TW201247656A

TW201247656A - 2,3,5-trisubstituted thiophene compounds and uses thereof

Info

Publication number: TW201247656A
Application number: TW100146704A
Authority: TW
Inventors: David Barnes; Scott Louis Cohen; ji-ping Fu; Lei Shu; Rui Zheng
Original assignee: Novartis Ag
Priority date: 2010-12-15
Filing date: 2011-12-15
Publication date: 2012-12-01

Abstract

The present invention provides a compound of formula I: a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

201247656 六、發明說明：【發明所屬之技術領域】本發明揭示化合物及組合物、其製備方法及其用於治療患者之至少部分由黃病毒科中之病毒介導之病毒感染的方 .法。【先前技術】慢性HCV感染為與肝硬化、肝細胞癌及肝衰竭相關的主要健康問題。估計全世界範圍内有1.7億慢性帶菌者 (chronic carrier)正處在產生肝病之風險中（Szabo, E.等人， Pathol.Oncol.Res. 2003, 9:215-221 Hoofnagle J.H., Hepatology 1997，26:15S-20S)。僅在美國，就有270萬人慢性感染hcv，且在2000年，估計與HCV相關的死亡人數在8,〇〇〇與1〇〇〇〇之間’預期此數字將逐年顯著增加。HCV感染在較高比例之慢性感染（及傳染性）攜帶者體内潛伏，該等攜帶者可能在許多年裏不會經歷臨床症狀。肝硬化最終會導致肝衰竭。現公認由慢性HCV感染所引起的肝衰竭為進行肝移植之主導原因。 HCV為侵襲動物及人類之RNA病毒之黃病毒科(F/aWWnWae family)的成員。基因組為具有約9600個鹼基之單股RNA，且由一個在5'端與3·端側接非轉譯區（5，_UTr及3，_UTR)之編碼具有約3000個胺基酸之聚合蛋白質的開放閱讀框架組成。該聚合蛋白質充當至少10種對於子代病毒粒子之複製及組裝關鍵的各別病毒蛋白之前驅體。HCV聚合蛋白質中結構蛋白質與非結構蛋白質的構成如下：C-El-E2-p7- 160983.doc 201247656 NS2-NS3-NS4a-NS4b-NS5a-NS5b。因為HCV之複製週期不涉及任何DNA中間物且病毒並不整合至宿主基因組中，所以在理論上HCV感染可以治癒。目前，對於慢性HCV之標準治療為聚乙二醇化干擾素α (IFN-α)與病毒唑（ribavirin)之組合，且此需要治療至少六 (6)個月。IFN-α屬於具有諸如抗病毒、免疫調節及抗腫瘤活性之特徵性生物作用的天然存在之小蛋白質家族，該等天然存在之小蛋白質係由大部分動物有核細胞對若干種疾病、尤其是病毒感染起反應而產生及分泌。IFN_a為影響細胞通訊及免疫控制之重要的生長及分化調節劑。用干擾素治療HCV通常產生不良副作用，諸如疲乏、發熱、寒戰、頭痛、肌痛、關節痛、輕度脫髮、精神病作用及相關病症、自體免疫現象及相關病症及曱狀腺功能障礙❶病毒唑（一種肌苷5，-單磷酸去氫酶（IMPDH)抑制劑）增強IFN-a在 HCV治療中之功效。儘管引入病毒嗤，但超過5〇〇/()之患者仍未因干擾素-a(IFN)及病毒唑之當前標準療法而消除病毒。至今’已將慢性C型肝炎之標準療法改成聚乙二醇化 IFN-a加病毒唑之組合。然而，許多患者仍有顯著副作用，該等副作用主要與病毒"坐有關。病毒峻在1 〇_20%經當前推薦劑量治療之患者體内引起顯著的溶血作用，且該藥物具有致畸性與胚胎毒性。儘管近來有改善，但大部分患者對於持續減少的病毒負荷無反應且明確需要HCV感染之更有效的抗病毒療法（Fried，M.W.等人，见£„g/. J Med 2002, 347:975-982)。 160983.doc 201247656 正在尋求多種方法以對抗病毒。此等方法包括例如應用反義寡核苷酸或核糖核酸酶以抑制HCV複製。此外，認為直接抑制HCV蛋白且干擾病毒複製之低分子量化合物為引人關注的控制HCV感染之策略。在病毒標靶中，認為 NS3/4a蛋白酶及NS5b RNA依賴性RNA聚合酶為新藥最具前景之病毒標乾（參見 Ni，Z. J.及 Wagman，A. S. Cwrr.201247656 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention discloses compounds and compositions, methods for their preparation, and methods for treating at least a portion of a viral infection mediated by a virus in the Flaviviridae family. [Prior Art] Chronic HCV infection is a major health problem associated with cirrhosis, hepatocellular carcinoma, and liver failure. It is estimated that 170 million chronic carriers worldwide are at risk of developing liver disease (Szabo, E. et al., Pathol. Oncol. Res. 2003, 9:215-221 Hoofnagle JH, Hepatology 1997, 26:15S-20S). In the United States alone, 2.7 million people are chronically infected with hcv, and in 2000, the estimated number of deaths associated with HCV was between 8, 〇〇〇 and 1〇〇〇〇. This number is expected to increase significantly year by year. HCV infection is lurking in a higher proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. Cirrhosis eventually leads to liver failure. It is now recognized that liver failure caused by chronic HCV infection is the leading cause of liver transplantation. HCV is a member of the F/aWWnWae family of RNA viruses that invade animals and humans. The genome is a single-stranded RNA of approximately 9600 bases and is encoded by a non-translated region (5, _UTr and 3, _UTR) flanked by 5' and 3' ends with a polymeric protein of approximately 3000 amino acids. The composition of the open reading frame. The polymeric protein acts as a precursor to at least 10 individual viral proteins that are critical for replication and assembly of progeny virions. The structure of structural and non-structural proteins in HCV polymeric proteins is as follows: C-El-E2-p7-160983.doc 201247656 NS2-NS3-NS4a-NS4b-NS5a-NS5b. Since the replication cycle of HCV does not involve any DNA intermediates and the virus does not integrate into the host genome, in theory HCV infection can be cured. Currently, the standard treatment for chronic HCV is a combination of pegylated interferon alpha (IFN-alpha) and ribavirin, and this requires treatment for at least six (6) months. IFN-α belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunomodulatory and antitumor activities, which are derived from most animal nucleated cells against several diseases, especially Viral infections are produced and secreted in response. IFN_a is an important growth and differentiation regulator that affects cell communication and immune control. Treatment of HCV with interferon usually produces adverse side effects such as fatigue, fever, chills, headache, myalgia, joint pain, mild hair loss, psychosis and related conditions, autoimmune and related disorders, and sputum dysfunction prion Azole, an inosine 5,-monophosphate dehydrogenase (IMPDH) inhibitor, enhances the efficacy of IFN-a in the treatment of HCV. Despite the introduction of viral sputum, patients over 5 〇〇/() have not eliminated the disease due to current standard therapies for interferon-a (IFN) and ribavirin. To date, the standard therapy for chronic hepatitis C has been changed to a combination of pegylated IFN-a plus ribavirin. However, many patients still have significant side effects, which are primarily related to the virus" sit. The virus causes significant hemolysis in 1 〇 -20% of patients who are currently recommended for dose therapy, and the drug is teratogenic and embryotoxic. Despite recent improvements, most patients do not respond to a continuously reduced viral load and are more aware of the need for more effective antiviral therapy for HCV infection (Fried, MW et al., see „g/. J Med 2002, 347:975- 982). 160983.doc 201247656 A variety of methods are being sought to combat viruses. Such methods include, for example, the use of antisense oligonucleotides or ribonucleases to inhibit HCV replication. Furthermore, low molecular weight that directly inhibits HCV protein and interferes with viral replication is believed to be involved. Compounds are an interesting strategy for controlling HCV infection. In viral targets, NS3/4a protease and NS5b RNA-dependent RNA polymerase are considered to be the most promising viral stems for new drugs (see Ni, ZJ and Wagman, AS Cwrr). .

Drwg Dbcov. Deve/. 2004，7, 446-459 ; Beaulieu, P. L.及 Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850 i ^.Griffith, R. C.^ A * Ann. Rep. Med. Chem 39, 223-237，2004)。然而，此等化合物中無一者進展至臨床試驗以後。鑒於HCV及黃病毒科其他成員在全世界範圍内之流行程度，且進一步鑒於有限的治療選擇，迫切需要用於治療由此等病毒所引起之感染的新穎有效藥物。【發明内容】在第一實施例中，本發明提供式（I)化合物、其組合物及使用其來治療病毒感染之方法。詳言之，如由式（I)所定義之本發明化合物適用於治療或預防C型肝炎病毒感染及與 HCV感染有關或由其引起之疾病。式（I)化合物之結構如下：Drwg Dbcov. Deve/. 2004, 7, 446-459 ; Beaulieu, PL and Tsantrizos, YS Curr. Opin. Investig. Drugs 2004, 5, 838-850 i ^.Griffith, RC^ A * Ann. Rep. Med. Chem 39, 223-237, 2004). However, none of these compounds progressed beyond clinical trials. In view of the worldwide mobility of other members of the HCV and Flaviviridae, and further in view of the limited treatment options, there is an urgent need for novel and effective drugs for the treatment of infections caused by such viruses. SUMMARY OF THE INVENTION In a first embodiment, the present invention provides a compound of formula (I), a composition thereof, and a method of using the same to treat a viral infection. In particular, the compounds of the invention as defined by formula (I) are useful for the treatment or prevention of hepatitis C virus infection and diseases associated with or caused by HCV infection. The structure of the compound of formula (I) is as follows:

160983.doc 201247656 式（I)中存在之變數的定義在下文中除非另外說明，否則;^ 4 r 貝]術§吾「本發明化合物」係指式（I)及其子式之t合物(必要時増加其他額外種類結構)、立前樂、化合物及/或前藥之鹽、化合物之水合物或溶劑合物、鹽及/或前藥以及所有立體異構體(包括非對映異構體及對映異構體）、互變異構體及經同位素標記之化合物（包括氘取代）’以及固有形成部分(例如多晶型物、溶劑合物及/或水合物）。在個貫施例中，提供一種醫藥組合物，其包含醫藥學上可接受之載劑及治療有效量之式⑴化合物。在其他實施例中，提供製備式⑴化合物及其組合物之方法及其治療用途。在一個實施例中，提供一種治療患者之至少部分由黃病毒科中之病毒介導之病毒感染的方法，其包含向該患者投與包含式⑴化合物或鹽之組合物。在一些態樣中，病毒感染係由c型肝炎病毒介導。160983.doc 201247656 The definition of the variables present in formula (I) is hereinafter unless otherwise stated; ^ 4 r ] § § ""The compound of the invention" refers to the compound of formula (I) and its subforms ( Addition of other additional types of structures, if necessary, to the salts of the compounds and/or prodrugs, hydrates or solvates of the compounds, salts and/or prodrugs, and all stereoisomers (including diastereoisomers) And enantiomers), tautomers and isotopically labeled compounds (including deuterium substitutions) and intrinsic forming moieties (eg polymorphs, solvates and/or hydrates). In a single embodiment, a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (1) is provided. In other embodiments, methods of preparing compounds of formula (1), compositions thereof, and therapeutic uses thereof are provided. In one embodiment, a method of treating a viral infection mediated by a virus in at least a portion of a Flaviviridae patient is provided, comprising administering to the patient a composition comprising a compound or salt of formula (1). In some aspects, viral infection is mediated by hepatitis C virus.

式（I)化合物包括其鹽定義。本發明之此等及其他實施例進一步描述於以下正文中。【實施方式】在本申清案中’提及關於化合物、組合物及方法之多個實施例。所述之多個實施例意欲提供多個說明性實例且不應理解為對替代物質之描述。實際上，應注意本文中所提供之多個實施例之描述可具有重疊範疇。本文中所討論之實施例僅為說明性且並不意欲限制本發明之範疇。為了解釋本說明書之目的，將應用以下定義，且只要適 160983.doc 201247656 當時’以單數使用之術語亦將包括複數，且反之亦然。 —如本文所用，術語「烧基」係、指具有至多20個碳原子之完全飽和分支鍵或未分支鍵煙部分。除非另外說明，否則烷基係指具有1至16個碳原子、1至1〇個碳原子、⑴個碳原子或1至4個碳原子之烴部分。院基之代表性實例包括 (但不限於)甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基3 f基己基、22_二甲基戊基、2,3二甲基戊基正庚基、正辛基、正壬基、正癸基及類似基團。如本文所用，術語「伸烷基」係指具有i至2〇個碳原子的如本文所疋義之二價烧基。其包含【至個碳原子，除非另外說明，否則伸烷基係指具有丨至16個碳原子' 丨至⑺ 個碳原子、1至7個碳原子或1至4個碳原子之部分。伸烷基之代表性實例包括（但不限於）亞甲基、伸乙基、伸正丙基、伸異丙基、伸正丁基、伸第二丁基、伸異丁基、伸第三丁基、伸正戊基、伸異戊基、伸新戊基、伸正己基、3_ 甲基伸己基、2,2-二甲基伸戊基' 2,3-二甲基伸戊基、伸正庚基、伸正辛基、伸正壬基、伸正癸基及其類似基團。如本文所用，術語「鹵烷基」係指如本文中所定義之烷基經一或多個如本文中所定義之齒基取代。齒烷基可為單函烧基、二函炫基或多鹵院基，包括全鹵烧基。單齒烧基可在烧基内具有一個碘、溴、氣或氟。二鹵烷基及多鹵烷基可在烧基内具有兩個或兩個以上相同鹵原子或不同鹵基之組合。多鹵烷基通常含有至多12個，或1〇個，或8個， 160983.doc 201247656 或4個，或3個或2個鹵基。鹵烷基之非限制性實例包括氟甲基、二氟甲基、三氟甲基、氣曱基、二氯甲基、一氣曱基、五氟乙基、七氟丙基、二氟氣甲基、二氯氟曱土氟乙基、二氟丙基、二氣乙基及二氣丙基。全鹵烷基係指所有氫原子皆㈣基原子取代之烧基。術'•吾芳基」係指在環部分中具有6-20個碳原子之芳族烴基。芳基通常為具有6_2〇個碳原子之單環、雙環或三環芳基。〈此外，如本文所用’術語「芳基」係指可為單芳環或多個稠合在一起之芳環的芳族取代基。非限制實例包括苯基、萘基或四氫萘基，其各自可視情況經1-4個諸如以下取代基取代：烷基、三氟曱基環烷基、鹵素、羥基 '烷氧基、醯基、烷基_c(〇)_〇_、芳基-Ο-、雜芳基、胺基、硫醇、烷基_s_、芳基_s_、硝基、氰基、羧基、烷基_〇_c(0)_、胺甲醯基、烷基_s(〇)_ 、磺醯基、磺醯胺基、笨基及雜環基。如本文所用，術語「烷氧基」係指烷基·〇_，其中烷基在上文中疋義。烷氧基之代表性實例包括（但不限於）甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、第三丁氧基、戊氧基、己氧基、環丙氧基_、環己氧基_及類似基團。烷氧基通常具有約1 -7個碳，更佳約1 _4個碳。如本文所用’術語「雜環基（heterocyclyl)」或「雜環 (heterocyclo)」係指飽和或不飽和非芳環或環系統，例如其為4員、5員、6員或7員單環；6員、7員、8員、9員、10 160983.doc •9- 201247656 員、Π員或12員雙環；或10員、u員、12員、13員、14員或15員二環系統，且含有至少一個選自〇、s&N之雜原子，其中N及S亦可視情況氧化成各種氧化態。雜環基可連接於雜原子或碳原子處。雜環基可包括稠環或橋聯環以及螺環。雜環之實例包括四氫呋喃（THF)、二氫呋喃、1，4_二噁烷、嗎啉、1，4-二噻咄、哌嗪、哌啶、i，3•二氧雜環戊院、味嗤咬、咪嗤啭、吼略琳、吼洛咬、四氣娘喃、二氮哌喃、氧硫雜環戊烷、二硫雜環戊烷、丨，3_二噁烷、〗3_ 二噻咄、噁噻咄及硫代嗎啉。術語「雜環基」另外係指經1至5個獨立地〜碾自由以下組成之群的取代基取代之如本文中所定義之雜環基 (a) 烧基； (b) 羥基（或受保護羥基）； (c) 鹵基； (d) 側氧基，亦即=〇 ; (e) 胺基、烷基胺基或二烷基胺基； (f) 烷氧基； (g) 環烷基； (h) 羧基； ⑴雜環氧基’其中雜環氧基表示經由氧橋鍵結之雜環基； ’ (j) 烷基-O-C(o)- ·， (k) 巯基； (l) 醯胺基或曱醯胺基； 160983.doc -10 - 201247656 (m) 氰基； (n) 胺磺醯基、磺胺基或磺醯胺基； (〇)芳基； (Ρ)烷基_c(o)-o-; (q) 芳基-C(0)-0-; (r) 芳基-S·; (s) 芳氧基； ⑴烷基-S-; φ (u)曱醯基，亦即HC(O)-; (v) 胺甲醯基； (w) 芳基-疼基-;及 (X)經烷基、環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH· 、烷基胺基、二烷基胺基或素取代之芳基； (y)經環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH·、烧基胺基、二烷基胺基或齒素取代之烷基。如本文所用，術語「環烧基」係指具有3-12個碳原子之籲飽和或不飽和單環、雙環或三環烴基。除非另外說明，否則環烷基係指具有3至9個環碳原子或3至7個環碳原子之環烴基，其各自可視情況經1個或2個或3個或3個以上獨立地選自由以下組成之群的取代基取代：烷基、齒基、側氧基、羥基、烷氧基、烷基-C(O)-、醯胺基、胺曱醯基、院基-NH-、（烧基）2N-、硫醇、烧基-S-、硝’基、氰基、緩基、烷基-O-C(O)-、磺醯基、磺醯胺基、胺磺醯基、續胺基及雜環基。例示性單環烴基包括（但不限於）環丙基、環 160983.doc • 11 · 201247656 丁基、環戊基、環戊烯基、環己基及環己烯基及其類似基團。例示性雙環烴基包括莰基、吲哚基、六氫吲哚基、四氫萘基、十氫萘基、雙環[2.1.1]己基、雙環[2.2」]庚基、雙環[2.2.1]庚烯基、6,6_二甲基雙環[3」庚基、2，M-三曱基雙環[3.1 _1]庚基、雙環[2 2 2]辛基及其類似基團。例示性三環烴基包括金剛烷基及其類似基團。如本文所用，術語「芳氧基」係指芳基與雜芳基’其中芳基及雜芳基在本文中經定義。如本文所用，術語「雜芳基」係指具有丨至8個選自N、〇或S之雜原子的5_14員單環或雙環或三環芳環系統。雜芳基通常為5-10員環系統（例如5_7員單環或8_1〇員雙環）或5_7 員環系統。典型雜芳基包括2_噻吩基或3噻吩基、呋喃基或3-呋喃基、2-吡咯基或3_吡咯基、2_咪唑基、4咪唑基或5-咪唑基、3_吡唑基、4_吡唑基或5吡唑基、2_噻唑基、4-噻唑基或5_噻唑基、3_異噻唑基、4_異噻唑基或5_ 異噻唑基、2-噁唑基、4-噁唑基或5·噁唑基、3_異噁唑基' 4-異噁唑基或5_異噁唑基、3切_***基或“从二唑基、4-1，2,3-***基或5-1，2,3-***基、四唑基、孓吡啶基、3-«•比啶基或4_„比啶基、3·噠嗪基或4_噠嗪基、3·吼嗪基、4-吼嗪基或5_扯嗪基、2_π比嗪基，及2_嘴啶基、心喊咬基或5 -嘴。定基。術語「雜芳基」亦指雜芳環與一或多個芳基、環脂族或雜環基環稠合之基團，其中該基團或連接點位於雜芳環上。非限制性實例包括^弓卜朵嗪基、2令朵嗪基、3“引哚 160983.doc 201247656 嗪基、5-吲哚嗪基、6·吲哚嗪基、7_吲哚嗪基或8_吲哚嗪基、1-異吲哚基、3-異吲哚基、4-異吲哚基、5_異吲哚基、6-異弓丨哚基或7·異吲哚基、2_吲哚基、3·吲哚基、4_ "引°木基、5-吲哚基、6_吲哚基或7_吲哚基、2_吲唑基、％吲°坐基、4-吲唑基、5·吲唑基、6_吲唑基或7-吲唾基、嘌呤基、4-嘌呤基、5_嘌呤基、6_嘌呤基、、嘌呤基或8_ 嘌呤基、1-喹嗪基、2_喹嗪基、3_喹嗪基、4_喹嗪基、6_ 喧嗪基、7-喹嗪基、8_喹嗪基或9_喹嗪基、2_喹啉基、％喹啉基、4-喹琳基、5_喹啉基、6_喹啉基、7_喹啉基或8_ 啥琳基、1-異啥琳基、3-異喧淋基、4-異喧琳基、5-異喹啉基、6-異喹啉基、7_異喹啉基或8_異喹啉基、丨酞嗪基、4-酞嗪基、5-酞嗪基、6-酞嗪基、7-酞嗪基或酞嗪基、2-嗱啶基、3-嗉啶基、4-嗱啶基、5-喑啶基或6-嗉啶基、2-噎嗤琳基、3-噎嗤淋基、5-喧唾琳基、6-啥峻琳基、7-嗜唾淋基或8-啥唾琳基、3-吟琳基、4-吟琳基、5-吟琳基、6-吟琳基、7-碎琳基或8-吟琳基、2-嗓。定基、4_ 喋啶基、6-喋啶基或7-喋啶基、l-4aH咔唑基、2-4aH#。坐基、3-4aH咔吐基、4-4aH咔唾基、5-4aH咔唑基、6-4aH味唑基、7-4aH咔唑基或8-4aH咔唑基、1-咔唑基、2·味嗤基、3-咔唑基、4-咔唑基、5-咔唑基、6-咔唑基、7-»卡唑基或8-咔唑基、1-咔琳基、3-咔淋基、4-咔琳基、5-味琳基、6-咔啉基、7-咔啉基、8-咔啉基或9-咔琳基、1_徘咬基、2-°扑°定基、3-啡°定基、4-°非°定基、咬基、7-啡咬基、8-啡啶基、9-啡啶基或10-啡啶基、1-吖啶基、2_。丫咬 160983.doc -13- 201247656 基、3-吖啶基、4-吖啶基、5-吖啶基、6-吖啶基、7-n丫唆基、8-吖啶基或9-吖啶基、1-咂啶基、2-呕啶基、4-喂。定基、5-呕啶基、6-咂咬基、7-呕啶基、8-呕啶基或9-啦咬基、2-啡啉基、3-啡啉基、4-啡啉基、5-啡啉基、6-啡琳基、8-啡啉基、9-啡啉基或10-啡啉基、丨_啡嗪基、2_啡嘻基、3-啡嗪基、4-啡嗪基、6-啡嗪基、7_啡嗪基、8_啡嘻基或9-啡嗪基、1 ·啡噻嗪基、2-啡噻嗪基、3_啡噻嗪基、 4-啡噻嗪基、6-啡噻嗪基、7-啡噻嗪基、8_啡噻嗪基、9_ 啡噻嗪基或10-啡噻嗪基、丨_啡噁嗪基、2啡噁嗪基、3·啡噁嗪基、4-啡噁嗪基、6_啡噁嗪基、7_啡噁嗪基、8_啡噁嗪基、9-啡噁嗪基或10-啡噁嗪基、2-苯并異喹啉基、3_苯并異喹啉基、4-笨并異喹啉基、5_苯并異喹啉基、6_苯并異喹啉基，或1·苯并異喹啉基' 3_苯并異喹啉基、4_苯并異喹啉基、5_苯并異喹啉基、6苯并異喹啉基、7苯并異喹啉基、8-苯并異喹啉基、9_苯并異喹啉基或1〇_苯并異喹啉基、2-噻吩并[2,3_b]呋喃基、3_噻吩并[2,3_b]呋喃基、 4_嘆吩并[2,3-b]°夫喃基或噻吩并[2,3-b]。夫喃基、m秦并[2,3-c]咔唑基、3·7Η·η比嗪并[2,3<]咔唑基、5_7Η·π比嗪 [，C]卡唑基、6-7Η-吡嗪并[2,3-c]咔唑基、7-7Η-。比嗪并[2’3-c]咔唑基、8 7Η_β比嗪并[2,3_小卡唑基m秦嗪、]卡唑基、1〇-7H•吡嗪并[2,3-习咔唑基或11-7H-吡 /并[2,3'啊唑基、2·2Η_吱喃并[3,2-b]-哌喊基、3_2H_吱 =并[3,2-b]-哌喃基、5_2札呋喃并μ外哌喃基并[3,2-b]-哌喃基或7_2Η·呋喃并[3 2 b]哌喃基·、2_ I60983.doc -14· 201247656 5H-吡啶并[2,3-d]-鄰噁嗪基、3_5H•吡啶并[2,3-d]-鄰噁嗪基、4-5H-吡啶并[2,3-d]-鄰噁嗪基' 5·5Η-吡啶并[2,3_d]_ 鄰噁嗪基、7-5H-吡啶并[2,3-d]-鄰噁嗪基或8-5H·吡啶并 [2,3-d]-鄰噁嗪基、1-1H-吡唑并[4,3_d]_i唑基、3_11}_吡唑并[4,3-d]_噁唑基或5-1H-吡唑并[4,3-d]-噁唑基、2-4H-咪唑并[4,5-d]噻唑基、4-4H-咪唑并[4,5-d]噻唑基或5_4h_ 咪唑并[4,5-d]噻唑基、3-吧嗪并[2,3_d]噠嗪基、5_d比嗪并 [2,3-d]噠嗪基或8-吼嗪并[2,3-d]噠嗪基、2-咪唑并[2^^] 鲁噻唑基、3_咪唑并[m]。塞唑基、5-咪唑并[2，l-b]噻唑基或6-咪唑并[2’i-b]噻唑基、；!·呋喃并[34_c]4啉基、3呋喃并[3,4_C]4啉基、6_呋喃并[3,4_c]4啉基、7_呋喃并 [3’4-c]咔啉基、8_呋喃并[3,c]啐啉基或9_呋喃并[3,4叫啐啉基、1-4H-吡啶并[2,3外卡唑基、比啶并[2 3中卡唑基、3-4Η-。比啶并[2,3-c]味唑基、4·4Η·β比啶并[2,3_啊唑基、5-4Η-吡啶并[2,3-c]味唑基、6_4Η_η比啶并[23c]味唑基、8-4H-。比咬并[2,3_c]^唾基、9_4Η·η比啶并[2 3_啊着唾基、10-4Η-吼咬并咔坐基、2_咪唑并[1，2_13][1，2,4]三嗪基、3_咪唑并⑴2_b] Π，2,4]三嗪基、6_咪唑并嗪基或7咪唑并 H，2-b][l，2,4]三嗪基、7-苯并[b]噻吩基、2_苯并噁唑基、 4-苯并㈣基、5.苯㈣唾基、6_苯并μ基或7_苯并。惡唑基、2-苯并咪唑基、4_苯并咪唑基、5_苯并咪唑基、6_ 苯并味嗤基或7-苯并味峻基、2_笨并㈣基、4_苯并嗟唾基、心苯并嗟唾基、5-苯并㈣基、6_苯并喧。坐基或7•笨 160983.doc •15· 201247656 并噻唑基、1-苯并氧呼基、2_笨并氧呼基、4_苯并氧呼基、5-苯并氧呼基、6_笨并氧呼基、7_苯并氧呼基、8_笨并氧呼基或9-苯并氧呼基、2·苯并噁嗪基、4-苯并噁嗪基、5-苯并噁嗪基、6_笨并噁嗪基、7_苯并噁嗪基或8_苯并。惡嗪基、1-1H-。比咯并[i，2-b][2]苯并氮呼基、2-1H-吡咯并n，2-b][2]苯并氮坪基、3-1Η-»比〇各并[l，2-b][2]苯并氮呼基、5-1Η-η比咯并[nwp]笨并氮呼基、6_1Η_β比咯并[12b] [2]笨并氮呼基、7-1H-"比咯并[l，2-b][2]苯并氮呼基、8-1H-0比σ各并[l，2-b][2]苯并氮呼基、9-1Η-°比"各并[l，2-b][2]苯并氮呼基、10-1Η-η比咯并[^^[2]笨并氮呼基或比咯并[l，2-b][2]苯并氮呼基。典型稠合雜芳基包括（但不限於）2-啥啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基、1_異喹啉基、3_異喹啉基、4_ 異喹啉基、5-異喹啉基、6-異喹啉基、7-異喹啉基或8-異喧琳基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-°引°朵基或7-吲哚基、2-苯并[b]噻吩基、3-苯并[b]噻吩基、 4·苯并[b]噻吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基或7-苯并[b]噻吩基、2-苯并噁唑基、4-苯并噁唑基、5_苯并噁 °坐基、6-苯并。惡唾基或7-苯并》惡唾基、2-苯并咪唑基、4-苯并咪唑基、5-苯并咪唑基、6-苯并咪唑基或7_苯并咪唑基’及2-苯并噻唑基、4-苯并噻唑基、5_苯并噻唑基、6_ 本并0坐基或7 -苯并嗟嗤基。雜芳基可經1至5個獨立地選自由以下組成之群的取代基取代： 160983.doc •16· 201247656 (a) 烧基； (b) 羥基（或受保護羥基）； (c) 鹵基； (d) 側氧基’亦即=0 ; (e) 胺基、烧基胺基或二烧基胺基； (f) 烷氧基； (g) 環烧基； (h) 羧基； (i) 雜環氧基，其中雜環氧基表示經由氧橋鍵結之雜環基； (j) 烷基-o-c(o)-; (k) 酼基； (l) 醯胺基或甲醯胺基； (m) 氰基； (η)胺磺醯基、磺胺基或磺醯胺基； (〇)芳基； (Ρ)烷基-C(0)-0-; (q) 芳基-C(0)-0-; (r) 芳基-S-; (s) 芳氧基； (t) 烧基-S -， (u) 甲醯基，亦即HC(0)-; (v) 胺甲醯基； (w) 芳基-院基-;及 160983.doc -17- 201247656 (χ)經烷基、環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH- 、烧基胺基、二烷基胺基或函素取代之芳基； (y)經環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH-、烷基胺基、二烷基胺基或函素取代之烷基。如本文所用’術語「鹵素」或「鹵基」係指氟、氯、溴及埃。除非另外說明，否則如本文所用之術語「視情況經取代」係指基團未經取代或經一或多個（通常為丨、2、3戋4 個）適合的非氫取代基取代，各取代基獨立地選自由以下組成之群： (a) 烷基； (b) 羥基（或受保護羥基）； (c) 鹵基； (d) 側氧基，亦即=〇 ; (e) 胺基、烷基胺基或二烷基胺基； (f) 烷氧基； (g) 環烷基； (h) 羧基； ⑴雜環氧基，其中雜環氧基表示經由氧橋鍵結之雜環基； ⑴烷基-O-C(o)-; (k)酼基； ⑴醯胺基或甲醯胺基； (m)氰基； 160983.doc •18- 201247656 (η)胺磺醢基、磺胺基或磺醯胺基； (〇)芳基； (Ρ)烷基-C(0)-0-; (q) 芳基-C(0)-0-; (r) 芳基-S-; (s) 芳氧基； ⑴烷基-S-; (u) 甲醯基，亦即HC(O)-; (v) 胺曱醯基； (w) 芳基-烷基-;及 (X)經烷基、環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH-、烷基胺基、二烷基胺基或函素取代之芳基； (y)經環烷基、烷氧基、羥基、胺基、烷基-C(0)-NH-、烷基胺基、二烷基胺基或齒素取代之烷基。在一個態樣中，提供式（I)化合物： 1.一種式（I)化合物：The compounds of formula (I) include their salt definitions. These and other embodiments of the invention are further described in the text below. [Embodiment] A plurality of embodiments relating to compounds, compositions and methods are mentioned in the present application. The various embodiments described are intended to provide a number of illustrative examples and are not to be construed as a description of alternatives. In fact, it should be noted that the description of the various embodiments provided herein may have overlapping categories. The embodiments discussed herein are merely illustrative and are not intended to limit the scope of the invention. For the purposes of this description, the following definitions will apply, and as long as the terms used in the singular are intended to include the plural, and vice versa. - As used herein, the term "alkyl" refers to a fully saturated or unbranched bond moiety having up to 20 carbon atoms. Unless otherwise stated, alkyl refers to a hydrocarbon moiety having from 1 to 16 carbon atoms, from 1 to 1 carbon atoms, (1) carbon atoms or from 1 to 4 carbon atoms. Representative examples of a hospital base include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isuf Base, neopentyl, n-hexyl 3 fylhexyl, 22-dimethylpentyl, 2,3 dimethylpentyl n-heptyl, n-octyl, n-decyl, n-decyl and the like. As used herein, the term "alkylene" refers to a valent alkyl group as defined herein having from i to 2 carbon atoms. It contains [to a carbon atom, and unless otherwise stated, an alkyl group means a moiety having from 丨 to 16 carbon atoms '丨 to (7) carbon atoms, 1 to 7 carbon atoms or 1 to 4 carbon atoms. Representative examples of alkylene groups include, but are not limited to, methylene, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, isobutyl, tert-butyl , pentyl group, isoamyl group, neopentyl group, hexyl group, 3_methyl hexyl group, 2,2-dimethyl-amyl group 2,3-dimethyl-amyl group, heptyl group It is an extension of the octyl group, the extension of the base, the extension of the base and its similar groups. As used herein, the term "haloalkyl" refers to an alkyl group as defined herein substituted with one or more dentate groups as defined herein. The dentate alkyl group may be a mono-, di-, or poly-halogen, including a perhalogenated group. The monodentate base may have an iodine, bromine, gas or fluorine in the base. The dihaloalkyl group and the polyhaloalkyl group may have two or more of the same halogen atoms or a combination of different halo groups in the alkyl group. The polyhaloalkyl group usually contains up to 12, or 1 ,, or 8, 160,983.doc 201247656 or 4, or 3 or 2 halo groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, gas sulfhydryl, dichloromethyl, monomethyl, pentafluoroethyl, heptafluoropropyl, difluoro gas Base, dichlorofluorocarbon fluoroethyl, difluoropropyl, diethylene ethyl and di-propyl. A perhaloalkyl group refers to a group in which all of the hydrogen atoms are substituted with a (iv) group atom. The 'an aryl group' refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. The aryl group is usually a monocyclic, bicyclic or tricyclic aryl group having 6 to 2 carbon atoms. Further, as used herein, the term "aryl" refers to an aromatic substituent which may be a single aromatic ring or a plurality of aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with from 1 to 4 substituents such as alkyl, trifluorodecylcycloalkyl, halogen, hydroxy 'alkoxy, hydrazine Base, alkyl group _c(〇)_〇_, aryl-Ο-, heteroaryl, amine, thiol, alkyl _s_, aryl _s_, nitro, cyano, carboxyl, alkyl _ 〇_c(0)_, amine mercapto, alkyl _s(〇)_, sulfonyl, sulfonylamino, strepyl and heterocyclic. As used herein, the term "alkoxy" refers to alkyl hydrazine, wherein alkyl is singular in the above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclo Propoxy-, cyclohexyloxy- and similar groups. The alkoxy group usually has about 1 to 7 carbons, more preferably about 1 to 4 carbons. As used herein, the term 'heterocyclyl' or 'heterocyclo' refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4 member, 5 member, 6 member or 7 member single ring. 6 members, 7 members, 8 members, 9 members, 10 160983.doc • 9- 201247656 members, employees or 12 members of the double ring; or 10 members, u members, 12 members, 13 members, 14 members or 15 members of the second ring a system comprising at least one hetero atom selected from the group consisting of hydrazine, s & N, wherein N and S are optionally oxidized to various oxidation states. The heterocyclic group may be attached to a hetero atom or a carbon atom. The heterocyclic group may include a fused ring or a bridged ring as well as a spiro ring. Examples of the heterocyclic ring include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiazide, piperazine, piperidine, i.3. dioxane, Miso bites, mites, 吼略琳, 吼洛bit, qi mai, diazapyran, oxathiolane, dithiolane, anthracene, 3_dioxane, 〗〖3 Dithiazin, oxathiazide and thiomorpholine. The term "heterocyclyl" additionally refers to a heterocyclyl (a) alkyl group, as defined herein, substituted by 1 to 5 substituents independently of the following composition: (b) hydroxy (or (c) a halogen group; (d) a pendant oxy group, ie = hydrazine; (e) an amine group, an alkylamino group or a dialkylamino group; (f) an alkoxy group; (g) a ring (h) a carboxyl group; (1) a heterocyclic oxy group wherein a heterocyclic oxy group represents a heterocyclic group bonded via an oxygen bridge; '(j) alkyl-OC(o)- ·, (k) fluorenyl; l) amidino or guanamine; 160983.doc -10 - 201247656 (m) cyano; (n) sulfonamide, sulfonamide or sulfonamide; (〇) aryl; Base _c(o)-o-; (q) aryl-C(0)-0-; (r) aryl-S·; (s) aryloxy; (1) alkyl-S-; φ (u a sulfhydryl group, that is, HC(O)-; (v) an amine carbenyl group; (w) an aryl-hetero group; and (X) an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, an amine group a group, an alkyl-C(0)-NH., an alkylamino group, a dialkylamino group or a substituted aryl group; (y) a cycloalkyl group, an alkoxy group, a hydroxyl group, an amine group, an alkyl group - C(0)-NH·, alkylamino, dialkylamine or dentate substituted alkane . As used herein, the term "cycloalkyl" refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group having from 3 to 12 carbon atoms. Unless otherwise stated, a cycloalkyl group means a cyclic hydrocarbon group having 3 to 9 ring carbon atoms or 3 to 7 ring carbon atoms, each of which may optionally be selected by 1 or 2 or 3 or more. Substituted by a substituent of a group consisting of: an alkyl group, a dentate group, a pendant oxy group, a hydroxyl group, an alkoxy group, an alkyl-C(O)-, a decylamino group, an amine fluorenyl group, a valence group-NH-, (alkyl) 2N-, thiol, alkyl-S-, nitrate', cyano, sulfhydryl, alkyl-OC(O)-, sulfonyl, sulfonylamino, sulfonyl, continuation Amine groups and heterocyclic groups. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, ring 160983.doc • 11 · 201247656 butyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. Exemplary bicyclic hydrocarbon groups include fluorenyl, fluorenyl, hexahydroindenyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2"]heptyl, bicyclo[2.2.1] Heptenyl, 6,6-dimethylbicyclo[3"heptyl, 2,M-trimethylbicyclo[3.1 _1]heptyl, bicyclo[2 2 2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl groups and the like. As used herein, the term "aryloxy" refers to aryl and heteroaryl, wherein aryl and heteroaryl are as defined herein. As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system having from 丨 to 8 heteroatoms selected from N, oxime or S. Heteroaryl groups are typically 5-10 member ring systems (e.g., 5-7 member single ring or 8_1 employee double ring) or 5-7 member ring systems. Typical heteroaryl groups include 2-thiophenyl or 3-thienyl, furyl or 3-furyl, 2-pyrrolyl or 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 3-pyrazole Or 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl, 2-oxazolyl , 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl 4-isoxazolyl or 5-isoxazolyl, 3-cut-triazolyl or "from diazolyl, 4-1 , 2,3-triazolyl or 5-1,2,3-triazolyl, tetrazolyl, indylpyridinyl, 3-«•pyridinyl or 4_„pyridinyl, 3·pyridazinyl or 4 _ oxazinyl, 3 oxazinyl, 4-pyridazinyl or 5-pyrazinyl, 2_π-pyrazinyl, and 2-meridinyl, singular or 5-n-mouth. Set the foundation. The term "heteroaryl" also refers to a radical in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings wherein the group or point of attachment is on the heteroaryl ring. Non-limiting examples include oxazolazine, 2 oxazino, 3" 哚160983.doc 201247656 azine, 5-pyridazinyl, hexazinyl, 7-pyridazinyl or 8_ pyrazinyl, 1-isoindenyl, 3-isoindolyl, 4-isoindolyl, 5-isodecyl, 6-isoindolyl or 7-isodecyl, 2_吲哚基,3·吲哚基,4_ "引木木基,5-mercapto, 6_fluorenyl or 7-fluorenyl, 2_carbazolyl, % 吲°, 4-oxazolyl, 5-oxazolyl, 6-oxazolyl or 7-indolyl, fluorenyl, 4-indenyl, 5-hydrazino, 6-fluorenyl, fluorenyl or 8-hydrazino, 1-quinazinyl, 2-quinazinyl, 3-quinazinyl, 4-quinazinyl, 6-pyridazinyl, 7-quinazinyl, 8-quinazinyl or 9-quinazinyl, 2-quinoxa Phytyl, % quinolyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-linyl, 1-isoindolyl, 3-isoindolinyl , 4-isoindolyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolyl or 8-isoquinolyl, pyridazinyl, 4-pyridazinyl, 5-indole Zinyl, 6-pyridazinyl, 7-pyridazinyl or pyridazinyl, 2-acridinyl, 3-acridinyl, 4-acridine , 5-azetidyl or 6-acridinyl, 2-mercapto, 3-indolyl, 5-indolyl, 6-indenyl, 7-saltyl or 8 -啥啥琳基, 3-吟琳基, 4-吟琳基, 5-吟琳基, 6-吟琳基, 7-碎琳基 or 8-吟琳基, 2-嗓.定基,4_ 喋Pyridyl, 6-acridinyl or 7-acridinyl, l-4aH carbazolyl, 2-4aH#. Sodium, 3-4aH oxime, 4-4aH oxime, 5-4aH carbazolyl , 6-4aH- oxazolyl, 7-4aH carbazolyl or 8-4aH oxazolyl, 1-oxazolyl, 2·micanyl, 3-oxazolyl, 4-oxazolyl, 5-carbazole , 6-carbazolyl, 7-»carbazolyl or 8-carbazolyl, 1-indolyl, 3-indolyl, 4-indolyl, 5-terinyl, 6-carbolinyl , 7-carbolinyl, 8-carbolinyl or 9-fluorenyl, 1_bite group, 2-° thiophene group, 3-morphyl group, 4-° non-localized base, bite base, 7- Carbityl, 8-cyridinyl, 9-cyridinyl or 10-cyridinyl, 1-acridinyl, 2_. bite 160983.doc -13- 201247656 base, 3-acridinyl, 4-anthracene Pyridyl, 5-acridinyl, 6-acridinyl, 7-n-decyl, 8-acridinyl or 9-acridinyl, 1-acridinyl, 2-oxaridinyl, 4-feed. Fixed 5-pyloryl , 6-bite, 7-voododinyl, 8- benzopyridyl or 9-leptyl, 2- morpholinyl, 3- morpholinyl, 4- morpholinyl, 5- morpholinyl, 6 -morphinyl, 8-cyanolinyl, 9-morpholinyl or 10-cyanoyl, indolylpyridinyl, 2-cyphthyl, 3-cyanoazinyl, 4-cyanoazinyl, 6-morphine Azinyl, 7-cyanozinyl, 8-cyanoguanidino or 9-cyanoazinyl, 1 · phenothiazinyl, 2-morphothazinyl, 3-phenylthiazinyl, 4-morphothazinyl, 6 -Phenylthiazinyl, 7-phutthiazinyl, 8-phenylthiazinyl, 9-phenothiazinyl or 10-cythiazinyl, indolyl-cyanoazinyl, 2-morphoxazinyl, 3·morphine Zinyl, 4-morphoxazinyl, 6-morphoxazinyl, 7-morphoxazinyl, 8-morphoxazinyl, 9-phinoxazinyl or 10-phinoxazinyl, 2-benziso Quinolinyl, 3-phenylisoisoquinolyl, 4-phenylisoisoquinolyl, 5-benzoisoquinolinyl, 6-benzisoquinolinyl, or 1·benziquinolinyl 3_Benzoisoquinolyl, 4-phenylisoisoquinolyl, 5-benzoisoquinolinyl, 6-benzoisoquinolyl, 7-benzoisoquinolyl, 8-benzoisoquinoline , 9-benzoisoquinolyl or 1〇-benzoisoquinolyl, 2-thieno[2,3_b]furanyl, 3-thieno[2,3_b]furanyl, 4_ The sigh is [2,3-b]°phoranyl or thieno[2,3-b]. Fumonyl, m-methyl-[2,3-c]oxazolyl, 3·7Η·η-pyrazino[2,3<]carbazolyl, 5-7 Η·π-pyrazine [,C]carbazolyl, 6 -7Η-pyrazino[2,3-c]oxazolyl, 7-7Η-. Bisino[2'3-c]carbazolyl, 8 7Η_βpyrazine[2,3_cacarbazolyl-m-pyrazine,]carbazolyl, 1〇-7H•pyrazine[2,3- Oxazolyl or 11-7H-pyridyl-[2,3'-oxazolyl, 2·2Η_吱-[3,2-b]-piperidinyl, 3_2H_吱=[3,2- b]-Pyloryl, 5-2, and it is [5,2-b]-pyranyl or 7_2Η·furo[3 2 b]pyranyl, 2_I60983.doc -14· 201247656 5H-Pyridino[2,3-d]-o-oxazinyl, 3_5H•pyrido[2,3-d]-o-oxazinyl, 4-5H-pyrido[2,3-d]-ortho Oxazinyl '5·5Η-pyrido[2,3_d]- o-oxazinyl, 7-5H-pyrido[2,3-d]-o-oxazinyl or 8-5H·pyridin[2,3 -d]-o-oxazinyl, 1-1H-pyrazolo[4,3_d]-ioxazolyl, 3_11}-pyrazolo[4,3-d]-oxazolyl or 5-1H-pyrazole [4,3-d]-oxazolyl, 2-4H-imidazo[4,5-d]thiazolyl, 4-4H-imidazo[4,5-d]thiazolyl or 5_4h_imidazo[4, 5-d]thiazolyl, 3-oxazino[2,3_d]pyridazinyl, 5-d-pyrazino[2,3-d]pyridazinyl or 8-pyridazino[2,3-d]pyridazine Base, 2-imidazo[2^^] thiathiazolyl, 3-imidazo[m]. Retazolyl, 5-imidazo[2,lb]thiazolyl or 6-imidazo[2'ib]thiazolyl, ;·furan[34_c]4 phenyl, 3furo[3,4_C]4 phenyl , 6-furo[3,4_c]4 phenyl, 7-furo[3'4-c] porphyrin, 8-furo[3,c] porphyrin or 9-furan[3, 4 is called porphyrin group, 1-4H-pyridine and [2,3 excarbazolyl, pyridinium [23 3 carazolyl, 3-4 Η-. Bis-pyrido[2,3-c]isozolyl, 4·4Η·β-pyridyl[2,3-oxazolyl, 5-4Η-pyrido[2,3-c]isozolyl, 6_4Η_η ratio Pyrido[23c]isoxazolyl, 8-4H-. More than bite [2,3_c]^salyl, 9_4Η·η is pyridine and [2 3_ 唾唾、, 10-4 Η 吼咔咔咔、、、、、、、、、、、、、、、、、、、、、、 2,4]triazinyl, 3-imidazo[1)2_b]indole, 2,4]triazinyl, 6-imidazozinyl or 7imidazolyl,H,2-b][l,2,4]triazinyl , 7-benzo[b]thienyl, 2-benzoxazolyl, 4-benzo(tetra)yl, 5-phenyl(tetra)saltyl, 6-benzohyl or 7-benzo. Oxazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzofuranyl or 7-benzo-benzoyl, 2-phenylidene, 4-phenylene And sputum, benzoindole, 5-benzo(tetra)yl, 6-benzopyrene. Sit-base or 7• stupid 160983.doc •15· 201247656 and thiazolyl, 1-benzoxaphthyl, 2-benzooxy-oxo, 4-benzoxaphthyl, 5-benzooxoyl, 6 _Bist and oxo group, 7_benzoxaphthyl, 8-phenyloxy-oxo or 9-benzooxoyl, 2·benzoxazinyl, 4-benzoxazinyl, 5-benzene And oxazinyl, 6-stupyloxazinyl, 7-benzoxazinyl or 8-benzoic. Oxazinyl, 1-1H-. Bis-[i,2-b][2]benzodiazepine, 2-1H-pyrrolo-n,2-b][2]benzodiazepine, 3-1Η-» l,2-b][2]benzazepine group, 5-1Η-η ratio 咯[nwp] 笨氮氮、, 6 Η Η β β β [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ 1H-"Bildo[l,2-b][2]benzozinyl, 8-1H-0 ratio σ and [l,2-b][2]benzodiazepine, 9- 1Η-° ratio " each [l,2-b][2]benzilidene group, 10-1Η-η ratio and [^^[2] stupid and nitrogen group or ratio [l, 2-b][2]benzilinyl. Typical fused heteroaryl groups include, but are not limited to, 2-carbolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8- Quinolinyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl or 8-isoindole Base, 2-indenyl, 3-indolyl, 4-indenyl, 5-indenyl, 6-indolyl or 7-fluorenyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4·benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl or 7-benzo[b]thienyl, 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxanthene, 6-benzo. Orythracene or 7-benzoxanthyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl or 7-benzimidazolyl' and 2 a benzothiazolyl group, a 4-benzothiazolyl group, a 5-benzothiazolyl group, a 6-benzoxyl group or a 7-benzofluorenyl group. The heteroaryl group may be substituted with from 1 to 5 substituents independently selected from the group consisting of: 160983.doc •16· 201247656 (a) alkyl group; (b) hydroxyl group (or protected hydroxyl group); (c) halogen (d) a pendant oxy group, ie, =0; (e) an amine group, an alkylamino group or a dialkylamino group; (f) an alkoxy group; (g) a cycloalkyl group; (h) a carboxyl group; (i) a heterocyclic oxy group, wherein the heterocyclic oxy group represents a heterocyclic group bonded via an oxygen bridge; (j) an alkyl-oc(o)-; (k) fluorenyl group; (l) an amidino group or a (m) cyano; (η) amine sulfonyl, sulfonyl or sulfonylamino; (〇) aryl; (Ρ)alkyl-C(0)-0-; (q) aryl -C(0)-0-; (r) aryl-S-; (s) aryloxy; (t) alkyl-S-, (u) methyl sulfhydryl, ie HC(0)-; (v) Aminomethyl thiol; (w) aryl-hospital-; and 160983.doc -17- 201247656 (χ) via alkyl, cycloalkyl, alkoxy, hydroxy, amine, alkyl-C (0)-NH-, alkylamino, dialkylamino or aryl substituted aryl; (y) cycloalkyl, alkoxy, hydroxy, amine, alkyl-C(0)- An alkyl group substituted with an NH-, an alkylamino group, a dialkylamino group or a functional group. The term "halogen" or "halo" as used herein refers to fluoro, chloro, bromo and argon. The term "optionally substituted" as used herein, unless otherwise indicated, refers to a group that is unsubstituted or substituted with one or more (usually 丨, 2, 3, 4) suitable non-hydrogen substituents, each The substituents are independently selected from the group consisting of: (a) an alkyl group; (b) a hydroxyl group (or a protected hydroxyl group); (c) a halogen group; (d) a pendant oxy group, that is, an anthracene; (e) an amine a group, an alkylamino group or a dialkylamino group; (f) an alkoxy group; (g) a cycloalkyl group; (h) a carboxyl group; (1) a heterocyclic oxy group, wherein the heterocyclic oxy group is bonded via an oxygen bridge Heterocyclic group; (1) alkyl-OC(o)-; (k) fluorenyl; (1) guanylamino or carbenamine; (m) cyano; 160983.doc • 18- 201247656 (η) amine sulfonyl , sulfonyl or sulfonamide; (〇) aryl; (Ρ)alkyl-C(0)-0-; (q) aryl-C(0)-0-; (r) aryl-S (s) aryloxy; (1) alkyl-S-; (u) methyl sulfhydryl, ie HC(O)-; (v) aminyl; (w) aryl-alkyl-; (X) an aryl group substituted with an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, an amine group, an alkyl-C(0)-NH-, an alkylamino group, a dialkylamino group or a peptidin; y) via cycloalkyl, alkoxy, hydroxy Amino, alkyl -C (0) -NH-, alkyl amino, dialkylamino, or substituted alkyl of prime teeth. In one aspect, a compound of formula (I) is provided: 1. A compound of formula (I):

或其鹽，其中 m為0、1或2 ; η為0或1，其中m+n為1、2或3 ; 160983.doc -19- 201247656Or a salt thereof, wherein m is 0, 1 or 2; η is 0 or 1, wherein m+n is 1, 2 or 3; 160983.doc -19- 201247656

Ri為C3-C1G炔基或苯基，該苯基經〇、1、2或3個獨立地選自由以下組成之群的取代基取代··鹵素、羥基、氰基、 Ci-C4烧基、鹵基q-C4院基及C1-C4院氧基，且該炔基視情況經C3_C7環烷基取代基取代，該環烷基視情況經1或2個獨立選擇之烷基取代； R2為co2h、四唑、c(o)n(h)s(o)2ch3或羧酸電子等排體； R3為經0、1、2或3個鹵素原子取代之c3-c7環烷基；Ri is a C3-C1G alkynyl group or a phenyl group which is substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, Ci-C4 alkyl, a halo-q-C4 or a C1-C4 alkoxy group, and the alkynyl group is optionally substituted by a C3_C7 cycloalkyl substituent, which is optionally substituted with 1 or 2 independently selected alkyl groups; R2 is Co2h, tetrazole, c(o)n(h)s(o)2ch3 or a carboxylic acid isostere; R3 is a c3-c7 cycloalkyl substituted with 0, 1, 2 or 3 halogen atoms;

Rh表示0、1、2、3或4個在每次出現時獨立地選自由以下組成之群的殘基：羥基、胺基、氰基、鹵素、^-(^烷基、C^C：6烷氧基’其中各烷基或烷氧基取代基係經〇、1 或2個獨立地選自以下之取代基取代：羥基、氰基、Ci_c4 烷氧基、CVC4烷基砜、N(R3b)2、C(0)N(R3b)、具有4至7 個環原子及1或2個選自N、0或S之環雜原子的雜環及5或6 員雜芳基；或兩個偕位Rh取代基組合起來形成螺環狀3至 6員環烷基或雜環； R3b在每次出現時獨立地選自氫、CrC4烷基、烧氧基C1-C4炫基及CrC4烧醯基；或N(R3b)2組合起來形成具有〇或1個選自N、0或S之其他環雜原子的4至6員雜環： X為〇、n-l-r4 或 cr5r6 ; L 為一鍵、s(0)2、c(0)或 C(0)0 ; R4為Ci-C；6坑基、C3-C7環烧基或C3-C7環院基C1-C4烧基’其各自經0、1或2個經基及0或1個選自以下之取代基取代：氰基、SCOh-CrG烷基、C02H、NR4aR4b、苯基或 160983.doc -20· 201247656 °比咬基’其中苯基或吼啶基取代基經〇、1或2個選自以下之取代基取代：烷基、鹵素、NR4aR4b或具有1或2個環氮原子之5或6員雜芳基；合雜芳基具有5或6個環原子，j 環雜原子，且該稠合雜芳基經〇烷基取代基取代，·或 R4為萘基或苯基，該苯基經〇、1、2或3個獨立地選自由以下組成之群的取代基取代：鹵素、氰基、Cl_c6烷基、齒基C「C6烷基、q-C6烷氧基、鹵基CVCe烷氧基、羥基、經基CrQ烷基、胺基c「C4烷基、CVCe烷基-OC(〇)NH-、 Ci-C4烷基-C(〇)NH-、NR4aR4b、C02H、-C(0)NR4aR4b、苯基、苯氧基、具有一或兩個環氮原子且具有〇、1或2個 CrC4烷基取代基之雜芳基，或兩個取代基組合形成稠合雜環或雜芳環，該稠合雜環具有5、6或7個環原子，具有^ 或2個選自n、〇或S之環雜原子，且該稠合雜環經〇、丨或二個獨立地選自q-C6烷基或側氧基之取代基取代，且該稠具有1或2個選自N、〇或S之〇、1或2個獨立選擇之Ci_C4 Ο或S之雜原子的5或6員雜芳Rh represents 0, 1, 2, 3 or 4 residues which, at each occurrence, are independently selected from the group consisting of hydroxyl, amine, cyano, halogen, ^-(^alkyl, C^C: 6 alkoxy' wherein each alkyl or alkoxy substituent is substituted with hydrazine, 1 or 2 substituents independently selected from the group consisting of hydroxy, cyano, Ci_c4 alkoxy, CVC4 alkyl sulfone, N ( R3b)2, C(0)N(R3b), a heterocyclic ring having 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, 0 or S, and a 5 or 6 membered heteroaryl group; or two The hydrazine substituents are combined to form a spirocyclic 3 to 6 membered cycloalkyl or heterocyclic ring; R3b is independently selected from the group consisting of hydrogen, CrC4 alkyl, alkoxy C1-C4 leuco, and CrC4 at each occurrence. a fluorenyl group; or N(R3b)2 is combined to form a 4 to 6 membered heterocyclic ring having hydrazine or 1 other ring heteroatom selected from N, 0 or S: X is hydrazine, nl-r4 or cr5r6; L is one Key, s(0)2, c(0) or C(0)0; R4 is Ci-C; 6 pit base, C3-C7 cycloalkyl or C3-C7 ring-based C1-C4 alkyl group' Substituted by 0, 1 or 2 radicals and 0 or 1 substituent selected from the group consisting of cyano, SCOh-CrG alkyl, CO 2H, NR 4aR 4b, phenyl or 160983.doc -20· 20 1247656 ° is more than a butyl group wherein the phenyl or acridine substituent is substituted with hydrazine, 1 or 2 substituents selected from alkyl, halogen, NR 4aR 4b or 5 or 6 members having 1 or 2 ring nitrogen atoms Heteroaryl; heteroaryl has 5 or 6 ring atoms, j ring heteroatom, and the fused heteroaryl is substituted with a decyl substituent, or R4 is naphthyl or phenyl, the phenyl group 〇, 1, 2 or 3 are independently substituted with a substituent selected from the group consisting of halogen, cyano, Cl_c6 alkyl, dentate C "C6 alkyl, q-C6 alkoxy, halo CVCe alkoxy" Base, hydroxyl group, trans-group CrQ alkyl group, amine group c "C4 alkyl group, CVCe alkyl-OC (〇) NH-, Ci-C4 alkyl-C(〇)NH-, NR4aR4b, C02H, -C(0 a NR4aR4b, a phenyl group, a phenoxy group, a heteroaryl group having one or two ring nitrogen atoms and having a fluorene, 1 or 2 CrC4 alkyl substituents, or a combination of two substituents to form a fused heterocyclic ring or a heteroaryl group a fused heterocyclic ring having 5, 6 or 7 ring atoms, having 2 or 2 ring heteroatoms selected from n, fluorene or S, and the fused heterocyclic ring is independently selected by hydrazine, hydrazine or two Substituted from a substituent of a q-C6 alkyl or pendant oxy group, and Having 1 or 2 billion selected from N, square or S or a 5 or 6-membered Ci_C4 Ο 1 or 2, or S heteroatoms of the heteroaryl are independently selected

個取代基組合起來形成具有5或6 J60983.doc R4為具有1至3個選自n、基’該雜芳基經0、1、2或3個多的取代基取代：齒素、氰基、基、c 1 - C 6院氣某、由其Γ1 i Π α .21. 201247656 個環原子、！或2個選自N、〇或8之雜原子的飽和雜環，且其中稠合雜環經〇、15戈2個獨立選擇之Ci铺基取代基取代且其中單環或雙％雜環在各環中具有1或2個環n、〇或S原子、5至7個環原子，且經〇、〗或2個獨立地選自由以下組成之群的取代基取代：齒冑、烧基、Cl_C6烧醯基、CVC6烧氧Μ基、Ci_c6烧氧基c(〇)N⑻、炫氧基C(0)N(H)CH2·、胺基（^(：4貌基、c】_c4燒氧基Ci_c4炫基 4aR1 2 3 4b且其中笨基或雜芳基取代基經〇、】或2個獨立選擇之選自以下之取代基取代：函素、c〇2H、氛基、烷基、c〗-c4院氧基、NR4aR4b、CH2NR4aR4b、c(〇)N“，或兩個苯基取代基組合形成二價_〇(CH2)q〇取代基，其中q為1、2或3 ;或 I為具有1個環氮及(^戈丨個選自N、〇或8之其他環雜原子的飽和雜環，該雜環經〇、丨或2個獨立地選自由以下組成之群的取代基取代：Cl_C6烧基、c〇2Ci_C6院基或c〇2苯甲基；在每次出現時獨立地選自由氫及烷基組成之群八中烷基取代基未經取代或經羥基、c]-C4烷氧基、胺基或單Cl-C4烷基胺基及二CrC4烷基胺基取代；The substituents are combined to form having 5 or 6 J60983.doc R4 is having 1 to 3 substituents selected from n. The heteroaryl group is substituted by 0, 1, 2 or 3 substituents: dentate, cyano , base, c 1 - C 6 courtyard gas, by its Γ 1 i Π α .21. 201247656 ring atoms,! Or 2 saturated heterocyclic rings selected from heteroatoms of N, oxime or 8, and wherein the fused heterocyclic ring is substituted with oxime, 15 ge 2 independently selected Ci-based substituents and wherein the monocyclic or double heterocyclic ring is Each ring has 1 or 2 ring n, hydrazine or S atoms, 5 to 7 ring atoms, and is substituted with hydrazine, or two substituents independently selected from the group consisting of: gums, alkyl groups, Cl_C6 sulphonate, CVC6 alkoxy fluorenyl, Ci_c6 alkoxy c(〇)N(8), ethoxyl C(0)N(H)CH2·, amine (^(:4), c]_c4 a group of Ci_c4 leuko 4aR1 2 3 4b and wherein the strepyl or heteroaryl substituent is substituted with hydrazine, or two independently selected substituents selected from the group consisting of: a peptidin, c〇2H, an aryl group, an alkyl group, c -c4 alkoxy, NR4aR4b, CH2NR4aR4b, c(〇)N", or two phenyl substituents combined to form a divalent 〇(CH2)q〇 substituent, wherein q is 1, 2 or 3; or I a saturated heterocyclic ring having one ring nitrogen and (other than another ring hetero atom selected from N, oxime or 8), the heterocyclic ring is substituted with ruthenium, osmium or two substituents independently selected from the group consisting of Substitution: Cl_C6 alkyl, c〇2Ci_C6 or Cu〇2 benzyl Each occurrence is independently selected from the group consisting of hydrogen and an alkyl group. The alkyl substituent is unsubstituted or via a hydroxyl group, a c]-C4 alkoxy group, an amine group or a mono-Cl-C4 alkyl group and two CrC4 alkylamino group substitution;

Rn在每次出現時獨立地選自由以下組成之群：氫、 160983.doc 1 6院基C3_C7i衣燒基、CrC4院酿基，及具有4至7個環 2 原子及1或2個在每次出現時獨立地選自N、〇或§之環雜原 3 子的雜環’其中烷基取代基未經取代或經以下取代：羥 4 基、cvc成氧基、胺基或單Ci_c▲基胺基及二Ci_C4燒基 201247656 胺基；或 NR4aR4b組合起來形成具有i個環氮原子及Mi個選自 N、〇及S之其他環雜原子的雜環，該雜環經〇、1、2或3個獨立地選自由以下組成之群的取代基取代：齒素、羥基、側氧基、胺基、CrC4烷基、鹵基烷基、羥基CVC4烷基、，胺基(^-(：4烧基、CVC^氧基、（VC4烧醯基、CVC4 烷氧基CpC4烷基及單匸!-。烷基胺基及二(^-(：4烷基胺基；Each occurrence of Rn is independently selected from the group consisting of hydrogen, 160983.doc, 16 yards of C3_C7i, and CrC4, and having 4 to 7 rings of 2 atoms and 1 or 2 per a heterocyclic ring which is independently selected from N, oxime or § ring hetero 3 of the 'wherein the alkyl substituent is unsubstituted or substituted by hydroxy 4, cvc to oxy, amine or mono Ci_c ▲ The amino group and the two Ci_C4 alkyl group 201247656 amine group; or NR4aR4b are combined to form a heterocyclic ring having i ring nitrogen atoms and Mi other ring hetero atoms selected from N, fluorene and S, the heterocyclic ring 2 or 3 substituents independently selected from the group consisting of dentate, hydroxyl, pendant oxy, amine, CrC4 alkyl, haloalkyl, hydroxy CVC4 alkyl, and amine (^-( : 4 alkyl, CVC oxy, (VC4 decyl, CVC4 alkoxy CpC4 alkyl and monoterpene--alkylamino and bis(^-(:4 alkylamino);

Rs不存在或選自由氫及(:广匕烷基組成之群；籲 R6為側氧基、氫、羥基、胺基、：N(H)-J-R7 ; J不存在、為c(0)或s(0)2 ;及尺7為CrC6烧基、苯基或苯曱基，各自視情況經以下取代.CpC6烷基、c「C6烷氧基、鹵素、苯基或苯氧基。本發明提供之某些式（I)化合物包括式（ia)化合物及其Rs is absent or is selected from the group consisting of hydrogen and (: extensive alkyl group; R6 is pendant oxy, hydrogen, hydroxy, amine, :N(H)-J-R7; J is absent, is c(0 Or s(0)2; and the ruler 7 is a CrC6 alkyl group, a phenyl group or a phenylhydrazine group, each of which is optionally substituted by the following: CpC6 alkyl group, c "C6 alkoxy group, halogen, phenyl group or phenoxy group. Certain compounds of formula (I) provided by the present invention include compounds of formula (ia) and

-一X R3a (la)-One X R3a (la)

Ri為C3-C8炔基或苯基’該苯基經(）、1、2或3個獨立地選自由以下組成之群的取代基取代：函素、羥基、氰基、 C1-C4烷基及CrC：4烷氧基，且該炔基視情況經c3_c7環烷基取代基取代，該環烷基視情況經i或2個獨立選擇之Ci_c4 160983.doc -23- 201247656 烷基取代；Ri is a C3-C8 alkynyl group or a phenyl group. The phenyl group is substituted with (1), 1, 2 or 3 substituents independently selected from the group consisting of: a hydroxyl group, a hydroxy group, a cyano group, a C1-C4 alkyl group. And CrC: 4 alkoxy, and the alkynyl group is optionally substituted by a c3_c7 cycloalkyl substituent, which is optionally substituted by i or 2 independently selected Ci_c4 160983.doc -23- 201247656 alkyl;

Rh表示0、1、2、3或4個在每次出現時獨立地選自由以下組成之群的殘基：羥基、胺基、Cl_c6烷基、Cl_c6烷氧基’其中各烷基或烷氧基取代基經〇、1或2個獨立地選自以下之取代基取代：羥基、Cl_C4烷氧基、— 基亞砜及Ν(υ ;或兩個偕位Rsa取代基組合起來形成螺環狀3至6 員環烷基或雜環；Rh represents 0, 1, 2, 3 or 4 residues which, at each occurrence, are independently selected from the group consisting of hydroxyl, amine, Cl_c6 alkyl, Cl_c6 alkoxy' wherein each alkyl or alkoxy The base substituent is substituted with hydrazine, 1 or 2 substituents independently selected from the group consisting of hydroxy, Cl_C4 alkoxy, sulfhydryl and hydrazine (or hydrazine; or two hydrazine Rsa substituents combined to form a spiro ring 3 to 6 membered cycloalkyl or heterocyclic;

Rsb在每次出現時獨立地選自氫、CpC4烷基' Cl_c4烷氧基<^-(：4燒基，或N(R3b)2組合起來形成具有〇或1個選自n、〇或S之其他環雜原子的4至6員雜環； X為 0、N-L-R4 或 CR5R6 ; L為一鍵、s(0)2 或 C(o); R·4為Ci-C6烷基或CrC7環烷基，其各自經個選自以下之取代基取代：C〇2H或NRhRb或基苯基，或 R4為萘基或苯基，該苯基經〇、1、2或3個獨立地選自由以下組成之群的取代基取代：齒素、氰基、CrC6烷基、鹵基(VC6烷基、CVC6烷氧基、鹵基Ci_c6烷氧基、胺基、羥基、單q-C6烷基胺基及二Cl_c0烷基胺基、羥基Ci_c4烷基、胺基C丨-C4烷基、c丨-c6烷基_〇c(〇)NH_、Ci_c4烷基-C(〇)NH-、-C(0)NR4aR4b、苯基、苯氧基、具有一或兩個環氮原子且具有0、個Cl_C4烷基取代基之雜芳基，或兩個取代基組合形成稍合雜環，該雜環具有5、6或7個環原子、！或2個選自N、〇或8之環雜原子且該雜環經〇、i 或2個獨立地選自Ci-C6炫基之取代基取代；或 160983.doc -24· 201247656 R·4為具有1至3個選自N、0或S之雜原子的5或6員雜芳基’該雜芳基經0、1或2個獨立地選自由以下組成之群的取代基取代.鹵素、氰基、C^-C6炫基、鹵基貌基、 Ci-C6烧氧基、鹵基c〗-C6炫氧基、經基、NR4aR4b、經基 C,-C4烷基、胺基C丨-C4烷基、C丨-C6烷基-〇c(〇)NH-、c3-c7 環烷基、Cs-C7環烯基、苯基、視情況經c〇2H取代之噻吩基’或飽和或部分不飽和單環或雙環雜環，該雜環在各環中具有1或2個環N、〇或S原子' 5至7個環原子且經〇、}*〗個獨立地選自由以下組成之群的取代基取代：C|_C6烷基、 CVQ烷醯基、烷氧基、^ 烷氧基、胺基c,-C4烷基、Cl_C4烷氧基C|_C4烷基及，或雜芳環上之兩個取代基組合形成稠合雜環，該雜環具有5、6或7個環原子、1或2個選自N、〇或8之環雜原子，且該雜環經〇、個獨立地選自（：1_(：6烷基之取代基取代，且其中苯基取代基未經取代或經以下取代：鹵素、CVC4院基或 C(0)NR4aR4b ;或 &為具有1個環氮及丨或丨個選自N、〇或8之其他環雜原子的飽和料’該雜環經〇、15戈2個獨立地選自由以下组成之群的取代基取代：Cl_a基、⑶2以成基或c〇2苯曱基； k在每次出現時獨立地選自由氫基组成之群，其中烧基取代基未經取代或經以下取代：減、CA 院氧基、胺基或單CVC成基胺基及二Ci_c说基胺基； R4b在每次出現時獨立地選自由以下组成之群：氫、Cl_c6 160983.doc -25- 201247656 烷基及Cl-C4烷醯基’其中烷基取代基未經取代或經以下取代.羥基、CrC4烷氧基、胺基或單Ci_c4烷基胺基及二 C1-C4烧基胺基；或 NR4aR4b組合起來形成具有1個環氮原子及〇或ί個選自 Ν、Ο及S之其他環雜原子的雜環，該雜環經〇、丨、2或3個獨立地選自由以下組成之群的取代基取代：鹵素、羥基、胺基、Ci-C4烷基、鹵基匚丨_(：4烷基、羥基c丨-C4烷基、胺基 (VC4烷基、cvc4烷氧基、C,-C4烷氧基(：,_<：4烷基及單C「C4 烷基胺基及二烷基胺基； R·5不存在或選自由氫及Ci-C：6烷基組成之群； Κ·6為側氧基、氫、經基、胺基、N(H)-J-R7 ; J不存在、為c(o)或s(o)2;及 R7為Ci-C6烷基、苯基或苯甲基’各自視情況經以下取代.0〗-(：6院基、Ci-C6院氧基、鹵素、苯基或苯氧基。在一個態樣中’式（I)化合物包括式（II)化合物及其鹽：Each occurrence of Rsb is independently selected from the group consisting of hydrogen, CpC4 alkyl 'Cl_c4 alkoxy <^-(:4 alkyl, or N(R3b)2 combined to form a oxime or one selected from n, oxime or 4 to 6 membered heterocyclic ring of other ring heteroatoms of S; X is 0, NL-R4 or CR5R6; L is a bond, s(0)2 or C(o); R·4 is a Ci-C6 alkyl group or CrC7 cycloalkyl, each of which is substituted with a substituent selected from C〇2H or NRhRb or phenyl, or R4 is naphthyl or phenyl, which is independently, 1, 2 or 3 independently Substituted by a substituent of the following composition: dentate, cyano, CrC6 alkyl, halo (VC6 alkyl, CVC6 alkoxy, halo-Ci-c6 alkoxy, amine, hydroxy, mono-q-C6 alkane Amino group and diCl_c0 alkylamino group, hydroxy Ci_c4 alkyl group, amino group C丨-C4 alkyl group, c丨-c6 alkyl group 〇c(〇)NH_, Ci_c4 alkyl-C(〇)NH-, -C(0)NR4aR4b, phenyl, phenoxy, heteroaryl having one or two ring nitrogen atoms and having 0, a C1-C4 alkyl substituent, or a combination of two substituents to form a slightly heterocyclic ring, The heterocyclic ring has 5, 6 or 7 ring atoms, ! or 2 ring heteroatoms selected from N, oxime or 8 and the heterocyclic ring is oxime, i Or 2 substituents independently selected from Ci-C6 leukoxyl; or 160983.doc -24·201247656 R·4 is a 5 or 6-membered heterocyclic having 1 to 3 heteroatoms selected from N, 0 or S The aryl 'the heteroaryl group is substituted by 0, 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C^-C6 leucoyl, halo-based, Ci-C6 alkoxy , halo c--C6 methoxy, thiol, NR4aR4b, trans-C, -C4 alkyl, amine C丨-C4 alkyl, C丨-C6 alkyl-〇c(〇)NH-, c3 a -c7 cycloalkyl group, a Cs-C7 cycloalkenyl group, a phenyl group, a thienyl group substituted by c〇2H, or a saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1 or 1 in each ring. 2 ring N, 〇 or S atoms '5 to 7 ring atoms and substituted by 〇,}* are independently selected from the group consisting of: C|_C6 alkyl, CVQ alkyl fluorenyl, alkoxy a fused heterocyclic ring having a 5-, alkoxy group, an amine group c, a C4 alkyl group, a Cl_C4 alkoxy group C|_C4 alkyl group, or a combination of two substituents on a heteroaromatic ring, the heterocyclic ring having 5 6 or 7 ring atoms, 1 or 2 ring heteroatoms selected from N, oxime or 8, and the heterocyclic ring is independently selected from ruthenium Substituting (:1_(:6 alkyl), and wherein the phenyl substituent is unsubstituted or substituted by halogen, CVC4 or K(0)NR4aR4b; or & has 1 ring nitrogen and hydrazine Or a saturated material selected from N, 〇 or other ring heteroatoms of '8' which is substituted with 15 substituents independently selected from the group consisting of: Cl_a group, (3) 2 to form a group or C〇2 phenyl fluorenyl; k is independently selected from the group consisting of hydrogen groups at each occurrence, wherein the alkyl substituent is unsubstituted or substituted by: minus, CA alkoxy, amine or mono CVC The amine group and the two Ci_c are arylamino groups; each occurrence of R4b is independently selected from the group consisting of hydrogen, Cl_c6 160983.doc -25- 201247656 alkyl and Cl-C4 alkyl fluorenyl' wherein the alkyl substituent Unsubstituted or substituted by hydroxy, CrC4 alkoxy, amine or mono-Ci_c4 alkylamino and di-C1-C4 alkylamino; or NR4aR4b combined to form a ring nitrogen atom and 〇 or ί a heterocyclic ring selected from the group consisting of ruthenium, osmium and other ring heteroatoms of S, which are independently selected from the group consisting of ruthenium, osmium, 2 or 3 Substituent: halogen, hydroxy, amine, Ci-C4 alkyl, halo 匚丨-(:4 alkyl, hydroxy c丨-C4 alkyl, amine (VC4 alkyl, cvc4 alkoxy, C,- a C4 alkoxy group (:, _<:4 alkyl group and a mono C "C4 alkylamino group and a dialkylamino group; R.5 is absent or selected from the group consisting of hydrogen and Ci-C: 6 alkyl group; Κ·6 is a pendant oxy group, hydrogen, a trans group, an amine group, N(H)-J-R7; J is absent, is c(o) or s(o)2; and R7 is a Ci-C6 alkyl group, Phenyl or benzyl are each replaced by the following. 0--(6 院, Ci-C6 oxy, halogen, phenyl or phenoxy). In one aspect, the compound of formula (I) includes a compound of formula (II) and salts thereof:

其中 z為CH或N ; R8係選自氫、C02H、CVC4烷基、c_c4烷氧基、氣基或 160983.doc -26- 201247656 鹵素； R9係選自CVC6烧基、CVC6烧氧基、苯基、NR9aR9b、 N(H)-C(0)-0-C〗-C4烧基及雜環，其中該雜環具有一或兩個環，各環具有5、6或7個環原子、丨個環氮原子及〇或1個選自N、Ο或S之其他環雜原子，且其中雜環未經取代或經 1、2或3個獨立地選自由以下組成之群的取代基取代：鹵素、羥基、胺基、Ci-C4烧基、鹵基C丨-C4烧基、羥基C丨-c4 烧基、胺基CrC4烷基、（VC4烷氧基、CVC4烷氧基(VC4 _ 烷基及單C1_C4烷基胺基及二烷基胺基；或 R·8與R9組合起來形成選自以下之二價殘基：_〇(CH2)p〇_ 、-o(ch2)2nh-或-〇(ch2)2n(ch3)-;Wherein z is CH or N; R8 is selected from the group consisting of hydrogen, CO2H, CVC4 alkyl, c_c4 alkoxy, gas group or 160983.doc -26- 201247656 halogen; R9 is selected from CVC6 alkyl, CVC6 alkoxy, benzene a group, NR9aR9b, N(H)-C(0)-0-C--C4 alkyl and a heterocyclic ring, wherein the heterocyclic ring has one or two rings, each ring having 5, 6 or 7 ring atoms, fluorene a ring nitrogen atom and hydrazine or 1 other ring hetero atom selected from N, hydrazine or S, and wherein the hetero ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of: Halogen, hydroxy, amine, Ci-C4 alkyl, halo C丨-C4 alkyl, hydroxy C丨-c4 alkyl, amine CrC4 alkyl, (VC4 alkoxy, CVC4 alkoxy (VC4 _ alkane) And a single C1_C4 alkylamino group and a dialkylamine group; or R.8 and R9 are combined to form a divalent residue selected from the group consisting of _〇(CH2)p〇_, -o(ch2)2nh- or -〇(ch2)2n(ch3)-;

Rpa係選自由氫及Ci-C：6烷基組成之群，其中烷基取代基未經取代或經以下取代：羥基、Cl_C4烷氧基、胺基或單 CrC4烷基胺基及二c^-C*烷基胺基；及Rpa is selected from the group consisting of hydrogen and Ci-C: 6 alkyl, wherein the alkyl substituent is unsubstituted or substituted by: hydroxy, Cl_C4 alkoxy, amine or mono-CrC4 alkyl amine and two c^ -C*alkylamino group;

Rm係選自由以下組成之群：氫、Cl-C6烷基及Ci-C4烷醯基’其中炫基取代基未經取代或經以下取代··羥基、C 鲁烧氧基、胺基或單&-<：4烷基胺基及二Cl_c4烷基胺基。在某些態樣中’式（II)化合物包括尺8選自氳、c〇2H、甲基、甲氧基或羥曱基之彼等化合物。某些其他式（II)化合物包括R9選自由以下組成之群的彼等化合物：嗎啉基、哌啶基、哌嗪基及吡咯啶基，其各自未經取代或經一或兩個選自由以下組成之群的取代基取代：（VC4烷基、羥基Cl_c4烷基、胺基Cl_c4烷基、（VC4 院氧基、單CrC4烷基胺基及二烷基胺基，及烷 160983.doc -27- 201247656 氧幾基。其他式（II)化合物包括Z為N之彼等化合物。在其他態樣中，式（II)化合物包括彼等化合物，其中心係選自氫、CChH、曱基、甲氧基或羥罕基； I係選自由以下組成之群：嗎啉基、哌啶基、哌嗪基及。比咯啶基，其各自未經取代或經一或兩個選自由以下組成之群的取代基取代：CrC4烷基、羥基(^-(^4烷基、胺基CrCU 燒基、eve：4烧氧基、單Cl_C4烷基胺基及二Ci_C4烷基胺基’及CVC4烷氧羰基；且z為N。在某些態樣中，式（I)、（la)或（Π)之化合物包括式（na)化合物及其鹽Rm is selected from the group consisting of hydrogen, Cl-C6 alkyl and Ci-C4 alkyl fluorenyl where the hydryl substituent is unsubstituted or substituted by hydroxy, C alkoxy, amine or single &-<:4 alkylamino group and diCl_c4 alkylamino group. In certain aspects, the compound of formula (II) includes the compound of rule 8 selected from the group consisting of hydrazine, c〇2H, methyl, methoxy or hydroxydecyl. Certain other compounds of formula (II) include those compounds wherein R9 is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and pyrrolidinyl, each unsubstituted or selected from one or two Substituents of the following group are substituted: (VC4 alkyl, hydroxyCl_c4 alkyl, amine Cl_c4 alkyl, (VC4 oxime, mono-CrC4 alkylamino and dialkylamine, and alkane 160983.doc - 27- 201247656 Oxygen group. Other compounds of formula (II) include those compounds wherein Z is N. In other aspects, the compound of formula (II) includes such compounds, the center of which is selected from the group consisting of hydrogen, CChH, sulfhydryl, Methoxy or hydroxyhanyl; I is selected from the group consisting of morpholinyl, piperidinyl, piperazinyl and pyrrolidinyl, each of which is unsubstituted or consists of one or two selected from the group consisting of Substituted substituents of the group: CrC4 alkyl, hydroxy (^-(^4 alkyl, amine CrCU alkyl, eve: 4 alkoxy, mono Cl_C4 alkyl amine and diCi_C4 alkyl amine) and CVC4 Alkoxycarbonyl; and z is N. In some aspects, the compound of formula (I), (la) or (Π) includes a compound of formula (na) and a salt thereof

γ為一鍵、0、NR174CR17R18 ;γ is a bond, 0, NR174CR17R18;

160983.doc •28· 201247656160983.doc •28· 201247656

Rla為 Η、F、Cl或 CH3 ; r8為氫、曱基、co2h或曱氡基； R13&R14各自獨立地選自氫或CVc4院基；Rla is Η, F, Cl or CH3; r8 is hydrogen, fluorenyl, co2h or fluorenyl; R13& R14 are each independently selected from hydrogen or CVc4;

Rl5及Rl6各自獨立地選自氩、CVC4烷基、羥基CVC4烷基、胺基’或早C1 - C4烧基胺基及二c丨_ c 4烧基胺基；Rl5 and Rl6 are each independently selected from the group consisting of argon, CVC4 alkyl, hydroxy CVC4 alkyl, amine' or early C1-C4 alkylamino and dic丨_c4 alkylamino;

Rl7係選自氫、Ci-C4烧基或CVC4燒氧幾基；及Rl7 is selected from the group consisting of hydrogen, Ci-C4 alkyl or CVC4 aerobic groups;

其中 R6為氫、羥基、胺基或N(H)-J-R7 ; J為 c(o)或 s(o)2 ; R7為（a)視情況經苯基或苯氧基取代之(^-(：4烷基，或 (b)視情況經(^-(：4烷基、鹵素或(：1-(：4烷氧基取代之苯基；Wherein R6 is hydrogen, hydroxy, amine or N(H)-J-R7; J is c(o) or s(o)2; R7 is (a) optionally substituted by phenyl or phenoxy (^) - (: 4 alkyl, or (b) as appropriate (^-(: 4 alkyl, halogen or (: 1-(: 4 alkoxy substituted phenyl;

Rio係選自氮及Ci_C6烧基’該烧基未經取代或經—咬兩個選自以下之取代基取代：OH、氰基、SOAH3、甲氧基、乙氧基、N(R10a)2及 C(0)(NR丨〇a)2 ;Rio is selected from nitrogen and Ci_C6 alkyl group. The alkyl group is unsubstituted or substituted by two substituents selected from the group consisting of OH, cyano, SOAH3, methoxy, ethoxy, N(R10a)2. And C(0)(NR丨〇a)2;

Ri〇a在每次出現時選自由氫及C〗-C4烷基組成之群，該 160983.doc •29· 201247656Ri〇a is selected from the group consisting of hydrogen and C-C4 alkyl at each occurrence, which is 160983.doc •29· 201247656

Crq烷基經0或！個選自羥基、曱氧基或乙氧基之取代基取代；Crq alkyl via 0 or! a substituent selected from a hydroxyl group, a decyloxy group or an ethoxy group;

Rm係選自由氫、氟、羥基&Cl-C4烷基組成之群。在另—態樣中，式（III)化合物包括以下化合物：其中r!〇為氫或經一或兩個羥基取代基或一個獨立地選自由以下組成之群之取代基取代的匕-匕烷基：氰基、s〇2CH3、甲氧基乙氧基、胺基、單Ci-C2烷基胺基及二Ci_c2烷基胺基、C(〇)NH2、C(0)N(H)Me及 C(0)NMe2。在式（111)之某些其他化合物中，G為經一或兩個羥基取代基或一個獨立地選自由以下組成之群之取代基取代的^-匕烷基：氰基、S〇2CH3、甲氧基、乙氧基、胺基或單Ci_c2烷基胺基及一C1-C2烧基胺基。在又一態樣中’式（I)化合物包括式（IV)化合物及其鹽：Rm is selected from the group consisting of hydrogen, fluorine, hydroxyl & Cl-C4 alkyl. In another aspect, the compound of formula (III) includes a compound wherein r! hydrazine is hydrogen or hydrazine-decane substituted with one or two hydroxy substituents or a substituent independently selected from the group consisting of: Base: cyano group, s〇2CH3, methoxyethoxy group, amine group, mono-Ci-C2 alkyl amine group and di-Ci_c2 alkyl amine group, C(〇)NH2, C(0)N(H)Me And C(0)NMe2. In certain other compounds of formula (111), G is ^-decylalkyl substituted with one or two hydroxy substituents or a substituent independently selected from the group consisting of: cyano, S〇2CH3, A methoxy, ethoxy, amine or mono-Ci_c2 alkylamino group and a C1-C2 alkylamino group. In still another aspect, the compound of formula (I) comprises a compound of formula (IV) and salts thereof:

(IV) 其中(IV) where

Rio、Rn獨立地選自氫及Ci-C6烧基，該烧基未經取代咬經一或兩個選自以下之取代基取代：〇H、S〇2CH3、氮基、曱氧基、乙氧基、N(R10a)2及C(O)N(R10a)2 ;Rio, Rn are independently selected from the group consisting of hydrogen and a Ci-C6 alkyl group which is substituted with one or two substituents selected from the group consisting of hydrazine H, S〇2CH3, nitrogen, decyloxy, and B. Oxyl, N(R10a)2 and C(O)N(R10a)2;

Ri〇a在每次出現時選自由氫及q-C4烷基組成之群，該 CrC4烷基經〇或1個選自羥基、曱氧基或乙氧基之取代基 160983.doc •30- 201247656 取代； 4N(Rl0a)2可形成3·6員環烷基或雜環 R!2係選自由氫及C丨-C4烷基組成之群。在另-態樣中，式㈤化合物包括以下化合物：其中吣為氫或經一或兩個羥基取代基或一個獨立地選自由以下組成之群之取代基取代的〇1<6烷基：氰基、SAC%、甲氧基、乙氧基、胺基、單Cl-c：2烷基胺基及二Ci_c2烷基胺基、C(〇)NH2、C(0)N(H)Me 及 C(〇)NMe2。在式（IV)之某籲些其他化合物中，R10為經一或兩個羥基取代基或一個獨立地選自由以下組成之群之取代基取代的C^C6烷基：氰基、SChCH3、甲氧基、乙氧基、胺基或單基胺基及一C1-C2烧基胺基。在一個態樣中，式（I)、（la)、（II)、（Iia)、（ΙΠ)或（IV)之化合物包括Ri為第三丁基乙炔基、苯基或經F、C1或曱基對位取代之苯基的彼等化合物。在某些情況下，鑑別式之化合物包括R!為苯基或第三丁基乙炔基之彼等化合物。在 ® 式⑴、（⑷、（II)、（Ila)、（III)及/或（IV)之某些其他化合物中，R!為苯基。在式（I)、（la)、（II)、（Ila)、（111)及 /或（IV) 之其他化合物中，R!為第三丁基乙炔基。在另一態樣中，式（I)、（II)、（Ila) ' (III)或（IV)化合物包括R_2為CO2H之彼等化合物。在一個態樣中，式（I)、（la)、（II)、（Ila)、（III)或（IV)化合物包括R3為環己基之彼等化合物。在又一態樣中，（III)之化合物包括R6為氫之彼等化合 160983.doc •31- 201247656 物；Ri〇a is selected from the group consisting of hydrogen and q-C4 alkyl at each occurrence, the CrC4 alkyl via hydrazine or a substituent selected from hydroxy, decyloxy or ethoxy groups 160983.doc • 30- 201247656 Substituted; 4N(R10a)2 can form a 3.6 membered cycloalkyl or heterocyclic ring R!2 is selected from the group consisting of hydrogen and C丨-C4 alkyl. In another aspect, the compound of formula (5) includes a compound wherein hydrazine is hydrogen or substituted with one or two hydroxy substituents or a substituent independently selected from the group consisting of &1 <6 alkyl: cyanide Base, SAC%, methoxy, ethoxy, amine, monoCl-c: 2 alkylamino and diCi_c2 alkyl amine, C(〇)NH2, C(0)N(H)Me and C (〇) NMe2. In some other compounds of formula (IV), R10 is C^C6 alkyl substituted with one or two hydroxy substituents or a substituent independently selected from the group consisting of: cyano, SChCH3, A An oxy, ethoxy, amine or monoamine group and a C1-C2 alkylamino group. In one aspect, the compound of formula (I), (la), (II), (Iia), (ΙΠ) or (IV) includes Ri as a third butyl ethynyl group, a phenyl group or via F, C1 or The compounds of the phenyl group substituted by a fluorenyl group. In some cases, the compounds of the formula include those wherein R! is phenyl or tert-butylethynyl. In some other compounds of formula (1), ((4), (II), (Ila), (III) and/or (IV), R! is phenyl. In formula (I), (la), (II) And R.sup.3, (II), The compound of (III) or (IV) includes those compounds wherein R 2 is CO 2 H. In one aspect, the compound of formula (I), (la), (II), (Ila), (III) or (IV) includes R 3 . In another aspect, the compound of (III) includes R6 which is a compound of hydrogen 160983.doc • 31-201247656;

Rio為氫或羥基Cl-C6烷基；及 Rll為氫、曱基、經基或氟。在又一態樣中，（III)之化合物包括1為氫之彼等化合物；Rio is hydrogen or a hydroxy C-C6 alkyl group; and R11 is hydrogen, fluorenyl, thiol or fluoro. In still another aspect, the compound of (III) includes a compound wherein 1 is hydrogen;

Rl〇為羥基CVC6烷基；及 Rii為氫、甲基、羥基或氟。在又一態樣中，（iv)之化合物包括Rl0為羥基c「C6烷基之彼等化合物；Rl is a hydroxy CVC6 alkyl group; and Rii is hydrogen, methyl, hydroxy or fluoro. In still another aspect, the compound of (iv) includes those compounds wherein R10 is a hydroxy c "C6 alkyl group;

Rll為氫或甲基；及Rll is hydrogen or methyl; and

Rl2為氫或甲基。在某些態樣中，提供式（111)化合物，其中R1為第三丁基乙炔基、苯基或經F、C1或甲基對位取代之苯基； R2為 co2h ; R3為環己基； R6為氫；第三丁基Rl2 is hydrogen or methyl. In certain aspects, a compound of formula (111) is provided, wherein R1 is a third butyl ethynyl group, a phenyl group or a phenyl group substituted with a F, C1 or methyl group; R2 is co2h; R3 is a cyclohexyl group; R6 is hydrogen; third butyl

Rio為經基Ci-C6燒基；及Rio is a base based Ci-C6 base; and

Rll為氫、經基、甲基咬敗。在某些態樣中，提供式(III)化合物，其中R,為乙炔基； R2為 C〇2H ; I為環己基； R6為氫；Rll is hydrogen, base, and methyl. In certain aspects, a compound of formula (III) is provided wherein R is ethynyl; R2 is C〇2H; I is cyclohexyl; R6 is hydrogen;

Rio為經基Ci-C6貌基；及 160983.doc -32- 201247656 R〗1為氫、羥基、甲基或氟。在某些態樣中，提供式（IV)化合物，其中Ri為第三丁基乙炔基； R2為 co2h ; R3為環己基；Rio is a radical based on Ci-C6; and 160983.doc -32- 201247656 R is 1 hydrogen, hydroxy, methyl or fluoro. In certain aspects, a compound of formula (IV) wherein Ri is a third butyl ethynyl group; R2 is co2h; R3 is cyclohexyl;

Rio為羥基CrCe烷基；及Rio is a hydroxyCrCe alkyl group;

Rii及Ru獨立地選自由氫及甲基組成之群。在某些其他態樣中，本發明提供式化合物Rii and Ru are independently selected from the group consisting of hydrogen and methyl. In certain other aspects, the invention provides a compound of the formula

(V) 或其鹽；其中 Rll為氫或甲基；(V) or a salt thereof; wherein R11 is hydrogen or methyl;

Rio為C2C6經燒基，其中經基為一級醇、二級醇或三級醇。舉例而言，R1。係、選自 _(CH2)a0H、_(CH2)bcH(CH3)OH 或-(CH2)bC(CH3)2〇H，其巾 a為 2、3 或 4且 b為 1、2 或 3。在式（V)之某些化合物中’ a為2或3且b為1或2。如本文所用，術語「異構體」係指具有相同分子式但原子排列及組態不同的不同化合物。亦如本文所用，術語「光學異構體」或「立體異構體」係指各種立體異構組態中之任一者，其可在本發明之既定化合物中存在且包括幾 160983.doc -33· 201247656 何異構體。應瞭解’取代基可在碳原子之對掌性中心處連接。因此，本發明包括化合物之對映異構體、非對映異構體或Μ旋體。「對映異構體」I —對立體異構體，其彼此為不可重疊鏡像。一對對映異構體之υ混合物為「外消旋」混合物。該術語適當時用以指示外消旋混合物。非對映異構體」為具有至少兩個不對稱原子，但其彼此不為鏡像之立體異構體。根據Cahn lng〇id p代I% 系統指定絕對立體化學。當化合物為純對映異構體時，可由及或沾定各對掌性碳處之立體化學。視化合物旋轉納〇線之波長下之平面偏振光之方向（右旋或左旋）而定，可指定絕對組態未知之經解析化合物為⑴或㈠。本文所述之某些化口物3彳《多個不對稱中心或軸，因此可產生可根據絕對立體化學定義為或⑺-之對映異構體、非對映異構體及其他立體異構形式。本發明意欲包括所有此等可能之異構體’包括外消旋混合物、光學純形式及中間物混合物可使用對掌性合成組元或對掌性試劑製備或使用習知技術解析光學活性⑷·異構體及⑺·異構體。若化合物含有雙鍵’則取代基可為阳組態。若化合物含有經二取代之環院基’則環院基取代基可具有順式或反式組態。亦意欲包括所有互變異構形式。如本文所用術5吾「鹽」係指本發明化合物之酸加成鹽或鹼加士鹽。「鹽」尤其包括「醫藥學上可接受之鹽」。術 τ!藥學上可接受之鹽」係指保留本發明化合物之生物效用及性質且通常不會在生物學上或其他方面不合需要之 160983.doc •34· 201247656 i。在許多情況下，本發明化合物藉助於存在胺基及/或羧基或其類似基團而能夠形成酸鹽及/或鹼鹽。醫藥學上可接受之酸加成鹽可用無機酸及有機酸形成，例如乙酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、溴化物/ 氫溴酸鹽 '碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、樟腦磺酸鹽、氣化物/鹽酸鹽、氣茶鹼鹽、檸檬酸鹽、乙烷二磺酉欠鹽、反丁浠二酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖搭酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁稀二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、曱基硫酸鹽、萘甲酸鹽、萘磺酸鹽、菸鹼酸鹽、硝酸鹽、十八酸鹽、油酸鹽、乙一酸鹽、掠櫚酸鹽、雙經萘酸鹽、鱗酸鹽/填酸氫鹽/磷酸二氫鹽、聚半乳糖醛酸鹽、丙酸鹽、硬脂酸鹽、丁二酸鹽、續基水楊酸鹽、酒石酸鹽、曱苯績酸鹽及三氟乙酸鹽。可產生鹽之無機酸包括例如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似酸。可用於產生鹽之有機酸包括例如乙酸、丙酸、乙醇酸、乙一酸、順丁婦二酸、丙二酸、丁二酸、反丁稀二酸、酒石酸、檸檬酸、苯甲酸、杏仁酸、曱烷磺酸、乙烧確酸、甲苯磺酸、磺基水楊酸及其類似酸。可用無機鹼及有機鹼形成醫藥學上可接受之鹼加成鹽。可用於產生鹽之無機鹼包括例如銨鹽及來自週期表之第 I攔至第XII欄之金屬。在某些實施例中，鹽衍生自納、 160983.doc •35· 201247656 鉀、銨、鈣、鎂、鐵、銀、鋅及銅；尤其適合之鹽包括銨鹽、斜鹽、納鹽、約鹽及錯鹽。可用於產生鹽之有機鹼包括例如一級胺、二級胺及三級胺；經取代之胺，包括天然存在之經取代之胺、環胺、鹼離子交換樹脂及其類似物。某些有機胺包括異丙胺、苄星 (benzathine)、膽驗鹽（cholinate)、二乙醇胺、二乙胺、離胺酸、葡甲胺、哌嗪及緩血酸胺。本發明之醫藥學上可接受之鹽可藉由習知化學方法自母體化合物（鹼性或酸性部分）來合成。一般而言，此等鹽可藉由使此等化合物之游離酸形式與化學計量之量的適當驗 (諸如Na、Ca、Mg或K之氫氧化物、碳酸鹽、碳酸氫鹽或其類似物）反應或藉由使此等化合物之游離鹼形式與化學計量之量的適當酸反應來製備。此等反應通常在水中或在有機溶劑中或在二者之混合物中進行。一般而言，在切實可行的情況下，需要使用非水性介質，如***、乙酸乙酯、乙醇、異丙醇或乙腈。其他適合之鹽的清單可見於例如「Remington's Pharmaceutical Sciences」，第 20版，Mack Publishing Company，Easton, Pa.，（1985);及「Handbook of Pharmaceutical Salts: Properties, Selection, and Use」， Stahl 及 Wermuth (Wiley-VCH，Weinheim，Germany, 2002) 中o 本文中給出之任何式均亦意欲表示化合物之未經標記形式以及經同位素標記之形式。經同位素標記之化合物具有由本文中給出之式描繪的結構，但一或多個原子經具有選 160983.doc -36· 201247656 定原子質量或質量數之原子置換。可併入本發明化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氣之同位素’分別諸如 2h、3H、UC、13c、14c、15N、18f、31p、 p ' s、36cl、1251。如本文中所定義，本發明包括各種經同位素標記之化合物，例如存在諸如3h、13c及14c之放Rio is a C2C6 alkyl group in which the radical is a primary alcohol, a secondary alcohol or a tertiary alcohol. For example, R1. And selected from _(CH2)a0H, _(CH2)bcH(CH3)OH or -(CH2)bC(CH3)2〇H, wherein towel a is 2, 3 or 4 and b is 1, 2 or 3. In certain compounds of formula (V) 'a is 2 or 3 and b is 1 or 2. As used herein, the term "isomer" refers to different compounds having the same molecular formula but differing in the arrangement and configuration of the atoms. Also as used herein, the term "optical isomer" or "stereoisomer" refers to any of a variety of stereoisomeric configurations which may be present in a given compound of the invention and include several 160983.doc - 33· 201247656 He isomer. It should be understood that the substituents may be attached at the palm center of the carbon atoms. Thus, the invention includes enantiomers, diastereomers or rotators of the compounds. "Enantiomers" I - are stereoisomers, which are non-superimposable mirror images of each other. The ruthenium mixture of the two enantiomers is a "racemic" mixture. This term is used to indicate a racemic mixture as appropriate. Diastereomers are stereoisomers having at least two asymmetric atoms but which are not mirror images of one another. Absolute stereochemistry is specified according to the Cahn lng〇id p generation I% system. When the compound is a pure enantiomer, the stereochemistry of each pair of palmitic carbons can be determined and characterized. Depending on the direction of the plane-polarized light at the wavelength of the compound's rotating nanowire (right-handed or left-handed), the resolved compound with an unknown configuration can be specified as (1) or (a). Certain of the hydration materials described herein are "a plurality of asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (7)- according to absolute stereochemistry. Form. The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures, which can be prepared using palmitic synthetic components or for palmitic reagents or by conventional techniques to resolve optical activity (4). Isomers and (7)·isomers. If the compound contains a double bond 'the substituent can be a positive configuration. If the compound contains a disubstituted ring-based group, the ring-based substituent may have a cis or trans configuration. It is also intended to include all tautomeric forms. As used herein, "salt" means an acid addition salt or an alkali salt of a compound of the present invention. "Salt" includes, inter alia, "pharmaceutically acceptable salts." τ! pharmaceutically acceptable salts are meant to retain the biological utility and properties of the compounds of the invention and are generally not biologically or otherwise undesirable. 160983.doc • 34· 201247656 i. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amine groups and/or carboxyl groups or the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, such as acetates, aspartates, benzoates, besylate, bromide/hydrobromide 'bicarbonate/ Carbonate, hydrogen sulfate/sulfate, camphor sulfonate, vapor/hydrochloride, gas theophylline, citrate, ethane disulfonate, succinic acid, glucoheptonic acid Salt, gluconate, gluconate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, cisplatin Dibasic acid salt, malonate, almond acid, methanesulfonate, sulfhydryl sulfate, naphthoate, naphthalene sulfonate, nicotinic acid salt, nitrate salt, octadecanoate, oleate , ethanoate, chlorate, dip-naphthate, sulphate/hydrogenate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate , contiguous salicylate, tartrate, phthalic acid salt and trifluoroacetate. Inorganic acids which can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids which can be used to produce salts include, for example, acetic acid, propionic acid, glycolic acid, ethylic acid, cis-butanic acid, malonic acid, succinic acid, butyl succinic acid, tartaric acid, citric acid, benzoic acid, mandelic acid , decanesulfonic acid, ethanoic acid, toluenesulfonic acid, sulfosalicylic acid and the like. A pharmaceutically acceptable base addition salt can be formed using an inorganic base and an organic base. Inorganic bases useful in the production of salts include, for example, ammonium salts and metals from Columns I to XII of the Periodic Table. In certain embodiments, the salt is derived from sodium, 160983.doc • 35· 201247656 potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, oblique salts, sodium salts, about Salt and wrong salt. Organic bases useful for the production of salts include, for example, primary amines, secondary amines, and tertiary amines; substituted amines include naturally occurring substituted amines, cyclic amines, base ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods. In general, such salts can be suitably tested by the free acid form of such compounds with a stoichiometric amount such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K. The reaction is prepared or by reacting the free base form of such compounds with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or in an organic solvent or a mixture of the two. In general, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are required where practicable. A list of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) o Any formula given herein is also intended to indicate the unlabeled form of the compound as well as the isotopically labeled form. The isotopically labeled compound has a structure depicted by the formula given herein, but one or more atoms are replaced by an atom having an atomic mass or mass number selected from 160983.doc - 36 · 201247656. Examples of isotopes which may be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and gas isotopes such as 2h, 3H, UC, 13c, 14c, 15N, 18f, 31p, p's, respectively. 36cl, 1251. As defined herein, the invention includes various isotopically labeled compounds, such as the presence of such as 3h, 13c, and 14c.

射性同位素的化合物。此等經同位素標記之化合物適用於代。射研九（用14C);反應動力學研究（用例如4或3印；偵測或成像技術，諸如正電子發射斷層攝影法（PET)或單光子發射電腦斷層攝影法（SPECT)，包括藥物或受質組織分佈 2析法；或患者之放射性治療。詳言之，PEMSPECT研九"T flb尤其需要F或經標δ己化合物。本發明之同位素標記之化合物及其前藥一般可藉由進行下域述流程或實例及製備中所揭不之程序，藉由用輕易可得之同位素標記試劑取代非同位素標記試劑來製備。 '此外以較重同位素，尤其用氘（亦即2Η或D)進行之取代可得到由較大代謝穩定性產生之某些治療優勢，例如活體内半衰期增加或劑量需求減小或治療指數改良。應瞭解，在此情形中，氘被視為式⑴化合物之取代基。此較重同位素（特定言之濃度可由同位素增濃因素 (刪opic enrichment factor)定義。如本文所用術語厂同位素增濃因素之間的比率。」意謂指定同位素之同位素豐度與天然豐度若本發明化合物中之取代基表示氘，則此化合物對於各指定氣原子之同位素增濃因素為至少3遍（各指定氛原子處52.5%気併入)、至少4〇〇〇(6〇%氣併入）、至 160983.doc •37- 201247656 少4500(67.5%氘併入）、至少5000(75%氘併入）、至少5500 (82.5%氘併入）、至少6000(90%氘併入）、至少6333.3(95% 氘併入）、至少6466.7(97%氘併入）、至少6600(99%氘併入）或至少6633.3(99.5%氘併入）。同位素標記之式（I)化合物一般可藉由熟習此項技術者已知之習知技術，或藉由類似於隨附實例及製備中所述方法之方法’使用適當同位素標記之試劑替代先前採用之未標記試劑來製備。本發明之醫藥學上可接受之溶劑合物包括結晶化溶劑可經同位素取代（例如DA、d6·丙酮、d6-DMSO)的溶劑合物。本發明化合物’亦即含有能夠充當氫鍵之供體及/或受體之基團的式（I)化合物可能夠與適合共晶體形成物形成共晶體。此等共晶體可藉由已知共晶體形成程序自式⑴化合物製備。此等程序包括在溶液中將式⑴化合物與共晶體形成物一起在結晶條件下研磨、加熱、共昇華、共熔融或接觸及分離藉此形成之共晶體，共晶體形成物包括w〇 2004/078163中描述之共晶體形成物。因此，本發明進一步提供包含式（I)化合物之共晶體。如本文所用，術語「醫藥學+ 苯予上3接受之載劑」包括任何及所有溶劑、分散介質、塗料、界面活性劑、抗氧化劑、防腐劑(例如抗細菌劑、抗真菌劑）、等張劑、吸收延遲劑、鹽、防腐劑、藥物、藥物衆物穩疋劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調 π木劑木枓及其類似物及其 160983.doc -38· 201247656 組合，如熟習此項技術者所知（參見例如Remington，sA compound of an isotope. These isotopically labeled compounds are suitable for use in generations.射研九 (using 14C); reaction kinetics studies (using, for example, 4 or 3 impressions; detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drugs Or the tissue distribution 2 method; or the patient's radiotherapy. In particular, PEMSPECT research "T flb especially requires F or the standard δ-hexa compound. The isotope-labeled compounds of the present invention and their prodrugs can generally be borrowed Prepared by substituting the procedures described in the below-described procedures or examples and preparations, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. 'In addition to heavier isotopes, especially ruthenium (ie 2 Η or D) Substitution can result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or improved therapeutic index. It should be understood that in this case, hydrazine is considered to be a compound of formula (1) Substituent. This heavier isotope (specifically, the concentration can be defined by the isotope enrichment factor). As used herein, the term isotope enrichment factor The ratio means "isotope abundance and natural abundance of the specified isotope. If the substituent in the compound of the present invention represents hydrazine, the isotope enrichment factor of the compound for each of the specified gas atoms is at least 3 times (52.5 for each designated atomic atom) %気 incorporation), at least 4〇〇〇 (6〇% gas incorporation), to 160983.doc •37- 201247656 less 4500 (67.5%氘 incorporation), at least 5000 (75%氘 incorporation), at least 5500 (82.5% 氘 incorporation), at least 6000 (90% 氘 incorporation), at least 6333.3 (95% 氘 incorporation), at least 6466.7 (97% 氘 incorporation), at least 6600 (99% 氘 incorporation) or at least 6633.3 (99.5% incorporation). Isotopically labeled compounds of formula (I) can generally be suitably used by conventional techniques known to those skilled in the art, or by methods analogous to the methods described in the accompanying examples and preparations. The isotope-labeled reagent is prepared in place of the previously used unlabeled reagent. The pharmaceutically acceptable solvate of the present invention includes a solvate in which the crystallization solvent can be isotopically substituted (for example, DA, d6.acetone, d6-DMSO). The compound of the invention 'is also capable of acting as a hydrogen bond The compound of formula (I) of the group of the body and/or the acceptor may be capable of forming a co-crystal with a suitable eutectic former. Such co-crystals may be prepared from a compound of formula (1) by known co-crystal formation procedures. The compound of formula (1) is ground, heated, co-sublimed, co-melted or contacted and separated in a solution under crystallization conditions, the co-crystal formation comprising the composition described in WO 2004/078163. Co-crystal formers. Accordingly, the present invention further provides co-crystals comprising a compound of formula (I). As used herein, the term "pharmaceutical + benzoic acid accepts carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg antibacterial, antifungal), etc. Tonicity, absorption delaying agent, salt, preservative, drug, drug stability agent, adhesive, excipient, disintegrating agent, lubricant, sweetener, π wood hibiscus and the like Its 160983.doc -38· 201247656 combination, as known to those skilled in the art (see for example Remington, s

Pharmaceutical Sciences，第 18版，Mack Printing Company， 1990，第1289-1329頁）。除了在任何習知載劑與活性成分均不相容之情況外，涵蓋其在治療或醫藥組合物中之用途。疋像韦欵量」係指引發個體之生術語本發明化合物物或醫學反應（例如降低或抑制酶或蛋白質活性，或改善症狀、緩解病狀、減緩或延遲疾病進展或預防疾病等）的Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It is intended to cover its use in therapeutic or pharmaceutical compositions, except where any conventional carrier is incompatible with the active ingredient. "疋"" refers to the initiation of an individual's terminology. A compound or medical response (such as reducing or inhibiting the activity of an enzyme or protein, or improving symptoms, alleviating a condition, slowing or delaying disease progression or preventing disease, etc.)

本發明化合物之量。在-個非限制性實_巾，術語「治療有效量」係指當投與至個體時有效達成以下之本發明化合物之量··⑴至少部分緩解、抑制、預防及，或改善⑴由赠感染介導，或⑼與HCV感染相關之病狀或病症或疾病；或⑺減少或抑制HCV之病毒複製或病毒負荷。在另一非限制性實施例中’術語「治療有效量」係指當投與至細胞或組織或非細胞生物物f或培養基時有效地至少部分降The amount of the compound of the invention. In the context of a non-limiting embodiment, the term "therapeutically effective amount" means an amount effective to achieve the following compounds of the invention when administered to an individual. (1) at least partially alleviating, inhibiting, preventing, and ameliorating (1) Infection-mediated, or (9) a condition or disorder or disease associated with HCV infection; or (7) reducing or inhibiting viral replication or viral load of HCV. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an effective at least partial reduction when administered to a cell or tissue or a non-cellular organism f or medium.

低或抑制NS5b活性；或至少部分減少或抑制HC 發明化合物之量。 7 + 動Γ1::，術語「個體」係指動物。動物通常為哺乳動物°個體亦指例如靈長類動物（例如性)、乳牛、綿羊、山羊、員男性或女鼠、魚、鳥及其類似物。在某”施：中4、大氣、小 ο 仞中，個體為靈長類動物在其他貫施例巾，個體為人類。如：文所用，術語「抑制」係指減輕或抑症狀或病症或疾病，或顯著物，舌性或過程之基線活 160983.doc -39- 201247656 性0 如本文所用，在一個實施例中，術語「治療」任何疾病或病症係指改善疾病或病症（亦即減緩或阻止或減少疾病或至少一種其臨床症狀之發展）。在另一實施例中，「治療j係指緩解或改善至少一個身體參數，包括患者可能不可辨別之身體參數。在又一實施例中，「治療」係指在身體上（例如穩定化可辨別之症狀）、生理上（例如穩定化身體參數）或兩方面調節疾病或病症。在又一實施例中，「治療」係指預防或延遲疾病或病症之發作或發展或進展。如本文所用，若個體將在生物學、醫學或生活品質方面自治療獲益，則該個體「需要」此治療。如本文所用，除非本文中另外說明或與上下文明顯抵觸’否則將本發明上下文中（尤其在申請專利範圍之上下文中)所用之術語「一」、「該」及類似術語視為與複數。 *非本文中另外說明或上下文另外明顯抵觸，否則本3 所述之所有方法均可以任何適合順序來進行。使用本文指供之任何及所有實例或例示性語言（例如「諸如」）僅意發較好地說明本發明，且不會對另外 '、成限制。不會對另外所主張之本發明範心本發明化合物之任原子⑽如碳或其類似原子勺可以外核或對映異構性增濃形式存在，例蝴_、处或 (λ，Θ-組態。在某些實施例中一飞（)-組態中各不對稱有至映異構體過量'至少峨對映異構體 160983.doc 201247656 過量、至少70%對映異構體過量、至少8〇%對映異構體過量、至少90。/。對映異構體過量、至少95%對映異構體過量或至少99%對映異構體過量.若可能，則具有不飽和鍵之原子處之取代基可以順式_(z)_或反式_(五)_形式存在。因此，如本文所用，本發明化合物可呈可能的異構體、旋轉異構體、滯轉異構體、互變異構體或其混合物_之一種形式，例如實質上純的幾何（順式或反式）異構體、非對映異構體、光學異構體（對映體）、外消旋體或其混合物。基於組分之物理化學差異，例如藉由層析法及/或分步 •、n Ba 1*將任何所仔之異構體混合物分離為純的或實質上純的幾何異構體或光學異構體、非對映異構體、外消旋體。最終產物或中間物之任何所得外消旋體均可藉由已知方法，例如藉由分離用光學活性酸或鹼獲得之其非對映異構及釋放光學活性酸性或鹼性化合物而解析為光學對映體1咩S之，鹼性部分因此可用以將本發明化合物解析為其$學對映體，例如藉由將用光學活性酸（例如酒石酸、二苯甲醯基酒石酸、二乙醯基酒石酸、二-α〇,·對甲苯甲醯基酒石酸、杏仁酸、蘋果酸或樟腦-1〇_磺酸）形成之鹽分步結晶來達^亦可藉由對掌性層析，例如使用對掌性吸附劑之高壓液相層析（HPLC)解析外消旋產物。本發明化合物係以游離形式'以其鹽形式或以其前藥衍生物形式獲得。當鹼性基團與酸性基團存在㈣—分子中時，本發明化 1609S3.doc -41 - 201247656 合物亦可形成内鹽’例如兩性離子分子。本發明亦提供本發明化合物之前藥，其在活體内轉化為本發明化合物。前藥為活性或非活性化合物，其在向個體投與該前藥之後經由活體内生理作用（諸如水解、新陳代謝及類似生理作用）經化學修飾成為本發明化合物。適用性及製造及使用前藥所涉及之技術已為熟習此項技術者所熟知。刚藥可在概念上劃分為兩種非互斥類別，即生物前驅體前藥及載劑前藥。參見Γ心〇/ ，第 31_34(Wermuth編，Academic p職，—Low or inhibiting NS5b activity; or at least partially reducing or inhibiting the amount of HC inventive compound. 7 + Γ 1:: The term "individual" means an animal. Animals are usually mammals. Individuals also refer to, for example, primates (e.g., sex), cows, sheep, goats, males or females, fish, birds, and the like. In a certain application: in the atmosphere, in the atmosphere, in the small 仞 ,, the individual is a primate in other cases, the individual is a human. As used herein, the term "inhibition" refers to alleviating or inhibiting symptoms or conditions or Baseline activity of disease, or significant, lingual or process 160983.doc -39- 201247656 property 0 As used herein, in one embodiment, the term "treating" any disease or condition refers to ameliorating a disease or condition (ie, slowing down) Or prevent or reduce the progression of the disease or at least one of its clinical symptoms. In another embodiment, "treatment j" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that the patient may not discern. In yet another embodiment, "treatment" refers to being physically (eg, stabilized and discernible) Symptoms), physiologically (eg, stabilizing physical parameters), or both, modulating a disease or condition. In yet another embodiment, "treatment" refers to preventing or delaying the onset or progression or progression of a disease or condition. As used herein, an individual "needs" the treatment if the individual will benefit from treatment in terms of biology, medicine, or quality of life. As used herein, the terms "a", "the", and <RTI ID=0.0> </ RTI> <RTIgt; </ RTI> are used in the context of the present invention, particularly in the context of the claims. * Not otherwise stated herein or otherwise clearly contradicted by the context, otherwise all of the methods described in this section can be performed in any suitable order. The use of any and all examples or exemplary language (such as "such as") The present invention does not claim that any of the atoms of the present invention (10) such as carbon or a similar atomic spoon may exist in an exo- or enantiomerically enriched form, for example, λ, 或, or (λ, Θ- Configuration. In some embodiments, each asymmetry has an enantiomeric excess of at least one enantiomer in a fly()-configuration. 160983.doc 201247656 Excess, at least 70% enantiomeric excess , at least 8 % enantiomeric excess, at least 90% by weight of the enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess. If possible, The substituent at the atom of the saturated bond may exist in the form of cis_(z)_ or trans-(f)_. Thus, as used herein, the compound of the invention may be a possible isomer, a rotamer, a stagnation a form of a transisomer, a tautomer or a mixture thereof, such as a substantially pure geometric (cis or trans) isomer, a diastereomer, an optical isomer (enantiomer) , racemate or mixture thereof. Based on physicochemical differences of the components, for example by chromatography and / or step by step, n Ba 1 * The mixture of isomers of the genus is isolated as a pure or substantially pure geometric isomer or optical isomer, diastereomer, racemate. Any resulting racemic of the final product or intermediate The body can be resolved into the optical enantiomer 1咩S by a known method, for example, by isolating its diastereoisomers obtained by using an optically active acid or base and releasing an optically active acidic or basic compound. The moiety can therefore be used to resolve a compound of the invention to its $en enantiomer, for example by using an optically active acid (eg tartaric acid, benzopyristyl tartaric acid, dimethyl tartaric acid, di-α 〇, · p-toluene) Salt formed by the formation of a salt of methic acid, mandelic acid, malic acid or camphor-1 〇 sulfonic acid, or by high pressure liquid chromatography using a palmitic adsorbent, for example, by palm chromatography (HPLC) Analyzes the racemic product. The compound of the invention is obtained in its free form as its salt form or as a prodrug derivative thereof. When a basic group and an acidic group are present in the (tetra)-molecular group, the invention is 1609S3.doc -41 - 201247656 compounds can also form Salts such as zwitterionic molecules. The invention also provides prodrugs of the compounds of the invention which are converted in vivo to the compounds of the invention. Prodrugs are active or inactive compounds which, after administration of the prodrug to an individual, via in vivo physiology The effects (such as hydrolysis, metabolism, and the like) are chemically modified to form the compounds of the present invention. Applicability and techniques involved in the manufacture and use of prodrugs are well known to those skilled in the art. The drug can be conceptually divided into two. Non-exclusive categories, ie bioprecursor prodrugs and carrier prodrugs. See Γ心〇 / , 31_34 (Wermuth ed., Academic p, -

Diego’ Calif·，2001)。一般而言，生物前驅體前藥為非活性或與相應活性藥物化合物相比具有低活性之化合物其含有-或多個保護基藉由代謝或溶劑分解作用而轉化成活性形式。活性藥物形式與任何釋放之代謝產物均應具有可接受之低毒性。載劑前藥為含有例如改良吸收及/或定位傳遞至作用部位之輸送部分的藥物化合物。對於此載劑前藥，需要藥物刀與輸送部分之間的連接為共價鍵，前藥為非活性或活性小=藥物化合物，且任何所釋放之輸送部分均為可接受地無’性。對於輸送部分意欲增強吸收之前藥’輸送部分之釋放通常為快逮的。在其他情況下，需要利用提供緩慢釋放之。p刀’例如某些聚合物或其他部分，諸如環糊精。載劑前藥可例如用於令自^ ^ 用於改良一或多種以下性質：提高親脂增加藥理作用持續時間、提高位點特異性、降低毒性及不良反應及/或改良藥物調配物（例如穩定性、水溶性、 160983.doc •42· 201247656 抑制不合需要之感官或生化性質）。舉例而言，可藉由（a) 羥基與親脂性羧酸（例如具有至少一個親脂性部分之缓酸）或（b)羧酸基與親脂性醇（例如具有至少一個親脂性部分之醇’例如脂族醇）之酯化反應提高親脂性。例示性前藥為例如游離羧酸與硫醇之S-醯基衍生物及醇或酚之0-醢基衍生物之酯，其中醯基具有如本文中定義之含義。適合之前藥通常為醫藥學上可接受之酯衍生物，其可在生理條件下藉由溶劑分解轉化為母體羧酸，例如此項技術中習用之低碳烷基酯、環烷基酯、低碳烯基酯、苯曱醋、單取代之低碳烧基酯或二取代之低碳院基酯，諸如-(胺基、單低碳烷基胺基或二低碳烷基胺基、羧基、低碳烷氧羰基）-低碳烷基酯、-(低碳烷醯氧基、低碳烷氧幾基或一低碳院基胺基幾基）-低碳烧基酯’諸如特戊酿氧曱酯及其類似物。另外，胺已經遮蔽為經芳基羰氧基甲基取代之衍生物，其由活體内酯酶裂解，從而釋放游離藥物及甲醛（Bundgaard，*/· MeA CTzew. 2503 (1989))。此外，含有酸性NH基之藥物（諸如咪唑、醯亞胺、吲哚及類似物）已經N_ 醯氧基甲基遮蔽（Bundgaard，£)以4« o/iWwgj，Elsevier (1985)) »已將羥基遮蔽為酯及醚。Ep 〇39 〇51(sl〇an&Diego’ Calif·, 2001). In general, bioprecursor prodrugs are compounds which are inactive or have low activity compared to the corresponding active pharmaceutical compound, which contain - or more protecting groups which are converted to the active form by metabolism or solvolysis. The active drug form and any released metabolites should have acceptable low toxicity. The carrier prodrug is a pharmaceutical compound containing, for example, improved delivery and/or localization of the delivery moiety to the site of action. For this carrier prodrug, the link between the drug knife and the delivery moiety is required to be a covalent bond, the prodrug is inactive or less active = the drug compound, and any delivered delivery portion is acceptably non-sexual. The release of the delivery portion of the drug prior to delivery of the portion intended to enhance absorption is generally rapid. In other cases, it is necessary to take advantage of the provision of slow release. The p-knife 'e.g., certain polymers or other parts, such as cyclodextrin. Carrier prodrugs can, for example, be used to modify one or more of the following properties: increase lipophilicity to increase the duration of pharmacological action, increase site specificity, reduce toxicity and adverse effects, and/or improve drug formulation (eg, Stability, water solubility, 160983.doc •42· 201247656 inhibits undesirable sensory or biochemical properties). For example, by (a) a hydroxyl group with a lipophilic carboxylic acid (eg, a slow acid having at least one lipophilic moiety) or (b) a carboxylic acid group and a lipophilic alcohol (eg, an alcohol having at least one lipophilic moiety) For example, the esterification reaction of an aliphatic alcohol increases lipophilicity. Exemplary prodrugs are, for example, the S-mercapto derivatives of free carboxylic acids and thiols and the esters of alcohols or 0-mercapto derivatives of phenols wherein the fluorenyl group has the meaning as defined herein. Suitable prodrugs are generally pharmaceutically acceptable ester derivatives which can be converted to the parent carboxylic acid by solvolysis under physiological conditions, such as the lower alkyl esters, cycloalkyl esters, low in the art. a nalyl ester, a benzoquinone vinegar, a monosubstituted low carbon alkyl ester or a disubstituted low carbon urethyl ester such as -(amino, monolower alkylamino or dilower alkylamino, carboxy , lower alkoxycarbonyl)-lower alkyl ester, -(lower alkyl alkoxy, lower alkoxy alkoxy or a lower carbon alkoxy group) - lower carboester - such as pentylene Stuffed oxime esters and their analogs. In addition, the amine has been masked as a derivative substituted with an arylcarbonyloxymethyl group which is cleaved by an in vivo esterase to release the free drug and formaldehyde (Bundgaard, */· MeA CTzew. 2503 (1989)). In addition, drugs containing acidic NH groups (such as imidazoles, quinones, anthraquinones and the like) have been masked by N_methoxymethyl (Bundgaard, £) to 4 « o/i Wwgj, Elsevier (1985)) » Hydroxyl groups are blocked as esters and ethers. Ep 〇39 〇51(sl〇an&

Little)揭示曼尼希驗（Mannich-base)氧將酸前藥、其製備及用途。此外，本發明化合物（包括其鹽）亦可以其水合物形式獲得或包括其結晶所用之其他溶劑。本發明化合物可固有地或有意地與醫藥學上可接受之溶劑（包括水）形成溶劑合 160983.doc -43- 201247656 物；因此，本發明意欲涵蓋溶合形式及非溶合形式。術語「溶劑合物」係指本發明化合物（包括其醫藥學上可接受之鹽）與一或多個溶劑分子之分子複合物《此等溶劑分子為醫藥技術中常用之溶劑分子，已知其對於接受者無害，例如為水、乙醇及其類似物❶術語「水合物」係指溶劑分子為水之複合物。本發明化合物（包括其鹽、水合物及溶劑合物）可固有地或有意地形成多晶型物。在另一態樣中’本發明提供一種醫藥組合物，其包含本發明化合物及醫藥學上可接受之載劑。醫藥組合物可經調配用於特定投藥途徑，諸如經口投與、非經腸投與及經直腸投與等。另外’本發明之醫藥組合物可以固體形式（包括（但不限於）膠囊、旋劑、丸劑、顆粒、散劑或栓劑）或液體形式（包括（但不限於）溶液、懸浮液或乳液）構成。可對醫藥組合物進行習知醫藥操作，諸如滅菌，及/或醫藥組合物可含有習知惰性稀釋劑、潤滑劑或緩衝劑，以及佐劑，諸如防腐劑、穩定劑、濕潤劑、乳化劑及緩衝劑等。醫藥組合物通常為包含活性成分以及以下之旋劑或明膠膠囊： a) 稀釋劑，例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糠醇、纖維素及/或甘胺酸； b) 湖滑劑，例如二氧化#、滑石、硬脂酸、其鎮鹽或鈣鹽及/或聚乙二醇；對於錠劑，亦包含： c) 黏合劑，例如矽酸鎂鋁、澱粉糊、明膠、黃蓍、甲 160983.doc 201247656 基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮；必要時包含 d) 崩解劑，例如澱粉、瓊脂、海藻酸或其鈉鹽或發泡混合物；及/或 e) 吸附劑、著色劑、香料及甜味劑。錠劑可根據此項技術中已知之方法經塗膜或包覆腸溶包衣。適用於經口投與之組合物包括有效量之本發明化合物，呈錠劑、***錠、水性或油性懸浮液、可分散散劑或顆粒、乳液、硬膠囊或軟膠囊或糖漿或酏劑之形式。意欲口服使用之組合物係根據此項技術中已知用於製造醫藥組合物之任何方法來製備，且此等組合物可含有一或多種選自由甜咮劑、調味劑、著色劑及防腐劑組成之群的試劑以提供醫藥學上美觀及適口之製劑。錠劑可含有活性成分與適用於製造錠劑之醫藥學上可接受之無毒賦形劑混合。此等賦形劑為例如惰性稀釋劑，諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；成粒劑及崩解劑，例如玉米澱粉或海藻酸；黏合劑，例如澱粉、明膠或***膠；及潤滑劑，例如硬脂酸鎂、硬脂酸或滑石。錠劑未經包覆包衣或藉由已知技術經包覆包衣以延遲在胃腸道中之崩解及吸收，藉此提供較長期持續作用。舉例而言，可採用延時物質，諸如單硬月a酸甘油酯或二硬脂酸甘油酯。供經口使用之調配物可以硬明膠膠囊形式呈現，其中使活性成分與例如碳酸約、磷酸鮮或高嶺土之惰性固體稀釋劑混合；或以軟明膠 1609S3.doc • 45· 201247656 膠囊形式呈現’其中使活性成分與水或例如花生油、液體石蠟或橄欖油之油介質混合》某些可注射組合物為水性等張溶液或懸浮液，且栓劑宜自脂肪乳液或懸浮液製備。該等組合物可經滅菌及/或含有佐劑，諸如防腐劑、穩定劑、濕潤劑或乳化劑、溶液促進劑、調節滲透壓之鹽及/或緩衝劑。另外，其亦可含有其他治療上有價值之物質。該等組合物係分別根據習知混合法、造粒法或塗佈法來製備，且含有約〇175%或含有約1-50%活性成分。Little) reveals Mannich-base oxygen prodrugs, their preparation and use. Furthermore, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may inherently or intentionally form a solvate with a pharmaceutically acceptable solvent, including water, 160983.doc-43-201247656; therefore, the invention is intended to cover both fused and non-fused forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including a pharmaceutically acceptable salt thereof) and one or more solvent molecules. These solvent molecules are solvent molecules commonly used in pharmaceutical technology, and are known. It is not harmful to the recipient, such as water, ethanol and the like. The term "hydrate" means that the solvent molecule is a complex of water. The compounds of the present invention, including their salts, hydrates and solvates, can form polymorphs intrinsically or intentionally. In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration, and rectal administration. Further, the pharmaceutical compositions of the present invention may be constructed in solid form (including, but not limited to, capsules, granules, pills, granules, powders or suppositories) or in liquid form (including but not limited to, solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization, and/or the pharmaceutical compositions may contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers. And buffers, etc. The pharmaceutical composition is usually a capsule or gelatin capsule containing the active ingredient and the following: a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lake a slip agent, such as dioxide #, talc, stearic acid, its salt or calcium salt and/or polyethylene glycol; for tablets, also includes: c) binders such as magnesium aluminum silicate, starch paste, gelatin , Astragalus, A. 160983.doc 201247656 Cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) a disintegrating agent such as starch, agar, alginic acid or its sodium salt or hair a mixture of bubbles; and/or e) an adsorbent, a colorant, a fragrance, and a sweetener. The lozenge can be coated or coated with an enteric coating according to methods known in the art. Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of a lozenge, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule or syrup or elixirs. form. Compositions intended for oral use are prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives. A group of reagents to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or arabic Glue; and a lubricant such as magnesium stearate, stearic acid or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer lasting effect. For example, a time delay material such as mono-hard glycerol or glyceryl distearate may be employed. The formulation for oral use can be presented as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as about carbonic acid, fresh phosphate or kaolin; or in the form of a soft gelatin 1609S3.doc • 45· 201247656 capsule The active ingredient is combined with water or an oil medium such as peanut oil, liquid paraffin or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from a fat emulsion or suspension. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain about 175% or about 1-50% active ingredient.

適用於經皮施用之組合物包括有效量之本發明化合物與適合載劑。適用於經皮傳遞之載劑包括可吸收之藥理學可接受之溶劑以輔助通過宿主之皮膚。舉例而言’經皮裝置呈包含以下之端帶的形式：襯底部件、含有化合物及視情況選用的載劑之儲集層、為長期在控制及預定速率下向宿主皮膚傳遞化合物而視情況制之料控制障壁，及將裝置固定於皮膚之構件》Compositions suitable for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. For example, a transdermal device is in the form of an end band comprising: a substrate member, a reservoir containing a compound and, optionally, a carrier, for delivering the compound to the host skin for a prolonged period of time at a controlled rate and at a predetermined rate, as appropriate The material control barrier and the components that fix the device to the skin

適用於局部施用（例如至皮膚及眼睛）之組合物包括水液、懸浮液、軟膏劑、乳膏劑、凝膠或例如藉由氣霧劑遞之可喷激調配物，或其類似物。此等局部傳遞系統將其適於皮膚施用，例如用於治療皮膚癌，例如以防曬霜洗劑、喷霧劑及其類似物之形式用於預防性用途。其因尤其適於局部使用’包括此項技術中熟知之化妝品、'調物。其可含有增溶劑、穩定劑、張力增_、緩衝劑及腐劑。 160983.doc •46- 201247656 、如本之所用’局部施用亦可關於吸入或鼻内施用。其宜以乾粉（單獨，混合物（例如與彡興礼糖之乾摻合物），或例如與碗月曰之混合組分粒子）形式自乾粉吸人劑喷霧呈現形式自加麗容器、〗氣霧汞噴灑益、霧化器或喷霧器（使用或不使用適合之推進劑）傳遞。因為水可促進某些化合物降解，所以本發明進一步提供 ,含本發明化合物作為活性成分之無水醫藥組合物及劑型。Compositions suitable for topical administration (e.g., to the skin and eyes) include aqueous liquids, suspensions, ointments, creams, gels or sprayable formulations such as by aerosol, or the like. Such topical delivery systems are suitable for dermal administration, e.g., for the treatment of skin cancer, for example, in the form of sunscreen lotions, sprays, and the like, for prophylactic use. It is particularly suitable for topical use' including cosmetics, 'modules well known in the art. It may contain a solubilizer, a stabilizer, a tension increase, a buffer, and a rot. 160983.doc • 46- 201247656 As used herein, 'topical administration' may also be inhaled or administered intranasally. It should be in the form of a dry powder (individually, a mixture (for example, a dry blend with 彡礼 sugar), or a mixed component powder such as a bowl of glutinous rice). Aerosol mercury spray benefits, atomizers or sprayers (with or without suitable propellants) are delivered. Since water promotes the degradation of certain compounds, the present invention further provides anhydrous pharmaceutical compositions and dosage forms containing the compound of the present invention as an active ingredient.

發明之無水醫藥組合物及劑型可使用無水成分或含低水为成分且在低水分或低濕度條件下來製The anhydrous pharmaceutical composition and dosage form of the invention can be prepared by using anhydrous ingredients or containing low water as components and under low moisture or low humidity conditions.

醫藥組合物且在使JL伴捭盔匕地@ 版備.、.、X 使八保持無水性質下儲存。因此，使用已知防止受潮之材料包裝無水組合物，使得其可包括於適合之配方套組中。適合包裝之實例包括（但不限於）密封箱、塑膠、單位劑量容器(例如小瓶)、泡殼包裝及條帶包裝。本發月it纟提供包含一或多種降低作為活性成分之本發明化合物之分解速率的試劑之醫藥組合物及劑型。此等試劑在本文中稱作「藉令澈丨 ,. _ ㈣穩疋劑」，包括（但不限於）抗氧化劑 (諸如抗壞血酸）、pH緩衝劑或鹽緩衝劑等。㈣$式或鹽形式之式1/(匕合物顯示有價值之藥理學性質’例如腿抑制性質，例如在以下章節中所提供之活體外及活體内測試中所示，因此指U於療法。. 在-個實施例中’本發明提供—種治療hcv相關病症之方法’其包含投與有需要之個體醫藥學上可接受之量的本發明化合物，以便治療HCV相關病症。 160983.doc •47· 201247656 在另一實施例中，本發明提供一種治療HIV感染之方法，其包含投與有需要之個體醫藥學上可接受之量的本發明化合物。在又一實施例中，本發明提供一種治療、抑制或預防有需要之個體中的HCV活性之方法，其包含投與個體醫藥學上可接受之量的本發明化合物。在一個實施例中，本發明化合物抑制NS2蛋白酶、NS3蛋白酶、NS3解螺旋酶、 NS5a蛋白及/或NS5b聚合酶之活性。在另一實施例中， NS3蛋白酶與NS4A輔因子之間的相互作用被破壞。在又一實施例中，本發明化合物防止或改變HCV之NS4A-NS4B、 NS4B-NS5A及NS5A-NS5B接合中一或多者的切斷（severing)。在另一實施例中，本發明提供一種抑制絲胺酸蛋白酶活性之方法，其包含使該絲胺酸蛋白酶與本發明化合物接觸之步驟。在另一實施例中，本發明提供一種治療、抑制或預防有需要之個體中的HCV活性之方法，其包含投與個體醫藥學上可接受之量的本發明化合物，其中該化合物與HCV 生命週期中的任何標靶相互作用。在一個實施例中，HCV 生命週期之標靶係選自由以下組成之群：NS2蛋白酶、 NS3蛋白酶、NS3解螺旋酶、NS5a蛋白及NS5b聚合酶。在另一實施例中，本發明提供一種降低有需要之個體中 HCV RNA負荷的方法，其包含投與個體靨藥學上可接受之量的本發明化合物。在另一實施例中，本發明化合物顯示HCV蛋白酶活性。在一個實施例中，化合物為HCV NS3-4A蛋白酶抑制劑。 160983.doc -48- 201247656 在另一實施例中，本發明提供一種治療個體之HCV相關病症的方法，其包含投與有需要之個體醫藥學上可接受之量的本發明化合物及醫藥學上可接受之載劑，以便治療 HCV相關病症。在另一實施例中，本發明提供一種治療HCV相關病症之方法，其包含投與有需要之個體醫藥學上有效量之本發明化合物以及醫藥學上有效量之其他HCV調節化合物，諸如干擾素或衍生化干擾素，或細胞色素P450單加氧酶抑制劑，以便治療HCV相關病症。在一個實施例中，其他HCV 調節化合物係選自由以下組成之群：NIM811、ITMN191、 MK-7009、TMC 435350、Sch 503034及 VX-950。在另一實施例中，本發明提供一種抑制細胞中C型肝炎病毒複製之方法，其包含使該細胞與本發明化合物接觸。在又一實施例中，本發明提供一種HCV相關病症治療包，其包含本發明之HCV調節化合物，與關於使用有效量之HCV調節化合物來治療HCV相關病症之說明書一起包裝。在某些實施例中，HCV相關病症係選自由以下組成之群：HCV感染、肝硬化、慢性肝病、肝細胞癌、冷球蛋白金症、非霍奇金氏淋巴瘤（non-Hodgkin’s lymphoma)、肝纖維化及抑制性先天細胞内免疫反應。在另一實施例中，本發明提供一種治療有需要之個體的 HCV感染、肝硬化、慢性肝病、肝細胞癌、冷球蛋白血症、非霍奇金氏淋巴瘤、肝纖維化及/或抑制性先天細胞 160983.doc •49- 201247656 内免疫反應之方法，其包含投與個體醫藥學上可接受之量的本發明化合物。在一個實施例中，待治療之Hcv選自任何HCV基因型。在另一實施例中’ HCV係選自HCV基因型1、2及/或3。本發明之醫藥組合物或組合可呈用於約5〇_7〇 kg個體之約1-1000 mg活性成分之單位劑量形式，或呈約15〇〇 mg 或約1-250 mg或約卜150 mg或約0.5-100 mg或約1-50 mg活性成分之單位劑量形式。化合物、醫藥組合物或其組合之治療有效劑量取決於個體物種、體重、年齡及個別狀況、所治療之病症或疾病或其嚴重程度。具一般技術之醫師、臨床醫師或獸醫可容易地確定預防、治療或抑制病症或疾病進展所必需之各活性成分之有效量。且使用哺乳動物（例如小鼠、大鼠、狗、猴）或經分離器 B組織及其製劑，在活體外及活體内測試中證明上述劑量丨生質本發明化合物可以溶液（例如水溶液）形式活體外施用’及例如以懸浮液形式或於水溶液中經腸、非經腸 (宜靜脈内）活體内施用。活體外劑量可介於約1〇·3莫耳濃度與10 9莫耳濃度之間。視投藥途徑而定，活體内治療有效量可在約0.1-500 mg/kg之間，或約hwomg/kgi間的範圍内》可藉由下文提供之活體外及活體内方法評估本發明化合物之活性。本發明化合物可與一或多種其他治療劑同時、在其之前或之後投與。本發明化合物可由相同或不同投藥途徑分別 160983.doc -50· 201247656 投與，或與其他藥拖丨& 樂齊1-起於同-醫藥組合物中投與。在一個實施例中，本發 ' 合物及至少m、供種產品’其包含式⑴化 a#、個m · 摩钔作為組合製劑以在療法中同戍毕戍盘；表’使用。在—個實施例中’療法為治療病毒病毒感染相關之疾病或由c型肝炎病毒介導之病狀。以組合製劑形式提供仆人物η ^ 合物，其包含式⑴ σ 、5子在於同一醫藥組合物中之其他治療劑，或The pharmaceutical composition is stored under the condition that the JL is accompanied by a mask. Therefore, the anhydrous composition is packaged using a material known to prevent moisture so that it can be included in a suitable formula set. Examples of suitable packaging include, but are not limited to, sealed boxes, plastics, unit dose containers (eg, vials), blister packs, and strip packs. The present invention provides a pharmaceutical composition and dosage form comprising one or more agents which reduce the rate of decomposition of the compound of the invention as an active ingredient. Such agents are referred to herein as "details, _ (four) stabilizers, including but not limited to antioxidants (such as ascorbic acid), pH buffers or salt buffers, and the like. (d) Formula 1 of the formula or salt form 1 (the chelate exhibits valuable pharmacological properties) such as leg inhibiting properties, as shown, for example, in the in vitro and in vivo tests provided in the following sections, thus referring to U in therapy In one embodiment, 'the invention provides a method of treating an hcv-related disorder' comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention for the treatment of an HCV-related disorder. • 47· 201247656 In another embodiment, the invention provides a method of treating HIV infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention. In yet another embodiment, the invention A method of treating, inhibiting or preventing HCV activity in an individual in need thereof, comprising administering to a subject a pharmaceutically acceptable amount of a compound of the invention. In one embodiment, the compound of the invention inhibits NS2 protease, NS3 protease , NS3 helicase, NS5a protein and/or NS5b polymerase activity. In another embodiment, the interaction between the NS3 protease and the NS4A cofactor is disrupted. In the embodiments, the compounds of the invention prevent or alter the severing of one or more of the NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B junctions of HCV. In another embodiment, the invention provides a method of inhibiting silkamine A method of acid protease activity comprising the step of contacting the serine protease with a compound of the invention. In another embodiment, the invention provides a method of treating, inhibiting or preventing HCV activity in an individual in need thereof, Included is a pharmaceutically acceptable amount of a compound of the invention administered to an individual, wherein the compound interacts with any target in the HCV life cycle. In one embodiment, the target of the HCV life cycle is selected from the group consisting of NS2 protease, NS3 protease, NS3 helicase, NS5a protein, and NS5b polymerase. In another embodiment, the invention provides a method of reducing HCV RNA load in an individual in need thereof, comprising administering to the individual pharmacy An acceptable amount of a compound of the invention. In another embodiment, the compound of the invention exhibits HCV protease activity. In one embodiment, the compound is HCV N S3-4A Protease Inhibitor. 160983.doc -48- 201247656 In another embodiment, the invention provides a method of treating an HCV-related disorder in an individual comprising administering to a subject in need thereof a pharmaceutically acceptable amount A compound of the invention and a pharmaceutically acceptable carrier for the treatment of a HCV-related disorder. In another embodiment, the invention provides a method of treating an HCV-related disorder comprising administering to a subject in need thereof a pharmaceutically effective amount The compounds of the invention and pharmaceutically effective amounts of other HCV modulating compounds, such as interferons or derivatized interferons, or cytochrome P450 monooxygenase inhibitors, are useful in the treatment of HCV related disorders. In one embodiment, the other HCV modulating compound is selected from the group consisting of NIM811, ITMN191, MK-7009, TMC 435350, Sch 503034, and VX-950. In another embodiment, the invention provides a method of inhibiting hepatitis C virus replication in a cell comprising contacting the cell with a compound of the invention. In still another embodiment, the invention provides a HCV-related disorder treatment kit comprising an HCV modulating compound of the invention, packaged together with instructions for using an effective amount of an HCV modulating compound to treat an HCV-related disorder. In certain embodiments, the HCV-related disorder is selected from the group consisting of HCV infection, cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma , liver fibrosis and inhibitory innate intracellular immune response. In another embodiment, the invention provides a method of treating HCV infection, cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma, liver fibrosis, and/or in a subject in need thereof A method of immunizing an innate immune cell of 160983.doc • 49-201247656 comprising administering to a subject a pharmaceutically acceptable amount of a compound of the invention. In one embodiment, the Hcv to be treated is selected from any HCV genotype. In another embodiment the 'HCV line is selected from the group consisting of HCV genotypes 1, 2 and/or 3. The pharmaceutical composition or combination of the present invention may be in a unit dosage form for from about 1 to 1000 mg of the active ingredient of about 5 〇 7 7 kg of the individual, or about 15 〇〇 mg or about 1-250 mg or about 150 A unit dosage form of mg or from about 0.5 to 100 mg or from about 1 to 50 mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will depend on the individual species, weight, age and individual condition, the condition or disease being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat or inhibit the progression of a condition or disease. And the use of mammals (eg, mice, rats, dogs, monkeys) or via separator B tissue and its formulations, demonstrates that the above doses of the prodrugs in the in vitro and in vivo tests can be in the form of solutions (eg, aqueous solutions). In vitro administration is administered in vivo, for example, in the form of a suspension or in an aqueous solution, enterally or parentally (suitably intravenously). The extracorporeal dose can be between about 1 〇 3 molar concentration and 10 9 molar concentration. Depending on the route of administration, a therapeutically effective amount in vivo may range from about 0.1 to 500 mg/kg, or between about hwomg/kgi. The compounds of the invention may be evaluated by the in vitro and in vivo methods provided below. active. The compounds of the invention may be administered simultaneously with, before or after, one or more other therapeutic agents. The compounds of the invention may be administered by the same or different routes of administration, respectively, 160983.doc -50.201247656, or may be administered in combination with other drug drag & In one embodiment, the present invention and at least m, a product of the invention comprise a formula (1) a#, a m-capricorn as a combined preparation for simultaneous use in a therapy; In one embodiment, the therapy is a disease associated with the treatment of a viral infection or a condition mediated by a hepatitis C virus. Providing a servant η compound in the form of a combined preparation comprising the formula (1) σ, 5 other therapeutic agents in the same pharmaceutical composition, or

式⑴化合物及各別形式之其他治療劑，例如呈套组形式。在一個實施例中，本發明提供一種醫藥組合物，其包含式⑴化°物及另一治療劑。如上所述，醫藥組合物可包含如上所述之醫藥學上可接受之賦形劑。在一個實施例中’本發明提供—種套組，其包含兩種或兩種以上各別醫藥組合物，其中至少一種含有式⑴化合物ϋ實施例中’該套組包含用於分別保存該等組合 :之構件’諸如容器、分隔瓶或分隔式落包裝。此套組之實例為通常用於封裝錠劑、膠囊及其類似物之泡殼包裝。本發明之套组可用於投與不同劑型（例如經口及非經腸劑型）’用於以不同給藥間隔投與各別組合物或用於相對於彼此滴定各別組合物。為有助於順應性，本發明之套組通常包含投藥說明書。在本發明之組合療法中，可由相同或不同製造者製造及/ 或調配本發明化合物及其他治療劑。此外，本發明化合物及其他治療劑可共同用於組合療法：在對醫師發行組合產品之前（例如在套組包含本發明化合物及其他治療劑之 160983.doc 51 201247656 情況下）；（ii)在投藥之箭 -樂之別不久由醫師親導下進行），♦㈣由患者本人丁（戍在4師心化合物及其他治療劑期間。卩例如在連續投與本發明二=供式⑴化合物用於治療由卿感染引起二另=之疾病或病狀的用途，其中該藥劑經製備1另一治療劍一起投與。本發明亦提供另-治療劑用於治療由HCV感染引起或與縻劑用 # ^ 埶染相關之疾病或病狀的用途’其中該樂劍與式⑴化合物—起投與。本發明亦提供一種式⑴化合物，其適用於治療由HCV感染引起或與HCV感染相關之疾病或病狀的方法令立中式 (1)化合物經製備以與另一治療劑一起投與。本發明亦提供另一治療劑’其適用於治療由Hcv感㈣起或與HO感毕相關之疾病或病狀之方法中，其中該另一治療劑經製備以與式⑴化合物-起投與。本發明亦提供式⑴化合物其適用於治療由⑽感㈣丨起或與Hcv㈣㈣之疾病或病狀的方法中’其中式⑴化合物與另一治療劑一起投與。本發明亦提供另一治療劑，其適用於治療由HCV感染引起或與 HCV感染相關之疾病或病狀之方法中，其中該另一治療劑與式（I)化合物一起投與。本發明亦提供式（I)化合物用於治療由HCV感染引起或與 HCV感染相關的疾病或病狀之用途，其中患者先前（例2 24小時内）已用另一治療劑治療。本發明亦提供另一治療劑用於治療由HCV感染引起或與Hcv感染相關的疾病或病狀之用途，其中患者先前（例如24小時内）已用式⑴化合物 160983.doc -52- 201247656 治療。在一個實施例中，其他治療劑係選自第二治療劑，其對病毒有活性，且尤其對HCV有活性。化合物及藥劑可於單一調配物或各別調配物中投與。對HCV有活性之藥劑包括 (但不限於）干擾素-α、聚乙二醇化干擾素-a(pegylated interferon-α ; peginterferon-α)、血清白蛋白融合干擾素-a2b (alb inter feron-a2b)(albIFN ， Novartis/Human GenomeThe compound of formula (1) and the other therapeutic agents of the various forms are, for example, in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (1) and another therapeutic agent. As stated above, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient as described above. In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (1), in the embodiment, wherein the kit comprises for separately storing the Combination: The component 'such as a container, a separate bottle or a separate drop package. An example of such a kit is a blister pack typically used to package tablets, capsules and the like. The kit of the invention can be used to administer different dosage forms (e.g., oral and parenteral dosage forms)' for administering the individual compositions at different dosing intervals or for titrating the respective compositions relative to one another. To aid compliance, the kit of the present invention typically includes a dosing instructions. In the combination therapies of the invention, the compounds of the invention and other therapeutic agents may be made and/or formulated by the same or different manufacturers. Furthermore, the compounds of the invention and other therapeutic agents may be used in combination therapy: prior to the release of the combination product to the physician (e.g., in the case of a kit comprising a compound of the invention and other therapeutic agents, 160983.doc 51 201247656); (ii) The arrow of the drug-learning is carried out by the physician. ♦ (4) The patient himself is sputum (during the 4th heart compound and other therapeutic agents. For example, in the continuous administration of the invention 2 = for the compound of formula (1) The use of a medicament for treating a disease or condition caused by a infection of the genus, wherein the medicament is administered together with another therapeutic sword of Preparation 1. The present invention also provides an additional therapeutic agent for treating or caused by an HCV infection. Use of #^ to infect a disease or condition associated with 'the sword and the compound of formula (1) - The present invention also provides a compound of formula (1) which is useful for treating or caused by HCV infection. The method of the disease or condition is such that the compound of formula (1) is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent which is suitable for treatment from Hcv (4) or with HO In a method of related diseases or conditions, wherein the other therapeutic agent is prepared for administration with a compound of formula (1). The invention also provides a compound of formula (1) which is useful for treating a disease caused by (10) sensation (4) or with Hcv (4) (d) Or a method of a condition wherein the compound of formula (1) is administered with another therapeutic agent. The invention also provides another therapeutic agent suitable for use in a method of treating a disease or condition caused by or associated with HCV infection. Wherein the additional therapeutic agent is administered with a compound of formula (I). The invention also provides the use of a compound of formula (I) for the treatment of a disease or condition caused by or associated with HCV infection, wherein the patient previously ( Example 2 has been treated with another therapeutic agent within 24 hours. The invention also provides for the use of another therapeutic agent for the treatment of a disease or condition caused by or associated with Hcv infection, wherein the patient has previously (eg within 24 hours) It has been treated with a compound of formula (1) 160983.doc -52 - 201247656. In one embodiment, the additional therapeutic agent is selected from a second therapeutic agent that is active against the virus and, in particular, active against HCV. The agents can be administered in a single formulation or in separate formulations. Agents active against HCV include, but are not limited to, interferon-alpha, pegylated interferon-alpha; peginterferon-alpha , serum albumin fusion interferon-a2b (alb inter feron-a2b) (albIFN, Novartis/Human Genome

Science)、PEG-干擾素 X(BMS/ZymoGenetics)、病毒e坐、左籲旋韋林（levovirin)、偉拉咪定（viramidine)、干擾素-α與病毒°坐之組合、聚乙二醇化干擾素-α與病毒。坐之組合、 albIFN與病毒°坐之組合、干擾素-α與左旋韋林之組合、聚乙二醇化干擾素-α與左旋韋林之組合，及albIFN與左旋韋林之組合。干擾素-α包括（但不限於）重組干擾素-a2a(諸如可購自 Hoffman-LaRoche，Nutley，NJ 之 ROFERON 干擾素）、干擾素-a2b(諸如可購自 Schering Corp.，Kenilworth, New Jersey，USA之Intron-A干擾素）、複合干擾素及經純化鲁之干擾素-α產品。聚乙二醇化干擾素-α包括（但不限於）PEG IFN-a2a(諸如可獲自 Hoffman-LaRoche，Nutley，NJ 之 Pegsys)、PEG IFN-a2b(諸如可獲自 Schering Corp.， Kenilworth，New Jersey，USA之Peglntron)。關於病毒0坐及其針對HCV之活性的討論，參見J.O. Saunders及S.A. Raybuck，「Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential, j Ann.Science), PEG-ZymoGenetics, virus e-sit, levovirin, viramidine, interferon-alpha and virus sit, PEGylation Interferon-alpha and virus. The combination of sitting, the combination of albIFN and virus, the combination of interferon-α and levovirin, the combination of pegylated interferon-α and levovirin, and the combination of albIFN and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon-a2b (such as commercially available from Schering Corp., Kenilworth, New Jersey). , USA's Intron-A interferon), complex interferon and purified interferon-α products. Pegylated interferon-α includes, but is not limited to, PEG IFN-a2a (such as Pegsys available from Hoffman-LaRoche, Nutley, NJ), PEG IFN-a2b (such as available from Schering Corp., Kenilworth, New). Jersey, Peglntron, USA). For a discussion of virus 0 sitting and its activity against HCV, see J.O. Saunders and S.A. Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential, j Ann.

Mec?. C/zem.，35:201-210 (2000) o 160983.doc •53- 201247656 對c型肝炎病毒有活性之藥劑亦包括抑制以下之藥劑： HCV NS2 或 NS3蛋白酶、HCV NS5B 聚合酶、HCV NS5A 蛋白、HCV NS3解螺旋酶、HCV NS4B蛋白、HCV p7蛋白、 HCV NS4A蛋白、HCV IRES及蛋白質轉譯、HCV進入、 HCV組裝、HCV釋放及肌苷5’-單磷酸去氫酶、親環素或 HCV複製所需之其他宿主因子。其他化合物包括WO 2004/0143 13及WO 2004/014852及本文所引用之參考文獻中所揭示的化合物。Mec?. C/zem., 35:201-210 (2000) o 160983.doc •53- 201247656 Agents active against hepatitis C virus also include agents that inhibit the following: HCV NS2 or NS3 protease, HCV NS5B polymerase , HCV NS5A protein, HCV NS3 helicase, HCV NS4B protein, HCV p7 protein, HCV NS4A protein, HCV IRES and protein translation, HCV entry, HCV assembly, HCV release and inosine 5'-monophosphate dehydrogenase, pro Cyclin or other host factors required for HCV replication. Other compounds include the compounds disclosed in WO 2004/0143 13 and WO 2004/014852, and references cited therein.

特定抗病毒劑包括 BI-201335(Boehringer Ingelheim) ' 特拉匹韋（telaprevir)(Vertex)、VX-813(Vertex)、VX-500(Vertex)、波普瑞韋（boceprevir)(Schering-Plough)、Sch 900518 (Schering-Plough)、ITMN-1 91 /R7227(Intermune/Roche)、 ITMN-5489(Intermune)、MK-7009(Merck)、TMC435(Tibotec)、 BMS-650032(Bristol-Myers-Squibb)、PHX1766(Phenomix)、Specific antiviral agents include BI-201335 (Boehringer Ingelheim) 'telaprevir (Vertex), VX-813 (Vertex), VX-500 (Vertex), boceprevir (Schering-Plough) Sch 900518 (Schering-Plough), ITMN-1 91 /R7227 (Intermune/Roche), ITMN-5489 (Intermune), MK-7009 (Merck), TMC435 (Tibotec), BMS-650032 (Bristol-Myers-Squibb) , PHX1766 (Phenomix),

GS-9256(Gilead)、VCH-916(Vertex)、VCH-759(Vertex)、 VCH.222/VX-222(Vertex)、ABT-333(Abbott)、ANA-598(Anadys)、 PF-868,554(Pfizer)、MK-3281(Merck)、PSI-7851(Pharmasset)、 R7128(Pharmasset/Roche)、R1626(Roche)、GS9190(Gilead)、 BI-207127(Boehringer Ingelheim) ' JTK-652(Japan Tobacco Inc.)、IDX375(Idenix)、瓦諾 °比他濱（Valopicitabine)/NM283 (Idenix)、IDX-184(Idenix)、AZD2836/A-831(Arrow/AstraZeneca)、 AZD7295/A-689(Arrow/AstraZeneca) ' BMS-790052(Bristol-Myers-Squibb)、PPI-461(Presidio)、EDP-239(Enanta)、色匹林（Ceplene)(Maxim Pharmaceuticals)、色瓦塞（Civacir) 160983.doc -54- 201247656 (Nabi Biopharmaceuticals Inc) ' VX-497(Vertex Pharmaceuticals Inc.)、XTL-002(XTL Biopharmaceuticals)、艾沙托立賓 (isatoribine)及其前藥 ANA971、ANA975及 ANA773(Anadys)、 NIM8 11 (Novartis)、DEBIO-025 (DebioPharm/Novartis)、 SCY-635(Scynexis) ’ 及硝0坐尼特（nitazoxanide)(Romark)、 IDN-6556(Idun Pharmaceuticals)、IP-501 (Indevus Pharmaceuticals)、 ISIS 14803(ISIS Pharmaceuticals Inc.)。在一些實施例中，本發明之組合物及方法含有本發明化合物及干擾素。在一些態樣中，干擾素係選自由以下組成之群：干擾素α2Β、聚乙二醇化干擾素α、複合干擾素、干擾素α2Α及類淋巴母細胞干擾素T(lymphoblastoid interferon tau) 〇在其他實施例中，本發明之組合物及方法含有本發明化合物及選自由以下組成之群的具有抗HCV活性之化合物：介白素2、介白素6、介白素12(增強1型T輔助細胞反應發展之化合物）、干擾RNA、反義RNA、咪奎莫特 (Imiquimod)、病毒嗤、肌苷5'-單填酸去數酶抑制劑、金剛胺（amantadine)及金剛乙胺（rimantadine)。在其他實施例中，具有抗HCV活性之化合物為病毒唑、左旋韋林、偉拉咪定、胸腺素α-1、NS3絲胺酸蛋白酶之抑制劑，及肌苦單填酸去氫酶之抑制劑、干擾素-α，或單獨或與病毒嗤或偉拉咪定組合之聚乙二醇化干擾素-α。在另一實施例中，具有抗HCV活性之化合物為對HCV有活性之該藥劑，亦即單獨或與病毒唑或偉拉咪定組合之干 160983.doc -55- 201247656 擾素-α或聚乙二醇化干擾素-α。通用合成方法本文中所揭示之化合物可根據下文所述之通用程序及實例來製備。應暸解’當給定典型或較佳製程條件（亦即反應溫度、時間、反應物之莫耳比、溶劑、壓力等）時，除非另作說明，否則亦可使用其他製程條件。最佳反應條件可隨所用之特定反應物或溶劑而變，但此等條件可由熟習此項技術者藉由常規最佳化程序來確定。另外’如熟習此項技術者將顯而易知，習知保護基可為防止某些官能基經歷不當反應所必需。適用於各種官能基之保護基以及適用於保護特定官能基及使特定官能基脫除保護基之條件在此項技術中已為熟知。舉例而言，眾多保護基描述於T. W. Greene及 G. M. Wuts，Pf〇teeting Gn)ups in Organic Synthesis，第 3版，Wiley，New γ〇ι% 1999及其中所引用之參考文獻中。若本發明化合物含有一或多個對掌性中心，則此等化合物可作為純立體異構體（亦即作為個別對映異構體或非對映異構體）或作為立體異構體增濃混合物來製備或分離。除非另有指示’否則所有此等立體異構體(及增漠混合物) 均包括於本發明之料内。純立體異構體（或增濃混合物）可使用例如此項技術中所熟知之光學活性起始物質或立體選擇性試劑來製備。或者’此等化合物之外消旋混合物可使用例如對掌性管㈣析法、對掌性解㈣及其類似分離。 160983.doc -56- 201247656 式（i)化合物通常可根據下文提供之流程來製備。通用程序GS-9256 (Gilead), VCH-916 (Vertex), VCH-759 (Vertex), VCH.222/VX-222 (Vertex), ABT-333 (Abbott), ANA-598 (Anadys), PF-868, 554 ( Pfizer), MK-3281 (Merck), PSI-7851 (Pharmasset), R7128 (Pharmasset/Roche), R1626 (Roche), GS9190 (Gilead), BI-207127 (Boehringer Ingelheim) 'JTK-652 (Japan Tobacco Inc.) ), IDX375 (Idenix), Valopicitabine/NM283 (Idenix), IDX-184 (Idenix), AZD2836/A-831 (Arrow/AstraZeneca), AZD7295/A-689 (Arrow/AstraZeneca) 'BMS-790052 (Bristol-Myers-Squibb), PPI-461 (Presidio), EDP-239 (Enanta), Ceplene (Maxim Pharmaceuticals), Civacir 160983.doc -54- 201247656 (Nabi Biopharmaceuticals Inc) 'VX-497 (Vertex Pharmaceuticals Inc.), XTL-002 (XTL Biopharmaceuticals), Isatoribine and its prodrugs ANA971, ANA975 and ANA773 (Anadys), NIM8 11 (Novartis) , DEBIO-025 (DebioPharm/Novartis), SCY-635 (Scynexis) ' and nitazoxanide (Romark), IDN-6556 (Idun Pharmaceuticals), IP-501 (Indevus Pharmaceuticals) ISIS 14803 (ISIS Pharmaceuticals Inc.). In some embodiments, the compositions and methods of the invention comprise a compound of the invention and an interferon. In some aspects, the interferon is selected from the group consisting of interferon alpha 2 Β, pegylated interferon alpha, consensus interferon, interferon alpha 2 Α, and lymphoblastoid interferon t (lymphoblastoid interferon tau) In other embodiments, the compositions and methods of the present invention comprise a compound of the present invention and a compound having anti-HCV activity selected from the group consisting of: interleukin 2, interleukin 6, and interleukin 12 (enhanced type 1 T Compounds that aid in the development of cellular responses), interfering RNA, antisense RNA, Imiquimod, viral sputum, inosine 5'-single-storage enzyme inhibitor, amantadine, and rimantadine ( Rimantadine). In other embodiments, the compound having anti-HCV activity is ribavirin, levovirin, vemuramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, and myostatin alone dehydrogenase Inhibitor, interferon-[alpha], or pegylated interferon-[alpha] alone or in combination with viral oxime or verapamil. In another embodiment, the compound having anti-HCV activity is an agent active against HCV, ie, alone or in combination with ribavirin or verapamil. 160983.doc -55 - 201247656 Interferon-α or poly Ethylated glycol interferon-α. General Synthetic Methods The compounds disclosed herein can be prepared according to the general procedures and examples described below. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions can be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents employed, but such conditions can be determined by those skilled in the art by routine optimization procedures. Further, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing an inappropriate reaction. Conditions suitable for protecting groups of various functional groups as well as for protecting a particular functional group and for removing a protecting group from a particular functional group are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Pf〇te eting Gn) ups in Organic Synthesis, 3rd edition, Wiley, New γ〇ι% 1999 and references cited therein. If a compound of the invention contains one or more pairs of palmitic centers, such compounds may act as pure stereoisomers (i.e., as individual enantiomers or diastereomers) or as stereoisomers. A concentrated mixture is prepared or isolated. All such stereoisomers (and desertification mixtures) are included in the materials of the present invention unless otherwise indicated. Pure stereoisomers (or concentrated mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be isolated using, for example, a palmar tube (four) assay, a palmitic solution (four), and the like. 160983.doc -56- 201247656 Compounds of formula (i) can generally be prepared according to the procedures provided below. General procedure

實例A 通用結構A-3之化合物可藉由以Cul及反式環己烷二胺作為促進劑使片段A-1與片段A-2之間發生偶合反應，接著在鹼性條件下水解曱酯來合成。EXAMPLE A A compound of the general structure A-3 can be subjected to a coupling reaction between the fragment A-1 and the fragment A-2 by using Cul and trans-cyclohexanediamine as a promoter, followed by hydrolysis of the oxime ester under basic conditions. To synthesize.

流程IProcess I

實例B 通用結構B-3之化合物可藉由以下方法（流程H)合成。 B-1可藉由在鹼性條件下水解曱酯，接著用HC1裂解B〇c而轉化為B-2。可使B-2與磺醯氣反應得到磺醯胺B_3 ^或B_2 可經歷用醛之還原性胺化，得到胺B_4。 160983.doc -57- 201247656Example B The compound of General Structure B-3 can be synthesized by the following method (Scheme H). B-1 can be converted to B-2 by hydrolysis of the oxime ester under basic conditions followed by cleavage of B〇c with HCl. The reaction of B-2 with sulfonium gas to give the sulfonamide B_3^ or B_2 can undergo reductive amination with an aldehyde to give the amine B_4. 160983.doc -57- 201247656

實例c 通用結構C-3及C-5之化合物可藉由以下方法合成。胺 C-1可藉由與吡啶磺醢氣反應而轉化為吡啶基磺醯胺C-2。用胺置換氣化物將提供C-3。可使C-1與4-氟苯磺醯氣反應得到C-4。用胺置換氟化物將得到C-5。Example c The compounds of the general structures C-3 and C-5 can be synthesized by the following methods. The amine C-1 can be converted to pyridylsulfonamide C-2 by reaction with pyridine sulfonium. Displacement of the vapor with an amine will provide C-3. C-1 can be reacted with 4-fluorobenzenesulfonate to give C-4. Substitution of the fluoride with an amine will give C-5.

流程IIIProcess III

160983.doc -58- 201247656 本發明進一步包括本發明方法之任何變化形式，其中將可於其任何階段獲得之中間產物用作起始物質且進行其餘步驟，或其中該等起始物質係在反應條件下於當場形成，或其中反應組分係以其鹽或光學純對映體之形式使用。本發明化合物及中間物亦可根據熟習此項技術者一般已知之方法彼此轉化。160983.doc -58- 201247656 The invention further comprises any variant of the process of the invention, wherein the intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or wherein the starting materials are in the reaction The conditions are formed on the spot, or wherein the reaction components are used in the form of their salts or optically pure enantiomers. The compounds and intermediates of the present invention can also be converted into each other according to methods generally known to those skilled in the art.

在本文之範疇内，除非上下文另有指示，否則僅不為本發明化合物之特定所需最終產物之組分的可輕易移除之基團經指定為「保護基」。此等保護基對官能基之保護、保護基本身及其裂解反應經描述於例如以下標準參考著作中：諸如 J. F. W. McOmie，「Protective Groups in Organic Chemistry」，Plenum Press, London and New York 1973 ; T. W. Greene 及 P. G. M. Wuts，「Protective Groups in Organic Synthesis」，第 3版，Wiley，New York 1999 ;「The Peptides」；第 3卷（E. Gross 及 J. Meienhofer 編），Academic Press，London and New York 1981 ;「Methoden der organischen Chemie」(Methods of Organic Chemistry), Houben Weyl，第 4版，第 15/1 卷，Georg Thieme Verlag， Stuttgart 1974 ; H.-D. Jakubke及H. Jeschkeit，「Aminosauren， Peptide, Proteine」（Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach,及 Basel 1982 ；及 Jochen Lehmann,「Chemie der Kohlenhydrate: Monosaccharide und Derivate」（Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, 160983.doc •59- 201247656Within the scope of this document, unless the context indicates otherwise, an easily removable group that is not a component of a particular desired end product of a compound of the invention is designated a "protecting group." The protection of these functional groups, the protection of the basic body and their cleavage reactions are described, for example, in the following standard reference works: such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene And PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999; "The Peptides"; Vol. 3 (E. Gross and J. Meienhofer), Academic Press, London and New York 1981; "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, 160983 .doc •59- 201247656

Stuttgart 1974。保護基之特徵在於其可例如藉由溶劑分解、還原、光解或者在生理條件下（例如藉由酶促裂解）輕易移除（亦即在未出現不當二次反應之情況下具有至少一個成鹽基團的本發明化合物之鹽可以熟習此項技術者所知之方式製備。舉例而言，具有酸基的本發明化合物之鹽可例如藉由用以下物質處理化合物來形成：金屬化合物，諸如適合有機羧酸之鹼金屬鹽，例如2_乙基己酸之鈉鹽；有機鹼金屬或鹼土金屬化合物，諸如相應氫氧化物、碳酸鹽或碳酸氫鹽，諸如鈉或鉀之氫氧化物、碳酸鹽或碳酸氫鹽；相應鈣化合物或氨或適合有機胺，較佳使用化學計量之量或僅稍微過量之成鹽劑。本發明化合物之酸加成鹽係以習用方式獲得，例如藉由用酸或適合陰離子交換試劑處理化合物來獲得。可例如藉由例如以弱鹼中和鹽（諸如酸加成鹽）至等電點，或藉由以離子交換劑處理來形成含有酸性及鹼性成鹽基團（例如游離羧基及游離胺基）之本發明化合物之内鹽。可根據熟習此項技術者所知之方法將鹽轉化為游離化合物。金屬及銨鹽可例如藉由用適合酸及酸加成鹽處理，例如藉由用適合驗性劑處理來轉化。根據本發明可獲得之異構體混合物可以熟習此項技術者已知之方式分離成個別異構體；非對映異構體可例如藉由在多相溶劑混合物之間分配、再結晶及/或層析分離（例如經矽膠）或藉由例如逆相管柱中壓液相層析來分離，且外消旋體可例如藉由與光學純成鹽試劑形成鹽及分離如此可 160983.doc 201247656 獲得之非對映異構體的混合物（例如藉助於分步結晶，或藉由光學活性管柱物質層析）來分離。中間物及最終產物可根據標準方法，例如使用層析法、分配法、（再）結晶及其類似方法來處理及/或純化。般而έ，以下條件適用於上文及下文中提及之所有製程。所有上述方法步驟均可在熟習此項技術者已知之反應條件下進行，包括特定提及之反應條件，在溶劑或稀釋劑 •(包括例如對所用試劑呈惰性且溶解所用試劑之溶劑或稀釋劑）不存在或通常存在下，在催化劑、縮合劑或中和劑 (例如離子交換劑，諸如陽離子交換劑，例如呈Η+形式，視反應及/或反應物之性質而定）不存在或存在下，在低恤、常溫或高溫下（例如在約_1〇(rc至約19〇β(：之溫度範圍内，包括例如約-80t：至約15(rc，例如在_8(rc至_6(rc 下在至溫下，在-20°C至4CTC下或在回流溫度下），在大氣壓下或在封閉容器中（適當時處於壓力下），及/或在惰性馨氛圍中（例如在氯氣或氮氣氛圍下）。在反應之所有階段，所形成之異構體混合物均可分離成個別異構體，例如非對映異構體或對映異構體，或異構體之任何所需混合物，例如非對映異構體之外消旋體或混合物，例如類似於在「其他方法步驟」下所述之方法。除非在方法描述中另外說明，否則可從中選擇適用於任何特定反應之彼等溶劑的溶劑包括特定提及之溶劑，或例如水；酯，諸如低碳烷基·低碳烷酸酯，例如乙酸乙酯； I60983.doc -61 - 201247656 醚，諸如脂族醚，例如***，嗔院；液幾芳族煙，諸如笨，甲二例如四㈣或二醇或一丙醇;猜本:::二類代諸”醇、乙甲烧或氯仿；酿胺，諸如二甲基甲酿胺戈=其例如二氣鹼，諸如雜環驗，例如。比 T基乙酿胺 Τ基°比°各°定-2-闕；翔酸酐’諸如低碳烷酸酐，例如酮，羧馱 π π G 0更酐，環烴、鏈烴，諸如環己烷、己烷赤旦$ ρ 鰱焱次刀支、或異戊烷、甲基環己烷；或彼等溶劑之混合物，例如水溶液。^ ^ ^ ^ ^ ^ ^ 一如藉由層析或分配實現之處理。W合物亦可用於例Stuttgart 1974. The protecting group is characterized in that it can be easily removed, for example by solvolysis, reduction, photolysis or under physiological conditions (for example by enzymatic cleavage) (i.e. having at least one in the absence of an undue secondary reaction). Salts of the salts of the compounds of the invention may be prepared in a manner known to those skilled in the art. For example, a salt of a compound of the invention having an acid group can be formed, for example, by treating a compound with a metal compound such as Suitable for alkali metal salts of organic carboxylic acids, such as sodium salt of 2-ethylhexanoic acid; organic alkali metal or alkaline earth metal compounds, such as corresponding hydroxides, carbonates or hydrogencarbonates, such as sodium or potassium hydroxides, a carbonate or bicarbonate; a corresponding calcium compound or ammonia or a suitable organic amine, preferably in a stoichiometric amount or only a slight excess of the salt forming agent. The acid addition salts of the compounds of the invention are obtained in a conventional manner, for example by Obtained by treating the compound with an acid or a suitable anion exchange reagent, for example by neutralizing a salt (such as an acid addition salt) with a weak base to an isoelectric point, or by The ion exchanger is treated to form an internal salt of a compound of the invention containing acidic and basic salt-forming groups (e.g., free carboxyl groups and free amine groups). The salt can be converted to the free compound by methods known to those skilled in the art. The metal and ammonium salts can be converted, for example, by treatment with a suitable acid and an acid addition salt, for example by treatment with a suitable inerting agent. The isomer mixtures obtainable according to the invention can be isolated in a manner known to those skilled in the art. Individual isomers; diastereomers can be separated, for example, by partitioning, recrystallization, and/or chromatographic separation between heterogeneous solvent mixtures (eg, via gelatin) or by, for example, a reverse phase column. Chromatography to separate, and the racemate can be formed, for example, by forming a salt with an optically pure salt forming reagent and isolating a mixture of diastereomers thus obtained by 160983.doc 201247656 (for example by means of fractional crystallization, or by borrowing Separation by optically active column chromatography. The intermediates and final products can be treated and/or purified according to standard methods, for example, using chromatography, partitioning, (re)crystallization, and the like. As a general rule, the following conditions apply to all of the processes mentioned above and below. All of the above process steps can be carried out under the reaction conditions known to those skilled in the art, including the specific reaction conditions mentioned, in the solvent or A diluent, (including, for example, a solvent or diluent which is inert to the reagents used and which dissolves the reagents used), in the absence or in the usual presence, in a catalyst, a condensing agent or a neutralizing agent (for example an ion exchanger such as a cation exchanger, for example Η+ form, depending on the nature of the reaction and/or reactants) in the absence or presence of low-tie, ambient or elevated temperatures (eg, in the temperature range of about 1:1 to rc to about 19 〇β (: , for example, from about -80t: to about 15 (rc, for example at _8 (rc to _6 (at rc to temperate, at -20 ° C to 4 CTC or at reflux temperature), at atmospheric pressure or at In a closed container (under pressure when appropriate), and / or in an inert atmosphere (for example under a chlorine or nitrogen atmosphere). At all stages of the reaction, the resulting mixture of isomers can be separated into individual isomers, such as diastereomers or enantiomers, or any desired mixture of isomers, such as diastereomeric Isomers racemates or mixtures, for example similar to those described under "Other Process Steps". Unless otherwise stated in the method description, solvents from which these solvents may be selected for any particular reaction include the specifically mentioned solvents, or, for example, water; esters, such as lower alkyl lower alkanates, such as acetic acid. Ethyl ester; I60983.doc -61 - 201247656 Ethers, such as aliphatic ethers, such as diethyl ether, brothels; liquid aromatic cigarettes, such as stupid, alpha two, such as tetrakis (tetra) or diol or monopropanol; Guess::: The second type of "alcohol, ethanesulfonic acid or chloroform; a stimulating amine, such as dimethyl ketoamine ge = which is, for example, a gas phase base, such as a heterocyclic ring, for example, a specific ratio of T-based ethylamine ° 阙-2-阙; octanic anhydride 'such as lower alkanoic anhydride, such as ketone, carboxy 驮 π π G 0 more anhydride, cyclic hydrocarbons, chain hydrocarbons, such as cyclohexane, hexane red denier ρ 鲢焱刀Or isopentane, methylcyclohexane; or a mixture of such solvents, such as an aqueous solution. ^ ^ ^ ^ ^ ^ ^ as a treatment by chromatography or partitioning.

化合物（包括其鹽）亦可以水合物形式獲得，或其晶體可例如包括用於結晶之溶劑。可存在不同結晶形式。本發明亦關於以下形式之方法：其中使用可在方法之任何階段以中間體形式獲得之化合物作為起始物質及進行其餘方法步驟’或其巾起始物f在反應條件下形成或以衍生物形式使用，例如以經保護形式或以鹽形式使用，或藉由The compound (including a salt thereof) can also be obtained in the form of a hydrate, or the crystal thereof can include, for example, a solvent for crystallization. Different crystalline forms may be present. The invention also relates to a process in which a compound obtainable in the form of an intermediate at any stage of the process is used as a starting material and the remaining process step 'or its starting material f is formed under the reaction conditions or as a derivative Form used, for example, in protected form or in salt form, or by

本發明方法可獲得之化合物係在方法條件下產生且當場經進一步處理》所有用以合成本發明化合物之起始物質、構築嵌段、試劑、酸、鹼、脫水劑、溶劑及催化劑均為市售或可藉由— 般技術者已知之有機合成方法（Houben-Weyl第4版》1952,The compounds obtainable by the process of the invention are produced under process conditions and further processed in the field. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts for synthesizing the compounds of the invention are commercially available. It can be sold by the organic synthesis method known to the general practitioner (Houben-Weyl 4th Edition) 1952,

Methods of 〇rganic Synthesis，Thieme，第 21 卷）製得。在一個實施例中’本發明提供一種調節個體體内病毒活性之方法’其中該方法包含投與個體治療有效量之根據式 (1)之定義的化合物。提供在個體體内抑制病毒複製或抑制 160983.doc -62· 201247656 病毒負荷之方、;^ 去其中該病毒為黃病毒科之成員，諸如型肝炎病毒。九在個實施例中，本發明提供一種治療個體之由感起或，、HCV感染相關之病症或疾病的方法，其中該方法包3技與個體治療有效量之根據式（I)之定義的化合物。實施例中，本發明提供一種治療個體之由HCV感染1起或與时乂感染相關之病症或疾病的方法’其中該病Methods of 〇rganic Synthesis, Thieme, Volume 21). In one embodiment, the invention provides a method of modulating viral activity in an individual' wherein the method comprises administering to the individual a therapeutically effective amount of a compound according to formula (1). Providing a means for inhibiting viral replication or inhibition of viral load in an individual, wherein the virus is a member of the Flaviviridae family, such as a hepatitis B virus. In one embodiment, the invention provides a method of treating a condition or disease associated with or caused by an HCV infection in an individual, wherein the method comprises a therapeutically effective amount of the individual according to the definition of formula (I) Compound. In an embodiment, the invention provides a method of treating a condition or disease associated with or associated with a sputum infection in an individual, wherein the disease

症或疾病係選自Hcv感染、肝硬化、慢性肝病、肝細胞 ’、求蛋白血症、非霍奇金氏淋巴瘤、肝纖維化及抑制性先天細胞内免疫反應。在個實施ί列中，本發明提供根據式⑴之定義之化合物，其係用作藥劑。在個實施例中，本發明提供根據式⑴之定義之化合物的用途，其係用於治療個體之由Hcv感染引起或與hcv感染相關之病症或疾病。在一個實施例中，本發明提供根據式⑴之定義之化合物的用途，其係用於製造用於治療個體之由HCV感染引起或與HCV感染相關之病症或疾病的藥劑’其中該病症或疾病尤其選自HCV感染、肝硬化、慢性肝病、肝細胞癌、冷球蛋白血症、非霍奇金氏淋巴瘤、肝纖維化及抑制性先天細胞内免疫反應。在-個實施例中’本發明提供根據式⑴之定義之化合物的用途，其係用於治療個體之由HCV感染引起或與HCv感木相關之病症或疾病，其中該病症或疾病係選自HCV感 160983.doc -63 - 201247656 染、肝硬化、慢性肝病、肝細胞癌、冷球蛋白血症、非霍奇金氏淋巴瘤、肝纖維化及抑制性先天細胞内免疫反應。在另一實施例中’本發明提供根據式⑴之定義之化合物’該等化合物包括下文提供之例示性化合物。本發明所提供之某些式（I)化合物包括選自由以下組成之群的化合物： 1· 3-((S)-2-環己基-5-側氧基比嘻咬-1_基）_5_苯基-嘆吩-2-甲酸 2. 3-(2-環己基-6-側氧基-旅唆-1-基）_5_苯基-嗟吩_2-甲酸 3· 3-(3-環己基-5-側氧基-嗎啉-4-基）-5-苯基-噻吩-2-甲酸 4· 3-[(R)-2-環己基-6-側氧基-4-(甲苯-4-續醯基）_〇辰嗪_ 1-基]-5 -苯基-。塞吩-2-甲酸 5* 3-(2-環己基-6-側氧基底咬-1-基）-5-(3,3 -二甲基-丁~ 1- 炔基）-噻吩-2-曱酸 6· 3_((S)-2-環己基-6-側氧基-哌啶-1-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 1' 3·(2-環己基-6-側氧基-哌啶-1-基）-5-(4-氟-笨基）-嗟吩-2-曱酸 8· 3-(2-環己基_6_側氧基-哌啶-1-基）-5-對甲苯基_嗟吩_ 2- 曱酸 9· 5-(4·氯-苯基）-3-(2-環己基-6-側氧基-哌啶-^基兴噻吩-2-甲酸 160983.doc -64- 201247656 10. 3-[2-環己基-4-(6-二丙胺基-咐《啶-3-磺醯基）·6-側氧基·派°秦-1-基]-5 -本基塞吩·2 -甲酸 11. 3-{(R)-2-環己基-4-[6-((R)-2-甲基比咯啶-1_基）_。比咬-3-項酿基]_6-侧氧基-旅嗓-1-基}_5-本基喧2 甲酸 12. 3-[(R)-2-環己基-6-側氧基-4-(6-吡咯啶-1-基比0定-3-續酿基底嗓_1_基]-5 -苯基-b塞吩-2-甲酸 13. 3-{(R)-2-環己基-4-[6-((2S，5R)-2,5-二甲基比洛咬· φ 1-基）-处啶-3-磺醯基]-6-側氧基-哌嗪-l-基}-5-苯基- β塞吩-2-甲酸 14. 3-[2-環己基-6-側氧基-4-(曱苯-4-磺醯基）_°底唤_1-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 15. 3-{(R)-2-環己基-4-[6-((2R，6S)-2,6-二甲基-嗎啉-4- 基）-»比啶-3-磺醯基]-6-側氧基-哌嗪-1-基}-5-苯基-噻吩-2-曱酸 16. 3-[2-環己基-4-(6-嗎啉-4-基-吡啶-3-磺醯基）-6-侧氧 • 基-哌嗪-1-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 17· 3-[(R)-2_壞己基-4-(6·二乙胺基·11比咬-3-橫趨基）-6-側氧基-略嘻-1-基]-5 -苯基-嗟吩-2-甲酸 18· 3-[(R)-2·環己基-6-側氧基-4-(3,4,5,6-四氫-2H-[1，2，] 聯σ比咬基-51-績酸基）-派°秦-1-基]-5 -苯基-嘆吩-2-曱酸 19· 3-((R)-4-環己基-2-側氧基噁唑啶_3-基）-5-(3,3·二曱基-丁-1-炔基）-噻吩·2_甲酸 160983.doc -65· 201247656 20. 3-[(R)-2-環己基-4-(6-嗎琳-4-基- η比咬_3_續酿基）·6_ 側氧基-0底嗪-1-基]-5 -苯基-嗔吩-2-甲酸 21. 3-[(R)-2-環己基-4-(4-甲氧基-苯磺醯基）·6_側氧基_ 0底嗓-1-基卜5-(3,3 -一曱基-丁-1-块基）-n塞吩_2·曱酸 22. 3-[(R)_2-環己基-4-(6-甲氧基·》比啶_3_磺醯基）_6_側氧基-哌嗪-1-基]-5-(3,3-二甲基-丁-ΐ_炔基）_噻吩_2_曱酸 23. 3-[(R)-2-環己基-4-(1-曱基-1Η-吡唑_3_磺醯基）_6_側氧基-哌嗪-1-基]-5-(3,3-二甲基·丁 ·ι_炔基）·噻吩·2_ 甲酸 24. 3-{(R)-2-環己基-4-[6-(8-氧雜-3-氧雜-雙環[3.2.1]辛· 3-基）-°比啶-3-績醯基]-6-側氧基-η底嗪·ι_基卜5_對甲苯基-噻吩-2-甲酸 25. 3-(2-環己基-5-側氧基-吡洛咬_ι_基）_5_(3,3·二甲基_ 丁-1-块基）-嘆吩-2-甲酸 26. 3-((R)-3-環己基-5·側氧基·嗎啉-4·基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2·甲酸 27.3-((48,511)-5-環己基-3,4-二曱基-2-側氧基-蛛<1坐咬_1_ 基）-5-(3,3-二曱基-丁-1-炔基）塞吩_2-曱酸 28. 5-(4-氣-苯基）-3-((R)-3-環己基_5_側氧基-嗎啉-4-基）- 噻吩-2-甲酸 29. 3-[(R)-5 -環己基-2-(2 -嗎淋-4 -基-2-侧氧基-乙基）-3_ 側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁 _1_炔基）·噻吩_ 2-曱酸 30. 3-[(R)-5-環己基-2-(3-羥基丙基）_3_側氧基-嗎啉_4_ 160983.doc -66· 201247656 基]-5-(3,3-二曱基_丁_卜炔基）_n塞吩_2_甲酸 31. 3-[(R)-5-環己基-2-(3-甲烷磺醯基-丙基）側氧基_ 嗎啉-4-基]-5-(3,3-二甲基-丁炔基）_噻吩_2_甲酸 32. 3-{(R)-5-環己基_2·[(2-甲氧基_乙胺基）_甲基]_3_側氧基-嗎啉-4-基}-5-(3,3-二曱基-丁 _丨_炔基）_噻吩_2_甲酸 33· 3-(4-環己基-2-側氧基υ]氧氮雜環己烷_3_基）_5-(3,3-—甲基-丁 _ 1 -炔基）-η塞吩_2·曱酸 34. 3-((R)-5-環己基_2-嗎啉-4-基曱基-3-側氧基-嗎啉-4-鲁基）-5-(3,3-一甲基-丁 -1 -快基）_嗟吩_2-甲酸 3 5. 3-[(2R，5R)-5-環己基-2-(3-經基-丙基）·2_甲基-3-側氣基_嗎啉-4-基]-5-(3,3-二曱基-丁 _ι_炔基）_噻吩·2_甲酸 36. 3-((2S，5R)-2-氰基甲基_5_環己基冬曱基·3_側氧基-嗎嘛-4-基）-5-(3,3-二甲基-丁 - i_炔基）_嗟吩·2_甲酸 37. 3-(6-環己基-3-經基-2-側氧基_11底咬-1_基）_5_(3,3-> 甲基"·丁-1-快基）-嘆吩-2-甲酸 38. 3-((R)_5·環己基-2,2-二甲基_3_側氧基-嗎琳_4-基）-5· • 對甲苯基·噻吩-2-曱酸 39. 3-(6-環己基-3-經基-2-側氧基- π底咬_1_基）_5-對甲笨基-噻吩-2-甲酸 40. 3-[(2S，5R)-5-環己基-2-(3 -羥基-3-甲基-丁基）-2-甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁-1-炔基）- 噻吩-2-曱酸 41. 3-[(2R,5R)-5-環己基-2-(3-羥基-3-曱基-丁基）-2-f 基-3-側氧基-嗎啉-4-基]-5-(3,3-二曱基·丁-1-炔基 160983.doc •67· 201247656 °塞吩-2 -曱酸 42. 3-[(2S，5R)-5-環己基-2-((R)-3-羥基-丁基）_2_ 甲基 _3_ 側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁-1-炔基）_噻吩_ 2-曱酸 43. 3-[(2R，5R)-5-環己基-2-((R)-3-羥基-丁基）·2_ 甲基 _3_ 側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁-1·炔基）_嗟吩_ 2-甲酸 44. 3-((S)-6-環己基-3-經基-2-側氧基- 基）_5_(3,3_ 二曱基-丁-1-炔基）-噻吩-2-曱酸 45. 3-[(2R，5R)-5-環己基-2-(2-羥基-乙基）·2·曱基-3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-f酸 46. 3-(6-環己基-3 -經基-3-甲基-2-側氧基底π定-1_基）_5_ 對曱苯基·噻吩_2_甲酸 47. 3-((R)-3-環己基-5-側氧基-1，9-二氧雜-4-氧雜-螺 [5.5] Ί--碳-4-基）-5-(3,3-二甲基-丁 -1 -炔基）-u塞吩 _2_ 甲酸 48. 3-[6-環己基-3-(3-羥基-丙基）-2-側氧基-哌啶-1-基]_ 5-(3,3-二甲基-丁-卜炔基）_噻吩-2-曱酸 49. 3-[(2S，5R)-5-環己基-2-(2,3-二羥基-丙基）-2-曱基-3-側氧基-嗎淋-4-基]-5-(3,3-二甲基-丁-1-炔基）-。塞吩-2-甲酸 50. 3-[(2S，5R)-5-環己基-2-(2-羥基-乙基）-2-曱基-3-側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 51. 3-((R)-5-環己基-2-羥甲基-3-側氧基-嗎啉-4-基）-5- 160983.doc • 68- 201247656 (3,3-二甲基-丁-1-炔基）-噻吩-2-曱酸 52. 3-[(2R，5R)-5-環己基 _2-(2,3-二羥基-丙基）_2_ 甲基-3-侧氧基-嗎啉-4-基]-5-(3，3-二甲基-丁 -1-炔基）_噻吩-2-甲酸 53. 3-[(2S，5R)_5·環己基-2-(2,3-二羥基-丙基）_3_側氧基-嗎嚇*-4 -基]-5-(3,3 - 一曱基-丁-1-块基）-嘆吩_2-甲酸 54. 3-[(2S，5R)-5-環己基-2-(2-羥基-乙基）-3_側氧基-嗎 «#-4-基]-5-(3,3-二曱基-丁-1-炔基塞吩_2_甲酸 55. 3-[6-環己基-3-經基-3-(3-經基-丙基）-2-側氧基-σ底。定_ 1_基]-5-(3,3-二曱基-丁-1-炔基）-噻吩-2_曱酸 56. 3-[(2R,5R)-5-環己基-2-(2,3-二羥基-丙基）·3_侧氧基-嗎淋-4-基]-5-(3，3-二甲基-丁-1-炔基）_嗟吩-甲酸 57. 3-[(2R，5R)-5-環己基-2-(2-經基-乙基）_3-側氧基-嗎淋-4-基]-5-(3,3-二甲基-丁-1-炔基）-。塞吩_2_甲酸 58. 3·[(2S，5R)-5-環己基-2-(3-羥基-丙基）-2-甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁 -1·炔基）_售吩_2-曱酸 59. 3-((S)-6-環己基-3-經基-2-側氧基-派啶_ι_基）-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-甲酸 60. 3-[(2R，5R)-5·環己基-2-(3-羥基-丙基）_3_側氧基-嗎郝-4-基]-5·(3,3-·—甲基-丁-1-快基）-嗟吩_2_甲酸 61. 3-[(2S，5R)-5-環己基-2-(3-經基-丙基）_3_側氧基-嗎淋-4-基]-5-(3,3-—曱基-丁 -1 -快基）-〇塞吩_2_甲酸 62. 3-[(2R，5R)-5-環己基-2-((R)-2-羥基-丙基）_3_ 側氧基 _ 嗎淋-4-基]-5-(3,3-二甲基-丁-1-炔基）塞吩_2_曱酸 160983.doc •69- 201247656 63. 3-[(2R，5R)-5-環己基-2-((S)-2-經基-丙基）·3_側氧基, 嗎琳-4-基]-5-(3,3-二甲基-丁-1-炔基）-〇塞吩_2-甲酸 64· 3-[(S)-6-環己基-3-(3-羥基-丙基）-2-側氧基-派咬丄基]-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-甲酸 65· 3-((S)-3-胺基-6-環己基-2-側氧基-哌啶_丨_基）_5_(3,3_ 二甲基-丁-1-炔基）-噻吩-2-甲酸 66· 3-[(S)-6-環己基-3_(2_羥基·乙基）_2_側氧基_派咬小基]-5-(3,3-二甲基-丁-1-炔基）-售吩-2-甲酸以下實例意欲說明本發明且不應被視為對其進行限制。溫度以攝氏度給出。若未另外提及，則所有蒸發均在減壓下’通常在約15 mm Hg與100 mm Hg(=20-133毫巴）之間進行。最終產物、中間物及起始物質之結構係藉由標準分析方法確認’例如微量分析及光譜特徵（例如MS、ir、 NMR) ^所用縮寫為此項技術中習知之縮寫。所有用以合成本發明化合物之起始物質、構築嵌段、試劑、酸、鹼、脫水劑、溶劑及催化劑均為市售的或可藉由一般技術者已知之有機合成方法（H〇uben_Weyl第4版 1952，Methods of Organic Synthesis, Thieme，第 21 卷）製得。此外’本發明化合物可藉由一般技術者已知之如以下實例中所示之有機合成方法製備。縮寫清單The disease or disease is selected from the group consisting of Hcv infection, cirrhosis, chronic liver disease, hepatocytes, proteinemia, non-Hodgkin's lymphoma, liver fibrosis, and inhibitory innate intracellular immune response. In one embodiment, the invention provides a compound according to the definition of formula (1) for use as a medicament. In one embodiment, the invention provides the use of a compound according to the definition of formula (1) for the treatment of a condition or disease caused by Hcv infection or associated with hcv infection in an individual. In one embodiment, the invention provides the use of a compound according to the definition of formula (1) for the manufacture of a medicament for treating a disorder or disease caused by or associated with HCV infection in an individual, wherein the disorder or disease In particular, it is selected from the group consisting of HCV infection, cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma, liver fibrosis, and inhibitory innate intracellular immune response. In one embodiment, the invention provides the use of a compound according to the definition of formula (1) for the treatment of a condition or disease caused by or associated with HCV infection in an individual, wherein the condition or disease is selected from HCV Sense 160983.doc -63 - 201247656 Dyeing, cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma, liver fibrosis and inhibitory innate intracellular immune response. In another embodiment, the invention provides a compound according to the definition of formula (1). The compounds include the exemplary compounds provided below. Certain compounds of formula (I) provided herein include a compound selected from the group consisting of: 1· 3-((S)-2-cyclohexyl-5-sideoxyl-bite-1_yl)_5 _Phenyl-expressor-2-carboxylic acid 2. 3-(2-cyclohexyl-6-sideoxy-tour 唆-1-yl)_5_phenyl-porphin-2-carboxylic acid 3· 3-(3 -cyclohexyl-5-oxo-morpholin-4-yl)-5-phenyl-thiophene-2-carboxylic acid 4·3-[(R)-2-cyclohexyl-6-sideoxy-4- (Toluene-4-Continuoyl)_Chinylazine_1-yl]-5-phenyl-. Cefeno-2-carboxylic acid 5* 3-(2-cyclohexyl-6-hydroxyl-l-yl)-5-(3,3-dimethyl-butan-1-yl)-thiophene-2 - citric acid 6.3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene 2-carboxylic acid 1' 3·(2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-styl)-porphin-2-decanoic acid 8· 3- (2-cyclohexyl-6-oxo-piperidin-1-yl)-5-p-tolyl_嗟 _-2- 2-decanoic acid 9· 5-(4·chloro-phenyl)-3-(2 -cyclohexyl-6-o-oxy-piperidine-^-thiophene-2-carboxylic acid 160983.doc -64- 201247656 10. 3-[2-Cyclohexyl-4-(6-dipropylamino-indole) -3-sulfonyl)·6-sideoxy·p-heptyl-1-yl]-5-propenylphene-2-carboxylate 11. 3-{(R)-2-cyclohexyl-4-[ 6-((R)-2-Methylpyrrolidine-1_yl)-.Bisbital-3-termyl]]6-sideoxy-tour-1-yl}_5-benyl 喧2 formic acid 12. 3-[(R)-2-Cyclohexyl-6-sideoxy-4-(6-pyrrolidin-1-yl ratio 0--3-continued base 嗓_1_yl]-5-benzene Base-b-cephen-2-carboxylic acid 13. 3-{(R)-2-cyclohexyl-4-[6-((2S,5R)-2,5-dimethylpyrobityl) φ 1-yl - pyridine-3-sulfonyl]-6-oxo-piperazine-l-yl}-5-phenyl-β-cephen-2-carboxylic acid 1 4. 3-[2-Cyclohexyl-6-sideoxy-4-(indolyl-4-sulfonyl)_° bottom _1-yl]-5-(3,3-dimethyl-butyl 1-(Alkynyl)-thiophene-2-carboxylic acid 15. 3-{(R)-2-cyclohexyl-4-[6-((2R,6S)-2,6-dimethyl-morpholine-4 -基)-»Bistidin-3-sulfonyl]-6-o-oxy-piperazin-1-yl}-5-phenyl-thiophene-2-decanoic acid 16. 3-[2-cyclohexyl- 4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-oxyl-piperazin-1-yl]-5-(3,3-dimethyl-but-1 -alkynyl)-thiophene-2-carboxylic acid 17·3-[(R)-2_dextyl-4-(6.diethylamino)11-bito-3-transactingyl)-6-sideoxy - slightly 嘻-1-yl]-5-phenyl-porphin-2-carboxylic acid 18· 3-[(R)-2·cyclohexyl-6-sideoxy-4-(3,4,5,6 -tetrahydro-2H-[1,2,] σ 比咬 - - 51 - 酸酸 ) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ((R)-4-cyclohexyl-2-oxooxyoxazolidine-3-yl)-5-(3,3·didecyl-but-1-ynyl)-thiophene-2-carboxylic acid 160983. Doc -65· 201247656 20. 3-[(R)-2-Cyclohexyl-4-(6-morphin-4-yl-η ratio bite_3_continuous base)·6_ sideoxy-0-piperazine -1-yl]-5-phenyl-porphin-2-carboxylic acid 21. 3-[(R)-2-cyclohexyl-4-(4-methoxy-benzenesulfonyl)·6_side oxygen Base _ 0 bottom 嗓 -1- 5-(3,3-monodecyl-but-1-yl)-n-cephen-2-islic acid 22. 3-[(R)_2-cyclohexyl-4-(6-methoxy· 》Bistidine_3_sulfonyl)_6_sideoxy-piperazin-1-yl]-5-(3,3-dimethyl-butan-alkynyl)-thiophene-2-indole 23 3-[(R)-2-Cyclohexyl-4-(1-indolyl-1Η-pyrazole-3-ylsulfonyl)-6-sideoxy-piperazin-1-yl]-5-(3 ,3-dimethyl-butan-I-alkynyl)-thiophene-2_carboxylic acid 24. 3-{(R)-2-cyclohexyl-4-[6-(8-oxa-3-oxa-bicyclic) [3.2.1] 辛·3-yl)-°-pyridin-3-yl fluorenyl]-6-side oxy-η-piperazine·ι_ kib 5_p-tolyl-thiophene-2-carboxylic acid 25. 3-(2-cyclohexyl-5-sideoxy-pyrobitone_ι_yl)_5_(3,3·dimethyl-but-1-yl)- sultin-2-carboxylic acid 26. 3- ((R)-3-Cyclohexyl-5·sideoxy·morpholin-4·yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2·carboxylic acid 27.3- ((48,511)-5-cyclohexyl-3,4-dimercapto-2-oxo-spira <1 sit-bit_1_yl)-5-(3,3-dimercapto-but-1- Alkynyl) phenan-2-oxoic acid 28. 5-(4-Gayl-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-thiophene 2-carboxylic acid 29. 3-[(R)-5-cyclohexyl-2-(2-oxalin-4-yl-2-yloxy-ethyl)-3_ oxooxy -morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)·thiophene-2-indoleic acid 30. 3-[(R)-5-cyclohexyl-2- (3-hydroxypropyl)_3_sideoxy-morpholine_4_ 160983.doc -66· 201247656 ki]-5-(3,3-dimercapto-buty-enyl)_n-septene_2_ Formic acid 3. 3-[(R)-5-cyclohexyl-2-(3-methanesulfonyl-propyl) pendant oxy-morpholin-4-yl]-5-(3,3-dimethyl -butynyl)_thiophene-2-carboxylic acid 32. 3-{(R)-5-cyclohexyl_2.[(2-methoxy-ethylamino)-methyl]_3_sideoxy-? Physo-4-yl}-5-(3,3-dimercapto-butanyl-alkynyl)-thiophene-2-carboxylic acid 33· 3-(4-cyclohexyl-2-yloxyhydrazine]oxygen Heterocyclohexane_3_yl)_5-(3,3--methyl-butyl-1-alkynyl)-n-septene-2·decanoic acid 34. 3-((R)-5-cyclohexyl_ 2-morpholin-4-ylmercapto-3-oxo-morpholin-4-luyl)-5-(3,3-monomethyl-butan-1-fastyl)-porphin-2- Formic acid 3 5. 3-[(2R,5R)-5-cyclohexyl-2-(3-carbyl-propyl)-2-methyl-3-oxo-yl-morpholin-4-yl]-5 -(3,3-dimercapto-buty-I-alkynyl)-thiophene-2-carboxylic acid 36. 3-((2S,5R)-2-cyanomethyl-5-cyclohexylindoleyl 3 _Sideoxy-??-4-yl)-5-(3,3-dimethyl-butyl-i-alkynyl)- porphin·2_carboxylic acid 37. 3-(6-Cyclohexyl-3-yl-2-yloxy_11-Bottom-1_yl)_5_(3,3->Methyl"·-1--1-yl)-叹 -2--2-carboxylic acid 38. 3-((R)_5·cyclohexyl-2,2-dimethyl_3_sideoxy-morphine-4-yl)-5· • p-tolyl-thiophene- 2- phthalic acid 39. 3-(6-cyclohexyl-3-yl-2-yloxy- π-bottom _1-yl)_5-p-methyl-thiophene-2-carboxylic acid 40. 3-[ (2S,5R)-5-cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-o-oxy-morphin-4-yl]-5-(3 , 3-dimercapto-but-1-ynyl)-thiophene-2-furoic acid 41. 3-[(2R,5R)-5-cyclohexyl-2-(3-hydroxy-3-indolyl-butyl ))-2-fyl-3-yloxy-morpholin-4-yl]-5-(3,3-diindenyl-but-1-ynyl 160983.doc •67·201247656 ° 2 -decanoic acid 42. 3-[(2S,5R)-5-cyclohexyl-2-((R)-3-hydroxy-butyl)_2_methyl_3_ oxo-morpholin-4-yl] -5-(3,3-dimethyl-but-1-ynyl)_thiophene-2-pyruic acid 43. 3-[(2R,5R)-5-cyclohexyl-2-((R)-3 -hydroxy-butyl)·2_methyl_3_ oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-yl-yl)- porphin _ 2-carboxylic acid 44 3-((S)-6-Cyclohexyl-3-yl-2-yloxy-yl)_5_(3,3-diindenyl-but-1-ynyl -thiophene-2-furoic acid 45. 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-ethyl)·2·indolyl-3-oxo-morpholine-4- 5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-f acid 46. 3-(6-cyclohexyl-3-yl-amino-3-methyl-2-氧基 · -1 _ _ _ _ _ 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 47 -oxa-spiro[5.5] Ί--carb-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-ucephene_2_carboxylic acid 48. 3-[6- Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-butan-yl)-thiophene-2-曱acid 49. 3-[(2S,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)-2-indolyl-3-yloxy-oxalin-4-yl] -5-(3,3-dimethyl-but-1-ynyl)-. Cetene-2-carboxylic acid 50. 3-[(2S,5R)-5-cyclohexyl-2-(2-hydroxy-ethyl)-2-indolyl-3-oxo-morpholin-4-yl ]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid 51. 3-((R)-5-cyclohexyl-2-hydroxymethyl-3- sideoxy Benzyl-morpholin-4-yl)-5-160983.doc • 68- 201247656 (3,3-Dimethyl-but-1-ynyl)-thiophene-2-furic acid 52. 3-[(2R, 5R)-5-cyclohexyl_2-(2,3-dihydroxy-propyl)_2_methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl- But-1-ynyl)-thiophene-2-carboxylic acid 53. 3-[(2S,5R)_5·cyclohexyl-2-(2,3-dihydroxy-propyl)_3_sideoxy-- 4-[(2S,5R)-5-cyclohexyl-2-(4-((2S,5R)-5-cyclohexyl-2-) 2-hydroxy-ethyl)-3_sideoxy-?«#-4-yl]-5-(3,3-dimercapto-but-1-ynyl-septene-2_carboxylic acid 55. 3- [6-Cyclohexyl-3-carbyl-3-(3-carbyl-propyl)-2-yloxy-σ bottom. _ 1_yl]-5-(3,3-didecyl- But-1-ynyl)-thiophene-2-decanoic acid 56. 3-[(2R,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)·3_sideoxy- 5-(3,3-dimethyl-but-1-ynyl)- porphin-carboxylic acid 57. 3-[(2R,5R)-5-cyclohexyl-2-( 2-base- Ethyl)_3-tertiaryoxy-oxalin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-.septene-2_carboxylic acid 58.3 [2S , 5R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-o-oxy-morphin-4-yl]-5-(3,3-didecyl-丁-1·alkynyl)_ phenoxy-2-oxoic acid 59. 3-((S)-6-cyclohexyl-3-yl-2-yloxy-pyridyl_ι_yl)-5- (3,3-dimercapto-but-1-ynyl)-thiophene-2-carboxylic acid 60. 3-[(2R,5R)-5.cyclohexyl-2-(3-hydroxy-propyl)_3_ 3-[(2S,5R)-5 3-((3,3-R-)-[(2S,5R)-5 -cyclohexyl-2-(3-carbyl-propyl)_3_sideoxy-oxalin-4-yl]-5-(3,3--fluorenyl-but-1-ylidene-coupling吩_2_carboxylic acid 62. 3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)_3_ oxo-oxyl-4-yl]-5- (3,3-Dimethyl-but-1-ynyl)ephedo-2_decanoic acid 160983.doc •69- 201247656 63. 3-[(2R,5R)-5-cyclohexyl-2-(( S)-2-yl-propyl-propyl)·3_sideoxy, morphin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-decetenophene -formic acid 64·3-[(S)-6-cyclohexyl-3-(3-hydroxy-propyl)-2-yloxy-pyrylate]-5-(3,3-didecyl- But-1-ynyl -thiophene-2-carboxylic acid 65· 3-((S)-3-amino-6-cyclohexyl-2-yloxy-piperidine-indenyl)_5_(3,3-dimethyl-butyr-1 -alkynyl)-thiophene-2-carboxylic acid 66· 3-[(S)-6-cyclohexyl-3_(2-hydroxyethyl)_2_sideoxy--small base]-5-(3, The following examples are intended to illustrate the invention and are not to be construed as limiting. The temperature is given in degrees Celsius. If not mentioned otherwise, all evaporation is carried out under reduced pressure' usually between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of the final product, intermediate and starting material is confirmed by standard analytical methods, e.g., microanalysis and spectral characteristics (e.g., MS, ir, NMR). The abbreviations used are abbreviations commonly known in the art. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts for synthesizing the compounds of the invention are either commercially available or can be synthesized by methods known to the general practitioner (H〇uben_Weyl 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21). Further, the compound of the present invention can be produced by an organic synthesis method known to a person skilled in the art as shown in the following examples. Abbreviated list

AcAc

ACN 乙醯基乙腈ACN acetonitrile acetonitrile

AcOEt/EtOAe乙酸乙醋 160983.doc -70- 201247656AcOEt/EtOAe ethyl acetate vinegar 160983.doc -70- 201247656

AcOH 乙酸 aq 含水 Ar 芳基 Bn 苯甲基 Bu 丁基（nBu=正丁基，tBu=第三丁基） CDI 羰基二咪唑 CH3CN 乙腈 DBU 1，8-二氮雜雙環[5.4.0]十一碳-7-烯 DCE 1，2-二氯乙烷 DCM 二氣甲烷 DIPEA N-乙基二異丙胺 DMAP 二甲胺基吡啶 DMF N，N’-二曱基甲醯胺 DMSO 二曱亞職 El 電喷霧電離 Et20 *** Et3N 三乙胺 Ether *** EtOH 乙醇 FC 急驟層析 h 小時 HATU 六氣填酸0-(7-氣雜苯并二。坐-1-基）- N，N,N'，N'-四甲錁 HBTU 六氟磷酸〇-(苯并***-1-基）-N，N，N’，Nf-四 160983.doc -71· 201247656 甲錁 HCl 鹽酸 HOBt 1-羥基苯并*** HPLC 高效液相層析 H20 水 L 公升 LC-MS 液相層析質譜分析 Me 曱基 Mel 碘曱烷 MeOH 曱醇 mg 毫克 min 分鐘 mL 毫升 MS 質譜分析 Pd/C 鈀/木炭 PG 保護基 Ph 苯基 Prep 製備型 Rf 前端比（ratio of fronts) RP 逆相 Rt 滯留時間 rt 室溫 Si02 矽膠 TBAF 氟化四丁銨 160983.doc -72- 201247656 TEA 三乙胺 TFA 三氟乙酸 THF 四氫呋喃 TLC 薄層層析 HPLC方法：AcOH acetic acid aq water Ar aryl Bn benzyl b butyl (nBu = n-butyl, tBu = tert-butyl) CDI carbonyl diimidazole CH3CN acetonitrile DBU 1,8-diazabicyclo [5.4.0] eleven Carbon-7-ene DCE 1,2-dichloroethane DCM Dimethylmethane DIPEA N-ethyldiisopropylamine DMAP Dimethylaminopyridine DMF N,N'-dimercaptocarhamamine DMSO Dioxa sub-election El Electrospray ionization Et20 Ethyl ether Et3N Triethylamine Ether Ethyl ether EtOH Ethanol FC flash chromatography h hour HATU six gas filling acid 0-(7-gas benzo benzo. sit-1-yl)- N, N, N', N'-tetramethyl hydrazine HBTU bismuth hexafluorophosphate-(benzotriazol-1-yl)-N,N,N',Nf-tetra 160983.doc -71· 201247656 formazan HCl hydrochloric acid HOBt 1-hydroxybenzo Triazole HPLC High Performance Liquid Chromatography H20 Water L liter LC-MS Liquid Chromatography Mass Spectrometry Analysis Me Mercapto Mel Iododecane MeOH Sterol Mmg Min Min mL mL MS MS Mass Spectrometry Pd/C Palladium/Charcoal PG Protecting Group Ph Phenyl Prep Preparation Rf front-end ratio RP reverse phase Rt retention time rt room temperature SiO 2 tannin TBAF tetrabutylammonium fluoride 160983.doc -72- 201247656 TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography HPLC method:

A. 4.6 mm><150 mm C18逆相管柱，5.0 μπι粒度，操作 5-95% MeCN/水（0.1% 甲酸）之梯度，以 1.5 mL/min 之流動速率在30°C下歷經20分鐘之時期。DAD-UV偵測，220-600 nm 〇 B. 3 mm X100 mm C18逆相管柱，3.0 μπι粒度，操作 5-95% MeCN/水（0.1%曱酸）之梯度，以1 mL/min之流動速率在40°(：下歷經7.45分鐘之時期。〇八〇-1；¥偵測，220-600 nm。 C. 4.6 mmx 5 0 mm C18逆相管柱，5.0 μπι粒度，操作 5-95% MeCN/水（0.1%曱酸）之梯度，以2 mL/min之流動速率在40°(：下歷經3.4分鐘之時期。〇八〇-1；¥偵測，220-600 nm 〇 D. 4.6 mmx50 mm C18逆相管柱，5.0 μπι粒度，操作 5-95% MeCN/水（0.1%曱酸銨）之梯度，以2 mL/min 之流動速率在40°C下歷經3.4分鐘之時期。DAD-UV 4貞測，220-600 nm。A. 4.6 mm><150 mm C18 reverse phase column, 5.0 μπι particle size, operated with a gradient of 5-95% MeCN/water (0.1% formic acid) at a flow rate of 1.5 mL/min at 30 °C. The period of minutes. DAD-UV detection, 220-600 nm 〇B. 3 mm X100 mm C18 reverse phase column, 3.0 μπι particle size, operating 5-95% MeCN/water (0.1% citric acid) gradient to 1 mL/min The flow rate is 40° (: period of 7.45 minutes). 〇八〇-1; ¥ detection, 220-600 nm. C. 4.6 mmx 5 0 mm C18 reverse phase column, 5.0 μπι particle size, operation 5-95 Gradient of % MeCN/water (0.1% citric acid) at a flow rate of 2 mL/min at 40° (: 3.4 minutes period) 〇〇〇 ;; ¥ detection, 220-600 nm 〇 D. A 4.6 mm x 50 mm C18 reverse phase column, 5.0 μπι particle size, operated with a gradient of 5-95% MeCN/water (0.1% ammonium citrate) at a flow rate of 2 mL/min at 40 ° C for a period of 3.4 minutes. DAD-UV 4 speculation, 220-600 nm.

E. 3.0 mm><3 3 mm C8逆相管柱，3.0 μπι粒度，操作 5-95% MeCN/水（0.1%甲酸銨）之梯度，以2 mL/min 之流動速率在50°C下歷經2.0分鐘之時期。DAD-UV 160983.doc -73- 201247656 摘測，220-600 nm 〇程序實例1 合成3-[2-環己基-4-(2-氟-苯確醢基）_6_側氧基_旅嗓基】 5-苯基-噻吩-2-甲酸[化合物40]E. 3.0 mm><3 3 mm C8 reverse phase column, 3.0 μπι particle size, operating a gradient of 5-95% MeCN/water (0.1% ammonium formate) at a flow rate of 2 mL/min at 50 °C After a period of 2.0 minutes. DAD-UV 160983.doc -73- 201247656 Excerpt, 220-600 nm 〇 Procedure Example 1 Synthesis of 3-[2-cyclohexyl-4-(2-fluoro-phenyl-indenyl)_6_sideoxy_ Tourism 5-phenyl-thiophene-2-carboxylic acid [Compound 40]

步驟1·合成[(R)-環己基-(甲氧基-甲基-胺甲醢基）_甲基卜胺基甲酸苯甲酯Step 1·Synthesis of [(R)-cyclohexyl-(methoxy-methyl-aminocarbamimidyl)-methyl-p-propyl benzoate

在-10°C下向（R)-苯甲氧基羰胺基_環己基_乙酸（25 g， mmol)之 DMF(100 mL)溶液中添加 HATU(36 7 g，％ mmol，1.0當量），接著添加N，〇_二甲基羥胺鹽酸鹽（1〇 3 g , 105 mmol，1.2當量）。接著向此溶液中緩慢添加n甲基嗎啉（28.9 mL，263 mm〇l，3·〇當量）。謹慎監測内部溫度。在添加期間，使内部溫度升至〇它。在〇r下攪拌溶液 2小時，此後以Et〇Ac(500 mL)稀釋溶液且以飽和NaHC〇3 水溶液、水、LO N HC1水溶液及鹽水洗務。㈣a2s〇4乾 160983.doc •74 201247656 燥有機層且在真空下移除包括DMF之溶劑。以Et〇Ae稀釋殘餘物且以水、鹽水洗滌溶液，乾燥（MgS〇4)且濃縮，得到產物[(R)-環己基-(甲氧基·甲基_胺曱醯基）_甲基]_胺基甲酸苯甲酯（26 g，產率90%)。步驟2.合成（(R)-l-環己基_2_側氧基乙基）胺基甲酸苯甲酯Add HATU (36 7 g, % mmol, 1.0 eq.) to a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (25 g, mmol) in DMF (100 mL). Then, N, 〇-dimethylhydroxylamine hydrochloride (1 〇 3 g, 105 mmol, 1.2 eq.) was added. Next, n-methylmorpholine (28.9 mL, 263 mm ,l, 〇〇 equivalent) was slowly added to the solution. Carefully monitor the internal temperature. During the addition, raise the internal temperature to 〇 it. The solution was stirred at 〇r for 2 hours, after which time the solution was diluted with Et EtOAc (500 mL) and washed with saturated aqueous NaHCI3, water, &lt (d) a2s 〇 4 dry 160983.doc • 74 201247656 Dry the organic layer and remove the solvent including DMF under vacuum. The residue was diluted with Et EtOAc and washed with water and brine, dried (MgSO. ] Benzyl carbazate (26 g, yield 90%). Step 2. Synthesis of ((R)-l-cyclohexyl_2_sideoxyethyl) benzyl carbamate

在-20 C下向[(R)-環己基-(曱氧基_曱基-胺曱醯基）_甲基]-胺基甲酸苯甲酯（27 g，82 mmol)之THF(400 mL)溶液中緩慢添加LiAlH4(4_06 g，l〇6 mmol，1.3當量）°LiAlH4 係自購自Aldrich之片粒新鮮研磨。在添加期間，謹慎監測内部溫度且使其不會升至〇°C以上。添加之後，在〇它下授拌混合物且藉由TLC及LCMS監測反應。在1小時之後，在-10°C下冷卻反應溶液且藉由緩慢添加飽和khso4水溶液來淬滅直至pH=5。使混合物分配於水與£t〇Ac之間。分離各相且濃縮有機層《將殘餘物溶解於Et〇Ac中且以水、鹽水洗務溶液’經Na；2S〇4乾燥且濃縮，得到產物（(R)_丨_環己基-2-側氧基-乙基）-胺基曱酸苯曱酯（22 g，99%)。該物質未經進一步純化即繼續用於下一步驟。步驟3.合成（(尺)-2_苯甲氧基羰胺基_2_環己基·乙胺基）_乙酸甲酯 160983.doc -75. 201247656Benzyl [(R)-cyclohexyl-(decyloxy-indolyl-amine fluorenyl)-methyl]-carbamic acid benzyl ester (27 g, 82 mmol) in THF (400 mL) LiAlH4 (4_06 g, 10 〇 6 mmol, 1.3 eq.) was slowly added to the solution. The LiAlH4 system was freshly ground from pellets from Aldrich. During the addition, carefully monitor the internal temperature so that it does not rise above 〇 °C. After the addition, the mixture was stirred under hydrazine and the reaction was monitored by TLC and LCMS. After 1 hour, the reaction solution was cooled at -10 ° C and quenched by slowly adding a saturated aqueous solution of khso 4 until pH = 5. The mixture was partitioned between water and £t〇Ac. The phases were separated and the organic layer was concentrated <RTI ID=0.0>(</RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Phenoxy-ethyl)-aminophenyl phthalate (22 g, 99%). This material was used in the next step without further purification. Step 3. Synthesis of ((foot)-2_benzyloxycarbonylamino-2-cyclohexylethylamine)-acetic acid methyl ester 160983.doc -75. 201247656

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在〇C 下向酿（25 g，91 mmol)之 CH2Cl2(350 mL)溶液中依次添加甲基甘胺酸鹽酸鹽（22.8 g，182 mmol，2.0當量）、DIPEA(23.8 mL，136 mmol，1.5 當量）》向溶液中添加二乙醯氧基棚氫化鈉（28.9 g，136 mmol，1.5當量）。在室溫下攪拌混合物3小時。藉由添加飽和NaHC〇3水溶液來淬滅反應直至pH=8。分離各相且以CH2C12萃取水層。以水、鹽水洗滌經合併之有機層，乾燥（MgSCU)且濃縮，得到產物（(R)-2·苯甲氧基羰胺基-2-環己基-乙胺基）-乙酸曱酯（34 g ’ 107%產率）^含有雜質及溶劑之粗產物未經進一步純化即繼續用於下一步驟。步驟4·合成（R)-6-環己基-哌嗪-2-酮 ΝνΛ,Methylglycine hydrochloride (22.8 g, 182 mmol, 2.0 eq.), DIPEA (23.8 mL, 136 mmol) was added to a solution of EtOAc (25 g, 91 mmol) in CH2Cl2 (350 mL). 1.5 equivalents)" To the solution was added diethyl hydroxide hydride sodium hydride (28.9 g, 136 mmol, 1.5 eq.). The mixture was stirred at room temperature for 3 hours. The reaction was quenched by the addition of a saturated aqueous solution of NaHC.sub.3 until pH = 8. The phases were separated and the aqueous layer was extracted with CH2C12. The combined organic layers were washed with water, brine, dried (MgSO.sub.sub.ss.ssssssssssssssssssssssssssssssssssss g '107% yield) The crude product containing impurities and solvent was used in the next step without further purification. Step 4· Synthesis of (R)-6-cyclohexyl-piperazin-2-one ΝνΛ,

在N2流下向含有（(R)-2-苯曱氧基羰胺基-2-環己基-乙胺基）-乙酸甲 S旨（27 g，77 mmol)之 MeOH(300 mL)溶液的 2.0 L圓底燒瓶中添加Pd(10%於碳上，4.1 g，0.05當量）。在 1.0 atm Hz下攪拌混合物持續18小時。以100 mL CH2C12稀釋混合物且經由矽藻土過濾。濃縮濾液，得到粗產物 160983.doc -76· 201247656 (R)-6-環己基-哌嗪-2-酮（18 g，127%)。含有雜質及溶劑之產物未經進一步純化即繼續用於下一步驟。步驟5·合成（R)_3-環己基-5-側氧基-哌嗪-1-甲酸第三丁酯 0、、‘·2.0 under a flow of N2 to a solution of ((R)-2-benzofluorenyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acid methyl S (27 g, 77 mmol) in MeOH (300 mL) Pd (10% on carbon, 4.1 g, 0.05 eq.) was added to the L round bottom flask. The mixture was stirred at 1.0 atm Hz for 18 hours. The mixture was diluted with 100 mL of CH.sub.2 C.sub.2 and filtered over Celite. The filtrate was concentrated to give a crude material. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The product containing the impurities and solvent was used in the next step without further purification. Step 5. Synthesis of (R)_3-cyclohexyl-5-sideoxy-piperazine-1-carboxylic acid tert-butyl ester 0,, ‘·

向（R)-6-環己基·哌嗪 _2-酮（7.3 g，40 mmol)之 CH2C12 (200 mL)溶液中添加（b〇c)2〇(i〇.5 g，ll.l mmol，1.2 當量）。在室溫下攪拌溶液1小時，此後在真空下移除溶劑。藉由矽膠管柱層析（丙酮/庚烷，40%)純化殘餘物。濃縮所收集之溶離份直至留下約1 〇〇 mL溶劑。過濾固體且乾燥，得到產物（R)-3-環己基-5-側氧基·哌嗪-1-甲酸第三丁酯（6.7 g，59%)。藉由對掌性SFC測定產物之ee>98%。步驟6.合成3-溴-5-苯基-噻吩-2-甲酸甲酯Add (b〇c)2〇(i〇.5 g,ll.l mmol) to a solution of (R)-6-cyclohexyl-piperazine-2-one (7.3 g, 40 mmol) in CH2C12 (200 mL) , 1.2 equivalents). The solution was stirred at room temperature for 1 hour, after which time the solvent was removed under vacuum. The residue was purified by hydrazine column chromatography (EtOAc/hexanes, 40%). The collected fractions were concentrated until about 1 mL of solvent was left. The solid was filtered and dried to give the titled <RTI ID=0.0>(</RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The ee > 98% of the product was determined by the palm SFC. Step 6. Synthesis of methyl 3-bromo-5-phenyl-thiophene-2-carboxylate

向配備有回流冷凝器之250圓底燒瓶中添加CuBr2(l 1.5 g，51 mmo卜1.2當量）、CH3CN(250 mL)及亞硝酸第三丁酯（6.63 g，64.3 mmol，1.5當量）。在65°C下加熱溶液且向此溶液中添加3-胺基-5-苯基-噻吩-2-甲酸甲酯（1〇.〇 g， 42·0 mmol)之CH3CN(50 mL)溶液。在65°C下加熱所得混合 160983.doc •77. 201247656 物1小時。接著在至溫下冷卻反應混合物且添加至1 〇 N HC1水溶液中。添加Et0Ac且分離各相。以Et〇Ac萃取水層。以水、鹽水洗滌有機層，乾燥（NadO4)且濃縮。藉由矽膠純化殘餘物，得到7.5 g產物3-溴-5-笨基-噻吩_2_甲酸曱醋。步稱7·合成（R)-3-環己基-4-(2-甲氧羰基苯基-嘆吩_3_ 基）-5-側氧基-派嗓-1-甲酸第三丁酯To a 250 round bottom flask equipped with a reflux condenser was added CuBr2 (1 1.5 g, 51 mmo, 1.2 eq.), CH3CN (250 mL), and butyl nitrite (6.63 g, 64.3 mmol, 1.5 eq.). The solution was heated at 65 ° C and a solution of methyl 3-amino-5-phenyl-thiophene-2-carboxylate (1 〇. 〇 g, 42·0 mmol) in CH3CN (50 mL) was added. The resulting mixture was heated at 65 ° C. 160983.doc • 77. 201247656 for 1 hour. The reaction mixture was then cooled to ambient temperature and added to a 1 〇N HCl aqueous solution. Add Et0Ac and separate the phases. The aqueous layer was extracted with Et〇Ac. The organic layer was washed with water and brine, dried (NdEtOAc) and evaporated. The residue was purified by silica gel to give 7.5 g of product 3-bromo-5-phenyl-thiophene-2-carboxylic acid. Step 7·Synthesis of (R)-3-cyclohexyl-4-(2-methoxycarbonylphenyl-thin-3-yl)-5-sideoxy-pyrene-1-carboxylic acid tert-butyl ester

向s中饋入反式環己烧—胺（162 mg ’ 1.42 mmol，〇 5當量）、K2C03(783 mg，5.67 mmol，2.0當量）、3-漠-5-笨基· °塞吩-2-甲酸曱酯（1.01 g，3.40 mmol，1.2當量）、Cul(270 mg，1.42 mmol ’ 0.5當量）、（R)-3-環己基_5_側氧基·略嗪_ 1-甲酸第三丁酯（800 mg，2.83 mmol，1·〇當量）及^-二嗯烷（3.0 接著用N2沖洗該管且密封。在110°c下加熱反應混合物72小時，此後以EtOAc稀釋且過滤。以1 .〇 n HC1 水溶液、鹽水洗務濾液，乾燥（Na2S04)且濃縮。藉由石夕膠管柱層析（EtOAc/庚烧，50%)純化殘餘物，得到415 mg產物（R)-3-環己基-4-(2-曱氧羰基-5-苯基-噻吩_3_基）-5-側氧基-哌嗪-1 -曱酸第三丁酯。步驟8·合成3-((R)-2-環己基-6-側氧基-哌嗪-1·基）_5-苯基· 160983.doc -78- 201247656 噻吩-2-甲酸s was fed with trans-cyclohexane-amine (162 mg ' 1.42 mmol, 〇 5 equivalents), K2C03 (783 mg, 5.67 mmol, 2.0 equivalents), 3-Mo-5-stupyl·°Cet-2 - decyl formate (1.01 g, 3.40 mmol, 1.2 eq.), Cul (270 mg, 1.42 mmol '0.5 eq.), (R)-3-cyclohexyl _5_ oxo-oxazine _ 1-carboxylic acid third Butyl ester (800 mg, 2.83 mmol, 1 〇 )) and ^-dioxane (3.0) The tube was then rinsed with N2 and sealed. The reaction mixture was heated at 110 ° C for 72 hours, then diluted with EtOAc and filtered. The residue was purified by EtOAc (EtOAc/EtOAc) (EtOAc) Cyclohexyl-4-(2-oximeoxycarbonyl-5-phenyl-thiophene-3-yl)-5-oxo-piperazine-1 -decanoic acid tert-butyl ester. Step 8·Synthesis 3-(( R)-2-cyclohexyl-6-oxo-piperazine-1·yl)_5-phenyl·160983.doc -78- 201247656 thiophene-2-carboxylic acid

向（R)-3-環己基-4-(2-甲氧羰基_5_苯基_噻吩_3基）·5側氧基-哌嗪-1-甲酸第二丁酯（1_8 g，36 mm〇l)之THF/水/ φ Me〇H(l/l/l，30 mL)溶液中添加單水合氫氧化鋰（〇 45 g， 10.8 mmol，3.0當量）且在55°C下加熱所得溶液1小時。藉由添加1.0 N HC1水溶液來淬滅反應直至pH=5。接著以 EtOAc萃取溶液。以鹽水洗滌有機層，乾燥（Na2S〇4)且濃縮，得到（R)-4-(2-羧基-5-苯基·噻吩_3·基）·3_環己基_5_側氧基-哌嗪-1-曱酸第三丁酯3-((R)_2_環己基_6•側氧基_哌嗪-1-基）-5-苯基-噻吩-2-甲酸（1.7 g，97%)。該物質未經進一步純化即繼續用於下一步驟。 φ 向（R)-4_(2·叛基-5-苯基-嗟吩-3-基）-3·環己基-5-側氧基_ 哌嗪-1-曱酸第三丁酯（1.7 g)2M_二噁烷（5_〇 mL)溶液中添加4.0 N HC1之二噁燒（2〇 mL)溶液，且在室溫下擾拌所得混合物2小時。接著在真空下移除溶劑，得到鹽酸鹽產物（1.4 g，95%) 〇步驟9.合成外消旋3_(2-環己基-6-側氧基-哌嗪-1-基）-5_笨基-噻吩-2-甲睃 160983.doc •79· 201247656To (R)-3-cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophene-3-yl)·5-oxyl-piperazine-1-carboxylic acid dibutyl ester (1_8 g, 36 Mm〇l) THF/water/φ Me〇H (l/l/l, 30 mL) was added with lithium hydroxide monohydrate (〇45 g, 10.8 mmol, 3.0 eq.) and heated at 55 °C. The solution was 1 hour. The reaction was quenched by the addition of a 1.0 N aqueous HCl solution until pH = 5. The solution was then extracted with EtOAc. The organic layer was washed with brine, dried (Na.sub.2.sub.4) and concentrated to afford (R)-4-(2-carboxy-5-phenyl-thiophene~3yl). Piperazine-1-decanoic acid tert-butyl 3-((R)_2_cyclohexyl-6(o)oxyl-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (1.7 g, 97%). This material was used in the next step without further purification. φ to (R)-4_(2.Rebel-5-phenyl-nonphen-3-yl)-3.cyclohexyl-5-sideoxy-piperazin-1-decanoic acid tert-butyl ester (1.7 g) A solution of 4.0 N HCl in dioxane (2 〇 mL) was added to a solution of 2M_dioxane (5 〇mL), and the mixture was stirred at room temperature for 2 hours. The solvent is then removed in vacuo to give the hydrochloride salt product (1. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; _Stupid-thiophene-2-carben 160983.doc •79· 201247656

在〇°C下向（R)-苯甲氧基羰胺基_環己基_乙酸（15 g，51 5 mmol)之CH2C12(60 mL)溶液中添加义甲基嗎啉（12 5 113 mmol，2.2當量）且在_25t下添加氣甲酸異丁酯（6 % mL，51·5 mmol，1.〇當量）。在_1〇艽下攪拌所得溶液"、時，此後向此溶液中添加N，〇_二曱基羥胺鹽酸鹽（5.52 g， 56.5 mmol，1.1當量）於ch2C12(60 mL)之懸浮液。接著在室溫下攪拌混合物3小時，此後以Et〇Ac(5〇〇 mL)稀釋溶液且以1.0 N HC1水溶液及鹽水洗滌。經]^幻8〇4乾燥有機層且濃縮。按照上述步驟2-8自此物質合成外消旋3_(2_環己基-6-側氧基-哌嗪基）_5_苯基_噻吩_2-甲酸。步驟10·合成3·[2-環己基-4-(2-氟-苯磺醯基）-6·側氧基_哌嗪-1-基]-5-苯基-嗅吩-2-甲酸To a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (15 g, 51 5 mmol) in CH2C12 (60 mL) 2.2 equivalents) and isobutylic acid (6 % mL, 51.5 mmol, 1. 〇 equivalent) was added at _25t. When the resulting solution was stirred at _1 Torr, a suspension of N, 〇-dimercaptohydroxylamine hydrochloride (5.52 g, 56.5 mmol, 1.1 eq.) in ch2C12 (60 mL) was added to this solution. . The mixture was then stirred at room temperature for 3 hours, after which time the solution was diluted with EtOAc (5 mL) and washed with aq. The organic layer was dried and concentrated. Racemic 3-(2-cyclohexyl-6-oxo-piperazinyl)-5-phenyl-thiophene-2-carboxylic acid was synthesized from this material according to the procedure 2-8 above. Step 10. Synthesis of 3-[2-cyclohexyl-4-(2-fluoro-phenylsulfonyl)-6. oxo-piperazin-1-yl]-5-phenyl- olenophene-2-carboxylic acid

在室溫下向3-(2-環己基-6-側氧基-哌嗪-1-基）-5-苯基-噻吩-2-甲酸（15.0 mg，0.036 mmol，1.0 當量）之 MeCN(0.2 mL)溶液中添加NaOH(0.40 mL，1.5 N溶液，0.60 mmol， 160983.doc -80- 201247656 16.7當量）及 2-氟-苯績酿氯（11.4 mg，0.059 mmol，1.64 當量）。在室溫下攪拌混合物30分鐘。以3 N HC1(0.3 mL)酸化混合物，接著以EtOAc(10 mL)稀釋。以水（5 mL)、鹽水 (5 mL)洗滌混合物，接著乾燥（經Na2S04)，過濾且在減壓下濃縮濾液。藉由HPLC(0.1% NH4OH)純化殘餘物，得到呈白色固體狀之產物（5.0 mg，24%)。MS: 543 [M-H+]。 'H-NMR (400 MHz, CDC13)： δ 1.12 (m, 3H), 1.34 (m, 1H), 1-45-1.90 (m, 7H), 2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-3-CN-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (15.0 mg, 0.036 mmol, 1.0 eq.). 0.2 mL) solution was added with NaOH (0.40 mL, 1.5 N solution, 0.60 mmol, 160983.doc -80 - 201247656 16.7 equivalent) and 2-fluoro-benzene-brewed chlorine (11.4 mg, 0.059 mmol, 1.64 eq.). The mixture was stirred at room temperature for 30 minutes. The mixture was acidified with EtOAc (10 mL). The mixture was washed with water (5 mL), brine (5 mL). The residue was purified by EtOAcqqqqqqqq MS: 543 [M-H+]. 'H-NMR (400 MHz, CDC13): δ 1.12 (m, 3H), 1.34 (m, 1H), 1-45-1.90 (m, 7H), 2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-

3.70 (m, 2H), 3.95 (d, 1H), 4.18 (d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H), 7.51-7.61 (m, 3H), 7.83 (t, 1H)。3.70 (m, 2H), 3.95 (d, 1H), 4.18 (d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H) , 7.51-7.61 (m, 3H), 7.83 (t, 1H).

實例2.合成3-[(R)-2-環己基-6-侧氧基-4·(6-吡咯啶-1-基-吡咬_3_續酿基）·哌嗪-1-基】-5-苯基-噻吩-2-甲酸【化合物135] 步称1.合成3-【(R)_4-(6·氯-»比啶-3-磺醯基）-2·環己基-6-側氧基-旅嗓-1_基】_5_苯基_噻吩_2_甲酸Example 2. Synthesis of 3-[(R)-2-cyclohexyl-6-sideoxy-4·(6-pyrrolidin-1-yl-pyroxyl_3_continuary)·piperazin-1-yl 】-5-phenyl-thiophene-2-carboxylic acid [Compound 135] Step 1. Synthesis of 3-[(R)_4-(6·chloro-»pyridin-3-sulfonyl)-2·cyclohexyl- 6-Sideoxy-Break-1-based]_5_Phenyl-thiophene-2-formic acid

在室溫下向3-(2-環己基-6-側氧基-哌嗪-1-基）-5-苯基-噻吩·2_ 曱酸（0.80 g，1.90 mmo卜 1.0當量）之MeCN(20 mL)溶液中添加6-氣-吡啶-3-磺醯氯（1.10 g，5.20 mmol，2.7當量）’接著逐滴添加Na〇H(6.94 mL，1·5 N溶液，10.4 mm〇1 ’ 5_5當量）。在室溫下攪拌混合物10分鐘。以3 Ν 160983.doc 201247656 HC1(2.5 mL)酸化混合物，接著以EtOAc(50 mL)稀釋。以水（25 mL)、鹽水（25 mL)洗滌混合物，乾燥（經Na2S〇4)，過濾且濃縮，得到呈黃綠色固體狀之粗產物（1 .〇 g， 94%)。MS: 560 [Μ·Η+]。步琢2.合成3-[(R)-2-環己基-6-側氧基咬-3-項酿基）-旅嗓-1-基】-5-苯基-嗟吩-2-甲酸To a solution of 3-CN in the form of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-indole (0.80 g, 1.90 mmo, 1.0 eq.) at room temperature Add 6-gas-pyridine-3-sulfonium chloride (1.10 g, 5.20 mmol, 2.7 equivalents) to a solution of 20 mL) and then add Na〇H (6.94 mL, 1·5 N solution, 10.4 mm〇1' dropwise. 5_5 equivalents). The mixture was stirred at room temperature for 10 minutes. The mixture was acidified with EtOAc (EtOAc) (50 mL). The mixture was washed with EtOAc (EtOAc) (EtOAc) MS: 560 [Μ·Η+]. Step 2. Synthesis of 3-[(R)-2-cyclohexyl-6-sideoxy-bito-3-yl-bristyl)-tourist-1-yl]-5-phenyl-porphin-2-carboxylic acid

在室溫下向3-[(R)-4-(6-氯-吡啶-3-磺醯基）-2-環己基-6-側氧基-哌嗪-1-基]-5-苯基噻吩_2·曱酸（1〇〇 mg，0.18 mmol’ 1.0當量）之DMF(0.8 mL)溶液中添加吡咯啶（127 mg ’ 1.79 mmol，10.0 當量）及 Et3N(0.37 mL，2.68 mmol， 15.0當量p在70°C下攪拌混合物2小時。接著將混合物冷卻至室溫且過濾。濃縮濾液且藉由HPLC(0.10/。NH4OH)純化’得到呈白色固體狀之產物（35 mg，33〇/0)。MS: 595 [M-H+]。i-NMR (400 MHZ，MeOD): δ 1.10-1.23 (m，5H)， 1.40-2.00 (mj ion), 3.04-3.12 (m, 2H), 3.20 (t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62 (s, 1H), 7.19 (s, 1H), 7.32 (t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83 (m，1H), 8.44 (d，1H)。實例3.合成3-((R)-3-環己基_5_側氧基_嗎啉_4·基）_5_(3,3_二 160983.doc .82· 201247656 甲基-丁 _1_炔基）_噻吩_2_甲酸[化合物236】To 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-benzene at room temperature Pyrrolidine (127 mg ' 1.79 mmol, 10.0 eq.) and Et3N (0.37 mL, 2.68 mmol, 15.0) were added to a solution of thiophene-2-decanoic acid (1 〇〇 mg, 0.18 mmol '1.0 eq.) in DMF (0.8 mL). The mixture was stirred for 2 hours at 70 ° C. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by HPLC (0.10 /. 0) MS: 595 [M-H+]. i-NMR (400 MHZ, MeOD): δ 1.10-1.23 (m, 5H), 1.40-2.00 (mj ion), 3.04-3.12 (m, 2H), 3.20 (t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62 (s, 1H), 7.19 (s, 1H), 7.32 ( t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83 (m, 1H), 8.44 (d, 1H). Example 3. Synthesis of 3-((R)-3-cyclohexyl_5 _Sideoxy-morpholine_4·yl)_5_(3,3_two 160983.doc .82· 201247656 methyl-but-1-ynyl)_thiophene-2-formic acid [Compound 236]

步帮1.合成（R)-5-環己基-嗎啉_3_酮Step 1. Integrate (R)-5-cyclohexyl-morpholine _3-ketone

向含有3.8 g(26.5 mmol，L〇當量）(R)_2_胺基_2_環己基_ 乙醇於100 mL THF中之溶液中添加氫化鈉（14 g，58.4 mmol，60%於礦物油中，2.2當量）。在25°c下攪拌反應混合物30分鐘’此時氫氣逸出已停止。在〇β(：下冷卻混合物且經5分鐘逐滴添加氣乙酸乙酯（3 3 g，26 $ mm〇i，1.〇當量）。在2 5 C下授拌反應混合物1小時，接著在回流下攪拌 2小時。在真空下移除溶劑且向殘餘物中添加1 〇 n HC1水溶液直至pH=6。以乙酸乙酯萃取混合物。以鹽水洗滌所得有機萃取物，經硫酸鈉乾燥且在真空中濃縮。使殘餘物自 EtOAc/庚院中再結晶’得到2.8 g產物。濃縮母液且藉由石夕膠管柱層析（丙酮/庚烷50%)純化殘餘物，得到丨3 g產物。組合產量為4.1 g(84°/〇)。步帮2.合成5-(3,3-二甲基-丁-1-快基）-隹吩_2-甲酸Add sodium hydride (14 g, 58.4 mmol, 60% in mineral oil) to a solution containing 3.8 g (26.5 mmol, L〇 equivalent) of (R)_2-amino-2-cyclohexyl-ethanol in 100 mL of THF. , 2.2 equivalents). The reaction mixture was stirred at 25 ° C for 30 minutes' at which time hydrogen evolution had ceased. The mixture was cooled at 〇β (: and the ethyl acetate (3 3 g, 26 $ mm〇i, 1. 〇 equivalent) was added dropwise over 5 minutes. The reaction mixture was stirred at 25 C for 1 hour, then After stirring for 2 hours under reflux, the solvent was removed in vacuo and aq. EtOAc EtOAc EtOAc EtOAc EtOAc. Concentration. The residue was recrystallized from EtOAc / EtOAc to yield </RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The yield was 4.1 g (84 ° / 〇). Step 2 2. Synthesis of 5-(3,3-dimethyl-butan-1-yl)-porphin-2-carboxylic acid

201247656 向350 mL厚壁圓底燒瓶中饋入TEA(33.7 mL，24 mmo卜 5.0當量）、BINAP(3.0 g，4·83 mmo卜 0‘1 當量）、5-溴-噻吩-2-曱酸（48.3!11111〇1，1.0當量）、0：111(0.184§，0.97 mmol，0.02當量）、Pd2dba3(2.2 g，2.4 mmol，0.05 當量）及 DMF(40.0 mL)。用N2沖洗燒瓶且向混合物中添加第三丁基乙炔（15.8 g，193 mmol，4.0當量）。密封混合物且在70。〇下攪拌48小時。在室溫下冷卻後，過濾反應混合物且在真空下濃縮濾液。以3.0 N HC1酸化殘餘物直至PH=4。以 EtOAc萃取水層。以鹽水洗滌有機層，經Na2S04乾燥，且濃縮。藉由石夕膠（EtOAc/庚烧5%至EtOAc/庚貌30%(含20/〇 AcOH))純化殘餘物，得到6.5 g產物（產率65%)。步驟3·合成3-溴-5-(3,3-二甲基-丁-1-炔基）_噻吩_2_甲酸201247656 Feed TEA (33.7 mL, 24 mmo 5.0 equivalents), BINAP (3.0 g, 4.83 mmo 0'1 eq.), 5-bromo-thiophene-2-decanoic acid into a 350 mL thick-walled round bottom flask (48.3!11111〇1, 1.0 eq.), 0:111 (0.184 §, 0.97 mmol, 0.02 eq.), Pd2dba3 (2.2 g, 2.4 mmol, 0.05 eq.) and DMF (40.0 mL). The flask was rinsed with N.sub.2 and tributyl acetylene (15.8 g, 193 mmol, 4.0 eq.) was added to the mixture. The mixture was sealed and at 70. Stir for 48 hours under the crucible. After cooling at room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was acidified with 3.0 N HCl until pH = 4. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified with EtOAc (EtOAc /EtOAcEtOAcEtOAcEtOAc. Step 3. Synthesis of 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid

在-78°C下向5-(3,3-二曱基-丁-1·炔基）_噻吩_2_甲酸（6 5 g，31.3 mmoh κο 當量）之 THF(15〇 mL)溶液中添加 nBuU (44.9 mL ’ 1.6 M於庚烷中，71 9 _〇1，23 當量）且在-78 C下授拌所得溶液i小時。接著向溶液中添加-二 /臭-1’1,2,2-四氟_乙坑（162§,62 5爪爪〇卜2〇當量）且使溶液經2小時溫至室溫。藉由添加飽和肌^水溶液淬滅反應且以EtOAc萃取混合物 NazSO4乾燥且濃縮。粗一步驟。物。合併有機層，以鹽水洗滌，經粗物質未經進一步純化即繼續用於下 160983.doc • 84 - 201247656 甲酸甲酯步驟4.合成m(3,3_二甲基叮+炔.基）·嗔吩_2.To a solution of 5-(3,3-dimercapto-but-1-alkynyl)-thiophene-2-carboxylic acid (6 5 g, 31.3 mmolh κο eq) in THF (15 mL) at -78 °C nBuU (44.9 mL '1.6 M in heptane, 71 9 _ 〇 1, 23 eq.) was added and the resulting solution was stirred at -78 C for one hour. Next, a -di/odor-1'1,2,2-tetrafluoro-acetonitrile (162 §, 62 5 pawl 〇 2 〇 equivalent) was added to the solution and the solution was allowed to warm to room temperature over 2 hours. The reaction was quenched by the addition of aq. A rough step. Things. The organic layers were combined, washed with brine and dried with EtOAc EtOAc EtOAc EtOAc.嗔 _2 _2.

將來自先前步驟之產物溶解於DMF(15 〇 mL)中且向溶液中添加 K2C〇3(8.6g’62.6mm〇1，2〇t_Mei(89g， 62.6随。1，2.0當量在室溫下_所得混合物Η小時。過滤混合物且在真空下濃縮渡液。藉切膠管柱層析（庚烧細Ac⑽）純化殘餘物，得到7〇g產物⑽ 為74%)。千步驟合成3-(⑻-3-環己基_5_側氧基嗎啉*基)邻夂二甲基-丁-1-炔基）-噻吩_2_甲酸甲酯 ’The product from the previous step was dissolved in DMF (15 mL) and K2C〇3 (8.6 g '62.6 mm 〇1,2〇t_Mei (89 g, 62.6 with .1, 2.0 equivalents at room temperature) was added to the solution. The mixture was filtered for hr. The mixture was filtered and concentrated under vacuum. 3-cyclohexyl_5_sideoxymorpholine*yl)o-p-dimethyl-but-1-ynyl)-thiophene-2-formic acid methyl ester

向厚壁燒瓶中饋入反式環己烷二胺（623 ，5 5 mmo卜0.5當量）、3_漠-5_(3,3_二曱基_丁+炔基）_嚷吩_2_ 甲酸曱醋（4.27 g，14.2 mmol’ 1.3當量）、k2C〇3(3〇2 21.8 mmo卜 2.0當量）、Cul(1.04 g，5 5 咖〇卜〇 5當量卜 5-環己基-嗎啉-3-酮P.0 g，10.9 mm〇1，丨〇當量）及14_二 °惡烧（10.0 mL)。用N2沖洗混合物且在11 〇。〇下授摔48 ^ 時。經由石夕藻土過遽混合物且在真空下濃縮濾液。藉由石夕膠（EtOAc/庚烷50%)純化殘餘物，得到28 g產物（產率 160983.doc -85 - 201247656 50%) ° 步爾6.合成3-((R)-3-環己基-5-側氧基-嗎嘴_4基）_5·(3 3 一甲基-丁-1-炔基）-噻吩-2-甲酸Feeding a thick-walled flask with trans-cyclohexanediamine (623, 5 5 mmo, 0.5 equivalents), 3_---5-(3,3-didecyl-butan-alkynyl)-porphin-2_carboxylic acid曱 vinegar (4.27 g, 14.2 mmol '1.3 eq), k2C 〇 3 (3 〇 2 21.8 mmo 2.0 equivalent), Cul (1.04 g, 5 5 〇〇〇 5 equivalents of 5-cyclohexyl-morpholine-3 - ketone P.0 g, 10.9 mm 〇 1, 丨〇 equivalent) and 14 _ 2 ° mei burn (10.0 mL). The mixture was rinsed with N2 and at 11 Torr. His Majesty gave a drop of 48 ^. The mixture was passed through a mixture of Shixia and the filtrate was concentrated under vacuum. The residue was purified by EtOAc (EtOAc/EtOAc) (EtOAc:EtOAc:EtOAc) Hexyl-5-sideoxy-mouth-_4yl)_5·(3 3 monomethyl-but-1-ynyl)-thiophene-2-carboxylic acid

向甲醋（35 mg’ 0.087 mmo 卜 1.〇當量）之 THF(〇5 紅）、To vinegar (35 mg' 0.087 mmo 1.2 〇 equivalent) of THF (〇5 red),

MeOH(〇.5 mL)、水（0.5 mL)溶液中添加單水合氫氧化鋰 (10.9 mg，0.26 mmol，3.0當量）。在5〇。(：下攪拌所得混合物1小時’此後藉由添加1.0 N HC1水溶液至pH=6來中和反應°以EtOAc萃取混合物。合併有機層，以鹽水洗滌，經 Na2S〇4乾燥且濃縮。藉由逆相HPLC純化殘餘物，得到產物（18 mg，產率53%)〇MS: 390.1 [M+H+]。W-NMR (400 MHz, CD3〇D)： 6.87 (s, 1H), 4.19 (s, 2H), 4.05 (m, 2H), 3.82 (s，1H)，l.43_190 (m，6H)，1.06-1.39 (m, 14H)。實例4.合成3-【(R)_5_環己基-2-(3-羥基-丙基）-3-側氧基-嗎淋-4·基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸[化合物 299]To a solution of MeOH (0.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (10.9 mg, 0.26 mmol, 3.0 eq.). At 5 〇. (The mixture was stirred for 1 hour). The mixture was then neutralized with EtOAc (EtOAc). EtOAc (EtOAc). The residue was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) 2H), 4.05 (m, 2H), 3.82 (s, 1H), 1.43_190 (m, 6H), 1.06-1.39 (m, 14H). Example 4. Synthesis of 3-[(R)_5_cyclohexyl- 2-(3-Hydroxy-propyl)-3-oxo-oxalin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid [ Compound 299]

OHOH

160983.doc 201247656 步驟1.合成環己基-4-(4-甲氧基-苯甲基）-嗎啉_3_酮160983.doc 201247656 Step 1. Synthesis of cyclohexyl-4-(4-methoxy-benzyl)-morpholine-3-one

在〇C下向5-環己基-嗎嚇*-3 -嗣（1.0 g，5.5 mm ο 1，1. 〇當童）之DMF(15.〇 mL)溶液中緩慢添加NaH(0.26 g，600/〇於油中’ 6.5 mmol ’ 1.2當量）。在室溫下攪拌混合物30分鐘，接著向其中添加PMBC1(0.94 g，6.0 mmol，1.1當量）。在至Jm下授摔2小時後’藉由添加至飽和1水溶液中來泮滅反應混合物。以EtOAc萃取混合物。合併有機層且以鹽水洗滌’經MgSCU乾燥且濃縮。藉由矽膠（丙酮/庚院3〇%) 純化殘餘物，得到1.5 g(91%)5-環己基-4-(4-曱氧基-苯甲基）-嗎嚇 - 3 -網。步驟2.合成2-[3-(第三丁基-二甲基-矽烷基氧基）_丙基】_5_ 環己基-4-(4-甲氧基-苯甲基）-嗎啉_3_酮Slowly add NaH (0.26 g, 600) to a solution of 5-cyclohexyl-?-*3-嗣 (1.0 g, 5.5 mm ο 1,1. 〇) in DMF (15.〇mL) at 〇C / 〇 '6.5 mmol '1.2 equivalents in oil). The mixture was stirred at room temperature for 30 minutes, and then PMBC1 (0.94 g, 6.0 mmol, 1.1 eq.) was added. After 2 hours of dropping to Jm, the reaction mixture was quenched by addition to a saturated aqueous solution of 1. The mixture was extracted with EtOAc. The organic layers were combined and washed with brine water dried and concentrated with EtOAc. The residue was purified by silica gel (yield: EtOAc/EtOAc) to afford 1.5 g (91%) of 5-cyclohexyl-4-(4-decyloxy-phenylmethyl)- ss. Step 2. Synthesis of 2-[3-(t-butyl-dimethyl-decyloxy)-propyl]_5_cyclohexyl-4-(4-methoxy-benzyl)-morpholine_3 _ketone

在-78C下向5-環己基-4-(4-甲氧基-苯甲基）-嗎琳_3_酮 (700 mg，2·3 mmol，1.0當量）之THF(10.0 mL)溶液中添加 n-BuLi( 1 ·5 8 mL ’ 1 ·6 Μ於庚炫中，2.54 mmol，1.1 當量）。在-78°C下攪拌所得溶液30分鐘，此後向其中添加第三丁基- (3-峨-丙氧基）-二甲基-石夕院（693 mg，2.3 mmol，1 .〇當 160983.doc -87- 201247656 量）之THF(1.0 mL)溶液。在_78°C下攪拌溶液3〇分鐘且在室溫下授拌2小時，此後藉由添加飽和NhCl水溶液將其淬滅。以EtOAc卒取混合物。合併有機層，經Mgs〇4乾燥且濃縮。藉由矽膠管柱層析（EtOAc/庚烷30%)純化殘餘物，得到480 mg產物（產率44%)。步称3.合成5-環己基- 2-(3-經基-丙基）-嗎琳-3-嗣To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morphin-3-one (700 mg, 2.3 mmol, 1.0 eq.) in THF (10.0 mL) Add n-BuLi (1 · 5 8 mL ' 1 ·6 Μ in Gengxuan, 2.54 mmol, 1.1 eq.). The resulting solution was stirred at -78 ° C for 30 minutes, after which a third butyl-(3-indole-propoxy)-dimethyl-Shi Xi Yuan (693 mg, 2.3 mmol, 1. jingle 160983 was added thereto. .doc -87- 201247656 THF (1.0 mL) solution. The solution was stirred at -78 °C for 3 minutes and at room temperature for 2 hours, after which it was quenched by the addition of a saturated aqueous solution of NhCl. The mixture was drawn with EtOAc. The organic layers were combined, dried over MgSO 4 and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Step 3. Synthesis of 5-cyclohexyl- 2-(3-carbyl-propyl)-Merlin-3-嗣

向2-[3-(第三丁基-二甲基-矽烷基氧基）_丙基]_5_環己基_ 4- (4-曱氧基-苯甲基）_ 嗎咐 _3_ 酮（400 mg，0.84 mmol，1,〇當量）於CH3CN(0_3 mL)及水（0.3 mL)中之溶液中添加 CAN(922 mg ’ 1.68 mmo卜2.0當量）。在室溫下攪拌混合物1小時’接著添加第二份CAN(900 mg)。在室溫下擾拌J 小時之後，以EtOAc稀釋反應混合物且分離各相。以鹽水洗滌有機層，經Na2S04乾燥且濃縮。藉由矽膠管柱層析 (EtOAc/庚烷50%至1〇〇% EtOAc)純化殘餘物，得到134 mg 5- 環己基-2-(3-羥基-丙基）-嗎啉-3-酮。步驟4.合成3-[(R)-5-環己基-2-(3-羥基-丙基）-3-側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸甲酯To 2-[3-(t-butyl-dimethyl-decyloxy)-propyl]_5-cyclohexyl-4-(4-indolyl-benzyl)-indenyl-3-one ( 400 mg (0.84 mmol, 1, 〇 equivalent) was added to a solution of CH3CN (0_3 mL) and water (0.3 mL) with CAN (922 mg ' 1.68 mmo, 2.0 equivalent). The mixture was stirred at room temperature for 1 hour' followed by the addition of a second portion of CAN (900 mg). After stirring for J hours at room temperature, the reaction mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAcEtOAcEtOAc . Step 4. Synthesis of 3-[(R)-5-cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl Methyl-but-1-ynyl)-thiophene-2-carboxylate

160983.doc -88 * 201247656 向10 mL厚壁小瓶中饋入反式環己烷二胺（11.8 mg，0.10 111111〇1，〇.5當量）、3-漠-5-(3,3-二甲基-丁-1-炔基）-嗓吩-2_ 甲酸曱酯（125 mg，0.41 mmol ’ 2.0當量）、K2C03(57 mg， 0.41 mmol，2.0 當量）、Cul(19.7 mg，0.10 mmol，0·5 當量）、5-環己基-2-(3-經基-丙基）-嗎淋-3-酿1(50 mg，0.21 mmol，1.0當量）及1，4-二噁烷（0.5 mL)。用N2沖洗混合物且在110°C下攪拌24小時。經由矽藻土過濾混合物且在真空下濃縮濾液。藉由矽膠（EtOAc/庚烷30%)純化殘餘物，得到10 mg產物（產率10%)。步驟5.合成3-【(R)-5_環己基-2-(3-羥基-丙基）-3-側氧基-嗎啉_4_基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸160983.doc -88 * 201247656 Feeding trans-cyclohexanediamine (11.8 mg, 0.10 111111〇1, 〇.5 equivalent), 3-di-5-(3,3-di) into a 10 mL thick-walled vial Methyl-but-1-ynyl)-porphin-2_ carboxylic acid decyl ester (125 mg, 0.41 mmol '2.0 equivalent), K2C03 (57 mg, 0.41 mmol, 2.0 eq.), Cul (19.7 mg, 0.10 mmol, 0 · 5 eq), 5-cyclohexyl-2-(3-carbyl-propyl)- chlorene-3-branche 1 (50 mg, 0.21 mmol, 1.0 eq.) and 1,4-dioxane (0.5 mL) ). The mixture was rinsed with N2 and stirred at 110 ° C for 24 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by EtOAc (EtOAc /EtOAc) Step 5. Synthesis of 3-[(R)-5-cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholine-4-yl]-5-(3,3-dimethyl G-but-1-ynyl)-thiophene-2-carboxylic acid

向曱酯（10 mg，0.022 mmo卜 1.0當量）於THF(0.2 mL)、 MeOH(0.2 mL)'水（0.2 mL)中之溶液中添加水合氫氧化链 (4.5 mg ’ 0.11 mmo卜5.0當量）。在50°C下攪拌所得混合物 30分鐘，此後藉由添加1.0 N HC1水溶液至pH=6來中和反應。以EtOAc萃取混合物《合併有機層，以鹽水洗滌，經 \&2804乾燥且濃縮。藉由逆相1^1^(：純化殘餘物，得到2.6 mg產物。MS: 448.5 [M+H+]。實例5·合成3-[(2R，5R)-5-環己基-2-(3-羥基-丙基）-2-甲基-3-側氧基-嗎啉-4-基】-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲 160983.doc -89- 201247656Add a hydrated hydroxide chain (4.5 mg '0.11 mmob 5.0 equivalents) to a solution of decyl ester (10 mg, 0.022 mmol, 1.0 eq.) in THF (0.2 mL), MeOH (0.2 mL) EtOAc. . The resulting mixture was stirred at 50 ° C for 30 minutes, after which the reaction was neutralized by adding 1.0 N HCl aqueous solution to pH = 6. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. By reverse phase 1^1^ (: purification of the residue, 2.6 mg of product was obtained. MS: 448.5 [M+H+]. Example 5. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-(3) -hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-methyl 160983.doc -89- 201247656

酸丨化合物311JStrontium compound 311J

步秘1· (R)-2-【3·(第三丁基-二甲基-發烷基氧基丙基】_5 環己基-4-(4-甲氧基_苯甲基）·2_甲基-嗎淋_3_酮Step 1·(R)-2-[3·(T-butyl-dimethyl-alkoxypropyl]_5 cyclohexyl-4-(4-methoxy-benzyl)·2 _Methyl-Lip _3_ ketone

在-78C下向二異丙胺mg，1.36 mmol，1.3當量）之 THF(6·0 mL)溶液中添加 n-BuLi(0.79 mL，1·6 mL 於庚院中’ L26 mm〇l’ 12當量）且在-78°C下攪拌所得溶液ίο分鐘。向溶液中添加2_[3-(第三丁基-二甲基-矽烷基氧基）·丙基]-5·環己基·4-(4·甲氧基-苯甲基）-嗎啉-3-酮（500 mg， 1.05 mmol，1.0當量）2THF(2 mL)溶液且在_78<>c下攪拌溶液30分鐘。添加MeI且在_78〇c下攪拌溶液i小時接著經2 小時緩慢溫至室溫。藉由添加飽和nH4C1水溶液來淬滅反應。以EtOAc萃取混合物。以鹽水洗滌有機層，經Na2S〇4 乾燥，且濃縮。藉由矽膠管柱層析（Et〇Ac/庚烷，2〇%)純化殘餘物，得到110 mg產物（S)-2-[3-(第三丁基-二甲基-矽烧基氧基）_丙基].5·環己基·4·(4_甲氧基_笨甲基）-2•甲基-嗎淋-3-酮及205 mg產物叫2_[3(第三丁基二甲基石夕炫基氧 160983.doc 201247656 基）-丙基]-5-環己基-4-(4-甲氧基·苯甲基）_2-甲基-嗎啉-3- 酮。步驟2.合成（R)-5-環己基-2-(3-羥基·丙基）_2_甲基-嗎啉-3-鲖Add n-BuLi (0.79 mL, 1·6 mL in Gengyuan 'L26 mm〇l' 12 equivalents to a solution of diisopropylamine mg, 1.36 mmol, 1.3 eq.) in THF (6.0 mL). And the resulting solution was stirred at -78 ° C for ίο min. To the solution was added 2_[3-(t-butyl-dimethyl-decyloxy)-propyl]-5·cyclohexyl·4-(4·methoxy-benzyl)-morpholine- A solution of 3-ketone (500 mg, 1.05 mmol, 1.0 eq.) in THF (2 mL) was stirred and stirred for 30 min. MeI was added and the solution was stirred at _78 〇c for an hour and then slowly warmed to room temperature over 2 hours. The reaction was quenched by the addition of a saturated aqueous solution of nH4C1. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2, and evaporated. The residue was purified by EtOAc EtOAc (EtOAc (EtOAc) Base)_propyl].5·cyclohexyl·4·(4-methoxy-stupylmethyl)-2•methyl-nor--3-one and 205 mg product called 2_[3 (t-butyl Dimethyl sulfonyloxy 160983.doc 201247656 yl)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)_2-methyl-morpholin-3-one. Step 2. Synthesis of (R)-5-cyclohexyl-2-(3-hydroxypropyl)_2-methyl-morpholine-3-indole

向 TBS 醚（200 mg，0.41 mmol，i.o 當量）於 CH3CN(l.〇 mL)及水（1.0 mL)中之溶液中添加caN(461 mg，0.82 mmol，2.0當量）。在室溫下攪拌混合物1小時，接著添加第二份CAN(400 mg)。在室溫下攪拌1小時之後，以Et〇Ac 稀釋反應混合物且分離各相。以鹽水洗滌有機層，經 NaJO4乾燥且濃縮。藉由矽膠管柱層析（EtOAc/庚烷5〇% 至100°/。EtOAc)純化殘餘物’得到45 mg產物（43%產率）。步驟3.合成3-[(2R，5R)_5_環己基_2_(3_羥基-丙基）_2·甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁-炔基）·噻吩_2_甲酸甲酯To a solution of TBS ether (200 mg, 0.41 mmol, i.o.s.) in CH.sub.3CN (l.sup.mL) and water (1.0 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a second portion of CAN (400 mg). After stirring at room temperature for 1 hour, the reaction mixture was diluted with Et 〇Ac and the phases were separated. The organic layer was washed with brine, dried over Na.sub.4 and concentrated. The residue was purified by EtOAc <RTI ID=0.0>(</RTI> EtOAc (Hept. Step 3. Synthesis of 3-[(2R,5R)_5_cyclohexyl_2_(3-hydroxy-propyl)_2.methyl-3-o-oxy-morphin-4-yl]-5-(3, Methyl 3-dimethyl-butanyl)-thiophene-2-formic acid

OH 向10 mL小瓶中添加反式環己烷二胺（13 4 mg，〇.12 mmol，！.〇當量）、3_溴 _5-(3,3·二甲基_丁4_ 炔基）噻吩_2_ 甲酸曱酯（70.8 mg，0.24 mmol ’ 2.0 當量）、K2C03(32.5 160983.doc -91 - 201247656OH Add trans-cyclohexanediamine (13 4 mg, 〇.12 mmol, !.〇 equivalent), 3_bromo-5-(3,3·dimethyl-butan-4-alkynyl) to a 10 mL vial Thiophene-2-carboxylic acid oxime ester (70.8 mg, 0.24 mmol '2.0 equivalent), K2C03 (32.5 160983.doc -91 - 201247656

混合物且在真空下濃縮濾液。基-丙基）-2-甲基-嗎嘴_3-酮 i)及 1，4-二噁烷（〇·4 mL)。用拌18小時。經由矽藻土過濾。藉由矽膠管柱層析（EtOAc/ 庚烧80%)純化殘餘物，得到15mg產物（產率26%)。The mixture was concentrated under vacuum. Base-propyl)-2-methyl-mouth _3-ketone i) and 1,4-dioxane (〇·4 mL). Mix for 18 hours. Filter through diatomaceous earth. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

向甲醋（15 mg，0.032 mmo卜 1.0當量）於THF(0.5 mL)、 ]^0叫0.5 1111^)、水（〇.5 1111〇中之溶液中添加氫氧化鋰（3.8 mg ’ 0·1ό mmol ’ 5.0當量）。在50°C下攪拌所得混合物30 分鐘’此後藉由添加丨.〇 N HC1水溶液至PH=6來中和反應。以EtOAc萃取混合物。合併有機層，以鹽水洗滌，經 ^'^23〇4乾燥且濃縮。藉由逆相11?1^(：純化殘餘物，得到4.3 mg產物（產率 29%)。MW: 462.2 [M+H]。W-NMR (400 MHz, MeOD): δ 6;91 (s, 1Η), 4.23 (d, 1H), 3.94 (d, 1H), 3-62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H)，1·32 (s，9H), 1.21 (m，4H)，1.05 (m，1H)。實例6.合成3-[(2S，5R)-5-環己基-2-(3-羥基-丙基）-2-甲基-3-側氧基·嗎啉-4-基卜5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 160983.doc -92- 201247656 [化合物ΉAdd lithium hydroxide (3.8 mg '0·) to a solution of methyl vinegar (15 mg, 0.032 mmo, 1.0 equivalent) in THF (0.5 mL), ^^0 0.51111^), water (〇.5 1111〇). 1 ό mmol '5.0 eq.) The resulting mixture was stirred at 50 ° C for 30 minutes. The reaction was then neutralized by the addition of aq. The mixture was dried and concentrated with EtOAc EtOAc (EtOAc: EtOAc) MHz, MeOD): δ 6;91 (s, 1Η), 4.23 (d, 1H), 3.94 (d, 1H), 3-62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m , 10H), 1.45 (s, 3H), 1·32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H). Example 6. Synthesis of 3-[(2S,5R)-5-ring Hexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxooxymorpholine-4-ylbu 5-(3,3-dimethyl-but-1-ynyl)- Thiophene-2-carboxylic acid 160983.doc -92- 201247656 [Compound Ή

OHOH

根據實例S步驟2_步驟4中之程序繼續使用來自實例5步驟1之（S)-2-[3-(第三丁基·二甲基-矽烷基氧基）_丙基]_5·環己基-4-(4-甲氧基·苯甲基）_2·甲基-嗎啉-3-酮，得到3-[(2S，5R)-5-環己基_2-(3-羥基-丙基）·2-曱基-3-側氧基-嗎啉· 4-基]-5-(3,3-二曱基-丁 -1-炔基）_噻吩-2-曱酸。MS: 462.2[M+H+] 〇 i-NNlR (400 MHz, CD3OD): δ 6.93 (s，1H)， 4.12 (d，1H)，3.91 (d，1H)，3.66 (s，1H)，3.54 (t，2H)，2.14 (m, 1H), 1.91 (m, 1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H), 1.06-1.37 (m，14H)。實例7·合成3_[(2r，5R)_5_環己基_2_(2,3_二羥基-丙基）_2_甲基-3-側氧基嗎啉_4_基】-5_(3,3_二甲基-丁-1-炔基）-噻吩-2-甲酸[化合物33〇】The (S)-2-[3-(t-butyl-dimethyl-decyloxy)-propyl]_5· ring from step 5 of Example 5 was continued according to the procedure in Example S, Step 2 - Step 4. Hexyl-4-(4-methoxy-benzyl)_2·methyl-morpholin-3-one gives 3-[(2S,5R)-5-cyclohexyl_2-(3-hydroxy-propyl ))·2-mercapto-3-oxo-morpholine 4-yl]-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-decanoic acid. MS: 462.2 [M+H+] 〇i-NNlR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.12 (d, 1H), 3.91 (d, 1H), 3.66 (s, 1H), 3.54 ( t, 2H), 2.14 (m, 1H), 1.91 (m, 1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H), 1.06-1.37 (m, 14H). Example 7·Synthesis of 3_[(2r,5R)_5_cyclohexyl_2_(2,3-dihydroxy-propyl)_2-methyl-3-oxooxymorpholine_4_yl]-5_(3, 3_Dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid [Compound 33〇]

步驟1·合成3-((R)-2-烯丙基-5-環己基-3_側氧基-嗎啉-4-基）-5-(3,3-二甲基_丁·p炔基）·噻吩·2_甲酸甲酯 160983.doc •93· 201247656Step 1· Synthesis of 3-((R)-2-allyl-5-cyclohexyl-3_sideoxy-morpholin-4-yl)-5-(3,3-dimethyl-butan p Alkynyl·thiophene-2-methyl formate 160983.doc •93· 201247656

在-78°C下向3-((R)-3-環己基-5-側氧基-嗎啉-4-基）-5-(3,3-二曱基-丁-1-炔基）_噻吩_2_曱酸曱酯（600 mg，1.49 mmol ’ 1 ·〇當量）之 THF(5.0 mL)溶液中添加 LDA(0·82 mL， 2.0 Μ於THF中’ 1.64 mmol，1.1當量）且在-78°C下攪拌所得溶液20分鐘。接著向溶液中添加烯丙基碘（3〇〇 mg，1.78 mmol，1.2當量）。使溶液升溫至室溫且在此溫度下攪拌3〇分鐘。藉由添加飽和NH4C1水溶液淬滅反應。以EtO Ac萃取混合物。以鹽水洗滌有機層，經Na2S04乾燥，且濃縮。藉由矽膠管柱層析（EtOAc/庚烷25%)純化殘餘物，得到140 mg 3-((2S，5R)-2-烯丙基-5-環己基-3-側氧基-嗎啉-4-基）-5-(3，3-二曱基-丁 -1-快基）-嗟吩·2-曱酸甲醋、60 mg 3-((2R,5R)-2-烯丙基-5-環己基-3-側氧基-嗎啉-4-基）-5-(3,3- 一甲基-丁·1-快基）-°塞吩-2-甲酸曱g旨及200 mg混合溶離份。步驟2.合成3-((2S，5R)-2-烯丙基-5-環己基-2-甲基-3-側氧基-嗎啉-4-基）-5-(3,3-二甲基-丁-1-炔基）_噻吩-2-甲酸甲酯及產物3-((2R，5R)-2-烯丙基-5-環己基-2-甲基-3-側氧基-嗎啉-4-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸甲酯To 3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimercapto-but-1-ynyl) at -78 °C Add LD (0·82 mL, 2.0 Μ in THF ' 1.64 mmol, 1.1 eq.) to a solution of thiophene-2- decanoate (600 mg, 1.49 mmol '1 · 〇 equivalent) in THF (5.0 mL) The resulting solution was stirred at -78 ° C for 20 minutes. Allyl iodide (3 mg, 1.78 mmol, 1.2 eq.) was then added to the solution. The solution was allowed to warm to room temperature and stirred at this temperature for 3 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) 4-yl)-5-(3,3-dimercapto-butan-1-yl)- porphin-2-pyruic acid methyl vinegar, 60 mg 3-((2R,5R)-2-allyl 5--5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-monomethyl-butyl-1-propanyl)-°cephen-2-carboxylic acid And 200 mg mixed dissolving. Step 2. Synthesis of 3-((2S,5R)-2-allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3- Methyl dimethyl-but-1-ynyl)-thiophene-2-carboxylate and the product 3-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl-3-sideoxy Methyl-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylate

160983.doc •94· 201247656 在-78°C下向3-((R)-2_烯丙基_5_環己基_3_側氧基_嗎啉- 4- 基）-5-(3,3-二甲基·丁·卜炔基）_噻吩_2_甲酸甲酯 mg ’ 0.27随〇卜u當量）之THF〇〇紅）溶液中添加 LDA(0.16 mL ’ 2.0 Μ於 THF 中 ’ 0.32 mmo卜 ι·2 當量）且在-78°C下攪拌所得溶液2〇分鐘。接著向溶液中添加甲基碘（192 mg，1.35 mm〇i，5.〇當量）。使溶液升溫至室溫且在此溫度下攪拌30分鐘。藉由添加飽*NH4C1水溶液淬滅反應。以EtOAc萃取混合物。以鹽水洗滌有機層，經 NaJCU乾燥，且濃縮。藉由矽膠管柱層析（Et〇Ac/庚烷 25%)純化殘餘物，得到18 mg產物3_((2S，5R)_2_烯丙基·％環己基-2-甲基-3-側氧基_嗎啉_4-基）-5-(3,3-二甲基-丁炔基）-噻吩-2-曱酸曱酯及50 mg產物3_((2R，5r)_2_烯丙基_ 5- 環己基-2-甲基-3-側氧基·嗎啉_4-基）-5-(3,3-二曱基·丁炔基）-°塞吩-2-曱酸甲醋。步驟3.合成3_[(2R，5R)_5·環己基·2·(23_二羥基·丙基）2甲基-3-側氧基·嗎啉_4_基卜5·(3,3_二甲基―丁^•炔基）·噻吩_2_ 甲酸甲酯160983.doc •94· 201247656 3-((R)-2-I-allyl_5_cyclohexyl_3_sideoxy-morpholine-4-yl)-5-(3) at -78 °C ,3-dimethyl-butan-alkynyl)-thiophene-2-formic acid methyl ester mg '0.27 with u u u equivalent) of THF 〇〇 red) solution added LDA (0.16 mL '2.0 Μ in THF' 0.32 mmo ι·2 eq) and the resulting solution was stirred at -78 ° C for 2 Torr. Methyl iodide (192 mg, 1.35 mm 〇i, 5. 〇 equivalent) was then added to the solution. The solution was allowed to warm to room temperature and stirred at this temperature for 30 minutes. The reaction was quenched by the addition of a saturated aqueous solution of NH4C1. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na EtOAc and concentrated. The residue was purified by EtOAc EtOAc (EtOAc (EtOAc) elute Oxyl-morpholine-4-yl)-5-(3,3-dimethyl-butynyl)-thiophene-2-decanoate and 50 mg of product 3_((2R,5r)_2_allyc _ 5-Cyclohexyl-2-methyl-3-oxooxymorpholine 4-yl)-5-(3,3-dimercaptobutynyl)-°Cet-2-indole A vinegar. Step 3. Synthesis of 3_[(2R,5R)_5·cyclohexyl·2·(23-dihydroxypropyl)2methyl-3-oxooxymorpholine_4_gib5·(3,3 _Dimethyl-butyl--alkynyl)·thiophene-2-carboxylic acid methyl ester

\= 在〇°C下向3-((2R，5R)-2-烯丙基_5_環己基_2_甲基-3-側氧基-嗎琳·4-基）·5-(3,3-二甲基-丁·N炔基）_噻吩_2_曱酸甲醋 (〇·4〇 g，0.87 mmol，1.0當量）之丙酮（6 〇 mL)溶液中依次 160983.doc .95- 201247656 添加N-曱基嗎啉氧化物（0.31 g，2.63 mmo卜3.0當量）、水 (2.〇1111^)及〇3〇4(〇.44叾，0.044 111111〇1，〇.〇5當量，2.5重量 %於第三丁醇中）。在室溫下攪拌混合物6〇分鐘，之後藉由添加鹽水溶液（0.5 mL)及EtOAc(10 mL)來淬滅反應。分離有機層’乾燥（經NajO4)且濃縮。粗物質未經進一步純化即繼續用於下一步驟。步驟4.合成3-[(2R，5R)-5-環己基-2-(2,3-二羥基-丙基）-2-甲基-3·側氧基-嗎啉基】-5-(3,3-二甲基-丁-i_炔基）_噻吩_2_ 甲酸\= 3-((2R,5R)-2-allyl_5_cyclohexyl-2-methyl-3-oxo-?-lin-4-yl)·5-(() at 〇 °C A solution of 3,3-dimethyl-butyl-N-alkynyl)-thiophene-2-indole-methylacetate (〇·4〇g, 0.87 mmol, 1.0 eq.) in acetone (6 〇mL). 95- 201247656 Add N-mercaptomorpholine oxide (0.31 g, 2.63 mmo b 3.0 equivalent), water (2.1111^) and 〇3〇4 (〇.44叾,0.044 111111〇1,〇.〇 5 equivalents, 2.5% by weight in the third butanol). The mixture was stirred at room temperature for 6 min, then quenched by aqueous brine (0.5 mL) and EtOAc (10 mL). The organic layer was separated and dried (NajO4) and concentrated. The crude material was taken to the next step without further purification. Step 4. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3. oxo-morpholinyl]-5- (3,3-dimethyl-butan-i-alkynyl)-thiophene_2_carboxylic acid

將來自先前步驟之3-[(2R，5R)-5-環己基-2-(2,3-二羥基_ 丙基）-2 -甲基-3-侧氧基-嗎琳-4-基]-5-(3,3-二甲基-丁 · 1 -块基）-噻吩-2-甲酸甲酯溶解於4.0 mL THF中且取出〇.3 mL溶液用於反應。向經攪拌之溶液中添加THF(0.3 mL)、3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-o-oxy-morphin-4-yl from the previous step ]-5-(3,3-Dimethyl-butyl-1-phenyl)-thiophene-2-carboxylic acid methyl ester was dissolved in 4.0 mL of THF and a solution of 〇. 3 mL was taken for the reaction. Add THF (0.3 mL) to the stirred solution,

MeOH(0.3 mL)、水（0.3 mL)及 Li0H«H20(25.6 mg，0.61 mmol，10.0當量）且在室溫下攪拌所得溶液3〇分鐘。藉由添加3.0 N HC1水溶液來淬滅反應直至PH=5。接著向溶液中添加EtOAc且分離各相。藉由EtOAc萃取水層。合併有機層，乾燥（經Na2S04)且濃縮。藉由HPLC(0.1% NH4OH， MeCN/H2〇，10%-90%)純化殘餘物，得到呈白色固體狀之產物（1111^，37.7%產率）。]^8:478 [1^-11+]。 160983.doc -96- 201247656 實例8·合成3-【(2R，5R)-5-環己基_2_(2_羥基-乙基）2甲基MeOH (0.3 mL), water (0.3 mL), and EtOAc (H.sub.2) (25.6 mg, 0.61 mmol, 10.0 eq.). The reaction was quenched by the addition of a 3.0 N aqueous HCl solution until pH = 5. Then EtOAc was added to the solution and the phases were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried (Na2SO4) and concentrated. The residue was purified by EtOAc EtOAcjjjjjjj ]^8:478 [1^-11+]. 160983.doc -96- 201247656 Example 8. Synthesis of 3-[(2R,5R)-5-cyclohexyl_2_(2-hydroxy-ethyl)2 methyl

步驟1.合成3-[(2R，5R)-5-環己基-2-(2-羥基-乙基）_2_甲基Step 1. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-ethyl)_2-methyl

將來自實例7步驟3之3-[(2R，5R)-5-環己基_2_(2,3·二羥基-丙基）-2-曱基-3-側氧基-嗎啉·4_基]_5_(3,3_二甲基丁卜炔基）-噻吩-2-甲酸曱酯溶解於4 ml THF中且取出3 7 ^^溶液用於反應。在〇°C下向經攪拌之溶液中添加THF(2 3 mL)、水（2.0 mL)，接著添加過碘酸鈉（〇 28 g，丨31 mmol，1.6當量）。在室溫下攪拌所得溶液3〇分鐘。接著在〇°c下將另一份過碘酸鈉（0·09 g，0 44 mm〇1，〇 5當量）添加至混合物中且在室溫下再攪拌3〇分鐘。藉由添加鹽水溶液（〇·5 mL)及EtOAc(10 mL)淬滅反應。分離有機層，乾燥 160983.doc •97- 201247656 (經NaJO4)且濃縮。將殘餘物溶解於乙醇（6〇爪[)中且在 o°c下向所得溶液中添加侧氣化_ 27 g，7 〇 _Qi，8 8 之後藉由添加水（2.0 當量）。在0°C下攪拌混合物15分鐘， mL)及EtOAc(10 mL)淬滅反應。分離有機層，乾燥（經 NajSO4)且濃縮，得到128 mg產物（產率35%)。粗產物未經進一步純化即繼續用於下一步驟。MS: 462 [M-H+]。步驟2.合成3-[(2R，5R)-5-環己基-2-(2-經基_乙基）_2_甲基· 3-側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁炔基噻吩甲酸3-[(2R,5R)-5-cyclohexyl_2_(2,3·dihydroxy-propyl)-2-indolyl-3-oxo-morpholine·4_ from step 7 of Example 7 The ]5-(3,3-dimethylsobutynyl)-thiophene-2-carboxylic acid decyl ester was dissolved in 4 ml of THF and a 3 7 ^^ solution was taken for the reaction. To the stirred solution was added THF (2 3 mL), water (2.0 mL), and then sodium succinate ( 〇 28 g, 丨 31 mmol, 1.6 eq.). The resulting solution was stirred at room temperature for 3 minutes. Next, another sodium periodate (0·09 g, 0 44 mm 〇1, 〇 5 equivalent) was added to the mixture at 〇 °c and stirred at room temperature for another 3 minutes. The reaction was quenched by the addition of brine (5 mL) and EtOAc (10 mL). The organic layer was separated, dried (yield: EtOAc, EtOAc) The residue was dissolved in ethanol (6 〇 [ [) and a side gasification _ 27 g, 7 〇 _Qi was added to the resulting solution at 0 ° C, followed by the addition of water (2.0 eq.). The mixture was stirred at 0<0>C for 15 min, EtOAc (EtOAc) The organic layer was separated, dried (NajEtOAc) eluted The crude product was taken to the next step without further purification. MS: 462 [M-H+]. Step 2. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-(2-trans-ethyl)-2-methyl-3-trioxy-morpholin-4-yl]-5- (3,3-dimethyl-butynylthiophenecarboxylic acid

向甲酯（128 mg，0.28 mmol，1.0 當量）之 THF(2_0 mL)、 MeOH(l.〇 mL)及水（1.0 mL)溶液中添加 Li0H*H20(93 mg，2.22 mmol ’ 8.0當量）且在室溫下攪拌所得溶液3〇分鐘。藉由添加3.0 N HC1水溶液來淬滅反應直至pH=5。接著向溶液中添加EtOAc且分離各相。藉由EtOAc萃取水層。合併有機層且乾燥（經Na2S04)，接著濃縮。藉由 HPLC(0.1°/〇 NH4OH，MeCN/H20，10%-90%)純化殘餘物，得到呈白色固體狀之產物（87 mg，78.2%產率）。MS: 448.3 [M+H+]。W-NMR (400 MHz，CD3OD): 6.87 (s，1H), 4.24 (tert, 1H), 3.93 (d, 1H), 3.62-3.82 (m, 3H), 2.08-2.21 (m5 1H), 1.88-2.04 (m, 2H), 1.56-1.87 (m, 4H), 1.43-1.56 (m, 4H)，0.98-1.35 (m，14H)。 160983.doc -98· 201247656 實例9.合成3-[(2R，SR)-S-環己基_2·(2_羥基_乙基）_3侧氧基-嗎啉-4-基]-5-(3,3-二甲基·丁炔基）_噻吩_2甲酸[化合物8] °To a solution of methyl ester (128 mg, 0.28 mmol, 1.0 eq.) in THF (2.times.mL), MeOH (1. EtOAc) and water (1.0 mL). The resulting solution was stirred at room temperature for 3 minutes. The reaction was quenched by the addition of a 3.0 N aqueous HCl solution until pH = 5. EtOAc was then added to the solution and the phases were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined and dried (Na2SO4) then concentrated. The residue was purified by EtOAc EtOAcjjjjjjj MS: 448.3 [M+H+]. W-NMR (400 MHz, CD3OD): 6.87 (s, 1H), 4.24 (tert, 1H), 3.93 (d, 1H), 3.62-3.82 (m, 3H), 2.08-2.21 (m5 1H), 1.88- 2.04 (m, 2H), 1.56-1.87 (m, 4H), 1.43-1.56 (m, 4H), 0.98-1.35 (m, 14H). 160983.doc -98· 201247656 Example 9. Synthesis of 3-[(2R,SR)-S-cyclohexyl_2·(2-hydroxy-ethyl)_3 pendant oxy-morpholin-4-yl]-5- (3,3-dimethylbutynyl)_thiophene-2-carboxylic acid [Compound 8] °

步驟1·合成3-[(2R，5R)-S-環己基_2_(2_羥基-乙基）_3·侧氧基-嗎啉-4-基]-5-(3,3-二甲基·丁炔基）_噻吩_2甲酸甲酯Step 1· Synthesis of 3-[(2R,5R)-S-cyclohexyl_2_(2-hydroxy-ethyl)_3·trioxy-morpholin-4-yl]-5-(3,3-dimethyl Methyl-butynyl)-thiophene-2-carboxylate

在〇°C下向3-((2R，5R)-2·烯丙基_5_環己基側氧基·嗎啉-4·基)-5-(3’3_二甲基_丁+炔基)_噻吩|甲酸甲醋(〇 2〇 g’〇.45mmol’ K0當量）之丙酮（3〇mL)溶液+依次添加沭曱基嗎琳氧化物（0.160 g’ 1.35 mm〇l，3.〇當量）、水（1〇 mL)及〇S〇4(〇,22 g，〇.023 mm〇卜〇〇5當量，2」重量％於3-((2R,5R)-2·allyl_5_cyclohexyloxy morpholine-4-yl)-5-(3'3_dimethyl-butene) at 〇 °C Alkynyl)-thiophene|formic acid methyl vinegar (〇2〇g'〇.45mmol' K0 equivalent) in acetone (3〇mL) solution + sequentially added hydrazinoline oxide (0.160 g' 1.35 mm〇l, 3 .〇 equivalent), water (1〇mL) and 〇S〇4 (〇, 22 g, 〇.023 mm 〇〇〇 5 equivalents, 2% by weight in

第三丁醇中）〇在室溫下攪拌混合物6〇分鐘，之後藉由添加鹽水溶液及EtOAc來淬滅反應。分離有機層，乾燥（經In the third butanol, the mixture was stirred at room temperature for 6 minutes, then quenched by the addition of brine and EtOAc. Separating the organic layer and drying it

NajO4)且濃縮。粗物質未經進一步純化即繼續用於下步驟。將來自先前步驟之粗物質溶解於3.0 ml ThF及水（1.〇 mL)中且在〇°c下向溶液中添加過碘酸鈉（〇 19吕，〇 % mm〇1，2.0當量）。在室溫下攪拌所得溶液30分鐘，之後添加鹽水溶液及EtOAc。分離有機層，乾燥（經Na2S〇4)且濃备目。將殘餘物溶解於乙醇（3·〇 mL)中且在〇〇c下向所得溶液 160983.doc -99- 201247656 中添加硼氫化鈉（0.136 g，3.6 mm〇卜8 〇當量）。在〇(t下攪拌混合物15分鐘，之後藉由添加水（2 〇 1111^)及£〖〇八£^1〇 mL)淬滅反應。分離有機層，乾燥（經Na2S〇4)且濃縮，得到45 mg產物（產率22%)。粗產物未經進一步純化即繼續用於下一步驟。步驟2.合成3-[(2R，5R)-5-環己基-2-(2-羥基-乙基）-3_側氧基-馬琳-4-基】-5-(3,3-一甲基··丁-1-快基）_售吩_2-甲酸NajO4) and concentrated. The crude material was used in the next step without further purification. The crude material from the previous step was dissolved in 3.0 ml of ThF and water (1. 〇 mL) and sodium periodate (〇 19 〇, 〇 % mm 〇 1, 2.0 eq.) was added to the solution at 〇 °c. The resulting solution was stirred at room temperature for 30 minutes, after which a brine solution and EtOAc were added. The organic layer was separated, dried (Na2S~4) and concentrated. The residue was dissolved in ethanol (3·〇 mL) and sodium borohydride (0.136 g, 3.6 mm 8 8 〇 equivalent) was added to the obtained solution 160983.doc -99-201247656 under 〇〇c. The mixture was stirred at rt for 15 minutes, then quenched by the addition of water (2 〇 1111^) and </ RTI> </ RTI> </ RTI> The organic layer was separated, dried (Na2SO4) and concentrated to afford 45 mg (yield 22%). The crude product was taken to the next step without further purification. Step 2. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-ethyl)-3_sideoxy-marin-4-yl]-5-(3,3-one Methyl··but-1-fast base)

向甲醋（45 mg ’ 0.10 mm〇h lo 當量）於 THF(2 〇 mL)、To methyl vinegar (45 mg '0.10 mm 〇h lo equivalent) in THF (2 〇 mL),

MeOH(l.〇 mL)及水（1.0 mL)中之溶液中添加 Li〇H*H2CK33 mg，0.8 mmol，8.0當量）且在室溫下攪拌所得溶液3〇分鐘。藉由添加3.0 N HC1水溶液來淬滅反應直至pH=5。接著向溶液中添加EtOAc且分離各相。藉由EtOAc萃取水層◊合併有機層且乾燥（經NaaSCU)，接著濃縮。藉由逆相 HPLC純化殘餘物’得到呈白色固體狀之產物（25 mg，57% 產率）。 MS: 434.2 [M+H+]。丨H-NMR (400 MHz，CD3OD): δ 6.90 (s, 1H), 4.24 (tert, 1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d，1H)，3.71 (d，1H)，3.66 (t，1H)，2.21 (m, 1H)，1.41-1.98 (m，8H)，1.05-1.37 (m，15H)。 160983.doc •100- 201247656Li 〇H*H2CK33 mg, 0.8 mmol, 8.0 eq.) was added to a solution of MeOH (1. 〇 mL) and water (1.0 mL), and the resulting solution was stirred at room temperature for 3 Torr. The reaction was quenched by the addition of a 3.0 N aqueous HCl solution until pH = 5. EtOAc was then added to the solution and the phases were separated. The aqueous layer was extracted with EtOAc and EtOAc evaporated and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) MS: 434.2 [M+H+].丨H-NMR (400 MHz, CD3OD): δ 6.90 (s, 1H), 4.24 (tert, 1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d,1H), 3.71 (d , 1H), 3.66 (t, 1H), 2.21 (m, 1H), 1.41-1.98 (m, 8H), 1.05-1.37 (m, 15H). 160983.doc •100- 201247656

實例10·合成3-【(2R，5R)-5-環己基-2-(3-羥基-两基）_2_曱基 3-側氧基-嗎啉-4-基】-5-(3,3-二甲基·丁-1炔基）_噻吩_2甲酸[化合物311JExample 10·Synthesis 3-[(2R,5R)-5-cyclohexyl-2-(3-hydroxy-diyl)_2-indolyl 3-yloxy-morpholin-4-yl]-5-(3 ,3-dimethyl-but-1-ynyl)_thiophene-2-carboxylic acid [compound 311J

在0 C下向3-((2R，5R)-2-烯丙基-5-環己基-2-甲基_3_側氧基-嗎淋-4-基）-5-(3,3-二甲基-丁 -1 _炔基）_嘆吩_2_曱酸甲酯 (50 mg，0.11 mm〇l，i.o當量）之thF(1.0 mL)溶液中添加 9_ BBN(THF 巾之 0.5 Μ溶液，0.55 m卜 0.27 mm〇卜 2.5 當量）。接著在室溫下攪拌反應混合物2小時。接著在冰水浴中冷卻溶液且向其中添加EtOH，接著添加NaOH水溶液及 H2〇2水溶液。在添加期間，將反應液内部溫度保持在51 與10°C之間。接著將反應混合物加熱至回流持續9〇分鐘。在室溫下冷卻之後，以EtOAc萃取反應混合物。經Na2S04 乾燥有機層且在真空中濃縮。藉由製備型HPLC純化殘餘物，得到26 mg產物。MW: 462.2 [M+H]+。iH-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H)，1.32 (s，9H)，1.21 (m，4H)，1.05 (m，1H)。實例11.合成3-((S)-2-環己基-6-側氧基-哌啶-1-基）-5-(3,3-二甲基-丁-l·快基）-嘆吩-2-甲酸[化合物35】 160983.doc -101 - 2012476563-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl_3_sideoxy-oxalin-4-yl)-5-(3,3) at 0 C Add 9_ BBN (0.5 of THF towel) to a solution of methyl dimethyl-butyr-1 ynyl) thiophene-2-methyl citrate (50 mg, 0.11 mm ,l, io equivalent) in thF (1.0 mL) Μ solution, 0.55 m Bu 0.27 mm 2.5 2.5 equivalents). The reaction mixture was then stirred at room temperature for 2 hours. Next, the solution was cooled in an ice water bath and EtOH was added thereto, followed by the addition of an aqueous NaOH solution and an aqueous H 2 〇 2 solution. During the addition, the internal temperature of the reaction liquid was maintained between 51 and 10 °C. The reaction mixture was then heated to reflux for 9 min. After cooling at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg. MW: 462.2 [M+H]+. iH-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 ( m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H). Example 11. Synthesis of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-butyl-l·fast-base)-sigh Phen-2-carboxylic acid [Compound 35] 160983.doc -101 - 201247656

步驟1·合成（S)-S-環己基苯基_乙胺基）_戊酸乙酯Step 1· Synthesis of (S)-S-cyclohexylphenyl-ethylamino)-pentanoic acid ethyl ester

PhPh

將 TiCl4 之 DCM 溶液（88 mL，DCM 中之 1.0 Μ 溶液，8.8 mmol ’ 0.5當量）逐滴添加至經劇烈攪拌之用冰冷卻之s_甲基苯曱胺（2.78 g，23.0 mmo卜 1.3 當量）及 TEA(l〇.7 g， 106 mmol，6.0當量）之dCM(50 mL)溶液中。將溶液加熱至回流且經1分鐘添加5-環己基側氧基-戊酸乙酯（4.〇 g， 17·6 mmol ’ 1.0當量）。接著在回流下加熱溶液2小時，之後將其冷卻至室溫且以***稀釋，經由矽藻土過濾。以飽和NaHC〇3水/谷液、鹽水洗務混濁溶液，經Mg§〇4乾燥且濃縮。將殘餘物溶解於EtOH(4〇〇 mL)中且在-78°C下添加 NaBH4。攪拌30分鐘之後’使反應混合物升溫至〇〇c且在 0C下攪拌30分鐘。接著向溶液中添加6 〇 N HCM水溶液直至pH=3 °在真空下移除有機溶劑且用飽和NaHC〇3水溶液鹼化殘餘物直至PH=S^以EtOAc萃取混合物且以鹽水洗滌有機層，經NasSO4乾燥且濃縮。藉由矽膠（Et〇Ac/庚烷〇_ 15〇/〇純化殘餘物，得到2.3以乍為自管柱首先溶離之主產物 160983.doc •102- 201247656 的產物（產率39%) 〇步麻2.合成（S)-6-環己基-旅咬-2-明Add a solution of TiCl4 in DCM (88 mL, 1.0 Μ solution in DCM, 8.8 mmol <""""""""""""""""""""" And TEA (1 〇.7 g, 106 mmol, 6.0 eq.) in dCM (50 mL). The solution was heated to reflux and ethyl 5-cyclohexyloxy-pentanoate (4. g, 17.6 mmol' 1.0 eq.) was added over 1 min. The solution was then heated under reflux for 2 hours, then cooled to room temperature and diluted with diethyl ether and filtered over Celite. The turbid solution was washed with saturated NaHC〇3 water/guar solution and brine, dried over Mg 〇 4 and concentrated. The residue was dissolved in EtOH (4 〇〇 mL) and NaBH4 was added at -78 °C. After stirring for 30 minutes, the reaction mixture was allowed to warm to 〇〇c and stirred at 0 C for 30 minutes. The aqueous solution was then added to a solution of EtOAc (N.sub.2). NasSO4 was dried and concentrated. The residue was purified by hydrazine (Et〇Ac / heptane 〇 15 〇 / , to give 2.3 as the product of the main product 160983.doc •102- 201247656 which was first dissolved from the column (yield 39%) Hemp 2. Synthesis (S)-6-cyclohexyl-Brigade bite-2- Ming

PhPh

向（S)-5-環己基-5-((S)-l-苯基-乙胺基）-戊酸乙酯（2.0 g， 6.0 mmo 卜 1.0 當量）之 MeOH(60 mL)溶液中添加 Pd(i.6 g， 10〇/〇於碳上，1.51 mmol，0.25 當量）及甲酸銨（3.8 g，60.3 mm〇i ’ 1 〇·〇當量）。將混合物加熱至回流持續2小時。接著在室溫下冷卻溶液且經由矽藻土過濾。濃縮濾液且藉由矽膠管柱層析（丙酮/庚烷50%)純化殘餘物，得到L05 g產物 (96°/。產率）。步驟3.合成3_((S)-2-環己基-6-側氧基-哌啶-1-基）_5_(3,3-二甲基-丁-1-炔基）-噻吩—2-甲酸甲酯Add to a solution of (S)-5-cyclohexyl-5-((S)-l-phenyl-ethylamino)-pentanoic acid ethyl ester (2.0 g, 6.0 mmol, 1.0 eq) in MeOH (60 mL) Pd (i.6 g, 10 〇/〇 on carbon, 1.51 mmol, 0.25 eq.) and ammonium formate (3.8 g, 60.3 mm 〇i '1 〇·〇 equivalent). The mixture was heated to reflux for 2 hours. The solution was then cooled at room temperature and filtered through celite. The filtrate was concentrated and the residue was purified EtOAcjjjjjjjjjj Step 3. Synthesis of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2- Methyl formate

向10 mL小瓶中添加反式環己烷二胺（283 mg，2 5 mmol，0.5當量）、3-溴-5-(3,3-二甲基-丁-1·炔基）·噻吩 _2_ 甲酸曱酯（2.24 g ’ 7.4 mmol ’ 1 ·5 當量）、K2C03(1.37 g， 9.9 mmol，2.0當量）、Cul(473 mg，2.5 mmo卜 0.5當量）、 (S)-6-環己基-派 e定 _2 -酮（900 mg，5.0 mmol，1 .〇當量）及 1，4-二噁烷（5.0 mL)。以N2沖洗混合物且在11〇。〇下搜拌48 160983.doc -103- 201247656 小時。經由矽藻土過濾混合物且在真空下濃縮濾液。藉由矽膠管柱層析（EtOAc/庚烷30°/。）純化殘餘物，得到800 mg 產物（產率40°/。）。步辣4·合成3-((S)-2-環己基-6-側氧基-旅咬-1-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸Add trans-cyclohexanediamine (283 mg, 2 5 mmol, 0.5 eq.), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)thiophene to a 10 mL vial 2_ decyl formate (2.24 g '7.4 mmol '1 ·5 eq), K2C03 (1.37 g, 9.9 mmol, 2.0 eq.), Cul (473 mg, 2.5 mmo, 0.5 eq.), (S)-6-cyclohexyl- ET-ketone (900 mg, 5.0 mmol, 1.0 〇 equivalent) and 1,4-dioxane (5.0 mL). The mixture was rinsed with N2 and at 11 Torr. Underarms search for 48 160983.doc -103- 201247656 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Step Spicy 4·Synthesis 3-((S)-2-cyclohexyl-6-sideoxy-Bentyl-1-yl)-5-(3,3-dimethyl-but-1-ynyl)- Thiophene-2-carboxylic acid

向甲酯（10 mg ’ 0.025 mmol ’ 1.0 當量）於 THF(0.3 mL)、 MeOH(0.3 mL)及水（0.3 mL)中之溶液中添加單水合氩氧化鋰（5.2 mg，0.12 mmol，5.0當量）。在50°C下攪拌所得混合物1小時，之後藉由添加1.0 N HC1水溶液將反應液中和至 pH=6。以EtOAc萃取混合物。合併有機層，以鹽水洗條，經Na2S〇4乾燥且濃縮。藉由逆相HPLC純化殘餘物，得到 6.0 mg產物（產率 62%)。MW: 388.4 [M+H]+。'H-NMR (400 MHz, MeOD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25 (m, 1H), 1.88-1.38 (m, 6H), 1.29 (s, 9H), 1.18 (m, 4H), l.〇6 (m, 4H) » 實例12.合成3-((S)-胺基_6-環己基-2-側氧基-哌啶基）_5_ (3,3-二甲基-丁-i_炔基）_噻吩_2·甲酸：丨化合物322】步驟1·合成3-((3S,6S)-6-環己基-3-羥基·2-側氧基_哌啶·ρ 基）-5-(3,3-二甲基_丁_1_块基）_咳吩_2_甲酸甲酯 160983.doc •104· 201247656To a solution of the methyl ester (10 mg '0.025 mmol '1.0 eq.) in THF (0.3 mL), MeOH (0.3 mL) and water (0.3 mL), EtOAc ( 5.2 mg, 0.12 mmol, 5.0 eq. ). The resulting mixture was stirred at 50 ° C for 1 hour, and then the reaction mixture was neutralized to pH = 6 by adding 1.0 N aqueous HCl. The mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na. The residue was purified by reverse phase EtOAc to yield EtOAc (yield: 62%). MW: 388.4 [M+H]+. 'H-NMR (400 MHz, MeOD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25 (m, 1H), 1.88-1.38 (m, 6H), 1.29 (s, 9H), 1.18 (m, 4H), l.〇6 (m, 4H) » Example 12. Synthesis of 3-((S)-amino-6-cyclohexyl-2-yloxy-piperidinyl)_5_ (3,3 - dimethyl-butan-i-alkynyl)-thiophene-2·carboxylic acid: hydrazine compound 322] Step 1·Synthesis of 3-((3S,6S)-6-cyclohexyl-3-hydroxy-2-pyrene _ piperidine·ρ yl)-5-(3,3-dimethyl-but-1-yl)-cough phene-2-methyl formate 160983.doc •104· 201247656

在-78°C下向3-((S)-2-環己基-6-側氧基-哌啶·^基）-^ (3,3 -二甲基-丁 -1-炔基）-噻吩-2-甲酸曱酯（3.2 g，7.97 mmo卜 1.0當量）之THF(15.0 ml)溶液中添加NaHMDS(1.0 Μ 於THF中）且在-78°C下攪拌所得溶液1.5小時。接著向此溶液中添加（S)-(+)-(樟腦磺醯基）噁吖丙烧（3.65 g，15.94 mmol ’ 2.0當量）之THF(10 ml)溶液且在_78。(：下攪拌反應混合物3小時。藉由添加飽和NH4C1水溶液來淬滅反應。以 EtOAc萃取混合物且經Na2S04乾燥經合併之有機層，且濃縮。藉由矽膠管柱層析（Et20/DCM 5%〜40%)純化殘餘物，得到1.5 g所需產物（產率45%)。MS: 418 [M+H+]。步驟 2.合成 5-(3,3-二甲基-丁 -1-炔基）-3-[(3S，6S)-6-(l-乙基-戊基）-3-羥基-2-側氧基_哌啶_ι_基卜噻吩_2_甲酸To 3-((S)-2-cyclohexyl-6-oxo-piperidineyl)-(3,3-dimethyl-but-1-ynyl)--78 ° C To a solution of thiophene-2-carboxylic acid decyl ester (3.2 g, 7.97 mmol, 1.0 eq.) in THF (15.0 ml) was added NaHMDS (1.0 EtOAc in THF) and the mixture was stirred at -78 ° C for 1.5 hours. To this solution was then added a solution of (S)-(+)-(camphorsulfonyl) oxazolidine (3.65 g, 15.94 mmol' 2.0 equivalent) in THF (10 ml) and at -78. (The reaction mixture was stirred for 3 hours. The reaction was quenched with EtOAc EtOAc EtOAc EtOAc (EtOAc) The residue was purified to give 1.5 g of the desired product (yield 45%). MS: 418 [M+H+]. Step 2. Synthesis of 5-(3,3-dimethyl-but-1-yne ))-3-[(3S,6S)-6-(l-ethyl-pentyl)-3-hydroxy-2-oxo-piperidine_ι_ thiophene-2-carboxylic acid

在室溫下向3-((3S,6S)-6-環己基-3-羥基-2-側氧基-哌啶-1_基）-5-(3,3_二甲基-丁-1-炔基）-噻吩-2-曱酸甲酯（1.5 g， 3·59 mm〇1’ 1 當量）之 THF/H2O/MeOH(5.0 mL/5.0 mL/1.0 mL)溶液中添加LiOH.H2O(0.79 g，17.56 mmol，5.0 當 160983.doc 201247656 量）°在50°C下攪拌反應混合物20分鐘。接著藉由添加3 〇 N HC1水溶液將反應液酸化至pH=5且以EtOAc萃取混合物。經NaJO4乾燥有機層且濃縮。藉由處於鹼性條件 (0.1% NH4OH，10% 〜45% CH3CN/H20，操作 1〇分鐘，4〇 ml/min)之製備型 HPLC(XBridge Prep C 18，5 μηι，30x50 mm)純化殘餘物，得到850 mg產物（產率57%)。MS: 404 [M+H+]。'H-NMR (400 MHz，MeOD): δ 6.95 (s，1H)，4.09 (m，1Η)，3_74 (m，1Η)，2.09 (m, 1Η)，1.94-1.67 (m, 8Η), 1.38 (m，1H), 1.33 (s，9H)，1.17 (m，5H)。實例13.合成3-(2-環己基-6-侧氧基-哌啶-l·基）_5_(4_氣_苯基）-噻吩-2-甲酸【化合物70]To 3-((3S,6S)-6-cyclohexyl-3-hydroxy-2-oxo-piperidine-1-yl)-5-(3,3-dimethyl-butyl- at room temperature Addition of LiOH.H2O to THF/H2O/MeOH (5.0 mL/5.0 mL/1.0 mL) of methyl 1-ethynyl)-thiophene-2-furate (1.5 g, 3·59 mm〇1'1 eq.) (0.79 g, 17.56 mmol, 5.0 when 160983.doc 201247656 amount) ° The reaction mixture was stirred at 50 ° C for 20 minutes. The reaction was then acidified to pH = 5 by addition of aq. The organic layer was dried over NaJO4 and concentrated. Purification of the residue by preparative HPLC (XBridge Prep C 18, 5 μηι, 30×50 mm) under basic conditions (0.1% NH4OH, 10% to 45% CH3CN/H20, 1 min, 4 〇ml/min) , 850 mg of product was obtained (yield 57%). MS: 404 [M+H+]. 'H-NMR (400 MHz, MeOD): δ 6.95 (s, 1H), 4.09 (m, 1 Η), 3_74 (m, 1 Η), 2.09 (m, 1 Η), 1.94-1.67 (m, 8 Η), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H). Example 13. Synthesis of 3-(2-cyclohexyl-6-oxo-piperidine-l.yl)-5-(4-hydrox-phenyl)-thiophene-2-carboxylic acid [Compound 70]

步驟1.合成3-(1-環己基-4-乙氧羰基-丁胺基）-噻吩-2-甲酸甲醋 ♦Step 1. Synthesis of 3-(1-cyclohexyl-4-ethoxycarbonyl-butylamino)-thiophene-2-carboxylic acid methyl ketone ♦

OHOH

向燒瓶中饋入3-胺基-噻吩-2-曱酸甲酯（600 mg，3.82 mmol ’ 1.0當量）、5-環己基-5-側氧基-戊酸乙酯（864 mg， 3·82 mmol，1.0當量）、苯基矽烷（496 mg，4.58 mmol，1.2 160983.doc .106- 201247656 ¥ 量）、一氣化二丁基锡（116 mg，0.38 mmol，0.1 當量）及二嗯烧（3.0 mL)。在60°C下加熱所得溶液18小時。接著濃縮溶液且藉由矽膠管柱層析（CH2C12/庚烷30°/〇至100%)純化殘餘物，得到3-(1-環己基-4-乙氧羰基-丁胺基）-噻吩-2·甲酸甲酯（810 mg，產率57%)。步驟2.合成3-(4-羧基-1-環己基-丁胺基）_嘍吩_2_甲酸甲酯The flask was fed with methyl 3-amino-thiophene-2-furate (600 mg, 3.82 mmol '1.0 eq.), 5-cyclohexyl-5-side oxy-pentanoic acid ethyl ester (864 mg, 3· 82 mmol, 1.0 eq.), phenyl decane (496 mg, 4.58 mmol, 1.2 160983.doc .106-201247656 ¥), mono-glycolized dibutyltin (116 mg, 0.38 mmol, 0.1 eq.) and dioxin (3.0 mL) ). The resulting solution was heated at 60 ° C for 18 hours. The solution was then concentrated and the residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 2. Methyl formate (810 mg, yield 57%). Step 2. Synthesis of methyl 3-(4-carboxy-1-cyclohexyl-butylamino)-porphin-2-formic acid

向甲酯（300 mg，0.82 mmol，1·〇當量）於THF(1 〇 mL)、To methyl ester (300 mg, 0.82 mmol, 1·〇 equivalent) in THF (1 〇 mL),

MeOH(l.〇 mL)及水（i.o mL)中之溶液中添加氫氧化鋰（58 6 mg，2·45 mm〇l，3.〇當量）。在室溫下攪拌所得混合物4小時，之後在真空下移除有機溶劑。藉由添加丨N HC1水溶液中和所得溶液直至PH=6。以EtOAc萃取混合物。合併有機層’經NkSCU乾燥且濃縮，得到所需曱酸。步驟3.合成3_(2_環己基_6_側氧基·哌啶—I基）噻吩_2甲酸甲酯Lithium hydroxide (58 6 mg, 2.45 mm 〇l, 3. 〇 equivalent) was added to the solution in MeOH (1. 〇 mL) and water (i.o mL). The resulting mixture was stirred at room temperature for 4 hours, after which the organic solvent was removed under vacuum. The resulting solution was neutralized by adding a 丨N HCl aqueous solution until pH = 6. The mixture was extracted with EtOAc. The combined organic layers were dried and concentrated by NkSCU to give the desired decanoic acid. Step 3. Synthesis of 3_(2_cyclohexyl-6-oxo-piperidine-I-based) thiophene-2carboxylic acid methyl ester

在0°C下向曱酸（700 mg，2.06 mmol，10當量）之曱笨 (30.0 mL)溶液中添加吡啶（816 mg，1〇 3随。卜5 〇當 160983.doc 107. 201247656 量）’接者添加亞硫醯氣（245 mg，2.06 mmol，1.0當量）。在下攪拌溶液1小時。藉由添加飽和NH4C1水溶液淬滅反應。以EtOAc萃取混合物。合併有機層，以鹽水洗滌，經NasSO4乾燥且濃縮《藉由矽膠（庚烷/Et〇Ac 1/1)純化殘餘物’得到350 mg產物（產率53%)。步驟4.合成3-(2-環己基_6_側氧基_哌啶·氟-苯基）-噻吩-2-甲酸甲酯Add pyridine (816 mg, 1 〇 3 with a solution of citric acid (700 mg, 2.06 mmol, 10 eq.) in a solution of decanoic acid (30.0 mL) at 0 ° C. 55 〇 160 160 983.doc 107. 201247656 'Additional sulfoxide gas (245 mg, 2.06 mmol, 1.0 eq.). The solution was stirred under 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with EtOAc. The organic layer was combined, washed with brine, dried over Nassssssssssssssssssssssssssssssssssss Step 4. Synthesis of methyl 3-(2-cyclohexyl-6-oxo-piperidine·fluoro-phenyl)-thiophene-2-carboxylate

向5 mL小瓶中饋入3_(2-環己基-6-側氧基-哌啶-1-基）·噻吩-2-曱酸曱酯（32 mg，〇.1〇 mmol，1.0當量）、1-溴-4-氟苯 (17 mg，0.10 mmol，1.0 當量）、碳酸鉀（20.6 mg，0· 15 mmol，1·5當量）、三環苯基膦四氟硼酸鹽（8·7 mg，0.024 mmo卜 0.24當量）、pd(〇Ac)2(2.7 mg，0.012 mmol，0.12當量）、特戊酸（6.1 mg，0.060 mmol，0.6 當量）及 DMA(0.3 mL)。以氮氣沖洗所得混合物且在loot下攪拌18小時。將混合物負載於矽膠管柱上且以EtOAc/庚烷67°/。沖洗，得到 27 mg產物（產率65°/〇)。步驟5.合成3-(2-環己基_6_側氧基-哌啶-1-基）-5-(4-氟-苯基）_噻吩-2-甲酸To a 5 mL vial was fed 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-decanoate (32 mg, 〇.1 mmol, 1.0 eq.), 1-Bromo-4-fluorobenzene (17 mg, 0.10 mmol, 1.0 eq.), potassium carbonate (20.6 mg, 0·15 mmol, 1.5 eq.), tricyclophenylphosphine tetrafluoroborate (8·7 mg) , 0.024 mmo (0.24 eq.), pd (〇Ac) 2 (2.7 mg, 0.012 mmol, 0.12 eq.), pivalic acid (6.1 mg, 0.060 mmol, 0.6 eq.) and DMA (0.3 mL). The resulting mixture was flushed with nitrogen and stirred at luot for 18 h. The mixture was loaded onto a ruthenium tube column with EtOAc / heptane 67 ° /. Rinse to give 27 mg of product (yield 65 ° / 〇). Step 5. Synthesis of 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid

160983.doc •108- 201247656 向曱酯（20 mg，0.048 mmol，1.0當量）於thf(0.5 mL)、160983.doc •108- 201247656 to decyl ester (20 mg, 0.048 mmol, 1.0 eq.) in thf (0.5 mL),

EtOH(0.2 mL)及水（〇·5 mL)中之溶液中添加單水合氫氧化鋰（19 mg ’ 0.48 mmol，10_0當量）。在55。(：下搜拌所得混合物3小時’之後在真空下濃縮混合物。藉由逆相hplc純化殘餘物，得到15.0 mg產物（產率78%)。實例14 :合成3-((R)-4-環己基-2-侧氧基_噁唑啶_3_基）5 (3,3-二甲基-丁-1·炔基）-噻吩-2-曱酸【化合物181jTo a solution of EtOH (0.2 mL) and water (5 mL) was added lithium hydroxide monohydrate (19 mg <RTIgt;> At 55. (The mixture was mixed for 3 hours) and the mixture was concentrated under vacuum. The residue was purified by reverse phase hplc to give 15.0 mg of product (yield 78%). Example 14: Synthesis of 3-((R)-4- Cyclohexyl-2-oxooxy-oxazolidine-3-yl)5 (3,3-dimethyl-but-1-ynyl)-thiophene-2-decanoic acid [Compound 181j]

步驟1.合成（R)-4-環己基-噁唑啶-2-_Step 1. Synthesis of (R)-4-cyclohexyl-oxazole pyridine-2-

在〇°C下向（R)-2-胺基-2-環己基-乙醇.鹽酸鹽（1〇 g， 5.57 mmol，i.o 當量）之 CH2Cl2(3〇〇 mL)溶液中添加 DIPEA(1.94 mL ’ 11·1 mmo卜2.0當量），接著添加三光氣 (4_95 g，16.7 mmol，3.0當量）且在室溫下攪拌所得溶液12 小時。接著濃縮溶液且以Et0Ac稀釋殘餘物。以水 '鹽水洗滌溶液，經NaJO4乾燥且濃縮。藉由矽膠管柱層析 (EtOAc 100%)純化殘餘物，得到52〇叫產物。步驟2.合成3_((R)_4_環己基_2_側氧基_噁唑啶·3基 160983.doc •109· 201247656Add DIPEA (1.94) to a solution of (R)-2-amino-2-cyclohexyl-ethanol. hydrochloride (1 〇g, 5.57 mmol, io eq.) in CH.sub.2. mL '11·1 mmob 2.0 equivalents), followed by addition of triphosgene (4_95 g, 16.7 mmol, 3.0 eq.) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water 'brine, dried over NaJO4 and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) Step 2. Synthesis of 3_((R)_4_cyclohexyl_2_sideoxy-oxazolidine·3 base 160983.doc •109· 201247656

向厚壁燒瓶中饋入反式環己烷二胺（18.9 mg，0.17 mmol，0.5 當量）、3-溴-5-(3，3-二曱基-丁 -1-炔基）-噻吩-2-甲酸曱酯（100 mg，0.332 mmol，1.0 當量）、K2C03(92 mg ’ 0.664 mmol，2.0當量）、Cul(31.6 mg，0.166 mmol， 0.5 當量）' (R)-4_ 環己基-噁唑啶-2-酮（56.2 mg，0.332 mmol，1.0當量）及1，4-二噁烧（0.5 mL)。以N2沖洗混合物且在110°C下攪拌18小時，之後經由矽藻土過濾混合物且在真空下濃縮濾液。藉由矽膠管柱層析（EtOAc/庚烧30〇/〇) 純化殘餘物，得到54 mg產物（產率42°/〇)。步称3.合成3-((R)-4-環己基-2-側氧基-噁唑咬-3-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸A thick-walled flask was fed with trans-cyclohexanediamine (18.9 mg, 0.17 mmol, 0.5 eq.), 3-bromo-5-(3,3-dimercapto-but-1-ynyl)-thiophene- Ethyl 2-formate (100 mg, 0.332 mmol, 1.0 eq.), K2C03 (92 mg '0.664 mmol, 2.0 eq.), Cul (31.6 mg, 0.166 mmol, 0.5 eq.) '(R)-4_cyclohexyl-oxazole Pyridin-2-one (56.2 mg, 0.332 mmol, 1.0 eq.) and 1,4-dioxin (0.5 mL). The mixture was flushed with N.sub.2 and stirred at <RTI ID=0.0>1 </RTI> <RTIgt; The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Step 3. Synthesis of 3-((R)-4-cyclohexyl-2-oxooxy-oxazole-3-yl)-5-(3,3-dimethyl-but-1-ynyl) -thiophene-2-carboxylic acid

向甲酯（50 mg，0.128 mmol，ΐ·〇當量）之thf(〇.5 mL)、To the methyl ester (50 mg, 0.128 mmol, ΐ·〇 equivalent) of thf (〇.5 mL),

MeOH(0.5 mL)及水（0.5 mL)溶液中添加單水合氫氧化鋰 160983.doc •110· 201247656 (16.2 mg ’ 0.3 8 mmol，3.0當量）。在50°C下攪拌所得混合物1小時’之後藉由添加1.0 N HC1水溶液將反應液中和至 pH=6。藉由逆相HPLC直接純化混合物.，得到28 mg產物 (產率 58%)。MS: 376·4 [M+H+]。Add NaOH (0.5 mL) and water (0.5 mL) to a solution of lithium hydroxide monohydrate 160983.doc • 110· 201247656 (16.2 mg '0.3 8 mmol, 3.0 eq.). After the resulting mixture was stirred at 50 ° C for 1 hour', the reaction solution was neutralized to pH = 6 by adding 1.0 N aqueous HCl. The mixture was directly purified by reverse phase HPLC to give 28 mg (yield: 58%). MS: 376·4 [M+H+].

實例15.合成3-(2-環己基-6-側氧基·旅咬-1-基）-5·苯基吩-2-甲酸丨化合物4JExample 15. Synthesis of 3-(2-cyclohexyl-6-sideoxyl bunge-1-yl)-5-phenyl phen-2-carboxylic acid hydrazine compound 4J

步驟1.合成3-(1-環己基-4-乙氧羰基-丁胺基苯基_噻吩 2-甲酸甲酯Step 1. Synthesis of 3-(1-cyclohexyl-4-ethoxycarbonyl-butylaminophenyl-thiophene 2-carboxylic acid methyl ester

向燒瓶中饋入3-胺基-5-苯基-噻吩_2-甲酸甲酯（515 mg， 2.2 mmol，1.0當量）、5·環己基_5_側氧基_戊酸乙酯（5〇〇 mg，2.2 mmol，1.0當量）、苯基矽烷（24〇 mg，22 mm〇i , l.o當量）、二氣化二丁基錫（67 mg，0 22 mm〇1，〇丨當量）及二噁烷（2.0 mL)。用微波在12〇它下加熱所得溶液2小 .時。接著濃縮溶液且藉由矽膠管柱層析（Et〇Ac/庚烷5%至 40〇/。）純化殘餘物，得到含有起始物質之油狀物。用矽膠管 I60983.doc • 111 . 201247656 柱層析（Et〇H/DCM 2%至10%)進一步純化該物質，得到 150 mg產物（產率 15°/。）。步驟2.合成3_(4-羧基-1-環己基-丁胺基）_5·苯基_噻吩_2甲酸甲酯The flask was fed with methyl 3-amino-5-phenyl-thiophene-2-carboxylate (515 mg, 2.2 mmol, 1.0 eq.), 5·cyclohexyl_5_sideoxy-pentanoic acid ethyl ester (5 〇〇mg, 2.2 mmol, 1.0 eq.), phenyl decane (24 〇 mg, 22 mm 〇i, lo equivalent), dibutyltin dihydrate (67 mg, 0 22 mm 〇1, 〇丨 equivalent) and dioxins Alkane (2.0 mL). The resulting solution was heated in a microwave under 12 Torr for 2 hours. The solution is then concentrated and the residue is purified by EtOAc EtOAc EtOAc EtOAc This material was further purified by column chromatography (Et 〇 H / DCM 2% to 10%) to give 150 mg of product (yield 15 s.). Step 2. Synthesis of methyl 3-(4-carboxy-1-cyclohexyl-butylamino)-5(phenyl)-thiophene-2-carboxylate

向3·(1-環己基-4-乙氧羰基-丁胺基）-5-苯基-噻吩·2_甲酸曱醋（40 mg，〇.〇9 mmol，1.0 當量）於 THF(0.4 mL)、 EtOH(0.2 mL)、水（0.4 mL)中之溶液中添加氫氧化鋰（18 9 mg，0·45 mmol，5.0當量）。在50°C下攪拌所得混合物2小時’之後在真空下移除有機溶劑。藉由添加1.ON HC1水溶液中和所得溶液直至pH=6。以EtOAc萃取混合物。合併有機層’經NaJCU乾燥且濃縮得到30 mg產物（產率83%)。步驟3.合成3·(2-環己基-6-側氧基-哌啶-1-基）-S-笨基-噻吩_ 2-甲酸甲酯To 3·(1-cyclohexyl-4-ethoxycarbonyl-butylamino)-5-phenyl-thiophene-2-carboxylic acid vinegar (40 mg, 〇.〇9 mmol, 1.0 eq.) in THF (0.4 mL Lithium hydroxide (18 9 mg, 0·45 mmol, 5.0 eq.) was added to a solution of EtOH (0.2 mL) and water (0.4 mL). The resulting mixture was stirred at 50 ° C for 2 hours' and then the organic solvent was removed under vacuum. The resulting solution was neutralized by adding a 1.ON HC1 aqueous solution until pH = 6. The mixture was extracted with EtOAc. The combined organic layers were dried over NaJCU and concentrated to give 30 mg (yield: 83%). Step 3. Synthesis of 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-S-phenyl-thiophene-2-carboxylate

•OH• OH

向含有3-(4-羧基-1·環己基_丁胺基）-5-苯基-噻吩_2•曱酸甲醋（40 mg，0.096 mmol，1.0 當量）之 1，2-二噁烷〇·〇 mL) 160983.doc -112- 201247656 溶液的小瓶中添加吡啶（3.8 mg ’ 0.048 mmol，0.5當量）及 Boc20(25 mg，0.166 mmol，1.2當量）。接著密封小瓶且在 65°C下加熱18小時。濃縮溶液且藉由矽膠管枉層析 (EtO Ac/庚烷5%至100%)純化殘餘物，得到15 mg產物（產率 39%)。步驟4·合成3-(2-環己基-6-側氧基-哌啶-1-基）-5-苯基-噻吩-2-甲酸To 1,2-dioxane containing 3-(4-carboxy-1·cyclohexyl-butylamino)-5-phenyl-thiophene-2-carboxylate (40 mg, 0.096 mmol, 1.0 eq.) 〇·〇mL) 160983.doc -112- 201247656 A solution was added to the vial with pyridine (3.8 mg '0.048 mmol, 0.5 eq.) and Boc20 (25 mg, 0.166 mmol, 1.2 eq.). The vial was then sealed and heated at 65 °C for 18 hours. The solution was concentrated and the residue was purified EtOAcjjjjjjjjjjj Step 4. Synthesis of 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid

R)R)

VH 向甲酯（15 mg ’ 0.038 mmo卜 1.0當量）於THF(0.2 mL)、VH to methyl ester (15 mg '0.038 mmob 1.0 equivalent) in THF (0.2 mL),

EtOH(0.2 mL)、水（0.1 mL)中之溶液中添加單水合氫氧化鋰（7.9 mg，0.19 mmol ’ 5.0當量）。在50°C下授拌所得混合物2小時，之後在真空下濃縮混合物。藉由逆相HPLC純化殘餘物，得到5.0 mg產物（產率35%)。MW: 384.1 鲁 [M+H]+。W-NMR (400 MHz, CDCI3): δ 7.43 (m，2H)，7.21 (m，3H)，6·94 (m，1H)，3.68 (m，1H)，2.45 (m，2H), 2.21 (m， 1H)，1.83-1.51 (m，12H)，1.32 (m，2H)。實例16·合成3-(2-環己基-4-經基-6-側氧基_旅咬_1_基）_5_苯基-噻吩-2-甲酸曱酯[化合物12] 步琢1. 3-(1-環己基-2-乙氧幾基-乙胺基）-5-苯基_嗟吩_2_甲酸甲酯 160983.doc •113· 201247656To a solution of EtOH (0.2 mL) and water (0.1 mL), lithium hydroxide monohydrate (7.9 mg, 0.19 mmol < The resulting mixture was mixed at 50 ° C for 2 hours, after which the mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to give 5.0 mg (yield: 35%). MW: 384.1 Lu [M+H]+. W-NMR (400 MHz, CDCI3): δ 7.43 (m, 2H), 7.21 (m, 3H), 6.94 (m, 1H), 3.68 (m, 1H), 2.45 (m, 2H), 2.21 ( m, 1H), 1.83-1.51 (m, 12H), 1.32 (m, 2H). Example 16·Synthesis of 3-(2-cyclohexyl-4-carbyl-6-sideoxyl_Brigade_1_yl)_5-phenyl-thiophene-2-carboxylic acid oxime ester [Compound 12] Step 1. Methyl 3-(1-cyclohexyl-2-ethoxyxo-ethylamino)-5-phenyl-porphin-2-carboxylate 160983.doc •113· 201247656

在室溫下向3-環己基-3-側氧基-丙酸乙酯（l.o g，5,〇 mmol，1.0當量）之THF(5.0 mL)溶液中添力〇3-胺基-5-笨基_ 嘆吩-2-曱酸甲酯（1.17 g，5.0 mmol，1_〇當量）及 SnBu2Cl2(〇. 15 g ’ 0.50 mmol，0.1 當量）。在室溫下授摔 5 分鐘之後’向溶液中添加PhSiH3。在65°C下在N2下授拌所得反應混合物1 8小時，之後在真空下濃縮溶液且藉由石夕膠鲁管柱層析（EtOAc/庚烧，10-60%)純化殘餘物，得到產物 (0.7 g)。MS: 416 [M+H+]。步琢2. 3-(2-叛基-1-環己基-乙胺基）·5-苯基-嗔吩_2_甲酸甲醋To a solution of 3-cyclohexyl-3-oxo-propionic acid ethyl ester (lo g, 5, 〇mmol, 1.0 eq.) in THF (5.0 mL) at rt. Stupid base _ 吩曱-2-methyl decanoate (1.17 g, 5.0 mmol, 1 〇 equivalent) and SnBu 2 Cl 2 (〇. 15 g '0.50 mmol, 0.1 eq.). After 5 minutes of dropping at room temperature, PhSiH3 was added to the solution. The resulting reaction mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; Product (0.7 g). MS: 416 [M+H+]. Step 2. 3-(2-Resyl-1-cyclohexyl-ethylamino)·5-phenyl-porphine_2_carboxylic acid methyl vinegar

向3-(1-環己基-2-乙氧羰基-乙胺基）_5_苯基_噻吩_2_甲酸甲醋（300 mg，0.72 賴〇卜 lo 當量）於 THF(2 〇 mL)、 EtOH(1.0 mL)及水（2.0 mL)中之溶液中添mU〇h#H2〇(152 mg，3.6 mmol’ 5.0當量）β在551下攪拌混合物2〇分鐘。接著蒸發有機溶劑。向所得溶液中添加3 〇N HQ水溶液直至pH 5 6。接著藉由過濾收集固體且以水洗滌。以萃取滤液Μ飽和歸叫水溶液、鹽水絲有機層，經 160983.doc •114· 201247656To 3-(1-cyclohexyl-2-ethoxycarbonyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl vinegar (300 mg, 0.72 lysole), in THF (2 〇mL), mU〇h#H2(R) (152 mg, 3.6 mmol' 5.0 eq.) was added to a solution of EtOH (1.0 mL) and water (2.0 mL). The organic solvent is then evaporated. To the resulting solution, a 3 〇N HQ aqueous solution was added until pH 5 6 was obtained. The solid was then collected by filtration and washed with water. The extraction filtrate is saturated with aqueous solution and brine organic layer, and is passed through 160983.doc •114· 201247656

Na2S〇4乾燥且在真空中濃縮。續用於下一步驟。粗物質未經進一步純化即繼步称3·合紅(2_環己基_4,6_:側氧基㈣小基）冬苯基_ 唾吩-2-甲酸甲輯Na2S〇4 was dried and concentrated in vacuo. Continued for the next step. The crude material was further weighed without further purification. (3_cyclohexyl_4,6_: pendant oxy (tetra) small group) Winter phenyl _ porphin-2-carboxylic acid

在〇C下向3-(2-羧基-1-環己基_乙胺基）5苯基噻吩·2_ 甲酸甲醋（200 mg，〇·52 _0卜i 〇當量）之D(：M(i 〇叫溶液中添加EDC⑽mg’0.77咖〇卜15當量卜觀八哪 mg’ 0.77 mmol，h5 當量）及米氏酸（Meldrum,s acid)(75D(:M(i) to 3-(2-carboxy-1-cyclohexyl-ethylamino)5-phenylthiophene-2-carboxylic acid methyl vinegar (200 mg, 〇·52 _0 i 〇 equivalent) at 〇C Add EDC (10) mg '0.77 curry b 15 equivalents of 观八 eight mg' 0.77 mmol, h5 equivalent) and Meldrum (s acid) (75)

mg，0.52 mmol，i.o當量）。接著使混合物升溫至室溫且在此溫度下攪拌3小時。接著向反應混合物中添加飽和 NaHS〇4水溶液。以DCM萃取混合物且以鹽水洗滌有機相，經NaJO4乾燥且在真空中濃縮。粗物質未經進一步純化即繼續用於下一步驟。將來自先前步驟之粗產物（240 mg , 0.47 mmol，1.0當量）溶解於EtOAc(5_〇 mL)中且將所得溶液加熱至回流持續2 小時。接著在室溫下向混合物中添加飽和NaHS〇4水溶液。以DCM萃取混合物且以鹽水洗滌有機相，經Na2S〇4乾燥且在真空中遭縮。藉由矽膠管柱層析（Et〇Ac/庚烷 100/。〜60%)純化殘餘物，得到產物（16〇 mg)。412 160983.doc •115 201247656 [M+H+] 〇步驟4.合成3-(2-環己基-4-羥基-6-側氧基-哌啶-1-基）-5-苯基-噻吩-2-甲酸甲酯Mg, 0.52 mmol, i.o equivalent). The mixture was then warmed to room temperature and stirred at this temperature for 3 hours. A saturated aqueous NaHS 4 solution was then added to the reaction mixture. The mixture was extracted with DCM and EtOAcq. The crude material was used in the next step without further purification. The crude product from the previous step (240 mg, 0.47 mmol, 1.0 eq.) was dissolved in EtOAc (5 EtOAc) and the mixture was warmed to reflux for 2 hr. A saturated NaHS 4 aqueous solution was then added to the mixture at room temperature. The mixture was extracted with DCM and the organic phase was washed with brine, dried over Na.sub.2, and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 412 160983.doc •115 201247656 [M+H+] 〇Step 4. Synthesis of 3-(2-cyclohexyl-4-hydroxy-6-oxo-piperidin-1-yl)-5-phenyl-thiophene- Methyl 2-formate

在〇°C下向經授拌之3-(2-環己基-4,6-二側氧基-派啶-1-基）-5-苯基-售吩-2 -甲酸甲酯（60 mg，0.15 mmol，1.0當量）之無水 DCM(1.0 mL)溶液中添加 NaBH4(l 1 mg > 0.29 mmo卜 2當量）及 AcOH(0.8 mg，0.01 mmol，0.1當量）。接著在室溫下攪拌反應混合物4小時，之後藉由添加水來淬滅反應。以DCM萃取混合物》以飽和NaHC03水溶液洗滌有機層’經Na2S04乾燥且在真空中濃縮。藉由矽膠管柱層析（EtOAc/庚烷1〇%〜60%)純化殘餘物，得到u mg產物。將產物溶解於THF(0.2 mL)、EtOH(0.1 mL)及水（0.2 mL) 中。向溶液中添加Li〇H*H2〇(7.6 mg，0.18 mmol，5當量）且在55°c下攪拌所得混合物1小時。接著蒸發有機溶劑且向所得溶液中添加！.〇 N HC1水溶液直至PH=4。以EtOAc萃取’谷液’且以飽和NaHC〇3水溶液、鹽水洗滌有機層，經3-(2-Cyclohexyl-4,6-di-oxy-pyridin-1-yl)-5-phenyl- phenoxy-2-carboxylic acid methyl ester (60) was stirred at 〇 °C In a solution of anhydrous DCM (1.0 mL), EtOAc (1 mL, EtOAc, EtOAc (EtOAc) The reaction mixture was then stirred at room temperature for 4 hours, after which time the reaction was quenched by the addition of water. The mixture was extracted with aq. EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc (EtOAc /EtOAc) elute The product was dissolved in THF (0.2 mL), EtOH (0.1 mL) and water (0.2 mL). To the solution was added Li 〇 H*H 2 〇 (7.6 mg, 0.18 mmol, 5 eq.) and the mixture was stirred at 55 ° C for 1 hour. The organic solvent is then evaporated and added to the resulting solution! .〇N HC1 aqueous solution until PH=4. The 'salt' was extracted with EtOAc and the organic layer was washed with aq.

Na2S〇4乾燥且在真空中濃縮。藉由HPLC純化殘餘物，得到 48 mg產物。ms: 400 [M+H+] » 實例17.合成3-(4-苯甲醯胺基-2-環己基側氧基-哌啶-1-160983.doc -116- 201247656Na2S〇4 was dried and concentrated in vacuo. The residue was purified by HPLC to give 48 mg. Ms: 400 [M+H+] » Example 17. Synthesis of 3-(4-Benzylguanidino-2-cyclohexyloxy-piperidine-1-160983.doc -116- 201247656

基）-S-苯基-噻吩-2-曱酸[化合物21JBase)-S-phenyl-thiophene-2-decanoic acid [Compound 21J

步称1.合成3-(4-胺基-2-環己基-6-側氧基-痕咬基）_5_苯基-噻吩-2-甲酸甲酯Step 1. Synthesis of 3-(4-amino-2-cyclohexyl-6-sideoxy-tide) _5-phenyl-thiophene-2-carboxylic acid methyl ester

向3-(2-環己基-4,6-二側氧基-哌啶_1_基）_5_苯基_噻吩_2_ 甲酸甲酯（400 mg，0.98 mmol，1.0 當量）之 MeOH(2,〇 mL) 溶液中添加NH4〇Ac(3 75 mg，4.86 mmol，5當量）且在室溫下攪拌所得溶液18小時《在真空中濃縮反應混合物且將殘餘物溶解於MeOH中。向溶液中添加NaCNBH3(247 mg， 1-16 mmol，1.2 當量）及 h〇Ac(56 mg，0.97 mmol，1 當里）在至〉瓜下授掉所得混合物18小時。接著在真空中移除溶劑。向殘餘物中添加飽和NaHC03水溶液直至ρΗ>8。以DCM萃取混合物。經^^^仏乾燥有機層且在真空中濃縮。粗物質未經進一步純化即繼續用於下一步驟。步驟2.合成3-【2-環己基_6_側氧基_4_(2_苯氧基·乙醯胺基）_ 160983.doc 201247656 旅啶-1-基】-S·苯基-噻吩_2·甲酸甲酯Methyl 3-(2-cyclohexyl-4,6-di-oxy-piperidine-1-yl)-5-phenyl-thiophene-2-carboxylate (400 mg, 0.98 mmol, 1.0 eq.) MeOH (2) 〇mL) NH4〇Ac (3 75 mg, 4.86 mmol, 5 eq.) was added to the solution and the resulting solution was stirred at room temperature for 18 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH. To the solution was added NaCNBH3 (247 mg, 1-16 mmol, 1.2 eq.) and h?Ac (56 mg, 0.97 mmol, 1) to give the mixture for 18 hours. The solvent is then removed in vacuo. A saturated aqueous solution of NaHCO 3 was added to the residue until ρ Η > The mixture was extracted with DCM. The organic layer was dried by ^^^ and concentrated in vacuo. The crude material was taken to the next step without further purification. Step 2. Synthesis of 3-[2-cyclohexyl_6_sideoxy_4_(2-phenoxyacetamido)_160983.doc 201247656 啶 -1--1-yl]-S·phenyl-thiophene _2·methyl formate

在0C下向3-(4-胺基-2-環己基-6-側氧基底〇定-1·基）-5-苯基-0塞吩_2-甲酸甲酯（3〇 mg，0.073 mmol，1.0當量）之 DCM(1.0 mL)溶液中添加苯氧基乙醯氯（〇〇2以，〇 145 mmol，2.0當量）及TEA(0.02 mL)。接著在〇。〇下授拌所得混合物20分鐘，之後在真空下移除溶劑。藉由矽膠管柱層析（EtOAc/庚烷1〇%〜80%)純化殘餘物，得到產物（2〇叫）。 MS: 547 [M+H+]。步驟3.合成3-[2-環己基-6-側氧基-4-(2-苯氧基-乙酿胺基）_ 旅咬-1-基]-5-苯基-嗟吩_2•甲酸Methyl 3-(4-amino-2-cyclohexyl-6-sideoxyl-l-yl)-5-phenyl-e-phene-2-carboxylate (0 〇 mg, 0.073) at 0C To a solution of mmol, 1.0 eq. of DCM (1.0 mL) was added phenoxyethyl chlorobenzene (?? Then hehe. The resulting mixture was stirred under ankle for 20 minutes, after which time the solvent was removed under vacuum. The residue was purified by EtOAc (EtOAc/EtOAc) elute MS: 547 [M+H+]. Step 3. Synthesis of 3-[2-cyclohexyl-6-oxo-oxy-4-(2-phenoxy-ethanoyl)_Bistylene-1-yl]-5-phenyl-porphin_2 • Formic acid

向曱 6旨（10 mg，0.018 mm〇l，υ 當量）於 THF(〇 2 mL)、 EtOH(0.1 mL)及水（0.2 mL)中之溶液中添MLi〇H#H2〇(8 mg, 0.18 mmo卜10當量在55t下攪拌混合物3〇分鐘，之後蒸發有機/谷劑。向所得溶液中添加3. 〇 n HC1水溶液直 160983.doc -118- 201247656 至pH=5。以EtOAc萃取溶液，且以飽和NaHC〇3水溶液、鹽水洗滌有機層，經NajO4乾燥且在真空中濃縮β藉由製備型HPLC純化殘餘物，得到6 mg產物。MS: 533[Μ+Η+]。 'H-NMR (400 MHz, DMSO): δ 10.31 (d, 1H), 7.63 (d, 2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98 (m, 3H), 4.61 (m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20 (m, 1H), 1.88-1.76 (m, 4H), 1.65-1.58 (m, 2H), 1.41-1.05 (m, 6H)。實例18.合成3_[(2R,5R)-5-環己基-2-(3-羥基-丙基）-3-側氧基·嗎啉-4-基】-5-(3,3-二甲基-丁炔基）_噻吩_2_甲酸及3_ [(2S，5R)-5-環己基-2-(3-羥基-丙基）·3_側氧基-嗎琳_4·基】· 5-(3,3-二甲基-丁-1-炔基）_噻吩_2_曱酸【化合物2】【化合物3】Add MLi〇H#H2〇 (8 mg, to a solution of 曱6 (10 mg, 0.018 mm〇, υ )) in THF (〇 2 mL), EtOH (0.1 mL) and water (0.2 mL) The mixture was stirred for 10 minutes at 55 t, then the organic/treasure was evaporated. To the resulting solution was added 3. 〇n HCl aqueous solution straight 160983.doc-118-201247656 to pH=5. The solution was extracted with EtOAc. The organic layer was washed with aq. EtOAc EtOAc (EtOAc m. (400 MHz, DMSO): δ 10.31 (d, 1H), 7.63 (d, 2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98 (m, 3H), 4.61 (m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20 (m, 1H), 1.88-1.76 (m, 4H) , 1.65-1.58 (m, 2H), 1.41-1.05 (m, 6H). Example 18. Synthesis of 3_[(2R,5R)-5-cyclohexyl-2-(3-hydroxy-propyl)-3- side Oxy-morpholin-4-yl]-5-(3,3-dimethyl-butynyl)-thiophene-2-carboxylic acid and 3_[(2S,5R)-5-cyclohexyl-2-(3 -hydroxy-propyl)·3_sideoxy-Merlin _4·yl] 5-(3,3-dimethyl-but-1-yne Base)_thiophene_2_decanoic acid [Compound 2] [Compound 3]

在〇°C下經10分鐘向3-((R)-2-烯丙基-5-環己基-3-側氧基_ 嗎淋-4-基）-5-(3,3-二曱基-丁 - i_炔基）_嘆吩_2_曱酸曱酿 (200 mg，0.45 mmol，1.0 當量）之 THF(4.0 mL)溶液中添加 9-BBN(2.2 mL ’ 0.5 Μ於 THF 中，Μ mmo卜 2.5 當量），且在室溫下攪拌所得溶液18小時。接著將溶液冷卻至〇它且向溶液中添加EtOH、NaOH水溶液、Ηζ〇2水溶液。將反應混合物加熱至回流持續90分鐘。冷卻至室溫之後，以 EtOAc萃取反應混合物《經NadO4乾燥有機層且藉由製備型HPLC純化殘餘物，得到產物3-[(2R，5R)-5-環己基-2-(3- 160983.doc -119- 201247656 羥基-丙基）-3-側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁 -1-炔基）-噻吩-2-甲酸（20 mg)及3-[(2S，5R)-5-環己基-2-(3-羥基-丙基）-3-側氧基-嗎啉-4-基]-5-(3,3-二甲基-丁 -1-炔基）-噻吩-2-曱酸（20 mg)。嗎啉酮之2位處的立體化學尚未確定。產物 1 : MW: 448.3 [M+H]+。W-NMR (400 MHz，CD3OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 2.02-1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m，6H)。產物 2 : MW: 448.3 [M+H]+。*H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.13 (m, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m, 6H) » 實例19 ·•合成3-【(R)-2-環己基-6-側氧基-4-(6-嘧啶-5-基-吡咬-3-磺酿基）·哌嗪基卜5_苯基_噻吩_2_甲酸丨化合物2〇6】To 3-((R)-2-allyl-5-cyclohexyl-3-oxooxyl-l-l-yl)-5-(3,3-dioxin) over 10 min at 〇 °C Addition of 9-BBN (2.2 mL '0.5 Μ in THF) to a solution of THF (4.0 mL) in a solution of thiophene-2-I alkynyl) (20 mg, 0.45 mmol, 1.0 eq.) , Μ mmo b 2.5 equivalents, and the resulting solution was stirred at room temperature for 18 hours. The solution was then cooled to hydrazine and EtOH, aqueous NaOH, and aqueous hydrazine 2 were added to the solution. The reaction mixture was heated to reflux for 90 minutes. After cooling to room temperature, the reaction mixture was extracted with EtOAc EtOAc EtOAcjjjjjjjjjjjjjj Doc -119- 201247656 Hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid ( 20 mg) and 3-[(2S,5R)-5-cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3- Dimethyl-but-1-ynyl)-thiophene-2-decanoic acid (20 mg). The stereochemistry at the 2 position of morpholinone has not been determined. Product 1 : MW: 448.3 [M+H]+. W-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 2.02-1.48 ( m, 10H), 1.32 (s, 9H), 1.25-1.17 (m, 6H). Product 2: MW: 448.3 [M+H]+. *H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.13 (m, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m, 6H) » Example 19 • Synthesis of 3-[(R)-2-cyclohexyl-6-sideoxy-4-(6- Pyrimidine-5-yl-pyridyl-3-sulfonyl) piperazinyl-5-phenyl-thiophene-2-formic acid hydrazine compound 2〇6]

在室溫下向3-[(R)-4-(6-氣·吡啶-3-磺醯基）-2-環己基-6-側氧基底嗪基]_5•苯基-噻吩_2_甲酸〇 2〇 g，2.14 mmol，1.0當量）之乙腈（15〇 mL)溶液中添加磷酸鉀（858 ml，1.0 Μ水溶液，40當量）及氯（2二環己基膦基_2，，4,，6,· 二異丙基-1,1’·聯苯）[2_(2_胺基乙基）苯基]pd(n) Me第三丁基醚加合物（〇·32 g，0.43 mm〇i，0.2當量在室溫下攪 I60983.doc 201247656 拌混合物10分鐘，形成儲備溶液。在室溫下向0.8 mL上述溶液中添加5-嘲咬基自明酸（17.7 mg，〇. 143 mmol，2.0當量）及乙腈（0.5 mL)。在80°C下攪拌混合物4小時。藉由 HPLC(〇.l% NH4OH)純化混合物，得到產物（15.9 mg， 36.9%) 0 MS: 603.2 [M-H+] ° 實例20 : 3-[(R)-2-環己基-4-(3-氟-2-嗎琳-4·基-苯曱基）-6-侧氧基-哌嗪-1-基]-5-苯基噻吩-2-甲酸[化合物266】To 3-[(R)-4-(6-Gas-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxoxyalkylazinyl]_5•phenyl-thiophene_2_ at room temperature Potassium phosphate (858 ml, 1.0 Μ aqueous solution, 40 eq.) and chlorine (2 dicyclohexylphosphino-2,4) were added to a solution of ruthenium formate (2, g, 2.14 mmol, 1.0 eq.) in acetonitrile (15 mL). ,6,·diisopropyl-1,1'·biphenyl)[2_(2-aminoethyl)phenyl]pd(n) Me tert-butyl ether adduct (〇·32 g, 0.43 Mm〇i, 0.2 eq. Stir at room temperature. I60983.doc 201247656 Mix the mixture for 10 minutes to form a stock solution. Add 5-trimute self-acid (17.7 mg, 〇. 143 mmol) to 0.8 mL of the above solution at room temperature. , 2.0 eq.) and acetonitrile (0.5 mL). The mixture was stirred at 80 ° C for 4 hr. The mixture was purified by HPLC (1% NH4OH) to give the product (15.9 mg, 36.9%) 0 MS: 603.2 [M- H+] ° Example 20: 3-[(R)-2-cyclohexyl-4-(3-fluoro-2-morphin-4-yl-phenylhydrazino)-6-oxo-piperazin-1- ]]-5-phenylthiophene-2-carboxylic acid [Compound 266]

在室溫下攪拌3-((R)-2-環己基-6-側氧基底嗓-1-基）-5- 苯基-噻吩-2-甲酸（50.0 mg，0.13 mmol，1.0當量）及3-氟_ 2-嗎啉基苯甲醛（108.8 mg，〇 52 mm〇1，4 〇當量）於乙酸 (0·2 mL)及曱醇（〇.5 mL)中之溶液持續6〇分鐘。接著將三乙醯氧基硼氫化鈉（110.2 mg，〇.52 mm〇1，4 〇當量）添加至混合物中且在75°C下攪拌所得混合物3小時。藉由Genevac 移除溶劑且將殘餘物溶解於Et〇Ac(6 mL)f。藉由鹽水（3 mL)洗滌有機相，經Na2S〇4乾燥且濃縮。藉由HpLC(〇 i% NH4OH)純化殘餘物，得到產物（9 ，12%)。ms: 577.2 [M-H+]。實例21.合成3-((S)-3·胺基-6-環己基_2_側氧基_哌啶基卜 160983.doc • 121 · 201247656 5-(3,3-二甲基-丁炔基）_噻吩_2·甲睃【化合物34〇ιStir 3-((R)-2-cyclohexyl-6-oxooxyindole-1-yl)-5-phenyl-thiophene-2-carboxylic acid (50.0 mg, 0.13 mmol, 1.0 eq) at room temperature and A solution of 3-fluoro-2-morpholinobenzaldehyde (108.8 mg, 〇52 mm〇1,4 〇 equivalent) in acetic acid (0.2 mL) and decyl alcohol (5 mL) for 6 min. Sodium triethoxy borohydride (110.2 mg, 〇.52 mm 〇 1,4 〇 equivalent) was then added to the mixture and the mixture was stirred at 75 ° C for 3 hours. The solvent was removed by Genevac and the residue was dissolved in Et EtOAc (6 mL). The organic phase was washed with brine (3 mL), dried over Naz. The residue was purified by H.sub.sub.sub.sub.sub. Ms: 577.2 [M-H+]. Example 21. Synthesis of 3-((S)-3.amino-6-cyclohexyl_2_sideoxy-piperidinyl b. 160983.doc • 121 · 201247656 5-(3,3-dimethyl-butyl Alkynyl)-thiophene-2-methylpyrazine [compound 34〇ι

步驟1·合成3-((S)-3-溴-6-環己基-2-側氧基-哌啶基）_5_ (3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸甲酯Step 1. Synthesis of 3-((S)-3-bromo-6-cyclohexyl-2-oxo-piperidinyl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene- Methyl 2-formate

在室溫下向3_((3S，6s)_6_環己基_3_羥基_2•側氧基旅啶_ 1-基）-5·(3’3-二甲基-丁小炔基）_噻吩_2·甲酸曱酯（2〇〇 mg ’ 〇·75 mmol，】當量）之CH2Cl2(1 〇 mL)溶液中添加 PBr3(l.〇 ]y[於CH2C12 中，0.09 mL，0.38 mmo卜 0.8當量）且在室溫下攪拌所得溶液18小時。接著在真空下濃縮反應溶液且藉由石夕膠管柱層析（EtOAc/庚烷，10%〜60%)純化殘餘 · 物’知·到產物（166 mg，產率 76%)。MS: 481 [M+H+]。步称2·合成3-((S)-3-疊氮基·6·環己基_2_側氧基-哌啶-ρ 基）5-(3,3-二甲基_丁 a_炔基）噻吩_2甲酸甲酯To 3_((3S,6s)_6_cyclohexyl_3_hydroxy_2• sideoxybendyl-1-yl)-5·(3'3-dimethyl-butyrynyl) at room temperature Add PBr3(l.〇]y to CH2Cl2(1 〇mL) solution of thiophene-2-carboxylate (2〇〇mg '〇·75 mmol,) equivalent) in CH2C12, 0.09 mL, 0.38 mmo 0.8 equivalent) and the resulting solution was stirred at room temperature for 18 hours. The reaction solution was then concentrated under vacuum and purified to purified (yield: <RTIgt;</RTI>> MS: 481 [M+H+]. Step 2·Synthesis of 3-((S)-3-azido·6·cyclohexyl_2_sideoxy-piperidine-pyl) 5-(3,3-dimethyl-buta-yne) Methyl thiophene-2carboxylate

160983.doc -122· 201247656 — 向3-((S)-3-溴-6-環己基-2-側氧基-哌啶-1-基）-5-(3,3 甲基-丁 _1_快基）-°塞吩-2-甲酸甲酿（78 mg，0.16 mmol，1.0 當量）之 DMF(1.0 mL)溶液中添加 NaN3(12 mg，0.19 mmol ’ 1.2當量）且在65°C下攪拌所得混合物18小時。接著在真空下移除溶劑。藉由矽膠管柱層析（Et〇Ac/庚烷， 10%~60%)純化殘餘物，得到42 mg產物（產率56%)。MS: 442 [M+H+]。步驟3.合成3-((S)-3-胺基-6-環己基_2·側氧基_哌啶·i•基）_5_ (3,3-二甲基-丁-1_炔基）_嗔吩·2_甲酸160983.doc -122· 201247656 — to 3-((S)-3-bromo-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3 methyl-buty_ Add a NaN3 (12 mg, 0.19 mmol '1.2 eq.) at 65 ° C in a solution of 1 phenoxy-2-carboxylic acid (78 mg, 0.16 mmol, 1.0 eq.) in DMF (1.0 mL) The resulting mixture was stirred for 18 hours. The solvent is then removed under vacuum. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) MS: 442 [M+H+]. Step 3. Synthesis of 3-((S)-3-amino-6-cyclohexyl_2. oxo-piperidine·i•yl)_5_ (3,3-dimethyl-but-1-ynyl) )_嗔,·2_formic acid

側氧基-哌啶-1-基）-5- 向3-((S)-3-疊氮基-6-環己基 (3’3_二甲基_丁小快基）_噻吩·2-甲酸甲酯（40 mg，0.09 mmol 1田里kMe〇H(〇 5叫溶液中添加SnCb(i7叫， • 09 mmol 1 s f )且在室溫下搜拌所得溶液u小時。接著在真空下移除溶劑。㈣餘物溶解於THF/H2Q/Me〇H(0.5 mL/0.5 mL/1.〇 mL)中且向溶液中添加[跡明η吨， mmol 5虽量）。在5〇 c下授拌反應混合物分鐘。在移除有機溶劑且藉由添加3.GNHC1水溶液將殘餘物 =化至pH 5。以EtOAc萃取混合物。經ΝΜ〇4乾燥有機，且在真空下濃縮。藉由處於鹼性條件(〇i% NH4〇H， 160983.doc •123- 201247656 10%〜45% CH3CN/H20’操作ι〇分鐘，4〇 m丨/min)之製備型 HPLC(XBridge Prep C 18 ’ 5 μιη，3〇x50 mm)純化殘餘物，得到 12 mg產物。MS: 403 [M+H+]。〗H-NMR (400 MHz, CD3〇D): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m，1H)，1.31 (s，9H), 1.16 (m, 5H)。實例22·合成3-((S)-6-環己基-3·(3·羥基-丙基）-2-側氧基-旅咬-1-基）-5-(3,3-二甲基-丁-1-快基）_嗟吩_2_甲酸[化合物 341]Oxyloxy-piperidin-1-yl)-5- to 3-((S)-3-azido-6-cyclohexyl (3'3-dimethyl-butanthyl)-thiophene-2 - Methyl formate (40 mg, 0.09 mmol 1 field kMe〇H (SnCb (i7 called, • 09 mmol 1 sf) was added to the solution and the resulting solution was mixed for u hours at room temperature. Then under vacuum Remove the solvent. (4) The residue is dissolved in THF/H2Q/Me〇H (0.5 mL/0.5 mL/1.〇mL) and added to the solution [trace η ton, mmol 5 amount). The reaction mixture was stirred for a few minutes. The organic solvent was removed and the residue was taken to pH 5 by the addition of aqueous 3. EtOAc. Preparative HPLC (XBridge Prep C 18 ' 5) in alkaline conditions (〇i% NH4〇H, 160983.doc •123- 201247656 10%~45% CH3CN/H20' operation 〇min, 4〇m丨/min) The residue was purified to give 12 mg of product. MS: 403 [M+H+]. H-NMR (400 MHz, CD3 〇D): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m,1H), 1.31 ( s, 9H), 1.16 (m, 5H). Example 22·Synthesis of 3-((S)-6-cyclohexyl-3·(3·hydroxy-propyl)-2-yloxy-Brigade bite-1- -5-(3,3-dimethyl-butan-1-yl)-porphin-2-carboxylic acid [Compound 341]

步驟1.合成3-((S)-3-烯丙基-6-環己基_2-側氧基_旅咬基）-5-(3,3-二甲基-丁 -1-炔基）_嗟吩-2_甲酸甲醋Step 1. Synthesis of 3-((S)-3-allyl-6-cyclohexyl_2-sideoxy-Bentyl)-5-(3,3-dimethyl-but-1-ynyl) )_嗟嗟-2_carboxylic acid methyl vinegar

在-78°C下向3-((S)-2-環己基-6-側氧基_哌啶-卜基卜^ (3,3-二曱基·丁 q •炔基噻吩_2·甲酸甲酯（2〇〇，〇 $ mmol，1.0當量）之THF(2.〇 mL)溶液中添加lda(2〇 M於To 3-((S)-2-cyclohexyl-6-oxo-piperidine-bubub^(3,3-didecyl-butyt-2-alkynylthiophene-2·) at -78 °C Add 1da (2〇M) to a solution of methyl formate (2〇〇, 〇$ mmol, 1.0 equivalent) in THF (2.〇mL)

THF中，0.3 mL’ 〇_6 mmol，K2當量）且在下搜摔所得溶 160983.doc -124- 201247656 液10分鐘。接著向溶液中添加3-碘-丙烯（250 mg，1.5 mmol，3.0當量）且在室溫下攪拌反應混合物15分鐘。藉由添加水來淬滅反應。wEt〇Ac萃取混合物。以飽和NaHC〇3 水’谷液及鹽水洗滌有機層’經Na2S〇4乾燥且在真空下濃縮。藉由矽膠管柱層析（庚烷/DCM(含有3% EtOAc))純化殘餘物’得到60 mg極性較小之非對映異構體及1〇〇 mg極性較大之非對映異構體。MS: 442 [M+H+]。步驟2·合成3-((s)_6-環己基-3-(3-羥基-丙基）-2-側氧基-哌啶-1-基）-5-(3,3-二甲基-丁·i炔基）_噻吩_2_甲酸In THF, 0.3 mL' 〇_6 mmol, K2 eq.) and the resulting solution was dissolved in 160983.doc -124-201247656 for 10 minutes. 3-iodo-propene (250 mg, 1.5 mmol, 3.0 eq.) was then added to the solution and the mixture was stirred at room temperature for 15 min. The reaction was quenched by the addition of water. The mixture was extracted with wEt〇Ac. The organic layer was washed with saturated NaHC 3 water & broth and brine. Purification of the residue by hydrazine gel column chromatography (heptane / DCM (EtOAc: EtOAc)) afforded 60 mg of the less polar diastereomers body. MS: 442 [M+H+]. Step 2· Synthesis of 3-((s)_6-cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl -butyl i-alkynyl)_thiophene-2-formic acid

在〇°C下向3-((S)-3-烯丙基-6-環己基-2-側氧基-哌啶_ι_ 基）-5-(3,3-二甲基_丁_1_炔基）_噻吩_2_甲酸甲酯（來自先前步驟之極性較小之非對映異構體）（6〇 mg，0.14 mmol，1.0 當量）之無水THF(2.0 ml)溶液中添加9-BBN(0.5 Μ於THF 中，0.68 ml，0.34 mmol，2.5當量）且在室溫下攪拌所得溶液2小時。接著在〇它下冷卻溶液且向溶液中添加Et〇H、 1.0 M NaOH水溶液及比〇2水溶液。將反應混合物加熱至回流持續90分鐘，接著在室溫下冷卻。以Et〇Ac萃取混合物。經NajO4乾燥有機層且在真空下濃縮。藉由製備型 HPLC(0’1% NH4〇H)純化殘餘物，得到20 mg所需產物（產 160983.doc •125· 201247656 率 33%)。MS: 446 [M+H+]。i-NMR (400 MHz，CD3OD): 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27(br, 1H), 1.97(m, 3H), 1.82-1.64(m, 7H), 1.58 (m, 2H), 1.37(m, 2H), 1.31(s，9H)，1.14(m，5H)。實例23·合成3-((S)-6-環己基-3-(2-羥基-乙基）-2-側氧基-哌啶-1-基）-5-(3,3_二甲基-丁-1-炔基）-噻吩_2_甲酸[化合物 343]3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidine-I-based)-5-(3,3-dimethyl-buty) at 〇 °C Add 1 - alkynyl)-thiophene-2-carboxylic acid methyl ester (from the less polar diastereomer of the previous step) (6 mg, 0.14 mmol, 1.0 eq.) in anhydrous THF (2.0 ml) 9-BBN (0.5 Μ in THF, 0.68 ml, 0.34 mmol, 2.5 eq.) and the mixture was stirred at room temperature for 2 hr. Next, the solution was cooled under hydrazine and Et~H, 1.0 M NaOH aqueous solution and a hydrazine 2 aqueous solution were added to the solution. The reaction mixture was heated to reflux for 90 minutes and then cooled at room temperature. The mixture was extracted with Et〇Ac. The organic layer was dried over NajEtOAc and concentrated in vacuo. The residue was purified by preparative HPLC (0 <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; MS: 446 [M+H+]. i-NMR (400 MHz, CD3OD): 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82-1.64 (m , 7H), 1.58 (m, 2H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H). Example 23·Synthesis of 3-((S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl)-5-(3,3-di -but-1-ynyl)-thiophene-2-formic acid [compound 343]

步驟1·合成3-[(S)-6-環己基-3-(2-羥基-乙基）-2-側氧基-哌啶-1-基]·5-(3,3-二甲基丁-1-炔基）_噻吩_2-甲酸甲酯Step 1· Synthesis of 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]·5-(3,3-dimethyl Methylbutan-1-ynyl)-thiophene-2-carboxylate

在〇°C下向3-((S)-3-烯丙基-6-環己基-2-側氧基-哌啶-卜基）-5-(3，3-二甲基-丁-1-炔基）·噻吩_2_甲酸甲酯（來自先前步驟之極性較小之非對映異構體）（2〇() mg，〇 45 mm〇1， 1_〇當量）之丙酮（3.0 mL)溶液中添加甲基嗎啉氧化物（160 mg，1.36 mm〇l，3 當量）、水（ι·0 mL)及〇s〇4(23〇 mg， 0·02 mmol，0.05當量卜在室溫下攪拌反應混合物丨小時。 160983.doc -126- 201247656 使溶液分配於鹽水與EtOAc之間。分離各相且經Na2S04乾燥有機層’且在真空下濃縮。將殘餘物溶解於THF/水（3.0 mL/1.0 mL中）。向溶液中添加NaI04(194 mg，0.9 mmo卜 2 當量），且在室溫下攪拌所得混合物30分鐘，之後添加另一份Nal〇4(0.5當量）。在室溫下攪拌3〇分鐘之後，使混合物分配於鹽水與EtOAc之間。分離有機層，經Na2S04乾燥且濃縮。將殘餘物溶解於EtOH(3.0 ml)中且在0°C下冷卻溶液。向溶液中添加NaBH4且在0°C下攪拌混合物15分鐘。藉由添加水（2.0 mL)及EtOAc(10.0 mL)淬滅反應》分離有機層，經NazSO4乾燥且濃縮。藉由矽膠管柱層析（庚烷 /EtOAc 1/1)純化殘餘物，得到123 mg產物（產率60%)。MS: 446 [M+H+]。步驟2.合成3-((S)-6-環己基-3-(2-羥基-己基）-2·側氧基-哌啶-1-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸To 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidine-buyl)-5-(3,3-dimethyl-butyl- at 〇 °C Methyl 1-alkynyl)-thiophene-2-carboxylate (diastereomeric diastereomer from the previous step) (2 〇() mg, 〇45 mm〇1, 1_〇 equivalent) of acetone ( 3.0 mL) solution of methylmorpholine oxide (160 mg, 1.36 mm〇l, 3 equivalents), water (ι·0 mL) and 〇s〇4 (23〇mg, 0·02 mmol, 0.05 equivalents) The reaction mixture was stirred at room temperature for </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Water (3.0 mL / 1.0 mL). NaI04 (194 mg, 0.9 mmo, 2 eq.) was added to the solution, and the mixture was stirred at room temperature for 30 minutes, and then another portion of Nal 4 (0.5 eq.) was added. After stirring at room temperature for 3 hrs, EtOAc (EtOAc m.) Add NaBH to the solution 4 and the mixture was stirred for 15 minutes at 0 ° C. The organic layer was separated by EtOAc (EtOAc) (EtOAc) / EtOAc 1/1) The residue was purified to give crystals (yield: 60%). MS: 446 [M+H+]. Step 2. Synthesis of 3-((S)-6-cyclohexyl-3-(2) -hydroxy-hexyl)-2. oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid

向3-[(S)-6-環己基-3-(2-羥基-乙基）-2-側氧基-哌啶-1-基]-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-甲酸曱酯（123 mg， 0.28 mmo卜 1 當量）之 THF/H2O/MeOH(1.0 mL/1.0 mL/0.5 mL)溶液中添加 LiOH*H2〇(60 mg，1.38 mmol，5 當量）且在 50°C下攪拌所得溶液20分鐘。接著藉由添加3.0 N HC1水溶 160983.doc -127- 201247656 液將溶液酸化至pH=5。以EtOAc萃取溶液。經Na2S04乾燥有機層且濃縮。藉由處於鹼性條件（0.1% NH40H， 10%〜45¾ CH3CN/H2〇’ 操作 10分鐘，40 ml/min)之製備型 HPLC(XBridge Prep C 18，5 μπι，30x50 mm)純化殘餘物，得到 28 mg產物（產率 23%)。MS: 432 [M+H+]。ιΗ_ NMR (400 MHZ，CD3OD)·· 6.85 (s，1H)，3.92 (br，1H)，3.67 (m，2H)，2.41 (br，1H)，2.15 (m，ih)，1.97 (m，2H)，1.78 (m 7H)，1.37 (m，2H)，1.31 (s，9H)，1.14 (m，5H)。實例24·合成3-【(2R，5R)-S-環己基_2-((R)_2_羥基_丙基）·3_To 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimercapto-butyl Add HCl/H2O/MeOH (1.0 mL/1.0 mL/0.5 mL) solution of -1-ynyl)-thiophene-2-carboxylic acid decyl ester (123 mg, 0.28 mmo b 1 eq) to LiOH*H2 〇 (60 mg) , 1.38 mmol, 5 eq.) and the resulting solution was stirred at 50 ° C for 20 minutes. The solution was then acidified to pH = 5 by the addition of 3.0 N HCl in water 160983.doc -127 - 201247656. The solution was extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC (XBridge Prep C 18, 5 μπι, 30×50 mm) under basic conditions (0.1% NH40H, 10% to 453⁄4 CH3CN/H2 〇 ' operation for 10 min, 40 ml/min). 28 mg product (yield 23%). MS: 432 [M+H+]. ιΗ_ NMR (400 MHZ, CD3OD)·· 6.85 (s,1H), 3.92 (br,1H), 3.67 (m,2H), 2.41 (br,1H), 2.15 (m,ih), 1.97 (m,2H) ), 1.78 (m 7H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H). Example 24·Synthesis 3-[(2R,5R)-S-cyclohexyl_2-((R)_2_hydroxy-propyl)·3_

側氧基-嗎啉·4·基】-S-(3,3-二甲基-丁·ρ炔基）_噻吩_2曱酸 [化合物336JSide oxy-morpholine·4·yl]-S-(3,3-dimethyl-butyl-p-alkynyl)-thiophene-2-decanoic acid [Compound 336J

及3-[(2R，SR)-5-環己基-2-((S)-2-經基-丙基）_3-側氧基嗎琳]·基】|(3,3_二甲基_ 丁小块基）·雀吩_2甲酸【化合物 337]And 3-[(2R,SR)-5-cyclohexyl-2-((S)-2-yl-propyl)-3-3-oxoline]-yl]|(3,3-dimethyl _ Ding small block base) · Finch 2 carboxylic acid [Compound 337]

步播1.合成3-[(2R，5R)_S_環己基_3·側氧基.2_(2·側氧基乙 160983.doc 201247656 基）-嗎琳-4-基1-5·(3,3_二f基-丁“块基）嘆吩2·甲酸甲醋Step 1. Synthesis of 3-[(2R,5R)_S_cyclohexyl_3·sideoxy.2_(2·Sideoxyethyl 160983.doc 201247656 base)-Mallin-4-yl 1-5·( 3,3_dif-butyl-block "block base" sigh 2, formic acid methyl vinegar

在〇°C下向3-((2R，5R)_2_烯丙基·5_環己基_3侧氧基嗎啉·4_基）_5·(3,3-二甲基-丁+炔基）_嗟吩_2•甲酸甲酿（3 15 φ g’ 7·10 mm〇卜L0當量）之丙_(40 mL)溶液中添加Ν_甲基嗎嘴氧化物（2.51 g, 21.30 _〇1，3.〇當量）、水〇4叫及四氧化餓（3.60 g，2.5重量％於THF中，〇36 mm〇1，〇〇5當量）在至溫下攪拌混合物60分鐘。在真空下移除丙酮且使殘餘物分配於EtOAc(80 mL)與鹽水〇5 mL)之間。分離各相且乾燥（經NhSCU)有機層且濃縮。向殘餘物中添加 THF(40 mL)及水（14 mL)。在(TC下，將過碘酸鈉（2 28 g， 1〇·65 mmol，1.5當量）添加至混合物中且在室溫下攪拌混 • 合物30分鐘。在〇°C下冷卻之後，添加另一份過碘酸鈉 (〇·76 g，3·55 mmol，0.5當量）。在室溫下再攪拌混合物3〇分鐘。在真空下移除揮發性溶劑且使殘餘物分配於 EtOAc(100 mL)與鹽水（1〇 mL)之間。分離有機層，乾燥 (經NazSO4)且濃縮。藉由矽膠管柱層析（Et〇Ac/庚烷，25% 至50%)純化殘餘物’得到產物（21 g，66%)。446.3 [M-H+]。步驟2.合成3-丨(2R，5R)-5-環己基-2-((R)-2-羥基-丙基）-3-側 160983.doc -129· 201247656 氧基-嗎琳-4-基】-5-(3,3-二甲基-丁-1-炔基）·嗟吩_2-甲酸甲酯及3-[(2R，5R)_5-環己基-2-((S)-2-經基-丙基）·3·側氣基嗎淋-4-基】-5-(3,3-二甲基·丁-1_快基）_嗔吩_2_甲酸甲醋3-((2R,5R)_2_allyl·5_cyclohexyl_3 side oxymorpholine·4_yl)_5·(3,3-dimethyl-butane+yne) at 〇°C Add Ν_methyl 嘴 mouth oxide (2.51 g, 21.30 _) to the solution of 嗟_(40 mL) in the propylene (3 15 φ g' 7·10 mm L L L0 equivalent) solution 〇1,3. 〇 equivalent), hydrazine 4 and tetraoxide (3.60 g, 2.5% by weight in THF, 〇36 mm 〇1, 〇〇5 equivalent) were stirred at ambient temperature for 60 minutes. Acetone was removed under vacuum and the residue was partitioned between EtOAc (EtOAc) The phases were separated and dried (NhSCU) organic layer and concentrated. To the residue were added THF (40 mL) and water (14 mL). Sodium periodate (2 28 g, 1 〇 · 65 mmol, 1.5 eq.) was added to the mixture at (TC) and the mixture was stirred at room temperature for 30 minutes. After cooling at 〇 ° C, it was added. Another portion of sodium periodate (〇·76 g, 3·55 mmol, 0.5 eq.). The mixture was stirred at room temperature for a further 3 min. The volatile solvent was removed in vacuo and the residue was partitionedEtOAc. Between the mL and the brine (1 mL). The organic layer was separated, dried (NazSO4) Product (21 g, 66%) 446.3 [M-H+] Step 2. Synthesis of 3-indole (2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3 - side 160983.doc -129· 201247656 oxy-morphin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)·porphin-2-carboxylic acid methyl ester and 3- [(2R,5R)_5-cyclohexyl-2-((S)-2-yl-propyl)·3·side gas thiophen-4-yl]-5-(3,3-dimethyl ·丁-1_快基)_嗔嗔_2_carboxylic acid methyl vinegar

在-10°C下向3-[(2R，5R)_5·環己基_3·側氧基·2_(2_側氣基乙基）-嗎琳-4-基]-5-(3,3-二甲基-丁-1-快基）_嗟吩_2_甲峻曱酯（1.9 g，4.26 mmo卜1.0當量）之THF(200 mL)溶液中添力 MeMgBr(1.85 mL ’ THF 中之 3.0 Μ 溶液，5.54 mmoh 1-3 卷量）。在-10°C下攪拌所得溶液20分鐘。藉由添加3.〇 n UC1 水溶液來淬滅反應直至pH= 1。在真空下移除揮發性溶劑且使殘餘物分配於EtOAc(100 mL)與鹽水（5 mL)之間。經 NajO4乾燥經分離之有機層且濃縮。藉由矽膠管柱層析 [Et20(2% EtOAc)/庚烷’ 25%至50%]純化殘餘物，得到3_ [(2R，5R)-5-i^己基- 2- ((R)-2-經基-丙基）-3 -側氧^基-嗎琳-4_ 基]-5-(3,3-二甲基-丁 -1-炔基）_噻吩-2-甲酸甲酯（0.57 g， 29.0%)及 3-[(2R，5R)-5-環己基-2-((S)-2-羥基-丙基）-3-侧氧基-嗎啉-4-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩_2_甲酸甲酯 (0.80 g ’ 40.7%)。MS: 462.4 [M-H+]。步驟3.合成3-[(2R，5R)-5-環己基-2-((R)-2-羥基-丙基）-3-側氧基-嗎啉-4-基】-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-甲酸 160983.doc •130· 2012476563-[(2R,5R)_5·cyclohexyl_3·sideoxy·2_(2_flamoethyl)-morphin-4-yl]-5-(3, at -10 °C 3-Methyl-butan-1-yl)- porphin-2_methylglycolate (1.9 g, 4.26 mmo, 1.0 equivalent) in THF (200 mL) in a solution of MeMgBr (1.85 mL 'THF 3.0 Μ solution, 5.54 mmoh 1-3 volume). The resulting solution was stirred at -10 °C for 20 minutes. The reaction was quenched by the addition of a 3. 〇 n UC1 aqueous solution until pH = 1. The volatile solvents were removed under vacuum and the residue was partitioned between EtOAc (EtOAc) The separated organic layer was dried over Naj.sub.4 and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) 2-Phenyl-propyl)-3-oxooxyl-m-lin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester ( 0.57 g, 29.0%) and 3-[(2R,5R)-5-cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]- Methyl 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylate (0.80 g '40.7%). MS: 462.4 [M-H+]. Step 3. Synthesis of 3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-( 3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid 160983.doc •130· 201247656

向3-[(2R，5R)-5-環己基-2-((R)-2-羥基-丙基）·3-側氧基· 嗎啉-4-基]-5-(3,3-二甲基-丁“·炔基）_噻吩·2_曱酸甲酯 (650 mg，1.41 mmol，1.0 當量）於丁财（1〇 mL)、Me〇H(5 mL)及水（5 mL)中之溶液中添加Li〇H_H20(177 mg，4.22 mmol，3.0當量）。在室溫下攪拌所得溶液2小時。在真空下移除揮發性溶劑且向殘餘物中添加水（丨5 mL)。將混合物冷卻至0°C且藉由添加3.0 N HC1水溶液酸化直至ph=1。藉由過濾分離沈澱物，得到呈白色固體狀之產物（586 mg，93%)。MS: 448.3 [M-H+]。4 NMR (400 MHz， CD3OD): 1.09-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.85 (m, 5H) 1-89-2.10 (m, 3H) 3.56-3.61 (m, lH) 3.93-4.00 (m, 1H) 4.00-4.10 (m，1H) 4.12-4.22 (m，2H) 6.99 (s，1H)。步驟4.合成3-[(2R，5R)-5·環己基-2-((8)-2-羥基-丙基）-3_側氧基-嗎淋-4-基】-5-(3,3-二甲基-丁-1-块基）_嗟吩_2_甲酸To 3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)·3-o-oxo-morpholin-4-yl]-5-(3,3 -Dimethyl-butyl "-alkynyl"-thiophene-2-yl decanoate (650 mg, 1.41 mmol, 1.0 eq.) in Dingcai (1 mL), Me〇H (5 mL) and water (5 Add Li〇H_H20 (177 mg, 4.22 mmol, 3.0 eq.) to the solution in mL). Stir the resulting solution for 2 hours at room temperature. Remove the volatile solvent under vacuum and add water to the residue (丨 5 mL) The mixture was cooled to 0 ° C and was acidified with EtOAc EtOAc EtOAc (EtOAc) -H+]. 4 NMR (400 MHz, CD3OD): 1.09-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.85 (m, 5H) 1-89-2.10 (m, 3H) 3.56-3.61 (m , lH) 3.93-4.00 (m, 1H) 4.00-4.10 (m, 1H) 4.12-4.22 (m, 2H) 6.99 (s, 1H). Step 4. Synthesis of 3-[(2R,5R)-5· Hexyl-2-((8)-2-hydroxy-propyl)-3_sideoxy-oxalin-4-yl]-5-(3,3-dimethyl-but-1-blockyl)_ Porphyrin_2_formic acid

向3-[(2R，5R)-5-環己基-2-(2-羥基-丙基）_3_側氧基-嗎琳· 4-基]-5-(3，3-二甲基-丁-1-炔基）-嗟吩_2_曱酸甲酯（420 160983.doc • 131 · 201247656 mg ’ 〇·91 m_ ’ 10 當量）於 THF(8 mL)、MeOH(4 mL)及水（4 mL)中之溶液中添加u〇h.H2〇(115叫，2 73爪则卜 3.0 s量）。在室溫下攪拌所得溶液一小時。在真空下移除揮發性溶劑且藉由添加3 〇 N HC1水溶液酸化殘餘物直至 pH-Ι。以Et〇Ac(50 mL)萃取混合物。以鹽水〇〇 mL)洗滌經分離之有機層，乾燥（經Na2S04)且濃縮。藉由HPLC (0.1% nh4oh)純化殘餘物，得到產物（68 mg，16 7%)。 MS: 448.2 [M-H+] 〇 nmr ^4〇〇 ΜΗζ^ ce>3〇D) δ j 〇7. 1.31 (m, 8Η) 1.32 (s, 9H) 1.45-1.60 (m, 2H) 1.63-1.85 (m, 4H) 1.87-1.98 (m, 1H) 2.02-2.11 (m, iH) 3.60-3.66 (m, 1H) 3.93-4.03 (m, 2H) 4.15 (d, 1H) 4.26-4.35 (m, 1H) 6.94 (s, 1H)。表1中提供本發明之其他非限制性例示性化合物。表j之化合物可類似於通用合成描述中提供之合成程序、實例j _ 20之程序，及/或藉由熟練醫藥化學家已知之合成方法製備。 160983.doc •132- 201247656 表1 化合物編號名稱結構 3-(2-環己基-5-側氧基-。比鳴·-1 -基)-5-苯基-π塞吩-2-曱酸To 3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-propyl)_3_sideoxy-morphine-4-yl]-5-(3,3-dimethyl- Methylbutan-1-ynyl)-porphin-2-indole (420 160983.doc • 131 · 201247656 mg ' 〇·91 m_ '10 equivalents) in THF (8 mL), MeOH (4 mL) and water (〇5. The resulting solution was stirred at room temperature for one hour. The volatile solvent was removed under vacuum and the residue was acidified with aq. The mixture was extracted with Et EtOAc (50 mL). The separated organic layer was washed with brine EtOAc (EtOAc) The residue was purified by EtOAc (EtOAc (EtOAc) MS: 448.2 [M-H+] 〇nmr ^4〇〇ΜΗζ^ce>3〇D) δ j 〇7. 1.31 (m, 8Η) 1.32 (s, 9H) 1.45-1.60 (m, 2H) 1.63-1.85 (m, 4H) 1.87-1.98 (m, 1H) 2.02-2.11 (m, iH) 3.60-3.66 (m, 1H) 3.93-4.03 (m, 2H) 4.15 (d, 1H) 4.26-4.35 (m, 1H ) 6.94 (s, 1H). Other non-limiting exemplary compounds of the invention are provided in Table 1. The compounds of Table j can be prepared analogously to the synthetic procedures provided in the general synthetic description, the procedures of Examples j-20, and/or by synthetic methods known to the skilled pharmaceutical chemist. 160983.doc •132- 201247656 Table 1 Compound No. Name Structure 3-(2-cyclohexyl-5-sideoxy-.bi-1·yl-)-5-phenyl-π-cephen-2-indole

2 3-[(2S，5R)-5-環己基-2-(3-經基-丙基)_ 3-側氧基-嗎嚇 -4-基]-5-(3,3-二曱基-丁 -1 -快基)-嘆吩-2- 曱酸2 3-[(2S,5R)-5-cyclohexyl-2-(3-carbyl-propyl)-3-yloxy-infrared-4-yl]-5-(3,3-diindole Ke-but-1 - fast base) - singer-2- citric acid

3 3-[(2R，5R)-5-環己基-2-(3-經基-丙基)_ 3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁-1-快基)-π塞吩-2-3- 3-((2R,5R)-5-cyclohexyl-2-(3-carbyl-propyl)-3-yloxy-morpholin-4-yl]-5-(3,3-diindole Base-but-1-fast base)-π-cephen-2-

甲酸Formic acid

4 3-(2-環己基-6-側氧基-派π定-1 -基)-5-苯基-噻吩-2-曱醆4 3-(2-Cyclohexyl-6-sideoxy-pyridin-1 -yl)-5-phenyl-thiophene-2-indole

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5 3-(6-環己基-3-經基-3-甲基-2-側氧基-哌啶-1-基)-5-對曱苯基-噻吩-2-曱酸〇5>0Η 0 6 3-((S)-2-環己基-5-側氧基比°各°定-1-基)-5-苯基-售吩-2-曱酸 Oc^〇 fl b OH 7 3-[(2S，5R)-5-環己基-2-(3-經基-丙基)-2-曱基-3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁-1-快基)-°塞吩-2-甲酸〇— DM OH 8 3-[(2R，5R)-5-環己基-2-(2-經基-乙基)-3 -側氧基-嗎琳-4-基]-5-(3,3·二曱基-丁 -1 -快基)-σ塞吩-2-曱酸 C~\厂 v \_/ \ /"'…1\ N、l〇H5- 3-(6-Cyclohexyl-3-yl-3-methyl-2-oxo-piperidin-1-yl)-5-p-phenylene-thiophene-2-nonanoate 5> 0 6 3-((S)-2-cyclohexyl-5-sideoxyl ratio °-decyl-1-yl)-5-phenyl-sodium-2-decanoic acid Oc^〇fl b OH 7 3 -[(2S,5R)-5-cyclohexyl-2-(3-carbyl-propyl)-2-indolyl-3-yloxy-morpholin-4-yl]-5-(3,3 -dimercapto-but-1-propanyl)-°Cet-2-carboxylic acid oxime — DM OH 8 3-[(2R,5R)-5-cyclohexyl-2-(2-trans-ethyl-ethyl) -3 - pendant oxy-morphin-4-yl]-5-(3,3·didecyl-but-1-yl-fast-)-σ-cephen-2-pyruic acid C~\厂v \_/ \ /"'...1\ N, l〇H

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20 3-(2-環己基-6-側氧基-4-苯基乙醯胺基-娘咬-1-基)-5-苯基_ 噻吩-2-甲酸 Or/ ry^s^Y OH 21 3-[2-環己基-6-側氧基-4-(2-苯氧基-乙醯胺基)-哌啶-1-基]-5-苯基-噻吩-2-曱酸 ry^b OH 22 3-[(2R，4S)-2-環己基-6-側氧基-4-(2-苯氧基-乙醯胺基)-哌啶-1-基]-5-苯基-噻吩-2-曱酸 0 ^ ΝΗ^°^ο ry^s^f OH20 3-(2-cyclohexyl-6-oxo-4-phenylethenylamino-nitrient-1-yl)-5-phenyl-thiophene-2-carboxylic acid Or/ ry^s^Y OH 21 3-[2-Cyclohexyl-6-oxo-oxy-4-(2-phenoxy-acetamido)-piperidin-1-yl]-5-phenyl-thiophen-2-indole ry ^b OH 22 3-[(2R,4S)-2-cyclohexyl-6-oxo-oxy-4-(2-phenoxy-acetamido)-piperidin-1-yl]-5-benzene Base-thiophene-2-furoic acid 0 ^ ΝΗ^°^ο ry^s^f OH

160983.doc •138· 201247656 23 3-((2R,4R)-4-胺基-2-壞己基-6-側氧基· 略淀-1-基)-5-苯基-噻吩-2-甲酸 CVf O^t； 24 3-((2S，4R)-4-苯甲醯胺基-2-¾己基-6-側氧基-娘。定-1_基)-5-苯基-噻吩-2-甲酸 Ο、 25 3-((2R,4R)-4-苯甲醯胺基-2-¾己基-6-側氧基-派咬-1-基)-5_ 苯基-噻吩-2-甲酸 0^0 Ο^ί； 26 3-(2-環己基-4-甲烷續酿基-6-側乳基-旅。秦_1_基)-5-苯基-σ塞吩-2-曱酸 ο^Γ /η α^ί8Η 160983.doc -139- 201247656160983.doc •138· 201247656 23 3-((2R,4R)-4-Amino-2-dehexyl-6-oxooxy-l-butyryl-1-yl)-5-phenyl-thiophene-2- Formic acid CVf O^t; 24 3-((2S,4R)-4-benzylidinium-2-3⁄4 hexyl-6-sideoxy-nietum.-1-1-yl)-5-phenyl-thiophene -2-carboxylic acid hydrazine, 25 3-((2R,4R)-4-benzylidinium-2-3⁄4 hexyl-6-sideoxy-trans-l-yl)-5-phenyl-thiophene-2 -formic acid 0^0 Ο^ί; 26 3-(2-cyclohexyl-4-methane aryl-6-side-milk-Brigade. Qin_1_yl)-5-phenyl-σ-Sentene-2 -曱酸ο^Γ /η α^ί8Η 160983.doc -139- 201247656

27 3-(2-環己基-6-側氧基-4-苯基甲烷磺醯基-。底唤-1 -基)-5-苯基—π塞吩_2_曱酸 ;/η 28 3-((2S，4R)-4-胺基-2-環己基-6-側氧基-旅咬-1 -基)-5-苯基-噻吩-2-曱酸 Ο、rf 29 3-[4-(3-羧基-4-曱氧基-苯磺醯基)-2-環己基-6-側氧基-派嗪-1-基]-5-苯基-噻吩-2-曱酸〇cf% HO ο^ΐ 30 3-[4-(4-羧基-苯磺醯基)-2-環己基-6-側氧基-略°秦-1-基]-5-苯基塞吩-2-甲酸對掌性 Vi 〇 /η 〇^t8H27 3-(2-cyclohexyl-6-oxo-4-phenylmethanesulfonyl-.-p-l-yl)-5-phenyl-π-cetin-2-indole; /η 28 3-((2S,4R)-4-Amino-2-cyclohexyl-6-sideoxy-Bigbit-1-yl)-5-phenyl-thiophene-2-ruthenate Ο, rf 29 3- [4-(3-carboxy-4-decyloxy-phenylsulfonyl)-2-cyclohexyl-6-o-oxy-pyrazine-1-yl]-5-phenyl-thiophene-2-indole 〇cf% HO ο^ΐ 30 3-[4-(4-carboxy-benzenesulfonyl)-2-cyclohexyl-6-sideoxy-slight-qin-1-yl]-5-phenyl thiophene -2-carboxylic acid to palm Vi 〇 / η 〇 ^ t8H

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31 3-[2·環己基-6-側氧基-4·(戍烧-1 -續酿基)-略°桊-1-基]-5-苯基-噻吩-2_曱酸 °\^ 32 3-[2-環己基-4-(3,5-二曱基-異噁唑-4-磺醯基)-6-側氧基-0底 α秦_ 1 •基]-5-苯基-π塞吩-2-曱酸 0 〇 \ /Λ 33 4-[4-(2-羧基-5-苯基_ π塞吩_3 -基)-3 -環己基-5-側氧基-哌唤_1-續酿基]-2,5-二曱基-呋喃-3-甲酸 °y0H Orjr /Λ 160983.doc 141 · 20124765631 3-[2·Cyclohexyl-6-sideoxy-4·(戍烧-1 -Continuous)-Slightly 桊-1-yl]-5-phenyl-thiophene-2_decanoic acid °\ ^ 32 3-[2-Cyclohexyl-4-(3,5-dimercapto-isoxazole-4-sulfonyl)-6-sideoxy-0- bottom α Qin _ 1 • group]-5- Phenyl-π-cephen-2-pyroic acid 0 〇\ /Λ 33 4-[4-(2-carboxy-5-phenyl- π-septene-3-yl)-3-cyclohexyl-5-side oxygen --pipecall _1-continuous base]-2,5-dimercapto-furan-3-carboxylic acid °y0H Orjr /Λ 160983.doc 141 · 201247656

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38 3-[2-環己基-4-(2-曱基-丙燒ι_1_確'酿基)_ 6-側氧基-。底°秦-1-基]-5-苯基-噻吩-2-甲酸38 3-[2-Cyclohexyl-4-(2-indolyl-propanone ι_1_ indeed 'bristyl)_6-side oxy-. Phenyl-1-yl]-5-phenyl-thiophene-2-carboxylic acid

39 40 41 3-[2-環己基-6-側氧基-4-(2-苯基-乙烧續醯基)-旅嗪-1-基]-5-苯基-噻吩-2-甲酸 3-[2- ί哀己基-4-(2-敦-苯續酿基)-6-側氧基-旅α秦-1-基]-5-苯基-噻吩-2-甲酸 3-[4-(2-缓基-乙烧確醯基)-2-環己基-6-側氧基-略°秦-1-基]-5-苯基-噻吩-2-甲酸 °\\/?39 40 41 3-[2-Cyclohexyl-6-oxo-oxy-4-(2-phenyl-ethylsulfanyl)-benzin-1-yl]-5-phenyl-thiophene-2-carboxylic acid 3-[2- 哀己 yl-4-(2-d-benzoyl)-6-sideoxy-bend α-methyl-1-yl]-5-phenyl-thiophene-2-carboxylic acid 3-[ 4-(2-Silyl-Ethylacetate)-2-cyclohexyl-6-sideoxy-succinyl-1-yl]-5-phenyl-thiophene-2-carboxylic acid °\\/?

對掌性Palm

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49 3-[2-環己基-6-側氧基-4-(曱苯-3-續醯基)-旅嗓-1-基]-5-苯基-噻吩-2-曱酸 50 3-[4-(4-乙醯胺基-苯磺醯基)-2-環己基-6-側氧基-'J底°秦-l-基]-5-苯基-噻吩-2-曱酸 Ν-^/ ΝΗ o^t8H。人 51 3-[2-環己基-6-側氧基_4-(4-苯氧基-苯續酿基)-派嗜-1-基]-5-苯基·噻吩-2-甲酸 a^fa。 52 3-(4-苯磺醯基-2-環己基-6-側氧基-0底嗪-1-基)-5-苯基-噻吩-2-甲酸〇〇 OrfO49 3-[2-Cyclohexyl-6-oxo-oxy-4-(indolyl-3-anthracenyl)-tv-yl-1-yl]-5-phenyl-thiophene-2-furic acid 50 3- [4-(4-Ethylamino-phenylsulfonyl)-2-cyclohexyl-6-sideoxy-'J-bottom-H-l-yl]-5-phenyl-thiophene-2-decanoic acid Ν-^/ ΝΗ o^t8H. Human 51 3-[2-cyclohexyl-6-oxo-[4-(4-phenoxy-benzoic)-p-Il-1-yl]-5-phenyl-thiophene-2-carboxylic acid a ^fa. 52 3-(4-Benzenesulfonyl-2-cyclohexyl-6-sideoxy-0-oxazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid 〇〇 OrfO

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53 3-[2-環己基-6-側氧基-4-(4-三氟甲氧基-苯續醯基)-旅唤-1-基]_5·[(Ζ)-1-乙-(Ε)-亞基-丁 -2-稀基]-噻吩-2-曱酸〇^： 54 3-[2-環己基-6·側氧基-4-(4-三氟曱基· 苯石黃醋基)-旅σ秦-l-基]-5-苯基-α塞吩-2-甲酸 a^t8H 55 3-[2·ί哀己基-4-(4-乙基-笨橫酿基)-6-側氧基-派嘻-1-基]-5-苯基-噻吩-2-曱酸 o^: 56 3-[2-ί哀己基-4-(4-乙基-苯續酿基)-6-側氧基-派嘻-1-基]-5-苯基·噻吩-2-曱酸 160983.doc -147· 20124765653 3-[2-Cyclohexyl-6-oxo-oxy-4-(4-trifluoromethoxy-benzo-indenyl)-Behind-1-yl]_5·[(Ζ)-1-B- (Ε)-subunit-but-2-yl]-thiophene-2-furoate 〇^: 54 3-[2-cyclohexyl-6·sideoxy-4-(4-trifluorodecyl·benzene Rhubarb vinegar base)-Brigade Sigma-l-yl]-5-phenyl-α-cetin-2-carboxylic acid a^t8H 55 3-[2·ί哀己基-4-(4-ethyl-stupid Styrene)-6-Sideoxy-Phenyl-1-yl]-5-phenyl-thiophene-2-furoic acid o^: 56 3-[2-ί哀己基-4-(4-ethyl- Benzene aryl)-6-sideoxy-pyridin-1-yl]-5-phenyl-thiophene-2-decanoic acid 160983.doc -147· 201247656

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60 3-[4-(聯苯-4-磺醯基)-2-環己基-6-側氧基-派σ秦-1-基]-5-本基塞吩-2-甲酸〇^s^〇〇H 61 3-[2-環己基-4-(1-曱基-1H-吲哚-5-磺醯基)-6-側氧基底°秦- 1- 基]-5-苯基-11塞吩- 2- 甲酸 0 0 62 3-[2-環己基-4-(1-曱基-1H- ntb °坐-3 -續酿基)-6-側氧基-旅嘻- 1- 基]·5-苯基-嗔吩- 2- 曱酸則3。- y /η ο^: 63 3-{2-壞己基-4-[3- 〇、、//〇 (2-曱基-嘧啶-4-基)- 苯續酿基]-6-側乳基-娘唤-1-基}-5-苯 ) v 基-π塞吩-2-甲酸 160983.doc -149- 201247656 64 3-[2-環己基-4-(1-甲基-1 Η-。引D朵-4-項酿基)-6-側氧基-略嘻- 1- 基]-5-苯基-噻吩- 2- 甲酸 °ν/0 Ο 65 3-[4-(聯苯-3-磺醢基)-2-環己基-6·側氧基-派°秦-1-基]-5-苯基-α塞吩-2-曱酸〇^i°0HO 66 3-[2-環己基-4-(4-H-3-三氟曱基-苯續酿基)-6-側氧基-略 °秦-1-基]-5-苯基-0塞吩-2-曱酸〇^8外 67 3-(2-環己基-6-側氧基-略σ定-1·基)-5-(2- 〇〇氟-苯基)-σ塞吩-2-甲 v-y 酸〇h60 3-[4-(Biphenyl-4-sulfonyl)-2-cyclohexyl-6-sideoxy-pyridinyl-1-yl]-5-bensylphen-2-carboxylic acid 〇^s ^〇〇H 61 3-[2-Cyclohexyl-4-(1-indolyl-1H-indole-5-sulfonyl)-6-sideoxyl-Heptyl-l-yl]-5-phenyl -11 thiophene- 2- formic acid 0 0 62 3-[2-cyclohexyl-4-(1-indolyl-1H- ntb ° sitting-3 -continuously based)-6-side oxy-tour - 1 -yl]·5-phenyl-porphin-2- 2-decanoic acid 3. - y /η ο^: 63 3-{2- Badhexyl-4-[3- 〇,, //〇(2-amidino-pyrimidin-4-yl)-benzoic acid]-6-flavor --娘- 1-yl}-5-phenyl) v-yl-cephen-2-carboxylic acid 160983.doc -149- 201247656 64 3-[2-cyclohexyl-4-(1-methyl-1 Η -. D--4-yl-branched)-6-sideoxy-slightly -1-yl]-5-phenyl-thiophene-2-carboxylic acid °ν/0 Ο 65 3-[4-(linked Benzene-3-sulfonyl)-2-cyclohexyl-6·sideoxy-p-heptyl-1-yl]-5-phenyl-α-cephen-2-indole 〇^i°0HO 66 3- [2-cyclohexyl-4-(4-H-3-trifluoromethyl-benzoic acid)-6-sideoxy-slightly-decyl-1-yl]-5-phenyl-e-phene- 2-曱〇〇 8 8 outside 67 3-(2-cyclohexyl-6-sideoxy-slightly sigma-1·yl)-5-(2- fluorinated phenyl-phenyl)-σ septene-2 -A vy 〇h

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I60983.doc -151 - 201247656 72 3-(2-環己基-6-側氧基-哌啶-1·基)-5-(4-乙基-苯基)-σ塞吩-2-曱酸 rY<v〇 OH 73 5-(4-氣-苯基)-3-(2-環己基-6-側氧基-哌唆-1-基)-〇塞吩-2-甲酸 C丨人^ 〇H 74 3-[4-(6-氮雜環丁烷-1-基-°比σ定-3 - 酿· 基)-2-環己基-6-側氧基-旅唤-l-基]-5-苯基-噻吩-2-曱酸 /η 0^s^r〇〇H 75 3-[2-環己基-4-(6-環己胺基-°比σ定-3 -確酿基)-6-側氧基-娘嗓- 1- 基]-5·苯基-噻吩- 2- 曱酸I60983.doc -151 - 201247656 72 3-(2-Cyclohexyl-6-oxo-piperidin-1yl)-5-(4-ethyl-phenyl)-σ-cephen-2-pyruic acid rY<v〇OH 73 5-(4-Gas-phenyl)-3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-dexoster-2-carboxylic acid C丨人^ 〇H 74 3-[4-(6-azetidin-1-yl-° ratio σ定-3 - brewing base)-2-cyclohexyl-6-sideoxy-------- ]-5-phenyl-thiophene-2-furoic acid/η 0^s^r〇〇H 75 3-[2-cyclohexyl-4-(6-cyclohexylamino-° ratio σ定-3 - indeed Styrene)-6-sideoxy-N。-l-yl]-5-phenyl-thiophene-2-nonanoic acid

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160983.doc •155- 201247656 88 3-[2-環己基-6-側氧基-4-(6-娘σ秦-1 -基_ 0比咬-3-績酿基)-略嗓-1_基]-5-苯基-嗟吩-2-曱酸160983.doc •155- 201247656 88 3-[2-Cyclohexyl-6-sideoxy-4-(6-Nang σ Qin-1 -yl _ 0 ratio bite-3-flavored base)- slightly 嗓-1 _ base]-5-phenyl-porphin-2-decanoic acid

89 3-{4-[6-(4-乙醯基-派°秦-1 -基)-°比咬-3 -續酿基]-2-環己基_ 6-側氧基-η底嗓-1-基}-5-苯基-11 塞吩-2-甲酸89 3-{4-[6-(4-Ethyl-pyryo-β-yl)-° ratio bite-3 - continuation base]-2-cyclohexyl_ 6-sideoxy-η bottom 嗓-1-yl}-5-phenyl-11 thiophene-2-carboxylic acid

90 3- {2-環己基-6-側氧基_4-[6-(四氫-派喃- 4- 基胺基)-η比β定-3-績酿基]-旅°秦-1-基}-5-苯基塞吩-2-曱酸90 3- {2-cyclohexyl-6-sideoxy_4-[6-(tetrahydro-pyran-4-ylamino)-n ratio β定-3-生粉基]-旅°秦- 1-yl}-5-phenylcephen-2-pyruic acid

91 3-{2-環己基-4-[6-(環己基-甲基-胺基)-°比。定-3-確酿基]-6-側氧基-派°秦-1-基}-5-苯基-11 塞吩-2-曱酸〇91 3-{2-cyclohexyl-4-[6-(cyclohexyl-methyl-amino)-° ratio.定-3-正酿基]-6-Sideoxy-Phenyl-l-yl}-5-phenyl-11-cephen-2-pyruic acid 〇

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92 3-{2-環己基-4-[6_ (2,5-二曱基·σ比洛咬· 1·基)-吡啶-3-磺醯基]-6-側氧基-略嘻_ 1- 基}-5-苯基-σ塞吩- 2- 甲酸〇cQ//〇 N I 93 3-[2-環己基-4-(4-經基·3,4,5,6·四氫-2H-[1,21]聯。比啶基-5·-磺酿基)-6·側氧基-娘嗓-1-基]-5-苯基-α塞吩-2-甲酸 0 94 3-[2-環己基-4-(4-曱氧基-3,4,5,6-四氫-2H-[1，2']聯吡啶基-5’-磺醯基)-6-側氧基-略嗓-1-基]-5-苯基-噻吩-2-甲酸〇 (^sAt°〇h 95 3-[2-環己基-4-(4,4-二氟-3,4,5,6- 四氫-2H-[1,2']聯吼啶基-5’-磺醯基)-6-側氧基-略嘻-l-基]-5-苯基-噻吩-2-甲酸 0 N I60983.doc -157- 201247656 96 3-[2-環己基-4-(4-曱基-3,4,5,6-四氫-2H-[1,2’]聯吼啶基-5·-磺酿基)-6-側氧基-0底 D秦-1-基]-5 -苯基-D塞吩-2-曱酸〇 97 3-[(R)-4-(3-氰基-苯續酿基)-2-壞己基-6-側氧基-ϋ底σ秦-l-基]-5-苯基·噻吩-2-甲酸 ο ✓ 〇 Ο〜qO Cr^i"L 98 3-[2-環己基-4-(4-曱基胺甲醯基-苯磺醯基)-6-側氧基-派°秦- 1- 基]-5-苯基-噻吩- 2- 甲酸 α^8Η 99 3-[2-環己基-4-(4-曱基-3,4-二氫-2H-吡。定并[3,2-b][l，4]噁嗓績酿基)-6-側氧基-旅σ秦_ 1 ·基]-5-苯基-11 塞吩-2-曱酸〇,s//^y〇、92 3-{2-cyclohexyl-4-[6_(2,5-diindenyl σ 比洛 · 1 1 ) ) ) ] ] ] ] ] ] ] ] ] ] ] ] ] ] 嘻嘻嘻嘻嘻嘻嘻嘻嘻嘻1-yl}-5-phenyl-σ-septene-2- 2-carboxylic acid hydrazine cQ//〇NI 93 3-[2-cyclohexyl-4-(4-carbyl·3,4,5,6·tetrahydro) -2H-[1,21]. Bipyridyl-5·-sulfonyl)-6. oxo-indolyl-1-yl]-5-phenyl-α-cephen-2-carboxylic acid 0 94 3-[2-Cyclohexyl-4-(4-decyloxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridyl-5'-sulfonyl)-6-氧基oxy-l-indol-1-yl]-5-phenyl-thiophene-2-carboxylic acid hydrazine (^sAt°〇h 95 3-[2-cyclohexyl-4-(4,4-difluoro-3, 4,5,6-tetrahydro-2H-[1,2']biacridinyl-5'-sulfonyl)-6-o-oxy-l-l-yl]-5-phenyl-thiophene -2-carboxylic acid 0 N I60983.doc -157- 201247656 96 3-[2-cyclohexyl-4-(4-mercapto-3,4,5,6-tetrahydro-2H-[1,2'] Acridinyl-5·-sulfonyl)-6-sideoxy-0 bottom D-methyl-1-yl]-5-phenyl-D-cephen-2-indole 〇97 3-[(R)- 4-(3-cyano-benzoic acid)-2-dextyl-6-sideoxy-deuterium σ Qin-l-yl]-5-phenyl-thiophene-2-carboxylic acid ο ✓ 〇Ο~ qO Cr^i"L 98 3-[2-cyclohexyl-4-(4-mercaptoaminemethanyl-benzenesulfonyl)-6-sideoxy-group °-Q-1 -yl]-5-phenyl-thiophene-2-carboxylic acid α^8Η 99 3-[2-cyclohexyl-4-(4-indolyl-3,4-dihydro-2H-pyrene. 2-b][l,4] 嗓嗓 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Y〇,

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100 3-[2-ί辰己基-4-(4-異丙基-苯續酿基)-6-側氧基-哌嗪-1-基]-5-苯基-售吩-2-甲酸 101 3-[2-環己基-6-側氧本續酿基)-痕。秦· 1 _ 基]-5-苯基-噻吩-2-甲酸 102 3-[2-環己基-4-(3,4-二甲氧基-苯續醯基)-6-侧氧基-略°秦- 1- 基]-5-苯基-D塞吩- 2- 甲酸 O^l·1 103 3-[2-環己基-4-(4-曱氧基-苯磺醯基)-6-側氧基-哌嗪-1-基]-5-苯基-噻吩-2-曱酸 I60983.doc 159* 201247656 104 3-[2-環己基-4-(3-氟-苯磺醯基)-6-側氧基-旅嘻-1-基]-5-苯基-噻吩-2-甲酸 0^ι8Η 105 3-[4-(4-第三丁基-苯磺醯基)-2-環己基-6-側氧基-略嗓· 1 -基]-5-苯基-σ塞吩-2-曱酸 ο^ί8Η 106 3-[2-環己基-4-(4-二敗甲氧基-苯績醞基)-6-側氧基-哌嗪- 1- 基]-5-苯基-嗟吩- 2- 曱酸〇^8Η Α 107 3-[(R)-2-環己基-4-(3-甲氧基-苯磺醯基)-6-側氧基-派嘻- 1- 基]-5_苯基-°塞吩- 2- 曱酸 °100 3-[2-ί辰-hexyl-4-(4-isopropyl-benzoic)-6-oxo-piperazin-1-yl]-5-phenyl-phenyl-2-carboxylic acid 101 3-[2-cyclohexyl-6-side oxygen presenting base)-mark. Qin·1 _ yl]-5-phenyl-thiophene-2-carboxylic acid 102 3-[2-cyclohexyl-4-(3,4-dimethoxy-benzoindolyl)-6-sideoxy- °°秦- 1-yl]-5-phenyl-D-cephen-2- 2-carboxylic acid O^l·1 103 3-[2-cyclohexyl-4-(4-decyloxy-phenylsulfonyl)- 6-Sideoxy-piperazin-1-yl]-5-phenyl-thiophene-2-furoic acid I60983.doc 159* 201247656 104 3-[2-Cyclohexyl-4-(3-fluoro-benzenesulfonate) ))-6-Sideoxy-Ben-1-yl]-5-phenyl-thiophene-2-carboxylic acid 0^ι8Η 105 3-[4-(4-Tertibutyl-benzenesulfonyl)- 2-cyclohexyl-6-sideoxy-slightly 嗓·1-yl]-5-phenyl-σ-septene-2-decanoic acid ο^ί8Η 106 3-[2-cyclohexyl-4-(4-di败methoxy-phenyl- fluorenyl)-6-o-oxy-piperazine-1-yl]-5-phenyl-porphin-2-yl phthalate Η^8Η Α 107 3-[(R)-2 -cyclohexyl-4-(3-methoxy-benzenesulfonyl)-6-sideoxy-pyrene-1-yl]-5-phenyl-° thiophene-2-pyruic acid °

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108 3-[2-環己基-6-側氧基_4-( °比-3-項酿基)·旅嘻-1-基]-5-苯基-噻吩-2-甲酸〇cf〇 109 3·[2-環己基-4-(4· 說-苯續酿基)-6-側氧基-σ底唤-1-基]-5-苯基-噻吩-2-甲酸 ο^ΐ 110 3-[2-ί哀己基-4-(奈-1-續酿基)·6-側氧基-旅嗓-1-基]-5-苯基-噻吩-2-甲酸 111 3-[2-環己基-4-(2,3-二氣-苯績酿基)-6-側氧基-哌嗪-1-基]-5-苯基-噻吩-2-甲酸 ο ο CI 皆 /Ν-{ ο^ΐ 160983.doc -161 - 201247656108 3-[2-cyclohexyl-6-sideoxy_4-(° ratio -3-), 嘻-1-yl]-5-phenyl-thiophene-2-carboxylic acid 〇cf〇109 3·[2-Cyclohexyl-4-(4·say-benzoic)-6-sideoxy-σ-acetyl-1-yl]-5-phenyl-thiophene-2-carboxylic acid ο^ΐ 110 3-[2-ί哀己基-4-(奈-1-Continuous)·6-Sideoxy-Ben-1-yl]-5-phenyl-thiophene-2-carboxylic acid 111 3-[2 -cyclohexyl-4-(2,3-digas-benzene-based)-6-o-oxy-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid ο ο CI Ν/Ν -{ ο^ΐ 160983.doc -161 - 201247656

112 4-[4-(2-羧基-5-苯基-π塞吩-3-基)-3-環己基-5-側氧基-哌 17秦-1-績酿基]-略咬-1-曱酸苯甲酯 o^?bv. α^8Η °ό 113 5-(4-第二丁基-苯基)-3-(2-環己基-6-側氧基-略咬-1-基)-噻吩-2-曱酸〇h 114 3-(2-環己基-6-側氧基-娘°定-1 -基)-5-(4-甲氧基-苯基)-噻吩-2-甲酸 0H 115 3-[(R)-5-環己基-2,2-雙(3-經基-丙基)-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁 ·1· 炔基)-噻吩-2-甲酸 ^OH /'Vs 〇H112 4-[4-(2-carboxy-5-phenyl-π-s-phen-3-yl)-3-cyclohexyl-5-sideoxy-piperidine 17-qin-1-yield base]-slightly bite- Benzene 1-nonanoate o^?bv. α^8Η °ό 113 5-(4-Second-butyl-phenyl)-3-(2-cyclohexyl-6-sideoxy-slightly bite-1 -yl)-thiophene-2-furoate 〇h 114 3-(2-cyclohexyl-6-sideoxy-N-butyl-1-yl)-5-(4-methoxy-phenyl)-thiophene -2-carboxylic acid 0H 115 3-[(R)-5-cyclohexyl-2,2-bis(3-carbyl-propyl)-3-yloxy-morphin-4-yl]-5-( 3,3-Dimethyl-butyl·1·alkynyl)-thiophene-2-carboxylic acid ^OH /'Vs 〇H

160983.doc -162- 201247656 116 3-(2-環己基-6-側氡基-哌啶-1-基)-5-(4-乙氧基·苯基)·σ塞吩-2-曱酸 Γτ 产。人，1 0Η 117 3-(2-環己基-6-側氧基-派σ定-1 -基)-5-(4-三氟甲基-苯基)-°塞吩-2-甲酸 mV oh F F 118 3-{2-環己基-4_[6-((R)-2-甲基-吡咯啶-1 -基)·σ比°定-3 -石黃酿基]-6-側氧基-旅嗓- 1- 基}-5-苯基-噻吩- 2- 甲酸〇^i8h 119 3-{2-環己基-4-[6-((S)-2-曱基-吡咯啶-1_基。比。定酿基]-6-側氧基_娘。秦_ 1- 基}-5-苯基塞吩- 2- 甲酸 ο^ΐ 160983.doc -163 - 201247656160983.doc -162- 201247656 116 3-(2-Cyclohexyl-6-oxanyl-piperidin-1-yl)-5-(4-ethoxyphenyl)·σ-cephen-2-pyrene Acid Γ τ production. Human, 10 Η 117 3-(2-cyclohexyl-6-o-oxy-pyrazine-1 -yl)-5-(4-trifluoromethyl-phenyl)-°cephen-2-carboxylic acid mV Oh FF 118 3-{2-cyclohexyl-4_[6-((R)-2-methyl-pyrrolidin-1-yl)·σ ratio ° -3 - zeolitic acid]-6-side oxygen --旅嗓- 1-yl}-5-phenyl-thiophene-2- 2-carboxylic acid oxime ^i8h 119 3-{2-cyclohexyl-4-[6-((S)-2-mercapto-pyrrolidine- 1_Base. Ratio. Stabilized base]-6-side oxy group 娘. Qin _ 1- yl}-5-phenyl thiophene-2- carboxylic acid ο^ΐ 160983.doc -163 - 201247656

120 3-{2-環己基-4-[6-((R)-3-敦-口比口各咬-1-基)-。比咬-3-續酿基]-6-側氧基-派嗪-1-基}-5-苯基嗟吩-2-甲酸 0、，,〇 /=N c a^t8H 121 3-{2-環己基-4-[6_ ((8)-3-氣-°比嘻咬-1· 基卜吼咬^-^^酿基]-6-側氧基-旅唤-1 -基}-5-苯基-噻吩-2-曱酸 /n^< (yH 122 3-{2-環己基-4-[6-((2R，4R)-4-羥基-2-甲基-σ比洛°定-1-基)_ 0比咬_ -3- 酿基]-6- 側氧基-哌嗪-1-基}-5-苯基-噻吩-2-曱酸〇^ς，0 N\ 、、〇H ο^ΐ 123 3-{2-環己基-4-[6-((R)-3-經基-D比洛咬_ 1 -基)-a 比〇定-3-基]-6-側氧基-旅°秦- 1- 基}-5-苯基-σ塞吩_ 2- 曱酸 ^ν^〇η /n^< o^t8H 160983.doc 164- 201247656120 3-{2-cyclohexyl-4-[6-((R)-3----------------------------------- More than bite-3-continuation base]-6-sideoxy-pyrazine-1-yl}-5-phenylporphin-2-carboxylic acid 0,,,〇/=N ca^t8H 121 3-{2 -cyclohexyl-4-[6_((8)-3- gas-° ratio bite-1·基卜吼 bit ^^^^) base-6-sideoxy-Brigade-1 -yl}- 5-phenyl-thiophene-2-furoic acid/n^<(yH 122 3-{2-cyclohexyl-4-[6-((2R,4R)-4-hydroxy-2-methyl-σ ratio洛°定-1-yl)_0 咬 _ -3- aryl]-6- oxo-piperazin-1-yl}-5-phenyl-thiophene-2-decanoic acid 〇^ς,0 N\ , , 〇H ο^ΐ 123 3-{2-cyclohexyl-4-[6-((R)-3-yl-based-D-Bile _ 1 -yl)-a 〇定-3- ]]-6-sideoxy-Big-Qin- 1-yl}-5-phenyl-σ-septene _ 2-decanoic acid ^ν^〇η /n^< o^t8H 160983.doc 164- 201247656

124 3-{2-環己基-4-[6-((S)-3-經基-吼洛咬_ 1 -基)_ σ 比ϋ定-3 - 酿基]-6-側氧基-旅°秦- 1- 基}-5-苯基-噻吩- 2- 曱酸〇<) ^Να〇Η ο^8η 125 3-{4-[6-(7-氧雜-雙環[2.2.1]庚-7-基)-吼咬-3·續酿基]-2- ί哀己基·6·側氧基-σ底 17秦-1 -基} -5 -苯基-嗟吩-2-曱酸 126 3-[2-環己基-4-((2S，6R)_2,6-二甲基-3,4,5,6-四氫-2H-[1，2]聯吼啶基-5'-磺醯基)-6-側氧基-哌嗓·1·基]-5-苯基-σ塞吩-2-甲酸 /Ν-( ο^ΐ 127 3-{2-環己基-4-[4-((R)-2-曱基-吡咯啶-1-基)-苯續醯基]-6-側氧基_σ底D秦-1-基}-5-笨基-噻吩-2-曱酸 /η 〇^ι8η 160983.doc -165- 201247656 128 3- [6-環己基-3-曱基- 4- (6-嗎啉-4-基-吡咬-3-績酿基)-2-側氧基-σ底嘻-1-基]-5-苯基-噻吩-2-曱酸 129 5-(4-氮基-苯基)-3-(2-環己基-6-側氧基-派咬-1-基)-σ塞吩-2-甲酸 rV^r。。〇H 130 3-{(R)-2-環己基_4_ [6-((R)-2-甲基-吡咯咬_ -1 -基)-°比咬峡· 醢基]-6-側氧基-派 °秦-1-基}-5-苯基-σ塞吩-2-曱酸 Q一 ο^ΐ 131 3-{(S)-2-環己基-4-[6-((R)-2-曱基-吡咯 -1_ 基)-σ 比咬_ -3 -醯基]-6-側氧基-派 Π秦-1_基}_5_苯基-σ塞吩-2-曱酸 /Nn124 3-{2-cyclohexyl-4-[6-((S)-3-yl-carbo-bito-1 -yl)_ σ ϋ定定-3 - aryl]-6-sideoxy-旅°秦- 1-基}-5-phenyl-thiophene-2-pyruic acid 〇<) ^Να〇Η ο^8η 125 3-{4-[6-(7-oxa-bicyclo[2.2. 1]g-7-yl)-bite-3·continuation base]-2- 哀己基 · 6 6 6 6 - - - 17 秦秦秦秦秦秦秦秦秦秦秦秦 -2 -2 -2 -2 - citric acid 126 3-[2-cyclohexyl-4-((2S,6R)_2,6-dimethyl-3,4,5,6-tetrahydro-2H-[1,2]biacridinyl -5'-sulfonyl)-6-hydroxyl-piperazine·1·yl]-5-phenyl-σ-cephen-2-carboxylic acid/Ν-( ο^ΐ 127 3-{2-cyclohexyl -4-[4-((R)-2-indolyl-pyrrolidin-1-yl)-benzoindolyl]-6-sideoxy-σ bottom D-methyl-1-yl}-5-styl -thiophene-2-decanoic acid/η 〇^ι8η 160983.doc -165- 201247656 128 3- [6-Cyclohexyl-3-indolyl-4-(6-morpholin-4-yl-pyridyl-3- -2 oxy-σ 嘻嘻-1-yl]-5-phenyl-thiophene-2-furic acid 129 5-(4-nitro-phenyl)-3-(2-ring Hexyl-6-sideoxy-deacetyl-1-yl)-σ-cement-2-carboxylic acid rV^r. 〇H 130 3-{(R)-2-cyclohexyl_4_ [6-((R )-2-methyl-pyrrole biting _ -1 -yl)-° than biting gorge · fluorenyl]-6-side oxy-p-°qin-1-yl}-5-benzene -σ塞吩-2-曱酸 Q一ο^ΐ 131 3-{(S)-2-cyclohexyl-4-[6-((R)-2-indolyl-pyrrole-1_yl)-σ ratio Bite _ -3 - fluorenyl]-6-side oxy-pyridinyl-1_yl}_5_phenyl-σ-cephen-2-pyruic acid/Nn

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132 3-[(S)-2-環己基-6-側氧基-4-(6-派°秦-1-基-。比酿基)-娘嗓-1-基]-5-苯基_ π塞吩-2-甲酸 0、，,〇 t_____^ 〇^8η 133 5-(3-亂本基)-3-(2_ ί哀己基-6-側氧基-派啶-1-基)-噻吩-2-曱酸 Cl 134 3-(2-環己基-6-側氧基旅唆-1-基)·5-間曱苯基-噻吩-2-甲酸 CV) 135 3-[(R)-2-環己基-6-側氧基-4-(6-。比π各 0定-1 -基-°比咬-3-績醯基)-哌嗪-1-基]-5-苯基-噻吩-2-甲酸 160983.doc •167- 201247656 136 3-[(S)-2-環己基-6-側氧基-4-(6- °比洛 0定 * 1 -基_ °比。定-3-酿基)-娘嘻基]-5-苯基-噻吩-2-曱酸132 3-[(S)-2-cyclohexyl-6-o-oxo-4-(6-p-Chentin-1-yl-.pyridyl)-indolyl-1-yl]-5-phenyl _ π cephene-2-carboxylic acid 0,,,〇t_____^ 〇^8η 133 5-(3-random base)-3-(2_ 哀己基 -6-6-sideoxy-pyridin-1-yl) -thiophene-2-decanoic acid Cl 134 3-(2-cyclohexyl-6-sideoxyl-l-yl)·5-m-decylphenyl-thiophene-2-carboxylic acid CV) 135 3-[(R )-2-cyclohexyl-6-sideoxy-4-(6-. than π each 0-set-1-yl-° ratio -3-yl)-piperazin-1-yl]-5- Phenyl-thiophene-2-carboxylic acid 160983.doc •167- 201247656 136 3-[(S)-2-cyclohexyl-6-sideoxy-4-(6- ° pyloc@0*1 -yl_ ° Ratio. Ding-3-bristyl)-N-mercapto]-5-phenyl-thiophene-2-furic acid

137 3-{(R)-2-環己基-4-[6-(4-曱基-ϊΤ辰嘻-1-基)-°比11 定-3 -項酿基]· 6-側氧基-略°秦-1 -基}-5-苯基_σ塞吩-2-曱酸137 3-{(R)-2-cyclohexyl-4-[6-(4-indolyl-indenyl-1-yl)-° ratio 11 -3 -termenyl]- 6-side oxy - slightly ° Qin-1 -yl}-5-phenyl_σ-cephen-2-pyruic acid

138 3-[(R)-4-(4-胺基-4-甲基-3,4,5,6-四氮-2H-[1，2’]聯吼啶基· 5*-磺醯基)-2-環己基-6-側氧基-娘σ秦- 1- 基]-5-苯基-σ塞吩- 2- 曱酸〇、、/138 3-[(R)-4-(4-Amino-4-methyl-3,4,5,6-tetrazo-2H-[1,2']biacridinyl·5*-sulfonate ))-2-cyclohexyl-6-sideoxy-Nangqi-N-yl]-5-phenyl-σ-septene-2- 2-decanoate,

160983.doc 168- 201247656 139 3-{(R)-2-環己基-4- [6-((S)-3-羥甲基-哌 0秦-1 -基)-°比-3-石黃醯基]-6-側氧基-哌 °秦_1_基}-5-苯基塞吩-2-甲酸160983.doc 168- 201247656 139 3-{(R)-2-cyclohexyl-4-[6-((S)-3-hydroxymethyl-piperidinyl-1-yl)-° ratio -3- stone Astragaloside-6-yloxy-piperidinyl-1_yl}-5-phenylcephen-2-carboxylic acid

OH 140 3-{(R)-2-環己基-4- [6-((R)-3-曱基-哌 π秦-1 -基)-α比0定-3-續醯基]-6-侧氧基底 °秦_1_基}_5_苯基塞吩-2-甲酸OH 140 3-{(R)-2-cyclohexyl-4-[6-((R)-3-indolyl-piperidinyl-1 -yl)-α than 0--3-indolyl]- 6-side oxyl bottom ° Qin_1_yl}_5_phenylcephen-2-carboxylic acid

141 3-{(R)-4-[6-((R)-3-胺基-洛咬-1-基)_ ϋ比0定-3-確酿基]-2-環己基-6-側氧基-哌。秦-1-基}-5-苯基-σ塞吩-2-甲酸141 3-{(R)-4-[6-((R)-3-Amino-L-di-1-yl)_ ϋ 0 0 定确确确确确 ] ] -2- -2- hexyl-6- Side oxy-pipeline. Qin-1-yl}-5-phenyl-σ-thiophene-2-carboxylic acid

160983.doc -169- 201247656 142 3-[(R)-4-((S)-3-胺基-3,4,5,6-四氫-2H-[1,2]聯扯啶基-5^磺酿基)-2-環己基-6-側氧基-旅°秦-1-基]_ 5-苯基-11 塞吩-2-甲酸〇 ✓〇〇'0¾ 〇^ΐ〇〇Η 143 3-[(R)-4-(4-胺基曱基-3,4,5,6-四氫-2H-[1，2’]聯吼啶基-5·-磺酿基)-2-環己基-6-側氧基-σ底嗓-1-基]_ 5-苯基-噻吩-2-甲酸〇、〇.......fju α^Η心 144 3-{(R)-4-[6-((S)-3-胺基-α比哈α定-1 -基)-吡啶-3-磺醯基]-2-環己基-6-側氧基-派嗪-1-基}-5-苯基-噻吩-2-甲酸 0、◊0 Ο〇Ό： Ο- 160983.doc 170· 201247656 145 3-{(R)-2-環己基-4- [6-((S)-3-甲基-哌嗪- 1 -基)-°比°定-3 -續酿基]-6-側氧基-σ底嘻- 1- 基}_5·苯基-σ塞吩- 2- 甲酸160983.doc -169- 201247656 142 3-[(R)-4-((S)-3-Amino-3,4,5,6-tetrahydro-2H-[1,2]-linked alkidine- 5^sulfonyl)-2-cyclohexyl-6-sideoxy-branches-qin-1-yl]_ 5-phenyl-11-cephen-2-carboxylic acid 〇✓〇〇'03⁄4 〇^ΐ〇〇 143 143 3-[(R)-4-(4-Aminoguanidino-3,4,5,6-tetrahydro-2H-[1,2']biacridinyl-5·-sulfonyl) -2-cyclohexyl-6-sideoxy-σ bottom 嗓-1-yl]_ 5-phenyl-thiophene-2-carboxylic acid oxime, 〇.......fju α^Η心144 3-4 (R)-4-[6-((S)-3-Amino-α-haha-α-l-yl)-pyridin-3-sulfonyl]-2-cyclohexyl-6-sideoxy- Peptazin-1-yl}-5-phenyl-thiophene-2-carboxylic acid 0, ◊0 Ο〇Ό: Ο-160983.doc 170· 201247656 145 3-{(R)-2-cyclohexyl-4-[ 6-((S)-3-Methyl-piperazine-1-yl)-° ratio °-3 -continuation base]-6-sideoxy-σ bottom 嘻- 1-yl}_5·phenyl -σ pheno- 2-carboxylic acid

146 3-{(R)-4-[6-((R)-3-第三丁氧羰基胺基-0比嗜·咬λ 1 -基)-α比。定-3-續酿基]-2-壞己基-6-側氧基-娘D秦- 1- 基}'-5-苯基-α塞吩- 2- 甲酸146 3-{(R)-4-[6-((R)-3-Tertidinoxycarbonylamino-0-too-bit λ 1 -yl)-α ratio.定-3-Continuous aryl]-2-dehexyl-6-sideoxy-Nang D-l-l-yl}'-5-phenyl-α-cetin-2-carboxylic acid

Η 〇^\ 147 3-[(R)-2-壞己基-4-(4-二甲胺基-3,4,5,6-四氫-2H-[1,2']聯。比啶基-5'-磺醯基)-6-側氧基-旅嗓-1-基]-5-苯基-噻吩-2-甲酸Η 〇^\ 147 3-[(R)-2-D-hexyl-4-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[1,2']. -5'-sulfonyl)-6-sideoxy-tourl-1-yl]-5-phenyl-thiophene-2-carboxylic acid

148 3-{(R)-2_ 壤己基-4·-[6-(4-乙基-旅唤-1-基)-吼啶-3-磺醯基]-6-側氧基-n底°秦-1-基}-5-苯基-·*塞吩-2-甲酸148 3-{(R)-2_ oxahexyl-4·-[6-(4-ethyl-tray-1-yl)-acridin-3-sulfonyl]-6-sideoxy-n °Qin-1-yl}-5-phenyl-·*cephen-2-carboxylic acid

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149 3-{(R)-4-[4_(第三丁氧羰基胺基-曱基)-3,4,5,6-四氮-2H-[1，2’]聯吼啶基-5·-磺酿基]-2-環己基-6-側氧基-派唤-1-基}· 5-苯基-σ塞吩-2-曱酸 150 3-{(R)-2-環己基-4-[6-((3R，5S)-3,5-二曱基-旅ϋ秦-1-基)-。比°定-3-續酿基]-6-側氧基-旅嗓-l-基}-5-苯基-噻吩-2-曱酸 Λ), o^8h ~Qh \ 151 (R)-4-{5-[(R)-4-(2-緩基-5-苯基-β塞吩-3-基)-3·ί哀己基-5-側氧基-η底唤-1-績酿基]-吡啶-2-基}-2-甲基·哌嗪-1-甲酸第三丁酯 o^8h s 0 152 3-{(R)-4-[6-(4-第三丁基-娘喚-1-基)-0比啶-3-磺醯基]-2-環己基-6·側氧基-旅 σ秦-l-基}-5-苯基塞吩-2-甲酸〇^ι8η _yN V149 3-{(R)-4-[4_(Tertidinoxycarbonylamino-indenyl)-3,4,5,6-tetrazo-2H-[1,2']biacridinyl-5 ·-sulfonyl]-2-cyclohexyl-6-sideoxy-p-but-1-yl}· 5-phenyl-σ-cephen-2-indole 150 3-{(R)-2-ring Hexyl-4-[6-((3R,5S)-3,5-dimercapto-tung Qin-1-yl)-.约定定-3-Continuous base]-6-side oxy-tv-l-yl}-5-phenyl-thiophene-2-decanoate Λ), o^8h ~Qh \ 151 (R)- 4-{5-[(R)-4-(2-sulfoyl-5-phenyl-β-s-phen-3-yl)-3·ί哀 ylyl-5-sideoxy-η bottom -1--1- Tribasic]-pyridin-2-yl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester o^8h s 0 152 3-{(R)-4-[6-(4-third Butyl-indiyl-1-yl)-0-pyridyl-3-sulfonyl]-2-cyclohexyl-6·sideoxy-Brigade Sigma-l-yl}-5-phenyl thiophene-2 -formic acid 〇^ι8η _yN V

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153 3-[(R)-4-(4-第三丁氧羰基胺基-4-曱基-3,4,5,6-四氫-2H-[1,2']聯吼啶基-51-磺酿基)·2-環己基-6· 側氧基-略嗓-1-基]-5-苯基-噻吩-2-甲酸 ο^8η 154 3-{(R)-2_ 環己基-4· [6-(2-乙基比洛咬-1 -基)-σ比°定-3-石黃酿基]-6-側氧基-派嗪- 1- 基}-5 -苯基-σ塞吩- 2- 曱酸 Q一 155 3-[(R)-2-環己基-4-(3-二甲胺基-3,4,5,6-四氫-2Η-[1，2·]聯吼啶基-5'-磺醯基)-6-側氧基-略嗓-l-基]_ 5-苯基-噻吩-2-曱酸 q一 N—/ 0^4, 156 3-{(R)-2-環己基-4-[6-((S)-3-二甲胺基- 。比略。定-1 -基)-°比σ定-3-磺醯基]-6-側氧基-派嗓-1-基}-5-苯基-噻吩-2-曱酸〇— o^8h 160983.doc -173- 201247656 157 3-{(R)-2-環己基-4· [6-(六氫化-D比嘻并咬-3-續酿基]-6-側氧基-旅°秦-1-基}-5-苯基-ϋ塞吩-2-甲酸 °vV==N\ q一r; ^ o^t8H 158 3-[(R)-4-((S)-3-第三丁氧羰基胺基-3,4,5,6-四氫-2H-[1，2’]聯。比啶基-5’-磺酿基)-2-環己基-6-側氧基-派嘻-1-基]-5-苯基-α塞吩-2-甲酸 ο^8η 5 〇 159 3-[(R)-4-((S)-3-第三丁氧羰基胺基-3,4,5,6- 四氫-2H-[1，2’]聯。比啶基-5·-磺醯基)-2-環己基-6-側氧基底唤_1_基]_ 5-苯基-噻吩-2-甲酸 o^8h 5 ° 160 3-{(R)-2-環己基-4-[6-(4-異丙基-略嘻-1 -基)。比。定-3 - 酿基]-6-側氧基-旅D秦· 1- 基}-5-苯基-σ塞吩- 2- 甲酸 /N~V α^8Η153 3-[(R)-4-(4-Tertidinoxycarbonylamino-4-mercapto-3,4,5,6-tetrahydro-2H-[1,2']biacridinyl- 51-sulfonyl)·2-cyclohexyl-6· oxo-o-l-yl-1-yl]-5-phenyl-thiophene-2-carboxylic acid ο^8η 154 3-{(R)-2_cyclohexyl -4· [6-(2-ethylpyrobitone-1 -yl)-σ ratio °-3-platinyl]-6-sideoxy-pyrazine-1-yl}-5-benzene Base-σ-Shen-2- 2-decanoic acid Q-155 3-[(R)-2-cyclohexyl-4-(3-dimethylamino-3,4,5,6-tetrahydro-2Η-[1 ,2·]bi-pyridinyl-5'-sulfonyl)-6-sideoxy-slightly-l-yl]_ 5-phenyl-thiophene-2-furic acid q-N-/ 0^4 , 156 3-{(R)-2-cyclohexyl-4-[6-((S)-3-dimethylamino-. s. slightly. -1 -yl)-° ratio sigma-3-sulfonate Indenyl]-6-sideoxy-pyridin-1-yl}-5-phenyl-thiophene-2-furoate 〇- o^8h 160983.doc -173- 201247656 157 3-{(R)-2 -cyclohexyl-4·[6-(hexahydro-D is more than hydrazine and biting-3-continuation)-6-sideoxy-Benqin-l-yl}-5-phenyl-hydrazine- 2-carboxylic acid °vV==N\ q-r; ^ o^t8H 158 3-[(R)-4-((S)-3-Tertidinoxycarbonylamino-3,4,5,6- Tetrahydro-2H-[1,2']. Bipyridyl-5'-sulfonyl)-2-cyclohexyl-6-sideoxy-pyridin-1-yl]-5-phenyl-α Sephen-2- Acid ο^8η 5 〇159 3-[(R)-4-((S)-3-Tertidinoxycarbonylamino-3,4,5,6-tetrahydro-2H-[1,2']比。啶啶 -5 · · · · · ) ) ) 环 _1 _1 _1 ] ] ] h h h h h h h h h h h h h h h h h h h h h h h h (R)-2-cyclohexyl-4-[6-(4-isopropyl-succinyl-1 -yl). Ratio. D--3 - Styrene]-6-sideoxy-Brigade D Qin·1 -yl}-5-phenyl-σ-cetin- 2- formic acid/N~V α^8Η

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161 (R)-4-{5-[(R)-4-(2-叛基-5-苯基-11塞吩-3-基)-3-環己基-5-側氧基-β底唤-1-績醯基]_D比σ定-2-基}'-2-經曱基-哌嗪-1-甲酸第三丁酯 Λ y___κι /OH / 〇ο α^8Η 162 (S)-4-{5-[(R)-4-(2-致基-5-苯基-嘆吩-3·基)-3-¾己基-5-側氧基-哌嗪-1-磺醯基]-0比σ定·2-基甲基-α辰嗓-1-甲酸第二丁酯〇...... /-Λ 、 α^8Η 163 3-{(R)-2·^ 己基-4· [6-((R)-3-二曱胺基-°比°定-1 -基)-°比σ定-3-續酿基]-6-側氧基-娘嘻_1-基}-5-苯基-噻吩-2-甲酸 Q一ν>〇 o^VH 164 3-{(R)-2-環己基-4-[6-((2S,5R)-2,5-二甲基· °比鳴"-1 -基)-0比淀-3-續酿基]-6-側氧基-σ底嘻-l-基}-5_ 苯基-σ塞吩-2-甲酸〇一 /Ν^( 0^ι8Η 160983.doc 175- 201247656 165 3-{(R)-4-[6-((S)-3-第三丁氧羰基胺基-0比σ定-1 -基)-°比。定-3-磺醯基]-2-環己基-6-側氧基-娘σ秦- 1- 基}-5-苯基塞吩· 2- 曱酸〇一 /Ν~/ α^8Η 166 3-[2-環己基-6-側氧基_4-(甲苯-4-項醯基）-旅°秦-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸 / ° 167 3-{(R)-2-環己基-4-[6-((2R，6S)-2,6-二甲基-嗎琳-4-基)-°比咬-3-確酿基]-6-側氧基-旅唤-1-基}-5-苯基-噻吩-2-甲酸 q一 /η \ o^8h 168 3-[2-環己基-4-(6-嗎琳 -4-基-α比α定-3- <5^ 醯基)-6-側氧基-D底嗪-1-基]-5-(3,3-二曱基-丁-1-快基)-°塞吩-2-甲酸 1 0161 (R)-4-{5-[(R)-4-(2-Resyl-5-phenyl-11sophen-3-yl)-3-cyclohexyl-5-sideoxy-β -1- 醯醯 ] ] ] ] ] ] ] ] ] ] ] ] ] ] -2- 基基基基基基基基基基基基 α α α α α α α α α α α α α α α α α α α α α α 4-{5-[(R)-4-(2-amino-5-phenyl-thin-3-yl)-3-3⁄4-hexyl-5-oxo-piperazin-1-sulfonyl ]-0 ratio σ定·2-ylmethyl-αchen嗓-1-carboxylic acid second butyl ester 〇... /-Λ, α^8Η 163 3-{(R)-2·^ hexyl -4· [6-((R)-3-diaminol-° ratio °-1 -yl)-° ratio σ定-3-Continuous]-6-sideoxy-Nianxi _1 -yl}-5-phenyl-thiophene-2-carboxylic acid Q-ν>〇o^VH 164 3-{(R)-2-cyclohexyl-4-[6-((2S,5R)-2,5 -Dimethyl·° 比鸣"-1 -yl)-0-precipitate-3-continuation base]-6-sideoxy-σ bottom 嘻-l-yl}-5_phenyl-σ-phene- 2-carboxylic acid hydrazine Ν/Ν^( 0^ι8Η 160983.doc 175- 201247656 165 3-{(R)-4-[6-((S)-3-3 butyloxycarbonylamino-0 σ σ -1 -yl)-° ratio. D-sulfonyl]-2-cyclohexyl-6-sideoxy-Nangqi Qin-1-1-yl}-5-phenyl thiophene-2-pyruphate Ν//~/ α^8Η 166 3-[2-cyclohexyl-6-sideoxy_4-(toluene-4-ylindenyl)-branches-qin-1-yl] -5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-furic acid / ° 167 3-{(R)-2-cyclohexyl-4-[6-((2R, 6S)-2,6-Dimethyl-morphin-4-yl)-°Bite -3-Actaining Group]-6-Sideoxy-Behind-1-yl}-5-Phenyl-thiophene -2-carboxylic acid q-/η \ o^8h 168 3-[2-cyclohexyl-4-(6-morphin-4-yl-α ratio α定-3- <5^ fluorenyl)-6- oxo-D-piperidin-1-yl]-5-(3,3-dimercapto-but-1-yl)-°Cet-2-carboxylic acid 1 0

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169 0、产 Ν Ο^ΐ 170 3-{(R)-4-[5-氣-6-((R)-2-甲基-吡咯啶-1-基)-°比啶-3-磺醯基]-2-環己基-6-側氧基-派°秦-1-基}-5-苯基-噻吩-2-甲酸〇一 w >-V Cl α^8Η 171 3-{(R)-2-環己基-4· [6·(⑸-2·甲氧基曱基·σ比1?§^定-1-基)·ϋ比咬_3_續酿基]-6-側氧基底嘻-1-基}-5-苯基-α塞吩-2-曱酸 Q一^N；〇^18η 172 3-[(R)-2- ί哀己基-4_ (5_甲基-6-吡咯啶小基比淀-3-續酿基)-6-側氧基-旅嗓-1-基]-5-苯基塞吩-2-甲酸 0、° /=N q一 o^t8H 160983.doc •177· 201247656169 0, calving Ο^ΐ 170 3-{(R)-4-[5-gas-6-((R)-2-methyl-pyrrolidin-1-yl)-°pyridin-3-sulfonate Mercapto]-2-cyclohexyl-6-sideoxy-p-heptyl-1-yl}-5-phenyl-thiophene-2-carboxylic acid hydrazine-w >-V Cl α^8Η 171 3-{( R)-2-cyclohexyl-4·[6·((5)-2·methoxyindolyl·σ ratio 1?§^定-1-yl)·ϋ比 bite_3_continued base]-6-氧基嘻嘻嘻-1-yl}-5-phenyl-α-cephen-2-pyruic acid Q-^N; 〇^18η 172 3-[(R)-2- 哀己基 -4- -6-6-pyrrolidine small group than lake 3-n-butyl)-6-sideoxy-tour -1-yl]-5-phenylcephen-2-carboxylic acid 0, ° /= N q o^t8H 160983.doc •177· 201247656

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160983.doc 183- 201247656 190 3-[(R)-2-環己基-4-(4-甲氧基-苯磺醯基)-6-側氧基-派唤-1-基]-5-(3,3-二曱基-丁 -1-快基)-0塞吩-2-曱酸 / 0 191 3-[(R)-2-環己基-4- (6-甲氧基-σ比咬-3-續酿基)-6-側氧基_ 娘°秦-1-基]-5-(3,3-二曱基-丁-1-快基)-σ塞吩-2-曱酸 / ° 192 3-[(R)-2-環己基-6· 側氧基-4·( °比。定-3-酿基)-旅σ秦-1-基]-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-曱酸 ^^t8h / ° 193 3-[(R)-2-環己基-4-(1-曱基-1H-吡唑-3-確酿基)-6-側氧基_ 哌嘻-1-基]-5-(3,3-二曱基-丁-1-快基)-°塞吩-2-甲酸 0，s'VN、 (ΛfN) /N^ / 0160983.doc 183- 201247656 190 3-[(R)-2-Cyclohexyl-4-(4-methoxy-benzenesulfonyl)-6-o-oxy-p-but-1-yl]-5- (3,3-dimercapto-but-1-yl)-0-phene-2-indole/ 0 191 3-[(R)-2-cyclohexyl-4-(6-methoxy-σ More than bite-3-continuation base)-6-sideoxy _ 娘秦秦-1-yl]-5-(3,3-dimercapto-but-1-fastyl)-σ-cephen-2- Tannic acid / ° 192 3-[(R)-2-cyclohexyl-6· sideoxy-4·(° ratio. -3--3-aryl)-Brigade σ-qin-1-yl]-5-(3 ,3-dimethyl-but-1-ynyl)-thiophene-2-furoic acid^^t8h / ° 193 3-[(R)-2-cyclohexyl-4-(1-indolyl-1H-pyridyl) Carbazole-3-actained)-6-sideoxy-piperidin-1-yl]-5-(3,3-dimercapto-but-1-yl)-°cephen-2-carboxylic acid ,s'VN, (ΛfN) /N^ / 0

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160983.doc 187- 201247656 200 5-(4-氣-苯基）-3· [(R)-2-環己基-4-(6-[1，4]氧氮雜環庚烷-4-基-°比 °定-3 · 基)-6-側氧基-娘°秦_ 1-基]-σ塞吩-2-甲酸 0 0 °-s{ / 0 /-\ /~N 〈 ......〈〉 ^ /Η 201 5-(4-氣-苯基）-3_ {(R)-2-環己基-4·[6-((R)-2-曱基-吡咯啶-1 -基) °比σ定-3 -續酿基]-6-側氧基-娘。秦-1·基}-σ塞吩-2-甲酸 Ν」 0 〇彳。 cljy^r〇〇H 202 3-((R)-2-環己基-4-{6-[4-(4-曱基-哌嗪-1-美炭基)-苯基]_。比。定-3-續酿基}-6-側氧基-娘嗓-l-基)-5-苯基-噻吩-2-曱酸〇4 Q、160983.doc 187- 201247656 200 5-(4-Gas-phenyl)-3· [(R)-2-Cyclohexyl-4-(6-[1,4]oxazepan-4-yl -° ratio ° -3 · yl)-6-side oxy-Niang ° Qin _ 1-yl]-σ cephene-2-carboxylic acid 0 0 °-s{ / 0 /-\ /~N 〈.. ....< 〉 ^ /Η 201 5-(4-Gas-phenyl)-3_ {(R)-2-cyclohexyl-4·[6-((R)-2-indolyl-pyrrolidine- 1 - base) ° ratio σ -3 - continuation of the base] - 6 - side oxy - mother. Qin-1·yl}-σcephen-2-carboxylic acid Ν” 0 〇彳. Cljy^r〇〇H 202 3-((R)-2-cyclohexyl-4-{6-[4-(4-indolyl-piperazin-1-methanyl)-phenyl]-. Ding-3-continuation base}-6-sideoxy-N-嗓-l-yl)-5-phenyl-thiophene-2-furoate 〇4 Q,

160983.doc -188- 201247656 203 3-{(R)-2-環己基-4-[6-(4-二甲胺基-苯基)-。比。定-3-確酿基]-6-側氧基-派°秦-1 -基}-5·苯基噻吩_2_ 甲酸 /Ν^ί 〇^8η 204 3-[(R)-2-環己基-4-(4’-曱氧基-[2,3]聯 0比咬基_5 -確酿基)-6-側氧基-派唤-1-基]-5-苯基塞吩-2-甲酸 w Η °\ o^t8H 205 3-{(R)-2-環己基·4-[6-(2,4-二氟-苯基)-^比σ定-3- 酿基]-6_ 側氧基"略。秦-1-基}-5-苯基-噻吩-2-甲酸 α^ι8Η 206 3-[(R)-2-環己基-6-側氧基-4-(6-嘧啶-5-基-〇比〇定-3-橫酿基) 旅π秦基]-5-苯基-噻吩-2_甲酸〇、//〇/=， f 掌性〇..........Η'Ο'Ο Cr1^： 160983.doc -189- 201247656160983.doc -188- 201247656 203 3-{(R)-2-Cyclohexyl-4-[6-(4-dimethylamino-phenyl)-. ratio.定-3-正酿基]-6-Sideoxy-Phenyl-1 -yl}-5-phenylthiophene_2_carboxylic acid/Ν^ί 〇^8η 204 3-[(R)-2-ring Hexyl-4-(4'-decyloxy-[2,3]-linked 0-bite-based 5-5-acyl--6-o-oxy-p-but-1-yl]-5-phenyl phenan -2-carboxylic acid w Η °\ o^t8H 205 3-{(R)-2-cyclohexyl·4-[6-(2,4-difluoro-phenyl)-^ ratio σ定-3- ]-6_ Side oxy " slightly. Qin-1-yl}-5-phenyl-thiophene-2-carboxylic acid α^ι8Η 206 3-[(R)-2-cyclohexyl-6-sideoxy-4-(6-pyrimidin-5-yl- 〇比〇定-3-横酿基) 旅π秦基]-5-phenyl-thiophene-2_carboxylic acid 〇, / / 〇 / =, f palm 〇 .......... Η 'Ο'Ο Cr1^: 160983.doc -189- 201247656

207 3-[(R)-4-([2,4]聯吡啶基-5-磺醯基)-2-環己基-6-側氧基-娘嗪-1-基]-5·[(Ε)-((Ζ)-1-丙烯基)-丁-1，3-二烯基]-噻吩-2-甲酸 / λ a^t8H 208 3-{(R)-2-環己基-4-[6-(4-嗎啉-4-基甲基-苯基)-°比咬-3-績醯基]-6-側氧基-π底 °秦-1-基丨-5-苯基塞吩-2-曱酸對掌性 /η 209 3-{(R)-2-環己基-6-側氧基-4-[6-(2H-。比。坐-3-基)-。比咬-3-石黃酿基]-派唤-1-基}-5_ 苯基-噻吩-2-甲酸 °. /? /=rN \_y\ ) iT /Nn 210 3-{(R)-4-[6-(5-羧基- σ塞吩-2-基)-σ比。定-3_ 續酿基]-2-壤己基-6-側氧基-略。秦-1-基}-5-苯基-σ塞吩-2-曱酸 &H 160983.doc •190· 201247656 211 3-{(R)-2-環己基-4- [6-(2-曱基-。夫°南-3-基)-π比σ定-3-續酿基]-6-側氧基-旅嘻_ 1 _ 基}-5-苯基·σ塞吩-2-甲酸207 3-[(R)-4-([2,4]bipyridyl-5-sulfonyl)-2-cyclohexyl-6-sideoxy-anthazin-1-yl]-5·[( Ε)-((Ζ)-1-propenyl)-butyl-1,3-dienyl]-thiophene-2-carboxylic acid / λ a^t8H 208 3-{(R)-2-cyclohexyl-4- [6-(4-morpholin-4-ylmethyl-phenyl)-° ratio -3- 醯 ]]-6-side oxy-π bottom ° Qin-1-ylindole-5-phenyl Cefeno-2-decanoic acid to palmity / η 209 3-{(R)-2-cyclohexyl-6-sideoxy-4-[6-(2H-. ratio. sit-3-yl)-.比特-3-石黄基基]-派派-1-基}-5_ phenyl-thiophene-2-carboxylic acid °. /? /=rN \_y\ ) iT /Nn 210 3-{(R)- 4-[6-(5-carboxy- σ-cephen-2-yl)-σ ratio.定-3_ Continued Brewing]-2-Lichexyl-6-sideoxy-slightly. Qin-1-yl}-5-phenyl-σ-cephen-2-indole & H 160983.doc •190· 201247656 211 3-{(R)-2-cyclohexyl-4-[6-(2 -曱基-.夫南南-3-yl)-π ratio σ定-3-Continuous]-6-sideoxy-tour _ 1 _ yl}-5-phenyl·σ-sentene-2 -formic acid

212 3-{(11)-2-環己基-4- [6-(3,4-二氫-2Η-苯并[b][l，4]二氧呼-7-基)-α比咬-3-續酿基]-6-側氧基-派°秦-1-基}-5-苯基-噻吩-2-曱酸〇./? /=1212 3-{(11)-2-cyclohexyl-4-[6-(3,4-dihydro-2Η-benzo[b][l,4]dioxoheptin-7-yl)-α ratio bite -3-Continuously-branched]-6-sideoxy-pyryo-heptyl-1-yl}-5-phenyl-thiophene-2-furoate 〇./? /=1

213 3-{(R)-4-[6-(2-氰基- 苯基)-°比啶-3-磺醯基]-2-環己基-6-側氧基-派嗓-1-基}-5-苯基-噻吩-2-甲酸213 3-{(R)-4-[6-(2-Cyano-phenyl)-~pyridin-3-sulfonyl]-2-cyclohexyl-6-sideoxy-pyrene-1- -5-5-phenyl-thiophene-2-carboxylic acid

214 3-[(R)-4-([2,3’]聯吡。定基-5-續酿基)-2_ 壞己基-6-側乳基-略唤-1-基]-5-苯基-嗟吩-2-甲酸214 3-[(R)-4-([2,3']bipyridyl.Delimited-5-continuation)-2_D-hexyl-6-side-milk-Slightly-l-yl]-5-benzene G-porphin-2-carboxylic acid

160983.doc -191 - 201247656 215 3-[(R)-2-環己基-4-(6-環戍-1 -稀基-σ比咬-3 -績酿基)-6-側氧基·派σ秦-1-基]-5-苯基塞吩-2-甲酸〇、、//〇 /=Ν 216 3-{(R)-2-環己基-4-[6-(8-氧雜-3-氧雜-雙環[3.2.1]辛-3-基)-。比唆-3- 酿基]-6-側氧基-旅嗓-1-基}-5-苯基-噻吩-2-曱酸 ο^8η 217 3-{(R)-2-環己基-4-[6-(2_氧雜-5-氧雜-雙環[2·2·1]庚-5-基)-口比0定-3 -績酿基]-6-側氧基_娘嘻-1-基}_ 5-苯基-α塞吩-2-曱酸 Q一 Cr^i" 218 3-{(R)-2-環己基-4-[6-(2,2-二乙基-嗎 -4- )-口比口定-3 -酿基]-6-側氧基-派唤-1-基}-5-苯基-。塞吩-2-甲酸〇rf〇e /η 160983.doc -192- 201247656160983.doc -191 - 201247656 215 3-[(R)-2-Cyclohexyl-4-(6-cycloindole-1 - dilute-σ ratio bite-3 - distillyl)-6-sideoxy group σ 秦 -1- -1- 基 -5 -5 -5 、、、、, / / 〇 / = Ν 216 3-{(R)-2-cyclohexyl-4-[6-(8-oxygen Hetero-3-oxa-bicyclo[3.2.1]oct-3-yl)-.唆-3- aryl]-6-sideoxy-tour 嗓-1-yl}-5-phenyl-thiophene-2-furic acid ο^8η 217 3-{(R)-2-cyclohexyl- 4-[6-(2_oxa-5-oxa-bicyclo[2·2·1]hept-5-yl)-port ratio 0--3 -chita-based]-6-side oxy group嘻-1-yl}_ 5-phenyl-α-cephen-2-pyruic acid Q-Cr^i" 218 3-{(R)-2-cyclohexyl-4-[6-(2,2-di Ethyl-?-4-)-portylation--3-bristyl]-6-sideoxy-p-but-1-yl}-5-phenyl-. Cefeno-2-carboxylic acid 〇rf〇e /η 160983.doc -192- 201247656

219 3-{(R)-2-環己基-4-[6-(3,3-二甲基-吡咯口定 1 基)-α比咬_ ·3_石黃醯基]-6-側氧基-娘 π秦-1 -基卜5-苯基-σ塞吩-2-甲酸〇\、/? /= Ν / 220 3-(2-環己基-5-側氧基-D比洛咬-1-基)-5_ (3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸 ’ OH 221 3-[(R)-2-環己基-6-側氧基-4-(丙烧-2_ 續酿基)-娘嗓-l-基]-5-(3,3-二甲基·丁-1-炔基)-噻吩-2-曱酸厂 n，乂 \ \itn.....y \ / 0 222 3- {(R)-2-壞己基，4· [6-(1·甲基_1H-吡唑· 4- 基)-°比°定-3-續酿基]-6-側氧基-旅°秦- 1- 基}-5-苯基-σ塞吩- 2- 曱酸 °0 //° N 160983.doc -193- 201247656 223 3-[(R)-2-環己基-6-側氧基-4-(4-三氟曱氧基-苯磺醯基)-哌嗪-1-基]-5-(3,3-二甲基-丁-1-快基)-σ塞吩-2-曱酸 / 0 224 3-{(R)-2-環己基_4_ [6'-(4-甲基-哌嗪-1-基)-[2,3']聯吼啶基-5-磺醯基]-6-側氧基-旅嘻-l-基}-5-苯基-噻吩-2-曱酸 \ )〈 \ N \_____/ 〇^8h 225 3-{(R)-2-環己基-4-[6-((R)-3-甲基-嗎嚇 -4-基)-Dtb -3 -醯基]-6-側氧基-哌 σ秦-l-基}-5-苯基_嗟吩-2-甲酸 / λ 160983.doc •194· 201247656 226 5-(4-氯-苯基）-3- {(R)-2-環己基-4-[6-((R)-3-甲基-嗎啉-4-基)-11比°定-3-續酿基]_ 6-側氧基-派σ秦-1-基}-噻吩-2-甲酸219 3-{(R)-2-cyclohexyl-4-[6-(3,3-dimethyl-pyrrole 1 1)-α ratio bite_·3_石醯醯基]-6-sideoxy - Niang π Qin-1 - kib 5-phenyl-σ-cetin-2-carboxylic acid 〇\, /? /= Ν / 220 3-(2-cyclohexyl-5-sideoxy-D than 洛 bite - 1-yl)-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-furoic acid 'OH 221 3-[(R)-2-cyclohexyl-6-sideoxy- 4-(C-burn-2_ continuation)-N-嗓-l-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-furic acid plant n, 乂\ \itn.....y \ / 0 222 3- {(R)-2-Messyl, 4·[6-(1·methyl_1H-pyrazole·4-yl)-°°°- 3-Continuously-branched]-6-sideoxy-Big-Qin- 1-yl}-5-phenyl-σ-septene-2- 2-decanoic acid °0 //° N 160983.doc -193- 201247656 223 3 -[(R)-2-cyclohexyl-6-oxooxy-4-(4-trifluoromethoxy-phenylsulfonyl)-piperazin-1-yl]-5-(3,3-di Methyl-butan-1-yl)-σ-cephen-2-indole/ 0 224 3-{(R)-2-cyclohexyl_4_[6'-(4-methyl-piperazin-1- ))-[2,3'] hydrazinyl-5-sulfonyl]-6-sideoxy-tv-l-yl}-5-phenyl-thiophene-2-furic acid\) N \_____/ 〇^8h 225 3-{(R)-2-cyclohexyl-4-[6-((R)-3-methyl-)-4-yl)-Dtb-3-yl] -6 - oxo-piperidinyl-l-yl}-5-phenyl-porphin-2-carboxylic acid / λ 160983.doc •194· 201247656 226 5-(4-chloro-phenyl)-3- {( R)-2-cyclohexyl-4-[6-((R)-3-methyl-morpholin-4-yl)-11 ratio °-3-continuation base]_ 6-side oxy-group σQin-1-yl}-thiophene-2-carboxylic acid

227 5-(4-氣-苯基）-3- {(R)-2-環己基-4-[6-(8-氧雜-3-氧雜-雙環[3.2.1]辛-3-基)-。比咬-3 -續酿基]-6-側氧基-°底喚-1 _基} -α塞吩-2-甲酸227 5-(4-Gas-phenyl)-3-{(R)-2-cyclohexyl-4-[6-(8-oxa-3-oxa-bicyclo[3.2.1]oct-3- base)-. Than bite-3 - continuation of the base]-6-side oxy-- bottom base -1 _ yl} - alpha thiophene-2-carboxylic acid

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160983.doc -197- 201247656 234 5-(4-氣-苯基）-3- {(R)-2-環己基-4-[4-((R)-2-曱基-0比洛π定_ 1-基)-苯磺醯基]-6-側氧基-旅°秦-1-基}-噻吩-2-甲酸160983.doc -197- 201247656 234 5-(4-Gas-phenyl)-3-{(R)-2-cyclohexyl-4-[4-((R)-2-fluorenyl-0) _ 1-yl)-phenylsulfonyl]-6-sideoxy-branches-qin-1-yl}-thiophene-2-carboxylic acid

235 3-[(R)-2-環己基-6- 側氧基-4-(3，4,5,6-四氫-2H-[1,2']聯。比啶基-5^續酿基)-派°秦-1-基]-5-(4-氟-苯基)-°塞吩-2-甲酸235 3-[(R)-2-Cyclohexyl-6- oxo-4-(3,4,5,6-tetrahydro-2H-[1,2'] hydrazine. Stuffed base)-派派秦-1-yl]-5-(4-fluoro-phenyl)-°cephen-2-carboxylic acid

236 3-((R)-3-環己基-5- 側氧基-嗎琳-4-基)-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-甲酸236 3-((R)-3-Cyclohexyl-5-o-oxy-morphin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2- Formic acid

237 3-((4S，5R)-5-環己基-3,4-二曱基-2-側氧基-咪唾咬-1-基)-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-曱酸237 3-((4S,5R)-5-cyclohexyl-3,4-dimercapto-2-yloxy-imidapi-1-yl)-5-(3,3-dimethyl-butyl -1-ynyl)-thiophene-2-furic acid

OH 160983.doc -198- 201247656 238 3-[(R)-4-(4-氰基-苯磺醯基)-2-環己基-6-側氧基-a底D秦-1 -基]-5-(3,3-二甲基-丁-1-快基)-°塞吩-2-甲酸OH 160983.doc -198- 201247656 238 3-[(R)-4-(4-cyano-benzenesulfonyl)-2-cyclohexyl-6-sideoxy-a bottom D-methyl-1 -yl] -5-(3,3-dimethyl-butan-1-yl)-°Cet-2-carboxylic acid

239 3-[(R)-2-環己基-4-(3-敗-苯確酿基)·6· 側氧基·旅°桊-1_基]-5-(3,3-二曱基·丁-1-快基)-σ塞吩-2-曱酸239 3-[(R)-2-cyclohexyl-4-(3-a-benzoyl)·6· ethoxy group · 桊°桊-1_yl]-5-(3,3-diindole Base·but-1-fast base)-σ-cephen-2-pyruic acid

240 3-[(R)-2-環己基-4-(5-甲基-異噁哇-4-續酿基)-6-側氧基-哌嗪-1-基]-5-(3,3-二甲基丁-1-快基)-°塞吩-2-曱酸240 3-[(R)-2-cyclohexyl-4-(5-methyl-isoxan-4-yl)-6-o-oxy-piperazin-1-yl]-5-(3 ,3-dimethylbutan-1-free radical)-°cephen-2-pyruic acid

241 3- [CR)-2-環己基-6-側氧基-4-(1Η-吡唑- 4- 磺醯基)-哌嗪-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸241 3- [CR)-2-Cyclohexyl-6-oxooxy-4-(1Η-pyrazole-4-sulfonyl)-piperazin-1-yl]-5-(3,3-diindole Ke-but-1-ynyl)-thiophene-2-decanoic acid

160983.doc -199- 201247656 242 3-[(R)-4-(3-氣-苯磺醯基)-2-環己基-6-側氧基-派17秦-1-基]-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-甲酸〇.........rfxya /Ν-Λ / 0 243 3-[(R)-2-環己基-4-(4-氣-苯續酿基)-6-側氧基底σ秦-1-基]-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-曱酸 Ο-〇bl Ύ F / 0 244 3-[(R)-2-環己基-4-(2,4-二甲基-噻唑-5-磺醯基)-6-側氧基-哌嗪-1-基]-5-(3,3-二曱基丁-1-块基)-嗟吩-2-曱酸〇〇^Ν / 0 245 3-((R)-2-環己基-4-環丙烧確酿基-6-側氧基-派唤-1-基)-5-(3,3-二曱基-丁-1-快基)-噻吩-2-曱酸。、:C /νΎ / ° 160983.doc •200- 201247656160983.doc -199- 201247656 242 3-[(R)-4-(3-Gas-Benzenesulfonyl)-2-cyclohexyl-6-sideoxy-Phenyl-l-yl-1-yl]-5- (3,3-Dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid hydrazine.........rfxya /Ν-Λ / 0 243 3-[(R)-2-ring Hexyl-4-(4-carbo-benzoic)-6-hydroxyl- bottom σ-methyl-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2 - 曱曱〇〇 Ύ Ύ F / 0 244 3-[(R)-2-cyclohexyl-4-(2,4-dimethyl-thiazol-5-sulfonyl)-6-sideoxy- Piperazin-1-yl]-5-(3,3-dimercapto-1-yl)-porphin-2-indole 〇〇^Ν / 0 245 3-((R)-2- ring Hexyl-4-cyclopropanol-furanyl-6-o-oxy-p-but-1-yl)-5-(3,3-dimercapto-butan-1-yl)-thiophene-2-decanoic acid . ,: C /νΎ / ° 160983.doc •200- 201247656

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249 3-[(R)-2-環己基-6-側氧基-4-(2-三氟甲氧基-苯磺醯基)-哌嗪-1-基]-5-(3,3-二曱基-丁-1-快基)·嗟吩-2-甲酸 Lf 。、:F / 0 250 3-[(R)-2-環己基-6-側氧基-4-(4-三氟甲基-苯磺醯基)-哌嗪-1-基]-5-(3,3-二甲基-丁-1-快基)-σ塞吩-2-甲酸〇 f / ° 251 3-[(R)-2-環己基-4-(2,6-二氟-苯磺醯基)-6-側氧基-哌嗪-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸 Ο..........〇0 F249 3-[(R)-2-Cyclohexyl-6-oxooxy-4-(2-trifluoromethoxy-phenylsulfonyl)-piperazin-1-yl]-5-(3,3 - Dimercapto-but-1-propanyl) · porphin-2-carboxylic acid Lf. , F / 0 250 3-[(R)-2-cyclohexyl-6-oxooxy-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-5- (3,3-Dimethyl-butan-1-yl)-σ-ceto-2-carboxylic acid 〇f / ° 251 3-[(R)-2-cyclohexyl-4-(2,6-difluoro -Benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-decanoate hydrazine... .......〇0 F

160983.doc •202· 201247656 252 3_[(R>)-2-壞己基-6· 側氧基-4-(2-側氧基-2,3-二鼠-苯并σ惡 α坐-5-續醯基)-旅嗓-1-基]-5-(3,3_ 二甲基-丁 _ 1 -快基)-σ塞吩_2_ 曱酸160983.doc •202· 201247656 252 3_[(R>)-2-Deterylhexyl-6·Sideoxy-4-(2-Sideoxy-2,3-dimur-benzo oxime α sitting-5 -Continued 醯基)-旅嗓-1-yl]-5-(3,3_ dimethyl-but-1- 1 -fast-based)-σ-septene_2_ decanoic acid

'8η ίΗ'8η ίΗ

253 3-[(R)-2-環己基-4-(4-甲基胺甲醯基-苯確酿基)-6-側氧基-哌嗪-1-基]-5-(3,3·二曱基-丁-1-炔基)-噻吩-2-甲酸253 3-[(R)-2-Cyclohexyl-4-(4-methylaminomethylindolyl-phenyl-carboxyl)-6-yloxy-piperazin-1-yl]-5-(3, 3·Dimercapto-but-1-ynyl)-thiophene-2-carboxylic acid

254 3-[(R)-2-環己基-4-(2-曱基-2H-吡唑-3-磺醯基)-6-側氧基-娘0秦-1-基]-5-(3,3-二曱基-丁 _1_快基)_0塞吩-2-曱酸〇、.〇254 3-[(R)-2-Cyclohexyl-4-(2-indolyl-2H-pyrazole-3-sulfonyl)-6-sideoxy-Nion 0 Qin-1-yl]-5- (3,3-dimercapto-but_1_fast group)_0cephen-2-pyruic acid 〇,.〇

255 3-[(R)-2-環己基-4-(2,3-二甲基-3H-咪唑-4-磺醯基)-6-側氧基-派°秦-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸255 3-[(R)-2-Cyclohexyl-4-(2,3-dimethyl-3H-imidazole-4-sulfonyl)-6-o-oxy-p-qin-1-yl]- 5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-furic acid

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160983.doc -205 - 201247656 263 3-[(R)-2-環己基-4-(3-曱基-苯曱基)-6-側氧基-派嗓_1_基]-5-苯基-噻吩-2-甲酸 /λ 264 3-[(R)-2-環己基-4-(2,6-二甲基-苯甲基)-6-側氧基-旅嘻- 1- 基]-5-苯基-°塞吩- 2- 曱酸 ο一 /ΝΎ 265 3-((R)-2-環己基-4-環己基曱基-6-側氧基-旅σ秦-1-基)-5-苯基-噻吩-2-曱酸 r~^i160983.doc -205 - 201247656 263 3-[(R)-2-Cyclohexyl-4-(3-indolyl-phenylhydrazino)-6-yloxy-pyrene-1-yl]-5-benzene -thiophene-2-carboxylic acid/λ 264 3-[(R)-2-cyclohexyl-4-(2,6-dimethyl-benzyl)-6-sideoxy-tv- 1-yl ]-5-Phenyl-°Cerve- 2- citric acid ο-/ΝΎ 265 3-((R)-2-cyclohexyl-4-cyclohexylfluorenyl-6-sideoxy-Brigade Sigma-1 -yl)-5-phenyl-thiophene-2-furoic acid r~^i

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160983.doc •209· 201247656 274 5-(4-氣-苯基）-3-{(R)-2-環己基-4-[(1艮411)-6-(2-氧雜-5-氧雜-雙環[2.2.1] 庚-5-基)-D比咬項· 醯基]-6-側氧基底嗓-l-基}-售吩-2-甲酸 Η Η p °^s{ 厂N ( >n"......< y w 275 3-[(R)-2-環己基-4-(1-乙基-1H-吡唑-4-續酿基)-6-側氧基-哌嗪-1-基]-5_(3,3-二曱基-丁-1-快基)-°塞吩-2-甲酸 /\ /N/ \=N \ ^Ίΐιι,,,,ν^ \ 276 3-[(R)-2-環己基-4-(2-氟-4,5-二曱氧基-苯磺醯基)-6-側氧基-派°秦-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-甲酸 O-rj 十 /N^( \160983.doc •209· 201247656 274 5-(4-Gas-phenyl)-3-{(R)-2-cyclohexyl-4-[(1艮411)-6-(2-oxa-5- Oxa-bicyclo[2.2.1]hept-5-yl)-D ratio bite thiol]-6-side oxy thiol-l-yl}- phenyl-2-carboxylic acid Η ° p °^s{ Plant N ( >n"......< yw 275 3-[(R)-2-cyclohexyl-4-(1-ethyl-1H-pyrazole-4-continuation)-6 -Phenoxy-piperazin-1-yl]-5-(3,3-dimercapto-but-1-yl)-°Cet-2-carboxylic acid/\ /N/ \=N \ ^Ίΐιι, ,,,ν^ \276 3-[(R)-2-Cyclohexyl-4-(2-fluoro-4,5-didecyloxy-phenylsulfonyl)-6-sideoxy-group -1-yl]-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-carboxylic acid O-rj 十/N^( \

160983.doc •210· 201247656 277 3-[(R)-2-環己基-4-(3,4-二甲氧基-苯續醯基)-6-側氧基-派嗪-1-基]-5-(3,3-二甲基-丁-1-快基)-11 塞吩-2-曱酸〇Q T°" / ° 278 3-{(R)-2-環己基-4-[6-((2R，6S)-2,6-二甲基-嗎嚇·_4-基)-°比变-3-磺醯基]-6-側氧基-哌嗪-1-基}-5-(4-敗-苯基)-噻吩-2-甲酸 0 〈〉"l......./ 〉160983.doc •210· 201247656 277 3-[(R)-2-Cyclohexyl-4-(3,4-dimethoxy-benzoindolyl)-6-o-oxy-pyrazine-1-yl ]-5-(3,3-dimethyl-butan-1-yl)-11 phene-2-pyrucate 〇QT°" / ° 278 3-{(R)-2-cyclohexyl-4 -[6-((2R,6S)-2,6-dimethyl-infrared _4-yl)-° ratio -3-sulfonyl]-6-oxo-piperazin-1-yl }-5-(4-Any-phenyl)-thiophene-2-carboxylic acid 0 〉"l......./ 〉

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160983.doc .225 - 201247656 316 3-[6-環己基-3-(1-經基-乙基)-2-側氧基-哌啶-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸160983.doc .225 - 201247656 316 3-[6-Cyclohexyl-3-(1-carbyl-ethyl)-2-yloxy-piperidin-1-yl]-5-(3,3-di Mercapto-but-1-ynyl)-thiophene-2-decanoic acid

OH 317 3-(6-環己基-3-羥基- 2-側氧基_派°定-1 -基)-5-對甲苯基-噻吩-2-曱酸OH 317 3-(6-cyclohexyl-3-hydroxy-2-one-oxyl-p-decyl-1 -yl)-5-p-tolyl-thiophene-2-furic acid

318 3-[(2S，5R)-5-環己基-2-(3-羥基-3-甲基-丁基)-2-甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-甲酸318 3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-o-oxy-morphin-4-yl]- 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid

319 3-[(2R，5R)-5-環己基-2-(3-經基-3-曱基-丁基)-2-甲基-3-側氧基_嗎琳_4_基]-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-甲酸319 3-[(2R,5R)-5-Cyclohexyl-2-(3-carbyl-3-indolyl-butyl)-2-methyl-3-oxooxy-[Merline_4_yl] -5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid

160983.doc 226- 201247656 320 3-[(2S,5R)-5-環己基-2-((R)-3-羥基-丁基)-2-甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁小炔基)-噻吩-2-曱酸 /\ 厂0 '、、、 \ )"*.......y V·'、、、' /Ν~~^ ^-Γ""ΟΗ 321 3-[(2R，5R)-5-環己基-2-((R)-3 -經基-丁基)-2-曱基-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁小炔基)-噻吩-2-曱酸 \__/ \ /\ / ~~^ '-r,MI OH 322 3-((3S，6S)-6-環己基-3-經基-2-側氧基-娘淀-1-基）-5-(3,3-二甲基-丁-1-炔基)-噻吩-2-曱酸 .......on w /Η 323 3-[(2R,5R)-5-環己基-2·(2-經基-乙基)_ 2-曱基-3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁-1-快基)-°塞吩-2-甲酸 160983.doc 227- 201247656 324 3-(6-環己基-3-羥基- 3-曱基-2-側氧基-哌啶-1-基)-5-對甲苯基-噻吩-2-甲酸160983.doc 226- 201247656 320 3-[(2S,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo------- 4-yl]-5-(3,3-dimethyl-butyrynyl)-thiophene-2-furic acid/\厂0 ',,, \ )"*.......y V · ',,, ' /Ν~~^ ^-Γ""ΟΗ 321 3-[(2R,5R)-5-cyclohexyl-2-((R)-3-yl-butyl-butyl)-2 -mercapto-3-epoxy-morphin-4-yl]-5-(3,3-dimercapto-butyrynyl)-thiophene-2-furic acid\__/ \ /\ / ~~ ^ '-r,MI OH 322 3-((3S,6S)-6-cyclohexyl-3-yl-2-yloxy-Nanyl-1-yl)-5-(3,3-dimethyl -but-1-ynyl)-thiophene-2-decanoic acid.......on w /Η 323 3-[(2R,5R)-5-cyclohexyl-2·(2-peramino- Ethyl) 2-nonyl-3-sided oxy-morpholin-4-yl]-5-(3,3-dimercapto-but-1-yl)-°Cet-2-carboxylic acid 160983 .doc 227- 201247656 324 3-(6-Cyclohexyl-3-hydroxy-3-hydroxy-3-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic acid

325 3-((R)-3-環己基-5- 側氧基-1,9-二氧雜-4-氧雜-螺[5.5]十一碳-4-基)·5-(3,3-二甲基-丁-1-快基)-。塞吩-2-曱酸325 3-((R)-3-Cyclohexyl-5- pendantoxy-1,9-dioxa-4-oxa-spiro[5.5]undec-4-yl)·5-(3, 3-dimethyl-butan-1-yl)-. Cephen-2-pyruic acid

326 3-[(2S，5R)-5-環己基-2-(2,3·二羥基-丙基)-2·甲基-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁-1·快基)-噻吩-2-曱酸326 3-[(2S,5R)-5-Cyclohexyl-2-(2,3·dihydroxy-propyl)-2·methyl-3-o-oxy-morphin-4-yl]-5- (3,3-dimethyl-but-1-yl)-thiophene-2-furoic acid

327 3-[(2S，5R)-5-環己基-2-(2,3·二羥基-丙基)·2-曱基-3-側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁-1-快基)-噻吩-2-曱酸327 3-[(2S,5R)-5-Cyclohexyl-2-(2,3·dihydroxy-propyl)·2-indolyl-3-yloxy-morphin-4-yl]-5- (3,3-dimethyl-butan-1-yl)-thiophene-2-decanoic acid

160983.doc -228· 201247656 328 3-[(2S，5R)-5-環己基-2-(2-經基-乙基)_ 2-曱基-3-側氧基-嗎啉 _4_ 基]-5-(3,3-二甲基-丁-1-快基)-0塞吩-2-曱酸 329 3-((R)-5-環己基-2-羥曱基-3-側氧基-嗎琳-4-基)_5-(3,3·二曱基-丁-1-快基)-σ塞吩-2-曱酸人N人 JL 〇H 〇 / 330 3-[(2R，5R)-5-環己基-2-(2,3-二經基-丙基)-2-曱基-3-側氧基-嗎啉_4_基]-5-(3,3-二甲基-丁-1-快基)-噻吩-2-曱酸 \______/ \ Γ...…，\ OH /N^{ w 331 3- [(2S,5R)-5-環己基-2-(2,3-二輕基-丙基)-3-側氧基_嗎琳_ 4- 基]-5-(3,3-二甲基-丁 -1 -快基)-σ塞吩-2-曱酸 160983.doc -229- 201247656160983.doc -228· 201247656 328 3-[(2S,5R)-5-Cyclohexyl-2-(2-trans-ethyl)-2-indolyl-3-yloxy-morpholine_4_yl ]-5-(3,3-dimethyl-butan-1-yl)-0-cephen-2-pyruic acid 329 3-((R)-5-cyclohexyl-2-hydroxydecyl-3- Side oxy-morphine-4-yl)_5-(3,3·didecyl-but-1-yl)-σ-cephen-2-indole human N-person JL 〇H 〇/ 330 3-[ (2R,5R)-5-cyclohexyl-2-(2,3-di-propyl-propyl)-2-indolyl-3-yloxy-morpholine-4-yl]-5-(3, 3-dimethyl-butan-1-yl)-thiophene-2-furic acid\______/ \ Γ..., \ OH /N^{ w 331 3- [(2S,5R)-5-ring Hexyl-2-(2,3-diheptyl-propyl)-3-oxo-[Merlin-4-yl]-5-(3,3-dimethyl-butan-1-propanyl)- σ塞斯特-2-曱酸160983.doc -229- 201247656

332 3-[(2S,5R)-5-環己基-2-(2-經基-乙基)-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁-1-快基)-σ塞吩-2-甲酸厂0\ η 333 3-[(R)-5-環己基-2,2-雙(2-經基-乙基)-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸 ^^s^T〇〇H 334 3-((3R,6S)-6-環己基-3-經基-2-側氧基-略σ定-1-基）-5-(3,3-二甲基·丁-1-炔基)-噻吩-2-甲酸 / \..........^ OH wi /V。 335 3-((S)-2-環己基-7-側氧基-氮雜環庚烧-1-基)-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-甲酸 oQ332 3-[(2S,5R)-5-Cyclohexyl-2-(2-carbyl-ethyl)-3-yloxy-morphin-4-yl]-5-(3,3-diindole Base-but-1-propanyl)-σ-cephen-2-carboxylic acid plant 0\ η 333 3-[(R)-5-cyclohexyl-2,2-bis(2-carbyl-ethyl)-3 -Sideoxy-morphin-4-yl]-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-furic acid^^s^T〇〇H 334 3-( (3R,6S)-6-cyclohexyl-3-yl-2-yloxy-slightly sigma-1-yl)-5-(3,3-dimethyl-but-1-ynyl)- Thiophene-2-carboxylic acid / \..........^ OH wi /V. 335 3-((S)-2-cyclohexyl-7-sideoxy-azepane-1-yl)-5-(3,3-dimercapto-but-1-ynyl)-thiophene -2-carboxylic acid oQ

160983.doc 230· 201247656 336 3-[(2R,5R)-5-環己基-2-((R)_2-經基-丙基)-3-側氧基-嗎嚇 4·基]-5-(3,3·二甲基-丁 _1，快基)-嗟吩-2-曱酸 /λ /—〇 Η \/ \ /…\ _/ \\ /”"…OH 337 3- [(2R，5R)-5-環己基-2-((S)-2-羥基-丙基側氧基-嗎嚇- 4- 基]-5_(3,3-二甲基-丁-1-快基)-σ塞吩-2-曱酸 /~~Λ /—0 Η \_/ \ /………\ /N V-OH 338 3-[(2S，5R)-5-環己基-2-(4-經基-丁基)-3-側氧基-嗎淋-4-基]-5-(3,3-二甲基-丁 -1·快基)_σ塞吩_2_ 曱酸 /~~~\ /—0 Η 339 3-[(S)-6-環己基-3-(3-經基-丙基)-2-側氧基-旅σ定-1-基]-5-(3,3-二曱基-丁-1-炔基)-噻吩-2-曱酸〇Η 340 3-((S)-3-胺基-6-環己基-2-側氧基·派。定-1_ 基)_5-(3,3-二曱基-丁-1-快基)-養吩-2-曱酸〈〉〈 V-nh2 w /Η 160983.doc 231 · 201247656 341 3-[(S)-6-環己基-3-(3-羥基-丙基)-2-側氧基-哌啶-1-基]-5-(3,3-二甲基-丁-1-炔基)-嘆吩-2-甲酸〇H 342 3-[(S)-6-環己基-3-(2-羥基-乙基)-2-側氧基-。底咬-丨-基]-5-(3,3-二甲基-丁小炔基)-噻吩-2-甲酸 343 3-[(S)-6-環己基-3-(2-羥基-乙基)-2-側氧基-略咬-1-基]-5-(3,3·二甲基-丁小炔基)-β塞吩-2-甲酸表2提供某些本發明化合物之NMR資料。表2 化合物編號 NMR資料 1 'H-NMR (400 MHz, CD3OD): δ 7.80 (d, 2H), 7.40 (t, 2H), 7.29 (t, 1H), 7.18 (s, 1H), 4.62 (m, 1H), 2.30 (m, 2H), 2.03 (m, 1H), 1.80-1.10 (m, 12H) 2 'H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.13 (m, 1H), 3.90 (m, 1H), 3,82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m，6H)。 3 *H-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 2.02-1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m，6H)。 160983.doc •232· 201247656 化合物編號 NMR資料 4 'H-NMR (400 MHz, CDC13)： δ 7.43 (m, 2H), 7.21 (m, 3H), 6.94 (m, 1H), 3.68 (m, 1H), 2.45 (m, 2H), 2.21 (m, 1H), 1.83-1.51 (m, 12H), 1.32 (m, 2H) 〇 5 1H NMR (400 MHz, CDC13)： δ 0.88-1.12 (m, 5H), 1.29 (m, 2H), 1.37 (s, 3H), 1.48-1.60 (m, 2H), 1.71 (m, 2H), 1.84 (m, 2H), 1.96 (m, 1H), 2.12 (m, 1H), 2.29 (s, 3H), 3.72 (m, 1H), 6.93 (s, 1H), 7.11 (d, 2H), 7.39 (d, 2H) 6 'H-NMR (400 MHz, DMSO-d6): δ 13.1 (s, 1H), 7.75 (d, 2H), 7.58 (s, 1H), 7.37-7.52 (m, 3H), 4.21 (m, 1H), 2.34 (m, 2H), 2.09 (m, 1H), 1.91 (m, 1H)，1.36-1.79 (m，5H)，0.91-1.31 (m，6H)。 7 ^-NMR (400 MHz, CD3OD): δ 6.93 (s} 1H), 4.12 (d, 1H), 3.91 (d, 1H), 3.66 (s, 1H), 3.54 (t, 2H), 2.14 (m, 1H), 1.91 (m, 1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H), 1.06-1.37 (m, 14H) 8 ^-NMR (400 MHz, CD3OD): δ 6.90 (s5 1H), 4.24 (tert, 1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d, 1H), 3.71 (d, 1H), 3.66 (t, 1H), 2.21 (m，lH)，1.41-1.98 (m, 8H), 1.05-1.37 (m，15H)。 10 !H-NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H), 7.32-7.45 (m, 6H), 7.28 (t, 3H), 7.20 (t, 1H), 5.45 (m, 1H), 2.52-2.63 (m, 3H), 1.89 (m, 1H)。 11 !H-NMR (400 MHz, CD3OD): δ 6.89 (s, 1H), 3.94 (m, 1H), 3.58 (m, 2H), 2.05 (m, 1H), 1.92-1.39 (m, 13H), 1.32 (s, 9H), 1.25-1.13 (m, 5H) 13 ^-NMR (400 MHz, CDC13)： δ 7.56 (d, 2H), 7.35 (m, 3H), 7.12 (s, 1H), 4.26 (tert, 2H), 3.98 (m, 2H), 3.60 (s, 1H), 0.94-1.93 (m, 11H) 18 ^-NMR (400 MHz, CD3OD): δ 7.74 (d, 2H), 7.65 (d, 2H), 7.49 (d, 2H), 7.41 (t, 2H), 7.33 (t, 1H), 7.21 (s, 1H), 4.12 (d, 1H), 3.95 (d, 1H), 3.93 (s, 1H), 3.37 (d, 1H), 3.02 (tert, 1H), 2.47 (s, 3H), 1.41-1.99 (m, 7H), 1.05-1.32 (m, 4H) 22 ^-NMR (400 MHz, DMSO): δ 10.31 (d, 1H), 7.63 (d, 2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98 (m, 3H), 4.61 (m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20 (m, 1H), 1.88-1.76 (m, 4H), 1.65-1.58 (m, 2H), 1.41-1.05 (m} 6H) 160983.doc •233 · 201247656 化合物編號 NMR資料 23 'H-NMR (400 MHz, DMSO): δ 8.55 (m, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.32 (t, 2H), 7.15 (s, 1H), 5.76 (s, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.33 (m, 2H), 2.07 (m, 1H), 1.80 (m, 2H), 1.61 (m, 3H), 1.38 (m, 2H), 1.03 (ms 5H) 35 'H-NMR (400 MHz, CD3OD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25 (m, 1H), 1.88-1.38 (m, 6H), 1.29 (s, 9H), 1.18 (m, 4H), 1.06 (m, 4H) 62 ^-NMR (400 MHz, CD3OD): δ 7.82 (d, 1H), 7.68 (d, 2H), 7.44 (m, 3H), 7.36 (s, 1H), 6.78 (d, 1H), 4.16 (d, 1H), 4.02 (s, 3H), 3.94 (d, 1H), 3.81 (s, 1H), 3.65 (d, 1H), 3.18 (tert, 1H), 2.00 (d, 1H), 1.36-1.87 (m, 6H), 1.05-1.29 (m, 4H) 135 'H-NMR (400 MHz, CD3OD): δ 8.47 (d, 1H), 7.85 (tert, 1H), 7.64 (d, 2H), 7.43 (t, 2H), 7.30 (m, 2H), 6.61 (d, 1H), 3.94 (s, 1H), 3.88 (d, 1H), 3.74 (d, 1H), 2.81-3.24 (m, 6H), 1.49-2.06 (m, 8H), 0.98-1.35 (m, 7H) 184 *H-NMR (400 MHz, CD3OD): δ 8.51 (d, 1H), 7.86 (tert, 1H), 7.64 (d, 2H), 7.41 (t, 2H), 7.32 (t, 1H), 7.19 (s, 1H), 7.91 (d, 1H), 4.10 (d, 1H), 3.96 (s, 1H), 3.89 (d, 1H), 3.65-3.81 (m, 8H), 3.41 (d, 1H), 3.06 (d, 1H), 1.37-1.98 (m, 8H), 1.03-1.26 (m, 3H) 185 1H NMR (400 MHz, CDC13)： δ 1.03 (m, 3H), 1.15 (d, 3H), 1.30 (m, 1H), 1.43 (m, 2H), 1.58 (m, 2H), 1.63 (m, 1H), 1.7-1.8 (m, 2H), 1.9 (d, 1H), 1.95-2.10 (m, 3H), 2.96 (d, 1H), 3.33 (d, 2H), 3.60 (s, 1H), 3.75 (s, 1H), 3.81 (d, 1H), 4.05 (s, 1H), 4.20 (d, 1H), 6.37 (d, 1H), 7.02-7.05 (m, 3H), 7.50-7.54 (m, 2H), 7.66 (m, 1H), 8.38 (s, 1H) 193 'H-NMR (400 MHz, CD3OD): δ 7.80 (d, 1H), 6.95 (s5 1H), 6.75 (d, 1H), 4.14 (d, 1H), 3.93 (d, 1H), 3.64 (d, 1H), 3.16 (m, 1H), 2.30 (m, 2H), 1.90 (m, 1H), 1.83 (m, 3H), 1.69 (m, 2H), 1.58 (t, 3H), 1.47 (m, 2H), 1.31 (s, 9H), 1.18 (m,4H) 196 1H NMR (400 MHz, CDC13)： δ 0.95-1.15 (m, 4H), 1.20 (m, 1H), 1.30-1.40 (m, 1H), 1.47 (m, 1H), 1.57 (m, 2H), 1.66 (s, 1H), 1.70-1.85 (m, 3H), 1.85-1.95 (m, 2H), 3.03 (m, 1H), 3.18 (d, 2H), 3.43 (d, 1H), 3.69 (s, 1H), 3.75-3.90 (m, 3H), 4.10 (d, 1H), 4.45 (s, 2H), 6.51 (d, 1H), 7.00-7.10 (m, 3H), 7.49 (m, 2H), 7.70 (m, 1H), 8.46 (s, 1H) 160983.doc •234· 201247656 化合物編號 NMR資料 200 1HNMR (400 MHz, CDC13)： δ 0.90-1.15 (m, 5H), 1.40-1.60 (m, 3H), 1.60-1.85 (m, 3H), 1.95 (m, 2H), 3.20 (d, 1H), 3.55 (d, 2H), 3.68 (m, 2H), 3.70-3.85 (m, 6H), 3.85-3.95 (m, 2H)} 6.48 (d, 1H), 7.02 (s, 1H), 7.27 (d, 2H), 7.42 (d, 2H), 7.67 (d5lH), 8.43 (d, 1H) 236 'H-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.19 (s, 2H), 4.05 (m, 2H), 3.82 (s, 1H), 1.43-1.90 (m, 6H), 1.06-1.39 (m, 14H) 、 279 lHNMR(400MHz, CDC13)： δ 0.93-1.15 (m, 4H), 1.29-1.39(m, 1H), 1.45 (m, 1H), 1.50-1.60 (m, 2H), 1.65 (m, 1H), 1.70-1.80 (d, 1H), 1.80-1.90 (d, 1H), 1.90-2.10 (m, 4H), 3.05 (d, 1H), 3.20 (m, 1H), 3.27 (s, 3H), 3.30 (m, 1H), 3.36-3.53 (m, 3H), 3.61-3.74 (m, 2H), 4.06 (d, 1H), 6.42 (s, 1H), 6.99-7.07 (m, 3H), 7.48 (m, 2H), 7.64 (d, 1H), 8.42 (s, 1H) 295 1H NMR (400 MHz, CDC13)： δ 0.96-1.14 (m, 4H), 1.32-1.44 (m, 1H), 1.48 (m, 1H), 1.57 (m, 2H), 1.67 (m, 1H), 1.76 (d, 1H), 1.83 (d, 1H), 2.30 (s, 3H), 2.98 (d, 1H), 3.40 (d, 1H), 3.67 (m, 1H), 3.79 (d, 1H), 3.91 (s} 3H), 4.10 (d, 1H), 7.06 (s, 1H), 7.15 (d, 2H), 7.42 (d, 2H), 7.71 (s, 1H), 7.75 (s, 1H) 302 1H NMR (400 MHz, CDC13): δ 0.97-1.15 (m, 4H), 1.27 (m, 1H), 1.47-1.64 (m, 3H), 1.68 (m, 1H), 1.76 (d, 1H), 1.84 (d, 1H), 2.28 (s, 3H), 2.73 (s, 3H), 3.31 (d, 1H), 3.52 (d, 1H), 3.71 (m, 1H), 3.85 (d, 1H), 4.14 (d, 1H), 7.06 (s, 1H), 7.12 (d, 1H), 7.40 (d, 2H), 7.45 (d, lH),8.13(d, 1H), 8.98 (s, 1H) 311 !H-NMR (400 MHz, CD3OD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H) 314 1HNMR(400 MHz, CDC13):50.94-1.13 (m，4H), 1.26 (m, 1H)，1.38 (m, 1H), 1.43 (s, 3H), 1.45 (s, 3H), 1.47-1.59 (m, 2H), 1.62 (m, 1H), 1.74 (d, 1H), 1.87 (d, 1H), 2.29 (s, 3H), 3.45 (m, 1H), 3.84 (d, 1H), 4.09 (d, 1H), 7.02 (s, 1H), 7.12 (d, 2H), 7.42 (d, 2H) 316 !H-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.23 (m, 1H), 3.80 (m, 1H), 2.49 (m, 1H), 2.06-1.42 (m, 10H), 1.32 (s, 9H), 1.22 (d, 3H), 1.12 (m，5H)。 160983.doc •235 · 201247656 化合物編號 NMR資料 318 ]H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1Η), 4.11 (d, 1H), 3.92 (d, 1H), 3.62 (m, 1H), 2.17 (m, 1H), 1.93 (m,lH), 1.62-1.85 (m, 4H), 1.45-1.62 (m, 4H), 1.37-1.44 (m, 3H), 1.27-1.37 (m, 10H), 1.11-1.27 (m, 10H) 319 !H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.18 (d, 1H), 3.94 (d, 1H), 3.53 (m, 1H), 2.17 (t, 1H), 1.95 (m,2H), 1.70-1.86 (m, 4H), 1.58-1.69 (m, 2H), 1.46-1.58 (m, 2H), 1.39-1.46 (m, 3H), 1.29-1.39 (m, 10H), 1.10-1.29 (m, 10H) 322 ^-NMR (400 MHz, CD3OD): δ 6.95 (s5 1H)S 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 323 *H-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.24 (tert, 1H), 3.93 (d, 1H), 3.62-3.82 (m, 3H), 2.08-2.21 (m, 1H), 1.88-2.04 (m, 2H), 1.56-1.87 (m, 4H), 1.43-1.56 (m, 4H), 0.98-1.35 (m, 14H) 324 1H NMR (400 MHz, CDC13): δ 0.88-1.13 (m} 4H), 1.32 (m, 2H), 1.43 (s, 3H), 1.48-1.67 (m, 3H), 1.69-1.87 (m, 4H), 1.96 (m, 1H), 2.06 (m, 1H)，2.31 (s，3H)，3.67 (m, 1H), 7.08 (s，1H)，7.15 (d，2H)，7.44 (d， 2H) 325 1H NMR (400 MHz, CDC13): δ 0.96-1.19 (m, 5H), 1.23 (s, 9H), 1.37 (m, 1H), 1.45 (m, 1H), 1.61 (m, 2H), 1.64-1.81 (m, 4H), 1.83 (m, 1H), 2.22 (m, 1H), 3.37 3.57-3.78 (m, 4H), 3.89 (d, 1H), 3.98 (d, 1H), 6.79 (s, 1H) 326 'H-NMR (400 MHz, CD3OD): δ 6.78 (s, 1H), 4.07 (m, 1H), 3.53 (m, 2H), 2.26 (m，1H)，1.96-1.38 (m，14H)，1.30 (s，9H)，1.14 (m，5H)。 328 ^-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.14 (tert, 1H), 3.92 (tert, 1H), 3.77 (d, 1H), 3.70 (t, 2H), 2.32 (m, 1H), 1.82-1.99 (m, 2H), 1.71-1.82 (m, 2H), 1.66 (m, 1H), 1.41-1.59 (m, 5H), 1.03-1.34 (m, 14H) 334 'H-NMR (400 MHz, CD3OD): δ 6.95 (s, 1H), 4.08 (m, 1H), 3.74 (m, 1H), 2.18 (m, 1H), 1.94-1.67 (m, 8H), 1.42 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 160983.doc -236- 201247656 化合物編號 NMR資料 336 NMR (400 MHz, CD3OD): δ 1.09-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.85 (m, 5H), 1.89-2.10 (m, 3H), 3.56-3.61 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.10 (m, 1H), 4.12-4.22 (m, 2H), 6.99 (s, 1H) 337 'H NMR (400 MHz, CD3OD): δ 1.07-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.60 (m, 2H), 1.63-1.85 (m, 4H)S 1.87-1.98 (m, 1H), 2.02-2.11 (m, 1H), 3.60-3.66 (m, 1H), 3.93-4.03 (m, 2H), 4.15 (d, 1H), 4.26-4.35 (m, 1H), 6.94 (s, 1H) 340 ^-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H)，1.31 (s，9H), 1.16 (m，5H) 341 'H-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82-1.64 (m, 7H), 1.58 (m, 2H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H) 343 !H-NMR (400 MHZ, CD3OD): δ 6.85 (s, 1H), 3.92 (br, 1H), 3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.78 (m, 7H), 1.37 (m, 2H), 1.31 (s，9H)，1.14 (m，5H)。生物學實例生物學實例1.抗c型肝炎活性化合物可藉由抑制HCV聚合酶、藉由抑制複製循環中所需之其他酶或藉由其他路徑來顯示抗C型肝炎活性。許多可用以評估此等活性之分析法已公開。頒予Miles等人之美國專利第5,738,985號揭示評估培養物中HCV病毒之總增量的通用方法。活體外分析法已報導於Ferrari等人，J>?/. of Vir., 73:1649-1654，1999 ; Ishii 等人， 29:1227-1235，1999 ; Lohmann等人，·/«/〇/ 5ζ·σ. C/iew., 274:10807-10815，1999 ;及 Yamashita 等人， 160983.doc -237- 201247656 CAem., 273:15479-15486, 1998 中。160983.doc 230· 201247656 336 3-[(2R,5R)-5-Cyclohexyl-2-((R)_2-yl-propyl-propyl)-3-yloxy-? -(3,3·Dimethyl-butyl-1, fast-group)-嗟-曱-2-曱酸/λ /—〇Η \/ \ /...\ _/ \\ /""...OH 337 3- [(2R,5R)-5-cyclohexyl-2-((S)-2-hydroxy-propyl-oxyl-oxo- 4-yl]-5-(3,3-dimethyl-but-1 - fast base) - σ 吩曱曱曱曱 / / ~ Λ / -0 Η \_ / \ /......... \ /N V-OH 338 3-[(2S,5R)-5-cyclohexyl- 2-(4-carbyl-butyl)-3-oxo-oxalin-4-yl]-5-(3,3-dimethyl-butan-1·fast-group)_σ-septene_2_ 曱Acid/~~~\ /—0 Η 339 3-[(S)-6-Cyclohexyl-3-(3-carbyl-propyl)-2-yloxy-Big sigma-1-yl]- 5-(3,3-Dimercapto-but-1-ynyl)-thiophene-2-decanoate 340 3-((S)-3-Amino-6-cyclohexyl-2-oxooxy ·派.定-1_基)_5-(3,3-Dimercapto-but-1-propanyl)-phenanthr-2-indole < 〉 < V-nh2 w /Η 160983.doc 231 · 201247656 341 3-[(S)-6-Cyclohexyl-3-(3-hydroxy-propyl)-2-yloxy-piperidin-1-yl]-5-(3,3-dimethyl-butyl- 1-alkynyl)-infrared-2-carboxylic acid hydrazine H 342 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-. -丨-yl]-5-(3,3-dimethyl-butyrynyl)-thiophene-2-carboxylic acid 343 3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl -2-Sideoxy-Stilt-1-yl]-5-(3,3·dimethyl-butyrynyl)-β-cephen-2-carboxylic acid Table 2 provides NMR of certain compounds of the invention Table 2 Compound No. NMR Data 1 'H-NMR (400 MHz, CD3OD): δ 7.80 (d, 2H), 7.40 (t, 2H), 7.29 (t, 1H), 7.18 (s, 1H), 4.62 (m, 1H), 2.30 (m, 2H), 2.03 (m, 1H), 1.80-1.10 (m, 12H) 2 'H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.13 ( m, 1H), 3.90 (m, 1H), 3,82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m, 6H). 3 *H-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H), 2.02- 1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m, 6H). 160983.doc • 232· 201247656 Compound number NMR data 4 'H-NMR (400 MHz, CDC13): δ 7.43 (m, 2H), 7.21 (m, 3H), 6.94 (m, 1H), 3.68 (m, 1H) ), 2.45 (m, 2H), 2.21 (m, 1H), 1.83-1.51 (m, 12H), 1.32 (m, 2H) 〇5 1H NMR (400 MHz, CDC13): δ 0.88-1.12 (m, 5H ), 1.29 (m, 2H), 1.37 (s, 3H), 1.48-1.60 (m, 2H), 1.71 (m, 2H), 1.84 (m, 2H), 1.96 (m, 1H), 2.12 (m, 1H), 2.29 (s, 3H), 3.72 (m, 1H), 6.93 (s, 1H), 7.11 (d, 2H), 7.39 (d, 2H) 6 'H-NMR (400 MHz, DMSO-d6) : δ 13.1 (s, 1H), 7.75 (d, 2H), 7.58 (s, 1H), 7.37-7.52 (m, 3H), 4.21 (m, 1H), 2.34 (m, 2H), 2.09 (m, 1H), 1.91 (m, 1H), 1.36-1.79 (m, 5H), 0.91-1.31 (m, 6H). 7 ^-NMR (400 MHz, CD3OD): δ 6.93 (s} 1H), 4.12 (d, 1H), 3.91 (d, 1H), 3.66 (s, 1H), 3.54 (t, 2H), 2.14 (m , 1H), 1.91 (m, 1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H), 1.06-1.37 (m, 14H) 8 ^-NMR (400 MHz, CD3OD): δ 6.90 (s5 1H), 4.24 (tert, 1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d, 1H), 3.71 (d, 1H), 3.66 (t, 1H), 2.21 (m, lH ), 1.41-1.98 (m, 8H), 1.05-1.37 (m, 15H). 10 !H-NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H), 7.32-7.45 (m, 6H), 7.28 (t, 3H), 7.20 (t, 1H), 5.45 (m, 1H) ), 2.52-2.63 (m, 3H), 1.89 (m, 1H). 11 !H-NMR (400 MHz, CD3OD): δ 6.89 (s, 1H), 3.94 (m, 1H), 3.58 (m, 2H), 2.05 (m, 1H), 1.92-1.39 (m, 13H), 1.32 (s, 9H), 1.25-1.13 (m, 5H) 13 ^-NMR (400 MHz, CDC13): δ 7.56 (d, 2H), 7.35 (m, 3H), 7.12 (s, 1H), 4.26 ( Tert, 2H), 3.98 (m, 2H), 3.60 (s, 1H), 0.94-1.93 (m, 11H) 18 ^-NMR (400 MHz, CD3OD): δ 7.74 (d, 2H), 7.65 (d, 2H), 7.49 (d, 2H), 7.41 (t, 2H), 7.33 (t, 1H), 7.21 (s, 1H), 4.12 (d, 1H), 3.95 (d, 1H), 3.93 (s, 1H ), 3.37 (d, 1H), 3.02 (tert, 1H), 2.47 (s, 3H), 1.41-1.99 (m, 7H), 1.05-1.32 (m, 4H) 22 ^-NMR (400 MHz, DMSO) : δ 10.31 (d, 1H), 7.63 (d, 2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98 (m, 3H) , 4.61 (m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20 (m, 1H), 1.88-1.76 (m, 4H), 1.65-1.58 (m , 2H), 1.41-1.05 (m} 6H) 160983.doc • 233 · 201247656 Compound Number NMR Data 23 'H-NMR (400 MHz, DMSO): δ 8.55 (m, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.32 (t, 2H), 7.15 (s, 1H), 5.76 (s, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.33 (m, 2H), 2.07 (m, 1H), 1.80 (m, 2H), 1.61 (m, 3H), 1.38 (m, 2H), 1.03 (ms 5H) 35 'H-NMR (400 MHz, CD3OD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25 (m, 1H), 1.88-1.38 (m, 6H), 1.29 (s, 9H), 1.18 (m, 4H), 1.06 (m, 4H) 62 ^-NMR (400 MHz, CD3OD): δ 7.82 (d, 1H), 7.68 (d, 2H), 7.44 (m, 3H), 7.36 (s, 1H), 6.78 (d, 1H), 4.16 (d, 1H), 4.02 (s, 3H), 3.94 (d, 1H), 3.81 (s, 1H), 3.65 (d, 1H), 3.18 (tert, 1H), 2.00 (d, 1H), 1.36-1.87 (m, 6H), 1.05-1.29 (m, 4H) 135 'H-NMR (400 MHz, CD3OD): δ 8.47 (d, 1H), 7.85 (tert, 1H), 7.64 (d, 2H), 7.43 (t, 2H), 7.30 (m, 2H), 6.61 (d, 1H), 3.94 (s, 1H), 3.88 (d, 1H), 3.74 (d, 1H), 2.81-3.24 (m, 6H), 1.49-2.06 (m, 8H), 0.98-1.35 ( m, 7H) 184 *H-NMR (400 MHz, CD3OD): δ 8.51 (d, 1H), 7.86 (tert, 1H), 7.64 (d, 2H), 7.41 (t, 2H), 7.32 (t, 1H) ), 7.19 (s, 1H), 7.91 (d, 1H), 4.10 (d, 1H), 3.96 (s, 1H), 3.89 (d, 1H), 3.65-3.81 (m, 8H), 3.41 (d, 1H), 3.06 (d, 1H), 1.37-1.98 (m, 8H), 1.03-1.26 (m, 3H) 185 1H NMR (400 MHz, CDC13): δ 1.03 (m, 3H), 1.15 (d, 3H ), 1.30 (m, 1H), 1.43 (m, 2H), 1. 58 (m, 2H), 1.63 (m, 1H), 1.7-1.8 (m, 2H), 1.9 (d, 1H), 1.95-2.10 (m, 3H), 2.96 (d, 1H), 3.33 (d, 2H), 3.60 (s, 1H), 3.75 (s, 1H), 3.81 (d, 1H), 4.05 (s, 1H), 4.20 (d, 1H), 6.37 (d, 1H), 7.02-7.05 (m , 3H), 7.50-7.54 (m, 2H), 7.66 (m, 1H), 8.38 (s, 1H) 193 'H-NMR (400 MHz, CD3OD): δ 7.80 (d, 1H), 6.95 (s5 1H ), 6.75 (d, 1H), 4.14 (d, 1H), 3.93 (d, 1H), 3.64 (d, 1H), 3.16 (m, 1H), 2.30 (m, 2H), 1.90 (m, 1H) , 1.83 (m, 3H), 1.69 (m, 2H), 1.58 (t, 3H), 1.47 (m, 2H), 1.31 (s, 9H), 1.18 (m,4H) 196 1H NMR (400 MHz, CDC13 ): δ 0.95-1.15 (m, 4H), 1.20 (m, 1H), 1.30-1.40 (m, 1H), 1.47 (m, 1H), 1.57 (m, 2H), 1.66 (s, 1H), 1.70 -1.85 (m, 3H), 1.85-1.95 (m, 2H), 3.03 (m, 1H), 3.18 (d, 2H), 3.43 (d, 1H), 3.69 (s, 1H), 3.75-3.90 (m , 3H), 4.10 (d, 1H), 4.45 (s, 2H), 6.51 (d, 1H), 7.00-7.10 (m, 3H), 7.49 (m, 2H), 7.70 (m, 1H), 8.46 ( s, 1H) 160983.doc • 234· 201247656 Compound Number NMR Data 200 1HNMR (400 MHz, CDC13): δ 0.90-1.15 (m, 5H), 1.40-1.60 (m, 3H), 1.60-1.85 (m, 3H ), 1.95 (m, 2H), 3 .20 (d, 1H), 3.55 (d, 2H), 3.68 (m, 2H), 3.70-3.85 (m, 6H), 3.85-3.95 (m, 2H)} 6.48 (d, 1H), 7.02 (s , 1H), 7.27 (d, 2H), 7.42 (d, 2H), 7.67 (d5lH), 8.43 (d, 1H) 236 'H-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.19 (s, 2H), 4.05 (m, 2H), 3.82 (s, 1H), 1.43-1.90 (m, 6H), 1.06-1.39 (m, 14H), 279 lHNMR (400MHz, CDC13): δ 0.93-1.15 (m, 4H), 1.29-1.39 (m, 1H), 1.45 (m, 1H), 1.50-1.60 (m, 2H), 1.65 (m, 1H), 1.70-1.80 (d, 1H), 1.80-1.90 (d, 1H), 1.90-2.10 (m, 4H), 3.05 (d, 1H), 3.20 (m, 1H), 3.27 (s, 3H), 3.30 (m, 1H), 3.36-3.53 (m, 3H ), 3.61-3.74 (m, 2H), 4.06 (d, 1H), 6.42 (s, 1H), 6.99-7.07 (m, 3H), 7.48 (m, 2H), 7.64 (d, 1H), 8.42 ( s, 1H) 295 1H NMR (400 MHz, CDC13): δ 0.96-1.14 (m, 4H), 1.32-1.44 (m, 1H), 1.48 (m, 1H), 1.57 (m, 2H), 1.67 (m , 1H), 1.76 (d, 1H), 1.83 (d, 1H), 2.30 (s, 3H), 2.98 (d, 1H), 3.40 (d, 1H), 3.67 (m, 1H), 3.79 (d, 1H), 3.91 (s} 3H), 4.10 (d, 1H), 7.06 (s, 1H), 7.15 (d, 2H), 7.42 (d, 2H), 7.71 (s, 1H), 7.75 (s, 1H) 302 1H NMR (400 MHz, CDC13): δ 0.97-1.15 (m, 4H), 1.27 (m, 1H), 1.47-1.64 (m, 3H), 1.68 (m, 1H), 1.76 (d, 1H), 1.84 (d, 1H), 2.28 (s, 3H), 2.73 (s, 3H), 3.31 (d, 1H), 3.52 (d, 1H), 3.71 (m, 1H), 3.85 (d, 1H), 4.14 (d, 1H), 7.06 (s, 1H), 7.12 (d, 1H), 7.40 (d, 2H), 7.45 (d, lH), 8.13 (d, 1H), 8.98 (s, 1H) 311 !H-NMR (400 MHz, CD3OD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s , 9H), 1.21 (m, 4H), 1.05 (m, 1H) 314 1H NMR (400 MHz, CDC13): 50.94-1.13 (m, 4H), 1.26 (m, 1H), 1.38 (m, 1H), 1.43 (s, 3H), 1.45 (s, 3H), 1.47-1.59 (m, 2H), 1.62 (m, 1H), 1.74 (d, 1H), 1.87 (d, 1H), 2.29 (s, 3H), 3.45 (m, 1H), 3.84 (d, 1H), 4.09 (d, 1H), 7.02 (s, 1H), 7.12 (d, 2H), 7.42 (d, 2H) 316 !H-NMR (400 MHz, CD3OD): δ 6.93 (s, 1H), 4.23 (m, 1H), 3.80 (m, 1H), 2.49 (m, 1H), 2.06-1.42 (m, 10H), 1.32 (s, 9H), 1.22 ( d, 3H), 1.12 (m, 5H). 160983.doc •235 · 201247656 Compound Number NMR Data 318 ]H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1Η), 4.11 (d, 1H), 3.92 (d, 1H), 3.62 (m, 1H) ), 2.17 (m, 1H), 1.93 (m, lH), 1.62-1.85 (m, 4H), 1.45-1.62 (m, 4H), 1.37-1.44 (m, 3H), 1.27-1.37 (m, 10H ), 1.11-1.27 (m, 10H) 319 !H-NMR (400 MHz, CD3OD): δ 6.97 (s, 1H), 4.18 (d, 1H), 3.94 (d, 1H), 3.53 (m, 1H) , 2.17 (t, 1H), 1.95 (m, 2H), 1.70-1.86 (m, 4H), 1.58-1.69 (m, 2H), 1.46-1.58 (m, 2H), 1.39-1.46 (m, 3H) , 1.29-1.39 (m, 10H), 1.10-1.29 (m, 10H) 322 ^-NMR (400 MHz, CD3OD): δ 6.95 (s5 1H)S 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 323 *H-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.24 (tert, 1H), 3.93 (d, 1H), 3.62-3.82 (m, 3H), 2.08-2.21 (m, 1H), 1.88-2.04 (m, 2H), 1.56-1.87 (m, 4H), 1.43-1.56 (m, 4H), 0.98-1.35 (m, 14H) 324 1H NMR (400 MHz, CDC13): δ 0.88-1.13 (m} 4H), 1.32 (m, 2H), 1.43 (s, 3H), 1.48-1.67 (m, 3H), 1.69-1.87 (m, 4H), 1.96 (m, 1H), 2.06 (m, 1H), 2.31 (s, 3) H), 3.67 (m, 1H), 7.08 (s, 1H), 7.15 (d, 2H), 7.44 (d, 2H) 325 1H NMR (400 MHz, CDC13): δ 0.96-1.19 (m, 5H), 1.23 (s, 9H), 1.37 (m, 1H), 1.45 (m, 1H), 1.61 (m, 2H), 1.64-1.81 (m, 4H), 1.83 (m, 1H), 2.22 (m, 1H) , 3.37 3.57-3.78 (m, 4H), 3.89 (d, 1H), 3.98 (d, 1H), 6.79 (s, 1H) 326 'H-NMR (400 MHz, CD3OD): δ 6.78 (s, 1H) , 4.07 (m, 1H), 3.53 (m, 2H), 2.26 (m, 1H), 1.96-1.38 (m, 14H), 1.30 (s, 9H), 1.14 (m, 5H). 328 ^-NMR (400 MHz, CD3OD): δ 6.87 (s, 1H), 4.14 (tert, 1H), 3.92 (tert, 1H), 3.77 (d, 1H), 3.70 (t, 2H), 2.32 (m , 1H), 1.82-1.99 (m, 2H), 1.71-1.82 (m, 2H), 1.66 (m, 1H), 1.41-1.59 (m, 5H), 1.03-1.34 (m, 14H) 334 'H- NMR (400 MHz, CD3OD): δ 6.95 (s, 1H), 4.08 (m, 1H), 3.74 (m, 1H), 2.18 (m, 1H), 1.94-1.67 (m, 8H), 1.42 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 160983.doc -236- 201247656 Compound Number NMR Data 336 NMR (400 MHz, CD3OD): δ 1.09-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.85 (m, 5H), 1.89-2.10 (m, 3H), 3.56-3.61 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.10 (m, 1H), 4.12- 4.22 (m, 2H), 6.99 (s, 1H) 337 'H NMR (400 MHz, CD3OD): δ 1.07-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.60 (m, 2H), 1.63-1.85 (m, 4H)S 1.87-1.98 (m, 1H), 2.02-2.11 (m, 1H), 3.60-3.66 (m, 1H), 3.93-4.03 (m, 2H), 4.15 (d, 1H ), 4.26-4.35 (m, 1H), 6.94 (s, 1H) 340 ^-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84 (m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.31 (s, 9H), 1.16 (m 5H) 341 'H-NMR (400 MHZ, CD3OD): δ 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82-1.64 (m, 7H), 1.58 (m, 2H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H) 343 !H-NMR (400 MHZ, CD3OD): δ 6.85 (s, 1H), 3.92 (br, 1H), 3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.78 (m, 7H), 1.37 ( m, 2H), 1.31 (s, 9H), 1.14 (m, 5H). Biological Examples Biological Examples 1. Anti-c hepatitis activity Compounds can exhibit anti-hepatitis C activity by inhibiting HCV polymerase, by inhibiting other enzymes required in the replication cycle, or by other pathways. Many assays available to assess such activity have been published. A general method for assessing the total increase in HCV virus in culture is disclosed in U.S. Patent No. 5,738,985. In vitro assays have been reported in Ferrari et al, J>?/. of Vir., 73:1649-1654, 1999; Ishii et al, 29:1227-1235, 1999; Lohmann et al., /«/〇/ 5ζ·σ. C/iew., 274:10807-10815, 1999; and Yamashita et al., 160983.doc -237- 201247656 CAem., 273:15479-15486, 1998.

Emory University 於 1996年 9 月 27 日申請之 WO 97/12033 (列出C. Hagedorn及A. Reinoldus作為發明者）（其主張1995 年9月所申請之美國臨時專利申請案第60/004,3 83之優先權）描述可用以評估本文所述之化合物之活性的HCV聚合酶分析法。Bartholomeusz等人，Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996:1(增刊 4) 18-24報導另一種HCV聚合酶分析法。頒予Katze等人之美國專利第6,030,785號、頒予〇6丨丫6(^11丨〇之美國專利第6,228,576號及頒予1111?丨11等人之美國專利第5,759,795號揭示量測由HCV藥物導致之激酶活性降低之篩選法。頒予Su等人之美國專利第5,861,267號、頒予De Francesco等人之美國專利第5,739,002號及頒予 Houghton等人之美國專利第5,597,691中揭示量測所提出之 HCV藥物之蛋白酶抑制活性的篩選法。生物學實例2.複製子分析法使用細胞株ET(Huh-lucubineo-ET)來篩選抑制HCV RNA依賴性RNA聚合酶之化合物。用含有I389luc-ubi-neo/NS3-3'/ET (具有螢火蟲螢光素酶-泛素-新黴素（neomycin)磷酸轉移酶融合蛋白及含有細胞培養物應變性突變（E1202G ; T1280I ; K1846T)的 EMCV-IRES驅動型 NS3-5B 聚合蛋白質之複製子）的RNA轉錄物穩定轉染ET細胞株（Krieger等人， 2001且未公開）。使ET細胞生長於補充有10%胎牛血清、2 201247656 mM麵醯胺酸、青黴素（Penicillin)(100 IU/mL)/鏈黴素 (Streptomycin)(100 pg/mL)、1χ非必需胺基酸及 250 pg/mL G418(「遺傳黴素（Geneticin)」）之DMEM(杜貝可氏經改質之伊格爾培養基（Dulbeco’s Modified Eagle’s Medium))中。試劑均可得自 Life TechnoIogies(Bethesda，MD)。以每孔 0.5-1.0xlO4個細胞將細胞接種於96孔盤中並培育24小時，隨後添加測試化合物。將化合物添加至細胞中以達成〇 _ 1 ηΜ至5〇 μΜ之最終濃度及0.5%之最終DMSO(二甲亞砜）濃度° 48小時後藉由添加溶解緩衝液及受質（目錄號⑴〜溶解緩衝液Ε2661及Bright-Glo螢光素酶系統Ε2620，Promega,WO 97/12033 (listed by C. Hagedorn and A. Reinoldus as inventors) filed on September 27, 1996 by Emory University (which claims US Provisional Patent Application No. 60/004, 3, filed in September 1995) Priority of 83) describes HCV polymerase assays that can be used to assess the activity of the compounds described herein. Bartholomeusz et al, Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996: 1 (Supp. 4) 18-24 reports another HCV polymerase assay. U.S. Patent No. 6,030,785 issued to Katze et al., issued to U.S. Patent No. 6,228,576, issued to U.S. Patent No. 6,228,576, issued to U.S. Pat. The screening method disclosed in U.S. Patent No. 5,861, 267 to Dess et al. Screening method for protease inhibitory activity of the proposed HCV drug. Biological example 2. Replicon assay Cell line ET (Huh-lucubineo-ET) was used to screen for compounds that inhibit HCV RNA-dependent RNA polymerase. -neo/NS3-3'/ET (with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES containing cell culture strain mutation (E1202G; T1280I; K1846T) The RNA transcript of the driven NS3-5B polymeric protein replicon was stably transfected into the ET cell line (Krieger et al., 2001 and not disclosed). The ET cells were grown in supplemented with 10% fetal bovine serum, 2 201247656 mM facial mask. Amino acid, blue Penicillin (100 IU/mL) / Streptomycin (100 pg / mL), 1 χ non-essential amino acid and 250 pg / mL G418 ("Geneticin") DMEM (Du Reagents are available from Dulbeco's Modified Eagle's Medium. The reagents are available from Life TechnoIogies (Bethesda, MD). Cells are seeded in 96-well plates at 0.5-1.0x10 cells per well. And incubated for 24 hours, then add the test compound. Add the compound to the cell to reach the final concentration of 〇_1 ηΜ to 5〇μΜ and 0.5% of the final DMSO (dimethyl sulfoxide) concentration. After 48 hours, add by dissolution. Buffer and substrate (Catalog No. (1) ~ Lysis Buffer Ε 2661 and Bright-Glo Luciferase System Ε 2620, Promega,

Madison，WI)來量測螢光素酶活性。分析期間細胞不應過於匯合。相對於無化合物對照來繪製複製資料之抑制百分比。為測定EQJ觀測到50%最大抑制之有效濃度），對於各化合物使用1 〇點、3倍連續稀釋液，其跨越丨〇〇〇倍之濃度範圍。藉由將各濃度下之抑制％擬合至以下方程式來計算ECs。值：抑制％ = 100%/[(EC5〇/[I])b+l] 其中b為希爾係數（Hiu，s coefficient)。在些態樣中，當根據實例2之分析法測試時，某些式 ⑴化合物展現等於或小於5〇。在其他態樣中， ECw等於或小於10 μΜ。在其他態樣中，ec^等於或小於^ μΜ。生物學實例3.重組型HCV-NSSb之選殖與表現使用WO 2〇〇5/〇12288之第⑽頁所示之引子，如 I60983.doc -239· 201247656 V·等人，（1999) <SWe«ce 285，110-113中所述，藉由PCR 自 pFKI3 89luc/NS3-37ET選殖NS5b蛋白之編碼序列。選殖片段缺失C端21個胺基酸取代基《將選殖片段*** IPTG誘導性（異丙基-β-D-硫代哌喃半乳糖苷）表現質體中，該表現質體在蛋白質之羧基端提供抗原決定基標籤 (His)6 » 使重組酶在XL-1細胞中表現且在誘導表現後，使用親和層析法在鎳-NTA(氮基三乙酸）管柱上純化蛋白。儲存條件為 10 mM Tris-HCl(pH 7.5)、50 mM NaC卜 0.1 mM EDTA (乙二胺四乙酸）、1 mM DTT(二硫蘇糖醇）及20%丙三醇，在-20°C下。生物學實例4.使用異聚物受質的HCV-NS5b酶分析法藉由量測使用生物素標記之異聚物模板（其包括HCV基因組之一部分）向RNA產物中併入經放射性標記的UTP來分析聚合酶活性。分析混合物（50 μ!〇通常含有1〇111]\47^3-HCl(pH 7.5)、5 mM MgCl2、0.2 mM EDTA、10 mM KC1、 1單位/微升RNAsin、1 mM DTT、10 μΜ各NTP(三磷酸核苷）（包括[3H]-UTP(三磷酸尿苷））及10 ng/ML異聚物模板。最初將測試化合物溶解於100% DMSO中且進一步在含有 5% DMSO之水性緩衝液中稀釋。化合物之測試濃度通常在1 nM與100 μΜ之間。添加酶後開始反應，且使其在37°C 下持續2小時。用8 μΐ^ 100 mM EDTA淬滅反應，且將反應混合物（30 μ!>)轉移至塗有抗生蛋白鍵菌素（streptavidin)之閃爍近接微量滴定盤（FlashPlates)中且在室溫下培育隔 160983.doc •240· 201247656 夜。藉由閃爍計數法測定放射能之併入。生物學實例S.使用均聚物受質的HCV-NS5b酶分析法藉由量測使用生物素標記之均聚物模板向RNA產物中併入經放射性標記的UTP來分析聚合酶活性。藉由以1:4之比率使腺苷均聚物黏接至由5'-生物素基團（生物素-U2Q)封端之尿苷20聚體來形成模板。通常，分析混合物（50 ML)含有 25 mM Tris-HCl(pH 7.5)、40 mM K(M、0.3 mM MgCl2、 0.05 mM EDTA、0.2 單位 /微升 Superase RNAse抑制劑、5 mM DTT、30 μΜ UTP(三磷酸尿苷）（包括[3H]-UTP(三磷酸尿苷），0·4 pCi/pL，最終濃度為1 μΜ)及50 nM均聚物模板。最初將測試化合物溶解於100% DMSO中且進一步在含有5¾ DMSO之水性緩衝液中稀釋。化合物之測試濃度通常在2 nM與5 0 μΜ之間》添加酶來起始反應且使其在 3 0°C下持續90分鐘。用8 pL 100 mM EDTA淬滅反應，且將反應混合物（30 μΙ〇轉移至塗有抗生蛋白鏈菌素之閃爍近接微量滴定盤（FlashPlates)中且在室溫下培育隔夜。藉由閃爍計數法測定放射能之併入。藉由添加測試化合物（10個點，以100% DMSO兩倍連續稀釋，最終反應濃度為5%)來測定抑制劑ICw值。如ητ計算ICw值：相對於化合物濃度繪製抑制％，且將數據擬合至受限四參數S形曲線，其等於「四參數邏輯方程式」，其中底部為最小Y值，頂部為最大Y值，且希爾斜率 (Hillslope)為半對數曲線之線性部分的斜率。頂部及底部分別限定為〇%及loo%之值。此等分析係使用Graphpad 160983.doc -241 · 201247656Madison, WI) to measure luciferase activity. Cells should not be confluent during the analysis. The percent inhibition of replication data was plotted against no compound control. To determine the effective concentration of 50% maximal inhibition observed in EQJ, 1 〇, 3 fold serial dilutions were used for each compound, which spans the concentration range of 丨〇〇〇 times. ECs were calculated by fitting the % inhibition at each concentration to the equation below. Value: Suppression % = 100% / [(EC5 〇 / [I]) b + l] where b is the Hill coefficient (Hiu, s coefficient). In some aspects, certain compounds of formula (1) exhibit equal to or less than 5 当 when tested according to the analytical method of Example 2. In other aspects, the ECw is equal to or less than 10 μΜ. In other aspects, ec^ is equal to or less than ^μΜ. Biological Examples 3. Selection and Expression of Recombinant HCV-NSSb Use the primers shown on page (10) of WO 2〇〇5/〇12288, eg I60983.doc -239· 201247656 V· et al., (1999) < The coding sequence of the NS5b protein was cloned from pFKI3 89luc/NS3-37ET by PCR as described in SWe«ce 285,110-113. The cloned fragment lacks the C-terminal 21 amino acid substituents. The inserted fragment was inserted into the IPTG-inducible (isopropyl-β-D-thiogalactopyranoside)-expressing plastid, which expresses the plastid in the protein. The carboxy terminus provides an epitope tag (His) 6 » The recombinase is expressed in XL-1 cells and after induction of expression, the protein is purified on a nickel-NTA (nitrotriacetic acid) column using affinity chromatography. Storage conditions were 10 mM Tris-HCl (pH 7.5), 50 mM NaC Bu 0.1 mM EDTA (ethylenediaminetetraacetic acid), 1 mM DTT (dithiothreitol) and 20% glycerol at -20 ° C. under. Biological Example 4. HCV-NS5b Enzyme Assay Using Heteromeric Substance The radiolabeled UTP was incorporated into RNA products by biotinylated heteropolymer template (which includes a portion of the HCV genome) by measurement. To analyze polymerase activity. Analyze the mixture (50 μ! 〇 usually contains 1〇111]\47^3-HCl (pH 7.5), 5 mM MgCl2, 0.2 mM EDTA, 10 mM KC1, 1 unit/μl RNAsin, 1 mM DTT, 10 μM each NTP (nucleoside triphosphate) (including [3H]-UTP (uric acid triphosphate)) and 10 ng/ML heteropolymer template. The test compound was initially dissolved in 100% DMSO and further in water containing 5% DMSO. Dilute in buffer. The test concentration of the compound is usually between 1 nM and 100 μΜ. The reaction is started after the enzyme is added and allowed to continue at 37 ° C for 2 hours. The reaction is quenched with 8 μM ^ 100 mM EDTA and will be The reaction mixture (30 μ!) was transferred to a scintavidin-coated scintillation proximity microtiter plate (FlashPlates) and incubated at room temperature for 160983.doc •240·201247656 night. Incorporation of radioactivity by counting method. Biological example S. HCV-NS5b enzyme assay using homopolymerization by radiolabeling into a RNA product by biotin-labeled homopolymer template UTP to analyze polymerase activity by adhering adenosine homopolymer to a 5'-bio in a ratio of 1:4 a uridine 20-mer terminated by a cyclin group (Biotin-U2Q) to form a template. Typically, the assay mixture (50 ML) contains 25 mM Tris-HCl (pH 7.5), 40 mM K (M, 0.3 mM MgCl2) 0.05 mM EDTA, 0.2 units/μl Superase RNAse inhibitor, 5 mM DTT, 30 μΜ UTP (uridine triphosphate) (including [3H]-UTP (uridine triphosphate), 0.4 pCi/pL, final concentration 1 μΜ) and 50 nM homopolymer template. The test compound was initially dissolved in 100% DMSO and further diluted in an aqueous buffer containing 53⁄4 DMSO. The test concentration of the compound is usually between 2 nM and 50 μM. Enzymes were added to initiate the reaction and allowed to continue for 90 minutes at 30 ° C. The reaction was quenched with 8 pL of 100 mM EDTA and the reaction mixture (30 μM was transferred to a scintillation-proximal trace of streptavidin coated with Incubation in a titration plate (FlashPlates) and overnight at room temperature. Incorporation of radioactivity was determined by scintillation counting. By adding test compound (10 points, serially diluted in 100% DMSO, the final reaction concentration was 5 %) to determine the inhibitor ICw value. For example, ητ calculates the ICw value: relative to the compound concentration % is suppressed and the data is fitted to a constrained four-parameter sigmoid curve equal to the "four-parameter logic equation" where the bottom is the minimum Y value, the top is the maximum Y value, and the Hill slope is a semi-logarithm The slope of the linear portion of the curve. The top and bottom are limited to the values of 〇% and loo%, respectively. These analyses are performed using Graphpad 160983.doc -241 · 201247656

Prism 4.0 版（Graphpad Software，Inc·)與 EXCEL 6.0 之 DS Accord(Accelrys，Microsoft Corp·)聯合進行。生物學實例6 亦藉由量測使用具有聚胞苷酸RNA模板之生物素標記寡 G13引子向RNA產物中併入經放射性標記的GTP來分析聚合酶活性。分析混合物（40 pL)通常含有50 mM HEPES(pH 7.3)、2.5 mM乙酸鎂、2 mM氣化鈉、37·5 mM乙酸鉀、5 mM DTT、0.4 U/mL RNasin、2.5%甘油、3 nM NS5B、20 nM polyC RNA模板、20 nM生物素-寡G13引子及0.2 μΜ氚化三磷酸鳥苷。最初將測試化合物溶解及稀釋於1 〇〇0/〇 DMSO中且進一步稀釋於水性緩衝液中，產生5% DMSO之最終濃度。化合物之測試濃度通常在〇 2 nM與10 μΜ之間°藉由添加氚化三磷酸鳥苷來起始反應且使其在3(rc下持續2小時。用1〇〇 pL含有1〇 mM EDTA及1 pg/mL塗有抗生蛋白键菌素之閃爍近接珠粒的終止緩衝液來淬滅反應。在4°C下培育反應盤1〇小時’接著藉由閃爍計數法測定放射能之併入。前述表1中之化合物已在生物學實例1之聚合酶分析法中進行測試且在下文表3中提供各化合物之1(：5<)值。表丨之大部分化合物在本文提供之生物學實例2之複製子分析法中展現1 μΜ或1 μΜ以下之IC5。或500 nM或500 nM以下之 IC50。舉例而言，實例編號2、3、5、7、8、1〇、u、19、 35、69、74、75、76、77、78、79、80、81 ' 82 ' 84、 85、86、87、88、89、90、91、91 ' 92、93、94、95、 160983.doc -242- 201247656 96、99、118、119、120、121、122 > 123、125、126、 127 、 130 、 135 、 137 、 138 、 140 、 141 、 143 、 145 、 146 、 147 、 148 、 149 、 150 、 151 、 152 、 154 、 155 、 156 、 157 、 158、160、161、162、163、164、165、167、168、169、 170 、 171 、 172 、 173 、 176 、 177 、 179 、 180 、 182 、 183 、 184 、 185 ' 186 、 187 、 188 、 189 、 190 、 191 、 192 、 193 、Prism version 4.0 (Graphpad Software, Inc.) was conducted in conjunction with DS Accord (Accelrys, Microsoft Corp.) of EXCEL 6.0. Biological Example 6 Polymerase activity was also analyzed by incorporation of radiolabeled GTP into an RNA product using a biotinylated oligo G13 primer with a polycytidine RNA template. The assay mixture (40 pL) typically contains 50 mM HEPES (pH 7.3), 2.5 mM magnesium acetate, 2 mM sodium sulphate, 37. 5 mM potassium acetate, 5 mM DTT, 0.4 U/mL RNasin, 2.5% glycerol, 3 nM NS5B, 20 nM polyC RNA template, 20 nM biotin-oligo G13 primer and 0.2 μ guanosine triphosphate. The test compound was initially dissolved and diluted in 1 〇〇0/〇 DMSO and further diluted in an aqueous buffer to give a final concentration of 5% DMSO. The test concentration of the compound is usually between n2 nM and 10 μΜ ° The reaction is initiated by the addition of guanosine triphosphate guanosine and allowed to continue at 3 (rc for 2 hours. 1 mM EDTA with 1 〇〇pL) And quenching the reaction with 1 pg/mL of stop buffer of scintillation proximity beads coated with streptavidin. Incubate the reaction plate at 4 ° C for 1 hour' followed by the incorporation of radioactivity by scintillation counting The compounds of the foregoing Table 1 have been tested in the polymerase assay of Biological Example 1 and the values of 1 (:5<) of each compound are provided in Table 3 below. Most of the compounds of the formula are provided herein. The replicon analysis of Example 2 exhibits IC5 of 1 μΜ or less, or IC50 of 500 nM or less. For example, example numbers 2, 3, 5, 7, 8, 1 , u, 19, 35, 69, 74, 75, 76, 77, 78, 79, 80, 81 ' 82 ' 84, 85, 86, 87, 88, 89, 90, 91, 91 '92, 93, 94, 95, 160983.doc -242- 201247656 96,99,118,119,120,121,122 > 123, 125, 126, 127, 130, 135, 137, 138, 140, 141, 143 145, 146, 147, 148, 149, 150, 151, 152, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 167, 168, 169, 170, 171, 172, 173, 176, 177, 179, 180, 182, 183, 184, 185 '186, 187, 188, 189, 190, 191, 192, 193,

194、195、196 ' 197、198、199、200、201 ' 202 ' 203、 208 、 212 、 213 、 216 、 217 、 218 ' 219 、 222 、 224 、 225 、 226 ' 227 ' 228 ' 229、231 ' 232、233、234、235 ' 236、 238 ' 239 、 240 、 241 、 243 、 244 、 246 、 247 、 248 、 250 、 251 、 253 、 256 ' 257 、 258 、 272 、 273 、 274 、 275 、 276 ' 277 、 278 、 279 、 280 、 281 、 283 、 284 、 285 、 286 、 287 、 288 、 289 、 290 、 291 、 292 、 295 ' 296 ' 297 、 298 、 299 、 301 、 302 、 303 、 304 、 305 、 307 、 308 、 310 、 311 、 312 、 313 、 314 、 315 、 316 、 318 、 319 、 320 、 321 、 322 、 323 、 325 、 327 、 328 、 329 、 330 、 332 、 334 、 336 、 337 、 339 、 340、341、342、343之化合物在生物學實例2之複製子分析法中展現100 nM或100 nM以下之IC50。實例編號1、4、 6、12、13、17、18、24、26、27、29 ' 31、36、37、 38、39、40、42、45 ' 46、47、48、49 ' 50、51、52、 53、54、55、56、58、59、60、61、62、63、64、65、 66、67、70、71、72、73 ' 83 ' 97、98、100、101 ' 102 、 103 、 104 、 105 、 106 、 107 、 108 、 109 、 113 、 114 、 115 、 116 、 124 、 128 、 129 、 131 、 136 、 139 、 142 、 144 、 • 243 - 160983.doc 201247656 153、159、178、181、204、205、206、207、209、211、 214 、 215 、 220 、 221 、 223 、 230 、 237 、 242 、 245 、 249 、 252 、 254 、 255 、 259 、 260 、 262 、 267 、 282 、 293 、 294 、 300 、 206 、 309 、 317 、 324 、 326 、 331 、 333 、 335 、—之化合物在生物學貫例2之複製子分析法中展現在〗〇〇 nM與 5.0 μΜ之間的 IC50。貫例編號 9、15、16、20、21、22、 23 、 25 、 28 、 30 、 32 、 33 、 34 、 41 、 47 、 57 、 110 、 111 、 U2' 117' 132' 166' 174、175、21〇、271 之化合物在生物學實例2之複製子分析法中展現5 〇 μΜ或5 〇 μΜ以上之 IC50。表3194, 195, 196 '197, 198, 199, 200, 201 '202 ' 203, 208, 212, 213, 216, 217, 218 '219, 222, 224, 225, 226 '227 '228 '229, 231 ' 232, 233, 234, 235 ' 236, 238 ' 239 , 240 , 241 , 243 , 244 , 246 , 247 , 248 , 250 , 251 , 253 , 256 ' 257 , 258 , 272 , 273 , 274 , 275 , 276 ' 277, 278, 279, 280, 281, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 295 '296 '297, 298, 299, 301, 302, 303, 304, 305, 307 , 308 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 318 , 319 , 320 , 321 , 322 , 323 , 325 , 327 , 328 , 329 , 330 , 332 , 334 , 336 , 337 , 339 , The compound of 340, 341, 342, 343 exhibits an IC50 of 100 nM or less in the replicon analysis of Biological Example 2. Example numbers 1, 4, 6, 12, 13, 17, 18, 24, 26, 27, 29 '31, 36, 37, 38, 39, 40, 42, 45 '46, 47, 48, 49 ' 50, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 70, 71, 72, 73 '83 '97, 98, 100, 101 ' 102, 103, 104, 105, 106, 107, 108, 109, 113, 114, 115, 116, 124, 128, 129, 131, 136, 139, 142, 144, • 243 - 160983.doc 201247656 153, 159 , 178, 181, 204, 205, 206, 207, 209, 211, 214, 215, 220, 221, 223, 230, 237, 242, 245, 249, 252, 254, 255, 259, 260, 262, 267 Compounds of 282, 293, 294, 300, 206, 309, 317, 324, 326, 331 , 333, 335, - are shown in the Replicon Analysis of Biological Case 2 at 〇〇nM and 5.0 μΜ The IC50 between. Example numbers 9, 15, 16, 20, 21, 22, 23, 25, 28, 30, 32, 33, 34, 41, 47, 57, 110, 111, U2' 117' 132' 166' 174, 175 The compound of 21〇, 271 exhibits an IC50 of 5 〇μΜ or more than 5 〇μΜ in the replicon analysis of Biological Example 2. table 3

NS5B-酶 3 _ MS [M+H+] 滞留時間 (分鐘） HPLC方法 1 0.1815 370.4 12.36 A 2 0.035 448.3 13.02 ---- A 3 0.004 448.3 13.03 1--- A 4 0.073 384.4 12.76 A 5 0.052 427.5 13.06 A 6 - 370.1 12.4 ----- A 7 0.006 462.2 13.72 ----- A 8 0.001 434.3 8.45 A 9 0.08 一 ^----- 398.2 11.64 *-_ A A 10 0.003 4643^ 7.96 11 0.008 461.9 12.25 1---- A 12 0.045 400.5 10.48/11.76 A 13 0.079 -,7^*~— 386.1 12.14 A 14 3.651 485.6 14.11 A 160983.doc "244. 201247656NS5B-Enzyme 3 _ MS [M+H+] Retention time (minutes) HPLC method 1 0.1815 370.4 12.36 A 2 0.035 448.3 13.02 ---- A 3 0.004 448.3 13.03 1--- A 4 0.073 384.4 12.76 A 5 0.052 427.5 13.06 A 6 - 370.1 12.4 ----- A 7 0.006 462.2 13.72 ----- A 8 0.001 434.3 8.45 A 9 0.08 a ^----- 398.2 11.64 *-_ AA 10 0.003 4643^ 7.96 11 0.008 461.9 12.25 1---- A 12 0.045 400.5 10.48/11.76 A 13 0.079 -,7^*~— 386.1 12.14 A 14 3.651 485.6 14.11 A 160983.doc "244. 201247656

15 0.0735 385.3 6.12 A 16 0.4205 489.3 12.73 A 17 0.024 475.2 12.48 A 18 0.002 539.6 14.19 A 19 0.015 388.6 14.3 A 20 0.128 517.6 12.55/13.80 A 21 0.97 533.6 13.11 A 22 0.02 533.6 13.45 A 23 0.245 399.5 5.89 A 24 0.0445 503.6 13.46 A 25 0.173 503.4 12.66 A 26 0.067 463.3 12.13 A 27 0.022 539.3 13.7 A 28 0.226 399.5 7.01 A 29 0.001 599.3 12.76 A 30 0.003 569.3 13.09 A 31 0.047 519.6 14.34 A 32 0.241 544.6 13.79 A 33 0.038 587.3 12.8 A 34 1.05 388.6 14.34 A 35 0.0095 388.4 14.35 A 36 0.058 546.6 14.69 A 37 0.072 492.6 12.8 A 38 0.065 505.6 13.75 A 39 0.051 553.4 14.19 A 40 0.013 543.3 13.87 A 41 0.218 521.3 11.71 A 42 0.148 517.6 13.73 A 43 553.6 15.49 A 44 553.6 12.91 A 45 4.9 505.6 13.55 A 160983.doc -245 - 20124765615 0.0735 385.3 6.12 A 16 0.4205 489.3 12.73 A 17 0.024 475.2 12.48 A 18 0.002 539.6 14.19 A 19 0.015 388.6 14.3 A 20 0.128 517.6 12.55/13.80 A 21 0.97 533.6 13.11 A 22 0.02 533.6 13.45 A 23 0.245 399.5 5.89 A 24 0.0445 503.6 13.46 A 25 0.173 503.4 12.66 A 26 0.067 463.3 12.13 A 27 0.022 539.3 13.7 A 28 0.226 399.5 7.01 A 29 0.001 599.3 12.76 A 30 0.003 569.3 13.09 A 31 0.047 519.6 14.34 A 32 0.241 544.6 13.79 A 33 0.038 587.3 12.8 A 34 1.05 388.6 14.34 A 35 0.0095 388.4 14.35 A 36 0.058 546.6 14.69 A 37 0.072 492.6 12.8 A 38 0.065 505.6 13.75 A 39 0.051 553.4 14.19 A 40 0.013 543.3 13.87 A 41 0.218 521.3 11.71 A 42 0.148 517.6 13.73 A 43 553.6 15.49 A 44 553.6 12.91 A 45 4.9 505.6 13.55 A 160983.doc -245 - 201247656

46 0.063 531.6 14.33 A 47 0.088 492.3 6.52 A 48 0.187 402.3 13.73 A 49 0.015 539.17 4.16 C 50 0.007 582.17 3.69 C 51 0.011 617.18 4.57 C 52 0.015 525.15 4.1 C 53 0.024 609.13 7.56 B 54 0.018 593.14 6.97 B 55 0.071 609.14 4.22 C 56 0.0071 553.18 4.4 C 57 0.26 578.18 8.23 B 58 0.088 539.17 6 B 59 0.039 609.13 6.75 B 60 0.009 601.18 4.73 C 61 0.003 578.18 8.98 B 62 0.011 529.16 7.84 B 63 0.042 617.19 9.78 B 64 0.031 578.17 9.18 B 65 0.045 601.18 7.23 B 66 0.049 611.13 4.39 C 67 0.1835 402.3 13.48 A 68 593.14 6.77 B 69 0.002 597.4 16.51 A 70 0.067 402.5 15.7 A 71 0.052 398.5 16.1 A 72 0.064 412.6 16.77 A 73 0.021 418.5 16.91 A 74 0.012 581.19 8.44 B 75 0.008 623.24 2.28 D 76 0.004 595.6 17.16 A 160983.doc -246- 20124765646 0.063 531.6 14.33 A 47 0.088 492.3 6.52 A 48 0.187 402.3 13.73 A 49 0.015 539.17 4.16 C 50 0.007 582.17 3.69 C 51 0.011 617.18 4.57 C 52 0.015 525.15 4.1 C 53 0.024 609.13 7.56 B 54 0.018 593.14 6.97 B 55 0.071 609.14 4.22 C 56 0.0071 553.18 4.4 C 57 0.26 578.18 8.23 B 58 0.088 539.17 6 B 59 0.039 609.13 6.75 B 60 0.009 601.18 4.73 C 61 0.003 578.18 8.98 B 62 0.011 529.16 7.84 B 63 0.042 617.19 9.78 B 64 0.031 578.17 9.18 B 65 0.045 601.18 7.23 B 66 0.049 611.13 4.39 C 67 0.1835 402.3 13.48 A 68 593.14 6.77 B 69 0.002 597.4 16.51 A 70 0.067 402.5 15.7 A 71 0.052 398.5 16.1 A 72 0.064 412.6 16.77 A 73 0.021 418.5 16.91 A 74 0.012 581.19 8.44 B 75 0.008 623.24 2.28 D 76 0.004 595.6 17.16 A 160983.doc -246- 201247656

77 0.003 625.6 17.66 A 78 0.005 599.2 7.91 B 79 0.004 627.18 17.35 A 80 0.006 657.24 9.57 B 81 0.009 612.23 4.74 B 82 0.006 609.22 7.11 B 83 0.003 629.21 7.16 B 84 0.004 609.22 16.76 A 85 0.002 583.5 16.78 A 86 0.006 585.18 7.1 B 87 0.005 639.23 17.73 A 88 0.002133 610.3 7.08 A 89 0.003 652.23 7.62 B 90 0.004 625.22 7.95 B 91 0.012 637.25 17.92 A 92 0.004 623.5 8.17 B 93 0.004 625.22 7.65 B 94 0.002 639.5 17.13 A 95 0.005 645.4 17.27 A 96 623.4 17.53 A 97 0.027 550.3 11.24 A 98 0.003 582.3 9.34 A 99 0.002 597.3 10.73 A 100 0.004 567.3 13.4 A 101 0.011 591.3 11.52 A 102 0.0045 585.3 10.83 A 103 0.002 555.3 11.42 A , 104 0.021 543.3 11.85 A 105 0.002 581.3 14.04 A 106 0.014 591.3 11.98 A 107 <0.001 555.3 11.66 A 160983.doc -247· 20124765677 0.003 625.6 17.66 A 78 0.005 599.2 7.91 B 79 0.004 627.18 17.35 A 80 0.006 657.24 9.57 B 81 0.009 612.23 4.74 B 82 0.006 609.22 7.11 B 83 0.003 629.21 7.16 B 84 0.004 609.22 16.76 A 85 0.002 583.5 16.78 A 86 0.006 585.18 7.1 B 87 0.005 639.23 17.73 A 88 0.002133 610.3 7.08 A 89 0.003 652.23 7.62 B 90 0.004 625.22 7.95 B 91 0.012 637.25 17.92 A 92 0.004 623.5 8.17 B 93 0.004 625.22 7.65 B 94 0.002 639.5 17.13 A 95 0.005 645.4 17.27 A 96 623.4 17.53 A 97 0.027 550.3 11.24 A 98 0.003 582.3 9.34 A 99 0.002 597.3 10.73 A 100 0.004 567.3 13.4 A 101 0.011 591.3 11.52 A 102 0.0045 585.3 10.83 A 103 0.002 555.3 11.42 A , 104 0.021 543.3 11.85 A 105 0.002 581.3 14.04 A 106 0.014 591.3 11.98 A 107 <0.001 555.3 11.66 A 160983.doc -247· 201247656

108 0.037 526.3 9.94 A 109 0.03 543.3 11.57 A 110 0.183 573.2] 12.89 A 111 0.243 593.2 13.18 A 112 0.173 666.4 12.61 A 113 0.044 440.6 16.03 A 114 0.09 414.5 12.96 A 115 0.004 506.3 11.8 A 116 0.064 428.6 13.88 A 117 0.739 452.5 13.93 A 118 0.002 609.4 12.09 A 119 0.009 609.4 12.12 A 120 0.006 613.3 10.87 A 121 0.007 613.3 10.87 A 122 0.002 625.4 9.33 A 123 0.002 611.3 8.46 A 124 0.004 611.3 8.46 A 125 0.018 621.4 12.74 A 126 0.011 637.3 13.87 A 127 0.003 608.3 12.96 A 128 0.009 625.3 9.86、10.06 A 129 0.096 409.2 12.3 A 130 0.001 609.3 14.24 A 131 0.261 609.3 14.27 A 132 0.108 610.3 7.09 A 133 418.2 14.01 A 134 398.5 13.56 A 135 0.002333 595.3 13.58 A 136 0.26 595.3 13.61 A 137 0.0015 624.3 7.15 A 138 0.001 638.3 7.21 A 160983.doc • 248 * 201247656108 0.037 526.3 9.94 A 109 0.03 543.3 11.57 A 110 0.183 573.2] 12.89 A 111 0.243 593.2 13.18 A 112 0.173 666.4 12.61 A 113 0.044 440.6 16.03 A 114 0.09 414.5 12.96 A 115 0.004 506.3 11.8 A 116 0.064 428.6 13.88 A 117 0.739 452.5 13.93 A 118 0.002 609.4 12.09 A 119 0.009 609.4 12.12 A 120 0.006 613.3 10.87 A 121 0.007 613.3 10.87 A 122 0.002 625.4 9.33 A 123 0.002 611.3 8.46 A 124 0.004 611.3 8.46 A 125 0.018 621.4 12.74 A 126 0.011 637.3 13.87 A 127 0.003 608.3 12.96 A 128 0.009 625.3 9.86, 10.06 A 129 0.096 409.2 12.3 A 130 0.001 609.3 14.24 A 131 0.261 609.3 14.27 A 132 0.108 610.3 7.09 A 133 418.2 14.01 A 134 398.5 13.56 A 135 0.002333 595.3 13.58 A 136 0.26 595.3 13.61 A 137 0.0015 624.3 7.15 A 138 0.001 638.3 7.21 A 160983.doc • 248 * 201247656

139 0.001 640.3 7.05 A 140 0.001 624.3 7.2 A 141 0.002 610.3 7.02 A 142 0.002 624.3 7.21 A 143 0.0019 638.3 7.14 A 144 0.002 610.3 6.98 A 145 0.001 624.3 7.19 A 146 0.002 710.4 2.23 D 147 0.001 652.4 2.34 D 148 0.002 638.3 2.17/ D 149 0.003 738.4 2.40/ D 150 0.004 638.3 2.21/ D 151 0.003 724.4 2.40/ D 152 0.003 666.4 2.31/ D 153 0.004 738.4 2.43/ D 154 0.003 623.3 2.28/ D 155 0.003 652.4 2.15 D 156 0.001 638.3 2.15 D 157 0.001 650.4 2.13 D 158 0.002 623.3 2.35 D 159 0.003 724.4 2.22 D 160 0.001 652.4 2.16 D 161 0.001 740.4 2.18 D 162 0.002 724.4 2.38 D 163 0.001 638.3 2.12 D 164 0.001 623.3 2.27 D 165 0.002 710.4 2.2 D 166 0.982 543.5 15.74 A 167 0.0035 639.3 14.32 A 168 3.8165 615.5 14.95 A 169 0.003 629.2 15.57 A I60983.doc -249- 201247656139 0.001 640.3 7.05 A 140 0.001 624.3 7.2 A 141 0.002 610.3 7.02 A 142 0.002 624.3 7.21 A 143 0.0019 638.3 7.14 A 144 0.002 610.3 6.98 A 145 0.001 624.3 7.19 A 146 0.002 710.4 2.23 D 147 0.001 652.4 2.34 D 148 0.002 638.3 2.17/ D 149 0.003 738.4 2.40/ D 150 0.004 638.3 2.21/ D 151 0.003 724.4 2.40/ D 152 0.003 666.4 2.31/ D 153 0.004 738.4 2.43/ D 154 0.003 623.3 2.28/ D 155 0.003 652.4 2.15 D 156 0.001 638.3 2.15 D 157 0.001 650.4 2.13 D 158 0.002 623.3 2.35 D 159 0.003 724.4 2.22 D 160 0.001 652.4 2.16 D 161 0.001 740.4 2.18 D 162 0.002 724.4 2.38 D 163 0.001 638.3 2.12 D 164 0.001 623.3 2.27 D 165 0.002 710.4 2.2 D 166 0.982 543.5 15.74 A 167 0.0035 639.3 14.32 A 168 3.8165 615.5 14.95 A 169 0.003 629.2 15.57 A I60983.doc -249- 201247656

170 0.004 643.2 16.03 A 171 0.002 639.3 14.02 A 172 0.0012 609.6 13.8 A 173 0.001 623.6 15 A 174 5.113 493.2 15.41 A 175 >10 389.2 6.89 A 176 1.41285 571.5 16.35 A 177 0.002 597.2 14.33 A 178 0.001 602.2 14.89 A 179 0.001 609.2 14.81 A 180 <0.0002 623.2 14.74 A 181 0.003 376.4 14.22 182 0.002 545.3 6.78 A 183 0.0018 623.5 15.31 A 184 0.0017 611.2 13.24 A 185 0.001 627.2 14.41 A 186 0.001 643.2 13.57 A 187 0.001 625.2 13.96 A 188 0.001 638.8 14.04 A 189 0.001 628.8 13.5 A 190 0.001 559.4 15.28 A 191 0.001 560.4 15.33 A 192 0.003 530.1 14.74 A 193 0.001 533.4 14.21 A 194 0.002 625.2 13.26 A 195 0.003 643.2 14.24 A 196 0.001 655.3 13.87 A 197 0.0046 639.2 14.58 A 198 0.001 651.3 14.21 A 199 0.002 645.2 14.63 A 200 0.001 659.3 14.75 A 160983.doc •250- 201247656170 0.004 643.2 16.03 A 171 0.002 639.3 14.02 A 172 0.0012 609.6 13.8 A 173 0.001 623.6 15 A 174 5.113 493.2 15.41 A 175 >10 389.2 6.89 A 176 1.41285 571.5 16.35 A 177 0.002 597.2 14.33 A 178 0.001 602.2 14.89 A 179 0.001 609.2 14.81 A 180 <0.0002 623.2 14.74 A 181 0.003 376.4 14.22 182 0.002 545.3 6.78 A 183 0.0018 623.5 15.31 A 184 0.0017 611.2 13.24 A 185 0.001 627.2 14.41 A 186 0.001 643.2 13.57 A 187 0.001 625.2 13.96 A 188 0.001 638.8 14.04 A 189 0.001 628.8 13.5 A 190 0.001 559.4 15.28 A 191 0.001 560.4 15.33 A 192 0.003 530.1 14.74 A 193 0.001 533.4 14.21 A 194 0.002 625.2 13.26 A 195 0.003 643.2 14.24 A 196 0.001 655.3 13.87 A 197 0.0046 639.2 14.58 A 198 0.001 651.3 14.21 A 199 0.002 645.2 14.63 A 200 0.001 659.3 14.75 A 160983.doc •250- 201247656

201 643.3 15.55 A 202 0.001 728.3 2.21 D 203 0.001 645.2 2.43 D 204 0.002 633.2 2.32 D 205 0.004 638.1 2.38 D 206 0.001 604.1 2.13 D 207 603.1 2.21 D 208 0.0014 701.2 2.29 D 209 0.001 592.1 2.14 D 210 0.003 652.1 1.79 D 211 0.002 606.1 2.36 D 212 0.002 674.2 2.38 D 213 0.001 627.1 2.25 D 214 0.001 603.1 2.16 D 215 0.002 592.2 2.34 D 216 0.001 637.3 13.63 A 217 0.001 623.2 12.73 A 218 0.001 667.3 15.39 A 219 623.2 14.75 A 220 0.015 374.2 14.17 221 0.019 495.1 14.79 A 222 0.002 606.2 2.14 D 223 0.009 613.2 16.14 A 224 701.3 7.4 A 225 0.001 625.2 13.72 A 226 0.009 659.1 15.15 A 227 0.001 671.2 14.94 A 228 641.3 12.97 A 229 0.001 657.2 14.1 A 230 0.006 598.1 15.77 A 231 0.001 628.2 15.91 A 160983.doc •251 - 201247656201 643.3 15.55 A 202 0.001 728.3 2.21 D 203 0.001 645.2 2.43 D 204 0.002 633.2 2.32 D 205 0.004 638.1 2.38 D 206 0.001 604.1 2.13 D 207 603.1 2.21 D 208 0.0014 701.2 2.29 D 209 0.001 592.1 2.14 D 210 0.003 652.1 1.79 D 211 0.002 606.1 2.36 D 212 0.002 674.2 2.38 D 213 0.001 627.1 2.25 D 214 0.001 603.1 2.16 D 215 0.002 592.2 2.34 D 216 0.001 637.3 13.63 A 217 0.001 623.2 12.73 A 218 0.001 667.3 15.39 A 219 623.2 14.75 A 220 0.015 374.2 14.17 221 0.019 495.1 14.79 A 222 0.002 606.2 2.14 D 223 0.009 613.2 16.14 A 224 701.3 7.4 A 225 0.001 625.2 13.72 A 226 0.009 659.1 15.15 A 227 0.001 671.2 14.94 A 228 641.3 12.97 A 229 0.001 657.2 14.1 A 230 0.006 598.1 15.77 A 231 0.001 628.2 15.91 A 160983 .doc •251 - 201247656

232 0.001 613.2 13.77 A 233 0.002 642.2 16.26 A 234 0.001 642.1 16.2 A 235 627.2 14.99 A 236 0.003 390.1 13.86 A 237 0.042 403.2 1.16 E 238 0.002 554.2 7.65 B 239 0.002 547.2 7.8 B 240 534.2 7.62 B 241 0.001 519.2 6.88 B 242 0.005 563.1 8.07 B 243 0.002 547.2 7.75 B 244 0.002 564.2 7.75 B 245 0.005 493.2 7.3 B 246 0.004 577.2 7.75 B 247 0.002 519.2 6.57 B 248 0.002 547.2 6.82 B 249 0.019 613.2 8.03 B 250 0.0055 597.2 8.06 B 251 0.004 565.2 7.73 B 252 0.002 586.2 7.22 B 253 0.002 586.2 7.13 B 254 0.015 533.2 7.49 B 255 0.005 547.2 6.57 B 256 0.001 557.2 8.07 B 257 0.002 559.2 7.74 B 258 0.007 559.2 7.54 B 259 0.007 554.2 15.23 A 260 0.008 547.1 14.54 A 261 0.199 540.1 2.44 D 262 0.025 558.1 2.14 D 160983.doc - 252- 201247656232 0.001 613.2 13.77 A 233 0.002 642.2 16.26 A 234 0.001 642.1 16.2 A 235 627.2 14.99 A 236 0.003 390.1 13.86 A 237 0.042 403.2 1.16 E 238 0.002 554.2 7.65 B 239 0.002 547.2 7.8 B 240 534.2 7.62 B 241 0.001 519.2 6.88 B 242 0.005 563.1 8.07 B 243 0.002 547.2 7.75 B 244 0.002 564.2 7.75 B 245 0.005 493.2 7.3 B 246 0.004 577.2 7.75 B 247 0.002 519.2 6.57 B 248 0.002 547.2 6.82 B 249 0.019 613.2 8.03 B 250 0.0055 597.2 8.06 B 251 0.004 565.2 7.73 B 252 0.002 586.2 7.22 B 253 0.002 586.2 7.13 B 254 0.015 533.2 7.49 B 255 0.005 547.2 6.57 B 256 0.001 557.2 8.07 B 257 0.002 559.2 7.74 B 258 0.007 559.2 7.54 B 259 0.007 554.2 15.23 A 260 0.008 547.1 14.54 A 261 0.199 540.1 2.44 D 262 0.025 558.1 2.14 D 160983.doc - 252- 201247656

263 0.108 489.2 2.39 D 264 0.538 503.2 2.43 D 265 0.601 481.2 2.49 D 266 0.142 578.2 2.39 D 267 0.064 510.1 2.2 D 268 0.62 489.2 2.36 D 269 0.33 489.2 2.37 D 270 0.019 518.2 2.34 D 271 2.47 482.2 2.12 D 272 0.001 609.2 14.15 A 273 0.001 641.4 12.87 A 274 0.001 657.2 14 A 275 0.002 547.4 14.31 A 276 0.002 607.5 15.04 A 277 0.002 589.2 14.81 A 278 0.001 657.3 14.46 A 279 0.0011 657.2 13.52 A 280 0.001 631.2 13.51 A 281 0.003 565.1 15.58 A 282 0.031 597.1 16.45 A 283 0.004 577.2 15.44 A 284 0.003 563.4 13.81 A 285 0.002 641.3 15.2 A 286 0.001 649.2 14.09 A 287 0.001 631.2 13.53 A 288 0.002 643.3 12.21 A 289 0.001 637.5 13.42 A 290 0.002 418.2 14.92 A 291 0.008 404.5 14.02 292 0.0023 656.8 15.79 A 293 0.005 420.1 13.56 A 160983.doc -253 - 201247656263 0.108 489.2 2.39 D 264 0.538 503.2 2.43 D 265 0.601 481.2 2.49 D 266 0.142 578.2 2.39 D 267 0.064 510.1 2.2 D 268 0.62 489.2 2.36 D 269 0.33 489.2 2.37 D 270 0.019 518.2 2.34 D 271 2.47 482.2 2.12 D 272 0.001 609.2 14.15 A 273 0.001 641.4 12.87 A 274 0.001 657.2 14 A 275 0.002 547.4 14.31 A 276 0.002 607.5 15.04 A 277 0.002 589.2 14.81 A 278 0.001 657.3 14.46 A 279 0.0011 657.2 13.52 A 280 0.001 631.2 13.51 A 281 0.003 565.1 15.58 A 282 0.031 597.1 16.45 A 283 0.004 577.2 15.44 A 284 0.003 563.4 13.81 A 285 0.002 641.3 15.2 A 286 0.001 649.2 14.09 A 287 0.001 631.2 13.53 A 288 0.002 643.3 12.21 A 289 0.001 637.5 13.42 A 290 0.002 418.2 14.92 A 291 0.008 404.5 14.02 292 0.0023 656.8 15.79 A 293 0.005 420.1 13.56 A 160983.doc -253 - 201247656

294 0.007 517.3 13.08 A 295 0.004 543.2 13.03 A 296 0.005 557.3 13.45 A 297 0.001 543.2 12.33 A 298 0.001 557.2 12.33 A 299 0.005 448.5 13.07 300 0.031 564.1 14.79 A 301 0.004 585.2 14.32 A 302 0.003 554.2 13.74 A 303 0.004 596.2 15.55 A 304 0.005 568.2 14.3 A 305 0.004 568.2 14.05 A 306 0.0053 510.1 13.32 307 0.006 477.2 7.32 ' 7.64 A 308 0.014 390.5 13.82 309 0.054 467.1 17.57 A 310 0.004 489.2 7.35 ' 7.85 A 311 0.002 461.8 12.88 A 312 0.002 443.2 14.94 A 313 0.0315 404.2 13.55 A 314 0.006 427.8 13.88 A 315 0.006 448.1 14.44 A 316 0.003 432.3 14.19 A 317 0.0241 414.2 12.27 A 318 0.014 490.3 14.7 A 319 0.004 490.2 14.04 A 320 0.006 476.2 14.29 A 321 0.002 476.2 13.52 A 322 0.006 404.2 13.07 A 323 0.003 448.3 12.86 A 324 0.085 427.9 12.45 A 160983.doc -254- 201247656294 。。。。。。。。。。。。。。。。。。 A 314 0.006 427.8 13.88 A 315 0.006 448.1 14.44 A 316 0.003 432.3 14.19 A 317 0.0241 414.2 12.27 A 318 0.014 490.3 14.7 A 319 0.004 490.2 14.04 A 320 0.006 476.2 14.29 A 321 0.002 476.2 13.52 A 322 0.006 404.2 13.07 A 323 0.003 448.3 12.86 A 324 0.085 427.9 12.45 A 160983.doc -254- 201247656

325 0.006 459.8 14.87 A 326 0.8815 446.3 13.68 A 327 0.004 478.6 12.57 ' 12.72 A 328 0.006 448.3 13.51 A 329 0.005 420.5 12.66 A 330 0.003 478.3 11.66 ' 11.93 A 331 0.008 464.3 7.92 A 332 0.012 434.2 8.32 A 333 0.01 478.3 11.7 A 334 0.003 403.8 13.5 A 335 0.024 402.1 A 336 0.003 448.3 10.28 A 337 0.002 448.2 10.89 A 338 0.031 462.3 [M-ΗΤ] 9.95 A 339 0.008 446 13.67 A 340 0.008 403.0 7.21 A 341 0.005 446 13.17 A 342 0.018 432 13.51 A 343 0.001 432 13.29 A。。。。。 0.003 403.8 13.5 A 335 0.024 402.1 A 336 0.003 448.3 10.28 A 337 0.002 448.2 10.89 A 338 0.031 462.3 [M-ΗΤ] 9.95 A 339 0.008 446 13.67 A 340 0.008 403.0 7.21 A 341 0.005 446 13.17 A 342 0.018 432 13.51 A 343 0.001 432 13.29 A

I60983.doc 255 -I60983.doc 255 -

Claims

201247656 七、申請專利範圍： 1 · 一種式（I)化合物，201247656 VII. Patent application scope: 1 · A compound of formula (I),

或其鹽，其中 φ m為 0、1 或2 ; η為〇或1，其中m+n為1、2或3 ; Ri為C3_Ci〇块基或苯基’該苯基經〇、1、2或3個獨立地選自由以下組成之群的取代基取代：鹵素、經基、氛基、CrC4烧基、鹵基C1-C4烧基及C^-C4烧氧基，且該決基視情況經CrC7環烷基取代基取代，該環烷基視情況經 1或2個獨立選擇之烷基取代； R2為C〇2H、四唑或羧酸電子等排體； # R3為經0、1、2或3個鹵素原子取代之c3-c7環烷基；表示0、1、2、3或4個在每次出現時獨立地選自由以下組成之群的殘基：羥基、胺基、氰基、鹵素、烷基、CrC6烷氧基，其中各烷基或烷氧基取代基係經〇、1或2個獨立地選自以下之取代基取代：羥基、氰基 Cl-C4烷氧基、CrC4烷基砜、N(R3b)2、 C(0)N(R_3b)、具有4至7個環原子及1或2個選自N、〇或$ 之環雜原子的雜環及5或6員雜芳基；或兩個偕位^取代 160983.doc 201247656 基組合起來形成螺環狀3至6員環烷基或雜環； Rsb在每次出現時獨立地選自氫、c丨·C4烷基、c丨·^烷氧基c「C4烧基及Ci-c：4烧酿基；或N(R3b)2組合起來形成具有0或1個選自N、0或S之其他環雜原子的4至6員雜環； X為 Ο、N-L-R4 或 CR5R6 ; L 為一鍵、S(0)2 或 C(O); 汉4為(：1-(：6烷基或CrC7環烷基，其各自經〇、個羥基及0或1個選自以下之取代基取代；氰基、s(〇)2_CiC4 烷基、C02H4NR4aR4b或苯基； R·4為萘基或苯基’該苯基經〇、1、2或3個獨立地選自由以下組成之群的取代基取代：齒素、氰基、^&烷基、鹵基C丨-C6烷基、Ci-C6烷氧基、鹵基c丨_c6烷氧基、胺基、羥基、單Cl-C6烷基胺基及二基胺基、羥基CVC4烷基、胺基烷基、CVC6烷基_〇C(0)NH·、 c「C4烷基·ί：(0)ΝΗ·、_c(0)NR4aR4b、苯基苯氧基具有一或兩個環氮原子且具有〇、個Ci_C4烷基取代基之雜芳基，或兩個取代基組合形成稠合雜環，該雜環具有5、6或7個環原子、丨或2個選自N、〇或3之環雜原子且該雜環經0、1或2個獨立地選自Ci_C6烷基之取代基取代；或 I為具有1至3個選自Ν、Ο或s之雜原子的5或6員雜芳基，該雜芳基經0、1或2個獨立地選自由以下組成之群的取代基取代：鹵素、氰基、Ci_C6烷基、鹵基Ci_C6烷 160983.doc 201247656 基、CVC6烷氧基、鹵基Cj-Ce烷氧基、羥基、NR4aR4b、經基C1-C4烧基、胺基Ci-C4烧基、CVC6烧基-0C(0)NH-、（:3_(：7環烷基、Cs-C7環烯基、苯基、具有丄或2個選自 Ν、Ο或S之％雜原子的55或ό員雜芳基，或飽和或部分不飽和單環或雙環雜環’該雜環在各環中具有1或2個環 Ν、Ο或S原子、5至7個環原子且經〇、1或2個獨立地選自由以下組成之群的取代基取代：鹵素、c〗_c6烷基、烷醯基、CVC6烷氧基C(0)N(H)_、_Ci_C6烷氧基 C(0)N(H)CH2·、胺基 Cl_C4 烷基、Ci_C4 烷氧基 Ci_C4 烷基及NR^Rc ’且其中該苯基或雜芳基取代基未經取代或經 1或2個獨立選擇之選自以下之取代基取代：函素、 C02H、氰基、Cl-C4院基、Cl_C4烧氧基、⑶以^‘或 C(0)NR4aR4b ;或 R·4為具有1個環氮及〇或1個選自N、〇或s之其他環雜原子的飽和雜環，該雜環經〇、1或2個獨立地選自由以下組成之群的取代基取代：Ci_C6烷基、c〇2Ci_C0烷基或 C〇2苯甲基； Rh在每次出現時獨立地選自由氫及Cl_C6烷基組成之群，其中該烷基取代基未經取代或經以下取代：羥基、 Ci-c：4烷氧基、胺基或單Ci_C4烷基胺基及二Ci_C4烷基胺基；土 Ru在每次出現時獨立地選自由以下組成之群：氫、烷基及Ci-C4烷醯基，其中該烷基取代基未經取代或經以下取代：羥基、Ci_C4烷氧基、胺基或單烷 160983.doc 201247656 基胺基及二Ci-q烷基胺基；或 Νυ*組合起來形成具有1個環氮原子及〇或1個選自 Ν、Ο及S之其他環雜原子的雜環，該雜環經〇、1、2或3 個獨立地選自由以下組成之群的取代基取代：_素、羥基、胺基、CVC4烷基、鹵基CVC4烷基、羥基CVC4烷基、胺基CVC4烧基、CVC4烧氧基、CVC4烧氧基Ci-C^烧基’及單c丨-C4烷基胺基及二c「C4烷基胺基； K·5不存在或選自由氫及Cl-c6烷基組成之群； R6為側氧基、氫、經基、胺基、N(H)-J-R7 ; J不存在、為c(o)或s(0)2 ;及心為C〗-C6烧基、苯基或苯甲基’各自視情況經以下取代_ CVC6垸基、Q-C6烧氧基、鹵素、苯基或苯氧基。 2.如請求項1之化合物’其中該化合物為式π化合物或其鹽：Or a salt thereof, wherein φ m is 0, 1 or 2; η is 〇 or 1, wherein m+n is 1, 2 or 3; Ri is C3_Ci 〇 block or phenyl 'the phenyl oxime, 1, 2 Or 3 substituents independently selected from the group consisting of halogen, thiol, aryl, CrC4 alkyl, halo C1-C4 alkyl and C^-C4 alkoxy, and the ruthenium is optionally Substituted by a CrC7 cycloalkyl substituent, which is optionally substituted with 1 or 2 independently selected alkyl groups; R2 is a C〇2H, tetrazole or carboxylic acid isostere; # R3 is via 0,1 a c3-c7 cycloalkyl group substituted with 2 or 3 halogen atoms; representing 0, 1, 2, 3 or 4 residues which are independently selected from the group consisting of: hydroxyl group, amine group, cyanide at each occurrence a halogen, an alkyl group, a CrC6 alkoxy group, wherein each alkyl or alkoxy substituent is substituted with hydrazine, 1 or 2 substituents independently selected from the group consisting of hydroxy, cyano-Cl-C4 alkoxy a CrC4 alkyl sulfone, N(R3b)2, C(0)N(R_3b), a heterocyclic ring having 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, hydrazine or $ and 5 or 6-membered heteroaryl; or two ^^^ replaced 160983.doc 201247656 based combination To form a spirocyclic 3 to 6-membered cycloalkyl or heterocyclic ring; Rsb is independently selected from hydrogen, c丨·C4 alkyl, c丨·· alkoxy c “C4 alkyl and Ci- at each occurrence. c:4 calcined base; or N(R3b)2 combined to form a 4- to 6-membered heterocyclic ring having 0 or 1 other ring hetero atom selected from N, 0 or S; X is deuterium, NL-R4 or CR5R6 L is a bond, S(0)2 or C(O); Han 4 is (: 1-(:6 alkyl or CrC7 cycloalkyl, each of which is oxime, a hydroxyl group and 0 or 1 selected from the following Substituted by a substituent; cyano, s(〇)2_CiC4 alkyl, C02H4NR4aR4b or phenyl; R·4 is naphthyl or phenyl'. The phenyl group is independently selected from the group consisting of ruthenium, 1, 2 or 3 Group substituent substitution: dentate, cyano, ^& alkyl, halo C丨-C6 alkyl, Ci-C6 alkoxy, halo c丨_c6 alkoxy, amine, hydroxy, single Cl-C6 alkylamino group and diylamino group, hydroxy CVC4 alkyl group, aminoalkyl group, CVC6 alkyl group 〇C(0)NH·, c "C4 alkyl · ί: (0) ΝΗ ·, _c (0) NR4aR4b, a phenylphenoxy group having one or two ring nitrogen atoms and having a heteroaryl group of a hydrazine, a Ci_C4 alkyl substituent, or a combination of two substituents a fused heterocyclic ring having 5, 6 or 7 ring atoms, fluorene or 2 ring heteroatoms selected from N, hydrazine or 3 and which are independently selected from Ci_C6 by 0, 1 or 2 Substituted with a substituent of an alkyl group; or I is a 5 or 6 membered heteroaryl group having 1 to 3 hetero atoms selected from ruthenium, osmium or s, the heteroaryl group being independently selected from 0, 1 or 2 by the following Substituted substituents of the group: halogen, cyano, Ci_C6 alkyl, haloCi_C6 alkane 160983.doc 201247656, CVC6 alkoxy, halo Cj-Ce alkoxy, hydroxy, NR4aR4b, trans-group C1-C4 An alkyl group, an amino-based Ci-C4 alkyl group, a CVC6 alkyl group - 0C(0)NH-, (: 3_(:7-cycloalkyl, Cs-C7 cycloalkenyl, phenyl, having an anthracene or two selected from fluorene) , Ο or S% of a hetero atom of 55 or a heteroaryl group, or a saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring. The heterocyclic ring has 1 or 2 ring Ν, Ο or S atoms in each ring, 5 to 7 ring atoms and substituted by hydrazine, 1 or 2 substituents independently selected from the group consisting of halogen, c _ c6 alkyl, alkyl fluorenyl, CVC 6 alkoxy C(0)N (H )_,_Ci_C6 alkoxy C(0)N(H)CH2·, amino-based Cl_C4 alkyl, Ci_C4 alkoxy Ci _C4 alkyl and NR^Rc ' and wherein the phenyl or heteroaryl substituent is unsubstituted or substituted with one or two independently selected substituents selected from the group consisting of: elemental, C02H, cyano, Cl-C4 a group, a Cl_C4 alkoxy group, (3) a ^' or C(0)NR4aR4b; or R·4 is a saturated heterocyclic ring having one ring nitrogen and hydrazine or one other ring hetero atom selected from N, hydrazine or s The heterocyclic ring is substituted with hydrazine, 1 or 2 substituents independently selected from the group consisting of Ci_C6 alkyl, c〇2Ci_C0 alkyl or C〇2 benzyl; Rh is independently selected on each occurrence a group of free hydrogen and a Cl_C6 alkyl group in which the alkyl substituent is unsubstituted or substituted by a hydroxyl group, a Ci-c:4 alkoxy group, an amine group or a mono-Ci_C4 alkylamine group, and a di-Ci-C4 alkylamine. Each of the soil Ru is independently selected from the group consisting of hydrogen, an alkyl group, and a Ci-C4 alkyl fluorenyl group, wherein the alkyl substituent is unsubstituted or substituted by a hydroxy group, a Ci_C4 alkoxy group. , amino or monoalkane 160983.doc 201247656 amide group and di-Ci-q alkylamine group; or Νυ* combined to form a ring nitrogen atom and hydrazine or 1 selected from hydrazine And a heterocyclic ring of another ring hetero atom of S, which is substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _, hydroxy, amine, CVC4 alkyl, halogen Base CVC4 alkyl, hydroxy CVC4 alkyl, amine CVC4 alkyl, CVC4 alkoxy, CVC4 alkoxy Ci-C^alkyl group and mono c丨-C4 alkyl amine group and di c "C4 alkyl amine K.5 is absent or selected from the group consisting of hydrogen and Cl-c6 alkyl; R6 is pendant oxy, hydrogen, thiol, amine, N(H)-J-R7; J is absent, c (o) or s(0)2; and the core is C--C6 alkyl, phenyl or benzyl', each of which is optionally substituted by _CVC6 fluorenyl, Q-C6 alkoxy, halogen, phenyl or Phenoxy. 2. The compound of claim 1 wherein the compound is a compound of the formula π or a salt thereof:

其中 ζ為CH或Ν ; R8係選自氫、co2h ' CVC4烷基、c-c4烷氧基、氰基或鹵素； Κ·9係選自Ci-Ce院基、CVC6烷氧基、苯基、NR9aR9b、 160983.doc , 201247656 N(H)-C(0)-0-Cl-C4炫基及雜環，其中該雜環具有一或兩個環，各環具有5、6或7個環原子、i個環氮原子及… 個選自N、0或s之其他環雜原子，且其中該雜環未經取代或經1、2或3個獨立地選自由以下組成之群的取代基取代：齒素、經基、胺基、Ci_C4院基、齒基基、輕基c,-c4烧基、胺基Cl_c4烧基、Ci_C4^氧基、CA 烷氧基cvc4烷基’及單Cl_c4烷基胺基及二Ci_c4烷基胺基；或 • 心與心組合起來形成選自以下之二價殘基：-0(CH2)p0_ 、-0(CH2)2NH-或·〇(〇Η2)2Ν(〇Η3)-; la係選自由氫及Cl-C6烷基組成之群，其中該烷基取代基未經取代或經以下取代：羥基、Ci_c4烷氧基、胺基或單C1-C4烷基胺基及二CrC：4烷基胺基；及 Rm係選自由以下組成之群：氫、Ci_c6烷基及Ci_c4烷酿基其中該燒基取代基未經取代或經以下取代：經基、C丨-C：4烷氧基、胺基或單Cl_c4烷基胺基及二Ci_C4烷基胺基。 3_如明求項化合物，其中該化合物為式m化合物或其鹽：Wherein ζ is CH or Ν; R8 is selected from hydrogen, co2h 'CVC4 alkyl, c-c4 alkoxy, cyano or halogen; Κ·9 is selected from Ci-Ce, CVC6 alkoxy, phenyl , NR9aR9b, 160983.doc, 201247656 N(H)-C(0)-0-Cl-C4 leukoxyl and heterocycle, wherein the heterocyclic ring has one or two rings, each ring having 5, 6 or 7 rings An atom, i ring nitrogen atoms and other ring heteroatoms selected from N, 0 or s, and wherein the heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of Substitution: dentate, mercapto, amine, Ci_C4, dentate, light base c, -c4 alkyl, amine Cl_c4 alkyl, Ci_C4 oxy, CA alkoxy cvc4 alkyl 'and single Cl_c4 Alkylamino group and diCi_c4 alkylamino group; or • Heart and heart are combined to form a divalent residue selected from the group consisting of -0(CH2)p0_, -0(CH2)2NH- or ·〇(〇Η2) 2Ν(〇Η3)-; la is selected from the group consisting of hydrogen and a C1-C6 alkyl group, wherein the alkyl substituent is unsubstituted or substituted by a hydroxyl group, a Ci_c4 alkoxy group, an amine group or a single C1-C4 group. An alkylamino group and a diCrC:4 alkylamino group; and an Rm system selected from the group consisting of a group of hydrogen, Ci_c6 alkyl and Ci_c4 alkyl wherein the alkyl substituent is unsubstituted or substituted by a trans group, a C丨-C:4 alkoxy group, an amine group or a monoCl_c4 alkylamino group. And two Ci_C4 alkylamino groups. 3) A compound of the formula wherein the compound is a compound of formula m or a salt thereof:

160983.doc 201247656 其中 Re為氫、羥基、胺基或N(H)-J-R7 ; J為 c(o)或 s(o)2; R7為（a)視情況經苯基或苯氧基取代iCl_C4院基，或 (b)視情況經（：丨-(：4烷基、鹵素或匕-匕烷氧基取代之苯基； Rio係選自氫及CrCe院基’該烧基經〇、1或2個經基及〇或1個選自以下之取代基取代：氰基、s〇2CH3、甲氧基’乙氧基〜：^化丨❶山及以。)…!^。^; R10a在每次出現時選自由氫及Cl_C4烷基組成之群，該 Ci-C4烷基經〇或丨個選自羥基、甲氧基或乙氧基之取代基取代； Rn係選自由氫、氟、氰基、羥基及烷基組成之 4.如請求項1之化合物，其中該化合物為式w化合物或其160983.doc 201247656 wherein Re is hydrogen, hydroxy, amine or N(H)-J-R7; J is c(o) or s(o)2; R7 is (a) optionally phenyl or phenoxy Substituting iCl_C4, or (b) as appropriate (: 丨-(: 4-alkyl, halogen or fluorenyl-decyloxy substituted phenyl; Rio is selected from hydrogen and CrCe) , 1 or 2 substituents and hydrazine or 1 substituent selected from the group consisting of: cyano group, s〇2CH3, methoxy 'ethoxy group~: ^ 丨❶ 丨❶ 山 and 。.)...!^.^ R10a is selected from the group consisting of hydrogen and a Cl_C4 alkyl group at each occurrence, the Ci-C4 alkyl group being substituted with hydrazine or a substituent selected from a hydroxyl group, a methoxy group or an ethoxy group; A compound of the formula 1, wherein the compound is a compound of the formula w, or a compound thereof

Rio及R"獨立地選自氫及(：1_(：6烷基，該烷基經0、1或 2個羥基及個選自以下之取代基取代：s〇2CH3、氰 160983.doc -6 · 201247656 基、曱氧基、乙氧基、N(R10a)2及C(0)N(R1Qa)2 ; R1〇a在每次出現時選自由氫及CrC4烷基組成之群，該 CrC4烧基經〇或1個選自以下之取代基取代：羥基、甲氧基或乙氧基，或N(R1Ga)2組合起來形成4至6員雜環； Ru係選自由氫及C〗-C4烷基組成之群。 5. 如凊求項1至4中任一項之化合物，其中Ri為第三丁基乙块基、苯基或經F、Cl、Me對位取代之苯基。 6. 如請求項1至4中任一項之化合物，其中&為第三丁基乙炔基。 7_如請求項【至斗中任一項之化合物，其中R2&c〇2H。 8. 如請求項1至4中任一項之化合物，其中&為環己基。 9. 如請求項3之化合物，其中&為氫； Rio為氫或羥基Cl-c6烷基；及 R"為氫、甲基、羥基或氟。 ίο.如請求項4之化合物，其中Rig為羥基Ci_c6烷基； Ru為氫或曱基；及 R]2為氫或甲基。 Π.如叫求項1之化合物，或其醫藥學上可接受之鹽，其選自由以下組成之群： 3 ((S)-2-環己基_5_側氧基-吡咯啶_丨_基）_5_苯基_噻吩_ 2-甲酸；環己基_6_側氧基-哌啶^―基）_5苯基-噻吩_2_ 酸； (3_環己基-5-側氧基·嗎啉_4_基）_5_笨基_噻吩_2_曱 160983.doc 201247656 酸； 3-[(R)-2-環己基-6-側氧基-4-(甲笨-4-磺醯基）-哌嗪-1-基]-5-苯基-噻吩-2-曱酸； 3-(2_環己基-6-側氧基·哌啶-1-基）-5-(3,3·二曱基-丁 ·1· 炔基）-噻吩-2-甲酸； 3-((S)-2-環己基-6-侧氧基-哌啶-1-基）-5-(3,3-二曱基-丁·l-炔基）-噻吩-2-甲酸； 3-(2-環己基-6-侧氧基-哌啶-1-基）-5-(4-氟-苯基）-噻吩_ 2- 甲酸； 3-(2-環己基-6-側氧基-娘咬-1-基）-5-對甲本基-°塞吩-2_ 甲酸； 5-(4-氣-苯基）-3-(2-環己基-6-側氧基-哌啶-1-基）-噻吩-2 -甲酸； 3-[2-環己基-4-(6-二丙胺基-吡啶-3-磺醯基）-6-側氧基· 0底嗓-1-基]-5-苯基-噻吩-2-甲酸； 3_{(R)-2-環己基-4_[6-((R)-2-曱基-吡咯啶-1-基）-吡啶- 3- 磺醯基]-6-側氧基-哌嗪-1_基}-5·苯基-噻吩-2-曱酸； 3_[(R)-2-環己基-6-側氧基- 4- (6-°比π各0定-1-基比咬_3 -續醯基）-旅嗪-1-基]-5-苯基-噻吩-2-曱酸； 3-{(R)-2-環己基-4-[6-((2S，5R)-2,5-二甲基·吡咯啶-1-基）-°比σ定-3-項酼基]-6-側氧基-α辰嗓-1-基}-5 -苯基-嗟吩-2 -甲酸； 3-[2-環己基-6-側氧基-4-(甲苯-4-磺醯基）-哌嗪-1-基]_ 5-(3,3-二甲基-丁-i_快基）_〇g吩_2_甲酸； I60983.doc • 8 - 201247656 3-{(R)-2-環己基-4-[6-((2R，6S)-2,6-二曱基-嗎啉-4-基）-。比啶-3-磺醯基]-6-側氧基-哌嗪-1-基}-5-笨基-噻吩-2-甲酸； 3-[2-環己基-4-(6-嗎啉-4-基-吡啶-3-磺醯基）-6-側氧基-派。秦-1-基]-5-(3，3-二曱基-丁-1-快基）-11塞吩-2-甲酸， 3-[(R)-2-環己基-4-(6-二乙胺基比啶-3-磺醯基）-6-側氧基底唤基]-5 -苯基-β塞吩-2-曱酸； 3-[(R)-2-環己基-6-側氧基-4-(3,4,5,6-四氩-2Η-[1，2']聯 φ 吡啶基-5'-磺醯基）-哌嗪-1-基]-5-苯基_噻吩-2-甲酸； 3-((R)-4-環己基-2-側氧基-噁唑啶_3·基）-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-曱酸； 3 - [(R)-2 -環己基-4-(6 -嗎琳-4-基-〇比咬-3-罐醯基）-6-側氧基-0底唤基]-5 -苯基-售吩-2-曱酸； 3-[(R)-2-環己基-4-(4-甲氧基-苯續酿基）_6-側氧基-痕嗪-1-基]-5-(3,3-二甲基-丁-1-炔基）·噻吩甲酸； 3-[(R)-2-環己基-4-(6-曱氧基-u比„定_3·績醯基）_6_側氧鲁基-〇底°秦-1 -基]-5-(3,3-二甲基-丁 -1 -炔基）塞吩_2_曱酸； 3-[(R)-2-環己基_4·(1-甲基-1Η-»比吐-3-續酿基）_6-側氧基-派°桊-1-基]-5-(3,3-二曱基-丁-i_炔基）_嘆吩_2_曱酸； 3-{(尺)-2-環己基-4-[6-(8-氧雜-3-氧雜-雙環[32.1]辛-3- 基）-°比咬-3-績酿基]-6-側氧基-派。秦_1_基}_5_對甲苯基-嗟吩-2-甲酸； 3-(2-環己基-5·側氧基比咯啶基）_5_(3,3_二甲基丁 _ 1-炔基）-噻吩-2-曱酸； 160983.doc 201247656 3-((R)-3-環己基-5-側氧基·嗎啉_4-基）-5-(3,3-二甲基· 丁-1-炔基）-噻吩-2-曱酸； 3-((4S，5R)-5-環己基-3,4-二甲基-2-側氧基·咪唑啶_1_ 基）-5-(3,3-二曱基-丁-1-炔基）_嗟吩_2_甲酸； 5-(4-氣-苯基）-3-((R)-3-環己基-5-側氧基-嗎啉-4-基）- 噻吩-2-甲酸； 3-[(R)-5·環己基-2-(2-嗎啉-4-基-2-側氧基·乙基）-3-側氧基-嗎啉-4-基]-5-(3,3-二甲基_丁_1_炔基）_噻吩_2_甲酸； 3-[(1〇-5-環己基-2-(3-羥基_丙基）_3-側氧基_嗎啉_4- 基]-5-(3,3-二甲基-丁 _1_炔基噻吩·2_甲酸； 3-[(R)-5·環己基-2-(3-甲烷磺醯基·丙基）_3_側氧基_嗎啉_4_基]·5-(3,3-二甲基·丁·ι_炔基）_噻吩_2·甲酸； 3-{(R)-5-環己基·2·[(2-甲氧基-乙胺基）_甲基]_3_側氧基-嗎啉_4-基}-5-(3,3-二曱基-丁 _ΐ·炔基广噻吩_2_甲酸； 3-(4-環己基-2-側氧基_[1，3]氧氮雜環己烷_3_基 (3,3-二曱基-丁-1-炔基）-1»塞吩_2_甲酸； 3-((R)-5-環己基-2-嗎啉-4-基曱基-3-側氧基-嗎啉_4_ 基）-5-(3,3-二甲基-丁-1-快基）_售吩甲酸； 3-[(2R，5R)-5-環己基-2-(3-羥基-丙基）_2_甲基_3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁_ι·炔基）_噻吩_2_甲酸； 3-((2S，5R)-2-氰基甲基_5_環己基-2-曱基側氧基-嗎琳-4-基）-5-(3，3-一曱基-丁 -1 -快基）-嗟吩曱酸； 3-(6-環己基-3-羥基-2-侧氧基-哌啶·二曱 160983.doc -10· 201247656 基-丁-1-炔基）-噻吩-2-甲酸； 3-((R)-5-環己基- 2,2-二曱基-3-側氧基-嗎嚇·_4-基）-5-對甲苯基-噻吩-2-甲酸； 3-(6-環己基-3-羥基-2-側氧基-哌啶-1-基）-5-對甲笨基_ 噻吩-2-甲酸； 3-[(2S，5R)-5-環己基-2-(3-羥基-3-曱基-丁基）-2-甲基-3-側氧基-嗎啉-4-基]-5-(3,3-二曱基-丁-1-炔基）_噻吩_2_ 甲酸； φ 3-[(2R，5R)-5-環己基-2-(3-羥基-3-甲基-丁基）_2_曱基- 3-側氧基-嗎淋-4-基]-5-(3,3-二甲基-丁-1-炔基）·嗔吩-2_ 甲酸； 3-[(28,51^)-5-環己基-2-((尺)-3-經基-丁基）-2-曱基-3-側氧基-嗎琳-4-基]-5-(3,3-二曱基-丁-1-快基）-嗟吩_2-甲酸； 3-[(2R，5R)-5-環己基- 2-((R)-3-經基-丁基）-2-曱基 _3_側氧基-嗎琳-4-基]-5-(3，3-二曱基-丁-1-炔基）_嚷吩_2_甲 Φ 酸； 3-((S)-6-環己基-3-經基_2_側氧基辰咬-1_基）_5_(3,3_ 二曱基-丁-1-炔基）-噻吩-2-甲酸； 3-[(2R，5R)-5 -環己基-2-(2 -經基-乙基）-2-甲基_3_側氧基-嗎淋-4-基]-5-(3,3-二曱基-丁-1-快基）-〇塞吩_2·甲酸； 3-(6-環己基-3-經基-3 -甲基-2-側氧基-«»辰咬_丨_基）-對曱苯基-噻吩-2-曱酸； 3-((R)-3-環己基-5-側氧基-1，9-二氧雜-4-氧雜_螺[5.5] 160983.doc -11 - 201247656 碳-4-基）-5-(3,3-二曱基-丁-1-快基）-〇塞吩_2-甲酸； 3-[6-環己基-3-(3-經基-丙基）-2-侧氧基底咬基] (3,3-二f基-丁-1-炔基）-噻吩-2-甲酸； 3-[(2S，5R)-5-環己基-2-(2,3-二羥基-丙基）_2_曱基_3_側氧基-嗎蛛-4-基]-5-(3,3-二甲基-丁-1-炔基）塞吩_2_甲酸； 3-[(2S，5R)-5-環己基- 2- (2-經基-乙基）_2_曱基_3_側氧基-嗎啦-4-基]-5-(3,3-二曱基-丁-1-快基）-嗟吩·2_甲酸； 3-((R)-5 -環己基-2-經甲基-3 -側氧基-嗎琳-4-基）_5_ (3,3·二甲基-丁-1-炔基）-噻吩-2·甲酸； 3-[(2R，5R)-5-環己基-2-(2,3-二羥基-丙基）_2_甲基_3_側氧基-嗎琳-4-基]-5-(3,3-二甲基-丁-1-炔基）塞吩_2_甲酸； 3-[(2S，5R)-5-環己基·2-(2,3-二經基-丙基）_3_側氧基-嗎淋-4-基]-5-(3，3-二甲基-丁-1-块基°塞吩-2-甲酸； 3-[(2S，5 R)-5-環己基-2-(2-經基-乙基）-3-側氧基-嗎琳_ 4-基]-5-(3,3-二甲基-丁-1-块基）-0塞吩-2-甲酸； 3-[6-環己基-3-經基-3-(3-經基-丙基）-2-侧氧基辰咬_ι_ 基]-5-(3,3-二曱基-丁-1-炔基）-噻吩-2-甲酸； 3-[(2R，5R)-5-環己基-2-(2,3-二羥基-丙基）_3_側氧基-嗎啉-4-基]-5·(3,3-二甲基-丁-1-炔基）-噻吩-2-曱酸； 3-[(2R，5R)-5-環己基-2-(2-羥基-乙基）_3_側氧基_嗎啉_ 4-基]-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-曱酸； 3-[(2S,5R)-5-環己基-2-(3-羥基-丙基）-2-甲基-3-側氧 160983.doc -12· 201247656 基-嗎淋-4-基]-5-(3，3-二甲基-丁 -1 -快基）-隹吩-2·甲酸； 3-((S)-6·環己基-3-經基-2-側氧基-派咬-1-基）-5-(3,3-二甲基-丁-1-炔基）-噻吩-2-曱酸； 3-[(2R，5R)-5-環己基-2-(3-輕基-丙基）-3-側氧基-嗎你-4-基]-5-(3，3-二曱基丁-1-炔基）-噻吩-2-曱酸； 3-[(2S，5R)-5-環己基-2-(3-經基-丙基）-3-側氧基-嗎琳_ 4·基]-5-(3，3- —曱基-丁 -1 -快基）-售吩-2-曱酸；Rio and R" are independently selected from the group consisting of hydrogen and (:1_(:6 alkyl) substituted by 0, 1 or 2 hydroxyl groups and substituents selected from the group consisting of: s〇2CH3, cyanogen 160983.doc -6 · 201247656 base, decyloxy, ethoxy, N(R10a)2 and C(0)N(R1Qa)2; R1〇a is selected from the group consisting of hydrogen and CrC4 alkyl at each occurrence, the CrC4 is burned The base is substituted with hydrazine or a substituent selected from the group consisting of a hydroxyl group, a methoxy group or an ethoxy group, or N(R1Ga)2 is combined to form a 4- to 6-membered heterocyclic ring; the Ru is selected from hydrogen and C--C4 The compound of any one of items 1 to 4, wherein Ri is a third butyl group, a phenyl group or a phenyl group substituted with a position of F, Cl, Me. The compound of any one of claims 1 to 4, wherein & is a third butyl acetylene group. 7_A compound according to any one of the claims, wherein R2 & c〇2H. The compound of any one of claims 1 to 4, wherein & is cyclohexyl. 9. The compound of claim 3, wherein & is hydrogen; Rio is hydrogen or hydroxy-Cl-c6 alkyl; and R" is hydrogen , methyl, hydroxyl or fluorine. ίο. as requested And a pharmaceutically acceptable salt thereof, wherein R is a hydroxy Ci_c6 alkyl group; The group consisting of the following components is selected: 3 ((S)-2-cyclohexyl_5_sideoxy-pyrrolidine_丨_yl)_5_phenyl_thiophene-2-carboxylic acid; cyclohexyl_6_sideoxy - piperidine^-yl)_5phenyl-thiophene-2-acid; (3_cyclohexyl-5-sideoxy morpholine _4_yl)_5_stylyl_thiophene_2_曱160983.doc 201247656 acid 3-[(R)-2-Cyclohexyl-6-oxo-4-(methylidene-4-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-indole Acid; 3-(2-cyclohexyl-6-oxooxypiperidin-1-yl)-5-(3,3·didecyl-butan-1·ynyl)-thiophene-2-carboxylic acid; -((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimercapto-butyl-1-ynyl)-thiophene-2-carboxylic acid; 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid; 3-(2-cyclohexyl-6-side Oxy-Nanden-1-yl)-5-p-methyl-based thiophene-2_carboxylic acid; 5-(4-carbo-phenyl)-3-(2-cyclohexyl-6-sideoxy- Piperidin-1-yl)-thiophene-2-carboxylic acid; 3-[2- Cyclohexyl-4-(6-dipropylamino-pyridinyl-3-sulfonyl)-6-oxooxy group 0-indenyl-1-yl]-5-phenyl-thiophene-2-carboxylic acid; 3_{( R)-2-cyclohexyl-4_[6-((R)-2-indolyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazine-1_ }}-5-phenyl-thiophene-2-furoic acid; 3_[(R)-2-cyclohexyl-6-sideoxy- 4- (6-° ratio π each 0--1-base ratio bite_ 3-(Continuation of fluorenyl)-benzal-1-yl]-5-phenyl-thiophene-2-furic acid; 3-{(R)-2-cyclohexyl-4-[6-((2S,5R) -2,5-dimethylpyrrolidin-1-yl)-° ratio sigma-3-ylindolyl]-6-sideoxy-α-chen嗓-1-yl}-5-phenyl-oxime Phen-2-carboxylic acid; 3-[2-cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-(3,3-dimethyl -丁-i_快基)_〇g-pheno-2_carboxylic acid; I60983.doc • 8 - 201247656 3-{(R)-2-cyclohexyl-4-[6-((2R,6S)-2, 6-Dimercapto-morpholin-4-yl)-. Pyridyl-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic acid; 3-[2-cyclohexyl-4-(6-morpholine) 4-yl-pyridine-3-sulfonyl)-6-sideoxy-pie. Qin-1-yl]-5-(3,3-dimercapto-butan-1-yl)-11-cephen-2-carboxylic acid, 3-[(R)-2-cyclohexyl-4-(6 -diethylaminopyridin-3-sulfonyl)-6-oxooxycarbazide]-5-phenyl-β-cephen-2-indole; 3-[(R)-2-cyclohexyl- 6-Sideoxy-4-(3,4,5,6-tetra-argon-2Η-[1,2']-linked φ pyridyl-5'-sulfonyl)-piperazin-1-yl]-5 -phenyl-thiophene-2-carboxylic acid; 3-((R)-4-cyclohexyl-2-oxo-oxazolidine-3-yl)-5-(3,3-dimercapto-butyl- 1-alkynyl)-thiophene-2-decanoic acid; 3 - [(R)-2-cyclohexyl-4-(6-morphin-4-yl-indole ratio -3-canthenyl)-6- Side oxy-0-butylide]-5-phenyl-sodium-2-decanoic acid; 3-[(R)-2-cyclohexyl-4-(4-methoxy-benzoic acid)_6 -Sideoxy-s-azin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophenecarboxylic acid; 3-[(R)-2-cyclohexyl-4-( 6-decyloxy-u ratio _6 _3· 醯 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ) _2 _2 曱曱 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3-桊-1-yl]-5-(3,3-dimercapto-butan-i-alkynyl)_septin_2_decanoic acid; 3-{(foot)-2-cyclohexyl-4-[6 -(8-oxygen -3-oxa-bicyclo[32.1]oct-3-yl)-° ratio biting to the base]-6-side oxy-group. Qin_1_yl}_5_p-tolyl-porphin -2-carboxylic acid; 3-(2-cyclohexyl-5. pendantoxypyrrolidyl)_5_(3,3-dimethylated-1-alkynyl)-thiophen-2-indole; 160983.doc 201247656 3-((R)-3-Cyclohexyl-5-oxooxymorpholine-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2- Citrate; 3-((4S,5R)-5-cyclohexyl-3,4-dimethyl-2-oxo-imidazolidine-1-yl)-5-(3,3-dimercapto-butyl 1-alkynyl)-porphin-2-carboxylic acid; 5-(4-carbo-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl) - thiophene-2-carboxylic acid; 3-[(R)-5.cyclohexyl-2-(2-morpholin-4-yl-2-yloxyethyl)-3-oxo-morpholine- 4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid; 3-[(1〇-5-cyclohexyl-2-(3-hydroxy-propyl) Base)_3-sideoxy-morpholine_4-yl]-5-(3,3-dimethyl-but-1-ynylthiophene-2-carboxylic acid; 3-[(R)-5.cyclohexyl -2-(3-methanesulfonyl propyl) _3_ oxo-morpholine _4_yl]·5-(3,3-dimethyl.butyl·ι_alkynyl)_thiophene_2 · formic acid; 3-{(R)-5-cyclohexyl·2·[(2-methoxy- Ethylamino)_methyl]_3_sideoxy-morpholine-4-yl}-5-(3,3-dimercapto-butan-anthracenyloxythiophene-2-carboxylic acid; 3-(4) -cyclohexyl-2-yloxy-[1,3]oxazepine_3_yl(3,3-dimercapto-but-1-ynyl)-1»cetin-2-carboxylic acid 3-((R)-5-Cyclohexyl-2-morpholin-4-ylindolyl-3-oxo-morpholine-4-yl)-5-(3,3-dimethyl-butyl- 1-fast-based _ benzoic acid; 3-[(2R,5R)-5-cyclohexyl-2-(3-hydroxy-propyl)_2-methyl-3-trioxy-morpholine-4- 5-(3,3-dimercapto-buty-i-alkynyl)-thiophene-2-carboxylic acid; 3-((2S,5R)-2-cyanomethyl-5-cyclohexyl-2 - fluorenyl-oxy-morphine-4-yl)-5-(3,3-indolyl-butan-1-yl)-indolic acid; 3-(6-cyclohexyl-3-hydroxyl -2-Sideoxy-piperidine·dioxin 160983.doc -10· 201247656 ke-but-1-ynyl)-thiophene-2-carboxylic acid; 3-((R)-5-cyclohexyl-2,2 -didecyl-3-o-oxy----- 4-yl)-5-p-tolyl-thiophene-2-carboxylic acid; 3-(6-cyclohexyl-3-hydroxy-2-o-oxy-peri- Pyridin-1-yl)-5-p-methylphenyl thiophene-2-carboxylic acid; 3-[(2S,5R)-5-cyclohexyl-2-(3-hydroxy-3-indolyl-butyl)- 2-methyl-3-oxo-morpholin-4-yl ]-5-(3,3-dimercapto-but-1-ynyl)_thiophene-2-carboxylic acid; φ 3-[(2R,5R)-5-cyclohexyl-2-(3-hydroxy-3- Methyl-butyl)_2-mercapto-3-oxo-oxalin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)·porphin-2_carboxylic acid; 3-[(28,51^)-5-cyclohexyl-2-(())-3-yl-butyl)-2-indolyl-3-yloxy-morphin-4-yl]- 5-(3,3-dimercapto-butan-1-yl)-porphin-2-carboxylic acid; 3-[(2R,5R)-5-cyclohexyl-2-((R)-3- Benzyl-butyl)-2-mercapto-3O-oxy-morphin-4-yl]-5-(3,3-dimercapto-but-1-ynyl)-porphin-2-a Φ acid; 3-((S)-6-cyclohexyl-3-yl-2-yloxyl-l-yl)_5_(3,3-didecyl-but-1-ynyl)-thiophene -2-carboxylic acid; 3-[(2R,5R)-5-cyclohexyl-2-(2-yl-ethyl)-2-methyl-3-trixyl-oxan-4-yl]- 5-(3,3-dimercapto-butan-1-yl)-dextran-2-carboxylic acid; 3-(6-cyclohexyl-3-yl-3-methyl-2-oxooxy -«»辰咬_丨_基)-p-phenyl-thiophene-2-decanoic acid; 3-((R)-3-cyclohexyl-5-sideoxy-1,9-dioxa-4 -oxa-spiro[5.5] 160983.doc -11 - 201247656 carbon-4-yl)-5-(3,3-dimercapto-but-1-propanyl)-deuterium _2-carboxylic acid; 3-[6-cyclohexyl-3-(3-carbyl-propyl)-2-yloxy carbylene] (3,3-dif-but-1-ynyl)-thiophene 2-carboxylic acid; 3-[(2S,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)_2-indolyl_3_sideoxy-pteran-4-yl] -5-(3,3-dimethyl-but-1-ynyl)cetin-2-carboxylic acid; 3-[(2S,5R)-5-cyclohexyl-2-(2-yl-ethyl-ethyl) _2 曱 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ R)-5-cyclohexyl-2-methyl-3-sideoxy-morphin-4-yl)_5_(3,3·dimethyl-but-1-ynyl)-thiophene-2·carboxylic acid 3-[(2R,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)_2-methyl_3_sideoxy-morphin-4-yl]-5-( 3,3-dimethyl-but-1-ynyl)cetin-2-carboxylic acid; 3-[(2S,5R)-5-cyclohexyl·2-(2,3-di-propyl-propyl) _3_Sideoxy-oxalin-4-yl]-5-(3,3-dimethyl-but-1-yl-pyrene-2-carboxylic acid; 3-[(2S,5 R)-5 -cyclohexyl-2-(2-trans)-ethyl-3-oxooxy-morphine-4-yl]-5-(3,3-dimethyl-but-1-blockyl)-0 Cetene-2-carboxylic acid; 3-[6-cyclohexyl-3-yl-3-(3-carbyl-propyl)-2-yloxy-nose _ι_yl]-5-(3,3 -didecyl-but-1-ynyl)-thiophene-2-carboxylic acid; 3-[(2R,5R)-5-cyclohexyl-2-(2,3-dihydroxy-propyl)_3_ side oxygen --morpholin-4-yl]-5·(3,3-dimethyl-but-1-ynyl)-thiophen-2-indole; 3-[(2R,5R)-5-cyclohexyl- 2-(2-hydroxy-ethyl)_3_sideoxy-morpholine-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophen-2-indole; 3-[(2S,5R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-oxo 160983.doc -12· 201247656 ke-l--4-yl] -5-(3,3-dimethyl-butan-1-propanyl)-porphin-2·carboxylic acid; 3-((S)-6·cyclohexyl-3-yl-2-yloxy- Benzyl-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophen-2-indole; 3-[(2R,5R)-5-cyclohexyl-2- (3-light-propyl)-3-tertiaryoxy-?--4-yl]-5-(3,3-dimercapto-1-ynyl)-thiophene-2-furic acid; -[(2S,5R)-5-cyclohexyl-2-(3-carbyl-propyl)-3-yloxy-morphine-4-yl]-5-(3,3--fluorenyl- Ding-1 - fast base) - sold phen-2-pyruic acid;

3-[(2R，5R)-5-環己基-2-((R)-2-羥基-丙基）·3_側氧基_嗎琳-4-基]-5-(3,3-二曱基-丁-1-炔基）_嗔吩_2_曱酸； 3-[(2R，5R)-5-環己基-2-((S)-2-經基-丙基）-3-側氧基_嗎啉-4-基]-5-(3,3-二曱基-丁-1-炔基）_噻吩_2_甲酸； 3-[(S)-6-環己基-3-(3-經基-丙基）_2_側氧基“辰啶丄基]-5-(3,3-二甲基-丁_1_快基）_0塞吩_2_甲酸； 3-((S)·3-胺基-6-環己基-2·側氧基·哌啶_；μ基）_5_(3,3、二甲基-丁-1-块基）-〇塞吩_2_曱酸；及 L 艰一多 _，，，卞Vi必-他°疋· i、基]-5-(3,3-二甲基_丁_1·快基）_α塞吩_2_甲酸。 12. -種醫藥組合物，其包含治療有效量之如請求項^至“ 中任-項之化合物及一或多種醫藥學上可接受之載劑。種、且σ 。羊5之一種醫藥組合，其包含治療有效量 ^請求項111ιΜ壬—項之化合物及—或多種劑。 & 14. 一種如請求項1至11中任-項之化合物的用途於製造供降低個體之病毒負荷的藥劑。其係用 160983.doc •13- 201247656 15,如請求項丨至丨丨中任一項之化合物，其係用作藥劑。 16 —種如請求項丨至丨丨中任一項之化合物的用途其係用於製造供治療個體之由HCV感染引起或與Hcv感染相關之病症或疾病的藥劑。 17·如請求項16之用途，其中該病症或疾病係選自HCv感染、肝硬化、慢性肝病、肝細胞癌、冷球蛋白血症、非霍奇金氏淋巴瘤（non-Hodgkin’s lymphoma)、肝纖維化及抑制性先天細胞内免疫反應。3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)·3_sideoxy-morphin-4-yl]-5-(3,3- Di-mercapto-but-1-ynyl)-porphin-2-indole; 3-[(2R,5R)-5-cyclohexyl-2-((S)-2-yl-propyl)- 3-sided oxy-morpholin-4-yl]-5-(3,3-dimercapto-but-1-ynyl)-thiophene-2-carboxylic acid; 3-[(S)-6-cyclohexyl -3-(3-trans)-propyl)_2_sideoxy "infraninyl]-5-(3,3-dimethyl-but-1-yl)#cetin-2-carboxylic acid; 3-((S)·3-Amino-6-cyclohexyl-2·sideoxy·piperidine _; μ group)_5_(3,3, dimethyl-but-1-blockyl)-coagulation吩_2_曱酸; and L 难一多_,,,卞Vi must-he °疋· i, ki]-5-(3,3-dimethyl-but-1-free base)_α塞_2 - Formic acid 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in the "To" and one or more pharmaceutically acceptable carriers. Kind, and σ. A pharmaceutical combination of sheep 5 comprising a therapeutically effective amount of a compound of claim 111 and a plurality of agents. & 14. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for reducing the viral load of an individual. It is used as a medicament for the use of a compound according to any one of the claims 983 。。。。。。。。。。。。。。。。。。。. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for treating a subject having a condition or disease associated with or associated with Hcv infection. 17. The use of claim 16, wherein the condition or disease is selected from the group consisting of HCV infection, cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia, non-Hodgkin's lymphoma, Liver fibrosis and inhibitory innate intracellular immune response.

160983.doc 14 201247656 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： • 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：160983.doc 14 201247656 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: • 5. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula:

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