TW202208374A - 經取代三環醯胺類、其類似物及使用其之方法 - Google Patents
經取代三環醯胺類、其類似物及使用其之方法 Download PDFInfo
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- TW202208374A TW202208374A TW110117087A TW110117087A TW202208374A TW 202208374 A TW202208374 A TW 202208374A TW 110117087 A TW110117087 A TW 110117087A TW 110117087 A TW110117087 A TW 110117087A TW 202208374 A TW202208374 A TW 202208374A
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- difluoro
- oxo
- pyrano
- tetrahydro
- carboxamide
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Abstract
本發明包括取代的三環醯胺、或其類似物、和包含其的組成物,其可用於治療或預防患者中的B型肝炎病毒(HBV)感染及/或D型肝炎病毒(HDV)感染。
Description
本案根據35 U.S.C.§ 119(e)要求2020年5月14日申請的美國臨時專利申請號63/024,559(其通過引用以其整體併入本文)的優先權。
本案係關於經取代三環醯胺類、其類似物及使用其之方法。
B型肝炎是世界上最流行的疾病之一,被美國過敏和傳染病研究所(NIAID)列為高度優先感興趣的領域。儘管大多數人會在急性症狀後解決感染,但是大約30%的病例會變成慢性病。據估計,全世界有3.5-4億人患有慢性B型肝炎,每年導致50-100萬人死亡,這主要是由於肝細胞癌、肝硬化及/或其它併發症的發展。
目前已批准用於管理慢性B型肝炎的藥物數量有限,包括抑制α-干擾素的兩種調配物(標準的和聚乙二醇化的)和抑制B型肝炎病毒(HBV)DNA聚合酶的五種核苷/核苷酸類似物(拉米夫定(lamivudine)、阿德福韋(adefovir)、恩替卡韋(entecavir)、替比夫定(telbivudine)、和替諾福韋(tenofovir))。目前,一線治療的選擇是恩替卡韋、替諾福韋及/或聚乙二醇干擾素α-2a。然而,聚乙二醇干擾素α-2a僅在三分之一的治療患者中達到了理想的血清學里程碑,並且經常伴有嚴重的副作用。恩替卡韋和替諾福韋是強力的HBV抑制劑,但需要長期或可能終生施用以持續抑制HBV複製,並可能由
於耐藥病毒的出現而最終失敗。因此,迫切需要為慢性B型肝炎引入新型、安全、和有效的療法。
HBV是一種非細胞病變的、向肝性(liver tropic)DNA病毒,屬於肝病毒科。前基因組(Pregenomic,pg)RNA是HBV DNA反轉錄複製的模板。pg RNA與病毒DNA聚合酶一起衣殼化為核衣殼對於隨後的病毒DNA合成至關重要。抑制pg RNA衣殼化可以阻止HBV複製,並為HBV治療提供新的治療方法。衣殼抑制劑通過直接或間接抑制衣殼蛋白的表現及/或功能而發揮作用:例如,它可以抑制衣殼裝配、誘導非衣殼聚合物形成、促進過量的衣殼裝配或衣殼裝配方向錯誤、影響衣殼穩定、及/或抑制RNA衣殼化。衣殼抑制劑還可以通過在複製過程中的一個或多個下游事件,諸如但不限於病毒DNA合成、鬆弛環狀DNA(RcDNA)轉運入細胞核中、共價閉合環狀DNA(cccDNA)形成、病毒成熟、出芽及/或釋放中抑制衣殼功能來發揮作用。
臨床上,抑制pg RNA衣殼化,或更普遍地抑制核衣殼組裝,可提供某些治療優勢。一方面,抑制pg RNA衣殼化可通過為不耐受或不受益於當前藥物的患者的亞群提供選擇來補充當前藥物。另一方面,基於其獨特的抗病毒機制,對pg RNA衣殼化的抑制可有效地抵抗對當前可用的DNA聚合酶抑制劑具有抗性的HBV變體。再另一方面,pg RNA衣殼化抑制劑與DNA聚合酶抑制劑組合療法可協同抑制HBV複製並防止耐藥的出現,因此為慢性B型肝炎感染提供更有效的治療。
D型肝炎病毒(HDV)是僅在HBV存在時才能繁殖的一種小的環狀包膜RNA病毒。具體而言,HDV需要HBV表面抗原蛋白自我繁殖。與單獨感染HBV相比,感染HBV和HDV兩者會導致更嚴重的併發症。這些併發症包括在急性感染中經歷肝衰竭的可能性更大,並迅速發展為肝硬化,並且增加在慢性感染中發展為肝癌的機會。與B型肝炎結合時,D型肝炎在所有肝炎感染中死亡率最高。HDV的傳播途徑與HBV相似。感染主要限於處於HBV感染的高風險人群,特別是注射吸毒者和接受凝血因子濃縮物的人。
當前,沒有有效的可用於治療急性或慢性D型肝炎的抗病毒療法。每週給予干擾素-α,持續12至18個月是D型肝炎的唯一許可療法。對該療法的反應有限,因為僅約四分之一的患者在療法後6個月無法檢測到血清HDV RNA。
在臨床上,抑制pg RNA衣殼化,或更普遍地抑制核衣殼裝配可為B型肝炎及/或D型肝炎的治療提供某些治療優勢。一方面,抑制pg RNA衣殼化可通過為不耐受或不受益於當前藥物的患者的亞群提供選擇來補充當前藥物。另一方面,基於其獨特的抗病毒機制,對pg RNA衣殼化的抑制可有效地抵抗對當前可用的DNA聚合酶抑制劑具有抗性的HBV及/或HDV變體。又另一方面,pg RNA衣殼化抑制劑與DNA聚合酶抑制劑的組合療法可以協同抑制HBV及/或HDV複製並防止耐藥性的出現,因此為慢性B型肝炎及/或D型肝炎感染提供更有效的治療。
因此,本領域中需要鑒定可用於在受試者中治療及/或預防HBV及/或HDV感染的新型化合物。在某些實施方式中,新型化合物抑制HBV及/或HDV核衣殼裝配。在其它實施方式中,新型化合物可用於HBV及/或HBV-HDV感染的患者、有被HBV及/或HBV-HDV感染的風險的患者、及/或感染了耐藥性HBV及/或HDV的患者中。本發明解決了這一需求。
本公開提供某些式(I)化合物,或其鹽、溶劑化物、前藥、立體異構物、互變異構物、或同位素標記的衍生物,或其任意混合物,其中(I)中的取代基在本文其它部分定義:
本公開進一步提供包含本公開的至少一種化合物的藥物組成物。在某些實施方式中,藥物組成物進一步包含至少一種醫藥上可接受之載劑。在其它實施方式中,藥物組成物進一步包含治療或預防肝炎病毒感染的至少一種其它劑。在又其它實施方式中,肝炎病毒是B型肝炎病毒(HBV)。在又其它實施方式中,肝炎病毒是D型肝炎病毒(HDV)。
本公開進一步提供治療、改善、及/或預防受試者中的肝炎病毒感染的方法。在某些實施方式中,方法包括向受試者投予治療有效量的本發明的化合物,或其鹽、溶劑化物、前藥、立體異構物、互變異構物、或任意混合物。在其它實施方式中,受試者感染有HBV。在又其它實施方式中,受試者感染有HDV。在又其它實施方式中,受試者感染有HBV和HDV。在又其它實施方式中,受試者被進一步投予用於治療、改善、及/或預防肝炎病毒感染的至少一種其它劑。在又其它實施方式中,受試者需要治療、改善、及/或預防。
當結合附圖閱讀時,將更好地理解以下對本發明的例示性實施方式的詳細描述。為了示例本發明,在附圖中顯示了例示性實施方式。然而,應當理解,本發明不限於附圖中所示實施方式的精確的佈置和手段。
圖1提供(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮的ORTEP表示,其中顯示了50%機率的熱橢球,限定了絕對構型。
本發明在某些方面中涉及用於治療及/或預防受試者中B型肝炎病毒(HBV)及/或D型肝炎病毒(HDV)感染和相關狀況的某些取代的脲類和醯胺類的發現。在某些實施方式中,本發明的化合物是
病毒衣殼抑制劑。
定義
如本文所使用的,以下術語中的每一個在本節中都具有與其相關的含義。除非另有定義,否則本文使用的所有技術和科學術語通常都具有與本發明所屬領域的普通技術人員通常所理解的相同的含義。通常,本文所用的命名法以及動物藥理學、藥物科學、分離科學、和有機化學中的實驗室程序是本領域公知的和常用的。應當理解,只要本教導仍然可操作,那麼步驟的順序或用於執行某些動作的順序是無關緊要的。章節標題的任何使用均旨在幫助閱讀文件,而不應理解為限制性的;與章節標題相關的信息可能發生在該特定章節之內或之外。該文件中引用的所有出版物、專利、和專利文件都通過引用以其整體併入本文,如同通過引用將其單獨併入。
在本申請中,在敘述元素或組分被包括在所敘述的元素或組分的列表中及/或選自所敘述的元素或組分的列表的情況下,應當理解,該元素或組分可以是所敘述的元素或組分中的任一個並且可以選自所敘述的元件或組分中的兩個或更多個。
在本文描述的方法中,可以以任何順序執行動作,除非明確地敘述了時間或操作序列。此外,指定的動作可以同時執行,除非明確的聲明語言敘述了它們是分開執行的。例如,可以在單個操作中同時進行要求保護的X動作和要求保護的Y動作,並且所得過程將落入要求保護的過程的字面範圍內。
在本文件中,除非上下文另外明確指出,否則術語「一」、「一種」、或「該」用於包括一個或多個。除非另有說明,否則術語「或」用於表示非排他性的「或」。陳述「A和B中的至少一個」或「A或B中的至少一個」具有與「A、B或A和B」相同的含義。
如本文所使用的,術語「約」將被本領域普通技術人員理解,並且將在使用它的上下文中在某種程度上變化。如本文所使用的,當「約」指代可測量值比如量、時間持續時間等時,旨在涵蓋與指定值具
有±20%、±10%、±5%、±1%、或±0.1%的變化,因為這樣的變化適合執行所公開的方法。
如本文所使用的,除非另有說明,否則單獨或與其它術語組合使用的術語「烯基」是指具有所闡述數目的碳原子的穩定的單不飽和或二不飽和直鏈或支鏈烴基。實例包括乙烯基、丙烯基(或烯丙基)、丁烯基(crotyl)、異戊烯基、丁二烯基、1,3-戊二烯基、1,4-戊二烯基和更高的同系物和異構物。代表烯烴的官能團的實例為-CH2-CH=CH2。
如本文所使用的,除非另有說明,否則單獨或與其它術語組合使用的術語「烷氧基」是指經由氧原子連接到分子的其餘部分的如本文其它地方所定義的具有指定數目的碳原子的烷基,諸如,例如甲氧基、乙氧基、1-丙氧基、2-丙氧基(或異丙氧基)和更高的同系物和異構物。具體實例是(C1-C3)烷氧基,諸如但不限於乙氧基和甲氧基。
如本文所使用的,除非另有說明,術語「烷基」本身或作為另一取代基的一部分是指具有指定數目的碳原子(即,C1-C10表示1至10個碳原子)的直鏈或支鏈烴,並且包括直鏈、支鏈、或環狀取代基。實例包括甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基、新戊基、己基、和環丙基甲基。具體實施方式是(C1-C6)烷基,諸如但不限於乙基、甲基、異丙基、異丁基、正戊基、正己基、和環丙基甲基。
如本文所使用的,除非另有說明,否則單獨或與其它術語組合使用的術語「炔基」是指具有所闡述數目的碳原子的具有碳-碳三鍵的穩定的直鏈或支鏈烴基。非限制性實例包括乙炔基和丙炔基,以及更高的同系物和異構物。術語「炔丙基」是指以-CH2-C≡CH為例的基團。術語「高炔丙基(homopropargylic)」是指以-CH2CH2-C≡CH為例的基團。
如本文所使用的,術語「芳族」是指具有一個或多個多不飽和環並且具有芳族特徵,即具有(4n+2)個離域的π電子(其中「n」
為整數)的碳環或雜環。
如本文所使用的,除非另有說明,否則單獨或與其它術語組合使用的術語「芳基」是指含有一個或多個環(通常為一個、兩個或三個環)的碳環芳族系統,其中這些環可以以側鏈方式連接在一起,如聯苯,或者可以稠合,如萘。實例包括苯基、蒽基和萘基。芳基還包括例如與一個或多個飽和或部分飽和的碳環(例如,雙環[4.2.0]八-1,3,5-三烯基或二氫茚基)稠合的苯環或萘環,其可以在芳環及/或飽和或部分飽和的環的一個或多個碳原子處被取代。
如本文所使用的,術語「芳基-(C1-C6)烷基」是指其中1至6個碳伸烷基鏈連接至芳基的官能團,例如,-CH2CH2-苯基或-CH2-苯基(或苄基)。具體實例是芳基-CH2-和芳基-CH(CH3)-。術語「取代的芳基-(C1-C6)烷基」是指其中芳基被取代的芳基-(C1-C6)烷基官能團。具體實例是取代的芳基(CH2)-。類似地,術語「雜芳基-(C1-C6)烷基」是指其中1至3個碳伸烷基鏈連接至雜芳基的官能團,例如,-CH2CH2-吡啶基。具體實例是雜芳基-(CH2)-。術語「取代的雜芳基-(C1-C6)烷基」是指其中雜芳基被取代的雜芳基-(C1-C6)烷基官能團。具體實例是取代的雜芳基-(CH2)-。
一方面,與受試者有關的術語「共同投予」和「共同給藥」是指向受試者投予本發明的化合物及/或組成物以及也可以治療或預防本文考慮的疾病或病症的化合物及/或組成物。在某些實施方式中,作為單一治療方法的一部分,共同投予的化合物及/或組成物單獨投予或以任何種類的組合投予。可以以任何種類的組合將共同投予的化合物及/或組成物配製成各種固體、凝膠、和液體調配物的固體和液體的混合物以及溶液。
如本文所使用的,除非另有說明,術語「環烷基」本身或作為另一取代基的一部分是指具有指定數目的碳原子的環鏈烴(即,C3-C6是指包括由3至6個碳原子組成的環基團的環狀基團)並且包括直鏈、支鏈或環狀取代基。(C3-C6)環烷基的實例是環丙基、環丁基、環
戊基和環己基。環烷基環可以可選擇地被取代。環烷基的非限制性實例包括:環丙基、2-甲基-環丙基、環丙烯基、環丁基、2,3-二羥基環丁基、環丁烯基、環戊基、環戊烯基、環戊二烯基、環己基、環己烯基、環庚基、環辛基、十氫萘基、2,5-二甲基環戊基、3,5-二氯環己基、4-羥基環己基、3,3,5-三甲基環己-1-基、八氫戊烯基、八氫-1H-茚基、3a,4,5,6,7,7a-六氫-3H-茚-4-基、十氫薁基;雙環[6.2.0]癸基、十氫萘基、和十二氫-1H-芴基。術語「環烷基」還包括雙環烴環,其非限制性實例包括雙環[2.1.1]己烷基、雙環[2.2.1]庚烷基、雙環[3.1.1]庚烷基、1,3-二甲基[2.2.1]庚烷-2-基、雙環[2.2.2]辛烷基、和雙環[3.3.3]十一烷基。
如本文所使用的,「疾病」是受試者的健康狀態,其中受試者不能維持體內穩態,並且其中如果疾病沒有得到改善,則受試者的健康繼續惡化。
如本文所使用的,受試者中的「病症」是其中受試者能夠維持穩態的健康狀態,但是其中受試者的健康狀態比沒有病症時的健康狀態不利。如果不治療,病症不一定會導致受試者的健康狀態進一步下降。
如本文所使用的,術語「鹵化物」是指帶有負電荷的鹵素原子。鹵化物陰離子為氟化物(F-)、氯化物(Cl-)、溴化物(Br-)、和碘化物(I-)。
如本文所使用的,除非另有說明,術語「鹵」或「鹵素」單獨或作為另一取代基的一部分是指氟、氯、溴或碘。
如本文所使用的,除非另有說明,術語「雜烯基」本身或與另一術語組合是指由所闡述數目的碳原子和選自O、N和S的一個或兩個雜原子組成的穩定的直鏈或支鏈單不飽和或二不飽和烴基,並且其中氮原子和硫原子可可選擇地被氧化,和氮雜原子可可選擇地被四級銨化。可以連續放置至多兩個雜原子。實例包括-CH=CH-O-CH3、-CH=CH-CH2-OH、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、和-
CH2-CH=CH-CH2-SH。
如本文所使用的,除非另有說明,術語「雜烷基」本身或與另一術語組合是指由所闡述數目的碳原子和選自O、N和S的一個或兩個雜原子組成的穩定的直鏈或支鏈烷基,並且其中氮原子和硫原子可以可選擇地被氧化,和氮雜原子可以可選擇地被四級銨化。雜原子(一個或多個)可位於雜烷基的任何位置,包括在雜烷基的其餘部分和其連接的片段之間,以及連接至雜烷基中最遠端的碳原子。實例包括:-OCH2CH2CH3、-CH2CH2CH2OH、-CH2CH2NHCH3、-CH2SCH2CH3、和-CH2CH2S(=O)CH3。至多兩個雜原子可以是連續的,諸如,例如-CH2NH-OCH3或-CH2CH2SSCH3。
如本文所使用的,術語「雜芳基」或「雜芳族」是指具有芳族特性的雜環。多環雜芳基可以包括一個或多個部分飽和的環。實例包括四氫喹啉和2,3-二氫苯并呋喃基。
如本文所使用的,除非另有說明,否則術語「雜環」或「雜環基」或「雜環的」本身或作為另一取代基的一部分是指包括碳原子和選自N、O和S的至少一個雜原子的未取代或取代的,穩定的單環或多環雜環系統,並且其中氮和硫雜原子可以可選擇地被氧化,和氮原子可以可選擇地被四級銨化。除非另有說明,雜環系統可以連接在提供穩定結構的任何雜原子或碳原子上。雜環本質上可以是芳族的或非芳族的。在某些實施方式中,雜環是雜芳基。
非芳族雜環的實例包括單環基團,如氮丙啶、環氧乙烷、硫環丙環(thiirane)、氮雜環丁烷、氧雜環丁烷、硫雜環丁烷、吡咯啶、吡咯啉、咪唑啉、吡唑烷、二氧戊環、環丁碸、2,3-二氫呋喃、2,5-二氫呋喃、四氫呋喃、四氫噻吩(thiophane)、哌啶、1,2,3,6-四氫吡啶、1,4-二氫吡啶、哌、嗎啉、硫代嗎啉、哌喃、2,3-二氫哌喃、四氫哌喃、1,4-二烷、1,3-二烷、高哌、高哌啶、1,3-二氧雜環庚烷、4,7-二氫-1,3-二呯、和環氧己烷(hexamethyleneoxide)。
雜芳基的實例包括吡啶基、吡基、嘧啶基(諸如但不限
於2-和4-嘧啶基)、嗒基、噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、唑基、吡唑基、異噻唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-三唑基、四唑基、1,2,3-噻唑基、1,2,3-二唑基、1,3,4-噻唑基、和1,3,4-二唑基。
多環雜環的實例包括吲哚基(諸如但不限於3-、4-、5-、6-和7-吲哚基)、二氫吲哚基、喹啉基、四氫喹啉基、異喹啉基(諸如,但不限於1-和5-異喹啉基)、1,2,3,4-四氫異喹啉基、啉基(cinnolinyl)、喹啉基(諸如但不限於2-和5-喹啉基)、喹唑啉基、呔基、1,8-啶基、1,4-苯并二烷基、香豆素、二氫香豆素、1,5-啶基、苯并呋喃基(諸如但不限於3-、4-、5-、6-和7-苯并呋喃基)、2,3-二氫苯并呋喃基、1,2-苯并唑基、苯并噻吩基(諸如,但不限於3-、4-、5-、6-和7-苯并噻吩基)、苯并唑基、苯并噻唑基(諸如但不限於2-苯并噻唑基和5-苯并噻唑基)、嘌呤基、苯并咪唑基、苯并三唑基、硫代黃嘌呤基(thioxanthinyl)、咔唑基、咔啉基、吖啶基、吡咯聯啶基(pyrrolizidinyl)、和喹啶基(quinolizidinyl)。
雜環基和雜芳基部分的上述列舉旨在是代表性的,而不是限制性的。
如本文所使用的,術語「藥物組成物」或「組成物」是指在本發明中有用的至少一種化合物與醫藥上可接受之載劑的混合物。藥物組成物促進將化合物投予至受試者。
如本文所使用的,術語「醫藥上可接受之」是指不消除本發明中有用的化合物的生物活性或特性並且相對無毒的材料,如載劑或稀釋劑,即可以在不引起不期望的生物效應或不會以有害方式與包含其的組成物的任何組分相互作用的情況下將該材料施用至受試者。
如本文所使用的,術語「醫藥上可接受之載劑」是指參與在受試者內或向受試者攜帶或運輸本發明中有用的化合物使得它可以執行預期的功能的醫藥上可接受之材料、組成物或載劑,如液體或固體填充劑、穩定劑、分散劑、懸浮劑、稀釋劑、賦形劑、增稠劑、溶劑或
封裝材料。典型地,將這種構建體從一個器官或身體的部分攜帶或運輸到另一器官或身體的部分。在與調配物的其它成分(包括本發明中有用的化合物)相容的意義上,每種載劑必須是「可接受的」,並且對受試者無害。可用作醫藥上可接受之載劑的材料的一些實例包括:糖,如乳糖、葡萄糖和蔗糖;澱粉,如玉米澱粉和馬鈴薯澱粉;纖維素及其衍生物,如羧甲基纖維素鈉、乙基纖維素和乙酸纖維素;粉末狀黃蓍膠;麥芽;明膠;滑石;賦形劑,如可可脂和栓劑蠟;油,如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油、山梨糖醇、甘露糖醇和聚乙二醇;酯,如油酸乙酯和月桂酸乙酯;瓊脂;緩衝劑,如氫氧化鎂和氫氧化鋁;表面活性劑;藻酸;無熱原水;等滲鹽水;林格氏溶液;乙醇;磷酸鹽緩衝溶液;和藥物調配物中使用的其它無毒的相容性物質。如本文所使用的,「醫藥上可接受之載劑」還包括與本發明中有用的化合物的活性相容的並且是受試者生理上可接受的任何和所有包衣、抗細菌和抗真菌劑,以及吸收延遲劑等。補充活性化合物也可以併入組成物中。「醫藥上可接受之載劑」可以進一步包括在本發明中有用的化合物的醫藥上可接受之鹽。在本發明的實踐中使用的藥物組成物中可以包含的其它另外的成分是本領域已知的,並且在例如Remington’s Pharmaceutical Sciences(Genaro,Ed.,Mack Publishing Co.,1985,EastoN,PA)中描述,其通過引用併入本文。
如本文所使用的,用語「醫藥上可接受之鹽」是指由包括無機酸、無機鹼、有機酸、無機鹼、溶劑化物(包括水合物)和其包合物(clathrate)的醫藥上可接受之無毒酸及/或鹼製備的所投予的化合物的鹽。
如本文所使用的,化合物的「藥學上有效量」、「治療有效量」、或「有效量」是足以向投予化合物的受試者提供有益作用的化合物的量。
如本文所使用的術語「預防(prevent)」、「預防(preventing)」、或「預防(prevention)」是指在開始投予劑或化合物
時在未發展出這種症狀的受試者中避免或延遲與疾病或狀況相關的症狀的發作。疾病、狀況和病症在本文可互換使用。
如本文所使用的術語「特異性結合(specifically bind)」或「特異性結合(specifically binds)」是指第一分子優先結合第二分子(例如,特定受體或酶),但不一定僅結合該第二分子。
如本文所使用的,術語「受試者」和「個體」和「患者」可以互換使用,並且可以指人類或非人類哺乳動物或鳥類。非人類哺乳動物包括例如牲畜和寵物,如綿羊、牛科、豬科、犬科、貓科和鼠科哺乳動物。在某些實施方式中,受試者是人類。
如本文所使用的,術語「取代的」是指原子或原子團已取代氫作為連接至另一基團的取代基。
如本文所使用的,術語「取代的烷基」、「取代的環烷基」、「取代的烯基」、或「取代的炔基」是指如本文其它部分所定義的烷基、環烷基、烯基、或炔基,其被獨立地選自鹵素、-OH、烷氧基、四氫-2-H-哌喃基、-NH2、NH(C1-C6烷基)、-N(C1-C6烷基)2、1-甲基-咪唑-2-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、-C(=O)OH、-C(=O)O(C1-C6)烷基、三氟甲基、-C≡N、-C(=O)NH2、-C(=O)NH(C1-C6)烷基、-C(=O)N((C1-C6)烷基)2、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-C(=NH)NH2、和-NO2的一個、兩個或三個取代基取代,在某些實施方式中含有獨立地選自鹵素、-OH、烷氧基、-NH2、三氟甲基、-N(CH3)2、和-C(=O)OH的一個或兩個取代基,在某些實施方式中獨立地選自鹵素、烷氧基和-OH。取代的烷基的實例包括但不限於2,2-二氟丙基、2-羧基環戊基和3-氯丙基。
對於芳基、芳基-(C1-C3)烷基和雜環基,適用於這些基團的環的術語「取代的」是指在允許這種取代的地方的任意取代水平,即單、二、三、四或五取代。取代基是獨立選擇的,並且取代可以在任意化學上可行的位置。在某些實施方式中,取代基的數目在1和4之間變化。在其它實施方式中,取代基的數目在1和3之間變化。在又另外實
施方式中,取代基的數目在1和2之間變化。在又其它實施方式中,取代基獨立地選自C1-C6烷基、-OH、C1-C6烷氧基、鹵素、胺基、乙醯胺基和硝基。如本文所使用的,在取代基是烷基或烷氧基的情況下,碳鏈可以是支鏈、直鏈或環狀的。
除非另有說明,當兩個取代基一起形成具有指定數目的環原子的環時(例如,Ri和Rii與它們所連接的氮一起形成具有3至7個環成員的環),該環可以具有碳原子和可選擇地一個或多個(例如,1至3個)獨立地選自氮、氧、或硫的另外的雜原子。該環可以是飽和的或部分飽和的,並且可以可選擇地被取代。
每當術語或其前綴根中的任一個出現在取代基的名稱中時,該名稱應解釋為包括本文提供的那些限制。例如,每當術語「烷基」或「芳基」或其前綴根中的任一個出現在取代基(例如,芳基烷基、烷基胺基)的名稱中時,該名稱應解釋為包括本文其它部分分別對「烷基」和「芳基」給出的那些限制。
在某些實施方式中,化合物的取代基以組或範圍公開。具體期望該描述包括這些組和範圍的成員的每一個以及每個單獨的子組合。例如,術語「C1-6烷基」具體旨在單獨公開C1、C2、C3、C4、C5、C6、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5、和C5-C6烷基。
本文所用的術語「治療(treat)」、「治療(treating)」和「治療(treatment)」是指藉由向受試者投予藥劑或化合物來降低受試者經歷疾病或病況的症狀的頻率或嚴重程度。
本文使用的某些縮寫如下:ACN,乙腈;cccDNA,共價閉合的環狀DNA;DAD,二極管陣列檢測器;DCE,1,2-二氯乙烷;DCM,二氯甲烷;DIEA或DIPEA,二異丙基乙胺;DMF,N,N-二甲基甲醯胺;DMSO,二甲基亞碸;d.r.,非鏡像異構物比例;EtOAc,乙酸乙酯;HATU,氮雜苯并三唑四甲基脲六氟磷酸鹽;HBsAg,HBV表面抗原;HBV,B型肝炎病毒;HDV,D型肝炎病毒;HPLC,高效
液相層析法;IPA,異丙醇(2-丙醇);LCMS,液相色譜質譜法;LG,離去基團;NARTI或NRTI,逆轉錄酶抑制劑;NMM,N-甲基嗎啉;NMR,核磁共振;NtARTI或NtRTI,核苷酸類似物逆轉錄酶抑制劑;pg RNA,前基因組RNA;rcDNA,鬆弛環狀DNA;RT,保留時間;sAg,表面抗原;SFC,超臨界流體色譜層析法;STAB,三乙醯氧基硼氫化鈉;TFA,三氟乙酸;TBDMS,第三丁基二甲基甲矽烷基(tert-butyldimethylsilyl);THF,四氫呋喃;TLC,薄層層析法;TMSOTf,三氟甲基磺酸三甲基矽酯(trimethylsilyl trifluoromethylsulfonate)。
範圍:貫穿本公開,本發明的各個方面可以以範圍形式來展示。應理解,範圍形式的描述僅是為了方便和簡潔,而不應被解釋為對本發明範圍的死板限制。因此,範圍的描述應被認為已具體公開了所有可能的子範圍以及此範圍內的個體數值。例如,諸如1至6的範圍的描述應被認為已具體公開了諸如1至3、1至4、1至5、2至4、2至6、3至6等的子範圍,以及此範圍內的個體數值,例如1、2、2.7、3、4、5、5.3和6。例如,範圍為「約0.1%至約5%」或「約0.1%至5%」應解釋為不僅包括約0.1%至約5%,還包括所指示範圍內的個體值(例如,1%、2%、3%和4%)和子範圍(例如,0.1%至0.5%、1.1%至2.2%、3.3%至4.4%)。除非另外指出,否則「約X至Y」的闡述與「約X至約Z」的含義相同。同樣地,除非另外指出,否則「約X、Y、或約Z」的闡述與「約X、約Y、或約Z」的含義相同。不管範圍寬度如何,這都適用。
化合物
本發明包括式(I)化合物,或其鹽、溶劑化物、前藥、同位素標記的衍生物、立體異構物(如,在非限制性實例中,對映異構物或非鏡像異構物及/或其任意混合物,如,在非限制性實例中,任意比例的其對映異構物及/或非鏡像異構物的混合物)、互變異構物和任意混合物,及/或其幾何異構物和任意混合物:
X、Y以及X與Y之間的鍵如下:
X是NR8,Y是C(=O),並且X與Y之間的鍵是單鍵,或
X是N,Y是CR11,並且X與Y之間的鍵是雙鍵;
環A選自:
R1選自R2C(=O)-、R2S(=O)2-、和天然存在的胺醯基;
以下中的一個適用:
(i)X1是N,X2是C(R4f),並且X3是C(R4g);
(ii)X2是N,X1是C(R4f),並且X3是C(R4g);
(iii)X3是N,X1是C(R4f),並且X2是C(R4g);
(v)X1是C(R4f),X2是C(R4g),並且X3是C(R4h);
以下中的一個適用:
(i)X4是N並且X5是C(R4e);或
(ii)X5是N並且X4是C(R4e);
X6a的每次出現獨立地是N或C(R4f);
X6b的每次出現獨立地是N或C(R4g);
X6c的每次出現獨立地是N或C(R4h);
X7的每次出現獨立地是S、O、或NR3a;
R3a的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R3b的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R4a、R4b、R4c、R4d、R4e、R4f、R4g、R4h、R4i、R4j和R4k的每次出現係獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇
經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、並且-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R5的每次出現獨立地選自H、C1-C6烷基、和C3-C8環烷基,其中烷基或環烷基用選自以下的至少一個可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵素、氰基、-OH、C1-C6烷氧基、C3-C8環烷氧基、C1-C6鹵代烷氧基、C3-C8鹵代環烷氧基、可選擇經取代之苯基、可選擇經取代之雜芳基、可選擇經取代之雜環基、-C(=O)OR10、-OC(=O)R10、-SR10、-S(=O)R10、-S(=O)2R10、-S(=O)2NR10R10、-N(R10)S(=O)2R10、-N(R10)C(=O)R10、-C(=O)NR10R10、和-NR10R10;
R6的每次出現獨立地選自H和可選擇經取代之C1-C6烷基;
R7是-(CH2)p-Q-(CH2)q-,其中p和q獨立地是0、1、或2,並且Q是鍵(不存在)、-O-、-S-、-S(O)-、-S(O)2-、-NR12、-CH(OH)-、-C(=O)-、-C(=O)O-、或-OC(=O)-,
其中R7中的每一個CH2用選自甲基、OR13、或鹵素的至少一個取代基可選擇地取代;
R8的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R9a、R9b、R9c、R9d、R9e、R9f、R9g、和R9h的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8
環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R10的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、和可選擇經取代之雜芳基;
R11的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代
之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R12的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C1-C6羥基烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、可選擇經取代之雜芳基、和可選擇經取代之C1-C6醯基;
R13的每次出現係獨立地選自H、可選擇經取代之C1-C6烷基、和-C(=O)C1-C6烷基。
在某些實施方式中,式(I)化合物是式(Ia-1)化合物:
。在某些實施方式中,式(I)化合物是式(Ia-2)化
合物:。在某些實施方式中,式(I)化合物是式(Ia-
3)化合物:。在某些實施方式中,式(I)化合物是
式(Ia-4)化合物:。在某些實施方式中,式(I)化
合物是式(Ia-5)化合物:。在某些實施方式中,
式(I)化合物是式(Ia-6)化合物:。在某些實施方
式中,式(I)化合物是式(Ia-7)化合物:。在某些
實施方式中,式(I)化合物是式(Ia-8)化合物:。
在某些實施方式中,式(I)化合物是式(Ia-9)化合物:
(Ia-9)。在某些實施方式中,式(I)化合物是式(Ia-10)化合物:
。在某些實施方式中,式(I)化合物是式(Ia-11)
化合物:。在某些實施方式中,式(I)化合物是
式(Ia-12)化合物:。在某些實施方式中,式(I)
化合物是式(Ib-1)化合物:。在某些實施方式中,
式(I)化合物是式(Ib-2)化合物:。在某些實施方
式中,式(I)化合物是式(Ib-3)化合物:。在某些
實施方式中,式(I)化合物是式(Ib-4)化合物:。
在某些實施方式中,式(I)化合物是式(Ib-5)化合物:
(Ib-5)。在某些實施方式中,式(I)化合物是式(Ib-6)化合物:
。在某些實施方式中,式(I)化合物是式(Ib-7)化
合物:。在某些實施方式中,式(I)化合物是式(Ib-
8)化合物:。在某些實施方式中,式(I)化合物是
式(Ib-9)化合物:。在某些實施方式中,式(I)化
合物是式(Ib-10)化合物:。在某些實施方式中,
式(I)化合物是式(Ib-11)化合物:。在某些實施
方式中,式(I)化合物是式(Ib-12)化合物:。
在某些實施方式中,烷基、烯基、炔基、或環烷基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵基、氰基(-CN)、-ORa、可選擇經取代之苯基(從而獲得,在非限制性實例中,可選擇經取代之苯基-(C1-C3烷基),諸如但不限於苄基或取代的苄基)、可選擇經取代之雜芳基、可選擇經取代之雜環基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa、和-N(Ra)(Ra),其中Ra的每次出現獨立地是H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之芳基、或可選擇經取代之雜芳基,或兩個Ra基團與它們所鍵結的N結合形成雜環。
在某些實施方式中,芳基或雜芳基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、苯基、C1-C6羥基烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、鹵素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、-N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、醯基、和C1-C6烷氧基羰基,其中Rb的每次出現獨立地是H、C1-C6烷基、或C3-C8環烷基,其中在Rb中,烷基或環烷基用選自以下的至少一個可選擇地取代:鹵素、-OH、C1-C6烷氧基、和雜芳基;或兩個相鄰碳原子上的取代基結合形成-O(CH2)1-3O-。
在某些實施方式中,芳基或雜芳基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、苯基、C1-C6羥基烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、鹵素、-ORb、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-
OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、和-N(Rb)S(=O)2Rb,其中Rb的每次出現獨立地是H、C1-C6烷基、或C3-C8環烷基,其中在Rb中,烷基或環烷基用選自以下的至少一個可選擇地取代:鹵素、-OH、C1-C6烷氧基和雜芳基;或兩個相鄰碳原子上的取代基結合形成-O(CH2)1-3O-。
在某些實施方式中,烷基、烯基、炔基、環烷基、雜芳基、雜環基、芳基、或苄基用選自以下的至少一個基團可選擇地獨立地取代:C1-C6烷基;C1-C6烷氧基;C1-C6鹵代烷基;C1-C6鹵代烷氧基;-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基)、鹵素、-OH;-CN;苯氧基、-NHC(=O)H、-NHC(=O)C1-C6烷基、-C(=O)NH2、-C(=O)NHC1-C6烷基、-C(=O)N(C1-C6烷基)(C1-C6烷基)、四氫哌喃基、嗎啉基、-C(=O)CH3、-C(=O)CH2OH、-C(=O)NHCH3、-C(=O)CH2OMe或其N-氧化物。
在某些實施方式中,雜芳基的每次出現獨立地選自喹啉基、咪唑并[1,2-a]吡啶基、吡啶基、嘧啶基、吡基、咪唑基、噻唑基、吡唑基、異唑基、二唑基(包括1,2,3-、1,2,4-、1,2,5-、和1,3,4-二唑基)和三唑基(如1,2,3-三唑基和1,2,4-三唑基)。
在某些實施方式中,雜環基的每次出現獨立地選自四氫呋喃基、四氫哌喃基、哌啶基、哌基、吡咯啶基、嗎啉基、硫代嗎啉基、1-氧橋-硫代嗎啉基、1,1-二氧橋-硫代嗎啉基、唑烷基、氮雜環丁烷基、及其相應的側氧基類似物(其中亞甲基環基被羰基替代)。
在某些實施方式中,胺醯基包括天然存在的胺醯基,或其對映異構物或非鏡像異構物,諸如但不限於甘胺醯基、丙胺醯基、纈胺醯基、亮胺醯基、異亮胺醯基、脯胺醯基、絲胺醯基、蘇胺醯基、半胱胺醯基(cysteinyl)、半胱胺醯基(cystinyl)、甲硫胺醯基、苯丙胺醯基、色胺醯基、酪胺醯基、天冬胺醯基、穀胺醯基、天冬醯胺醯基(asparagyl)、穀胺醯基、離胺醯基、精胺醯基及/或組胺醯基。
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在某些實施方式中,R3a是H。在某些實施方式中,R3a是甲基。
在某些實施方式中,R3b是H。在某些實施方式中,R3b是甲基。
在某些實施方式中,R5選自H、甲基、乙基、異丙基、正丙基、環丙基、正丁基、異丁基、仲丁基、第三丁基、環丁基、異丙基甲基、-(CH2)2-6OH、-(CH2)2-6O(C1-C6烷基)、13CD3、可選擇經取代之苄基、和可選擇經取代之苯基。
在某些實施方式中,R6選自H、D、和甲基。在某些實施方式中,R6是H。在某些實施方式中,R6是D。在某些實施方式中,R6是甲基。
在某些實施方式中,當Q是-O-、-S-、-S(O)-、-S(O)2-、或-NR11時,p獨立地是1或2。
在某些實施方式中,R7是選自以下的二價基團:-CH2CH2-、-CH2CH2CH2-、-CH2OCH2-、-CH2CH2CH2CH2-、-CH2OCH2CH2-、和-CH2CH2OCH2-,其中每一個CH2基團用一個或兩個CH3基團可選擇地取代。
在某些實施方式中,R7是選自以下的二價基團:-CH2CH2-、-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-、-CH(CH3)CH(CH3)-、-CH(CH3)C(CH3)2-、-C(CH3)2CH(CH3)-、和-C(CH3)2C(CH3)2-。
在某些實施方式中,R7是選自以下的二價基團:-CH2OCH2-、-CH(CH3)OCH2-、-CH2OCH(CH3)-、-CH(CH3)OCH(CH3)-、-C(CH3)2OCH2-、-CH2OC(CH3)2-、-C(CH3)2OCH(CH3)-、-CH(CH3)OC(CH3)2-、和C(CH3)2OC(CH3)2-。
在某些實施方式中,R7是選自以下的二價基團:-CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-CH(CH3)CH(CH3)CH2-、-CH(CH3)CH2CH(CH3)-、-CH2CH(CH3)CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、-CH2CH2C(CH3)2-、-CH(CH3)CH(CH3)CH(CH3)-、-C(CH3)2CH(CH3)CH2-、-C(CH3)2CH2CH(CH3)-、-CH(CH3)C(CH3)2CH2-、-CH2C(CH3)2CH(CH3)-、-CH(CH3)CH2C(CH3)2-、-CH2CH(CH3)C(CH3)2-、-C(CH3)2CH(CH3)CH(CH3)-、-C(CH3)2C(CH3)2CH2-、-C(CH3)2CH2C(CH3)2-、-CH(CH3)C(CH3)2CH(CH3)-、CH2C(CH3)2C(CH3)2-、-CH(CH3)CH(CH3)C(CH3)2-、-CH(CH3)C(CH3)2C(CH3)2-、-C(CH3)2CH(CH3)C(CH3)2-、-C(CH3)2C(CH3)2CH(CH3)-、和-C(CH3)2C(CH3)2C(CH3)2-。
在某些實施方式中,R7是選自以下的二價基團:-CH2OCH2CH2-、-CH(CH3)OCH2CH2-、-CH2OCH(CH3)CH2-、-CH2OCH2CH(CH3)-、-CH(CH3)OCH(CH3)CH2-、-CH(CH3)OCH2CH(CH3)-、-CH2OCH(CH3)CH(CH3)-、-C(CH3)2OCH2CH2-、-CH2OC(CH3)2CH2-、-CH2OCH2C(CH3)2-、-CH(CH3)OCH(CH3)CH(CH3)-、-C(CH3)2OCH(CH3)CH2-、-C(CH3)2OCH2CH(CH3)-、-CH(CH3)OC(CH3)2CH2-、-CH2OC(CH3)2CH(CH3)-、-CH(CH3)OCH2C(CH3)2-、-CH2OCH(CH3)C(CH3)2-、-C(CH3)2OCH(CH3)CH(CH3)-、-C(CH3)2OC(CH3)2CH2-、-C(CH3)2OCH2C(CH3)2-、-CH(CH3)OC(CH3)2CH(CH3)-、-CH2OC(CH3)2C(CH3)2-、-CH(CH3)OCH(CH3)C(CH3)2-、-CH(CH3)OC(CH3)2C(CH3)2-、-C(CH3)2OCH(CH3)C(CH3)2-、-C(CH3)2OC(CH3)2CH(CH3)-、和-C(CH3)2OC(CH3)2C(CH3)2-。
在某些實施方式中,R7是選自以下的二價基團:-CH2CH2OCH2-、-CH(CH3)CH2OCH2-、-CH2CH(CH3)OCH2-、-CH2CH2OCH(CH3)-、-CH(CH3)CH(CH3)OCH2-、-CH(CH3)CH2OCH(CH3)-、-CH2CH(CH3)OCH(CH3)-、-C(CH3)2CH2OCH2-、-CH2C(CH3)2OCH2-、-CH2CH2OC(CH3)2-、-CH(CH3)CH(CH3)OCH(CH3)-、-C(CH3)2CH(CH3)OCH2-、-C(CH3)2CH2OCH(CH3)-、-CH(CH3)C(CH3)2OCH2-、-CH2C(CH3)2OCH(CH3)-、-CH(CH3)CH2OC(CH3)2-、-CH2CH(CH3)OC(CH3)2-、-C(CH3)2CH(CH3)OCH(CH3)-、-C(CH3)2C(CH3)2OCH2-、-C(CH3)2CH2OC(CH3)2-、-CH(CH3)C(CH3)2OCH(CH3)-、-CH2C(CH3)2OC(CH3)2-、-CH(CH3)CH(CH3)OC(CH3)2-、-CH(CH3)C(CH3)2OC(CH3)2-、-C(CH3)2CH(CH3)OC(CH3)2-、-C(CH3)2C(CH3)2OCH(CH3)-、和-C(CH3)2C(CH3)2OC(CH3)2-。
在某些實施方式中,R7是選自以下的二價基團:-CH2N(CH3)CH2-、-CH2N(CH3)CH(CH3)-、-CH2N(CH3)C(CH3)2-、-CH(CH3)N(CH3)CH2-、-CH(CH3)N(CH3)CH(CH3)-、-CH(CH3)N(CH3)C(CH3)2-、-C(CH3)2N(CH3)CH2-、-C(CH3)2N(CH3)CH(CH3)-、-C(CH3)2N(CH3)C(CH3)2-、-CH2NHCH2-、-CH2NHCH(CH3)-、-CH2NHC(CH3)2-、-CH(CH3)NHCH2-、-CH(CH3)NHCH(CH3)-、-CH(CH3)NHC(CH3)2-、-C(CH3)2NHCH2-、-C(CH3)2NHCH(CH3)-、和-C(CH3)2NHC(CH3)2-。
在某些實施方式中,R7是選自-CH2N((C=O)CH3)CH2-和-CH2N(CH2CH2OH)CH2-的二價基團。
在某些實施方式中,R7是選自-CH2CH2CH(OH)-、-CH2CH(OH)CH2-、和-CH(OH)CH2CH2-的二價基團。
在某些實施方式中,R7是選自以下的二價基團:-CH(OH)OCH2-、-CH2OCH(OH)-、-CH(OCH3)OCH2-、-CH2OCH(OCH3)-、-CH(O(C=O)CH(CH3)2)OCH2-、-CH2OCH(O(C=O)CH(CH3)2)-、-CH(O(C=O)CH(CH3CH2)2)OCH2-、和-CH2OCH(O(C=O)CH(CH3CH2)2)-。
在某些實施方式中,R7是選自以下的二價基團:-CH2OCHF-、-CH2OCF2-、-CHFOCH2-、-CHFOCHF-、-CHFOCF2-、-CF2OCH2-、-CF2OCHF-、和-CF2OCF2-。
在某些實施方式中,R7是選自-CH2S(=O)CH2-和-CH2S(=O)2CH2-的二價基團。
在某些實施方式中,R8是H。在其它實施方式中,R8是甲基。在又其它實施方式中,R8是乙基。在又其它實施方式中,R8是1-(2,2,2-三氟乙基)。在又其它實施方式中,R8是1-丙基。在又其它實施方式中,R8是異丙基。在又其它實施方式中,R8是環丙基。在又其它實施方式中,R8是1-(2-羥基)乙基。在又其它實施方式中,R8是1-(2-甲氧基)乙基。在又其它實施方式中,R8是1-(3-羥基)丙基。在又
其它實施方式中,R8是1-(3-甲氧基)丙基。在又其它實施方式中,R8是三唑基甲基。在又其它實施方式中,R8是2-羥乙基。在又其它實施方式中,R8是2-胺乙基。
在某些實施方式中,R11是H。在其它實施方式中,R11是甲氧基。在又其它實施方式中,R11是乙氧基。在又其它實施方式中,R11是甲基。在又其它實施方式中,R11是乙基。在又其它實施方式中,R11是2-羥基乙氧基。在又其它實施方式中,R11是胺基。在又其它實施方式中,R11是甲胺基。在又其它實施方式中,R11是乙胺基。在又其它實施方式中,R11是二甲胺基。在又其它實施方式中,R11是(2-羥乙基)胺基。在又其它實施方式中,R11是(2-胺乙基)胺基。在又其它實施方式中,R11是三唑基。在又其它實施方式中,R11是三唑基甲氧基。在又其它實施方式中,R11是(N-甲基三唑基)甲基。在又其它實施方式中,R11是三唑基甲胺基。在又其它實施方式中,R11是(N-甲基三唑基)甲胺基。在又其它實施方式中,R11是CN。在又其它實施方式中,R11是羥甲基。在又其它實施方式中,R11是羧基。在又其它實施方式中,R11是胺羰基。在又其它實施方式中,R11是甲胺基羰基。在又其它實施方式中,R11是二甲胺基羰基。在又其它實施方式中,R11是甲磺醯。在又其它實施方式中,R11是吡啶基甲氧基。在又其它實施方式中,R11是(2-胺乙基)羥基。
在某些實施方式中,所述化合物是本文公開的任意化合物,或其鹽、溶劑化物、前藥、被同位素標記、立體異構物、立體異構物的任意混合物、互變異構物、及/或互變異構物的任意混合物。
在某些實施方式中,所述化合物是選自表1中的至少一種,或其鹽、溶劑化物、前藥、被同位素標記、立體異構物、立體異構物的任意混合物、互變異構物、及/或互變異構物的任意混合物。
在某些實施方式中,所述化合物是:
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基二氫吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;
4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;
5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基二氫吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;
3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;
N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;
2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基乙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;
4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;
4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;
2-胺基-2-(4-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
2-胺基-2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;
4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;
1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;
7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;
3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;
1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
5,6-二氟-N-甲基-N-(4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;
5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;
2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;和
2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
或其鹽、溶劑化物、前藥、被同位素標記、立體異構物、立體異構物的任意混合物、互變異構物、及/或互變異構物的任意混合物。
在某些實施方式中,所述化合物是:
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;
(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;
(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;
(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;
(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;
(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;
(N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;
(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;
(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;
(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;
(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;
(R)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;
(R)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;
(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-3-苯丙醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-3-苯丙醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;
(S)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;
(R)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;
(S)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;
(R)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(S)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;
2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基乙醯胺;
2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基乙醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;
(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;
(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;
(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;
(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;
(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;
(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;
(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;
(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;
(S)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;
(S)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;
(S)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(S)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;
(R)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;
(S)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(R)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(S)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(R)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
(S)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(R)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(S)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(R)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;
(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;
(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
(R)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
(S)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
(R)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;
(S)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
(R)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;
(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
(S)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
(S)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((R)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;
(R)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;
(S)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(R)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;
(S)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
(R)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;
(S)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(S)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;
(R)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(R)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
(S)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(R)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
5,6-二氟-N-甲基-N-((1S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
5,6-二氟-N-甲基-N-((1S,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
5,6-二氟-N-甲基-N-((1S,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
5,6-二氟-N-甲基-N-((1R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
5,6-二氟-N-甲基-N-((1R,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
5,6-二氟-N-甲基-N-((1R,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;
(S)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;
(R)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
(R)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
2-氯-N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
2-氯-N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
(R)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;
(S)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;和
(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
或其鹽、溶劑化物、前藥、被同位素標記、立體異構物、立體異構物的任意混合物、互變異構物、及/或互變異構物的任意混合物。
本發明的化合物可以具有一個或多個立體異構中心,並且每個立體異構中心可以以(R)或(S)構型獨立存在。在某些實施方式中,本文所述的化合物以旋光或外消旋形式存在。本文所述的化合物包括具有本文所述的治療有用特性的外消旋、旋光、區域異構和立體異構形式或其組合。旋光形式的製備以任意合適的方式實現,作為非限制性實例,包括通過用重結晶技術外消旋形式的解析、由旋光原材料合成、手性合成、或使用手性固定相進行色譜分離。本文由外消旋式示例的化合物進一步代表兩種對映異構物或其任意混合物,或者在兩個或更多個手性中心存在的情況下,代表所有非鏡像異構物或其任意混合物。
在某些實施方式中,本發明的化合物以互變異構物存在。所有互變異構物均包括在本文敘述的化合物的範圍內。
本文所述的化合物還包括同位素標記的化合物,其中一個或多個原子被具有相同原子序數但原子質量或原子質量數不同於通常在自然界發現的原子質量或原子質量數的原子替代。適於包含在本文所述的化合物中的同位素的實例包括但不限於2H、3H、11C、13C、14C、36Cl、18F、123I、125I、13N、15N、15O、17O、18O、32P、和35S。在某些實施方式中,用較重的同位素比如氘取代提供更高的化學穩定性。通過任意合適的方法或通過使用合適的同位素標記的試劑代替否則採用未標記的試劑的過程製備同位素標記的化合物。
在某些實施方式中,本文所述的化合物通過其它手段標記,包括但不限於使用發色團或熒光部分、生物發光標記、或化學發光標記。
在本文提供的所有實施方式中,合適的任選取代基的實例不旨在限制要求保護的發明的範圍。本發明的化合物可以包含本文提供
的任意取代基或取代基的組合。
鹽
本文所述的化合物可與酸或鹼形成鹽,並且這種鹽包括在本發明中。術語「鹽」包括在本發明的方法中有用的游離酸或鹼的加成鹽。術語「醫藥上可接受之鹽」是指具有在藥學應用中有用的範圍內的毒性特徵的鹽。在某些實施方式中,鹽是醫藥上可接受之鹽。然而,藥學上不可接受的鹽可以具有比如高結晶度的性質,其在本發明的實踐中具有實用性,諸如,例如在本發明的方法中有用的化合物的合成、純化或配製過程中的實用性。
合適的醫藥上可接受之酸加成鹽可以由無機酸或由有機酸製備。無機酸的實例包括硫酸鹽、硫酸氫鹽(hydrogen sulfate)、鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、硫酸、和磷酸(包括磷酸氫鹽和磷酸二氫鹽)。合適的有機酸可以選自脂族、脂環族、芳族、芳脂族、雜環、羧酸和磺酸類的有機酸,其實例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、葡糖醛酸、馬來酸、富馬酸、丙酮酸、天冬胺酸、谷胺酸、苯甲酸、鄰胺基苯甲酸、4-羥基苯甲酸、苯乙酸、扁桃酸、撲酸(或帕莫酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、磺胺酸、2-羥基乙磺酸、三氟甲磺酸、對甲苯磺酸、環己基胺基磺酸、硬脂酸、海藻酸、β-羥基丁酸、水楊酸、半乳糖二酸、半乳糖醛酸、甘油膦酸和糖精(例如,糖精鹽(saccharinate)、糖酸鹽(saccharate))。相對於本發明的任意化合物,鹽可以由1莫耳當量、1或多於1莫耳當量的酸或鹼的部分組成。
本發明的化合物的合適的醫藥上可接受之鹼加成鹽包括例如銨鹽和金屬鹽,包括鹼金屬、鹼土金屬和過渡金屬鹽,諸如,例如鈣、鎂、鉀、鈉和鋅鹽。醫藥上可接受之鹼加成鹽還包括由鹼性胺,諸如,例如N,N’-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、葡甲胺(或N-甲葡糖胺)和普魯卡因製備的有機鹽。所有這些鹽可以通過例如使合適的酸或鹼與化合物反應而由相應的化合物製備。
組合療法
在一個方面,本發明的化合物與用於治療HBV及/或HDV感染的一種或多種另外的試劑組合用於本發明的方法中。這些另外的試劑可以包括本文鑒定的化合物或組成物,或已知用於治療、預防或減輕HBV及/或HDV感染的症狀的化合物(例如,商業上可獲得的化合物)。
用於治療、改善、及/或預防HBV及/或HDV感染的一種或多種另外的試劑的非限制性實例包括:(a)逆轉錄酶抑制劑;(b)衣殼抑制劑;(c)cccDNA形成抑制劑;(d)RNA去穩定劑;(e)靶向HBV基因組的寡聚核苷酸;(f)免疫刺激劑,如檢查點抑制劑(例如,PD-L1抑制劑);和(g)靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和(h)治療疫苗。
(a)逆轉錄酶抑制劑
在某些實施方式中,逆轉錄酶抑制劑是逆轉錄酶抑制劑(NARTI或NRTI)。在其它實施方式中,逆轉錄酶抑制劑是核苷酸類似物逆轉錄酶抑制劑(NtARTI或NtRTI)。
報導的逆轉錄酶抑制劑包括但不限於恩替卡韋、克拉夫定、替比夫定、拉米夫定、阿德福韋、和替諾福韋、替諾福韋二吡呋酯(tenofovir disoproxil)、替諾福韋艾拉酚胺、阿德福韋酯(adefovir dipovoxil)、(1R,2R,3R,5R)-3-(6-胺基-9H-9-嘌呤基)-2-氟-5-(羥甲基)-4-亞甲基環戊-1-醇(描述於美國專利號8,816,074中,通過引用以其整體併入本文)、恩曲他濱、阿巴卡韋、依維他濱(elvucitabine)、更昔洛韋、洛布卡韋、泛昔洛韋、噴昔洛韋、和氨多索韋(amdoxovir)。
報導的逆轉錄酶抑制劑進一步包括但不限於恩替卡韋、拉米夫定、和(1R,2R,3R,5R)-3-(6-胺基-9H-9-嘌呤基)-2-氟-5-(羥甲基)-4-亞甲基環戊-1-醇。
報導的逆轉錄酶抑制劑進一步包括但不限於上面提到的
逆轉錄酶抑制劑的共價結合的胺基磷酸酯或膦醯胺部分,或例如美國專利號8,816,074、美國專利申請公開號US 2011/0245484 A1和US 2008/0286230A1中描述的,所有這些通過引用以其整體併入本文。
報導的逆轉錄酶抑制劑進一步包括但不限於包括胺基磷酸酯部分的核苷酸類似物,諸如,例如甲基((((1R,3R,4R,5R)-3-(6-胺基-9H-嘌呤-9-基)-4-氟-5-羥基-2-亞甲基環戊基)甲氧基)(苯氧基)磷醯基)-(D或L)-丙胺酸酯和甲基((((1R,3R,4R,5R)-3-氟-2-羥基-5-亞甲基-4-(6-側氧-1,6-二氫-9H-嘌呤-9-基)環戊基)甲氧基)(苯氧基)磷醯基)-(D或L)-丙胺酸酯。還包括其單獨的非鏡像異構物,其包括例如((R)-(((1R,3R,4R,5R)-3-(6-胺基-9H-嘌呤-9-基)-4-氟-5-羥基-2-亞甲基環戊基)甲氧基)甲基(苯氧基)磷醯基)-(D或L)-丙胺酸酯和甲基((S)-(((1R,3R,4R,5R)-3-(6-胺基-9H-嘌呤-9-基)-4-氟-5-羥基-2-亞甲基環戊基)甲氧基)(苯氧基)磷醯基)-(D或L)-丙胺酸酯。
報導的逆轉錄酶抑制劑進一步包括但不限於包括膦醯胺部分的化合物,諸如,例如替諾福韋艾拉酚胺,以及在美國專利申請公開號US 2008/0286230 A1中描述的那些,通過引用以其整體併入本文。在例如,美國專利號8,816,074以及美國專利申請公開號US 2011/0245484 A1和US 2008/0286230 A1中描述了用於製備含有立體選擇性胺基磷酸酯或膦醯胺的活性物的方法,其全部通過引用以其整體併入本文。
(b)衣殼抑制劑
如本文所描述的,術語「衣殼抑制劑」包括能夠直接或間接抑制衣殼蛋白的表現及/或功能的化合物。例如,衣殼抑制劑可以包括但不限於抑制衣殼裝配、誘導非衣殼聚合物形成、促進過量的衣殼裝配或衣殼裝配方向錯誤、影響衣殼穩定、及/或抑制RNA(pgRNA)衣殼化的任何化合物。衣殼抑制劑還包括在複製過程的下游事件(一個或多個)(例如,病毒DNA合成、鬆弛環狀DNA(rcDNA)轉運到細胞核、共價閉合環狀DNA(cccDNA)形成、病毒成熟、出芽及/或釋放
等)中抑制衣殼功能的任何化合物。例如,在某些實施方式中,該抑制劑可檢測地抑制衣殼蛋白的表現水平或生物活性,例如使用本文所述的測定法所測量的。在某些實施方式中,抑制劑將rcDNA和病毒生命週期下游產物的水平抑制至少5%、至少10%、至少20%、至少50%、至少75%、或至少90%。
報導的衣殼抑制劑包括但不限於在國際專利申請公開號WO 2013006394、WO2014106019、和WO2014089296中描述的化合物,其全部通過引用以其整體併入本文。
報導的衣殼抑制劑還包括但不限於以下化合物和其醫藥上可接受之鹽及/或溶劑化物:Bay-41-4109(參見國際專利申請公開號WO 2013144129)、AT-61(參見國際專利申請公開號WO 1998033501;和King,et al.,1998,Antimicrob.Agents Chemother.42(12):3179-3186)、DVR-01和DVR-23(參見國際專利申請公開號WO 2013006394;和Campagna,et al.,2013,J.Virol.87(12):6931,其全部通過引用以其整體併入本文。
另外,報導的衣殼抑制劑包括但不限於在美國專利申請公開號US 2015/0225355、US 2015/0132258、US 2016/0083383、US 2016/0052921、US 2019/0225593、和國際專利申請公開號WO2013096744、WO 2014165128、WO 2014033170、WO 2014033167、WO 2014033176、WO2014131847、WO 2014161888、WO 2014184350、WO 2014184365、WO 2015059212、WO2015011281、WO 2015118057、WO 2015109130、WO 2015073774、WO 2015180631、WO2015138895、WO 2016089990、WO 2017015451、WO 2016183266、WO 2017011552、WO2017048950、WO2017048954、WO 2017048962、WO 2017064156、WO 2018052967、WO 2018172852、WO 2020023710中總體地和具體地描述的那些,並通過引用以其整體併入本文。
(c)scccDNA形成抑制劑
共價封閉的環狀DNA(cccDNA)在病毒rcDNA的細胞核中產生,並用作病毒mRNA的轉錄模板。如本文所描述的,術語「cccDNA形成抑制劑」包括能夠直接或間接抑制cccDNA的形成及/或穩定性的化合物。例如,cccDNA形成抑制劑可以包括但不限於抑制衣殼解體,rcDNA進入細胞核,及/或將rcDNA轉化為cccDNA的任何化合物。例如,在某些實施方式中,抑制劑可檢測地抑制cccDNA的形成及/或穩定性,例如使用本文所述的測定法所測量的。在某些實施方式中,抑制劑將cccDNA的形成及/或穩定性抑制至少5%、至少10%、至少20%、至少50%、至少75%、或至少90%。
報導的cccDNA形成抑制劑包括但不限於在國際專利申請公開號WO 2013130703中描述的化合物,並且通過引用以其整體併入本文。
另外,報導的cccDNA形成抑制劑包括但不限於在美國專利申請公開號US 2015/0038515 A1中總體地和具體描述的那些,並且通過引用以其整體併入本文。
(d)RNA去穩定劑
如本文所使用的,術語「RNA去穩定劑」是指在哺乳動物細胞培養物中或在活的人類受試者中減少HBV RNA總量的分子或其鹽或溶劑化物。在非限制性實例中,RNA去穩定劑減少了編碼一種或多種以下HBV蛋白的RNA轉錄物(一種或多種)的量:表面抗原、核心蛋白、RNA聚合酶、和e抗原。在某些實施方式中,RNA去穩定劑使哺乳動物細胞培養物中或活的類人受試者中的HBV RNA的總量減少至少5%、至少10%、至少20%、至少50%、至少75%、或至少90%。
報導的RNA去穩定劑包括在美國專利號8,921,381中描述的化合物,以及在美國專利申請公開號US 2015/0087659和US 2013/0303552中描述的化合物,其全部通過引用以其整體併入本文。
另外,報導的RNA去穩定劑包括但不限於在國際專利申
請公開號WO 2015113990、WO 2015173164、US 2016/0122344、WO 2016107832、WO 2016023877、WO 2016128335、WO2016177655、WO 2016071215、WO 2017013046、WO 2017016921、WO 2017016960、WO2017017042、WO 2017017043、WO 2017102648、WO 2017108630、WO 2017114812、WO2017140821、WO 2018085619中總體地和具體地描述的那些,並且通過引用以其整體併入本文。
(e)靶向HBV基因組的寡聚核苷酸
報導的靶向HBV基因組的寡聚核苷酸包括但不限於Arrowhead-ARC-520(參見美國專利號8,809,293;和Wooddell et al.,2013,Molecular Therapy 21(5):973-985,其全部通過引用以其整體併入本文)。
在某些實施方式中,寡聚核苷酸可以設計為靶向HBV基因組的一個或多個基因及/或轉錄物。靶向HBV基因組的寡聚核苷酸還包括但不限於分離的雙鏈siRNA分子,每個siRNA分子包括有義鏈和與有義鏈雜交的反義鏈。在某些實施方式中,siRNA靶向HBV基因組的一個或多個基因及/或轉錄物。
(f)免疫刺激劑
檢查點抑制劑
如本文所描述的,術語「檢查點抑制劑」包括能夠抑制作為免疫系統調節劑(例如,刺激或抑制免疫系統活性)的免疫檢查點分子的任何化合物。例如,一些檢查點抑制劑阻斷抑制性檢查點分子,從而刺激免疫系統功能,如刺激針對癌細胞的T細胞活性。檢查點抑制劑的非限制性實例是PD-L1抑制劑。
如本文所描述的,術語「PD-L1抑制劑」包括能夠直接或間接抑制程序性死亡配體1(PD-L1)蛋白的表現及/或功能的任何化合物。PD-L1,也稱為分化簇274(CD274)或B7同系物1(B7-H1),是在抑制妊娠期間的免疫系統適應性臂、組織同種異體移植、自身免疫
性疾病、和肝炎中起重要作用的1型跨膜蛋白。PD-L1與其受體、抑制性檢查點分子PD-1(在激活的T細胞、B細胞、和骨髓細胞上發現)結合,以便調節免疫系統適應性臂的激活或抑制。在某些實施方式中,PD-L1抑制劑將PD-L1的表現及/或功能抑制至少5%、至少10%、至少20%、至少50%、至少75%、或至少90%。
報導的PD-L1抑制劑包括但不限於以下專利申請出版物之一中敘述的化合物:US 2018/0057455;US 2018/0057486;WO 2017/106634;WO 2018/026971;WO 2018/045142;WO2018/118848;WO 2018/119221;WO 2018/119236;WO 2018/119266;WO 2018/119286;WO2018/121560;WO 2019/076343;WO 2019/087214;並且通過引用以其整體併入本文。
(g)靶向HBV基因轉錄物的GalNAc-siRNA綴合物
「GalNAc」是N-乙醯基半乳糖胺的縮寫,而「siRNA」是小干擾RNA的縮寫。在本發明的實踐中有用的GalNAc-siRNA綴合物中,將靶向HBV基因轉錄體的siRNA與GalNAc共價結合。儘管不希望受到理論的束縛,但據信GalNAc與肝細胞上的脫唾液酸糖蛋白受體結合,從而促進siRNA靶向感染HBV的肝細胞。siRNA進入感染的肝細胞,並通過RNA干擾現象刺激HBV基因轉錄物的破壞。
在本發明的這一方面的實踐中有用的GalNAc-siRNA綴合物的實例在公開的國際申請PCT/CA2017/050447(2017年10月19日公開的PCT申請公開號WO/2017/177326)中闡述,其通過引用以其整體併入本文。
(h)治療疫苗
在某些實施方式中,治療疫苗的投予在實踐本公開以用於治療受試中的病毒性疾病是有用的。在某些實施方式中,病毒性疾病是肝炎病毒。在某些實施方式中,肝炎病毒是選自B型肝炎病毒(HBV)和D型肝炎病毒(HDV)中的至少一種。在某些實施方式中,受試者是人類。
例如,可以使用適當的方法計算協同效應如,如,例如Sigmoid-Emax方程(Holford & Scheiner,1981,Clin.Pharmacokinet.6:429-453),Loewe Additivity方程(Loewe & Muischnek,1926,Arch.Exp.Pathol Pharmacol.114:313-326)和中效方程(Chou & Talalay,1984,Adv.Enzyme Regul.22:27-55)。本文中其它部分提及的每個方程均可應用於實驗數據以生成相應的圖,以幫助評估藥物組合的影響。與本文其它部分提及的方程相關聯的對應的圖分別為濃度-效應曲線、等效線圖解法曲線和組合指數曲線。
合成
本發明進一步提供製備本發明的化合物的方法。本教導的化合物可以通過使用本領域技術人員已知的標準合成方法和程序,根據本文概述的程序,由商業上可獲得的起始原料、文獻中已知的化合物、或容易製備的中間體製備。可從相關的科學文獻或從本領域的標準教科書中容易地獲得用於製備有機分子以及官能團轉化和操縱的標準合成方法和程序。
應當理解,除非另有說明,在給出典型的或優選的工藝條件(即,反應溫度、時間、反應物的莫耳比、溶劑、壓力等)的情況下,也可以使用其它工藝條件。最佳反應條件可以隨所使用的特定反應物或溶劑而變化,但是這種條件可以由本領域技術人員通過習用優化程序來確定。有機合成領域的技術人員將認識到,出於優化本文所述化合物的形成的目的,可以改變所呈現的合成步驟的性質和順序。
可以根據本領域中已知的任何合適的方法來監測本文描述的過程。例如,產物形成可以通過光譜方法(spectroscopic means),如核磁共振光譜法(例如,1H或13C)、紅外光譜法、分光光度法(例如,紫外可見)、質譜法,或通過層析法如高效液相層析法(HPLC)、氣相層析法(GC)、凝膠滲透層析法(GPC)、或薄層層析法(TLC)來監測。
化合物的製備可以涉及各種化學基團的保護和脫保護。保護和脫保護的需要以及合適保護基團的選擇可以由本領域技術人員容易地確定。保護基團化學可以在例如Greene et al.,Protective Groups in Organic Synthesis,2d.Ed.(Wiley&Sons,1991)中找到,出於所有目的通過引用將其全部公開內容併入本文。
本文所述的反應或方法可以在有機合成領域的技術人員可以容易選擇的合適溶劑中進行。在進行反應的溫度下,即在溶劑的冷凍溫度至溶劑的沸騰溫度的範圍內的溫度下,合適的溶劑通常基本上不與反應物、中間體、及/或產物反應。給定的反應可以在一種溶劑或多於一種溶劑的混合物中進行。取決於特定的反應步驟,可以選擇用於特定反應步驟的合適溶劑。
式(I)化合物可以例如根據流程1中概述的合成方法,由商業上可獲得的或先前記載的起始原料來製備。
二環酮或三環酮IV可由1,3-二酮II和羧酸衍生物III通過以下製備:在金屬催化劑,諸如但不限於碘化亞銅的存在下通過偶合反應(當III中的LG是合適的離去基團時,在非限制性實例中,為鹵素、三氟甲磺酸根、甲苯磺酸根、甲磺酸根等),或通過醛醇式縮合(當III是β-酮酸或β-酮酯時),隨後所生成的中間體--經分離或在原位--與氨或胺的反應,然後可選擇地通過烷基化。在後一種情況下,O-烷基化提供酮IV-A。酮IV和IV-A與胺縮合,並且所得的中間體亞胺與還原劑,諸如但不限於硼氫化鈉,或碳基親核試劑,諸如但不限於格氏試劑或烷基/芳基鋰試劑反應以提供胺V,或V-B。在某些實施方式中,一級R’NH2胺可包含手性中心,該手性中心可以是外消旋的、成
比例消旋的(scalemic)、或是對映純的(enantiopure),並且可用於影響亞胺還原或碳基親核加成的立體化學結果。所得的二級胺可進一步與醛和還原劑,諸如但不限於三乙醯氧基硼氫化鈉反應,並且R’基團可被去除以提供V,或V-B。可選擇地,IV和IV-A可與一級亞磺醯胺反應形成亞磺醯亞胺(sulfinimine),亞磺醯亞胺隨後與還原劑,諸如但不限於硼氫化鈉,或碳基親核試劑,諸如但不限於格氏試劑或烷基/芳基鋰反應。在某些實施方式中,一級亞磺醯胺可以是外消旋的、成比例消旋的、或是對映純的,並且可用於影響亞磺醯亞胺還原的立體化學結果。所得的二級亞磺醯胺可進一步在鹼,諸如但不限於氫化鈉的存在下,用親電子試劑,諸如但不限於烷基鹵官能化,並且亞磺醯胺基可被移除以提供V,或V-B。用多種親電子試劑,例如活化的羧酸衍生物VI,或磺醯氯VII對V或V-B官能化分別提供I、I-B、I-C、或I-D。
本文其它部分併入的方案示例了本發明的代表性化合物的合成。類似化合物可使用適當取代的中間體和試劑以與所示例的化合物類似的方式合成。
方法
本發明提供治療、改善、及/或預防受試者中的肝炎病毒感染的方法。在某些實施方式中,感染包括B型肝炎病毒(HBV)感染。在其它實施方式中,感染包括D型肝炎病毒(HDV)感染。在又其它實施方式中,感染包括HBV感染和HDV感染。在又其它實施方式中,該方法包括向需要其的受試者投予治療有效量的至少一種本發明的化合物。在又其它實施方式中,至少一種本發明的化合物是投予至受試者的唯一抗病毒劑。在又其它實施方式中,將至少一種化合物在醫藥上可接受之組成物中投予至受試者。在又其它實施方式中,進一步向受試者投予用於治療、改善、及/或預防肝炎感染的至少一種另外的劑。在又其它實施方式中,至少一種另外的劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶
向HBV基因組的寡聚核苷酸;免疫刺激劑,如檢查點抑制劑(例如,PD-L1抑制劑);靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。在又其它實施方式中,向受試者共同投予至少一種化合物和至少一種另外的劑。在又其它實施方式中,至少一種化合物和至少一種另外的劑是共同配製的。
本發明進一步提供在受試者中直接或間接抑制病毒衣殼蛋白的表現及/或功能的方法。在某些實施方式中,該方法包括向需要其的受試者投予治療有效量的至少一種本發明的化合物。在其它實施方式中,將至少一種化合物在醫藥上可接受之組成物中投予至受試者。在又其它實施方式中,至少一種本發明的化合物是投予至受試者的唯一抗病毒劑。在又其它實施方式中,進一步向受試者投予用於治療、改善、及/或HBV感染的至少一種另外的劑。在又其它實施方式中,至少一種另外的劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑,如檢查點抑制劑(例如,PD-L1抑制劑);靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。在又其它實施方式中,向受試者共同投予至少一種化合物和至少一種另外的劑。在又其它實施方式中,至少一種化合物和至少一種另外的劑是共同配製的。
在某些實施方式中,受試者是哺乳動物。在其它實施方式中,哺乳動物是人。
藥物組成物和調配物
本發明提供包括至少一種本發明的化合物或其鹽或溶劑化物的藥物組成物,其用於實踐本發明的方法。這樣的藥物組成物可由適合投予至受試者的形式的至少一種本發明的化合物或鹽或溶劑化物組成,或藥物組成物可以包括至少一種本發明的化合物或其鹽或溶劑化物以及一種或多種醫藥上可接受之載劑、一種或多種另外的成分、或這些的任意組合。如本領域公知,至少一種本發明的化合物可以以生理學
上可接受的鹽的形式,如與生理學上可接受的陽離子或陰離子組合存在於藥物組成物中。
在某些實施方式中,可以投予用於實踐本發明的方法的藥物組成物遞送1ng/kg/天和100mg/kg/天之間的劑量。在其它實施方式中,可以投予用於實踐本發明的藥物組成物遞送1ng/kg/天和1,000mg/kg/天之間的劑量。
本發明的藥物組成物中的活性成分、醫藥上可接受之載劑、和任何另外的成分的相對量將會變化,這取決於所治療的受試者的身份、體型(size)和病症,並且進一步取決於組成物將被投予的途徑。舉例而言,組成物可以包括0.1%和100%(w/w)之間的活性成分。
用於本發明的方法中的藥物組成物可以適當地開發用於經鼻、吸入、口服、直腸、陰道、胸膜、腹膜、腸胃外、局部、經皮、經肺、鼻內、含服、眼內、硬膜外、鞘內、靜脈內、或其它投予途徑。可以將在本發明的方法中使用的組成物直接投予至哺乳動物或鳥類的中樞神經系統的大腦、腦幹、或任何其它部分。其它考慮的調配物包括經設計(project)的納米顆粒、微球、脂質體調配物、包被的顆粒、聚合物綴合物、含有活性成分的重新密封的紅細胞、和基於免疫學的調配物。
在某些實施方式中,本發明的組成物是藥物基質的一部分,其允許處理不溶性物質並改善其生物利用度、開發控釋或緩釋產品、和產生均質組成物。舉例而言,可以使用熱熔擠出、固溶體、固體分散體、尺寸減小技術、分子複合物(例如,環糊精等)、微粒、和顆粒與調配物包衣工藝來製備藥物基質。非晶相或結晶相可用於這種工藝中。
投予途徑(一種或多種)對技術人員來說是顯而易見的,並且將取決於許多因素,包括所治療的疾病的類型和嚴重程度、所治療的獸醫或人類患者的類型和年齡等。
本文描述的藥物組成物的調配物可以通過藥理學和製藥學領域中已知的或以後開發的任何方法來製備。通常,這種製備方法包
括以下步驟:使活性成分與載劑或一種或多種其它輔助成分結合,然後,如果需要或期望,將產品成型或包裝成所需的單劑量或多劑量單位。
如本文所使用的,「單位劑量」是包括預定量的活性成分的離散量的藥物組成物。活性成分的量通常等於將被投予至受試者的活性成分的劑量或這樣的劑量的方便部分,如,例如這樣的劑量的一半或三分之一。單位劑型可以是單次日劑量或多次日劑量之一(例如,每天約1至4次或更多次)。當使用多次日劑量時,每次給藥的單位劑型可以相同或不同。
儘管本文提供的藥物組成物的描述主要針對適合於對人類進行倫理施用的藥物組成物,但是技術人員將理解,這種組成物通常適合於投予至各種動物。為了使組成物適合於向各種動物投予,適合於向人投予的藥物組成物的改進是眾所周知的,並且普通技術的獸醫藥理師可以僅通過普通的實驗來設計和進行這種改進。所考慮向其投予本發明的藥物組成物的受試者包括但不限於人和其它靈長類動物、哺乳動物,包括與商業相關的哺乳動物,如牛、豬、馬、綿羊、貓、和狗。
在某些實施方式中,使用一種或多種醫藥上可接受之賦形劑或載劑配製本發明的組成物。在某些實施方式中,本發明的藥物組成物包括治療有效量的至少一種本發明的化合物和醫藥上可接受之載劑。有用的醫藥上可接受之載劑包括但不限於甘油、水、鹽水、乙醇、重組人白蛋白(例如,RECOMBUMIN®)、可溶凝膠(例如,GELOFUSINE®)、和其它醫藥上可接受之鹽溶液,如磷酸鹽和有機酸的鹽。在Remington’s Pharmaceutical Sciences(1991,Mack Publication Co.,New Jersey)中描述了這些和其它醫藥上可接受之載劑的實例。
載劑可以是溶劑或分散介質,其包含例如水、乙醇、多元醇(例如,甘油、丙二醇、和液體聚乙二醇等)、重組人白蛋白、可溶明膠、其合適的混合物,以及植物油。例如,可以通過使用包衣,如卵磷脂,通過在分散體存在的情況下維持所需的粒徑以及通過使用表面活
性劑來維持合適的流動性。可以通過各種抗細菌劑和抗真菌劑,例如,對羥基苯甲酸酯、三氯第三丁醇、苯酚、抗壞血酸、硫柳汞等防止微生物的作用。在許多情況下,組成物中包含等滲劑,例如,糖、氯化鈉、或多元醇,如甘露糖醇和山梨糖醇。可以通過在組成物中包含延遲吸收的劑,例如,單硬脂酸鋁或明膠來實現可注射組成物的延長吸收。
調配物可以與習用賦形劑混合使用,即,適合於口服、腸胃外、經鼻、吸入、靜脈內、皮下、經皮腸內、或本領域已知的任意其它合適的投予方式的醫藥上可接受之有機或無機載劑物質。可以對藥物調配物進行滅菌,並且如果需要,可以與輔助劑,例如,潤滑劑、防腐劑、穩定劑、潤濕劑、乳化劑、用於影響滲透壓緩衝劑的鹽、著色劑、調味劑、及/或賦予香氣的物質等混合。在需要時,它們也可以與其它活性劑,例如,其它鎮痛劑、抗焦慮劑或催眠劑組合。如本文所使用的,「另外的成分」包括但不限於可用作藥物載劑的一種或多種成分。
本發明的組成物可以包括按組成物的總重量計約0.005%至2.0%的防腐劑。在暴露於環境中的污染物的情況下,防腐劑用於防止變質。根據本發明有用的防腐劑的實例包括但不限於選自苄醇、山梨酸、對羥基苯甲酸、咪脲及其任意組合的防腐劑。一種這樣的防腐劑是約0.5%至2.0%的苄醇和0.05至0.5%的山梨酸的組合。
該組成物可以包括抑制化合物降解的抗氧化劑和螯合劑。對於某些化合物,抗氧化劑是BHT、BHA、α-生育酚和抗壞血酸,按組成物的總重量計,其例示性範圍為按重量計約0.01%至0.3%,或BHT範圍為按重量計0.03%至0.1%。按組成物的總重量計,螯合劑存在的量可以是按重量計0.01%至0.5%。按組成物的總重量計,例示性螯合劑包括在約0.01%至0.20%的重量範圍內或在按重量計0.02%至0.10%的範圍內的乙二胺四乙酸鹽(例如乙二胺四乙酸二鈉)和檸檬酸。螯合劑可用於螯合組成物中的金屬離子,這可能對調配物的保存期限有害。對於某些化合物,儘管BHT和乙二胺四乙酸二鈉分別是例示性的抗氧化劑和螯合劑,但是如本領域技術人員所知,可以用其它合適的和
等同的抗氧化劑和螯合劑替代。
可以使用習用方法製備液體懸浮液,以使活性成分懸浮在水性或油性媒介物中。水性媒介物包括例如水和等滲鹽水。油性媒介物包括例如杏仁油、油性酯、乙醇、植物油(如花生油、橄欖油、芝麻油、或椰子油)、分餾的植物油和礦物油,如液體石蠟。液體懸浮液可以進一步包括一種或多種另外的成分,包括但不限於懸浮劑、分散劑或潤濕劑、乳化劑、緩和劑、防腐劑、緩衝劑、鹽、調味劑、著色劑、和甜味劑。油性懸浮液可以進一步包括增稠劑。已知的懸浮劑包括但不限於山梨糖醇糖漿劑、氫化可食用脂肪、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍樹膠、阿拉伯樹膠、和纖維素衍生物,如羧甲基纖維素鈉、甲基纖維素、羥丙甲基纖維素。已知的分散劑或潤濕劑包括但不限於天然存在的磷脂,如卵磷脂,烯化氧與脂肪酸、與長鏈脂族醇、與源自脂肪酸和己糖醇的偏酯、或與源自脂肪酸和己糖醇酐的偏酯(例如,分別是聚氧乙烯硬脂酸酯、十七碳亞乙氧基鯨蠟醇、聚氧乙烯山梨醇單油酸酯、和聚氧乙烯山梨聚糖單油酸酯)的縮合產物。已知的乳化劑包括但不限於卵磷脂、阿拉伯膠、和離子或非離子表面活性劑。已知的防腐劑包括但不限於對羥基苯甲酸甲酯、對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯、抗壞血酸、和山梨酸。已知的甜味劑包括例如甘油、丙二醇、山梨糖醇、蔗糖、和糖精。
可以以與液體懸浮液基本相同的方式製備活性成分在水性或油性溶劑中的液體溶液,主要區別在於活性成分是溶解而不是懸浮在溶劑中的。如本文所使用的,「油性」液體是包括含碳液體分子並且展現出比水小的極性的液體。本發明的藥物組成物的液體溶液可包含關於液體懸浮液描述的組分中的每一種,應當理解,懸浮劑不一定會幫助活性成分溶解在溶劑中。水性溶劑包括例如水和等滲鹽水。油性溶劑包括例如杏仁油、油性酯、乙醇、植物油(如花生油、橄欖油、芝麻油、或椰子油)、分餾的植物油、和礦物油,如液體石蠟。
可以使用已知方法製備本發明的藥物調配物的粉末狀和
顆粒調配物。這樣的調配物可以直接投予至受試者,例如,用於形成錠劑、填充膠囊,或通過向其中添加水性或油性媒介物來製備水性或油性懸浮液或溶液。這些調配物中的每一種可以進一步包括分散劑或潤濕劑、懸浮劑、離子和非離子表面活性劑、和防腐劑中的一種或多種。這些調配物中還可以包括另外的賦形劑,比如填充劑和甜味劑、調味劑、或著色劑。
本發明的藥物組成物也可以水包油乳劑或油包水乳劑的形式製備、包裝、或出售。油相可以是植物油(如橄欖油或花生油)、礦物油(如液體石蠟)、或這些的組合。這樣的組成物可以進一步包含一種或多種乳化劑,如天然存在的樹膠(如阿拉伯樹膠或黃蓍樹膠);天然存在的磷脂,如大豆或卵磷脂;源自脂肪酸和己糖醇酐的組合的酯或偏酯,如山梨聚糖單油酸酯,以及這種偏酯與環氧乙烷的縮合產物,如聚氧乙烯山梨聚糖單油酸酯。這些乳劑還可以包含另外的成分,包括例如甜味劑或調味劑。
用化學組成物浸漬或塗覆材料的方法在本領域中是已知的,並且包括但不限於將化學組成物沉積或結合到表面上的方法、在合成材料(即,如使用生理學上可降解的材料)期間將化學組成物結合到材料結構中的方法、以及將水性或油性溶液或懸浮液吸收到吸收性材料中,隨後進行乾燥或不進行乾燥的方法。將組分混合的方法包括本領域技術人員已知的物理研磨、在固體和懸浮液調配物中使用丸粒以及在透皮貼劑中混合。
投予/給藥
給藥方案可能會影響有效量的構成。可以在疾病或病症發作之前或之後將治療調配物投予至患者。此外,可以每天或順序投予幾種分開的劑量以及交錯劑量,或者可以連續輸注該劑量,或者可以是彈丸注射。此外,治療調配物的劑量可以根據治療或預防情況的緊急程度成比例地增加或減少。
可以使用已知的程序,以有效治療本文考慮的疾病或病症的劑量和時間段將本發明的組成物投予至患者,如哺乳動物,如人。實現治療效果所必需的治療化合物的有效量可以根據以下因素而變化,如所採用的特定化合物的活性;投予時間;該化合物的排泄速率;治療的持續時間;與該化合物組合使用的其它藥物、化合物或材料;疾病或病症的狀態,所治療患者的年齡、性別、體重、狀況、一般健康狀況以及既往病史,以及醫學領域公知的類似因素。可以調整劑量方案以提供最佳的治療反應。例如,如治療狀況的緊急情況所指示,可以每天投予數個分開的劑量或可以成比例地減少劑量。本發明的治療化合物的有效劑量範圍的非限制性實例為每天約0.01mg/kg至100mg/kg體重。本領域普通技術人員將能夠研究相關因素並確定治療化合物的有效量而無需過度實驗。
可以將該化合物每天幾次頻繁地投予至動物,或者可以較不頻繁地投予,如每天一次、每週一次、每兩週一次、每月一次、或甚至較不頻繁地,如每幾個月一次,或甚至一年一次或更低。應當理解,在非限制性實例中,每天給藥的化合物的量可以每天、每隔一天、每2天、每3天、每4天、或每5天投予一次。例如,每隔一天投予一次,可以在星期一開始5mg的每日劑量,在星期三投予第一個隨後5mg的每日劑量,在星期五投予第二個隨後5mg的每日劑量等等。劑量的頻率對技術人員而言是顯而易見的,並且取決於許多因素,諸如但不限於所治療的疾病的類型和嚴重程度以及動物的類型和年齡。
可以改變本發明的藥物組成物中活性成分的實際劑量水平,以便獲得有效實現特定患者、組成物、和給藥方式所需的治療反應的活性成分的量,而對患者是無毒的。
具有本領域普通技術的醫生,例如,醫師或獸醫,可以容易地確定和開處方所需的有效量的藥物組成物。例如,醫師或獸醫可以以低於所需要的水平開始在藥物組成物中使用的本發明化合物的劑量,以便獲得所需的治療效果並逐漸增加劑量,直到獲得所需的效果。
在具體實施方式中,以劑量單位形式配製化合物對於施用的容易性和劑量的均勻性是特別有利的。如本文所使用的劑量單位形式是指適合作為待治療患者的單位劑量的物理上離散的單位;每個單位都包含預定量的治療化合物,該化合物經計算可與所需的藥物媒介物結合以產生所需的治療效果。本發明的劑量單位形式由以下決定並直接取決於(a)治療化合物的獨特特徵和要實現的特定治療效果,以及(b)在複配/配製用於治療患者的疾病或病症的這種治療化合物的領域中固有的局限性。
在某些實施方式中,本發明的組成物以每天一至五次或更多次的範圍內的劑量投予至患者。在其它實施方式中,本發明的組成物以包括但不限於每天一次、每兩天一次、每三天一次至一週一次、以及每兩週一次的劑量範圍投予至患者。對於本領域技術人員而言顯而易見的是,本發明的各種組合組成物的投予頻率將因受試者而異,這取決於許多因素,包括但不限於年齡、待治療的疾病或病症、性別、整體健康狀況、和其它因素。因此,本發明不應被解釋為限於任何特定的劑量方案,並且將由主治醫師考慮到患者的所有其它因素來確定要投予至任何患者的精確劑量和組成。
用於投予的本發明的化合物可以在以下範圍內:約1μg至約7,500mg、約20μg至約7,000mg、約40μg至約6,500mg、約80μg至約6,000mg、約100μg至約5,500mg、約200μg至約5,000mg、約400μg至約4,000mg、約800μg至約3,000mg、約1mg至約2,500mg、約2mg至約2,000mg、約5mg至約1,000mg、約10mg至約750mg、約20mg至約600mg、約30mg至約500mg、約40mg至約400mg、約50mg至約300mg、約60mg至約250mg、約70mg至約200mg、約80mg至約150mg,和它們之間的任意完整增量和部分增量。
在一些實施方式中,本發明的化合物的劑量為約0.5μg和約5,000mg。在一些實施方式中,本文描述的組成物中使用的本發明的
化合物的劑量小於約5,000mg、或小於約4,000mg、或小於約3,000mg、或小於約2,000mg、或小於約1,000mg、或小於約800mg、或小於約600mg、或小於約500mg、或小於約200mg、或小於約50mg。類似地,在一些實施方式中,如本文描述的第二化合物的劑量小於約1,000mg、或小於約800mg、或小於約600mg、或小於約500mg、或小於約400mg、或小於約300mg、或小於約200mg、或小於約100mg、或小於約50mg、或小於約40mg、或小於約30mg、或小於約25mg、或小於約20mg、或小於約15mg、或小於約10mg、或小於約5mg、或小於約2mg、或小於約1mg、或小於約0.5mg,和其任意完全增量和部分增量。
在某些實施方式中,本發明涉及包裝的藥物組成物,其包含單獨地或與第二種藥物組合地容納治療有效量的本發明化合物的容器;以及使用該化合物治療、預防、或減輕患者中的疾病或病症的一種或多種症狀的說明書。
術語「容器」包括用於容納藥物組成物或用於管理穩定性或水吸收的任何接受器(receptacle)。例如,在某些實施方式中,容器是包含藥物組成物的包裝,如存在於雙室中的液體(溶液和懸浮液)、半固體、凍乾固體、溶液和粉末或凍乾調配物。在其它實施方式中,容器不是包含藥物組成物的包裝,即,容器是接受器,如包含包裝的藥物組成物或未包裝的藥物組成物以及藥物組成物使用說明書的盒子或小瓶。此外,包裝技術是本領域公知的。應當理解,藥物組成物的使用說明書可以包含在含有藥物組成物的包裝上,因此說明書與包裝的產品形成增加的功能關係。然而,應當理解,說明書中可能包含有關該化合物執行其預期功能的能力,例如,治療、預防、及/或減輕患者中的疾病或病症的信息。
給藥
本發明任何組成物的給藥途徑包括吸入、口服、經鼻、直
腸、腸胃外、舌下、經皮、經粘膜(例如,舌下、舌、(經)含服、(經)尿道、陰道(例如,經陰道和陰道周圍)、鼻(內)、和(經)直腸)、膀胱內、肺內、十二指腸內、胃內、鞘內、硬膜外、胸膜內、腹膜內、皮下、肌內、皮內、動脈內、靜脈內、支氣管內、吸入、和局部投予。
合適的組成物和劑型包括例如錠劑、膠囊、囊片、丸劑、軟膠囊、口含錠、乳劑、分散劑、懸浮劑、溶液、糖漿劑、顆粒劑、珠劑、透皮貼劑、凝膠劑、粉末、丸粒、乳漿劑(magma)、菱形錠、乳膏、糊劑、膏藥、洗劑、片劑(discs)、栓劑、用於經鼻或口服投予的液體噴霧劑、用於吸入的乾粉或霧化調配物、用於膀胱內投予的組成物和調配物等。應當理解,可用於本發明的調配物和組成物不限於本文描述的特定調配物和組成物。
口服投予
對於口服投予,特別地合適的是錠劑、糖衣錠、液體、滴劑、膠囊、囊片和軟膠囊。其它適合口服投予的調配物包括但不限於粉末或顆粒調配物、水性或油性懸浮劑、水性或油性溶液、糊劑、凝膠劑、牙膏、漱口劑、包衣劑、口腔沖洗劑、或乳劑。可以根據本領域已知的任何方法來製備預期用於口服使用的組成物,並且這種組成物可以包含選自適合用於製造錠劑的惰性,無毒,通常被認為是安全的(GRAS)藥學上的賦形劑的一種或多種試劑。這種賦形劑包括例如惰性稀釋劑,如乳糖;製粒劑和崩解劑,如玉米澱粉;粘合劑,如澱粉;和潤滑劑,如硬脂酸鎂。
錠劑可以是未被塗覆的,或者可以使用已知方法塗覆,以在受試者的胃腸道中實現延遲崩解,從而提供活性成分的持續釋放和吸收。舉例而言,可以使用如單硬脂酸甘油酯或二硬脂酸甘油酯的材料塗覆錠劑。進一步舉例而言,可以使用在美國專利號4,256,108;4,160,452;和4,265,874中描述的方法塗覆錠劑以形成滲透控釋錠劑。錠劑可以進一步包含甜味劑、調味劑、著色劑、防腐劑、或這些的某種組合,以提供藥學上鮮美(elegant)且可口的調配物。包含活性成分的
硬膠囊可以使用生理學上可降解的組成物,如明膠來製備。膠囊包含活性成分,並且可以進一步包含另外的成分,包括例如惰性固體稀釋劑,如碳酸鈣、磷酸鈣、或高嶺土。
包含活性成分的硬膠囊可以使用生理學上可降解的組成物,如明膠來製備。這種硬膠囊包含活性成分,並且可以進一步包含另外的成分,包括例如惰性固體稀釋劑,如碳酸鈣、磷酸鈣、或高嶺土。
包含活性成分的軟膠囊可以使用生理學上可降解的組成物,如來自動物膠原或羥丙甲纖維素(纖維素的改性形式)的明膠來製備,並使用明膠、水和增塑劑,如山梨糖醇或甘油的任選的混合物製造。這樣的軟膠囊包括可以與水或油介質,如花生油、液體石蠟、或橄欖油混合的活性成分。
對於口服投予,本發明的化合物可以是通過習用手段與醫藥上可接受之賦形劑,如粘合劑;填充劑;潤滑劑;崩解劑;或潤濕劑製備的錠劑或膠囊的形式。如果需要,可以使用合適的方法和包衣材料,如可獲得自ColorcoN,West Point,Pa.(例如,OPADRY® OY型、OYC型、有機腸溶型OY-P型、水性腸溶型OY-A型、OY-PM型和OPADRY® White,32K18400)的OPADRY®膜包衣系統塗覆錠劑。應當理解,可以使用其它公司的類似類型的膜塗層或聚合產物。
包含活性成分的錠劑可以例如通過將活性成分可選擇地與一種或多種另外的成分一起壓製或模製來製備。製備壓製錠劑可以通過在合適的裝置中壓製自由流動形式的活性成分,如粉末或顆粒調配物,可選擇地與粘合劑、潤滑劑、賦形劑、表面活性劑和分散劑中的一種或多種混合。模製錠劑可以通過在合適的裝置中模製活性成分、醫藥上可接受之載劑、和至少足以潤濕混合物的液體的混合物來製備。用於製造錠劑的醫藥上可接受之賦形劑包括但不限於惰性稀釋劑、製粒劑和崩解劑、粘合劑和潤滑劑。已知的分散劑包括但不限於馬鈴薯澱粉和羥甲基澱粉鈉。已知的表面活性劑包括但不限於月桂基硫酸鈉。已知的稀釋劑包括但不限於碳酸鈣、碳酸鈉、乳糖、微晶纖維素、磷酸鈣、磷酸
氫鈣、和磷酸鈉。已知的製粒劑和崩解劑包括但不限於玉米澱粉和藻酸。已知的粘合劑包括但不限於明膠、阿拉伯膠、預糊化的玉米澱粉、聚乙烯吡咯啶酮、和羥丙基甲基纖維素。已知的潤滑劑包括但不限於硬脂酸鎂、硬脂酸、二氧化矽、和滑石。
製粒技術在製藥領域是公知的,用於改性活性成分的起始粉末或其它顆粒材料。通常將粉末與粘合劑材料混合成較大的永久性自由流動的附聚物或顆粒,稱為「製粒」。例如,使用溶劑的「濕法」製粒工藝的一般特徵是,將粉末與粘合劑材料混合,並在一定條件下用水或有機溶劑潤濕,形成濕的粒狀物料,然後必須將溶劑從中蒸發。
熔融製粒通常包括使用在室溫下為固體或半固體的材料(即,具有相對較低的軟化或熔點範圍),在基本上沒有添加水或其它液體溶劑的情況下促進粉末或其它材料的製粒。當加熱到熔點範圍內的溫度時,低熔點固體液化以充當粘合劑或製粒介質。液化的固體將其自身散佈在與之接觸的粉末狀材料的表面上,並在冷卻後形成固體顆粒狀物質,在其中將初始物質粘合在一起。然後可以將所得的熔融製粒提供給壓片機或封裝以製備口服劑型。熔融製粒通過形成固體分散體或固溶體來改善活性物質(即,藥物)的溶解速率和生物利用度。
美國專利號5,169,645公開了具有改善的流動特性的可直接壓縮的含蠟顆粒。當蠟在熔體中與某些改善流動性的添加劑混合,然後將混合物冷卻並製粒時,可得到顆粒。在某些實施方式中,在蠟(一種或多種)和添加劑(一種或多種)的熔融組成物中只有蠟本身熔融,並且在其它情況下,蠟(一種或多種)和添加劑(一種或多種)二者都將熔融。
本發明還包括多層錠劑,其包括提供用於延遲釋放在本發明的方法中有用的一種或多種化合物的層,和提供用於立即釋放在本發明的方法中有用的一種或多種化合物的其它層。使用蠟/pH敏感的聚合物混合物,可以獲得胃不溶性組成物,其中捕獲(entrap)了活性成分,從而確保了其延遲釋放。
用於口服投予的液體調配物可以是溶液、糖漿劑或懸浮劑的形式。液體調配物可以通過習用手段用醫藥上可接受之添加劑,如懸浮劑(例如,山梨糖醇糖漿劑、甲基纖維素或氫化可食用脂肪);乳化劑(例如,卵磷脂或阿拉伯膠);非水性媒介物(例如,杏仁油、油性酯或乙醇);和防腐劑(例如,對羥基苯甲酸甲酯或對羥基苯甲酸丙酯或山梨酸)製備。適用於口服投予的本發明的藥物組成物的液體調配物可以以液體形式或乾燥產物的形式製備、包裝、和出售,該乾燥產物旨在在使用前用水或另一種合適的載劑重構。
腸胃外投予
如本文所使用的,藥物組成物的「腸胃外投予」包括特徵在於對受試者的組織進行物理破壞和通過組織中的缺口投予藥物組成物的任何投予途徑。因此腸胃外投予包括但不限於通過注射組成物投予藥物組成物、通過外科切口投予組成物、通過穿透組織的非外科傷口投予組成物等方式投予藥物組成物。具體地,預期腸胃外投予包括但不限於皮下、靜脈內、腹膜內、肌內、胸骨內注射、和腎透析輸注技術。
適用於腸胃外投予的藥物組成物的調配物包括與醫藥上可接受之載劑,如無菌水或無菌等滲鹽水組合的活性成分。這樣的調配物可以以適合於彈丸投予或連續投予的形式製備、包裝、或出售。可注射調配物可以以單位劑型,如在含有防腐劑的安瓿或多劑量容器中製備、包裝、或出售。還可以在裝置,如患者自控的鎮痛(PCA)裝置中製備、包裝、或出售可注射調配物。腸胃外投予的調配物包括但不限於混懸劑、溶液、在油性或水性媒介物中的乳劑、膏劑、和可植入的緩釋或生物可降解的調配物。這樣的調配物可以進一步包含一種或多種另外的成分,包括但不限於懸浮劑、穩定劑、或分散劑。在用於腸胃外投予的調配物的一個實施方式中,活性成分以乾燥(即,粉末或顆粒)形式提供,以與合適的媒介物(例如,無菌無熱原水)重構,然後腸胃外投予重構的組成物。
藥物組成物可以以無菌可注射的水性或油性懸浮液或溶
液的形式製備、包裝、或出售。該懸浮液或溶液可以根據已知技術配製,並且除了活性成分外還可以包含另外的成分,如本文所述的分散劑、潤濕劑、或懸浮劑。可以使用無毒的腸胃外可接受的稀釋劑或溶劑,如,例如水或1,3-丁二醇來製備這種無菌可注射調配物。其它可接受的稀釋劑和溶劑包括但不限於林格氏溶液、等滲氯化鈉溶液、和不揮發性油,如合成的甘油單酯或甘油二酯。有用的其它可腸胃外投予的調配物包括包含活性成分的那些調配物,該活性成分為重組人白蛋白、流化明膠、脂質體調配物、或生物可降解的聚合物體系的組分中的微晶形式。用於持續釋放或植入的組成物可以包含醫藥上可接受之聚合物或疏水材料,如乳劑、離子交換樹脂、微溶聚合物、或微溶鹽。
局部投予
局部投予藥物調配物的障礙是表皮的角質層。角質層是由蛋白質、膽固醇、鞘脂、游離脂肪酸和各種其它脂質組成的高抗蝕層,並且包括角質化細胞和活細胞。限制化合物穿過角質層的滲透率(通量)的因素之一是可以負載或施加到皮膚表面上的活性物質的量。每單位皮膚面積施加的活性物質的量越大,皮膚表面與皮膚下層之間的濃度梯度越大,進而活性物質穿過皮膚的擴散力越大。因此,與濃度較低的調配物相比,含有較高濃度的活性物質的調配物更可能導致更多的活性物質以更一致的速率滲透穿過皮膚,並且不止是皮膚,所有其它內容都是一樣的。
適用於局部投予的調配物包括但不限於液體或半液體調配物,如擦劑、洗劑、水包油或油包水乳劑,如乳膏、藥膏或糊劑,以及溶液或懸浮液。儘管活性成分的濃度可與活性成分在溶劑中的溶解度極限相同,但可局部投予的調配物可以例如包括約1%至約10%(w/w)的活性成分。用於局部投予的調配物可以進一步包括一種或多種本文所述的另外的成分。
可以使用滲透促進劑。這些材料增加了藥物穿過皮膚的滲透率。本領域中典型的促進劑包括乙醇、單月桂酸甘油酯、PGML(聚
乙二醇單月桂酸酯)、二甲基亞碸等。其它促進劑包括油酸、油醇、乙氧基乙二醇、月桂氮酮、鏈烷羧酸、二甲基亞碸、極性脂質、或N-甲基-2-吡咯啶酮。
用於局部遞送本發明的一些組成物的一種可接受的媒介物可以包含脂質體。脂質體的組成及其用途是本領域已知的(即,美國專利號6,323,219)。
在可選的實施方式中,局部活性藥物組成物可以可選擇地與其它成分,如佐劑、抗氧化劑、螯合劑、表面活性劑、發泡劑、潤濕劑、乳化劑、增粘劑、緩衝劑、防腐劑等組合。在其它實施方式中,滲透或滲透促進劑包含在組成物中,並且相對於缺乏滲透促進劑的組成物,對於改善活性成分滲透到皮膚中和穿過角質層是有效的。各種滲透促進劑,包括油酸、油醇、乙氧基乙二醇、月桂氮酮、鏈烷羧酸、二甲基亞碸、極性脂質、或N-甲基-2-吡咯啶酮是本領域技術人員已知的。另一方面,組成物可以進一步包含水溶助劑,其起到增加角質層結構的病症的作用,並因此允許增加穿過角質層的運輸。各種水溶助劑,如異丙醇、丙二醇、或二甲苯磺酸鈉是本領域技術人員已知的。
局部活性藥物組成物應以有效影響所需變化的量施用。如本文所使用的「有效量」是指足以覆蓋需要改變的皮膚表面區域的量。活性化合物應該以按組成物的重量體積計約0.0001%至約15%的量存在。例如,它應該以組成物的約0.0005%至約5%的量存在;例如,它應該以組成物的約0.001%至約1%的量存在。這樣的化合物可源自合成或天然。
口頰投予
本發明的藥物組成物可以適合於口頰投予的調配物來製備、包裝、或出售。這樣的調配物可以例如為使用習用方法製備的錠劑或菱形錠的形式,並且可以包含例如0.1至20%(w/w)的活性成分,餘量包括口腔可溶解的或可降解的組成物,以及可選擇地本文所述的一種或多種另外的成分。可選擇地,適合口頰投予的調配物可以包括包含
活性成分的粉末狀或氣霧化(aerosolized)或噴霧化(atomized)溶液或懸浮液。當分散時,這種粉末狀,氣霧化,或噴霧化的調配物可具有在約0.1至約200納米範圍內的平均顆粒或液滴尺寸,並且可以進一步包括一種或多種本文所述的另外的成分。本文描述的調配物的實例不是窮舉的,並且應當理解,本發明包括本文未描述但本領域技術人員已知的這些和其它調配物的另外的變型。
直腸投予
本發明的藥物組成物可以以適於直腸投予的調配物製備、包裝、或出售。這樣的組成物可以是例如栓劑、保留灌腸調配物、和用於直腸或結腸灌洗的溶液的形式。
栓劑調配物可通過將活性成分與無刺激性的醫藥上可接受之賦形劑混合來製備,該賦形劑在正常室溫(即,約20℃)下呈固體,並且在受試者的直腸溫度(即,在健康人體內約37℃)下呈液體。合適的醫藥上可接受之賦形劑包括但不限於可可脂、聚乙二醇、和各種甘油酯。栓劑調配物可以進一步包含各種另外的成分,包括但不限於抗氧化劑和防腐劑。
用於直腸或結腸灌洗的保留灌腸調配物或溶液可通過將活性成分與醫藥上可接受之液體載劑混合來製備。如本領域公知的,可以使用適合於受試者的直腸解剖結構的遞送裝置來投予灌腸調配物,並且可以將灌腸調配物包裝在遞送裝置內。灌腸調配物可以進一步包含各種另外的成分,包括但不限於抗氧化劑和防腐劑。
另外的投予形式
本發明的另外的劑型包括如在美國專利號6,340,475、6,488,962、6,451,808、5,972,389、5,582,837、和5,007,790中描述的劑型。本發明的另外的劑型還包括如在美國專利申請號20030147952、20030104062、20030104053、20030044466、20030039688、和20020051820中描述的劑型。本發明的另外的劑型還包括如在PCT申請號WO 03/35041、WO03/35040、WO 03/35029、
WO 03/35177、WO 03/35039、WO 02/96404、WO 02/32416、WO 01/97783、WO 01/56544、WO 01/32217、WO 98/55107、WO 98/11879、WO 97/47285、WO 93/18755、和WO 90/11757中描述的劑型。
控釋調配物和藥物遞送系統:
在某些實施方式中,本發明的組成物及/或調配物可以是但不限於短期的、快速起效的(rapid-onset)及/或快速失效(rapid-offset)的,以及受控的,例如,持續釋放、延遲釋放和脈衝釋放調配物。
術語持續釋放在其習用意義上是指可在延長的時間段內逐漸釋放藥物的藥物調配物,儘管不一定,但在延長的時間段內可導致藥物的血液水平基本恒定。該時間段可以長達一個月或更長時間,並且應該是長於以彈丸形式投予相同量的釋放。
為了持續釋放,可以將化合物與合適的聚合物或疏水材料一起配製,聚合物或疏水材料為化合物提供持續釋放特性。由此,用於本發明方法的化合物可以以微粒形式,通過例如注射投予,或者以晶片或圓盤形式通過植入投予。
在本發明的某些實施方式中,使用緩釋調配物將本發明中有用的化合物單獨或與另一種藥物調配物組合投予至受試者。
術語延遲釋放在本文中在其習用意義上是指在藥物投予後的一定延遲之後提供藥物的初始釋放的藥物調配物,並且儘管不是必須的,但是可以包括從約10分鐘直至約12小時。
術語脈衝釋放在本文中在其習用意義上是指以藥物投予後產生脈衝血漿分佈的方式提供藥物釋放的藥物調配物。
術語立即釋放在其習用意義上是指在藥物投予後立即提供釋放藥物的藥物調配物。
如本文所使用的,短期指在藥物投予之後的任何時間段,
至多並且包括在藥物投予之後約8小時、約7小時、約6小時、約5小時、約4小時、約3小時、約2小時、約1小時、約40分鐘、約20分鐘、或約10分鐘和其任意或所有完整增量或部分增量。
如本文所使用的,快速失效指在藥物投予之後的任何時間段,至多並且包括在藥物投予之後約8小時、約7小時、約6小時、約5小時、約4小時、約3小時、約2小時、約1小時、約40分鐘、約20分鐘、或約10分鐘,和其任意完整增量和部分增量。
僅使用習用實驗,本領域技術人員將認識到或能夠確定本文所述的具體程序、實施方式、申請專利範圍、和實施例的許多等同方案。這樣的等同方案被認為在本發明的範圍內,並由所附申請專利範圍涵蓋。例如,應當理解,利用本領域公認的可選方案並且僅使用習用實驗,包括但不限於反應時間、反應規格(size)/體積、和實驗試劑,如溶劑、催化劑、壓力、大氣條件,例如氮氣氣氛、以及還原劑/氧化劑的反應條件的修改均在本申請的範圍內。
應當理解,無論在本文何處提供數值和範圍,範圍格式的描述僅是為了方便和簡潔,而不應被解釋為對本發明範圍的死板限制。因此,這些值和範圍所涵蓋的所有值和範圍意在被涵蓋在本發明的範圍內。此外,本申請還考慮了落入這些範圍內的所有值以及該值的範圍的上限或下限。範圍的描述應被認為已明確公開了所有可能的子範圍以及該範圍內的單個數值,以及在合適時該範圍內的數值的部分整數。例如,對範圍從1到6的描述應被視為已明確公開了1到3、1到4、1到5、2到4、2到6、3到6等的子範圍,以及該範圍內的單個數值,例如1、2、2.7、3、4、5、5.3和6。無論該範圍的廣度如何,這都適用。
以下實施例進一步示例了本發明的方面。然而,它們決不是對本文所述的本發明的教導或公開內容的限制。
實施例
現在參考以下實施例描述本發明。提供這些實施例僅出於
示例的目的,並且本發明不限於這些實施例,而是涵蓋由於本文提供的教導而顯而易見的所有變型。
材料&方法
以下程序可用於評估和選擇抑制B型肝炎病毒感染的化合物。
利用HBV rcDNA的bDNA定量的HepDE19測定:
HepDE19細胞培養系統是一種HepG2(人類肝癌)衍生的細胞系,以四環素(Tet)調控的方式支持HBV DNA複製和cccDNA形成,並產生HBV rcDNA和依賴於cccDNA產生和維持的可檢測報告分子(Guo,等人,2007,J.Virol.81:12472-12484)。
將HepDE19(50,000個細胞/孔)鋪板於DMEM/F12培養基中的96孔膠原蛋白包被的組織培養處理的微量滴定板中,該培養基補充有10%的胎牛血清、1%的青黴素-鏈黴素和1μg/mL的四環素,並在加濕培養箱中於37℃和5%CO2下過夜。第二天,將細胞轉移至不含四環素的新鮮培養基中,並在37℃和5%CO2下溫育4小時。用新鮮的不含Tet的培養基處理細胞,該培養基所具有的化合物的濃度從25μM開始,並且連續的1/2 log,8點滴定系列,一式兩份。測定中的最終DMSO濃度為0.5%。將板在37℃和5%CO2下於加濕培養箱中溫育7天。在溫育7天后,使用Quantigene 2.0 bDNA測定試劑盒(Affymetrix,Santa Clara,CA),結合HBV特異性的定製探針組和製造商的說明書,測量抑制劑處理過的孔中存在的rcDNA的水平。同時,使用複製板評估化合物對細胞活力的影響,將板以5,000個細胞/孔的密度鋪板並溫育4天,以按照製造商的說明書使用細胞滴度glo試劑(CTG;Promega CorporatioN,MadisoN,WI)確定作為細胞活力的量度的ATP含量。使用Victor發光板讀數器(PerlkinElmer Model 1420 Multilabel計數器)讀取板,並將每個孔生成的相對發光單位
(RLU)數據計算為未處理的對照孔的抑制百分比,並使用Microsoft Excel中的XL-Fit模塊進行分析以使用4參數曲線擬合算法確定EC50和EC90(bDNA)和CC50(CTG)的值。
LCMS方法:
LCMS方法A:Waters Acquity UPLC系統,採用Waters Acquity UPLC BEH C18,1.7μM,50 x 2.1mm柱,其中水性乙腈基(aqueous acetonitrile based)溶劑梯度為9.5分鐘內2-98%的CH3CN/H2O(0.05% TFA)。流速=0.8mL/min。
LCMS方法B:Waters Acquity UPLC系統,採用Waters Acquity UPLC BEH C18,1.7μM,50 x 2.1mm柱,其中水性乙腈基溶劑梯度為1.0分鐘內2-98%的CH3CN/H2O(0.05% TFA)。流速=0.8mL/min。
LCMS方法C:Shimadzu UFLC系統,採用ACE UltraCore Super PhenylHexyl,2.5μm,50 x 2.1mm柱,其中水性乙腈基溶劑梯度為5.0分鐘內5-100%的CH3CN/H2O(0.05%甲酸)。流速=1.0mL/min。
LCMS方法D:Waters Acquity UPLC系統,採用Waters Acquity UPLC BEH C18,1.7μm,50 x 2.1mm柱,其中水性乙腈基溶劑梯度為5.0分鐘內2-98%的CH3CN/H2O(0.05% TFA)。流速=0.8mL/min。
LCMS方法E:Waters Acquity UPLC系統,採用Waters Acquity UPLC BEH C18 2.1 x 50mm;1.7μm,流動相-A:H2O中的0.05% FA。流動相-B:CAN中的0.05% FA;梯度:T/%B:0-5;0.3-5;2.5-95,3.7-95,4-5;4.6-5;流速:0.6mL/min;柱溫:40℃。
如本文所述,「對映異構物I」或「非鏡像異構物I」是指在
針對本文其它部分提供的實例詳述的特定手性分析條件下從手性柱逸出的第一對映異構物或非鏡像異構物;而「對映異構物II」或「非鏡像異構物II」是指在針對本文其它部分提供的實例詳述的特定手性分析條件下從手性柱逸出的第二對映異構物或非鏡像異構物。對於這些化合物,這種命名法並不暗示或賦予任何具體的相對及/或絕對的構型。
實施例1:化合物
8-氟-4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(IVa)
步驟i:將5-氟-2-碘-苯甲酸(IIIa,2.51g,9.44mmol)、四氫哌喃-3,5-二酮(IIa,3.23g,28.31mmol)、碘化亞銅(0.18g,0.94mmol)、L-脯胺酸(0.22g,1.89mmol)、和碳酸氫鉀(8.69g,37.74mmol)合併到管中,並用氮氣排空和填充。加入乾燥的DMSO(30mL),並且反應混合物用氮氣吹掃,密封,並在室溫下攪拌10分鐘,然後在90℃下2.5小時。使反應混合物冷卻至室溫,用8mL水稀釋,用2M HCl酸化至pH<2,並用乙酸乙酯萃取(3 x 100mL)。合併的有機萃取物用水洗滌3次和用鹽水洗滌一次,經硫酸鈉乾燥,並過濾。在高真空下蒸發溶劑以提供粗產物,粗產物在高真空下被進一步乾燥過夜(在發生徹底固化時)並用於下一步驟中而無需進一步純化。
步驟ii:在120℃下於密封管內將先前步驟中獲得的粗5-氟-2-(3-羥基-5-側氧-2H-哌喃-4-基)苯甲酸(2.38g,9.44mmol)和醋酸銨(7.27g,94.37mmol)在1,2-二氯乙烷(100mL)中攪拌5小時。反應混合物用二氯甲烷/甲醇稀釋並吸附在矽膠上,然後經受快速層析法(矽膠,MeOH/DCM 0-10%)。所期望的產物進一步與EtOAc/己烷研磨以提供8-氟-4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(1.15g,
52.3%)。LCMS m/z實測值234.1[M+H]+;RT=0.77miN,(方法B);1H NMR(400MHz,DMSO-d 6 )δ 12.18(s,1H),9.06(dd,1H),7.86(dd,1H),7.70(ddd,1H),4.76(s,2H),4.25(s,2H).
8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)
將鈦酸四異丙酯(1.04mL,3.43mmol)加入到在1,4-二烷(9mL)中的8-氟-4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(Iva,200.0mg,0.86mmol)與在THF中的2M甲胺溶液(1.29mL,2.57mmol)的混合物中。在50℃下於氮氣下攪拌混合物2小時。移除小的等分試樣並用甲醇中的硼氫化鈉處理。LCMS分析指示起始原料完全轉換為產物。使剩餘的反應混合物冷卻至室溫,用3mL無水甲醇稀釋,並在0℃下用硼氫化鈉(64.9mg,1.72mmol)處理。5分鐘後移除冷卻浴,並攪拌反應混合物1小時。通過加入鹽水(1.5mL)使反應猝滅,用20mL乙酸乙酯稀釋,並攪拌15分鐘,然後通過CELITE®過濾。濾餅用另外的25mL乙酸乙酯洗滌,並將合併的有機溶液經硫酸鈉乾燥,過濾,並在減壓下使溶劑蒸發。殘餘物吸附在矽膠上,並且溶劑被蒸發。產物通過快速層析法(矽膠,MeOH/DCM 0-10%梯度)分離。LCMS:m/z實測值249.2[M+H]+;RT=0.49miN,(方法B);1H NMR(400MHz,CDCl3)δ 8.00-7.92(M,1H),7.68(dd,1H),7.42(dddd,1H),4.60(d,1H),4.53-4.44(M,1H),4.36(dd,1H),3.60(dd,1H),3.55(dt,1H),2.55(d,3H).
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物1和2)
向室溫下0.11g(0.66mmol)1H-吲哚-2-羧酸(VIa)在3mL DMF中的攪拌後的溶液加入0.32mL(1.81mmol)DIPEA,之後加入0.28g(0.72mmol)HATU並使攪拌持續15分鐘。在室溫下向該混合物中加入0.15g(0.60mmol)8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va),並使攪拌持續6小時。反應混合物用冰冷的水(20mL)稀釋並在室溫下再攪拌15分鐘。所形成的固體通過過濾收集,用水洗滌,並在真空下乾燥。固體產物與乙酸乙酯(5mL)研磨,通過過濾收集,並在真空下乾燥以提供0.16g(0.40mmol,66%)N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相2-丙醇:CO2-35:65。管柱:Chiralpak IC(30 x 250mm),5μ,流速:100g/min。
對映異構物I(化合物1):LCMS:m/z實測值392.3[M+H]+,RT=3.77miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.68(br s,2H),7.92-7.88(M,1H),7.65-7.58(M,2H),7.54-7.43(M,2H),7.22-7.18(M,1H),7.06-7.02(M,1H),6.90(s,1H),5.76-5.75(M,1H),4.63(d,1H),4.48(d,1H),4.16(d,1H),4.06(d,1H),3.15(s,3H);手性分析SFC:RT=4.09miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物2):LCMS:m/z實測值392.2[M+H]+,RT=3.77miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.68(br s,2H),7.92-7.88(M,1H),7.65-7.58(M,2H),7.54-
7.43(M,2H),7.22-7.18(M,1H),7.06-7.02(M,1H),6.90(s,1H),5.76-5.75(M,1H),4.63(d,1H),4.48(d,1H),4.16(d,1H),4.06(d,1H),3.15(s,3H);手性分析SFC:RT=5.58miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺(化合物3和4)
步驟i:向室溫下0.19g(0.76mmol)(S)-1-(第三丁氧基羰基)二氫吲哚-2-羧酸(VIb)在2mL DMF中的攪拌後的溶液加入0.40mL(0.76mmol)DIPEA,之後加入0.35g(0.91mmol)HATU,並將混合物攪拌15分鐘。在室溫下向該混合物加入0.20g(0.76mmol)8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va),並使攪拌持續16小時。然後混合物用冰冷的水(30mL)稀釋並在室溫下再攪拌2小時。所得沉澱通過過濾收集,用水洗滌,並在真空下乾燥。在室溫下與正戊烷(15mL)研磨固體產物15分鐘,通過過濾收集,並在真空下乾燥以提供275mg(0.55mmol,73%)(2S)-2-((8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)二氫吲哚-1-羧酸第三丁酯,取其原樣用於下一步驟:LCMS:m/z實測值494.29[M+H]+,2非鏡像異構物:RT=2.05min和2.07min(方法A)。
步驟ii:向0℃下、在氮氣氛下的0.27g(0.54mmol)(2S)-2-((8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)二氫吲哚-1-羧酸第三丁酯在5.4mL二氯甲烷中
的攪拌後的溶液加入0.24g(1.09mmol)三氟甲基磺酸三甲基矽酯(TMSOTf),並在室溫下將混合物攪拌1小時。然後在減壓下將混合物濃縮,並用飽和NaHCO3溶液(15mL)將殘餘物鹼化。固體沉澱通過過濾收集,並在高真空下乾燥以提供0.21g(0.53mmol,97%)(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺。隨後通過製備SFC分離非鏡像異構物:等度法,流動相2-丙醇:CO2-20:80。管柱:Daicel DCPACK(30 x 250mm),5μm,流速:90g/min。
非鏡像異構物I(化合物3):LCMS:m/z實測值394.3[M+H]+,RT=2.64miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.58(br s,1H),7.89(d,1H),7.57-7.52(M,1H),7.28-7.25(M,1H),7.01-6.93(M,2H),6.61-6.56(M,2H),5.74(s,1H),5.54(s,1H),4.74-4.70(M,1H),4.59(d,1H),4.43(d,1H),4.03-3.93(M,2H),3.31-3.25(M,1H),2.90-2.85(M,1H),2.84(s,3H);手性分析SFC:RT=4.44miN,管柱:DC PAK SFC-B(4.6 x 150mm)5μM,20%的甲醇,流速:3.0g/min.
非鏡像異構物II(化合物4):LCMS:m/z實測值394.2[M+H]+,RT=2.42miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.58(br s,1H),7.91-7.87(M,1H),7.62-7.56(M,1H),7.46-7.42(M,1H),7.01(d,1H),6.963-6.92(M,1H),6.59-6.54(M,2H),5.74(s,1H),5.59(s,1H),4.69-4.64(M,1H),4.58(d,1H),4.43(d,1H),3.99-3.89(M,2H),3.32-3.30(M,1H),3.19-3.13(M,1H),2.85(s,3H);手性分析SFC:RT=6.33miN,管柱:DC PAK SFC-B(4.6 x 150mm)5μM,20%的甲醇,流速:3.0g/min.
4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺:(化合物19和20)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-氟-1H-吲哚-2-羧酸(VIc)合成外消旋4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μ,流速:110g/min。
對映異構物I(化合物19):LCMS:m/z實測值410.2[M+H]+,RT=3.95miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),7.91-7.88(M,1H),7.65-7.62(M,1H),7.54-7.50(M,1H),7.29(d,1H),7.21-7.16(M,1H)6.93(s,1H),6.84-6.79(t,1H),5.75(br s,1H),4.61(d,1H),4.46(d,1H),4.15(d,1H),4.03(d,1H),3.15(s,3H);手性分析SFC:RT=2.82miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物20):LCMS:m/z實測值410.2[M+H]+,RT=3.95miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),7.91-7.88(M,1H),7.65-7.62(M,1H),7.54-7.50(M,1H),7.29(d,1H),7.21-7.16(M,1H)6.93(s,1H),6.84-6.79(t,1H),5.75(br s,1H),4.61(d,1H),4.46(d,1H),4.15(d,1H),4.03(d,1H),3.15(s,3H);手性分析SFC:RT=3.21miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]
異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物29和30)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5-氟-1H-吲哚-2-羧酸(VId)合成外消旋5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-35:65。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物29):LCMS:m/z實測值410.2[M+H]+,RT=3.90miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.79(br s 2H),7.90(dd,1H),7.62-7.59(M,1H),7.52-7.44(M,2H),7.35(dd,1H),7.09-7.04(M,1H),6.88(s,1H),5.74(br s,1H),4.62(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.13(s,3H);手性分析SFC:RT=3.12miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物30):LCMS:m/z實測值410.2[M+H]+,RT=3.90miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.79(br s 2H),7.90(dd,1H),7.61-7.57(M,1H),7.51-7.44(M,2H),7.35(dd,1H),7.09-7.04(M,1H),6.87(s,1H),5.74(br s,1H),4.62(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.13(s,3H);手性分析SFC:RT=3.75miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物31和32)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和6-氟-1H-吲哚-2-羧酸(VIe)合成外消旋6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-35:65。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物31):LCMS:m/z實測值410.2[M+H]+,RT=3.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.76(br s 2H),7.84(dd,1H),7.63-7.55(M,2H),7.50-7.46(M,1H),7.18(dd,1H),6.93-6.89(M,2H),6.88(s,1H),5.74(br s,1H),4.60(d,1H),4.46(d,1H),4.14(d,1H),4.03(d,1H),3.14(s,3H);手性分析SFC:RT=3.16miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物32):LCMS:m/z實測值410.2[M+H]+,RT=3.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.76(br s 2H),7.84(dd,1H),7.63-7.55(M,2H),7.50-7.46(M,1H),7.18(dd,1H),6.93-6.89(M,2H),6.88(s,1H),5.74(br s,1H),4.60(d,1H),4.46(d,1H),4.14(d,1H),4.03(d,1H),3.14(s,3H);手性分析SFC:RT=3.85miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物33和34)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和7-氟-1H-吲哚-2-羧酸(VIf)合成外消旋7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物33):LCMS:m/z實測值410.2[M+H]+,RT=3.90miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),7.91-7.89(M,1H),7.66-7.54(M,2H),7.42-7.40(M,1H),7.04-6.99(M,2H)6.91(d,1H),5.74(br s,1H),4.60(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.08(s,3H);手性分析SFC:RT=3.59miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物34):LCMS:m/z實測值410.2[M+H]+,RT=3.90miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),7.91-7.89(M,1H),7.66-7.54(M,2H),7.42-7.40(M,1H),7.04-6.99(M,2H)6.91(d,1H),5.74(br s,1H),4.60(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.08(s,3H);手性分析SFC:RT=5.00miN,管柱:CHIRALPAK IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物35和36)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4,6-二氟-1H-吲哚-2-羧酸(VIg)合成外消旋4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel-OD-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物35):LCMS:m/z實測值428.2[M+H]+,RT=4.20miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.88(br s 2H),7.89(dd,1H),7.63-7.59(M,1H),7.52-7.48(M,1H),7.07(dd,1H),6.97(s,1H),6.91-6.86(M,1H),5.75(br s,1H),4.62(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.15(s,3H);手性分析SFC:RT=2.35miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物36):LCMS:m/z實測值428.2[M+H]+,RT=4.20miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.88(br s 2H),7.89(dd,1H),7.63-7.59(M,1H),7.52-7.48(M,1H),7.07(dd,1H),6.97(s,1H),6.91-6.86(M,1H),5.75(br s,1H),4.62(d,1H),4.46(d,1H),4.16(d,1H),4.04(d,1H),3.15(s,3H);手性分析SFC:RT=2.84miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物37和38)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4,5-二氟-1H-吲哚-2-羧酸(VIh)合成外消旋4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-35:65。管柱:Chiralpak AS-H(30 x 250mm),5μm,流速:120g/min。
對映異構物I(化合物37):LCMS:m/z實測值428.2[M+H]+,RT=4.12miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.91(br s,2H),7.90-7.87(M,1H),7.63-7.58(M,1H),7.52-7.48(M,1H),7.26-7.20(M,2H),6.99(s,1H),5.74(s,1H),4.61(d,1H),4.47(d,1H),4.16(d,1H),4.05(d,1H),3.14(s,3H);手性分析SFC:RT=3.75miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%的甲醇,流速:3.0g/min.
對映異構物II(化合物38):LCMS:m/z實測值428.2[M+H]+,RT=4.12miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.91(br s,2H),7.90-7.87(M,1H),7.63-7.58(M,1H),7.52-7.48(M,1H),7.26-7.20(M,2H),6.99(s,1H),5.74(s,1H),4.61(d,1H),4.47(d,1H),4.16(d,1H),4.05(d,1H),3.14(s,3H);手性分析SFC:RT=5.62miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%的甲醇,流速:3.0g/min.
5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物49和50)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel-OD-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物49):LCMS:m/z實測值428.2[M+H]+,RT=4.12miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.80-11.65(br s,2H),7.89-7.86(M,1H),7.61-7.56(M,2H),7.49-7.45(M,1H),7.40-7.36(M,1H),6.91(s,1H),5.73(s,1H),4.60(d,1H),4.46(d,1H),4.15(d,1H),4.03(d,1H),3.16(s,3H);手性分析SFC:RT=3.79miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,30%的甲醇,流速:3.0g/min.
對映異構物II(化合物50):LCMS:m/z實測值428.2[M+H]+,RT=4.62miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.89(s,1H),11.61(br s,1H),7.92-7.89(M,1H),7.66-7.59(M,2H),7.52-7.49(M,1H),7.40-7.36(M,1H),6.92(s,1H),5.74(s,1H),4.64(d,1H),4.48(d,1H),4.16(d,1H),4.05(d,1H),3.13(s,3H);手性分析SFC:RT=5.62miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,30%的甲醇,流速:3.0g/min.
4-溴-3,5-二氟-N-(8-氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物166和167)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-溴-3,5-二氟苯甲酸(VIcp)合成外消旋4-溴-3,5-二氟-N-(8-氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(MeOH:MeCN(1:1)):CO2-50:50。管柱:Chiralpak-IG(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物166):LCMS:m/z實測值467.1[M+H]+,RT=5.76miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.51(s,1 H),7.90(dd,1 H),7.75(dt,1 H),7.61-7.57(M,1 H),7.40(d,2 H),5.65(s,1 H),4.60(d,1 H),4.43(d,1 H),4.27(d,1 H),4.03-3.99(M,1 H),2.67(s,3 H);手性分析SFC:RT=1.21miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,50%的(MeOH:MeCN(1:1)),流速:3.0g/min.
對映異構物II(化合物167):LCMS:m/z實測值467.1[M+H]+,RT=5.76miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.51(s,1 H),7.90(dd,1 H),7.75(dt,1 H),7.61-7.57(M,1 H),7.40(d,2 H),5.65(s,1 H),4.60(d,1 H),4.43(d,1 H),4.27(d,1 H),4.03-3.99(M,1 H),2.67(s,3 H);手性分析SFC:RT=2.97 miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,50%的(MeOH:MeCN(1:1)),流速:3.0g/min.
4-氯-3,5-二氟-N-(8-氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物174和175)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-氯-3,5-二氟苯甲酸(VIcq)合成外消旋4-氯-3,5-二氟-N-(8-氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(MeOH:MeCN(1:1)):CO2-50:50。管柱:Chiralpak-IG(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物174):LCMS:m/z實測值423.3[M+H]+,RT=6.29miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.58(s,1H),7.91-7.88(dd,1 H),7.77-7.72(M,1 H),7.61-7.57(M,1 H),7.47-7.33(M,2 H),5.65(s,1 H),4.58(d,1 H),4.42(d,1 H),4.27(d,1 H),4.03-3.99(M,1 H),2.67(s,3 H);手性分析SFC:RT=1.1miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,50%的(MeOH:MeCN(1:1)),流速:3.0g/min.
對映異構物II(化合物175):LCMS:m/z實測值423.3[M+H]+,RT=6.29miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.58(s,1H),7.91-7.88(dd,1 H),7.77-7.72(M,1 H),7.61-7.57(M,1 H),7.47-7.33(M,2 H),5.65(s,1 H),4.58(d,1 H),4.42(d,1 H),4.27(d,1 H),4.03-3.99(M,1 H),2.67(s,3 H);手性分析SFC:RT=2.41miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,50%的(MeOH:MeCN(1:1)),流速:3.0g/min.
4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物178和179)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-(二氟甲基)-3,5-二氟苯甲酸(VIcr)合成外消旋4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相EtOH:CO2-30:70。管柱:Chiralpak-IA(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物178):LCMS:m/z實測值439.3[M+H]+,RT=6.07miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.61(s,1 H),7.91(dd,1 H),7.78-7.73(M,1 H),7.61-7.57(M,1 H),7.45-7.19(M,3 H),5.63(s,1 H),4.58(d,1 H),4.46(d,1 H),4.29(d,1 H),4.02(dd,1 H),2.66(s,3 H);手性分析SFC:RT=1.1miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,30%的EtOH,流速:3.0g/min.
對映異構物II(化合物179):LCMS:m/z實測值439.3[M+H]+,RT=6.07miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.61(s,1 H),7.91(dd,1 H),7.78-7.73(M,1 H),7.61-7.57(M,1 H),7.45-7.19(M,3 H),5.63(s,1 H),4.58(d,1 H),4.46(d,1 H),4.29(d,1 H),4.02(dd,1 H),2.66(s,3 H);手性分析SFC:RT=2.94miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,30%的EtOH,流速:3.0g/min.
4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物181和182)
以與上文所述類似的方式由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-(二氟甲基)-1H-吲哚-2-羧酸(VIcs)合成外消旋4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相MeOH:CO2-40:60。管柱:Chiralpak-AS-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物181):LCMS:m/z實測值442.3[M+H]+,RT=7.00miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.05(s,1 H),11.64(s,1 H),7.92(dd,1 H),7.64(d,2 H),7.55(br s,1 H),7.42-7.11(M,3 H),7.00(s,1 H),5.76(s,1 H),4.63(d,1 H),4.49(d,1 H),4.02(d,1 H),3.14(s,3 H);手性分析SFC:RT=1.74miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,40%的MeOH,流速:3.0g/min.
對映異構物II(化合物182):LCMS:m/z實測值442.3[M+H]+,RT=7.00miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.05(s,1 H),11.64(s,1 H),7.92(dd,1 H),7.64(d,2 H),7.55(br s,1 H),7.42-7.11(M,3 H),7.00(s,1 H),5.76(s,1 H),4.63(d,1 H),4.49(d,1 H),4.02(d,1 H),3.14(s,3 H);手性分析SFC:RT=2.42miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,40%的MeOH,流速:3.0g/min.
8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(Ivb)
步驟i:將4,5-二氟-2-碘-苯甲酸(IIIb,7.50g,26.4mmol)、四氫哌喃-3,5-二酮(IIa,7.53g,66.0mmol)、碘化亞銅(0.50g,2.64mmol)、L-脯胺酸(0.61g,5.28mmol)、和碳酸鉀(21.3g,92.43mmol)合併到250mL圓底燒瓶中,然後將圓底燒瓶排空並用氮氣回填。加入無水DMSO(90mL)並用氮氣吹掃反應混合物,並在室溫下於氮氣氛下攪拌10分鐘,然後在90℃(預熱的浴溫)4小時。將反應混合物冷卻至室溫,用水緩慢稀釋直至均質,並在0℃下用2M水性HCl酸化至pH<2,並用乙酸乙酯萃取(3 x 400mL)。合併的有機萃取物用5%鹽水洗滌3次和用飽和鹽水洗滌一次,經硫酸鈉乾燥,並在真空下使溶劑蒸發成殘餘物,殘餘物進一步通過與甲苯(50mL)共沸蒸發進行乾燥,然後在高真空下過夜以提供粗8,9-二氟-4H-哌喃并[3,4-c]異色烯-1,6-二酮,其用於下一步驟中而無需進一步純化。1H NMR(400MHz,DMSO-d 6)δ 8.72(ddd,1H),8.25(ddd,1H),4.82(s,2H),4.35(d,2H).
步驟ii:在120℃下,在密封管內將獲自上述步驟的粗8,9-二氟-4H-哌喃并[3,4-c]異色烯-1,6-二酮和醋酸銨(10.2g,132.1mmol)在1,2-二氯乙烷(150mL)中攪拌5小時。在真空下使揮發物蒸發並將殘餘物懸浮於水中,並攪拌15分鐘,然後產物通過過濾收集,用水洗滌,之後用甲醇洗滌,再後用二乙醚洗滌,並在高真空下乾燥過夜以提供8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(4.53g,68%)。252.2[M+H]+;RT=0.74min(方法B);1H NMR(400MHz,DMSO-d 6)δ 12.33(s,1H),8.90(dd,1H),8.08(dd,1H),4.77(s,2H),4.27(s,2H).
8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉
-6-酮(Vb)
以與上文關於Va所述類似的方式,以87%產率,由8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVb)和甲胺合成8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮。LCMS m/z實測值267.1[M+H]+;RT=0.45min(方法B);1H NMR(400MHz,CDCl3)δ 11.40(s,1H),8.16(dd,1H),7.54(dd,1H),4.66(d,1H),4.56(d,1H),4.43(d,1H),3.63(dd,1H),3.49(d,1H),2.61(s,3H).
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基二氫吲哚-2-甲醯胺(化合物5、6、7和8)
步驟i:向室溫下530mg(18.8mmol,1.0eq.)1-(第三丁氧基羰基)-5-氟二氫吲哚-2-羧酸(VIj)在10mL DMF中的攪拌後的溶液加入1mL(56.4mmol,3.0eq.)DIPEA和1.07g(28.2mmol,1.5eq.)HATU,並將混合物攪拌15分鐘。向該混合物中加入500mg(18.8mmol,1.0eq.)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb),並在室溫下將所得混合物攪拌16小時。在反應完成(通過TLC)後,反應混合物用水(30mL)稀釋並過濾。所得固體產物用戊烷(2 x 10mL)洗滌以獲得作為四種立體異構物的混合物的2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]
異喹啉-1-基)(甲基)胺基甲醯基)-5-氟二氫吲哚-1-羧酸第三丁酯(710mg)。
步驟ii:該混合物的手性製備SFC分級分離(fractionation):等度法,流動相甲醇:CO2-15:85。管柱:Chiralpak AS(30 x 250mm),5μm,流速:100g/min提供兩個級分(fractions):A(300mg,2種異構物的混合物)和B(300mg,2種異構物的混合物)。隨後通過對這兩種級分(A和B)中的每一種進行手性製備SFC分級分離來分離單獨的立體異構物:等度法,流動相甲醇:CO2-25:75。管柱:Chiralpak IG(30 x 250mm),5μm,流速:100g/min。
步驟iii:以與上文關於化合物3和4(步驟ii)所述類似的方式將如上所述分離的2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5-氟二氫吲哚-1-羧酸第三丁酯的中間立體異構物各自轉化為終產物。基於LCMS保留時間和1H NMR同一性來指定(assigned)所分離的對映異構物的非對映對。
立體異構物Ia(化合物5):與20mL二乙醚研磨進行純化。LCMS:m/z實測值430.2[M+H]+,RT=3.00miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.65(s,1H),8.13-8.08(M,1H),7.08-7.03(M,1H),6.85-6.83(M,1H),6.78-6.73(M,1H),6.58-6.55(M,1H),5.66(s,1H),5.50(s,1H),4.75-4.71(M,1H),4.61-4.57(d,1H),4.44-4.40(d,1H),4.03-4.00(d,1H),3.96-3.93(M,1H),3.29-3.26(M,1H),2.91-2.85(M,4H);手性分析SFC:RT=2.15miN,管柱:Chiralpak AS-H3(4.6 x 150mm)3μM,40%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物IIa(化合物6,化合物5的對映異構物):與二乙醚(20mL)研磨進行純化,之後進行製備HPLC(柱:X BRIDGE(19 x 250,5μm)流動相A:10mM在水中的碳酸氫銨,流動相B:乙腈,梯度,流速:15ml/min。LCMS:m/z實測值430.2[M+H]+,RT=3.00miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.65(s,
1H),8.13-8.08(M,1H),7.08-7.03(M,1H),6.85-6.83(M,1H),6.78-6.73(M,1H),6.58-6.55(M,1H),5.66(s,1H),5.50(s,1H),4.75-4.71(M,1H),4.61-4.57(d,1H),4.44-4.40(d,1H),4.03-4.00(d,1H),3.96-3.93(M,1H),3.29-3.26(M,1H),2.91-2.85(M,4H);手性分析SFC:RT=4.04miN,管柱:Chiralpak AS-H3(4.6 x 150mm)3μM,40%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物Ib(化合物7):與10mL二乙醚研磨進行純化。LCMS:m/z實測值430.2[M+H]+,RT=2.83miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.65(s,1H),8.13-8.08(M,1H),7.30-7.25(M,1H),6.89-6.86(M,1H),6.77-6.72(M,1H),6.54-6.51(M,1H),5.71(s,1H),5.53(s,1H),4.75-4.71(M,1H),4.61-4.57(d,1H),4.44-4.40(d,1H),4.01-3.98(d,1H),3.92-3.89(M,1H),3.37-3.20(M,2H),2.86(s,3H);手性分析SFC:RT=3.07miN,管柱:Chiralpak AS-H3(4.6 x 150mm)3μM,25%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物IIb(化合物8,化合物7的對映異構物):與10mL二乙醚研磨進行純化。LCMS:m/z實測值430.2[M+H]+,RT=2.83miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.65(s,1H),8.14-8.09(M,1H),7.31-7.26(M,1H),6.98-6.96(M,1H),6.85-6.83(M,1H),6.74-6.71(M,1H),5.54(s,1H),4.88-4.84(M,1H),4.61-4.57(d,1H),4.45-4.41(d,1H),4.04-4.01(d,1H),3.92-3.89(M,1H),3.46-3.39(M,1H),3.30-3.24(M,1H),2.87(s,3H);手性分析SFC:RT=3.65miN,管柱:Chiralpak AS-H3(4.6 x 150mm)3μM,40%甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺(化合物13、14、15、16)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和外消旋1-(第三丁氧基羰基)-4,6-二氟二氫吲哚-2-羧酸(VIk)合成N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺。
立體異構物Ia(化合物13):LCMS:m/z實測值448.2[M+H]+,RT=3.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.67(s,1H),8.14-8.09(M,1H),7.08-7.03(M,1H),6.62(M,1H,可互換的),6.27-6.22(M,2H),5.50(M,1H),4.89-4.86(M,1H),4.61-4.57(M,1H),4.45-4.41(M,1H),4.04-3.94(M,2H),3.28-3.25(M,1H),2.85-2.75(M,4H);手性分析SFC:RT=1.70miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物IIa(化合物14,13的對映異構物):LCMS:m/z實測值448.2[M+H]+,RT=3.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.67(s,1H),8.14-8.09(M,1H),7.08-7.03(M,1H),6.51(M,1H,可互換的),6.27-6.22(M,2H),5.50(M,1H),4.89-4.86(M,1H),4.61-4.57(M,1H),4.45-4.41(M,1H),4.04-3.94(M,2H),3.28-3.25(M,1H),2.85-2.75(M,4H),3.29-3.26(M,1H),2.91-2.85(M,4H);手性分析SFC:RT=2.15miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物Ib(化合物15):LCMS:m/z實測值448.2
[M+H]+,RT=3.98miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.67(s,1H),8.14-8.09(M,1H),7.28-7.23(M,1H),6.51(M,1H,可互換的),6.25-6.17(M,2H),5.53(M,1H),4.89-4.85(M,1H),4.61-4.57(M,1H),4.45-4.41(M,1H),4.05-4.02(M,1H),3.92-3.89(M,1H),3.34-3.30(M,1H),3.19-3.15(M,1H),2.77(s,3H);手性分析SFC:RT=4.70miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,25%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
立體異構物IIb(化合物15,16的對映異構物):LCMS:m/z實測值448.2[M+H]+,RT=3.98miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.67(s,1H),8.14-8.09(M,1H),7.28-7.23(M,1H),6.53(M,1H,可互換的),6.25-6.17(M,2H),5.53(M,1H),4.89-4.85(M,1H),4.61-4.57(M,1H),4.45-4.41(M,1H),4.05-4.02(M,1H),3.92-3.89(M,1H),3.34-3.30(M,1H),3.19-3.15(M,1H),2.86(s,3H);手性分析SFC:RT=4.41miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇(含0.2%的改性劑DEA),流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基二氫吲哚-2-甲醯胺(化合物56、57、58、59)
步驟i:向0℃下100mg(0.34mmol,1.0eq.)1-(第三丁氧基羰基)-3,3-二甲基二氫吲哚-2-羧酸(VIr,單一對映異構物)在2.0mL二氯甲烷中的攪拌後的溶液加入65μL(0.686mmol,2.0eq.)草醯氯,並在室溫下將反應攪拌1小時。反應完成後,在減壓下使
反應混合物濃縮,並進一步與甲苯(2 x 5mL)共沸以獲得棕色糖漿,該糖漿用乾燥的二氯甲烷(2mL)稀釋並加入到0℃下90mg(0.34mmol,1.0eq.)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)在1mL DMF中的攪拌後的溶液,並在室溫下將混合物攪拌2小時。在減壓下去除二氯甲烷,並將反應混合物傾倒入冰冷的水(20mL)中。過濾所沉澱的固體並用水(20mL)洗滌。與正戊烷(10mL)研磨粗產物以提供180mg(0.33mmol,60%)灰白色固體2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-3,3-二甲基二氫吲哚-1-羧酸第三丁酯(兩種非鏡像異構物的混合物)。
步驟ii:以與上文關於化合物3和4(步驟ii)所述類似的方式將2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-3,3-二甲基二氫吲哚-1-羧酸第三丁酯轉化為N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基-二氫吲哚-2-甲醯胺。隨後通過製備SFC分離非鏡像異構物:等度法,流動相甲醇:CO2-40:60。管柱:DCPAK P4CP(21 x 250mm),5μm,流速:70g/min。
以與上文所述類似的方式將1-(第三丁氧基羰基)-3,3-二甲基二氫吲哚-2-羧酸(VIr的相反對映異構物)轉化為N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基-二氫吲哚-2-甲醯胺的剩餘的立體異構物。基於LCMS保留時間和1H NMR同一性來指定所分離的對映異構物的非對映對。
非鏡像異構物IIa(化合物56):LCMS:m/z實測值440.2[M+H]+,RT=3.24miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.5(s,1H),8.11(M,1H),7.29(M,1H),6.93(M,2H),6.56(M,2H),5.77(s,1H),5.52(s,1H),4.57(d,1H),4.46(s,1H),4.45(d,1H),3.95-3.87(M,2H),2.88(s,3H),1.36(s,3H),1.26(s,3H);手性分析SFC:RT=3.14miN,管柱:Chiralcel OD-3(4.6
x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
非鏡像異構物Ia(化合物57,化合物56的對映異構物):LCMS:m/z實測值440.2[M+H]+,RT=3.24miN,(方法A);1H NMR(400MHz,DMSO-d6 δ 11.5(s,1H),8.11(M,1H),7.29(M,1H),6.93(M,2H),6.56(M,2H),5.77(s,1H),5.52(s,1H),4.57(d,1H),4.46(s,1H),4.45(d,1H),3.95-3.87(M,2H),2.88(s,3H),1.36(s,3H),1.26(s,3H);手性分析SFC:RT=2.27miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
非鏡像異構物Ib(化合物58):LCMS:m/z實測值440.3[M+H]+,RT=3.51miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.64(s,1H),8.05(t,1H),7.21(M,1H),6.93(M,2H),6.55(M,2H),5.68(s,1H),5.51(s,1H),4.53(d,1H),4.46(s,1H),4.40(d,1H),4.05(d,1H),3.90(dd,1H),2.87(s,3H),1.28(s,3H),1.17(s,3H);手性分析SFC:RT=2.09miN,管柱:(R,R)-Whelk-01(4.6 x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
非鏡像異構物IIb(化合物59,化合物58的對映異構物):LCMS:m/z實測值440.2[M+H]+,RT=3.49miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.64(s,1H),8.05(t,1H),7.21(M,1H),6.93(M,2H),6.55(M,2H),5.68(s,1H),5.51(s,1H),4.53(d,1H),4.46(s,1H),4.40(d,1H),4.05(d,1H),3.90(dd,1H),2.87(s,3H),1.28(s,3H),1.17(s,3H);手性分析SFC:RT=2.56miN,管柱:(R,R)-Whelk-01(4.6 x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
向室溫下135mg(0.75mmol,1.0eq.)8-氟吲哚-2-羧酸(VIm)在5mL DMF中的攪拌後的溶液加入0.4mL(2.25mmol,3.0eq.)DIPEA和343mg(0.90mmol,1.2eq.)HATU,並將混合物攪拌15分鐘。向該混合物加入200mg(0.75mmol,1.0eq.)外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb),並在室溫下將所得混合物攪拌16小時。然後用水(20mL)稀釋反應混合物並通過過濾收集所沉澱的固體。真空乾燥後,所得固體與戊烷(15mL)研磨並過濾,以獲得258mg(0.60mmol,78%)外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。柱Chiralpak IC(30 x 250mm),5μm,流速:105g/min。
對映異構物I(化合物9):LCMS:m/z實測值428.2[M+H]+,RT=3.80miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.69(brs,1H),8.14-8.09(M,3H),7.46-7.41(M,1H),6.77(s,1H),6.63(d,2H),5.71(s,1H),4.61(d,1H),4.46(d,1H),4.16(d,1H),4.03(d,1H),3.02(s,3H);手性分析SFC:RT=3.89miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物10):LCMS:m/z實測值428.2[M+H]+,RT=3.80miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.69(brs,1H),8.14-8.09(M,3H),7.46-7.41(M,1H),6.77
(s,1H),6.63(d,2H),5.71(s,1H),4.61(d,1H),4.46(d,1H),4.16(d,1H),4.03(d,1H),3.02(s,3H);手性分析SFC:RT=5.36miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的甲醇,流速:3.0g/min.
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吲哚-2-羧酸(VIn)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak-IA(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物11):LCMS:m/z實測值410.2[M+H]+,RT=3.59miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.69(s,1H),8.24(d,1H),8.14-8.09(M,1H),7.92(s,1H),7.47-7.41(M,2H),6.75-6.72(M,1H),6.64-6.59(M,2H),5.72(s,1H),4.63-4.59(M,1H),4.48-4.44(M,1H),4.17-4.14(M,1H),4.04-4.02(M,1H),3.03(s,3H);手性分析SFC:RT=2.95miN,管柱:Chiralpak-IA-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物12):LCMS:m/z實測值410.3[M+H]+,RT=3.59miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.69(s,1H),8.24(d,1H),8.14-8.09(M,1H),7.92(s,1H),
7.47-7.41(M,2H),6.75-6.72(M,1H),6.64-6.59(M,2H),5.72(s,1H),4.63-4.59(M,1H),4.48-4.44(M,1H),4.17-4.14(M,1H),4.04-4.02(M,1H),3.03(s,3H);手性分析SFC:RT=4.46miN,管柱:Chiralpak-IA-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和8-氯吲哚-2-羧酸(VIo)合成外消旋8-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-45:55。管柱:Chiralpak IC(30 x 250mm),5μ,流速:110g/min。
對映異構物I(化合物17):LCMS:m/z實測值444.2/446.2[M+H]+,RT=4.11miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.68(br s,1H),8.27(d,1H),8.12-8.07(M,2H),7.44-7.39(M,1H),6.95(d,1H),6.73(s,1H),6.66-6.62(t,1H),5.71(br s,1H),4.57(d,1H),4.43(d,1H),4.15(d,1H),4.01(d,1H),3.02(s,3H);手性分析SFC:RT=3.54miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%的甲醇,流速:3.0g/min.
對映異構物II(化合物18):LCMS:m/z實測值444.2/446.2[M+H]+,RT=4.11miN,(方法A);1H NMR(400MHz,
DMSO-d6):δ 11.68(br s,1H),8.27(d,1H),8.12-8.07(M,2H),7.44-7.39(M,1H),6.95(d,1H),6.73(s,1H),6.66-6.62(t,1H),5.71(br s,1H),4.57(d,1H),4.43(d,1H),4.15(d,1H),4.01(d,1H),3.02(s,3H);手性分析SFC:RT=4.87miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺:(化合物21和22)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-45:55。管柱:Chiralpak IC(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物21):LCMS:m/z實測值410.2[M+H]+,RT=3.99miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.71(br s,2H),8.13-8.08(M,1H),7.61(d,1H),7.49-7.46(M,2H),7.22(t,1H),7.05(t,1H),6.95-(s,1H),5.77(d,1H),4.63(d,1H),4.48(d,1H),4.18-4.03(M,2H)3.17(s,3H);手性分析SFC:RT=3.57miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物22):LCMS:m/z實測值410.2[M+H]+,RT=3.99miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.71(br s,2H),8.13-8.08(M,1H),7.61(d,1H),7.49-7.46
(M,2H),7.22(t,1H),7.05(t,1H),6.95(s,1H),5.77(d,1H),4.63(d,1H),4.48(d,1H),4.18-4.03(M,2H),3.17(s,3H);手性分析SFC:RT=6.17miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物23和24)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氟-1H-吲哚-2-羧酸(VIc)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物23):LCMS:m/z實測值428.2[M+H]+,RT=4.16miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),8.11-8.06(M,1H),7.41(M,1H),7.36(d,1H),7.21-7.16(M,1H)6.97(s,1H),6.84-6.80(M,1H)5.74(br s,1H),4.58(d,1H),4.46(d,1H),4.15(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=2.34miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物24):LCMS:m/z實測值428.2[M+H]+,RT=4.16miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 12.1(br s,2H),8.11-8.06(M,1H),7.41(M,1H),7.36(d,
1H),7.21-7.16(M,1H)6.97(s,1H),6.84-6.80(M,1H)5.74(br s,1H),4.58(d,1H),4.46(d,1H),4.15(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=3.03miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物25和26)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-氟-1H-吲哚-2-羧酸(VIe)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-45:55。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物25):LCMS:m/z實測值428.2[M+H]+,RT=4.14miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(br s,2H),8.13-8.08(M,1H),7.65-7.61(M,1H),7.45-7.40(M,1H),7.17(d,1H),6.99(s,1H),6.95-690(M,1H),5.75(br s,1H),4.61(d,1H),4.45(d,1H),4.14(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=3.03miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物26):LCMS:m/z實測值428.2[M+H]+,RT=4.14miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(br s,2H),8.13-8.08(M,1H),7.65-7.61(M,1H),7.45-7.40(M,1H),7.17(d,1H),6.99(s,1H),6.95-690(M,1H),5.75
(br s,1H),4.61(d,1H),4.45(d,1H),4.14(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=3.73miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物27和28)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氟-1H-吲哚-2-羧酸(VId)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物27):LCMS:m/z實測值428.2[M+H]+,RT=4.10miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,1H),8.12-8.07(M,1H),7.48-7.35(M,3H),7.10-7.05(M,1H),6.92(s,1H),5.74(s,1H),4.63(d,1H),4.46(d,1H),4.16(d,1H),4.03(d,1H),3.15(s,3H);手性分析SFC:RT=2.56miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物28):LCMS:m/z實測值428.2[M+H]+,RT=4.10miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,1H),8.12-8.07(M,1H),7.48-7.35(M,3H),7.10-7.05(M,1H),6.92(s,1H),5.74(s,1H),4.63(d,1H),4.46(d,1H),4.16(d,1H),4.03(d,1H),3.15(s,3H);手性分析SFC:RT=3.54
miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物39和40)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氟-1H-吲哚-2-羧酸(VIf)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-45:55。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物39):LCMS:m/z實測值428.2[M+H]+,RT=4.11miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.12(br s,2H),8.11(t,1H),7.43-7.39(M,2H),7.03-6.95(M,3H),5.72(s,1H),4.62(d,1H),4.47(d,1H),4.18(d,1H),4.05(d,1H),3.09(s,3H);手性分析SFC:RT=2.95miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物40):LCMS:m/z實測值428.2[M+H]+,RT=4.11miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.03(br s,2H),8.10(t,1H),7.43-7.37(M,2H),7.03-6.95(M,3H),5.72(s,1H),4.62(d,1H),4.47(d,1H),4.18(d,1H),4.05(d,1H),3.09(s,3H);手性分析SFC:RT=5.04miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物41和42)
以與上文所述(化合物9和10)類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物41):LCMS:m/z實測值446.2[M+H]+,RT=5.08miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.92(br s,1H,exch.),11.74(br s,1H,exch.),8.12(dd,1H),7.61(dd,1H),7.41(M,2H),6.97(s,1H),5.75(s,1H),4.64(d,1H),4.53-4.43(M,1H),4.17(d,1H),4.08-3.99(M,1H),3.15(s,3H);手性分析SFC:RT=2.20miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物42):LCMS:m/z實測值446.2[M+H]+,RT=5.08miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.92(br s,1H,exch.),11.74(br s,1H,exch.),8.12(dd,1H),7.61(dd,1H),7.41(M,2H),6.97(s,1H),5.75(s,1H),4.64(d,1H),4.53-4.43(M,1H),4.17(d,1H),4.08-3.99(M,1H),3.15(s,3H);手性分析SFC:RT=2.69miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min。也通過手性分析,從
鏡像異構純(enantiomerically pure)(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)起始,獨立地製備對映異構物II(化合物42)(參見本文其它部分)。
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物43和44)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4,6-二氟-1H-吲哚-2-羧酸(VIg)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-35:65。管柱:Chiralpak IC(30 x 250mm)5μm,流速:110g/min。
對映異構物I(化合物43):LCMS:m/z實測值446.2[M+H]+,RT=4.40miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.77-12.11(br s,2H),8.14-8.09(M,1H),7.45-7.40(M,1H),7.08-7.02(M,2H),6.92-6.87(M,1H),5.74(s,1H),4.64(d,1H),4.48(d,1H),4.15(d,1H),4.05(d,1H),3.16(s,3H);手性分析SFC:RT=1.87miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物44):LCMS:m/z實測值446.2[M+H]+,RT=4.40miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.95(br s,2H),8.13-8.08(M,1H),7.44-7.39(M,1H),7.09-7.02(M,2H),6.92-6.86(M,1H),5.74(s,1H),4.63(d,1H),4.47
(d,1H),4.17(d,1H),4.03(d,1H),3.16(s,3H);手性分析SFC:RT=2.21miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物45和46)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4,5-二氟-1H-吲哚-2-羧酸(VIh)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-35:65。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物45):LCMS:m/z實測值446.2[M+H]+,RT=4.32miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(br s,2H),8.11-8.06(M,1H),7.40-7.35(M,1H),7.27-7.21(M,2H),7.04(s,1H),5.73(br s,1H),4.58(d,1H),4.43(d,1H),4.18(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=2.18miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物46):LCMS:m/z實測值446.2[M+H]+,RT=4.32miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(br s,2H),8.11-8.06(M,1H),7.40-7.35(M,1H),7.27-7.21(M,2H),7.04(s,1H),5.73(br s,1H),4.58(d,1H),4.43(d,
1H),4.18(d,1H),4.02(d,1H),3.16(s,3H);手性分析SFC:RT=2.54miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺(化合物47和48)
以與上文所述類似的方式由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,5-二氟-4,5,6,7-四氫-1H-吲哚-2-羧酸(VIp)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相乙腈/甲醇(1:1,v/v):CO2-30:60。管柱:Chiralcel-OX-H(30 x 250mm)5μm,流速:100g/min。
對映異構物I(化合物47):LCMS:m/z實測值446.2[M+H]+,RT=4.32miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.65(br s,1H),11.39(s,1H),8.07(t,1H),7.35(br s,1H),6.39(s,1H),5.68(s,1H),4.58(d,1H),4.42(d,1H),4.05-3.97(M,2H),3.02-2.98(M,5H),2.76(t,2H),2.23-2.18(M,2H);手性分析SFC:RT=3.15miN,管柱:Chiralcel-OX-3(4.6 x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物48):LCMS:m/z實測值446.2
[M+H]+,RT=4.32miN,(方法A);1H NMR(400MHz,DMSO-d6 δ 11.65(br s,1H),11.39(s,1H),8.07(t,1H),7.35(br s,1H),6.39(s,1H),5.68(s,1H),4.58(d,1H),4.42(d,1H),4.05-3.97(M,2H),3.02-2.98(M,5H),2.76(t,2H),2.23-2.18(M,2H);手性分析SFC:RT=3.67miN,管柱:Chiralcel-OX-3(4.6 x 150mm)3μM,30%的(0.2%在1:1乙腈:甲醇中的7M甲醇銨),流速:3.0g/min.
(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIa)
將鈦酸四異丙酯(1.95mL,6.43mmol)加入到8-氟-4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(Iva,500mg,2.14mmol)和(1R)-1-(4-甲氧基苯基)乙胺(400μL,2.65mmol)的混合物中,合併到1,4-二烷(5mL)中。在氮氣下於80℃下將混合物攪拌3小時。反應混合物用5mL二烷稀釋,然後冷卻至-12℃,並用在10mL無水MeOH中的硼氫化鈉(162mg,4.29mmol)處理。將反應混合物攪拌1h,從而允許冷卻浴溫熱至0℃。在0℃下使攪拌持續30分鐘,然後在0℃下通過加入3mL鹽水和15mL EtOAc使反應猝滅。將混合物傾倒入10mL鹽水和40mL EtOAc的攪拌後的混合物中,並維持在室溫下。15分鐘後,通過CELITE®使混合物過濾,並再用40mL EtOAc洗滌濾餅。將合併的濾液經硫酸鈉乾燥,過濾,並在減壓下使溶劑蒸發以提供粗材料--非鏡像異構物(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮和(R)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮的混合物,非鏡像異構物比(d.r.)為約5:1(通過LCMS DAD整合)。主要非鏡像異構物通過快速層析法(矽膠,MeOH/DCM 0-2%,15分鐘梯度,然後2%等度,MeOH/DCM)分離以提供(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIa,522.0mg,66%產率;d.r.=49:1,通過LCMS DAD整合)。LCMS:m/z實測值369.3[M+H]+;RT=0.59,(方法B);1H NMR(400MHz,CDCl3)δ 11.12(s,1H),8.04(dd,1H),7.87(dd,1H),7.47(dddd,1H),7.34-7.23(M,2H),6.92-6.80(M,2H),4.63(d,1H),4.56-4.47(M,1H),4.17-4.03(M,2H),3.87(t,1H),3.78(d,3H),3.52(dd,1H),1.45(dd,3H).
(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXa)
將鏡像異構純的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIa,120mg,0.33mmol)、甲醛(70μL,0.85mmol)水溶液(37%)、三乙醯氧基硼氫化鈉(124mg,0.59mmol)、和醋酸(34μL,0.59mmol)的混合物在1,2-二氯乙烷(1.5mL)中於室溫下攪拌過夜。然後用5mL二氯甲烷將反應混合物稀釋,並用1M水性NaOH中和。水相用二氯甲烷萃取兩次,並用鹽水(1.5mL)洗滌合併的有機萃取物,乾燥(硫酸鈉),並在減壓下使溶劑蒸發。進一步通過快速層析法(矽膠,EtOAc/己烷)純化產物以提供鏡像異構純的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXa,80.6mg,65%)。LCMS m/z實測值397.4[M+H]+;RT=0.64min(方法B);1H NMR(400MHz,CDCl3)δ 12.03(s,1H),8.11(dd,1H),8.02(dd,1H),7.39(ddd,1H),7.03(d,2H),6.74-6.65(M,2H),4.77(d,1H),4.64-4.49(M,2H),4.19-4.06(M,2H),3.74(s,3H),3.66(dd,1H),2.83(dq,1H),2.72(dq,1H),1.48(d,3H),0.90(t,3H).
(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXb)
以與上文關於IXa所述類似的方式,以86%產率,從鏡像異構純的(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIa)和乙醛起始來合成鏡像異構純的(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮。LCMS m/z實測值397.4[M+H]+;RT=0.64min(方法B);1H NMR(400MHz,CDCl3)δ 12.03(s,1H),8.11(dd,1H),8.02(dd,1H),7.39(ddd,1H),7.03(d,2H),6.74-6.65(M,2H),4.77(d,1H),4.64-4.49(M,2H),4.19-4.06(M,2H),3.74(s,3H),3.66(dd,1H),2.83(dq,1H),2.72(dq,1H),1.48(d,3H),0.90(t,3H).
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIb)
以與上文關於VIIIa所述類似的方式,以69%產率,從8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVb)和(1R)-1-(4-甲氧基苯基)乙胺起始來合成鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮。LCMS m/z實測值387.27[M+H]+;RT=0.60min(方法B);1H NMR(400MHz,CDCl3)δ 11.29(bs,1H),8.14(dd,1H),7.67(dd,1H),7.31-7.27(M,2H),6.90-6.79(M,2H),4.61(d,1H),4.55-4.46(M,1H),4.23-4.15(M,1H),4.08(q,1H),3.84-3.76(M,1H),3.78(s,3H),3.54(dd,1H),1.75(bs,1H),1.47(d,3H).通過X-射線晶體學明確地測定了VIIIb的絕對構型。
VIIIb的X-射線結構測定
以二氯甲烷為溶劑並以1:2 v/v二乙醚:己烷為抗溶劑,通過蒸汽擴散使VIIIb的晶體生長。VIIIb(分子式:C21H20F2N2O3)在單斜空間群C2(系統缺失hkl:h+k=基數)中結晶,其中a=16.6854(3)Å,b=7.42270(10)Å,c=30.0803(5)Å,β=93.8300(10)°,V=3717.15(10)Å3,Z=8,並且dcalc=1.381g/cm3。在裝備有HPC面積檢測器(HyPix-6000HE)的Rigaku XtaLAB Synergy-S繞射儀[1]上並採用100K溫度下的共聚焦多層光學單色Cu-Kα輻射(λ=1.54184Å)收集X射線強度數據。初步指標化(Preliminary indexing)是從60個0.5°的旋轉框架執行的,其中θ=±47.199°曝光0.5秒並且θ=107.75°曝光2秒。採用ω掃描,其中晶體與檢測器的距離為34.0mm,旋轉寬度為0.5mm°,且θ=±47.199°曝光0.5秒並且θ=107.75°和-86.25°曝光2秒,總共收集了6758框架(53次運行)。
使用CrysAlisPro[2]整合旋轉框架,從而生成非平均F2和σ(F2)值的列表。在5.892θ148.978°,-19h20,-9k9,-37l37的範圍內測量了總共42362個反射,產生7486個獨特反射(Rint=0.0573)。使用SCALE3 ABSPACK[3](最小和最大透射為0.5308、1.0000)對強度數據進行Lorentz和偏振效應校正以及對吸收校正。該結構通過直接法-SHELXT[4]求解。不對稱單元中有兩個晶體學上獨立的分子。使用SHELXL-2018[5],基於F2,通過全矩陣最小二乘法進行細化。在細化過程中使用全部反射。採用的加權方案為w=1/[σ2(Fo 2)+(0.0530P)2+10.5599P],其中P=(Fo 2+2Fc 2)/3。非氫原子經各向異性細化,而氫原子採用騎式模型(riding model)細化。對於7232個所觀察到的反射,F>4σ(F),細化收斂到R1=0.0573和wR2=0.1568,而σ(F)對於全部7486個獨特的非零反射和509個變量,細化收斂到R1=0.0585且wR2=0.1575且GOF=1.136。最小二乘法的最後一個週期中的最大值△/σ是0.001,並且最終差分傅裡葉中兩個最突出的峰為+0.44和-0.30e/Å3。Hooft絕
對結構參數y[6]是用PLATON[7]計算出來的。所得的值是y=0.03(4),表明絕對結構已經正確分配。Flack參數[7]細化到類似的值0.03(5)。如果這些參數等於0(在3個標準差內),則絕對結構已正確分配;如果它們是1,則相反的鏡像異構物已被建模。
表1列出了VIIIb的單元信息、數據收集參數和細化數據,而VIIIb的最終位置和等效熱參數在表2中提供。圖1提供VIIIb的ORTEP表示,其中顯示了50%機率的熱橢球,將VIIIb的絕對構型限定為(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮。
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXc)
以與上文關於IXa所述類似的方式,以82%產率,從鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(VIIIb)起始來合成鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二
氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮。LCMS m/z實測值401.3[M+H]+;RT=2.24min(方法A);1H NMR(400MHz,CDCl3)δ 12.01(s,1H),8.14(dd,1H),8.03(dd,1H),7.22-7.10(M,2H),6.85-6.74(M,2H),4.70(d,1H),4.53(dd,1H),4.45(d,1H),4.19-4.06(M,1H),3.90(q,1H),3.78(s,3H),3.63(dd,1H),2.14(s,3H),1.51(d,3H).
(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮
在室溫下,在氮氣下,於二氯甲烷(20.0mL)中將(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXc,1.93g,4.82mmol)與三氟乙酸(20mL,175.4mmol)攪拌過夜。然後用40mL MeOH處理反應混合物並將混合物攪拌20分鐘,這時深紫色的不透明混合物過渡成黃色透明的溶液。將揮發物蒸發,並通過與1:1 v/v甲醇/甲苯混合物共沸蒸發進一步使殘餘物乾燥,然與甲苯共沸蒸發一次。與二乙醚研磨15分鐘生成沉澱,沉澱通過過濾收集,用二乙醚洗滌,並在高真空下乾燥以提供作為單三氟醋酸鹽的鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(1.67g,91%)。LCMS實測值m/z 267.2[M+H]+;RT=0.47min(方法B);1H NMR(400MHz,甲醇-d 4 )δ 8.17(dd,1H),7.83(dd,1H),4.89(s,1H),4.76-4.60(M,2H),4.58(s,1H),4.51(dd,1H),3.98(dd,1H),2.86(s,3H)。使如上獲得的Vb的TF鹽的一部分在乙酸乙酯和飽和碳酸氫鈉之間分配。用乙酸乙酯進一步萃取水相,確保在最終萃取後pH>8.5,
並使合併的有機萃取物經硫酸鈉乾燥,過濾,在減壓下使溶劑蒸發,並在高真空下進一步使固體殘餘物乾燥以提供作為游離鹼的鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)。1H NMR(400MHz,DMSO-d 6)δ 11.40(br s,1H),8.03(dd,1H),7.73(dd,1H),4.41(d,1H),4.34(d,1H),4.22(dd,1H),3.59-3.51(M,1H),3.33(s,1H),2.39(s,3H),1.90(br s,1H).
(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺(化合物51)
在室溫下用DIPEA(125μL,0.71mmol)和HATU(81mg,0.21mmol)處理6-氯咪唑并[1,2-a]吡啶-2-羧酸(VIq,39mg,0.20mmol)在DMF(1mL)中的攪拌後的溶液10分鐘。接下來加入鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,70mg TF鹽,0.19mmol)並使反應持續2小時。通過加入5mL飽和碳酸氫鈉使反應猝滅,並用乙酸乙酯萃取兩次(每次30mL)。合併的有機萃取物用鹽水洗滌一次(10mL),經硫酸鈉乾燥,過濾,並在減壓下使溶劑蒸發。產物通過快速層析法(矽膠,乙酸乙酯/己烷0-100% 5分鐘,然後等度100%乙酸乙酯)分離以提供鏡像異構純的(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺(46mg,55%):LCMS m/z實測值445.2/447.1[M+H]+;RT=2.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(d,1H),8.94(dd)*,8.86(dd,1H),8.46(d)*,8.40(d,1H),8.11(ddd,1H),7.76(dd)*,
7.73-7.62(M,1H),7.45-7.33(m)*,6.37(s)*,5.72(s,1H),4.61(dd,1H),4.45(t,1H),4.20-4.12(M,1H),4.01(ddd,1H),3.22(s,3H),2.80(s).*(註:"*"表示所觀察到的次要醯胺旋轉異構物的信號。)
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物42)
以與上文所述(化合物51)類似的方式由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS:m/z實測值446.2[M+H]+,RT=5.08miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.92(br s,1H,exch.),11.74(br s,1H,exch.),8.12(dd,1H),7.61(dd,1H),7.41(M,2H),6.97(s,1H),5.75(s,1H),4.64(d,1H),4.53-4.43(M,1H),4.17(d,1H),4.09-3.99(M,1H),3.15(s,3H).
(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺(化合物52)
以與上文所述類似的方式由鏡像異構物(S)-8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXa)和6-氯咪唑并[1,2-a]吡啶-2-羧酸(VIq)合成鏡像異構純的(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺。LCMS m/z實測值427.2/428.8[M+H]+;RT=2.56min(方法A);1H NMR(400MHz,甲醇-d 4)δ 8.69(ddd,1H),8.41(d)*,8.28-8.23(M,1H),8.02-7.92(M,1H),7.70(dt,1H),7.66-7.43(M,2H),7.38(dt,1H),6.40(s)*,5.86(s,1H),4.68(d,1H),4.62-4.49(M,1H),4.45(d)*,4.39-4.30(M,1H),4.10(ddd,1H),3.20(s,3H),2.95(s)*。(註:"*"表示所觀察到的屬次要醯胺旋轉異構物的信號。)
(S)-6-氯-N-乙基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)咪唑并[1,2-a]吡啶-2-甲醯胺(化合物53)
以與上文所述類似的方式由鏡像異構純的(S)-1-(乙基((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXb)和6-氯咪唑并[1,2-a]吡啶-2-羧酸(VIq)合成鏡像異構純的(S)-6-氯-N-乙基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)咪唑并[1,2-a]吡啶-2-甲醯胺。LCMS m/z實測值441.2[M+H]+;RT=2.93min(方法A);1H NMR(400MHz,甲醇-d 4)δ 8.74-8.69(M,1H)*,8.69-8.65(M,1H)*,8.39(s,1H),8.26(s,1H),7.96(ddd,2H,兩個旋轉異構物的重疊信號),7.74-7.43(M,6H,兩個旋轉異構物的重疊信號),7.38(dd,1H),7.35(dd)*,6.36
(s)*,5.90(s,1H),4.69(d,2H,兩個旋轉異構物的重疊信號),4.55(t,2H,兩個旋轉異構物的重疊信號),4.43(d,1H)*,4.29(d,1H),4.12-3.97(M,3H,兩個旋轉異構物的重疊信號),3.71-3.41(M,3H,兩個旋轉異構物的重疊信號),0.94(t,3H)*,0.82(t,3H)。(註:"*"表示在近乎1:1的混合物中次要旋轉異構物的可區分的信號。)
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺(化合物64)
以與上文所述類似的方式由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吡唑并[1,5-a]吡啶-2-羧酸(VIs)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺。LCMS m/z實測值411.2[M+H]+;RT=3.28min(方法A);1H NMR(400MHz,氯仿-d)δ 12.35(s,1H),8.42(dq,1H),8.20(dt,1H),7.69-7.48(M,2H),7.33-7.10(M,2H),6.97-6.79(M,2H),6.09(s*),5.97-5.91(M,1H),4.85(dd,1H),4.72-4.59(M,1H),4.51-4.40(M,1H),4.17-4.00(M,1H),3.21(s,3H),3.01(s)*。(註:"*"表示所觀察到的次要醯胺旋轉異構物的信號。)
以與上文所述類似的方式由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吡咯并[1,2-b]嗒-6-羧酸(VIt)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡咯并[1,2-b]嗒-6-甲醯胺。LCMS m/z實測值411.2[M+H]+;RT=3.35min(方法A);1H NMR(400MHz,氯仿-d)δ 11.70(s,1H),8.20(dd,1H),8.13-7.97(M,2H),7.73(dd,1H),7.49(dd,1H),6.74(d,1H),6.57(dd,1H),5.88(d,1H),4.78(d,1H),4.67-4.57(M,1H),4.40(d,1H),4.07(dd,1H),3.13(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺(化合物66)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和喹啉-7-羧酸(VIu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=2.30min(方法A);1H NMR(400MHz,氯仿-d)δ 12.29(s,1H),8.96(dd,1H),8.28-8.14(M,2H),
8.15-8.00(M,1H),7.92(d,1H),7.67-7.56(M,2H),7.47(dd,1H),5.96-5.91(M,1H),4.83(d,1H),4.72-4.63(M,1H),4.53-4.45(M,1H),4.18-4.06(M,1H),2.92(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺(化合物67)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和喹啉-6-羧酸(VIv)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=2.19min(方法A);1H NMR(400MHz,氯仿-d)δ 12.29(s,1H),8.98(dd,1H),8.30-8.13(M,3H),7.92(d,1H),7.72(dd,1H),7.62(dd,1H),7.47(dd,1H),5.97-5.91(M,1H),4.84(d,1H),4.74-4.64(M,1H),4.49(d,1H),4.13(dd,1H),2.89(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺(化合物70)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和[1,2,4]三唑并[4,3-a]吡啶-6-羧酸(VIw)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺。LCMS m/z實測值412[M+H]+;RT=2.08min(方法C);1H NMR(400MHz,甲醇-d 4)δ 9.22(d,1H),8.81-8.75(M,1H),8.17(dd,1H),7.83(d,1H),7.59-7.49(M,2H),5.81(d,1H),4.68(d,1H),4.57(d,1H),4.41(d,1H),4.12(dd,1H),2.98(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺(化合物71)
以與上文所述類似的方式由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和喹啉-3-羧酸(VIy)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=3.16min(方法A);1H NMR(400MHz,氯仿-d)δ 12.42-12.37(M,1H),8.96(d,1H),8.30-8.20(M,2H),8.17-8.10(M,1H),7.91-7.84(M,1H),7.79(ddd,1H),7.66-7.55(M,2H),5.96-5.90(M,1H),4.85(d,1H),4.75-4.65(M,1H),4.54-4.46(M,1H),4.19-4.06(M,1H),2.95(s,3H).
以與上文所述類似的方式由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和喹啉-6-羧酸(VIz)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺。LCMS m/z實測值423[M+H]+;RT=2.42min(方法C);1H NMR(400MHz,氯仿-d)δ 12.35(s,1H),8.90(q,2H),8.30-8.16(M,2H),8.13(d,1H),7.83(dd,1H),7.60(dd,1H),5.97-5.91(M,1H),4.85(d,1H),4.74-4.62(M,1H),4.49(d,1H),4.19-4.06(M,1H),2.91(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物73)
在室溫下用DIEA(105uL,0.60mmol)和HATU(114mg,0.30mmol)處理6-(三氟甲基)吡啶-3-羧酸(VIaa,32mg,0.17mmol)在DMF(1mL)中的攪拌後的溶液10分鐘。加入鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,56mg TF鹽,0.15mmol)並使攪拌持續2小時。通過
加入5mL飽和氯化銨(通過逐滴加入2M HCl使pH調節至約為4)使反應猝滅,然後用乙酸乙酯萃取兩次(每次30mL)。用飽和氯化銨(通過逐滴加入2M HCl將pH調節至約為4)洗滌合併的有機萃取物兩次,每次25mL,之後用飽和碳酸氫鈉洗滌兩次,每次25mL,然後用水(25mL)洗滌一次,並用鹽水(20mL)一次,經硫酸鈉乾燥,過濾並使溶劑蒸發。產物通過快速層析法(矽膠,20分鐘內甲醇/二氯甲烷0-10%)分離以提供(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(產率:38mg,58%)。LCMS m/z實測值440.1[M+H]+;RT=3.95min(方法A);1H NMR(400MHz,氯仿-d)δ 12.45-12.40(M,1H),8.80-8.75(M,1H),8.24(dd,1H),8.00-7.92(M,1H),7.78(dd,1H),7.48(dd,1H),5.90-5.84(M,1H),4.85(d,1H),4.69(dd,1H),4.49-4.40(M,1H),4.12(dd,1H),2.88(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺(化合物74)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氟-4-(三氟甲基)苯甲酸(VIab)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值457.2[M+H]+;RT=4.69min(方法A);1H NMR(400MHz,氯仿-d)δ 12.27(s,1H),8.25(dd,1H),7.69(t,1H),7.48(dd,1H),7.31-7.22(M,2H),5.88-5.82(M,1H),4.83(d,1H),4.68(dd,1H),4.42(d,1H),4.10(dd,1H),
2.83(s,3H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺(化合物75)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氯-3-氟苯甲酸(VIac)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺。LCMS m/z實測值423.1[M+H]+;RT=4.61min(方法A);1H NMR(400MHz,氯仿-d)δ 11.95(s,1H),8.24(dd,1H),7.53-7.43(M,2H),7.29-7.19(M,1H),7.15(ddt,1H),5.83(s,1H),4.80(d,1H),4.71-4.61(M,1H),4.40(d,1H),4.09(dd,1H),2.85(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺(化合物76)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3,4,5-三氟苯甲酸(VIad)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺。LCMS m/z實測值425.2[M+H]+;RT=4.49min(方法A);
1H NMR(400MHz,氯仿-d)δ 12.05(s,1H),8.24(dd,1H),7.45(dd,1H),7.08(dd,2H),5.82-5.76(M,1H),4.81(d,1H),4.71-4.61(M,1H),4.43-4.35(M,1H),4.08(dd,1H),2.86(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺(化合物83)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氟煙酸(VIae)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺。LCMS m/z實測值390.1[M+H]+;RT=3.27min(方法A);1H NMR(400MHz,氯仿-d)δ 12.41(s,1H),8.55(d,1H),8.48(t,1H),8.24(dd,1H),7.56-7.43(M,2H),5.87-5.82(M,1H),4.84(d,1H),4.73-4.63(M,1H),4.47-4.38(M,1H),4.10(dd,1H),2.89(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺(化合物84)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氯煙酸(VIaf)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-
1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺。LCMS m/z實測值406.1/408.1[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,氯仿-d)δ 12.12(s,1H),8.68-8.62(M,1H),8.54(d,1H),8.25(dd,1H),7.77(dd,1H),7.48(dd,1H),5.87-5.81(M,1H),4.83(d,1H),4.68(dd,1H),4.42(dd,1H),4.10(dd,1H),2.89(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺(化合物85)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-氟異煙酸(VIag)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺。LCMS m/z實測值390.2[M+H]+;RT=3.36min(方法A);1H NMR(400MHz,氯仿-d)δ 12.04(s,1H),8.34(dd,1H),8.25(dd,1H),7.45(dd,1H),7.18(ddd,1H),6.94(ddd,1H),5.87-5.81(M,1H),4.82(d,1H),4.67(dd,1H),4.40(d,1H),4.10(dd,1H),2.82(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺(化合物86)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(二氟甲基)苯甲酸(VIah)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺。LCMS m/z實測值421.2[M+H]+;RT=4.07min(方法A);1H NMR(400MHz,氯仿-d)δ 12.38(s,1H),8.23(dd,1H),7.63-7.45(M,5H),6.68(t,1H),5.91-5.85(M,1H),4.83(d,1H),4.72-4.62(M,1H),4.43(dd,1H),4.10(dd,1H),2.84(s,3H).
(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺(化合物87)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(S)-2-羥基-3-苯基丙酸(VIai)合成鏡像異構純的(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺。LCMS m/z實測值415.2[M+H]+;RT=3.69min(方法A);1H NMR(400MHz,氯仿-d)δ 12.10(s,1H),8.18(dd,1H),7.39-7.27(M,3H),7.32-7.25(M,3H),5.75-5.69(M,1H),4.77(d,1H),4.66(ddd,1H),4.64-4.49(M,1H),4.06(dd,1H),3.96-3.80(M,2H),3.09(dd,1H),3.01(dd,1H),2.74(s,3H).
(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺(化合物88)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(R)-2-羥基-3-苯基丙酸(VIaj)合成鏡像異構純的(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺。LCMS m/z實測值415.2[M+H]+;RT=3.95min(方法A);1H NMR(400MHz,氯仿-d)δ 11.27(bs,1H),8.23(dd,1H),7.35-7.13(M,5H),5.75-5.69(M,1H),4.79(d,1H),4.73-4.52(M,2H),4.29(dd,1H),4.00(dd,1H),3.81(d,1H),2.85(s,3H*),2.85(s,1H,重疊*),2.84(s,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物91)
在室溫下用二異丙基乙胺(105μL,0.60mmol)和HATU(171mg,0.45mmol)處理苯甲酸(VIak,20mg,0.17mmol)在DMF(1mL)中的攪拌後的溶液10min。然後加入鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,40mg的游離鹼,0.15mmol)並使反應持續2小時。通過加入5mL飽和氯化銨(通過逐滴加入2M HCl將pH調節至約為4)使反應猝滅,然後用乙酸乙酯萃取兩次(每次30mL)。合併的有機萃取物
用水(25mL)洗滌一次,並且用鹽水(15mL)洗滌一次,經硫酸鈉乾燥,過濾並使溶劑蒸發。產物通過快速層析法(矽膠,15分鐘內甲醇/二氯甲烷0-2.5%梯度)分離,之後通過最小量的甲醇進行研磨以提供鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(123mg,23%)。LCMS m/z實測值371.2[M+H]+;RT=4.24min(方法A);1H NMR(400MHz,氯仿-d)δ 11.61(s,1H),8.23(dd,1H),7.56(dd,1H),7.47-7.37(M,5H),5.88(s,1H),4.78(d,1H),4.65(dd,1H),4.43(d,1H),4.10(dd,1H),2.84(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺(化合物92)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3,4-二氟苯甲酸(VIal)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺。LCMS m/z實測值407.1[M+H]+;RT=4.60min(方法A);1H NMR(400MHz,氯仿-d)δ 11.80(s,1H),8.24(dd,1H),7.49(dd,1H),7.33-7.13(M,3H),5.82(d,1H),4.80(d,1H),4.70-4.61(M,1H),4.41(d,1H),4.09(dd,1H),2.86(s,3H).
(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺(化合物93)
在0℃下用N-甲基嗎啉(67μL,0.60mmol)處理(S)-2-羥基-2-苯基丙酸(VIaM,28mg,0.17mmol)、鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,40mg的游離鹼,0.15mmol)、和HATU(86mg,0.23mmol)在DMF(0.5mL)中的攪拌後的溶液,並使反應溫熱至室溫並持續16小時。通過加入5mL飽和氯化銨使反應猝滅,再用5mL水稀釋,然後用乙酸乙酯萃取兩次(每次30mL)。合併的有機萃取物用水(50mL)洗滌一次,並用鹽水(20mL)洗滌一次,經硫酸鈉乾燥,過濾並使溶劑蒸發。產物通過快速層析法(矽膠,乙酸乙酯/己烷25-100%梯度)分離以提供鏡像異構純的(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺(24mg,39%)。LCMS m/z實測值415.2[M+H]+;RT=4.51min(方法A);1H NMR(400MHz,氯仿-d)δ 11.92(s,1H),8.16(dd,1H),7.45-7.20(M,6H),5.82-5.76(M,1H),4.85(s,1H),4.66(d,1H),4.60-4.50(M,1H),4.23(d,1H),4.01(dd,1H),2.48(s,3H),1.81(s,3H).
(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺(化合物94)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(R)-2-羥基-2-苯基丙酸(VIan)合成鏡像異構純的(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺。LCMS m/z實測值415.3[M+H]+;RT=4.39min(方法A);1H NMR(400MHz,氯仿-d/甲醇-d 4 )δ 8.05(dd,1H),7.38-7.30(M,2H),7.30-7.12(M,4H),5.63(d,1H),4.46(d,1H),4.42-4.33(M,1H),3.90(dd,1H),3.33(d,1H),3.21(s,exch.Hs),2.42(s,3H),1.81(s,3H).
(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺(化合物95)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(S)-2-羥基-2-苯基醋酸(VIao)合成鏡像異構純的(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺。LCMS m/z實測值401.2[M+H]+;RT=4.06min(方法A);1H NMR(400MHz,氯仿-d)δ 12.27(s,1H),8.18(dd,1H),7.53-7.31(M,6H),5.82(M,1H),5.25(d,1H),4.83(d,1H),4.69(d,1H),4.56(dd,1H),4.04(dd,1H),3.94(dd,1H),2.62(s,3H).
(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺(化合物96)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(R)-2-羥基-2-苯基醋酸(VIap)合成鏡像異構純的(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺。LCMS m/z實測值401.1[M+H]+;RT=4.00min(方法A);1H NMR(400MHz,氯仿-d)δ 12.08(s,1H),8.09(dd,1H),7.39-7.29(M,5H),7.05(dd,1H),5.71-5.65(M,1H),5.26(d,1H),4.82(d,1H),4.71(d,1H),4.61-4.47(M,1H),4.34-4.26(M,1H),3.98(dd,1H),2.65(s,3H).
(R)-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基乙醯胺(化合物138)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(R)-2-(3-氯苯基)-2-羥基醋酸(VIbl)合成鏡像異構物(R)-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基乙醯胺。LCMS m/z 435.1/437.2[M+H]+;RT=5.94min(方法A);1H NMR(400MHz,氯仿-d)δ 11.64(s,1H),8.04(dd,1H),7.42(q,1H),7.41-7.28(M,3H),6.97(dd,1H),5.84(d,
1H),5.53-5.46(M,2H),4.55(d,1H),4.40(dd,1H),4.05(dd,1H),3.95(dd,1H),2.73(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺(化合物139)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3,5-二氟-4-(三氟甲基)苯甲酸(VIbm)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值411.1/413.1[M+H]+;RT=5.86min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(s,1H),8.12(dd,1H),7.78(d,1H),7.43-7.29(M,2H),5.60(d,1H),4.59(d,1H),4.50-4.41(M,1H),4.18(d,1H),4.00(dd,1H),2.85(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺(化合物140)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氯噻吩-3-羧酸(VIbn)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側
氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺。LCMS m/z實測值411.1/413.1[M+H]+;RT=5.86min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(s,1H),8.12(dd,1H),7.78(d,1H),7.43-7.29(M,2H),5.60(d,1H),4.59(d,1H),4.50-4.41(M,1H),4.18(d,1H),4.00(dd,1H),2.85(s,3H).
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻唑-5-甲醯胺(化合物141)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-氯噻唑-5-羧酸(VIbo)合成鏡像異構純的(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻唑-5-甲醯胺。LCMS m/z實測值412.0/414.1[M+H]+;RT=5.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.17-8.07(M,2H),7.32(dd,1H),5.58(s,1H),4.62(d,1H),4.46(d,1H),4.18(d,1H),3.98(dd,1H),3.07(s,3H).
(2R,3R)-2-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-羥基-N-甲基丁醯胺,甲酸鹽(化合物142)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(((9H-芴-9-基)甲氧基)羰基)-D-別蘇胺酸(VIbp)合成鏡像異構純(2R,3R)-2-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-羥基-N-甲基丁醯胺,之後在室溫下用乙腈中的乙胺(10eq.)使中間體Fmoc保護的胺去保護1小時。產物通過反相製備hplc(C18柱,水/乙腈5-70%梯度,用0.05%甲酸改性)純化並被分離為甲酸鹽。LCMS m/z實測值368.2[M+H]+;RT=4.15min(方法A);1H NMR(400MHz,DMSO-d 6)δ 8.26(s,1H),8.08(dd,1H),7.31(dd,1H),5.52-5.46(M,1H),4.57(d,1H),4.42(dd,1H),4.02-3.88(M,2H),3.66-3.57(M,2H),2.85(s,3H),1.10(d,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺(化合物97)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4,5,6-三氟-1H-吲哚-2-羧酸(VIaq)合成鏡像異構純的(S)-N-(8,9-二
氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值464.2[M+H]+;RT=5.60min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.24(s,1H),11.74(s,1H),8.12(dd,1H),7.42(dd,1H),7.27(dd,1H),7.14-7.08(M,1H),5.74(s,1H),4.64(d,1H),4.53-4.43(M,1H),4.17(d,1H),4.04(dd,1H),3.16(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺(化合物98)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(三氟甲基)苯甲酸(VIar)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值439.2[M+H]+;RT=5.27min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.14(dd,1H),7.84(d,2H),7.66-7.59(M,2H),7.49(dd,1H),5.69(d,1H),4.59(d,1H),4.47(dd,1H),4.31(d,1H),4.08-3.99(M,1H),2.68(s,3H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物99)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氯苯甲酸(VIas)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS m/z實測值405.2/407.2[M+H]+;RT=5.10min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.13(dd,1H),7.57-7.40(M,5H),5.66(s,1H),4.58(d,1H),4.46(d,1H),4.27(d,1H),4.03(dd,1H),2.70(s,3H).
(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺(化合物100)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氰基-3-氟苯甲酸(VIat)合成鏡像異構純的(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺。LCMS m/z實測值414.2[M+H]+;RT=4.65min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.18-8.08(M,1H),8.04(ddd,1H),7.68(dd,1H),7.50-7.37(M,2H),5.65(s,1H),4.59(d,1H),4.46(d,1H),4.32(d,1H),4.01(dd,1H),2.68(s,
3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺(化合物109)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(二氟甲基)-4-氟苯甲酸(VIau)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺。LCMS m/z實測值439.2[M+H]+;RT=4.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(s,1H),8.13(dd,1H),7.76-7.63(M,2H),7.53-7.42(M,2H),7.24(t,1H),5.67(d,1H),4.59(d,1H),4.46(d,1H),4.31(d,1H),4.02(dd,1H),2.72(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺(化合物110)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲基)-3-氟苯甲酸(VIav)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟
-N-甲基苯甲醯胺。LCMS m/z實測值439.2[M+H]+;RT=5.02min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.13(dd,1H),7.73(t,1H),7.54-7.42(M,2H),7.37-7.33(M,1H),7.18(d,1H),5.66(t,1H),4.59(d,1H),4.46(d,1H),4.30(d,1H),4.02(dd,1H),2.69(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺(化合物111)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲基)苯甲酸(VIaw)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺。LCMS m/z實測值421.1[M+H]+;RT=4.98min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.13(dd,1H),7.66(dt,2H),7.57-7.44(M,2H),7.08(t,1H),5.72-5.66(M,1H),4.59(d,1H),4.51-4.42(M,1H),4.28(d,1H),4.09-3.97(M,1H),2.69(d,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺(化合物112)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氯-4-氟苯甲酸(VIax)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺。LCMS m/z實測值423.1/425.2[M+H]+;RT=5.30min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(s,1H),8.12(dd,1H),7.72(dd,1H),7.55-7.38(M,3H),5.65(d,1H),4.59(d,1H),4.46(d,1H),4.30(d,1H),4.01(dd,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺(化合物125)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(三氟甲基)-1H-吡唑-5-羧酸(VIay)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺。LCMS m/z實測值429.2[M+H]+;RT=4.80min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(s,1H),8.12(dd,1H),7.36(dd,1H),7.21(d,1H),5.67(d,1H),4.63(d,1H),4.47(d,1H),4.16(d,1H),4.01(dd,1H),3.02(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺(化合物126)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(4-氟苯基)-1H-吡唑-5-羧酸(VIaz)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺。LCMS m/z實測值455.2[M+H]+;RT=5.01min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.69(br s,1H),11.73(s,1H),8.13(dd,1H),7.92-7.84(M,2H),7.44-7.27(M,3H),7.17(d,1H),5.71(s,1H),4.62(d,1H),4.48(d,1H),4.15(d,1H),4.03(d,1H),3.11(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺(化合物127)
以與上文所述類似的方式,用DIPEA而非NMM作為鹼,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氟苯甲酸(VIbc)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺。LCMS m/z實測值389.2[M+H]+;RT=5.19min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.13(t,1H),7.54-7.45(M,2H),7.34-7.28(M,2H),7.21(d,1H),5.67(s,
1 H),4.58(d,1H),4.46(d,1H),4.27(d,1H),4.04-4.01(M,1H),2.7(s,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物128)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氯苯甲酸(VIbd)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS m/z實測值405.2/407.2[M+H]+;RT=5.47min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.13(t,1H),7.54-7.45(M,4H),7.34(d,1H),5.67(s,1H),4.58(d,1H),4.46(d,1H),4.29(d,1H),4.02(d,1H),2.69(s,3H).
(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物129)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-溴苯甲酸(VIbe)合成鏡像異構純的(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS
m/z實測值449.2/451.1[M+H]+;RT=5.70min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.15-8.11(M,1H),7.67-7.63(M,2H),7.5-7.37(M,3H),5.66(s,1H),4.58(d,1H),4.46(d,1H),4.29(d,1H),4.03-3.99(M,1H),2.69(s,3H).
(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺(化合物130)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-溴-3-氟苯甲酸(VIbf)合成鏡像異構純的(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺。LCMS m/z實測值467.2/469.2[M+H]+;RT=5.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.13(t,1H),7.80(t,1 H),7.51-7.44(M,2H),7.18(d,1H),5.65(s,1H),4.59(d,1H),4.46(d,1H),4.29(d,1H),4.03-4.0(M,1H),2.7(s,3H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物131)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-
溴-苯甲酸(VIbg)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS m/z實測值449.2/451.1[M+H]+;RT=5.71min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.15-8.11(M,1H),7.66(d,2H),7.49-7.44(M,1H),7.36(d,2H),5.66(s,1 H),4.58(d,1H),4.46(d,1H),4.26(d,1H),4.04-4.0(M,1H),2.69(s,3H).
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物135)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氰基苯甲酸(VIbh)合成鏡像異構純的(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS m/z實測值396.1[M+H]+;RT=5.42min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7(br s,1H),8.12(t,1H),7.96-7.92(M,2H),7.74-7.65(M,2H),7.5-7.45(M,1H),5.67(s,1H),4.58(d,1H),4.46(d,1H),4.29(d,1H),4.04-4.01(M,1H),2.69(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺(化合物136)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氟-4-(三氟甲氧基)苯甲酸(VIbi)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺。LCMS m/z實測值473.1[M+H]+;RT=6.39min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.15-8.11(M,1H),7.68-7.65(M,2H),7.48-7.43(M,1H),7.35(d,1H),5.66(s,1H),4.59(d,1H),4.46(d,1H),4.29(d,1H),4.04-4.0(M,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺(化合物137)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氟-4-甲基苯甲酸(VIbj)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺。LCMS m/z實測值403.2[M+H]+;RT=5.98min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.13(t,1H),7.49-7.44(M,1H),7.37(t,1H),7.22(d,1H),7.12(d,1H),5.65(s,1H),4.58(d,1H),4.46(d,1H),4.25(d,1H),4.02(d,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺(化合物147)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-乙基-3-氟苯甲酸(VIbk)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺。LCMS m/z實測值417.2[M+H]+;RT=6.69min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.13(t,1H),7.44-7.35(M,2H),7.15(d,2H),5.66(s,1 H),4.58(d,1H),4.46(d,1H),4.2(d,1H),4.04(d,1H),2.64(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺(化合物153)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲氧基)-3-氟苯甲酸(VIcl)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺。LCMS m/z實測值455.3[M+H]+;RT=4.08min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.15-8.11(t,1H),7.55(d,2 H),7.49-7.44(M,1H),7.36(t,1H),7.1(s,
1H),5.66(s,1H),4.62(d,1H),4.46(d,1H),4.26(d,1H),4.04-4.0(M,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺(化合物154)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(2-羥基丙-2-基)苯甲酸(VIcm)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺。LCMS m/z實測值429.3[M+H]+;RT=3.07min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.13(t,1H),7.54-7.45(M,3H),7.33(d,2H),5.68(s,1H),5.08(s,1H),4.58(d,1H),4.46(d,1H),4.23(d,1H),4.06-4.02(M,1H),2.72(s,3H),1.42(s,6H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺(化合物155)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(2-羥基丙-2-基)苯甲酸(VIcn)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺。LCMS m/z實測值429.3[M+H]+;RT=4.03min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.16-8.11(M,1H),7.52-7.47(M,3H),7.37(t,1H),7.19(d,1H),5.69(s,1H),5.10(s,1H),4.58(d,1H),4.46(d,1H),4.25(d,1H),4.06-4.02(M,1H),2.69(s,3H),1.42(s,6H).
4-溴-N-(8,9-二氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺(化合物172)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-溴-3,5-二氟苯甲酸(VIcp)合成鏡像異構純4-溴-N-(8,9-二氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺。LCMS m/z實測值487.1[M+H]+;RT=8.12min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.12(t,1H),7.48-7.43(M,1H),7.38(d,2H),5.62(s,1H),4.60(d,1H),4.44(d,1H),4.30(d,1H),4.01(dd,1H),2.71(s,3H).
4-氯-N-(8,9-二氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺(化合物173)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氯-3,5-二氟苯甲酸(VIcq)合成鏡像異構純4-氯-N-(8,9-二氟-6-側氧-2,4,5,6-四氫-1H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺。LCMS m/z實測值441.3[M+H]+;RT=8.08min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.12(t,1H),7.48-7.44(M,3H),5.62(s,1H),4.60(d,1H),4.47(d,1H),4.30(d,1H),4.01(dd,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺(化合物180)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲基)-3,5-二氟苯甲酸(VIcr)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺。LCMS m/z實測值457.3[M+H]+;RT=6.16min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,
1H),8.13(t,1H),7.48-7.19(M,4H),5.63(s,1H),4.58(d,1H),4.47(d,1H),4.30(d,1H),4.01(d,1H),2.70(s,3H).
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺(化合物353和354)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和外消旋6-氟-4-(1-羥乙基)-1H-吲哚-2-羧酸(VIeg)合成N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過手性製備SFC分離非鏡像異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak-OJ(30 x 250mm),5μm,流速:60g/min。
非鏡像異構物I(化合物353):LCMS:m/z實測值472.1[M+H]+,RT=3.45miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.77(br s,1H),11.71(s,1H),8.12(t,1H),7.47(t,1H),7.04(d,2H),6.93(d,1H),5.76(s,1H),5.29(d,1H),5.11(t,1H),4.64(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.17(s,3H),1.39(d,3H);手性分析SFC:RT=1.58miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%甲醇,流速:3.0g/min.
非鏡像異構物II(化合物354):LCMS:m/z實測值472.1[M+H]+,RT=3.52miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.77(br s,1H),11.71(s,1H),8.12(t,1H),7.45(t,1H),
7.04(d,2H),6.92(d,1H),5.76(s,1H),5.29(d,1H),5.11(t,1H),4.64(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.17(s,3H),1.38(d,3H);手性分析SFC:RT=2.97miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%甲醇,流速:3.0g/min.
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺(化合物189)
在0℃下向39mg(0.26mmol,1.4eq.)2-苯基丙烯酸(VIcz)在2mL DCM中的攪拌後的溶液加入0.05mL(0.56mmol,3eq.)草醯氯和催化量的DMF,並在室溫下將反應混合物攪拌4h。使反應混合物蒸發至乾燥。取所獲得的醯基氯到2mL DCM中,並加入0.08mL(0.56mmol,3eq.)TEA,之後在0℃下加入50mg(0.19mmol,1eq.)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)並在室溫下將反應攪拌16小時。反應完成後,將混合物傾倒入冰冷的水(30mL)中並攪拌30分鐘。由反應形成的固體通過過濾收集並在真空下乾燥。所獲得的材料通過製備HPLC[柱/尺寸:X-BRIDGE PHENYLE(19 x 250,5μm)流動相A:10mM在水中的碳酸氫銨流動相B:乙腈梯度(時間/%B):0/25,1/25,8/55,12/55,12.1/100,16/100,16.1/25,18/25。流速:18ml/min]純化以提供20mg(0.05mmol,26%產率)N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺,為灰白色固體。LCMS m/z實測值397.3[M+H]+;RT=4.36min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(s,1H),8.14-8.09(M,1H),7.49-7.44(M,3H),7.40-7.34
(M,3H),5.85(s,1H),5.69(s,1H),5.32(s,1H),4.57(d,1H),4.45(d,1H),4.20(d,1H),4.04(dd,1H),2.68(s,3H).
2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺(化合物199和200)
步驟i. 向室溫下128mg(0.375mmol,1.2eq.)(S)-2-((第三丁氧基羰基)胺基)-2-(4-氯苯基)醋酸(VIda)在2mL THF中的攪拌後的溶液加入0.2mL(1.12mmol,3eq.)DIPEA、87mg(0.56mmol,1.5eq.)EDCI,之後加入76mg(0.56mmol,1.5eq.)HOBt,並在室溫下將反應混合物攪拌15分鐘。將(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,100mg,0.495mmol,1eq.)加入到反應混合物中並使攪拌持續16小時。反應完成後,將反應混合物傾倒入冰冷的飽和NaHCO3溶液(10mL)中,攪拌30分鐘,這時沉澱出固體。固體通過過濾收集,用水洗滌,並在真空下乾燥。管柱層析法(採用30%在石油醚中的乙酸乙酯作為線性梯度)提供呈灰白色固體的外消旋的85mg(0.15mmol,42%產率)(1-(4-氯苯基)-2-(((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基)-2-側氧乙基)胺基甲酸第三丁酯。LCMS m/z實測值532.37[M-H]-。
步驟ii. (1-(4-氯苯基)-2-(((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基)-2-側氧乙基)胺基甲酸第三丁酯的非鏡像異構物隨後通過手性製備SFC分離:等度
法,流動相甲醇:CO2-30:70。管柱:Lux纖維素-2(30 x 250mm),5μm,流速:110g/min。
步驟iii. 通過在0℃下用在二烷中的4N HCl進行處理,將如上所述分離的(1-(4-氯苯基)-2-(((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基)-2-側氧乙基)胺基甲酸第三丁酯的每一個單獨的非鏡像異構物轉化為終產物,之後在室溫下攪拌10小時,在減壓下去除揮發物。取來自每一個反應的所得殘餘物到飽和NaHCO3溶液中並攪拌10分鐘。所沉澱的固體通過過濾收集,並通過與二乙醚研磨和過濾而進一步純化,並且在高真空下乾燥。
非鏡像異構物I(化合物199):LCMS:m/z實測值434.2[M+H]+,RT=3.73miN,(方法A);1H NMR(400MHz,DMSO-d6)δ):δ 11.5(bs,1H),8.13-8.08(M,11H1 H),7.59-7.28(M,5H),5.58(s,1H),4.85(s,1H),4.58-4.39(M,2H),4.24-4.04(M,2H)2.67(s,3H),2.60(bs,2H);手性分析SFC:RT=2.67miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,20%(0.5%的甲醇中的DEA),流速:3.0g/min.
非鏡像異構物II(化合物200):LCMS:m/z實測值434.2[M+H]+,RT=3.67miN,(方法A);1H NMR(400MHz,DMSO-d6)δ):δ 11.50(bs,1H),8.04-7.30(M,5H),6.84-6.79(M,1H),5.49(s,1H),4.88(s,1H),4.57-4.38(M,2H),4.05-3.92(M,2H)2.76(s,3H),2.59(bs,2H);手性分析SFC:RT=4.14miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,20%(0.5%的甲醇中的DEA),流速:3.0g/min.
2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺(化合物202和203)
以與上文(關於化合物199、200)所述類似的方式,由(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和(S)-2-((第三丁氧基羰基)胺基)-2-(3-氯苯基)醋酸(VIdb)製備2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺的單獨的非鏡像異構物。
非鏡像異構物I(化合物202):LCMS:m/z實測值434.4[M+H]+,RT=4.86miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.28(bs,1H),8.06(bs,1H),7.44-7.33(M,5H),5.59(s,1H),4.94(s,1H),4.528(d,1H),4.38(d,1H),3.89-3.78(M,2H),2.70(s,3H),2.60(bs,2H);手性分析SFC:RT=2.49miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%(0.2%在乙腈:甲醇中的7M甲醇銨)(1:1),流速:3.0g/min.
非鏡像異構物II(化合物203):LCMS:m/z實測值434.4[M+H]+,RT=5.96miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.67(bs,1H),8.04(bs,1H),7.38-7.28(M,4H),6.96(t,1H),5.54(s,1H),4.88(s,1H),4.54(d,1H),4.40(d,1H),4.05(s,1H),3.95(d,1H),2.78(s,3H),2.35-2.07(M,2H);手性分析SFC:RT=3.80miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%(0.2%在乙腈:甲醇中的7M甲醇銨)(1:1),流速:3.0g/min.
(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)
在密封管內,向250mg(0.647mmol,1.1eq.)(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXc)加入3.7mL(15 vol)三氟乙酸。在65℃下將反應混合物攪拌2小時。反應完成(通過TLC)後,在減壓下使反應混合物濃縮並與二乙醚(2 x 20mL)研磨。所獲得的粗材料用10% aq.Na2CO3溶液鹼化並用EtOAc(2 x 60mL)萃取。有機萃取物用水(30mL)、鹽水(30mL)洗滌,經無水Na2SO4乾燥,並在減壓下濃縮以提供作為白色固體的(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(135mg,82%產率)。LCMS m/z實測值251.33[M-H]-,RT=2.24min(方法E).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)和吲哚-2-羧酸(VIn)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)吲哚-2-甲醯胺。LCMS m/z實測值396.1[M+H]+;RT=6.07min(方法A);1H NMR(400
MHz,DMSO-d 6)δ 11.60(s,1H),8.57(d,1H),8.21(d,1H),8.12-8.05(M,2H),7.47-7.475(M,2H),6.85(s,1H),6.72-6.68(M,1H),6.58(t,1H),5.20(d,1H),4.55-4.45(M,2H),4.01(d,1H),3.88(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺(化合物156)
向室溫下42mg(0.22mmol,1.1eq.)5,6-二氟-1H-吲哚-2-羧酸(VIi)在0.75mL THF中的攪拌後的溶液加入0.17mL(1mmol,5eq.)DIPEA、113mg(0.6mmol,3eq.)EDCI、和80mg(0.6mmol,3eq.)HOBt,並在室溫下將反應混合物攪拌15分鐘。向此混合物中加入50mg(0.2mmol,1eq.)(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)並將所得混合物攪拌2小時。反應完成(通過TLC)後,將反應混合物傾倒在冰水(10mL)上並用EtOAc(2 x 30mL)萃取。有機層用水(20mL)洗滌,經Na2SO4乾燥,並在減壓下濃縮。所獲得的粗材料與水(10mL)和二乙醚/正戊烷(1:1,2 x 10ml)研磨以提供作為白色固體的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺(24mg,28%產率)。LCMS m/z實測值432.3[M+H]+;RT=4.80min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.75(bs,2H),8.94(d,1H),8.09(t,1H),7.63-7.58(M,1H),7.48-7.43(M,1H),7.36-7.32(M,1H),7.22(s,1H),5.21(d,1H),4.56-4.61(M,2H),4.04(d,1H),3.93-3.90(M,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺(化合物157)
以與上文所述類似的方式,由鏡像異構純的(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)和4,6-二氟-1H-吲哚-2-羧酸(VIg)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺。LCMS m/z實測值432.3[M+H]+;RT=4.24min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.1(s,1H),11.64(s,1H),8.97(d,1H),8.13-8.08(M,1H),7.48-7.44(M,1H),7.32(s,1H),7.03(d,1H),6.86(t,1H),5.22(d,1H),4.57-4.47(M,2H),4.06(d,1H),3.92(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺(化合物158)
以與上文所述類似的方式,由鏡像異構純的(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)和3-氟-
4-(三氟甲基)苯甲酸(VIab)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值441[M-H]-;RT=3.06min(方法C);1H NMR(400MHz,DMSO-d 6)δ 11.67(s,1H),9.19(d,1H),8.11(t,1H),7.95-7.88(M,3H),7.42-7.38(M,1H),5.19(d,1H),4.51(M,2,H),4.08(d,1H),3.91(d,1H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺(化合物159)
以與上文所述類似的方式,由鏡像異構純的(S)-1-胺基-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vo)和4-氯-3-氟苯甲酸(VIac)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺。LCMS m/z實測值409.2[M+H]+;RT=4.94min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.63(s,1H),9.02(d,1H),8.12-8.08(M,1H),7.92-7.89(M,1H),7.79-7.76(M,1H),7.69(t,1H),7.40-7.36(M,1H),5.17(d,1H),4.54-4.45(M,2H),4.05(d,1H),3.91-3.88(M,1H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-氟吲哚-2-羧酸(VIcu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值428.3[M+H]+;RT=5.17min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(s,1H),8.45(bs,1H),8.14-8.10(M,1H),7.93(s,1H),7.54-7.41(M,2H),6.86-6.81(M,1H),6.75(s,1H),5.71(s,1H),4.63(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.02(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物230)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二
氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值478.3[M+H]+;RT=6.79min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.16(bs,1H),11.72(bs,1H),8.15-8.10(M,1H),7.48-7.19(M,2H),7.07(s,1H),6.76(s,1H),5.75(s,1H),4.66(d,1H),4.51(d,1H),4.21(d,1H),4.06(d,1H),3.66(bs,1H),3.15(s,3H).
步驟i. 向室溫下4-氟吡啶醛(4-fluoropicolinaldehyde)在20mL 1,4-二烷和10mL水的攪拌後的溶液中加入0.53mL(5.91mmol,1eq.)丙烯酸甲酯、40mg(0.36mmol,0.06eq.)DABCO,然後在室溫下將反應攪拌16小時。反應完成後,混合物用水(50mL)稀釋並用EtOAc(3 x 50mL)萃取。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮以提供410mg粗化合物。通過Combi快速層析法(矽膠),採用30-40%的在石油醚中的乙酸乙酯作為洗脫液來純化粗產物,以提供作為灰白色固體的250mg(20%產率)2-((4-氟吡啶-2-基)(羥基)甲基)丙烯酸甲酯。LCMS m/z實測值212.16[M+H]+;1H NMR(400MHz,CDCl3)δ 8.48(q,1H),7.33-7.30(M,1H),7.21-7.17(M,1H),6.20(s,1H),6.07(d,1H),5.87(t,1H),5.51(s,1H),3.61(s,3H)。註:以1g的規模如上所述重複反應並獲得了一致的結果。
步驟ii.向700mg(3.31mmol,1eq.)2-((4-氟吡啶-2-基)(羥基)甲基)丙烯酸甲酯在DCM(7mL)中的溶液加入0.4mL(4.97mmol,1.5eq.)吡啶,和在0℃下逐滴加入355mg(4.97mmol,1.5eq.)AcCl,並在室溫下將反應攪拌1小時。反應完成後,將混合
物傾倒入飽和NaHCO3溶液(50mL)中並用EtOAc(3 x 50mL)萃取。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮以提供作為黃色油的0.7g(粗)2-(乙酸基(4-氟吡啶-2-基)甲基)丙烯酸甲酯。取這樣的所獲得的粗化合物到下一步驟中。
步驟iii. 將700mg(粗)(2.76mmol,1eq.)2-(乙酸基(4-氟吡啶-2-基)甲基)丙烯酸甲酯在甲苯(14mL)中的溶液加熱回流16小時。反應完成後,將混合物蒸發至乾燥。將所獲得的粗化合物與相同量的另一批料(batch)混合,並通過Combi快速層析法(矽膠),採用0-40%的在石油醚中的乙酸乙酯作為洗脫液來純化以提供作為灰白色固體的300mg(23%產率)7-氟吲哚-2-羧酸甲基酯。LCMS m/z實測值194.07[M+H]+;1H NMR(400MHz,DMSO-d6)δ 8.36(t,1H),8.09(s,1H),7.28(dd,1H),6.76-6.72(M,1H),6.68(s,1H),3.79(s,3H).
步驟iv. 向450mg(2.33mmol,1eq.)7-氟吲哚-2-羧酸甲基酯在THF:Water:MeOH(2:1:1)(9mL)的混合物中的攪拌後的溶液加入279mg(11.67mmol,5eq.)氫氧化鋰,並在室溫下將反應攪拌16小時。反應完成後,將混合物蒸發至乾燥。取所獲得的殘餘物到10% KHSO4溶液(10mL)中並攪拌10分鐘。所沉澱的固體通過過濾收集並在真空下乾燥以提供作為棕色固體的210mg(50%產率)7-氟吲哚-2-羧酸(VIco)。LCMS m/z實測值180.17[M+H]+;1H NMR(400MHz,DMSO-d6)δ 8.35(t,1H),8.10(s,1H),7.26(dd,1H),6.73-6.68(M,1H),6.64(s,1H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和7-氟吲哚-2-羧酸(VIco)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值428.3[M+H]+;RT=6.23min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(s,1H),8.32(bs,1H),8.14-8.10(M,1H),7.90(s,1H),7.43-7.21(M,2H),6.68-6.58(M,2H),5.75(s,1H),4.63(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.00(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物254)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIcw)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值478.3
[M+H]+;RT=7.68min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.18(bs,1H),11.73(bs,1H),8.15-8.10(M,1H),7.66-7.65(M,1H),7.59-7.32(M,2H)7.22-7.17(t,1H),7.07(s,1H),5.75(s,1H),4.66(d,1H),4.51(d,1H),4.22(d,1H),4.06(d,1H),3.14(s,3H).
步驟i. 向室溫下10g(74.1mmol,1eq.)吡啶-2,6-二甲醛在100mL苯中的攪拌後的溶液加入4.1mL(66.6mmol,0.9eq.)乙烷-1,2-二醇、1.2g(7.4mmol,0.1eq.)對甲苯磺酸,然後在100℃下將反應攪拌4小時,利用Dean-Stark儀器去除水。反應完成後,混合物用水(50mL)稀釋並用EtOAc(3 x 50mL)萃取。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮以提供13g粗化合物。通過Combi快速(矽膠),採用30-40%的石油醚中的乙酸乙酯作為洗脫液來純化材料以提供作為灰白色固體的3.4g(26%產率)6-(1,3-二氧戊環-2-基)吡啶醛。LCMS m/z實測值180.31[M+H]+,RT=1.13miN,(方法E).
步驟ii. 向室溫下3.5g 6-(1,3-二氧戊環-2-基)吡啶醛在35mL 1,4-二烷和3.5mL水的攪拌後的溶液中加入0.53mL(5.9mmol,1eq.)丙烯酸甲酯、3g(0.36mmol,0.06eq.)DABCO,然後在室溫下將反應混合物攪拌16小時。反應完成後,混合物用水(50
mL)稀釋並用EtOAc(3 x 50mL)萃取。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮以提供5g粗化合物。材料通過Combi快速(矽膠),採用30-40%的在石油醚中的乙酸乙酯作為洗脫液來純化以提供3.1g(57%產率)2-((6-(1,3-二氧戊環-2-基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯。LCMS m/z實測值265.91[M+H]+,RT=1.21min,(方法E).
步驟iii. 向3.1g(11.6mmol,1eq.)2-((6-(1,3-二氧戊環-2-基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯中加入Ac2O(30mL),並將混合物加熱回流16小時。反應完成後,將反應混合物蒸發至乾燥。將所獲得的粗化合物與相同量的另一批料混合並通過Combi快速(矽膠),採用0-40%的在石油醚中的乙酸乙酯作為洗脫液來純化以提供作為淺黃色固體的720mg(24%產率)5-(1,3-二氧戊環-2-基)吲哚-2-羧酸甲基酯。LCMS m/z實測值247.98[M+H]+,RT=1.77miN,(方法E).
步驟iv. 在0℃下向720mg(2.9mmol,1eq.)5-(1,3-二氧戊環-2-基)吲哚-2-羧酸甲基酯在10mL MeOH中的攪拌後的溶液緩慢地逐滴加入0.5mL(11.6mmol,4eq.)甲酸,並在室溫下使攪拌持續16小時。反應完成後,將混合物緩慢地逐滴傾倒在冰上並用乙酸乙酯(2 x 100mL)萃取。有機層被分離,用水洗滌,經無水Na2SO4乾燥並在減壓下濃縮。所獲得的粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的乙酸乙酯作為洗脫液來純化以提供作為白色固體的220mg(37%產率)5-甲醯基吲哚-2-羧酸甲基酯。LCMS m/z實測值203.95[MH]+,RT=1.80miN,(方法E).
步驟v. 在0℃下向220mg(1.08mmol,1eq.)5-甲醯基吲哚-2-羧酸甲基酯在10mL DCM中的攪拌後的溶液緩慢地逐滴加入1.08mL(3.25mmol,3eq.)DAST,並使攪拌持續16小時。反應完成後,將混合物緩慢地逐滴傾倒在冰上並用乙酸乙酯(2 x 100mL)萃取。有機層被分離,用水洗滌,經無水Na2SO4乾燥並在減壓下
濃縮。所獲得的粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的乙酸乙酯作為洗脫液來純化以提供作為白色固體的48mg(20%產率)5-(二氟甲基)吲哚-2-羧酸甲基酯。LCMS m/z實測值225.94[MH]+,(方法E).
步驟vi. 在0℃下向48mg(0.21mmol,1eq.)5-(二氟甲基)吲哚-2-羧酸甲基酯在THF:水:MeOH(2:1:1)(3mL)的混合物中的攪拌後的溶液加入28mg(1.2mmol,2.5eq.)LiOH,並在室溫下將反應攪拌4小時。反應完成後,使揮發物蒸發並用10% aq.KHSO4溶液酸化至pH約為2。所沉澱的固體通過過濾收集,用水洗滌,並在真空下乾燥以提供作為白色固體的35mg(77%產率)5-(二氟甲基)吲哚-2-羧酸(VIdc)。LCMS m/z實測值211.92[M+H]+,RT=1.44miN,(方法E).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-(二氟甲基)吲哚-2-羧酸(VIdc)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值460.3[M+H]+;RT=7.68min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.12(t,1H),7.92(s,1H),7.68(d,1H),7.51-7.28(M,2H),7.07(d,1H),6.87(t,2H),5.72(s,1H),4.61(d,1H),4.47(d,1H),4.19(d,1H),4.05-4.02(M,1H),3.01(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物283)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3'-氟-[1,1'-聯苯基]-4-羧酸(VIcx)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值465.2[M+H]+;RT=4.84min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.14(t,1H),7.80(d,2H),7.57-7.49(M,6H),7.23(t,1H),5.71(s,1H),4.60(d,1H),4.48(d,1H),4.29(d,1H),4.07-4.03(M,1H),2.78(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物285)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2'-
氟-[1,1'-聯苯基]-4-羧酸(VIdd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值465.2[M+H]+;RT=4.75min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.14(t,1H),7.64(d,2H),7.58-7.42(M,5H),7.36-7.30(M,1H),5.71(s,1H),4.60(d,1H),4.48(d,1H),4.29(d,1H),4.08-4.04(M,1H),2.77(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物286)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3',5'-二氟-[1,1'-聯苯基]-4-羧酸(VIde)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值483.2[M+H]+;RT=5.01min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.14(t,1H),7.84(d,2H),7.54-7.49(M,5H),7.29-7.24(M,1H),5.71(s,1H),4.60(d,1H),4.47(d,1H),4.29(d,1H),4.08-4.03(M,1H),2.75(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-
c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物287)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2,3',5'-三氟-[1,1'-聯苯基]-4-羧酸(VIdf)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值501.1[M+H]+;RT=5.16min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.14(t,1H),7.69(d,1H),7.52-7.45(M,2H),7.37-7.32(M,4H),5.69(s,1H),4.60(d,1H),4.47(d,1H),4.30(d,1H),4.06-4.02(M,1H),2.76(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺(化合物288)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和
[1,1'-聯苯基]-3-羧酸(VIdg)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺。LCMS m/z實測值447.2[M+H]+;RT=4.68min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.14(t,1H),7.75(d,1H),7.68(d,3H),7.57-7.47(M,4H),7.41-7.35(M,2H),5.73(s,1H),4.59(d,1H),4.47(d,1H),4.31(d,1H),4.07-4.03(M,1H),2.75(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺(化合物289)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4'-氟-[1,1'-聯苯基]-3-羧酸(VIdh)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺。LCMS m/z實測值465.2[M+H]+;RT=4.75min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.14(t,1H),7.75-7.72(M,3H),7.66(s,1H),7.57-7.52(M,2H),7.35-7.29(M,3H),5.73(s,1H),4.59(d,1H),4.47(d,1H),4.31(d,1H),4.07-4.03(M,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺(化合物290)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3'-氟-[1,1'-聯苯基]-3-羧酸(VIcy)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺。LCMS m/z實測值465.2[M+H]+;RT=4.75min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.14(t,1H),7.79(s,1H),7.73(s,1H),7.56-7.52(M,5H),7.38(d,1H),7.25-7.21(M,1H),5.73(s,1H),4.59(d,1H),4.48(d,1H),4.31(d,1H),4.07-4.03(M,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺(化合物291)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3',5-二氟-[1,1'-聯苯基]-3-羧酸(VIdi)合成鏡像異構純的(S)-N-(8,9-
二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺。LCMS m/z實測值483.2[M+H]+;RT=4.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(bs,1H),8.12(t,1H),7.70(s,1H),7.63-7.49(M,5H),7.28-7.24(M,2H),5.69(s,1H),4.59(d,1H),4.46(d,1H),4.33(d,1H),4.05-4.01(M,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺(化合物292)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-苯氧基苯甲酸(VIdj)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺。LCMS m/z實測值463.2[M+H]+;RT=4.68min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(bs,1H),8.12(t,1H),7.48-7.38(M,4H),7.22-7.03(M,5H),6.95(s,1H),5.63(s,1H),4.57(d,1H),4.44(d,1H),4.23(d,1H),4.03-3.99(M,1H),2.68(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺(化合物293)
鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺以與上文所述類似的方式,合成由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(4-氟苯氧基)苯甲酸(VIdk)。LCMS m/z實測值481.2[M+H]+;RT=4.72min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.68(bs,1H),8.12(t,1H),7.46(t,1H),7.40-7.35(M,1H),7.23(t,2H),7.12-7.06(M,4H),6.90(s,1H),5.63(s,1H),4.57(d,1H),4.45(d,1H),4.23(d,1H),4.03-3.99(M,1H),2.67(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺(化合物295)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(甲磺醯)苯甲酸(VIdl)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺。LCMS m/z實測值449.1[M+H]+;RT=5.31min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7(bs,1H),8.14(t,1H),8.01
(d,2H),7.67(d,2H),7.51-7.46(M,1H),5.7(s,1H),4.59(d,1H),4.47(d,1H),4.31(d,1H),4.06-4.02(M,1H),3.26(s,3H),2.69(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺(化合物296)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(N-甲基胺磺醯)苯甲酸(VIdm)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺。LCMS m/z實測值464.2[M+H]+;RT=5.48min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7(s,1H),8.14(t,1H),7.85(d,1H),7.79(s,1H),7.72-7.68(M,2H),7.58(d,1H),7.52-7.47(M,1H),5.69(s,1H),4.60(d,1H),4.47(d,1H),4.32(d,1H),4.05-4.02(M,1H),2.71(s,3H).),2.42(d,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺(化合物297)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-
(甲基亞磺醯胺基)苯甲酸(VIdn)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺。LCMS m/z實測值464.2[M+H]+;RT=6.00min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7(s,1H),9.90(bs,1H),8.16-8.11(M,1H),7.52-7.39(M,2H),7.34-7.27(M,1H),7.19(s,1H),7.11(d,1H),5.66(s,1H),4.59(d,1H),4.46(d,1H),4.23(d,1H),4.06-4.02(M,1H),3.0(s,3H),2.70(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺(化合物298)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(甲磺醯)苯甲酸(VIdo)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺。LCMS m/z實測值449.1[M+H]+;RT=6.04min(方法A);1H NMR(400MHz,DMSO-d 6)δ 10.82(bs,1H),8.11(t,1H),8.01(t,1H),7.96(s,1H),7.74(d,2H),7.5-7.45(M,1H),5.69(s,1H),4.54(d,1H),4.45(d,1H),4.33(d,1H),4.04-4.01(M,1H),3.27(s,3H),2.70(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺(化合物303)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氟-5-苯氧基苯甲酸(VIdp)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺。LCMS m/z實測值481.2[M+H]+;RT=4.93min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(bs,1H),8.11(M,1H),7.42(t,2H),7.34(M,1H),7.21(t,1H),7.10(M,2H),7.00(M,2H),6.73(s,1H),5.60(s,1H),4.57(d,1H),4.44(d,1H),4.24(d,1H),3.99(M,1H),2.67(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺(化合物322)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(3-氟苯氧基)苯甲酸(VIdq)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺。LCMS m/z實測值481.2[M+H]+;RT=4.78min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.66(bs,1H),8.08(t,
1H),7.51-7.34(M,3H),7.16(t,2H),7.03-6.85(d,4H),5.62(s,1H),4.54(d,1H),4.42(d,1H),4.23(d,1H),4.0(d,1H),2.68(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺(化合物324)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-甲氧基-1H-吲哚-2-羧酸(VIdr)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值440.2[M+H]+;RT=3.88min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(bs,1H),11.57(bs,1H),8.12(t,1H),7.45-7.35(M,2H),7.06(s,1H),6.88-6.85(M,2H),5.76(s,1H),4.64(d,1H),4.48(d,1H),4.16(d,1H),4.05(d,1H),3.74(s,3H),3.16(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物325)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氯-1H-吲哚-2-羧酸(VIds)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值444.2[M+H]+;RT=4.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.92(bs,1H),11.72(bs,1H),8.13(t,1H),7.66(s,1H),7.49-7.45(M,2H),7.22(d,1H),6.93(s,1H),5.75(s,1H),4.64(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.15(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺(化合物326)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-甲基-1H-吲哚-2-羧酸(VIdt)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值424.2[M+H]+;RT=4.44min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(bs,1H),11.58(bs,1H),8.15-8.10(M,1H),7.45-7.35(M,3H),7.04(d,1H),6.84(s,1H),5.76(s,1H),4.64(d,1H),4.48(d,1H),4.15(d,1H),4.05(d,1H),3.16(s,3H),2.36(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺(化合物327)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-(三氟甲氧基)-1H-吲哚-2-羧酸(VIdu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺。LCMS m/z實測值494.2[M+H]+;RT=4.92min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.0(s,1H),11.72(s,1H),8.13(t,1H),7.60-7.54(M,2H),7.46-7.41(M,1H),7.20(d,1H),7.01(s,1H),5.75(s,1H),4.66(d,1H),4.49(d,1H),4.19(d,1H),4.05(d,1H),3.16(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺(化合物328)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-乙基-1H-吲哚-2-羧酸(VIdv)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值438.2[M+H]+;RT=4.82min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),11.59(s,
1H),8.12(t,1H),7.47-7.37(M,3H),7.08(d,1H),6.86(s,1H),5.76(s,1H),4.64(d,1H),4.48(d,1H),4.17(d,1H),4.05(d,1H),3.16(s,3H),2.68-2.63(M,2H),1.27-1.18(t,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺(化合物329)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-甲氧基-1H-吲哚-2-羧酸(VIdw)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值440.2[M+H]+;RT=4.00min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.73(bs,2H),8.12(t,1H),7.43(bs,1H),7.15-7.05(M,2H),6.88(s,1H),6.52(d,1H),5.75(s,1H),4.64(d,1H),4.48(d,1H),4.15(d,1H),4.05(d,1H),3.85(s,3H),3.17(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物330)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟
-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-甲基-1H-吲哚-2-羧酸(VIdx)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值424.2[M+H]+;RT=4.36min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.72(bs,1H),11.68(bs,1H),8.13(t,1H),7.47(bs,1H),7.29(d,1H),7.10(t,1H),6.96(s,1H),6.83(d,1H),5.77(s,1H),4.65(d,1H),4.49(d,1H),4.19-4.04(M,2H),3.19(s,3H),2.47(s,3H).
(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物341)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氰基-6-氟-1H-吲哚-2-羧酸(VIdy)合成鏡像異構純的(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值453.2[M+H]+;RT=4.10min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.92(bs,2H),8.11(t,1H),7.55-6.86(M,4H),5.74(s,1H),4.62(d,1H),4.47(d,1H),4.19(d,1H),4.04(d,1H),3.19(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物342)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)4-乙基-6-氟-1H-吲哚-2-羧酸(VIdz)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值456.2[M+H]+;RT=4.85min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.76(bs,2H),8.12(M,H1HH),7.46(bs,1H),7.01(d,2H),6.76(d,1H),5.76(s,1H),4.64(d,1H),4.48(d,1H),4.17(d,1H),4.04(d,1H),3.18(bs,3H),2.86(d,2H),1.24(t,3H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物343)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氯-6-氟-1H-吲哚-2-羧酸(VIea)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值462.1[M+H]+;RT=4.81
min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.0(bs,2H),8.10(t,1H),7.48-7.36(M,1H),7.21-7.14(M,2H),6.97-6.92(M,1H),5.74(s,1H),4.62(d,1H),4.46(d,1H),4.17(d,1H),4.03(d,1H),3.17(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物344)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-氟-4-甲基-1H-吲哚-2-羧酸(VIeb)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值442.1[M+H]+;RT=4.52min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.75(bs,2H),8.12(t,1H),7.45(bs,1H),7.0(bs,2H),6.74(d,1H),5.76(s,1H),4.65(d,1H),4.48(d,1H),4.16(d,1H),4.05(d,1H),3.18(bs,3H),2.48(s,3H).
(S)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物345)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-氰基-1H-吲哚-2-羧酸(VIec)合成鏡像異構純的(S)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值435.3[M+H]+;RT=3.69min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.29(bs,1H),11.73(bs,1H),8.18-8.10(M,2H),7.63-7.54(M,2H),7.46-7.41(M,1H),7.09(s,1H),5.74(s,1H),4.68(d,1H),4.52(d,1H),4.20(d,1H),4.08(d,1H),3.16(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺(化合物346)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-(甲磺醯)-1H-吲哚-2-羧酸(VIed)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺。LCMS m/z實測值488.1[M+H]+;RT=3.04min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.07(bs,2H),
8.23(s,1H),8.10(t,1H),7.73-7.65(M,2H),7.42-7.38(M,1H),7.18(s,1H),5.75(s,1H),4.62(d,1H),4.47(d,1H),4.18(d,1H),4.05(d,1H),3.16(s,6H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物347)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-氯-1H-吲哚-2-羧酸(VIee)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值444.1[M+H]+;RT=4.56min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.10(bs,1H),11.73(bs,1H),8.13(t,1H),7.45(d,2H),7.21(t,1H),7.13(d,1H),6.90(s,1H),5.76(s,1H),4.64(d,1H),4.49(d,1H),4.20(d,1H),4.05(d,1H),3.18(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-溴吲哚-2-羧酸(VIef)合成鏡像異構純的(S)-6-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值488.3[M+H]+;1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.60(s,1H),8.12(t,1H),7.92(s,1H),7.14(d,2H),6.84(d,1H),6.74(s,1H),5.71(s,1H),4.61(d,1H),4.46(d,1H),4.15(d,1H),4.03(d,1H),3.0(s,3H).
6-氟-4-(羥甲基)-1H-吲哚-2-羧酸(VIeh)
步驟i. 向30%的NaOMe/MeOH在15mL MeOH中的攪拌後的溶液加入5g(24.3mmol,1eq.)2-溴-4-氟苯甲醛,並在-15℃下逐滴加入15mL MeOH中的7g(54.2mmol,2.2eq.)2-疊氮乙酸乙基酯。在相同溫度下將反應混合物攪拌3小時。反應完成(通過TLC監測)後,將混合物逐滴傾倒在攪拌的冰上並使攪拌再持續30分鐘。所沉澱的固體通過過濾收集,用水洗滌,乾燥,並通過管柱層析法(矽膠100-200目和10%乙酸乙酯/石油醚)純化以提供2g(27%產率)(Z)-2-疊氮基-3-(2-溴-4-氟苯基)丙烯酸甲酯。1H NMR(400MHz,DMSO-d 6 )δ 8.22-8.18(M,1H),7.73-7.70(M,1H),7.38-7.33(M,1H),7.04(s,1H),3.88(s,3H).
步驟ii. 在220℃下,採用具有開式冷凝器(open
condenser)的加熱套對2g(29.8mmol,1eq.)(Z)-2-疊氮基-3-(2-溴-4-氟苯基)丙烯酸甲酯在20mL 1,2-二氯苯中的溶液加熱1小時。反應完成(通過TLC監測)後,將混合物用石油醚(30mL)稀釋並在0℃下攪拌10分鐘。所沉澱的固體通過過濾收集,石油醚(20mL)洗滌,並在真空下乾燥以提供作為灰白色固體的900mg(49%產率)4-溴-6-氟-1H-吲哚-2-羧酸甲基酯。LCMS m/z實測值271.84[M+H]+,RT:2.09min(方法E).
步驟iii. 向500mg(1.83mmol,1eq.)4-溴-6-氟-1H-吲哚-2-羧酸甲基酯在5mL DMF(10 vol)中的攪拌後的溶液加入0.65mL(2.2mmol,1.2eq.)三丁基乙烯基錫。所得混合物用氬氣脫氣15分鐘。在室溫下加入Pd(PPh3)2Cl2(130mg,0.18mmol,0.1eq.)並在90℃下將反應混合物攪拌16小時。反應完成(通過TLC監測)後,混合物通過CELITE®墊(pad)過濾,並用冰-水(100mL)稀釋濾液和用乙酸乙酯(2 x 100mL)萃取。合併的有機層用冰-水(50mL)洗滌,經無水Na2SO4乾燥,過濾,並在減壓下濃縮。所獲得的化合物通過管柱層析法(矽膠100-200目和10%乙酸乙酯/石油醚)純化以提供作為灰白色固體的300mg(74%產率)6-氟-4-乙烯基-1H-吲哚-2-羧酸甲基酯。LCMS m/z實測值220.24[M+H]+,RT=2.07min(方法E).
步驟iv. 向0℃下300mg(1.36mmol,1eq.)6-氟-4-乙烯基-1H-吲哚-2-羧酸甲基酯在3mL THF和3mL水中的攪拌後的溶液加入5mg(0.013mmol,0.01eq.)K2OSO4和670mg(3.18mmol,2.3eq.)NaIO4,並在室溫下將反應混合物攪拌16小時。反應完成(通過TLC監測)後,混合物通過CELITE®墊(pad)過濾,並用水(30mL)稀釋濾液和用乙酸乙酯(2 x 100mL)萃取。合併的有機層用水(30mL)洗滌,經無水Na2SO4乾燥,過濾並在減壓下濃縮。所獲得的化合物通過管柱層析法(矽膠100-200目和10%乙酸乙酯/石油醚)純化以提供作為灰白色固體的150mg(49%產率)6-氟-4-甲醯
基-1H-吲哚-2-羧酸甲基酯。LCMS m/z實測值222.20[M+H]+,RT=1.72min(方法E).
步驟v. 在0℃下,向在室溫下於惰性氣氛下的240mg(0.9mmol,1eq.)6-氟-4-甲醯基-1H-吲哚-2-羧酸甲基酯在3mL甲醇中的攪拌後的溶液分批(portion-wise)加入51mg(1.35mmol,1.5eq.)NaBH4,並在室溫下將反應混合物攪拌4小時。反應完成(通過TLC監測和LCMS分析)後,混合物用水(50mL)稀釋,過濾並用乙酸乙酯(50ml)洗滌所收集的固體。將有機層分離,並用乙酸乙酯(3 x 50mL)萃取水層。合併的有機萃取物經無水Na2SO4乾燥,過濾,並在減壓下濃縮。所得產物與二乙醚(10mL)研磨並在真空下乾燥以提供作為淺棕色固體的200mg 6-氟-4-(羥甲基)-1H-吲哚-2-羧酸甲基酯,將該固體轉入(carried into)下一步驟而無需進一步純化。LCMS m/z實測值238.21[M+H]+.
步驟vi. 在0℃下,向180mg(0.8mmol,1eq.)6-氟-4-(羥甲基)-1H-吲哚-2-羧酸甲基酯在THF:水:MeOH(2:1:1)(5mL)的混合物中的攪拌後的溶液加入169mg(2.53mmol,3eq.)LiOH,並在室溫下將反應攪拌4小時。反應完成(通過TLC監測)後,使揮發物蒸發並用10% aq.KHSO4溶液將殘餘物酸化至pH約為2。所沉澱的固體通過過濾收集,用水洗滌,並在真空下乾燥以提供作為白色固體的130mg(77%產率)6-氟-4-(羥甲基)-1H-吲哚-2-羧酸(VIeh)。LCMS m/z實測值222.16[M-H]-,RT=1.39miN,(方法E).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺(化合物355)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-氟-4-(羥甲基)-1H-吲哚-2-羧酸(VIeh)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值458.2[M+H]+;RT=3.29min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.79(bs,1H),11.71(bs,1H),8.12(t,1H),7.44(bs,1H),7.04(t,2H),6.92(d,1H),5.75(s,1H),5.30(t,1H),4.76(bs,2H),4.64(d,1H),4.48(d,1H),4.16(d,1H),4.04(d,1H),3.16(s,3H).
6-氟-4-(甲基亞磺醯胺基)-1H-吲哚-2-羧酸(Viei)
步驟i. 向在室溫下於惰性氣氛下的500mg(1.83mmol,1eq.)4-溴-6-氟-1H-吲哚-2-羧酸甲基酯在5mL DMSO中的攪拌後的溶液加入52mg(0.36mmol,0.2eq.)Cu2O、347mg(5.51mmol,3eq.)NaN3、和105mg(0.36mmol,0.2eq.)L-脯胺酸,並在100℃將混合物攪拌16小時。反應完成(通過TLC監測和LCMS分析)後,混合物用水(50mL)稀釋,過濾,並用乙酸乙酯(50mL)萃取非均質的混合物。將有機層分離,並用乙酸乙酯(3 x 50mL)萃取水層。合併的有機層經無水Na2SO4乾燥,過濾並在減壓下濃縮。所得產物與二乙醚(10mL)研磨,過濾並在真空下乾燥以提供作為淺棕色固
體的200mg 4-胺基-6-氟-1H-吲哚-2-羧酸甲基酯,將該固體轉入下一步驟而無需進一步純化。LCMS m/z實測值207.12[M-H]-,RT=1.32min(方法E)
步驟ii. 向400mg(1.48mmol,1eq.)4-胺基-6-氟-1H-吲哚-2-羧酸酯在3mL DCM中的溶液加入0.13mL(4.46mmol,3eq.)甲磺醯氯和吡啶(0.17mL,1.5eq.),並在室溫下將反應混合物攪拌4小時。反應完成(通過TLC監測)後,將混合物冷卻至室溫並傾倒入冰冷的水(20mL)中,然後用EtOAC(2 x 50mL)萃取。合併的有機層用鹽水(50mL)洗滌,經無水Na2SO4乾燥,過濾並在減壓下濃縮。所得粗產物與二乙醚研磨以提供320mg(77%產率)6-氟-4-(甲基亞磺醯胺基)-1H-吲哚-2-羧酸甲基酯。LCMS m/z實測值285.17[M-H]-,RT=1.41min(方法E).
步驟iii.以與上文關於VIeh所述類似的方式,將步驟ii中所獲得的6-氟-4-(甲基亞磺醯胺基)-1H-吲哚-2-羧酸甲基酯轉化為6-氟-4-(甲基亞磺醯胺基)-1H-吲哚-2-羧酸(VIei)。LCMS m/z實測值271.23[M-H]-,RT=1.13min(方法E).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺(化合物362)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-氟-4-(甲基亞磺醯胺基)-1H-吲哚-2-羧酸(VIei)合成鏡像異構純的(S)-
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺。LCMS m/z實測值521.2[M+H]+;RT=3.54min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.89(bs,1H),11.73(bs,1H),9.98(bs,1H),8.13(t,1H),7.46(bs,2H),6.94-6.87(M,2H),5.76(s,1H),4.65(d,1H),4.49(d,1H),4.17-4.03(M,2H),3.17(s,3H),3.05(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺(化合物363)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(三氟甲氧基)-1H-吲哚-2-羧酸(VIej)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺。LCMS m/z實測值494.2[M+H]+;RT=4.84min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.17(bs,1H),11.72(s,1H),8.13(t,1H),7.51-7.43(M,2H),7.28(t,1H),7.04(d,1H),6.94(bs,1H),5.75(s,1H),4.64(d,1H),4.49(d,1H),4.20(d,1H),4.05(d,1H),3.16(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺(化合物364)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-甲氧基-1H-吲哚-2-羧酸(VIek)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值440.2[M+H]+;RT=3.98min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(bs,1H),11.53(bs,1H),8.12(t,1H),7.48(d,2H),6.91(d,2H),6.70(dd,1H),5.76(bs,1H),4.64(d,1H),4.48(d,1H),4.14(d,1H),4.04(d,1H),3.78(s,3H),3.16(s,3H).
6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物217和218)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成外消旋6-(二氟甲基)-5-氟-N-(8-氟-6-
側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相MeOH:CO2-25:75。管柱:Chiralcel-IC(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物217):LCMS:m/z實測值460.3[M+H]+,RT=5.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.11(s,1H),11.7(s,1H),7.9-7.8(M,1H),7.79-7.64(d,2H),7.59-7.51(M,2H),7.2(s,1H),6.9(s,1H),5.75(s,1H),4.65(d,1H),4.54(d,1H),4.16(d,1H),4.04(dd,1H),3.12(s,3H);手性分析SFC:RT=3.40miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30% MeOH,流速:3.0g/min.
對映異構物II(化合物218):LCMS:m/z實測值460.3[M+H]+,RT=5.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.11(s,1H),11.7(s,1H),7.9-7.8(M,1H),7.79-7.64(d,2H),7.59-7.51(M,2H),7.2(s,1H),6.9(s,1H),5.75(s,1H),4.65(d,1H),4.54(d,1H),4.16(d,1H),4.04(dd,1H),3.12(s,3H);手性分析SFC:RT=4.32miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30% MeOH,流速:3.0g/min.
4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物238和239)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-
1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)合成外消旋4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相MeOH:CO2-50:50。管柱:Chiralpak-IA(30 x 250mm),5μ,流速:110g/min。
對映異構物I(化合物238):LCMS:m/z實測值460.3[M+H]+,RT=6.74miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.96(bs,2H),7.87(d,1H),7.58-7.48(M,2H),7.44-7.30(M,3H),7.01(s,1H),5.74(s,1H),4.58(d,1H),4.44(d,1H),4.16(d,1H),4.03(d,1H),3.13(s,3H);手性分析SFC:RT=2.30miN,管柱:Chiralcel IA-3(4.6 x 150mm)3μM,30% MeOH,流速:3.0g/min.
對映異構物II(化合物239):LCMS:m/z實測值460.3[M+H]+,RT=6.74miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.96(bs,2H),7.87(d,1H),7.58-7.48(M,2H),7.44-7.30(M,3H),7.01(s,1H),5.74(s,1H),4.58(d,1H),4.44(d,1H),4.16(d,1H),4.03(d,1H),3.13(s,3H);手性分析SFC:RT=5.35miN,管柱:Chiralcel IA-3(4.6 x 150mm)3μM,30% MeOH,流速:3.0g/min.
4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物255和256)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIcw)合成外消旋4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相MeOH:CO2-50:50。管柱:Chiralpak-IA(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物255):LCMS:m/z實測值460.3[M+H]+,RT=7.57miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.14(bs,1H),11.70(bs,1H),7.92-7.90(M,1H),7.66-7.37(M,4H),7.21-7.16(M,1H),7.02(s,1H),5.75(s,1H),4.65(d,1H),4.50(d,1H),4.21(d,1H),4.07(d,1H),3.12(s,3H);手性分析SFC:RT=2.19miN,管柱:Chiralcel IA-3(4.6 x 150mm)3μM,40%(甲醇:ACN(1:1)),流速:3.0g/min.
對映異構物II(化合物256):LCMS:m/z實測值460.3[M+H]+,RT=7.57miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.14(bs,1H),11.70(bs,1H),7.92-7.90(M,1H),7.66-7.37(M,4H),7.21-7.16(M,1H),7.02(s,1H),5.75(s,1H),4.65(d,1H),4.50(d,1H),4.21(d,1H),4.07(d,1H),3.12(s,3H);手性分析SFC:RT=4.23miN,管柱:Chiralcel IA-3(4.6 x 150mm)3μM,40%(甲醇:ACN(1:1)),流速:3.0g/min.
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺(化合物229)
在0℃下,用4-甲基嗎啉(33μL,2eq.)處理鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,40mg,0.15mmol)、2-羥基-2,2-二苯基醋酸(VIby,34mg,0.15mmol)1-乙基-3-二甲胺基丙基碳二亞胺鹽酸鹽(3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride)(EDCI,32mg,0.17mmol)、和1-羥基苯并三唑(HOBt,23mg,0.17mmol)在DMF(0.5mL)中的攪拌後的混合物,然後使反應持續4小時,從而使其溫熱至室溫。使反應混合物分配在乙酸乙酯和水之間,並將有機萃取物乾燥(硫酸鈉),過濾,並使揮發物蒸發。通過製備反相hplc(GilsoN,C18柱,水/乙腈0-75%,用0.05% v/v FA作為調節劑)分離產物,之後凍乾,以提供(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺。LCMS m/z實測值477.3[M+H]+;RT=5.54min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.63(s,1H),8.07(dd,1H),7.48-7.17(M,10H),6.94(s,1H),5.58-5.52(M,1H),4.48(d,1H),4.37(d,1H),4.09(d,1H),3.92(dd,1H),2.59(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺(化合物123)
在0℃下,向苯并[d]噻唑-2-羧酸(VIba)(50mg,0.28mmol)在DCM(2mL)中的攪拌後的溶液加入DMF(cat.),之後逐滴加入草醯氯(105mg,0.84mmol)。在室溫下將反應混合物攪拌2小時。然後在減壓下將反應混合物濃縮。將殘餘物溶解在DMF(2mL)中,冷卻至0℃,並加入吡啶(110mg,1.35mmol),之後加入鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,TF鹽,74mg,0.279mmol)。然後在室溫下將反應混合物攪拌1小時。將反應混合物再次冷卻至0℃並加入水(5mL)。所沉澱的固體通過過濾收集,在真空下乾燥,隨後通過快速管柱層析法,採用2% MeOH-DCM作為洗脫液進行純化以提供(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺(23mg,19%)。LCMS m/z實測值428.1[M+H]+;RT=5.69min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.75(s,1H),8.28-8.22(M,1H),8.16-8.11(M,2H),7.63-7.33(M,3H),6.39-5.69(M,1H),4.64(d,1H),4.52-4.45(M,1H),4.34-4.26(M,1H),4.07-4.03(M,1H),3.329(s,2H),2.9(s,1H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和苯并[d]唑-2-羧酸(VIbb)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-2-甲醯胺。LCMS m/z實測值412.2[M+H]+;RT=5.24min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.75(s,1H),8.168-8.10(M,1H),7.94-7.88(M,2H),7.69-7.33(M,3H),5.87-5.69(M,1H),4.65-4.60(M,1H),4.52-4.44(M,1H),4.36-4.22(M,1H),4.07-4.04(M,1H),3.16(s,2H),2.88(s,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺(化合物188)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1-甲基-1H-吡唑-4-羧酸(VIbq)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺。LCMS m/z實測值375.2[M+H]+;RT=2.38min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.67(s,1H),8.18(s,1H),8.08(dd,1H),7.79(s,1H),7.35(dd,1H),5.65(s,1H),4.59
(d,1H),4.43(dd,H),4.05(d,1H),3.97(dd,1H),3.84(s,3H),2.97(s,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺(化合物194)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-溴噻吩-3-羧酸(VIbr)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺。LCMS m/z實測值455.1[M+H]+;RT=4.20min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.69(s,1H),8.10(dd,1H),7.87(d,1H),7.50-7.25(M,2H),5.59(s,1H),4.57(d,1H),4.43(d,1H),4.16(d,1H),4.06-3.93(M,1H),2.82(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺(化合物195)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2,3-二氫-1H-茚-2-羧酸(VIbs)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧
-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺。LCMS m/z實測值411.3[M+H]+;RT=4.42min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.67(s,1H),8.09(dd,1H),7.32-6.99(M,5H),5.72-5.46(M,1H),4.58(d,1H),4.41(d,1H),4.07-3.97(M,1H),3.92(dd,1H),3.76-3.59(M,1H),3.26(dd,1H),3.14(dd,2H),3.02-2.92(M,1H),2.90(s,3H).
(S)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺(化合物196)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1-(第三丁基)-1H-吡唑-4-羧酸(VIbt)合成鏡像異構純的(S)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺。LCMS m/z實測值417.2[M+H]+;RT=3.52min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.69(s,1H),8.20(s,1H),8.09(t,1H),7.81(s,1H),7.38(dd,1H),5.67(s,1H),4.59(d,1H),4.43(d,1H),4.05(d,1H),3.96(d,1H),2.99(s,3H),1.51(s,9H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺(化合物197)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1-(三氟甲基)-1H-吡唑-4-羧酸(VIbu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺。LCMS m/z實測值429.2[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.70(s,1H),8.94(s,1H),8.28(s,1H),8.10(dd,1H),7.35(dd,1H),5.64(s,1H),4.60(d,1H),4.44(d,1H),4.12(d,1H),3.98(dd,1H),2.97(s,3H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺(化合物198)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-溴-1H-吡咯-2-羧酸(VIbv)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺。LCMS m/z實測值440.1[M+H]+;RT=4.04min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 12.02(s,1H),11.72(s,
1H),8.16-8.06(M,1H),7.39(t,1H),7.11(d,1H),6.71(s,1H),5.69(s,1H),4.62(d,1H),4.45(dd,Hz,1H),4.08(d,1H),3.99(d,J=12.0Hz,1H),3.04(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺(化合物211)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1-羥基環己烷-1-羧酸(VIbw)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺。LCMS m/z實測值393.3[M+H]+;RT=4.03min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.66(s,1H),8.08(ddd,1H),7.16(dd,1H),5.53(s,1H),5.28(s,1H),4.53(d,1H),4.39(d,1H),3.99-3.86(M,2H),3.08-3.02(M,3H),1.83(d,1H),1.78-1.34(M,8H),1.22(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺(化合物225)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-(三氟甲基)-1H-咪唑-5-羧酸(VIbx)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺。1H NMR(400MHz,DMSO-d 6 )δ 11.69(d,1H),8.14-8.04(M,1H),7.98(s,1H),7.66(M,1H)*,7.34(dd,1H),6.54(s,1H)*,6.01(s,1H),5.67(t,1H),4.58(dd,1H),4.43(dd,1H),4.09(d,1H),3.98(ddd,1H),3.12(s,3H),2.73(s,3H)*。註:"*"表示次要的旋轉異構物或互變異構物。
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺(化合物233)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6-二氟-2,3-二氫-1H-茚-2-羧酸(VIbz)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺。LCMS m/z實測值447.3[M+H]+;RT=5.70min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.67(s,1H),8.08(dd,1H),7.25(ddd,2H),7.15(dd,1H),5.60-5.54(M,1H),4.57(d,1H),4.45-4.36(M,1H),4.00(d,1H),3.92(dd,1H),3.80-3.67(M,1H),3.22(dd,1H),3.12(dd,2H),2.98-2.89(M,1H),2.87(d,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺(化合物234)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1-(4-氟苯基)-1H-吡唑-4-羧酸(VIca)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺。LCMS m/z實測值455.3[M+H]+;RT=5.40min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.71(s,1H),8.90(s,1H),8.15-8.05(M,2H),7.98-7.88(M,2H),7.44-7.30(M,3H),5.68(t,1H),4.61(d,1H),4.45(dd,1H),4.10(d,1H),3.99(dd,1H),3.04(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-(4-氟苯基)-1,2,4-二唑-3-羧酸鋰(VIcb)合成鏡像異構純的(S)-N-
(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(4-氟苯基)-N-甲基-1,2,4-二唑-3-甲醯胺。LCMS m/z實測值457.3[M+H]+;RT=5.70min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.75(s,1H),8.28-8.05(M,3H),7.63(dd,1H)*,7.59-7.43(M,2H),7.31(dd,1H),5.69-5.63(M,1H),4.97(s,1H)*,4.65-4.54(M,1H),4.52-4.38(M,1H),4.20(d,1H),4.17-4.09(M,1H)*,4.04(dd,1H),3.86(dd,1H)*,2.87(s,3H),2.84(s,3H)*。註:"*"表示可分辨的次要阻轉異構物的信號。
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-(4-氟苯基)異唑-5-羧酸(VIcc)合成鏡像異構純的((S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基異唑-5-甲醯胺。LCMS m/z實測值456.2[M+H]+;RT=5.89min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.75(s,1H),8.12(dd,1H),8.07-7.94(M,2H),7.67(d,1H),7.44-7.27(M,3H),5.65-5.59(M,1H),4.62(d,1H),4.47(d,1H),4.20(d,1H),4.01(dd,1H),2.99(d,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺(化合物237)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(3-氟苯氧基)苯甲酸(VIcd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺。LCMS m/z實測值481.3[M+H]+;RT=6.22min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.69(s,1H),8.10(dd,1H),7.43(tt,4H),7.13-7.05(M,2H),7.09-6.91(M,2H),6.88(dd,1H),5.65(t,1H),4.57(d,1H),4.44(d,1H),4.23(d,1H),4.02(dd,1H),2.73(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺(化合物249)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4-(4-氟苯氧基)苯甲酸(VIce)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺。LCMS m/z實測值481.3[M+H]+;RT=6.63min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.69(s,1H),8.10(dd,1H),7.50-7.38(M,3H),7.24(t,2H),7.19-7.08(M,2H),7.03
-6.95(M,2H),5.64(t,1H),4.56(d,1H),4.44(d,1H),4.22(d,1H),4.01(dd,1H),2.73(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物250)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4'-氟-[1,1'-聯苯基]-4-羧酸(VIcf)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值465.3[M+H]+;RT=6.62min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.70(s,1H),8.12(dd,1H),7.78-7.68(M,4H),7.54-7.43(M,3H),7.35-7.24(M,2H),5.71-5.65(M,1H),4.58(d,1H),4.45(d,1H),4.26(d,1H),4.03(dd,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺(化合物262)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和
2,4'-二氟-[1,1'-聯苯基]-4-羧酸(VIcg)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺。LCMS m/z實測值483.3[M+H]+;RT=7.45min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.71(s,1H),8.12(dd,1H),7.66-7.55(M,3H),7.52-7.37(M,2H),7.37-7.25(M,3H),5.66(d,1H),4.58(d,1H),4.50-4.41(M,1H),4.28(d,1H),4.02(dd,1H),2.75(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5-(4-氟苯基)異唑-3-羧酸(VIch)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(4-氟苯基)-N-甲基異唑-3-甲醯胺。LCMS m/z實測值456.3[M+H]+;RT=7.18min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.73(d,1H),8.11(dt,1H),8.07-7.94(M,2H),7.50-7.28(M,4H),5.69-5.63(M,1H),4.65-4.54(M,1H),4.51-4.37(M,1H),4.19(d,1H),4.03(dd,1H),2.92(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺(化合物275)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-羥基-2,3-二氫-1H-茚-2-羧酸(VIci)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺。LCMS m/z實測值427.3[M+H]+;RT=7.21min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.67(s,1H),8.09(dd,1H),7.28-7.08(M,5H),5.93(s,1H),5.51(t,1H),4.56(d,1H),4.41(d,1H),4.02(d,1H),3.92(dd,1H),3.74(d,1H),3.45(d,1H),3.11-3.01(d,2H),3.03(s,3H).
5,6-二氟-2-羥基-2,3-二氫-1H-茚-2-羧酸(Vicj)
步驟i. 在0-20℃下,用48%在水中的氫氧化鈉(1.90mL,19.0mmol)和四丁基溴化銨(54mg,0.17mmol)分批處理甲苯(65mL)中的1,2-雙(溴甲基)-4,5-二氟-苯(1.00g,3.33mmol)和3-側氧丁酸乙基酯(0.45mL,0.46g,3.50mmol)。在室溫下將混合物攪拌4小時。用飽和氯化銨使反應猝滅,將層分離,並將有機溶液乾燥(硫酸鈉),過濾,並使揮發物蒸發。產物通過快速層析法(矽
膠,EtOAc/己烷0-75%)純化以提供2-乙醯基-5,6-二氟-2,3-二氫-1H-茚-2-羧酸乙基酯(530mg,59%產率)。LCMS m/z實測值269.25[M+H]+,RT=1.2min(方法B);1H NMR(400MHz,CDCl3)δ 7.01-6.92(M,2H),4.22(qd,2H),3.53-3.38(M,4H),2.23(d,3H),1.27(td,3H).
步驟ii. 在室溫下,用3-甲基過氧苯甲酸(3-methylbenzenecarboperoxoic acid)(苯甲酸中約70%,2g,9.88mmol)分批處理DCM(10mL)中的2-乙醯基-5,6-二氟-2,3-二氫-1H-茚-2-羧酸乙基酯(530mg,1.98mmol)和三氟甲磺酸(87.21μL,148mg,0.99mmol)。在45℃下將混合物攪拌16小時。將反應混合物冷卻至室溫,用10mL DCM稀釋,過濾,用30% NaHSO3溶液洗滌,然後用飽和NaHCO3溶液洗滌,乾燥(MgSO4),過濾並使溶劑蒸發。產物通過快速層析法(矽膠,EtOAc/己烷)分離以提供2-乙酸基-5,6-二氟-2,3-二氫-1H-茚-2-羧酸乙基酯(150mg,27%產率)。LCMS m/z實測值285.2[M+H]+,RT=1.27min(方法B);1H NMR(400MHz,CDCl3)δ 7.16-6.91(M,2H),4.22(qd,2H),3.64(dt,2H),3.28(d,2H),2.06(d,3H),1.32-1.20(M,3H).
步驟iii. 在室溫下,用水(0.5mL)中的氫氧化鋰(63mg,2.64mmol)處理2mL THF中的2-乙酸基-5,6-二氟-2,3-二氫-1H-茚-2-羧酸乙基酯(150mg,0.53mmol)16h。反應混合物用2N HCl酸化至pH約為2.5-3,並用乙酸乙酯萃取,乾燥(硫酸鎂),過濾並使溶劑蒸發。以最小量的乙酸乙酯和己烷(1:3,v/v)研磨產物,並在真空下使固體乾燥以提供5,6-二氟-2-羥基-2,3-二氫-1H-茚-2-羧酸(VIcj,78mg,69%產率)。1H NMR(400MHz,甲醇-d 4 )δ 7.10(t,2H),4.91(s,2H),3.50(dt,2H),3.02(d,2H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺(化合物276)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6-二氟-2-羥基-2,3-二氫-1H-茚-2-羧酸(VIcj)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺。LCMS m/z實測值463.3[M+H]+;RT=7.33min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.67(s,1H),8.09(dd,1H),7.25(ddd,2H),7.12(dd,1H),6.06(s,1H),5.49(d,1H),4.56(d,1H),4.46-4.36(M,1H),4.01(d,1H),3.91(dd,1H),3.71(d,1H),3.41(d,1H),3.07-2.98(d,2H),3.04(s,3H).
6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)
步驟i. 向4g(24.8mmol,1eq.)3-(二氟甲基)-4-氟苯胺在40mL DMSO(10vol)中的攪拌後的溶液加入3.74g(32.3mmol,1.3eq.)丙酮酸乙酯和1.5g(24.8mmol)AcOH以及1g活化的4Å分子篩。在氮氣氛下將反應混合物加熱至70℃ 2小時。接下來,在室溫下加入0.55g(2.48mmol,0.1eq.)Pd(OAc)2,並在氧氣球(1atm)下於70℃下將反應混合物攪拌16h。反應完成後,通過CELITE®墊過濾混合物並用冰-水(100mL)稀釋濾液,並用乙酸乙酯
(2 x 100mL)萃取。合併的有機層用冰-水洗滌,經無水Na2SO4乾燥並在減壓下濃縮。所獲得的材料通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的乙酸乙酯作為洗脫液進行純化以提供2.0g(7.78mmol,31%產率)6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸乙基酯。LCMS m/z實測值256.22[M-H]-,1H NMR(400MHz,DMSO-d 6)δ 12.31(s,1H),7.68(d,1H),7.61(d,1H),7.39-7.12(M,2H),4.39-4.34(M,2H),1.26(t,3H).
步驟ii. 在0℃下,向900mg(3.5mmol,1eq.)6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸乙基酯(步驟i中獲得的)在THF:水:MeOH(2:1:1)(9mL)的混合物中的攪拌後的溶液加入367mg(8.75mmol,2.5eq.)LiOH-H2O,並在室溫下將反應攪拌4小時。反應完成後,將揮發物從反應混合物中蒸發並用10% aq.KHSO4溶液將殘餘物酸化至pH約為2。所沉澱的固體通過過濾收集,用水洗滌並在真空下乾燥以提供600mg(2.62mmol,75%產率)6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)。LCMS:m/z實測值228.0[M-H]-,RT=2.64miN,(方法C);1H NMR(400MHz,DMSO-d 6 )δ 13.29(bs,1H),12.19(s,1H),7.67(d,1H),7.59(d,1H),7.39-7.12(M,2H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物212)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6-
(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值477.9[M+H]+;RT=4.41min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.17(s,1H),11.75(s,1H),8.12(dd,1H),7.70(d,1H),7.54(d,1H),7.48-7.37(M,1H),7.26(s,1H),7.01(d,1H),5.75(d,1H),4.64(d,1H),4.53-4.44(M,1H),4.19(d,1H),4.09-3.97(M,1H),3.16(s,3H).
((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(X)
步驟i. 用三乙胺(0.4mL,2.7mmol)處理(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,480
mg,1.8mmol)在5mL THF中的溶液,之後用二碳酸二第三丁酯(433mg,2.0mmol)處理。加入完成後,在室溫下於氮氣氛下將反應攪拌過夜。混合物用30mL DCM稀釋,用0.5M HCl(20mL)洗滌,然後用5% NaHCO3(20mL)、水(20mL)、和鹽水(20mL)洗滌,在硫酸鎂上乾燥,過濾,濃縮,並通過快速層析法(矽膠,13分鐘內EtOAc/己烷0-10%)純化產物。LCMS m/z實測值367.3[M+H]+,RT=0.92min(方法B);1H NMR(400MHz,CDCl3)δ 12.52(s,1H)*,12.45(s,1H),8.14(dd,1H),7.47(dd,1H),7.36(dd,1H)*,5.36-5.30(M,1H),5.07-5.02(M,1H)*,4.78(d,1H),4.58(dd,1H),4.28-4.17(M,1H),3.95(dt,1H),2.69(s,3H),1.52(s,6H)。註:"*"指示可觀察到的屬次要胺基甲酸酯旋轉異構物的信號。
步驟ii. 在45℃下,在氮氣下,將步驟i中獲得的N-甲基-N-[(1S)-8,9-二氟-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-1-基]胺基甲酸第三丁酯(633mg,1.73mmol)、碘甲烷(1.4mL,22.6mmol)、和碳酸銀(1.2g,4.3mmol)在氯仿(40mL)中攪拌16小時。使反應混合物冷卻至室溫,用DCM稀釋,並通過C.ELITE®過濾。在減壓下使溶劑蒸發,並通過快速層析法(矽膠,EtOAc/己烷0-30%)純化產物。[粗反應混合物中觀察到僅一種區域異構物(regioisomer),與O-甲基化一致。]LCMS m/z實測值381.3[M+H]+,RT=6.19min(方法A);1H NMR(400MHz,CDCl3)δ 7.99(dt,1H),7.56(ddd,1H),5.53-5.47(M,1H),5.25(s,1H)*,4.82(d,1H),4.66(d,1H),4.31-4.19(M,1H),4.08(s,3H),3.97(ddd,1H),2.65(d,3H),1.53(s,6H)。註:"*"指示可觀察到的屬次要胺基甲酸酯旋轉異構物的信號。
((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(Xia)
在80℃下,用1-溴吡咯啶-2,5-二酮(47mg,0.26mmol)和過氧化苯甲醯(3mg,0.01mmol)處理5mL四氯化碳中的((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(X,100mg,0.26mmol)1小時。將反應混合物過濾,並使溶劑蒸發。將殘餘物溶解於THF/水(1:1 v/v,12mL)中,並用1mL的1M NaOH溶液處理並在75℃下攪拌1小時。將反應混合物冷卻至室溫並用2M HCl處理,之後用飽和碳酸氫鈉處理達到pH約為6,並用EtOAc萃取。將有機萃取物經硫酸鈉乾燥,過濾並使溶劑蒸發。產物通過快速層析法(矽膠,EtOAc/己烷0-55%)分離以提供作為約7:1的內半縮醛異頭物(lactol anomers)混合物的((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(Xia)。LCMS m/z實測值397.3[M+H]+,RT=5.07min(主要異頭物)(方法A).1H NMR(400MHz,CDCl3)δ 7.99(dt,1H),7.63(ddd,1H),5.97(s,1H),5.48(d,1H),5.21(d,1H)*,4.61(td,1H),4.14(s,3H),4.11-3.99(M,1H),3.85(s,1H),2.58(s,3H),1.52(s,6H)。註:"*"指示可觀察到的屬次要胺基甲酸酯旋轉異構物的信號。
(S)-(8,9-二氟-6-甲氧基-4-側氧-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(Xib)
用氯鉻酸吡啶鹽(453mg,2.1mmol)處理10mL DCM
中的((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(X,200mg,0.53mmol),並在密封管內於55℃下將反應攪拌72小時。使反應混合物冷卻至室溫,用DCM稀釋並使其吸附在矽膠上。將溶劑蒸發並將殘餘物乾燥裝載到快速柱上,隨後將洗脫產物(Isco,矽膠,乙酸乙酯/己烷0-45%,11min)以提供(S)-(8,9-二氟-6-甲氧基-4-側氧-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(XIb,流程3)。LCMS m/z實測值395.2[M+H]+,RT=1.15min(方法B).1H NMR(400MHz,CDCl3)δ 8.11(dd,1H),7.97(dd,1H),5.98(d,1H),4.82(dd,1H),4.72(dd,1H),4.25(s,3H),2.68(s,3H),1.52(s,9H).
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物187)
步驟i. 在室溫下,用二烷中的4M氯化氫(3mL,12mmol)處理((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(Xia,83mg,0.21mmol)1小時。將水(1.3mL,71mmol)逐滴加入並使反應持續16小時。將揮發物蒸發,並將殘餘物與甲苯共沸,然後在高真空下乾燥1小時。LCMS m/z 283.1[M+H]+,RT=0.45min(次要異頭物:RT=0.50min)(方法B)。粗材料直接用於下一步驟而無需進一步純化。
步驟ii. 以與上文所述類似的方式,由步驟i的粗產物和5,6-二氟-1H-吲哚-2-羧酸(Vii)合成N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-
1H-吲哚-2-甲醯胺,作為約7:1的4-位差向異構物混合物。LCMS m/z實測值462.3[M+H]+,444.3[M-OH]+;RT=4.53min(次要);4.59min(主要)(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.90(s,1H),11.84(s,1H),11.60(s,1H)*,8.13(ddd,1H),7.67-7.56(M,1H),7.59-7.45(M,1H),7.37(dd,1H),7.27(d,1H),6.99-6.91(M,1H),5.80(M,1H)*,5.68(dd,2H),5.57(d,1H)*,4.47(dd,1H),4.11(d,1H)*,3.92(d,1H),3.09(d,3H)。註:"*"指示試驗性地指定為次要4-位內半縮醛差向異構物的信號。
(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物321)
以與上文所述類似的方式,由鏡像異構純(S)-(8,9-二氟-6-甲氧基-4-側氧-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(XIb)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值460.1[M+H]+,RT=4.32min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.96(s,1H),11.84(s,1H),8.28-8.19(M,1H),7.93(s,1H),7.62(td,1H),7.37(dd,1H),7.00(dt,1H),6.28(s,1H),5.01(d,1H),4.80(d,1H),3.14-3.08(M,3H).
(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯(化合物300)
將N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(15mg,0.03mmol)、2-甲基丙酸(6mg,0.07mmol)和N,N-二甲基吡啶-4-胺(2mg,0.02mmol)合併,並在0℃下於DCM(0.5mL)中攪拌。加入1-乙基-3-二甲胺基丙基碳二亞胺鹽酸鹽(19mg,0.1mmol)並使反應混合物溫熱至室溫並攪拌16小時。反應混合物用10mL DCM稀釋並用5% NaHCO3(10mL)洗滌,然後用鹽水(10mL)洗滌,經硫酸鈉乾燥,過濾並使溶劑蒸發。通過快速層析法(矽膠,15-100% EtOAc/己烷)分離產物以提供(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯(12.8mg,74%產率)。LCMS m/z實測值532.1[M+H]+,444.3[M-iPrCO2]+,RT=8.10min(主要);8.16min(次要),主要/次要=7:1(方法A);1H NMR(400MHz,CDCl3)δ 11.92(s,1H),11.66(s,1H)*,10.00(d,1H),8.23(dt,1H),7.54(dd,1H),7.46(dd,1H)*,7.38(dd,1H),7.34-7.24(M,1H),6.90(s,1H),6.86(d,1H),6.79(d,1H)*,6.12(t,1H)*,5.99(d,1H),4.53(dd,1H),4.35(dd,1H)*,4.28-4.17(M,1H),3.27(d,3H),2.84-2.74(h,1H)*,2.67(h,1H),1.30-1.25(M,6H)*,1.23(dd,6H)。註:"*"指示可觀察到的指定為次要C-4差向異構物的次要異構物的信號。
(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯(化合物331)
以與上文所述類似的方式,由N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(187)和2-乙基丁酸合成(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯。LCMS m/z實測值560.2[M+H]+,444.1[M-(3-Pent)CO2]+,RT=5.66min(主要,>95%)(方法A);1H NMR(400MHz,CDCl3)δ 11.40(s,1H),9.95(s,1H),8.24(dd,1H),7.52(dd,1H),7.38(dd,1H),7.33-7.24(M,1H),6.93(s,1H),6.88-6.82(M,1H),5.98(d,1H),4.55(dd,1H),4.25(d,1H),3.26(s,3H),2.34(tt,1H),1.80-1.46(M,4H),0.91(ddd,6H).
N-((1S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物320)
在無水甲醇(1mL)中攪拌N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(15mg,0.03mmol)和4-甲基苯磺酸(6mg,0.03mmol)1周。使溶劑蒸發,並將殘餘物直接裝載到快速色譜柱上。通過快速層析法(矽膠,0-100% EtOAc/己烷)分離產物。LCMS m/z實測值476.2[M+H]+,RT=4.54min(方法A);1H NMR(400MHz,
CDCl3)δ 11.10(s,1H),9.63(d,1H),8.28-8.14(M,1H),7.51(dd,1H),7.38(dt,1H),7.31-7.20(M,1H),6.86(d,1H),5.89(d,1H),5.45(s,1H),4.48(dd,1H),4.17-4.06(M,1H),3.66(s,3H),3.27(s,3H).
5,6-二氟-N-甲基-N-((1S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺(化合物411)
用N,N-二乙基-1,1,1-三氟-14-磺胺(DAST,17mg,0.1mmol)處理0℃下N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(24mg,0.05mmol)在DCM(0.5mL)中的攪拌後的懸浮液,然後使反應溫熱至室溫並再攪拌1小時。反應混合物用20mL DCM稀釋,用10mL的5%碳酸氫鈉溶液洗滌,然後用10mL鹽水洗滌。在硫酸鎂上將有機溶液乾燥,過濾,並在減壓下使溶劑蒸發。通過快速層析法(ISCO,矽膠,EtOAc/己烷0-75%)分離產物以提供作為約7:1的4-位差向異構物混合物的5,6-二氟-N-甲基-N-((1S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺(8mg,33%產率)。LCMS m/z實測值464.3[M+H]+,RT(主要)=4.50min(方法A).1H NMR(主要,400MHz,CDCl3)δ 11.51(s,1H),9.95(s,1H),8.37-8.27(M,1H),7.57(dd,1H),7.38(dd,1H),7.30(dd,1H),6.88(s,1H),6.34(d,1H),6.02(s,1H),4.61(d,1H),4.43-4.27(M,1H),3.26(s,3H).
步驟i:在110℃下,於氮氣氛下將3.0g(10.56mmol,1.0eq.)4-氟-2-溴苯甲酸(IIIc)、2.7g(12.68,1.2eq.)3,5-二側氧哌啶-1-羧酸第三丁酯(IIb)、5.8g(42.2mmol,4.0eq.)碳酸鉀、0.25g(2.11mmol,0.2eq.)L-脯胺酸和0.2g(1.05mmol,0.1eq.)碘化亞銅在15mL乾燥的DMSO中的混合物攪拌16小時(註:以3 x 3g的規模平行地執行反應)。一冷卻至室溫,就將三個重複的反應混合物合併,並用冷水(100mL)稀釋。然後用飽和檸檬酸溶液(100mL)將混合物酸化。將所得懸浮液過濾,並用乙酸乙酯(3 x 200mL)萃取濾液。合併的有機層用鹽水(100mL)洗滌,經無水硫酸鈉乾燥,過濾並在減壓下濃縮以提供12.2g 8-氟-1,6-二側氧-1,2,4,6-四氫-3H-異色烯并[3,4-c]吡啶-3-羧酸第三丁酯與2-(1-(第三丁氧基羰基)-5-羥基-3-側氧-1,2,3,6-四氫吡啶-4-基)-4-氟苯甲酸的混合物,取該化合物到下一步驟中而無需純化。
步驟ii:向密封管中6g的以上製備的8-氟-1,6-二側氧-1,2,4,6-四氫-3H-異色烯并[3,4-c]吡啶-3-羧酸第三丁酯與2-(1-(第三丁氧基羰基)-5-羥基-3-側氧-1,2,3,6-四氫吡啶-4-基)-4-氟苯甲酸的粗混合物在30mL 1,2-二氯乙烷中的混合物加入3.4g(4.54mmol,2.5eq.)醋酸銨,並在120℃下將混合物加熱16小時。(註:以2 x 6g的規模平行地執行反應)。一冷卻至室溫,就將兩個重複的反應混合物合併,傾倒在冰冷的水(200mL)中,並且用乙酸乙酯(2 x 25mL)萃取。合併的有機萃取物用鹽水(50mL)洗滌,經無水硫酸鈉乾燥,過濾並在減壓下濃縮。所得粗產物與丙酮(50mL)研磨以提供作為棕色固體的3.8g(經兩個步驟1.14mmol,28%)8-氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVc)。LCMS:m/z實測值331.47[M-H]-;1H NMR(400MHz,DMSO-d 6 ):δ 12.45
(br s,1H),9.03-8.97(M,1H),8.12(dd,1H),7.9(dd,1H),4.71(br s,2H),4.18(br s,2H),1.42(s,9H).
向密封管中在室溫下、氮氣氛下的2.0g(6.02mmol,1.0eq.)8-氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVc)在10mL THF中的攪拌後的溶液加入THF中的3.6mL(7.2mmol,1.2eq.)2M甲胺溶液,之後加入10mL(5 vol)異丙醇鈦並在70℃下將反應混合物加熱3小時。將混合物使冷卻至室溫並進一步冷卻至0℃,並用甲醇(2mL)稀釋。在0℃下,向此混合物分批加入0.69mg(18.64mmol,3.0eq.)NaBH4並在室溫下使反應持續2小時。然後用飽和鹽水(15mL)和10%在DCM(200mL)中的MeOH稀釋混合物。攪拌30分鐘後,將非均質的混合物過濾並用10%在DCM(50mL)中的MeOH洗滌。濾液經無水硫酸鈉乾燥並在減壓下濃縮。所得粗產物與正戊烷(50mL)研磨,所沉澱的固體通過過濾收集並在真空下乾燥以提供1.3g 8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)。LCMS:m/z實測值348.32[M+H]+.
步驟i:向室溫下0.15g(0.93mmol,1.0eq.)1H-吲哚-2-羧酸(VIa)在6mL DMF中的攪拌後的溶液加入0.45mL(2.89mmol,3.0eq.)DIPEA、0.49g(1.29mmol,1.eq.)HATU,並將混合物攪拌10分鐘。向此混合物加入0.3g(0.86mmol,1.0eq.)8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)並在室溫下將所得反應混合物攪拌16小時。然後用冷水(20mL)稀釋反應混合物並再攪拌30分鐘。所得固體通過過濾收集並用水洗滌(10mL)以提供0.3g(0.61mmol,70%)8-氟-1-(N-甲基-1H-吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。LCMS:m/z實測值489.51[M+H]+.
步驟ii:隨後通過手性製備SFC分離8-氟-1-(N-甲基-1H-吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯的對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OJ(21 x 250mm),5μ,流速:70g/min。
步驟iii:以與上文關於化合物3和4(步驟ii)所述類似的方式,將如上文所述分離的8-氟-1-(N-甲基-1H-吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯的每一種單獨的對映異構物轉化為終產物並通過製備反相hplc進行純化:柱/尺寸:X-Bridge C18(19 x 150mm)5μm,流動相A:水中的10mM碳酸氫銨;流動相B:乙腈,梯度,流速:15ml/min。
對映異構物I(化合物77):LCMS:m/z實測值391.2[M+H]+,RT=3.31miN,(方法A);1H NMR(400MHz,DMSO-d6 δ 11.80(s,2H),11.55(s,1H),7.89(M,1H),7.60(M,2H),7.46
(M,2H),7.20(M,1H),7.03(M,1H),6.86(s,1H),5.69(br s,1H),3.80(d,1H),3.67(d,1H),3.17(M,2H),3.14(s,3H);手性分析SFC:RT=6.04miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物78):LCMS:m/z實測值391.2[M+H]+,RT=3.31miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.80(s,2H),11.55(s,1H),7.89(M,1H),7.60(M,2H),7.46(M,2H),7.20(M,1H),7.03(M,1H),6.86(s,1H),5.69(br s,1H),3.80(d,1H),3.67(d,1H),3.17(M,2H),3.14(s,3H);手性分析SFC:RT=8.05miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文(關於化合物77、78)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-溴-3,5-二氟苯甲酸(VIcp)製備4-溴-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物170):LCMS:m/z實測值466.1[M+H]+,RT=4.86miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(M,1H),7.75-7.70(M,1H),7.53-7.49(M,1H),7.38-7.36(d,2H),5.56(s,1H),3.75(d,1H),3.63
(d,1H),3.32-3.25(M,1H),3.12-3.08(M,1H),2.76-2.71(M,1H),2.66(s,3H);手性分析SFC:RT=3.75miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物171):LCMS:m/z實測值466.1[M+H]+,RT=4.86miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(M,1H),7.75-7.70(M,1H),7.53-7.49(M,1H),7.38-7.36(d,2H),5.56(s,1H),3.75(d,1H),3.63(d,1H),3.32-3.25(M,1H),3.12-3.08(M,1H),2.76-2.71(M,1H),2.66(s,3H);手性分析SFC:RT=4.74miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物77、78)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-氯-3,5-二氟苯甲酸(VIcq)製備4-氯-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物176):LCMS:m/z實測值422.2[M+H]+,RT=3.67miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(dd,1H),7.75-7.70(M,1H),7.53-
7.49(M,1H),7.43(d,2H),5.56(s,1H),3.75(d,1H),3.63(d,1H),3.26(s,1H),3.12-3.08(M,1H),2.67(M,4H);手性分析SFC:RT=3.11miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物177):LCMS:m/z實測值422.2[M+H]+,RT=3.67miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(dd,1H),7.75-7.70(M,1H),7.53-7.49(M,1H),7.43(d,2H),5.56(s,1H),3.75(d,1H),3.63(d,1H),3.26(s,1H),3.12-3.08(M,1H),2.67(M,4H);手性分析SFC:RT=3.84miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物77、78)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-(二氟甲基)-3,5-二氟苯甲酸(VIcr)製備4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物185):LCMS:m/z實測值438.3[M+H]+,RT=6.40miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(dd,1H),7.76-7.67(M,1H),7.59-7.49(M,1H),7.45-7.19(M,3H),5.56(br s,1H),3.75(d,1H),
3.64(d,1H),3.27(M,1H),3.10(M,1H),2.75(M,1H),2.66(s,3H);手性分析SFC:RT=2.03miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物186):LCMS:m/z實測值438.3[M+H]+,RT=6.40miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),7.89-7.86(dd,1H),7.76-7.67(M,1H),7.59-7.49(M,1H),7.45-7.19(M,3H),5.56(br s,1H),3.75(d,1H),3.64(d,1H),3.27(M,1H),3.10(M,1H),2.75(M,1H),2.66(s,3H);手性分析SFC:RT=2.54miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物77、78)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-(二氟甲基)-1H-吲哚-2-羧酸(VIcs)製備N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物,除了關於最終的去保護步驟,所分離的中間體1-(4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺基)-8-氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯的異構物是在0℃下用DCM中的TFA(5.0eq.)代替TMSOTf處理的。
對映異構物I(化合物209):LCMS:m/z實測值441.3[M+H]+,RT=4.51miN,(方法A);1H NMR(400MHz,DMSO-
d6)δ 12.04(bs,1H),11.56(bs,1H),7.99-7.88(d,1H),7.64-7.60(M,2H),7.48-7.27(M,4H),6.96(s,1H),5.69(s,1H),3.82(d,1H),3.69(d,1H),3.32-3.12(M,6H);手性分析SFC:RT=2.90miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物210):LCMS:m/z實測值441.3[M+H]+,RT=4.51miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.04(bs,1H),11.56(bs,1H),7.99-7.88(d,1H),7.64-7.60(M,2H),7.48-7.27(M,4H),6.96(s,1H),5.69(s,1H),3.82(d,1H),3.69(d,1H),3.32-3.12(M,6H);手性分析SFC:RT=4.42miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物209、210)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)製備4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物259):LCMS:m/z實測值459.4[M+H]+,RT=6.19miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.12(bs,1H),11.60(bs,1H),7.9(d,1H),7.62(t,1H),7.46-
7.18(M,4H),6.99(s,1H),5.68(s,1H),3.80(d,1H),3.66(d,1H),3.16-3.13(M,4H),2.91-2.76(M,2H);手性分析SFC:RT=1.22miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物260):LCMS:m/z實測值459.4[M+H]+,RT=6.19miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.12(bs,1H),11.60(bs,1H),7.9(d,1H),7.62(t,1H),7.46-7.18(M,4H),6.99(s,1H),5.68(s,1H),3.80(d,1H),3.66(d,1H),3.16-3.13(M,4H),2.91-2.76(M,2H);手性分析SFC:RT=1.65miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物209、210)所述類似的方式,由外消旋8-氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vc)和4-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIcw)製備4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物271):LCMS:m/z實測值459.3[M+H]+,RT=6.78miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.15(bs,1H),11.57(bs,1H),7.90-7.87(M,1H),7.65-7.31(M,4H),7.21-7.16(M,1H),6.95(d,1H),5.67(s,1H),3.82-3.64
(M,2H),3.24-2.84(M,6H);手性分析SFC:RT=1.86miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物272):LCMS:m/z實測值459.3[M+H]+,RT=6.78miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.15(bs,1H),11.57(bs,1H),7.90-7.87(M,1H),7.65-7.31(M,4H),7.21-7.16(M,1H),6.95(d,1H),5.67(s,1H),3.82-3.64(M,2H),3.24-2.84(M,6H);手性分析SFC:RT=3.24miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
步驟i:向0℃下2.0g(6.024mmol,1.0eq.)8-氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVc)在20mL DCM中的攪拌後的溶液加入1.6mL(9.03mmol,1.5eq.)三氟甲基磺酸三甲基矽酯,並在室溫下將所得反應混合物攪拌1小時。在減壓下去除揮發物並與飽和碳酸氫鈉溶液(20mL)研磨殘餘物。固體通過過濾收集並在真空下乾燥以提供作為棕色固體的1.3g(5.85mmol,93%)8-氟-3,4-二氫苯并[c][1,7]啶-1,6-(2H,5H)-二酮。LCMS:m/z實測值233.36[M-H]-.
步驟ii:向1.75g(7.54mmol,1.0eq.)8-氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮在17.5mL甲醇中的攪拌後的溶液加入1.96g(11.31,1.5eq.)2-((第三丁基二甲基甲矽烷基)氧基)乙醛、0.87mL醋酸和0.95g(15.08mmol,2.0eq.)氰基硼氫化鈉,
並在室溫下將所得反應混合物攪拌16小時。然後將反應混合物濃縮,並將殘餘物用水(50mL)稀釋和攪拌30分鐘。所沉澱的固體通過過濾收集並在真空下乾燥以提供1.3g(3.3mmol,45%)3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8-氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVd)。LCMS:m/z實測值391.17[M+H]-.
通過與上文關於Vc所述程序類似的程序,由甲胺和3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8-氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVd)製備3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8-氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。LCMS:m/z實測值406.5[M-H]-.
步驟i:通過與上文所述程序類似的程序,將1H-吲哚-2-羧酸(VIa)和3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8-氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Vd)轉化為N-(8-氟-3-(2-(羥基-t)乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS:m/z實測值423.51[M+H]+.
步驟ii:向0℃下0.35g(0.63mmol,1.0eq.)N-(8-氟-3-(2-(羥基-t)乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺在7mL THF中的攪拌後的溶液加入0.95mL(0.95mmol,1.5eq.)TBAF,並在室溫下將反應混合物攪拌2小時。然後用MeOH(1mL)使反應猝滅,然後在減壓下將揮發物蒸發。殘餘物用水(20mL)稀釋並用乙酸乙酯(2 x 30mL)萃取。合併的有機層用鹽水(20mL)洗滌,經硫酸鈉乾燥,並被濃縮以提供作為灰白色固體的0.24g(0.40mmol 85%)N-(8-氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺,其進一步通過反相HPLC純化。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:DCPAK P4VP(21 x 250mm),5μm,流速:70g/min。
對映異構物I(化合物79):LCMS:m/z實測值435.3[M+H]+,RT=3.29miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.66(M,2H),7.90-7.80(M,1H),7.60-7.50(M,2H),7.46-7.40(M,2H)7.21(t,1H),7.05(M,1H),6.85(s,1H),5.83(s,1H),4.53(s,1H),3.88(d,1H),3.53-3.58(M,2H),3.15(s,3H),3.02(d,2H),2.83(M,1H),2.67(M,2H);手性分析SFC:RT=4.08miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物80):LCMS:m/z實測值435.2[M+H]+,RT=3.29miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.66(M,2H),7.90-7.80(M,1H),7.60-7.50(M,2H),7.46-7.40(M,2H)7.21(t,1H),7.05(M,1H),6.85(s,1H),5.83(s,1H),4.53(s,1H),3.88(d,1H),3.53-3.58(M,2H),3.15(s,3H),3.02(d,2H),2.83(M,1H),2.67(M,2H);手性分析SFC:RT=6.49miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
向1.0g(4.31mmol,1.0eq.)8,9-二氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(如上文關於IVd,步驟i所述獲得的)在10mL甲醇中的攪拌後的溶液加入5mL 37%甲醛水溶液和0.54g(8.62mmol,2.0eq.)氰基硼氫化鈉,並在室溫下將所得混合物攪拌16小時。然後用水(150mL)將混合物稀釋並用乙酸乙酯(3 x 150mL)萃取。合併的有機萃取物經無水硫酸鈉乾燥並在減壓下濃縮以提供粗0.75g(3.17mmol,78%)8-氟-3-甲基-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVe)。LCMS:m/z實測值247.19[M+H]+.
以與上文關於Vd所述類似的方式,由8-氟-3-甲基-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVe)和甲胺合成外消旋8-氟-3-甲基-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。LCMS:m/z實測值262.29[M+H]+.
以與上文所述類似的方式,由外消旋8-氟-3-甲基-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Ve)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8-氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物60):LCMS:m/z實測值405.2[M+H]+,RT=2.99miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.66(br s,2H),7.90-7.87(M,1H)7.63-7.57(M,2H),7.47-7.42(M,2H),7.20(t,1H),7.07(t,1H),6.85(s,1H),5.82(s,1H),3.72(d,1H),3.14-3.01(M,5H),2.73-2.69(M,1H),2.35(s,3H);手性分析SFC:RT=3.59miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的(0.5%在MeOH中的DEA),流速:3.0g/min.
對映異構物II(化合物61):LCMS:m/z實測值405.2[M+H]+,RT=2.99miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.66(br s,2H),7.90-7.87(M,1H)7.63-7.57(M,2H),7.47-7.42(M,2H),7.20(t,1H),7.07(t,1H),6.85(s,1H),5.82(s,1H),3.72(d,1H),3.14-3.01(M,5H),2.73-2.69(M,1H),2.35(s,3H);手性分析SFC:RT=5.71miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的(0.5%在MeOH中的DEA),流速:3.0g/min.
向0.5g(2.16mmol,3.0eq.)氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(如上文關於IVd,步驟i所述獲得的)在5mL二氯甲烷中的攪拌後的溶液加入0.6mL(4.31mmol,2.0eq.)三乙胺和0.20mL(2.16mmol,1.0eq.)乙酸酐,並在室溫下將混合物攪拌4小時。將反應混合物濃縮,並用水(20mL)洗滌以提供作為淺黃色固體的0.4g 3-乙醯基-8-氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVf)。LCMS:m/z實測值275.25[M+H]+;1H NMR(400MHz,DMSO-d 6 ):δ 9.13-9.09(M,1H),7.89-7.86(M,1H),7.73-7.68(M,1H),4.80-479(d,2H),4.34-4.28(M,2H),2.13-2.10(M,3H).
以與上文關於Vd所述類似的方式,由3-乙醯基-8-氟-3,4-二氫苯并[c][1,7]啶-1,6(2H,5H)-二酮(IVf)和甲胺合成外消旋3-乙醯基-8-氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。LCMS:m/z實測值288.4[M-H]+.
以與上文所述類似的方式,由外消旋3-乙醯基-8-氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Vf)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(3-乙醯基-8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-45:65。管柱:Chiralpak IC(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物68):LCMS:m/z實測值433.2[M+H]+,RT=3.95miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.70(br s,2H),7.92-7.89(M,1H),7.65-7.59(M,2H),7.46-7.48(M,2H),7.20-7.23(M,1H),7.04-7.06(M,1H),6.86-6.95(M,1H),5.87-5.90(M,1H),5.02-4.18(M,4H),2.91(s,3H),2.08(s,3H);手性分析SFC:RT=5.88miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
對映異構物II(化合物69):LCMS:m/z實測值433.2[M+H]+,RT=3.95miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.70(br s,2H),7.92-7.89(M,1H),7.65-7.59(M,2H),7.46-7.48(M,2H),7.20-7.23(M,1H),7.04-7.06(M,1H),6.86-6.95(M,1H),5.87-5.90(M,1H),5.02-4.18(M,4H),2.91(s,3H),2.08(s,3H);手性分析SFC:RT=9.81miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
以與上文關於IVc所述類似的方式,由3,5-二側氧哌啶-1-羧酸第三丁酯(IIb)和4,5-二氟-2-碘-苯甲酸(IIIb)合成8,9-二氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。1H NMR(400MHz,DMSO-d6):δ 12.45(br s,1H),9.03-8.97(M,1H),8.12(dd,1H),4.71(br s,2H),4.18(br s,2H),1.42(s,9H).
以與上文關於Vc所述類似的方式,由8,9-二氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVg)和甲胺合成外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。LCMS:m/z實測值366.3[M+H]+.
通過上述關於Vd所述程序類似的程序,由8,9-二氟-1,6-
二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVg)、2-((第三丁基二甲基甲矽烷基)氧基)乙醛、和甲胺製備外消旋3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。LCMS:m/z實測值422.5[M-H]-.
以與上文關於Ve所述類似的方式,由8,9-二氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVg)、甲醛、和甲胺合成外消旋8,9-二氟-3-甲基-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。
以與上文關於Vf所述類似的方式,由8,9-二氟-1,6-二側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(IVg)、乙酸酐、和甲胺合成外消旋3-乙醯基-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮。LCMS:m/z實測值308.29[M-H]+.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在甲醇中的7M甲醇銨):CO2-40:60。管柱:Chiralcel-ODH(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物54):LCMS:m/z實測值409.2[M+H]+,RT=3.17miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.70(br s,2H),8.10(M,1H),7.66(d,1H),7.47(d,1H),7.29(M,1H),7.21(t,1H),6.84(s,1H),5.96(br s,1H),3.80(d,1H),3.66(d,1H),3.40(M,2H),3.16(s,3H),2.98(M,2H);手性分析SFC:RT=2.57miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物55):LCMS:m/z實測值409.2[M+H]+,RT=3.17miN,(方法A);1H NMR(400MHz,DMSO-d6 δ 11.70(br s,2H),8.10(M,1H),7.66(d,1H),7.47(d,1H),7.29(M,1H),7.21(t,1H),6.84(s,1H),5.96(br s,1H),3.80(d,1H),3.66(d,1H),3.40(M,2H),3.16(s,3H),2.98(M,2H);手性分析SFC:RT=3.77miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-氟-1H-吲哚-2-羧酸(VId)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(甲醇:乙腈(1:1)):CO2-40:60。管柱:Chiralcel-OX-H(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物101):LCMS:m/z實測值427.2[M+H]+,RT=4.46miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,2H),8.12-8.06(M,1H),7.48-7.44(M,1H),7.36-7.24(M,2H),7.09-7.05(M,1H),6.88(s,1H),5.67(s,1H),3.78(d,1H),3.63(d,1H),3.17(s,3H),3.17-3.27(M,3H);手性分析SFC:RT=3.14miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物102):LCMS:m/z實測值427.2[M+H]+,RT=4.46miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,2H),8.12-8.06(M,1H),7.48-7.44(M,1H),7.36-7.24(M,2H),7.09-7.05(M,1H),6.88(s,1H),5.67(s,1H),3.78(d,1H),3.63(d,1H),3.17(s,3H),3.17-3.27(M,3H);手性分析SFC:RT=5.01miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-氟-1H-吲哚-2-羧酸(VIc)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-40:60。管柱:Chiralcel-OX-H(30 x 250mm),5μm,流速:70g/min。
對映異構物I(化合物105):LCMS:m/z實測值427.2[M+H]+,RT=4.73miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.04(brs,1H),11.64(brs,1H);8.13-8.06(M,1H),7.31-7.25(M,2H),7.21-7.16(M,1H),6.94(s,1H),6.84-6.80(M,1H),5.67(s,1H),3.79(d,1H),3.63(d,1H),3.16-2.77(M,6H);手性分析SFC:RT=3.26miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物106):LCMS:m/z實測值427.2[M+H]+,RT=4.73miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.04(brs,1H),11.64(brs,1H);8.13-8.06(M,1H),7.31-7.25(M,2H),7.21-7.16(M,1H),6.94(s,1H),6.84-6.80(M,1H),5.67(s,1H),3.79(d,1H),3.63(d,1H),3.16-2.77(M,6H);手性分析SFC:RT=5.66miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0
g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-氟-1H-吲哚-2-羧酸(VIe)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-40:60。管柱:Chiralcel-OX-H(30 x 250mm),5μm,流速:70g/min。
對映異構物I(化合物107):LCMS:m/z實測值427.2[M+H]+,RT=4.74miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.8(brs,2H),8.12-8.08(M,1H),7.64-7.61(M,1H),7.30-7.25(M,1H),7.16(d,1H),6.94-6.90(M,2H),5.68(s,1H),3.78(d,1H),3.63(d,1H),3.15-2.75(M,6H);手性分析SFC:RT=3.72miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物108):LCMS:m/z實測值427.2[M+H]+,RT=4.74miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.8(brs,2H),8.12-8.08(M,1H),7.64-7.61(M,1H),7.30-7.25(M,1H),7.16(d,1H),6.94-6.90(M,2H),5.68(s,1H),3.78(d,1H),3.63(d,1H),3.15-2.75(M,6H);手性分析SFC:RT=5.55miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在
ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和7-氟-1H-吲哚-2-羧酸(VIf)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-30:70。管柱:Chiralcel-OJ-3(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物113):LCMS:m/z實測值427.2[M+H]+,RT=4.81miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(brs,1H),11.62(br s,1H),8.13-8.09(M,1H),7.42(d,1H),7.31-7.26(M,1H),7.05-7.0(M,2H),6.92(d,1H),5.64(s,1H),3.78(d,1H),3.63(d,1H),3.31-2.77(M,6H);手性分析SFC:RT=1.46miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物114):LCMS:m/z實測值427.2[M+H]+,RT=4.81miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(brs,1H),11.62(br s,1H),8.13-8.09(M,1H),7.42(d,1H),7.31-7.26(M,1H),7.05-7.0(M,2H),6.92(d,1H),5.64(s,1H),3.78(d,1H),3.63(d,1H),3.31-2.77(M,6H);手性分析SFC:RT=2.11miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%
的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-40:60。柱Chiralcel-OX-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物115):LCMS:m/z實測值445.2[M+H]+,RT=4.89miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,2H),8.12-8.08(M,1H),7.63-7.58(M,1H),7.40-7.35(M,1H),7.29-7.25(M,1H),6.92(s,1H),5.66(s,1H),3.82(d,1H),3.63(d,1H),3.16-2.66(M,6H);手性分析SFC:RT=3.21miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物116):LCMS:m/z實測值445.2[M+H]+,RT=4.89miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,2H),8.12-8.08(M,1H),7.63-7.58(M,1H),7.40-7.35(M,1H),7.29-7.25(M,1H),6.92(s,1H),5.66(s,1H),3.82(d,1H),3.63(d,1H),3.16-2.66(M,6H);手性分析SFC:RT=5.14miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,40%的(0.2%在
ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4,6-二氟-1H-吲哚-2-羧酸(VIg)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-40:60。柱Chiralcel-OX-H(30 x 250mm),5μm,流速:70g/min。
對映異構物I(化合物117):LCMS:m/z實測值445.2[M+H]+,RT=4.93miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.12(brs,2H);8.13-8.08(M,1H),7.29-7.24(t,1H),7.61(d,1H),6.97(s,1H),6.92-6.87(M,1H),5.68(s,1H),3.78(d,1H),3.63(d,1H),3.15-2.76(M,6H);手性分析SFC:RT=2.92miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物118):LCMS:m/z實測值445.2[M+H]+,RT=4.93miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.12(brs,2H);8.13-8.08(M,1H),7.29-7.24(t,1H),7.61(d,1H),6.97(s,1H),6.92-6.87(M,1H),5.68(s,1H),3.78(d,1H),3.63(d,1H),3.15-2.76(M,6H);手性分析SFC:RT=4.74miN,
管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4,5-二氟-1H-吲哚-2-羧酸(VIh)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-40:60。柱Chiralcel-OX-H(30 x 250mm)5μm,流速:70g/min。
對映異構物I(化合物119):LCMS:m/z實測值445.2[M+H]+,RT=4.89miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(brs,1H);11.6(brs,1H),8.13-8.05(M,1H),7.29-7.21(M,3H),7.01(s,1H),5.66(s,1H),3.78(d,1H),3.63(d,1H),3.15-2.76(M,6H);手性分析SFC:RT=2.83miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物120):LCMS:m/z實測值445.2[M+H]+,RT=4.89miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.1(brs,1H);11.6(brs,1H),8.13-8.05(M,1H),7.29-7.21(M,3H),7.01(s,1H),5.66(s,1H),3.78(d,1H),3.63(d,1H),
3.15-2.76(M,6H);手性分析SFC:RT=4.68miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-氯吲哚-2-羧酸(VIbh)合成外消旋6-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在ACN:MeOH(1:1)中的7M甲醇銨):CO2-50:50。柱Chiralcel-OX-H(30 x 250mm),5μ,流速:120g/min。
對映異構物I(化合物121):LCMS:m/z實測值443.2/445.2[M+H]+,RT=4.78miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.5(brs,1H),8.52(s,1H),8.13-8.03(M,1H),7.90(s,1H),7.48(d,1H),7.31-7.26(M,1H),6.78-6.72(M,2H),5.63(s,1H),3.75(d,1H),3.61(d,1H),3.14(s,2H),2.99(s,3H),2.75(s,1H);手性分析SFC:RT=3.55miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,50%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
對映異構物II(化合物122):LCMS:m/z實測值443.2/445.2[M+H]+,RT=4.78miN,(方法A);1H NMR(400MHz,
DMSO-d6)δ 11.5(brs,1H),8.52(s,1H),8.13-8.03(M,1H),7.90(s,1H),7.48(d,1H),7.31-7.26(M,1H),6.78-6.72(M,2H),5.63(s,1H),3.75(d,1H),3.61(d,1H),3.14(s,2H),2.99(s,3H),2.75(s,1H);手性分析SFC:RT=5.04miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,50%的(0.2%在ACN:MeOH(1:1)中的7M甲醇銨),流速:3.0g/min.
步驟i:以與上文(化合物77、78)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和8-氟吲哚-2-羧酸(Vim)合成外消旋8,9-二氟-1-(8-氟-N-甲基吲哚-2-甲醯胺基)-6-側氧-1,2,5,6-四氫苯并[c][1,7]啶-3(4H)-羧酸第三丁酯。
步驟ii:隨後通過手性製備SFC分離8,9-二氟-1-(8-氟-N-甲基吲哚-2-甲醯胺基)-6-側氧-1,2,5,6-四氫苯并[c][1,7]啶-3(4H)-羧酸第三丁酯的對映異構物:等度法,流動相甲醇:CO2-30:70,柱:Chiralcel OX-H(30 x 250mm),5μm,流速:100g/min。
步驟iii:以與上文關於化合物3和4(步驟ii)所述類似的方式,將如上文所述分離的8,9-二氟-1-(8-氟-N-甲基吲哚-2-甲醯胺基)-6-側氧-1,2,5,6-四氫苯并[c][1,7]啶-3(4H)-羧酸第三丁酯的每一種單獨的對映異構物轉化為終產物並通過SFC純化:等度法,流動相甲醇:CO2-40:60,柱:DCPAK-P4VP(21 x 250mm),5μm,流速:65g/min。
對映異構物I(化合物160):LCMS:m/z實測值427.3[M+H]+,RT=3.93miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.15-8.06(M,3H),7.32-7.27(M,1H),6.75(s,1H),6.65-6.61(M,2H),5.62(br s,1H),3.80-3.62(M,2H),3.15-3.11(M,2H),3.02(s,3H),2.80-2.76(M,1H);手性分析SFC:RT=3.32miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,15%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物161):LCMS:m/z實測值427.3[M+H]+,RT=3.93miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.15-8.06(M,3H),7.32-7.27(M,1H),6.75(s,1H),6.65-6.61(M,2H),5.62(br s,1H),3.80-3.62(M,2H),3.15-3.11(M,2H),3.02(s,3H),2.80-2.76(M,1H);手性分析SFC:RT=4.30miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,15%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和7-氟吲哚-2-羧酸(VIco)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物162):LCMS:m/z實測值427.3[M+H]+,RT=3.87miN,(方法A);1H NMR(400MHz,DMSO-
d6)δ 11.61(s,1H),8.31(t,1H),8.10(t,1H),7.87(s,1H),7.31-7.21(M,2H),6.67(t,1H),6.56(s,1H)5.62(s,1H),3.77(d,1H),3.63(d,1H),3.28-3.20(M,2H),2.98(s,3H),2.74(br s,1H);手性分析SFC:RT=5.80miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物163):LCMS:m/z實測值427.3[M+H]+,RT=3.87miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.31(t,1H),8.10(t,1H),7.87(s,1H),7.31-7.21(M,2H),6.67(t,1H),6.56(s,1H)5.62(s,1H),3.77(d,1H),3.63(d,1H),3.28-3.20(M,2H),2.98(s,3H),2.74(br s,1H);手性分析SFC:RT=6.97miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-溴-3,5-二氟苯甲酸(VIcp)製備4-溴-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物164):LCMS:m/z實測值484.2[M+H]+,RT=4.67miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.10(t,1H),7.36-7.29(M,3H),5.52-4.49(br
s,1H),3.76(d,1H),3.62(d,1H),3.31-3.26(M,1H),3.12-3.08(M,1H),2.78-2.72(M,1H),2.71(s,3H);手性分析SFC:RT=3.15miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物165):LCMS:m/z實測值484.2[M+H]+,RT=4.67miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.10(t,1H),7.36-7.29(M,3H),5.52-4.49(br s,1H),3.76(d,1H),3.62(d,1H),3.31-3.26(M,1H),3.12-3.08(M,1H),2.78-2.72(M,1H),2.71(s,3H);手性分析SFC:RT=3.76miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-氯-3,5-二氟苯甲酸(VIcq)製備4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物168):LCMS:m/z實測值440.2[M+H]+,RT=5.02miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.13-8.03(M,1H),7.41(d,2H),7.33-7.28(M,1H),5.52(s,1H),3.76(d,1H),3.65(d,1H),3.32-3.27(d,1H),
3.12-3.08(M,1H),2.80-2.76(M,1H),2.72(s,3H);手性分析SFC:RT=2.62miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物169):LCMS:m/z實測值440.2[M+H]+,RT=5.02miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.13-8.03(M,1H),7.41(d,2H),7.33-7.28(M,1H),5.52(s,1H),3.76(d,1H),3.65(d,1H),3.32-3.27(d,1H),3.12-3.08(M,1H),2.80-2.76(M,1H),2.72(s,3H);手性分析SFC:RT=3.15miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7] 啶-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺(化合物183和184)
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-(二氟甲基)-3,5-二氟苯甲酸(VIcr)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物183):LCMS:m/z實測值456.3[M+H]+,RT=6.45miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),8.12(t,1H),7.45-7.19(M,4H),5.60(br s,1H),3.87(d,1H),3.72(d,1H),3.21-3.19(M,2H),2.70(M,1H),2.68(s,3H);手性分析SFC:RT=1.75miN,管柱:Chiralcel OX-
3(4.6 x 150 mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物184):LCMS:m/z實測值456.3[M+H]+,RT=6.45miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),8.12(t,1H),7.45-7.19(M,4H),5.60(br s,1H),3.87(d,1H),3.72(d,1H),3.21-3.19(M,2H),2.70(M,1H),2.68(s,3H);手性分析SFC:RT=2.09miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-(二氟甲基)-1H-吲哚-2-羧酸(VIcs)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物,除了關於最終的去保護步驟,所分離的中間體1-(4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯的異構物是在0℃下用DCM中的TFA(5.0eq.)代替TMSOTf處理的。
對映異構物I(化合物207):LCMS:m/z實測值459.3[M+H]+,RT=5.07miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.07(s,1H),11.64(bs,1H),8.11(t,1H),7.64(d,1H),7.41-
7.14(M,4H),7.00(s,1H),5.68(s,1H),3.81(d,1H),3.66(d,1H),3.15(M,5H);手性分析SFC:RT=4.34miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,15%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物208):LCMS:m/z實測值459.3[M+H]+,RT=5.07miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.07(s,1H),11.64(bs,1H),8.11(t,1H),7.64(d,1H),7.41-7.14(M,4H),7.00(s,1H),5.68(s,1H),3.81(d,1H),3.66(d,1H),3.15(M,5H);手性分析SFC:RT=5.25miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,15%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物207、208)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物220):LCMS:m/z實測值477.3[M+H]+,RT=5.09miN,(方法A);1H NMR(400MHz,DMSO-
d6)δ 12.14(bs,1H),11.65(bs,1H),8.13-8.08(M,1H),7.69(d,1H),7.53(d,1H),7.39-7.11(M,2H),6.95(s,1H),5.67(s,1H),3.81(d,1H),3.66(d,1H),3.14-2.78(M,6H);手性分析SFC:RT=3.97miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,25%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物221):LCMS:m/z實測值477.3[M+H]+,RT=5.09miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.14(bs,1H),11.65(bs,1H),8.13-8.08(M,1H),7.69(d,1H),7.53(d,1H),7.39-7.11(M,2H),6.95(s,1H),5.67(s,1H),3.81(d,1H),3.66(d,1H),3.14-2.78(M,6H);手性分析SFC:RT=5.12miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,25%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-氟吲哚-2-羧酸(VIcu)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基吲哚-2-甲醯胺的單獨的對映異構物,除了關於最終步驟,所分離的中間體8,9-二氟-1-(6-氟-N-甲基吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯的異構物是在0℃下用二烷(5.0eq.)中的HCl 4N代替TMSOTf處理的。
對映異構物I(化合物222):LCMS:m/z實測值427.3[M+H]+,RT=4.09miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(bs,1H),8.45(bs,1H),8.10(t,1H),7.91(s,1H),7.54-7.50(M,1H),7.32-7.27(M,1H),6.85-6.73(M,2H),5.63(s,1H),3.77(d,1H),3.63(d,1H),3.15(s,2H),2.99(s,4H);手性分析SFC:RT=4.04miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,25%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物223):LCMS:m/z實測值427.3[M+H]+,RT=4.09miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(bs,1H),8.45(bs,1H),8.10(t,1H),7.91(s,1H),7.54-7.50(M,1H),7.32-7.27(M,1H),6.85-6.73(M,2H),5.63(s,1H),3.77(d,1H),3.63(d,1H),3.15(s,2H),2.99(s,4H);手性分析SFC:RT=5.31miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,25%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物207、208)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物257):LCMS:m/z實測值477.4[M+H]+,RT=6.29miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.15(bs,1H),11.68(bs,1H),8.11(M,1H),7.45-7.18(M,4H),7.03(s,1H),5.67(s,1H),3.81(d,1H),3.66(d,1H),3.14-2.93(M,5H),2.7(s,1H);手性分析SFC:RT=2.29miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物258):LCMS:m/z實測值477.4[M+H]+,RT=6.29miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.15(bs,1H),11.68(bs,1H),8.11(M,1H),7.45-7.18(M,4H),7.03(s,1H),5.67(s,1H),3.81(d,1H),3.66(d,1H),3.14-2.93(M,5H),2.7(s,1H);手性分析SFC:RT=3.76miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物207、208)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIcw)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺的單獨的對映異
構物。
對映異構物I(化合物264):LCMS:m/z實測值477.3[M+H]+,RT=7.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.17(bs,1H),11.65(bs,1H),8.11(t,1H),7.66-7.27(M,3H),7.19(t,1H),7.03(s,1H),5.67(s,1H),3.81(d,1H),3.69(d,1H),3.23-3.13(M,5H),2.79(s,1H);手性分析SFC:RT=1.51miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物265):LCMS:m/z實測值477.3[M+H]+,RT=7.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 12.17(bs,1H),11.65(bs,1H),8.11(t,1H),7.66-7.27(M,3H),7.19(t,1H),7.03(s,1H),5.67(s,1H),3.81(d,1H),3.69(d,1H),3.23-3.13(M,5H),2.79(s,1H);手性分析SFC:RT=2.82miN,管柱:Chiralcel AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和3'-氟-[1,1'-聯苯基]-4-羧酸(VIcx)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺的單獨的對映異構物。
對映異構物I(化合物301):LCMS:m/z實測值464.2
[M+H]+,RT=3.79miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(bs,1H),8.12(t,2H),7.79(d,2H),7.57-7.35(M,6H),7.23(t,1H),5.62(s,1H),3.77(d,1H),3.65(d,1H),3.32-3.15(M,2H),2.75(s,3H);手性分析SFC:RT=3.81miN,管柱:LUX纖維素(4.6 x 150mm)3μM,30%甲醇,流速:3.0g/min.
對映異構物II(化合物302):LCMS:m/z實測值464.2[M+H]+,RT=3.79miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(bs,1H),8.12(t,2H),7.79(d,2H),7.57-7.35(M,6H),7.23(t,1H),5.62(s,1H),3.77(d,1H),3.65(d,1H),3.32-3.15(M,2H),2.75(s,3H);手性分析SFC:RT=6.45miN,管柱:LUX纖維素(4.6 x 150mm)3μM,30%甲醇,流速:3.0g/min.
以與上文(關於化合物160、161)所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和3'-氟-[1,1'-聯苯基]-3-羧酸(VIcy)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺的單獨的對映異構物。
對映異構物I(化合物304):LCMS:m/z實測值464.2[M+H]+,RT=3.71miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(bs,1H),8.12(t,1H),7.78(d,1H),7.68(s,1H),7.58-7.49(M,4H),7.43-7.37(M,2H),7.23(t,1H),5.63(s,1H),3.77(d,1H),3.65(d,1H),3.18-3.14(M,2H),2.83-2.73(M,4H);手性
分析SFC:RT=6.06miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物305):LCMS:m/z實測值464.2[M+H]+,RT=3.71miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(bs,1H),8.12(t,1H),7.78(d,1H),7.68(s,1H),7.58-7.49(M,4H),7.43-7.37(M,2H),7.23(t,1H),5.63(s,1H),3.77(d,1H),3.65(d,1H),3.18-3.14(M,2H),2.83-2.73(M,4H);手性分析SFC:RT=7.44miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和3-(N-甲基胺磺醯)苯甲酸(VIdm)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物319):LCMS:m/z實測值463.1[M+H]+,RT=2.21miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.63(bs,1H),8.12(t,1H),7.84(d,1H),7.76-7.64(M,4H),7.38-7.33(M,1H),5.60(s,1H),3.77(d,1H),3.65(d,1H),3.28-3.12(M,2H),2.81-2.71(M,4H),2.42(d,3H);手性分析SFC:RT=4.63miN,管柱:(R,R)Whelk 01(4.6 x 150mm)3μM,30%(0.5%
在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物318):LCMS:m/z實測值463.1[M+H]+,RT=2.21miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.63(bs,1H),8.12(t,1H),7.84(d,1H),7.76-7.64(M,4H),7.38-7.33(M,1H),5.60(s,1H),3.77(d,1H),3.65(d,1H),3.28-3.12(M,2H),2.81-2.71(M,4H),2.42(d,3H);手性分析SFC:RT=5.25miN,管柱:(R,R)Whelk 01(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和3-(3-氟苯氧基)苯甲酸(VIdq)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺的單獨的對映異構物。
對映異構物I(化合物339):LCMS:m/z實測值480.2[M+H]+,RT=3.70miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.12-8.07(M,1H),7.51-7.39(M,2H),7.30-7.25(M,1H),7.16-7.15(M,2H),7.02-6.85(M,4H),5.55(s,1H),3.77-3.60(M,2H),3.24-3.1101(M,2H),2.85-2.64(M,4H);手性分析SFC:RT=2.48miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物340):LCMS:m/z實測值480.2[M+H]+,RT=3.70miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.12-8.07(M,1H),7.51-7.39(M,2H),7.30-7.25(M,1H),7.16-7.15(M,2H),7.02-6.85(M,4H),5.55(s,1H),3.77-3.60(M,2H),3.24-3.11(M,2H),2.85-2.64(M,4H);手性分析SFC:RT=4.69miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和吲哚-2-羧酸(Vin)製備N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物506):LCMS:m/z實測值409.2[M+H]+,RT=5.57miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.61(br s,1H),8.24(d,1H),8.12-8.08(M,1H),7.89(M,1H),7.42(M,1H),7.33-7.01(M,1H),6.75-6.72(M,3H),5.64-5.23(s,1H),3.78(d,1H),3.65(d,1H),3.15(M,2H),3.01-2.77(M,4H);手性分析SFC:RT=1.27miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物507):LCMS:m/z實測值409.2[M+H]+,RT=5.57miN,(方法A);1H NMR(400MHz,DMSO-
d6)δ 11.61(br s,1H),8.24(d,1H),8.12-8.08(M,1H),7.89(M,1H),7.42(M,1H),7.33-7.01(M,1H),6.75-6.72(M,3H),5.64-5.23(s,1H),3.78(d,1H),3.65(d,1H),3.15(M,2H),3.01-2.77(M,4H);手性分析SFC:RT=1.75miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和8-氯吲哚-2-羧酸(VIo)製備8-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺的單獨的對映異構物。
對映異構物I(化合物508):LCMS:m/z實測值443.2[M+H]+,RT=6.02miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(br s,1H),8.28(d,1H),8.13-8.02(M,2H),7.33-7.28(M,1H),6.96(d,1H),6.72(s,1H),6.64(t,1H),5.64(s,1H),3.78(d,1H),3.64(d,1H),3.16(M,2H),3.01-2.76(M,4H);手性分析SFC:RT=1.29miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物509):LCMS:m/z實測值443.2[M+H]+,RT=6.02miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.62(br s,1H),8.28(d,1H),8.13-8.02(M,2H),7.33-7.28
(M,1H),6.96(d,1H),6.72(s,1H),6.64(t,1H),5.64(s,1H),3.78(d,1H),3.64(d,1H),3.16(M,2H),3.01-2.76(M,4H);手性分析SFC:RT=1.58miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-3-甲基-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Vi)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8,9-二氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物62):LCMS:m/z實測值423.2[M+H]+,RT=3.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.69(br s,2H),8.13-8.08(M,1H)7.62(d,1H),7.47(d,1H),7.32-7.29(M,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H),5.82(s,1H),3.72(d,1H),3.16(s,3H),3.08-2.9(M,2H),2.73-2.69(M,1H),2.32(s,3H);手性分析SFC:RT=2.92miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物63):LCMS:m/z實測值423.2[M+H]+,RT=3.20miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.69(br s,2H),8.13-8.08(M,1H)7.62(d,1H),7.47(d,
1H),7.32-7.29(M,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H),5.82(s,1H),3.72(d,1H),3.16(s,3H),3.08-2.9(M,2H),2.73-2.69(M,1H),2.32(s,3H);手性分析SFC:RT=5.78miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由外消旋3-乙醯基-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Vj)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(3-乙醯基-8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-50:50。管柱:Chiralpak IA(30 x 250mm),5μm,流速:120g/min。
對映異構物I(化合物81):LCMS:m/z實測值451.2[M+H]+,RT=4.15miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.82(br s,2H),8.12(t,1H)7.61(dd,1H),7.48(d,1H),7.41-7.32(M,1H),7.22(t,1H),7.05(t,1H),6.99(s,1H),5.92-5.86(s,1H),5.08(d,1H),4.67(d,1H),3.99(d,1H),3.72(d,1H),2.97(s,3H),2.13(s,3H);手性分析SFC:RT=3.01miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,50%的MeOH,流速:3.0g/min.
對映異構物II(化合物82):LCMS:m/z實測值451.2[M+H]+,RT=4.15miN,(方法A);1H NMR(400MHz,DMSO-d6)
δ 11.82(br s,2H),8.12(t,1H)7.61(dd,1H),7.48(d,1H),7.41-7.32(M,1H),7.22(t,1H),7.05(t,1H),6.99(s,1H),5.92-5.86(s,1H),5.08(d,1H),4.67(d,1H),3.99(d,1H),3.72(d,1H),2.97(s,3H),2.13(s,3H);手性分析SFC:RT=6.43miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,50%的MeOH,流速:3.0g/min.
以與上文所述類似的方式,由外消旋3-(2-((第三丁基二甲基甲矽烷基)氧基)乙基)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫苯并[c][1,7]啶-6(2H)-酮(Vh)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8,9-二氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-50:50。管柱:Chiralpak IC(30 x 250mm),5μm,流速:120g/min。
對映異構物I(化合物89):LCMS:m/z實測值453.2[M+H]+,RT=4.06miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.70(br s,2H),8.11(t,1H),7.60(d,1H),7.47(d,1H),7.33(dd,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H),5.83(s,1H),4.55(s,1H),3.83(d,1H),3.58(d,2H),3.20(s,3H),3.15(M,2H),2.82(M,1H),2.60(M,2H);手性分析SFC:RT=2.05miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%的甲醇,流速:3.0g/min.
對映異構物II(化合物90):LCMS:m/z實測值453.2
[M+H]+,RT=4.06miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.70(br s,2H),8.11(t,1H),7.60(d,1H),7.47(d,1H),7.33(dd,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H),5.83(s,1H),4.55(s,1H),3.83(d,1H),3.58(d,2H),3.20(s,3H),3.15(M,2H),2.82(M,1H),2.60(M,2H);手性分析SFC:RT=3.74miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%的甲醇,流速:3.0g/min.
8,9-二氟-2H-硫代哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(Ivh)
步驟i:在110℃下,在氮氣氛下將5.0g(17.6mmol,1.0eq.)4,5-二氟-2-碘代苯甲酸(IIIb)、2.74g(21.12mmol,1.2eq.)2H-噻喃-3,5(4H,6H)-二酮(IIc)、9.7g(70.4mmol,4.0eq.)碳酸鉀、0.41g(3.5mmol,0.2eq.)L-脯胺酸和0.33g(1.17mmol,0.1eq.)碘化亞銅在30mL乾燥的DMSO中的混合物攪拌16小時(註:以4 x 5g的規模平行地執行反應)。一冷卻至室溫,就將反應混合物合併,並用冷水(100mL)稀釋和用2M HCl溶液(30mL)酸化。所得懸浮液過濾,並用乙酸乙酯(3 x 500mL)萃取濾液。合併的有機萃取物用鹽水(150mL)洗滌,經無水Na2SO4乾燥,過濾並在減壓下濃縮以提供15.2g的8,9-二氟硫代哌喃并[3,4-c]異色烯-1,6(2H,4H)-二酮和4,5-二氟-2-(5-羥基-3-側氧-3,6-二氫-2H-噻喃-4-基)苯甲酸,取其原樣用於下一步驟而無需純化。
步驟ii:向-35℃下鋼製反應釜中5g(1.86mmol,1.0eq.)上文製備的8,9-二氟硫代哌喃并[3,4-c]異色烯-1,6(2H,4H)-二酮和4,5-二氟-2-(5-羥基-3-側氧-3,6-二氫-2H-噻喃-4-基)苯甲酸的粗混合物的混合物加入100mL 7M甲醇銨。將容器密封並在120℃下將混
合物加熱1小時。然後使混合物冷卻至室溫並在減壓下濃縮。用10vol的DMSO:水(1:9)將殘餘物攪拌30分鐘獲得固體,該將固體過濾並用水洗滌以提供1.3g(4.8mmol,26%)8,9-二氟-2H-硫代哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVh)。LCMS:m/z實測值266.17[M-H]-.
8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮(Vk)
以與上文所述類似的方式,由8,9-二氟-2H-硫代哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVh)和甲胺合成外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮。LCMS:m/z實測值283.3[M+H]+.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮(Vk)和8-氟吲哚-2-羧酸(VIm)合成外消旋N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak-IC(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物103):LCMS:m/z實測值444.2[M+H]+,RT=5.51miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.71(br s,1H),8.15-8.08(M,3H)7.27-7.22(M,1H),6.76(s1H),6.67-6.62(M,2H),5.89(s,1H),3.79(d,1H),3.67(d,1H),3.49-3.41(M,1H),3.11-3.01(M,1H),3.02(s,3H);手性分析SFC:RT=5.14miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的MeOH,流速:3.0g/min.
對映異構物II(化合物104):LCMS:m/z實測值444.2[M+H]+,RT=5.51miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.71(br s,1H),8.15-8.08(M,3H)7.27-7.22(M,1H),6.76(s1H),6.67-6.62(M,2H),5.89(s,1H),3.79(d,1H),3.67(d,1H),3.49-3.41(M,1H),3.11-3.01(M,1H),3.02(s,3H);手性分析SFC:RT=6.60miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%的MeOH,流速:3.0g/min.
8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3-氧化物(Vp)
向室溫下850mg(282mmol,1eq.)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮(Vk)在10mL乙腈:水(1:1)中的攪拌後的溶液加入740mg(2.44mmol,0.8eq.)過一硫酸氫鉀,並將所得反應混合物攪拌6小時。然後將混合物濃縮並用甲醇(20mL)稀釋。將懸浮液過濾後,在減壓下將濾液濃縮以提供粗的(700mg)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3-氧化物(Vp)。在接下來的步驟中使用此材料而無需進一步純化。LCMS:m/z實測值299.24[M+H]+.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3-氧化物(Vp)和8-氟吲哚-2-羧酸(VIm)合成N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺(四種立體異構物的混合物)。隨後通過製備SFC分離外消旋非鏡像異構物:等度法,流動相甲醇:CO2-35:65。管柱:DCPAK P4VP(20 x 250mm)5μm,流速:60g/min.
非鏡像異構物I,外消旋(化合物150):LCMS:m/z實測值460.3.[M+H]+,RT=3.45miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),8.18-8.10(M,3H),7.34-7.29(M,1H),6.77(s,1H),6.65-6.63(M,2H),6.29(t,1H),4.38(d,1H),3.90(d,1H),3.62-3.58(M,1H),3.20-3.15(M,1H),2.81(s,3H);手性分析SFC:RT=6.02和10.66miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,50%(0.5%在甲醇中的DEA),流速:3.0g/min.
非鏡像異構物II,外消旋(化合物149):LCMS:m/z實測值460.3[M+H]+,RT=3.54miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.71(s,1H),8.16-8.08(M,3H),7.32-7.27(M,1H),6.75(s,1H),6.64-6.63(M,2H),6.25(t,1H),4.18-4.13(M,2H),3.68-3.64(M,1H),3.32(M,1H),2.87(s,3H);手性分析SFC:RT=7.52和9.86miN,管柱:Chiralcel OX-3(4.6 x 150mm)3
μM,50%(0.5%在甲醇中的DEA),流速:3.0g/min.
8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3,3-二氧化物(Vq)
向0℃下700mg(2.48mmol,1eq.)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮(Vk)在5mL ACN和5mL水中的攪拌後的溶液加入2.28g(7.44mmol,3eq.)過一硫酸氫鉀,並在室溫下將所得反應混合物攪拌16小時。反應完成後,在減壓下將反應混合物濃縮以提供殘餘物,該殘餘物用甲醇(20mL)稀釋並攪拌20分鐘。將懸浮液過濾後,在減壓下將濾液濃縮以提供粗產物,與二乙醚(10mL)研磨該粗產物以提供作為棕色固體的700mg(2.22mmol,89%產率)8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3,3-二氧化物(Vq)。LCMS m/z實測值315.24[M+H]+,RT=0.50min(方法E).
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-1,5-二氫-2H-硫代哌喃并[3,4-c]異喹啉-6(4H)-酮3,3-二氧化物
(Vq)和8-氟吲哚-2-羧酸(VIm)合成外消旋N-(8,9-二氟-3,3-二氧橋-6-側氧-2,4,5,6-四氫-1H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-50:50。管柱:Chiralpak-OD-H(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物151):LCMS:m/z實測值476.2[M+H]+,RT=3.84miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.73(s,1H),8.16-8.10(M,3H),7.29(M,1H),6.77(s,1H),6.65-6.63(M,2H),6.26(t,1H),4.85(d,1H),4.13(d,1H),3.80(M,1H),3.70-3.64(M,1H),2.84(s,3H);手性分析SFC:RT=2.29miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,50%的MeOH,流速:3.0g/min.
對映異構物II(化合物152):LCMS:m/z實測值476.2[M+H]+,RT=3.84miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.73(s,1H),8.16-8.10(M,3H),7.29(M,1H),6.77(s,1H),6.65-6.63(M,2H),6.26(t,1H),4.85(d,1H),4.13(d,1H),3.80(M,1H),3.70-3.64(M,1H),2.84(s,3H);手性分析SFC:RT=4.64miN,管柱:Chiralcel OD-3(4.6 x 150mm)3μM,50%的MeOH,流速:3.0g/min.
4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(IVi)
步驟i:在氮氣氛下將2-碘代苯甲酸(IIId,0.99g,4.0mmol)、四氫哌喃-3,5-二酮、(IIa,0.55g,4.8mmol)、碘化亞銅(76mg,0.4mmol)、和磷酸鉀(1.19g,5.6mmol)合併到管中。加入無水1,4-二烷(10mL)並用氮氣吹掃反應管,並在室溫下攪拌
30分鐘,然後在110℃下再攪拌3小時。反應混合物用乙酸乙酯(10mL)稀釋,通過CELITE®過濾並用乙酸乙酯(3 x 10mL)洗滌墊。在高真空下蒸發濾液並通過快速層析法(矽膠,乙酸乙酯/己烷0-90%)純化殘餘物以提供0.41g(47%產率)4H-哌喃并[3,4-c]異色烯-1,6-二酮。LCMS m/z實測值217.1[M+H]+;RT=0.94min(方法B);1H NMR(400MHz,CDCl3)δ 8.92(M,1H),8.30(M,1H),7.84(M,1H),7.59(M,1H),4.74(d,2H),4.36-4.30(M,2H).
步驟ii:在密封管內,於140℃下在1,2-二氯乙烷(4mL)中攪拌4H-哌喃并[3,4-c]異色烯-1,6-二酮(80mg,0.37mmol)和醋酸銨(0.17g,2.22mmol)7小時。將反應混合物冷卻至室溫,用二氯甲烷/甲醇稀釋,並使其吸附在矽膠上。產物通過快速層析法(矽膠,乾燥裝載,MeOH/DCM 0-4%)分離以提供60mg(75%產率)4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮。LCMS:m/z實測值216.1[M+H]+;RT=0.87min(方法B);1H NMR(400MHz,DMSO-d 6)δ 12.12(s,1H),9.02(M,1H),8.23(M,1H),7.82(M,1H),7.56(M,1H),4.79(d,2H),4.27(d,2H).
1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vl)
將鈦酸四異丙酯(0.56mL,1.86mmol)加入到4,5-二氫哌喃并[3,4-c]異喹啉-1,6-二酮(IVi,0.10g,0.46mmol)和THF(0.46mL,0.93mmol)中的2M甲胺溶液的混合物和1,4-二烷(5mL)中。然後在80℃下,在氮氣下將混合物攪拌3小時。反應混合物用2mL無水MeOH稀釋,冷卻至0℃,用硼氫化鈉(35mg,0.93mmol)處理並使其攪拌1小時。通過加入鹽水(1.5mL)使反應猝滅,用20mL乙酸乙酯稀釋,並再攪拌15分鐘。混合物通過CELITE®過
濾,並再用25mL乙酸乙酯洗滌濾餅。合併的濾液經硫酸鈉乾燥,過濾,並在減壓下使溶劑蒸發。產物通過快速層析法(矽膠,MeOH/DCM 0-10%)分離以提供86mg(80%產率)外消旋1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮。LCMS:m/z實測值200.1[M-(MeNH)]+;RT=0.59miN,(方法B);1H NMR(400MHz,CDCl3)δ 11.61(s,1H),8.46-8.39(M,1H),7.79-7.68(M,2H),7.49(ddd,1H),4.72(d,1H),4.60(dd,1H),4.42(d,1H),3.69-3.60(M,2H),2.62(s,3H).
3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺(化合物132)
以與上文所述類似的方式,由外消旋1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vl)和3-氟-4-(三氟甲基)苯甲酸(VIab)合成外消旋3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值421.1[M+H]+;RT=5.67min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.49(s,1H),8.28-8.18(M,1H),7.97-7.79(M,2H),7.64(d,1H),7.61-7.49(M,2H),7.45-7.38(M,1H),5.68(t,1H),4.59(d,1H),4.47(dd,1H),4.29(d,1H),4.03(dd,1H),2.66(s,3H).
6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮(Ivj)
以與上文所述類似的方式,由4-溴噻吩-3-羧酸(IIIe)和四氫哌喃-3,5-二酮(IIa)合成6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮。LCMS m/z實測值222.1[M+H]+;RT=0.58min(方法B);1H NMR(400MHz,DMSO-d6)δ 12.28(s,1H),7.71(d,1H),7.51(d,1H),4.83(s,2H),4.35(s,2H).
9-(甲胺基)-8,9-二氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮(Vm)
以與上文所述類似的方式,由6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4,9(5H,8H)-二酮(IVj)和甲胺合成9-(甲胺基)-8,9-二氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮。LCMS m/z實測值237.1[M+H]+;RT=0.40min(方法B);1H NMR(400MHz,CDCl3)δ 10.72(s,1H),8.37(dd,1H),7.45-7.38(M,1H),4.58(d,1H),4.47(dd,1H),4.29(dd,1H),3.64(dd,1H),3.52(p,1H),2.58(s,3H).
3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺(化合物133)
以與上文所述類似的方式,由外消旋9-(甲胺基)-8,9-二氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-4(5H)-酮(Vm)和3-氟-4-(三氟甲基)苯甲酸(VIab)合成外消旋3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值427.1[M+H]+;RT=5.60min(方法A);1H NMR(400MHz,DMSO-d 6)δ 10.83(s,1H),8.53-8.44(M,1H),7.88(t,1H),7.72(d,1H),7.55-7.47(M,2H),5.60(d,1H),4.48(d,1H),4.40-4.20(M,2H),4.00(dd,1H),2.69(s,3H).
1,6-二側氧-4,5-二氫哌喃并[3,4-c]異喹啉-8-腈(Ivk)
以與上文所述類似的方式,由5-氰基-2-碘-苯甲酸(IIIf)和四氫哌喃-3,5-二酮(IIa)合成1,6-二側氧-4,5-二氫哌喃并[3,4-c]異喹啉-8-腈。LCMS m/z實測值241.2[M+H]+,RT=2.17min(方法C);1H NMR(400MHz,DMSO-d6)δ 12.45(s,1H),9.11(d,1H),8.53(d,1H),8.16(dd,1H),4.80(s,2H),4.29(s,2H).
1-(甲胺基)-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-8-腈(Vn)
以與上文所述類似的方式,由1,6-二側氧-4,5-二氫哌喃并[3,4-c]異喹啉-8-腈(IVk)和甲胺合成1-(甲胺基)-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-8-腈。LCMS m/z實測值256.2[M+H]+,RT=0.44min(方法B);1H NMR(400MHz,甲醇-d4)δ 8.63-8.58(M,1H),7.93(dd,1H),7.84(d,1H),4.59(d,1H),4.48(dd,1H),4.42-4.33(M,1H),3.70-3.55(M,2H),2.55(s,3H).
N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺(化合物134)
以與上文所述類似的方式,由外消旋1-(甲胺基)-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-8-腈(Vn)和3-氟-4-(三氟甲基)苯甲酸(VIab)合成外消旋N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺。LCMS m/z實測值446.2[M+H]+;RT=5.72min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.88(s,1H),8.57(d,1H),8.20(dd,1H),7.88(t,1H),7.67(d,2H),7.45(d,1H),5.74-5.68(M,1H),4.63(d,1H),4.50(dd,1H),4.31(d,1H),4.04(dd,1H),2.66(s,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺(化合物143)
用在0℃下攪拌10分鐘的3-氯-4-氟-苯磺醯氯(VIIa,23.5uL,0.17mmol)在200μL DMF中的溶液逐滴處理DIPEA(105μL,0.60mmol)和鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,56mg TF鹽,0.15mmol)在DMF(1mL)中的攪拌後的溶液,然後將其溫熱至室溫並再攪拌1小時。通過加入2.5mL飽和氯化銨和2.5mL水使反應猝滅,並將pH調節至3-4(逐滴使用2M HCl),然後用乙酸乙酯(2 x 30mL)萃取。合併的有機萃取物用飽和氯化銨(2 x 25mL)洗滌,之後用飽和碳酸氫鈉(2 x 25mL)、水(25mL)和鹽水(25mL)洗滌,然後經硫酸鈉乾燥,過濾並使溶劑蒸發。產物通過快速層析法(矽膠,甲醇/二氯甲烷0-3% 15分鐘內)分離以提供鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺(12.9mg,19%產率):LCMS m/z實測值459.1/461.1[M+H]+;RT=4.88min(方法A);1H NMR(400MHz,氯仿-d)δ 12.14(s,1H),8.18(dd,1H),8.00(M,1H),7.91(dd,1H),7.86-7.78(M,1H),7.37(t,1H),5.18-5.12(M,1H),4.72(d,1H),4.52(dt,1H),3.91(d,1H),3.76(dd,1H),2.79(s,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺(化合物144)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,TF鹽)和3-氯苯磺醯氯(VIIb)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺。LCMS m/z實測值441.1/443.2[M+H]+;RT=4.84min(方法A);1H NMR(400MHz,氯仿-d)δ 12.06(s,1H),8.17(dd,1H),8.01-7.88(M,2H),7.80(ddd,1H),7.64(ddd,1H),7.61-7.50(M,1H),5.18-5.12(M,1H),4.70(d,1H),4.56-4.46(M,1H),3.92-3.84(M,1H),3.74(dd,1H),2.79(s,3H).
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺(化合物145)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,TF鹽)和3-氰基苯磺醯氯(VIIc)合成鏡像異構純的(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺。LCMS m/z實測值432.2[M+H]+;RT=4.64min(方法A);1H NMR(400MHz,氯仿-d)δ 11.70(s,1H),8.24-8.11(M,3H),7.95(dt,1H),7.87(dd,1H),7.76(td,1H),5.17(d,1H),4.69(d,1H),4.52(d,1H),3.90-3.81(M,1H),3.76(dd,1H),2.81(s,3H).
(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺(化合物146)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,TF鹽)和3-氰基-4-氟苯磺醯氯(VIId)合成鏡像異構純的(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺。LCMS m/z實測值450.1[M+H]+;RT=4.81min(方法A);1H NMR(400MHz,氯仿-d)δ 11.60(s,1H),8.26-8.11(M,3H),7.86(dd,1H),7.48(dd,1H),5.18(d,1H),4.69(d,1H),4.57-4.48(M,1H),3.89(dd,1H),3.79(dd,1H),2.80(s,3H).
(S)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物240)
步驟i. 向室溫下350mg(0.785mmol,1eq.)(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(42)在3.5mL THF中的攪拌後的溶
液加入0.25mL(1.8mmol,2.3eq.)Et3N、205mg(0.94mmol,1.2eq.)二碳酸二第三丁酯和9.5mg(0.08mmol,0.1eq.)DMAP,並在室溫下將反應混合物攪拌3小時。反應完成(通過TLC)後,反應混合物用水(20mL)猝滅並用EtOAc(2 x 70mL)萃取。合併的有機層用水(20mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。所獲得的材料通過管柱層析法,採用矽膠(100-200目)和80% EtOAc/石油醚作為洗脫液進行純化,以提供(250mg,58%產率)作為淺棕色固體的(S)-2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯。
步驟ii. 在室溫下向80mg(0.146mmol,1.0eq.)(S)-2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯(來自步驟i)在1mL DMF中的攪拌後的溶液加入20mg(0.146mmol,1eq.)K2CO3和0.02mL(0.293mmol,2eq.)甲基碘。在80℃下將所得混合物攪拌16小時。反應混合物通過CELITE®墊過濾,並用EtOAc(30mL)洗滌CELITE®床。所獲得的濾液用水(20mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮以提供粗70mg(0.125mmol,85%產率)(S)-2-((8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯。
步驟iii. 在0℃下,向70mg(0.125mmol,1eq.)(S)-2-((8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯(來自步驟ii)在DCM(0.5mL)中的溶液加入0.045mL(0.25mmol,2eq.)TMSOTf,並在同一溫度下將所得反應混合物攪拌1h。反應完成(通過TLC監測)後,在減壓下將揮發物去除。取所得殘餘物到飽和NaHCO3溶液(10mL)中並用乙酸乙酯(2 x 30mL)萃取。合併的有機層用水(20mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮。所獲得的粗材料通過手性SFC純化以提供作為灰白色固體的19mg(33%
產率)(S)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值460.3[M+H]+;RT=7.03min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.92(bs,1H),8.12(t,1H),7.69(t,1H),7.46-7.36(M,2H),6.98(s,1H),5.79(s,1H),4.98(d,1H),4.68(d,1H),4.16(d,1H),4.01(d,1H),3.46(s,3H),3.15(s,3H).
(S)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物241)
步驟i. 在室溫下向80mg(0.1467mmol,1eq.)(S)-2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯(來自上文程序中的步驟i)在1mL甲苯中的攪拌後的溶液加入40mg(0.1467mmol,1eq.)Ag2CO3和0.02mL(o.29mmol,2eq.)甲基碘。在80℃下將所得混合物攪拌16小時。反應完成(通過TLC)後,混合物通過CELITE®墊過濾並用EtOAc(30mL)洗滌CELITE®床。所獲得的濾液用水(20mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮,以提供作為棕色固體的80mg粗(S)-2-((8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯。
步驟ii. 通過與上文中步驟iii中的程序類似的程序,通過用TMSOTf進行處理,將步驟i中獲得的粗(S)-2-((8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-羧酸第三丁酯轉化為(S)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值460.3[M+H]+;RT=7.91min(方法A);
1H NMR(400MHz,DMSO-d 6 )δ 11.94(bs,1H),8.16(t,1H),7.7-7.58(M,2H),7.41-7.37(M,1H),6.96(s,1H),6.02(s,1H),4.85(d,1H),4.71(d,1H),4.25(d,1H),4.12(M,4H),3.09(s,3H).
(2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(IXe)和(2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙基)胺基甲酸苄基酯(Ixd)
在0℃下,向(500mg,0.12mmol,1.0eq.)(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(IXc)在5mL DMF中的攪拌後的溶液加入36mg NaH(0.14mmol,1.2eq.),並將反應混合物攪拌15分鐘。加入760mg(2-碘乙基)胺基甲酸苄基酯(0.25mmol,2eq.)並將反應混合物加熱至80℃ 3h。將混合物冷卻至室溫,用冰-水猝滅並用EtOAc(2 x 100mL)萃取。合併的有機層用冰-水洗滌,經無水Na2SO4乾燥,過濾並使溶劑蒸發。所獲得的材料通過管柱層析法(矽膠100-200目,20%在石油醚中的乙酸乙酯作為線性梯度)純化以提供作為淺黃色濃稠液體的220mg(42%產率)(2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(IXe)。LCMS m/z實測值578.70[M+H]+,RT=1.77min(方法E)。也將(2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙基)胺基甲酸苄基酯(IXd)進行分離(320mg)。
(S)-(2-((8,9-二氟-1-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(Vr)
在0℃下,向400mg(0.69mmol,1eq.)(2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(IXe)在4mL DCM中的攪拌後的溶液加入2mL TFA,並在室溫下將反應混合物攪拌12h。反應完成(通過TLC監測)後,混合物用10% aq.NaHCO3猝滅並用EtOAc(2 x 50mL)萃取。合併的有機層用冰-水洗滌,經無水Na2SO4乾燥,過濾並使溶劑蒸發,以提供20mg粗的(S)-(2-((8,9-二氟-1-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(Vr),其用於下一步驟中而無需進一步純化。LCMS m/z實測值444.32[MH]+,RT=2.02min(方法E).
(S)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物280)
步驟i. 向室溫下160mg(0.45mmol,1.2eq.)5,6-二氟-1H-吲哚-2-羧酸(VIi)在2mL DMF中的攪拌後的溶液加入0.24
mL(1.35mmol,3eq.)DIPEA、172mg(1.12mmol,1.5eq.)HATU,之後加入80mg(0.22mmol,1eq.)(S)-(2-((8,9-二氟-1-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(Vr)。在室溫下將所得混合物攪拌16小時。反應完成(通過TLC)後,將反應混合物傾倒入冰冷的水(20mL)中並攪拌30分鐘。由該反應形成的固體通過過濾收集,用Et2O(2 x 10mL)洗滌並在真空下乾燥以提供200mg粗的(S)-(2-((1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯,其直接用於下一步驟中。LCMS m/z實測值621.21[M-H]-,RT=2.02min(方法E).
步驟ii. 向200mg(0.32mmol,1eq.)(S)-(2-((1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙基)胺基甲酸苄基酯(來自步驟i)在10mL MeOH中的攪拌後的溶液加入100mg(0.11mmol,0.6eq.)Pd/C,並在氫氣下(1atm)將混合物攪拌6小時。反應完成(通過TLC監測)後,通過CELITE®墊過濾混合物,該混合物進一步用10% DMF/MeOH(20mL)洗滌。在減壓下將合併的濾液濃縮,並通過製備HPLC純化該材料以提供38mg(32%產率)(S)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值489.2[M+H]+;RT=6.71min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.93(s,1H),8.35(t,1H),7.68-7.58(M,2H),7.41-7.37(q,1H),6.96(s,1H),6.01(s,1H),4.82(d,1H),4.68(d,1H),4.43-4.38(M,2H),4.26(d,1H),4.11(d,1H),3.09-2.99(M,7H).
((S)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物316)
以與上文所述類似的方式,由鏡像異構純區域異構物(2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙基)胺基甲酸苄基酯(IXd)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的((S)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值489.2[M+H]+;RT=3.56min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.92(br s,1H),8.17(M,1H),7.62(M,1H),7.41(M,2H),6.96(s,1H),5.78(s,1H),5.16(d,1H),4.74(d,1H),4.16(d,1H),4.00-3.80(M,3H),3.15(s,3H),2.84(t,2H),2.1(br s,exch.Hs).
2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(IXg)和2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙酸乙酯(Ixf)
在0℃下,向600mg(1.5mmol,1eq.)8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]
異喹啉-6(4H)-酮(IXc)在mL DMF中的攪拌後的溶液加入5mg NaH(2.2mmol,1.5eq.),並將反應混合物攪拌15分鐘。向其中加入642mg 2-碘代乙酸乙酯(3.0mmol,2eq.)並將反應混合物加熱至80℃3h。反應完成(通過TLC監測)後,將混合物冷卻至rt,用冰-水猝滅並用EtOAc(2 x 100mL)萃取。合併的有機層用冰-水(50mL)洗滌,經無水Na2SO4乾燥,過濾並使溶劑蒸發。所獲得的材料通過管柱層析法(矽膠100-200目,20%在石油醚中的乙酸乙酯作為線性梯度)純化,以提供130mg(26%產率)2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(IXg),LCMS m/z實測值487.3[M+H]+,RT=1.79min,和150mg(20%產率)2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙酸乙酯(IXf),LCMS m/z實測值487.3[M+H]+,RT=1.87min(方法E).
(S)-2-(8,9-二氟-1-(甲胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(Vs)
以與上文所述類似的方式,由2-((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(IXg)合成鏡像異構純的(S)-2-(8,9-二氟-1-(甲胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(Vs)。LCMS m/z實測值352.9[MH]+,RT=1.09min(方法
E).
(S)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物315)
步驟i. 以與上文所述類似的方式,由(S)-2-(8,9-二氟-1-(甲胺基)-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯(Vs)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(S)-2-(1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯。LCMS m/z實測值530.1[M-H]-,RT=1.09min(方法E).
步驟ii.在0℃下,向65mg(0.14mmol,1eq.)(S)-2-(1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,2,4,6-四氫-5H-哌喃并[3,4-c]異喹啉-5-基)乙酸乙酯在1mL MeOH中的攪拌後的溶液加入41mg K2CO3(0.3mmol,2eq.),並在室溫下將反應混合物攪拌2h。反應完成(通過TLC監測)後,將混合物過濾並使揮發物蒸發。製備HPLC純化提供22mg(26%產率)(S)-N-(8,9-二氟-5-(2-羥乙基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值490.1[M+H]+;RT=4.34min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.94(s,1H),8.31(t,1H),7.66-7.59(M,2H),7.39(t,1H),6.96(s,1H),6.02(s,1H),5.00(t,1H),4.82(d,1H),4.69(d,1H),4.49-4.43(M,2H),4.25(d,1H),4.11(d,1H),3.85-3.81(M,2H),3.09
(s,3H).
(S)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物317)
以與上文所述類似的方式,由鏡像異構純區域異構物2-(((S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)氧基)乙酸乙酯(IXf)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(S)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值490.2[M+H]+;RT=4.88min(方法A);1H NMR(400MHz,DMSO-d 6 )δ 11.91(s,1H),8.19(t,1H),7.64-7.59(M,1H),7.46-7.37(M,2H),6.98(s,1H),5.79(s,1H),5.18(d,1H),5.07-5.04(M,1H),4.73(d,1H),4.16(d,1H),4.06-3.92(M,3H),3.74-3.66(M,2H),3.14(s,3H).
6-氯-8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(Ivl)
用5mL甲苯中的500mg(1.9mmol,1eq.)8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVb)對圓底燒瓶進料。
在惰性氣氛下加入POCl3(1.3mL,4eq.)。在110℃下將反應混合物攪拌4小時。反應完成(通過TLC監測和LCMS分析)後,用飽和NaHCO3溶液(50mL)鹼化混合物。將固體過濾並用乙酸乙酯(3 x 200mL)萃取濾液。合併的有機層用鹽水(100mL)洗滌,經無水Na2SO4乾燥,過濾並在減壓下濃縮以提供作為淺黃色固體的480mg 6-氯-8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮,取其到下一步驟中無需純化。
8,9-二氟-6-(甲胺基)-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(Ivm)
向密封管內400mg(1.48mmol,1eq.)6-氯-8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(IVl)在4mL DMSO中的溶液加入THF(1M)中的2.2mL(4.46mmol,3eq.)甲胺和DIPEA(0.5mL),並在50℃下將混合物加熱16小時。反應完成(通過TLC監測)後,將混合物冷卻至室溫並傾倒入冰冷的水(20mL)中。然後用EtOAc(2 x 50mL)萃取。合併的有機層用鹽水(50mL)洗滌,經無水Na2SO4乾燥,過濾並在減壓下濃縮。所得粗產物與二乙醚研磨以提供作為棕色固體的320mg(81%產率)8,9-二氟-6-(甲胺基)-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮。LCMS m/z實測值265.3[M+H]+.
8,9-二氟-N1,N6-二甲基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1,6-聯胺(Vt)
以與上文所述類似的方式,由8,9-二氟-6-(甲胺基)-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(IVm)和甲胺合成8,9-二氟-N1,N6-二甲基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1,6-聯胺。LCMS m/z實測值280.2[M+H]+.
N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物333和334)
以與上文所述類似的方式,由外消旋8,9-二氟-N1,N6-二甲基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1,6-聯胺(Vt)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在甲醇中的(7M甲醇銨)):CO2-25:75。管柱:Chiralpak-IC(30 x 250mm)5μm,流速:100g/min。
對映異構物I(化合物333):LCMS:m/z實測值459.2[M+H]+,RT=3.50miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.91(br s,1H),8.37-8.31(M,1H),7.72(d,1H),7.62-7.57(M,1H),7.50-7.45(M,1H),7.40-7.36(M,1H),6.93(s,1H),5.87(s,1H),4.70(d,1H),4.58(d,1H),4.20(d,1H),4.05(d,1H),3.08(s,3H),2.96(d,3H);手性分析SFC:RT=1.91miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
對映異構物II(化合物334):LCMS:m/z實測值459.2[M+H]+,RT=3.50miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.91(br s,1H),8.37-8.31(M,1H),7.72(d,1H),7.62-7.57
(M,1H),7.50-7.45(M,1H),7.40-7.36(M,1H),6.93(s,1H),5.87(s,1H),4.70(d,1H),4.58(d,1H),4.20(d,1H),4.05(d,1H),3.08(s,3H),2.96(d,3H);手性分析SFC:RT=2.38miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物335和336)
以與上文所述類似的方式,由6-氯-8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(Ivl)、2-胺基乙酸乙酯鹽酸鹽、甲胺、和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(0.2%在甲醇中的(7M甲醇銨)):CO2-25:75。管柱:ChiralpakIC-3(30 x 250mm),5μ,流速:100g/min。
對映異構物I(化合物335):LCMS:m/z實測值489.2[M+H]+,RT=3.46miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.91(br s,1H),8.46-8.41(M,1H),7.68-7.65(M,1H),7.62-7.54(M,1H),7.50-7.44(M,1H),7.40-7.35(M,1H),6.93(s,1H),5.86(s,1H),4.76(bs,1H),4.68(d,1H),4.56(d,1H),4.19(d,1H),4.05(d,1H),3.63-3.52(M,4H),3.09(s,3H);手性分析SFC:RT=2.35miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
對映異構物II(化合物336):LCMS:m/z實測值489.2[M+H]+,RT=3.46miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.91(br s,1H),8.46-8.41(M,1H),7.68-7.65(M,1H),7.62-7.54(M,1H),7.50-7.44(M,1H),7.40-7.35(M,1H),6.93(s,1H),5.86(s,1H),4.76(bs,1H),4.68(d,1H),4.56(d,1H),4.19(d,1H),4.05(d,1H),3.63-3.52(M,4H),3.09(s,3H);手性分析SFC:RT=3.62miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的MeOH,流速:3.0g/min.
N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物351和352)
以與上文所述類似的方式,由6-氯-8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1(4H)-酮(Ivl)、(2-胺乙基)胺基甲酸苄基酯、甲胺、和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成外消旋(2-((1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)胺基)乙基)胺基甲酸苄基酯。向140mg(0.19mmol,1eq.)粗的(2-((1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-6-基)胺基)乙基)胺基甲酸苄基酯在10mL MeOH中的攪拌後的溶液加入50mg(0.11mmol,0.6eq.)Pd/C,並將反應攪拌6小時。反應完成(通過TLC監測)後,通過CELITE®
墊過濾混合物,該混合物進一步用MeOH(30mL)洗滌。在減壓下將合併的濾液濃縮以提供75mg(32%產率)外消旋N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-25:75。管柱:Chiralpak OX-3(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物351):LCMS:m/z實測值488.2[M+H]+,RT=3.50miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.78(br s,1H),8.49-8.44(M,1H),7.63-7.58(M,2H),7.48-7.36(M,2H),6.93(s,1H),5.86(s,1H),4.70-4.54(M,2H),4.25-4.00(M,2H),3.46(M,2H),3.08(s,3H),2.81(t,2H);手性分析SFC:RT=2.32miN,管柱:Chiralpak OX-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物352):LCMS:m/z實測值488.2[M+H]+,RT=3.50miN,(方法A);1H NMR(400MHz,DMSO-d6)δ 11.78(br s,1H),8.49-8.44(M,1H),7.63-7.58(M,2H),7.48-7.36(M,2H),6.93(s,1H),5.86(s,1H),4.70-4.54(M,2H),4.25-4.00(M,2H),3.46(M,2H),3.08(s,3H),2.81(t,2H);手性分析SFC:RT=3.45miN,管柱:Chiralpak OX-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺(化合物190)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-1H-吡咯并[2,3-b]吡啶-2-羧酸(VIfa)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺。LCMS m/z實測值429.3[M+H]+;RT=2.23min(方法D);1H NMR(400MHz,氯仿-d)δ 10.58(s,1H),10.04(s,1H),8.39(t,1H),8.23(dd,1H),7.67(dd,1H),7.43(dd,1H),6.84(d,1H),5.90(s,1H),4.77(d,1H),4.65(d,1H),4.39(d,1H),4.08(dd,1H),3.33(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺(化合物191)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-1H-吡咯并[2,3-b]吡啶-2-羧酸(VIfb)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺。LCMS m/z實測值445.3[M+H]+;RT=2.48min(方法D);1H NMR(400MHz,氯仿-d)δ 10.10(s,1H),9.92(s,1H),8.43(d,1H),8.22(dd,1H),7.96(d,1H),7.42(dd,1H),6.81(d,1H),5.89(s,1H),4.74(d,1H),4.63(d,1H),4.39(d,1H),4.08(dd,1H),3.32(s,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺(化合物192)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-溴-1H-吡咯并[2,3-b]吡啶-2-羧酸(VIfc)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺。LCMS m/z實測值489.2[M+H]+;RT=2.55min(方法D);1H NMR(400MHz,氯仿-d)δ 10.76(s,1H),10.15(s,1H),8.52(d,1H),8.23(dd,1H),8.12(d,1H),7.43(dd,1H),6.80(d,1H),5.90(s,1H),4.78(d,1H),4.65(d,1H),4.40(d,1H),4.08(dd,1H),3.32(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺(化合物193)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和6-側氧-5-(三氟甲基)-1H-吡啶-3-羧酸(VIfd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺。LCMS m/z實測值456.2[M+H]+;RT=1.97min(方法D);1H NMR(400MHz,DMSO-d 6)
δ 12.61(s,1H),11.69(s,1H),8.10(dd,1H),7.98(s,2H),7.47(s,1H),5.55(s,1H),4.57(d,1H),4.43(d,1H),4.27(d,1H),3.93(dd,1H),2.84(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺(化合物201)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-6-側氧-1H-吡啶-2-羧酸(VIfe)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=1.82min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.77(s,1H),11.70(s,1H),8.11(dd,1H),7.80-7.69(M,1H),7.39(dd,1H),6.30-6.13(M,1H),5.59-5.46(M,1H),4.57(d,1H),4.44(d,1H),4.32-4.23(M,1H),3.93(d,1H),2.72(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物204)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIff)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值445.2[M+H]+;RT=2.25min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.42(s,1H),11.74(s,1H),8.60(s,1H),8.12(dd,1H),7.67(s,1H),7.41(dd,1H),6.93(s,1H),5.72(s,1H),4.62(d,1H),4.47(d,1H),4.19(d,1H),4.03(dd,1H),3.09(s,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺(化合物205)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-溴-6-側氧-1H-吡啶-3-羧酸(VIfg)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺。LCMS m/z實測值466.1[M+H]+;RT=1.86min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.44(s,1H),11.70(s,1H),8.12(dd,1H),8.03(d,1H),7.73(s,1H),7.46(s,1H),5.55(s,1H),4.58(d,1H),4.44(d,1H),4.25(d,1H),3.95(dd,1H),2.85(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺(化合
物206)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-1H-吡咯并[3,2-b]吡啶-2-羧酸(VIfh)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺。LCMS m/z實測值445.2[M+H]+;RT=2.45min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.24(s,1H),11.76(s,1H),8.13(dd,1H),7.89(d,1H),7.44(dd,1H),7.28(d,1H),7.06(s,1H),5.76(d,1H),4.65(d,1H),4.49(d,1H),4.20(d,1H),4.04(dd,1H),3.15(s,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物213)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfi)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值489.2[M+H]+;RT=2.47min(方法D;1H NMR(400MHz,DMSO-d 6)
δ 12.44(s,1H),11.76(s,1H),8.61(s,1H),8.23-8.02(M,1H),7.83(s,1H),7.43(dd,1H),6.94(s,1H),5.74(s,1H),4.64(d,1H),4.49(d,1H),4.21(d,1H),4.04(d,1H),3.11(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺(化合物214)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-羧酸(VIfj)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺。LCMS m/z實測值479.2[M+H]+;RT=2.70min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.87(s,1H),11.77(s,1H),8.69(s,1H),8.48(s,1H),8.18-8.11(M,1H),7.43(dd,1H),7.03(d,1H),5.71(s,1H),4.64(d,1H),4.49(d,1H),4.22(d,1H),4.05(d,1H),3.08(s,3H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺(化合物215)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-6-側氧-1H-吡啶-3-羧酸(VIfk)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=1.80min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.49(s,1H),11.71(s,1H),8.17-8.06(M,1H),7.86(s,1H),7.70(s,1H),7.51-7.40(M,1H),5.55(s,1H),4.58(d,1H),4.44(d,1H),4.25(d,1H),3.96(dd,1H),2.85(s,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺(化合物216)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-6-側氧-1H-吡啶-3-羧酸(VIfl)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺。LCMS m/z實測值466.1[M+H]+;RT=2.06min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.75(s,1H),11.72(s,1H),8.13(dd,1H),8.03-7.90(M,1H),7.41(dd,1H),6.22-6.08(M,1H),5.53(s,1H),4.59(d,1H),4.45(d,1H),4.29(d,1H),3.95(d,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯
胺(化合物219)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-羧酸(VIfm)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺。LCMS m/z實測值479.2[M+H]+;RT=2.80min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.44(s,1H),11.77(s,1H),8.14(dd,1H),8.07(d,1H),7.70(d,1H),7.45(dd,1H),7.27(s,1H),5.77(s,1H),4.66(d,1H),4.50(d,1H),4.22(d,1H),4.06(dd,1H),3.17(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺(化合物226)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-6-側氧-1H-吡啶-3-羧酸(VIfn)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺。LCMS m/z實測值406.3[M+H]+;RT=
1.90min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.45(s,1H),11.70(s,1H),8.12(dd,1H),7.54(d,2H),7.43(s,1H),5.55(s,1H),4.59(d,1H),4.44(d,1H),4.23(d,1H),4.00-3.92(M,1H),2.85(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺(化合物232)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-1H-吡咯并[3,2-b]吡啶-2-羧酸(VIfo)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺。LCMS m/z實測值429.3[M+H]+;RT=2.89min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.17(s,1H),11.73(s,1H),8.11(dd,1H),7.98(t,1H),7.43(dd,1H),7.02-6.95(M,2H),5.74(s,1H),4.63(d,1H),4.47(d,1H),4.17(d,1H),4.03(dd,1H),3.14(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-羥基-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺(化合物243)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-羥基-6-側氧-1,6-二氫吡啶-2-羧酸(VIfp)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-羥基-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺。LCMS m/z實測值404.2[M+H]+;RT=2.51min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.10(s,1H),11.71(s,1H),9.52(s,1H),8.12(dd,1H),7.50-7.34(M,1H),6.70(s,1H),6.21(s,1H),5.54(s,1H),4.59(d,1H),4.45(d,1H),4.24(d,1H),3.95(d,1H),2.78(s,3H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺(化合物244)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-溴-2,3-二氟-苯甲酸(VIfq)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺。LCMS m/z實測值485.1[M+H]+;RT=3.56min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.14(dd,1H),7.70
-7.64(M,1H),7.40(dd,1H),7.36-7.30(M,1H),5.65(s,1H),4.59(d,1H),4.47(d,1H),4.25(d,1H),4.03(dd,1H),2.67(s,3H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺(化合物245)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-溴-2,5-二氟-苯甲酸(VIfr)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺。LCMS m/z實測值485.1[M+H]+;RT=3.56min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.13(dd,1H),7.88(dd,1H),7.75-7.65(M,1H),7.38(dd,1H),5.62(s,1H),4.59(d,1H),4.46(d,1H),4.25(d,1H),4.02(dd,1H),2.65(s,3H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺(化合物246)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-溴-
2,6-二氟-苯甲酸(VIfs)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺。LCMS m/z實測值485.1[M+H]+;RT=3.55min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.75(s,1H),8.14(dd,1H),7.72-7.62(M,2H),7.33(dd,1H),5.68-5.63(M,1H),4.60(d,1H),4.48(d,1H),4.10-4.05(M,2H),2.73-2.63(M,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺(化合物247)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和6-側氧-5-(三氟甲基)-1H-吡啶-2-羧酸(VIft)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺。LCMS m/z實測值456.2[M+H]+;RT=2.92min(方法D);1H NMR(400MHz,DMSO-d 6)δ 13.03(s,1H),11.74(s,1H),8.13(dd,1H),7.98(d,1H),7.46-7.36(M,1H),6.31(d,1H),5.54(s,1H),4.60(d,1H),4.46(d,1H),4.31(d,1H),3.95(d,1H),2.74(s,3H).
5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfu)
步驟i. 在室溫下攪拌4-甲基-5-硝基-2-(三氟甲基)吡啶
(0.22g,1.1mmol)和草酸二乙酯(0.65mL,4.8mmol)的混合物,然後逐滴加入DBU(0.38mL,2.6mmol)。在室溫下將所得深紅紫色混合物攪拌18小時。在減壓下蒸發混合物。混合物用AcOH(10mL)稀釋並在氮氣下溫熱至60℃,然後將鐵粉(0.12g,2.1mmol)加入到劇烈攪拌後的溶液中。在70℃下,在氮氣下將反應混合物加熱過夜。將懸浮液冷卻至室溫並用水(50mL)稀釋。將固體過濾,用水(2 x 25mL)漂洗,並通過抽吸進行部分乾燥。取固體到EtOAc(50mL)中,經Na2SO4乾燥並通過CELITE®塞過濾。在減壓下蒸發濾液以提供作為棕色固體的5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(0.24g,87%產率)。LCMS m/z實測值259.2[M+H]+;RT=1.00min(方法B);1H NMR(400MHz,DMSO-d 6 )δ 12.93(s,1H),8.95(s,1H),8.23(s,1H),7.36(s,1H),4.40(q,2H),1.36(t,3H).
步驟ii. 在室溫下將5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(0.24g,0.93mmol)在aq.NaOH溶液(1M,4mL)中的懸浮液攪拌2小時。將反應混合物冷卻至5℃並用aq.HCl溶液(1M,~5mL)酸化。將混合物攪拌10分鐘,然後用EtOAc(50mL)萃取。將層分離。有機層經Na2SO4乾燥,過濾和蒸發,然後經歷高真空1小時以提供作為淺棕色固體的5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfu)(0.21g,97%產率)。LCMS m/z實測值231.1[M+H]+;RT=0.97min(方法B);1H NMR(400MHz,DMSO-d 6 )δ 13.72(s,1H),12.80(s,1H),8.92(s,1H),8.22(s,1H),7.29(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物251)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值479.3[M+H]+;RT=3.61min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.75(s,1H),11.77(s,1H),8.95(s,1H),8.21-8.09(M,2H),7.46(dd,1H),7.16(s,1H),5.77(s,1H),4.66(d,1H),4.51(d,1H),4.24(d,1H),4.07(dd,1H),3.14(s,3H).
(S)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺(化合物252)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和2-(3-溴苯基)-2,2-二氟-醋酸(VIfv)合成鏡像異構純的(S)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺。LCMS m/z實測值499.2[M+H]+;RT=4.03min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.11(dd,1H),7.80(d,1H),7.70(s,1H),7.62(d,1H),7.51(t,1H),7.12(dd,1H),5.55(s,1H),4.55(d,1H),4.43(d,1H),4.13(d,1H),
3.98(dd,1H),2.69(s,3H).
(S)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺(化合物253)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和2-(4-溴苯基)-2,2-二氟-醋酸(VIfw)合成鏡像異構純的(S)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺。LCMS m/z實測值499.2[M+H]+;RT=4.02min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.10(dd,1H),7.76(d,2H),7.55(d,2H),7.04(dd,1H),5.52(s,1H),4.54(d,1H),4.43(d,1H),4.12(d,1H),3.98(dd,1H),2.67(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺(化合物512)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和2,2-二氟-2-苯基-醋酸(VIfx)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺。LCMS m/z實測值421.3[M+H]+;RT=4.17min(方法D);
1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.09(t,1H),7.62-7.50(M,5H),7.09(dd,1H),5.56(s,1H),4.53(d,1H),4.42(d,1H),4.11(d,1H),3.98(dd,1H),2.68(s,3H).
5-溴-1H-吡咯并[3,2-b]吡啶-2-羧酸(Vify)
步驟i. 用6-溴-2-碘-吡啶-3-胺(0.50g,1.7mmol)、DABCO(0.56g,5.0mmol)、2-側氧丙酸(0.44g,5.0mmol)和乾燥的DMF(10mL)對乾燥的具有攪拌棒的大的微波小瓶進料。將混合物攪拌並用氮氣吹掃15分鐘,然後加入Pd(OAc)2(376mg,1.67mmol)並使吹掃持續10分鐘。將小瓶密封並在130℃下於防爆屏蔽後的反應區段中加熱4小時,然後冷卻至室溫。觀察到氣壓升高並經由遠離防爆屏蔽後的化學家指向的針將其小心地釋放。在減壓下蒸發DMF。取殘餘物到EtOAc(100mL)中用並NaOH水溶液(2N,2 x 50mL)萃取。合併的水層用EtOAc(50mL)萃取。將水層冷卻至0-5℃並用aq.HCl溶液(2N,105mL)酸化至pH 3-4。用EtOAc(4 x 50mL)萃取酸性的水性混合物。合併的有機層用飽和aq.鹽水溶液(50mL)洗滌,經Na2SO4乾燥,通過CELITE®過濾,並在減壓下蒸發以提供作為黃色固體的5-溴-1H-吡咯并[3,2-b]吡啶-2-羧酸(VIfy)(0.19g,47%產率)。LCMS m/z實測值241.1[M+H]+;RT=1.07min(方法B);1H NMR(400MHz,DMSO-d 6 )δ 13.53(s,1H),12.33(s,1H),7.78(dd,1H),7.41(d,1H),7.13(dd,1H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺(化合物268)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-溴-1H-吡咯并[3,2-b]吡啶-2-羧酸(VIfy)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺。LCMS m/z實測值489.2[M+H]+;RT=3.95min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.24(s,1H),11.73(s,1H),8.13(dd,1H),7.80(d,1H),7.45(dd,1H),7.39(d,1H),7.07(s,1H),5.76(s,1H),4.65(d,1H),4.49(d,1H),4.20(d,1H),4.04(dd,1H),3.15(s,3H).
(S)-1-(4-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺(化合物513)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(4-氯苯基)氮雜丁烷-3-羧酸(VIfz)合成鏡像異構純的(S)-1-(4-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺。LCMS m/z實測值460.3[M+H]+;RT=4.13min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.11(dd,1H),7.28-7.18(M,3H),6.50-6.44(M,2H),5.56(s,1H),
4.57(d,1H),4.42(d,1H),4.13-3.87(M,6H),3.78(t,1H),2.72(s,3H).
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺(化合物269)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和二環[4.2.0]八-1,3,5-三烯-7-羧酸(VIfza)合成N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺的非鏡像異構物混合物。LCMS m/z實測值397.3[M+H]+;RT=4.05min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.65(s,1H),8.16-8.06(M,1H),7.27-6.88(M,5H),5.57-5.50(M,1H),4.76-4.68(M,1H),4.60(d,1H),4.44(d,1H),4.08-3.90(M,2H),3.59-3.21(M,2H),3.01-2.94(M,3H).
N-[(1S)-8,9-二氟-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-1-基]-5-氟-N-甲基-6-側氧-1H-吡啶-2-甲醯胺(化合物270)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-
6-側氧-1H-吡啶-2-羧酸(VIfzb)合成鏡像異構純N-[(1S)-8,9-二氟-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-1-基]-5-氟-N-甲基-6-側氧-1H-吡啶-2-甲醯胺(按Bioorganic & Medicinal Chemistry(2009),17(16),6106-6122中所描述的製備)。LCMS m/z實測值406.3[M+H]+;RT=3.30min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.75(s,1H),11.72(s,1H),8.13(dd,1H),7.44-7.37(M,2H),6.20(s,1H),5.54(s,1H),4.59(d,1H),4.45(d,1H),4.27(d,1H),3.96(d,1H),2.74(s,3H).
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺(化合物279)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-氟二環[4.2.0]八-1,3,5-三烯-7-羧酸(VIfzc)合成N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺的非鏡像異構物混合物。LCMS m/z實測值415.3[M+H]+;RT=4.15min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.12(dd,1H),7.23-6.77(M,4H),5.57-5.47(M,1H),4.75-4.65(M,1H),3.52-3.06(M,2H),4.64-4.57(M,1H),4.48-4.41(M,1H),4.09-3.98(M,1H),3.98-3.90(M,1H),2.97-2.90(M,3H).
1-(噻吩-3-基)氮雜丁烷-3-羧酸(Vifzd)
步驟i. 在真空下將氮雜丁烷-3-羧酸甲酯鹽酸鹽(250.0mg,1.7mmol)、3-噻吩硼酸(253.0mg,2.0mmol)、醋酸銅(449.0mg,2.5mmol)、TEA(1.2mL,8.3mmol)和活化的3Å MS在乾燥的1,2-DCE(30mL)中的混合物脫氣。將反應置於氧氣氛下(經由氣球)並在室溫下將深藍色的混合物攪拌過夜。反應混合物通過CELITE®塞過濾並用CH2Cl2(50mL)漂洗濾餅。將綠色的濾液蒸發成固體並經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並蒸發,以提供作為黃褐色油的1-(3-噻吩基)氮雜丁烷-3-羧酸甲酯(57.6mg,18%產率)。LCMS m/z實測值198.1[M+H]+;RT=2.37min(方法C);1H NMR(400MHz,CDCl3)δ 7.19(dd,1H),6.58-6.51(M,1H),5.98-5.93(M,1H),4.07-3.96(M,4H),3.74(s,3H),3.59-3.50(M,1H).
步驟ii. 在1打蘭小瓶(dram vial)中,向1-(3-噻吩基)氮雜丁烷-3-羧酸甲酯(57.6mg,0.29mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物加入LiOH(8.4mg,0.35mmol)。在室溫下將懸浮液攪拌過夜。將反應混合物蒸發至乾燥以提供1-(3-噻吩基)氮雜丁烷-3-羧酸(VIfzd)(53.5mg,>100%產率),作為鋰鹽,為黃褐色固體。LCMS m/z實測值184.1[M+H]+;RT=1.20min(方法B);1H NMR(400MHz,DMSO-d 6 )δ 7.31(dd,1H),6.52(dd,1H),5.90(dd,1H),3.75(dd,3H),3.68(t,3H),2.98(tt,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺(化合物282)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(3-噻吩基)氮雜丁烷-3-羧酸(VIfzd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺。LCMS m/z實測值432.3[M+H]+;RT=4.05min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.11(dd,1H),7.41-7.36(M,1H),7.24(dd,1H),6.63-6.59(M,1H),6.11-6.07(M,1H),5.55(s,1H),4.57(d,1H),4.42(d,1H),4.05-3.84(M,6H),3.72(t,1H),2.70(s,3H).
1-(4-溴噻吩-3-基)氮雜丁烷-3-羧酸(VIfze)
步驟i. 在真空下將氮雜丁烷-3-羧酸甲酯鹽酸鹽(1.00g,6.6mmol)、(4-溴-3-噻吩基)硼酸(1.64g,7.92mmol)、醋酸銅(1.80g,9.90mmol)、TEA(4.60mL,33.0mmol)和3Å MS在乾燥的1,2-DCE(30mL)中的混合物脫氣。將反應置於氧氣氛下(經由氣球)並在室溫下將深藍色的混合物攪拌一周。通過CELITE®塞過濾藍綠色的懸浮液並用CH2Cl2漂洗濾餅。將綠色濾液蒸發並經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並在減壓下蒸發以提供作為黃褐色油的1-(4-溴-3-噻吩基)氮雜丁烷-3-羧酸甲酯(66.8mg,4%產率)。LCMS m/z實測值276.1[M+H]+;RT=2.93min(方法C);1H NMR(400MHz,CDCl3)δ 7.18-7.12(M,1H),6.13-6.05(M,1H),4.23-4.17(M,2H),4.07-4.01(M,2H),3.74(s,
3H),3.58-3.48(M,1H).
步驟ii. 在1打蘭的小瓶中,向1-(4-溴-3-噻吩基)氮雜丁烷-3-羧酸甲酯(66.8mg,0.24mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物加入LiOH(7.0mg,0.3mmol)。在室溫下將懸浮液攪拌過夜。將反應混合物蒸發至乾燥以提供1-(4-溴-3-噻吩基)氮雜丁烷-3-羧酸(VIfze)(63.4mg,>100%產率),作為鋰鹽,為灰白色固體。LCMS m/z實測值262.1[M+H]+;RT=1.20min(方法B);1H NMR(400MHz,DMSO-d 6 )δ 7.49(d,1H),6.23(d,1H),3.89(dd,3H),3.77(t,3H),2.93(tt,1H).
(S)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺(化合物284)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(4-溴-3-噻吩基)氮雜丁烷-3-羧酸(VIfze)合成鏡像異構純的(S)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺。LCMS m/z實測值510.2[M+H]+;RT=4.42min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.69(s,1H),8.15-8.07(M,1H),7.58(dd,1H),7.25(dd,1H),6.45(dd,1H),5.56(s,1H),4.57(d,1H),4.42(d,1H),4.18-4.08(M,2H),4.07-3.97(M,2H),3.96-3.79(M,3H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物
307)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzf)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值411.2[M+H]+;RT=1.24min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.23(s,1H),11.76(s,1H),8.84(s,1H),8.18-8.09(M,2H),7.59(d,1H),7.44(dd,1H),6.98(s,1H),5.76(s,1H),4.65(d,1H),4.49(d,1H),4.20(d,1H),4.08-4.02(M,1H),3.14(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺(化合物308)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1H-吡咯并[3,2-c]吡啶-2-羧酸(VIfzg)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺。LCMS m/z實測值411.2[M+H]+;RT=1.22min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.14(s,1H),
11.76(s,1H),8.91(s,1H),8.24(d,1H),8.13(dd,1H),7.48-7.38(M,2H),7.11(s,1H),5.76(s,1H),4.65(d,1H),4.49(d,1H),4.19(d,1H),4.05(dd,1H),3.17(s,3H).
(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺(化合物309)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和6-氯-1H-吡咯并[3,2-c]吡啶-2-羧酸(VIfzh)合成鏡像異構純的(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺。LCMS m/z實測值445.2[M+H]+;RT=1.87min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.29(s,1H),11.76(s,1H),8.73(s,1H),8.13(dd,1H),7.48-7.40(M,2H),7.16(s,1H),5.75(s,1H),4.65(d,1H),4.49(d,1H),4.19(d,1H),4.08-4.00(M,1H),3.16(s,3H).
5-氟-1H-吡咯并[2,3-c]吡啶-2-羧酸(Vifzi)
步驟i. 向室溫下2-氟-4-甲基-5-硝基-吡啶(1.0g,6.4mmol)和草酸二乙酯(2.2mL,16.0mmol)的溶液逐滴加入DBU(1.1mL,7.1mmol)。在室溫下將混合物攪拌4小時。混合物用EtOAc(50mL)稀釋,然後用AcOH(1mL)和水(20mL)的混合物稀釋。將層分離並用EtOAc(2 x 20mL)萃取水層。合併的有機層用水(20
mL)和飽和NaCl溶液(20mL)洗滌。有機層經Na2SO4乾燥,過濾並在減壓下蒸發。所回收的油經由正相SiO2層析法(0%-40% EtOAc/己烷)純化。收集所期望的級分並在減壓下蒸發以提供作為櫻桃紅固體的3-(2-氟-5-硝基吡啶-4-基)-2-側氧丙酸乙酯(0.42g)作為。LCMS m/z實測值255.1[M+H]+;RT=2.75min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.91(s,1H),7.89(s,1H),6.72(d,1H),4.71(s,1H),4.31(q,2H),1.30(t,3H).
步驟ii. 將來自上文的櫻桃紅固體(0.42g)溶解於AcOH(10mL)中並在氮氣下溫熱至60℃,然後加入鐵粉(0.72g,12.8mmol)。在70℃,在氮氣下將混合物加熱。2小時後,將混合物冷卻至室溫,然後用水(25mL)稀釋。將所得固體過濾,用水漂洗並通過抽吸進行部分乾燥。將固體懸浮於MeOH(20mL)中,超聲處理1分鐘,然後通過CELITE®塞過濾。在減壓下蒸發濾液以提供作為黃褐色固體的5-氟-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(0.31g,22%產率)。LCMS m/z實測值209.1[M+H]+;RT=2.57min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 12.51(s,1H),8.48-8.43(M,1H),7.35-7.30(M,1H),7.19-7.15(M,1H),4.38(q,2H),1.35(t,4H).
步驟iii. 在室溫下將5-氟-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(150mg,0.72mmol)在aq.NaOH溶液(1M,3mL)中的懸浮液攪拌2小時,得到溶液。將反應混合物冷卻至5℃並用aq.HCl溶液(1M,~4mL)酸化。將混合物攪拌10分鐘,然後過濾,用水漂洗並通過抽吸進行部分乾燥。在高真空下將固體乾燥過夜以提供作為灰白色固體的5-氟-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzi)(129.6mg,99%)。LCMS m/z實測值181.1[M+H]+;RT=1.88min(方法C);1H NMR(400MHz,DMSO-d6)δ 13.63(s,1H),12.38(s,1H),8.44-8.40(M,1H),7.33-7.29(M,1H),7.12-7.08(M,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合
物310)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzi)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值429.2[M+H]+;RT=2.03min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.32(s,1H),11.75(s,1H),8.43(s,1H),8.14(dd,1H),7.43(dd,1H),7.26(s,1H),6.96(s,1H),5.74(s,1H),4.64(d,1H),4.49(d,1H),4.21(d,1H),4.05(dd,1H),3.11(s,3H).
4-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸(Vifzj)
步驟i. 向室溫下3-溴-4-甲基-5-硝基-吡啶(1.0g,4.6mmol)和草酸二乙酯(2.9mL,21mmol)的溶液逐滴加入DBU(0.76mL,5.1mmol)。在室溫下,在氮氣下將反應混合物攪拌過夜。在減壓下,在70℃的水浴下使反應混合物蒸發。將殘餘物溶解在AcOH(10mL)中並溫熱至60℃,然後加入鐵粉(0.51g,9.2mmol)。在氮氣下將反應混合物劇烈攪拌並在70℃下加熱。2小時後,將反應混合物冷卻至室溫,用30mL水稀釋並將所得沉澱過濾和用水漂洗,並通過抽吸進行部分乾燥。將固體懸浮於MeOH中,超聲處理1分鐘,然後通過CELITE®塞過濾,用MeOH漂洗濾餅。將濾液蒸發以提供作為深紅
棕色固體的4-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(0.60g,46%產率)。LCMS m/z實測值269.0[M+H]+;RT=2.23min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 12.88(s,1H),8.82(s,1H),8.34(s,1H),7.07(d,1H),4.39(q,2H),1.36(t,3H).
步驟ii. 在室溫下將4-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(150mg,0.56mmol)在aq.NaOH溶液(1M,3mL)中的懸浮液攪拌過夜。向該懸浮液再加入aq.NaOH溶液(1M,1mL)和MeOH(1mL)並在室溫下將混合物攪拌4小時。將反應混合物冷卻至5℃並用aq.HCl溶液(1M,~5mL)酸化。將混合物攪拌10分鐘,然後用EtOAc(50mL)萃取。將層分離。有機層經Na2SO4乾燥,過濾並蒸發,然後經歷高真空1小時以提供作為淺棕色固體的4-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzj)(134mg,100%產率)。LCMS m/z實測值241.0[M+H]+;RT=1.01min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 13.74(s,1H),12.77(s,1H),8.80(s,1H),8.32(s,1H),7.02(d,1H).
(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物312)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-溴-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzj)合成鏡像異構純的(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值489.1
[M+H]+;RT=1.53min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.66(s,1H),11.76(s,1H),8.81(s,1H),8.29(s,1H),8.14(dd,1H),7.45(dd,1H),6.89(s,1H),5.74(s,1H),4.64(d,1H),4.49(d,1H),4.23(d,1H),4.08-4.01(M,1H),3.13(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺(化合物313)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和2-(二氟甲基)吡啶-4-羧酸(VIfzk)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺。LCMS m/z實測值422.1[M+H]+;RT=1.97min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.79(d,1H),8.18-8.11(M,1H),7.75(s,1H),7.60(d,1H),7.48(dd,1H),7.02(t,1H),5.68(s,1H),4.59(d,1H),4.47(d,1H),4.36(d,1H),4.07-3.96(M,1H),2.68(s,3H).
7-溴呋喃并[3,2-c]吡啶-2-羧酸(VIfzl)
步驟i. 向室溫下3-溴-5-甲基-4-硝基-吡啶(0.50g,2.3mmol)和草酸二乙酯(1.44mL,10.6mmol)的溶液逐滴加入DBU(0.38mL,2.5mmol)。在室溫下,在氮氣下將反應混合物攪拌48小時。在100℃下將混合物加熱1小時。將反應混合物冷卻至室溫。將
殘餘物溶解在AcOH(10mL)中並溫熱至60℃,然後加入鐵粉(0.26g,4.6mmol)。在氮氣下將反應混合物劇烈攪拌並在70℃下加熱2小時。將反應混合物冷卻至室溫,用30mL水稀釋並將所得沉澱過濾,用水漂洗並通過抽吸進行部分乾燥。粗的紅棕色固體不含所期望的產物物質(mass);然而,酸性的水層包含所期望的物質。在減壓下將水層蒸發以提供深棕色的粘性樹脂。使該樹脂分配在水(50mL)和EtOAc(50ml)之間,然後用aq.K2CO3溶液(1M)小心地使其變成鹼性,達到pH 9。用EtOAc(2 x 50mL)萃取水層。用水(2 x 50mL)洗滌合併的有機層,然後用飽和NaCl溶液(15mL)洗滌。有機層經Na2SO4乾燥,過濾並在減壓下蒸發。殘餘物經由正相SiO2層析法(0-100% EtOAc/己烷)純化。收集所期望的級分並蒸發,以提供作為淺黃色固體的7-溴呋喃并[3,2-c]吡啶-2-羧酸乙基酯(26.7mg,4%產率)。LCMS m/z實測值269.9[M+H]+;RT=2.72min(方法C);1H NMR(400MHz,CDCl3)δ 8.94(s,1H),8.71(s,1H),7.63(s,1H),4.48(q,2H),1.45(t,3H).
步驟ii. 用7-溴呋喃并[3,2-c]吡啶-2-羧酸乙基酯(26.7mg,0.10mmol)、MeOH(0.5mL)和NaOH溶液(1M,0.5mL,5eq.)對具有攪拌棒的1打蘭小瓶進料,並將混合物劇烈攪拌。4小時後,用HCl溶液(1M,0.6mL)調節混合物pH。將所得沉澱過濾並用水漂洗。使該固體與MeOH(2 x 10mL)共沸以提供作為白色固體的7-溴呋喃并[3,2-c]吡啶-2-羧酸(VIfzl)(16.7mg,71%產率)。使用所回收的材料而無需進一步純化。LCMS m/z實測值243.0[M+H]+;RT=1.02min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 9.05(s,1H),8.77(s,1H),7.89(s,1H).
(S)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺(化合物356)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和7-溴呋喃并[3,2-c]吡啶-2-羧酸(VIfzl)合成鏡像異構純的(S)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺。LCMS m/z實測值490.0[M+H]+;RT=1.99min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.76(s,1H),9.01(s,1H),8.74(s,1H),8.23-8.09(M,1H),7.79(s,1H),7.40(dd,1H),5.67(s,1H),4.64(d,1H),4.49(d,1H),4.23(d,1H),4.08-3.99(M,1H),3.10(s,3H).
3-氯-1-(二氟甲基)-2H-吲唑-6-羧酸(Vifzm)、3-氯-2-(二氟甲基)-2H-吲唑-6-羧酸(Vifzn)、2-(二氟甲基)-3-甲氧基-2H-吲唑-6-羧酸(VIfzo)和3-甲氧基-1H-吲唑-6-羧酸(Vifzp)
步驟i. 向1H-吲唑-6-羧酸甲基酯(1.0g,5.7mmol)在乾燥的DMF(10mL)中的攪拌後的溶液加入N-氯代琥珀醯亞胺
(0.83g,6.2mmol),並在室溫下將混合物攪拌過夜。將水(50mL)加入到混合物中,劇烈攪拌以產生濃稠的蠟狀固體。將固體過濾並用水漂洗。將蠟狀固體溶解在EtOAc(50mL)中並將殘餘的水層分離。用飽和aq.Na2S2O3溶液(10mL)、水(2 x 10mL)和飽和aq.NaCl溶液(10mL)洗滌有機層。有機層經Na2SO4乾燥,過濾並在減壓下蒸發以提供作為白色固體的甲基3-氯-1H-吲唑-6-羧酸酯(1.16g,97%產率)。LCMS m/z實測值211.0[M+H]+;RT=2.66min(方法C);1H NMR(400MHz,CDCl3)δ 10.12(s,1H),8.23(s,1H),7.92-7.89(M,1H),7.76(d,1H),3.98(s,3H).
步驟ii. 向具有攪拌棒和帶有橡膠隔板的蓋的乾燥的閃光小瓶加入3-氯-1H-吲唑-6-羧酸甲基酯(0.10g,0.47mmol)和無水氟化鉀(60mg,0.95mmol),並將小瓶密封並保持在氮氣氛下。經由注射器加入乾燥的乙腈(5mL)。將混合物劇烈攪拌5分鐘,然後經由注射器加入(溴二氟甲基)膦酸二乙酯(80μL,0.47mmol)。在室溫下,在氮氣下將混合物攪拌過夜。再加入氟化鉀(60mg,0.95mmol)和(溴二氟甲基)膦酸二乙酯(80μL,0.47mmol),並將懸浮液劇烈攪拌24小時。通過CELITE®塞過濾混合物並用EtOAc漂洗。在減壓下蒸發濾液。殘餘物通過快速SiO2層析法(0-40% EtOAc/己烷)純化。收集所期望的級分並蒸發,以提供作為灰白色固體,第一洗脫峰的3-氯-1-(二氟甲基)-1H-吲唑-6-羧酸甲基酯(44.1mg,36%產率)。LCMS m/z實測值261.1[M+H]+;RT=3.18min(方法C);1H NMR(400MHz,CDCl3)δ 8.46(t,1H),8.05(dd,1H),7.79(dd,1H),7.40(d,1H),4.00(s,3H).3-氯-2-(二氟甲基)-2H-吲唑-6-羧酸甲基酯(44.1mg,36%產率)作為灰白色固體,第二洗脫峰。LCMS m/z實測值261.0[M+H]+;RT=2.97min(方法C);1H NMR(400MHz,CDCl3)δ 8.46(t,1H),7.79(dd,1H),7.65(dd,1H),7.54(t,1H),3.97(s,3H).
步驟iii. 用3-氯-1-(二氟甲基)-1H-吲唑-6-羧酸甲基酯
(44mg,0.17mmol)、MeOH(0.5mL)和aq.NaOH溶液(1M,0.9mL,5eq.)對具有攪拌棒的1打蘭小瓶進料。在室溫下將反應混合物劇烈攪拌過夜。將反應混合物冷卻至0-5℃並加入aq.HCl溶液(1N,~1mL)以將pH調節至約5-6。將所得懸浮液攪拌,過濾,用水漂洗並通過抽吸進行乾燥,以提供作為白色固體的3-氯-1-(二氟甲基)-1H-吲唑-6-羧酸(VIfzm)(39.9mg,95%產率)。LCMS m/z實測值247.0[M+H]+;RT=2.74min(方法C);1H NMR(400MHz,DMSO-d6)δ 13.61(s,1H),8.52(d,1H),8.36(t,1H),7.99(dd,1H),7.94(dd,1H).
步驟iv. 以與上文所述類似的方式使3-氯-2-(二氟甲基)-2H-吲唑-6-羧酸酯(89mg,0.34mmol)反應而無需純化,以提供作為白色固體的2-(二氟甲基)-3-甲氧基-2H-吲唑-6-羧酸(Vifzo)、3-甲氧基-1H-吲唑-6-羧酸(VIfzp)和所期望的3-氯-1-(二氟甲基)-2H-吲唑-6-羧酸(VIfzn)(81mg,75%產率)的粗混合物。LCMS m/z實測值247.0[M+H]+;RT=2.53min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 13.38(s,1H),8.51-8.33(M,1H),8.27(t,1H),7.80(dd,1H),7.71(dd,1H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺(化合物357)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和3-氯-
1-(二氟甲基)-1H-吲唑-6-羧酸(VIfzm)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺。LCMS m/z實測值495.1[M+H]+;RT=2.70min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.43-8.11(M,2H),8.02(s,1H),7.96-7.90(M,1H),7.55(dd,1H),7.46-7.40(M,1H),5.73(s,1H),4.60(d,1H),4.48(d,1H),4.34(d,1H),4.05(dd,1H),2.74-2.68(M,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺(化合物358)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和粗3-氯-2-(二氟甲基)-2H-吲唑-6-羧酸(VIfzn)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺。LCMS m/z實測值495.1[M+H]+;RT=2.51min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.46-8.11(M,2H),7.83-7.78(M,2H),7.53(dd,1H),7.23-7.17(M,1H),5.71(s,1H),4.60(d,1H),4.47(d,1H),4.33(d,1H),4.05(dd,1H),2.74(d,3H).
3-氯-1-(二氟甲基)吲唑-5-羧酸(VIfzq)和3-氯-2-(二氟甲基)吲唑-5-羧酸(Vifzr)
步驟i. 向1H-吲唑-5-羧酸甲基酯(1.0g,5.7mmol)在乾燥的DMF(10mL)中的攪拌後的溶液加入N-氯代琥珀醯亞胺(0.83g,6.2mmol)。在室溫下將混合物攪拌過夜。將水(50mL)加入到混合物中,劇烈攪拌以產生濃稠的蠟狀固體。將固體過濾並用水漂洗。將蠟狀固體溶解在EtOAc(50mL)中並將殘餘的水層分離。用飽和aq.Na2S2O3溶液(10mL)、水(2 x 10mL)和飽和aq.NaCl溶液(10mL)洗滌有機層。有機層經Na2SO4乾燥,過濾並蒸發以提供作為灰白色固體的3-氯-1H-吲唑-5-羧酸甲基酯(1.10g,92%產率)。LCMS m/z實測值211.1[M+H]+;RT=2.61min(方法C);1H NMR(400MHz,CDCl3)δ 10.21(s,1H),8.49(s,1H),8.16-8.12(M,1H),7.52-7.48(M,1H),3.97(s,3H).
步驟ii. 向具有攪拌棒和帶有橡膠隔板的蓋的乾燥的閃光小瓶加入3-氯-1H-吲唑-5-羧酸甲基酯(0.25g,1.2mmol)和無水氟化鉀(0.28g,4.7mmol),並將小瓶密封並保持在氮氣氛下。經由注射器加入乾燥的乙腈(5mL)。將混合物劇烈攪拌5分鐘,然後經由注射器加入(溴二氟甲基)膦酸二乙酯(0.32mL,1.8mmol)。在室溫下,在氮氣下將混合物攪拌5小時。混合物通過CELITE®塞過濾並用EtOAc漂洗。將濾液蒸發並經由正相SiO2層析法(0-30% EtOAc/己烷)純化殘餘物。收集所期望的級分並蒸發,以提供作為灰白色固體,
第一洗脫峰的3-氯-1-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(127.3mg,44%產率)。LCMS m/z實測值261.0[M+H]+;RT=3.15min(方法C);1H NMR(400MHz,CDCl3)δ 8.50-8.48(M,1H),8.25(dd,1H),7.81-7.76(M,1H),7.38(t,1H),3.99(s,3H)。3-氯-2-(二氟甲基)-2H-吲唑-5-羧酸酯(110.1mg,36%產率)作為灰白色固體,第二洗脫峰。LCMS m/z實測值261.0[M+H]+;RT=2.94min(方法C);1H NMR(400MHz,CDCl3)δ 8.47-8.43(M,1H),7.97(dd,1H),7.72-7.68(M,1H),7.52(t,1H),3.97(s,3H).
步驟iii. 將3-氯-1-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(127.3mg,0.49mmol)在aq.NaOH溶液(1M,2.5mL)中的懸浮液劇烈攪拌過夜。將反應混合物冷卻至0-5℃並加入aq.HCl溶液(1N,~2.5mL)以將pH調節至約5-6。將所得懸浮液攪拌,過濾,用水漂洗並通過抽吸進行乾燥,以提供作為白色固體的3-氯-1-(二氟甲基)-1H-吲唑-5-羧酸(VIfzq)(113.7mg,94%產率)。LCMS m/z實測值247.0[M+H]+;RT=2.69min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 13.37(s,1H),8.35(dd,1H),8.28(t,1H),8.23(dd,1H),8.02(d,1H).
步驟iv. 以與上文所述類似的方式使3-氯-2-(二氟甲基)-2H-吲唑-5-羧酸酯(110.1mg,0.42mmol)反應而無需純化,以提供作為黃褐色固體的2-(二氟甲基)-3-甲氧基-2H-吲唑-5-羧酸(Vifzs)、3-甲氧基-1H-吲唑-5-羧酸(VIfzt)和所期望的3-氯-2-(二氟甲基)-2H-吲唑-5-羧酸(Vifzr)的粗混合物(77mg,74%產率)。LCMS m/z實測值247.0[M+H]+;RT=2.45min(方法C).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺(化合物359)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和3-氯-1-(二氟甲基)-1H-吲唑-5-羧酸(VIfzq)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值495.1[M+H]+;RT=2.60min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.41-8.09(M,2H),7.99(d,1H),7.93(s,1H),7.72(dd,1H),7.58(dd,1H),5.73(s,1H),4.60(d,1H),4.48(d,1H),4.37(d,1H),4.04(dd,1H),2.74(s,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺(化合物360)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和粗3-氯-2-(二氟甲基)-2H-吲唑-5-羧酸(VIfzr)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺。LCMS m/z實測值495.1
[M+H]+;RT=2.39min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.64(s,1H),8.43-8.09(M,2H),7.81(d,1H),7.78(s,1H),7.54(dd,1H),7.39(d,1H),5.70(s,1H),4.58(d,1H),4.45(d,1H),4.32(d,1H),4.05-3.98(M,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺(化合物367)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和粗2-(二氟甲基)-3-甲氧基-2H-吲唑-6-羧酸(VIfzo)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺。LCMS m/z實測值491.1[M+H]+;RT=2.15min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.64(s,1H),8.20-8.05(M,1H),8.04-7.78(M,2H),7.58-7.41(M,2H),6.93-6.82(M,1H),5.70(s,1H),4.59(d,1H),4.52-4.37(M,4H),4.30(d,1H),4.12-3.99(M,1H),2.74(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺(化合物368)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和粗2-(二氟甲基)-3-甲氧基-2H-吲唑-5-羧酸(VIfzs)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺。LCMS m/z實測值491.1[M+H]+;RT=2.12min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.18-7.79(M,3H),7.59-7.49(M,2H),7.21(d,1H),5.70(s,1H),4.60(d,1H),4.46(d,4H),4.29(d,1H),4.09-3.98(M,1H),2.78(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺(化合物369)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和粗3-甲氧基-1H-吲唑-5-羧酸(VIfzt)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值441.2[M+H]+;RT=1.85min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.18(s,1H),11.70(s,
1H),8.18-8.10(M,1H),7.65(s,1H),7.61-7.52(M,1H),7.42(d,1H),7.37(d,1H),5.70(s,1H),4.59(d,1H),4.46(d,1H),4.29(d,1H),4.07-4.01(M,1H),4.00(s,3H),2.76(s,3H).
1-(5-氯噻吩-3-基)氮雜丁烷-3-羧酸(Vifzu)
步驟i. 在真空下將氮雜丁烷-3-羧酸甲基酯鹽酸鹽(1.0g,6.6mmol)、(5-氯-3-噻吩基)硼酸(1.3g,7.9mmol)、醋酸銅(1.8g,9.9mmol)、TEA(4.6mL,33mmol)和3Å MS(2.0g)在乾燥的1,2-DCE(30mL)中的混合物脫氣。將反應置於氧氣氛下(經由氣球)並在室溫下將深藍色的混合物攪拌18小時。通過CELITE®塞過濾藍綠色的懸浮液並用CH2Cl2漂洗濾餅。將綠色濾液蒸發並經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並在減壓下蒸發以提供作為黃褐色油的1-(5-氯噻吩-3-基)氮雜丁烷-3-羧酸甲基酯(103mg,6%產率)。LCMS m/z實測值232.1[M+H]+;RT=3.00min(方法C);1H NMR(400MHz,CDCl3)δ 6.41(d,1H),5.68(d,1H),4.03-3.92(M,4H),3.74(s,3H),3.57-3.48(M,1H).
步驟ii. 在1打蘭小瓶中,向1-(5-氯噻吩-3-基)氮雜丁烷-3-羧酸甲基酯(103mg,0.44mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物加入LiOH(13mg,0.53mmol)。在室溫下將懸浮液攪拌過夜。將反應混合物蒸發至乾燥以提供粗1-(5-氯噻吩-3-基)氮雜丁烷-3-羧酸(VIfzu)(101mg),作為鋰鹽,為紅棕色固體。LCMS m/z實測值218.0[M+H]+;RT=2.63min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 6.60-6.58(M,1H),5.79-5.76(M,1H),3.73-3.68(M,2H),3.67-3.62(M,2H),2.96-2.86(M,1H).
(S)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四
氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺(化合物370)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(5-氯噻吩-3-基)氮雜丁烷-3-羧酸(VIfzu)合成鏡像異構純的(S)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺。LCMS m/z實測值466.1[M+H]+;RT=2.63min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.68(s,1H),8.10(dd,1H),7.24(dd,1H),6.72(d,1H),5.98(d,1H),5.55(s,1H),4.57(d,1H),4.42(d,1H),4.07-3.83(M,6H),3.71(t,1H),2.69(s,3H).
(S)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物371)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和7-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzv)合成鏡像異構純的(S)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值445.1
[M+H]+;RT=2.01min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.58(s,1H),11.76(s,1H),8.15(dd,1H),7.96(dd,1H),7.61(d,1H),7.46(dd,1H),6.94(s,1H),5.72(s,1H),4.63(d,1H),4.49(d,1H),4.24(d,1H),4.05(dd,1H),2.97(s,3H).
(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺(化合物372)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-氯-1H-吡咯并[3,2-c]吡啶-2-羧酸(VIfzw)合成鏡像異構純的(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺。LCMS m/z實測值445.1[M+H]+;RT=1.87min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.28(s,1H),11.75(s,1H),8.73(s,1H),8.13(t,1H),7.47-7.39(M,2H),7.15(s,1H),5.75(s,1H),4.65(d,1H),4.49(d,1H),4.19(d,1H),4.04(d,1H),3.16(s,3H).
4-溴-5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(Vifzx)
步驟i. 向室溫下3-溴-2-氯-4-甲基-5-硝基-吡啶(1.2g,4.9mmol)和草酸二乙酯(3.0mL,22mmol)的溶液逐滴加入DBU(0.80mL,5.3mmol)。在室溫下,在氮氣下將反應混合物攪拌過夜。
在減壓下,在70℃水浴溫度下使反應混合物蒸發。將殘餘物溶解在AcOH(10mL)中並溫熱至60℃,然後加入鐵粉(0.54g,9.7mmol)。在氮氣下將反應混合物劇烈攪拌並在70℃下加熱2小時。將反應混合物冷卻至室溫,用水(30mL)稀釋並將所得沉澱過濾並用水漂洗,並通過抽吸進行部分乾燥。粗的紅棕色固體經由正相SiO2層析法(0-10% MeOH/CH2Cl2)純化。收集所期望的級分並蒸發,以提供含雜質的深黃色固體(112mg)。所回收的固體經由正相SiO2層析法(2% MeOH/CH2Cl2等度洗脫)再次純化。收集所期望的級分並在減壓下蒸發,以提供作為淺黃色固體的4-溴-5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(46.6mg,3%產率)。LCMS m/z實測值305.0[M+H]+;RT=3.16min(方法D);1H NMR(400MHz,DMSO-d 6 )δ 13.04(s,1H),8.67-8.62(M,1H),7.08-7.04(M,1H),4.40(q,2H),1.37(t,3H).
步驟ii. 在室溫下將4-溴-5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸乙基酯(46.6mg,0.15mmol)在aq.NaOH溶液(1M,0.75mL)和MeOH(0.25mL)中的懸浮液攪拌過夜。將反應混合物冷卻至5℃並用aq.HCl溶液(1M,~1mL)酸化。將混合物攪拌10分鐘,然後用EtOAc(50mL)萃取。將層分離。水層含有所期望的產物並用CHCl3-MeOH(9:1 v/v,3 x 10mL)萃取。合併有機氯仿層並經Na2SO4乾燥,過濾並蒸發,然後經歷高真空1小時,以提供作為黃色固體的粗4-溴-5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzx)(44mg)。LCMS m/z實測值276.9[M+H]+;RT=2.58min(方法D);1H NMR(400MHz,DMSO-d 6 )δ 12.17(s,1H),10.26(s,1H),8.45(s,1H),6.62(s,1H).
(S)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺(化合物384)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4-溴-5-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸(VIfzx)合成鏡像異構純4-溴-5-氯-N-[(1S)-8,9-二氟-6-側氧-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-1-基]-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺。LCMS m/z實測值523.0[M+H]+;RT=2.55min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.74(br s,1H),11.73(br s,1H)8.62(s,1H),8.17-8.11(M,1H),7.49-7.41(M,1H),6.89(s,1H),5.73(s,1H),4.64(d,1H),4.49(d,1H),4.24(d,1H),4.07-4.01(M,1H),3.12(s,3H).
(S)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺(化合物410)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和4,6-二氯-1H-吡咯并[3,2-c]吡啶-2-羧酸(VIfzy)合成鏡像異構純的(S)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺。LCMS m/z實測值479.1[M+H]+;RT=2.55min(方法D);1H NMR(400MHz,DMSO-d 6)
δ 12.69(s,1H),11.75(s,1H),8.13(dd,1H),7.47(s,1H),7.44(dd,1H),7.08(s,1H),5.73(s,1H),4.64(d,1H),4.49(d,1H),4.21(d,1H),4.03(dd,1H),3.16(s,3H).
3-氯-1-甲基-1H-吲唑-5-羧酸(Vifzz)
步驟i. 向3-氯-1H-吲唑-5-羧酸甲基酯(250.0mg,1.19mmol)在乾燥的MeCN(3mL)中的攪拌後的懸浮液逐滴加入DBU(195uL,1.31mmol),並在室溫下攪拌15分鐘,然後加入碘甲烷(81uL,1.3mmol)並將混合物攪拌過夜。將反應混合物傾倒入水(25mL)中並用EtOAc(2 x 25mL)萃取。合併的有機層經MgSO4乾燥,過濾並蒸發。殘餘物經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並在減壓下蒸發,以提供作為灰白色固體,第一洗脫峰的3-氯-1-甲基-1H-吲唑-5-羧酸甲基酯(203.2mg,76%產率)。LCMS m/z實測值225.0[M+H]+;RT=2.93min(方法C);1H NMR(400MHz,CDCl3)δ 8.45(dd,1H),8.11(dd,1H),7.39(dd,1H),4.06(s,3H),3.96(s,3H).3-氯-2-甲基-2H-吲唑-5-羧酸甲基酯(10.2mg,3.8%產率)作為灰白色固體,第二洗脫峰。LCMS m/z實測值225.0[M+H]+;RT=2.67min(方法C);1H NMR(400MHz,CDCl3)δ 8.41(dd,1H),7.92(dd,1H),7.64(dd,1H),4.19(s,3H),3.95(s,3H).
步驟ii. 將氫氧化鋰(7.0mg,0.29mmol)加入到3-氯-1-甲基-1H-吲唑-5-羧酸甲基酯(55mg,0.24mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物中並在室溫下攪拌過夜。再加入LiOH(3mg)並使攪拌持續24小時。將揮發物蒸發以提供3-氯-1-甲
基-1H-吲唑-5-羧酸(VIfzz)(70mg,>100%產率),作為鋰鹽,為灰白色固體。LCMS m/z實測值211.0[M+H]+;RT=2.40min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.11(dd,1H),8.06(dd,1H),7.49(dd,1H),3.99(s,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺(化合物415)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和3-氯-1-甲基-吲唑-5-羧酸(VIfzz)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值459.2[M+H]+;RT=2.31min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.17-8.10(M,1H),7.79(d,1H),7.74(s,1H),7.58(dd,1H),7.51(d,1H),5.72(s,1H),4.59(d,1H),4.47(d,1H),4.34(d,1H),4.05(s,4H),2.74(s,3H).
3-氯-1-乙基-1H-吲唑-5-羧酸(Vifzza)
步驟i. 向3-氯-1H-吲唑-5-羧酸甲基酯(250mg,1.19mmol)在乾燥的MeCN(3mL)中的攪拌後的懸浮液逐滴加入DBU(195uL,1.31mmol),並在室溫下攪拌15分鐘,然後加入碘乙烷
(105uL,1.31mmol),並在室溫下將混合物攪拌過夜。將反應混合物傾倒入水(25mL)中並用EtOAc(2 x 25mL)萃取。合併的有機層經MgSO4乾燥,過濾並蒸發。殘餘物經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並蒸發,以提供作為灰白色固體,第一洗脫峰的3-氯-1-乙基-1H-吲唑-5-羧酸甲基酯(216.6mg,76%產率)。LCMS m/z實測值239.0[M+H]+;RT=3.13min(方法C);1H NMR(400MHz,CDCl3)δ 8.45(dd,1H),8.10(dd,1H),7.40(dd,1H),4.39(q,2H),3.96(s,3H),1.53(t,3H).3-氯-2-乙基-2H-吲唑-5-羧酸甲基酯(32.7mg,11%產率)作為透明的樹脂,第二洗脫峰。LCMS m/z實測值239.0[M+H]+;RT=2.89min(方法C);1H NMR(400MHz,CDCl3)δ 8.42-8.40(M,1H),7.94-7.89(M,1H),7.65(d,1H),4.52(q,2H),3.95(s,3H),1.62-1.57(M,3H).
步驟ii. 將氫氧化鋰(6.6mg,0.28mmol)加入到3-氯-1-乙基-1H-吲唑-5-羧酸甲基酯(55mg,0.23mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物中。在室溫下將混合物攪拌過夜。再加入LiOH(3mg)並使攪拌持續24小時。將揮發物蒸發以提供粗3-氯-1-乙基-1H-吲唑-5-羧酸(VIfzza)(68mg,>100%產率),作為鋰鹽,為灰白色固體。LCMS m/z實測值225.0[M+H]+;RT=2.61min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.07(s,1H),8.02(d,1H),7.50(d,1H),4.36(q,2H),1.36(t,3H).
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺(化合物416)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二
氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和3-氯-1-乙基-1H-吲唑-5-羧酸(VIfzza)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值473.1[M+H]+;RT=2.54min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.18-8.11(M,1H),7.83(d,1H),7.74(s,1H),7.58(dd,1H),7.50(d,1H),5.72(s,1H),4.60(d,1H),4.51-4.40(M,3H),4.34(d,1H),4.08-4.00(M,1H),2.75(s,3H),1.40(t,3H).
1-(二氟甲基)-3-甲基-1H-吲唑-5-羧酸(VIfzzb)
步驟i. 向具有攪拌棒和帶有橡膠隔板的蓋的乾燥的閃光小瓶加入3-甲基-1H-吲唑-5-羧酸甲基酯(250mg,1.3mmol)和無水氟化鉀(305mg,5.26mmol),並將小瓶密封並保持在氮氣氛下。經由注射器加入乾燥的乙腈(5mL)。將混合物劇烈攪拌5分鐘,然後經由注射器加入(溴二氟甲基)膦酸二乙酯(0.35mL,2.0mmol)。在室溫下,在氮氣下將混合物攪拌過夜。通過CELITE®塞過濾混合物並用EtOAc漂洗。在減壓下蒸發濾液並經由正相SiO2層析法(0-50% EtOAc/己烷)純化殘餘物。收集所期望的級分並蒸發,以提供作為灰白色固體,第一洗脫峰的1-(二氟甲基)-3-甲基-1H-吲唑-5-羧酸甲基酯(11.8mg,3.8%產率)。LCMS m/z實測值241.0[M+H]+;RT=2.94min(方法C);1H NMR(400MHz,CDCl3)δ 8.46(dd,1H),8.17(dd,1H),7.73(dd,1H),7.40(t,1H),3.97(s,3H),2.62-2.60(M,3H).2-(二氟甲基)-3-甲基-2H-吲唑-5-羧酸甲基酯(276.7mg,87%產率)作為灰白色固體,第二洗脫峰。LCMS m/z實測值241.0[M+H]+;RT=2.76min(方法C);1H NMR(400MHz,CDCl3)δ 8.47(dd,
1H),7.92(dd,1H),7.64(dd,1H),7.49(t,1H),3.95(s,3H),2.88-2.85(M,3H).
步驟ii. 將氫氧化鋰(1.4mg,0.06mmol)加入到1-(二氟甲基)-3-甲基-1H-吲唑-5-羧酸甲基酯(11.8mg,0.05mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物中。在室溫下將混合物攪拌過夜。再加入LiOH(1mg)並使攪拌持續24小時。將揮發物蒸發以提供粗1-(二氟甲基)-3-甲基-1H-吲唑-5-羧酸(VIfzzb)(15.7mg,>100%產率),作為鋰鹽,為灰白色固體。LCMS m/z實測值227.1[M+H]+;RT=2.48min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.24-8.22(M,1H),8.10(dd,1H),8.03(t,1H),7.57(d,1H),2.52(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺(化合物417)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(二氟甲基)-3-甲基-1H-吲唑-5-羧酸(VIfzzb)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值475.2[M+H]+;RT=2.40min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.28-7.82(M,4H),7.62-7.55(M,2H),5.74(s,1H),4.60(d,1H),4.48(d,1H),4.31(d,1H),4.09-4.02(M,1H),2.76(s,3H),2.56(s,3H).
3-(二氟甲基二氟甲基二氟甲基)-1-甲基-1H-吲唑-5-羧酸(VIfzzc)
步驟i. 經由注射器,向3-甲醯基-1H-吲唑-5-羧酸甲基酯(100mg,0.49mmol)在乾燥的CH2Cl2(3mL)中的攪拌後的懸浮液逐滴加入三氟化硫嗎啉(179uL,1.47mmol)。在室溫下將混合物攪拌3天。將反應混合物緩慢加入冷的飽和aq.NaHCO3溶液(25mL)中。將混合物攪拌15-20分鐘,直到所有氣體逸出停止。混合物用CH2Cl2(3 x 10mL)萃取。合併的有機層經Na2SO4乾燥,過濾並在減壓下蒸發。殘餘物經由正相SiO2層析法(0-3% MeOH/CH2Cl2)純化。收集所期望的級分並在減壓下蒸發,以提供作為深橙色固體的3-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(51.4mg,46%產率)。LCMS m/z實測值227.1[M+H]+;RT=2.66min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 13.97(s,1H),8.50(s,1H),8.02(dd,1H),7.75(dd,1H),7.45(t,1H),3.89(s,3H).
步驟ii. 向3-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(51.3mg,0.23mmol)在乾燥的MeCN(3mL)中的攪拌後的懸浮液逐滴加入DBU(37uL,0.25mmol),並攪拌15分鐘,然後加入碘甲烷(16uL,0.25mmol)並在室溫下將混合物攪拌過夜。將反應混合物傾倒入水(25mL)中並用EtOAc(2 x 25mL)萃取。合併的有機層經MgSO4乾燥,過濾並蒸發。殘餘物經由正相SiO2層析法(0-50% EtOAc/己烷)純化。收集所期望的級分並在減壓下蒸發,以提供作為灰白色固體的3-(二氟甲基)-1-甲基-1H-吲唑-5-羧酸甲基酯(29.0mg,53%產率)。LCMS m/z實測值241.0[M+H]+;RT=2.92min(方法C);1H NMR
(400MHz,CDCl3)δ 8.68(dd,1H),8.14(dd,1H),7.45(dd,1H),6.97(t,1H),4.12(t,3H),3.97(s,3H).
步驟iii. 將氫氧化鋰(3.5mg,0.15mmol)加入3-(二氟甲基)-1-甲基-1H-吲唑-5-羧酸甲基酯(29.0mg,0.12mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物中。在室溫下將混合物攪拌6天。在減壓下蒸發揮發物以提供粗3-(二氟甲基)-1-甲基-1H-吲唑-5-羧酸(VIfzzc)(32.5mg,定量的),作為鋰鹽,為黃褐色固體。LCMS m/z實測值227.1[M+H]+;RT=2.36min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.32-8.29(M,1H),8.05(dd,1H),7.52(dd,1H),7.31(t,1H),4.08-4.05(M,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺(化合物436)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和3-(二氟甲基)-1-甲基-1H-吲唑-5-羧酸(VIfzzc)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值475.2[M+H]+;RT=2.26min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.18-8.11(M,1H),7.90(s,1H),7.84(d,1H),7.60-7.25(M,3H),5.72(s,1H),4.59(d,1H),4.48(d,1H),4.34(d,1H),4.13(s,3H),4.09-4.00(M,1H),2.74(s,3H).
1-(二氟甲基)-1H-吲唑-5-羧酸(VIfzzd)
步驟i. 在氫氣下(1atM,經由氣球),將3-氯-1-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(50.00mg,0.19mmol)和碳載鈀(10wt%)(10.2mg,0.01mmol)在MeOH(2mL)中的懸浮液攪拌18小時。通過CELITE®塞過濾懸浮液,用CH2Cl2漂洗,並在減壓下蒸發濾液,以提供作為黃褐色固體的1-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(43mg,99%產率)。LCMS m/z實測值227.0[M+H]+;RT=2.75min(方法C);1H NMR(400MHz,CDCl3)δ 8.55-8.53(M,1H),8.22-8.18(M,2H),7.81(d,1H),7.48(t,1H),3.97(s,3H).
步驟ii. 將氫氧化鋰(5.5mg,0.23mmol)加入到1-(二氟甲基)-1H-吲唑-5-羧酸甲基酯(43mg,0.19mmol)在THF-MeOH(9:1,1mL)中的攪拌後的混合物中。在室溫下將混合物攪拌4天。在減壓下蒸發揮發物以提供粗1-(二氟甲基)-1H-吲唑-5-羧酸(VIfzzd)(49mg,>100%),作為鋰鹽,為黃褐色固體。LCMS m/z實測值213.1[M+H]+;RT=2.27min(方法C);1H NMR(400MHz,DMSO-d 6 )δ 8.38-8.36(M,1H),8.29-7.97(M,3H),7.63(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺(化合物437)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二
氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(二氟甲基)-1H-吲唑-5-羧酸(VIfzzd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺。LCMS m/z實測值461.1[M+H]+;RT=2.27min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.48(s,1H),8.23(t,1H),8.15(dd,1H),8.00(s,1H),7.92(d,1H),7.64(dd,1H),7.56(dd,1H),5.72(s,1H),4.60(d,1H),4.48(d,1H),4.31(d,1H),4.06(dd,1H),2.75(s,3H).
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(VIIIb-d)
以與上文關於VIIIa所述類似的方式,以57%產率,從8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVb)起始,之後用硼氘化鈉還原來合成鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(VIIIb-d)。LCMS m/z實測值388.2[M+H]+;RT=1.55min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.35(s,1H),8.01(dd,1H),7.75(dd,1H),7.24-7.16(M,2H),6.81-6.73(M,2H),4.38(d,1H),4.29(d,1H),4.06(q,1H),4.00(d,1H),3.69(s,3H),3.48(d,1H),2.00(s,1H),1.33(d,3H).
(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基-
13
C-d
3
)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(IXc-d)
在0℃下,將鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(VIIIb-d)(457mg,1.18mmol)、甲醛-13C-d 2溶液(氧化氘中約20wt%)(0.98mL,5.90mmol)、醋酸-d 4(0.53mL,8.74mmol)和硼氘化鈉(104mg,2.48mmol)的混合物在乾燥的1,2-二氯乙烷(3mL)中攪拌,並在兩小時內使其溫熱至室溫。反應混合物用二氯甲烷(10mL)稀釋並用飽和aq.NaHCO3溶液中和。用二氯甲烷再萃取水相兩次,並將合併的萃取物經MgSO4乾燥,過濾,並在減壓下使溶劑蒸發以提供鏡像異構純的(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(IXc-d)(479.4mg,96%產率)。LCMS m/z實測值406.2[M+H]+;RT=1.58min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.48(s,1H),8.05(dd,1H),7.99(dd,1H),7.18-7.13(M,2H),6.85-6.80(M,2H),4.45(d,1H),4.31(d,1H),4.23(d,1H),3.98-3.86(M,1H),3.70(s,3H),3.54(d,1H),1.41(d,3H).
(S)-8,9-二氟-1-((甲基-
13
C-d
3)
胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(Vb-d)
以與上文關於Vb所述類似的方式,以88%產率,從(S)-8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(IXc-d)起始,之後用碳酸鉀水溶液中和來合成鏡像異構純的(S)-8,9-二氟-1-((甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(Vb-d)。LCMS m/z實測值237.0[M+H]+;RT=0.58min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.40(s,1H),8.03(dd,1H),7.75(dd,1H),4.42(d,1H),4.34(d,1H),4.22(d,1H),3.55(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基- 13 C-d 3 )-1H-吲哚-2-甲醯胺(化合物514)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-((甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(Vb-d)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d 3)-1H-吲哚-2-甲醯胺。LCMS m/z實測值451.2[M+H]+;RT=2.65min(方法D);1H NMR(400MHz,DMSO-d 6)δ 11.92(s,1H),11.74(s,1H),8.13(dd,1H),7.62(dd,1H),7.44(dd,1H),7.38(dd,1H),6.97(s,1H),4.64(d,1H),4.48(d,1H),4.16(d,1H),4.03(d,1H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-
13
C-d
3
)-1H-吲哚-2-甲醯胺(化合物515)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-((甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(Vb-d)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d 3)-1H-吲哚-2-甲醯胺。LCMS m/z實測值483.5[M+H]+;RT=2.69min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.17(s,1H),11.75(s,1H),8.13(dd,1H),7.70(d,1H),7.54(d,1H),7.45(dd,1H),7.26(d,1H),7.01(s,1H),4.65(d,1H),4.49(d,1H),4.19(d,1H),4.04(d,1H).
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-
13
C-d
3
)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物516)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-((甲基-13C-d 3)胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮-1-d(Vb-d)和2-氯-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhm)合成鏡像異構純的(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d 3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值455.1[M+H]+;RT=2.78min(方法D);1H
NMR(400MHz,DMSO-d 6)δ 12.01(s,1H),11.73(s,1H),8.12(dd,1H),7.51-7.40(M,1H),7.09(s,1H),6.93(s,1H),4.63(d,1H),4.47(d,1H),4.12(d,1H),4.01(d,1H).
(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-4,6-二酮鹽酸鹽(Vbiv)
在室溫下將鏡像異構純的(S)-(8,9-二氟-6-甲氧基-4-側氧-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(XIb)(241mg,0.61mmol)和氯化氫(對二烷中4.0M)(4.58mL,18.3mmol)在對二烷(2mL)中攪拌1小時。再加入氯化氫(對二烷中4.0M)(4.58mL,18.3mmol)並在室溫下攪拌1小時,並消耗>70% SM。將混合物冷卻至0-5℃,然後逐滴加入水(2mL)並將混合物攪拌15分鐘,並緩慢溫熱至室溫過夜。將溶劑蒸發至乾燥,使殘餘物與甲苯(30mL)共沸兩次並經歷高真空以提供粗鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-4,6-二酮鹽酸鹽(Vbiv)(221.8mg,>100%產率)。LCMS m/z實測值281.1[M+H]+;RT=0.52min(方法D);1H NMR(400MHz,DMSO-d 6)δ 12.03(s,1H),9.70-9.51(M,1H),9.50-9.34(M,1H),8.41(dd,1H),8.26(dd,1H),5.11-4.98(M,2H),4.90(dd,1H),2.72(s,3H).
(S)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物477)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-4,6-二酮鹽酸鹽(Vbiv)和2-氯-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhm)合成鏡像異構純的(S)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值463.9[M+H]+;RT=4.56min(方法A);1H NMR(400MHz,DMSO)δ 12.08(s,1H),11.83(s,1H),8.25(dd,1H),7.95(s,1H),7.10(s,1H),6.99(d,1H),6.27(d,1H),5.01(dd,1H),4.76(d,1H),3.09(s,3H).
(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物478)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-4,6-二酮鹽酸鹽(Vbiv)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成鏡像異構純的(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z
實測值492.2[M+H]+;RT=3.16min(方法C);1H NMR(400MHz,DMSO)δ 12.21(s,1H),11.86(s,1H),8.26(dd,1H),7.95(s,1H),7.70(d,1H),7.56(d,1H),7.26(d,1H),7.06(d,1H),6.32-6.27(M,1H),5.03(dd,1H),4.84(d,1H),3.13(s,3H).
(1S)-8,9-二氟-4-羥基-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vbvi)
向((1S)-8,9-二氟-4-羥基-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲酸第三丁酯(XIa)(154.9mg,0.39mmol)在對二烷(1mL)中的攪拌後的溶液逐滴加入氯化氫(對二烷中4.0M)(4.10mL,16.4mmol)。在室溫下將混合物攪拌1小時。通過LC/MS觀察到顯著但不完全的去保護。在0-5℃下使混合物冷卻,然後逐滴加入水(0.84mL,46.5mmol)。將反應攪拌並緩慢溫熱至室溫過夜以提供紫色溶液。通過LC/MS,反應是不完全的。在室溫下再將混合物攪拌24小時。將反應混合物蒸發至乾燥,然後與甲苯(2 x 20mL)共沸,並使殘餘物經歷高真空1小時以提供(1S)-8,9-二氟-4-羥基-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vbvi)(128.4mg,85%產率),作為HCl鹽,為紫色固體。1H NMR(400MHz,DMSO)δ 12.03-11.59(M,1H),9.30-8.76(M,2H),8.19-8.04(M,2H),5.66-5.54(M,1H),4.70-4.49(M,1H),4.45-4.02(M,2H),2.82-2.57(M,3H).
2-氯-N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物487)
以與上文所述類似的方式,由(1S)-8,9-二氟-4-羥基-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vbvi)和2-氯-3a,6a-二氫-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhm)合成2-氯-N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺的非鏡像異構物混合物。LCMS m/z實測值465.9[M+H]+;RT=4.31min(方法A);1H NMR(400MHz,DMSO)δ 12.00(s,1H),11.83(s,1H),8.13(dd,1H),7.64-7.37(M,1H),7.25(d,1H),7.09(s,1H),6.98-6.91(M,1H),5.72-5.54(M,2H),4.47(d,1H),3.90(d,1H),3.06(s,3H).
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物488)
以與上文所述類似的方式,由(1S)-8,9-二氟-4-羥基-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vbvi)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲
基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺的非鏡像異構物混合物。LCMS m/z實測值494.1[M+H]+;RT=4.16min(方法A);1H NMR(400MHz,DMSO)δ 12.20-12.13(M,1H),11.90-11.58(M,1H),8.20-8.10(M,1H),7.77-7.62(M,1H),7.60-7.47(M,2H),7.43-7.09(M,2H),7.05-6.97(M,1H),5.72(d,1H),5.69(d,1H),4.53-4.46(M,1H),3.96(d,1H),3.15-3.09(M,3H).
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物365)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-溴-6-(三氟甲基)煙酸(VIel)合成鏡像異構純的(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺。LCMS m/z實測值518.0[M+H]+;RT=4.47min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.78(s,1H),8.56(s,1H),8.13(t,1H),7.51-7.47(M,1H),5.66(s,1H),4.61(d,1H),4.47(d,1H),4.35(d,1H),4.03-3.99(M,1H),2.76(s,3H).
步驟i. 在-78℃下向2-溴異煙醛(10.0g,53.8mmol)在DCM(50mL)中的攪拌後的溶液逐滴加入DAST(21.3mL,161mmol,3eq.),然後在室溫下將混合物攪拌5小時。將反應混合物緩慢傾倒在冰上並用DCM(2 x 200mL)萃取。將有機層分離,用水洗滌,經Na2SO4乾燥並在減壓下濃縮。通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化粗化合物,以提供作為淺黃色液體的2-溴-4-(二氟甲基)吡啶(5.5g,49%產率)。1H NMR(400MHz,DMSO-d 6 )δ 7.23-6.96(M,1H),7.66-7.64(M,1H),7.86(s,1H),8.59-8.58(M,1H).
步驟ii. 在CO氣氛下(50psi),在250mL鋼製反應釜中向2-溴-4-(二氟甲基)吡啶(5.0g,24mmol)在MeOH(50mL)中的攪拌後的溶液加入醋酸鉀(4.7g,48mmol,2eq.)和Pd(dppf)Cl2(0.88g,1.2mmol,0.05eq.)。將反應混合物加熱至90℃並攪拌16小時。反應完成(通過TLC監測)後,反應混合物通過CELITE®墊過濾並在減壓下蒸發濾液。殘餘物用水(100mL)稀釋並用EtOAc(2 x 100mL)萃取。合併的有機層用水洗滌,經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和15%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的4-(二氟甲基)吡啶甲酸甲基酯(methyl 4-(difluoromethyl)picolinate)(2.5g,55%產率)。LCMS m/z實測值187.9[M+H]+;1H NMR(400MHz,
DMSO-d 6 )δ 3.92(s,3H),7.35-7.08(M,1H),7.86-7.85(M,1H),8.19(s,1H),8.91-8.90(M,1H).
步驟iii. 在-78℃下向4-(二氟甲基)吡啶甲酸甲基酯(2.5g,13.2mmol)在THF(28mL)中的攪拌後的溶液逐滴加入DIBAL-H(22.6mL,22.6mmol,1.7eq.),並將反應混合物攪拌3小時。用aq.飽和NH4Cl溶液使反應混合物猝滅。反應混合物通過CELITE®墊過濾,濾液經Na2SO4乾燥並在減壓下濃縮。所獲得的粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的4-(二氟甲基)吡啶甲醛(1.4g,66%產率)。LCMS m/z實測值160.0[M+H]+;RT=1.09min(方法E).
步驟iv. 在室溫下向4-(二氟甲基)甲基吡啶醛(1.6g,10.1mmol)在1,4-二烷:水(3:1,50mL)中的攪拌後的溶液加入丙烯酸甲酯(1.1mL,12.22mmol,1.2eq.)和DABCO(68mg)。在室溫下將所得反應混合物攪拌16小時。將反應混合物濃縮並用水(40mL)稀釋並用EtOAc(2 x 70mL)萃取。將有機層分離,經Na2SO4乾燥並在減壓下濃縮。所獲得的粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的2-((4-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,60%產率)。LCMS m/z實測值244.0[M+H]+;RT=1.16min(方法E).
步驟v. 在0℃下向2-((4-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,6.17mmol)在DCM(15mL)中的攪拌後的溶液加入吡啶(0.84mL,9.3mmol,1.5eq.)和乙醯氯(0.69mLg(8.64mmol,1.4eq.)。在室溫下將所得反應混合物攪拌3小時。反應混合物用水(40mL)稀釋並用EtOAc(2 x 100mL)萃取。合併的有機層用水(50mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。所獲得的粗化合物用甲苯(15mL)稀釋並回流16小時。將反應混合物在減
壓下濃縮並通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的7-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,36%產率)。LCMS m/z實測值226.1[M+H]+;RT=1.82min(方法E).
步驟vi. 在0℃下向7-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,2.22mmol)在THF:水:MeOH(2:1:1,10mL)混合物中的攪拌後的溶液加入LiOH(200mg,11.1mmol,5.0eq.),並在室溫下將反應攪拌4小時。將揮發物從反應混合物蒸發並用aq.KHSO4溶液(10wt%)使殘餘物酸化成pH約為2。所沉澱的固體通過過濾收集,用水洗滌並在真空下乾燥,以提供作為白色固體的7-(二氟甲基)吲哚-2-羧酸(VIem)(300mg,64%產率)。LCMS m/z實測值212.4[M+H]+;RT=1.40min(方法E).
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和7-(二氟甲基)吲哚-2-羧酸(VIem)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值460.2[M+H]+;RT=3.94min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.36(d,1H),8.15-8.06(M,2H),7.72(s,1H),7.47-7.43(M,1H),7.08-6.73(M,3H),5.72(s,1H),4.61(d,1H),4.47(d,1H),4.17(d,1H),4.04(d,1H),3.02(s,3H).
步驟i. 在-78℃下向6-溴煙鹼醛(10.0g,53.8mmol)在DCM(50mL)中的攪拌後的溶液逐滴加入DAST(21.3mL,161mmol,3eq.),並在室溫下將混合物攪拌3小時。將反應混合物緩慢傾倒在冰上並用DCM(2 x 200mL)萃取。將有機層分離,用水洗滌,經Na2SO4乾燥並在減壓下濃縮。所獲得的粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的2-溴-5-(二氟甲基)吡啶(5.5g,49%產率)。LCMS m/z實測值208.1[M+H]+;RT=1.76min(方法E).
步驟ii. 在鋼反應容器中,用氬氣將2-溴-5-(二氟甲基)吡啶(3.0g,14mmol)在MeOH(30mL)中的溶液脫氣20分鐘,然後加入醋酸鉀(2.82g,28.8mmol,2.0eq.)和Pd(dppf)Cl2(527mg,0.72mmol,0.05eq.),並用氬氣將混合物脫氣5分鐘。在90℃下,在CO氣體下(50psi)將反應混合物攪拌16小時。反應混合物通過CELITE®墊過濾並將濾液蒸發。所獲得的粗材料通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色固體的5-(二氟甲基)吡啶甲酸甲基酯(2.0g,74%產率)。LCMS m/z實測值188.2[M+H]+;RT=1.15min(方法E).
步驟iii. 在-78℃下向5-(二氟甲基)吡啶甲酸甲基酯(2.8g,15mmol)在THF(28mL)中的攪拌後的溶液逐滴加入DIBAL-
H(25mL,25mmol,1.7eq.)並攪拌3小時。反應混合物用aq.飽和NH4Cl溶液猝滅。反應混合物通過CELITE®墊過濾,濾液經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的5-(二氟甲基)甲基吡啶醛(1.6g,68%產率)。LCMS m/z實測值160.0[M+H]+;RT=1.09min(方法E).
步驟iv. 在室溫下向5-(二氟甲基)甲基吡啶醛(1.6g,10mmol)在1,4-二烷:水(3:1,50mL)中的攪拌後的溶液加入丙烯酸甲酯(1.1mL,12mmol,1.2eq.)和DABCO(68mg)。在室溫下將所得反應混合物攪拌16小時。將反應混合物濃縮並用水(40mL)稀釋並用EtOAc(2 x 70mL)萃取。將有機層分離,經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的2-((5-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,60%產率)。LCMS m/z實測值244.0[M+H]+;RT=1.16min(方法E).
步驟v. 在0℃下向2-((5-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,6.2mmol)在DCM(15mL)中的攪拌後的溶液加入吡啶(0.84mL,9.3mmol,1.5eq.)和乙醯氯(0.69mL,8.64mmol,1.4eq.)。在室溫下將所得反應混合物攪拌3小時。反應混合物用水(40mL)稀釋並用EtOAc(2 x 100mL)萃取。合併的有機層用水(50mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。粗化合物用甲苯(15mL)稀釋並回流16小時。將反應混合物在減壓下濃縮並通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的6-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,36%產率)。LCMS m/z實測值226.1[M+H]+;RT=1.82min(方法E).
步驟vi. 在0℃下向6-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,2.22mmol)在THF:水:MeOH(2:1:1,10mL)混合物中
的攪拌後的溶液加入LiOH(200mg,11.1mmol,5.0eq.),並在室溫下將反應攪拌4小時。將揮發物蒸發並用aq.KHSO4溶液(水中10wt%)將殘餘物酸化成pH約為2。所沉澱的固體通過過濾收集,用水洗滌並在真空下乾燥,以提供作為白色固體的6-(二氟甲基)吲哚-2-羧酸(VIen)(300mg,64%產率)。LCMS m/z實測值212.4[M+H]+;RT=1.40min(方法E).
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和6-(二氟甲基)吲哚-2-羧酸(VIen)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值460.2[M+H]+;RT=4.00min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.60(s,1H),8.12-8.05(M,2H),7.75-7.44(M,2H),7.13-6.76(M,3H),5.72(s,1H),4.47(d,1H),4.47(d,1H),4.16(d,1H),4.03(d,1H),3.01(s,3H).
1-(((二-第三丁氧基磷醯基)氧基)甲基)-5,6-二氟-1H-吲哚-2-羧酸(Vieo)
步驟i. 向室溫下5,6-二氟-1H-吲哚-2-羧酸(2.0g,10.15mmol)在DCM(20mL)中的攪拌後的溶液加入DCC(2.09g,10.2mmol,1eq.)和DMAP(0.25g,2.0mmol,0.2eq.),之後加入苄基醇(1.30mL,12.6mmol,1.25eq.)。在室溫下將反應混合物攪拌16小時。反應混合物通過CELITE®墊過濾並分配在EtOAc(200mL)和水(200mL)之間。將有機層分離,經Na2SO4乾燥並在減壓下濃縮。用石油醚洗滌粗材料以提供作為灰白色固體的5,6-二氟-1H-吲哚-2-羧酸苄基酯(1.31g,45%產率)。1H NMR(400MHz,DMSO-d 6 ):12.13(s,1H),7.70-7.65(M,1H),7.50-7.48(M,2H),7.44-7.35(M,4H),7.22-7.21(M,1H),5.38(s,2H).
步驟ii. 在0℃下,向0℃下5,6-二氟-1H-吲哚-2-羧酸苄基酯(1.0g,3.5mmol,1.0eq.)在DMF(10mL)中的攪拌後的溶液加入NaH(礦物油中60wt%,0.15g,3.8mmol,1.1eq.)並攪拌15分鐘。在0℃下向混合物加入二-第三丁基(氯甲基)磷酸酯(1.0g,7.0mmol,2.0eq.)並在室溫下將反應混合物攪拌16小時。將反應混合物加入到冰冷的水中並用EtOAc萃取。將有機層分離,經Na2SO4乾燥並在減壓下蒸發。粗材料通過管柱層析法,採用矽膠(100-200目),25-30% EtOAc/石油醚作為洗脫液來純化,以提供作為灰白色固體的1-
(((二-第三丁氧基磷醯基)氧基)甲基)-5,6-二氟-1H-吲哚-2-羧酸苄基酯(0.57g,32%產率)。1H NMR(400MHz,CDCl3):7.43(M,1H),7.39-7.34(M,7H),6.42-6.40(d,2H),5.36(s,2H),1.51(s,18H).
步驟iii. 向室溫下1-(((二-第三丁氧基磷醯基)氧基)甲基)-5,6-二氟-1H-吲哚-2-羧酸苄基酯(700mg,1.37mmol,1.0eq.)在EtOAc(25mL)中的攪拌後的溶液加入Pd/C(碳載10wt%,70mg),並在氫氣氛下(氣球,1atm)於室溫下將反應混合物攪拌30分鐘。反應混合物通過CELITE®墊過濾並在減壓下蒸發濾液。所回收的固體用Et2O(15mL)洗滌並在真空下乾燥,以提供作為白色固體的1-(((二-第三丁氧基磷醯基)氧基)甲基)-5,6-二氟-1H-吲哚-2-羧酸(0.43g,75%產率)。LCMS m/z實測值418.4[M-H]-;RT=1.99min(方法E).
(S)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯(化合物376)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1-(((二-第三丁氧基磷醯基)氧基)甲基)-5,6-二氟-1H-吲哚-2-羧酸(VIeo)合成鏡像異構純的(S)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-
1-基)甲基)磷酸酯。LCMS m/z實測值668.2[M+H]+;RT=5.41min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7(s,1H),8.13(t,1H),7.79-7.74(M,1H),7.65(t,1H),7.54-7.49(M,1H),6.91(s,1H),6.23-6.08(M,2H),5.68(s,1H),4.62(d,1H),4.47(d,1H),4.31(d,1H),4.04(d,1H),3.0(s,3H),1.24(s,9H),1.14(s,9H).
(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物377)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氯-6-(三氟甲基)煙酸(VIep)合成鏡像異構純的(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺。LCMS m/z實測值474.1[M+H]+;RT=4.41min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,2H),8.44(bs,1H),8.13(t,1H),7.51-7.46(M,1H),5.66(s,1H),4.61(d,1H),4.47(d,1H),4.36(d,1H),4.03-3.99(M,1H),2.76(s,3H).
5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物378,379)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5-氯-6-(三氟甲基)煙酸(VIep)合成外消旋5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralcel OD-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物378):LCMS m/z實測值456.1[M+H]+;RT=4.17min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.77(s,1H),8.44(s,1H),7.92-7.89(M,1H),7.77-7.72(M,1H),7.65-7.61(M,1H),5.69(s,1H),4.60(d,1H),4.47(d,1H),4.33(d,1H),4.05-4.01(M,1H),2.72(s,3H);手性分析SFC:RT=1.59miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物379):LCMS m/z實測值456.1[M+H]+;RT=4.17min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.77(s,1H),8.44(s,1H),7.92-7.89(M,1H),7.77-7.72(M,1H),7.65-7.61(M,1H),5.69(s,1H),4.60(d,1H),4.47(d,1H),4.33(d,1H),4.05-4.01(M,1H),2.72(s,3H);手性分析SFC:RT=1.83miN,管柱:Chiralcel OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物380、381)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫
-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhf)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-50:50。管柱:Chiralpak OJ-H(30 x 250mm),5μm,流速:75g/min。
對映異構物I(化合物380):LCMS m/z實測值398.1[M+H]+;RT=3.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.79(br s,1H),11.62(br s,1H),7.90-7.88(M,1H),7.61(t,1H),7.52(bs,1H),7.42(d,1H),7.00(d,1H),6.91(bs,1H),5.73(bs,1H),4.62(d,1H),4.47(d,1H),4.13-4.02(M,2H),3.11(s,3H);手性分析SFC:RT=2.55miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
對映異構物II(化合物381):LCMS m/z實測值398.1[M+H]+;RT=3.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.79(br s,1H),11.62(br s,1H),7.90-7.88(M,1H),7.61(t,1H),7.52(bs,1H),7.42(d,1H),7.00(d,1H),6.91(bs,1H),5.73(bs,1H),4.62(d,1H),4.47(d,1H),4.13-4.02(M,2H),3.11(s,3H);手性分析SFC:RT=4.68miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物382、383)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-氰基-6-氟-1H-吲哚-2-
羧酸(VIdy)合成外消旋4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak OJ-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物382):LCMS m/z實測值435.2[M+H]+;RT=3.88min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.41(br s,1H),11.64(bs,1H),7.91-7.37(M,5H),6.97(s,1H),5.75(s,1H),4.63(d,1H),4.48(d,1H),4.19(d,1H),4.06(d,1H),3.17(s,3H);手性分析SFC:RT=2.60miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
對映異構物II(化合物383):LCMS m/z實測值435.2[M+H]+;RT=3.88min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.41(br s,1H),11.64(bs,1H),7.91-7.37(M,5H),6.97(s,1H),5.75(s,1H),4.63(d,1H),4.48(d,1H),4.19(d,1H),4.06(d,1H),3.17(s,3H);手性分析SFC:RT=6.16miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和7-(二氟甲基)吲哚-2-羧酸(VIem)合成外消旋1-(7-(二氟甲基)-N-甲基吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,
流動相甲醇:CO2-40:60。管柱:Chiralcel IA-3(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物385):LCMS m/z實測值459.2[M+H]+;RT=3.20min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.36(d,1H),8.10(t,1H),8.04(s,(,(,1H),7.71(s,1H),7.33-7.28(M,1H),7.08-6.72(M,3H),5.64(s,1H),3.78(d,1H),3.64(d,1H),3.16(bs,2H),3.03-2.76(M,4H);手性分析SFC:RT=1.75miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物386):LCMS m/z實測值459.2[M+H]+;RT=3.20min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.36(d,1H),8.10(t,1H),8.04(s,(,(,1H),7.71(s,1H),7.33-7.28(M,1H),7.08-6.72(M,3H),5.64(s,1H),3.78(d,1H),3.64(d,1H),3.16(bs,2H),3.03-2.76(M,4H);手性分析SFC:RT=4.20miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-(二氟甲基)吲哚-2-羧酸(VIen)合成外消旋1-(6-(二氟甲基)-N-甲基吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-
3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OX-H(30 x 250mm),5μ,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物387):LCMS m/z實測值459.2[M+H]+;RT=3.28min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7177(bs,1H),8.61(bs,1H),8.13(t,1H),8.04(s,1H),7.57(d,1H),7.33-7.28(M,1H),7.13-6.84(M,2H),6.74(s,1H),5.75(s,1H),3.93-3.80(M,2H),3.2(bs,2H),2.96-2.73(M,4H).手性分析SFC:RT=1.63miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物388):LCMS m/z實測值459.2[M+H]+;RT=3.28min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.7177(bs,1H),8.61(bs,1H),8.13(t,1H),8.04(s,1H),7.57(d,1H),7.33-7.28(M,1H),7.13-6.84(M,2H),6.74(s,1H),5.75(s,1H),3.93-3.80(M,2H),3.2(bs,2H),2.96-2.73(M,4HH).手性分析SFC:RT=3.85miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和吲哚-6-羧酸(VIer)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-
基)-N-甲基吲哚-6-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OX-H(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物389):LCMS m/z實測值392.2[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.60(bs,1H),8.52(bs,1H),7.91(d,1H),7.74(t,1H),7.62(bs,2H),7.44(d,1H),6.81(bs,1H),6.67(d,1H),6.45(bs,1H),5.66(s,1H),4.59(d,1H),4.47(d,1H),4.22(d,1H),4.04(d,1H),2.84(s,3H);手性分析SFC:RT=2.27miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
對映異構物II(化合物390):LCMS m/z實測值392.2[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.60(bs,1H),8.52(bs,1H),7.91(d,1H),7.74(t,1H),7.62(bs,2H),7.44(d,1H),6.81(bs,1H),6.67(d,1H),6.45(bs,1H),5.66(s,1H),4.59(d,1H),4.47(d,1H),4.22(d,1H),4.04(d,1H),2.84(s,3H);手性分析SFC:RT=3.94miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和吲哚-6-羧酸(VIer)合成外消旋8,9-二氟-1-(N-甲基吲哚-6-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過
製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:纖維素-2(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物391):LCMS m/z實測值409.2[M+H]+;RT=3.10min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.52(bs,1H),8.12(t,1H),7.63(s,1H),7.46-7.34(M,2H),6.81(bs,1H),6.66(d,1H),6.45(bs,1H),5.56(s,1H),3.77(d,1H),3.64(d,1H),3.22-3.13(M,2H),2.85-2.65(M,4H);手性分析SFC:RT=2.07miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物II(化合物392):LCMS m/z實測值409.2[M+H]+;RT=3.10min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.52(bs,1H),8.12(t,1H),7.63(s,1H),7.46-7.34(M,2H),6.81(bs,1H),6.66(d,1H),6.45(bs,1H),5.56(s,1H),3.77(d,1H),3.64(d,1H),3.22-3.13(M,2H),2.85-2.65(M,4H);手性分析SFC:RT=5.37miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物393、394)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-乙基-6-氟-1H-吲哚-2-羧酸(VIdz)合成外消旋4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-
2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IA-3(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物393):LCMS m/z實測值438.2[M+H]+;RT=4.62min(方法A);1H NMR(400MHz,DMSO-d 6)δ 646411.72(bs,1H),11.64(bs,1H),7.9(d,1H),7.63(t,1H),7.54(bs,1H),6.99(t,2H),6.75(d,1H),5.77(s,1H),4.64(d,1H),4.49(d,1H),4.15(d,1H),4.05(d,1H),3.16(s,3H),2.87-2.80(M,2H),1.23(t,3H);手性分析SFC:RT=8.83miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物394):LCMS m/z實測值438.2[M+H]+;RT=4.62min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.72(bs,1H),11.64(bs,1H),7.9(d,1H),7.63(t,1H),7.54(bs,1H),6.99(t,2H),6.75(d,1H),5.77(s,1H),4.64(d,1H),4.49(d,1H),4.15(d,1H),4.05(d,1H),3.16(s,3H),2.87-2.80(M,2H),1.23(t,3H);手性分析SFC:RT=10.50miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺(化合物395、396)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5-(甲磺醯)-1H-吲哚-2-
羧酸(VIed)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IA-3(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物395):LCMS m/z實測值470.2[M+H]+;RT=2.80min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.20(bs,1H),11.70(bs,1H),8.23(bs,1H),7.91(d,1H),7.72(d,1H),7.67-7.62(M,2H),7.55-7.52(M,1H),7.14(s,1H),5.76(s,1H),4.64(d,1H),4.49(d,1H),4.19(d,1H),4.07(d,1H),3.16(s,3H),3.15(s,3H);手性分析SFC:RT=5.36miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
對映異構物II(化合物396):LCMS m/z實測值470.2[M+H]+;RT=2.80min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.20(bs,1H),11.70(bs,1H),8.23(bs,1H),7.91(d,1H),7.72(d,1H),7.67-7.62(M,2H),7.55-7.52(M,1H),7.14(s,1H),5.76(s,1H),4.64(d,1H),4.49(d,1H),4.19(d,1H),4.07(d,1H),3.16(s,3H),3.15(s,3H);手性分析SFC:RT=8.69miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物397、398)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5-氰基-1H-吲哚-2-羧酸(VIec)合成外消旋5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并
[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OJ-3(30 x 250mm)5μm,流速:110g/min。
對映異構物I(化合物397):LCMS m/z實測值417.1[M+H]+;RT=3.47min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.27(bs,1H),11.64(bs,1H),8.17(bs,1H),7.91(d,1H),7.66-7.50(M,4H),7.04(s,1H),5.75(s,1H),4.64(d,1H),4.49(d,1H),4.17(d,1H),4.06(d,1H),3.14(s,3H);手性分析SFC:RT=1.77miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
對映異構物II(化合物398):LCMS m/z實測值417.1[M+H]+;RT=3.47min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.27(bs,1H),11.64(bs,1H),8.17(bs,1H),7.91(d,1H),7.66-7.50(M,4H),7.04(s,1H),5.75(s,1H),4.64(d,1H),4.49(d,1H),4.17(d,1H),4.06(d,1H),3.14(s,3H);手性分析SFC:RT=2.34miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-氰
基-6-氟-1H-吲哚-2-羧酸(VIdy)合成外消旋1-(4-氰基-6-氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-25:75。管柱:Chiralpak IA-3(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物399):LCMS m/z實測值452.2[M+H]+;RT=3.34min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.44(bs,1H),11.65(bs,1H),8.11(t,1H),7.67-7.57(M,2H),7.28(t,1H),7.01(s,1H),5.66(s,1H),3.81(d,1H),3.62(d,1H),3.19-3.16(M,6H).手性分析SFC:RT=2.34miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
對映異構物II(化合物400):LCMS m/z實測值452.2[M+H]+;RT=3.34min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.44(bs,1H),11.65(bs,1H),8.11(t,1H),7.67-7.57(M,2H),7.28(t,1H),7.01(s,1H),5.66(s,1H),3.81(d,1H),3.62(d,1H),3.19-3.16(M,6H).手性分析SFC:RT=3.45miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-乙基-6-氟-1H-吲哚-2-羧酸(VIdz)合成外消旋1-(4-乙基-6-氟-N-甲基
-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-25:75。管柱:Chiralpak IA-3(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物401):LCMS m/z實測值455.2[M+H]+;RT=3.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,1H),11.64(bs,1H),8.10(bs,1H),7.32-7.27(M,1H),7.01-6.97(M,2H),6.75(d,1H),5.69(s,1H),3.81(d,1H),3.65(d,1H),3.21-2.78(M,8H),1.23(t,3H);手性分析SFC:RT=2.53miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物402):LCMS m/z實測值455.2[M+H]+;RT=3.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,1H),11.64(bs,1H),8.10(bs,1H),7.32-7.27(M,1H),7.01-6.97(M,2H),6.75(d,1H),5.69(s,1H),3.81(d,1H),3.65(d,1H),3.21-2.78(M,8H),1.23(t,3H);手性分析SFC:RT=4.82miN,管柱:Chiralpak OJ-3(4.6 x 150mm)3μM,20%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-(甲
磺醯)-1H-吲哚-2-羧酸(VIed)合成外消旋8,9-二氟-1-(N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物403):LCMS m/z實測值487.1[M+H]+;RT=2.37min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.27(bs,1H),11.65(bs,1H),8.23(bs,1H),8.11(t,1H),7.73-7.65(M,2H),7.31-7.26(M,1H),7.14(bs,1H),5.68(s,1H),3.81(d,1H),3.66(d,1H),3.16-2.78(M,9H);手性分析SFC:RT=4.04miN,管柱:Chiralpak OD-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物404):LCMS m/z實測值487.1[M+H]+;RT=2.37min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.27(bs,1H),11.65(bs,1H),8.23(bs,1H),8.11(t,1H),7.73-7.65(M,2H),7.31-7.26(M,1H),7.14(bs,1H),5.68(s,1H),3.81(d,1H),3.66(d,1H),3.16-2.78(M,9H);手性分析SFC:RT=5.23miN,管柱:Chiralpak OD-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側
氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-氰基-1H-吲哚-2-羧酸(VIec)合成外消旋1-(5-氰基-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相(1:1MeCN-甲醇):CO2-30:70。管柱:Chiralpak IA-3(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物405):LCMS m/z實測值434.2[M+H]+;RT=2.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.29(bs,1H),11.71(bs,1H),8.18-8.10(M,2H),7.63-7.54(M,2H),7.27(t,1H),7.06(s,1H),5.76(s,1H),3.90-3.77(M,2H),3.17-3.12(M,5H),2.93-2.91(M,1H);手性分析SFC:RT=2.28miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,50%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物406):LCMS m/z實測值434.2[M+H]+;RT=2.96min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.29(bs,1H),11.71(bs,1H),8.18-8.10(M,2H),7.63-7.54(M,2H),7.27(t,1H),7.06(s,1H),5.76(s,1H),3.90-3.77(M,2H),3.17-3.12(M,5H),2.93-2.91(M,1H);手性分析SFC:RT=3.26miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,50%(0.5%在甲醇中的DEA),流速:3.0g/min.
步驟i. 在-78℃下向2-溴煙鹼醛(10.0g,53.8mmol,1.0eq.)在DCM(50mL)中的攪拌後的溶液逐滴加入DAST(21.3mL,161mmol,3eq.),並在室溫下將反應混合物攪拌5小時。將反應混合物緩慢傾倒在冰上並用DCM(2 x 200mL)萃取。將有機層分離,用水洗滌,經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的2-溴-3-(二氟甲基)吡啶(5.5g,49%產率)。1H NMR(400MHz,DMSO-d 6 ):8.57(d,1H),8.12(d,1H),7.65(M,1H),7.29(t,1H).
步驟ii. 在CO氣氛下(50psi),在250mL鋼反應容器中向2-溴-3-(二氟甲基)吡啶(5.0g,24mmol,1.0eq.)在MeOH(50mL)中的攪拌後的溶液加入醋酸鉀(4.7g,48mmol,2eq.)和Pd(dppf)Cl2(0.88g,1.2mmol,0.05eq.)。將反應混合物加熱至90℃並攪拌16小時。反應混合物通過CELITE®床的墊過濾並將濾液蒸發。殘餘物用水(100mL)稀釋並用EtOAc(2 x 100mL)萃取。合併的有機層用水洗滌,經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和15%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的3-(二氟甲基)吡啶甲酸甲基酯(2.5g,55%產率)。LCMS m/z實測值188.1[M+H]+;RT=1.30min(方法E).
步驟iii. 在-78℃下向3-(二氟甲基)吡啶甲酸甲基酯
(2.50g,13.2mmol,1.0eq.)在THF(28mL)中的攪拌後的溶液逐滴加入DIBAL-H(THF中1.0M,22.6mL,22.6mmol,1.7eq.)並攪拌3小時。反應混合物用aq.飽和NH4Cl溶液猝滅。反應混合物通過CELITE®墊過濾,濾液經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的3-(二氟甲基)甲基吡啶醛(1.4g,66%產率)。LCMS m/z實測值160.0[M+H]+;RT=1.09min(方法E).
步驟iv. 在室溫下向3-(二氟甲基)甲基吡啶醛(1.60g,10.2mmol,1.0eq.)在1,4-二烷:水(3:1,50mL)中的攪拌後的溶液加入丙烯酸甲酯(1.10mL,12.2mmol,1.2eq.)和DABCO(68mg)。在室溫下將所得反應混合物攪拌16小時。將反應混合物濃縮並用水(40mL)稀釋並用EtOAc(2 x 70mL)萃取。將有機層分離,經Na2SO4乾燥並在減壓下濃縮。粗化合物通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的2-((3-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,60%產率)。LCMS m/z實測值244.0[M+H]+;RT=1.16min(方法E).
步驟v. 在0℃下向2-((3-(二氟甲基)吡啶-2-基)(羥基)甲基)丙烯酸甲酯(1.5g,6.2mmol,1.0eq.)在DCM(15mL)中的攪拌後的溶液加入吡啶(0.84mL,9.3mmol,1.5eq.)和乙醯氯(0.69mL,8.6mmol,1.4eq.)。在室溫下將所得反應混合物攪拌3小時。反應混合物用水(40mL)稀釋並用EtOAc(2 x 100mL)萃取。合併的有機層用水(50mL)洗滌,經Na2SO4乾燥並在減壓下濃縮。粗化合物用甲苯(15mL)稀釋並回流16小時。反應混合物在減壓下濃縮並通過管柱層析法,採用矽膠(100-200目)和10%在石油醚中的EtOAc作為洗脫液來純化,以提供作為淺黃色液體的8-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,36%產率)。LCMS m/z實測值226.1[M+H]+,
RT=1.73min(方法E).
步驟vi. 在0℃下向8-(二氟甲基)吲哚-2-羧酸甲基酯(500mg,2.22mmol,1.0eq.)在THF:水:MeOH(2:1:1,10mL)混合物中的攪拌後的溶液加入LiOH(200mg,11.1mmol,5.0eq.)並在室溫下將反應攪拌4小時。將揮發物從反應混合物蒸發並用aq.KHSO4溶液(水中10wt%)酸化成pH約為2。所沉澱的固體通過過濾收集,用水洗滌並在真空下乾燥,以提供作為白色固體的8-(二氟甲基)吲哚-2-羧酸(300mg,64%產率)。LCMS m/z實測值212.4[M+H]+;RT=1.40min(方法E).
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和8-(二氟甲基)吲哚-2-羧酸(VIes)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺。LCMS m/z實測值460.2[M+H]+;RT=3.80min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.4(d,1H),8.12(t,1H),8.06(s,1H),7.48-7.44(M,1H),7.33-7.06(M,2H),6.79(s,1H),6.72(t,1H),5.72(s,1H),4.64(d,1H),4.49(d,1H),4.17(d,1H),4.06(d,1H),3.03(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺(化合物408)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和2,3-二氫-1H-茚-5-羧酸(VIet)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺。LCMS m/z實測值411.2[M+H]+;RT=4.34min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(bs,1H),8.13(t,1H),7.52-7.47(M,1H),7.29-7.24(M,2H),7.12(d,1H),5.68(s,1H),4.58(d,1H),4.46(d,1H),4.23(d,1H),4.03(d,1H),2.87(t,4H),2.70(s,3H),2.02(t,2H).
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和苯并[d]唑-6-羧酸(VIeu)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-6-甲醯胺。LCMS m/z實測值412.2[M+H]+;RT=2.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.85(t,1H),8.14
(t,1H),7.88(d,1H),7.56-7.51(M,1H),7.41(d,1H),5.761(s,1H),4.59(d,1H),4.47(d,1H),4.31(d,1H),4.07-4.03(M,1H),2.73(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物412)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和5-氟-6-(三氟甲基)煙酸(VIev)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺。LCMS m/z實測值458.2[M+H]+;RT=4.15min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,1H),8.67(bs,1H),8.31(d,1H),8.16(t,1H),7.50(M,1H),5.66(s,1H),4.63(d,1H),4.49(d,1H),4.35(d,1H),4.03(d,1H),2.93(s,3H).
5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺(化合物413、414)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和5-氟-6-(三氟甲基)煙酸
(VIev)合成外消旋5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak IG(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物413):LCMS m/z實測值440.2[M+H]+;RT=3.89min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.69(bs,1H),8.30(bs,1H),7.91(d,1H),7.77(t,1H),7.63(M,1H),5.69(s,1H),4.62(d,1H),4.49(d,1H),4.33(d,1H),4.05(d,1H),2.72(s,3H);手性分析SFC:RT=1.03miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物414):LCMS m/z實測值440.2[M+H]+;RT=3.89min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.69(bs,1H),8.30(bs,1H),7.91(d,1H),7.77(t,1H),7.63(M,1H),5.69(s,1H),4.62(d,1H),4.49(d,1H),4.33(d,1H),4.05(d,1H),2.72(s,3H);手性分析SFC:RT=2.42miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-氯
-6-(三氟甲基)煙酸(VIep)合成外消旋1-(5-氯-N-甲基-6-(三氟甲基)菸鹼醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物418):LCMS m/z實測值473.1[M+H]+;RT=3.42min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.73(bs,1H),8.41(bs,1H),8.13(t,1H),7.38(M,1H),5.55(s,1H),3.80(d,1H),3.67(d,1H),3.36(d,1H),3.12(d,1H),2.76(s,4H);手性分析SFC:RT=0.79miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物419):LCMS m/z實測值473.1[M+H]+;RT=3.42min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),8.73(bs,1H),8.41(bs,1H),8.13(t,1H),7.38(M,1H),5.55(s,1H),3.80(d,1H),3.67(d,1H),3.36(d,1H),3.12(d,1H),2.76(s,4H);手性分析SFC:RT=1.61miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhf)合成外消旋8,9-二氟-1-(N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm),5μ,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物420):LCMS m/z實測值415.1[M+H]+;RT=3.03min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.80(bs,1H),11.63(bs,1H),8.12(t,1H),7.43(d,1H),7.28(M,1H),7.00(d,1H),6.92(bs,1H),5.61(s,1H),3.82(d,1H),3.66(d,1H),3.11-2.65(M,6H);手性分析SFC:RT=5.70miN,管柱:Chiralpak OD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物421):LCMS m/z實測值415.1[M+H]+;RT=3.03min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.80(bs,1H),11.63(bs,1H),8.12(t,1H),7.43(d,1H),7.28(M,1H),7.00(d,1H),6.92(bs,1H),5.61(s,1H),3.82(d,1H),3.66(d,1H),3.11-2.65(M,6H);手性分析SFC:RT=7.70miN,管柱:Chiralpak OD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物422,423)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-甲基-1H-吲哚-2-羧酸(VIdx)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IA-3(30 x 250mm)5μm,流速:110g/min。
對映異構物I(化合物422):LCMS m/z實測值406.2[M+H]+;RT=4.15min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.64(bs,2H),7.91(q,1H),7.64(t,1H),7.5(bs,1H),7.2(d,1H),7.1(t,1H),)6.9(d,1H),6.67(d,1H),5.77(s,1H),4.59(d,1H),4.47(d,1H),4.22(d,1H),4.04(d,1H),3.1(s,3H),2.4(s,3H);手性分析SFC:RT=2.49miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
對映異構物II(化合物423):LCMS m/z實測值406.2[M+H]+;RT=4.15min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.64(bs,2H),7.91(q,1H),7.64(t,1H),7.5(bs,1H),7.2(d,1H),7.1(t,1H),)6.9(d,1H),6.67(d,1H),5.77(s,1H),4.59(d,1H),4.47(d,1H),4.22(d,1H),4.04(d,1H),3.1(s,3H),2.4(s,3H);手性分析SFC:RT=9.61miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物424、425)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-氯-1H-吲哚-2-羧酸(VIee)合成外消旋4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(乙腈:甲醇)(1:1):CO2-50:50。管柱:Chiralpak IA-3(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物424):LCMS m/z實測值426.1[M+H]+;RT=4.35min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.08(bs,1H),11.64(bs,1H),7.92(d,1H),7.62(t,1H),7.55(bs,1H),7.46(d,1H),7.23(t,1H),7.14(d,1H),6.85(bs,1H),5.76(s,1H),4.66(d,1H),4.51(d,1H),4.20(d,1H),4.07(d,1H),3.16(s,3H);手性分析SFC:RT=2.49miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
對映異構物II(化合物425):LCMS m/z實測值406.2[M+H]+;RT=4.15min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.08(bs,1H),11.64(bs,1H),7.92(d,1H),7.62(t,1H),7.55(bs,1H),7.46(d,1H),7.23(t,1H),7.14(d,1H),6.85(bs,1H),5.76(s,1H),4.66(d,1H),4.51(d,1H),4.20(d,1H),4.07(d,1H),3.16(s,3H);手性分析SFC:RT=8.99miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d] 唑-5-甲醯胺(化合物426)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和苯并[d]唑-5-羧酸(VIew)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-5-甲醯胺。LCMS m/z實測值412.1[M+H]+;RT=2.89min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),8.84(bs,1H),8.16(t,1H),7.87(d,2H),7.57-7.45(M,2H),5.71(s,1H),4.61(d,1H),4.49(d,1H),4.33(d,1H),4.06(M,1H),2.73(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺(化合物427)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和苯并[d]噻唑-5-羧酸(VIex)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺。LCMS m/z實測值428.1[M+H]+;RT=3.14min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),9.48(t,1H),8.28(d,1H),8.17(t,2H),7.59-7.49(M,2H),5.74(s,1H),4.62(d,1H),
4.50(d,1H),4.35(d,1H),4.08(M,1H),2.75(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺(化合物428)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和苯并[d]噻唑-6-羧酸(VIey)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺。LCMS m/z實測值428.1[M+H]+;RT=3.06min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.69(bs,1H),9.48(s,1H),8.30(t,1H),8.16(t,1H),7.56-7.52(M,2H),5.72(s,1H),4.62(d,1H),4.50(d,1H),4.31(d,1H),4.07(d,1H),2.75(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺(化合物429)
以與上文所述類似的方式,由鏡像異構純的(1S)-8,9-二氟-1-(甲胺基)-1,2,4,5-四氫哌喃并[3,4-c]異喹啉-6-酮(Vb)和1H-吲唑-5-羧酸(VIez)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺。
LCMS m/z實測值411.3[M+H]+;RT=1.42min(方法E);1H NMR(400MHz,DMSO-d 6)δ 13.25(bs,1H),11.66(bs,1H),8.15(t,1H),7.86(d,1H),7.61(M,1H),7.39(md 1H),5.71(s,1H),4.61(d,1H),4.49(d,1H),4.29(d,1H),4.07(d,1H),2.77(s,3H).
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和8-(二氟甲基)吲哚-2-羧酸(VIes)合成外消旋1-(8-(二氟甲基)-N-甲基吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Lux纖維素(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物430):LCMS m/z實測值459.1[M+H]+;RT=3.01min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.40(d,1H),8.13(M,2H),7.32-7.05(M,3H),6.78-6.95(M,2H),5.65(s,1H),3.80(d,1H),3.66(d,1H),3.50(d,1H),3.48(d,1H),2.76(s,4H);手性分析SFC:RT=4.63miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物431):LCMS m/z實測值459.1
[M+H]+;RT=3.01min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.40(d,1H),8.13(M,2H),7.32-7.05(M,3H),6.78-6.95(M,2H),5.65(s,1H),3.80(d,1H),3.66(d,1H),3.50(d,1H),3.48(d,1H),2.76(s,4H);手性分析SFC:RT=6.33miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-(二氟甲基)吲哚-2-羧酸(VIdc)合成外消旋1-(5-(二氟甲基)-N-甲基吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相[(0.2%在7M甲醇銨(甲醇:ACN)(1:1)]:CO2-40:60。管柱:Lux纖維素-2(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物432):LCMS m/z實測值459.1[M+H]+;RT=3.09min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.13(bs,1H),7.90(bs,1H),7.75(d,1H),7.54-7.28(M,2H),7.07(d,1H),6.93(M,2H),5.64(s,1H),3.87(d,1H),3.80(d,1H),3.2-3.13(M,2H),2.99(s,4H);手性分析SFC:RT=3.60miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%
(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物433):LCMS m/z實測值459.1[M+H]+;RT=3.09min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.61(bs,1H),8.13(bs,1H),7.90(bs,1H),7.75(d,1H),7.54-7.28(M,2H),7.07(d,1H),6.93(M,2H),5.64(s,1H),3.87(d,1H),3.80(d,1H),3.2-3.13(M,2H),2.99(s,4H);手性分析SFC:RT=6.08miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和5-氟-6-(三氟甲基)煙酸(VIev)合成外消旋8,9-二氟-1-(5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物434):LCMS m/z實測值457.1[M+H]+;RT=3.19min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.63(bs,1H),8.64(bs,1H),8.29(d,1H),8.14(t,1H),7.36(M,
1H),5.55(s,1H),3.80(d,1H),3.67(d,1H),3.32(d,1H),3.14(d,1H),2.76(s,4H);手性分析SFC:RT=0.90miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物435):LCMS m/z實測值457.1[M+H]+;RT=3.19min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.63(bs,1H),8.64(bs,1H),8.29(d,1H),8.14(t,1H),7.36(M,1H),5.55(s,1H),3.80(d,1H),3.67(d,1H),3.32(d,1H),3.14(d,1H),2.76(s,4H);手性分析SFC:RT=1.84miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物438、439)
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和4-氯-6-氟-1H-吲哚-2-羧酸(VIea)合成外消旋4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相(乙腈:甲醇)(1:1):CO2-50:50。管柱:Chiralpak IA-3(30 x 250mm),5μ,流速:110g/min。
對映異構物I(化合物438):LCMS m/z實測值444.0[M+H]+;RT=4.59min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.90(bs,2H),7.90(d,1H),7.62-7.50(M,2H),7.21-7.13(M,
2H),6.87(bs,1H),5.74(s,1H),4.64(d,1H),4.49(d,1H),4.19(d,1H),4.06(d,1H),3.15(s,3H);手性分析SFC:RT=2.20miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
對映異構物II(化合物439):LCMS m/z實測值444.0[M+H]+;RT=4.59min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.90(bs,2H),7.90(d,1H),7.62-7.50(M,2H),7.21-7.13(M,2H),6.87(bs,1H),5.74(s,1H),4.64(d,1H),4.49(d,1H),4.19(d,1H),4.06(d,1H),3.15(s,3H);手性分析SFC:RT=6.17miN,管柱:Chiralpak IA-3(4.6 x 150mm)3μM,40%(乙腈:甲醇)(1:1),流速:3.0g/min.
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-氯-1H-吲哚-2-羧酸(VIee)合成外消旋1-(4-氯-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak IA(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物440):LCMS m/z實測值443.1[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,DMSO-d 6)
δ 12.11(bs,1H),11.74(bs,1H),8.14(t,1H),7.45(d,1H),7.33-7.28(M,1H),7.22(t,1H),7.14(d,1H),6.89(s,1H),5.81(s,1H),4.10-3.80(M,2H),3.30-3.20(M,2H),3.12(s,3H);手性分析SFC:RT=2.79miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物441):LCMS m/z實測值443.1[M+H]+;RT=3.63min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.11(bs,1H),11.74(bs,1H),8.14(t,1H),7.45(d,1H),7.33-7.28(M,1H),7.22(t,1H),7.14(d,1H),6.89(s,1H),5.81(s,1H),4.10-3.80(M,2H),3.30-3.20(M,2H),3.12(s,3H);手性分析SFC:RT=8.01miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吲哚-6-羧酸(VIer)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺。LCMS m/z實測值410.3[M+H]+;RT=4.65min(方法A);1H NMR(400MHz,甲醇-d 4)δ 8.41(s,1H),8.17(dd,1H),7.57-7.52(M,2H),7.42(d,1H),6.82(M,1H),6.66(d,1H),6.47(d,1H),5.78(s,1H),4.67(d,1H),4.56(d,1H),4.36(d,1H),4.11(dd,1H),3.00(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吲哚-7-羧酸(VIha)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺。LCMS m/z實測值410.3[M+H]+;RT=4.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.33-8.26(M,1H),8.13(M,1H),7.64(d,1H),7.57(s,1H),7.50(s,1H),6.82(M,1H),6.56(M,2H),5.65(s,1H),4.60(d,1H),4.46(d,1H),4.25(d,1H),4.07-3.98(M,1H),2.84(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6,7,8-四氫吲哚-2-羧酸(VIhb)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-
5,6,7,8-四氫吲哚-2-甲醯胺。LCMS m/z實測值414.3[M+H]+;RT=5.24min(方法A);1H NMR(400MHz,氯仿-d)δ 11.50(s,1H),8.19(M,1H),7.49(t,1H),7.02(d,1H),6.14-6.09(M,1H),5.86(s,1H),4.77(d,1H),4.61(d,1H),4.34(d,1H),4.03(d,1H),3.95(t,2H),3.10(s,3H),2.75(t,2H),2.00-1.90(M,2H),1.82(M,2H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吲哚-3-羧酸(VIhc)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-3-甲醯胺。LCMS m/z實測值410.3[M+H]+;RT=5.89min(方法A);1H NMR(400MHz,氯仿-d)δ 11.13(s,1H),9.17(M,1H),8.22(M,1H),7.62(s,1H),7.46(M,1H),7.09(d,1H),6.95(M,1H),6.80-6.72(M,1H),6.46(M,1H),5.86(s,1H),4.78(d,1H),4.69-4.60(M,1H),4.45(d,1H),4.17-4.07(M,1H),3.20(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和吲哚-1-羧酸(VIhd)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-1-甲醯胺。LCMS m/z實測值410.3[M+H]+;RT=5.67min(方法A);1H NMR(400MHz,氯仿-d)δ 11.16(s,1H),8.21(M,1H),8.05-7.93(M,2H),7.68(s,1H),7.28-7.22(M,1H),6.98(M,1H),6.91(d,1H),6.67(M,1H),5.90(s,1H),4.77(d,1H),4.63(d,1H),4.47(d,1H),4.11(M,1H),3.13(s,3H).
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-甲基吲哚-6-羧酸(VIhe)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,2-二甲基吲哚-6-甲醯胺。LCMS m/z實測值424[M+H]+;RT=3.03min(方法C);
1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.46(s,1H),8.13(M,1H),7.48(s,1H),7.43(s,1H),7.32(d,1H),6.64(d,1H),6.27(s,1H),5.66-5.60(M,1H),4.60(d,1H),4.46(d,1H),4.23(d,1H),4.03(M,1H),2.85(s,3H),2.24(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物278)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhf)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值416[M+H]+;RT=2.87min(方法C);1H NMR(400MHz,DMSO-d 6)δ 11.86(s,1H),11.73(s,1H),8.12(M,1H),7.44(M,2H),7.03-6.95(M,2H),5.74(s,1H),4.64(d,1H),4.52-4.42(M,1H),4.12(d,1H),4.03(d,1H),3.13(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺(化合物294)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和6H-噻吩并[2,3-b]吡咯-5-羧酸(VIhg)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺。LCMS m/z實測值416[M+H]+;RT=2.89min(方法C);1H NMR(400MHz,DMSO-d 6)δ 12.05(s,1H),11.73(s,1H),8.12(M,1H),7.45(s,1H),7.07(d,1H),6.99(d,1H),6.87(d,1H),5.74(s,1H),4.63(d,1H),4.51-4.42(M,1H),4.12(d,1H),4.02(d,1H),3.13(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺(化合物299)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和咪唑并[1,5-a]吡啶-6-羧酸(VIhh)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺。LCMS m/z實測值411[M+H]+;RT=2.02
min(方法C);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.64-8.59(M,1H),8.43(s,1H),8.14(M,1H),7.61(d,1H),7.48(M,1H),7.41(s,1H),6.78(d,1H),5.65(s,1H),4.60(d,1H),4.47(d,1H),4.26(d,1H),4.03(M,1H),2.85(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺(化合物306)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和咪唑并[1,2-a]吡啶-6-羧酸(VIhi)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺。LCMS m/z實測值411[M+H]+;RT=1.80min(方法C);1H NMR(400MHz,DMSO-d 6)δ 11.73(s,1H),8.86(s,1H),8.19-8.09(M,1H),8.02(s,1H),7.68-7.59(M,2H),7.51(M,1H),7.28(d,1H),5.67(s,1H),4.61(d,1H),4.47(d,1H),4.28(d,1H),4.08-4.00(M,1H),2.85(s,3H).
步驟i:將6-甲基吡啶-3-羧酸甲基酯(1.00g,6.62mmol)和3-溴-1,1,1-三氟-丙烷-2-酮(0.81mL,7.80mmol)在3mL丙酮中的混合物加熱回流過夜。將揮發物蒸發,並與5%在己烷中的乙酸乙酯研磨該材料,經硫酸鈉乾燥並轉而形成粗物質。將碳酸氫鈉(0.98g,11.7mmol)加入到粗的6-甲基-1-(3,3,3-三氟-2-側氧-丙基)吡啶-1-鎓-3-甲酸甲基酯溴化物(2.00g,5.85mmol)在10mL乙醇中的溶液中。將混合物加熱回流。回流4小時後,在室溫下將混合物攪拌過夜。混合物通過棉塞過濾並蒸發至乾燥。取所得的深色油到50mL DCM中並用水(25mL)和鹽水(25mL)洗滌。有機物經硫酸鈉乾燥並在減壓下蒸發。該材料通過快速層析法(矽膠,EtOAc/己烷5-30%)分離以提供2-(三氟甲基)吲哚-6-羧酸甲基酯(0.18g,13%)。1H NMR(400MHz,氯仿-d)δ 8.72(dd,1H),7.66(d,1H),7.44-7.37(M,1H),7.33-7.19(M,1H),6.66(s,1H),3.94(s,3H).
步驟ii:將氫氧化鋰水合物(35mg,0.82mmol)在2mL水中的溶液緩慢加入2-(三氟甲基)吲哚-6-羧酸甲基酯(100mg,0.41mmol)在3mL 1,4-二烷中的溶液中。在室溫下攪拌過夜後,在真空下去除揮發物。用2N HCl將殘餘物酸化成pH=1。所得沉澱通過真空過濾收集,並在真空下乾燥以提供2-(三氟甲基)吲哚-6-羧酸(VIhj,75mg,80%)。1H NMR(400MHz,DMSO-d6)δ 13.19(s,1H),9.10(M,1H),8.26(t,1H),7.56(d,1H),7.22(M,1H),6.81(s,1H).
步驟iii:以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)2-(三氟甲基)吲哚-6-羧酸(VIhj)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)吲哚-6-甲醯胺。LCMS m/z實測值478[M+H]+;RT=3.27min(方法C);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),8.61(s,1H),8.14(M,2H),7.58(d,1H),7.48(M,1H),6.89(d,1H),6.78(s,1H),5.68-5.62(M,1H),4.61(d,1H),4.47(d,1H),4.26(d,1H),4.03(M,1H),2.85(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺(化合物314)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和4H-呋喃并[3,2-b]吡咯-5-羧酸(VIhk)合成鏡像異構純的(S)-N-(8,9-二氟
-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值400.3[M+H]+;RT=3.45min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),11.45(s,1H),8.11(M,1H),7.73(d,1H),7.45(s,1H),6.68(s,1H),6.59(d,1H),5.72(s,1H),4.63(d,1H),4.46(d,1H),4.11(d,1H),4.02(d,1H),3.09(s,3H).
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺(化合物332)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-氯-4H-呋喃并[3,2-b]吡咯-5-羧酸(VIhl)合成鏡像異構純的(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值434.2/436.2[M+H]+;RT=4.18min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),11.63(s,1H),8.10(M,1H),7.42(s,1H),6.70(s,2H),5.69(s,1H),4.61(d,1H),4.44(d,1H),4.09(d,1H),3.99(d,1H),3.06(s,3H).
(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物349)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-氯-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhm)合成鏡像異構純的(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值450.1/452.0[M+H]+;RT=4.56min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.01(s,1H),11.73(s,1H),8.12(M,1H),7.43(d,1H),7.09(s,1H),6.96-6.91(M,1H),5.73(s,1H),4.63(d,1H),4.47(d,1H),4.12(d,1H),4.02(d,1H),3.11(s,3H).(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物350)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氯-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhn)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值450.0
[M+H]+;RT=4.33min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.35(s,1H),11.74(s,1H),8.12(M,1H),7.46(M,2H),6.98(s,1H),5.71(s,1H),4.63(d,1H),4.47(d,1H),4.14(d,1H),4.07-3.99(M,1H),3.10(s,3H).
(S)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺(化合物361)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3,4-二氯苯甲酸(VIho)合成鏡像異構純((S)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺。LCMS m/z實測值439.1[M+H]+;RT=4.56min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.13(M,1H),7.78-7.69(M,2H),7.47(M,1H),7.38(M,1H),5.65(d,1H),4.59(d,1H),4.46(d,1H),4.31(d,1H),4.00(M,1H),2.70(s,3H).(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚 -6-甲醯胺(化合物366)
步驟i:將N-氯代琥珀醯亞胺(34mg,0.25mmol)在DCM(0.30mL)中的懸浮液加入到箔包裹的燒瓶中0℃下的吲哚-6-羧酸甲基酯(40mg,0.23mmol)在0.2mL DCM(0.2mL)中的
溶液中。30分鐘後,用15mL EtOAc稀釋反應混合物,並用飽和硫代硫酸鈉(2 x 3mL)和3mL鹽水洗滌。有機物經硫酸鈉乾燥並蒸發至乾燥。通過快速層析法(矽膠,DCM/己烷20-80%)純化,提供純的3-氯吲哚-6-羧酸甲基酯(36mg,76%)。1H NMR(400MHz,氯仿-d)δ 8.75(dt,1H),7.37(dd,1H),7.29-7.18(M,1H),6.81(dd,1H),6.51(dd,1H),3.94(s,3H).
步驟ii:將氫氧化鋰水合物(10mg,0.23mmol)在0.6mL水中的溶液加入到3-氯吲哚-6-羧酸甲基酯(32mg,0.15mmol)在0.5mL 1,4-二烷中的溶液中。在室溫下150分鐘攪拌後,用2N HCl將混合物酸化成pH=1。混合物用EtOAc(3 x 4mL)萃取。合併的有機物經硫酸鈉乾燥,過濾,並真空旋轉(rotovaced),以提供作為黃色固體的3-氯吲哚-6-羧酸(VIhp,29mg,97.5%)。1H NMR(400MHz,甲醇-d 4)δ 8.75(M,1H),7.46(M,1H),7.22(dd,1H),6.87(dd,1H),6.58(d,1H).
步驟iii:以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氯吲哚-6-羧酸(VIhp)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺。LCMS m/z實測值444.1/446.1[M+H]+;RT=4.46min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.72(s,1H),
8.26(s,1H),8.18-8.08(M,1H),7.61-7.49(M,2H),6.96(d,1H),6.78-6.71(M,1H),6.62(d,1H),5.66(s,1H),4.60(d,1H),4.47(d,1H),4.35(d,1H),4.06-3.97(M,1H),2.82(s,3H).
步驟i:分3部分將N-氯代琥珀醯亞胺(105mg,0.78mmol)加入到箔包裹的燒瓶中吲哚-7-羧酸甲基酯(125mg,0.71mmol)在0.2mL DCM中的0℃溶液中。在0℃下5小時後,反應混合物用15mL EtOAc稀釋,並用飽和硫代硫酸鈉(2 x 3mL)和3mL鹽水洗滌。有機物經硫酸鈉乾燥並蒸發至乾燥。通過快速層析法(矽膠,DCM/己烷0-50%)純化提供純的3-氯吲哚-7-羧酸甲基酯(VIhq,72mg,48%)。NMR(400MHz,氯仿-d)δ 8.19(M,1H),7.92(M,1H),7.30-7.17(M,1H),6.82(M,1H),6.78-6.72(M,1H),3.92(s3H).
步驟ii:將氫氧化鋰水合物(17mg,0.40mmol)在1mL水中的溶液加入到3-氯吲哚-7-羧酸甲基酯(56mg,0.27mmol)在1mL 1,4-二烷中的溶液中。3小時後,用2N HCl將混合物酸化至pH=1。混合物用EtOAc(3 x 4mL)萃取。合併的有機物經硫酸鈉乾燥,過濾,並蒸發以提供3-氯吲哚-7-羧酸(45mg,86%)。1H NMR(400MHz,DMSO-d 6)δ 12.93(s,1H),8.23-8.10(M,2H),7.16(M,1H),7.03(dd,1H),6.94-6.86(M,1H).
步驟iii:以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和3-氯吲哚-7-羧酸(VIhq)合成鏡像異構純的(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺。LCMS m/z實測值444.2/446.1[M+H]+;RT=4.48min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(s,1H),8.18-8.11(M,2H),7.69(s,1H),7.50(t,1H),6.95(d,1H),6.85-6.77(M,1H),6.71(d,1H),5.65(s,1H),4.60(d,1H),4.47(d,1H),4.27(d,1H),4.07-3.98(M,1H),2.84(s,3H).
((S)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物468)
步驟i:向N,N-二甲基甲醯胺(0.60mL,7.70mmol)在10mL 1,2-二氯乙烷中的溶液逐滴加入三氯氧磷(0.48mL,5.13mmol)。30分鐘後,加入4H-噻吩并[3,2-b]吡咯-5-羧酸乙基酯(0.50g,2.57mmol)在14mL 1,2-二氯乙烷中的溶液。將混合物加熱回流2h。冷卻後,將混合物緩慢傾倒入20mL水中,然後在減壓下蒸發去除1,2-二氯乙烷。混合物用EtOAc(3 x 25mL)萃取。合併的有機物用飽和水性碳酸氫鈉(2 x 20mL)和20mL鹽水洗滌,並經硫酸鈉乾燥。產物通過快速層析法(矽膠,EtOAc/DCM 0-40%)分離,以提供
作為第一洗脫區域異構物的6-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸乙基酯(198mg,35%)和作為第二洗脫區域異構物的2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸乙基酯(162mg,28%)。乙基2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸酯:1H NMR(400MHz,氯仿-d)δ 9.93(s,1H),9.29(s,1H),7.64(d,1H),7.16(M,1H),4.41(q,2H),1.41(t,3H).
步驟ii:製備2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸乙基酯(160mg,0.73mmol)在3.4mL THF和2.3mL MeOH中的溶液。加入氫氧化鋰水合物(122mL,2.90mmol)在1.2mL水中的溶液。將混合物加熱至50℃過夜。在真空下去除揮發物。用2N HCl將水性殘餘物酸化至pH=1。形成黃褐色沉澱。通過真空過濾收集沉澱並在真空下乾燥以提供2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸(70mg)。濾液用30mL EtOAc萃取。將有機層分離,並用40mL EtOAc萃取水層。合併的有機物經硫酸鈉乾燥,過濾,真空旋轉,並在真空下乾燥。將該材料雨上述產物合併以提供粗2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸(145mg)。1H NMR(400MHz,DMSO-d 6)δ 13.13(s,1H),12.47(s,1H),9.94(s,1H),7.95(d,1H),7.12(M,1H).
步驟iii:將粗2-甲醯基-4H-噻吩并[3,2-b]吡咯-5-羧酸(75mg,0.38mmol)和鹽酸羥胺(59mg,0.85mmol)在2M無水DMF中的混合物加熱至125℃過夜。在真空下去除揮發物。將所得殘餘物懸浮於15mL水和15mL EtOAc中,並將層分離。水層用2 x 15mL EtOAc萃取。合併的有機物用鹽水(10mL)洗滌,經硫酸鈉乾燥,蒸發至乾燥並在高真空下乾燥,以提供粗2-氰基-4H-噻吩并[3,2-b]吡
咯-5-羧酸(VIhr,72mg)。1H NMR(400MHz,DMSO-d 6)δ 13.13(s,1H),12.52-12.46(M,1H),7.88(s,1H),7.16-7.10(M,1H).
步驟iv:以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和2-氰基-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhr)合成鏡像異構純的(S)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS m/z實測值441.2[M+H]+;RT=3.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.41(s,1H),11.74(s,1H),8.17-8.09(M,1H),7.88(s,1H),7.47-7.39(M,1H),7.05(s,1H),5.71(s,1H),4.63(d,1H),4.47(d,1H),4.16(d,1H),4.07-3.98(M,1H),3.11(s,3H).
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺(化合物442和443)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和2,3-二氫-1H-茚-5-羧酸(VIet)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并
[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel-IG-H(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物442):LCMS:m/z實測值393.1[M+H]+,RT=4.09miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.51(bs,1H),7.91(d,1H),7.78(t,1H),7.67(M,1H),7.28(M,2H),7.13(d,1H),5.68(s,1H),4.59(d,1H),4.48(d,1H),4.22(d,1H),4.04(d,1H),2.88(t,4H),2.67(s,3H)2.03(M,2H);手性分析SFC:RT=2.02miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,50%甲醇,流速:3.0g/min.
對映異構物II(化合物443):LCMS:m/z實測值393.1[M+H]+,RT=4.10miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.51(bs,1H),7.91(d,1H),7.78(t,1H),7.67(M,1H),7.28(M,2H),7.13(d,1H),5.68(s,1H),4.59(d,1H),4.48(d,1H),4.22(d,1H),4.04(d,1H),2.88(t,4H),2.67(s,3H)2.03(M,2H);手性分析SFC:RT=5.40miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,45%甲醇,流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺(化合物444和445)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和苯并[d]噻唑-5-羧酸(VIex)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺。隨後通過製備SFC分
離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel-IG(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物444):LCMS:m/z實測值410.1[M+H]+,RT=2.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.61(bs,1H),9.48(bs,1H),8.27(d,1H),8.10(bs,1H),7.93(d,1H),7.83(t,1H),7.71(M,1H),7.51(d,1H),5.75(s,1H),4.61(d,1H),4.50(d,1H),4.33(d,1H),4.08(d,1H),2.71(s,3H);手性分析SFC:RT=4.01miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇/乙腈(1:1),流速:3.0g/min.
對映異構物II(化合物445):LCMS:m/z實測值410.1[M+H]+,RT=2.94miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.61(bs,1H),9.48(bs,1H),8.27(d,1H),8.10(bs,1H),7.93(d,1H),7.83(t,1H),7.71(M,1H),7.51(d,1H),5.75(s,1H),4.61(d,1H),4.50(d,1H),4.33(d,1H),4.08(d,1H),2.71(s,3H);手性分析SFC:RT=8.06miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇/乙腈(1:1),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺(化合物446和447)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和苯并[d]噻唑-6-羧酸(VIey)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-60:40。管柱:Chiralcel-
IG(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物446):LCMS:m/z實測值410.1[M+H]+,RT=2.82miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.60(bs,1H),9.48(bs,1H),8.28(bs,1H),8.15(d,1H),7.93(d,1H),7.80(t,1H),7.69(M,1H),7.57(d,1H),5.72(s,1H),4.61(d,1H),4.50(d,1H),4.29(d,1H),4.08(d,1H),2.72(s,3H);手性分析SFC:RT=2.38miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇/乙腈(1:1),流速:3.0g/min.
對映異構物II(化合物447):LCMS:m/z實測值410.1[M+H]+,RT=2.82miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.60(bs,1H),9.48(bs,1H),8.28(bs,1H),8.15(d,1H),7.93(d,1H),7.80(t,1H),7.69(M,1H),7.57(d,1H),5.72(s,1H),4.61(d,1H),4.50(d,1H),4.29(d,1H),4.08(d,1H),2.71(s,3H);手性分析SFC:RT=5.38miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇/乙腈(1:1),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺(化合物448和449)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和1H-吲唑-5-羧酸(VIez)合成外消旋N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel-IG(30 x 250mm),5μm,流速:100g/min。
對映異構物I(化合物448):LCMS:m/z實測值393.1[M+H]+,RT=2.35miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 13.23(bs,1H),11.60(bs,1H),8.13(bs,1H),7.93(d,1H),7.84(s,1H),7.79(t,1H),7.69(t,1H),7.60(d,1H),7.39(d,1H),5.72(s,1H),4.60(d,1H),4.49(d,1H),4.27(d,1H),4.07(d,1H),2.74(s,3H);手性分析SFC:RT=2.19miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
對映異構物II(化合物449):LCMS:m/z實測值393.2[M+H]+,RT=2.36miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 13.23(bs,1H),11.60(bs,1H),8.13(bs,1H),7.93(d,1H),7.84(s,1H),7.79(t,1H),7.69(t,1H),7.60(d,1H),7.39(d,1H),5.72(s,1H),4.60(d,1H),4.49(d,1H),4.27(d,1H),4.07(d,1H),2.74(s,3H);手性分析SFC:RT=3.72miN,管柱:Chiralcel IG-3(4.6 x 150mm)3μM,40%的甲醇,流速:3.0g/min.
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺(化合物450)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1H-吲唑-6-羧酸(VIhs)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺。LCMS m/z實測值411.1[M+H]+;RT=2.83min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.21(bs,1H),11.65(bs,1H),8.16
(t,2H),7.85(d,1H),7.56(M,2H),7.09(d,1H),5.72(s,1H),4.60(d,1H),4.49(d,1H),4.32(d,1H),4,07(d,1H),2.71(s,3H).
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺(化合物451)
以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和1H-苯并[d]咪唑-6-羧酸(VIht)合成鏡像異構純的(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺。LCMS m/z實測值411.1[M+H]+;RT=1.82min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.16(bs,1H),8.30(s,1H),8.13(t,1H),7.65-7.52(M,3H),7.22(d,1H),5.71(s,1H),4.58(d,1H),4.46(d,1H),4.29(d,1H),4.05(d,1H),2.74(s,3H).
2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物452)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和2-氯-4H-噻吩并
[3,2-b]吡咯-5-羧酸(VIhm)合成外消旋2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺。LCMS:m/z實測值432.0[M+H]+,RT=4.33miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.94(bs,1H),11.62(bs,1H),7.91-7.88(M,1H),7.62(t,1H),7.50(bs,1H),7.09(s,1H),6.89(s,1H),5.71(s,1H),4.62(d,1H),4.47(d,1H),4.12(d,1H),4.02(d,1H),3.09(bs,3H).
6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物455)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va)和6-氟-4-甲基-1H-吲哚-2-羧酸(VIeb)合成外消旋6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS:m/z實測值424.4[M+H]+,RT=4.30miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.72(s,1H),11.63(s,1H),7.92-7.89(M,1H),7.65-7.53(M,2H),6.98(t,2H),6.73(d,1H),5.76(s,1H),4.64(d,1H),4.48(d,1H),4.16(d,1H),4.05(d,1H),3.17(s,3H),2.46(s,3H).
(S)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(化合物486)
向室溫下鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb,200mg,0.99mmol)和4-溴-3-氟苯甲醛(0.24g,1.19mmol)在2mL DCE中的攪拌後的溶液加入催化劑量的醋酸,之後加入三乙醯氧基硼氫化鈉(0.53g,2.50mmol)。在室溫下將所得混合物攪拌1小時。將反應混合物傾倒入冰冷的水(10mL)中,用EtOAc(2 x 50mL)萃取,經硫酸鈉乾燥,並在真空下濃縮。粗化合物通過手性SFC純化以提供(S)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(20mg,17%)。LCMS m/z實測值453.1/455.1[M+H]+;RT=3.31min(方法A);1H NMR(400MHz,DMSO-d6)δ 11.12(bs,1H),8.06(t,1H),7.92(t,1H),7.58(t,1H),7.08(d,1H),6.94(d,1H),4.50(t,2H),4.37(d,1H)3.89(s,1H)3.83(d,1H),3.61(d,2H),2.25(s,3H).
(S)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(化合物494)
步驟i:向室溫下5,6-二氟-1H-吲哚-2-羧酸(0.30g,1.52mmol)在1mL THF中的攪拌後的溶液加入DIPEA(6.1mL,15.5mmol)和HATU(0.86g,2.28mmol)。在室溫下攪拌15分鐘後,加入N,O-二甲基鹽酸羥胺(178mg,1.82mmol)。在室溫下進一步攪拌16小時後,將反應混合物傾倒入冰冷的飽和碳酸氫鈉溶液(10
mL)中並攪拌30分鐘。形成固體沉澱。通過真空過濾收集固體,用水洗滌並在真空下乾燥。產物通過快速層析法(矽膠,30%在石油醚中的乙酸乙酯)分離,以提供作為灰白色固體的5,6-二氟-N-甲氧基-N-甲基-1H-吲哚-2-甲醯胺(200mg,54%)。LCMS:m/z實測值241.2[MH+]-.
步驟ii:向0℃下180mg(0.74mmol,1.0eq.)5,6-二氟-N-甲氧基-N-甲基-1H-吲哚-2-甲醯胺(180mg,0.74mmol)在2mL THF中的攪拌後的溶液加入LiAlH4溶液(THF中1M,0.89mL,0.89mmol)。在0℃下2小時後,將反應混合物傾倒入冰冷的飽和氯化銨溶液(10mL)中並用EtOAc(2 x 20mL)萃取。有機物經硫酸鈉乾燥並在真空下濃縮以提供粗5,6-二氟-1H-吲哚-2-甲醛(VIga,130mg)。LCMS:m/z實測值181.9[MH+]-.
步驟iii:以與上文所述類似的方式,由鏡像異構純的(S)-8,9-二氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vb)和5,6-二氟-1H-吲哚-2-甲醛(VIga)合成鏡像異構純的(S)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮。LCMS:m/z實測值432.1[M+H]+;RT=3.23min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.44(bs,1H),11.05(bs,1H),8.0(t,1H),7.75-7.70(M,1H),7.40(t,1H),7.28-7.24(M,1H),6.22(s,1H),4.52-4.47(M,2H),4.34(d,
1H),3.92(d,2H),3.79(d,1H),3.59-3.55(M,1H),2.32(s,3H).
8,9-二氟-2,3,4,5-四氫啡啶-1,6-二酮(IVn)
步驟i:以與上文所述類似的方式,由4,5-二氟-2-碘-苯甲酸(IIIb)和環己烷-1,3-二酮(IId)合成8,9-二氟-3,4-二氫-2H-苯并[c]色烯-1,6-二酮。1H NMR(400MHz,CDCl3)δ 8.99(dd,1H),8.04(dd,1H),2.94(t,2H),2.73-2.58(M,2H),2.24-2.12(M,2H).
步驟ii:以與上文所述類似的方式,由8,9-二氟-3,4-二氫-2H-苯并[c]色烯-1,6-二酮和醋酸銨合成8,9-二氟-2,3,4,5-四氫啡啶-1,6-二酮。LCMS:m/z實測值250.1[M+H]+;RT=0.90min(方法B);1H NMR(400MHz,DMSO-d 6)δ 12.15(s,1H),9.14(dd,1H),8.06(dd,1H),2.88(t,2H),2.54(dd,2H),2.02(h,2H).
8,9-二氟-1-(甲胺基)-2,3,4,5-四氫-1H-啡啶-6-酮(Vu)
將鈦酸四異丙酯(0.48mL,1.58mmol)加入到8,9-二氟-2,3,4,5-四氫啡啶-1,6-二酮(0.1g,0.40mmol)和1,4-二烷(5mL)中THF(0.36mL,0.71mmol)中的2M甲胺溶液的混合物中。在氮氣下,在室溫下將混合物攪拌2小時。向反應中再加入0.1mL 2M甲胺溶液和0.2mL鈦酸四異丙酯並在室溫下使攪拌持續2小時,然後在45℃下再持續1小時。反應混合物用2mL無水甲醇稀釋並在冰浴中冷卻。以一部分將硼氫化鈉(30mg,0.79mmol)加入,將反應
混合物攪拌5分鐘並去除冰浴。又15分鐘後,通過加入鹽水(1.5mL)使反應猝滅,用20mL乙酸乙酯稀釋,並再攪拌15分鐘。混合物通過CELITE®過濾並用25mL乙酸乙酯洗滌濾餅。產物通過快速層析法(矽膠,MeOH/DCM 0-10%)分離以提供84mg(80%產率)8,9-二氟-1-(甲胺基)-2,3,4,5-四氫-1H-啡啶-6-酮。LCMS:m/z實測值265.2[M+H]+,234.1[M-MeNH]+;RT=0.70miN,(方法B);1H NMR(400MHz,CDCl3)δ 8.02(dd,1H),7.33(dd,1H),3.65(dd,1H),3.59-3.37(bs,可互換的質子),2.59-2.45(M,5H),2.21-2.11(M,1H),1.96-1.79(M,1H),1.78(tt,1H),1.49(tt,1H).
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物466和467)
以與上文所述類似的方式,由外消旋8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:ChiralPak IC-3(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物466):LCMS:m/z實測值408.1[M+H]+,RT=4.24miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.70(bs,1H),11.5(bs,1H),8.11(t,1H),7.60(d,1H),7.47(d,1H),7.27-7.19(M,2H),7.05(t,1H),6.91(s,1H)5.92(s,1H),2.9(s,3H),2.74(t,1H),2.6(t,1H),2.01(t,1H),1.9(d,2H),1.79(M,1H);手性分析SFC:RT=5.28miN,管柱:Chiralpak IC-3(4.6
x 150mm)3μM,30%的含0.5% DEA的甲醇,流速:3.0g/min.
對映異構物II(化合物467):LCMS:m/z實測值408.1[M+H]+,RT=4.24miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.70(bs,1H),11.5(bs,1H),8.11(t,1H),7.60(d,1H),7.47(d,1H),7.27-7.19(M,2H),7.05(t,1H),6.91(s,1H)5.92(s,1H),2.9(s,3H),2.74(t,1H),2.6(t,1H),2.01(t,1H),1.9(d,2H),1.79(M,1H);手性分析SFC:RT=8.20miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,30%的含0.5% DEA的甲醇,流速:3.0g/min.
8-氟-2,3,4,5-四氫啡啶-1,6-二酮(Ivo)
步驟i:在氮氣氛下將5-氟-2-碘-苯甲酸(IIIa,543.7mg,2.04mmol)、環己烷-1,3-二酮(IId,275.02mg,2.45mmol)、碘化亞銅(38.93mg,0.20mmol)、和磷酸鉀(606.64mg,2.86mmol)合併到管中。加入無水1,4-二烷(1.5mL)並用氮氣吹掃反應管並在室溫下攪拌30分鐘,並在110℃下加熱4小時。使反應混合物冷卻至室溫,用乙酸乙酯(10mL)稀釋,通過CELITE®過濾,並用乙酸乙酯(3 x 25mL)洗滌該墊。合併的有機萃取物經硫酸鈉乾燥,過濾並在高真空下蒸發溶劑,以提供令人滿意純度的434mg(91%產率)8-氟-3,4-二氫-2H-苯并[c]色烯-1,6-二酮。1H NMR(400MHz,CDCl3)δ 9.11(ddd,1H),7.91(ddd,1H),7.49(ddd,1H),2.93(t,2H),2.69-2.58(M,2H),2.23-2.11(M,2H).
步驟ii:在密封管內,在140℃下將來自步驟i的8-氟-3,4-二氫-2H-苯并[c]色烯-1,6-二酮(434.00mg,1.87mmol)和醋酸銨(1.44g,18.69mmol)在1,2-二氯乙烷(2mL)中攪拌10小時。使反應混合物冷卻並用二氯甲烷稀釋,並用飽和氯化銨洗滌。用二氯甲烷萃取水相三次並使合併的有機萃取物經硫酸鈉乾燥,然後過濾。將溶
劑蒸發,並通過快速層析法(矽膠,甲醇/二氯甲烷0-5%梯度)分離產物以提供225mg(52%產率)8-氟-2,3,4,5-四氫啡啶-1,6-二酮(IVo)。LCMS:m/z實測值232.1[M+H]+;RT=0.82miN,(方法B);1H NMR(400MHz,CDCl3)δ 9.21(dd,1H),7.87(ddd,1H),7.38(dddd,1H),2.83(t,2H),2.57(dd,2H),2.09(dt,2H).
8-氟-1-(甲胺基)-2,3,4,5-四氫-1H-啡啶-6-酮(Vv)
以與上文所述類似的方式,由8-氟-2,3,4,5-四氫啡啶-1,6-二酮(IVo)和甲胺合成8-氟-1-(甲胺基)-2,3,4,5-四氫-1H-啡啶-6-酮。LCMS:m/z實測值216.1[M-MeNH)]+;RT=0.60miN,(方法B);1H NMR(400MHz,CDCl3)δ 10.49(s,1H),8.12-7.97(M,1H),7.69(dd,1H),7.43(ddd,1H),3.86-3.82(M,1H),2.65(dd,1H),2.58(s,3H),2.24(dd,1H),2.08-1.91(M,1H),1.85(dt,1H),1.56(tt,1H),1.25(M,1H).
N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物475和476)
以與上文所述類似的方式,由外消旋8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和1H-吲哚-2-羧酸(VIa)合成外消旋N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2
-40:60。管柱:ChiralPak IC-3(30 x 250mm),5μm,流速:110g/min。
對映異構物I(化合物475):LCMS:m/z實測值390.1[M+H]+,RT=4.06miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.70(bs,1H),11.5(bs,1H),7.87-7.82(dd,1H),7.59-7.58(t,2H),7.45(M,2H),7.2(t,1H),7.05(t,1H),6.9(s,1H),5.9(s,1H),2.9(s,3H),2.68(t,1H),2.62(M,1H),2.06(M,1H),1.94-1.91(M,3H);手性分析SFC:RT=4.81miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%甲醇/乙腈(1:1)流速:3.0g/min.
對映異構物II(化合物476):LCMS:m/z實測值390.1[M+H]+,RT=4.06miN,(方法A);1H NMR(400MHz,DMSO-d6):δ 11.70(bs,1H),11.5(bs,1H),7.87-7.82(dd,1H),7.59-7.58(t,2H),7.45(M,2H),7.2(t,1H),7.05(t,1H),6.9(s,1H),5.9(s,1H),2,9(s,3H),2.68(t,1H),2.62(M,1H),2.06(M,1H),1.94-1.91(M,3H);手性分析SFC:RT=6.38miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,50%甲醇/乙腈(1:1)流速:3.0g/min.
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物480)
步驟i:向室溫下、惰性氣氛下的8,9-二氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(IVN,3.0g,11.9mmol)在30mL 1,4-二烷中的攪拌後的溶液加入(R)-1-(4-甲氧基苯基)乙烷-1-胺(2.1mL,14.31mmol),之後加入15mL(5vol)異丙醇鈦。將反
應混合物加熱至90℃ 24小時。使反應冷卻至0℃並用甲醇(2mL)稀釋。在0℃下向此混合物分批加入NaBH4(85mg,2.20mmol)並在室溫下攪拌4小時。反應完成後,用水(50mL)稀釋反應混合物。將非均質的混合物過濾並用乙酸乙酯(50mL)洗滌。將有機層分離,並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機物經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(10mL)研磨。收集所得沉澱並在真空下乾燥以提供8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(VIIIc,1.7g,36%)。LCMS:m/z實測值385.22[M+H]+.
步驟ii:向室溫下、惰性氣氛下8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(1.00g,2.5mmol)在10mL 1,2-DCE中的攪拌後的溶液加入甲醛溶液(37%水性的,1.06mL,12.95mmol),之後加入三滴醋酸。然後加入三乙醯氧基硼氫化鈉(1.15g,3.8mmol)。在室溫下攪拌16小時後,反應混合物用水(50mL)稀釋。將非均質的混合物過濾並用乙酸乙酯(50mL)洗滌。將有機層分離,並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(10mL)和EtOH(5mL)研磨。通過過濾收集沉澱並在真空下乾燥以提供8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(IXh,0.75g,72%)。
步驟iii:向室溫下、惰性氣氛下8,9-二氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(1.50g,0.9mmol)在15mL DCM中的攪拌後的溶液加入7.5mL TFA。在室溫下攪拌24後,在減壓下使反應混合物濃縮,並用10%飽和碳酸鈉溶液(50mL)鹼化。將有機層分離,並乙酸乙酯(3 x 100mL)萃取水層。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(20mL)研磨。將所得固體過濾並在真空下乾燥以提供(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu,600mg,60%)。LCMS m/z 263.25實測值[M-H]-.1H NMR(400MHz,DMSO-d6):11.26(bs,1H),8.01(M,1H),7.63(M,1H),3.66(s,1H),2.47(t,2H),2.39(s,3H),2.13(d,1H),1.87(M,1H),1.66(d,2H),1.43(t,1H).
步驟iv:以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和5-氟-1H-吲哚-2-羧酸(VId)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值426.2[M+H]+;RT=4.38min(方法A);1H NMR(400
MHz,DMSO-d 6)δ 11.9(bs,1H),11.59(bs,1H),8.09(t,1H),7.50-7.44(M,1H),7.35(d,1H),7.27-7.22(M,1H),7.08(t,1H),6.89(bs,1H),5.91(s,1H),2.96(s,3H),2.75-2.59(M,2H),2.07-1.79(M,4H).
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物481)
以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值444.2[M+H]+;RT=4.53min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.89(bs,1H),11.6(bs,1H),8.09(t,1H),7.61(t,1H),7.38(t,1H),7.24(t,1H),6.93(bs,1H),5.91(s,1H),2.96(s,3H),2.75-2.58(M,2H),2.07-1.79(M,4H).
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物482)
以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和6-(二氟甲基)-5-氟-1H-吲哚-2-羧酸(VIct)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值476.1[M+H]+;RT=4.59min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.19(bs,1H),11.6(bs,1H),8.09(t,1H),7.70(d,1H),7.53(d,1H),7.39-7.11(M,2H),6.96(bs,1H),5.91(s,1H),2.96(s,3H),2.76-2.54(M,2H),2.07-1.79(M,4H).
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物483)
以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值476.1[M+H]+;RT=4.58min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.16(bs,1H),11.6(bs,1H),8.09(t,1H),7.77-7.17(M,4H),7.04(bs,1H),5.91(s,1H),2.97(s,3H),2.76-2.59(M,2H),2.07-1.79(M,4H).
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物484)
以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和4-甲基-1H-吲哚-2-羧酸(VIdx)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=4.55min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.67(bs,1H),11.59(bs,1H),8.09(t,1 H),7.29(d,2H),7.1(t,1H),6.92(bs,1H),6.83(d,1H),5.93(s,1H),3.0(s,3H),2.82-2.56(M,2H),2.46(s,3H),2.08-1.79(M,4H).
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物485)
以與上文所述類似的方式,由鏡像異構純的(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu)和6-氟-4-甲基-1H-吲哚-2-羧酸(VIeb)合成鏡像異構純的(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值440.1[M+H]+;RT=4.70min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,1H),11.6(bs,1H),8.09(t,1H),
7.29-7.24(M,1H),7.0-6.96(M,2H),6.74(d,1H),5.91(s,1H),2.99(s,3H),2.76-2.56(M,2H),2.47(s,3H),2.06(bs,1H),1.90-1.79(M,3H).
(R)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物489)
步驟i:向室溫下、惰性氣氛下8-氟-2H-哌喃并[3,4-c]異喹啉-1,6(4H,5H)-二酮(Ivo,3.0g,11.9mmol)在30mL 1,4-二烷中的攪拌後的溶液加入(R)-1-(4-甲氧基苯基)乙烷-1-胺(2.1mL,14.31mmol),之後加入15mL(5vol)異丙醇鈦。將反應混合物加熱至90℃ 24小時。使反應冷卻至0℃並用甲醇(2mL)稀釋。在0℃下向此混合物分批加入NaBH4(85mg,2.20mmol)並在室溫下攪拌4小時。反應完成後,用水(50mL)稀釋反應混合物。將非均質的混合物過濾並用乙酸乙酯(50mL)洗滌。將有機層分離,並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機物經無水Na2SO4乾燥並在減壓下濃縮。所得殘餘物與二乙醚(10mL)研磨。收集所得沉澱並在真空下乾燥以提供8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(VIIId,1.7g,36%)。LCMS:m/z實測值367.15[M+H]+.
步驟ii:向室溫下、惰性氣氛下8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(1.00g,2.5mmol)在10mL 1,2 DCE中的攪拌後的溶液加入1.06mL(12.95mmol,5.0eq.)37%的甲醛溶液(37%水性的,1.06mL,12.95mmol)和三滴AcOH。加入三乙醯氧基硼氫化鈉(1.15g,3.8mmol)。在室溫下攪拌16小時後,用水(50mL)稀釋反應混合物。將非均質的混合物過濾並用乙酸乙酯(50mL)洗滌。將有機層分離並用乙酸乙酯(3 x 100mL)萃取水相。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(10mL)和EtOH(5mL)研磨。通過過濾收集沉澱並在真空下乾燥以提供8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(IXi,0.75g,72%)。LCMS:m/z實測值379.1[M-H]-.
步驟iii:向室溫下、惰性氣氛下8-氟-1-(((R)-1-(4-甲氧基苯基)乙基)(甲基)胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(1.50g,0.9mmol)在15mL DCM中的攪拌後的溶液加入7.5mL TFA。在室溫下攪拌24後,在減壓下使反應混合物濃縮,並用10%飽和碳酸鈉溶液
(50mL)鹼化。將有機層分離,並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(20mL)研磨。將所得固體過濾並在真空下乾燥以提供(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv,600mg,60%)。LCMS:m/z 245.41實測值[M-H]-.
步驟iv:以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和5-氟-1H-吲哚-2-羧酸(VId)合成鏡像異構純的(R)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值408.1[M+H]+;RT=4.17min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.79(bs,1H),11.51(bs,1H),7.88(d,1H),7.59(t,1H),7.47-7.42(M,2H)7.34(d,1H),7.07(t,1H),6.85(s,1H),5.92(s,1H),2.94(s,3H),2.73(M,1H),2.58(M,1H),2.07-1.80(M,4H).
(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物479)
以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和5-氟-6-(二氟甲基)-1H-吲哚-2-羧酸(VIct)合成鏡像異構純的(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值458.2[M+H]+;RT=4.45min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.16(bs,1H),11.5(bs,1H),7.87-7.84(t,1H),7.75-7.65(d,1H),7.64-7.60(t,2H),7.42(M,1H),7.22(t,1H),6.9(s,1H),5.92(s,1H),2.9(s,3H),2.70(M,2H),2.07-1.80(M,4H).
(R)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物490)
以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成鏡像異構純的(R)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值426.1[M+H]+;RT=4,36min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.87(bs,1H),11.51(bs,1H),7.88(dd,1H),7.62-7.57(M,2H),7.42-7.35(M,2H)6.90(s,1H)5.91(s,1H)2.94(s,3H)2.68(M,1H),2.56(M,1H),2.05-1.80(M,4H).
(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物491)
以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和4-甲基-1H-吲哚-2-羧酸(VIdx)合成鏡像異構物(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值404.1[M+H]+;RT=4.39min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.64(s,1H),11.51(bs,1H),7.88(M,1H),7.59(M,1H),7.45(M,1H),7.29(d,1H),7.10(t,1H),6.88-6.82(M,2H),5.95(s,1H),2.99(s,3H),2.75(M,1H),2.59(M,1H),2.45(s,3H),2.09-1.81(M,4H).
(R)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺(化合物492)
以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和6-氟-4-甲基-1H-吲哚-2-羧酸(VIeb)合成鏡像異構純((R)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值422.2[M+H]+;RT=4.52min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.71(bs,1H),11.52(bs,1H),7.88(M,1H),7.57(M,1H),
7.43(M,1H),7.00(d,1H),6.92(s,1H),6.74(d,1H),5.94(s,1H),2.98(s,3H),2.68(M,1H),2.59(M,1H),2.46(s,3H),2.06-1.81(M,4H).
(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物493)
以與上文所述類似的方式,由鏡像異構純的(R)-8-氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vv)和4-(二氟甲基)-6-氟-1H-吲哚-2-羧酸(VIcv)合成鏡像異構純的(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺。LCMS m/z實測值458.1[M+H]+;RT=4.41min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.13(bs,1H),11.51(bs,1H),7.89(M,1H),7.59(M,1H),7.44-7.36(M,2H),7.31(s,1H),7.19(M,1H),7.01(s,1H),5.93(s,1H),2.95(s,3H),2.70(M,1H),2.57(M,1H),2.07-1.81(M,4H).
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和2-氯-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhm)合成外消旋1-(2-氯-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak OX-H(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物453):LCMS m/z實測值449.4[M+H]+;RT=3.62min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.96(bs,1H),11.64(bs,1H),8.1(t,1H),7.29-7.24(M,1H),7.09(bs,1H),6.89(s,1H),5.67(s,1H),3.82(d,1H),3.66(d,1H),3.15-3.08(M,6H);手性分析SFC:RT=1.92miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物454):LCMS m/z實測值449.1[M+H]+;RT=3.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.96(bs,1H),11.64(bs,1H),8.1(t,1H),7.29-7.24(M,1H),7.09(bs,1H),6.89(s,1H),5.67(s,1H),3.82(d,1H),3.66(d,1H),3.15-3.08(M,6H);手性分析SFC:RT=2.95miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-甲基-1H-吲哚-2-羧酸(VIdx)合成外消旋1-(N,4-二甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak OX-H(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物456):LCMS m/z實測值423.2[M+H]+;RT=3.45min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.66(M,2H),8.13(t,1H),7.29(d,2H),7.10(t,1H),6.94(s,1H),6.83(d,1H),5.81(bs,1H),3.98(d,1H),3.79(d,1H),3.3-3.05(M,5H),2.47(s,3H);手性分析SFC:RT=1.8miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物457):LCMS m/z實測值423.2[M+H]+;RT=3.44min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.66(M,2H),8.13(t,1H),7.29(d,2H),7.10(t,1H),6.94(s,1H),6.83(d,1H),5.81(bs,1H),3.98(d,1H),3.79(d,1H),3.3-3.05(M,5H),2.47(s,3H);手性分析SFC:RT=2.57miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和6-氟-4-甲基-1H-吲哚-2-羧酸(VIeb)合成外消旋8,9-二氟-1-(6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC(30 x 250mm)5μm,流速:100g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物458):LCMS m/z實測值441.2[M+H]+;RT=3.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,1H),11.64(bs,1H),8.11(t,1H),7.31-7.27(M,1H),7.00-6.95(M,2H),6.74(d,1H),5.69(s,1H),3.81(d,1H),3.66(d,1H),3.17(bs,5H),2.79(bs,1H),2.47(s,3H).手性分析SFC:RT=1.53miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物459):LCMS m/z實測值441.2[M+H]+;RT=3.60min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,1H),11.64(bs,1H),8.11(t,1H),7.31-7.27(M,1H),7.00-6.95(M,2H),6.74(d,1H),5.69(s,1H),3.81(d,1H),3.66(d,1H),3.17(bs,5H),2.79(bs,1H),2.47(s,3H).手性分析SFC:
RT=1.96miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和4-氯-6-氟-1H-吲哚-2-羧酸(VIea)合成外消旋1-(4-氯-6-氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:Chiralpak OX-H(30 x 250mm)5μm,流速:100g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物460):LCMS m/z實測值441.2[M+H]+;RT=3.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.14(bs,1H),11.68(bs,1H),8.10(t,1H),7.30-7.14(M,3H),6.88(s,1H),5.67(s,1H),3.81(d,1H),3.65(d,1H),3.16-2.76(M,6H).手性分析SFC:RT=1.60miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物461):LCMS m/z實測值441.2[M+H]+;RT=3.60min(方法A);1H NMR(400MHz,DMSO-d 6)δ 12.15(bs,1H),11.69(bs,1H),8.10(t,1H),7.30-7.14(M,3H),6.88(s,1H),5.67(s,1H),3.81(d,1H),3.65(d,1H),3.16-2.76
(M,6H).手性分析SFC:RT=2.43miN,管柱:Chiralpak AS-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和苯并[d]噻唑-5-羧酸(VIex)合成外消旋8,9-二氟-1-(N-甲基苯并[d]噻唑-5-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:LUX CELLOSE(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物462):LCMS m/z實測值427.1[M+H]+;RT=2.47min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.65(bs,1H),9.48(bs,1H),8.27(d,1H),8.15-8.07(M,2H),7.49-7.40(M,2H),5.64(s,1H),3.73(d,1H),3.65(d,1H),3.26-3.15(M,2H),2.83-2.67(M,4H).手性分析SFC:RT=7.46miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物463):LCMS m/z實測值427.2[M+H]+;RT=2.49min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),9.48(bs,1H),8.27(d,1H),8.15-8.07(M,2H),
7.49-7.40(M,2H),5.64(s,1H),3.73(d,1H),3.65(d,1H),3.26-3.15(M,2H),2.83-2.67(M,4H).手性分析SFC:RT=12.84miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和苯并[d]噻唑-6-羧酸(VIey)合成外消旋8,9-二氟-1-(N-甲基苯并[d]噻唑-6-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-30:70。管柱:ChiralPak IA(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物464):LCMS m/z實測值427.1[M+H]+;RT=2.33min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.62(bs,1H),9.48(bs,1H),8.27(d,1H),8.14(t,2H),7.52(d,1H),7.43-7.38(M,1H),5.64(s,1H),3.77(d,1H),3.65(d,1H),3.27-3.15(M,2H),2.79-2.74(M,4H).手性分析SFC:RT=1.74miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物465):LCMS m/z實測值427.2
[M+H]+;RT=2.33min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.64(bs,1H),9.48(bs,1H),8.27(d,1H),8.15-8.1(M,2H),7.52(d,1H),7.43-7.38(M,1H),5.63(s,1H),3.77(d,1H),3.65(d,1H),3.27-3.15(M,2H),2.79-2.74(M,4H).手性分析SFC:RT=3.88miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和2,3-二氫-1H-茚-5-羧酸(VIet)合成外消旋8,9-二氟-1-(N-甲基-2,3-二氫-1H-茚-5-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OX-3(30 x 250mm),5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物471):LCMS m/z實測值410.1[M+H]+;RT=3.31min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.60(bs,1H),8.13(t,1H),7.38-7.33(M,1H),7.28(d,1H),7.21(s,1H),7.09(d,1H),5.59(s,1H),3.75(d,1H),3.63(d,1H),3.22(d,1H),3.15-3.11(M,1H),2.87(t,4H),2.69(s,3H),2,03(t,2H).手性分析SFC:RT=2.25miN,管柱:Chiralpak AD-3(4.6 x
150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物472):LCMS m/z實測值410.1[M+H]+;RT=3.31min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.60(bs,1H),8.11(t,1H),7.38-7.33(M,1H),7.28(d,1H),7.21(s,1H),7.09(d,1H),5.59(s,1H),3.75(d,1H),3.63(d,1H),3.22(d,1 H),3.15-3.11(M,1H),2.87(t,4H),2.69(s,3H),2.03(t,2H).手性分析SFC:RT=4.41miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,30%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和1-(第三丁氧基羰基)-1H-吲唑-5-羧酸(VIhw)合成外消旋1-(1-(第三丁氧基羰基)-N-甲基-1H-吲唑-5-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralcel OX-3(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物473):LCMS m/z實測值410.1[M+H]+;RT 1.90min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.28(bs,1H),11.66(bs,1H),8.19-8.15(M,2H),7.88(s,1H),7.65(d,1H),7.49-7.40(M,2H),5.68(s,1H),3.81(d,1H),3.69(d,1H),3.31-3.2(M,2H),2.81(s,4H).手性分析SFC:RT=2.04
miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物474):LCMS m/z實測值410.1[M+H]+;RT=1.92min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.23(bs,1H),11.61(bs,1H),8.15-8.10(M,2H),7.83(s,1H),7.60(d,1H),7.44-7.34(M,2H),5.63(s,1H),3.76(d,1H),3.64(d,1H),3.25-3.14(M,2H),2.76(s,4H).手性分析SFC:RT=3.15miN,管柱:Chiralpak IG-3(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺(化合物469、470)
1-(第三丁氧基羰基)-1H-吲唑-6-羧酸(VIhu)。
在室溫下向1H-吲唑-6-羧酸(0.20g,1.23mmol)在5mL 1,4-二烷/水(1:1)中的攪拌後的溶液加入NaOH(58mg,2.46mmol)。在室溫下10分鐘後,加入二碳酸二第三丁基(0.54mL,2.46mmol)。5小時後,反應混合物用水(100mL)猝滅。混合物用EtOAc(2 x 200mL)萃取。合併的有機物用鹽水(200mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮。在室溫下與正戊烷(10mL)研磨所獲得的粗產物,過濾,並在真空下乾燥,以提供作為灰白色固體的1-(第三丁氧基羰基)-1H-吲唑-6-羧酸(VIhu,0.28g,86%)。LCMS m/z實測值263.2[M+H]+.
以與上文所述類似的方式,由8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Vg)和1-(第三丁氧基羰基)-1H-吲唑-6-羧酸(VIhu)合成外消旋6-((8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-1H-吲唑-1-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm)5μm,流速:110g/min,之後以與上文所述類似的方式對所分離的對映異構物進行Boc去保護。
對映異構物I(化合物469):LCMS m/z實測值393.0[M+H]+;RT=2.58min(方法A);1H NMR(400MHz,DMSO-d 6)13.22(bs,1H),11.61(bs,1H),8.2(s,1H),7.93-7.91(M,1H),7.84-7.76(M,2H),7.69-7.66(M,1H),7.60(s,1H),7.09(d,1H),5.73(s,1H),4.59(d,1H),4.47(d,1H),4.29(d,1H),4.08-4.04(M,1H),2.69(s,3H).手性分析SFC:RT=1.81miN,管柱:Chiralpak AD-H(4.6 x 150mm)3μM,50%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物470):LCMS m/z實測值393.1[M+H]+;RT=2.61min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.22(bs,1H),11.61(bs,1H),8.2(s,1H),7.93-7.91(M,1H),7.84-7.77(M,2H),7.69-7.66(M,1H),7.53(s,1H),7.09(d,1H),5.73(s,1H),4.58(d,1H),4.47(d,1H),4.29(d,1H),4.08-4.04(M,1H),2.69(s,3H).手性分析SFC:RT=1.81miN,管柱:Chiralpak AD-3(4.6 x 150mm)3μM,50%(0.5%在甲醇中的DEA),
流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和1-(第三丁氧基羰基)-1H-吲唑-6-羧酸(VIhu)合成外消旋1-(1-(第三丁氧基羰基)-N-甲基-1H-吲唑-6-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm),5μ,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物495):LCMS m/z實測值410.1[M+H]+;RT 2.24min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.27(bs,1H),11.67(bs,1H),8.13(t,2H),7.84(d,1H),7.5(s,1H),7.44-7.39(M,1H),7.07(d,1H),5.64(s,1H),3.78-3.62(M,2H),3.28-3.64(d,2H),2.77(bs,1H),2.71(s,3H).手性分析SFC:RT=4.42miN,管柱:Chiralpak AS-H(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物496):LCMS m/z實測值410.1[M+H]+;RT=2.23min(方法A);1H NMR(400MHz,DMSO-d 6)δ 13.20(bs,1H),11.62(bs,1H),8.13(t,2H),7.84(d,1H),7.5(s,1H),7.44-7.39(M,1H),7.07(d,1H),5.64(s,1H),3.78-3.62(M,
2H),3.28-3.61(d,2H),2.78(bs,1H),2.71(s,3H).手性分析SFC:RT=1.85miN,管柱:Chiralpak AS-H(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
2-氟-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸
步驟i:向4H-噻吩并[3,2-b]吡咯-5-羧酸甲基酯(10g,52.2mmol)在100mL THF中的攪拌後的0℃溶液加入NaH(礦物油中60%,6.6g,166mmol)。在加入後,在室溫下將反應攪拌10分鐘,之後加入2-(三甲基甲矽烷基)乙氧基甲基氯(14.6mL,82.3mmol)。在室溫下使反應混合物攪拌1小時。反應混合物用水(100mL)猝滅並用EtOAc(2 x 200mL)萃取。合併的有機物用鹽水(200mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮。在室溫下與正戊烷(50mL)研磨所獲得的粗產物,過濾,在真空下乾燥,以提供作為灰白色固體的4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲基酯(10g,75%)。LCMS:m/z實測值312.28[M+H]+.
步驟ii:向4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲基酯(10g,32.1mmol)在100mL EtOH中的攪拌後的溶液加入LiOH(3.8g,160.5mmol)。在加入後,在室溫下將反應攪拌30分鐘。反應混合物用1M HCl(50mL)中和並用二氯甲烷(2 x 20mL)中的10%甲醇萃取水層。合併的有機層用鹽水(20mL)洗滌,經無水Na2SO4乾燥並在減壓下濃縮。在室溫下與
正戊烷(50mL)研磨所獲得的粗產物,過濾,在真空下乾燥,以提供作為灰白色固體的(4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(8g,83%)。LCMS:m/z實測值298.44[M+H]+.
步驟iii:向-78℃下4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(6.0g,20.17mmol)和2,2,6,6-四甲基哌啶(7,6mL,40.34mmol)在60mL乾燥的THF中的攪拌後的溶液逐滴加入n-BuLi(己烷中的2.5M溶液,16.13mmol,40.34mmol)。在-78℃下將反應混合物攪拌30分鐘。在-78℃下向反應混合物加入N-氟苯磺醯亞胺(7.6g,24.2mmol)。使混合物溫熱至RT並攪拌16小時。反應混合物用水(100mL)稀釋並用乙酸乙酯(2 x 100mL)萃取。合併的有機層經無水Na2SO4乾燥並在減壓下濃縮。粗產物通過反相半製備MPLC純化,以提供作為灰白色固體的2-氟-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhv,1.8g,28%)。LCMS:m/z實測值324.29[M+H]+,1H NMR(400MHz,DMSO-d6):12.55(bs,1H),7.19(s,1H),7.17(d,1H),5.81(s,2H),3.44(t,2H),0.77(t,2H),0.18(s,9H).
2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(化合物497、498)
步驟i:向室溫下2-氟-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhv,305mg,0.96mmol)在1mL DMF中的攪拌後的溶液加入DIPEA(0.45mL,2.42mmol)、EDC.HCl(231mg,1.2mmol)、和HOBt(164mg,1.2mmol)。在室溫下攪拌15分鐘後,加入外消旋8-氟-1-(甲胺基)-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮(Va,0.20g,0.81mmol)。在室溫下攪拌16小時後,將反應混合物傾倒入冰冷的水(10mL)中,攪拌30分鐘。所得沉澱通過過濾收集,用水洗滌,並在真空下乾燥,以提供150mg(0.27mmol,34%)2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(150mg,0.27mmol)。LCMS:m/z實測值546.16[M+H]+.
步驟ii:向-15℃下2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(200mg,0.36mmol)在DCM(1mL)中的溶液加入TMS-OTf(0.16mL,0.73mmol)。在-15℃下將所得反應混合物攪拌30分鐘。用10%飽和Na2CO3溶液(10mL)使反應猝滅並用EtOAc(3 x 50mL)萃取。合併的有機物經硫酸鈉乾燥和濃縮。殘餘物與二乙醚(10mL)研磨並過濾。在真空下使固體乾燥以提供作為灰白色固體的2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺(13mg,67%)。LCMS:m/z實測值416.32[M+H]+.隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:
Chiralpak IA-3(30 x 250mm)5μm,流速:110g/min。
對映異構物I(化合物497):LCMS m/z實測值416.0[M+H]+;RT 3.97min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.93(bs,1H),11.62(bs,1H),7.90-7.88(dd,1H),7.64-7.59(M,1H),7.50(bs,1H),6.88(s,1H),6.78(bs,1H),5.71(s,1H),4.62(d,1H),4.46(d,1H),4.12-4.01(M,2H),3.09(s,3H).手性分析SFC:RT=6.44miN,管柱:Chiralpak AS-H(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
對映異構物II(化合物498):LCMS m/z實測值416.0[M+H]+;RT=3.97min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.94(bs,1H),11.62(bs,1H),7.91-7.88(dd,1H),7.64-7.59(M,1H),7.50(bs,1H),6.88(bs,1H),6.78(bs,1H),5.71(s,1H),4.62(d,1H),4.47(d,1H),4.09-4.04(M,2H),3.09(s,3H).手性分析SFC:RT=4.42miN,管柱:Chiralpak AS-H(4.6 x 150mm)3μM,40%(0.5%在甲醇中的DEA),流速:3.0g/min.
以與上文所述類似的方式,由8,9-二氟-1-(甲胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯(Vg)和2-氟-4-((2-(三甲基甲矽烷基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(VIhv)合成外消旋8,9-二氟-1-(2-氟-N-甲基-4-((2-(三甲基甲矽烷
基)乙氧基)甲基)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺基)-6-側氧-1,4,5,6-四氫苯并[c][1,7]啶-3(2H)-羧酸第三丁酯。隨後通過製備SFC分離對映異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm)5μm,流速:110g/min,並且以與上文(關於化合物160、161)所述類似的方式將每一個都轉化為終產物。
對映異構物I(化合物499):LCMS m/z實測值433.0[M+H]+;RT 3.27min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.86(bs,2H),8.1(t,1H),7.28(bs,1H),6.87(d,1H),6.77(bs,1H),5.79(s,1H),4.02(d,1H),3.66(d,1H),3.26-2.99(M,5H),2.85(d,1H).手性分析SFC:RT=3.26miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,50%(0.2%在1:1乙腈/甲醇中的甲醇中7N銨),流速:3.0g/min.
對映異構物II(化合物500):LCMS m/z實測值433.0[M+H]+;RT=3.31min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.74(bs,2H),8.10(t,1H),7.28(bs,1H),6.89-6.77(M,2H),5.79(s,1H),4.02(d,1H),3.66(d,1H),3.26-2.99(M,5H),2.85(d,1H).手性分析SFC:RT=2.36miN,管柱:Chiralcel OX-3(4.6 x 150mm)3μM,50%(0.2%在1:1乙腈/甲醇中的甲醇中7N銨),流速:3.0g/min.
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物504和505)
步驟i.向室溫下、惰性氣氛下(R)-8,9-二氟-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vu,0.50g,1.80mmol)在5mL DCM中的攪拌後的溶液加入DIPEA(0.99mL,5.60mmol),之後加入BOC酸酐(0.67g,2.20mmol)。在室溫下將混合物攪拌16小時。反應混合物用水(50mL)稀釋,並且用乙酸乙酯(50mL)萃取。將有機層分離並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機物經無水Na2SO4乾燥並在減壓下濃縮。所得粗產物與二乙醚(10mL)研磨。收集所得沉澱並在真空下乾燥以提供粗(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(500mg)。LCMS:m/z實測值365.3[M+H]+.
在室溫下,向室溫下1.5g(4.11mmol,1.0eq.)(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(1.50g,4.11mmol)在70mL甲苯中的攪拌後的溶液加入Ag2CO3(2.27g,8.2mmol)和甲基碘(0.89mL,14.04mmol)。在60℃下將反應混合物攪拌16小時。一經冷卻,就通過CELITE®墊過濾反應混合物。用EtOAc(100mL)洗滌CELITE®床。在減壓下濃縮合併的濾液並通過快速層析法(矽膠,EtOAc/己烷,10-20%梯度)分離粗化合物,以提供(8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(Xa)(0.82g,52%)。LCMS m/z實測值379.2[M+H]+;RT=1.76min(方法E).
步驟ii.在室溫下,向室溫下(8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(Xa,0.20g,2.4mmol)在6mL DCM中的攪拌後的溶液加入N-溴代琥珀醯亞胺(187mg,2.4mmol)。在室溫下將反應混合物攪拌16小時。反應混合物通過CELITE®墊過濾並用EtOAc(100mL)洗滌CELITE®床。在減壓下濃縮合併的濾液並通過快速層析法(矽膠,EtOAc/石油醚,10-20%梯度)分離粗化合物,以提供作為非鏡像異構物混合物的(4-溴-8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(120mg,
49%)。LCMS m/z實測值457[M-H]+.
在室溫下,向室溫下(4-溴-8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-1-基)(甲基)胺基甲酸第三丁酯(1.2g,2.6mmol)在12mL醋酸中的攪拌後的溶液加入醋酸銀(0.43g,4.9mmol)。在80℃下將反應混合物攪拌2小時。一經冷卻,就用10N NaOH(10mL)使反應混合物猝滅並用DCM(100mL)萃取。將有機物過濾並在減壓下濃縮。粗化合物通過快速層析法(矽膠,EtOAc/石油醚,10-20%梯度)分離以提供260mg 1-((第三丁氧基羰基)(甲基)胺基)-8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-4-基醋酸酯(XIc,0.26g,22%)。LCMS m/z實測值437.3[M+H]+;RT=1.76min(方法E);
步驟iii.在0℃下,向室溫下260mg(0.59mmol,1.0eq.)1-((第三丁氧基羰基)(甲基)胺基)-8,9-二氟-6-甲氧基-1,2,3,4-四氫啡啶-4-基醋酸酯(0.26g,0.59mmol)在10mL 1,4-二烷中的攪拌後的溶液加入二烷(2.5mL)中的4M HCl。然後在室溫下將反應混合物攪拌16小時。在減壓下將反應混合物濃縮並用MeOH(10mL)稀釋粗混合物。加入碳酸鉀(83mg,0.59mmol)。在室溫下將混合物攪拌1小時。反應混合物用水(50mL)稀釋,並用乙酸乙酯(50mL)萃取。將有機層分離並用乙酸乙酯(3 x 100mL)萃取水層。合併的有機物經無水Na2SO4乾燥並在減壓下濃縮。粗產物與二乙醚(10mL)研磨。所得沉澱通過過濾收集並在真空下乾燥以提供150mg 8,9-二氟-4-羥基-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vy,150mg)。LCMS m/z實測值281.27[M+H]+.RT=1.56min(方法E);
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(化合物504和505)
向室溫下1H-吲哚-2-羧酸(Via,41mg,0.25mmol)在1mL DMF中的攪拌後的溶液加入DIPEA(0.16mL,0.91mmol)、EDCI-HCl(63mg,0.32mmol)、和HOBt(45mg,0.33mmol)。在室溫下攪拌15分鐘後,加入9-二氟-4-羥基-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vy,60mg,0.22mmol)。在室溫下將混合物再攪拌16小時。將反應混合物傾倒入冰冷的水(10mL)中並攪拌30分鐘。將所得沉澱過濾,用水洗滌並在真空下乾燥,以提供作為非鏡像異構物混合物的N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺(45mg,49%)。
隨後通過製備SFC分離非鏡像異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak IC-3(30 x 250mm)5μm,流速:110g/min。
非鏡像異構物I(化合物504):LCMS m/z實測值421.41[M-H]-;RT=1.75min(方法A);1H NMR(400MHz,DMSO-d 6)11.75(bs,2H),8.11(t,1H),7.61(t,1H),7.46(t,1H),7.33-7.28(M,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H)5.92(bs,1H),4.52(bs,1H),2.98(s,3H),2.07-1.88(M,4H).手性分析SFC:RT=3.97miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
非鏡像異構物II(化合物505):LCMS m/z實測值424.3[M+H]+;RT=1.79min(方法E);1H NMR(400MHz,DMSO-d 6)δ 11.70(bs,2H),8.12(t,1H),7.61(d,1H),7.47(d,1H),7.34-7.29(M,1H),7.21(t,1H),7.04(t,1H),6.90(s,1H)5.93(bs,1H),4.6(t,1H),2.98(s,3H),2.27-1.75(M,4H).手性分析SFC:RT=5.48miN,管柱:Chiralpak IC-3(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺(化合物501和502)
以與上文所述類似的方式,由(1R)-8,9-二氟-4-羥基-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vy)的非鏡像異構物混合物和5-氟-1H-吲哚-2-羧酸(VId)合成N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺的非鏡像異構物混合物。隨後通過製備SFC分離非鏡像異構物:等度法,流動相甲醇:CO2-40:60。管柱:Chiralpak Lux纖維素(30 x 250mm)5μm,流速:110g/min。
非鏡像異構物I(化合物501):LCMS m/z實測值442.0[M+H]+;RT=3.97min(方法A);1H NMR(400MHz,DMSO-d 6)11.8(bs,2H),8.11(t,1H),7.48-7.44(M,1H),7.36-7.23(M,2H),7.07(t,1H),6.88(s,1H),5.90(t,1H),4.60(t,1H),2.93(s,3H),2.07-2.33(M,2H),1.85-1.75(M,2H).手性分析SFC:RT=3.97miN,管柱:Chiralpak Lux Cellulose(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
非鏡像異構物II(化合物502):LCMS m/z實測值442.1[M+H]+;RT=3.95min(方法A);1H NMR(400MHz,DMSO-d 6)δ 11.8(bs,2H),8.11(t,1H),7.48-7.44(M,1H),7.36-7.27(M,2H),7.07(t,1H),6.89(s,1H),5.91(t,1H),4.53(t,1H),2.97(s,3H),2.1-1.86(M,4H).手性分析SFC:RT=5.48miN,管柱:Chiralpak Lux Cellulose(4.6 x 150mm)3μM,40%甲醇,流速:3.0g/min.
N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺(化合物503)
以與上文所述類似的方式,由(1R)-8,9-二氟-4-羥基-1-(甲胺基)-1,3,4,5-四氫啡啶-6(2H)-酮(Vy)的非鏡像異構物混合物和5,6-二氟-1H-吲哚-2-羧酸(VIi)合成N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺的非鏡像異構物(2:3)混合物。LCMS:m/z實測值460.0[M+H]+,RT=4.15miN,(方法A);1H NMR(400MHz,DMSO-d6):11.90(bs,1H),11.30(bs,1H),8.12(t,1H),7.60(t,1H),7.40-7.27(M,2H),6.93(bs,1H),5.90(t,1H),5.67(bs,1H),4.57(d,1H),2.94(d,3H),2.27-2.05(M,2H),1.93-1.76(M,2H).
實施例2:生物學結果
如本文其它部分所描述的,在HepDE19測定中測試了本發明的代表性化合物抑制鬆弛環狀DNA(rcDNA)形成的能力。結果列於表3中。
列舉的實施方式
提供以下例示性實施方式,其編號不應解釋為指定重要程度:
實施方式1提供式(I)化合物,或其鹽、溶劑化物、前藥、立體異構物、互變異構物、或同位素標記的衍生物,或其任意混合物:
其中:
X、Y以及X與Y之間的鍵是這樣的:
X是NR8,Y是C(=O),並且X與Y之間的鍵是單鍵,或
X是N,Y是CR11,並且X與Y之間的鍵是雙鍵;
環A選自:
R1選自R2C(=O)-、R2S(=O)2-、和胺醯基;
R2選自:
以下中的一個適用:
(i)X1是N,X2是C(R4f),並且X3是C(R4g);
(ii)X2是N,X1是C(R4f),並且X3是C(R4g);
(iii)X3是N,X1是C(R4f),並且X2是C(R4g);
(v)X1是C(R4f),X2是C(R4g),並且X3是C(R4h);
以下中的一個適用:
(i)X4是N和X5是C(R4e);或
(ii)X5是N和X4是C(R4e);
X6a的每次出現獨立地是N或C(R4f);
X6的每次出現b獨立地是N或C(R4g);
X6c的每次出現獨立地是N或C(R4h);
X7的每次出現獨立地是S、O、或NR3a;
R3a的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R3b的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R4a、R4b、R4c、R4d、R4e、R4f、R4g、R4h、R4i、R4j和R4k的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R5的每次出現獨立地選自H、C1-C6烷基、和C3-C8環烷基,其中烷基或環烷基用選自以下的至少一個可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵素、氰基、-OH、C1-C6烷氧基、C3-C8環烷氧基、C1-C6鹵代烷氧基、C3-C8鹵代環烷氧基、可選擇經取代之苯基、可選擇經取代
之雜芳基、可選擇經取代之雜環基、-C(=O)OR10、-OC(=O)R10、-SR10、-S(=O)R10、-S(=O)2R10、-S(=O)2NR10R10、-N(R10)S(=O)2R10、-N(R10)C(=O)R10、-C(=O)NR10R10、和-NR10R10;
R6的每次出現獨立地選自H和可選擇經取代之C1-C6烷基;
R7是-(CH2)p-Q-(CH2)q-,其中p和q獨立地是0、1、或2,並且Q是鍵(不存在)、-O-、-S-、-S(O)-、-S(O)2-、-NR12、-CH(OH)-、-C(=O)-、-C(=O)O-、或-OC(=O)-,
其中R7中的每一個CH2用選自甲基、OR13、或鹵素的至少一個取代基可選擇地取代;
R8的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;
R9a、R9b、R9c、R9d、R9e、R9f、R9g、和R9h的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可
選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R10的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、和可選擇經取代之雜芳基;
R11的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;
R12的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C1-C6羥基烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、可選擇經取代之雜芳基、和可選擇經取代之C1-C6醯基;
R13的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和-C(=O)C1-C6烷基。
實施方式2提供實施方式1的化合物,芳基或雜芳基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、苯基、C1-C6羥基烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、鹵素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、醯基、和C1-C6烷氧基羰基,其中Rb的每次出現獨立地是H、C1-C6烷基、或C3-C8環烷基,其中在Rb中,烷基或環烷基用選自以下的至少一個可選擇地取代:鹵素、-OH、C1-C6烷氧基、和雜芳基;或兩個相鄰碳原子上的取代基結合形成-O(CH2)1-3O-。
實施方式3提供實施方式1-2中任一項的化合物,其中烷基、烯基、炔基、或環烷基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵基、氰基(-CN)、-ORa、可選擇經取代之苯基、可選擇經取代之雜芳基、可選擇經取代之雜環基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa、和-N(Ra)(Ra),其中Ra的每次出現獨立地是H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之芳基、或可選擇經取代之雜芳基,或兩個Ra基團與它們所鍵結的N結合形成雜環。
實施方式5提供實施方式1-4中任一項的化合物,其中R3a和R3b中每一個獨立地是H或甲基。
實施方式6提供實施方式1-5中任一項的化合物,其中R5選自H、甲基、乙基、異丙基、正丙基、環丙基、正丁基、異丁基、仲丁基、第三丁基、環丁基、異丙基甲基、-(CH2)2-6OH、-(CH2)2-6O(C1-C6烷基)、13CD3、可選擇經取代之苄基、和可選擇經取代之苯基。
實施方式7提供實施方式1-6中任一項的化合物,其中
R6選自H、D、和CH3。
實施方式8提供實施方式1-7中任一項的化合物,其選自:
實施方式9提供實施方式1-8中任一項的化合物,其選自:
實施方式10提供實施方式1-9中任一項的化合物,其選自:
實施方式11提供實施方式1-10中任一項的化合物,其選自:
實施方式12提供實施方式1-11中任一項的化合物,其是選自以下中的至少一個:N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基二氫吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;8-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基二氫吲哚-2-甲醯胺;N-(8-氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡咯并[1,2-b]嗒-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;N-(3-乙醯基-8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(3-乙醯基-8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺;N-(8,9-二氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;6-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)吲哚-2-甲醯胺;N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-3,3-二氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-溴-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;4-氯-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡喹-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡喹-4-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;2-胺基-2-(4-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;2-胺基-2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;
5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基異唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5,6,7,8-四氫吲哚-2-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-1-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(4-氟苯基)-N-甲基異唑-3-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,2-二甲基吲哚-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)吲哚-6-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;N-(8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;6-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;
3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-6-甲醯胺;4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;5-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-6-甲醯胺;4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;5,6-二氟-N-甲基-N-(4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;2-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-5-甲醯胺;N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-6-甲醯胺;2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-2-氟-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;8-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;和2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;或其鹽、溶劑化物、前藥、同位素標記的衍生物、立體異構物、或互變異構物,或其任意混合物。
實施方式13提供實施方式1-12中任一項的化合物,其是選自以下中的至少一個:(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;
(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;(N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;
N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(R)-8-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;(S)-8-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;(R)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;(R)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;
(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;(R)-N-(8-氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-3-甲基-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡咯并[1,2-b]嗒-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡咯并[1,2-b]嗒-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(R)-N-(3-乙醯基-8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(3-乙醯基-8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8-氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(3-乙醯基-8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(3-乙醯基-8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-3-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-3-苯丙醯胺;(R)-N-(8,9-二氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-3-(2-羥乙基)-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(S)-6-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;
(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;(S)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;(R)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;(S)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;(R)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;
(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基乙醯胺;2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;
(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-3-氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-3,3-二氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-3,3-二氧橋-6-側氧-1,4,5,6-四氫-2H-硫代哌喃并[3,4-c]異喹啉-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;
(S)-4-溴-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;(R)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;
(S)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;(R)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;(R)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;(R)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;(S)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;
(S)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(S)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-(二氟甲基)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基異唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基異唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5,6,7,8-四氫吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5,6,7,8-四氫吲哚-2-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(R)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(S)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(R)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-1-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-1-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(4-氟苯基)-N-甲基異唑-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(4-氟苯基)-N-甲基異唑-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;(S)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,2-二甲基吲哚-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,2-二甲基吲哚-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;(S)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(R)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;
(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)吲哚-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)吲哚-6-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;N-((1S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((1R,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;
(S)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-6-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;(R)-6-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;
N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((R)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;(R)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;(S)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;(S)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(R)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(S)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;
(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-7-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;(R)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-7-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吲哚-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-6-甲醯胺;(S)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(S)-5-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氰基-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-6-甲醯胺;(S)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;5,6-二氟-N-甲基-N-((1S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1S,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1S,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(R)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-8-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-(二氟甲基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;
(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;(R)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-2-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;
(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;
(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(R)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;2-氯-N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(S,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;2-氯-N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
(S)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(R)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-2-氟-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-2-氟-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;
N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(R)-8-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(S)-8-氯-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫苯并[c][1,7]啶-1-基)-N-甲基吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;
(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;和(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;或其鹽、溶劑化物、前藥、同位素標記的衍生物、立體異構物、或互變異構物,或其任意混合物。
實施方式14提供包含實施方式1-13中任一項的至少一種化合物和醫藥上可接受之載劑的藥物組成物。
實施方式15提供實施方式14的藥物組成物,其進一步包含用於治療、改善、及/或預防B型肝炎病毒感染的至少一種其它劑。
實施方式16提供實施方式15的藥物組成物,其中所述至少一種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
實施方式17提供治療、改善、及/或預防受試者中的B型肝炎病毒(HBV)感染的方法,方法包括向需要其的受試者投予治療有效量的實施方式1-13中任一項的至少一種化合物及/或實施方式14-16中任一項的至少一種藥物組成物。
實施方式18提供實施方式17的方法,其中受試者進一步感染有D型肝炎病毒(HDV)。
實施方式19提供實施方式中任一項的方法17-18,其中所述至少一種化合物及/或組成物在醫藥上可接受之組成物中投予至受試者。
實施方式20提供實施方式17-19中任一項的方法,其中受試者進一步被投予用於治療、改善、及/或預防B型肝炎病毒感染的
至少一種其它劑。
實施方式21提供實施方式20的方法,其中所述至少一種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
實施方式22提供實施方式21的方法,其中免疫刺激劑是檢查點抑制劑。
實施方式23提供實施方式22的方法,其中檢查點抑制劑是PD-L1抑制劑。
實施方式24提供實施方式20-23中任一項的方法,其中受試者被共同投予所述至少一種化合物及/或組成物和所述至少一種其它劑。
實施方式25提供實施方式20-24中任一項的方法,其中所述至少一種化合物及/或組成物與所述至少一種其它劑共同配製。
實施方式26提供在感染B型肝炎病毒的受試者中直接或間接抑制病毒衣殼蛋白的表現及/或功能的方法,方法包括向需要其的受試者投予治療有效量的實施方式1-13中任一項的至少一種化合物及/或實施方式14-16中任一項的至少一種藥物組成物。
實施方式27提供實施方式26的方法,其中受試者進一步感染有D型肝炎病毒(HDV)。
實施方式28提供實施方式26-27中任一項的方法,其中所述至少一種化合物及/或組成物在醫藥上可接受之組成物中投予至受試者。
實施方式29提供實施方式26-28中任一項的方法,其中受試者進一步被投予用於治療、改善、及/或預防B型肝炎病毒感染的至少一種其它劑。
實施方式30提供實施方式29的方法,其中所述至少一
種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
實施方式31提供實施方式30的方法,其中免疫刺激劑是檢查點抑制劑。
實施方式32提供實施方式31的方法,其中檢查點抑制劑是PD-L1抑制劑。
實施方式33提供實施方式29-32中任一項的方法,其中受試者被共同投予所述至少一種化合物及/或組成物和所述至少一種其它劑。
實施方式34提供實施方式29-33中任一項的方法,其中所述至少一種化合物及/或組成物與所述至少一種其它劑共同配製。
實施方式35提供實施方式17-34中任一項的方法,其中受試者是哺乳動物。
實施方式36提供實施方式35的方法,其中哺乳動物是人。
本文引用的每篇專利、專利申請和出版物的公開內容通過引用以其整體併入本文。儘管已經參考具體實施方式公開了本發明,但是顯而易見的是,本領域的其他技術人員可以設計出本發明的其它實施方式和變型而不背離本發明的真實精神和範圍。所附申請專利範圍旨在被解釋為包括所有這樣的實施方式和等同變型。
Claims (36)
- 一種式(I)化合物,或其鹽、溶劑化物、前藥、立體異構物、互變異構物、或同位素標記的衍生物,或其任意混合物:其中:X、Y以及X與Y之間的鍵是這樣的:X是NR8,Y是C(=O),並且X與Y之間的鍵是單鍵,或X是N,Y是CR11,並且X與Y之間的鍵是雙鍵;環A選自:R1選自R2C(=O)-、R2S(=O)2-和胺醯基;R2選自:以下中的一個適用:(i)X1是N,X2是C(R4f),並且X3是C(R4g);(ii)X2是N,X1是C(R4f),並且X3是C(R4g);(iii)X3是N,X1是C(R4f),並且X2是C(R4g);(v)X1是C(R4f),X2是C(R4g),並且X3是C(R4h);以下中的一個適用:(i)X4是N並且X5是C(R4e);或(ii)X5是N並且X4是C(R4e);X6a的每次出現獨立地是N或C(R4f);X6b的每次出現獨立地是N或C(R4g);X6c的每次出現獨立地是N或C(R4h);X7的每次出現獨立地是S、O、或NR3a;R3a的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;R3b的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;R4a、R4b、R4c、R4d、R4e、R4f、R4g、R4h、R4i、R4j和R4k的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;R5的每次出現獨立地選自H、C1-C6烷基、和C3-C8環烷基,其中所述烷基或環烷基用選自以下的至少一個可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵素、氰基、-OH、C1-C6烷氧基、C3-C8環烷氧基、C1-C6鹵代烷氧基、C3-C8鹵代環烷氧基、可選擇經取代之苯基、可選擇經 取代之雜芳基、可選擇經取代之雜環基、-C(=O)OR10、-OC(=O)R10、-SR10、-S(=O)R10、-S(=O)2R10、-S(=O)2NR10R10、-N(R10)S(=O)2R10、-N(R10)C(=O)R10、-C(=O)NR10R10、和-NR10R10;R6的每次出現獨立地選自H和可選擇經取代之C1-C6烷基;R7是-(CH2)p-Q-(CH2)q-,其中p和q獨立地是0、1、或2,並且Q是鍵(不存在)、-O-、-S-、-S(O)-、-S(O)2-、-NR12、-CH(OH)-、-C(=O)-、-C(=O)O-、或-OC(=O)-,其中R7中的每一個CH2用選自甲基、OR13、或鹵素的至少一個取代基可選擇地取代;R8的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和可選擇經取代之C3-C8環烷基;R9a、R9b、R9c、R9d、R9e、R9f、R9g、和R9h的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷氧基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可 選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;R10的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、和可選擇經取代之雜芳基;R11的每次出現獨立地選自H、鹵素、-CN、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之C1-C6烷氧基、可選擇經取代之C3-C8環烷氧基、可選擇經取代之苯基、可選擇經取代之雜環基、可選擇經取代之雜芳基、-S(可選擇經取代之C1-C6烷基)、-SO(可選擇經取代之C1-C6烷基)、-SO2(可選擇經取代之C1-C6烷基)、-C(=O)OH、-C(=O)O(可選擇經取代之C1-C6烷基)、-C(=O)O(可選擇經取代之C3-C8環烷基)、-O(可選擇經取代之C1-C6烷基)、-O(可選擇經取代之C3-C8環烷基)、-NH2、-NH(可選擇經取代之C1-C6烷基)、-NH(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、-N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基)、-C(=O)NH2、-C(=O)NH(可選擇經取代之C1-C6烷基)、-C(=O)NH(可選擇經取代之C3-C8環烷基)、-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C1-C6烷基)、-C(=O)N(可選擇經取代之C3-C8環烷基)(可選擇經取代之C3-C8環烷基)、和-C(=O)N(可選擇經取代之C1-C6烷基)(可選擇經取代之C3-C8環烷基;R12的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、可選擇經取代之C1-C6羥基烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之苯基、可選擇經取代之雜芳基、和可選擇經取代之C1-C6醯基;R13的每次出現獨立地選自H、可選擇經取代之C1-C6烷基、和-C(=O)C1-C6烷基。
- 根據請求項1所述的化合物,其中芳基或雜芳基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、苯基、C1-C6羥基烷基、(C1-C6烷氧基)-C1-C6烷基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、鹵素、-CN、-ORb、-N(Rb)(Rb)、-NO2、-C(=O)N(Rb)(Rb)、-C(=O)ORb、-OC(=O)Rb、-SRb、-S(=O)Rb、-S(=O)2Rb、N(Rb)S(=O)2Rb、-S(=O)2N(Rb)(Rb)、醯基、和C1-C6烷氧基羰基,其中Rb的每次出現獨立地是H、C1-C6烷基、或C3-C8環烷基,其中在Rb中,所述烷基或環烷基用選自以下的至少一個可選擇地取代:鹵素、-OH、C1-C6烷氧基、和雜芳基;或兩個相鄰碳原子上的取代基結合形成-O(CH2)1-3O-。
- 根據請求項1至2中任一項所述的化合物,其中烷基、烯基、炔基、或環烷基的每次出現獨立地用選自以下的至少一個取代基可選擇地取代:C1-C6烷基、C3-C8環烷基、鹵基、氰基(-CN)、-ORa、可選擇經取代之苯基、可選擇經取代之雜芳基、可選擇經取代之雜環基、-C(=O)ORa、-OC(=O)Ra、-SRa、-S(=O)Ra、-S(=O)2Ra、-S(=O)2NRaRa、-N(Ra)S(=O)2Ra、-N(Ra)C(=O)Ra、-C(=O)NRaRa、和-N(Ra)(Ra),其中Ra的每次出現獨立地是H、可選擇經取代之C1-C6烷基、可選擇經取代之C3-C8環烷基、可選擇經取代之芳基、或可選擇經取代之雜芳基,或兩個Ra基團與它們所鍵結的N結合形成雜環。
- 根據請求項1至4中任一項所述的化合物,其中R3a和R3b中每一個獨立地是H或甲基。
- 根據請求項1至5中任一項所述的化合物,其中R5選自H、甲基、乙基、異丙基、正丙基、環丙基、正丁基、異丁基、仲丁 基、第三丁基、環丁基、異丙基甲基、-(CH2)2-6OH、-(CH2)2-6O(C1-C6烷基)、13CD3、可選擇經取代之苄基和可選擇經取代之苯基。
- 根據請求項1至6中任一項所述的化合物,其中R6選自H、D和CH3。
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根據請求項1至11中任一項所述的化合物,其是選自以下所組成群組中的至少一者:N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基二氫吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,3,3-三甲基二氫吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-3-苯丙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯丙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2-苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;2-胺基-2-(4-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;2-胺基-2-(3-氯苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;5,6-二氟-N-甲基-N-(4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;和2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;或其鹽、溶劑化物、前藥、同位素標記的衍生物、立體異構物、或互變異構物,或其任意混合物。
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根據請求項1至12中任一項所述的化合物,其是選自以下所組成群組中的至少一者:(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;(2S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N-甲基二氫吲哚-2-甲醯胺;(2R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N-甲基二氫吲哚-2-甲醯胺;(N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-5-氟-N-甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-4,6-二氟-N-甲基二氫吲哚-(2S)-甲醯胺;(S)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(R)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(S)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基二氫吲哚-2-甲醯胺;(R)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-7-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-7-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,5-二氟-N-甲基-4,5,6,7-四氫-1H-吲哚-2-甲醯胺;(R)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5,6-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-2-甲醯胺;(R)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;(S)-6-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-乙基咪唑并[1,2-a]吡啶-2-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1R)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2R)-甲醯胺;N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-(1S)-基)-N,3,3-三甲基二氫吲哚-(2S)-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基吡唑并[1,5-a]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-7-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,2,4]三唑并[4,3-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基喹啉-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4,5-三氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基菸鹼醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-氟-N-甲基異菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N-甲基苯甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-3-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-3-苯丙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,4-二氟-N-甲基苯甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯丙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯丙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基-2-苯乙醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基-2-苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,5,6-三氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-4-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-N-甲基苯甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(三氟甲基)-1H-吡唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯基)-N-甲基-1H-吡唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基苯甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(S)-3-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;(S)-3-氟-N-甲基-N-(6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(三氟甲基)苯甲醯胺;(R)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;(S)-3-氟-N-甲基-N-(4-側氧-4,5,8,9-四氫-6H-哌喃并[3,4-b]噻吩并[3,4-d]吡啶-9-基)-4-(三氟甲基)苯甲醯胺;(R)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8-氰基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-4-(三氟甲氧基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N,4-二甲基苯甲醯胺;2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2R)-羥基-N-甲基乙醯胺;2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(2S)-羥基-N-甲基乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基-4-(三氟甲基)苯甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2R)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3R)-羥基-N-甲基丁醯胺;(2S)-胺基-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-(3S)-羥基-N-甲基丁醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯磺醯胺;(R)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(S)-3-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基苯磺醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲氧基)-3-氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(2-羥基丙-2-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4,6-二氟-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-4-(三氟甲基)苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟苯甲醯胺;(S)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-溴-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-氯-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-4-(二氟甲基)-3,5-二氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-3,5-二氟-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-苯基丙烯醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-3-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基噻吩-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;(R)-1-(第三丁基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(三氟甲基)-1H-吡唑-4-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯-2-甲醯胺;(S)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(4-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(4-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(S)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(R)-2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(3-氯苯基)-N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;2-胺基-2-(3-氯苯基)-N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基乙醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-羥基-N-甲基環己烷-1-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-1,6-二氫吡啶-2-甲醯胺;(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2-(三氟甲基)-1H-咪唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-側氧-1,6-二氫吡啶-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,2-二苯乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(4-氟苯基)-N-甲基-1H-吡唑-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(3-氟苯氧基)-N-甲基苯甲醯胺;(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-5-甲基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-甲氧基-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3-二氟-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,5-二氟-N-甲基苯甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,6-二氟-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-側氧-5-(三氟甲基)-1,6-二氫吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(4-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(R)-2-(3-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(S)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(R)-2-(4-溴苯基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,4'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-2-羥基-N-甲基-2,3-二氫-1H-茚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-氟-N-甲基二環[4.2.0]八-1(6),2,4-三烯-7-甲醯胺;(S)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(6-(2-胺基乙氧基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1-(噻吩-3-基)氮雜丁烷-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(R)-1-(4-溴噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2'-氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5'-二氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,3',5'-三氟-N-甲基-[1,1'-聯苯基]-4-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3'-氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3',5-二氟-N-甲基-[1,1'-聯苯基]-3-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-苯氧基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(4-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6H-噻吩并[2,3-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(甲磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(N-甲基胺磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲基亞磺醯胺基)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-3-(甲磺醯)苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,5-a]吡啶-6-甲醯胺;(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基異丁酸酯;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-氟-N-甲基-5-苯氧基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基咪唑并[1,2-a]吡啶-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(S)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-6-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-4-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基異菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-5-(2-羥乙基)-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(5-(2-胺乙基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-(2-羥基乙氧基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4R)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R,4S)-8,9-二氟-4-甲氧基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(3-氟苯氧基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,5-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-乙基-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(1S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1S,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1S,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R,4S)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(1R,4R)-1-(5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺基)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-4-基2-丁酸乙酯;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-呋喃并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-(甲胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-((2-羥乙基)胺基)-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-4-乙基-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-5-(甲磺醯)-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(6-((2-胺乙基)胺基)-8,9-二氟-1,4-二氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((R)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((R)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;N-((S)-8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-((S)-1-羥乙基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-4-(羥甲基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;(R)-7-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基呋喃并[3,2-c]吡啶-2-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-6-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-N-甲基-2H-吲唑-5-甲醯胺;(S)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(R)-3,4-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-氟-N-甲基-4-(甲基亞磺醯胺基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4-(三氟甲氧基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-甲氧基-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-溴-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2-(二氟甲基)-3-甲氧基-N-甲基-2H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-甲氧基-N-甲基-1H-吲唑-5-甲醯胺;(S)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(R)-1-(5-氯噻吩-3-基)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基氮雜丁烷-3-甲醯胺;(S)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-7-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-4-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(S)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;(R)-二-第三丁基((2-((8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)(甲基)胺基甲醯基)-5,6-二氟-1H-吲哚-1-基)甲基)磷酸酯;(S)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氰基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(R)-4-溴-5-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[2,3-c]吡啶-2-甲醯胺;(S)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-乙基-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氰基-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(S)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;(R)-4,6-二氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吡咯并[3,2-c]吡啶-2-甲醯胺;5,6-二氟-N-甲基-N-((1S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1S,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1S,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R,4S)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;5,6-二氟-N-甲基-N-((1R,4R)-4,8,9-三氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-5-氟-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(R)-5-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-6-(三氟甲基)菸鹼醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(S)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;(R)-3-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-乙基-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N,3-二甲基-1H-吲唑-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-3-(二氟甲基)-N,1-二甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-1-(二氟甲基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-4-氯-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-2,3-二氫-1H-茚-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-5-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基苯并[d]噻唑-6-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-5-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-苯并[d]咪唑-6-甲醯胺;(R)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-2-氯-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氰基-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(S)-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-1H-吲唑-6-甲醯胺;(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氯-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-4,6-二側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-6-(二氟甲基)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-4-(二氟甲基)-6-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-6-氟-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(R)-1-((4-溴-3-氟苄基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;2-氯-N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(S,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;2-氯-N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R,R)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R,S)-2-氯-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-6-(二氟甲基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-5,6-二氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(S)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N,4-二甲基-1H-吲哚-2-甲醯胺;(R)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-4-(二氟甲基)-6-氟-N-(8-氟-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(R)-1-(((5,6-二氟-1H-吲哚-2-基)甲基)(甲基)胺基)-8,9-二氟-1,5-二氫-2H-哌喃并[3,4-c]異喹啉-6(4H)-酮;(S)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;(R)-2-氟-N-(8-氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-N-甲基-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5-氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-5,6-二氟-N-甲基-1H-吲哚-2-甲醯胺;N-((1R)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;N-((1S)-8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R,R)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(R,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S,S)-N-(8,9-二氟-4-羥基-6-側氧-1,2,3,4,5,6-六氫啡啶-1-基)-N-甲基-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基)-2,2-二氟-N-甲基-2-苯乙醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-5,6-二氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(S)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(R)-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-6-(二氟甲基)-5-氟-N-(甲基-13C-d3)-1H-吲哚-2-甲醯胺;(S)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;和(R)-2-氯-N-(8,9-二氟-6-側氧-1,4,5,6-四氫-2H-哌喃并[3,4-c]異喹啉-1-基-1-d)-N-(甲基-13C-d3)-4H-噻吩并[3,2-b]吡咯-5-甲醯胺;或其鹽、溶劑化物、前藥、同位素標記的衍生物、立體異構物或互變異構物,或其任意混合物。
- 一種藥物組成物,其包含請求項1至13中任一項所述的至少一種化合物和醫藥上可接受之載劑。
- 根據請求項14所述的藥物組成物,其進一步包含用於治療、改善及/或預防B型肝炎病毒感染的至少一種其它劑。
- 根據請求項15所述的藥物組成物,其中該至少一種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
- 一種治療、改善及/或預防受試者中的B型肝炎病毒(HBV)感染的方法,該方法包括向需要其的受試者投予治療有效量的請求項1至13中任一項所述的至少一種化合物及/或請求項14至16中任一項所述的至少一種藥物組成物。
- 根據請求項17所述的方法,其中該受試者進一步感染有D型肝炎病毒(HDV)。
- 根據請求項17至18中任一項所述的方法,其中該至少一種化合物及/或組成物在醫藥上可接受之組成物中投予至該受試者。
- 根據請求項17至19中任一項所述的方法,其中該受試者進一步被投予用於治療、改善、及/或預防B型肝炎病毒感染的至少一種其它劑。
- 根據請求項20所述的方法,其中該至少一種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
- 根據請求項21所述的方法,其中該免疫刺激劑是檢查點抑制劑。
- 根據請求項22所述的方法,其中該檢查點抑制劑是PD-L1抑制劑。
- 根據請求項20至23中任一項所述的方法,其中該受試者被共同投予該至少一種化合物及/或組成物和該至少一種其它劑。
- 根據請求項20至24中任一項所述的方法,其中該至少一種化合物及/或組成物與該至少一種其它劑共同配製。
- 一種在感染B型肝炎病毒的受試者中直接或間接抑制病毒衣殼蛋白的表現及/或功能的方法,該方法包括向需要其的受試者投予治療有效量的請求項1至13中任一項所述的至少一種化合物及/或請求項14至16中任一項所述的至少一種藥物組成物。
- 根據請求項26所述的方法,其中該受試者進一步感染有D型肝炎病毒(HDV)。
- 根據請求項26至27中任一項所述的方法,其中該至少一種化合物及/或組成物在醫藥上可接受之組成物中投予至該受試者。
- 根據請求項26至28中任一項所述的方法,其中該受試者進一步被投予用於治療、改善、及/或預防B型肝炎病毒感染的至少一種其它劑。
- 根據請求項29所述的方法,其中該至少一種其它劑包括選自以下中的至少一種:逆轉錄酶抑制劑;衣殼抑制劑;cccDNA形成抑制劑;RNA去穩定劑;靶向HBV基因組的寡聚核苷酸;免疫刺激劑;靶向HBV基因轉錄物的GalNAc-siRNA綴合物;和治療疫苗。
- 根據請求項30所述的方法,其中該免疫刺激劑是檢查點抑制劑。
- 根據請求項31所述的方法,其中該檢查點抑制劑是PD-L1抑制劑。
- 根據請求項29至32中任一項所述的方法,其中該受試者被共同投予該至少一種化合物及/或組成物和該至少一種其它劑。
- 根據請求項29至33中任一項所述的方法,其中該至少一種化合物及/或組成物與該至少一種其它劑共同配製。
- 根據請求項17至34中任一項所述的方法,其中該受試者是哺乳動物。
- 根據請求項35所述的方法,其中該哺乳動物是人。
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