基_2_(4-氟基 -苯基)-5-異丙氧基-苯并呋喃羧酸甲醯胺(2〇〇毫克、584 微莫耳)之無水乙腈(8毫升)溶液。令反應經分析LC/MS條件 偵測,並加水(4毫升)止熱。濃縮乾後,令粗產物經製備hplc (反相C18,乙腈/水加上〇·1%乙酸)純化,提供97毫克(45%) 之6 -乙基胺基-2-(4-氟基-苯基)-5-異丙氧基-苯并吱喃_3-叛 酸甲醯胺與63毫克(27%)之6-二乙基胺基-2-(4-氟基-苯基) -5-異丙氧基-苯并咬喃-3-叛酸甲總胺。 實例24 2-(4-氟基-苯基)-5-異丙氧基-6-嗎福琳-4-基-苯并吱喃_3-致 酸甲醯胺之製備 88828.doc -81 - 200418452 a·复A_化合物溴基-2-(4-氟基-苯墓)-5-異丙氧基-苯并吱喃-3-複酸)。21 (h) Compound 21 (g) (440.7 g, 1.082 mol) was mixed with dichloromethane (4.4 liter) 'and stirred under argon. Add carbonyldiimidazole (236 8 g, 1.46 mol) in one portion. Allow the mixture to stir for 2 hours, then cool in an ice / ethanol bath. In 15 minutes, 88828.doc -80-THF of methylamine mole concentration precooled in an ice / ethanol bath; each solution (705.2 g, 1.6 mole) was added to the reaction. Allow the reaction to stir at room temperature. The reaction was cooled by ice (500 grams) and water (2 liters). Next, add HC1 until pH 2. The layers were separated and the organic layer was washed with water (2 x 2 liters). The combined aqueous layers were extracted with monochloromethane. The organic layers were combined and evaporated to remove volatiles. Ethanol (1 liter) was added after solids started to form. When the crystallization started, a 5% water (1 liter) solution was added. The mixture was cooled to room temperature and stirred overnight. The solid was isolated by centrifugation, wet with 20% water in ethanol (1 liter), and dried to provide 380.75 g of the desired product. Example 22 Meeting Example 23 6-Ethylamino-2- (4-fluoro-phenyl) _5-isopropoxy_benzofurancarboxylic acid formamidine and 6-ethylethyl-2- Preparation of (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine mono-aryl propylethylamine (407 μl, 2.34 mmol) and chihua Ethyl alcohol (187 liters, 2.34¾ moles) was added to the amino-2- (4-fluoro-phenyl) -5-isopropoxy-benzofurancarboxylic acid formamidine (made in Example μ) 200 mg, 584 μmol) of anhydrous acetonitrile (8 ml). The reaction was detected by analytical LC / MS conditions, and water (4 ml) was added to stop the heat. After concentrating to dryness, the crude product was purified by preparative hplc (reverse phase C18, acetonitrile / water plus 0.1% acetic acid) to provide 97 mg (45%) of 6-ethylamino-2- (4-fluoro group) -Phenyl) -5-isopropoxy-benzocran_3-methanemetamide and 63 mg (27%) of 6-diethylamino-2- (4-fluoro-phenyl) ) -5-isopropoxy-benzoanan-3-methanoic acid total amine. Example 24 Preparation of 2- (4-fluoroyl-phenyl) -5-isopropoxy-6-morpholin-4-yl-benzofuran_3-acid methylformamide 88828.doc -81 -200418452 a. Compound A-compound bromo-2- (4-fluoro-benzene grave) -5-isopropoxy-benzofuran-3-polyacid).
將溴(純的,1.1毫升、20.70毫莫耳)經30分鐘時間逐滴加 入30〇_watt燈光下之化合物16(a)(5.0克、0.016莫耳)之1,4-二啰烷(160毫升)之攪拌溶液。另外攪拌20分鐘後,令反應 混合物與水混合,並經乙酸乙酯萃取。以水與鹽液洗有機 相’經MgS〇4脫水,並減壓濃縮以產生黃色固體。經3〇%乙 酸乙醋之己燒研製產物,產生4.1克(66%)白色固體之所需產 物。 b·皇化合物24(b)(6-溴基-2-(4-氟基-苯基異丙氧基_ 苯并呋喃-3-羧酸甲醯胺)。Bromine (pure, 1.1 ml, 20.70 mmol) was added dropwise over 30 minutes to 30-watt compound 16 (a) (5.0 g, 0.016 mole) of 1,4-dioxane ( 160 ml) of stirred solution. After stirring for an additional 20 minutes, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic phase 'was washed with water and brine, dried over MgS04, and concentrated under reduced pressure to give a yellow solid. The product was developed by sintering with 30% ethyl acetate and yielded 4.1 g (66%) of the desired product as a white solid. b. Compound 24 (b) (6-bromo-2- (4-fluoro-phenylisopropoxy-benzofuran-3-carboxylic acid formamidine).
將苯并三唆-1-基氧基參p比洛淀基鱗六氟鱗酸鹽 (10.79克、20.76毫莫耳)與甲胺(43 ·0毫升、86亳莫耳)(2 〇莫 耳;辰度之THF洛液)加入根據前述步驟製成之氣氣下之化人 物24(a)(6.8克、17.3毫莫耳)之DMF (10.0毫升)溶液。於室溫 攪拌12小時後,令反應混合物經水處理,並經乙酸乙酉旨萃 88828.doc -82- 200418452 取。令有機層經水與鹽液洗,經MgS〇4脫水,並減壓濃縮 。令粗產物經官柱層析(矽膠,5〇〜1〇〇%乙酸乙酯/己烷)純 化,產生6.5克(92%)白色固體之所需產物。 c.2_z£4-氟基-苯某V5-異嗎福啉_4·基-苯并哇嘀 -3-叛酸甲醯胺之製備〇 將化合物24(b)(120毫克、0·30毫莫耳)、參(二苯亞甲基丙 酮)二鈀(54毫克、0·0059毫莫耳)與(2_二環己基膦_2,_ν,ν_ 二甲基胺基)-二苯基(3·0毫克、2.4莫耳%)加入烤箱乾燥之 100笔升圓底燒瓶。以橡皮隔間將燒瓶密封,脫氣並以氬氣 清洗。將嗎福啉(31微升、〇·35毫莫耳)與鋰雙(三甲基矽烷 基醯胺)(650微升、〇·65毫莫耳,丨莫耳濃度之ΤΗρ溶液)加入 反應混合物。快速移除隔間,並將迴流冷凝器放置於燒瓶 。再次將反應燒瓶脫氣並以氬氣清洗。然後,將反應混合 物加熱至65°C達12小時,並冷卻至室溫。添加丨莫耳濃度氫 氯酸(600微升),並攪拌反應混合物5分鐘,隨之通過小片 CeliteTM。以水稀釋濾液,並以乙酸乙酯萃取。令有機層經 水與鹽液洗,經MgS〇4脫水,並減壓濃縮。令粗產物經管 柱層析(矽膠,20〜40%之乙酸乙酯的己烷液)純化,提供7〇 毫克(57%)白色固體之所需產物。 實例25 氧基-4-甲基-2-苯基-苯先生^赌胺之傷備 化合物25(a)(4-澳基-5-羥基-2-苯基-苯并呋喃_3_羧 酸乙酯)。 88828.doc »83-Benzotrifluoren-1-yloxysamidine pilolidene hexafluoroscale salt (10.79 g, 20.76 mmol) and methylamine (43.0 ml, 86 mmol) (200 mmol) Ear; Chendu's THF solution) was added to the DMF (10.0 ml) solution of the character 24 (a) (6.8 g, 17.3 mmol) in the gas prepared according to the previous steps. After stirring at room temperature for 12 hours, the reaction mixture was treated with water and extracted with ethyl acetate 88828.doc -82- 200418452. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50 to 100% ethyl acetate / hexane) to give 6.5 g (92%) of the desired product as a white solid. c. 2_z £ 4-Fluoro-benzene V5-isomorpholine_4-yl-benzowazine-3-methanoic acid formamidine. Compound 24 (b) (120 mg, 0.30 Millimoles), ginseng (diphenylmethyleneacetone) dipalladium (54 mg, 0.0059 millimoles) and (2-dicyclohexylphosphine_2, _ν, ν_dimethylamino) -diphenyl Base (3.0 mg, 2.4 mole%) was added to an oven-dried 100-pen round bottom flask. The flask was sealed with a rubber compartment, degassed and purged with argon. Morpholine (31 microliters, 0.35 millimoles) and lithium bis (trimethylsilylfluorenamine) (650 microliters, 0.65 millimoles, τΗρ solution in molarity) were added to the reaction mixture. Quickly remove the compartment and place the reflux condenser in the flask. The reaction flask was degassed again and washed with argon. The reaction mixture was then heated to 65 ° C for 12 hours and cooled to room temperature. Add molar concentration of hydrochloric acid (600 μl) and stir the reaction mixture for 5 minutes before passing through small pieces of CeliteTM. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20-40% ethyl acetate in hexane) to provide 70 mg (57%) of the desired product as a white solid. Example 25 Mr. Oxy-4-methyl-2-phenyl-benzoylamine compound 25 (a) (4-Ao-5-hydroxy-2-phenyl-benzofuran_3_carboxyl Acid ethyl ester). 88828.doc »83-
200418452 將根據實例2製成之化合物2(a)(450毫克、1.595毫莫耳) 溶於氬氣下之CS2:CH3CN (3:1)(8,0毫升)之混合物。將溶液 冷卻至〇°C,並一次添加N-溴琥珀亞醯胺(312毫克、1.755 毫莫耳)。令反應於0°C攪拌4小時,然後,冷卻至室溫。蒸 發溶劑,並溶殘渣於乙酸乙酯,以水與鹽液洗之,經MgS04 脫水,並減壓濃縮。令粗產物經HPLC (矽膠,以10〜100% 之乙酸乙酯的己燒液溶離)純化,提供396毫克(69%)之所需 產物。 b.製備化合物25(bK4-溴某-5-甲氧基-2-苯基-苯并呋喃-3- 羧酸乙酯)。200418452 A mixture of CS2: CH3CN (3: 1) (8,0 ml) in argon was dissolved in compound 2 (a) (450 mg, 1.595 mmol) prepared according to Example 2. The solution was cooled to 0 ° C and N-bromosuccinimide (312 mg, 1.755 mmol) was added in one portion. The reaction was allowed to stir at 0 ° C for 4 hours and then cooled to room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with water and a saline solution, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by HPLC (silica gel, dissolved with 10-100% ethyl acetate in hexane) to provide 396 mg (69%) of the desired product. b. Preparation of compound 25 (bK4-bromo-5-methoxy-2-phenyl-benzofuran-3-carboxylic acid ethyl ester).
於氬氣下,將碳酸鉀(3 65毫克、2.638毫莫耳)與碘化鉀烷 (1·3毫升、21.1毫莫耳)加入化合物25(a)(380毫克、1.055毫 莫耳)之乙腈(5.0毫升)溶液。於迴流條件下擾拌4小時後, 將反應混合物冷卻至室溫,以水稀釋並經乙酸乙酯萃取。 令有機層經水與鹽液洗,以MgS04脫水,並減壓濃縮,提 供385毫克(98%)之所需產物。 c·製備化金物25(^(5-甲氧基-4-甲基-2-苯基-苯并呋喃-3 - 88828.doc -84- 200418452 羧酸乙酯)。Under argon, potassium carbonate (3 65 mg, 2.638 mmol) and potassium iodide (1.3 ml, 21.1 mmol) were added to compound 25 (a) (380 mg, 1.055 mmol) in acetonitrile ( 5.0 ml) solution. After stirring for 4 hours under reflux, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgS04, and concentrated under reduced pressure to provide 385 mg (98%) of the desired product. c. Preparation of gold compound 25 (5-methoxy-4-methyl-2-phenyl-benzofuran-3-88828.doc -84- 200418452 ethyl carboxylate).
於氬氣下,將化合物25(b)(30毫克、0.082毫莫耳)與Ag20 (46·5毫克、0.201毫莫耳)、甲基W酸(6.0毫克、0.0884毫莫 耳)、K2C03 (34.0毫克、0.246毫莫耳)、1,1-雙(二苯基膦二 茂鐵)二氯鈀(II)與二氯甲烷錯合物(1: l)(Pd(dppf)Cl2)(6.0毫 克、10莫耳%)與THF (脫氣、1·0毫升)於管中混合。將壓力 管密封,並令反應混合物於80°C攪拌12小時,冷卻至室溫 ,並以30% H202 (5毫升)與10% NaOH混合物止熱。令反應 混合物經水稀釋並以乙酸乙酯萃取。令有機相經水與鹽液 洗,經MgS04脫水,並減壓濃縮。令粗產物經反相HPLC純 化,提供16.9毫克(64%)之所需產物。 d.製備化合物25(dK5-甲氧基-4-甲基-2-苯基-苯并呋喃-3-羧酸)。Under argon, compound 25 (b) (30 mg, 0.082 mmol) and Ag20 (46.5 mg, 0.201 mmol), methyl W acid (6.0 mg, 0.0884 mmol), K2C03 ( 34.0 mg, 0.246 mmol), 1,1-bis (diphenylphosphineferrocene) dichloropalladium (II) and dichloromethane complex (1: 1) (Pd (dppf) Cl2) (6.0 Mg, 10 mole%) and THF (degassed, 1.0 ml) in a tube. The pressure tube was sealed, and the reaction mixture was stirred at 80 ° C for 12 hours, cooled to room temperature, and cooled with a mixture of 30% H202 (5 ml) and 10% NaOH. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saline, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to provide 16.9 mg (64%) of the desired product. d. Preparation of compound 25 (dK5-methoxy-4-methyl-2-phenyl-benzofuran-3-carboxylic acid).
25(d) 將化合物25(c)(16.9毫克、0.0545毫莫耳)溶於乙醇(2.0毫 升)並添加12莫耳濃度NaOH (200微升)。將反應加熱至100°C 達6小時,並冷卻至室溫。減壓蒸發溶劑。溶殘查於水,以 10% HC1水溶液酸化,並經乙酸乙酯萃取。令有機層經水與 88828.doc -85- 200418452 鹽液洗,以MgS〇4脫水,並減壓濃縮,提供13·5毫克(87%) 之所需產物。 基_4·甲基^羧酸甲醯胺之製25 (d) Compound 25 (c) (16.9 mg, 0.0545 millimoles) was dissolved in ethanol (2.0 milliliters) and 12 mol NaOH (200 microliters) was added. The reaction was heated to 100 ° C for 6 hours and cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was checked in water, acidified with 10% HC1 aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and 88828.doc -85- 200418452 salt solution, dehydrated with MgS04, and concentrated under reduced pressure to provide 13.5 mg (87%) of the desired product. Of 4-methylmethylformamide carboxylate
將溴-參-吡咯啶基_鳞六氟磷酸鹽(PyBr〇p)(25 ()毫克、 0.(^26毫莫耳)與甲胺(0.5毫升、2·〇莫耳濃度之ΤΗρ溶液)加 入氬氣下之化合物25(d)(13.5毫克、〇·479毫莫耳)之DMF (1 ·0笔升))谷液。於室溫攪拌丨2小時後,以水處理反應混合 物,並經乙酸乙酯萃取。令有機層經水與鹽液洗,以MgS〇4 脫水,並減壓濃縮。經管柱層析(矽膠,乙酸乙酯/己烷)純 化粗產物,·提供9.0毫克(64%)標題化合物。 實例26 1讯基ij·-,夺基·本并嗅喃_3 _讀酸〒龜胺之寧備 L氣遍―化合物26(a)(乙酸4-氰基-2-苯基乙炔基-苯基酯)。A solution of bromo-ginsyl-pyrrolidinyl-quat hexafluorophosphate (PyBrOp) (25 (mg), 0.1 (26 mol) and methylamine (0.5 ml, 2.0 mol concentration of TMP) ) Add the compound 25 (d) (13.5 mg, 0.479 mmol) in DMF (1.0 pen liters)) argon under argon. After stirring at room temperature for 2 hours, the reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgS04, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate / hexane) to provide 9.0 mg (64%) of the title compound. Example 26 1xyl ij ·-, dynyl · benzyl _3 _ read chloridamine Ningbei L gas pass ― compound 26 (a) (acetic acid 4-cyano-2-phenylethynyl- Phenyl ester).
將1,4-二噚烷(2.5毫升、無水)加入經無水隔間封蓋之燒瓶 之Cul (8.0¾:克、2莫耳%)與二氯雙(苯甲腈)把(n)(24毫克、3 莫耳%)之攪拌懸浮液,並經常以氬氣清洗。以注射筒將三· 第三-丁基膦(542微升、〇·25莫耳濃度之ι,4-二噚烷溶液)、二 異丙胺(350微升、4.17毫莫耳)、乙酸溴基氰基_苯基酯 (500毫克、2.08毫莫耳)與苯乙炔(254毫克、2·71毫莫耳)加入 攪拌之反應混合物。令反應混合物攪拌6小時,然後,經乙酸 88828.doc •86- 200418452 乙酯稀釋,並通過小矽膠片。濃縮濾液,並令粗產物經管 柱層析(矽膠,以5〜20%之乙酸乙酯的己烷液溶離)純化,提 供390毫克(72%)之所需產物。 b.製備化合物26(b)(4-羥基-3-茉某乙炔基-苯甲腈)。Add 1,4-dioxane (2.5 ml, anhydrous) to Cul (8.0¾: g, 2 mole%) and dichlorobis (benzonitrile) (n) ( 24 mg, 3 mole%) of the stirred suspension, and often washed with argon. In a syringe, tris-tertiary-butylphosphine (542 μl, 0.25 mol concentration of 4-dioxane solution), diisopropylamine (350 μl, 4.17 mmol), bromoacetate The cyano-phenyl ester (500 mg, 2.08 mmol) and phenylacetylene (254 mg, 2.71 mmol) were added to the stirred reaction mixture. The reaction mixture was allowed to stir for 6 hours, then diluted with ethyl acetate 88828.doc • 86-200418452 and passed through a small piece of silicone. The filtrate was concentrated and the crude product was purified by column chromatography (silica gel, dissolved with 5-20% ethyl acetate in hexane) to provide 390 mg (72%) of the desired product. b. Preparation of compound 26 (b) (4-hydroxy-3-jasmine ethynyl-benzonitrile).
將碳酸鉀(309毫克、2.24毫莫耳)加入化合物26(&)(390毫 克、1.49毫莫耳)之甲醇(10.0毫升)溶液。令反應混合物於室 溫攪拌隔夜,然後減壓蒸乾溶劑。以水處理殘渣並經乙酸 乙酯萃取。令有機層經水與鹽液洗,經MgS04脫水,並減 壓濃縮。令粗產物經管柱層析(矽膠,經5〜25%乙酸乙酯之 己烷溶液溶離)純化,提供180毫克(55%)所需產物。 c.製備化合物26(cV5-氰基-2-苯某茉并咭喃-3-藉酸甲酯)。Potassium carbonate (309 mg, 2.24 mmol) was added to a solution of compound 26 (&) (390 mg, 1.49 mmol) in methanol (10.0 ml). The reaction mixture was stirred at room temperature overnight, and then the solvent was evaporated to dryness under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgS04, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dissolved in 5 to 25% ethyl acetate in hexane) to provide 180 mg (55%) of the desired product. c. Preparation of compound 26 (cV5-cyano-2-benzyljamopyran-3-boronic acid methyl ester).
令化合物26(b)(100毫克、0.4566毫莫耳)混合以硫基尿素 (2·0毫克、5莫耳%)、CBr4 (378.5毫克、1.141毫莫耳)、碳酸 铯(445毫克、1.3 67毫莫耳)、卩412(8.2毫克、5莫耳%)與甲醇 (2毫升)。令反應混合物經室溫之一氧化碳氣流處理5分鐘, 並經45°C處理10分鐘。持續於45°C之一氧化碳氣壓下(氣球) 攪拌隔夜。然後令反應混合物通過小片之矽膠,經乙酸乙 88828.doc -87- 200418452 酉旨潤濕。濃縮滤液’並令粗產物經管柱層析(硬膠,經5〜1 〇% 乙酸乙酯之己烷溶液溶離)純化,提供74毫克60:40之化合物 26(c)與2-苯基-苯并呋喃-5-羰腈之混合物。 d.製備化合物26(d) (5-氣基-2-冬基-冬并唉喃致酸)。Let compound 26 (b) (100 mg, 0.4566 mmol) be mixed with thiourea (2.0 mg, 5 mole%), CBr4 (378.5 mg, 1.141 mmol), cesium carbonate (445 mg, 1.3 67 millimoles), tritium 412 (8.2 mg, 5 mole%) and methanol (2 mL). The reaction mixture was treated with a stream of carbon monoxide at room temperature for 5 minutes and 45 ° C for 10 minutes. Continue stirring at 45 ° C under carbon monoxide pressure (balloon) overnight. The reaction mixture was then passed through small pieces of silicone and moistened with ethyl acetate 88828.doc -87- 200418452. The filtrate was concentrated and the crude product was purified by column chromatography (hard gum, dissolved with 5 to 10% ethyl acetate in hexane) to provide 74 mg of 60:40 compound 26 (c) and 2-phenyl- A mixture of benzofuran-5-carbonitrile. d. Preparation of Compound 26 (d) (5-Amino-2-Deryl-Deropentosulfuric Acid).
26(d) 將上述化合物26(c)與2-苯基-苯并咳喃-5_羰腈(74毫克) 之混合物溶於乙醇(2.0毫升)並經12莫耳濃度Na〇H (2〇〇微 升)處理。將反應加熱至5 0 °C達6小時,然後冷卻至室溫, 並減壓濃縮溶劑。溶殘渣於水,以10%HC1水溶液酸化,並 經乙酸乙酯萃取。令有機層經水與鹽液洗,以MgS〇4脫水 ,並減壓濃縮。令粗產物經管柱層析(矽膠,經3〇〜4〇%乙酸 乙酯/己烷溶離)純化,產生30毫克(由步騾c_d為25%產率)之 所需產物。 e.Ol基-2-苯某-苯并呋胺之 該目標產物(16.G毫克、51%)實質上是根據實例25、步驟 之-般方法製成’然而’以化合物26⑷取代化合物25⑷< ^1127 吡啶-4-基-基进酸甲酿胺之盤備 異丙氧基分)。 h3ct26 (d) A mixture of the above compound 26 (c) and 2-phenyl-benzocystan-5_carbonylnitrile (74 mg) was dissolved in ethanol (2.0 ml) and subjected to a concentration of 12 mol NaOH (2 〇〇μΙ) for processing. The reaction was heated to 50 ° C for 6 hours, then cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was dissolved in water, acidified with 10% HC1 aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgS04, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluting with 30-40% ethyl acetate / hexane) to yield 30 mg (25% yield from step c_d) of the desired product. e. The target product (16.G mg, 51%) of Olyl-2-benzyl-benzofuramine was essentially made according to the method of Example 25 and the procedure 'However', the compound 25 was substituted for the compound 25 '& lt ^ 1127 A plate of pyridin-4-yl-methyl methanoate prepared with isopropyloxy). h3ct
OHOH
XX 27(a) 88828.doc -88- 200418452 將2-碘化丙烷(27.22毫升、〇·27莫耳)加入對苯二紛(3〇克 、0 · 2 7莫耳)之乙醇(3 〇毫升)之揽掉混合物,並將反應混合 物加熱至60°C。溶氫氧化鉀(15.3克、0.27莫耳)於水(5〇毫升) ’並以1小時逐滴加入反應混合物。於6〇它攪拌5小時後, 將混合物冷卻至室溫,並減壓去除溶劑。令殘渣經6當量濃 度HC1酸化,並以乙_萃取。令有機層經水與鹽液洗過,經 MgS〇4脫水,並濃縮。令粗產物經管柱層析(碎膠,以1〇〜3 之乙酸乙酯/己烷溶離)純化,產生20·3克(49%)之所需產物。 b.製備化合物27(b)i2-溴某-4-異丙氧基-酚)。XX 27 (a) 88828.doc -88- 200418452 Add 2-iodopropane (27.22 ml, 0.27 mole) to terephthalic acid (30 g, 0.27 mole) in ethanol (30 Ml), and the reaction mixture was heated to 60 ° C. Dissolve potassium hydroxide (15.3 g, 0.27 mole) in water (50 ml) 'and add the reaction mixture dropwise over 1 hour. After it was stirred at 60 ° C for 5 hours, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was acidified with 6 equivalents of HC1 and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated. The crude product was purified by column chromatography (crushed gel, dissolved in ethyl acetate / hexane of 10 to 3) to yield 20.3 g (49%) of the desired product. b. Preparation of compound 27 (b) i2-bromo-4-isopropoxy-phenol).
將1溴琥珀亞醯胺(5.85克、0.033莫耳)加入化合物27(a) (5·0克、0.033莫耳)之二硫化碳(132毫升)之攪拌溶液。令反 應混合物於室溫攪拌2小時,然後減壓將溶劑蒸乾。令殘渣 經水處理並以乙酸乙酯萃取。令有機層經水與鹽液洗,以 MgS〇4脫水並濃縮。令粗產物經管柱層析(矽膠,以5〜1〇。/〇之 乙酸乙酯/己烷溶離)純化,產生4.65克(61%)之所需產物。 c.製備化*合物27(c) ί乙酸2-溴基-4-異丙氧基-苯基醋)。1 Bromosuccinimide (5.85 g, 0.033 mole) was added to a stirred solution of compound 27 (a) (5.0 g, 0.033 mole) in carbon disulfide (132 ml). The reaction mixture was allowed to stir at room temperature for 2 hours, and then the solvent was evaporated to dryness under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saline, dried over MgSO and concentrated. The crude product was purified by column chromatography (silica gel, eluting with ethyl acetate / hexane at 5-10%) to yield 4.65 g (61%) of the desired product. c. Preparation of compound 27 (c) 2-bromo-4-isopropoxy-phenylacetate acetate).
27(c) 〇 -89 - 88828.doc 200418452 將4-二甲基胺基吡啶(催化性)與三乙胺(6 9毫升、〇·〇50莫 耳)加入化合物27(b)(4.6克、0.02毫莫耳)之二氯甲烷(20毫升) 的攪拌溶液。令反應混合物攪拌1〇分鐘,然後添加乙酐(4.5 笔升、0.48莫耳)。攪拌4小時後,加水至反應混合物。令混 合物經乙酸乙酯萃取,並令有機層經水與鹽液洗,經MgS04 脫水並濃縮。令粗產物經管柱層析(矽膠,以〇〜1〇%之乙酸 乙酯/己烷溶離)純化,產生4.75克(87%)之所需產物。 肯」匕合物27(d)(4-三甲基矽烷基乙块基-吡啶)。27 (c) 〇-89-88828.doc 200418452 Add 4-dimethylaminopyridine (catalytic) and triethylamine (69 ml, 0.050 mole) to compound 27 (b) (4.6 g , 0.02 mmol of methylene chloride (20 ml). The reaction mixture was allowed to stir for 10 minutes, and then acetic anhydride (4.5 pen liters, 0.48 moles) was added. After stirring for 4 hours, water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over MgS04 and concentrated. The crude product was purified by column chromatography (silica gel, eluting with 0 to 10% ethyl acetate / hexane) to yield 4.75 g (87%) of the desired product. Ken "27 (d) (4-trimethylsilylethyl-pyridine).
JH3 H3C Si CHj -JH3 H3C Si CHj-
27(d)27 (d)
化合物27(d)(2.4克、53%)實質上是根據實例26、步騾a所 述之一般方法製成,然而,以4-溴峨淀鹽酸鹽與(三甲基矽 燒基)乙炔取代乙酸2-溴-4-氰基-苯酯與苯乙炔。 gA合物27(e)之製備(4-乙炔基-吡啶)。Compound 27 (d) (2.4 g, 53%) was substantially prepared according to the general method described in Example 26, Step 骡 a. However, 4-bromoanedian hydrochloride and (trimethylsilyl) were used. Acetylene replaces 2-bromo-4-cyano-phenyl acetate and phenylacetylene. Preparation of gA compound 27 (e) (4-ethynyl-pyridine).
27(e) 將氫氧化鉀(21.0毫克、3.0莫耳%)加入化合物27(d)(2.2克 0.0126毫莫耳)之脫氣甲醇(8〇毫升)溶液。攪拌3〇分鐘後 加水並以二氯甲烷萃取混合物。令有機層經水與鹽液洗 88828.doc -90- 200418452 ,以MgS〇4脫水,並濃縮以產生640毫克(53%)所需產物。 f.化合物27(f)之製備(乙酸冬異丙氧基-2-吡淀基乙块 基-苯基S旨)。27 (e) Potassium hydroxide (21.0 mg, 3.0 mole%) was added to a solution of compound 27 (d) (2.2 g 0.0126 mmol) in degassed methanol (80 ml). After stirring for 30 minutes, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and saline 88828.doc -90- 200418452, dehydrated with MgSO4, and concentrated to give 640 mg (53%) of the desired product. f. Preparation of compound 27 (f) (isopropyloxy-2-pyridylethylethyl-phenylphenyl).
27(f) δ 化合物27(f)(564毫克、61%)實質上是根據實例26、步騾a 所述之一般方法製成,然而,以化合物27(c)與化合物27(e) 取代2-溴-4-氰基-苯酯與苯乙炔。 g.化合物27(g)之製備(4-異丙氧基-2-吡啶-4-基乙決基-酚)。27 (f) δ Compound 27 (f) (564 mg, 61%) is substantially prepared according to the general method described in Example 26, Step 骡 a, however, Compound 27 (c) and Compound 27 (e) are substituted 2-bromo-4-cyano-phenyl ester and phenylacetylene. g. Preparation of compound 27 (g) (4-isopropoxy-2-pyridin-4-ylethoxy-phenol).
將聯胺(9.5毫升、0.5莫耳濃度之THF溶液)加入化合物 27(f)(564毫克、1.91毫莫耳)之THF (3.0毫升)之攪拌溶液。 攪:拌3 0分鐘後’加水並以乙酸乙酉旨萃取產物。令有機層經 水(3 X 100¾升)與鹽液洗’以MgS〇4脫水並濃縮,提供470 毫克(97%)白色固體之所需產物。 h·也合物27(h)之製備(5-異丙氧基-2-p比淀-4-基-苯并吱喃 -3-羧酸甲酯)。Hydrazine (9.5 ml, 0.5 mole solution in THF) was added to a stirred solution of compound 27 (f) (564 mg, 1.91 mmol) in THF (3.0 ml). Stir: After 30 minutes, add water and extract the product with ethyl acetate. The organic layer was washed with water (3 x 100 ¾ liters) and brine ', dehydrated with MgSO and concentrated to provide 470 mg (97%) of the desired product as a white solid. h. Preparation of compound 27 (h) (5-isopropoxy-2-p ratio yodo-4-yl-benzofuran-3-carboxylic acid methyl ester).
88828.doc -91 - 200418452 中間體化合物(430毫克、74%)實質上是根據實例26、步 ••flc所述之一般方法製成,然而,以化合物27(g)取代化合物 26(b)。 氧基某-笨并呋喃-3-#酸甲醯胺之制舞〇 將氫氧化鐘(540毫克)與水(ι·〇毫升)加入溶於丨,^二噚烷 之化合物27(g)(200毫克、〇·644毫莫耳)之溶液。令反應混合 物於80 C攪拌12小時。將該混合物冷卻至室溫,並減壓濃 縮溶劑。溶殘渣於水,以1〇% HC1使之成pH 7.0,並經乙酸 乙酯萃取。令有機層經水與鹽液洗,以MgS〇4脫水並減壓 濃縮,提供130毫克(68%)之酸。 將上述之酸(65毫克、0.22毫莫耳)、苯并三唑-1-基氧基參 外匕嘻咬基鱗六氟磷酸鹽(PyBOP)(148毫克、0.284毫莫耳)溶 於DMF (0.5毫升)與甲胺(2.2毫升、2.0莫耳濃度之THF溶液) 。檀拌12小時後,加水並以乙酸乙酯萃取粗產物。令有機 層經水與鹽液洗,以MgSCU脫水並濃縮。令粗產物經管柱 層析(矽膠、經0〜5%甲醇/乙酸乙酯溶離)純化,提供65毫克 (96%)之標題化合物。 實例28 6-(3,5-二甲基-異今吐-4-基)-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸甲醯胺之製備 a·盤備化合物28(a)(2-(4-氟苯基)-5 -甲氧基苯并唉喃-3-羧 酸乙酯)。88828.doc -91-200418452 Intermediate compound (430 mg, 74%) is essentially prepared according to the general method described in Example 26, step • flc, however, compound 27 (g) is substituted for compound 26 (b) . Oxygen-benzylfuran-3- # acid formamidine production 0. Bell hydroxide (540 mg) and water (ι · mL) were added to compound 27 (g) dissolved in dioxane (200 mg, 0.644 mmol). The reaction mixture was allowed to stir at 80 C for 12 hours. The mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was dissolved in water, brought to pH 7.0 with 10% HC1, and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated under reduced pressure to provide 130 mg (68%) of the acid. The above-mentioned acid (65 mg, 0.22 mmol), benzotriazol-1-yloxy, and hexafluorophosphate (PyBOP) (148 mg, 0.284 mmol) were dissolved in DMF (0.5 ml) and methylamine (2.2 ml, 2.0 Molar THF solution). After stirring for 12 hours, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgSCU and concentrated. The crude product was purified by column chromatography (silica gel, dissolved in 0 to 5% methanol / ethyl acetate) to provide 65 mg (96%) of the title compound. Example 28 6- (3,5-Dimethyl-isopent-4-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine Preparation of amines a. Prepare compound 28 (a) (2- (4-fluorophenyl) -5-methoxymethoxybenzo-3-carboxylic acid ethyl ester).
88828.doc -92- 200418452 將化合物21(b)(50.0克、〇·167莫耳,根據實例21所述之一般 方法製成)溶於氬氣下之無水1-甲基-2-吡咯啶酮(176毫升) ,同時機械攪拌。一旦呈均質化後,以i 5分鐘時間分批添 加蛟酸铯(108.8克、0.334莫耳)。以5分鐘時間添加碘化甲烷 (32·2笔升、〇·516莫耳)。將反應加熱至5〇。〇達1 $小時,然後 々卻土 1溫,以濃氫氧化銨(3 9毫升),並攪拌3 〇分鐘。以庚 虼(1000¾升)稀釋混合物並經水(3xl〇〇〇毫升)洗。令合併 之有機物經硫酸鎂脫水並蒸乾。令生成之固體於己烷中攪 掉18小時,過濾並乾燥。因為反應未完全(藉質子nmr得知) ,再令分離之固體經無水^^基―:吡咯啶酮(176毫升)處理 。一旦呈均質化後,添加碳酸铯(4〇〇克、〇123莫耳)與碘化 甲烷(20.0¾升、0.321莫耳)。將反應再次加熱至咒它達u 小時,冷卻至室溫,以氫氧化銨(24毫升)稀釋,並擾掉% 分鐘。以水(1_毫升)稀釋混合物,並以第三丁基甲基酸萃 取(3X3GGU)。令合併之有機物經水(3⑽毫升)洗,並經 硫酸鎂脫水。蒸發溶劑後,經熱庚烷結晶產物,提供Μ」 克(61%)褐色固體之所需產物。 b.歷氟苯基甲氧基苯并呋喃_3·羧 酸)。88828.doc -92- 200418452 Compound 21 (b) (50.0 g, 0.167 mol, prepared according to the general method described in Example 21) Anhydrous 1-methyl-2-pyrrolidine under argon Ketone (176 ml) while mechanically stirring. Once homogenized, cesium gallate (108.8 g, 0.334 mol) was added in portions over 5 minutes. Methane iodide (32.2 pen liters, 0.516 mol) was added over 5 minutes. The reaction was heated to 50. 〇 reached 1 $ hours, then chrysanthemum 1 temperature to concentrated ammonium hydroxide (39 ml), and stirred for 30 minutes. The mixture was diluted with heptane (1000 ¾ liters) and washed with water (3 x 1000 ml). The combined organics were dehydrated over magnesium sulfate and evaporated to dryness. The resulting solid was stirred in hexane for 18 hours, filtered and dried. Because the reaction was not complete (known by the proton nmr), the separated solid was treated with anhydrous ^^-: pyrrolidone (176 ml). Once homogenized, cesium carbonate (400 g, 0123 mol) and methane iodide (20.0¾ liter, 0.321 mol) were added. The reaction was reheated to utah for u hours, cooled to room temperature, diluted with ammonium hydroxide (24 mL), and disturbed for% minutes. The mixture was diluted with water (1-mL) and extracted with tert-butyl methyl acid (3X3GGU). The combined organics were washed with water (3 ml) and dehydrated over magnesium sulfate. After evaporation of the solvent, the product was crystallized from hot heptane to provide M "g (61%) of the desired product as a brown solid. b. Lifluorophenylmethoxybenzofuran-3.carboxylic acid).
0.112 令化合物28⑷(32克、(U〇2莫耳)與4氧化却(63克 88828.doc -93- 200418452 莫耳)於乙醇(80毫升)與水(8〇毫升)中合併。令該反應混合 物溫和迴流隔夜。經TLC分析顯示反應不完全,因此添加 额外量之氫氧化鉀(2.0克、0.035莫耳)。1小時後,將溶劑蒸 發至一半體積。以水(4〇〇毫升)稀釋該溶液,並經乙酸乙酯 (2 X 3 00毫升)萃取。以3莫耳濃度HC1酸化水溶液,並過濾生成 之沉澱,水洗之並乾燥,提供28.9克(99%)白色固體之產物。 c·製備化t物28(c)(6-溴基-2-(4-氟苯基)-5-甲氧基苯并呋 喃-3-叛酸)。0.112 Compound 28⑷ (32 g, (U02 Molar) and 4 oxidized (63 g 88828.doc -93- 200418452 Molar) was combined in ethanol (80 ml) and water (80 ml). Let this The reaction mixture was gently refluxed overnight. Analysis by TLC showed that the reaction was incomplete, so an additional amount of potassium hydroxide (2.0 g, 0.035 mol) was added. After 1 hour, the solvent was evaporated to half the volume. Water (400 ml) The solution was diluted and extracted with ethyl acetate (2 × 300 ml). The aqueous solution was acidified with 3 molar HC1 and the resulting precipitate was filtered, washed with water and dried to provide 28.9 g (99%) of the product as a white solid. c. Preparation of compound 28 (c) (6-bromo-2- (4-fluorophenyl) -5-methoxybenzofuran-3-metanoic acid).
令化合物28(b) (28.9克、0.101莫耳)溶於氬氣下之無水ι,4-二气烷(725毫升)。令生成之溶液於氣體分散管經氬氣脫氣 10分鐘。以45分鐘時間,經注射筒逐滴添加溴(8.8毫升、 0.170莫耳)。添加完成後,令反應於室溫攪拌3〇分鐘。以5 分鐘時間逐滴添加額外量之溴(〇·5毫升、〇.〇1莫耳)。令混合 物經乙酸乙酯(1800毫升)稀釋,水(5 X 350毫升)洗,並經硫 酸鍰脫水。蒸發溶劑,並溶解剩餘固體於乙酸乙酯(250毫 升)。再次蒸發去除溶劑。重複溶解於乙酸乙酯與隨後之蒸 發步驟,直至溶劑沒有顏色為止。令生成之固體於80/20之 己烷/乙酸乙酯(500毫升)中經超音波震盪,並經過濾分離粗 產物。濃縮漉液,並令生成之固體於80/20之己烷/乙酸乙酯 混合物(300毫升)中經超音波震盪。過濾分離固體,並合併 88828.doc -94- 粗產物。令固體經95/5之己烷/乙酸乙酯混合物(100毫升)洗 然後為己。令固體經真空乾燥脫水,提供28.4克(77%) 褐色固體之所需產物。 d.匕合物6-溴基-2-(4-氟苯基)-5-甲氧基笨并呋 喃-3-羧酸甲酯)。Compound 28 (b) (28.9 g, 0.101 mole) was dissolved in anhydrous, 4-dioxane (725 ml) under argon. The resulting solution was degassed in a gas dispersion tube under argon for 10 minutes. Bromine (8.8 ml, 0.170 mol) was added dropwise via a syringe over 45 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 30 minutes. An additional amount of bromine (0.5 ml, 0.01 mole) was added dropwise over 5 minutes. The mixture was diluted with ethyl acetate (1800 ml), washed with water (5 X 350 ml), and dehydrated with sodium sulfate. The solvent was evaporated and the remaining solid was dissolved in ethyl acetate (250 mL). The solvent was removed by evaporation again. The dissolution in ethyl acetate and subsequent evaporation steps were repeated until the solvent was colorless. The resulting solid was sonicated in 80/20 hexane / ethyl acetate (500 ml), and the crude product was isolated by filtration. The mash was concentrated, and the resulting solid was sonicated in an 80/20 hexane / ethyl acetate mixture (300 ml). The solid was isolated by filtration and the 88828.doc -94- crude product was combined. The solid was washed with a 95/5 hexane / ethyl acetate mixture (100 ml) and then was taken as hexane. The solid was dried under vacuum to provide 28.4 g (77%) of the desired product as a brown solid. d. 6-bromo-2- (4-fluorophenyl) -5-methoxybenzyfuran-3-carboxylic acid methyl ester).
將磨碎之碳酸鉀(40.6克、0.294莫耳)與碘化甲烷(92.0毫 升、1.47莫耳)加入化合物28(c)(53.6克、0.147莫耳,可根據 前述步驟製成)之1-甲基-2-吡咯啶酮(1〇〇〇毫升)之攪掉溶液 。令反應混合物於50°C攪拌18小時。於冷卻時,令反應經 水(2200毫升)稀釋,並經乙酸乙酯萃取(5χ6〇〇毫升合併 有機物,水(3 X 1000毫升)洗,並經硫酸鎂脫水。蒸發溶劑 ,並令粗產物經90/10之己烷/乙酸乙酯混合物超音波震湯i 小時純化。過滤去除固體,經己烷洗並真空乾燥,提供47 4 克(125莫耳、85%)白色固體之所需產物。 e.l備化合物28(en6-(3.5-二甲基異噚唑-4·基)-2-(4-氣笨 基)-5-甲氧基-苯并呋喃-3-羧酸甲酯)。Add ground potassium carbonate (40.6 g, 0.294 mole) and methane iodide (92.0 ml, 1.47 mole) to compound 28 (c) (53.6 g, 0.147 mole, which can be made according to the previous steps) The solution was stirred off with methyl-2-pyrrolidone (1000 ml). The reaction mixture was allowed to stir at 50 ° C for 18 hours. Upon cooling, the reaction was diluted with water (2200 ml) and extracted with ethyl acetate (5 x 600 ml combined organics, washed with water (3 x 1000 ml) and dehydrated over magnesium sulfate. The solvent was evaporated and the crude product was allowed to Purified by 90/10 hexane / ethyl acetate mixture sonic soup for 1 hour. Filtered to remove solids, washed with hexane and dried in vacuo to provide 47.4 g (125 moles, 85%) of the desired product as a white solid. El compound 28 (en6- (3.5-dimethylisoxazol-4-yl) -2- (4-aminobenzyl) -5-methoxy-benzofuran-3-carboxylic acid methyl ester) .
88828.doc >95- 200418452 於氬氣下,將化合物28(d)(12.0克、〇·〇3 16莫耳)溶於甲苯 (900毫升)、乙醇(420毫升)與水(24毫升)。令生成之溶液於 氣體分散管中經氬氣脫氣10分鐘。添加碳酸鈉(8.37克、79 0 毫莫耳)、3,5-二甲基異噚唑-4-_酸(6.69克、47.5毫莫耳)與 肆-三苯膦-鈀(〇)(1·83克、1·58毫莫耳),並令反應溫和迴流 21小時。蒸發溶劑,並以乙酸乙醋(500毫升)與水(3〇〇毫升) 稀釋反應。令各層分離,並以水(2 X 500毫升)洗有機相。合 併水洗物,並經乙酸乙酯(300毫升)萃取。合併有機物,經 鹽液洗,並經硫酸鎂脫水。蒸發溶劑,並令粗產物經急驟 層析(矽膠,乙酸乙酯/己烷梯度)純化,提供10.4克(83%)灰 白色固體之所需產物。 化合物28(TV6-H.5-二甲基異噚唑-4-基)-2-(4-氟苯 基)-5-甲氧基苯并呋喃_3•羧酸)。88828.doc > 95- 200418452 Under argon, compound 28 (d) (12.0 g, 0.03 16 mole) was dissolved in toluene (900 ml), ethanol (420 ml) and water (24 ml) . The resulting solution was degassed in a gas dispersion tube with argon for 10 minutes. Add sodium carbonate (8.37 g, 79 0 mmol), 3,5-dimethylisoxazole-4-_acid (6.69 g, 47.5 mmol) and tris-triphenylphosphine-palladium (〇) ( 1.83 g, 1.58 mmol), and the reaction was allowed to reflux gently for 21 hours. The solvent was evaporated and the reaction was diluted with ethyl acetate (500 ml) and water (300 ml). The layers were separated and the organic phase was washed with water (2 X 500 ml). The washings were combined and extracted with ethyl acetate (300 ml). The organics were combined, washed with saline and dehydrated with magnesium sulfate. The solvent was evaporated and the crude product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 10.4 g (83%) of the desired product as an off-white solid. Compound 28 (TV6-H.5-dimethylisoxazol-4-yl) -2- (4-fluorophenyl) -5-methoxybenzofuran_3 • carboxylic acid).
令化合物28(e)(10.4克、26.3毫莫耳)與氫氧化鉀(5·90克、 105毫莫耳)於乙醇(5〇〇毫升)與水(5〇〇毫升)中合併,並溫和 迴流4小時。冷卻後,蒸發2/3溶劑,並以水(3〇〇毫升)稀釋 /4液。令溶液濾過一片CeliteTM503,以去除來自先前步驟 之少量1巴。以6莫耳濃度HC1酸化溶液,並過濾沉澱物,經 水與己燒洗,並於真空部分乾燥以提供白色固體之所需產 物。將未經純化之產物直接用於下一步騾。 88828.doc -96- 200418452 一基異唠唑-4-某)-2-ί4-氟笨基)_5·甲氮某苯并 生藉酸甲醯胺)之塑備。 令化合物28(f) (10.0克、0.0262莫耳)、苯并三峻-1-基氧基 參吡咯啶基鱗六氟磷酸鹽(PyBOPKMj克、0.0315莫耳)與 甲胺(131毫升、2莫耳濃度之THF溶液、0.262莫耳)於DMF (16愛升)中合併。令反應於室溫氬氣下攪拌丨8小時。蒸發溶 劑,並溶生成之固體於乙酸乙酯(250毫升)與水(300毫升)。 令各層分離,並以乙酸乙酯(4X200毫升)萃取水相。合併有 機物,經水(3X150毫升)與鹽液(3〇〇毫升)洗,並經硫酸鎂 脫水。蒸發溶劑,並令粗產物與90/10之己烷/乙酸乙酯(1〇〇 毫升)混合物混合。過濾混合物,並令固體經己烷洗,並真 空乾燥,提供8.16克(79%)白色固體之所需產物。 稍後令粗產物於合併數批其他化合物後,經結晶(熱乙醇 與水)純化,以提供白色針狀之標題化合物。 實例29 2-(4-氟基-苯基)-6-(甲烷磺醯基-甲基-胺基)-5_甲氧基-苯并 呋喃-3-羧酸甲醯胺之製備 a.l.備化合物,2.9.(a)(2-(4-氟基-苯基)-5-經基-6-甲烷磺醯 基胺基-苯并呋喃-3-羧酸甲醯胺)。Combine compound 28 (e) (10.4 g, 26.3 mmol) with potassium hydroxide (5.90 g, 105 mmol) in ethanol (500 ml) and water (500 ml), and Gently reflux for 4 hours. After cooling, 2/3 of the solvent was evaporated and diluted with water (300 mL). The solution was filtered through a piece of CeliteTM 503 to remove a small amount of 1 bar from the previous step. The solution was acidified with 6 mol HC1, and the precipitate was filtered, washed with water and hexane, and partially dried under vacuum to provide the desired product as a white solid. The unpurified product was used directly in the next step. 88828.doc -96- 200418452 One base isoxazolyl-4-one) -2-ί4-fluorobenzyl) _5 · methylazine benzoxanthine methylformamide)). Let compound 28 (f) (10.0 g, 0.0262 mole), benzotrisol-1-yloxypyrrolidinyl hexafluorophosphate (PyBOPKMj g, 0.0315 mole) and methylamine (131 ml, Molar concentration of THF solution, 0.262 Molar) was combined in DMF (16 liters). The reaction was allowed to stir at room temperature under argon for 8 hours. The solvent was evaporated and the resulting solid was dissolved in ethyl acetate (250 ml) and water (300 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (4 × 200 mL). The organics were combined, washed with water (3 × 150 ml) and saline (300 ml), and dried over magnesium sulfate. The solvent was evaporated and the crude product was mixed with a 90/10 hexane / ethyl acetate (100 mL) mixture. The mixture was filtered and the solid was washed with hexane and dried in vacuo to provide 8.16 g (79%) of the desired product as a white solid. The crude product was later purified by crystallization (hot ethanol and water) after combining several batches of other compounds to provide the title compound as a white needle. Example 29 Preparation of 2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5-methoxy-benzofuran-3-carboxylic acid formamide Compound, 2.9. (A) (2- (4-fluoro-phenyl) -5-acryl-6-methanesulfonylamino-benzofuran-3-carboxylic acid formamidine).
將三氯化硼(60毫升之1莫耳濃度二氯甲烷溶液)以1〇分鐘 88828.doc -97- 200418452 加入2-(4-氟基-苯基)-5-異丙氧基-6-甲燒續縫基胺基-苯并 呋喃-3-叛酸甲醯胺(7.1〇克、16.9毫莫耳,可根據實例21所 述方法之一製成)之二氯甲烷(200毫升)。令混合物攪拌2〇 小時,然後小心以1當量濃度HC1 (10毫升)止熱。添加額外 量之4當量濃度HC1 (100毫升),並令混合物攪拌24小時。漉 除沉澱固體,水洗,乾燥並經乙酸乙酯/己烷研製,提供6.39 克(100%)白色固體之所需產物。 b. 1:14-氟基-苯基)-6-(甲院石蓊酸某-甲基-胺某)-5-甲氫甚_ 喃_3-#酸曱醯胺之製備。 將碳酸鉀(0.30克、2· 17毫莫耳)與碘化甲烷(〇.1〇毫升、161 晕莫耳)加入化合物29(a)(0.11克、0.291毫莫耳,可根據前 述步騾製成)之2-丁酮(20毫升)溶液。令該反應混合物迴流 1〜2小時,然後冷卻至室溫並濃縮。溶粗產物於乙酸乙酯, 並以1莫耳濃度鹽酸洗之。濃縮有機層,並藉急驟層析(石夕 膠、乙酸乙酯/己烷梯度)純化產物,提供73毫克(62〇/〇)白色 固體之所需產物。 實例30 2-(4 -氟基-苯基)-5-藉基-(4-甲氧基-爷氧基)-6-嗎福琳-4-基一 苯并呋喃-3-羧酸甲醯胺之製備 a·製備化合物30(aK2-(4-氟基-苯基)-5-羥基-6-嗎福啉 基-苯并咬喃-3 -叛酸甲酸胺)。Boron trichloride (60 ml of a 1 molar solution of dichloromethane) was added in 10 minutes 88828.doc -97- 200418452 to 2- (4-fluoro-phenyl) -5-isopropoxy-6 -Methanesulfonylamino-benzofuran-3-methanoic acid formamidine (7.10 g, 16.9 mmol, prepared by one of the methods described in Example 21) methylene chloride (200 ml) . The mixture was allowed to stir for 20 hours, then carefully stopped at 1 equivalent of HC1 (10 mL). An additional 4 equivalents of HC1 (100 ml) was added and the mixture was allowed to stir for 24 hours.漉 The precipitated solid was removed, washed with water, dried and triturated with ethyl acetate / hexane to provide 6.39 g (100%) of the desired product as a white solid. b. Preparation of 1: 14-fluoro-phenyl) -6- (a-yuan berberine-methyl-amine) -5-methylhydroxanthran-3- # acidamine. Potassium carbonate (0.30 g, 2.17 mmol) and methane iodide (0.10 ml, 161 hamol) were added to compound 29 (a) (0.11 g, 0.291 mmol). Made of) 2-butanone (20 ml) solution. The reaction mixture was refluxed for 1 to 2 hours, then cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate and washed with 1 molar hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (stone gum, ethyl acetate / hexane gradient) to provide 73 mg (620/0) of the desired product as a white solid. Example 30 2- (4-Fluoro-phenyl) -5-boryl- (4-methoxy-neoxy) -6-morpholin-4-yl-benzofuran-3-carboxylic acid methyl ester Preparation of amidamine a. Preparation of compound 30 (aK2- (4-fluoro-phenyl) -5-hydroxy-6-morpholinyl-benzoanan-3 -metamic acid amine).
88828.doc -98- 200418452 將三氯化硼(1莫耳濃度之二甲苯溶液,5 〇毫升、5 〇毫莫 耳)加入溶於二氯甲烷(3〇毫升)之2彳4-氟基-苯基)-5-異丙氧 基-6-嗎福琳-4-基·苯并吱喃-3-叛酸甲醯胺(0.71克、1·7毫莫 耳’可根據上述實例24製成)溶液。令反應混合物迴流3〇分 鐘’冷卻至室溫,經1莫耳濃度氫氯酸(1〇毫升)止熱並攪拌1 小時。条發去除有機物,並添加碳酸氫鋼之飽和溶液直至 ρΗ=8-9。以乙酸乙酯萃取產物,並藉管柱層析(無水負載於 矽膠、乙酸乙酯/己烷梯度)純化,提供〇,53克(84%)之所需 產物。 b.U4-氟基-茉某)-544-甲氲基-芊氣基)-6-嗎福啉-4-甚_ 產並及喃_3-#酸甲醯胺之製備。 將碳酸鉀(0·40克、2·89毫莫耳)與4-甲氧苄基氯(0.20毫升 、1.47毫莫耳)加入化合物30(a)(0311克、〇·84〇毫莫耳)之乙 腈(20毫升)溶液。令該反應混合物迴流12小時,冷卻至室溫 並濃縮。溶粗產物於乙酸乙酯,並經1莫耳濃度氫氯酸洗。 濃縮有機層,並藉急騾層析(矽膠、乙酸乙酯/己烷梯度)純 化產物,提供296毫克(72%)白色固體之所需產物。 實例3 1 2-(4-氟基-苯基)-6-[甲烷磺醯基-(4-甲氧基-苄基)-胺基] _5_(4-甲氧基-苄氧基)-苯并呋喃-3-羧酸甲醯胺之製備 將碳酸鉀(0.040克、0.285毫莫耳)與4-甲氧芊基氯(0.026 毫升、0.190毫莫耳)加入化合物29(a)(0.036克、0.095毫莫耳 ’可根據上述實例29、步驟a製成)之2-丁酮(10毫升)溶液。 令該反應於20°C攪拌72小時。濃縮反應混合物,溶粗產物 88828.doc -99- 200418452 於乙酸乙酯,並以1莫耳濃度氫氯酸洗之。濃縮有機層,並 藉急驟層析(矽膠、乙酸乙酯/己烷梯度)純化產物,提供34 毫克(58%)白色固體之所需產物。 實例32 5-乙氧基_6_(乙基-甲烷磺醯基-胺基)-2-(4-氟基-苯基;)_苯并 呋喃-3-羧酸甲醯胺之製備 將竣酸鉀(〇·1〇克、〇·72毫莫耳)與碘化乙烷(〇1〇毫升、125 耄莫耳)加入化合物29(a)(0.036克、0.095毫莫耳,可根據上 述實例29、步騾a製成)之2_ 丁酮(15毫升)溶液,並令該反應 混合物於20°C攪拌72小時。濃縮反應混合物,溶粗產物於 乙酸乙酯,並以1莫耳濃度氫氯酸洗之。濃縮有機層,並藉 急驟層析(矽膠、乙酸乙酯/己烷梯度)純化產物,提供25毫 克(61%)白色固體之標題化合物。 實例33 2-(4-氟基-苯基嗎福琳-4-基-5-〇塞峻-2-基甲氧基)_苯并 呋喃-3-羧酸甲醯胺之製備 a · (2 -氯甲某-違峻)之製傭〇 將亞硫醯氯(2毫升、27.4毫莫耳)加入2-羥基甲基禮吐 (0.15克、1.30毫莫耳)之二氯甲烷(2毫升)溶液。令反應混合 物迴流加熱3秒鐘,然後冷卻並於室溫攪拌2〇分鐘。濃縮反 應,於高度真空幫浦乾燥,並直接用於下一步驟。 b.K4-氟笨基)-6-嗎福淋-4_基_5_(^宣嘁-2_某甲氧其 苯并吹,喃_3.ϋ酸甲醯胺之寧備〇 將碳酸鉀(〇·1〇克、〇·72毫莫耳)與2_氯甲基^塞唑(〇〇21克 88828.doc -100- 200418452 、0.157毫莫耳)加入化合物3〇(a)(0,050克、〇135毫莫耳,可 根據上述實例30、步驟(a)製成)之乙腈(15毫升)溶液。令該 反應迴流2小時,然後於60°C加熱達16小時。將反應冷卻並 濃縮,溶粗產物於乙酸乙酯,並經丨莫耳濃度氫氯酸洗。濃 縮有機層,並藉急驟層析(矽膠、乙酸乙酯/己烷梯度)純化 產物,生成37毫克(59%)白色固體之所需產物。 實例34 2 (4-氟基-本基)-5-異丙氧基-6-[甲燒續gf基_ (2_氧基-丙基)_ 胺基]-苯并咬喃-3-羧酸甲醯胺之製備 將2-(4-氟基-苯基)-5-異丙氧基-6-甲烷磺醯基胺基_苯并 呋喃-3-羧酸甲醯胺)(〇.〇93克、0.221毫莫耳,可根據實例21 所述的方法之一製成)溶於2_ 丁酮(20毫升)。於20°C時,添 加蚊酸鉀(〇·2〇克、1.45毫莫耳)與氯化丙酮(01〇毫升、125 笔莫耳)。令該反應混合物迴流2小時,冷卻至室溫並濃縮 。溶粗產物於乙酸乙酯,並經丨莫耳濃度氫氯酸洗。濃縮有 機層’並藉急驟層析(矽膠、乙酸乙酯/己烷梯度)純化產物 ’提供99毫克(94%)白色固體之標題化合物。 實例35 (4氣基-冬基)-6-媽福琳-4-基- 5- (ρ塞峻-4-基甲氧基)-苯并 呋喃-3-羧酸甲醯胺之製備 將碳酸鉀(0.200克、1.45毫莫耳)與4-(氯甲基)嘧唑鹽酸鹽 (0.100克、0.588毫莫耳)加入化合物30(a)(0.100克、0.270毫 莫耳’可根據上述實例30、步驟a製成)之2-丁酮(15毫升)溶 液。令該反應迴流加熱16小時,然後冷卻至室溫。濃縮該混 88828.doc -101 - 200418452 口物,並溶殘渣於乙酸乙酯,並經水洗。濃縮有機層,並 藉管柱層析(無水負載於矽膠、乙酸乙酿/己烷梯度,隨之為 1%甲醇/乙酸乙酯)純化產物,提供粗產物。令固體經乙酸 乙酯研製,過滤並於高度真空幫浦乾燥,提供45毫克(36%) 白色固體之標題化合物。 實例3 6 2-(4-氟基-苯基)-5-異丙氧基_6兴甲烷磺醯基_噻唑基甲基 -胺基)-苯并咬喃-3-叛酸甲疏胺之製備 將碳酸鉀(0.050克、0.357毫莫耳)與4-(氯甲基)嘍唑鹽酸 鹽(0.041毫升、0.238毫莫耳)加入2-(4-氟基-苯基)-5-異丙氧 基-6 -甲燒績酸基胺基-苯并咬喃幾酸甲酸胺(0.050克、 0.119毫莫耳,可根據上述實例21所述的方法之一製成)之乙 腈(10毫升)溶液。令該反應迴流1小時,藉TLC無可見之產 物形成,因此將碘化鉀(0.020克、0.120毫莫耳)加入反應物 。令該反應再迴流2小時,然後冷卻至室溫。濃縮反應混合 物,溶殘渣於乙酸乙酯,並經水洗。濃縮產物,並藉急驟 層析(矽膠、乙酸乙酯/己烷梯度)純化,提供30毫克(48%) 白色固體之所需產物。 實例37 氩某)-6-(5-蕤甲基二#哼基)-5-異丙氧基-苯 并咕哺-3 -幾酸甲酸胺之製備_ a·^化合物37U) (2-(4-氟基-苯基>6-甲醯基-5-異丙氧 基-苯并呋喃-3-羧酸乙酯)。 88828.doc -102-88828.doc -98- 200418452 Boron trichloride (1 mol xylene solution, 50 ml, 50 mmol) was added to 2 彳 4-fluoro group dissolved in dichloromethane (30 ml). -Phenyl) -5-isopropoxy-6-morpholin-4-yl · benzobenzo-3-carbamate (0.71 g, 1.7 mmol) Made) solution. The reaction mixture was refluxed for 30 minutes and allowed to cool to room temperature. The reaction mixture was cooled with 1 molar hydrochloric acid (10 ml) and stirred for 1 hour. Remove organic matter from the hair and add a saturated solution of bicarbonate steel until ρΗ = 8-9. The product was extracted with ethyl acetate and purified by column chromatography (anhydrous loading on silica gel, ethyl acetate / hexane gradient) to provide 0.53 g (84%) of the desired product. b. U4-Fluoro-jamo) -544-methylamidino-pyridyl) -6-morpholine-4-even- and the preparation of sulfan-3- # acid formamidine. Potassium carbonate (0.40 g, 2.89 mmol) and 4-methoxybenzyl chloride (0.20 ml, 1.47 mmol) were added to compound 30 (a) (0311 g, 0.84 mmol) ) In acetonitrile (20 ml). The reaction mixture was refluxed for 12 hours, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate and washed with 1 mole hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 296 mg (72%) of the desired product as a white solid. Example 3 1 2- (4-Fluoro-phenyl) -6- [methanesulfonyl- (4-methoxy-benzyl) -amino] _5_ (4-methoxy-benzyloxy)- Preparation of benzofuran-3-carboxylic acid formamidine Potassium carbonate (0.040 g, 0.285 mmol) and 4-methoxyfluorenyl chloride (0.026 ml, 0.190 mmol) are added to compound 29 (a) (0.036 Grams, 0.095 millimoles' can be prepared according to the above Example 29, step a) 2-butanone (10 ml) solution. The reaction was allowed to stir at 20 ° C for 72 hours. The reaction mixture was concentrated, and the crude product 88828.doc -99- 200418452 was dissolved in ethyl acetate and washed with 1 molar hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 34 mg (58%) of the desired product as a white solid. Example 32 Preparation of 5-ethoxy-6- (ethyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl;) _ benzofuran-3-carboxylic acid formamidine will be completed Potassium acid (0.10 g, 0.72 mmol) and ethane iodide (0.10 ml, 125 μmol) were added to compound 29 (a) (0.036 g, 0.095 mmol). Example 29, a solution of 2-butanone (15 ml) made in step (a), and the reaction mixture was stirred at 20 ° C for 72 hours. The reaction mixture was concentrated, and the crude product was dissolved in ethyl acetate and washed with 1 mol hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 25 mg (61%) of the title compound as a white solid. Example 33 Preparation of 2- (4-fluoroyl-phenylmorpholin-4-yl-5-oxethen-2-ylmethoxy) _benzofuran-3-carboxylic acid formamide 2-Chloromethyl-Violent) 〇 Add thionyl chloride (2 ml, 27.4 mmol) to 2-hydroxymethyl ritual (0.15 g, 1.30 mmol) in dichloromethane (2 Ml) solution. The reaction mixture was heated at reflux for 3 seconds, then cooled and stirred at room temperature for 20 minutes. The reaction was concentrated, dried on a high vacuum pump, and used directly in the next step. b. K4-fluorobenzyl) -6-morpholin-4_yl_5 _ (^ Xuan 嘁 -2_ some methoxy and its benzopyridine, _3. Preparation of formamidine sulfonate 〇 carbonic acid Potassium (0.10 g, 0.72 mmol) and 2-chloromethyl ^ xazole (0021 g 88828.doc -100- 200418452, 0.157 mmol) were added to compound 3 (a) ( 0,050 grams, 0135 millimoles, which can be prepared according to the above example 30, step (a)) in acetonitrile (15 ml). The reaction was refluxed for 2 hours, and then heated at 60 ° C for 16 hours. The reaction was cooled And concentrated, the crude product was dissolved in ethyl acetate and washed with hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to give 37 mg (59 %) Desired product as a white solid. Example 34 2 (4-Fluoro-benzyl) -5-isopropoxy-6- [methylbenzene gf group_ (2_oxy-propyl) _amino group ] -Benzobenzo-3-carboxylic acid formamide Preparation of 2- (4-fluoro-phenyl) -5-isopropoxy-6-methanesulfonylamino_benzofuran-3 -Formamidine carboxylate) (0.093 g, 0.221 mmol, made according to one of the methods described in Example 21) dissolved in 2-butanone 20 ml). At 20 ° C, potassium mosquito acid (0.20 g, 1.45 mmol) and acetone chloride (01 ml, 125 pen moles) were added. The reaction mixture was refluxed for 2 hours, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate, and washed with molar hydrochloric acid. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 99 mg (94%) of the title compound as a white solid. Example 35 Preparation of (4-Aroyl-Dongyl) -6-Mafulin-4-yl- 5- (ρoselam-4-ylmethoxy) -benzofuran-3-carboxylic acid formamide Potassium carbonate (0.200 g, 1.45 mmol) and 4- (chloromethyl) pyrazole hydrochloride (0.100 g, 0.588 mmol) can be added to compound 30 (a) (0.100 g, 0.270 mmol). A solution of 2-butanone (15 ml) prepared in the above Example 30, Step a). The reaction was heated at reflux for 16 hours and then cooled to room temperature. The mixture was concentrated to 88828.doc -101-200418452, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and the product was purified by column chromatography (anhydrous loading on silica gel, ethyl acetate / hexane gradient followed by 1% methanol / ethyl acetate) to provide the crude product. The solid was triturated with ethyl acetate, filtered and dried under high vacuum to provide 45 mg (36%) of the title compound as a white solid. Example 3 6 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methanesulfonamido_thiazolylmethyl-amino) -benzoanan-3-methanosamine Preparation: Potassium carbonate (0.050 g, 0.357 mmol) and 4- (chloromethyl) oxazole hydrochloride (0.041 ml, 0.238 mmol) were added to 2- (4-fluoro-phenyl) -5 -Isopropoxy-6-methylalaninoamino-benzoanilic acid carboxylic acid amine (0.050 g, 0.119 millimolar, which can be made according to one of the methods described in Example 21 above) 10 ml) solution. The reaction was refluxed for 1 hour. No visible product was formed by TLC, so potassium iodide (0.020 g, 0.120 mmol) was added to the reaction. The reaction was allowed to reflux for another 2 hours and then cooled to room temperature. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with water. The product was concentrated and purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 30 mg (48%) of the desired product as a white solid. Example 37 Preparation of argon) -6- (5-fluorenylmethyl di # hexyl) -5-isopropoxy-benzocopol-3-amine-carboxylic acid amine_a · ^ Compound 37U) (4-Fluoro-phenyl> 6-methylmethyl-5-isopropoxy-benzofuran-3-carboxylic acid ethyl ester) 88828.doc -102-
將六次甲基四胺(3·07克、21·9毫莫耳)與化合物6(c)(5〇 克、14.6¾莫耳,可根據上述實例步騾c製成)溶於三氟 乙酸(10毫升)。令反應混合物加熱至80°C,直至經TLC顯示 80%反應冗成為止。令反應混合物冷卻至室溫、真空濃縮, 並於乙fei乙酿與水間進行區分。令水層經乙酸乙醋洗,然 後令合併之有機層經鹽液洗,脫水(MgS04)並真空濃縮。藉 管柱層析(矽膠,乙酸乙酯/己烷梯度)純化,提供2.39克 (44%)白色固體之所需產物。 200418452 b·蓋備化i物37(b) (2-(4-氟基-苯基垔亞胺基-甲基) -5-異丙氧基-苯并呋喃-3-羧酸乙酯)。Dissolve hexamethylenetetramine (3.07 g, 21.9 mmol) and compound 6 (c) (50 g, 14.6¾ moles, which can be made according to step 骡 c of the above example) in trifluoro Acetic acid (10 ml). The reaction mixture was heated to 80 ° C until 80% of the reaction was found to be redundant by TLC. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo, and distinguished between ethyl alcohol and water. The aqueous layer was washed with ethyl acetate, then the combined organic layers were washed with saline, dehydrated (MgS04) and concentrated in vacuo. Purification by column chromatography (silica gel, ethyl acetate / hexane gradient) provided 2.39 g (44%) of the desired product as a white solid. 200418452 b. Preparation of compound 37 (b) (2- (4-fluoro-phenylphosphoniumimino-methyl) -5-isopropoxy-benzofuran-3-carboxylic acid ethyl ester) .
將溶於水(10毫升)之醋酸鈉三水合物(0.497克、3.65毫莫 耳)加入化合物37(a)(1.23克、3.32毫莫耳)之乙醇(1〇毫升) 與THF (25毫升)溶液,隨之添加羥基胺鹽酸鹽(0.254克、3.65 毫莫耳)。令反應混合物經熱水浴溫和加熱,然後令其緩慢 冷卻至室溫。真空濃縮反應,並於乙酸乙酯與水間進行區 分。令水相經乙酸乙S旨洗’然後令合併之有機層經鹽液洗 88828.doc -103- 200418452 ,脫水(MgS04)並真空濃縮,提供1·44克(>100%)之所需產 物。該產物不經進一步純化即用於下一步驟。 c.篁備化合物37(cK2-(4-氟基-笨基)-5-異丙氧基-6-[5-(四 氫喊喃_2-基氧基甲基)-異吟唑-3-基]-苯并吱喃-3-叛酸乙酯)。Sodium acetate trihydrate (0.497 g, 3.65 mmol) dissolved in water (10 ml) was added to compound 37 (a) (1.23 g, 3.32 mmol) in ethanol (10 ml) and THF (25 ml). ) Solution, followed by the addition of hydroxylamine hydrochloride (0.254 g, 3.65 mmol). The reaction mixture was heated gently in a hot water bath and then allowed to cool slowly to room temperature. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic layers were washed with salt solution 88828.doc -103- 200418452, dehydrated (MgS04) and concentrated in vacuo to provide 1.44 g (> 100%) of product. This product was used in the next step without further purification. c. Preparation of compound 37 (cK2- (4-fluoro-benzyl) -5-isopropoxy-6- [5- (tetrahydroxan-2-yloxymethyl) -isoindazole- 3-yl] -benzocrean-3-acetic acid ethyl ester).
將化合物37(b)(0.300克、0.778毫莫耳)之氯仿(7毫升)溶液 逐滴加入N-氯琥珀亞醯胺(〇·ι〇4克、0.778毫莫耳)與吡啶(催 化性)之氯仿(3毫升)溶液。令反應混合物加熱至5〇°c達4小 時,然後冷卻至室溫。添加三乙胺(0.219毫升、1.55毫莫耳) ’然後為四氫-2-(2-丙块氧基)-2H-哌喃(0.108毫升、0.778毫 莫耳)。將該反應加熱至70°C,達16小時,冷卻至室溫,經 二氯甲烷稀釋,並以1莫耳濃度11(:1與鹽液洗,脫水(MgS〇4) 並真空濃縮。藉管柱層析(矽膠,乙酸乙酯/己烷梯度)純化 ,提供0.22克(54%)白色固體之所需產物。 d·製備化—金物37(d)(2-(4-氟基-苯基)-6-(5-經甲基-異吟峻 -3-基)-5-異丙氧基-苯并咬喃_3_幾酸乙酯)。A solution of compound 37 (b) (0.300 g, 0.778 mmol) in chloroform (7 ml) was added dropwise to N-chlorosuccinimide (0.44 g, 0.778 mmol) and pyridine (catalytic ) Solution in chloroform (3 ml). The reaction mixture was heated to 50 ° C for 4 hours and then cooled to room temperature. Triethylamine (0.219 ml, 1.55 mmol) was added followed by tetrahydro-2- (2-propoxy) -2H-piran (0.108 ml, 0.778 mmol). The reaction was heated to 70 ° C for 16 hours, cooled to room temperature, diluted with dichloromethane, washed with 1 mol concentration 11 (: 1 and saline solution, dehydrated (MgS04) and concentrated in vacuo. Borrow Purification by column chromatography (silica gel, ethyl acetate / hexane gradient) provided 0.22 g (54%) of the desired product as a white solid. D · Preparation—Gold 37 (d) (2- (4-fluoro- Phenyl) -6- (5- via methyl-isoamycin-3-yl) -5-isopropoxy-benzoanan-3-ethyl hexanoate).
88828.doc 104 > 200418452 將吡啶鹽對-甲苯磺酸酯(7毫克、〇·〇28毫莫耳)加入化合 物27(c)(0.15克、0.28毫莫耳)之乙醇(5毫升)與THF (5毫升) /谷液。於室溫授掉4天後,添加1 /1混合物之乙醇/thf (1 〇毫 升)與額外量之吡啶鹽對-甲苯磺酸酯(7毫克、〇 〇28毫莫耳) 。令反應混合物加熱至5 0 C達3 0分鐘,然後冷卻至室溫, 並真空濃縮。令殘渣於乙酸乙酯與水間進行取分。以乙酸 乙酯洗水相,並以鹽液洗合併之有機層,脫水(MgS〇4)並真 空濃縮,提供0.13克(100%)之所需產物。 e.U待化合物37(e)(2-(4-氟基·苯基)-6-(5-經甲基-異4 口坐 -3-基)-5-異丙氧基-苯并呋喃-3-叛酸)。88828.doc 104 > 200418452 Pyridine salt p-toluenesulfonate (7 mg, 0.028 mmol) was added to compound 27 (c) (0.15 g, 0.28 mmol) in ethanol (5 ml) and THF (5 ml) / cereal. After 4 days of incubation at room temperature, a 1/1 mixture of ethanol / thf (10 mL) and an additional amount of pyridinium p-toluenesulfonate (7 mg, 0.0028 mmol) were added. The reaction mixture was heated to 50 C for 30 minutes, then cooled to room temperature and concentrated in vacuo. The residue was taken between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic layers were washed with brine, dried (MgS04) and concentrated in vacuo to provide 0.13 g (100%) of the desired product. eU Compound 37 (e) (2- (4-fluoro-phenyl) -6- (5-methyl-iso-4-iso-3-yl) -5-isopropoxy-benzofuran- 3-Acid Acid).
將氫氧化卸溶液(4當量濃度,〇·ΐ8毫升、〇·74毫莫耳)加入 化合物37(d)(0.13克、0·29毫莫耳)之乙醇(1毫升)懸浮液。令 反應混合物於室溫攪拌16小時,迴流加熱1/2小時,然後冷 卻至室溫。令混合物經4莫耳濃度HCl(aq)(0.l8毫升、〇.74毫 莫耳)中和,過濾並經乙醇/水(1 /1、2毫升)洗。令該母體液 經乙酸乙酯萃取(2x),經鹽液洗,脫水(MgS〇4)並真空濃縮 。合併二者之殘渣,並經管柱層析(矽膠,99/1乙酸乙酯/ 乙酸)純化,提供0.078克(65%)之所需產物。 f.K4-齓基二苯基)_6-(5•幾^甲基-吳^^坐·3_基)_5_異丙氣基 二苯并峡喃_3酸甲酸胺之掣僻〇 88828.doc -105- 200418452 將4·甲基嗎福啉(23微升、〇·210毫莫耳)、隨之為氯化甲 酸異丁醋(27微升、2毫升之THF溶液、0.210毫莫耳)加入冰 冷之化合物27(e)(0.078克、0.190毫莫耳)之THF (5毫升)溶液 。令▲反應混合物棍掉5分鐘,然後添加甲基胺(2莫耳濃度 之THF溶液、0.19毫升、0.38毫莫耳)。令反應回溫至室溫並 攪拌16小時。令混合物於乙酸乙酯與水間進行區分。令各 層分離,並以乙酸乙酯洗水層(2x)。令合併之有基層經鹽液 洗,脫水(MgS〇4)並真空濃縮。經乙酸乙酯結晶提供1〇毫克 (12%)之標題化合物。 實例38 乙氧基_-2-(4-氟基-苯基)-6-(甲烷磺醯某-甲某-胺某苯并 呋喃-3-羧酸甲醯胺之_備 a.^j贵化合物38(a)(5-(第三-丁基-二甲基·矽烷基氧基)-2_ (4-氟基-苯基)-6-甲燒績酿基胺基-苯并嗅喃_3_叛酸甲酿胺)。A solution of hydroxide (4 equivalents, 0.8 ml, 0.74 mmol) was added to a suspension of compound 37 (d) (0.13 g, 0.29 mmol) in ethanol (1 ml). The reaction mixture was allowed to stir at room temperature for 16 hours, heated at reflux for 1/2 hour, and then cooled to room temperature. The mixture was neutralized with 4 mol HCl (aq) (0.18 ml, 0.74 mol), filtered and washed with ethanol / water (1 / 1,2 ml). The mother liquor was extracted with ethyl acetate (2x), washed with brine, dehydrated (MgS04) and concentrated in vacuo. The two residues were combined and purified by column chromatography (silica gel, 99/1 ethyl acetate / acetic acid) to provide 0.078 g (65%) of the desired product. f.K4-fluorenyldiphenyl) _6- (5 • Ji ^ methyl-Wu ^^ Zi_3_yl) _5_Isopropylamino dibenzoxan_3 acid ammonium formate .doc -105- 200418452 Put 4 · methylmorpholine (23 µl, 0.210 mmol) followed by isobutyl chloroformate (27 µl, 2 ml of THF solution, 0.210 mmol) Ear) Add ice-cold compound 27 (e) (0.078 g, 0.190 mmol) in THF (5 ml). Let the reaction mixture smash for 5 minutes, and then add methylamine (2 Molar THF solution, 0.19 ml, 0.38 mmol). The reaction was warmed to room temperature and stirred for 16 hours. The mixture was allowed to distinguish between ethyl acetate and water. The layers were separated and the aqueous layer was washed with ethyl acetate (2x). The combined base layers were washed with saline, dehydrated (MgS04) and concentrated in vacuo. Crystallization from ethyl acetate provided 10 mg (12%) of the title compound. Example 38 Ethoxy--2- (4-fluoro-phenyl) -6- (methanesulfonium-methyl-amine-amine and benzofuran-3-carboxylic acid formamidine Noble compound 38 (a) (5- (Third-butyl-dimethyl · silyloxy) -2_ (4-fluoro-phenyl) -6-methylpyridylamino-benzoxyl喃 _3_ Methylamine succinate).
令化合物29(a)(6.39克、16.9毫莫耳,可根據上述實例29 、步驟a製成)、咪嗤(5·00克、73.5毫莫耳)與第三丁基二甲 基石夕燒基氯化物(5.00克、33·2毫莫耳)的混合物之乙腈(7〇 t升)溶液攪拌20小時。真2去除溶劑,並溶粗產物於1當 量濃度HC1,並經乙酸乙酯萃取。真空濃縮合併之有機層, 然後藉管柱層析(石夕膠,乙酸乙酉旨)純化,提供7.2〇克(87%) 88828.doc -106- 200418452 白色固體之所需產物。 b.皇^_化合物3_iiM(5-(第三-丁基-二甲基-矽烷基氧基)-2-(4-氟基-苯基)-6-(甲烷磺醯基-甲基-胺基)_苯并呋喃-3-羧酸 甲醯胺)。Let compound 29 (a) (6.39 grams, 16.9 millimoles, which can be prepared according to the above Example 29, step a), imidazole (5.0 grams, 73.5 millimoles), and tertiary butyl dimethyl stone A solution of a mixture of alkyl chloride (5.00 g, 33.2 mmol) in acetonitrile (70 t liter) was stirred for 20 hours. The solvent was removed in true 2 and the crude product was dissolved in 1 equivalent of HC1 and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo and purified by column chromatography (stone gum, ethyl acetate) to provide 7.20 g (87%) 88828.doc -106- 200418452 of the desired product as a white solid. b. Compound ii_ (M (5- (third-butyl-dimethyl-silyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl- Amine) _benzofuran-3-carboxylic acid formamidine).
將化合物38(a)(5.50克、11.2毫莫耳)、碳酸鉀(8.〇克、58 耄莫耳)與碘化甲烷(17克、0.12毫莫耳)之乙腈(12〇毫升)溶 液20 °C攪拌20小時,然後倒入於1當量濃度HC1 (100毫升) 。於真空中去除有機溶劑,並以乙酸乙酯萃取水性殘渣。 於真空中濃縮合併之有機層,並令生成之固體經乙酸乙酯/ 己烷研製,生成5.60克(99%)白色固體之所需產物。 C.M備化合物3 氟*基-苯基)-5-¾基- 6-(甲燒石菱酉藍 基-甲基-胺基)-苯并呋喃-3-羧酸甲醯胺)。A solution of compound 38 (a) (5.50 g, 11.2 mmol), potassium carbonate (8.0 g, 58 μmol) and methane iodide (17 g, 0.12 mmol) in acetonitrile (120 mL) Stir at 20 ° C for 20 hours, then pour into 1 equivalent of HC1 (100 ml). The organic solvent was removed in vacuo, and the aqueous residue was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo and the resulting solid was triturated with ethyl acetate / hexane to give 5.60 g (99%) of the desired product as a white solid. C.M prepared compound 3 fluoro * yl-phenyl) -5-¾yl-6- (methyl pyrone blue-methyl-amino) -benzofuran-3-carboxylic acid formamidine).
令化合物38(b)(7.80克、15.4毫莫耳,可根據前述步驟製 成)之THF (1〇〇毫升)溶液經1莫耳濃度四丁基胺氟化物6 毫升、16毫莫耳)之THF溶液處理。1小時後真空去除溶劑, 並溶粗產物於1當量濃度HC1,並經乙酸乙酯萃取。真空濃 88828.doc -107- 200418452 縮合併之有機層,並令生成土 m ΛζΤζ r ^ 、 上v玍成惑固髌經乙鉍乙酯/己烷研製, 生成5.61克(99%)白色固體之所需產物。 基并呋喃-3jJ兔酸甲醯胺夕〇 令化合物38(C)(0·600克、153毫莫耳)、碳酸卸(〇58克、 4.2毫莫耳)與琪化乙燒(1•⑼克、6.41毫莫耳)之&腈⑽毫升) 溶液迴流攪拌3小時。真空去除溶劑,溶粗產物於丨當量濃 度HC1,並經乙酸乙酯萃取。真空濃縮合併之有機層,並令 生成之固體經絕對乙醇再結晶。濾出沉澱產物並^燥以提 供0.54克(84%)白色固體之標題化合物。 f例3 9A solution of compound 38 (b) (7.80 g, 15.4 millimoles, which can be prepared according to the previous steps) in THF (100 ml) was subjected to 1 mole of tetrabutylamine fluoride, 6 ml, 16 mmol. THF solution. After 1 hour, the solvent was removed in vacuo, and the crude product was dissolved in 1 equivalent of HC1 and extracted with ethyl acetate. Concentrated in vacuum 88828.doc -107- 200418452 The organic layer was condensed, and the resulting soil m ΛζΤζ r ^, was v. Solidified. After trituration with ethyl bismuth ethyl ester / hexane, 5.61 g (99%) of white solid was produced. Desired product. Methylfuran-3jJ formamidine aranate oxidized compound 38 (C) (0.600 g, 153 mmol), carbonic acid (0.58 g, 4.2 mmol), and Qihua acetic acid (1 • The solution was stirred under reflux for 3 hours. The solvent was removed in vacuo and the crude product was dissolved in an equivalent concentration of HC1 and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo and the resulting solid was recrystallized from absolute ethanol. The precipitated product was filtered off and dried to provide 0.54 g (84%) of the title compound as a white solid. fExample 3 9
MliLlzi基二基)-6-(甲;醯基甲某一脍支上3_甲某胺甲 并吱喃_5_基氡甲基1_2_衮甚-苄I之製傭 a.^i^il2X^_(2,2,7_三甲基·苯并[1,3>二崎畊 _4_酮)。 ;κ 方。 39(a) 將4-(二甲基胺基)吡啶(DMAP)(0.40克、3.29毫莫耳)與丙 酮(6_27毫升、85.44毫莫耳)加入4-甲基柳酸(10.0克、65.72 毫莫耳)的1,2-一甲氧基乙燒(DME)(50毫升)溶液。溶亞硫酉盛 氯(6.7毫升、92.01毫莫耳)於DME (5毫升)並緩慢加入反應 混合物。令反應於室溫攪拌36小時。濃縮混合物,並溶粗 產物於乙酸乙酯並以水洗。濃縮有機物,並藉急騾層析(矽 88828.doc -108- 200418452 膠,乙酸乙酯/己烷梯度)純化產物,提供14〇克(11%)黃色 固體之所需產物。 溴甲基-2,2-二甲基-苯并[up二嘮 畊-4-酮)。 H3CyCH3MliLlzi-based diyl) -6- (A; a methyl group, a methyl group, a 3-methylamine amine methyl group and a squeaking _5_yl methyl group 1_2_an even-benzyl I. a. ^ I ^ il2X ^ _ (2,2,7_trimethyl · benzo [1,3 > Nisaki Ken_4_one); κ side. 39 (a) 4- (dimethylamino) pyridine ( DMAP) (0.40 g, 3.29 mmol) and acetone (6_27 ml, 85.44 mmol) with 4-methylsalicylic acid (10.0 g, 65.72 mmol) in 1,2-monomethoxyethoxybenzene DME) (50 ml) solution. Dissolve thionyl chloride (6.7 ml, 92.01 mmol) in DME (5 ml) and slowly add the reaction mixture. Allow the reaction to stir at room temperature for 36 hours. Concentrate the mixture and dissolve the crude The product was washed with ethyl acetate and water. The organics were concentrated and the product was purified by flash chromatography (silica 88828.doc -108- 200418452 gel, ethyl acetate / hexane gradient) to provide 14 g (11%) of a yellow solid. The desired product: bromomethyl-2,2-dimethyl-benzo [up dioxen-4-one). H3CyCH3
將N-溴琥珀亞醯胺(〇·74克、418毫莫耳)與芊醯過氧化物 (0.068克、0.279毫莫耳)加入化合物39(a)(〇67克、3 49毫莫 耳,可根據前述步驟製成)之四氯化碳(15毫升)溶液。令反 應迴/瓦,並以熱燈放射5小時。然後冷卻反應,並濾出固體 。濃縮滤液,溶於乙酸乙酯並以水洗。濃縮有機層,並令 產物經急驟層析(矽膠,乙酸乙酯/己烷梯度)純化,提供175 毫克(19%)白色固體之所需產物。 c.l備化金身J^£^(5_(2,2_二甲基-4-氧基-4H-苯并[ι,3]-二嘮畊-7-基甲氧基)_2_(4_氟基-苯基)_6_(甲烷磺醯基-甲基_ 胺基)-苯并呋喃-3-羧酸甲醯胺)。N-Bromosuccinimide (0.74 g, 418 mmol) and gadolinium peroxide (0.068 g, 0.279 mmol) were added to compound 39 (a) (〇67 g, 3 49 mmol) , Can be made according to the previous steps) carbon tetrachloride (15 ml) solution. The reaction was returned / watt and radiated with a heat lamp for 5 hours. The reaction was then cooled and the solids were filtered off. The filtrate was concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, ethyl acetate / hexane gradient) to provide 175 mg (19%) of the desired product as a white solid. cl 备 化 金身 J ^ £ ^ (5_ (2,2_dimethyl-4-oxy-4H-benzo [ι, 3] -dihydrazone-7-ylmethoxy) _2_ (4_ Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -benzofuran-3-carboxylic acid formamidine).
88828.doc -109- 200418452 將碳酸鉀(0.19克、1·38毫莫耳)與化合物39⑻(〇·25克、 0.917毫莫耳)加入化合物38(d)(〇18克、〇·459毫莫耳,可根 據上逑貫例38步驟d製成)之乙腈(15毫升)溶液。令反應混合 物迴w 4小時,然後真芝丨辰縮。落粗產物於乙酸乙酯並經水 洗。將有機層濃縮成固體,並令其經2〇%乙酸乙酯/己烷研 製,過濾並乾燥,提供240毫克(90%)灰白色固體之所需產 物。 d.izj2-(4-氟基-苯基甲烷磺醯基一甲甚-咹某甲華 苯并呋喃-5-某氧基甲某1_2_羥臬-苄酩夕事備η 將UOH單水合物(0.015克、〇·343毫莫耳)加入化合物 39(c)(0.1〇克、〇·172毫莫耳)之水/THF(1〇毫升/1〇毫升)懸浮 液。令反應於室溫攪拌4小時。藉旋轉蒸發去除thf,並添 加1莫耳濃度HC1,直至達酸性pH。濾出沉澱物並乾燥,提 供65毫克(70%)灰白色固體之標題化合物。 實例40 基-苯基1^(5-衮甲某—I崎唑-3-基VS-甲氧盖-笨并 生喃-3-#酸甲醯胺之製備 a.製備化合物40(>丨〇88828.doc -109- 200418452 Potassium carbonate (0.19 g, 1.38 mmol) and compound 39⑻ (0.25 g, 0.917 mmol) were added to compound 38 (d) (〇18 g, 0.495 mmol) Moore can be prepared according to step 38d) of the above example) in acetonitrile (15 ml). Allow the reaction mixture to return to w for 4 hours, and then shrink back. The crude product was dropped in ethyl acetate and washed with water. The organic layer was concentrated to a solid and triturated with 20% ethyl acetate / hexane, filtered and dried to provide 240 mg (90%) of the desired product as an off-white solid. d.izj2- (4-Fluoro-phenylmethanesulfonyl-monomethyl-pyrene-methylhuabenzobenzofuran-5-oxylmethyl-1_2-hydroxypyrene-benzylacetate) η monohydrate UOH (0.015 g, 0.343 mmol) was added to a suspension of compound 39 (c) (0.10 g, 0.172 mmol) in water / THF (10 ml / 10 ml). The reaction was allowed to proceed in the chamber. Stir gently for 4 hours. Remove thf by rotary evaporation and add 1 mol HC1 until acidic pH is reached. The precipitate is filtered off and dried to provide 65 mg (70%) of the title compound as an off-white solid. Example 40 Methyl-phenyl 1 ^ (5-pyrene-I-zazol-3-yl VS-methoxycap-benzylpyran-3- # acid formamidine a. Preparation of Compound 40 (> 丨 〇
HOHO
ch3 40(a) 令5-羥基-3H-苯并吃喃_2-酮(10·8克、71.9毫莫耳)與 88828.doc -110- 200418452ch3 40 (a) Let 5-hydroxy-3H-benzoxan-2-one (10 · 8 g, 71.9 mmol) and 88828.doc -110- 200418452
Amberlyst®-15 (8·00克)之無水甲醇(25毫升)溶液於22°C攪 拌72小時。蒸發溶劑前,令反應混合物濾過CeliteTM 5〇3片 。令生成之固體經急騾管柱層析(矽膠,2〇 ·· 8〇乙酸乙酯/ 己燒)純化,提供12.84克(98%)白色固體之所需產物。 b.製備化合物〇 iA solution of Amberlyst®-15 (8.0 g) in anhydrous methanol (25 ml) was stirred at 22 ° C for 72 hours. Before evaporating the solvent, the reaction mixture was filtered through CeliteTM 503 pieces. The resulting solid was purified by flash column chromatography (silica gel, 2.00 · 80 ethyl acetate / hexane) to provide 12.84 g (98%) of the desired product as a white solid. b. Preparation of compound
ο 40(b) 將4-氟-苄醯氯(4·20毫升、35.7毫莫耳)之二氯甲烷(1〇毫 升)溶液以15分鐘時間逐滴加入〇。〇之化合物125(a)(3·〇〇克 、16_5毫莫耳)與三乙胺(5.00毫升、35.9毫莫耳)之二氯甲烷 (70耄升)溶液。令反應混合物於22°C攪拌18小時,然後濃縮 ’經1當量濃度HC1 (100¾升)稀釋,並經乙酸乙酉旨萃取。將 有機層濃縮成粗油,令其經急騾管柱層析(矽膠,乙酸乙酉旨 /己烷梯度)純化,提供6.81克(97%)白色固體之所需化合物。 c-ϋ 4匕合物40(c)(3-(4-氟基·爷驢基)-5-幾基- 3H-苯并吱 喃-2 - S同)。40 (b) A solution of 4-fluoro-benzylhydrazone (4.20 ml, 35.7 mmol) in dichloromethane (10 ml) was added dropwise over 15 minutes. A solution of compound 125 (a) (3.0 g, 16-5 mmol) and triethylamine (5.00 ml, 35.9 mmol) in dichloromethane (70 ml). The reaction mixture was allowed to stir at 22 ° C for 18 hours, then concentrated ', diluted with 1 equivalent of HC1 (100¾ liters), and extracted with ethyl acetate. The organic layer was concentrated to a crude oil and purified by flash column chromatography (silica gel, ethyl acetate / hexane gradient) to provide 6.81 g (97%) of the desired compound as a white solid. The c-fluorene 4-dagger compound 40 (c) (3- (4-fluoro group · donkey group) -5-quinyl-3H-benzofuran-2-S is the same).
40(c) 令氫化鋼(9 5%之油溶液’ 0.123克、5.13毫莫耳)懸浮於〇。〇 88828.doc -111 - 200418452 之無水THF (0毫升),並一次添加化合物125(b)(1.05克,2.46 毫莫耳)。令反應混合物於22°C攪拌24小時。經由水小心止 熱後,令反應混合物經乙酸乙酯稀釋,並經1當量濃度HC1 與鹽液萃取,然後濃縮以生成深色油。令該粗油經急驟管 柱層析(矽膠,60%乙酸乙酯/己烷)純化,提供〇·74克(100%) 之所需化合物。 d.製備化合物40(d)(2-(4-氟基-苯某V5-羥基-笨并呋喃-3-羧酸乙酯)。40 (c) Suspend hydrogenated steel (9 5% oil solution '0.123 g, 5.13 mmol) in 0. 88828.doc -111-200418452 anhydrous THF (0 ml), and compound 125 (b) (1.05 g, 2.46 mmol) was added in one portion. The reaction mixture was allowed to stir at 22 ° C for 24 hours. After carefully stopping the heat through water, the reaction mixture was diluted with ethyl acetate, extracted with 1 equivalent of HC1 and saline, and then concentrated to produce a dark oil. This crude oil was purified by flash column chromatography (silica gel, 60% ethyl acetate / hexane) to provide 0.74 g (100%) of the desired compound. d. Preparation of compound 40 (d) (2- (4-fluoro-benzene V5-hydroxy-benzylfuran-3-carboxylic acid ethyl ester).
令化合物40(c)(0.74克,2.46毫莫耳)之無水甲醇(50毫升) 溶液經濃硫酸(0.2毫升)處理,並令混合物迴流加熱25小時 。濃縮反應混合物,並令生成之固體藉急騾管柱層析(矽膠 ,10%乙酸乙酯/己烷)純化,提供0.580克(78%)白色固體之 所需產物。 e.製備化合物40(e)。A solution of compound 40 (c) (0.74 g, 2.46 mmol) in anhydrous methanol (50 ml) was treated with concentrated sulfuric acid (0.2 ml), and the mixture was heated at reflux for 25 hours. The reaction mixture was concentrated and the resulting solid was purified by flash column chromatography (silica gel, 10% ethyl acetate / hexane) to provide 0.580 g (78%) of the desired product as a white solid. e. Preparation of compound 40 (e).
40(e) 該中間體化合物實質上是根據上述實例12、步驟!3之一般 方法製成,然而,以化合物40(d)取代化合物12(a)⑴與 12(a)(ii) ° 88828.doc -112- 200418452 苯并呋喃-3-羧酸乙酯)。40 (e) This intermediate compound is essentially prepared according to the general method of Example 12, step 3 above, however, compound 40 (d) is substituted for compound 12 (a) ⑴ and 12 (a) (ii) ° 88828 .doc -112- 200418452 benzofuran-3-carboxylic acid ethyl ester).
將四氯化鈦99%(15·4毫升、140毫莫耳)加入〇。(:氬氣下之 —氯甲基甲基酸(6.45¾升、71.0毫莫耳)之二氯甲燒 (1〇〇毫升)溶液。添加完成後,將化合物40(e)(2〇 〇克、63·6 *莫耳)之二氯甲烷(75毫升)溶液逐滴加入溶液。添加完成 半小時後,令反應於冰浴中冷卻,並逐滴加水(丨⑻毫升)。 以一氯甲燒稀釋反應至成均質化。令各層分離,並以3莫耳 濃度HC1 (1X100毫升)與鹽液(1χι〇〇毫升)洗有機層,經 MgS〇4脫水’過滤並真空濃縮。溶該殘逢於乙酸乙酯(1升) 與足夠之氯仿’以使所有東西皆成溶液。令該溶液濾過 Florisil®塞子,真空濃縮,並經由乙酸乙酯藉結晶純化,提 供5.90克(27%)之所需化合物。 g.鼓備化合物_4.Q(g)(2-(4-氟基-苯基)-6-(幾亞胺基·甲基) -5-甲氧基-苯并呋喃-3_羧酸乙酯)。99% of titanium tetrachloride (15.4 ml, 140 mmol) was added. (: Chloromethylmethyl acid (6.45 ¾ liter, 71.0 mmol) under argon in dichloromethane (100 ml). After the addition is complete, compound 40 (e) (200) G, 63 · 6 * mol) of dichloromethane (75 ml) was added dropwise to the solution. After the addition was completed for half an hour, the reaction was cooled in an ice bath, and water (丨 ⑻ ml) was added dropwise. Monochloro The reaction was diluted with methylbenzene until it became homogeneous. The layers were separated, and the organic layer was washed with 3 mol HC1 (1 × 100 ml) and saline (1 × 100 ml), dried over MgS04 and filtered and concentrated in vacuo. Residual in ethyl acetate (1 liter) and enough chloroform to make everything into a solution. The solution was filtered through a Florisil® stopper, concentrated in vacuo, and purified by crystallization from ethyl acetate to provide 5.90 g (27%) The required compound is g. Prepare compound_4.Q (g) (2- (4-fluoro-phenyl) -6- (guidoiminomethyl) -5-methoxy-benzo Furan-3_carboxylic acid ethyl ester).
將酷酸鋼三水合物(1.44克、10.6毫莫耳)之水(2〇毫升)溶 88828.doc -113 - 200418452 液,然後為羥基胺鹽酸鹽(0.73克、10·6毫莫耳)加入將化合 物40(f)(3.29克、9.61毫莫耳)之THF (200毫升)懸浮液。;[小 時後,真空濃縮反應,並將殘渣懸浮於水中。過漉固體以 生成3.20克(93%)之所需產物。該產物不經進一步純化直接 進行下一步騾。 h.製備化合物40(h) (2-(4·氣基-冬基)-5 -甲氧基-6- [5-(四氫 -旅喃-2-基氧基甲基)-異噚唑-3-基]-苯并吱喃-3-叛酸乙酯)。Water (20 ml) of cool acid steel trihydrate (1.44 g, 10.6 mmol) was dissolved in 88828.doc -113-200418452, and then hydroxylamine hydrochloride (0.73 g, 10.6 mmol) ) A suspension of compound 40 (f) (3.29 g, 9.61 mmol) in THF (200 ml) was added. [After an hour, the reaction was concentrated in vacuo and the residue was suspended in water. The solid was filtered over to give 3.20 g (93%) of the desired product. The product was carried on to the next step without further purification. h. Preparation of compound 40 (h) (2- (4 · Gas-D Winteryl) -5 -methoxy-6- [5- (tetrahydro-bran-2-yloxymethyl) -isoamidine Ethazol-3-yl] -benzocran-3-acrylic acid ethyl ester).
將化合物40(g)(3.20克、8·95毫莫耳)之;DMF (120毫升)溶 液逐滴加入Ν-氯琥珀亞醯胺(1· 19克、8·95毫莫耳)與吡啶(催 化量)之DMF (60毫升)溶液。令反應混合物加熱至6〇它達2〇 小時’在此時將額外量之N-氯琥靖亞酸胺(q.238克、1 79毫 莫耳)加入反應中。化合物40(b)消耗完後(藉TLC偵測),令 反應冷卻至室溫。添加三乙胺(1 · 2 6毫升、8 · 9 5毫莫耳),隨 之為四氫-2-(2-丙炔氧基)-2H-哌喃(2.51毫升、17.9毫莫耳) 。令反應加熱至60°C達2小時,冷卻至室溫,並經乙酸乙酯 萃取(2 X 100¾升)。令合併之有機層經冰水(數次)與鹽液洗 ,脫水(MgSCU)並真空濃縮。藉管柱層析(矽膠,乙酸乙酯/ 己烷梯度)純化,提供2·05克(46%)白色固體之所需產物。 i.l盤牝合盤^1(2-(4-氟基-苯基)_5•甲氧基_6_[5_(四氫_ 88828.doc -114- 200418452 峰喃-2-基氧基甲基)-異崎咬-3-基]-苯并吱喃-3-叛酸)。A solution of compound 40 (g) (3.20 g, 8.95 mmol); DMF (120 ml) was added dropwise to N-chlorosuccinimide (1.19 g, 8.95 mmol) and pyridine (Catalytic amount) in DMF (60 ml). The reaction mixture was heated to 60 to 20 hours' at which time an additional amount of N-chlorosuccinimide (q.238 g, 179 mmol) was added to the reaction. After the consumption of compound 40 (b) (detected by TLC), the reaction was allowed to cool to room temperature. Add triethylamine (1.26 ml, 8.95 mmol) followed by tetrahydro-2- (2-propynyloxy) -2H-piran (2.51 ml, 17.9 mmol) . The reaction was heated to 60 ° C for 2 hours, cooled to room temperature, and extracted with ethyl acetate (2 X 100 ¾ liters). The combined organic layers were washed with ice water (several times) and saline, dehydrated (MgSCU) and concentrated in vacuo. Purification by column chromatography (silica gel, ethyl acetate / hexane gradient) provided 2.05 g (46%) of the desired product as a white solid. il plate coupling plate ^ 1 (2- (4-fluoro-phenyl) _5 • methoxy_6_ [5_ (tetrahydro_ 88828.doc -114- 200418452 peak ran-2-yloxymethyl) -Isaki-3-yl] -benzofuran-3-acid).
將氫氧化鉀溶液(4當量濃度,1.34毫升、5.35毫莫耳)加 入化合物40(h)(1.06克、2.14毫莫耳)之乙醇(1〇毫升)懸浮液 。令反應混合物迴流加熱2小時,然後,冷卻至室溫。令反 應混合物經4莫耳濃度HCl(aq)(1.34毫升、5.35毫莫耳),過濾 、風乾並真空乾燥,提供0.95克(95%)之所需產物。 J· ·製備化合物40(1)( 2-(4 -氟基-苯基)·5 -甲氧基_6-[5-(四氮_ I喃-2-基氧基甲基)-異4唑-3-基]-苯并吱喃-3-叛酸甲醯胺)。A potassium hydroxide solution (4 equivalents, 1.34 ml, 5.35 mmol) was added to a suspension of compound 40 (h) (1.06 g, 2.14 mmol) in ethanol (10 ml). The reaction mixture was heated at reflux for 2 hours and then cooled to room temperature. The reaction mixture was passed through 4 mol HCl (aq) (1.34 ml, 5.35 mmol), filtered, air-dried and dried under vacuum to provide 0.95 g (95%) of the desired product. J ·· Preparation of compound 40 (1) (2- (4-Fluoro-phenyl) · 5-methoxy-6- [5- (tetrazol-Iran-2-yloxymethyl) -iso 4azol-3-yl] -benzocrean-3-methanoate (formamide).
將羰基二咪唑(0.401克、2·47毫莫耳)加入化合物4〇⑴ (0.958克、2.06¾吴耳)之一鼠甲坑懸浮液。令生成之溶液於 室溫攪拌1小時。添加N-甲基胺(2.0莫耳濃度之thf溶液, 1.55毫升、3.09毫莫耳),並允許反應於室溫攪拌2〇小時。 然後,令混合物迴流加熱1小時,冷卻至室溫並於水與二氯 甲烷間進行區分。令水層經乙酸乙酯洗,並令合併之有機 88828.doc -115- 200418452 層經鹽液洗,脫水(MgSCU)、過濾並真空濃縮。藉管柱層析 (石夕膠’乙酸乙酯/己烷梯度)純化,提供〇46克(46%)之所需 產物。 k.(U4-基-笨基)-6-(5-羚甲某-異4基)-5-甲氣基-苯差呋喃-3-#酸甲醯胺之製備〇 將咐啶鹽對·甲苯磺酸酯(7毫克、0.028毫莫耳)加入化合 物40(e)(0.135克、0.281毫莫耳)之乙醇(1〇毫升)、thf (3毫 升)與水之溶液。令反應混合物於室溫攪拌2〇小時。然後, 將反應混合物加熱至9 5 C達4小時,冷卻至室溫並真空濃縮 。令殘渣於乙酸乙酯與水間進行取分。以鹽液洗有機層, 脫水(MgSCU)並真空濃縮。藉管柱層析(石夕膠,乙酸乙酯/己 火元梯度)純化並由乙乙g旨結晶’提供5 〇毫克(4 5 %)之標題 化合物。 實例41 2-(4 -氟基-苯基)-6-[4-(2-經基-乙基)·異π号峻_3_基]-5 -甲氧基 -苯并呋喃-3-羧酸甲醯胺之製備 a·盤備化合物41 (a) (2-(4-氟基·苯基)-5 -甲氧基_6-(3a,4,5,6a_ 四氫-呋喃[3,2-d]-異噚唑-3-基苯并呋喃_3_羧酸乙酯)。Carbonyldiimidazole (0.401 g, 2.47 mmol) was added to one of the compounds 40 g (0.958 g, 2.06 ¾ ng) of rat pit suspension. The resulting solution was allowed to stir at room temperature for 1 hour. N-methylamine (2.0 moles of thf solution, 1.55 ml, 3.09 mmol) was added and the reaction was allowed to stir at room temperature for 20 hours. The mixture was then heated at reflux for 1 hour, cooled to room temperature, and distinguished between water and dichloromethane. The aqueous layer was washed with ethyl acetate, and the combined organic 88828.doc -115- 200418452 layers were washed with saline, dehydrated (MgSCU), filtered, and concentrated in vacuo. Purification by column chromatography (stone gum 'ethyl acetate / hexane gradient) provided 046 g (46%) of the desired product. k. Preparation of (U4-yl-benzyl) -6- (5-antenuolinyl-iso4-yl) -5-methylamino-phenylchafuran-3- # formamidine. -Tosylate (7 mg, 0.028 mmol) was added to a solution of compound 40 (e) (0.135 g, 0.281 mmol) in ethanol (10 ml), thf (3 ml) and water. The reaction mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was then heated to 95 C for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was taken between ethyl acetate and water. The organic layer was washed with saline, dehydrated (MgSCU) and concentrated in vacuo. Purified by column chromatography (Shijiao, ethyl acetate / hexane flame gradient) and crystallized from ethyl acetate to provide 50 mg (45%) of the title compound. Example 41 2- (4-Fluoro-phenyl) -6- [4- (2-Cyclo-ethyl) · iso-π-Jun_3_yl] -5 -methoxy-benzofuran-3 -Preparation of Formamidine Carboxylic Acid a · Compound 41 (a) (2- (4-Fluoro · phenyl) -5 -methoxy-6- (3a, 4,5,6a_ tetrahydro-furan [3,2-d] -isoxazol-3-ylbenzofuran-3-carboxylic acid ethyl ester).
將N-氯琥珀亞醯胺(0.747克、5.59毫莫耳)與吡淀(催化性) 加入化合物40(8)(2.00克、5.59毫莫耳,可根據上述實例4〇 88828.doc -116- 200418452 、步騾g製成)之DMF (100毫升)溶液。令反應混合物加熱至 60°C達20小時。添加三乙胺(〇·78毫升、5.59毫莫耳),然後 為2,3-二氫呋喃(0.85毫升、11.2毫莫耳)。將該反應加熱至 60°C ’達1小時’冷卻至室溫,以水稀釋至5〇〇毫升,並經 乙酸乙酯(3X75毫升)萃取。令合併之有機層經冰水洗數次 ’鹽液洗一次’然後脫水(MgS04)並真空濃縮,提供2.27克 (95%)之所需產物。 bUf 化舍物 41(b)(2_(4-氟基-苯基)-5-甲氧基-6-(3a,4,5,6a-四氫-咬喃[3,2_d]_異4唑_3_基)-苯并嗅喃叛酸)。Add N-chlorosuccinimide (0.747 g, 5.59 mmol) and pyridine (catalytic) to compound 40 (8) (2.00 g, 5.59 mmol), according to the above example 4888828.doc -116 -200418452 (made by Buzhig) in DMF (100ml) solution. The reaction mixture was heated to 60 ° C for 20 hours. Triethylamine (0.78 ml, 5.59 mmol) was added followed by 2,3-dihydrofuran (0.85 ml, 11.2 mmol). The reaction was heated to 60 ° C 'for 1 hour', cooled to room temperature, diluted with water to 500 ml, and extracted with ethyl acetate (3 x 75 ml). The combined organic layers were washed with ice water several times, 'salt solution once', then dehydrated (MgS04) and concentrated in vacuo to provide 2.27 g (95%) of the desired product. bUf chemical 41 (b) (2_ (4-fluoro-phenyl) -5-methoxy-6- (3a, 4,5,6a-tetrahydro-octane [3,2_d] _iso4 Azole_3_yl) -benzoxanthene).
將氫氧化鉀溶液(4當量濃度,〇·73毫升、2.93毫莫耳)加 入化合物41(a)(0.500克、1.17毫莫耳)之乙醇(7毫升)與水(2 耄升)之懸浮液。令反應混合物迴流加熱1 · 5小時,然後,冷 卻至室溫。令反應混合物經4莫耳濃度HC1(aq)(〇73毫升、2·93 毫莫耳)中和,過濾、風乾並真空乾燥,提供〇·502克(定量 的)之所需產物,其不經進一步純化即進行至下一步騾。 氟基苯基)_5_ 甲氧基 _6_(3a,4,5,6a_ 四氩-吱喃[3,2-d]-兴4 °坐-3-基)-苯并吱喃_3_叛酸曱酿胺)。A potassium hydroxide solution (4 equivalents, 0.73 ml, 2.93 mmol) was added to a suspension of compound 41 (a) (0.500 g, 1.17 mmol) in ethanol (7 ml) and water (2 ml). liquid. The reaction mixture was heated at reflux for 1.5 hours, and then cooled to room temperature. The reaction mixture was neutralized with 4 mol HC1 (aq) (〇73 ml, 2.93 mmol), filtered, air-dried and vacuum-dried to provide 0.52 g (quantitative) of the desired product. Proceed to the next step after further purification. Fluorophenyl) _5_methoxy_6_ (3a, 4,5,6a_ tetraargon-squeeze [3,2-d] -Xing 4 ° sit-3-yl) -benzocryso_3_bet Acid amines).
88828.doc -117- 200418452 將談基二咪唑(0.20克、1·27毫莫耳)加入化合物41(b)(0.42 克、1.05毫莫耳)之二氯甲烷懸浮液。令生成之溶液於室溫 攪拌2小時。添加仏甲基胺(2·〇莫耳濃度之thf溶液,0.79 t升、1 · 5 8毫莫耳),並令混合物迴流加熱3小時,冷卻至室 溫並於水與乙酸乙酿間進行區分。令水層經乙酸乙酿洗, 並令合併之有機層經鹽液洗,脫水(MgSCU)、過漉並真空濃 縮。藉管柱層析(矽膠,乙酸乙酯/己烷梯度)純化產物,提 供0.30克(70%)之所需產物。 d.(2-(4-氟基-笨某V6-「4-(2-羥基-乙某V晨基1-5· 1氧基-苯并呋喃-3-淼酸甲醯胺之製備。 令化合物41(c)(0.160克,0.38毫莫耳)懸浮於乙醇〇5毫升) 與濃HC1 (3滴)。令反應迴流加熱50小時,冷卻至室溫,並 於乙酸乙酯與水間進行區分。令各層分離,並以鹽液洗有 機層,脫水(MgSCU)、過濾並真空濃縮。藉管柱層析(碎膠 ,乙酸乙酯/己烷梯度)純化,並經乙酸乙酯結晶以提供5〇 毫克(31%)之標題化合物。 實例42 2-(4-氟基-苯基)-6-[(2-藉基-乙基)-甲燒續醯基_胺美]$甲 氧基-苯并呋喃-3-羧酸甲醯胺之製備 a ·製備化合物-氟基-苯基)-5 -#呈基硝芙苯并 呋喃-3-羧酸乙酯)。88828.doc -117- 200418452 Tandiimidazole (0.20 g, 1.27 mmol) was added to a dichloromethane suspension of compound 41 (b) (0.42 g, 1.05 mmol). The resulting solution was allowed to stir at room temperature for 2 hours. Add methylamine (thf solution at 2.0 mol concentration, 0.79 t liter, 1.58 mol), and heat the mixture at reflux for 3 hours, cool to room temperature and perform in water and ethyl acetate distinguish. The aqueous layer was washed with ethyl acetate, and the combined organic layers were washed with saline, dehydrated (MgSCU), filtered, and concentrated in vacuo. The product was purified by column chromatography (silica gel, ethyl acetate / hexane gradient) to provide 0.30 g (70%) of the desired product. d. Preparation of (2- (4-fluoro-benzyl-V6- "4- (2-hydroxy-ethmyl-vinyl-1-5- 1oxy-benzofuran-3-maurate). Compound 41 (c) (0.160 g, 0.38 mmol) was suspended in 0.05 ml of ethanol) and concentrated HC1 (3 drops). The reaction was heated at reflux for 50 hours, cooled to room temperature, and between ethyl acetate and water. Differentiate. Separate the layers, wash the organic layer with brine, dehydrate (MgSCU), filter, and concentrate in vacuo. Purify by column chromatography (crumb, ethyl acetate / hexane gradient), and crystallize from ethyl acetate To provide 50 mg (31%) of the title compound. Example 42 2- (4-Fluoro-phenyl) -6-[(2-Beryl-ethyl) -methylarsino-amido] amine Preparation of methoxy-benzofuran-3-carboxylic acid formamidine a-Preparation of compound -fluoro-phenyl) -5-#-nitrophenylfurfuryl-3-carboxylic acid ethyl ester).
88828.doc -118- 200418452 將三氯化硼(106毫升、0.106莫耳)逐滴加入化合物21⑷ ⑵)·5克、〇.053莫耳,可根據上述實例21步驟^製成)加入 $氣下之無水二氣甲烷(264毫升)溶液。令反應混合物於室 溫攪拌隔夜。令反應經冰水止熱並經三氯甲即χ)萃取。合 併有機層,經硫酸鎂脫水,過濾並蒸發。令生成之固體於 己k中起首波震盈,過濾並乾燥,提供17 82克(99%)黃色固 體之產物。 b.l備化合物42(b)(2-(4-氟基-苯基)-5-甲氧基-6-硝基-苯 并吱喃-3-羧酸乙酯)。88828.doc -118- 200418452 Boron trichloride (106 ml, 0.106 mole) is added dropwise to the compound 21⑷ ⑵) · 5g, 0.053 mole, which can be prepared according to the procedure of the above example 21) A solution of anhydrous digas methane (264 ml). The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched with ice water and extracted with chloroform (x). The organic layers were combined, dehydrated over magnesium sulfate, filtered and evaporated. The resulting solid was shaken in the first wave, filtered and dried to provide 17 82 g (99%) of the product as a yellow solid. b.l Prepare compound 42 (b) (2- (4-fluoro-phenyl) -5-methoxy-6-nitro-benzo-3-ancarboxylic acid ethyl ester).
將碳酸铯(33.04克、0.101莫耳)與碘化甲烷(31.6毫升、 0.507莫耳)加入化合物42(a)(l 7.5克、0.053莫耳)之1_甲基-2-吡咯啶酮(250毫升)溶液。令反應混合物於50°C加熱隔夜, 以水止熱,經乙酸乙酯(3 X)萃取,並濾除一部分之不溶產 物。合併有機層,脫水(MgS04)、並濃縮。將生成之固體與 先前分離之固體合併,提供14.91克(82%)黃色固體之產物。 c.製備化合物42(c)(6-胺基-2-(4 -氟基-豕基)-5 -甲氧基-笨 并吱喃-3·叛酸乙酯)。Add cesium carbonate (33.04 g, 0.101 mole) and methyl iodide (31.6 ml, 0.507 mole) to 1-methyl-2-pyrrolidone (42 (a) (l 7.5 g, 0.053 mole)) 250 ml) solution. The reaction mixture was heated at 50 ° C overnight, quenched with water, extracted with ethyl acetate (3X), and a portion of the insoluble product was filtered off. The organic layers were combined, dehydrated (MgS04), and concentrated. The resulting solid was combined with the previously isolated solid to provide 14.91 g (82%) of the product as a yellow solid. c. Preparation of compound 42 (c) (6-amino-2- (4-fluoro-fluorenyl) -5 -methoxy-benzyl-3 -ethyl methanoate).
88828.doc 119- 200418452 將 10% Pd/C (0.900 克)加入化合物 42(b)(7.0 克、0.0195 莫 耳)之乙酸異丙酯(32.0毫升)混合物。令反應混合物於5〇 psig氫氣之Parr振藍器振盪隔夜。令反應混合物滤過CeliteTM ,經乙酸乙酯與甲醇潤濕。真空濃縮濾液。使用相同量之 溶劑反應物重覆此反應,並合併二者反應之產物,提供總 量12.8克(99%)固體之所需產物。 d.製備化合物42(dV2-r4-氟基-苯基)-6-甲烷磺醯基胺基 -5-甲氧基-苯并呋喃-3-羧酸乙酯)。88828.doc 119-200418452 10% Pd / C (0.900 g) was added to a mixture of compound 42 (b) (7.0 g, 0.0195 mol) in isopropyl acetate (32.0 ml). The reaction mixture was shaken overnight in a Parr blue shaker with 50 psig of hydrogen. The reaction mixture was filtered through CeliteTM and wet with ethyl acetate and methanol. The filtrate was concentrated in vacuo. This reaction was repeated using the same amount of solvent reactant and the products of the two reactions were combined to provide the desired product in a total amount of 12.8 g (99%) solids. d. Preparation of compound 42 (dV2-r4-fluoro-phenyl) -6-methanesulfonamido-5-methoxy-benzofuran-3-carboxylic acid ethyl ester).
CH3 42(d) 將甲燒磺醯氯(0.64毫升、85.6毫莫耳)加入化合物42(c) (12.8克’ 12.8毫莫耳)之無水二氯甲烷(13〇毫升)的冰(〇。〇冰 /水浴)溶液。然後,利用乙醇/冰浴冷卻反應混合物,並添 加N,N-二異丙基乙胺(16·93毫升,97·2毫莫耳)。令反應混合 物於室溫揽拌隔夜。令反應混合物經水稀釋,並以二氯甲 烷(3 X )萃取。合併有機層,經硫酸鎂脫水、並蒸發以提供 18·7克(99%)固體之所需產物。 氟基-苯基;甲烷磺醯基胺基_5_ 甲氧基•苯并吱喃_3_叛酸)。CH3 42 (d) Toluenesulfonyl chloride (0.64 ml, 85.6 mmol) was added to compound 42 (c) (12.8 g '12.8 mmol) in anhydrous dichloromethane (130 ml) on ice (0). 〇 ice / water bath) solution. Then, the reaction mixture was cooled in an ethanol / ice bath, and N, N-diisopropylethylamine (16.93 ml, 97.2 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3X). The organic layers were combined, dehydrated over magnesium sulfate, and evaporated to provide 18.7 g (99%) of the desired product as a solid. Fluoro-phenyl; methanesulfonylamino_5_methoxy • benzocrean_3_metanoic acid).
CH, 88828.doc 120- 200418452 將氫氧化鉀(51·5克、0.918毫莫耳)加入氬氣下之化合物 42(d)(18.7克、0.0459莫耳)之乙醇(2〇〇毫升)與水(1〇〇毫升) 之混合物。令反應混合物迴流加熱約7小時,然後,於室溫 攪拌隔夜。濃縮反應混合物,並溶殘澳於水。令水之混合 物經6當量濃度HC1酸化直至形成固體沉澱。過滤產物,經 水洗並乾燥,提供15.0克(86%)褐色固體之所需產物。 f·监備化合物4_21£)(2-(4-氟基-苯基)-6-甲燒績S盛基胺基-5-甲氧基苯并呋喃-3-羧酸甲醯胺)。CH, 88828.doc 120-200418452 Potassium hydroxide (51.5 g, 0.918 mmol) was added to compound 42 (d) (18.7 g, 0.0459 mole) in ethanol (200 ml) under argon and A mixture of water (100 ml). The reaction mixture was heated at reflux for about 7 hours, and then stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in water. The water mixture was acidified with 6 equivalents of HC1 until a solid precipitate formed. The product was filtered, washed with water and dried to provide 15.0 g (86%) of the desired product as a brown solid. f · Preparation of compound 4-21 £) (2- (4-fluoro-phenyl) -6-methylsulfonylamino-5-methoxybenzofuran-3-carboxylic acid formamidine).
將1,1-羰基二咪唑(8.66克、53.3莫耳),隨之為甲胺(2.0 莫耳濃度之THF溶液,30.0毫升、59·3毫莫耳)加入氬氣下之 化合物42(e)(15克、39.5毫莫耳)之二氯甲烷(155毫升)懸浮 液。令該反應混合物於室溫攪拌隔夜,以水稀釋,經二氯 甲烷萃取(3χ),並濾除一部分之不溶產物並旁置。合併有機 層’經硫酸鎂脫水並濃縮。令生成之固體於水中經超音波 震盪,過漉並與先前分離之產物合併以提供總量14 42克 (92%)之所需產物。 g.C2z.(4-氟基-苯基.,乙基甲烷碏醯某-胺篡1 甲乳基_苯_止咳逾g蠢胺之製備〇 將碘化钾(80毫克、0.48毫莫耳)、碳酸鉀(2.82克、2〇.4毫 莫耳)與二溴化乙醇(3.62毫升、51毫莫耳)加入氬氣下之溶 88828.doc -121 - 200418452 於典水DMF(100^:升)之化合物42(f)(4.0克、1〇·2毫莫耳)溶 液。令混合物加熱至50°C達7小時,然後添加額外量之碘化 鉀(80毫克、0.48毫莫耳)與2-溴化乙醇(1.81毫升、25·5毫莫 耳)。令混合物於50°C攪拌隔夜,然後添加額外量之碳酸鉀 (19 · 7 3克)。令反應混合物於8 5 °C攪拌約4小時,以水稀釋並 t乙乙酉曰萃取(3X)。合併有機層並蒸發。令剩餘之固體經 水稀釋,超晋波震盪並過濾。以水洗數次後,乾燥固體以 提供3.14克粗產物’其後續由熱乙醇結晶。 f例43 5-環丙基_2-(4-氟基-苯基)_6_[(2-羥基_乙基)_甲烷磺醯基_胺 基l·苯并呋喃-3-羧酸甲醯胺之製備 a.環丙基_酸之製備。 環丙基_酸係根據文獻之方法:Wallace,D. j.,Chen,c.,Add 1,1-carbonyldiimidazole (8.66 g, 53.3 mol) followed by methylamine (a 2.0 mol THF solution, 30.0 ml, 59.3 mmol) to compound 42 (e ) (15 g, 39.5 mmol) in dichloromethane (155 ml). The reaction mixture was allowed to stir at room temperature overnight, diluted with water, extracted with dichloromethane (3x), and a portion of the insoluble product was filtered off and set aside. The combined organic layers were dehydrated over magnesium sulfate and concentrated. The resulting solids were sonicated in water, subjected to sonication, and combined with previously separated products to provide a total of 14 42 g (92%) of the desired product. g. C2z. (4-fluoro-phenyl., ethylmethane, amine-amine 1) Preparation of methylalanyl-benzene-cough amine, g. potassium iodide (80 mg, 0.48 mmol), Potassium carbonate (2.82 g, 20.4 mmol) and dibromoethanol (3.62 ml, 51 mmol) were dissolved under argon gas 88828.doc -121-200418452 in DMF (100 ^: liter) ) Solution of compound 42 (f) (4.0 g, 10.2 mmol). Heat the mixture to 50 ° C for 7 hours, then add additional amounts of potassium iodide (80 mg, 0.48 mmol) and 2- Ethanol bromide (1.81 ml, 25.5 mmol). Stir the mixture at 50 ° C overnight, then add additional amount of potassium carbonate (19.73 g). Stir the reaction mixture at 8 5 ° C for about 4 Hours, diluted with water and extracted with ethyl acetate (3X). The organic layers were combined and evaporated. The remaining solids were diluted with water, shaken and filtered. After washing several times with water, the solids were dried to provide 3.14 g of crude product. 'It was subsequently crystallized from hot ethanol. FExample 43 5-Cyclopropyl_2- (4-fluoro-phenyl) _6 _ [(2-hydroxy_ethyl) _methanesulfonyl_amino group l · benzo Methylfuran-3-carboxylic acid Preparation of a-cyclopropyl acid _ _ cyclopropyl acid-based process according to the literature:.... Wallace, D j, Chen, c,.
Tetrahedron Lett· 2002, 43, 6987_6990,以 4克之規模由溴化 環丙基鎂製成。 b·製備n...物4KU(2-(4-氟基-苯基)-6_硝基_5_三氟甲烷 績驗氧基-苯并吱喃-3-幾酸乙酉旨)。Tetrahedron Lett. 2002, 43, 6987-6990, made of cyclopropylmagnesium bromide on a 4 g scale. b. Preparation of 4 ... (2- (4-fluoro-phenyl) -6_nitro_5_trifluoromethane (tested with oxy-benzo-3-an-2-acetic acid)).
43(b) 將n,n-二異丙基乙胺(8.8毫升、56毫莫耳)與4_(二甲基胺 基)吡啶(0.618克、5.06毫莫耳)加入氬氣下之化合物42(a) (17.5克、50.6毫莫耳,可根據上述實例42、步驟&製成)之無 88828.doc -122- 200418452 水二氯甲燒(毫升)溶液。令反應混合物於冰/水浴冷卻至 o°c,然後添加三氟甲烷磺酸酐(9·34毫升、%毫莫耳)。人 反應於Α溫攪掉約5小時,然後添加額外量之ν.二異丙芙 乙胺(4.4毫升、28毫莫耳)與三氟甲烷磺酸酐(4·67毫升、μ 毫莫耳)。令反應於室溫攪拌隔夜,以水稀釋,並經二氯甲 烷(3χ)萃取。令有機層經水㈠“與丨當量濃度1^〇 οχ)洗,合 併、經硫酸鎂脫水並蒸發。令殘渣經第三丁基甲基醚再結 晶,提供總量20.36克(84%)黃色固體之所需產物。 環丙基-2-(4-氟基_苯基)_6_硝基-苯 并呋喃-3-羧酸乙酯)。43 (b) Add n, n-diisopropylethylamine (8.8 ml, 56 mmol) and 4- (dimethylamino) pyridine (0.618 g, 5.06 mmol) to compound 42 under argon (a) (17.5 grams, 50.6 millimoles, which can be made according to the above Example 42, steps &) Wu 88882.doc -122- 200418452 solution in methylene chloride (ml). The reaction mixture was allowed to cool to 0 ° C in an ice / water bath, and then trifluoromethanesulfonic anhydride (9.34 ml,% mmol) was added. The human reaction was stirred at A temperature for about 5 hours, and then additional amounts of ν. Diisopropylethylamine (4.4 ml, 28 mmol) and trifluoromethanesulfonic anhydride (4.67 ml, μ mmol) were added. . The reaction was allowed to stir at room temperature overnight, diluted with water, and extracted with dichloromethane (3x). The organic layer was washed with water and "equivalent concentration 1 ^ 〇οχ), combined, dehydrated with magnesium sulfate and evaporated. The residue was recrystallized from tert-butyl methyl ether to provide a total of 20.36 g (84%) of a yellow solid. Desired product: cyclopropyl-2- (4-fluoroyl-phenyl) -6-nitro-benzofuran-3-carboxylic acid ethyl ester).
將無水甲苯(10·0毫升)加入環丙基g朋酸(0·271克、314毫 莫耳)、氟化鉀二水合物(0.652克、6·92毫莫耳)、溴化鈉(0.216 克、2.16毫莫耳)、肆(三苯膦)鈀(0)(0·073克、〇〇629毫莫耳) 與化合物43(b)(1.0克、2.09毫莫耳)之混合物。令生成之溶 液經氣體分散管藉由氬氣脫氣1 〇分鐘。令反應混合物迴流 加熱隔夜,以水稀釋並經乙酸乙酯(3x)萃取。合併有機層, 經硫酸鎂脫水並蒸發。令粗產物藉管柱層析(矽膠,無水負 載,己烷/乙酸乙酯梯度)純化,以提供0.670克固體之 所需產物。 d.製備ϋ物43(d)(6-胺基-5-環丙基-2-(4 -氟基-苯基)_苯 88828.doc -123- 200418452 并呋喃-3-羧酸乙酯)。Anhydrous toluene (10.0 ml) was added to cyclopropylgopenic acid (0.271 g, 314 mmol), potassium fluoride dihydrate (0.652 g, 6.92 mmol), and sodium bromide ( A mixture of 0.216 g, 2.16 mmoles, palladium (triphenylphosphine) palladium (0) (0.073 g, 0.00629 mmoles) and compound 43 (b) (1.0 g, 2.09 mmoles). The resulting solution was degassed through a gas dispersion tube with argon for 10 minutes. The reaction mixture was refluxed and heated overnight, diluted with water and extracted with ethyl acetate (3x). The organic layers were combined, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, anhydrous load, hexane / ethyl acetate gradient) to provide 0.670 g of the desired product as a solid. d. Preparation of phosphonium 43 (d) (6-amino-5-cyclopropyl-2- (4-fluoro-phenyl) _benzene 88828.doc -123- 200418452 ethyl benzofuran-3-carboxylic acid ).
將10% Pd/C (0.150克)與1當量濃度HC1 (7滴)加入化合物 43(c)(0.665克、1.8毫莫耳)之乙酸乙酯(70.〇毫升)溶液。令 反應混合物於50 psig氫氣之Parr振盪器振盪隔夜。令反應混 合物濾過CeliteTM,經乙酸乙酯與甲醇潤濕。真空濃縮滤液 ,提供0.540克(88%)固體之所需產物。 ei備化舍物43(e)(5-環丙基-2-(4-氟基-苯基)_6-甲烷磺 睡基胺基-苯并咬喃-3 -複酸乙酉旨)。10% Pd / C (0.150 g) and 1 equivalent of HC1 (7 drops) were added to a solution of compound 43 (c) (0.665 g, 1.8 mmol) in ethyl acetate (70.0 ml). The reaction mixture was shaken overnight on a Parr shaker with 50 psig of hydrogen. The reaction mixture was filtered through CeliteTM and wet with ethyl acetate and methanol. The filtrate was concentrated in vacuo to provide 0.540 g (88%) of the desired product as a solid. ei prepared chemical house 43 (e) (5-cyclopropyl-2- (4-fluoro-phenyl) -6-methanesulfonylamino-benzoanan-3 -acetate).
將甲烷磺醯氯(0.270毫升、3.48毫莫耳)加入化合物43(d) (0.535克、1.58毫莫耳)之二氣甲烷(6毫升)之冰溶液(0°C、 冰/水浴)。令反應混合物進一步於乙醇/冰浴冷卻,然後添 加N,N-二異丙基乙胺(〇.688毫升、3.95毫莫耳)。令反應於室 溫攪拌隔夜,以水稀釋並經二氯甲烷萃取(3x)。合併有機層 ’經硫酸鎂脫水,並蒸發以提供0.653克(86%)之雙(磺醯化) 中間體。 88828.doc -124- 200418452 將氫氧化鉀(1·52克、27毫莫耳)加入氬氣下之雙(磺醯化) 中間體(0.670克、1·35毫莫耳)之乙醇(1〇.〇毫升)與水(5·〇毫 升)溶液。令反應迴流加熱隔夜,然後真空濃縮。溶剩餘之 固體於水,並以1當量濃度HC1酸化溶液直至形成沉澱。過 濾固體並乾燥,提供0.532克(99%)之所需產物。 f.製備化合物43(fl(5-環丙基-2-(4-氟基-苯基)_6_甲烷磺 驢基胺基-苯并吱喃-3 -幾酸甲酸胺)。Methanesulfonyl chloride (0.270 ml, 3.48 mmol) was added to an ice solution (0 ° C, ice / water bath) of compound 43 (d) (0.535 g, 1.58 mmol) in digas methane (6 ml). The reaction mixture was further cooled in an ethanol / ice bath, and then N, N-diisopropylethylamine (0.688 ml, 3.95 mmol) was added. The reaction was allowed to stir at room temperature overnight, diluted with water and extracted with dichloromethane (3x). The combined organic layers were dehydrated over magnesium sulfate and evaporated to provide 0.653 g (86%) of the bis (sulfonated) intermediate. 88828.doc -124- 200418452 Potassium hydroxide (1.52 g, 27 mmol) was added to the bis (sulfonated) intermediate (0.670 g, 1.35 mmol) in ethanol (1 (0.0 ml) and a solution of water (5.0 ml). The reaction was heated at reflux overnight and then concentrated in vacuo. The remaining solid was dissolved in water and the solution was acidified with 1 equivalent of HC1 until a precipitate formed. The solid was filtered and dried to provide 0.532 g (99%) of the desired product. f. Preparation of compound 43 (fl (5-cyclopropyl-2- (4-fluoro-phenyl) -6-methanesulfonyldonylamino-benzoic acid-3-amine).
將苯并三η坐-1 -基氧基參峨洛淀鱗六氟嶙酸鹽(PyBOP) (1·02克、1.97毫莫耳)加入氬氣下之甲胺(12.0毫升、16.3毫 莫耳,2.0莫耳濃度之THF溶液)、DMF (1.0毫升)與化合物 43(e)(0.530毫克、1.36毫莫耳)之混合物。令反應於室溫攪 拌隔夜’然後於真芝濃縮。以水稀釋殘逢,並經乙酸乙酯 萃取(3X)。合併有機層,水洗,經硫酸鎂脫水並風乾,提供 0.347克(63%)粗產物。令一份之粗產物(1〇〇毫克)經反相 HPLC (乙腈/水梯度)純化,提供0.050克之所需產物。 g.製Jj_化合物43(g)5-環丙基-2-(4-氟基-苯基)-6-[甲烷續 酸基- (2-苯氧基-乙基)-胺基]-苯并吱喃-3-叛酸甲驢胺)。 88828.doc -125 - 200418452Benzotri-n-syl-1 -yloxyselenium hexafluorophosphonate (PyBOP) (1.02 g, 1.97 mmol) was added to methylamine (12.0 ml, 16.3 mmol) under argon Ear, 2.0 Molar THF solution), DMF (1.0 ml) and compound 43 (e) (0.530 mg, 1.36 mmol). The reaction was allowed to stir at room temperature overnight 'and then concentrated in Shinji. The residual compound was diluted with water and extracted with ethyl acetate (3X). The organic layers were combined, washed with water, dehydrated with magnesium sulfate and air-dried to provide 0.347 g (63%) of the crude product. A portion of the crude product (100 mg) was purified by reverse phase HPLC (acetonitrile / water gradient) to provide 0.050 g of the desired product. g. Preparation of Jj_Compound 43 (g) 5-cyclopropyl-2- (4-fluoro-phenyl) -6- [methanecontinyl- (2-phenoxy-ethyl) -amine] -Benzoan-3-methylmetanosylamine). 88828.doc -125-200418452
將碳酸鉀(0.125克、〇·91毫莫耳)與芊基2-溴乙基醚(0.105 毫升、0.67莫耳)加入氬氣下之化合物43(g)(0.120克、0.0003 莫耳)之乙腈(1.5毫升)溶液。令反應混合物迴流加熱隔夜, 以水稀釋殘逢,並經二氯甲貌萃取(3x)。合併有機層,經硫 酸鎂脫水並蒸發。令粗產物藉乙酸乙酯/己烷再結晶純化, 並令分離出之固體不經進一步純化,直接進行下一步騾。 h.G·環丙基-2·ί4-氟基-苯某)-6-ΙΎ2-羥基-乙基V甲烷續酸 基·•胺基1-苯并哇喃-3-羧酸甲醯胺)之製備)。 將 10% Pd/C (0.100 克)加入化合物 43(g)(0.162 克、0.41 毫 莫耳)之乙酸乙酯(20毫升)混合物。令反應混合物於5〇 psig 氫氣之Pair振盪器振盪隔夜。令反應混合物濾過CeliteTM, 經乙酸乙酯與甲醇潤濕。真空濃縮濾液,並溶粗產物於乙 酸乙酯且經己烷沉澱。過濾分離固體,提供〇 〇83克褐色固 體之所需產物。 實例44 乙基-2-(4-氟基-苯基)_6_甲烷磺醯基胺基-苯并呋喃_3 _羧 酸甲醯胺之製備 匕合物三氟-甲烷磺酸2_(4_氟基-苯基甲 88828.doc -126- 200418452 燒磺醯基胺基-3-甲基胺甲醯基-苯并呋喃_5_基酯)。Potassium carbonate (0.125 g, 0.91 mol) and fluorenyl 2-bromoethyl ether (0.105 ml, 0.67 mol) were added to compound 43 (g) (0.120 g, 0.0003 mol) under argon. Acetonitrile (1.5 ml) solution. The reaction mixture was heated at reflux overnight, diluted with water and extracted with dichloromethane (3x). The organic layers were combined, dried over magnesium sulfate and evaporated. The crude product was purified by recrystallization from ethyl acetate / hexane, and the isolated solid was directly subjected to the next step without further purification. hG · Cyclopropyl-2 · ί4-Fluoro-Benzene) -6-ΙΎ2-Hydroxy-ethyl Vmethane acid group · • Amino group 1-Benzowan-3-carboxylic acid formamidine) preparation). 10% Pd / C (0.100 g) was added to a mixture of compound 43 (g) (0.162 g, 0.41 mmol) in ethyl acetate (20 ml). The reaction mixture was shaken overnight on a Pair shaker at 50 psig of hydrogen. The reaction mixture was filtered through CeliteTM and wet with ethyl acetate and methanol. The filtrate was concentrated in vacuo and the crude product was dissolved in ethyl acetate and precipitated with hexane. The solid was isolated by filtration to provide 0.083 g of the desired product as a brown solid. Example 44 Preparation of ethyl-2- (4-fluoro-phenyl) _6_methanesulfonamido-benzofuran_3_carboxylic acid formamidine trifluoro-methanesulfonic acid 2_ (4 _Fluoro-phenylmethyl 88828.doc -126- 200418452 (sulfofluorenylamino-3-methylaminomethylfluorenyl-benzofuran-5-yl ester).
將N-苯基triflimide (14.2克、3 9.68毫莫耳)之無水二氯甲烷 (20毫升)溶液,隨之為三乙胺(5.4毫升、52.9毫莫耳)導入 、氬氣下之化合物38 (a) (10克、26.45毫莫耳,其可根據上述 貫例3 8、步騾a製成)之無水二氯甲烷(1丨〇毫升)溶液。令反 應混合物於室溫攪拌隔夜。將反應混合物倒入水(15〇毫升) ,並令各層分離。令水層經二氯甲烷(3 χ .1〇〇毫升)萃取。 令合併之有機層脫水(MgSCU),並真空濃縮。令粗產物藉再 結晶(1 : 1乙酸乙酯/己烷)純化,提供12 7克(94%)淡橙色結 晶之所需產物。 b·麗備化合物44(b)(2-(4-氟基-苯基)-6-甲燒磺酸基胺基 -5-乙烯基-苯并呋喃_3_羧酸甲醯胺)。A solution of N-phenyl triflimide (14.2 g, 3 9.68 mmol) in anhydrous dichloromethane (20 ml) followed by triethylamine (5.4 ml, 52.9 mmol) was introduced under argon. 38 (a) An anhydrous dichloromethane (10 ml) solution of (10 g, 26.45 mmol, which can be prepared according to the above-mentioned Example 38, step (a)). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water (150 ml) and the layers were allowed to separate. The aqueous layer was extracted with dichloromethane (3 x .100 ml). The combined organic layers were dehydrated (MgSCU) and concentrated in vacuo. The crude product was purified by recrystallization (1: 1 ethyl acetate / hexane) to provide 127 g (94%) of the desired product as pale orange crystals. b. Rebecca Compound 44 (b) (2- (4-fluoro-phenyl) -6-methanesulfonylamino-5-vinyl-benzofuran-3-carboxylic acid formamidine).
將氯化鋰(498毫克、11.75毫莫耳)、肆(三苯膦)免(〇)(90 笔克、0.08¾莫耳)、三苯膦(83毫克、〇·31毫莫耳)與2,6-二-第三-丁基-4-甲酚(約16毫克、〇.〇8毫莫耳)加入氬氣下之化 合物44(a)(2.0克、3.92毫莫耳)之無水二吟烷(17.6毫升) 88828.doc -127- 落液。令反麻益Λτ # %、精虱氧脫氣15分鐘。經注射筒導入三_正_丁基 乙缔基錫(1〗7其· _±1 \ •毛升)’然後,將反應加熱至1 〇〇°c達18小時 知反底此口物倒入氟化钾(5〇毫升)之飽和水溶液,並劇烈 授掉4小時。冬久駄八 各層刀離,並以二氯甲烷萃取水層(3 X 5〇毫 升)。^合併之有機層經1〇%氫氧化銨(3 X 50毫升)溶液洗。 以-*m萃取後—水層(5G毫升)。合併全部有機層,脫水 (MgS04)並濃縮。令殘逢藉急驟層析(硬膠、己燒、然後為 氯甲烷/己烷梯度)純化,並再結晶(乙酸乙酯)以提供1.10 克(72%)之所需產物。 基基X-甲烷碏醯基胺基·笨并哇喃 :i_-羧酸_甲醯胺乏_ t 〇 刼1〇/。Pd/C (50*克)加入化合物44(b)(500毫克、1.29毫 莫耳)又乙酸乙酯(50毫升)混合物。令反應混合物於5〇 psig 氫氣之Parr振盈詻振盪2天。令反應混合物濾過CeliteTM,經 乙酸乙酯與乙醇潤濕,並藉HpLC (反相,乙腈/水梯度加上 0.1%乙酸)純化,提供342毫克(74%)之所需產物。 實例45 5-乙基-2-(4-氟基-苯基)-6-(甲烷磺醯基_〒基-胺基)_苯并呋 喃-3-羧酸甲醯胺之製備 標題化合物實質上是根據上述實例3 8、步騾b之一般方法 製成’然而’以5-乙基-2-(4-氟基-苯基)-6-甲燒績g盡基胺基_ 苯并呋喃-3-羧酸甲醯胺(可根據實例44製成)取代化合物 3 8(a)。藉HPLC純化粗產物,提供64%產率之產物。 -實例46 88828.doc -128- 200418452 >乙基-2-(4-氟基-苯基)-6-[(2-經基-乙基)-甲境績驢基-胺基] -苯并呋喃-3-羧酸甲醯胺之製備 物46(.gjL(6K2-爷氧基-乙基)-甲燒續g盒基-胺基] 2-(4 -氟基_苯基)_5_乙晞基_苯并吱喃-3-叛酸甲酸胺)。Lithium chloride (498 mg, 11.75 mmol), triphenylphosphine (0) (90 grams, 0.08¾ mole), triphenylphosphine (83 mg, 0.31 mmol) and 2,6-Di-tert-butyl-4-cresol (approximately 16 mg, 0.08 mmol) was added to compound 44 (a) (2.0 g, 3.92 mmol) under argon anhydrous Dioxane (17.6 ml) 88828.doc -127- Falling liquid. Anti-Ma Yi Λτ #%, oxygen degassing of sperm lice for 15 minutes. Introduce tri-n-butyl ethylenyl tin (1 7 7 _ ± 1 \ • gross liter) through a syringe 'Then, the reaction was heated to 1000 ° C for 18 hours until the mouth was poured. A saturated aqueous solution of potassium fluoride (50 ml) was added, and the mixture was vigorously dissipated for 4 hours. Tokuhisa Hachiba The layers were cut off, and the aqueous layer was extracted with dichloromethane (3 x 50 ml). ^ The combined organic layers were washed with a 10% ammonium hydroxide (3 x 50 ml) solution. After extraction with-* m-water layer (5G ml). All organic layers were combined, dehydrated (MgS04) and concentrated. The residue was purified by flash chromatography (hard gum, hexane, and then a methyl chloride / hexane gradient) and recrystallized (ethyl acetate) to provide 1.10 g (72%) of the desired product. Benzyl X-methanefluorenylamino. Benzowalan: i_-carboxylic acid_formamidine _ t 〇 刼 10 /. Pd / C (50 * g) was added to a mixture of compound 44 (b) (500 mg, 1.29 mmol) and ethyl acetate (50 ml). The reaction mixture was shaken with Parr at 50 psig of hydrogen for 2 days. The reaction mixture was filtered through CeliteTM, wet with ethyl acetate and ethanol, and purified by HpLC (reverse phase, acetonitrile / water gradient plus 0.1% acetic acid) to provide 342 mg (74%) of the desired product. Example 45 Preparation of 5-ethyl-2- (4-fluoro-phenyl) -6- (methanesulfonyl_fluorenyl-amino) _benzofuran-3-carboxylic acid formamidine The above is made according to the general method of the above Example 3 8. Step 骡 b. However, the 5-ethyl-2- (4-fluoro-phenyl) -6-methylamine g benzoamino_benzo Formamidine furan-3-carboxylate (which can be prepared according to Example 44) replaces compound 38 (a). The crude product was purified by HPLC to provide the product in 64% yield. -Example 46 88828.doc -128- 200418452 > Ethyl-2- (4-fluoro-phenyl) -6-[(2-Cyclo-ethyl) -formyl-amino-amino]- Preparation of benzofuran-3-carboxylic acid formamidine 46 (.gjL (6K2-ethoxy-ethyl) -methylbenzene g-boxyl-amino group] 2- (4-fluoro-phenyl) _5_Ethylfluorenyl_benzocrean-3-amine acid formate).
將苄基-2-溴乙基醚(448微升、2.82毫莫耳)加入氬氣壓下 之根據上述實例44、步騾a-b製成之化合物44(b)(500毫克、 1.28¾莫耳)與碳酸钾(534毫克、3.86毫莫耳)之無水乙腈(6.4 毫升)。令混合物迴流加熱12小時,倒入水(1〇〇毫升)中,並 以一氯甲燒萃取(3 X 100毫升)。合併有機層,經鹽液洗(1 〇〇 Φ升)’經MgSCU脫水並濃縮。令粗產物經急驟層析(石夕膠、 一鼠甲燒/甲醇梯度)純化,提供650毫克(97%)之所需產物。 bj-乙基-2-(4 -耽基-苯基)-6-「(2_轉某-乙基甲燒石靑基-胺基1-笨并咭喃-3-羧酸甲醯胺之製靖。 將10% Pd/C (添加3次之50毫克/天,總量150毫克)加入化 合物46(a)(650毫克、1.28毫莫耳)之乙酸乙酯(65毫升)混合 物。令反應混合物於50 psig氫氣下之parr振盪器中振盪4天 。令反應混合物濾過CeliteTM,經乙酸乙酯潤濕。真空濃縮 濾液,並分離出固體。令粗產物藉HPLC(反相,乙腈/水梯 度加上0.1%乙酸)純化,提供398毫克(78%)之標題化合物。 實例47 88828.doc -129- 200418452 6-(1-乙驢基_吡咯啶_2_基>2-(4-氟基_苯基)_5_甲氧基-苯并 呋喃-3-羧酸甲醯胺之製備 •溴基-2-(4-氟基·苯基)-5-甲氧基-苯 并呋喃-3-羧酸甲醯胺)。Benzyl-2-bromoethyl ether (448 µl, 2.82 mmol) was added to compound 44 (b) (500 mg, 1.28¾ mole) made according to the above Example 44, Step 骡 ab under argon pressure. With potassium carbonate (534 mg, 3.86 mmol) in anhydrous acetonitrile (6.4 ml). The mixture was heated at reflux for 12 hours, poured into water (100 ml), and extracted with chloroform (3 x 100 ml). The organic layers were combined, washed with saline (1000 liters) ', dehydrated with MgSCU and concentrated. The crude product was purified by flash chromatography (Shi Xijiao, 1 murine / methanol gradient) to provide 650 mg (97%) of the desired product. Preparation of bj-ethyl-2- (4-pentanyl-phenyl) -6-"(2_Transferred-ethylmethylcarbofluorenyl-amino 1-benzylpyran-3-carboxylic acid formamide Jing. Add 10% Pd / C (50 mg / day three times, 150 mg total) to a mixture of compound 46 (a) (650 mg, 1.28 mmol) in ethyl acetate (65 ml). Let the reaction The mixture was shaken in a parr shaker under 50 psig of hydrogen for 4 days. The reaction mixture was filtered through CeliteTM and wet with ethyl acetate. The filtrate was concentrated in vacuo and the solids were separated. The crude product was subjected to HPLC (reverse phase, acetonitrile / water gradient). Purified with addition of 0.1% acetic acid) to provide 398 mg (78%) of the title compound. Example 47 88828.doc -129- 200418452 6- (1-ethyldonyl_pyrrolidin_2_yl) 2- (4- Preparation of Fluoro_phenyl) _5_methoxy-benzofuran-3-carboxylic acid formamidine • Bromo-2- (4-fluoro · phenyl) -5-methoxy-benzofuran -3-carboxylic acid formamidine).
47(a) 中間體化合物實質上是根據上述實例28、步騾g之一般方 法製成,然而,以化合物28(c)取代化合物28(f)。 b’^i^^iaK2-[2-(4_氟基_苯基甲氧基_3-甲基 胺甲驗基-苯并呋喃冬基]•吡咯小叛酸第三·丁酯)。47 (a) The intermediate compound is substantially prepared according to the general method of Example 28, Step 骡 g described above. However, Compound 28 (c) is substituted for Compound 28 (f). b '^ i ^^ iaK2- [2- (4-fluoro group_phenylmethoxy_3-methylaminomethanyl-benzofuranyl) • pyrrole minor acid tert-butyl ester).
於室溫下,將固體Na2C〇3 (371毫克、3.5毫莫耳)與肆(三 苯膦)鈀(0)(81毫克、〇·07毫莫耳)加入化合物47(a)(527毫克 、1.40¾莫耳,可根據前述步驟之一般方法製成)、(第三 -丁氧羰基)-吡咯-2-_酸(445毫克、2.1〇毫莫耳)之甲苯/乙醇 /水(20¾升/10¾升/〇·5毫升)之脫氣溶液。於85。〇之氬氣壓 下攪拌20小時後,令反應經水止熱,並經乙酸乙酯萃取。 令有機相經水與鹽液洗,經MgS〇4脫水並減壓濃縮。令粗 88828.doc -130- 200418452 產物經管柱層析(矽膠、20%乙酸乙酯/己烷)純化,產生550 毫克(85%)淡黃色固體之所需產物。 c·盤jf化合物4」ΖΧ^1(2-[2-(4-氟基-苯基)-5-甲氧基-3-甲基 胺甲醯基-苯并呋喃-6-基]-吡咯-1-羧酸-第三-丁酯)。At room temperature, solid Na2CO3 (371 mg, 3.5 mmol) and (triphenylphosphine) palladium (0) (81 mg, 0.07 mmol) were added to compound 47 (a) (527 mg , 1.40 ¾ mole, which can be made according to the general method of the previous steps), (Third-butoxycarbonyl) -pyrrole-2-_acid (445 mg, 2.10 mmol) toluene / ethanol / water Liter / 10¾ liter / 0.5 ml) of degassed solution. At 85. After stirring for 20 hours under argon pressure, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgS04 and concentrated under reduced pressure. The crude 88828.doc -130- 200418452 product was purified by column chromatography (silica gel, 20% ethyl acetate / hexane) to give 550 mg (85%) of the desired product as a pale yellow solid. c · pan jf compound 4 ″ ×× ^ 1 (2- [2- (4-fluoroyl-phenyl) -5-methoxy-3-methylaminomethylamido-benzofuran-6-yl]- Pyrrole-1-carboxylic acid-tertiary-butyl ester).
將活化之10% Pd/C (200毫克、10%重)加入化合物47(b) (500毫克、1·〇8毫莫耳)之4 : 1乙酸乙酯:乙醇溶液中。令 混合物於50 psig氫氣下之parr振盪器中以室溫振盪隔夜。添 加另一份之活化的10% Pd/c (200毫克、10%重)。令混合物 於50 psig氫氣下之Parr振盪器中以室溫振盪24小時。然後, 令反應漉過,經乙酸乙酯潤濕。濃縮滤液,生成 480毫克(95%)白色固體之純的預期化合物。 d·.製備化合物」·7(ά)(2-(4-氟基-苯基)-5-甲氧基-6-外1:洛淀 -2 -基-表并咬喃-3 -叛酸-甲酸胺)。Activated 10% Pd / C (200 mg, 10% by weight) was added to a 4: 1 ethyl acetate: ethanol solution of compound 47 (b) (500 mg, 1.08 mmol). The mixture was shaken overnight at room temperature in a parr shaker under 50 psig of hydrogen. Add another portion of activated 10% Pd / c (200 mg, 10% weight). The mixture was shaken in a Parr shaker under 50 psig of hydrogen at room temperature for 24 hours. The reaction was then allowed to pass through and wet with ethyl acetate. The filtrate was concentrated to give 480 mg (95%) of the pure expected compound as a white solid. d. Preparation of compounds "· 7 (ά) (2- (4-fluoro-phenyl) -5-methoxy-6-external 1: Luodian-2 -yl-epoxy and octane-3 -bet Acid-amine formate).
令化合物47(c)(450毫克、0.96毫莫耳)之20%(體積)三氟乙 之一氯甲fe溶液於室溫擴:拌1小時。然後,減壓去除溶劑 88828.doc -131 - 200418452 ’並溶殘;旦於二氯甲燒,並經過量三乙胺處理3〇分鐘。真 空去除溶劑,殘渣不經進一步純化即用於下一步驟。 e.izXlz乙羞基jb咯咬二基·笨某)_5_甲氣基_ t并呋喃-3_二羧酸甲醯胺之H。 將乙酸酐(18微升、0.186毫莫耳)逐滴加入〇。〇之化合物 47(c)(45*克、0.124¾莫耳)之二氯甲烷溶液。令生成之溶 液於0°C至室溫攪拌24小時。令反應經水止熱,並萃取入乙 酸乙酯。以NaHC〇3與鹽液洗有機層,經Na2S〇4脫水,並減 歷:条發。令粗材料經管柱層析(石夕膠,1 〇%甲醇之乙酸乙酯 4液)純化’ ί疋供40愛克(80%)白色固體之所需產物。 實例48 2-(4-氟基-苯基)-5-甲氧基-6-(2-氧基^号唑啶基苯并呋 喃-3-羧酸甲醯胺之製備 a·复—備化合J? 48(a)(2_(4-氟基_苯基)_6_甲醯基-5-甲氧基_ 苯并呋喃-3-羧酸甲醯胺)。A solution of compound 47 (c) (450 mg, 0.96 mmol) in 20% (volume) trifluoromethylene chloride was expanded at room temperature: stir for 1 hour. Then, the solvent 88828.doc -131-200418452 ′ was removed under reduced pressure and dissolved; once burned in dichloromethane, and treated with triethylamine for 30 minutes. The solvent was removed in vacuo and the residue was used in the next step without further purification. e.izXlz ethynyl jb bite diyl · Benmou) _5_methanyl_t-furan-3_dicarboxylic acid formamidine H. Acetic anhydride (18 μl, 0.186 mmol) was added dropwise. Solution of compound 47 (c) (45 * g, 0.124¾ mole) in methylene chloride. The resulting solution was stirred at 0 ° C to room temperature for 24 hours. The reaction was quenched with water and extracted into ethyl acetate. The organic layer was washed with NaHC03 and a saline solution, dehydrated with Na2SO4, and reduced in number: hair. The crude material was purified by column chromatography (Shijiao, 4% 10% methanol in ethyl acetate) to provide 40 gram (80%) of the desired product as a white solid. Example 48 Preparation of 2- (4-fluoro-phenyl) -5-methoxy-6- (2-oxy ^ azolidinylbenzofuran-3-carboxylic acid formamidine Compound J? 48 (a) (2- (4-fluoro-phenyl) -6-methylfluorenyl-5-methoxy-benzofuran-3-carboxylic acid formamide).
將TiCl4 (276微升、3.0毫莫耳)緩慢加入〇〇c之α,α_二氯甲 基甲基醚(107微升、1.20毫莫耳)之二氯甲烷(1毫升)溶液, 隨之添加化合物47(a)(300毫克、1毫莫耳,可根據上述實例 47、步驟a製成)之二氯甲烷毫升)懸浮液。添加完成後, 去除冰浴。令混合物於室溫攪拌1 5小時,然後倒入冰水並 88828.doc -132- 200418452 以乙酸乙酯萃取。以水與鹽液洗有機相,經執脫水, 並減壓濃縮。令粗產物經管柱層析(石夕膠,3〇_5〇%乙酸乙醋 之己烷溶液)純化,生成196毫克(6〇%)之白色固體。 曰 b.$備m48_{九)(6-(氯基-三甲基矽烷基氧基·甲基)_2-[2-(4-氟基-苯基)]-5-甲氧基-苯并呋喃羧酸甲醯胺)。TiCl4 (276 μl, 3.0 mmol) was slowly added to a solution of α, α-dichloromethyl methyl ether (107 μl, 1.20 mmol) in dichloromethane (1 mL). To this was added a suspension of compound 47 (a) (300 mg, 1 millimolar, which can be prepared according to the above Example 47, step a) in methylene chloride). After the addition is complete, remove the ice bath. The mixture was allowed to stir at room temperature for 15 hours, then poured into ice water and extracted 88828.doc -132- 200418452 with ethyl acetate. The organic phase was washed with water and saline, dehydrated, and concentrated under reduced pressure. The crude product was purified by column chromatography (stone gum, 30-50% ethyl acetate in hexane) to give 196 mg (60%) of a white solid. B. $ 备 m48_ {九) (6- (chloro-trimethylsilyloxy · methyl) _2- [2- (4-fluoro-phenyl)]-5-methoxy-benzene Benzofurancarboxylic acid formamidine).
48(b) 將Znl2 (催化量)加入〇°C之化合物48(a)(80毫克、0.25毫莫 耳)與三甲基矽烷氰化物(40微升、〇·3毫莫耳)之二氯甲燒(1 毫升)混合物。於0°C之攪拌30分鐘後,添加另一份之三甲 基矽烷氰化物(30微升)。令生成之混合物於0它攪拌丨小時, 室溫2小時。令反應經水止熱,並經二氯甲烷萃取。令有機 相經水與鹽液洗,經MgS04脫水並減壓濃縮。令粗產物(9〇 毫克)不經進一步純化,即進行下一步騾。 c·兔備化合物48(c)(6-(2 -胺基-1-¾基-乙基)-2-(4 -氣基-苯 基)-5-甲氧基-苯并呋喃-3-羧酸甲醯胺)。48 (b) Add Znl2 (catalytic amount) to 0 ° C compound 48 (a) (80 mg, 0.25 mmol) and trimethylsilyl cyanide (40 μl, 0.3 mmol) Methyl chloride (1 mL) mixture. After stirring at 0 ° C for 30 minutes, another portion of trimethylsilane cyanide (30 µl) was added. The resulting mixture was allowed to stir at room temperature for 2 hours and at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with water and saline, dried over MgS04 and concentrated under reduced pressure. The crude product (90 mg) was taken to the next step without further purification. c · Rabbit Compound 48 (c) (6- (2-Amino-1-¾lyl-ethyl) -2- (4-Amino-phenyl) -5-methoxy-benzofuran-3 -Formamidine carboxylate).
將活化之10% Pd/C (20毫克)加入化合物48(c)(90毫克之 10:1乙醇/乙酸)之溶液。令混合物於50 psig氫氣下之Parr振 88828.doc -133- 200418452 盈态中以室溫振盪48小時。令反應混合物濾過CeliteTM片, 經乙酸乙酯潤濕。減壓濃縮濾液,提供6〇毫克(經lc/MS純 度達90%)產物。 氟基-苯基羞-6_(2_氫某-啐崎啶_5_某)-茉Activated 10% Pd / C (20 mg) was added to a solution of compound 48 (c) (90 mg of 10: 1 ethanol / acetic acid). The mixture was shaken at 50 psig in Parr 88828.doc -133- 200418452 in the surplus state at room temperature for 48 hours. The reaction mixture was filtered through a CeliteTM sheet and wet with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 60 mg (90% purity by lc / MS) of the product. Fluoro-phenylsulfan-6_ (2_hydrogen-sakizidine_5_some) -moth
於密封管中充填以磁性攪拌棒、化合物24(b)(1.22克、3 〇 毫莫耳,可根據上述實例24、步驟b製成)、乙酸鈀(11)(34 毫克、0·015毫莫耳)、[1,Γ-雙(二苯基膦基)丙烷](Dppp)(136 毫克、0.33毫莫耳)、丁基乙基醚(1.92毫升、15毫莫耳)與 K2C03 (622毫克、4.5毫莫耳)之DMF (5毫升)溶液。將管充 -134- 88828.doc 200418452 以氬氣,密封並加熱至10(rc達24小時,然後冷卻至室邋。 以20分鐘時間逐滴添加5% Ηα (2〇毫升),並令乙酸乙醍萃 取混合物。令有機層經水與鹽液洗,經MgSCu脫水,並減 壓濃縮。令粗材料經管柱層析(矽膠,2〇%乙酸乙酯之己虼 溶液)純化,生成〇·94克(85%)之所需產物。 備..化合物4_2χ^6_乙醯基-2-(4-氟基-苯基)-5-羥基-笨 并呋喃-3-羧酸甲醯胺)。Fill a sealed tube with a magnetic stir bar, compound 24 (b) (1.22 g, 30 millimoles, which can be prepared according to the above example 24, step b), palladium acetate (11) (34 mg, 0.015 mmol) Mol), [1, Γ-bis (diphenylphosphino) propane] (Dppp) (136 mg, 0.33 mmol), butyl ethyl ether (1.92 ml, 15 mmol) and K2C03 (622 Mg, 4.5 mmol) in DMF (5 ml). Fill the tube with -134- 88828.doc 200418452 with argon, seal and heat to 10 (rc for 24 hours, then cool to room temperature. Add 5% Ηα (20 ml) dropwise over 20 minutes and let acetic acid The mixture was extracted with acetamidine. The organic layer was washed with water and saline solution, dehydrated with MgSCu, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to produce 0 · 94 g (85%) of the desired product. Preparation: Compound 4_2χ ^ 6_ethylamido-2- (4-fluoro-phenyl) -5-hydroxy-benzyfuran-3-carboxylic acid formamidine ).
將三氯化硼(27·1毫升、1·〇莫耳濃度之二氯甲烷溶液)緩 慢加入0°C、氬氣下之化合物49(a)(5.0克、13·6毫莫耳)之二 氯甲烷(58毫升)溶液。令該混合物於〇°C至室溫攪拌1小時。 將混合物倒入冰水(250毫升),並以乙酸乙醋萃取。令有機 層經飽和NaHC03與鹽液洗,經MgS〇4脫水並減壓濃縮。令 粗材料經管柱層析(矽膠,3〇%乙酸乙酯之己烷溶液)純化, 產生3.85克(87%)之所需產物。 c.製備化合物醯基-2-(4-氟基-苯基)-5-甲氧基-冬并唉喃-3 -叛酸甲驗胺)。Slowly add boron trichloride (27.1 ml, dichloromethane solution at 1.0 mole concentration) to the compound 49 (a) (5.0 g, 13.6 mmol) at 0 ° C under argon. Dichloromethane (58 mL) solution. The mixture was allowed to stir at 0 ° C to room temperature for 1 hour. The mixture was poured into ice water (250 ml) and extracted with ethyl acetate. The organic layer was washed with saturated NaHC03 and a saline solution, dried over MgS04 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to yield 3.85 g (87%) of the desired product. c. Preparation of the compound fluorenyl-2- (4-fluoro-phenyl) -5-methoxy-aspartyl-3-methanomethamine.
88828.doc _ 135 - 200418452 將碘化甲烷(〇·65毫升、10.2毫莫耳)加入化合物49(bKl.35 克、4.1¾莫耳)與碳酸铯(2·7克、8.3毫莫耳)之NMP(2毫升) 混合物。令生成之混合物於室溫攪拌24小時。令反應經水 (50毫升)止熱,並經乙酸乙酯萃取Q令有機層經水與鹽液洗 ’經MgSCU脫水並減壓濃縮。令粗產物經管柱層析(矽膠, 3 5%乙酸乙酯之己烷溶液)純化,產生117克(83%)之所需產 物。 氟基苯基輕基-1-甲某-乙基甲氣某苯 羧酸甲醯胺之f備。 將化合物49(c)(500毫克、1·5毫莫耳)之THF (1毫升)加入〇t: 之/臭化甲基鎂(1·4莫耳濃度之甲苯/thF,2·6毫升、3·6毫莫 耳)之攪拌溶液。令生成之混合物於〇°C至室溫攪拌丨小時。 令反應經ΝΗβΙ (1毫升)止熱,並經乙酸乙酯萃取。令有機 層經水與鹽液洗,經MgS〇4脫水並減壓濃縮。令粗材料經 管柱層析(矽膠,50%乙酸乙酯之己烷溶液)純化,以提供361 毫克(70%)之所需產物。 實例50 2-(4-氣基-丰基)_5_甲氧基-6-(5·甲基-「1,2.4]ρ号-哇-3-基) 苯并呋喃-3-羧酸甲醯胺之製備 氰基-2-(4-氟基-苯基)_5-甲氧基_苯 并吃喃-3 -叛酸甲酯)。88828.doc _ 135-200418452 Methane iodide (0.65 ml, 10.2 mmol) was added to compound 49 (bKl.35 g, 4.1¾ mole) and cesium carbonate (2.7 g, 8.3 mmol) NMP (2 ml) mixture. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was quenched with water (50 ml), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSCU and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 3 5% ethyl acetate in hexane) to yield 117 g (83%) of the desired product. Preparation of fluorophenyl light-l-methyl-1-methyl-ethyl-methyl benzoate. Compound 49 (c) (500 mg, 1.5 millimoles) in THF (1 ml) was added to 0 t: of / methyl magnesium odor (toluene / thF of 1.4 mole moles, 2.6 ml , 3.6 millimoles). The resulting mixture was allowed to stir at 0 ° C to room temperature for 1 hour. The reaction was quenched with ΝβΙΙ (1 mL) and extracted with ethyl acetate. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 50% ethyl acetate in hexane) to provide 361 mg (70%) of the desired product. Example 50 2- (4-Gas-fungyl) _5-methoxy-6- (5 · methyl- "1,2.4] ρ-Wa-3-yl) Benzofuran-3-carboxylic acid methyl Preparation of amidoamine cyano-2- (4-fluoro-phenyl) _5-methoxy_benzoanan-3 -metanoate methyl ester).
88828.doc -136- 200418452 將無水1-甲基吡咯啶酮(60毫升)加入化合物28(d)(2.2 克、5.80毫莫耳,可根據上述實例28、步驟a-d製成)與氰化 亞銅(1)(1.04克、11.61毫莫耳)之混合物,並加熱至170°C。 於氬氣下,攪拌丨6小時後,將反應混合物冷卻至室溫。加 水(200毫升)與乙酸乙酯(3 00毫升),並將溶液濾過CeliteTM 片’經乙酸乙酯潤濕。分開有機層,並經水(3 X 100毫升) 與鹽液洗,經MgS04脫水,並減壓濃縮。令粗材料經管柱 層析(石夕膠,20-40%乙酸乙酯之己烷溶液)純化,生成11.5 克(79%)之所需產物。 b·复复复金物50(b)(2-(4_氟基-苯基)-6-(N-羥基亞胺胺基 甲基)-5-甲氧基-苯并吱喃_3_幾酸甲酯)。88828.doc -136- 200418452 Anhydrous 1-methylpyrrolidone (60 ml) was added to compound 28 (d) (2.2 g, 5.80 mmol, which can be prepared according to the above example 28, step ad) and subcyanide A mixture of copper (1) (1.04 g, 11.61 mmol) and heated to 170 ° C. After stirring for 6 hours under argon, the reaction mixture was cooled to room temperature. Water (200 ml) and ethyl acetate (300 ml) were added, and the solution was filtered through CeliteTM tablets' and wet with ethyl acetate. The organic layer was separated, washed with water (3 X 100 ml) and brine, dried over MgS04, and concentrated under reduced pressure. The crude material was purified by column chromatography (stone gum, 20-40% ethyl acetate in hexane) to yield 11.5 g (79%) of the desired product. b. Compound 50 (b) (2- (4-Fluoro-phenyl) -6- (N-hydroxyiminoaminomethyl) -5-methoxy-benzocran_3_ Methyl a few acid).
將羥基胺鹽酸鹽(182毫克、2.615毫莫耳)加入化合物5〇(a) (340¾克、ι·〇46*莫耳)之乙醇(5〇毫升)與三乙胺(393微升 、2.842¾莫耳)< 攪拌懸浮液。令該混合物於乃它攪拌12 小時,冷部至罜溫,以水稀釋(1〇〇毫升)並過濾。.令分離之 固體經水與己烷洗, 並於真空烤箱乾燥,產生300毫克(80%) 之所需化合物。Hydroxylamine hydrochloride (182 mg, 2.615 mmol) was added to compound 50 (a) (340 ¾ g, ιο46 * mol) in ethanol (50 ml) and triethylamine (393 μl, 2.842¾ mole) < Stir the suspension. The mixture was allowed to stir for 12 hours, cold to warm to room temperature, diluted with water (100 mL) and filtered. The separated solid was washed with water and hexane and dried in a vacuum oven to produce 300 mg (80%) of the desired compound.
-[1,2,4]’ 一嗤-3-基)-苯并吱喃 -3-叛酸甲醋)。 88828.doc -137- 200418452-[1,2,4] 'monofluoren-3-yl) -benzocran-3-methylacetate). 88828.doc -137- 200418452
將说% (65亳克、3.35 19毫莫耳)隨之為乙酸酐(237微升、 2.55¾莫耳)加入含化合物5〇(b)(3〇〇毫克、〇·838毫莫耳)之 1’2-—氯乙燒(1〇毫升)溶液。於氬氣壓下迴流12小時後,令 反應’吧合物冷卻至室溫,以水稀釋並經二氯甲烷萃取。令 有機層經水與鹽液洗,經MgS〇4脫水並濃縮。令粗產物經 巨枉層析(矽膠,1〇_3〇%乙酸乙酯之己烷溶液)純化,提供 3.80*克(5〇%)之所需產物。 甲氣某-6-Γ5-甲甚-「1 9 羧酸甲醯夕寧j科。 標題化合物(5·55毫克)實質上是根據上述實例15、步·驟b 努^之一般方法製成,然而,在步騾b使用化合物5〇(cU 化合物15(a)。 代 精通當地選取適合之起始材料,可根據前述實例所述方 去製成本务明之其他化合物。因此所製備之進一步之苯并 失南衍生物與類似物之代表性實例列於下表1。 、 ϋAdd 5% (65 g, 3.35 19 mol) followed by acetic anhydride (237 μl, 2.55 ¾ mol) with compound 50 (b) (300 mg, 0.838 mol) 1'2-chloroethane (10 ml) solution. After refluxing under argon pressure for 12 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was washed with water and saline, dehydrated with MgSO and concentrated. The crude product was purified by hydration chromatography (silica gel, 10-30% ethyl acetate in hexane) to provide 3.80 * g (50%) of the desired product. Methane-6-Γ5-methan- "1 9 carboxylic acid formazaninaceae. The title compound (5.55 mg) was essentially prepared according to the general method of Example 15, step b, step ^ above. However, in step 骡 b, compound 5〇 (cU compound 15 (a) is used. Generation is proficient in selecting suitable starting materials, and can be made into other compounds of this subject according to the previous examples. Therefore, the preparation is further Representative examples of benzoxanthan derivatives and analogues are listed in Table 1 below.
88828.doc -138- 200418452 實例 編號 Ri R2 r3 R4 Rs r6 1. Η -〇ch3 H H ch3 2. Η -〇cf3 H H ch3 3. Η -och3 H H ch3 4. Η -OCH(CH3)2 H H ch3 H 5. Η -〇ch(ch3)2 H H ch3 6. Η -OCH(CH3)2 ΟνΛ H ch3 ^0^F 7. Η -〇chf2 H H ch3 8. Η -OCH(CH3)2 -NH(CH2)2OCH3 H ch3 9. Η -ch3 H H ch3 10. Η -ch3 H H ch3 11. Η -och2cf3 H H ch3 12· Η -och3 H H ch3 心F 13. Η -och3 Br H ch3 14. Η -och3 ch3 H ch3 15. Η -OCH(CH3)2 ρΛ i^N H ch3 ^0~F 16. Η -och(ch3)2 nh2 H ch3 17. Η -〇ch3 nh2 H ch3 18. Η -och3 -NH(C=0)CH3 H ch3 19. Η -OCH(CH3)2 -nhch3 H ch3 -139- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs Re 20. Η -OCH(CH3)2 -n(ch3)2 H ch3 21. Η -OCH(CH3)2 -NH(S02)CH3 H ch3 22. Η -och(ch3)2 -NHCH2CH3 H ch3 23. Η -OCH(CH3)2 -N(CH2CH3)2 H ch3 24. Η -och(ch3)2 〇〇Λ H ch3 25. ch3 -och3 H H ch3 26. Η -CN H H ch3 27. Η -OCH(CH3)2 H H ch3 28· Η -och3 h3c ch3 H ch3 29. Η -och3 -N(CH3)S02CH3 H ch3 30. Η > 〇〇Λ H ch3 31. Η > H3C^O^N^ I 1 2 ch3 H ch3 32. Η -OCH2CH3 -n(ch2ch3)so2ch3 H ch3 33. Η 〇〇Λ H ch3 34. Η -OCH(CH3)2 ch3 H ch3 35. Η 4S1 0 N〜 〇〇Λ H ch3 -140- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs r6 36. Η -OCH(CH3)2 H ch3 ^〇-F 37. Η -OCH(CH3)2 ho’Vn H ch3 38. Η -OCH2CH3 /S〇2 π 1 ch3 H ch3 39. Η OH V /S〇2 π in3 H ch3 \Qn 40. Η -och3 HO X〇-N H ch3 ^0"f 41. Η -och3 0-N H ch3 F〇~f 42. Η '-OCH3 H,s\4 、 HO H ch3 43. Η /S〇2 -7 π OH H ch3 44. Η -CH2CH3 -nhso2ch3 H ch3 45. Η -CH2CH3 ^so2 , Η3〇 "νΛ ch3 H ch3 ^0"f 46. Η -CH2CH3 OH H ch3 47. Η -0CH3 广 H ch3 48. Η -OCH3 〇 H ch3 -141 - 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs 49. Η -och3 -C(OH)(CH3)2 H ch3 ^0~F 50. Η -〇ch3 h3c H ch3 51. Η -0(CH2)3-〇H h3c ch3 H ch3 ^0"f 52. Η Q V 1 ch3 H ch3 ^0"F 53. Η V H H ch3 54. Η -〇ch3 H H ch3 ^O~0CH3 55. Η -och3 H H ch3 .Cp3 56. Η -och3 H H ch3 K^CF; 57. Η -OCH2CH3 H H ch3 58. Η -OCH3 H H ch3 59. Η -OCH(CH3)2 H H ch3 60. Η -0(CH2)3CH3 H H ch3 61. Η -0(CH2)2CH3 H H ch3 62· Η -och3 H H ch3 63. Η -0CH3 H ch3 ch3 64. Η -OCH2CF3 H H ch3 65. Η -OCH(CH3)2 H H ch3 -142- 88828.doc 20041845288828.doc -138- 200418452 Instance number Ri R2 r3 R4 Rs r6 1. Η -〇ch3 HH ch3 2. Η -〇cf3 HH ch3 3. Η -och3 HH ch3 4. Η -OCH (CH3) 2 HH ch3 H 5. Η -〇ch (ch3) 2 HH ch3 6. Η -OCH (CH3) 2 ΟνΛ H ch3 ^ 0 ^ F 7. Η -〇chf2 HH ch3 8. Η -OCH (CH3) 2 -NH (CH2) 2OCH3 H ch3 9. Η -ch3 HH ch3 10. Η -ch3 HH ch3 11. Η -och2cf3 HH ch3 12 · Η -och3 HH ch3 heart F 13. Η -och3 Br H ch3 14. Η -och3 ch3 H ch3 15 Η -OCH (CH3) 2 ρΛ i ^ NH ch3 ^ 0 ~ F 16. Η -och (ch3) 2 nh2 H ch3 17. Η -〇ch3 nh2 H ch3 18. Η -och3 -NH (C = 0) CH3 H ch3 19. Η -OCH (CH3) 2 -nhch3 H ch3 -139- 88828.doc 200418452 Example number Ri R2 R3 R4 Rs Re 20. Η -OCH (CH3) 2 -n (ch3) 2 H ch3 21. Η -OCH (CH3) 2 -NH (S02) CH3 H ch3 22. Η -och (ch3) 2 -NHCH2CH3 H ch3 23. Η -OCH (CH3) 2 -N (CH2CH3) 2 H ch3 24. Η -och (ch3) 2 〇〇Λ H ch3 25. ch3 -och3 HH ch3 26. Η -CN HH ch3 27. Η -OCH (CH3) 2 HH ch3 28 · Η -och3 h3c ch3 H ch3 29. Η -och3 -N (CH3) S02CH3 H ch3 30. Η > 〇〇Λ H ch3 31. Η > H3C ^ O ^ N ^ I 1 2 ch3 H ch3 32. Η -OCH2CH3 -n (ch2ch3) so2ch3 H ch3 33. Η 〇〇Λ H ch3 34. Η -OCH (CH3) 2 ch3 H ch3 35. Η 4S1 0 N ~ 〇〇Λ H ch3 -140- 88828.doc 200418452 Example number Ri R2 R3 R4 Rs r6 36. Η -OCH (CH3) 2 H ch3 ^ 〇-F 37. Η -OCH (CH3) 2 ho'Vn H ch3 38. Η -OCH2CH3 / S〇2 π 1 ch3 H ch3 39. Η OH V / S〇2 π in3 H ch3 \ Qn 40. Η -och3 HO X〇-NH ch3 ^ 0 " f 41. Η -och3 0-NH ch3 F〇 ~ f 42. Η '-OCH3 H, s \ 4, HO H ch3 43. Η / S〇2 -7 π OH H ch3 44. Η -CH2CH3 -nhso2ch3 H ch3 45. Η -CH2CH3 ^ so2, Η3〇 " νΛ ch3 H ch3 ^ 0 " f 46. Η -CH2CH3 OH H ch3 47. Η -0CH3 HH ch3 48. Η -OCH3 〇H ch3 -141-88828.doc 200418452 Example number Ri R2 R3 R4 Rs 49. Η -och3 -C (OH) (CH3) 2 H ch3 ^ 0 ~ F 50. Η -〇ch3 h3c H ch3 51. Η -0 (CH2) 3-〇H h3c ch3 H ch3 ^ 0 " f 52. Η QV 1 ch3 H ch3 ^ 0 " F 53. Η VHH ch3 54. Η -〇ch3 HH ch3 ^ O ~ 0CH3 55. Η -och3 HH ch3 .Cp3 56. Η -och3 HH ch3 K ^ CF; 57. Η -OC H2CH3 HH ch3 58. Η -OCH3 HH ch3 59. Η -OCH (CH3) 2 HH ch3 60. Η -0 (CH2) 3CH3 HH ch3 61. Η -0 (CH2) 2CH3 HH ch3 62 · Η -och3 HH ch3 63. Η -0CH3 H ch3 ch3 64. Η -OCH2CF3 HH ch3 65. Η -OCH (CH3) 2 HH ch3 -142- 88828.doc 200418452
實例 編號 Ri r2 r3 R4 Rs R6 66. Η -och3 H H ch3 Cl 67. Η Η och3 H ch3 68. Η -〇ch3 H H ch3 69. Η -och3 H H ch3 70. Η -och3 H H ch3 K3^Br 71. Η -och3 H H ch3 ch3 K^f 72. Η -och3 H ch3 ch3 73. Η " Cl H H ch3 74. Η t-butyl H H ch3 75. Η Cl H H ch3 ^0-CH3 76. Η -och3 H H ch3 Cl 77· Η -och3 H H ch3 78. Η -ch2och3 H H ch3 79. Η -OCH(CH3)2 ch3 H ch3 80. Η -OCH(CH3)2 H ch3 ch3 81. Η -〇ch3 ch3 H ch3 82. Η F H H ch3 83. Η F H H ch3 ^Q-ch2ch3 84. Η -ch2ch3 H H ch3 \QExample number Ri r2 r3 R4 Rs R6 66. Η -och3 HH ch3 Cl 67. Η Η och3 H ch3 68. Η -〇ch3 HH ch3 69. Η -och3 HH ch3 70. Η -och3 HH ch3 K3 ^ Br 71. Η -och3 HH ch3 ch3 K ^ f 72. Η -och3 H ch3 ch3 73. Η " Cl HH ch3 74. Η t-butyl HH ch3 75. Η Cl HH ch3 ^ 0-CH3 76. Η -och3 HH ch3 Cl 77 · och -och3 HH ch3 78. Η -ch2och3 HH ch3 79. Η -OCH (CH3) 2 ch3 H ch3 80. Η -OCH (CH3) 2 H ch3 ch3 81. Η -〇ch3 ch3 82. Η FHH ch3 83. Η FHH ch3 ^ Q-ch2ch3 84. Η -ch2ch3 HH ch3 \ Q
88828.doc -143- 200418452 實例 編號 Ri R2 R3 R4 Rs R6 85. Η -och3 H H ch3 Cl 86. Η -ch(ch3)2 H H ch3 87. Η -och2ch3 H H ch3 Cl 88. Η -och3 H H ch3 89· Η Cl H H ch3 K) 90. Η -OCH(CH3) H H ch3 91. Η -och(ch3)3 H H ch3 92. Η -〇ch(ch3)2 Br H ch3 93. Η -och3 H H ch3 94. Η -och3 och3 H ch3 95. Η -OCH(CH3)2 H H ch3 96. Η F H H ch3 97. Η -OCH(CH3)COOH ch3 H ch3 98. Η -och(ch3)2 -NH(C=0)CH3 H ch3 99. Η -OCH(CH3)2 H H ch3 100. Η -OCH(CH3)2 o、 H ch3 101. Η -OCH(CH3)2 〇Λ H ch3 102. Η -och3 -〇ch3 H ch3 -144- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs 103. Η - och3 〇〇Λ Η ch3 104. Η -OCH(CH3)2 H Η ch3 105. Η -och(ch3)2 H Η ch3 OH 106. Η -och(ch3)2 H Η ch3 ^〇~cn 107. Η -och3 H Η ch3 108. Η -och(ch3)2 H3C^S〇2 Η ch3 109. Η -OCH(CH3)2 ΟνΛ Η ch3 110. Η -OCH(CH3)2 ρΛ HO Η ch3 111. Η -OCH(CH3)2 -N(CH3)S02CH3 Η ch3 ^0~F 112. Η -OCH(CH3)2 Η ch3 113. Η -OCH(CH3)2 H〇v ^ HO’ Η ch3 ^0"F 114. Η -och(ch3)2 -NHCH(CH3)2 Η ch3 115. Η -och(ch3)2 Η ch3 116. Η -och3 Η ch3 117. Η 〇〇Λ Η ch3 ^0^F 118. Η -ch2oh Η Η ch3 119. Η -OCH(CH3)2 η3〇-°^χνΛ ch3 Η ch3 H〇~f -145 - 88828.doc 200418452 實例1 編號,K1 R2 R3 R4 Rs iu 120. Η cr°^ nh2 H ch3 121. Η -OCH(CH3)2 H H ch3 122. Η -och3 -NH(S02)CH3 H ch3 123. Η -och(ch3)2 H ch3 124. Η -OH 〇〇Λ H ch3 125. Η 〇〇Λ H ch3 ^〇-F 126. Η -och3 Cl H ch3 K^f 127. Η -OCH(CH3)2 ch3 h H ch3 KD^f 128. Η 〇〇Λ H ch3 ^0~F 129. Η -OCH(CH3)2 -CN H ch3 130. Η -och3 H H -ch2ch3 131. Η -OCH(CH3)2 1 H H ch3 \^\)rY 132. Η -OCH(CH3)2 H ch3 133. Η -OCH(CH3)2 c丨^^气 H H ch3 心F 134. Η -OCH(CH3)2 。汾 H ch3 135. Η -〇ch(ch3)2 -NHC(=0)NH2 H ch3 136. Η -OCH(CH3)2 -n(ch(ch3)2so2ch3 H ch3 -146- 88828.doc 200418452 實例 編號 Ri r2 R3 R4 Rs R6 137. Η -OCH(CH3)2 〇>-νΛ H3C V H ch3 138. Η -OCH(CH3)2 ch3 H ch3 139. Η -OCH(CH3)2 ν·ν-λ V% H ch3 140. Η -OCH(CH3)2 广νΛ H ch3 141. Η -OCH(CH3)2 OH H ch3 142. Η -OCH(CH3)2 〇0^ H ch3 143. Η -OCH(CH3)2 -so2nhch3 H ch3 144. Η -OCH(CH3)2 -S02N(CH3)2 H ch3 145. Η -och(ch3)2 -NH(S02)CH(CH3)2 H ch3 146. Η -och(ch3)2 -C(=0)NH2 H ch3 147. Η -OCH(CH3)2 H ch3 148. Η -och(ch3)2 -NHC(CH3)3 H ch3 149. Η -OCH(CH3)2 -so2nh2 H ch3 ^〇-p 150. Η -OCH(CH3)2 crK8 H ch3 151. Η -OCH(CH3)2 H ch3 -147- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 R5 R6 152. Η -OCH(CH3)2 H ch3 153. Η -OCH(CH3)2 H ch3 ^0"F 154. Η -OCH(CH3)2 〇》si H ch3 155.」 Η -OCH(CH3)2 4 0 H ch3 心F 156. * Η -OCH(CH3)2 h3c> H ch3 157. Η -OCH(CH3)2 H ch3 158. Η -OCH(CH3)2 -och3 H ch3 159. Η -och(ch3)2 h3C\ ch3 H ch3 160. Η -och(ch3)2 -C(=0)H H ch3 161. Η -OCH(CH3)2 F N H ch3 162. Η -OCH(CH3)2 -CH2NHS02CH3 H ch3 163. Η -OCH(CH3)2 CH, 。0 H ch3 ^0"f 164. Η -〇ch(ch3)2 Η〇〜νΛ H3cA H ch3 hChF 165. Η OH -och3 H ch3 166. Η -OCH2CH3 〇〇Λ H ch3 -148- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs 167. Η Fxx〇v > 〇0^ H ch3 168. Η -OCH(CH3)2 H ch3 169. Η -OCH(CH3)2 H ch3 170. Η -OCH(CH3)2 F-M F H ch3 171. ' Η -och(ch3)2 H ch3 f〇~F 172. Η -ochf2 〇〇Λ H ch3 173. Η Cr°> 〇〇Λ H ch3 174. Η -OH -nhso2ch3 H ch3 175. Η -OCH(CH3)2 H ch3 176. Η -OCH(CH3)2 p。 HO H ch3 177. Η -OCH(CH3)2 H ch3 心F 178. Η -〇ch(ch3)2 h3c, H ch3 \Όη 179. Η -OCH(CH3)2 -30^ H ch3 ^〇-f 180. Η 〇〇Λ H ch3 -149- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs R6 181. Η -och3 (ΧοΛ Η ch3 182. Η -OH -nh2 Η ch3 183. Η 0uv > Η ch3 184… Η -OCH(CH3)2 〇Γ Η ch3 185、 Η -och(ch3)2 Η2ΝγΝ^ 〇 Η ch3 186. Η -OCH(CH3)2 3〇Λ Η ch3 187. Η -OCH(CH3)2 -COOH Η ch3 188. Η -OCH(CH3)2 广νΛ Η ch3 189. Η -OCH(CH3)2 Η ch3 190. Η -〇ch(ch3)2 Η ch3 191. Η -OCH(CH3)2 0 Η ch3 192. Η -OH -ορ Η ch3 193. Η -OCH(CH3)2 η/。2 Η ch3 ^0"f 194. Η -OCH(CH3)2 (ΤοΛ Η ch3 -150- 88828.doc 200418452 實例 編號 Ri r2 Ra R4 ^5 R6 195. Η -OCH(CH3)2 ^so2 , H3C 、ΝΛ ch2 Η ch3 196. Η -OCH(CH3)2 -C(=0)CH3 Η ch3 197. Η -och(ch3)2 -nhso2ch3 Η -CH(CH3)2 198.: Η -〇ch(ch3)2 y=^N h3c Η ch3 199、 Η -OCH(CH3)2 -NHS02CH3 Η fO-F 200. Η -OCH(CH3)2 -NHSO2CH3 Η -ch2ch3 201. 、Η 〇〇Λ Η ch3 202. Η -och(ch3)2 -C(CH3)20H Η ch3 心F 203. Η ch3 CH3 ^ 〇Ολ Η ch3 204. Η ch3 H3C^X〇v h3c > 〇Ολ Η ch3 205. Η -OCH(CH3)2 \^N Η ch3 ^〇-F 206. Η Cl—^ Jf 〇〇Λ Η ch3 207. Η H-C /TO N.人V 〇〇Λ Η ch3 心F 208. Η -och3 -OH Η ch3 -151 - 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs 209. Η ν^μ 〇〇Λ Η ch3 210. Η /CH3 〇〇Λ Η ch3 211. Η -och3 Η ch3 212. Η F^rv CH3 〇〇Λ Η ch3 213. Η Nlv 〇Ολ Η ch3 ^0^F 214. Η 尸3 0 〇、人〇〆 〇Ολ Η ch3 215. Η -0CH2C(=0)CH3 〇Ολ Η ch3 216. Η 9 〇Ολ Η ch3 217. Η n^ch3 h3c 〇Ολ Η ch3 ^0"f 218. Η 〇0Λ Η ch3 219. Η -OCH(CH3)2 Η ch3 220. Η -OCH(CH3)2 Η ch3 -152- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs 221. Η -och3 ^so2 , H3C ΝΛ h3c 人^ch3 H ch3 ^0^F 222. Η -OCH(CH3)2 -CH(OH)CH3 H ch3 223. Η -och(ch3)2 H ch3 心F 224. Η -OCH(CH3)2 -ch2oh H ch3 225. Η 〇〇Λ H ch3 226. * Η -0(CH2)20CH3 〇〇Λ H ch3 227. Η -OCH(CH3)2 H ch3 228. Η h3C\ /N、n Wv Cl 〇〇Λ H ch3 229. Η ch3 〇Ολ H ch3 ^0"F 230. Η -och(ch3)2 H ch3 231. Η -och(ch3)2 cf77 -\η3 H ch3 232. Η -OCH(CH3)2 fY^ N-N h3c H ch3 233. Η -och(ch3)2 h3c H ch3 234. Η -〇ch(ch3)2 ,S〇2 , ¥ V\ Cl H ch3 -153 - 88828.doc 200418452 實例 編號 Ri R2 r3 R4 r5 Re 235. Η -och(ch3)2 ch3 h3c H ch3 236. Η -och3 H ch3 H〇^f 237. Η -OCH(CH3)2 -CH2N(CH3)2 H ch3 238. Η -OCH(CH3)2 -CH(OH)CH(CH3)2 H ch3 239. Η -OCH(CH3)2 r H ch3 240. Η -och3 s 〇、ch3 H ch3 241. Η -OCH(CH3)2 r H ch3 242. Η -OCH(CH3)2 H3C-〇 H ch3 243. Η H -nhso2ch3 H ch3 244. Η -och(ch3)2 H ch3 H〇^f 245. Η -OCH(CH3)2 ch3 H ch3 ❹F 246. Η -OCH(CH3)2 ch3 it ch3 H ch3 H〇^f 247. Η -OCH(CH3)2 H ch3 Η〇^ρ -154- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs R6 248. Η -och(ch3)2 rN ch3 Η ch3 249. Η -och(ch3)2 -CH2N(CH3)S〇2CH3 Η ch3 ^0^F 250. Η ΗΟν ch3 〇〇Λ Η ch3 251. Η Xv h3c r 〇〇Λ Η ch3 252. Η OH H3C^^〇yi 〇〇Λ Η ch3 ^0~F 253. Η -OCH(CH3)2 ho、^ch3 >ο2 h3c Η ch3 254. Η CH3 〇〇Λ Η ch3 255. Η -OCH(CH3)2 s〇2 h3c Η ch3 ^0"f 256. Η -och3 ch3 H CH3 Η ch3 257. Η -OCH(CH3)2 Ο"7 H CH3 Η ch3 258. Η V〇'ch3 Η Η ch3 ^0"f 259. Η H〇>XX〇y Η Η ch3 ^0~F 260. Η °γ-0Η Η Η ch3 -155 - 88828.doc 200418452 實例 編號 Ri r2 r3 R4 Rs 261. Η -och3 -C(=0)CH3 H ch3 262. Η 〇〇Λ H ch3 ^0'F 263. Η V0kch3 〇〇Λ H ch3 264. Η -OCH(CH3)2 ch3 H3C CH3 H ch3 265. Η -OCH(CH3)2 cr^ H ch3 266. Η -och3 -CN H ch3 267. Η η〇ΛΧΧ〇^ 〇〇Λ H ch3 \Qn 268. Η °γ-ΟΗ 〇〇Λ H ch3 269. Η -OCH(CH3)2 h3c-so2 ch3 H ch3 270. Η -OCH(CH3)2 h3C 一 〇、ch3 H ch3 271. Η -OCH(CH3)2 S-3 N气 ch3 H ch3 V\jTy 156- 88828.doc 200418452 實例 編號 Ri R2 r3 R| Rs R6 272. Η -OCH(CH3)2 h3c - OH H ch3 ^〇-f 273. Η -OCH(CH3)2 H ch3 心F 274. Η -OCH(CH3)2 〇-N H ch3 心F 275. Η -OCH(CH3)2 ct7 S〇2 CH3 H ch3 276. Η -OH -C(=0)CH3 H ch3 277. Η -och3 Η3〇^〇2-νΛ h3c> H ch3 278. Η -och3 Η n H ch3 279. Η -OCH(CH3)2 H ch3 280. Η -〇ch3 ch3 〇、ch3 H ch3 ^0"f 281. Η -OCH(CH3)2 η”〇2、Λ H ch3 282. Η -OCH(CH3)2 ^.so2 , H3C、νΛ ch3 H ch3 心F 283. Η -OCH(CH3)2 O-N H ch3 -157- 88828.doc 200418452 實例 編號 Ri r2 r3 R4 Rs R6 284. Η -och(ch3)2 ^so2 ¥ H3C^ H ch3 285. Η -OCH(CH3)2 cv H ch3 ^0F 286. Η -OCH(CH3)2 〇 H ch3 287. Η -OH /s〇2 , ch3 H ch3 ^〇-F 288. Η H2c^^°y ^so2 ^ ch2 H ch3 289. Η -och3 /S〇2 , H3C H3cA〇 H ch3 290. Η -och3 η”\λ NC^〇h3 H ch3 291. Η -och3 Η/\Λ ct1 H ch3 ^〇-ρ 292. Η -OCH(CH3)2 /SO, ¥ 〇 H ch3 293. Η h3c ch3 0 乂0 V 〇〇Λ H ch3 -158- 88828.doc 200418452 實例 編5虎 Ri r2 r3 R4 Rs Re 294. Η h3c ch3 0 乂0 ό^° V /S02 -T ¥ 'Λ h3c」 H ch3 295. Η -och3 H ch3 296., Η -och3 H ch3 ^0F 297. Η -OH /S〇2 , Μ H3c」 H ch3 298. Η -ochf2 /S〇2 -T H3C ch3 H ch3 ^0~F 299. Η -och3 h广 3〇2、Λ (y H ch3 300. Η -ch3 -C(CH3)2〇H H ch3 301. Η -ch3 -C(=0)CH3 H ch3 H〇^f 302. Η h3c ch3 〇X〇 V /S〇2 -r H3C "νΛ ch3 H ch3 303. Η -〇ch3 哕丫\ h3〆、 H ch3 304. Η -och3 H3C^yZZ7 HN ch3 H ch3 305. Η 〇-ch3 °"χλ V /S〇2 -r ΊΛ ch3 H ch3 ^0"f 159- 88828.doc 200418452 實例 編5虎 Ri R2 R3 «4 Rs R6 306. Η Y〇-CH3 δ, V ^so2 ^ CH3 H ch3 307. Η -och3 F H ch3 308. Η -och3 c— H ch3 ^0^F 309. 4 Η -och3 Ct7 f〇2 ch3 H ch3 310. Η -och3 V 0、 、ch3 H ch3 311. Η OH V ch3 H ch3 312. Η °Y〇H V /S02 1 CH3 H ch3 313. Η -och3 Vn H ch3 314. Η -OH h3c ch3 H ch3 315. Η -och3 〇 H ch3 -160- 88828.doc 200418452 實例 編號 Ri r2 R3 R4 Rs 316. Η -och3 〇’cf3 H ch3 317. Η -och3 H ch3 318. Η -och3 h3c ch3 H ch3 〇 h3c> 319. Η /^N s人V ^so2 , H^c ch3 H ch3 320. Η H.C - s 人 〇yJ ^S〇2 1 H3C ch3 H ch3 321. Η /S〇2 ^ ¥ ch3 H ch3 322. Η -OCH(CH3)2 /S〇2 -7 \-^OH Φ F H ch3 ^0"f 323. Η -〇ch3 CC ch3 H ch3 324. Η n^ch3 ch3 /S〇2 -T h3c νΛ ch3 H ch3 ^〇-F 325. Η 〇XH3 V /S〇2 -7 ¥ ch3 H ch3 326. Η -OH /S02 ^ π H3C 丫1 ch3 H ch3 -161 - 88828.doc 20041845288828.doc -143- 200418452 Instance number Ri R2 R3 R4 Rs R6 85. Η -och3 HH ch3 Cl 86. Η -ch (ch3) 2 HH ch3 87. Η -och2ch3 HH ch3 Cl 88. Η -och3 HH ch3 89 Η Cl HH ch3 K) 90. Η -OCH (CH3) HH ch3 91. Η -och (ch3) 3 HH ch3 92. Η -〇ch (ch3) 2 Br H ch3 93. Η -och3 HH ch3 94. Och -och3 och3 H ch3 95. Η -OCH (CH3) 2 HH ch3 96. Η FHH ch3 97. Η -OCH (CH3) COOH ch3 H ch3 98. Η -och (ch3) 2 -NH (C = 0) CH3 H ch3 99. Η -OCH (CH3) 2 HH ch3 100. Η -OCH (CH3) 2 o, H ch3 101. Η -OCH (CH3) 2 〇Λ H ch3 102. Η -och3 -〇ch3 H ch3 -144- 88828.doc 200418452 Example number Ri R2 r3 R4 Rs 103. Η-och3 〇〇Λ ch3 104. Η -OCH (CH3) 2 H Η ch3 105. Η -och (ch3) 2 H Η ch3 OH 106 Η -och (ch3) 2 H Η ch3 ^ 〇 ~ cn 107. Η -och3 H Η ch3 108. Η -och (ch3) 2 H3C ^ S〇2 Η ch3 109. Η -OCH (CH3) 2 ΟνΛ Η ch3 110. Η -OCH (CH3) 2 ρΛ HO Η ch3 111. Η -OCH (CH3) 2 -N (CH3) S02CH3 Η ch3 ^ 0 ~ F 112. Η -OCH (CH3) 2 Η ch3 113. Η- OCH (CH3) 2 H〇v ^ HO 'Η ch3 ^ 0 " F 114. Η -och (ch3) 2 -NHCH (CH3) 2 Η ch3 115. Η -och (ch3) 2 Η ch3 116. Η -och3 Η ch3 117. Η 〇〇Λ Η ch3 ^ 0 ^ F 118. Η -ch2oh Η Η ch3 119. Η -OCH (CH3) 2 η3〇- ° ^ χνΛ ch3 Η ch3 H〇 ~ f -145-88828.doc 200418452 Example 1 number, K1 R2 R3 R4 Rs iu 120. Η cr ° ^ nh2 H ch3 121. Η -OCH (CH3) 2 HH ch3 122. Η -och3 -NH (S02) CH3 H ch3 123. Η -och (ch3) 2 H ch3 124. Η -OH 〇〇Λ H ch3 125. Η 〇〇Λ H ch3 ^ 〇-F 126. Η -och3 Cl H ch3 K ^ f 127. Η -OCH (CH3) 2 ch3 h H ch3 KD ^ f 128. Η 〇〇Λ H ch3 ^ 0 ~ F 129. Η -OCH (CH3) 2 -CN H ch3 130. Η -och3 HH -ch2ch3 131. Η -OCH (CH3) 2 1 HH ch3 \ ^ \) rY 132. Η -OCH (CH3) 2 H ch3 133. Η -OCH (CH3) 2 c 丨 ^^ H H ch3 Heart F 134. O -OCH (CH3) 2. Fen H ch3 135. Η -〇ch (ch3) 2 -NHC (= 0) NH2 H ch3 136. Η -OCH (CH3) 2 -n (ch (ch3) 2so2ch3 H ch3 -146- 88828.doc 200418452 Example number Ri r2 R3 R4 Rs R6 137. Η -OCH (CH3) 2 〇 > -νΛ H3C VH ch3 138. Η -OCH (CH3) 2 ch3 H ch3 139. Η -OCH (CH3) 2 ν · ν-λ V % H ch3 140. Η -OCH (CH3) 2 ννH H ch3 141. Η -OCH (CH3) 2 OH H ch3 142. Η -OCH (CH3) 2 〇0 ^ H ch3 143. Η -OCH (CH3) 2 -so2nhch3 H ch3 144. Η -OCH (CH3) 2 -S02N (CH3) 2 H ch3 145. Η -och (ch3) 2 -NH (S02) CH (CH3) 2 H ch3 146. Η -och (ch3 ) 2 -C (= 0) NH2 H ch3 147. Η -OCH (CH3) 2 H ch3 148. Η -och (ch3) 2 -NHC (CH3) 3 H ch3 149. Η -OCH (CH3) 2 -so2nh2 H ch3 ^ 〇-p 150. Η -OCH (CH3) 2 crK8 H ch3 151. Η -OCH (CH3) 2 H ch3 -147- 88828.doc 200418452 Example number Ri R2 r3 R4 R5 R6 152. Η -OCH ( CH3) 2 H ch3 153. Η -OCH (CH3) 2 H ch3 ^ 0 " F 154. Η -OCH (CH3) 2 〇》 si H ch3 155. '' O -OCH (CH3) 2 4 0 H ch3 Heart F 156. * Η -OCH (CH3) 2 h3c > H ch3 157. Η -OCH (CH3) 2 H ch3 158. Η -OCH (CH3) 2 -och3 H ch3 159. Η -och (ch3) 2 h3C \ ch3 H ch3 160. Η -och (ch3) 2 -C (= 0) HH ch3 161. Η -OCH (CH3) 2 FNH ch3 162. Η -OCH (CH3) 2 -CH2NHS02CH3 H ch3 163. Η -OCH (CH3) 2 CH,. 0 H ch3 ^ 0 " f 164. Η -〇ch (ch3) 2 Η〇 ~ νΛ H3cA H ch3 hChF 165. Η OH -och3 H ch3 166. Η -OCH2CH3 〇〇Λ H ch3 -148- 88828.doc 200418452 Example number Ri R2 R3 R4 Rs 167. Η Fxx〇v > 〇0 ^ H ch3 168. Η -OCH (CH3) 2 H ch3 169. Η -OCH (CH3) 2 H ch3 170. Η -OCH (CH3) 2 FM FH ch3 171. 'Η -och (ch3) 2 H ch3 f〇 ~ F 172. Η -ochf2 〇〇Λ H ch3 173. Η Cr ° > 〇〇Λ H ch3 174. Η -OH -nhso2ch3 H ch3 175. Η -OCH (CH3) 2 H ch3 176. Η -OCH (CH3) 2 p. HO H ch3 177. Η -OCH (CH3) 2 H ch3 Heart F 178. Η -〇ch (ch3) 2 h3c, H ch3 \ Όη 179. Η -OCH (CH3) 2 -30 ^ H ch3 ^ 〇-f 180. Η 〇〇Λ H ch3 -149- 88828.doc 200418452 Example number Ri R2 r3 R4 Rs R6 181. Η -och3 (ΧοΛ Η ch3 182. Η -OH -nh2 Η ch3 183. Η 0uv > Η ch3 184 … -OCH (CH3) 2 〇Γ Η ch3 185, Η -och (ch3) 2 Η2ΝγΝ ^ 〇Η ch3 186. Η -OCH (CH3) 2 3〇Λ Η ch3 187. Η -OCH (CH3) 2- COOH Η ch3 188. Η -OCH (CH3) 2 ννΛ Η ch3 189. Η -OCH (CH3) 2 Η ch3 190. Η -〇ch (ch3) 2 Η ch3 191. Η -OCH (CH3) 2 0 Η ch3 192. Η -OH -ορ Η ch3 193. Η -OCH (CH3) 2 η /. 2 Η ch3 ^ 0 " f 194. Η -OCH (CH3) 2 (ΤοΛ Η ch3 -150- 88828.doc 200418452 Example Number Ri r2 Ra R4 ^ 5 R6 195. Η -OCH (CH3) 2 ^ so2, H3C, ΝΛ ch2 Η ch3 196. Η -OCH (CH3) 2 -C (= 0) CH3 Η ch3 197. Η -och ( ch3) 2 -nhso2ch3 Η -CH (CH3) 2 198 .: Η -〇ch (ch3) 2 y = ^ N h3c Η ch3 199, Η -OCH (CH3) 2 -NHS02CH3 Η fO-F 200. Η -OCH (CH3) 2 -NHSO2CH3 Η -ch2ch3 201. Η 〇〇Λ ch3 202. Η -och (ch3) 2 -C (CH3) 20H Η ch3 Heart F 203. Η ch3 CH3 ^ 〇〇λ λ ch3 204. Η ch3 H3C ^ X〇v h3c > 〇〇λ ch ch3 205. Η -OCH (CH3) 2 \ ^ N Η ch3 ^ 〇-F 206. Η Cl— ^ Jf 〇〇Λ Η ch3 207. Η HC / TO N. Human V 〇〇Λ Η ch3 heart F 208. Η -och3 -OH ch3 -151-88828.doc 200418452 Example number Ri R2 r3 R4 Rs 209. Η ν ^ μ 〇〇Λ ch3 210. Η / CH3 〇〇Λ ch3 211. Η -och3 Η ch3 212. Η F ^ rv CH3 〇〇Λ Η ch3 213. Η Nlv 〇〇λ ch ch3 ^ 0 ^ F 214. Η Corpse 3 0 〇, person 〇〆〇〇λ ch3 215. Η -0CH2C (= 0) CH3 〇〇λ Η ch3 216. Η 9 〇〇λ Η ch3 217. Η n ^ ch3 h3c 〇〇λ Η ch3 ^ 0 " f 218. Η 〇0Λ Η ch3 219. Η -OCH (CH3) 2 Η ch3 220. Η -OCH (CH3) 2 Η ch3 -152- 88828.doc 200418452 instance number Ri R2 R3 R4 Rs 221. Η -och3 ^ so2, H3C ΝΛ h3c human ^ ch3 H ch3 ^ 0 ^ F 222. Η -OCH (CH3) 2 -CH (OH ) CH3 H ch3 223. Η -och (ch3) 2 H ch3 Heart F 224. Η -OCH (CH3) 2 -ch2oh H ch3 225. Η 〇〇Λ H ch3 226. * Η -0 (CH2) 20CH3 〇〇Λ H ch3 227. Η -OCH (CH3) 2 H ch3 228. Η h3C \ / N, n Wv Cl 〇〇Λ H ch3 229. Η ch3 〇〇λ H ch3 ^ 0 " F 230. Η -och (ch3) 2 H ch3 231. Η -och (ch3) 2 cf77-\ η3 H ch3 232. Η -OCH (CH3) 2 fY ^ NN h3c H ch3 233. Η -och (ch3) 2 h3c H ch3 234. Η -〇ch (ch3) 2, S〇2, ¥ V \ Cl H ch3 -153-88828.doc 200418452 instance number Ri R2 r3 R4 r5 Re 235. Η -och (ch3) 2 ch3 h3c H ch3 236. Η -och3 H ch3 H〇 ^ f 237. Η -OCH (CH3) 2 -CH2N (CH3) 2 H ch3 238. Η -OCH (CH3) 2 -CH (OH) CH (CH3) 2 H ch3 239. Η- OCH (CH3) 2 r H ch3 240. Η -och3 s 〇, ch3 H ch3 241. Η -OCH (CH3) 2 r H ch3 242. Η -OCH (CH3) 2 H3C-〇H ch3 243. Η H- nhso2ch3 H ch3 244. Η -och (ch3) 2 H ch3 H〇 ^ f 245. Η -OCH (CH3) 2 ch3 H ch3 ❹F 246. Η -OCH (CH3) 2 ch3 it ch3 H ch3 H〇 ^ f 247 Η -OCH (CH3) 2 H ch3 Η〇 ^ ρ -154- 88828.doc 200418452 Example number Ri R2 R3 R4 Rs R6 248. Η -och (ch3) 2 rN ch3 Η ch3 249. Η -och (ch3) 2 -CH2N (CH3) S〇2CH3 Η ch3 ^ 0 ^ F 250. Η ΗΟν ch3 〇〇Λ Η ch3 251. Η Xv h3c r 〇〇Λ Η ch3 252. Η OH H3C ^^ 〇yi 〇〇Λ ch ch3 ^ 0 ~ F 253. Η -OCH (CH3) 2 ho, ^ ch3 > ο2 h3c Η ch3 254 Η CH3 〇〇Λ Η ch3 255. Η -OCH (CH3) 2 s〇2 h3c Η ch3 ^ 0 " f 256. Η -och3 ch3 H CH3 Η ch3 257. Η -OCH (CH3) 2 〇 " 7 H CH3 Η ch3 258. Η V〇'ch3 Η Η ch3 ^ 0 " f 259. Η H〇 > XX〇y Η ch ch3 ^ 0 ~ F 260. Η ° γ-0Η Η ch ch3 -155-88828.doc 200418452 Example number Ri r2 r3 R4 Rs 261. Η -och3 -C (= 0) CH3 H ch3 262. Η 〇〇Λ H ch3 ^ 0'F 263. Η V0kch3 〇〇Λ H ch3 264. Η -OCH (CH3 ) 2 ch3 H3C CH3 H ch3 265. Η -OCH (CH3) 2 cr ^ H ch3 266. Η -och3 -CN H ch3 267. Η η〇ΛΧΧ〇 ^ 〇〇Λ H ch3 \ Qn 268. Η ° γ- ΟΗ 〇〇Λ H ch3 269. Η -OCH (CH3) 2 h3c-so2 ch3 H ch3 270. Η -OCH (CH3) 2 h3C 10, ch3 H ch3 271. Η -OCH (CH3) 2 S-3 N Gas ch3 H ch3 V \ jTy 156- 88828.doc 200418452 Example number Ri R2 r3 R | Rs R6 272. Η -OCH (CH3) 2 h3c-OH H ch3 ^ 〇-f 273. Η -OCH (CH3) 2 H ch3 heart F 274. Η -OCH (CH3) 2 〇-NH ch3 heart F 275. Η -OCH (CH3) 2 ct7 S〇2 CH3 H ch3 276. Η -OH -C (= 0) CH3 H ch3 277. Η -och3 Η3〇 ^ 〇2-νΛ h3c > H ch3 278. Η -och3 Η n H ch3 279. Η -OCH (CH3) 2 H ch3 280. Η -〇ch3 ch3 〇, ch3 H ch3 ^ 0 " f 281. Η -OCH (CH3) 2 η ”〇 2. Λ H ch3 282. Η -OCH (CH3) 2 ^ .so2, H3C, νΛ ch3 H ch3 Heart F 283. Η -OCH (CH3) 2 ON H ch3 -157- 88828.doc 200418452 instance number Ri r2 r3 R4 Rs R6 284. Η -och (ch3) 2 ^ so2 ¥ H3C ^ H ch3 285. Η -OCH (CH3) 2 cv H ch3 ^ 0F 286. Η -OCH (CH3) 2 〇H ch3 287. Η -OH / s〇2, ch3 H ch3 ^ 〇-F 288. Η H2c ^^ ° y ^ so2 ^ ch2 H ch3 289. Η -och3 / S〇2, H3C H3cA〇H ch3 290. Η -och3 η "\ λ NC ^ 〇h3 H ch3 291. Η -och3 Η / \ Λ ct1 H ch3 ^ 〇-ρ 292. Η -OCH (CH3) 2 / SO, ¥ 〇H ch3 293. Η h3c ch3 0 乂 0 V 〇〇Λ H ch3 -158- 88828.doc 200418452 Examples 5 Tiger Ri r2 r3 R4 Rs Re 294. Η h3c ch3 0 乂 0 ό ^ ° V / S02 -T ¥ 'Λ h3c 」H ch3 295. Η -och3 H ch3 296 ., Η -och3 H ch3 ^ 0F 297. Η -OH / S〇2 Μ H3c '' H ch3 298. Η -ochf2 / S〇2 -T H3C ch3 H ch3 ^ 0 ~ F 299. Η -och3 h 广 302, Λ (y H ch3 300. Η -ch3 -C (CH3) 2〇HH ch3 301. Η -ch3 -C (= 0) CH3 H ch3 H〇 ^ f 302. Η h3c ch3 〇X〇V / S〇2 -r H3C " νΛ ch3 H ch3 303. Η -〇ch3哕 丫 \ h3〆, H ch3 304. Η -och3 H3C ^ yZZ7 HN ch3 H ch3 305. Η 〇-ch3 ° " χλ V / S〇2 -r ΊΛ ch3 H ch3 ^ 0 " f 159- 88828.doc 200418452 Example series 5 Tiger Ri R2 R3 «4 Rs R6 306. Η Y〇-CH3 δ, V ^ so2 ^ CH3 H ch3 307. Η -och3 FH ch3 308. Η -och3 c— H ch3 ^ 0 ^ F 309. 4 Η -och3 Ct7 f〇2 ch3 H ch3 310. Η -och3 V 0, ch3 H ch3 311. Η OH V ch3 H ch3 312. Η ° Y〇HV / S02 1 CH3 H ch3 313. Η -och3 Vn H ch3 314. Η -OH h3c ch3 H ch3 315. Η -och3 〇H ch3 -160- 88828.doc 200418452 instance number Ri r2 R3 R4 Rs 316. Η -och3 〇'cf3 H ch3 317. Η -och3 H ch3 318. Η -och3 h3c ch3 H ch3 〇h3c > 319. Η / ^ N s person V ^ so2, H ^ c ch3 H ch3 320. Η HC-s person 〇yJ ^ S〇2 1 H3C ch3 H ch3 321. Η / S〇2 ^ ¥ ch3 H ch3 322. Η -OCH (CH3) 2 / S〇2 -7 \-^ OH Φ FH ch3 ^ 0 " f 323. Η -〇ch3 CC ch3 H ch3 324. Η n ^ ch3 ch3 / S〇2 -T h3c νΛ ch3 H ch3 ^ 〇-F 325. Η 〇XH3 V / S〇2 -7 ¥ ch3 H ch3 326. Η -OH / S02 ^ π H3C y1 ch3 H ch3 -161-88828.doc 200418452
實例 編號 Ri R2 R3 R4 Rs 327. Η °Α V /S02 -r ch3 H ch3 328. Η Ο, V /S02 1 ch3 H ch3 329. Η h3c η3〇^°Τ° V /S〇2 1 H3C ch3 H ch3 330. Η -och3 /S〇2 -, ¥ H ch3 ^0"F 331· Η -och3 η/\Λ V N h3c H ch3 ^0"f 332. Η -F /S02 1 H H ch3 ^0~F 333. Η -F /S〇2 -r h3c^ H ch3 ^0~F 334. Η -och3 h3c,s〇2 H ch3 ^OκF 335. Η -CH2CH3 ? Η〆。 H ch3 ^0*~f 336. Η -OCH3 H3C\ , ch3 H ch3 ^0F -162- 88828.doc 200418452Example number Ri R2 R3 R4 Rs 327. Η ° Α V / S02 -r ch3 H ch3 328. Η 〇, V / S02 1 ch3 H ch3 329. Η h3c η3〇 ^ ° Τ ° V / S〇2 1 H3C ch3 H ch3 330. Η -och3 / S〇2-, ¥ H ch3 ^ 0 " F 331 · Η -och3 η / \ Λ VN h3c H ch3 ^ 0 " f 332. Η -F / S02 1 HH ch3 ^ 0 ~ F 333. Η -F / S〇2 -r h3c ^ H ch3 ^ 0 ~ F 334. Η -och3 h3c, so2 H ch3 ^ OκF 335. Η -CH2CH3??. H ch3 ^ 0 * ~ f 336. Η -OCH3 H3C \, ch3 H ch3 ^ 0F -162- 88828.doc 200418452
實例 編號 Ri r2 R3 R4 Rs R6 337. Η -CH2CH3 Άλ F H ch3 338. Η -o(ch2)2ch3 ch3 H ch3 339. Η -CH2CH3 -c(ch3)2oh H ch3 ^0^F 340. Η -ch2ch3 -C(=0)CH3 H ch3 hcyp 341… Η -OH ηνΛ h3c^ H ch3 hcyp 342. C1 -h3c ^ h3c^ H ch3 F〇~f 343. Η -CH2CH3 ¥ cf .H ch3 \Qn 344. Η -OCH3 h3C\ H ch3 345. Η -OCH3 〇 H ch3 \Qr^ 346. Η ;A V /S02 ^ H3C 、νΛ 1 ch3 H ch3 ^0~F 347. Η 〇CH V /S02 1 H3° ννΛ ch3 H ch3 348. Η -0(CH2)2CH3 /S〇2 -T CH3 H ch3 ❹F -163- 88828.doc 200418452 實例 編號 Ri r2 R3 «4 Rs Re 349. Η H2C'v /S02 -r H3C "Λ CH3 H ch3 350. Η •och3 h3c^° 〇-n H ch3 351. Η ^SOz 1 h3° ch3 H ch3 352. Η 〇/CH3 / 〇 h3c °y /S02 ¥ ch3 H ch3 353. Η so. HsC· χχ V /S〇2 -T H^c ch3 H ch3 ^o~p 354. Η -OH HV 〇 H ch3 355. Η 0 、ch3 ^so2 ^ 1 ch3 H ch3 \Qn 356. Η N V /S02 ¥ ch3 H ch3 \QtY 357. Η V /S〇2 -T ¥ CH3 H ch3 358. Η -och3 H ch3 -164- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs R6 359. Η Ιν Ν r Ρ 〇-Λ ch3 ^S02 1 π 1 ch3 H ch3 ^0^F 360… Η F ^so2 ^ ¥ CH3 H ch3 ^0"f 361. * Η -OCH(CH3)2 ^so2 , ¥ cy H ch3 362. Cl -och3 N 7 h3c^ H ch3 ^0F 363. Cl -och3 h3c^ H ch3 364. Η -OH h3c^ H ch3 365. Η Br h3c」 H ch3 366. Η h3c^ H ch3 367. Η H.C HN^ h3c^ H ch3 hG^f 368. Η -och3 rr^ V-N ΓΝΗ2 H ch3 \Qn 369. Η h3c r /S02 1 ¥ CH3 H ch3 -165- 88828.doc 200418452 實例 編號 Ri R2 R3 R4 Rs R6 370. Η ΟΗ 人V h3c ^ /S〇2 -T H3C CH3 H ch3 371. Η Ν^κ, 卜V CH3 ^so2 H3° ννΛ ch3 H ch3 372. Η •och3 h3c 0 〇-N H ch3 373. Η /S、N h3c二〆 H3C^ ^S〇2 1 H3C 、ΝΛ 1 CH3 H ch3 374. Η /S02 1 HaC ννΛ 〇h3 H ch3 心F 375. Η -OCH(CH3)2 HzN^ HO \ ch3 H ch3 376. Η -och(ch3)2 h3c ^ η3〇Λ^ H ch3 ^0~F 377. Η -och3 〇 H ch3 378. Η -och3 ch3 it ch3 H -ch2ch3 ^0^F 379. Η -och3 ch3 妒 ch3 H -CH(CH3)2 F〇~f 380. Η -och3 ch3 ch3 H ^0F 381. Η -OCH(CH3)2 〇 H ch3 -166- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs R6 382. Η h3c ^so2 i h3c νΛ έπ3 H ch3 ^0^F 383. Η -〇ch3 H3CV 丫^ n-nh H ch3 384. Η -och3 H,C H3C NH2 H ch3 \Qn 385. Η -och3 h3c H H3U NH >hCH3 〇 H ch3 386. Η j_〇 h〇^^ /S〇2 -T HaC ch3 H ch3 387. Η -och3 ch3 H ch3 \J\JTY 388. Η ^so2 ^ H3° χνΛ ch3 H ch3 ^〇-f 389. Η -och3 0 H ch3 390. Η -och3 HX NH h3c’S〇2 H ch3 391. Η V ςΫ Br^ H ch3 392. Η r° y ch3 /so: i ch3 H ch3 393. Η ho y /S〇2 -7 ¥ ch3 H ch3 -167- 88828.doc 200418452 實例 編號 Ri r2 r3 R4 Rs R6 394. Η -och3 'Λ ch3 H ch3 ^0^F 395. Η Νν ν ^so2 , H3C ch3 H ch3 396. Η ^so2 H^c CH3 H ch3 397." Η ,^Ν /S02 , ch3 H ch3 398. Η CCv /S〇2 1 H3C "νΛ I ch3 H ch3 ^0F 399. Η 0.0, /S〇2 ^ H3C ch3 H ch3 400. Η -och3 h3c ch3 H ch3 F 401. Η <χν H,C ch3 H ch3 H〇~f 402. Η Η?Ν Ίν ^so2 H3C έπ3 H ch3 心F 403. Η h3c、 ν^μ ν^ν CI /S02 -, H3C ch3 H ch3 404. Η ϋ〜ν /S〇2 -, H3C ' ch3 H ch3 f〇~F 405. Η /S〇2 -7 H^c CH3 H ch3 ❹F 406. Η -〇ch3 H -7 ηΛ H ch3 -168- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs 407. Η OWCH3 ch3 ^S02 1 ¥ H Η ch3 408. Η Ογν ch3 ^so2 , CH3 Η ch3 409. Η y〇、N h3cAA^o^ h3c ch3 Η ch3 \Qn 410. Η HaC ch3 Η ch3 411. Η H -C(=0)CH3 Η ch3 K^f 412. Η -H^ch3 h3c Oy ^so2 1 CH3 Η ch3 ^0F 413. Η H,产V h3c /S02 -7 ΊΛ ch3 Η ch3 414. Η -OCH2CH3 h3c ch3 Η ch3 415. Η /S〇2 ” H3C ch3 Η ch3 416. Η /S02 ^ H^c ch3 Η ch3 F〇~f 417. Η h3c h3c^X 1 3 N N 1 H V \ ,s〇2 -, HaC ννΛ ch3 Η ch3 \Qn 418. Η /S02 1 π Η Η ch3 Ky- -169- 88828.doc 200418452 實例 編號 Ri r2 R3 R4 Rs R6 419. Η V h3c it ch3 H ch3 420. Η ^so2 , H3C 'νΛ H H ch3 421. Η Ίν Η /S02 -T ¥ Ά 1 ch3 H ch3 422. Η 户〇2 H3C H ch3 ^0F 423. Η -OCH2CH3 叩 一"νΛ η3〇^ H ch3 424. Η 0 ^so2 π in3 H ch3 ^0F 425. Η ch3 /S〇2 -Γ H3C ch3 H ch3 426. Η H r-S〇2 工 H3C 、νΛ Η H ch3 ^0"f 427. Η V^v ch3 h3c ch3 H ch3 ^〇-F 428. Η h3c ch3 H ch3 429. Η 〇YCH3 ch3 H.C 'tt ch3 H ch3 V\JTY 430. Η -och3 h3c H ch3 -170- 88828.doc 200418452 實例 編號 Ri R2 r3 R4 Rs 431. Η -och3 N Η0<Λλ H ch3 432. Cl -och3 H3C^N^ Λ / h3c H ch3 心F 433. Η Q V h3c ch3 H ch3 434. Η .0〜V h3c CH3 H ch3 435. Η -/==:N S丄 H H ch3 436. Η -och3 -C(=0)CH20H H ch3 心F 437. Η /s〇2 ch3 H ch3 438. Η -OH ,S〇2 -7 π 〈νΛ *Y^h3 OH H ch3 439. Η -och3 ^so2 i k^〇H3 OH H ch3 440. Η -ch2ch3 Y0 h3c H ch3 ^0"f 441. Η a ^so2 ^ ¥ 、νΛ H H ch3 442. Η -och3 a" H ch3 -171 - 88828.doc 200418452Instance number Ri r2 R3 R4 Rs R6 337. Η -CH2CH3 Άλ FH ch3 338. Η -o (ch2) 2ch3 ch3 H ch3 339. Η -CH2CH3 -c (ch3) 2oh H ch3 ^ 0 ^ F 340. Η -ch2ch3 -C (= 0) CH3 H ch3 hcyp 341… Η -OH ηνΛ h3c ^ H ch3 hcyp 342. C1 -h3c ^ h3c ^ H ch3 F〇 ~ f 343. Η -CH2CH3 ¥ cf .H ch3 \ Qn 344. Η -OCH3 h3C \ H ch3 345. Η -OCH3 〇H ch3 \ Qr ^ 346. Η; AV / S02 ^ H3C, νΛ 1 ch3 H ch3 ^ 0 ~ F 347. ΗCHV / S02 1 H3 ° ννΛ ch3 H ch3 348. Η -0 (CH2) 2CH3 / S〇2 -T CH3 H ch3 ❹F -163- 88828.doc 200418452 instance number Ri r2 R3 «4 Rs Re 349. Η H2C'v / S02 -r H3C " Λ CH3 H ch3 350. Η • och3 h3c ^ ° 〇-n H ch3 351. ^ ^ SOz 1 h3 ° ch3 H ch3 352. Η 〇 / CH3 / 〇h3c ° y / S02 ¥ ch3 H ch3 353. Η so. HsC Χχ V / S〇2 -TH ^ c ch3 H ch3 ^ o ~ p 354. Η -OH HV 〇H ch3 355. Η 0, ch3 ^ so2 ^ 1 ch3 H ch3 \ Qn 356. Η NV / S02 ¥ ch3 H ch3 \ QtY 357. Η V / S〇2 -T ¥ CH3 H ch3 358. Η -och3 H ch3 -164- 88828.doc 200418452 Example number Ri R2 R3 R4 Rs R6 359. Η Ιν Ν r 〇-Λ ch3 ^ S02 1 π 1 ch3 H ch3 ^ 0 ^ F 360 ... Η F ^ so2 ^ ¥ CH3 H ch3 ^ 0 " f 361. * Η -OCH (CH3) 2 ^ so2, ¥ cy H ch3 362. Cl -och3 N 7 h3c ^ H ch3 ^ 0F 363. Cl -och3 h3c ^ H ch3 364. Η -OH h3c ^ H ch3 365. Η Br h3c '' H ch3 366. Η h3c ^ H ch3 367. Η HC HN ^ h3c ^ H ch3 hG ^ f 368. Η -och3 rr ^ VN ΓΝΗ2 H ch3 \ Qn 369. Η h3c r / S02 1 ¥ CH3 H ch3 -165- 88828.doc 200418452 instance number Ri R2 R3 R4 Rs R6 370. Η ΟΗ Human V h3c ^ / S〇2 -T H3C CH3 H ch3 371. Η Ν ^ κ, V V CH3 ^ so2 H3 ° ννΛ ch3 H ch3 372. Η • och3 h3c 0 〇-NH ch3 373. Η / S, N h3c 〆H3C ^ ^ S〇2 1 H3C, ΝΛ 1 CH3 H ch3 374. Η / S02 1 HaC ννΛ 〇h3 H ch3 Heart F 375. Η -OCH (CH3) 2 HzN ^ HO \ ch3 H ch3 376. Η -och (ch3) 2 h3c ^ η3〇Λ ^ H ch3 ^ 0 ~ F 377. Η -och3 〇H ch3 378. Η -och3 ch3 it ch3 H -ch2ch3 ^ 0 ^ F 379. Η -och3 ch3 jealous ch3 H -CH (CH3) 2 F〇 ~ f 380. Η -och3 ch3 ch3 H ^ 0F 381. Η -OCH (CH3) 2 〇H ch3 -166- 88828.doc 200418452 Example number Ri R2 r3 R4 Rs R6 382 . Η h3c ^ so2 i h3c νΛ έπ3 H ch3 ^ 0 ^ F 383. Η -〇ch3 H3CV ^^-nh H ch3 384. Η -och3 H, C H3C NH2 H ch3 \ Qn 385. Η -och3 h3c H H3U NH > hCH3 〇H ch3 386. Η j_〇h〇 ^^ / S〇2 -T HaC ch3 H ch3 387. Η -och3 ch3 H ch3 \ J \ JTY 388. Η ^ so2 ^ H3 ° χνΛ ch3 H ch3 ^ 〇-f 389. Η -och3 0 H ch3 390. Η -och3 HX NH h3c'S〇2 H ch3 391. Η V ς Br ^ H ch3 392. Η r ° y ch3 / so: i ch3 H ch3 393 Η ho y / S〇2 -7 ¥ ch3 H ch3 -167- 88828.doc 200418452 instance number Ri r2 r3 R4 Rs R6 394. Η -och3 'Λ ch3 H ch3 ^ 0 ^ F 395. Η Νν ν ^ so2 , H3C ch3 H ch3 396. Η ^ so2 H ^ c CH3 H ch3 397. " Η, ^ Ν / S02, ch3 H ch3 398. Η CCv / S〇2 1 H3C " νΛ I ch3 H ch3 ^ 0F 399 Η 0.0, / S〇2 ^ H3C ch3 H ch3 400. Η -och3 h3c ch3 H ch3 F 401. Η < χν H, C ch3 H ch3 H〇 ~ f 402. Η Η? Ν Ίν ^ so2 H3C έπ3 H ch3 heart F 403. Η h3c, ν ^ μ ν ^ ν CI / S02-, H3C ch3 H ch3 404. Η ϋ ~ ν / S〇2-, H3C 'ch3 H ch3 f〇 ~ F 405. Η / S 〇2 -7 H ^ c CH3 H ch3 ❹F 406. Η -〇ch3 H -7 ηΛ H ch3 -168- 88828.doc 200418452 instance number Ri R2 r3 R4 Rs 407. Η OWCH3 ch3 ^ S02 1 ¥ H Η ch3 408. Η 〇γν ch3 ^ so2, CH3 Η ch3 409. Η y〇, N h3cAA ^ o ^ h3c ch3 Η ch3 \ Qn 410. Η HaC ch3 Η ch3 411. Η H -C (= 0) CH3 Η ch3 K ^ f 412. Η -H ^ ch3 h3c Oy ^ so2 1 CH3 Η ch3 ^ 0F 413. Η H, producing V h3c / S02 -7 ΊΛ ch3 Η ch3 414. Η -OCH2CH3 h3c ch3 Η ch3 415. Η / S〇2 ”H3C ch3 Η ch3 416. Η / S02 ^ H ^ c ch3 Η ch3 F〇 ~ f 417. Η h3c h3c ^ X 1 3 NN 1 HV \, s〇2-, HaC ννΛ ch3 Η ch3 \ Qn 418. Η / S02 1 π Η ch ch3 Ky-- 169- 88828.doc 200418452 Example number Ri r2 R3 R4 Rs R6 419. Η V h3c it ch3 H ch3 420. Η ^ so2, H3C 'νΛ HH ch3 421. Η Ίν Η / S02 -T ¥ Ά 1 ch3 H ch3 422 〇 户 〇2 H3C H ch3 ^ 0F 423. Η -OCH2CH3 叩 一 " νΛ η3〇 ^ H ch3 424. Η 0 ^ so2 π in3 H ch3 ^ 0F 425. Η ch3 / S〇2 -Γ H3C ch3 H ch3 426. Η H rS〇2 H3C, νΛ Η H ch3 ^ 0 " f 427. Η V ^ v ch3 h3c ch3 H ch3 ^ 〇-F 428. Η h3c ch3 H ch3 429. Η 〇YCH3 ch3 HC 'tt ch3 H ch3 V \ JTY 430. Η -och3 h3c H ch3 -170- 88828.doc 200418452 Example number Ri R2 r3 R4 Rs 431. Och -och3 N Η0 < Λλ H ch3 432. Cl -och3 H3C ^ N ^ Λ / h3c H ch3 heart F 433. Η QV h3c ch3 H ch3 434. Η .0 ~ V h3c CH3 H ch3 435. Η-/ = =: NS 丄 HH ch3 436. Η -och3 -C (= 0) CH20H H ch3 Heart F 437. Η / s〇2 ch3 H ch3 438. Η -OH , S〇2 -7 π <νΛ * Y ^ h3 OH H ch3 439. Η -och3 ^ so2 ik ^ 〇H3 OH H ch3 440. Η -ch2ch3 Y0 h3c H ch3 ^ 0 " f 441. Η a ^ so2 ^ ¥, νΛ HH ch3 442. Η -och3 a " H ch3 -171-88828.doc 200418452
實例 編號 Ri R2 R3 R4 Rs 443. Η -0(CH2)2CH3 /S〇2 , π l H ch3 444. Η -OH in3 H ch3 ^0F 445. Η -0(CH2)2CH3 ^so2 , H ch3 ^0~F 446. * Η Vv /S〇2 -T l H ch3 447. Η N /S〇2 -7 π l H ch3 448. Η -OCH(CH3)2 H ch3 心F 449. Η -och3 H ch3 ^〇-F 450. Η a ch3 H ch3 \Qn 451. Η -OH /S02 1 1 F H ch3 ^0"F 452. Η -och3 H H ch3 453. Η -OH H H ch3 \Q 172- 88828.doc 200418452 表2.所列為表1所列實例之另外的實驗資料。 表2 實例 編號 名稱 - NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A=彡 0·5 /iM B= 03 to <:5.0 C= 5.0 to ^30 D= >30 μΜ 複製子 (liM) 1. _ 2。夫喃各基-5-甲氧 基-苯弁吱喃-3-幾酸 甲醯胺 氺氺氺 (M+H)^ 272 B <30 2. 2-苯_基-5-三氟甲氧 基-苯并呋喃-3-羧酸 甲醯胺 lH NMR in Dimethyl-^ Sulfoxide (DMSO): 8.47-8.49 (d, J=4.69Hz, H); 7.88-7.91 (dd, J=1.76Hz, 8.21Hz, 2H); 7.80-7.83 (d, J=9.38Hz, 1H); 7.50-7.57 (m, 3H); 7.38-7.41 (d, J=8.79Hz, 1H); 2.83-2.84 (d, J=4.69Hz, 3H) (M+H)+ = 336 B 氺氺氺 3. 2-(3,4-二氟基-苯基) -5-甲氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.44 (s, 1H); 7.98 (m, 1H); 7.74 (m, 1H); 7.60 (m, 2H); 7.12 (m, 1H); 7.03 (m, 1H); 3.82 (s, 3H); 2.85 (d, J=4.2Hz, 3H) (M+H)+ = 318 A <10 4. 2-[4-(乙醯基胺基-甲基)-木基]-5-異丙 氧基-苯并呋喃-3-幾 酸甲醯胺 *H NMR in DMSO: 835 (bm, 2H); 7.78 (d, 2H, J=8.21); 7.52 (d, 1H, J=8.79); 7.36 (d, 2H, J=7.03); 7.04 (d, 1H, J=2.34); 6.93 (dd, 1H, J=8.79, 2.34); 4.59 (m, 1H); 4.28 (d, 2H, J=5.86); 2.80 (d, 3H, J=4.69); 1.87 (s, 3H); 1.26 (d, 6H, J=5.86) (M+H)+ = 381 B <30 5. 2-(4-羥基-苯基)-5- 異丙氧基-苯并p失喃 -3-羧酸甲醯胺 'H NMR in DMSO: 9.91 (s, 1H); 8.20 (d, 1H, J=4.69); 7.70 (d, 2H, J=8.79); 7.47 (d, 1H, J=8.79); 7.02 (d, 1H, J=2.34); 6.86 (m, 3H); 4.57 (m, 1H); 2.79 (d, 3H, J=4.69); 1.26 (d, 6H, J=5.86) (M-H)·= 324 B <10 6. 2-(4-氟基-苯基)-5- 異丙氧基-6·^比各淀 -1-裏-私并17夫喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.26 (d, J=4.84, 1H); 7.89-7.84 (m, 2H); 7.31 (t, J=8.79, 2H); 6.98 (s, 1H); 6.90 (s, 1H); 4.56 (septet, J=6.15, 1H); 3.33-3.29 (m, 4H); 2.81 (d, 1=4.40, 3H); 1.90-1.86 (m, 4H); 1.29 (d, J=6.15,6H) (M+H)+ = 397 A <1 7. 5-二氟甲氧基-2-(4-氟基-苯基)-苯并 呋喃-3-羧酸甲醯胺 lHNMR in 二氯甲烷4(0)03): 7.92 (m, 2H); 7.61 (d, 1H, J=2.93); 7.48 (d, 1H, 1=8.79); 7.22-7.13 (m, 3H); 6.54 (t, 1H, J=74); 5.80 (brs, 1H); 3.00 (d, 3H, J=5.27) (M+H)+ = 336 B <10 8. 2-(4-氟基·苯基)-5-異丙氧基各(2-甲氧 基-乙基胺基)-苯并 呋喃-3-羧酸曱醯胺 lH NMR in DMSO: 8.25 (d, J=4.69, 1H); 7.88-7.83 (m, 2H); 7.31 (t, J=8.79, 2H); 6.97 (s, 1H); 6.83 (s, 1H); 5.04 (t, J=5.27, 1H); 4.62-4.50 (septet, J=5.27, 1H); 3.56 (t, J=5.27, 2H); 3.33-3.30 (m, 5H); 2.82 (d7 J=4.69, 3H); 1.31 (d, J=5.86, 6H) (M+H)+ = 401 A <1 9. 5-甲基-2-苯基-苯并 呋喃-3-羧酸甲醯胺 *H NMR in CDCI3: 7.91-7.86 (m, 2H); 7.66 (s, 1H); 7.52-7.37 (m, 4H);7.14(d, J=8.8Hz, lH);5.8t (brs, 1H); 2.97 (d, J=4.7Hz, 3H); 2.46 (s, 3H) (M 十 H)+ = 266 B <10 173- 88828.doc 200418452 實例, 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50 (/iM) A= ^0.5 μΜ B= 0.5 to ^5.0 μΜ C= 5.0 to ^30 μΜ D=>30 μΜ 複製子 _) 10· 5-甲基-2-(4-象基-苯 基)-苯并呋喃-3-羧 酸甲醯胺 kH NMR in CDCb: 7.97-7.93 (rn, 2H); 7.59 (s, 1H); 7.39 (d, J=8.2Hz, 1H); 7.19-7.14 (m, 3H); 5.81 (brs, 1H); 3.02 (d, J=5.3Hz, 3H); 2.47 (s, 3H) (M+H)+ = 284 B <10 11. 2-苯基-5-(2,2,2-三 氟基-乙氧基)-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.87 (dd, 2H); 7.65 (dd, 1H); 7.47-7.54 (m, 4H); 7.08 (dd, 1H); 5.8 (s, br, 1H); 3.93 (s, 2H); 2.97 (d, 3H) ppm (M+H)+ = 350 D <30 12. 2-(ί·氟基-皋基)二5: 甲氧基-苯并呋喃-3-羧酸曱醯胺 lH NMR in DMSO: 8.37 (br.s, iH); 7.91-7.96 (ra, 2H); 7.56-7.58 (d, J=8.79Hz 1H); 7.34-7.40 (t, J=8.79Hz, 2H); 7.09-7.10 (d, J=2.35Hz, 1H); 6.97-7.00 (dd, J=2.35Hz, 8.79Hz, 1H); 3.82 (sr 3H); 2.83-2.8 (d, J=4.69Hz, 3H) (M+H)+ = 299.9 A <10 13. 6-溴基-2-(4-氟基-苯 基)-5-曱氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.42 (d, J=4.69Hz, 1H); 8.01 (s, 1H); 7.90-7.94 (m, 2H); 7.35-7.41 (t, J=8.79Hz, 2H); 7.23 (s, 1H); 3.91 (s, 3H); 2.83-2.85 (d, J=4.69Hz, 3H) 氺氺木 A <1 14. 5-甲氧基-6-甲基-2- 苯基-苯并呋喃-3-幾 酸甲醯胺 lH NMR in DMSO: 8.34-8.36 (d, J=4.69Hz, IH); 7.83-7.86 (dd, J= 1.76Hz, 8.79Hz, 2H); 7.43-7.53 (m, 4H); 7.04 (s, 1H); 3.85 (s, 3H); 2.83-2.84 (d, J=4.69Hz, 3H); 2.28 (s, 3H) (M+H)+ = 296 A <1 15. 6_(3-胺基比哈淀-1 -基)-2-(4-氟基-苯基) -5-異丙氧基-2,3-二 氫-苯并吱喃-3-叛酸 甲醯胺 *氺氺 (M+H)+ = 412 C <30 16. 6-胺基-2-(4-氟基-苯 基)-5-異丙氧基-苯 并呋喃-3-羧酸 甲醯胺 lH NMR in CDC13: 7.82 (dd, 2H, J=5.5 and 8.7Hz); 7.22 (s, 1H); 7.18 (t, 2H, J=8.7Hz); 6.84 (s, 1H); 5.76 (bs, 1H); 4.61 (heptuplet, J=6.iHz); 2.96 (d, J=4.9Hz, 3H); 1.92 (bs, 2H); 1.40 (d, J=6.1Hz, 6H) (M+H)+ = 343 A <10 17. 6-胺基-2-(4-獻^-苯 基)-5-甲氧基-苯并 呋喃-3-幾酸甲醯胺 lH NMR in methanol-山(CD3〇D): 7.81 (m, 2H); 7.20 (m, 2H); 7.02 (s, 1H); 6.91 (s, 1H); 4.72 (s, 1H); 3.91 (s, 3H); 2.93 (s, 3H) (M+H)+ = 315 B <10 18. 6-乙酸基胺基-2-(4-氟基-苯基)-5-甲氧 基-苯并呋喃-3-羧酸 甲醯胺 lH NMR in CDC13: 7.95 (bs, 1H); 7.83 (ra, 2H); 7.46 (m, 1H); 738 (s, IH); 7.28 (m, 2H); 5.76 (bs, 1H); 3.96 (s, 3H); 2.98 (s,3H); 2.21 (s,3H) (Μ+ΗΓ = 357 A <1 19. 2-(4-氟基-苯基)-5- 異丙氧基-6-甲基胺 基-苯并呋喃-3-¾酸 甲醯 NMR in CDC13: ' 7.81 (dd, J=8.7 Sc 5.iHz, 2H); 7.25 (s, 1H); 7.14 (t, J=9.3Hz, 2H); 6.66 (s, 1H); 5.78 (bs, IH); 4.63 (septupled J=6.3Hz, 1H); 4.55 (bs, 1H); 2.97 (d, J=4.8Hz, 3H); 2.91 (s, 3H); 1.37 (d, J=6.3Hz, 6H) (M+H)+ = 357 A <1 -174- 88828.doc 200418452 實例 編號 名稱, NMR data Mass Spec HCY pol -BB7 IC5〇 (/tM) A= μ,Μ B= (K5 to i 5.0 /iM C= 5.0 to ^:30 μΜ D= >30 μΜ 複製子 (μΜ) 20. 6二二甲基胺基-2-(4-氟基-苯基)-5-異丙 氧基-苯并咬喃-3-¾ 酸甲醯胺 Ή NMR in CDCh: 7.51 (dd, J=8.7 & 5.1Hz, 2H); 7.28 (s, 1H); 7.26 (m, 3H); 5.80 (bs, 1H); 4.70 (septupled J=6.3Hzt 1H); 2.98 (d, J=4.9Hz, 3H); 2.91 (s, 6H); 1.42 (d, J=6.3Hz, 6H) (M+H)+ = 371 A <1 21. 2-(4-氟基-苯基)-5- 異丙氧基-6-甲烷磺 酉盔基胺基-苯并吱4 -3-羧酸甲醯胺 lH NMR in CDC13: 7.81 (dd, J=8.7 & 4.1Hz,2H); 7.73 (s, 1H); 7.42 (s,1H); 7.19 (U=8.7Hz,2H); 6.90 (s, 1H); 5.81 (bs, 1H); 4.75 (septuple^ J=6.3Hz, 1H); 2.98 (s, 3H); 2.95 (d, J=2.6Hzt 3H); 1.40 (d, J=6.3Hz, 6H) (M+H)+ = 421 A <1 22. 6-乙基胺基-2-(4-氣 基-苯基)-5-異丙氧 基-木并咬喃-3-¾酸 甲醯胺 lH NMR in CDCh: 7.81 (ddt J=8.8, 5.3Hz, 2H); 7.18 (s, 1H); 7.16 (t, J=8.8Hz, 2H); 6.67 (s, 1H); 5.76 (bs, 1H); 4.61 (heptuplet, J=6.2HzT 1H,); 3.20 (quaduplet, J=7.0Hz, 2H); 2.97 (d, J=4.8Hz, 3H); 1.38 (d, J=6.2Hz, 6H); 1.32 (t, J=7.0Hz, 3H) (M+H)+ = 371 A <1 23. 6二三乙基胺基-2-(4-氟基-苯基)-5-異丙 氧基-苯并呋喃·3-無 酸甲醯胺 'HNMRinCDCb: 7.83 (dd, J=8.8,5.3Hzt 2H); 7.26 (s, 1H); 7.15 (d, J=8.8Hz, 2H); 7.05 (s, 1H); 5.78 (bs, 1H,; 4.17 (heptuplet, J=6.1Hz, 1H); 3.18 (m, 4H); 2.95 (d, 5.0Hz, 3H); 1.38 (d, J=6.1HzT 6H); 1.32 (tt J=7.0Hz, 6H) (Μ+ΗΓ = 399 A <1 24. :2-(4-氟基-苯基)-5-, 異丙氧基-6-嗎福淋 -4-基-苯并咬喃-3- 羧酸甲醯胺 lHNMRin DMSO: 8.30-8.3 l(d,J=4.69Hz, 1H); 7.88-7.93 (m, 2H); 7.31-7.37 (t, J=8.79Hz, 2H); 7.19 (s, 1H); 7.07 (s, 1H); 4.58-4.66 (septet, J=6.45Hz, 1H); 3.75-3.77 (m, 4H); 3.02-3.05 (m, 4H); 2.82-2.83 (dt J=4.69Hz, 3H); 1.29-1.31 (d, J=6.45Hz? 6H) (M+H)+ = 413 A <1 25. 5-甲氧基-4-甲基-2- 苯:苯并吱喃-3 -幾 酸甲醯胺 lH NMR in CDC13: 7.84-7.81 (m, 2H); 7.48-7.40 (m, 3H); 7.30-7.26 (m, 1H); 6.93 (d, J=8.7Hz, 1H); 3.86 (s, 3H); 3.01 (d, J=4.8Hz, 3H); 2.40 (sy 3H) (M+H)+ = 296 D >30 26. 5-氰基-2-苯基-苯并 呋喃-3-羧酸曱醯胺 lH NMR in CDCl3: 8.32 (s, 1H); 7.89-7.85 (m, 2H); 1.62-1 ΛΊ (ra, 5H); 5.80 (s, 1H); 2.98 (d, J=5.1Hz, 3H); (M-Η)'= 275 C <30 27. 5-異丙氧基-2-吡啶 -4-基-豕并p夫喃-3 - 叛酸甲St胺 Ή NMR in CDCl3: 8.70 (d, J=5.4Hz, 2H); 7.84 (dd, J=1.2Hz, 4.2HZ, 2H); 7.43 (d, J=8.7Hz, 1H); 7.21 (d, J=2.7Hz, 1H); 7.00 (dd, J=2.1Hz, 8.7Hz, 1H); 5.91 (bs, 1H); 4.54 (m, 1H); 3.07 (d, J=5.1Hz, 3H); 1.36 (d, J=5.7Hz, 3H) (M+H)'= 311 C >30 28. 6-(3,5-二甲基-異呤 唑-4-基)-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDCl3: 7.85-7.89 (m, 2H); 7.43 (s, 1H); 7.25 (s, 1H); 7.18-7.23 (t, J=8.79 Hz, 2H); 5.79 (brs, 1H); 3.86 (s, 3H); 3.00-3.02 (d, J=5.2^ Hz, 3H); 2.32 (s,3H); 2.18 (s,3H) (M+H)+ = 395 A <1 175 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 〇iM) A= μΜ B= 0*5 to <5.0 μΜ C= 5.0 to ^30 fiM D= >30 μΜ 複製子 _) 29. 2-(4_氟基-苯基)-6· (甲烷磺醯基-甲基-胺基)-5-甲氧基-苯 并呋喃-3-羧酸甲 龜胺 *H NMR in CDC13: 7.86 (m, 2H); 7.56 (s, 1H); 7.45 (s, IH); 7.28 (U 8.3Hz, 2H); 5.77 (brs, 1H); 3.98 (s, 3H); 3.33 (s, 3H); 2.98 (d, J=5.2Hz, 3H); 2.96 (s, 3H) (M+H)+ = 407 A <1 30. 2-(4-氟基-苯基;) -5-(4-甲氧基-苄氧 基)-嗎福琳-4-基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDCi3: 7.84 (dd, J=8.4, 5.2Hz, 2H); 7.40 (d, J=8.3Hz, 2H); 7.37 (s, 1H); 7.15 (t, J=B.4Hz, 2H); 7.06 (s, 1H); 6.93 (dt J=8.8Hz, 2H); 5.82 (d, J=3.9Hz, 1H); 5.09 (s, 2H);3.85 (t, J=4.4Hz, 4H); 3.82 (s, 3H); 3.11 (t, J=4.4Hz, 4H); 2.97 (d, J=4.8Hz, 3H) (M+H)+ = 491 A <1 31. 2-(4-氟基-苯基)-6-[ 甲土充績酸基-(4-甲氧 基·芊10-胺基]-5-(4-甲氧基-苄氧基)_ 苯并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.38 (d, J=4.1Hz, 1H); 7.88 (dd, J=8.4, 5.2Hz, 2H); 7.48 (d, J=8.8Hz, 2H); 7.34 (t, J= 8.8Hz, 2H); 7.29 (s, 1H); 7.28 (s, 1H); 7.12 (d, J= 8.8Hz, 2H); 7.00 (d, J=8.2Hz, 2H); 6.79 (d, J=8.8Hz, 2H); 5.13 (s, 2H); 4.60 (br rn, 2H); 3.77 (s, 3H); 3.66 (s, 3H); 2.94 (s, 3H); 2.80 (d, J=4.7Hz, 3H) (M+H)+ = 619 A <1 32, 5-乙氧基-6-(乙基-甲烷磺醯基-胺基) -2-(4-氟基-苯基)-苯 并呋喃-3-¾酸甲 醯胺 lH NMR in DMSO: 8.41 (d, J= 4.1Hz, IH); 7.94 (dd, J=8.2, 5.3Hz, 2H); 7.55 (s, 1H); 7.36 (t, J=8.2Hz, 2H); 7.16 (s, 1H); 4.14 (q, J=7.0Hz, 2H); 3.62 (q, J=7.0Hz, 2H); 3.01 (s, 3H); 2.82 (d, J=4.7Hz, 3H); 1.38 (t, J=7.0Hz, 3H); 1.05 (t, J=7.0Hz, 3H) (M+H)+ = 435 A <1 33. 2·(4·-氣基-苯基)-6_ 嗎福琳-4-基-5-0塞 唑-2-基甲氧基)-苯 并吡喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.35 (d, J=4.4Hz, 1H); 7.95-7.80 (m, 4H); Ί35-125 (m, 4H); 5.49 (s, 2H); 3.78 (m, 4H); 3.06 (in, 4H); 2.83 (d, J=4.4Hz, 3H) (M+H)+ =468 A <1 34. 2-(4-氣基-苯基)-5_ 異丙氧基-6-[甲烷磺 醯基-(2-氧基-丙基)-胺基]-本并咬喃-3-羧酸甲醯胺 [H NMR in DMSO: 8.38 (d, J=4.8Hz, 1H); 7.94 (dd, J=8.4,5.3Hz, 2H); 7.71 (s, 1H); 7.36 (t, J=8.8Hz, 2H); 7.15 (s,lH); 4.77 (septet, J=6.1Hz, 1H); 4.04 (s, 2H); 3.04 (s, 3H); 2.81 (d, i=4.4Hz, 3H); 2.11 (s, 3H); 1.36 (d, J=6.1Hz, 6H) (M+H)+ = 477 A <1 35. 2-(4-氟基-苯基)-6-嗎福^林-^·- 5 - (口塞 唑-4-基甲氧基)-苯 并呋喃;羧酸甲 醯胺 lH NMR in CDCl3: 8.84 (d, 1H, J=1.76); 7.88 (m, 2H); 7.44 (s, 2H); 7.17 (t, 2H, J=8.79); 7.10 (s, 1H); 5.77 (brs, 1H); 5.37 (s, 2H); 3.89 (m, 4H); 3.16 (m, 4H); 3.00 (d, 3H, J=4.69) (M+H)+ =468 A <1 176- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A= fiM B= 03 to ^5.0 /iM C= 5.0 to <30 pM D=>30 μΜ 複製子 _) 36. 2_(4_氣基-苯基)-5_ 異丙氧基-6-(甲烷磺 醯基-嘧唑-4-基甲基 -胺基)-苯并咬喃-3-叛酸甲醯胺 lH NMR in CDC13: 8.69 (d, 1H, J=2.20 Hz); 7.77 (m, 2H); 7.40 (s, 1H); 7.37 (s,lH); 7.30 (d, 1H, J=2.20 Hz); 7.18 (t, 2H, J=8.79 Hz); 5.67 (brs, 1H); 5.03 (brs, 2H); 4.79(m,lH); 3.07 (s, 3H); 2.95 (d, 3H, J=4.84 Hz); 1.44 (d, 6H, J=5.72 Hz) (M+H)+ = 518 A <1 37. 2_(4_氣基-苯基)-6_ (5-羥甲基-異崎唑 -3-基)-5-異丙氧基-苯并呋喃-3-羧酸甲 醯胺 lH NMR in CD3OD: 7.94 (s, 1H); 7.92 (dd, J=9.2,5.3 Hz, 2H); 7.32 (s, 1H); 7.25 (apparent triplet, J=8.8 Hz, 2H); 6.87 (s,lH); 4.75 (m, 1H); 4.72 (s, 2H); 2.95 (s, 3H); 1.39 (d, J=5.7 Hz, 6H) (M+H)+ = 425 A <1 38. 5-乙氧基-2-(4-氟基-苯基)-6-(甲烷磺醯 基-甲基-胺基):苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.39 (d, J=4.0Hz, 1H); 7.92 (dd, J=8.8t 5.3Hz, 2H); 7.59 (s, 1H); 7.36 (t, J=8.8Hz, 2H); 7.17 (s, 1H); 4.16 (q, J=7.0Hz, 2H); 3.19 (s, 3H); 3.01 (s, 3H); 2.81 (d, J=4.4Hz, 3H); 1.40 (t, J=7.0Hz, 3H) (M+H)+ = 421 A <1 39. 4-[2-(4-氟基-苯基) -6-(甲垸橫醯基-甲 基:胺基)-3-甲基胺 甲酿基-苯并咬喃_5_ 基氧甲基]-2-經基-芊酸 lH NMR in DMSO: 8.39 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.84 (d, 1H, J=8.21Hz); 7.72 (s, 1H); 7.39 (t, 2H, J=8.79Hz); 7.30 (s, 1H); 7.12 (m, 2H); 5.27 (s, 2H); 3.24 (s, 3H); 3.00 (s, 3H); 2.83 (d, 3H, J=4.69Hz) (M-H)·= 541 A <10 40. 2·(4-氟基-苯基) -6-(5-羥甲基-異哼 唑-3-基)-5-甲氧基-苯并呋喃-3-m酸甲 醯胺 NMR in DMSO: 8.44 (bq, J=4.83Hz, 1H); 7.97 (m, 3H); 7.39 (t, J=8.79Hz, 2H); 7.29 (s, 1H); 6.80 (d, J=0.879Hz, 1H); 5.66 (t, J=6.15 & 5.71 Hz, 1H); 4.63 (d, J=6.15Hz, 2H); 3.93 (s, 3H); 2.86 (d, J=4.39Hz, 3H) (M+H)+ = 397.0 A <1 41. 2-(4-氟基-苯基) -6-[4-(2-經基-乙基)-異呤嗤-3-基]-5-甲 乳基-表并咬喃-3-¾ 酸甲醯胺 lH NMR in CDC13: 8.40 (s, 1H); 7.86 (dd, J=5.27, 8.79 Hz, 2H); 7.52 (s, 1H); 7.45(s, 1H); 7.20 (t, J=8.35, 8.79 Hz, 2H); 5.81 (bs, 1H); 3.87 (s, 3H); 3.69 (q, J=6.15 Hz, 2H); 3.00 (d, J=4.83 Hz, 3H); 2.64 (t, J=6.15 HzT 2H); 1.45 (t, J=5.27,5.71 Hz, 1H). (M+H)+ = 411 A <1 42. 2-(4-氟基-苯基) -6-[(2-羥基-乙基)- 甲烷磺醯基-胺基] -5-甲氧基-苯并呋喃 -3-羧酸甲醯胺 NMR in DMSO: 8.49 (d, J=4.84 Hz, 1H); 7.96-7.90 (m, 2H); 7.66 (s, 1H); 7.41 (t, J=7.03 Hz, 2H); 7.2 (s, 1H); 4.75 (t, J=5.71 Hz, 2H); 3.9( (s, 3H); 3.44 (bs, 1H); 3.41 (d, J=5.27 Hz, 2H); 3.05 (s, 3H); 2.84 (d, J=4.39 Hz, 3H) (M+H)+ = 437 A <i 43. 5-^丙基-2-(4-氟基-苯基)-6-[(2_經基-乙 基甲烷磺醯基-胺 基]-苯并呋喃各羧 酸甲醯胺 lH NMR in CDC13: 7.90-7.85 (m, 2H); 7.55 (s, 1H); 7.35 (s, 1H); 7.22-7.16 (m, 2H); 5.74 (bs, 1H); 4.09-4.03 (m, 1H); 3.75 (s, 3H); 3.14 (s, 3H); 2.99 (d, J=4.40Hz, 3H); 2.40-2.30 (m, 1H); 1.95 (m, 1H); i.10-0.98 (m, 2H); 0.88 (m, 1H); 0.68 (m, IH) (M+H)+ = 447 A <1 177- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= /iM B= 03 to <:5.0 μΜ C= 5.0 to ^:30 μΜ D= >30 μΜ 複製子 (μΜ) 44. 5-乙基-2-(4-氟基-苯 基)-6-甲烷磺醯基胺 基-苯并咬‘3-幾酸 甲醯胺 'H NMR in DMSO: 9.20 (bs, 1H); 8.61 (m, 1H); 7.93 (dd, J=5.3 & 8.8 Hz, 2H); 7.60 (s, 1H); 7.48 (s, 1H); 7.37 (t, J=8.8 Hz, 2H); 3.05 (s, 3H); 2.83 (d, J=4.7 Hz, 3H); 2.81 (q, J=7.7 Hz, 2H); 1.21 (ζ J=7.7 Hz, 3H) (M+H)+ = 391 A <10 45. 5-乙基-2-(4-氟基-苯 基)-6-(甲烷磺醯基-曱基-胺基)-苯并呋 喃-3-羧酸甲醯胺 lH NMRinDMSO: 8.50 (m, 1H); 7.94 (dd, J=5.3 & 8.8Hz, 2H); 7.89 (s, 1H); 7.54 (s, 1H); 7.60 (t, J=8.8Hz, 2H); 3.29 (q, 1=7^ 2H); 3.21 (s, 3H); 3.13 (s, 3H); 2.83 (d, J=4.7Hz, 3H); 1.21 (t, J=7.0Hz, 3H) (M+H)+ = 405 A <1 46. 5-乙基-2-(4-氣基•麥 基)-6-[(2-羥基-乙 基)-甲坑續S&基-胺 基]-苯并呋喃-3-羧 酸甲醯胺 lH NMR in DMSO: 8.45 (m, 1H); 7.94 (dd, J=5.3 & 9.4Hz, 2H); 7.81 (s, 1H); 7.55 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 3.72 (m, 1H); 3.58 (m, 1H); 3.4 (m, 3H); 3.15 (s, 3H); 2.84 (d, J=4.7Hz, 3H); 2.82 (q, J=7.0Hz, 2H); 1.25 (t, J=7.0Hz, 3H) (M+H)+ = 435 A <1 47. ό-( 1 -乙酿基-p比p各淀 -2-基)-2-(4-氟基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.85 (m, 2H); 7.36 (s, 1H); 7.20 (m, 3H); 5.78 (brs, 1H); 5.40 (in, 1H); 3.92 (s, 3H); 3.40-3.91 (m, 2H); 2.99 (d, J=4.8Hz, 3H); 1.51-2.0 (m, 4H); 1.85 (s, 3H) (M-H)·= 411.1 A <1 48. 2-(4-氣基-苯基)-5_ 甲氧基-6-(2-氧基-噚唑淀-5-基)-苯并 吱喃-3-竣酸甲醯胺 *H NMR in (CD3)2CO: 8.03 (m, 2H); 7.68 (s, 1H); 7.40 (brs, 1H); 7.20-7.31 (4H); 5.14 (ra, 1H); 3.90 (s, 3H); 3.60 (m, 1H); 3.38 (m, 1H); 2.94 (d, J=4.8 Hz, 3H) (M+H)+ = 385.0 A <10 49. 氟基-苯基) 基-1-甲基-乙基)-5-甲氧基-苯 并呋喃-3-叛酸甲 醯胺 lH NMR in CDC13: 7.85 (m, 2H); 7.50 (s, 1H); 7.39 (s, 1H); 7.20 (m, 2H); 5.75 (brs, 1H); 4.17 (s, 1H); 3.99 (s, 3H); 2.98 (d, J=4.8 Hz, 3H); 1.66 (s, 6H) (M+H)+ = 358.1 A <1 50. 2-(4-氟基-苯基)-5·-甲氧基-6-(5-甲基 _[1,2,4]噚二唑-3-基) -苯并咬喃-3 -¾酸甲 醯胺 lH NMR in CDC13: 8.12 (s, 1H); 7.90 - 7.86 (m, 2H); 7.48 (s, 1H); 7.24 - 7.18 (m, 2H); 5.78 (s, 1H); 4.03 (s, 3H); 3.0 (d, J=4.8 Hz, 3H); 2.67 (s, 3H) (M+H)+ =382 A <1 51. 6-(3,5-二甲基-異噚 唑-4-基)-2-(4-氟基-苯基)-5-(3-羥基-丙 氧基)-苯并吱喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.41-8.43 (d, J=4.69 Hz, 1H); 7.92-7.97 (m, 2H); 151 (sT 1H); 7.35-7.41 (t, J=8.79 Hz, 2H); 7.23 (s, 1H); 4.49-4.52 (t, J=5.28 Hz, 1H); 4.06-4.11 (t, J=6.45 Hz, 2H); 3.43-3.49 (q, J=5.86 Hz, 2H); 2.84-2.86 (d, J=4.69 Hz, 3H); 2.29 (s, 3H) (M+H)+ =439.0 A <1 178- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV po! -BB7 IC5〇 QiM) A=彡 0·5 μΜ B= 0.5 to ^5.0 μΜ C= 5.0 to ^30 /iM D= >30 複製子 轉) 52. 氣基-苯基)各 (甲烷磺醯基-甲基-胺基)-5-(2-嗎福啉 -4-基-乙氧基)-苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.40 (brd, J=4.40 Hz, 1H); 7.94 (m, 2H); 7.60 (s, 1H); 7.38 (t, J=8.79 Hz, 2H); 7.24 (s, 1H); 4.21 (t, J=5.28 Hz, 2H); 3.57 (1¾ 4H); 3.23 (s, 3H); 3.10 (s, 3H); 2.84 (d, J=4.84 Hz, 3H); 2.76 (t, J=5.28 Hz, 2H); 2.48 (m, 4H). (M+H)+ =506 A <1 53. 5-(.一本基-2-塞-甲 氧基)-2-苯基-苯并 呋喃-3-羧酸甲醯胺 *H NMR in DMSO: 2.82 (d, 3H); 5.0 (s, 2H) 6.96 (m, 1H); 7.32-7.96 (m, 16H); 8.34 (d, 1H) ppm (M+H)+ = 434 C <30 54. 5-甲氧基-2-(4-甲氧 基-苯基)-苯并呋喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.31 (br s, 1H); 7.82-7.84 (d, J=7.03Hz, 2H); 7.52-7^5 (d, J=8.79Hz, 1H); 7.06-7.10 (m, 3H); 6.93-6.96 (dd, J=2.35Hz, 8.79Hz, 1H); 3.83 (s, 3H); 3.81 (s, 3H); 2.81-2.83 (d, J=4.69Hz, 3H) 氺氺* B <10 55. 5-甲氧基-2-(3-三氟 甲基-苯基)-苯并呋 喃各羧酸甲醯胺 lH NMR in DMSO: 8.47-8.49 (d, J=4.69Hzt 1H); 8.19 (s, 1H); 8.15-8.18 (d, J=7.62Hz, 1H); 7.74-7.84 (m, 2H); 7.61-7.64 (d, J=9.38Hz, 1H); 7.13 (d, J=2.34Hz, 1H); 7.01-7.05 (dd, J=2.34Hz, 7.62Hz, 1H); 2.83-2.85 (d, J=4.69Hz, 3H) 氺氺氺 B <30 56. 5-甲氧基-2-(4-三氟 甲基-苯基)-苯并呋 喃-3-羧酸甲醯胺 JH NMR in DMSO: 8.48-8.49 (d, Ι=4.69Ηζ, 1H); 8.06-8.09 (d, J=8.21Hz, 2H); 7.88-7.90 (d, J=8.21Hz, 2H); 7.61-7.64 (d, J=8.79Hz, 1H); 7.12-7.13 (d, J=2.93Hz, 1H); 7.02-7.06 (dd, J=2.93, 8.79Hz, 1H); 3.83 (s, 3H); 2.85-2.86 (d, J=4.69Hz, 3H) 氺氺氺 B <10 57. 5-乙氧基-2-苯基-苯 并呋喃-3-羧酸甲 醯胺 'H NMR in CDCb: 7.85 (dd, 2H); 735-7.52 (m, 5H); 6.95 (d, 1H); 5.8 (s, br, 1H); 4.14 (q, 2H); 2.97 (d, 3H) 1.41 (t, 3H) ppm (M+H)+ = 296 B >30 58. 2-(2-氟基-苯基)-5- 甲氧基-苯并呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.05-8.07 (d, J=4.69Hz, 1H); 7.72-7.77 (t of d, J=1.76Hz, 7.62Hz, 1H); 7.52-7.63 (in, 2H); 7.37-7.39 (d, J=7.62Hz lH); 7.33-7.38 (m, 1H); 7.18-7.19 (d, J=2.35Hz, 1H); 6.99-7.03 (m, 2H); 3.83 (s, 3H); 2.75-2.76 (d, J=4.69Hz, 3H) (M+H)+ = 300 B <10 59. 5-異丙氧基-2-苯基-苯并呋喃-3-羧酸甲 醯胺 'H NMR in CDCb: 7.87 (d, 2H); 7.52-7.37 (m, 5H); 6.94 (d, 1H); 5.78 (s, br, 1H); 4.6 (m, 1H); 2.98 (d, 3H); 1.38 (d, 6H) ppm (M+H)+ = 310 B <30 60. 5-Y氧基-2-苯基-苯 并呋喃-3-羧酸甲 醯胺 *H NMR in CDCb: 7.87 (m, 2H), 7.51-7.3 (m, 5H); 6.97 (d, 1H); 5.78 (s, br, 1H); 4.06 (m, 2H); 2.98 (d, 3H); 1.83-1.54 (m, 4H); 1.02 (m, 3H) ppm (M+H)+ = 324 B <30 61. 2-苯基-5-丙氧基-苯 并呋喃-3-叛酸甲 醯胺 (H NMR in CDCb: 7.86 (ra, 2H); 7.5-7.27 (m, 5H); 6.96 (dd, 1H); 5.76 (s, br, 1H); 3.99 (t, 2H); 2.98 (d, 3H); 1.84 (m, 2H); (t, 3H) ppm (M+H)+ = 310 B <30 62. 5-甲氧基-2-(2,4,5- 三氟基-苯基)-苯并 呋喃-3-羧酸甲酿胺 lH NMR in DMSO: 8.08-8.09 (d, J=4.69Hz, 1H); 7.86-7.95 (m, 1H); 7.71-7.80 (m, 1H); 7.58-7.61 (d, J=9.38Hz, 1H); 7.22-7.23 (d,J=2.35Hz, 1H); 7.02-7.06 (dd, J=2.93Hz, 9.38Hz, 1H); 3.83 (s, 3H); 2.76-2.77 (d, J=4.69Hz, 3H) 氺氺氺 C <30 179- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50〇iM) A= <0*5 /iM B= 05 to ^5.0 fiM C= 5.0 to ^:30 μΜ D=>30 /iM 複製子 (μΜ) 63. 5-甲氧基-7-甲基-2- 苯基-苯并吱喃-3-叛 酸曱醯胺 lH NMR in DMSO: 8.33-8.34 (d, J=4.69Hz, 1H); 7.87-7.89 (d, J=7.62Hz, 2H); 7.45-7.55 (m, 3H); 6.89-6.90 (d, J=2.34HzT 1H); 6.83-6.84 (d, J=2.34Hz, 1H); 3.80 (s, 3H); 2.82-2.84 (d, J=4.69Hz, 3H); 2.50 (s, 3H) (M+H)+ = 296 B <10 64. 2-(4-氟基-苯基) -:5-(之2,2-三氟基-乙 乳基)-笨并咬喃-3-羧酸甲醸胺 lHNMR in CDC13: 8.06 (dd, 1H); 7.41 (dd, 2H); 7.17 (m, 2H); 7.02 (dd, 1H); 5.76 (m, br, 1H); 4.42 (q, 2H); 2.99 (d, 3H) ppm (M+H)+ = 368 B 氺氺氺 65. 2_(4-氣基-苯基)-5_ 異丙氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDC13: 7.90 (dd, 2H); 7.29 (dd, 2H); 7.16 (dd, 1H); 6.92 (dd, 1H); 5.82 (s, br, 1H); 4.58 (m, 1H); 2.99 (d, 3H); 1.34 (s, 3H) (M+H)+ = 328 B <30 66. 2_(2•氯基-苯基)-5-甲氣墓-木并p夫喃-3-羧酸甲醯胺 lH NMR in DMSO: 7.85-7.86 (d, J=4.69Hz,1H); 7.47-7.69 (m, 5H); 7.27-7.28 (d, J=2.34HzT 1H); 7.00-7.04 (dd, J=2.93Hz, 9.38Hz, 1H); 3.84 (s, 3H); 2.72-2.73 (d, J=4.69Hz, 3H) (Μ+ΗΓ = 315.9 C >30 67. 6-甲氧基-2-苯基-苯 并呋喃各羧酸甲 醯胺 *H NMR in CDC13: 7.86 (m, 2H); 7.73 (d, J=8.87Hz, 1H); 7.51-7.42 (m, 3H); 7.04 (d, J=2.4Hz, 1H); 6.94 (d of d, J=8.8Hz, 1H); 5.81 (brs, 1H); 3.87 (s, 3H); 2.98 (d, J=4.7Hzt 3H) (M+H)+ = 282 B <10 68. 2-呋喃-2-基-5-甲氧 基-苯并呋喃-3-幾酸 甲醯胺 lHNMR in DMSO: 8.28-8.29 (d, i=H.10Hz 1H); 7.92 (s, 3H); 7.54-7.57 (d, J=8.79Hz, 1H); 7.18-7.19 (d, J=3.52Hz, 1H); 7.15-7.16 (d, J=2.35Hz, 1H); 6.96-7.00 (dd, J=2.35, 8.79Hz, 1H); 6.71-6.72 (m, 1H); 3.82 (s, 3H); 2.84-2.86 (d, J=4.10Hz, 3H) M = 271 B <30 69. 2-(3-1基冰甲基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.42 (s, 1H); 7.63 (in, 3H); 7.43 (m, 1H); 7.09 (m, 1H); 7.00 (m, 1H); 3.82 (s, 3H); 2.84 (d, J=4.8Hz, 3H); 2.30 (s, 3H) (M+H)+ = 314 A <10 70. _2-(4—-溴基-苯基)-5-甲氧基-苯并呋喃各 羧酸甲醯胺 lH NMR in DMSO: 8.41 (m, 1H); 7.81 (d, J=7.5Hz, 2H); 7.72 (d, J=8.4Hz, 2H); 7.58 (d, J=9.3Hz, 1H); 7.09 (s, 1H); 7.01 (d, J=8.7Hz, 1H); 3.82 (s, 3H); 2.83 (d, J=4.2Hz, 3H) (Μ+ΗΓ = 361 A <10 71. 2-(4-氟基-3-甲基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸甲酿胺 lH NMR in DMSO: 8.33 (ra, 1H); 7.80 (dd, J=8.1, 1.8Hz, 1H); 7.75 (m, 1H); 7.56 (d, J=9.0Hz, 1H); 7.29 (m, 1H); 7.09 (d, J=2.4Hz, 1H); 6.97 (dd, J=8.1, 2.1Hz, 1H); 3.81 (s, 3H); 2.84 (d, i=4.2Hz, 3H); 2.35 (s, 3H) (M+H)+ = 314 A <30 72. 2-(4-氣基-参基)-5_ 甲氧基-7-甲基-苯并 咬喃-3-致酸甲酿胺 lH NMR in DMSO: 8.3 (d, br, 1H); 7.94 (dd, 2H); 7.35 (dd, 2H); 6.89 (d, 1H), 6.81 (d, 1H); 3.83 (s, 3H); 2.80 (d, 3H); 2.47 (s, 3H) ppm (M+H)+ = 314 A <10 73. 5-氣基-2-(4_氟基-苯 基)-苯并咬喃-3身 酸曱醯胺 lH NMR in CDCl3: 7.96-7.91 (ra, 2H); 7.81 (d, J=2.4Hz, 1H); 7.42 (d, J=8.7Hz, 1H); 7.30 (d, d, J=2.4, 8.7Hz, 1H); 7.21-7.16 (m, 2H); 5.789 (s, IH); 3.01 (d, J=4.8Hz, 3H) (M+H)+ = 304.27, 306.13 B <10 180- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ic50 〇iM) A= <0*5 /iM B= 03 to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 nM 複製子 (μΜ) 74. 5-第三-丁基-2-苯基 -苯并呋喃-3-幾酸甲 醯胺 *Η NMR in CDC13: 7.87-7.84 (m, 3H); 7.52-7.39 (m, 5H); 5.79 (br s, 1H); 2.99 (d, J=4.7Hz, 3H); 139 (s, 9H) (M+H)+ = 308 A <10 75. 5二氯基-2-對-甲烷基 -苯并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.90 (d, J=1.8Hz, 1H); 7.75 (d, J=7.8Hz, 2H); 7.43-7.40 (m, 1H); 7.32-7.27 (in, 3H); 2.97 (d, J=4.8Hz, 3H); 2.43 (s, 3H) (M+H)+ = 300 A <10 76. 2-(3-氯基4-氟基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 *H NMR in CDC13: 8.62 (s, 1H); 8.08 (dd, J=7.2,1.8Hz, 1H); 7.88 (m, 1H); 7.58 (m, 2H); 7.10 (d, J= 2.4Hz, 1H); 6.98 (dd, J=8:l, 2.4Hz, 1H); 3.82 (s, 3H); 2.84 ((t J=4.8Hz,3H) (M+H)+ = 334 B <10 77. 2-(4-氯基-3-氟基-苯 基>5-甲氧基4辞 吱喃-3-羧酸甲酿胺 *Η NMR in CDC13: 8.48 (s, IH); 7.93 (d, J=1.2Hz, 1H); 7.90 (m, 2H); 159 (d, J=9.0HzT 1H); 7.12 (d, J=2.4Hz, 1H); 7.04 (dd, J=9.0, 2.4Hz, 1H); 3.82 (s, 3H); 2.85 (d, J=4.5Hz, 3H) (M+H)+ = 334 A <10 78. 5-甲氧甲基-2-苯基- 苯并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.90 (d of d, J=8.2Hz, 2H); 7.83 (sT 1H); 7.51-7.42 (m, 4H); 7.34 (d, J=8.8Hz, 1H); 5.83 (brs, 1H); 4.56 (s, 2H); 3.41 (s, 3H); 3.00 (d, J=4.7Hz, 3H) (M+H)+ = 296 B <30 79. 2_(4_氣基-苯基)-5_ 異丙氧基-6-甲基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CD30D: 7.85 (dd, 2H); 7.31 (s, 1H); 7.20 (dd, 2H); 7.10 (s, 1H); 4.61 (ra, 1H); 2.92 (s, 3H); 2.29 (s, 3H); 1.37 (d, 6H) ppm (M+H)+ = 342 A <10 80. _2-(4-氣基-苯基)-5-異丙氧基-7-甲基-苯 并呋喃-3-複酸甲 醯胺 lH NMR in CD30D: 7.85 (dd, 2H); 7.25 (d, 1H); 7.20 (dd, 2H); 6.80 (d, 1H); 4.61 (m, 1H); 2.92 (s, 3H); 2.38 (s,3H); 1.37 (d, 6H) ppm (M+H)+ = 342 B <30 81. 2-(4-氣基-本基)-5- 甲氧基-6-甲基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDCI3: 7.9 (dd, 2H); 7.26 (st 1H); 7.22 (s, 1H); 7.16 (dd, 2H); 5.78 (s, 1H, br); 3.89 (s, 3H); 2.98 (d, 3H); 2.33 (s, 3H) ppm (M+H)+ = 314 A <10 82. 5-氟基-2-(4-氟基-表 基)-苯并呋喃_3_羧 酸甲醯胺 lH NMR in CDCi3: 7.93-7.88 (in, 2H); 7.48 (dd, J=2.7HzT 8.4Hz, 1H); 7.41 (dd, J=3.9Hz, 8.7Hz, 1H); 7.21-7.14 (m, 2H); 7.06 (td, J=2.7Hz, 8.7Hz, 1H); 5.86 (s, 1H); 2.98 (d, J=4.8Hz, 3H) (M+H)+ = 288 B <30 83. 2-(4-乙基-苯基)-5- 氟基-苯并呋喃-3身 酸甲醯胺 lH NMR in CDC13: 7.77 (d, J=7.8Hz, 2H); 7.59 (dd, J=2.7Hz, 8.4Hz, 1H); 7.41 (dd, J=4.5Hz, 8.7Hz, 1H); 7.33 (d, J=8.4Hz, 2H); 7.03 (td, J=2.4Hz, 8.7Hz, 1H); 5.79 (s, 1H); 2.96 (d, J=5.1Hz, 3H); 2.72 (q, J=7.8Hz, 15.3Hz, 2H); 1-29 (t, J=7.5Hz, 3H) (M+H)+ = 298 A <10 84. 5-乙基-2-苯基-苯并 呋喃-3-羧酸甲酿胺 lH NMR in CDCb: 7.89 (m, 3H); 7.70 (s, 1H); 7.5-7.37 (m, 3H); 7.15 (m, 1H); 5.81 (br s, 1H); 3.0 (d, 3H); 2.76 (q,2H); 1.25 (t, 3H) (Μ+ΗΓ = 280 B <30 85. 2-(5-氯基塞吩-2-基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.32 (s, 1H); 7.67 (d, J=4.2Hz, 1H); 7.54 (d, J=9.0Hz, 1H); 7.22 (d, J=4.2Hz, 1H); 7.15 (s, 1H); 6.98 (d, J=6.9Hz, 1H); 3.81 (s, 3H); 2.84 (d, J=4.5Hz, 3H) (Μ+ΗΓ = 322 A <10 181 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= μΜ. B= 03 to ^5.0 μΜ C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 86. 5-異丙氧基-2-苯基-苯并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13 : 7.87 (m, 2H); 7.74 (s, 1H); 7.54-7.43 (m, 4H); Ί21-123 (m, 1H); 5.82 (br s, 1H); 3.10-3.00 (m+d, 4H); 1.33 (d, 6H) (2M + Na)+ = 609.2 A <10 87. 2-(5-氣基-p塞吩-2-基)-5-乙氧基-苯并 呋喃-3-羧酸甲醯胺 lHNMRinCDCl3: 7.72 (d, J=3.6Hz, 1H); 738 (d, J=8.1HzT 1H); 7.14 (d, J=2.4Hz, 1H); 6.95 (d, J=3.9Hz, 1H); 6.92 (d, J=2.4HzT 1H); 5.98 (s, 1H) 4.10 (q, 2H); 3.07 (d, J=4.5Hz, 3H); 1.45 (t, 3H) (M+H)+ = 336 A <10 88. 5-甲氧基-2-嘧吩-2- 基-苯并呋喃-3-幾酸 甲醯胺 lH NMR in DMSO: 8.38 (s, 1H); 7.83 (d, J=3.3Hz, 1H); 7.76 (d, J=5.4Hzt 1H); 7.55 (d, J=9.0Hz, 1H); 7.21 (m, 1H); 7.11 (cU=2.1Hz,1H); 6.97 (dd,J=9.0, 2.4Hz, 1H); 3.82 (s, 3H); 2.86 (dT J=4.5HzT 3H) (M+H)+ = 288 B <30 89. 5-氯基-2-吡啶-3-基- 苯并呋喃-3-幾酸甲 醯胺. Ή NMR in CDC13: 9.15-9.14 (m, 1H); 8.68-8.66 (m, 1H); 8.33-8.29 (m, 1H); 7.77 (d, J=2.1Hz, 1H); 7.49-7.39 (m, 2H); 7.34 (dd, J=2.1Hz, 8.7Hz, 1H); 6.0 (s, 1H); 3.04 (cU=4.8Hz,3H) (M+H)+ = 286.9 B >30 90. 2-(4-溴基-3-氟基苯 基)-5·異丙氧基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.45 (d, J=3.9Hz, 1H); 7.88 (dd, J=8.4, 2.4Hz, 1H); 7.85 (d, J=3.0Hz, 1H); 7.67 (dd, J=9.0, 1.8Hz, 1H); 7.57 (d, J=8.1Hz, IH); 7.10 (d, J=2.4Hz, 1H); 7.02 (dd, J=9.3, 2.7Hz, 1H); 4.64 (m, 1H); 2.84 (d, J=4.8Hz, 3H); 1.29 (d, J=6.0Hz, 6H) (M+H)+ = 406 A <10 91. 2-(2,4-二氟基-苯 基)-5-異丙氧基-苯 并呋喃-3-叛酸甲醯 胺 NMR in DMSO: 8.04 (d, J=7.2Hz, 1H); 7.82 (d, J=6.3Hz, 1H); 7.56 (d, J=9.3Hz, 1H); 7.46 (d, J=9.3Hz, 1H); 7.30 (d, J=2.4Hz, 1H); 7.20 (d, J=2.1Hz, 1H); 6.99 (dd, J=8.1T 2.4Hz, 1H); 4.61 (m, 1H); 2.75 (d, J=4.8Hz, 3H); 1.30 (d, J=6.0Hz, 6H) (Μ+ΗΓ = 345 A <30 92. 6-溴基-2-(4-氟基-苯 基)-5-異丙氧基-苯 并呋喃-3-羧酸甲 醯胺 *氺氺 (M+H)+ = 406 A <1 93. 5-甲氧基-2-(4-嗎福 琳-4-基-苯墓)-苯并 呋喃-3-羧酸曱醯胺 'H NMR in CDC13: 7.76 (dd, J=4.8, 3.0Hz, 2H); 7.37 (m, 2H); 6.97 (dd, J=9.0, 1.8Hz, 2H); 6.89 (dd, J=8.1, 2.1Hz, 1H); 5.84 (m, 1H); 3.87 (s, 3H); 3.88 (t, 4H); 3.27 (t, 4H); 2.96 (d, J=5.4Hz, 3H) (M+H)+ = 367 B >30 94. 5,6-二甲氧基冬苯 基-苯并咬^-3-幾酸 甲醯胺 lH NMR in CDC13: 7.79 (d, 6.4Hz, 2H); 7.52-7.40 (m, 3H); 7.38 (s, 1H); 7.06 (s, 1H); 5.78 (brs, 1H); 3.96 (s, 3H); 3.94 (s, 3H); 2.96 (d, J=4.7Hz, 3H) (M+H)+ = 312 A <1 95. 5-異丙氧j基-2-(4-1^ 咯啶-1-基-苯基)-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: . 8.16 (s, iH); 7.71 (d, J=8.1Hz, 2H); 7.45 (d, J=8.1Hz, 1H); 7.01 (d, J=1.8Hz, 1H); 6.85 (dd, J=8.1, 2.1Hz, 1H); 6.62 (d, J=8.1Hz, 2H); 4.58 (m, 1H); 2.81 (d, J=3.9Hz, 3H); 2.00 (m, 4H); 1.38 (d, J=6.0Hz, 6H) (M+H)+ = 379 C <30 96. 5-氣基-2-17比淀-4-基- 苯并呋喃各羧酸甲 醯胺 lH NMR in CDCb: 8.75-8.73 (m, 2H); 7.87-7.84 (m, 2H); 7.53-7.43 (m, 2H); 7.18-7.10 (m, 1H); 5.92 (bs, 1H);3.09 (d, J=4.8Hz, 3H) (M+H)+ = 271 B >30 182- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICs〇(/iM) A=彡0*5 /iM B= 03 to ^5.0 C= 5.0 to ^30 μΜ D= >30 fiM 複製子 (μΜ) 97. …2-[2-0-氟基-苯 基>6-甲基-3-甲基 胺申酿基-苯并吱喃 -5-基氧基]-丙酸 lH NMR in acetic-rfj acid-rf (CD3C02D): 8.75-8.73 (m, 2H); 7.87-7.84 (m, 2H); 7.53-7.43 (mT 2H); 7.18-7.10 (m, 1H); 5.92 (bs, 1H); 3.09 (d, J=4.8Hz, 3H) (M+H)+ = 371 c >30 98. 6-乙醯基胺基-2-(4-氟基-苯基)-5-異丙 氧基-苯并呋喃-3-#复 酸甲醯胺 lH NMR in CDC13: 8.66 (s, 1H); 7.99 (s, 1H); 7.82 (dd, 2H, J=5.2 & 8.7Hz); 7.37 (s, 1H); 7.18 (t, 2H, J=8.7Hz); 5.78 (bs, 1H); 4.70 (heptuplet, J=6.1Hz); 2.96 (df 3H, J=4.9Hz); 2.24 (s, 3H); 1.41 (d, 6H, J=6.1Hz) (M+H)+ = 85 A <10 99. 2-(4-胺基-苯基)-5_ 異丙氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDC13: 7.64-7.67 (d, J=8.79Hz, 2H); 7.41-7.42 (d, J=2.93Hz, 1H); 7.32-7.35 (d, J=8.79Hz, 1H); 6.86-6.90 (dofd, J=2.33Hz, 8.79Hz, 1H); 6.74-6.77 (d, J=7.03Hz? 2H); 5.84 (br.s, 1H); 4.56-4.64 (septet, J=6.45Hz, 1H); 2.96-2.97 (d, J=4.69Hz, 3H); 1.35-1.37 (d, J=6.45Hz, 6H) (M+H)+ = 325 B <30 100. 2-(4-敦基-表基)-5_ 異丙氧基-6-(2-嗎福 p森4-基-乙基胺塞)-苯并呋喃-3-複酸甲 醯胺 lH NMR in DMSO: 8.22-8.24 (d, J=4.69Hz, 1H); 7.82-7.87 (m, 2H); 7.28-7.34 (t, i=8.79Hz, 2H); 6.98 (s, 1H); 6.79 (s, 1H); 5.28 (brs, 1H); 4.56 (brs, 1H); 3.60 (brs, 3H); 3.23 (brs, 3H); 2.81-2.82 (d, J=4.69Hz, 3H); 2.61 (brs, 1H); 2.43 (brs, 3H); 1.31-1.33 (d, J=5.86Hz, 6H) (M+H)+ = 456 B <30 101. 2-(4-氟基-苯基)-5- 異丙氧基-6-六氫峨 症-1-基-苯并咬喃 -3-羧酸曱醯胺 lH NMR in CDCI3: 7.89-7.84 (m, 2H); 7.23 (s, 1H); 7.14 (t, J=8.79, 2H); 7.04 (s, 1H); 5.78 (bs, 1H); 4.69-4.29 (septet, J=6.15, 1H); 3.05-3.01 (ra, 4H); 2.98 (d, J=5.27, 3H); 1.77-1.72 (m, 4H); 1.60-1.59 (rn, 2H); 1.36 (d, J=6.15, 6H) (M+H)+ = 411 A <1 102. 2_(4_氟基-苯基) -5,6-二甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.85-7.81 (m, 2H); 7.32 (s, 1H); 7.25-7.20 (m, 2H); 7.05 (s, 1H); 5.75 (brs, 1H); 3.96 (s, 3H); 3.947 (s, 3H); 2.98 (d, J=4.2Hz, 3H) (M+H)+ = 330 A <1 103. 2-(4-氣基-表基)-5 -甲氧i-6-嗎福^7林-4-i-冬并咬喃-3-竣 甲醯胺 TH NMR in CDCl3: 7.85-7.81 (m, 2H); 7.30 (s, IH); 7.17 (t, J=8.8Hz, 2H); 7.08 (s, 1H); 3.94 (s, 3H); 3.94-3.91 (m, 4H); 3.11-3.09 (m, 4H); 2.98 (d, J=4.7Hz, 3H) (M+H)+ = 385 A <1 104. 2-(4- >臭基-苯基)-5- 異丙氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDCI3: 7.80 (d, 2H, J=8.79); 7.61 (d, 2H, J=8.79); 7.39 (d, 1H, J=8.79); 7.28 (d, 1H, J=2.34); 6.94 (dd, 1H, J=8.79, 2.34); 5.80 (brs, 1H); 4.58 (m, 1H); 3.01 (d, 3H, J=4.69); 1.36 (d, 6H, J=6.45) , (M+H)+ = 288 A <10 105. 2-(4-氟基-3-羥基-苯 基)-5-異丙氧基-苯 并呋喃-3-複酸甲 醯胺 lH NMR in DMSO: 10.18 (brs, 1H); 8.32 (d, 1H, J=4.69); 7.50 (rn, 2H); 7.26 (in, 2H); 7.03 (d, 1H, J=2.34); 6.93 (dd, 1H, J=8.79, 2.34); 4.58 (m, 1H); 2.81 (d, 3H, J=4.69); 1.26 (d, 6H, J=5.86) (M+H)+ = 344 C <30 106. 2_(4_氣基-本基)-5 - 異丙氧基-苯并吱喃 各羧酸甲醯胺 Ή NMR in CDCI3: 8.11 (d, 2H, J=8.21); 7.74 (d, 2H, J=8.79); 7.43 (d, 1H, J=9.38); 7.20 (d, 1H, J=2.34); 7.00 (dd, IH, J=8.79, 2.34); 5.88 (brs, 1H); 4.58 (m, IH); 3.06 (d, 3H, J=4.69); 1.36 (d, 6H, J=6.45) (M+H)+ = 335 B <30 183 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 QiM) A= <0*5 /«M B= 0*5 to s5.0 /tM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 107. 5-甲氧基-2-吡啶冰 基-苯异咬喃-3-幾酸 甲醯胺 lH NMR in CDC13: 8.72 (d, J=5.4H3, 2H); 7.83 (dd, J-1.8H3, 4.5H3, 2H); 7.45 (d, J=9.0H3, 1H); 7.20 (d, J=2.2H3, 1H); 7.01 (dd, J=2.7H3, 8.7H3, 1H); 5.90 (bs, 1H); 3.88 (s, 3H); 3.08 (d, J=4.8H3, 3H) (M+H)+ = 283 B <100 108. 2-(4-氟基-苯基)-5-異丙氧基-6-(3-甲燒 橫St基-峨4淀小 基)-苯并啥喃-3-幾 酸甲醯胺 lU NMR in DMSO: 7.90 (dd, J=1.8,5.3Hz, 2H); 7.33 (t, J=8.8Hz, 2H); 7.07 (s, 1H); 7.05 (s, 1H); 4.63 (p, J=6.4Hz, 1H); 3.96 - 3.86 (m, 2H); 3.49 - 3.32 (m, 2H); 3.03 (s, 3H); 2.82 (s, 3H); 231 (m, 2H); 1.33 (d, J=1.2Hzt 6H) (M+H)+ = 475 A <1 109. 6-三亞甲五胺基-1-基_2_(4-氣基-苯基) -5-異為乳基-苯并咬 喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.82 (dd, J=5.3, 8.8Hz, 2H); 7.13 (s, 1H); 7.13 (t, J=8.2Hz, 2H); 6.54 (s, 1H); 4.60 (p, J=5.9Hz,1H); 3.96 (t, J=7.6Hz, 4H); 2.97 (d, J=5.3Hz, 3H); 2.29 (p, J=7.0Hz, 2H); 1.36 (d, J=6.4Hz, 6H) (M+H)+ = 383 A <1 110. 厶(4-氟i-苯基) -6-(3-經基-p比洛啶 -1 -基)-5-異丙氧基-苯并呋喃-3-幾酸甲 醯胺 氺氺氺 (M+H)+ = 413 A <1 111. 2-(4-氟基-苯基)-5-異丙氧基-6-(曱烷磺 醯基-甲基-胺基)-苯 并呋喃-3-複酸甲 醯胺 *H NMR in CDC13: 7.81 (2H, dd, J=5.3, 8.8Hz); 7.56 (1H, s) 7.42 (1H, s); 7.20 (2H, r, J=8.8Hz); 5.70 (1H, bs); 4.80 (1H, heptuplet, J=6.2Hz); 3.32 (3H, s); 2.98 (3H, s); 2.96 (3H, s); 1.42 (3H, d, J=6.2Hz) (M+H)+ = 435 A <1 112. 2_(4_氣基·苯基)-6_ [(吱喃-3_基甲基)-胺 基]-5-異丙氧基-苯 并吱喃-3-幾酸甲 醯胺 lH NMR in CDC13: 7.76 - 7.81 (m, 2H); 7.37 (d, J=U7, 1H); 7.17 (s, 1H); 7.086 - 7.145 (t, J=8.79, 2H); 6.746 (s, 1H); 6.319 - 6.328 (m, 1H); 6.242 - 6.252 (d, J=2.93, 1H); 5.86 (bs, 1H); 4.565 - 4.645 (septet, J=6.45, 1H); 4.365 (s, 2H); 2.940 -2.955 (d, J=4.69, 3H); 1.375 - 1.254 (d, J=6.45,6H) (M+H)+ = 423 A <1 113. 6-(2,3-二經基·丙基 胺墓)-2-(4-氣基-苯 基)-5-異丙氧基-苯 并呋喃-3-羧酸甲 醯胺 (Η NMR in CDCl3: 7.78 (bs, 2H); 7.12 (rn, 4H); 6.72 (bs, 1H); 5.84 (d, J=4.7 Hz, 1H); 4.60 (p, J=5.9 Hz, 1H); 4.01 (m, 1H); 3.80 (dd, J=3.52, 11.1 HZ, IH);3.66 (dd, J=5.9, 11.1 Hz, 1H); 2.96 (d, 1=4.1 Hz, 3H); 1.37 (dd, J=1.8, 5.9 Hz, 6H) (M+H)+ = 417 B <10 114. 2_(4·氟基-苯基)-5-異丙氧基-6-異丙基 胺基-苯并ρ夫喃-3-複 酸甲醯胺 *H NMR in CDCI3: 7.805 -7.834 (m, 2H); 7.151 (s, 1H); 7.100-7.127 (m, 2H); 6.680 (s, lH); 5.900 (bs, 1H); 4.580 - 4.600 (septet, J=5.861, 1H); 3.662 - 3.686 (septet, J=7.033, 1H); 2.955 -2.971 (d, J=4.688, 3H); 2.057 (s, 1H); 1.361 -1.381 (d, J=5.861, 6H); 1.258 - 1.277 (d, J=5.861,6H) (M+H)+ = 385 A <1 184- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= μΜ B= 03 to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 /iM 複製子 (μΜ) 115. 6-(環丙基甲基-胺 基)-2-(4-氣基-冬基) -5-異丙氧基-苯并呋 喃-3-羧酸甲酿胺 lH NMR in CDC13: 7.780 - 7.866 (m, 2H); 7.176 (s, IH); 7.104 -7.160 (m, 2H); 6.664 (s, 1H); 5.781 (bs, 1H); 4.567 - 4.647 (septet, J=5.86l, 1H); 3.000 -3.024 (d, J=7.033,2H); 2.965 - 2.981 (d, J=4.689, 3H); 1.502 - 1.676 (m, 1H); 1.383 -1.402 (m, 1H); 1.211 - 1.172 (m, 1H); 0.557 -0.619 (m, 1H); 0.262 - .0311 (m, 1H) (M+H)+ = 397 A <1 116. 2-(4-氟基-苯基)-5^ 甲氧基-6-吡咯啶-1- 基-苯并吱喃-3-複酸 甲醯胺 lH NMR in CDC13: 8.28 (d, 1=4.40, 1H); 7.89 - 7.84 (m, 2H); 7.31 (t, J=8.79, 2H); 7.00 (s, 1H); 6.91 (s, 1H); 3.81 (s, 3H); 3.29 (m, 4H); 2.82 (d, J=4.40, 3H); i.88 (m,4H) (M+HT = 369 A <1 117. 5'芊氧基-2-(4-氟基-苯基)_6-嗎福啉>4-基-冬并咬喃-3-棱fe 甲醯胺- j ------ NMR in CDCb: 7.788 - 7.83 (m, 2H); 7.60 - 7.09 (m, 9H); 5.71 (bs, 1H); 5.19 (s, 2H); 3.90 - 3.87 (m, 4H); 3.17 - 3.15 (m, 4H); 2.98 (d, J=51.Hz, 3H) (M+H)+ = 461 A <1 118. 5-羥甲基-2-苯基,苯 并呋喃-3-複酸甲 醯胺 lH NMR in CDC13: 7.98-7.87 (m, 3H); 7.53-7.43 (mT 4H); 7.38 (d, J=7.0Hz, 1H); 5.84 (br s, 1H); 4.83 (d, J=6.0Hz, 2H); 2.99 (d, J=5.3Hz, 3H) (M+H)+ = 282 C >100 119. 2-(4-氣基-苯基)-5_ 異丙氧基-6-K2-甲 氧基-乙基)-甲基-胺 基]-苯并呋喃各羧 酸甲醯胺 *H NMR in CDCI3: 7.86 - 7.82 (m, 2H); 7.26 - 7.24 (m, 1H); 7.15 (t, J=8.35Hz, 2H); 7.08 (s, 1H); 5.76 (s, 1H); 4.70 - 4.62 (septet, J=6.15Hz, 1H); 3.59 (tt J=6.15Hz, 2H); 3.37 - 3.35 (m, 2H); 3.33 (s, IH); 2.98 (d, J=4.83Hz, 3H); 2.92 (s, 3H); 1.39 (d, J=6.15Hz, 6H) (M+H)+ = 415 A <1 120. 6-胺基-5-苄氧基 -2-(4-氟基-苯基)-苯 并呋喃-3-幾酸甲 醯胺 lH NMR in CDC13: 7.86 - 7.80 (m, 2H); 7.45 - 7.33 (m, 5H); 7.287 (s, 1H); 7.17 - 7.12 (m, 2H); 6.85 (s, 1H); 5.71 (brs, 1H); 5.15 (s, 2H); 2.97 (d, J=5.3Hz, 3H) (M+H)+ = 391 A <10 121. 5-異丙氧基 基-吱喃-2-基)-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDCI3: 7.664 - 7.674 (d, J=2.931, 1H); 7.512 - 7.518 (d, J=L.759, 1H); 7.319 - 7.348 (d, J=8.792, 1H); 6.893 - 6.932 (d of d, J=2.931, 5.861, 1H); 6.721 (bs, 1H); 6.448 - 6.453 (d, J=1.759, IH); 4.584 - 4.664 (septet, J=5.861, 1H); 3.006 - 3.024 (d, J=5.275, 3H); 2.322 (s, 3H); 1.344 - 1.363 (d, J=5.861, 6H) 氺氺氺 B <30 122. 2_(4氟基苯基)-6_ 甲烷磺醯基胺基-5-甲氧基-苯并呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.37 (m, 1H);7.93 (dd,J = 5.1 & 9.1 Hz, 2H); 7.56 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.17 (s, iH); 3.90 (s, 3H); 2.98 (s, 3H); 2.83 (d, J = 4.9 Hz, 3H) (M+H)+ = 393 A <1 185 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= μΜ B= 0 J to ^5.0 μ,Μ C= 5.0 to ^30 fiM D= >30 μΜ 複製子 <JiM) 123. 2-(4-氟基-苯基)-5-異丙氧基-6-[(四鼠-4喃-2-基甲墓)-胺 基]-苯并呋喃-3-羧 酸甲醯胺 lH NMR in DMSO: 8.27 (d, br, 1H); 7.88 (dd, 2H); 7.31 (dd, 2H); 6.92 (s, 1H); 6.84 (s, 1H); 4.98 (m, 1H); 4.57 (m, 1H); 4.11 (m, 1H); 3.8 - 3.64 (mt 2H); 3.16 (m, 1H); 2.82 (d, 3H); 1.84-1.42 (m, 4H); 1.35 (d, 6H) (M+H)+ = 427 A <10 124. . 5(4-氟基-苯基)-5-岁f基·_6-嗎福ρ·ϋ-4-基 -苯并呋喃-3-幾酸甲 醯胺 lH NMR in CDC13: 8.00 - 7.95 (m, 2H); 7.36 - 7.26 (m, 2H); 7.21 -7.18 (m, 2H); 6.98 (bs, 1H); 5.83 (bs, 1H); 3.95 - 3.92 (m, 4H); 3.04 (d, J=5.1Hz, 3H); 2.97 - 2.96 (m, 4H) (M+H)+ = 370 B <10 125. 5-環丙甲氧基-2-(4-氟基-苯基)-6-嗎福 4-4-基-苯并吱喃 -3-羧酸甲醯胺 lH NMR in CDCb: 7.89 - 7.84 (m, 2H); 7.30 (s, 1H); 7.22 - 7.16 (m, 2H); 7.08 (s, 1H); 5.76 (bs, 1H); 3.94 -3.97 (m,6H); 3.20 - 3.17 (m,2H); 3.01 (d, J=4.8, 2H); 0.71 - 0.64 (m, 2H); 0.42 - 0.38 (m, 2H) (M+H)+ = 425 A <1 126. 6-亂基-2-(4-氣基-冬 基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.86 - 7.81 (m, 2H); 7.54 (s, 1H); 7.42 (s, 1H); 7.23 - 716 (m, 2H); 5.77 (brs, 1H); 3.96 (S, 3H); 2.98 (d, )=4.1 Hz, 3H) (M+H)+ = 334.0 A <1 127. 6-(2,5-二甲基-2H-吡唑-3-基胺基) -2-(4-氟基-苯基)·5-異丙氧基-苯并4喃 -3-羧酸甲醯胺 *H NMR in CDC13: 7.782-7.826 (m, 2H); 7.352 (s, 1H); 7.137-7.194 (m, 2H); 6.840 (s, 1H); 6.069 (s, 1H); 5.930 (s, iH); 5.795 (bs, 1H); 4.686-4.746 (septet, J=6.447, 1H); 3.695 (s, 3H); 2.986-3.004 (d, J=5.275, 3H); 2.287 (s, 1H); 1.645 (bs, 2H); i.436-1.457 (d, J=6.447, 3H) (M+H)+ = 437.0 C 氺氺氺 128. 2_(4_氟基-苯基)-6_ 嗎福p林-4-墓-5-(^7比 啶-4-基甲氧基)-苯 并呋喃-3-幾酸甲 醯胺 'H NMR in CDC13: 8.68-8.65 (m, 2H); 7.87-7.82 (m, 2H); 7.40-7.43 (m, 3H); 7.25-7.15 (ra, 3H); 5.70 (bs, 1H); 5.23 (3, 2H): 3.98-3.92 (m, 4H); 3.15-3.21 (m, 4H): 2.99 (d, J=48 Hz, 3H) (M+H)+ = 462 A 氺氺氺 129. 6- 基-2-(4-氣基-苯 基)-5-異禹氧基-苯 并呋喃-3-幾酸甲 醯胺 *H NMR in CDC13: 7.87-7.82 (m, 2H): 7.67 (s, iH); 7.45 (s, 1H); 7.26-7.19 (m, 2H); 5.73 (bs, 1H); 4.75-4.67 (m, iH); 2.98 (d, J=4.8 Hz, 3H); 1.43 (d, J=6.3 Hz, 6H) (M+H)+ = 353 A 氺氺氺 130. 5-甲氧基-2-苯基-苯 并啥喃-3-幾酸乙 醯胺 lH NMR in CDC13: 7.86 (dd, J= 2.1, 7.4 Hz, 2H); 7.47 (m, 3H); 7.39 (ra, 2H); 5.78 (brs, 1H); 3.88 (s, 3H); 6.94 (dd, J= 2.6, 9.0 Hz, 1H); 3.48 (dq, J= 1.3, 7.2 Hz, 2H); 1.17(t,7.2 Hz, 3H) (M+H)+ = 295 C <10 131. 2-(4-氟基-苯基)-5-異丙氧基-6-(4淀 斗基胺基)-苯并呋 喃-3-羧酸甲醯胺 lH NMR in CDCi3: 8.29-8.31 (d, 2H, J=5.86Hz); 7.80-7.84 (m, 2H); 7.51 (s, iH); 7.36 (s, 1H); 7.13-7.19 (t, 2H, J=8.21Hz); 6.95-6.98 (m, 2H); 6.62 (s, 1H); 6.13-6.15 (d, 1H, J=4.69Hz); 4.60-4.68 (septet, lH, J=5.86Hz); 2.97-2.99 (d, 3H, J=5.28Hz); 1.37-1.39 (d, 6H, J=5.86Hz) (M+H)+ = 420 B <30 186- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= ί0·5 /ιΜ B= (K5 to 彡5.0 /iM C= 5.0 to ^30 /iM D= >30 μΜ 複製子 _ 132. 2-(4-氟基-苯基)-5-異丙氧基-6-(4-甲基 -六氫吡畊-1-基)-苯 并呋喃复酸甲 龜胺 lH NMR in DMSO: 7.80-7.86 (m, 2H); 7.21 (s, 1H); 7.09-7.15 (t, 2H, J= 8.79Hz); 6.99 (s, 1H); 6.12-6.14 (d, 1H, J= 4.69Hz); 4.58-4.66 (septet, 9H, J= 6.45 Hz); 3.10 (brs, 4H); 2.95-2.96 (dT 3H, J= 4.69Hz); 2.58 (brs, 4H); 2.34 (s, 3H); 134-1.36 (d, 6H, J= 6.45 Hz) (M+H)+ = 426 C >30 133. 氣基-丙:fe-1 -績 酿基胺基)-2-(4-氟 基-苯基)-5-異丙氧 基-苯并p夫喃-3-叛酸 甲醯胺 'H NMR in DMSO: 9.1 i (s,lH); 8.37 (m, 1H); 7.92 (dd, J= 8.8& 5.7 Ha 2H); 7.56 (s,1H); 7.36 仏 J= 8·8 Hz, 2H); 7.16 (s7 IH); 4.74 (heptuplet, J= 5.7 Hz, IH); 3.74 (t, J= 6.6Hz, 2H); 3.21 (m, 2H); 2.82 (d, J= 4.8Hz, 3H); 2.21 (m, 2H); 135 (d, J= 5.7Hz, 6H) (M-H)·= 481; 483 B <1 134. 6-(1,1-二氧基-1λ6-異嘧唑啶-2-基) -2-(4-氣基-苯基)-5-異南氧!基-本并味喃 •3_羧酸甲醯胺 lH NMR in DMSO: 8.40 (ra, 1H); 7.92 (dd, J=5.5 d 9.2 Hz, 2H); 7.60 (s, 1H); 7.37 (t, J=9.2 Hz, 2H); 7.19 (s, 1H); 4.69 (heptuplet, J=5.9 Hz, 1H); 3.75 (t, J=7.0 Hz, 2H); 3.37 (m, 2H); 2.82 (d, J=4.9 Hz, 3H); 2.43 (p, J=7.0 Hz, 2H); 1.34 (d, J=5.9 Hz, 6H) (M+HT = 447 B <10 135. 2_(4_氟基-苯基)-< 異丙氧基-6-腺基-苯 并呋喃-3-複酸甲 醯胺 'H NMR in DMSO: 8.38 (s, 1H); 8.28 (m, 1H); 7.87 (dd, J=5.3 & 9.2 Hz, 2H); 7.30 (t, J=8.8 Hz, 2 H); 7.09 (s, 1H); 6.39 (bs, 2H); 4.62 (heptuplet, J=6.1 Hz, 1H); 2.80 (d, J=4.8 Hz, 3H); 1.88 (s, 1H); 1.32 (d,J=5.7 Hz, 6H) (M+H)+ = 486 A <10 136. 2-(4-氣基-苯基)-5_ 異丙氧基-6-(異丙基 -甲烷磺醯基-胺基)-苯并呋喃胃3-叛酸甲 醯胺 lH NMR in DMSO: 8.40 (m, 1H); 7.90 (dd, J=5.3 & 8.84 Hz, 2H); 7.69 (s, 1H); 7.36 (t, J=8.8 Hz, 2H); 7.11 (s, 1H); 4.75 (heptuplet, J=6.6 Hz, 2H); 4.22 (heptuplet, J=7.1 Hz, 1H); 3.06 (s, 3H); 2.80 (d, J=7.1 Hz, 3H); 1.32 (t, J=6.6 Hz, 6H); 1.20 (d, J=7.1 Hz, 3H); 1.05 (d, J=7.1 Hz, 3H) (M+H)+ = 463 A <1 137. 6-(環丙甲基-甲貌續 醯基-胺基>2-(4-氟 基-苯基)-5-異丙氧 基-苯并呋喃-3-羧酸 甲醯胺 lH NMR iQ DMSO: 8.44 (m, 1H); 7.94 (dd,J=5.1 & 9.1 Hz, 2H); 7.57 (s, 1H); 7.38 (t, J=8.8 Hz, 2H); 7.16 (s, 1H); 6.78 (heptuplet, J=5.7Hz, 1H); 3.01 (s, 3H); 2.83 (d, J=4.4 Hz, 3H); 1.33 (d, J=5.7 Hz, 6H); 0.85 (m, 1H); 0.37 (m, 2H) (M 十 H)+ = 475 A <1 138. 6-(2,6-二甲基-嗎福 14-基)-2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃-3-叛酸甲 醯胺 lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.28 (d, J=8.79 Hz, 1H); 7.17 (T, J=8.79 Hz, 2H); 7.04 (s, 1H); 5.77 (s, 1H); 4.69-4.61 (septet, J=6.15 Hz, IH); 3.95-3.89 (m, 2H); 3.46 (d, J=11.43 Hz, 2H); 2.98 (d, J=4.84 Hz, 3H); 2.37 (T, J=l〇'.55 Hz, 2H); 1.37 (d, J=6.15 Hz, 6H); 1.25 (d, J=6.15 Hz, 6H) (M+H)+ = 441 B <10 139. 2-(4**氟基-苯基)-5_ 異丙氧基-6-(1Η-四 峻-5-基)-苯弁呋喃 -3-羧酸甲醯胺 lH NMR ia CDCi3: 8.547 (s, 1H); 7.89-7.84 (m, 2H); 7.61 (s, 1H); 7.60-7.20 (m, 2H); 5.8 (bs, 1H); 5.0-4.92 (m, 1H); 3.26 (bs, 1H); 2.99 (d, J=5.iHz, 3H); 1.52 (d, J=6.0Hz, 6H) (M+H)+ =3% B >30 187- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A= μΜ B= 03 to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 140. 2-(4-氟基-苯基) -6-(4-羥基-六氫吡 淀-1-基>5-異丙氧 基-苯并呋喃-3-幾酸 甲酿胺 lH NMR in DMSO: 8.28 (d, J=4.84Hz, 1H); 7.92-7.86 (m, 2H); 7.33 (t, J=8.79Hz, 2H); 7.16 (s, 1H); 7.03 (s, 1H); 4.64-4.56 (m, 2H); 3.61 (m, 1H); 3.35 (m, 2H); 2.82 (d, J=4.40Hz, 3H); 2.74-2.67 (m, 2H); 1.88-1.85 (m, 2H); 1.62-1.52 (m, 2H); 1.29 (d, J=5.72Hz, 6H) (M+H)+ = 427 B <10 141. 2-(4-氟基-苯基) -6-(3-羥基-六氫外匕 读>1-基;)-5-異丙氧 基-苯并呋喃-3-m酸 甲醯胺 lH NMR in DMSO: 8.29 (d, J=4.84Hz, 1H); 7.92-7.87 (m, 2H); 7.33 (t, J=8.79HzT 2H); 7.14 (s, 1H); 7.03 (s, 1H); 4.73 (ci J=4.84Hz, 1H); 4.63-4.55 (septet, J=6.15Hz,1H); 3·67·3·65 (m,1H); 3.49 (d, J=8.79Hz, 2H); 2.82 (d, J=4.40Hz, 3H); 2.5 (m, 1H); 2.33 (t, J=9.67Hz, 1H); 1.95-1.91 (m, 1H); 1.74 (m, 1H); 1.62-1.58 (m, 2H); 1.29 (d, J=6.15Hz, 3H); 1.28 (d, J=5.71, 3H) (M+H)+ = 427 B <10 142. 2_(4_氟基-苯基):5_ 異丙乳基^-6-(嗎福^林 -4-磺醯基)-苯并呋 喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.48-8.47 (d, J=4.69Hz, 1H); 8.01 (s, 1H); 8.00-7.95 (m, 2H); 7.44-7.38 (t, J=8.79Hz, 2H); 734 (s, iH); 4.91-4.83 (septet, J=5.86Hz, 1H); 3.62-3.59 (m, 4H); 3.16-3.13 (m, 4H); 2.85-2.84 (d, J=4.69Hz, 3H); 1.37-1.35 (d, J=5.86Hz, 6H) (M+H, = 477 A <10 143. 2-(4-氟基-苯基)-5-異丙氧基-6-甲基月安 石菱s&i-苯并咬喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.46-8.45 (d, J=4.10Hz, 1H); 7.99-7.95 (m, 2H); 7.95 (s, 1H); 7.43-7.37 (t, J=8.79Hz, 2H); 7.32 (s, 1H); 6.64 (d, J=4.69Hz, 1H); 4.90-4.82 (septet, J=5.86Hz, 1H); 2.85-2.83 (d, J=4.69Hz, 3H); 2.48-2.46 (d, J=4.69Hz, 3H); 1.38-1.36 (d, J=5.86Hz, 6H) (Μ+ΗΓ = 421 A >30 144. 6-二甲基胺磺醯基― -2-(4-氣基-苯基)-5- 異丙氧基-苯并4喃 各羧酸甲醯胺 lH NMR in DMSO: 8.461=8.451 (d, J=4.689Hz, 1H); 8.016-7.949 (m, 3H); 7.436-7.377 (t, J=8.791Hz, 2H); 7.323 (s, 1H); 4.904-4.823 (septet, J=5.861Hz, 1H); 2.848-2.832 (dT J=4.689Hz, 3H); 2.775 (s, 6H); 1.365-1.344 (d, J=6.447Hz, 6H) (M+H)+ = 435 A <30 145. 2-(4-氟基-苯基)-5-異丙氧基-6-(丙烷 磺醯基胺基)-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.85 (s, 1H); 8.36 (m, 1H); 7.91 (dd, J=9.2, 5.3Hz, 2H); 7.59 (s, 1H); 736 (t, J=8.8HzT 2H); 7.13 (s, 1H); 4.75 (heptuplet, J=5.6Hz, 1H); 3.21 (heptuplet, J=5.5Hz, 1H); 2.82 (d, J=4.9Hz, 3H); 1.36 (d, J=5.5Hz, 6H); 1.28 (d, J=5.6Hz, 6H) (M+H)+ = 449 B <10 146. 2-(4-貌基-苯基)-5_ 異丙氧基-苯并呋喃 -3,6-二羧酸6-醯胺 -3-甲醯胺 lU NMR in CDC13: 8.33 (s, 1H); 8.10 (bs, 1H); 7.88-7.84 (m, 2H); 7.48 (s, 1H); 7.25-7.18 (m, 2H); 5.88 (bs, 1H); 5.75 (bs, 1H); 4.88-4.80 (in, 1H);'2.99 (d, J=5.4Hz, 3H); 1.46 (d, J=6.3Hz, 6H) (M+H)+ = 371 B >30 147. 2-(4-氣基-木基)-5- 異丙氧基 墓-苯并咬喃各複酸 甲醯胺 lH NMR in DMSO: 9.13 (s, 1H); 8.99 (s, 2H); 8.41 (q, br, 1H); 7.92 (m, 2H); 7.82 (s, 1H); 7.36 (m, 2H); 7.27 (s, 1H); 4.64 (m, 1H); 2.83 (d, 3H); 1.23 (d, 6H) (M+H)+ = 406 A <10 188- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= B= 0»5 to 彡5.0 /iM C= 5.0 to ^30 μΜ D= >30 /iM 複製子 (μΜ) 148. 6-第三-丁基胺基 -2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃 -3-羧酸甲醯胺 ^NMR in CDC13: 7.85-7.80 (m, 2H); 7.18 (s, 1H); 7.14 (t, J=8.79Hz, 2H); 6.98 (s, 1H); 5.74 (bs, 1H); 4.60-4.52 (septet, J=6.15Hz, 1H); 4.57 (s, 1H); 2.97 (d, J=4.84Hz, 3H); 1.41 (s, 9H); 1.37 (d, J=6.15Hz, 6H) (M+H)+ = 399 A <10 149. 2-(4-氣基-木基)-5_ 異丙氧基-6-胺磺醯 基-苯+夫喃-3-叛酸 甲醯胺 jH NMR in DMSO: 8.39-8.37 (d, J=4.69Hz, 1H); 7.97-7.93 (m, 2H); 7.91 (s, 1H); 7.39-7.33 (t, J=8.79Hz, 2H); 7.07 (s, 1H); 4.66 (septet, J=6.45Hz, 1H); 2.84-2.82 (d, J=4.69Hz, 3H); 1.30-1.28 (d, J=6.45Hz, 6H) (M-H)·= 406.0 C >30 150. 6-環丁基胺績醯基 -2-(4-氣基-苯基)-5-異禹氧基-苯并4喃 -3-羧酸甲醯胺 lH NMR in CDC13: 8.057 (st 1H); 7.869-7.823 (m, 2H); 7.522 (s, 1H); 7.248-7.205 (rat 2H); 5.766 (bs, 1H); 5.156-5.125 (d, J=9.377Hz, 1H); 4.895-4.813 (septet, J=5.862Hz, 1H); 3J87-3.707 (sextet, J=8.206Hz, 1H); 2.984-2.969 (d, J=4.689Hz, 3H); 2.063-1.967 (m, 2H); 1.828-1.734 (m, 2H); 1.580-1.512 (m, 2H); 1.494-1.475 (d, J=5.862Hz, 6H) (M+H)+ = 461.0 B <30 151. 2-(4-氟基-苯基)-6_ 咬喃-2-基-5-異与氧 基-苯并咬喃-3-幾酸 甲醯胺 lH NMR in CDCl3: 7.96 (s, iH); 7.88 (m, 2H); 7.48 (d, 1H); 7.37 (s, 1H); 7.17 (m, 2H); 7.08 (d, IH); 6.51 (d, 1H); 5.75 (s, br, 1H); 4.79 (m, IH); 2.99 (d, 3H); 1.45 (d, 6H) (M+H)+ = 394 A <30 152. 2-(4-氣基-苯基)_6_ 呋喃-3-基-5-異丙氧 基-苯并呋喃-3-羧酸 甲醯胺 *H NMR in CDCb: 8.12 (s, 1H); 7.90 (m, 2H); 7.61 (s, 1H); 7.48 (d, 1H); 7.38 (s, 1H); 7.18 (m, 2H); 6.83 (d, 1H); 5.75 (s, br, 1H); 4.79 (mT 1H); 2.99 (d, 3H); 1.45 (d, 6H) (M+H)+ = 394 A <10 153. 2-(4-氟基-苯基)-5- 異丙氧 基-苯并呋喃-3-羧酸 甲醯胺 NMR in CDC13: 8.80 (d, 1H); 8.57 (dd, 2H); 7.92 (m, 3H); 7.45 (s, 2H); 7.33 (dd, 1H); 7.20 (m, 2H); 5.80 (s, br, 1H); 4.56 (m, 1H); 2.99 (d, 3H); 1.28 (d, 6H) (M+H)+ = 405 A <10 154. 2-(4-氟基-苯基>5: 異呙氧基-6十比洛淀 -1-績醯基)-苯并吱 喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.455-8.471 (m, 1H); 8.028 (s, 1H); 7.996-7.949 (m, 2H); 7.436-7.375 (m, 2H); 7.321 (s, 1H); 4.918-4.838 (septet, J=5.861Hz, 1H); 2.846-2.832 (d, J=4.103, 3H); 2.512-2.486 (peatet, J=1.758Hz, 4H); 1.779-1.736 (t, J=6.447Hz, 4H); 1.371-1.350 (d, J=6.447Hzt 6H) (M+H)+ = 461.0 A <10 155. 6-壤丙基胺績酿基 ·2·(4-鼠基-苯基)-5-異丙氧基-苯并4喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.47-8.46 (d, J=41.0Hz, 1H); 8.03 (s, 1H); 8.00-7.94 (m, 2H); 7.44-7.38 (t, J=8.79Hz, 2H); 7.32 (s, 1H); 7.21 (s, 1H); 4.B9-4.85 (septet, J=5.86Hz, 1H); 2.85-2.83 (d, J=4.69Hz, 3H); 2.17 (m, 1H); 1.38-136 (cl, J=5.86Hz, 6H); 0.44 (m, 4H) (M+H)+ = 447.0 A <10 156. 孓乙基胺磺醯基 -2-(4-乱基-私基)-5- 異丙氧基··苯并士喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.87 (s, 1H); 8.36 (m, 1H); 7.91 (dd, J=9.0, 5.3Hz, 2H); 7.56 (s, 1H); 7.36 (t, J=8.8Hz, 2H); 7.14 (s, 1H); 4.75 (heptuplet, J=6.1Hz, 1H); 3.05 (quadruplet, J=7.5Hz, 2H); 2.82 (cl, J=4.8Hz, 3H); 1.33 (d, J=6.1Hz, 6H); 1.26 (t, J=7.5Hz,3H) (M+H)+ = 435 A <10 189- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A= μΜ B= 03 to ^5.0 μΜ C= 5.0 to <30 μΜ D=>30 μΜ 複製子 (μΜ) 157. 2-(4- 異丙氧基-6-乙烯基-苯并呋喃-3-幾酸甲 醯胺 lH NMR in DMSO: .8.39 (q, br, 1H); 7.91 (dd, 2H); 7.82 (s, 1H); 7.35 (dd, 2H); 7.12 (s, 1H); 7.05 (dd, 1H); 6.89 (d, 1H); 5.27 (d, 1H); 4.60 (m, 1H); 2.81 (d, 3H); 1.31 (d, 6H) (M+H)+ = 354 A <10 158. 2-(4-氟基-苯基)-5- 異丙氧基-6-甲氧基-苯并呋喃-3-獲酸甲 醯胺 lHNMRinCDCl3: 7.86 (m, 2H); 7.34 (s, 1H); 7.16 (t, J=8.79Hz, 2H); 7.05 (s, 1H); 5.75 (brs, 1H); 4.55 (m, 1H); 3.91 (s, 3H); 2.99 (d, J=4.69Hz, 3H); 1.39 (d,J=5.86Hz, 6H) (M+H)+ = 358 A <10 159. 6-(3,5-二甲基-異嘮 唑冬:1〇-2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃-3-幾酸甲 醯胺 lHNMRinCDCl3: 7.90-7.85 (m, 2H); 7.63 (s7 2H); 7.23-7.17 (m, 3H); 5.78 (brst 1H); 4.52-4.48 (m, 1H); 3.0 (d, J=4.8Hz, 3H); 2.32 (s, 3H); 2.20 (s, 3H); 1.24 (d, J=6.3Hz, 6H) (M+H)+ = 423 A <1 160. 2-(4- 甲醯基-5-異丙氧基-苯并呋喃-3-幾酸甲 醯胺 lH NMR in CDC13: 10.524 (s, 1H); 7.93 (s, 1H); 7.90-7.85 (m, 2H); 7.44 (s, 1H); 7.25-7.19 (m, 2H); 5.78 (br, 1H); 4.76 (pent, 1H); 2.98 (d, 3H); 1.43 (d, 6H) (M+H)+ =355.9 A <30 161. 2-(4-氟基-苯基) 氣基比淀-3-基)-5-異丙氧基-苯 并呋喃-3-幾酸甲 醯胺 *H NMR in CDCb: 8.52 (s, 1H); 8.45 (d, 1H); 7.88 (dd, 2H); 7.45 (s, 1H); 7.38 (m, 1H); 7.26 (s, 1H); 7.20 (dd, 2H); 5.77 (s, br, 1H); 4.55 (m, 1H); 2.99 (d, 3H); 1.24 (d, 6H) (M+H)+ = 423 A <10 162. 2-(4-氟基-苯基)-5-異丙氧基·6-(曱垸績 醯基胺基-甲基)-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.85-7.81 (m, 2H); 7.44 (s, 1H); 7.41 (s, 1H); 7.23-7.17 (m, 2H); 5.73 (s, 1H); 4.98 (t, J=5.4Hz, 1H); 4.78-4.71 (m, 1H); 4.39 (d, J=6.6Hz, 3H); 2.97 (d, J=4.8Hz, 3H); 2.74 (s, 3H); 1.40(d, J=5.7Hz,6H) (M+H)+ = 435 B <10 163. 6-(環戊基-甲烷磺醯 基-胺基)-2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J=6.2 & 8.8Hz, 2H); 7.53 (s, 1H); 7.38 (t, J=8.8Hz, 2H); 7.13 (s, 1H); 4.76 (heptupiet, J=5.7Hz, 1H); 4.28 (quintuplet, J=8.8Hzt 1H); 3.11 (s, 3H); 2.83 (m, 3H); 1.93 (m, 2H); 1.45 (m, 2H); 1.34 (m, 4H) (M+H)+ = 489 A <1 164. 2-(4-氟基-苯基) _6-[(2-羥基-乙基)_ 甲烷磺醯基-胺基] -5-異丙氧基-苯并呋 喃-3-羧酸曱醯胺 lH NMR in DMSO: , 8.41 (m, 1H); 7.93 (dd, J=5.2Hz, 2H); 7.60 (s, 1H); 7.38 (t, J=8.8Hz, 2H); 7.16 (s, 1H); 4.78 (heptupiet, J=5.8Hz, 1H); 4.67 (t, J=5.7Hz, 1H); 3.60 (bs, 1H); 3.04 (s, 3H); 2.83 (d, J=4.8Hz, 3H); 1.34 (d, J=5.7Hz, 6H) (M+H)+ = 465 A <10 190- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A= /tM B= 0*5 to ii.O /iM C= 5.0 to ^30 μΜ D= >30 μ,Μ 複製子 〇iM) 165. 2-(4-氣基-苯基)-5-輕基-6-甲氧基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.94 (m, 2H); 7.28 (s, 1H); 7.15 (t, 2H, J=8.79 Hz); 7.04 (s, 1H); 5.82 (brs, 1H); 5.59 (s, 1H); 3.97 (s, 3H); 3.01 (d, 3H, J=5.28 Hz) (M+H)" = 316 C >30 166. 5-乙乳基-2-(4- 氣基-苯基)-6-嗎福啉-4-基-苯并咬喃-3-複酸 甲醯胺 *H NMR in DMSO: 8.30 (m, 1H); 7.88 (m, 2H); 7.32 (t, 2H, J=8.79 Hz); 7.16 (s, 1H); 7.04 (s, 1H); 4.06 (q, 2H,J=7.03 Hz); 3.74 (bm» 4H); 3.02 (bm,4H); 2.80 (d, 3H, J=4.69 Hz); 1.36 (t, 3H, J=7.03 Hz) (M+H)+ = 399 B <10 167. 5-(4-氟基-¥氧基) -2-(4-敦基-苯基)-6-嗎福琳-4-基-苯奔p夫 喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.30 (m, 1H); 7.88 (m, 2H); 7.55 (m, 2H); 7.33 (t, 2H, J=8.79 Hz); 7.27-7.20 (m, 4H); 5.14 (s, 2H); 3.72 (bm, 4H); 3.03 (bm, 4H); 2.82 (d, 3H, J=4.69) (M+H)+ = 479 B <1 168. 2_(4_氣基-苯基)-5_ 異丙氧基-6-崎吐-5-基-苯并呋喃-3-叛酸 甲醯胺 lH NMR in CDC13: 7.91- 7.83 (m, 4H); 7.69 (s, 1H); 7.41 (s, 1H); 7.22- 7.14 (m, 2H); 5.79 (bs, 1H); 4.86-4.78 (m, 1H); 2.99 (d, J=4.8Hz, 2H); 1.46 (d, J=6.3Hz, 6H) (M+H)+ = 395 A <10 169. 2-(4-氟基-苯基) -6-(4-經基-六氩外匕 淀-1-續龜基)-5-異 丙氧基-苯并呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.47-8.49 (d, 1H, J=4.69Hz); 8.01 (s, 1H); 7.95-8.00 (m, 2H); 738-7.44 (t, 2H, J=8.79Hz); 7.32 (s, 1H); 4.82-4.90 (septet, 1H, J=5.86Hz); 4.67-4.69 (d, 1H, J=4.10Hz); 3.58-3.59 (in, 1H); 3.35-3.45 (m, 2H); 3.24-3.30 (m, IH); 2.92-3.00 (m, 2H); 2.84-2.85 (d, 3H, J=4.69Hz); 1.69-1.73 (in, 2H); 1.36-1.41 (m, 1H); 1.34-1.36 (d, 6HT J=5.86Hz) (M+H)+ = 491 A <1 170. 6-(4,4-二氟基-六氫 口比淀-1 -基)-2-(4胃氟 基-苯基)-5-異丙氧 基-苯并呋喃-3-叛酸 甲醯胺 lH NMR in CDC13: 7.87 (m, 2H); 7.31 (s7 1H); 7.17 (U J=8.35 Hz, 2H); 7.07 (s, 1H); 5.74 (s, 1H); 4.69-4.61 (septet, J=6.16 Hz, 1H); 3.23-3.19 (m, 4H); 2.98 (d, J=5.27 Hz, 3H); 2.24-2.11 (m, 4H); 1.39 (d, J=6.16Hz, 6H) (M+H)+ = 447 C <1 171. 2-(4-氟基-苯基) -6-(4-氟基-六氫叶匕 淀-1-基)-5-異丙氧 基-苯并呋喃-3-¾酸 甲醯胺 lH NMR in CDC13: 7.89-7.83 (m, 2H); 7.28 (s, 1H); 7.16 (t, J=B.79 Hz, 2H); 7.07 (s, IH); 5.76 (s, 1H); 4.92-4.72 (m, 1H); 4.69-4.61 (septet, J=6.16 Hz, 1H); 3.24-3.22 (m, 2H); 3.08-3.01 (m, 2H); 2.98 (d, J=4.84 Hz, 3H); 2.18-2.02 (m, 4H); 1.38 (d, J=5.71 Hz, 6H) (M+H)+ = 429 B <i 172. 5-二氟甲氧基-2-(4- 氟基-苯基>6-嗎福 p林-4-塞-苯并吱喃 -3-羧酸甲醯胺 lH NMR in CDCI3: \ 7.87 (dd, J=8.8,5.7Hz, 2H); 7.54 (s, 1H); 7.16 (t, J=8.8Hz, 2H); 7.11 (s, 1H); 6.57 (t, J=75.6Hz, 1H); 5.92 (d, J=4.7Hz, 1H); 3.87 (t, J=4.0Hz, 4H); 3.08 (t, J=4.0Hz, 4H); 2.98 (d, J=4.9Hz, 3H) (M+H)f = 421 A <1 191 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCVpol -BB7 ic50 0iM) A= μ,Μ B= 05 to ^5.0 μΜ C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 173. 5-環戊氧基-2-(4-氟 基-苯盖)-6-嗎福琳 -4-墓-冬并咬喃-3 - 羧酸甲醯胺 *H NMR in CDC13: 7.86 (dd, J=9.4, 5.3Hz, 2H); 7.28 (s, 1H); 7.16 (t, J=9.4Hz, 2H); 7.04 (s, 1H); 5.74 (brs, 1H); 4.90 (in, 1H); 3.90 (t, J=4.7Hzt 4H); 3.11 (t, J=4.7Hz, 1H); 2.98 (d, J=4.7Hz, 3H); 1.95 (m, 4H); 1.80 (m, 2H); 1.70 (m, 2H) (M-H)· = 437 A <1 174. 2-(4•氟基-苯基)-5- 經基-6_甲烷磺醯基 胺基-苯并呋喃-3-叛 酸甲醯胺 lH NMR in DMSO: 8.36 (dt J=4.7Hzt 1H); 7.91 (dd, J=8.8, 3.0Hz, 2H); 7.48 (s, 1H); 7.36 (ζ J=8.8Hz, 2H); 7.08 (s, 1H); 2.98 (st 1H); 2.82 (d, J=4.7Hz, 3H) (M+H)+ = 379 B <30 175. 2-(4-氣基-苯基)-5_ 異丙氧基-6-(硫嗎福 ϊ»林_4->5買酿基)-私并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.47-8.48 (d, 1H J+4.10Hz); 8.03 (s 1H); 7.95-8.00 (m, 2H); 7.38-7.44 (t, 2H, J=8.79Hz); 7.33 (s, 1H); 4.84-4.92 (septet, 1H, J=6.45Hz); 3.42-3.46 (m, 4H); 2.83-2.85 (d, 3H, J=4.69Hz); 2.62-2.65 (in, 4H); 1.35-1.37 (d, 6H, J=5.86Hz) (M+H)+ = 493 A <1 176. 2-(4-氟基-苯基) -6-(3-羥基-吡咯啶 -1 -續醯基)-5-異丙 氧基-苯并吱喃-3 -叛 酸甲醯胺 lH NMR in DMSO: 8.46-8.48 (d, 1H, J=4.69Hz); 8.03 (s, 1H); 7.95-7.99 (m, 2H); 7.38-7.43 (t, 2H, J=8.79Hz); 7.31 (s, 1H); 4.99 (br.s, 1H); 4.82-4.80 (septet, 1H, J=5.86Hz); 4.24 (br.s, 1H); 3.38-3.46 (m, 4H); 3.07-3.11 (dd, 1H, J=2.35Hz, 9.96Hz); 2.83-2.84 (d, 3H, J=4.69Hz); 1.79-1.86 (m, 1H); 1.68-1.77 (m, 1H); 1.35-1.37 (d, 6H, J=5.86Hz) (M+H)+ = 477 A <1 177. 2-(4-氟基-苯基)-5-兴丙氧基-6-0比1^-4-基-苯并呋喃各#复酸 甲醯胺 NMR in DMSO: 8.6 i (m, 2H); 8.42 (s, 1H); 7.94 (dd, 2H); 7.72 (s, 1H); 7.60 (d, 2H); 7.36 (dd, 2H); 7.25 (s, 1H); 4.6 (m, 1H); 2.84 (d, 3H); 1.22 (d, 6H) (M+H)+ = 405 A <10 178. *2-(4;氟基-苯:&)-5_ 異丙氧基-6-(3-甲烷 磺醯基-苯基 > 苯并 呋喃-3-羧酸甲醯胺 NMR in DMSO: 8.42 (m, 1H); 8.16 (m, 1H); 7.98-7.88 (m, 4H); 7.72 (s, 1H); 7.69 (t, 1H); 7.39 (dd, 2H); 7.27 (s, 1H); 4.60 (m, 1H); 3.26 (s, 3H); 2.86 (d, 3H); 1.29 (d, 6H) (M+H)+ = 482 A <10 179. 2-(4-氣基-苯基)-5-異丙氧基-6-(4-甲烷 績感基-表基)-私并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.43 (m, 1H); 7.99-7.94 (m, 4H); 7.84 (d, 2H); 7.70 (s, 1H); 7.41 (dd, 2H); 7.27 (s, IH); 4.62 (m, 1H); 3.28 (s, 3H); 2.85 (d, 3H); 1.24 (d, 6H) \ (M+H)+ = 482 A <10 180. 5<2-氯基-乙氧基) -2-(4-氟基-苯基)-6- 嗎福p林-4-基-苯無嗅 喃-3-羧酸曱縫胺 lH NMR in CDCb: 7.85-7.80 (m, 2H); 7.32 (s, 1H); 7.20-7.15 (m, 2H); 7.08 (s, 2H); 5.75 (bs, 2H); 4.37-4.33 (m, 2H); 4.94-4.89 (m, 6H); 3.17-3.14 (m, 4H); 2.97 (d, J=5.4Hz, 3H) (M+H)+ = 433 A >30 192- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICs〇 〇iM) A= μΜ B= 03 to i5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 181. 6孑氧基-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸甲 醯胺 [H NMR in DMSO: 7.80 (dd, J=8.8,5.3Hz, 2H); 7.50 (m, 2H); 7.40 (m, 3H); 7.34 (s, 1H); 7.16 (t, J=8.8Hz, 2H); 7.05 (s, 1H); 5.75 (br d, J=4.7Hz, 1H); 5.22 (s, 1H); 3.96 (s, 3H); 2.99 (d, J=4.7Hz, 3H) (M+H)+ = 406 A <10 182. 6-胺基-2-(4-氟基-苯 基)-5-經基-苯并< 喃-3-羧酸甲酸胺 NMRinDMSO: 10.55 (br s, 1H); 8.40 (d, J=4.7Hz, 1H); 7.90 (dd, J=8.8, 5.3Hz, 2H); 7.61 (sT 1H); 7.34 (t, J=8.8Hz, 2H); 7.16 (s, 1H); 2.79 (dt J=4.7Hz, 3H) (M+H)+ =301 B <30 183. 5,6-雙-苄氧基-2-(4- 氟基-苯基)-苯并呋 喃-3-羧酸甲醯胺 'H NMR in DMSO: 8.29 (m,lH); 7.86 (m^H); 7.49-7.30 (m, 13H); 7.23 (s, 1H); 5.22 (s, 2H); 5.14 (s, 2H); 2.80 (d,3H, J=4.10) (M+H)+ = 482 D <10 184. 2普氟基縣)-5-異丙氧基-6-(5-三氟 甲基-[1,2,4]呤二唑 -3-基)-苯并呋喃-3- 羧酸甲醯胺 lH NMR in CDCi3: 8.17 (s, 1H); 7.91-7.86 (mT 2H); 7.54 (s, 1H); 7.25-7.19 (mT 2H); 5.77 (bs, 1H); 4.81-4.73 (m, 1H); 3.0 (d, J=4.8Hz, 3H); 1.44 (d, J=6.3Hz, 6H) (M+H)+ = 464 B <30 V 185. [2-(4-氣基-苯基)-5_ 異丙氧基-3-甲基月安 甲酿基苯并咬喃-6-基]-六氫峨17井-1-羧 酸醯胺 lH NMR in CDC13: 7.87-7.81 (m, 2H); 7.31 (s, 1H); 7.16 (t, J=8.35 Hz, 2H); 7.03 (s, 1H); 5.80 (s, 1H); 4.69-4.61 (septet, J=6.15 Hz, 1H); 4.53 (s, 2H); 3.60-3.57 (m, 4H); 3.12-3.09 (m, 4H); 2.98 (d, J=5.27 Hz, 3H); 1.38 (d, J=6.15 Hz, 6H) (M+H)+ = 455 C <10 186. 2-(4-氣基苯基)-5_ 異丙氧基-6-硫嗎福 琳_4_基-冬并咬喃 - 3-羧酸甲醯胺 *H NMR in CDCl3: 7.87-7.83 (m, 2H); 7.29 (s, 1H); 7.16 (t, J=8.35 Hz, 2H); 7.05 (s, 1H); 5.73 (s, 1H); 4.65-4.62 (septet, J=5.71 Hz, 1H); 3.34 (m, 4H); 2.98 (d, J=4.84 Hz, 3H); 2.84 (m, 4H); 1.37 (d, J=6.15Hz, 6H) (M+H)+ = 429 A <1 187. 2-(4-氣基-冬基)-5_ 異丙氧基-3-甲基月安 甲醯基-苯并吱喃-6-羧酸 lH NMR in CDC13: 8.41-8.42 (d, 1H, J=4.69Hz); 7.93-7.97 (m, 2H); 7.80 (s, 1H); 7.35-7.41(t, 2H, J=8.79Hz); 7.20 (s, 1H); 4.58-4.66 (septet, 1H, J=5.86Hz); 2.83-2.84 (d, 3H, J=4.69Hz); 1.28-1.30 (d, 6H, J=5.86Hz) (M-Η)'= 370 C <10 188. 2-(4-氣基-苯基)-5_ 異丙乳基-6-(1-乳基 -硫嗎福^林-^·-基-)-麥 并呋喃各羧酸甲 醯胺 lH NMR in CDC13: 7.84-7.82 (m, 2H); 7.34 (s, 1H); 7,18 (t, J=8.35, 2H); 7.13 (s, 1H); 5.76 (s,11H); 4.69-4.65 (septet, J=5.71 Hz, 1H); 3.75-3.68 (m, 2H); 3.39-3.35 (m, 2H); 3.10 (s, 4H); 2.99 (d, J=4.40 Hzt 3H); 1.41 (d, J=6.15 Hz, 6H) (M+H)+ = 445 C <10 193 88828.doc 200418452 :實例 編號 名稱 NMRdata Mass Spec HCV po! -BB7 IC50O1M) A= B= 03 to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 189. {P-(4-氟基-苯基) -5-異丙氧基-3-甲基 胺甲酿基-苯并咬喃 -6-基]-甲燒續醯基-胺基卜乙酸 lH NMR in DMSO: 10.9 (s, iH); 8.43 (m, IH); 7.96 (m, 2H); 7.66 (s, 1H); 7.38 (m, 2H); 7.17 (s, 1H); 4.79 (heptuplet, J=6.1Hz, 1H); 4.28 (s, 2H); 3.08 (s, 3H); 2.83 (d, J=4.8 Hz, 3H); 1.35 (d, J=6.1Hz, 6H) (M+H)+ = 479 B <1 190. 6-(環丁基·甲烷磺醯 基-胺基)-2-(4- 氣基-苯基)-5-異丙氧基-苯并呋喃-3-羧酸甲 醯胺 lH NMRinDMSO: 8.43 (in, 1H); 7.93 (dd, J=3.1 & 6.6Hz, 2H); 7J7 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 7.15 (s, 1H); 4.78 (heptuplet, J=6.1Hz, 1H); 3.2 (m, 1H); 3.02 (s, 3H); 2.83 (d, J=5.8Hz, 3H); 2.46 (m, 6H); 2.38 (d, 6.1Hz, 6H) (M+H)+ = 475 A <1 191. 2-(4-氟基縣)-5-異丙氧基-6-j:^烷磺 酿基-(2-嗎福淋-4-基-乙基)-胺基]-苯 并呋喃-3-羧酸甲 醯胺 *H NMR in DMSO: 8.42 (d, J= 4.7Hz, 1H); 7.93 (dd, J= 7.0 & 9.4 Hzt 2H); 7^8 (s, 1H); 7.38 (t, J=8.8 Hz, 2H); 7.16 (s, 1H); 4.79 (heptuplet, J=5.8Hz, 1H); 3.50 (t, J= 4.6Hz, 4H); 3.16 (m, 2H); 3.06 (s, 3H); 2.83 (d, J= 4.6Hz, 3H) (M+H)+ = 534 A <1 192. 2-(4-氣基-私基) -5,6-二經基-苯并呋 喃各羧酸甲酿胺 lH NMR in DMSO: 8.25 (brs, 1H); 7.83 (m, 2H); 7.28 (m, 2H); 6.96 (d, 1H, J=2.34 Hz); 6.90 (d, 1H, J=2.34 Hz); 2.77 (brd, 3H, J=6.45 Hz) (M+H)+ = 302 C >30 193. 2-(4-氟基-苯基)-5_ 異呙氧基-6-[甲ί完續 醯基-(2-曱氧基-乙 基)-胺基 > 苯并呋喃 -3-羧酸甲醯胺 NMR in DMSO: 8.48 (m, 1H); 7.95 (dd, J=5.2 & 8.7 Hz, 2H); 7.53 (s, 1H); 7.39 (t, J = 8.8Hz, 2H); 7.17 (s, 1H); 4.79 (heptuplet, J= 5.9 Hz, 1H); 3.34 (m, 6H); 3.18 (s 3H); 3.05 (s, 3H); 2.83 (d, J= 4.7Hz, 3H); 1.34 (d, J= 5.8Hz, 6H) (M+H)+ = 479 A <1 194. 6-爷氧基-2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.85 (m, 2H); 7.47 (m, 2H); 7.41-7.31 (m, 4H); 7.15 (t, 2H, J=8.79 Hz); 7.08 (s, 1H); 5.75 (brs, 1H); 5.17 (s, 2H); 4.55 (m, 1H); 2.99 (d, 3H, J=5.28 Hz); 1.38 (d, 6H, J=6.45 Hz) (M+H)+ = 434 B 木氺氺 195. 6-(烯丙基-甲烷磺醯 基-胺基)-2-(4-氟太-苯基)-5-異丙氧基-苯并呋喃-3-¾酸甲 醯胺 'H NMR in DMSO: 8.41 (ra, 1H); 7.93 (dd, J=5.3 & 8.8Hz, 2H); 7.38 (s, 1H); 7.34 (t, J=8.8Hz, 2H); 5.81 (m, 1H); 5.10 (dd, J=1.8 & 17 Hz, 1H); 5.02 (dd, J= l.l & 10 Hz, 1H); 4.79 (heptuplet, J= 6.4 Hz, 1H); 4.22 (m, 2H); 3.06 (s, 3H); 2.82 (d, J=4.7 Hz, 3H) (M+H)+ = 461 A <1 196. 6-乙醯基-2-(4-氟基-苯基)-5-異丙氧基-苯并呋喃-3-複酸甲 醯胺 lH NMR in CDC13: 7.88 (s, 1H); 7.86 (m, 2H); 7.41 (s, 1H); 7.18 (m, 2H); 5.77 (brs, 1H); 4.79 (m, 1H); 3.00 (d, J=4.8Hz, 3H); 2.69 (s, 3H); 1.44 (d, J=6.0 Hz, 6H) (M+H)+ =370.0 A <1 194- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= s(K5 μΜ B= to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 197. 2-(4_氣基-本基)-5- 異丙氧基-6-甲烷磺 酉έ基胺基·苯并咬喃 -3-羧酸異丙胺 *H NMR in CDC13: 7.85-7.80 (m, 2H); 7.74 (s, 1H); 7.43 (s, 1H); 7.19 a J=8.79 Hz, 2H); 6.95 (s, 1H); 5.53-5.50 (m, IH); 4.78-4.70 (septet, J=6.15 Hz, 1H); 4.38-4.26 (septet, J=7.03 Hz, 1H); 2.95 (s, 3H); 1.40 (d, J=5.44 Hz, 6H); 1.18 (d, J=6.49 Hz, 6H) (M+H)+ = 449 C <10 198. 2-(4-氣基-苯基)-5_ 異丙氧基-6-(5-甲基 _[1,2,4竹咢二^坐-3-基) -苯并呋喃-3-羧酸甲 醯胺 *HNMR inCDCl3: 8.07 (s, 1H); 7.92-7.87 (m, 1H); 7.49 (s, 1H); 7.23-7.17 (m, 2H); 5.80 (bs, 1H); 4.70-4.64 (s, 1H); 3.00 (d, J=4.8Hz, 3H); 2.65 (s, 3H); 1.41 (d, J=6.3Hz, 6H) (M+H)+ = 410 A <1 199. 2-(4-氟基-苯基>5- 異丙氧基-6-甲烷磺 酿基胺基-苯并咳喃 -3-羧酸環丙醯胺 lH NMR in CDC13: 7.79-7.74 (m, 2H); 7.73 (s, 1H); 7.47 (s, 1H); 7.20 (T, J=8.79Hz, 2H); 6.95 (s, 1H); 5.8 (s, 1H); 4.78-4.70 (septet, J^.lSHz, 1H); 2.95 (s, 3H); 2.90-2.86 (m, 1H); 1.40 (d, J=6.15Hz, 6H); 0.89-0.82 (m, 2H); 0.53-0.48 (m, 2H) (M+H)+ = 447 A <1 200. 2-(4-氟基-苯基)-5 - 異丙氧基-6-甲燒續 醯基胺基-苯并呋喃 -3-羧酸乙醯胺 lH NMR in CDCI3: 7.85-7.79 (m, 2H); 7.74 (s, 1H); 7.44 (s, 1H); 7.19 (t, J=8.35Hz, 2H); 6.95 (s, 1H); 5.7 (s, 1H); 4.80-4.68 (septet, J=6.15Hz, 1H); 3.52-3.43 (m;2H); 2.95 (s, 3H); 1.39 (d, J=5.71, 6H); 1.17(T, J=7.47, 3H) (M+H)+ = 435 A <1 201. 2-(4-敦基-苯基) -5-(2-甲基-嘧唑-4-基甲氧基)-6-嗎福啉 -4-基-苯并p夫喃-3 - 羧酸甲醯胺 lH NMR in CDCi3: 7.89 (m, 2H); 7.41 (s, 1H); 7.16 (m, 3H); 7.10 (s? 1H); 5.78 (brs, 1H); 5.25 (s, 2H); 3.90 (m, 4H); 3.16 (m, 4H); 3.00 (d, 3H, J=4.69 Hz); 2.74 (s, 3H) (M+H)+ = 482 A <1 202. 2_(4-氣基-苯基) _6-(1-#莖基-1-甲基-乙基)-5-異丙氧基-苯并呋喃-3-幾酸甲 醯胺 lH NMR in CDCI3: 7.84 (m, 2H); 7.49 (s, 1H); 7.39 (s, 1H); 7.19 (m, 2H); 5.73 (brs, 1H); 3.56 (m, 1H); 2.99 (d, J=4.8 Hz, 3H); 1.38 (d, J=6.1Hz, 6H) (M+H)+ = 386.1 A <1 203. 5-[5-(3,5-二曱基-異 呤唑-4-基)-[1,2,4]噚 二唑-3-基甲氧基)] -2-(4-氟基-苯基)-6-嗎福#-4-基-苯舁吱 喃-3-羧酸甲醯胺 ^NMR in CDCI3: 7.86 (m, 2H); 7.52 (s, 1H); 7.18 (t, 2H, J=8.79 Hz); 7.12 (s, 1H); 5.75 (brs, 1H); 5.36 (s, 2H); 3.92 (m, 4H); 3.19 (in, 4H); 2.98 (d, 3H, J=4.69 Hz); 2.81 (s, 3H); 2.59 (s, 3H) (M+H广 = 548 B <10 195 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ic50 〇iM) A=μΜ B= 03 to ^5.0 μΜ C= 5.0 to <30 D= >30 μΜ 複製子 (μΜ) 204. 5-(5-第三-丁基 -[1,2,4]哼二峻-3-基 甲氧基)-2-(4-氟基-苯基>6-嗎福琳·4-基-苯并咬喃-3-幾酸 甲醯胺 *H NMR in DMSO: 8.28 (br 叽 1H); 7.90 (m,2H); 7.33 (t,2H, J=8.79 Hz); 7.24 (s, 1H); 7.22 (s, 1H); 5.28 (s, 2H); 3.74 (m, 4H); 3.06 (m, 4H); 2.81 (d, 3H, J=4.69); 1.40 (s, 9H) (M+H)+ = 509 A <1 205. 2_(4_氟基-苯基)-5-異丙氧基各[1,2,4] 吟二唑-3-基-苯#呋 喃-3-羧酸甲醯胺 lHNMRinCDCl3: 8.75 (s, 1H); 8.14 (s, 1H); 7.93-7.88 (m, 2H); 7.53 (s, 1H); 7.24-7.17 (m, 2H); 5.78 (bs, 1H); 4.70^.68 (m, 1H); 3.0 (d, J=4.8Hz, 3H); 1.42 (d, J=5.7Hz, 6H) (M+H)+ = 396 A <1 206. 5-(5-氯基-[1,2,外塞 二嗤;基甲氧基) -2-(4-氟基-苯基)-6- 嗎福啉-4-基-苯并呋 喃-3-羧酸甲酿胺 lH NMR in DMSO: 8.38 (brdr 1H, J=4.69 Hz); 7.95 (m, 2H); 7.76 (s, 1H); 7.58 (s, 1H); 7.38 (t, 2H, J=8.79 Hz); 4.75 (s, 2H); 3.52 (m, 4H); 2.98 (in, 4H); 2.80 (d, 3H, J=4.69 Hz) (M+H)+ = 504 B <1 207. 2-(4-氣基·苯基)-6_ 嗎福。珠-4-基^-5 -(5 -對 -甲苯基-[1,3,4]嘮二 唑-2基甲氧基)-苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.31 (brd, 1H, J=4.69 Hz); 7.90 (m, 4H); 7.43 (d, 2H, J=7.62 Hz); 7.34 (m,3H); 7.25 (s, 1H); 5.48 (s, 2H); 3.69 (m, 4H); 3.02 (m, 4H); 2.81 (d, 3H, J=4.69 Hz); 2.40 (s, 3H) (M+H)+ = 543 C <10 208. 2-(4-氣基-琴基)-6_ #基-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 'H NMR in DMSO: 9.33 (s, 1H); 8.28 (d, J=4.4HzT 1H); 7.85 (dd, J=8.8, 5.3Hz, 2H); 7.30 (t, J=8.8Hz, 2H); 7.06 (s, 1H); 7.02 (s, 1H); 3.81 (s, 3H); 2.80 (d, J=4.4Hzt 3H) (M+H)+ = 316 B <30 209. 2-(4-氣基-苯基) -5-(1-甲基-1H-四唑 -5-基甲氧基)各嗎 福琳-4-基-苯并啥喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.31 (d, J=4.4Hz, 1H); 7.88 (dd, J=8.8, 5.3Hz, 2H); 7.36 (t, J=8.8Hz, 2H); 7.33 (s,lH); 7.25 (s,lH); 5.54 (s,2H); 4.14 (s,3H); 3.68 (t, J=4.4Hz, 4H); 2.98 (t, J=4.4Hz, 4H); 2.81 (d, J=4.4Hz, 3H)) (M+H)+ = 467 B <10 210. 2-(4-氟基-苯基) -5-(3-甲氧基-苄氧 基)-6-嗎福淋-4-基- 苯并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.30 (d, J=4.4Hz, 1H); 7.88 (dd, J=8.8, 5.3Hz, 2H); 7.32 (ra, 3H); 7.22 (s, 1H); 7.19 (s, 1H); 7.07 (m, 2H); 6.87 (m, 1H); 5.13 (s, 2H); 3.76 (s, 3H); 3.73 (brs, 4H); 3.05 (brs, 4H); 2.81 (d, J=4.4Hz, 3H) (M+H)* = 491 A <1 196- 88828.doc 200418452 實例 編5虎 名稱 NMRdata Mass Spec HCY pol -BB7 IC5〇 〇tM) A= μ,Μ B= 03 to ^5.0 C= 5.0 to ^30 μΜ. D= >30 /iM 複製子 (μΜ) 211. 2-(4-氟基-苯基)-5甲 氧基-6-(1-甲基-lH-四口坐-5-基甲氧基)-苯并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.32 (d, J=4.4Hz, 1H); 7.87 (dd, J=8.3, 5.7Hz, 2H); 7.55 (s, 1H); 7.33 (t, J=8.8Hz, 2H); 7.11 (s, 1H); 5.56 (s, 2H); 4.15 (s, 3H); 3.81 (s, 3H); 2.80 (d, J=4.4Hz, 3Η» (M+H)+ = 412 A <1 212. 2_(4_氣基·苯基) -5-[l-(4-氟基-苯基)-乙氧基]-6-嗎福4木 冬墓-苯并咬喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.86 (dd, J=8.8,5.3Hz, 2H); 7.38 (dd, J=8.8, 5.3Hz, 2H); 7.12 (t, J=8.8Hz, 2H); 7.03 (t, J=8.8Hz, 2H); 5.62 (d, J=4.9Hz, 1H); 5.37 (q, J=6.1Hz, 1H); 3.88 (m, 4H); 3.14 (m, 4H); 2.92 (d, J=4.9 Hz, 3H); 1.65 (d, J=6.1Hz, 3H) (M+H)+ = 493 A <1 213. 上(4-氰基-芊甲氧 基)-2-(十氟^>苯基) -6-嗎福琳-4-基-苯 并呋喃-3-羧酸甲 醯胺 'H NMR in DMSO: 8.28 (dr J=4.4Hz, 1H); 7.88 (m, 4H); 7.70 (d, J=8.0Hz, 2H); 7.33 (t, J=8.8Hz, 2H); 7.24 (s, 1H); 7.20 (s,lH); 5.27 (s,lH); 3.74 (m, 4H); 3.04 (m,4H); 2.81 (d, J=4.4Hz, 3H) (M+H)+ = 486 B <10 214. 1-(4-氟基-苯基) -5-[5-(4-甲氧基-苯 基)-[1,2,4]咩二吐-3_ 基甲氧基]-6-嗎福啉 -4-基-苯并咬喃-3 -羧酸甲醯胺 lH NMR in DMSO: 8.35 (d, J=4.4Hz, 1H); 7.92 (m, 4H); 7.37 (m, 3H); 7.25 (s, 1H); 7.17 (d, J=8.8Hz, 2H); 5.47 (s, 2H); 3.84 (s, 3H); 3.69 (s, 4H); 3.02 (s, 4H); 2.80 (d, J=4.4Hz, 3H) (M+H)+ = 559 B <1 215. 2-(4-氣基-苯基)-6_ 嗎福琳-4-基-5-(2-氧 基-丙氧基)-苯并呋 喃-3-羧酸曱醯胺 lH NMR in DMSO: 8.26 (d, J=4.4Hz, 1H); 7.87 (dd, J=8.3, 5.7 HzT 2H); 7.32 (t, J=8.8Hz, 2H);7.20 (s,lH); 7.00 (s,lH); 4.80 (s,2H); 3.76 (t, J=4.7Hz, 4H); 3.06 (t, J=4.7Hz, 4H); 2.80 (d, J=4.8Hz, 3H); 2.21 (s, 3H) (M+H)+ = 427 B <10 216. 5-( 1 -卞基-1H-味口坐 少基甲氧基)-2-(4-氟基-苯基)-纟_嗎福 p林-4-墓-苯并吱喃 -3-羧酸甲醯胺 *H NMR in DMSO: 8.26 (brd, 1H, J=4.69 Hz); 7.90 (m, 2H); 7.35-7.16 (m, 10H); 6.94 (m, 1H); 5.37 (s, 2H); 5.17 (s, 2H); 3.66 (m, 4H); 2.95 (m, 4H); 2.82( d, 3H, J=4.69 Hz) (M+H)+ = 541 A <1 217. 5-(3,5-二甲基-異吟 唑基甲氧基) _2-(4_氣基-冬基)-6-嗎福p林-4-基-冬并17夫 喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.30( d, 1H, J=4.39); 7.82 (m,2H); 7.33 (t, 2H, J=8.79); 7.20 (m, 2H); 5.00 (s, 2M); 3.69 (m, 4H); 2.98 (m, 4H); 2.82 (d, 3H, J=4.39 Hz); 2.39 (s, 3H); 2.26 (s, 3H) (M+H)+ = 480 B <10 197- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A= μΜ B= 0*5 to s5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 〇iM) 218. 2-(4-氟基-苯基) -5-(5-甲基-異噚唑 -3-基甲氧基 福琳-4-基-苯并吱喃 -3-羧酸甲醯胺 'H NMR in DMSO: 8.28 (brd, 1H, J=4?39 Hz); 7.90 (m, 2H); 7.33 (t, 2HT J=8.79); 7.22 (m, 2H); 6.34 (s, 1H); 5.18 (s, 2H); 3.73 (m, 4H); 3.03 (m, 4H); 2.82 (d, 3H, J=4.39 Hz); 2.42 (s, 3H) (M+H)+ =466 A <1 219. 2-(4-氣基-苯基)-5-異丙氧基-6-0塞咬-2-基-苯#吱喃-3-幾酸 甲醯胺 lH NMR in DMSO: 8.50 (s,lH); 8.46-8.47 (d, J=4.69Hz, 1H); 7.97- 8.02 (m, 3H); 7.80-7.81 (d, J=3.5Hz, 1H); 7.38-7.44 (ζ J=8.79Hz, 2H); 7.36 (s, 1H); 4.97- 5.06 (septet, J=6,45Hz, 1H); 2.84-2.86 (d, J=5.27Hz, 3H); 1.47-1.49 (d, J=5.86Hz, 6H) (M+H)+ =410.9 A <10 220. 2-(4_氣基-苯基)-5_ 異丙氧基-6-(1Η-吡 咯·2-基)-苯并呋喃 -3-羧酸甲S&联 ^NMRinCDCla: 7.90-7.86 (m, 2H); 7.77 (s, 1H); 7.43 (s,lH); 7.26-7.17 (m, 3H); 6.90 (s, 1H); 6.67 (s, 1H); 631 (s, 1H); 5.8 (s, 1H, br); 4.78 (m, 1H); 3.0 (d,3H); 1.46 (d, 6H) (M+H)+ = 393 A <10 221. ΐ-(4-氟基-苯基)-6-( 異丙基-甲烷磺醯基 -胺基)-5-甲氧基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.44 (ιη,ΙΗ); 7.94 (dd, 2H, J=5.28, 8.8Hz); 7.556 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 7.20 (s,lH); 4.27 (heptuplet, J=6.4Hz,lH); 3.86 (s ,3H); 3.09 (s, 3H); 2.84 (d, J=4.7Hz, 3H); 1.21 (d, J=7.lHzf 3H); 1.01 (d, J=6.5Hz, 3H) (M+H)+ = 435 A <1 222. 2_(4_氟基-苯基) -6-( 1 -¾ 基-乙基)-5_ 異丙氧基-苯并4喃 -3-羧酸甲醯胺 lH NMR in CDCb: 7.87-7.83 (m, 2H); 7.50 (s, 1H); 734 (s, 1H); 7.21-7.16 (m, 2H); 5.72 (bs,lH); 5.19-5.13 (m, 1H); 4.78-4.69 (m, 1H); 2.98 (d, J=5.1Hz, 3H); 2.78 (d, J=5.1Hz, 1H); 1.55 (d, J=6.6Hz, 3H); 1.41 (dd,J=3.6Hz,6,0Hz, 6H) (M+H)+ = 372 A <1 223. 2-(4-氣基-苯基)-5_ 異丙氧基-6-嗎福4木 -4·-基—基-苯非咬喃 -3-羧酸甲醯胺 lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.57 (s, 1H); 7.31 (s, 1H); 7.20-7.16 (m, 2H); 5.74 (bs, 1H); 4.64-4.60 (m, 1H); 3.75-3.72 (m, 4H); 3.64 (s, 2H); 2.98 (d, J=5.1Hz, 3H); 2.55-2.52 (m, 4H); 1.36 (d, J=6.3Hz, 3H) (M+H)+ = 427 C <10 224. 2-(4-氣基-苯基)-6-經¥i-5-異丙氧基-苯并呋喃-3-¾酸甲 醯胺 IHNMRCDCI3: 7.87-7.83 (in, 2H); 7.43 (s, 1H); 7.35 (s, 1H); 7.21-7.15 (m, 2H); 5.73 (bs, 1H„ 4.76-4.68 (m, 3H); 2.98 (d, J=5.1Hz, 3H); 2.52-2.50 (m, 1H); 1.40 (d, J=6.0Hz, 6H) (M+H)+ = 358 A <10 225. _ 2-(4-氟基-苯基) -5-C3H-咪唑-4-基甲 氧基)-6-嗎福淋-4- 基-苯并呋喃-3身酸 甲醯胺 lH NMR in DMSO: ' 8.27 (brd, 1H, J=4.39 Hz); 7.89 (m, 2H); 7.33 (t, 2H, J=8.79 Hz); 7.28 (s, IH); 7.19 (s, 1H); 7.15 (brs, 1H); 6.90 (brs, 1H); 5.10 (s, 2H); 3.69 (ra, 4H); 3.02 (m, 4H); 2.83 (d, 3H, J=4.39 Hz) (M+H)+ = 451 A <10 198- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (/iM) A= ^:0.5 B= 03 to ^5.0 μΜ C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 226. 2-(4-氟基-苯基) -5-(2-甲|基-乙氧 基)-6-嗎福琳-4-基-苯并呋喃;羧酸甲 醯胺 lH NMR in DMSO: 8.28 (d, 1H, J=4.69 Hz); 7.89 (m, 2H); 7.32 (t, 2H, J=8.79 Hz); 7.16 (s, 1H); 7.06 (s, 1H); 4.13 (in, 2H); 3.72 (ra, 6H); 3.33 (s, 3H); 3.04 (m, 4H); 2.81 (d, 3H, J=4.69 Hz) (M+H)+ = 429 A <1 227. 2-(4_氣基-冬基)-5_ 異丙氧基-6-噻峻-5- 基-苯痒咬喃-3 -叛酸 甲醯胺 *H NMR in DMSO: 9.07 (s, 1H); 8.53 (s, 1H); 8.41-8.42 (d, J=4.69 Hzt 1H); 8.19 (s, 1H); 7.93-7.98 (m, 2H); 7.36-7.42 (t, J=8.79 Hz, 2H); 7.28 (s, 1H); 4.82-4.90 (septet, J=5.86Hz, 1H); 2.84-2.86 (d, J=4.69Hz, 3H); 1.38-1.40 (d, J=5.86Hz, 6H) (M+H)+ = 411 A <1 228. 5-(4-氯基-1-甲基 -1H-吡峻-3-基甲氧 基)-2-(4-氣基-苯; -6-嗎福57林-4-基-苯 并呋喃-3-羧酸甲 醯胺 *Η NMR in COCh: 7.93 (mt 2H); 7.47 (s, 1H); 7.39 (s, 1H); 7.17 (t, 2H, J=8.79 Hz); 7.08 (s, 1H); 5.86 (brs, 1H); 5.17 (s, 2H); 3.89 (m, 7H); 3.16 (m, 4H); 3.04 (d, 3H, J=4.84 Hz) (M+H)+ = 499 A <1 229. 5-ϋ基-甲基-甲氧 基)冬(土氟基-苯基) -6-嗎福琳-4-基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.90 (m, 2H); 7.52 (s, 1H); 7.17 (m, 3H); 5.84 (brs.lH); 5.17 (q, 1H, J=7.03 Hz); 3.89 (t, 4H, J=4.69 Hz); 3.20 (ra, 2H); 3.00 (m, 5H); 1.80 (d, 3H, J=6.45 Hz) (M+H)+ = 424 A <10 230. 2-(4-氟基-苯基)-5-異丙氧基-6-(2H-吡 峻-3-基)-苯弁呋喃 -3-羧酸甲醯胺 lH NMR in CDC13: 7.87 (m, 2H); 7.80 (s, 1H); 7.62 (d, J=2.4Hz, 1H); 7.49 (s, 1H); 7.24 (m, 2H); 6.69 ( d, J=2.4Hz, 1H); 5.77 (brs, 1H); 4.83 (mt 1H); 2.99 (d, J=5.4Hz, 3H); 1.48 (d, J=5.7Hz, 6H) (M+H)+ = 394.1 A <10 231. 2-(4_氣基-表基)-5_ 異丙氧基-6-(2-甲基 -2H-吡唑-3-基)-苯 并呋喃各羧酸甲 醯胺 lH NMR in CDC13: 7.88 (m, 2H); 7.52 (d, J=1.8 Hz, 1H); 7.45 (s, 1H); 7.39 (s, 1H); 7.22 (m, 2H); 6.26 (d, J=1.8Hz, 1H); 5.87 (brs, 1H); 4.48 (m, 1H); 3.76 (s, 3H); 3.00 (d, J=4.8Hz, 3H); 1.23 (d, J=5.7Hz, 6H) (M+H)+ = 408.1 A <1 232. 2-(4-氣基-本基)-5-異丙氧基-6-(1-甲基 -1H-吡唑各基)-苯 并呋喃-3-叛酸甲 醯胺 lH NMR in CDC13: 8.10 (s, 1H); 7.87 (m, 2H); 7.37 (d, J=2.1 Hz, 1H); 7.36 (s, 1H); 7.18 (m, 2H); 6.91 (d, J=2.1Hz, 1H); 5.82 (brs, 1H); 4.67 (m, 1H); 3.96 (s, 3H); 2.99 (d, J=4.8Hz, 3H); 1.39 (d, J=6.0Hz, 6H) 4 (M+H)+ = 408.1 B <10 233. 2-(4-氣基-本基)-5-異丙氧基-6-(3-甲基 -異哼吐-5-基)-苯并 吱喃-3-¾酸申酸胺 lH NMR in DMSO: 8.42 (dt J=4.8Hz, 1H); 8.03 (s, 1H); 7.95 (dd, J=5.7, 5.2, 8.8Hz, 2H); 7.37 (apparent triplet, J=8.8Hz, 2H); 7.28 (s, 1H); 6.79 (s, 1H); 4.84 (m, 1H); 2.83 (d, J=4.4Hz, 3H); 2.30 (s, 3H); 1.38 (d, J=5.7Hz, 6H) (M+H)+ = 409.21 B <30 199- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICse(/iM) A= μΜ B= to ^5.0 μΜ C= 5.0 to i30 /iM D= >30 aM 複製子 _) 234. 6-[(5-鼠基-[1,2,4]口塞 二唑-3-基甲基)-甲 烷磺醯基-胺基>2-(4_氟基-苯基)-5-異 禹氧基-5-基-苯并p夫 喃-3-羧酸甲酿胺 'H NMR in CDC13: 7.81 (m, 2H); 7.69 (s, 1H); 7.40 (s, 1H); 7.19 (t, 2H, J=8.79 Hz); 5.69 (brs, 1H); 5.09 (brs, 2H); 4.78 (m, 1H); 3.09 (s ,3H); 2.95 (d, 3H, J=4.84 Hz); 1.42 (d, 6H, J=6.15 Hz) (M+H)+ =553 A <10 235. 6-(3,5-二甲基-異二 嗤基胺基)-2-(4-氟基-苯基)-5-異丙 氧基-苯并呋喃-3-幾 酸甲醯胺 lH NMR in CDC13: 7.79-7.74 (m, 2H); 7.32 (s, 1H); 7.14 (t, J=8.79 Hz, 2H); 6.43 (s, 1H); 5.73 (s, 1H); 5.50 (s, 1H); 4.73-4.67 (septet, J=6.15 Hz, 1H); 2.97 (d, J=5.27, 3H); 2.32 (s, 3H); 2.13 (s, 3H); 1.43 (d, J=6.15 Hz, 6H) (M+H)+ = 438 C >30 236. 2-(4-氟基-苯基)-5-甲氧基-6-t7比淀-3-基 -苯并呋喃-3-羧酸甲 醯胺 *H NMR in DMSO: 8.75 (s, 1H); 8.55 (s, 1H, br); 8.43 (d, 1H); 7.98-7.93 (m, 2H); 7.68 (s, IH); 7.49-7.35 (ra, 3H); 7.26 (s, 1H); 3.84 (s, 3H); 2.84 (dT 3H) (M+H)+ = 377 A <1 237. 6-二甲基胺基甲基 -2-(4-氟基-苯基)-5- 異丙氧基-5-基-苯并 吱喃-3-¾酸甲醯胺 lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.54 (s, iH); 7.31 (s, 1H); 7.21-7.15 (m, 2H); 5.55 (bs, 1H); 4.66-4.60 (m, 1H); 3.64 (S> 2H); 2.99 (d, J=5.1Hz, 3H); 2.34 (s, 6H); 1.37 (d, J=5.7Hz, 6H) (M+H)+ = 385 C <30 238. 2-(4-氟基-苯基)-6-(1-羥基-2-甲基-丙 基)-5-異丙氧基-苯 并呋喃-3-叛酸甲 醯胺 lH NMR ia CDC13: 7.89-7.84 (m, 2H); 7.43 (s, 1H); 7.32 (s, 1H); 7.22-7.16 (m, 2H); 5.76 (bs; 1H); 4.74-4.60 (m, 2H); 2.99 (d, J=4.8Hz, 3H); 2.61 (d, J=6.5Hz, 1H); 2.14-2.09 (m, 1H); 1.40 (dd, J=11.7, 6.0Hz, 6H); 1.04 (d, J=6.6Hz, 3H); 0.85 (d, J=6.9Hz, 3H) (M+H)" = 400 A <1 239. 2-(4·氟基-苯基)-5_ 異丙氧基-6-(1β吡 唑斗基)-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDCb: 8.10 (s, 2H); 7.87 (m, 2H); 7.65 (s, 1H); 7.39 (s, 2H); 7.18 (m, 2H); 5.79 (brs, 1H); 4.72 (m, 1H); 3.00 (d, J = 5.1Hz, 3H); 1.41 (d, J=6.0 Hz, 6H) (M+H)+ = 394.1 C <10 240. 2-(4-氣基-冬基)-6-[ 甲烷磺醯基-(2-甲氧 基-乙基)-胺基]-5-甲 氧基-苯并咬喃-3-幾 酸甲醯胺 lH NMR ia DMSO: 8.49 (m, IH); 8.00 (dd, J=5.1 & 8.8 Hz, 2H); 7.63 (s, 1H); 7.42 (t, J=8.8 Hz, 2H); 7.26 (s, 1H); 3.97 (s, 3H); 3.78 (m, 1H); 3.35 (m, 6H); 3.25 (s, 3H); 3.11 (s, 3H); 2.90 (d, J=3.3 Hz, 3H) (Μ+ΗΓ = 451.1 A <1 241. 6-(3-環丙基-異哼唑 -5-基)-2-(4-氟基苯 基)-5-異丙氧基-苯 并呋喃各羧酸甲 醯胺 lH NMR ia DMSO: 8.44 (broad quartet, J=4.4Hz, 1H); 8.02 (s, 1H); 7.96 (dd, J=5.7, 5.3, 9.2 Hz, 2H); 7.39 (apparent triplet; J=8.8, 9.2 Hz, 2H); 7.29 (s, 1H); 6.64 (s,lH); 4.84 (m, IH); 2.85 (d, J=4.8Hz, 3H); 2.08 (m, 1H); 1.39 (d, J=5.7Hz, 6H); 1.05 (m, 2H);0.84 (m, 2H) (M+H)如 = 435 B <10 -200- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV po! -BB7 IC50 〇iM) A= /iM B= to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 242. 2_(4-氣基-苯基)-5_ 異丙氧基-6-(3-甲氧 甲基-異噚吐-5-基)-苯并呋喃-3-瘦酸甲 醯胺 lH NMR in DMSO: 8.45 (broad quartet, J=4.8Hz, 1H); 8.10 (s, 1H); 7.97 (dd, J=5.7,8.8Hz, 2H); 7.40 (t, J=8.8Hz7 2H); 7.32 (s, 1H); 6.92 (s, 1H); 4.88 (quintet, 1H); 4.55 (sT 2H); 3.29 (s, 3H); 2.85 (d, J=4.4Hz, 3H); 1.40 (d, J=6.1Hz, 6H) (M+H)+ = 439 B 30 243. 2-(4-氟基-苯基)-6- 甲烷磺醯基胺基-苯 并呋喃-3-叛酸甲 醯胺 lH NMR m DMSO: 8.37 (m, 1H); 7.93 (ddt J=5.7 & 8.8Hz, 2H); 7.53 (d, J=8.8Hz, 1H); 7.45 (d, J=1.7Hz, 1H); 736 a J=8.8Hz, 2H); 7.14 (dd, J=1.7 & 8.8Hz, 1H); 4.17 (bst 1H); 2.96 (s, 3H); 2.82 (d, Ι=4.8Ηζ, 3H) (M+H)+ = 363 B <10 244. 2-(4-氣基-苯基)-6-(lH-咪唑-2-基)-5- 異丙氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDC13: 10.70 (s, 1H); 8.43 (s, 1H); 7.86 - 7.81 (m, 2H); 7.48 (s, 1H); 7.21 - 7.15 (m, 3H); 7.12 (s, 1H); 5.96 (s, 1H); 4.91 - 4.83 (m, 1H); 2.99 (d, J=4.8Hz, 3H); 1.49 (d, J=6.0Hz, 6H) (M+H)+ = 394 A <1 245. 6-(2,5-二甲基-2H-吡唑-3-基)·2-(4-氟 基-苯基)-5-異丙氧 基-苯并咬喃-3-複酸 甲醯胺 lH NMR in CDC13: 8.08 (s, 1H); 7.88 (m, 2H); 7.35 (s, 1H); 7.19 (m, 2H); 6.67 (s, 1H); 5.78 (brs, 1H); 4.67 (m, 1H); 3.84 (s, 3H); 3.00 (d, J=4.8Hz, 3H); 2.33 (s, 3H); 1.39 (d, J=6.0Hz, 6H) (M+H)+ = 422.1 B <10 246. 6-(3,5-二甲基-1H-P比峻-4-基)-2-(4-氟 基-冬基)-5-兴丙氧 基-苯并呋喃-3-叛酸 甲酿胺 lH NMR ia CDC13: 7.91 (ra, 2H); 7.40 (s, 1H); 7.28 (s, lH); 7.18 (ra, 2H); 5.80 (brs, 1H); 4.36 (m, iH); 3.00 (d, J=5.4Hz, 3H); 2.21(s, 6H); 1.20 (d, J=5.7 Hz, 6H) (M+H)+ = 422.1 A <1 247. 2-(4-氟基-苯基)-5-異丙氧基-6-(5-甲基 -2H-吡唑-3-基)-苯 并呋喃-3-複酸甲 醯胺 lH NMR in CDCl3: 7.87 (in, 2H); 7.75 (s, 1H); 7.47 (s, 1H); 7.20 (m, 2H); 6.47 (s, 1H); 5.75 (brs, 1H); 4.82 (m, 1H); 2.99 (d, J=5.1Hz, 3H); 2.36 (s, 3H); 1.46 (d, J=6.0Hz, 6H) (M+H)+ = 408.1 B <10 248. 6-(1,5-二甲基-1H-吡唑-3-基)-2-(4-氟 基-苯基)-5-異丙氧 基-苯并呋喃各叛酸 甲醯胺 lH NMR in CDC13: 7.88 (m, 2H); 7.44 (s, 1H); 7.38 (s, 1H); 7.20 (m, 2H); 6.04 (s, 1H); 5.68 (brs, 1H); 4.44 (m, 1H); 3.68 (s, 3H); 3.00 (dt J=4.8Hz, 3H); 2.32 (s, 3H); 1.25 (d, J=6.3Hz, 6H) (M+H)+ = 422.1 B <10 249. 2-(4-氟基-苯基)-5-異丙氧基-6-[(甲烷 磺醯基-甲基-胺基)-甲基]-苯并呋喃-3-羧酸甲醯胺 lHNMR ia CDC13: 1 7.86 - 7.83 (m, 2H); 7.58 (s, 1H); 7.37 (s, IH); 7.22 - 7.17 (m, 2H); 5.75 (s, 1H); 4.74 - 4.66 (m, 1H); 4.47 (s, 2H); 2.99 (d, J=5.lHz, 3H); 2.87 (d, J=5.7Hz, 6H); 1.39 (d, J=6.3Hz, 6H) (M+H)+ = 449 A <10 201 - 88828.doc 200418452 實例 編號 NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= /iM B= 03 to 5:5.0 /iM C= 5.0 to <30 /iM D= >30 /iM 複製子 (μΜ) 250. 2-(4-氣基-苯基) -5-(2-幾基-2-甲基-丙氧基)-6-嗎福淋 -4-墓-苯并p夫喃-3- 羧酸甲醯胺 .lHNMRinCDCl3: 7.87 (dd, J=8.8 & 5.3 Hz, 2H); 7.40 (s, 1H); 7.20 (U=8.8 Hz, 2H); 7.12 (s,1H); 5.80 (brs, 1H); 3.98 (s, 2H); 3.92 (t, J=4.4 Hz, 4H); 3.10 (t, J=4.4 Hz, 4H); 2.96 (d, J=4.4 Hz, 3H); 1.35 (s,6H) (M+H)+ = 443 B <10 251. -5-(2-經基-2-甲基-丁氧基)-6-嗎福51 林 -4-基-苯并呋喃各 羧酸甲醯胺 lHNMRinCDCi3: 7.86 (dd, J=8.8, 53 Hz, 2H); 7.40 (s, 2H); 7.22 (t, J=8.8 Hz, 2H); 7.12 (s, 1H); 5.90 (brs, 1H); 4.00 (m, 2H); 3.95 (t, J=4.4 Hz, 4H); 3.10 (t, J=4.4 Hz, 4H); 2.95 (dt J=4.4 Hz, 3H); 2.30 (brs, 1H); 1.70 (in, 2H); 1.24 (s, 3H); 0.95 (t, J=7.0Hz, 3H) (M+H)+ = 457 B <10 252. _ 2-(4-氟基-苯基) -5-(2-羥基-丙氧基) -6-嗎彳自?林_4·-基-率· 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.28 (d, J=4.4 Hz, 1H); 7.88 (dd, J-5.3 & 8.8 Hz, 2H); 7.32 (t, J=8.8 Hz, 2H); 7.16 (s, 1H); 7.06 (s, 1H); 4.82 (d, J=4.7 Hz, 1H); 4.00-3.90 (m, 3H); 3.74 (brs, 4H); 3.04 (brs, 4H); 2.81 (d, J=4.0 Hz, 3H); 1.19 (d, J=4.7 Hz, 3H) (M+H)+ = 429 B <10 253. 2-(4-氟基-苯基) _6-[(2_岁至基-丙基)- 甲烷磺醯基-胺基 ]-5-異丙氧基-苯并 呋喃-3-羧酸甲酿胺 lH NMR ia DMSO: 8.40 (dt J=4.4 Hz, 1H); 7.94 (dd, J=8.8 & 5.3 Hz, 2H); 7.63 (brs, 1H); 7.36 (t, J=8.8 Hz, 2H); 7.14 (s, 1H); 4.77 (septet, J=6.1 Hz, 1H); 4.62 (brs, 1H); 3.60-3.40 (m, 3H); 3.00 (s, 3H); 2.81 (d, J=4.4 Hz, 3H); 1.33 (d, J=6.1 Hz (M+H)+ = 479 A <1 254. 2-(4-氣基-苯基)-6_ 嗎福啉冰基-5-(1-¾ 吐-2-基-乙氧基)-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDC13: 7.88 (dd, J=8.8,5.3Hz, 2H); 7.76 (d, J=3.1Hz, 1H); 7.33 (brs, 2H); 7.14 (t, J=8.8Hz, 2H); 7.08 (s, 1H); 5.82 (q, J=6.6Hz, 1H); 5.79 (brs, 1H); 3.83 (m, 4H); 3.15 (ra, 4H); 2.97 (d, J=4.9Hz, 3H); 1.78 (d, J=6.1Hz, 3H) (M+H)+ = 482 A <1 255. 6-(乙基-甲烷磺醯基 -胺基)-2-(4-氣-苯 基>5-異丙氧基-苯 并呋喃-3-m酸甲 醯胺 lH NMR ia CDCi3: 7.83 (dd, J=8.3, 3.1Hz, 2H); 7.51 (s, 1H); 7.40 (s, 1H); 7.20 (t, J=8.3Hz, 2H); 5.72 (brs, 1H); 4.78 (septet, J=6.1Hz, 1H); 3.72 (brs, 2H); 2.97 (d, J=4.4Hz, 3H); 2.96 (s, 3H); 1.40 (d, J=6.1Hz, 6H); 1.13 (t, J=7.0Hz, 3H) (M+H)+ = 449 A <1 256. 6-(3,5-二甲基-1H-吡唑-4-基)-2-(4-氟 基-苯基)-5-甲氧基-苯并呋喃-3-羧酸甲 醯胺 *H NMR ia CDC13: 7.88 (m, 2H); 7.39 (s, 1H); 7.26 (s, 1H); 7.19 (m, 2H); 5.78 (brd, 1H); 3.86 (s, 3H); 3.01 (d, J=4.8Hz, 3H); 2.25 (s, 6H) ' (M+H, = 394.1 A <1 257. 2-(4-氟基-苯基>5-異丙氧基-6-(5-甲基 -1H-吡唑-4-基)-苯 并呋喃-3-羧酸甲 醯胺 ^ NMR in CDC13: 7.87 (m, 2H); 7.74 (s, 1H); 7.38 (s, 2H); 7.18 (m, 2H); 5.81 (brs, 1H); 4.52 (m, 1H); 3.00 (d, J=5.4Hz, 3H); 2.38 (s, 3H); 1.28 (d, J=6.0Hz, 6H) (Μ+ΗΓ = 408.1 A <1 202 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A= μΜ B= 03 to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 nM 複製子 (μΜ) 258. 3-[2-(4-氟基-苯基) -3-甲基胺甲醯基-苯 并呋喃-5-基氧甲基] 芊酸甲酯 lH NMR in DMSO: 8.34 (brd, 1H, J=4.10Hz); 8.07 (s, 1H); 7.92 (m, 3H); 7.76 (d, 1H, J=7.62Hz); 7.56 (m, 2H); 735 (t, 2H, J=7.03Hz); 7.21 (dt 1H, J=2.34Hz); 7.07 (ddt 1H, J=8.79, 2.34Hz); 5.24 (s, 2H); 3.86 (s, 3H); 2.81 (d, 3H, J=4.69Hz) (M+H)+ = 434 A >30 259. 4-[2·(4_氣基-苯基) -3-甲基胺甲醯基·苯 并呋喃_5-基氧甲基] 苄酸 lH NMR in DMSO: 8.38 (brd, 1H, J=4.10Hz); 7.90 (m, 4H); 7.56 (d, 1H, J=8.79Hz); 7.35(m, 4H); 7.20 (s, 1H); 7.05 (d, 1H, J=9.38Hz); 5.13 (s, 2H); 2.82 (d, 3H, J=4.69Hz) (M-H)' = 418 B <30 260. 3-[2-(ί-氟基-苯基)· -3-甲基胺甲醯基-苯 并呋喃-5-基氧甲基] 芊酸 JH NMR in DMSO: 12.98 (brs, 1H); 834 (br m, 1H); 8.05 (s, 1H); 7.91 (m, 3H); 7.72 (d, 1H, J=6.45Hz); 7.56 (m, 2H); 7.35 (t, 2H, J=8.79Hz); 7.21 (s, 1H); 7.08 (d, 1H, J=8.79Hz); 5.23 (s, 2H); 2.81 (d, 3H, J=6.71Hz) (M-H)' = 418 A >30 261. 6-乙醯基-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-幾酸甲 醯胺 'H NMR in CDC13: 7.84 (m, 2H); 7.83 (s, 1H); 7.37 (s, 1H); 7.19 (m, 2H); 5.95 (brs, 1H); 3.97 (s, 3H); 3.00 (d, J=4.8Hz,3H); 2.64 (s, 3H) (M+H)+ = 342.1 A <1 262. 4-[2-(4-氟基-苯基)— -3-甲基胺甲醯基各 嗎福琳-4-基-苯并唉 喃_5_基氧甲基] 酸甲酯 lH NMR in CDCl3: 8.09 (d, 2H, J=8.21Hz); 7.85 (m, 2H); 7.57 (d, 2H, J=8.21Hz); 7.42 (s, 1H); 7.18 (t, 2H, J=8.21); 7.12 (s, 1H); 5.72 (brs, 1H); 5.24 (s, 2H); 3.94 (s, 3H); 3.89 (m, 4H); 3.16 (m, 4H); 2.98 (d, 3H, J=4.69Hz) (M+H)+ = 519 A <10 263. 3-[2-(4-氟基-苯基) -3-甲基胺甲醯基-6-嗎福57林-4-基-苯并咬 喃-5-基氧甲表]-爷 酸甲酯 lH NMR in CDC13: 8.25 (s, 1H); 8.05 (d, 1H, J=8.21Hz); 7.87 (m, 2H); 7.67 (d, 1H, J=7.62Hz); 7.51 (t, 1H, J=7.62Hz); 7.45 (s, 1H); 7.20 (t, 2H, J=8.79Hz); 7.13 (s, 1H); 5.75 (brs, 1H); 5.24 (s, 2H); 3.97 (s, 3H); 3.93 (m, 4H); 3.18 (m, 4H); 3.00 (d, 3H, J=5.28) (M+H)" = 519 A <10 264. 2爾(4_一氣基-苯·基 異丙氧基-6-(l,3,5-三甲基-1H-吡吐-4-基)-苯并呋喃-3-羧 酸甲醯胺 lH NMR in CDC13: 7.90 (m, 2H); 7.38 (s, 1H); 7.25 (s, 1H); 7.18 (m, 2H); 5.78 (brs, 1H); 4.36 (in, 1H); 3.79 (s, 3H); 3.01 (d, J=4.8 Hz, 3H); 2.17 (s, 3H); 2.14 (s7 3H); 1.20 (d, J=6.0 Hz, 6H) (M+HV = 436.1 B <10 265. 2_(4_氣基-冬基)-5_ 異丙氧基-6·峨p各淀 -2-基-苯并咬喃-3 -羧酸甲醯胺 lH NMR in CDC13: 7.82 (m, 2H); 7.52 (s, 1H); 7.32 (s, 1H); 7.18 (m, 2H); 6.76 (brs, 2H); 5.80 (brs, 1H); 4.75 (m, 1H); 4.72 (m, IH); 3.28 (m, 2H); 2.97 (d, J=5.4 Hz, 3H); 2.28 (m, 1H); 2.03 (m, 3H); 1.41 (d, J=6.0 Hz, 6H) (M+H)+ = 397.1 C >30 266. 6-氣基-2-(4-氣基-木 基)-5-甲氧基-苯并 咬喃-3-叛酸甲酿胺 NMR in CDC13: 7.89 -7.83 (m,2H);7.83 (s, 1H);7.45 (s, 1H); 7.25 - 7.20 (m, 2H); 5.74 (s, 1H); 3.99 (s, 3H); 2.99 (d, J=5.6 Hz,3H) (M+H)+ = 325 A <1 203 > 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50〇tM) A= μΜ B= 03 to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 267. 4-[2-(4-氣基-苯基) - 3-甲基胺甲醯基-6-嗎福p林-4-基-麥并咬 喃-5-基氧甲基]-苄 酸 lH NMR in DMSO: 8.32 (brdT 1H, J=4.69Hz); 7.90 (m, 4H); 7.41 -7.31 (rn, 4H); 7.23 (s, 2H); 5.16 (s, 2H); 3.75 (m, 4H); 3.07 (m, 4H); 2.84 (d, 3H, J=4.10) (Μ+ΗΓ = 505 A <10 268. 3-[2-(4-氟基苯勒 -3-甲基胺T醯基各 嗎福啉_4_基-苯并呋 喃-5-基氧甲基j-芊酸 lH NMR in DMSO: 8.33 (brd, 1H, J=4.69Hz); 8.02 (s, 1H); 7.92 (m, 2H); 7.80 (d, 1H, J=7.03Hz); 7.41 - 7.26 (in, 4H); 7.23 (d, 2Ht J=4.10Hz); 5.16 (s, 2H); 3.76 (m, 4H); 3.07 (m, 4H); 2.84 (d, 3H, J=4.10Hz) (M+H)+ = 505 A <10 269. 2-(4-氟基·苯基)-5_ 異丙氧基各[甲烷磺 醯基-(1_甲基-1H-四 唑基甲基)-胺基]-苯并呋喃-3-幾酸甲 醯胺 lH NMR in DMSO: 8.43 (brd, 1H, J=4.69); 7.92 (m, 2H); 7.60 (s, 1H); 737 (t, 2H, J=8.79Hz); 7.14 (s, 1H); 5.19 (s, 2H); 4.78 (m, 1H); 4.10 (s, 3H); 3.20 (s, 3H); 2.82 (d, 3H, J=4.69Hz); 1.35 (d, 6H, J=6.45Hz) (M+H, = 517 A <1 270. 4-({[2-(4-氟基-苯基 )-5-異丙氧基-3-甲 基胺甲醯基-苯并呋 喃-6-基]-甲坑續酿 基-胺基}-甲基)-爷 酸甲酯 'H NMR in CDCi3: 7.91 (d, 2H, J=8.21Hz); 7.75 (m, 2H); 7.41 (s, 1H); 7.34 (d, 2H, J=8.21Hz); 7.20 - 7.14 (m, 3H); 5.66 (brs, 1H); 4.84 (br m, 3H); 3.87 (s, 3H); 3.04 (s, 3H); 2.94 (d, 3Hf J=5.27Hz); 1.48 (d, 6H, J=5.86Hz) (M+H)+ = 569 A <1 271. 2-(4-氟基-苯基)-5^ 異丙氧基-6-[甲烷磺 醯基-(2-甲基-噻唑 斗基甲基)-胺基]-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in CDCl3: 7.80 (m, 2H); 7.43 (s, 1H); 7.39 (s, 1H); 7.18 (t, 2H, J=8.79Hz); 7.07 (s, 1H); 5.68 (brs, 1H); 4.93 (brs,2H); 4.78 (m, 1H); 3.06 (s,3H); 2.95 (d, 3H, J=4.69Hz); 2.63 (s, 3H); 1.43 (d, 6H, J=6.45Hz) (M+H)+ = 532 A <10 272. 4-({[2-(4-氟基-苯 基)5-異丙氧基-3- 甲基胺甲醯基-苯并 呋喃各基]-甲烷磺 醯基-胺基丨-甲基)-芊酸 lH NMR in DMSO: 8.36 (brd, 1H, J=4.69 Hz); 7.89 - 7.82 (m, 4H); 7.40 (m, 3H); 7.32 (t, 2H, J=8.79 Hz); 7.10 (s, 1H); 4.80 (br m, 3H); 3.13 (s, 3H); 2.79 (d, 3H, J=4.10 Hz); 1.38 (d, 6H, J=5.86 Hz) \ (M+H)+ = 555 A <1.0 273. 2-(4-氣基-苯基)-5 -異丙氧基-6-(5-甲氧 甲基-異崎峻-3-基)-苯并呋喃-3-叛酸甲 醯胺 lH NMR in DMSO: 8.43 (q, J=4.4 Hz, 1H); 7.98 (s, 1H); 7.97 (dd, J=5.3, 8.8 Hz, 2H); 7.39 (apparent triplet, J=8.8 Hz, 2H); 7.29 (s, 1H); 6.93 (s, 1H); 4.76 (m, J=6.1, 5.7 Hz, 1H); 4.62 (s, 2H); 3.36 (s, 3H); 2.85 (d, J=4.4 Hz, 3H); 1.34 (d, J=6.1 Hz, 6H) (M+H)+ =439.05 A <1 204- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A= iO-5 μΜ B= 0.5 to ^5.0 μΜ C= 5.0 to ^30 /iM D= >30 μΜ 複製子 (μΜ) 274. 6-(5-環丙基-異嘮唑 -3-基)-2-(4-氣基-苯 基)-5-異丙氧基-苯 并呋喃-3-羧酸甲 醯胺 *H NMR in DMSO: 8.42 (q, J=4.4 Hz, 1H); 7.96 (dd, J=5.3, 8.8 Hz, 2H); 7.92 (s, 1H); 7.38 (apparent triplet, J=8.8 Hz, 2H); 7.26 (s, 1H); 6.61 (s, 1H); 4.72 (m, J=6.15Hz, iH); 2.84 (d, J=4.4 Hz, 3H); 2.22 (m, 1H); 1.33 (d, J=6.15 Hz, 6H); 1.10 (m, 2H); 0.94 (m, 2H) (M+H)+ = 435.12 A <1 275. 氟基-苯基)-5-異丙氧基-6-(1-甲烷 橫酸基-p比略淀-2-基)-苯并呋喃-3-幾 酸甲醯胺 lH NMR in CD€13: 7.84 (m, 2H); 7.56 (s, 1H); 7.30 (s, 1H); 7.21 (mt 2H); 5.73 (brs, 1H); 5.21 (dd, J=8.4 Hz, 2.4 Hz, IH); 4.69 (m, 1H); 3.70 (m, 1H); 3.55 (m, 1H); 2.97 (d, J=3.9 Hz, 3H); 2.84 (s, 3H); 2.35 (m, 1H); 1.95 (m, 3H); 1.39 (d, J=6.3 Hz) (M+H)+ = 475.1 A <1 276. 6-乙醯基-2-(4-氟基-冬基)-5-:¾基-苯并 呋喃-3-羧酸甲遍胺 lH NMR in CDC13: 12.16 (s, 1H); 8.03 (m, 2H); 7.87 (s, 1H); 7.19 (ra, 2H); 5.86 (br, 1H); 3.02 (d, J=4.8Hz, 3H); 2.71 (s, 3H) (M+H)+ =328.0 B <10 277. 6-(乙基-甲烷磺醯基 -胺基)-2-(4-氟基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 'H NMR ia DMSO: 8.43 (d, J=4.69Hz, 1H); 7.96 - 7.91 (ra, 2H); 7.6 (s, 1H); 7.38 (t, J=8.79Hz, 2H); 7.21 (s, 1H); 3.9 (s, 3H); 3.62 (q, J=7.03, 2H); 3.02 (s, 3H); 2.84 (d, J=4.69HzT 3H); 1.02 (t, J=7.03Hz, 3H) (M+H)+ = 421.1 A <1 278. 4-[2-(4-氟基-苯基) -5-甲氧基-3-甲基胺 甲醯基-苯并吱喃-6-基]-2-氧基-吡咯啶 -3-羧酸甲醯胺 'H NMR ia DMSO: 8.36 (q, 1H, br); 8.00 (q, 1H, br); 7.97-7.68 (ra, 3H); 7.53 (s, 1H); 7.77 (m, 2H); 7.U (s, 1H); 4.20 (q, 1H); 3.84 (s, 3H); 3.57 (m, 2H); 3.16 (t, 1H); 2.82 (d, 3H); 2.57 (d, 3H) (M+H)+ = 440 A <10 279. 2-(4·氟基-苯基)_5_ 異丙氧基 -6-·(4Η·[1,2,4]三唑 -3-基)-苯并4喃-3-羧酸甲醯胺 lH NMR in CDC13: 8.47 (s, 1H); 8.03 (s, 1H); 7.84 - 7.89 (m, 2H); 7.57 (s, 1H); 7.19 - 7.25 (t, 2H, J=8.79 Hz); 5.80 (br.s, 1H); 4.90-4.98 (septet, 1H, J=5.86 Hz); 2.98 - 3.00 (d, 3H, J=4.69 Hz); 1.52 -1.54 (d, 6H, J=6.45 Hz) (M+H)+ =395.0 A <30 280. 2-(4-氟基-苯基)-5-甲氧基-6-(5-甲氧甲 基-3-甲基-異今坐 -4-基)-苯并呋喃-3-羧酸甲醯胺 *H NMR in CDCi3: 7.86 (dd, J=8.8 and 5.1 Hz, 2H); 7.43 (s, 1H); 7.35 (s, 1H); 7.21 (apparent t, J=8.8 and 8.4 Hz, 2H); 5.78 (brs 1H); 4.42 (s, 2H); 3.86 (s, 3H); 3.36 (s, 3H); 3.01 (d, J=5.1 Hz, 3H); 2.21 (s, 3H) (M+H)+ = 425 A <1 205 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= /iM B= to ^:5.0 μΜ C= 5.0 to <:30 /iM D= >30 /iM 複製子 (μΜ) 281. 2-(4-氟基-苯基)-5_ 異丙氧基-6-[甲烷磺 醯基-(4-甲氧基-芊 基)-胺基]-苯并咬喃 -3-叛疲甲醯胺 lH NMR in CDC13: 7.76 (m, 2H); 7.38 (s, 1H); 7.20-7.12 (m, 5H); 6.75 (d, 2H, J=8.79 Hz); 5.86 (brs, 1H); 4.90-4.70 (br m, 3H); 3.74 (s, 3H); 3.03 (s, 3H); 2.95 (d, 3H, J=4.69 Hz); 1.47 (d, 6Hy J=6.45 Hz) (M-H)·= 539 A <1 282. 2_(4_氟基-苯基)-5-異丙氧基-6-[甲燒磺 醯基-(5-甲基-異嘮 峻_3-基甲基)-胺基]-苯并呋喃-3-叛酸甲 醯胺 lH NMR in CDCi3: 7.79 (m, 2H); 7.42 (s, 1H); 7.34 (s, 1H); 7.19 (t, 2H, J=8.79 Hz); 6.21 (s, 1H); 5.86 (brs, 1H); 4.83 (br m, 3H); 3.04 (s, 3H); 2.96 (d, 3H, J=4.69 Hz); 2.38 (s, 3H); 1.45 (d, 6H, J=5.86 Hz) (M-H)* = 514 A <1 283. 2-(4-氣基-苯墓)-5_ 異丙氧基-6-(5-甲基 -異17号峻-3 -基)-本并 呋喃-3-羧酸甲醯胺 lH NMR in CDCb: 8.015 (s, 1H); 7.87 (dd, J=5.3, 8.3 Hz, 2H); 7.43 (s, 1H); 7.19 (apparent triplet, d, J=8.3 Hz, 2H); 6.58 (s, 1H); 5.79 (bs, 1H); 4.68 (m, 1H); 2.99 (d, J=4.8 Hz, 3H); 2.48 (s, 3H); 1.38 (d, J=5.7 Hz, 6H) 氺氺氺 A <1 284.; 6-[(3,5-二甲基-異吟 唑-4-基甲基)-甲烷 磺醯基-胺基]-2-(4-氟基-苯基)-5-異丙 氧基-苯并呋喃-3-夢复 酸甲醯胺 lH NMR in DMSO: 8.41 (brd, 1H, J=4.69 Hz); 7.91 (m, 2H); 7.36 (m, 3H); 7.12 (s, 1H); 4.79 (m, 1H); 4.64 (br m, 2H); 3.13 (s, 3H); 2.82 (d, 3H, J=4.69 Hz); 2.08 (s, 3H); 2.05 (s, 3H); 1.37 (d, 6H, J=5.86 Hz) (M+H)+ = 530 A <10 285. 2-(4-氟基-苯基)-5-異丙氧基-6-(甲纟充績 醯基-嘧唑-2-基甲基 -胺基)-苯并呋喃-3- 羧酸甲醯胺 NMR in DMSO: 8.42 (brd, 1H, J=4.69 Hz); 7.92 (ra, 2H); 7.67 (d, 1H, J=3.52 Hz); 7.65 (d, 1H, J=3.52 Hz); 7.45 (s, 1H); 7.36 (t, 2H, J=8.79 Hz); 7.18 (s, 1H); 5.12 (brs, 2H); 4.83 (m, 1H); 3.16 (s, 3H); 2.82 (d, 3H, J=4.69 Hz); 1.39 (d, 6H, J=6.45 Hz) (M+H)+ = 518 A <1 286. 2-([[2:όίϋ 苯基 )-5-異丙氧基-3-甲 基胺曱醯基-苯并呋 喃-6-基]-甲虎續醯 基-胺基}-曱基 塞 吨冰羧酸乙酯 'H NMR in DMSO: 8.49 (s, 1H); 8.42 (brd, 1H, J=4.10 Hz); 7.93 (m7 2H); 7.54 (s, 1H); 7.37 (t, 2H, J=8.79 Hz); 7.20 (s, 1H); 5.13 (brs, 2H); 4.84 (m, 1H); 4.25 (q, 2H, J=7.03 Hz); 3.18 (s, 3H); 2.82 (d, 3H, i=4.69 Hz); 1.39 (d, 6H, J=6.45 Hz); 1.26 (t, 3H, J=7.03 Hz) ' (M+H)+ = 590 A <10 206- 88828.doc 200418452 .實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A= μΜ B= 03 to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 /iM 複製子 OiM) 287. 2-(4-氟基-苯基)-5- 羥基-6-(〒烷磺醯基 -甲基-胺基)-苯并吱 喃-3-羧酸甲醯胺 lH NMR in DMSO: 9.98 (s, 1H); 8.39 (d, J=4.4 Hz, 1H); 7.91 (mT 2H); 7.51 (s, 1H); 7.35 (U J=8.8 Hz, 2H); 7.09 (s, 1H); 3.20 (s, 3H); 3.08 (s, 3H); 2.80 (d, J=4.4Hz, 3H) (M+H)+ = 393 A <10 288. 6-(晞丙基-甲烷磺醯 基-胺基)-5-晞丙氧 基-2-(4-氟基-苯基)-苯并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.40 (dt J=4.7 Hz, 1H); 7.93 (dd, J=9.0, 5.3 Hz, 2H); 7.57 (s, 1H); 7.35 (t, J=9.0 Hz, 2H); 7.33 (s, 1H); 6.10 (mT 1H); 5.80 (m, 1H); 5.50 (m, 1H); 5.30 (m, 1H); 5.10 (m, 1H); 5.00 (ra, 1H); 4.70 (d, J=3.5 Hz, 2H); 4.20 (brs, 2H); 3.05 (s, 3H); 2.81 (d, J=4.7 Hz, 3H) (M+H)+ = 459 A <1 289. 6-(乙醯基-甲烷磺醯 基-胺基)-2-(4-_氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸甲 醯胺 lH NMR in DMSO: 8.48 (d, J=4.39 HzT 1H); 7.96 - 7.91 (m, 2H); 7.86 (s, IH); 7.39 (t, J=8.79 Hz, 2H); 7.27 (s, 1H); 3.93 (s, 3H); 3.49 (s, 3H); 2.84 (d, J=4.39, 3H); 1.89 (s, 3H) (M+H)+ =435.0 A <1 290. 6-[(3,5-二曱基-異呤 唑-4-基甲基甲烷 磺醯基-胺基>2-(4-氟基-苯基)-5-甲氧 基-苯并呋喃-3-羧酸 甲醯胺 lH NMR in DMSO: 8.44 (m, 1H); 7.94-7.90 (m, 2H); 7.43-7.33 (m, 3H); 7.16 (s, 1H); 4.67 (bs, 2H); 3.9 (s, 3H); 3.13 (ra, 3H); 2.84-2.82 (m, 3H); 2.11 (ct J=3.52 Hz, 3H); 2.06 (d, J=3.52, 3H) (M+H)+ = 502.1 A <10 291. 2-(4-氟基-苯基)-6-( 甲:k績醯基塞峻-4-基甲基-胺基)-5-甲 氧基-苯并咬喃-3-叛 酸甲醯胺 lH NMR in DMSO: 9.01 (s, 1H); 8.41 (d, J=4.84 Hz, 1H); 7.93-7.88 (m, 2H); 7.55 (m, 1H); 7.48 (s, 1H); 7.36 (t, J=8.35 Hz, 2H); 7.17 (s, 1H); 4.93 (bs, 2H); 3.90 (s, 3H); 3.15 (st 3H); 2.83 (d, J=4.84 hz, 3H) (M+H)+ 490.0 A <1 292. 2-({[2-(4-氟基-苯 基)-5_異丙氧基-3- 甲基胺甲醯基-苯并 呋喃-6-基]-曱烷磺 醯基-胺基卜甲基)-噻唑-4-羧酸 *H NMR in DMSO: 8.42 (brm, 2H); 7.93 (m, 2H); 7.53 (d, 1H, J=1.17 Hz); 7.36 (t, 2H, J=8.79 Hz); 7.19 (s, 1H); 5.12 (brs, 2H); 4.84 (m, 1H); 3.19 (s, 3H); 2.82 (d, 3H, 1=3.52 Hz); 1.39 (d, 6H, J=5.28 Hz) (M+H)+ = 562 A >100 293. 5-(2,2-二甲基-4-氧 基-4H-苯并[1,3]-二 呤畊-5-基甲氧基) -2-(4-氣基-苯基)-6-嗎福啉-4-基-苯并呋 喃-3-羧酸曱醯胺 lH NMR in DMSO: 8.32 (brd, 1H, J=4.40 Hz); 8.08 (s, 1H); 7.90 (m, 2H); 7.80 (d, 1H, J=8.79 Hz); 7.35 (t, 2H, J=8.79 Hz); 7.26-7.19 (m, 3H); 5.20 (s, 2H); 3.77 (m, 4H); 3.06 (m, 4H); 2.83 (d, 3H, J=4.00 Hz); 1.72 (s,6H) (M+H)+ = 561 B <10 207- 88828.doc 200418452 實例 編"5虎 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 〇iM) A= 只 M B= 03 to ^5.0 C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 294. 5-(2,2-二甲基-4-氧 基-4H-苯并[1,3]-二 吟畊·5_基甲氧基) -6-(乙基-甲烷磺醯 基-胺基)-2-(4-氟基-苯基)-苯并咬‘-3-羧酸甲醯胺 *H NMR in DMSO: 8.42 (brd, 1H, J=4.40 Hz); 8.05 (d, 1H, J=1.76 Hz); 7.93 (m, 2H); 7.85 (d, 1H, J=8.35 Hz); 7.65 (s, 1H); 7.39 (ζ 2H, J=8.79 Hz); 7.34 (s, 1H); 7.19 (d, 1H, J=8.35 Hz); 5.26 (s, 2H); 3.63 (m, 2H); 2.93 (s, 3H); 2.84 (d, 3H, J=4.40 Hz); 1.71 (s, 6H); 1.03 (t, 3H, J=7.03 Hz) (M+H)+ = 597 A <1 295. 2-(4-氟基-苯基) -6-(1Η-咪唑-4-基;) -5-甲氧基-苯并呋喃 -3-羧酸甲醯胺 lH NMR ia CDC13: 7.96-7.85 (m, 3H); 7.74 (s, 1H); 7.61 (s, 1H); 7.45 (s, 1H); 7.24-7.18 (m, 2H); 5.82 (s, 1H); 4.04 (s, 3H); 3.0 (d, J=4.8Hz, 3H) (M+H)+ = 466 A <10 296. 2_(4·氣基-木基) -6-(1Η-咪唑-2-基) -5-甲氧基-苯并呋喃 -3-羧酸甲醯胺 'H NMR in CDC13: 10.6 (s, 1H); 8.48 (s, 1H); 7.88-7.84 (m, 2H); 7.50 (s, 1H); 7.26-7.20 (m, 3H); 7.18 (s, 1H); 7.13 (s, 1H); 5.84 (s, 1H); 4.14 (s, 3H); 3.0 (d, J=6.8Hz, 3H) (M+H)+ = 466 A <1 297. 6-(乙基-甲烷磺酿基 -胺基)-2-(4-氟基·苯 基)-5-#基-苯并呋 喃-3-羧酸甲醯胺 lH NMR in DMSO: 9.96 (s, 1H); 8.40 (d, J=4.4Hz, 1H); 7.92 (dd, J=8.8, 5.3Hz, 2H); 7.46 (s, 1H); 7.37 (t, J=8.8Hz, 2H); 7.09 (s, 1H); 3.60 (q, J=7.0Hz, 2H); 3.01 (s, 3H); 2.80 (d, J=4.4Hz, 3H); 1.00 (t, J=7.0Hz, 3H) (M-H)* = 405 A <10 298. 5-二氟甲氧基-2-(4-氟基-苯基)-6-(甲烷 磺醯基-甲基-胺基)-苯并呋喃各羧酸甲 醯胺 lH NMR in CDCb: 7.86 (dd, J=8.8, 5.3Hz, 2H); 7.70 (s, 1H); 7.62 (s, 1H); 7.24 (t, J=8.8Hz, 2H); 6.69 (t, J=73.4Hz, 1H); 5.74 (brs, 1H); 3.33 (s, 3H); 3.03 (s, 3H); 2.98 (d, J=4.8Hz, 3H) (M+H)+ = 443 A <1 299. 2-(4_氟基-苯基)-6_ (甲烷磺醯基-峨啶 -4-基甲基-胺基)-5-甲氧基-苯并咬4-3-羧酸甲醯胺 氺氺* (M+H)+ = 484 A <1 300. 2-(4-氟基-苯基) -6-(1-經基小甲基_ 乙基)_5_甲基-苯并 呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.95 (m, 2H); 7.69 (s, 1H); 7.56 (s, 1H); 7.16 (mt 2H); 5.83 (brs, 1H); 3.02 (d, J=4.6 Hz, 3H); 2.69 (s, 1H); 2.64 (d, J=3.9 Hz, 3H); 1.72 (s, 6H) (M+H)"= 342.1 A <10 301. 6-乙醯基-2-(4-氟基-苯基)-5-甲基-苯并 呋喃各羧酸甲驢胺 'H NMR in CDC13: 7.94 (m, 2H); 7.79 (s, 1H); 7.69 (s, 1H); 7.20 (m, 2H); 5.83 (brs, 1H); 3.02 (d, J=4.8 Hz, 3H); 2.64 (s, 3H); 2.96 (s, 3H) (M+H)+ = 326.1 A <10 208 - 88828.doc 200418452 :實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A= μΜ B= 0.5 to 2:5.0 fiM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 〇iM) 302. 5-(2,2-二曱基-4·氧 基-4H-苯并[1,3]-二 噚4-7-基甲氧基) -2-(4-敦基-苯基)-6-( 甲烷磺醯基-甲基-胺基)-苯并呋喃-3-羧酸甲醯胺 NMR in DMSO: 8.39 (brd, 1H, J=4.69 Hz); 7.92 (m, 3H); 7.74 (s, 1H); 7.37 (m, 3H); 7.29 (d, 2H, J=1.76 Hz); 5.32 (brs, 2H); 3.23 (s, 3H); 3.01 (s, 3H); 2.82 (d, 3H, J=4.10 Hz); 1.71 (s, 6H) (M+H)+ = 583 A <1 303. 2-(4-氟基-苯基) 甲烷磺醯基-甲墓-胺基)-乙基]-5-甲氧基-表并咬喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.50 (s, 1H); 7.39 (s, 1H); 7.27-7.19 (m, 2H); 5.76 (s, 1H); 5.63-5.56 (m, 1H); 3.95 (s, 3H); 3.00 (d, J=4.8Hz, 3H); 2.82 (s, 3H); 2.69 (s, 3H); i.65 (d, J=6.9Hz, 3H) (M+H)+ = 435 A <1 304. —2-(ϊ-氟基-笨基)-5-甲氧基-6-(1-甲基胺 基-乙基)-苯并呋喃 -3-羧酸甲醯胺 lH NMR in CDC13: 7.88-7.83 (m, 3H); 7.47 (s, 1H); 7.33 (s, 1H); 7.21-7.16 (m, 6H); 5.75 (s, 1H); 4.20-4.16 (m, 1H); 3.92 (s, 3H); 3.47 (s, 1H); 2.99 (d, J=4.5Hz, 3H); 2.34 (s, 3H); 1.44 (d, J=6.3Hz, 3H) (M+H)+ = 357 B >30 305. 4-[2-(4-氟基-苯基) -6-(甲燒績酿基-曱 基-胺基)-3-甲基胺 甲醯基-苯并吱喃-5-基氧甲基]-苄酸 甲酯 Ή NMR in DMSO: 8.40 (brd, 1H, J=4.69); 8.02 (d, 2H, J=8.21); 7.93 (m, 2H); 7.70 (111, 3H); 7.39 (t, 2H, J=8.79 Hz); 7.34 (s, 1H); 5.34 (s, 2H); 3.87 (s, 3H); 3.22 (s, 3H); 2.97 (s, 3H); 2.84 (d, 3H, J=4.10Hz) (M+H)+ = 541 A <1 306. 2-[2-(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基;H3-甲基胺 甲醯基-苯并吱喃 -5-基氧甲酸 甲酯 lH NMR in DMSO: 8.39 (brd, 1H, J=5.28 Hz); 8.15 (s, 1H); 7.93 (ra, 3H); 7.82 (d, 1H, J=7.62 Hz); 7.68 (s, 1H); 7.58 (ζ 1H, J=7.62 Hz); 7.37 (m, 3H); 5.32 (s, 2H); 3.86 (s, 3H); 3.20 (s, 3H); 2.94 (s, 3H); 2.82 (d, 3H, J=4.10 Hz) (M+H)+ = 541 A <1 307. 6-ί(2-氟基-乙基)-甲 ^完績龜基-胺塞] -2-(4-氟基-苯基)-5-甲氧基-苯并呋喃-3-羧酸甲醯胺 *H NMR in DMSO: 8.43 (m, 1H); 7.93 (dd, J=5.3 & 8.8Hz, 2H); 7.62 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 7.22 (s, 1H); 4.54 (t, J=5.3Hz, 1H); 4.39 (t, J=4.7Hz, 1H); 3.92 (m, 4H); 3.84 (m, 1H); 3.06 (s, 3H); 2.83 (d, J=4.7Hz, 3H) (M+H)+ = 439 A <1 308. _2-(4-氟基-苯基)-6-[甲烷磺醯基-(2,2,2-三氟乙基)-胺基]-5- 甲氧基-苯并吱‘3-羧酸曱醯胺 lH NMR in DMSO: 8.45 (m7 1H); 7.93 (dd, J=5.3 & 8.8Hz, 2H); 7.65 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 7.25 (s, IH); 4.40 (m, 2H); 3.94 (s, 3H); 3.10 (s, 3H); 2.83 (d, J=4.7Hz, 3H) (M+H)+ = 475 A <i 209- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICs〇 〇iM) A= /iM B= 0 J to ^5.0 /iM C= 5.0 to ^30 /iM D= >30 μΜ 複製子 (μΜ) 309. 2_(4·氟基-苯基) -6-(1-甲烷磺醯基_ 吡咯啶-2-基)-5-甲 氧基-木并咬喃-3-幾 酸甲醯胺 NMR in CDC13: 7.84 (m, 2H); 7.58 (s, 1H); 7.26 (s, 1H); 7.18 (m, 2H); 5.76 (brs, 1H); 5.22 (m, 1H); 3.91 (s, 3H); 3.75 (m, 1H); 3.55 (m, 1H); 3.18 (m, 1H); 3.00 (d, J=4.6 Hzt 3H); 2.84 (s, 3H); 1.92 (m, 2H); 1.84 (m, 2H) M+= 446 (GCVMS) A <1 310. 6-(3-環丙基-5-甲氧 甲基-異吟嗤-4-基) -2-(4-氣基-苯基)-5-甲氧基-苯并呋4-3-羧酸甲醯胺 lH NMR in CDCl3: 7.87 (dd, J=8.8 and J=5.1Hzt 2H); 7.44 (s, 1H); 7.42 (s, 1H); 7.20 (apparent t, J=8.8 and 8.4 Hz, 2H); 5.81 (brs, 1H); 4.40 (s, 2H); 3.87 (s, 3H); 3.34 (s, 3H); 3.01 (d, J=4.8Hz, 3H); 1.65 (m, 1H); 1.02 (m, 2H); 0.88 (m, 2H) (M-Η)'= 449 A <1 311. 4-[2-(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基)-3-甲基胺 甲醯基-苯并呋喃-5-基氧甲基]-苄酸 lH NMR in DMSO: 8.41 (brd, 1H, J=4.10Hz); 7.95 (mt 4H); 7.69 (s, 1H); 7.58 (d, 2H, J=8.21Hz); 7.37 (mt 3H); 5.29 (s, 2H); 3.21 (s, 3H); 2.94 (s, 3H); 2.84 (d, 3H, J=4.69Hz) (M+H)+ = 527 A <10 312. 3-[2_(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基)-3-甲基胺 甲酿基-苯并峡喃-5-基氧甲基]-芊酸 lH NMR in DMSO: 8.41 (brd, 1H, J=4.10Hz); 8.14 (s, 1H); 7.94 (m, 3H); 7.80 (d, 1H, J=7.62Hz); 7.69 (s, 1H); 7.57 (t, 1H, J=8.21Hz); 7.38 (m, 3H); 5.33 (s, 2H); 3.22 (s, 3H); 2.95 (s, 3H); 2.84 (d, 3H, J=4.10Hz) (M+H)+ = 527 A <1 313. 2-(4-氟基-苯基)-5-甲氧基-6-(5-甲氧甲 基-異哼峻各基苯 并吱喃-3-幾酸甲 醯胺 lH NMR in CDCl3: 8.03 (s, 1H); 7.87 (ddt J=5.27 & 8.8Hz, 2H); 7.45 (s, 1H); 7.20 (apparent triplet, J=8.8 & 8.3Hz, 2H); 6.83 (s, 1H); 5.80 (bs, 1H); 4.61 (s, 2H); 3.96 (s, 3H); 3.48 (s, 3H); 3.00 (d, J=4.8Hz, 3H) (M+H)+ = 411 A <1 314. 6-(3,5-二甲基-異哼 唑-4-基)-2_(4_氟基- 苯基>5-羥基-苯并 呋喃-3-羧酸甲酿胺 lH NMR in CDC13: 7.90 (m, 2H); 7.56 (s, 1H); 7.22 (mT 3H); 6.04 (brs, 1H); 5.83 (brs, 1H); 3.00 (d, 3H, J=4.69Hz); 2.36 (s, 3H); 2.22 (s, 3H) (M+H)+ = 381 A <1 315. 2-(4-氟基-苯基)-5_ 甲氧基-6-(5-氧基-吡咯啶-3-基 > 苯并 呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.36 (m, 1H, br); 7.92 (dd, 2H); 7.64 (s, 1H, br); 7.54 (s, 1H); 7.34 (dd, 2H); 7.11 (s, 1H); 3.89 (m, 1H); 3.86 (s, 3H); 3.6 (m, 1H); 3.21 (m, 2H); 2.81 (d, 3H); 2.48-2.37 (m, 2H) (M+H)+ = 383 A <10 316. 2-(4-氣基-木基)-6_ [甲烷磺醯基-(2-三 氣甲氧基-乙墓)-月安 基]-5-甲氧基-苯并 呋喃-3-羧酸甲醯胺 *H NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J=5.9 & 8.8Hz, 2H); 7.57 (s, 1H); 7.38 (t, J=8.8Hz, 2H); 7.23 (s, 1H); 4.11 (m, 2H); 3.92 (m, 5H); 3.06 (s, 3H); 2.84 (d, J=4.7Hz, 3H) (M+H)+ = 505 B <1 210- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV po卜BB7 ICs〇 (μΜ) A= J /iM B= 0*5 to s5.0 μΜ C= 5.0 to <:30 D= >30 m 複製子 _ 317. 2-(4-氟基-苯基)-5-甲氧基-6-(1Η-吡咯 θ-基)-苯弁p夫喃-3- 羧酸甲醯胺 {H NMR in CDC13: 832 (m, 1H); 7.89 (m, 2H); 7.66 (s, 1H); 7.42 (m, 1H); 7.33 (s, 1H); 7.25 (m, 2H); 6.86 (m, 1H); 6.67 (in, 1H); 5.81 (q, 1H); 3.96 (s, 3H); 3.01 (d,3H) (M+H)+ = 365 C <1 318. 6-(3,5-二甲基-異崎 唑冬基)-2-(2-乙氧 基-4-氟基-苯基)-5-甲氧基-苯并呋喃-3-羧酸甲醯胺 lH NMR in CDC13: 7.63 (s, 1H); 7.54-7.60 (m, 1H); 7.24-7.26 (m, 1H); 7.227 (s, 1H); 6.80-6.86 (t of d, 1H, J=2.34Hz & 8.21Hz); 6.75-6.79 (d of d, 1H,); J=2.34 & 11.14Hz); 5.80 (brs 1H); 4.05-4.12 (q,2H,J=7.03Hz); 3.87 (s,3H); 2.32 (s,3H); 2.18 (s, 3H); 1.37-1.42 (t, 3H, J=7.03Hz) (M+H)+ = 439.1 A >30 319. 2-(4- (甲烷磺醯基-甲基-胺基)-5-(噻唑-4-基 甲氧基)-苯并呋喃 -3-羧酸甲醯胺 lH NMR in DMSO: 9.17 (d, 1H, J = 1.76Hz); 8.40 (brd, 1H, J=4.69Hz); 7.95 (m, 2H); 7.86 (d, 1H, J=2.34Hz); 7.65 (s, 1H); 7.39 (m, 3H); 5.39 (s, 2H); 3.20 (s, 3H); 2.97(s, 3H); 2.85 (d, 3H, J=4.69Hz) (M+H)+ = 490 B <1 320. 2-(4-氣基-本基)-6- (甲烷磺醯基-甲基-胺基)-5-(2-甲基-口塞 峻-4-基甲氧基)-苯 并呋喃各羧酸曱 醯胺 lH NMR in DMSO: 8.41 (brd, 1H, J=4.10Hz); 7.95 (m, 2H); 7.64 (s, 1H); 7.60 (s, 1H); 7.38 (m, 3H); 5.28 (s, 2H); 3.20 (s, 3H); 3.00 (s? 3H); 2.85 (d, 3H, J=4.69Hz); 2.68 (s, 3H) (M+H)+ = 504 A <1 321. 5-(3-氯曱基-[1,2,4] ¥二。坐-5-基氧墓) -2-(4-乳基-苯基)-6- (甲烷磺醯基-甲基· 胺基)-苯并呋喃-3-羧酸甲醯胺 lH NMR in DMSO: 8.49 (brd, 1H, J=4.69Hz); 8.19 (s, 1H); 7.99 (m, 2H); 7.90 (s, 1H); 7.43 (t, 2H, J=8.79Hz); 4.74 (s, 2H); 3.16 (s, 3H); 3.10 (s, 3H); 2.82 (d,3H, J=4.10Hz) (M+H)+ = 524.9 A <1 322. 2-(4-氟基-苯基) -6-{[2-(4-氟基-苯 基)_2邊基-乙基]-甲 fe績酿基-胺基}-5-異丙氧基-苯并啥喃 -3-羧酸甲醯胺 lH NMR in DMSO: 8.40 (d, J=4.4Hz, 1H); 7.90 (m, 2H); 7.37 (t, J=8.8Hz, 2H); 7.30-7.10 (m, 6H); 5.50 (m, 1H); 4.78 (septet, J=6.lHz, IH); 4.50 (m, 1H); 3.90 (m, 1H); 3.42 (m, 1H); 3.00 (s, 3H); 2.82 (d, J=4.2Hz, 3H); 1.31 (d, J=6.1Hz, 6H) (M+H)+ = 559 A <1 323. 2-(4-氟基-苯基)-5-甲氧基-6-(2-甲基 -2Η-[1,2,4]-三嗤-3-基)-苯并ρ臭喃-3身 酸甲醯胺 lH NMR in DMSO: 8.46-8.48 (d, 1H, J=4.69Hz); 8.01 (s, 1H); 7.94-7.99 (ra, 2H); 7.71 (s, IH); 7-36-7.43 (t, 2H, J=8.79Hz); 7.31 (s, 1H); 3.89 (s, 3H); 3.69 (s, 3H); 2.86-2.87 (d, 3H, J=4.69Hz) (M+H)+ = 381 A <1 211 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (fiM) A= μ,Μ. B= to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (_ 324. 5二(3,5-二甲基-異呤 唑斗基甲氧基) -2-(4-氣基-苯基)-6-(甲垸磺醯基-甲基-胺基)-苯并呋喃_3_ 羧酸甲醯胺 lH NMR in DMSO: 8.45 (brd, 1H, J=4.69Hz); 7.94 (m, 2H); 7.70 (s, 1H); 7.39 (m, 3H); 5.05 (s, 2H); 3.14 (s, 3H); 2.94 (s, 3H); 2.85 (d, 3Hf J=4.i0Hz); 2.44 (s, 3H); 2.27 (s, 3H) (M+H)+ = 502 A <1 325. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲基-胺基)-5-(3-曱氧基-苄氧基)-苯并呋喃 各羧酸-甲醯胺 lH NMR in DMSO: 8.40 (brdT 1H, J=4.10Hz); 7.93 (m, 2H); 7.70 (s, 1H); 7.42-7.31(iru 4H); 7.12 (m, 2H); 6.92 (d, 1H, J=8.21Hz); 5.21 (s, 2H); 3.77 (s, 3H); 3.21 (s, 3H); 2.97 (s, 3H); 2.84 (d, 3H, J=4.10Hz) (M+H)+ = 513 A <1 326. 厶(4-氟基-苯基)-5-羥基-6-(異丁基-甲 燒續酸墓-胺基)-苯 并呋喃-3-羧酸-甲 醯胺 NMRinDMSO: 10.05 (s, 1H); 8.40 (d, J=4.4HzT 1H); 7.93 (dd, J=5.3 & 8.8Hz, 2H); 7.48 (s, 1H); 7.35 (t, J=8.8Hz, 2H); 7.10 (s, iH); 3.40 (d, J=7.5Hz, 2H); 2.98 (s, 3H); 2.80 (d, J=4.4Hz, 3H); 1.50 (m, 1H); 0.88 (d, J=6.6Hz, 6H) (M+H)+ = 435 B <30 327. 2-(4-氟基-苯基)-6-(甲烷磺醯基-甲基-胺基)-5-(4-甲氧基-+氧基)-苯咬喃 -3-羧酸-甲醯胺 lH NMR in DMSO: 8.40 (brd, 1H, J =4.69Hz); 7.94 (m, 2H); 7.66 (s, 1H); 7.47 (d, 2H, J=8.79Hz); 7.39 (m, 3H); 6.98 (d, 2H, J=8.79Hz); 5.15 (s, 2H); 3.78 (s, 3H); 3.17 (s, 3H); 2.90 (S, 3H); 2.85 (d, 3H, J=4.69Hz) ' (M+H)"= 513 A <1 328. 2-(4-氟基-苯基)-6-(甲烷磺醯基-甲基-胺基)-5-(吡啶-4-基 甲氧基)-苯并呋喃 -3-羧酸-甲醯胺 Ή NMR in DMSO: 8.62 (d, 2H, J=5.86Hz); 8.40 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.74 (s, 1H); 7.55 (d, 2H, J=5.28Hz); 7.39 (t, 2H, J=8.79Hz); 7.31 (s, 1H); 5.32 (s, 2H); 3.26 (s, 3H); 3.02 (s, 3H); 2.83 (d, 3H, J=4.69Hz) (M+H)+ = 484 A <1 329. 5-(2,2-二曱基斗氧 基-4H-苯并[1,3]-二 吟畊-6-基甲氧基) -2-(4-氟基-苯;&)-6-( 甲烷磺醯基-曱基-胺基)-苯并呋喃-3-羧酸曱醯胺 *H NMR in DMSO: 8.41 (brd, 1H, J=4.69Hz); 8.06 (s, 1H); 7.94 (m, 2H); 7.87 (dd, 1H, J=8.21 & 2.34Hz); 7.69 (s, 1H); 7.37 (ra, 3H); 7.19 (d, 1H, J=8.79Hz); 5.27 (s, 2H); 3.20 (s, 3H); 2.95 (s, 3H); 2.84 (d, 3H, J=4.69Hz); 1.72 (s, 6H) (M+H)+ = 583 A <1 330. 6-(環丙甲基-甲烷磺 醯基-胺基)-2-(4-氟 基-苯基)-5-甲氧基-苯并呋喃-3-羧酸-甲 醯胺 Ή NMR in DMSO: 8.44 (m, 1H); 7.94 (dd, J=5.9 & 9.4Hz, 2H); 7.62 (s, 1H); 7.38 (ζ J=8.8Hz, 2H); 7.20 (s, 1H); 3.90 (s, 3H); 3.44 (m, 2H); ?.92(s,3H); 2.84 (d, J=4.7Hz, 3H); 0.87 (m, 1H); 0.35 (d, J=1.7Hz,2H); 0.05 (m,2H) (M+H)+ = 447 A <1 331. 2-(4_氟基-苯基)-6」 (甲烷磺醯基-甲基 胺甲醯基甲基-胺 基)-5-甲氧基-苯并 吱喃-3-複酸-甲醯胺 4Η NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J=5.9 & 9.4 Hz, 2H); 7.90 (s, 1H); 7.83 (m, 1H); 7.38 (t, J=8.8 Hz, 2H); 7.20 (s, 1H); 4.17 (s, 2H); 3.92 (s, 3H); 3.12 (s, 3H); 2.84 (d, J=4.7Hz, 3H); 2.58 (dT J=4.7Hz, 3H) (M+H)+ = 464 A <1 212- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= μΜ B= to ^5.0 /iM C= 5.0 to ^30 /iM D= >30 μΜ 複製子 (μΜ) 332. 5-狀基-2-(4-氣基•苯 基)-6-甲烷磺醯基胺 基-苯并p夫喃-3 -叛酸 甲醯胺 lH NMR in CDC13: 7.89-7.85 (m, 2H); 7.87 (d, J= 6.3 Hz, 1H); 7.70 (d, J=9.9 Hz, 1H); 7.24 - 7.19 (m, 2H); 656 (s, 1H); 5.74 (s, 1H); 3.04 (s, 1H); 2.99 (d, J=4.8Hz, 3H) (M+H)+ = 381 B <10 333. 6-(乙基-甲烷磺醯基 -胺基)-5-氟基冬(4-氟基-苯基)-苯并呋 喃-3-羧酸-甲酸胺 lH NMR in CDC13: 7.90-7.86 (m, 2H); 7.66 (d, J= 10.5 Hz, 1H); 7.57 (d, J=6.0 Hz, 1H); 7.24-7.18 (m, 2H); 5.74 (s, 1H); 3.77 (q, J=2.4 &14.4 Hz, 2H); 2.99-2.98 (m, 6H); U7 (t, J=7.5 Hz, 3H) (M+H)+ = 409 A <10 334. 2-(4-氣基-本基) -6-(1-甲烷磺醯基-吡咯啶-3-基)-5-甲 氧基-苯并咬喃-3-¾ 酸-甲醯胺 *H NMR in CDCb: 7.85 (m, 2H); 7.36 (s, 1H); 7.32 (s, 1H); 7.20 (m, 2H); 5.78 (brs, 1H); 3.91 (s, 3H); 3.83 (m, 2H); 3.60 (m, iH); 3.47 (m, 1H); 3.00 (d, J=4.8Hz, 3H); 2.87 (s, 3H); 2.34 (m, 1H); 2.16 (m, 1H) (M+H)+ = 447 A <1 335. 5:乙基-2:(4:成基-苯 基)-6-[〒烷磺醯基 -(2-甲氧基-乙基 >胺 基]苯并呋喃-3-幾酸 _甲醯胺 j ---- *H NMR in DMSO: 8.45 (ra, 1H); 7.94 (dd, J=5.3 & 9.4 Hz, 2H); 7.78 (s, 1H); 7.56 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 3.32 (in, 2H); 3.30 (s, 3H); 3.13 (s, 3H); 2.84 (d, J=4.7 Hz, 3H); 2.82 (q, J=7.1Hz, 2H); 1.24(t,J=7.1 Hz, 3H) (M+H)+ = 449 A <1 336. 2_(4-氟基-苯基)-5-甲氧基-6-(3-甲氧基 甲基-5-甲基-異噚唑 -4-基 > 苯并咬喃-3-羧酸-甲醯胺 *H NMR in CDC13: 7.87 (dd, J=7.0 and 5.1Hz, 2H); 7.41 (s, 1H); 7.40 (s, 1H); 7.20 (t, J=8.8Hz, 2H); 5.81 (brs, 1H); 4.45 (s, 2H); 3.86 (s, 3H); 3.30 (s, 3H); 3.00 (d, J=4.8Hz, 3H); 2.35 (s, 3H) (M+H)+ = 425 A <1 337. 5-乙基-6-[(2-氟基- 乙基)-曱fe續酿基-胺基]-2-(4-氟基-苯 基)苯并呋喃-3-羧酸 -甲醯胺 *H NMR in DMSO: 8.47 (m, 1H); 7.94 (dd, J=5.3 & 8.8Hz, 2H); 7.84 (s, 1H); 7.57 (s, 1H); 7.39 (t, J=8.8Hz, 2H); 4.65-4.25 (m, 2H, F-coupling); 3.98 (t, J=4.1Hz, 1H); 3.89 (t, J=4.1Hz, 1H); 3.14 (s, 3H); 2.84 (d, J=4.7Hz, 3H); 2.82 (q, J=7.6Hz, 2H) 1.24 (t, J=7.6Hz, 3H) (M+H)+ = 437 A <1 338. 2-(4-氟基-苯基)-6- (甲fe橫龜基-丙基-胺基)-5-丙氧基-苯 并呋喃-3身酸-曱 醯胺 lH NMR in DMSO: 8.40 (d, J=4.7Hz, iH); 7.90 (m, 2H); 7.56 (s, 1H); 7.36 (t, J=8.2Hz, 2H); 7.17 (s, 1H); 4.04 (t, J=6.5Hz, 2H); 3.53 (s, 2H); 2.99 (s, 3H); 2.82 (d, J=4.7Hz, 3H); i.80 (m, 2H); 1.39 (m, 2H); 1.02 (t, J=7.6Hz, 3H); 0.85 (t, J=4.1Hz, 3H) (M+H)+ = 463.1 A <1 339. 5-乙基-2-(4-氟基-苯 基)-6-(1-#呈基-1-甲 基-乙基)-苯并呋喃 -3-羧酸-甲醯胺 NMR in CDCl3: , 7.90 (m, 2H); 7.66 (s, IH); 7.65 (s, IH); 7.17 (m, 2H); 5.80 (brs, 1H); 3.08 (q, J=7.5Hz, 2H); 3.02 (d, J=4.8Hz, 3H); 1.73 (s, 6H); 1.33 (t, J=7.5Hz, 3H) (M+H)f = 356.1 A <1 340. 6-乙醯基-5-乙基 -2_(4-氟基-苯基)-苯 弁吱喃-3-羧酸-甲醯胺 咕 NMR in CDCb: 7.95 (m, 2H); 7.80 (s, iH); 7.69 (s, IH); 7.19 (m, 2H); 5.82 (brs, 1H); 3.01 (d, J=4.8Hz, 3H); 2.62 (s, 3H); 2.97 (q, J=7.5Hz, 2H); 1.22 (U=7.5Hz, 3H) (M+H)+ = 340.1 A <1 213- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICso(mM) A= /iM B= 0·5 to 彡5.0 μΜ C= 5.0 to <30 μΜ D= >30 複製子 〇iM) 341. 4-乱基-6-乙基胺基 -2-(4-氟基苯基)-5- 羥基·苯并呋喃-3-幾 酸-甲醯胺 NMR in DMSO: 9.82 (s, 1H); 8.38 (d, J=4.4 Hz, 1H); 7.88 (dd, J=8.8, 5.3 Hz, 2H); 7.35 (tT J=8.8 Hz, 2H); 6.89 (s, 1H); 4.48 (t, J=7.0 Hz, 1H); 3.37 (q, J=7.0 Hz, 2H); 2.80 (d, J=4.4 Hz, 3H); 1.07 (t, J=7.0 Hz, 3H) (M+H)+ = 363 B >100 342. 甲烷磺^4-氯基-6-乙基胺基-2-(4-氣基 -苯基)各甲基胺曱 酿基-苯并咬喃-5-基酉旨 NMR in DMSO: 8.42 (dT J=3.7 Hz, 1H); 7.90 (dd, J=8.8,5.3 Hz, 2H); 7.46 (s, 1H); 7.37 (t, J=8.8 HzT 2H); 4.96 (t, J=6.8 Hz, 1H); 3.48 (s, 3H); 3.39 (pent, J=7.0 Hz, 2H); 2.80 (d, J=3.7 Hz, 3H); 1.10(U=7-0 Hz, 2H) (M+H)+ = 441 A <10 343. 基-2-(4-氟基-苯 基)-6-(甲烷磺醯基-嘧唑-4-基甲基-胺 基]苯并咬喃-3 -複酸 -甲醯胺 lH NMR in DMSO: 9.06 (d, J = 1.8Hz, 1H); 8.43 (m, 1H); 7.91 (dd, J = 5.3 & 8.8 Hz, 2H); 7.59 (s, 1H); 7.45 (m, 2H); 7.38 (t, J = 8.8Hz, 2H); 5.01 (d, J = 4.9Hz, 1H); 4.83 (d, J = 4.9Hz, 1H); 3.14 (s, 3H); 2.81 (d, J = 4.7Hz, 3H); 2.65 (q, J = 7.6Hz, 2H); 1.24 (t, J = 7.6Hz, 3H) (M+H)+ = 488 A <1 344. 6-(5-環丙基-3-甲氧 甲基·異p号哇冰盖) (4_氟基-苯基)-5-甲氧苯并4喃-3-羧酸-甲醯胺 lH NMR in CDCb: 7.87 (dd, J=8.8 and 5.4Hz, 2H); 7.46 (s, 1H); 7.41 (s, 1H); 7.20 (apparent t, J=8.8 and 8.4Hz, 2H); 5.80 (brs, 1H); 4.44 (s, 2H); 3.87 (s, 3H); 3.28 (s, 3H); 3.00 (d, J=5.1Hz, 3H); 1.92 (m, 1H); 1.13 (m, 2H); 0.97 (m, 2H) (M+H)+ = 451 A <1 345. 6-(1-乙醯基-p比洛症 -3-基)-2-(4-氟基-苯 基)-5-甲氧基-苯并 呋喃-3-羧酸-甲醯胺 lH NMR in CDC13: 7.85 (m, 2H); 7.32 (m,lH); 7.25 (m, 3H); 5.77 (brs.lH); 3.92 (s,3H); 3.71-4.12 (m,2H); 3.32-3.70 (m,3H); 2.99 (d,J=4.8Hz,3H); 2.18-2.39 (m, 2H);2.10(s, 3H) (M+H)+ = 411 A <10 346. 5-(3,4-二氟基-苄氧 基)-2-(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基)-苯并呋喃 -3-羧酸-甲醯胺 *Η NMR in DMSO: 8.39 (d, J=4.4Hz, 1H); 7.91 (m, 2H); 7.70 (s, IH); 7.55-7.30 (m, 6H); 5.21 (s, 2H); 3.18 (s, 3H); 2.96 (s, 3H); 2.82 (mT 3H) (M+H)+ = 519.0 A <1 347. 5-(2-二氟曱氧基-苄 氧基)-2-(4-氟基-苯 基)-6-(甲烷磺醯基-甲基-胺基)-苯并呋 喃各羧酸-甲醯胺 lH NMR in CDCb: 7.86 (m, 2H); 7.57-7.42 (m, 3H); 7.31-7.20 (m, 5H); 6.63 (t, 1H, J=73.4Hz); 5.74 (brs, 1H); 5.24 (s, 2H); 3.28 (s, 3H); 2.99 (d, 3H, J=4.84Hz); 2.81 (s, 3H) (M+H)+ = 549 A <1 348. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲基-基)-5-丙氧基-苯 并呋喃各羧酸-曱 醯胺 'H NMR in DMSO: 8.39 (brd, 1H, J=5.86); 7.92 (m, 2H); 7.60 (s, 1H); 7.36 (t, 2H, J=8.79Hz); 7.18 (s, 1H); 4.04 (t, 2H, J=7.03); 3.20 (s, 3H); 3.02 (s, 3H); 2.82 (d, 3H, J=4.10Hz); 1.82 (m, 2H): 1.03 (t, 3H, J=7.03Hz) (M+H)+ = 435 A <1 214- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ICsoOiM) A= μΜ B= to ^5.0 μΜ C= 5.0 to <30 μΜ D= >30 μΜ 名稱 (μΜ) 349. 5-晞丙氧基-2-(4-氟 基-苯基)-6-(甲烷磺 醯基-甲基-胺基)-苯 并呋喃-3-羧酸-甲 醯胺 lU NMR in DMSO: 8.37 (brm, 1H); 7.92 (m, 2H); 7.63 (s, 1H); 7.36 (t, 2H, J=8.79Hz); 7.21 (s, 1H); 6.18-6.06 (m, 1H); 5.47 (m, 1H); 5.30 (m, 1H); 4.70 (d, 2H, J=4.69Hz); 3.20 (s, 3H); 3.02 (s, 3H); 2.82 (d, 3H, J=4.10Hz) (M+H)+ = 433 A <ι 350. 6-(5-乙氧甲基-異噚 峻-3-基)-2-(4-氣基-苯基)-5-甲氧基-苯 并呋喃-3-#复酸-甲 醯胺 lH NMR in CDC13: 8.03 (s, 1H); 7.87 (dd, J=5.28 & 8.79Hz, 2H); 7.45 (s; IH); 7.20 (ζ J=8.79Hz, 2H); 6.82 (s, 1H); 5.79 (bs, 1H); 4.64 (s, 2H); 3.96 (s, 3H); 3.65 (q, J=7.03Hz, 2H); 3.00 (d, J=4.84Hz, 3H); 1.276 (t,J=7.03, 6.59Hz, 3H) (Μ+ΗΓ = 425.21 A <1 351. 5-環丙甲氧基-2-(4-氟基-苯基)-6-(甲烷 續酿基-甲基-胺基)-苯并呋喃-3-羧酸-甲 醯胺 lH NMR in DMSO: 8.38 (d, J=4.4Hz, 1H); 7.92 (m, 2H); 7.60 (s, 1H); 7.38 (tt J=9.2Hz, 2H); 7.16 (s, 1H); 3.95 (d, l=7.0Hz, 2H); 3.25 (s, 3H); 3.08 (s, 3H); 2.83 (d, J=4.4Hz, 3H); 1.20 (m, 1H); 0.62 (d, J=7.0Hz, 2H); 0.39 (d, J=5.3Hzi 2H) (M+H)+ = 447 A <1 352. 5-(3,5-二甲氧基-苄 氧基)-2-(4-氟基-苯 基)-6-(甲烷磺醯基-甲基-胺基)-苯并呋 喃-3-¾酸-甲醯胺 'H NMR in DMSO: 8.39 (brd, 1H, J=4.69); 7.93 (ra, 2H); 7.71 (s, 1H); 7.38 (t, 2H, J=8.79); 7.31 (s, 1H); 6.72 (d, 2H, J=2.34); 6.46 (m, 1H); 5.17 (s, 2H); 3.75 (s, 6H); 3.22 (s, 3H); 3.00 (s, 3H); 2.83 (d, 3H, J=4.69Hz) · (M+H)+ = 543 A <i 353. 2-(4-氟基-苯基) -5-(4-甲烷磺醯基-苄氧基)-6-(甲燒續 醯基-甲基-胺基)-苯 并呋喃-3-叛酸-曱 醯胺 *H NMR in DMSO: 8.39 (brd, 1H, J=4.40Hz); 7.98-7.89 (m, 4H); 7.80 (dt 2H, J=8.4Hz); 7.7 i (s, 1H); 7.37 (m, 3H); 5.36 (s, 2H); 3.28 (s, 3H); 3.22 (s, 3H); 2.98 (s, 3H); 2.8 l(d, 3H, J=4.40Hz) (M-H)'= 559 A <1 354. 2-(4-氣基-冬基)-5_ 羥基-6-[甲烷磺醯基 -(2-氧基·丙基)-胺 基]-苯并呋喃-3-幾 酸·甲醯胺 lH NMR in CDCb: 8.15 (s, 1H); 7.93 (in, 2H); 7.39 (s, 1H); 7.15 (t, J=2.5Hz, 2H); 5.79 (s, 1H); 4.54 (s, IH); 4.49 (s, 1H); 334 (s, 3H); 3.24 (s, 1H); 3.19 (s, 1H); 1.79 (s,2H) (Μ+ΗΓ = 437.22 B <10 355. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲基-胺基)-5-[2-(4-甲氧 基-苯基)_2_氧基-乙 氧基]-苯并呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.36 (d, J=4.8Hz, lH); 8.04 (d, J=8.79Hz, 2H); 7.90 (m, 2H); 7.60 (s, 1H); 7.36 (t, J=8.79Hz, 2H); 7.28 (s, 1H); 7.08 (dt J=9.35Hz, 2H); 5.67 (s, 2H); 3.86 (s, 3H); 3.29 (s, 3H); 3.07 (s, 3H); 2.77 (d, J=4.41Hz, 3H) (Μ+ΗΓ = 541 A <1 215- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC5〇 〇tM) A= /iM B= 0〇 to ^5.0 μΜ C= 5.0 to ^30 μΜ D=>30 μΜ 複製子 (μΜ) 356. 5-(3·氰基-爷氧基) -2-(4-氣基-苯基)-6 -(甲烷磺醯基-甲基-胺基)·苯并呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.39 (brd, 1H, J=4.69Hz); 8.00 (s, 1H); 7-94- 7.81 (m, 3H); 7.72 (s, 1H); 7.64 (t, 2H, J=7.62Hz); 7.37 (t, 2H, J=8.79Hz); 7.30 (s, 1H); 5.29 (s, 2H); 3.19 (st 3H); 2.97 (s, 3H); 2.82 (d,3H, J=4.69Hz) (M-Η).= 506 A <1 357. 基-卞乳基) -2-(4-氟基-冬基)-6-(甲烷磺醯基-甲基-胺基)-苯并呋喃-3-羧酸-甲醯胺 'H NMR in DMSO: 8.37 (brd, 1H, J=4.84Hz); 7.90 (m, 4H); 7.72 (m, 3H); 7.37 (t, 2H, J=8.79Hz); 730 (s, 1H); 5.33 (s, 2H); 3.21 (s, 3H); 2.97 (s, 3H); 2.81(d, 3H, J=4.0Hz) (M+H)+ = 508 A <1 358. 2-(4-氣基-苯基)-5-甲氧基-6-(2H-[1,2,4]三唑-3-基)-苯 并呋喃-3-癸复酸-甲 醯胺 lHNMRinCDCl3: 8.49 (s, 1H); 8.05 (s, 1H); 7.86-7.91 (m, 2H); 7.58 (s, 1H); 7.20-7.26 (m, 2H); 5.82 (brs, 1H); 4.15 (s, 3H); 3.00-3.02 (d, 3H, J=5.28Hz) (M+H)+ = 366 GCMS A <1 359. 4-{2-[2-(4-氟基-苯 基)-6-(曱烷磺醯基-甲基-胺基)-3-甲基 胺甲醯基-苯并呋喃 -5-基氧基]-乙醯基 胺基卜芊酸乙酯 'H NMR in DMSO: 10.37 (s, 1H); 8.39 (brd, 1H, J=4.84Hz); 7.91 (m, 4H); 7.75 (d, 2H, J=8.35Hz); 7.70 (s, 1H); 7.37 (t, 2H, J=8.79Hz); 7.20 (s, 1H); 4.93 (s, 2H); 4.28 (q, 2H, J=7.03Hz); 3.28 (s, 3H); 3.14 (s, 3H); 2.78 (d, 3H, J=4.40Hz); 1.30 (t, 3H, J=7.03Hz) (M-Η)'= 596 A <10 360. 2-(4-氣基-苯基) -5-[2-(4-氟基-苯基) -2_氧基-乙氧基]-6- (甲烷磺醯基-甲基-胺基)-苯并呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.38 (brd, 1H, J=5.28Hz); 8.17 (m, 2H); 7.90 (m, 2H); 7.62 (s, 1H); 7.45-7.31 (m, 5H); 5.73 (s, 2H); 3.29 (s, 3H); 3.06 (s, 3H); 2.78 (d, 3H, J=4.69Hz) (M-H)·= 527 A <1 361. 6-(芊基-甲烷磺醯基 -胺基)-2-(4-氟基-苯 基)-5-異丙氧基-苯 并呋喃-3-幾SH-甲 醯胺 *H NMR in DMSO: 8.38 (brd, 1H, J=4.69Hz); 7.86 (m, 2H); 7.33 (t, 2Ht J=8.79Hz); 7.28-7.16 (m, 6H); 7.10 (s, 1H); 4.80 (brm, 3H); 3.11 (s, 3H); 2.79 (d, 3H, J=4.69Hz); 1.38 (d, 6H, J=5.86Hz) (M+H)+ = 511 A <1 362. 4-氯基-6-(乙基-甲 基-胺基)-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸-甲 醯胺 lH NMR in DMSO: 8.38 (d, J=4.4HzT 1H); 7.90 (m, 2H); 7.36 (t, J=8.4Hz, 2H); 7.05 (s, 1H); 3.86 (s, 3H); 3.09 (q, J=7.03Hz, 2H); 2.81 (d, J=4.4Hz, 3H); 2.75 (s, 3H); 0.93 (t, J=7.1Hz, 3¾ (Μ+ΗΓ = 391.0 A <10 363. 4-氯基-6-乙基胺^基 -2-(4-氟基-苯:^)-5-甲氧墓-苯并p夫喃-3.-羧酸-甲醯胺 lH NMR in DMSO: 8.34 (d, J=4.8Hz> 1H); 7.86 (m, 2H); 7.33 (t, J=9.2Hz, 2H); 6.99 (s, 1H); 4.67 (t, J=6.6Hz, 1H); 3.89 (s, 3H); 3.38 (q, J=7.04Hz, 2H); 2.80 (d, J=4.4Hz, 3H); 1.07 (t, J=7.0Hz, 3H) (M+H)+ = 377.0 A <1 216- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICse 〇iM) A= μΜ B= 0.5 to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 /iM 複製子 (μΜ) 364. 6-乙基胺基-2-(4-氣 基-苯基)-5-羥基-苯 并呋喃-3-羧酸-甲 醯胺 *H NMR in DMSO: 8.20 (d, J=4.7Hz, iH); 7.88 (dd, J=8.8, 5.3Hz, 2H); 7.29 (t, J=8.8Hz, 2H); 6.83 (s, 1H); 6.66 (s, 1H); 4.83 (t, J=5.0Hz, 1H); 3.11 (ra, 2H); 2.79 (d, J=4.7Hz, 3H); 1.19 (t, J=7.0Hz, 3H) * (M+H)+ = 329 B >30 365. 5_(3_溴基-丙氧基) -6- 6基胺基-2-(4-氟 基-苯基)-苯并呋喃 -3-羧酸-甲醯胺 lH NMR in DMSO: 8.30 (d, J=4.7Hz, 1H); 7.86 (dd, J=8.8, 5.3Hz, 2H); 7.30 (t, J=8.8Hz, 2H); 6.93 (s, 1H); 6.75 (s, 1H); 5.20 (t, J=5.0Hz, IH); 4.14 (t, J=4.8Hz, 2H); 3.78 (t, J=6.7Hz, 2H); 3.20 (m, 2H); 2.81 (d, J=4.7HzT 3H); 2.36 (m, 2H); 1.23 (t, J=7.0Hz, 3H) (M+H)+ = 499,451 A <1 366. 5-晞丙氧基-6-乙基 胺基-2-(4-氟基-苯 基)-苯并咬喃-3 -幾 酸·甲醯胺 'HNMR in DMSO: 8.20 (d, J=4.7Hz, 1H); 7.80 (dd, J=8.8, 5.3Hz, 2H); 7.31 (t, J=8.8Hz, 2H); 6.93 (s, 1H); 6.74 (s, 1H); 6.10 (m, 1H); 5.50 (m, 1H); 5.30 (m, 1H); 5.00 (t, J=5.0Hz, 1H); 4.60 (m, 2H); 3.18 (m, 2H); 2.80 (d, J=4.7Hz, 2H); 1.20 (t, J=7.0Hz, 3H) (M+H)+ = 369 A <1 367. 5-(3-乙氧基-丙氧 墓)-6-乙基胺基 -2-(4-氟基縣苯 并咬喃-3-叛酸-甲 醯胺 lH NMR in DMSO: 8.20 (d, J=4.4Hz, 1H); 7.80 (dd, J=8.8, 5.3Hz, 2H); 7.31 (t, J=8.8Hz, 2H); 6.90 (s7 1H); 6.72 (s,1H); 5.01 (U=5.7Hz,1H); 4.07 (ζ J=6.5Hz, 2H); 3.56 (U J=6.4Hz, 2H); 3.42 (q, J=7.0Hz,2H); 3.20 (m,2H); 2.80 (d,J=4.4Hz, 3H); 2.00 (t, J=6.5Hz, 2H); 1.20 (t, J=7.0Hz, 3H); 1.10(t, J=7.0Hz, 3H) (M+H)+ = 415 A <1 368. 2-[2-(4-亂基-苯基) -5-甲氧基-3-甲基胺 甲醯基-苯并呋喃-6-基]-吡咯淀小複酸 醯胺 *H NMR in CDC13: 7.83 (m, 2H); 7.15 (s, 1H); 7.14 (s, 1H); 7.10 (m, 2H); 5.76 (brs, 1H); 5.18 (d, J=8.353Hz, 1H); 4.25 (s, 2H); 3.93 (s, 3H); 3.72 (m, 2H); 2.99 (d, J=4.836Hz? 3H); 1.89 (m, 2H); 1.25 (s, 2H) (M+H)+ = 412 A <1 369. 2-(4-氣基-苯基)-6_ (甲烷磺醯基-甲基-胺基)-5-(2-氧基-丙 氧基)-苯并士南-3-羧酸-甲醯胺 NMR in DMSO: 8.38 (brd, 1H, J=4.69Hz); 7.90 (m, 2H); 7.62 (s, 1H); 7.36 a 2H, J=8.79Hz); 7.12 (s, iH); 4.97 (s, 2H); 3:24 (s, 3H); 3.04 (s, 3H); 2.81 (d, 3H, J=4.10Hz); 2.20 (s, 3H) (M-H)* = 447 A <1 370. 2-(4-氟基-苯基) -5-(2-羥基-丙氧基) -6-(甲烷磺醯基-甲 基-胺基)-苯并呋喃 -3-羧酸-曱醯胺 NMR ia DMSO: 8.41 (brd, 1H, J=4.69Hz); 7.94 (m, 2H); 7.60 (s, 1H); 7.38 (t, 2H, J=8.79Hz); 7.20 (s, 1H); 4.87 (d, 1H, J=4.69Hz); 4.06 (m, iH); 3.96 (m, 2H); 3.24 (s, 3H); 3.06 (s, 3H); 2.84 (d, 3H, J=4.69Hz); 1.22 (d, 3H, J=5.86) (M-H)'= 449 A <1 371. _2-(4—-氟基-苯基)各 (甲烷磺醯基-甲基-胺基)-5-(1·甲基 -1H-四吐-5-基甲氧 基)-苯并呋喃-3-羧 酸-甲醯胺 lH NMR ia DMSO: 8.44 (brd, iHt J=4.10Hz); 7.94 (in, 2H); 7.76 (s, 1H); 7.48 (s, 1H); 7.40 (t, 2H, J=8.79); 5.65 (s, 2H); 4.18 (s, 3H); 3.18(s, 3H); 3.02 (s, 3H); 2.86 (d, 3H, J=4.10Hz) (Μ+ΗΓ = 489 A <1 217- 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50 〇iM) A= μΜ 0*5 to 彡5.0 fiM C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 372. 2-(4_氟基-苯基) -6-(5-異丙氧基甲基 -異噚吐基)-5-甲 氧基-苯并呋喃-3-羧 酸-甲醯胺 lHNMR in CDC13: 7.96 (s, 1H); 7.85 (dd, J=5.28 & 8.79Hz, 2H); 7.40 (s, 1H); 7.18 (t, J=B.35& 8.79Hz, 2H); 6.78 (s, 1H); 5.98 (bs, 1H); 4.64 (s, 2H); 3.94 (s, 3H); 3.78 (septet, J=6.15Hz, 1H); 3.01 (d, J=4.83Hzt 3H); 1.25 (d, J=6.15Hz, 6H) (M+H)+ = 439 A <1 373. 5-(5-二乙基胺基 -[1,2,4]嘍二也 3-基 甲氧基)-2-(4-氟基-苯基>6-(甲烷磺醯 基-甲基-胺基)-苯并 呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 838 (brd, 1H, J=4.40Hz); 7.94 (m, 2H); 7.61 (s, 1H); 7.37 (m, 3H); 5.22 (s, 2H); 3.47 (brm, 4H); 3.28 (s, 3H); 3.08 (s, 3H); 2.84 (d, 3H, J=4.84Hz); 1.18 (t, 6H, J=7.03Hz) (M+H)+ = 562 A <1 374. 5-[5-(環丙基甲基-胺墓)-[1,2,外塞二峻 -3-基甲氧基]-2<4-氟基-苯基)-6-(甲烷 磺醯基-甲基-胺基 苯并呋喃-3-幾酸-甲 醯胺 lH NMR in DMSO: 8.60 (bnn, 1H); 838 (brd, 1H, J=4.10Hz); 7.94 (m, 2H); 7.61 (s, 1H); 7.38 (m, 3H); 5.19 (brs, 2H); 3.26 (s, 3H); 3.18 (ζ 2H7 J=5.86Hz); 3.07 (s, 3H); 2.84 (d, 3H, J=4.69Hz); 1.10 (m, 1H); 0.48 (m, 2H); 0.24 (m, 2H) (M+H)+ = 560 A <1 375. 6-(2-胺基小羥基-1-甲基-乙基)-2-(4-氟 基-苯基)-5-異丙氧 基-苯并咬喃-3-幾酸 甲醯胺 'H NMR in CDCl3: 7.85 (m, 2H); 7.71 (s, 1H); 7.19 (s, 1H); 7.16 (m, 2H); 6.35 (brs, 1H); 4.76 (in, 1H); 4.60 (brs, 2H); 3.48 (m, 2H); 2.99 (d, J=4.69 Hz, 3H); 1.47 (s, 3H); 1.40 (d, J=5.86 Hz, 3H); 1.37 (d, J=5.86 Hz, 3H) (M+H)" = 401.1 B <30 376. 6-(1-胺i小甲基-乙 基)-2-(4_氟基-苯基) -5-異丙氧基-苯并咬 喃各羧酸-甲醯胺 lH NMR in CDC13: 7.84 (ra, 2H); 7.49 (s, 1H); 7.37 (s, 1H); 7.26 (m, 2H); 5.74 (brs, 1H); 4.84 (septet, J=6.15 Hz, 1H); dd 4.53 (brs, 2H); 2.99 (d, J=2.64 Hz, 3H); 1.67 (s, 6H); 1.47 (d, J=6.16 Hzt 6H) (M+H)+ = 386 A <1 377. 2-[2-(4-氟基-苯基) -5-甲氧基各甲基胺 甲醯基-苯并呋喃-6-基]-ρ比洛淀-1 -讀_ fee-甲醯胺 Ή NMR in CDCI3: 7.85 (m, 2H); 734 (s, 1H); 7.30 (s, 1H); 7.18 (ra, 2H); 5.77 (s, 1H); 4.03 (d, J=4.39 Hz, 1H); 3.94 (s, 3H); 3.71 (m, 2H); 2.99 (d, J=1.32 Hz, 3H); 2.71 (d, J=1.32 Hz, 3H); 2.38 (ra, 1H); 1.86 (m,3H) (M+H)+ = 426 A <10 378. 6-(3,5-二甲基-異呤 峻冰基)_2_(4_氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸-乙 醯胺 lH NMR in DMSO: 8.53 (s, 1H); 7.94-7.99 (m, 2H); 7-61 (s, 1H); 7.37-7.43 (t, 2H, J=9.38Hz); 7.22 (s, 1H); 3.85 (s, 3H); 3.36-3.40 (t, 2H, J=5.86Hz); 2.31 (s, 3H); 2.12 (s, 3H); 1.16-1.20 (t, 3H, J=5.28Hz) (M+H)+ = 409 A <1 •218· 88828.doc 200418452 1實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 IC50 〇iM) A= μΜ B= 0*5 to 彡5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 379. 6-(3,5-二甲基-異嘮 唑斗基)-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸-異丙 醯胺 lHNMR inDMSO: 8.42-8.45 (dT 1H, J=8.21Hz); 7.93-7.98 (m, 2H); 7.59 (s, 1H); 7.37-7.42 (U 2H, J=8.79Hz); 7.18 (s, 1H); 4.18-4.24 (septet, 1H, J=7.03Hz); 3.83 (s, 3H); 2.30 (s, 3H); 2.11 (s, 3H); 1.19-1.21 (d, 6H, J=7.03Hz) (M+H)+ = 423 B >30 380. 二:甲基-異噚 唑_4-基)-2-(4-氟基-苯基)-5-甲氧基-苯 并呋喃-3-叛酸-環丙 醯胺 lH NMR in DMSO: 8.59-8.61 (d, 1H, J=4.10Hz); 7.90-7.94 (m, 2H); 7.95 (s, 1H); 7.36-7.42 (t, 2H, J=8.79Hz); 7.16 (s, 1H); 3.83 (s, 3H); 2.93-2.99 (m, 1H); 2.29 (s, 3H); 2.10 (s, 3H); 0.71-0.77 (m, 2H); 0.54-0.60 (m, 2H) (M+H)+ = 421 A <1 381. 2_(4-氣 ΐ-苯基)-5-異丙氧基-6-(5-^基 -2-氧基^号唑徒_5_ 基)-苯并吱喃-3-幾 酸-甲醯胺 *H NMR in CDC13: 7.85 (m, 2H); 7.77 (s, 1H); 7.35 (s, 1H); 7.19 (m, 2H); 5.74 (brs, 1H); 5.03 (brs, 1H); 4.76 (m, 1H); 3.78 (dd, J=2.2 & 8.4 Hz, 2H); 2.97 (d, J=5.2 Hz, 3H); 1.82 (s, 3H); 1.40 (d, J=5.2 Hz, 3H); 1.37 (d,J=5.2 Hz, 3H) (M+H)+ = 427.1 A <1 382. [2-(4-氟基-苯基)-6- (甲燒續醯基-甲基-胺基)-3-甲基胺甲醯 基-苯并呋喃-5-基氧 基]-乙酸第三-丁酯 lH NMR in DMSO: 8.38 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.63 (s, 1H); 738 (t, 2H, J=8.79Hz); 7.10 (s, 1H); 4.82 (s, 2H); 3.26 (s, 3H); 3.07 (s, 3H); 2.82 (d, 3H, J=4.69Hz); 1.46 (s, 9H) (M+ h2〇)+ =524 A <1 383. 2-(4-氣基-苯基)-5_ 甲氧基-6-(5-甲基 -2H-[1,2,4]三唑-3-基)-苯并17美喃-3-幾 酸-甲醯胺 *Η NMR in DMSO: 13.42 (s, 1H); 8.44-8.46 (d, 1H, J=4.69 Hz); 8.25 (s, 1H); 7.94-7.99 (m, 2H); 7.36-7.42 (t, 2H, J=8.79 Hz); 7.27 (s, 1H); 4.02 (s, 3H); 2.85-2.86 (d, 3H, J=4.69 Hz); 2.34 (s, 3H) (M+H)+ = 381 B <10 384. 6-(1-胺基-1-甲基-乙 基)-2-(4-氟基-苯基) -5-甲氧基-苯并呋喃 -3-羧酸-甲醯胺 lH NMR in CDCl3: 7.84 (m, 2H); 7.51 (s, 1H); 7.32 (s, 1H); 7.17 (1¾ 2H); 5.84 (brs, 1H); 3.95 (s, 3H); 2.97 (d, J=4.84Hz, 3H); 2.19 (brs, 2H); 1.59 (s, 6H) (M+H-NH2)+ = 340 B <30 385. 6-( 1 -乙酿基胺基小 甲基-乙基)冬(4-氟 基-苯基)-5-甲氧基-苯并呋喃-3-羧酸-甲 醯胺 ^ NMR in CDCI3: 7.84 (m, 2H); 7.52 (s, 1H); 7.31 (s, 1H); 7.15 (m, 2H); 6.03 (brs, 1H); 5.76 (brs, 1H); 3.92 (s, 3H); 2.96 (d, J=4.84Hz, 3H); 1.92 (s, 3H); 1.80 (s, 6H) (M+H-NHAc)+ = 340 A <1 386. [2-(4-氟i-苯基)各 (甲烷磺醯基-甲基-胺基)各甲基胺甲醯 基-苯并呋喃-5-基氧 基 > 乙酸 lH NMR in DMSO: 8.39 (brd, 1HT J=4.69Hz); 7.93 (m, 2H); 7.62 (s, 1H); 7.38 (t, 2H, J=8.79Hz); 7.17 (s, iH); 4.86 (s, 2H); 3.26 (s, 3H); 3.06 (s, 3H); 2.83 (d, 3H, J=4.69Hz) (M-H)* = 449 A <30 219- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= <0*5 /iM B= 0.5 to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μ,Μ. 複製子 (μΜ) 387. 6-(2,5-二甲基 _2H-[1,2,4]三唑-3-基)-2-(4-氟基-苯基) -5-甲氧基-苯并呋喃 -3-羧酸-甲醯胺 'H NMR in DMSO: 8.45-8.47 (d, 1H, J=4.69Hz); 7.93-7.98 (m, 2H); 7.69 (s,1H); 7.36-7.42 α 2H, J=8.79Hz); 7.29 (st 1H); 3.88 (s, 3H); 3.60 (s, 3H); 2.85-2.86 (d, 3H, J=4.10Hz); 2.28 (s, 3H) (M+H)+ = 395 B <10 388. _2-(4-氟基箱)-6: (曱燒續醯基-甲基_ 胺基)-5七塞吨基 甲氧基)-苯并呋喃 -3-羧酸-甲醯胺 lH NMR in DMSO: 8.40 (brrn, 1H); 7.95 (m, 2H); 7.89 (d, 1H, J=2.93Hz); 7.82 (d, 1H, J=2.93); 7.70 (s, 1H); 7.40 (m, 3H); 5.60 (s, 2H); 3.25 (s, 3H); 3.02 (s, 3H); 2.85 (d, 3H, J=4.69Hz) (M+H)+ = 490 A <1 389. 2-(4-氟基-苯基)-5· 甲氧基-6-(4-甲基 -2,5-二氧基-咪唑啶 -4-基)-苯并咬喃-3-羧酸-甲醯胺 lH NMR in DMSO: 10.59 (brs, 1H); 8.37 (m, 1H); 7.96 (s, 1H); 7.94 (m,2H); 7.71 (s,lH); 7.39 (m,2H); 7.15 (s,lH); 3.77 (s,3H); 2.82 (d, J=4.8Hz,3H); 1.71 (s,3H) (M+H)+ = 412 A <10 390. 2-(4-氟基-苯基) -6-(1-甲烷磺醯基胺 基-1 -甲基-乙基)-5-甲氧基-苯并呋喘-3-羧酸-甲醯胺 lH NMR in CDC13: 7.84 (m, 2H); 7.51 (s, 1H); 7.44 (s, 1H); 7.19 (m, 2H); 5.88 (s, 1H); 5.79 (brs, 1H); 4.00 (s, 3H); 2.98 (d, J=4.84 Hz, 3H); 2.52 (s, 3H); i.82 (s, 6H) (M+H- NH- S02Me)+ = 340 A <10 391. 5-(6-溴甲基-吡啶-2-基甲氧基)-6-[(6-溴 曱基-吡啶-2-基甲 基)-甲烷磺醯基-胺 基]-2-(4-氟基-苯基) -苯并呋喃-3-#复酸-曱醯胺 lH NMR in DMSO: 8.38 (d, J=4.8 Hz, 1H); 7.90 (rat 3H); 7.73 (t, J=7.1 Hz, 1H); 7.64 (s, 1H); 7.60 (d, J=7.5 Hz, 1H); 7.53 (d, J=7.5 Hz, 1H); 7.48 (d, J=7.5 Hz, 1H); 7.37 (m, 3H); 731 (s, 1H); 5.33 (s, 2H); 4.98 (s, 2H); 4.72 (s, 2H); 4.61 (s, 2H); 3.18 (s, 3H); 2.81 (d, J=4.8 Hz, 3H) (M+H)+ = 746 A <10 392. 2-[2-(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基)各甲基胺 甲醯基-苯并呋喃-5-基氧基甲基]-噻唑 -4-致酸乙酯 lH NMR in DMSO: 8.60 (s, 1H); 8.40 (brd, 1H, J=4.69Hz); 7.95 (m, 2H); 7.73 (s, 1H); 7.40 (m, 3H); 5.63 (s, 2H); 4.32 (q, 2H, J=7.03Hz); 3.27 (s, 3H); 3.06 (s, 3H); 2.84 (d, 3H, J=4.69Hz); 1.32 (t, 3H, J=7.03) (M+H)+ = 562 A <i 393. -2-[2-(4-氟基-苯基) -6-(甲烷磺醯基-甲 基-胺基)-3-甲基胺 曱醯基-苯并呋喃-5-基氧基_ 斗羧酸 lH NMR in DMSO: t 8.52 (s, 1H); 8.41 (brd, 1H, J=4.69Hz); 7.95 (m, 2H); 7.73 (s, 1H); 7.40 (ra, 3H); 5.61 (s, 2H); 3.26 (s, 3H); 3.06 (s, 3H); 2.85 (d, 3H, J=4.69Hz) (M-Η)'= 532 A >30 220- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ICso 〇iM) A= ^0.5 μΜ B= 03 to ^5.0 /iM C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 394. 6-二甲基胺基-2-(4-氟基-苯基)-5-甲氧 墓-苯并p夫喃-3-叛酸 _甲醯胺 *H NMR in CDC13: 7.85 (dd, J=8.8 & 5.3Hz, 2H); 7.26 (s, 1H); 7.17 (t, J=8.8Hz, 2H); 7.14 (s, 1H); 5.80 (brs, 1H); 3.96 (s, 3H); 2.98 (d, J=4.8Hz, 3H); 2.84 (s, 6H) (Μ+ΗΓ = 343 A <1 395. 5-氰甲氧基-2-(4-氟 基-苯基>6-(甲烷磺 酿基-甲基-胺基)-笨 并呋喃-3-瘦酸-甲 醯胺 lH NMR in DMSO: 8.44 (brd, 1H, J=4.10Hz); 7.93 (m, 2H); 7.77 (s, 1H); 7.41 (m, 3H); 5.32 (s, 2H); 3.22 (s, 3H); 3.08 (s, 3H); 2.84 (d, 3H, J=4.69Hz) (M+H)+ = 432; A <1 396. 2-(4-氣基-冬基)-6-(甲烷磺醯基-甲基-胺基)-5-(5-甲基-異 呤唑-3-基甲氧基)-苯并呋喃-3:羧酸-甲 酿胺 lH NMR in DMSO: 8.40 (brd, lHt J=4.69Hz); 7.95 (m, 2H); 7.68 (s, 1H); 7.38 (m, 3H); 6.40 (s, 1H); 5.30 (s, 2H); 3.21 (s, 3H); 3.00 (s, 3H); 2.84 (d, 3H, J=4.10Hz); 2.44 (s, 3H) (M+H)+ = 488 A <1 397. 5-(5-氯基-[1,2,3]嘧 二唑-4-基甲氧基) -12-(4-氣基-苯墓)各( 甲烷磺醯基-甲基-胺基)-苯并呋喃_3_ 羧酸-甲醯胺 lH NMR in DMSO: 8.46 (brd, 1H, J=4.l0Hz); 7.98 (m, 2H); 7.69 (s, 1H); 7.51 (s, 1H); 7.40 (t, 2H, J=8.79Hz); 5.66 (s, 2H); 3.17 (s, 3H); 2.95 (s, 3H); 2.87 (d, 3H, J=4.69Hz) (M+H)+ = 525 A <1 398. 2-(4-氟基-苯基)-6-(甲烷磺醯基-曱基-胺基>5-(1-甲基 -1H-咪峻-2-基甲氧 基)-苯并咬喃-3-幾 酸-甲醯胺 lH NMR in DMSO: 8.42 (brd, 1H, J=4.69); 7.98 (m, 2H); 7.70 (s, 1H); 7.52 (s, 1H); 7.39 (t, 2H, J=8.79); 7.21 (s, 1H); 6.91 (s, 1H); 5.27 (s, 2H); 3.74 (s, 3H); 3.15 (s, 3H); 2.94 (s, 3H); 2.87 (d, 3H, J=4.69Hz) (M+H)+ = 487 A <1 399. 5-(1-芊基-1H-咪唑 _2_基甲氧基)-2-(4-氟基-苯基)-6·(甲烷 磺醯基-甲基-胺基)-苯并呋喃-3-羧酸-甲 醯胺 *Η NMR in DMSO: 8.42 (brm, 1H); 7.95 (m» 2H); 7.68 (s, 1H); 7.51 (s, 1H); 7.42-7.20 (m, 8H); 7.00 (s, 1H); 5.38 (s, 2H); 5.25 (s, 2H); 3.04 (s, 3H); 2.91 (s, 3H); 2.86 (d, 3H, J=4.10Hz) (M+H)+ = 563 A 氺氺氺 400. 」-(2,4-二氟基-苯基) -6-(3,5-二甲基-異呤 峻_4_基)-5-甲氧基- 苯并呋喃各羧酸-甲 醯胺 lH NMR in DMSO: 8.10-8.12, (d, 1H, J=4.69Hz); 7.78-7.86 (q, 1H, J=6.45Hz); 7.61 (s, 1H); 7.4^-7.49 (ra, 1H); 7.33 (s, 1H); 7.27-7.32 (m, 1H); 3.85 (s, 3H); 2.77-2.78 (d, 3H, J=4.69Hz); 2.29 (s, 3H);2.10(s, 3H) (M+H)+ = 413 A 氺氺氺 221 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ICs« (/iM) A= μΜ B= 05 to <:5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 401. 6-(3,5-二甲基-異嘮 芒f基)_2_(4-氟基-丰基)-5十塞唑-4-基 甲氧斧)-苯并呋喃 -3-叛破-甲酿胺 lHNMR in DMSO: 9.13 (d, 1H, J=1.17 Hz); 8.41-8.43 (d, 1H, J=4.69 Hz); 7.94-7.99 (m, 2H); 7.64-7.65 (d, 1H, J=U7 Hz); 7.61 (s, 1H); 7.45 (s, 1H); 7.36-7.42 (t, 2H, J=8.79 Hz); 5.28 (s, 2H); 2.86-2.88 (d, 3H, J=4.69 Hz); 2.29 (s, 3H); 2.1 l(s, 3H) (M+H)+ = 478 A <1 402. 5-(ϋ 基-4H-[1,2,4] 三吨-3-基曱氧基) -2-(4-氟基-苯基)-6-( 甲烷磺醯基-甲基-胺基)-苯并p夫喃-3-羧酸-甲醯胺 lH NMR in DMSO: 11.94 (brs, 1H); 8.36 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.57 (s, 1H); 7.36 (m, 3H); 5.96 (brs, 2H); 5.01 (s, 2H); 3.19 (s, 3H); 2.99 (s, 3H); 2.83 (d, 3H, J=4.10Hz) (M+H)+ = 489 A <1 403. 5-(4-氯基甲基 -1H-吡咬-3-基甲氧 基)-2-(4-氟基:苯基) -6-(甲烷磺醯基-甲 基-胺基)-苯并唉喃 _3-羧酸-甲醯胺 ^NMRinDMSO: 8.44 (brd, 1H, J=4.69Hz); 7.96 (m, 3H); 7.62 (s, 1H); 7.47 (s, 1H); 7.38 (t, 2H, J=8.79Hz); 5.16 (s, 2H); 3.84 (s, 3H); 3.16 (s, 3H); 2.93 (s, 3H); 2.86 (d, 3H, J=4.69Hz) (M+H)+ = 521 A <1 404. 2-(4-氣基-苯基)-6-(甲烷磺醯基-甲基-無基)-5-(2-p比峻-1-基乙氧基)-苯并呋 喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.42 (brm, 1H); 7.97-7.90 (m, 3H); 7.56 (s, 1H); 7.47 (s, 1H); 7.38 (t, 2H, J=8.79); 7.23 (s, 1H); 6.27 (m, 1H); 4.60 (brm, 2H); 4.54 (brm, 2H); 2.99 (s, 3H); 2.84 (m, 6H) (M+H)+ = 487 A <1 405. _ 2-(4-氟基-苯基) -5-(1Η-咪嗤-2-基甲 氧基)-6-(甲燒績酿 基-甲基-胺基)-苯并 呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 12.24 (brs, 1H); 8.41 (brd, 1H, J=4.10Hz); 7.95 (m, 2H); 7.63 (s, IH); 7.47 (s, 1H); 7.39 (t, 2H, J=8.79Hz); 7.19 (s, 1H); 6.95 (s, 1H); 5.20 (s, 2H); 3:16 (s, 3H); 2.91 (s, 3H); 2.86 (d? 3H, J=4.69Hz) (M+H)+ = 473 A <1 406. 6-(2,5-二氧基-咪^坐 淀-4-基)-2-(4-氣基-苯基)-5-甲氧基-苯 并呋喃-3-羧酸-甲 醯胺 lH NMR in DMSO: 8.38 (m, 1H); 8.08 (s, 1H); 7.93 (m,2H); 7.56 (s,lH); 7.34 (m, 2H); 7.15 (s,lH); 5.29 (s,lH); 3.90 (s,lH); 3.80 (s?3H); 2.82 (d, J=3.6Hz,3H) (M+H)+ = 398 B <10 407. 5-ά5-二甲基-異呤 吨冬基)-2-(4-氟基-苯基)-6-甲烷磺醯基 胺基•苯并咬喃-3-幾 酸-甲醯胺 … ——j - —— *Η NMR in DMSO: , 9.18 (bs, 1H); 8.37 (d, J=2.20Hz, 1H); 7.98-7.93 (m, 2H); 7.72 (s, 1H); 7.41-7.34 (m, 3H); 3.01 (s, 3H); 2.79 (dt J=4.84Hz, 3H); 2.22 (s, 3H); 2.04 (s, 3H) (M-H)·= 456.0 <10 222 - 88828.doc 200418452 實例 編號 名稱 NMR data Mass Spec HCV pol -BB7 ICs〇 〇iM) A= μΜ B= 0 J to ^5.0 |tM C= 5.0 to <30 /iM D= >30 μΜ 複製子 _) 408. 2-(4-氟基-苯基)-6-(甲烷磺醯基-甲基-胺基)-5-(1-嘧唑-2-基-乙氧基)-苯并呋 喃-3-羧酸-曱醯胺 lH NMR in DMSO: 8.33 (brd, IH, J=4.10); 7.92 (m, 2H); 7.84 (d, 1H, J=2.93Hz); 7.75 (d, 1H, J=2.93); 7.66 (s, 1H); 7.38 (t, 2H, J=8.79Hz); 7.30 (s, 1H); 6.03 (q, 1H, J=6.45Hz); 3.26 (s, 3H); 3.09 (s, 3H); 2.82 (d, 3H, J=4.69Hz); 1.76 (d, 3H, J=6.45) (M+H)+ = 504 氺氺氺 <1 409. 6-(3,5-二甲基-異哼 唑_4_基)-2-(4-氟基-苯基)-5-(5-甲基-異 呤峻-3-基甲氧基)-苯并呋喃-3-羧酸-曱 醯胺 lH NMR ia DMSO: 8.41 (brd, iHt J=4.69); 7.95 (m, 2H); 7.62 (s, 1H); 7.40 (m, 3H); 6.16 (s, 1H); 5.20 (s, 2H); 2.86 (d, 3H, J=4.69Hz); 2.41 (s, 3H); 2.28 (s, 3H);2.i0(s, 3H) (M+H)+ = 476 A <1 410. 6-(3,5-二甲基-異吟 u坐-4-基)-2-(4-乳基-苯基>5-(嘧峻-2-基 甲氧基)-苯并呋喃 -3-羧酸-甲酿胺 lH NMR ia DMSO: 8.41 (brd, 1H, J=4.10Hz); 7.95 (m, 2H); 7.83 (d, 1H, J=2.34Hz); 7.75 (d, 1H, J=2.93Hz); 7.64 (s, 1H); 7.46 (s, IH); 7.38 (t, 2H, J=8.79Hz); 5.49 (s, 2H); 2.86 (d, 3H, J=4.10Hz); 2.30 (s, 3H); 2.12 (s, 3H) (M+H)+ = 478 A <1 411. 6-乙醯基-2-(4-氟基-苯基)-苯并呋喃-3-羧酸-甲醯胺 lH NMR in CD3〇D: 8.22 (in, 1H); 7.98 (m, 3H); 7.76 (m, 1H); 7.27 (m, 2H); 2.96 (s, 3H); 2.67 (s, 3H) (M+H)+ = 312 B 氺氺本 412. 2-(4_氟基-苯基) -5-(2-羥基-2-甲基-丙氧基)-6-(甲貌續 酿基-甲基-無基)-苯 并吱喃-3-幾酸-甲 醯胺 lH NMR in DMSO: 8.41 (brra, 1H); 7.94 (m, 2H); 7.64 (s, 1H); 7.38 (t, 2H, J=8.79Hz); 7.20 (s, 1H); 4.61 (s, IH); 3.86 (s, 2H); 3.24 (s, 3H); 3.08 (s, 3H); 2.83 (d, 3H, J=4.69Hz); 1.28 (s, 6H) (M-Η)'= 463 A *氺氺 413. 5-二乙基甲醯基 甲氧基-2-(4-氟基-苯墓)-6-( _燒續驢 基-甲基-胺基)-苯并 咬喃-3-致酸-甲酿胺 lH NMR in DMSO: 8.42 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.60 (s, iH); 7.38 (t, 2H, J=8.79Hz); 7.10 (s, 1H); 4.98 (s, 2H); 3.36 (m, 4H); 3.27 (s, 3H); 3.09 (s, 3H); 2.81 (d, 3H, J=4.69Hz); 1.21 (t, 3H, J=7.03Hz); 1.06 (t, 3H, J=7.03) (M+H)+ = 506 A 氺氺氺 414. 6二(3,5-二甲基-異口号 唑冬基)_5-乙氧基 _2-(4_氟基-冬ί·)-丰 并呋喃-3-#复酸-甲 醯胺 lH NMR in DMSO: 8.41-8.42 (d, 1H, J=4.69 Hz); 7.92-7.97 (m, 2H); 7.58 (s, 1H); 7.35-7.41 (t, 2H, J=8.79 Hz); 7.21 (s, 1H); 4.05-4.12 (q, 2H, J=7.03 Hz); 2.84-2.85 (d, 3H, J=4.69 Hz); 2.30 (s, 3H); 2.12 (s, 3H); 1.27-1.32 (t, 3H, J=7.03 Hz) ' (M+H)+ = 409.0 A 氺氺氺 415. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲基-胺基>5-(嘧唑-2-基 胺甲醯基甲氧基)-苯并呋喃-3-羧酸-甲 醯胺 lH NMR in DMSO: 12.30 (brs, 1H); 8.41 (brd, 1H, J=4.69Hz); 7.92 (m, 2H); 7.67 (s, 1H); 7.51 (d, 1H, J=3.52Hz); 7.38 (t, 2H, J=8.79Hz); 7.27 (d, 1H, J=3.52Hz); 7.18 (s, 1H); 5.06 (s, 2H); 3.12 (m, 6H); 2.79 (d, 3H, J=4.69Hz) (M-H)' = 531 A <1 223 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A= ^〇J5 μΜ B= to ^5.0 μΜ C= 5.0 to ^30 μΜ D= >30 μΜ 複製子 (μΜ) 416. 氣基-苯基)-6_ (甲烷磺醯基-甲基-胺基)-5-([ 1,3,外塞二 唑-2-基胺甲醯基甲 氧基)-苯并呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 12.81 (brs, 1H); 9.22 (s, 1H); 8.42 (brm, 1H); 7.92 (m, 2H); 7.67 (s, 1H); 7.39 (t, 2H, J=8.79Hz); 7.18 (s, 1H); 5.12 (s, 2H); 3.17 (s, 3H); 3.10 (s, 3H); 2.79 (d, 3H, J=4.10Hz) (M-H)* = 532 A <1 417. 5-[(4,5-二甲基-噻唑 -2-基胺甲醯基)-甲 氧基]-2-(4-氟基-苯 基)各(甲烷磺醯基-甲基-胺基)-苯并呋 喃-3-複酸-甲醯胺 *H NMR ifl DMSO: 12.05 (brs, 1H); 8.41 (brd, 1H, J=4.10Hz); 7.92 (m, 2H); 7.66 (s, 1H); 7.39 (t, 2H, J=8.79Hz); 7.16 (s, 1H); 5.00 (s, 2H); 3.28 (s, 3H); 3.10 (s, 3H); 2.80 (d, 3H, J=4.10Hz); 2.24 (s, 3H);2.17(s, 3H) (M+H)+ = 561 A <1 418. 5-¾丙基-2-(4-氣基_ 苯基)_6_甲烷磺醯基 胺基-苯并咬喃-3-複 酸-甲醯胺- lH NMR in DMSO: 9.32 (bs, 1H); 8.36 (m, 1H); 7.94 (dd, J=5.3 & 8.8Hz, 2H); 7.58 (s, 1H); 7.36 (t, J=8.8Hz, 2H); 7.14 (s, 1H); 3.03 (s, 3H); 2.83 (d, J=4.6Hz, 3H); 2.31 (m, 1H); 1.00 (m, 2H); 0.68 (m, 2H) (M+H)+ = 403 A <1 419. 5-[2-(4-氰基-六氫口比 淀-i _基)-乙氧基] -6-(3,5-二甲基-異p咢 口坐-4-基)-2-(4-氣基-冬基)-冬并咬喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.41-8.43 (d, 1H, J=4.69Hz); 7.93-7.97 (m, 2H); 7.58 (sT 1H); 7.35-7.41 (t, 2H, J=8.79Hz); 7.26 (s,1H); 4.084.12 (t,2H, J=5.86Hz); 2.85-2.86 (d, 3H, J=4.69Hz); 2.82-2.86 (m, 1H); 2.63-2.66 (ζ 2H, J=5.86Hz); 2.50-2.55 (m, 3H); 2.31 (s, 3H); 2.26-2.31 (m, 1H); 2.14 (s, 3H); 1.77-1.84 (m, 2H); 1.63-1.70 (m, 2H) (M+H)+ = 517.1 A <1 420. 2-(4- 甲烷磺醯基-胺基-5-噻吩-2-基-苯并呋喃 -3-羧酸-甲醯胺 lH NMR in DMSO: 9.29 (sf 1H); 8.48 (d, J=4.84Hz, 1H); 8.02-7.97 (m, 2H); 7.75 (s, 1H); 7.97 (s, 1H); 7.64 (d, J=5.27Hz, 1H); 7.45-7.37 (m, 3H); 7.19-7.16 (m, 1H); 2.94 (s, 3H); 2.84 (d, J=4.40Hz, 3H) (M-H)'= 443 A <1 421. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲基-胺基)-5-甲基胺甲醯 基甲氧基-苯并呋喃 -3-羧酸-甲醯胺 'H NMR in DMSO: 8.40 (brd, 1H, J=4.69Hz); 7.93 (m, 3H); 7.70 (s, 1H); 7.39 (t, 2H, J=8.79Hz); 7.16 (s, 1H); 4.66 (s, 2H); 3.25 (s, 3H); 3.13 (s, 3H); 2.83 (d, 3H, J=4.69Hz); 2.68 (d, 3H, J=4.69Hz) (M+H)+ = 464 A <1 422. 2_(4_氟基-苯基) -5-(1-羥甲基-環丙 基甲氧基)-6-[(1-經 甲基-¾•丙基甲基)-甲烷磺醯基-胺基]-苯并呋喃-3-¾酸-甲 酿胺 lH NMR in DMSO: 8.53 (d, J=4.8H2, iH); 8.07 (dd, J=8.8, 5.3Hz, 2H); 7.72 (s, 2H); 7.52 (t, J=8.8Hz, 2H); 4.50 (brd, 1H); 4.15 (t, J=9.3Hz, 1H);14.07 (d, J=9.9Hz, 1H); 3.60 (m, 2H); 3.50 (m, 1H); 3.30 (d, J=11.0Hz, 1H); 3.17 (s, 3H); 2.94 (d, J=4.8Hz, 3H); 0.75 (s, 4H) (M-H)'= 545 B <10 224- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ICse 〇iM) A= /iM B= 03 to ^5.0 /iM C= 5.0 to ^30 μΜ D= >30 /iM 複製子l _) 423. 6-二乙基胺基-5-乙 甲氧基-2-(4-氟基-苯基)-苯并呋喃-3-羧酸-甲醯胺 lHNMRinCIX:l3: 7.85 (dd, J=8.8T 5.3Hz, 2H); 7.30 (s, 1H); 7.77 (t, J=8.8Hz, 2H); 6.67 (st 1H); 5.75 (brs, 1H); 4.10 (q, J=7.0Hz, 2H); 3.20 (q, J=7.0Hz, 4H); 1.40 (t, J=7.0Hzt 6H); 1.30 (t, J=7.0Hz, 3H) (M+H)+ = 385 A <1 424. 5-胺甲醯基甲氧基 -2-(4-轨基-苯基)-6- (甲烷磺醯基-甲基-胺基)-苯并呋喃各 羧酸-甲醯胺 'HNMR in DMSO: 8.41 (brd, 1H, J=4.69Hz); 7.93 (m, 2H); 7.72 (s, 1H); 7.40 (m, 4H); 7.15 (s, 1H); 4.64 (s, 2H); 3.26 (s, 3H); 3.13 (s, 3H); 2.84 (d, 3H, J=4.69Hz) (M-H)- = 448 A <1 425. 5-[2-(3,5-二甲基4匕 唑-1-基)-乙氧基] -2-(4-氣墓-冬基)-6- (甲烷磺醯基-甲基-胺基)-苯并呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.41 (brd, 1H, J=4.69Hz); 7.94 (m, 2H); 7.60 (sy 1H); 7.38 (ζ 2H, J=8.79Hz); 7.22 (st 1H); 5.81 (s, 1H); 4.44 (brd, 2H, J=4.69Hz); 4.40 (brd, 2H, J=4.69Hz); 3.06 (s, 3H); 2.89 (s, 3H); 2.84 (d, 3H, J=4.69Hz); 2.28 (s, 3H); 2.08 (s, 3H) (M+H)+ = 515 A <1 426. 2-(4-氟基-苯基)-5-吱喃-2-基-6-甲燒橫 醯基胺基-苯并呋喃 各羧酸-甲醯胺 lH NMR in DMSO: 9.34 (s, 1H); 8.50 (d, J=4.40Hz, 2H); 7.99-7.96 (m, 2H); 7.91 (st 1H); 7.82 (s, 1H); 7.74 (s, 1H); 7.40 (t, J=8.79Hz> 2H); 7.09 (d, J=3.52Hz, 1H); 6.65 (s, 1H); 3.04 (s, 3H); 2.85 (d, J=4.40Hz, 3H) (M-H)* = 427.0 A <1 427. 6-(3,5-二甲基-異噚 唑-4.-2-(4-氟基-苯基)-5-(1-甲基 -1H-四吐-5-基甲氧 基)-苯并咬喃-3 -叛 酸-甲醯胺 *H NMR in DMSO: 8.44-8.45 (d, 1H, J=4.69Hz); 7.93-7.97 (m, 2H); 7.63 (s, 1H); 7.53 (s, 1H); 7.36-7.42 (t, 2Ht J=8.79Hz); 5.56 (s, 2H); 3.93 (s, 3H); 2.86-2.88 (dt 3H, J=4.69Hz); 2.24 (s, 3H); 2.07 (s,3H) (M+H)+ = 477 A <1 428. ^ 5-環丙基甲氧基 -6-(3,5-二曱基-異崎 唑_4_基)-2-(4-氟基- 苯基)-苯并呋喃-3-羧酸-甲醯胺 lH NMRinDMSO: 8.39-8.41 (d, 1H, J=4.69Hz); 7.91-7.96 (m, 2H); 7.58 (st 1H); 7.35-7.41 (ζ 2H, J=8.79Hz); 7.18 (s, 1H); 3.86-3.88 (d, 2H, J=7.03Hz); 2.83-2.85 (d, 3H, J=4.69Hz); 2.32 (s, 3H); 2.15 (s, 3H); 1.12-1.20 (ra, 1H); 0.51-0.57 (m, 2H); 0.26-0.3 l(m, 2H) (M+H)+ = 435 A <1 429. 6-(3;二甲基-異崎 唑斗基)-5-(3,5-二 甲基-異呤吐-4-基甲 氧基)-2-(4-氣基-丰 基)-本并咬喃-3 -致 酸-甲醯胺 'H NMRinDMSO: 8.43-8.45 (d, 1H, J=4.69Hz); 7.92-7.96 (m, 2H); 7.59 (s, 1H); 7.44 (s, 1H); 7.36-7.41 (t, 2H, J=8.79Hz); 4.97 (s, 2H); 2.86-2.87 (d, 3H, J=4.69Hz); 2.28 (s, 3H); 2.2i (s, 3H); 2.03 (s, 3H); 1.97 (s, 3H) X (M+H)+ = 490 A <1 430. 2-(4-氟基-苯基)-5_ 甲氧基-6-(5-甲基 _队3,4?咢二唑-2-基) -苯并呋喃-3-羧酸-甲醢胺 lHNMRinCDCl3: 8.05 (s, 1H); 7.92-7.87 (m, 2H); 7.52 (s, 1H); 7.27-7.23 (mt 2H); 5.80 (s, 1H); 4.03 (s, 3H); 3.02 (d, J=4.5 Hz, 3H); 2.65 (s, 3H) (M+H)+ = 381 A <10 225 - 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 ICsoOtM) A= μΜ 03 to ^5.0 μΜ. C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 431. 6-(3-氰基-4-羥基-2-氧基-2,5-二氫-吡咯 小基甲基)-2-(4-氟 基-苯基)-5-甲氧基-苯并吡喃-3-幾酸-甲 醯胺 lHNMRinDMSO: 8.36-8.34 (m, 1H); 7.94-7.89 (m, 2H); 7.36-7.28 (ra, 3H); 7.10 (s, 1H); 4.47 (sr.2H); 3.85 (s, 2H);2.81(d,J=4.2 Hz, 3H) (M+H)+ = 436 A *氺氺 432. 4-氣基-6-[乙基-(2_ 甲氧基-乙酿基)-胺 基]-2-(4-氟基-苯至) -5-甲氧基-苯并吱喃 -3-幾酸-甲酿胺 lHNMRinCDCl3: 7.90 (ddt J=8.3,5.3Hz, 2H); 7.40 (s, 1H); 7.20 (t, J=8.3Hz, 2H); 5.90 (brs, 1H); 3.91 (s, 3H); 3.80-3.70 (m, 2H); 3.62 (s, 2H); 3.30 (s, 3H); 2·98 (汰 J=4.4Hz, 3H); 1.10 (t, J=7.0Hz, 3H) (M+H)+ = 343 B <10 433. 6-(3>二—甲基-異呤 α坐_4_基)-2-(4-氣基-苯基)-5-(2-嗎福啉 斗基乙氧基)-苯并 呋喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.41-8.42 (d, 1H, J=4.69Hz); 7.93-7.97 (m, 2H); 7^8 (s, 1H); 7.35-7.41 (t, 2H, J=8.79Hz); 7.26 (s, 1H); 4.11-4.14 (t, 2H, J=5.28Hz); 3.52-3.55 (t, 4H, J=4.10Hz); 2.84-2.86 (d, 3H, J-4.69HZ); 2.61-2.65 (t, 2H, J=5.86Hz); 2.36-2.40 (t, 4H, J=4.10Hz); 2.31 (s, 3H); 2.15 (s, 3H) (M+H)+ = 494 A 氺氺氺 434. 6-(3,5-二甲基-異呤 峻-4-基)-2-(4-氣基-苯基)-5-(3-六氫吡 淀-1 -基-為氧基)-苯 并呋喃-3-幾酸-甲 醯胺 'H NMR ia DMSO: 8.42-8.44 (d, 1H, J=4.69Hz); 7.92-7.97 (m, 2H); 7.58 (s, 1H); 7.35-7.41 (t, 2H, J=8.79Hz); 7.22 (s, 1H); 4.01-4.06 (t, 2H, J=6.45Hz); 2.84-2.85 (d, 3H, J=4.69Hz); 2.28 (s, 3H); 2.25-2.28 (m, 4H); 2.11 (s, 3H); 1.91 (s, 2H); 1.75-1.84 (in, 2H); 1.36-1.48 (m, 4H); 0.84-0.86 (m, 2H) (M+H)+ = 506.1 B 氺氺氺 435. 2-(4·氣基-苯基)_5_ (嘧唑4-基甲氧基)-苯并呋喃-3-幾酸-甲 醯胺 lH NMR in DMSO: 9.12 (s, 1H); 8.34 (d, J=4.0 Hz, 1H); 7.92 (m, 2H); 7.79 (s, 1H); 7.57 (d, J=8.8 Hz, 1H); 7.34 (t, J=8.3Hz, 2H); 7.23 (s, 1H); 7.07(ra, 1H); 5.25 (s, 2H); 2.82(d, J=3.5Hz, 3H) (M+H)+ = 383.0 B >30 436. ^2-(4-氣基-笨基) -6<2-羥基-乙醯基) -5-甲氧基-苯并呋喃 -3-羧酸-甲醯胺 'H NMR in CDC13: 8.20 (s, 1H); 7.87 (m, 2H); 7.45 (s, 1H); 7.22 (m, 2H); 5.77 (brs, 1H); 4.82 (s, 2H); 4.01 (s, 3H); 3.75 (brs, 1H); 3.00 (dt J=4.8 Hz, 3H) (M+H)+ = 358.1 A <10 437. 5-環丙基-2-(4-氣基-苯基)-6-(甲燒橫St 基-曱基-胺基)-苯并 吱喃-3-叛酸-曱醯胺 lH NMR in DMSO: 8.39 (d, J=4.40Hz, 1H); 7.95-7.90 (m, 2H); 7.81 (s, 1H); 7.39-7.33 (m, 2H); 7.13 (s, 1H); 3.22 (s, 3H); 3.14 (s, 3H); 2.82 (d, J=4.40Hz, 3H); 2.33-2.24 (m, 1H); 0.96 (d, J=8.35Hz, 2H); 0.79-0.63 (mt 2H) (M+H)+ = 417 A <1 438. 2-(4-氟基-苯基)_5_ 羥基-6-[(2-羥基-丙 基)-甲fe績sS基-胺· 基]-本并咬喃_3_複 酸-甲醯胺 lH NMR in DMSO: 9.97 (s, 1H); 8.40 (brd, 1H, J=4.10Hz); 7.92 (m, 2H); 7.55 (s, 1H); 7.35 (t, 2H, J=8.79Hz); 7.09 (s, 1H); 4.72 (brs, 1H); 3.58-3.40 (m, 3H); 3.01 (s, 3H); 2.80 (d, 3H, J=4.69Hz); 1.03 (d, 3H, J=5.86Hz) (M-H)- = 435 A 氺氺氺 -226- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 Κ^(μΜ) A= ^0.5 μΜ B= 05 to ^5.0 μΜ C= 5.0 to ^30 D= >30 μΜ 複製子 (μΜ) 439. 2-(4-氟基-苯基) _6-[(2-喪基-丙基)_ 甲烷磺醯基-胺基J -5-甲氧基-苯并呋喃 -3-羧酸-甲醯胺 ^HNMRinDMSO: 8.41 (brd, 1H, J=5.28Hz); 7.92 (m, 2H); 7.66 (s, 1H); 7.36 (t, 2H, J=8.79Hz); 7.18 (s, 1H); 4.66 (brs, 1H); 3.89 (s, 3H); 3.56 (bnn, 3H); 3.00 (s, 3H); 2.82 (d, 3H, J=4.69Hz); 1.03 (d, 3H, J=5.28Hz) (M-H)* = 449 A 氺氺氺 440. 6-〇乙醯基4比洛淀 -2-基)-5-乙基-2-(4- 氟基-苯基 > 苯并呋 喃各羧酸-甲醯胺 lHNMRinCDCl3: (mixture of two enantiomers) 7.90 (m, 2H); 7.68 (s, 1H); 7.21 (s, 1H); 7.15 (m, 2H); 5.80 (brs, 1H); 5.20 (dd, J=2.1Hz, J=8.4Hz, 1H); 3.85 (m, 1H); 3.65 (m, 1H); 3.20-3.40 (1H); 3.01 (d, J=5.2Hz, 3H); 2.70-2.90, 2H); 2.30-2 JO, 1H); 1.80-2.10, 2H); 1.82 (s, 3H); 1.34(t, J=7.5Hz, 3H) (M+H)+ = 409.1 A 氺氺氺 441. 2_(4_·氣基-苯基)-6_ 甲烷磺醯基胺基-5-(四氫-呋喃基)-苯 并呋喃-3-羧酸-甲 醯胺 lHNMRinDMSO: 9.15 (s, 1H); 8.44 (d, J=4.40Hz, 1H); 7.94-7.89 (m, 2H); 7.62 (d, J=4.40Hz, 2H); 7.39-7.34 (m, 2H); 5.21 (t, J=7.47Hzt 1H); 4.06-4.03 (m, 1H); 3.82-3.80 (m, 1H); 3.08 (s, 3H); 2.82 (d, J=4.40Hz, 3H); 2.45-2.41 (m, 1H); 1.98-1.94 (m, 2H); 1.65 (m, 1H) (M-H).= 431.0 A <1 442. 2-(4-氣基-苯基)-5_ 甲氧基-6-(四氫-吱 喃-3-基)-苯并咬喃 -3-羧酸-甲醯胺 lHNMRinDMSO: 8.34-8.36 (d, 1H, J=4.69Hz); 7.90-7.95 (m, 2H); 7.53 (s, 1H); 7.33-7.39 (t, 2H, J=8.79Hz); 7.10 (s, 1H); 4.00-4.06 (t, 1H, J=7.62Hz); 3.90-3,97 (m, 1H); 3.89 (s, 3H); 3.68-3.85 (m, 2H); 3.56-3.61 (t, 1H, J=7.62Hz); 2.83-2.84 (d, 3H, J=4.69Hz); 2.21-2.31 (m, 1H); 1.95-2.06 (m, 1H) (M+H)+ = 370.0 A <1 443. 2-(4-氟基-苯基)-6- (甲烷磺醯基-甲氧 甲基-胺基)-5-丙氧 基-苯并呋喃-3-羧酸 _曱醯胺 'HNMR in DMSO: 8.40 (d, J=4.2Hz, 1H); 7.94 (dd, J=8.8, 5.3Hz, 2H); 7.65 (s, 1H); 7.36 (t, J=8.8Hz, 2H); 7.19 (s, 1H); 5.94 (brs, 2H); 4.03 (t, J=7.0Hz, 2H); 3.32 (s, 3H); 3.08 (s, 3H); 2.81 (d, J=4.2Hz, 3H); 1.80 (sextet, J=7.0Hzt 2H); 1.01 (t, J=7.0Hz, 3H) (M+H)+ = 465 A <1 444. 2-(4-氣基-苯基)-5-羥基-6-(甲烷磺醯基 -甲氧甲基-胺基)-苯 并呋喃各羧酸-甲 醯胺 lHNMRia DMSO: 10.08 (s, 1H); 8.40 (d, J=4.4Hz, 1H); 7.92 (dd, J=8.8, 5.7Hz, 2H); 7.53 (s, 1H); 7.35 (t, J=8.8Hz, 2H); 7.12 (s, 1H); 4.92 (brs, 2H); 3.31 (s, 3H); 3.08 (s, 3H); 2.80 (d, J=4.8Hz, 3H) (M-H)'= 421 A <10 445. 2_(4·氣基·"苯基)-6_ 甲烷磺醯基胺基-5-丙氧基-苯并咬喃-3-羧酸-甲醯胺 lH NMR in CDC13: 7.82 (dd, J=8.8 & 6.3Hz, 2H); 7.73 (s, 1H); 7.41 (s, 1H); 7.18 (t, J=8.8Hz, 2H); 6.92 (s, 1H); 5.77 (brs, 1H); 4.07 (t, J=6.6Hz, 2H); 2.98 (d, J=9.8Hz, 3H); 2.95 (s, 3H); 1.85 (sextet, J=7.0Hz, 2H); 1.06 (t, J=7.0Hz, 3H) (M+H)"= 421 A <1 446. 5-(4-氣基-爷氧基) -2-(4-氟基-苯裏)-6-(甲烷磺醯基-甲氧 申基-胺基)-苯并4 喃-3-羧酸-甲醯胺 lH NMR in DMSO: 8.40 (d, J=4.6Hz, 1H); 7.93 (dd, J=8.8, 5.3Hz, 2H); 7.88 (d, J=8.2Hz, 2H); 7.75 (s, 1H); 7.71 (d, J=8.2Hz, 2H); 7.37 (t, J=8.8Hz, 2H); 7.31 (s, 1H); 5.33 (s, 2H); 4.94 (brs, 2H); 3.31 (s7 3H); 3.04 (s, 3H); 2.81 (d, J=4.6Hz, 3H) (M-H)'= 536 A <1 227- 88828.doc 200418452 實例 編號 名稱 NMRdata Mass Spec HCV pol -BB7 IC50O1M) A= μ,Μ B= 0*5 to 彡 5·0 /iM C= 5.0 to ^30 μΜ D=>30 μΜ 複製子 (μΜ) 447. —5_(3_氰基-芊氧基) -2-(4-氟基-苯基)-6-(甲烷磺醯基-甲氧 ♦基-胺基)-苯 喃-3-羧酸-甲醯胺 'HNMRinDMSO: 8.40 (d, J=4.4Hz, 1H); 8.00 (s, 1H); 7.90-7.80 (m, 4H); 7.75 (s, 1H); 7.62 (t, J=8.0HzT 1H); 7.39 (t, J=8.0Hz, 2H); 7.31 (s, 1H); 5.28 (s, 2H); 4.92 (brs, 2H); 3.31 (s, 3H); 3.04 (s, 3H); 2.82 (d,J=4.4Hz, 3H) (M+H)+ = 536 A <1 448. 6-(1:環丙烷羰基-吡 4 淀-2-基)-2-(4-氣 基-苯基)-5-異丙氧 基-苯并咬喃-3-幾酸 _甲醯胺 ^NMRinCDCb: 7.84 (m, 2H); 7.34 (s, 1H); 7.18-7.23 (m, 3H); 5.74 (brs, 1H); 5.50 (d, J=7.47Hz, 1H); 4.73 (septet, J=5.72Hz, 1H); 3.85 (m, 1H); 3.82 (m, 1H); 2.99 (d, J=4.84Hz, 3H); 2.22-2.43 (m, 1H); 1.92-2.00 (in, 2H); 1.79-1.80 (m, 2H); 1.40 (m, 6H); 0.85-1.01 (m, 4H) (M+H)+ = 465 A 氺氺氺 1 449. 2-(4-氣基-苯基)-5_ 甲氧基办[1,3,4]哼 二峻-2-基-苯蚌吱喃 -3-羧酸-甲醯胺 ^NMRia CDC13: 8^1 (s, 1H); 8.11 (s, 1H); 7.91-7.87 (m, 2H); 7.54 (s, 1H); 7.26-7.20 (rat 2H); 5.80 (s, 1H); 4.04 (s,3H); 2.99 (cU=5.4Hz,3H) (M+H)+ = 368 A 氺氺氺 450. 2-(4-氟基-苯基)各 (甲烷磺醯基-甲氧 甲基-胺基)-5-嘧吩 -2-基-苯并咬喃-3-羧酸-甲醯胺 lH NMRinDMSO: 8.48 (m, 1H); 7.98-7.96 (m, 3H); 7.83 (m, 1H); 7.61-7.60 (m, 1H); 7.42-7.36 (mt 3H); 7.13 (m, 1H); 3.16 (s, 3H); 3.08 (s, 3H); 2.66 (d, J=3.96Hz, 3H) (M+H)+ = 458.9 A 氺*氺 451. 2-(4-氟基-苯基) -6-{[2-(4-氟基-苯 基)-2-羥基-乙基]-甲 fe續酿基-胺基}·_5-經秦苯并吱喃-3 -叛 酸-甲醯胺 *H NMR in DMSO: 10.03 (brs, 1H); 8.42 (brd, 1H, J=4.69Hz); 7.94 (m, 2H); 7.38 (t, 2H, J=8.79Hz); 7.32 (m, 3H); 7.13 (m, 3H); 5.58 (m, 1H); 4.62 (m, 1H); 3.70 (brm, 2H); 3.01 (s, 3H); 2.82 (d, 3H, J=4.10Hz) (M-H)' = 515 A 氺本氺 452. 5-甲氧基-ί-苯基-苯 并呋喃-3-複酸-甲 醯胺 氺氺氺 氺氺氺 A <10 _《 453. 5-羥基-2-苯基-苯并 呋喃-3-¾酸-甲醯胺 氺氺氺 氺氺氺 C 氺氺氺 * 除非另有說明,否則所有的咕NMR與13C NMR光譜皆是 經由Varian Mercury VX 300分光儀取得,並以四甲基石夕燒 (TMS)為參考指標。 **質譜資料若非以(Μ + H)即是以(M-Η)之分子離子之質量 對電荷比表示。 * * *顯示資料未收集。 228 - 88828.doc 200418452 表3.所列為表1所列之選擇性化合物之醫藥可接受的鹽。 、_號 454.Example number Ri R2 R3 R4 Rs 443. Η -0 (CH2) 2CH3 / S〇2, π l H ch3 444. Η -OH in3 H ch3 ^ 0F 445. Η -0 (CH2) 2CH3 ^ so2, H ch3 ^ 0 ~ F 446. * Η Vv / S〇2 -T l H ch3 447. Η N / S〇2 -7 π l H ch3 448. Η -OCH (CH3) 2 H ch3 heart F 449. Η -och3 H ch3 ^ 〇-F 450. Η a ch3 H ch3 \ Qn 451. Η -OH / S02 1 1 FH ch3 ^ 0 " F 452. Η -och3 HH ch3 453. Η -OH HH ch3 \ Q 172- 88828.doc 200418452 Table 2. Additional experimental data for the examples listed in Table 1. Table 2 Examples No.Name-NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A = 彡 0 · 5 / iM B = 03 to <: 5.0 C = 5.0 to ^ 30 D = > 30 μΜ replicon (liM) 1. _ 2. Fulfanyl-5-methoxy-phenylsulfan-3-carboxylic acid formamidine 醯 (M + H) ^ 272 B < 30 2. 2-Benzyl-5-trifluoromethoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in Dimethyl- ^ Sulfoxide (DMSO): 8.47-8.49 (d, J = 4.69 Hz, H); 7.88-7.91 (dd, J = 1.76Hz, 8.21Hz, 2H); 7.80-7.83 (d, J = 9.38Hz, 1H); 7.50-7.57 (m, 3H); 7.38-7.41 (d , J = 8.79Hz, 1H); 2.83-2.84 (d, J = 4.69Hz, 3H) (M + H) + = 336 B 氺 氺 氺 3. 2- (3,4-difluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.44 (s, 1H); 7.98 (m, 1H); 7.74 (m, 1H); 7.60 (m, 2H) ; 7.12 (m, 1H); 7.03 (m, 1H); 3.82 (s, 3H); 2.85 (d, J = 4.2Hz, 3H) (M + H) + = 318 A < 10 4. 2- [4- (Ethylamidoamino-methyl) -xyloyl] -5-isopropoxy-benzofuran-3-chimonoformamidine * H NMR in DMSO: 835 (bm, 2H); 7.78 (d, 2H, J = 8.21); 7.52 (d, 1H, J = 8.79); 7.36 (d, 2H, J = 7.03); 7.04 (d, 1H, J = 2.34); 6.93 (dd, 1H, J = 8.79, 2.34); 4.59 (m, 1H); 4.28 (d, 2H, J = 5.86); 2.80 (d, 3H, J = 4.69); 1.87 (s, 3H); 1.26 (d, 6H, J = 5.86) (M + H) + = 381 B < 30 5. 2- (4-Hydroxy-phenyl) -5-isopropoxy-benzoporan-3-carboxylic acid formamidine'H NMR in DMSO: 9.91 (s, 1H); 8.20 (d, 1H, J = 4.69); 7.70 (d, 2H, J = 8.79); 7.47 (d, 1H, J = 8.79); 7.02 (d, 1H, J = 2.34); 6.86 (m, 3H); 4.57 (m, 1H); 2.79 (d, 3H, J = 4.69); 1.26 (d, 6H, J = 5.86) (MH) · = 324 B < 10 6. 2- (4-Fluoro-phenyl) -5-isopropoxy-6 · ^ than Gyodo-1-Li-private 17-furan-3-carboxylic acid formamidine 1H NMR in DMSO: 8.26 (d, J = 4.84, 1H); 7.89-7.84 (m, 2H); 7.31 (t, J = 8.79, 2H); 6.98 (s, 1H); 6.90 (s, 1H); 4.56 ( septet, J = 6.15, 1H); 3.33-3.29 (m, 4H); 2.81 (d, 1 = 4.40, 3H); 1.90-1.86 (m, 4H); 1.29 (d, J = 6.15, 6H) (M + H) + = 397 A < 1 7. 5-Difluoromethoxy-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid formamidine 1HNMR in dichloromethane 4 (0) 03): 7.92 ( m, 2H); 7.61 (d, 1H, J = 2.93); 7.48 (d, 1H, 1 = 8.79); 7.22-7.13 (m, 3H); 6.54 (t, 1H, J = 74); 5.80 (brs , 1H); 3.00 (d, 3H, J = 5.27) (M + H) + = 336 B < 10 8. 2- (4-Fluorophenyl) -5-isopropoxy each (2-methoxy-ethylamino) -benzofuran-3-carboxylic acid amidine 1H NMR in DMSO: 8.25 (d, J = 4.69, 1H); 7.88-7.83 (m, 2H); 7.31 (t, J = 8.79, 2H); 6.97 (s, 1H); 6.83 (s, 1H); 5.04 ( t, J = 5.27, 1H); 4.62-4.50 (septet, J = 5.27, 1H); 3.56 (t, J = 5.27, 2H); 3.33-3.30 (m, 5H); 2.82 (d7 J = 4.69, 3H ); 1.31 (d, J = 5.86, 6H) (M + H) + = 401 A < 1 9. 5-methyl-2-phenyl-benzofuran-3-carboxylic acid formamidine * H NMR in CDCI3: 7.91-7.86 (m, 2H); 7.66 (s, 1H); 7.52- 7.37 (m, 4H); 7.14 (d, J = 8.8Hz, lH); 5.8t (brs, 1H); 2.97 (d, J = 4.7Hz, 3H); 2.46 (s, 3H) (M ten H) + = 266 B < 10 173- 88828.doc 200418452 Example, No. Name NMR data Mass Spec HCV pol -BB7 IC50 (/ iM) A = ^ 0.5 μΜ B = 0.5 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μM replicon_) 10 · 5-methyl-2- (4-imidyl-phenyl) -benzofuran-3-carboxylic acid formamide kH NMR in CDCb: 7.97-7.93 (rn, 2H); 7.59 (s, 1H); 7.39 (d, J = 8.2Hz, 1H); 7.19-7.14 (m, 3H); 5.81 (brs, 1H); 3.02 (d, J = 5.3Hz, 3H); 2.47 (s, 3H) (M + H) + = 284 B < 10 11. 2-phenyl-5- (2,2,2-trifluoro-ethoxy) -benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.87 (dd, 2H) ; 7.65 (dd, 1H); 7.47-7.54 (m, 4H); 7.08 (dd, 1H); 5.8 (s, br, 1H); 3.93 (s, 2H); 2.97 (d, 3H) ppm (M + H) + = 350 D < 30 12. 2- (Fluoro-fluorenyl) di 5: methoxy-benzofuran-3-carboxylic acid amidine 1H NMR in DMSO: 8.37 (br.s, iH); 7.91- 7.96 (ra, 2H); 7.56-7.58 (d, J = 8.79Hz 1H); 7.34-7.40 (t, J = 8.79Hz, 2H); 7.09-7.10 (d, J = 2.35Hz, 1H); 6.97- 7.00 (dd, J = 2.35Hz, 8.79Hz, 1H); 3.82 (sr 3H); 2.83-2.8 (d, J = 4.69Hz, 3H) (M + H) + = 299.9 A < 10 13. 6-bromo-2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.42 (d, J = 4.69Hz, 1H); 8.01 (s, 1H); 7.90-7.94 (m, 2H); 7.35-7.41 (t, J = 8.79Hz, 2H); 7.23 (s, 1H); 3.91 (s, 3H); 2.83-2.85 (d, J = 4.69Hz, 3H) Tochigi A < 1 14. 5-Methoxy-6-methyl-2-phenyl-benzofuran-3-quinic acid formamidine 1H NMR in DMSO: 8.34-8.36 (d, J = 4.69Hz, IH) ; 7.83-7.86 (dd, J = 1.76Hz, 8.79Hz, 2H); 7.43-7.53 (m, 4H); 7.04 (s, 1H); 3.85 (s, 3H); 2.83-2.84 (d, J = 4.69 Hz, 3H); 2.28 (s, 3H) (M + H) + = 296 A < 1 15. 6_ (3-Aminopyridine-1 -yl) -2- (4-fluoro-phenyl) -5-isopropoxy-2,3-dihydro-benzofuran -3- Methofenamine * 氺 氺 (M + H) + = 412 C < 30 16. 6-amino-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.82 (dd, 2H , J = 5.5 and 8.7Hz); 7.22 (s, 1H); 7.18 (t, 2H, J = 8.7Hz); 6.84 (s, 1H); 5.76 (bs, 1H); 4.61 (heptuplet, J = 6. iHz); 2.96 (d, J = 4.9Hz, 3H); 1.92 (bs, 2H); 1.40 (d, J = 6.1Hz, 6H) (M + H) + = 343 A < 10 17. 6-Amino-2- (4-Hexyl-phenyl) -5-methoxy-benzofuran-3-quinoline formamidine 1H NMR in methanol-Mountain (CD3〇D) : 7.81 (m, 2H); 7.20 (m, 2H); 7.02 (s, 1H); 6.91 (s, 1H); 4.72 (s, 1H); 3.91 (s, 3H); 2.93 (s, 3H) ( M + H) + = 315 B < 10 18. 6-acetamido-2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.95 (bs, 1H); 7.83 (ra, 2H); 7.46 (m, 1H); 738 (s, IH); 7.28 (m, 2H); 5.76 (bs, 1H); 3.96 (s, 3H); 2.98 (s, 3H ); 2.21 (s, 3H) (Μ + ΗΓ = 357 A < 1 19. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methylamino-benzofuran-3-¾carboxylic acid formamidine NMR in CDC13: '7.81 (dd, J = 8.7 Sc 5.iHz, 2H); 7.25 (s, 1H); 7.14 (t, J = 9.3Hz, 2H); 6.66 (s, 1H); 5.78 (bs, IH); 4.63 (septupled J = 6.3 Hz, 1H); 4.55 (bs, 1H); 2.97 (d, J = 4.8Hz, 3H); 2.91 (s, 3H); 1.37 (d, J = 6.3Hz, 6H) (M + H) + = 357 A < 1 -174- 88828.doc 200418452 Example number name, NMR data Mass Spec HCY pol -BB7 IC50 (/ tM) A = μ, Μ B = (K5 to i 5.0 / iM C = 5.0 to ^: 30 μΜ D = > 30 μM replicon (μM) 20. 6 dimethylamino-2- (4-fluoro-phenyl) -5-isopropoxy-benzoanan-3-¾ acid Diamine NMR in CDCh: 7.51 (dd, J = 8.7 & 5.1Hz, 2H); 7.28 (s, 1H); 7.26 (m, 3H); 5.80 (bs, 1H); 4.70 (septupled J = 6.3Hzt 1H); 2.98 (d, J = 4.9Hz, 3H); 2.91 (s, 6H); 1.42 (d, J = 6.3Hz, 6H) (M + H) + = 371 A < 1 21. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methanesulfonylamino-benzyl-4-3-carboxylic acid formamidine 1H NMR in CDC13 : 7.81 (dd, J = 8.7 & 4.1Hz, 2H); 7.73 (s, 1H); 7.42 (s, 1H); 7.19 (U = 8.7Hz, 2H); 6.90 (s, 1H); 5.81 (bs , 1H); 4.75 (septuple ^ J = 6.3Hz, 1H); 2.98 (s, 3H); 2.95 (d, J = 2.6Hzt 3H); 1.40 (d, J = 6.3Hz, 6H) (M + H) + = 421 A < 1 22. 6-Ethylamino-2- (4-amino-phenyl) -5-isopropoxy-wood and sulfan-3--3-carboxylic acid formamidine 1H NMR in CDCh: 7.81 ( ddt J = 8.8, 5.3Hz, 2H); 7.18 (s, 1H); 7.16 (t, J = 8.8Hz, 2H); 6.67 (s, 1H); 5.76 (bs, 1H); 4.61 (heptuplet, J = 6.2HzT 1H,); 3.20 (quaduplet, J = 7.0Hz, 2H); 2.97 (d, J = 4.8Hz, 3H); 1.38 (d, J = 6.2Hz, 6H); 1.32 (t, J = 7.0Hz , 3H) (M + H) + = 371 A < 1 23. 6 Ditriethylamino-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran · 3-acid formamidine'HNMRinCDCb: 7.83 (dd, J = 8.8,5.3Hzt 2H); 7.26 (s, 1H); 7.15 (d, J = 8.8Hz, 2H); 7.05 (s, 1H); 5.78 (bs, 1H ,; 4.17 (heptuplet, J = 6.1Hz , 1H); 3.18 (m, 4H); 2.95 (d, 5.0Hz, 3H); 1.38 (d, J = 6.1HzT 6H); 1.32 (tt J = 7.0Hz, 6H) (Μ + ΗΓ = 399 A < 1 24 .: 2- (4-Fluoro-phenyl) -5-, isopropoxy-6-morpholin-4-yl-benzoanan-3-carboxylic acid formamidine 1HNMRin DMSO : 8.30-8.3 l (d, J = 4.69Hz, 1H); 7.88-7.93 (m, 2H); 7.31-7.37 (t, J = 8.79Hz, 2H); 7.19 (s, 1H); 7.07 (s, 1H); 4.58-4.66 (septet, J = 6.45Hz, 1H); 3.75-3.77 (m, 4H); 3.02-3.05 (m, 4H); 2.82-2.83 (dt J = 4.69Hz, 3H); 1.29- 1.31 (d, J = 6.45Hz? 6H) (M + H) + = 413 A < 1 25. 5-Methoxy-4-methyl-2-benzene: benzobenzo-3-methylimineamine 1H NMR in CDC13: 7.84-7.81 (m, 2H); 7.48-7.40 ( m, 3H); 7.30-7.26 (m, 1H); 6.93 (d, J = 8.7Hz, 1H); 3.86 (s, 3H); 3.01 (d, J = 4.8Hz, 3H); 2.40 (sy 3H) (M + H) + = 296 D > 30 26. 5-cyano-2-phenyl-benzofuran-3-carboxylic acid amidine 1H NMR in CDCl3: 8.32 (s, 1H); 7.89-7.85 (m, 2H); 1.62-1 ΛΊ (ra, 5H); 5.80 (s, 1H); 2.98 (d, J = 5.1Hz, 3H); (M-Η) '= 275 C < 30 27. 5-isopropoxy-2-pyridin-4-yl-pyrano-p-furan-3-methylamine succinate NMR in CDCl3: 8.70 (d, J = 5.4Hz, 2H); 7.84 (dd, J = 1.2Hz, 4.2HZ, 2H); 7.43 (d, J = 8.7Hz, 1H); 7.21 (d, J = 2.7Hz, 1H); 7.00 (dd, J = 2.1Hz, 8.7Hz , 1H); 5.91 (bs, 1H); 4.54 (m, 1H); 3.07 (d, J = 5.1Hz, 3H); 1.36 (d, J = 5.7Hz, 3H) (M + H) '= 311 C > 30 28. 6- (3,5-dimethyl-isopurazol-4-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxyl Formamidine acid 1H NMR in CDCl3: 7.85-7.89 (m, 2H); 7.43 (s, 1H); 7.25 (s, 1H); 7.18-7.23 (t, J = 8.79 Hz, 2H); 5.79 (brs, 1H); 3.86 (s, 3H); 3.00-3.02 (d, J = 5.2 ^ Hz, 3H); 2.32 (s, 3H); 2.18 (s, 3H) (M + H) + = 395 A < 1 175-88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 IC5〇 〇iM) A = μΜ B = 0 * 5 to < 5.0 μΜ C = 5.0 to ^ 30 fiM D = > 30 μΜ replicon_) 29. 2- (4-fluoro-phenyl) -6 · (methanesulfonyl-methyl-amino)- 5-methoxy-benzofuran-3-carboxylic acid methochloramine * H NMR in CDC13: 7.86 (m, 2H); 7.56 (s, 1H); 7.45 (s, IH); 7.28 (U 8.3Hz, 2H); 5.77 (brs, 1H); 3.98 (s, 3H); 3.33 (s, 3H); 2.98 (d, J = 5.2Hz, 3H); 2.96 (s, 3H) (M + H) + = 407 A < 1 30. 2- (4-Fluoro-phenyl;)-5- (4-methoxy-benzyloxy) -morpholin-4-yl-benzofuran-3-carboxylic acid formamidine Amine 1H NMR in CDCi3: 7.84 (dd, J = 8.4, 5.2Hz, 2H); 7.40 (d, J = 8.3Hz, 2H); 7.37 (s, 1H); 7.15 (t, J = B.4Hz, 2H ); 7.06 (s, 1H); 6.93 (dt J = 8.8Hz, 2H); 5.82 (d, J = 3.9Hz, 1H); 5.09 (s, 2H); 3.85 (t, J = 4.4Hz, 4H) ; 3.82 (s, 3H); 3.11 (t, J = 4.4Hz, 4H); 2.97 (d, J = 4.8Hz, 3H) (M + H) + = 491 A < 1 31. 2- (4-Fluoro-phenyl) -6- [methyl clay acid- (4-methoxy · fluoren 10-amino) -5- (4-methoxy- Benzyloxy) _benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.38 (d, J = 4.1Hz, 1H); 7.88 (dd, J = 8.4, 5.2Hz, 2H); 7.48 (d , J = 8.8Hz, 2H); 7.34 (t, J = 8.8Hz, 2H); 7.29 (s, 1H); 7.28 (s, 1H); 7.12 (d, J = 8.8Hz, 2H); 7.00 (d , J = 8.2Hz, 2H); 6.79 (d, J = 8.8Hz, 2H); 5.13 (s, 2H); 4.60 (br rn, 2H); 3.77 (s, 3H); 3.66 (s, 3H); 2.94 (s, 3H); 2.80 (d, J = 4.7Hz, 3H) (M + H) + = 619 A < 1 32, 5-ethoxy-6- (ethyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl) -benzofuran-3-¾formamidine 1H NMR in DMSO: 8.41 (d, J = 4.1Hz, IH); 7.94 (dd, J = 8.2, 5.3Hz, 2H); 7.55 (s, 1H); 7.36 (t, J = 8.2Hz, 2H); 7.16 (s, 1H); 4.14 (q, J = 7.0Hz, 2H); 3.62 (q, J = 7.0Hz, 2H); 3.01 (s, 3H); 2.82 (d, J = 4.7Hz, 3H); 1.38 (t, J = 7.0Hz, 3H); 1.05 (t, J = 7.0Hz, 3H) (M + H) + = 435 A < 1 33. 2 · (4 · -amino-phenyl) -6_morpholin-4-yl-5-0 sezol-2-ylmethoxy) -benzopyran-3-carboxylic acid Formamidine 1H NMR in DMSO: 8.35 (d, J = 4.4Hz, 1H); 7.95-7.80 (m, 4H); Ί35-125 (m, 4H); 5.49 (s, 2H); 3.78 (m, 4H ); 3.06 (in, 4H); 2.83 (d, J = 4.4Hz, 3H) (M + H) + = 468 A < 1 34. 2- (4-Amino-phenyl) -5_ isopropoxy-6- [methanesulfonyl- (2-oxy-propyl) -amino] -benzyl- Formamidine 3-carboxylic acid [H NMR in DMSO: 8.38 (d, J = 4.8Hz, 1H); 7.94 (dd, J = 8.4, 5.3Hz, 2H); 7.71 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.15 (s, lH); 4.77 (septet, J = 6.1Hz, 1H); 4.04 (s, 2H); 3.04 (s, 3H); 2.81 (d, i = 4.4Hz, 3H); 2.11 (s, 3H); 1.36 (d, J = 6.1Hz, 6H) (M + H) + = 477 A < 1 35. 2- (4-Fluoro-phenyl) -6-morpholin ^-^-5-(oroxazol-4-ylmethoxy) -benzofuran; formamidine carboxylic acid Amine 1H NMR in CDCl3: 8.84 (d, 1H, J = 1.76); 7.88 (m, 2H); 7.44 (s, 2H); 7.17 (t, 2H, J = 8.79); 7.10 (s, 1H); 5.77 (brs, 1H); 5.37 (s, 2H); 3.89 (m, 4H); 3.16 (m, 4H); 3.00 (d, 3H, J = 4.69) (M + H) + = 468 A < 1 176- 88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A = fiM B = 03 to ^ 5.0 / iM C = 5.0 to < 30 pM D = > 30 μM replicon_) 36. 2_ (4-amino-phenyl) -5_ isopropoxy-6- (methanesulfonyl-pyrimazol-4-ylmethyl- Amine) -Benzanan-3-formamide Methylamine 1H NMR in CDC13: 8.69 (d, 1H, J = 2.20 Hz); 7.77 (m, 2H); 7.40 (s, 1H); 7.37 (s , lH); 7.30 (d, 1H, J = 2.20 Hz); 7.18 (t, 2H, J = 8.79 Hz); 5.67 (brs, 1H); 5.03 (brs, 2H); 4.79 (m, lH); 3.07 (s, 3H); 2.95 (d, 3H, J = 4.84 Hz); 1.44 (d, 6H, J = 5.72 Hz) (M + H) + = 518 A < 1 37. 2- (4-amino-phenyl) -6- (5-hydroxymethyl-isoazazol-3-yl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine Amine 1H NMR in CD3OD: 7.94 (s, 1H); 7.92 (dd, J = 9.2, 5.3 Hz, 2H); 7.32 (s, 1H); 7.25 (apparent triplet, J = 8.8 Hz, 2H); 6.87 (s , lH); 4.75 (m, 1H); 4.72 (s, 2H); 2.95 (s, 3H); 1.39 (d, J = 5.7 Hz, 6H) (M + H) + = 425 A < 1 38. 5-ethoxy-2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino): benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.39 (d, J = 4.0Hz, 1H); 7.92 (dd, J = 8.8t 5.3Hz, 2H); 7.59 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.17 (s, 1H); 4.16 (q, J = 7.0Hz, 2H); 3.19 (s, 3H); 3.01 (s, 3H); 2.81 (d, J = 4.4Hz, 3H); 1.40 (t, J = 7.0Hz, 3H) (M + H) + = 421 A < 1 39. 4- [2- (4-Fluoro-phenyl) -6- (formamidine, fluorenyl-methyl: amino) -3-methylaminomethyl-benzoyl- 5-Methoxymethyl] -2-Hexyl-arsanoic acid 1H NMR in DMSO: 8.39 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.84 (d, 1H, J = 8.21Hz); 7.72 (s, 1H); 7.39 (t, 2H, J = 8.79Hz); 7.30 (s, 1H); 7.12 (m, 2H); 5.27 (s, 2H); 3.24 (s, 3H); 3.00 (s , 3H); 2.83 (d, 3H, J = 4.69Hz) (MH) · 541 A < 10 40.2 (4-Fluoro-phenyl) -6- (5-hydroxymethyl-isohumazol-3-yl) -5-methoxy-benzofuran-3-m acid Amidine NMR in DMSO: 8.44 (bq, J = 4.83Hz, 1H); 7.97 (m, 3H); 7.39 (t, J = 8.79Hz, 2H); 7.29 (s, 1H); 6.80 (d, J = 0.879Hz, 1H); 5.66 (t, J = 6.15 & 5.71 Hz, 1H); 4.63 (d, J = 6.15Hz, 2H); 3.93 (s, 3H); 2.86 (d, J = 4.39Hz, 3H ) (M + H) + = 397.0 A < 1 41. 2- (4-Fluoro-phenyl) -6- [4- (2-acyl-ethyl) -isopurin-3-yl] -5-methyllactyl-epoxy Benzene-3-¾methamidine 1H NMR in CDC13: 8.40 (s, 1H); 7.86 (dd, J = 5.27, 8.79 Hz, 2H); 7.52 (s, 1H); 7.45 (s, 1H); 7.20 (t, J = 8.35, 8.79 Hz, 2H); 5.81 (bs, 1H); 3.87 (s, 3H); 3.69 (q, J = 6.15 Hz, 2H); 3.00 (d, J = 4.83 Hz, 3H) ; 2.64 (t, J = 6.15 HzT 2H); 1.45 (t, J = 5.27,5.71 Hz, 1H). (M + H) + = 411 A < 1 42. 2- (4-Fluoro-phenyl) -6-[(2-hydroxy-ethyl) -methanesulfonyl-amino] -5-methoxy-benzofuran-3- Carboxamide carboxylate NMR in DMSO: 8.49 (d, J = 4.84 Hz, 1H); 7.96-7.90 (m, 2H); 7.66 (s, 1H); 7.41 (t, J = 7.03 Hz, 2H); 7.2 (s, 1H); 4.75 (t, J = 5.71 Hz, 2H); 3.9 ((s, 3H); 3.44 (bs, 1H); 3.41 (d, J = 5.27 Hz, 2H); 3.05 (s, 3H ); 2.84 (d, J = 4.39 Hz, 3H) (M + H) + = 437 A < i 43. 5- ^ propyl-2- (4-fluoro-phenyl) -6-[(2-methyl-ethylmethanesulfonyl-amino) -benzofuran each carboxylic acid Lamine 1H NMR in CDC13: 7.90-7.85 (m, 2H); 7.55 (s, 1H); 7.35 (s, 1H); 7.22-7.16 (m, 2H); 5.74 (bs, 1H); 4.09-4.03 ( m, 1H); 3.75 (s, 3H); 3.14 (s, 3H); 2.99 (d, J = 4.40Hz, 3H); 2.40-2.30 (m, 1H); 1.95 (m, 1H); i.10 -0.98 (m, 2H); 0.88 (m, 1H); 0.68 (m, IH) (M + H) + = 447 A < 1 177- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A = / iM B = 03 to <: 5.0 μΜ C = 5.0 to ^: 30 μΜ D = > 30 μΜ replicon (μΜ) 44. 5-ethyl-2- (4-fluoro-phenyl) -6-methanesulfonylamine Benzene-benzobenzamidine'3-chiamate formamidine'H NMR in DMSO: 9.20 (bs, 1H); 8.61 (m, 1H); 7.93 (dd, J = 5.3 & 8.8 Hz, 2H); 7.60 ( s, 1H); 7.48 (s, 1H); 7.37 (t, J = 8.8 Hz, 2H); 3.05 (s, 3H); 2.83 (d, J = 4.7 Hz, 3H); 2.81 (q, J = 7.7 Hz, 2H); 1.21 (ζ J = 7.7 Hz, 3H) (M + H) + = 391 A < 10 45. 5-ethyl-2- (4-fluoro-phenyl) -6- (methanesulfonyl-fluorenyl-amino) -benzofuran-3-carboxylic acid formamidine 1H NMRinDMSO : 8.50 (m, 1H); 7.94 (dd, J = 5.3 & 8.8Hz, 2H); 7.89 (s, 1H); 7.54 (s, 1H); 7.60 (t, J = 8.8Hz, 2H); 3.29 (q, 1 = 7 ^ 2H); 3.21 (s, 3H); 3.13 (s, 3H); 2.83 (d, J = 4.7Hz, 3H); 1.21 (t, J = 7.0Hz, 3H) (M + H) + = 405 A < 1 46. 5-Ethyl-2- (4-amino-methyl) -6-[(2-hydroxy-ethyl) -methyl pentoxide S & yl-amino] -benzofuran-3 -Formamidine carboxylic acid 1H NMR in DMSO: 8.45 (m, 1H); 7.94 (dd, J = 5.3 & 9.4Hz, 2H); 7.81 (s, 1H); 7.55 (s, 1H); 7.39 (t , J = 8.8Hz, 2H); 3.72 (m, 1H); 3.58 (m, 1H); 3.4 (m, 3H); 3.15 (s, 3H); 2.84 (d, J = 4.7Hz, 3H); 2.82 (q, J = 7.0Hz, 2H); 1.25 (t, J = 7.0Hz, 3H) (M + H) + = 435 A < 1 47. ό- (1-Ethyl-p-p-p-Yodo-2-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxy Formamidine acid 1H NMR in CDC13: 7.85 (m, 2H); 7.36 (s, 1H); 7.20 (m, 3H); 5.78 (brs, 1H); 5.40 (in, 1H); 3.92 (s, 3H) ; 3.40-3.91 (m, 2H); 2.99 (d, J = 4.8Hz, 3H); 1.51-2.0 (m, 4H); 1.85 (s, 3H) (MH) · 411.1 A < 1 48. 2- (4-Amino-phenyl) -5_methoxy-6- (2-oxy-oxazolyt-5-yl) -benzobenzoan-3-carboxylic acid formamidine Amine * H NMR in (CD3) 2CO: 8.03 (m, 2H); 7.68 (s, 1H); 7.40 (brs, 1H); 7.20-7.31 (4H); 5.14 (ra, 1H); 3.90 (s, 3H ); 3.60 (m, 1H); 3.38 (m, 1H); 2.94 (d, J = 4.8 Hz, 3H) (M + H) + = 385.0 A < 10 49. Fluoro-phenyl) yl-1-methyl-ethyl) -5-methoxy-benzofuran-3-methanoic acid formamidine 1H NMR in CDC13: 7.85 (m, 2H) ; 7.50 (s, 1H); 7.39 (s, 1H); 7.20 (m, 2H); 5.75 (brs, 1H); 4.17 (s, 1H); 3.99 (s, 3H); 2.98 (d, J = 4.8 Hz, 3H); 1.66 (s, 6H) (M + H) + = 358.1 A < 1 50. 2- (4-Fluoro-phenyl) -5 · -methoxy-6- (5-methyl_ [1,2,4] pyridazol-3-yl) -benzo Tetramethyl-3 -¾formamidine 1H NMR in CDC13: 8.12 (s, 1H); 7.90-7.86 (m, 2H); 7.48 (s, 1H); 7.24-7.18 (m, 2H); 5.78 (s , 1H); 4.03 (s, 3H); 3.0 (d, J = 4.8 Hz, 3H); 2.67 (s, 3H) (M + H) + = 382 A < 1 51. 6- (3,5-dimethyl-isoxazol-4-yl) -2- (4-fluoro-phenyl) -5- (3-hydroxy-propoxy) -benzene Benzene-3-carboxylic acid formamidine 1H NMR in DMSO: 8.41-8.43 (d, J = 4.69 Hz, 1H); 7.92-7.97 (m, 2H); 151 (sT 1H); 7.35-7.41 (t , J = 8.79 Hz, 2H); 7.23 (s, 1H); 4.49-4.52 (t, J = 5.28 Hz, 1H); 4.06-4.11 (t, J = 6.45 Hz, 2H); 3.43-3.49 (q, J = 5.86 Hz, 2H); 2.84-2.86 (d, J = 4.69 Hz, 3H); 2.29 (s, 3H) (M + H) + = 439.0 A < 1 178- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV po! -BB7 IC50〇QiM) A = 彡 0 · 5 μΜ B = 0.5 to ^ 5.0 μΜ C = 5.0 to ^ 30 / iM D = > 30 replicon trans) 52. Gas-phenyl) (Methanesulfonyl-methyl-amino) -5- (2-morpholin-4-yl-ethoxy) -benzofuran-3 -Formamidine carboxylic acid 1H NMR in DMSO: 8.40 (brd, J = 4.40 Hz, 1H); 7.94 (m, 2H); 7.60 (s, 1H); 7.38 (t, J = 8.79 Hz, 2H); 7.24 (s, 1H); 4.21 (t, J = 5.28 Hz, 2H); 3.57 (1¾ 4H); 3.23 (s, 3H); 3.10 (s, 3H); 2.84 (d, J = 4.84 Hz, 3H); 2.76 (t, J = 5.28 Hz, 2H); 2.48 (m, 4H). (M + H) + = 506 A < 1 53. 5-(. monobenzyl-2-plug-methoxy) -2-phenyl-benzofuran-3-carboxylic acid formamidine * H NMR in DMSO: 2.82 (d, 3H) ; 5.0 (s, 2H) 6.96 (m, 1H); 7.32-7.96 (m, 16H); 8.34 (d, 1H) ppm (M + H) + = 434 C < 30 54. 5-methoxy-2- (4-methoxy-phenyl) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.31 (br s, 1H); 7.82- 7.84 (d, J = 7.03Hz, 2H); 7.52-7 ^ 5 (d, J = 8.79Hz, 1H); 7.06-7.10 (m, 3H); 6.93-6.96 (dd, J = 2.35Hz, 8.79Hz , 1H); 3.83 (s, 3H); 3.81 (s, 3H); 2.81-2.83 (d, J = 4.69Hz, 3H) 氺 氺 * B < 10 55. 5-methoxy-2- (3-trifluoromethyl-phenyl) -benzofuran formamidine carboxylic acid 1H NMR in DMSO: 8.47-8.49 (d, J = 4.69Hzt 1H ); 8.19 (s, 1H); 8.15-8.18 (d, J = 7.62Hz, 1H); 7.74-7.84 (m, 2H); 7.61-7.64 (d, J = 9.38Hz, 1H); 7.13 (d, J = 2.34Hz, 1H); 7.01-7.05 (dd, J = 2.34Hz, 7.62Hz, 1H); 2.83-2.85 (d, J = 4.69Hz, 3H) 氺 氺 氺 B < 30 56. 5-methoxy-2- (4-trifluoromethyl-phenyl) -benzofuran-3-carboxylic acid formamidine JH NMR in DMSO: 8.48-8.49 (d, Ι = 4.69 Ηζ, 1H); 8.06-8.09 (d, J = 8.21Hz, 2H); 7.88-7.90 (d, J = 8.21Hz, 2H); 7.61-7.64 (d, J = 8.79Hz, 1H); 7.12-7.13 (d, J = 2.93Hz, 1H); 7.02-7.06 (dd, J = 2.93, 8.79Hz, 1H); 3.83 (s, 3H); 2.85-2.86 (d, J = 4.69Hz, 3H) 氺 氺 氺B < 10 57. 5-ethoxy-2-phenyl-benzofuran-3-carboxylic acid formamidine'H NMR in CDCb: 7.85 (dd, 2H); 735-7.52 (m, 5H); 6.95 (d, 1H); 5.8 (s, br, 1H); 4.14 (q, 2H); 2.97 (d, 3H) 1.41 (t, 3H) ppm (M + H) + = 296 B > 30 58.2 -(2-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.05-8.07 (d, J = 4.69Hz, 1H); 7.72-7.77 (t of d, J = 1.76Hz, 7.62Hz, 1H); 7.52-7.63 (in, 2H); 7.37-7.39 (d, J = 7.62Hz lH); 7.33-7.38 (m, 1H); 7.18-7.19 (d, J = 2.35Hz, 1H); 6.99-7.03 (m, 2H); 3.83 (s, 3H); 2.75-2.76 (d, J = 4.69Hz, 3H) (M + H) + = 300 B < 10 59. 5-isopropoxy-2-phenyl-benzofuran-3-carboxylic acid formamidine'H NMR in CDCb: 7.87 (d, 2H); 7.52-7.37 (m, 5H); 6.94 (d, 1H); 5.78 (s, br, 1H); 4.6 (m, 1H); 2.98 (d, 3H); 1.38 (d, 6H) ppm (M + H) + = 310 B < 30 60. 5-Yoxy-2-phenyl-benzofuran-3-carboxylic acid formamidine * H NMR in CDCb: 7.87 (m, 2H), 7.51-7.3 (m, 5H); 6.97 (d, 1H); 5.78 (s, br, 1H); 4.06 (m, 2H); 2.98 (d, 3H); 1.83-1.54 (m, 4H); 1.02 (m, 3H) ppm (M + H) + = 324 B < 30 61. 2-phenyl-5-propoxy-benzofuran-3-methanoic acid formamide (H NMR in CDCb: 7.86 (ra, 2H); 7.5-7.27 (m, 5H); 6.96 (dd, 1H); 5.76 (s, br, 1H); 3.99 (t, 2H); 2.98 (d, 3H); 1.84 (m, 2H); (t, 3H) ppm (M + H) + = 310 B < 30 62. 5-methoxy-2- (2,4,5-trifluoro-phenyl) -benzofuran-3-carboxylic acid methylamine 1H NMR in DMSO: 8.08-8.09 (d, J = 4.69Hz, 1H); 7.86-7.95 (m, 1H); 7.71-7.80 (m, 1H); 7.58-7.61 (d, J = 9.38Hz, 1H); 7.22-7.23 (d, J = 2.35Hz , 1H); 7.02-7.06 (dd, J = 2.93Hz, 9.38Hz, 1H); 3.83 (s, 3H); 2.76-2.77 (d, J = 4.69Hz, 3H) 氺 氺 氺 C < 30 179- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 IC50〇iM) A = < 0 * 5 / iM B = 05 to ^ 5.0 fiM C = 5.0 to ^: 30 μΜ D => 30 / iM replicon (μΜ) 63. 5-methoxy-7-methyl-2-benzene Benzene-benzoic acid-3-ammonium acetamide 1H NMR in DMSO: 8.33-8.34 (d, J = 4.69Hz, 1H); 7.87-7.89 (d, J = 7.62Hz, 2H); 7.45-7.55 (m, 3H); 6.89-6.90 (d, J = 2.34HzT 1H); 6.83-6.84 (d, J = 2.34Hz, 1H); 3.80 (s, 3H); 2.82-2.84 (d, J = 4.69Hz , 3H); 2.50 (s, 3H) (M + H) + = 296 B < 10 64. 2- (4-Fluoro-phenyl)-: 5- (of 2,2-trifluoro-ethyllactyl) -benzyl-3-carboxylic acid formamidine 1HNMR in CDC13 : 8.06 (dd, 1H); 7.41 (dd, 2H); 7.17 (m, 2H); 7.02 (dd, 1H); 5.76 (m, br, 1H); 4.42 (q, 2H); 2.99 (d, 3H) ) ppm (M + H) + = 368 B 氺 氺 氺 65. 2_ (4-Gas-phenyl) -5_ isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.90 (dd, 2H); 7.29 (dd, 2H); 7.16 (dd, 1H); 6.92 (dd, 1H); 5.82 (s, br, 1H); 4.58 (m, 1H); 2.99 (d, 3H); 1.34 (s, 3H) (M + H) + = 328 B < 30 66. 2_ (2-Chloro-phenyl) -5-methylpyrene-wood-p-furan-3-carboxylic acid formamidine 1H NMR in DMSO: 7.85-7.86 (d, J = 4.69Hz , 1H); 7.47-7.69 (m, 5H); 7.27-7.28 (d, J = 2.34HzT 1H); 7.00-7.04 (dd, J = 2.93Hz, 9.38Hz, 1H); 3.84 (s, 3H); 2.72-2.73 (d, J = 4.69Hz, 3H) (M + ΗΓ = 315.9 C > 30 67. 6-methoxy-2-phenyl-benzofuran formamidine carboxylic acid * H NMR in CDC13 : 7.86 (m, 2H); 7.73 (d, J = 8.87Hz, 1H); 7.51-7.42 (m, 3H); 7.04 (d, J = 2.4Hz, 1H); 6.94 (d of d, J = 8.8 Hz, 1H); 5.81 (brs, 1H); 3.87 (s, 3H); 2.98 (d, J = 4.7Hzt 3H) (M + H) + = 282 B < 10 68. 2-Furan-2-yl-5-methoxy-benzofuran-3-quinoformamidine 1HNMR in DMSO: 8.28-8.29 (d, i = H.10Hz 1H); 7.92 ( s, 3H); 7.54-7.57 (d, J = 8.79Hz, 1H); 7.18-7.19 (d, J = 3.52Hz, 1H); 7.15-7.16 (d, J = 2.35Hz, 1H); 6.96-7.00 (dd, J = 2.35, 8.79Hz, 1H); 6.71-6.72 (m, 1H); 3.82 (s, 3H); 2.84-2.86 (d, J = 4.10Hz, 3H) M = 271 B < 30 69. 2- (3-1ylmethylmethyl-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.42 (s, 1H); 7.63 (in, 3H); 7.43 (m, 1H); 7.09 (m, 1H); 7.00 (m, 1H); 3.82 (s, 3H); 2.84 (d, J = 4.8Hz, 3H); 2.30 (s, 3H) (M + H) + = 314 A < 10 70. _2- (4-Bromo-phenyl) -5-methoxy-benzofuran formamidine carboxylic acid 1H NMR in DMSO: 8.41 (m, 1H); 7.81 (d, J = 7.5Hz, 2H); 7.72 (d, J = 8.4Hz, 2H); 7.58 (d, J = 9.3Hz, 1H); 7.09 (s, 1H); 7.01 (d, J = 8.7Hz, 1H); 3.82 (s, 3H); 2.83 (d, J = 4.2Hz, 3H) (Μ + ΗΓ = 361 A < 10 71. 2- (4-Fluoro-3-methyl-phenyl) -5-methoxy-benzofuran-3-carboxylic acid methylamine 1H NMR in DMSO: 8.33 (ra, 1H) ; 7.80 (dd, J = 8.1, 1.8Hz, 1H); 7.75 (m, 1H); 7.56 (d, J = 9.0Hz, 1H); 7.29 (m, 1H); 7.09 (d, J = 2.4Hz, 1H); 6.97 (dd, J = 8.1, 2.1Hz, 1H); 3.81 (s, 3H); 2.84 (d, i = 4.2Hz, 3H); 2.35 (s, 3H) (M + H) + = 314 A < 30 72. 2- (4-Gas-Phenyl) -5_methoxy-7-methyl-benzoanan-3-acid methylamine 1H NMR in DMSO: 8.3 (d, br, 1H); 7.94 (dd, 2H); 7.35 (dd, 2H); 6.89 (d, 1H), 6.81 (d, 1H); 3.83 (s, 3H); 2.80 (d, 3H); 2.47 (s, 3H ) ppm (M + H) + = 314 A < 10 73. 5-Gas-2- (4-fluoro-phenyl) -benzoanan-3H-methylamine 1H NMR in CDCl3: 7.96-7.91 (ra, 2H); 7.81 (d , J = 2.4Hz, 1H); 7.42 (d, J = 8.7Hz, 1H); 7.30 (d, d, J = 2.4, 8.7Hz, 1H); 7.21-7.16 (m, 2H); 5.789 (s, IH); 3.01 (d, J = 4.8Hz, 3H) (M + H) + = 304.27, 306.13 B < 10 180- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 ic50 〇iM) A = < 0 * 5 / iM B = 03 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = &30; 30 nM replicon (μΜ) 74. 5-tertiary-butyl-2-phenyl-benzofuran Formamidine-3-chitoate * Η NMR in CDC13: 7.87-7.84 (m, 3H); 7.52-7.39 (m, 5H); 5.79 (br s, 1H); 2.99 (d, J = 4.7Hz, 3H ); 139 (s, 9H) (M + H) + = 308 A < 10 75. 5 Dichloro-2-p-methyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.90 (d, J = 1.8Hz, 1H); 7.75 (d, J = 7.8Hz, 2H); 7.43-7.40 (m, 1H); 7.32-7.27 (in, 3H); 2.97 (d, J = 4.8Hz, 3H); 2.43 (s, 3H) (M + H) + = 300 A < 10 76. 2- (3-chloro4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine * H NMR in CDC13: 8.62 (s, 1H) ; 8.08 (dd, J = 7.2,1.8Hz, 1H); 7.88 (m, 1H); 7.58 (m, 2H); 7.10 (d, J = 2.4Hz, 1H); 6.98 (dd, J = 8: l , 2.4Hz, 1H); 3.82 (s, 3H); 2.84 ((t J = 4.8Hz, 3H) (M + H) + = 334 B < 10 77. 2- (4-Chloro-3-fluoro-phenyl) > 5-methoxy 4-methyl-3-carboxylic acid methylamine * Η NMR in CDC13: 8.48 (s, IH ); 7.93 (d, J = 1.2Hz, 1H); 7.90 (m, 2H); 159 (d, J = 9.0HzT 1H); 7.12 (d, J = 2.4Hz, 1H); 7.04 (dd, J = 9.0, 2.4Hz, 1H); 3.82 (s, 3H); 2.85 (d, J = 4.5Hz, 3H) (M + H) + = 334 A < 10 78. 5-methoxymethyl-2-phenyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.90 (d of d, J = 8.2Hz, 2H); 7.83 (sT 1H); 7.51-7.42 (m, 4H); 7.34 (d, J = 8.8Hz, 1H); 5.83 (brs, 1H); 4.56 (s, 2H); 3.41 (s, 3H); 3.00 (d, J = 4.7Hz, 3H) (M + H) + = 296 B < 30 79. 2_ (4-amino-phenyl) -5_ isopropoxy-6-methyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CD30D: 7.85 (dd, 2H); 7.31 (s, 1H); 7.20 (dd, 2H); 7.10 (s, 1H); 4.61 (ra, 1H); 2.92 (s, 3H); 2.29 (s, 3H); 1.37 (d, 6H) ppm ( M + H) + = 342 A < 10 80. _2- (4-Gas-phenyl) -5-isopropoxy-7-methyl-benzofuran-3-methanoformamidine 1H NMR in CD30D: 7.85 (dd, 2H ); 7.25 (d, 1H); 7.20 (dd, 2H); 6.80 (d, 1H); 4.61 (m, 1H); 2.92 (s, 3H); 2.38 (s, 3H); 1.37 (d, 6H) ppm (M + H) + = 342 B < 30 81. 2- (4-Gasyl-benzyl) -5-methoxy-6-methyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDCI3: 7.9 (dd, 2H) ; 7.26 (st 1H); 7.22 (s, 1H); 7.16 (dd, 2H); 5.78 (s, 1H, br); 3.89 (s, 3H); 2.98 (d, 3H); 2.33 (s, 3H) ppm (M + H) + = 314 A < 10 82. 5-Fluoro-2- (4-fluoro-epoxy) -benzofuran-3-carboxylic acid formamide 1H NMR in CDCi3: 7.93-7.88 (in, 2H); 7.48 (dd , J = 2.7HzT 8.4Hz, 1H); 7.41 (dd, J = 3.9Hz, 8.7Hz, 1H); 7.21-7.14 (m, 2H); 7.06 (td, J = 2.7Hz, 8.7Hz, 1H); 5.86 (s, 1H); 2.98 (d, J = 4.8Hz, 3H) (M + H) + = 288 B < 30 83. 2- (4-ethyl-phenyl) -5-fluoro-benzofuran-3-carboxamide 1H NMR in CDC13: 7.77 (d, J = 7.8Hz, 2H); 7.59 (dd, J = 2.7Hz, 8.4Hz, 1H); 7.41 (dd, J = 4.5Hz, 8.7Hz, 1H); 7.33 (d, J = 8.4Hz, 2H); 7.03 (td, J = 2.4Hz, 8.7Hz, 1H); 5.79 (s, 1H); 2.96 (d, J = 5.1Hz, 3H); 2.72 (q, J = 7.8Hz, 15.3Hz, 2H); 1-29 (t, J = 7.5Hz , 3H) (M + H) + = 298 A < 10 84. 5-ethyl-2-phenyl-benzofuran-3-carboxylic acid methylamine 1H NMR in CDCb: 7.89 (m, 3H); 7.70 (s, 1H); 7.5-7.37 (m , 3H); 7.15 (m, 1H); 5.81 (br s, 1H); 3.0 (d, 3H); 2.76 (q, 2H); 1.25 (t, 3H) (Μ + ΗΓ = 280 B < 30 85. 2- (5-chlorosethen-2-yl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.32 (s, 1H); 7.67 (d, J = 4.2Hz, 1H); 7.54 (d, J = 9.0Hz, 1H); 7.22 (d, J = 4.2Hz, 1H); 7.15 (s, 1H); 6.98 (d, J = 6.9Hz , 1H); 3.81 (s, 3H); 2.84 (d, J = 4.5Hz, 3H) (Μ + ΗΓ = 322 A < 10 181-88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ. B = 03 to ^ 5.0 μΜ C = 5.0 to ^ 30 D = > 30 μΜ replicon (μΜ) 86.5 5-isopropoxy-2-phenyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.87 (m, 2H); 7.74 (s, 1H); 7.54-7.43 (m, 4H); Ί21-123 (m, 1H); 5.82 (br s, 1H); 3.10-3.00 (m + d, 4H); 1.33 (d, 6H) (2M + Na) + = 609.2 A < 10 87. 2- (5-Gas-p-phenen-2-yl) -5-ethoxy-benzofuran-3-carboxylic acid formamide 1HNMRinCDCl3: 7.72 (d, J = 3.6Hz, 1H); 738 (d, J = 8.1HzT 1H); 7.14 (d, J = 2.4Hz, 1H); 6.95 (d, J = 3.9Hz, 1H); 6.92 (d, J = 2.4HzT 1H); 5.98 (s, 1H) 4.10 (q, 2H); 3.07 (d, J = 4.5Hz, 3H); 1.45 (t, 3H) (M + H) + = 336 A < 10 88. 5-Methoxy-2-pyrimin-2-yl-benzofuran-3-quinoformamidine 1H NMR in DMSO: 8.38 (s, 1H); 7.83 (d, J = 3.3 Hz, 1H); 7.76 (d, J = 5.4Hzt 1H); 7.55 (d, J = 9.0Hz, 1H); 7.21 (m, 1H); 7.11 (cU = 2.1Hz, 1H); 6.97 (dd, J = 9.0, 2.4Hz, 1H); 3.82 (s, 3H); 2.86 (dT J = 4.5HzT 3H) (M + H) + = 288 B < 30 89. 5-Chloro-2-pyridin-3-yl-benzofuran-3-chitoic acid formamidine. Ή NMR in CDC13: 9.15-9.14 (m, 1H); 8.68-8.66 (m, 1H); 8.33-8.29 (m, 1H); 7.77 (d, J = 2.1Hz, 1H); 7.49-7.39 (m, 2H); 7.34 (dd, J = 2.1Hz, 8.7Hz, 1H); 6.0 ( s, 1H); 3.04 (cU = 4.8Hz, 3H) (M + H) + = 286.9 B > 30 90. 2- (4-bromo-3-fluorophenyl) -5 · isopropoxy -Benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.45 (d, J = 3.9Hz, 1H); 7.88 (dd, J = 8.4, 2.4Hz, 1H); 7.85 (d, J = 3.0 Hz, 1H); 7.67 (dd, J = 9.0, 1.8Hz, 1H); 7.57 (d, J = 8.1Hz, IH); 7.10 (d, J = 2.4Hz, 1H); 7.02 (dd, J = 9.3 , 2.7Hz, 1H); 4.64 (m, 1H); 2.84 (d, J = 4.8Hz, 3H); 1.29 (d, J = 6.0Hz, 6H) (M + H) + = 406 A < 10 91. 2- (2,4-difluoro-phenyl) -5-isopropoxy-benzofuran-3-methanoic acid formamide NMR in DMSO: 8.04 (d, J = 7.2Hz , 1H); 7.82 (d, J = 6.3Hz, 1H); 7.56 (d, J = 9.3Hz, 1H); 7.46 (d, J = 9.3Hz, 1H); 7.30 (d, J = 2.4Hz, 1H ); 7.20 (d, J = 2.1Hz, 1H); 6.99 (dd, J = 8.1T 2.4Hz, 1H); 4.61 (m, 1H); 2.75 (d, J = 4.8Hz, 3H); 1.30 (d , J = 6.0Hz, 6H) (Μ + ΗΓ = 345 A < 30 92. 6-bromo-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine * 氺 氺 (M + H) + = 406 A < 1 93. 5-methoxy-2- (4-morpholin-4-yl-benzene grave) -benzofuran-3-carboxylic acid amidine 'H NMR in CDC13: 7.76 (dd, J = 4.8, 3.0Hz, 2H); 7.37 (m, 2H); 6.97 (dd, J = 9.0, 1.8Hz, 2H); 6.89 (dd, J = 8.1, 2.1Hz, 1H); 5.84 (m, 1H) ; 3.87 (s, 3H); 3.88 (t, 4H); 3.27 (t, 4H); 2.96 (d, J = 5.4Hz, 3H) (M + H) + = 367 B > 30 94. 5,6 -Dimethoxytolyl-benzobenzamidine-3-Heptachlor methionamine 1H NMR in CDC13: 7.79 (d, 6.4Hz, 2H); 7.52-7.40 (m, 3H); 7.38 (s, 1H ); 7.06 (s, 1H); 5.78 (brs, 1H); 3.96 (s, 3H); 3.94 (s, 3H); 2.96 (d, J = 4.7Hz, 3H) (M + H) + = 312 A < 1 95. 5-Isopropoxylyl-2- (4-1 ^ pyridin-1-yl-phenyl) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO:. 8.16 ( s, iH); 7.71 (d, J = 8.1Hz, 2H); 7.45 (d, J = 8.1Hz, 1H); 7.01 (d, J = 1.8Hz, 1H); 6.85 (dd, J = 8.1, 2.1 Hz, 1H); 6.62 (d, J = 8.1Hz, 2H); 4.58 (m, 1H); 2.81 (d, J = 3.9Hz, 3H); 2.00 (m, 4H); 1.38 (d, J = 6.0 Hz, 6H) (M + H) + = 379 C < 30 96. 5-amino-2-17-pyridin-4-yl-benzofuran carboxylic acid formamidine 1H NMR in CDCb: 8.75-8.73 (m, 2H); 7.87-7.84 (m, 2H ); 7.53-7.43 (m, 2H); 7.18-7.10 (m, 1H); 5.92 (bs, 1H); 3.09 (d, J = 4.8Hz, 3H) (M + H) + = 271 B > 30 182- 88828.doc 200418452 Instance data name NMR data Mass Spec HCV pol -BB7 ICs〇 (/ iM) A = 彡 0 * 5 / iM B = 03 to ^ 5.0 C = 5.0 to ^ 30 μM D = > 30 fiM Replicon (μM) 97.… 2- [2-0-Fluoro-phenyl> 6-methyl-3-methylamine Shen-benzo-benzo-5-yloxy] -propionic acid lH NMR in acetic-rfj acid-rf (CD3C02D): 8.75-8.73 (m, 2H); 7.87-7.84 (m, 2H); 7.53-7.43 (mT 2H); 7.18-7.10 (m, 1H); 5.92 ( bs, 1H); 3.09 (d, J = 4.8Hz, 3H) (M + H) + = 371 c > 30 98. 6-Ethylamido-2- (4-fluoro-phenyl)- 5-isopropoxy-benzofuran-3- # methaneformamide 1H NMR in CDC13: 8.66 (s, 1H); 7.99 (s, 1H); 7.82 (dd, 2H, J = 5.2 & 8.7 Hz); 7.37 (s, 1H); 7.18 (t, 2H, J = 8.7Hz); 5.78 (bs, 1H); 4.70 (heptuplet, J = 6.1Hz); 2.96 (df 3H, J = 4.9Hz); 2.24 (s, 3H); 1.41 (d, 6H, J = 6.1Hz) (M + H) + = 85 A < 10 99. 2- (4-Amino-phenyl) -5_ isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.64-7.67 (d, J = 8.79Hz, 2H); 7.41-7.42 (d, J = 2.93Hz, 1H); 7.32-7.35 (d, J = 8.79Hz, 1H); 6.86-6.90 (dofd, J = 2.33Hz, 8.79Hz, 1H); 6.74- 6.77 (d, J = 7.03Hz? 2H); 5.84 (br.s, 1H); 4.56-4.64 (septet, J = 6.45Hz, 1H); 2.96-2.97 (d, J = 4.69Hz, 3H); 1.35 -1.37 (d, J = 6.45Hz, 6H) (M + H) + = 325 B < 30 100. 2- (4-Dentyl-epiyl) -5_ isopropoxy-6- (2-morpho-pson 4-yl-ethylamine plug) -benzofuran-3-fatanoate Lamine 1H NMR in DMSO: 8.22-8.24 (d, J = 4.69Hz, 1H); 7.82-7.87 (m, 2H); 7.28-7.34 (t, i = 8.79Hz, 2H); 6.98 (s, 1H) ; 6.79 (s, 1H); 5.28 (brs, 1H); 4.56 (brs, 1H); 3.60 (brs, 3H); 3.23 (brs, 3H); 2.81-2.82 (d, J = 4.69Hz, 3H); 2.61 (brs, 1H); 2.43 (brs, 3H); 1.31-1.33 (d, J = 5.86Hz, 6H) (M + H) + = 456 B < 30 101. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-hexahydroethan-1-yl-benzoanan-3-carboxylic acid amidine 1H NMR in CDCI3: 7.89-7.84 (m, 2H); 7.23 (s, 1H); 7.14 (t, J = 8.79, 2H); 7.04 (s, 1H); 5.78 (bs, 1H); 4.69-4.29 (septet, J = 6.15, 1H); 3.05-3.01 (ra, 4H); 2.98 (d, J = 5.27, 3H); 1.77-1.72 (m, 4H); 1.60-1.59 (rn, 2H); 1.36 (d, J = 6.15, 6H) (M + H) + = 411 A < 1 102. 2_ (4-fluoro-phenyl) -5,6-dimethoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.85-7.81 (m, 2H); 7.32 (s, 1H); 7.25-7.20 (m, 2H); 7.05 (s, 1H); 5.75 (brs, 1H); 3.96 (s, 3H); 3.947 (s, 3H); 2.98 (d, J = 4.2Hz, 3H) (M + H) + = 330 A < 1 103. 2- (4-Gasyl-epoxy) -5-methoxyi-6-morpho ^ 7 Lin-4-i-dong and bitanan-3-carboxamide TH NMR in CDCl3 : 7.85-7.81 (m, 2H); 7.30 (s, IH); 7.17 (t, J = 8.8Hz, 2H); 7.08 (s, 1H); 3.94 (s, 3H); 3.94-3.91 (m, 4H ); 3.11-3.09 (m, 4H); 2.98 (d, J = 4.7Hz, 3H) (M + H) + = 385 A < 1 104. 2- (4- > Stylo-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDCI3: 7.80 (d, 2H, J = 8.79); 7.61 (d, 2H, J = 8.79); 7.39 (d, 1H, J = 8.79); 7.28 (d, 1H, J = 2.34); 6.94 (dd, 1H, J = 8.79, 2.34); 5.80 (brs, 1H); 4.58 (m, 1H); 3.01 (d, 3H, J = 4.69); 1.36 (d, 6H, J = 6.45), (M + H) + = 288 A < 10 105. 2- (4-Fluoro-3-hydroxy-phenyl) -5-isopropoxy-benzofuran-3-methanoic acid formamidine 1H NMR in DMSO: 10.18 (brs, 1H) ; 8.32 (d, 1H, J = 4.69); 7.50 (rn, 2H); 7.26 (in, 2H); 7.03 (d, 1H, J = 2.34); 6.93 (dd, 1H, J = 8.79, 2.34); 4.58 (m, 1H); 2.81 (d, 3H, J = 4.69); 1.26 (d, 6H, J = 5.86) (M + H) + = 344 C < 30 106. 2_ (4-Gasyl-benzyl) -5-isopropoxy-benzocarboxamidine carboxylic acid formamide NMR in CDCI3: 8.11 (d, 2H, J = 8.21); 7.74 (d, 2H, J = 8.79); 7.43 (d, 1H, J = 9.38); 7.20 (d, 1H, J = 2.34); 7.00 (dd, IH, J = 8.79, 2.34); 5.88 (brs, 1H ); 4.58 (m, IH); 3.06 (d, 3H, J = 4.69); 1.36 (d, 6H, J = 6.45) (M + H) + = 335 B < 30 183-88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 IC5〇 QiM) A = < 0 * 5 / «MB = 0 * 5 to s5.0 / tM C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon (μΜ) 107.5 5-methoxy-2-pyridylbenzyl- 1H NMR in CDC13: 8.72 (d, J = 5.4H3, 2H); 7.83 (dd, J-1.8H3, 4.5H3, 2H); 7.45 (d, J = 9.0H3, 1H); 7.20 (d, J = 2.2H3, 1H); 7.01 (dd, J = 2.7H3, 8.7H3, 1H); 5.90 (bs, 1H); 3.88 (s, 3H); 3.08 (d , J = 4.8H3, 3H) (M + H) + = 283 B < 100 108. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (3-methylsulfonyl-St-yl-E4Yodo small group) -benzoxan-3-a Formamidine acid 1U NMR in DMSO: 7.90 (dd, J = 1.8,5.3Hz, 2H); 7.33 (t, J = 8.8Hz, 2H); 7.07 (s, 1H); 7.05 (s, 1H); 4.63 (p, J = 6.4Hz, 1H); 3.96-3.86 (m, 2H); 3.49-3.32 (m, 2H); 3.03 (s, 3H); 2.82 (s, 3H); 231 (m, 2H); 1.33 (d, J = 1.2Hzt 6H) (M + H) + = 475 A < 1 109. 6-trimethylenepentamin-1-yl_2_ (4-amino-phenyl) -5-iso-methyl-benzyl-3-carboxylic acid formamidine 1H NMR in CDC13: 7.82 (dd, J = 5.3, 8.8Hz, 2H); 7.13 (s, 1H); 7.13 (t, J = 8.2Hz, 2H); 6.54 (s, 1H); 4.60 (p, J = 5.9Hz (1H); 3.96 (t, J = 7.6Hz, 4H); 2.97 (d, J = 5.3Hz, 3H); 2.29 (p, J = 7.0Hz, 2H); 1.36 (d, J = 6.4Hz, 6H ) (M + H) + = 383 A < 1 110. hydrazone (4-fluoroi-phenyl) -6- (3-meryl-p-pyrolodin-1-yl) -5-isopropoxy-benzofuran-3-chinoic acid Amine (M + H) + = 413 A < 1 111. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (methanesulfonyl-methyl-amino) -benzofuran-3-fatty acid formamidine Amine * H NMR in CDC13: 7.81 (2H, dd, J = 5.3, 8.8Hz); 7.56 (1H, s) 7.42 (1H, s); 7.20 (2H, r, J = 8.8Hz); 5.70 (1H, bs); 4.80 (1H, heptuplet, J = 6.2Hz); 3.32 (3H, s); 2.98 (3H, s); 2.96 (3H, s); 1.42 (3H, d, J = 6.2Hz) (M + H) + = 435 A < 1 112. 2_ (4-Aminophenyl) -6 _ [(crean-3_ylmethyl) -amino] -5-isopropoxy-benzocran-3-chinoic acid Lamine 1H NMR in CDC13: 7.76-7.81 (m, 2H); 7.37 (d, J = U7, 1H); 7.17 (s, 1H); 7.086-7.145 (t, J = 8.79, 2H); 6.746 (s , 1H); 6.319-6.328 (m, 1H); 6.242-6.252 (d, J = 2.93, 1H); 5.86 (bs, 1H); 4.565-4.645 (septet, J = 6.45, 1H); 4.365 (s, 2H); 2.940 -2.955 (d, J = 4.69, 3H); 1.375-1.254 (d, J = 6.45,6H) (M + H) + = 423 A < 1 113. 6- (2,3-Dimethynylpropylamine grave) -2- (4-Gasyl-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid methyl ester Amidine (Η NMR in CDCl3: 7.78 (bs, 2H); 7.12 (rn, 4H); 6.72 (bs, 1H); 5.84 (d, J = 4.7 Hz, 1H); 4.60 (p, J = 5.9 Hz, 1H); 4.01 (m, 1H); 3.80 (dd, J = 3.52, 11.1 HZ, IH); 3.66 (dd, J = 5.9, 11.1 Hz, 1H); 2.96 (d, 1 = 4.1 Hz, 3H); 1.37 (dd, J = 1.8, 5.9 Hz, 6H) (M + H) + = 417 B < 10 114. 2_ (4-Fluoro-phenyl) -5-isopropoxy-6-isopropylamino-benzofuran-3-methanoate * H NMR in CDCI3: 7.805 -7.834 (m, 2H); 7.151 (s, 1H); 7.100-7.127 (m, 2H); 6.680 (s, lH); 5.900 (bs, 1H); 4.580-4.600 (septet, J = 5.861, 1H ); 3.662-3.686 (septet, J = 7.033, 1H); 2.955 -2.971 (d, J = 4.688, 3H); 2.057 (s, 1H); 1.361 -1.381 (d, J = 5.861, 6H); 1.258- 1.277 (d, J = 5.861,6H) (M + H) + = 385 A < 1 184- 88828.doc 200418452 Instance number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 / iM Copy (ΜΜ) 115. 6- (Cyclopropylmethyl-amino) -2- (4-amino-winteryl) -5-isopropoxy-benzofuran-3-carboxylic acid methylamine 1H NMR in CDC13: 7.780-7.866 (m, 2H); 7.176 (s, IH); 7.104 -7.160 (m, 2H); 6.664 (s, 1H); 5.781 (bs, 1H); 4.567-4.647 (septet, J = 5.86l, 1H); 3.000 -3.024 (d, J = 7.033,2H); 2.965-2.981 (d, J = 4.689, 3H); 1.502-1.676 (m, 1H); 1.383 -1.402 (m, 1H) ; 1.211-1.172 (m, 1H); 0.557 -0.619 (m, 1H); 0.262-.0311 (m, 1H) (M + H) + = 397 A < 1 116. 2- (4-Fluoro-phenyl) -5 ^ methoxy-6-pyrrolidin-1-yl-benzofuran-3-methaneformate 1H NMR in CDC13: 8.28 (d, 1 = 4.40, 1H); 7.89-7.84 (m, 2H); 7.31 (t, J = 8.79, 2H); 7.00 (s, 1H); 6.91 (s, 1H); 3.81 (s, 3H) ; 3.29 (m, 4H); 2.82 (d, J = 4.40, 3H); i.88 (m, 4H) (M + HT = 369 A < 1 117.5 5'-Methoxy-2- (4-fluoro-phenyl) -6-morpholine > --- NMR in CDCb: 7.788-7.83 (m, 2H); 7.60-7.09 (m, 9H); 5.71 (bs, 1H); 5.19 (s, 2H); 3.90-3.87 (m, 4H); 3.17- 3.15 (m, 4H); 2.98 (d, J = 51.Hz, 3H) (M + H) + = 461 A < 1 118. 5-Hydroxymethyl-2-phenyl, benzofuran-3-methanoate, 1H NMR in CDC13: 7.98-7.87 (m, 3H); 7.53-7.43 (mT 4H); 7.38 (d, J = 7.0Hz, 1H); 5.84 (br s, 1H); 4.83 (d, J = 6.0Hz, 2H); 2.99 (d, J = 5.3Hz, 3H) (M + H) + = 282 C > 100 119. 2- (4-Amino-phenyl) -5-isopropoxy-6-K2-methoxy-ethyl) -methyl-amino] -benzofuran Amidine * H NMR in CDCI3: 7.86-7.82 (m, 2H); 7.26-7.24 (m, 1H); 7.15 (t, J = 8.35Hz, 2H); 7.08 (s, 1H); 5.76 (s, 1H ); 4.70-4.62 (septet, J = 6.15Hz, 1H); 3.59 (tt J = 6.15Hz, 2H); 3.37-3.35 (m, 2H); 3.33 (s, IH); 2.98 (d, J = 4.83 Hz, 3H); 2.92 (s, 3H); 1.39 (d, J = 6.15Hz, 6H) (M + H) + = 415 A < 1 120. 6-Amino-5-benzyloxy-2- (4-fluoro-phenyl) -benzofuran-3-guidate formamidine 1H NMR in CDC13: 7.86-7.80 (m, 2H); 7.45-7.33 (m, 5H); 7.287 (s, 1H); 7.17-7.12 (m, 2H); 6.85 (s, 1H); 5.71 (brs, 1H); 5.15 (s, 2H); 2.97 (d, J = 5.3Hz, 3H) (M + H) + = 391 A < 10 121. 5-Isopropyloxy-succin-2-yl) -benzofuran-3-carboxylic acid formamidine 1H NMR in CDCI3: 7.664-7.674 (d, J = 2.931, 1H); 7.512-7.518 (d, J = L.759, 1H); 7.319-7.348 (d, J = 8.792, 1H); 6.893-6.932 (d of d, J = 2.931, 5.861, 1H); 6.721 (bs, 1H ); 6.448-6.453 (d, J = 1.759, IH); 4.584-4.664 (septet, J = 5.861, 1H); 3.006-3.024 (d, J = 5.275, 3H); 2.322 (s, 3H); 1.344- 1.363 (d, J = 5.861, 6H) 氺 氺 氺 B < 30 122. 2_ (4-fluorophenyl) -6_methanesulfonylamino-5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.37 (m, 1H) ; 7.93 (dd, J = 5.1 & 9.1 Hz, 2H); 7.56 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.17 (s, iH); 3.90 (s, 3H); 2.98 (s, 3H); 2.83 (d, J = 4.9 Hz, 3H) (M + H) + = 393 A < 1 185-88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 0 J to ^ 5.0 μ, Μ C = 5.0 to ^ 30 fiM D = > 30 μM replicon < JiM) 123. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-[(tetramus-4an-2-ylmethyl grave) -amino] -benzofuran- 3-carboxylic acid formamidine 1H NMR in DMSO: 8.27 (d, br, 1H); 7.88 (dd, 2H); 7.31 (dd, 2H); 6.92 (s, 1H); 6.84 (s, 1H); 4.98 (m, 1H); 4.57 (m, 1H); 4.11 (m, 1H); 3.8-3.64 (mt 2H); 3.16 (m, 1H); 2.82 (d, 3H); 1.84-1.42 (m, 4H) ; 1.35 (d, 6H) (M + H) + = 427 A < 10 124. .5 (4-fluoro-phenyl) -5-year-old f-yl-6-morphoρ · fluoren-4-yl-benzofuran-3-quinoline formamidine 1H NMR in CDC13 : 8.00-7.95 (m, 2H); 7.36-7.26 (m, 2H); 7.21 -7.18 (m, 2H); 6.98 (bs, 1H); 5.83 (bs, 1H); 3.95-3.92 (m, 4H) ; 3.04 (d, J = 5.1Hz, 3H); 2.97-2.96 (m, 4H) (M + H) + = 370 B < 10 125. 5-Cyclopropylmethoxy-2- (4-fluoro-phenyl) -6-morphol 4-4-yl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDCb: 7.89-7.84 (m, 2H); 7.30 (s, 1H); 7.22-7.16 (m, 2H); 7.08 (s, 1H); 5.76 (bs, 1H); 3.94 -3.97 (m, 6H); 3.20-3.17 (m, 2H); 3.01 (d, J = 4.8, 2H); 0.71-0.64 (m, 2H); 0.42-0.38 (m, 2H) (M + H) + = 425 A < 1 126. 6-Ethyl-2- (4-amino-winteryl) -5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.86-7.81 (m, 2H); 7.54 (s, 1H); 7.42 (s, 1H); 7.23-716 (m, 2H); 5.77 (brs, 1H); 3.96 (S, 3H); 2.98 (d,) = 4.1 Hz, 3H ) (M + H) + = 334.0 A < 1 127.6- (2,5-dimethyl-2H-pyrazol-3-ylamino) -2- (4-fluoro-phenyl) · 5-isopropoxy-benzo4 Methane-3-carboxylic acid formamidine * H NMR in CDC13: 7.782-7.826 (m, 2H); 7.352 (s, 1H); 7.137-7.194 (m, 2H); 6.840 (s, 1H); 6.069 (s , 1H); 5.930 (s, iH); 5.795 (bs, 1H); 4.686-4.746 (septet, J = 6.447, 1H); 3.695 (s, 3H); 2.986-3.004 (d, J = 5.275, 3H) ; 2.287 (s, 1H); 1.645 (bs, 2H); i.436-1.457 (d, J = 6.447, 3H) (M + H) + = 437.0 C 氺 氺 氺 128. 2_ (4_fluoro group- Phenyl) -6-morpholin plin-4-methyl-5-(^ 7bipyridin-4-ylmethoxy) -benzofuran-3-chimonate formamidine'H NMR in CDC13: 8.68-8.65 (m, 2H); 7.87-7.82 (m, 2H); 7.40-7.43 (m, 3H); 7.25-7.15 (ra, 3H); 5.70 (bs, 1H); 5.23 (3, 2H): 3.98-3.92 (m, 4H); 3.15-3.21 (m, 4H): 2.99 (d, J = 48 Hz, 3H) (M + H) + = 462 A 氺 氺 氺 129. 6-yl-2- (4-gas Methyl-phenyl) -5-isoamyloxy-benzofuran-3-quinoline formamidine * H NMR in CDC13: 7.87-7.82 (m, 2H): 7.67 (s, iH); 7.45 (s, 1H); 7.26-7.19 (m, 2H); 5.73 (bs, 1H); 4.75-4.67 (m, iH); 2.98 (d, J = 4.8 Hz, 3H); 1.43 (d, J = 6.3 Hz, 6H ) (M + H) + = 353 A 氺 氺 氺 130. 5-methoxy-2-phenyl-benzoxan-3-acetamidine 1H NMR in CDC13: 7.86 (dd, J = 2.1, 7.4 Hz, 2H); 7.47 (m, 3H); 7.39 (ra, 2H); 5.78 (brs, 1H); 3.88 (s, 3H); 6.94 (dd, J = 2.6, 9.0 Hz, 1H); 3.48 (dq, J = 1.3, 7.2 Hz, 2H); 1.17 (t, 7.2 Hz, 3H) (M + H) + = 295 C < 10 131. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (4-amidoamino) -benzofuran-3-carboxylic acid formamidine 1H NMR in CDCi3 : 8.29-8.31 (d, 2H, J = 5.86Hz); 7.80-7.84 (m, 2H); 7.51 (s, iH); 7.36 (s, 1H); 7.13-7.19 (t, 2H, J = 8.21Hz ); 6.95-6.98 (m, 2H); 6.62 (s, 1H); 6.13-6.15 (d, 1H, J = 4.69Hz); 4.60-4.68 (septet, lH, J = 5.86Hz); 2.97-2.99 ( d, 3H, J = 5.28Hz); 1.37-1.39 (d, 6H, J = 5.86Hz) (M + H) + = 420 B < 30 186- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = ί0.5 · / ιΜ B = (K5 to 彡 5.0 / iM C = 5.0 to ^ 30 / iM D = > 30 μM replicon_ 132. 2- (4-fluoro-phenyl) -5-isopropoxy-6- (4-methyl-hexahydropyrine-1-yl) -benzofuran complex Methylamine 1H NMR in DMSO: 7.80-7.86 (m, 2H); 7.21 (s, 1H); 7.09-7.15 (t, 2H, J = 8.79Hz); 6.99 (s, 1H); 6.12-6.14 ( d, 1H, J = 4.69Hz); 4.58-4.66 (septet, 9H, J = 6.45 Hz); 3.10 (brs, 4H); 2.95-2.96 (dT 3H, J = 4.69Hz); 2.58 (brs, 4H) ; 2.34 (s, 3H); 134-1.36 (d, 6H, J = 6.45 Hz) (M + H) + = 426 C > 30 133. Gas-propyl: fe-1-phenylamino -2- (4-Fluoro-phenyl) -5-isopropoxy-benzo-p-furan-3-methanamine'H NMR in DMSO: 9.1 i (s, lH); 8.37 (m , 1H); 7.92 (dd, J = 8.8 & 5.7 Ha 2H); 7.56 (s, 1H); 7.36 仏 J = 8.8 Hz, 2H); 7.16 (s7 IH); 4.74 (heptuplet, J = 5.7 Hz, IH); 3.74 (t, J = 6.6Hz, 2H); 3.21 (m, 2H); 2.82 (d, J = 4.8Hz, 3H); 2.21 (m, 2H); 135 (d, J = 5.7 Hz, 6H) (MH) = 481; 483 B < 1 134. 6- (1,1-Dioxy-1λ6-isopyrimidin-2-yl) -2- (4-amino-phenyl) -5-isonanoxy! yl-benzyl Wean · 3_carboxylic acid formamidine 1H NMR in DMSO: 8.40 (ra, 1H); 7.92 (dd, J = 5.5 d 9.2 Hz, 2H); 7.60 (s, 1H); 7.37 (t, J = 9.2 Hz, 2H); 7.19 (s, 1H); 4.69 (heptuplet, J = 5.9 Hz, 1H); 3.75 (t, J = 7.0 Hz, 2H); 3.37 (m, 2H); 2.82 (d, J = 4.9 Hz, 3H); 2.43 (p, J = 7.0 Hz, 2H); 1.34 (d, J = 5.9 Hz, 6H) (M + HT = 447 B < 10 135.2 2- (4-fluoro-phenyl)- < Isopropoxy-6-adenosyl-benzofuran-3-metanoformamide'H NMR in DMSO: 8.38 (s, 1H); 8.28 (m, 1H); 7.87 (dd, J = 5.3 & 9.2 Hz, 2H); 7.30 (t, J = 8.8 Hz, 2 H); 7.09 (s, 1H); 6.39 (bs, 2H); 4.62 (heptuplet, J = 6.1 Hz, 1H); 2.80 (d , J = 4.8 Hz, 3H); 1.88 (s, 1H); 1.32 (d, J = 5.7 Hz, 6H) (M + H) + = 486 A < 10 136. 2- (4-Amino-phenyl) -5_ isopropoxy-6- (isopropyl-methanesulfonyl-amino) -benzofuran stomach 3-metamethamine lH NMR in DMSO: 8.40 (m, 1H); 7.90 (dd, J = 5.3 & 8.84 Hz, 2H); 7.69 (s, 1H); 7.36 (t, J = 8.8 Hz, 2H); 7.11 (s, 1H); 4.75 (heptuplet, J = 6.6 Hz, 2H); 4.22 (heptuplet, J = 7.1 Hz, 1H); 3.06 (s, 3H); 2.80 (d, J = 7.1 Hz, 3H); 1.32 (t, J = 6.6 Hz, 6H); 1.20 (d, J = 7.1 Hz, 3H); 1.05 (d, J = 7.1 Hz, 3H) (M + H) + = 463 A < 1 137.6- (Cyclopropylmethyl-methylsulfonyl-amino) > 2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid Formamidine 1H NMR iQ DMSO: 8.44 (m, 1H); 7.94 (dd, J = 5.1 & 9.1 Hz, 2H); 7.57 (s, 1H); 7.38 (t, J = 8.8 Hz, 2H); 7.16 (s, 1H); 6.78 (heptuplet, J = 5.7Hz, 1H); 3.01 (s, 3H); 2.83 (d, J = 4.4 Hz, 3H); 1.33 (d, J = 5.7 Hz, 6H); 0.85 (m, 1H); 0.37 (m, 2H) (M ten H) + = 475 A < 1 138.6 6- (2,6-dimethyl-morpho 14-yl) -2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-metanoic acid Formamidine 1H NMR in CDC13: 7.89-7.84 (m, 2H); 7.28 (d, J = 8.79 Hz, 1H); 7.17 (T, J = 8.79 Hz, 2H); 7.04 (s, 1H); 5.77 ( s, 1H); 4.69-4.61 (septet, J = 6.15 Hz, IH); 3.95-3.89 (m, 2H); 3.46 (d, J = 11.43 Hz, 2H); 2.98 (d, J = 4.84 Hz, 3H ); 2.37 (T, J = l0 '. 55 Hz, 2H); 1.37 (d, J = 6.15 Hz, 6H); 1.25 (d, J = 6.15 Hz, 6H) (M + H) + = 441 B < 10 139. 2- (4 ** Fluoro-phenyl) -5_ isopropoxy-6- (1Η-tetra-5-yl) -phenylbenzofuran-3-carboxylic acid formamide 1H NMR ia CDCi3: 8.547 (s, 1H); 7.89-7.84 (m, 2H); 7.61 (s, 1H); 7.60-7.20 (m, 2H); 5.8 (bs, 1H); 5.0-4.92 (m, 1H) ; 3.26 (bs, 1H); 2.99 (d, J = 5.iHz, 3H); 1.52 (d, J = 6.0Hz, 6H) (M + H) + = 3% B > 30 187- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A = μΜ B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon (μΜ) 140. 2- (4 -Fluoro-phenyl) -6- (4-hydroxy-hexahydropyridine-1-yl) > 5-isopropoxy-benzofuran-3-chinoic acid methylamine 1H NMR in DMSO: 8.28 ( d, J = 4.84Hz, 1H); 7.92-7.86 (m, 2H); 7.33 (t, J = 8.79Hz, 2H); 7.16 (s, 1H); 7.03 (s, 1H); 4.64-4.56 (m , 2H); 3.61 (m, 1H); 3.35 (m, 2H); 2.82 (d, J = 4.40Hz, 3H); 2.74-2.67 (m, 2H); 1.88-1.85 (m, 2H); 1.62- 1.52 (m, 2H); 1.29 (d, J = 5.72Hz, 6H) (M + H) + = 427 B < 10 141. 2- (4-Fluoro-phenyl) -6- (3-hydroxy-hexahydroxyl) >1-yl;)-5-isopropoxy-benzofuran-3- Formamidine m acid 1H NMR in DMSO: 8.29 (d, J = 4.84Hz, 1H); 7.92-7.87 (m, 2H); 7.33 (t, J = 8.79HzT 2H); 7.14 (s, 1H); 7.03 (s, 1H); 4.73 (ci J = 4.84Hz, 1H); 4.63-4.55 (septet, J = 6.15Hz, 1H); 3.67 · 3 · 65 (m, 1H); 3.49 (d, J = 8.79Hz, 2H); 2.82 (d, J = 4.40Hz, 3H); 2.5 (m, 1H); 2.33 (t, J = 9.67Hz, 1H); 1.95-1.91 (m, 1H); 1.74 (m, 1H); 1.62-1.58 (m, 2H); 1.29 (d, J = 6.15Hz, 3H); 1.28 (d, J = 5.71, 3H) (M + H) + = 427 B < 10 142.2 2- (4-fluoro-phenyl): 5-isopropyllactyl ^ -6- (morpholin ^ sulfonyl) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.48-8.47 (d, J = 4.69Hz, 1H); 8.01 (s, 1H); 8.00-7.95 (m, 2H); 7.44-7.38 (t, J = 8.79Hz, 2H); 734 ( s, iH); 4.91-4.83 (septet, J = 5.86Hz, 1H); 3.62-3.59 (m, 4H); 3.16-3.13 (m, 4H); 2.85-2.84 (d, J = 4.69Hz, 3H) ; 1.37-1.35 (d, J = 5.86Hz, 6H) (M + H, = 477 A < 10 143. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methyl monthanite s & i-benzoanan-3-carboxylic acid formamidine 1H NMR in DMSO: 8.46-8.45 (d, J = 4.10Hz, 1H); 7.99-7.95 (m, 2H); 7.95 (s, 1H); 7.43-7.37 (t, J = 8.79Hz, 2H); 7.32 (s , 1H); 6.64 (d, J = 4.69Hz, 1H); 4.90-4.82 (septet, J = 5.86Hz, 1H); 2.85-2.83 (d, J = 4.69Hz, 3H); 2.48-2.46 (d, J = 4.69Hz, 3H); 1.38-1.36 (d, J = 5.86Hz, 6H) (M + ΗΓ = 421 A > 30 144. 6-dimethylaminesulfonyl- -2- (4-gas (Phenyl-phenyl) -5-isopropoxy-benzo-4anthidine carboxylic acid formamide 1H NMR in DMSO: 8.461 = 8.451 (d, J = 4.689Hz, 1H); 8.016-7.949 (m, 3H) ; 7.436-7.377 (t, J = 8.791Hz, 2H); 7.323 (s, 1H); 4.904-4.823 (septet, J = 5.861Hz, 1H); 2.848-2.832 (dT J = 4.689Hz, 3H); 2.775 (s, 6H); 1.365-1.344 (d, J = 6.447Hz, 6H) (M + H) + = 435 A < 30 145. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (propanesulfonylamino) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO : 8.85 (s, 1H); 8.36 (m, 1H); 7.91 (dd, J = 9.2, 5.3Hz, 2H); 7.59 (s, 1H); 736 (t, J = 8.8HzT 2H); 7.13 (s , 1H); 4.75 (heptuplet, J = 5.6Hz, 1H); 3.21 (heptuplet, J = 5.5Hz, 1H); 2.82 (d, J = 4.9Hz, 3H); 1.36 (d, J = 5.5Hz, 6H ); 1.28 (d, J = 5.6Hz, 6H) (M + H) + = 449 B < 10 146. 2- (4-Syridyl-phenyl) -5_ isopropoxy-benzofuran-3,6-dicarboxylic acid 6-amidamine-3-carboxamide 1U NMR in CDC13: 8.33 (s, 1H); 8.10 (bs, 1H); 7.88-7.84 (m, 2H); 7.48 (s, 1H); 7.25-7.18 (m, 2H); 5.88 (bs, 1H); 5.75 (bs, 1H) ); 4.88-4.80 (in, 1H); '2.99 (d, J = 5.4Hz, 3H); 1.46 (d, J = 6.3Hz, 6H) (M + H) + = 371 B > 30 147.2 -(4-Gasyl-wood-based) -5-isopropoxymethyl-benzoylpyranoate, 1H NMR in DMSO: 9.13 (s, 1H); 8.99 (s, 2H); 8.41 ( q, br, 1H); 7.92 (m, 2H); 7.82 (s, 1H); 7.36 (m, 2H); 7.27 (s, 1H); 4.64 (m, 1H); 2.83 (d, 3H); 1.23 (d, 6H) (M + H) + = 406 A < 10 188- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = B = 0 »5 to 彡 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 / iM Replicon (μM) 148. 6-Third-butylamino-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine NMR in CDC13: 7.85-7.80 (m, 2H); 7.18 (s, 1H); 7.14 (t, J = 8.79Hz, 2H); 6.98 (s, 1H); 5.74 (bs, 1H); 4.60-4.52 (septet, J = 6.15Hz, 1H); 4.57 (s, 1H); 2.97 (d, J = 4.84Hz, 3H); 1.41 (s, 9H); 1.37 (d, J = 6.15Hz, 6H) (M + H) + = 399 A < 10 149. 2- (4-Gas-wood-based) -5_ isopropoxy-6-aminosulfonyl-benzene + furan-3-methanamine jH NMR in DMSO: 8.39-8.37 (d, J = 4.69Hz, 1H); 7.97-7.93 (m, 2H); 7.91 (s, 1H); 7.39-7.33 (t, J = 8.79Hz, 2H); 7.07 (s, 1H); 4.66 ( septet, J = 6.45Hz, 1H); 2.84-2.82 (d, J = 4.69Hz, 3H); 1.30-1.28 (d, J = 6.45Hz, 6H) (MH) = 406.0 C > 30 150. 6 -Cyclobutylamine-2-methyl-4- (4-amino-phenyl) -5-isopyroxy-benzo-4an-3-carboxylic acid formamidine 1H NMR in CDC13: 8.057 (st 1H) ; 7.869-7.823 (m, 2H); 7.522 (s, 1H); 7.248-7.205 (rat 2H); 5.766 (bs, 1H); 5.156-5.125 (d, J = 9.377Hz, 1H); 4.895-4.813 ( septet, J = 5.862Hz, 1H); 3J87-3.707 (sextet, J = 8.206Hz, 1H); 2.984-2.969 (d, J = 4.689Hz, 3H); 2.063-1.967 (m, 2H); 1.828-1.734 (m, 2H); 1.580-1.512 (m, 2H); 1.494-1.475 (d, J = 5.862Hz, 6H) (M + H) + = 461.0 B < 30 151. 2- (4-Fluoro-phenyl) -6_ sulfan-2-yl-5-iso and oxy-benzoxan-3-chimonic acid formamidine 1H NMR in CDCl3: 7.96 (s, iH); 7.88 (m, 2H); 7.48 (d, 1H); 7.37 (s, 1H); 7.17 (m, 2H); 7.08 (d, IH); 6.51 (d, 1H); 5.75 ( s, br, 1H); 4.79 (m, IH); 2.99 (d, 3H); 1.45 (d, 6H) (M + H) + = 394 A < 30 152. 2- (4-Gas-phenyl) -6-furan-3-yl-5-isopropoxy-benzofuran-3-carboxylic acid formamidine * H NMR in CDCb: 8.12 (s , 1H); 7.90 (m, 2H); 7.61 (s, 1H); 7.48 (d, 1H); 7.38 (s, 1H); 7.18 (m, 2H); 6.83 (d, 1H); 5.75 (s, br, 1H); 4.79 (mT 1H); 2.99 (d, 3H); 1.45 (d, 6H) (M + H) + = 394 A < 10 153. 2- (4-Fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine NMR in CDC13: 8.80 (d, 1H); 8.57 (dd, 2H); 7.92 (m, 3H); 7.45 (s, 2H); 7.33 (dd, 1H); 7.20 (m, 2H); 5.80 (s, br, 1H); 4.56 (m, 1H); 2.99 (d , 3H); 1.28 (d, 6H) (M + H) + = 405 A < 10 154. 2- (4-Fluoro-phenyl) > 5: isoamyloxy-6-debiloline-1-phenylfluorenyl-benzobenzo-3-carboxylic acid formamidine 1H NMR in DMSO: 8.455-8.471 (m, 1H); 8.028 (s, 1H); 7.996-7.949 (m, 2H); 7.436-7.375 (m, 2H); 7.321 (s, 1H); 4.918-4.838 (septet , J = 5.861Hz, 1H); 2.846-2.832 (d, J = 4.103, 3H); 2.512-2.486 (peatet, J = 1.758Hz, 4H); 1.779-1.736 (t, J = 6.447Hz, 4H); 1.371-1.350 (d, J = 6.447Hzt 6H) (M + H) + = 461.0 A < 10 155. 6-Phosylpropylamine, 2- (4-muryl-phenyl) -5-isopropoxy-benzo-4an-3-carboxylic acid formamidine 1H NMR in DMSO : 8.47-8.46 (d, J = 41.0Hz, 1H); 8.03 (s, 1H); 8.00-7.94 (m, 2H); 7.44-7.38 (t, J = 8.79Hz, 2H); 7.32 (s, 1H ); 7.21 (s, 1H); 4.B9-4.85 (septet, J = 5.86Hz, 1H); 2.85-2.83 (d, J = 4.69Hz, 3H); 2.17 (m, 1H); 1.38-136 ( cl, J = 5.86Hz, 6H); 0.44 (m, 4H) (M + H) + = 447.0 A < 10 156. Ethylaminesulfonyl-2- (4-ranyl-private) -5-isopropoxy · benzobenzo-3-carboxylic acid formamidine 1H NMR in DMSO: 8.87 (s, 1H); 8.36 (m, 1H); 7.91 (dd, J = 9.0, 5.3Hz, 2H); 7.56 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.14 (s , 1H); 4.75 (heptuplet, J = 6.1Hz, 1H); 3.05 (quadruplet, J = 7.5Hz, 2H); 2.82 (cl, J = 4.8Hz, 3H); 1.33 (d, J = 6.1Hz, 6H ); 1.26 (t, J = 7.5Hz, 3H) (M + H) + = 435 A < 10 189- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 03 to ^ 5.0 μΜ C = 5.0 to < 30 μΜ D = > 30 μΜ replicon (μΜ) 157.2 2- (4-isopropoxy-6-vinyl-benzofuran-3-quinoline formamidine 1H NMR in DMSO: .8.39 (q, br, 1H); 7.91 (dd, 2H); 7.82 (s, 1H); 7.35 (dd, 2H); 7.12 (s, 1H); 7.05 (dd, 1H); 6.89 (d, 1H); 5.27 (d, 1H); 4.60 (m, 1H); 2.81 (d, 3H); 1.31 (d, 6H) (M + H) + = 354 A < 10 158.2. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methoxy-benzofuran-3-methaneformamide 1HNMRinCDCl3: 7.86 (m, 2H); 7.34 (s, 1H); 7.16 (t, J = 8.79Hz, 2H); 7.05 (s, 1H); 5.75 (brs, 1H); 4.55 (m, 1H); 3.91 (s, 3H); 2.99 (d , J = 4.69Hz, 3H); 1.39 (d, J = 5.86Hz, 6H) (M + H) + = 358 A < 10 159. 6- (3,5-dimethyl-isoxazolone: 10-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-gui Formamidine acid 1HNMRinCDCl3: 7.90-7.85 (m, 2H); 7.63 (s7 2H); 7.23-7.17 (m, 3H); 5.78 (brst 1H); 4.52-4.48 (m, 1H); 3.0 (d, J = 4.8Hz, 3H); 2.32 (s, 3H); 2.20 (s, 3H); 1.24 (d, J = 6.3Hz, 6H) (M + H) + = 423 A < 1 160. 2- (4-methylfluorenyl-5-isopropoxy-benzofuran-3-quinic acid formamidine 1H NMR in CDC13: 10.524 (s, 1H); 7.93 (s, 1H) ; 7.90-7.85 (m, 2H); 7.44 (s, 1H); 7.25-7.19 (m, 2H); 5.78 (br, 1H); 4.76 (pent, 1H); 2.98 (d, 3H); 1.43 (d , 6H) (M + H) + = 355.9 A < 30 161. 2- (4-Fluoro-phenyl) amino group-3-yl) -5-isopropoxy-benzofuran-3-quinoline formamidine * H NMR in CDCb: 8.52 (s, 1H); 8.45 (d, 1H); 7.88 (dd, 2H); 7.45 (s, 1H); 7.38 (m, 1H); 7.26 (s, 1H); 7.20 (dd, 2H); 5.77 (s, br, 1H); 4.55 (m, 1H); 2.99 (d, 3H); 1.24 (d, 6H) (M + H) + = 423 A < 10 162. 2- (4-Fluoro-phenyl) -5-isopropoxy6-6- (methylaminoamino-methyl) -benzofuran-3-carboxylic acid formamidine lH NMR in CDC13: 7.85-7.81 (m, 2H); 7.44 (s, 1H); 7.41 (s, 1H); 7.23-7.17 (m, 2H); 5.73 (s, 1H); 4.98 (t, J = 5.4Hz, 1H); 4.78-4.71 (m, 1H); 4.39 (d, J = 6.6Hz, 3H); 2.97 (d, J = 4.8Hz, 3H); 2.74 (s, 3H); 1.40 (d, J = 5.7Hz, 6H) (M + H) + = 435 B < 10 163. 6- (Cyclopentyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine Amine 1H NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J = 6.2 & 8.8Hz, 2H); 7.53 (s, 1H); 7.38 (t, J = 8.8Hz, 2H); 7.13 (s , 1H); 4.76 (heptupiet, J = 5.7Hz, 1H); 4.28 (quintuplet, J = 8.8Hzt 1H); 3.11 (s, 3H); 2.83 (m, 3H); 1.93 (m, 2H); 1.45 ( m, 2H); 1.34 (m, 4H) (M + H) + = 489 A < 1 164.2 2- (4-Fluoro-phenyl) _6-[(2-hydroxy-ethyl) _methanesulfonyl-amino] -5-isopropoxy-benzofuran-3- Carboxamide 1H NMR in DMSO:, 8.41 (m, 1H); 7.93 (dd, J = 5.2Hz, 2H); 7.60 (s, 1H); 7.38 (t, J = 8.8Hz, 2H); 7.16 (s, 1H); 4.78 (heptupiet, J = 5.8Hz, 1H); 4.67 (t, J = 5.7Hz, 1H); 3.60 (bs, 1H); 3.04 (s, 3H); 2.83 (d, J = 4.8Hz, 3H); 1.34 (d, J = 5.7Hz, 6H) (M + H) + = 465 A < 10 190- 88828.doc 200418452 Instance data name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = / tM B = 0 * 5 to ii.O / iM C = 5.0 to ^ 30 μΜ D = > 30 μ, M replicon 0M) 165.2 2- (4-Gas-phenyl) -5-lightyl-6-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.94 (m, 2H); 7.28 (s, 1H); 7.15 (t, 2H, J = 8.79 Hz); 7.04 (s, 1H); 5.82 (brs, 1H); 5.59 (s, 1H); 3.97 (s, 3H); 3.01 (d, 3H, J = 5.28 Hz) (M + H) " = 316 C > 30 166. 5-Ethoxy-2- (4-amino-phenyl) -6-? Fluoroline-4-yl-benzoanan-3-methanoate * H NMR in DMSO: 8.30 (m, 1H); 7.88 (m, 2H); 7.32 (t, 2H, J = 8.79 Hz) ; 7.16 (s, 1H); 7.04 (s, 1H); 4.06 (q, 2H, J = 7.03 Hz); 3.74 (bm »4H); 3.02 (bm, 4H); 2.80 (d, 3H, J = 4.69 Hz); 1.36 (t, 3H, J = 7.03 Hz) (M + H) + = 399 B < 10 167. 5- (4-Fluoro- ¥ oxy) -2- (4-denyl-phenyl) -6-morpholin-4-yl-phenylbenzfuran-3-carboxylic acid Lamine 1H NMR in DMSO: 8.30 (m, 1H); 7.88 (m, 2H); 7.55 (m, 2H); 7.33 (t, 2H, J = 8.79 Hz); 7.27-7.20 (m, 4H); 5.14 (s, 2H); 3.72 (bm, 4H); 3.03 (bm, 4H); 2.82 (d, 3H, J = 4.69) (M + H) + = 479 B < 1 168. 2_ (4-Gasyl-phenyl) -5_ isopropoxy-6-azet-5-yl-benzofuran-3-methanoic acid formamidine 1H NMR in CDC13: 7.91- 7.83 (m, 4H); 7.69 (s, 1H); 7.41 (s, 1H); 7.22- 7.14 (m, 2H); 5.79 (bs, 1H); 4.86-4.78 (m, 1H); 2.99 (d, J = 4.8Hz, 2H); 1.46 (d, J = 6.3Hz, 6H) (M + H) + = 395 A < 10 169. 2- (4-Fluoro-phenyl) -6- (4-Cyclo-hexaarginyl-1-continyl) -5-isopropoxy-benzofuran-3 -Formamidine carboxylate 1H NMR in DMSO: 8.47-8.49 (d, 1H, J = 4.69Hz); 8.01 (s, 1H); 7.95-8.00 (m, 2H); 738-7.44 (t, 2H, J = 8.79Hz); 7.32 (s, 1H); 4.82-4.90 (septet, 1H, J = 5.86Hz); 4.67-4.69 (d, 1H, J = 4.10Hz); 3.58-3.59 (in, 1H); 3.35 -3.45 (m, 2H); 3.24-3.30 (m, IH); 2.92-3.00 (m, 2H); 2.84-2.85 (d, 3H, J = 4.69Hz); 1.69-1.73 (in, 2H); 1.36 -1.41 (m, 1H); 1.34-1.36 (d, 6HT J = 5.86Hz) (M + H) + = 491 A < 1 170. 6- (4,4-difluoroyl-hexahydropyridine-1 -yl) -2- (4-pyridylfluoro-phenyl) -5-isopropoxy-benzofuran- 3-Hydroxymethoxamine 1H NMR in CDC13: 7.87 (m, 2H); 7.31 (s7 1H); 7.17 (UJ = 8.35 Hz, 2H); 7.07 (s, 1H); 5.74 (s, 1H); 4.69 -4.61 (septet, J = 6.16 Hz, 1H); 3.23-3.19 (m, 4H); 2.98 (d, J = 5.27 Hz, 3H); 2.24-2.11 (m, 4H); 1.39 (d, J = 6.16 Hz, 6H) (M + H) + = 447 C < 1 171.2 2- (4-Fluoro-phenyl) -6- (4-fluoro-hexahydropyridine-1-yl) -5-isopropoxy-benzofuran-3-¾ Formamidine acid 1H NMR in CDC13: 7.89-7.83 (m, 2H); 7.28 (s, 1H); 7.16 (t, J = B.79 Hz, 2H); 7.07 (s, IH); 5.76 (s, 1H); 4.92-4.72 (m, 1H); 4.69-4.61 (septet, J = 6.16 Hz, 1H); 3.24-3.22 (m, 2H); 3.08-3.01 (m, 2H); 2.98 (d, J = 4.84 Hz, 3H); 2.18-2.02 (m, 4H); 1.38 (d, J = 5.71 Hz, 6H) (M + H) + = 429 B < i 172. 5-Difluoromethoxy-2- (4-fluoro-phenyl) > 6-morpholin plin-4-ser-benzocaran-3-carboxylic acid formamidine 1H NMR in CDCI3: \ 7.87 (dd, J = 8.8,5.7Hz, 2H); 7.54 (s, 1H); 7.16 (t, J = 8.8Hz, 2H); 7.11 (s, 1H); 6.57 (t, J = 75.6Hz, 1H); 5.92 (d, J = 4.7Hz, 1H); 3.87 (t, J = 4.0Hz, 4H); 3.08 (t, J = 4.0Hz, 4H); 2.98 (d, J = 4.9Hz , 3H) (M + H) f = 421 A < 1 191-88828.doc 200418452 Instance number name NMRdata Mass Spec HCVpol -BB7 ic50 0iM) A = μ, Μ B = 05 to ^ 5.0 μΜ C = 5.0 to ^ 30 D = > 30 μΜ replicon (μΜ) 173. 5-Cyclopentyloxy-2- (4-fluoro-benzyl) -6-morpholin-4 tomb-Dongfanganan-3 -carboxamidine carboxylic acid * H NMR in CDC13: 7.86 (dd, J = 9.4, 5.3Hz, 2H); 7.28 (s, 1H); 7.16 (t, J = 9.4Hz, 2H); 7.04 (s, 1H); 5.74 (brs, 1H); 4.90 (in, 1H); 3.90 (t, J = 4.7Hzt 4H); 3.11 (t, J = 4.7Hz, 1H); 2.98 (d, J = 4.7Hz, 3H); 1.95 (m, 4H); 1.80 (m, 2H ); 1.70 (m, 2H) (MH) = 437 A < 1 174. 2- (4 • Fluoro-phenyl) -5- mesyl-6-methanesulfonylamino-benzofuran-3-methanoformamide 1H NMR in DMSO: 8.36 (dt J = 4.7Hzt 1H); 7.91 (dd, J = 8.8, 3.0Hz, 2H); 7.48 (s, 1H); 7.36 (ζ J = 8.8Hz, 2H); 7.08 (s, 1H); 2.98 (st 1H ); 2.82 (d, J = 4.7Hz, 3H) (M + H) + = 379 B < 30 175. 2- (4-Gasyl-phenyl) -5_isopropoxy-6- (thiomorpholine »Lin_4- > 5 buy brewer group) -Priprofuran-3-carboxy Formamidine acid 1H NMR in DMSO: 8.47-8.48 (d, 1H J + 4.10Hz); 8.03 (s 1H); 7.95-8.00 (m, 2H); 7.38-7.44 (t, 2H, J = 8.79Hz) ; 7.33 (s, 1H); 4.84-4.92 (septet, 1H, J = 6.45Hz); 3.42-3.46 (m, 4H); 2.83-2.85 (d, 3H, J = 4.69Hz); 2.62-2.65 (in , 4H); 1.35-1.37 (d, 6H, J = 5.86Hz) (M + H) + = 493 A < 1 176. 2- (4-Fluoro-phenyl) -6- (3-hydroxy-pyrrolidin-1 -continyl) -5-isopropoxy-benzocran-3 -renic acid Formamidine 1H NMR in DMSO: 8.46-8.48 (d, 1H, J = 4.69Hz); 8.03 (s, 1H); 7.95-7.99 (m, 2H); 7.38-7.43 (t, 2H, J = 8.79Hz ); 7.31 (s, 1H); 4.99 (br.s, 1H); 4.82-4.80 (septet, 1H, J = 5.86Hz); 4.24 (br.s, 1H); 3.38-3.46 (m, 4H); 3.07-3.11 (dd, 1H, J = 2.35Hz, 9.96Hz); 2.83-2.84 (d, 3H, J = 4.69Hz); 1.79-1.86 (m, 1H); 1.68-1.77 (m, 1H); 1.35 -1.37 (d, 6H, J = 5.86Hz) (M + H) + = 477 A < 1 177. 2- (4-Fluoro-phenyl) -5-oxopropoxy-6-0 to 1 ^ -4-yl-benzofuran each #methanoformamine NMR in DMSO: 8.6 i (m, 2H); 8.42 (s, 1H); 7.94 (dd, 2H); 7.72 (s, 1H); 7.60 (d, 2H); 7.36 (dd, 2H); 7.25 (s, 1H); 4.6 (m, 1H); 2.84 (d, 3H); 1.22 (d, 6H) (M + H) + = 405 A < 10 178. * 2- (4; fluoro-benzene: &)-5_ isopropoxy-6- (3-methanesulfonyl-phenyl) > benzofuran-3-carboxylic acid formamidine Amine NMR in DMSO: 8.42 (m, 1H); 8.16 (m, 1H); 7.98-7.88 (m, 4H); 7.72 (s, 1H); 7.69 (t, 1H); 7.39 (dd, 2H); 7.27 (s, 1H); 4.60 (m, 1H); 3.26 (s, 3H); 2.86 (d, 3H); 1.29 (d, 6H) (M + H) + = 482 A < 10 179. 2- (4-Gasyl-phenyl) -5-isopropoxy-6- (4-methanesulfonyl-epoxy) -primofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.43 (m, 1H); 7.99-7.94 (m, 4H); 7.84 (d, 2H); 7.70 (s, 1H); 7.41 (dd, 2H); 7.27 (s, IH); 4.62 ( m, 1H); 3.28 (s, 3H); 2.85 (d, 3H); 1.24 (d, 6H) \ (M + H) + = 482 A < 10 180. 5 < 2-Chloro-ethoxy) -2- (4-fluoro-phenyl) -6-morpholin plin-4-yl-benzene odorless 3-carboxylic acid quiltamine 1H NMR in CDCb: 7.85-7.80 (m, 2H); 7.32 (s, 1H); 7.20-7.15 (m, 2H); 7.08 (s, 2H); 5.75 (bs, 2H); 4.37-4.33 (m, 2H); 4.94-4.89 (m, 6H); 3.17-3.14 (m, 4H); 2.97 (d, J = 5.4Hz, 3H) (M + H) + = 433 A > 30 192- 88828.doc 200418452 instance number name NMR data Mass Spec HCV pol -BB7 ICs〇〇iM) A = μΜ B = 03 to i5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon (μΜ) 181.6 -(4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine [H NMR in DMSO: 7.80 (dd, J = 8.8, 5.3Hz, 2H); 7.50 ( m, 2H); 7.40 (m, 3H); 7.34 (s, 1H); 7.16 (t, J = 8.8Hz, 2H); 7.05 (s, 1H); 5.75 (br d, J = 4.7Hz, 1H) ; 5.22 (s, 1H); 3.96 (s, 3H); 2.99 (d, J = 4.7Hz, 3H) (M + H) + = 406 A < 10 182.6 6-Amino-2- (4-fluoro-phenyl) -5-acyl-benzo < Amino-3-carboxylic acid amine NMRinDMSO: 10.55 (br s, 1H); 8.40 (d, J = 4.7Hz, 1H); 7.90 (dd, J = 8.8, 5.3Hz, 2H); 7.61 (sT 1H ); 7.34 (t, J = 8.8Hz, 2H); 7.16 (s, 1H); 2.79 (dt J = 4.7Hz, 3H) (M + H) + = 301 B < 30 183. 5,6-bis-benzyloxy-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid formamidine'H NMR in DMSO: 8.29 (m, lH) ; 7.86 (m ^ H); 7.49-7.30 (m, 13H); 7.23 (s, 1H); 5.22 (s, 2H); 5.14 (s, 2H); 2.80 (d, 3H, J = 4.10) (M + H) + = 482 D < 10 184.2 Pefoxy county) -5-isopropoxy-6- (5-trifluoromethyl- [1,2,4] pyridazol-3-yl) -benzofuran-3 -Formamidine carboxylate 1H NMR in CDCi3: 8.17 (s, 1H); 7.91-7.86 (mT 2H); 7.54 (s, 1H); 7.25-7.19 (mT 2H); 5.77 (bs, 1H); 4.81- 4.73 (m, 1H); 3.0 (d, J = 4.8Hz, 3H); 1.44 (d, J = 6.3Hz, 6H) (M + H) + = 464 B < 30 V 185. [2- (4-Gasyl-phenyl) -5_ isopropoxy-3-methylmonthlyl methylbenzo-6-yl] -Hexane 17- 1-carboxylic acid amidine 1H NMR in CDC13: 7.87-7.81 (m, 2H); 7.31 (s, 1H); 7.16 (t, J = 8.35 Hz, 2H); 7.03 (s, 1H); 5.80 (s, 1H); 4.69-4.61 (septet, J = 6.15 Hz, 1H); 4.53 (s, 2H); 3.60-3.57 (m, 4H); 3.12-3.09 (m, 4H); 2.98 (d, J = 5.27 Hz , 3H); 1.38 (d, J = 6.15 Hz, 6H) (M + H) + = 455 C < 10 186. 2- (4-Aminophenyl) -5_ isopropoxy-6-thiomorpholin_4_yl-donganan-2-methylcarboxamidine 3-carboxylic acid * H NMR in CDCl3 : 7.87-7.83 (m, 2H); 7.29 (s, 1H); 7.16 (t, J = 8.35 Hz, 2H); 7.05 (s, 1H); 5.73 (s, 1H); 4.65-4.62 (septet, J = 5.71 Hz, 1H); 3.34 (m, 4H); 2.98 (d, J = 4.84 Hz, 3H); 2.84 (m, 4H); 1.37 (d, J = 6.15Hz, 6H) (M + H) + = 429 A < 1 187. 2- (4-Amino-winteryl) -5_ isopropoxy-3-methylmonthlylmethyl-benzoan-6-carboxylic acid lH NMR in CDC13: 8.41-8.42 (d, 1H, J = 4.69Hz); 7.93-7.97 (m, 2H); 7.80 (s, 1H); 7.35-7.41 (t, 2H, J = 8.79Hz); 7.20 (s, 1H); 4.58- 4.66 (septet, 1H, J = 5.86Hz); 2.83-2.84 (d, 3H, J = 4.69Hz); 1.28-1.30 (d, 6H, J = 5.86Hz) (M-Η) '= 370 C < 10 188. 2- (4-Amino-phenyl) -5_ isopropyllactyl-6- (1-lactyl-thiomorpholine lin- ^ · -yl-)-melfuran carboxylic acids Formamidine 1H NMR in CDC13: 7.84-7.82 (m, 2H); 7.34 (s, 1H); 7,18 (t, J = 8.35, 2H); 7.13 (s, 1H); 5.76 (s, 11H) ; 4.69-4.65 (septet, J = 5.71 Hz, 1H); 3.75-3.68 (m, 2H); 3.39-3.35 (m, 2H); 3.10 (s, 4H); 2.99 (d, J = 4.40 Hzt 3H) ; 1.41 (d, J = 6.15 Hz, 6H) (M + H) + = 445 C < 10 193 88828.doc 200418452: Instance number name NMRdata Mass Spec HCV po! -BB7 IC50O1M) A = B = 03 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon (μΜ) 189 . {P- (4-Fluoro-phenyl) -5-isopropoxy-3-methylaminomethyl-benzoyl-benzo-6-yl] -methanesulfonyl-aminoacetic acid lH NMR in DMSO: 10.9 (s, iH); 8.43 (m, IH); 7.96 (m, 2H); 7.66 (s, 1H); 7.38 (m, 2H); 7.17 (s, 1H); 4.79 (heptuplet , J = 6.1Hz, 1H); 4.28 (s, 2H); 3.08 (s, 3H); 2.83 (d, J = 4.8 Hz, 3H); 1.35 (d, J = 6.1Hz, 6H) (M + H ) + = 479 B < 1 190. 6- (Cyclobutylmethanesulfonyl-amino) -2- (4-amino-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine Amine 1H NMRinDMSO: 8.43 (in, 1H); 7.93 (dd, J = 3.1 & 6.6Hz, 2H); 7J7 (s, 1H); 7.39 (t, J = 8.8Hz, 2H); 7.15 (s, 1H ); 4.78 (heptuplet, J = 6.1Hz, 1H); 3.2 (m, 1H); 3.02 (s, 3H); 2.83 (d, J = 5.8Hz, 3H); 2.46 (m, 6H); 2.38 (d , 6.1Hz, 6H) (M + H) + = 475 A < 1 191.2. 2- (4-Fluoroyl) -5-isopropoxy-6-j: alkanesulfonyl- (2-morpholin-4-yl-ethyl) -amino group] -Benzofuran-3-carboxylic acid formamidine * H NMR in DMSO: 8.42 (d, J = 4.7Hz, 1H); 7.93 (dd, J = 7.0 & 9.4 Hzt 2H); 7 ^ 8 (s, 1H); 7.38 (t, J = 8.8 Hz, 2H); 7.16 (s, 1H); 4.79 (heptuplet, J = 5.8Hz, 1H); 3.50 (t, J = 4.6Hz, 4H); 3.16 (m, 2H); 3.06 (s, 3H); 2.83 (d, J = 4.6Hz, 3H) (M + H) + = 534 A < 1 192. 2- (4-Gas-private) -5,6-diaxyl-benzofuran carboxylic acid methylamine 1H NMR in DMSO: 8.25 (brs, 1H); 7.83 (m, 2H); 7.28 (m, 2H); 6.96 (d, 1H, J = 2.34 Hz); 6.90 (d, 1H, J = 2.34 Hz); 2.77 (brd, 3H, J = 6.45 Hz) (M + H) + = 302 C > 30 193. 2- (4-Fluoro-phenyl) -5_ isoamyloxy-6- [methyl fluorenyl- (2-fluorenyl-ethyl) -amino > Benzofuran-3-carboxylic acid formamidine NMR in DMSO: 8.48 (m, 1H); 7.95 (dd, J = 5.2 & 8.7 Hz, 2H); 7.53 (s, 1H); 7.39 (t, J = 8.8Hz, 2H); 7.17 (s, 1H); 4.79 (heptuplet, J = 5.9 Hz, 1H); 3.34 (m, 6H); 3.18 (s 3H); 3.05 (s, 3H); 2.83 (d , J = 4.7Hz, 3H); 1.34 (d, J = 5.8Hz, 6H) (M + H) + = 479 A < 1 194. 6-Ethoxy-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.85 (m, 2H); 7.47 (m, 2H); 7.41-7.31 (m, 4H); 7.15 (t, 2H, J = 8.79 Hz); 7.08 (s, 1H); 5.75 (brs, 1H); 5.17 (s, 2H ); 4.55 (m, 1H); 2.99 (d, 3H, J = 5.28 Hz); 1.38 (d, 6H, J = 6.45 Hz) (M + H) + = 434 B wood chip 195.6- (ene Propyl-methanesulfonyl-amino) -2- (4-fluorotai-phenyl) -5-isopropoxy-benzofuran-3-¾formamidine'H NMR in DMSO: 8.41 ( ra, 1H); 7.93 (dd, J = 5.3 & 8.8Hz, 2H); 7.38 (s, 1H); 7.34 (t, J = 8.8Hz, 2H); 5.81 (m, 1H); 5.10 (dd, J = 1.8 & 17 Hz, 1H); 5.02 (dd, J = ll & 10 Hz, 1H); 4.79 (heptuplet, J = 6.4 Hz, 1H); 4.22 (m, 2H); 3.06 (s, 3H ); 2.82 (d, J = 4.7 Hz, 3H) (M + H) + = 461 A < 1 196. 6-Ethyl-2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-methanoformamidine 1H NMR in CDC13: 7.88 (s, 1H); 7.86 (m, 2H); 7.41 (s, 1H); 7.18 (m, 2H); 5.77 (brs, 1H); 4.79 (m, 1H); 3.00 (d, J = 4.8Hz, 3H); 2.69 (s, 3H); 1.44 (d, J = 6.0 Hz, 6H) (M + H) + = 370.0 A < 1 194- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = s (K5 μΜ B = to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ Copy (ΜΜ) 197.2 2- (4-Gasyl-benzyl) -5-isopropoxy-6-methanesulfonylamino, benzobenzo-3-carboxylic acid isopropylamine * H NMR in CDC13: 7.85-7.80 (m, 2H); 7.74 (s, 1H); 7.43 (s, 1H); 7.19 a J = 8.79 Hz, 2H); 6.95 (s, 1H); 5.53-5.50 (m, IH) ; 4.78-4.70 (septet, J = 6.15 Hz, 1H); 4.38-4.26 (septet, J = 7.03 Hz, 1H); 2.95 (s, 3H); 1.40 (d, J = 5.44 Hz, 6H); 1.18 ( d, J = 6.49 Hz, 6H) (M + H) + = 449 C < 10 198.2. 2- (4-Gasyl-phenyl) -5_isopropoxy-6- (5-methyl_ [1,2,4bamboobiphenyl-3-yl) -benzo Furan-3-carboxylic acid formamidine * HNMR inCDCl3: 8.07 (s, 1H); 7.92-7.87 (m, 1H); 7.49 (s, 1H); 7.23-7.17 (m, 2H); 5.80 (bs, 1H ); 4.70-4.64 (s, 1H); 3.00 (d, J = 4.8Hz, 3H); 2.65 (s, 3H); 1.41 (d, J = 6.3Hz, 6H) (M + H) + = 410 A < 1 199. 2- (4-Fluoro-phenyl) > 5-isopropoxy-6-methanesulfonylamino-benzopyran-3-carboxylic acid cyclopropylamidine 1H NMR in CDC13 : 7.79-7.74 (m, 2H); 7.73 (s, 1H); 7.47 (s, 1H); 7.20 (T, J = 8.79Hz, 2H); 6.95 (s, 1H); 5.8 (s, 1H); 4.78-4.70 (septet, J ^ .lSHz, 1H); 2.95 (s, 3H); 2.90-2.86 (m, 1H); 1.40 (d, J = 6.15Hz, 6H); 0.89-0.82 (m, 2H) ; 0.53-0.48 (m, 2H) (M + H) + = 447 A < 1 200. 2- (4-Fluoro-phenyl) -5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid acetamidine 1H NMR in CDCI3: 7.85-7.79 (m, 2H); 7.74 (s, 1H); 7.44 (s, 1H); 7.19 (t, J = 8.35Hz, 2H); 6.95 (s, 1H); 5.7 (s, 1H); 4.80 -4.68 (septet, J = 6.15Hz, 1H); 3.52-3.43 (m; 2H); 2.95 (s, 3H); 1.39 (d, J = 5.71, 6H); 1.17 (T, J = 7.47, 3H) (M + H) + = 435 A < 1 201. 2- (4-Dentyl-phenyl) -5- (2-methyl-pyrazol-4-ylmethoxy) -6-morpholine-4-yl-benzop-furan -3-Formamidine carboxylate 1H NMR in CDCi3: 7.89 (m, 2H); 7.41 (s, 1H); 7.16 (m, 3H); 7.10 (s? 1H); 5.78 (brs, 1H); 5.25 ( s, 2H); 3.90 (m, 4H); 3.16 (m, 4H); 3.00 (d, 3H, J = 4.69 Hz); 2.74 (s, 3H) (M + H) + = 482 A < 1 202. 2_ (4-Gasyl-phenyl) _6- (1- # stemyl-1-methyl-ethyl) -5-isopropoxy-benzofuran-3-quinic acid formamidine Amine 1H NMR in CDCI3: 7.84 (m, 2H); 7.49 (s, 1H); 7.39 (s, 1H); 7.19 (m, 2H); 5.73 (brs, 1H); 3.56 (m, 1H); 2.99 ( d, J = 4.8 Hz, 3H); 1.38 (d, J = 6.1Hz, 6H) (M + H) + = 386.1 A < 1 203. 5- [5- (3,5-Difluorenyl-isopurazol-4-yl)-[1,2,4] fluorenediazole-3-ylmethoxy)]-2- (4-Fluoro-phenyl) -6-morphol # -4-yl-phenylsulfan-3-carboxylic acid formamidine NMR in CDCI3: 7.86 (m, 2H); 7.52 (s, 1H) ; 7.18 (t, 2H, J = 8.79 Hz); 7.12 (s, 1H); 5.75 (brs, 1H); 5.36 (s, 2H); 3.92 (m, 4H); 3.19 (in, 4H); 2.98 ( d, 3H, J = 4.69 Hz); 2.81 (s, 3H); 2.59 (s, 3H) (M + Hwide = 548 B < 10 195-88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 ic50 〇iM) A = μΜ B = 03 to ^ 5.0 μΜ C = 5.0 to < 30 D = > 30 μΜ replicon (μΜ) 204. 5- (5-Third-butyl- [1,2,4] humidin-3-ylmethoxy) -2- (4 -Fluoro-phenyl-> 6-morpholin · 4-yl-benzoanan-3-methylacetamidine * H NMR in DMSO: 8.28 (br 叽 1H); 7.90 (m, 2H); 7.33 (t, 2H, J = 8.79 Hz); 7.24 (s, 1H); 7.22 (s, 1H); 5.28 (s, 2H); 3.74 (m, 4H); 3.06 (m, 4H); 2.81 (d , 3H, J = 4.69); 1.40 (s, 9H) (M + H) + = 509 A < 1 205.2 2- (4-fluoro-phenyl) -5-isopropoxy each [1,2,4] indoxazol-3-yl-benzene # furan-3-carboxylic acid formamide 1HNMRinCDCl3 : 8.75 (s, 1H); 8.14 (s, 1H); 7.93-7.88 (m, 2H); 7.53 (s, 1H); 7.24-7.17 (m, 2H); 5.78 (bs, 1H); 4.70 ^. 68 (m, 1H); 3.0 (d, J = 4.8Hz, 3H); 1.42 (d, J = 5.7Hz, 6H) (M + H) + = 396 A < 1 206. 5- (5-Chloro- [1,2, examidine; methoxy) -2- (4-fluoro-phenyl) -6-morpholine-4-yl -Benzofuran-3-carboxylic acid methylamine 1H NMR in DMSO: 8.38 (brdr 1H, J = 4.69 Hz); 7.95 (m, 2H); 7.76 (s, 1H); 7.58 (s, 1H); 7.38 (t, 2H, J = 8.79 Hz); 4.75 (s, 2H); 3.52 (m, 4H); 2.98 (in, 4H); 2.80 (d, 3H, J = 4.69 Hz) (M + H) + = 504 B < 1 207.2 2- (4-Amino-phenyl) -6-? Bead-4-yl ^ -5-(5 -p-tolyl- [1,3,4] fluorenediazole-2ylmethoxy) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO : 8.31 (brd, 1H, J = 4.69 Hz); 7.90 (m, 4H); 7.43 (d, 2H, J = 7.62 Hz); 7.34 (m, 3H); 7.25 (s, 1H); 5.48 (s, 2H); 3.69 (m, 4H); 3.02 (m, 4H); 2.81 (d, 3H, J = 4.69 Hz); 2.40 (s, 3H) (M + H) + = 543 C < 10 208. 2- (4-Gasyl-phenyl) -6- # yl-5-methoxy-benzofuran-3-carboxylic acid formamidine'H NMR in DMSO: 9.33 (s, 1H) ; 8.28 (d, J = 4.4HzT 1H); 7.85 (dd, J = 8.8, 5.3Hz, 2H); 7.30 (t, J = 8.8Hz, 2H); 7.06 (s, 1H); 7.02 (s, 1H ); 3.81 (s, 3H); 2.80 (d, J = 4.4Hzt 3H) (M + H) + = 316 B < 30 209.2 2- (4-Amino-phenyl) -5- (1-methyl-1H-tetrazol-5-ylmethoxy) glypholine-4-yl-benzoxan -3-carboxylic acid formamidine 1H NMR in DMSO: 8.31 (d, J = 4.4Hz, 1H); 7.88 (dd, J = 8.8, 5.3Hz, 2H); 7.36 (t, J = 8.8Hz, 2H) ; 7.33 (s, lH); 7.25 (s, lH); 5.54 (s, 2H); 4.14 (s, 3H); 3.68 (t, J = 4.4Hz, 4H); 2.98 (t, J = 4.4Hz, 4H); 2.81 (d, J = 4.4Hz, 3H)) (M + H) + = 467 B < 10 210. 2- (4-Fluoro-phenyl) -5- (3-methoxy-benzyloxy) -6-morpholin-4-yl-benzofuran-3-carboxylic acid Lamine 1H NMR in DMSO: 8.30 (d, J = 4.4Hz, 1H); 7.88 (dd, J = 8.8, 5.3Hz, 2H); 7.32 (ra, 3H); 7.22 (s, 1H); 7.19 (s , 1H); 7.07 (m, 2H); 6.87 (m, 1H); 5.13 (s, 2H); 3.76 (s, 3H); 3.73 (brs, 4H); 3.05 (brs, 4H); 2.81 (d, J = 4.4Hz, 3H) (M + H) * = 491 A < 1 196- 88828.doc 200418452 Example 5 Tiger name NMRdata Mass Spec HCY pol -BB7 IC50〇tM) A = μ, Μ B = 03 to ^ 5.0 C = 5.0 to ^ 30 μΜ. D = > 30 / iM replicon (μM) 211.2 2- (4-fluoro-phenyl) -5methoxy-6- (1-methyl-1H-tetramethyl-5-ylmethoxy) -benzo Furan-3-carboxylic acid formamidine 1H NMR in DMSO: 8.32 (d, J = 4.4Hz, 1H); 7.87 (dd, J = 8.3, 5.7Hz, 2H); 7.55 (s, 1H); 7.33 (t , J = 8.8Hz, 2H); 7.11 (s, 1H); 5.56 (s, 2H); 4.15 (s, 3H); 3.81 (s, 3H); 2.80 (d, J = 4.4Hz, 3Η »(M + H) + = 412 A < 1 212.2 2- (4-Gasylphenyl) -5- [l- (4-fluoro-phenyl) -ethoxy] -6-morpho 4 Tomb of winter wood-benzopyran- 3-carboxamidine 1H NMR in CDC13: 7.86 (dd, J = 8.8, 5.3Hz, 2H); 7.38 (dd, J = 8.8, 5.3Hz, 2H); 7.12 (t, J = 8.8Hz, 2H ); 7.03 (t, J = 8.8Hz, 2H); 5.62 (d, J = 4.9Hz, 1H); 5.37 (q, J = 6.1Hz, 1H); 3.88 (m, 4H); 3.14 (m, 4H ); 2.92 (d, J = 4.9 Hz, 3H); 1.65 (d, J = 6.1Hz, 3H) (M + H) + = 493 A < 1 213. (4-cyano-fluorenylmethoxy) -2- (decafluoro ^ > phenyl) -6-morpholin-4-yl-benzofuran-3-carboxylic acid formamidine Amine'H NMR in DMSO: 8.28 (dr J = 4.4Hz, 1H); 7.88 (m, 4H); 7.70 (d, J = 8.0Hz, 2H); 7.33 (t, J = 8.8Hz, 2H); 7.24 (s, 1H); 7.20 (s, lH); 5.27 (s, lH); 3.74 (m, 4H); 3.04 (m, 4H); 2.81 (d, J = 4.4Hz, 3H) (M + H) + = 486 B < 10 214.1 1- (4-fluoro-phenyl) -5- [5- (4-methoxy-phenyl)-[1,2,4] pyridine-3-ylmethoxy] -6-morpholine-4-yl-benzoanan-3 -carboxylic acid formamidine 1H NMR in DMSO: 8.35 (d, J = 4.4Hz, 1H); 7.92 (m, 4H); 7.37 (m , 3H); 7.25 (s, 1H); 7.17 (d, J = 8.8Hz, 2H); 5.47 (s, 2H); 3.84 (s, 3H); 3.69 (s, 4H); 3.02 (s, 4H) ; 2.80 (d, J = 4.4Hz, 3H) (M + H) + = 559 B < 1 215.2 2- (4-Amino-phenyl) -6-morpholin-4-yl-5- (2-oxy-propoxy) -benzofuran-3-carboxylic acid sulfonamide lH NMR in DMSO: 8.26 (d, J = 4.4Hz, 1H); 7.87 (dd, J = 8.3, 5.7 HzT 2H); 7.32 (t, J = 8.8Hz, 2H); 7.20 (s, lH); 7.00 (s, lH); 4.80 (s, 2H); 3.76 (t, J = 4.7Hz, 4H); 3.06 (t, J = 4.7Hz, 4H); 2.80 (d, J = 4.8Hz, 3H); 2.21 (s, 3H) (M + H) + = 427 B < 10 216. 5- (1-fluorenyl-1H-taste group oligomethoxy) -2- (4-fluoro-phenyl) -fluorene_morpholin p-4 Methyl-3-carboxamidine * H NMR in DMSO: 8.26 (brd, 1H, J = 4.69 Hz); 7.90 (m, 2H); 7.35-7.16 (m, 10H); 6.94 (m, 1H) ; 5.37 (s, 2H); 5.17 (s, 2H); 3.66 (m, 4H); 2.95 (m, 4H); 2.82 (d, 3H, J = 4.69 Hz) (M + H) + = 541 A < 1 217. 5- (3,5-Dimethyl-isoinzolylmethoxy) _2- (4-Gasyl-tolyl) -6-morpholine 1H NMR of sulfan-3-carboxylic acid formamidine in DMSO: 8.30 (d, 1H, J = 4.39); 7.82 (m, 2H); 7.33 (t, 2H, J = 8.79); 7.20 (m, 2H) ; 5.00 (s, 2M); 3.69 (m, 4H); 2.98 (m, 4H); 2.82 (d, 3H, J = 4.39 Hz); 2.39 (s, 3H); 2.26 (s, 3H) (M + H) + = 480 B < 10 197- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 0 * 5 to s5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ Copy 〇iM) 218. 2- (4-Fluoro-phenyl) -5- (5-methyl-isoxazol-3-ylmethoxyfurin-4-yl-benzofuran-3- Formamidine carboxylate'H NMR in DMSO: 8.28 (brd, 1H, J = 4? 39 Hz); 7.90 (m, 2H); 7.33 (t, 2HT J = 8.79); 7.22 (m, 2H); 6.34 (s, 1H); 5.18 (s, 2H); 3.73 (m, 4H); 3.03 (m, 4H); 2.82 (d, 3H, J = 4.39 Hz); 2.42 (s, 3H) (M + H) + = 466 A < 1 219. 2- (4-Gasyl-phenyl) -5-isopropoxy-6-0 sulfan-2-yl-benzene # crean-3-chitoic acid formamidine 1H NMR in DMSO : 8.50 (s, lH); 8.46-8.47 (d, J = 4.69Hz, 1H); 7.97- 8.02 (m, 3H); 7.80-7.81 (d, J = 3.5Hz, 1H); 7.38-7.44 (ζ J = 8.79Hz, 2H); 7.36 (s, 1H); 4.97- 5.06 (septet, J = 6,45Hz, 1H); 2.84-2.86 (d, J = 5.27Hz, 3H); 1.47-1.49 (d, J = 5.86Hz, 6H) (M + H) + = 410.9 A < 10 220. 2- (4-Amino-phenyl) -5_isopropoxy-6- (1fluorene-pyrrole · 2-yl) -benzofuran-3-carboxylic acid methyl S & biNMRNMRCDCla: 7.90-7.86 (m, 2H); 7.77 (s, 1H); 7.43 (s, lH); 7.26-7.17 (m, 3H); 6.90 (s, 1H); 6.67 (s, 1H); 631 (s, 1H); 5.8 (s, 1H, br); 4.78 (m, 1H); 3.0 (d, 3H); 1.46 (d, 6H) (M + H) + = 393 A < 10 221. fluorene- (4-fluoro-phenyl) -6- (isopropyl-methanesulfonyl-amino) -5-methoxy-benzofuran-3-carboxylic acid formamidine lH NMR in DMSO: 8.44 (ιη, ΙΗ); 7.94 (dd, 2H, J = 5.28, 8.8Hz); 7.556 (s, 1H); 7.39 (t, J = 8.8Hz, 2H); 7.20 (s, lH ); 4.27 (heptuplet, J = 6.4Hz, lH); 3.86 (s, 3H); 3.09 (s, 3H); 2.84 (d, J = 4.7Hz, 3H); 1.21 (d, J = 7.lHzf 3H ); 1.01 (d, J = 6.5Hz, 3H) (M + H) + = 435 A < 1 222.2 2- (4-fluoro-phenyl) -6- (1 -¾-yl-ethyl) -5_ isopropoxy-benzo-4-an-3-carboxylic acid formamidine 1H NMR in CDCb : 7.87-7.83 (m, 2H); 7.50 (s, 1H); 734 (s, 1H); 7.21-7.16 (m, 2H); 5.72 (bs, lH); 5.19-5.13 (m, 1H); 4.78 -4.69 (m, 1H); 2.98 (d, J = 5.1Hz, 3H); 2.78 (d, J = 5.1Hz, 1H); 1.55 (d, J = 6.6Hz, 3H); 1.41 (dd, J = 3.6Hz, 6,0Hz, 6H) (M + H) + = 372 A < 1 223. 2- (4-Gasyl-phenyl) -5_ isopropoxy-6-morpho-4 wood-4 · -yl-yl-phenyl nonanhydro-3-carboxylic acid formamidine 1H NMR in CDC13: 7.89-7.84 (m, 2H); 7.57 (s, 1H); 7.31 (s, 1H); 7.20-7.16 (m, 2H); 5.74 (bs, 1H); 4.64-4.60 (m, 1H ); 3.75-3.72 (m, 4H); 3.64 (s, 2H); 2.98 (d, J = 5.1Hz, 3H); 2.55-2.52 (m, 4H); 1.36 (d, J = 6.3Hz, 3H) (M + H) + = 427 C < 10 224. 2- (4-Gas-phenyl) -6- via i-5-isopropoxy-benzofuran-3-¾formamidine IHNMRCDCI3: 7.87-7.83 (in, 2H ); 7.43 (s, 1H); 7.35 (s, 1H); 7.21-7.15 (m, 2H); 5.73 (bs, 1H „4.76-4.68 (m, 3H); 2.98 (d, J = 5.1Hz, 3H ); 2.52-2.50 (m, 1H); 1.40 (d, J = 6.0Hz, 6H) (M + H) + = 358 A < 10 225. _ 2- (4-Fluoro-phenyl) -5-C3H-imidazol-4-ylmethoxy) -6-morpholin-4-yl-benzofuran-3carboxylic acid Lamine 1H NMR in DMSO: '8.27 (brd, 1H, J = 4.39 Hz); 7.89 (m, 2H); 7.33 (t, 2H, J = 8.79 Hz); 7.28 (s, IH); 7.19 (s, 1H); 7.15 (brs, 1H); 6.90 (brs, 1H); 5.10 (s, 2H); 3.69 (ra, 4H); 3.02 (m, 4H); 2.83 (d, 3H, J = 4.39 Hz) ( M + H) + = 451 A < 10 198- 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC5〇 (/ iM) A = ^: 0.5 B = 03 to ^ 5.0 μΜ C = 5.0 to ^ 30 D = > 30 μΜ Replicon (μM) 226. 2- (4-Fluoro-phenyl) -5- (2-methyl | yl-ethoxy) -6-morpholin-4-yl-benzofuran; carboxylic acid methyl Amidine 1H NMR in DMSO: 8.28 (d, 1H, J = 4.69 Hz); 7.89 (m, 2H); 7.32 (t, 2H, J = 8.79 Hz); 7.16 (s, 1H); 7.06 (s, 1H ); 4.13 (in, 2H); 3.72 (ra, 6H); 3.33 (s, 3H); 3.04 (m, 4H); 2.81 (d, 3H, J = 4.69 Hz) (M + H) + = 429 A < 1 227. 2- (4-Gas-Dongyl) -5_-Isopropoxy-6-thiazol-5-yl-benzoic acid 3 -Metylamine metabolite * H NMR in DMSO: 9.07 (s, 1H); 8.53 (s, 1H); 8.41-8.42 (d, J = 4.69 Hzt 1H); 8.19 (s, 1H); 7.93-7.98 (m, 2H); 7.36-7.42 (t, J = 8.79 Hz, 2H); 7.28 (s, 1H); 4.82-4.90 (septet, J = 5.86Hz, 1H); 2.84-2.86 (d, J = 4.69Hz, 3H); 1.38-1.40 (d, J = 5.86Hz, 6H) (M + H) + = 411 A < 1 228. 5- (4-chloro-1-methyl-1H-pyridin-3-ylmethoxy) -2- (4-airyl-benzene; -6-morpho 57 lin-4 -Methyl-benzofuran-3-carboxylic acid formamidine * Η NMR in COCh: 7.93 (mt 2H); 7.47 (s, 1H); 7.39 (s, 1H); 7.17 (t, 2H, J = 8.79 Hz ); 7.08 (s, 1H); 5.86 (brs, 1H); 5.17 (s, 2H); 3.89 (m, 7H); 3.16 (m, 4H); 3.04 (d, 3H, J = 4.84 Hz) (M + H) + = 499 A < 1 229. 5-fluorenyl-methyl-methoxy) te (terfluorofluoro-phenyl) -6-morpholin-4-yl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.90 (m, 2H); 7.52 (s, 1H); 7.17 (m, 3H); 5.84 (brs.lH); 5.17 (q, 1H, J = 7.03 Hz); 3.89 (t, 4H, J = 4.69 Hz); 3.20 (ra, 2H); 3.00 (m, 5H); 1.80 (d, 3H, J = 6.45 Hz) (M + H) + = 424 A < 10 230. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (2H-pyridin-3-yl) -phenylphosphofuran-3-carboxylic acid formamide 1H NMR in CDC13: 7.87 (m, 2H); 7.80 (s, 1H); 7.62 (d, J = 2.4Hz, 1H); 7.49 (s, 1H); 7.24 (m, 2H); 6.69 (d, J = 2.4 Hz, 1H); 5.77 (brs, 1H); 4.83 (mt 1H); 2.99 (d, J = 5.4Hz, 3H); 1.48 (d, J = 5.7Hz, 6H) (M + H) + = 394.1 A < 10 231. 2- (4-Amino-epoxy) -5_isopropoxy-6- (2-methyl-2H-pyrazol-3-yl) -benzofuran lH NMR in CDC13: 7.88 (m, 2H); 7.52 (d, J = 1.8 Hz, 1H); 7.45 (s, 1H); 7.39 (s, 1H); 7.22 (m, 2H); 6.26 (d, J = 1.8Hz, 1H); 5.87 (brs, 1H); 4.48 (m, 1H); 3.76 (s, 3H); 3.00 (d, J = 4.8Hz, 3H); 1.23 (d, J = 5.7Hz, 6H ) (M + H) + = 408.1 A < 1 232. 2- (4-Gasyl-benzyl) -5-isopropoxy-6- (1-methyl-1H-pyrazolyl) -benzofuran-3-metanoic acid formamidine Amine 1H NMR in CDC13: 8.10 (s, 1H); 7.87 (m, 2H); 7.37 (d, J = 2.1 Hz, 1H); 7.36 (s, 1H); 7.18 (m, 2H); 6.91 (d, J = 2.1Hz, 1H); 5.82 (brs, 1H); 4.67 (m, 1H); 3.96 (s, 3H); 2.99 (d, J = 4.8Hz, 3H); 1.39 (d, J = 6.0Hz, 6H) 4 (M + H) + = 408.1 B < 10 233. 2- (4-Gasyl-benzyl) -5-isopropoxy-6- (3-methyl-isohumant-5-yl) -benzoconan-3-¾ acid Selenium 1H NMR in DMSO: 8.42 (dt J = 4.8Hz, 1H); 8.03 (s, 1H); 7.95 (dd, J = 5.7, 5.2, 8.8Hz, 2H); 7.37 (apparent triplet, J = 8.8 Hz, 2H); 7.28 (s, 1H); 6.79 (s, 1H); 4.84 (m, 1H); 2.83 (d, J = 4.4Hz, 3H); 2.30 (s, 3H); 1.38 (d, J = 5.7Hz, 6H) (M + H) + = 409.21 B < 30 199- 88828.doc 200418452 Instance data name NMR data Mass Spec HCV pol -BB7 ICse (/ iM) A = μΜ B = to ^ 5.0 μΜ C = 5.0 to i30 / iM D = > 30 aM replicon_ ) 234. 6-[(5-Mutyl- [1,2,4] acetodiazol-3-ylmethyl) -methanesulfonyl-amino group> 2- (4-fluoro-phenyl group ) -5-Isoyloxy-5-yl-benzofran-3-carboxylic acid methylamine'H NMR in CDC13: 7.81 (m, 2H); 7.69 (s, 1H); 7.40 (s, 1H); 7.19 (t, 2H, J = 8.79 Hz); 5.69 (brs, 1H); 5.09 (brs, 2H); 4.78 (m, 1H); 3.09 (s, 3H); 2.95 (d, 3H, J = 4.84 Hz); 1.42 (d, 6H, J = 6.15 Hz) (M + H) + = 553 A < 10 235. 6- (3,5-dimethyl-isodiamidinoamino) -2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-gui Formamidine acid 1H NMR in CDC13: 7.79-7.74 (m, 2H); 7.32 (s, 1H); 7.14 (t, J = 8.79 Hz, 2H); 6.43 (s, 1H); 5.73 (s, 1H) ; 5.50 (s, 1H); 4.73-4.67 (septet, J = 6.15 Hz, 1H); 2.97 (d, J = 5.27, 3H); 2.32 (s, 3H); 2.13 (s, 3H); 1.43 (d , J = 6.15 Hz, 6H) (M + H) + = 438 C > 30 236. 2- (4-fluoro-phenyl) -5-methoxy-6-t7 Benzofuran-3-carboxylic acid formamidine * H NMR in DMSO: 8.75 (s, 1H); 8.55 (s, 1H, br); 8.43 (d, 1H); 7.98-7.93 (m, 2H); 7.68 (s, IH); 7.49-7.35 (ra, 3H); 7.26 (s, 1H); 3.84 (s, 3H); 2.84 (dT 3H) (M + H) + = 377 A < 1 237.6 6-Dimethylaminomethyl-2- (4-fluoro-phenyl) -5-isopropoxy-5-yl-benzofuran-3-¾formamidine lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.54 (s, iH); 7.31 (s, 1H); 7.21-7.15 (m, 2H); 5.55 (bs, 1H); 4.66-4.60 (m, 1H); 3.64 (S >2H); 2.99 (d, J = 5.1Hz, 3H); 2.34 (s, 6H); 1.37 (d, J = 5.7Hz, 6H) (M + H) + = 385 C < 30 238. 2- (4-Fluoro-phenyl) -6- (1-hydroxy-2-methyl-propyl) -5-isopropoxy-benzofuran-3-carbamate Amine 1H NMR ia CDC13: 7.89-7.84 (m, 2H); 7.43 (s, 1H); 7.32 (s, 1H); 7.22-7.16 (m, 2H); 5.76 (bs; 1H); 4.74-4.60 (m , 2H); 2.99 (d, J = 4.8Hz, 3H); 2.61 (d, J = 6.5Hz, 1H); 2.14-2.09 (m, 1H); 1.40 (dd, J = 11.7, 6.0Hz, 6H) ; 1.04 (d, J = 6.6Hz, 3H); 0.85 (d, J = 6.9Hz, 3H) (M + H) " = 400 A < 1 239. 2- (4-Fluoro-phenyl) -5_ isopropoxy-6- (1βpyrazolidyl) -benzofuran-3-carboxylic acid formamidine 1H NMR in CDCb: 8.10 (s, 2H); 7.87 (m, 2H); 7.65 (s, 1H); 7.39 (s, 2H); 7.18 (m, 2H); 5.79 (brs, 1H); 4.72 (m, 1H); 3.00 ( d, J = 5.1Hz, 3H); 1.41 (d, J = 6.0 Hz, 6H) (M + H) + = 394.1 C < 10 240. 2- (4-Gas-Winter) -6- [methanesulfonyl- (2-methoxy-ethyl) -amino] -5-methoxy-benzoanan Formamidine-3-chitoate 1H NMR ia DMSO: 8.49 (m, IH); 8.00 (dd, J = 5.1 & 8.8 Hz, 2H); 7.63 (s, 1H); 7.42 (t, J = 8.8 Hz , 2H); 7.26 (s, 1H); 3.97 (s, 3H); 3.78 (m, 1H); 3.35 (m, 6H); 3.25 (s, 3H); 3.11 (s, 3H); 2.90 (d, J = 3.3 Hz, 3H) (Μ + ΗΓ = 451.1 A < 1 241.6 6- (3-Cyclopropyl-isohumazol-5-yl) -2- (4-fluorophenyl) -5-isopropoxy-benzofuran formamide lH NMR ia DMSO: 8.44 (broad quartet, J = 4.4Hz, 1H); 8.02 (s, 1H); 7.96 (dd, J = 5.7, 5.3, 9.2 Hz, 2H); 7.39 (apparent triplet; J = 8.8, 9.2 Hz, 2H); 7.29 (s, 1H); 6.64 (s, lH); 4.84 (m, IH); 2.85 (d, J = 4.8Hz, 3H); 2.08 (m, 1H); 1.39 (d, J = 5.7Hz, 6H); 1.05 (m, 2H); 0.84 (m, 2H) (M + H) if = 435 B < 10 -200- 88828.doc 200418452 Example number name NMR data Mass Spec HCV po! -BB7 IC50 〇iM) A = / iM B = to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 μΜ Replicon (μΜ) 242.2 2- (4-Amino-phenyl) -5_-isopropoxy-6- (3-methoxymethyl-isofluorene-5-yl) -benzofuran-3-le Formamidine acid 1H NMR in DMSO: 8.45 (broad quartet, J = 4.8Hz, 1H); 8.10 (s, 1H); 7.97 (dd, J = 5.7, 8.8Hz, 2H); 7.40 (t, J = 8.8 Hz7 2H); 7.32 (s, 1H); 6.92 (s, 1H); 4.88 (quintet, 1H); 4.55 (sT 2H); 3.29 (s, 3H); 2.85 (d, J = 4.4Hz, 3H); 1.40 (d, J = 6.1Hz, 6H) (M + H) + = 439 B 30 243. 2- (4-fluoro-phenyl) -6-methanesulfonylamino-benzofuran-3- Formamidine mesitamine 1H NMR m DMSO: 8.37 (m, 1H); 7.93 (ddt J = 5.7 & 8.8Hz, 2H); 7.53 (d, J = 8.8Hz, 1H); 7.45 (d, J = 1.7 Hz, 1H); 736 a J = 8.8Hz, 2H); 7.14 (dd, J = 1.7 & 8.8Hz, 1H); 4.17 (bst 1H); 2.96 (s, 3H); 2.82 (d, Ι = 4.8 Ηζ, 3H) (M + H) + = 363 B < 10 244.4 2- (4-Amino-phenyl) -6- (lH-imidazol-2-yl) -5-isopropoxy-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 10.70 (s, 1H); 8.43 (s, 1H); 7.86-7.81 (m, 2H); 7.48 (s, 1H); 7.21-7.15 (m, 3H); 7.12 (s, 1H); 5.96 ( s, 1H); 4.91-4.83 (m, 1H); 2.99 (d, J = 4.8Hz, 3H); 1.49 (d, J = 6.0Hz, 6H) (M + H) + = 394 A < 1 245.6- (2,5-dimethyl-2H-pyrazol-3-yl) 2- (4-fluoroyl-phenyl) -5-isopropoxy-benzopyran- 3-Hydroxyformamidine 1H NMR in CDC13: 8.08 (s, 1H); 7.88 (m, 2H); 7.35 (s, 1H); 7.19 (m, 2H); 6.67 (s, 1H); 5.78 (brs , 1H); 4.67 (m, 1H); 3.84 (s, 3H); 3.00 (d, J = 4.8Hz, 3H); 2.33 (s, 3H); 1.39 (d, J = 6.0Hz, 6H) (M + H) + = 422.1 B < 10 246. 6- (3,5-Dimethyl-1H-P than Jun-4-yl) -2- (4-fluoroyl-dongyl) -5-hexylpropoxy-benzofuran- 3-Hydroxymethamamine 1H NMR ia CDC13: 7.91 (ra, 2H); 7.40 (s, 1H); 7.28 (s, lH); 7.18 (ra, 2H); 5.80 (brs, 1H); 4.36 (m , iH); 3.00 (d, J = 5.4Hz, 3H); 2.21 (s, 6H); 1.20 (d, J = 5.7 Hz, 6H) (M + H) + = 422.1 A < 1 247.4 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (5-methyl-2H-pyrazol-3-yl) -benzofuran-3- double acid Formamidine 1H NMR in CDCl3: 7.87 (in, 2H); 7.75 (s, 1H); 7.47 (s, 1H); 7.20 (m, 2H); 6.47 (s, 1H); 5.75 (brs, 1H); 4.82 (m, 1H); 2.99 (d, J = 5.1Hz, 3H); 2.36 (s, 3H); 1.46 (d, J = 6.0Hz, 6H) (M + H) + = 408.1 B < 10 248. 6- (1,5-Dimethyl-1H-pyrazol-3-yl) -2- (4-fluoroyl-phenyl) -5-isopropoxy-benzofuran Formamidine acid 1H NMR in CDC13: 7.88 (m, 2H); 7.44 (s, 1H); 7.38 (s, 1H); 7.20 (m, 2H); 6.04 (s, 1H); 5.68 (brs, 1H) ; 4.44 (m, 1H); 3.68 (s, 3H); 3.00 (dt J = 4.8Hz, 3H); 2.32 (s, 3H); 1.25 (d, J = 6.3Hz, 6H) (M + H) + = 422.1 B < 10 249.2 2- (4-Fluoro-phenyl) -5-isopropoxy-6-[(methanesulfonyl-methyl-amino) -methyl] -benzofuran-3- Formamidine carboxylate 1HNMR ia CDC13: 1 7.86-7.83 (m, 2H); 7.58 (s, 1H); 7.37 (s, IH); 7.22-7.17 (m, 2H); 5.75 (s, 1H); 4.74 -4.66 (m, 1H); 4.47 (s, 2H); 2.99 (d, J = 5.lHz, 3H); 2.87 (d, J = 5.7Hz, 6H); 1.39 (d, J = 6.3Hz, 6H ) (M + H) + = 449 A < 10 201-88828.doc 200418452 Example No. NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A = / iM B = 03 to 5: 5.0 / iM C = 5.0 to < 30 / iM D = > 30 / iM replicon (μM) 250. 2- (4-amino-phenyl) -5- (2-quinyl-2-methyl-propoxy) -6 -Morphine-4-Tomb-Benzofuran-3-carboxylic acid formamide. LHNMRinCDCl3: 7.87 (dd, J = 8.8 & 5.3 Hz, 2H); 7.40 (s, 1H); 7.20 (U = 8.8 Hz, 2H); 7.12 (s, 1H); 5.80 (brs, 1H); 3.98 (s, 2H); 3.92 (t, J = 4.4 Hz, 4H); 3.10 (t, J = 4.4 Hz, 4H ); 2.96 (d, J = 4.4 Hz, 3H); 1.35 (s, 6H) (M + H) + = 443 B < 10 251. -5- (2-Ethyl-2-methyl-butoxy) -6-morphol 51 Lin-4-yl-benzofuran carboxylic acid formamide 1HNMRinCDCi3: 7.86 (dd, J = 8.8, 53 Hz, 2H); 7.40 (s, 2H); 7.22 (t, J = 8.8 Hz, 2H); 7.12 (s, 1H); 5.90 (brs, 1H); 4.00 (m, 2H); 3.95 (t, J = 4.4 Hz, 4H); 3.10 (t, J = 4.4 Hz, 4H); 2.95 (dt J = 4.4 Hz, 3H); 2.30 (brs, 1H); 1.70 (in, 2H); 1.24 (s, 3H); 0.95 (t, J = 7.0Hz, 3H) (M + H) + = 457 B < 10 252. _ 2- (4-Fluoro-phenyl) -5- (2-hydroxy-propoxy) -6-morpholine? 4-L-yl-rate-pyranfuran-3- Formamidine carboxylate 1H NMR in DMSO: 8.28 (d, J = 4.4 Hz, 1H); 7.88 (dd, J-5.3 & 8.8 Hz, 2H); 7.32 (t, J = 8.8 Hz, 2H); 7.16 (s, 1H); 7.06 (s, 1H); 4.82 (d, J = 4.7 Hz, 1H); 4.00-3.90 (m, 3H); 3.74 (brs, 4H); 3.04 (brs, 4H); 2.81 ( d, J = 4.0 Hz, 3H); 1.19 (d, J = 4.7 Hz, 3H) (M + H) + = 429 B < 10 253. 2- (4-Fluoro-phenyl) _6-[(2_year-old to propyl) -methanesulfonyl-amino] -5-isopropoxy-benzofuran- 3-carboxylic acid methylamine 1H NMR ia DMSO: 8.40 (dt J = 4.4 Hz, 1H); 7.94 (dd, J = 8.8 & 5.3 Hz, 2H); 7.63 (brs, 1H); 7.36 (t, J = 8.8 Hz, 2H); 7.14 (s, 1H); 4.77 (septet, J = 6.1 Hz, 1H); 4.62 (brs, 1H); 3.60-3.40 (m, 3H); 3.00 (s, 3H); 2.81 (d, J = 4.4 Hz, 3H); 1.33 (d, J = 6.1 Hz (M + H) + = 479 A < 1 254.2 2- (4-Gasyl-phenyl) -6_ morpholine benzyl-5- (1-¾ thio-2-yl-ethoxy) -benzofuran-3-carboxylic acid methyl Amidine 1H NMR in CDC13: 7.88 (dd, J = 8.8,5.3Hz, 2H); 7.76 (d, J = 3.1Hz, 1H); 7.33 (brs, 2H); 7.14 (t, J = 8.8Hz, 2H ); 7.08 (s, 1H); 5.82 (q, J = 6.6Hz, 1H); 5.79 (brs, 1H); 3.83 (m, 4H); 3.15 (ra, 4H); 2.97 (d, J = 4.9Hz , 3H); 1.78 (d, J = 6.1Hz, 3H) (M + H) + = 482 A < 1 255.6 6- (ethyl-methanesulfonyl-amino) -2- (4-gas-phenyl) 5-isopropoxy-benzofuran-3-m formamidine 1H NMR ia CDCi3: 7.83 (dd, J = 8.3, 3.1Hz, 2H); 7.51 (s, 1H); 7.40 (s, 1H); 7.20 (t, J = 8.3Hz, 2H); 5.72 (brs, 1H) ; 4.78 (septet, J = 6.1Hz, 1H); 3.72 (brs, 2H); 2.97 (d, J = 4.4Hz, 3H); 2.96 (s, 3H); 1.40 (d, J = 6.1Hz, 6H) ; 1.13 (t, J = 7.0Hz, 3H) (M + H) + = 449 A < 1 256.6- (3,5-dimethyl-1H-pyrazol-4-yl) -2- (4-fluoroyl-phenyl) -5-methoxy-benzofuran-3- Formamidine carboxylate * H NMR ia CDC13: 7.88 (m, 2H); 7.39 (s, 1H); 7.26 (s, 1H); 7.19 (m, 2H); 5.78 (brd, 1H); 3.86 (s, 3H); 3.01 (d, J = 4.8Hz, 3H); 2.25 (s, 6H) '(M + H, = 394.1 A < 1 257. 2- (4-Fluoro-phenyl) > 5-isopropoxy-6- (5-methyl-1H-pyrazol-4-yl) -benzofuran-3-carboxylic acid Formamidine NMR in CDC13: 7.87 (m, 2H); 7.74 (s, 1H); 7.38 (s, 2H); 7.18 (m, 2H); 5.81 (brs, 1H); 4.52 (m, 1H); 3.00 (d, J = 5.4Hz, 3H); 2.38 (s, 3H); 1.28 (d, J = 6.0Hz, 6H) (Μ + ΗΓ = 408.1 A < 1 202-88828.doc 200418452 Instance number name NMRdata Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 nM replicon ( μM) 258.3 3- [2- (4-Fluoro-phenyl) -3-methylaminomethylmethyl-benzofuran-5-yloxymethyl] methyl gallate 1H NMR in DMSO: 8.34 ( brd, 1H, J = 4.10Hz); 8.07 (s, 1H); 7.92 (m, 3H); 7.76 (d, 1H, J = 7.62Hz); 7.56 (m, 2H); 735 (t, 2H, J = 7.03Hz); 7.21 (dt 1H, J = 2.34Hz); 7.07 (ddt 1H, J = 8.79, 2.34Hz); 5.24 (s, 2H); 3.86 (s, 3H); 2.81 (d, 3H, J = 4.69Hz) (M + H) + = 434 A > 30 259. 4- [2 · (4-Gas-phenyl) -3-methylaminomethylmethyl-benzofuran 5-yloxy Methyl) benzyl acid 1H NMR in DMSO: 8.38 (brd, 1H, J = 4.10Hz); 7.90 (m, 4H); 7.56 (d, 1H, J = 8.79Hz); 7.35 (m, 4H); 7.20 ( s, 1H); 7.05 (d, 1H, J = 9.38Hz); 5.13 (s, 2H); 2.82 (d, 3H, J = 4.69Hz) (MH) '= 418 B < 30 260. 3- [2- (ί-fluoro-phenyl) · -3-methylaminomethylmethyl-benzofuran-5-yloxymethyl] gallic acid JH NMR in DMSO: 12.98 ( brs, 1H); 834 (br m, 1H); 8.05 (s, 1H); 7.91 (m, 3H); 7.72 (d, 1H, J = 6.45Hz); 7.56 (m, 2H); 7.35 (t, 2H, J = 8.79Hz); 7.21 (s, 1H); 7.08 (d, 1H, J = 8.79Hz); 5.23 (s, 2H); 2.81 (d, 3H, J = 6.71Hz) (MH) '= 418 A > 30 261. 6-Ethyl-2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-quinoformamidine'H NMR in CDC13: 7.84 ( m, 2H); 7.83 (s, 1H); 7.37 (s, 1H); 7.19 (m, 2H); 5.95 (brs, 1H); 3.97 (s, 3H); 3.00 (d, J = 4.8Hz, 3H ); 2.64 (s, 3H) (M + H) + = 342.1 A < 1 262. 4- [2- (4-Fluoro-phenyl)-3-methylaminomethylcarbamoyl fulin-4-yl-benzopyran-5-yloxymethyl] LH NMR in CDCl3: 8.09 (d, 2H, J = 8.21Hz); 7.85 (m, 2H); 7.57 (d, 2H, J = 8.21Hz); 7.42 (s, 1H); 7.18 (t, 2H, J = 8.21); 7.12 (s, 1H); 5.72 (brs, 1H); 5.24 (s, 2H); 3.94 (s, 3H); 3.89 (m, 4H); 3.16 (m, 4H); 2.98 (d, 3H, J = 4.69Hz) (M + H) + = 519 A < 10 263. 3- [2- (4-Fluoro-phenyl) -3-methylamine formamyl-6-morpho 57 lin-4-yl-benzoan-5-yloxymethyl Table] 1H NMR of Methyl Esterate in CDC13: 8.25 (s, 1H); 8.05 (d, 1H, J = 8.21Hz); 7.87 (m, 2H); 7.67 (d, 1H, J = 7.62Hz); 7.51 (t, 1H, J = 7.62Hz); 7.45 (s, 1H); 7.20 (t, 2H, J = 8.79Hz); 7.13 (s, 1H); 5.75 (brs, 1H); 5.24 (s, 2H ); 3.97 (s, 3H); 3.93 (m, 4H); 3.18 (m, 4H); 3.00 (d, 3H, J = 5.28) (M + H) " = 519 A < 10 264.2 2 (4-Mono-phenyl-isopropyloxy-6- (l, 3,5-trimethyl-1H-pyridine-4-yl) -benzofuran-3- Formamidine carboxylate 1H NMR in CDC13: 7.90 (m, 2H); 7.38 (s, 1H); 7.25 (s, 1H); 7.18 (m, 2H); 5.78 (brs, 1H); 4.36 (in, 1H) ); 3.79 (s, 3H); 3.01 (d, J = 4.8 Hz, 3H); 2.17 (s, 3H); 2.14 (s7 3H); 1.20 (d, J = 6.0 Hz, 6H) (M + HV = 436.1 B < 10 265. 2_ (4_Gas-Dongyl) -5_isopropoxy-6 · Epgoline-2-yl-benzoanan-3 -carboxylic acid formamidine 1H NMR in CDC13: 7.82 (m, 2H); 7.52 (s, 1H); 7.32 (s, 1H); 7.18 (m, 2H); 6.76 (brs, 2H); 5.80 (brs, 1H); 4.75 (m, 1H); 4.72 (m, IH); 3.28 (m, 2H); 2.97 (d, J = 5.4 Hz, 3H); 2.28 (m, 1H); 2.03 (m, 3H); 1.41 (d, J = 6.0 Hz, 6H) (M + H) + = 397.1 C > 30 266.6 6-Gas-2- (4-Gas-Mulyl) -5-methoxy-benzoanan-3-methanoic acid NMR in CDC13: 7.89 -7.83 (m, 2H); 7.83 (s, 1H); 7.45 (s, 1H); 7.25-7.20 (m, 2H); 5.74 (s, 1H); 3.99 (s, 3H); 2.99 (d, J = 5.6 Hz, 3H) (M + H) + = 325 A < 1 203 > 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50〇tM) A = μΜ B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 μΜ Copy (ΜΜ) 267. 4- [2- (4-Gasyl-phenyl) -3-methylaminomethylmethyl-6-morpholin-4-yl-mycyl-5-yloxy Methyl] -benzoic acid 1H NMR in DMSO: 8.32 (brdT 1H, J = 4.69Hz); 7.90 (m, 4H); 7.41 -7.31 (rn, 4H); 7.23 (s, 2H); 5.16 (s, 2H ); 3.75 (m, 4H); 3.07 (m, 4H); 2.84 (d, 3H, J = 4.10) (Μ + ΗΓ = 505 A < 10 268. 3- [2- (4-Fluorobenzyl-3-methylamine T-methyl morpholine_4-yl-benzofuran-5-yloxymethyl j-gallate 1H NMR in DMSO: 8.33 (brd, 1H, J = 4.69Hz); 8.02 (s, 1H); 7.92 (m, 2H); 7.80 (d, 1H, J = 7.03Hz); 7.41-7.26 (in, 4H) ; 7.23 (d, 2Ht J = 4.10Hz); 5.16 (s, 2H); 3.76 (m, 4H); 3.07 (m, 4H); 2.84 (d, 3H, J = 4.10Hz) (M + H) + = 505 A < 10 269. 2- (4-Fluorophenyl) -5-isopropoxy each [methanesulfonyl- (1-methyl-1H-tetrazolylmethyl) -amino] -benzo 1H NMR in DMSO: 8.43 (brd, 1H, J = 4.69); 7.92 (m, 2H); 7.60 (s, 1H); 737 (t, 2H, J = 8.79Hz) ; 7.14 (s, 1H); 5.19 (s, 2H); 4.78 (m, 1H); 4.10 (s, 3H); 3.20 (s, 3H); 2.82 (d, 3H, J = 4.69Hz); 1.35 ( d, 6H, J = 6.45Hz) (M + H, = 517 A < 1 270. 4-({[2- (4-Fluoro-phenyl) -5-isopropoxy-3-methylamine methylamidino-benzofuran-6-yl] -formaldehyde Ethyl-amino group} -methyl) -coate methyl ester'H NMR in CDCi3: 7.91 (d, 2H, J = 8.21Hz); 7.75 (m, 2H); 7.41 (s, 1H); 7.34 (d , 2H, J = 8.21Hz); 7.20-7.14 (m, 3H); 5.66 (brs, 1H); 4.84 (br m, 3H); 3.87 (s, 3H); 3.04 (s, 3H); 2.94 (d , 3Hf J = 5.27Hz); 1.48 (d, 6H, J = 5.86Hz) (M + H) + = 569 A < 1 271. 2- (4-Fluoro-phenyl) -5 ^ isopropoxy-6- [methanesulfonyl- (2-methyl-thiazolylmethyl) -amino] -benzene 1H NMR in CDCl3: 7.80 (m, 2H); 7.43 (s, 1H); 7.39 (s, 1H); 7.18 (t, 2H, J = 8.79Hz); 7.07 ( s, 1H); 5.68 (brs, 1H); 4.93 (brs, 2H); 4.78 (m, 1H); 3.06 (s, 3H); 2.95 (d, 3H, J = 4.69Hz); 2.63 (s, 3H ); 1.43 (d, 6H, J = 6.45Hz) (M + H) + = 532 A < 10 272. 4-({[2- (4-Fluoro-phenyl) 5-isopropoxy-3-methylaminemethylamido-benzofuranyl] -methanesulfonyl-amine 1H NMR in DMSO: 8.36 (brd, 1H, J = 4.69 Hz); 7.89-7.82 (m, 4H); 7.40 (m, 3H); 7.32 (t, 2H, J = 8.79 Hz); 7.10 (s, 1H); 4.80 (br m, 3H); 3.13 (s, 3H); 2.79 (d, 3H, J = 4.10 Hz); 1.38 (d, 6H, J = 5.86 Hz) \ (M + H) + = 555 A < 1.0 273. 2- (4-Gasyl-phenyl) -5-isopropoxy-6- (5-methoxymethyl-iso-azine-3-yl) -benzofuran-3-benzyl Formamidine acid 1H NMR in DMSO: 8.43 (q, J = 4.4 Hz, 1H); 7.98 (s, 1H); 7.97 (dd, J = 5.3, 8.8 Hz, 2H); 7.39 (apparent triplet, J = 8.8 Hz, 2H); 7.29 (s, 1H); 6.93 (s, 1H); 4.76 (m, J = 6.1, 5.7 Hz, 1H); 4.62 (s, 2H); 3.36 (s, 3H); 2.85 (d , J = 4.4 Hz, 3H); 1.34 (d, J = 6.1 Hz, 6H) (M + H) + = 439.05 A < 1 204- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A = iO-5 μΜ B = 0.5 to ^ 5.0 μΜ C = 5.0 to ^ 30 / iM D = > 30 μΜ Replicon (μM) 274.6- (5-cyclopropyl-isoxazol-3-yl) -2- (4-amino-phenyl) -5-isopropoxy-benzofuran-3- Formamidine carboxylate * H NMR in DMSO: 8.42 (q, J = 4.4 Hz, 1H); 7.96 (dd, J = 5.3, 8.8 Hz, 2H); 7.92 (s, 1H); 7.38 (apparent triplet, J = 8.8 Hz, 2H); 7.26 (s, 1H); 6.61 (s, 1H); 4.72 (m, J = 6.15Hz, iH); 2.84 (d, J = 4.4 Hz, 3H); 2.22 (m, 1H ); 1.33 (d, J = 6.15 Hz, 6H); 1.10 (m, 2H); 0.94 (m, 2H) (M + H) + = 435.12 A < 1 275. Fluoro-phenyl) -5-isopropoxy-6- (1-methane transverse acid-p-pyridine-2-yl) -benzofuran-3-chitoic acid formamidine lH NMR in CD € 13: 7.84 (m, 2H); 7.56 (s, 1H); 7.30 (s, 1H); 7.21 (mt 2H); 5.73 (brs, 1H); 5.21 (dd, J = 8.4 Hz, 2.4 Hz, IH); 4.69 (m, 1H); 3.70 (m, 1H); 3.55 (m, 1H); 2.97 (d, J = 3.9 Hz, 3H); 2.84 (s, 3H); 2.35 (m, 1H); 1.95 (m, 3H); 1.39 (d, J = 6.3 Hz) (M + H) + = 475.1 A < 1 276. 6-Ethylfluorenyl-2- (4-fluoro-winteryl) -5-: ¾-yl-benzofuran-3-carboxylic acid mepanimine 1H NMR in CDC13: 12.16 (s, 1H ); 8.03 (m, 2H); 7.87 (s, 1H); 7.19 (ra, 2H); 5.86 (br, 1H); 3.02 (d, J = 4.8Hz, 3H); 2.71 (s, 3H) (M + H) + = 328.0 B < 10 277.6 6- (Ethyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine ' H NMR ia DMSO: 8.43 (d, J = 4.69Hz, 1H); 7.96-7.91 (ra, 2H); 7.6 (s, 1H); 7.38 (t, J = 8.79Hz, 2H); 7.21 (s, 1H ); 3.9 (s, 3H); 3.62 (q, J = 7.03, 2H); 3.02 (s, 3H); 2.84 (d, J = 4.69HzT 3H); 1.02 (t, J = 7.03Hz, 3H) ( M + H) + = 421.1 A < 1 278. 4- [2- (4-Fluoro-phenyl) -5-methoxy-3-methylamine formamido-benzocran-6-yl] -2-oxy- Pyrrolidine-3-carboxylic acid formamidine'H NMR ia DMSO: 8.36 (q, 1H, br); 8.00 (q, 1H, br); 7.97-7.68 (ra, 3H); 7.53 (s, 1H); 7.77 (m, 2H); 7.U (s, 1H); 4.20 (q, 1H); 3.84 (s, 3H); 3.57 (m, 2H); 3.16 (t, 1H); 2.82 (d, 3H) ; 2.57 (d, 3H) (M + H) + = 440 A < 10 279. 2- (4 · Fluoro-phenyl) _5_ isopropoxy-6- · (4Η · [1,2,4] triazol-3-yl) -benzo4an-3- Formamidine carboxylate 1H NMR in CDC13: 8.47 (s, 1H); 8.03 (s, 1H); 7.84-7.89 (m, 2H); 7.57 (s, 1H); 7.19-7.25 (t, 2H, J = 8.79 Hz); 5.80 (br.s, 1H); 4.90-4.98 (septet, 1H, J = 5.86 Hz); 2.98-3.00 (d, 3H, J = 4.69 Hz); 1.52 -1.54 (d, 6H, J = 6.45 Hz) (M + H) + = 395.0 A < 30 280. 2- (4-Fluoro-phenyl) -5-methoxy-6- (5-methoxymethyl-3-methyl-isoxan-4-yl) -benzofuran Formamidine-3-carboxylic acid * H NMR in CDCi3: 7.86 (dd, J = 8.8 and 5.1 Hz, 2H); 7.43 (s, 1H); 7.35 (s, 1H); 7.21 (apparent t, J = 8.8 and 8.4 Hz, 2H); 5.78 (brs 1H); 4.42 (s, 2H); 3.86 (s, 3H); 3.36 (s, 3H); 3.01 (d, J = 5.1 Hz, 3H); 2.21 (s, 3H) (M + H) + = 425 A < 1 205-88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 IC5〇 (μΜ) A = / iM B = to ^: 5.0 μΜ C = 5.0 to <: 30 / iM D = > 30 / iM replicon (μM) 281.2 2- (4-fluoro-phenyl) -5_ isopropoxy-6- [methanesulfonyl- (4-methyl Oxy-fluorenyl) -amino] -benzoanan-3-carbamidine 1H NMR in CDC13: 7.76 (m, 2H); 7.38 (s, 1H); 7.20-7.12 (m, 5H) ; 6.75 (d, 2H, J = 8.79 Hz); 5.86 (brs, 1H); 4.90-4.70 (br m, 3H); 3.74 (s, 3H); 3.03 (s, 3H); 2.95 (d, 3H, J = 4.69 Hz); 1.47 (d, 6Hy J = 6.45 Hz) (MH) = 539 A < 1 282.2 2- (4-Fluoro-phenyl) -5-isopropoxy-6- [methylsulfonyl- (5-methyl-isoammonium 3-ylmethyl) -amine Benzyl] -benzofuran-3-methanomethamine 1H NMR in CDCi3: 7.79 (m, 2H); 7.42 (s, 1H); 7.34 (s, 1H); 7.19 (t, 2H, J = 8.79 Hz ); 6.21 (s, 1H); 5.86 (brs, 1H); 4.83 (br m, 3H); 3.04 (s, 3H); 2.96 (d, 3H, J = 4.69 Hz); 2.38 (s, 3H); 1.45 (d, 6H, J = 5.86 Hz) (MH) * = 514 A < 1 283. 2- (4-Gasyl-benzene grave) -5_ isopropoxy-6- (5-methyl-iso-17ajun-3 -yl) -benzofuran-3-carboxylic acid form Lamine 1H NMR in CDCb: 8.015 (s, 1H); 7.87 (dd, J = 5.3, 8.3 Hz, 2H); 7.43 (s, 1H); 7.19 (apparent triplet, d, J = 8.3 Hz, 2H); 6.58 (s, 1H); 5.79 (bs, 1H); 4.68 (m, 1H); 2.99 (d, J = 4.8 Hz, 3H); 2.48 (s, 3H); 1.38 (d, J = 5.7 Hz, 6H ) 氺 氺 氺 A < 1 284 .; 6-[(3,5-dimethyl-isoindazol-4-ylmethyl) -methanesulfonyl-amino] -2- (4-fluoro-phenyl)- 5-isopropoxy-benzofuran-3-menfate methamidamine 1H NMR in DMSO: 8.41 (brd, 1H, J = 4.69 Hz); 7.91 (m, 2H); 7.36 (m, 3H); 7.12 (s, 1H); 4.79 (m, 1H); 4.64 (br m, 2H); 3.13 (s, 3H); 2.82 (d, 3H, J = 4.69 Hz); 2.08 (s, 3H); 2.05 ( s, 3H); 1.37 (d, 6H, J = 5.86 Hz) (M + H) + = 530 A < 10 285. 2- (4-Fluoro-phenyl) -5-isopropoxy-6- (formamidine-pyrimidinyl-pyrazol-2-ylmethyl-amino) -benzofuran -3- Formamidine Carboxylate NMR in DMSO: 8.42 (brd, 1H, J = 4.69 Hz); 7.92 (ra, 2H); 7.67 (d, 1H, J = 3.52 Hz); 7.65 (d, 1H, J = 3.52 Hz); 7.45 (s, 1H); 7.36 (t, 2H, J = 8.79 Hz); 7.18 (s, 1H); 5.12 (brs, 2H); 4.83 (m, 1H); 3.16 (s, 3H ); 2.82 (d, 3H, J = 4.69 Hz); 1.39 (d, 6H, J = 6.45 Hz) (M + H) + = 518 A < 1 286. 2-([[2: όίϋ phenyl) -5-isopropoxy-3-methylaminofluorenyl-benzofuran-6-yl] -methyloxofluorenyl-amino ) -Ethyl acetoethyl carboxylate'H NMR in DMSO: 8.49 (s, 1H); 8.42 (brd, 1H, J = 4.10 Hz); 7.93 (m7 2H); 7.54 (s, 1H); 7.37 (t, 2H, J = 8.79 Hz); 7.20 (s, 1H); 5.13 (brs, 2H); 4.84 (m, 1H); 4.25 (q, 2H, J = 7.03 Hz); 3.18 (s, 3H) ; 2.82 (d, 3H, i = 4.69 Hz); 1.39 (d, 6H, J = 6.45 Hz); 1.26 (t, 3H, J = 7.03 Hz) '(M + H) + = 590 A < 10 206- 88828.doc 200418452 .Instance number name NMRdata Mass Spec HCV pol -BB7 IC50 〇iM) A = μΜ B = 03 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 / iM replicon OiM) 287.2 2- (4-Fluoro-phenyl) -5-hydroxy-6- (methanesulfonyl-methyl-amino) -benzocaran-3-carboxylic acid formamidine 1H NMR in DMSO: 9.98 (s, 1H); 8.39 (d, J = 4.4 Hz, 1H); 7.91 (mT 2H); 7.51 (s, 1H); 7.35 (UJ = 8.8 Hz, 2H); 7.09 (s, 1H ); 3.20 (s, 3H); 3.08 (s, 3H); 2.80 (d, J = 4.4Hz, 3H) (M + H) + = 393 A < 10 288.6 6- (fluorenyl-methanesulfonyl-amino) -5-fluorenylpropoxy-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid formamidine Amine 1H NMR in DMSO: 8.40 (dt J = 4.7 Hz, 1H); 7.93 (dd, J = 9.0, 5.3 Hz, 2H); 7.57 (s, 1H); 7.35 (t, J = 9.0 Hz, 2H); 7.33 (s, 1H); 6.10 (mT 1H); 5.80 (m, 1H); 5.50 (m, 1H); 5.30 (m, 1H); 5.10 (m, 1H); 5.00 (ra, 1H); 4.70 ( d, J = 3.5 Hz, 2H); 4.20 (brs, 2H); 3.05 (s, 3H); 2.81 (d, J = 4.7 Hz, 3H) (M + H) + = 459 A < 1 289. 6- (Ethylfluorenyl-methanesulfonyl-amino) -2- (4-_fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid formamidine Amine 1H NMR in DMSO: 8.48 (d, J = 4.39 HzT 1H); 7.96-7.91 (m, 2H); 7.86 (s, IH); 7.39 (t, J = 8.79 Hz, 2H); 7.27 (s, 1H ); 3.93 (s, 3H); 3.49 (s, 3H); 2.84 (d, J = 4.39, 3H); 1.89 (s, 3H) (M + H) + = 435.0 A < 1 29. 6-[(3,5-Difluorenyl-isopurazol-4-ylmethylmethanesulfonyl-amino group) > Oxy-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.44 (m, 1H); 7.94-7.90 (m, 2H); 7.43-7.33 (m, 3H); 7.16 (s, 1H) ; 4.67 (bs, 2H); 3.9 (s, 3H); 3.13 (ra, 3H); 2.84-2.82 (m, 3H); 2.11 (ct J = 3.52 Hz, 3H); 2.06 (d, J = 3.52, 3H) (M + H) + = 502.1 A < 10 291. 2- (4-Fluoro-phenyl) -6-((A: K-Cyridin-4-ylmethyl-amino) -5-methoxy-benzoanan- 3-Methylmetamidine 1H NMR in DMSO: 9.01 (s, 1H); 8.41 (d, J = 4.84 Hz, 1H); 7.93-7.88 (m, 2H); 7.55 (m, 1H); 7.48 (s , 1H); 7.36 (t, J = 8.35 Hz, 2H); 7.17 (s, 1H); 4.93 (bs, 2H); 3.90 (s, 3H); 3.15 (st 3H); 2.83 (d, J = 4.84 hz, 3H) (M + H) + 490.0 A < 1 292. 2-({[2- (4-Fluoro-phenyl) -5-isopropoxy-3-methylaminomethylmethyl-benzofuran-6-yl] -pyranesulfonate Fluorenyl-aminomethyl) -thiazole-4-carboxylic acid * H NMR in DMSO: 8.42 (brm, 2H); 7.93 (m, 2H); 7.53 (d, 1H, J = 1.17 Hz); 7.36 (t, 2H, J = 8.79 Hz); 7.19 (s, 1H); 5.12 (brs, 2H); 4.84 (m, 1H); 3.19 (s, 3H); 2.82 (d, 3H, 1 = 3.52 Hz); 1.39 ( d, 6H, J = 5.28 Hz) (M + H) + = 562 A > 100 293. 5- (2,2-dimethyl-4-oxy-4H-benzo [1,3] -di Ringen-5-ylmethoxy) -2- (4-amino-phenyl) -6-morpholin-4-yl-benzofuran-3-carboxylic acid amidine 1H NMR in DMSO: 8.32 (brd, 1H, J = 4.40 Hz); 8.08 (s, 1H); 7.90 (m, 2H); 7.80 (d, 1H, J = 8.79 Hz); 7.35 (t, 2H, J = 8.79 Hz); 7.26 -7.19 (m, 3H); 5.20 (s, 2H); 3.77 (m, 4H); 3.06 (m, 4H); 2.83 (d, 3H, J = 4.00 Hz); 1.72 (s, 6H) (M + H) + = 561 B < 10 207- 88828.doc 200418452 example editor " 5 Tiger name NMRdata Mass Spec HCV pol -BB7 IC50〇iM) A = MB only = 03 to ^ 5.0 C = 5.0 to ^ 30 μΜ D = > 30 μΜ Replicon (μΜ) 294. 5- (2,2-Dimethyl-4-oxy-4H-benzo [1,3] -diginyl · 5-ylmethoxy) -6- (ethyl -Methanesulfonyl-amino) -2- (4-fluoro-phenyl) -benzobenzamine-3-carboxylic acid formamidine * H NMR in DMSO: 8.42 (brd, 1H, J = 4.40 Hz ); 8.05 (d, 1H, J = 1.76 Hz); 7.93 (m, 2H); 7.85 (d, 1H, J = 8.35 Hz); 7.65 (s, 1H); 7.39 (ζ 2H, J = 8.79 Hz) ; 7.34 (s, 1H); 7.19 (d, 1H, J = 8.35 Hz); 5.26 (s, 2H); 3.63 (m, 2H); 2.93 (s, 3H); 2.84 (d, 3H, J = 4.40 Hz); 1.71 (s, 6H); 1.03 (t, 3H, J = 7.03 Hz) (M + H) + = 597 A < 1 295. 2- (4-Fluoro-phenyl) -6- (1fluoren-imidazol-4-yl;)-5-methoxy-benzofuran-3-carboxylic acid formamidine 1H NMR ia CDC13: 7.96-7.85 (m, 3H); 7.74 (s, 1H); 7.61 (s, 1H); 7.45 (s, 1H); 7.24-7.18 (m, 2H); 5.82 (s, 1H); 4.04 ( s, 3H); 3.0 (d, J = 4.8Hz, 3H) (M + H) + = 466 A < 10 296. 2_ (4-Gas-wood-based) -6- (1fluoren-imidazol-2-yl) -5-methoxy-benzofuran-3-carboxylic acid formamidine'H NMR in CDC13 : 10.6 (s, 1H); 8.48 (s, 1H); 7.88-7.84 (m, 2H); 7.50 (s, 1H); 7.26-7.20 (m, 3H); 7.18 (s, 1H); 7.13 (s , 1H); 5.84 (s, 1H); 4.14 (s, 3H); 3.0 (d, J = 6.8Hz, 3H) (M + H) + = 466 A < 1 297.6 6- (Ethyl-methanesulfonyl-amino) -2- (4-fluorophenyl) -5- # yl-benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 9.96 (s, 1H); 8.40 (d, J = 4.4Hz, 1H); 7.92 (dd, J = 8.8, 5.3Hz, 2H); 7.46 (s, 1H); 7.37 (t, J = 8.8 Hz, 2H); 7.09 (s, 1H); 3.60 (q, J = 7.0Hz, 2H); 3.01 (s, 3H); 2.80 (d, J = 4.4Hz, 3H); 1.00 (t, J = 7.0 Hz, 3H) (MH) * = 405 A < 10 298. 5-Difluoromethoxy-2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -benzofuran formamidine carboxylic acid 1H NMR in CDCb: 7.86 (dd, J = 8.8, 5.3Hz, 2H); 7.70 (s, 1H); 7.62 (s, 1H); 7.24 (t, J = 8.8Hz, 2H); 6.69 (t, J = 73.4Hz, 1H); 5.74 (brs, 1H); 3.33 (s, 3H); 3.03 (s, 3H); 2.98 (d, J = 4.8Hz, 3H) (M + H) + = 443 A < 1 299.2 2- (4-Fluoro-phenyl) -6_ (methanesulfonyl-eridin-4-ylmethyl-amino) -5-methoxy-benzo 4-4- Formamidine carboxylate * (M + H) + = 484 A < 1 300. 2- (4-Fluoro-phenyl) -6- (1-meryl small methyl_ethyl) _5_methyl-benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.95 (m, 2H); 7.69 (s, 1H); 7.56 (s, 1H); 7.16 (mt 2H); 5.83 (brs, 1H); 3.02 (d, J = 4.6 Hz, 3H); 2.69 ( s, 1H); 2.64 (d, J = 3.9 Hz, 3H); 1.72 (s, 6H) (M + H) " = 342.1 A < 10 301. 6-Ethyl-2- (4-fluoro-phenyl) -5-methyl-benzofuran medonylamine of each carboxylic acid 'H NMR in CDC13: 7.94 (m, 2H); 7.79 (s, 1H); 7.69 (s, 1H); 7.20 (m, 2H); 5.83 (brs, 1H); 3.02 (d, J = 4.8 Hz, 3H); 2.64 (s, 3H); 2.96 (s , 3H) (M + H) + = 326.1 A < 10 208-88828.doc 200418452: Instance data name NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = 0.5 to 2: 5.0 fiM C = 5.0 to ^ 30 μΜ D = > 30 μΜ Copy 〇iM) 302. 5- (2,2-Difluorenyl-4 · oxy-4H-benzo [1,3] -difluorene 4-7-ylmethoxy) -2- (4-denyl -Phenyl) -6- (methanesulfonyl-methyl-amino) -benzofuran-3-carboxylic acid formamidine NMR in DMSO: 8.39 (brd, 1H, J = 4.69 Hz); 7.92 (m , 3H); 7.74 (s, 1H); 7.37 (m, 3H); 7.29 (d, 2H, J = 1.76 Hz); 5.32 (brs, 2H); 3.23 (s, 3H); 3.01 (s, 3H) ; 2.82 (d, 3H, J = 4.10 Hz); 1.71 (s, 6H) (M + H) + = 583 A < 1 303. 2- (4-Fluoro-phenyl) methanesulfonyl-methylpyridyl-amino) -ethyl] -5-methoxy-epimethyl-3-carboxylic acid formamidine lH NMR in CDC13: 7.89-7.84 (m, 2H); 7.50 (s, 1H); 7.39 (s, 1H); 7.27-7.19 (m, 2H); 5.76 (s, 1H); 5.63-5.56 (m, 1H); 3.95 (s, 3H); 3.00 (d, J = 4.8Hz, 3H); 2.82 (s, 3H); 2.69 (s, 3H); i.65 (d, J = 6.9Hz, 3H) ( M + H) + = 435 A < 1 304. --2- (fluorenyl-fluoro-benzyl) -5-methoxy-6- (1-methylamino-ethyl) -benzofuran-3-carboxylic acid formamidine 1H NMR in CDC13: 7.88-7.83 (m, 3H); 7.47 (s, 1H); 7.33 (s, 1H); 7.21-7.16 (m, 6H); 5.75 (s, 1H); 4.20-4.16 (m, 1H) ); 3.92 (s, 3H); 3.47 (s, 1H); 2.99 (d, J = 4.5Hz, 3H); 2.34 (s, 3H); 1.44 (d, J = 6.3Hz, 3H) (M + H ) + = 357 B > 30 305. 4- [2- (4-Fluoro-phenyl) -6- (methylpyridyl-fluorenyl-amino) -3-methylaminomethyl- Benzofuran-5-yloxymethyl] -benzoic acid methyl esterΉ NMR in DMSO: 8.40 (brd, 1H, J = 4.69); 8.02 (d, 2H, J = 8.21); 7.93 (m, 2H) ; 7.70 (111, 3H); 7.39 (t, 2H, J = 8.79 Hz); 7.34 (s, 1H); 5.34 (s, 2H); 3.87 (s, 3H); 3.22 (s, 3H); 2.97 ( s, 3H); 2.84 (d, 3H, J = 4.10Hz) (M + H) + = 541 A < 1 306. 2- [2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino group; H3-methylaminomethylmethyl-benzo-benzoan-5- Methyloxyformate 1H NMR in DMSO: 8.39 (brd, 1H, J = 5.28 Hz); 8.15 (s, 1H); 7.93 (ra, 3H); 7.82 (d, 1H, J = 7.62 Hz); 7.68 ( s, 1H); 7.58 (ζ 1H, J = 7.62 Hz); 7.37 (m, 3H); 5.32 (s, 2H); 3.86 (s, 3H); 3.20 (s, 3H); 2.94 (s, 3H) ; 2.82 (d, 3H, J = 4.10 Hz) (M + H) + = 541 A < 1 307.6 6-((2-Fluoro-ethyl) -methyl ^ complete guaranyl-amine plug] -2- (4-fluoro-phenyl) -5-methoxy-benzofuran Formamidine-3-carboxylic acid * H NMR in DMSO: 8.43 (m, 1H); 7.93 (dd, J = 5.3 & 8.8Hz, 2H); 7.62 (s, 1H); 7.39 (t, J = 8.8 Hz, 2H); 7.22 (s, 1H); 4.54 (t, J = 5.3Hz, 1H); 4.39 (t, J = 4.7Hz, 1H); 3.92 (m, 4H); 3.84 (m, 1H); 3.06 (s, 3H); 2.83 (d, J = 4.7Hz, 3H) (M + H) + = 439 A < 1 308. _2- (4-Fluoro-phenyl) -6- [methanesulfonyl- (2,2,2-trifluoroethyl) -amino] -5-methoxy-benzo 1H NMR of stilbene 3-carboxylate in DMSO: 8.45 (m7 1H); 7.93 (dd, J = 5.3 & 8.8Hz, 2H); 7.65 (s, 1H); 7.39 (t, J = 8.8Hz , 2H); 7.25 (s, IH); 4.40 (m, 2H); 3.94 (s, 3H); 3.10 (s, 3H); 2.83 (d, J = 4.7Hz, 3H) (M + H) + = 475 A < i 209- 88828.doc 200418452 Instance data name NMR data Mass Spec HCV pol -BB7 ICs〇〇iM) A = / iM B = 0 0 J to ^ 5.0 / iM C = 5.0 to ^ 30 / iM D = > 30 μΜ replicon (μΜ) 309.2- (4-fluoro-phenyl) -6- (1-methanesulfonyl-pyrrolidin-2-yl) -5-methoxy-xylo-amino-3 -Formamidine chitomate NMR in CDC13: 7.84 (m, 2H); 7.58 (s, 1H); 7.26 (s, 1H); 7.18 (m, 2H); 5.76 (brs, 1H); 5.22 (m, 1H) ); 3.91 (s, 3H); 3.75 (m, 1H); 3.55 (m, 1H); 3.18 (m, 1H); 3.00 (d, J = 4.6 Hzt 3H); 2.84 (s, 3H); 1.92 ( m, 2H); 1.84 (m, 2H) M + = 446 (GCVMS) A < 1 310. 6- (3-Cyclopropyl-5-methoxymethyl-isoindan-4-yl) -2- (4-amino-phenyl) -5-methoxy-benzo Furfuryl 4-3-carboxylic acid formamidine 1H NMR in CDCl3: 7.87 (dd, J = 8.8 and J = 5.1Hzt 2H); 7.44 (s, 1H); 7.42 (s, 1H); 7.20 (apparent t, J = 8.8 and 8.4 Hz, 2H); 5.81 (brs, 1H); 4.40 (s, 2H); 3.87 (s, 3H); 3.34 (s, 3H); 3.01 (d, J = 4.8Hz, 3H); 1.65 (m, 1H); 1.02 (m, 2H); 0.88 (m, 2H) (M-Η) '= 449 A < 1 311. 4- [2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -3-methylaminomethylmethyl-benzofuran-5- 1H NMR in DMSO: 8.41 (brd, 1H, J = 4.10Hz); 7.95 (mt 4H); 7.69 (s, 1H); 7.58 (d, 2H, J = 8.21Hz); 7.37 (mt 3H); 5.29 (s, 2H); 3.21 (s, 3H); 2.94 (s, 3H); 2.84 (d, 3H, J = 4.69Hz) (M + H) + = 527 A < 10 312. 3- [2_ (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -3-methylaminomethyl-benzoxan-5- 1H NMR in DMSO: 8.41 (brd, 1H, J = 4.10Hz); 8.14 (s, 1H); 7.94 (m, 3H); 7.80 (d, 1H, J = 7.62Hz) ; 7.69 (s, 1H); 7.57 (t, 1H, J = 8.21Hz); 7.38 (m, 3H); 5.33 (s, 2H); 3.22 (s, 3H); 2.95 (s, 3H); 2.84 ( d, 3H, J = 4.10Hz) (M + H) + = 527 A < 1 313. 2- (4-Fluoro-phenyl) -5-methoxy-6- (5-methoxymethyl-isohumic acid lH NMR in CDCl3: 8.03 (s, 1H); 7.87 (ddt J = 5.27 & 8.8Hz, 2H); 7.45 (s, 1H); 7.20 (apparent triplet, J = 8.8 & 8.3Hz, 2H); 6.83 (s, 1H); 5.80 (bs, 1H); 4.61 (s, 2H); 3.96 (s, 3H); 3.48 (s, 3H); 3.00 (d, J = 4.8Hz, 3H) (M + H) + = 411 A < 1 314.6. 6- (3,5-dimethyl-isohumazol-4-yl) -2_ (4-fluoro-phenyl) > 5-hydroxy-benzofuran-3-carboxylic acid methyl alcohol Amine 1H NMR in CDC13: 7.90 (m, 2H); 7.56 (s, 1H); 7.22 (mT 3H); 6.04 (brs, 1H); 5.83 (brs, 1H); 3.00 (d, 3H, J = 4.69Hz ); 2.36 (s, 3H); 2.22 (s, 3H) (M + H) + = 381 A < 1 315. 2- (4-Fluoro-phenyl) -5_methoxy-6- (5-oxy-pyrrolidin-3-yl) benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.36 (m, 1H, br); 7.92 (dd, 2H); 7.64 (s, 1H, br); 7.54 (s, 1H); 7.34 (dd, 2H); 7.11 (s, 1H); 3.89 (m, 1H); 3.86 (s, 3H); 3.6 (m, 1H); 3.21 (m, 2H); 2.81 (d, 3H); 2.48-2.37 (m, 2H) (M + H) + = 383 A < 10 316. 2- (4-Gasyl-wood-based) -6_ [methanesulfonyl- (2-tris-methoxy-ethyl-tomb) -moonyl] -5-methoxy-benzo Furan-3-carboxylic acid formamidine * H NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J = 5.9 & 8.8Hz, 2H); 7.57 (s, 1H); 7.38 (t, J = 8.8Hz, 2H); 7.23 (s, 1H); 4.11 (m, 2H); 3.92 (m, 5H); 3.06 (s, 3H); 2.84 (d, J = 4.7Hz, 3H) (M + H) + = 505 B < 1 210- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV po BB7 ICs〇 (μΜ) A = J / iM B = 0 * 5 to s5.0 μΜ C = 5.0 to <: 30 D = > 30 m replicon_ 317.2 2- (4-fluoro-phenyl) -5-methoxy-6- (1Η-pyrrole θ-yl) -benzene 弁 pfran- Formamidine 3-carboxylic acid {H NMR in CDC13: 832 (m, 1H); 7.89 (m, 2H); 7.66 (s, 1H); 7.42 (m, 1H); 7.33 (s, 1H); 7.25 ( m, 2H); 6.86 (m, 1H); 6.67 (in, 1H); 5.81 (q, 1H); 3.96 (s, 3H); 3.01 (d, 3H) (M + H) + = 365 C < 1 318. 6- (3,5-dimethyl-isoazazolyl) -2- (2-ethoxy-4-fluoro-phenyl) -5-methoxy-benzofuran 1H NMR of 3-carboxylic acid formamidine in CDC13: 7.63 (s, 1H); 7.54-7.60 (m, 1H); 7.24-7.26 (m, 1H); 7.227 (s, 1H); 6.80-6.86 (t of d, 1H, J = 2.34Hz &8.21Hz); 6.75-6.79 (d of d, 1H,); J = 2.34 &11.14Hz); 5.80 (brs 1H); 4.05-4.12 (q, 2H, J = 7.03Hz); 3.87 (s, 3H); 2.32 (s, 3H); 2.18 (s, 3H); 1.37-1.42 (t, 3H, J = 7.03Hz) (M + H) + = 439.1 A > 30 319. 2- (4- (methanesulfonyl-methyl-amino) -5- (thiazol-4-ylmethoxy) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO : 9.17 (d, 1H, J = 1.76Hz); 8.40 (brd, 1H, J = 4.69Hz); 7.95 (m, 2H); 7.86 (d, 1H, J = 2.34Hz); 7.65 (s, 1H) ; 7.39 (m, 3H); 5.39 (s, 2H); 3.20 (s, 3H); 2.97 (s, 3H); 2.85 (d, 3H, J = 4.69Hz) (M + H) + = 490 B < 1 320. 2- (4-Gasyl-benzyl) -6- (methanesulfonyl-methyl-amino) -5- (2-methyl-oxan-4-ylmethoxy ) -Benzofuran carboxylic acid amidine 1H NMR in DMSO: 8.41 (brd, 1H, J = 4.10Hz); 7.95 (m, 2H); 7.64 (s, 1H); 7.60 (s, 1H); 7.38 (m, 3H); 5.28 (s, 2H); 3.20 (s, 3H); 3.00 (s? 3H); 2.85 (d, 3H, J = 4.69Hz); 2.68 (s, 3H) (M + H) + = 504 A < 1 321. 5- (3-Chlorofluorenyl- [1,2,4] ¥ 2. Sit-5-yloxy tomb) -2- (4-lactyl-phenyl) -6- (methanesulfonate Fluorenyl-methyl-amino) -benzofuran-3-carboxylic acid formamidine 1H NMR in DMSO: 8.49 (brd, 1H, J = 4.69Hz); 8.19 (s, 1H); 7.99 (m, 2H ); 7.90 (s, 1H); 7.43 (t, 2H, J = 8.79Hz); 4.74 (s, 2H); 3.16 (s, 3H); 3.10 (s, 3H); 2.82 (d, 3H, J = 4.10Hz) (M + H) + = 524.9 A < 1 322.2 2- (4-Fluoro-phenyl) -6-{[2- (4-fluoro-phenyl) _2 side-group-ethyl] -formyl-amino group- 5-isopropoxy-benzoxan-3-carboxylic acid formamidine 1H NMR in DMSO: 8.40 (d, J = 4.4Hz, 1H); 7.90 (m, 2H); 7.37 (t, J = 8.8 Hz, 2H); 7.30-7.10 (m, 6H); 5.50 (m, 1H); 4.78 (septet, J = 6.lHz, IH); 4.50 (m, 1H); 3.90 (m, 1H); 3.42 ( m, 1H); 3.00 (s, 3H); 2.82 (d, J = 4.2Hz, 3H); 1.31 (d, J = 6.1Hz, 6H) (M + H) + = 559 A < 1 323. 2- (4-Fluoro-phenyl) -5-methoxy-6- (2-methyl-2fluorene- [1,2,4] -trimethyl-3-yl) -benzene 1H NMR in DMSO: 8.46-8.48 (d, 1H, J = 4.69Hz); 8.01 (s, 1H); 7.94-7.99 (ra, 2H); 7.71 (s, IH); 7-36-7.43 (t, 2H, J = 8.79Hz); 7.31 (s, 1H); 3.89 (s, 3H); 3.69 (s, 3H); 2.86-2.87 (d, 3H, J = 4.69Hz) (M + H) + = 381 A < 1 211-88828.doc 200418452 Instance data name NMR data Mass Spec HCV pol -BB7 IC50 (fiM) A = μ, M. B = to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ Replicon (_ 324.5 bis (3,5-dimethyl-isopurazolidinylmethoxy) -2- (4-amino-phenyl) -6- (formamidinesulfonyl-methyl -Amine) -benzofuran-3-carboxylic acid formamide 1H NMR in DMSO: 8.45 (brd, 1H, J = 4.69Hz); 7.94 (m, 2H); 7.70 (s, 1H); 7.39 (m, 3H); 5.05 (s, 2H); 3.14 (s, 3H); 2.94 (s, 3H); 2.85 (d, 3Hf J = 4.i0Hz); 2.44 (s, 3H); 2.27 (s, 3H) ( M + H) + = 502 A < 1 325. 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5- (3-fluorenyl-benzyloxy) -benzofuran each Carboxylic acid-formamide 1H NMR in DMSO: 8.40 (brdT 1H, J = 4.10Hz); 7.93 (m, 2H); 7.70 (s, 1H); 7.42-7.31 (iru 4H); 7.12 (m, 2H) ; 6.92 (d, 1H, J = 8.21Hz); 5.21 (s, 2H); 3.77 (s, 3H); 3.21 (s, 3H); 2.97 (s, 3H); 2.84 (d, 3H, J = 4.10 Hz) (M + H) + = 513 A < 1 326. hydrazone (4-fluoro-phenyl) -5-hydroxy-6- (isobutyl-methanepic acid-amine) -benzofuran-3-carboxylic acid-methaneamine NMRinDMSO : 10.05 (s, 1H); 8.40 (d, J = 4.4HzT 1H); 7.93 (dd, J = 5.3 & 8.8Hz, 2H); 7.48 (s, 1H); 7.35 (t, J = 8.8Hz, 2H); 7.10 (s, iH); 3.40 (d, J = 7.5Hz, 2H); 2.98 (s, 3H); 2.80 (d, J = 4.4Hz, 3H); 1.50 (m, 1H); 0.88 ( d, J = 6.6Hz, 6H) (M + H) + = 435 B < 30 327. 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5- (4-methoxy- + oxy) -benzoyl- 3-carboxylic acid-formamidine 1H NMR in DMSO: 8.40 (brd, 1H, J = 4.69Hz); 7.94 (m, 2H); 7.66 (s, 1H); 7.47 (d, 2H, J = 8.79Hz) ; 7.39 (m, 3H); 6.98 (d, 2H, J = 8.79Hz); 5.15 (s, 2H); 3.78 (s, 3H); 3.17 (s, 3H); 2.90 (S, 3H); 2.85 ( d, 3H, J = 4.69Hz) '(M + H) " = 513 A < 1 328.2 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5- (pyridin-4-ylmethoxy) -benzofuran-3 -Carboxylic acid-formamide NMR in DMSO: 8.62 (d, 2H, J = 5.86Hz); 8.40 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.74 (s, 1H); 7.55 (d, 2H, J = 5.28Hz); 7.39 (t, 2H, J = 8.79Hz); 7.31 (s, 1H); 5.32 (s, 2H); 3.26 (s, 3H); 3.02 (s, 3H ); 2.83 (d, 3H, J = 4.69Hz) (M + H) + = 484 A < 1 329. 5- (2,2-Difluorenyloxy-4H-benzo [1,3] -diginyl-6-ylmethoxy) -2- (4-fluoro-benzene ; &)-6- (methanesulfonyl-fluorenyl-amino) -benzofuran-3-carboxylic acid sulfonamide * H NMR in DMSO: 8.41 (brd, 1H, J = 4.69 Hz); 8.06 (s, 1H); 7.94 (m, 2H); 7.87 (dd, 1H, J = 8.21 &2.34Hz); 7.69 (s, 1H); 7.37 (ra, 3H); 7.19 (d, 1H, J = 8.79Hz); 5.27 (s, 2H); 3.20 (s, 3H); 2.95 (s, 3H); 2.84 (d, 3H, J = 4.69Hz); 1.72 (s, 6H) (M + H) + = 583 A < 1 330. 6- (Cyclopropylmethyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid-methyl Amidine NMR in DMSO: 8.44 (m, 1H); 7.94 (dd, J = 5.9 & 9.4Hz, 2H); 7.62 (s, 1H); 7.38 (ζ J = 8.8Hz, 2H); 7.20 (s , 1H); 3.90 (s, 3H); 3.44 (m, 2H);? .92 (s, 3H); 2.84 (d, J = 4.7Hz, 3H); 0.87 (m, 1H); 0.35 (d, J = 1.7Hz, 2H); 0.05 (m, 2H) (M + H) + = 447 A < 1 331.2 2- (4-Fluoro-phenyl) -6 '' (methanesulfonyl-methylaminomethylmethylmethyl-amino) -5-methoxy-benzocran-3 -Folic acid-formamidine 4 醯 NMR in DMSO: 8.42 (m, 1H); 7.94 (dd, J = 5.9 & 9.4 Hz, 2H); 7.90 (s, 1H); 7.83 (m, 1H); 7.38 ( t, J = 8.8 Hz, 2H); 7.20 (s, 1H); 4.17 (s, 2H); 3.92 (s, 3H); 3.12 (s, 3H); 2.84 (d, J = 4.7Hz, 3H); 2.58 (dT J = 4.7Hz, 3H) (M + H) + = 464 A < 1 212- 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50 (μΜ) A = μΜ B = to ^ 5.0 / iM C = 5.0 to ^ 30 / iM D = > 30 μΜ Copy (ΜΜ) 332.5 5-formyl-2- (4-amino-phenyl) -6-methanesulfonylamino-benzo-p-furan-3 -formylmethanamine 1H NMR in CDC13: 7.89-7.85 (m, 2H); 7.87 (d, J = 6.3 Hz, 1H); 7.70 (d, J = 9.9 Hz, 1H); 7.24-7.19 (m, 2H); 656 (s, 1H); 5.74 (s, 1H); 3.04 (s, 1H); 2.99 (d, J = 4.8Hz, 3H) (M + H) + = 381 B < 10 333. 6- (ethyl-methanesulfonyl-amino) -5-fluoro Dong (4-fluoro-phenyl) -benzofuran-3-carboxylic acid-formic acid amine 1H NMR in CDC13 : 7.90-7.86 (m, 2H); 7.66 (d, J = 10.5 Hz, 1H); 7.57 (d, J = 6.0 Hz, 1H); 7.24-7.18 (m, 2H); 5.74 (s, 1H); 3.77 (q, J = 2.4 & 14.4 Hz, 2H); 2.99-2.98 (m, 6H); U7 (t, J = 7.5 Hz, 3H) (M + H) + = 409 A < 10 334. 2- (4-Gasyl-benzyl) -6- (1-methanesulfonyl-pyrrolidin-3-yl) -5-methoxy-benzoanan-3-¾ acid -Formamidine * H NMR in CDCb: 7.85 (m, 2H); 7.36 (s, 1H); 7.32 (s, 1H); 7.20 (m, 2H); 5.78 (brs, 1H); 3.91 (s, 3H ); 3.83 (m, 2H); 3.60 (m, iH); 3.47 (m, 1H); 3.00 (d, J = 4.8Hz, 3H); 2.87 (s, 3H); 2.34 (m, 1H); 2.16 (m, 1H) (M + H) + = 447 A < 1 335.5: ethyl-2: (4: formyl-phenyl) -6- [methanesulfonyl- (2-methoxy-ethyl) > amino] benzofuran-3 -Chloric acid_formamidine j ---- * H NMR in DMSO: 8.45 (ra, 1H); 7.94 (dd, J = 5.3 & 9.4 Hz, 2H); 7.78 (s, 1H); 7.56 (s , 1H); 7.39 (t, J = 8.8Hz, 2H); 3.32 (in, 2H); 3.30 (s, 3H); 3.13 (s, 3H); 2.84 (d, J = 4.7 Hz, 3H); 2.82 (q, J = 7.1Hz, 2H); 1.24 (t, J = 7.1 Hz, 3H) (M + H) + = 449 A < 1 336.2 2- (4-fluoro-phenyl) -5-methoxy-6- (3-methoxymethyl-5-methyl-isoxazol-4-yl > Pyran-3-carboxylic acid-formamidine * H NMR in CDC13: 7.87 (dd, J = 7.0 and 5.1Hz, 2H); 7.41 (s, 1H); 7.40 (s, 1H); 7.20 (t, J = 8.8Hz, 2H); 5.81 (brs, 1H); 4.45 (s, 2H); 3.86 (s, 3H); 3.30 (s, 3H); 3.00 (d, J = 4.8Hz, 3H); 2.35 (s, 3H) (M + H) + = 425 A < 1 337. 5-Ethyl-6-[(2-fluoro-ethyl) -fluorene-continuous-amino-amino] -2- (4-fluoro-phenyl) benzofuran-3- Carboxylic acid-formamide * H NMR in DMSO: 8.47 (m, 1H); 7.94 (dd, J = 5.3 & 8.8Hz, 2H); 7.84 (s, 1H); 7.57 (s, 1H); 7.39 ( t, J = 8.8Hz, 2H); 4.65-4.25 (m, 2H, F-coupling); 3.98 (t, J = 4.1Hz, 1H); 3.89 (t, J = 4.1Hz, 1H); 3.14 (s , 3H); 2.84 (d, J = 4.7Hz, 3H); 2.82 (q, J = 7.6Hz, 2H) 1.24 (t, J = 7.6Hz, 3H) (M + H) + = 437 A < 1 38. 2- (4-Fluoro-phenyl) -6- (methylfetrapyridyl-propyl-amino) -5-propoxy-benzofuran-3carboxylic acid-pyridamine lH NMR in DMSO: 8.40 (d, J = 4.7Hz, iH); 7.90 (m, 2H); 7.56 (s, 1H); 7.36 (t, J = 8.2Hz, 2H); 7.17 (s, 1H); 4.04 (t, J = 6.5Hz, 2H); 3.53 (s, 2H); 2.99 (s, 3H); 2.82 (d, J = 4.7Hz, 3H); i.80 (m, 2H); 1.39 (m , 2H); 1.02 (t, J = 7.6Hz, 3H); 0.85 (t, J = 4.1Hz, 3H) (M + H) + = 463.1 A < 1 339.3 5-ethyl-2- (4-fluoro-phenyl) -6- (1- # presenting group-1-methyl-ethyl) -benzofuran-3-carboxylic acid-formyl Amidine NMR in CDCl3:, 7.90 (m, 2H); 7.66 (s, IH); 7.65 (s, IH); 7.17 (m, 2H); 5.80 (brs, 1H); 3.08 (q, J = 7.5Hz , 2H); 3.02 (d, J = 4.8Hz, 3H); 1.73 (s, 6H); 1.33 (t, J = 7.5Hz, 3H) (M + H) f = 356.1 A < 1 34.6. 6-Ethyl-5-ethyl-2_ (4-fluoro-phenyl) -phenylsulfan-3-carboxylic acid-formamide NMR in CDCb: 7.95 (m, 2H ); 7.80 (s, iH); 7.69 (s, IH); 7.19 (m, 2H); 5.82 (brs, 1H); 3.01 (d, J = 4.8Hz, 3H); 2.62 (s, 3H); 2.97 (q, J = 7.5Hz, 2H); 1.22 (U = 7.5Hz, 3H) (M + H) + = 340.1 A < 1 213- 88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 ICso (mM) A = / iM B = 0.5 · 5 to 彡 5.0 μΜ C = 5.0 to < 30 μM D = > 30 replicon (iM) 341.4 4-ranyl-6-ethylamino-2- (4-fluorophenyl) -5-hydroxybenzofuran-3-gui Acid-formamide NMR in DMSO: 9.82 (s, 1H); 8.38 (d, J = 4.4 Hz, 1H); 7.88 (dd, J = 8.8, 5.3 Hz, 2H); 7.35 (tT J = 8.8 Hz, 2H); 6.89 (s, 1H); 4.48 (t, J = 7.0 Hz, 1H); 3.37 (q, J = 7.0 Hz, 2H); 2.80 (d, J = 4.4 Hz, 3H); 1.07 (t, J = 7.0 Hz, 3H) (M + H) + = 363 B > 100 342. Methanesulfonyl 4-chloro-6-ethylamino-2- (4-amino-phenyl) methyl Aminopyrene-benzo-2-an-5-yl radical NMR in DMSO: 8.42 (dT J = 3.7 Hz, 1H); 7.90 (dd, J = 8.8,5.3 Hz, 2H); 7.46 (s, 1H) ; 7.37 (t, J = 8.8 HzT 2H); 4.96 (t, J = 6.8 Hz, 1H); 3.48 (s, 3H); 3.39 (pent, J = 7.0 Hz, 2H); 2.80 (d, J = 3.7 Hz, 3H); 1.10 (U = 7-0 Hz, 2H) (M + H) + = 441 A < 10 343. Methyl-2- (4-fluoro-phenyl) -6- (methanesulfonyl-pyrimazol-4-ylmethyl-amine) Amidine 1H NMR in DMSO: 9.06 (d, J = 1.8Hz, 1H); 8.43 (m, 1H); 7.91 (dd, J = 5.3 & 8.8 Hz, 2H); 7.59 (s, 1H); 7.45 ( m, 2H); 7.38 (t, J = 8.8Hz, 2H); 5.01 (d, J = 4.9Hz, 1H); 4.83 (d, J = 4.9Hz, 1H); 3.14 (s, 3H); 2.81 ( d, J = 4.7Hz, 3H); 2.65 (q, J = 7.6Hz, 2H); 1.24 (t, J = 7.6Hz, 3H) (M + H) + = 488 A < 1 344. 6- (5-Cyclopropyl-3-methoxymethyl · iso-p-wow ice sheet) (4-fluoro-phenyl) -5-methoxybenzo 4-ran-3-carboxy Acid-formamidine 1H NMR in CDCb: 7.87 (dd, J = 8.8 and 5.4Hz, 2H); 7.46 (s, 1H); 7.41 (s, 1H); 7.20 (apparent t, J = 8.8 and 8.4Hz, 2H); 5.80 (brs, 1H); 4.44 (s, 2H); 3.87 (s, 3H); 3.28 (s, 3H); 3.00 (d, J = 5.1Hz, 3H); 1.92 (m, 1H); 1.13 (m, 2H); 0.97 (m, 2H) (M + H) + = 451 A < 1 345. 6- (1-Ethyl-p-pylonol-3-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid -Formamidine 1H NMR in CDC13: 7.85 (m, 2H); 7.32 (m, lH); 7.25 (m, 3H); 5.77 (brs.lH); 3.92 (s, 3H); 3.71-4.12 (m, 2H); 3.32-3.70 (m, 3H); 2.99 (d, J = 4.8Hz, 3H); 2.18-2.39 (m, 2H); 2.10 (s, 3H) (M + H) + = 411 A < 10 346. 5- (3,4-difluoro-benzyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -benzo Furan-3-carboxylic acid-formamidine * Η NMR in DMSO: 8.39 (d, J = 4.4Hz, 1H); 7.91 (m, 2H); 7.70 (s, IH); 7.55-7.30 (m, 6H) ; 5.21 (s, 2H); 3.18 (s, 3H); 2.96 (s, 3H); 2.82 (mT 3H) (M + H) + = 519.0 A < 1 347. 5- (2-Difluorofluorenyl-benzyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -benzo Furan carboxylic acid-formamide 1H NMR in CDCb: 7.86 (m, 2H); 7.57-7.42 (m, 3H); 7.31-7.20 (m, 5H); 6.63 (t, 1H, J = 73.4Hz); 5.74 (brs, 1H); 5.24 (s, 2H); 3.28 (s, 3H); 2.99 (d, 3H, J = 4.84Hz); 2.81 (s, 3H) (M + H) + = 549 A < 1 348. 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-yl) -5-propoxy-benzofuran each carboxylic acid-fluorenamine'H NMR in DMSO: 8.39 (brd, 1H, J = 5.86); 7.92 (m, 2H); 7.60 (s, 1H); 7.36 (t, 2H, J = 8.79Hz); 7.18 (s, 1H); 4.04 (t , 2H, J = 7.03); 3.20 (s, 3H); 3.02 (s, 3H); 2.82 (d, 3H, J = 4.10Hz); 1.82 (m, 2H): 1.03 (t, 3H, J = 7.03 Hz) (M + H) + = 435 A < 1 214- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 ICsoOiM) A = μΜ B = to ^ 5.0 μΜ C = 5.0 to < 30 μΜ D = > 30 μΜ name (μΜ) 349.5 5-methylpropoxy-2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino)- Benzofuran-3-carboxylic acid-formamidine 1U NMR in DMSO: 8.37 (brm, 1H); 7.92 (m, 2H); 7.63 (s, 1H); 7.36 (t, 2H, J = 8.79Hz); 7.21 (s, 1H); 6.18-6.06 (m, 1H); 5.47 (m, 1H); 5.30 (m, 1H); 4.70 (d, 2H, J = 4.69Hz); 3.20 (s, 3H); 3.02 (s, 3H); 2.82 (d, 3H, J = 4.10Hz) (M + H) + = 433 A < ι 350. 6- (5-ethoxymethyl-isoamyl-3-yl) -2- (4-amino-phenyl) -5-methoxy-benzofuran-3- # complex Acid-formamide 1H NMR in CDC13: 8.03 (s, 1H); 7.87 (dd, J = 5.28 & 8.79Hz, 2H); 7.45 (s; IH); 7.20 (ζ J = 8.79Hz, 2H); 6.82 (s, 1H); 5.79 (bs, 1H); 4.64 (s, 2H); 3.96 (s, 3H); 3.65 (q, J = 7.03Hz, 2H); 3.00 (d, J = 4.84Hz, 3H ); 1.276 (t, J = 7.03, 6.59Hz, 3H) (Μ + ΗΓ = 425.21 A < 1 351. 5-Cyclopropylmethoxy-2- (4-fluoro-phenyl) -6- (methane continuous-methyl-amino-)-benzofuran-3-carboxylic acid-methyl Lamine 1H NMR in DMSO: 8.38 (d, J = 4.4Hz, 1H); 7.92 (m, 2H); 7.60 (s, 1H); 7.38 (tt J = 9.2Hz, 2H); 7.16 (s, 1H) ; 3.95 (d, l = 7.0Hz, 2H); 3.25 (s, 3H); 3.08 (s, 3H); 2.83 (d, J = 4.4Hz, 3H); 1.20 (m, 1H); 0.62 (d, J = 7.0Hz, 2H); 0.39 (d, J = 5.3Hzi 2H) (M + H) + = 447 A < 1 352.5 5- (3,5-Dimethoxy-benzyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -benzene Benzofuran-3-¾ acid-formamidine'H NMR in DMSO: 8.39 (brd, 1H, J = 4.69); 7.93 (ra, 2H); 7.71 (s, 1H); 7.38 (t, 2H, J = 8.79); 7.31 (s, 1H); 6.72 (d, 2H, J = 2.34); 6.46 (m, 1H); 5.17 (s, 2H); 3.75 (s, 6H); 3.22 (s, 3H); 3.00 (s, 3H); 2.83 (d, 3H, J = 4.69Hz) · (M + H) + = 543 A < i 353. 2- (4-Fluoro-phenyl) -5- (4-methanesulfonyl-benzyloxy) -6- (methylsulfanyl-methyl-amino) -benzo Furan-3-metanoic acid-amidamine * H NMR in DMSO: 8.39 (brd, 1H, J = 4.40Hz); 7.98-7.89 (m, 4H); 7.80 (dt 2H, J = 8.4Hz); 7.7 i (s, 1H); 7.37 (m, 3H); 5.36 (s, 2H); 3.28 (s, 3H); 3.22 (s, 3H); 2.98 (s, 3H); 2.8 l (d, 3H, J = 4.40Hz) (MH) '= 559 A < 1 354.2 2- (4-Amino-winteryl) -5_hydroxy-6- [methanesulfonyl- (2-oxy · propyl) -amino] -benzofuran-3-chinic acid · Formamidine 1H NMR in CDCb: 8.15 (s, 1H); 7.93 (in, 2H); 7.39 (s, 1H); 7.15 (t, J = 2.5Hz, 2H); 5.79 (s, 1H); 4.54 (s, IH); 4.49 (s, 1H); 334 (s, 3H); 3.24 (s, 1H); 3.19 (s, 1H); 1.79 (s, 2H) (Μ + ΗΓ = 437.22 B < 10 355.2 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5- [2- (4-methoxy-phenyl) _2_oxy -Ethoxy] -benzofuran-3-carboxylic acid-formamidine 1H NMR in DMSO: 8.36 (d, J = 4.8Hz, lH); 8.04 (d, J = 8.79Hz, 2H); 7.90 ( m, 2H); 7.60 (s, 1H); 7.36 (t, J = 8.79Hz, 2H); 7.28 (s, 1H); 7.08 (dt J = 9.35Hz, 2H); 5.67 (s, 2H); 3.86 (s, 3H); 3.29 (s, 3H); 3.07 (s, 3H); 2.77 (d, J = 4.41Hz, 3H) (Μ + ΗΓ = 541 A < 1 215- 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50〇tM) A = / iM B = 0〇to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ Replicon (μΜ) 356.5 5- (3 · Cyano-Ethyloxy) -2- (4-amino-phenyl) -6-(methanesulfonyl-methyl-amino) · benzofuran -3-carboxylic acid-formamidine 1H NMR in DMSO: 8.39 (brd, 1H, J = 4.69Hz); 8.00 (s, 1H); 7-94- 7.81 (m, 3H); 7.72 (s, 1H) ; 7.64 (t, 2H, J = 7.62Hz); 7.37 (t, 2H, J = 8.79Hz); 7.30 (s, 1H); 5.29 (s, 2H); 3.19 (st 3H); 2.97 (s, 3H ); 2.82 (d, 3H, J = 4.69Hz) (M-Η). = 506 A < 1 357. Methyl-fluorenyl) -2- (4-fluoro-winteryl) -6- (methanesulfonyl-methyl-amino) -benzofuran-3-carboxylic acid-formamidine Amine'H NMR in DMSO: 8.37 (brd, 1H, J = 4.84Hz); 7.90 (m, 4H); 7.72 (m, 3H); 7.37 (t, 2H, J = 8.79Hz); 730 (s, 1H ); 5.33 (s, 2H); 3.21 (s, 3H); 2.97 (s, 3H); 2.81 (d, 3H, J = 4.0Hz) (M + H) + = 508 A < 1 358.2. 2- (4-Amino-phenyl) -5-methoxy-6- (2H- [1,2,4] triazol-3-yl) -benzofuran-3-dec 1HNMR in CDCl3: 8.49 (s, 1H); 8.05 (s, 1H); 7.86-7.91 (m, 2H); 7.58 (s, 1H); 7.20-7.26 (m, 2H); 5.82 (brs , 1H); 4.15 (s, 3H); 3.00-3.02 (d, 3H, J = 5.28Hz) (M + H) + = 366 GCMS A < 1 35. 4- {2- [2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -3-methylaminomethyl-benzo-benzo Furan-5-yloxy] -ethylammonium aminopeptanoic acid ethyl ester'H NMR in DMSO: 10.37 (s, 1H); 8.39 (brd, 1H, J = 4.84Hz); 7.91 (m, 4H) ; 7.75 (d, 2H, J = 8.35Hz); 7.70 (s, 1H); 7.37 (t, 2H, J = 8.79Hz); 7.20 (s, 1H); 4.93 (s, 2H); 4.28 (q, 2H, J = 7.03Hz); 3.28 (s, 3H); 3.14 (s, 3H); 2.78 (d, 3H, J = 4.40Hz); 1.30 (t, 3H, J = 7.03Hz) (M-Η) '= 596 A < 10 360. 2- (4-Gas-phenyl) -5- [2- (4-fluoro-phenyl) -2-oxy-ethoxy] -6- (methanesulfonyl- Methyl-amino) -benzofuran-3-carboxylic acid-methaneamine 1H NMR in DMSO: 8.38 (brd, 1H, J = 5.28Hz); 8.17 (m, 2H); 7.90 (m, 2H); 7.62 (s, 1H); 7.45-7.31 (m, 5H); 5.73 (s, 2H); 3.29 (s, 3H); 3.06 (s, 3H); 2.78 (d, 3H, J = 4.69Hz) (MH ) · = 527 A < 1 36. 6- (fluorenyl-methanesulfonyl-amino) -2- (4-fluoro-phenyl) -5-isopropoxy-benzofuran-3-chi SH-formamidine Amine * H NMR in DMSO: 8.38 (brd, 1H, J = 4.69Hz); 7.86 (m, 2H); 7.33 (t, 2Ht J = 8.79Hz); 7.28-7.16 (m, 6H); 7.10 (s, 1H); 4.80 (brm, 3H); 3.11 (s, 3H); 2.79 (d, 3H, J = 4.69Hz); 1.38 (d, 6H, J = 5.86Hz) (M + H) + = 511 A < 1 362.6 4-Chloro-6- (ethyl-methyl-amino) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid- Formamidine 1H NMR in DMSO: 8.38 (d, J = 4.4HzT 1H); 7.90 (m, 2H); 7.36 (t, J = 8.4Hz, 2H); 7.05 (s, 1H); 3.86 (s, 3H ); 3.09 (q, J = 7.03Hz, 2H); 2.81 (d, J = 4.4Hz, 3H); 2.75 (s, 3H); 0.93 (t, J = 7.1Hz, 3¾ (Μ + ΗΓ = 391.0 A < 10 363. 4-Chloro-6-ethylamine ^ yl-2- (4-fluoroyl-benzene: ^)-5-methoxy-toluene-benzofuran-3.-carboxylic acid-formyl Lamine 1H NMR in DMSO: 8.34 (d, J = 4.8Hz >1H); 7.86 (m, 2H); 7.33 (t, J = 9.2Hz, 2H); 6.99 (s, 1H); 4.67 (t, J = 6.6Hz, 1H); 3.89 (s, 3H); 3.38 (q, J = 7.04Hz, 2H); 2.80 (d, J = 4.4Hz, 3H); 1.07 (t, J = 7.0Hz, 3H) ( M + H) + = 377.0 A < 1 216- 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 ICse 〇iM) A = μΜ B = 0.5 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 / iM replicon (μΜ) 364.6 6-Ethylamino-2- (4-amino-phenyl) -5-hydroxy-benzofuran-3-carboxylic acid-formamidine * H NMR in DMSO: 8.20 (d, J = 4.7Hz, iH); 7.88 (dd, J = 8.8, 5.3Hz, 2H); 7.29 (t, J = 8.8Hz, 2H); 6.83 (s, 1H); 6.66 (s, 1H); 4.83 ( t, J = 5.0Hz, 1H); 3.11 (ra, 2H); 2.79 (d, J = 4.7Hz, 3H); 1.19 (t, J = 7.0Hz, 3H) * (M + H) + = 329 B > 30 36. 5_ (3-bromo-propoxy) -6- 6-aminoamino-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid-methaneamine 1H NMR in DMSO: 8.30 (d, J = 4.7Hz, 1H); 7.86 (dd, J = 8.8, 5.3Hz, 2H); 7.30 (t, J = 8.8Hz, 2H); 6.93 (s, 1H); 6.75 ( s, 1H); 5.20 (t, J = 5.0Hz, IH); 4.14 (t, J = 4.8Hz, 2H); 3.78 (t, J = 6.7Hz, 2H); 3.20 (m, 2H); 2.81 ( d, J = 4.7HzT 3H); 2.36 (m, 2H); 1.23 (t, J = 7.0Hz, 3H) (M + H) + = 499,451 A < 1 366. 5-Hydroxypropoxy-6-ethylamino-2- (4-fluoro-phenyl) -benzoanan-3 -chitoic acid · methanamine'HNMR in DMSO: 8.20 (d, J = 4.7Hz, 1H); 7.80 (dd, J = 8.8, 5.3Hz, 2H); 7.31 (t, J = 8.8Hz, 2H); 6.93 (s, 1H); 6.74 (s, 1H) ; 6.10 (m, 1H); 5.50 (m, 1H); 5.30 (m, 1H); 5.00 (t, J = 5.0Hz, 1H); 4.60 (m, 2H); 3.18 (m, 2H); 2.80 ( d, J = 4.7Hz, 2H); 1.20 (t, J = 7.0Hz, 3H) (M + H) + = 369 A < 1 367. 5- (3-ethoxy-propoxy tomb) -6-ethylamino-2- (4-fluoroxylbenzoanan-3-metanoic acid-formamidine 1H NMR in DMSO: 8.20 (d, J = 4.4Hz, 1H); 7.80 (dd, J = 8.8, 5.3Hz, 2H); 7.31 (t, J = 8.8Hz, 2H); 6.90 (s7 1H); 6.72 (s, 1H); 5.01 (U = 5.7Hz, 1H); 4.07 (ζ J = 6.5Hz, 2H); 3.56 (UJ = 6.4Hz, 2H); 3.42 (q, J = 7.0Hz, 2H); 3.20 (m, 2H); 2.80 (d, J = 4.4Hz, 3H); 2.00 (t, J = 6.5Hz, 2H); 1.20 (t, J = 7.0Hz, 3H); 1.10 (t, J = 7.0Hz, 3H) (M + H) + = 415 A < 1 368. 2- [2- (4-Ranyl-phenyl) -5-methoxy-3-methylamine formamidine-benzofuran-6-yl] -pyrrole sulfonate Amine * H NMR in CDC13: 7.83 (m, 2H); 7.15 (s, 1H); 7.14 (s, 1H); 7.10 (m, 2H); 5.76 (brs, 1H); 5.18 (d, J = 8.353Hz , 1H); 4.25 (s, 2H); 3.93 (s, 3H); 3.72 (m, 2H); 2.99 (d, J = 4.836Hz? 3H); 1.89 (m, 2H); 1.25 (s, 2H) (M + H) + = 412 A < 1 369. 2- (4-Gas-phenyl) -6_ (methanesulfonyl-methyl-amino) -5- (2-oxy-propoxy) -benzonan-3 -Carboxylic acid-formamide NMR in DMSO: 8.38 (brd, 1H, J = 4.69Hz); 7.90 (m, 2H); 7.62 (s, 1H); 7.36 a 2H, J = 8.79Hz); 7.12 (s , iH); 4.97 (s, 2H); 3:24 (s, 3H); 3.04 (s, 3H); 2.81 (d, 3H, J = 4.10Hz); 2.20 (s, 3H) (MH) * = 447 A < 1 37. 2- (4-Fluoro-phenyl) -5- (2-hydroxy-propoxy) -6- (methanesulfonyl-methyl-amino) -benzofuran-3- Carboxylic acid-amine NMR ia DMSO: 8.41 (brd, 1H, J = 4.69Hz); 7.94 (m, 2H); 7.60 (s, 1H); 7.38 (t, 2H, J = 8.79Hz); 7.20 ( s, 1H); 4.87 (d, 1H, J = 4.69Hz); 4.06 (m, iH); 3.96 (m, 2H); 3.24 (s, 3H); 3.06 (s, 3H); 2.84 (d, 3H , J = 4.69Hz); 1.22 (d, 3H, J = 5.86) (MH) '= 449 A < 1 371. _2- (4--Fluoro-phenyl) each (methanesulfonyl-methyl-amino) -5- (1-methyl-1H-tetramethyl-5-ylmethoxy ) -Benzofuran-3-carboxylic acid-formamidine 1H NMR ia DMSO: 8.44 (brd, iHt J = 4.10Hz); 7.94 (in, 2H); 7.76 (s, 1H); 7.48 (s, 1H) ; 7.40 (t, 2H, J = 8.79); 5.65 (s, 2H); 4.18 (s, 3H); 3.18 (s, 3H); 3.02 (s, 3H); 2.86 (d, 3H, J = 4.10Hz ) (Μ + ΗΓ = 489 A < 1 217- 88828.doc 200418452 Example number name NMR data Mass Spec HCV pol -BB7 IC50 〇iM) A = μΜ 0 * 5 to 彡 5.0 fiM C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon ( μM) 372.2 2- (4-Fluoro-phenyl) -6- (5-isopropoxymethyl-isopentetyl) -5-methoxy-benzofuran-3-carboxylic acid-methyl Lamine 1HNMR in CDC13: 7.96 (s, 1H); 7.85 (dd, J = 5.28 & 8.79Hz, 2H); 7.40 (s, 1H); 7.18 (t, J = B.35 & 8.79Hz, 2H) ; 6.78 (s, 1H); 5.98 (bs, 1H); 4.64 (s, 2H); 3.94 (s, 3H); 3.78 (septet, J = 6.15Hz, 1H); 3.01 (d, J = 4.83Hzt 3H ); 1.25 (d, J = 6.15Hz, 6H) (M + H) + = 439 A < 1 373. 5- (5-Diethylamino- [1,2,4] pyridine 3-ylmethoxy) -2- (4-fluoroyl-phenyl) 6- (methane Sulfonyl-methyl-amino) -benzofuran-3-carboxylic acid-methaneamine 1H NMR in DMSO: 838 (brd, 1H, J = 4.40Hz); 7.94 (m, 2H); 7.61 (s , 1H); 7.37 (m, 3H); 5.22 (s, 2H); 3.47 (brm, 4H); 3.28 (s, 3H); 3.08 (s, 3H); 2.84 (d, 3H, J = 4.84Hz) ; 1.18 (t, 6H, J = 7.03Hz) (M + H) + = 562 A < 1 374. 5- [5- (Cyclopropylmethyl-amine tomb)-[1,2, exobijun-3-ylmethoxy] -2 < 4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino-benzofuran-3-guinic acid-formamidine 1H NMR in DMSO: 8.60 (bnn, 1H); 838 ( brd, 1H, J = 4.10Hz); 7.94 (m, 2H); 7.61 (s, 1H); 7.38 (m, 3H); 5.19 (brs, 2H); 3.26 (s, 3H); 3.18 (ζ 2H7 J = 5.86Hz); 3.07 (s, 3H); 2.84 (d, 3H, J = 4.69Hz); 1.10 (m, 1H); 0.48 (m, 2H); 0.24 (m, 2H) (M + H) + = 560 A < 1 375.6 6- (2-Amino small hydroxy-1-methyl-ethyl) -2- (4-fluoro-phenyl) -5-isopropoxy-benzoanan-3- Formamidine chitoate'H NMR in CDCl3: 7.85 (m, 2H); 7.71 (s, 1H); 7.19 (s, 1H); 7.16 (m, 2H); 6.35 (brs, 1H); 4.76 (in, 1H); 4.60 (brs, 2H); 3.48 (m, 2H); 2.99 (d, J = 4.69 Hz, 3H); 1.47 (s, 3H); 1.40 (d, J = 5.86 Hz, 3H); 1.37 ( d, J = 5.86 Hz, 3H) (M + H) " = 401.1 B < 30 376. 6- (1-Amine-i-methyl-ethyl) -2- (4-fluoro-phenyl) -5-isopropoxy-benzoanan lH NMR in CDC13: 7.84 (ra, 2H); 7.49 (s, 1H); 7.37 (s, 1H); 7.26 (m, 2H); 5.74 (brs, 1H); 4.84 (septet, J = 6.15 Hz, 1H ); dd 4.53 (brs, 2H); 2.99 (d, J = 2.64 Hz, 3H); 1.67 (s, 6H); 1.47 (d, J = 6.16 Hzt 6H) (M + H) + = 386 A < 1 377. 2- [2- (4-Fluoro-phenyl) -5-methoxymethylmethylformamidine-benzofuran-6-yl] -ρ-bilodine-1-read _ fee-formamidineΉ NMR in CDCI3: 7.85 (m, 2H); 734 (s, 1H); 7.30 (s, 1H); 7.18 (ra, 2H); 5.77 (s, 1H); 4.03 (d, J = 4.39 Hz, 1H); 3.94 (s, 3H); 3.71 (m, 2H); 2.99 (d, J = 1.32 Hz, 3H); 2.71 (d, J = 1.32 Hz, 3H); 2.38 (ra, 1H); 1.86 (m, 3H) (M + H) + = 426 A < 10 378. 6- (3,5-Dimethyl-isophosphinobenzyl) _2_ (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid-acetamidine Amine 1H NMR in DMSO: 8.53 (s, 1H); 7.94-7.99 (m, 2H); 7-61 (s, 1H); 7.37-7.43 (t, 2H, J = 9.38Hz); 7.22 (s, 1H ); 3.85 (s, 3H); 3.36-3.40 (t, 2H, J = 5.86Hz); 2.31 (s, 3H); 2.12 (s, 3H); 1.16-1.20 (t, 3H, J = 5.28Hz) (M + H) + = 409 A < 1 • 218 · 88828.doc 200418452 1 Instance number name NMR data Mass Spec HCV pol -BB7 IC50 〇iM) A = μΜ B = 0 * 5 to 彡 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μM replicon (μM) 379.6- (3,5-dimethyl-isoxazolone) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3- Carboxylic acid-isopropylamidine 1HNMR inDMSO: 8.42-8.45 (dT 1H, J = 8.21Hz); 7.93-7.98 (m, 2H); 7.59 (s, 1H); 7.37-7.42 (U 2H, J = 8.79Hz ); 7.18 (s, 1H); 4.18-4.24 (septet, 1H, J = 7.03Hz); 3.83 (s, 3H); 2.30 (s, 3H); 2.11 (s, 3H); 1.19-1.21 (d, 6H, J = 7.03Hz) (M + H) + = 423 B > 30 380. Di: methyl-isoxazole_4-yl) -2- (4-fluoro-phenyl) -5-form Oxy-benzofuran-3-metanoic acid-cyclopropylamidine 1H NMR in DMSO: 8.59-8.61 (d, 1H, J = 4.10Hz); 7.90-7.94 (m, 2H); 7.95 (s, 1H) ; 7.36-7.42 (t, 2H, J = 8.79Hz); 7.16 (s, 1H); 3.83 (s, 3H); 2.93-2.99 (m, 1H); 2.29 (s, 3H); 2.10 (s, 3H ); 0.71-0.77 (m, 2H); 0.54-0.60 (m, 2H) (M + H) + = 421 A < 1 381.2 2- (4-Azo-phenyl) -5-isopropoxy-6- (5- ^ yl-2-oxy ^ oxazolyt-5-yl) -benzocran-3 -Chinoic acid-formamidine * H NMR in CDC13: 7.85 (m, 2H); 7.77 (s, 1H); 7.35 (s, 1H); 7.19 (m, 2H); 5.74 (brs, 1H); 5.03 ( brs, 1H); 4.76 (m, 1H); 3.78 (dd, J = 2.2 & 8.4 Hz, 2H); 2.97 (d, J = 5.2 Hz, 3H); 1.82 (s, 3H); 1.40 (d, J = 5.2 Hz, 3H); 1.37 (d, J = 5.2 Hz, 3H) (M + H) + = 427.1 A < 1 382. [2- (4-Fluoro-phenyl) -6- (methylsulfanyl-methyl-amino) -3-methylaminomethylmethyl-benzofuran-5-yl Oxy] -acetic acid tert-butyl ester 1H NMR in DMSO: 8.38 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.63 (s, 1H); 738 (t, 2H, J = 8.79 Hz); 7.10 (s, 1H); 4.82 (s, 2H); 3.26 (s, 3H); 3.07 (s, 3H); 2.82 (d, 3H, J = 4.69Hz); 1.46 (s, 9H) ( M + h2〇) + = 524 A < 1 383. 2- (4-Amino-phenyl) -5-methoxy-6- (5-methyl-2H- [1,2,4] triazol-3-yl) -benzo 17 Melan-3-quinic acid-formamidine * Η NMR in DMSO: 13.42 (s, 1H); 8.44-8.46 (d, 1H, J = 4.69 Hz); 8.25 (s, 1H); 7.94-7.99 (m , 2H); 7.36-7.42 (t, 2H, J = 8.79 Hz); 7.27 (s, 1H); 4.02 (s, 3H); 2.85-2.86 (d, 3H, J = 4.69 Hz); 2.34 (s, 3H) (M + H) + = 381 B < 10 384. 6- (1-amino-1-methyl-ethyl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid-methyl Lamine 1H NMR in CDCl3: 7.84 (m, 2H); 7.51 (s, 1H); 7.32 (s, 1H); 7.17 (1¾ 2H); 5.84 (brs, 1H); 3.95 (s, 3H); 2.97 ( d, J = 4.84Hz, 3H); 2.19 (brs, 2H); 1.59 (s, 6H) (M + H-NH2) + = 340 B < 30 385. 6- (1-Ethylaminoaminomethyl-ethyl) dong (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid-formamidine Amine ^ NMR in CDCI3: 7.84 (m, 2H); 7.52 (s, 1H); 7.31 (s, 1H); 7.15 (m, 2H); 6.03 (brs, 1H); 5.76 (brs, 1H); 3.92 ( s, 3H); 2.96 (d, J = 4.84Hz, 3H); 1.92 (s, 3H); 1.80 (s, 6H) (M + H-NHAc) + = 340 A < 1 386. [2- (4-fluoroi-phenyl) each (methanesulfonyl-methyl-amino) each methylamine methylamidino-benzofuran-5-yloxy > acetic acid lH NMR in DMSO: 8.39 (brd, 1HT J = 4.69Hz); 7.93 (m, 2H); 7.62 (s, 1H); 7.38 (t, 2H, J = 8.79Hz); 7.17 (s, iH); 4.86 (s, 2H); 3.26 (s, 3H); 3.06 (s, 3H); 2.83 (d, 3H, J = 4.69Hz) (MH) * = 449 A < 30 219- 88828.doc 200418452 Example No. Name NMRdata Mass Spec HCV pol -BB7 IC5〇 (μΜ) A = < 0 * 5 / iM B = 0.5 to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μ, M. Replicon (μΜ) 387.6- (2,5-dimethyl_2H- [1,2,4] triazol-3-yl) -2- (4-fluoro-phenyl) -5-methoxy-benzofuran-3-carboxylic acid-formamidine'H NMR in DMSO : 8.45-8.47 (d, 1H, J = 4.69Hz); 7.93-7.98 (m, 2H); 7.69 (s, 1H); 7.36-7.42 α 2H, J = 8.79Hz); 7.29 (st 1H); 3.88 (s, 3H); 3.60 (s, 3H); 2.85-2.86 (d, 3H, J = 4.10Hz); 2.28 (s, 3H) (M + H) + = 395 B < 10 388. _2- (4-fluoro-based box) -6: (pyridinium-methyl-amino) -5 hexetantylmethoxy) -benzofuran-3-carboxylic acid- Formamidine 1H NMR in DMSO: 8.40 (brrn, 1H); 7.95 (m, 2H); 7.89 (d, 1H, J = 2.93Hz); 7.82 (d, 1H, J = 2.93); 7.70 (s, 1H ); 7.40 (m, 3H); 5.60 (s, 2H); 3.25 (s, 3H); 3.02 (s, 3H); 2.85 (d, 3H, J = 4.69Hz) (M + H) + = 490 A < 1 389. 2- (4-Fluoro-phenyl) -5 · methoxy-6- (4-methyl-2,5-dioxy-imidazol-4-yl) -benzobite 1H NMR in DMSO: 10.59 (brs, 1H); 8.37 (m, 1H); 7.96 (s, 1H); 7.94 (m, 2H); 7.71 (s, lH); 7.39 (m, 2H); 7.15 (s, lH); 3.77 (s, 3H); 2.82 (d, J = 4.8Hz, 3H); 1.71 (s, 3H) (M + H) + = 412 A < 10 390. 2- (4-Fluoro-phenyl) -6- (1-methanesulfonylamino-1 -methyl-ethyl) -5-methoxy-benzofuran-3 -Carboxylic acid-formamide 1H NMR in CDC13: 7.84 (m, 2H); 7.51 (s, 1H); 7.44 (s, 1H); 7.19 (m, 2H); 5.88 (s, 1H); 5.79 (brs , 1H); 4.00 (s, 3H); 2.98 (d, J = 4.84 Hz, 3H); 2.52 (s, 3H); i.82 (s, 6H) (M + H- NH- S02Me) + = 340 A < 10 391. 5- (6-Bromomethyl-pyridin-2-ylmethoxy) -6-[(6-bromofluorenyl-pyridin-2-ylmethyl) -methanesulfonyl-amino ] -2- (4-fluoro-phenyl) -benzofuran-3- # polyacid-amidamine 1H NMR in DMSO: 8.38 (d, J = 4.8 Hz, 1H); 7.90 (rat 3H); 7.73 (t, J = 7.1 Hz, 1H); 7.64 (s, 1H); 7.60 (d, J = 7.5 Hz, 1H); 7.53 (d, J = 7.5 Hz, 1H); 7.48 (d, J = 7.5 Hz, 1H); 7.37 (m, 3H); 731 (s, 1H); 5.33 (s, 2H); 4.98 (s, 2H); 4.72 (s, 2H); 4.61 (s, 2H); 3.18 (s , 3H); 2.81 (d, J = 4.8 Hz, 3H) (M + H) + = 746 A < 10 392. 2- [2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) each methylamine methylamido-benzofuran-5-yloxy Methylmethyl] -thiazole-4-acid ethyl ester 1H NMR in DMSO: 8.60 (s, 1H); 8.40 (brd, 1H, J = 4.69Hz); 7.95 (m, 2H); 7.73 (s, 1H) ; 7.40 (m, 3H); 5.63 (s, 2H); 4.32 (q, 2H, J = 7.03Hz); 3.27 (s, 3H); 3.06 (s, 3H); 2.84 (d, 3H, J = 4.69 Hz); 1.32 (t, 3H, J = 7.03) (M + H) + = 562 A < i 393. -2- [2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -3-methylaminofluorenyl-benzofuran-5 -Alkyloxy-B-carboxylic acid lH NMR in DMSO: t 8.52 (s, 1H); 8.41 (brd, 1H, J = 4.69Hz); 7.95 (m, 2H); 7.73 (s, 1H); 7.40 (ra , 3H); 5.61 (s, 2H); 3.26 (s, 3H); 3.06 (s, 3H); 2.85 (d, 3H, J = 4.69Hz) (M-Η) '= 532 A > 30 220- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 ICso 〇iM) A = ^ 0.5 μΜ B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 D = > 30 μΜ replicon (μΜ) 394. 6-Dimethylamino-2- (4-fluoro-phenyl) -5-methoxypyridine-benzo-p-furan-3-metanoic acid-formamidine * H NMR in CDC13: 7.85 (dd, J = 8.8 & 5.3Hz, 2H); 7.26 (s, 1H); 7.17 (t, J = 8.8Hz, 2H); 7.14 (s, 1H); 5.80 (brs, 1H); 3.96 (s, 3H) ; 2.98 (d, J = 4.8Hz, 3H); 2.84 (s, 6H) (Μ + ΗΓ = 343 A < 1 395.5. 5-Cyanomethoxy-2- (4-fluoro-phenyl) > 6- (methanesulfonyl-methyl-amino) -benzfuran-3- leptate-formamidine Amine 1H NMR in DMSO: 8.44 (brd, 1H, J = 4.10Hz); 7.93 (m, 2H); 7.77 (s, 1H); 7.41 (m, 3H); 5.32 (s, 2H); 3.22 (s, 3H); 3.08 (s, 3H); 2.84 (d, 3H, J = 4.69Hz) (M + H) + = 432; A < 1 396. 2- (4-Amino-winteryl) -6- (methanesulfonyl-methyl-amino) -5- (5-methyl-isopurazol-3-ylmethoxy) ) -Benzofuran-3: carboxylic acid-methylamine 1H NMR in DMSO: 8.40 (brd, lHt J = 4.69Hz); 7.95 (m, 2H); 7.68 (s, 1H); 7.38 (m, 3H) ; 6.40 (s, 1H); 5.30 (s, 2H); 3.21 (s, 3H); 3.00 (s, 3H); 2.84 (d, 3H, J = 4.10Hz); 2.44 (s, 3H) (M + H) + = 488 A < 1 397. 5- (5-Chloro- [1,2,3] pyrimidazol-4-ylmethoxy) -12- (4-amino-benzene grave) each (methanesulfonyl- Methyl-amino) -benzofuran-3-carboxylic acid-methaneamine 1H NMR in DMSO: 8.46 (brd, 1H, J = 4.10Hz); 7.98 (m, 2H); 7.69 (s, 1H); 7.51 (s, 1H); 7.40 (t, 2H, J = 8.79Hz); 5.66 (s, 2H); 3.17 (s, 3H); 2.95 (s, 3H); 2.87 (d, 3H, J = 4.69Hz ) (M + H) + = 525 A < 1 39. 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-fluorenyl-amino group) > 5- (1-methyl-1H-imid-2-ylmethoxy Phenyl) -benzoanan-3-guinic acid-formamidine 1H NMR in DMSO: 8.42 (brd, 1H, J = 4.69); 7.98 (m, 2H); 7.70 (s, 1H); 7.52 (s, 1H); 7.39 (t, 2H, J = 8.79); 7.21 (s, 1H); 6.91 (s, 1H); 5.27 (s, 2H); 3.74 (s, 3H); 3.15 (s, 3H); 2.94 (s, 3H); 2.87 (d, 3H, J = 4.69Hz) (M + H) + = 487 A < 1 399.9 5- (1-fluorenyl-1H-imidazol-2-ylmethoxy) -2- (4-fluoro-phenyl) -6 · (methanesulfonyl-methyl-amine ) -Benzofuran-3-carboxylic acid-formamidine * Η NMR in DMSO: 8.42 (brm, 1H); 7.95 (m »2H); 7.68 (s, 1H); 7.51 (s, 1H); 7.42- 7.20 (m, 8H); 7.00 (s, 1H); 5.38 (s, 2H); 5.25 (s, 2H); 3.04 (s, 3H); 2.91 (s, 3H); 2.86 (d, 3H, J = 4.10Hz) (M + H) + = 563 A 氺 氺 氺 400. "-(2,4-difluoroyl-phenyl) -6- (3,5-dimethyl-isopyridin-4-yl ) -5-methoxy-benzofuran carboxylic acid-formamide 1H NMR in DMSO: 8.10-8.12, (d, 1H, J = 4.69Hz); 7.78-7.86 (q, 1H, J = 6.45Hz ); 7.61 (s, 1H); 7.4 ^ -7.49 (ra, 1H); 7.33 (s, 1H); 7.27-7.32 (m, 1H); 3.85 (s, 3H); 2.77-2.78 (d, 3H, J = 4.69Hz); 2.29 (s, 3H); 2.10 (s, 3H) (M + H) + = 413 A 氺 氺 氺 221-88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 ICs «( / iM) A = μΜ B = 05 to <: 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ replicon (μΜ) 401.6- (3,5-dimethyl-isoimonyl f-group) _2_ (4-fluoro-fluoro Yl) -5 dexazol-4-yl methoxy axe) -benzofuran-3-rebellion-methylamine 1HNMR in DMSO: 9.13 (d, 1H, J = 1.17 Hz); 8.41-8.43 (d, 1H, J = 4.69 Hz); 7.94-7.99 (m, 2H); 7.64-7.65 (d, 1H, J = U7 Hz); 7.61 (s, 1H); 7.45 (s, 1H); 7.36-7.42 (t , 2H, J = 8.79 Hz); 5.28 (s, 2H); 2.86-2.88 (d, 3H, J = 4.69 Hz); 2.29 (s, 3H); 2.1 l (s, 3H) (M + H) + = 478 A < 1 402. 5- (fluorenyl-4H- [1,2,4] three ton-3-ylfluorenyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl -Methyl-amino) -benzo-p-furan-3-carboxylic acid-formamidine 1H NMR in DMSO: 11.94 (brs, 1H); 8.36 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.57 (s, 1H); 7.36 (m, 3H); 5.96 (brs, 2H); 5.01 (s, 2H); 3.19 (s, 3H); 2.99 (s, 3H); 2.83 (d, 3H , J = 4.10Hz) (M + H) + = 489 A < 1 403. 5- (4-chloromethyl-1H-pyridin-3-ylmethoxy) -2- (4-fluoro: phenyl) -6- (methanesulfonyl-methyl -Amine) -benzopyran-3-carboxylic acid-formamidine ^ NMRinDMSO: 8.44 (brd, 1H, J = 4.69Hz); 7.96 (m, 3H); 7.62 (s, 1H); 7.47 (s , 1H); 7.38 (t, 2H, J = 8.79Hz); 5.16 (s, 2H); 3.84 (s, 3H); 3.16 (s, 3H); 2.93 (s, 3H); 2.86 (d, 3H, J = 4.69Hz) (M + H) + = 521 A < 1 404.2. 2- (4-Gasyl-phenyl) -6- (methanesulfonyl-methyl-unradical) -5- (2-pbicyclo-1-ylethoxy) -benzene 1H NMR in DMSO: 8.42 (brm, 1H); 7.97-7.90 (m, 3H); 7.56 (s, 1H); 7.47 (s, 1H); 7.38 (t, 2H, J = 8.79); 7.23 (s, 1H); 6.27 (m, 1H); 4.60 (brm, 2H); 4.54 (brm, 2H); 2.99 (s, 3H); 2.84 (m, 6H) (M + H) + = 487 A < 1 405. _ 2- (4-Fluoro-phenyl) -5- (1Η-imid-2-ylmethoxy) -6- (methylamino-methyl-amino)- Benzofuran-3-carboxylic acid-formamidine 1H NMR in DMSO: 12.24 (brs, 1H); 8.41 (brd, 1H, J = 4.10Hz); 7.95 (m, 2H); 7.63 (s, IH); 7.47 (s, 1H); 7.39 (t, 2H, J = 8.79Hz); 7.19 (s, 1H); 6.95 (s, 1H); 5.20 (s, 2H); 3:16 (s, 3H); 2.91 (s, 3H); 2.86 (d? 3H, J = 4.69Hz) (M + H) + = 473 A < 1 40. 6- (2,5-dioxy-imidazine-4-yl) -2- (4-amino-phenyl) -5-methoxy-benzofuran-3- Carboxylic acid-formamide 1H NMR in DMSO: 8.38 (m, 1H); 8.08 (s, 1H); 7.93 (m, 2H); 7.56 (s, lH); 7.34 (m, 2H); 7.15 (s, lH); 5.29 (s, lH); 3.90 (s, lH); 3.80 (s? 3H); 2.82 (d, J = 3.6Hz, 3H) (M + H) + = 398 B < 10 407. 5-ά5-Dimethyl-isoxanthenyl) -2- (4-fluoro-phenyl) -6-methanesulfonamido -Formamidine ... ——j-—— * Η NMR in DMSO:, 9.18 (bs, 1H); 8.37 (d, J = 2.20Hz, 1H); 7.98-7.93 (m, 2H); 7.72 (s, 1H); 7.41-7.34 (m, 3H); 3.01 (s, 3H); 2.79 (dt J = 4.84Hz, 3H); 2.22 (s, 3H); 2.04 (s, 3H) (MH) · 456.0 < 10 222-88828.doc 200418452 Example No. Name NMR data Mass Spec HCV pol -BB7 ICs〇 〇iM) A = μΜ B = 0 0 J to ^ 5.0 tM C = 5.0 to < 30 / iM D = > 30 μM replicon_) 408.2 2- (4-fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5- (1-pyrimidine Azole-2-yl-ethoxy) -benzofuran-3-carboxylic acid-amidamine 1H NMR in DMSO: 8.33 (brd, IH, J = 4.10); 7.92 (m, 2H); 7.84 (d, 1H, J = 2.93Hz); 7.75 (d, 1H, J = 2.93); 7.66 (s, 1H); 7.38 (t, 2H, J = 8.79Hz); 7.30 (s, 1H); 6.03 (q, 1H , J = 6.45Hz); 3.26 (s, 3H); 3.09 (s, 3H); 2.82 (d, 3H, J = 4.69Hz); 1.76 (d, 3H, J = 6.45) (M + H) + = 504 氺 氺 氺 < 1 409.6 6- (3,5-dimethyl-isohumidazole_4-yl) -2- (4-fluoro-phenyl) -5- (5-methyl-isoxanthine-3 -Ylmethoxy) -benzofuran-3-carboxylic acid-amidamine 1H NMR ia DMSO: 8.41 (brd, iHt J = 4.69); 7.95 (m, 2H); 7.62 (s, 1H); 7.40 ( m, 3H); 6.16 (s, 1H); 5.20 (s, 2H); 2.86 (d, 3H, J = 4.69Hz); 2.41 (s, 3H); 2.28 (s, 3H); 2.i0 (s , 3H) (M + H) + = 476 A < 1 41. 6- (3,5-dimethyl-iso-indolizyl-4-yl) -2- (4-lactyl-phenyl) > 5- (pyrimidin-2-ylmethoxy) ) -Benzofuran-3-carboxylic acid-methylamine 1H NMR ia DMSO: 8.41 (brd, 1H, J = 4.10Hz); 7.95 (m, 2H); 7.83 (d, 1H, J = 2.34Hz); 7.75 (d, 1H, J = 2.93Hz); 7.64 (s, 1H); 7.46 (s, IH); 7.38 (t, 2H, J = 8.79Hz); 5.49 (s, 2H); 2.86 (d, 3H , J = 4.10Hz); 2.30 (s, 3H); 2.12 (s, 3H) (M + H) + = 478 A < 1 41. 6-Ethylfluorenyl-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid-methaneamine 1H NMR in CD3D: 8.22 (in, 1H); 7.98 (m, 3H); 7.76 (m, 1H); 7.27 (m, 2H); 2.96 (s, 3H); 2.67 (s, 3H) (M + H) + = 312 B Copy 412.2 2- ( 4-Fluoro-phenyl) -5- (2-hydroxy-2-methyl-propoxy) -6- (formamyl-methyl-unsubstituted) -benzocran-3-chi Acid-formamide 1H NMR in DMSO: 8.41 (brra, 1H); 7.94 (m, 2H); 7.64 (s, 1H); 7.38 (t, 2H, J = 8.79Hz); 7.20 (s, 1H); 4.61 (s, IH); 3.86 (s, 2H); 3.24 (s, 3H); 3.08 (s, 3H); 2.83 (d, 3H, J = 4.69Hz); 1.28 (s, 6H) (M-Η ) '= 463 A * 氺 氺 413. 5-Diethylmethylamidomethoxy-2- (4-fluoro-phenylbenzene grave) -6- (_ burning continyl-methyl-amine)- Benzalan-3-acid-methylamine 1H NMR in DMSO: 8.42 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.60 (s, iH); 7.38 (t, 2H, J = 8.79Hz); 7.10 (s, 1H); 4.98 (s, 2H); 3.36 (m, 4H); 3.27 (s, 3H); 3.09 (s, 3H); 2.81 (d, 3H, J = 4.69 Hz); 1.21 (t, 3H, J = 7.03Hz); 1.06 (t, 3H, J = 7.03) (M + H) + = 506 A 氺 氺 氺 414. 6 bis (3,5-dimethyl- Iso-slogazolyl) _5-ethoxy_2- (4-fluoro -Hydroxy] -Ferrofuran-3- # polyacid-formamidine 1H NMR in DMSO: 8.41-8.42 (d, 1H, J = 4.69 Hz); 7.92-7.97 (m, 2H); 7.58 ( s, 1H); 7.35-7.41 (t, 2H, J = 8.79 Hz); 7.21 (s, 1H); 4.05-4.12 (q, 2H, J = 7.03 Hz); 2.84-2.85 (d, 3H, J = 4.69 Hz); 2.30 (s, 3H); 2.12 (s, 3H); 1.27-1.32 (t, 3H, J = 7.03 Hz) '(M + H) + = 409.0 A 氺 氺 氺 415. 2- (4 -Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) > 5- (pyrimazol-2-ylaminomethylmethylmethoxy) -benzofuran-3-carboxylic acid- Formamidine 1H NMR in DMSO: 12.30 (brs, 1H); 8.41 (brd, 1H, J = 4.69Hz); 7.92 (m, 2H); 7.67 (s, 1H); 7.51 (d, 1H, J = 3.52 Hz); 7.38 (t, 2H, J = 8.79Hz); 7.27 (d, 1H, J = 3.52Hz); 7.18 (s, 1H); 5.06 (s, 2H); 3.12 (m, 6H); 2.79 ( d, 3H, J = 4.69Hz) (MH) '= 531 A < 1 223-88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 IC50 (μM) A = ^ 〇J5 μΜ B = to ^ 5.0 μΜ C = 5.0 to ^ 30 μΜ D = > 30 μΜ Copy (ΜΜ) 416. Gaso-phenyl) -6_ (methanesulfonyl-methyl-amino) -5-([1,3, exedadiazol-2-ylaminemethylmethylmethoxy ) -Benzofuran-3-carboxylic acid-formamidine 1H NMR in DMSO: 12.81 (brs, 1H); 9.22 (s, 1H); 8.42 (brm, 1H); 7.92 (m, 2H); 7.67 (s , 1H); 7.39 (t, 2H, J = 8.79Hz); 7.18 (s, 1H); 5.12 (s, 2H); 3.17 (s, 3H); 3.10 (s, 3H); 2.79 (d, 3H, J = 4.10Hz) (MH) * = 532 A < 1 417. 5-[(4,5-Dimethyl-thiazol-2-ylaminemethylamidino) -methoxy] -2- (4-fluoro-phenyl) each (methanesulfonyl -Methyl-amino) -benzofuran-3-valerate-formamidine * H NMR ifl DMSO: 12.05 (brs, 1H); 8.41 (brd, 1H, J = 4.10Hz); 7.92 (m, 2H ); 7.66 (s, 1H); 7.39 (t, 2H, J = 8.79Hz); 7.16 (s, 1H); 5.00 (s, 2H); 3.28 (s, 3H); 3.10 (s, 3H); 2.80 (d, 3H, J = 4.10Hz); 2.24 (s, 3H); 2.17 (s, 3H) (M + H) + = 561 A < 1 418. 5-¾propyl-2- (4-Gas_phenyl) _6_methanesulfonamido-benzoanan-3-valerate-formamidine-lH NMR in DMSO: 9.32 (bs, 1H); 8.36 (m, 1H); 7.94 (dd, J = 5.3 & 8.8Hz, 2H); 7.58 (s, 1H); 7.36 (t, J = 8.8Hz, 2H); 7.14 ( s, 1H); 3.03 (s, 3H); 2.83 (d, J = 4.6Hz, 3H); 2.31 (m, 1H); 1.00 (m, 2H); 0.68 (m, 2H) (M + H) + = 403 A < 1 419. 5- [2- (4-Cyano-hexahydropyridine-i-yl) -ethoxy] -6- (3,5-dimethyl-iso-pyridyl-4 -Yl) -2- (4-airyl-dongyl) -Hydroxybenzo-3-carboxylic acid-formamidine 1H NMR in DMSO: 8.41-8.43 (d, 1H, J = 4.69 Hz); 7.93- 7.97 (m, 2H); 7.58 (sT 1H); 7.35-7.41 (t, 2H, J = 8.79Hz); 7.26 (s, 1H); 4.084.12 (t, 2H, J = 5.86Hz); 2.85- 2.86 (d, 3H, J = 4.69Hz); 2.82-2.86 (m, 1H); 2.63-2.66 (ζ 2H, J = 5.86Hz); 2.50-2.55 (m, 3H); 2.31 (s, 3H); 2.26-2.31 (m, 1H); 2.14 (s, 3H); 1.77-1.84 (m, 2H); 1.63-1.70 (m, 2H) (M + H) + = 517.1 A < 1 420.2 2- (4-Methanesulfonyl-amino-5-thiophen-2-yl-benzofuran-3-carboxylic acid-methaneamine 1H NMR in DMSO: 9.29 (sf 1H); 8.48 (d, J = 4.84Hz, 1H); 8.02-7.97 (m, 2H); 7.75 (s, 1H); 7.97 (s, 1H); 7.64 (d, J = 5.27Hz, 1H); 7.45-7.37 ( m, 3H); 7.19-7.16 (m, 1H); 2.94 (s, 3H); 2.84 (d, J = 4.40Hz, 3H) (MH) '= 443 A < 1 421.2 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methyl-amino) -5-methylaminomethylmethylmethoxy-benzofuran-3- Carboxylic acid-formamide'H NMR in DMSO: 8.40 (brd, 1H, J = 4.69Hz); 7.93 (m, 3H); 7.70 (s, 1H); 7.39 (t, 2H, J = 8.79Hz); 7.16 (s, 1H); 4.66 (s, 2H); 3.25 (s, 3H); 3.13 (s, 3H); 2.83 (d, 3H, J = 4.69Hz); 2.68 (d, 3H, J = 4.69Hz ) (M + H) + = 464 A < 1 422.2 2- (4-fluoro-phenyl) -5- (1-hydroxymethyl-cyclopropylmethoxy) -6-[(1-methyl-¾ • propylmethyl) -Methanesulfonyl-amino group] -benzofuran-3-¾ acid-methylamine 1H NMR in DMSO: 8.53 (d, J = 4.8H2, iH); 8.07 (dd, J = 8.8, 5.3Hz, 2H); 7.72 (s, 2H); 7.52 (t, J = 8.8Hz, 2H); 4.50 (brd, 1H); 4.15 (t, J = 9.3Hz, 1H); 14.07 (d, J = 9.9Hz, 1H); 3.60 (m, 2H); 3.50 (m, 1H); 3.30 (d, J = 11.0Hz, 1H); 3.17 (s, 3H); 2.94 (d, J = 4.8Hz, 3H); 0.75 ( s, 4H) (MH) '= 545 B < 10 224- 88828.doc 200418452 Instance number name NMRdata Mass Spec HCV pol -BB7 ICse 〇iM) A = / iM B = 03 to ^ 5.0 / iM C = 5.0 to ^ 30 μΜ D = > 30 / iM Copy L) 423. 6-Diethylamino-5-ethoxy-2- (4-fluoro-phenyl) -benzofuran-3-carboxylic acid-formamidine 1HNMRinCIX: 13: 7.85 (dd, J = 8.8T 5.3Hz, 2H); 7.30 (s, 1H); 7.77 (t, J = 8.8Hz, 2H); 6.67 (st 1H); 5.75 (brs, 1H); 4.10 (q, J = 7.0Hz, 2H); 3.20 (q, J = 7.0Hz, 4H); 1.40 (t, J = 7.0Hzt 6H); 1.30 (t, J = 7.0Hz, 3H) (M + H) + = 385 A < 1 424. 5-Aminomethylamidomethoxy-2- (4-railyl-phenyl) -6- (methanesulfonyl-methyl-amino) -benzofuran each carboxylic acid-formaldehyde Amidine 'HNMR in DMSO: 8.41 (brd, 1H, J = 4.69Hz); 7.93 (m, 2H); 7.72 (s, 1H); 7.40 (m, 4H); 7.15 (s, 1H); 4.64 (s , 2H); 3.26 (s, 3H); 3.13 (s, 3H); 2.84 (d, 3H, J = 4.69Hz) (MH)-= 448 A < 1 425. 5- [2- (3,5-Dimethyl-4-dazol-1-yl) -ethoxy] -2- (4-air grave-dongyl) -6- (methanesulfonium -Methyl-amino) -benzofuran-3-carboxylic acid-formamidine 1H NMR in DMSO: 8.41 (brd, 1H, J = 4.69Hz); 7.94 (m, 2H); 7.60 (sy 1H) ; 7.38 (ζ 2H, J = 8.79Hz); 7.22 (st 1H); 5.81 (s, 1H); 4.44 (brd, 2H, J = 4.69Hz); 4.40 (brd, 2H, J = 4.69Hz); 3.06 (s, 3H); 2.89 (s, 3H); 2.84 (d, 3H, J = 4.69Hz); 2.28 (s, 3H); 2.08 (s, 3H) (M + H) + = 515 A < 1 426. 2- (4-Fluoro-phenyl) -5-crean-2-yl-6-methylpyridinylamino-benzofuran each carboxylic acid-formamide 1H NMR in DMSO : 9.34 (s, 1H); 8.50 (d, J = 4.40Hz, 2H); 7.99-7.96 (m, 2H); 7.91 (st 1H); 7.82 (s, 1H); 7.74 (s, 1H); 7.40 (t, J = 8.79Hz >2H); 7.09 (d, J = 3.52Hz, 1H); 6.65 (s, 1H); 3.04 (s, 3H); 2.85 (d, J = 4.40Hz, 3H) (MH ) * = 427.0 A < 1 427. 6- (3,5-Dimethyl-isoxazole-4.-2- (4-fluoro-phenyl) -5- (1-methyl-1H-tetramethyl-5- Methylmethoxy) -benzoanan-3 -metanoic acid-formamidine * H NMR in DMSO: 8.44-8.45 (d, 1H, J = 4.69Hz); 7.93-7.97 (m, 2H); 7.63 ( s, 1H); 7.53 (s, 1H); 7.36-7.42 (t, 2Ht J = 8.79Hz); 5.56 (s, 2H); 3.93 (s, 3H); 2.86-2.88 (dt 3H, J = 4.69Hz ); 2.24 (s, 3H); 2.07 (s, 3H) (M + H) + = 477 A < 1 428. ^ 5-Cyclopropylmethoxy-6- (3,5-difluorenyl-isoazazol-4-yl) -2- (4-fluoro-phenyl) -benzofuran -3-carboxylic acid-formamidine 1H NMRinDMSO: 8.39-8.41 (d, 1H, J = 4.69Hz); 7.91-7.96 (m, 2H); 7.58 (st 1H); 7.35-7.41 (ζ 2H, J = 8.79Hz); 7.18 (s, 1H); 3.86-3.88 (d, 2H, J = 7.03Hz); 2.83-2.85 (d, 3H, J = 4.69Hz); 2.32 (s, 3H); 2.15 (s, 3H); 1.12-1.20 (ra, 1H); 0.51-0.57 (m, 2H); 0.26-0.3 l (m, 2H) (M + H) + = 435 A < 1 429. 6- (3; dimethyl-isoazazolyl) -5- (3,5-dimethyl-isopurin-4-ylmethoxy) -2- (4-gas Phenyl-fungyl) -benzyl-3-acid-formamidine'H NMRinDMSO: 8.43-8.45 (d, 1H, J = 4.69Hz); 7.92-7.96 (m, 2H); 7.59 (s, 1H); 7.44 (s, 1H); 7.36-7.41 (t, 2H, J = 8.79Hz); 4.97 (s, 2H); 2.86-2.87 (d, 3H, J = 4.69Hz); 2.28 (s, 3H ); 2.2i (s, 3H); 2.03 (s, 3H); 1.97 (s, 3H) X (M + H) + = 490 A < 1 430.3 2- (4-Fluoro-phenyl) -5_methoxy-6- (5-methyl_3,4? fluorenediazol-2-yl) -benzofuran-3- Carboxylic acid-formamide 1HNMRinCDCl3: 8.05 (s, 1H); 7.92-7.87 (m, 2H); 7.52 (s, 1H); 7.27-7.23 (mt 2H); 5.80 (s, 1H); 4.03 (s, 3H); 3.02 (d, J = 4.5 Hz, 3H); 2.65 (s, 3H) (M + H) + = 381 A < 10 225-88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 ICsoOtM) A = μΜ 03 to ^ 5.0 μΜ. C = 5.0 to ^ 30 D = > 30 μΜ replicon (μΜ) 431.6 -(3-cyano-4-hydroxy-2-oxy-2,5-dihydro-pyrrole small methyl) -2- (4-fluoro-phenyl) -5-methoxy-benzo Pyran-3-guinic acid-formamidine 1HNMRinDMSO: 8.36-8.34 (m, 1H); 7.94-7.89 (m, 2H); 7.36-7.28 (ra, 3H); 7.10 (s, 1H); 4.47 (sr .2H); 3.85 (s, 2H); 2.81 (d, J = 4.2 Hz, 3H) (M + H) + = 436 A * 氺 氺 432.4 4-amino-6- [ethyl- (2_ Oxy-ethyl group) -amino group] -2- (4-fluoro group-benzene to) -5-methoxy-benzocran-3-guinic acid-methyl group 1HNMRinCDCl3: 7.90 (ddt J = 8.3,5.3Hz, 2H); 7.40 (s, 1H); 7.20 (t, J = 8.3Hz, 2H); 5.90 (brs, 1H); 3.91 (s, 3H); 3.80-3.70 (m, 2H); 3.62 (s, 2H); 3.30 (s, 3H); 2.98 (TJ = 4.4Hz, 3H); 1.10 (t, J = 7.0Hz, 3H) (M + H) + = 343 B < 10 433. 6- (3 > Di-methyl-isopurine α-s_4_yl) -2- (4-amino-phenyl) -5- (2-morpholinolinylethoxy ) -Benzofuran-3-carboxylic acid-formamidine 1H NMR in DMSO: 8.41-8.42 (d, 1H, J = 4.69Hz); 7.93-7.97 (m, 2H); 7 ^ 8 (s, 1H) ; 7.35-7.41 (t, 2H, J = 8.79Hz); 7.26 (s, 1H); 4.11-4.14 (t, 2H, J = 5.28Hz); 3.52-3.55 (t, 4H, J = 4.10Hz); 2.84-2.86 (d, 3H, J-4.69HZ); 2.61-2.65 (t, 2H, J = 5.86Hz); 2.36-2.40 (t, 4H, J = 4.10Hz); 2.31 (s, 3H); 2.15 (s, 3H) (M + H) + = 494 A 氺 氺 氺 434. 6- (3,5-dimethyl-isopyridin-4-yl) -2- (4-amino-phenyl) -5- (3-Hexahydropyridine-1 -yl-is oxy) -benzofuran-3-guinic acid-formamidine'H NMR ia DMSO: 8.42-8.44 (d, 1H, J = 4.69Hz ); 7.92-7.97 (m, 2H); 7.58 (s, 1H); 7.35-7.41 (t, 2H, J = 8.79Hz); 7.22 (s, 1H); 4.01-4.06 (t, 2H, J = 6.45 Hz); 2.84-2.85 (d, 3H, J = 4.69Hz); 2.28 (s, 3H); 2.25-2.28 (m, 4H); 2.11 (s, 3H); 1.91 (s, 2H); 1.75-1.84 (in, 2H); 1.36-1.48 (m, 4H); 0.84-0.86 (m, 2H) (M + H) + = 506.1 B 氺 氺 氺 435. 2- (4-Gas-phenyl) _5_ ( Pyrimazole 4-ylmethoxy) -benzofuran-3-guinic acid-formamidine 1H NMR in DMSO: 9.12 (s, 1H); 8.34 (d, J = 4.0 Hz, 1H); 7.92 (m, 2H); 7.79 (s, 1H); 7.57 (d, J = 8.8 Hz, 1H); 7.34 (t, J = 8.3Hz, 2H); 7.23 (s, 1H); 7.07 (ra, 1H); 5.25 (s, 2H); 2.82 (d, J = 3.5Hz, 3H) (M + H) + = 383.0 B > 30 436. ^ 2- (4-air-benzyl) -6 < 2-Hydroxy-ethenyl) -5-methoxy-benzofuran-3-carboxylic acid-formamidine'H NMR in CDC13: 8.20 (s, 1H); 7.87 (m, 2H); 7.45 (s, 1H); 7.22 (m, 2H); 5.77 (brs, 1H); 4.82 (s, 2H); 4.01 (s, 3H); 3.75 (brs, 1H); 3.00 (dt J = 4.8 Hz, 3H ) (M + H) + = 358.1 A < 10 437. 5-Cyclopropyl-2- (4-amino-phenyl) -6- (methylsulfanyl-St-yl-fluorenyl-amino) -benzocran-3-metanoic acid-fluorene Lamine 1H NMR in DMSO: 8.39 (d, J = 4.40Hz, 1H); 7.95-7.90 (m, 2H); 7.81 (s, 1H); 7.39-7.33 (m, 2H); 7.13 (s, 1H) ; 3.22 (s, 3H); 3.14 (s, 3H); 2.82 (d, J = 4.40Hz, 3H); 2.33-2.24 (m, 1H); 0.96 (d, J = 8.35Hz, 2H); 0.79- 0.63 (mt 2H) (M + H) + = 417 A < 1 438. 2- (4-Fluoro-phenyl) _5_hydroxy-6-[(2-hydroxy-propyl) -methyl-s-s-yl-amine] -benzyl_3_ complex Acid-formamidine 1H NMR in DMSO: 9.97 (s, 1H); 8.40 (brd, 1H, J = 4.10Hz); 7.92 (m, 2H); 7.55 (s, 1H); 7.35 (t, 2H, J = 8.79Hz); 7.09 (s, 1H); 4.72 (brs, 1H); 3.58-3.40 (m, 3H); 3.01 (s, 3H); 2.80 (d, 3H, J = 4.69Hz); 1.03 (d , 3H, J = 5.86Hz) (MH)-= 435 A 氺 氺 氺 -226- 88828.doc 200418452 Example number name NMRdata Mass Spec HCV pol -BB7 Κ ^ (μΜ) A = ^ 0.5 μΜ B = 05 to ^ 5.0 μΜ C = 5.0 to ^ 30 D = > 30 μΜ replicon (μΜ) 439.2 2- (4-fluoro-phenyl) _6-[(2-benzyl-propyl) _ methanesulfonyl- Amine J-5-methoxy-benzofuran-3-carboxylic acid-formamidine ^ HNMRinDMSO: 8.41 (brd, 1H, J = 5.28Hz); 7.92 (m, 2H); 7.66 (s, 1H) ; 7.36 (t, 2H, J = 8.79Hz); 7.18 (s, 1H); 4.66 (brs, 1H); 3.89 (s, 3H); 3.56 (bnn, 3H); 3.00 (s, 3H); 2.82 ( d, 3H, J = 4.69Hz); 1.03 (d, 3H, J = 5.28Hz) (MH) * = 449 A 氺 氺 氺 440. 6-〇Ethyl 4-bilodine-2-yl) -5 -Ethyl-2- (4-fluoro-phenyl) > benzofuran carboxylic acid-formamidine 1HNM RinCDCl3: (mixture of two enantiomers) 7.90 (m, 2H); 7.68 (s, 1H); 7.21 (s, 1H); 7.15 (m, 2H); 5.80 (brs, 1H); 5.20 (dd, J = 2.1 Hz, J = 8.4Hz, 1H); 3.85 (m, 1H); 3.65 (m, 1H); 3.20-3.40 (1H); 3.01 (d, J = 5.2Hz, 3H); 2.70-2.90, 2H); 2.30-2 JO, 1H); 1.80-2.10, 2H); 1.82 (s, 3H); 1.34 (t, J = 7.5Hz, 3H) (M + H) + = 409.1 A 氺 氺 氺 441. 2_ (4_ Gaso-phenyl) -6-methanesulfonylamino-5- (tetrahydro-furyl) -benzofuran-3-carboxylic acid-formamidine 1HNMRinDMSO: 9.15 (s, 1H); 8.44 (d , J = 4.40Hz, 1H); 7.94-7.89 (m, 2H); 7.62 (d, J = 4.40Hz, 2H); 7.39-7.34 (m, 2H); 5.21 (t, J = 7.47Hzt 1H); 4.06-4.03 (m, 1H); 3.82-3.80 (m, 1H); 3.08 (s, 3H); 2.82 (d, J = 4.40Hz, 3H); 2.45-2.41 (m, 1H); 1.98-1.94 ( m, 2H); 1.65 (m, 1H) (MH). = 431.0 A < 1 442. 2- (4-Amino-phenyl) -5_methoxy-6- (tetrahydro-crean-3-yl) -benzoanan-3-carboxylic acid-methaneamine 1HNMRinDMSO : 8.34-8.36 (d, 1H, J = 4.69Hz); 7.90-7.95 (m, 2H); 7.53 (s, 1H); 7.33-7.39 (t, 2H, J = 8.79Hz); 7.10 (s, 1H ); 4.00-4.06 (t, 1H, J = 7.62Hz); 3.90-3,97 (m, 1H); 3.89 (s, 3H); 3.68-3.85 (m, 2H); 3.56-3.61 (t, 1H , J = 7.62Hz); 2.83-2.84 (d, 3H, J = 4.69Hz); 2.21-2.31 (m, 1H); 1.95-2.06 (m, 1H) (M + H) + = 370.0 A < 1 443. 2- (4-Fluoro-phenyl) -6- (methanesulfonyl-methoxymethyl-amino) -5-propoxy-benzofuran-3-carboxylic acid_fluorene Amidine 'HNMR in DMSO: 8.40 (d, J = 4.2Hz, 1H); 7.94 (dd, J = 8.8, 5.3Hz, 2H); 7.65 (s, 1H); 7.36 (t, J = 8.8Hz, 2H ); 7.19 (s, 1H); 5.94 (brs, 2H); 4.03 (t, J = 7.0Hz, 2H); 3.32 (s, 3H); 3.08 (s, 3H); 2.81 (d, J = 4.2Hz , 3H); 1.80 (sextet, J = 7.0Hzt 2H); 1.01 (t, J = 7.0Hz, 3H) (M + H) + = 465 A < 1 44. 2- (4-Gas-phenyl) -5-hydroxy-6- (methanesulfonyl-methoxymethyl-amino) -benzofuran each carboxylic acid-methaneamine 1HNMRia DMSO : 10.08 (s, 1H); 8.40 (d, J = 4.4Hz, 1H); 7.92 (dd, J = 8.8, 5.7Hz, 2H); 7.53 (s, 1H); 7.35 (t, J = 8.8Hz, 2H); 7.12 (s, 1H); 4.92 (brs, 2H); 3.31 (s, 3H); 3.08 (s, 3H); 2.80 (d, J = 4.8Hz, 3H) (MH) '= 421 A < 10 445. 2_ (4 · Gas · " phenyl) -6_ methanesulfonylamino-5-propoxy-benzoanan-3-carboxylic acid-formamidine 1H NMR in CDC13: 7.82 (dd, J = 8.8 & 6.3Hz, 2H); 7.73 (s, 1H); 7.41 (s, 1H); 7.18 (t, J = 8.8Hz, 2H); 6.92 (s, 1H); 5.77 ( brs, 1H); 4.07 (t, J = 6.6Hz, 2H); 2.98 (d, J = 9.8Hz, 3H); 2.95 (s, 3H); 1.85 (sextet, J = 7.0Hz, 2H); 1.06 ( t, J = 7.0Hz, 3H) (M + H) " = 421 A < 1 446. 5- (4-Gasyloxy group) -2- (4-fluoroyl-phenylene) -6- (methanesulfonyl-methoxymethyl-amino) -benzo 4 1H NMR in DMSO: 8.40 (d, J = 4.6Hz, 1H); 7.93 (dd, J = 8.8, 5.3Hz, 2H); 7.88 (d, J = 8.2Hz, 2H); 7.75 (s, 1H); 7.71 (d, J = 8.2Hz, 2H); 7.37 (t, J = 8.8Hz, 2H); 7.31 (s, 1H); 5.33 (s, 2H); 4.94 ( brs, 2H); 3.31 (s7 3H); 3.04 (s, 3H); 2.81 (d, J = 4.6Hz, 3H) (MH) '= 536 A < 1 227- 88828.doc 200418452 Instance number name NMRdata Mass Spec HCV pol -BB7 IC50O1M) A = μ, Μ B = 0 * 5 to 彡 5.0 · i / iM C = 5.0 to ^ 30 μΜ D = > 30 μM replicon (μM) 447. —5_ (3-cyano-fluorenyloxy) -2- (4-fluoro-phenyl) -6- (methanesulfonyl-methoxy-amino-amino)- Benzo-3-carboxylic acid-formamidine'HNMRinDMSO: 8.40 (d, J = 4.4Hz, 1H); 8.00 (s, 1H); 7.90-7.80 (m, 4H); 7.75 (s, 1H); 7.62 (t, J = 8.0HzT 1H); 7.39 (t, J = 8.0Hz, 2H); 7.31 (s, 1H); 5.28 (s, 2H); 4.92 (brs, 2H); 3.31 (s, 3H); 3.04 (s, 3H); 2.82 (d, J = 4.4Hz, 3H) (M + H) + = 536 A < 1 448.6 6- (1: cyclopropanecarbonyl-pyridine-2-yl) -2- (4-amino-phenyl) -5-isopropoxy-benzoanan-3-gui Acid-formamidine ^ NMRinCDCb: 7.84 (m, 2H); 7.34 (s, 1H); 7.18-7.23 (m, 3H); 5.74 (brs, 1H); 5.50 (d, J = 7.47Hz, 1H); 4.73 (septet, J = 5.72Hz, 1H); 3.85 (m, 1H); 3.82 (m, 1H); 2.99 (d, J = 4.84Hz, 3H); 2.22-2.43 (m, 1H); 1.92-2.00 (in, 2H); 1.79-1.80 (m, 2H); 1.40 (m, 6H); 0.85-1.01 (m, 4H) (M + H) + = 465 A 氺 氺 氺 1 449.2 2- (4- Carbyl-phenyl) -5_methoxyban [1,3,4] Hexajun-2-yl-benzyl-3-carboxylic acid-formamidine ^ NMRia CDC13: 8 ^ 1 (s, 1H); 8.11 (s, 1H); 7.91-7.87 (m, 2H); 7.54 (s, 1H); 7.26-7.20 (rat 2H); 5.80 (s, 1H); 4.04 (s, 3H); 2.99 ( cU = 5.4Hz, 3H) (M + H) + = 368 A 氺 氺 氺 450. 2- (4-fluoro-phenyl) each (methanesulfonyl-methoxymethyl-amine) -5- Pyridin-2-yl-benzopyran-3-carboxylic acid-formamidine 1H NMRinDMSO: 8.48 (m, 1H); 7.98-7.96 (m, 3H); 7.83 (m, 1H); 7.61-7.60 ( m, 1H); 7.42-7.36 (mt 3H); 7.13 (m, 1H); 3.16 (s, 3H); 3.08 (s, 3H); 2.66 (d, J = 3.96Hz, 3H) (M + H) + = 458.9 A 氺 * 氺 451.2 -(4-Fluoro-phenyl) -6-{[2- (4-fluoro-phenyl) -2-hydroxy-ethyl] -methyl-fe continuous group-amino group} · 5- Benzene-3 -metanoic acid-formamidine * H NMR in DMSO: 10.03 (brs, 1H); 8.42 (brd, 1H, J = 4.69Hz); 7.94 (m, 2H); 7.38 (t, 2H, J = 8.79Hz); 7.32 (m, 3H); 7.13 (m, 3H); 5.58 (m, 1H); 4.62 (m, 1H); 3.70 (brm, 2H); 3.01 (s, 3H); 2.82 ( d, 3H, J = 4.10Hz) (MH) '= 515 A 氺 本 氺 45. 5-methoxy-ί-phenyl-benzofuran-3-fatty acid-formamidine 氺 氺 氺 氺 氺 氺A < 10 _ "453. 5-Hydroxy-2-phenyl-benzofuran-3-¾ acid-formamidine 氺 氺 氺 氺 氺 氺 C 氺 氺 氺 * Unless otherwise stated, all NMR and The 13C NMR spectra were all obtained through a Varian Mercury VX 300 spectrometer, with TMS as the reference index. ** Mass spectrum data is expressed by the mass-to-charge ratio of molecular ion of (M-Η) unless it is (M + H). * * * Show data not collected. 228-88828.doc 200418452 Table 3. Pharmaceutically acceptable salts of the selective compounds listed in Table 1. , _ Number 454.
Structure 名稱 NMR Data* h3c—S〇2、n- CH, h3c/\Structure Name NMR Data * h3c—S〇2, n- CH, h3c / \
κ. 2_(4_氟基-苯基)-5- 異丙氧基-6-甲烷 磺醯基胺基-苯并 呋喃-3-羧酸-甲醯 胺;鉀鹽 Ή NMR in DMSO 8.18-8.15 (br m, 1H); 7.87-7.81 (m, 2H); 7.28- 7.22 (1¾ 2H); 6.77 (s,lH); 4.57 (sept. J= 6.45 Hz, 1H); 2.78 (cU=4.7Hz, 3H); 2.55 (s, 3H); 1.18 (d, J=5.86 Hz, 6H) 455. CH,κ. 2_ (4-fluoro-phenyl) -5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid-formamidine; potassium salt Ή in DMSO 8.18- 8.15 (br m, 1H); 7.87-7.81 (m, 2H); 7.28- 7.22 (1¾ 2H); 6.77 (s, lH); 4.57 (sept. J = 6.45 Hz, 1H); 2.78 (cU = 4.7Hz , 3H); 2.55 (s, 3H); 1.18 (d, J = 5.86 Hz, 6H) 455. CH,
2_(4_氟基-苯基)-5- 異丙氧基-6-甲烷 續醯塞胺基-苯并 呋喃-3-羧酸-甲醯 胺;鈉鹽2_ (4-Fluoro-phenyl) -5-isopropoxy-6-methane Continued-Acetylenyl-benzofuran-3-carboxylic acid-formamidine; sodium salt
lH NMR in DMSO 8.18-8.15 (br nou 1H); 7.87-7.81 (m, 2H); 7.28-7.22 (m, 2H); 6.77 (s,lH); 4.57 (sept. J= 6.45 Hz, 1H); 2.78 (d,J=4.7Hz, 3H); 2.55 (s,3H); U8 (d, J=5.86 Hz, 6H) 456.lH NMR in DMSO 8.18-8.15 (br nou 1H); 7.87-7.81 (m, 2H); 7.28-7.22 (m, 2H); 6.77 (s, lH); 4.57 (sept. J = 6.45 Hz, 1H); 2.78 (d, J = 4.7Hz, 3H); 2.55 (s, 3H); U8 (d, J = 5.86 Hz, 6H) 456.
2-(4-氟基-苯基)-6- 曱烷磺醯基胺基 -5-甲氧基-苯并呋 喃-3-羧酸-甲醯胺 ;鉀鹽 88828.doc 229- 2004184522- (4-Fluoro-phenyl) -6-pyranesulfonylamino-5-methoxy-benzofuran-3-carboxylic acid-formamidine; potassium salt 88828.doc 229- 200418452
88828.doc 230- 20041845288828.doc 230- 200418452
* 除非另有說明,否則所有的4 NMR與13C NMR光譜皆是 經由Varian Mercury VX 300分光儀取得,並以四甲基石夕虎 (TMS)為參考指標。化學轉移與偶合常數分別皆以百萬分之 一(ppm)與赫茲(Hz)表示。 實例464 病毒RNA複製之抑制 首先在含HCV複製子(BB7序列)之人類肝臟衍生之細胞 株(Huh-7-Clone A)進行本發明代表性化合物之抗病毒活性 評估(參照 Lohmann等人· Science. 1999,285 : 110,3; Blight KJ等人·,Science· 2000, 290: 1972-4; Pietschmann,Τ·等人·,J. Virol. 2001,73 : 1252-1264 ;與 Lohmann,V.等人·,J· Virol· 2001,75 ·· 1437-1449)。HCV複製子為表現其複製所需之HCV 蛋白質之次基因體病毒RNA。這些蛋白包括非結構性蛋白 NS3、NS4A、NS4B、NS5A與NS5B。該複製子亦包含編碼 88828.doc -231 - 200418452 藥物選取標示者(新黴素磷酸轉移酶)之外來基因,以允許 G41 8 (新黴素)之選取包含複製子的細胞。 將含複製子之細胞保溫於不同化合物濃度72小時後,使 用ELISA (酶連接之免疫吸附分析)決定本發明範疇内之化 合物對HCV NS5A蛋白產量之效果。使用COSTAR® 96槽細 胞培養盤,但亦可使用其他已知之細胞培養盤。保溫後, 由槽中去除培養液,並利用0.05%戊二醛將細胞固定於分析 盤。經1小時保溫,然後,利用磷酸緩衝鹽液(PBS)洗掉戊 二醛;並利用例如SUPERBLOCK®試劑(阻斷緩衝液)之PBS 溶液阻斷非專一性之抗體結合。經37°C、1小時後,以PBS 將阻斷劑由細胞潤濕掉,並將初級單株抗體加入每個含化 合物之槽中。將初級抗體保溫於37°C、1小時,並於添加山 葵過氧化酶(HRP)共輛之二級抗體前,以含0.02%吐溫-20tm 之PBS潤濕3次。將HRP保溫於37X:、1小時並潤濕數次,首 先是以PBS/吐溫-20TM,隨之為單獨之PBS。為定量過氧化 酶活性,將3,3’,5,5’-四甲基對二胺基聯苯(TMB)受質加入培 養盤,而且經30分鐘後,於ELISA培養盤讀取機中以OD 650 nm讀取培養盤。以系列稀釋之8點的劑量曲線測定化合物之 劑量反應,決定50%之抑制濃度(EC5G值)。本發明之代表性 化合物顯示細胞内之NS5A量之劑量依賴型抑制。表2所列 為本發明範疇内代表性化合物之50%有效濃度之範圍 (EC5Gs)。較佳化合物之50%有效濃度範圍為約30微莫耳濃度 或更低,更佳化合物之50%有效濃度範圍為約5微莫耳濃度 或更低,至於最佳化合物之50%有效濃度範圍為約0.5微莫 88828.doc -232 - 200418452 耳濃度或更低。 實例465 病毒RNA依賴型RNA聚合酶(RdRp)之抑制 HCV NS5B針對性RdRp活性,係利用衍生自經HCV基因型 lb病毒(BB7)感染之病患之共識序列之純的HCV NS5B蛋白 之標準活體外生化分析所建立,並定其特徵。(請參照Blight KJ 等人·,Science· 2000, 290 : 1972-4)。該 NS5B 共識序列係 經選殖並在大腸桿菌(E. coli)中以組胺酸標識 (GSHHHHHH)之融合蛋白型式表現;其中,去除羧基端之 21個胺基酸以增加溶解度。 除了在複製子分析中評估其活性之外,亦利用此分析評 估如前述表中之實例1-453所示之本發明範疇内之代表性 化合物之抗病毒活性。本發明化合物之抑制活性測定可表 現為IC5G值。IC5G值代表RdRp受到50%抑制時之化合物濃度 。由HCV之RdRp活性抑制分析之結果,NS5B蛋白為受測化 合物之實質多數之結果透露,IC5〇值範圍為由<0.5至約30微 莫耳濃度。這些達成50% RdRp抑制所需要之受測化合物之 低濃度顯示,本發明化合物可有效抑制藉由病毒之RdRp酶 之RNA合成。 儘管本發明已經藉較佳之具體實施例加以說明與例示, 對熟諳此藝者而言,其他具體實施例也會很清楚。因而, 本發明並不侷限於說明與例示之特定之具體實施例;而且 ,能做不偏離本發明精神之修飾或變化,其全部範疇是由 附屬之專利申請範圍所解構。 88828.doc - 233 -* Unless otherwise stated, all 4 NMR and 13C NMR spectra were obtained using a Varian Mercury VX 300 spectrometer, with TMS as the reference index. Chemical transfer and coupling constants are expressed in parts per million (ppm) and hertz (Hz), respectively. Example 464 Inhibition of viral RNA replication First, the antiviral activity of a representative compound of the present invention was evaluated in a human liver-derived cell line (Huh-7-Clone A) containing HCV replicon (BB7 sequence) (see Lohmann et al. Science 1999, 285: 110, 3; Blight KJ et al., Science 2000, 290: 1972-4; Pietschmann, T. et al., J. Virol. 2001, 73: 1252-1264; and Lohmann, V. Et al., J. Virol. 2001, 75. 1437-1449). The HCV replicon is a sub-viral viral RNA expressing the HCV protein required for its replication. These proteins include the non-structural proteins NS3, NS4A, NS4B, NS5A and NS5B. The replicon also contains foreign genes encoding 88828.doc -231-200418452 drug selection marker (neomycin phosphotransferase) to allow G41 8 (neomycin) to select cells containing replicons. After incubating replicon-containing cells at different compound concentrations for 72 hours, ELISA (enzyme-linked immunosorbent analysis) was used to determine the effect of compounds within the scope of the present invention on HCV NS5A protein production. COSTAR® 96-well cell culture plates are used, but other known cell culture plates can also be used. After incubation, the culture medium was removed from the tank, and the cells were fixed to the analysis plate with 0.05% glutaraldehyde. After 1 hour incubation, glutaraldehyde is washed off with phosphate buffered saline (PBS); non-specific antibody binding is blocked with a PBS solution such as SUPERBLOCK® reagent (blocking buffer). After 1 hour at 37 ° C, the blocking agent was wetted from the cells with PBS, and the primary monoclonal antibody was added to each compound-containing tank. Incubate the primary antibody at 37 ° C for 1 hour, and moisten it 3 times with PBS containing 0.02% Tween-20tm before adding secondary antibodies of wasabi peroxidase (HRP). HRP was incubated at 37X: for 1 hour and moistened several times, first with PBS / Tween-20TM, followed by PBS alone. In order to quantify peroxidase activity, 3,3 ', 5,5'-tetramethyl-p-diaminobiphenyl (TMB) was added to the culture plate, and after 30 minutes, it was read in an ELISA plate reader. The plate was read at OD 650 nm. The dose response of the compound was determined using a series of 8-dose dose curves to determine the 50% inhibitory concentration (EC5G value). A representative compound of the present invention shows a dose-dependent inhibition of the amount of NS5A in a cell. Table 2 shows the 50% effective concentration range (EC5Gs) of representative compounds within the scope of the present invention. The 50% effective concentration range of the preferred compound is about 30 micromoles or less, and the 50% effective concentration range of the better compound is about 5 micromoles or less, and the 50% effective concentration range of the best compound The ear concentration is about 0.5 μmol 88828.doc -232-200418452 or lower. Example 465 Inhibition of HCV NS5B targeted RdRp activity by viral RNA-dependent RNA polymerase (RdRp), a standard living organism using pure HCV NS5B protein derived from consensus sequences of patients infected with HCV genotype lb virus (BB7) Exochemical analysis is established and its characteristics are determined. (See Blight KJ et al., Science 2000, 290: 1972-4). The NS5B consensus sequence was selected and expressed in the form of a histidine tag (GSHHHHHH) fusion protein in E. coli; among them, the 21 amino acids at the carboxyl terminus were removed to increase solubility. In addition to evaluating its activity in a replicon analysis, this analysis was also used to evaluate the antiviral activity of a representative compound within the scope of the present invention as shown in Examples 1-453 in the foregoing table. The inhibitory activity of the compounds of the present invention can be measured as an IC5G value. The IC5G value represents the concentration of the compound when RdRp is inhibited by 50%. As a result of the analysis of the inhibition of RdRp activity of HCV, the result that NS5B protein is a substantial majority of the tested compounds revealed that the IC50 value ranges from < 0.5 to about 30 micromolar concentration. The low concentration of these test compounds required to achieve 50% RdRp inhibition shows that the compounds of the present invention are effective in inhibiting RNA synthesis by the viral RdRp enzyme. Although the present invention has been illustrated and exemplified by preferred embodiments, other embodiments will be clear to those skilled in the art. Therefore, the present invention is not limited to the specific specific embodiments described and exemplified; moreover, modifications or changes can be made without departing from the spirit of the present invention, and its entire scope is deconstructed by the scope of the attached patent application. 88828.doc-233-
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42329102P | 2002-11-01 | 2002-11-01 | |
US46107703P | 2003-04-08 | 2003-04-08 | |
US48906003P | 2003-07-21 | 2003-07-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW200418452A true TW200418452A (en) | 2004-10-01 |
Family
ID=38812836
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW92130711A TW200418452A (en) | 2002-11-01 | 2003-11-03 | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR041733A1 (en) |
PA (1) | PA8587401A1 (en) |
PE (1) | PE20040901A1 (en) |
TW (1) | TW200418452A (en) |
UY (1) | UY28054A1 (en) |
-
2003
- 2003-10-31 PE PE2003001102A patent/PE20040901A1/en not_active Application Discontinuation
- 2003-10-31 AR ARP030103993 patent/AR041733A1/en not_active Application Discontinuation
- 2003-10-31 UY UY28054A patent/UY28054A1/en not_active Application Discontinuation
- 2003-10-31 PA PA8587401A patent/PA8587401A1/en unknown
- 2003-11-03 TW TW92130711A patent/TW200418452A/en unknown
Also Published As
Publication number | Publication date |
---|---|
UY28054A1 (en) | 2004-06-30 |
PA8587401A1 (en) | 2005-02-04 |
PE20040901A1 (en) | 2004-12-10 |
AR041733A1 (en) | 2005-05-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7265152B2 (en) | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases | |
CA2787121C (en) | Aminopyridine derivatives as anti-malarial agents | |
JP6140170B2 (en) | Substituted benzylindazoles for use as BUB1 kinase inhibitors in the treatment of hyperproliferative diseases | |
TWI246510B (en) | Thiazolidine derivatives and pharmaceutical uses thereof | |
CN103588704B (en) | Inhibitors of focal adhesion kinase | |
JP5782377B2 (en) | Compounds that regulate intracellular calcium | |
US7994171B2 (en) | Compounds for the treatment of hepatitis C | |
JP5685191B2 (en) | Compounds for the treatment of hepatitis C | |
JP2019055964A (en) | Compounds that modulate intracellular calcium | |
JP5623289B2 (en) | Viral polymerase inhibitor | |
TW200808775A (en) | Fused phenyl amido heterocyclic compounds | |
WO2006088246A1 (en) | Agent for controlling function of gpr34 receptor | |
WO2019101086A1 (en) | Halo-allylamine ssao/vap-1 inhibitor and use thereof | |
JP6619333B2 (en) | Heterocyclic derivatives and uses thereof | |
CN102300862A (en) | Pyrazine Derivatives Useful As Inhibitors Of Atr Kinase | |
JP2013522192A (en) | Compounds for the treatment of hepatitis C | |
TW200815423A (en) | Hetero compound | |
WO2013170774A1 (en) | Acetylene derivative having antineoplastic activity | |
JP2022508751A (en) | PFKFB3 Inhibitors and Their Use | |
WO2010037210A1 (en) | Viral polymerase inhibitors | |
JP2010535156A (en) | Viral polymerase inhibitor | |
JP2018509401A (en) | Novel compounds for the treatment of hepatitis C | |
TW200418452A (en) | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases | |
CN116406359A (en) | Bicyclo [1.1.1] pentanes for the treatment and prevention of hepatitis B virus infection | |
WO2022180003A1 (en) | Benzothiazolyl bicyclo[1.1.1]pentane derivatives for the treatment and prophylaxis of hepatitis b virus infection |